Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus

The emergence and spread of multidrug-resistant gram-positive bacteria represent a serious clinical problem. Telavancin is a novel lipoglycopeptide antibiotic that possesses rapid in vitro bactericidal activity against a broad spectrum of clinically relevant gram-positive pathogens. Here we demonstrate that telavancin's antibacterial activity derives from at least two mechanisms. As observed with vancomycin, telavancin inhibited late-stage peptidoglycan biosynthesis in a substrate-dependent fashion and bound the cell wall, as it did the lipid II surrogate tripeptide N,N'-diacetyl-L-lysinyl-D-alanyl-D-alanine, with high affinity. Telavancin also perturbed bacterial cell membrane potential and permeability. In methicillin-resistant Staphylococcus aureus, telavancin caused rapid, concentration-dependent depolarization of the plasma membrane, increases in permeability, and leakage of cellular ATP and K(+). The timing of these changes correlated with rapid , concentration-dependent loss of bacterial viability, suggesting that the early bactericidal activity of telavancin results from dissipation of cell membrane potential and an increase in membrane permeability. Binding and cell fractionation studies provided direct evidence for an interaction of telavancin with the bacterial cell membrane; stronger binding interactions were observed with the bacterial cell wall and cell membrane relative to vancomycin. We suggest that this multifunctional mechanism of action confers advantageous antibacterial properties.     

DETECTION OF STREPTOCOCCAL GROUP-SPECIFIC ANTIBODIES IN HUMAN SERA

Two serologically distinct antibodies directed against different antigenic sites on the Group A carbohydrate were detected in human sera by agglutination techniques. Agglutinins with A-variant specificity were demonstrable by the direct agglutination of purified A-variant cell walls, whereas indirect Coombs-type agglutinins with Group A specificity were demonstrable with Group A cell walls. Selective adsorption with homologous cell walls as well as inhibition studies with the soluble carbohydrates confirmed the specificity of the two types of agglutinins. There was an obvious correlation between the magnitude of the antistreptolysin O titer, and the direct Group A-variant and the indirect Group titers. These data suggest that indirect anti-Group A agglutinins and direct anti-Group A-variant agglutinins are produced following a Group A streptococcal infection.     

Systems level modeling of a neuronal network subserving intrinsic alertness

Cognitive control of alertness in unwarned situations (intrinsic alertness) relies on a predominantly right hemisphere cortical and subcortical network. In a previous functional activation study, we have demonstrated that this network comprises the anterior cingulate gyrus, the dorsolateral and polar frontal as well as the inferior parietal cortex, the thalamus and ponto-mesencephalic parts of the brain stem. The aim of this study was to study effective connectivity of this network by employing structural equation modeling. Fifteen right-handed male subjects participated in the PET study. The functional network showed stronger connectivity in the right hemisphere. Furthermore, there were strong effective connections between thalamus and brainstem on the one hand and between thalamus and anterior cingulate on the other. Our results suggest that the anterior cingulate functions as the central coordinating structure for the right hemispheric neural network of intrinsic alertness and that the anterior cingulate gyrus is modulated mainly by prefrontal and parietal cortex.     

Increased tubular proliferation as an adaptive response to glomerular albuminuria

Renal tubular atrophy accompanies many proteinuric renal diseases, suggesting that glomerular proteinuria injures the tubules. However, local or systemic inflammation and filtration of abnormal proteins known to directly injure tubules are also present in many of these diseases and animal models; therefore, whether glomerular proteinuria directly causes tubular injury is unknown. Here, we examined the renal response to proteinuria induced by selective podocyte loss. We generated mice that express the diphtheria toxin receptor exclusively in podocytes, allowing reproducible dose-dependent, specific ablation of podocytes by administering diphtheria toxin. Ablation of <20% of podocytes resulted in profound albuminuria that resolved over 1-2 weeks after the re-establishment of normal podocyte morphology. Immediately after the onset of albuminuria, proximal tubule cells underwent a transient burst of proliferation without evidence of tubular damage or increased apoptosis, resulting in an increase in total tubular cell numbers. The proliferative response coincided with detection of the growth factor Gas6 in the urine and phosphorylation of the Gas6 receptor Axl in the apical membrane of renal tubular cells. In contrast, ablation of >40% of podocytes led to progressive glomerulosclerosis, profound tubular injury, and renal failure. These data suggest that glomerular proteinuria in the absence of severe structural glomerular injury activates tubular proliferation, potentially as an adaptive response to minimize the loss of filtered proteins.     

