Preadaptation of pandemic GII.4 noroviruses in unsampled virus reservoirs years before emergence

The control of re-occurring pandemic pathogens requires understanding the origins of new pandemic variants and the factors that drive their global spread. This is especially important for GII.4 norovirus, where vaccines under development offer promise to prevent hundreds of millions of annual gastroenteritis cases. Previous studies have hypothesized that new GII.4 pandemic viruses arise when previously circulating pandemic or pre-pandemic variants undergo substitutions in antigenic regions that enable evasion of host population immunity, as described by conventional models of antigenic drift. In contrast, we show here that the acquisition of new genetic and antigenic characteristics cannot be the proximal driver of new pandemics. Pandemic GII.4 viruses diversify and spread over wide geographical areas over several years prior to simultaneous pandemic emergence of multiple lineages, indicating that the necessary sequence changes must have occurred before diversification, years prior to pandemic emergence. We confirm this result through serological assays of reconstructed ancestral virus capsids, demonstrating that by 2003, the ancestral 2012 pandemic strain had already acquired the antigenic characteristics that allowed it to evade prevailing population immunity against the previous 2009 pandemic variant. These results provide strong evidence that viral genetic changes are necessary but not sufficient for GII.4 pandemic spread. Instead, we suggest that it is changes in host population immunity that enable pandemic spread of an antigenically preadapted GII.4 variant. These results indicate that predicting future GII.4 pandemic variants will require surveillance of currently unsampled reservoir populations. Furthermore, a broadly acting GII.4 vaccine will be critical to prevent future pandemics

A re-appraisal of the reliability of the 20 m multi-stage shuttle run test

This is the author's PDF version of an article published in European journal of applied physiology in 2007. The original publication is available at www.springerlink.co

Hemolysis and methemoglobinemia due to hepatitis E virus infection in patient with G6PD deficiency

published_or_final_versionSpringer Open Choice, 21 Feb 201

Neonatal-onset multisystem inflammatory disease responsive to interleukin-1 beta inhibition

BACKGROUND:Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation.METHODS:We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an interleukin-1-receptor antagonist (1 to 2 mg per kilogram of body weight per day subcutaneously). In 11 patients, anakinra was withdrawn at three months until a flare occurred. The primary end points included changes in scores in a daily diary of symptoms, serum levels of amyloid A and C-reactive protein, and the erythrocyte sedimentation rate from baseline to month 3 and from month 3 until a disease flare.RESULTS:All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. Withdrawal of anakinra uniformly resulted in relapse within days; retreatment led to rapid improvement. There were no drug-related serious adverse events.CONCLUSIONS:Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with neonatal-onset multisystem inflammatory disease, with or without CIAS1 mutations

Prevalence and treatment implications of ICD-11 complex PTSD in Australian treatment-seeking current and ex-serving military members

Background: Despite growing support for the distinction between posttraumatic stress disorder (PTSD) and complex PTSD (CPTSD) as separate diagnoses within the ICD-11 psychiatric taxonomy, the prevalence and treatment implications of CPTSD among current and ex-serving military members have not been established. Objective: The study aims were to a) establish the prevalence of provisional ICD-11 CPTSD diagnosis relative to PTSD in an Australian sample of treatment-seeking current and ex-serving military members, and b) examine the implications of CPTSD diagnosis for intake profile and treatment response. Methods: The study analysed data collected routinely from Australian-accredited treatment programmes for military-related PTSD. Participants were 480 current and ex-serving military members in this programmes who received a provisional ICD-11 diagnosis of PTSD or CPTSD at intake using proxy measures. Measures of PTSD symptoms, disturbances in self-organisation, psychological distress, mental health and social relationships were considered at treatment intake, discharge, and 3-month follow-up. Results: Among participants with a provisional ICD-11 diagnosis, 78.2% were classified as having CPTSD, while 21.8% were classified as having PTSD. When compared to ICD-11 PTSD, participants with CPTSD reported greater symptom severity and psychological distress at intake, and lower scores on relationship and mental health dimensions of the quality of life measure. These relative differences persisted at each post-treatment assessment. Decreases in PTSD symptoms between intake and discharge were similar across PTSD (dRM = −0.81) and CPTSD (dRM = −0.76) groups, and there were no significant post-treatment differences between groups when controlling for initial scores. Conclusions: CPTSD is common among treatment-seeking current and ex-serving military members, and is associated with initially higher levels of psychiatric severity, which persist over time. Participants with CPTSD were equally responsive to PTSD treatment; however, the tendency for those with CPTSD to remain highly symptomatic post-treatment suggests additional treatment components should be considered

The effect of Ku on telomere replication time is mediated by telomere length but is independent of histone tail acetylation

Peer reviewedPublisher PD

Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer.

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer

A Spatial Cluster Analysis of Tractor Overturns in Kentucky from 1960 to 2002

Agricultural tractor overturns without rollover protective structures are the leading cause of farm fatalities in the United States. To our knowledge, no studies have incorporated the spatial scan statistic in identifying high-risk areas for tractor overturns. The aim of this study was to determine whether tractor overturns cluster in certain parts of Kentucky and identify factors associated with tractor overturns.A spatial statistical analysis using Kulldorff's spatial scan statistic was performed to identify county clusters at greatest risk for tractor overturns. A regression analysis was then performed to identify factors associated with tractor overturns.The spatial analysis revealed a cluster of higher than expected tractor overturns in four counties in northern Kentucky (RR = 2.55) and 10 counties in eastern Kentucky (RR = 1.97). Higher rates of tractor overturns were associated with steeper average percent slope of pasture land by county (p = 0.0002) and a greater percent of total tractors with less than 40 horsepower by county (p<0.0001).This study reveals that geographic hotspots of tractor overturns exist in Kentucky and identifies factors associated with overturns. This study provides policymakers a guide to targeted county-level interventions (e.g., roll-over protective structures promotion interventions) with the intention of reducing tractor overturns in the highest risk counties in Kentucky

Excitotoxicity Triggered by Neurobasal Culture Medium

Neurobasal defined culture medium has been optimized for survival of rat embryonic hippocampal neurons and is now widely used for many types of primary neuronal cell culture. Therefore, we were surprised that routine medium exchange with serum- and supplement-free Neurobasal killed as many as 50% of postnatal hippocampal neurons after a 4 h exposure at day in vitro 12–15. Minimal Essential Medium (MEM), in contrast, produced no significant toxicity. Detectable Neurobasal-induced neuronal death occurred with as little as 5 min exposure, measured 24 h later. D-2-Amino-5-phosphonovalerate (D-APV) completely prevented Neurobasal toxicity, implicating direct or indirect N-methyl-D-aspartate (NMDA) receptor-mediated neuronal excitotoxicity. Whole-cell recordings revealed that Neurobasal but not MEM directly activated D-APV-sensitive currents similar in amplitude to those gated by 1 µM glutamate. We hypothesized that L-cysteine likely mediates the excitotoxic effects of Neurobasal incubation. Although the original published formulation of Neurobasal contained only 10 µM L-cysteine, commercial recipes contain 260 µM, a concentration in the range reported to activate NMDA receptors. Consistent with our hypothesis, 260 µM L-cysteine in bicarbonate-buffered saline gated NMDA receptor currents and produced toxicity equivalent to Neurobasal. Although NMDA receptor-mediated depolarization and Ca2+ influx may support survival of young neurons, NMDA receptor agonist effects on development and survival should be considered when employing Neurobasal culture medium