Healthy, mtDNA-mutation free mesoangioblasts from mtDNA patients qualify for autologous therapy

BACKGROUND: Myopathy and exercise intolerance are prominent clinical features in carriers of a point-mutation or large-scale deletion in the mitochondrial DNA (mtDNA). In the majority of patients, the mtDNA mutation is heteroplasmic with varying mutation loads between tissues of an individual. Exercise-induced muscle regeneration has been shown to be beneficial in some mtDNA mutation carriers, but is often not feasible for this patient group. In this study, we performed in vitro analysis of mesoangioblasts from mtDNA mutation carriers to assess their potential to be used as source for autologous myogenic cell therapy. METHODS: We assessed the heteroplasmy level of patient-derived mesoangioblasts, isolated from skeletal muscle of multiple carriers of different mtDNA point-mutations (n = 25). Mesoangioblast cultures with < 10% mtDNA mutation were further analyzed with respect to immunophenotype, proliferation capacity, in vitro myogenic differentiation potential, mitochondrial function, and mtDNA quantity. RESULTS: This study demonstrated that mesoangioblasts in half of the patients contained no or a very low mutation load (< 10%), despite a much higher mutation load in their skeletal muscle. Moreover, none of the large-scale mtDNA deletion carriers displayed the deletion in mesoangioblasts, despite high percentages in skeletal muscle. The mesoangioblasts with no or a very low mutation load (< 10%) displayed normal mitochondrial function, proliferative capacity, and myogenic differentiation capacity. CONCLUSIONS: Our data demonstrates that in half of the mtDNA mutation carriers, their mesoangioblasts are (nearly) mutation free and can potentially be used as source for autologous cell therapy for generation of new muscle fibers without mtDNA mutation and normal mitochondrial function

Functional treatment versus plaster for simple elbow dislocations (FuncSiE): a randomized trial

Background. Elbow dislocations can be classified as simple or complex. Simple dislocations are characterized by the absence of fractures, while complex dislocations are associated with fractures. After reduction of a simple dislocation, treatment options include immobilization in a static plaster for different periods of time or so-called functional treatment. Functional treatment is characterized by early active motion within the limits of pain with or without the use of a sling or hinged brace. Theoretically, functional treatment should prevent stiffness without introducing increased joint instability. The primary aim of this randomized controlled trial is to compare early functional treatment versus plaster immobilization following simple dislocations of the elbow. Methods/Design. The design of the study will be a multicenter randomized controlled trial of 100 patients who have sustained a simple elbow dislocation. After reduction of the dislocation, patients are randomized between a pressure bandage for 5-7 days and early functional treatment or a plaster in 90 degrees flexion, neutral position for pro-supination for a period of three weeks. In the functional group, treatment is started with early active motion within the limits of pain. Function, pain, and radiographic recovery will be evaluated at regular intervals over the subsequent 12 months. The primary outcome measure is the Quick Disabilities of the Arm, Shoulder, and Hand score. The secondary outcome measures are the Mayo Elbow Performance Index, Oxford elbow score, pain level at both sides, range of motion of the elbow joint at both sides, rate of secondary interventions and complication rates in both groups (secondary dislocation, instability, relaxation), health-related quality of life (Short-Form 36 and EuroQol-5D), radiographic appearance of the elbow joint (degenerative changes and heterotopic ossifications), costs, and cost-effectiveness. Discussion. The successful completion of this trial will provide evidence on the effectiveness of a functional treatment for the management of simple elbow dislocations. Trial Registration. The trial is registered at the Netherlands Trial Register (NTR2025)

Skin fluorescence as a clinical tool for non-invasive assessment of advanced glycation and long-term complications of diabetes

Glycation is important in the development of complications of diabetes mellitus and may have a central role in the well-described glycaemic memory effect in developing these complications. Skin fluorescence has emerged over the last decade as a non-invasive method for assessing accumulation of advanced glycation endproducts. Skin fluorescence is independently related to micro- and macrovascular complications in both type 1 and type 2 diabetes mellitus and is associated with mortality in type 2 diabetes. The relation between skin fluorescence and cardiovascular disease also extends to other conditions with increased tissue AGE levels, such as renal failure. Besides cardiovascular complications, skin fluorescence has been associated, more recently, with other prevalent conditions in diabetes, such as brain atrophy and depression. Furthermore, skin fluorescence is related to past long-term glycaemic control and clinical markers of cardiovascular disease. This review will discuss the technique of skin fluorescence, its validation as a marker of tissue AGE accumulation, and its use as a clinical tool for the prediction of long-term complications in diabetes mellitus

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Absence of nodular regenerative hyperplasia after low-dose 6-thioguanine maintenance therapy in inflammatory bowel disease patients

