The role of the p75 neurotrophin receptor in cholinergic dysfunction in Alzheimer's disease.

Degeneration of basal forebrain cholinergic neurons is a common feature of Alzheimer's disease and is proposed to be an early and key event in the condition's etiology. This review discusses recent findings that strongly link the p75 neurotrophin receptor (p75(NTR)) to both cholinergic neuron degeneration and the production of toxic forms of amyloid-beta (Abeta), which is found deposited as amyloid plaques in the brains of Alzheimer's disease patients. Although elucidating the underlying molecular mechanisms and the clinical significance of these findings will require further experimentation, a number of possible scenarios and future research directions are presented.

Distribution of microtubule organizing centers in migrating sheets of endothelial cells.

This study was designed to investigate the relationship between the position of the microtubule organizing center (MTOC) and the direction of migration of a sheet of endothelial cells (EC). Using immunofluorescence and phase microscopy the MTOC's of migrating EC were visualized as the cells moved into an in vitro experimental wound produced by mechanical denudation of part of a confluent monolayer culture. Although the MTOC's in nonmigrating EC were randomly positioned in relation to the nucleus, in migrating cells the position of the MTOC's changed so that 80% of the cells had the MTOC positioned in front of the nucleus toward the direction of movement of the endothelial sheet. This repositioning of the MTOC occurred within the first 4 h after wounding and was associated with the beginning of migration of EC's into the wounded area as seen by time-lapse cinemicrophotography. These studies focus attention on the MTOC as a cytoskeletal structure that may play a role in determining the direction of cell movement.

Comparison of event rates and survival in patients with unexplained syncope without documented ventricular tachyarrhythmias versus patients with documented sustained ventricular tachyarrhythmias both treated with implantable cardioverter-defibrillators.

Patients with unexplained syncope and inducible ventricular tachyarrhythmias during electrophysiologic testing have an increased cardiac mortality rate. We compared event rates and survival of 178 patients with unexplained syncope and no documented ventricular arrhythmias (syncope group) versus 568 patients with documented sustained ventricular tachycardia (VT or fibrillation (VF) (VT/VF group) treated, as part of a lead (Ventritex TVL) investigation, with similar implantable cardioverter-defibrillators (ICDs) capable of extensive data storage. The 2 groups shared similar clinical characteristics. The mean follow-up was 11 months for the syncope group and 14 months for the VT/VF group. The mean time from device implantation to first appropriate therapy was similar in the 2 groups (109 +/- 140 vs 93 +/- 131 days, p = 0.40). Actuarial probability of appropriate ICD therapy was 49% and 55% at 1 and 2 years, respectively, in syncope group and 49% and 58% in VT/VF group (p = 0.57). Recurrent syncope was associated with ventricular tachyarrhythmias in 85% and 92% of the syncope group and VT/VF group, respectively (p = 0.54). At 2 years, actuarial survival was 91% in the syncope group and 93% in VT/VF group (p = 0.85). We conclude that patients treated with ICD with unexplained syncope and induced VT/VF have an equally high incidence of appropriate ICD therapy and low mortality compared with similar patients with documented VT/VF. These findings, plus the high association between recurrent syncope and ventricular arrhythmias, indicate that VT/VF are likely etiologies in selected patients with unexplained syncope and support ICD therapy in such cases.

Pentagon surface wipe sampling health risk assessment.

Within hours after the terrorist attack on the Pentagon on September 11, 2001, an extensive sampling effort was initiated within the building to include surface wipe sampling for select coplanar polychlorinated biphenyls (PCBs), congeners of polychlorinated dibenzo(p)dioxins and dibenzofurans (dioxins/furans) and lead. A risk-based screening level method was utilized to determine the necessity of additional sampling and to assess the potential for emergency response crews, remediation crews, and returning Pentagon workers to have adverse health impact from exposure to the PCBs. dioxins/furans, and lead on nonporous surfaces. The screening level method included all exposure pathways: dermal absorption, incidental ingestion, and inhalation. Various U.S. Environmental Protection Agency (USEPA) guidance documents provided the basis for the method. The underlying assumptions were that the PCBs, dioxins/furans, and lead were contained in the dust or soot layer found on nonporous surfaces, that sampling results were representative of the surfaces from which they were taken, and that the analytical methods employed were able to detect 100% of these substances. A few of the limitations associated with this method included the lack of toxicity values for dermal absorption and the lack of accurate, discrete dermal-exposure values. Evaluation results indicated that additional sampling was not necessary and that concentrations of PCBs, dioxins/furans, and lead on nonporous surfaces were below levels expected to cause adverse health impacts to emergency response crews, remediation crews, and returning Pentagon workers.

Sudden death in recipients of transvenous implantable cardioverter defibrillator systems: terminal events, predictors, and potential mechanisms.

INTRODUCTION: Transvenous implantable cardioverter defibrillator (ICD) systems are very effective in preventing sudden death; however, little is known about terminal events and potential causes and mechanisms of sudden death in recipients of these devices. METHODS AND RESULTS: We analyzed 74 cases of sudden death among patients enrolled in several clinical investigations of transvenous ICD systems. Eighty-one percent were men (mean age 68+/-10 years), 86% had coronary artery disease, mean left ventricular ejection fraction was 0.27+/-0.11, and two thirds presented with sustained ventricular tachycardia. The final event was witnessed in 65 patients (81%). Based on reported ICD shocks, documented rhythm, and/or postmortem device data, sudden death was deemed tachyarrhythmic in 49 cases (66%), nontachyarrhythmic in 12 (16%), and indeterminate in the remaining 13 (18%). Multivariate analysis of several clinical and nonclinical factors found advanced age (> 65 years, P = 0.03, odds ratio [OR] 1.75, 95 % confidence interval [CI] 1.05 to 2.92), reduced left ventricular ejection fraction (< 0.35, P < 0.01, OR 3.51, CI 1.66 to 7.40), and having antibradycardia pacing ICDs (P = 0.02, OR 5.26, CI 1.37 to 20.0) to be independent predictors of sudden death. One or more predisposing factors and/or potential causes of sudden death were identified in 21 patients (28%). CONCLUSION: In this select group of transvenous ICD recipients, (1) sudden death was associated with ventricular tachycardia/ventricular fibrillation in at least two thirds of cases, (2) nearly one third of patients had one or more factors, some device related, that could have been associated with sudden death, and (3) death ensued despite appropriate ICD therapies and, in many cases, external resuscitation, suggesting acute adverse events as common terminal factors.