Brain-Derived Neurotrophic Factor Ameliorates Brain Stem Cardiovascular Dysregulation during Experimental Temporal Lobe Status Epilepticus

Background: Status epilepticus (SE) is an acute, prolonged epileptic crisis with a mortality rate of 20–30%; the underlying mechanism is not completely understood. We assessed the hypothesis that brain stem cardiovascular dysregulation occurs during SE because of oxidative stress in rostral ventrolateral medulla (RVLM), a key nucleus of the baroreflex loop; to be ameliorated by brain-derived neurotrophic factor (BDNF) via an antioxidant action. Methodology/Principal Findings: In a clinically relevant experimental model of temporal lobe SE (TLSE) using Sprague-Dawley rats, sustained hippocampal seizure activity was accompanied by progressive hypotension that was preceded by a reduction in baroreflex-mediated sympathetic vasomotor tone; heart rate and baroreflex-mediated cardiac responses remained unaltered. Biochemical experiments further showed concurrent augmentation of superoxide anion, phosphorylated p47 phox subunit of NADPH oxidase and mRNA or protein levels of BDNF, tropomyosin receptor kinase B (TrkB), angiotensin AT1 receptor subtype (AT1R), nitric oxide synthase II (NOS II) or peroxynitrite in RVLM. Whereas pretreatment by microinjection bilaterally into RVLM of a superoxide dismutase mimetic (tempol), a specific antagonist of NADPH oxidase (apocynin) or an AT1R antagonist (losartan) blunted significantly the augmented superoxide anion or phosphorylated p47 phox subunit in RVLM, hypotension and the reduced baroreflex-mediated sympathetic vasomotor tone during experimental TLSE, pretreatment with a recombinant human TrkB-Fc fusion protein or an antisense bdn

Different definition of sarcopenia and mortality in cancer: A meta-analysis

Objectives: Sarcopenia has been an emerging theme in clinical oncology. Various definitions of sarcopenia have been proposed, but their prognostic performance have yet to be evaluated and compared. The aim of this meta-analysis is to comprehensively evaluate the performance of different cutoff definitions of sarcopenia in cancer mortality prognostication. / Methods: This is a meta-analysis. Cohort studies on lean mass and mortality published before December 20, 2017 were obtained by systematic search on PubMed, Cochrane Library, and Embase. Inclusion criteria were cohort studies reporting binary lean mass categorized according to clearly defined cutoffs, and with all-cause mortality as study outcome. Studies were stratified according to the cutoff(s) used in defining low lean mass. The cutoff-specific hazard ratios (HRs) and 95% confidence intervals (CIs) of low lean mass on cancer mortality were pooled with a random-effects model and compared. / Results: Altogether 81 studies that studied binary lean mass were included. The pooled HRs on cancer mortality using the 3 most used definitions were: 1.74 (95% CI, 1.46–2.07) using the definition proposed by International Consensus of Cancer Cachexia, 1.45 (95% CI, 1.21–1.75) using that by Martin, and 1.58 (95% CI, 1.35–1.84) using that by Prado. The associations between sarcopenia and cancer mortality using other definitions were all statistically significant, despite different estimates were observed. / Conclusions: The association of low lean mass with increased mortality was consistent across different definitions; this provides further evidence on the poorer survival in cancer patients with sarcopenia. However, further studies evaluating the performance of each definition are warranted

Deriving a mutation index of carcinogenicity using protein structure and protein interfaces

With the advent of Next Generation Sequencing the identification of mutations in the genomes of healthy and diseased tissues has become commonplace. While much progress has been made to elucidate the aetiology of disease processes in cancer, the contributions to disease that many individual mutations make remain to be characterised and their downstream consequences on cancer phenotypes remain to be understood. Missense mutations commonly occur in cancers and their consequences remain challenging to predict. However, this knowledge is becoming more vital, for both assessing disease progression and for stratifying drug treatment regimes. Coupled with structural data, comprehensive genomic databases of mutations such as the 1000 Genomes project and COSMIC give an opportunity to investigate general principles of how cancer mutations disrupt proteins and their interactions at the molecular and network level. We describe a comprehensive comparison of cancer and neutral missense mutations; by combining features derived from structural and interface properties we have developed a carcinogenicity predictor, InCa (Index of Carcinogenicity). Upon comparison with other methods, we observe that InCa can predict mutations that might not be detected by other methods. We also discuss general limitations shared by all predictors that attempt to predict driver mutations and discuss how this could impact high-throughput predictions. A web interface to a server implementation is publicly available at http://inca.icr.ac.uk/

