A case history of a 31-year-old male schizophrenic patient is presented. The man was treated with olanzapine for three weeks be-fore he died. After one week on a 10 mg daily dose of olanzapine, his fasting blood glucose was elevated to 11.3 mmol/L (203 mg/dL). In order to treat more aggressively his psychosis, the olanzapine dose was raised to 20 mg daily resulting in his fasting blood glucose climbing to 15.8 mmol/L (284 mg/dL). On the days preceding his death, he became progressively weaker, and developed polydipsia with polyuria. He had no personal or family history of diabetes mellitus and he was on no other medication at the time of his death. Postmortem blood, vitreous humor, and urine glucose concentrations were 53 mmol/L (954 mg/dL), 49 mmol/L (882 mg/dL), and 329 mmol/L (5922 mg/dL), respectively. Drug screen on urine and blood indicated only a small amount or olanzapine and no alcohols. Peripheral blood olanza-pine concentration was within therapeutic limits, 45 ng/mL. Analysis of vitreous humor and urine revealed severe dehydration with small amounts of ketones. Death was attributed to hyperosmolar nonke-totic diabetic coma, and olanzapine was felt most likely to be the cause. Another atypical neuroleptic, clozapine, has also been associated with the development and exacerbation of diabetes mellitus or diabetic ke-toacidosis. We recommend including vitreous glucose and -hydroxybutyrate analysis as part of postmortem toxicology work up when the drug screen reveals the presence of either olanzapine or clozapine.
Progressive multifocal leukoencephalopathy (PML), the only known demyelinating disease of the CNS caused by a virus, results from the activation of the human neurotropic polyomavirus, JC virus (JCV). It almost exclusively affects immunocompromised patients, with more than 80% of cases occurring in patients with HIV. Though PMLassociated mortality has improved during the last decade since HAART therapy has become the standard treatment regimen, the incidence of PML in HIV patients remains steady, and survival is still poor, averaging 1.8 years after diagnosis. PML is characterized by extensive myelin loss, preferentially involving the subcortical white matter. Apoptosis, a mechanism of disposing of damaged cells, is virtually absent in PML. Recently, we described the ability of JCV to activate the survivin protein, a normally dormant apoptosis inhibitor. We present 3 cases of HIVassociated PML evaluated first for survivin expression and then assessed for apoptotic activity. Infection by JCV was verified by the presence of both the T antigen and the VP1 capsid. Survivin expression was evaluated by immunohistochemistry (IHC) with a survivin-specific antibody. To evaluate apoptosis, TUNEL assays and IHC were used for the detection of fragmented DNA and for cleaved caspases, respectively. Survivin expression was detected preferentially in the nuclei of oligodendrocytes harboring JCV inclusion bodies. Non-JCV-infected cells in normal areas of the same samples were negative for the presence of survivin. Furthermore, the presence of survivin was associated with ablation of apoptosis as evidenced by negative TUNEL assays and the absence of caspase activity. We propose that activation of the survivin protein by the JCV virus is a mechanism that may prevent apoptosis, thus permitting the virus time to process through its lytic replication cycle and effectively disseminate. Understanding this novel pathway may provide a potential antiviral therapeutic target against a thus far untreatable disease.
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