Adult North Star Network (ANSN): Consensus Guideline For The Standard Of Care Of Adults With Duchenne Muscular Dystrophy.

There are growing numbers of adults with Duchenne Muscular Dystrophy living well into their fourth decade. These patients have complex medical needs that to date have not been addressed in the International standards of care. We sought to create a consensus based standard of care through a series of multi-disciplinary workshops with specialists from a wide range of clinical areas: Neurology, Cardiology, Respiratory Medicine, Gastroenterology, Endocrinology, Palliative Care Medicine, Rehabilitation, Renal, Anaesthetics and Clinical Psychology. Detailed reports of evidence reviewed and the consensus building process were produced following each workshop and condensed into this final document which was approved by all members of the Adult North Star Network including service users. The aim of this document is to provide a framework to improve clinical services and multi-disciplinary care for adults living with Duchenne Muscular Dystrophy.

T-cell immunity in myocardial inflammation: pathogenic role and therapeutic manipulation.

T-cell-mediated immunity has been linked not only to a variety of heart diseases, including classic inflammatory diseases such as myocarditis and post-myocardial infarction (Dressler's) syndrome, but also to conditions without an obvious inflammatory component such as idiopathic dilated cardiomyopathy and hypertensive cardiomyopathy. It has been recently proposed that in all these conditions, the heart becomes the focus of T-cell-mediated autoimmune inflammation following ischaemic or infectious injury. For example, in acute myocarditis, an inflammatory disease of heart muscle, T-cell responses are thought to arise as a consequence of a viral infection. In a number of patients, persistent T-cell-mediated responses in acute viral myocarditis can lead to autoimmunity and chronic cardiac inflammation resulting in dilated cardiomyopathy. In spite of the major progress made in understanding the mechanisms of pathogenic T-cell responses, effective and safe therapeutic targeting of the immune system in chronic inflammatory diseases of the heart has not yet been developed due to the lack of specific diagnostic and prognostic biomarkers at an early stage. This has also prevented the identification of targets for patient-tailored immunomodulatory therapies that are both disease- and organ-selective. In this review, we discuss current knowledge of the development and functional characteristics of pathogenic T-cell-mediated immune responses in the heart, and, in particular, in myocarditis, as well as recent advances in experimental models which have the potential to translate into heart-selective immunomodulation. LINKED ARTICLES: This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.

Adiponectin promotes coxsackievirus B3 myocarditis by suppression of acute anti-viral immune responses.

Adiponectin (APN) is an immunomodulatory adipocytokine that improves outcome in patients with virus-negative inflammatory cardiomyopathy and mice with autoimmune myocarditis. Here, we investigated whether APN modulates cardiac inflammation and injury in coxsackievirus B3 (CVB3) myocarditis. Myocarditis was induced by CVB3 infection of APN-KO and WT mice. APN reconstitution was performed by adenoviral gene transfer. Expression analyses were performed by qRT-PCR and immunoblot. Cardiac histology was analyzed by H&E-stain and immunohistochemistry. APN-KO mice exhibited diminished subacute myocarditis with reduced viral load, attenuated inflammatory infiltrates determined by NKp46, F4/80 and CD3/CD4/CD8 expression and reduced IFNß, IFNγ, TNFα, IL-1ß and IL-12 levels. Moreover, myocardial injury assessed by necrotic lesions and troponin I release was attenuated resulting in preserved left ventricular function. Those changes were reversed by APN reconstitution. APN had no influence on adhesion, uptake or replication of CVB3 in cardiac myocytes. In acute CVB3 myocarditis, cardiac viral load did not differ between APN-KO and WT mice. However, APN-KO mice displayed an enhanced acute immune response, i.e. increased expression of myocardial CD14, IFNß, IFNγ, IL-12, and TNFα resulting in increased cardiac infiltration with pro-inflammatory M1 macrophages and activated NK cells. Up-regulation of cardiac CD14 expression, type I and II IFNs and inflammatory cell accumulation in APN-KO mice was inhibited by APN reconstitution. Our observations indicate that APN promotes CVB3 myocarditis by suppression of toll-like receptor-dependent innate immune responses, polarization of anti-inflammatory M2 macrophages and reduction of number and activation of NK cells resulting in attenuated acute anti-viral immune responses.

Assessment of cardiac inflammation and remodeling during the development of streptozotocin-induced diabetic cardiomyopathy in vivo: a time course analysis.

