Early onset facioscapulohumeral dystrophy - a systematic review using individual patient data

Infantile or early onset is estimated to occur in around 10% of all facioscapulohumeral dystrophy (FSHD) patients. Although small series of early onset FSHD patients have been reported, comprehensive data on the clinical phenotype is missing. We performed a systematic literature search on the clinical features of early onset FSHD comprising a total of 43 articles with individual data on 227 patients. Additional data from four cohorts was provided by the authors. Mean age at reporting was 18.8 years, and 40% of patients were wheelchair-dependent at that age. Half of the patients had systemic features, including hearing loss (40%), retinal abnormalities (37%) and developmental delay (8%). We found an inverse correlation between repeat size and disease severity, similar to adult-onset FSHD. De novo FSHD1 mutations were more prevalent than in adult-onset FSHD. Compared to adult FSHD, our findings indicate that early onset FSHD is overall characterized by a more severe muscle phenotype and a higher prevalence of systemic features. However, similar as in adults, a significant clinical heterogeneity was observed. Based on this, we consider early onset FSHD to be on the severe end of the FSHD disease spectrum. We found natural history studies and treatment studies to be very scarce in early onset FSHD, therefore longitudinal studies are needed to improve prognostication, clinical management and trial-readiness

Randomized controlled trial using bosentan to enhance the impact of exercise training in subjects with type 2 diabetes mellitus

In type 2 diabetes patients, endothelin (ET) receptor blockade may enhance blood flow responses to exercise training. The combination of exercise training and ET receptor blockade may represent a more potent stimulus than training alone to improve vascular function, physical fitness and glucose homeostasis. We assessed the effect of an 8 week exercise training programme combined with either ET blockade or placebo on vasculature, fitness and glucose homeostasis in people with type 2 diabetes. In a double-blind randomized controlled trial, brachial endothelium-dependent and -independent dilatation (using flow-mediated dilatation and glyceryl trinitrate, respectively), glucose homeostasis (using Homeostasis Model Assessment for Insulin Resistance (HOMA-IR)) and physical fitness (maximal cycling test) were assessed in 18 men with type 2 diabetes (60 ± 6 years old). Subjects underwent an 8 week exercise training programme, with half of the subjects receiving ET receptor blockade (bosentan) and the other half a placebo, followed by reassessment of the tests above. Exercise training improved physical fitness to a similar extent in both groups, but we did not detect changes in vascular function in either group. This study suggests that there is no adaptation in brachial and femoral artery endothelial function after 8 weeks of training in type 2 diabetes patients. Endothelin receptor blockade combined with exercise training does not additionally alter conduit artery endothelial function or physical fitness in type 2 diabetes

Vascular Function and Structure in Veteran Athletes after Myocardial Infarction.

PURPOSE: Although athletes demonstrate lower cardiovascular risk and superior vascular function compared with sedentary peers, they are not exempted from cardiac events (i.e., myocardial infarction [MI]). The presence of an MI is associated with increased cardiovascular risk and impaired vascular function. We tested the hypothesis that lifelong exercise training in post-MI athletes, similar as in healthy controls, is associated with a superior peripheral vascular function and structure compared with a sedentary lifestyle in post-MI individuals. METHODS: We included 18 veteran athletes (ATH) (>20 yr) and 18 sedentary controls (SED). To understand the effect of lifelong exercise training after MI, we included 20 veteran post-MI athletes (ATH + MI) and 19 sedentary post-MI controls (SED + MI). Participants underwent comprehensive assessment using vascular ultrasound (vascular stiffness, intima-media thickness, and endothelium (in)dependent mediated dilatation). Lifetime risk score was calculated for a 30-yr risk prediction of cardiovascular disease mortality of the participants. RESULTS: ATH demonstrated a lower vascular stiffness and smaller femoral intima-media thickness compared with SED. Vascular function and structure did not differ between ATH + MI and SED + MI. ATH (4.0% ± 5.1%) and ATH + MI (6.1% ± 3.7%) had a significantly better lifetime risk score compared with their sedentary peers (SED: 6.9% ± 3.7% and SED + MI: 9.3% ± 4.8%). ATH + MI had no secondary events versus two recurrent MI and six elective percutaneous coronary interventions within SED + MI (P < 0.05). CONCLUSION: Although veteran post-MI athletes did not have a superior peripheral vascular function and structure compared with their sedentary post-MI peers, benefits of lifelong exercise training in veteran post-MI athletes relate to a better cardiovascular risk profile and lower occurrence of secondary events

