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Serum Leptin Levels and the Risk of Stroke: The Framingham Study. - Stroke; a journal of cerebral circulation
Leptin is a major adipokine that regulates weight balance and energy homeostasis. There is inconsistent evidence linking circulating leptin levels to risk of stroke. We tested the hypothesis that leptin levels are associated with risk of incident stroke in an elderly community based sample.Serum leptin levels were assayed in 757 stroke free individuals (mean age, 79 years; 62% women) from the Framingham Original Cohort at the 22nd examination cycle (1990-1994). Incidence of all -stroke and ischemic stroke were prospectively ascertained.During a mean follow up of 10 years, 119 individuals developed stroke (99 ischemic strokes). In multivariable Cox regression models, log leptin levels were not associated with incidence of all -stroke or ischemic stroke (hazard ratios per SD increment in log leptin 0.90 [0.73-1.09] and 0.89 [0.72-1.11], respectively). The results were suggestive for potential effect modification by waist/hip ratio for the association between leptin and stroke (P=0.03). Adjusting for age, sex, and established stroke risk factors, analysis stratified by waist/hip ratio quartiles revealed a lower incidence of first-ever all-stroke and ischemic stroke associated with higher leptin levels among only subjects in the top waist/hip ratio quartile (hazard ratio, 0.64 [0.43, 0.95] versus 0.98 [0.77, 1.25] for incident all-stroke and 0.61 [0.39, 0.95] versus 0.96 [0.74, 1.26] for ischemic stroke).Leptin levels were not directly related to the risk of incident stroke overall but there was an inverse association with stroke in the top waist/hip ratio quartile. Further investigations are required to confirm these findings and explore possible mechanisms for the observed association.Â© 2015 American Heart Association, Inc.
Treatment of sporadic inclusion body myositis with bimagrumab. - Neurology
To study activin signaling and its blockade in sporadic inclusion body myositis (sIBM) through translational studies and a randomized controlled trial.We measured transforming growth factor Î² signaling by SMAD2/3 phosphorylation in muscle biopsies of 50 patients with neuromuscular disease (17 with sIBM). We tested inhibition of activin receptors IIA and IIB (ActRII) in 14 patients with sIBM using one dose of bimagrumab (n = 11) or placebo (n = 3). The primary outcome was the change in right thigh muscle volume by MRI at 8 weeks. Lean body mass, strength, and function were secondary outcomes. Twelve of the patients (10 bimagrumab, 2 placebo) participated in a subsequent 16-week observation phase.Muscle SMAD2/3 phosphorylation was higher in sIBM than in other muscle diseases studied (p = 0.003). Eight weeks after dosing, the bimagrumab-treated patients increased thigh muscle volume (right leg +6.5% compared with placebo, p = 0.024; left leg +7.6%, p = 0.009) and lean body mass (+5.7% compared with placebo, p = 0.014). Subsequently, bimagrumab-treated patients had improved 6-minute walking distance, which peaked at 16 weeks (+14.6%, p = 0.008) compared with placebo. There were no serious adverse events; the main adverse events with bimagrumab were mild acne and transient involuntary muscle contractions.Transforming growth factor Î² superfamily signaling, at least through ActRII, is implicated in the pathophysiology of sIBM. Inhibition of ActRII increased muscle mass and function in this pilot trial, offering a potential novel treatment of sIBM.This study provides Class I evidence that for patients with inclusion body myositis, bimagrumab increases thigh muscle volume at 8 weeks.Â© 2014 American Academy of Neurology.
Prospect for pharmacological therapies to treat skeletal muscle dysfunction. - Calcified tissue international
Skeletal muscle weakness is a leading cause of mobility disability in the elderly (sarcopenia), as a complication of acute or chronic illness (cachexia), and due to inherited or acquired muscle diseases (muscular dystrophies, myositides, etc.). As of now, there are no approved drugs that can reliably increase muscle strength and function. However, with our understanding of the regulation of myocyte signaling and homeostasis evolving rapidly, experimental treatments are now entering the clinic. We review the current status of clinical research in pharmacological therapies for muscle disorders.
