Socio-demographic and trauma-related predictors of depression within eight weeks of motor vehicle collision in the AURORA study.
This is the first report on the association between trauma exposure and depression from the Advancing Understanding of RecOvery afteR traumA(AURORA) multisite longitudinal study of adverse post-traumatic neuropsychiatric sequelae (APNS) among participants seeking emergency department (ED) treatment in the aftermath of a traumatic life experience. We focus on participants presenting at EDs after a motor vehicle collision (MVC), which characterizes most AURORA participants, and examine associations of participant socio-demographics and MVC characteristics with 8-week depression as mediated through peritraumatic symptoms and 2-week depression. Eight-week depression prevalence was relatively high (27.8%) and associated with several MVC characteristics (being passenger v. driver; injuries to other people). Peritraumatic distress was associated with 2-week but not 8-week depression. Most of these associations held when controlling for peritraumatic symptoms and, to a lesser degree, depressive symptoms at 2-weeks post-trauma. These observations, coupled with substantial variation in the relative strength of the mediating pathways across predictors, raises the possibility of diverse and potentially complex underlying biological and psychological processes that remain to be elucidated in more in-depth analyses of the rich and evolving AURORA database to find new targets for intervention and new tools for risk-based stratification following trauma exposure.


Internal consistency and factor structure of the Portuguese version of the Liebowitz Social Anxiety Scale among alcoholic patients.
Liebowitz Social Anxiety Scale is an instrument used to evaluate the severity of social phobia. It has been widely used in different contexts and cultures, presenting variable psychometric properties. The objective of this article is to investigate the internal consistency and the factor structure of this scale. In a sample of 300 alcoholic patients hospitalized in 3 mental clinics in Southern Brazil, 74 of them were social phobics (24.6%). The Structured Clinical Interview for DSM-IV-Axis I Disorders - Patient Edition, a semi-structured clinical interview based on DSM-IV, was used to check for the diagnosis of social phobia. The internal consistency was measured by Cronbach's alpha. Data were subjected to a factor analysis with the principal component method of parameter estimation. Questionnaire items loading at 0.35 or above were considered in the final factor solution. The coefficient of internal consistency was 0.95. All items showed corrected item-total correlation coefficient above 0.15, considered the minimum requested index. The factor analysis resulted in 5 dimensions which corresponded to 52.9% of the total variance. The five factors extracted were: factor I - speaking in a group, factor II - activity in public, factor III - social interaction with unknown person, factor IV - attitude of disagreement or disapproval and factor V - social interaction in leisure activity. The scale proved to be reliable and structurally valid instrument for use in a population of alcoholic patients. The possibility of screening for social phobia through the use of the instrument may be helpful in identifying probable cases of the disorder among alcoholics.


Impact of ocean warming on sustainable fisheries management informs the Ecosystem Approach to Fisheries.
An integrated ecosystem model including fishing and the impact of rising temperatures, relative to species' thermal ranges, was used to assess the cumulative effect of future climate change and sustainable levels of fishing pressure on selected target species. Historically, important stocks of cod and whiting showed declining trends caused by high fisheries exploitation and strong top-down control by their main predators (grey seals and saithe). In a no-change climate scenario these stocks recovered under sustainable management scenarios due to the cumulative effect of reduced fishing and predation mortalities cascading through the food-web. However, rising temperature jeopardised boreal stenothermal species: causing severe declines in grey seals, cod, herring and haddock, while eurythermal species were not affected. The positive effect of a higher optimum temperature for whiting, in parallel with declines of its predators such as seals and cod, resulted in a strong increase for this stock under rising temperature scenarios, indicating a possible change in the contribution of stocks to the overall catch by the end of the century. These results highlight the importance of including environmental change in the ecosystem approach to achieve sustainable fisheries management.


The home visit.
With the advent of effective home health programs, an increasing proportion of medical care is being delivered in patients' homes. Since the time before World War II, direct physician involvement in home health care has been minimal. However, patient preferences and key changes in the health care system are now creating an increased need for physician-conducted home visits. To conduct home visits effectively, physicians must acquire fundamental and well-defined attitudes, knowledge and skills in addition to an inexpensive set of portable equipment. "INHOMESSS" (standing for: immobility, nutrition, housing, others, medication, examination, safety, spirituality, services) is an easily remembered mnemonic that provides a framework for the evaluation of a patient's functional status and home environment. Expanded use of the telephone and telemedicine technology may allow busy physicians to conduct time-efficient "virtual" house calls that complement and sometimes replace in-person visits.


Mapping of ligand-binding cavities in proteins.
The complex interactions between proteins and small organic molecules (ligands) are intensively studied because they play key roles in biological processes and drug activities. Here, we present a novel approach to characterize and map the ligand-binding cavities of proteins without direct geometric comparison of structures, based on Principal Component Analysis of cavity properties (related mainly to size, polarity, and charge). This approach can provide valuable information on the similarities and dissimilarities, of binding cavities due to mutations, between-species differences and flexibility upon ligand-binding. The presented results show that information on ligand-binding cavity variations can complement information on protein similarity obtained from sequence comparisons. The predictive aspect of the method is exemplified by successful predictions of serine proteases that were not included in the model construction. The presented strategy to compare ligand-binding cavities of related and unrelated proteins has many potential applications within protein and medicinal chemistry, for example in the characterization and mapping of "orphan structures", selection of protein structures for docking studies in structure-based design, and identification of proteins for selectivity screens in drug design programs.


The fungal T-2 toxin alters the activation of primary macrophages induced by TLR-agonists resulting in a decrease of the inflammatory response in the pig.
T-2 toxin is known to be one of the most toxic trichothecene mycotoxins. Exposure to T-2 toxin induces many hematologic and immunotoxic disorders and is involved in immuno-modulation of the innate immune response. The objective of this work was to evaluate the effects of T-2 toxin on the activation of macrophages by different agonists of Toll-like receptors (TLR) using an in vitro model of primary porcine alveolar macrophages (PAM). Cytotoxic effects of T-2 toxin on PAM were first evaluated. An IC50 of 19.47 ± 0.9753 nM was determined for the cytotoxicity of T-2 toxin. A working concentration of 3 nM of T-2 toxin was chosen to test the effect of T-2 toxin on TLR activation; this dose was not cytotoxic and did not induce apoptosis as demonstrated by Annexin/PI staining. A pre-exposure of macrophages to 3 nM of T-2 toxin decreased the production of inflammatory mediators (IL-1 beta, TNF-alpha, nitric oxide) in response to LPS and FSL1, TLR4 and TLR2/6 agonists respectively. The decrease of the pro-inflammatory response is associated with a decrease of TLR mRNA expression. By contrast, the activation of TLR7 by ssRNA was not modulated by T-2 toxin pre-treatment. In conclusion, our results suggest that ingestion of low concentrations of T-2 toxin affects the TLR activation by decreasing pattern recognition of pathogens and thus interferes with initiation of inflammatory immune response against bacteria and viruses. Consequently, mycotoxins could increase the susceptibility of humans and animals to infectious diseases.


Promoting the psychological well-being of Italian youth: a pilot study of a high school mental health program.
School is potentially one of the most important and effective agencies for the promotion of mental health. For this reason, in Italy, the Mental Health Department of The National Health Institute has developed an intervention based on a structured handbook. The aim of this intervention is to promote the psychological well-being of the students. In this study, we have evaluated the efficacy of this intervention through a quasi-experimental study design of four classes (two were control) of secondary education, including 79 students aged 14 to 16 years (15.35 ± 0.68). Assessments were administered before and after the intervention. The results showed improvement in perceived self-efficacy (p ≤ .001), emotional coping (p = .003), and overall well-being (p < .05). The students' perception of usefulness was also increased (p < .05); the intervention successfully promoted the idea of life as a continuous process of learning, in change and growth (p < .05). The intervention was effective despite some limitations described by authors related to a lack of involvement of relatives and the team teachers, as well as the absence of homework; however, the adoption of a program promoting life skills, problem solving, and goal definition training is recommended with the use of a revised handbook.


Intragenesis and cisgenesis as alternatives to transgenic crop development.
One of the major concerns of the general public about transgenic crops relates to the mixing of genetic materials between species that cannot hybridize by natural means. To meet this concern, the two transformation concepts cisgenesis and intragenesis were developed as alternatives to transgenesis. Both concepts imply that plants must only be transformed with genetic material derived from the species itself or from closely related species capable of sexual hybridization. Furthermore, foreign sequences such as selection genes and vector-backbone sequences should be absent. Intragenesis differs from cisgenesis by allowing use of new gene combinations created by in vitro rearrangements of functional genetic elements. Several surveys show higher public acceptance of intragenic/cisgenic crops compared to transgenic crops. Thus, although the intragenic and cisgenic concepts were introduced internationally only 9 and 7 years ago, several different traits in a variety of crops have currently been modified according to these concepts. Five of these crops are now in field trials and two have pending applications for deregulation. Currently, intragenic/cisgenic plants are regulated as transgenic plants worldwide. However, as the gene pool exploited by intragenesis and cisgenesis are identical to the gene pool available for conventional breeding, less comprehensive regulatory measures are expected. The regulation of intragenic/cisgenic crops is presently under evaluation in the EU and in the US regulators are considering if a subgroup of these crops should be exempted from regulation. It is accordingly possible that the intragenic/cisgenic route will be of major significance for future plant breeding.


