Seasonal variation characteristic of inhalable microbial communities in PM2.5 in Beijing city, China.
Bacteria and fungi are primary constituents of airborne microbes in fine particulate matter (PM2.5) and significantly impact human health. However, hitherto, seasonal variation and effect of air pollution on microbial community composition and structure are poorly understood. This study analyzed the bacterial and fungal composition of PM2.5 under different air pollution levels during different seasons in Beijing. We altogether collected 75PM2.5 samples during four seasons from April 2014 to January 2015, under different air pollution levels and employed high-throughput sequencing methods to analyze microbial composition. The results showed that air pollution decreased species richness and community diversity of bacteria in PM2.5. The variation in bacterial and fungal community composition and structure was significantly related to the season but there was no correlation between their abundance and pollution levels. Pathogenic bacteria and fungi were more abundant in winter than other seasons. To best of our knowledge, this is the first study that demonstrates seasonal variation characteristics of bacteria and fungi in PM2.5 in heavy haze contaminated areas and highlights the effects of air pollution on the atmospheric microbial community. This study would be useful to other bioaerosol studies focusing on the role of the atmospheric particulate matter on human health.


Spending money on others promotes happiness.
Although much research has examined the effect of income on happiness, we suggest that how people spend their money may be at least as important as how much money they earn. Specifically, we hypothesized that spending money on other people may have a more positive impact on happiness than spending money on oneself. Providing converging evidence for this hypothesis, we found that spending more of one's income on others predicted greater happiness both cross-sectionally (in a nationally representative survey study) and longitudinally (in a field study of windfall spending). Finally, participants who were randomly assigned to spend money on others experienced greater happiness than those assigned to spend money on themselves.


Novel elastic response in twist-bend nematic models.
Bent-shaped liquid crystals have attracted significant attention recently due to their novel mesostructure and the intriguing behavior of their elastic constants, which are strongly anisotropic and have an unusual temperature dependence. Though theories explain the onset of the twist-bend nematic phase (NTB) through spontaneous symmetry breaking concomitant with transition to a negative bend (K3) elastic constant, this has not been observed as yet in experiments. There, the small bend elastic constant has a strongly non-monotonic temperature dependence, which first increases after crossing the isotropic (I)-nematic (N) transition, then dips near the nematic (N)-twist-bend (NTB) transition before it increases again as the transition is crossed. The molecular mechanisms responsible for this exotic behavior are unclear. Here, we utilize density of states algorithms in Monte Carlo simulation applied to a variant of the Lebwohl-Lasher model which includes bent-shaped-like interactions to analyze the mechanism behind elastic response in this novel mesostructure and understand the temperature dependence of its Frank-Oseen elastic constants.


Human bocavirus: clinical significance and implications.
Human bocavirus (HBoV), a parvovirus, was discovered in 2005 with the use of nonspecific genome amplification techniques. Since its discovery, HBoV has been identified worldwide. This review will focus on the epidemiology and clinical features associated with HBoV infection. Initial studies demonstrated the presence of HBoV DNA in respiratory specimens of individuals with respiratory tract disease. Data from some studies suggest that HBoV may be the etiological agent responsible for respiratory tract disease, particularly in young children. HBoV, however, is frequently detected in the presence of other common respiratory viruses. HBoV is not confined to the respiratory tract as evidence of the virus has been detected in serum and stool, the significance of which remains unclear. Presence of the virus in respiratory secretions, serum and stool suggests that this virus may cause systemic illness. HBoV is an emerging human parvovirus. The full spectrum of disease associated with HBoV remains to be defined.


Induction of heme oxygenase-1 and heat shock protein 70 in rat hepatocytes: the role of calcium signaling.
Stress response genes including heat shock proteins are induced under a variety of conditions to confer cellular protection. This study investigated the role of calcium signaling in the induction of two stress response genes, heme oxygenase-1/hsp32 and hsp70, in isolated rat hepatocytes. Both genes were induced by cellular glutathione depletion. This induction could be inhibited by BAPTA-AM. Culturing in a calcium-free medium prevented the induction of hsp70 gene expression after glutathione depletion without affecting heme oxygenase-1 gene expression. Thapsigargin increased the gene expression of heme oxygenase-1 but not that of hsp70. Thapsigargin-induced heme oxygenase-1 induction was completely inhibited by BAPTA-AM. Incubation with the Ca(2+)-ionophore A23187 augmented heme oxygenase-1 (two-fold) and hsp70 (5.2-fold) mRNA levels. Our data suggests a significant role of Ca(2+)-dependent pathways in the induction of the two stress genes. An increase in the cytoplasmic Ca(2+) activity seems to play a key role in the cascade of signaling leading to the induction of the two genes. However, the source of Ca(2+) that fluxes into the cytoplasm seems to be different. Our data provides evidence for a compartmentalization of calcium fluxes, i.e. the Ca(2+) flux from intracellular stores (e.g. the endoplasmic reticulum) plays a major role in the induction of heme oxygenase-1. By contrast, Ca(2+) flux from the extracellular medium seems to be a mechanism initiating the cellular signaling cascade leading to hsp70 gene induction.


Synergy between Lactobacillus paracasei and its bacterial products to counteract stress-induced gut permeability and sensitivity increase in rats.
Stressful events result in the alteration of gut permeability and sensitivity. Lactobacillus paracasei NCC2461 (Lpa) therapy prevents antibiotic-induced visceral hyperalgesia in mice. This study aimed at evaluating the influence of 3 probiotic strains: Bifidobacterium lactis NCC362, Lactobacillus johnsonii NCC533, and Lpa on stress-mediated alterations of colorectal hyperalgesia, on gut paracellular permeability and whether bacteria and/or bacterial products present in the spent culture medium (SCM) were involved in the antinociceptive properties of the effective strain. Rat pups were separated from their mothers 3 h/d during postnatal d 2-14. At wk 13, gut paracellular permeability was determined as a percentage of urinary excreted (51)Cr-EDTA and visceral sensitivity to colorectal distension (CRD), assessed by abdominal muscle electromyography. Visceral sensitivity was also analyzed in adults rats subjected to partial restraint stress (PRS, 2 h restriction of body movements). Rats received either the probiotics resuspended in SCM or fresh growth medium as control for 2 wk. Maternal deprivation significantly increased colonic sensitivity in response to CRD and enhanced gut paracellular permeability compared with control rats. Only Lpa treatment significantly improved stress-induced visceral pain and restored normal gut permeability. Similarly, among the 3 probiotics tested, only Lpa prevented PRS-mediated visceral hyperalgesia. Both bacteria and bacterial products present in Lpa SCM were required for the antinociceptive properties against PRS. This study illustrates strain-specific effects and suggests a synergistic interplay between L. paracasei bacteria and bacterial products generated during fermentation and growth that confers the ability to suppress PRS-induced hypersensitivity in rats.


Spermatogonial deubiquitinase USP9X is essential for proper spermatogenesis in mice.
USP9X (ubiquitin-specific peptidase 9, X chromosome) is the mammalian orthologue of Drosophila deubiquitinase fat facets that was previously shown to regulate the maintenance of the germ cell lineage partially through stabilizing Vasa, one of the widely conserved factors crucial for gametogenesis. Here, we demonstrate that USP9X is expressed in the gonocytes and spermatogonia in mouse testes from newborn to adult stages. By using Vasa-Cre mice, germ cell-specific conditional deletion of Usp9x from the embryonic stage showed no abnormality in the developing testes by 1 week and no appreciable defects in the undifferentiated and differentiating spermatogonia at postnatal and adult stages. Interestingly, after 2 weeks, Usp9x-null spermatogenic cells underwent apoptotic cell death at the early spermatocyte stage, and then, caused subsequent aberrant spermiogenesis, which resulted in a complete infertility of Usp9x conditional knockout male mice. These data provide the first evidence of the crucial role of the spermatogonial USP9X during transition from the mitotic to meiotic phases and/or maintenance of early meiotic phase in Usp9x conditional knockout testes.


Reciprocal human dendritic cell-natural killer cell interactions induce antitumor activity following tumor cell infection by oncolytic reovirus.
Oncolytic virotherapy may mediate antitumor effects via direct oncolysis or immune-mediated tumor regression. Although the ability of oncolytic viruses to generate adaptive antitumor immunity has been characterized, their interactions with the innate immune system are relatively unclear. Using a human in vitro system, this study investigates the innate immunological consequences of reovirus therapy and its potential to activate NK cell-mediated antitumor activity. Dendritic cells (DC) loaded with reovirus-infected human melanoma Mel888 cells (DC-MelReo), but not reovirus-infected tumor cells alone, induced IFN-gamma production within the NK cell population upon coculture with PBMC, in a cell-to-cell contact-dependent manner. DC-MelReo secreted the chemokines CCL2, 3, 4, 5, 7, 8, 11, and CXCL10; these culture supernatants induced NK cell chemotaxis. Coculture of DC-MelReo with purified NK cells induced reciprocal contact-dependent phenotypic DC maturation, while DC-MelReo elicited up-regulation of the activation marker CD69 on NK cells, in a partially contact and partially IL-12 dependent manner. Significantly, DC-MelReo induced NK cell cytotoxicity toward tumor cells by a type I IFN dependent mechanism. These data demonstrate that tumor infection by reovirus can act via DC to induce NK cell recruitment, activation, and cytotoxicity, along with reciprocal DC maturation. These findings suggest that reciprocal DC-NK cell interactions, following reovirus therapy, may play an important role in altering the immune milieu of the tumor microenvironment and mediating tumor regression.


Regulation of the MPG1 hydrophobin gene in the rice blast fungus Magnaporthe grisea.
The hydrophobin-encoding gene MPG1 of the rice blast fungus Magnaporthe grisea is highly expressed during the initial stages of host plant infection and targeted deletion of the gene results in a mutant strain that is reduced in virulence, conidiation, and appressorium formation. The green fluorescent protein-encoding allele sGFP was used as a reporter to investigate regulatory genes that control MPG1 expression. The MAP kinase-encoding gene PMK1 and the wide domain regulators of nitrogen source utilization, NPR1 and NUT1, were required for full expression of MPG1 in response to starvation stress. The CPKA gene, encoding the catalytic subunit of protein kinase A, was required for repression of MPG1 during growth in rich nutrient conditions. During appressorium morphogenesis, high-level MPG1 expression was found to require the CPKA and NPR1 genes. Expression of a destabilized GFP allele indicated that de novo MPG1 expression occurs during appressorium formation. Three regions of the MPG1 promoter were identified which are required for high-level expression of MPG1 during appressorium formation and are necessary for the biological activity of the MPG1 hydrophobin during spore formation and plant infection.


