Elevated polygenic burden for autism is associated with differential DNA methylation at birth.
Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder characterized by deficits in social communication and restricted, repetitive behaviors, interests, or activities. The etiology of ASD involves both inherited and environmental risk factors, with epigenetic processes hypothesized as one mechanism by which both genetic and non-genetic variation influence gene regulation and pathogenesis. The aim of this study was to identify DNA methylation biomarkers of ASD detectable at birth. We quantified neonatal methylomic variation in 1263 infants-of whom ~ 50% went on to subsequently develop ASD-using DNA isolated from archived blood spots taken shortly after birth. We used matched genotype data from the same individuals to examine the molecular consequences of ASD-associated genetic risk variants, identifying methylomic variation associated with elevated polygenic burden for ASD. In addition, we performed DNA methylation quantitative trait loci (mQTL) mapping to prioritize target genes from ASD GWAS findings. We identified robust epigenetic signatures of gestational age and prenatal tobacco exposure, confirming the utility of DNA methylation data generated from neonatal blood spots. Although we did not identify specific loci showing robust differences in neonatal DNA methylation associated with later ASD, there was a significant association between increased polygenic burden for autism and methylomic variation at specific loci. Each unit of elevated ASD polygenic risk score was associated with a mean increase in DNA methylation of - 0.14% at two CpG sites located proximal to a robust GWAS signal for ASD on chromosome 8. This study is the largest analysis of DNA methylation in ASD undertaken and the first to integrate genetic and epigenetic variation at birth. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with disease, and of using mQTL to refine the functional and regulatory variation associated with ASD risk variants.


Mutated form of the Newcastle disease virus hemagglutinin-neuraminidase interacts with the homologous fusion protein despite deficiencies in both receptor recognition and fusion promotion.
The Newcastle disease virus (NDV) hemagglutinin-neuraminidase (HN) protein mediates attachment to cellular receptors. The fusion (F) protein promotes viral entry and spread. However, fusion is dependent on a virus-specific interaction between the two proteins that can be detected at the cell surface by a coimmunoprecipitation assay. A point mutation of I175E in the neuraminidase (NA) active site converts the HN of the Australia-Victoria isolate of the virus to a form that can interact with the F protein despite negligible receptor recognition and fusion-promoting activities. Thus, I175E-HN could represent a fusion intermediate in which HN and F are associated and primed for the promotion of fusion. Both the attachment and fusion-promoting activities of this mutant HN protein can be rescued either by NA activity contributed by another HN protein or by a set of four substitutions at the dimer interface. These substitutions were identified by the evaluation of chimeras composed of segments from HN proteins derived from two different NDV strains. These findings suggest that the I175E substitution converts HN to an F-interactive form, but it is one for which receptor binding is still required for fusion promotion. The data also indicate that the integrity of the HN dimer interface is critical to its receptor recognition activity.


Rational design of stealthy hyperuniform two-phase media with tunable order.
Disordered stealthy hyperuniform materials are exotic amorphous states of matter that have attracted recent attention because of their novel structural characteristics (hidden order at large length scales) and physical properties, including desirable photonic and transport properties. It is therefore useful to devise algorithms that enable one to design a wide class of such amorphous configurations at will. In this paper, we present several algorithms enabling the systematic identification and generation of discrete (digitized) stealthy hyperuniform patterns with a tunable degree of order, paving the way towards the rational design of disordered materials endowed with novel thermodynamic and physical properties. To quantify the degree of order or disorder of the stealthy systems, we utilize the discrete version of the τ order metric, which accounts for the underlying spatial correlations that exist across all relevant length scales in a given digitized two-phase (or, equivalently, a two-spin state) system of interest. Our results impinge on a myriad of fields, ranging from physics, materials science and engineering, visual perception, and information theory to modern data science.


Functions of personal experience and of expression of regret.
Although learning and preparing for future behavior are well-established functions of regret, social functions have been largely ignored. We suggest a new model of the functions of regret, the Privately Experienced Versus Expressed Regret model, in which private experience and public expression differentially serve these functions. The current research examined this model using both naturalistic and experimental approaches. In Study 1, we coded tweets about regret posted on social media to examine whether this content emphasized social relationships versus learning and preparation. Study 2 experimentally examined the hypothesized social closeness function for expression of regrets. Study 3 further examined how privately experienced and publicly expressed regrets differ on the social closeness and learning and preparatory functions. Studies 4 and 5 confirmed the specific social closeness function rather than global social benefits. This research suggests that the social expression of regret differs from private experience in both form and function.


P element activity and molecular structure in Drosophila melanogaster populations from Firtina Valley, Turkey.
In order to study P element dynamics in natural populations of Drosophila melanogaster, 88 isofemale lines were examined from the Firtina Valley, Turkey. The P-M gonadal dysgenesis characteristics and the molecular patterns of P and KP elements were analyzed. Gonadal dysgenesis tests showed a slight variation both for P activity and P susceptibility, however the results showed a predominant M' phenotype for this region. The P and KP element were also characterized by polymerase chain reaction. The molecular analyses showed that all the populations examined had the entire 1.15 kb KP element. The molecular patterns of KP elements were the same for the populations studied. No clear relationship was found between phenotype and genomic P element composition. The correlations between the level of gonadal dysgenesis percentage (as an index for P activity and P susceptibility) and several geoclimatic factors were tested, and no general effects of altitude, temperature, rainfall, or humidity were found. The theoretical P' strain, which is very rare in natural populations, was also recorded for this region.


Development of a fluorometric measurement system used in biological samples upon the determination of iron (II) metal ion.
2-thioxanthone thioacetic acid (TXSCH2COOH, T), which has a fluorometric character, was used for new fluorometric system upon Fe(II) analysis in biological samples as the main target. T-BSA binary complex was firstly consisted with non-covalent interactions between T and BSA at the equilibrium concentration as 1.77 × 10-4.M. T-BSA binary complex emission was increased at the ratio of 24.40% due to stabilization property of BSA (pH:7), compared with T emission intensity. Fluorescence emission spectroscopy was used for the all measurements because of an economic, a sensitive and a practical method compared with other spectroscopic analysis. T-BSA-Fe(II) triple complex was also obtained by adding Fe(II) ion to T-BSA binary complex solution. Its characterization was performed to be investigated with optimum excitation wavelength, buffer concentration, pH and temperature as 297 nm, 10-3 M Tris HCl (10-2M NaCI), pH:7.2 at 25 °C, respectively. The results of Fe(II) analysis in serum showed a certain response in fluorometric T-BSA-Fe(II) triple complex measurement system as 50.42 ± 5.8 µg/dL. The analyses of our fluorometric triple complex system were compared with the reference electrochemiluminescence method and similar results were obtained. Fluorometric measurements of T-BSA-Fe(II) triple complex, its characterization and Fe(II) analysis in this system have not been investigated in literature gives originality to our study.


Stochastic game dynamics under demographic fluctuations.
Frequency-dependent selection and demographic fluctuations play important roles in evolutionary and ecological processes. Under frequency-dependent selection, the average fitness of the population may increase or decrease based on interactions between individuals within the population. This should be reflected in fluctuations of the population size even in constant environments. Here, we propose a stochastic model that naturally combines these two evolutionary ingredients by assuming frequency-dependent competition between different types in an individual-based model. In contrast to previous game theoretic models, the carrying capacity of the population, and thus the population size, is determined by pairwise competition of individuals mediated by evolutionary games and demographic stochasticity. In the limit of infinite population size, the averaged stochastic dynamics is captured by deterministic competitive Lotka-Volterra equations. In small populations, demographic stochasticity may instead lead to the extinction of the entire population. Because the population size is driven by fitness in evolutionary games, a population of cooperators is less prone to go extinct than a population of defectors, whereas in the usual systems of fixed size the population would thrive regardless of its average payoff.


Global transcriptome analysis uncovers the gene co-expression regulation network and key genes involved in grain development of wheat (Triticum aestivum L.).
Wheat grain development is a robust biological process that largely determines grain quality and yield. In this study, we investigated the grain transcriptome of winter wheat cv. Xiaoyan-6 at four developmental stages (5, 10, 15, and 20 days post-anthesis), using high-throughput RNA sequencing (RNA-Seq). We identified 427 grain-specific transcription factors (TFs) and 1653 differentially expressed TFs during grain development as well as a grain co-expression regulation network (GrainNet) of the TFs and their predicted co-expressed genes. Our study identified ten putative key TFs and the predicted regulatory genes of these TFs in wheat grain development of Xiaoyan-6. The analysis was given a firm basis through the study of additional wheat tissues, including root, stem, leaf, flag leaf, grain, spikes (from wheat plants at booting or heading stages) to provide a dataset of 92,478 high-confidence protein-coding genes that were mostly evenly distributed among subgenomes, but unevenly distributed across each of the chromosomes or each of the seven homeologous groups. Within this larger framework of the transcriptomes, we identified 4659 grain-specific genes (SEGs) and 26,500 differentially expressed genes (DEGs) throughout grain development stages tested. The SEGs identified mainly associate with regulation and signaling-related biological processes, while the DEGs mainly involve in cellular component organization or biogenesis and nutrient reservoir activity during grain development of Xiaoyan-6. This study establishes new targets for modifying genes related to grain development and yield, to fine-tune expression in different varieties and environments.


BMGE (Block Mapping and Gathering with Entropy): a new software for selection of phylogenetic informative regions from multiple sequence alignments.
The quality of multiple sequence alignments plays an important role in the accuracy of phylogenetic inference. It has been shown that removing ambiguously aligned regions, but also other sources of bias such as highly variable (saturated) characters, can improve the overall performance of many phylogenetic reconstruction methods. A current scientific trend is to build phylogenetic trees from a large number of sequence datasets (semi-)automatically extracted from numerous complete genomes. Because these approaches do not allow a precise manual curation of each dataset, there exists a real need for efficient bioinformatic tools dedicated to this alignment character trimming step. Here is presented a new software, named BMGE (Block Mapping and Gathering with Entropy), that is designed to select regions in a multiple sequence alignment that are suited for phylogenetic inference. For each character, BMGE computes a score closely related to an entropy value. Calculation of these entropy-like scores is weighted with BLOSUM or PAM similarity matrices in order to distinguish among biologically expected and unexpected variability for each aligned character. Sets of contiguous characters with a score above a given threshold are considered as not suited for phylogenetic inference and then removed. Simulation analyses show that the character trimming performed by BMGE produces datasets leading to accurate trees, especially with alignments including distantly-related sequences. BMGE also implements trimming and recoding methods aimed at minimizing phylogeny reconstruction artefacts due to compositional heterogeneity. BMGE is able to perform biologically relevant trimming on a multiple alignment of DNA, codon or amino acid sequences. Java source code and executable are freely available at ftp://ftp.pasteur.fr/pub/GenSoft/projects/BMGE/.