In this study, we examined cardiac inflammation, fibrosis and left ventricular (LV) function during the development of streptozotocin (STZ)-induced diabetic cardiomyopathy using an animal model of diabetes mellitus (DM). Diabetes was induced in 22 Sprague­Dawley rats by an intraperitoneal single injection of STZ (70 mg/kg). Non-diabetic animals served as the controls (n=6). LV function was documented using the conductance catheter technique 2 and 6 weeks after the induction of diabetes. Cardiac tissue was analyzed for cardiac immune cell infiltration, oxidative stress and remodeling in rats with STZ-induced diabetes at 2 different time points by immunohistochemistry. Cardiac function was significantly impaired in the diabetic animals. After 2 weeks, the induction of diabetes resulted in impaired cardiac function indexed by a decrease in systolic and diastolic LV function. This impairment of LV performance continued for up to 6 weeks after the STZ injection. This was associated with an increase in cardiac CD3+ and CD8a+ immune cell invasion and fibrosis, indexed by an increase in collagen content (p<0.05). Furthermore, oxidative stress response and matrix remodeling were increased after 2 weeks and this continued for up to 6 weeks after the induction of diabetes. In conclusion, cardiac dysfunction is associated with cardiac inflammation and adverse remodeling in experimental diabetic cardiomyopathy. Our results suggest that the model of STZ-induced diabetic cardiomyopathy is a robust model for investigating cardiac immune response and LV remodeling processes under diabetic conditions.

Quaternary cytoreductive surgery in ovarian cancer: does surgical effort still matter?

BACKGROUND: To evaluate surgical outcome and survival benefit after quaternary cytoreduction (QC) in epithelial ovarian cancer (EOC) relapse. METHODS: We systematically evaluated all consecutive patients undergoing QC in our institution over a 12-year period (October 2000-January 2012). All relevant surgical and clinical outcome parameters were systematically assessed. RESULTS: Forty-nine EOC patients (median age: 57; range: 28-76) underwent QC; in a median of 16 months (range:2-142) after previous chemotherapy. The majority of the patients had an initial FIGO stage III (67.3%), peritoneal carcinomatosis (77.6%) and no ascites (67.3%). At QC, patients presented following tumour pattern: lower abdomen 85.7%; middle abdomen 79.6% and upper abdomen 42.9%. Median duration of surgery was 292 min (range: a total macroscopic tumour clearance could be achieved. Rates of major operative morbidity and 30-day mortality were 28.6% and 2%, respectively.Mean follow-up from QC was 18.41 months (95% confidence interval (CI):12.64-24.18) and mean overall survival (OS) 23.05 months (95% CI: 15.5-30.6). Mean OS for patients without vs any tumour residuals was 43 months (95% CI: 26.4-59.5) vs 13.4 months (95% CI: 7.42-19.4); P=0.001. Mean OS for patients who received postoperative chemotherapy (n=18; 36.7%) vs those who did not was 40.5 months (95% CI: 27.4-53.6) vs 12.03 months (95% CI: 5.9-18.18); P<0.001.Multivariate analysis indentified multifocal tumour dissemination to be of predictive significance for incomplete tumour resection, higher operative morbidity and lower survival, while systemic chemotherapy subsequent to QC had a protective significant impact on OS. No prognostic impact had ascites, platinum resistance, high grading and advanced age. CONCLUSION: Even in this highly advanced setting of the third EOC relapse, maximal therapeutic effort combining optimal surgery and chemotherapy appear to significantly prolong survival in a selected patients 'group'.

Mesenchymal stem cells improve murine acute coxsackievirus B3-induced myocarditis.

AIMS: Coxsackievirus B3 (CVB3)-induced myocarditis, initially considered a sole immune-mediated disease, also results from a direct CVB3-mediated injury of the cardiomyocytes. Mesenchymal stem cells (MSCs) have, besides immunomodulatory, also anti-apoptotic features. In view of clinical translation, we first analysed whether MSCs can be infected by CVB3. Next, we explored whether and how MSCs could reduce the direct CVB3-mediated cardiomyocyte injury and viral progeny release, in vitro, in the absence of immune cells. Finally, we investigated whether MSC application could improve murine acute CVB3-induced myocarditis. METHODS AND RESULTS: Phase contrast pictures and MTS viability assay demonstrated that MSCs did not suffer from CVB3 infection 4-12-24-48 h after CVB3 infection. Coxsackievirus B3 RNA copy number decreased in this time frame, suggesting that no CVB3 replication took place. Co-culture of MSCs with CVB3-infected HL-1 cardiomyocytes resulted in a reduction of CVB3-induced HL-1 apoptosis, oxidative stress, intracellular viral particle production, and viral progeny release in a nitric oxide (NO)-dependent manner. Moreover, MSCs required priming via interferon-γ (IFN-γ) to exert their protective effects. In vivo, MSC application improved the contractility and relaxation parameters in CVB3-induced myocarditis, which was paralleled with a reduction in cardiac apoptosis, cardiomyocyte damage, left ventricular tumour necrosis factor-α mRNA expression, and cardiac mononuclear cell activation. Mesenchymal stem cells reduced the CVB3-induced CD4- and CD8- T cell activation in an NO-dependent way and required IFN-γ priming. CONCLUSION: We conclude that MSCs improve murine acute CVB3-induced myocarditis via their anti-apoptotic and immunomodulatory properties, which occur in an NO-dependent manner and require priming via IFN-γ.