Assessment of valvular heart disease by cardiovascular magnetic resonance imaging: a review.
CMR is a comprehensive non-invasive tool capable of evaluating all aspects of valvular heart disease. It has advantages over echo including direct quantification of regurgitant lesions, highly accurate assessment of ventricular size and function, visualisation myocardial scar, and interrogation of extracardiac abnormalities. Although these gains can be realised with current scanning techniques, CMR's full potential has yet to be realised, and further studies of clinical outcomes are needed before CMR data can be integrated into the management algorithms for patients with significant valvular lesions.


Interactions between rail and road safety in Great Britain.
This paper discusses the results of an investigation into ways in which the safety risks of travel on road and rail interact with each other in Great Britain, other than through physical contact such as at level crossings. The two main foci of the paper are: (1) an analysis of the 'whole journey' risks of journeys for which the national rail system is the main mode, but which also include stages by other transport modes to provide access to the railway system; and (2) an analysis of the effect on safety risk of inter-modal transfers between rail and road. On (1), walking to and from stations was estimated to account on average for 65% of the overall door-to-door risk of being killed on rail journeys; the rail system itself accounts for 21% of the risk, and other access modes account for the remaining 14%. The average distance walked to and from stations is 0.9 km per rail journey, and this walking accounts for 5% of all walking nationally. On (2), it was found that increasing rail fares to fund railway safety measures may lead passengers to switch from rail to car, but for most sensible rail safety measures, the additional risks from such diversions are small compared with the intended rail safety benefits. However, for high-cost rail safety measures funded by passengers, the additional risks from diversions may be of the same order as the intended safety benefits. The last section of the paper explores the effects of variations in the casualty rates of rail users as pedestrians and car users, because their road risks may be different from those of all road users. Such variations could alter the detailed conclusions of the paper, but the scale of such effects appears to be modest.


A Clinical Roadmap to Investigate the Genetic Basis of Pediatric Pheochromocytoma: Which Genes Should Physicians Think About?
Pheochromocytoma is very rare at a pediatric age, and when it is present, the probability of a causative genetic mutation is high. Due to high costs of genetic surveys and an increasing number of genes associated with pheochromocytoma, a sequential genetic analysis driven by clinical and biochemical phenotypes is advised. The published literature regarding the genetic landscape of pediatric pheochromocytoma is scarce, which may hinder the establishment of genotype-phenotype correlations and the selection of appropriate genetic testing at this population. In the present review, we focus on the clinical phenotypes of pediatric patients with pheochromocytoma in an attempt to contribute to an optimized genetic testing in this clinical context. We describe epidemiological data on the prevalence of pheochromocytoma susceptibility genes, including new genes that are expanding the genetic etiology of this neuroendocrine tumor in pediatric patients. The clinical phenotypes associated with a higher pretest probability for hereditary pheochromocytoma are presented, focusing on differences between pediatric and adult patients. We also describe new syndromes, as well as rates of malignancy and multifocal disease associated with these syndromes and pheochromocytoma susceptibility genes published more recently. Finally, we discuss new tools for genetic screening of patients with pheochromocytoma, with an emphasis on its applicability in a pediatric population.


HIV and Cocaine Impact Glial Metabolism: Energy Sensor AMP-activated protein kinase Role in Mitochondrial Biogenesis and Epigenetic Remodeling.
HIV infection and cocaine use have been identified as risk factors for triggering neuronal dysfunction. In the central nervous system (CNS), energy resource and metabolic function are regulated by astroglia. Glia is the major reservoir of HIV infection and disease progression in CNS. However, the role of cocaine in accelerating HIV associated energy deficit and its impact on neuronal dysfunction has not been elucidated yet. The aim of this study is to elucidate the molecular mechanism of HIV associated neuropathogenesis in cocaine abuse and how it accelerates the energy sensor AMPKs and its subsequent effect on mitochondrial oxidative phosphorylation (OXPHOS), BRSKs, CDC25B/C, MAP/Tau, Wee1 and epigenetics remodeling complex SWI/SNF. Results showed that cocaine exposure during HIV infection significantly increased the level of p24, reactive oxygen species (ROS), ATP-utilization and upregulated energy sensor AMPKs, CDC25B/C, MAP/Tau and Wee1 protein expression. Increased ROS production subsequently inhibits OCR/ECAR ratio and OXPHOS, and eventually upregulate epigenetics remodeling complex SWI/SNF in CHME-5 cells. These results suggest that HIV infection induced energy deficit and metabolic dysfunction is accelerated by cocaine inducing energy sensor AMPKs, mitochondrial biogenesis and chromatin remodeling complex SWI/SNF activation, which may lead to neuroAIDS disease progression.


A large scale multivariate parallel ICA method reveals novel imaging-genetic relationships for Alzheimer's disease in the ADNI cohort.
The underlying genetic etiology of late onset Alzheimer's disease (LOAD) remains largely unknown, likely due to its polygenic architecture and a lack of sophisticated analytic methods to evaluate complex genotype-phenotype models. The aim of the current study was to overcome these limitations in a bi-multivariate fashion by linking intermediate magnetic resonance imaging (MRI) phenotypes with a genome-wide sample of common single nucleotide polymorphism (SNP) variants. We compared associations between 94 different brain regions of interest derived from structural MRI scans and 533,872 genome-wide SNPs using a novel multivariate statistical procedure, parallel-independent component analysis, in a large, national multi-center subject cohort. The study included 209 elderly healthy controls, 367 subjects with amnestic mild cognitive impairment and 181 with mild, early-stage LOAD, all of them Caucasian adults, from the Alzheimer's Disease Neuroimaging Initiative cohort. Imaging was performed on comparable 1.5 T scanners at over 50 sites in the USA/Canada. Four primary "genetic components" were associated significantly with a single structural network including all regions involved neuropathologically in LOAD. Pathway analysis suggested that each component included several genes already known to contribute to LOAD risk (e.g. APOE4) or involved in pathologic processes contributing to the disorder, including inflammation, diabetes, obesity and cardiovascular disease. In addition significant novel genes identified included ZNF673, VPS13, SLC9A7, ATP5G2 and SHROOM2. Unlike conventional analyses, this multivariate approach identified distinct groups of genes that are plausibly linked in physiologic pathways, perhaps epistatically. Further, the study exemplifies the value of this novel approach to explore large-scale data sets involving high-dimensional gene and endophenotype data.


Utility of bone marrow examination for workup of fever of unknown origin in patients with HIV/AIDS.
The utility of bone marrow aspiration and biopsy (BMAB) as a diagnostic tool in patients with HIV/AIDS and fever of unknown origin (FUO) is a subject of debate. Because highly active antiretroviral therapy has reduced incidence of opportunistic infections, it is important to reassess the efficacy of BMAB for this diagnostic purpose. To our knowledge, no such studies have been performed in Harris County which has the highest incidence of HIV in the state of Texas. We reviewed all BMABs from patients with HIV/AIDS and FUO or persistent cytopenia(s) from 2007 to 2011. Of 57 evaluable patients, BMAB was positive in 24 samples by acid fast bacilli (AFB) or Gomori methenamine silver (GMS) stains (17.5%), presence of granuloma and/or lymphohistiocytic aggregates (31.6%), culture (21.0%) or a combination. Cultures demonstrated Mycobacterium avium/intracellulare (4), M tuberculosis (2), M gordonae (1), Histoplasma capsulatum (3) and Cryptococcus neoformans (2). There were three cases in which a pathogen was grown in culture but that had a negative of 'direct examination' on tissue sections (negative AFB and GMS special stains, no morphological evidence of granuloma/lymphohistiocytic infiltrates). This study supports the use of diagnostic BMAB as a rapid decision-making tool in patients with HIV and FUO in the proper clinical setting. BMAB demonstrated infection-related evidence prior to positive bone marrow culture in 75% of cases. Special stains and blood cultures had similar diagnostic yield, but BMAB offers faster results. Thus, this procedure assists in clinical decision making and the refinement of treatment in a more timely manner.


Klotho gene polymorphism, brain structure and cognition in early-life development.
Variation in the klotho gene is linked to differences in health outcomes: klotho allele KL-VS heterozygosity is associated with longevity, better cognition and greater right frontal grey matter volume in late life. Contradicting reports, however, suggest that KL-VS's effect on health might be age-dependent. Here we examine the relationship between KL-VS genotype, cognition and brain structure in childhood and adolescence. We hypothesized that KL-VS has early influences on cognitive and brain development. We investigated the associations of KL-VS carrier status with cognition and brain morphology in a cohort of 1387 children and adolescents aged 3-21 years, examining main effects and interactions between age, sex and socioeconomic circumstance. KL-VS had no main effect on either cognition or brain structure, though there was a significant KL-VS × age interaction for cognition (specifically executive function, attention, episodic memory, and general cognition), total grey matter and total brain volume. KL-VS heterozygotes had better cognition than non-carriers before age 11, but lower cognition after age 11. Heterozygotes had smaller brains than non-carriers did in early childhood. Sex moderated the association between KL-VS and white matter volume. Among girls, KL-VS heterozygotes had smaller white matter volumes than non-carriers. Among boys, heterozygotes had greater white matter volumes than non-carriers. However, a replication in a cohort of 2306 children aged 6-12 years showed no significant associations. In contrast to findings in late life, these results show that KL-VS does not have a main effect on cognition and brain structure. Furthermore, KL-VS's influence may depend on age and sex.


Profiling and validation of individual and patterns of Chlamydia trachomatis-specific antibody responses in trachomatous trichiasis.
Ocular Chlamydia trachomatis (Ct) infection causes trachoma, the leading infectious cause of blindness. A Ct D/UW3 proteome microarray and sera from Gambian adults with trachomatous trichiasis (TT) or healthy matched controls previously identified several novel antigens, which suggested differential recognition in adults with TT. We re-analysed this serological microarray data using more robust microarray analysis techniques accounting for typical problems associated with highly dimensional data. We examined the Ct-specific antibody profile concerning the overall diversity of responses, antigen expression stage and cellular localisation of antigens. We tested differentially recognised antigens by further serological testing of the screened sera and used larger independent sample sets for validation. Antibody responses identified High-Performance on antigens expressed early and late in the Ct developmental cycle and those secreted or localised to the outer membrane. Eight antigens were preferentially recognised by scarred individuals and one antigen by healthy individuals. Three of these antigens, two associated with scarring (CT667 and CT706) and one healthy-associated (CT442), were not associated with the presence or absence of scarring following specific serological testing of the arrayed sera and sera from larger, independent case-control cohorts. This study identified focussed Ct-specific antibody profiles targeting proteins expressed during entry and exit from cells and localised to interact with the host. A small panel of antibody responses could discriminate between adults with and without TT in a trachoma-endemic community. Heterogenous responses in the independent validation of these antibody targets highlighted the need for large sample sizes, clearly defined clinical phenotypes and follow-up work.


