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Background: Exploration of cerebrospinal fluid (CSF) amino acids and the impact of dietary intake on central levels may provide a comprehensive understanding of the metabolic component of Alzheimer’s disease. Objective: The objective of this exploratory study was to investigate the effects of two diets with varied nutrient compositions on change in CSF amino acids levels in adults with mild cognitive impairment (MCI) and normal cognition (NC). Secondary objectives were to assess the correlations between the change in CSF amino acids and change in Alzheimer’s disease biomarkers. Methods: In a randomized, parallel, controlled feeding trial, adults (NC, n = 20; MCI, n = 29) consumed a high saturated fat (SFA)/glycemic index (GI) diet [HIGH] or a low SFA/GI diet [LOW] for 4 weeks. Lumbar punctures were performed at baseline and 4 weeks. Results: CSF valine increased and arginine decreased after the HIGH compared to the LOW diet in MCI (ps = 0.03 and 0.04). This pattern was more prominent in MCI versus NC (diet by diagnosis interaction ps = 0.05 and 0.09), as was an increase in isoleucine after the HIGH diet (p = 0.05). Changes in CSF amino acids were correlated with changes in Alzheimer’s disease CSF biomarkers Aβ42, total tau, and p-Tau 181, with distinct patterns in the relationships by diet intervention and cognitive status. Conclusion: Dietary intake affects CSF amino acid levels and the response to diet is differentially affected by cognitive status.

Context Familial partial lipodystrophy (FPL), Dunnigan variety is characterized by skeletal muscle hypertrophy and insulin resistance besides fat loss from the extremities. The cause for the muscle hypertrophy and its functional consequences is not known. Objective To compare muscle strength and endurance, besides muscle protein synthesis rate between subjects with FPL and matched controls (n = 6 in each group). In addition, we studied skeletal muscle mitochondrial function and gene expression pattern to help understand the mechanisms for the observed differences. Methods Body composition by dual-energy X-ray absorptiometry, insulin sensitivity by minimal modelling, assessment of peak muscle strength and fatigue, skeletal muscle biopsy and calculation of muscle protein synthesis rate, mitochondrial respirometry, skeletal muscle transcriptome, proteome, and gene set enrichment analysis. Results Despite increased muscularity, FPL subjects did not demonstrate increased muscle strength but had earlier fatigue on chest press exercise. Decreased mitochondrial state 3 respiration in the presence of fatty acid substrate was noted, concurrent to elevated muscle lactate and decreased long-chain acylcarnitine. Based on gene transcriptome, there was significant downregulation of many critical metabolic pathways involved in mitochondrial biogenesis and function. Moreover, the overall pattern of gene expression was indicative of accelerated aging in FPL subjects. A lower muscle protein synthesis and downregulation of gene transcripts involved in muscle protein catabolism was observed. Conclusion Increased muscularity in FPL is not due to increased muscle protein synthesis and is likely due to reduced muscle protein degradation. Impaired mitochondrial function and altered gene expression likely explain the metabolic abnormalities and skeletal muscle dysfunction in FPL subjects.

Background The increasing incidence of breast cancer necessitates the need to explore alternate screening strategies that circumvent the setbacks of conventional techniques especially among population that report earlier age at diagnosis. Serum autoantibodies is one such potential area of interest. However, their ubiquitous presence across cancer types limits its applicability to any one specific type of cancer. This review was therefore carried out to explore and consolidate available evidence on autoantibodies for early detection of breast cancer and to identify those that demonstrated a higher sensitivity. Methods A diagnostic test accuracy (DTA) review was carried out to ascertain serum autoantibodies that could be used for early detection of breast cancer among women. All relevant articles that investigated the role of autoantibodies in early detection of breast cancer were included for the review. MEDLINE, Scopus, ProQuest, Ovid SP, and Cochrane Library were searched extensively for eligible studies. Quality of the included studies was assessed using Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 tool. RevMan 5.3 was used for exploratory and MetaDTA 2019 for hierarchical analyses. The review helped identify the most frequently investigated autoantibodies and a meta-analysis further consolidated the findings. Results A total of 53 articles were included for the final analysis that reported over a 100 autoantibodies that were studied for early detection of breast cancer in women. P53, MUC1, HER2, HSP60, P16, Cyclin B1, and c-Myc were the most frequently investigated autoantibodies. Of these P53, MUC1, HER2, and HSP60 exhibited higher summary sensitivity measures. While the individual pooled sensitivity estimates ranged between 10 and 56%, the panel sensitivity values reported across studies were higher with an estimated range of 60–87%. Conclusion Findings from the review indicate a higher sensitivity for an autoantibody panel in comparison to individual assays. A panel comprising of P53, MUC1, HER2, and HSP60 autoantibodies has the potential to be investigated as an early detection biomarker for breast cancer.

Esophageal perforation is a rare complication of foreign body ingestion. The most common foreign bodies causing esophageal perforation in adults are fish and chicken bones. We present the case of an octogenarian man with mild cognitive impairment presenting with respiratory complaints of dyspnoea and orthopnoea in the emergency room. He had hyponatremia induced confusion in addition to his mild cognitive impairment. The diagnosis for his clinical condition was not evident. Evaluation by imaging detected the "missing link" chicken bone as the cause of esophageal double perforation with mediastinitis and bilateral pleural effusion. Following multidisciplinary discussion, the minimally invasive endoscopic approach was decided as the definitive therapy. After medical stabilization in ICU, he underwent endoscopic retrieval of the foreign body followed by fully covered self-expandable metallic stenting. He recovered well and the stent removed after three weeks. Six months down the lane he is doing well and under neurology follow up for mild cognitive impairment. This clinical case shows the atypical, delayed perplexing presentation of esophageal foreign body in the elderly and the need for individualized treatment decision making for a successful outcome.

INTRODUCTION The objective of this study was to systematically review the maternal and fetal outcomes in pregnant women who underwent percutaneous balloon mitral valvuloplasty (PBMV) during pregnancy. MATERIAL AND METHODS A search was conducted on MEDLINE and Embase databases to identify studies published between 2000 and 2018 that reported on maternal and fetal outcomes following PBMV performed in pregnancy. Randomized controlled trials, cohort studies, case-control studies, cross-sectional studies and case series with four or more pregnancies in which PBMV was performed during pregnancy were included. Reference lists from relevant articles were also hand-searched for relevant citations. A successful procedure was defined as one where there was a reported improvement in the valve area or reduction in the mitral valve gradient. A random effects model was used to derive pooled estimates of various outcomes and the final estimates were reported as percentages with a 95% confidence interval (95% CI). RESULTS Twenty-one observational studies reporting 745 pregnancies were included in the review, all of them having reported outcomes without a comparison group. Most of the studies fell into the low-risk category as determined using the Joanna Briggs Institute (JBI) critical appraisal checklist for case series. Most of the studies (86%) were reported from low- to middle-income countries and PBMV was mostly performed during the second trimester of pregnancy. Forty-three procedures (5.7%) were unsuccessful, nearly half (n = 19) of them reported among women with the severe subvalve disease (Wilkins subvalve score 3 or more). There were 11 maternal deaths among those with suboptimal valve anatomy (severe subvalve disease or Wilkin score >8). Mitral regurgitation was the most common cardiac complication (12.7%; 95% CI 7.3%-19.1%), followed by restenosis (2.4%; 95% CI 0.02%-7.2%). Pooled incidence of cesarean section was 12.1% (95% CI 3.6%-23.8%), preterm delivery 3.9% (95% CI 0.6%-9.0%), stillbirth 0.9% (95%CI 0.2%-2.2%) and low birthweight 5.4% (95% CI 0.2%-14.7%). CONCLUSIONS PBMV may be an effective and safe procedure for optimizing outcomes in pregnant women with mitral stenosis in the absence of severe subvalve disease.