Cardiac inflammation contributes to changes in the extracellular matrix in patients with heart failure and normal ejection fraction.

BACKGROUND: The pathophysiology of heart failure with normal ejection fraction (HFNEF) is still under discussion. Here we report the influence of cardiac inflammation on extracellular matrix (ECM) remodeling in patients with HFNEF. METHODS AND RESULTS: We investigated left ventricular systolic and diastolic function in 20 patients with HFNEF and 8 control patients by conductance catheter methods and echocardiography. Endomyocardial biopsy samples were also obtained, and ECM proteins as well as cardiac inflammatory cells were investigated. Primary human cardiac fibroblasts were outgrown from the endomyocardial biopsy samples to investigate the gene expression of ECM proteins after stimulation with transforming growth factor-ß. Diastolic dysfunction was present in the HFNEF patients compared with the control patients. In endomyocardial biopsy samples from HFNEF patients, we found an accumulation of cardiac collagen, which was accompanied by a decrease in the major collagenase system (matrix metalloproteinase-1) in the heart. Moreover, a subset of inflammatory cells, which expressed the profibrotic growth factor transforming growth factor-ß, could be documented in the HFNEF patients. Stimulation of primary human cardiac fibroblasts from HFNEF patients with transforming growth factor-ß resulted in transdifferentiation of fibroblasts to myofibroblasts, which produced more collagen and decreased the amount of matrix metalloproteinase-1, the major collagenase in the human heart. A positive correlation between cardiac collagen, as well as the amount of inflammatory cells, and diastolic dysfunction was evident and suggests a direct influence of inflammation on fibrosis triggering diastolic dysfunction. CONCLUSIONS: Cardiac inflammation contributes to diastolic dysfunction in HFNEF by triggering the accumulation of ECM.

Adult granulosa cell tumors of the ovary: tumor dissemination pattern at primary and recurrent situation, surgical outcome.

OBJECTIVE: Granulosa-cell-tumors of the ovary (GCT) constitute a rare group of neoplasms with malignant potential. Due to the rarity of the disease intraoperative tumor-dissemination-patterns are not well defined and are mostly based on retrospective data. Aim of the present study was to describe surgical and clinical outcome and dissemination pathways in the primary and recurrent situation of the disease. METHODS: All primary and relapsed GCT-patients, operated between 01/2001 and 02/2010 in our institution were evaluated using a systematic intraoperative documentation-tool (IMO). Surgical outcome, intraoperative tumor-dissemination-pattern and pathological and findings were separately analyzed for the primary and recurrent situation. RESULTS: Overall, 45 patients were analyzed; including eighteen patients with primary and 27 patients with recurrent GCT. Tumor-dissemination-patterns differed significantly between primary and recurrent patients, by the latter having significantly higher rates of diffuse peritoneal involvement (15.8% vs. 52%; p=0.027) and of extraovarian tumor involvement of the middle (15.8% vs. 48.1%; p=0.05) and upper abdomen (0 vs. 33.3%; p=0.006). While all primary patients could be operated tumor-free, this was the case for 85.2% of the relapsed patients (p=0.13). A multivisceral operative approach with extensive peritonectomy, intestinal or diaphragmatic resection, splenectomy and partial hepatectomy/panceratectomy had to be performed only in recurrent GCT (55.6%). CONCLUSIONS: Tumor-dissemination-pathways followed in primary and recurrent GCT differ significantly by higher rates of multivisceral tumor involvement in the recurrent situation of the disease. While at primary presentation extrapelvic involvement with peritoneal carcinosis appears only rare, surgical cytoreduction during relapse is more challenging involving a multivisceral approach.

Rational of the use of aliskiren in hypertension and beyond.

Arterial hypertension is an independent risk factor for cardiovascular diseases and one of the major causes for mortality worldwide. Drugs, that control hypertension effectively are therefore needed to reduce hypertension induced morbidity and mortality. The inhibition of the renin-angiotensin-aldosterone-system (RAAS) is one target to control blood pressure in these patients. The new direct renin inhibitor aliskiren is one new substance on the market to inhibit the RAAS effectively by suppression of the plasma renin activity, which inhibits the RAAS at its rate-limiting step. Therefore, aliskiren in monotherapy and in combination might yield beneficial effects for the patients. Nevertheless, blood pressure lowering has to be combined with a reduction of target organ damage for all drug classes prescribed to patients with hypertension. Therefore, we review here the major effects of this new drug not only in regard to hypertension but also in regard to target organ damage reduction and possible changes in morbidity and mortality, which future trials will investigate.