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  1. Metabolic and Body Composition Risk Factors Associated with Metabolic Syndrome in a Cohort of Women with a High Prevalence of Cardiometabolic Disease

    PubMed Central

    Norris, Shane A.; Jaff, Nicole G.; Crowther, Nigel J.

    2016-01-01

    Background The aetiology of the metabolic syndrome and the inter-relationship between risk factors for this syndrome are poorly understood. The purpose of this investigation was to determine the risk factors for metabolic syndrome and their interactions in a cohort of women with a high prevalence of metabolic syndrome. Materials and Methods Abdominal and whole body composition (ultrasound and dual-energy X-ray absorptiometry), blood pressure, and cardiometabolic and demographic factors were measured in a cross-sectional study of 702 black African women from Soweto, Johannesburg. Data was analysed using multivariate logistic regression. Results Metabolic syndrome was present in 49.6% of the study cohort. Logistic regression analysis demonstrated that adiponectin (odds ratio [95% CIs]: 0.84 [0.77, 0.92], p<0.0005) and abdominal subcutaneous fat (0.56 [0.39, 0.79], p = 0.001) reduced metabolic syndrome risk whilst insulin resistance (1.31 [1.16, 1.48], p<0.0005) and trunk fat-free soft-tissue mass (1.34 [1.10, 1.61], p = 0.002) increased risk. Within this group of risk factors, the relationship of adiponectin with metabolic syndrome risk, when analysed across adiponectin hexiles, was the least affected by adjustment for the other risk factors. Conclusions Adiponectin has a significant protective role against metabolic syndrome and is independent of other risk factors. The protective and possible augmentive effects of abdominal subcutaneous fat and lean trunk mass, respectively on metabolic syndrome risk demonstrate the existence of novel interactions between body composition and cardiometabolic disease. PMID:27589387

  2. The Relationship of Metabolic Syndrome with Stress, Coronary Heart Disease and Pulmonary Function - An Occupational Cohort-Based Study

    PubMed Central

    Nowobilski, Roman; Dropinski, Jerzy; Kotula-Horowitz, Katarzyna; Laskowicz, Bartosz; Stanisz, Andrzej; Lelakowski, Jacek

    2015-01-01

    Background and Aims Higher levels of stress impact the prevalence of metabolic syndrome (MetS) and coronary heart disease. The association between MetS, impaired pulmonary function and low level of physical activity is still pending assessment in the subjects exposed to stress. The study aimed to examine whether higher levels of stress might be related to MetS and the plaque presence, as well as whether MetS might affect pulmonary function. Design and Methods The study embraced 235 police officers (mean age 40.97 years) from the south of Poland. The anthropometrics and biochemical variables were measured; MetS was diagnosed using the International Diabetes Federation criteria. Computed tomography coronary angiography of coronary arteries, exercise ECG, measurements of brachial flow-mediated dilation, and carotid artery intima-media thickness were completed. In order to measure the self-perception of stress, 10-item Perceived Stress Scale (PSS-10) was applied. Pulmonary function and physical activity levels were also addressed. Multivariate logistic regression analyses were applied to determine the relationships between: 1/ incidence of coronary plaque and MetS per se, MetS components and the number of classical cardiovascular risk factors, 2/ perceived stress and MetS, 3/ MetS and pulmonary function parameters. Results Coronary artery atherosclerosis was less associated with MetS (OR = 2.62, 95%CI 1.24–5.52; p = 0.011) than with a co-existence of classical cardiovascular risk factors (OR = 5.67, 95% CI 1.07–29.85, p = 0.03; for 3 risk factors and OR = 9.05; 95% CI 1.24–66.23, p = 0.02; for 6 risk factors, respectively). Perceived stress increased MetS prevalence (OR = 1.07, 95% CI 1.03–1.13; p = 0.03), and impacted coronary plaque prevalence (OR = 1.05, 95% CI 1.001–1.10; p = 0.04). Leisure-time physical activity reduced the chances of developing MetS (OR = 0.98 95% CI 0.96–0.99; p = 0.02). MetS subjects had significantly lower values of certain

  3. Anthropometric and Metabolic Risk Factors for ESRD Are Disease-Specific: Results from a Large Population-Based Cohort Study in Austria

    PubMed Central

    Zitt, Emanuel; Pscheidt, Constanze; Concin, Hans; Kramar, Reinhard; Lhotta, Karl; Nagel, Gabriele

    2016-01-01

    Background Anthropometric and metabolic risk factors for all-cause end-stage renal disease (ESRD) may vary in their impact depending on the specific primary renal disease. Methods In this Austrian population-based prospective cohort study (n = 185,341; 53.9% women) the following data were collected between 1985 and 2005: age, sex, body mass index (BMI), fasting blood glucose (FBG) from 1988, blood pressure, total cholesterol (TC), triglycerides (TG), gamma-glutamyl transferase (GGT) and smoking status. These data were merged with the Austrian Dialysis and Transplant Registry to identify ESRD patients. Cox proportional hazards models were applied to calculate hazard ratios (HR) for all-cause ESRD as well as for cause-specific ESRD due to the following primary renal diseases: autosomal dominant polycystic kidney disease (ADPKD), vascular nephropathy (VN), diabetic nephropathy (DN) and other diseases (OD). Results During a mean follow-up of 17.5 years 403 participants developed ESRD (ADPKD 36, VN 97, DN 86, and OD 184). All parameters except TG and GGT were significantly associated with all-cause ESRD risk. Particular cause-specific ESRD risk factor patterns were found: for ADPKD increased risk from hypertension (HR 11.55); for VN from smoking (HR 1.81), hypertension (HR 2.37), TG (≥5.70 vs. <1.17 mmol/L: HR 9.27); for DN from smoking (HR 1.77), BMI (≥30 vs. 18.5–24.9 kg/m2: HR 7.55), FBG (≥6.94 vs. <5.55 mmol/L: HR 7.67), hypertension (HR 1.08), TG (≥5.70 vs. <1.17 mmol/L: HR 2.02), GGT (HR 2.14); and for OD from hypertension (HR 2.29), TG (≥5.70 vs. <1.17 mmol/L: HR 6.99) and TC (≥6.22 vs. <5.18 mmol/L: HR 1.56). Conclusions Particular anthropometric and metabolic ESRD risk factors differ in importance depending on the primary renal disease. This needs to be considered for future preventive and therapeutic strategies addressing cause-specific ESRD. PMID:27537361

  4. [Rare metabolic diseases].

    PubMed

    Wendel, U; Burgard, P

    2007-12-01

    Rare metabolic diseases are chronic, progressive, present frequently with a life-threatening course and may result in severe handicaps. They demand high diagnostic and therapeutic standards and efforts from physicians and patients. The challenge for society and health systems in dealing with patients affected by one of these diseases is to offer comprehensive service by a multi-professional team of specialists and evidence-based as well as economic (i.e. necessary, sufficient and effective) treatment. Patients and families should be treated in specialized metabolic centres guaranteeing continuous improvement of the scientific and clinical principles of treatment, standardized outcome evaluation, strict quality assurance as well as optimal psychosocial care and counselling. Networking of national and international metabolic centres seems imperative for clinical research in the field of rare metabolic diseases in order to provide adequate sample sizes and to yield substantial results.

  5. The cohort effect in childhood disease dynamics.

    PubMed

    He, Daihai; Earn, David J D

    2016-07-01

    The structure of school terms is well known to influence seasonality of transmission rates of childhood infectious diseases in industrialized countries. A less well-studied aspect of school calendars that influences disease dynamics is that all children enter school on the same day each year. Rather than a continuous inflow, there is a sudden increase in the number of susceptible individuals in schools at the start of the school year. Based on the standard susceptible-exposed-infectious-recovered (SEIR) model, we show that school cohort entry alone is sufficient to generate a biennial epidemic pattern, similar to many observed time series of measles incidence. In addition, cohort entry causes an annual decline in the effective transmission that is evident in observed time series, but not in models without the cohort effect. Including both cohort entry and school terms yields a model fit that is significantly closer to observed measles data than is obtained with either cohort entry or school terms alone (and just as good as that obtained with Schenzle's realistic age-structured model). Nevertheless, we find that the bifurcation structure of the periodically forced SEIR model is nearly identical, regardless of whether forcing arises from cohort entry, school terms and any combination of the two. Thus, while detailed time-series fits are substantially improved by including both cohort entry and school terms, the overall qualitative dynamic structure of the SEIR model appears to be insensitive to the origin of periodic forcing. PMID:27440254

  6. Metabolic mediators of the effects of body-mass index, overweight, and obesity on coronary heart disease and stroke: a pooled analysis of 97 prospective cohorts with 1·8 million participants

    PubMed Central

    2014-01-01

    Summary Background Body-mass index (BMI) and diabetes have increased worldwide, whereas global average blood pressure and cholesterol have decreased or remained unchanged in the past three decades. We quantified how much of the effects of BMI on coronary heart disease and stroke are mediated through blood pressure, cholesterol, and glucose, and how much is independent of these factors. Methods We pooled data from 97 prospective cohort studies that collectively enrolled 1·8 million participants between 1948 and 2005, and that included 57 161 coronary heart disease and 31 093 stroke events. For each cohort we excluded participants who were younger than 18 years, had a BMI of lower than 20 kg/m2, or who had a history of coronary heart disease or stroke. We estimated the hazard ratio (HR) of BMI on coronary heart disease and stroke with and without adjustment for all possible combinations of blood pressure, cholesterol, and glucose. We pooled HRs with a random-effects model and calculated the attenuation of excess risk after adjustment for mediators. Findings The HR for each 5 kg/m2 higher BMI was 1·27 (95% CI 1·23–1·31) for coronary heart disease and 1·18 (1·14–1·22) for stroke after adjustment for confounders. Additional adjustment for the three metabolic risk factors reduced the HRs to 1·15 (1·12–1·18) for coronary heart disease and 1·04 (1·01–1·08) for stroke, suggesting that 46% (95% CI 42–50) of the excess risk of BMI for coronary heart disease and 76% (65–91) for stroke is mediated by these factors. Blood pressure was the most important mediator, accounting for 31% (28–35) of the excess risk for coronary heart disease and 65% (56–75) for stroke. The percentage excess risks mediated by these three mediators did not differ significantly between Asian and western cohorts (North America, western Europe, Australia, and New Zealand). Both overweight (BMI ≥25 to <30 kg/m2) and obesity (BMI ≥30 kg/m2) were associated with a

  7. A Prospective Cohort Study of Mineral Metabolism After Kidney Transplantation

    PubMed Central

    Wolf, Myles; Weir, Matthew R.; Kopyt, Nelson; Mannon, Roslyn B.; Von Visger, Jon; Deng, Hongjie; Yue, Susan; Vincenti, Flavio

    2016-01-01

    Background Kidney transplantation corrects or improves many complications of chronic kidney disease, but its impact on disordered mineral metabolism is incompletely understood. Methods We performed a multicenter, prospective, observational cohort study of 246 kidney transplant recipients in the United States to investigate the evolution of mineral metabolism from pretransplant through the first year after transplantation. Participants were enrolled into 2 strata defined by their pretransplant levels of parathyroid hormone (PTH), low PTH (>65 to ≤300 pg/mL; n = 112), and high PTH (>300 pg/mL; n = 134) and underwent repeated, longitudinal testing for mineral metabolites. Results The prevalence of posttransplant, persistent hyperparathyroidism (PTH >65 pg/mL) was 89.5%, 86.8%, 83.1%, and 86.2%, at months 3, 6, 9, and 12, respectively, among participants who remained untreated with cinacalcet, vitamin D sterols, or parathyroidectomy. The results did not differ across the low and high PTH strata, and rates of persistent hyperparathyroidism remained higher than 40% when defined using a higher PTH threshold greater than 130 pg/mL. Rates of hypercalcemia peaked at 48% at week 8 in the high PTH stratum and then steadily decreased through month 12. Rates of hypophosphatemia (<2.5 mg/dL) peaked at week 2 and then progressively decreased through month 12. Levels of intact fibroblast growth factor 23 decreased rapidly during the first 3 months after transplantation in both PTH strata and remained less than 40 pg/mL thereafter. Conclusions Persistent hyperparathyroidism is common after kidney transplantation. Further studies should determine if persistent hyperparathyroidism or its treatment influences long-term posttransplantation clinical outcomes. PMID:26177089

  8. Metabolic disease in animals.

    PubMed

    Liu, Si-Kwang

    2002-12-01

    Rickets is a metabolic bone disorder characterized by osteopenic changes resulting from the failure of calcification of the osteoid matrix and absent mineralization of hypertrophic cartilage cells at the epiphyseal growth plates in growing primates, herbivores, swine, carnivores, and birds. The causes of rickets include inadequate dietary provision of calcium, phosphorus, and vitamin D. Osteomalacia in reptiles, simian bone disease in nonhuman primates, and osteodystrophia fibrosa (secondary hyperparathyroidism) or "bran disease" in herbivores are caused by a diet that has a much higher content of phosphorus than calcium, combined with inadequate exposure to direct sunlight. Medullary bone consists of interconnected spicules of bone resembling embryonic bone and is established in relation to the shell formation cycle of laying birds. Hypertrophic osteodystrophy develops in large-breed growing dogs, chickens, and guinea pigs and is possibly caused by vitamin C deficiency. Tibial dyschondroplasia is a defect in endochondral ossification characterized by a widened proximal tibial physis that is not penetrated by metaphyseal vascular sprouts, commonly found in growing broiler chickens, turkeys, and exotic birds. PMID:12541191

  9. Diagnosis of metabolic bone disease

    SciTech Connect

    Grech, P.; Martin, T.J.; Barrington, N.A.; Ell, P.J.

    1986-01-01

    This book presents a reference on the radiologic evaluation, features, and differential diagnosis of metabolic diseases involving the whole skeleton, calcium deficiencies resulting from pharmacologic agents, and bone changes related to endocrine disturbances. It also stresses how radiology, nuclear medicine, and biochemistry - either alone or in concert - contribute to clinical diagnosis. It covers renal bone disease, Paget's disease, hyperphosphatasia, extraskeletal mineralization, metabolic bone disorders related to malnutrition, tumors, plus radionuclide studies including materials and methods.

  10. Metabolic syndrome and eye diseases.

    PubMed

    Poh, Stanley; Mohamed Abdul, Riswana Banu Binte; Lamoureux, Ecosse L; Wong, Tien Y; Sabanayagam, Charumathi

    2016-03-01

    Metabolic syndrome is becoming a worldwide medical and public health challenge as it has been seen increasing in prevalence over the years. Age-related eye diseases, the leading cause of blindness globally and visual impairment in developed countries, are also on the rise due to aging of the population. Many of the individual components of the metabolic syndrome have been shown to be associated with these eye diseases. However, the association of metabolic syndrome with eye diseases is not clear. In this review, we reviewed the evidence for associations between metabolic syndrome and certain ocular diseases in populations. We also reviewed the association of individual metabolic syndrome components with ocular diseases due to a paucity of research in this area. Besides, we also summarised the current understanding of etiological mechanisms of how metabolic syndrome or the individual components lead to these ocular diseases. With increasing evidence of such associations, it may be important to identify patients who are at risk of developing metabolic syndrome as prompt treatment and intervention may potentially decrease the risk of developing certain ocular diseases.

  11. Thiazolidinediones and Parkinson Disease: A Cohort Study.

    PubMed

    Connolly, John G; Bykov, Katsiaryna; Gagne, Joshua J

    2015-12-01

    Thiazolidinediones, a class of medications indicated for the treatment of type 2 diabetes mellitus, reduce inflammation and have been shown to provide a therapeutic benefit in animal models of Parkinson disease. We examined the association between treatment with thiazolidinediones and the onset of Parkinson disease in older individuals. We performed a cohort study of 29,397 Medicare patients enrolled in state pharmaceutical benefits programs who initiated treatment with thiazolidinediones or sulfonylureas during the years 1997 through 2005 and had no prior diagnosis of Parkinson disease. New users of thiazolidinediones were propensity score matched to new users of sulfonylureas and followed to determine whether they were diagnosed with Parkinson disease. We used Cox proportional hazards models to compare time to diagnosis of Parkinson disease in the propensity score-matched populations. To assess the association with duration of use, we performed several analyses that required longer continuous use of medications. In the primary analysis, thiazolidinedione users had a hazard ratio for a diagnosis of Parkinson disease of 1.09 (95% confidence interval: 0.71, 1.66) when compared with sulfonylurea users. Increasing the duration-of-use requirements to 10 months did not substantially change the association; the hazard ratios ranged from 1.00 (95% confidence interval: 0.49, 2.05) to 1.17 (95% confidence interval: 0.60, 2.25). Thiazolidinedione use was not associated with a longer time to diagnosis of Parkinson disease than was sulfonylurea use, regardless of duration of exposure.

  12. Metabolic disease in HIV infection.

    PubMed

    Lake, Jordan E; Currier, Judith S

    2013-11-01

    The treatment of metabolic disease is becoming an increasingly important component of the long-term management of patients with well controlled HIV on antiretroviral therapy (ART). Metabolic diseases probably develop at the intersection of traditional risk factors (such as obesity, tobacco use, and genetic predisposition) and HIV-specific and ART-specific contributors (including chronic inflammation and immune activation). This Review discusses present knowledge on adipose tissue dysfunction, insulin-glucose homoeostasis, lipid disturbances, and cardiovascular disease risk in people with HIV on ART. Although new antiretroviral drugs are believed to induce fewer short-term metabolic perturbations than do older drugs, the long-term effects of these drugs are not fully understood. Additionally, patients remain at increased risk of cardiovascular disease and other metabolic comorbidities. Research and treatment should focus on selection of ART that is both virologically effective and has minimum metabolic effects, minimisation of traditional risk factors for metabolic disease, and development of novel therapies to treat metabolic disease in patients with HIV, including use of anti-inflammatory and immunomodulatory drugs.

  13. Lysophosphatidylinositol Signalling and Metabolic Diseases.

    PubMed

    Arifin, Syamsul A; Falasca, Marco

    2016-01-01

    Metabolism is a chemical process used by cells to transform food-derived nutrients, such as proteins, carbohydrates and fats, into chemical and thermal energy. Whenever an alteration of this process occurs, the chemical balance within the cells is impaired and this can affect their growth and response to the environment, leading to the development of a metabolic disease. Metabolic syndrome, a cluster of several metabolic risk factors such as abdominal obesity, insulin resistance, high cholesterol and high blood pressure, and atherogenic dyslipidaemia, is increasingly common in modern society. Metabolic syndrome, as well as other diseases, such as diabetes, obesity, hyperlipidaemia and hypertension, are associated with abnormal lipid metabolism. Cellular lipids are the major component of cell membranes; they represent also a valuable source of energy and therefore play a crucial role for both cellular and physiological energy homeostasis. In this review, we will focus on the physiological and pathophysiological roles of the lysophospholipid mediator lysophosphatidylinositol (LPI) and its receptor G-protein coupled receptor 55 (GPR55) in metabolic diseases. LPI is a bioactive lipid generated by phospholipase A (PLA) family of lipases which is believed to play an important role in several diseases. Indeed LPI can affect various functions such as cell growth, differentiation and motility in a number of cell-types. Recently published data suggest that LPI plays an important role in different physiological and pathological contexts, including a role in metabolism and glucose homeostasis. PMID:26784247

  14. Lysophosphatidylinositol Signalling and Metabolic Diseases

    PubMed Central

    Arifin, Syamsul A.; Falasca, Marco

    2016-01-01

    Metabolism is a chemical process used by cells to transform food-derived nutrients, such as proteins, carbohydrates and fats, into chemical and thermal energy. Whenever an alteration of this process occurs, the chemical balance within the cells is impaired and this can affect their growth and response to the environment, leading to the development of a metabolic disease. Metabolic syndrome, a cluster of several metabolic risk factors such as abdominal obesity, insulin resistance, high cholesterol and high blood pressure, and atherogenic dyslipidaemia, is increasingly common in modern society. Metabolic syndrome, as well as other diseases, such as diabetes, obesity, hyperlipidaemia and hypertension, are associated with abnormal lipid metabolism. Cellular lipids are the major component of cell membranes; they represent also a valuable source of energy and therefore play a crucial role for both cellular and physiological energy homeostasis. In this review, we will focus on the physiological and pathophysiological roles of the lysophospholipid mediator lysophosphatidylinositol (LPI) and its receptor G-protein coupled receptor 55 (GPR55) in metabolic diseases. LPI is a bioactive lipid generated by phospholipase A (PLA) family of lipases which is believed to play an important role in several diseases. Indeed LPI can affect various functions such as cell growth, differentiation and motility in a number of cell-types. Recently published data suggest that LPI plays an important role in different physiological and pathological contexts, including a role in metabolism and glucose homeostasis. PMID:26784247

  15. Is Cancer a Metabolic Disease?

    PubMed Central

    Coller, Hilary A.

    2015-01-01

    Although cancer has historically been viewed as a disorder of proliferation, recent evidence has suggested that it should also be considered a metabolic disease. Growing tumors rewire their metabolic programs to meet and even exceed the bioenergetic and biosynthetic demands of continuous cell growth. The metabolic profile observed in cancer cells often includes increased consumption of glucose and glutamine, increased glycolysis, changes in the use of metabolic enzyme isoforms, and increased secretion of lactate. Oncogenes and tumor suppressors have been discovered to have roles in cancer-associated changes in metabolism as well. The metabolic profile of tumor cells has been suggested to reflect the rapid proliferative rate. Cancer-associated metabolic changes may also reveal the importance of protection against reactive oxygen species or a role for secreted lactate in the tumor microenvironment. This article reviews recent research in the field of cancer metabolism, raising the following questions: Why do cancer cells shift their metabolism in this way? Are the changes in metabolism in cancer cells a consequence of the changes in proliferation or a driver of cancer progression? Can cancer metabolism be targeted to benefit patients? PMID:24139946

  16. Observations of a large Dent disease cohort.

    PubMed

    Blanchard, Anne; Curis, Emmanuel; Guyon-Roger, Tiphaine; Kahila, Diana; Treard, Cyrielle; Baudouin, Véronique; Bérard, Etienne; Champion, Gérard; Cochat, Pierre; Dubourg, Julie; de la Faille, Renaud; Devuyst, Olivier; Deschenes, Georges; Fischbach, Michel; Harambat, Jérôme; Houillier, Pascal; Karras, Alexandre; Knebelmann, Bertrand; Lavocat, Marie-Pierre; Loirat, Chantal; Merieau, Elodie; Niaudet, Patrick; Nobili, François; Novo, Robert; Salomon, Rémi; Ulinski, Tim; Jeunemaître, Xavier; Vargas-Poussou, Rosa

    2016-08-01

    Dent disease classically combines low-molecular-weight proteinuria, hypercalciuria with nephrocalcinosis, and renal failure. Nephrotic range proteinuria, normal calciuria, and hypokalemia have been rarely reported. It is unknown whether the changes in phenotype observed over time are explained by a decrease in glomerular filtration rate (GFR) or whether there is any phenotype-genotype relationship. To answer this we retrospectively analyzed data from 109 male patients with CLCN5 mutations (Dent-1) and 9 patients with mutation of the OCRL gene (Dent-2). In Dent-1 disease, the estimated GFR decreased with age, by 1.0 to 1.6 ml/min per 1.73 m(2)/yr in the absence and presence of nephrocalcinosis, respectively, with no significant difference. Median values of low-molecular-weight proteinuria were in the nephrotic range and remained at the same level even in late renal disease. End-stage renal disease occurred in 12 patients, at a median age of 40 years. Hypercalciuria decreased with glomerular filtration and was absent in 40% of the patients under 30 and 85% of those over the age of 30. Hypophosphatemia did not resolve with age and calcitriol concentrations were in the upper normal range. Kalemia decreased with age, with half of the patients over the age of 18 presenting with hypokalemia. Thus, no phenotype/genotype correlation was observed in this cohort of patients with Dent disease.

  17. Transgenerational inheritance of metabolic disease.

    PubMed

    Stegemann, Rachel; Buchner, David A

    2015-07-01

    Metabolic disease encompasses several disorders including obesity, type 2 diabetes, and dyslipidemia. Recently, the incidence of metabolic disease has drastically increased, driven primarily by a worldwide obesity epidemic. Transgenerational inheritance remains controversial, but has been proposed to contribute to human metabolic disease risk based on a growing number of proof-of-principle studies in model organisms ranging from Caenorhabditis elegans to Mus musculus to Sus scrofa. Collectively, these studies demonstrate that heritable risk is epigenetically transmitted from parent to offspring over multiple generations in the absence of a continued exposure to the triggering stimuli. A diverse assortment of initial triggers can induce transgenerational inheritance including high-fat or high-sugar diets, low-protein diets, various toxins, and ancestral genetic variants. Although the mechanistic basis underlying the transgenerational inheritance of disease risk remains largely unknown, putative molecules mediating transmission include small RNAs, histone modifications, and DNA methylation. Due to the considerable impact of metabolic disease on human health, it is critical to better understand the role of transgenerational inheritance of metabolic disease risk to open new avenues for therapeutic intervention and improve upon the current methods for clinical diagnoses and treatment.

  18. Transgenerational Inheritance of Metabolic Disease

    PubMed Central

    Stegemann, Rachel; Buchner, David A.

    2015-01-01

    Metabolic disease encompasses several disorders including obesity, type 2 diabetes, and dyslipidemia. Recently, the incidence of metabolic disease has drastically increased, driven primarily by a worldwide obesity epidemic. Transgenerational inheritance remains controversial, but has been proposed to contribute to human metabolic disease risk based on a growing number of proof-of-principle studies in model organisms ranging from C. elegans to M. musculus to S. scrofa. Collectively, these studies demonstrate that heritable risk is epigenetically transmitted from parent to offspring over multiple generations in the absence of a continued exposure to the triggering stimuli. A diverse assortment of initial triggers can induce transgenerational inheritance including high-fat or high-sugar diets, low-protein diets, various toxins, and ancestral genetic variants. Although the mechanistic basis underlying the transgenerational inheritance of disease risk remains largely unknown, putative molecules mediating transmission include small RNAs, histone modifications, and DNA methylation. Due to the considerable impact of metabolic disease on human health, it is critical to better understand the role of transgenerational inheritance of metabolic disease risk to open new avenues for therapeutic intervention and improve upon the current methods for clinical diagnoses and treatment. PMID:25937492

  19. Cellular metabolism and disease: what do metabolic outliers teach us?

    PubMed Central

    DeBerardinis, Ralph J.; Thompson, Craig B.

    2012-01-01

    An understanding of metabolic pathways based solely on biochemistry textbooks would underestimate the pervasive role of metabolism in essentially every aspect of biology. It is evident from recent work that many human diseases involve abnormal metabolic states – often genetically programmed – that perturb normal physiology and lead to severe tissue dysfunction. Understanding these metabolic outliers is now a crucial frontier in disease-oriented research. This review discusses the broad impact of metabolism in cellular function, how modern concepts of metabolism can inform our understanding of common diseases like cancer, and considers the prospects of developing new metabolic approaches to disease treatment. PMID:22424225

  20. Cancer as a metabolic disease

    PubMed Central

    2010-01-01

    Emerging evidence indicates that impaired cellular energy metabolism is the defining characteristic of nearly all cancers regardless of cellular or tissue origin. In contrast to normal cells, which derive most of their usable energy from oxidative phosphorylation, most cancer cells become heavily dependent on substrate level phosphorylation to meet energy demands. Evidence is reviewed supporting a general hypothesis that genomic instability and essentially all hallmarks of cancer, including aerobic glycolysis (Warburg effect), can be linked to impaired mitochondrial function and energy metabolism. A view of cancer as primarily a metabolic disease will impact approaches to cancer management and prevention. PMID:20181022

  1. Is osteoarthritis a metabolic disease?

    PubMed

    Sellam, Jérémie; Berenbaum, Francis

    2013-12-01

    Obesity, together with aging and injury, is among the main risk factors for osteoarthritis. Obesity-related osteoarthritis can affect not only the weight-bearing joints, but also the hands, suggesting a role for circulating mediators released by the adipose tissue and known as adipokines. Thus, osteoarthritis may have a systemic metabolic component. Evidence from both epidemiological and biological studies support the concept of metabolic osteoarthritis, defined as a broad clinical phenotype that includes obesity-related osteoarthritis. Thus, osteoarthritis can be related to metabolic syndrome or to an accumulation of metabolic abnormalities. In addition, studies have demonstrated associations linking osteoarthritis to several components of the metabolic syndrome, such as hypertension and type 2 diabetes, independently from obesity or any of the other known risk factors for osteoarthritis. Both in vitro and in vitro findings indicate a deleterious effect of lipid and glucose abnormalities on cartilage homeostasis. Chronic low-grade inflammation is a feature shared by osteoarthritis and metabolic disorders and may contribute to the genesis of both. Thus, osteoarthritis is emerging as a disease that has a variety of phenotypes including a metabolic phenotype, in addition to the age-related and injury-related phenotypes.

  2. Iron Metabolism in Hodgkin's Disease

    PubMed Central

    Beamish, M. R.; Jones, P. Ashley; Trevett, D.; Evans, I. Howell; Jacobs, A.

    1972-01-01

    An evaluation of iron metabolism has been carried out in 23 untreated patients with Hodgkin's disease and 6 patients with other lymphomata. The reduction in red cell life span is related to the stage of the disease. There is an almost universal impairment of iron release from the reticuloendothelial system with a consequent sideropenia and failure of iron delivery to the bone marrow for erythropoiesis. This defect is found in all stages of the disease and is not related to systemic symptoms. PMID:4567182

  3. [Metabolic syndrome, a mitochondrial disease?].

    PubMed

    Gastaldi, G; Giacobino, J P; Ruiz, J

    2008-06-01

    The metabolic syndrome is a cluster of metabolic risk factors including: atherogenic dyslipidemia, elevated blood pressure, high plasma glucose and a prothrombotic and proinflammatory state, frequently associated to overweight. Impaired cell metabolism has been suggested as a relevant pathophysiological process. Indeed, the accumulation of intracellular fatty acylCoA and diacylglycerol, which then activate critical signal transduction pathways that ultimatly lead to suppression of insulin signalisation. Therefore a defect in mitochondrial function may be responsible for insulin resistance. Moreover, mitochondrial dysfunction has been found to take place in organs such as skeletal muscle, liver, pancreas and smoth vascular cells suggesting that mitochondrial defect could play a critical role in the occurence of cardiovascular diseases.

  4. Sirtuin and metabolic kidney disease.

    PubMed

    Wakino, Shu; Hasegawa, Kazuhiro; Itoh, Hiroshi

    2015-10-01

    Sirtuin is a nicotinamide adenine dinucleotide-dependent deacetylase. One of its isoforms, Sirt1, is a key molecule in glucose, lipid, and energy metabolism. The renal protective effects of Sirt1 are found in various models of renal disorders with metabolic impairment, such as diabetic nephropathy. Protective effects include the maintenance of glomerular barrier function, anti-fibrosis effects, anti-oxidative stress effects, and regulation of mitochondria function and energy metabolism. Various target molecules subject to direct deacetylation or epigenetic gene regulation have been identified as effectors of the renal protective function of sirtuin. Recently, it was demonstrated that Sirt1 expression decreases in proximal tubules before albuminuria in a mouse model of diabetic nephropathy, and that albuminuria is suppressed in proximal tubule-specific mice overexpressing Sirt1. These findings suggest that decreased Sirt1 expression in proximal tubular cells causes abnormal nicotine metabolism and reduces the supply of nicotinamide mononucleotide from renal tubules to glomeruli. This further decreases expression of Sirt1 in glomerular podocytes and increases expression of a tight junction protein, claudin-1, which results in albuminuria. Activators of the sirtuin family of proteins, including resveratrol, may be important in the development of new therapeutic strategies for treating metabolic kidney diseases, including diabetic nephropathy.

  5. Sirtuin and metabolic kidney disease

    PubMed Central

    Wakino, Shu; Hasegawa, Kazuhiro; Itoh, Hiroshi

    2015-01-01

    Sirtuin is a nicotinamide adenine dinucleotide–dependent deacetylase. One of its isoforms, Sirt1, is a key molecule in glucose, lipid, and energy metabolism. The renal protective effects of Sirt1 are found in various models of renal disorders with metabolic impairment, such as diabetic nephropathy. Protective effects include the maintenance of glomerular barrier function, anti–fibrosis effects, anti–oxidative stress effects, and regulation of mitochondria function and energy metabolism. Various target molecules subject to direct deacetylation or epigenetic gene regulation have been identified as effectors of the renal protective function of sirtuin. Recently, it was demonstrated that Sirt1 expression decreases in proximal tubules before albuminuria in a mouse model of diabetic nephropathy, and that albuminuria is suppressed in proximal tubule–specific mice overexpressing Sirt1. These findings suggest that decreased Sirt1 expression in proximal tubular cells causes abnormal nicotine metabolism and reduces the supply of nicotinamide mononucleotide from renal tubules to glomeruli. This further decreases expression of Sirt1 in glomerular podocytes and increases expression of a tight junction protein, claudin-1, which results in albuminuria. Activators of the sirtuin family of proteins, including resveratrol, may be important in the development of new therapeutic strategies for treating metabolic kidney diseases, including diabetic nephropathy. PMID:26083654

  6. Niacin metabolism and Parkinson's disease.

    PubMed

    Fukushima, Tetsuhito

    2005-01-01

    Epidemiological surveys suggest an important role for niacin in the causes of Parkinson's disease, in that niacin deficiency, the nutritional condition that causes pellagra, appears to protect against Parkinson's disease. Absorbed niacin is used in the synthesis of nicotinamide adenine dinucleotide (NAD) in the body, and in the metabolic process NAD releases nicotinamide by poly(ADP-ribosyl)ation, the activation of which has been reported to mediate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease. Recently nicotinamide N-methyltransferase (EC2.1.1.1) activity has been discovered in the human brain, and the released nicotinamide may be methylated to 1-methylnicotinamide (MNA), via this enzyme, in the brain. A deficiency in mitochondrial NADH: ubiquinone oxidoreductase (complex 1) activity is believed to be a critical factor in the development of Parkinson's disease. MNA has been found to destroy several subunits of cerebral complex 1, leading to the suggestion that MNA is concerned in the pathogenesis of Parkinson's disease. Based on these findings, it is hypothesized that niacin is a causal substance in the development of Parkinson's disease through the following processes: NAD produced from niacin releases nicotinamide via poly(ADP-ribosyl)ation, activated by the hydroxyl radical. Released excess nicotinamide is methylated to MNA in the cytoplasm, and superoxides formed by MNA via complex I destroy complex 1 subunits directly, or indirectly via mitochondrial DNA damage. Hereditary or environmental factors may cause acceleration of this cycle, resulting in neuronal death.