Influence of exercise on the metabolic profile caused by 28 days of bed rest with energy deficit and amino acid supplementation in healthy men. - International journal of medical sciences
Muscle loss and metabolic changes occur with disuse [i.e. bed rest (BR)]. We hypothesized that BR would lead to a metabolically unhealthy profile defined by: increased circulating tumor necrosis factor (TNF)-Î±, decreased circulating insulin-like-growth-factor (IGF)-1, decreased HDL-cholesterol, and decreased muscle density (MD; measured by mid-thigh computerized tomography).We investigated the metabolic profile after 28 days of BR with 8 Â± 6% energy deficit in male individuals (30-55 years) randomized to resistance exercise with amino acid supplementation (RT, n=24) or amino acid supplementation alone (EAA, n=7). Upper and lower body exercises were performed in the horizontal position. Blood samples were taken at baseline, after 28 days of BR and 14 days of recovery.We found a shift toward a metabolically unfavourable profile after BR [compared to baseline (BLN)] in both groups as shown by decreased HDL-cholesterol levels (EAA: BLN: 39 Â± 4 vs. BR: 32 Â± 2 mg/dL, RT: BLN: 39 Â± 1 vs. BR: 32 Â± 1 mg/dL; p<0.001) and Low MD (EAA: BLN: 27 Â± 4 vs. BR: 22 Â± 3 cm(2), RT: BLN: 28 Â± 2 vs. BR: 23 Â± 2 cm(2); p<0.001). A healthier metabolic profile was maintained with exercise, including NormalMD (EAA: BLN: 124 Â± 6 vs. BR: 110 Â± 5 cm(2), RT: BLN: 132 Â± 3 vs. BR: 131 Â± 4 cm(2); p<0.001, time-by-group); although, exercise did not completely alleviate the unfavourable metabolic changes seen with BR. Interestingly, both groups had increased plasma IGF-1 levels (EAA: BLN:168 Â± 22 vs. BR 213 Â± 20 ng/mL, RT: BLN:180 Â± 10 vs. BR: 219 Â± 13 ng/mL; p<0.001) and neither group showed TNFÎ± changes (p>0.05).We conclude that RT can be incorporated to potentially offset the metabolic complications of BR.
Insulin-like growth factor-1 and risk of Alzheimer dementia and brain atrophy. - Neurology
To relate serum insulin-like growth factor-1 (IGF-1) to risk of Alzheimer disease (AD) dementia and to brain volumes in a dementia-free community sample spanning middle and older ages.Dementia-free Framingham participants from generation 1 (n = 789, age 79 Â± 4 years, 64% women) and generation 2 (n = 2,793, age 61 Â± 9 years, 55% women; total = 3,582, age 65 Â± 11 years, 57% women) had serum IGF-1 measured in 1990-1994 and 1998-2001, respectively, and were followed prospectively for incident dementia and AD dementia. Brain MRI was obtained in stroke- and dementia-free survivors of both generations 1 (n = 186) and 2 (n = 1,867) during 1999-2005. Baseline IGF-1 was related to risk of incident dementia using Cox models and to total brain and hippocampal volumes using linear regression in multivariable models adjusted for age, sex, APOE Îµ4, plasma homocysteine, waist-hip ratio, and physical activity.Mean IGF-1 levels were 144 Â± 60 Î¼g/L in generation 1 and 114 Â± 37 Î¼g/L in generation 2. We observed 279 cases of incident dementia (230 AD dementia) over a mean follow-up of 7.4 Â± 3.1 years. Persons with IGF-1 in the lowest quartile had a 51% greater risk of AD dementia (hazard ratio = 1.51, 95% confidence interval: 1.14-2.00; p = 0.004). Among persons without dementia, higher IGF-1 levels were associated with greater total brain volumes (Î²/SD increment in IGF-1 was 0.55 Â± 0.24, p = 0.025; and 0.26 Â± 0.06, p < 0.001, for generations 1 and 2, respectively).Lower serum levels of IGF-1 are associated with an increased risk of developing AD dementia and higher levels with greater brain volumes even among middle-aged community-dwelling participants free of stroke and dementia. Higher levels of IGF-1 may protect against subclinical and clinical neurodegeneration.