Combined aerobic and resistance exercise training decreases peripheral but not central artery wall thickness in subjects with type 2 diabetes

Objective Little is known about the impact of exercise training on conduit artery wall thickness in type 2 diabetes. We examined the local and systemic impact of exercise training on superficial femoral (SFA), brachial (BA), and carotid artery (CA) wall thickness in type 2 diabetes patients and controls. Methods Twenty patients with type 2 diabetes and 10 age- and sex-matched controls performed an 8-week training study involving lower limb-based combined aerobic and resistance exercise training. We examined the SFA to study the local effect of exercise, and also the systemic impact of lower limb-based exercise training on peripheral (i.e. BA) and central (i.e. CA) arteries. Wall thickness (WT), diameter and wall:lumen(W:L)-ratios were examined using automated edge detection of ultrasound images. Results Exercise training did not alter SFA or CA diameter in type 2 diabetes or controls (all P > 0.05). BA diameter was increased after training in type 2 diabetes, but not in controls. Exercise training decreased WT and W:L ratio in the SFA and BA, but not in CA in type 2 diabetes. Training did not alter WT or W:L ratio in controls (P > 0.05). Conclusion Lower limb-dominant exercise training causes remodelling of peripheral arteries, supplying active and inactive vascular beds, but not central arteries in type 2 diabetes

Chorioamnionitis Causes Kidney Inflammation, Podocyte Damage, and Pro-fibrotic Changes in Fetal Lambs

BACKGROUND: Perinatal complications, such as prematurity and intrauterine growth restriction, are associated with increased risk of chronic kidney disease. Although often associated with reduced nephron endowment, there is also evidence of increased susceptibility for sclerotic changes and podocyte alterations. Preterm birth is frequently associated with chorioamnionitis, though studies regarding the effect of chorioamnionitis on the kidney are scarce. In this study, we aim to unravel the consequences of premature birth and/or perinatal inflammation on kidney development using an ovine model. METHODS: In a preterm sheep model, chorioamnionitis was induced by intra-amniotic injection of lipopolysaccharide (LPS) at either 2, 8, or 15 days prior to delivery. Control animals received intra-amniotic injections of sterile saline. All lambs were surgically delivered at 125 days’ gestation (full term is 150 days) and immediately euthanized for necropsy. Kidneys were harvested and processed for staining with myeloperoxidase (MPO), Wilms tumor-1 (WT1) and alpha-smooth muscle actine (aSMA). mRNA expression of tumor necrosis factor alpha (TNFA), Interleukin 10 (IL10), desmin (DES), Platelet derived growth factor beta (PDGFB), Platelet derived growth factor receptor beta (PDGFRB), synaptopodin (SYNPO), and transforming growth factor beta (TGFB) was measured using quantitative PCR. RESULTS: Animals with extended (but not acute) LPS exposure had an inflammatory response in the kidney. MPO staining was significantly increased after 8 and 15 days (p = 0.003 and p = 0.008, respectively). Expression of TNFA (p = 0.016) and IL10 (p = 0.026) transcripts was increased, peaking on day 8 after LPS exposure. Glomerular aSMA and expression of TGFB was increased on day 8, suggesting pro-fibrotic mesangial activation, however, this was not confirmed with PDFGB or PDGFRB. The number of WT1 positive nuclei in the glomerulus, as well as expression of synaptopodin, decreased, indicating podocyte injury. CONCLUSION: We report that, in an ovine model of prematurity, LPS-induced chorioamnionitis leads to inflammation of the immature kidney. In addition, this process was associated with podocyte injury and there are markers to support pro-fibrotic changes to the glomerular mesangium. These data suggest a potential important role for antenatal inflammation in the development of preterm-associated kidney disease, which is frequent