BackgroundDiffusion tensor imaging (DTI) appears as a sensitive method to study Parkinson’s disease (PD) pathophysiology and severity. Fractional anisotropy (FA) value is one of the scalar derivatives of DTI used to find out anisotropy within a voxel in a tissue and used for determining white matter integrity in aging and neurodegenerative diseases. We studied DTI derived FA in early PD subjects as their routine MRI scans were normal.Methods40 patients with early PD and 40 healthy controls were employed to evaluate changes in microstructural white and grey matter in the brain’s using DTI derived FA values. Comparison of FA values in the brain’s white and grey matter of patients with PD and age matched controls at the corpus callosum, centrum semiovale, pons, putamen, caudate nucleus, substantia nigra, cerebral peduncles and cerebellar peduncles, was done using a region of interest (ROI) technique, with b-value 1000s/mm2 and TE=100 milliseconds using 1.5T MRI system.ResultsPD patients showed differences in FA values in both the grey and white matter areas of the brain’s compared to healthy controls. Our study revealed the presence of damage in the substantia nigra, corpus callosum, putamen and cerebral peduncles mainly in the PD group.ConclusionOur findings indicate that DTI and region of interest (ROI) methods can be used in patients with early PD to study microstructural alterations mainly in the substantia nigra, putamen and corpus callosum.

Description, SEV may serve as new biomarkers for predicting the individual response of insulin sensitivity to exercising., High-intensity interval training (HIIT) improves cardiorespiratory fitness (VO2max), but its impact on metabolism remains unclear. We hypothesized that 12-week HIIT increases insulin sensitivity in males with or without type 2 diabetes [T2D and NDM (nondiabetic humans)]. However, despite identically higher VO2max, mainly insulin-resistant (IR) persons (T2D and IR NDM) showed distinct alterations of circulating small extracellular vesicles (SEVs) along with lower inhibitory metabolic (protein kinase Cε activity) or inflammatory (nuclear factor κB) signaling in muscle of T2D or IR NDM, respectively. This is related to the specific alterations in SEV proteome reflecting down-regulation of the phospholipase C pathway (T2D) and up-regulated antioxidant capacity (IR NDM). Thus, SEV cargo may contribute to modulating the individual metabolic responsiveness to exercise training in humans.

Despite the strong association between diabetes and dementia, it remains to be fully elucidated how insulin deficiency adversely affects brain functions. We show that insulin deficiency in streptozotocin-induced diabetic mice decreased mitochondrial ATP production and/or citrate synthase and cytochrome oxidase activities in the cerebrum, hypothalamus, and hippocampus. Concomitant decrease in mitochondrial fusion proteins and increased fission proteins in these brain regions likely contributed to altered mitochondrial function. Although insulin deficiency did not cause any detectable increase in reactive oxygen species (ROS) emission, inhibition of monocarboxylate transporters increased ROS emission and further reduced ATP production, indicating the causative roles of elevated ketones and lactate in counteracting oxidative stress and as a fuel source for ATP production during insulin deficiency. Moreover, in healthy mice, intranasal insulin administration increased mitochondrial ATP production, demonstrating a direct regulatory role of insulin on brain mitochondrial function. Proteomics analysis of the cerebrum showed that although insulin deficiency led to oxidative post-translational modification of several proteins that cause tau phosphorylation and neurofibrillary degeneration, insulin administration enhanced neuronal development and neurotransmission pathways. Together these results render support for the critical role of insulin to maintain brain mitochondrial homeostasis and provide mechanistic insight into the potential therapeutic benefits of intranasal insulin.—Ruegsegger, G. N., Manjunatha, S., Summer, P., Gopala, S., Zabeilski, P., Dasari, S., Vanderboom, P. M., Lanza, I. R., Klaus, K. A., Nair, K. S. Insulin deficiency and intranasal insulin alter brain mitochondrial function: a potential factor for dementia in diabetes.

There is increasing interest in the development of minimally invasive biomarkers for the diagnosis and prognosis of NAFLD via extracellular vesicles (EV). Plasma EVs were isolated by differential ultracentrifugation and quantified by nanoparticle tracking analysis from pre (n = 28) and post (n = 28) weight loss patients. In the pre weight loss group 22 had NAFLD. Nanoplasmon enhanced scattering (nPES) of gold nanoparticles conjugated to hepatocyte-specific antibodies was employed to identify hepatocyte-specific EVs. Complex lipid panel and targeted sphingolipids were performed. Logistic regression analysis was used to identify predictors of NAFLD. Plasma levels of EVs and hepatocyte-derived EVs are dynamic and decrease following NAFLD resolution due to weight loss surgery. Hepatocyte-derived EVs correlate with steatosis in NAFLD patients and steatosis and inflammation in NASH patients. Plasma levels of small EVs correlate with EV sphingolipids in patients with NASH. Hepatocyte-derived EVs measured by the nPES assay could serve as a point-of-care test for NAFLD.

Muscle glucose metabolism is improved by either aerobic or resistance exercise (RE) training, but the mechanisms leading to improved metabolism for each of these exercise modes are not identical. Much work has been done onimproved oxidative metabolism by aerobic exercise, but far less is known about how RE impacts fuel metabolism. Here, TCA and amino acid metabolites are measured in skeletal muscle after a single bout of RE. Twenty one healthy subjects performed a session of one-legged knee extension RE that consisted of 3 sets of 10 reps at 70% of their 1 rep max. Two muscle biopsies were obtained from the vastus lateralis of each leg. From the RE leg, biopsies were obtained ≤10min post-RE (0hr PEX) and approximately 1hr post-RE (1hr PEX), respectively. From the non-RE leg, biopsies were obtained before and 1hr PEX, respectively. Muscle samples were frozen and stored until mass spectrometry analysis of metabolites was performed. A 2-fold increase in plasma lactate (P Disclosure M. W. Pataky: None. A. Prabha kumar: None. K. Klaus: None. K. Nair: None. Funding National Institutes of Health (R01AG062859)

Cymothoid isopods are parasitic crustaceans that cause serious impact on marine fish and might lead to fish mortality and consequently, economic losses. Histopathological alterations caused by Anilocra spp. have not been studied well. This study aims to report the histopathological changes caused by Cymothoid, Anilocra leptosoma Bleeker, 1857 in the skin of Bloch's gizzard shad, Nematalosa nasus (Bloch, 1795). Histopathological examination of processed skin tissues showed changes caused by A. leptosoma, such as hyperplasia and erosions of the epidermis associated dermal oedema and muscle degeneration. The host response also included an aggregation of subepithelial dense sheets of hemosiderin-laden macrophages within the dense mixed inflammatory cells. The cymothoid, A. leptosoma are serious parasites of marine fish that can cause severe economic loss in the commercially important fish species. The present study represents the first record of the parasitic cymothoid, A. leptosoma on N. nasus from India.

BACKGROUND Type 1 diabetes (T1D) is a risk factor for dementia and structural brain changes. It remains to be determined whether transient insulin deprivation that frequently occurs in insulin-treated individuals with T1D alters brain function. METHODS We therefore performed functional and structural magnetic resonance imaging, magnetic resonance spectroscopy, and neuropsychological testing at baseline and following 5.4 ± 0.6 hours of insulin deprivation in 14 individuals with T1D and compared results with those from 14 age-, sex-, and BMI-matched nondiabetic (ND) participants with no interventions. RESULTS Insulin deprivation in T1D increased blood glucose, and β-hydroxybutyrate, while reducing bicarbonate levels. Participants with T1D showed lower baseline brain N-acetyl aspartate and myo-inositol levels but higher cortical fractional anisotropy, suggesting unhealthy neurons and brain microstructure. Although cognitive functions did not differ between participants with T1D and ND participants at baseline, significant changes in fine motor speed as well as attention and short-term memory occurred following insulin deprivation in participants with T1D. Insulin deprivation also reduced brain adenosine triphosphate levels and altered the phosphocreatine/adenosine triphosphate ratio. Baseline differences in functional connectivity in brain regions between participants with T1D and ND participants were noted, and on insulin deprivation further alterations in functional connectivity between regions, especially cortical and hippocampus-caudate regions, were observed. These alterations in functional connectivity correlated to brain metabolites and to changes in cognition. CONCLUSION Transient insulin deprivation therefore caused alterations in executive aspects of cognitive function concurrent with functional connectivity between memory regions and the sensory cortex. These findings have important clinical implications, as many patients with T1D inadvertently have periods of transient insulin deprivation. TRIAL REGISTRATION ClinicalTrials.gov NCT03392441. FUNDING Clinical and Translational Science Award (UL1 TR002377) from the National Center for Advancing Translational Science; NIH grants (R21 AG60139 and R01 AG62859); the Mayo Foundation.

