Cost-effectiveness of changes in alcohol taxation in Denmark: a modelling study.
Excessive alcohol consumption is a public health problem in many countries including Denmark, where 6% of the burden of disease is due to alcohol consumption, according to the new estimates from the Global Burden of Disease 2010 study. Pricing policies, including tax increases, have been shown to effectively decrease the level of alcohol consumption. We analysed the cost-effectiveness of three different scenarios of changed taxation of alcoholic beverages in Denmark (20% and 100% increase and 10% decrease). The lifetime health effects are estimated as the difference in disability-adjusted life years between a Danish population that continues to drink alcohol at current rates and an identical population that changes their alcohol consumption due to changes in taxation. Calculation of cost offsets related to treatment of alcohol-related diseases and injuries, was based on health care system costs from Danish national registers. Cost-effectiveness was evaluated by calculating cost-effectiveness ratios (CERs) compared to current practice. The two scenarios of 20% and 100% increased taxation could avert 20,000 DALY and 95,500 DALY respectively, and yield cost savings of -€119 million and -€575 million, over the life time of the Danish population. Both scenarios are thus cost saving. The tax decrease scenario would lead to 10,100 added DALY and an added cost of €60 million. For all three interventions the health effects build up and reach their maximum around 15-20 years after implementation of the tax change. Our results show that decreased taxation will lead to an increased burden of disease and related increases in health care costs, whereas both a doubling of the current level of alcohol taxation and a scenario where taxation is only increased by 20% can be cost-saving ways to reduce alcohol related morbidity and mortality. Our results support the growing evidence that population strategies are cost-effective and should be considered for policy making and prevention of alcohol abuse.


Climate-driven population divergence in sex-determining systems.
Sex determination is a fundamental biological process, yet its mechanisms are remarkably diverse. In vertebrates, sex can be determined by inherited genetic factors or by the temperature experienced during embryonic development. However, the evolutionary causes of this diversity remain unknown. Here we show that live-bearing lizards at different climatic extremes of the species' distribution differ in their sex-determining mechanisms, with temperature-dependent sex determination in lowlands and genotypic sex determination in highlands. A theoretical model parameterized with field data accurately predicts this divergence in sex-determining systems and the consequence thereof for variation in cohort sex ratios among years. Furthermore, we show that divergent natural selection on sex determination across altitudes is caused by climatic effects on lizard life history and variation in the magnitude of between-year temperature fluctuations. Our results establish an adaptive explanation for intra-specific divergence in sex-determining systems driven by phenotypic plasticity and ecological selection, thereby providing a unifying framework for integrating the developmental, ecological and evolutionary basis for variation in vertebrate sex determination.


Current options for the treatment of idiopathic thrombocytopenic purpura.
Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease characterized by low platelets and bleeding. Platelet autoantibodies result in accelerated platelet destruction by the reticuloendothelial cells in the spleen and liver, overwhelming the compensatory capability of the bone marrow to increase platelet production. The goal of treatment for patients with ITP is to raise the platelet count to high enough levels to prevent bleeding using the least toxic therapy, recognizing the generally benign nature of the illness. Corticosteroids, intravenous immune globulin, and splenectomy remain mainstays of treatment; however, newer therapies including rituximab and the thrombopoietin receptor agonists are remodeling conventional treatment algorithms. Immune suppressant medications and cytotoxic drugs continue to be used in patients with severe and chronic refractory ITP with some success; however, estimates of the effect of these and other treatments are limited by the lack of randomized trials using clinical end points. In this article, treatments for ITP are reviewed with a focus on their mechanism of action and the best available evidence from clinical studies. A move towards early aggressive therapy may alter the natural history of this self-perpetuating illness.


Keemei: cloud-based validation of tabular bioinformatics file formats in Google Sheets.
Bioinformatics software often requires human-generated tabular text files as input and has specific requirements for how those data are formatted. Users frequently manage these data in spreadsheet programs, which is convenient for researchers who are compiling the requisite information because the spreadsheet programs can easily be used on different platforms including laptops and tablets, and because they provide a familiar interface. It is increasingly common for many different researchers to be involved in compiling these data, including study coordinators, clinicians, lab technicians and bioinformaticians. As a result, many research groups are shifting toward using cloud-based spreadsheet programs, such as Google Sheets, which support the concurrent editing of a single spreadsheet by different users working on different platforms. Most of the researchers who enter data are not familiar with the formatting requirements of the bioinformatics programs that will be used, so validating and correcting file formats is often a bottleneck prior to beginning bioinformatics analysis. We present Keemei, a Google Sheets Add-on, for validating tabular files used in bioinformatics analyses. Keemei is available free of charge from Google's Chrome Web Store. Keemei can be installed and run on any web browser supported by Google Sheets. Keemei currently supports the validation of two widely used tabular bioinformatics formats, the Quantitative Insights into Microbial Ecology (QIIME) sample metadata mapping file format and the Spatially Referenced Genetic Data (SRGD) format, but is designed to easily support the addition of others. Keemei will save researchers time and frustration by providing a convenient interface for tabular bioinformatics file format validation. By allowing everyone involved with data entry for a project to easily validate their data, it will reduce the validation and formatting bottlenecks that are commonly encountered when human-generated data files are first used with a bioinformatics system. Simplifying the validation of essential tabular data files, such as sample metadata, will reduce common errors and thereby improve the quality and reliability of research outcomes.


Child care demand and labor supply of young mothers over time.
This paper uses panel data from the National Longitudinal Survey of Youth (NLSY) to analyze jointly fertility, employment, and child care decisions of young women over time. As these young women age (from 21 to 25 years on average) they become increasingly likely to have young children, to be employed, and to use non-relative forms of child care. A multivariate analysis reveals that rising wage rates and changes in household structure are important determinants of these upward trends. Further analysis reveals a considerable amount of movement each year among states defined by the presence of young children, employment, and child care arrangement. Overall the young women in the NLSY can be characterized as being in a volatile stage of their lives, when many economic and demographic factors are changing. They appear to respond to these changes by altering their labor supply and child care behavior.


Control of molecular weight cut-off for immunoisolation by multilayering glycol chitosan-alginate polyion complex on alginate-based microcapsules.
Glycol chitosan is a positively charged polysaccharide which is water-soluble at pH 7.4, and is able to form a polyion complex (PIC) with anionic polymers, such as alginate. The authors attempt to develop a novel type of alginate-based microcapsule using this glycol chitosan for a islets-encapsulated bioartificial pancreas. The number of layers composed of glycol chitosan-alginate (GC-Alg) PIC were optimized, in order to cut off immunoglobulin transport and to protect encapsulated islets from the host immune reaction, and the transport characteristics were evaluated of glucose, bovine serum albumin (BSA) and gamma-globulin. To add mechanical stability to the microcapsule, calcium ions, which crosslinked the alginate polymers close to the interface between core Ca-alginate and multilayered membrane, were partially substituted with barium ions after the formation of multilayered Ca-alginate gel beads. The partition coefficients of BSA and gamma-globulin were decreased with the increasing number of layers. The immunoisolation was achieved against gamma-globulin with four layers of the GC-Alg PIC membrane, while BSA could permeate the membrane. The four-layered Ba-alginate gel bead had a good permeability for glucose, giving a diffusion coefficient corresponding to 80% of that in pure water. Insulin secretion from the islets in the four-layered Ba-alginate microcapsule was satisfactorily observed with the fractional stimulation ratio of 2.17. This result indicates that the encapsulated islets maintained their viability even after encapsulation. It was, thus, shown that the Ba-alginate microcapsule with four layers of the GC-Alg PIC membrane is promising as the microencapsulation material for a bioartificial pancreas.


Biobehavioral Factors That Shape Nutrition in Low-Income Populations: A Narrative Review.
Although evidence exists for an association between income level and diet quality, a causal relationship has not been established. A number of studies found that the price of nutritious food and the time cost to prepare foods are economically driven reasons for this relationship. However, in addition to economic constraints, low-income individuals and families face a number of additional challenges linked with food choice, eating behaviors, and diet-related chronic conditions that contribute to diet quality and health. Low-income individuals have a higher burden of employment-, food-, and housing-related insecurity that threaten the livelihood of their household. Poverty and exposure to these insecurities are hypothesized to activate biobehavioral and psychological mechanisms-endocrine, immune, and neurologic systems-that influence food choice and consumption. Examples of biobehavioral and psychological factors that influence diet are stress, poor sleep, and diminished cognitive capacity. High levels of stress, poor sleep, and cognitive overload compound the challenges of economic constraints, creating a mentality of scarcity that leads to poor diet quality.


Efficacy of low level laser therapy on wound healing in patients with chronic diabetic foot ulcers-a randomised control trial.
Foot ulcers are serious complications of Diabetes Mellitus (DM) and are known to be resistant to conventional treatment. They may herald severe complications if not treated wisely. Electromagnetic radiations in the form of photons are delivered to the ulcers in laser form to stimulate healing. This study was conducted to evaluate the efficacy of Low Level Laser Therapy (LLLT) in diabetic ulcer healing dynamics. To determine mean percentage reduction of wound area in study and control groups. KLES Dr. Prabhakar Kore Hospital and Medical Research Centre, Belgaum. Randomized-Control Study. A total of 68 patients with Type 2 DM having Meggitt-Wagner Grade I foot ulcers of atleast more than 4 weeks duration, less than 6 × 6 cm(2) with negative culture were studied. Patients were randomized into two groups of 34 each. Patients in study group received LLLT with conventional therapy and those in control group were treated with conventional therapy alone. Healing or percentage reduction in ulcer area over a period of 15 days after commencement of treatment was recorded. Unpaired Student T Test and Mann Whitney U test. Mean age of the patients was 50.94 years in control group and 54.35 years in study group (p = 0.065). There was no significant difference between control and study group with respect to mean FBS and HbA1c levels (p > 0.05), suggesting no biochemical differences between two groups. Initial ulcer area was 2608.03 mm(2) in study group and 2747.17 mm(2) in control group (p = 0.361). Final ulcer area was 1564.79 mm(2) in study group and 2424.75 mm(2) in control group (p = 0.361). Percentage ulcer area reduction was 40.24 ± 6.30 mm(2) in study group and 11.87 ± 4.28 mm(2) in control group (p < 0.001, Z = 7.08). Low Level Laser Therapy is beneficial as an adjunct to conventional therapy in the treatment of diabetic foot ulcers (DFU).


