Hydrogen sulfide induced neuronal death occurs via glutamate receptor and is associated with calpain activation and lysosomal rupture in mouse primary cortical neurons

Hydrogen sulfide (H(2)S) is a cytotoxic gas recently proposed as a novel neuromodulator. Endogenous levels of H(2)S in the brain range between 50 and 160 microM and perturbed H(2)S synthesis has been reported in the brains from stroke, Alzheimer's disease and Down syndrome patients. Recently, in immature non-glutamate receptor expressing mouse cortical neurons H(2)S was shown to inhibit cell death exhibited by high concentrations of glutamate whereas H(2)S was not cytotoxic. Due to the reported role of H(2)S in facilitating LTP through NMDA receptors we examined the effects of H(2)S on glutamate receptor functioning using mature cortical neurons expressing functional glutamate receptor subtypes. Addition of 100 microM glutamate exhibited extensive cell death which was exacerbated by co-incubation with < or = 200 microM of the H(2)S donor sodium hydrosulfide (NaHS). At <200 microM NaHS induced apoptosis whereas >200 microM NaHS induced necrosis. Cell death was inhibited by pharmacological glutamate receptor antagonists MK801 and APV (NMDA receptor antagonists), and CNQX (kainate and AMPA receptor antagonist) but not kynurenate (broad spectrum glutamate receptor antagonist), GYKI52466 (more selective AMPA receptor antagonist) and CYZ (AMPA receptor potentiator). Although markers of apoptosis were observed, we did not detect caspase activation either by Western blotting or fluorescence assays and caspase inhibitors did not prevent cell death. Rather, H(2)S induced calpain activation and lysosomal membrane destabilization; processes inhibited by preferential antagonists of NMDA and kainate receptors. These data suggest that H(2)S induced neuronal death through ionotropic glutamate receptors, which recruits apoptosis to ensure cellular demise and employs calpains and lysosomal rupture. This study provides novel insights into cell death observed in neurodegenerative diseases involving glutamate receptor activation and perturbed H(2)S synthesis.     

Aneurysmal bone cyst arising in fibrous dysplasia during pregnancy

A case of two secondary aneurysmal bone cysts arising in fibrous dysplasia during pregnancy is reported. Marked radiographic changes were seen in one lesion over a 3-week period. The development of these cysts during pregnancy strongly suggests that the hemodynamic and/or hormonal changes of pregnancy were responsible for their formation.     

Prion protein is ubiquitinated after developing protease resistance in the brains of scrapie-infected mice

Although the key event in the pathology of prion diseases is thought to be the conversion of cellular prion protein (PrP(C)) to the protease-resistant scrapie species termed PrP(Sc), the factors that contribute to neurodegeneration in scrapie-infected animals are poorly understood. One probable determinant could be when the accumulation of PrP(Sc) in infected brain overwhelms the ubiquitin-proteasome system and triggers the degenerative cascade. In the present study, it was found that in mouse brains infected with the ME7 scrapie strain, the level of ubiquitin protein conjugates increased significantly at approximately 144 days post-infection (pi) when clinical signs first become apparent. This elevation correlated with the detection of protease-resistant PrP(Sc) and a decline in two endopeptidase activities associated with proteasome function. However, ubiquitination of PrP was only detected at the terminal stage, 3 weeks after the development of clinical symptoms (approximately 165 days pi). These results suggest that ubiquitination of PrP is a late event phenomenon and this conjugation occurs after the formation of protease-resistant PrP(Sc). Whether this post-translational modification and the impairment of proteasome function are pivotal events in the pathogenesis of prion diseases remains to be determined.     

An Enhanced Method for Identifying Obstetric Deliveries: Implications for Estimating Maternal Morbidity

Objectives The accuracy of maternal morbidity estimates from hospital discharge data may be influenced by incomplete identification of deliveries. In maternal/infant health studies, obstetric deliveries are often identified only by the maternal outcome of delivery code (International Classification of Diseases code = V27). We developed an enhanced delivery identification method based on additional delivery-related codes and compared the performance of the enhanced method with the V27 method in identifying estimates of deliveries as well as estimates of maternal morbidity. Methods The enhanced and standard V27 methods for identifying deliveries were applied to data from the 1998–2004 Healthcare Cost and Utilization Project Nationwide Inpatient Sample, an annual nationwide representative survey of U.S. hospitalizations. Odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression were used to examine predictors of deliveries not identified using the V27 method. Results The enhanced method identified 958,868 (3.4%) more deliveries than the 27,128,539 identified using the V27 code alone. Severe complications including major puerperal infections (OR = 3.1, 95% CI 2.8–3.4), hysterectomy (OR = 6.0, 95% CI 5.3–6.8), sepsis (OR = 11.9, 95% CI 10.3–13.6) and respiratory distress syndrome (OR = 16.6, 95% CI 14.4–19.2) were strongly associated with deliveries not identified by the V27 method. Nationwide prevalence rates of severe maternal complications were underestimated with the V27 method compared to the enhanced method, ranging from 9% underestimation for major puerperal infections to 40% underestimation for respiratory distress syndrome. Conclusion Deliveries with severe obstetric complications may be more likely to be missed using the V27 code. Researchers should be aware that selecting deliveries from hospital stay records by V27 codes alone may affect the accuracy of their findings. Presentations: The results were presented as a poster at the Second American Congress of Epidemiology, Seattle, WA, June 21–24, 2006. Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the view of the Centers for Disease Control and Prevention or the National Institutes of Health.     

Cancers in Australia in 2010 attributable to total breastfeeding durations of 12 months or less by parous women

Objectives: To estimate the proportion and number of cancers occurring in Australia in 2010 attributable to parous women having breastfed for total durations of ≤12 months. Methods: We estimated the population attributable fraction (PAF) of breast cancers (the only cancer site with convincing evidence of causal association) associated with women breastfeeding for ≤12 months in total, using standard formulae incorporating breastfeeding prevalence data, relative risks associated with breastfeeding and cancer incidence. We also estimated the proportion change in disease incidence (potential impact fraction [PIF]) that might have occurred under two hypothetical scenarios of women breastfeeding for longer durations. Results: An estimated 235 (1.7%) breast cancer cases that occurred in Australian in 2010 could be attributed to women breastfeeding for total durations of ≤12 months. Assuming a hypothetical increase in breastfeeding, we estimated that the number of breast cancers prevented would range from 36 to 51 (prevented fraction = 0.3% to 0.4%). Conclusions: More than 200 breast cancers were attributable to women breastfeeding for total durations of ≤12 months. Implications: Policies to increase breastfeeding duration may help prevent breast cancers in the future.