Summary Multi-organ failure contributes to mortality in bacterial sepsis. Platelet and immune cell activation contribute to organ injury during sepsis, but the mechanisms by which bacterial virulence factors initiate these responses remain poorly defined. We demonstrate that during lethal sepsis, Staphylococcus aureus α-toxin simultaneously alters platelet activation and promotes neutrophil inflammatory signaling through interactions with its cellular receptor ADAM10. Platelet intoxication prevents endothelial barrier repair and facilitates formation of injurious platelet-neutrophil aggregates, contributing to lung and liver injury that is mitigated by ADAM10 deletion on platelets and myeloid lineage cells. While plateletor myeloid-specific ADAM10 knockout does not alter sepsis mortality, double-knockout animals are highly protected. These results define a pathway by which a single bacterial toxin utilizes a widely expressed receptor to coordinate progressive, multi-organ disease in lethal sepsis. As an expression-enhancing ADAM10 polymorphism confers susceptibility to severe human sepsis, these studies highlight the importance of understanding molecular host-microbe interactions.

Immunomodulatory cytotoxins are prominent virulence factors produced by Staphylococcus aureus, a leading cause of bacterial sepsis, skin infection, and pneumonia. S. aureus α-toxin is a pore-forming toxin that utilizes a widely expressed receptor, ADAM10, to injure the host epithelium, endothelium, and immune cells. As each host tissue is characterized by a unique composition of resident cells and recruited immune cells, the outcome of α-toxin-mediated injury may depend on the infected tissue environment. Utilizing myeloid lineage-specific Adam10 knockout mice, we show that α-toxin exerts tissue-specific effects on innate immunity to staphylococcal infection. Loss of ADAM10 expression exacerbates skin infection, yet affords protection against lethal pneumonia. These diverse outcomes are not related to altered immune cell recruitment, but rather correlate with a defect in toxin-induced IL-1β production. Extension of these studies through analysis of ADAM10 double-knockout mice affecting both the myeloid lineage and either the skin or lung epithelium highlight the prominence of toxin-induced injury to the epithelium in governing the outcome of infection. Together, these studies provide evidence of tissue specificity of pore-forming cytotoxin action in the modulation of host immunity, and illustrate that the outcome of infection is a collective manifestation of all effects of the toxin within the tissue microenvironment.

Staphyococcus aureus frequently causes recurrent skin and soft-tissue infection (SSTI). In the pediatric population, elevated serum antibody targeting S. aureus α-toxin is correlated with a reduced incidence of recurrent SSTI. Using a novel model of recurrent SSTI, we demonstrated that expression of α-toxin during primary infection increases the severity of recurrent disease. Antagonism of α-toxin by either a dominant-negative toxin mutant or a small molecule inhibitor of the toxin receptor ADAM10 during primary infection reduces reinfection abscess severity. Early neutralization of α-toxin activity during S. aureus SSTI therefore offers a new therapeutic strategy to mitigate primary and recurrent disease.

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Authorshe cost of overactive bladder (OAB) is a significant financial burden on patients, families, and the health care system. In 2000, the total economic cost of OAB in the United States was estimated at $18.2 billion, which is more than either osteoporosis or Parkinson' s disease. OAB costs at the community level were approximately $13.8 billion, while costs at institutions were $4.4 billion.1 A study examining insurance claims showed that total annual claims among OAB patients was $5,018 versus $1,767 among non-OAB controls (1995 dollars). 2Drug Treatment for OAB Head-to-head studies comparing 2 immediate-release forms of antimuscarinic drug therapy, oxybutynin, and tolterodine, have shown that they have similar efficacy; however, tolterodine has an improved side-effect profile, most notably less dry mouth, and is associated with fewer treatment withdrawals as a result of drug-related adverse events. 3-7The side effects from OAB drug therapy have resulted in poor compliance and, subsequently, low persistence with therapy over time. 4,8,9 Persistence with drug therapy is important for achieving long-term treatment benefits. In a number of retrospective claims studies, patients receiving tolterodine have been shown to remain on therapy longer than those receiving oxybutynin. 6,[9][10][11][12][13][14][15] There is also evidence that suggests that OAB patients who are able to continue with medication have greater symptom improvement and use fewer resources. 16Phase III clinical trials of controlled-release oxybutynin have indicated better patient compliance, reduced side effects, and equivalent efficacy as compared to oxybutynin IR. [17][18][19] Both extended-release tolterodine and controlled-release oxybutynin have been shown to be more effective and better tolerated than immediate-release tolterodine. 20,21 These data further suggest that extended-release tolterodine has better tolerability and fewer side effects than controlled-release oxybutynin. Although there are no head-to-head studies to suggest that one of the extended-release drugs is more efficacious than the other, one recent study compared extended-release tolterodine to controlled-release oxybutynin using a 4-way crossover design in a small number of patients. 22 Using change in bladder capacity as a surrogate for efficacy, a 6 mg dose of extended-release tolterodine was found to be equivalent to a 20 mg dose of oxybutynin. However, the 6 mg dose of extended-release tolterodine produced a side-effect profile with respect to dry mouth similar to the 10 mg dose of controlled-release oxybutynin. This implies that extended-release tolterodine might be as efficacious as oxybutynin but has an improved tolerability profile. T A B S T R A C TOBJECTIVE: To compare the estimated first-line treatment costs of extended-release tolterodine versus controlled-release oxybutynin in patients with overactive bladder (OAB).METHODS: We developed a decision-analysis model to estimate the patterns of treatment, resource consumption, and cost impact of treating OAB with...

Ovotesticular disorder of sex development is historically thought to confer a relatively low risk of germ cell malignancy relative to other disorders of sex development. This is likely due in part to the high prevalence of a normal 46,XX karyotype in these patients. However, disorders of sex development represent a broad phenotypic spectrum, and often patients cannot be neatly categorized with a single diagnosis. We report an atypical case of ovotesticular disorder of sex development in a child with ambiguous genitalia and 45,X/46,XY mosaic karyotype. Prophylactic bilateral gonadectomy was performed at age 14 months.