Age- Matched Comparison of Children Hospitalized for 2009 Pandemic H1N1 Influenza with Those Hospitalized for Seasonal H1N1 and H3N2

BACKGROUND: A wide spectrum of clinical manifestation ranging from deaths to a mild course of disease has been reported in children infected with the 2009 pandemic H1N1 (pH1N1) influenza. METHODOLOGY/MAJOR FINDINGS: We conducted an age-matched control study comparing children hospitalized for pH1N1 with historic controls infected with seasonal H1N1 and H3N2 influenza to correct for the effect of age on disease susceptibility and clinical manifestations. We also compared children with pH1N1 to children concurrently admitted for seasonal influenza during the pandemic period to adjust for differences in health-seeking behavior during the pandemic or other potential bias associated with historic controls. There was no death or intensive care admission. Children with pH1N1 were more likely to have at least one risk condition for influenza, an underlying chronic pulmonary condition, more likely to have asthma exacerbation and to be treated with oseltamivir. There was no difference in other aspects of the clinical course or outcome. CONCLUSION: Disease manifestation of children hospitalized for pH1N1 infection was mild in our patient population

Effect of remote ischemic preConditioning on liver injury in patients undergoing liver resection: the ERIC-LIVER trial

OBJECTIVE: Novel hepatoprotective strategies are needed to improve clinical outcomes during liver surgery. There is mixed data on the role of remote ischemic preconditioning (RIPC). We investigated RIPC in partial hepatectomy for primary hepatocellular carcinoma (HCC). METHODS: This was a Phase II, single-center, sham-controlled, randomized controlled trial (RCT). The primary hypothesis was that RIPC would reduce acute liver injury following surgery indicated by serum alanine transferase (ALT) 24 h following hepatectomy in patients with primary HCC, compared to sham. Patients were randomized to receive either four cycles of 5 min/5 min arm cuff inflation/deflation immediately prior to surgery, or sham. Secondary endpoints included clinical, biochemical and pathological outcomes. Liver function measured by Indocyanine Green pulse densitometry was performed in a subset of patients. RESULTS: 24 and 26 patients were randomized to RIPC and control groups respectively. The groups were balanced for baseline characteristics, except the duration of operation was longer in the RIPC group. Median ALT at 24 h was similar between groups (196 IU/L IQR 113.5-419.5 versus 172.5 IU/L IQR 115-298 respectively, p = 0.61). Groups were similar in secondary endpoints. CONCLUSION: This RCT did not demonstrate beneficial effects with RIPC on serum ALT levels 24 h after partial hepatectomy

A Novel Pathogenic Mechanism of Highly Pathogenic Avian Influenza H5N1 Viruses Involves Hemagglutinin Mediated Resistance to Serum Innate Inhibitors

