Comparison of weight in middle age, weight at 18 years, and weight change between, in predicting subsequent 14 year mortality and coronary events: Caerphilly Prospective Study

Objective-The prevalence of obesity is increasing in many European countries and in the United States. This report examines the mortality and morbidity associated with being overweight and obese in the Caerphilly Prospective Study and the relative effects of weight in middle age and self reported weight at 18 years.

Respiratory syncytial virus NS1 protein degrades STAT2 by using the elongin-cullin E3 ligase

Respiratory syncytial virus (RSV) infection causes bronchiolitis and pneumonia in infants. RSV has a linear single-stranded RNA genome encoding 11 proteins, 2 of which are nonstructural (NS1 and NS2). RSV specifically downregulates STAT2 protein expression, thus enabling the virus to evade the host type I interferon response. Degradation of STAT2 requires proteasomal activity and is dependent on the expression of RSV NS1 and NS2 (NS1/2). Here we investigate whether RSV NS proteins can assemble ubiquitin ligase (E3) enzymes to target STAT2 to the proteasome. We demonstrate that NS1 contains elongin C and cullin 2 binding consensus sequences and can interact with elongin C and cullin 2 in vitro; therefore, NS1 has the potential to act as an E3 ligase. By knocking down expression of specific endogenous E3 ligase components using small interfering RNA, NS1/2, or RSV-induced STAT2, degradation is prevented. These results indicate that E3 ligase activity is crucial for the ability of RSV to degrade STAT2. These data may provide the basis for therapeutic intervention against RSV and/or logically designed live attenuated RSV vaccines.

The respiratory syncytial virus small hydrophobic protein is phosphorylated via a mitogen-activated protein kinase p38-dependent tyrosine kinase activity during virus infection

The phosphorylation status of the small hydrophobic (SH) protein of respiratory syncytial virus (RSV) was examined in virus-infected Vero cells. The SH protein v.,as isolated from [S-35]methionine- and [P-33]orthophosphate-labelled IRSV-infected cells and analysed by SDS-PAGE. In each case, a protein product of the expected size for the SH protein was observed. Phosphoamino acid analysis and reactivity with the phosphotyrosine specific antibody PY20 showed that the SH protein was modified by tyrosine phosphorylation. The role or tyrosine kinase activity in SH protein phosphorylation was confirmed by the use of genistein, a broad-spectrum tyrosine kinase inhibitor, to inhibit SH protein phosphorylation. Further analysis showed that the different glycosylated forms of the SH protein were phosphorylated, as was the oligomeric form of the protein. Phosphorylation of the SH protein was specifically inhibited by the mitogen-activated protein kinase (MAPK) p38 inhibitor SB203580, suggesting that SH protein phosphorylation occurs via a MAPK p38-dependent pathway. Analysis of virus-infected cells using fluorescence microscopy showed that, although the SH protein was distributed throughout the cytoplasm, it appeared to accumulate, at low levels, in the endoplasmic reticulum/Golgi complex, confirming recent observations. However, in the presence of SB203580. an increased accumulation of the SH protein in the Golgi complex was observed, although other virus structures, such as virus filaments and inclusion bodies, remained largely unaffected. These results showed that during RSV infection, the SH protein is modified by an MAPK p38-dependant tyrosine kinase activity and that this modification influences its cellular distribution.

How community ecology links natural mortality, growth, and production of fish populations

Size-spectrum theory is used to show that (i) predation mortality is a decreasing function of individual size and proportional to the consumption rate of predators; (ii) adult natural mortality M is proportional to the von Bertalanffy growth constant K; and (iii) productivity rate P/B is proportional to the asymptotic weight W8 -1/3. The constants of proportionality are specified using individual level parameters related to physiology or prey encounter. The derivations demonstrate how traditional fisheries theory can be connected to community ecology. Implications for the use of models for ecosystem-based fisheries management are discussed.