  7. Inflammatory Bowel Disease Cohort Studies in Korea: Present and Future

    PubMed Central

    Lee, Jung Won; Cheon, Jae Hee; Kim, You Sun; Kim, Joo Sung; Han, Dong Soo

    2015-01-01

    Inflammatory bowel disease (IBD) is defined as a chronic and relapsing inflammatory disorder of the intestine. Intestinal inflammation in IBD has been proposed to be attributable to the interplay between microbial, genetic, environmental, and immunological factors. The incidence and prevalence rates of IBD are rapidly increasing apparently in other parts of the world, with dramatic increases especially in East Asia. Generally, cohort studies are useful for estimating the incidence, prevalence, natural course, prognosis, and risk factors of diseases. In particular, cohort studies performed in Western countries have well described the prevalence, risk factors, and natural course of IBD and investigated its genetic pathophysiology. However, the outcomes of IBD cohort studies performed in Korea are not as persuasive as those of Western studies because of the relatively low prevalence of IBD and short follow-up periods of the cohorts in Korea. Despite this critical limitation, members of the Korean Association for the Study of Intestinal Diseases have demonstrated outstanding results. Some unique features of IBD patients in Korea are well demonstrated, such as thiopurine-induced leukopenia or risks of opportunistic tuberculosis infection in patients receiving tumor necrosis factor-α inhibitors. In this review, the present authors summarized the key points of the results of the cohort studies performed in Korea and explored future perspectives. PMID:26130995

  8. Opportunities for genetic improvement of metabolic diseases

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Metabolic disorders are disturbances to one or more of the metabolic processes in dairy cattle. Dysfunction of any of these processes is associated with the manifestation of metabolic diseases or disorders. In this review, data recording, incidences, genetic parameters, predictors and status of gene...

  9. Ketone body metabolism and cardiovascular disease

    PubMed Central

    Cotter, David G.; Schugar, Rebecca C.

    2013-01-01

    Ketone bodies are metabolized through evolutionarily conserved pathways that support bioenergetic homeostasis, particularly in brain, heart, and skeletal muscle when carbohydrates are in short supply. The metabolism of ketone bodies interfaces with the tricarboxylic acid cycle, β-oxidation of fatty acids, de novo lipogenesis, sterol biosynthesis, glucose metabolism, the mitochondrial electron transport chain, hormonal signaling, intracellular signal transduction pathways, and the microbiome. Here we review the mechanisms through which ketone bodies are metabolized and how their signals are transmitted. We focus on the roles this metabolic pathway may play in cardiovascular disease states, the bioenergetic benefits of myocardial ketone body oxidation, and prospective interactions among ketone body metabolism, obesity, metabolic syndrome, and atherosclerosis. Ketone body metabolism is noninvasively quantifiable in humans and is responsive to nutritional interventions. Therefore, further investigation of this pathway in disease models and in humans may ultimately yield tailored diagnostic strategies and therapies for specific pathological states. PMID:23396451

  10. Metabolic disease network and its implication for disease comorbidity

    NASA Astrophysics Data System (ADS)

    Lee, Deok-Sun; Oltvai, Zoltan; Christakis, Nicholas; Barabasi, Albert-Laszlo

    2008-03-01

    Given that most diseases are the result of the breakdown of some cellular processes, a key aim of modern medicine is to establish the relationship between disease phenotypes and the various disruptions in the underlying cellular networks. Here we show that our current understanding of the structure of the human metabolic network can provide insight into potential relationships among often distinct disease phenotypes. Using the known enzyme-disease associations, we construct a human metabolic disease network in which nodes are diseases and two diseases are linked if the enzymes associated with them catalyze adjacent metabolic reactions. We find that the more connected a disease is, the higher is its prevalence and the chance that it is associated with a high mortality. The results indicate that the cellular network-level relationships between metabolic pathways and the associated disease provide insights into disease comorbidity, with potential important consequences on disease diagnosis and prevention.

  11. Prenatal diagnosis of inherited metabolic diseases.

    PubMed Central

    Diukman, R; Goldberg, J D

    1993-01-01

    Advances in the prenatal diagnosis of inherited metabolic disease have provided new reproductive options to at-risk couples. These advances have occurred in both sampling techniques and methods of analysis. In this review we present an overview of the currently available prenatal diagnostic approaches for the diagnosis of metabolic disease in a fetus. Images PMID:8236980

  12. Epilepsy in adults with mitochondrial disease: A cohort study

    PubMed Central

    Devine, Helen E.; Gorman, Grainne S.; Schaefer, Andrew M.; Horvath, Rita; Ng, Yi; Nesbitt, Victoria; Lax, Nichola Z.; McFarland, Robert; Cunningham, Mark O.; Taylor, Robert W.; Turnbull, Douglass M.

    2015-01-01

    Objective The aim of this work was to determine the prevalence and progression of epilepsy in adult patients with mitochondrial disease. Methods We prospectively recruited a cohort of 182 consecutive adult patients attending a specialized mitochondrial disease clinic in Newcastle upon Tyne between January 1, 2005 and January 1, 2008. We then followed this cohort over a 7‐year period, recording primary outcome measures of occurrence of first seizure, status epilepticus, stroke‐like episode, and death. Results Overall prevalence of epilepsy in the cohort was 23.1%. Mean age of epilepsy onset was 29.4 years. Prevalence varied widely between genotypes, with several genotypes having no cases of epilepsy, a prevalence of 34.9% in the most common genotype (m.3243A>G mutation), and 92.3% in the m.8344A>G mutation. Among the cohort as a whole, focal seizures, with or without progression to bilateral convulsive seizures, was the most common seizure type. Conversely, all of the patients with the m.8344A>G mutation and epilepsy experienced myoclonic seizures. Patients with the m.3243A>G mutation remain at high risk of developing stroke‐like episodes (1.16% per year). However, although the standardized mortality ratio for the entire cohort was high (2.86), this ratio did not differ significantly between patients with epilepsy (2.96) and those without (2.83). Interpretation Epilepsy is a common manifestation of mitochondrial disease. It develops early in the disease and, in the case of the m.3243A>G mutation, often presents in the context of a stroke‐like episode or status epilepticus. However, epilepsy does not itself appear to contribute to the increased mortality in mitochondrial disease. Ann Neurol 2015;78:949–957 PMID:26381753

  13. Achieving Synergy: Linking an Internet-Based Inflammatory Bowel Disease Cohort to a Community-Based Inception Cohort and Multicentered Cohort in Inflammatory Bowel Disease

    PubMed Central

    Aldridge, Molly; Cook, Suzanne Follan; Bright, Renee; Mallette, Meaghan; Moniz, Heather; Shah, Samir A; LeLeiko, Neal S; Shapiro, Jason; Sands, Bruce E; Chen, Wenli; Jaeger, Elizabeth; Galanko, Joseph; Long, Millie D; Martin, Christopher F; Sandler, Robert S; Kappelman, Michael D

    2016-01-01

    Background Traditional cohort studies are important contributors to our understanding of inflammatory bowel diseases, but they are labor intensive and often do not focus on patient-reported outcomes. Internet-based studies provide new opportunities to study patient-reported outcomes and can be efficiently implemented and scaled. If a traditional cohort study was linked to an Internet-based study, both studies could benefit from added synergy. Existing cohort studies provide an opportunity to develop and test processes for cohort linkage. The Crohn’s and Colitis Foundation of America’s (CCFA) Partners study is an Internet-based cohort of more than 14,000 participants. The Ocean State Crohn’s and Colitis Area Registry (OSCCAR) is an inception cohort. The Sinai-Helmsley Alliance for Research Excellence (SHARE) is a multicentered cohort of inflammatory bowel disease patients. Both the later cohorts include medical record abstraction, patient surveys, and biospecimen collection. Objective Given the complementary nature of these existing cohorts, we sought to corecruit and link data. Methods Eligible OSCCAR and SHARE participants were invited to join the CCFA Partners study and provide consent for data sharing between the 2 cohorts. After informed consent, participants were directed to the CCFA Partners website to complete enrollment and a baseline Web-based survey. Participants were linked across the 2 cohorts by the matching of an email address. We compared demographic and clinical characteristics between OSCCAR and SHARE participants who did and did not enroll in CCFA Partners and the data linkage. Results Of 408 participants in the OSCCAR cohort, 320 were eligible for participation in the CCFA Partners cohort. Of these participants, 243 consented to participation; however, only 44 enrolled in CCFA Partners and completed the linkage. OSCCAR participants who enrolled in CCFA Partners were better educated (17% with doctoral degrees) than those who did not (3% with

  14. Bariatric surgery: the indications in metabolic disease.

    PubMed

    Neff, K J; le Roux, C W

    2014-01-01

    As well as the pronounced effect on body mass index (BMI), bariatric surgery is increasingly recognized as being associated with improvements in morbidity and mortality in a range of conditions, from airways disease to cancer. In metabolic disease, the impact of bariatric surgery is particularly obvious with marked improvements in glycemic control in patients with type 2 diabetes mellitus, to the point of effecting diabetes remission in some. Hypertension and dyslipidemia, key components of the metabolic syndrome, also respond to bariatric surgery. Despite the increasing evidence of benefit in metabolic disease, the major national guidelines for selecting candidates for bariatric surgery retain their emphasis on body weight. In these guidelines, a BMI ≥35 kg/m(2) is needed to indicate surgery, even in those with profound metabolic disturbance. The recent International Diabetes Federation guidelines have identified the need to reorientate our focus from BMI to metabolic disease. In this review, we examine the developing indications for the use of bariatric surgery in metabolic disease. We will focus on type 2 diabetes mellitus and the metabolic syndrome. Within this, we will outline the data for using bariatric surgery as metabolic surgery, including those with a BMI <35 kg/m(2). PMID:23838610

  15. Circadian rhythms in liver metabolism and disease.

    PubMed

    Ferrell, Jessica M; Chiang, John Y L

    2015-03-01

    Mounting research evidence demonstrates a significant negative impact of circadian disruption on human health. Shift work, chronic jet lag and sleep disturbances are associated with increased incidence of metabolic syndrome, and consequently result in obesity, type 2 diabetes and dyslipidemia. Here, these associations are reviewed with respect to liver metabolism and disease.

  16. Circadian rhythms in liver metabolism and disease.

    PubMed

    Ferrell, Jessica M; Chiang, John Y L

    2015-03-01

    Mounting research evidence demonstrates a significant negative impact of circadian disruption on human health. Shift work, chronic jet lag and sleep disturbances are associated with increased incidence of metabolic syndrome, and consequently result in obesity, type 2 diabetes and dyslipidemia. Here, these associations are reviewed with respect to liver metabolism and disease. PMID:26579436

  17. Metabolic Disturbances in Diseases with Neurological Involvement

    PubMed Central

    Duarte, João M. N.; Schuck, Patrícia F.; Wenk, Gary L.; Ferreira, Gustavo C.

    2014-01-01

    Degeneration of specific neuronal populations and progressive nervous system dysfunction characterize neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. These findings are also reported in inherited diseases such as phenylketonuria and glutaric aciduria type I. The involvement of mitochondrial dysfunction in these diseases was reported, elicited by genetic alterations, exogenous toxins or buildup of toxic metabolites. In this review we shall discuss some metabolic alterations related to the pathophysiology of diseases with neurological involvement and aging process. These findings may help identifying early disease biomarkers and lead to more effective therapies to improve the quality of life of the patients affected by these devastating illnesses. PMID:25110608

  18. Metabolic Syndrome Prevalence and Associations in a Bariatric Surgery Cohort from the Longitudinal Assessment of Bariatric Surgery-2 Study

    PubMed Central

    Selzer, Faith; Smith, Mark D.; Berk, Paul D.; Courcoulas, Anita P.; Inabnet, William B.; King, Wendy C.; Pender, John; Pomp, Alfons; Raum, William J.; Schrope, Beth; Steffen, Kristine J.; Wolfe, Bruce M.; Patterson, Emma J.

    2014-01-01

    Abstract Background: Metabolic syndrome is associated with higher risk for cardiovascular disease, sleep apnea, and nonalcoholic steatohepatitis, all common conditions in patients referred for bariatric surgery, and it may predict early postoperative complications. The objective of this study was to determine the prevalence of metabolic syndrome, defined using updated National Cholesterol Education Program criteria, in adults undergoing bariatric surgery and compare the prevalence of baseline co-morbid conditions and select operative and 30-day postoperative outcomes by metabolic syndrome status. Methods: Complete metabolic syndrome data were available for 2275 of 2458 participants enrolled in the Longitudinal Assessment of Bariatric Surgery-2 (LABS-2), an observational cohort study designed to evaluate long-term safety and efficacy of bariatric surgery in obese adults. Results: The prevalence of metabolic syndrome was 79.9%. Compared to those without metabolic syndrome, those with metabolic syndrome were significantly more likely to be men, to have a higher prevalence of diabetes and prior cardiac events, to have enlarged livers and higher median levels of liver enzymes, a history of sleep apnea, and a longer length of stay after surgery following laparoscopic Roux-en-Y gastric bypass (RYGB) and gastric sleeves but not open RYGB or laparoscopic adjustable gastric banding. Metabolic syndrome status was not significantly related to duration of surgery or rates of composite end points of intraoperative events and 30-day major adverse surgical outcomes. Conclusions: Nearly four in five participants undergoing bariatric surgery presented with metabolic syndrome. Establishing a diagnosis of metabolic syndrome in bariatric surgery patients may identify a high-risk patient profile, but does not in itself confer a higher risk for short-term adverse postsurgery outcomes. PMID:24380645

  19. Cohort profile: the Finnish Medication and Alzheimer's disease (MEDALZ) study

    PubMed Central

    Tolppanen, Anna-Maija; Taipale, Heidi; Koponen, Marjaana; Lavikainen, Piia; Tanskanen, Antti; Tiihonen, Jari; Hartikainen, Sirpa

    2016-01-01

    Purpose The aim of the Medicine use and Alzheimer's disease (MEDALZ) study is to investigate the changes in medication and healthcare service use among persons with Alzheimer's disease (AD) and to evaluate the safety and effectiveness of medications in this group. This is important, because the number of persons with AD is rapidly growing and even though they are a particularly vulnerable patient group, the number of representative, large-scale studies with adequate follow-up time is limited. Participants MEDALZ contains all residents of Finland who received a clinically verified diagnosis of AD between 2005 and 2011 and were community-dwelling at the time of diagnosis (N=70 719). The diagnosis is based on the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCS-ADRDA) and Diagnostic and Statistical Manual Fourth Edition (DSM-IV) criteria for Alzheimer's disease. The cohort contains socioeconomic data (education, occupational status and taxable income, 1972–2012) and causes of death (2005–2012), data from the prescription register (1995–2012), the special reimbursement register (1972–2012) and the hospital discharge register (1972–2012). Future updates are planned. The average age was 80.1 years (range 34.5–104.6 years). The majority of cohort (65.2%) was women. Currently, the average length of follow-up after AD diagnosis is 3.1 years and altogether 26 045 (36.8%) persons have died during the follow-up. Findings Altogether 53% of the cohort had used psychotropic drugs within 1 year after AD diagnoses. The initiation rate of for example, benzodiazepines and related drugs and antidepressants began to increase already before AD diagnosis. Future plans We are currently assessing if these, and other commonly used medications are related to adverse events such as death, hip fractures, head injuries and pneumonia. PMID:27412109

  20. Cancer as a mitochondrial metabolic disease

    PubMed Central

    Seyfried, Thomas N.

    2015-01-01

    Cancer is widely considered a genetic disease involving nuclear mutations in oncogenes and tumor suppressor genes. This view persists despite the numerous inconsistencies associated with the somatic mutation theory. In contrast to the somatic mutation theory, emerging evidence suggests that cancer is a mitochondrial metabolic disease, according to the original theory of Otto Warburg. The findings are reviewed from nuclear cytoplasm transfer experiments that relate to the origin of cancer. The evidence from these experiments is difficult to reconcile with the somatic mutation theory, but is consistent with the notion that cancer is primarily a mitochondrial metabolic disease. PMID:26217661

  1. [Metabolic correction: a biochemical option against diseases].

    PubMed

    Miranda-Massari, Jorge R; González, Michael J; Rodriguez-Gomez, José R; Duconge, Jorge; Allende-Vigo, Myriam Z; Jiménez Ramirez, Francisco J; Cintrón, Kenneth; Ricart, Carlos; Zaragoza-Urdaz, Rafael; Berdiel, Miguel Jabbar; Vázquez, Alex

    2015-01-01

    Human development and its physiology depends on a number of complex biochemical body processes, many of which are interactive and codependent. The speed and the degree in which many physiological reactions are completed depend on enzyme activity, which in turn depends on the bioavailability of co-factors and micronutrients such as vitamins and minerals. To achieve a healthy physiological state, organism need that biochemical reactions occur in a controlled and specific way at a particular speed and level or grade fully completed. To achieve this, is required an optimal metabolic balance. Factors such as, a particular genetic composition, inadequate dietary consumption patterns, traumas, diseases, toxins and environmental stress all of these factors rising demands for nutrients in order to obtain optimal metabolic balance. Metabolic correction is a biochemical and physiological concept that explains how improvements in cellular biochemistry of an organism can help the body achieve metabolic and physiological optimization. We summarize the contribution of several pioneers in understanding the role of micronutrients in health management. The concept of metabolic correction is becoming a significant term due to the presence of genetic variants that affect the speed of reactions of enzymes, causing metabolic alterations that enhance or promote the state/development of multiple diseases. Decline in the nutritional value of the food we eat, the increase in demand for certain nutrients caused by normal development, diseases and medications induce, usually, nutrients consumption. These nutritional deficiencies and insufficiencies are causing massive economic costs due to increased morbidity and mortality in our society. In summary, metabolic correction improves the enzymatic function, which favors the physiological normal functions, thus, contributing to improving health and the welfare of the human being. The purpose of this paper is to describe and introduce the concept

  2. Chronic kidney disease and bone metabolism.

    PubMed

    Kazama, Junichiro James; Matsuo, Koji; Iwasaki, Yoshiko; Fukagawa, Masafumi

    2015-05-01

    Chronic kidney disease-related mineral and bone disease (CKD-MBD) is a syndrome defined as a systemic mineral metabolic disorder associated with CKD, and the term renal osteodystrophy indicates a pathomorphological concept of bone lesions associated with CKD-MBD. Cortical bone thinning, abnormalities in bone turnover and primary/secondary mineralization, elevated levels of circulating sclerostin, increased apoptosis in osteoblasts and osteocytes, disturbance of the coupling phenomenon, iatrogenic factors, accumulated micro-crackles, crystal/collagen disorientation, and chemical modification of collagen crosslinks are all possible candidates found in CKD that could promote osteopenia and/or bone fragility. Some of above factors are the consequences of abnormal systemic mineral metabolism but for others it seem unlikely. We have used the term uremic osteoporosis to describe the uremia-induced bone fragility which is not derived from abnormal systemic mineral metabolism. Interestingly, the disease aspect of uremic osteoporosis appears to be similar to that of senile osteoporosis. PMID:25653092

  3. Contribution of Macrophage Polarization to Metabolic Diseases.

    PubMed

    Komohara, Yoshihiro; Fujiwara, Yukio; Ohnishi, Koji; Shiraishi, Daisuke; Takeya, Motohiro

    2016-01-01

    Macrophage activation is one of the major immunological events in the pathogenesis of various diseases. Recent studies have disclosed that complicated mechanisms are involved in macrophage activation and polarization, and many published research articles have been based on the M1/M2 polarization concept. It is considered that M1- and M2-like macrophages are associated with T helper (Th)1-type and Th2-type immune responses, respectively, via several immune mediators. In this article, we summarize the correlations between macrophage polarization and metabolic disorders in both humans and mice and discuss the contribution of macrophage polarization to the pathogenic process of metabolic diseases.

  4. Metabolic bone disease in gut diseases.

    PubMed

    Lipkin, E W

    1998-06-01

    A wide spectrum of gastrointestinal illnesses impairs bone health and can result in bone pain, demineralization, and fracture. This article summarizes current knowledge of the skeletal pathology exhibited in patients with diseases of the liver, biliary tree, pancreas, and bowel. Mechanisms responsible for these syndromes and treatment options are discussed. This article enhances the practicing gastroenterologist's knowledge of the implications of gastrointestinal illness for bone. PMID:9650030

  5. Clinical presentation of metabolic liver disease.

    PubMed

    Odievre, M

    1991-01-01

    Some clinical clues should alert paediatricians to the possibility of metabolic liver diseases. They can be classified into three categories: (i) Manifestations due to hepatocellular necrosis, acute or subacute, which can reveal galactosaemia, hereditary fructose intolerance, tyrosinaemia type I, Wilson disease and alpha 1-antitrypsin deficiency. Symptoms and signs suggestive of Reye syndrome should lead to a study of fatty acid oxidation and urea cycle enzymes. All these manifestations may necessitate a rapid diagnosis and treatment when liver dysfunction is severe. (ii) Cholestatic jaundice can reveal alpha 1-antitrypsin deficiency, Byler's disease, cystic fibrosis, Niemann-Pick disease and some disorders of peroxisome biogenesis. (iii) Hepatomegaly can reveal disorders with liver damage but also storage diseases such as glycogen storage diseases, cholesteryl ester storage disease and, when associated with splenomegaly, lysosomal storage diseases. Appropriate investigations for recognizing all these entities are proposed.

  6. Neurodegenerative disorders and metabolic disease.

    PubMed

    Pierre, Germaine

    2013-08-01

    Most genetic causes of neurodegenerative disorders in childhood are due to neurometabolic disease. There are over 200 disorders, including aminoacidopathies, creatine disorders, mitochondrial cytopathies, peroxisomal disorders and lysosomal storage disorders. However, diagnosis can pose a challenge to the clinician when patients present with non-specific problems like epilepsy, developmental delay, autism, dystonia and ataxia. The variety of specialist tests involved can also be daunting. This review aims to give a practical approach to the investigation and diagnosis of neurometabolic disease from the neonatal period to late childhood while prioritising disorders where there are therapeutic options. In particular, patients who have a complex clinical picture of several neurological and non-neurological features should be investigated.

  7. Metabolomics reveals metabolic biomarkers of Crohn's disease

    SciTech Connect

    Jansson, J.K.; Willing, B.; Lucio, M.; Fekete, A.; Dicksved, J.; Halfvarson, J.; Tysk, C.; Schmitt-Kopplin, P.

    2009-06-01

    The causes and etiology of Crohn's disease (CD) are currently unknown although both host genetics and environmental factors play a role. Here we used non-targeted metabolic profiling to determine the contribution of metabolites produced by the gut microbiota towards disease status of the host. Ion Cyclotron Resonance Fourier Transform Mass Spectrometry (ICR-FT/MS) was used to discern the masses of thousands of metabolites in fecal samples collected from 17 identical twin pairs, including healthy individuals and those with CD. Pathways with differentiating metabolites included those involved in the metabolism and or synthesis of amino acids, fatty acids, bile acids and arachidonic acid. Several metabolites were positively or negatively correlated to the disease phenotype and to specific microbes previously characterized in the same samples. Our data reveal novel differentiating metabolites for CD that may provide diagnostic biomarkers and/or monitoring tools as well as insight into potential targets for disease therapy and prevention.

  8. Metabolic Syndrome and Periodontal Disease Progression in Men.

    PubMed

    Kaye, E K; Chen, N; Cabral, H J; Vokonas, P; Garcia, R I

    2016-07-01

    Metabolic syndrome, a cluster of 3 or more risk factors for cardiovascular disease, is associated with periodontal disease, but few studies have been prospective in design. This study's aim was to determine whether metabolic syndrome predicts tooth loss and worsening of periodontal disease in a cohort of 760 men in the Department of Veterans Affairs Dental Longitudinal Study and Normative Aging Study who were followed up to 33 y from 1981 to 2013. Systolic and diastolic blood pressures were measured with a standard mercury sphygmomanometer. Waist circumference was measured in units of 0.1 cm following a normal expiration. Fasting blood samples were measured in duplicate for glucose, triglyceride, and high-density lipoprotein. Calibrated periodontists served as dental examiners. Periodontal outcome events on each tooth were defined as progression to predefined threshold levels of probing pocket depth (≥5 mm), clinical attachment loss (≥5 mm), mobility (≥0.5 mm), and alveolar bone loss (≥40% of the distance from the cementoenamel junction to the root apex, on radiographs). Hazards ratios (95% confidence intervals) of tooth loss or a periodontitis event were estimated from tooth-level extended Cox proportional hazards regression models that accounted for clustering of teeth within individuals and used time-dependent status of metabolic syndrome. Covariates included age, education, smoking status, plaque level, and initial level of the appropriate periodontal disease measure. Metabolic syndrome as defined by the International Diabetes Federation increased the hazards of tooth loss (1.39; 1.08 to 1.79), pocket depth ≥5 mm (1.37; 1.14 to 1.65), clinical attachment loss ≥5 mm (1.19; 1.00 to 1.41), alveolar bone loss ≥40% (1.25; 1.00 to 1.56), and tooth mobility ≥0.5 mm (1.43; 1.07 to 1.89). The number of positive metabolic syndrome conditions was also associated with each of these outcomes. These findings suggest that the metabolic disturbances that

  9. Metabolic bone diseases in kidney transplant recipients.

    PubMed

    Zhang, Rubin; Chouhan, Kanwaljit K

    2012-10-01

    Metabolic bone disease after kidney transplantation has a complex pathophysiology and heterogeneous histology. Pre-existing renal osteodystrophy may not resolve completely, but continue or evolve into a different osteodystrophy. Rapid bone loss immediately after transplant can persist, at a lower rate, for years to come. These greatly increase the risk of bone fracture and vertebral collapse. Each patient may have multiple risk factors of bone loss, such as steroids usage, hypogonadism, persistent hyperparathyroidism (HPT), poor allograft function, metabolic acidosis, hypophosphatemia, vitamin D deficiency, aging, immobility and chronic disease. Clinical management requires a comprehensive approach to address the underlying and ongoing disease processes. Successful prevention of bone loss has been shown with vitamin D, bisphosphonates, calcitonin as well as treatment of hypogonadism and HPT. Novel approach to restore the normal bone remodeling and improve the bone quality may be needed in order to effectively decrease bone fracture rate in kidney transplant recipients. PMID:24175250

  10. [Serum sclerostin levels and metabolic bone diseases].

    PubMed

    Yamauchi, Mika; Sugimoto, Toshitsugu

    2013-06-01

    Serum sclerostin levels are being investigated in various metabolic bone diseases. Since serum sclerostin levels are decreased in primary hyperparathyroidism and elevated in hypoparathyroidism, parathyroid hormone (PTH) is thought to be a regulatory factor for sclerostin. Serum sclerostin levels exhibit a significant positive correlation with bone mineral density. On the other hand, a couple of studies on postmenopausal women have shown that high serum sclerostin levels are a risk factor for fracture. Although glucocorticoid induced osteoporosis and diabetes are both diseases that reduce bone formation, serum sclerostin levels have been reported to be decreased in the former and elevated in the latter, suggesting differences in the effects of sclerostin in the two diseases. Serum sclerostin levels are correlated with renal function, and increase with reduction in renal function. Serum sclerostin level may be a new index of bone assessment that differs from bone mineral density and bone metabolic markers.

  11. Obesity and Metabolic Disease After Childhood Cancer.

    PubMed

    Barnea, Dana; Raghunathan, Nirupa; Friedman, Danielle Novetsky; Tonorezos, Emily S

    2015-11-01

    As care for the childhood cancer patient has improved significantly, there is an increasing incidence of treatment-related late effects. Obesity and type 2 diabetes mellitus are common and significant metabolic conditions in some populations of adult survivors of childhood cancer. Results from the Childhood Cancer Survivor Study and other large cohorts of childhood cancer survivors reveal that long-term survivors of acute lymphoblastic leukemia and those who received total body irradiation or abdominal radiotherapy are at highest risk. The potential mechanisms for the observed increase in risk, including alterations in leptin and adiponectin, pancreatic insufficiency, poor dietary habits, sedentary lifestyle, and perhaps changes in the composition of the gut microbiota, are reviewed. Discussion of exercise and diet intervention studies shows that further research about the barriers to a healthy lifestyle and other interventions in childhood cancer survivors is warranted.

  12. Adipocytokines in obesity and metabolic disease.

    PubMed

    Cao, Haiming

    2014-02-01

    The current global obesity pandemic is the leading cause for the soaring rates of metabolic diseases, especially diabetes, cardiovascular disease, hypertension, and non-alcoholic hepatosteatosis. Efforts devoted to find cures for obesity and associated disorders in the past two decades have prompted intensive interest in adipocyte biology, and have led to major advances in the mechanistic understanding of adipose tissue as an essential endocrine organ. Adipose tissue secretes an array of hormones (adipokines) that signal key organs to maintain metabolic homeostasis, and their dysfunction has been causally linked to a wide range of metabolic diseases. In addition, obesity induces production of inflammatory cytokines (often referred to together with adipokines as adipocytokines) and infiltration of immune cells into adipose tissue, which creates a state of chronic low-grade inflammation. Metabolic inflammation has been increasingly recognized as a unifying mechanism linking obesity to a broad spectrum of pathological conditions. This review focuses on classic examples of adipocytokines that have helped to form the basis of the endocrine and inflammatory roles of adipose tissue, and it also details a few newly characterized adipocytokines that provide fresh insights into adipose biology. Studies of adipocytokines in clinical settings and their therapeutic potential are also discussed.

  13. Cerebral glucose metabolism in Parkinson's disease.

    PubMed

    Martin, W R; Beckman, J H; Calne, D B; Adam, M J; Harrop, R; Rogers, J G; Ruth, T J; Sayre, C I; Pate, B D

    1984-02-01

    Local cerebral glucose utilization was measured in patients with predominantly unilateral Parkinson's disease using 18F-2-fluoro-deoxyglucose and positron emission tomography. Preliminary results indicate the presence of asymmetric metabolic rates in the inferior basal ganglia. The structure comprising the largest portion of basal ganglia at this level is globus pallidus. These findings are consistent with metabolic studies on animals with unilateral nigrostriatal lesions in which pallidal hypermetabolism on the lesioned side has been demonstrated. Increased pallidal activity is likely secondary to a loss of inhibitory dopaminergic input to the striatum from substantia nigra.

  14. Metabolic therapy: lessons from liver diseases.

    PubMed

    Garcia-Ruiz, Carmen; Marí, Montserrat; Colell, Anna; Morales, Albert; Fernandez-Checa, Jose C

    2011-12-01

    Fatty liver disease is one of most prevalent metabolic liver diseases, which includes alcoholic (ASH) and nonalcoholic steatohepatitis (NASH). Its initial stage is characterized by fat accumulation in the liver, that can progress to steatohepatitis, a stage of the disease in which steatosis is accompanied by inflammation, hepatocellular death, oxidative stress and fibrosis. Recent evidence in experimental models as well as in patients with steatohepatitis have uncovered a role for cholesterol and sphingolipids, particularly ceramide, in the transition from steatosis to steatohepatitis, insulin resistance and hence disease progression. Cholesterol accumulation and its trafficking to mitochondria sensitizes fatty liver to subsequent hits including inflammatory cytokines, such as TNF/Fas, in a pathway involving ceramide generation by acidic sphingomyelinase (ASMase). Thus, targeting both cholesterol and/or ASMase may represent a novel therapeutic approach of relevance in ASH and NASH, two of the most common forms of liver diseases worldwide. PMID:21933146

  15. Metabolic Syndrome: An Important Risk Factor for Parkinson's Disease

    PubMed Central

    Tian, Bo

    2014-01-01

    Metabolic syndrome is becoming commoner due to a rise in obesity rates among adults. Generally speaking, a person with metabolic syndrome is twice as likely to develop cardiovascular disease and five times as likely to develop diabetes as someone without metabolic syndrome. Increasing oxidative stress in metabolic syndrome and Parkinson's disease is mentioned in the comprehensive articles; however, the system review about clear relation between metabolic syndrome and Parkinson's disease is deficient. In this review, we will focus on the analysis that the metabolic syndrome may be a risk factor for Parkinson's disease and the preventions that reduce the incident of Parkinson's disease by regulating the oxidative stress. PMID:24955210

  16. Circulatory disease mortality in the Massachusetts tuberculosis fluoroscopy cohort study.

    PubMed

    Little, Mark P; Zablotska, Lydia B; Brenner, Alina V; Lipshultz, Steven E

    2016-03-01

    High-dose ionizing radiation is associated with circulatory disease. Risks from lower-dose fractionated exposures, such as from diagnostic radiation procedures, remain unclear. In this study we aimed to ascertain the relationship between fractionated low-to-medium dose radiation exposure and circulatory disease mortality in a cohort of 13,568 tuberculosis patients in Massachusetts, some with fluoroscopy screenings, between 1916 and 1961 and follow-up until the end of 2002. Analysis of mortality was in relation to cumulative thyroid (cerebrovascular) or lung (all other circulatory disease) radiation dose via Poisson regression. Over the full dose range, there was no overall radiation-related excess risk of death from circulatory disease (n = 3221; excess relative risk/Gy -0.023; 95% CI -0.067, 0.028; p = 0.3574). Risk was somewhat elevated in hypertensive heart disease (n = 89; excess relative risk/Gy 0.357; 95% CI -0.043, 1.030, p = 0.0907) and slightly decreased in ischemic heart disease (n = 1950; excess relative risk/Gy -0.077; 95% CI -0.130, -0.012; p = 0.0211). However, under 0.5 Gy, there was a borderline significant increasing trend for all circulatory disease (excess relative risk/Gy 0.345; 95% CI -0.032, 0.764; p = 0.0743) and for ischemic heart disease (excess relative risk/Gy 0.465; 95% CI, -0.032, 1.034, p = 0.0682). Pneumolobectomy increased radiation-associated risk (excess relative risk/Gy 0.252; 95% CI 0.024, 0.579). Fractionation of dose did not modify excess risk. In summary, we found no evidence of radiation-associated excess circulatory death risk overall, but there are indications of excess circulatory death risk at lower doses (<0.5 Gy). Although consistent with other radiation-exposed groups, the indications of higher risk at lower doses are unusual and should be confirmed against other data. PMID:26255039

  17. Glutathione Metabolism and Parkinson’s Disease

    PubMed Central

    Smeyne, Michelle

    2013-01-01

    It has been established that oxidative stress, defined as the condition when the sum of free radicals in a cell exceeds the antioxidant capacity of the cell, contributes to the pathogenesis of Parkinson’s disease. Glutathione is a ubiquitous thiol tripeptide that acts alone, or in concert with enzymes within cells to reduce superoxide radicals, hydroxyl radicals and peroxynitrites. In this review, we examine the synthesis, metabolism and functional interactions of glutathione, and discuss how this relates to protection of dopaminergic neurons from oxidative damage and its therapeutic potential in Parkinson’s disease. PMID:23665395

  18. Lipoproteins and lipoprotein metabolism in periodontal disease

    PubMed Central

    Griffiths, Rachel; Barbour, Suzanne

    2010-01-01

    A growing body of evidence indicates that the incidence of atherosclerosis is increased in subjects with periodontitis – a chronic infection of the oral cavity. This article summarizes the evidence that suggests periodontitis shifts the lipoprotein profile to be more proatherogenic. LDL-C is elevated in periodontitis and most studies indicate that triglyceride levels are also increased. By contrast, antiatherogenic HDL tends to be low in periodontitis. Periodontal therapy tends to shift lipoprotein levels to a healthier profile and also reduces subclinical indices of atherosclerosis. In summary, periodontal disease alters lipoprotein metabolism in ways that could promote atherosclerosis and cardiovascular disease. PMID:20835400

  19. The Intestinal Microbiota in Metabolic Disease

    PubMed Central

    Woting, Anni; Blaut, Michael

    2016-01-01

    Gut bacteria exert beneficial and harmful effects in metabolic diseases as deduced from the comparison of germfree and conventional mice and from fecal transplantation studies. Compositional microbial changes in diseased subjects have been linked to adiposity, type 2 diabetes and dyslipidemia. Promotion of an increased expression of intestinal nutrient transporters or a modified lipid and bile acid metabolism by the intestinal microbiota could result in an increased nutrient absorption by the host. The degradation of dietary fiber and the subsequent fermentation of monosaccharides to short-chain fatty acids (SCFA) is one of the most controversially discussed mechanisms of how gut bacteria impact host physiology. Fibers reduce the energy density of the diet, and the resulting SCFA promote intestinal gluconeogenesis, incretin formation and subsequently satiety. However, SCFA also deliver energy to the host and support liponeogenesis. Thus far, there is little knowledge on bacterial species that promote or prevent metabolic disease. Clostridium ramosum and Enterococcus cloacae were demonstrated to promote obesity in gnotobiotic mouse models, whereas bifidobacteria and Akkermansia muciniphila were associated with favorable phenotypes in conventional mice, especially when oligofructose was fed. How diet modulates the gut microbiota towards a beneficial or harmful composition needs further research. Gnotobiotic animals are a valuable tool to elucidate mechanisms underlying diet–host–microbe interactions. PMID:27058556

  20. The Intestinal Microbiota in Metabolic Disease.

    PubMed

    Woting, Anni; Blaut, Michael

    2016-01-01

    Gut bacteria exert beneficial and harmful effects in metabolic diseases as deduced from the comparison of germfree and conventional mice and from fecal transplantation studies. Compositional microbial changes in diseased subjects have been linked to adiposity, type 2 diabetes and dyslipidemia. Promotion of an increased expression of intestinal nutrient transporters or a modified lipid and bile acid metabolism by the intestinal microbiota could result in an increased nutrient absorption by the host. The degradation of dietary fiber and the subsequent fermentation of monosaccharides to short-chain fatty acids (SCFA) is one of the most controversially discussed mechanisms of how gut bacteria impact host physiology. Fibers reduce the energy density of the diet, and the resulting SCFA promote intestinal gluconeogenesis, incretin formation and subsequently satiety. However, SCFA also deliver energy to the host and support liponeogenesis. Thus far, there is little knowledge on bacterial species that promote or prevent metabolic disease. Clostridium ramosum and Enterococcus cloacae were demonstrated to promote obesity in gnotobiotic mouse models, whereas bifidobacteria and Akkermansia muciniphila were associated with favorable phenotypes in conventional mice, especially when oligofructose was fed. How diet modulates the gut microbiota towards a beneficial or harmful composition needs further research. Gnotobiotic animals are a valuable tool to elucidate mechanisms underlying diet-host-microbe interactions. PMID:27058556

  1. Omega-3 fatty acids: role in metabolism and cardiovascular disease.

    PubMed

    Gerber, Philipp A; Gouni-Berthold, Ioanna; Berneis, Kaspar

    2013-01-01

    The inverse association of cardiovascular risk with intake of omega-3 polyunsaturated fatty acids was suspected early in populations that are known to have a high consumption of fish and fish oil. Subsequent cohort studies confirmed such associations in other populations. Further evidence of possible beneficial effects on metabolism and cardiovascular health was provided by many studies that were able to show specific mechanisms that may underlie these observations. These include improvement of the function of tissues involved in the alterations occurring during the development of obesity and the metabolic syndrome, as adipose tissue, the liver and skeletal muscle. Direct action on the cardiovascular system was not only shown regarding vascular function and the formation of atherosclerotic plaques, but also by providing antiarrhythmic effects on the heart. Data on these effects come from in vitro as well as in vivo studies that were conducted in animal models of disease, in healthy humans and in humans suffering from cardiovascular disease. To define prophylactic as well as treatment options in primary and secondary prevention, large clinical trial assessed the effect of omega-3 polyunsaturated fatty acids on end points as cardiovascular morbidity and mortality. However, so far these trials provided ambiguous data that do allow recommendations regarding the use of omega-3 polyunsaturated fatty acids in higher dosages and beyond the dietary advice of regular fish intake only in few clinical situations, such as severe hypertriglyceridemia.