Plasma Hsp72 (HSPA1A) and Hsp27 (HSPB1) expression under heat stress: influence of exercise intensity.
Extracellular heat-shock protein 72 (eHsp72) expression during exercise-heat stress is suggested to increase with the level of hyperthermia attained, independent of the rate of heat storage. This study examined the influence of exercise at various intensities to elucidate this relationship, and investigated the association between eHsp72 and eHsp27. Sixteen male subjects cycled to exhaustion at 60% and 75% of maximal oxygen uptake in hot conditions (40°C, 50% RH). Core temperature, heart rate, oxidative stress, and blood lactate and glucose levels were measured to determine the predictor variables associated with eHsp expression. At exhaustion, heart rate exceeded 96% of maximum in both conditions. Core temperature reached 39.7°C in the 60% trial (58.9 min) and 39.0°C in the 75% trial (27.2 min) (P < 0.001). The rate of rise in core temperature was 2.1°C h(-1) greater in the 75% trial than in the 60% trial (P < 0.001). A significant increase and correlation was observed between eHsp72 and eHsp27 concentrations at exhaustion (P < 0.005). eHsp72 was highly correlated with the core temperature attained (60% trial) and the rate of increase in core temperature (75% trial; P < 0.05). However, no common predictor variable was associated with the expression of both eHsps. The similarity in expression of eHsp72 and eHsp27 during moderate- and high-intensity exercise may relate to the duration (i.e., core temperature attained) and intensity (i.e., rate of increase in core temperature) of exercise. Thus, the immuno-inflammatory release of eHsp72 and eHsp27 in response to exercise in the heat may be duration and intensity dependent.


Dysbiosis and compositional alterations with aging in the gut microbiota of patients with heart failure.
Emerging evidence has suggested a potential impact of gut microbiota on the pathophysiology of heart failure (HF). However, it is still unknown whether HF is associated with dysbiosis in gut microbiota. We investigated the composition of gut microbiota in patients with HF to elucidate whether gut microbial dysbiosis is associated with HF. We performed 16S ribosomal RNA gene sequencing of fecal samples obtained from 12 HF patients and 12 age-matched healthy control (HC) subjects, and analyzed the differences in gut microbiota. We further compared the composition of gut microbiota of 12 HF patients younger than 60 years of age with that of 10 HF patients 60 years of age or older. The composition of gut microbial communities of HF patients was distinct from that of HC subjects in both unweighted and weighted UniFrac analyses. Eubacterium rectale and Dorea longicatena were less abundant in the gut microbiota of HF patients than in that of HC subjects. Compared to younger HF patients, older HF patients had diminished proportions of Bacteroidetes and larger quantities of Proteobacteria. The genus Faecalibacterium was depleted, while Lactobacillus was enriched in the gut microbiota of older HF patients. These results suggest that patients with HF harbor significantly altered gut microbiota, which varies further according to age. New concept of heart-gut axis has a great potential for breakthroughs in the development of novel diagnostic and therapeutic approach for HF.


Low Pulse Pressure After Acute Ischemic Stroke is Associated With Unfavorable Outcomes: The Taiwan Stroke Registry.
Pulse pressure (PP) is related to cardiac function, arterial stiffness, fluid status, and vascular events. This study aimed to explore the prognostic role of PP upon admission in patients with acute ischemic stroke (AIS) based on a nation-wide stroke registry. We evaluated the association between PP upon admission and outcomes 3 months after a stroke in patients who had an AIS registered in the Taiwan Stroke Registry, including 56 academic and community hospitals between 2006 and 2013. Three months after the stroke, unfavorable outcomes were defined using a modified Rankin scale of 3 to 6. Of 33 530 patients (female, 40.6%; mean age, 68.8±13.3 years) who had an AIS, PP upon admission had a reverse J-curve association with an unfavorable outcome. After adjusting for clinical variables, including AIS subtypes, initial National Institutes of Health Stroke Scale, and systolic and diastolic blood pressure upon admission, a PP of <50 mm Hg was associated with unfavorable outcomes (P<0.0001). Compared with patients with a PP of 50 to 69 mm Hg, the odds ratios for unfavorable outcomes were 1.24 (95% CI, 1.14-1.36) with a PP of 30 to 49 mm Hg and 1.85 (95% CI, 1.50-2.28) with a PP of <30 mm Hg. Moreover, the prognostic impact of PP upon admission was similar across all AIS subtypes. Low PP upon admission was associated with unfavorable patient outcomes in AIS.


Patients' perceptions of medical students in a longitudinal family medicine clerkship.
Although educational characteristics of ambulatory clinical environments are becoming clearer, less is known concerning patient opinions about participating in medical student instruction in ambulatory settings. Such perceptions may have an important influence on recruitment and retention of community faculty. Surveys were administered to 121 patients seen by medical students during a longitudinal family medicine clerkship. The survey explored patients' opinions regarding the extent of direct student involvement in their care, students'competence, and patient feelings about participating in medical student instruction. Patients felt that students were highly involved in providing care and that they performed competently and professionally. Patients found participation in medical education enjoyable, not excessively time-consuming or disruptive, and believed that students' participation improved the quality of care they received. Patients in our family medicine clerkship do not have negative perceptions about their participation in medical student education. In fact, this study suggests that such participation may actually enhance patient satisfaction.


Human mesenchymal factors induce rat hippocampal- and human neural stem cell dependent oligodendrogenesis.
The generation of new oligodendrocytes is essential for adult brain repair in diseases such as multiple sclerosis. We previously identified the multifunctional p57kip2 protein as a negative regulator of myelinating glial cell differentiation and as an intrinsic switch of glial fate decision in adult neural stem cells (aNSCs). In oligodendroglial precursor cells (OPCs), p57kip2 protein nuclear exclusion was recently found to be rate limiting for differentiation to proceed. Furthermore, stimulation with mesenchymal stem cell (MSC)-derived factors enhanced oligodendrogenesis by yet unknown mechanisms. To elucidate this instructive interaction, we investigated to what degree MSC secreted factors are species dependent, whether hippocampal aNSCs respond equally well to such stimuli, whether apart from oligodendroglial differentiation also tissue integration and axonal wrapping can be promoted and whether the oligodendrogenic effect involved subcellular translocation of p57kip2. We found that CC1 positive oligodendrocytes within the hilus express nuclear p57kip2 protein and that MSC dependent stimulation of cultured hippocampal aNSCs was not accompanied by nuclear p57kip2 exclusion as observed for parenchymal OPCs after spontaneous differentiation. Stimulation with human MSC factors was observed to equally promote rat stem cell oligodendrogenesis, axonal wrapping and tissue integration. As forced nuclear shuttling of p57kip2 led to decreased CNPase- but elevated GFAP expression levels, this indicates heterogenic oligodendroglial mechanisms occurring between OPCs and aNSCs. We also show for the first time that dominant pro-oligodendroglial factors derived from human fetal MSCs can instruct human induced pluripotent stem cell-derived NSCs to differentiate into O4 positive oligodendrocytes.


Tele-emergency behavioural health in rural and underserved areas.
Challenges accessing behavioural health services in rural and underserved areas are compounded by severe shortages of behavioural health specialists, and difficulties placing patients. Tele-emergency (tele-ED) behavioural health is a promising solution for enhancing access to specialists and assisting in patient placement. This paper describes two tele-ED behavioural health models in the Midwest delivering mental- and substance use disorder services to rural and underserved adult populations. We performed an in-depth examination of two tele-ED behavioural health programmes and their consultation processes. We provide a retrospective case-control analysis of patient characteristics, patient diagnoses, and disposition status for each model. Data were collected from 19 spoke hospitals across the two programmes between November 2015 and December 2017. Tele-ED was activated in 15% of the Avera Health sample and 58% of the Union Hospital sample. This is primarily a reflection of the sample selection process in each model and how each programme is operationalised. Suicide and/or poisoning by drugs were the most frequent diagnoses followed by mood disorders. Rate of transfer to another inpatient facility was much higher for tele-ED cases than controls in both models. This paper describes how two distinct tele-ED behavioural health models operating in unique contexts address challenges in access and placement for patients in rural and underserved areas presenting to EDs with behavioural health conditions. The notable difference in disposition rates between cases and controls is indicative of the impact each model is having on care practices and processes.


Improved production of long-chain fatty acid in Escherichia coli by an engineering elongation cycle during fatty acid synthesis (FAS) through genetic manipulation.
The microbial biosynthesis of fatty acid of lipid metabolism, which can be used as precursors for the production of fuels of chemicals from renewable carbon sources, has attracted significant attention in recent years. The regulation of fatty acid biosynthesis pathways has been mainly studied in a model prokaryote, Escherichia coli. During the recent period, global regulation of fatty acid metabolic pathways has been demonstrated in another model prokaryote, Bacillus subtilis, as well as in Streptococcus pneumonia. The goal of this study was to increase the production of long-chain fatty acids by developing recombinant E. coli strains that were improved by an elongation cycle of fatty acid synthesis (FAS). The fabB, fabG, fabZ, and fabI genes, all homologous of E. coli, were induced to improve the enzymatic activities for the purpose of overexpressing components of the elongation cycle in the FAS pathway through metabolic engineering. The beta-oxoacyl-ACP synthase enzyme catalyzed the addition of acyl-ACP to malonyl-ACP to generate beta- oxoacyl-ACP. The enzyme encoded by the fabG gene converted beta-oxoacyl-ACP to beta-hydroxyacyl-ACP, the fabZ catalyzed the dehydration of beta-3-hydroxyacyl-ACP to trans-2-acyl-ACP, and the fabI gene converted trans-2- acyl-ACP to acyl-ACP for long-chain fatty acids. In vivo productivity of total lipids and fatty acids was analyzed to confirm the changes and effects of the inserted genes in E. coli. As a result, lipid was increased 2.16-fold higher and hexadecanoic acid was produced 2.77-fold higher in E. coli JES1030, one of the developed recombinants through this study, than those from the wild-type E. coli.


Raters Interpret Positively and Negatively Worded Items Similarly in a Quality of Life Instrument for Children.
Measurement invariance is an important assumption to meaningfully compare children's quality of life (QoL) between different raters (eg, children and parents) and across genders. Moreover, QoL instruments may combine using negatively and positively worded items-a common method to reduce response bias. However, the wording effects may have different levels of impact on different raters and genders. Our aim was to investigate the measurement invariance of Kid-KINDL, a commonly used QoL instrument, across genders and raters and to consider the wording effects simultaneously. Third to sixth graders (208 boys and 235 girls) completed the self-rated Kid-KINDL, and 1 parent each of 241 children completed the parent-rated Kid-KINDL. The wording effects were accounted for by correlated traits-uncorrelated methods model. The measurement invariance was examined using multigroup confirmatory factor analysis. Item loadings and item intercepts were invariant across gender and rater when we simultaneously accounted for the wording effects of Kid-KINDL. Our results suggest that Kid-KINDL could be used to compare QoL across gender and that parent-rated Kid-KINDL could be used to measure children's QoL. Specifically, the invariant factor loadings across child-rated and parent-rated Kid-KINDL suggest that the score weights in each item were the same for both children and parents (ie, the important items identified by the children are the same items identified by the parents). The invariant item intercepts suggest that both children and parents share the same threshold for each item. Based on the results, we tentatively recommend that each score of a parent-rated Kid-KINDL can stand for each child's QoL.