Clinical classification of cancer cachexia: phenotypic correlates in human skeletal muscle. - PloS one
Cachexia affects the majority of patients with advanced cancer and is associated with a reduction in treatment tolerance, response to therapy, and duration of survival. One impediment towards the effective treatment of cachexia is a validated classification system.41 patients with resectable upper gastrointestinal (GI) or pancreatic cancer underwent characterisation for cachexia based on weight-loss (WL) and/or low muscularity (LM). Four diagnostic criteria were used >5%WL, >10%WL, LM, and LM+>2%WL. All patients underwent biopsy of the rectus muscle. Analysis included immunohistochemistry for fibre size and type, protein and nucleic acid concentration, Western blots for markers of autophagy, SMAD signalling, and inflammation.Compared with non-cachectic cancer patients, patients with LM or LM+>2%WL, mean muscle fibre diameter was reduced by about 25% (pâ€Š=â€Š0.02 and pâ€Š=â€Š0.001 respectively). No significant difference in fibre diameter was observed if patients had WL alone. Regardless of classification, there was no difference in fibre number or proportion of fibre type across all myosin heavy chain isoforms. Mean muscle protein content was reduced and the ratio of RNA/DNA decreased in patients with either >5%WL or LM+>2%WL. Compared with non-cachectic patients, SMAD3 protein levels were increased in patients with >5%WL (pâ€Š=â€Š0.022) and with >10%WL, beclin (pâ€Š=â€Š0.05) and ATG5 (pâ€Š=â€Š0.01) protein levels were increased. There were no differences in phospho-NFkB or phospho-STAT3 levels across any of the groups.Muscle fibre size, biochemical composition and pathway phenotype can vary according to whether the diagnostic criteria for cachexia are based on weight loss alone, a measure of low muscularity alone or a combination of the two. For intervention trials where the primary end-point is a change in muscle mass or function, use of combined diagnostic criteria may allow identification of a more homogeneous patient cohort, reduce the sample size required and enhance the time scale within which trials can be conducted.
Biomarkers of sarcopenia in clinical trials-recommendations from the International Working Group on Sarcopenia. - Journal of cachexia, sarcopenia and muscle
Sarcopenia, the age-related skeletal muscle decline, is associated with relevant clinical and socioeconomic negative outcomes in older persons. The study of this phenomenon and the development of preventive/therapeutic strategies represent public health priorities. The present document reports the results of a recent meeting of the International Working Group on Sarcopenia (a task force consisting of geriatricians and scientists from academia and industry) held on June 7-8, 2011 in Toulouse (France). The meeting was specifically focused at gaining knowledge on the currently available biomarkers (functional, biological, or imaging-related) that could be utilized in clinical trials of sarcopenia and considered the most reliable and promising to evaluate age-related modifications of skeletal muscle. Specific recommendations about the assessment of aging skeletal muscle in older people and the optimal methodological design of studies on sarcopenia were also discussed and finalized. Although the study of skeletal muscle decline is still in a very preliminary phase, the potential great benefits derived from a better understanding and treatment of this condition should encourage research on sarcopenia. However, the reasonable uncertainties (derived from exploring a novel field and the exponential acceleration of scientific progress) require the adoption of a cautious and comprehensive approach to the subject.