  2. Combined Effects of Sleep Disordered Breathing and Metabolic Syndrome on Endothelial Function: The Wisconsin Sleep Cohort Study

    PubMed Central

    Korcarz, Claudia E.; Stein, James H.; Peppard, Paul E.; Young, Terry B.; Barnet, Jodi H.; Nieto, F. Javier

    2014-01-01

    Study Objectives: To examine the combined impact of sleep disordered breathing (SDB) and metabolic syndrome (MetS) in endothelial dysfunction. Design: Cross-sectional assessment of endothelial function, MetS and SDB status in a population-based sample. Setting: Community-based cohort. Participants: Participants (n = 431) from the Wisconsin Sleep Cohort were studied between 2004 and 2007. MetS was defined following the National Cholesterol Education Program criteria. SDB severity was defined by the apnea-hypopnea index ([AHI] events/h of sleep) during overnight polysomnography. Fasting lipids, glucose, and insulin were measured and homeostasis model assessment was calculated to quantify insulin resistance (HOMA-IR). Multivariable linear regression was used to assess associations of brachial artery flow-mediated dilation (FMD) with SDB, MetS, and their interaction. Intervention: None. Measurements and Results: Participants averaged 60.2 years of age (SD 7.8 years), 44% were female, and 97% Caucasian. MetS was present in 35%; 22% had AHI ≥ 15 events/hour. Of the no-MetS group, 7% had AHI ≥ 15 events/hour. FMD (mean 5.5%; SD 3.5%) was inversely associated with age (r = -0.16, P = 0.001) and mean brachial artery diameter (r = -0.29, P < 0.001). Multivariate linear models adjusted for CVD risk factors showed that the negative association between SDB and FMD was present among subjects with MetS (β FMDper unit log2(AHI+1) = -0.55%, P = 0.014), but not among subjects with normal metabolic function (β = 0.13, not significant), P for interaction = 0.011. Conclusion: Sleep disordered breathing and concurrent metabolic syndrome are synergistically associated with worse endothelial function. Individuals with both of these conditions appear to be at a significantly higher risk for cardiovascular disease complications. Citation: Korcarz CE, Stein JH, Peppard PE, Young TB, Barnet JH, Nieto FJ. Combined effects of sleep disordered breathing and metabolic syndrome on

  3. Glucose tolerance status is a better predictor of diabetes and cardiovascular outcomes than metabolic syndrome: a prospective cohort study

    PubMed Central

    2012-01-01

    Backround To evaluate the importance of oral glucose tolerance test (OGTT) in predicting diabetes and cardiovascular disease in patients with and without Metabolic Syndrome from a population treated in a primary care unit. Research design and methods A prospective cohort study was conducted with subjects regularly attending the primary care unit of Hospital de Clínicas de Porto Alegre. Participants underwent a 75 g OGTT. Metabolic syndrome definition was based on the criteria of IDF/AHA/NHLBI-2010. Results Participants mean age was 61 ± 12 years (males: 38%; whites: 67%). Of the 148 subjects included, 127 (86%) were followed for 36 ± 14 months, 21 (14%) were lost. Subjects were classified into four groups based on baseline OGTT: 29% normal (n = 43), 28% impaired fasting glucose (IFG; n = 42), 26% impaired glucose tolerance (IGT; n = 38), and 17% diabetes (n = 25). Metabolic syndrome prevalence was lower in normal group (28%), intermediate in IFG (62%) and IGT (65%) groups, and higher among subjects with diabetes (92%; P <0.001). Incidence of diabetes increased along with the stages of glucose metabolism disturbance (normal: 0%, IFG: 16%, IGT: 28%; P = 0.004). No patient with normal OGTT developed diabetes, regardless metabolic syndrome presence. Diabetes at baseline was the major determinant of cardiovascular disease occurrence (normal: 0%, IFG: 4%, IGT: 0%, diabetes: 24%; P = 0.001). In Cox-regression analysis, only the 2 h OGTT results were associated with diabetes (OR = 1.03; 95%CI 1.01–1.06; P <0.001) and cardiovascular disease development (OR = 1.013; 95%CI 1.002–1.025; P = 0.024). Conclusions In this sample of subjects undergoing diabetes screening, the OGTT predicted diabetes and cardiovascular disease more effectively than the metabolic syndrome status. PMID:22682107

  4. Salivary Biomarkers in Pediatric Metabolic Disease Research.

    PubMed

    Hartman, Mor-Li; Goodson, J Max; Barake, Roula; Alsmadi, Osama; Al-Mutawa, Sabiha; Ariga, Jitendra; Soparkar, Pramod; Behbehani, Jawad; Behbehani, Kazem

    2016-03-01

    The increasing prevalence of childhood obesity and obesity-related metabolic disorders is now considered a global pandemic. The main goal of the pediatric obesity research community is to identify children who are at risk of becoming obese before their body mass index rises above age norms. To do so, we must identify biomarkers of metabolic health and immunometabolism that can be used for large-scale screening and diagnosis initiatives among at-risk children. Because blood sampling is often unacceptable to both parents and children when there is no direct benefit to the child, as in a community-based research study, there is a clear need for a low-risk, non-invasive sampling strategy. Salivary analysis is now well recognized as a likely candidate for this purpose. In this review, we discuss the physiologic role of saliva and its strengths and limitations as a fluid for biomarker discovery, obesity screening, metabolic disease diagnosis, and response monitoring after interventions. We also describe the current state of the salivary biomarker field as it pertains to metabolic research, with a special emphasis on studies conducted in children and adolescents. Finally, we look forward to technological developments, such as salivary "omics" and point of service diagnostic devices, which have the potential to accelerate the pace of research and discovery in this vitally important field. PMID:27116847

  5. Lipoprotein metabolism in nonalcoholic fatty liver disease

    PubMed Central

    Jiang, Zhenghui Gordon; Robson, Simon C.; Yao, Zemin

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD), an escalating health problem worldwide, covers a spectrum of pathologies characterized by fatty accumulation in hepatocytes in early stages, with potential progression to liver inflammation, fibrosis, and failure. A close, yet poorly understood link exists between NAFLD and dyslipidemia, a constellation of abnormalities in plasma lipoproteins including triglyceride-rich very low density lipoproteins. Apolipoproteins are a group of primarily liver-derived proteins found in serum lipoproteins; they not only play an extracellular role in lipid transport between vital organs through circulation, but also play an important intracellular role in hepatic lipoprotein assembly and secretion. The liver functions as the central hub for lipoprotein metabolism, as it dictates lipoprotein production and to a significant extent modulates lipoprotein clearance. Lipoprotein metabolism is an integral component of hepatocellular lipid homeostasis and is implicated in the pathogenesis, potential diagnosis, and treatment of NAFLD. PMID:23554788

  6. Physical activity and risk of Metabolic Syndrome in an urban Mexican cohort

    PubMed Central

    Méndez-Hernández, Pablo; Flores, Yvonne; Siani, Carole; Lamure, Michel; Dosamantes-Carrasco, L Darina; Halley-Castillo, Elizabeth; Huitrón, Gerardo; Talavera, Juan O; Gallegos-Carrillo, Katia; Salmerón, Jorge

    2009-01-01

    Background In the Mexican population metabolic syndrome (MS) is highly prevalent. It is well documented that regular physical activity (PA) prevents coronary diseases, type 2 diabetes and MS. Most studies of PA have focused on moderate-vigorous leisure-time activity, because it involves higher energy expenditures, increase physical fitness, and decrease the risk of MS. However, for most people it is difficult to get a significant amount of PA from only moderately-vigorous leisure activity, so workplace activity may be an option for working populations, because, although may not be as vigorous in terms of cardio-respiratory efforts, it comprises a considerable proportion of the total daily activity with important energy expenditure. Since studies have also documented that different types and intensity of daily PA, including low-intensity, seem to confer important health benefits such as prevent MS, we sought to assess the impact of different amounts of leisure-time and workplace activities, including low-intensity level on MS prevention, in a sample of urban Mexican adults. Methods The study population consisted of 5118 employees and their relatives, aged 20 to 70 years, who were enrolled in the baseline evaluation of a cohort study. MS was assessed according to the criteria of the National Cholesterol Education Program, ATP III and physical activity with a validated self-administered questionnaire. Associations between physical activity and MS risk were assessed with multivariate logistic regression models. Results The prevalence of the components of MS in the study population were: high glucose levels 14.2%, high triglycerides 40.9%, high blood pressure 20.4%, greater than healthful waist circumference 43.2% and low-high density lipoprotein 76.9%. The prevalence of MS was 24.4%; 25.3% in men and 21.8% in women. MS risk was reduced among men (OR 0.72; 95%CI 0.57–0.95) and women (OR 0.78; 95%CI 0.64–0.94) who reported an amount of ≥30 minutes/day of leisure

  7. The metabolic syndrome: a brain disease?

    PubMed

    Buijs, Ruud M; Kreier, Felix

    2006-09-01

    The incidence of obesity with, as consequence, a rise in associated diseases such as diabetes, hypertension and dyslipidemia--the metabolic syndrome--is reaching epidemic proportions in industrialized countries. Here, we provide a hypothesis that the biological clock which normally prepares us each morning for the coming activity period is altered due to a modern life style of low activity during the day and late-night food intake. Furthermore, we review the anatomical evidence supporting the proposal that an unbalanced autonomic nervous system output may lead to the simultaneous occurrence of diabetes type 2, dyslipidemia, hypertension and visceral obesity.

  8. Vascular and metabolic reserve in Alzheimer's disease.

    PubMed

    Nagata, K; Kondoh, Y; Atchison, R; Sato, M; Satoh, Y; Watahiki, Y; Hirata, Y; Yokoyama, E

    2000-01-01

    Vascular and metabolic reserve were analyzed in probable Alzheimer's disease (AD) and vascular dementia (VaD). Cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral metabolic rate of oxygen (CMRO(2)), and oxygen extraction fraction (OEF) were measured quantitatively with positron emission tomography (PET). Vascular reactivity (VR) was also calculated by comparing the CBF during 5% CO(2) inhalation with the CBF during normal breathing. Vascular transit time (VTT) that was calculated as a ratio of CBV/CBF and VR reflect vasodilating capacity of the small resistance vessels, whereas OEF designates metabolic (oxygen-extraction) reserve in threatening brain ischemia. Significant increase in OEF was seen in the parieto-temporal cortex and both VTT and VR were preserved in AD patients. By constrast, there was no significant increase in OEF whereas VTT was prolonged and VR was markedly depressed in VaD patients. The increase of OEF and preserved VTT and VR seen in AD patients indicate the possible participation of vascular factors in the pathogenesis of AD perhaps at the capillary level.

  9. Metabolic profiling of Alzheimer's disease brains

    NASA Astrophysics Data System (ADS)

    Inoue, Koichi; Tsutsui, Haruhito; Akatsu, Hiroyasu; Hashizume, Yoshio; Matsukawa, Noriyuki; Yamamoto, Takayuki; Toyo'Oka, Toshimasa

    2013-08-01

    Alzheimer's disease (AD) is an irreversible, progressive brain disease and can be definitively diagnosed after death through an examination of senile plaques and neurofibrillary tangles in several brain regions. It is to be expected that changes in the concentration and/or localization of low-molecular-weight molecules are linked to the pathological changes that occur in AD, and determining their identity would provide valuable information regarding AD processes. Here, we propose definitive brain metabolic profiling using ultra-performance liquid chromatography coupled with electrospray time-of-flight mass spectrometry analysis. The acquired data were subjected to principal components analysis to differentiate the frontal and parietal lobes of the AD/Control groups. Significant differences in the levels of spermine and spermidine were identified using S-plot, mass spectra, databases and standards. Based on the investigation of the polyamine metabolite pathway, these data establish that the downstream metabolites of ornithine are increased, potentially implicating ornithine decarboxylase activity in AD pathology.

  10. Childhood stunting and the metabolic syndrome components in young adults from a Brazilian birth cohort study

    PubMed Central

    Grillo, L P; Gigante, D P; Horta, B L; de Barros, F C F

    2016-01-01

    Background/Objectives: The aim of this study was to investigate the association between stunting in the second year of life and metabolic syndrome components in early adulthood among subjects who have been prospectively followed-up since birth, in a city in Southern Brazil. Subjects/Methods: In 1984, we attempted to follow-up the entire cohort; the subjects were examined and their mothers interviewed. Stunting was defined by a length-for-age Z-score 2 s.d. or more below the mean, in accordance with the World Health Organization reference. Between 2004 and 2005, we again tried to follow the entire cohort; during this period the subjects were evaluated for the following metabolic syndrome components: high-density lipoprotein (HDL) cholesterol, triglycerides, random blood glucose, waist circumference and systolic and diastolic blood pressure. Family income at the time of the baby's birth, asset index, mother's education, mother's smoking during pregnancy and duration of breastfeeding were considered possible confounders. Linear regression was used in the unadjusted and adjusted analyses. Results: Among men, stunting was inversely associated with triglycerides (β=−11.90, confidence interval (CI)=−22.33 to −1.48) and waist circumference (β=−4.29, CI=−5.62 to −2.97), whereas for women stunting was negatively related to HDL-cholesterol (β=−4.50, CI=−6.47 to −2.52), triglycerides (β=−9.61, CI=−17.66 to −1.56) and waist circumference (β=−1.14, CI=−4.22 to −1.02). However, after controlling for confounding variables, these associations vanished. Conclusions: The findings suggest that stunting in childhood is not associated with metabolic syndrome components in young adults. PMID:26733042

  11. The association between gallstones and metabolic syndrome in urban Han Chinese: a longitudinal cohort study.

    PubMed

    Zhu, Qian; Sun, Xiubin; Ji, Xiaokang; Zhu, Lin; Xu, Jing; Wang, Chunxia; Zhang, Chengqi; Xue, Fuzhong; Liu, Yanxun

    2016-01-01

    The precise association between metabolic syndrome (MetS) and gallstone disease remains unclear in China. This study aimed to clarify the relationship between MetS and gallstone and evaluate whether counts of metabolic abnormalities had influence on gallstone disease. We fitted gender-specific generalized estimating equation (GEE) regression models with data from a large-scale longitudinal study over 6-year follow-up to elucidate the real association. This study included 18291 participants with 3 times repeated measures at least who were free from a prior history of gallstone disease and cholecystectomy. A total of 873 cases of gallstones occurred during 6-year follow-up. The incidence density of gallstone in the group of subjects with MetS was higher than the group without MetS (10.27 vs 5.79). The GEE analyses confirmed and clarified the association between MetS and gallstone disease in males (RR = 1.33, P = 0.0020), while this association was not significant in females (RR = 1.15, P = 0.4962). With numbers of metabolic syndrome components increasing, the risk of gallstone disease showed corresponding increasing in males. In conclusion, the associations of MetS and gallstone are different in males and in females. And the risk of gallstone disease increases with the number of components of MetS for males but not for females.

  12. The association between gallstones and metabolic syndrome in urban Han Chinese: a longitudinal cohort study

    PubMed Central

    Zhu, Qian; Sun, Xiubin; Ji, Xiaokang; Zhu, Lin; Xu, Jing; Wang, Chunxia; Zhang, Chengqi; Xue, Fuzhong; Liu, Yanxun

    2016-01-01

    The precise association between metabolic syndrome (MetS) and gallstone disease remains unclear in China. This study aimed to clarify the relationship between MetS and gallstone and evaluate whether counts of metabolic abnormalities had influence on gallstone disease. We fitted gender-specific generalized estimating equation (GEE) regression models with data from a large-scale longitudinal study over 6-year follow-up to elucidate the real association. This study included 18291 participants with 3 times repeated measures at least who were free from a prior history of gallstone disease and cholecystectomy. A total of 873 cases of gallstones occurred during 6-year follow-up. The incidence density of gallstone in the group of subjects with MetS was higher than the group without MetS (10.27 vs 5.79). The GEE analyses confirmed and clarified the association between MetS and gallstone disease in males (RR = 1.33, P = 0.0020), while this association was not significant in females (RR = 1.15, P = 0.4962). With numbers of metabolic syndrome components increasing, the risk of gallstone disease showed corresponding increasing in males. In conclusion, the associations of MetS and gallstone are different in males and in females. And the risk of gallstone disease increases with the number of components of MetS for males but not for females. PMID:27443986

  13. Nutrigenomic programming of cardiovascular and metabolic diseases.

    PubMed

    Ozanne, Susan

    2014-10-01

    Over twenty five years ago epidemiological studies revealed that there was a relationship between patterns of early growth and subsequent risk of diseases such as type 2 diabetes, cardiovascular disease and the metabolic syndrome. Studies of identical twins, individuals who were in utero during periods of famine, discordant siblings and animal models have provided strong evidence that the early environment plays an important role in mediating these relationships. Early nutrition is one such important environmental factor. The concept of early life programming is therefore widely accepted and the underlying mechanisms starting to emerge. These include: (1) Permanent structural changes in an organ due to exposure to suboptimal levels of essential hormones or nutrients during a critical period of development leading to permanent changes in tissue function (2) Persistent epigenetic changes such as DNA methylation and histone modifications and miRNAs leading to changes in gene expression. (3) Permanent effects on regulation of cellular ageing through increases in oxidative stress and mitochondrial dysfunction leading to DNA damage and telomere shortening. Further understanding of these processes will enable the development of preventative and intervention strategies to combat the burden of common diseases such as type 2 diabetes and cardiovascular disease.

  14. Nutrigenomic programming of cardiovascular and metabolic diseases.

    PubMed

    Ozanne, Susan

    2014-10-01

    Over twenty five years ago epidemiological studies revealed that there was a relationship between patterns of early growth and subsequent risk of diseases such as type 2 diabetes, cardiovascular disease and the metabolic syndrome. Studies of identical twins, individuals who were in utero during periods of famine, discordant siblings and animal models have provided strong evidence that the early environment plays an important role in mediating these relationships. Early nutrition is one such important environmental factor. The concept of early life programming is therefore widely accepted and the underlying mechanisms starting to emerge. These include: (1) Permanent structural changes in an organ due to exposure to suboptimal levels of essential hormones or nutrients during a critical period of development leading to permanent changes in tissue function (2) Persistent epigenetic changes such as DNA methylation and histone modifications and miRNAs leading to changes in gene expression. (3) Permanent effects on regulation of cellular ageing through increases in oxidative stress and mitochondrial dysfunction leading to DNA damage and telomere shortening. Further understanding of these processes will enable the development of preventative and intervention strategies to combat the burden of common diseases such as type 2 diabetes and cardiovascular disease. PMID:26461282

  15. Weight for gestational age and metabolically healthy obesity in adults from the Haguenau cohort

    PubMed Central

    Matta, Joane; Carette, Claire; Levy Marchal, Claire; Bertrand, Julien; Pétéra, Mélanie; Zins, Marie; Pujos-Guillot, Estelle; Comte, Blandine; Czernichow, Sébastien

    2016-01-01

    Background An obesity subphenotype, named ‘metabolically healthy obese’ (MHO) has been recently defined to characterise a subgroup of obese individuals with less risk for cardiometabolic abnormalities. To date no data are available on participants born with small weight for gestational age (SGA) and the risk of metabolically unhealthy obesity (MUHO). Objective Assess the risk of MUHO in SGA versus appropriate for gestational age (AGA) adult participants. Methods 129 young obese individuals (body mass index ≥30 kg/m²) from data of an 8-year follow-up Haguenau cohort (France), were identified out of 1308 participants and were divided into 2 groups: SGA (n=72) and AGA (n=57). Metabolic characteristics were analysed and compared using unpaired t-test. The HOMA-IR index was determined for the population and divided into quartiles. Obese participants within the first 3 quartiles were considered as MHO and those in the fourth quartile as MUHO. Relative risks (RRs) and 95% CI for being MUHO in SGA versus AGA participants were computed. Results The SGA-obese group had a higher risk of MUHO versus the AGA-obese group: RR=1.27 (95% CI 1.10 to 1.6) independently of age and sex. Conclusions In case of obesity, SGA might confer a higher risk of MUHO compared with AGA. PMID:27580829

  16. Novel metabolic biomarkers of cardiovascular disease.

    PubMed

    Jensen, Majken K; Bertoia, Monica L; Cahill, Leah E; Agarwal, Isha; Rimm, Eric B; Mukamal, Kenneth J

    2014-11-01

    Coronary heart disease (CHD) accounts for one in every six deaths in US individuals. Great advances have been made in identifying important risk factors for CHD, such as hypertension, diabetes mellitus, smoking and hypercholesterolaemia, which have led to major developments in therapy. In particular, statins represent one of the greatest successes in the prevention of CHD. While these standard risk factors are important, an obvious opportunity exists to take advantage of ongoing scientific research to better risk-stratify individuals and to identify new treatment targets. In this Review, we summarize ongoing scientific research in a number of metabolic molecules or features, including lipoproteins, homocysteine, calcium metabolism and glycaemic markers. We evaluate the current state of the research and the strength of evidence supporting each emerging biomarker. We also discuss whether the associations with CHD are strong and consistent enough to improve current risk stratification metrics, and whether these markers enhance our understanding of the underlying biology of CHD and thus point towards new treatment options.

  17. Risk factors for metabolic syndrome in a cohort study in a north China urban middle-aged population.

    PubMed

    Strand, Mark A; Perry, Judy; Wang, Ping; Liu, Shuangfeng; Lynn, Henry

    2015-03-01

    As China undergoes urbanization, lifestyles and disease profiles are changing. In this study, metabolic syndrome (MetS) was discovered in 53.5% and 42.7% of men and women, respectively. In 3 age cohorts (44, 48, and 52 years), prevalence of MetS among women was 33.3%, 41.4%, and 50.8%, respectively (χ(2) = 10.27, P = .006), whereas among men it was 51.5%, 56.3%, and 52.3%, respectively (χ(2) = 0.46, P = .796). The component contributing to the presence of MetS was increased waist circumference, especially among women. MetS among men results from higher rates of elevated triglycerides, blood pressure, and blood glucose when compared with women. Risk factors for MetS included less than 60 minutes of exercise a week (odds ratio [OR] = 1.7, 95% confidence interval [CI] = 1.3-2.4) and rarely consuming milk (OR = 1.7, 95% CI = 1.2-2.3). Abstaining from or occasionally consuming alcohol (OR = 0.7, 95% CI = 0.4-1.1) and having parents with no chronic disease (OR = 0.4, 95% CI = 0.2-0.6) suggest increased protection against MetS.

  18. Invited review: Opportunities for genetic improvement of metabolic diseases.

    PubMed

    Pryce, J E; Parker Gaddis, K L; Koeck, A; Bastin, C; Abdelsayed, M; Gengler, N; Miglior, F; Heringstad, B; Egger-Danner, C; Stock, K F; Bradley, A J; Cole, J B

    2016-09-01

    Metabolic disorders are disturbances to one or more of the metabolic processes in dairy cattle. Dysfunction of any of these processes is associated with the manifestation of metabolic diseases or disorders. In this review, data recording, incidences, genetic parameters, predictors, and status of genetic evaluations were examined for (1) ketosis, (2) displaced abomasum, (3) milk fever, and (4) tetany, as these are the most prevalent metabolic diseases where published genetic parameters are available. The reported incidences of clinical cases of metabolic disorders are generally low (less than 10% of cows are recorded as having a metabolic disease per herd per year or parity/lactation). Heritability estimates are also low and are typically less than 5%. Genetic correlations between metabolic traits are mainly positive, indicating that selection to improve one of these diseases is likely to have a positive effect on the others. Furthermore, there may also be opportunities to select for general disease resistance in terms of metabolic stability. Although there is inconsistency in published genetic correlation estimates between milk yield and metabolic traits, selection for milk yield may be expected to lead to a deterioration in metabolic disorders. Under-recording and difficulty in diagnosing subclinical cases are among the reasons why interest is growing in using easily measurable predictors of metabolic diseases, either recorded on-farm by using sensors and milk tests or off-farm using data collected from routine milk recording. Some countries have already initiated genetic evaluations of metabolic disease traits and currently most of these use clinical observations of disease. However, there are opportunities to use clinical diseases in addition to predictor traits and genomic information to strengthen genetic evaluations for metabolic health in the future. PMID:27372587

  19. Invited review: Opportunities for genetic improvement of metabolic diseases.

    PubMed

    Pryce, J E; Parker Gaddis, K L; Koeck, A; Bastin, C; Abdelsayed, M; Gengler, N; Miglior, F; Heringstad, B; Egger-Danner, C; Stock, K F; Bradley, A J; Cole, J B

    2016-09-01

    Metabolic disorders are disturbances to one or more of the metabolic processes in dairy cattle. Dysfunction of any of these processes is associated with the manifestation of metabolic diseases or disorders. In this review, data recording, incidences, genetic parameters, predictors, and status of genetic evaluations were examined for (1) ketosis, (2) displaced abomasum, (3) milk fever, and (4) tetany, as these are the most prevalent metabolic diseases where published genetic parameters are available. The reported incidences of clinical cases of metabolic disorders are generally low (less than 10% of cows are recorded as having a metabolic disease per herd per year or parity/lactation). Heritability estimates are also low and are typically less than 5%. Genetic correlations between metabolic traits are mainly positive, indicating that selection to improve one of these diseases is likely to have a positive effect on the others. Furthermore, there may also be opportunities to select for general disease resistance in terms of metabolic stability. Although there is inconsistency in published genetic correlation estimates between milk yield and metabolic traits, selection for milk yield may be expected to lead to a deterioration in metabolic disorders. Under-recording and difficulty in diagnosing subclinical cases are among the reasons why interest is growing in using easily measurable predictors of metabolic diseases, either recorded on-farm by using sensors and milk tests or off-farm using data collected from routine milk recording. Some countries have already initiated genetic evaluations of metabolic disease traits and currently most of these use clinical observations of disease. However, there are opportunities to use clinical diseases in addition to predictor traits and genomic information to strengthen genetic evaluations for metabolic health in the future.

  20. The implications of relationships between human diseases and metabolic subpathways.

    PubMed

    Li, Xia; Li, Chunquan; Shang, Desi; Li, Jing; Han, Junwei; Miao, Yingbo; Wang, Yan; Wang, Qianghu; Li, Wei; Wu, Chao; Zhang, Yunpeng; Li, Xiang; Yao, Qianlan

    2011-01-01

    One of the challenging problems in the etiology of diseases is to explore the relationships between initiation and progression of diseases and abnormalities in local regions of metabolic pathways. To gain insight into such relationships, we applied the "k-clique" subpathway identification method to all disease-related gene sets. For each disease, the disease risk regions of metabolic pathways were then identified and considered as subpathways associated with the disease. We finally built a disease-metabolic subpathway network (DMSPN). Through analyses based on network biology, we found that a few subpathways, such as that of cytochrome P450, were highly connected with many diseases, and most belonged to fundamental metabolisms, suggesting that abnormalities of fundamental metabolic processes tend to cause more types of diseases. According to the categories of diseases and subpathways, we tested the clustering phenomenon of diseases and metabolic subpathways in the DMSPN. The results showed that both disease nodes and subpathway nodes displayed slight clustering phenomenon. We also tested correlations between network topology and genes within disease-related metabolic subpathways, and found that within a disease-related subpathway in the DMSPN, the ratio of disease genes and the ratio of tissue-specific genes significantly increased as the number of diseases caused by the subpathway increased. Surprisingly, the ratio of essential genes significantly decreased and the ratio of housekeeping genes remained relatively unchanged. Furthermore, the coexpression levels between disease genes and other types of genes were calculated for each subpathway in the DMSPN. The results indicated that those genes intensely influenced by disease genes, including essential genes and tissue-specific genes, might be significantly associated with the disease diversity of subpathways, suggesting that different kinds of genes within a disease-related subpathway may play significantly

  1. Modelling the effect of conjugate vaccines in pneumococcal disease: cohort or population models?

    PubMed

    Standaert, Baudouin; Demarteau, Nadia; Talbird, Sandra; Mauskopf, Josephine

    2010-11-19

    Cohort and population models estimate vaccine impact on disease events, and yield different estimates in countries with different demographic compositions. We compared administration of the new 10-valent pneumococcal Haemophilus influenzae-protein D conjugate vaccine (PHiD-CV) with no vaccination in two countries, the United Kingdom (UK) and Mexico, using two modelling strategies: a cohort model and a population model. The cohort model followed a birth cohort over a lifetime, beginning 10 years after initiation of the vaccine program, when vaccine efficacy steady state had been reached. The population model examined the country-specific population over 1 year, also beginning 10 years after initiation of the vaccine program. Both models included the same age-specific disease rates of meningitis, bacteraemia, pneumonia, and otitis media. The output variables were the numbers of specific events, with and without indirect vaccine effects. Without indirect effects, the cohort and population models produced similar results for both countries (deviation of <20% difference per output measure for most outcomes). The difference between the model types was much greater when indirect vaccine effects were included, especially in Mexico (up to 120% difference). Cohort and population modelling methods produce different results depending on the disease, the intervention, the demographic composition, and the time horizon evaluated. Results from the two model types provide different information about the impact of interventions on events: accumulated vaccine benefit for an individual in a cohort model; vaccine benefit for a whole population at a specific time point in a population model.

  2. Deregulation of sphingolipid metabolism in Alzheimer's disease

    PubMed Central

    He, Xingxuan; Huang, Yu; Li, Bin; Gong, Cheng-Xing; Schuchman, Edward H.