Dietary calcium and risk for prostate cancer: a case-control study among US veterans.
The objective of this study was to examine the association between calcium intake and prostate cancer risk. We hypothesized that calcium intake would be positively associated with lower risk for prostate cancer. We used data from a case-control study conducted among veterans between 2007 and 2010 at the Durham Veterans Affairs Medical Center. The study consisted of 108 biopsy-positive prostate cancer cases, 161 biopsy-negative controls, and 237 healthy controls. We also determined whether these associations differed for blacks and whites or for low-grade (Gleason score <7) and high-grade prostate cancer (Gleason score ≥7). We administered the Harvard food frequency questionnaire to assess diet and estimate calcium intake. We used logistic regression models to obtain odds ratios (ORs) and 95% confidence intervals (CIs). Intake of calcium from food was inversely related to risk for prostate cancer among all races in a comparison of cases and biopsy-negative controls (P = .05) and cases and healthy controls (P = .02). Total calcium was associated with lower prostate cancer risk among black men but not among white men in analyses of healthy controls. The highest tertile of calcium from food was associated with lower risk for high-grade prostate cancer in a comparison of high-grade cases and biopsy-negative controls (OR, 0.37; 95% CI, 0.15-0.90) and high-grade cases and healthy controls (OR, 0.38; 95% CI, 0.17-0.86). Calcium from food is associated with lower risk for prostate cancer, particularly among black men, and lower risk for high-grade prostate cancer among all men.


Familial leucine-sensitive hypoglycemia of infancy due to a dominant mutation of the beta-cell sulfonylurea receptor.
Familial leucine-sensitive hypoglycemia of infancy was described in 1956 as a condition in which symptomatic hypoglycemia was provoked by protein meals or the amino acid, leucine. The purpose of this study was to determine the genetic basis for hypoglycemia in a family diagnosed with leucine-sensitive hypoglycemia in 1960. Recently diagnosed family members showed a dominantly transmitted pattern of diazoxide-responsive hyperinsulinism (HI). However, they did not fit the characteristics of HI caused by glutamate dehydrogenase gene mutations, previously felt to explain leucine-sensitive hypoglycemia. Islet function was examined using acute insulin response (AIR) tests to calcium, leucine, glucose, and tolbutamide as well as oral protein tolerance tests. Five of five affected family members showed an abnormal positive calcium AIR, and two of five showed a positive leucine AIR. Protein-induced hypoglycemia was demonstrated in five of six affected subjects. Mutation analysis of four known HI genes (sulfonylurea receptor 1, Kir6.2, glutamate dehydrogenase, and glucokinase) in family members identified an R1353H missense mutation in exon 33 of SUR1. (86)Rb(+) efflux and electrophysiological studies of R1353H SUR1 coexpressed with wild-type Kir6.2 in COSm6 cells demonstrated partially impaired ATP-dependent potassium channel function. Leucine-sensitive hypoglycemia in this family was found to result from a dominantly expressed SUR1 mutation.


Regression analysis of properties of [Au(IPr)(CHR2)] complexes.
New [Au(IPr)(CHR2)] complexes have been synthesised through protonolysis reactions of [Au(IPr)(OH)] with moderately acidic substrates, CH2R2. An array of spectroscopic (IR and NMR), structural (X-ray), electronic (DFT) and experimental (reactivity) parameters was collected to quantify the variation in stereoelectronic properties of these new and previously reported [Au(IPr)(CHR2)] complexes. Variation of the R substituents on the carbanion ligands (CHR2-) was found to have a crucial impact on parameters characterising the resulting gold complexes. A regression analysis of both experimental and modelled parameters, guided by network analysis techniques, produced linear models that supported trends within the [Au(IPr)(CHR2)] complexes.


Factors Associated with Risk of Stroke-Associated Pneumonia in Patients with Dysphagia: A Systematic Review.
Dysphagia is associated with increased risk of stroke-associated pneumonia (SAP). However, it is unclear what other factors contribute to that risk or which measures may reduce it. This systematic review aimed to provide evidence on interventions and care processes associated with SAP in patients with dysphagia. Studies were screened for inclusion if they included dysphagia only patients, dysphagia and non-dysphagia patients or unselected patients that included dysphagic patients and evaluated factors associated with a recorded frequency of SAP. Electronic databases were searched from inception to February 2017. Eligible studies were critically appraised. Heterogeneity was evaluated using I2. The primary outcome was SAP. Eleven studies were included. Sample sizes ranged from 60 to 1088 patients. There was heterogeneity in study design. Measures of immunodepression are associated with SAP in dysphagic patients. There is insufficient evidence to justify screening for aerobic Gram-negative bacteria. Prophylactic antibiotics did not prevent SAP and proton pump inhibitors may increase risk. Treatment with metoclopramide may reduce SAP risk. Evidence that nasogastric tube (NGT) placement increases risk of SAP is equivocal. A multidisciplinary team approach and instrumental assessment of swallowing may reduce risk of pneumonia. Patients with impaired mobility were associated with increased risk. Findings should be interpreted with caution given the number of studies, heterogeneity and descriptive analyses. Several medical interventions and care processes, which may reduce risk of SAP in patients with dysphagia, have been identified. Further research is needed to evaluate the role of these interventions and care processes in clinical practice.


Relative social standing and suicide ideation among Kenyan males: the interpersonal theory of suicide in context.
The purpose of this study is to investigate the association between subjective social status and suicide ideation in a sample of young Kenyan men (age 18-34 years). Situating insights from the interpersonal theory of suicide within social determinants of health framework, we consider whether lower subjective social status predicts lower collective self-esteem (CSE), hopelessness, less meaning in life and more loneliness, and whether these characteristics mediate associations between subjective social status and suicide ideation. A community-based, semi-rural sample (n = 532) of young men, aged 18-34 years, was collected using a standardized questionnaire. The survey questionnaire included the following validated scale items: the short form of the Social and Emotional Loneliness Scale for Adults, CSE, Herth Hope Index, the Meaning in Life Questionnaire, and the Modified Scale for Suicide Ideation. Regression and mediation analyses were used to test hypotheses. Nearly 12% of respondents reported suicide ideation. Suicide ideation was significantly more common among survey respondents who reported lower subjective social standing. In the first of two mediation models, we found that lower CSE and more loneliness mediate the association between lower subjective social status and suicide ideation. In the second model, we found that respondents with lower CSE and more loneliness expressed lower hope and meaning in life, which also mediated pathways to suicide ideation. Findings show a novel synthesis of social determinants literature with the interpersonal theory of suicide. Suicide ideation, along with other mental and social outcomes, may figure more prominently than previously appreciated in the benefits of socio-economic equality. Those who do not participate equally in socio-economic development may be at greater risk of engaging in suicide ideation and behaviors. Suicide prevention research and programmatic responses should adopt a health equity perspective to ensure that prevention is targeted where people are more likely to engage in suicide ideation.


Imputation of genotypes from low density (50,000 markers) to high density (700,000 markers) of cows from research herds in Europe, North America, and Australasia using 2 reference populations.
Combining data from research herds may be advantageous, especially for difficult or expensive-to-measure traits (such as dry matter intake). Cows in research herds are often genotyped using low-density single nucleotide polymorphism (SNP) panels. However, the precision of quantitative trait loci detection in genome-wide association studies and the accuracy of genomic selection may increase when the low-density genotypes are imputed to higher density. Genotype data were available from 10 research herds: 5 from Europe [Denmark, Germany, Ireland, the Netherlands, and the United Kingdom (UK)], 2 from Australasia (Australia and New Zealand), and 3 from North America (Canada and the United States). Heifers from the Australian and New Zealand research herds were already genotyped at high density (approximately 700,000 SNP). The remaining genotypes were imputed from around 50,000 SNP to 700,000 using 2 reference populations. Although it was not possible to use a combined reference population, which would probably result in the highest accuracies of imputation, differences arising from using 2 high-density reference populations on imputing 50,000-marker genotypes of 583 animals (from the UK) were quantified. The European genotypes (n=4,097) were imputed as 1 data set, using a reference population of 3,150 that included genotypes from 835 Australian and 1,053 New Zealand females, with the remainder being males. Imputation was undertaken using population-wide linkage disequilibrium with no family information exploited. The UK animals were also included in the North American data set (n=1,579) that was imputed to high density using a reference population of 2,018 bulls. After editing, 591,213 genotypes on 5,999 animals from 10 research herds remained. The correlation between imputed allele frequencies of the 2 imputed data sets was high (>0.98) and even stronger (>0.99) for the UK animals that were part of each imputation data set. For the UK genotypes, 2.2% were imputed differently in the 2 high-density reference data sets used. Only 0.025% of these were homozygous switches. The number of discordant SNP was lower for animals that had sires that were genotyped. Discordant imputed SNP genotypes were most common when a large difference existed in allele frequency between the 2 imputed genotype data sets. For SNP that had ≥ 20% discordant genotypes, the difference between imputed data sets of allele frequencies of the UK (imputed) genotypes was 0.07, whereas the difference in allele frequencies of the (reference) high-density genotypes was 0.30. In fact, regions existed across the genome where the frequency of discordant SNP was higher. For example, on chromosome 10 (centered on 520,948 bp), 52 SNP (out of a total of 103 SNP) had ≥ 20% discordant SNP. Four hundred and eight SNP had more than 20% discordant genotypes and were removed from the final set of imputed genotypes. We concluded that both discordance of imputed SNP genotypes and differences in allele frequencies, after imputation using different reference data sets, may be used to identify and remove poorly imputed SNP.


