Genome-wide association study to characterize serum bilirubin elevations in patients with HCV treated with GS-9256, an HCV NS3 serine protease inhibitor.

Background: Protease inhibitors for the treatment of HCV can cause mild and reversible elevations of unconjugated bilirubin. We sought to characterize genetic determinants of bilirubin elevations using a genome-wide approach among patients with genotype 1 HCV who received combination therapy that included GS-9256, a novel potent inhibitor of HCV NS3 serine protease, as part of a Phase IIb trial.

Methods: Of the 200 patients sampled, 176 had confirmed European ancestry and were included in the analysis.

Reduction in cortical gamma synchrony during depolarized state of slow wave activity in mice.

EEG gamma band oscillations have been proposed to account for the neural synchronization crucial for perceptual integration. While increased gamma power and synchronization is generally observed during cognitive tasks performed during wake, several studies have additionally reported increased gamma power during sleep or anesthesia, raising questions about the characteristics of gamma oscillation during impaired consciousness and its role in conscious processing. Phase-amplitude modulation has been observed between slow wave activity (SWA, 0.

Eliminating encephalitogenic T cells without undermining protective immunity.

The current clinical approach for treating autoimmune diseases is to broadly blunt immune responses as a means of preventing autoimmune pathology. Among the major side effects of this strategy are depressed beneficial immunity and increased rates of infections and tumors. Using the experimental autoimmune encephalomyelitis model for human multiple sclerosis, we report a novel alternative approach for purging autoreactive T cells that spares beneficial immunity.

DNA-based methodology for the quantification of gastrointestinal nematode eggs in sheep faeces.

The presence of gastrointestinal nematode eggs in faecal samples is diagnostic of infection by these parasites. However, this technique cannot be used to distinguish between species of importance. The faecal culture technique and subsequent microscopic analysis of developed larvae is currently used to determine which parasite species are present in the samples, but these techniques take a week to perform and have inherent limitations.

Measuring chromatin interaction dynamics on the second time scale at single-copy genes.

The chromatin immunoprecipitation (ChIP) assay is widely used to capture interactions between chromatin and regulatory proteins, but it is unknown how stable most native interactions are. Although live-cell imaging suggests short-lived interactions at tandem gene arrays, current methods cannot measure rapid binding dynamics at single-copy genes. We show, by using a modified ChIP assay with subsecond temporal resolution, that the time dependence of formaldehyde cross-linking can be used to extract in vivo on and off rates for site-specific chromatin interactions varying over a ~100-fold dynamic range.

Chronic Ketamine Reduces the Peak Frequency of Gamma Oscillations in Mouse Prefrontal Cortex Ex vivo.

Abnormalities in EEG gamma band oscillations (GBO, 30-80 Hz) serve as a prominent biomarker of schizophrenia (Sz), associated with positive, negative, and cognitive symptoms. Chronic, subanesthetic administration of antagonists of N-methyl-D-aspartate receptors (NMDAR), such as ketamine, elicits behavioral effects, and alterations in cortical interneurons similar to those observed in Sz. However, the chronic effects of ketamine on neocortical GBO are unknown.

Co-expressed genes prepositioned in spatial neighborhoods stochastically associate with SC35 speckles and RNA polymerase II factories.

Chromosomally separated, co-expressed genes can be in spatial proximity, but there is still debate about how this nuclear organization is achieved. Proposed mechanisms include global genome organization, preferential positioning of chromosome territories, or gene-gene sharing of various nuclear bodies. To investigate this question, we selected a set of genes that were co-expressed upon differentiation of human multipotent stem cells.

Quantifying transcription factor kinetics: at work or at play?

Transcription factors (TFs) interact dynamically in vivo with chromatin binding sites. Here we summarize and compare the four different techniques that are currently used to measure these kinetics in live cells, namely fluorescence recovery after photobleaching (FRAP), fluorescence correlation spectroscopy (FCS), single molecule tracking (SMT) and competition ChIP (CC). We highlight the principles underlying each of these approaches as well as their advantages and disadvantages.

Vitamin D receptor (VDR) polymorphisms and severe RSV bronchiolitis: a systematic review and meta-analysis.

Background: A number of small studies have suggested a relationship between vitamin D status and severe acute lower respiratory tract infection (ALRI), including RSV-bronchiolitis. The objective of this study was to evaluate the relationship between vitamin D receptor (VDR) polymorphism and severe RSV-bronchiolitis through a systemic literature review and meta-analysis.

Methods: A comprehensive electronic literature search was conducted to identify all studies published before January 2013.

Monitoring dynamic binding of chromatin proteins in vivo by single-molecule tracking.

Single-molecule fluorescence microscopy has been used for decades to quantify macromolecular dynamics occurring in specimens that are in direct contact with a coverslip. This has permitted in vitro analysis of single-molecule motion in various biochemically reconstituted systems as well as in vivo studies of single-molecule motion on cell membranes. More recently, thanks to improvements in fluorescent tags and microscopes, it has been possible to follow individual molecules inside thicker specimens such as the nucleus of living cells.

Genome-wide haploinsufficiency screen reveals a novel role for γ-TuSC in spindle organization and genome stability.