Racial Disparities in Depression and Life Satisfaction After Spinal Cord Injury: A Mediational Model

Purpose:

To identify the relationship of race and gender with 3 aspects of life satisfaction and depressive symptoms after spinal cord injury (SCI), evaluating the extent to which socioeconomic factors mediate any observed relationships.

Methods:

Adults with traumatic SCI of at least 1-year duration (N = 1,549) were identified through a Southeastern United States SCI Model System of care, and cross-sectional survey data were collected at a Southeastern United States medical university. Three aspects of life satisfaction (home life satisfaction, vocational satisfaction, global satisfaction) were measured using 20 satisfaction items from the Life Situation Questionnaire-Revised. The Older Adult Health and Mood Questionnaire measured depressive symptoms. MANCOVA assessed mediation of socioeconomic status between race and life satisfaction and depression.

Results:

Home life satisfaction and vocational satisfaction were significantly related to race, with White participants scoring higher than Black participants during the first stage of the regression. However, socioeconomic factors mediated the relationships such that race was no longer significant after considering economic factors. Race was significantly associated with global satisfaction after adjusting for socioeconomic factors. Depression was not significantly related to race. Gender was unrelated to all study outcomes. Of the socioeconomic mediators, family income was a significant predictor of each outcome, whereas education was only predictive of vocational satisfaction.

Conclusion:

Socioeconomic factors are important mediators of the relationship between race and certain aspects of life satisfaction among persons with SCI. Family income and, to a lesser extent, education should be considered when evaluating race differences in life satisfaction after SCI.     

Gainful employment and risk of mortality after spinal cord injury: effects beyond that of demographic, injury and socioeconomic factors

Objective:To evaluate the association of three levels of gainful employment with the risk of mortality after traumatic spinal cord injury (SCI) while controlling for known predictors of mortality status (including education and income).Study design:Prospective cohort studySetting:A total of 20 federally funded SCI Model Systems of care in the United States.Methods:Participants included 7955 adults with traumatic SCI. Preliminary assessments were conducted between 1995 and 2006. Mortality status was determined by the Social Security Death Index (1308 deaths). A two-stage logistic regression model was used to estimate the chance of dying in any given year. Life expectancy was calculated under different economic assumptions.Results:Compared with those who were working 30+?h per week, the odds of mortality was 1.37 for those who worked 1-29?h and 1.67 for those who were unemployed. The addition of gainful employment only modestly reduced the effects of household income and education, both of which remained significant. For instance, the odds of mortality for household income (referent $75?000+) decreased from 1.50 to 1.38 for $25?000-$75?000 and from 2.10 to 1.82 for <$25?000. Life expectancy varied widely depending on socioeconomic characteristics more than doubling under certain assumptions.Conclusion:Substantial variation in mortality is attributable to employment, above and beyond the effects of previously established demographic, injury and socioeconomic predictors. Although some excess mortality may be the inevitable consequence of SCI, risk is substantially increased with poor socioeconomic characteristics.     

Ebola Risk Perception in Germany, 2014

Ebola virus disease (EVD) outbreaks have occurred during the past 5 decades, but none has affected European countries like the 2014 epidemic in West Africa. We used an online questionnaire to investigate risk perceptions in Germany during this epidemic peak. Our questionnaire covered risk perceptions, knowledge about transmission routes, media use, reactions to the outbreak, attitudes toward measures to prevent the spread of EVD and vaccination against EVD, and willingness to volunteer for aid missions. Of 974 participants, 29% indicated that they worried about EVD, 4% correctly stated virus transmission routes, and 75% incorrectly rated airborne transmission and transmission by asymptomatic patients as possible. Many indicated that if a patient were flown to Germany for treatment in a nearby hospital, they would adapt preventive behavior. Although most participants were not worried about EVD at the current stage of the epidemic, misperceptions regarding transmission were common and could trigger inappropriate behavior changes.