Assessment of left ventricular systolic function in man from simultaneous echocardiographic and pressure measurements.
Simultaneous measurements of left ventricular dimension and wall thickness by echocardiography, and of pressure by micromanometer, were made at cardiac catheterization in 30 patients with heart disease, in order to study mechanisms of impairment of left ventricular systolic function. Echocardiograms and pressure traces were digitized so that continuous measurements of left ventricular wall thickness and dimensions with their rates of change could be obtained. Ejection fraction was estimated from digitized cineangiograms. In all patients, except those with severe mitral regurgitation, there was close correlation (r=0.92) between peak left ventricular dP/dt and peak rate of reduction of dimension. Myocardial power values, calculated as the product of circumferential shortening rates and wall stress were plotted throughout the cardiac cycle, and peak values in patients with normal left ventricular function were in the range 30 to 60 mW cm-3 myocardium. Pressure-dimension loops were constructed, which reflected the relation between the function of a localized region of cavity studied by echocardiography and that of the ventricle as a whole in the pressure wave form. Incoordinate contraction was associated with distortion of the loop and a reduction in its area to less than 75% that of the maximum for the cycle in question (cycle efficiency). In patients with left ventricular disease, ejection fraction, peak power, and cycle efficiency were all reduced, either singly or in combination. There was no consistent pattern, however, suggesting that clinical left ventricular disease may be the resultant of a number of different types of disturbance. These include structural abnormalities, reduction in peak rates of myocardial shortening or power development, and incoordinate contraction. The present investigation suggests ways in which these may be separated and studied in individual patients.


Therapeutic effect of anti-tumor necrosis factor-alpha antibody on the murine model of viral myocarditis induced by encephalomyocarditis virus.
Tumor necrosis factor-alpha (TNF-alpha) has been reported to have an antiviral effect in vitro; however, its in vivo effect remains to be clarified. To investigate the role of TNF-alpha in viral myocarditis using a murine model induced by encephalomyocarditis virus (EMCV), we evaluated (1) plasma TNF-alpha levels by enzyme-linked immunosorbent assay (ELISA), (2) the effect of recombinant human TNF-alpha for its possible antiviral effect in vivo, and (3) the effect of anti-murine TNF-alpha monoclonal antibody (mAb) in vivo. Four-week-old DBA/2 mice were inoculated intraperitoneally with EMCV (day 0). Mice were injected intravenously daily with 1 microgram of TNF-alpha or 2 x 10(3) units of anti-TNF-alpha mAb starting on day -1, day 0, or day 1 until day 2 (TNF-alpha study) or day 4 (anti-TNF-alpha mAb study). A portion of the mice were killed on day 5 (protocol 1); their hearts were removed, and plaque assays were performed to demonstrate the myocardial virus content. The remaining mice were killed on day 14 (protocol 2); myocardial lesions were examined histopathologically in terms of severity, and their survival rates were determined. Plasma TNF-alpha concentration was elevated in the blood of infected mice compared with uninfected mice 3, 5, and 7 days after virus inoculation. The myocardial virus content was higher in the TNF-alpha-treated group than in the control group. Histopathological analysis revealed that myocardial necrosis and cellular infiltration were more prominent in the TNF-alpha group than in the control group. The anti-TNF-alpha mAb improved survival and myocardial lesions when its treatment was started 1 day before virus inoculation. However, it showed no therapeutic effect when administered simultaneously with the inoculation or on day 1. TNF-alpha may play an important role in the very early stage of the immune response, and anti-TNF-alpha mAb may prevent the early pathway of acute viral myocarditis.


Epidemiologic risks for food allergy.
This article reviews possible risk factors and theories for the development of food allergy. It is noted that previous strategies to prevent food allergy through allergen avoidance during pregnancy, breast-feeding, and infancy have more recently been called into question. Alternative hypotheses are examined with respect to food allergy, namely the hygiene hypothesis, the dietary fat hypothesis, the antioxidant hypothesis, and the vitamin D hypotheses. An alternative hypothesis is proposed, suggesting that sensitization to allergen occurs through environmental exposure to allergen through the skin and that consumption of food allergen induces oral tolerance. This hypothesis provides a possible explanation for the close link between eczema and the development of food allergies. It also suggests novel interventional strategies to prevent the development of food allergies.


Structures of KIX domain of CBP in complex with two FOXO3a transactivation domains reveal promiscuity and plasticity in coactivator recruitment.
Forkhead box class O 3a (FOXO3a) is a transcription factor and tumor suppressor linked to longevity that determines cell fate through activating transcription of cell differentiation, survival, and apoptotic genes. Recruitment of the coactivator CBP/p300 is a crucial step in transcription, and we revealed that in addition to conserved region 3 (CR3) of FOXO3a, the C-terminal segment of CR2 (CR2C) binds CBP/p300 and contributes to transcriptional activity. CR2C and CR3 of FOXO3a interact with the KIX domain of CBP/p300 at both "MLL" and "c-Myb" binding sites simultaneously. A FOXO3a CR2C-CR3 peptide in complex with KIX exists in equilibrium between two equally populated conformational states, one of which has CR2C bound to the MLL site and CR3 bound to the c-Myb site, whereas in the other, CR2C and CR3 bind the c-Myb and MLL sites, respectively. This promiscuous interaction between FOXO3a and CBP/p300 is further supported by additional binding sites on CBP/p300, namely, the TAZ1 and TAZ2 domains. In functional studies, our structure-guided mutagenesis showed that both CR2C and CR3 are involved in the activation of certain endogenous FOXO3a target genes. Further, phosphorylation of S626, a known AMP-dependent protein kinase target in CR3, increased affinity for CBP/p300 and the phosphomimetic mutation enhanced transactivation of luciferase. These findings underscore the significance of promiscuous multivalent interactions and posttranslational modification in the recruitment of transcriptional coactivators, which may allow transcription factors to adapt to various gene-specific genomic and chromatin structures and respond to cell signals.


Matrix metalloproteinase 7 restrains Helicobacter pylori-induced gastric inflammation and premalignant lesions in the stomach by altering macrophage polarization.
Helicobacter pylori is the strongest risk factor for the development of gastric cancer. Although the specific mechanisms by which this pathogen induces carcinogenesis have not been fully elucidated, high-expression interleukin (IL)-1β alleles are associated with increased gastric cancer risk among H. pylori-infected persons. In addition, loss of matrix metalloproteinase 7 (MMP7) increases mucosal inflammation in mouse models of epithelial injury, and we have shown that gastric inflammation is increased in H. pylori-infected MMP7(-/-) C57BL/6 mice. In this report, we define mechanisms that underpin such responses and extend these results into a genetic model of MMP7 deficiency and gastric cancer. Wild-type (WT) or MMP7(-/-) C57BL/6 mice were challenged with broth alone as an uninfected control or the H. pylori strain PMSS1. All H. pylori-challenged mice were successfully colonized. As expected, H. pylori-infected MMP7(-/-) C57BL/6 mice exhibited a significant increase in gastric inflammation compared with uninfected or infected WT C57BL/6 animals. Loss of MMP7 resulted in M1 macrophage polarization within H. pylori-infected stomachs, as assessed by Luminex technology and immunohistochemistry, and macrophages isolated from infected MMP7-deficient mice expressed significantly higher levels of the M1 macrophage marker IL-1β compared with macrophages isolated from WT mice. To extend these findings into a model of gastric cancer, hypergastrinemic WT INS-GAS or MMP7(-/-) INS-GAS mice were challenged with H. pylori strain PMSS1. Consistent with findings in the C57BL/6 model, H. pylori-infected MMP7-deficient INS-GAS mice exhibited a significant increase in gastric inflammation compared with either uninfected or infected WT INS-GAS mice. In addition, the incidence of gastric hyperplasia and dysplasia was significantly increased in H. pylori-infected MMP7(-/-) INS-GAS mice compared with infected WT INS-GAS mice, and loss of MMP7 promoted M1 macrophage polarization. These results suggest that MMP7 exerts a restrictive role on H. pylori-induced gastric injury and the development of premalignant lesions by suppressing M1 macrophage polarization.


Use of apparent diffusion coefficient images to predict response to induction chemotherapy in sinonasal cancer.
The purpose of this study is to identify a set of radiomic features extracted from apparent diffusion coefficient (ADC) maps, obtained using baseline diffusion weighted magnetic resonance imaging (DW-MRI), which are able to predict the outcome of induction chemotherapy (IC) in sinonasal cancers. Such prediction could help the clinician defining the better treatment for a particular patient. Eighty-eight radiomic features were extracted from the ADC maps of 15 patients that underwent IC. A preliminary filtering of the features was made by assessing their stability to geometrical transformations of the region of interest (ROI). Mann-Whitney tests corrected for control of false discoveries were performed to identify the features that could discriminate between responsive and nonresponsive patients (4 and 11 respectively). Twenty features were found to be able to discriminate the two groups and they can potentially be used for prediction of response to treatment.


MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer.
Targeted therapy for metastatic diseases relies on the identification of functionally important metastasis genes from a large number of random genetic alterations. Here we use a computational algorithm to map minimal recurrent genomic alterations associated with poor-prognosis breast cancer. 8q22 genomic gain was identified by this approach and validated in an extensive collection of breast tumor samples. Regional gain of 8q22 elevates expression of the metastasis gene metadherin (MTDH), which is overexpressed in more than 40% of breast cancers and is associated with poor clinical outcomes. Functional characterization of MTDH revealed its dual role in promoting metastatic seeding and enhancing chemoresistance. These findings establish MTDH as an important therapeutic target for simultaneously enhancing chemotherapy efficacy and reducing metastasis risk.