Quantitative Analysis of Proteome Modulations in Alveolar Epithelial Type II Cells in Response to Pulmonary Aspergillus fumigatus Infection.
The ubiquitous mold Aspergillus fumigatus threatens immunosuppressed patients as inducer of lethal invasive aspergillosis. A. fumigatus conidia are airborne and reach the alveoli, where they encounter alveolar epithelial cells (AEC). Previous studies reported the importance of the surfactant-producing AEC II during A. fumigatus infection via in vitro experiments using cell lines. We established a negative isolation protocol yielding untouched primary murine AEC II with a purity >90%, allowing ex vivo analyses of the cells, which encountered the mold in vivo By label-free proteome analysis of AEC II isolated from mice 24h after A. fumigatus or mock infection we quantified 2256 proteins and found 154 proteins to be significantly differentially abundant between both groups (ANOVA p value ≤ 0.01, ratio of means ≥1.5 or ≤0.67, quantified with ≥2 peptides). Most of these proteins were higher abundant in the infected condition and reflected a comprehensive activation of AEC II on interaction with A. fumigatus This was especially represented by proteins related to oxidative phosphorylation, hence energy production. However, the most strongly induced protein was the l-amino acid oxidase (LAAO) Interleukin 4 induced 1 (IL4I1) with a 42.9 fold higher abundance (ANOVA p value 2.91-10). IL4I1 has previously been found in B cells, macrophages, dendritic cells and rare neurons. Increased IL4I1 abundance in AEC II was confirmed by qPCR, Western blot and immunohistology. Furthermore, A. fumigatus infected lungs showed high levels of IL4I1 metabolic products. Importantly, higher IL4I1 abundance was also confirmed in lung tissue from human aspergilloma. Because LAAO are key enzymes for bactericidal product generation, AEC II might actively participate in pathogen defense. We provide insights into proteome changes of primary AEC II thereby opening new avenues to analyze the molecular changes of this central lung cell on infectious threats. Data are available via ProteomeXchange with identifier PXD005834.


Cellular scaling rules for the brain of afrotherians.
Quantitative analysis of the cellular composition of rodent, primate and eulipotyphlan brains has shown that non-neuronal scaling rules are similar across these mammalian orders that diverged about 95 million years ago, and therefore appear to be conserved in evolution, while neuronal scaling rules appear to be free to vary in evolution in a clade-specific manner. Here we analyze the cellular scaling rules that apply to the brain of afrotherians, believed to be the first clade to radiate from the common eutherian ancestor. We find that afrotherians share non-neuronal scaling rules with rodents, primates and eulipotyphlans, as well as the coordinated scaling of numbers of neurons in the cerebral cortex and cerebellum. Afrotherians share with rodents and eulipotyphlans, but not with primates, the scaling of number of neurons in the cortex and in the cerebellum as a function of the number of neurons in the rest of the brain. Afrotheria also share with rodents and eulipotyphlans the neuronal scaling rules that apply to the cerebral cortex. Afrotherians share with rodents, but not with eulipotyphlans nor primates, the neuronal scaling rules that apply to the cerebellum. Importantly, the scaling of the folding index of the cerebral cortex with the number of neurons in the cerebral cortex is not shared by either afrotherians, rodents, or primates. The sharing of some neuronal scaling rules between afrotherians and rodents, and of some additional features with eulipotyphlans and primates, raise the interesting possibility that these shared characteristics applied to the common eutherian ancestor. In turn, the clade-specific characteristics that relate to the distribution of neurons along the surface of the cerebral cortex and to its degree of gyrification suggest that these characteristics compose an evolutionarily plastic suite of features that may have defined and distinguished mammalian groups in evolution.


G-Protein Coupled Receptor Protein Synthesis on a Lipid Bilayer Using a Reconstituted Cell-Free Protein Synthesis System.
Membrane proteins are important drug targets which play a pivotal role in various cellular activities. However, unlike cytosolic proteins, most of them are difficult-to-express proteins. In this study, to synthesize and produce sufficient quantities of membrane proteins for functional and structural analysis, we used a bottom-up approach in a reconstituted cell-free synthesis system, the PURE system, supplemented with artificial lipid mimetics or micelles. Membrane proteins were synthesized by the cell-free system and integrated into lipid bilayers co-translationally. Membrane proteins such as the G-protein coupled receptors were expressed in the PURE system and a productivity ranging from 0.04 to 0.1 mg per mL of reaction was achieved with a correct secondary structure as predicted by circular dichroism spectrum. In addition, a ligand binding constant of 27.8 nM in lipid nanodisc and 39.4 nM in micelle was obtained by surface plasmon resonance and the membrane protein localization was confirmed by confocal microscopy in giant unilamellar vesicles. We found that our method is a promising approach to study the different classes of membrane proteins in their native-like artificial lipid bilayer environment for functional and structural studies.


Bacteriophage ecology in a commercial cucumber fermentation.
To reduce high-salt waste from cucumber fermentations, low-salt fermentations are under development. These fermentations may require the use of starter cultures to ensure normal fermentations. Because potential phage infection can cause starter culture failure, it is important to understand phage ecology in the fermentations. This study investigated the phage ecology in a commercial cucumber fermentation. Brine samples taken from a fermentation tank over a 90-day period were plated onto deMan-Rogosa-Sharpe agar plates. A total of 576 lactic acid bacterial isolates were randomly selected to serve as potential hosts for phage isolation. Filtered brine served as a phage source. Fifty-seven independent phage isolates were obtained, indicating that 10% of the bacterial isolates were sensitive to phage attack. Phage hosts include Lactobacillus brevis (67% of all hosts), Lactobacillus plantarum (21%), Weissella paramesenteroides, Weissella cibaria, and Pediococcus ethanolidurans. Nearly 50% of phages were isolated on day 14, and the majority of them attacked L. brevis. Some phages had a broad host range and were capable of infecting multiple hosts in two genera. Other phages were species specific or strain specific. About 30% of phage isolates produced turbid pinpoint plaques or only caused reduced cell growth on the bacterial lawns. Six phages with distinct host ranges were characterized. The data from this study showed that abundant and diverse phages were present in the commercial cucumber fermentation, which could cause significant mortality to the lactic acid bacteria population. Therefore, a phage control strategy may be needed in low-salt cucumber fermentations.


Case management: evolution of the concept in the 80's and 90's.
Case Management is a term that is present in almost every American health care situation. It is mostly used to coordinate community services with satisfactory results for the patient within a certain period of time, with limited resources. Through time, it has been used for different purposes. The goal of this study was to show the historical evolution of case management as expressed by the American nursing literature, in the 80's and 90's, according to its use, meaning, and application, and following a theoretical framework for concept analysis. The data was extracted from two journals: "Nursing Management" and "Journal of Nursing Administration". The publications showed case management portrayed as a process that serves a common goal; where quality and cost of care were the prevalent and influential elements along time, and its practice focusing in a given population defined as of high risk and high cost for health care.


Events in the immortalizing process of primary human mammary epithelial cells by the catalytic subunit of human telomerase.
The in vitro immortalization of primary human mammary epithelial (HME) cells solely by the exogenous introduction of the catalytic subunit of human telomerase (hTERT) has been achieved. Early passage hTERT-transfected HME (T-HME) cells continuously decreased the length and density of telomeres even in the presence of telomerase activity, with a significant number of cells staining positive for senescence-associated beta-galactosidase (SA-beta-gal). Subsequently, with the increase in cell passages, the copy number of the exogenously transfected hTERT gene and the percentage of SA-beta-gal positive cells were found to decrease. Eventually, a single copy of the exogenous hTERT gene was observed in the relatively later passage T-HME cells in which telomere length was elongated and stabilized without obvious activation of endogenous hTERT and c-Myc expression. In T-HME cells, the expression of two p53 regulated genes p21(WAF) and HDM2 increased (as in primary senescent HME cells), and was found to be further elevated as the function of p53 was activated by treatment with DNA-damaging agents. p16(INK4a) was shown to be significantly higher in the primary senescent HME and the early passage T-HME cells when compared with the primary presenescent HME cells, with a dramatic repression of p16(INK4a) observed in the later passage T-HME cells. In addition, the expression of E2F1 and its transcription factor activity were found to be significantly higher in the later passage T-HME cells when compared with the earlier passage T-HME cells. Together, our results indicate that in vitro immortalization in HME cells may require the activation of the function of telomerase and other genetic alterations such as the spontaneous loss of p16(INK4a) expression.


Antidiuretic function in Sheehan's syndrome.
Twenty patients with postpartum hypopituitarism underwent a dehydration test followed by the administration of synthetic arginine-vasopressin (DDAVP; desmopressin). Panhypopituitarism was confirmed by hormonal assays in the basal state and after stimulation with combined luteinising hormone releasing hormone-thyrotrophin releasing hormone-insulin. All the patients were given replacement therapy with hydrocortisone and thyroid hormones. Results were compared with those in 12 normal women. Urinary concentrating ability was diminished in the patients as compared with the controls (maximum urine osmolality 688 (SEM 23) mmol (mosmol)/kg in the patients v 967 (SEM 29) mmol/kg in the controls). Also the change in urine osmolality after administration of desmopressin was greater in the patients (+9.55 (SEM 1.98)% in the patients v 2.49 (SEM 0.96)% in the controls). Partial diabetes insipidus is apparently common in Sheehan's syndrome. This association should be borne in mind when managing these patients, especially those in acute failure.


