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

Prednisolone is associated with a worse lipid profile than hydrocortisone in patients with adrenal insufficiency

Objective: Prednisolone is used as glucocorticoid replacement therapy for adrenal insufficiency (AI). Recent data indicate that its use in AI is associated with low bone mineral density. Data on risk factors for cardiovascular disease in patients with AI treated with prednisolone are scarce, despite this condition being the predominant cause of excess mortality. We aimed to address this question using real-world data from the European Adrenal Insufficiency Registry (EU-AIR). // Design/methods: EU-AIR, comprising of 19 centres across Germany, the Netherlands, Sweden and the UK, commenced enrolling patients with AI in August 2012. Patients receiving prednisolone (3–6 mg/day, n = 50) or hydrocortisone (15–30 mg/day, n = 909) were identified and grouped at a ratio of 1:3 (prednisolone:hydrocortisone) by matching for gender, age, duration and type of disease. Data from baseline and follow-up visits were analysed. Data from patients with congenital adrenal hyperplasia were excluded. // Results: Significantly higher mean ± S.D. total (6.3 ± 1.6 vs 5.4 ± 1.1 mmol/L; P = 0.003) and low-density lipoprotein (LDL) cholesterol levels (3.9 ± 1.4 vs 3.2 ± 1.0 mmol/L; P = 0.013) were identified in 47 patients on prednisolone vs 141 receiving hydrocortisone at baseline and at follow-up (P = 0.005 and P = 0.006, respectively). HbA1c, high-density lipoprotein and triglyceride levels, body mass index, systolic and diastolic blood pressure and waist circumference were not significantly different. // Conclusions: This is the first matched analysis of its kind. Significantly higher LDL levels in patients receiving prednisolone relative to hydrocortisone could predict a higher relative risk of cardiovascular disease in the former group

The effects of low and high glycemic index foods on exercise performance and beta-endorphin responses

Τhe aim of this study was to examine the effects of the consumption of foods of various glycemic index values on performance, β-endorphin levels and substrate (fat and carbohydrate) utilization during prolonged exercise. Eight untrained healthy males underwent, in a randomized counterbalanced design, three experimental conditions under which they received carbohydrates (1.5 gr. kg-1 of body weight) of low glycemic index (LGI), high glycemic index (HGI) or placebo. Food was administered 30 min prior to exercise. Subjects cycled for 60 min at an intensity corresponding to 65% of VO2max, which was increased to 90% of VO2max, then they cycled until exhaustion and the time to exhaustion was recorded. Blood was collected prior to food consumption, 15 min prior to exercise, 0, 20, 40, and 60 min into exercise as well as at exhaustion. Blood was analyzed for β-endorphin, glucose, insulin, and lactate. The mean time to exhaustion did not differ between the three conditions (LGI = 3.2 ± 0.9 min; HGI = 2.9 ± 0.9 min; placebo = 2.7 ± 0.7 min). There was a significant interaction in glucose and insulin response (P < 0.05) with HGI exhibiting higher values before exercise. β-endorphin increased significantly (P < 0.05) at the end of exercise without, however, a significant interaction between the three conditions. Rate of perceived exertion, heart rate, ventilation, lactate, respiratory quotient and substrate oxidation rate did not differ between the three conditions. The present study indicates that ingestion of foods of different glycemic index 30 min prior to one hour cycling exercise does not result in significant changes in exercise performance, β-endorphin levels as well as carbohydrate and fat oxidation during exercise

Therapy of endocrine disease: Perspectives on the management of adrenal insufficiency: clinical insights from across Europe.