Clinical course after surgical treatment of active isolated native mitral valve endocarditis.
Isolated mitral valve endocarditis (MVE) forms a particular subgroup within native infective valve endocarditis (NVE). We characterized this particular subgroup and analyzed the course of patients undergoing cardiac surgery. Between 1997 and 2011, 474 patients underwent cardiac surgery at our institution for NVE treatment. Of these, 89 patients (18.8%) suffered from MVE. Valve replacement was undertaken in 84.2% and valve repair in 15.8%. Follow-up was completed with 267 patient years. A delay between the onset of first symptoms and surgery of 4.7±1.2 weeks was observed. Hence, most patients were in a critical preoperative state characterized by severe sepsis and destruction of the mitral valve. About 19.4% were emergency procedures. The MVE group presented with a higher prevalence of preoperative stroke, atrial fibrillation, coronary artery disease and chronic obstructive pulmonary disease in comparison with remaining NVE cases. MVE was more likely caused by Staphylococcus aureus; Staphylococcus epidermidis and Staphylococcus viridans were less frequent (P<0.01 each). Early mortality (6.7%) was caused by persistent sepsis. ICU stay >7 days and time on artificial ventilation >40 h led to a higher risk of in-hospital death. Five-year survival was 59.6% and affected by extracardiac comorbidities. Isolated MVE was characterized by a long delay before surgery, differences in microbiological findings and a higher prevalence of preoperative strokes in comparison to NVE. Surgery for MVE can be conducted with good clinical results, but mid-term outcome is limited by extracardiac comorbidities.


Multidentate silyl ligands in transition metal chemistry.
Silyl ligands are of great interest in transition metal coordination chemistry since they exhibit a strong trans-influence and create electron rich metals centres, which are in turn eligible to activate reagents. This review presents and discusses the use of multidentate Si-based ligand systems in transition metal coordination chemistry. These include tri- and tetradentate pincer and scorpionate-type ligands, which have been developed in recent years in order to tailor both steric and electronic properties for achieving a defined control over the reactivity of a transition metal complex. A discussion of synthetic and structural aspects of several subgroups of ligand architectures is presented. Some compounds allow for a detailed insight into the activation process of silanes or are capable of activating small molecules.


Effects of repeated blood donations on iron status and hematologic variables of canine blood donors.
To evaluate the bone marrow regenerative response and iron status of canine blood donors subjected to repeated blood collections for 1 year. Prospective cohort study. 57 blood donor dogs. Hematologic variables, including reticulocyte percentage, were evaluated before and 10 days after each blood collection in 16 dogs donating 13% of total blood volume (TBV) every 2 months (group 1), 16 dogs donating 13% of TBV every 3 months (group 2), and 25 dogs donating 15% of TBV every 3 months (group 3) for 1 year. Serum concentrations of iron, transferrin, and ferritin were analyzed before inclusion in the study and 10 days after the last donation. Significant increases in RBC distribution width, platelet count, WBC count, and reticulocyte percentage were detected after blood donation in all groups. Dogs of group 2 had a significantly higher serum ferritin concentration than did dogs of group 1; dogs of group 1 had a significant decrease in serum ferritin concentration. A positive correlation between the number of blood donations and both RBC distribution width and reticulocyte percentage was found for all groups. All blood donation regimens induced a bone marrow regenerative response, which was able to restore depleted blood cells within 10 days after blood donation while maintaining iron status within the calculated reference range. However, dogs donating 13% of TBV every 2 months had a significant decrease in iron stores, which suggested that iron-related variables must be monitored during prolonged blood donor programs.


Molecular Motion in Aggregates: Manipulating TICT for Boosting Photothermal Theranostics.
Planar donor and acceptor (D-A) conjugated structures are generally believed to be the standard for architecting highly efficient photothermal theranostic agents, in order to restrict intramolecular motions in aggregates (nanoparticles). However, other channels of extra nonradiative decay may be blocked. Now this challenge is addressed by proposing an "abnormal" strategy based on molecular motion in aggregates. Molecular rotors and bulky alkyl chains are grafted to the central D-A core to lower intermolecular interaction. The enhanced molecular motion favors the formation of a dark twisted intramolecular charge transfer state, whose nonradiative decay enhances the photothermal properties. Result shows that small-molecule NIRb14 with long alkyl chains branched at the second carbon exhibits enhanced photothermal properties compared with NIRb6, with short branched chains, and much higher than NIR6, with short linear chains, and the commercial gold nanorods. Both in vitro and in vivo experiments demonstrate that NIRb14 nanoparticles can be used as nanoagents for photoacoustic imaging-guided photothermal therapy. Moreover, charge reversal poly(β-amino ester) makes NIRb14 specifically accumulate at tumor sites. This study thus provides an excited molecular motion approach toward efficient phototheranostic agents.


Circulating DNA: a potential marker of sickle cell crisis.
Free circulating DNA is present in the plasma of healthy subjects, and is elevated in conditions characterized by increased cell death, such as cancer and physical trauma. Analysis of circulating DNA in plasma could provide a useful biomarker in sickle cell disease (SCD) in view of the increased cell turnover through chronic ongoing haemolysis, recurrent vaso-occlusion and inflammation. Plasma DNA was determined by real-time quantitative polymerase chain reaction (PCR) amplification of the beta-globin gene (HBB) in 154 patients with SCD [105 haemoglobin (Hb)SS, 46 HbSC and three HbS/beta(0) thalassaemia] and 53 ethnically matched controls. Blood samples were obtained from all patients in steady state; 21 of the 154 patients were also sampled during admission to hospital for acute pain. Median concentration of circulating plasma DNA in acute pain was more than 10-fold that in steady state and in controls - 10070 vs. 841 and 10070 vs. 933 genome equivalents/ml respectively (P < 0.0001, in both cases). During steady state, patients had plasma DNA levels similar to controls. Plasma DNA levels in SCD correlated with C-reactive protein levels (P < 0.005) and total white cell counts (P < 0.05) in steady state. The study shows that plasma DNA concentration may have potential as a biomarker in sickle cell patients.


Obstructive sleep apnea in patients admitted for acute myocardial infarction. Prevalence, predictors, and effect on microvascular perfusion.
We investigated the prevalence and predictors of obstructive sleep apnea (OSA) in patients admitted to the hospital for acute myocardial infarction and whether OSA has any association with microvascular perfusion after primary percutaneous coronary intervention (PCI). Recruited patients were scheduled to undergo an overnight sleep study between 2 and 5 days after primary PCI. An apnea-hypopnea index (AHI) of > or = 15 was considered diagnostic of OSA. Impaired microvascular perfusion after primary PCI was defined as an ST-segment resolution of < or = 70%, myocardial blush grade 0 or 1, or a corrected Thrombolysis in Myocardial Infarction (TIMI) [antegrade flow scale] frame count > 28. Sleep study was performed in 120 patients and completed in 105 patients (study cohort, mean age 53 +/- 10 years, male 98%) with uncomplicated myocardial infarction. An AHI was > or = 15 in 69 patients (OSA-positive), giving a prevalence of 65.7%. Diabetes mellitus was found to be a significant risk factor for OSA (odds ratio, 2.86; 95% confidence interval, 1.06 to 8.24; p = 0.033). There were no differences between OSA-positive and OSA-negative groups with regard to the percentage of patients with < or = 70% ST-segment resolution (73% vs 64%, respectively; p = 0.411), myocardial blush grade 0 or 1 (39.1% vs 38.9%, respectively; p = 1.000), or corrected TIMI frame count > 28 (21.7% vs 25.0%, respectively; p = 0.807). We found a high prevalence of previously undiagnosed OSA in patients admitted with acute myocardial infarction. Diabetes mellitus was independently associated with OSA. No evidence indicated that OSA is associated with impaired microvascular perfusion after primary PCI.


Deficiency of pantothenate kinase 2 (Pank2) in mice leads to retinal degeneration and azoospermia.
Pantothenate kinase-associated neurodegeneration (PKAN, formerly known as Hallervorden-Spatz syndrome) is a rare but devastating neurodegenerative disorder, resulting from an inherited defect in coenzyme A biosynthesis. As pathology in the human condition is limited to the central nervous system, specifically the retina and globus pallidus, we have generated a mouse knock-out of the orthologous murine gene (Pank2) to enhance our understanding of the mechanisms of disease and to serve as a testing ground for therapies. Over time, the homozygous null mice manifest retinal degeneration, as evidenced by electroretinography, light microscopy and pupillometry response. Specifically, Pank2 mice show progressive photoreceptor decline, with significantly lower scotopic a- and b-wave amplitudes, decreased cell number and disruption of the outer segment and reduced pupillary constriction response when compared with those of wild-type littermates. Additionally, the homozygous male mutants are infertile due to azoospermia, a condition that was not appreciated in the human. Arrest occurs in spermiogenesis, with complete absence of elongated and mature spermatids. In contrast to the human, however, no changes were observed in the basal ganglia by MRI or by histological exam, nor were there signs of dystonia, even after following the mice for one year. Pank2 mice are 20% decreased in weight when compared with their wild-type littermates; however, dysphagia was not apparent. Immunohistochemistry shows staining consistent with localization of Pank2 to the mitochondria in both the retina and the spermatozoa.


Effect of statistical fluctuation in Monte Carlo based photon beam dose calculation on gamma index evaluation.
The γ-index test has been commonly adopted to quantify the degree of agreement between a reference dose distribution and an evaluation dose distribution. Monte Carlo (MC) simulation has been widely used for the radiotherapy dose calculation for both clinical and research purposes. The goal of this work is to investigate both theoretically and experimentally the impact of the MC statistical fluctuation on the γ-index test when the fluctuation exists in the reference, the evaluation, or both dose distributions. To the first order approximation, we theoretically demonstrated in a simplified model that the statistical fluctuation tends to overestimate γ-index values when existing in the reference dose distribution and underestimate γ-index values when existing in the evaluation dose distribution given the original γ-index is relatively large for the statistical fluctuation. Our numerical experiments using realistic clinical photon radiation therapy cases have shown that (1) when performing a γ-index test between an MC reference dose and a non-MC evaluation dose, the average γ-index is overestimated and the gamma passing rate decreases with the increase of the statistical noise level in the reference dose; (2) when performing a γ-index test between a non-MC reference dose and an MC evaluation dose, the average γ-index is underestimated when they are within the clinically relevant range and the gamma passing rate increases with the increase of the statistical noise level in the evaluation dose; (3) when performing a γ-index test between an MC reference dose and an MC evaluation dose, the gamma passing rate is overestimated due to the statistical noise in the evaluation dose and underestimated due to the statistical noise in the reference dose. We conclude that the γ-index test should be used with caution when comparing dose distributions computed with MC simulation.


