Background— In this prospective follow-up study, the effect of myocardial fibrosis on myocardial performance in symptomatic severe aortic stenosis was investigated, and the impact of fibrosis on clinical outcome after aortic valve replacement (AVR) was estimated. Methods and Results— Fifty-eight consecutive patients with isolated symptomatic severe aortic stenosis underwent extensive baseline characterization before AVR. Standard and tissue Doppler echocardiography and cardiac magnetic resonance imaging (late-enhancement imaging for replacement fibrosis) were performed at baseline and 9 months after AVR. Endomyocardial biopsies were obtained intraoperatively to determine the degree of myocardial fibrosis. Patients were analyzed according to the severity of interstitial fibrosis in cardiac biopsies (severe, n=21; mild, n=15; none, n=22). The extent of histologically determined cardiac fibrosis at baseline correlated closely with New York Heart Association functional class and markers of longitudinal systolic function (all P <0.001) but not global ejection fraction or aortic valve area. Nine months after AVR, the degree of late enhancement remained unchanged, implying that AVR failed to reduce the degree of replacement fibrosis. Patients with no fibrosis experienced a marked improvement in New York Heart Association class from 2.8±0.4 to 1.4±0.5 ( P <0.001). Only parameters of longitudinal systolic function predicted this functional improvement. Four patients with severe fibrosis died during follow-up, but no patient from the other groups died. Conclusions— Myocardial fibrosis is an important morphological substrate of postoperative clinical outcome in patients with severe aortic stenosis and was not reversible after AVR over the 9 months of follow-up examined in this study. Because markers of longitudinal systolic function appear to indicate sensitively both the severity of myocardial fibrosis and the clinical outcome, they may prove valuable for preoperative risk assessment in patients with aortic stenosis.

IntroductionChronic nonbacterial osteomyelitis (CNO) is an inflammatory disorder of unknown etiology. In children and adolescents CNO predominantly affects the metaphyses of the long bones, but lesions can occur at any site of the skeleton. Prospectively followed cohorts using a standardized protocol in diagnosis and treatment have rarely been reported.MethodsThirty-seven children diagnosed with CNO were treated with naproxen continuously for the first 6 months. If assessment at that time revealed progressive disease or no further improvement, sulfasalazine and short-term corticosteroids were added. The aims of our short-term follow-up study were to describe treatment response in detail and to identify potential risk factors for an unfavorable outcome.ResultsNaproxen treatment was highly effective in general, inducing a symptom-free status in 43% of our patients after 6 months. However, four nonsteroidal anti-inflammatory drug (NSAID) partial-responders were additionally treated with sulfasalazine and short-term corticosteroids. The total number of clinical detectable lesions was significantly reduced. Mean disease activity estimated by the patient/physician and the physical aspect of health-related quality of life including functional ability (global assessment/childhood health assessment questionnaire and childhood health assessment questionnaire) and pain improved significantly. Forty-one percent of our patients showed radiological relapses, but 67% of them were clinically silent.ConclusionsMost children show a favorable clinical course in the first year of anti-inflammatory treatment with NSAIDs. Relapses and new radiological lesions can occur at any time and at any site in the skeleton but may not be clinically symptomatic. Whole-body magnetic resonance imaging proved to be very sensitive for initial and follow-up diagnostics.

Influenza viruses (IV) cause pneumonia in humans with progression to lung failure and fatal outcome. Dysregulated release of cytokines including type I interferons (IFNs) has been attributed a crucial role in immune-mediated pulmonary injury during severe IV infection. Using ex vivo and in vivo IV infection models, we demonstrate that alveolar macrophage (AM)-expressed IFN-β significantly contributes to IV-induced alveolar epithelial cell (AEC) injury by autocrine induction of the pro-apoptotic factor TNF-related apoptosis-inducing ligand (TRAIL). Of note, TRAIL was highly upregulated in and released from AM of patients with pandemic H1N1 IV-induced acute lung injury. Elucidating the cell-specific underlying signalling pathways revealed that IV infection induced IFN-β release in AM in a protein kinase R- (PKR-) and NF-κB-dependent way. Bone marrow chimeric mice lacking these signalling mediators in resident and lung-recruited AM and mice subjected to alveolar neutralization of IFN-β and TRAIL displayed reduced alveolar epithelial cell apoptosis and attenuated lung injury during severe IV pneumonia. Together, we demonstrate that macrophage-released type I IFNs, apart from their well-known anti-viral properties, contribute to IV-induced AEC damage and lung injury by autocrine induction of the pro-apoptotic factor TRAIL. Our data suggest that therapeutic targeting of the macrophage IFN-β-TRAIL axis might represent a promising strategy to attenuate IV-induced acute lung injury.

Background-Identification of key molecular players in myocardial healing could lead to improved therapies, reduction of scar formation, and heart failure after myocardial infarction (MI). We hypothesized that clotting factor XIII (FXIII), a transglutaminase involved in wound healing, may play an important role in MI given prior clinical and mouse model data. Methods and Results-To determine whether a truly causative relationship existed between FXIII activity and myocardial healing, we prospectively studied myocardial repair in FXIII-deficient mice. All FXIII Ϫ/Ϫ and FXIII Ϫ/ϩ (FXIII activity Ͻ5% and 70%) mice died within 5 days after MI from left ventricular rupture. In contradistinction, FXIII Ϫ/Ϫ mice that received 5 days of intravenous FXIII replacement therapy had normal survival rates; however, cardiac MRI demonstrated worse left ventricular remodeling in these reconstituted FXIII Ϫ/Ϫ mice. Using a FXIII-sensitive molecular imaging agent, we found significantly greater FXIII activity in wild-type mice and FXIII Ϫ/Ϫ mice receiving supplemental FXIII than in FXIII Ϫ/Ϫ mice (PϽ0.05). In FXIII Ϫ/Ϫ but not in reconstituted FXIII Ϫ/Ϫ mice, histology revealed diminished neutrophil migration into the MI. Reverse transcriptase-polymerase chain reaction studies suggested that the impaired inflammatory response in FXIII Ϫ/Ϫ mice was independent of intercellular adhesion molecule and lipopolysaccharideinduced CXC chemokine, both important for cell migration. After MI, expression of matrix metalloproteinase-9 was 650% higher and collagen-1 was 53% lower in FXIII Ϫ/Ϫ mice, establishing an imbalance in extracellular matrix turnover and providing a possible mechanism for the observed cardiac rupture in the FXIII Ϫ/Ϫ mice. Conclusions-These data suggest that FXIII has an important role in murine myocardial healing after infarction.