Arginine infusion in patients with septic shock increases nitric oxide production without haemodynamic instability.
Arginine deficiency in sepsis may impair nitric oxide (NO) production for local perfusion and add to the catabolic state. In contrast, excessive NO production has been related to global haemodynamic instability. Therefore, the aim of the present study was to investigate the dose-response effect of intravenous arginine supplementation in post-absorptive patients with septic shock on arginine-NO and protein metabolism and on global and regional haemodynamics. Eight critically ill patients with a diagnosis of septic shock participated in this short-term (8 h) dose-response study. L-Arginine-HCl was continuously infused [intravenously (IV)] in three stepwise-increasing doses (33, 66 and 99 μmol·kg-1·h-1). Whole-body arginine-NO and protein metabolism were measured using stable isotope techniques, and baseline values were compared with healthy controls. Global and regional haemodynamic parameters were continuously recorded during the study. Upon infusion, plasma arginine increased from 48±7 to 189±23 μmol·l-1 (means±S.D.; P<0.0001). This coincided with increased de novo arginine (P<0.0001) and increased NO production (P<0.05). Sepsis patients demonstrated elevated protein breakdown at baseline (P<0.001 compared with healthy controls), whereas protein breakdown and synthesis both decreased during arginine infusion (P<0.0001). Mean arterial and pulmonary pressure and gastric mucosal-arterial partial pressure of carbon dioxide difference (Pr-aCO2) gap did not alter during arginine infusion (P>0.05), whereas stroke volume (SV) increased (P<0.05) and arterial lactate decreased (P<0.05). In conclusion, a 4-fold increase in plasma arginine with intravenous arginine infusion in sepsis stimulates de novo arginine and NO production and reduces whole-body protein breakdown. These potential beneficial metabolic effects occurred without negative alterations in haemodynamic parameters, although improvement in regional perfusion could not be demonstrated in the eight patients with septic shock who were studied.


Transabdominal near infrared oximetry of hypoxic stress in fetal sheep brain in utero.
The feasibility of transabdominal near-infrared (NIR) spectroscopy for detecting and quantifying fetal hypoxia in utero is demonstrated in a pregnant ewe model. A frequency domain NIR spectroscopy probe, consisting of two detectors and six sources operating at three wavelengths (675, 786, and 830 nm), was placed on the maternal abdomen directly above the fetal head. Fetal hypoxia was indirectly induced through occlusion of uterine blood flow for approximately 3 min. NIR photon diffusion measurements were made during a baseline period, during hypoxia of the fetus, and during recovery. Fetal blood samples were drawn from the fetal brachial artery and jugular veins at several time points during the cycle. Seven hypoxic cycles were induced in a total of five pregnant ewes. The NIR measurements were analyzed by using a two-layer diffusion model to deconvolve the fetal blood saturation from that of the pregnant ewe. Fetal hypoxia was detected. Good agreement was found between fetal blood saturation determined by the transabdominal NIR method and arterial and venous fetal blood saturation quantified from fetal blood samples by using a hemoximeter.


Adding mindfulness-based cognitive therapy to maintenance antidepressant medication for prevention of relapse/recurrence in major depressive disorder: Randomised controlled trial.
Mindfulness-based cognitive therapy (MBCT) and maintenance antidepressant medication (mADM) both reduce the risk of relapse in recurrent depression, but their combination has not been studied. Our aim was to investigate whether the addition of MBCT to mADM is a more effective prevention strategy than mADM alone. This study is one of two multicenter randomised trials comparing the combination of MBCT and mADM to either intervention on its own. In the current trial, recurrently depressed patients in remission who had been using mADM for 6 months or longer (n=68), were randomly allocated to either MBCT+mADM (n=33) or mADM alone (n=35). Primary outcome was depressive relapse/recurrence within 15 months. Key secondary outcomes were time to relapse/recurrence and depression severity. Analyses were based on intention-to-treat. There were no significant differences between the groups on any of the outcome measures. The current study included patients who had recovered from depression with mADM and who preferred the certainty of continuing medication to the possibility of participating in MBCT. Lower expectations of mindfulness in the current trial, compared with the parallel trial, may have caused selection bias. In addition, recruitment was hampered by the increasing availability of MBCT in the Netherlands, and even about a quarter of participants included in the trial who were allocated to the control group chose to get MBCT elsewhere. For this selection of recurrently depressed patients in remission and using mADM for 6 months or longer, MBCT did not further reduce their risk for relapse/recurrence or their (residual) depressive symptoms.


Brain motor system function in a patient with complete spinal cord injury following extensive brain-computer interface training.
Although several features of brain motor function appear to be preserved even in chronic complete SCI, previous functional MRI (fMRI) studies have also identified significant derangements such as a strongly reduced volume of activation, a poor modulation of function and abnormal activation patterns. It might be speculated that extensive motor imagery training may serve to prevent such abnormalities. We here report on a unique patient with a complete traumatic SCI below C5 who learned to elicit electroencephalographic signals beta-bursts in the midline region upon imagination of foot movements. This enabled him to use a neuroprosthesis and to "walk from thought" in a virtual environment via a brain-computer interface (BCI). We here used fMRI at 3T during imagined hand and foot movements to investigate the effects of motor imagery via persistent BCI training over 8 years on brain motor function and compared these findings to a group of five untrained healthy age-matched volunteers during executed and imagined movements. We observed robust primary sensorimotor cortex (SMC) activity in expected somatotopy in the tetraplegic patient upon movement imagination while such activation was absent in healthy untrained controls. Sensorimotor network activation with motor imagery in the patient (including SMC contralateral to and the cerebellum ipsilateral to the imagined side of movement as well as supplementary motor areas) was very similar to the pattern observed with actual movement in the controls. We interpret our findings as evidence that BCI training as a conduit of motor imagery training may assist in maintaining access to SMC in largely preserved somatopy despite complete deafferentation.


Impact of pituitary suppression on antral follicle count and oocyte recovery after ovarian stimulation.
To investigate the potential influence of short-term pituitary suppression on antral follicle count (AFC) and correlate the AFC with the number of oocytes retrieved after ovarian stimulation. Retrospective study. University fertility center. A total of 1,479 infertile patients. Patients had baseline AFC, when they were not on any medications known to cause pituitary suppression, and follow-up AFC (suppressed AFC) while on E2, GnRH agonist (GnRH-a), oral contraceptive (OC) pills, or OC pills/GnRH-a in preparation for ovarian stimulation, performed within 6 months of initial baseline AFC. The AFC at baseline, AFC during pituitary suppression, and the number of oocytes retrieved. Although there was an average unadjusted decline of 0.4, 0.9, 2.2, and 3.0 in AFC while patients were on E2, GnRH-a, OC pills, and OC pills/GnRH-a, respectively, this decline was driven by age, baseline AFC, and the hormones used. Although baseline and suppressed AFC were found to be good predictors of the number of oocytes retrieved after ovarian stimulation, statistically, suppressed AFC was found to be a marginally better predictor. Short-term pituitary suppression has a negative impact on AFC. This decline in AFC may influence the number of oocytes retrieved, suggesting the suppressive impact of exogenous hormones on the biological capacity of the ovary during stimulation.


[Update on infective endocarditis].
Infective endocarditis has continuously evolved since its first clinical description by William Osler in the late 19th century. The epidemiological and microbiological profile of the disease has changed as the result of the progress of the medical care and demographic mutation in industrialized countries. Furthermore, advances in anti-infective therapy and in cardiovascular surgery have contributed to an improvement in the management and the prognosis of this severe infectious disease. During the past decade, the recommendations on antibiotic prophylaxis against infective endocarditis have changed dramatically. Guidelines on management of infective endocarditis and state-of-the-art articles have been published recently and this work aims to outline current recommendations about this evolving disease.


Codeine intoxication associated with ultrarapid CYP2D6 metabolism.
Life-threatening opioid intoxication developed in a patient after he was given small doses of codeine for the treatment of a cough associated with bilateral pneumonia. Codeine is bioactivated by CYP2D6 into morphine, which then undergoes further glucuronidation. CYP2D6 genotyping showed that the patient had three or more functional alleles, a finding consistent with ultrarapid metabolism of codeine. We attribute the toxicity to this genotype, in combination with inhibition of CYP3A4 activity by other medications and a transient reduction in renal function.


Long-term effects of incident diabetes mellitus on cardiovascular outcomes in people treated for hypertension: the ALLHAT Diabetes Extension Study.
Thiazide-type diuretics are associated with an increased incidence of diabetes compared with other antihypertensive medications. In this study, we determined the long-term cardiovascular disease (CVD) consequences of incident diuretic-associated diabetes compared with the effects of incident diabetes associated with calcium channel blocker and angiotensin-converting enzyme inhibitor use. A total of 22 418 participants from the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) with baseline diabetes, incident diabetes (7.5% with chlorthalidone, 5.6% with amlodipine, and 4.3% with lisinopril), or no diabetes at 2 years of in-trial follow-up were followed for a mean total of 6.9 years (2.9 years in-trial and 4 additional years posttrial) through the use of national databases. The primary outcome was CVD mortality (death from coronary heart disease [CHD], stroke, heart failure, or other CVD). Among other outcomes were all-cause mortality, non-CVD mortality, and CHD (nonfatal myocardial infarction or fatal CHD). Participants on chlorthalidone with incident diabetes versus no diabetes had consistently lower, nonsignificant risk for CVD mortality (hazard ratio [HR], 1.04; 95% CI, 0.74-1.47), all-cause mortality (HR, 1.04; 95% CI, 0.82-1.30), and non-CVD mortality (HR, 1.05; 95% CI, 0.77-1.42) than participants on amlodipine or lisinopril with incident diabetes (HR range, 1.22-1.53). Participants with incident diabetes had elevated CHD risk compared with those with no diabetes (HR, 1.46; 95% CI, 1.09-1.96), but those on chlorthalidone had significantly lower risk than those on lisinopril (HR, 1.18 versus 2.57; P=0.04 for interaction). The findings suggest that thiazide-related incident diabetes has less adverse long-term CVD impact than incident diabetes that develops while on other antihypertensive medications.


