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Rahman S.,University College London | Rahman S.,Metabolic Unit | Rahman S.,Center for Neuromuscular Diseases | Hall A.M.,University College London
Pediatric Nephrology

Kidneys are highly aerobic organs. They receive roughly a quarter of the cardiac output and contain a high density of mitochondria, particularly in the cortical tubules, which are required to produce adenosine triphosphate (ATP) in sufficient quantity to power the re-uptake of over 98 % of the filtered load. Given the dependence of renal function on aerobic metabolism, it is not surprising that impairment of normal mitochondrial function - due to insults such as ischaemia, drug toxicity and genetic mitochondrial disease - can lead to kidney failure. In this edition of Pediatric Nephrology, D'Aco and colleagues (doi: 10.1007/s00467-012-2354-y) describe a patient who developed end-stage renal failure caused by a pathogenic mutation (m.586G > A) in the gene encoding the mitochondrial tRNA for phenylalanine, which adversely affects the translation of mitochondrial DNA. The pathogenicity of this mutation was confirmed in cybrid studies using fibroblasts obtained from the patient. In light of this report, m.586G > A should now be added to the rapidly expanding list of mitochondrial and nuclear gene mutations causing mitochondrial disease with renal involvement. Furthermore, mitochondrial disease should be considered as an underlying aetiology in cases of unexplained renal failure, particularly in the context of a multisystem disorder. Renal replacement therapy is an option for patients with mitochondrial disease, but life expectancy even with this therapy may be limited by co-morbidities. © 2012 IPNA. Source

Mackay L.,Metabolic Unit
The Cochrane database of systematic reviews

There is conflicting information about the impact of the menopause on glycaemic control amongst women with type 1 diabetes. Some menopausal women with type 1 diabetes are treated with hormone replacement therapy (HRT) but the effects of this treatment have, to date, not been established. To assess the effects of HRT for women with type 1 diabetes mellitus. We searched The Cochrane Library, MEDLINE, EMBASE, CINAHL and PsycINFO from their inception to June 2012. The last search was run for all databases on 18 June 2012. We selected randomised controlled trials or controlled clinical trials that involved peri- or postmenopausal women with type 1 diabetes undergoing HRT as an intervention. Two researchers independently applied the inclusion criteria to the identified studies and assessed risk of bias. Disagreements were resolved by discussion or by intervention by a third party. Descriptive analysis was conducted for the review. Ninety-two publications were screened. No studies met the inclusion criteria exclusively but one study that included both type 1 and type 2 diabetes participants was considered. This randomised clinical trial (RCT) compared HRT (N = 27) with placebo (N = 29) over 12 months. The outcome measures were cardiovascular risk factors, including lipid profile, glycaemic control, blood pressure and body weight. No significant differences between placebo and HTR were detected. Patient-important outcomes like all-cause mortality, cardiovascular disease, diabetic complications or health-related quality of life were not investigated. There is a lack of evidence around the use of HRT in women with type 1 diabetes. The one study that has been undertaken in this area is underpowered. More RCTs are required in the area to examine the impact of HRT on glycaemic control and cardiovascular outcomes. Source

Feinkohl I.,Center for Population Health science | Price J.F.,Center for Population Health science | Strachan M.W.J.,Metabolic Unit | Frier B.M.,Queens Medical Research Institute
Alzheimer's Research and Therapy

Older people with type 2 diabetes are at increased risk of developing cognitive impairment, for which several potential risk factors have been proposed. The present article reviews evidence in people with type 2 diabetes for associations of cognitive impairment with a range of vascular, metabolic, and psychosocial risk factors, many of which have a higher prevalence in people with type 2 diabetes than in non-diabetic adults of a similar age. Definitive research studies in this field are few in number. The risk factors may be involved in causal pathways or may act as useful markers of cerebrovascular damage (or both), and for which relatively consistent evidence is available, include poor glycemic control, hypoglycemia, microvascular disease, inflammation, and depression. For macrovascular disease, the strength of the association with cognitive impairment appears to depend on which vascular system has been examined. A role for pre-morbid ability in young adulthood as influencing the risk of both diabetes and cognitive impairment has also been suggested. The importance of considering inter-relationships between risk factors when investigating their potential contribution to cognitive impairment in future investigations is discussed. © 2015 Feinkohl et al. Source

