Suicide attempts in veterans with bipolar disorder during treatment with lithium, divalproex, and atypical antipsychotics.

Suicide attempt rates were assessed in 1306 subjects in this 6 year retrospective study of Bipolar disorder. Participants were Veterans from 5 different Veterans Administration Hospitals who met criteria for bipolar type 1 or 2 and who had at least one prescription for lithium or divalproex or both during the study period. This study focused on the impact of atypical antipsychotics on the suicide attempt rate when used in addition to or in place of lithium or divalproex. Medication exposure was calculated using computerized pharmacy records. Suicide attempts were established through chart review including emergency room records, inpatient records, and outpatient records. There were a total of 117 suicide attempts and 2 suicide completions during the study period. Most attempts (59%) occurred when patients were on no medications. Nearly 90% of subjects spent an average of 45 months during the 6 year period on none of the aforementioned medications. The lowest percentage of suicide attempts (15%) occurred while on lithium, 21% while on divalproex and 24% while on atypical antipsychotics. When total months of exposure were taken into account, the lowest attempt rate occurred on lithium plus divalproex (6.3 attempts per 10,000 months of exposure), followed by divalproex alone (7.0 attempts/10,000 months of exposure), and lithium alone (7.7 attempts per 10,000 months of exposure). Patients on atypical antipsychotics alone had an attempt rate of 26.1 attempts per 10,000 months of exposure. In this study, lithium and divalproex provided protection against suicide attempts. Results need to be replicated in future prospective studies and clearly strategies for improving medication compliance among veterans are warranted.

Investigating autophagy: quantitative morphometric analysis using electron microscopy.

Autophagy is a compensatory pathway involving isolation and subsequent degradation of cytosolic material and organelles in eukaryotic cells.(1) The autophagic process can provide a "housekeeping" function by removing damaged proteins and organelles in a selective or nonselective fashion in order to exert a protective effect following stress.(2) Remarkably, after being discovered to be much more of a targeted process than a random one, the role of autophagy became implicated in many normal cellular and disease processes.(3) Several methodologies are routinely employed to monitor the entire autophagic process.(4) Microtubule-associated protein light chain 3, a mammalian homolog of yeast Atg8, has been widely used as a specific marker to monitor autophagy in numerous cell types.(5) While monitoring autophagic flux is extremely important, it is also beneficial to perform a detailed analysis by electron microscopy (EM) to evaluate changes in various autophagic structures, quantify the areas involved, and determine if any particular organelle(s) or area of the cell cytoplasm is being targeted for degradation.(6) The following article describes methods to localize and quantify subcellular areas of autophagy using transmission EM. Also discussed are methods for subcellular localization of specific proteins by employing immunogold EM; this method becomes particularly useful in detecting early changes in cellular homeostasis that may occur before later signs of cellular insult can be observed morphologically.

Autophagy following heat stress: the role of aging and protein nitration.

Stress can originate from a variety of sources (e.g., physical, chemical, etc.,) and cause protein denaturation, DNA damage and possibly death. In an effort to prevent such deleterious consequences, most organisms possess one or more ways to counteract or even prevent the harmful effect(s) from a given stressor. Such compensation by an organism is known as a stress response; this involves inhibition of housekeeping genes and subsequent activation of genes associated with the stress response. One of the most widely studied groups of stress response genes is a family of molecular chaperones known as heat shock proteins (HSPs). Work from our laboratory agrees with many other studies showing an age-related decline in stress-induced synthesis of HSPs. A decline in the availability and/or function of HSPs with age can lead to accumulation of damaged proteins, which in turn damages cells. Recently, our laboratory found a significant increase in mitochondrial damage as well as evidence of increased autophagy in rat hepatocytes following heat stress. These results, along with findings of increased protein nitration with age, suggest a major role for reactive nitrogen species (RNS) in both the decline in HSP induction and increased hepatocyte pathology observed in old rats following heat stress.

Aging results in increased autophagy of mitochondria and protein nitration in rat hepatocytes following heat stress.

The natural breakdown of cells, tissues, and organ systems is a significant consequence of aging and is at least partially caused by a decreased ability to tolerate environmental stressors. Based on quantitative ultrastructural analysis using transmission electron microscopy and computer imaging, we show significant differences in hepatocyte morphology between young and old rats during a 48-hr recovery period following a 2-day heat stress protocol. Mitochondrial injury was greater overall in old compared with young rats. Autophagy was observed in both young and old rats, with autophagy greater overall in old compared with young hepatocytes. Lipid peroxidation and protein nitration were evaluated by localization and quantification of 4-hydroxy-2-nonenal (4-HNE)-modified protein adducts and 3-nitrotyrosine (3-NT) levels, respectively. Levels of 3-NT but not 4-HNE-protein adducts were significantly elevated in hepatocytes of old rats in comparison with young at 90 min after heat stress, suggesting a major role for reactive nitrogen species in the pathology observed at this time point. These results show a differential response of hepatocyte mitochondria to heat stress with aging, as well as greater levels of both autophagic and nitrative damage in old vs young hepatocytes. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.