Predisposing factors, incidence and mortality of pneumothorax in neonates.
Incidence, risk factors, morbidity and mortality of pneumothorax in neonates vary widely. We aimed to evaluate characteristics, predisposing factors and associated primary lung conditions of pneumothorax in neonates. Neonates diagnosed to have pneumothoraces in a neonatal unit of university teaching hospital between May 2006 and August 2008 were studied. Pneumothorax was defined as accumulation of air in the pleural cavity as confirmed by chest radiograph. A total of 25 neonates with pneumothorax were studied. Among them, 32% were inborn, 62% were male and 52% were term neonates. Mean birth weight and median gestation were 2336 g and 37 weeks, respectively. Incidence among inborn neonates was 0.27% and among term and preterm, 0.13% and 0.79%, respectively. Incidence among Neonatal Intensive Care Unit admissions was 1.86%. Ten pneumothoraces occurred in neonates receiving ventilation with an incidence of 1.85%. Incidence of pneumothorax among ventilated neonates was not significantly different from nonventilated (P=0.8). About 84% of pneumothorax occurred within 48 hours of life. Pneumothorax was unilateral in 84% and more common on right side. Underlying pulmonary pathology was observed in 72% and included hyaline membrane disease (HMD) in 40%, meconium aspiration syndrome (MAS) in 24% and pneumonia in 8%. Mean intrapleural drainage was 2.5 days and 9 neonates died. Incidence of pneumothorax was similar to reports in the literature and higher among preterm than term neonates. HMD and MAS were common underlying lung conditions for neonatal pneumothorax. Incidence among ventilated neonates was lower than other reports.


Local hybrid functionals with orbital-free mixing functions and balanced elimination of self-interaction error.
The recently introduced density overlap regions indicator (DORI) [P. de Silva and C. Corminboeuf, J. Chem. Theory Comput. 10(9), 3745-3756 (2014)] is a density-dependent scalar field revealing regions of high density overlap between shells, atoms, and molecules. In this work, we exploit its properties to construct local hybrid exchange-correlation functionals aiming at balanced reduction of the self-interaction error. We show that DORI can successfully replace the ratio of the von Weizsäcker and exact positive-definite kinetic energy densities, which is commonly used in mixing functions of local hybrids. Additionally, we introduce several semi-empirical parameters to control the local and global admixture of exact exchange. The most promising of our local hybrids clearly outperforms the underlying semi-local functionals as well as their global hybrids.


Optimization of bioprocess productivity based on metabolic-genetic network models with bilevel dynamic programming.
One of the main goals of metabolic engineering is to obtain high levels of a microbial product through genetic modifications. To improve the productivity of such a process, the dynamic implementation of metabolic engineering strategies has been proven to be more beneficial compared to static genetic manipulations in which the gene expression is not controlled over time, by resolving the trade-off between growth and production. In this work, a bilevel optimization framework based on constraint-based models is applied to identify an optimal strategy for dynamic genetic and process level manipulations to increase productivity. The dynamic enzyme-cost flux balance analysis (deFBA) as underlying metabolic network model captures the network dynamics and enables the analysis of temporal regulation in the metabolic-genetic network. We apply our computational framework to maximize ethanol productivity in a batch process with Escherichia coli. The results highlight the importance of integrating the genetic level and enzyme production and degradation processes for obtaining optimal dynamic gene and process manipulations.


Burden of Invasive Staphylococcus aureus Infections in Hospitalized Infants.
Staphylococcus aureus is a frequent cause of infection in hospitalized infants. These infections are associated with increased mortality and morbidity and longer hospital stays, but data on the burden of S aureus disease in hospitalized infants are limited. To compare demographics and mortality of infants with invasive methicillin-resistant S aureus (MRSA) and methicillin-susceptible S aureus (MSSA), to determine the annual proportion of S aureus infections that were MRSA, and to contrast the risk of death after an invasive MRSA infection with the risk after an invasive MSSA infection. Multicenter retrospective study of a large, nationally representative cohort at 348 neonatal intensive care units managed by the Pediatrix Medical Group. Participants were 3888 infants with an invasive S aureus infection who were discharged from calendar year 1997 through calendar year 2012. Invasive S aureus infection. The incidence of invasive S aureus infections, as well as infant characteristics and mortality after MRSA or MSSA infection. The 3888 infants had 3978 invasive S aureus infections (2868 MSSA and 1110 MRSA). The incidence of invasive S aureus infection was 44.8 infections per 10,000 infants. The yearly proportion of invasive infections caused by MRSA increased from calendar year 1997 through calendar year 2006 and has moderately decreased since then. Infants with invasive MRSA or MSSA infections had similar gestational ages and birth weights. Invasive MRSA infections occurred more often at a younger postnatal age. For infants with available mortality data, more infants with invasive MSSA infections (n = 237) died before hospital discharge than infants with invasive MRSA infections (n = 110). The proportions of infants who died after invasive MSSA and MRSA infections were similar at 237 of 2474 (9.6%) and 110 of 926 (11.9%), respectively (P = .05). The adjusted risk of death before hospital discharge was similar after invasive MSSA and MRSA infections (risk ratio, 1.19; 95% CI, 0.96-1.49). The risks of death at 7 and 30 days after invasive infection were similar between infants with invasive MSSA infection and infants with invasive MRSA infection. Infant mortality after invasive MRSA and MSSA infections is similar, but MSSA causes more infections and more deaths in infants than MRSA. Measures to prevent S aureus infection should include MSSA in addition to MRSA.


Beyond Chelation: EDTA Tightly Binds Taq DNA Polymerase, MutT and dUTPase and Directly Inhibits dNTPase Activity.
EDTA is commonly used as an efficient chelator of metal ion enzyme cofactors. It is highly soluble, optically inactive and does not interfere with most chemicals used in standard buffers making EDTA a common choice to generate metal-free conditions for biochemical and biophysical investigations. However, the controversy in the literature on metal-free enzyme activities achieved using EDTA or by other means called our attention to a putative effect of EDTA beyond chelation. Here, we show that EDTA competes for the nucleotide binding site of the nucleotide hydrolase dUTPase by developing an interaction network within the active site similar to that of the substrate. To achieve these findings, we applied kinetics and molecular docking techniques using two different dUTPases. Furthermore, we directly measured the binding of EDTA to dUTPases and to two other dNTPases, the Taq polymerase and MutT using isothermal titration calorimetry. EDTA binding proved to be exothermic and mainly enthalpy driven with a submicromolar dissociation constant considerably lower than that of the enzyme:substrate or the Mg:EDTA complexes. Control proteins, including an ATPase, did not interact with EDTA. Our findings indicate that EDTA may act as a selective inhibitor against dNTP hydrolyzing enzymes and urge the rethinking of the utilization of EDTA in enzymatic experiments.


Reconstruction of partially occluded objects encoded in three-dimensional scenes by using digital holograms.
We propose a task-specific digital holographic capture system for three-dimensional scenes, which can reduce the amount of data sent from the camera system to the receiver and can effectively reconstruct partially occluded objects. The system requires knowledge of the object of interest, but it does not require a priori knowledge of either the occlusion or the distance the object is from the camera. Subwindows of the camera-plane Fresnel field are digitally propagated to reveal different perspectives of the scene, and these are combined to overcome the unknown foreground occlusions. The nature of the occlusions and the effect of subwindows are analyzed thoroughly by using the Wigner distribution function. We demonstrate that a careful combination of reconstructions from subwindows can reveal features that are not apparent in a reconstruction from the whole hologram. We provide results by using optically captured digital holograms of real-world objects and simulated occlusions.


Inflammatory aspects of epileptogenesis: contribution of molecular inflammatory mechanisms.
Epilepsy is a chronic neurological disease characterised with seizures. The aetiology of the most generalised epilepsies cannot be explicitly determined and the seizures are pronounced to be genetically determined by disturbances of receptors in central nervous system. Besides, neurotransmitter distributions or other metabolic problems are supposed to involve in epileptogenesis. Lack of adequate data about pharmacological agents that have antiepileptogenic effects point to need of research on this field. Thus, in this review, inflammatory aspects of epileptogenesis has been focussed via considering several concepts like role of immune system, blood-brain barrier and antibody involvement in epileptogenesis. We conducted an evidence-based review of the literatures in order to evaluate the possible participation of inflammatory processes to epileptogenesis and also, promising agents which are effective to these processes. We searched PubMed database up to November 2015 with no date restrictions. In the present review, 163 appropriate articles were included. Obtained data suggests that inflammatory processes participate to epileptogenesis in several ways like affecting fibroblast growth factor-2 and tropomyosin receptor kinase B signalling pathways, detrimental proinflammatory pathways [such as the interleukin-1 beta (IL-1β)-interleukin-1 receptor type 1 (IL-1R1) system], mammalian target of rapamycin pathway, microglial activities, release of glial inflammatory proteins (such as macrophage inflammatory protein, interleukin 6, C-C motif ligand 2 and IL-1β), adhesion molecules that are suggested to function in signalling pathways between neurons and microglia and also linkage between these molecules and proinflammatory cytokines. The literature research indicated that inflammation is a part of epileptogenesis. For this reason, further studies are necessary for assessing agents that will be effective in clinical use for therapeutic treatment of epileptogenesis.


Acclimation of microalgae to wastewater environments involves increased oxidative stress tolerance activity.
A wastewater environment can be particularly toxic to eukaryotic microalgae. Microalgae can adapt to these conditions but the specific mechanisms that allow strains to tolerate wastewater environments are unclear. Furthermore, it is unknown whether the ability to acclimate microalgae to tolerate wastewater is an innate or species-specific characteristic. Six different species of microalgae (Chlamydomonas debaryana, Chlorella luteoviridis, Chlorella vulgaris, Desmodesmus intermedius, Hindakia tetrachotoma and Parachlorella kessleri) that had never previously been exposed to wastewater conditions were acclimated over an 8-week period in secondary-treated municipal wastewater. With the exception of C. debaryana, acclimation to wastewater resulted in significantly higher growth rate and biomass productivity. With the exception of C. vulgaris, total chlorophyll content was significantly increased in all acclimated strains, while all acclimated strains showed significantly increased photosynthetic activity. The ability of strains to acclimate was species-specific, with two species, C. luteoviridis and P. kessleri, able to acclimate more efficiently to the stress than C. debaryana and D. intermedius. Metabolic fingerprinting of the acclimated and non-acclimated microalgae using Fourier transform infrared spectroscopy was able to differentiate strains on the basis of metabolic responses to the stress. In particular, strains exhibiting greater stress response and altered accumulation of lipids and carbohydrates could be distinguished. The acclimation to wastewater tolerance was correlated with higher accumulation of carotenoid pigments and increased ascorbate peroxidase activity.