Supplemental oxygen and hyperbaric treatment at high altitude: Cardiac and respiratory response

Introduction: The most effective treatment for high altitude sickness is prompt descent. However, rapid descent is sometimes impossible and alternative solutions are desirable. Supplemental oxygen at ambient pressure and hyperbaric oxygen in a hyperbaric tent have both been demonstrated to improve symptoms and increase arterial oxygenation (SaO(2)) in those with high altitude sickness; however, their use in combination has not previously been described in a controlled study. Methods and Results: In this feasibility study, the SaO(2) of six healthy, well-acclimatized participants rose from 76.5 to 97.5% at 4900 m and 72.5 to 96.0% at 5700 m following the administration of oxygen via a nasal demand circuit (33 ml of oxygen per pulse) inside a hyperbaric tent (107 mmHg above ambient barometric pressure) (p

Impaired endothelium-dependent vasodilatation is a novel predictor of mortality in intensive care

Objective: Endothelial function may be impaired in critical illness. We hypothesized that impaired endothelium-dependent vasodilatation is a predictor of mortality in critically ill patients.
Design: Prospective observational cohort study.
Setting: Seventeen-bed adult intensive care unit in a tertiary referral university teaching hospital. Patients: Patients were recruited within 24 hrs of admission to the intensive care unit.
Interventions: The SphygmoCor Mx system was used to derive the aortic augmentation index from radial artery pulse pressure waveforms. Endothelium-dependent vasodilatation was calculated as the change in augmentation index in response to an endothelium-dependent vasodilator (salbutamol).
Measurements and Main Results: Demographics, severity of illness scores, and physiological parameters were collected. Statistically significant predictors of mortality identified using single regressor analysis were entered into a multiple logistic regression model. Receiver operator characteristic curves were generated. Ninety-four patients completed the study. There were 80 survivors and 14 nonsurvivors. The Simplified Acute Physiology Score II, the Sequential Organ Failure Assessment score, leukocyte count, and endothelium-dependent vasodilatation conferred an increased risk of mortality. In logistic regression analysis, endothelium-dependent vasodilatation was the only predictor of mortality with an adjusted odds ratio of 26.1 (95% confidence interval [CI], 4.3-159.5). An endothelium-dependent vasodilatation value of 0.5% or less predicted intensive care unit mortality with a sensitivity of 79% (CI, 59-88%) and specificity of 98% (CI, 94-99%).
Conclusions: In vivo bedside assessment of endothelium-dependent vasodilatation is an independent predictor of mortality in the critically ill. We have shown it to be superior to other validated severity of illness scores with high sensitivity and specificity.

Area of residence and alcohol-related mortality risk: a five-year follow-up study

Aims

Elucidating the molecular physiopathology of acute respiratory distress syndrome in severe acute respiratory syndrome patients

Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury. It is a response to various diseases of variable etiology, including SARS-CoV infection. To date, a comprehensive study of the genomic physiopathology of ARDS (and SARS) is lacking, primarily due to the difficulty of finding suitable materials to study the disease process at a tissue level (instead of blood, sputa or swaps). Hereby we attempt to provide such study by analyzing autopsy lung samples from patient who died of SARS and showed different degrees of severity of the pulmonary involvement. We performed real-time quantitative PCR analysis of 107 genes with functional roles in inflammation, coagulation, fibrosis and apoptosis: some key genes were confirmed at a protein expression level by immunohistochemistry and correlated to the degree of morphological severity present in the individual samples analyzed. Significant expression levels were identified for ANPEP (a receptor for CoV), as well as inhibition of the STAT1 pathway, IFNs production and CXCL10 (a T-cell recruiter). Other genes unassociated to date with ARDS/SARS include C1Qb, C5R1, CASP3, CASP9, CD14, CD68, FGF7, HLA-DRA, ICF1, IRF3, MALAT-1, MSR1, NFIL3, SLPI, USP33, CLC, GBP1 and TACI. As a result, we proposed to therapeutically target some of these genes with compounds such as ANPEP inhibitors, SLPI and dexamethasone. Ultimately, this study may serve as a model for future, tissue-based analyses of fibroinflammatory conditions affecting the lung. (C) 2009 Elsevier B.V. All rights reserved.