    2010-01-01

    Abnormal sphingolipid metabolism has been previously reported in Alzheimer's disease (AD). To extend these findings, several sphingolipids and sphingolipid hydrolases were analyzed in brain samples from AD patients and age-matched normal individuals. We found a pattern of elevated acid sphingomyelinase (ASM) and acid ceramidase (AC) expression in AD, leading to a reduction in sphingomyelin and elevation of ceramide. More sphingosine also was found in the AD brains, although sphingosine-1-phosphate (S1P) levels were reduced. Notably, significant correlations were observed between the brain ASM and S1P levels and the levels of amyloid beta peptide (Aβ) and phosphorylated tau protein. Based on these findings, neuronal cell cultures were treated with Aβ oligomers, which were found to activate ASM, increase ceramide, and induce apoptosis. Pre-treatment of the neurons with purified, recombinant AC prevented the cells from undergoing Aβ-induced apoptosis. We propose that ASM activation is an important pathological event leading to AD, perhaps due to Aβ deposition. The downstream consequences of ASM activation are elevated ceramide, activation of ceramidases, and production of sphingosine. The reduced levels of S1P in the AD brain, together with elevated ceramide, likely contribute to the disease pathogenesis. PMID:18547682

  3. UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells

    ClinicalTrials.gov

    2016-07-27

    Adrenoleukodystrophy; Batten Disease; Mucopolysaccharidosis II; Leukodystrophy, Globoid Cell; Leukodystrophy, Metachromatic; Neimann Pick Disease; Pelizaeus-Merzbacher Disease; Sandhoff Disease; Tay-Sachs Disease; Brain Diseases, Metabolic, Inborn

  4. Inherited metabolic diseases affecting the carrier.

    PubMed

    Endres, W

    1997-03-01

    The objective of this review is to draw attention to those inherited metabolic traits which are potentially harmful also for the carrier, and to outline preventive measures, at least for obligate heterozygotes, i.e. parents of homozygous children. Concerning carriers of food-dependent abnormalities, early vascular disease in homocystinuria, hyperammonaemic episodes in ornithine transcarbamylase deficiency, presenile cataracts in galactosaemia as well as galactokinase deficiency, spastic paraparesis in X-linked adrenoleukodystrophy, and HELLP syndrome in mothers of babies with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency have to be mentioned. In the group of food-independent disorders, clinical features in carriers may be paraesthesias and corneal dystrophy in Fabry disease, lens clouding in Lowe syndrome, lung and/or liver diseases in alpha 1-antitrypsin deficiency, and renal stones in cystinuria type II and III. Finally, two monogenic carrier states are known which in pregnant individuals could possibly afflict the developing fetus, i.e. heterozygosity for galactosaemia and for phenylketonuria. Elevated levels of galactose-1-phosphate have been found in red blood cells of infants heterozygous for galactosaemia born to heterozygous mothers. Aspartame in very high doses is reported to increase blood phenylalanine levels in heterozygotes for phenylketonuria, thus being a risk for the fetus of a heterozygous mother. For some of these carrier states preventive measures can be recommended, e.g. restriction of lactose in parents and heterozygous grandparents of children with galactosaemia and galactokinase deficiency as well as transiently in infants heterozygous for galactosaemia, dietary supplementation with monounsaturated fatty acids in symptomatic carriers for X-linked adrenoleukodystrophy, avoidance of smoking and alcohol in heterozygotes for alpha 1-antitrypsin deficiency, avoidance of episodes of dehydration in heterozygotes for cystinuria, and

  5. Periodontal disease: the influence of metabolic syndrome

    PubMed Central

    2012-01-01

    Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors that include obesity, impaired glucose tolerance or diabetes, hyperinsulinemia, hypertension, and dyslipidemia. Recently, more attention has been reserved to the correlation between periodontitis and systemic health. MetS is characterized by oxidative stress, a condition in which the equilibrium between the production and the inactivation of reactive oxygen species (ROS) becomes disrupted. ROS have an essential role in a variety of physiological systems, but under a condition of oxidative stress, they contribute to cellular dysfunction and damage. Oxidative stress may act as a common link to explain the relationship between each component of MetS and periodontitis. All those conditions show increased serum levels of products derived from oxidative damage, promoting a proinflammatory state. Moreover, adipocytokines, produced by the fat cells of fat tissue, might modulate the balance between oxidant and antioxidant activities. An increased caloric intake involves a higher metabolic activity, which results in an increased production of ROS, inducing insulin resistance. At the same time, obese patients require more insulin to maintain blood glucose homeostasis – a state known as hyperinsulinemia, a condition that can evolve into type 2 diabetes. Oxidation products can increase neutrophil adhesion and chemotaxis, thus favoring oxidative damage. Hyperglycemia and an oxidizing state promote the genesis of advanced glycation end-products, which could also be implicated in the degeneration and damage of periodontal tissue. Thus, MetS, the whole of interconnected factors, presents systemic and local manifestations, such as cardiovascular disease and periodontitis, related by a common factor known as oxidative stress. PMID:23009606

  6. [Impact of metabolic syndrome on chronic kidney disease].

    PubMed

    Calò, L A

    2006-12-01

    Metabolic syndrome has been recognized as possible risk factor for renal damage and the increased prevalence of both metabolic syndrome and renal disease justifies the increasing interest of the nephrology community toward the metabolic syndrome as another possible inducing cause of chronic renal disease, although the available evidence about a direct causal relationship between metabolic syndrome and development of renal disease so far is scanty. The not easy separation of the negative effects on renal function of metabolic syndrome from those derived from hypertension and diabetes per se, however, does not reduce the interest toward a possible direct impact of metabolic syndrome on renal disease. This also in consideration that other important factors linked with metabolic syndrome, such as for example obesity, have direct independent impact on the development of abnormalities such as microalbuminuria and or overt renal disease. Planning of clinical trials specifically for patients with metabolic syndrome could be helpful to give definitive answers on a possible direct impact of metabolic syndrome on chronic renal disease.

  7. The Cohort Study on Prediction of Incidence of All-Cause Mortality by Metabolic Syndrome

    PubMed Central

    Li, Zhixia; Yang, Xinghua; Yang, Jun; Yang, Zhirong; Wang, Shengfeng

    2016-01-01

    Aim The aim was to evaluate the impact of metabolic syndrome (MS), MS individual components and 32 kinds of MS specific component combinations on all-cause mortality risk in a fixed cohort of MJ check-up population. Methods We observed the events of death in a fixed cohort, where the population was composed of 45,542 individuals aged 35–74 who were examined at MJ Health check-up Center in 1997 as baseline examination, and were followed up to 2005. Median duration of follow-up was 7.44 years. MS was defined according to the National Cholesterol Educational Program (the revised NCEP-ATPIII for Asian in 2004), the prevalence of MS was standardized according to China’s fifth census data. We constructed common Cox regression model, simultaneously adjusting the classic risk factors (such as age, sex, smoking, alcohol drinking, physical activity, family history, etc.) to examine the relationship between MS, MS individual components and 32 kinds of MS specific component combinations on the occurrence of death with the fixed cohort. Results The standardized prevalence of MS was 29.75% (male: 30.36%, female: 29.51%). There were 1,749 persons who died during the median 7.44-years follow-up, the mortality rate was 46 per 10,000 person years. The mortality rates were 71 and 35 per 10,000 person years for those with and without MS, respectively. After adjustment for age, sex and classical risk factors, compared with subjects without MS, the hazard ratio of all-cause mortality was 1.26 (95% CI: 1.14–1.40). The all-cause mortality were more highly significant than other combinations (P <0.05) when the following combinations exist: “elevated blood pressure”, “elevated fasting plasma glucose + low high-density lipoprotein cholesterol”, “elevated blood pressure + elevated triglyceride + elevated fasting plasma glucose”, “elevated fasting plasma glucose + low high-density lipoprotein cholesterol + elevated blood pressure + elevated triglyceride”. After adjusting

  8. Gestational dating by metabolic profile at birth: a California cohort study

    PubMed Central

    Jelliffe-Pawlowski, Laura L.; Norton, Mary E.; Baer, Rebecca J.; Santos, Nicole; Rutherford, George W.

    2016-01-01

    Background Accurate gestational dating is a critical component of obstetric and newborn care. In the absence of early ultrasound, many clinicians rely on less accurate measures, such as last menstrual period or symphysis-fundal height during pregnancy, or Dubowitz scoring or the Ballard (or New Ballard) method at birth. These measures often underestimate or overestimate gestational age and can lead to misclassification of babies as born preterm, which has both short- and long-term clinical care and public health implications. Objective We sought to evaluate whether metabolic markers in newborns measured as part of routine screening for treatable inborn errors of metabolism can be used to develop a population-level metabolic gestational dating algorithm that is robust despite intrauterine growth restriction and can be used when fetal ultrasound dating is not available. We focused specifically on the ability of these markers to differentiate preterm births (PTBs) (<37 weeks) from term births and to assign a specific gestational age in the PTB group. Study Design We evaluated a cohort of 729,503 singleton newborns with a California birth in 2005 through 2011 who had routine newborn metabolic screening and fetal ultrasound dating at 11–20 weeks’ gestation. Using training and testing subsets (divided in a ratio of 3:1) we evaluated the association among PTB, target newborn characteristics, acylcarnitines, amino acids, thyroid-stimulating hormone, 17-hydroxyprogesterone, and galactose-1-phosphate-uridyl-transferase. We used multivariate backward stepwise regression to test for associations and linear discriminate analyses to create a linear function for PTB and to assign a specific week of gestation. We used sensitivity, specificity, and positive predictive value to evaluate the performance of linear functions. Results Along with birthweight and infant age at test, we included 35 of the 51 metabolic markers measured in the final multivariate model comparing PTBs and

  9. Diurnal Cortisol Patterns, Future Diabetes, and Impaired Glucose Metabolism in the Whitehall II Cohort Study

    PubMed Central

    Kivimäki, Mika; Kumari, Meena; Steptoe, Andrew

    2016-01-01

    Context: The hypothalamic pituitary-adrenal axis is thought to play a role in type 2 diabetes (T2D). However, evidence for an association between cortisol and future glucose disturbance is sparse. Objective: The aim was to examine the association of diurnal cortisol secretion with future T2D and impaired glucose metabolism in a community-dwelling population. Design: This is a prospective cohort study of salivary cortisol measured at the 2002–2004 clinical examination of the Whitehall II study, United Kingdom. We measured cortisol (nmol/l) from six saliva samples obtained over the course of a day: at waking, +30 minutes, +2.5 hours, +8 hours, +12 hours, and bedtime. Participants who were normoglycemic in 2002–2004 (phase 7) were reexamined in 2012–2013 (phase 11). Setting: The occupational cohort was originally recruited in 1985–1988. Participants: A total of 3270 men and women with an average age of 60.85 years at phase 7 (2002–2004). Outcome Measures: Incident T2D and impaired fasting glucose in 2012–2013 were measured. Results: Raised evening cortisol at phase 7 was predictive of new-onset T2D at phase 11 (odds ratio [OR], 1.18; 95% confidence interval [CI], 1.01–1.37) with a trend for a flatter slope in participants with incident T2D (odds ratio, 1.15; 95% CI, 0.99–1.33). When expanding this analysis to a broader category of glucose disturbance we found that a flattened diurnal cortisol slope at phase 7 was predictive of future impaired fasting glucose or T2D at phase 11 (OR, 1.12; 95% CI, 1.02–1.22), as was high bedtime cortisol (OR, 1.10; 95% CI, 1.01–1.20). Conclusions: In this nonclinical population, alterations in diurnal cortisol patterns were predictive of future glucose disturbance. PMID:26647151

  10. Hepatocyte transplantation for inherited metabolic diseases of the liver.

    PubMed

    Jorns, C; Ellis, E C; Nowak, G; Fischler, B; Nemeth, A; Strom, S C; Ericzon, B G

    2012-09-01

    Inherited metabolic diseases of the liver are characterized by deficiency of a hepatic enzyme or protein often resulting in life-threatening disease. The remaining liver function is usually normal. For most patients, treatment consists of supportive therapy, and the only curative option is liver transplantation. Hepatocyte transplantation is a promising therapy for patients with inherited metabolic liver diseases, which offers a less invasive and fully reversible approach. Procedure-related complications are rare. Here, we review the experience of hepatocyte transplantation for metabolic liver diseases and discuss the major obstacles that need to be overcome to establish hepatocyte transplantation as a reliable treatment option in the clinic.

  11. Pediatric liver transplantation in metabolic disease: clinical decision making.

    PubMed

    Shneider, Benjamin L

    2002-02-01

    Proper utilization of liver transplantation in the management of pediatric metabolic diseases requires a comprehensive understanding of both metabolic disease and the risk and benefits of transplantation. This brief review focuses on issues that pertain to the treatment of tyrosinemia type I, bile acid biosynthesis disorders, primary hyperoxaluria, Crigler-Najjar Type I, and mitochondrial diseases. These entities are used as prototypes to illustrate many of the principles that are applied in a more general sense to the management of metabolic diseases. The natural history of these disorders are considered in the context of the risks of liver transplantation. Indications, contraindications, and both current and future alternatives to transplantation, are considered.

  12. Chronic Kidney Disease Is Often Unrecognized among Patients with Coronary Heart Disease: The REGARDS Cohort Study

    PubMed Central

    McClellan, William M.; Newsome, Britt B.; McClure, Leslie A.; Cushman, Mary; Howard, George; Audhya, Paul; Abramson, Jerome L.; Warnock, David G.

    2008-01-01

    Introduction Individuals with kidney disease are at increased risk for coronary heart disease (CHD) and CHD is associated with an increased prevalence of chronic kidney disease (CKD). Awareness of CKD may potentially influence diagnostic decisions, life-style changes and pharmacologic interventions targeted at modifiable CHD risk factors. We describe here the degree to which persons with CHD are aware of their CKD. Methods The Reasons for Geographical and Racial Difference in Stroke (REGARDS) cohort study, a population-based sample of US residents aged 45 and older. We included in our analyses 28,112 REGARDS participants recruited as of June 2007. We estimated GFR (eGFR) using the MDRD equation, defined CKD as a GFR <60 ml/min/1.73 m2, and ascertained awareness of chronic kidney disease and coronary heart disease through self-report. We used the odds ratio to compare the association between awareness of kidney disease, as measured by GFR <60 ml/min/1.73 m2, among individuals with and without self-reported CHD by both the presence of CKD and the severity of impaired kidney function. Results Coronary heart disease was reported by 3,803 (14.1%) of subjects, and 11.3% of subjects had CKD by eGFR. Among all individuals with a GFR <60 ml/min/ 1.73 m2, 9.6% reported having been told by a physician that they had kidney disease. Among those with CHD and CKD, 5.0% were aware of their CKD compared to 2.0% in those without CHD [OR (95% CI) = 2.57 (2.08, 3.28)]. This difference persisted after controlling for the level of kidney function [aOR (95% CI) = 1.87 (1.43, 2.41)]. Conclusion There was a high prevalence of CKD and a low prevalence of awareness of kidney disease among older adults in the US population with or without coronary heart disease. These findings support recent recommendations that patients with cardiovascular disease be systematically screened for and educated about CKD. PMID:18663284

  13. Shiftwork and impaired glucose metabolism: a 14-year cohort study on 7104 male workers.

    PubMed

    Suwazono, Yasushi; Dochi, Mirei; Oishi, Mitsuhiro; Tanaka, Kumihiko; Kobayashi, Etsuko; Sakata, Kouichi

    2009-07-01

    The aim of this study was to assess the effect of shiftwork on hemoglobin A1c (HbA1c) level, as an index of glucose metabolism. A 14 yr prospective cohort study was conducted on day (n = 4219) and alternating shiftworkers (n = 2885) who received annual health checkups between 1991 and 2005 at a Japanese steel company. The endpoints were either a 10%, 15%, 20%, 25%, or 30% increase in HbA1c during the period of observation, compared to HbA1c at entry to the study. The association between the type of job schedule and increase in HbA1c was investigated after adjusting for age, body mass index, mean arterial pressure, total serum cholesterol, creatinine, alanine aminotransferase, gamma-glutamyl transpeptidase, uric acid, drinking habit, smoking habit, and habitual exercise using multivariate pooled logistic regression analyses. Shiftwork was significantly associated with the various HbA1c endpoints (> or =10% HbA1c increase, odds ratio 1.35 [95% confidence interval 1.26-1.44]; > or =15% HbA1c increase, odds ratio 1.29 [95% confidence interval, 1.19-1.40]; > or =20% HbA1c increase, odds ratio 1.23 [95% confidence interval 1.11-1.37]; and > or =25% HbA1c increase, odds ratio 1.19 [95% confidence interval 1.03-1.36]). Age, body mass index, alanine aminotransferase, and gamma-glutamyl transpeptidase were associated positively with all five HbA1c endpoints. Uric acid was associated negatively with all five HbA1c endpoints. Our study on male Japanese workers revealed alternating shiftwork (in addition to other established factors, such as age and body mass index) was a consistent risk factor for impaired glucose metabolism. PMID:19637051

  14. Serum lipids and bone metabolism in Spanish men: the Camargo cohort study.

    PubMed

    Hernández, José L; Olmos, José M; Ramos, Carmen; Martínez, Josefina; de Juan, Julia; Valero, Carmen; Nan, Daniel; González-Macías, Jesus

    2010-01-01

    There is growing evidence of a link between lipid and bone metabolism, although data on this association in European men are scarce. This cross-sectional study from a community-based prospective cohort aims to explore the association of serum lipids with different aspects of bone metabolism in Spanish men. Demographic and anthropometric measurements, biochemical parameters including serum lipids, bone remodelling markers and calciotropic hormones, bone mineral density (BMD) assessed by dual X-ray absorptiometry and heel quantitative ultrasound, and prevalent vertebral and non-vertebral fractures, were evaluated in 289 men. Calciotropic hormones or bone markers were not associated with serum lipids. Serum total (TC) and LDL cholesterol, as well as LDL/HDL ratio were positively correlated to BMD at lumbar spine and hip. No significant correlation was noted for triglycerides or HDL. We observed a positive association between triglycerides, LDL/HDL ratio and BUA, and between TC/HDL ratio and both, QUI and BUA. BMD at the femoral neck and total hip was significantly higher in men with hypercholesterolemia after controlling for all the covariates (p=0.007). We did not observe any association between serum lipids and prevalent vertebral fractures. However, we found that TC (p=0.03) and LDL (p=0.04) were lower in subjects with non-vertebral fractures. In conclusion, we have found that a more unfavorable lipid profile (mainly higher LDL-C levels) is associated with higher BMD at lumbar spine and hip in Spanish men. Moreover, we did not observe any association between hypercholesterolemia and prevalent vertebral fractures, but we found lower serum TC and LDL-C levels in men with prevalent non-vertebral fractures.

  15. RNA metabolism in the pathogenesis of Parkinson׳s disease.

    PubMed

    Lu, Bingwei; Gehrke, Stephan; Wu, Zhihao

    2014-10-10

    Neurodegenerative diseases such as Parkinson׳s disease are progressive disorders of the nervous system that affect the function and maintenance of specific neuronal populations. While most disease cases are sporadic with no known cause, a small percentage of disease cases are caused by inherited genetic mutations. The identification of genes associated with the familial forms of the diseases and subsequent studies of proteins encoded by the disease genes in cellular or animal models have offered much-needed insights into the molecular and cellular mechanisms underlying disease pathogenesis. Recent studies of the familial Parkinson׳s disease genes have emphasized the importance of RNA metabolism, particularly mRNA translation, in the disease process. It is anticipated that continued studies on the role of RNA metabolism in Parkinson׳s disease will offer unifying mechanisms for understanding the cause of neuronal dysfunction and degeneration and facilitate the development of novel and rational strategies for treating this debilitating disease.

  16. Herpes zoster infection increases the risk of peripheral arterial disease: A nationwide cohort study.

    PubMed

    Lin, Te-Yu; Yang, Fu-Chi; Lin, Cheng-Li; Kao, Chia-Hung; Lo, Hsin-Yi; Yang, Tse-Yen

    2016-08-01

    Varicella-zoster virus infection can cause meningoencephalitis, myelitis, ocular disorders, and vasculopathy. However, no study has investigated the association between herpes zoster (HZ) and peripheral arterial disease (PAD).We identified newly diagnosed HZ from the Taiwan's National Health Insurance Research Database recorded during 2000 to 2010, with a follow-up period extending until December 31, 2011. In addition, we included a comparison cohort that was randomly frequency-matched with the HZ cohort according to age, sex, and index year. We analyzed the risk of PAD with respect to sex, age, and comorbidities by using Cox proportional-hazards regression models.In total, 35,391 HZ patients and 141,556 controls were enrolled in this study. The risk of PAD was 13% increased in the HZ cohort than in the comparison cohort after adjustment for age, sex, and comorbidities. The Kaplan-Meier survival curve showed that the risk of PAD was significantly higher in the HZ cohort than in the non-HZ cohort (P < 0.001).This nationwide population-based cohort study revealed a higher risk of PAD in patients with HZ infection than in those without the infection. Careful follow-up and aggressive treatment is recommended for patients with HZ to reduce the risk of PAD. PMID:27583856

  17. Associations Between Genetic Ancestries and Nicotine Metabolism Biomarkers in the Multiethnic Cohort Study.

    PubMed

    Wang, Hansong; Park, Sungshim L; Stram, Daniel O; Haiman, Christopher A; Wilkens, Lynne R; Hecht, Stephen S; Kolonel, Laurence N; Murphy, Sharon E; Le Marchand, Loïc

    2015-12-01

    Differences in internal dose of nicotine and tobacco-derived carcinogens among ethnic/racial groups have been observed. In this study, we explicitly examined the relationships between genetic ancestries (genome-wide average) and 19 tobacco-derived biomarkers in smokers from 3 admixed groups in the Multiethnic Cohort Study (1993-present), namely, African ancestry in African Americans (n = 362), Amerindian ancestry in Latinos (n = 437), and Asian and Native Hawaiian ancestries in Native Hawaiians (n = 300). After multiple comparison adjustment, both African and Asian ancestries were significantly related to a greater level of free cotinine; African ancestry was also significantly related to lower cotinine glucuronidation (P's < 0.00156). The predicted decrease in cotinine glucuronidation was 8.6% (P = 4.5 × 10(-6)) per a 20% increase in African ancestry. Follow-up admixture mapping revealed that African ancestry in a 12-Mb region on chromosome 4q was related to lower cotinine glucuronidation (P's < 2.7 × 10(-7), smallest P = 1.5 × 10(-9)), although this is the same region reported in our previous genome-wide association study. Our results implicate a genetic ancestral component in the observed ethnic/racial variation in nicotine metabolism. Further studies are needed to identify the underlying genetic variation that could potentially be ethnic/racial specific. PMID:26568573

  18. Impact of metabolic syndrome components on incident stroke subtypes: a Chinese cohort study.

    PubMed

    Chen, Y-C; Sun, C-A; Yang, T; Chu, C-H; Bai, C-H; You, S-L; Hwang, L-C; Chen, C-H; Wei, C-Y; Chou, Y-C

    2014-11-01

    Limited evidence is available on the risk differences in the development of stroke subtypes in relation to particular clustering patterns of the metabolic syndrome (MetS) components. A follow-up study of a Chinese cohort involving 10,292 individuals was performed to assess the roles of cluster patterns of the MetS components in the prediction of incident stroke subtypes. During follow-up, there were 161 incident cases of ischemic strokes and 41 incident cases of hemorrhagic strokes. Among MetS components, only the hypertensive trait was associated with significantly elevated risks of both ischemic and hemorrhagic strokes. Furthermore, MetS with hypertension as components was associated with increased risk of ischemic and hemorrhagic strokes (adjusted hazards ratio (95% confidence interval) was 2.96 (1.94-4.50) and 2.93 (1.25-6.90), respectively) as compared with those who had neither hypertension nor MetS. Notably, as the number of the MetS components increased, the risk of ischemic stroke significantly and dose-dependently increased. This implies a cumulative effect of MetS components in elevating the risk of ischemic stroke. These findings suggest that MetS comprises heterogenous clusters with respect to the risk of developing the subtype of stroke.

  19. Metabolic diseases and pro- and prebiotics: Mechanistic insights

    PubMed Central

    2012-01-01

    Metabolic diseases, such as obesity and type 2 diabetes, are world-wide health problems. The prevalence of metabolic diseases is associated with dynamic changes in dietary macronutrient intake during the past decades. Based on national statistics and from a public health viewpoint, traditional approaches, such as diet and physical activity, have been unsuccessful in decreasing the prevalence of metabolic diseases. Since the approaches strongly rely on individual’s behavior and motivation, novel science-based strategies should be considered for prevention and therapy for the diseases. Metabolism and immune system are linked. Both overnutrition and infection result in inflammation through nutrient and pathogen sensing systems which recognize compounds with structural similarities. Dietary macronutrients (fats and sugars) can induce inflammation through activation of an innate immune receptor, Toll-like receptor 4 (TLR4). Long-term intake of diets high in fats and meats appear to induce chronic systemic low-grade inflammation, endotoxicity, and metabolic diseases. Recent investigations support the idea of the involvement of intestinal bacteria in host metabolism and preventative and therapeutic potentials of probiotic and prebiotic interventions for metabolic diseases. Specific intestinal bacteria seem to serve as lipopolysaccharide (LPS) sources through LPS and/or bacterial translocation into the circulation due to a vulnerable microbial barrier and increased intestinal permeability and to play a role in systemic inflammation and progression of metabolic diseases. This review focuses on mechanistic links between metabolic diseases (mainly obesity and type 2 diabetes), chronic systemic low-grade inflammation, intestinal environment, and nutrition and prospective views of probiotic and prebiotic interventions for the diseases. PMID:22713169

  20. Early growth and coronary heart disease and type 2 diabetes: findings from the Helsinki Birth Cohort Study (HBCS).

    PubMed

    Eriksson, Johan G

    2011-12-01

    A slow rate of intrauterine growth is a major risk factor for several common noncommunicable diseases, which include the following: coronary heart disease (CHD), hypertension, and type 2 diabetes. Likewise, growth patterns in infancy and childhood have been identified as important factors linked to the pathogenesis of these disorders. In this overview, patterns of growth associated with CHD, type 2 diabetes, and related metabolic traits in adult life are presented on the basis of findings from the Helsinki Birth Cohort Study (HBCS) 1934-1944. Later risk of CHD was associated with small body size at birth and during infancy, followed by an increase in body size later in childhood. This pattern of growth has been associated with dyslipidemia in later life, which offers an explanation for the observed findings. Type 2 diabetes and CHD share several risk factors. The early growth of persons who later develop type 2 diabetes includes a small body size at birth as well as a small body size during infancy. An early age at adiposity rebound was associated with a markedly increased risk of type 2 diabetes in adulthood. The patterns of growth associated with type 2 diabetes are also associated with alterations in body composition, which predisposes to insulin resistance and the metabolic syndrome. The presented findings suggest that to be able to understand the pathogenesis of several noncommunicable diseases, the diseases need to be studied from a life-course perspective, and prenatal and childhood growth as well as adult characteristics need to be taken into account.

  1. Metabolic syndrome and chronic kidney disease.

    PubMed

    Belarbia, Anis; Nouira, Safa; Sahtout, Wissal; Guedri, Yosra; Achour, Abdellatif

    2015-09-01

    To determine the prevalence of metabolic syndrome (MS) in chronic kidney disease (CKD) patients as well as its effects on the progression of CKD, we conducted a prospective, longitudinal study including 180 patients with chronic renal failure followed at the outpatient service of Nephrology at the Saloul's University Hospital of Sousse (Tunisia) over six months. Our study population consisted of 101 men and 79 women. Chronic glomerulonephritis (36.6%) was the most frequent nephropathy. The mean serum creatinine was 249 ± 200 mmol/L and the mean estimated glomerular filtration rate (eGFR) was 55.8 ± 49.2 mL/min. Cardiovascular (CV) impairment was found in 27.2% of the patients. The prevalence of MS was 42.2%. Women had significantly more abdominal obesity than men. Subjects with MS were significantly older and predominantly females who had higher blood pressure and body mass index (BMI). CV complications were more frequent among the MS subjects than among the controls. Glycemia, triglycerides, total cholesterol and low-density lipoprotein-cholesterol (LDL-c) were significantly higher in the group of CKD patients with MS. However, the occurrence of MS was not influenced by the nature of nephropathy, the degree of the CKD and the use of renin-angiotensin blockers or statins. In multivariate analysis, predictors of occurrence of MS in our series included older age, female gender and higher BMI and LDL-c levels. The prevalence of MS in patients with CKD is higher than the general population. These patients should receive special multidisciplinary care to limit CV complications.

  2. Transition dynamics of HIV disease in a cohort of African prostitutes: a Markov model approach.

    PubMed

    Nagelkerke, N J; Plummer, F A; Holton, D; Anzala, A O; Manji, F; Ngugi, E N; Moses, S

    1990-08-01

    The progression of HIV-related disease from infection to death is represented as a staged Markov model. Transitions between stages are considered reversible. The model is fitted to data from a cohort of African prostitutes by means of maximum likelihood. It appears that the progression to symptomatic disease (Centers for Disease Control stage IV) in this population is considerably more rapid than that reported from studies in Western countries. PMID:2175619

  3. Transition dynamics of HIV disease in a cohort of African prostitutes: a Markov model approach.

    PubMed

    Nagelkerke, N J; Plummer, F A; Holton, D; Anzala, A O; Manji, F; Ngugi, E N; Moses, S

    1990-08-01

    The progression of HIV-related disease from infection to death is represented as a staged Markov model. Transitions between stages are considered reversible. The model is fitted to data from a cohort of African prostitutes by means of maximum likelihood. It appears that the progression to symptomatic disease (Centers for Disease Control stage IV) in this population is considerably more rapid than that reported from studies in Western countries.

  4. Cancer as a metabolic disease: implications for novel therapeutics.

    PubMed

    Seyfried, Thomas N; Flores, Roberto E; Poff, Angela M; D'Agostino, Dominic P

    2014-03-01

    Emerging evidence indicates that cancer is primarily a metabolic disease involving disturbances in energy production through respiration and fermentation. The genomic instability observed in tumor cells and all other recognized hallmarks of cancer are considered downstream epiphenomena of the initial disturbance of cellular energy metabolism. The disturbances in tumor cell energy metabolism can be linked to abnormalities in the structure and function of the mitochondria. When viewed as a mitochondrial metabolic disease, the evolutionary theory of Lamarck can better explain cancer progression than can the evolutionary theory of Darwin. Cancer growth and progression can be managed following a whole body transition from fermentable metabolites, primarily glucose and glutamine, to respiratory metabolites, primarily ketone bodies. As each individual is a unique metabolic entity, personalization of metabolic therapy as a broad-based cancer treatment strategy will require fine-tuning to match the therapy to an individual's unique physiology.

  5. Cancer as a metabolic disease: implications for novel therapeutics.

    PubMed

    Seyfried, Thomas N; Flores, Roberto E; Poff, Angela M; D'Agostino, Dominic P

    2014-03-01

    Emerging evidence indicates that cancer is primarily a metabolic disease involving disturbances in energy production through respiration and fermentation. The genomic instability observed in tumor cells and all other recognized hallmarks of cancer are considered downstream epiphenomena of the initial disturbance of cellular energy metabolism. The disturbances in tumor cell energy metabolism can be linked to abnormalities in the structure and function of the mitochondria. When viewed as a mitochondrial metabolic disease, the evolutionary theory of Lamarck can better explain cancer progression than can the evolutionary theory of Darwin. Cancer growth and progression can be managed following a whole body transition from fermentable metabolites, primarily glucose and glutamine, to respiratory metabolites, primarily ketone bodies. As each individual is a unique metabolic entity, personalization of metabolic therapy as a broad-based cancer treatment strategy will require fine-tuning to match the therapy to an individual's unique physiology. PMID:24343361

  6. [Relationship between metabolic syndrome and urinary stone disease].

    PubMed

    Yamaguchi, Satoshi

    2011-10-01

    Epidemiologically, there are many same characteristics among patients with urolithiasis, life-style related diseases and metabolic syndrome. In a comparison with the major urological diseases, the patients with stone disease have the largest amount of visceral fat on computerized tomography. The patients who finally had a diagnosis of metabolic syndrome in urolithiasis were 43% of men and female 31%. The clinical features of the patients include increased urinary oxalate excretion, abnormal uric acid metabolism, and acidic urine. The basic studies by the animal experiments suggest that there is a close relationship between urolithiasis and metabolic syndrome. After the treatment of the urinary stone, it is very important to make a long-term follow-up by not only the prevention of recurrent stone episode but also life style management and medical treatment for metabolic syndrome. PMID:21960234

  7. Recent developments in metabolic bone diseases: a gnathic perspective.

    PubMed

    Raubenheimer, Erich J; Noffke, Claudia E; Hendrik, Hilde D

    2014-12-01

    Metabolic bone diseases often are asymptomatic and progress sub clinically. Many patients present at a late stage with catastrophic skeletal and extra skeletal complications. In this article, we provide an overview of normal bone remodeling and a synopsis of recent developments in the following conditions: osteoporosis, rickets/osteomalacia, endocrine-induced bone disease, chronic kidney disease-mineral bone disorder and Paget's disease of bone. Our discussion will emphasize the clinical and microscopic manifestations of these diseases in the jaws.

  8. Quantifying prion disease penetrance using large population control cohorts.

    PubMed

    Minikel, Eric Vallabh; Vallabh, Sonia M; Lek, Monkol; Estrada, Karol; Samocha, Kaitlin E; Sathirapongsasuti, J Fah; McLean, Cory Y; Tung, Joyce Y; Yu, Linda P C; Gambetti, Pierluigi; Blevins, Janis; Zhang, Shulin; Cohen, Yvonne; Chen, Wei; Yamada, Masahito; Hamaguchi, Tsuyoshi; Sanjo, Nobuo; Mizusawa, Hidehiro; Nakamura, Yosikazu; Kitamoto, Tetsuyuki; Collins, Steven J; Boyd, Alison; Will, Robert G; Knight, Richard; Ponto, Claudia; Zerr, Inga; Kraus, Theo F J; Eigenbrod, Sabina; Giese, Armin; Calero, Miguel; de Pedro-Cuesta, Jesús; Haïk, Stéphane; Laplanche, Jean-Louis; Bouaziz-Amar, Elodie; Brandel, Jean-Philippe; Capellari, Sabina; Parchi, Piero; Poleggi, Anna; Ladogana, Anna; O'Donnell-Luria, Anne H; Karczewski, Konrad J; Marshall, Jamie L; Boehnke, Michael; Laakso, Markku; Mohlke, Karen L; Kähler, Anna; Chambert, Kimberly; McCarroll, Steven; Sullivan, Patrick F; Hultman, Christina M; Purcell, Shaun M; Sklar, Pamela; van der Lee, Sven J; Rozemuller, Annemieke; Jansen, Casper; Hofman, Albert; Kraaij, Robert; van Rooij, Jeroen G J; Ikram, M Arfan; Uitterlinden, André G; van Duijn, Cornelia M; Daly, Mark J; MacArthur, Daniel G

    2016-01-20

    More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance-the probability that a carrier of the purported disease-causing genotype will indeed develop the disease-is generally unknown. We assess the impact of variants in the prion protein gene (PRNP) on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 population control exomes, and 531,575 individuals genotyped by 23andMe Inc. We show that missense variants in PRNP previously reported to be pathogenic are at least 30 times more common in the population than expected on the basis of genetic prion disease prevalence. Although some of this excess can be attributed to benign variants falsely assigned as pathogenic, other variants have genuine effects on disease susceptibility but confer lifetime risks ranging from <0.1 to ~100%. We also show that truncating variants in PRNP have position-dependent effects, with true loss-of-function alleles found in healthy older individuals, a finding that supports the safety of therapeutic suppression of prion protein expression. PMID:26791950

  9. Validation of metabolic syndrome using medical records in the SUN cohort

    PubMed Central

    2011-01-01

    Background The objective of this study was to evaluate the validity of self reported criteria of Metabolic Syndrome (MS) in the SUN (Seguimiento Universidad de Navarra) cohort using their medical records as the gold standard. Methods We selected 336 participants and we obtained MS related data according to Adult Treatment Panel III (ATP III) and International Diabetes Federation (IDF). Then we compared information on the self reported diagnosis of MS and MS diagnosed in their medical records. We calculated the proportion of confirmed MS, the proportion of confirmed non-MS and the intraclass correlation coefficients for each component of the MS. Results From those 336 selected participants, we obtained sufficient data in 172 participants to confirm or reject MS using ATP III criteria. The proportion of confirmed MS was 91.2% (95% CI: 80.7- 97.1) and the proportion of confirmed non-MS was 92.2% (95% CI: 85.7-96.4) using ATP III criteria. The proportion of confirmed MS using IDF criteria was 100% (95% CI: 87.2-100) and the proportion of confirmed non-MS was 97.1% (95% CI: 85.1-99.9). Kappa Index was 0.82 in the group diagnosed by ATP III criteria and 0.97 in the group diagnosed by IDF criteria. Intraclass correlation coefficients for the different component of MS were: 0.93 (IC 95%:0.91- 0.95) for BMI; 0.96 (IC 95%: 0.93-0.98) for waist circumference; 0.75 (IC 95%: 0.66-0.82) for fasting glucose; 0.50 (IC 95%:0.35-0.639) for HDL cholesterol; 0.78 (IC 95%: 0.70-0.84) for triglycerides; 0.49 (IC 95%:0.34-0.61) for systolic blood pressure and 0.55 (IC 95%: 0.41-0.65) for diastolic blood pressure. Conclusions Self-reported MS based on self reported components of the SM in a Spanish cohort of university graduates was sufficiently valid as to be used in epidemiological studies. PMID:22085407

  10. Fatty acid metabolism: Implications for diet, genetic variation, and disease

    PubMed Central

    Suburu, Janel; Gu, Zhennan; Chen, Haiqin; Chen, Wei; Zhang, Hao; Chen, Yong Q.