Racial Differences in Mortality from Severe Acute Respiratory Failure in the United States, 2008-2012.
Racial disparities in health and healthcare in the United States are well documented and are increasingly recognized in acute critical illnesses such as sepsis and acute respiratory failure. Using a large, representative, U.S. nationwide database, we examined the hypothesis that black and Hispanic patients with severe acute respiratory failure have higher mortality rates when compared with non-Hispanic whites. This retrospective analysis used discharge data from the Agency for Healthcare Research and Quality, Nationwide Inpatient Sample, Healthcare Cost and Utilization Project, for the years 2008-2012. We identified hospitalizations with acute respiratory failure using a combination of International Classification of Diseases, Ninth Revision, Clinical Modification, codes. A logistic regression model was fitted to compare in-hospital mortality rates by race. After adjusting for sex, age, race, disease severity, type of hospital, and median household income for patient ZIP code, blacks had a greater odds ratio of in-hospital death when compared with non-Hispanic whites (odds ratio [OR], 1.13; 95% confidence interval [CI], 1.11-1.14; P < 0.001), and Hispanics also had a greater odds ratio of in-hospital death when compared with non-Hispanic whites (OR, 1.17; 95% CI, 1.15-1.19; P < 0.001), and so did Asian and Pacific Islanders (OR, 1.15; 95% CI, 1.12-1.18; P < 0.001) and Native Americans (OR, 1.08; 95% CI, 1.00-1.15; P < 0.001) when compared with non-Hispanic whites (OR, 1.0). Blacks, Hispanics, and other racial minorities in the United States were observed to exhibit significantly higher in-hospital sepsis-related respiratory failure associated mortality when compared with non-Hispanic whites.


Extreme weather and climate events with ecological relevance: a review.
Robust evidence exists that certain extreme weather and climate events, especially daily temperature and precipitation extremes, have changed in regard to intensity and frequency over recent decades. These changes have been linked to human-induced climate change, while the degree to which climate change impacts an individual extreme climate event (ECE) is more difficult to quantify. Rapid progress in event attribution has recently been made through improved understanding of observed and simulated climate variability, methods for event attribution and advances in numerical modelling. Attribution for extreme temperature events is stronger compared with other event types, notably those related to the hydrological cycle. Recent advances in the understanding of ECEs, both in observations and their representation in state-of-the-art climate models, open new opportunities for assessing their effect on human and natural systems. Improved spatial resolution in global climate models and advances in statistical and dynamical downscaling now provide climatic information at appropriate spatial and temporal scales. Together with the continued development of Earth System Models that simulate biogeochemical cycles and interactions with the biosphere at increasing complexity, these make it possible to develop a mechanistic understanding of how ECEs affect biological processes, ecosystem functioning and adaptation capabilities. Limitations in the observational network, both for physical climate system parameters and even more so for long-term ecological monitoring, have hampered progress in understanding bio-physical interactions across a range of scales. New opportunities for assessing how ECEs modulate ecosystem structure and functioning arise from better scientific understanding of ECEs coupled with technological advances in observing systems and instrumentation.This article is part of the themed issue 'Behavioural, ecological and evolutionary responses to extreme climatic events'.


Utilization of oil by-product from the purification process of conjugated linoleic Acid as feeding supplements for the accumulation of conjugated linoleic acid in the egg yolk.
This study was performed to examine an efficient way to use oil by-product which is obtained during the purification process of conjugated linoleic acid (CLA) from safflower oil. The CLA by-product (CBP) was fed to the laying hens to accumulate CLA in the egg yolk. Egg yolk samples from 3 different dietary groups were analyzed: control; CBP, 2%; and CLA-80 (which contained 80% free form of CLA), 2%. Fatty acids from the yolk were analyzed by gas chromatography, and the parameters of egg quality were determined. During the feeding trial, there was little alteration in the egg quality and egg production of the tested groups. The CLA contents in the test group with CBP, which contain CLA as glyceride form, significantly increased in the first week of feeding and had the highest level among the tested groups throughout the feeding trials, whereas the CLA group showed an increase in CLA contents from the third week. Moreover, the contents of total CLA isomers in CLA-80 and CBP oils were decreased by 12.92 and 0.51% after heat treatment in 48 h, and the contents of linoleic acid (LA) isomer in LA-80 (which contained 80% free form of LA) and LA by-product (LBP) oils were decreased by 19.63 and 5.78%, respectively. It was confirmed that a major form of fats in CBP was mainly esterified forms, whereas the fats in CLA-80 and LA-80 were composed of free fatty acids. There was no significant difference in the egg quality and production among the tested groups. It is meaningful that the oil by-product could be utilized as a source for functional foods of animal origin without influencing egg quality and production.


Lack of ADCC Breadth of Human Nonneutralizing Anti-HIV-1 Antibodies.
Anti-human immunodeficiency virus type 1 (HIV-1) nonneutralizing antibodies (nnAbs) capable of antibody-dependent cellular cytotoxicity (ADCC) have been identified as a protective immune correlate in the RV144 vaccine efficacy trial. Broadly neutralizing antibodies (bNAbs) also mediate ADCC in cell culture and rely on their Fc region for optimal efficacy in animal models. Here, we selected 9 monoclonal nnAbs and 5 potent bNAbs targeting various epitopes and conformations of the gp120/41 complex and analyzed the potency of the two types of antibodies to bind and eliminate HIV-1-infected cells in culture. Regardless of their neutralizing activity, most of the selected antibodies recognized and killed cells infected with two laboratory-adapted HIV-1 strains. Some nnAbs also bound bystander cells that may have captured viral proteins. However, in contrast to the bNAbs, the nnAbs bound poorly to reactivated infected cells from 8 HIV-positive individuals and did not mediate effective ADCC against these cells. The nnAbs also inefficiently recognize cells infected with 8 different transmitted-founder (T/F) isolates. The addition of a synthetic CD4 mimetic enhanced the binding and killing efficacy of some of the nnAbs in an epitope-dependent manner without reaching the levels achieved by the most potent bNAbs. Overall, our data reveal important qualitative and quantitative differences between nnAbs and bNAbs in their ADCC capacity and strongly suggest that the breadth of recognition of HIV-1 by nnAbs is narrow.IMPORTANCE Most of the anti-HIV antibodies generated by infected individuals do not display potent neutralizing activities. These nonneutralizing antibodies (nnAbs) with antibody-dependent cellular cytotoxicity (ADCC) have been identified as a protective immune correlate in the RV144 vaccine efficacy trial. However, in primate models, the nnAbs do not protect against simian-human immunodeficiency virus (SHIV) acquisition. Thus, the role of nnAbs with ADCC activity in protection from infection remains debatable. In contrast, broadly neutralizing antibodies (bNAbs) neutralize a large array of viral strains and mediate ADCC in cell culture. We analyzed the capacities of 9 nnAbs and 5 bNAbs to eliminate infected cells. We selected 18 HIV-1 strains, including virus reactivated from the reservoir of HIV-positive individuals and transmitted-founder isolates. We report that the nnAbs bind poorly to cells infected with primary HIV-1 strains and do not mediate potent ADCC. Overall, our data show that the breadth of recognition of HIV-1 by nnAbs is narrow.


Associations between environmental exposures and asthma control and exacerbations in young children: a systematic review.
To complete a systematic review of the literature describing associations between all environmental exposures and asthma symptoms and exacerbations in children up to mean age of 9 years. Systematic review. Reference lists of identified studies and reviews were searched for all articles published until November 2013 in electronic databases (MEDLINE, EMBASE, CINAHL, Cochrane Controls Trials Register). Studies were selected which examined a link between exposure to environmental factors and asthma symptoms and exacerbations where the study participants were children with a mean age of ≤9 years. Indices of asthma symptoms, control and exacerbations. A total of 27 studies were identified including eight where inhaled allergens and four where environmental tobacco smoke (ETS) were the exposures of interest. There was evidence that exposure to allergen, ETS, poor air quality and unflued heaters had a modest magnitude of effect (ORs between 2 and 3). There was also evidence of interactions observed between exposures such as allergen and ETS. Exposure to inhaled allergens, ETS, unflued heaters and poor air quality has an important effect on exacerbations in young children with asthma and should be minimised or, ideally, avoided. Better understanding of the effect of exposure to damp housing, air conditioning and dietary factors plus interactions between environmental exposures associated with exacerbations is required.


A case of scarred uterine rupture at 11 weeks of gestation having a uterine scar places induced by in vitro fertilization-embryo transfer.
Having a uterine scar places a woman at increased risk of complications, such as Cesarean scar pregnancy (CSP), uterine rupture, placenta previa, and placenta accreta, in subsequent pregnancies. We report a case of uterine rupture at 11 weeks of gestation in a woman with a previous Cesarean section. A 43-year-old woman with a history of abdominal myomectomy and Cesarean section had her pregnancy induced by in vitro fertilization with donor eggs. The exact location of the gestational sac was identified on her first day of hospitalization, and her pregnancy was suspected to be a CSP. The following day, the patient complained of sudden lower abdominal pain. A uterine scar rupture was diagnosed, and an emergency surgery was required. It may be that first-trimester screening could allow the early recognition of patients at risk for these perinatal complications.