Biliary excretion of acetaminophen-glutathione as an index of toxic activation of acetaminophen: effect of chemicals that alter acetaminophen hepatotoxicity.
Acetaminophen (AA) is converted, presumably by cytochrome P-450, to an electrophile which is conjugated with glutathione (GS). AA-GS is excreted into bile, therefore the biliary excretion rate of AA-GS may reflect the rate of activation of AA in vivo. In order to test this hypothesis, the effect of agents capable of altering the activation of AA including cytochrome P-450 inducers and inhibitors, cobaltous chloride which decreases the amount of P-450, prostaglandin synthetase inhibitors (indomethacin and naproxen), antioxidants (butylated hydroxyanisole, alpha-tocopherol, ascorbic acid and ascorbic acid palmitate) and other chemicals known to decrease AA hepatotoxicity (dimethylsulfoxide and cysteamine), on the biliary excretion of AA-GS was studied in hamsters, the species most sensitive to AA-induced hepatotoxicity. The biliary excretion of AA-GS increased linearly up to 1 mmol/kg of AA i.v., but at higher dosages exhibited saturation kinetics. Dosages above 0.5 mmol/kg lowered hepatic GS concentration. Of the cytochrome P-450 inducers, 3-methylcholanthrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin, increased the biliary excretion of AA-GS (2.9- and 3.2-fold, respectively) whereas ethanol and isoniazid did not affect it, and pregnenolone-16 alpha-carbonitrile tended to decrease it (43%). Phenobarbital tended to increase the biliary excretion of AA-GS, but not in a statistically significant manner. Several cytochrome P-450 inhibitors [metyrapone, 8-methoxypsoralen, 2-(4,6-dichloro-biphenyloxy) ethylamine, alpha-naphthoflavone and cimetidine] decreased the biliary excretion of AA-GS, although SKF 525-A and piperonyl butoxide did not. Cobaltous chloride decreased dramatically the biliary excretion of AA-GS.(ABSTRACT TRUNCATED AT 250 WORDS)


Poststroke Seizure and Epilepsy: A Review of Incidence, Risk Factors, Diagnosis, Pathophysiology, and Pharmacological Therapies.
Stroke is the most common cause of epilepsy and ultimately leads to a decrease in the quality of life of those affected. Ischemic and hemorrhagic strokes can both lead to poststroke epilepsy (PSE). Significant risk factors for PSE include age < 65age less than 65 years, stroke severity measured by the National Institutes of Health Stroke Scale (NIHSS), cortical involvement, and genetic factors such as TRPM6 polymorphism. The diagnosis of PSE is made by using imaging modalities, blood biomarkers, and prognostic criteria. Electroencephalography (EEG) is currently the gold standard to diagnose PSE, while new combinations of modalities are being tested to increase diagnostic specificity. This literature review uncovers a newly found mechanism for the pathology of poststroke epilepsy. The pathogenesis of early-onset and late-onset is characterized by sequelae of neuronal cellular hypoxia and disruption of the blood-brain barrier, respectively. Interleukin-6 is responsible for increasing the activity of glial cells, causing gliosis and hyperexcitability of neurons. Epinephrine, high-mobility group protein B1, downregulation of CD32, and upregulation of HLA-DR impact the pathology of poststroke epilepsy by inhibiting the normal neuronal immune response. Decreased levels of neuropeptide Y, a neurotransmitter, act through multiple unique mechanisms, such as inhibiting intracellular Ca2+ accumulation and acting as an anti-inflammatory, also implemented in the worsening progression of poststroke epilepsy. Additionally, CA1 hippocampal resonant neurons that increase theta oscillation are associated with poststroke epilepsy. Hypertensive small vessel disease may also have an implication in the temporal lobe epilepsy by causing occult microinfarctions. Furthermore, this review highlights the potential use of statins as primary prophylaxis against PSE, with multiple studies demonstrating a reduction in incidence using statins alone, statins in combination with antiepileptic drugs (AEDs), and statins with aspirin. The evidence strongly suggests that the second generation AEDs are a superior treatment method for PSE. Data from numerous studies demonstrate their relative lack of significant drug interactions, increased tolerability, and potential superiority in maintaining seizure-free status.


An alternative splicing product of the murine trpv1 gene dominant negatively modulates the activity of TRPV1 channels.
Transient receptor potential vanilloid 1 (TRPV1), or vanilloid receptor 1, is the founding member of the vanilloid type of TRP superfamily of nonselective cation channels. TRPV1 is activated by noxious heat, acid, and alkaloid irritants as well as several endogenous ligands and is sensitized by inflammatory factors, thereby serving important functions in detecting noxious stimuli in the sensory system and pathological states in different parts of the body. Whereas numerous studies have been carried out using the rat and human TRPV1 cDNA, the mouse TRPV1 cDNA has not been characterized. Here, we report molecular cloning of two TRPV1 cDNA variants from dorsal root ganglia of C57BL/6 mice. The deduced proteins are designated TRPV1alpha and TRPV1beta and contain 839 and 829 amino acids, respectively. TRPV1beta arises from an alternative intron recognition signal within exon 7 of the trpv1 gene. We found a predominant expression of TRPV1alpha in many tissues and significant expression of TRPV1beta in dorsal root ganglia, skin, stomach, and tongue. When expressed in HEK 293 cells or Xenopus oocytes, TRPV1alpha formed a Ca(2+)-permeable channel activated by ligands known to stimulate TRPV1. TRPV1beta was not functional by itself but its co-expression inhibited the function of TRPV1alpha. Furthermore, although both isoforms were synthesized at a similar rate, less TRPV1beta than TRPV1alpha protein was found in cells and on the cell surface, indicating that the beta isoform is highly unstable. Our data suggest that TRPV1beta is a naturally occurring dominant-negative regulator of the responses of sensory neurons to noxious stimuli.


A 10-year population-based study of people with multiple sclerosis in Stockholm, Sweden: use of and satisfaction with care and the value of different factors in predicting use of care.
The national strategy for treatment of chronic diseases - including MS - and changes in the Swedish welfare system, call for analyses of the use of, and patient satisfaction with, care in a long-term perspective. The aim was therefore to explore the use of care and the predictive value of personal factors, disease-specific factors and functioning on the use of care and to explore patient satisfaction with care in a 10-year perspective. Information regarding personal factors, disease-specific factors, functioning and satisfaction with care was collected by home-visits; use of care was collected from the Stockholm County Council computerised register. Data from 121 people with MS (PwMS) was collected. Primary care accounted for the majority of all care. Neurology and Rehabilitation Departments together accounted for two-thirds of all hospital outpatient care. Rehabilitation Departments accounted for one-third of the total number of inpatient days. Lower coping capacity, impaired manual dexterity and activity of daily living dependency at baseline, together with progress in MS disability predicted a higher use of care. Overall, patient satisfaction with care was stable over time. The extensive use of care offers challenges to care coordination. Implementation of person-centred care could be a strategy to increase efficacy/outcome of care.


In-depth characterization of the cisplatin mutational signature in human cell lines and in esophageal and liver tumors.
Cisplatin reacts with DNA and thereby likely generates a characteristic pattern of somatic mutations, called a mutational signature. Despite widespread use of cisplatin in cancer treatment and its role in contributing to secondary malignancies, its mutational signature has not been delineated. We hypothesize that cisplatin's mutational signature can serve as a biomarker to identify cisplatin mutagenesis in suspected secondary malignancies. Knowledge of which tissues are at risk of developing cisplatin-induced secondary malignancies could lead to guidelines for noninvasive monitoring for secondary malignancies after cisplatin chemotherapy. We performed whole genome sequencing of 10 independent clones of cisplatin-exposed MCF-10A and HepG2 cells and delineated the patterns of single and dinucleotide mutations in terms of flanking sequence, transcription strand bias, and other characteristics. We used the mSigAct signature presence test and nonnegative matrix factorization to search for cisplatin mutagenesis in hepatocellular carcinomas and esophageal adenocarcinomas. All clones showed highly consistent patterns of single and dinucleotide substitutions. The proportion of dinucleotide substitutions was high: 8.1% of single nucleotide substitutions were part of dinucleotide substitutions, presumably due to cisplatin's propensity to form intra- and interstrand crosslinks between purine bases in DNA. We identified likely cisplatin exposure in nine hepatocellular carcinomas and three esophageal adenocarcinomas. All hepatocellular carcinomas for which clinical data were available and all esophageal cancers indeed had histories of cisplatin treatment. We experimentally delineated the single and dinucleotide mutational signature of cisplatin. This signature enabled us to detect previous cisplatin exposure in human hepatocellular carcinomas and esophageal adenocarcinomas with high confidence.


Joint hypermobility and fibromyalgia in schoolchildren.
To test the hypothesis that joint hypermobility may play a part in the pathogenesis of pain in fibromyalgia, schoolchildren were examined for the coexistence of joint hypermobility and fibromyalgia. The study group consisted of 338 children (179 boys, 159 girls; mean age 11.5 years, range 9-15 years) from one public school in Beer-Sheva, Israel. In the assessment of joint hypermobility, the criteria devised by Carter and Bird were used. Any child who met at least three of five criteria was considered to have joint hypermobility. Children were considered to have fibromyalgia if they fulfilled the 1990 American College of Rheumatology criteria for the diagnosis of fibromyalgia, namely, widespread pain in combination with tenderness of 11 or more of the 18 specific tender point sites. The blind assessments of joint hypermobility (by AG) and fibromyalgia (by DB) were carried out independently. Of the 338 children 43 (13%) were found to have joint hypermobility and 21 (6%) fibromyalgia; 17 (81%) of the 21 with fibromyalgia had joint hypermobility and 17 (40%) of the 43 with joint hypermobility had fibromyalgia. Using chi 2 statistical analysis, joint hypermobility and fibromyalgia were found to be highly associated. This study suggests that there is a strong association between joint hypermobility and fibromyalgia in schoolchildren. It is possible that joint hypermobility may play a part in the pathogenesis of pain in fibromyalgia. More studies are needed to establish the clinical significance of this observation.