Background & aims: Unacylated ghrelin (UnAG) modulates insulin sensitivity. Low plasma UnAG occurs in obesity and potentially contributes to obesity-associated insulin resistance. We hypothesized that improvements in insulin sensitivity in obese people induced by moderate caloric restriction (CR) may be paralleled and at least in part explained by concurrent increases in UnAG levels. Methods: 20 general community obese people were randomly assigned to 16-week CR (n = 11) or control diet (n = 9). We investigated the impact of CR on the interaction between insulin sensitivity changes [area under the curve (AUCg) of glucose infusion to maintain euglycemia during hyperinsulinemic-euglycemic clamp] and plasma total (TotalG), acylated (AG) and Unacylated ghrelin (UnAG). Plasma pro-inflammatory tumor necrosis factor alpha (TNFα) and anti-inflammatory interleukin-10 (IL-10) were also measured since changes in inflammation may contribute to UnAG activities. Results: CR reduced BMI and increased insulin sensitivity (p < 0.05). TotalG and UnAG but not AG increased in CR but not in Control (p < 0.05). Il-10 and IL-10/TNFα ratio also increased in CR (p < 0.05). Changes in UnAG were positively associated with changes in AUCg in all subjects (n = 20; p < 0.01) also after adjustment for treatment and changes in BMI and cytokines. Conclusions: Caloric restriction modifies circulating ghrelin profile with selective increase in unacylated hormone in obese individuals. The current study supports the hypothesis that higher unacylated ghrelin contributes to improvements in insulin sensitivity following diet-induced weight loss in human obesity.

Objective This study was conducted to assess the incidence of sudden cardiac death (SCD) in post myocardial infarction patients and to determine the predictive value of various risk markers in identifying cardiac mortality and SCD. Methods Left ventricular function, arrhythmias on Holter and microvolt T wave alternans (MTWA) were assessed in patients with prior myocardial infarction and ejection fraction ≤ 40%. The primary outcome was a composite of cardiac death and resuscitated cardiac arrest during follow up. Secondary outcomes included total mortality and SCD. Results Fifty-eight patients were included in the study. Eight patients (15.5%) died during a mean follow-up of 22.3 ± 6.6 months. Seven of them (12.1%) had SCD. Among the various risk markers studied, left ventricular ejection fraction (LVEF) ≤ 30% (Hazard ratio 5.6, 95% CI 1.39 to 23) and non-sustained ventricular tachycardia (NSVT) in holter (5.7, 95% CI 1.14 to 29) were significantly associated with the primary outcome in multivariate analysis. Other measures, including QRS width, heart rate variability, heart rate turbulence and MTWA showed no association. Conclusions Among patients with prior myocardial infarction and reduced left ventricular function, the rate of cardiac death was substantial, with most of these being sudden cardiac death. Both LVEF ≤30% and NSVT were associated with cardiac death whereas only LVEF predicted SCD. Other parameters did not appear useful for prediction of events in these patients. These findings have implications for decision making for the use of implantable cardioverter defibrillators for primary prevention in these patients.

Insulin resistance has been linked to cognitive dysfunction and increased risk for Alzheimer’s disease and other dementias. It is unclear if cognitive decline during insulin resistance is due to systemic or brain-specific insulin resistance. Previous studies demonstrated that brain mitochondrial function is reduced concurrent to diminished insulin signaling in high fat-fed mice. However, it remains to be determined whether insulin signaling in the brain directly impacts brain mitochondrial function and cognition. Therefore, we developed a tamoxifen inducible brain-specific insulin receptor knockout (BIRKO) mouse by breeding C57/BL6J mice with a floxed insulin receptor gene with mice that express a tamoxifen-inducible Nestin-Cre. These BIRKO mice were used to identify if brain insulin signaling is required for maintenance of brain mitochondrial function and cognition. Four weeks after tamoxifen administration, we confirmed using western blotting that the insulin receptor was completely absent in all regions of the brain, but not the muscle, heart, liver, kidney, or adipose from the BIRKO mice. Spatial learning was reduced (P Disclosure M.W. Pataky: None. G. Ruegsegger: None. K. Klaus: None. P. Starski: None. K. Nair: None. Funding National Institutes of Health (T32DK07352)

Objectives. To evaluate the effects of atomoxetine on complex attention and other neurocognitive domains in idiopathic Parkinson’s disease (PD).Methods. Interventional trials reporting changes in complex attention and other neurocognitive functions (Diagnostic and Statistical Manual of Mental Disorders-5) following administration of atomoxetine for at least 8 weeks in adults with idiopathic PD were included. Effect sizes (Cohen’sd), the standardized mean difference in the scores of each cognitive domain, were compared using a random-effects model (MetaXL version 5.3).Results. Three studies were included in the final analysis. For a change in complex attention in PD with mild cognitive impairment (MCI), the estimated effect size was small and nonsignificant (0.16 (95% CI: −0.09, 0.42),n = 42). For changes in executive function, perceptual-motor function, language, social cognition, and learning and memory, the estimated effect sizes were small and medium, but nonsignificant. A deteriorative trend in executive function was observed after atomoxetine treatment in PD with MCI. For a change in global cognitive function in PD without MCI, the estimated effect size was large and significant.Conclusion. In idiopathic PD with MCI, atomoxetine does not improve complex attention. Also, a deteriorative trend in the executive function was noted.

Increased life expectancy combined with the aging Baby Boomer Generation has resulted in an unprecedented global expansion of the elderly population. The growing population of older adults and increased rate of age-related chronic illness has caused a substantial socio-economic burden. The gradual and progressive age-related decline in hormone production and action has a detrimental impact on human health by increasing risk for chronic disease and reducing life span. Here we review the age-related decline in hormone production, as well as age-related biochemical and body composition changes that reduce the bioavailability and actions of some hormones. The impact of hormonal changes on various chronic conditions including frailty, diabetes, cardiovascular disease and dementia are also discussed. Hormone replacement therapy has been attempted in many clinical trials to reverse and/or prevent the hormonal decline in aging to combat the progression of age-related diseases. Unfortunately, hormone replacement therapy is not a panacea, as it often results in various adverse events which outweigh its potential health benefits. Therefore, except in some specific individual cases, hormone replacement is not recommended. Rather, positive lifestyle modifications such as regular aerobic and resistance exercise programs and/or healthy calorically restricted diet can favorably affect endocrine and metabolic functions and act as countermeasures to various age-related diseases. Here we provide a critical review of the available data and offer recommendations which hopefully will form the groundwork for physicians/scientists to develop and optimize new endocrine-targeted therapies and lifestyle modifications that can better address age-related decline in heath.

Exercise provides a robust physiological stimulus that evokes cross-talk among multiple tissues that when repeated regularly (i.e., training) improves physiological capacity, benefits numerous organ systems, and decreases the risk for premature mortality. However, a gap remains in identifying the detailed molecular signals induced by exercise that benefits health and prevents disease. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to address this gap and generate a molecular map of exercise. Preclinical and clinical studies will examine the systemic effects of endurance and resistance exercise across a range of ages and fitness levels by molecular probing of multiple tissues before and after acute and chronic exercise. From this multi-omic and bioinformatic analysis, a molecular map of exercise will be established. Altogether, MoTrPAC will provide a public database that is expected to enhance our understanding of the health benefits of exercise and to provide insight into how physical activity mitigates disease.