Primary in vitro culture of porcine tracheal epithelial cells in an air-liquid interface as a model to study airway epithelium and Aspergillus fumigatus interactions.
Since the airway epithelium is the first tissue encountered by airborne fungal spores, specific models are needed to study this interaction. We developed such a model using primary porcine tracheal epithelial cells (PTEC) as a possible alternative to the use of primary human cells. PTEC were obtained from pigs and were cultivated in an air-liquid interface. Fluorescent brightener was employed to quantify the internalization of Aspergillus fumigatus conidia. Potential differences (Vt) and transepithelial resistances (Rt) after challenge with the mycotoxin, verruculogen, were studied. Primers for porcine inflammatory mediator genes IL-8, TNF-alpha, and GM-CSF were designed for a quantitative real-time PCR procedure to study cellular responses to challenges with A. fumigatus conidia. TEM showed the differentiation of ciliated cells and the PTEC ability to internalize conidia. The internalization rate was 21.9 ± 1.4% after 8 h of incubation. Verruculogen (10(-6) M) significantly increased Vt without having an effect on the Rt. Exposure of PTEC to live A. fumigatus conidia for 24 h induced a 10- to 40-fold increase in the mRNA levels of inflammatory mediator genes. PTEC behave similarly to human cells and are therefore a suitable alternative to human cells for studying interaction between airway epithelium and A. fumigatus.


Bio-inorganic effects of D-penicillamine in children and in the elderly.
The principle mechanisms of action of dimethylcysteine (D-penicillamine) are thiazolidine formation, sulphhydryl -disulphide exchange, chelation and superoxide dismutase-like activity; as a consequence, it can enter into many varied biological interactions. Thiazolidine formation with maturing collagen makes D-penicillamine potentially teratogenic; sulphhydryl -disulphide exchange allows the formation of a mixed disulphide with L-cysteine from the L-cystine dimer; chelation permits it to bind metals such as copper; and superoxide scavenging makes it theoretically capable of influencing the inflammatory response of specific cell systems. Not surprising, D-penicillamine is of value in the treatment of cystinuria, Wilson's disease, juvenile rheumatism, rheumatoid arthritis and various other conditions.


Extraction Orthodontic Treatment in an Autistic Patient.
Autism is a condition that restricts brain development. Early diagnostic criteria are as follows: less responsive to social stimuli, inability to develop natural speaking skills, lack of communication skills, and limited and repetitive behaviors. Orthodontic treatment is a challenging process for doctors in autistic patients. The clinical and cephalometric examination of a 17-year and 7-month-old autistic patient revealed class I malocclusion, increased vertical dimensions, proclined upper and lower incisors, and inconsistent lip closure. The treatment plan involved four premolar extractions from each quadrant. Upper and lower 1. premolar extraction with fixed treatment caused reduction in vertical dimensions and significant improvement in lip closure and incisor inclination. Due to the increased metabolic activity in these patients, treatment was completed in 13 months. As a result, autistic patients can be successfully treated. In this process, it is important to include communication as a major part of treatment.


Role of water in the catalytic cycle of E. coli dihydrofolate reductase.
Dihydrofolate reductase (DHFR) catalyzes the nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of 7,8-dihydrofolate (H2F) to 5,6,7,8-tetrahydrofolate (H4F). Because of the absence of any ionizable group in the vicinity of N5 of dihydrofolate it has been proposed that N5 could be protonated directly by a water molecule at the active site in the ternary complex of the Escherichia coli enzyme with cofactor and substrate. However, in the X-ray structures representing the Michaelis complex of the E. coli enzyme, a water molecule has never been observed in a position that could allow protonation of N5. In fact, the side chain of Met 20 blocks access to N5. Energy minimization reported here revealed that water could be placed in hydrogen bonding distance of N5 with only minor conformational changes. The r.m.s. deviation between the conformation of the M20 loop observed in the crystal structures of the ternary complexes and the conformation adopted after energy minimization was only 0.79 A. We performed molecular dynamics simulations to determine the accessibility by water of the active site of the Michaelis complex of DHFR. Water could access N5 relatively freely after an equilibration time of approximately 300 psec during which the side chain of Met 20 blocked water access. Protonation of N5 did not increase the accessibility by water. Surprisingly the number of near-attack conformations, in which the distance between the pro-R hydrogen of NADPH and C6 of dihydrofolate was less than 3.5 A and the angle between C4 and the pro-R hydrogen of NADPH and C6 of dihydrofolate was greater than 120 degrees, did not increase after protonation. However, when the hydride was transferred from NADPH to C6 of dihydrofolate before protonation, the side chain of Met 20 moved away from N5 after approximately 100 psec thereby providing water access. The average time during which water was found in hydrogen bonding distance to N5 was significantly increased. These results suggest that hydride transfer might occur early to midway through the reaction followed by protonation. Such a mechanism is supported by the very close contact between C4 of NADP+ and C6 of folate observed in the crystal structures of the ternary enzyme complexes, when the M20 loop is in its closed conformation.


Application of microchip assay system for the measurement of C-reactive protein in human saliva.
In the last decade, saliva has been advocated as a non-invasive alternative to blood as a diagnostic fluid. However, use of saliva has been hindered by the inadequate sensitivity of current methods to detect the lower salivary concentrations of many constituents compared to serum. Furthermore, developments in the areas related to lab-on-a-chip systems for saliva-based point of care diagnostics are complicated by the high viscosity and heterogeneous properties associated with this diagnostic fluid. The biomarker C-reactive protein (CRP) is an acute phase reactant and a well-accepted indicator of inflammation. Numerous clinical studies have established elevated serum CRP as a strong, independent risk factor for the development of cardiovascular disease (CVD). CVD has also been associated with oral infections (i.e. periodontal diseases) and there is evidence that systemic CRP may be a link between the two. Clinical measurements of CRP in serum are currently performed with "high sensitivity" CRP (hsCRP) enzyme-linked immunosorbent assay (ELISA) tests that lack the sensitivity for the detection of this important biomarker in saliva. Because measurement of salivary CRP may represent a novel approach for diagnosing and monitoring chronic inflammatory disease, including CVD and periodontal diseases, the objective of this study was to apply an ultra-sensitive microchip assay system for the measurement of CRP in human saliva. Here, we describe this novel lab-on-a-chip system in its first application for the measurement of CRP in saliva and demonstrate its advantages over the traditional ELISA method. The increased sensitivity of the microchip system (10 pg ml(-1) of CRP with 1000-fold dilution of saliva sample) is attributed to its inherent increased signal to noise ratio, resulting from the higher bead surface area available for antigen/antibody interactions and the high stringency washes associated with this approach. Finally, the microchip assay system was utilized in this study to provide direct experimental evidence that chronic periodontal disease may be associated with higher levels of salivary CRP.


Hippocampal glutamate-glutamine (Glx) in adults with Down syndrome: a preliminary study using in vivo proton magnetic resonance spectroscopy ((1)H MRS).
Down syndrome (DS), or trisomy 21, is one of the most common autosomal mutations. People with DS have intellectual disability (ID) and are at significantly increased risk of developing Alzheimer's disease (AD). The biological associates of both ID and AD in DS are poorly understood, but glutamate has been proposed to play a key role. In non-DS populations, glutamate is essential to learning and memory and glutamate-mediated excitotoxicity has been implicated in AD. However, the concentration of hippocampal glutamate in DS individuals with and without dementia has not previously been directly investigated. Proton magnetic resonance spectroscopy ((1)H MRS) can be used to measure in vivo the concentrations of glutamate-glutamine (Glx). The objective of the current study was to examine the hippocampal Glx concentration in non-demented DS (DS-) and demented DS (DS+) individuals. We examined 46 adults with DS (35 without dementia and 11 with dementia) and 39 healthy controls (HC) using (1)H MRS and measured their hippocampal Glx concentrations. There was no significant difference in the hippocampal Glx concentration between DS+ and DS-, or between either of the DS groups and the healthy controls. Also, within DS, there was no significant correlation between hippocampal Glx concentration and measures of overall cognitive ability. Last, a sample size calculation based on the effect sizes from this study showed that it would have required 6,257 participants to provide 80% power to detect a significant difference between the groups which would indicate that there is a very low likelihood of a type 2 error accounting for the findings in this study. Individuals with DS do not have clinically detectable differences in hippocampal Glx concentration. Other pathophysiological processes likely account for ID and AD in people with DS.


Evidence for a genetical contribution to non-smoking-related lung cancer.
The majority of lung cancers are smoking-related, with environmental and genetical factors contributing. The interplay between environmental and genetical contributions in non-smoking-related lung cancers is less clear. We analysed a population-based computerised genealogy resource linked to a state-wide cancer registry of lung cancer cases (n=5544) for evidence of a genetical contribution to lung cancer predisposition in smoking (n=1747) and non-smoking cases (n=784). Statistical methods were used to test for significant excess relatedness of cases and estimate relative risk (RR) in close and distant relatives of lung cancer cases. Significant excess relatedness was observed for all lung cancer cases (p<0.001) and for the subsets of smoking-related (p<0.001) and non-smoking-related (p<0.001) cases when all pairwise relationships were considered. Only the non-smoking-related subset of cases showed significant excess relatedness when close relationships were ignored (p=0.020). First-degree, second-degree, and fourth-degree relatives of non-smoking-related lung cancer cases had significantly elevated RR. An even higher elevated RR was observed for first-degree, second-degree, third-degree and fourth-degree relatives of smoking-related lung cancer cases. Non-smoking-related lung cancer cases show significant excess relatedness for close and distant relationships, providing strong evidence for a genetical contribution as well as an environmental contribution. Significant excess relatedness for only close family relationships in all lung cancer cases and in only smoking-related lung cancer cases implies environmental contribution. Additionally, the highest RR for lung cancer was observed in the relatives of smoking-related lung cancer, suggesting predisposition gene carriers who smoke are at highest risk for lung cancer. Screening and gene identification should focus on high-risk pedigrees.


Induced pluripotent stem cell line (PEIi003-A) derived from an apparently healthy male individual.
Induced pluripotent stem cells (iPSCs) are a useful tool to investigate pathomechanistic and cellular processes due to their differentiation potential into different somatic cell types in vitro. Here, we have generated iPSCs from an apparently healthy male individual using an integration-free reprogramming method. The resulting iPSCs are pluripotent and display a normal karyotype. Furthermore, we demonstrate that this iPSC line can be differentiated into all three germ layers.