Fluoxetine inhibits corticotropin-releasing factor (CRF)-induced behavioural responses in rats.
Corticotropin-releasing factor (CRF) is a potent neuromodulator of stress-related behaviour but the neural mechanisms underlying these effects are not clear. Studies were designed to test the hypothesis that CRF-induced behavioural arousal involves interactions with brainstem serotonergic systems. To examine interactions between CRF and serotonergic systems in the regulation of behaviour, CRF (1 microg, intracerebroventricular (i.c.v.)) or vehicle was infused in the presence or absence of the selective serotonin re-uptake inhibitor fluoxetine (0, 0.1, 1 or 10 mg/kg, intravenous (i.v.)). Fluoxetine was used at these doses because it is known to decrease serotonin cell firing rates while increasing extracellular serotonin concentrations in select forebrain regions. We then measured behavioural, neurochemical and endocrine responses. CRF increased locomotion and spontaneous non-ambulatory motor activity (SNAMA) in the home cages. Fluoxetine decreased tissue 5-hydroxyindoleacetic acid concentrations, a measure of serotonin metabolism, in specific limbic brain regions of CRF-treated rats (nucleus accumbens shell region, entorhinal cortex, central nucleus of the amygdala). Furthermore, fluoxetine inhibited CRF-induced SNAMA. CRF and fluoxetine independently increased plasma corticosterone concentrations, but the responses had distinct temporal profiles. Overall, these data are consistent with the hypothesis that CRF-induced facilitation of behavioural activity is dependent on brainstem serotonergic systems. Therefore, fluoxetine may attenuate or alleviate some behavioural responses to stress by interfering with CRF-induced responses.


Comparison of in house polymerase chain reaction with conventional techniques for the detection of Mycobacterium tuberculosis DNA in granulomatous lymphadenopathy.
To evaluate the usefulness of the devR based polymerase chain reaction (PCR) in the detection of Mycobacterium tuberculosis in lymph node aspirates and tissues of lymphadenitis and to compare PCR with conventional diagnostic techniques. Coded specimens of fine needle aspirates and biopsies from 22 patients with tuberculous lymphadenitis, 14 patients with non-tubercular lymphadenitis, and nine patients with granulomatous lymphadenitis were processed and subjected to analysis by PCR, smear microscopy, M tuberculosis culture, histology, and cytology. Tuberculous lymphadenitis was correctly diagnosed by PCR in 18 patients, by culture in five patients, by histology in 13 patients, and by cytology in seven patients. PCR gave two false positive results in 14 patients with non-tubercular lymphadenitis. The sensitivity of the conventional techniques was significantly higher with biopsies (17 of 22 specimens; 77%) than with fine needle aspirates (nine of 22 specimens; 41%). However, the sensitivity of PCR was not significantly higher with biopsies (68%) in comparison with fine needle aspirates (55%). The sensitivity of either biopsy PCR or fine needle aspirate PCR was not significantly different from that of either histology combined with culture or cytology combined with culture. The overall combined specificity of PCR was 86%. Mycobacterium tuberculosis DNA was detected in six of nine patients with granulomatous lymphadenitis. PCR is the most sensitive single technique available to date for the demonstration of M tuberculosis in specimens derived from patients with a clinical suspicion of tuberculous lymphadenitis. The value of PCR lies in its use as an adjunct test in the diagnosis of tuberculous lymphadenitis, particularly in those patients where conventional methods fail. Because fine needle aspiration is not an invasive procedure, it is the procedure of choice, and PCR should be performed initially on these samples. Excisional biopsy histology and PCR should be recommended only for patients in whom fine needle aspirate PCR is negative or when there is discrepancy with the clinical impression.


Importance of Completing Hybrid Cardiac Rehabilitation for Long-Term Outcomes: A Real-World Evaluation.
Community-based hybrid cardiac rehabilitation (CR) programs offer a viable alternative to conventional centre-based CR, however their long-term benefits are unknown. We conducted a secondary analysis of the CR Participation Study conducted in London, Ontario, between 2003 and 2006. CR eligible patients hospitalized for a major cardiac event, who resided within 60 min, were referred to a hybrid CR program; 381 of 544 (64%) referred patients initiated CR; an additional 1,498 CR eligible patients were not referred due to distance. For the present study, CR participants were matched using propensity scores to CR eligible non-participants who resided beyond 60 min, yielding 214 matched pairs. Subjects were followed for a mean (standard deviation, SD) of 8.56 (3.38) years for the outcomes of mortality or re-hospitalization for a major cardiac event. Hybrid CR participation was associated with a non-significant 16% lower event rate (Hazard Ratio [HR]: 0.84, 95% CI: 0.59⁻1.17). When restricting to pairs where CR participants achieved a greater than 0.5 metabolic equivalent exercise capacity increase (123 pairs), CR completion was associated with a 51% lower event rate (HR: 0.49, 95% CI: 0.29⁻0.81). Successful completion of a community-based hybrid CR program may be associated with decreased long-term mortality or recurrent cardiac events.


A minimally invasive optical trapping system to understand cellular interactions at onset of an immune response.
T-cells and antigen presenting cells are an essential part of the adaptive immune response system and how they interact is crucial in how the body effectively fights infection or responds to vaccines. Much of the experimental work studying interaction forces between cells has looked at the average properties of bulk samples of cells or applied microscopy to image the dynamic contact between these cells. In this paper we present a novel optical trapping technique for interrogating the force of this interaction and measuring relative interaction forces at the single-cell level. A triple-spot optical trap is used to directly manipulate the cells of interest without introducing foreign bodies such as beads to the system. The optical trap is used to directly control the initiation of cell-cell contact and, subsequently to terminate the interaction at a defined time point. The laser beam power required to separate immune cell pairs is determined and correlates with the force applied by the optical trap. As proof of concept, the antigen-specific increase in interaction force between a dendritic cell and a specific T-cell is demonstrated. Furthermore, it is demonstrated that this interaction force is completely abrogated when T-cell signalling is blocked. As a result the potential of using optical trapping to interrogate cellular interactions at the single cell level without the need to introduce foreign bodies such as beads is clearly demonstrated.


Nocturnal excretion of a urinary melatonin metabolite among electric utility workers.
The effects of 60-Hz magnetic field and ambient light exposures on the pineal hormone melatonin were studied among electric utility workers. Personal exposure was measured at 15-second intervals over 3 consecutive 24-hour periods. Exposure metrics based on magnetic field intensity, intermittence, or temporal stability were calculated for periods of work, home, and sleep. A rate-of-change metric (RCM) was used to estimate intermittence, and the standardized RCM (RCMS = RCM/standard deviation) was used to evaluate temporal stability. The effects of magnetic field exposure on total overnight 6-hydroxymelatonin sulfate (6-OHMS) excretion and creatinine-adjusted nocturnal 6-OHMS (6-OHMS/cr) concentration were analyzed with adjustment for age, month, and light exposure. Magnetic field intensity, intermittence, or cumulative exposure had little influence on nocturnal 6-OHMS excretion. Residential RCMS magnetic field exposures were associated with lower nocturnal 6-OHMS/cr concentrations. In multivariate statistical analyses, the interaction term for geometric mean and RCMS magnetic field exposures at home was associated with lower nocturnal 6-OHMS/cr and overnight 6-OHMS levels. Modest reductions in the mean 6-OHMS levels occurred after RCMS exposures during work. The greatest reductions occurred when RCMS exposures both at work and at home were combined; therefore the effects of temporally stable magnetic fields may be integrated over a large portion of the day. Results from this study provide evidence that temporally stable magnetic field exposures are associated with reduced nocturnal 6-OHMS excretion in humans.


Efficacy of pitolisant in patients with high burden of narcolepsy symptoms: pooled analysis of short-term, placebo-controlled studies.
To evaluate the efficacy of pitolisant, a histamine 3 (H3)-receptor antagonist/inverse agonist, in adult patients with high burden of narcolepsy symptoms. Data were pooled from two randomized, placebo-controlled, 7- or 8-week studies of pitolisant (titrated to a potential maximum dose of 35.6 mg/day) in adults with narcolepsy. Analyses included three independent patient subgroups: Epworth Sleepiness Scale (ESS) baseline score ≥16, Maintenance of Wakefulness Test (MWT) sleep latency ≤8 min, and ≥15 cataplexy attacks per week. The analysis populations included 118 patients for ESS (pitolisant, n = 60; placebo, n = 58), 105 for MWT (pitolisant, n = 59; placebo, n = 46), and 31 for cataplexy (pitolisant, n = 20; placebo, n = 11). On the ESS, least-squares mean change from baseline was significantly greater for pitolisant (-6.1) compared with placebo (-2.3; P < 0.001). Significantly more pitolisant-treated patients were classified as treatment responders: ESS score reduction ≥3, 69.0% in the pitolisant group versus 35.1% in the placebo group (P = 0.001); final ESS score ≤10, 36.2% versus 10.5%, respectively (P = 0.005). On the MWT, mean sleep latency increased from 3.5 min to 10.4 min with pitolisant and from 3.4 min to 6.8 min with placebo (P = 0.017). Least-squares mean change in the weekly rate of cataplexy was significantly greater for pitolisant (-14.5; baseline, 23.9; final, 9.4) compared with placebo (-0.1; baseline, 23.1; final, 23.0; P = 0.004). Headache was the most common adverse event with pitolisant. Pitolisant, at once-daily doses up to 35.6 mg, was efficacious for reducing excessive daytime sleepiness and cataplexy in patients with severe narcolepsy symptom burden.


Nomogram prediction for prostate cancer and aggressive prostate cancer at time of biopsy: utilizing all risk factors and tumor markers for prostate cancer.
There is a large amount of confusion in interpreting prostate specific antigen (PSA) values for prostate cancer. More precise risk assessments for prostate cancer detection are needed for men faced with an abnormal PSA. We studied a sample of 2,637 men who underwent a prostate biopsy for an abnormal digital rectal exam (DRE) or PSA. Using factors including age, ethnicity, family history of prostate cancer, previous negative biopsy, presence of voiding symptoms, prostate volume, DRE and PSA, we constructed nomograms to predict the probability of prostate cancer at biopsy. Of the 2,637 men, 1,282 men (48.6%) had prostate cancer detected. Age, ethnicity, family history of prostate cancer, a previous negative biopsy, prostate volume, DRE and PSA were all significant predictors of prostate cancer. Nomograms were constructed based on these factors to predict the risk of prostate cancer and of aggressive prostate cancer (defined as a Gleason Score 7 or more). The positive predictive value varied from 5% to 95% based on the nomograms. The nomograms were validated using bootstrapping methods and the expected and observed proportions were found to be highly concordant. For men with an abnormal PSA or DRE, the risk for prostate cancer can be accurately estimated using a nomogram based on age, ethnicity, family history of prostate cancer, previous negative biopsy, presence of voiding symptoms, prostate volume, DRE and PSA. This tool will aid physicians and patients in determining the need for prostate biopsy.