Metformin, the world’s most prescribed anti-diabetic drug, is also effective in preventing type 2 diabetes in people at high risk1,2. More than 60% of this effect is attributable to the ability of metformin to lower body weight in a sustained manner3. The molecular mechanisms by which metformin lowers body weight are unknown. Here we show—in two independent randomized controlled clinical trials—that metformin increases circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15), which has been shown to reduce food intake and lower body weight through a brain-stem-restricted receptor. In wild-type mice, oral metformin increased circulating GDF15, with GDF15 expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to a high-fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GDNF family receptor α-like (GFRAL). In obese mice on a high-fat diet, the effects of metformin to reduce body weight were reversed by a GFRAL-antagonist antibody. Metformin had effects on both energy intake and energy expenditure that were dependent on GDF15, but retained its ability to lower circulating glucose levels in the absence of GDF15 activity. In summary, metformin elevates circulating levels of GDF15, which is necessary to obtain its beneficial effects on energy balance and body weight, major contributors to its action as a chemopreventive agent. In mouse studies, metformin treatment results in increased secretion of growth/differentiation factor 15 (GDF15), which prevents weight gain in response to high-fat diet, and GDF15-independent lowering of circulating blood glucose.

Objective Studies of dehydroepiandrosterone (DHEA) therapy in older adults suggest sex-specific effects on bone mineral density (BMD) and body composition, but the ability of a single study to reach this conclusion was limited. We evaluated the effects of DHEA on sex hormones, BMD, fat mass and fat-free mass in older women and men enrolled in four similar clinical trials. Design Pooled analyses of data from four double-blinded, randomized controlled trials. Participants Women (n = 295) and men (n = 290) aged 55 years or older who took DHEA or placebo tablet daily for 12 months. Measurements Twelve-month changes in BMD, fat mass, fat-free mass and serum DHEA sulphate (DHEAS), (17)estradiol, testosterone and insulin-like growth factor-1 (IGF-1). Results Women on DHEA had increases (mean ± SD; all P Conclusions Dehydroepiandrosterone therapy may be an effective approach for preserving bone and muscle mass in women. Key questions are (a) the extent to which longer duration DHEA can attenuate the loss of bone and muscle in women, and (b) whether DHEA has a more favourable benefit-to-risk profile for women than oestrogen therapy.

Insulin deficiency and uncontrolled diabetes lead to a catabolic state with decreased muscle strength, contributing to disease-related morbidity. FoxO transcription factors are suppressed by insulin and thus are key mediators of insulin action. To study their role in diabetic muscle wasting, we created mice with muscle-specific triple knockout of FoxO1/3/4 and induced diabetes in these M-FoxO-TKO mice with streptozotocin (STZ). Muscle mass and myofiber area were decreased 20–30% in STZ-Diabetes mice due to increased ubiquitin-proteasome degradation and autophagy alterations, characterized by increased LC3-containing vesicles, and elevated levels of phosphorylated ULK1 and LC3-II. Both the muscle loss and markers of increased degradation/autophagy were completely prevented in STZ FoxO-TKO mice. Transcriptomic analyses revealed FoxO-dependent increases in ubiquitin-mediated proteolysis pathways in STZ-Diabetes, including regulation of Fbxo32 (Atrogin1), Trim63 (MuRF1), Bnip3L, and Gabarapl. These same genes were increased 1.4- to 3.3-fold in muscle from humans with type 1 diabetes after short-term insulin deprivation. Thus, FoxO-regulated genes play a rate-limiting role in increased protein degradation and muscle atrophy in insulin-deficient diabetes.

Health benefits of aerobic exercise are indisputable and are closely related to the maintenance of mitochondrial energy homeostasis and insulin sensitivity. Flockhart et al. (2021) demonstrate, however, that a high volume of high-intensity aerobic exercise adversely affects mitochondrial function and may cause impaired glucose tolerance.

Background Neonatal pneumonia is one of the leading factors contributing to neonatal mortality. The objective of this review was to identify the barriers associated with case management of neonatal pneumonia in India by conducting a scoping review. Methods Nine databases (PubMed, ProQuest, Ovid Medline, CINAHL, Web of Science, EMBASE, IndMED, SCOPUS and WHOLIS) were searched to identify relevant studies in India. The population of interest were neonates. Outcome of interest was barriers associated with case management of neonatal pneumonia. Data was charted and reported in accordance with the ‘guidance for conducting systematic scoping reviews'. Results From 5942 citations screened, 244 articles underwent full text screening and two studies with qualitative information met the eligibility criteria. Barriers were classified as patient-related, caregiver-related and healthcare delivery system-related. Delay in seeking care was due to spiritual healers being first point of contact in addition to traditional and home remedies tried by mothers at home and inaccessible healthcare mostly owing to healthcare delivery system were some of the major barriers associated with case management of neonatal pneumonia. Conclusion This scoping review concludes that there is a paucity of studies on neonatal pneumonia in India particularly with respect to barriers to case management and that many of the barriers described here are applicable to a broad range of neonatal disease conditions which occur in the community and not just specific to neonatal pneumonia.

Background Randomised controlled trials (RCTs) are gold standard in assessing the effectiveness of a clinical intervention because of their high internal validity. However, the same does not hold true for interventions conducted at the population level like public health interventions. Well-designed RCTs are not easy to conduct at population level. Similarly, well planned, high-quality non-RCTs or observational studies can complement RCTs. Because of this, several systematic reviews of public health interventions are assessed with other study designs, namely non-RCTs and observational studies. In such situations, studies of similar study design are pooled together to obtain an overall effect estimate. This is inevitable, because the principle of meta-analysis does not offer an opportunity for combining effect estimates coming from various study designs. If the meta-analysis performed for each study design provides contrasting results, then this introduces a quandary for the decision makers and public health policy makers to call for a decision. Objective The present study aims to integrate the results coming from a variety of study designs in order to obtain a single estimate of effect of intervention. Methodology Bayesian approach to meta-analysis was used by formulating prior distribution from observational studies or non-RCTs and likelihood function from RCTs. Five systematic reviews of public health intervention were used to demonstrate the methodology. Results/conclusions By formulating prior distribution from observational studies, the posterior estimates were found to be different than that from the results of RCTs or other study designs. The posterior pooled-estimate was found to be precise and the width of the credible interval narrowed. Inclusion of the relevant observational studies (or non-RCTs) in the systematic review is a potential advantage for evaluating the effectiveness of public health intervention.

Background: Depression is one of the more common mental health conditions found among people suffering from chronic diseases. Its presence in patients with type 2 diabetes could hinder the adherence to and effectiveness of treatment. Most studies on depression among patients with diabetes are hospital-based suggesting the need for a community-based study to assess the correlates of depression among patients with diabetes. Aim: This study aimed to estimate the prevalence and to identify the factors influencing depression among patients with type 2 diabetes in Udupi taluk situated in southern India. Subjects and Methods: This study recruited 200 patients with type 2 diabetes from both rural and urban areas. Demographic, clinical, and diabetes-related information were collected using a semi-structured questionnaire. Depression was assessed using Patient Health Questionnaire-9; a standardized questionnaire developed in the United States of America and validated in the Indian population. Results: The prevalence of depression among patients with diabetes in the community was found to be 37.5%. Most frequently, depression was mild (42, 21%) in nature with severe depression (9, 4.5%) seen the least. Several factors were found to be positively associated with depression including female gender, rural residence, unemployment, and the status of being unmarried. The presence of diabetic complications and other chronic diseases such as hypertension and obesity also were found to be associated with depression. Conclusion: Depression was found to be particularly high among the study population. Since depression could significantly hinder patient's adherence to treatment, there is an urgent need for early diagnosis and treatment. This calls for the integration of mental health care into the management of diabetes.