BACKGROUND: The use of 6-thioguanine has been proposed as a rescue drug for inflammatory bowel disease patients. Initial data on short-term efficacy and toxicity of 6-thioguanine were promising; however, these have been challenged by reports concerning its potential hepatotoxic effect (nodular regenerative hyperplasia). We proposed that these histological liver abnormalities may well be dose- or level-dependent. AIMS: We performed a prospective multi-centre study on the hepatotoxic potential of long-term and (as compared with prior studies) low-dose 6-thioguanine use. PATIENTS: Inflammatory bowel disease patients using 6-thioguanine for at least 30 consecutive months and consenting to undergo a liver biopsy were enrolled. METHODS: Liver biopsy specimens were scored by two pathologists, unaware of clinical data. Laboratory parameters, determined prior to initiation of 6-thioguanine therapy and prior to biopsy, were reviewed. RESULTS: Twenty-eight biopsies were analysed. The majority of patients (89%) were azathioprine and/or 6-mercaptopurine intolerant inflammatory bowel disease patients. In 26 patients (93%) no signs of nodular regenerative hyperplasia were detected; in two additional patients nodular regenerative hyperplasia could not be excluded due to inconclusive pathological findings. The mean 6-thioguanine dosage, 6-thioguaninenucleotides level, duration of use and cumulative dosage were 19.5mg, 564 pmol/8 x 10(8) RBC, 38 months and 22491 mg, respectively. CONCLUSIONS: We have demonstrated that low-dose 6-thioguanine maintenance therapy in inflammatory bowel disease patients is not likely to be associated with induction of nodular regenerative hyperplasia. The induction of nodular regenerative hyperplasia appears to be 6-thioguanine dose or 6-thioguaninenucleotides level dependent

Novel pathogenic SLC25A46 splice-site mutation causes an optic atrophy spectrum disorder

The inherited optic neuropathies comprise a group of genetically heterogeneous disorders causing optic nerve dysfunction. In some cases, optic neuropathies are associated with cerebellar atrophy which mainly affects the vermis. Here, we describe a Moroccan girl of consanguineous parents with optic atrophy and cerebellar atrophy. Exome sequencing revealed a novel homozygous mutation (c.283+3G&gt;T) in the donor splice site for exon 1 of SLC25A46. RNA analysis revealed that an alternative splice site within exon 1 was used leading to a premature termination codon within exon 2. SLC25A46 mRNA expression showed there is no wild-type transcript present in the patient and the mutant transcript does not undergo nonsense mediated mRNA decay. Futhermore, we observed c.283+3G&gt;T SLC25A46 mutation induces mitochondrial fragmentation. An additional 10 patients with optic atrophy and cerebellar atrophy, which were negative for mtDNA and OPA1 variants, were tested for pathogenic mutations in the SLC25A46 gene. However, no additional variants were identified. Our findings confirm the recent report of pathogenic SLC25A46 mutations as a novel cause for optic atrophy spectrum disorder.</p

Aortic Disease in Patients with Marfan Syndrome:Aortic Volume Assessment for Surveillance

<p>Purpose: To assess the reproducibility of aortic volume estimates and to serially test their use in patients with Marfan syndrome.</p><p>Materials and Methods: The study was approved by the medical ethics committee and all subjects gave written informed consent. In 81 patients with Marfan syndrome and seven healthy control subjects, aortic volumes and diameters at baseline were estimated by means of contrast material-enhanced magnetic resonance (MR) imaging. At 3 years of follow-up, aortic expansion rate were calculated in a subgroup of 22 patients with Marfan syndrome. Total aortic volume was defined as volume measurement from the level of the aortic annulus to the aortic bifurcation. Intra-and inter-observer agreement of aortic volume were calculated by using the intraclass correlation coefficient. Differences in variables were analyzed with the Student t test and logistic regression. Effect size was calculated.</p><p>Results: Intra-and interobserver agreement of aortic volume calculation was 0.996 and 0.980, respectively. Mean aortic volume was significantly greater in patients with Marfan syndrome than in control subjects (104 mL/m(2); 95% confidence interval [CI]: 95, 114 mL/m(2) vs 74 mL/m(2); 95% CI: 62, 87 mL/m(2); P <.001). In 22 patients with Marfan syndrome, mean aortic volume was increased at 3 years of follow-up (17 mL; 95% CI: 8, 26 mL; P = .001; effect size, 0.29), while mean aortic diameter did not increase significantly (0.4 mm; 95% CI: 0.0, 0.9 mm; P = .171; effect size, 0.13).</p><p>Conclusion: Assessment of aortic volume is highly reproducible and may be suited for use in the detection of aortic expansion in patients with Marfan syndrome. (C) RSNA, 2013</p>

Limited relevance and progression of histological alterations in the liver during thioguanine therapy in inflammatory bowel disease patients

Background: Thioguanine is associated with liver toxicity, especially nodular regenerative hyperplasia (NRH). We assessed if liver histology alters during long-term maintenance treatment with thioguanine in patients with inflammatory bowel disease (IBD). Methods: Liver specimens of thioguanine treated IBD patients with at least two liver biopsies were revised by two independent liver pathologists, blinded to clinical characteristics. Alterations in histopathological findings between first and sequential liver specimen were evaluated and associated clinical data, including laboratory parameters and abdominal imaging reports, were collected. Results: Twenty-five IBD patients underwent sequential liver biopsies prior to, at time of, or after cessation of thioguanine treatment. The median time between the first and second biopsy was 25 months (range: 14–54). Except for one normal liver specimen, any degree of irregularities including inflammation, steatosis, fibrosis and some vascular disturbances were observed in the biopsies. The rates of perisinusoidal fibrosis (91%), sinusoidal dilatation (68%) and nodularity (18%) were the same in the first and second liver biopsies. A trend towards statistical significance was observed for phlebosclerosis (36% of the first vs. 68% of the second biopsies, p =.092). Presence of histopathological liver abnormalities was not associated with clinical outcomes. Furthermore, two patients in this cohort had portal hypertension in presence of phlebosclerosis. In another two patients, nodularity of the liver resolved upon thioguanine withdrawal. Conclusion: Vascular abnormalities of the liver were commonly observed in thioguanine treated IBD patients, although these were not progressive and remained of limited clinical relevance over time