Rosacea: update on management and emerging therapies.
Rosacea is a common chronic skin disorder that has significant impact on the self-esteem and quality of life of affected individuals. Currently understood as an inflammatory condition that occurs in the context of an altered innate immune response, the available topical and systemic therapies function as immunomodulators to restore cutaneous homeostasis. The goals of therapy include reduction of papules, pustules, erythema and physical discomfort with improvement in quality of life. Standard topical treatments include metronidazole and azelaic acid, although many other agents and regimens have been presented. Subantimicrobial/antiinflammatory dose oral doxycycline was US FDA approved in 2006 for the management of rosacea, but Health Canada clearance was only recently granted for this indication. Furthermore, renewed research interest has led to the development of other emerging therapies including topical ivermectin, brimonidine and oxymetazoline that hold promise for patients suffering from this condition.


Hormones act downstream of TTG and GL2 to promote root hair outgrowth during epidermis development in the Arabidopsis root.
The Arabidopsis root produces a position-dependent pattern of hair-bearing and hairless cell types during epidermis development. Five loci (TRANSPARENT TESTA GLABRA [TTG], GLABRA2 [GL2], ROOT HAIR DEFECTIVE6 [RHD6], CONSTITUTIVE TRIPLE RESPONSE1 [CTR1], and AUXIN RESISTANT2 [AXR2]) and the plant hormones ethylene and auxin have been reported to affect the production of root hair and hairless cells in the Arabidopsis root. In this study, genetic, molecular, and physiological tests were employed to define the roles of these loci and hormones. Epistasis tests and reporter gene studies indicated that the hairless cell-promoting genes TTG and GL2 are likely to act early to negatively regulate the ethylene and auxin pathways. Studies of the developmental timing of the hormone effects indicated that ethylene and auxin pathways promote root hair outgrowth after cell-type differentiation has been initiated. The genetic analysis of ethylene-and auxin-related mutations showed that root hair formation is influenced by a network of hormone pathways, including a partially redundant ethylene signaling pathway. A model is proposed in which the patterning of root epidermal cells in Arabidopsis is regulated by the cell position-dependent action of the TTG/GL2 pathway, and the ethylene and auxin hormone pathways act to promote root hair outgrowth at a relatively late stage of differentiation.


Respiratory outcomes after neonatal prone versus supine positioning following scheduled cesarean delivery: a randomized trial.
Prone positioning is a common practice after vaginal birth promoting skin to skin contact and has been associated with improved oxygenation in mechanically ventilated neonates in the recent analysis. Neonates of women not in labor delivered via C-section are at increased risk of respiratory distress; it is unclear whether vigorous neonates without a need of resuscitation would benefit from prone positioning immediately after birth. To determine whether prone positioning of vigorous term neonates for the first 5 min after scheduled cesarean delivery will decrease the incidence of respiratory distress and therapeutic interventions, characterized by the frequency and duration of respiratory support (RS). In a single center, randomized parallel clinical trial, vigorous term neonates delivered via scheduled cesarean delivery were positioned prone or supine and their heart rate, oxygen saturation and signs of respiratory distress were recorded at 1-min intervals for the first 5 min. Infants not reaching target oxygen saturations suggested by the neonatal resuscitation guidelines received RS via Neopuff in supine position; respiratory support was discontinued once oxygen saturation targets were met and infant was free of respiratory symptoms. Primary outcomes measured were frequency and duration of RS, secondary outcomes were admission to the NICU for respiratory distress, length of stay, heart rate and oxygen saturation during the initial 5 min of life. Two hundred twenty-five neonates in prone and 231 in supine position completed the study out of 500 randomized subjects. Frequency of RS (31 versus 30%, p = .93), mean RS duration (4.08 versus 4.39 min; p = .71), frequency of admission to the NICU (5% in both groups; p = .95) and mean length of stay (0.14 versus 0.28 days; p = .42) were similar between the prone and supine groups. The supine cohort had higher initial oxygen saturation (p = .02) as well as heart rate (p = .004). Prone or supine positioning of term neonates after scheduled cesarean delivery resulted in comparable respiratory outcomes including the need for resuscitation in the first minutes of life.


Correlation and discrepancy of phospholipase A2 receptor staining in membranous nephropathy in paraffin-embedded kidney biopsies.
Distinguishing primary from secondary forms of membranous nephropathy (MN) in paraffin-embedded kidney biopsies is challenging. Previous studies have measured the accuracy, sensitivity, and specificity of phospholipase A2 receptor (PLA2R) on MN. However, due to the absence of a gold standard method for diagnosis, further studies are necessary. Here, we measure the correlation and discrepancy of PLA2R on MN in paraffin-embedded kidney biopsies by correlating PLA2R findings with immunofluorescence (IF), light microscopy (LM), and electron microscopy (EM) results. A total of 116 kidney biopsies were investigated including 87 MN and 29 nonmembranous kidney diseases. PLA2R was examined by indirect IF assay. A total of 79 MN cases were subjected to PLA2R staining and histopathological analyses. The remaining eight cases were excluded due to the lack of the glomeruli in the sections. The correlation and discrepancy between PLA2R and IF findings were seen in 65.45% and 34.55%, respectively. PLA2R and EM findings showed a 65.52% correlation and 34.48% discrepancy. LM features and PLA2R findings showed a correlation of 58.44% and discrepancy of 41.56%. Overall correlation between histopathology and PLA2R was seen in 65.82% and 34.18% showed discordant cases. All 29 non-membranous MN cases were negative for PLA2R. Staining for PLA2R could be a useful adjunctive tool in the stratification of cases of MN. The findings of this study strongly recommend the use of PLA2R IF staining method as a routine test for all MN cases.


Patients' perceptions of web self-service applications in primary healthcare.
This paper presents the preliminary findings of a case study of patients' acceptance and usage of web self-service - online appointment system - in a primary health care centre in a regional area in Australia. After two months of implementation, structured interviews were undertaken over three months to ascertain patients' perceptions of the web self-service application. The findings indicates that patients' acceptance of the web self-service application maybe hindered by their relative lower computer ownership or inadequate computer skills and access to the internet, their preference for flexible personal communication for appointment making and inadequate flexibility of the appointment system compared to phone call. Our preliminary findings may suggest that more than half of the healthcare consumers in this area are likely to accept the PCEHR initiative, however the decision makers of the PCEHR system need to carefully design the strategies and practice for the introduction of the innovation to overcome the substantial barriers to consumers' ability to access the internet-based e-health solutions.


Diagnosis and management of primary pulmonary leiomyosarcoma.
Leiomyosarcomas are cancers of smooth muscle cells that can arise from any location but occur most often in the uterus, retroperitoneum, or intraabdominal region. Primary leiomyosarcomas of the lung are extremely rare and are often diagnosed as a mass on routine chest radiography. Metastasis is uncommon and typically occurs late in the disease process, indicating the importance of early detection. Surgical excision is generally curative, offering patients optimal prognoses. The authors describe a 56-year-old asymptomatic man who was found to have a pulmonary mass on routine chest radiography. Further testing revealed a primary pulmonary leiomyosarcoma. The tumor was excised and postoperative osteopathic manipulative treatment was applied to help facilitate patient recovery. A brief discussion of the typical clinical presentation, prevalence, and medical management of these tumors is included.


Microplate alamar blue assay versus BACTEC 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium.
In response to the need for rapid, inexpensive, high-throughput assays for antimycobacterial drug screening, a microplate-based assay which uses Alamar blue reagent for determination of growth was evaluated. MICs of 30 antimicrobial agents against Mycobacterium tuberculosis H37Rv, M. tuberculosis H37Ra, and Mycobacterium avium were determined in the microplate Alamar blue assay (MABA) with both visual and fluorometric readings and compared to MICs determined in the BACTEC 460 system. For all three mycobacterial strains, there was < or = 1 dilution difference between MABA and BACTEC median MICs in four replicate experiments for 25 to 27 of the 30 antimicrobics. Significant differences between MABA and BACTEC MICs were observed with 0, 2, and 5 of 30 antimicrobial agents against H37Rv, H37Ra, and M. avium, respectively. Overall, MICs determined either visually or fluorometrically in MABA were highly correlated with those determined in the BACTEC 460 system, and visual MABA and fluorometric MABA MICs were highly correlated. MICs of rifampin, rifabutin, minocycline, and clarithromycin were consistently lower for H37Ra compared to H37Rv in all assays but were similar for most other drugs. M. tuberculosis H37Ra may be a suitable surrogate for the more virulent H37Rv strain in primary screening of compounds for antituberculosis activity. MABA is sensitive, rapid, inexpensive, and nonradiometric and offers the potential for screening, with or without analytical instrumentation, large numbers of antimicrobial compounds against slow-growing mycobacteria.


Imaging the evolution of metallic states in a correlated iridate.
The Ruddlesden-Popper series of iridates (Srn+1IrnO3n+1) have been the subject of much recent attention due to the anticipation of emergent phenomena arising from the cooperative action of spin-orbit-driven band splitting and Coulomb interactions. However, an ongoing debate over the role of correlations in the formation of the charge gap and a lack of understanding of the effects of doping on the low-energy electronic structure have hindered experimental progress in realizing many of the predicted states. Using scanning tunnelling spectroscopy we map out the spatially resolved density of states in Sr3Ir2O7 (Ir327). We show that its parent compound, argued to exist only as a weakly correlated band insulator, in fact possesses a substantial ~ 130 meV charge excitation gap driven by an interplay between structure, spin-orbit coupling and correlations. We find that single-atom defects are associated with a strong electronic inhomogeneity, creating an important distinction between the intrinsic and spatially averaged electronic structure. Combined with first-principles calculations, our measurements reveal how defects at specific atomic sites transfer spectral weight from higher energies to the gap energies, providing a possible route to obtaining metallic electronic states from the parent insulating states in the iridates.