External Cephalic Version (ECV) reduces breech presentation at term and thus contribute to the reduction of cesarean section. This study was done to determine the factors associated with the successful ECV in women with breech presentation after 36 weeks' gestation and also to develop and validate a clinical score which could be utilized for individual patient counseling in future.This was a retrospective cohort study conducted in a tertiary care center and teaching hospital in south India. Prospectively collected data from the register maintained for all ECVs performed on pregnant women with breech presentation at or more than 36 weeks' gestation. Clinical and ultrasound parameters at the time of performing the procedure were used in the analysis. Multiple logistic regression with a stepwise backward selection procedure was used selecting potential variable to construct the model and internal validation was done with bootstrapping. Primary outcome was successful ECV defined as cephalic presentation at the end of the procedure.Among 611 women who underwent ECV, it was successful in 70.4%. In the multiple logistic regression model, multiparity (OR4.48), AFI ≥ 7 (OR = 3.06), type of breech, posterior placental location (OR = 1.57), sacro-anterior position of breech (OR = 2.83), normal uterine tone (OR = 1.82) and fetal pole not engaged (OR = 2.82) were found to be predictive of successful ECV with good discrimination (AUC = 0.782) and acceptable calibration. Combining these factors from the model a predictive score (score 0-13) is proposed for clinical utility.Combining clinical and ultrasound parameters into a predictive score, which is simple and effective, could be utilized in the clinical practice, once validated externally.

Insulin resistance associates with increased risk for cognitive decline and dementia; however, the underpinning mechanisms for this increased risk remain to be fully defined. As insulin resistance impairs mitochondrial oxidative metabolism and increases ROS in skeletal muscle, we considered whether similar events occur in the brain, which - like muscle - is rich in insulin receptors and mitochondria. We show that high-fat diet-induced (HFD-induced) brain insulin resistance in mice decreased mitochondrial ATP production rate and oxidative enzyme activities in brain regions rich in insulin receptors. HFD increased ROS emission and reduced antioxidant enzyme activities, with the concurrent accumulation of oxidatively damaged mitochondrial proteins and increased mitochondrial fission. Improvement of insulin sensitivity by both aerobic exercise and metformin ameliorated HFD-induced abnormalities. Moreover, insulin-induced enhancement of ATP production in primary cortical neurons and astrocytes was counteracted by the insulin receptor antagonist S961, demonstrating a direct effect of insulin resistance on brain mitochondria. Further, intranasal S961 administration prevented exercise-induced improvements in ATP production and ROS emission during HFD, supporting that exercise enhances brain mitochondrial function by improving insulin action. These results support that insulin sensitizing by exercise and metformin restores brain mitochondrial function in insulin-resistant states.

This protocol for a Cochrane Review has been withdrawn as the subject matter of the proposed review is covered in another review "Non‐hormonal, pharmacological treatments for hot flushes in perimenopausal women".

Introduction: Diabetes is associated with impaired cognition but the effect of the transient insulin deprivation on cognition and its underlying mechanisms remain unclear. Objective: We determined whether transient insulin deprivation in type 1 diabetic adults (T1D) and adolescents alters brain structure, functions and blood flow compared to nondiabetics (ND). Methods: We performed structural MRI, phosphorous31 NMR spectroscopy, and neuropsychiatric testing at baseline and following 6 hours of insulin deprivation in 14 adolescent (14-17 years) and adult (18-44 years) T1D and age- sex- and BMI-matched ND controls. Results: There were no significant changes on baseline structural MRI between the groups. After insulin deprivation, T1D had a significantly greater blood glucose (272 vs. 85 mg/dL), greater beta hydroxybutyrate (1.45 vs. 0.3 mmol/L), and decreased bicarbonate level (25.5 vs. 21.5 mmol/L) at six hours compared to ND. Following insulin deprivation, there was a significant difference in T1D left cortical volume compared to ND. On diffusion tensor imaging at baseline and after insulin deprivation, T1D had a higher fractional anisotropy compared to ND. T1D also had a significant decline in phosphocreatine/ATP after insulin deprivation compared to ND. Lastly after insulin deprivation, T1D failed to have learned improvement on repeat neuropsychiatric testing, with ND having significantly greater improvements in executive function, attention and working memory compared to T1D. Conclusion: Transient hyperglycemia and insulin deprivation caused a significant decline in some important aspects of cognition and brain energy metabolism, indicating that even transient insulin deprivation affects brain function and morphology. This may have important clinical implications as many diabetic patients inadvertently have occasional periods of transient insulin deprivation. Disclosure A. Creo: Consultant; Self; Ultragenyx. T.M. Cortes: None. A.R. Huebner: None. A. Lteif: None. J. Port: None. K. Nair: None.

Insulin resistance increases the risk for Alzheimer’s disease and other dementias; however, the underpinning mechanisms for this increased risk remain to be fully defined. Insulin resistance impairs mitochondrial oxidative metabolism and increases reactive oxygen species (ROS) in skeletal muscle, both of which are counteracted by aerobic exercise (AE). Therefore, we considered whether similar events occur in the brain, specifically in regions such as cerebrum and hippocampus which are rich in insulin receptors and mitochondria. We determined whether AE would counteract mitochondrial deficits in hippocampal and cerebral mitochondrial function in high fat diet (HFD) induced insulin resistance. Four weeks of HFD in mice induced hippocampal insulin resistance which was corrected by AE. HFD decreased ATP production and increased ROS emission in isolated cerebral mitochondria, which were rescued with AE. Impairments in mitochondrial function with HFD were paralleled by reductions in mtDNA copy number, mRNA expression of mitochondrial genes, and oxidative enzyme activities (e.g., citrate synthase, COX) in the hippocampus, which were corrected by AE. We also observed excessive mitochondrial fission in the hippocampus following HFD, which was prevented by AE. Proteomic analysis of the hippocampus showed that HFD led to oxidative post-translational modifications (PTMs) of mitochondrial proteins; however, this increase in oxidative PTMs to mitochondrial proteins with HFD was almost completely reversed by AE. Further, intranasal administration of the insulin receptor antagonist S961 prevented AE-induced improvements in ATP production and ROS emission in isolated cerebral mitochondrial during HFD, demonstrating that AE enhances cerebral mitochondrial function during HFD by resensitizing brain insulin signaling. Disclosure G. Ruegsegger: None. P.M. Vanderboom: None. S. Dasari: Consultant; Self; The Binding Site. K. Klaus: None. K. Nair: None.

Diet-induced insulin resistance (IR) adversely affects human health and life span. We show that muscle-specific overexpression of human mitochondrial transcription factor A (TFAM) attenuates high-fat diet (HFD)–induced fat gain and IR in mice in conjunction with increased energy expenditure and reduced oxidative stress. These TFAM effects on muscle are shown to be exerted by molecular changes that are beyond its direct effect on mitochondrial DNA replication and transcription. TFAM augmented the muscle tricarboxylic acid cycle and citrate synthase facilitating energy expenditure. TFAM enhanced muscle glucose uptake despite increased fatty acid (FA) oxidation in concert with higher β-oxidation capacity to reduce the accumulation of IR-related carnitines and ceramides. TFAM also increased pAMPK expression, explaining enhanced PGC1α and PPARβ, and reversing HFD-induced GLUT4 and pAKT reductions. TFAM-induced mild uncoupling is shown to protect mitochondrial membrane potential against FA-induced uncontrolled depolarization. These coordinated changes conferred protection to TFAM mice against HFD-induced obesity and IR while reducing oxidative stress with potential translational opportunities.