Chorioamnionitis Causes Kidney Inflammation, Podocyte Damage, and Pro-fibrotic Changes in Fetal Lambs

Background: Perinatal complications, such as prematurity and intrauterine growth restriction, are associated with increased risk of chronic kidney disease. Although often associated with reduced nephron endowment, there is also evidence of increased susceptibility for sclerotic changes and podocyte alterations. Preterm birth is frequently associated with chorioamnionitis, though studies regarding the effect of chorioamnionitis on the kidney are scarce. In this study, we aim to unravel the consequences of premature birth and/or perinatal inflammation on kidney development using an ovine model. Methods: In a preterm sheep model, chorioamnionitis was induced by intra-amniotic injection of lipopolysaccharide (LPS) at either 2, 8, or 15 days prior to delivery. Control animals received intra-amniotic injections of sterile saline. All lambs were surgically delivered at 125 days' gestation (full term is 150 days) and immediately euthanized for necropsy. Kidneys were harvested and processed for staining with myeloperoxidase (MPO), Wilms tumor-1 (WT1) and alpha-smooth muscle actine (aSMA). mRNA expression of tumor necrosis factor alpha (TNFA), Interleukin 10 (IL10), desmin (DES), Platelet derived growth factor beta (PDGFB), Platelet derived growth factor receptor beta (PDGFRB), synaptopodin (SYNPO), and transforming growth factor beta (TGFB) was measured using quantitative PCR. Results: Animals with extended (but not acute) LPS exposure had an inflammatory response in the kidney. MPO staining was significantly increased after 8 and 15 days (p = 0.003 and p = 0.008, respectively). Expression of TNFA (p = 0.016) and IL10 (p = 0.026) transcripts was increased, peaking on day 8 after LPS exposure. Glomerular aSMA and expression of TGFB was increased on day 8, suggesting pro-fibrotic mesangial activation, however, this was not confirmed with PDFGB or PDGFRB. The number of WT1 positive nuclei in the glomerulus, as well as expression of synaptopodin, decreased, indicating podocyte injury. Conclusion: We report that, in an ovine model of prematurity, LPS-induced chorioamnionitis leads to inflammation of the immature kidney. In addition, this process was associated with podocyte injury and there are markers to support pro-fibrotic changes to the glomerular mesangium. These data suggest a potential important role for antenatal inflammation in the development of preterm-associated kidney disease, which is frequent

Liver transplantation for NASH cirrhosis is not performed at the expense of major post-operative morbidity

Background: Non-alcoholic steatohepatitis (NASH) is an emerging indication for liver transplantation (LT) and coexists with multiple comorbidities. Obese and cirrhotic patients experience more perioperative complications. Limited data exist about short-term complications after LT for NASH cirrhosis. Aim: Investigate short-term complications in patients transplanted for NASH cirrhosis. Methods: Single center retrospective cohort study including patients >18 years who underwent LT between 2009-2015. Exclusion criteria were LT for acute liver failure and non-cirrhotic disease. Post-operative complications and severity within 90-days were classified using the Clavien-Dindo classification of surgical complications and comprehensive complication index (CCI). P <0.05 was significant. Results: Out of 169 eligible patients, 34 patients (20.1%) were transplanted for NASH cirrhosis. These patients were significantly older (59.2 vs. 54.8 years, P = 0.01), more obese (61.8% vs. 8.1%, P <0.01), had more diabetes mellitus (73.5% vs. 20%, P <0.01), metabolic syndrome (83.3% vs. 37.8%, P <0.01) and cardiovascular disease (29.4% vs. 11.1%, P <0.01). More grade 1 complications (OR 1.64, 95% CI 1.03-2.63, P = 0.04) and more grade 2 urogenital infections (OR 3.4, 95% CI 1.1-10.6, P = 0.03) were found. Major complications, CCI, 90-day mortality and graft survival were similar. Conclusion: Despite significantly increased comorbidities in patients transplanted for NASH cirrhosis, major morbidity, mortality and graft survival after 90 days were comparable to patients transplanted for other indications