Liquid-Liquid Extraction of Formic Acid with 2-Methyltetrahydrofuran: Experiments, Process Modeling, and Economics.
Formic acid (FA) is an interesting hydrogen (H2) and carbon monoxide (CO) carrier that can be produced by the electrochemical reduction of carbon dioxide (CO2) using renewable energy. The separation of FA from water is challenging due to the strong (cross)association of the components and the presence of a high boiling azeotrope. For the separation of dilute FA solutions, liquid-liquid extraction is preferred over conventional distillation because distilling large amounts of water is very energy-intensive. In this study, we use 2-methyltetrahydrofuran (2-MTHF) to extract FA from the CO2 electrolysis process, which typically contains <20 wt % of FA. Vapor-liquid equilibrium (VLE) data of the binary system 2-MTHF-FA and liquid-liquid equilibrium (LLE) data of the ternary system 2-MTHF-FA-water are obtained. Continuous extraction and distillation experiments are performed to test the extraction power and recovery of 2-MTHF from the extract. The VLE and LLE data are used to design a hybrid extraction and distillation process to produce a commercial grade product (85 wt % of FA). A detailed economic analysis of this hybrid extraction-distillation process is presented and compared with the existing FA separation methods. It is shown that 2-MTHF is a cost-effective solvent for FA extraction from dilute streams (<20 wt % FA).


A Scalable Multicore Architecture With Heterogeneous Memory Structures for Dynamic Neuromorphic Asynchronous Processors (DYNAPs).
Neuromorphic computing systems comprise networks of neurons that use asynchronous events for both computation and communication. This type of representation offers several advantages in terms of bandwidth and power consumption in neuromorphic electronic systems. However, managing the traffic of asynchronous events in large scale systems is a daunting task, both in terms of circuit complexity and memory requirements. Here, we present a novel routing methodology that employs both hierarchical and mesh routing strategies and combines heterogeneous memory structures for minimizing both memory requirements and latency, while maximizing programming flexibility to support a wide range of event-based neural network architectures, through parameter configuration. We validated the proposed scheme in a prototype multicore neuromorphic processor chip that employs hybrid analog/digital circuits for emulating synapse and neuron dynamics together with asynchronous digital circuits for managing the address-event traffic. We present a theoretical analysis of the proposed connectivity scheme, describe the methods and circuits used to implement such scheme, and characterize the prototype chip. Finally, we demonstrate the use of the neuromorphic processor with a convolutional neural network for the real-time classification of visual symbols being flashed to a dynamic vision sensor (DVS) at high speed.


Modelling the determinants of 2000 m rowing ergometer performance: a proportional, curvilinear allometric approach.
Previous studies have investigated the determinants of indoor rowing using correlations and linear regression. However, the power demands of ergometer rowing are proportional to the cube of the flywheel's (and boat's) speed. A rower's speed, therefore, should be proportional to the cube root (0.33) of power expended. Hence, the purpose of the present study was to explore the relationship between 2000 m indoor rowing speed and various measures of power of 76 elite rowers using proportional, curvilinear allometric models. The best single predictor of 2000 m rowing ergometer performance was power at VO(2max)(WVO(2max))(0.28), that explained R(2)=95.3% in rowing speed. The model realistically describes the greater increment in power required to improve a rower's performance by the same amount at higher speeds compared with that at slower speeds. Furthermore, the fitted exponent, 0.28 (95% confidence interval 0.226-0.334) encompasses 0.33, supporting the assumption that rowing speed is proportional to the cube root of power expended. Despite an R(2)=95.3%, the initial model was unable to explain "sex" and "weight-class" differences in rowing performances. By incorporating anaerobic as well as aerobic determinants, the resulting curvilinear allometric model was common to all rowers, irrespective of sex and weight class.


High waist-to-hip ratio levels are associated with insulin resistance markers in normal-weight women.
To assess the association between high waist-to-hip ratio (WHR) levels and insulin resistance (IR) or hyperinsulinemia after oral glucose tolerance test (OGTT) in a sample of normal-weight women. We conducted an analytical cross-sectional study in euthyroid non-diabetic women, who attended the outpatient service of a private clinic in Lima-Peru from 2012 to 2016. Participants were divided in two groups according to the presence or absence of high WHR levels, IR or hyperinsulinemia after OGTT. We considered WHR values > 0.85 as high levels. IR was defined as a Homeostasis Model Assessment (HOMA-IR) value > 2.39 and hyperinsulinemia after OGTT as a serum insulin value ≥ 80μU/mL after 120 min of 75-g glucose intake. We elaborated crude and adjusted Poisson generalized linear models to evaluate the association between high WHR levels and IR or hyperinsulinemia after OGTT and reported the prevalence ratio (PR) with their respective 95% confidence intervals (95%CI). We analyzed the data of 248 euthyroid, non-diabetic and normal-weight women. The prevalence of high WHR levels was 68.9% (n = 171) while the prevalence of IR and hyperinsulinemia after OGTT was 25% (n = 62) and 15.3% (n = 38), respectively. WHR values were positively correlated with HOMA-IR (r = 0.307; p < 0.001) and serum insulin after OGTT (r = 0.260; p < 0.001). In the adjusted model, high WHR levels were associated with both IR (aPR = 2.63; 95%CI: 1.39-5.01) and hyperinsulinemia after OGTT (aPR = 2.35; 95%CI: 1.03-5.38). High WHR levels were associated with both IR markers used in our study, appearing to be a useful anthropometric indicator to assess IR in euthyroid normal-weight women without type 2 diabetes mellitus.


Selective nonoperative management of gunshot wounds of the anterior abdomen.
To investigate the role of selective nonoperative management of gunshot wounds to the abdomen. A prospective, protocol-guided study including all gunshot wounds of the anterior abdomen. The patients were assessed and managed according to a written protocol. Patients with hemodynamic instability or peritonitis or associated spinal cord or head injury or requiring a general anesthetic for an extra-abdominal injury were managed by laparotomy. The test of the patients were selected for initial nonoperative management with serial physical examinations. During a 16-month period, 309 patients with gunshot wounds of the anterior abdomen were treated. Eighteen patients in extremis (5.8%) underwent an emergency department-performed thoracotomy. Another 185 patients (59.9%) met the criteria for operation and underwent a laparotomy. The incidence of nontherapeutic operations was 2.2%, and that of negative operations was 8.6%. One hundred six patients (34.3%) were selected for observation. Fourteen of the initially observed patients underwent a late operation, but it was therapeutic in only 5. Overall, 92 patients (29.8%) were successfully managed nonoperatively. The overall sensitivity of the initial physical examination was 97.1%. The estimated bullet trajectory was not reliable in identifying the need for operation because of 224 patients with likely peritoneal penetration only 169 (75.4%) had significant injuries requiring surgical repair. In the appropriate environment, many civilian abdominal gunshot wounds can be managed non-operatively.


Bending moments of zirconia and titanium implant abutments supporting all-ceramic crowns after aging.
To test the fracture load and fracture patterns of zirconia abutments restored with all-ceramic crowns after fatigue loading, exhibiting internal and external implant-abutment connections as compared to restored and internally fixed titanium abutments. A master abutment was used for the customization of 5 groups of zirconia abutments to a similar shape (test). The groups differed according to their implant-abutment connections: one-piece internal connection (BL; Straumann Bonelevel), two-piece internal connection (RS; Nobel Biocare ReplaceSelect), external connection (B; Branemark MkIII), two-piece internal connection (SP, Straumann StandardPlus) and one-piece internal connection (A; Astra Tech AB OsseoSpeed). Titanium abutments with internal implant-abutment connection (T; Straumann Bonelevel) served as control group. In each group, 12 abutments were fabricated, mounted to the respective implants and restored with glass-ceramic crowns. All samples were embedded in acrylic holders (ISO-Norm 14801). After aging by means of thermocycling in a chewing simulator, static load was applied until failure (ISO-Norm 14801). Fracture load was analyzed by calculating the bending moments. Values of all groups were compared with one-way ANOVA followed by Scheffé post hoc test (P-value<0.05). Failure mode was analyzed descriptively. The mean bending moments were 464.9 ± 106.6 N cm (BL), 581.8 ± 172.8 N cm (RS), 556.7 ± 128.4 N cm (B), 605.4 ± 54.7 N cm (SP), 216.4 ± 90.0 N cm (A) and 1042.0 ± 86.8 N cm (T). No difference of mean bending moments was found between groups BL, RS, B and SP. Test group A exhibited significantly lower mean bending moment than the other test groups. Control group T had significantly higher bending moments than all test groups. Failure due to fracture of the abutment and/or crown occurred in the test groups. In groups BL and A, fractures were located in the internal part of the connection, whereas in groups RS and SP, a partial deformation of the implant components occurred and cracks and fractures of the zirconia abutment were detected. The differently connected zirconia abutments exhibited similar bending moments with the exception of one group. Hence, the type of connection only had a minor effect on the stability of restored zirconia abutments. In general, restored titanium abutments exhibited the highest bending moments.


A prospective study of telomere length measured by monochrome multiplex quantitative PCR and risk of non-Hodgkin lymphoma.
Telomere length plays an important role in the maintenance of chromosomal stability and in tumorigenesis. We hypothesized that telomere length in peripheral WBC DNA obtained from healthy individuals would be a predictor of future risk of developing non-Hodgkin lymphoma. Using a new assay to measure relative telomere length, monochrome multiplex quantitative PCR, which strongly correlates with telomere length measured by Southern blot (Spearman r = 0.91, P < 0.0001) and has high precision (coefficient of variation = 7%), we compared telomere length in peripheral WBC DNA in 107 incident male non-Hodgkin lymphoma cases and 107 matched controls within the prospective Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort. Median (10th, 90th percentile) telomere length was 1.10 (0.79, 1.43) in cases and 1.02 (0.78, 1.26) in controls (P = 0.0017, Wilcoxon sign test). There was a strong dose-response relationship between quartiles of telomere length and risk of non-Hodgkin lymphoma overall [odds ratios (95% confidence intervals) by quartile: 1.0; 1.1 (0.4-2.7); 1.8 (0.7-4.9); and 3.6 (1.4-8.9); P trend = 0.003], and this association was similar across the most common non-Hodgkin lymphoma subtypes present in this study. These results suggest that longer telomere length may be a potential predictor for future risk of non-Hodgkin lymphoma.