    2014-01-01

    Cultures across the globe, especially Western societies, are burdened by chronic diseases such as obesity, metabolic syndrome, cardiovascular disease, and cancer. Several factors, including diet, genetics, and sedentary lifestyle, are suspected culprits to the development and progression of these health maladies. Fatty acids are primary constituents of cellular physiology. Humans can acquire fatty acids by de novo synthesis from carbohydrate or protein sources or by dietary consumption. Importantly, regulation of their metabolism is critical to sustain balanced homeostasis, and perturbations of such can lead to the development of disease. Here, we review de novo and dietary fatty acid metabolism and highlight recent advances in our understanding of the relationship between dietary influences and genetic variation in fatty acid metabolism and their role in chronic diseases. PMID:24511462

  11. Long-Term Mortality in Patients Diagnosed with Meningococcal Disease: A Danish Nationwide Cohort Study

    PubMed Central

    Roed, Casper; Omland, Lars Haukali; Engsig, Frederik Neess; Skinhoj, Peter; Obel, Niels

    2010-01-01

    Background In contrast to the case fatality rate of patients diagnosed with meningococcal disease (MD) the long-term mortality in these patients is poorly documented. Methodology/Principal Findings We performed a nationwide, population-based cohort study including all Danish patients diagnosed with MD from 1977 through 2006 and alive one year after diagnosis. Data was retrieved from the Danish National Hospital Register, the Danish Civil Registration System and the Danish Register of Causes of Death. For each patient four age- and gender-matched individuals were identified from the population cohort. The siblings of the MD patients and of the individuals from the population cohort were identified. We constructed Kaplan-Meier survival curves and used Cox regression analysis, cumulative incidence function and subdistribution hazard regression to estimate mortality rate ratios (MRR) and analyze causes of death. We identified 4,909 MD patients, 19,636 individuals from the population cohort, 8,126 siblings of MD patients and 31,140 siblings of the individuals from the population cohort. The overall MRR for MD patients was 1.27 (95% confidence interval (CI), 1.12–1.45), adjusted MRR, 1.21 (95% CI, 1.06–1.37). MD was associated with increased risk of death due to nervous system diseases (MRR 3.57 (95% CI, 1.82–7.00). No increased mortality due to infections, neoplasms or cardiovascular diseases was observed. The MRR for siblings of MD patients compared with siblings of the individuals from the population cohort was 1.17 (95% CI, 0.92–1.48). Conclusions Patients surviving the acute phase of MD have increased long-term mortality, but the excess risk of death is small and stems mainly from nervous system diseases. PMID:20300639

  12. The role of RNA metabolism in neurological diseases

    PubMed Central

    Abou Al-Shaar, H; Shariff, RK; Albakr, A

    2015-01-01

    Abstract Neurodegenerative disorders are commonly encountered in medical practices. Such diseases can lead to major morbidity and mortality among the affected individuals. The molecular pathogenesis of these disorders is not yet clear. Recent literature has revealed that mutations in RNA-binding proteins are a key cause of several human neuronal-based diseases. This review discusses the role of RNA metabolism in neurological diseases with specific emphasis on roles of RNA translation and microRNAs in neurodegeneration, RNA-mediated toxicity, repeat expansion diseases and RNA metabolism, molecular pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia, and neurobiology of survival motor neuron (SMN) and spinal muscular atrophy. PMID:27785391

  13. Metabolic resting-state brain networks in health and disease.

    PubMed

    Spetsieris, Phoebe G; Ko, Ji Hyun; Tang, Chris C; Nazem, Amir; Sako, Wataru; Peng, Shichun; Ma, Yilong; Dhawan, Vijay; Eidelberg, David

    2015-02-24

    The delineation of resting state networks (RSNs) in the human brain relies on the analysis of temporal fluctuations in functional MRI signal, representing a small fraction of total neuronal activity. Here, we used metabolic PET, which maps nonfluctuating signals related to total activity, to identify and validate reproducible RSN topographies in healthy and disease populations. In healthy subjects, the dominant (first component) metabolic RSN was topographically similar to the default mode network (DMN). In contrast, in Parkinson's disease (PD), this RSN was subordinated to an independent disease-related pattern. Network functionality was assessed by quantifying metabolic RSN expression in cerebral blood flow PET scans acquired at rest and during task performance. Consistent task-related deactivation of the "DMN-like" dominant metabolic RSN was observed in healthy subjects and early PD patients; in contrast, the subordinate RSNs were activated during task performance. Network deactivation was reduced in advanced PD; this abnormality was partially corrected by dopaminergic therapy. Time-course comparisons of DMN loss in longitudinal resting metabolic scans from PD and Alzheimer's disease subjects illustrated that significant reductions appeared later for PD, in parallel with the development of cognitive dysfunction. In contrast, in Alzheimer's disease significant reductions in network expression were already present at diagnosis, progressing over time. Metabolic imaging can directly provide useful information regarding the resting organization of the brain in health and disease.

  14. Combined Effects of Smoking and Alcohol on Metabolic Syndrome: The LifeLines Cohort Study

    PubMed Central

    Slagter, Sandra N.; van Vliet-Ostaptchouk, Jana V.; Vonk, Judith M.; Boezen, H. Marieke; Dullaart, Robin P. F.; Kobold, Anneke C. Muller.; Feskens, Edith J. M.; van Beek, André P.; van der Klauw, Melanie M.; Wolffenbuttel, Bruce H.R.

    2014-01-01

    Introduction The development of metabolic syndrome (MetS) is influenced by environmental factors such as smoking and alcohol consumption. We determined the combined effects of smoking and alcohol on MetS and its individual components. Methods 64,046 participants aged 18–80 years from the LifeLines Cohort study were categorized into three body mass index (BMI) classes (BMI<25, normal weight; BMI 25–30, overweight; BMI≥30 kg/m2, obese). MetS was defined according to the revised criteria of the National Cholesterol Education Program’s Adult Treatment Panel III (NCEP ATP III). Within each BMI class and smoking subgroup (non-smoker, former smoker, <20 and ≥20 g tobacco/day), the cross-sectional association between alcohol and individual MetS components was tested using regression analysis. Results Prevalence of MetS varied greatly between the different smoking-alcohol subgroups (1.7–71.1%). HDL cholesterol levels in all alcohol drinkers were higher than in non-drinkers (0.02 to 0.29 mmol/L, P values<0.001). HDL cholesterol levels were lower when they were also a former or current smoker (<20 and ≥20 g tobacco/day). Consumption of ≤1 drink/day indicated a trend towards lower triglyceride levels (non-significant). Concurrent use alcohol (>1 drink/day) and tobacco showed higher triglycerides levels. Up to 2 drinks/day was associated with a smaller waist circumference in overweight and obese individuals. Consumption of >2 drinks/day increased blood pressure, with the strongest associations found for heavy smokers. The overall metabolic profile of wine drinkers was better than that of non-drinkers or drinkers of beer or spirits/mixed drinks. Conclusion Light alcohol consumption may moderate the negative associations of smoking with MetS. Our results suggest that the lifestyle advice that emphasizes smoking cessation and the restriction of alcohol consumption to a maximum of 1 drink/day, is a good approach to reduce the prevalence of MetS. PMID:24781037

  15. Associations of Exhaled Carbon Monoxide and Fractional Exhaled Nitric Oxide with Metabolic Syndrome: A Cohort Study

    PubMed Central

    Guo, Yanjun; Ma, Jixuan; Lu, Wei; He, Jintong; Zhang, Runbo; Yuan, Jing; Chen, Weihong

    2016-01-01

    Exhaled carbon monoxide (eCO) and fractional exhaled nitric oxide (FeNO) could reflect underlying inflammatory and oxidative stresses, which play important roles in pathogenetic pathways of metabolic syndrome (MetS). However, epidemiologic evidence was limited. We conducted a study in Wuhan-Zhuhai (WHZH) cohort of 3649 community participants to investigate the association between eCO, FeNO and MetS in both cross-sectional and prospective ways. The results showed that higher eCO and FeNO were associated cross-sectionally with a higher prevalence of MetS. The multivariable-adjusted odds ratios for MetS at baseline were 1.22 (95% confidence interval [CI]: 1.11 to 1.35) associated with per log eCO and 1.14 (95% CI: 1.00 to 1.30) associated with per log FeNO. During a follow-up of 3 years, 358/2181 new developed MetS cases were identified. Compared with lowest quartile of eCO and FeNO, the multivariable-adjusted risk ratios (95% CI) for MetS were 1.48 (1.06 to 2.06) related to the highest quartile of eCO. These findings remained consistent across sex but not smoking status, eCO was only associated with MetS in non-smokers when stratified by smoking status. In conclusion, our study demonstrated that eCO and FeNO were independently and positively associated with the prevalence of MetS cross-sectionally, while only eCO was positively related with the incidence of MetS prospectively. PMID:27076211

  16. Area-level socioeconomic characteristics and incidence of metabolic syndrome: a prospective cohort study

    PubMed Central

    2013-01-01

    Background The evidence linking socioeconomic environments and metabolic syndrome (MetS) has primarily been based on cross-sectional studies. This study prospectively examined the relationships between area-level socioeconomic position (SEP) and the incidence of MetS. Methods A prospective cohort study design was employed involving 1,877 men and women aged 18+ living in metropolitan Adelaide, Australia, all free of MetS at baseline. Area-level SEP measures, derived from Census data, included proportion of residents completing a university education, and median household weekly income. MetS, defined according to International Diabetes Federation, was ascertained after an average of 3.6 years follow up. Associations between each area-level SEP measure and incident MetS were examined by Poisson regression Generalised Estimating Equations models. Interaction between area- and individual-level SEP variables was also tested. Results A total of 156 men (18.7%) and 153 women (13.1%) developed MetS. Each percentage increase in the proportion of residents with a university education corresponded to a 2% lower risk of developing MetS (age and sex-adjusted incidence risk ratio (RR) = 0.98; 95% confidence interval (CI) =0.97-0.99). This association persisted after adjustment for individual-level income, education, and health behaviours. There was no significant association between area-level income and incident MetS overall. For the high income participants, however, a one standard deviation increase in median household weekly income was associated with a 29% higher risk of developing MetS (Adjusted RR = 1.29; 95%CI = 1.04-1.60). Conclusions While area-level education was independently and inversely associated with the risk of developing MetS, the association between area-level income and the MetS incidence was modified by individual-level income. PMID:23886070

  17. Adipokines, insulin resistance, metabolic syndrome, and breast cancer recurrence: a cohort study

    PubMed Central

    2011-01-01

    Introduction Several in vitro studies have suggested the effects of adipokines and insulin resistance on breast cancer cell proliferation and survival. However, little is known about the clinical significance of these findings. Methods We examined associations between breast cancer recurrence and adiponectin, leptin, insulin resistance, and metabolic syndrome (MetS) in a cohort of 747 patients from 2001 to 2004. Results Adjusted hazard ratios showed an inverse trend across the quartiles for serum adiponectin concentration in estrogen receptor (ER)/progesterone receptor (PR) -negative patients (P for trend = 0.027) but not in ER/PR-positive patients. Compared to the highest quartile for adiponectin level, the lowest quartile showed a hazard ratio of 2.82 (1.03 to 7.68). Homeostasis model assessment for insulin resistance (HOMA-IR) showed a positive trend for recurrence in the ER/PR-negative group (P for trend = 0.087) and a negative trend in the ER/PR-positive group (P for trend = 0.081). Leptin did not show any associations (P for trend >0.05). A linear trend was observed with the number of components of MetS in ER/PR-negative patients (P for trend = 0.044). This association disappeared when adjusted for adiponectin and HOMA-IR. Conclusions Adiponectin and HOMA-IR have prognostic significance in breast cancer recurrence and interventions related to these factors may protect against recurrence in ER/PR-negative patients. These findings were not observed in the case of ER/PR-positive patients. Further evaluation of these insignificant associations is needed because it might be biased by adjuvant chemotherapy or other confounders. PMID:21450081

  18. POLYBROMINATED BIPHENYL EXPOSURE AND BENIGN BREAST DISEASE IN A COHORT OF US WOMEN. (R825300)

    EPA Science Inventory

    PURPOSE: We examined the relation between serum polybrominated biphenyl (PBB) levels and the risk of benign breast disease in a cohort of Michigan women unintentionally exposed to PBBs in 1973 and interviewed in 1997.

    METHODS: We used extend...

  19. Pregnancy in women with inherited metabolic disease

    PubMed Central

    2015-01-01

    An increasing number of women with rare inherited disorders of metabolism are becoming pregnant. Whilst, in general, outcomes for women and their children are good, there are issues that need to be considered. Due to the rarity of many conditions, there is limited specific guidance available on best management. Prepregnancy counselling with information on inheritance, options for reproduction, teratogenicity risk, potential impact on maternal health and long-term health of children should be offered. With appropriate specialist management, the teratogenic risk of conditions such as maternal phenylketonuria (PKU) can be eliminated, and the risk of metabolic decompensation in other disorders of intoxication or energy metabolism significantly reduced. Newer therapies, such as enzyme replacement therapy, appear to be safe in pregnancy, but specific advice should be sought. Multidisciplinary management, and close liaison between obstetricians and other specialists is required for women in whom there is cardiac, renal, respiratory, joint or other organ involvement. PMID:27512458

  20. [Updates on Lifestyle-Related Diseases and Bone Metabolism. Bidirectional relationship between lifestyle-related diseases and bone metabolism].

    PubMed

    Sato, Shingo; Takeda, Shu

    2014-11-01

    Lifestyle-related diseases such as diabetes mellitus, chronic kidney disease, and hypertension were previously considered to be unrelated to osteoporosis. However, recent investigations have demonstrated that lifestyle-related diseases have a significant effect on the regulation of bone metabolism. In addition, it has been also revealed that osteocalcin or fibroblast growth factor 23 (FGF23) , which is produced by osteoblasts, has an important role in glucose metabolism, fat metabolism, or calcium homeostasis. These findings suggest that bone is not only a target organ of hormones but also involved in regulating other organs as an endocrine organ. This review introduces such a bidirectional relationship between several lifestyle-related diseases and bone metabolism. PMID:25355142

  1. [Updates on Lifestyle-Related Diseases and Bone Metabolism. Bidirectional relationship between lifestyle-related diseases and bone metabolism].

    PubMed

    Sato, Shingo; Takeda, Shu

    2014-11-01

    Lifestyle-related diseases such as diabetes mellitus, chronic kidney disease, and hypertension were previously considered to be unrelated to osteoporosis. However, recent investigations have demonstrated that lifestyle-related diseases have a significant effect on the regulation of bone metabolism. In addition, it has been also revealed that osteocalcin or fibroblast growth factor 23 (FGF23) , which is produced by osteoblasts, has an important role in glucose metabolism, fat metabolism, or calcium homeostasis. These findings suggest that bone is not only a target organ of hormones but also involved in regulating other organs as an endocrine organ. This review introduces such a bidirectional relationship between several lifestyle-related diseases and bone metabolism.

  2. Gamma images in benign and metabolic bone diseases: volume 1

    SciTech Connect

    Sy, W.M.

    1981-01-01

    Volume 1 of ''Gamma images in benign and metabolic bone diseases'' comprises chapters devoted to: general remarks and considerations, radiopharmaceuticals, Paget disease, osteomyelitis, trauma, benign bone tumors, chronic renal dialysis, acute renal failure, osteomalacia and rickets, and osteoporosis. Although published in 1981, the most recent references in the book were 1978 and most are 1977 or earlier. One of the strongest aspects of the volume are tables which categorize diseases, pathophysiology of disease, and image abnormalities. (JMT)

  3. Bile Acid Signaling in Metabolic Disease and Drug Therapy

    PubMed Central

    Li, Tiangang

    2014-01-01

    Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates hepatobiliary secretion of lipids, lipophilic metabolites, and xenobiotics. In the intestine, bile acids are essential for the absorption, transport, and metabolism of dietary fats and lipid-soluble vitamins. Extensive research in the last 2 decades has unveiled new functions of bile acids as signaling molecules and metabolic integrators. The bile acid–activated nuclear receptors farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, vitamin D receptor, and G protein–coupled bile acid receptor play critical roles in the regulation of lipid, glucose, and energy metabolism, inflammation, and drug metabolism and detoxification. Bile acid synthesis exhibits a strong diurnal rhythm, which is entrained by fasting and refeeding as well as nutrient status and plays an important role for maintaining metabolic homeostasis. Recent research revealed an interaction of liver bile acids and gut microbiota in the regulation of liver metabolism. Circadian disturbance and altered gut microbiota contribute to the pathogenesis of liver diseases, inflammatory bowel diseases, nonalcoholic fatty liver disease, diabetes, and obesity. Bile acids and their derivatives are potential therapeutic agents for treating metabolic diseases of the liver. PMID:25073467

  4. Synergistic Effects of Six Chronic Disease Pairs on Decreased Physical Activity: The SMILE Cohort Study

    PubMed Central

    Dörenkamp, Sarah; Mesters, Ilse; Vos, Rein; Schepers, Jan; van den Akker, Marjan; Teijink, Joep; de Bie, Rob

    2016-01-01

    Little is known about whether and how two chronic diseases interact with each other in modifying the risk of physical inactivity. The aim of the present study is to identify chronic disease pairs that are associated with compliance or noncompliance with the Dutch PA guideline recommendation and to study whether specific chronic disease pairs indicate an extra effect on top of the effects of the diseases individually. Cross-sectional data from 3,386 participants of cohort study SMILE were used and logistic regression analysis was performed to study the joint effect of the two diseases of each chronic disease pair for compliance with the Dutch PA guideline. For six chronic disease pairs, patients suffering from both diseases belonging to these disease pairs in question show a higher probability of noncompliance to the Dutch PA guideline, compared to what one would expect based on the effects of each of the two diseases alone. These six chronic disease pairs were chronic respiratory disease and severe back problems; migraine and inflammatory joint disease; chronic respiratory disease and severe kidney disease; chronic respiratory disease and inflammatory joint disease; inflammatory joint disease and rheumatoid arthritis; and rheumatoid arthritis and osteoarthritis of the knees, hips, and hands. PMID:27274994

  5. Folate: metabolism, genes, polymorphisms and the associated diseases.

    PubMed

    Nazki, Fakhira Hassan; Sameer, Aga Syed; Ganaie, Bashir Ahmad

    2014-01-01

    Folate being an important vitamin of B Complex group in our diet plays an important role not only in the synthesis of DNA but also in the maintenance of methylation reactions in the cells. Folate metabolism is influenced by several processes especially its dietary intake and the polymorphisms of the associated genes involved. Aberrant folate metabolism, therefore, affects both methylation as well as the DNA synthesis processes, both of which have been implicated in the development of various diseases. This paper reviews the current knowledge of the processes involved in folate metabolism and consequences of deviant folate metabolism, particular emphasis is given to the polymorphic genes which have been implicated in the development of various diseases in humans, like vascular diseases, Down's syndrome, neural tube defects, psychiatric disorders and cancers. PMID:24091066

  6. SY 06-4 THE RISK OF METABOLICALLY HEALTHY OBESITY IN CARDIOVASCULAR DISEASE.

    PubMed

    Sung, Ki Chul

    2016-09-01

    BMI is a proxy measure for adiposity in population-based studies and it is well established that increasing body fat is strongly associated with component features of the metabolic syndrome (MetS), such as dyslipidaemia (low high density lipoprotein cholesterol (HDL-C) and high triglyceride concentrations, increased glucose concentrations, high blood pressure, hypertension, and type 2 diabetes. Whether any or all of these components of the MetS account for relationships between body fatness and all cause mortality is uncertain, but we have recently shown in a large Korean cohort that co-existing cardiovascular disease (CVD), diabetes or hypertension explained much of the increased risk of CVD mortality in obese individuals. Recently, the concept of metabolically healthy obesity (MHO) has been used to try and help explain the 'obesity paradox', where there is decreased mortality in some people with obesity. Additionally, whether any association between underweight and increased all cause mortality is due to the presence of pre-existing cardiovascular and metabolic disease states (or risk factors) is not fully understood. Therefore, i will discuss whether BMI was associated with mortality outcomes after subjects with established risk factors and diseases such as diabetes, cardiovascular disease, hypertension and features of the MetS had been excluded. PMID:27642935

  7. Glucose Metabolism: A Sweet Relief of Alzheimer's Disease.

    PubMed

    Duran-Aniotz, Claudia; Hetz, Claudio

    2016-09-12

    Patients and individuals at risk for Alzheimer's disease show reduced glucose metabolism in the brain. A new study takes advantage of a fly model of Alzheimer's disease to demonstrate that enhancing glucose uptake in neurons has strong neuroprotective effects involving improved proteostasis. PMID:27623263

  8. [Bone diseases caused by impaired glucose and lipid metabolism].

    PubMed

    Kanazawa, Ippei; Sugimoto, Toshitsugu

    2013-11-01

    The number of patients with lifestyle-related diseases is rapidly increasing in Japan. Metabolic syndrome caused by abdominal fat accumulation induces diabetes mellitus, dyslipidemia, and hypertension, resulting in an increase in cardiovascular diseases. On the other hand, recent studies have shown that the lifestyle-related diseases are risk factors of osteoporotic fractures. Although it remains still unclear how metabolic disorders affect bone tissue, oxidative stress and/or glycation stress might directly have negative impacts on bone tissue and increase the risk of fractures. In this review, we describe the association of diabetes mellitus and dyslipidemia with the fracture risk through oxidative stress and glycation stress.

  9. Baseline Analysis of a Young Alpha-1-AT Deficiency Liver Disease Cohort Reveals Frequent Portal Hypertension

    PubMed Central

    Teckman, Jeffrey H; Rosenthal, Philip; Abel, Robert; Bass, Lee M.; Michail, Sonia; Murray, Karen F.; Rudnick, David A.; Thomas, Daniel W.; Spino, Cathie; Arnon, Ronen; Hertel, Paula M.; Heubi, James; Kamath, Binita M.; Karnsakul, Wikrom; Loomes, Kathleen M.; Magee, John C.; Molleston, Jean P.; Romero, Rene; Shneider, Benjamin L; Sherker, Averell H; Sokol, Ronald J

    2015-01-01

    Objective Alpha-1-antitrypsin deficiency (A1AT) is a common genetic disease with unpredictable and highly variable course. The Childhood Liver Disease Research and Education Network (ChiLDREN) is an NIH, multi-center, longitudinal consortium studying pediatric liver diseases, with the objective of prospectively defining natural history and identifying disease modifiers. Methods Longitudinal, cohort study of A1AT patients birth through 25 years diagnosed with liver disease, type PIZZ or PISZ. Medical history, physical exam, laboratory, imaging, and standardized survey tool data were collected during the provision of standard of care. Results In this report of the cohort at baseline, 269 subjects were enrolled between Nov. 2008 and Oct. 2012 (208 with their native livers and 61 post-liver transplant). Subjects with mild disease (native livers and no portal hypertension [PHT]) compared to severe disease (with PHT or post-liver transplant) were not different in age at presentation. 57% of subjects with mild disease and 76% with severe disease were jaundiced at presentation (p=0.0024). 29% of subjects with native livers had PHT, but age at diagnosis and growth were not different between the no PHT and PHT groups (p>0.05). Subjects with native livers and PHT were more likely to have elevated bilirubin, ALT, AST, INR, and GGTP than the no PHT group (p≪0.001), but overlap was large. Chemistries alone could not identify PHT. Conclusion Many A1AT subjects presenting with elevated liver tests and jaundice improve spontaneously. Subjects with PHT have few symptoms and normal growth. Longitudinal cohort follow up will identify genetic and environmental disease modifiers. NCT00571272. PMID:25651489

  10. Modeling Metabolism and Disease in Bioarcheology

    PubMed Central

    Qualls, Clifford; Appenzeller, Otto

    2015-01-01

    We examine two important measures that can be made in bioarcheology on the remains of human and vertebrate animals. These remains consist of bone, teeth, or hair; each shows growth increments and each can be assayed for isotope ratios and other chemicals in equal intervals along the direction of growth. In each case, the central data is a time series of measurements. The first important measures are spectral estimates in spectral analyses and linear system analyses; we emphasize calculation of periodicities and growth rates as well as the comparison of power in bands. A low frequency band relates to the autonomic nervous system (ANS) control of metabolism and thus provides information about the life history of the individual of archeological interest. Turning to nonlinear system analysis, we discuss the calculation of SM Pinus' approximate entropy (ApEn) for short or moderate length time series. Like the concept that regular heart R-R interval data may indicate lack of health, low values of ApEn may indicate disrupted metabolism in individuals of archeological interest and even that a tipping point in deteriorating metabolism may have been reached just before death. This adds to the list of causes of death that can be determined from minimal data. PMID:26347356

  11. Modeling Metabolism and Disease in Bioarcheology.

    PubMed

    Qualls, Clifford; Appenzeller, Otto

    2015-01-01

    We examine two important measures that can be made in bioarcheology on the remains of human and vertebrate animals. These remains consist of bone, teeth, or hair; each shows growth increments and each can be assayed for isotope ratios and other chemicals in equal intervals along the direction of growth. In each case, the central data is a time series of measurements. The first important measures are spectral estimates in spectral analyses and linear system analyses; we emphasize calculation of periodicities and growth rates as well as the comparison of power in bands. A low frequency band relates to the autonomic nervous system (ANS) control of metabolism and thus provides information about the life history of the individual of archeological interest. Turning to nonlinear system analysis, we discuss the calculation of SM Pinus' approximate entropy (ApEn) for short or moderate length time series. Like the concept that regular heart R-R interval data may indicate lack of health, low values of ApEn may indicate disrupted metabolism in individuals of archeological interest and even that a tipping point in deteriorating metabolism may have been reached just before death. This adds to the list of causes of death that can be determined from minimal data. PMID:26347356

  12. Birth Weights in Sickle Cell Disease Pregnancies: A Cohort Study

    PubMed Central

    Robinson, Susan E.; Macleod, David

    2016-01-01

    Pregnancy in women with Sickle Cell Disease (SCD) has been linked with an increased incidence of adverse foetal outcomes when compared to women without haemoglobinopathies (HbAA). There’s a paucity of data into foetal outcomes for infants born to women with SCD. Customised growth charts have been demonstrated to be better than population-based growth charts at identifying unhealthy small babies. We analysed the mean birth weight and customised birth weight centiles of infants born to mothers with SCD versus mothers with HbAA genotype, to quantify the risk of having a smaller baby. Birth weight and birth weight centiles were analysed for 88 women with SCD (50 HbSS; 38 HbSC) and 176 controls (HbAA). Statistically significant differences were seen in the mean birth weight (P value = 0.004) and the mean birth weight centiles (P value = 0.016). We conclude that SCD is a risk factor for having a smaller baby. PMID:27776167

  13. IQ in Childhood and the Metabolic Syndrome in Middle Age: Extended Follow-Up of the 1946 British Birth Cohort Study

    ERIC Educational Resources Information Center

    Richards, Marcus; Black, Stephanie; Mishra, Gita; Gale, Catharine R.; Deary, Ian J.; Batty, David G.

    2009-01-01

    IQ in early adulthood has been inversely associated with risk of the metabolic syndrome in midlife. We tested this association in the British 1946 birth cohort, which assessed IQ at age eight years and ascertained the metabolic syndrome at age 53 years based on modified (non-fasting blood) ATPIII criteria. Childhood IQ was inversely associated…

  14. Vitamin-Dependent Methionine Metabolism and Alcoholic Liver Disease1

    PubMed Central

    Halsted, Charles H.; Medici, Valentina

    2011-01-01

    Emerging evidence indicates that ethanol-induced alterations in hepatic methionine metabolism play a central role in the pathogenesis of alcoholic liver disease (ALD). Because malnutrition is a universal clinical finding in this disease and hepatic methionine metabolism is dependent upon dietary folate and vitamins B-6 and B-12, ALD can be considered an induced nutritional disorder that is conditioned by alcohol abuse. The present review describes the etiologies of these 3 vitamin deficiencies in ALD and how they interact with chronic ethanol exposure to alter hepatic methionine metabolism. Subsequent sections focus on molecular mechanisms for the interactions of aberrant methionine metabolism with ethanol in the pathogenesis of ALD, in particular the role of S-adenosylmethionine (SAM) in regulating the epigenetic expressions of genes relevant to pathways of liver injury. The review will conclude with descriptions of studies on the efficacy of SAM in the treatment of ALD and with discussion of potentially fruitful future avenues of research. PMID:22332083

  15. Inflammation Meets Metabolic Disease: Gut Feeling Mediated by GLP-1.

    PubMed

    Zietek, Tamara; Rath, Eva

    2016-01-01

    Chronic diseases, such as obesity and diabetes, cardiovascular, and inflammatory bowel diseases (IBD) share common features in their pathology. Metabolic disorders exhibit strong inflammatory underpinnings and vice versa, inflammation is associated with metabolic alterations. Next to cytokines and cellular stress pathways, such as the unfolded protein response (UPR), alterations in the enteroendocrine system are intersections of various pathologies. Enteroendocrine cells (EEC) have been studied extensively for their ability to regulate gastrointestinal motility, secretion, and insulin release by release of peptide hormones. In particular, the L-cell-derived incretin hormone glucagon-like peptide 1 (GLP-1) has gained enormous attention due to its insulinotropic action and relevance in the treatment of type 2 diabetes (T2D). Yet, accumulating data indicate a critical role for EEC and in particular for GLP-1 in metabolic adaptation and in orchestrating immune responses beyond blood glucose control. EEC sense the lamina propria and luminal environment, including the microbiota via receptors and transporters. Subsequently, mediating signals by secreting hormones and cytokines, EEC can be considered as integrators of metabolic and inflammatory signaling. This review focuses on L cell and GLP-1 functions in the context of metabolic and inflammatory diseases. The effects of incretin-based therapies on metabolism and immune system are discussed and the interrelation and common features of metabolic and immune-mediated disorders are highlighted. Moreover, it presents data on the impact of inflammation, in particular of IBD on EEC and discusses the potential role of the microbiota as link between nutrients, metabolism, immunity, and disease. PMID:27148273

  16. Metabolic Profiling of Children Undergoing Surgery for Congenital Heart Disease

    PubMed Central

    Correia, Goncalo D. S.; Wooi Ng, Keng; Wijeyesekera, Anisha; Gala-Peralta, Sandra; Williams, Rachel; MacCarthy-Morrogh, S.; Jiménez, Beatriz; Inwald, David; Macrae, Duncan; Frost, Gary; Holmes, Elaine

    2015-01-01

    Objective: Inflammation and metabolism are closely interlinked. Both undergo significant dysregulation following surgery for congenital heart disease, contributing to organ failure and morbidity. In this study, we combined cytokine and metabolic profiling to examine the effect of postoperative tight glycemic control compared with conventional blood glucose management on metabolic and inflammatory outcomes in children undergoing congenital heart surgery. The aim was to evaluate changes in key metabolites following congenital heart surgery and to examine the potential of metabolic profiling for stratifying patients in terms of expected clinical outcomes. Design: Laboratory and clinical study. Setting: University Hospital and Laboratory. Patients: Of 28 children undergoing surgery for congenital heart disease, 15 underwent tight glycemic control postoperatively and 13 were treated conventionally. Interventions: Metabolic profiling of blood plasma was undertaken using proton nuclear magnetic resonance spectroscopy. A panel of metabolites was measured using a curve-fitting algorithm. Inflammatory cytokines were measured by enzyme-linked immunosorbent assay. The data were assessed with respect to clinical markers of disease severity (Risk Adjusted Congenital heart surgery score-1, Pediatric Logistic Organ Dysfunction, inotrope score, duration of ventilation and pediatric ICU-free days). Measurements and Main Results: Changes in metabolic and inflammatory profiles were seen over the time course from surgery to recovery, compared with the preoperative state. Tight glycemic control did not significantly alter the response profile. We identified eight metabolites (3-d-hydroxybutyrate, acetone, acetoacetate, citrate, lactate, creatine, creatinine, and alanine) associated with surgical and disease severity. The strength of proinflammatory response, particularly interleukin-8 and interleukin-6 concentrations, inversely correlated with PICU-free days at 28 days. The interleukin

  17. Inflammation Meets Metabolic Disease: Gut Feeling Mediated by GLP-1

    PubMed Central

    Zietek, Tamara; Rath, Eva

    2016-01-01

    Chronic diseases, such as obesity and diabetes, cardiovascular, and inflammatory bowel diseases (IBD) share common features in their pathology. Metabolic disorders exhibit strong inflammatory underpinnings and vice versa, inflammation is associated with metabolic alterations. Next to cytokines and cellular stress pathways, such as the unfolded protein response (UPR), alterations in the enteroendocrine system are intersections of various pathologies. Enteroendocrine cells (EEC) have been studied extensively for their ability to regulate gastrointestinal motility, secretion, and insulin release by release of peptide hormones. In particular, the L-cell-derived incretin hormone glucagon-like peptide 1 (GLP-1) has gained enormous attention due to its insulinotropic action and relevance in the treatment of type 2 diabetes (T2D). Yet, accumulating data indicate a critical role for EEC and in particular for GLP-1 in metabolic adaptation and in orchestrating immune responses beyond blood glucose control. EEC sense the lamina propria and luminal environment, including the microbiota via receptors and transporters. Subsequently, mediating signals by secreting hormones and cytokines, EEC can be considered as integrators of metabolic and inflammatory signaling. This review focuses on L cell and GLP-1 functions in the context of metabolic and inflammatory diseases. The effects of incretin-based therapies on metabolism and immune system are discussed and the interrelation and common features of metabolic and immune-mediated disorders are highlighted. Moreover, it presents data on the impact of inflammation, in particular of IBD on EEC and discusses the potential role of the microbiota as link between nutrients, metabolism, immunity, and disease. PMID:27148273

  18. Assessment of cardiometabolic risk in children in population studies: underpinning developmental origins of health and disease mother-offspring cohort studies.