BackgroundThe incidence of neonatal sepsis in India is the highest in the world. Evidence regarding its risk factors can guide clinical practice and prevention strategies.ObjectiveTo review, assess and synthesize the available literature from India on the risk factors of sepsis among neonates.MethodologyA systematic review was conducted. We searched PubMed, CINAHL, Scopus, Web of Science, Popline, IndMed, Indian Science Abstracts and Google Scholar from inception up to March 23, 2018 to identify observational analytical studies reporting on risk factors of laboratory-confirmed neonatal sepsis in India. Two authors independently screened studies (title, abstract and full-text stages), extracted data, and assessed quality. A random-effects meta-analysis was performed as substantial heterogeneity was anticipated. Subgroup and sensitivity analyses were additionally performed. Effect size in our review included odds ratio and standardized mean difference.ResultsFifteen studies were included from 11,009 records, of which nine were prospective in design. Birthweight and gestational age at delivery were the most frequently reported factors. On meta-analyses, it was found that male sex (OR: 1.3, 95% CI: 1.02, 1.68), out born neonates (OR: 5.5, 95% CI: 2.39, 12.49), need for artificial ventilation (OR: 5.61; 95% CI: 8.21, 41.18), gestational age ConclusionsMale neonates, outborn admissions, need for artificial ventilation, gestational age

Insulin deficiency in cystic fibrosis (CF) is the primary cause of impaired glucose tolerance and diabetes. However, along with insulin deficiency, insulin sensitivity may also play an important role. Herein we aimed to quantify insulin action and secretion in nondiabetic CF adults in comparison with healthy controls after an oral glucose tolerance test (OGTT) with the oral minimal model method. Sixteen nondiabetic CF (7F; age=22±2 y; BMI=22±2 kg/m2; BW=66±10 kg) and seven healthy adults (3F; age=22±2 y; BMI=22±2 kg/m2; BW=66±9 kg) underwent an OGTT. Plasma glucose, insulin and C-peptide were measured for 5 h. The oral glucose and C-peptide minimal models were used to quantify indices of glucose absorption, insulin sensitivity, β-cell responsiveness and disposition index. Insulin sensitivity was similar (mean±SE; p-value from two-sample t-test) in CF and healthy (23±3 and 16±3 10-4 dL/kg/min per uU/mL; NS), while percentage of glucose absorbed within the first two hours was significantly higher in CF (70±3 vs. 53±4 %; p In conclusion, the oral minimal model method showed that abnormal glucose tolerance in our cohort of CF patients is due to an impaired β-cell function, while insulin action is similar and glucose absorption is higher. Disclosure M. Schiavon: None. G.M. Toffolo: None. C. Cobelli: None. K. Nair: None. A. Moran: Other Relationship; Self; Novo Nordisk Inc. Funding National Institutes of Health (R01DK101402); National Center for Advancing Translational Sciences (UL1-TR-000114)

Caregivers of children living with HIV/AIDS (CLWHA) face unique challenges due to disease-related stigma and discrimination, isolation from society, financial constraints, grief and mortality of loved one. A descriptive cross-sectional study was conducted at Udupi ART centre to assess the caregiver burden, psychological distress and their associated factors among the caregivers of CLWHA in Udupi District. The convenience sampling technique was used to collect the data from 171 caregivers and analysed with the help of SPSS version 15.0. Majority of caregivers were female (64.9%) with mean age of 38.1 ± 9.6 years. About 64.3% caregivers were HIV-positive and 63.2% were biological parents of CLWHA. Mild-to-severe caregiver burden on Zarit Burden Inventory (ZBI) was reported among 84.8% of caregivers, and mild-to-severe psychological distress on General Health Questionnaire (GHQ-12) was reported among 49.7% caregivers. Relationship with child was found to be a significant predictor of caregiver burden as compared to other relatives/foster (P

Background: Early recognition of mental health problems gives an individual the opportunity for better long-term outcomes if intervention is initiated early. Mental health literacy is a related concept which is increasingly seen as an important measure of the awareness and knowledge of mental health disorders. Aim and Objectives: This study aimed at assessing the mental health literacy, help-seeking behavior and beliefs and attitudes related to mental illnesses among adolescents attending preuniversity colleges. Materials and Methods: A cross-sectional study was conducted among randomly selected preuniversity college students (n = 916). Data were collected through self-administered questionnaires. Data were computed using STATA. Analysis and interpretation were carried out using descriptives and Chi-square test. Results: Of the 916 respondents, 54.15% were male while 45.85% were female. The majority (78.60%) of the respondents ascribed to the Hindu religion, hailed largely from rural areas (57.21%) and were mostly studying in the 11th standard (72.49%). The percentage of mental health literacy among the respondents was very low, i.e., depression was identified by 29.04% and schizophrenia/psychosis was recognized by 1.31%. The study findings indicate that adolescents preferred reaching out more to informal sources including family members such as mothers than formal sources for self than for others indicating deeply prevalent stigmatizing attitudes toward mental health conditions. Conclusions: There is a need for immediate improvement in the knowledge of adolescents on mental health literacy which suggests that programs need to be developed such that adolescents can seek help from valid resources if the need were to arise and have appropriate knowledge on whom to approach for help.

Dehydroepiandrosterone (DHEA) and T hormones are advertised as antiaging, antiobesity products. However, the evidence that these hormones have beneficial effects on adipose tissue metabolism is limited.The objective of the study was to determine the effect of DHEA and T supplementation on systemic lipolysis during a mixed-meal tolerance test (MMTT) and an iv glucose tolerance test (IVGTT).This was a 2-year randomized, double-blind, placebo-controlled trial.The study was conducted at a general clinical research center.Sixty elderly women with low DHEA concentrations and 92 elderly men with low DHEA and bioavailable T concentrations participated in the study.Elderly women received 50 mg DHEA (n = 30) or placebo (n = 30). Elderly men received 75 mg DHEA (n = 30), 5 mg T (n = 30), or placebo (n = 32).In vivo measures of systemic lipolysis (palmitate rate of appearance) during a MMTT or IVGTT.At baseline there was no difference in insulin suppression of lipolysis measured during MMTT and IVGTT between the treatment groups and placebo. For both sexes, a univariate analysis showed no difference in changes in systemic lipolysis during the MMTT or IVGTT in the DHEA group and T group when compared with placebo. There was no change in the results after adjusting for the resting energy expenditure, except for a small, but significant (P = .03) lowering of MMTT nadir palmitate rate of appearance in women who received DHEA.In elderly individuals with concentrations of DHEA (men and women) or T (men) below the normal range for young adults, supplementation of these hormones has no effect on insulin suppression of systemic lipolysis.

Poor glycemic control in individuals with type 1 diabetes (T1D) is associated with both micro- and macrovascular complications, but good glycemic control does not fully prevent the risk of these complications.The objective of the study was to determine whether T1D with good glycemic control have persistent abnormalities of metabolites and pathways that exist in T1D with poor glycemic control.We compared plasma metabolites in T1D with poor (glycated hemoglobin ≥ 8.5%, T1D[-] and good (glycated hemoglobin6.5%, T1D[+]) glycemic control with nondiabetic controls (ND).The study was conducted at the clinical research unit.T1D with poor (n = 14), T1D(-) and good, T1D(+) (n = 15) glycemic control and matched (for age, sex, and body mass index) ND participants were included in the study.There were no intervention.Comparison of qualitative and quantitative profiling of metabolome was performed.In T1D(-), 347 known metabolites belonging to 38 metabolic pathways involved in cholesterol, vitamin D, tRNA, amino acids (AAs), bile acids, urea, tricarboxylic acid cycle, immune response, and eicosanoids were different from ND. In T1D(+),154 known metabolites belonging to 26 pathways including glycolysis, gluconeogenesis, bile acids, tRNA biosynthesis, AAs, branch-chain AAs, retinol, and vitamin D metabolism remained altered from ND. Targeted measurements of AA metabolites, trichloroacetic acid, and free fatty acids showed directional changes similar to the untargeted metabolomics approach.Comprehensive metabolomic profiling identified extensive metabolomic abnormalities in T1D with poor glycemic control. Chronic good glycemic control failed to normalize many of these perturbations, suggesting a potential role for these persistent abnormalities in many complications in T1D.