Vibration induced nystagmus in normal subjects and in patients with dizziness. A videonystagmography study.
To analyze the incidence and characteristics of vibration-induced nystagmus in normal subjects and in patients with vertigo. This is a prospective analysis of the effect of vibration on several points of the skull in 38 normal subjects, 10 patients who had undergone labyrinthectomy and 125 consecutive patients with dizziness referred to a tertiary care center. Nystagmus was documented and its corresponding slow phase velocity measured with a videonystagmography system. In 81.6% of normal subjects and 80.8% of all patients, nystagmus could be provoked by stimulation of at least one of the points on the skull to which the vibrator was applied. In normals, however, no subject had nystagmus greater than 2.8 degrees s-1 whereas 35.2% of patients did. The value of the slow-phase velocity of vibration-induced nystagmus can be used to identify a sizeable proportion of patients with a vestibular disorders. Vibration-induced nystagmus is a frequent sign in patients with dizziness and can provide complimentary information about vestibular system function.


Effect of direct-to-consumer genetic tests on health behaviour and anxiety: a survey of consumers and potential consumers.
Direct-to-consumer (DTC) genetic tests can be purchased over the internet. Some companies claim to provide relative genetic risks for various diseases and thus encourage healthy behaviour. There are concerns that exposure to such information may actually discourage healthy behaviour or increase health anxiety. An online survey was conducted (n = 275). Respondents were composed of individuals who had purchased a DTC genetic test and received their results (consumers, n = 189), as well as individuals who were either awaiting test results or considering purchasing a test (potential consumers, n = 86). Consumers were asked if their health behaviour or health anxiety had changed after receiving their results. Respondents' current health behaviour and health anxiety were queried and compared. In total, 27.3 % of consumers claimed a change in health behaviour, all either positive or neutral, with no reported cessation of any existing health behaviour. A change in health anxiety was claimed by 24.6 % of consumers, 85.3 % of which were a reduction. Consumers had significantly better health behaviour scores than potential consumers (p = 0.02), with no significant difference in health anxiety. This study points towards an association between receipt of DTC genetic test results and increased adoption of healthy behaviours for a minority of consumers based on self-report, with more mixed results in relation to health anxiety.


How young people communicate risks of snowmobiling in northern Norway: a focus group study.
This study aims to understand how the risks of snowmobiling are communicated among northern Norwegian youths. Study design. A qualitative design with focus group interviews was chosen. Interviews centred on safety precautions and estimation of risks related to snowmobiling and driving patterns. Eighty-one students (31 girls and 50 boys) aged between 16 and 23 years from 8 high schools were interviewed in 17 focus groups that were segregated by gender. Interview data were analysed using qualitative content analysis. Boys and girls communicated differently about risks. Peer-group conformity appeared stronger among boys than girls. Boys did not spontaneously relate risks to their snowmobile activities, while girls did. Boys focused upon training, coping and balance between control and lack of control while driving. Girls talked about risks, were aware of risks and sought to avoid risky situations, in contrast to boys. Boys' risk communication in groups was about how to manage challenging situations. Their focus overall was on trying to maintain control while simultaneously testing their limits. Three risk categories emerged: those who drive as they ought to (mostly girls), those who occasionally take some risks (boys and girls) and those who are extreme risk-takers (a smaller number of boys). Perceptions of and communication about risk are related to gender, peer group and familiarity with risk-taking when snowmobiling. Northern Norwegian boys' driving behaviour highlights a specific need for risk reduction, but this must also draw upon factors such as acceptance of social and cultural codes and common sense related to snowmobiling.


Altitude training and haemoglobin mass from the optimised carbon monoxide rebreathing method determined by a meta-analysis.
To characterise the time course of changes in haemoglobin mass (Hbmass) in response to altitude exposure. This meta-analysis uses raw data from 17 studies that used carbon monoxide rebreathing to determine Hbmass prealtitude, during altitude and postaltitude. Seven studies were classic altitude training, eight were live high train low (LHTL) and two mixed classic and LHTL. Separate linear-mixed models were fitted to the data from the 17 studies and the resultant estimates of the effects of altitude used in a random effects meta-analysis to obtain an overall estimate of the effect of altitude, with separate analyses during altitude and postaltitude. In addition, within-subject differences from the prealtitude phase for altitude participant and all the data on control participants were used to estimate the analytical SD. The 'true' between-subject response to altitude was estimated from the within-subject differences on altitude participants, between the prealtitude and during-altitude phases, together with the estimated analytical SD. During-altitude Hbmass was estimated to increase by ∼1.1%/100 h for LHTL and classic altitude. Postaltitude Hbmass was estimated to be 3.3% higher than prealtitude values for up to 20 days. The within-subject SD was constant at ∼2% for up to 7 days between observations, indicative of analytical error. A 95% prediction interval for the 'true' response of an athlete exposed to 300 h of altitude was estimated to be 1.1-6%. Camps as short as 2 weeks of classic and LHTL altitude will quite likely increase Hbmass and most athletes can expect benefit.


Randomized comparison of biodegradable polymer sirolimus-eluting stents versus durable polymer everolimus-eluting stents for percutaneous coronary revascularization: rationale and design of the BIOSCIENCE trial.
Biodegradable polymers for release of antiproliferative drugs from metallic drug-eluting stents aim to improve long-term vascular healing and efficacy. We designed a large scale clinical trial to compare a novel thin strut, cobalt-chromium drug-eluting stent with silicon carbide-coating releasing sirolimus from a biodegradable polymer (O-SES, Orsiro; Biotronik, Bülach, Switzerland) with the durable polymer-based Xience Prime/Xpedition everolimus-eluting stent (EES) (Xience Prime/Xpedition stent, Abbott Vascular, IL) in an all-comers patient population. The multicenter BIOSCIENCE trial (NCT01443104) randomly assigned 2,119 patients to treatment with biodegradable polymer sirolimus-eluting stents (SES) or durable polymer EES at 9 sites in Switzerland. Patients with chronic stable coronary artery disease or acute coronary syndromes, including non-ST-elevation and ST-elevation myocardial infarction, were eligible for the trial if they had at least 1 lesion with a diameter stenosis >50% appropriate for coronary stent implantation. The primary end point target lesion failure (TLF) is a composite of cardiac death, target vessel myocardial infarction, and clinically driven target lesion revascularization within 12 months. Assuming a TLF rate of 8% at 12 months in both treatment arms and accepting 3.5% as a margin for noninferiority, inclusion of 2,060 patients would provide more than 80% power to detect noninferiority of the biodegradable polymer SES compared with the durable polymer EES at a 1-sided type I error of 0.05. Clinical follow-up will be continued through 5 years. The BIOSCIENCE trial will determine whether the biodegradable polymer SES is noninferior to the durable polymer EES with respect to TLF.


A prospective study on dietary acrylamide intake and the risk for breast, endometrial, and ovarian cancers.
Acrylamide is a probable human carcinogen formed during cooking of many common foods. Epidemiologic studies on acrylamide and breast cancer risk have been null; however, positive associations with ovarian and endometrial cancers have been reported. We studied acrylamide intake and risk for breast, endometrial, and ovarian cancers in a prospective cohort study. We assessed acrylamide intake among 88,672 women in the Nurses' Health Study using food frequency questionnaires administered every 4 years. Between 1980 and 2006, we identified 6,301 cases of invasive breast cancer, 484 cases of invasive endometrial adenocarcinoma, and 416 cases of epithelial ovarian cancer. We used Cox proportional hazards models to study the association between acrylamide and cancer risk. We found no association between acrylamide intake and breast cancer overall or according to estrogen and progesterone receptor status. We found an increased risk for endometrial cancer among high acrylamide consumers (adjusted relative risk for highest versus lowest quintile = 1.41; 95% CI, 1.01-1.97; P for trend = 0.03). We observed a nonsignificant suggestion of increased risk for ovarian cancer overall (relative risk, 1.25; 95% CI, 0.88-1.77; P trend = 0.12), with a significantly increased risk for serous tumors (relative risk, 1.58; 95% CI, 0.99-2.52; P trend = 0.04). Associations did not differ by smoking status. We observed no association between acrylamide and breast cancer. Risk for endometrial cancer and possibly ovarian cancer was greater among high acrylamide consumers. This is the second prospective study to report positive associations with endometrial and ovarian cancers. These associations should be further evaluated to inform public health policy.


Real-time probing of structural dynamics by interaction between chromophores.
We present an investigation of structural dynamics in excited-state cations probed in real-time by femtosecond time-resolved ion photofragmentation spectroscopy. From photoelectron spectroscopy data on 1,3-dibromopropane we conclude that the pump pulse ionizes the molecule, populating an excited electronic state of the radical cation. In this state a coherent torsional vibration of the bromomethylene groups with a period of 700 fs is started and probed by photoinduced fragmentation of the molecular cation. The vibrational coherence dephases with the decay of the excited state to the ground state of the cation in 1.6 ps. The real-time probing of the excited-state dynamics is made possible by exploiting the interaction between the two bromine chromophores and its dependence on molecular conformation. This experiment therefore illustrates the applicability of the concept of probing ultrafast molecular dynamics using the intramolecular interaction between two chromophores.


EMMPRIN regulates β1 integrin-mediated adhesion through Kindlin-3 in human melanoma cells.
EMMPRIN is known to promote tumor invasion through extracellular matrix (ECM) degradation. Here we report that EMMPRIN can regulate melanoma cell adhesion to the ECM through an interaction with β1 integrin involving kindlin-3. In this study, EMMPRIN knockdown in the human melanoma cell line M10 using siRNA decreased cell invasion and significantly increased cell adhesion and spreading. A morphological change from a round to a spread shape was observed associated with enhanced phalloidin-labelled actin staining. In situ proximity ligation assay and co-immunoprecipitation revealed that EMMPRIN silencing increased the interaction of β1 integrin with kindlin-3, a focal adhesion protein. This was associated with an increase in β1 integrin activation and a decrease in the phosphorylation of the downstream integrin kinase FAK. Moreover, the expression at both the transcript and protein level of kindlin-3 and of β1 integrin was inversely regulated by EMMPRIN. EMMPRIN did not regulate either talin expression or its interaction with β1 integrin. These results are consistent with our in vivo demonstration that EMMPRIN inhibition increased β1 integrin activation and its interaction with kindlin-3. To conclude, these findings reveal a new role of EMMPRIN in tumor cell migration through ß1 integrin/kindlin-3-mediated adhesion pathway.