Anaerobic degradation of pimelate by newly isolated denitrifying bacteria.
A C7 dicarboxylic (pimelic) acid derivative is postulated as an intermediate in anaerobic degradation of benzoate. Four strains of Gram-negative, nitrate-reducing bacteria capable of growth with both pimelate and benzoate as sole carbon and energy source were isolated. The metabolism of strain LP-1, which was enriched from activated sludge with pimelate as substrate, was studied in detail. This strain grew only with oxygen or with oxidized nitrogen compounds as electron acceptor. In the presence of nitrate, a wide range of substrates excluding C1 compounds was degraded. The new isolate was catalase- and oxidase-positive, and had one single polar flagellum. Strain LP-1 was tentatively classified within the family Pseudomonadaceae. The catabolism of pimelate and benzoate was studied in cell-free extracts of strain LP-1. Both acids were activated with coenzyme A in a Mg(2E)- and ATP-dependent reaction. The corresponding acyl-CoA synthetases were specifically induced by the respective growth substrate. Pimelate was also activated by CoA transfer from succinyl-CoA. Pimelyl-CoA was oxidized by cell-free extracts in the presence of potassium ferricyanide. Degradation to glutaryl-CoA and acetyl-CoA proceeded by a sequence of beta-oxidation-like reactions. Glutaryl-CoA dehydrogenase and glutaconyl-CoA decarboxylase activities were expressed in cells grown with pimelate or benzoate, indicating the specific involvement of these enzyme activities in anaerobic degradation of these two acids. Enzyme activities responsible for further degradation of the resulting crotonyl-CoA to acetyl-CoA via classical beta-oxidation were also detected.


Cardiac autophagy is a maladaptive response to hemodynamic stress.
Cardiac hypertrophy is a major predictor of heart failure and a prevalent disorder with high mortality. Little is known, however, regarding mechanisms governing the transition from stable cardiac hypertrophy to decompensated heart failure. Here, we tested the role of autophagy, a conserved pathway mediating bulk degradation of long-lived proteins and cellular organelles that can lead to cell death. To quantify autophagic activity, we engineered a line of "autophagy reporter" mice and confirmed that cardiomyocyte autophagy can be induced by short-term nutrient deprivation in vivo. Pressure overload induced by aortic banding induced heart failure and greatly increased cardiac autophagy. Load-induced autophagic activity peaked at 48 hours and remained significantly elevated for at least 3 weeks. In addition, autophagic activity was not spatially homogeneous but rather was seen at particularly high levels in basal septum. Heterozygous disruption of the gene coding for Beclin 1, a protein required for early autophagosome formation, decreased cardiomyocyte autophagy and diminished pathological remodeling induced by severe pressure stress. Conversely, Beclin 1 overexpression heightened autophagic activity and accentuated pathological remodeling. Taken together, these findings implicate autophagy in the pathogenesis of load-induced heart failure and suggest it may be a target for novel therapeutic intervention.


Use of small molecule inhibitors of the Wnt and Notch signaling pathways during Xenopus development.
Small molecule inhibitors of growth factor signaling pathways are extremely convenient reagents for investigation of embryonic development. The chemical may be introduced at a precise time, the dose can be altered over a large range and the chemical may be removed simply by replacing the medium surrounding the embryo. Because small molecule modulators are designed to target conserved features of a protein, they are usually effective across species. Ideally the chemicals offer remarkable specificity for a particular signaling pathway and exhibit negligible off-target effects. In this study we examine the use of small molecules to modulate the Wnt and Notch signaling pathways in the Xenopus embryo. We find that IWR-1 and XAV939 are effective inhibitors of the canonical Wnt signaling pathway while BIO is an excellent activator. For Notch signaling, we find that both DAPT and RO4929097 are effective inhibitors, but that RO4929097 is the more potent reagent. This report provides researchers with useful working concentrations of reagents and a small series of genetic and biological assays that may be used to characterize the role of Wnt and Notch signaling during embryonic development.


Passion or addiction? Correlates of healthy versus problematic use of videogames in a sample of French-speaking regular players.
A criticism of current diagnostic approaches to gaming disorder is that they fail to take into account that high and repeated engagement is not problematic per se, nor is it necessarily associated with adverse consequences. To tackle this controversy, we used Confirmatory Factor Analysis (CFA) to test, in regular gamers (N = 268), whether high (but healthy) engagement can be distinguished from problematic engagement by using the Addiction-Engagement Questionnaire (Charlton & Danforth, 2007). We then tested whether differential relationships exist between the engagement and addiction constructs, DSM-5 criteria for Internet gaming disorder (IGD), and psychological factors linked to gaming use and misuse (self-reported impulsivity, motives to play, and depression). Results indicated that a model holding engagement and addiction as two distinct, but related, constructs fits the data well. Second, we showed that although both constructs are linked to the number of IGD criteria endorsed, the relationship is more pronounced for the addiction construct. Third, a differential pattern of correlations was observed with the other study variables, further supporting the need to distinguish the two constructs. Our study emphasizes that research is needed to refine the diagnostic approach to gaming disorder to avoid conflating healthy passion with pathological behavior.


Chk1 and Hsp90 cooperatively regulate phosphorylation of endothelial nitric oxide synthase at serine 1179.
The effects of DNA damage on NO production have not been completely elucidated. Using ultraviolet (UV) irradiation as a DNA-damaging agent, we studied its effect on NO production in bovine aortic endothelial cells (BAEC). UV irradiation acutely increased NO production, the phosphorylation of endothelial NO synthase (eNOS) at serine 1179, and eNOS activity. No alterations in eNOS expression nor phosphorylation at eNOS Thr(497) or eNOS Ser(116) were found. SB218078, a checkpoint kinase 1 (Chk1) inhibitor, inhibited UV-irradiation-stimulated eNOS-Ser(1179) phosphorylation and NO production. Similarly, ectopic expression of small interference RNA for Chk1 or a dominant-negative Chk1 repressed the UV-irradiation stimulatory effect, whereas wild-type Chk1 increased basal eNOS-Ser(1179) phosphorylation. Purified Chk1 directly phosphorylated eNOS Ser(1179) in vitro. Confocal microscopy and coimmunoprecipitation studies revealed a colocalization of eNOS and Chk1. In basal BAEC, heat shock protein 90 (Hsp90) predominantly interacted with Chk1. This interaction, which decreased significantly in response to UV irradiation, was accompanied by increased interaction of Hsp90 with eNOS. The Hsp90 inhibitor geldanamycin attenuated UV-irradiation-stimulated eNOS-Ser(1179) phosphorylation by dissociating Hsp90 from eNOS. UV irradiation and geldanamycin did not alter the interaction between eNOS and Chk1. Overall, this is the first study demonstrating that Chk1 directly phosphorylates eNOS Ser(1179) in response to UV irradiation, which is dependent on Hsp90 interaction.


Automatic registration with continuous pose updates for marker-less surgical navigation in spine surgery.
Established surgical navigation systems for pedicle screw placement have been proven to be accurate, but still reveal limitations in registration or surgical guidance. Registration of preoperative data to the intraoperative anatomy remains a time-consuming, error-prone task that includes exposure to harmful radiation. Surgical guidance through conventional displays has well-known drawbacks, as information cannot be presented in-situ and from the surgeon's perspective. Consequently, radiation-free and more automatic registration methods with subsequent surgeon-centric navigation feedback are desirable. In this work, we present a marker-less approach that automatically solves the registration problem for lumbar spinal fusion surgery in a radiation-free manner. A deep neural network was trained to segment the lumbar spine and simultaneously predict its orientation, yielding an initial pose for preoperative models, which then is refined for each vertebra individually and updated in real-time with GPU acceleration while handling surgeon occlusions. An intuitive surgical guidance is provided thanks to the integration into an augmented reality based navigation system. The registration method was verified on a public dataset with a median of 100% successful registrations, a median target registration error of 2.7 mm, a median screw trajectory error of 1.6°and a median screw entry point error of 2.3 mm. Additionally, the whole pipeline was validated in an ex-vivo surgery, yielding a 100% screw accuracy and a median target registration error of 1.0 mm. Our results meet clinical demands and emphasize the potential of RGB-D data for fully automatic registration approaches in combination with augmented reality guidance.


[The mechanisms of taxodione-induced apoptosis in BCR-ABL-positive leukemia cells].
Chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) are caused by a fusion protein, BCR-ABL, which induces cellular transformation by activating the signaling molecules, STAT5 and Akt. The specific BCR-ABL inhibitors including imatinib, nilotinib, and dasatinib, are clinically utilized in the treatment with CML and ALL patients. Although these BCR-ABL inhibitors are initially successful in the treatment of leukemia, many patients develop drug resistance due to the appearance of the gatekeeper mutation of BCR-ABL, T315I. Recently, we found that taxodione, a quinone methide diterpene isolated from a conifer, Taxodium distichum, significantly induced apoptosis in human myelogenous leukemia-derived K562 cells, which is positive for the bcr-abl gene. Taxodione reduced the activities of mitochondrial respiratory chain complex III, leading to the production of reactive oxygen species (ROS). An antioxidant agent, N-acetylcysteine (NAC), canceled taxodione-induced ROS production and apoptotic cell death, suggesting that taxodione induced apoptosis through ROS accumulation. Furthermore, in K562 cells treated with taxodione, BCR-ABL, STAT5 and Akt were sequestered in mitochondrial fraction, and their localization changes decrease their abilities to stimulate cell proliferation. Strikingly, NAC canceled these taxodione-caused inhibition of BCR-ABL, STAT5 and Akt. In addition, taxodione significantly induced apoptosis in transformed Ba/F3 cells by not only BCR-ABL but also T315I-mutated BCR-ABL through the generation of ROS, suggesting that taxodione has potential as anti-tumor drug with high efficacy to overcome BCR-ABL T315I mutation-mediated resistance in leukemia cells. It's also expected that these knowledge becomes an important clue in the development of anti-cancer drugs against the broad range of tumors.