Glial cell line-derived neurotrophic factor mediates the desirable actions of the anti-addiction drug ibogaine against alcohol consumption.
Alcohol addiction manifests as uncontrolled drinking despite negative consequences. Few medications are available to treat the disorder. Anecdotal reports suggest that ibogaine, a natural alkaloid, reverses behaviors associated with addiction including alcoholism; however, because of side effects, ibogaine is not used clinically. In this study, we first characterized the actions of ibogaine on ethanol self-administration in rodents. Ibogaine decreased ethanol intake by rats in two-bottle choice and operant self-administration paradigms. Ibogaine also reduced operant self-administration of ethanol in a relapse model. Next, we identified a molecular mechanism that mediates the desirable activities of ibogaine on ethanol intake. Microinjection of ibogaine into the ventral tegmental area (VTA), but not the substantia nigra, reduced self-administration of ethanol, and systemic administration of ibogaine increased the expression of glial cell line-derived neurotrophic factor (GDNF) in a midbrain region that includes the VTA. In dopaminergic neuron-like SHSY5Y cells, ibogaine treatment upregulated the GDNF pathway as indicated by increases in phosphorylation of the GDNF receptor, Ret, and the downstream kinase, ERK1 (extracellular signal-regulated kinase 1). Finally, the ibogaine-mediated decrease in ethanol self-administration was mimicked by intra-VTA microinjection of GDNF and was reduced by intra-VTA delivery of anti-GDNF neutralizing antibodies. Together, these results suggest that GDNF in the VTA mediates the action of ibogaine on ethanol consumption. These findings highlight the importance of GDNF as a new target for drug development for alcoholism that may mimic the effect of ibogaine against alcohol consumption but avoid the negative side effects.


Antispasmodic and vasodilator activities of Morinda citrifolia root extract are mediated through blockade of voltage dependent calcium channels.
Morinda citrifolia (Noni) is an edible plant with wide range of medicinal uses. It occurs exclusively in tropical climate zone from India through Southeast Asia and Australia to Eastern Polynesia and Hawaii. The objective of this study was to explore the possible mode(s) of action for its antispasmodic, vasodilator and cardio-suppressant effects to rationalize its medicinal use in gut and cardiovascular disorders. Isolated tissue preparations such as, rabbit jejunum, rat and rabbit aorta and guinea pig atria were used to test the antispasmodic and cardiovascular relaxant effects and the possible mode of action(s) of the 70% aqueous-ethanolic extract of Morinda citrifolia roots (Mc.Cr). The Mc.Cr produced a concentration-dependent relaxation of spontaneous and high K(+) induced contractions in isolated rabbit jejunum preparations. It also caused right ward shift in the concentration response curves of Ca(++), similar to that of verapamil. In guinea-pig right atria, Mc.Cr caused inhibition of both atrial force and rate of spontaneous contractions. In rabbit thoracic aortic preparations, Mc.Cr also suppressed contractions induced by phenylephrine (1.0 μM) in normal- Ca(++) and Ca(++)-free kreb solutions and by high K(+), similar to that of verapamil. In rat thoracic aortic preparations, Mc.Cr also relaxed the phenylephrine (1.0 μM)-induced contractions. The vasodilatory responses were not altered in the presence of L-NAME (0.1 mM) or atropine (1.0 μM) and removal of endothelium. These results suggest that the spasmolytic and vasodilator effects of Mc.Cr root extract are mediated possibly through blockade of voltage-dependent calcium channels and release of intracellular calcium, which may explain the medicinal use of Morinda citrifolia in diarrhea and hypertension. However, more detailed studies are required to assess the safety and efficacy of this plant.


Telomere dysfunction and evolution of intestinal carcinoma in mice and humans.
Telomerase activation is a common feature of advanced human cancers and facilitates the malignant transformation of cultured human cells and in mice. These experimental observations are in accord with the presence of robust telomerase activity in more advanced stages of human colorectal carcinogenesis. However, the occurrence of colon carcinomas in telomerase RNA (Terc)-null, p53-mutant mice has revealed complex interactions between telomere dynamics, checkpoint responses and carcinogenesis. We therefore sought to determine whether telomere dysfunction exerts differential effects on cancer initiation versus progression of mouse and human intestinal neoplasia. In successive generations of ApcMin Terc-/- mice, progressive telomere dysfunction led to an increase in initiated lesions (microscopic adenomas), yet a significant decline in the multiplicity and size of macroscopic adenomas. That telomere dysfunction also contributes to human colorectal carcinogenesis is supported by the appearance of anaphase bridges (a correlate of telomere dysfunction) at the adenoma-early carcinoma transition, a transition recognized for marked chromosomal instability. Together, these data are consistent with a model in which telomere dysfunction promotes the chromosomal instability that drives early carcinogenesis, while telomerase activation restores genomic stability to a level permissive for tumor progression. We propose that early and transient telomere dysfunction is a major mechanism underlying chromosomal instability of human cancer.


Elemental analysis of hair among hydrofluoric acid exposed workers.
The concentrations of fluorine (F), sodium (Na), magnesium (Mg), aluminum (Al), potassium (K), phosphorus (P), calcium (Ca), iron (Fe), nickel (Ni), zinc (Zn) and iodine (I) in the hair of 142 hydrofluoric acid (HF) exposed workers and 273 control subjects were analyzed by wavelength dispersive X-ray fluorescence spectrometry. Postshift urine and serum specimens were also collected for the determination of fluoride. To determine whether external contamination influences hair analysis, the control hair samples were kept in the work environment for one week. With the exception of lower K and Fe values, the levels of F and other elements in the hair of HF workers were higher than in the control subjects. The concentrations of F in hair and in postshift urine were in good correlation (r = 0.65). In the hair of HF workers F and Ca, F and Mg, F and P, F and Al were well correlated with each other (r greater than 0.6). F concentration in the hair increased after the sample was retained, however, it decreased to the reference value after washing. The levels of Ca, Mg and other elements did not change during the experiment.


Prevalence, co-morbidity and correlates of mental disorders in the general population: results from the German Health Interview and Examination Survey (GHS).
The German National Health Interview and Examination Survey (GHS) is the first government mandated nationwide study to investigate jointly the prevalence of somatic and mental disorders within one study in the general adult population in Germany. This paper reports results from its Mental Health Supplement (GHS-MHS) on 4-week 12-month, and selected lifetime prevalence of a broad range of DSM-IV mental disorders, their co-morbidity and correlates in the community. The sample of the GHS-MHS (n=4181; multistage stratified random sample drawn from population registries; conditional response rate: 87.6%) can be regarded as representative for the German population aged 18-65. Diagnoses are based on fully structured computer assisted clinical interviews (M-CIDI), conducted by clinically trained interviewers. 12-month prevalence for any DSM-IV study disorder is 31% (lifetime: 43%; 4-week: 20%) with anxiety disorders, mood disorders and somatoform syndromes being the most frequent diagnoses. Retrospective age of onset information reveals that most disorders begin early in life. Co-morbidity rates among mental disorders range from 44% to 94%. Correlates of increased rates of mental disorders and co-morbidity were: female gender (except for substance disorders), not being married, low social class, and poor somatic health status. Health care utilization for mental disorders depended on co-morbidity (30% in 'pure', 76% in highly co-morbid cases) and varied from 33% for substance use disorders to 75% for panic disorder. Results confirm and extend results from other national studies using the same assessment instruments with regard to prevalence, co-morbidity and sociodemographic correlates, covering a broader range of DSM-IV disorders [i.e. somatoform disorders, all anxiety disorders (except PTSD), mental disorders due to substance or general medical factor, eating disorders]. Intervention rates were higher than in previous studies, yet still low overall.


Advances in small animal mesentery models for in vivo flow cytometry, dynamic microscopy, and drug screening.
Using animal mesentery with intravital optical microscopy is a well-established experimental model for studying blood and lymph microcirculation in vivo. Recent advances in cell biology and optical techniques provide the basis for extending this model for new applications, which should generate significantly improved experimental data. This review summarizes the achievements in this specific area, including in vivo label-free blood and lymph photothermal flow cytometry, super-sensitive fluorescence image cytometry, light scattering and speckle flow cytometry, microvessel dynamic microscopy, infrared (IR) angiography, and high-speed imaging of individual cells in fast flow. The capabilities of these techniques, using the rat mesentery model, were demonstrated in various studies; e.g., real-time quantitative detection of circulating and migrating individual blood and cancer cells, studies on vascular dynamics with a focus on lymphatics under normal conditions and under different interventions (e.g. lasers, drugs, nicotine), assessment of lymphatic disturbances from experimental lymphedema, monitoring cell traffic between blood and lymph systems, and high-speed imaging of cell transient deformability in flow. In particular, the obtained results demonstrated that individual cell transportation in living organisms depends on cell type (e.g., normal blood or leukemic cells), the cellos functional state (e.g., live, apoptotic, or necrotic), and the functional status of the organism. Possible future applications, including in vivo early diagnosis and prevention of disease, monitoring immune response and apoptosis, chemo- and radio-sensitivity tests, and drug screening, are also discussed.


A systems approach to healthcare: agent-based modeling, community mental health, and population well-being.
Explore whether agent-based modeling and simulation can help healthcare administrators discover interventions that increase population wellness and quality of care while, simultaneously, decreasing costs. Since important dynamics often lie in the social determinants outside the health facilities that provide services, this study thus models the problem at three levels (individuals, organizations, and society). The study explores the utility of translating an existing (prize winning) software for modeling complex societal systems and agent's daily life activities (like a Sim City style of software), into a desired decision support system. A case study tests if the 3 levels of system modeling approach is feasible, valid, and useful. The case study involves an urban population with serious mental health and Philadelphia's Medicaid population (n=527,056), in particular. Section 3 explains the models using data from the case study and thereby establishes feasibility of the approach for modeling a real system. The models were trained and tuned using national epidemiologic datasets and various domain expert inputs. To avoid co-mingling of training and testing data, the simulations were then run and compared (Section 4.1) to an analysis of 250,000 Philadelphia patient hospital admissions for the year 2010 in terms of re-hospitalization rate, number of doctor visits, and days in hospital. Based on the Student t-test, deviations between simulated vs. real world outcomes are not statistically significant. Validity is thus established for the 2008-2010 timeframe. We computed models of various types of interventions that were ineffective as well as 4 categories of interventions (e.g., reduced per-nurse caseload, increased check-ins and stays, etc.) that result in improvement in well-being and cost. The 3 level approach appears to be useful to help health administrators sort through system complexities to find effective interventions at lower costs.