A full genomic characterization of the development of a stable Small Colony Variant cell-type by a clinical Staphylococcus aureus strain.
A key to persistent and recurrent Staphylococcus aureus infections is its ability to adapt to diverse and toxic conditions. This ability includes a switch into a biofilm or to the quasi-dormant Small Colony Variant (SCV). The development and molecular attributes of SCVs have been difficult to study due to their rapid reversion to their parental cell-type. We recently described the unique induction of a matrix-embedded and stable SCV cell-type in a clinical S. aureus strain (WCH-SK2) by growing the cells with limiting conditions for a prolonged timeframe. Here we further study their characteristics. They possessed an increased viability in the presence of antibiotics compared to their non-SCV form. Their stability implied that there had been genetic changes; we therefore determined both the genome sequence of WCH-SK2 and its stable SCV form at a single base resolution, employing Single Molecular Real-Time (SMRT) sequencing that enabled the methylome to also be determined. The genetic features of WCH-SK2 have been identified; the SCCmec type, the pathogenicity and genetic islands and virulence factors. The genetic changes that had occurred in the stable SCV form were identified; most notably being in MgrA, a global regulator, and RsbU, a phosphoserine phosphatase within the regulatory pathway of the sigma factor SigB. There was a shift in the methylomes of the non-SCV and stable SCV forms. We have also shown a similar induction of this cell-type in other S. aureus strains and performed a genetic comparison to these and other S. aureus genomes. We additionally map RNAseq data to the WCH-SK2 genome in a transcriptomic analysis of the parental, SCV and stable SCV cells. The results from this study represent the unique identification of a suite of epigenetic, genetic and transcriptional factors that are implicated in the switch in S. aureus to its persistent SCV form.


[Significance of the endocannabinoid system in migraine].
Based on the traditional pain-relieving effect of Cannabis species an endogenous cannabinoidlike system was discovered in the human body. Endocannabinoids have important role in the homeostasis of the body, such as stress response and mood control, feeding behaviour, energy balance and metabolism, immunological processes, and also play important role in controlling pain processing. Previous studies suggested that an endokannabinoid dysfunction, namely endokannabinoid deficit, might contribute to the development of migraine and its chronification. Although, the exact nature of the relationship between migraine and endokannabinoid system is not fully understood yet, in this brief review we summarise research results suggesting that the endokannabinoid system may be a potential drug target in the migraine therapy.


Effects for Sequential Treatment of siAkt and Paclitaxel on Gastric Cancer Cell Lines.
Real-time screening of cellular response on the drugs could provide valuable insights for the early detection of therapeutic efficiency and the evaluation of disease progression. Cancer cells have the ability to vary widely in response to stress in a manner to adjust the signaling pathway to promote the survival or having a resistance to stimulation. Cell-based label-free technologies using electronic impedance sensor have strategies for constructing the signature profiles of each cells. To achieve exquisite sensitivity to substantially change of live-cell response have an important role that predict the potential of therapeutic effects. In this study, we use an impedance-based real-time cell analysis system to investigate dynamic phenotypes of cells described as a cellular index value. We show that gastric cancer cells generated characteristic kinetic patterns that corresponded to the treatment order of therapeutics. The kinetic feature of the cells offers insightful information that cannot be acquired from a conventional single end-point assay. Furthermore, we employ a 'sequential treatment strategy' to increase cytotoxic effects with minimizing the use of chemotherapeutics. Specifically, treatment of paclitaxel (PTX) after down-regulating Akt gene expression using RNAi reduces the cell proliferation and increases apoptosis. We propose that the sequential treatment may exhibit more effective approach rather than traditional combination therapy. Moreover, the dynamic monitoring of cell-drug interaction enables us to obtain a better understanding of the temporal effects in vitro.


How to Obtain Forty Percent Less Environmental Impact by Healthy, Protein-Optimized Snacks for Older Adults.
It is well known that meals containing less meat are more sustainable, but little is known about snack-meals, which typically do not contain meat. This study investigates the diversity in environmental impacts associated with snack production based on 20 common recipes optimized for protein content, energy content and sensory aspects for older adults. The purpose is to improve sustainability of public procurement by serving more sustainable snack-meals. Public procurement serves Danish older adults over millions of snack-meals every year, and millions more are served in countries with a similar social service. The environmental impact of snack production was estimated by consequential life cycle assessment. The average impact of producing the 10 least environmentally harmful snacks was 40% less than the average impact of producing the 10 most harmful snacks. This is true whether the functional unit was mass, energy, or protein content, and whether the environmental impact was measured as global warming potential or the monetized value of 16 impact categories. We conclude that large-scale public procurement of snack-meals by private and municipal kitchens can be reduced by up to 40% if the kitchens evaluate the environmental impact of all their snacks and serve the better half more frequently.


Protein ground state candidates in a simple model: an enumeration study.
The concept of the reduced set of contact maps is introduced. Using this concept we find the ground state candidates for a hydrophobic-polar lattice model on a two-dimensional square lattice. Using these results we exactly enumerate the native states of all proteins for a wide range of energy parameters. In this way, we show that there are some sequences which have an absolute native state. Moreover, we study the scale dependence of the number of members of the reduced set, the number of ground state candidates, and the number of perfectly stable sequences by comparing the results for sequences with lengths of 6 up to 20.


Fluorescent Light Incites a Conserved Immune and Inflammatory Genetic Response within Vertebrate Organs (Danio Rerio, Oryzias Latipes and Mus Musculus).
Fluorescent light (FL) has been utilized for ≈60 years and has become a common artificial light source under which animals, including humans, spend increasing amounts of time. Although the solar spectrum is quite dissimilar in both wavelengths and intensities, the genetic consequences of FL exposure have not been investigated. Herein, we present comparative RNA-Seq results that establish expression patterns within skin, brain, and liver for Danio rerio, Oryzias latipes, and the hairless mouse (Mus musculus) after exposure to FL. These animals represent diurnal and nocturnal lifestyles, and ≈450 million years of evolutionary divergence. In all three organisms, FL induced transcriptional changes of the acute phase response signaling pathway and modulated inflammation and innate immune responses. Our pathway and gene clustering analyses suggest cellular perception of oxidative stress is promoting induction of primary up-stream regulators IL1B and TNF. The skin and brain of the three animals as well as the liver of both fish models all exhibit increased inflammation and immune responses; however, the mouse liver suppressed the same pathways. Overall, the conserved nature of the genetic responses observed after FL exposure, among fishes and a mammal, suggest the presence of light responsive genetic circuitry deeply embedded in the vertebrate genome.


The effect of amyloid-β peptide on synaptic plasticity and memory is influenced by different isoforms, concentrations, and aggregation status.
The increase of oligomeric amyloid-beta (oAβ) has been related to synaptic dysfunction, thought to be the earliest event in Alzheimer's disease pathophysiology. Conversely, the suppression of endogenous Aβ impaired synaptic plasticity and memory, suggesting that the peptide is needed in the healthy brain. However, different species, aggregation forms and concentrations of Aβ might differently influence synaptic function/dysfunction. Here, we have tested the contribution of monomeric and oligomeric Aβ42 and Aβ40 at 200 nM and 200 pM concentrations on hippocampal long-term potentiation and spatial memory. We found that, when at 200 nM, oAβ40, oAβ42, and monomeric Aβ42 impaired long-term potentiation and memory, whereas only oAβ42 200 pM enhanced synaptic plasticity and memory and rescued the detrimental effect due to depletion of endogenous Aβ. Interestingly, quantification of monomer-like and oligomer-like species carried out by transmission electron microscopy revealed an increase of the monomer/oligomer ratio in the oAβ42 200 pM preparation, suggesting that the content of monomers and oligomers depends on the final concentration of the solution.


Implementation and Effect of a Novel Electronic Medical Record Format for Patient Allergy Information.
Adverse drug events (ADEs) are critical. Approximately 10% of fatal ADEs are believed to be allergic reactions. Therefore, sharing patient allergy information is beneficial to medical staff members in avoiding potentially lethal complications. We previously performed a nationwide study of patient allergy information in Japanese hospitals. The report showed that most of the responding hospitals needed a standard format for reporting the information. To establish this, we implemented a novel format for recording patient allergy information into the hospital information system at Tohoku University Hospital; this format was created through vigorous discussion among medical staff members with a variety of specialties, including doctors, nurses, pharmacists, nutritionists, and medical safety managers. In this study, we followed the amount of inputted allergy information and the number of incidents involving medication after implementation. The amount of allergy information inputted increased slightly. Although incidents involving medication also increased slightly, ADEs due to allergy significantly decreased. We believe that our findings will be useful in helping to determine the optimal characteristics of drug allergy information and to improve the dissemination of information regarding potential allergens and subsequent ADEs.


[Ayurveda diet and the nursing consultation: a care proposal].
The present text is based on the final paper on a subject from the graduate program of the Federal University of Santa Catarina. In this paper, I propose the implementation of nursing consultations providing ayurvedic dietary advice as part of the services offered in Primary Care Units for assisting patients with diabetes mellitus and high blood pressure. For a better understanding, I bring a brief revision on both ayurveda medicine and diet, emphasizing the importance of balance and harmony of the doshas for maintaining or reaching a good quality of living. I believe that through the ayurveda diet we nurses can contribute to the health of our patients offering something we all need, a correct diet according to our nutritional biotype. Another positive result that can be anticipated from practicing this philosophical and methodological proposal lies in the relationship we establish with other persons, in knowing the characteristics of their doshas, because it is this knowledge that enables us to aid people in their conquests and defeats.


Dynamic in situ cytometry uncovers T cell receptor signaling during immunological synapses and kinapses in vivo.
Upon antigen recognition, T cells form either static (synapses) or migratory (kinapses) contacts with antigen-presenting cells. Addressing whether synapses and kinapses result in distinct T cell receptor (TCR) signals has been hampered by the inability to simultaneously assess T cell phenotype and behavior. Here, we introduced dynamic in situ cytometry (DISC), a combination of intravital multiphoton imaging and flow cytometry-like phenotypic analysis. Taking advantage of CD62L shedding as a marker of early TCR signaling, we examined how T cells sense TCR ligands of varying affinities in vivo. We uncovered three modes of antigen recognition: synapses with the strongest TCR signals, kinapses with robust signaling, and kinapses with weak signaling. As illustrated here, the DISC approach should provide unique opportunities to link immune cell behavior to phenotype and function in vivo.