How subunit dosage contributes to the assembly and function of multimeric complexes is an important question with implications in understanding biochemical, evolutionary, and disease mechanisms. Toward identifying pathways that are susceptible to decreased gene dosage, we performed a genome-wide screen for haploinsufficient (HI) genes that guard against genome instability in Saccharomyces cerevisiae. This led to the identification of all three genes (SPC97, SPC98, and TUB4) encoding the evolutionarily conserved γ-tubulin small complex (γ-TuSC), which nucleates microtubule assembly.

Vitamin D deficiency in surgical congenital heart disease: prevalence and relevance.

Vitamin D is a pleiotropic hormone important for the proper functioning of multiple organ systems. An emerging body of adult and pediatric critical care literature strongly suggests that vitamin D deficiency contributes to secondary organ pathophysiology, prolongs ICU stay, and worsens outcome in critically ill populations. Recent clinical studies suggest that a significant number of children with congenital heart disease (CHD) have post-operative vitamin D deficiency which appears to be associated with greater cardiovascular dysfunction.

CKAP2 ensures chromosomal stability by maintaining the integrity of microtubule nucleation sites.

Integrity of the microtubule spindle apparatus and intact cell division checkpoints are essential to ensure the fidelity of distributing chromosomes into daughter cells. Cytoskeleton-associated protein 2, CKAP2, is a microtubule-associated protein that localizes to spindle poles and aids in microtubule stabilization, but the exact function and mechanism of action are poorly understood. In the present study, we utilized RNA interference to determine the extent to which the expression of CKAP2 plays a role in chromosome segregation.

A survey of stated physician practices and beliefs on the use of steroids in pediatric fluid and/or vasoactive infusion-dependent shock.

Objective: Limited evidence exists on the use of corticosteroids in pediatric shock. We sought to determine physicians' practices and beliefs with regard to the management of pediatric shock.

Design: Cross-sectional, Internet-based survey.

Sofosbuvir for previously untreated chronic hepatitis C infection.

Background: In phase 2 trials, the nucleotide polymerase inhibitor sofosbuvir was effective in previously untreated patients with chronic hepatitis C virus (HCV) genotype 1, 2, or 3 infection.

Methods: We conducted two phase 3 studies in previously untreated patients with HCV infection. In a single-group, open-label study, we administered a 12-week regimen of sofosbuvir plus peginterferon alfa-2a and ribavirin in 327 patients with HCV genotype 1, 4, 5, or 6 (of whom 98% had genotype 1 or 4).

Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options.

Background: Patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3 for whom treatment with peginterferon is not an option, or who have not had a response to prior interferon treatment, currently have no approved treatment options. In phase 2 trials, regimens including the oral nucleotide polymerase inhibitor sofosbuvir have shown efficacy in patients with HCV genotype 2 or 3 infection.

Methods: We conducted two randomized, phase 3 studies involving patients with chronic HCV genotype 2 or 3 infection.

The relationship between vitamin D status and adrenal insufficiency in critically ill children.

Context: Recent studies in critically ill populations have suggested both adrenal insufficiency (AI) and vitamin D deficiency to be associated with worse clinical outcome. There are multiple mechanisms through which these pleiotropic hormones might synergistically influence critical illness.

Objective: The aim of the study was to investigate potential relationships between vitamin D status, adrenal status, and cardiovascular dysfunction in critically ill children.

Intervention for infants at risk of developing autism: a case series.

Theory and evidence suggest the potential value of prodromal intervention for infants at risk of developing autism. We report an initial case series (n = 8) of a parent-mediated, video-aided and interaction-focused intervention with infant siblings of autistic probands, beginning at 8-10 months of age. We outline the theory and evidence base behind this model and present data on feasibility, acceptability and measures ranging from parent-infant social interaction, to infant atypical behaviors, attention and cognition.

Impact of anesthesia and surgery for congenital heart disease on the vitamin d status of infants and children: a prospective longitudinal study.

Background: Vitamin D is recognized as a pleiotropic hormone important for the functioning of organ systems, including those central to critical illness pathophysiology. Recent studies have reported associations between vitamin D status and outcome among critically ill adults and children. Preoperative vitamin D status, impact of operative techniques, and relationship between immediate postoperative vitamin D levels and clinical course have not been described in the pediatric congenital heart disease (CHD) population.

Impaired GABAergic neurotransmission in schizophrenia underlies impairments in cortical gamma band oscillations.

Impairment of cortical circuit function is increasingly believed to be central to the pathophysiology of schizophrenia (Sz). Such impairments are suggested to result in abnormal gamma band oscillatory activity observed in Sz patients, and likely underlie the psychosis and cognitive deficits linked to this disease. Development of improved therapeutic strategies to enhance functional outcome of Sz patients is contingent upon a detailed understanding of the mechanisms behind cortical circuit development and maintenance.

The association of self-reported sleep, weight status, and academic performance in fifth-grade students.

Background: To improve support and justification for health promotion efforts in schools, it is helpful to understand how students' health behaviors affect academic performance.

Methods: Fifth-grade students completed an online school-administered health survey with questions regarding their eating behavior, physical activity, academic performance, and sleep patterns. Differences in health behaviors were examined by sex, self-reported weight status, and sufficient (≥9 hours) versus insufficient sleep.