Background: Objective of the study was to assess the effectiveness of the family level counseling to mothers on breastfeeding practices and weight gain in children. Methods: A community based cluster randomized controlled trial was conducted in Udupi District in Karnataka State, South India. All the children born to pregnant mothers registered in the third trimester were followed until 2 years of age in selected Anganwadi (AW) centres. Results: Baseline characteristics of the subjects were found to be similar in both intervention and control groups. The baseline knowledge assessed on a 15-point scale showed similar mean score in both groups. Mean measured weight increased significantly in the intervention group (0.794 kg, p < 0.002) at 24 months of age. At 24 months more babies in intervention group were receiving breastfeeding than control group (68.6 % vs. 14.7 %, 95 % CI 2.01 – 10.80, and p < 0.001). Frequency of breast feeding at 4 months was 77.1 % in intervention and 57.8 % in control group (p < 0.0001) while at 6 months it was 77.1 % in intervention and 33.3 % in control group (p < 0.0001). The breastfeeding position assessed on a ten-point scale showed mothers in intervention group followed more than 7 correct positions than control group at birth, 4 months and 6 months of age (p < 0.001). Conclusions: The study shows promotion of child nutrition and breastfeeding practices in developing countries through family level counselling (IYCF strategy) will improve the nutritional status of children less than 2 years of age.

Diet-induced insulin resistance (IR) adversely affects human health and life span. We show that muscle-specific overexpression of human mitochondrial transcription factor A (TFAM) attenuates high-fat diet (HFD)-induced fat gain and IR in mice in conjunction with increased energy expenditure and reduced oxidative stress. These TFAM effects on muscle are shown to be exerted by molecular changes that are beyond its direct effect on mitochondrial DNA replication and transcription. TFAM augmented the muscle tricarboxylic acid cycle and citrate synthase facilitating energy expenditure. TFAM enhanced muscle glucose uptake despite increased fatty acid (FA) oxidation in concert with higher β-oxidation capacity to reduce the accumulation of IR-related carnitines and ceramides. TFAM also increased pAMPK expression, explaining enhanced PGC1α and PPARβ, and reversing HFD-induced GLUT4 and pAKT reductions. TFAM-induced mild uncoupling is shown to protect mitochondrial membrane potential against FA-induced uncontrolled depolarization. These coordinated changes conferred protection to TFAM mice against HFD-induced obesity and IR while reducing oxidative stress with potential translational opportunities.

Accumulating evidence indicates a strong association between diabetic status and degenerative brain disease, including cognitive impairment. Here we hypothesized that although insulin is not necessary for glucose metabolism in brain, like in skeletal muscle insulin is critical for mitochondrial function in brain. We measured oxygen consumption rate (OCR), maximal ATP production rate (MAPR), and reactive oxygen species (ROS) production in isolated brain mitochondria of streptozotocin (STZ) diabetic mice. STZ mice deprived of insulin treatment for 96 hours (D-I), in comparison to nondiabetic mice (ND) showed a significant reduction in State 3 MAPR [1.77±0.14 vs. 2.35±0.27 (pmol/s/ug)], phosphorylation efficiency [0.42±0.04 vs. 0.54±0.07 (mol ATP produced/mol of oxygen consumed)] and respiratory control ratio [2.95±0.16 vs. 3.12±0.18] indicating reduced mitochondrial coupling efficiency during insulin deprivation. Citrate synthase and cytochrome c oxidase activities were significantly decreased in the hypothalamus of D-I compared ND. Surprisingly, no significant differences in ROS emission were detected between ND and D-I suggesting additional factors, potentially elevated ketone bodies, may protect against increased oxidative stress in the D-I brain. Proteomics analysis of the cerebrum found post-translational modification involving oxidative damage of several mitochondrial proteins that potentially cause tau phosphorylation and neurofibrillary degeneration in D-I vs. ND. In STZ mice with continued insulin treatment (D+I), state 3 OCR, MAPR, and phosphorylation efficiency were comparable to ND, demonstrating the restorative effects of insulin and euglycemia on brain mitochondrial function. We conclude that insulin deprivation and hyperglycemia significantly alter brain mitochondrial function. Insulin treatment and control of glycemia could have salutary effects on these parameters. Disclosure G. Ruegsegger: None. M. Shankarappa: None. P. Summer: None. S. Gopala: None. P. Zabielski: None. K. Klaus: None. S. Dasari: None. I.R. Lanza: None. K. Nair: None.

Objective: Statins are well known to cause myalgia and in very rare cases rhabdomyolysis. It remains to be determined whether statin treatment causes any adverse effects on muscle precluding benefits of exercise. We investigated the impact of statin therapy on exercise capacity, muscle strength, mitochondrial respiration, and gene expression in older adults before and after a 12 week exercise program consisting of either aerobic interval (HIIT), resistance (RT), or combined aerobic and resistance (CT) training. Design: Participants aged 65 and older reported in a prior exercise study were analyzed to determine the impact of statin use. Anthropometric measurements, muscle strength, exercise tolerance and a muscle biopsy for determination of mitochondrial respiration and gene transcripts (RNA sequence) were obtained at baseline and then repeated after 12 weeks of exercise training. Results: Among participants, 7 were in CT (2 on statins, 5 not on statins), 8 were in HIIT (4 on statins, 4 not on statins), and 8 were in RT (2 on statins, 6 not on statins) groups. Statin and non-statin users at baseline had no observed significant difference in BMI (p=0.936), VO2 (p=0.812), leg press strength (p=0.916), state 2 respiration (p=0.266), state 3 respiration complex I and II (p=0.345), stage 4 respiration (p=0.231) or gene transcripts of 15232 genes examined. Following 12 week exercise program, no significant differences were noted between statin and non-statin users in their BMI (9=0.149), VO2 (p=0.681), leg press strength (p=0.925), state 2 respiration (p=0.078), state 3 respiration complex 1 and II (p=0.142), or state 4 respiration (p=0.945). Significant differences were noted in gene transcripts in statin and non-statin users in CT+RT group (6 genes) and HIIT group (33 genes). Conclusion: Although there is a slight difference in gene expression in statin and non-statin users, this difference does not have a significant effect on exercise tolerance, muscle strength or mitochondrial respiration after a 12 week exercise program. Disclosure T.M. Cortes: None. S. Dasari: None. M.M. Robinson: None. K. Nair: None.

Background: Familial Partial Lipodystrophy, Dunnigan variety (FPLD) is characterized by post-natal fat loss leading to severe insulin resistance. Affected individuals also display striking skeletal muscle hypertrophy, but there is limited information on muscle function and energy metabolism. We therefore systematically investigated muscle and mitochondrial function in 6 individuals with FPLD and 6 matched controls. Methods: Body composition and intramyocellular lipid content (IMCL) were assessed by DEXA and magnetic resonance spectroscopy, respectively. Maximal voluntary strength and fatigue were assessed for both recumbent leg press and seated chest press. Vastus lateralis muscle biopsies were obtained prior to and following a high fat (40%) mixed-meal. Oxygen consumption in isolated mitochondria was measured using substrates supporting carbohydrate or lipid-based respiration. Insulin Sensitivity Index (SI) was calculated by minimal modelling. Results: Individuals with FPLD had significantly lower SI, lower body fat content, and higher lean mass. Peak leg press and chest press force were not different, but FPLD individuals had earlier fatigue during chest press (number of repetitions: 15 ± 0.6 vs. 20 ± 0.3, p = 0.01). They also had a 50-60% decrease in state 3 respiration measured using substrates supporting lipid-based respiration (p = 0.04). Further, mitochondrial oxidative capacity showed a strong correlation with muscle fatigue (r = 0.76, p = 0.003), and inversely correlated with fasting and post-prandial lipemia and measures of insulin resistance. Conclusion: Individuals with FPLD have higher lean body mass and lower insulin sensitivity. Despite preserved peak muscle strength, they demonstrated earlier muscle fatigue. Decreased mitochondrial fatty acid oxidative capacity, likely related to elevated IMCL, may contribute to muscular and metabolic abnormalities. Disclosure V. Simha: None. I.R. Lanza: None. N. LeBrasseur: None. K. Klaus: None. J. Port: None. M.C. Laurenti: Other Relationship; Self; GlySens Incorporated. C. Cobelli: Research Support; Self; Sanofi-Aventis. Advisory Panel; Self; Novo Nordisk Inc.. K. Nair: None.