Development of internalizing problems from adolescence to emerging adulthood: Accounting for heterotypic continuity with vertical scaling.
Manifestations of internalizing problems, such as specific symptoms of anxiety and depression, can change across development, even if individuals show strong continuity in rank-order levels of internalizing problems. This illustrates the concept of heterotypic continuity, and raises the question of whether common measures might be construct-valid for one age but not another. This study examines mean-level changes in internalizing problems across a long span of development at the same time as accounting for heterotypic continuity by using age-appropriate, changing measures. Internalizing problems from age 14-24 were studied longitudinally in a community sample (N = 585), using Achenbach's Youth Self-Report (YSR) and Young Adult Self-Report (YASR). Heterotypic continuity was evaluated with an item response theory (IRT) approach to vertical scaling, linking different measures over time to be on the same scale, as well as with a Thurstone scaling approach. With vertical scaling, internalizing problems peaked in mid-to-late adolescence and showed a group-level decrease from adolescence to early adulthood, a change that would not have been seen with the approach of using only age-common items. Individuals' trajectories were sometimes different than would have been seen with the common-items approach. Findings support the importance of considering heterotypic continuity when examining development and vertical scaling to account for heterotypic continuity with changing measures. (PsycINFO Database Record


Underwhelming the immune response: effect of slow virus growth on CD8+-T-lymphocyte responses.
The speed of virus replication has typically been seen as an advantage for a virus in overcoming the ability of the immune system to control its population growth. Under some circumstances, the converse may also be true: more slowly replicating viruses may evoke weaker cellular immune responses and therefore enhance their likelihood of persistence. Using the model of lymphocytic choriomeningitis virus (LCMV) infection in mice, we provide evidence that slowly replicating strains induce weaker cytotoxic-T-lymphocyte (CTL) responses than a more rapidly replicating strain. Conceptually, we show a "bell-shaped" relationship between the LCMV growth rate and the peak CTL response. Quantitative analysis of human hepatitis C virus infections suggests that a reduction in virus growth rate between patients during the incubation period is associated with a spectrum of disease outcomes, from fulminant hepatitis at the highest rate of viral replication through acute resolving to chronic persistence at the lowest rate. A mathematical model for virus-CTL population dynamics (analogous to predator [CTL]-prey [virus] interactions) is applied in the clinical data-driven analysis of acute hepatitis B virus infection. The speed of viral replication, through its stimulus of host CTL responses, represents an important factor influencing the pathogenesis and duration of virus persistence within the human host. Viruses with lower growth rates may persist in the host because they "sneak through" immune surveillance.


Analysis of fluorescent pseudomonads based on 23S ribosomal DNA sequences.
The regions from positions 1391 to 1545 and 1620 to 1865 (Escherichia coli numbers) of the 23S ribosomal DNA sequences have been analyzed for a number of Pseudomonas fluorescens and P. putida isolates. Variability was observed only in three smaller regions from positions 1484 to 1508, 1531 to 1542, and 1714 to 1748, corresponding to helices 58, 59, and 63, respectively, where up to 53% dissimilarity was found. Sequence analysis did not allow clear distinctions among P. fluorescens biovars, P. chlororaphis, and P. putida biovar B.


Strategies to improve treatment outcome in gastric cancer: a retrospective analysis of patients from two high-volume hospitals in Korea and China.
China has high incidence of gastric cancer (GC). However, the treatment outcomes of China were unsatisfactory compared to those of Korea. We performed this study to compare tumour characteristics, treatment parameters, and survival outcomes of GC patients between Korea and China based on the databases of two high-volume hospitals, with the aim of identifying indicators of GC prognosis. Data of patients undergoing gastrectomy for GC from 2006 to 2010 were analysed retrospectively. Subgroup survival analyses, stratified by clinicopathologic factors and multivariable analyses, were performed. The interactive roles of chemotherapy and D2 lymphadenectomy for overall survival were also investigated. Among 1365 Chinese and 4981 Korean patients, the proportion of early cancer detection in Chinese patients was much lower relative to that of Korean patients. There were no significant differences between countries in terms of surgical morbidity and mortality. The overall 5-year survival rates were 54.3% and 81.4%; when stratified by clinicopathologic factors, the survival were generally statistically higher in Korean patients. Gender, age, T stage, N stage, extent of lymphadenectomy, radicality of surgery, resection type, and chemotherapy were independently associated with survival in patients without metastasis. Survival rates for stage II and III GC differed significantly between the two countries, but this difference was eliminated among patients who underwent D2 lymphadenectomy or received chemotherapy. These treatments were given to patients with advanced-stage diagnoses (approximately 20% and 80% of patients, respectively). Treatment type was selected as independent prognostic factors in stage I-III and D2/D2+, with chemotherapy resulting in the best prognosis. Many differences in GC tumour characteristics exist between two countries. Early cancer detection and standardized treatment in Korea contribute to superior survival rates. Promotion of an early screening program, training and dissemination of standard D2 lymphadenectomy, and appropriate applications of chemotherapy would improve survival outcomes.


Valence electronic structure of cobalt phthalocyanine from an optimally tuned range-separated hybrid functional.
We analyse the valence electronic structure of cobalt phthalocyanine (CoPc) by means of optimally tuning a range-separated hybrid functional. The tuning is performed by modifying both the amount of short-range exact exchange (α) included in the hybrid functional and the range-separation parameter (γ), with two strategies employed for finding the optimal γ for each α. The influence of these two parameters on the structural, electronic, and magnetic properties of CoPc is thoroughly investigated. The electronic structure is found to be very sensitive to the amount and range in which the exact exchange is included. The electronic structure obtained using the optimal parameters is compared to gas-phase photo-electron data and GW calculations, with the unoccupied states additionally compared with inverse photo-electron spectroscopy measurements. The calculated spectrum with tuned γ, determined for the optimal value of α = 0.1, yields a very good agreement with both experimental results and with GW calculations that well-reproduce the experimental data.


Modelling the failure modes in geobag revetments.
In recent years, sand filled geotextile bags (geobags) have been used as a means of long-term riverbank revetment stabilization. However, despite their deployment in a significant number of locations, the failure modes of such structures are not well understood. Three interactions influence the geobag performance, i.e. geobag-geobag, geobag-water flow and geobag-water flow-river bank. The aim of the research reported here is to develop a detailed understanding of the failure mechanisms in a geobag revetment using a discrete element model (DEM) validated by laboratory data. The laboratory measured velocity data were used for preparing a mapped velocity field for a coupled DEM simulation of geobag revetment failure. The validated DEM model could identify well the critical bag location in varying water depths. Toe scour, one of the major instability factors in revetments, and its influence on the bottom-most layer of the bags were also reasonably represented in this DEM model. It is envisaged that the use of a DEM model will provide more details on geobag revetment performance in riverbanks.


Brain gene expression profiles of Cln1 and Cln5 deficient mice unravels common molecular pathways underlying neuronal degeneration in NCL diseases.
The neuronal ceroid lipofuscinoses (NCL) are a group of children's inherited neurodegenerative disorders, characterized by blindness, early dementia and pronounced cortical atrophy. The similar pathological and clinical profiles of the different forms of NCL suggest that common disease mechanisms may be involved. To explore the NCL-associated disease pathology and molecular pathways, we have previously produced targeted knock-out mice for Cln1 and Cln5. Both mouse-models replicate the NCL phenotype and neuropathology; the Cln1-/- model presents with early onset, severe neurodegenerative disease, whereas the Cln5-/- model produces a milder disease with a later onset. Here we have performed quantitative gene expression profiling of the cortex from 1 and 4 month old Cln1-/- and Cln5-/- mice. Combined microarray datasets from both mouse models exposed a common affected pathway: genes regulating neuronal growth cone stabilization display similar aberrations in both models. We analyzed locus specific gene expression and showed regional clustering of Cln1 and three major genes of this pathway, further supporting a close functional relationship between the corresponding gene products; adenylate cyclase-associated protein 1 (Cap1), protein tyrosine phosphatase receptor type F (Ptprf) and protein tyrosine phosphatase 4a2 (Ptp4a2). The evidence from the gene expression data, indicating changes in the growth cone assembly, was substantiated by the immunofluorescence staining patterns of Cln1-/- and Cln5-/- cortical neurons. These primary neurons displayed abnormalities in cytoskeleton-associated proteins actin and beta-tubulin as well as abnormal intracellular distribution of growth cone associated proteins GAP-43, synapsin and Rab3. Our data provide the first evidence for a common molecular pathogenesis behind neuronal degeneration in INCL and vLINCL. Since CLN1 and CLN5 code for proteins with distinct functional roles these data may have implications for other forms of NCLs as well.


Neuronal replacement in microcircuits of the adult olfactory system.
The local-circuit inhibitory interneurons containing gamma-aminobutyric acid (GABA) are continuously replaced in the adult olfactory bulb. Here, we describe how the production of new GABAergic interneurons is adapted to experience-induced plasticity. In particular, we discuss how such an adaptation is sensitive to the level of sensory inputs and how, in turn, neurogenesis may adjust the neural network functioning to optimize processing of sensory information. Finally, this review brings together recently described properties of interneurons as well as emerging principles of their functions that indicate a much more complex role for these cells than just that of gatekeepers providing inhibition.


