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Jesudason D.,CSIRO | Jesudason D.,University of Adelaide | Jesudason D.,University of South Australia | Nordin B.E.C.,Clinical Chemistry | And 4 more authors.
American Journal of Clinical Nutrition | Year: 2013

Background: It has been hypothesized that hip-fracture rates are higher in developed than in developing countries because high-protein (HP) Western diets induce metabolic acidosis and hypercalciuria. Confounders include interactions between dietary protein and calcium, sodium, and potassium. Objective: We determined whether an HP or a high-normal-protein (HNP) weight-loss diet caused greater loss in bone mineral density (BMD) over 24 mo. Design: The Weight Loss, Protein and Bone Density Study was conducted from 2008 to 2011 in 323 overweight [body mass index (BMI; in kg/m2) >27] postmenopausal women, with a total hip BMD t score less than 22.0. Subjects were randomly assigned to receive an isocaloric calcium-replete HP (≥90 g protein/d) or HNP (≤80 g protein/d) weight-loss diet, with the aim of a difference of 20 g protein/d. A total of 186 subjects (90 subjects in the HP group, 96 subjects in the HNP group) completed 12 mo, and 137 subjects (69 subjects in the HP group, 68 subjects in the HNP group) completed 24 mo. Results: Biomarkers confirmed a difference in protein intake of 16 and 13.1 g at 12 and 24 mo, respectively. Mean (±SE) weight loss was equal; HP subjects lost 7.9 ± 0.9 kg and HNP subjects lost 8.9 ± 0.9 kg at 24 mo. Subjects lost 1-2% BMD annually at lumbar spine vertebrae 2-4, the forearm, the femoral neck, and hip. ANCOVA showed no effect of the HP or HNP diet (P > 0.05 for diet and diet-time interactions). A diet-by-time analysis showed that the HNP diet increased C-terminal telopeptide and osteocalcin (P ≤ 0.001 for each) despite hypercalciuria (P = 0.029). Conclusion: High dietary protein intake during weight loss has no clinically significant effect on bone density but slows bone turnover. This trial was registered at the Australian and New Zealand Clinical Trials Registry (http://www.anzctr.org.au) as ACTRN12608000229370. © 2013 American Society for Nutrition.

Borthwick H.-A.,Darlington Memorial Hospital | Brunt L.K.,Clinical Chemistry | Mitchem K.L.,Prince Charles Hospital | Chaloner C.,Central Manchester NHS Foundation Trust
Annals of Clinical Biochemistry | Year: 2012

Background: There is a need for practical, efficient and effective prognostic markers for patients admitted to the intensive care unit (ICU) with sepsis, to identify patients at highest risk and guide and monitor treatment. Although many biomarkers and scoring systems have been advocated, none have yet achieved this elusive combination. Most ICUs already use blood lactate concentrations to monitor patients but the evidence base for this application is unclear. Methods: A systematic review of the last five years of evidence of effectiveness of lactate measurement in prediction of outcome in ICUs was performed. Results: It was found that there is a lack of high-quality evidence, and no specific studies of prognostic accuracy. D-orL-Lactate concentrations measured in plasma, serum, whole blood or colonic washings were raised at admission in almost all patient groups, and were higher in patient groups who had the worst outcomes (in-hospital mortality, sequential organ failure). However, there was significant overlap in individual concentrations measured in those who died within 28 days of admission, or who developed multiple organ failure, and those who did not. For serum L-lactate concentrations, no specific cut-off value capable of predicting in-hospital mortality or sequential organ failure could be recommended. Conclusions: The evidence reviewed suggested that whole blood, plasma or serum lactate measurement could not provide specific prognostic information for individual patients. There may be a role for monitoring for normalization of serum D-orL-lactate concentrations during goal-directed therapy in the ICU but further good-quality studies are needed. Measurement of the D-lactate stereoisomer shows promise, such that further studies are warranted.

Korthagen N.M.,St. Antonius Hospital | Van Moorsel C.H.M.,St. Antonius Hospital | Van Moorsel C.H.M.,University Utrecht | Kazemier K.M.,University Utrecht | And 3 more authors.
Immunogenetics | Year: 2012

Idiopathic pulmonary fibrosis (IPF) is a rare and devastating lung disease of unknown aetiology. Genetic variations in the IL1RN gene, encoding the interleukin-1 receptor antagonist (IL-1Ra), have been associated with IPF susceptibility. Several studies investigated the variable number tandem repeat (VNTR) or single nucleotide polymorphisms rs408392, rs419598 and rs2637988, with variable results. The aim of this study was to elucidate the influence of polymorphisms in IL1RN on IPF susceptibility and mRNA expression. We performed a meta-analysis of the five case-control studies that investigated an IL1RN polymorphism in IPF in a Caucasian population. In addition, we investigated whether IL1RN mRNA expression was influenced by IL1RN polymorphisms. The VNTR, rs408392 and rs419598 were in tight linkage disequilibrium, with D' > 0.99. Furthermore, rs2637988 was in linkage disequilibrium with the VNTR (D' = 0.90). A haploblock of VNTR*2 and the minor alleles of rs408392and rs419598 was constructed. Meta-analysis revealed that this VNTR*2 haploblock is associated with IPF susceptibility both with an allelic model (odds ratio01.42, p=0.002) and a carriership model (odds ratio01.60, p=0.002). IL1RN mRNA expression was significantly influenced by rs2637988, with lower levels found in carriers of the (minor) GG genotype (p<0.001). From this meta-analysis, we conclude that the VNTR*2 haploblock is associated with susceptibility to IPF. In addition, polymorphisms in IL1RN influence IL-1Ra mRNA expression, suggesting that lower levels of IL-1Ra predispose to developing IPF. Together these findings demonstrate that the cytokine IL-1Ra plays a role in IPF pathogenesis. © The Author(s) 2012.