Plasma pyridoxal-5-phosphate is inversely associated with systemic markers of inflammation in a population of U.S. adults. - The Journal of nutrition
Low vitamin B-6 status, based on plasma concentrations of pyridoxal-5-phosphate (PLP), has been identified in inflammatory diseases, including cardiovascular disease, rheumatoid arthritis, inflammatory bowel disease, and diabetes. Our objective was to examine the association between plasma PLP and multiple markers of inflammation in a community-based cohort [n = 2229 participants (55% women, mean age 61 Â± 9 y)]. We created an overall inflammation score (IS) as the sum of standardized values of 13 individual inflammatory markers. Multivariable-adjusted regression analysis was used to assess the associations between the IS and plasma PLP. Geometric mean plasma PLP concentrations were lower in the highest tertile category of IS relative to the lowest (61 vs. 80 nmol/L; P-trend < 0.0001). Similarly, the prevalence of PLP insufficiency was significantly higher for participants in the highest compared with the lowest tertiles for IS categories. These relationships persisted after accounting for vitamin B-6 intake. Also, there were significant inverse relationships between plasma PLP and 4 IS based on functionally related markers, including acute phase reactants, cytokines, adhesion molecules, and oxidative stress. In addition, secondary analyses revealed that many of the individual inflammatory markers were inversely associated with plasma PLP after adjusting for plasma C-reactive protein concentration. This study, in combination with past findings, further supports our hypothesis that inflammation is associated with a functional deficiency of vitamin B-6. We discuss 2 possible roles for PLP in the inflammatory process, including tryptophan metabolism and serine hydroxymethyltransferase activity.
Prospects for the development of effective pharmacotherapy targeted at the skeletal muscles in chronic obstructive pulmonary disease: a translational review. - Thorax
Skeletal muscle dysfunction is a prevalent and clinically important systemic manifestation of chronic obstructive pulmonary disease (COPD) that predicts morbidity and mortality. Skeletal muscle retains its plasticity in response to anabolic stimuli such as exercise in COPD and is therefore a promising target for novel pharmacological therapies aimed at reducing disability and healthcare utilisation and improving mortality. In this article, we outline the steps the academic and pharmaceutical communities need to undertake for such therapeutic advances to be realised.
Plasma phosphatidylcholine concentrations of polyunsaturated fatty acids are differentially associated with hip bone mineral density and hip fracture in older adults: the Framingham Osteoporosis Study. - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Polyunsaturated fatty acids (PUFAs) may influence bone health. The objective of this work was to examine associations between plasma phosphatidylcholine (PC) PUFA concentrations and hip measures: (1) femoral neck bone mineral density (FN-BMD) (nâ€‰=â€‰765); (2) 4-year change in FN-BMD (nâ€‰=â€‰556); and (3) hip fracture risk (nâ€‰=â€‰765) over 17-year follow-up among older adults in the Framingham Osteoporosis Study. BMD measures were regressed on quintile of plasma PC PUFAs (docosahexaenoic acid [DHA], linoleic acid [LA], and arachidonic acid [AA]), adjusted for covariates. Hazard ratios (HR) and 95% confidence interval (CI) for hip fracture were estimated by quintile of plasma PC PUFAs, adjusted for covariates. Higher concentrations of PC DHA were associated with loss of FN-BMD over 4 years in women (p-trendâ€‰=â€‰0.04), but was protective in men in the uppermost quintile compared to men grouped in the lower four quintiles, in post hoc analysis (pâ€‰=â€‰0.01). PC LA concentrations were inversely associated with baseline FN-BMD in women (p-trendâ€‰=â€‰0.02), and increased hip fracture risk in women and men (p-trendâ€‰=â€‰0.05), but body mass index (BMI) adjustment attenuated these associations (p-trendâ€‰=â€‰0.12 and p-trendâ€‰=â€‰0.14, respectively). A trend toward a protective association was observed between PC AA and baseline FN-BMD in men (p-trendâ€‰=â€‰0.06). Women and men with the highest PC AA concentrations had 51% lower hip fracture risk than those with the lowest (HRâ€‰=â€‰0.49, 95% CIâ€‰=â€‰0.24-1.00). Opposing effects of PC DHA on FN-BMD loss observed in women and men need further clarification. Bone loss associated with PC LA may be confounded by BMI. High PC AA concentrations may be associated with reduced hip fracture risk.Copyright Â© 2012 American Society for Bone and Mineral Research.
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