Prevalence and determinants of non-alcoholic fatty liver disease in lifelines: A large Dutch population cohort

Background & aims Non-alcoholic fatty liver disease is an increasing health issue that develops rather unnoticed with obesity, type 2 diabetes mellitus and metabolic syndrome. We investigated prevalence, determinants and associated metabolic abnormalities of non-alcoholic fatty liver disease in the largest population-based cohort to date. Methods Biochemical characteristics, type 2 diabetes mellitus and metabolic syndrome were determined in the Lifelines Cohort Study (N = 167,729), a population-based cohort in the North of the Netherlands. Non-alcoholic fatty liver disease was defined as Fatty Liver Index (FLI)>= 60. Exclusion criteria were age Results Out of 37,496 included participants (median age 44 years, 62.1% female), 8,259 (22.0%) had a FLI >= 60. Individuals with a FLI >= 60 were more often male, older, obese, had higher levels of hemoglobinA1c, fasting glucose, liver enzymes, total cholesterol, low-density lipoprotein cholesterol, triglycerides, c-reactive protein and leucocytes and lower high-density lipoprotein cholesterol (all P= 60 showed higher prevalence of type 2 diabetes mellitus (9.3% vs. 1.4%), metabolic syndrome (54.2% vs. 6.2%), impaired renal function (20.1% vs. 8.7%) and cardiovascular disease (4.6% vs. 1.6%) (all P Conclusion Twenty-two percent (22.0%) of the population in the North of the Netherlands is suspected to suffer from non-alcoholic fatty liver disease, coinciding with a significant increased risk of type 2 diabetes mellitus, metabolic syndrome, cardiovascular disease and impaired renal function

Interval exercise, but not endurance exercise, prevents endothelial ischemia-reperfusion injury in healthy subjects

Endothelial ischemia-reperfusion (I/R) injury importantly contributes to the poor prognosis during ischemic (myocardial) events. Preconditioning, i.e., repeated exposure to short periods of ischemia, effectively reduces endothelial I/R injury. In the present study, we examined the hypothesis that exercise has preconditioning effects on endothelial I/R injury. Therefore, we studied whether an acute bout of endurance or interval exercise is able to protect against endothelial I/R injury. In 17 healthy young subjects, we examined changes in brachial artery endothelial function using flow-mediated dilation (FMD) before and after a bout of high-intensity interval exercise, moderate-intensity endurance exercise, or a control intervention. Subsequently, I/R injury was induced by inflation of a blood pressure cuff around the upper arm to 220 mmHg for 20 min and 20 min of reperfusion followed by another FMD measurement. Near-infrared spectrometry was used to examine local tissue oxygenation during exercise. No differences in brachial artery FMD were found at baseline for the three conditions. I/R induced a significant decline in FMD (7.1 ± 2.3 to 4.3 ± 2.3, P < 0.001). When preceded by the interval exercise bout, no change in FMD was present after I/R (7.7 ± 3.1 to 7.2 ± 3.1, P = 0.56), whereas the decrease in FMD after I/R could not be prevented by the endurance exercise bout (7.8 ± 3.1 to 3.8 ± 1.7, P < 0.001). In conclusion, a single bout of lower limb interval exercise, but not moderate-intensity endurance exercise, effectively prevents brachial artery endothelial I/R injury. This indicates the presence of a remote preconditioning effect of exercise, which is selectively present after short-term interval but not continuous exercise in healthy young subjects