BACKGROUND: Conventional glucocorticoid (GC) replacement for patients with adrenal insufficiency (AI) is inadequate. Patients with AI continue to have increased mortality and morbidity and compromised quality of life despite treatment and monitoring. OBJECTIVES: i) To review current management of AI and the unmet medical need based on literature and treatment experience and ii) to offer practical advice for managing AI in specific clinical situations. METHODS: The review considers the most urgent questions endocrinologists face in managing AI and presents generalised patient cases with suggested strategies for treatment. RESULTS: Optimisation and individualisation of GC replacement remain a challenge because available therapies do not mimic physiological cortisol patterns. While increased mortality and morbidity appear related to inadequate GC replacement, there are no objective measures to guide dose selection and optimisation. Physicians must rely on experience to recognise the clinical signs, which are not unique to AI, of inadequate treatment. The increased demand for corticosteroids during periods of stress can result in a life-threatening adrenal crisis (AC) in a patient with AI. Education is paramount for patients and their caregivers to anticipate, recognise and provide proper early treatment to prevent or reduce the occurrence of ACs. CONCLUSIONS: This review highlights and offers suggestions to address the challenges endocrinologists encounter in treating patients with AI. New preparations are being developed to better mimic normal physiological cortisol levels with convenient, once-daily dosing which may improve treatment outcomes

The paradoxical nature of sexuality in anorexia nervosa

Psychosexual dysfunctioning is often put forward as an etiological factor in anorexia nervosa. In contrast, we hypothesize that anorexia nervosa patients were in general psychosexually normal before their illness, and that the problems in their sexual life arise only after the emergence of hypogonadism, as a consequence of emaciation. Our study shows that patients, before they became anorectic, were indeed rather similar to normal subjects with respect to sexual attitude. Moreover, patients reported a considerably decreased sexual interest during their anorectic period when compared with normal controls. We conclude that these results corroborate our hypotheses. In the discussion we sketch a theoretical account of the origin and course of anorexia nervosa, according to which the hormonal and associated psychosexual changes are central to its pathogenesis

Increased long-term remission after adequate medical cortisol suppression therapy as presurgical treatment in Cushing's disease

Objective In the last decade, pre-operative medical cortisol suppression therapy has frequently been used in Cushing's disease to normalize cortisol concentrations pre-operatively. Our aim was to assess the efficacy of presurgical medical cortisol suppression therapy in Cushing's disease. Design and Methods We retrospectively assessed the medical files of all patients with Cushing's disease that received presurgical cortisol suppression therapy with ketoconazole or metyrapone and underwent subsequent transsphenoidal surgery between 1990 and 2010 at our centre. We retrieved the pretreatment regimen, adequacy of pretreatment, early postoperative serum cortisol levels, adverse effects and long-term remission status. Results Nineteen of 33 patients (58%) obtained long-term remission after pituitary surgery without additional postoperative therapy. Thirteen of 16 patients with adequate presurgical cortisol suppression therapy had postoperative cortisol concentrations <50 nmol/l. The 16 patients with adequate presurgical cortisol suppression had a higher long-term remission rate after primary surgery compared with the 13 patients with borderline or inadequate pretreatment (81% vs 38%; P < 0·05). Conclusions Adequate presurgical cortisol suppression treatment with ketoconazole or metyrapone in Cushing's disease seems to be associated with suppressed postoperative cortisol concentrations and an increased long-term remission rate

The atherogenic plasma remnant-like particle cholesterol concentration is increased in the fasting and postprandial state in active acromegalic patients

