An unexpected but underestimated case of disseminated toxoplasmosis.

Toxoplasma gondii is a ubiquitous intracellular parasite that can cause disseminated infection following reactivation in immunocompromised hosts. We describe a 58-year-old man who died of refractory shock because of disseminated toxoplasmosis. The diagnosis was only made postmortem on autopsy. We discuss the importance of considering toxoplasmosis on the differential diagnosis in high-risk patients, and review the role of screening and chemoprophylaxis in preventing infection.

The ontogeny of P-glycoprotein in the developing human blood-brain barrier: implication for opioid toxicity in neonates.

BACKGROUND: Neonates have been shown to have a heightened sensitivity to the central depressive effects of opioids compared to older infants and adults. The limited development of P-glycoprotein (P-gp) may limit the ability of the neonate to efflux morphine from the brain back to the systemic circulation. The objective of the study was to determine the ontogeny of P-gp in the human brain. METHODS: Postmortem cortex samples from gestational age (GA) 20-26 wk, GA 36-40 wk, postnatal age (PNA) 0-3 mo, PNA 3-6 mo, and adults were immunostained for P-gp. RESULTS: The intensity of P-gp staining in adults was significantly higher compared to at GA 20-26 wk (P < 0.05), GA 36-40 wk (P < 0.05), and PNA 0-3 mo (P < 0.05). P-gp intensity at GA 20-26 wk (P < 0.05), GA 36-40 wk (P < 0.05), and PNA 0-3 mo (P < 0.05) was significantly lower compared to at PNA 3-6 mo. CONCLUSION: P-gp expression in the brain is limited at birth, increases with postnatal maturation, and reaches adult levels at ~3-6 mo of age. Given the immaturity of blood-brain barrier (BBB) P-gp after birth, morphine may concentrate in the brain. This provides mechanistic support to life threatening opioid toxicity seen with maternal codeine use during breastfeeding.

Leukocyte elastase induces epithelial apoptosis: role of mitochondial permeability changes and Akt.

During acute inflammation, neutrophil-mediated injury to epithelium may lead to disruption of epithelial function, including the induction of epithelial apoptosis. Herein, we report the effects of neutrophil transmigration and of purified leukocyte elastase on epithelial cell survival. Neutrophil transmigration induced apoptosis of epithelial cells [control monolayers: 5 +/- 1 cells/25 high-power fields (HPF) vs. neutrophil-treated monolayers: 29 +/- 10 cells/HPF, P < 0.05, n = 3 as determined by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay] as did low concentrations (0.1 U/ml) of purified leukocyte elastase (control monolayers: 6.4 +/- 2.5% apoptotic vs. elastase: 26.2 +/- 2.9% apoptotic, P < 0.05, as determined by cytokeratin 18 cleavage). Treatment with elastase resulted in decreased mitochondrial membrane potential, release of cytochrome c to the cytosol, and cleavage of caspases-9 and -3 as determined by Western blot analysis, implicating altered mitochondrial membrane permeability as a primary mechanism for elastase-induced apoptosis. Additionally, incubation of epithelial cells with leukocyte elastase resulted in an early increase followed by a decrease in the phosphorylation of epithelial Akt, a serine/threonine kinase important in cell survival. Inhibition of epithelial Akt before elastase treatment potentiated epithelial cell apoptosis, suggesting that the initial activation of Akt represents a protective response by the epithelial cells to the proapoptotic effects of leukocyte elastase. Taken together, these observations suggest that epithelial cells exhibit a dual response to cellular stress imposed by leukocyte elastase with a proapoptotic response mediated via early alterations in mitochondrial membrane permeability countered by activation of the survival pathway involving Akt.

Fabry's disease presenting as stroke in a young female.

BACKGROUND: Fabry's disease is an X-linked disorder, caused by a deficiency of the lysosomal enzyme alpha-galactosidase A which results in the accumulation of the glycosphingolipid, ceramide trihexose in the vascular endothelium and can lead to cerebral infarction. Male hemizygotes are generally more severely affected than heterozygote females. Clinical disease in females is thought to be due to unequal X chromosome inactivation. CASE: A 19-year-old woman, who was previously well, presented with neurological deficits secondary to basal ganglia and pontine infarction. Extensive cardiac, arterial and hematologic investigations did not identify the etiology of her stroke. Muscle biopsy revealed endothelial lysosomal aggregates most consistent with a diagnosis of Fabry's disease. The diagnosis was confirmed on the basis of molecular genotype analysis. DISCUSSION: Inherited causes of stroke such as Fabry's disease should be considered in young patients with stroke if an etiologic diagnosis is not reached after complete investigations. Muscle biopsy can assist with the diagnosis and guide further investigations. This report summarizes the biochemical and histological features of Fabry's disease and the associated genetic abnormalities.

Enhanced disease severity in Helicobacter pylori-infected mice deficient in Fas signaling.

Recent evidence suggests that immune-mediated gastric epithelial cell apoptosis through Fas-Fas ligand interactions participates in Helicobacter pylori disease pathogenesis. To define the role of Fas signaling in vivo, H. pylori strain SS1 infection in C57BL/6 mice was compared to that in mice deficient in the Fas ligand (gld). gld mice had a degree of gastritis similar to that of C57BL/6 mice after 6 weeks (gastritis score, 5.2 +/- 0.6 [mean +/- standard error] versus 3.5 +/- 0.8) and 12 weeks (4.0 +/- 0.7 versus 3.4 +/- 0.5) of infection. Bacterial colonization was comparable in each group of mice at 12 weeks of infection (2.1 +/- 0.3 versus 1.6 +/- 0.3 for gld and C57BL/6, respectively; the difference is not significant). Sixty-seven percent of H. pylori-infected gld mice displayed atrophic changes in the gastric mucosa, compared with 37% of infected C57BL/6 mice, at 12 weeks. In addition, atrophic changes were more severe in H. pylori-infected gld mice (P < 0.05). Splenocytes isolated from H. pylori-infected C57BL/6 mice had a twofold increase in production of the Th1 cytokine gamma interferon (IFN-gamma) in response to H. pylori antigens at both 6 and 12 weeks compared to controls (143 +/- 65 versus 69 +/-26 pg/ml and 336 +/- 73 versus 172 +/- 60, respectively). In contrast, there was a lack of detectable IFN-gamma in gld mice infected with the bacterium. H. pylori-infected C57BL/6 mice had increased epithelial cell apoptosis compared with sham-infected C57BL/6 mice (35.0 +/- 8.9 versus 12.3 +/- 6.9; P < 0.05). Epithelial cell apoptosis did not differ between H. pylori-infected and control gld mice (5.2 +/- 1.6 versus 6.5 +/- 2.9 [not significant]). These data demonstrate that mice with mutations in the Fas ligand develop more severe premalignant mucosal changes in response to infection with H. pylori in association with both an impaired gastric epithelial cell apoptotic response and IFN-gamma production. The Fas death pathway modulates disease pathophysiology following murine infection with H. pylori. Deregulation of the Fas pathway could be involved in the transition from gastritis to gastric cancers during H. pylori infection.