Ng J.,University College London | Heales S.J.R.,Clinical Chemistry | Heales S.J.R.,Neurometabolic Unit | Kurian M.A.,University College London
Pediatric Drugs | Year: 2014

Childhood neurotransmitter disorders are increasingly recognised as an expanding group of inherited neurometabolic syndromes. They are caused by disturbance in synthesis, metabolism, and homeostasis of the monoamine neurotransmitters, including the catecholamines (dopamine, norepinephrine, and epinephrine) and serotonin. Disturbances in monoamine neurotransmission will lead to neurological symptoms that often overlap with clinical features of other childhood neurological disorders (such as hypoxic ischaemic encephalopathy, cerebral palsy, other movement disorders, and paroxysmal conditions); consequently, neurotransmitter disorders are frequently misdiagnosed. The diagnosis of neurotransmitter disorders is made through detailed clinical assessment, analysis of cerebrospinal fluid neurotransmitters, and further supportive diagnostic investigations. Early and accurate diagnosis of neurotransmitter disorders is important, as many are amenable to therapeutic intervention. The principles of treatment for monoamine neurotransmitter disorders are mainly directly derived from understanding these metabolic pathways. In disorders characterized by enzyme deficiency, we aim to increase monoamine substrate availability, boost enzyme co-factor levels, reduce monoamine breakdown, and replace depleted levels of monoamines with pharmacological analogs as clinically indicated. Most monoamine neurotransmitter disorders lead to reduced levels of central dopamine and/or serotonin. Complete amelioration of motor symptoms is achievable in some disorders, such as Segawa's syndrome, and, in other conditions, significant improvement in quality of life can be attained with pharmacotherapy. In this review, we provide an overview of the clinical features and current treatment strategies for childhood monoamine neurotransmitter disorders. © 2014 The Author(s).

Zhelev Z.,University of Exeter | Hyde C.,University of Exeter | Youngman E.,University of Exeter | Rogers M.,University of Exeter | And 5 more authors.
BMJ (Online) | Year: 2015

Objective: To obtain summary estimates of the accuracy of a single baseline measurement of the Elecsys Troponin T high-sensitive assay (Roche Diagnostics) for the diagnosis of acute myocardial infarction in patients presenting to the emergency department. Design: Systematic review and meta-analysis of diagnostic test accuracy studies. Data sources: Medline, Embase, and other relevant electronic databases were searched for papers published between January 2006 and December 2013. Study selection: Studies were included if they evaluated the diagnostic accuracy of a single baseline measurement of Elecsys Troponin T high-sensitive assay for the diagnosis of acute myocardial infarction in patients presenting to the emergency department with suspected acute coronary syndrome. Study appraisal and data synthesis: The first author screened all titles and abstracts identified through the searches and selected all potentially relevant papers. The screening of the full texts, the data extraction, and the methodological quality assessment, using the adapted QUADAS-2 tool, were conducted independently by two reviewers with disagreements being resolved through discussion or arbitration. If appropriate, meta-analysis was conducted using the hierarchical bivariate model. Results: Twenty three studies reported the performance of the evaluated assay at presentation. The results for 14 ng/L and 3-5 ng/L cut-off values were pooled separately. At 14 ng/L (20 papers), the summary sensitivity was 89.5% (95% confidence interval 86.3% to 92.1%) and the summary specificity was 77.1% (68.7% to 83.7%). At 3-5 ng/L (six papers), the summary sensitivity was 97.4% (94.9% to 98.7%) and the summary specificity was 42.4% (31.2% to 54.5%). This means that if 21 of 100 consecutive patients have the target condition (21%, the median prevalence across the studies), 2 (95% confidence interval 2 to 3) of 21 patients with acute myocardial infarction will be missed (false negatives) if 14 ng/L is used as a cut-off value and 18 (13 to 25) of 79 patients without acute myocardial infarction will test positive (false positives). If the 3-5 ng/L cut-off value is used, <1 (0 to 1) patient with acute myocardial infarction will be missed and 46 (36 to 54) patients without acute myocardial infarction will test positive. Conclusions: The results indicate that a single baseline measurement of the Elecsys Troponin T high-sensitive assay could be used to rule out acute myocardial infarction if lower cut-off values such as 3 ng/L or 5 ng/L are used. However, this method should be part of a comprehensive triage strategy and may not be appropriate for patients who present less than three hours after symptom onset. Care must also be exercised because of the higher imprecision of the evaluated assay and the greater effect of lot-to-lot reagent variation at low troponin concentrations. Systematic review registration: PROSPERO registration number CRD42013003926. © 2015, BMJ Publishing Group. All rights reserved.

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