Mathiesen E.R.,Copenhagen University | Hod M.,Tel Aviv University | Ivanisevic M.,University of Zagreb | Garcia S.D.,Hospital Universitario Of Valme | And 4 more authors.
Diabetes Care

OBJECTIVE - This randomized, controlled noninferiority trial aimed to compare the efficacy and safety of insulin detemir (IDet) versus neutral protamine Hagedorn (NPH) (both with prandial insulin aspart) in pregnant women with type 1 diabetes. RESEARCH DESIGN AND METHODS - Patients were randomized and exposed to IDet or NPH up to 12 months before pregnancy or at 8-12 weeks gestation. The primary analysis aimed to demonstrate noninferiority of IDet to NPH with respect to A1C at 36 gestational weeks (GWs) (margin of 0.4%). The data were analyzed using linear regression, taking several baseline factors and covariates into account. RESULTS - A total of 310 type 1 diabetic women were randomized and exposed to IDet (n = 152) or NPH (n = 158) up to 12 months before pregnancy (48%) or during pregnancy at 8-12 weeks (52%). The estimated A1C at 36 GWs was 6.27% for IDet and 6.33% for NPH in the full analysis set (FAS). IDet was declared noninferior to NPH (FAS, -0.06% [95% CI -0.21 to 0.08]; per protocol, -0.15%[-0.34 to 0.04]). Fasting plasma glucose (FPG) was significantly lower with IDet versus NPH at both 24 GWs (96.8 vs. 113.8 mg/dL, P = 0.012) and 36 GWs (85.7 vs. 97.4 mg/dL, P = 0.017). Major and minor hypoglycemia rates during pregnancy were similar between groups. CONCLUSIONS - Treatment with IDet resulted in lower FPG and noninferior A1C in late pregnancy compared with NPH insulin. Rates of hypoglycemia were comparable. © 2012 by the American Diabetes Association. Source

Vidyasagar D.,University of Illinois at Chicago | Velaphi S.,Metabolic Unit | Bhat V.B.,JIPMER

Background: Since the first successful report of surfactant replacement therapy (SRT) in infants with respiratory distress syndrome (RDS), numerous randomized clinical trials have shown that SRT reduces mortality and morbidity in RDS. Surfactant is now a standard therapy for RDS. However, the use of SRT in the developing world has been extremely slow. Objective: The objective of this paper is to review the published information regarding the usage and barriers encountered in the use of SRT in developing countries. Methods: We reviewed the available literature and also gathered information from countries with a high burden of prematurity and high infant mortality rate regarding replacement therapy and the barriers to use of SRT. Results: We reviewed the available literature and found that developing countries bear a high burden of prematurity and RDS that contribute to high neonatal and infant mortality rates. Based on the effectiveness of SRT in RDS, surfactant preparations were included in the Essential Drug List of WHO in 2008. However, the use of SRT in developing countries is still limited because of (1) high cost, (2) lack of skilled personnel to administer SRT, and (3) lack of support systems after the SRT. The cost of SRT may exceed the per-capita GNP (300-500 USD) in some countries. Data from India and South Africa suggests that SRT is limited to rescue therapy in babies with potential for better survival, usually >28 weeks' gestation. Recent studies show that infants with RDS respond well to initial continuous positive airway pressure (CPAP) followed by SRT for those who do not respond. Conclusions: In developing countries, CPAP may be used as the primary mode of management of RDS. SRT may be reserved for non-responders to CPAP. Alternate simpler methods of delivery of surfactant (aerosol technique) are also being explored. There is a need for further studies to develop and assess efficient and less expensive methods of application of CPAP and SRT in developing countries. Copyright © 2011 S. Karger AG, Basel. Source

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