    PubMed

    Huang, R-C; Prescott, Susan L; Godfrey, Keith M; Davis, Elizabeth A

    2015-01-01

    Pregnancy and birth cohorts have been utilised extensively to investigate the developmental origins of health and disease, particularly in relation to understanding the aetiology of obesity and related cardiometabolic disorders. Birth and pregnancy cohorts have been utilised extensively to investigate this area of research. The aim of the present review was twofold: first to outline the necessity of measuring cardiometabolic risk in children; and second to outline how it can be assessed. The major outcomes thought to have an important developmental component are CVD, insulin resistance and related metabolic outcomes. Conditions such as the metabolic syndrome, type 2 diabetes and CHD all tend to have peak prevalence in middle-aged and older individuals but assessments of cardiometabolic risk in childhood and adolescence are important to define early causal factors and characterise preventive measures. Typically, researchers investigating prospective cohort studies have relied on the thesis that cardiovascular risk factors, such as dyslipidaemia, hypertension and obesity, track from childhood into adult life. The present review summarises some of the evidence that these factors, when measured in childhood, may be of value in assessing the risk of adult cardiometabolic disease, and as such proceeds to describe some of the methods for assessing cardiometabolic risk in children. PMID:26090093

  19. Dry Eye Disease Incidence Associated with Chronic Graft-Host Disease: Nonconcurrent Cohort Study (An American Ophthalmological Society Thesis)

    PubMed Central

    Mian, Shahzad I.; De la Parra-Colín, Paola; De Melo-Franco, Rafael; Johnson, Christopher; Barrientos-Gutierrez, Tonatiuh

    2015-01-01

    Purpose: To determine if chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) is associated with stable or progressive dry eye disease and to determine the true incidence in patients with no prior history of dry eye disease. Methods: A nonconcurrent cohort study at a single institution with 136 patients who had no previous history of dry eye disease before HSCT. Survival analysis was used to estimate dry eye disease incidence. The incidence rate was calculated using life tables as the number of observed dry eye disease cases divided by the person-time at risk accumulated by the cohort. Transition probabilities were calculated from time of transplant to time of diagnosis, and then to last recorded visit. Results: Incidence rate was 0.8 cases of dry eye disease per person-year, and half of the population at risk developed dry eye disease during the first 10 months post transplant. Time to develop dry eye disease was 2.5 months for mild dry eye disease, 9.6 months for moderate dry eye disease, and 13.2 months for severe dry eye disease. In terms of cumulative incidence, 73% of subjects developed dry eye disease (50% mild, 16% moderate, and 7% severe) at the time of diagnosis. Conclusions: Our findings suggest that dry eye disease associated with cGVHD is an extremely frequent event and shows a wide spectrum of severity, with a mild form presenting early and a moderate to severe form presenting later after HSCT. These findings need to be studied further to elucidate if these are two different pathophysiological entities or just different expressions of the same pathology. PMID:27507907

  20. A clinical perspective of obesity, metabolic syndrome and cardiovascular disease.

    PubMed

    Han, Thang S; Lean, Mike Ej

    2016-01-01

    The metabolic syndrome is a condition characterized by a special constellation of reversible major risk factors for cardiovascular disease and type 2 diabetes. The main, diagnostic, components are reduced HDL-cholesterol, raised triglycerides, blood pressure and fasting plasma glucose, all of which are related to weight gain, specifically intra-abdominal/ectopic fat accumulation and a large waist circumference. Using internationally adopted arbitrary cut-off values for waist circumference, having metabolic syndrome doubles the risk of cardiovascular disease, but offers an effective treatment approach through weight management. Metabolic syndrome now affects 30-40% of people by age 65, driven mainly by adult weight gain, and by a genetic or epigenetic predisposition to intra-abdominal/ectopic fat accumulation related to poor intra-uterine growth. Metabolic syndrome is also promoted by a lack of subcutaneous adipose tissue, low skeletal muscle mass and anti-retroviral drugs. Reducing weight by 5-10%, by diet and exercise, with or without, anti-obesity drugs, substantially lowers all metabolic syndrome components, and risk of type 2 diabetes and cardiovascular disease. Other cardiovascular disease risk factors such as smoking should be corrected as a priority. Anti-diabetic agents which improve insulin resistance and reduce blood pressure, lipids and weight should be preferred for diabetic patients with metabolic syndrome. Bariatric surgery offers an alternative treatment for those with BMI ≥ 40 or 35-40 kg/m(2) with other significant co-morbidity. The prevalence of the metabolic syndrome and cardiovascular disease is expected to rise along with the global obesity epidemic: greater emphasis should be given to effective early weight-management to reduce risk in pre-symptomatic individuals with large waists. PMID:26998259

  1. A clinical perspective of obesity, metabolic syndrome and cardiovascular disease

    PubMed Central

    Lean, Mike EJ

    2016-01-01

    The metabolic syndrome is a condition characterized by a special constellation of reversible major risk factors for cardiovascular disease and type 2 diabetes. The main, diagnostic, components are reduced HDL-cholesterol, raised triglycerides, blood pressure and fasting plasma glucose, all of which are related to weight gain, specifically intra-abdominal/ectopic fat accumulation and a large waist circumference. Using internationally adopted arbitrary cut-off values for waist circumference, having metabolic syndrome doubles the risk of cardiovascular disease, but offers an effective treatment approach through weight management. Metabolic syndrome now affects 30–40% of people by age 65, driven mainly by adult weight gain, and by a genetic or epigenetic predisposition to intra-abdominal/ectopic fat accumulation related to poor intra-uterine growth. Metabolic syndrome is also promoted by a lack of subcutaneous adipose tissue, low skeletal muscle mass and anti-retroviral drugs. Reducing weight by 5–10%, by diet and exercise, with or without, anti-obesity drugs, substantially lowers all metabolic syndrome components, and risk of type 2 diabetes and cardiovascular disease. Other cardiovascular disease risk factors such as smoking should be corrected as a priority. Anti-diabetic agents which improve insulin resistance and reduce blood pressure, lipids and weight should be preferred for diabetic patients with metabolic syndrome. Bariatric surgery offers an alternative treatment for those with BMI ≥ 40 or 35–40 kg/m2 with other significant co-morbidity. The prevalence of the metabolic syndrome and cardiovascular disease is expected to rise along with the global obesity epidemic: greater emphasis should be given to effective early weight-management to reduce risk in pre-symptomatic individuals with large waists. PMID:26998259

  2. [Application of precision medicine in obesity and metabolic disease surgery].

    PubMed

    Wang, Cunchuan; Gao, Zhiguang

    2016-01-01

    The U. S. A. president Obama called for a new initiative to fund precision medicine during his State of Union Address on January 20th, 2015, which meant that the human medicine enters a new era. The meaning of "precision medicine" is significantly similar to the concept of precision obesity and metabolic disease surgery, which was proposed by the author in early August 2011. Nowadays, obesity and metabolic disease surgery has been transformed from open surgery to laparoscopic surgery, the extensive mode to the precision mode. The key value concept is to minimize postoperative complication, minimize postoperative hospital stay and obtain the best effect of weight loss by accurate preoperative assessment, delicate operation, excellent postoperative management and scientific follow-up. The precision obesity and metabolic disease surgery has more development space in the future. PMID:26797833

  3. Association of Autoimmune Addison's Disease with Alleles of STAT4 and GATA3 in European Cohorts

    PubMed Central

    Mitchell, Anna L.; Macarthur, Katie D. R.; Gan, Earn H.; Baggott, Lucy E.; Wolff, Anette S. B.; Skinningsrud, Beate; Platt, Hazel; Short, Andrea; Lobell, Anna; Kämpe, Olle; Bensing, Sophie; Betterle, Corrado; Kasperlik-Zaluska, Anna; Zurawek, Magdalena; Fichna, Marta; Kockum, Ingrid; Nordling Eriksson, Gabriel; Ekwall, Olov; Wahlberg, Jeanette; Dahlqvist, Per; Hulting, Anna-Lena; Penna-Martinez, Marissa; Meyer, Gesine; Kahles, Heinrich; Badenhoop, Klaus; Hahner, Stephanie; Quinkler, Marcus; Falorni, Alberto; Phipps-Green, Amanda; Merriman, Tony R.; Ollier, William; Cordell, Heather J.; Undlien, Dag; Czarnocka, Barbara; Husebye, Eystein; Pearce, Simon H. S.

    2014-01-01

    Background Gene variants known to contribute to Autoimmune Addison's disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for. Aim To investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts. Methods A sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls). In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls). In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity. Results We report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P = 0.00016; rs10931481: P = 0.0007). In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-κB1 and IL23A genes in the UK and Italian cohorts respectively. Conclusions Variants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis. PMID:24614117

  4. Metabolic aspects of adult patients with nonalcoholic fatty liver disease.

    PubMed

    Abenavoli, Ludovico; Milic, Natasa; Di Renzo, Laura; Preveden, Tomislav; Medić-Stojanoska, Milica; De Lorenzo, Antonino

    2016-08-21

    Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease and it encompasses a spectrum from simple steatosis to steatohepatitis, fibrosis, or cirrhosis. The mechanisms involved in the occurrence of NAFLD and its progression are probably due to a metabolic profile expressed within the context of a genetic predisposition and is associated with a higher energy intake. The metabolic syndrome (MS) is a cluster of metabolic alterations associated with an increased risk for the development of cardiovascular diseases and diabetes. NAFLD patients have more than one feature of the MS, and now they are considered the hepatic components of the MS. Several scientific advances in understanding the association between NAFLD and MS have identified insulin resistance (IR) as the key aspect in the pathophysiology of both diseases. In the multi parallel hits theory of NAFLD pathogenesis, IR was described to be central in the predisposition of hepatocytes to be susceptible to other multiple pathogenetic factors. The recent knowledge gained from these advances can be applied clinically in the prevention and management of NAFLD and its associated metabolic changes. The present review analyses the current literature and highlights the new evidence on the metabolic aspects in the adult patients with NAFLD. PMID:27610012

  5. The metabolic syndrome as a concept of adipose tissue disease.

    PubMed

    Oda, Eiji

    2008-07-01

    The metabolic syndrome is a constellation of interrelated metabolic risk factors that appear to directly promote the development of diabetes and cardiovascular disease. However, in 2005, the American Diabetes Association and the European Association for the Study of Diabetes jointly stated that no existing definition of the metabolic syndrome meets the criteria of a syndrome, and there have been endless debates on the pros and cons of using the concept of this syndrome. The controversy may stem from confusion between the syndrome and obesity. Obesity is an epidemic, essentially contagious disease caused by an environment of excess nutritional energy and reinforced by deeply rooted social norms. The epidemic of obesity should be prevented or controlled by social and political means, similar to the approaches now being taken to combat global warming. The diagnosis of metabolic syndrome is useless for this public purpose. The purpose of establishing criteria for diagnosing metabolic syndrome is to find individuals who are at increased risk of diabetes and cardiovascular disease and who require specific therapy including diet and exercise. The syndrome may be an adipose tissue disease different from obesity; in that case, it would be characterized by inflammation clinically detected through systemic inflammatory markers such as high-sensitivity C-reactive protein and insulin resistance reflecting histological changes in adipose tissue. However, many problems in defining the optimal diagnostic criteria remain unresolved.

  6. Metabolic aspects of adult patients with nonalcoholic fatty liver disease

    PubMed Central

    Abenavoli, Ludovico; Milic, Natasa; Di Renzo, Laura; Preveden, Tomislav; Medić-Stojanoska, Milica; De Lorenzo, Antonino

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease and it encompasses a spectrum from simple steatosis to steatohepatitis, fibrosis, or cirrhosis. The mechanisms involved in the occurrence of NAFLD and its progression are probably due to a metabolic profile expressed within the context of a genetic predisposition and is associated with a higher energy intake. The metabolic syndrome (MS) is a cluster of metabolic alterations associated with an increased risk for the development of cardiovascular diseases and diabetes. NAFLD patients have more than one feature of the MS, and now they are considered the hepatic components of the MS. Several scientific advances in understanding the association between NAFLD and MS have identified insulin resistance (IR) as the key aspect in the pathophysiology of both diseases. In the multi parallel hits theory of NAFLD pathogenesis, IR was described to be central in the predisposition of hepatocytes to be susceptible to other multiple pathogenetic factors. The recent knowledge gained from these advances can be applied clinically in the prevention and management of NAFLD and its associated metabolic changes. The present review analyses the current literature and highlights the new evidence on the metabolic aspects in the adult patients with NAFLD. PMID:27610012

  7. Metabolic aspects of adult patients with nonalcoholic fatty liver disease

    PubMed Central

    Abenavoli, Ludovico; Milic, Natasa; Di Renzo, Laura; Preveden, Tomislav; Medić-Stojanoska, Milica; De Lorenzo, Antonino

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease and it encompasses a spectrum from simple steatosis to steatohepatitis, fibrosis, or cirrhosis. The mechanisms involved in the occurrence of NAFLD and its progression are probably due to a metabolic profile expressed within the context of a genetic predisposition and is associated with a higher energy intake. The metabolic syndrome (MS) is a cluster of metabolic alterations associated with an increased risk for the development of cardiovascular diseases and diabetes. NAFLD patients have more than one feature of the MS, and now they are considered the hepatic components of the MS. Several scientific advances in understanding the association between NAFLD and MS have identified insulin resistance (IR) as the key aspect in the pathophysiology of both diseases. In the multi parallel hits theory of NAFLD pathogenesis, IR was described to be central in the predisposition of hepatocytes to be susceptible to other multiple pathogenetic factors. The recent knowledge gained from these advances can be applied clinically in the prevention and management of NAFLD and its associated metabolic changes. The present review analyses the current literature and highlights the new evidence on the metabolic aspects in the adult patients with NAFLD.

  8. Early growth and coronary heart disease and type 2 diabetes: findings from the Helsinki Birth Cohort Study (HBCS).

    PubMed

    Eriksson, Johan G

    2011-12-01

    A slow rate of intrauterine growth is a major risk factor for several common noncommunicable diseases, which include the following: coronary heart disease (CHD), hypertension, and type 2 diabetes. Likewise, growth patterns in infancy and childhood have been identified as important factors linked to the pathogenesis of these disorders. In this overview, patterns of growth associated with CHD, type 2 diabetes, and related metabolic traits in adult life are presented on the basis of findings from the Helsinki Birth Cohort Study (HBCS) 1934-1944. Later risk of CHD was associated with small body size at birth and during infancy, followed by an increase in body size later in childhood. This pattern of growth has been associated with dyslipidemia in later life, which offers an explanation for the observed findings. Type 2 diabetes and CHD share several risk factors. The early growth of persons who later develop type 2 diabetes includes a small body size at birth as well as a small body size during infancy. An early age at adiposity rebound was associated with a markedly increased risk of type 2 diabetes in adulthood. The patterns of growth associated with type 2 diabetes are also associated with alterations in body composition, which predisposes to insulin resistance and the metabolic syndrome. The presented findings suggest that to be able to understand the pathogenesis of several noncommunicable diseases, the diseases need to be studied from a life-course perspective, and prenatal and childhood growth as well as adult characteristics need to be taken into account. PMID:21613556

  9. Cardiac rehabilitation programs improve metabolic parameters in patients with the metabolic syndrome and coronary heart disease.

    PubMed

    Pérez, Ignacio P; Zapata, Maria A; Cervantes, Carlos E; Jarabo, Rosario M; Grande, Cristina; Plaza, Rose; Garcia, Sara; Rodriguez, Miriam L; Crespo, Silvia; Perea, Jesús

    2010-05-01

    This study was performed to determine the effectiveness of a cardiac rehabilitation and exercise training program on metabolic parameters and coronary risk factors in patients with the metabolic syndrome and coronary heart disease. The study involved 642 patients with coronary heart disease. Of them, 171 (26.7%) fulfilled criteria for the metabolic syndrome. Clinical data, laboratory tests, and exercise testing were performed before and after the program, which lasted 2 to 3 months. Except for waist circumference, there were no significant differences between groups; blood pressure, high-density lipoprotein cholesterol, triglycerides, and fasting glucose improvements during the follow-up were higher in patients with the metabolic syndrome (all P<.001). At study end, in patients with the metabolic syndrome, functional capacity increased by 26.45% ( P<.001), as measured by metabolic equivalents, with a slight increase of 1.25% ( P=not significant) in the double product. Patients with the metabolic syndrome who took part in this secondary prevention program reported improvements in cardiovascular risk profile and functional capacity.

  10. Altered cholesterol and fatty acid metabolism in Huntington disease.

    PubMed

    Block, Robert C; Dorsey, E Ray; Beck, Christopher A; Brenna, J Thomas; Shoulson, Ira

    2010-01-01

    Huntington disease is an autosomal dominant neurodegenerative disorder characterized by behavioral abnormalities, cognitive decline, and involuntary movements that lead to a progressive decline in functional capacity, independence, and ultimately death. The pathophysiology of Huntington disease is linked to an expanded trinucleotide repeat of cytosine-adenine-guanine (CAG) in the IT-15 gene on chromosome 4. There is no disease-modifying treatment for Huntington disease, and novel pathophysiological insights and therapeutic strategies are needed. Lipids are vital to the health of the central nervous system, and research in animals and humans has revealed that cholesterol metabolism is disrupted in Huntington disease. This lipid dysregulation has been linked to specific actions of the mutant huntingtin on sterol regulatory element binding proteins. This results in lower cholesterol levels in affected areas of the brain with evidence that this depletion is pathologic. Huntington disease is also associated with a pattern of insulin resistance characterized by a catabolic state resulting in weight loss and a lower body mass index than individuals without Huntington disease. Insulin resistance appears to act as a metabolic stressor attending disease progression. The fish-derived omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, have been examined in clinical trials of Huntington disease patients. Drugs that combat the dysregulated lipid milieu in Huntington disease may help treat this perplexing and catastrophic genetic disease.

  11. Endoplasmic Reticulum Stress and the Inflammatory Basis of Metabolic Disease

    PubMed Central

    Hotamisligil, Gökhan S.

    2010-01-01

    The endoplasmic reticulum (ER) is the major site in the cell for protein folding and trafficking and is central to many cellular functions. Failure of the ER's adaptive capacity results in activation of the unfolded protein response (UPR), which intersects with many different inflammatory and stress signaling pathways. These pathways are also critical in chronic metabolic diseases such as obesity, insulin resistance, and type 2 diabetes. The ER and related signaling networks are emerging as a potential site for the intersection of inflammation and metabolic disease. PMID:20303879

  12. Cardiovascular Disease Risk of Abdominal Obesity versus Metabolic Abnormalities

    PubMed Central

    Wildman, Rachel P.; McGinn, Aileen P.; Lin, Juan; Wang, Dan; Muntner, Paul; Cohen, Hillel W.; Reynolds, Kristi; Fonseca, Vivian; Sowers, MaryFran R.

    2011-01-01

    It remains unclear whether abdominal obesity increases cardiovascular disease (CVD) risk independent of the metabolic abnormalities which often accompany it. Therefore, the objective of the current study was to evaluate the independent effects of abdominal obesity versus metabolic syndrome and diabetes on the risk for incident coronary heart disease and stroke. The Framingham Offspring, Atherosclerosis Risk in Communities, and Cardiovascular Health studies were pooled to assess the independent effects of abdominal obesity (waist circumference >102 cm for men and >88 cm for women) versus metabolic syndrome (excluding the waist circumference criterion) and diabetes on risk for incident coronary heart disease and stroke in 20,298 men and women aged ≥45 years. The average follow-up was 8.3 (standard deviation 1.9) years. There were 1,766 CVD events. After adjustment for demographic factors, smoking, alcohol intake, number of metabolic syndrome components and diabetes, abdominal obesity was not significantly associated with an increased risk of CVD (hazard ratio [95% confidence interval] 1.09 [0.98, 1.20]). However, after adjustment for demographics, smoking, alcohol intake, and abdominal obesity, having 1–2 metabolic syndrome components, the metabolic syndrome, and diabetes were each associated with a significantly increased risk of CVD (2.12 [1.80, 2.50], 2.82 [1.92, 4.12] and 5.33 [3.37, 8.41], respectively). Although abdominal obesity is an important clinical tool for identification of individuals likely to possess metabolic abnormalities, these data suggest that the metabolic syndrome and diabetes are considerably more important prognostic indicators of CVD risk. PMID:20725064

  13. Investigation of Multiple Susceptibility Loci for Inflammatory Bowel Disease in an Italian Cohort of Patients

    PubMed Central

    Latiano, Anna; Palmieri, Orazio; Latiano, Tiziana; Corritore, Giuseppe; Bossa, Fabrizio; Martino, Giuseppina; Biscaglia, Giuseppe; Scimeca, Daniela; Valvano, Maria Rosa; Pastore, Maria; Marseglia, Antonio; D'Incà, Renata; Andriulli, Angelo; Annese, Vito

    2011-01-01

    Background Recent GWAs and meta-analyses have outlined about 100 susceptibility genes/loci for inflammatory bowel diseases (IBD). In this study we aimed to investigate the influence of SNPs tagging the genes/loci PTGER4, TNFSF15, NKX2-3, ZNF365, IFNG, PTPN2, PSMG1, and HLA in a large pediatric- and adult-onset IBD Italian cohort. Methods Eight SNPs were assessed in 1,070 Crohn's disease (CD), 1,213 ulcerative colitis (UC), 557 of whom being diagnosed at the age of ≤16 years, and 789 healthy controls. Correlations with sub-phenotypes and major variants of NOD2 gene were investigated. Results The SNPs tagging the TNFSF15, NKX2-3, ZNF365, and PTPN2 genes were associated with CD (P values ranging from 0.037 to 7×10−6). The SNPs tagging the PTGER4, NKX2-3, ZNF365, IFNG, PSMG1, and HLA area were associated with UC (P values 0.047 to 4×10−5). In the pediatric cohort the associations of TNFSF15, NKX2-3 with CD, and PTGER4, NKX2-3, ZNF365, IFNG, PSMG1 with UC, were confirmed. Association with TNFSF15 and pediatric UC was also reported. A correlation with NKX2-3 and need for surgery (P  =  0.038), and with HLA and steroid-responsiveness (P  =  0.024) in UC patients was observed. Moreover, significant association in our CD cohort with TNFSF15 SNP and colonic involvement (P  =  0.021), and with ZNF365 and ileal location (P  =  0.024) was demonstrated. Conclusions We confirmed in a large Italian cohort the associations with CD and UC of newly identified genes, both in adult and pediatric cohort of patients, with some influence on sub-phenotypes. PMID:21818367

  14. Turner's syndrome presenting as metabolic bone disease

    PubMed Central

    Kamalanathan, Sadishkumar; Balachandran, Karthik; Ananthakrishnan, Ramesh; Hamide, Abdoul

    2012-01-01

    Turner's syndrome is a genetic disorder with a complete or partial absence of one X chromosome with characteristic phenotypic features. The prevalence of renal anomalies in turner syndrome is 30–40%. However, the renal function is usually normal. We report a case of Turner's syndrome presenting with chronic kidney disease and renal osteodystrophy. PMID:22837932

  15. Metabolic biomarkers for predicting cardiovascular disease

    PubMed Central

    Montgomery, Jana E; Brown, Jeremiah R

    2013-01-01

    Cardiac and peripheral vascular biomarkers are increasingly becoming targets of both research and clinical practice. As of 2008, cardiovascular-related medical care accounts for greater than 20% of all the economic costs of illness in the United States. In the age of burgeoning financial pressures on the entire health care system, never has it been more important to try to understand who is at risk for cardiovascular disease in order to prevent new events. In this paper, we will discuss the cost of cardiovascular disease to society, clarify the definition of and need for biomarkers, offer an example of a current biomarker, namely high-sensitivity C-reactive protein, and finally examine the approval process for utilizing these in clinical practice. PMID:23386789

  16. Mitochondria in metabolic disease: getting clues from proteomic studies.

    PubMed

    Peinado, Juan R; Diaz-Ruiz, Alberto; Frühbeck, Gema; Malagon, Maria M

    2014-03-01

    Mitochondria play a key role as major regulators of cellular energy homeostasis, but in the context of mitochondrial dysfunction, mitochondria may generate reactive oxidative species and induce cellular apoptosis. Indeed, altered mitochondrial status has been linked to the pathogenesis of several metabolic disorders and specially disorders related to insulin resistance, such as obesity, type 2 diabetes, and other comorbidities comprising the metabolic syndrome. In the present review, we summarize information from various mitochondrial proteomic studies of insulin-sensitive tissues under different metabolic states. To that end, we first focus our attention on the pancreas, as mitochondrial malfunction has been shown to contribute to beta cell failure and impaired insulin release. Furthermore, proteomic studies of mitochondria obtained from liver, muscle, and adipose tissue are summarized, as these tissues constitute the primary insulin target metabolic tissues. Since recent advances in proteomic techniques have exposed the importance of PTMs in the development of metabolic disease, we also present information on specific PTMs that may directly affect mitochondria during the pathogenesis of metabolic disease. Specifically, mitochondrial protein acetylation, phosphorylation, and other PTMs related to oxidative damage, such as nitrosylation and carbonylation, are discussed.

  17. Childhood-Onset Disease Predicts Mortality in an Adult Cohort of Patients with Systemic Lupus Erythematosus

    PubMed Central

    Hersh, Aimee O.; Trupin, Laura; Yazdany, Jinoos; Panopalis, Peter; Julian, Laura; Katz, Patricia; Criswell, Lindsey A.; Yelin, Edward

    2013-01-01

    Objective To examine childhood-onset disease as a predictor of mortality in a cohort of adult patients with systemic lupus erythematosus (SLE). Methods Data were derived from the University of California Lupus Outcomes Study, a longitudinal cohort of 957 adult subjects with SLE that includes 98 subjects with childhood-onset SLE. Baseline and follow-up data were obtained via telephone interviews conducted between 2002-2007. The number of deaths during 5 years of follow-up was determined and standardized mortality ratios (SMRs) for the cohort, and across age groups, were calculated. Kaplan-Meier life table analysis was used to compare mortality rates between childhood (defined as SLE diagnosis <18 years) and adult-onset SLE. Multivariate Cox proportional hazard models were used to determine predictors of mortality. Results During the median follow-up period of 48 months, 72 deaths (7.5% of subjects) occurred, including 9 (12.5%) among those with childhood-onset SLE. The overall SMR was 2.5 (CI 2.0-3.2). In Kaplan-Meier survival analysis, after adjusting for age, childhood-onset subjects were at increased risk for mortality throughout the follow-up period (p<0.0001). In a multivariate model adjusting for age, disease duration and other covariates, childhood-onset SLE was independently associated with an increased mortality risk (hazard ratio [HR]: 3.1; 95% confidence interval [CI]: 1.3-7.3), as was low socioeconomic status measured by education (HR: 1.9; 95% CI 1.1-3.2) and end stage renal disease (HR: 2.1; 95% CI 1.1-4.0). Conclusion Childhood-onset SLE was a strong predictor of mortality in this cohort. Interventions are needed to prevent early mortality in this population. PMID:20235215

  18. Biotin in metabolism and its relationship to human disease.

    PubMed

    Pacheco-Alvarez, Diana; Solórzano-Vargas, R Sergio; Del Río, Alfonso León

    2002-01-01

    Biotin, a water-soluble vitamin, is used as cofactor of enzymes involved in carboxylation reactions. In humans, there are five biotin-dependent carboxylases: propionyl-CoA carboxylase; methylcrotonyl-CoA carboxylase; pyruvate carboxylase, and two forms of acetyl-CoA carboxylase. These enzymes catalyze key reactions in gluconeogenesis, fatty acid metabolism, and amino acid catabolism; thus, biotin plays an essential role in maintaining metabolic homeostasis. In recent years, biotin has been associated with several diseases in humans. Some are related to enzyme deficiencies involved in biotin metabolism. However, not all biotin-responsive disorders can be explained based on the classical role of the vitamin in cell metabolism. Several groups have suggested that biotin may be involved in regulating transcription or protein expression of different proteins. Biotinylation of histones and triggering of transduction signaling cascades have been suggested as underlying mechanisms behind these non-classical biotin-deficiency manifestation in humans.

  19. A Metabolic Study of Huntington’s Disease

    PubMed Central

    Kalliolia, Eirini; Ottolenghi, Chris; Hindmarsh, Peter; Hill, Nathan R.; Costelloe, Seán J.; Martin, Nicholas G.; Positano, Vincenzo; Watt, Hilary C.; Frost, Chris; Björkqvist, Maria; Warner, Thomas T.

    2016-01-01

    Background Huntington’s disease patients have a number of peripheral manifestations suggestive of metabolic and endocrine abnormalities. We, therefore, investigated a number of metabolic factors in a 24-hour study of Huntington’s disease gene carriers (premanifest and moderate stage II/III) and controls. Methods Control (n = 15), premanifest (n = 14) and stage II/III (n = 13) participants were studied with blood sampling over a 24-hour period. A battery of clinical tests including neurological rating and function scales were performed. Visceral and subcutaneous adipose distribution was measured using magnetic resonance imaging. We quantified fasting baseline concentrations of glucose, insulin, cholesterol, triglycerides, lipoprotein (a), fatty acids, amino acids, lactate and osteokines. Leptin and ghrelin were quantified in fasting samples and after a standardised meal. We assessed glucose, insulin, growth hormone and cortisol concentrations during a prolonged oral glucose tolerance test. Results We found no highly significant differences in carbohydrate, protein or lipid metabolism markers between healthy controls, premanifest and stage II/III Huntington’s disease subjects. For some markers (osteoprotegerin, tyrosine, lysine, phenylalanine and arginine) there is a suggestion (p values between 0.02 and 0.05) that levels are higher in patients with premanifest HD, but not moderate HD. However, given the large number of statistical tests performed interpretation of these findings must be cautious. Conclusions Contrary to previous studies that showed altered levels of metabolic markers in patients with Huntington’s disease, our study did not demonstrate convincing evidence of abnormalities in any of the markers examined. Our analyses were restricted to Huntington’s disease patients not taking neuroleptics, anti-depressants or other medication affecting metabolic pathways. Even with the modest sample sizes studied, the lack of highly significant results

  20. Metabolic evaluation of stone disease patients: a practical approach.

    PubMed

    Norman, R W

    2001-07-01

    The high success rates of extracorporeal shockwave lithotripsy and endourological techniques, together with their ease of use, in the treatment of urinary stones often overshadow the importance of the metabolic component of stone disease. It is my opinion that the prevention of further stones complements management of the acute episode. This review summarizes a variety of approaches to the measurement and manipulation of individual risk factors in recurrent urinary stone disease.

  1. Assessing the human gut microbiota in metabolic diseases.

    PubMed

    Karlsson, Fredrik; Tremaroli, Valentina; Nielsen, Jens; Bäckhed, Fredrik

    2013-10-01

    Recent findings have demonstrated that the gut microbiome complements our human genome with at least 100-fold more genes. In contrast to our Homo sapiens-derived genes, the microbiome is much more plastic, and its composition changes with age and diet, among other factors. An altered gut microbiota has been associated with several diseases, including obesity and diabetes, but the mechanisms involved remain elusive. Here we discuss factors that affect the gut microbiome, how the gut microbiome may contribute to metabolic diseases, and how to study the gut microbiome. Next-generation sequencing and development of software packages have led to the development of large-scale sequencing efforts to catalog the human microbiome. Furthermore, the use of genetically engineered gnotobiotic mouse models may increase our understanding of mechanisms by which the gut microbiome modulates host metabolism. A combination of classical microbiology, sequencing, and animal experiments may provide further insights into how the gut microbiota affect host metabolism and physiology.

  2. Assessing the Human Gut Microbiota in Metabolic Diseases

    PubMed Central

    Karlsson, Fredrik; Tremaroli, Valentina; Nielsen, Jens; Bäckhed, Fredrik

    2013-01-01

    Recent findings have demonstrated that the gut microbiome complements our human genome with at least 100-fold more genes. In contrast to our Homo sapiens–derived genes, the microbiome is much more plastic, and its composition changes with age and diet, among other factors. An altered gut microbiota has been associated with several diseases, including obesity and diabetes, but the mechanisms involved remain elusive. Here we discuss factors that affect the gut microbiome, how the gut microbiome may contribute to metabolic diseases, and how to study the gut microbiome. Next-generation sequencing and development of software packages have led to the development of large-scale sequencing efforts to catalog the human microbiome. Furthermore, the use of genetically engineered gnotobiotic mouse models may increase our understanding of mechanisms by which the gut microbiome modulates host metabolism. A combination of classical microbiology, sequencing, and animal experiments may provide further insights into how the gut microbiota affect host metabolism and physiology. PMID:24065795

  3. Incident Cardiovascular Disease Events in Metabolically Benign Obese Individuals

    PubMed Central

    Ogorodnikova, Alexandra D.; Kim, Mimi; McGinn, Aileen; Muntner, Paul; Khan, Unab I.; Wildman, Rachel P.