Phosphorylation of VE-cadherin is modulated by haemodynamic forces and contributes to the regulation of vascular permeability in vivo.
Endothelial adherens junctions maintain vascular integrity. Arteries and veins differ in their permeability but whether organization and strength of their adherens junctions vary has not been demonstrated in vivo. Here we report that vascular endothelial cadherin, an endothelial specific adhesion protein located at adherens junctions, is phosphorylated in Y658 and Y685 in vivo in veins but not in arteries under resting conditions. This difference is due to shear stress-induced junctional Src activation in veins. Phosphorylated vascular endothelial-cadherin is internalized and ubiquitinated in response to permeability-increasing agents such as bradykinin and histamine. Inhibition of Src blocks vascular endothelial cadherin phosphorylation and bradykinin-induced permeability. Point mutation of Y658F and Y685F prevents vascular endothelial cadherin internalization, ubiquitination and an increase in permeability by bradykinin in vitro. Thus, phosphorylation of vascular endothelial cadherin contributes to a dynamic state of adherens junctions, but is not sufficient to increase vascular permeability in the absence of inflammatory agents.


Surgical anatomy of the spinal accessory nerve and the trapezius branches of the cervical plexus.
A thorough understanding of the topographical anatomy of the spinal accessory nerve and the cervical plexus branches is a basic prerequisite for positive results when operating on the neck. To give an exact description of the topographical and surgical anatomy of the spinal accessory nerve (SAN) and the trapezius branches of the cervical plexus. Anatomic analysis of the SAN and the trapezius branches of the cervical plexus. The topographical anatomy of the SAN and the cervical plexus branches were studied in the anterior and posterior triangles of the necks of 46 perfusion-fixed human cadavers of both sexes, which ranged in age from 55 to 97 years (mean age, 83 years). The SAN can be identified on the posterior border of the sternocleidomastoid (SCM) muscle, 8.2 + 1.01 cm cranial to the clavicle. In 37% of cases, the SAN enters the posterior triangle of the neck dorsal to the SCM muscle, where it passes through the muscle in 63% of these cases. In the anterior triangle of the neck, the SAN crosses the internal jugular vein ventrally in 56% of the cases and dorsally in 44%. Regarding the cervical plexus, 1 trapezius branch could be found in 9% of the specimens, 2 in 61%, and 3 in 30%. None of the branches merged with the SAN medial to the anterior border of the trapezius muscle. In most cases, a tiny additional branch could be found arising from the SAN about 2 cm medial to the trapezius muscle. This branch enters the descendant part of the muscle approximately 2 to 3 cm cranial to the main nerve. Surprisingly, available data on topographical as well as surgical anatomy of the SAN and the trapezius branches of the cervical plexus are confusing and often wrong. The descriptions given herein can help to minimize the risk of injuring the SAN during neck surgery and preserve the additional innervation of the trapezius muscle granted by the rami trapezii of the cervical plexus.


Leveraging terminological resources for mapping between rare disease information sources.
Rare disease information sources are incompletely and inconsistently cross-referenced to one another, making it difficult for information seekers to navigate across them. The development of such cross-references established manually by experts is generally labor intensive and costly. To develop an automatic mapping between two of the major rare diseases information sources, GARD and Orphanet, by leveraging terminological resources, especially the UMLS. We map the rare disease terms from Orphanet and ORDR to the UMLS. We use the UMLS as a pivot to bridge between the rare disease terminologies. We compare our results to a mapping obtained through manually established cross-references to OMIM. Our mapping has a precision of 94%, a recall of 63% and an F1-score of 76%. Our automatic mapping should help facilitate the development of more complete and consistent cross-references between GARD and Orphanet, and is applicable to other rare disease information sources as well.


Aging. Aging-induced type I interferon response at the choroid plexus negatively affects brain function.
Aging-associated cognitive decline is affected by factors produced inside and outside the brain. By using multiorgan genome-wide analysis of aged mice, we found that the choroid plexus, an interface between the brain and the circulation, shows a type I interferon (IFN-I)-dependent gene expression profile that was also found in aged human brains. In aged mice, this response was induced by brain-derived signals, present in the cerebrospinal fluid. Blocking IFN-I signaling within the aged brain partially restored cognitive function and hippocampal neurogenesis and reestablished IFN-II-dependent choroid plexus activity, which is lost in aging. Our data identify a chronic aging-induced IFN-I signature, often associated with antiviral response, at the brain's choroid plexus and demonstrate its negative influence on brain function, thereby suggesting a target for ameliorating cognitive decline in aging.


Molecular epidemiology of current classical swine fever virus isolates of wild boar in Germany.
Classical swine fever (CSF) has caused significant economic losses in industrialized pig production, and is still present in some European countries. Recent CSF outbreaks in Europe were mainly associated with strains of genogroup 2 (subgroup 2.3). Although there are extensive datasets regarding 2.3 strains, there is very little information available on longer fragments or whole classical swine fever virus (CSFV) genomes. Furthermore, there are no detailed analyses of the molecular epidemiology of CSFV wild boar isolates available. Nevertheless, complete genome sequences are supportive in phylogenetic analyses, especially in affected wild boar populations. Here, German CSFV strains of subgroup 2.3 were fully sequenced using two different approaches: (i) a universal panel of CSFV primers that were developed to amplify the complete genome in overlapping fragments for chain-terminator sequencing; and (ii) generation of a single full-length amplicon of the CSFV genome obtained by long-range RT-PCR for deep sequencing with next-generation sequencing technology. In total, five different strains of CSFV subgroup 2.3 were completely sequenced using these newly developed protocols. The approach was used to study virus spread and evolutionary history in German wild boar. For the first time, the results of our study clearly argue for the possibility of a long-term persistence of genotype 2.3 CSFV strains in affected regions at an almost undetectable level, even after long-term oral vaccination campaigns with intensive monitoring. Hence, regional persistence in wild boar populations has to be taken into account as an important factor in the continual outbreaks in affected areas.


Validity of treadmill- and track-based individual calibration methods for estimating free-living walking speed and VO2 using the Actigraph accelerometer.
For many patients clinical prescription of walking will be beneficial to health and accelerometers can be used to monitor their walking intensity, frequency and duration over many days. Walking intensity should include establishment of individual specific accelerometer count, walking speed and energy expenditure (VO2) relationships and this can be achieved using a walking protocol on a treadmill or overground. However, differences in gait mechanics during treadmill compared to overground walking may result in inaccurate estimations of free-living walking speed and VO2. The aims of this study were to compare the validity of track- and treadmill-based calibration methods for estimating free-living level walking speed and VO2 and to explain between-method differences in accuracy of estimation. Fifty healthy adults [32 women and 18 men; mean (SD): 40 (13) years] walked at four pre-determined speeds on an outdoor track and a treadmill, and completed three 1-km self-paced level walks while wearing an Actigraph monitor and a mobile oxygen analyser. Speed- and VO2-to-Actigraph count individual calibration equations were computed for each calibration method. Between-method differences in calibration equation parameters, prediction errors, and relationships of walking speed with VO2 and Actigraph counts were assessed. The treadmill-calibration equation overestimated free-living walking speed (on average, by 0.7 km · h(-1)) and VO2 (by 4.99 ml · kg(-1) · min(-1)), while the track-calibration equation did not. This was because treadmill walking, from which the calibration equation was derived, produced lower Actigraph counts and higher VO2 for a given walking speed compared to walking on a track. The prediction error associated with the use of the treadmill-calibration method increased with free-living walking speed. This issue was not observed when using the track-calibration method. The proposed track-based individual accelerometer calibration method can provide accurate and unbiased estimates of free-living walking speed and VO2 from walking. The treadmill-based calibration produces calibration equations that tend to substantially overestimate both VO2 and speed.


Adequacy of reporting race/ethnicity in clinical trials in areas of health disparities.
Although federal initiatives have mandated broader inclusion of minorities in clinical research on diseases that have disparities in health by race and ethnicity, it is not clear whether these initiatives have affected reporting of trial results. The objective of this study was to examine the reporting of race/ethnicity in clinical trials reports in areas of known disparities in health (i.e., diabetes, cardiovascular disease, HIV/AIDS, and cancer) and to determine what factors were associated with reporting of race/ethnicity in results. We performed a Medline search covering the period January 1989 to Oct 2000 to identify clinical trials of diabetes, cardiovascular disease, HIV/AIDS, and cancer published in the Annals of Internal Medicine, JAMA, and New England Journal of Medicine. The main outcome measure was the reporting of participation and of results by race/ethnicity of trial participants. Of 253 eligible trials, 40% (n=102) were non race-focused yet did not report race, while 2% (n=4) were non gender-focused and did not report gender. Forty-six percent of trials that reported the race/ethnicity of the sample reported only one or two racial/ethnic categories, and in 43% of these trials the total number of individuals reported in each race/ethnicity category did not equal the total reported sample size. Analysis of results by race/ethnicity was reported in only two trials, and by gender in only three trials. In diseases with known racial and ethnic disparities, many clinical trials do not report the race/ethnicity of the study participants, and almost none report analyses by race/ethnicity. Although federal initiatives mandate inclusion of minority groups in research, that inclusion has not translated to reporting of results that might guide therapeutic decisions.


Clinical and Radiological Evaluation of Turmeric Powder as a Pulpotomy Medicament in Primary Teeth: An in vivo Study.
Many plants with biological and antimicrobiological properties have been studied since there has been a relevant increase in the incidence of antibiotic overuse and misuse. In dentistry, phytomedicines have been used as anti-inflammatory, antibiotic, analgesic, and sedative agents. Turmeric is used extensively in foods for its flavor and color, as well as having a long tradition of use in the Chinese and Ayurvedic systems of medicine, particularly as an anti-inflammatory and for the treatment of flatulence, jaundice, menstrual difficulties, hematuria, hemorrhage, and colic. This article studies ahead with a new idea of using powdered turmeric as a material of pulpotomy procedure in primary teeth. Purohit RN, Bhatt M, Purohit K, Acharya J, Kumar R, Garg R. Clinical and Radiological Evaluation of Turmeric Powder as a Pulpotomy Medicament in Primary Teeth: An in vivo Study. Int J Clin Pediatr Dent 2017;10(1):37-40.


