RESUMO
BACKGROUND: Genome-wide association studies are powerful tools for nominating pathogenic variants, but offer little insight as to how candidate genes affect disease outcome. Such is the case for SH2B adaptor protein 3 (SH2B3), which is a negative regulator of multiple cytokine signaling pathways and is associated with increased risk of myocardial infarction (MI), but its role in post-MI inflammation and fibrosis is completely unknown. METHODS AND RESULTS: Using an experimental model of MI (left anterior descending artery occlusion/reperfusion injury) in wild-type and Sh2b3 knockout rats (Sh2b3(em2Mcwi)), we assessed the role of Sh2b3 in post-MI fibrosis, leukocyte infiltration, angiogenesis, left ventricle contractility, and inflammatory gene expression. Compared with wild-type, Sh2b3(em2Mcwi) rats had significantly increased fibrosis (2.2-fold; P<0.05) and elevated leukocyte infiltration (>2-fold; P<0.05), which coincided with decreased left ventricle fractional shortening (-Δ11%; P<0.05) at 7 days post left anterior descending artery occlusion/reperfusion injury. Despite an increased angiogenic potential in Sh2b3(em2Mcwi) rats (1.7-fold; P<0.05), we observed no significant differences in left ventricle capillary density between wild-type and Sh2b3(em2Mcwi) rats. In total, 12 genes were significantly elevated in the post left anterior descending artery occluded/reperfused hearts of Sh2b3(em2Mcwi) rats relative to wild-type, of which 3 (NLRP12, CCR2, and IFNγ) were significantly elevated in the left ventricle of heart failure patients carrying the MI-associated rs3184504 [T] SH2B3 risk allele. CONCLUSIONS: These data demonstrate for the first time that SH2B3 is a crucial mediator of post-MI inflammation and fibrosis.
Assuntos
Proteínas Musculares/metabolismo , Infarto do Miocárdio/metabolismo , Miocardite/metabolismo , Proteínas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Modelos Animais de Doenças , Fibrose , Proteínas Musculares/genética , Infarto do Miocárdio/complicações , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Miocardite/etiologia , Miocardite/genética , Miocardite/patologia , Proteínas/genética , Ratos , Ratos MutantesRESUMO
OBJECTIVE: To calculate the costs of influenza hospitalization at a tertiary care children's hospital as the basis of a cost-benefit analysis of the new influenza vaccine recommendation for children age 6 to 23 months. STUDY DESIGN: We reviewed the medical records of all patients admitted to Children's Memorial Hospital (CMH) in 2002 diagnosed with influenza. Total hospital costs were obtained from the Business Development Office. RESULTS: Thirty-five charts were analyzed. Both of the 2 patients requiring mechanical ventilation and 4 of 6 patients admitted to the intensive care unit had high-risk underlying medical conditions. Nine children were age 6 to 23 months; 4 of these 9 had no preexisting medical conditions. Had all 18 high-risk children over age 6 months been protected from influenza, approximately $350,000 in hospital charges could have been saved. CONCLUSIONS: Preventing the additional 4 hospitalizations in the otherwise low-risk children age 6 to 23 months for whom vaccine is currently recommended would have cost approximately $281,000 ($46/child) more than the hospital charges saved. When all children age 6 to 23 months are considered, influenza vaccination is less costly than other prophylactic measures. Addition of indirect costs, deaths, outpatient costs, and the cost of secondary cases would favor the cost:benefit ratio for influenza vaccination of all children age 6 to 23 months.