    2012-01-01

    OBJECTIVE While several studies have demonstrated a high prevalence of metabolically benign obesity, little is known about the incidence of cardiovascular disease (CVD) in this group. RESEARCH DESIGN AND METHODS Using pooled data from the Atherosclerosis Risk in Communities and Cardiovascular Health Studies, we assessed the association of metabolically benign obesity with incident CVD (coronary heart disease and stroke) using three existing definitions of metabolically benign obesity: (1) the ATP-III metabolic syndrome definition (≤2 of the ATP-III components, excluding waist), (2) the expanded ATP-III definition (≤1 of: the ATP-III components, HOMA-IR>75th percentile, systemic inflammation [WBC>75th percentile]), and (3) the insulin resistance (IR) based definition (sex-specific lowest quartile of the HOMA-IR distribution among non-diabetic obese). RESULTS The sample included 4,323 normal weight and 6,121 obese individuals. Among obese, 27.0%, 18.1%, and 20.4% were metabolically benign by the three definitions, respectively. CVD incidence among metabolically benign obese defined by the three definitions (mean follow-up 11.8 years) was 8.7%, 7.2%, and 10.3%, respectively, versus 7.9% in low-risk normal weight individuals. Multivariate-adjusted hazard ratios (95% CI) of incident CVD in metabolically benign obese compared to low-risk normal weight individuals were 1.24 (0.99-1.57), 1.16 (0.86-1.56), and 1.28 (1.01-1.62), respectively. CONCLUSIONS Regardless of the definition used, we observed a high prevalence of metabolically benign obesity. All three commonly used definitions were similar in terms of both classification and subsequent risk of CVD, with the expanded ATP-III criteria perhaps identifying the obese group at lowest risk of CVD. PMID:21799477

  4. Metabolic syndrome in patients with hematological diseases.

    PubMed

    Annaloro, Claudio; Airaghi, Lorena; Saporiti, Giorgia; Onida, Francesco; Cortelezzi, Agostino; Deliliers, Giorgio Lambertenghi

    2012-08-01

    The term metabolic syndrome (MS) defines a clustering of cardiovascular risk factors, formerly known as syndrome X. There is some debate about the diagnostic criteria; but the most widely accepted framework is that defined by the National Cholesterol Education Program Adult Treatment Panel III, which requires the simultaneous occurrence of at least three of abdominal obesity, arterial hypertension, hyperglycemia, hypertrigliceridemia and low high-density lipoprotein cholesterol (HDL-C). The prevalence of MS increases with age and varies depending on genetic factors. An abnormally high prevalence has been observed in patients with heterogeneous conditions, such as solid organ transplant recipients, AIDS patients and long-term cancer survivors. As some of the pathogenetic factors possibly involved include cyclosporine A, corticosteroids and cancer chemoradiotherapy, it is possible that MS may also be a complication in hematological patients. Some of the characteristics of MS have been reported with a certain frequency in thalassemia patients, and are mainly attributed to iron overload. Impaired hemostasis is a feature of MS rather than a factor predisposing to its development. In oncohematology, an abnormally high prevalence of MS features has been observed in survivors of pediatric acute lymphoblastic leukemia. In addition to corticosteroid- and cancer therapy-related hypogonadism, hypothyroidism and defective growth hormone incretion are other factors related to the development of MS. Moreover, the highest frequency of MS is observed in hematopoietic stem cell transplantation (HSCT) recipients. Pediatric patients and allogeneic HSCT recipients have been the subject of foremost investigations; but adult patients and autologous HSCT recipients have also been studied more recently. A wide range of factors may contribute to the development of MS in HSCT recipients. Unfortunately, the real entity of the problem is far from clear because of the retrospective design of

  5. Dyslipidemia and Cardiovascular Disease Risk Factor Management in HIV-1-Infected Subjects Treated with HAART in the Spanish VACH Cohort

    PubMed Central

    Domingo, Pere; Suarez-Lozano, Ignacio; Teira, Ramón; Lozano, Fernando; Terrón, Alberto; Viciana, Pompeyo; González, Juan; Galindo, Mª José; Geijo, Paloma; Vergara, Antonio; Cosín, Jaime; Ribera, Esteban; Roca, Bernardino; Garcia-Alcalde, Mª Luisa; Sánchez, Trinitario; Torres, Ferran; Lacalle, Juan Ramón; Garrido, Myriam

    2008-01-01

    Background: There is increasing evidence that metabolic adverse effects associated with antiretroviral therapy may translate into an increased cardiovascular risk in HIV-1-infected patients. Objectives: To determine the prevalence of risk factors for cardiovascular disease (CVD) among HIV-1-infected persons, and to investigate any association between them, stage of HIV-1 disease, and use of antiretroviral therapies. Methods: Multicentric, cross-sectional analysis of CVD risk factors of treated patients in the VACH cohort. The data collected includes: demographic variables, cigarette smoking, diabetes mellitus, hypertension, dyslipidemia, body mass index, stage of HIV-1 infection, and antiretroviral therapy. Results: The analysis included 2358 patients. More than 18% of the study population was at an age of appreciable risk of CVD. 1.7% had previous CVD and 59.2% were smokers. Increased prevalence of elevated total cholesterol was observed among subjects receiving an NNRTI but no PI [odds ratio (OR), 3.34; 95% confidence interval (CI), 1.77–6.31], PI but no NNRTI (OR, 4.04; 95% CI, 2.12–7.71), or NNRTI + PI (OR, 17.77; 95% CI, 7.24–43.59) compared to patients treated only with nucleoside reverse transcriptase inhibitors (NRTI). Higher CD4 cell count, lower plasma HIV-1 RNA levels, clinical signs of lipodystrophy, longer exposure times to NNRTI and PI, and older age were all also associated with elevated cholesterol levels. The use of lipid lowering agents was very low among our patients. Conclusion: Patients in the VACH cohort present multiple known risk factors for CVD, and a very low rate of lipid lowering therapy use. NNRTI and/or PI-based antiretroviral therapies are associated with the worst lipid profile. This is more frequent in older subjects with greater CD4 counts and controlled HIV-1 replication. PMID:18923695

  6. Calcium metabolism in health and disease.

    PubMed

    Peacock, Munro

    2010-01-01

    This brief review focuses on calcium balance and homeostasis and their relationship to dietary calcium intake and calcium supplementation in healthy subjects and patients with chronic kidney disease and mineral bone disorders (CKD-MBD). Calcium balance refers to the state of the calcium body stores, primarily in bone, which are largely a function of dietary intake, intestinal absorption, renal excretion, and bone remodeling. Bone calcium balance can be positive, neutral, or negative, depending on a number of factors, including growth, aging, and acquired or inherited disorders. Calcium homeostasis refers to the hormonal regulation of serum ionized calcium by parathyroid hormone, 1,25-dihydroxyvitamin D, and serum ionized calcium itself, which together regulate calcium transport at the gut, kidney, and bone. Hypercalcemia and hypocalcemia indicate serious disruption of calcium homeostasis but do not reflect calcium balance on their own. Calcium balance studies have determined the dietary and supplemental calcium requirements needed to optimize bone mass in healthy subjects. However, similar studies are needed in CKD-MBD, which disrupts both calcium balance and homeostasis, because these data in healthy subjects may not be generalizable to this patient group. Importantly, increasing evidence suggests that calcium supplementation may enhance soft tissue calcification and cardiovascular disease in CKD-MBD. Further research is needed to elucidate the risks and mechanisms of soft tissue calcification with calcium supplementation in both healthy subjects and CKD-MBD patients.

  7. Optical diagnosis of a metabolic disease: cystinosis

    NASA Astrophysics Data System (ADS)

    Cinotti, Elisa; Perrot, Jean Luc; Labeille, Bruno; Espinasse, Marine; Ouerdane, Youcef; Boukenter, Aziz; Thuret, Gilles; Gain, Philippe; Campolmi, Nelly; Douchet, Catherine; Cambazard, Frédéric

    2013-04-01

    Nephropathic cystinosis (NC) is a rare autosomal recessive storage disease characterized by the lysosomal accumulation of cystine crystals throughout the body, particularly in blood cells, the cornea, skin, kidneys, the central nervous system, and the muscles. The skin and the cornea are the most accessible sites to explore, and in vivo reflectance confocal microscopy (IVCM) helps identify crystals in both but does not provide any information to help define their composition. Raman spectroscopy (RS) allows cystine to be easily recognized thanks to its characteristic signature with a band at 499 cm-1. Two dermatology confocal microscopes were used to visualize crystals in both the skin and the ocular surface of a cystinosis patient, and an ex vivo Raman examination of a skin biopsy and of the cornea was performed and removed during a corneal graft to confirm the cystine composition of the crystals. Recently, RS has been performed in vivo and coupled with IVCM. In the future, it is suggested that crystals in NC and other deposits in storage diseases could be identified with this noninvasive in vivo technique that combines IVCM to recognize the deposits and RS to confirm their chemical nature.

  8. [A birth cohort study on allergic diseases among toddlers in Northwest Germany].

    PubMed

    Pohlabeln, H; Jacobs, S; Böhmann, J

    2012-06-01

    In the late 1990s, a birth cohort study was conducted in the cities of Delmenhorst, Wilhelmshaven and Leer, where more than 3,000 newborn children were recruited in five hospitals. The baseline survey in the clinics was followed by three follow-up surveys 6, 12 and 24 months later. The prime concern of the study was to estimate prevalences and to conduct analyses concerning the association between breastfeeding as well as exposure to pets and the occurrence of allergy symptoms. Children living together with a dog in the same household were at higher risk of disease only if a familial predisposition of allergic diseases was present - without such a familial predisposition a dog in the same household seems to reduce the risk for atopic diseases during the first 2 years of life. A protective effect due to long breastfeeding could be observed in our study in particular in case of a paternal history of allergic diseases, whereas an exclusive maternal history of allergic diseases seems to increase the risk. The concept of the study has proved itself. Contacting mothers in obstetrical departments in hospitals as well as in medical offices of self-employed pediatricians has proven to be very practicable. With comparatively little effort a relatively large cohort was recruited, which allowed us to analyze longitudinal data, adequately taking into account several confounders as well as effect-modifying factors. PMID:22736168

  9. Metabolic disruption identified in the Huntington's disease transgenic sheep model.

    PubMed

    Handley, Renee R; Reid, Suzanne J; Patassini, Stefano; Rudiger, Skye R; Obolonkin, Vladimir; McLaughlan, Clive J; Jacobsen, Jessie C; Gusella, James F; MacDonald, Marcy E; Waldvogel, Henry J; Bawden, C Simon; Faull, Richard L M; Snell, Russell G

    2016-02-11

    Huntington's disease (HD) is a dominantly inherited, progressive neurodegenerative disorder caused by a CAG repeat expansion within exon 1 of HTT, encoding huntingtin. There are no therapies that can delay the progression of this devastating disease. One feature of HD that may play a critical role in its pathogenesis is metabolic disruption. Consequently, we undertook a comparative study of metabolites in our transgenic sheep model of HD (OVT73). This model does not display overt symptoms of HD but has circadian rhythm alterations and molecular changes characteristic of the early phase disease. Quantitative metabolite profiles were generated from the motor cortex, hippocampus, cerebellum and liver tissue of 5 year old transgenic sheep and matched controls by gas chromatography-mass spectrometry. Differentially abundant metabolites were evident in the cerebellum and liver. There was striking tissue-specificity, with predominantly amino acids affected in the transgenic cerebellum and fatty acids in the transgenic liver, which together may indicate a hyper-metabolic state. Furthermore, there were more strong pair-wise correlations of metabolite abundance in transgenic than in wild-type cerebellum and liver, suggesting altered metabolic constraints. Together these differences indicate a metabolic disruption in the sheep model of HD and could provide insight into the presymptomatic human disease.

  10. Metabolic disruption identified in the Huntington's disease transgenic sheep model.

    PubMed

    Handley, Renee R; Reid, Suzanne J; Patassini, Stefano; Rudiger, Skye R; Obolonkin, Vladimir; McLaughlan, Clive J; Jacobsen, Jessie C; Gusella, James F; MacDonald, Marcy E; Waldvogel, Henry J; Bawden, C Simon; Faull, Richard L M; Snell, Russell G

    2016-01-01

    Huntington's disease (HD) is a dominantly inherited, progressive neurodegenerative disorder caused by a CAG repeat expansion within exon 1 of HTT, encoding huntingtin. There are no therapies that can delay the progression of this devastating disease. One feature of HD that may play a critical role in its pathogenesis is metabolic disruption. Consequently, we undertook a comparative study of metabolites in our transgenic sheep model of HD (OVT73). This model does not display overt symptoms of HD but has circadian rhythm alterations and molecular changes characteristic of the early phase disease. Quantitative metabolite profiles were generated from the motor cortex, hippocampus, cerebellum and liver tissue of 5 year old transgenic sheep and matched controls by gas chromatography-mass spectrometry. Differentially abundant metabolites were evident in the cerebellum and liver. There was striking tissue-specificity, with predominantly amino acids affected in the transgenic cerebellum and fatty acids in the transgenic liver, which together may indicate a hyper-metabolic state. Furthermore, there were more strong pair-wise correlations of metabolite abundance in transgenic than in wild-type cerebellum and liver, suggesting altered metabolic constraints. Together these differences indicate a metabolic disruption in the sheep model of HD and could provide insight into the presymptomatic human disease. PMID:26864449

  11. [Metabolic disorders and nutritional status in autoimmune thyroid diseases].

    PubMed

    Kawicka, Anna; Regulska-Ilow, Bożena; Regulska-Ilow, Bożena

    2015-01-02

    In recent years, the authors of epidemiological studies have documented that autoimmune diseases are a major problem of modern society and are classified as diseases of civilization. Autoimmune thyroid diseases (ATDs) are caused by an abnormal immune response to autoantigens present in the thyroid gland - they often coexist with other autoimmune diseases. The most common dysfunctions of the thyroid gland are hypothyroidism, Graves-Basedow disease and Hashimoto's disease. Hashimoto's thyroiditis can be the main cause of primary hypothyroidism of the thyroid gland. Anthropometric, biochemical and physicochemical parameters are used to assess the nutritional status during the diagnosis and treatment of thyroid diseases. Patients with hypothyroidism are often obese, whereas patients with hyperthyroidism are often afflicted with rapid weight loss. The consequence of obesity is a change of the thyroid hormones' activity; however, weight reduction leads to their normalization. The activity and metabolic rate of thyroid hormones are modifiable. ATDs are associated with abnormalities of glucose metabolism and thus increased risk of developing diabetes mellitus type 1 and type 2. Celiac disease (CD) also increases the risk of developing other autoimmune diseases. Malnutrition or the presence of numerous nutritional deficiencies in a patient's body can be the cause of thyroid disorders. Coexisting deficiencies of such elements as iodine, iron, selenium and zinc may impair the function of the thyroid gland. Other nutrient deficiencies usually observed in patients suffering from ATD are: protein deficiencies, vitamin deficiencies (A, C, B6, B5, B1) and mineral deficiencies (phosphorus, magnesium, potassium, sodium, chromium). Proper diet helps to reduce the symptoms of the disease, maintains a healthy weight and prevents the occurrence of malnutrition. This article presents an overview of selected documented studies and scientific reports on the relationship of metabolic

  12. Risk of mortality from circulatory diseases in Mayak workers cohort following occupational radiation exposure.

    PubMed

    Azizova, T V; Grigorieva, E S; Hunter, N; Pikulina, M V; Moseeva, M B

    2015-09-01

    Mortality from circulatory diseases (CD) (ICD-9 codes 390-459) was studied in an extended Mayak worker cohort, which included 22,377 workers first employed at the Mayak Production Association in 1948-1982 and followed up to the end of 2008. The enlarged cohort and extended follow-up as compared to the previous analyses provided an increased number of deaths from CD and improved statistical power of this mortality study. The analyses were based on dose estimates provided by a new Mayak Worker Dosimetry System 2008 (MWDS-2008). For the first time in the study of non-cancer effects in this cohort quantitative smoking data (smoking index) were taken into account. A significant increasing trend for CD mortality with increasing dose from external gamma-rays was found after having adjusted for non-radiation factors; the excess relative risk per unit dose (ERR/Gy) was 0.05 (95% confidence interval (CI):  >0, 0.11). Inclusion of an additional adjustment for dose from internal alpha-radiation to the liver resulted in a two-fold increase of ERR/Gy = 0.10 (95% CI: 0.02, 0.21). A significant increasing trend in CD mortality with increasing dose from internal alpha-radiation to the liver was observed (ERR/Gy = 0.27, 95% CI: 0.12, 0.48). However the ERR/Gy decreased and lost its significance after adjusting for dose from external gamma-rays. Results of the current study are in good agreement with risk estimates obtained for the Japanese LSS cohort as well as other studies of cohorts of nuclear workers.

  13. Submaximal fitness and mortality risk reduction in coronary heart disease: a retrospective cohort study of community-based exercise rehabilitation

    PubMed Central

    Taylor, Claire; Tsakirides, Costas; Moxon, James; Moxon, James William; Dudfield, Michael; Witte, Klaus K; Ingle, Lee; Carroll, Sean

    2016-01-01

    Objectives To examine the association between submaximal cardiorespiratory fitness (sCRF) and all-cause mortality in a cardiac rehabilitation (CR) cohort. Design Retrospective cohort study of participants entering CR between 26 May 1993 and 16 October 2006, followed up to 1 November 2013 (median 14 years, range 1.2–19.4 years). Setting A community-based CR exercise programme in Leeds, West Yorkshire, UK. Participants A cohort of 534 men (76%) and 136 women with a clinical diagnosis of coronary heart disease (CHD), aged 22–82 years, attending CR were evaluated for the association between baseline sCRF and all-cause mortality. 416 participants with an exercise test following CR (median 14 weeks) were examined for changes in sCRF and all-cause mortality. Main outcome measures All-cause mortality and change in sCRF expressed in estimated metabolic equivalents (METs). Results Baseline sCRF was a strong predictor of all-cause mortality; compared to the lowest sCRF group (<5 METs for women and <6 METs for men), mortality risk was 41% lower in those with moderate sCRF (HR 0.59; 95% CI 0.42 to 0.83) and 60% lower (HR 0.40; 95% CI 0.25 to 0.64) in those with higher sCRF levels (≥7 METs women and ≥8 METs for men). Although improvement in sCRF at 14 weeks was not associated with a significant mortality risk reduction (HR 0.91; 95% CI 0.79 to 1.06) for the whole cohort, in those with the lowest sCRF (and highest all-cause mortality) at baseline, each 1-MET improvement was associated with a 27% age-adjusted reduction in mortality risk (HR 0.73; 95% CI 0.57 to 0.94). Conclusions Higher baseline sCRF is associated with a reduced risk of all-cause mortality over 14 years in adults with CHD. Improving fitness through exercise-based CR is associated with significant risk reduction for the least fit. PMID:27363816

  14. The impact of metabolic disease associated with metabolic syndrome on human pregnancy.

    PubMed

    Malek, Antoine

    2014-01-01

    Metabolic diseases induced by metabolic syndrome (MS) have been increased during the past two decades. During healthy pregnancy maternal organs and placenta are challenged to adapt to the increasingly physiological changes. In addition to the increasingly proatherogenic MS, pregnant woman develops a high cardiac output, hypercoagulability, increased inflammatory activity and insulin resistance with dyslipidemia. The MS describes a cluster of metabolic changes associated with an impact on the physiology of many organs. While the metabolic syndrome is directly responsible for the development of atherosclerotic cardiovascular disease, additional impact on human pregnancy like preterm delivery with low-birth-weight infants as well as the development of diseases such as diabetes, preeclampsia and hypertension. Recent evidence suggests that MS is originated in fetal life in association with maternal nutrition during pregnancy and fetal programming which apparently increases the susceptibility for MS in children and later life. This review will describe the MS in association with the origin of the emerging diseases during pregnancy such as diabetes, preeclampsia and others. The influence of perinatal environment and maternal diet and smoking on MS as well as the genetic biomarkers of MS will be described.

  15. Endothelial cell metabolism in normal and diseased vasculature

    PubMed Central

    Eelen, Guy; de Zeeuw, Pauline; Simons, Michael; Carmeliet, Peter

    2015-01-01

    Higher organisms rely on a closed cardiovascular circulatory system with blood vessels supplying vital nutrients and oxygen to distant tissues. Not surprisingly, vascular pathologies rank among the most life-threatening diseases. At the crux of most of these vascular pathologies are (dysfunctional) endothelial cells (ECs), the cells lining the blood vessel lumen. ECs display the remarkable capability to switch rapidly from a quiescent state to a highly migratory and proliferative state during vessel sprouting. This angiogenic switch has long been considered to be dictated by angiogenic growth factors (eg vascular endothelial growth factor; VEGF) and other signals (eg Notch) alone, but recent findings show that it is also driven by a metabolic switch in ECs. Furthermore, these changes in metabolism may even override signals inducing vessel sprouting. Here, we review how EC metabolism differs between the normal and dysfunctional/diseased vasculature and how it relates to or impacts the metabolism of other cell types contributing to the pathology. We focus on the biology of ECs in tumor blood vessel and diabetic ECs in atherosclerosis as examples of the role of endothelial metabolism in key pathological processes. Finally, current as well as unexplored ‘EC metabolism’-centric therapeutic avenues are discussed. PMID:25814684

  16. Dietary inorganic nitrate: From villain to hero in metabolic disease?

    PubMed Central

    McNally, Ben; Griffin, Julian L.

    2015-01-01

    Historically, inorganic nitrate was believed to be an inert by‐product of nitric oxide (NO) metabolism that was readily excreted by the body. Studies utilising doses of nitrate far in excess of dietary and physiological sources reported potentially toxic and carcinogenic effects of the anion. However, nitrate is a significant component of our diets, with the majority of the anion coming from green leafy vegetables, which have been consistently shown to offer protection against obesity, type 2 diabetes and metabolic diseases. The discovery of a metabolic pathway in mammals, in which nitrate is reduced to NO, via nitrite, has warranted a re‐examination of the physiological role of this small molecule. Obesity, type 2 diabetes and the metabolic syndrome are associated with a decrease in NO bioavailability. Recent research suggests that the nitrate‐nitrite‐NO pathway may be harnessed as a therapeutic to supplement circulating NO concentrations, with both anti‐obesity and anti‐diabetic effects, as well as improving vascular function. In this review, we examine the key studies that have led to the re‐evaluation of the physiological function of inorganic nitrate, from toxic and carcinogenic metabolite, to a potentially important and beneficial agent in the treatment of metabolic disease. PMID:26227946

  17. Dietary inorganic nitrate: From villain to hero in metabolic disease?

    PubMed

    McNally, Ben; Griffin, Julian L; Roberts, Lee D

    2016-01-01

    Historically, inorganic nitrate was believed to be an inert by-product of nitric oxide (NO) metabolism that was readily excreted by the body. Studies utilising doses of nitrate far in excess of dietary and physiological sources reported potentially toxic and carcinogenic effects of the anion. However, nitrate is a significant component of our diets, with the majority of the anion coming from green leafy vegetables, which have been consistently shown to offer protection against obesity, type 2 diabetes and metabolic diseases. The discovery of a metabolic pathway in mammals, in which nitrate is reduced to NO, via nitrite, has warranted a re-examination of the physiological role of this small molecule. Obesity, type 2 diabetes and the metabolic syndrome are associated with a decrease in NO bioavailability. Recent research suggests that the nitrate-nitrite-NO pathway may be harnessed as a therapeutic to supplement circulating NO concentrations, with both anti-obesity and anti-diabetic effects, as well as improving vascular function. In this review, we examine the key studies that have led to the re-evaluation of the physiological function of inorganic nitrate, from toxic and carcinogenic metabolite, to a potentially important and beneficial agent in the treatment of metabolic disease.

  18. Phytanic acid metabolism in health and disease.

    PubMed

    Wanders, Ronald J A; Komen, Jasper; Ferdinandusse, Sacha

    2011-09-01

    Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a branched-chain fatty acid which cannot be beta-oxidized due to the presence of the first methyl group at the 3-position. Instead, phytanic acid undergoes alpha-oxidation to produce pristanic acid (2,6,10,14-tetramethylpentadecanoic acid) plus CO(2). Pristanic acid is a 2-methyl branched-chain fatty acid which can undergo beta-oxidation via sequential cycles of beta-oxidation in peroxisomes and mitochondria. The mechanism of alpha-oxidation has been resolved in recent years as reviewed in this paper, although some of the individual enzymatic steps remain to be identified. Furthermore, much has been learned in recent years about the permeability properties of the peroxisomal membrane with important consequences for the alpha-oxidation process. Finally, we present new data on the omega-oxidation of phytanic acid making use of a recently generated mouse model for Refsum disease in which the gene encoding phytanoyl-CoA 2-hydroxylase has been disrupted.

  19. Disease Combinations Associated with Physical Activity Identified: The SMILE Cohort Study

    PubMed Central

    Dörenkamp, Sarah; Mesters, Ilse; Schepers, Jan; Vos, Rein; van den Akker, Marjan; Teijink, Joep; de Bie, Rob

    2016-01-01

    In the search of predictors of inadequate physical activity, an investigation was conducted into the association between multimorbidity and physical activity (PA). So far the sum of diseases used as a measure of multimorbidity reveals an inverse association. How specific combinations of chronic diseases are associated with PA remains unclear. The objective of this study is to identify clusters of multimorbidity that are associated with PA. Cross-sectional data of 3,386 patients from the 2003 wave of the Dutch cohort study SMILE were used. Ward's agglomerative hierarchical clustering was executed to establish multimorbidity clusters. Chi-square statistics were used to assess the association between clusters of chronic diseases and PA, measured in compliance with the Dutch PA guideline. The highest rate of PA guideline compliance was found in patients the majority of whom suffer from liver disease, back problems, rheumatoid arthritis, osteoarthritis, and inflammatory joint disease (62.4%). The lowest rate of PA guideline compliance was reported in patients with heart disease, respiratory disease, and diabetes mellitus (55.8%). Within the group of people with multimorbidity, those suffering from heart disease, respiratory disease, and/or diabetes mellitus may constitute a priority population as PA has proven to be effective in the prevention and cure of all three disorders. PMID:26881231

  20. Exosomes as the source of biomarkers of metabolic diseases

    PubMed Central

    Lee, Min-Jae; Park, Dong-Ho

    2016-01-01

    Exosomes are extracellular vesicles that contain molecules that regulate the metabolic functions of adjacent or remote cells. Recent in vitro, in vivo and clinical studies support the hypothesis that exosomes released from various cell types play roles in the progression of metabolic disorders including type 2 diabetes. Based on this concept and advances in other diseases, the proteins, mRNA, microRNA and lipids in exosomes isolated from biological fluids have been proposed as biomarkers in metabolic disorders. However, several problems with the development of clinically applicable biomarkers have not been resolved. In this review, the biologic functions of exosomes are briefly introduced, and we discuss the technical and practical pros and cons of different methods of exosome isolation for the identification of exosomal biomarkers of metabolic disorders. Standardization of preanalytical variables and isolation of high-purity exosomes from fully characterized biological fluids will be necessary for the identification of useful exosomal biomarkers that can provide insights into the pathogenic mechanisms of complications of metabolic syndrome and of whole-body metabolism. PMID:27777903

  1. Associations between Sugar Intake from Different Food Sources and Adiposity or Cardio-Metabolic Risk in Childhood and Adolescence: The Korean Child-Adolescent Cohort Study.

    PubMed

    Hur, Yang-Im; Park, Hyesook; Kang, Jae-Heon; Lee, Hye-Ah; Song, Hong Ji; Lee, Hae-Jeung; Kim, Ok-Hyun

    2015-12-31

    The increasing prevalence of childhood obesity is a serious public health problem associated with co-morbidities in adulthood, as well as childhood. This study was conducted to identify associations between total sugar intake and sugar intake from different foods (fruit, milk, and sugar-sweetened beverages (SSBs)), and adiposity and continuous metabolic syndrome scores (cMetS) among Korean children and adolescents using cohort data. The study subjects were children (n = 770) who participated in the 4th year (2008) of the Korean Child-Adolescent Cohort Study (KoCAS). Dietary intake data were collected via three-day 24-h food records, and sugar intake was calculated for the total sugar content of foods using our database compiled from various sources. Anthropometric measurements, assessments of body composition, and blood sample analysis were performed at baseline and at follow-up four years later. The cMetS was calculated based on waist circumference, triglycerides, high-density lipoprotein cholesterol, glucose, and mean arterial blood pressure. According to multiple linear regression analysis, there were no significant associations between total sugar intake and adiposity and cMetS. However, higher intake of fruit sugar at baseline was significantly associated with lower body mass index (BMI) z-scores and body fat percentages at baseline (β = -0.10, p = 0.02 and β = -0.78, p < 0.01, respectively). At follow-up, sugar intake from fruit at baseline was still negatively associated with the above outcomes, but only the relationship with BMI z-scores retained statistical significance (β = -0.08, p < 0.05). There was a significant positive relationship between consumption of sugar from SSBs and cMetS at baseline (β = 0.04, p = 0.02), but that relationship was not observed at follow-up (p = 0.83). Differences in consumption sugars from fruit and SSBs might play an important role in the risk of adiposity and metabolic disease in children and adolescents. Our results

  2. Associations between Sugar Intake from Different Food Sources and Adiposity or Cardio-Metabolic Risk in Childhood and Adolescence: The Korean Child–Adolescent Cohort Study

    PubMed Central

    Hur, Yang-Im; Park, Hyesook; Kang, Jae-Heon; Lee, Hye-Ah; Song, Hong Ji; Lee, Hae-Jeung; Kim, Ok-Hyun

    2015-01-01

    The increasing prevalence of childhood obesity is a serious public health problem associated with co-morbidities in adulthood, as well as childhood. This study was conducted to identify associations between total sugar intake and sugar intake from different foods (fruit, milk, and sugar-sweetened beverages (SSBs)), and adiposity and continuous metabolic syndrome scores (cMetS) among Korean children and adolescents using cohort data. The study subjects were children (n = 770) who participated in the 4th year (2008) of the Korean Child–Adolescent Cohort Study (KoCAS). Dietary intake data were collected via three-day 24-h food records, and sugar intake was calculated for the total sugar content of foods using our database compiled from various sources. Anthropometric measurements, assessments of body composition, and blood sample analysis were performed at baseline and at follow-up four years later. The cMetS was calculated based on waist circumference, triglycerides, high-density lipoprotein cholesterol, glucose, and mean arterial blood pressure. According to multiple linear regression analysis, there were no significant associations between total sugar intake and adiposity and cMetS. However, higher intake of fruit sugar at baseline was significantly associated with lower body mass index (BMI) z-scores and body fat percentages at baseline (β = −0.10, p = 0.02 and β = −0.78, p < 0.01, respectively). At follow-up, sugar intake from fruit at baseline was still negatively associated with the above outcomes, but only the relationship with BMI z-scores retained statistical significance (β = −0.08, p < 0.05). There was a significant positive relationship between consumption of sugar from SSBs and cMetS at baseline (β = 0.04, p = 0.02), but that relationship was not observed at follow-up (p = 0.83). Differences in consumption sugars from fruit and SSBs might play an important role in the risk of adiposity and metabolic disease in children and adolescents. Our

  3. The genetic basis of kidney cancer: a metabolic disease

    PubMed Central

    Linehan, W. Marston; Srinivasan, Ramaprasad; Schmidt, Laura S.

    2010-01-01

    Kidney cancer is not a single disease but encompasses a number of different types of cancer that occur in the kidney, each caused by a different gene with a different histology and clinical course that responds differently to therapy. Each of the seven known kidney cancer genes, VHL, MET, FLCN, TSC1, TSC2, FH and SDH, is involved in pathways that respond to metabolic stress and/or nutrient stimulation. The VHL protein is a component of the oxygen and iron sensing pathway that regulates HIF levels in the cell. HGF/MET signaling affects the LKB1/AMPK energy sensing cascade. The FLCN/FNIP1/FNIP2 complex binds AMPK and therefore may interact with the cellular energy and nutrient sensing pathways, AMPK-TSC1/2-mTOR and PI3K-Akt-mTOR. TSC1/TSC2 are downstream of AMPK and negatively regulate mTOR in response to cellular energy deficit. FH and SDH play a central role in the mitochondrial tricarboxylic acid (TCA) cycle whose activities are coupled to energy production through oxidative phosphorylation. Mutations in each of these kidney cancer genes result in dysregulation of metabolic pathways involved in oxygen, iron, energy and/or nutrient sensing suggesting that kidney cancer is a disease of cell metabolism. Targeting the fundamental metabolic abnormalities in kidney cancer provides a unique opportunity for the development of more effective forms of therapy for this disease. PMID:20448661

  4. Ulcer Disease, Metabolic Alkalosis and Hyperparathyroidism: A Mechanism of Interrelationship?

    PubMed Central

    Kaplan, Edwin L.; Peskin, Gerald W.; Deveney, Clifford; Way, Lawrence; Jaffe, Bernard

    1974-01-01

    In both normal volunteers and in patients with primary hyperparathyroidism, the induction of a metabolic alkalosis by infusion of sodium bicarbonate results in a decrease in serum calcium ion and in an increase of circulating parathyroid hormone concentrations. Bicarbonate infusion may serve in man as a new provocative test for release of parathyroid hormone. Furthermore, we speculate that the metabolic alkalosis which is found at times in patients with the Zollinger-Ellison syndrome and severe peptic ulcer disease may result in parathyroid gland stimulation. PMID:4416767

  5. Birth cohorts in asthma and allergic diseases: report of a NIAID/NHLBI/MeDALL joint workshop.

    PubMed

    Bousquet, Jean; Gern, James E; Martinez, Fernando D; Anto, Josep M; Johnson, Christine C; Holt, Patrick G; Lemanske, Robert F; Le Souëf, Peter N; Tepper, Robert S; von Mutius, Erika R M; Arshad, S Hasan; Bacharier, Leonard B; Becker, Allan; Belanger, Kathleen; Bergström, Anna; Bernstein, David I; Cabana, Michael D; Carroll, Kecia N; Castro, Mario; Cooper, Philip J; Gillman, Matthew W; Gold, Diane R; Henderson, John; Heinrich, Joachim; Hong, Soo-Jong; Jackson, Daniel J; Keil, Thomas; Kozyrskyj, Anita L; Lødrup Carlsen, Karin C; Miller, Rachel L; Momas, Isabelle; Morgan, Wayne J; Noel, Patricia; Ownby, Dennis R; Pinart, Mariona; Ryan, Patrick H; Schwaninger, Julie M; Sears, Malcolm R; Simpson, Angela; Smit, Henriette A; Stern, Debra A; Subbarao, Padmaja; Valenta, Rudolf; Wang, Xiaobin; Weiss, Scott T; Wood, Robert; Wright, Anne L; Wright, Rosalind J; Togias, Alkis; Gergen, Peter J

    2014-06-01

    Population-based birth cohorts on asthma and allergies increasingly provide new insights into the development and natural history of the diseases. More than 130 birth cohorts focusing on asthma and allergy have been initiated in the last 30 years. A National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; Mechanisms of the Development of Allergy (MeDALL; Framework Programme 7 of the European Commission) joint workshop was held in Bethesda, Maryland, on September 11-12, 2012, with 3 objectives: (1) documenting the knowledge that asthma/allergy birth cohorts have provided, (2) identifying the knowledge gaps and inconsistencies, and (3) developing strategies for moving forward, including potential new study designs and the harmonization of existing asthma birth cohort data. The meeting was organized around the presentations of 5 distinct workgroups: (1) clinical phenotypes, (2) risk factors, (3) immune development of asthma and allergy, (4) pulmonary development, and (5) harmonization of existing birth cohorts. This article presents the workgroup reports and provides Web links (AsthmaBirthCohorts.niaid.nih.gov or www.medall-fp7.eu), where the reader will find tables describing the characteristics of the birth cohorts included in this report, the type of data collected at differing ages, and a selected bibliography provided by the participating birth cohorts.