TRPV3 expression and purification for structure determination by Cryo-EM.
The transient receptor potential vanilloid-superfamily member 3 (TRPV3) channel is implicated in a variety of physiological processes, including temperature sensing, nociception and itch, maintenance of the skin barrier, wound healing, hair growth, and embryonic development. TRPV3 is also associated with various skin diseases, including Olmsted syndrome, atopic dermatitis, and rosacea. Studies of TRPV3 are of fundamental importance for structural pharmacology aimed at the design of drugs targeting this channel and for understanding the molecular basis of temperature sensing. Here we describe a detailed protocol for expression and purification of chemically pure and stable TRPV3 protein that is suitable for structural and functional characterization of this channel, in particular for cryo-EM sample preparation and high-resolution 3D reconstruction.


Interventions for preventing delirium in older people in institutional long-term care.
Delirium is a common and distressing complication of a range of stressor events including infection, new medications and environment change that is often experienced by older people with frailty and dementia. Older people living in institutional long-term care (LTC)are at high risk of delirium, which increases the risk of admission to hospital, development of or worsening of dementia, and mortality.Delirium is also associated with substantial healthcare costs. Although it is possible to prevent delirium in the hospital setting by providing multicomponent delirium prevention interventions it is currently unclear whether interventions to prevent delirium in LTCare effective. To assess the effectiveness of interventions for preventing delirium in older people in long term care. We searched ALOIS (www.medicine.ox.ac.uk/alois) - the Cochrane Dementia and Cognitive Improvement Group's Specialised Register- on 23 April 2013. The search was as sensitive as possible to identify all studies on ALOIS relating to delirium. We ran additional separate searches in major healthcare databases, trial registers, the Cochrane Central Register of Controlled Trials (CENTRAL) and grey literature sources, to ensure that the search was as comprehensive as possible. We included randomised controlled trials (RCTs) and cluster-randomised controlled trials (cluster-RCTs) of single- and multi componentn on-pharmacological and pharmacological interventions for preventing delirium in older people (aged 65 years and over) in permanent LTC residence. Two independent review authors examined the titles and abstracts of citations identified by the search for eligibility and extracted data, with any disagreements settled by consensus. Primary outcomes were prevalence, incidence and severity of delirium. Secondary outcomes included new diagnosis of dementia, activities of daily living, quality of life and adverse outcomes. We used risk ratios (RRs)as measures of treatment effect for dichotomous outcomes and hazard ratios (HR) for time to event data.Main results We included two trials that recruited 3636 participants.Both were complex single-component non-pharmacological delirium prevention interventions. Risk of bias for many items was unclear due to inadequate reporting. Notably, there was no evidence of blinding of trial participants or assessors in either trial. One small cluster-RCT (n = 98) of a hydration-based intervention reported no reduction in delirium incidence in the intervention group compared to control (RR 0.85, 95% confidence interval (CI) 0.18 to 4.00, analysis not adjusted for clustering, very low quality evidence). Results were imprecise and there were serious limitations evident in trial design.One large cluster-RCT (n = 3538) of a computerised system to identify medications that may contribute to delirium risk and trigger a pharmacist-led medication review reported a large reduction in delirium incidence (12-month HR 0.42, CI 0.34 to 0.51, moderat equality evidence) but no clear evidence of reduction in hospital admissions (HR 0.89, CI 0.72 to 1.10, moderate quality evidence), in mortality (HR 0.88, CI 0.66 to 1.17, moderate quality evidence) or in falls risk (HR 1.03, CI 0.92 to 1.15, moderate quality evidence).Authors' conclusions Our review identified very limited evidence on interventions for preventing deliriumin older people in LTC. Introduction of a software based intervention to identify medications that could contribute to delirium risk so that a pharmacist-led medication review and monitoring plan can be initiated may reduce incidence of delirium for older people in institutional LTC. This is based on one large RCT in the United States and may not be practical in other countries which do not have comparable information technology services available in care homes. Our review identified only one ongoing pilot trial of a multicomponent delirium prevention intervention and no trials of pharmacological agents. Future trials of computerised medication management systems and multicomponent non-pharmacological and pharmacological delirium prevention interventions for older people in LTC are needed to help inform the provision of evidence based care for this vulnerable group.


Geographical structuring in the mtDNA of Italians.
Geographical patterns of mtDNA variation were studied in 12 Italian samples (1072 individuals) by two different spatial autocorrelation methods. Separate analyses of the frequencies of 12 restriction morphs show North-South clines, differences between Sardinia and the mainland populations, and the effects of isolation by distance. A recently developed autocorrelation statistic summarizing molecular similarity at all sites (AIDA; autocorrelation index for DNA analysis) confirms the presence of a clinical pattern; differences between random pairs of haplotypes tend to increase with their geographical distance. The partition of gene diversity, however, reveals that most variability occurs within populations, whereas differences between populations are minor (GST = 0.057). When the data from the 12 samples are pooled, two descriptors of genetic variability (number of polymorphic sites and average sequence difference between pairs of individuals) do not behave as expected under neutrality. The presence of clinal patterns, Tajima's tests, and a simulation experiment agree in suggesting that population sizes increased rapidly in Italy and Sicily but not necessarily so in Sardinia. The distribution of pairwise sequence differences in the Italian peninsula (excluding Sardinia) permits a tentative location of the demographic increase between 8000 and 20,500 years ago. These dates are consistent with archaeological estimates of two distinct expansion processes, occurring, respectively, in the Neolithic and after the last glacial maximum in the Paleolithic. Conversely, there is no genetic evidence that such processes have had a major impact on the Sardinian population.


A companion perturbation theory for state-specific multireference coupled cluster methods.
A partitioning scheme is applied to the state-specific Mukherjee multireference coupled cluster method to derive a companion perturbation theory (Mk-MRPT2). A production-level implementation of Mk-MRPT2 is reported. The effectiveness of the Mk-MRPT2 method is demonstrated by application to the classic F(2) dissociation problem and the lowest-lying electronic states of meta-benzyne, including computations with up to 766 atomic orbitals. We show that Mk-MRPT2 theory is particularly useful in multireference focal point extrapolations to determine ab initio limits.


Independent Relevance of Different Measures of Adiposity for Carotid Intima-Media Thickness in 40 000 Adults in UK Biobank.
Background Uncertainty persists about carotid intima-media thickness (CIMT) as a marker of subclinical atherosclerosis and the independent relevance of different measures of adiposity for CIMT. We assessed the independent relevance of general adiposity (body mass index), central adiposity (waist circumference), and body composition (fat mass index and fat-free mass index) with CIMT among adults in the United Kingdom. Methods and Results Multivariable linear regression of cross-sectional analyses of UK Biobank assessed the mean percentage difference in CIMT associated with equivalent differences in adiposity measures. To assess independent associations, body mass index and waist circumference were mutually adjusted, as were fat mass index and fat-free mass index. Among 39 367 participants (mean [SD] age 64 [8] years, 52% female, 97% White), median (interquartile range) CIMT was 0.65 (0.14) mm in women and 0.69 (0.18) mm in men. All adiposity measures were linearly and positively associated with CIMT after adjusting for confounders. Fat-free mass index was most strongly associated with CIMT after adjustment for fat mass index (% difference in CIMT: 1.23 [95% CI 0.93-1.53] women; 3.44 [3.01-3.86] men), while associations of fat mass index were attenuated after adjustment for fat-free mass index (0.28 [-0.02, 0.58] women; -0.59 [-0.99, -0.18] men). After mutual adjustment, body mass index remained positively associated with CIMT, but waist circumference was completely attenuated. Conclusions Fat-free mass index was the adiposity measure most strongly associated with CIMT, suggesting that CIMT may reflect vascular compensatory remodeling rather than atherosclerosis. Hence, screening for subclinical atherosclerosis should evaluate carotid plaques in addition to CIMT.


Palaeogenetic evidence supports a dual model of Neolithic spreading into Europe.
The peopling of Europe is a complex process. One of the most dramatic demographic events, the Neolithic agricultural revolution, took place in the Near East roughly 10000 years ago and then spread through the European continent. Nevertheless, the nature of this process (either cultural or demographic) is still a matter of debate among scientists. We have retrieved HVRI mitochondrial DNA sequences from 11 Neolithic remains from Granollers (Catalonia, northeast Spain) dated to 5500 years BP. We followed the proposed authenticity criteria, and we were also able, for the first time, to track down the pre-laboratory-derived contaminant sequences and consequently eliminate them from the generated cloning dataset. Phylogeographic analysis shows that the haplogroup composition of the Neolithic population is very similar to that found in modern populations from the Iberian Peninsula, suggesting a long-time genetic continuity, at least since Neolithic times. This result contrasts with that recently found in a Neolithic population from Central Europe and, therefore, raises new questions on the heterogeneity of the Neolithic dispersals into Europe. We propose here a dual model of Neolithic spread: acculturation in Central Europe and demic diffusion in southern Europe.


Self-organising coordinate transformation with peaked and monotonic gain modulation in the primate dorsal visual pathway.
We study a self-organising neural network model of how visual representations in the primate dorsal visual pathway are transformed from an eye-centred to head-centred frame of reference. The model has previously been shown to robustly develop head-centred output neurons with a standard trace learning rule, but only under limited conditions. Specifically it fails when incorporating visual input neurons with monotonic gain modulation by eye-position. Since eye-centred neurons with monotonic gain modulation are so common in the dorsal visual pathway, it is an important challenge to show how efferent synaptic connections from these neurons may self-organise to produce head-centred responses in a subpopulation of postsynaptic neurons. We show for the first time how a variety of modified, yet still biologically plausible, versions of the standard trace learning rule enable the model to perform a coordinate transformation from eye-centred to head-centred reference frames when the visual input neurons have monotonic gain modulation by eye-position.


Patient preoperative expectations of total hip replacement in European orthopedic centers.
Patient expectations have been identified as a factor that may account for individual differences in recovery after total hip replacement (THR) surgery. However, patient expectations have not been studied within a valid theoretical framework. This study employed the World Health Organization's model of health, the International Classification of Functioning, Disability and Health (ICF), to classify the content of preoperative patient expectations of THR. A European cohort of 1,108 patients preoperatively reported 2 types of expectations. Patients reported what they anticipated surgery would enable them to do that they needed to be able to do ("need" expectation), and what they would like to be able to do ("desire" expectation) in a year's time. Free-text responses were independently classified by 2 researchers to 1 or more of the ICF constructs of impairment, activity limitation, and participation restriction. Interrater reliability was high (κ = ≥0.87). All patient expectations were classified to the ICF constructs. Less than 5% of patient expectations were identified as impairment, 58% of "need" expectations were identified as activity limitations, and 45% of "desire" expectations were identified as activity limitations and participation restrictions combined. The ICF is a suitable theoretical framework to study patient expectations of THR. THR targets impairment; however, few patient expectations were classified to the ICF definition of impairment. The majority of patient expectations were classified as activity limitation or a combination of activity limitation and participation restriction. Therefore, patient expectations of surgery focus on recovering valued activities rather than reversal of bodily impairments.