BACKGROUND: Premature atherosclerosis is a clinical feature in untreated acromegaly. Increased postprandial lipoprotein remnant levels are associated with premature atherosclerosis. In most studies, remnants have been measured indirectly using retinyl esters (RE) as a chylomicron core label. Remnants can also be directly quantified by immunoseparation using monoclonal antibodies to apolipoprotein (apo) AI and apo B100 to remove nonremnant lipoproteins. Cholesterol is quantified in the remaining apo E-rich remnant fraction (RLP-C). OBJECTIVE: The aim of the present study was to investigate the role of postprandial lipaemia in patients with acromegaly to further define abnormalities leading to increased susceptibility for atherosclerosis. PATIENTS: In a case-control study, the plasma postprandial lipoprotein remnant fraction (RLP-C and RE) were analysed in six patients with active acromegaly [two females, four males; aged 53 +/- 9 years; body mass index (BMI), 29 +/- 4 kg/m2] and in six normolipidaemic control subjects (matched for age, gender, BMI and apo E genotype). They underwent an oral vitamin A fat loading test. RESULTS: Baseline plasma triglycerides (TG) were not significantly different in patients (1.75 +/- 0.71 mM) and controls (1.15 +/- 0.46 mM). Lipoprotein lipase activity was significantly lower in patients than in controls (108 +/- 21 vs. 141 +/- 19 U/l, respectively; P <0.05). Baseline plasma apo E levels were higher in patients (60.8 +/- 7.9 mg/l) than in controls (48.3 +/- 5.9 mg/l; P <0.05). No differences were found in the area under the postprandial TG curve (AUC-TG), the incremental AUC-TG (DeltaAUC-TG) and AUC-RE in the Sf <1000 remnant fraction. However, fasting plasma RLP-C concentrations, isolated by immunoseparation, were increased in patients with active acromegaly (0.41 +/- 0.13 mM) compared to control subjects (0.20 +/- 0.07 mM; P <0.05). Incremental postprandial RLP-C response (corrected for fasting values) was also significantly elevated in patients (2.14 +/- 1.19 mM/h/l) compared to controls (0.86 +/- 0.34 mM/h/l; P <0.05). In both groups, the maximal RLP-C concentration was reached between 2 and 4 h. CONCLUSIONS: In conclusion, the atherogenic postprandial remnants, represented by RLP-C, were significantly elevated at baseline and in the postprandial period, whereas the larger-sized remnants, represented by retinyl esters (Sf <1000), were not different from controls. The disturbances in the postprandial RLP-C response increased the susceptibility for premature atherosclerosis as observed in patients with acromegal

Glucocorticoid replacement is associated with hypertriglyceridaemia, elevated glucose and higher non-HDL cholesterol and may diminish the association of HDL cholesterol with the-629C &gt; A CETP promoter polymorphism in GH-receiving hypopituitary patients

Objectives The effect of glucocorticoid substitution on the prevalence of metabolic syndrome components (NCEP ATP III criteria) and serum lipid levels was determined in GH-replaced hypopituitary patients. As glucocorticoid replacement is associated with a pronounced decrease in plasma cholesteryl ester transfer protein (CETP) activity, we also tested associations of HDL cholesterol with the -629C > A CETP promoter polymorphism in subjects with and without ACTH deficiency. Design and patients In a university setting, we retrieved protocolized clinical and laboratory data from 165 adult hypopituitary patients, who had received GH for 1 year. Results After adjustment for age, sex and smoking, non-HDL cholesterol (P = 0.05) and triglycerides (P = 0.004) were higher, but HDL cholesterol was not decreased in 117 glucocorticoid (mainly cortisone acetate in two divided doses) receiving subjects compared to 48 ACTH-sufficient subjects. The prevalence of elevated plasma glucose and/or diabetes (P = 0.04) and hypertriglyceridaemia (P = 0.005), but not of other metabolic syndrome components, was higher in glucocorticoid-replaced subjects. HDL cholesterol was higher in -629 A allele carriers compared to -629CC homozygotes in ACTH-sufficient subjects (P = 0.04), but not in glucocorticoid-treated subjects (P = 0.13). Multiple linear regression analysis demonstrated that only in ACTH-sufficient subjects, HDL cholesterol was independently related to this CETP gene variation (P = 0.03). Conclusions In GH- and glucocorticoid-replaced hypopituitary patients, serum non-HDL cholesterol and triglycerides are higher and the prevalence of hyperglycaemia is increased, but HDL cholesterol is not decreased. Conventional glucocorticoid replacement appears to diminish the association of HDL cholesterol with a common CETP gene variation