Dyadic incongruence in chronic heart failure: Implications for patient and carer psychological health and self-care.
To examine whether chronic heart failure patient-carer dyads who disagree about the division of illness management tasks (incongruent) experience poorer psychosocial health and self-care, than those who agree (congruent). Informal carers often assist patients with chronic heart failure in the complex management of their illness, but little is known about how relationship dynamics may affect psychosocial health. A prospective cross-sectional study was adopted with a purposeful sample of 25 chronic heart failure patient-carer dyads residing in Australia. Data were collected via mail-out questionnaires. Dyads were classified as congruent or incongruent using the Heart Failure Care Assessment Scale. Depression, anxiety, stress and quality of life were assessed in patients and carers. Additionally, self-care and relationship quality were assessed in patients; and burden and esteem were assessed in carers. Differences in congruent and incongruent patient and carer outcomes were examined. Dyads were predominantly spousal and around a third demonstrated incongruence. No significant differences were found between congruent (n = 16) and incongruent (n = 9) dyads, although patients in incongruent dyads tended to have been diagnosed more recently. In chronic heart failure patient-carer dyads incongruence exists even for patients with relatively mild chronic heart failure symptoms. These findings indicate that dyadic incongruence in illness management might not affect high-functioning chronic heart failure heart failure patients or their carers. Given the prevalence of dyadic incongruence and the possibility of further negative outcomes with disease progression, it is important to examine factors such as length of time since diagnosis or type of carer relationship. By implementing self-care education and management strategies that focus on the dyad, rather than the individual, nurses have the potential to improve both patient and carer outcomes.


The Snail repressor positions Notch signaling in the Drosophila embryo.
The maternal Dorsal nuclear gradient initiates the differentiation of the mesoderm, neurogenic ectoderm and dorsal ectoderm in the precellular Drosophila embryo. Each tissue is subsequently subdivided into multiple cell types during gastrulation. We have investigated the formation of the mesectoderm within the ventral-most region of the neurogenic ectoderm. Previous studies suggest that the Dorsal gradient works in concert with Notch signaling to specify the mesectoderm through the activation of the regulatory gene sim within single lines of cells that straddle the presumptive mesoderm. This model was confirmed by misexpressing a constitutively activated form of the Notch receptor, Notch(IC), in transgenic embryos using the eve stripe2 enhancer. The Notch(IC) stripe induces ectopic expression of sim in the neurogenic ectoderm where there are low levels of the Dorsal gradient. sim is not activated in the ventral mesoderm, due to inhibition by the localized zinc-finger Snail repressor, which is selectively expressed in the ventral mesoderm. Additional studies suggest that the Snail repressor can also stimulate Notch signaling. A stripe2-snail transgene appears to induce Notch signaling in 'naïve' embryos that contain low uniform levels of Dorsal. We suggest that these dual activities of Snail, repression of Notch target genes and stimulation of Notch signaling, help define precise lines of sim expression within the neurogenic ectoderm.


Tie2cre-induced inactivation of the miRNA-processing enzyme Dicer disrupts invariant NKT cell development.
MicroRNAs (miRNAs) are a class of evolutionarily conserved small noncoding RNAs that are increasingly being recognized as important regulators of gene expression. The ribonuclease III enzyme Dicer is essential for the processing of miRNAs. CD1d-restricted invariant natural killer T (iNKT) cells are potent regulators of diverse immune responses. The role of Dicer-generated miRNAs in the development and function of immune regulatory iNKT cells is unknown. Here, we generated a mouse strain with a tissue-specific disruption of Dicer, and showed that lack of miRNAs after the deletion of Dicer by Tie2-Cre (expressed in hematopoietic cells and endothelial cells) interrupted the development and maturation of iNKT cells in the thymus and significantly decreased the number of iNKT cells in different immune organs. Thymic and peripheral iNKT cell compartments were changed in miRNA-deficient mice, with a significantly increased frequency of CD4(+)CD8(+) iNKT cells in the thymus and a significantly decreased frequency of CD4(+) iNKT cells in the spleen. MiRNA-deficient iNKT cells display profound defects in alpha-GalCer-induced activation and cytokine production. Bone marrow (BM) from miRNA-deficient mice poorly reconstituted iNKT cells compared to BM from WT mice. Also, using a thymic iNKT cell transfer model, we found that iNKT cell homeostasis was impaired in miRNA-deficient recipient mice. Our data indicate that miRNAs expressed in hematopoietic cells and endothelial cells are potent regulators of iNKT cell development, function, and homeostasis.


Monosaccharide inhibition of cytotoxic T-cell function: demonstration of clone-specific effects.
A range of monosaccharides has been tested for their capacity to influence the induction and effector function of alloreactive cytotoxic T (Tc) cells. Strain-specific differences in the capacity of monosaccharides to inhibit Tc cell induction have been demonstrated. Monosaccharides can also inhibit effector function of target cell lysis, but this could only be demonstrated by assessing the effect of sugars added to limiting dilution cultures of alloantigen-stimulated T cells. B10.A(4R) anti-BALB/c Tc cells have been reproducibly inhibited by D-glucosamine and D-galactosamine, as well as D-galacturonic acid, at both the induction and effector phases of the Tc cell response. Analysis of monosaccharide inhibition of cytotoxicity in limiting dilution cultures has confirmed that D-glucosamine is the most effective inhibitor of B10.A(4R) anti-BALB/c Tc cells, while D-galactosamine and D-galacturonic acid inhibit cytotoxicity in only some limiting dilution wells. Analysis of several B10.A(4R) anti-BALB/c Tc cell clones has revealed at least two different 'clone-specific' patterns of inhibition by D-glucose, D-glucuronic acid and D-galacturonic acid. Since Tc cell recognition of antigen is generally specific for class I major histocompatibility complex (MHC) antigens, this data implicates a role for MHC-associated carbohydrate structures expressed by target cells in T-lymphocyte interactions with antigen.


Minocycline for the treatment of mental health and neurological conditions: study protocol of a systematic review and meta-analysis.
Due to the anti-inflammatory, antioxidant and anti-apoptotic properties of minocycline, clinical trials have evaluated the potential of this drug to treat several psychiatric and neurological disorders, including major depressive disorder, schizophrenia, bipolar disorder, stroke and amyotrophic lateral sclerosis. This protocol proposes a systematic review (and potential meta-analysis) that aims to identify and critically evaluate randomised controlled trials of minocycline for treating psychiatric and neurological disorders. PubMed, Embase, Cochrane Central Register of Controlled Clinical Trials, PsycINFO and Cumulative Index to Nursing and Allied Health Literature (CINAHL) will be used to identify randomised controlled trials that used minocycline to treat psychiatric and neurological disorders. Double-blind, randomised, controlled, clinical trials of participants aged 18 years or older and written in English will be included in the review. Data will be extracted by two independent reviewers. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines will be followed and the Cochrane Collaboration's 'Risk of Bias' tool will be used to assess the risk of bias in all studies included in the systematic review. The Grading of Recommendations, Assessment, Development and Evaluation system will be used to access the overall quality of the level of evidence of the studies. If sufficient evidence is identified, a meta-analysis will be conducted using the standardised mean difference approach and reported with 95% CIs. Heterogeneity of evidence will be evaluated using the I2 model. This systematic review will evaluate only published data; therefore, ethical approval is not required. The systematic review will be published in a peer-reviewed journal and presented at relevant research conferences. CRD42020153292.


Relationships of age and axis I diagnoses in victims of completed suicide: a psychological autopsy study.
Psychiatric illness is a potent risk factor for suicide, rates of which differ markedly with age. The purpose of this study was to examine whether the psychiatric diagnoses of suicide victims vary predictably with age. DSM-III-R axis I diagnoses of 141 persons aged 21 to 92 years who had completed suicide were established by the psychological autopsy method. Multiple logistic regression analyses were used to determine whether age, gender, or their interaction predicted the presence of specific disorders. One or more axis I conditions were diagnosable in 90.1% of the suicide victims. Substance use disorders were most frequent, followed by mood disorders and primary psychotic illness. Younger age at death was a significant predictor of substance abuse or dependence and primary psychoses, while older age predicted major mood disorders. Comorbidity of substance use and mood disorders was common. Among victims with substance abuse or dependence, older age at death predicted major depression; among victims with mood disorders, younger age at death predicted comorbid substance abuse or dependence. The distribution of psychiatric illnesses in suicide victims differs across the life course. Age-related patterns of addictive and psychotic disorders echo their prevalence in the general population. In contrast, the relationship between age and mood disorders among suicide victims is distinctly different from that of the general population. These findings suggest that risk for suicide increases with age in individuals with major affective illness. Depressed elderly men are particular targets for suicide prevention strategies.


Assessment of NER solutions against the first and second CALBC Silver Standard Corpus.
Competitions in text mining have been used to measure the performance of automatic text processing solutions against a manually annotated gold standard corpus (GSC). The preparation of the GSC is time-consuming and costly and the final corpus consists at the most of a few thousand documents annotated with a limited set of semantic groups. To overcome these shortcomings, the CALBC project partners (PPs) have produced a large-scale annotated biomedical corpus with four different semantic groups through the harmonisation of annotations from automatic text mining solutions, the first version of the Silver Standard Corpus (SSC-I). The four semantic groups are chemical entities and drugs (CHED), genes and proteins (PRGE), diseases and disorders (DISO) and species (SPE). This corpus has been used for the First CALBC Challenge asking the participants to annotate the corpus with their text processing solutions. All four PPs from the CALBC project and in addition, 12 challenge participants (CPs) contributed annotated data sets for an evaluation against the SSC-I. CPs could ignore the training data and deliver the annotations from their genuine annotation system, or could train a machine-learning approach on the provided pre-annotated data. In general, the performances of the annotation solutions were lower for entities from the categories CHED and PRGE in comparison to the identification of entities categorized as DISO and SPE. The best performance over all semantic groups were achieved from two annotation solutions that have been trained on the SSC-I.The data sets from participants were used to generate the harmonised Silver Standard Corpus II (SSC-II), if the participant did not make use of the annotated data set from the SSC-I for training purposes. The performances of the participants' solutions were again measured against the SSC-II. The performances of the annotation solutions showed again better results for DISO and SPE in comparison to CHED and PRGE. The SSC-I delivers a large set of annotations (1,121,705) for a large number of documents (100,000 Medline abstracts). The annotations cover four different semantic groups and are sufficiently homogeneous to be reproduced with a trained classifier leading to an average F-measure of 85%. Benchmarking the annotation solutions against the SSC-II leads to better performance for the CPs' annotation solutions in comparison to the SSC-I.


