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We examined longitudinal associations between ApoE4 + status and several cognitive outcomes and tested effect modification by sex. Data on 644 Non-Hispanic White adults, from the Baltimore Longitudinal Study of Aging (BLSA) were used. Dementia onset, cognitive impairment and decline were assessed longitudinally. After 27.5 years median follow-up, 113 participants developed dementia. ApoE4 + predicted dementia significantly (HR=2.89; 95% CI: 1.93-4.33), with non-significant sex differences. Taking all time points for predicting cognition, women had significantly stronger positive associations than men between ApoE4 + status and impairment or decline on the California Verbal Learning Test (CVLT-delayed recall and List A total recall) and on Verbal Fluency Test-Categories. This ApoE4×sex interaction remained significant with bonferroni correction only for CVLT-delayed recall. Taking time points prior to dementia for cognitive predictions, the positive association between impairment in CVLT-delayed recall and ApoE4 + status remained stronger among women, though only before bonferroni correction. While ApoE4+ status appears to be a sex neutral risk factor for dementia, its association with verbal memory and learning decline and impairment was stronger among women.

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Objective In the hospital setting, several studies have reported proton pump inhibitor (PPI) overuse, a majority of which is continued after discharge. In addition to being expensive, PPIs are associated with an increased risk of infections, osteoporosis and serious drug interactions. We examined the trends and predictors of PPI guidelines non-compliance among academic and non-academic hospitalists in USA. Methods and Patients Oral PPI prescriptions initiated by 2 academic and 2 non-academic hospitalist groups were reviewed. Prescription indications were recorded when explicitly stated in the chart. Otherwise, qualified physicians reviewed the chart to make such determination. Indications were then compared to the published guidelines. Several variables were tested to determine independent predictors of initiation and post discharge continuation of guideline non-compliant prescriptions. Results Of the 400 PPI prescriptions 39% were guideline compliant. Academic hospitalists were significantly more compliant with PPI prescription guidelines (50 vs 29%). Gastrointestinal ulcer bleeding prophylaxis (GIP) for low risk patients was the most common indication for non-compliant prescriptions, while that of guideline compliant prescriptions was dyspepsia treatment. Independent predictors of the initiation of guideline non-compliant prescriptions were non-academic hospitalist group, PPI indication not documented in the chart, and GIP as part of the admission orderset. The latter was an independent predictor of those prescriptions continuation post-discharge (protective) in addition to non-academic hospitalists group. Conclusion Hospitalists overprescribe PPI to a level comparable to that of the non-hospitalist providers in the literature. Understanding the determinants of increased compliance among academic groups is instrumental to design interventions aimed at increasing PPI prescription compliance.

Signaling via p38 MAP kinase has been implicated in the mechanotransduction associated with mechanical stress and ventilator-induced lung injury (VILI). However, the critical downstream mediators of alveolar injury remain incompletely defined. We provide evidence that high-tidal volume mechanical ventilation (HVt MV) rapidly activates caspases within the lung, resulting in increased alveolar cell apoptosis. Antagonism of MV-induced p38 MAP kinase activity with SB-203580 suppresses both MV-induced caspase activity and alveolar apoptosis, placing p38 MAP kinase upstream of MV-induced caspase activation and programmed cell death. The reactive oxygen species (ROS)-producing enzyme xanthine oxidoreductase (XOR) is activated in a p38 MAP kinase-dependent manner following HVt MV. Allopurinol, a XOR inhibitor, also suppresses HVt MV-induced apoptosis, implicating HVt MV-induced ROS in the induction of alveolar cell apoptosis. Finally, systemic administration of the pan-caspase inhibitor, z-VAD-fmk, but not its inactive peptidyl analog, z-FA-fmk, blocks ventilator-induced apoptosis of alveolar cells and alveolar-capillary leak, indicating that caspase-dependent cell death is necessary for VILI-associated barrier dysfunction in vivo.

In addition to its critical role in purine metabolism, xanthine oxidoreductase (XOR) has been implicated in the development of tissue oxidative damage in a wide variety of respiratory and cardiovascular disorders such as acute lung injury, ischemia-reperfusion injury, atherosclerosis, heart failure, and arterial hypertension. Although much remains to be clarified about the regulation and signaling pathways of this enzyme, it is quite evident from abundant investigation in animal models and some human trials that XOR inhibition can favorably alter critical disease processes and impact outcomes. From promising bench-to-bedside data, a better understanding of this enigmatic enzyme is emerging. However, the positive findings related to XOR inhibition need to be confirmed in large-scale, well-designed clinical trials. This will hopefully provide new opportunities for therapeutic intervention. This article reviews the available evidence involving XOR in oxidative states with specific emphasis on respiratory and cardiovascular diseases.

Due to potential genetic differences between CO- and CO+ groups, empowering U.S. adults with central obesity to make related behavioral changes may be especially effective in improving their vitamin D status and metabolic profile.