Endocrine manifestations in adults with 22q11.2 deletion syndrome: a retrospective single-center cohort study.

INTRODUCTION AND OBJECTIVE: Patients with the 22q11.2 deletion syndrome (22q11DS) frequently display cardiological and psychiatric diseases, but are also at increased risk for endocrine manifestations. The aim of this study was to evaluate the screening, prevalence, and management of hypoparathyroidism and thyroid disease in patients with 22q11DS, to evaluate the metabolic profile, and to compare these results with current literature and guidelines. DESIGN: We performed a retrospective study of patients with genetically confirmed 22q11DS, followed at the center for human genetics of the University Hospitals Leuven, resulting in a cohort of 75 patients. Medical history, medication, and laboratory results concerning hypoparathyroidism, thyroid dysfunction, and the metabolic profile were collected. RESULTS: Of the total cohort, 26 patients (35%) had at least one hypocalcaemic episode. During hypocalcaemia, parathyroid hormone (PTH) was measured in only 12 patients with 11 having normal or low PTH, confirming a diagnosis of hypoparathyroidism. Recurrent episodes of hypocalcaemia occurred in seventeen patients (23%). Adherence to the guidelines was low, with 13% of patients having a yearly serum calcium evaluation, 12% receiving daily calcium supplements, and 20% receiving non-active vitamin D. Hypothyroidism was present in 31 patients (44%) and hyperthyroidism in 6 patients (8%). Information on body mass index (BMI) was available in 52 patients (69%), of which 38% were obese (BMI ≥ 30 kg/m2). CONCLUSION: Hypoparathyroidism, hypothyroidism, and obesity are common endocrine manifestations in patients with 22q11DS but are probably underdiagnosed and undertreated, indicating the need for multidisciplinary follow-up including an endocrinologist.

Low cytochrome oxidase 4I1 links mitochondrial dysfunction to obesity and type 2 diabetes in humans and mice.

OBJECTIVES: Cytochrome oxidase (COX) dysfunction is associated with mitochondrial oxidative stress. We determined the association between COX expression, obesity and type 2 diabetes. SUBJECTS/METHODS: COX4I1 and COX10 genes were measured in monocytes of 24 lean controls, 31 glucose-tolerant and 67 diabetic obese patients, and 17 morbidly obese patients before and after bariatric surgery. We investigated the effect of caloric restriction and peroxisome proliferator-activated receptor (PPAR) agonist treatment on Cox in obese diabetic mice, and that of diet-induced insulin resistance in Streptozotocin-treated mice. RESULTS: Low COX4I1 was associated with type 2 diabetes in obese patients, adjusting for age, gender, smoking, interleukin-6 and high-sensitivity C-reactive protein, all related to metabolic syndrome (MetS; odds ratio: 6.1, 95% confidence interval: 2.3-16). In contrast, COX10 was low in glucose-tolerant and diabetic obese patients. In morbidly obese patients, COX4I1 was lower in visceral adipose tissue collected at bariatric surgery. In their monocytes, COX4I1 decreased after bariatric surgery, and low COX4I1 at 4 months was associated with MetS at 7 years. In leptin-deficient obese diabetic mice, Cox4i1 was low in white visceral adipose tissue (n=13; P<0.001) compared with age-matched lean mice (n=10). PPARγ-agonist treatment (n=13), but not caloric restriction (n=11), increased Cox4i1 (P<0.001). Increase in Cox4i1 depended on the increase in glucose transporter 4 (Glut4) expression and insulin sensitivity, independent of the increase in blood adiponectin. In streptozotocin-treated mice (three groups of seven mice, diet-induced insulin resistance decreased Cox4i1 and Glut4 (P<0.001 for both). CONCLUSION: COX4I1 depression is related to insulin resistance and type 2 diabetes in obesity. In peripheral blood monocytes, it may be a diagnostically useful biomarker.

Stevioside inhibits atherosclerosis by improving insulin signaling and antioxidant defense in obese insulin-resistant mice.