Induction of Phosphoenolpyruvate Carboxykinase (PEPCK) during Acute Acidosis and Its Role in Acid Secretion by V-ATPase-Expressing Ionocytes.
Vacuolar-Type H(+)-ATPase (V-ATPase) takes the central role in pumping H(+) through cell membranes of diverse organisms, which is essential for surviving acid-base fluctuating lifestyles or environments. In mammals, although glucose is believed to be an important energy source to drive V-ATPase, and phosphoenolpyruvate carboxykinase (PEPCK), a key enzyme for gluconeogenesis, is known to be activated in response to acidosis, the link between acid secretion and PEPCK activation remains unclear. In the present study, we used zebrafish larva as an in vivo model to show the role of acid-inducible PEPCK activity in glucose production to support higher rate of H(+) secretion via V-ATPase, by utilizing gene knockdown, glucose supplementation, and non-invasive scanning ion-selective electrode technique (SIET). Zebrafish larvae increased V-ATPase-mediated acid secretion and transiently expression of Pck1, a zebrafish homolog of PEPCK, in response to acid stress. When pck1 gene was knocked down by specific morpholino, the H(+) secretion via V-ATPase decreased, but this effect was rescued by supplementation of glucose into the yolk. By assessing changes in amino acid content and gene expression of respective enzymes, glutamine and glutamate appeared to be the major source for replenishment of Krebs cycle intermediates, which are subtracted by Pck1 activity. Unexpectedly, pck1 knockdown did not affect glutamine/glutamate catalysis, which implies that Pck1 does not necessarily drive this process. The present study provides the first in vivo evidence that acid-induced PEPCK provides glucose for acid-base homeostasis at an individual level, which is supported by rapid pumping of H(+) via V-ATPase at the cellular level.


Competition-Level Differences on the Lower Quarter Y-Balance Test in Baseball Players.
Decreased performance in dynamic balance has previously been associated with a history of ulnar collateral ligament injury in baseball players. Previous research on dynamic balance in soccer players has shown that test performance depends on competition level. However, dynamic balance has yet to be examined in baseball players. To understand normative values and determine differences in dynamic balance, as measured by the Lower Quarter Y-Balance Test, across competition levels in baseball players. Cross-sectional study. Preseason physical examinations. Dynamic balance was measured in 88 high school (HS), 78 collegiate (COL), and 90 professional (PRO) baseball players. All participants completed the Lower Quarter Y-Balance Test using the standard protocol. In unilateral stance, they reached with 1 foot in the anterior, posteromedial, and posterolateral directions. We calculated 1-way analyses of variance to compare performance, composite score, and reach asymmetry for each direction as well as the sum of the asymmetry values (P < .05). Composite score was calculated by averaging the maximum normalized reach scores. Reach asymmetry was determined by calculating bilateral differences in reach ability. In comparison with the HS and COL groups, the PRO players exhibited greater posteromedial (P < .01; effect size index [ESI]HS = 1.06, ESICOL = 0.95) and posterolateral reach (P < .01; ESIHS = 0.82, ESICOL = 0.84) as well as a greater composite score (P < .01; ESIHS = 0.60, ESICOL = 0.87). In contrast, HS baseball players exhibited increased anterior reach (P < .01; ESICOL = 0.60, ESIPRO = 0.39) compared with the COL and PRO cohorts. No significant differences in reach asymmetry were observed among groups. Lower extremity dynamic balance performance differed based on the baseball players' competition level. These baseline data may be helpful in identifying low-performing athletes who might benefit from neuromuscular interventions.


The "Bird's Eye" and "Upper Deck" Views in Hip Arthroscopy: Powerful Arthroscopic Perspectives for Acetabuloplasty.
Arthroscopic acetabuloplasty involves trimming of bone from the acetabular rim. Although early techniques often involved detachment of the labrum prior to bone resection, recent studies have reported on acetabuloplasty without labral detachment. This method has the benefit of preserving the labro-osseous junction, but visualization of the acetabular rim may be more difficult. Compromised visualization can lead to incomplete resection and residual impingement. We describe an arthroscopic perspective called the "bird's eye" and "upper deck" views that facilitates optimal visualization of the acetabuloplasty without labral detachment.


Usefulness of contrast-enhanced transabdominal ultrasonography in the diagnosis of intraductal papillary mucinous tumors of the pancreas.
The differentiation of benign from malignant intraductal papillary mucinous tumors (IPMT) is often difficult even by various examination methods. We evaluated the qualitative and quantitative diagnostic ability of contrast-enhanced transabdominal ultrasonography (CE-US), mainly in differentiating benign from malignant tumors in patients with IPMT. There were 21 patients with IPMT who underwent CE-US and endoscopic ultrasonography (EUS). Surgery was performed in all 21 patients. Pathological findings were 4 with carcinoma and 17 with adenoma. CE-US was performed using a contrast agent (Levovist; Tanabe, Osaka, Japan) consisting of galactose microbubbles and a small (0.1%) admixture of palmitic acid, and the following items were evaluated by the following procedure. (1) Two reviewers with experienced sonographic and endosonographic ability evaluated CE-US images before and after contrast enhancement and classified the enhancement effects into three grades. In addition, the presence or absence of enhancement effects by CE-US was compared with that of mural nodules visualized by EUS. (2) In all 21 patients, changes in intensity after contrast enhancement were quantitatively measured using an HDI Lab. HDI Lab was provided by ATL (Philips; Bothell, WA) and these software tools rapidly quantify image characteristics within multiple ROI (regions of interest) and make comparisons between several areas or images. In both the early and late phases, the post-enhancement intensity, difference between pre- and post-enhancement intensity, and the percentage change ((post-enhancement value-pre-enhancement value)/pre-enhancement value) were compared between malignant and benign lesions, and the ability of CE-US to differentiate between benign and malignant lesions was evaluated in comparison with the ability of EUS to diagnose the degree of malignancy. (1) In both the early and the late phases, both reviewers observed enhancement effects in all 21 patients. And both reviewers observed mural nodules by EUS in all 21 patients. (2) In all 21 patients who underwent resection of IPMT, the intensity increased in both the early and late phases. When the patients with carcinoma were compared with those with adenoma, the post-enhancement intensity was significantly higher, and the difference between pre- and post-enhancement intensity and the percentage change in the early phase and the late phase was significantly more marked in the carcinoma group (p= 0.019, p= 0.002, p= 0.015, p= 0.012, and p= 0.039, respectively). CE-US was useful for qualitatively diagnosing tumor lesions in patients with IPMT. Moreover, quantitative changes in intensity can be a parameter for the differential diagnosis of benign and malignant tumors.


Time-to-event analysis for sports injury research part 1: time-varying exposures.
'How much change in training load is too much before injury is sustained, among different athletes?' is a key question in sports medicine and sports science. To address this question the investigator/practitioner must analyse exposure variables that change over time, such as change in training load. Very few studies have included time-varying exposures (eg, training load) and time-varying effect-measure modifiers (eg, previous injury, biomechanics, sleep/stress) when studying sports injury aetiology. To discuss advanced statistical methods suitable for the complex analysis of time-varying exposures such as changes in training load and injury-related outcomes. Time-varying exposures and time-varying effect-measure modifiers can be used in time-to-event models to investigate sport injury aetiology. We address four key-questions (i) Does time-to-event modelling allow change in training load to be included as a time-varying exposure for sport injury development? (ii) Why is time-to-event analysis superior to other analytical concepts when analysing training-load related data that changes status over time? (iii) How can researchers include change in training load in a time-to-event analysis? and, (iv) Are researchers able to include other time-varying variables into time-to-event analyses? We emphasise that cleaning datasets, setting up the data, performing analyses with time-varying variables and interpreting the results is time-consuming, and requires dedication. It may need you to ask for assistance from methodological peers as the analytical approaches presented this paper require specialist knowledge and well-honed statistical skills. To increase knowledge about the association between changes in training load and injury, we encourage sports injury researchers to collaborate with statisticians and/or methodological epidemiologists to carefully consider applying time-to-event models to prospective sports injury data. This will ensure appropriate interpretation of time-to-event data.


Endogenous non-retroviral RNA virus elements in mammalian genomes.
Retroviruses are the only group of viruses known to have left a fossil record, in the form of endogenous proviruses, and approximately 8% of the human genome is made up of these elements. Although many other viruses, including non-retroviral RNA viruses, are known to generate DNA forms of their own genomes during replication, none has been found as DNA in the germline of animals. Bornaviruses, a genus of non-segmented, negative-sense RNA virus, are unique among RNA viruses in that they establish persistent infection in the cell nucleus. Here we show that elements homologous to the nucleoprotein (N) gene of bornavirus exist in the genomes of several mammalian species, including humans, non-human primates, rodents and elephants. These sequences have been designated endogenous Borna-like N (EBLN) elements. Some of the primate EBLNs contain an intact open reading frame (ORF) and are expressed as mRNA. Phylogenetic analyses showed that EBLNs seem to have been generated by different insertional events in each specific animal family. Furthermore, the EBLN of a ground squirrel was formed by a recent integration event, whereas those in primates must have been formed more than 40 million years ago. We also show that the N mRNA of a current mammalian bornavirus, Borna disease virus (BDV), can form EBLN-like elements in the genomes of persistently infected cultured cells. Our results provide the first evidence for endogenization of non-retroviral virus-derived elements in mammalian genomes and give novel insights not only into generation of endogenous elements, but also into a role of bornavirus as a source of genetic novelty in its host.