In this study, the effect of innate serum inhibitors on influenza virus infection was addressed. Seasonal influenza A(H1N1) and A(H3N2), 2009 pandemic A(H1N1) (H1N1pdm) and highly pathogenic avian influenza (HPAI) A(H5N1) viruses were tested with guinea pig sera negative for antibodies against all of these viruses as evaluated by hemagglutination-inhibition and microneutralization assays. In the presence of serum inhibitors, the infection by each virus was inhibited differently as measured by the amount of viral nucleoprotein produced in Madin-Darby canine kidney cells. The serum inhibitors inhibited seasonal influenza A(H3N2) virus the most, while the effect was less in seasonal influenza A(H1N1) and H1N1pdm viruses. The suppression by serum inhibitors could be reduced by heat inactivation or treatment with receptor destroying enzyme. In contrast, all H5N1 strains tested were resistant to serum inhibitors. To determine which structure (hemagglutinin (HA) and/or neuraminidase (NA)) on the virus particles that provided the resistance, reverse genetics (rg) was applied to construct chimeric recombinant viruses from A/Puerto Rico/8/1934(H1N1) (PR8) plasmid vectors. rgPR8-H5 HA and rgPR8-H5 HANA were resistant to serum inhibitors while rgPR8-H5 NA and PR8 A(H1N1) parental viruses were sensitive, suggesting that HA of HPAI H5N1 viruses bestowed viral resistance to serum inhibition. These results suggested that the ability to resist serum inhibition might enable the viremic H5N1 viruses to disseminate to distal end organs. The present study also analyzed for correlation between susceptibility to serum inhibitors and number of glycosylation sites present on the globular heads of HA and NA. H3N2 viruses, the subtype with highest susceptibility to serum inhibitors, harbored the highest number of glycosylation sites on the HA globular head. However, this positive correlation cannot be drawn for the other influenza subtypes

Ezrin interacts with the SARS coronavirus spike protein and restrains infection at the entry stage

© 2012 Millet et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background: Entry of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and its envelope fusion with host cell membrane are controlled by a series of complex molecular mechanisms, largely dependent on the viral envelope glycoprotein Spike (S). There are still many unknowns on the implication of cellular factors that regulate the entry process. Methodology/Principal Findings: We performed a yeast two-hybrid screen using as bait the carboxy-terminal endodomain of S, which faces the cytosol during and after opening of the fusion pore at early stages of the virus life cycle. Here we show that the ezrin membrane-actin linker interacts with S endodomain through the F1 lobe of its FERM domain and that both the eight carboxy-terminal amino-acids and a membrane-proximal cysteine cluster of S endodomain are important for this interaction in vitro. Interestingly, we found that ezrin is present at the site of entry of S-pseudotyped lentiviral particles in Vero E6 cells. Targeting ezrin function by small interfering RNA increased S-mediated entry of pseudotyped particles in epithelial cells. Furthermore, deletion of the eight carboxy-terminal amino acids of S enhanced S-pseudotyped particles infection. Expression of the ezrin dominant negative FERM domain enhanced cell susceptibility to infection by SARS-CoV and S pseudotyped particles and potentiated S-dependent membrane fusion. Conclusions/Significance: Ezrin interacts with SARS-CoV S endodomain and limits virus entry and fusion. Our data present a novel mechanism involving a cellular factor in the regulation of S-dependent early events of infection.This work was supported by the Research Grant Council of Hong Kong (RGC#760208)and the RESPARI project of the International Network of Pasteur Institutes

Proactive and politically skilled professionals: What is the relationship with affective occupational commitment?

The aim of this study is to extend research on employee affective commitment in three ways: (1) instead of organizational commitment the focus is on occupational commitment; (2) the role of proactive personality on affective occupational commitment is examined; and (3) occupational satisfaction is examined as a mediator and political skills as moderator in the relationship between proactive personality and affective occupational commitment. Two connected studies, one in a hospital located in the private sector and one in a university located in the public sector, are carried out in Pakistan, drawing on a total sample of over 400 employees. The results show that proactive personality is positively related to affective occupational commitment, and that occupational satisfaction partly mediates the relationship between proactive personality and affective occupational commitment. No effect is found for a moderator effect of political skills in the relationship between proactive personality and affective occupational commitment. Political skills however moderate the relationship between proactive personality and affective organizational commitment

State-of-the-art management of nasopharyngeal carcinoma: current and future directions

Nasopharyngeal carcinoma (NPC) is a distinct type of head and neck cancer. Approximately 70% of patients with newly diagnosed NPC present with locally advanced disease. Phase III clinical trials support the addition of chemotherapy to radiotherapy for the initial treatment of these patients. Once metastatic disease develops, practices become varied. Further experience needs to be gained with both targeted therapies and immunotherapy to gauge whether they will improve treatment outcomes in NPC