Preterm Cognitive Function Into Adulthood.
Very preterm (VP; gestational age <32 weeks) and very low birth weight (VLBW; <1500 g) births are related to impaired cognitive function across the life span. It is not known how stable cognitive functions are from childhood to adulthood for VP/VLBW compared with term-born individuals and how early adult cognitive function can be predicted. The Bavarian Longitudinal Study is a prospective geographically defined cohort study that followed 260 VP/VLBW and 229 term-born individuals from birth to adulthood. Data on cognitive function were assessed with developmental and IQ tests at 5 and 20 months and at 4, 6, 8, and 26 years of age. Across all assessments, VP/VLBW individuals had significantly lower IQ scores than term-born controls, even when individuals with severe cognitive impairment (n = 69) were excluded. IQ scores were found to be more stable over time for VP/VLBW than term-born individuals, yet differences in stability disappeared when individuals with cognitive impairment were excluded. Adult IQ could be predicted with fair certainty (r > 0.50) from age 20 months onward for the whole VP/VLBW sample (n = 260) and from 6 years onward for term-born individuals (n = 229). VP/VLBW individuals more often suffer from cognitive problems across childhood into adulthood and these problems are relatively stable from early childhood onward. VP/VLBW children's risk for cognitive problems can be reliably diagnosed at the age of 20 months. These findings provide strong support for the timing of cognitive follow-up at age 2 years to plan special support services for children with cognitive problems.


Gene expression profiles and molecular mechanism of cultured human chondrocytes' exposure to T-2 toxin and deoxynivalenol.
T-2 toxin and deoxynivalenol (DON) are secondary metabolites produced by Fusarium fungi and are commonly found on food and feed. Although T-2 toxin and DON have been suggested as the etiology of Kashin-Beck disease (KBD), an endemic osteochondropathy, little is known about the mechanism when human chondrocytes are exposed to T-2 toxin and DON. The purpose of this study is to identify the gene expression differences and underlying molecular changes modulated by T-2 toxin and DON in vitro in human chondrocytes. After the experiments of cell viability, the gene expression profiles were analyzed in cells that were treated with 0.01 μg/ml T-2 toxin and 1.0 μg/ml DON for 72 h by Affymetrix Human Gene Chip. The array results showed that 882 and 2118 genes were differentially expressed for T-2 toxin and DON exposure, respectively. Enrichment analysis revealed that diverse cellular processes including DNA damage, cell cycle regulation and metabolism of extracellular matrix were affected when human chondrocytes were exposed to T-2 toxin and DON. These results demonstrate the gene expression differences and molecular mechanism of cultured human chondrocytes exposure to T-2 toxin and DON, and provide a new insight into future research in the etiology of KBD.


Stable mucus-associated bacterial communities in bleached and healthy corals of Porites lobata from the Arabian Seas.
Coral reefs are subject to coral bleaching manifested by the loss of endosymbiotic algae from coral host tissue. Besides algae, corals associate with bacteria. In particular, bacteria residing in the surface mucus layer are thought to mediate coral health, but their role in coral bleaching is unknown. We collected mucus from bleached and healthy Porites lobata colonies in the Persian/Arabian Gulf (PAG) and the Red Sea (RS) to investigate bacterial microbiome composition using 16S rRNA gene amplicon sequencing. We found that bacterial community structure was notably similar in bleached and healthy corals, and the most abundant bacterial taxa were identical. However, fine-scale differences in bacterial community composition between the PAG and RS were present and aligned with predicted differences in sulfur- and nitrogen-cycling processes. Based on our data, we argue that bleached corals benefit from the stable composition of mucus bacteria that resemble their healthy coral counterparts and presumably provide a conserved suite of protective functions, but monitoring of post-bleaching survival is needed to further confirm this assumption. Conversely, fine-scale site-specific differences highlight flexibility of the bacterial microbiome that may underlie adjustment to local environmental conditions and contribute to the widespread success of Porites lobata.


A draft genome sequence of the elusive giant squid, Architeuthis dux.
The giant squid (Architeuthis dux; Steenstrup, 1857) is an enigmatic giant mollusc with a circumglobal distribution in the deep ocean, except in the high Arctic and Antarctic waters. The elusiveness of the species makes it difficult to study. Thus, having a genome assembled for this deep-sea-dwelling species will allow several pending evolutionary questions to be unlocked. We present a draft genome assembly that includes 200 Gb of Illumina reads, 4 Gb of Moleculo synthetic long reads, and 108 Gb of Chicago libraries, with a final size matching the estimated genome size of 2.7 Gb, and a scaffold N50 of 4.8 Mb. We also present an alternative assembly including 27 Gb raw reads generated using the Pacific Biosciences platform. In addition, we sequenced the proteome of the same individual and RNA from 3 different tissue types from 3 other species of squid (Onychoteuthis banksii, Dosidicus gigas, and Sthenoteuthis oualaniensis) to assist genome annotation. We annotated 33,406 protein-coding genes supported by evidence, and the genome completeness estimated by BUSCO reached 92%. Repetitive regions cover 49.17% of the genome. This annotated draft genome of A. dux provides a critical resource to investigate the unique traits of this species, including its gigantism and key adaptations to deep-sea environments.


Displacement of an E-box-binding repressor by basic helix-loop-helix proteins: implications for B-cell specificity of the immunoglobulin heavy-chain enhancer.
The activity of the immunoglobulin heavy-chain (IgH) enhancer is restricted to B cells, although it binds both B-cell-restricted and ubiquitous transcription factors. Activation of the enhancer in non-B cells upon overexpression of the basic helix-loop-helix (bHLH) protein E2A appears to be mediated not only by the binding of E2A to its cognate E box but also by the resulting displacement of a repressor from that same site. We have identified a "two-handed" zinc finger protein, denoted ZEB, the DNA-binding specificity of which mimics that of the cellular repressor. By employing a derivative E box that binds ZEB but not E2A, we have shown that the repressor is active in B cells and the IgH enhancer is silenced in the absence of binding competition by bHLH proteins. Hence, we propose that a necessary prerequisite of enhancer activity is the B-cell-specific displacement of a ZEB-like repressor by bHLH proteins.


Study and characterization of an ancient European flint white maize rich in anthocyanins: Millo Corvo from Galicia.
In the second half of the last century, the American dent hybrids began to be widely grown, leading to the disappearance or marginalization of the less productive traditional varieties. Nowadays the characterization of traditional landraces can help breeders to discover precious alleles that could be useful for modern genetic improvement and allow a correct conservation of these open pollinated varieties (opvs). In this work we characterized the ancient coloured cultivar "Millo Corvo" typical of the Spanish region of Galicia. We showed that this cultivar accumulates high amounts of anthocyanins (83.4 mg/100g flour), and by TLC (Thin Layer Chromatography) and HPLC (High Pressure Liquid Chromatography) analysis, we demonstrated that they mainly consisted of cyanidin. Mapping and sequencing data demonstrate that anthocyanin pigmentation is due to the presence of the red color1 gene(r1), a transcription factor driving the accumulation of this pigment in the aleurone layer. Further chemical analysis showed that the kernels are lacking in carotenoids, as confirmed by genetic study. Finally a DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging ability test showed that Millo Corvo, even though lacking carotenoids, has a high antioxidant ability, and could be considered as a functional food due to the presence of anthocyanins.


Continued high risk sexual behavior following diagnosis with acute HIV infection in South Africa and Malawi: implications for prevention.
Understanding sexual behavior following diagnosis of acute HIV infection (AHI) is key to developing prevention programs targeting individuals diagnosed with AHI. We conducted separate qualitative and quantitative interviews with individuals newly diagnosed (n = 19) with AHI at 1-, 4- and 12-weeks post-diagnosis and one qualitative interview with individuals who had previously been diagnosed with AHI (n = 18) in Lilongwe, Malawi and Johannesburg, South Africa between October 2007 and June 2008. The majority of participants reported engaging in sexual activity following diagnosis with AHI with a significant minority reporting unprotected sex during this time. Most participants perceived to have changed their behavior following diagnosis. However, participants reported barriers to condom use and abstinence, in particular, long term relationships and the need for disclosure of sero-status. Understanding of increased infectiousness during AHI was limited. Participants reported a desire for a behavioral intervention at the time of AHI diagnosis, however, there were differences by country in the types of interventions participants found acceptable. Studies are underway to determine the feasibility, acceptability and potential effectiveness of interventions designed for individuals with AHI.


Reduced TCR-dependent activation through citrullination of a T-cell epitope enhances Th17 development by disruption of the STAT3/5 balance.
Citrullination is a post-translational modification of arginine that commonly occurs in inflammatory tissues. Because T-cell receptor (TCR) signal quantity and quality can regulate T-cell differentiation, citrullination within a T-cell epitope has potential implications for T-cell effector function. Here, we investigated how citrullination of an immunedominant T-cell epitope affected Th17 development. Murine naïve CD4(+) T cells with a transgenic TCR recognising p89-103 of the G1 domain of aggrecan (agg) were co-cultured with syngeneic bone marrow-derived dendritic cells (BMDC) presenting the native or citrullinated peptides. In the presence of pro-Th17 cytokines, the peptide citrullinated on residue 93 (R93Cit) significantly enhanced Th17 development whilst impairing the Th2 response, compared to the native peptide. T cells responding to R93Cit produced less IL-2, expressed lower levels of the IL-2 receptor subunit CD25, and showed reduced STAT5 phosphorylation, whilst STAT3 activation was unaltered. IL-2 blockade in native p89-103-primed T cells enhanced the phosphorylated STAT3/STAT5 ratio, and concomitantly enhanced Th17 development. Our data illustrate how a post-translational modification of a TCR contact point may promote Th17 development by altering the balance between STAT5 and STAT3 activation in responding T cells, and provide new insight into how protein citrullination may influence effector Th-cell development in inflammatory disorders.