Development of a negative selectable marker for Entamoeba histolytica.
Entamoeba histolytica is the causative agent of amebiasis and infects up to 10% of the world's population. The molecular techniques that have enabled the up- and down-regulation of gene expression rely on the transfection of stably maintained plasmids. While these have increased our understanding of Entamoeba virulence factors, the capacity to integrate exogenous DNA into genome, which would allow reverse genetics experiments, would be a significant advantage in the study of this parasite. The challenges presented by this organism include inability to select for homologous recombination events and difficulty to cure episomal plasmid DNA from transfected trophozoites. The later results in a high background of exogenous DNA, a major problem in the identification of trophozoites in which a bona fide genomic integration event has occurred. We report the development of a negative selection system based upon transgenic expression of a yeast cytosine deaminase and uracil phosphoribosyl transferase chimera (FCU1) and selection with prodrug 5-fluorocytosine (5-FC). The FCU1 enzyme converts non-toxic 5-FC into toxic 5-fluorouracil and 5-fluorouridine-5'-monophosphate. E. histolytica lines expressing FCU1 were found to be 30 fold more sensitive to the prodrug compared to the control strain.


Analysis of the DNA-binding activity of p53 mutants using functional protein microarrays and its relationship to transcriptional activation.
Sequence-specific DNA binding is the key function through which tumor suppressor p53 exerts transactivation of the downstream target genes, often being impaired in cancer cells by mutations in the TP53 gene. Functional protein microarray technology enables a high-throughput parallel analysis of protein properties within one experiment under the same conditions. Using an array approach, we analyzed the DNA binding activity of wild type p53 protein and of 49 variants. Our results show significant differences in the binding properties between the p53 mutants. The C-terminal mutant R337C displayed the highest DNA binding activity on the array. However, the same mutant showed only a partial activation in the reporter gene assay and almost no activation of downstream target genes after transfection of expression vector into cells lacking endogenous p53. These observations demonstrate that DNA binding itself is not sufficient for activating the p53 target genes in at least some of the p53 mutants and, therefore, in vitro studies might not always reflect in vivo conditions.


Analysis of the mouse embryonic stem cell regulatory networks obtained by ChIP-chip and ChIP-PET.
Genome-wide approaches have begun to reveal the transcriptional networks responsible for pluripotency in embryonic stem (ES) cells. Chromatin Immunoprecipitation (ChIP) followed either by hybridization to a microarray platform (ChIP-chip) or by DNA sequencing (ChIP-PET), has identified binding targets of the ES cell transcription factors OCT4 and NANOG in humans and mice, respectively. These studies have provided an outline of the transcriptional framework involved in maintaining pluripotency. Recent evidence with comparing multiple technologies suggests that expanding these datasets using different platforms would be a useful resource for examining the mechanisms underlying pluripotency regulation. We have now identified OCT4 and NANOG genomic targets in mouse ES cells by ChIP-chip and provided the means to compare these data with previously reported ChIP-PET results in mouse ES cells. We have mapped the sequences of OCT4 and NANOG binding events from each dataset to genomic coordinates, providing a valuable resource to facilitate a better understanding of the ES cell regulatory circuitry. Interestingly, although considerable differences are observed in OCT4 and NANOG occupancy as identified by each method, a substantial number of targets in both datasets are enriched for genes that have known roles in cell-fate specification and that are differentially expressed upon Oct4 or Nanog knockdown. This study suggests that each dataset is a partial representation of the overall ES cell regulatory circuitry, and through integrating binding data obtained by ChIP-chip and ChIP-PET, the methods presented here provide a useful means for integrating datasets obtained by different techniques in the future.


The histone H3K79 methyltransferase Dot1L is essential for mammalian development and heterochromatin structure.
Dot1 is an evolutionarily conserved histone methyltransferase specific for lysine 79 of histone H3 (H3K79). In Saccharomyces cerevisiae, Dot1-mediated H3K79 methylation is associated with telomere silencing, meiotic checkpoint control, and DNA damage response. The biological function of H3K79 methylation in mammals, however, remains poorly understood. Using gene targeting, we generated mice deficient for Dot1L, the murine Dot1 homologue. Dot1L-deficient embryos show multiple developmental abnormalities, including growth impairment, angiogenesis defects in the yolk sac, and cardiac dilation, and die between 9.5 and 10.5 days post coitum. To gain insights into the cellular function of Dot1L, we derived embryonic stem (ES) cells from Dot1L mutant blastocysts. Dot1L-deficient ES cells show global loss of H3K79 methylation as well as reduced levels of heterochromatic marks (H3K9 di-methylation and H4K20 tri-methylation) at centromeres and telomeres. These changes are accompanied by aneuploidy, telomere elongation, and proliferation defects. Taken together, these results indicate that Dot1L and H3K79 methylation play important roles in heterochromatin formation and in embryonic development.


Childhood Maltreatment and Lifetime Suicidal Behaviors Among New Soldiers in the US Army: Results From the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS).
Understanding suicide risk is a priority for the US military. We aimed to estimate associations of childhood maltreatment with pre-enlistment suicidal behaviors in new Army soldiers. Cross-sectional survey data from 38,237 soldiers reporting for basic training from April 2011 through November 2012 were analyzed. Scales assessing retrospectively reported childhood abuse and neglect were derived and subjected to latent class analysis, which yielded 5 profiles: No Maltreatment, Episodic Emotional Maltreatment, Frequent Emotional/Physical Maltreatment, Episodic Emotional/Sexual Abuse, and Frequent Emotional/Physical/Sexual Maltreatment. Discrete-time survival analysis was used to estimate associations of maltreatment profiles with suicidal behaviors (assessed with a modified Columbia-Suicide Severity Rating Scale), adjusting for sociodemographics and mental disorders. Nearly 1 in 5 new soldiers was classified as experiencing childhood maltreatment. Relative to No Maltreatment, all multivariate maltreatment profiles were associated (P values < .001) with elevated odds of lifetime suicidal ideation (adjusted odds ratios [AORs] = 3.10-4.93), plan (AORs = 3.75-10.77), attempt (AORs = 3.60-15.95), and onset of plan among those with ideation (AORs = 1.40-3.10). Several profiles also predicted attempts among those with plans (AORs = 2.01-2.47), and Frequent Emotional/Physical/Sexual Maltreatment predicted unplanned attempts among ideators (AOR = 5.32). Adjustment for mental disorders attenuated but did not eliminate these associations. Childhood maltreatment is strongly associated with suicidal behavior among new soldiers, even after adjusting for intervening mental disorders. Among soldiers with lifetime ideation, certain maltreatment profiles are associated with elevated odds of subsequently planning and/or attempting suicide. Focus on childhood maltreatment might reveal avenues for risk reduction among new soldiers.


The nucleotide sequence of the PRI1 gene related to DNA primase in Saccharomyces cerevisiae.
The PRI1 gene of Saccharomyces cerevisiae encodes for the p48 polypeptide of DNA primase. We have determined the nucleotide sequence of a 1,965 bp DNA fragment containing the PRI1 locus. The entire coding sequence of the gene lies within an open reading frame, and there are 409 amino acids in the single polypeptide protein if translation is assumed to start at the first ATG in this frame. The 5' and 3' end-points of PRI1 mRNA have been determined by S1 mapping and primer extension analysis. The primary structure and the codon usage of PRI1 suggest that this essential gene is poorly expressed in yeast cells.


The Correlation and Accuracy of Glucose Levels between Interstitial Fluid and Venous Plasma by Continuous Glucose Monitoring System.
Clinical experience with the continuous glucose monitoring systems (CGMS) is limited in Korea. The objective of this study is to evaluate the accuracy of the CGMS and the correlation between interstitial fluid and venous plasma glucose level in Korean healthy male subjects. Thirty-two subjects were served with glucose solution contained same amount of test food's carbohydrate and test foods after separate overnight fasts. CGMS was performed over 3 days during hopitalization for each subjects. Venous plasma glucose measurements were carried out during 4 hours (0, 0.25, 0.5, 0.75, 1, 2, 4 hours) just before and after glucose solution and test food load. The performance of the CGMS was evaluated by comparing its readings to those obtained at the same time by the hexokinase method using the auto biochemistry machine (Hitachi 7600-110). Also, correlations between glucose recorded with CGMS and venous plasma glucose value were examined. CGMS slightly underestimated the glucose value as compared with the venous plasma glucose level (16.3 ± 22.2 mg/dL). Correlation between CGMS and venous plasma glucose values throughout sensor lifetime is 0.73 (regression analysis: slope = 1.08, intercept = 8.38 mg/dL). Sensor sensitivity can deteriorate over time, with correlations between venous blood glucose and CGMS values dropping from 0.77 during 1st day to 0.65 during 2nd and 3rd day. The accuracy of data provided by CGMS may be less than expected. CGMS sensor sensitivity is decreased with the passage of time. But, from this study, CGMS can be used for glucose variability tendency monitoring conveniently to the Korean.


The effect of growth factor signaling on keratocytes in vitro and its relationship to the phases of stromal wound repair.
To determine the relationship between signaling by different growth factors and the phases of corneal stromal wound repair. The authors hypothesize that the process involves sequential signaling, resulting first in proliferation and then in extracellular matrix (ECM) synthesis. The effects of IGF-I, TGF-beta1, FGF-2, and PDGF on proliferation and ECM production by primary cultured bovine keratocytes were evaluated. DNA synthesis was determined by (3)H-thymidine incorporation, and maximal cell density was determined by measurement of DNA content. Relative levels of ECM components synthesized by keratocytes and secreted into the media were evaluated by (3)H-glycine incorporation into total ECM protein and collagen, by (3)H-glucosamine incorporation into chondroitin sulfate, keratan sulfate, and hyaluronan, and by Western blotting with antibodies specific to procollagen types Iota and IotaIotaIota. FGF-2 stimulated the highest level of proliferation and the lowest level of glycosaminoglycan synthesis and inhibited the synthesis of collagen types Iota and IotaIotaIota. IGF-I, in contrast, stimulated the lowest level of proliferation and the highest levels of collagen synthesis. PDGF and TGF-beta1 had intermediate effects on proliferation and collagen synthesis. Although FGF-2 inhibited collagen production, it could be restored by subsequent treatment with IGF-I, TGF-beta1, and PDGF. The results of this study showed that the level of proliferation induced by the growth factors was inversely related to the levels of collagen production. The authors suggest that FGF-2 initiates the hypercellular phase of corneal wound healing and that IGF-I and PDGF are involved in the restoration of a normal ECM.