The transferrin receptor-1 membrane stub undergoes intramembrane proteolysis by signal peptide peptidase-like 2b.
The successive events of shedding and regulated intramembrane proteolysis are known to comprise a fundamental biological process of type I and II membrane proteins (e.g. amyloid precursor protein, Notch receptor and pro-tumor necrosis factor-α). Some of the resulting fragments were shown to be involved in important intra- and extracellular signalling events. Although shedding of the human transferrin receptor-1 (TfR1) has been known for > 30 years and soluble TfR1 is an accepted diagnostic marker, the fate of the remaining N-terminal fragment (NTF) remains unknown. In the present study, we demonstrate for the first time that TfR1-NTF is subject to regulated intramembrane proteolysis and, using MALDI-TOF-TOF-MS, we have identified the cleavage site as being located C-terminal from Gly-84. We showed that the resulting C-terminal peptide is extracellularly released after regulated intramembrane proteolysis and it was detected as a monomer with an internal disulfide bridge. We further identified signal peptide peptidase-like 2a and mainly signal peptide peptidase-like 2b as being responsible for the intramembrane proteolysis of TfR1-NTF.


A vesicular Na+/Ca2+ exchanger in coral calcifying cells.
The calcium carbonate skeletons of corals provide the underlying structure of coral reefs; however, the cellular mechanisms responsible for coral calcification remain poorly understood. In osteoblasts from vertebrate animals, a Na+/Ca2+ exchanger (NCX) present in the plasma membrane transports Ca2+ to the site of bone formation. The aims of this study were to establish whether NCX exists in corals and its localization within coral cells, which are essential first steps to investigate its potential involvement in calcification. Data mining identified genes encoding for NCX proteins in multiple coral species, a subset of which were more closely related to NCXs from vertebrates (NCXA). We cloned NCXA from Acropora yongei (AyNCXA), which, unexpectedly, contained a peptide signal that targets proteins to vesicles from the secretory pathway. AyNCXA subcellular localization was confirmed by heterologous expression of fluorescently tagged AyNCXA protein in sea urchin embryos, which localized together with known markers of intracellular vesicles. Finally, immunolabeling of coral tissues with specific antibodies revealed AyNCXA was present throughout coral tissue. AyNCXA was especially abundant in calcifying cells, where it exhibited a subcellular localization pattern consistent with intracellular vesicles. Altogether, our results demonstrate AyNCXA is present in vesicles in coral calcifying cells, where potential functions include intracellular Ca2+ homeostasis and Ca2+ transport to the growing skeleton as part of an intracellular calcification mechanism.


Targeted Methylation Analyses: From Bisulfite Treatment to Quantification.
DNA methylation constitutes the most studied epigenetic mechanism, regulating gene expression in several physiological and pathological states. Targeted methylation polymerase chain reaction (PCR)-based analyses are among the most universal and commonly used techniques in research. They can be of use for validating methylation-based biomarkers to include in clinical practice. Optimal execution and interpretation of data is fundamental for achieving accurate and reproducible results.In this chapter we describe the backbone procedures behind targeted methylation analyses: bisulfite conversion and downstream PCR-based techniques, including real-time quantitative methylation-specific PCR (qMSP) and high-resolution melting (HRM) methylation-sensitive analyses. Specifically, we give details about the protocol, discuss the pros and cons of these methodologies, and give practical tips for achieving optimal results and for troubleshooting.


The characterization of caffeine and nine individual catechins in the leaves of green tea (Camellia sinensis L.) by near-infrared reflectance spectroscopy.
Near-infrared reflectance spectroscopy (NIRS) was used to determine the contents of caffeine and nine individual catechins in tea leaves. A total of 665 samples were scanned by NIRS, and also by high performance liquid chromatography coupled to a diode array detector to determine the contents of caffeine and nine individual catechins. The calibration models for caffeine, EGC, C, EGCG, EC, ECG, and total catechins had high r(2) (more than 0.90) and RSP (the ratio of standard deviation of reference data to SEP(C) in the external validation set) values (more than 4.1), indicating a good correlation between reference values and NIRS predicted values. In contrast, the calibration models of GC and EGCG-3Me had low r(2) and RSP values (below 0.8 and 2.0). Therefore, these results suggest that NIRS could be applied for the rapid determination of the contents of caffeine, EGC, C, EGCG, EC, ECG, and total catechins in tea leaves for breeding programs that develop high-quality tea plants.


No difference between aspirin and warfarin after extracardiac Fontan in a propensity score analysis of 475 patients.
The most effective method of long-term thromboprophylaxis after the Fontan procedure is not clear. We compared the rates of thromboembolic events between patients receiving aspirin and warfarin after an extracardiac conduit Fontan procedure in a bi-national registry. All patients who underwent an extracardiac conduit Fontan procedure from 1997 to 2010 in Australia and New Zealand were identified. Medication status and routine follow-up and echocardiographic data were obtained from all patients. Survival analysis with propensity score matching and adjustment was performed to determine the treatment effect of warfarin compared with that of aspirin beyond the first year of follow-up, after which time patients had settled on their long-term thromboprophylaxis strategy. Of 570 eligible patients, the data of 475 patients who were regularly followed up without mechanical valve replacement were available for analysis. Long-term thromboprophylaxis consisted of warfarin in 301 patients (63%), aspirin in 157 (33%) and none in 17 (4%). The 10-year rate of freedom from all thromboembolic events was 91% [95% confidence interval (CI) 88-94%]. Thromboembolic events beyond the first year of follow-up occurred in 18 patients (6 on aspirin and 12 on warfarin). After (i) propensity score adjustment and (ii) matching yielding 164 pairs, the hazard rates of thromboembolic events beyond the first year were not statistically different between the warfarin and aspirin groups [(i) hazard ratio (HR) 2.3, 95% CI 0.7-7.4, P = 0.2 and (ii) HR 1.5, 95% CI 0.5-4.7, P = 0.5, respectively]. No difference in the hazard rates of late thromboembolic events was observed between aspirin and warfarin beyond the first year after the extracardiac conduit Fontan procedure.


JAK2V617F influences epigenomic changes in myeloproliferative neoplasms.
Negative valine (V) to phenylalanine (F) switch at the Janus kinase (JAK2) 617 codon (V617F) is the dominant driver mutation in patients with myeloproliferative neoplasms (MPNs). JAK2V617F was proved to be sufficient for cell transformation; however, independent mutations might influence the following epigenomic modifications. To assess the JAK2V617F-induced downstream epigenomic changes without interferences, we profiled the epigenomic changes in ectopically expressed JAK2V617F in Ba/F3 cells. Antibodies against phosphorylated signal transducer and activator of transcription 3 (pSTAT3) and enhancer of zeste homolog 2 (EZH2) were used for chromatin-immunoprecipitation sequencing (ChIP-seq) to detect the downstream epigenomic targets in the JAK2-STAT3 signaling pathway. To confirm the JAK2V617F-induced epigenetic changes in vivo, DNA methylation changes in the target loci in patients with MPNs were detected through methylation-specific polymerase chain reaction and were clustered against the changes within controls. We found that ectopically expressed JAK2V617F in Ba/F3 cells reduced the binding specificity; it was associated with cis-regulatory elements and recognized DNA motifs in both pSTAT3-downstream and EZH2-associated targets. Overlapping target loci between the control and JAK2V617F were <3% and 0.4%, respectively, as identified through pSTAT3 and EZH2 ChIP-seq. Furthermore, the methylation changes in the direct target loci (FOXH1, HOXC9, and SRF) were clustered independently from the control locus (L1TD1) and other mutation genes (HMGA2 and Lin28A) in the analyzed MPN samples. Therefore, JAK2V617F influences target binding in both pSTAT3 and EZH2. Without mutations in epigenetic regulators, JAK2V617F can induce downstream epigenomic modifications. Thus, epigenetic changes in JAK2 downstream targets might be trackable in vivo.


Metabolome in schizophrenia and other psychotic disorders: a general population-based study.
Persons with schizophrenia and other psychotic disorders have a high prevalence of obesity, impaired glucose tolerance, and lipid abnormalities, particularly hypertriglyceridemia and low high-density lipoprotein. More detailed molecular information on the metabolic abnormalities may reveal clues about the pathophysiology of these changes, as well as about disease specificity. We applied comprehensive metabolomics in serum samples from a general population-based study in Finland. The study included all persons with DSM-IV primary psychotic disorder (schizophrenia, n = 45; other non-affective psychosis (ONAP), n = 57; affective psychosis, n = 37) and controls matched by age, sex, and region of residence. Two analytical platforms for metabolomics were applied to all serum samples: a global lipidomics platform based on ultra-performance liquid chromatography coupled to mass spectrometry, which covers molecular lipids such as phospholipids and neutral lipids; and a platform for small polar metabolites based on two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC × GC-TOFMS). Compared with their matched controls, persons with schizophrenia had significantly higher metabolite levels in six lipid clusters containing mainly saturated triglycerides, and in two small-molecule clusters containing, among other metabolites, (1) branched chain amino acids, phenylalanine and tyrosine, and (2) proline, glutamic, lactic and pyruvic acids. Among these, serum glutamic acid was elevated in all psychoses (P = 0.0020) compared to controls, while proline upregulation (P = 0.000023) was specific to schizophrenia. After adjusting for medication and metabolic comorbidity in linear mixed models, schizophrenia remained independently associated with higher levels in seven of these eight clusters (P < 0.05 in each cluster). The metabolic abnormalities were less pronounced in persons with ONAP or affective psychosis. Our findings suggest that specific metabolic abnormalities related to glucoregulatory processes and proline metabolism are specifically associated with schizophrenia and reflect two different disease-related pathways. Metabolomics, which is sensitive to both genetic and environmental variation, may become a powerful tool in psychiatric research to investigate disease susceptibility, clinical course, and treatment response.


Multiple-scattering effects on differential absorption for the transmission of a plane-parallel beam in a homogeneous medium.
The transmission, including all scattering orders, of a plane-parallel beam in a homogeneous scattering medium containing aerosols (e.g., water cloud) mixed with an absorbing gas (e.g., ozone) is computed with a two-stream radiative transfer model. From differential transmission the concentration of the gas is deduced. The effect of multiple-scattering on the deduced concentration is shown for conservative scattering aerosols for which the multiple scattering by the aerosols is differentially absorbed by the gas and for nonconservative scattering aerosols for which the multiple scattering is differentially absorbed by the aerosols as well as differentially absorbed by the gas. The two-stream analytical model (with no dependence on the field of view) shows good qualitative agreement (especially for a small field of view) with a numerical radiative transfer model in which the trace gas concentration is computed for the different detector's field of view.