Blood gas measurement during exercise: a comparative study between arterialized earlobe sampling and direct arterial puncture in adults.
Sampling arterialized earlobe blood is thought to be easier and less painful than direct arterial puncture, and to allow measurement of blood gas values during exercise without the need to insert an arterial cannula. However, arterialized earlobe oxygen tension (PO2) often underestimates arterial PO2 at rest, and is not fully validated during exercise. We have therefore conducted a prospective study to compare values of PO2 and carbon dioxide tension (PCO2) and the discomfort experienced by adult subjects undergoing the two methods of blood sampling during exercise. Seventy consecutive adult patients were studied. Blood samples were drawn simultaneously from the radial artery and arterialized earlobe of each patient during the last minute of an 8 min exercise. Values of PO2 and PCO2 were measured by means of blood gas electrodes. The correlation coefficients between the two samples were 0.92 for PO2 and 0.91 for PCO2. However, the bias and the limits of agreement between the two methods were wide for PO2 (mean+/-2SD of the differences between the two methods: 0.63+/-1.50 kPa (4.7+/-11.2 mmHg)). The bias and the limits of agreement were smaller for PCO2. Patients felt that the earlobe method was not associated with less discomfort than radial artery puncture. We conclude that arterialized earlobe blood oxygen tension is not a good substitute for arterial oxygen tension during exercise, and should not be used to assess arterial oxygen tension in adults during exercise.


Noninvasive quantification of fluid mechanical energy losses in the total cavopulmonary connection with magnetic resonance phase velocity mapping.
A major determinant of the success of surgical vascular modifications, such as the total cavopulmonary connection (TCPC), is the energetic efficiency that is assessed by calculating the mechanical energy loss of blood flow through the new connection. Currently, however, to determine the energy loss, invasive pressure measurements are necessary. Therefore, this study evaluated the feasibility of the viscous dissipation (VD) method, which has the potential to provide the energy loss without the need for invasive pressure measurements. Two experimental phantoms, a U-shaped tube and a glass TCPC, were scanned in a magnetic resonance (MR) imaging scanner and the images were used to construct computational models of both geometries. MR phase velocity mapping (PVM) acquisitions of all three spatial components of the fluid velocity were made in both phantoms and the VD was calculated. VD results from MR PVM experiments were compared with VD results from computational fluid dynamics (CFD) simulations on the image-based computational models. The results showed an overall agreement between MR PVM and CFD. There was a similar ascending tendency in the VD values as the image spatial resolution increased. The most accurate computations of the energy loss were achieved for a CFD grid density that was too high for MR to achieve under current MR system capabilities (in-plane pixel size of less than 0.4 mm). Nevertheless, the agreement between the MR PVM and the CFD VD results under the same resolution settings suggests that the VD method implemented with a clinical imaging modality such as MR has good potential to quantify the energy loss in vascular geometries such as the TCPC.


Intracellular invasion of green algae in a salamander host.
The association between embryos of the spotted salamander (Ambystoma maculatum) and green algae ("Oophila amblystomatis" Lamber ex Printz) has been considered an ectosymbiotic mutualism. We show here, however, that this symbiosis is more intimate than previously reported. A combination of imaging and algal 18S rDNA amplification reveals algal invasion of embryonic salamander tissues and cells during development. Algal cells are detectable from embryonic and larval Stages 26-44 through chlorophyll autofluorescence and algal 18S rDNA amplification. Algal cell ultrastructure indicates both degradation and putative encystment during the process of tissue and cellular invasion. Fewer algal cells were detected in later-stage larvae through FISH, suggesting that the decline in autofluorescent cells is primarily due to algal cell death within the host. However, early embryonic egg capsules also contained encysted algal cells on the inner capsule wall, and algal 18S rDNA was amplified from adult reproductive tracts, consistent with oviductal transmission of algae from one salamander generation to the next. The invasion of algae into salamander host tissues and cells represents a unique association between a vertebrate and a eukaryotic alga, with implications for research into cell-cell recognition, possible exchange of metabolites or DNA, and potential congruence between host and symbiont population structures.


Draining T-Tube Jejunostomy: A Technique to Get Out of Trouble.
A perforated viscus in the postpancreaticoduodenectomy setting is a rare phenomenon and a devastating complication. In this situation, adherence to damage-control principles demands minimizing the operative intervention while addressing the intestinal perforation as a way to mitigate the injurious effects on a complex gastrointestinal reconstruction. Herein, we describe our intraoperative decision-making with an unconventional approach in the management of a perforated viscus in the postpancreaticoduodenectomy setting using a draining T-tube jejunostomy. Our patient recovered remarkably well from this and was discharged from the hospital in six days with a controlled draining T-tube jejunostomy, which was subsequently removed on postoperative day 35. Our case illustrates an important option when dealing with a perforated viscus in the complex gastrointestinal surgery patient that has minimal morbidity, adequate source control, and the potential for an excellent clinical outcome. As surgical care continues to be delivered in a specialty-driven manner, a draining T-tube jejunostomy presents the ideal technique to get out of trouble for the general surgeon practicing in the community who may not be as experienced with complex gastrointestinal surgery.


Effect of obesity on telomere length: Systematic review and meta-analysis.
The main objective of this systematic review is to assess the effects of obesity on telomere length. The following databases were searched: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), LILACS, SPORTdiscus, and Web of Science from inception to August 2014. The search was performed using the following combinations of terms: telomere AND "overweight" OR "obesity" OR "adiposity," without language restriction. Sixty-three original studies were included in this systematic review, comprising 119,439 subjects. Thirty-nine studies showed either weak or moderate correlation between obesity and telomere length; however, they showed an important heterogeneity. There is a tendency toward demonstrating negative correlation between obesity and telomere length. The selected studies showed weak to moderate correlation for the main search, and there was an important heterogeneity. For this reason, the causal relationship of obesity and telomere length remains open. Additional controlled longitudinal studies are needed to investigate this issue.


Intra-Cardiac Release of Extracellular Vesicles Shapes Inflammation Following Myocardial Infarction.
A rapid and massive influx of inflammatory cells occurs into ischemic area after myocardial infarction (MI), resulting in local release of cytokines and growth factors. Yet, the mechanisms regulating their production are not fully explored. The release of extracellular vesicles (EVs) in the interstitial space curbs important biological functions, including inflammation, and influences the development of cardiovascular diseases. To date, there is no evidence for in situ release of cardiac EVs after MI. The present study tested the hypothesis that local EV generation in the infarcted heart coordinates cardiac inflammation after MI. Coronary artery ligation in mice transiently increases EV levels in the left ventricle when compared with sham animals. EVs from infarcted hearts were characterized as large vesicles (252±18 nm) expressing cardiomyocyte and endothelial markers and small EVs (118±4 nm) harboring exosomal markers, such as CD (cluster of differentiation) 63 and CD9. Cardiac large EVs generated after MI, but not small EVs or sham EVs, increased the release of IL (interleukin)-6, CCL (chemokine ligand) 2, and CCL7 from fluorescence-activated cell-sorted Ly6C+ cardiac monocytes. EVs of similar diameter were also isolated from fragments of interventricular septum obtained from patients undergoing aortic valve replacement, thus supporting the clinical relevance of our findings in mice. The present study demonstrates that acute MI transiently increases the generation of cardiac EVs characterized as both exosomes and microvesicles, originating mainly from cardiomyocytes and endothelial cells. EVs accumulating in the ischemic myocardium are rapidly taken up by infiltrating monocytes and regulate local inflammatory responses.


Subchronic perinatal asphyxia increased anxiety-and depression-like behaviors in the rat offspring.
Perinatal asphyxia is one of the major cause of mortality in newborns and cause of neurological disorders in adulthood. Brain damage is of the most concern due to high sensitivity of nervous system to suboptimal intrauterine oxygen condition. The aim of this study was to assess effect of subchronic prenatal asphyxia (SPA) during sensitive stages of brain maturation on behavioral changes in rats, as a method of prenatal programming of anxiety and depression-like behavior. Pregnant Wistar/DV females were exposed to environment containing lower oxygen (10.5% O2) during sensitive stages of brain maturation (day 19-20 of gestation) for 4h a day and anxiety- and depression-like behaviors in offspring were assessed using battery of behavioral tests--Open field (OF), Elevated plus maze (EPM), Light/dark test (L/D), Forced swim test (FST), and Stress induced hyperthermia (SIH). OF did not induced changes of locomotor and exploration activities. The anxiety-like behavior was induced by SPA in EPM and L/D. These results were significant in males SPA group only. The higher response to the stress stimulus in SIH was recorded in both males and females SPA group. The intensity of climbing on the walls of cylinder in FST in males SPA group was significantly decreased indicating depression-like behavior in adulthood. In conclusion, we found out that perinatal asphyxia on 19th and 20th day of gestation caused anxiety- and depression-like behaviors in the rat offspring. Our model of SPA has proved to be useful to study the conditions of asphyxia during pregnancy, and could be suitable model for studies uncovering the mechanisms of prenatal programming of psychiatric diseases.


Second neoplasms in survivors of childhood cancer: findings from the Childhood Cancer Survivor Study cohort.
To review the reports of subsequent neoplasms (SNs) in the Childhood Cancer Survivor Study (CCSS) cohort that were made through January 1, 2006, and published before July 31, 2008, and to discuss the host-, disease-, and therapy-related risk factors associated with SNs. SNs were ascertained by survivor self-reports and subsequently confirmed by pathology findings or medical record review. Cumulative incidence of SNs and standardized incidence ratios for second malignant neoplasms (SMNs) were calculated. The impact of host-, disease-, and therapy-related risk factors was evaluated by Poisson regression. Among 14,358 cohort members, 730 reported 802 SMNs (excluding nonmelanoma skin cancers). This represents a 2.3-fold increase in the number of SMNs over that reported in the first comprehensive analysis of SMNs in the CCSS cohort, which was done 7 years ago. In addition, 66 cases of meningioma and 1,007 cases of nonmelanoma skin cancer were diagnosed. The 30-year cumulative incidence of SMNs was 9.3% and that of nonmelanoma skin cancer was 6.9%. Risk of SNs remains elevated for more than 20 years of follow-up for all primary childhood cancer diagnoses. In multivariate analyses, risks differ by SN subtype, but include radiotherapy, age at diagnosis, sex, family history of cancer, and primary childhood cancer diagnosis. Female survivors whose primary childhood cancer diagnosis was Hodgkin's lymphoma or sarcoma and who received radiotherapy are at particularly increased risk. Analyses of risk associated with radiotherapy demonstrated different dose-response curves for specific SNs. Childhood cancer survivors are at a substantial and increasing risk for SNs, including nonmelanoma skin cancer and meningiomas. Health care professionals should understand the magnitude of these risks to provide individuals with appropriate counseling and follow-up.