Vibrational dynamics of LiBH(4) by infrared pump-probe and 2D spectroscopy.
Employing femtosecond IR pump-probe and 2D spectroscopy, we measure the vibrational dynamics of LiBH(4) and several of its deuterium isotopomers. We find that the vibrational lifetime of various BH and BD stretching modes uniformly is approximately 1.5 ps for all BH(4-x)D(x)(-) units (0 <or=x <or=4). Subsequently, vibrational energy cascades down through BH and BD bending, facilitated by a strong Fermi resonance, into external (librational and translational) modes with a 3 ps time constant. Final thermalization of the energy is completed in about 100 ps. The vibrational spectra are purely homogeneously broadened indicating low inhomogeneity due to static disorder. We furthermore measured the anharmonic constants of various modes, which sets the benchmark for future ab initio calculations, and completed the first FTIR assignment of the stretching vibrations for the five BH(4-x)D(x)(-) units.


Detection of innate immune response modulating impurities in therapeutic proteins.
Therapeutic proteins can contain multiple impurities, some of which are variants of the product, while others are derived from the cell substrate and the manufacturing process. Such impurities, even when present at trace levels, have the potential to activate innate immune cells in peripheral blood or embedded in tissues causing expression of cytokines and chemokines, increasing antigen uptake, facilitating processing and presentation by antigen presenting cells, and fostering product immunogenicity. Currently, while products are tested for host cell protein content, assays to control innate immune response modulating impurities (IIRMIs) in products are focused mainly on endotoxin and nucleic acids, however, depending on the cell substrate and the manufacturing process, numerous other IIRMI could be present. In these studies we assess two approaches that allow for the detection of a broader subset of IIRMIs. In the first, we use commercial cell lines transfected with Toll like receptors (TLR) to detect receptor-specific agonists. This method is sensitive to trace levels of IIRMI and provides information of the type of IIRMIs present but is limited by the availability of stably transfected cell lines and requires pre-existing knowledge of the IIRMIs likely to be present in the product. Alternatively, the use of a combination of macrophage cell lines of human and mouse origin allows for the detection of a broader spectrum of impurities, but does not identify the source of the activation. Importantly, for either system the lower limit of detection (LLOD) of impurities was similar to that of PBMC and it was not modified by the therapeutic protein tested, even in settings where the product had inherent immune modulatory properties. Together these data indicate that a cell-based assay approach could be used to screen products for the presence of IIRMIs and inform immunogenicity risk assessments, particularly in the context of comparability exercises.


Jackpot Structural Features: Rollover Effect and Goal-Gradient Effect in EGM Gambling.
Relatively little research has been undertaken on the influence of jackpot structural features on electronic gaming machine (EGM) gambling behavior. This study considered two common features of EGM jackpots: progressive (i.e., the jackpot incrementally growing in value as players make additional bets), and deterministic (i.e., a guaranteed jackpot after a fixed number of bets, which is determined in advance and at random). Their joint influences on player betting behavior and the moderating role of jackpot size were investigated in a crossed-design experiment. Using real money, players gambled on a computer simulated EGM with real jackpot prizes of either $500 (i.e., small jackpot) or $25,000 (i.e., large jackpot). The results revealed three important findings. Firstly, players placed the largest bets (20.3 % higher than the average) on large jackpot EGMs that were represented to be deterministic and non-progressive. This finding was supportive of a hypothesized 'goal-gradient effect', whereby players might have felt subjectively close to an inevitable payoff for a high-value prize. Secondly, large jackpots that were non-deterministic and progressive also promoted high bet sizes (17.8 % higher than the average), resembling the 'rollover effect' demonstrated in lottery betting, whereby players might imagine that their large bets could be later recouped through a big win. Lastly, neither the hypothesized goal-gradient effect nor the rollover effect was evident among players betting on small jackpot machines. These findings suggest that certain high-value jackpot configurations may have intensifying effects on player behavior.


No influence of body composition on serum growth hormone response to acute dynamic exercise.
Physical effort is a strong physiological stimulus that provokes an increase in blood growth hormone (GH) concentration. Interactions between GH and body composition are very complex. Seven athletes and seven age-matched controls completed a single 30-min bout of upright cycling exercise (5 % of VO(2max).) in order to estimate the influence of body composition on serum GH concentration during exercise. The serum GH concentration was measured in blood samples by standard immunoradiometric (IRMA) method. Anthropometric measurements were used for the calculation of body composition. There were no significant differences in total body mass or body mass index between the groups. The athletes had significantly less fat and higher bone and muscle mass. Serum GH concentration was 2.39 times higher in the athlets versus the control in the period of rest. During acute exercise, the serum GH concentration increased in both groups. No statistically significant differences between the groups in serum GH concentration were found either during the exercise or in the recovery. No correlation between body composition and serum GH concentration was found. Body composition depends on the level of physical activities but if the total body mass is in physiologycal range it does not influence the serum GH response to acute exercise.


Transgene insertion induced dominant male sterility and rescue of male fertility using round spermatid injection.
Transgene insertions in the mouse often cause mutations at chromosomal loci. Analysis of insertion mutations that cause male sterility may lead to the identification of novel molecular mechanisms implicated in male fertility. Here we show a line of transgenic mice with dominant inheritance of male sterility (DMS) that was found amid several lines that were normally fertile. Transgene-positive males from this line invariably were sterile, whereas transgenic females and transgene-negative male littermates were fertile. Histologic analysis and TUNEL staining for apoptotic cells in DMS testis showed spermatogenesis arrest at metaphase of meiosis I (M-I), accompanied by massive apoptosis of spermatocytes. Meiosis I arrest was incomplete, however, as small numbers of spermatids and spermatozoa were found. Both round spermatids and spermatozoa were evaluated for their permissiveness in the assisted reproductive technologies intracytoplasmic sperm injection (ICSI) and round spermatid injection (ROSI). Surprisingly, ROSI but not ICSI gave live offspring, suggesting that mature sperm had deteriorated by the time of recovery from the epididymis. Mapping the transgene insertion by fluorescence in situ hybridization revealed a site on chromosome 14 D3-E1. Two candidate genes, GFR alpha 2 and GnRH, that were previously mapped to that region and the functions of which in spermatogenesis are well established were not altered in DMS. As a consequence, positional cloning of the DMS locus will be essential to identify new molecules potentially involved in arrest at M-I. Furthermore, mice carrying this genetic trait might be useful for studies of assisted reproductive technologies and male contraceptives.


A Wearable System for Attenuating Essential Tremor Based on Peripheral Nerve Stimulation.
Currently available treatments for kinetic tremor can cause intolerable side effects or be highly invasive and expensive. Even though several studies have shown the positive effects of external feedback (i.e., electrical stimulation) for suppressing tremor, such approaches have not been fully integrated into wearable real-time feedback systems. We have developed a wireless wearable stimulation system that analyzes upper limb tremor using a three-axis accelerometer and that modulates/attenuates tremor using peripheral-nerve electrical stimulation with adjustable stimulation parameters and a real-time tremor detection algorithm. We outfitted nine subjects with tremor with a wearable system and a set of surface electrodes placed on the skin overlying the radial nerve and tested the effects of stimulation with nine combinations of parameters for open- and closed-loop stimulation on tremor. To quantify the effects of the stimulation, we measured tremor movements, and analyzed the dominant tremor frequency and tremor power. Baseline tremor power gradually decreased over the course of 18 stimulation trials. During the last trial, compared with the control trial, the reduction rate of tremor power was 42.17 ± 3.09%. The dominant tremor frequency could be modulated more efficiently by phase-locked closed-loop stimulation. The tremor power was equally reduced by open- and closed-loop stimulation. Peripheral nerve stimulation significantly affects tremor, and stimulation parameters need to be optimized to modulate tremor metrics. Clinical Impact: This preliminary study lays the foundation for future studies that will evaluate the efficacy of the proposed closed-loop peripheral nerve stimulation method in a larger group of patients with kinetic tremor.


Ribavirin treatment of experimental respiratory syncytial viral infection. A controlled double-blind study in young adults.
The effect of ribavirin aerosol on experimental respiratory syncytial virus (RSV) infection was evaluated in a double-blind controlled study of 16 young adult volunteers. Two days after intranasal inoculation with RSV, half of the subjects were treated with a small-particle aerosol of ribavirin and half with placebo for a total of 12 hours each day for three days. Seven of eight placebo-treated and six of eight ribavirin-treated subjects became infected. Viral shedding was diminished in the ribavirin-treated group. The proportion of infected volunteers still shedding virus on days 6 through 9 was significantly less than in the placebo-treated group. Ribavirin appeared to have no effect on minor upper respiratory tract signs, but systemic complaints and fever occurred significantly less often in the ribavirin-treated group. Ribavirin aerosol therapy was well tolerated and produced no significant changes in pulmonary function test results or signs of toxicity. This suggests that such therapy might be further evaluated in infants with RSV lower respiratory tract disease.


State of the art and recommendations. Kangaroo mother care: application in a high-tech environment.
Since Kangaroo Mother Care (KMC) was developed in Colombia in the 1970s, two trends in clinical application emerged. In low-income settings, the original KMC modelis implemented. This consists of continuous (24 h/day; 7 days/week) and prolonged mother/parent-infant skin-to-skin contact; early discharge with the infant in the kangaroo position; (ideally) exclusive breastfeeding and, adequate follow up. In affluent settings, intermittent KMC with sessions of one or a few hours skin-to-skin contact for a limited period is common. As a result of the increasing evidence of the benefits of KMC for both infants and families in all intensive care settings, KMC in a high-tech environment was chosen as the topic for the first European Conference on KMC, and the clinical implementation of the KMC modelin all types of settings was discussed at the 7th International Workshop on KMC Kangaroo Mother Care protocols in high-tech Neonatal Intensive Care Units (NICU) should specify criteria for initiation, kangaroo position, transfer to/from KMC, transport in kangaroo position, kangaroo nutrition, parents'role, modification of the NICU environment, performance of care in KMC, and KMCin case of infant instability. Implementation of the original KMC method, with continuous skin-to-skin contact whenever possible, is recommended for application in high-tech environments, although scientific evaluation should continue.