OBJECTIVE: Stevioside is a non-caloric natural sweetener that does not induce a glycemic response, making it attractive as sweetener to diabetics and others on carbohydrate-controlled diets. Obesity is frequently associated with insulin resistance and increased inflammation and oxidative stress. Therefore, we investigated its effects on insulin resistance, inflammation and oxidative stress related to atherosclerosis in obese insulin-resistant mice. RESEARCH DESIGN: Twelve-week-old mice were treated with stevioside (10 mg kg(-1), n=14) or placebo (n=20) for 12 weeks. RESULTS: Stevioside had no effect on weight and triglycerides, but lowered glucose and insulin. Stevioside treatment improved adipose tissue maturation, and increased glucose transport, insulin signaling and antioxidant defense in white visceral adipose tissues. Together, these increases were associated with a twofold increase of adiponectin. In addition, stevioside reduced plaque volume in the aortic arch by decreasing the macrophage, lipid and oxidized low-density lipoprotein (ox-LDL) content of the plaque. The higher smooth muscle cell-to-macrophage ratio was indicative for a more stable plaque phenotype. The decrease in ox-LDL in the plaque was likely due to an increase in the antioxidant defense in the vascular wall, as evidenced by increased Sod1, Sod2 and Sod3. Circulating adiponectin was associated with improved insulin signaling and antioxidant defense in both the adipose tissue and the aorta of stevioside-treated mice. CONCLUSION: Stevioside treatment was associated with improved insulin signaling and antioxidant defense in both the adipose tissue and the vascular wall, leading to inhibition of atherosclerotic plaque development and inducing plaque stabilization.

End cap versus no end cap in intramedullary nailing for displaced midshaft clavicle fractures: influence on implant-related irritation.

PURPOSE: Implant-related irritation at the entry site is a known disadvantage of intramedullary nailing for clavicle fractures. The purpose of this study was to compare implant-related irritation rates of intramedullary nailing with or without an end cap for displaced midshaft clavicle fractures. METHODS: Two cohorts of patients treated with intramedullary nailing with or without an end cap were matched and compared. Primary outcome was patient-reported implant-related irritation. Secondary outcome parameters were complications. RESULTS: A total of 34 patients with an end cap were matched with 68 patients without an end cap. There was no difference in implant-related irritation (41 versus 53%, P = 0.26). Significantly more minor revisions were observed in the group without an end cap (15 versus 0%, P = 0.03). For complications requiring major revision surgery, significantly more implant failures were observed in the end cap group (12 versus 2%, P = 0.04). Regardless of their treatment, patients with complex fractures (AO/OTA B2-B3) reported significantly more medial irritation compared to patients with simple fractures (AO/OTA B1)(P = 0.02). CONCLUSION: The use of an end cap after intramedullary nailing for displaced midshaft clavicle fractures did not result in lower patient-reported irritation rates. Although less minor revisions were observed, more major revisions were reported in the end cap group. Based on the results of this study, no end caps should be used after intramedullary nailing for displaced midshaft clavicle fractures. However, careful selection of simple fractures might be effective in reducing implant-related problems after intramedullary nailing.

Predicting suitability of intramedullary fixation for displaced midshaft clavicle fractures.

PURPOSE: Implant-related irritation is a technique-specific complication seen in a substantial number of patients treated with intramedullary nailing for clavicle fractures. The purpose of this study was to identify predictors for developing implant-related irritation in patients with displaced midshaft clavicle fractures treated with elastic stable intramedullary nailing. METHODS: A retrospective analysis of the surgical database in two level 2 trauma centers was performed. Patients who underwent intramedullary nailing for displaced midshaft clavicle fractures between 2005 and 2012 in the first hospital were included. Age, gender, fracture comminution and fracture location were assessed as possible predictors for developing irritation using multivariate logistic regression analysis. These predictors were externally validated using data of patients treated in another hospital. RESULTS: Eighty-one patients were included in initial analysis. In the multivariate analysis, comminuted fractures in comparison to non-comminuted fractures (72 vs. 38%, p = 0.027) and fracture location (p < 0.001) were significantly associated with the development of implant-related irritation. In particular, lateral diaphyseal fractures caused irritation compared to fractures on the medial side of the cut-off point (88 vs. 26%). External validation of these predictors in 48 additional patients treated in another hospital showed a similar predictive value of the model and a good fit. CONCLUSION: Comminuted and lateral diaphyseal fractures were found to be statistically significant and independent predictors for developing implant-related irritation. We, therefore, believe that intramedullary nailing might not be suitable for these types of fractures. Future studies are needed to determine whether alternative surgical techniques or implants would be more suitable for these specific types of fractures.

Probabilistic analysis of accident precursors in the nuclear industry.

Feedback of operating experience has always been an important issue in the nuclear industry. A probabilistic safety analysis (PSA) can be used as a tool to analyse how an operational event might have developed adversely in order to obtain a quantitative assessment of the safety significance of the event. This process is called PSA-based event analysis (PSAEA). A comprehensive set of PSAEA guidelines was developed by an international project. The main characteristics of this methodology are summarised. This approach to analyse incidents can be used to meet different objectives of utilities or nuclear regulators. The paper describes the main objectives and the experiences of the Belgian nuclear regulatory organisation AVN with the application of PSA-based event analysis. Some interesting aspects of the process of PSAEA are further developed and underlined. Several case studies are discussed and an overview of the obtained results is given. Finally, the interest of a broad and interactive forum on PSAEA is highlighted.