A role for protein kinase C and its substrates in the action of valproic acid in the brain: implications for neural plasticity

Valproic acid (VPA) is a broad-spectrum anticonvulsant with well-documented teratogenic effects, but whose mechanism of action is largely unknown. In the present study we have examined the effects of VPA on the expression of two prominent substrates for protein kinase C (PKC) in the brain, MARCKS and GAP-43, which have been implicated in actin-membrane plasticity and neurite outgrowth during neuronal differentiation, respectively, and are essential to normal brain development. Immortalized hippocampal HN33 cells exposed to VPA exhibited reduced MARCKS protein expression and demonstrated increased GAP-43 protein expression, with concomitant alterations in cellular morphology, including an increase in the number and length of neurites and accompanied by a reduction in cell growth rate. The effects of VPA were observed at clinically relevant concentrations following chronic (>1 day) VPA exposure. We also present evidence for a VPA-induced alteration in PKC activity, as well as temporal changes in individual PKC isozyme expression. Inhibition of PKC with the PKC-selective inhibitor, LY333531, prevented the VPA-induced down-regulation of membrane-associated MARCKS, but had no effect on the cytosolic MARCKS reduction or the GAP-43 up-regulation. Inhibition of PKC by LY333531 enhanced the differentiating effects of VPA; additionally, LY333531 alone induced greater neurite outgrowth in this cell line. Collectively, these data indicate that VPA induces neuronal differentiation, associated with a reduction in MARCKS expression and an increase in GAP-43 expression, consistent with the hypothesis that a reduction in MARCKS at the membrane may be permissive for cytoskeletal plasticity during neurite outgrowth.     

cGMP and S-nitrosylation: two routes for modulation of neuronal excitability by NO

The nitric oxide (NO)-cGMP signaling cascade has been implicated in synaptic plasticity and, more broadly, in the control of many forms of electrical activity. This raises the issue of how these second messengers regulate ion channels. The field of ion-channel modulation is dominated by G proteins; NO and cGMP are often treated as poor cousins. However, recent advances surveyed here could change this perception. A surprising new dimension to NO signaling is the direct cGMP-independent action of NO on channel proteins through S-nitrosylation. The existence of two effector pathways has important functional implications, expanding and enriching the possibilities for modulating neuronal excitability.     

Subjective quality of life in severely disabled long-stay schizophrenic patients

In the controversy about severely chronic mental patients, who still reside in the psychiatric hospital after decades of deinstitutionalization, their quality of life (QoL) has become a main topic. On the basis of a critique of the dominant, mere standardized approach to QoL this method is compared with a qualitative approach in such a schizophrenic "residual" patient group (n = 144). While in the standardized approach a high level of subjective QoL could be found that correlated positively with the duration of hospitalisation, the open interviews yielded specific experiences of deficiencies. The appraisal of the quality of life especially of chronic or hospitalized patients is reconsidered.     

Schizophrenic patients,who still live in psychiatric hospitals despite decades of deinstitutionalization. Part 1 of the Hessian Deinstitutionalisation Study

Deinstitutionalization (DI) of most of the chronic long-stay patients has taken place in the last decades in Germany. However, a "residual" group of patients often remains in psychiatric hospitals, with an ongoing controversy on an appropriate type of their care (community based vs. hospital). Clinical, functional and social characteristics of such schizophrenic patients still residing in the long-stay wards in the German state of Hesse after decades of DI are presented. The n = 266 patients investigated displayed a marked degree of negative symptoms and moderate positive symptoms but, however, severe social disabilities. In addition, the patients were very dependent in daily living, had an extremely impoverished social network and leisure activities. The findings contribute to the research on "difficult-to-place" patients described in the literature.     

Use of evidence-based data to drive your patient safety program

The Agency for Health Care Research and Quality (AHRQ) is committed to conducting and supporting health services research and promoting technical improvements that enhance the quality of health care delivered in the United States. A significant focus of AHRQ's efforts has been its work on patient safety, and it had depended on numerous collaborative efforts both inside and outside of the federal government to exponentially increase what it could accomplish alone. In 2001 fiscal year, Congress appropriated $50 million for the AHRQ's patient safety research initiatives that were collectively aimed at expanding the nation's capacity to conduct research in this field.The portfolio is guided by a user-driven patient safety research agenda that was developed at the September 2000 National Summit on Medical Errors and Patient Safety Research. The research results generated by this initiative will provide an evidentiary base for system improvements that, when implemented, will greatly enhance the safety of the nation's health care system.     

Body mass index and mortality: the influence of physical activity and smoking

PURPOSE: To study the association between body mass index (BMI) and mortality, and to evaluate the effect of physical activity during leisure time and smoking on this association in a general male population. METHODS: During 1974-1978, all men aged 35-49 yr living in three Norwegian counties were invited to a cardiovascular screening, and 87.1% attended and had their weight and height measured. Men with recognized cardiovascular diseases, diabetes mellitus, or cancer at screening were excluded. The cohort (N = 22,304) was followed for an average of 16.3 yr with respect to total and cause-specific mortality. RESULTS: During follow-up, 1909 men died. We found a J-shaped association between BMI and total mortality, and the form of association was similar for death from cardiovascular diseases. Although not statistically significant, a J-shaped association was also suggested in never-smokers. Irrespective of BMI level, ex- and never-smokers had lower mortality than current smokers. Obese smoking men had a relative risk of dying of 2.01 (95% CI: 1.29-3.11) compared with obese never-smokers, and a relative risk of 4.55 (95% CI: 3.34-6.20) compared with normal weight never-smokers (BMI 22-24.9 kg x m(-2)). Within each category of physical activity during leisure time, obese men had a similar increased relative risk of death compared with normal-weight individuals. However, the U- to J-shaped association between BMI and mortality seemed to disappear by increasing level of physical activity, but this finding was not significant. CONCLUSION: This study suggests a J-shaped association between BMI and total mortality, also when stratified on smoking habits and physical activity. The suggested linear trend in the most physical active men needs to be reassessed.