Transient, severe forebrain or global ischemia leads to delayed cell death of pyramidal neurons in the hippocampal CA1. The precise molecular mechanisms underlying neuronal cell death after global ischemia are as yet unknown. Glutamate receptor-mediated Ca2+ influx is thought to play a critical role in this cell death. In situ hybridization revealed that the expression of mRNA encoding GluR2 (the subunit that limits Ca2+ permeability of AMPA-type glutamate receptors) was markedly and specifically reduced in gerbil CA1 pyramidal neurons after global ischemia but before the onset of neurodegeneration. To determine whether the change in GluR2 expression is functionally significant, we examined the AMPA receptor-mediated rise in cytoplasmic free Ca2+ level ([Ca2+]i) in individual CA1 pyramidal neurons by optical imaging with the Ca2+ indicator dye fura-2 and by intracellular recording. Seventy-two hours after ischemia, CA1 neurons that retained the ability to fire action potentials exhibited a greatly enhanced AMPA-elicited rise in [Ca2+]i. Basal [Ca2+]i in these neurons was unchanged. These findings provide evidence for Ca2+ entry directly through AMPA receptors in pyramidal neurons destined to die. Downregulation of GluR2 gene expression and an increase in Ca2+ influx through AMPA receptors in response to endogenous glutamate are likely to contribute to the delayed neuronal death after global ischemia.

The magnitude and dynamics of [Ca2+] changes in spines and dendrites of hippocampal CA1 pyramidal neurons have been characterized using a low affinity fluorescent indicator, mag-Fura 5, that is sensitive to Ca2+ in the micromolar range. During tetanic stimulation (1 s), we observed progressive [Ca2+] increases in distal CA1 spines to as much as 20-40 microM, both in organotypic slice culture and acute slice. Similar accumulations were reached during continuous depolarization (+10 mV, 1 s) when K+ channels had been blocked, but not with spike trains driven by postsynaptic current injection. The large [Ca2+] increases due to tetanic stimulation were blocked by APV, indicating that NMDA receptor-dependent influx was critical for the large responses. These findings have significant implications for low affinity Ca(2+)-dependent biochemical processes and show a new upper limit for [Ca2+] changes measured in these neurons during stimulation.

We conclude that desensitization with IVIG+rituximab is clinically and cost-effective, with both financial savings and an estimated 17.6% greater probability of 3-year survival associated with desensitization versus dialysis alone. However, the benefits of desensitization and transplantation are limited by organ availability and allocation policies.

Patients' adherence to antiretroviral medications is a primary determinant of both the effectiveness of treatment and the clinical course of HIV/AIDS. This empirical review is intended to compare the relative importance of patient and treatment characteristics on nonadherence behavior and the impact of nonadherence on treatment failure. Articles cited in PubMed and published between 2006 and June 2008 (n = 200) were reviewed to select those that address patient or treatment characteristics associated with nonadherence. Twenty-two articles were selected that provided odds ratio or hazard ratio statistics that quantified predictors of patients' level of nonadherence (e.g., <80%, 80%-95% and >95%). Results were summarized using random effects meta-analytic models. Predictors of nonadherence were divided into four predictive clusters (clinical predictors, comorbid predictors, treatment competence predictors, and dosing predictors). The summary odds ratios (ORs) of nonadherence for each cluster (in order of strength) were treatment competence 2.0 (95% confidence interval [CI]: 1.6-2.6), clinical predictors 1.6 (95% CI: 1.4-1.8), comorbid predictors 1.6 (95% CI: 1.4-1.8), and dosing predictors 1.5 (95% CI: 1.3-1.7). The effect of nonadherence on treatment failure supported the findings of two prior empirical reviews (OR 2.0, 95% CI: 1.6-2.5). Within dosing predictors, a pill burden of more versus less than 10 pills per day was associated with a much higher odds of nonadherence than twice versus once daily dosing or small differences in the number of types of antiretroviral treatments in a regimen. These results provide insight into the relative importance of various determinants of patient nonadherence that may inform the design of patient educational initiatives and initiatives to simplify treatment regimens.

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