Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperferritinemic systemic inflammatory disorders. Although profound cytotoxic impairment causes familial HLH (fHLH), the mechanisms driving non-fHLH and MAS are largely unknown. MAS occurs in patients with suspected rheumatic disease, but the mechanistic basis for its distinction is unclear. Recently, a syndrome of recurrent MAS with infantile enterocolitis caused by NLRC4 inflammasome hyperactivity highlighted the potential importance of interleukin-18 (IL-18). We tested this association in hyperferritinemic and autoinflammatory patients and found a dramatic correlation of MAS risk with chronic (sometimes lifelong) elevation of mature IL-18, particularly with IL-18 unbound by IL-18 binding protein, or free IL-18. In a mouse engineered to carry a disease-causing germ line NLRC4 mutation, we observed inflammasome-dependent, chronic IL-18 elevation. Surprisingly, this NLRC4-induced systemic IL-18 elevation derived entirely from intestinal epithelia. NLRC4 intestines were histologically normal but showed increased epithelial turnover and upregulation of interferon-γ-induced genes. Assessing cellular and tissue expression, classical inflammasome components such as , and predominated in neutrophils, whereas and were distinctly epithelial. Demonstrating the importance of free IL-18, transgenic mice exhibited free IL-18 elevation and more severe experimental MAS. NLRC4 mice, whose free IL-18 levels were normal, did not. Thus, we describe a unique connection between MAS risk and chronic IL-18, identify epithelial inflammasome hyperactivity as a potential source, and demonstrate the pathogenicity of free IL-18. These data suggest an IL-18-driven pathway, complementary to the cytotoxic impairment of fHLH, with potential as a distinguishing biomarker and therapeutic target in MAS.

Together these data demonstrate that autologous MSCs can be safely delivered in an adult heart failure model, producing substantial structural and functional reverse remodelling. These findings demonstrate the safety and efficacy of autologous MSC therapy and support clinical trials of MSC therapy in patients with chronic ischaemic cardiomyopathy.

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Introduction— Single-institution series have suggested that men receiving orthotopic heart transplantation from female donors have decreased survival. No multi-institutional series has comprehensively addressed the issue of donor and recipient sex matching for both male and female orthotopic heart transplantation recipients. Methods and Results— We used data from the multi-institutional prospectively collected United Network for Organ Sharing open transplantation cohort to review 18 240 adult patients who received orthotopic heart transplantation from 1999 to 2007. Four donor recipient strata were identified (male donor/male recipient, N=10 750; female donor/female recipient, N=2201; male donor/female recipient, N=2121; and female donor/male recipient, N=3168). The primary end point of all cause posttransplant mortality was compared among groups using a Cox proportional hazard regression model with additional propensity adjustment. Female recipients, irrespective of donor sex, had 3.6% lower overall survival at 5 years posttransplant ( P =0.003). Men who received organs from male donors had the highest cumulative survival at 5 years (74.5%). Men receiving female hearts had a 15% increase in the risk of adjusted cumulative mortality (hazard ratio, 1.15; 95% CI, 1.02 to 1.30; P =0.02). No significant increase in the relative hazard for death occurred for women receiving opposite sex donor organs (1.24; 0.92 to 1.35; P =0.31). Conclusions— The United Network for Organ Sharing data set has provided a large sample examining donor recipient sex pairing in orthotopic heart transplantation. Men receiving organs for same sex donors have significantly improved short- and long-term survival. No survival advantage was seen for women with same sex donors.