Aims To evaluate the effect of metformin on various parameters of exercise capacity [oxygen consumption (VO2), peak oxygen consumption (VO2peak), heart rate (HR), exercise test duration, respiratory exchange ratio (RER), rating of perceived exertion (RPE), lactate and ventilatory anaerobic threshold (VAT)]. Methods Studies reporting change in VO2 or VO2peak after metformin administration were included. Subgroup analyses were performed as applicable. Mean difference with 95% CIs were pooled using random-effects model [RevMan (v5.3)]. Results There were no changes in VO2 and VO2peak in the overall population [VO2: n = 388, mean difference: −0.12 ml/kg/min, 95% CI: −0.74, 0.51, p = 0.71 (i2 = 0%, p = 0.99); VO2peak: n = 345, mean difference: 0.41 ml/kg/min, 95% CI: −0.51, 1.33, p = 0.38 (i2 = 0%, p = 0.89)], healthy volunteers and patients (type 2 diabetes mellitus, insulin resistance, impaired glucose tolerance/impaired fasting glucose and metabolic syndrome). For patients with insulin resistance, there was a decrease in VO2peak, but not VO2. In the overall population, there was a significant decrease in HR and RER, a significant increase in RPE, and no changes in exercise test duration and VAT. In addition, there was an increased VAT in the healthy volunteers. Conclusions In the overall population, metformin did not affect VO2, VO2peak, exercise test duration and VAT, although it significantly decreased HR, RER and increased RPE.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the efficacy and safety of pertussis vaccination in pregnancy for preventing whooping cough in early infancy.

Objective: To identify factors influencing union of congenital pseudarthrosis of the tibia (CPT), refractures, and integrity of the tibia at maturity. Methods: Data of 119 children operated for Crawford-type IV CPT and followed-up till skeletal maturity were analyzed. Logistic regression and recursive partitioning analyses were used to test associations between several variables and the outcome. Results: Primary union occurred in 86% of children. At maturity, 69% remained soundly united. The odds ratio for failure of primary union was 3.89 (95% confidence interval, 1.05-14.40; P=0.042) when bone morphogenetic protein was used, and children who had a combination of the Ilizarov technique and intramedullary nailing were at risk for unsound union at maturity (odds ratio, 6.19; 95% confidence interval, 1.24-30.83; P=0.026). No other association reached statistical significance. On recursive partitioning, use of the Ilizarov technique, transfixing the ankle and subtalar joints, use of cortical graft and not operating on the fibula were associated with a better outcome; use of bone morphogenetic protein and combining intramedullary nailing with the Ilizarov technique were associated with poor results. Conclusions: A larger sample is needed to confirm which factors truly influence the outcome of CPT. This may be feasible if data are collected prospectively through a multicenter registry.

Insulin deficiency and uncontrolled diabetes lead to a catabolic state with decreased muscle strength, contributing to disease-related morbidity. FoxO transcription factors are key mediators of insulin action. To study their role in diabetic muscle wasting, we created mice with musclespecific triple knockout of FoxO1/3/4 and induced diabetes in these M-FoxO-TKO mice with streptozotocin (STZ). Muscle mass and myofiber area were decreased 20-30% in STZ-Diabetes mice due to increased ubiquitinproteasome degradation and autophagy, characterized by increased pULK1 and LC3-II. Both the muscle loss and markers of increased degradation/autophagy were completely prevented in STZ-FoxO-TKO mice. Transcriptomic analyses revealed FoxO-dependent increases in ubiquitin-mediated proteolysis pathways in STZ-Diabetes, including regulation of Fbxo32 (Atrogin1), Trim63 (MuRF1), Bnip3L, and Gabarapl. These same genes were increased 1.4- to 3.3-fold in muscle from type 1 diabetics after shortterm insulin deprivation. Thus, FoxO-regulated genes play a rate-limiting role in increased protein degradation and muscle atrophy in insulin-deficient diabetes.

Insulin and nutrients have profound effects on proteome homeostasis. Currently no reliable methods are available to measure postprandial protein turnover. A triple-tracer method was developed using phenylalanine stable isotope tracers to estimate appearance rates of ingested (Ra meal) and endogenous phenylalanine and the rate of phenylalanine disposal (Rd). This was compared with the “traditional” dual-tracer method, using one (1-CM)- and two (2-CM)-compartment models. For both methods, [13C6]phenylalanine was given orally, and [15N]phenylalanine was constantly infused; the triple-tracer method added [2H5]phenylalanine, infused at rates to mimic meal [13C6]phenylalanine appearance. Additionally, incorporation of meal-derived phenylalanine into specific proteins was measured after purification by two-dimensional electrophoresis. The triple-tracer approach reduced modeling errors, allowing improved reconstruction of Ra meal with a tracer-to-tracee ratio that was more constant and better estimated Rd. The 2-CM better described phenylalanine kinetics and Rd than 1-CM. Thus, the triple-tracer approach using 2-CM is superior for measuring non-steady-state postprandial protein turnover. This novel approach also allows measurement of postprandial synthesis rates of specific plasma proteins. We offer a valid non-steady-state model to measure postprandial protein turnover and synthesis of plasma proteins that can safely be applied in adults, children, and pregnant women.

Insulin plays pivotal role in cellular fuel metabolism in skeletal muscle. Despite being the primary site of energy metabolism, the underlying mechanism on how insulin deficiency deranges skeletal muscle mitochondrial physiology remains to be fully understood. Here we report an important link between altered skeletal muscle proteome homeostasis and mitochondrial physiology during insulin deficiency. Deprivation of insulin in streptozotocin-induced diabetic mice decreased mitochondrial ATP production, reduced coupling and phosphorylation efficiency, and increased oxidant emission in skeletal muscle. Proteomic survey revealed that the mitochondrial derangements during insulin deficiency were related to increased mitochondrial protein degradation and decreased protein synthesis, resulting in reduced abundance of proteins involved in mitochondrial respiration and β-oxidation. However, a paradoxical upregulation of proteins involved in cellular uptake of fatty acids triggered an accumulation of incomplete fatty acid oxidation products in skeletal muscle. These data implicate a mismatch of β-oxidation and fatty acid uptake as a mechanism leading to increased oxidative stress in diabetes. This notion was supported by elevated oxidative stress in cultured myotubes exposed to palmitate in the presence of a β-oxidation inhibitor. Together, these results indicate that insulin deficiency alters the balance of proteins involved in fatty acid transport and oxidation in skeletal muscle, leading to impaired mitochondrial function and increased oxidative stress.

SummaryExercise provides many health benefits, including improved metabolism, cardiovascular health, and cognition. We have shown previously that FNDC5, a type I transmembrane protein, and its circulating form, irisin, convey some of these benefits in mice. However, recent reports questioned the existence of circulating human irisin both because human FNDC5 has a non-canonical ATA translation start and because of claims that many human irisin antibodies used in commercial ELISA kits lack required specificity. In this paper we have identified and quantitated human irisin in plasma using mass spectrometry with control peptides enriched with heavy stable isotopes as internal standards. This precise state-of-the-art method shows that human irisin is mainly translated from its non-canonical start codon and circulates at ∼3.6 ng/ml in sedentary individuals; this level is increased to ∼4.3 ng/ml in individuals undergoing aerobic interval training. These data unequivocally demonstrate that human irisin exists, circulates, and is regulated by exercise.