  6. Birth cohorts in asthma and allergic diseases: Report of a NIAID, NHLBI, MeDALL joint workshop

    PubMed Central

    Bousquet, J; Gern, JE; Martinez, FD; Anto, JM; Johnson, CC; Holt, PG; Lemanske, RF; Le Souef, PN; Tepper, R; von Mutius, ERM; Arshad, SH; Bacharier, LB; Becker, A; Belanger, K; Bergstrom, A; Bernstein, D; Cabana, MD; Carroll, KN; Castro, M; Cooper, PJ; Gillman, MW; Gold, DR; Henderson, J; Heinrich, J; S-J, Hong; Jackson, DJ; Keil, T; Kozyrskyj, AL; Lodrup-Carlsen, K; Miller, RL; Momas, I; Morgan, WJ; Noel, P; Ownby, DR; Pinart, M; Ryan, P; Schwaninger, JM; Sears, MR; Simpson, A; Smit, HA; Stern, D; Subbarao, P; Valenta, R; Wang, X; Weiss, ST; Wood, R; Wright, AL; Wright, RJ; Togias, A; Gergen, PJ

    2014-01-01

    Population-based birth cohorts on asthma and allergies increasingly provide new insights into the development and natural history of the diseases. Over 130 birth cohorts focusing on asthma and allergy have been initiated in the last 30 years. A NIAID (National Institute of Allergy and Infectious Diseases), NHLBI (National Heart Lung and Blood Institute), MeDALL (Mechanisms of the Development of Allergy, Framework Programme 7 of the European Commission) joint workshop was held in Bethesda, MD, USA September 11–12, 2012 with 3 objectives (1) documenting the knowledge that asthma/allergy birth cohorts have provided, (2) identifying the knowledge gaps and inconsistencies and (3) developing strategies for moving forward, including potential new study designs and the harmonization of existing asthma birth cohort data. The meeting was organized around the presentations of 5 distinct workgroups: (1) clinical phenotypes, (2) risk factors, (3) immune development of asthma and allergy, (4) pulmonary development and (5) harmonization of existing birth cohorts. This manuscript presents the workgroup reports and provides web links (AsthmaBirthCohorts.niaid.nih.gov or www.medall-fp7.eu) where the reader will find tables describing the characteristics of the birth cohorts included in this report, type of data collected at differing ages, and a selected bibliography provided by the participating birth cohorts. PMID:24636091

  7. Modeling metabolic homeostasis and nutrient sensing in Drosophila: implications for aging and metabolic diseases

    PubMed Central

    Owusu-Ansah, Edward; Perrimon, Norbert

    2014-01-01

    Over the past decade, numerous reports have underscored the similarities between the metabolism of Drosophila and vertebrates, with the identification of evolutionarily conserved enzymes and analogous organs that regulate carbohydrate and lipid metabolism. It is now well established that the major metabolic, energy-sensing and endocrine signaling networks of vertebrate systems are also conserved in flies. Accordingly, studies in Drosophila are beginning to unravel how perturbed energy balance impinges on lifespan and on the ensuing diseases when energy homeostasis goes awry. Here, we highlight several emerging concepts that are at the nexus between obesity, nutrient sensing, metabolic homeostasis and aging. Specifically, we summarize the endocrine mechanisms that regulate carbohydrate and lipid metabolism, and provide an overview of the neuropeptides that regulate feeding behavior. We further describe the various efforts at modeling the effects of high-fat or -sugar diets in Drosophila and the signaling mechanisms involved in integrating organ function. Finally, we draw attention to some of the cardinal discoveries made with these disease models and how these could spur new research questions in vertebrate systems. PMID:24609035

  8. Asthma–Chronic Obstructive Pulmonary Diseases Overlap Syndrome Increases the Risk of Incident Tuberculosis: A National Cohort Study

    PubMed Central

    Yeh, Jun-Jun; Wang, Yu-Chiao; Kao, Chia-Hung

    2016-01-01

    Purpose The association between asthma–chronic obstructive pulmonary diseases (COPD) overlap syndrome (ACOS) and tuberculosis (TB) has yet to be studied. Methods The newly diagnosed TB patients (age > 20 y) treated from January 2000 to December 2008 were included (ACOS cohort, n = 10 751; non-ACOS cohort, n = 42 966). The non-ACOS cohort involved patients with confirmed absence of ACOS. We calculated incidence rate ratios (IRRs) for TB in the ACOS and non-ACOS cohorts by using poisson regression analysis. Cox proportional hazards regression models were used to determine the adjusted HR (aHR) for TB in the ACOS cohort compared with the non-ACOS cohort. Results The aHR for TB was 2.41 (95% confidence interval [CI], 2.19–2.66) in the ACOS cohort. The TB risk was significantly higher in the ACOS cohort than in the non-ACOS cohort when stratified by age, sex, comorbidities, and atopy. Within the ACOS cohort, the aHR was higher among patients receiving SABAs+SAMAs, LABAs+LAMAs, and ICSs (aHR [95% CI]: 3.06 [2.75–3.41], 3.68 [2.93–4.61], and 2.79 [1.25–6.22], respectively; all P < .05). Furthermore, patients with more than 15 outpatient visits and hospitalizations per year demonstrated the highest aHR (8.09; 95% CI, 6.85–9.56). Conclusions ACOS cohort potentially develop incident TB, regardless of the age,sex, comorbidities and atopy; even without receiving the inhalers.This risk is higher, especially in the ACOS cohort have a high frequency of medical services or receiving the inhalers such as SABAs+SAMAs, LABAs+LAMAs and ICSs. PMID:27448309

  9. Cortical metabolism, acetylcholinesterase staining and pathological changes in Alzheimer's disease.

    PubMed

    McGeer, E G; McGeer, P L; Kamo, H; Tago, H; Harrop, R

    1986-11-01

    The local cerebral metabolic rate for glucose (LCMRgl) was determined by positron emission tomography (PET) using the 18F-fluorodeoxyglucose method in a series of Alzheimer patients and normal controls. The LCMRgl declined in the cerebral cortex with age, but the decrement was significantly greater in the clinically diagnosed Alzheimer's cases. Comparison of PET and psychological data indicated that, as the disease progressed clinically, the reduction in cortical LCMRgl and the number of cortical regions involved also increased. Variable regions of cortex were involved in the early stages but the temporal, parietal and frontal regions were most typically affected. One case coming to autopsy showed that the severity of the LCMRgl decline paralleled loss of neurons in the cortex and their replacement with astroglia. A case of Pick's disease coming to autopsy had shown a different and highly characteristic pattern of cortical metabolic defect. In this case also a poor metabolic rate was associated with extensive gliosis. Acetylcholinesterase (AChE) staining of the cerebral cortex in elderly normals and Alzheimer's disease cases with a new, highly sensitive method showed that in Alzheimer's disease there was an extensive loss of AChE-positive fibers with senile plaques frequently incorporating AChE-positive fiber debris. AChE staining of the substantia innominata area, where the cells giving rise to these neocortical fibers are presumably located, also showed evidence of degenerating cells and fibers.

  10. Evolution of disease phenotype in adult and pediatric onset Crohn’s disease in a population-based cohort

    PubMed Central

    Lovasz, Barbara Dorottya; Lakatos, Laszlo; Horvath, Agnes; Szita, Istvan; Pandur, Tunde; Mandel, Michael; Vegh, Zsuzsanna; Golovics, Petra Anna; Mester, Gabor; Balogh, Mihaly; Molnar, Csaba; Komaromi, Erzsebet; Kiss, Lajos Sandor; Lakatos, Peter Laszlo

    2013-01-01

    AIM: To investigate the evolution of disease phenotype in adult and pediatric onset Crohn’s disease (CD) populations, diagnosed between 1977 and 2008. METHODS: Data of 506 incident CD patients were analyzed (age at diagnosis: 28.5 years, interquartile range: 22-38 years). Both in- and outpatient records were collected prospectively with a complete clinical follow-up and comprehensively reviewed in the population-based Veszprem province database, which included incident patients diagnosed between January 1, 1977 and December 31, 2008 in adult and pediatric onset CD populations. Disease phenotype according to the Montreal classification and long-term disease course was analysed according to the age at onset in time-dependent univariate and multivariate analysis. RESULTS: Among this population-based cohort, seventy-four (12.8%) pediatric-onset CD patients were identified (diagnosed ≤ 17 years of age). There was no significant difference in the distribution of disease behavior between pediatric (B1: 62%, B2: 15%, B3: 23%) and adult-onset CD patients (B1: 56%, B2: 21%, B3: 23%) at diagnosis, or during follow-up. Overall, the probability of developing complicated disease behaviour was 49.7% and 61.3% in the pediatric and 55.1% and 62.4% in the adult onset patients after 5- and 10-years of follow-up. Similarly, time to change in disease behaviour from non stricturing, non penetrating (B1) to complicated, stricturing or penetrating (B2/B3) disease was not significantly different between pediatric and adult onset CD in a Kaplan-Meier analysis. Calendar year of diagnosis (P = 0.04), ileal location (P < 0.001), perianal disease (P < 0.001), smoking (P = 0.038) and need for steroids (P < 0.001) were associated with presence of, or progression to, complicated disease behavior at diagnosis and during follow-up. A change in disease location was observed in 8.9% of patients and it was associated with smoking status (P = 0.01), but not with age at diagnosis. CONCLUSION: Long

  11. metabolicMine: an integrated genomics, genetics and proteomics data warehouse for common metabolic disease research.

    PubMed

    Lyne, Mike; Smith, Richard N; Lyne, Rachel; Aleksic, Jelena; Hu, Fengyuan; Kalderimis, Alex; Stepan, Radek; Micklem, Gos

    2013-01-01

    Common metabolic and endocrine diseases such as diabetes affect millions of people worldwide and have a major health impact, frequently leading to complications and mortality. In a search for better prevention and treatment, there is ongoing research into the underlying molecular and genetic bases of these complex human diseases, as well as into the links with risk factors such as obesity. Although an increasing number of relevant genomic and proteomic data sets have become available, the quantity and diversity of the data make their efficient exploitation challenging. Here, we present metabolicMine, a data warehouse with a specific focus on the genomics, genetics and proteomics of common metabolic diseases. Developed in collaboration with leading UK metabolic disease groups, metabolicMine integrates data sets from a range of experiments and model organisms alongside tools for exploring them. The current version brings together information covering genes, proteins, orthologues, interactions, gene expression, pathways, ontologies, diseases, genome-wide association studies and single nucleotide polymorphisms. Although the emphasis is on human data, key data sets from mouse and rat are included. These are complemented by interoperation with the RatMine rat genomics database, with a corresponding mouse version under development by the Mouse Genome Informatics (MGI) group. The web interface contains a number of features including keyword search, a library of Search Forms, the QueryBuilder and list analysis tools. This provides researchers with many different ways to analyse, view and flexibly export data. Programming interfaces and automatic code generation in several languages are supported, and many of the features of the web interface are available through web services. The combination of diverse data sets integrated with analysis tools and a powerful query system makes metabolicMine a valuable research resource. The web interface makes it accessible to first

  12. Newly Diagnosed Anemia Increases Risk of Parkinson’s disease: A Population-Based Cohort Study

    PubMed Central

    Hong, Chien Tai; Huang, Yao Hsien; Liu, Hung Yi; Chiou, Hung-Yi; Chan, Lung; Chien, Li-Nien

    2016-01-01

    Anemia and low hemoglobin have been identified to increase Parkinson’s disease (PD) risk. This population-based cohort study investigated PD risk in newly diagnosed anemic patients by using data from the Taiwan National Health Insurance Research Database. All newly diagnosed anemic patients (n = 86,334) without a history of stroke, neurodegenerative diseases, traumatic brain injury, major operations, or blood loss diseases were enrolled. A cohort of nonanemic controls, 1:1 matched with anemic patients on the basis of the demographics and pre-existing medical conditions, was also included. Competing risk analysis was used to evaluate PD risk in anemic patients compared with that in their matched controls. The adjusted hazard ratio (aHR) of PD risk in the anemic patients was 1.36 (95% confidence interval [CI]: 1.22–1.52, p < 0.001). Iron deficiency anemia (IDA) patients tended to exhibit a higher PD risk (aHR: 1.49; 95% CI: 1.24–1.79, p < 0.001). Furthermore, Iron supplement did not significantly affect the PD risk: the aHRs for PD risk were 1.32 (95% CI: 1.07–1.63, p < 0.01) and 1.86 (95% CI: 1.46–2.35, p < 0.001) in IDA patients with and without iron supplementation, respectively. The population-based cohort study indicated newly diagnosed anemia increases PD risk. PMID:27412825

  13. Improved design of prodromal Alzheimer's disease trials through cohort enrichment and surrogate endpoints.

    PubMed

    Macklin, Eric A; Blacker, Deborah; Hyman, Bradley T; Betensky, Rebecca A

    2013-01-01

    Alzheimer's disease (AD) trials initiated during or before the prodrome are costly and lengthy because patients are enrolled long before clinical symptoms are apparent, when disease progression is slow. We hypothesized that design of such trials could be improved by: 1) selecting individuals at moderate near-term risk of progression to AD dementia (the current clinical standard) and 2) by using short-term surrogate endpoints that predict progression to AD dementia. We used a longitudinal cohort of older, initially non-demented, community-dwelling participants (n = 358) to derive selection criteria and surrogate endpoints and tested them in an independent national data set (n = 6,243). To identify a "mid-risk" subgroup, we applied conditional tree-based survival models to Clinical Dementia Rating (CDR) scale scores and common neuropsychological tests. In the validation cohort, a time-to-AD dementia trial applying these mid-risk selection criteria to a pool of all non-demented individuals could achieve equivalent power with 47% fewer participants than enrolling at random from that pool. We evaluated surrogate endpoints measureable over two years of follow-up based on cross-validated concordance between predictions from Cox models and observed time to AD dementia. The best performing surrogate, rate of change in CDR sum-of-boxes, did not reduce the trial duration required for equivalent power using estimates from the validation cohort, but alternative surrogates with better ability to predict time to AD dementia should be able to do so. The approach tested here might improve efficiency of prodromal AD trials using other potential measures and could be generalized to other diseases with long prodromal phases. PMID:23629586

  14. Microvesicles/exosomes as potential novel biomarkers of metabolic diseases

    PubMed Central

    Müller, Günter

    2012-01-01

    Biomarkers are of tremendous importance for the prediction, diagnosis, and observation of the therapeutic success of common complex multifactorial metabolic diseases, such as type II diabetes and obesity. However, the predictive power of the traditional biomarkers used (eg, plasma metabolites and cytokines, body parameters) is apparently not sufficient for reliable monitoring of stage-dependent pathogenesis starting with the healthy state via its initiation and development to the established disease and further progression to late clinical outcomes. Moreover, the elucidation of putative considerable differences in the underlying pathogenetic pathways (eg, related to cellular/tissue origin, epigenetic and environmental effects) within the patient population and, consequently, the differentiation between individual options for disease prevention and therapy – hallmarks of personalized medicine – plays only a minor role in the traditional biomarker concept of metabolic diseases. In contrast, multidimensional and interdependent patterns of genetic, epigenetic, and phenotypic markers presumably will add a novel quality to predictive values, provided they can be followed routinely along the complete individual disease pathway with sufficient precision. These requirements may be fulfilled by small membrane vesicles, which are so-called exosomes and microvesicles (EMVs) that are released via two distinct molecular mechanisms from a wide variety of tissue and blood cells into the circulation in response to normal and stress/pathogenic conditions and are equipped with a multitude of transmembrane, soluble and glycosylphosphatidylinositol-anchored proteins, mRNAs, and microRNAs. Based on the currently available data, EMVs seem to reflect the diverse functional and dysfunctional states of the releasing cells and tissues along the complete individual pathogenetic pathways underlying metabolic diseases. A critical step in further validation of EMVs as biomarkers will rely on

  15. Predictors of time to requiring dopaminergic treatment in 2 Parkinson's disease cohorts.

    PubMed

    Marras, Connie; McDermott, Michael P; Marek, Ken; Rochon, Paula; Naglie, Gary; Tanner, Caroline M; Rudolph, Alice; Shoulson, Ira; Lang, Anthony E

    2011-03-01

    The rate of progression of Parkinson's disease (PD) is highly variable. Knowledge of factors associated with disease milestones and commonly used research outcome measures helps with patient counseling and guides the design and interpretation of clinical studies. The objective of the study was to identify prognostic factors for time to acquiring disability requiring dopaminergic therapy that are reproducible within 2 large prospectively followed cohorts. Potential prognostic factors were identified using data from the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial, and their reproducibility was examined using data from the Parkinson Research Examination of CEP-1347 trial (PRECEPT). In multivariable analyses of the DATATOP cohort, higher baseline Unified Parkinson's Disease Rating Scale (UPDRS) scores, full-time employment, a lesser smoking history, and onset on the left side were associated with a shorter time to disability requiring dopaminergic therapy. PRECEPT data confirmed the associations of higher baseline UPDRS scores and full-time employment with shorter time to requiring treatment. Any clinical trial using the end point of time to disability requiring dopaminergic therapy should ensure that groups are well balanced with respect to baseline UPDRS scores and the proportion of subjects employed full time and should consider including these variables as covariates in the statistical model for primary analysis of treatment effects. We suspect that individuals employed full time may have a lower threshold for requiring dopaminergic therapy because of occupational demands. PMID:21287602

  16. Conditional Disease Development extracted from Longitudinal Health Care Cohort Data using Layered Network Construction

    PubMed Central

    Kannan, Venkateshan; Swartz, Fredrik; Kiani, Narsis A.; Silberberg, Gilad; Tsipras, Giorgos; Gomez-Cabrero, David; Alexanderson, Kristina; Tegnèr, Jesper

    2016-01-01

    Health care data holds great promise to be used in clinical decision support systems. However, frequent near-synonymous diagnoses recorded separately, as well as the sheer magnitude and complexity of the disease data makes it challenging to extract non-trivial conclusions beyond confirmatory associations from such a web of interactions. Here we present a systematic methodology to derive statistically valid conditional development of diseases. To this end we utilize a cohort of 5,512,469 individuals followed over 13 years at inpatient care, including data on disability pension and cause of death. By introducing a causal information fraction measure and taking advantage of the composite structure in the ICD codes, we extract an effective directed lower dimensional network representation (100 nodes and 130 edges) of our cohort. Unpacking composite nodes into bipartite graphs retrieves, for example, that individuals with behavioral disorders are more likely to be followed by prescription drug poisoning episodes, whereas women with leiomyoma were more likely to subsequently experience endometriosis. The conditional disease development represent putative causal relations, indicating possible novel clinical relationships and pathophysiological associations that have not been explored yet. PMID:27211115

  17. Conditional Disease Development extracted from Longitudinal Health Care Cohort Data using Layered Network Construction.

    PubMed

    Kannan, Venkateshan; Swartz, Fredrik; Kiani, Narsis A; Silberberg, Gilad; Tsipras, Giorgos; Gomez-Cabrero, David; Alexanderson, Kristina; Tegnèr, Jesper

    2016-01-01

    Health care data holds great promise to be used in clinical decision support systems. However, frequent near-synonymous diagnoses recorded separately, as well as the sheer magnitude and complexity of the disease data makes it challenging to extract non-trivial conclusions beyond confirmatory associations from such a web of interactions. Here we present a systematic methodology to derive statistically valid conditional development of diseases. To this end we utilize a cohort of 5,512,469 individuals followed over 13 years at inpatient care, including data on disability pension and cause of death. By introducing a causal information fraction measure and taking advantage of the composite structure in the ICD codes, we extract an effective directed lower dimensional network representation (100 nodes and 130 edges) of our cohort. Unpacking composite nodes into bipartite graphs retrieves, for example, that individuals with behavioral disorders are more likely to be followed by prescription drug poisoning episodes, whereas women with leiomyoma were more likely to subsequently experience endometriosis. The conditional disease development represent putative causal relations, indicating possible novel clinical relationships and pathophysiological associations that have not been explored yet. PMID:27211115

  18. Polysomnographic Findings and Clinical Correlates in Huntington Disease: A Cross-Sectional Cohort Study

    PubMed Central

    Piano, Carla; Losurdo, Anna; Della Marca, Giacomo; Solito, Marcella; Calandra-Buonaura, Giovanna; Provini, Federica; Bentivoglio, Anna Rita; Cortelli, Pietro

    2015-01-01

    Study Objectives: To evaluate the sleep pattern and the motor activity during sleep in a cohort of patients affected by Huntington disease (HD). Design: Cross-sectional cohort study. Setting: Sleep laboratory. Patients: Thirty HD patients, 16 women and 14 men (mean age 57.3 ± 12.2 y); 30 matched healthy controls (mean age 56.5 ± 11.8 y). Interventions: Subjective sleep evaluation: Epworth Sleepiness Scale (ESS); Berlin's Questionnaire, interview for restless legs syndrome (RLS), questionnaire for REM sleep behavior disorder (RBD). Clinical evaluation: disease duration, clinical severity (unified Huntington disease motor rating scale [UHDMRS]), genetic tests. Laboratory-based full-night attended video-polysomnography (V-PSG). Measurements and Results: The duration of the disease was 9.4 ± 4.4 y, UHMDRS score was 55.5 ± 23.4, CAG repeats were 44.3 ± 4.1. Body mass index was 21.9 ± 4.0 kg/m2. No patients or caregivers reported poor sleep quality. Two patients reported symptoms of RLS. Eight patients had an ESS score ≥ 9. Eight patients had high risk of obstructive sleep apnea. At the RBD questionnaire, two patients had a pathological score. HD patients, compared to controls, showed shorter sleep, reduced sleep efficiency index, and increased arousals and awakenings. Four patients presented with sleep disordered breathing (SDB). Periodic limb movements (PLMs) during wake and sleep were observed in all patients. No episode of RBD was observed in the V-PSG recordings, and no patients showed rapid eye movement (REM) sleep without atonia. The disease duration correlated with ESS score (P < 0.02). UHMDRS correlated positively with the ESS score (P < 0.005), and negatively with the percentage of REM sleep. Conclusions: Patients with Huntington disease showed a severe sleep disruption and a high prevalence of periodic limb movements, but no evidence of sleep disordered breathing or REM sleep behavior disorder. Citation: Piano C, Losurdo A, Della Marca G, Solito M

  19. Incidence of sickle cell disease in an unselected cohort of neonates born in Berlin, Germany.

    PubMed

    Lobitz, Stephan; Frömmel, Claudia; Brose, Annemarie; Klein, Jeannette; Blankenstein, Oliver

    2014-08-01

    Sickle cell disease (SCD) does not occur in the indigenous German population. However, with the increasing numbers of immigrants its prevalence is steadily rising. Nevertheless, robust epidemiological data is not available for Germany and, consequently, the German newborn screening (NBS) program does not include SCD. Between 1 September 2011 and 30 November 2012, an unselected cohort of 34,084 Berlin newborns was tested for SCD. The results of 14 newborns were consistent with SCD and 265 babies were identified as hemoglobin S (Hb S) carriers. These data indicate a 95% probability that the incidence of SCD in Berlin is at least 2.5/10,000.

  20. Influence of metabolic syndrome on upper gastrointestinal disease.

    PubMed

    Sogabe, Masahiro; Okahisa, Toshiya; Kimura, Tetsuo; Okamoto, Koichi; Miyamoto, Hiroshi; Muguruma, Naoki; Takayama, Tetsuji

    2016-08-01

    A recent increase in the rate of obesity as a result of insufficient physical exercise and excess food consumption has been seen in both developed and developing countries throughout the world. Additionally, the recent increased number of obese individuals with lifestyle-related diseases associated with abnormalities in glucose metabolism, dyslipidemia, and hypertension, defined as metabolic syndrome (MS), has been problematic. Although MS has been highlighted as a risk factor for ischemic heart disease and arteriosclerotic diseases, it was also recently shown to be associated with digestive system disorders, including upper gastrointestinal diseases. Unlike high body weight and high body mass index, abdominal obesity with visceral fat accumulation is implicated in the onset of various digestive system diseases because excessive visceral fat accumulation may cause an increase in intra-abdominal pressure, inducing the release of various bioactive substances, known as adipocytokines, including tumor necrosis factor-α, interleukin-6, resistin, leptin, and adiponectin. This review article focuses on upper gastrointestinal disorders and their association with MS, including obesity, visceral fat accumulation, and the major upper gastrointestinal diseases. PMID:27372302

  1. Mechanistic modeling of aberrant energy metabolism in human disease

    PubMed Central

    Sangar, Vineet; Eddy, James A.; Simeonidis, Evangelos; Price, Nathan D.

    2012-01-01

    Dysfunction in energy metabolism—including in pathways localized to the mitochondria—has been implicated in the pathogenesis of a wide array of disorders, ranging from cancer to neurodegenerative diseases to type II diabetes. The inherent complexities of energy and mitochondrial metabolism present a significant obstacle in the effort to understand the role that these molecular processes play in the development of disease. To help unravel these complexities, systems biology methods have been applied to develop an array of computational metabolic models, ranging from mitochondria-specific processes to genome-scale cellular networks. These constraint-based (CB) models can efficiently simulate aspects of normal and aberrant metabolism in various genetic and environmental conditions. Development of these models leverages—and also provides a powerful means to integrate and interpret—information from a wide range of sources including genomics, proteomics, metabolomics, and enzyme kinetics. Here, we review a variety of mechanistic modeling studies that explore metabolic functions, deficiency disorders, and aberrant biochemical pathways in mitochondria and related regions in the cell. PMID:23112774

  2. Peroxisome proliferator-activated receptors, metabolic syndrome and cardiovascular disease.

    PubMed

    Azhar, Salman

    2010-09-01

    Metabolic syndrome (MetS) is a constellation of risk factors including insulin resistance, central obesity, dyslipidemia and hypertension that markedly increase the risk of Type 2 diabetes (T2DM) and cardiovascular disease (CVD). The peroxisome proliferators-activated receptor (PPAR) isotypes, PPARα, PPARδ/ß and PPARγ are ligand-activated nuclear transcription factors, which modulate the expression of an array of genes that play a central role in regulating glucose, lipid and cholesterol metabolism, where imbalance can lead to obesity, T2DM and CVD. They are also drug targets, and currently, PPARα (fibrates) and PPARγ (thiazolodinediones) agonists are in clinical use for treating dyslipidemia and T2DM, respectively. These metabolic characteristics of the PPARs, coupled with their involvement in metabolic diseases, mean extensive efforts are underway worldwide to develop new and efficacious PPAR-based therapies for the treatment of additional maladies associated with the MetS. This article presents an overview of the functional characteristics of three PPAR isotypes, discusses recent advances in our understanding of the diverse biological actions of PPARs, particularly in the vascular system, and summarizes the developmental status of new single, dual, pan (multiple) and partial PPAR agonists for the clinical management of key components of MetS, T2DM and CVD. It also summarizes the clinical outcomes from various clinical trials aimed at evaluating the atheroprotective actions of currently used fibrates and thiazolodinediones. PMID:20932114

  3. Evaluation of fasts for investigating hypoglycaemia or suspected metabolic disease.

    PubMed Central

    Morris, A A; Thekekara, A; Wilks, Z; Clayton, P T; Leonard, J V; Aynsley-Green, A

    1996-01-01

    AIM--To assess the value and safety of fasts for investigating hypoglycaemia or suspected metabolic disease. STUDY DESIGN--Review of all diagnostic fasts performed over a 2.5 year period. SETTING--The neonatal intensive care unit and programmed investigation unit at a tertiary referral centre for endocrinology and metabolic disease. RESULTS--138 diagnostic fasts were performed during the study period. Hypoglycaemia (< 2.6 mmol/l) occurred in 54 cases but in only four did the blood glucose concentration fall below 1.5 mmol/l. One patient became unwell as a result of a fast, but prompt treatment averted any sequelae. Specific endocrine or metabolic defects were identified in 30 cases, the most common being hyperinsulinism and beta-oxidation defects. CONCLUSIONS--Fasting is safe if conducted on an experienced unit with appropriate guidelines. It continues to provide useful information for diagnosis and management, particularly in cases of hyperinsulinism. Diagnoses should, however, be established by lower risk procedures whenever possible. Thus specimens for metabolic and endocrine studies should be obtained during the presenting episode and blood acylcarnitine species should be analysed prior to fasting. PMID:8869190

  4. Obesity dependent metabolic signatures associated with nonalcoholic fatty liver disease progression

    PubMed Central

    Barr, J.; Caballería, J.; Martínez-Arranz, I.; Domínguez-Díez, A.; Alonso, C.; Muntané, J.; Pérez-Cormenzana, M.; García-Monzón, C.; Mayo, R.; Martín-Duce, A.; Romero-Gómez, M.; Iacono, O. Lo; Tordjman, J.; Andrade, R.J.; Pérez-Carreras, M.; Le Marchand-Brustel, Y.; Tran, A.; Fernández-Escalante, C.; Arévalo, E.; García–Unzueta, M.; Clement, K.; Crespo, J.; Gual, P.; Gómez-Fleitas, M.; Martínez-Chantar, M.L.; Castro, A.; Lu, S.C.; Vázquez-Chantada, M.; Mato, J.M.

    2012-01-01

    Our understanding of the mechanisms by which nonalcoholic fatty liver disease (NAFLD) progresses from simple steatosis to steatohepatitis (NASH) is still very limited. Despite the growing number of studies linking the disease with altered serum metabolite levels, an obstacle to the development of metabolome-based NAFLD predictors has been the lack of large cohort data from biopsy-proven patients matched for key metabolic features such as obesity. We studied 467 biopsied individuals with normal liver histology (n=90) or diagnosed with NAFLD (steatosis, n=246; NASH, n=131), randomly divided into estimation (80% of all patients) and validation (20% of all patients) groups. Qualitative determinations of 540 serum metabolite variables were performed using ultra-performance liquid chromatography coupled to mass spectrometry (UPLC-MS). The metabolic profile was dependent on patient body-mass index (BMI), suggesting that the NAFLD pathogenesis mechanism may be quite different depending on an individual’s level of obesity. A BMI-stratified multivariate model based on the NAFLD serum metabolic profile was used to separate patients with and without NASH. The area under the receiver operating characteristic curve was 0.87 in the estimation and 0.85 in the validation group. The cutoff (0.54) corresponding to maximum average diagnostic accuracy (0.82) predicted NASH with a sensitivity of 0.71 and a specificity of 0.92 (negative/positive predictive values = 0.82/0.84). The present data, indicating that a BMI-dependent serum metabolic profile may be able to reliably distinguish NASH from steatosis patients, have significant implications for the development of NASH biomarkers and potential novel targets for therapeutic intervention. PMID:22364559

  5. Metabolic health is more closely associated with prevalence of cardiovascular diseases or stroke than obesity

    PubMed Central

    Byun, A Ri; Kwon, Seungwon; Lee, Sang Wha; Shim, Kyung Won; Lee, Hong Soo

    2016-01-01

    Abstract Mounting evidence suggests that not all obese subjects are at increased cardiovascular risk. However, the relationship between the metabolically healthy obese (MHO) phenotype and cardiovascular diseases (CVDs) or stroke remains unclear. Therefore, we retrospectively investigated the prevalence of CVDs or stroke according to metabolic health with obese. We studied 3695 subjects (40–85 years) from the Fifth Korean National Health and Nutrition Examination Survey. Participants were divided into 2 groups and 6 subgroups based on the body mass index (BMI) and metabolic syndrome (MetS) components: healthy (exhibiting none of the 5 MetS components) with the followings: healthy-normal weight (BMI < 23 kg/m2), healthy-overweight (BMI = 23–24.9 kg/m2), and healthy-obese (BMI ≥ 25 kg/m2); and unhealthy (exhibiting 2 or more MetS components) with the followings: unhealthy-normal weight, unhealthy-overweight, and unhealthy-obese. In the healthy group (n = 1726), there were 76 CVDs or stroke patients (4.4%), whereas in the unhealthy group (n = 1969), there were 170 (8.6%). The prevalence was significantly different between the 2 groups (P < 0.001). However, the prevalence was not significantly different among healthy subgroups (P = 0.4072). The prevalence in unhealthy subgroups also demonstrated no statistically significant difference (P = 0.3798). We suggest that the prevalence of CVDs or stroke is different between metabolically healthy and unhealthy phenotype. Furthermore, MHO did not reveal higher CVDs or stroke prevalence rather than metabolically healthy other groups. Additional cohort studies are needed to explain causality between CVDs or stroke incidence and subjects exhibiting the MHO phenotype. PMID:27310991

  6. A computer model simulating human glucose absorption and metabolism in health and metabolic disease states.

    PubMed

    Naftalin, Richard J

    2016-01-01

    A computer model designed to simulate integrated glucose-dependent changes in splanchnic blood flow with small intestinal glucose absorption, hormonal and incretin circulation and hepatic and systemic metabolism in health and metabolic diseases e.g. non-alcoholic fatty liver disease, (NAFLD), non-alcoholic steatohepatitis, (NASH) and type 2 diabetes mellitus, (T2DM) demonstrates how when glucagon-like peptide-1, (GLP-1) is synchronously released into the splanchnic blood during intestinal glucose absorption, it stimulates superior mesenteric arterial (SMA) blood flow and by increasing passive intestinal glucose absorption, harmonizes absorption with its distribution and metabolism. GLP-1 also synergises insulin-dependent net hepatic glucose uptake (NHGU). When GLP-1 secretion is deficient post-prandial SMA blood flow is not increased and as NHGU is also reduced, hyperglycaemia follows. Portal venous glucose concentration is also raised, thereby retarding the passive component of intestinal glucose absorption.   Increased pre-hepatic sinusoidal resistance combined with portal hypertension leading to opening of intrahepatic portosystemic collateral vessels are NASH-related mechanical defects that alter the balance between splanchnic and systemic distributions of glucose, hormones and incretins.The model reveals the latent contribution of portosystemic shunting in development of metabolic disease. This diverts splanchnic blood content away from the hepatic sinuses to the systemic circulation, particularly during the glucose absorptive phase of digestion, resulting in inappropriate increases in insulin-dependent systemic glucose metabolism.  This hastens onset of hypoglycaemia and thence hyperglucagonaemia. The model reveals that low rates of GLP-1 secretion, frequently associated with T2DM and NASH, may be also be caused by splanchnic hypoglycaemia, rather than to intrinsic loss of incretin secretory capacity. These findings may have therapeutic implications on GLP

  7. A computer model simulating human glucose absorption and metabolism in health and metabolic disease states

    PubMed Central

    Naftalin, Richard J.

    2016-01-01

    A computer model designed to simulate integrated glucose-dependent changes in splanchnic blood flow with small intestinal glucose absorption, hormonal and incretin circulation and hepatic and systemic metabolism in health and metabolic diseases e.g. non-alcoholic fatty liver disease, (NAFLD), non-alcoholic steatohepatitis, (NASH) and type 2 diabetes mellitus, (T2DM) demonstrates how when glucagon-like peptide-1, (GLP-1) is synchronously released into the splanchnic blood during intestinal glucose absorption, it stimulates superior mesenteric arterial (SMA) blood flow and by increasing passive intestinal glucose absorption, harmonizes absorption with its distribution and metabolism. GLP-1 also synergises insulin-dependent net hepatic glucose uptake (NHGU). When GLP-1 secretion is deficient post-prandial SMA blood flow is not increased and as NHGU is also reduced, hyperglycaemia follows. Portal venous glucose concentration is also raised, thereby retarding the passive component of intestinal glucose absorption.   Increased pre-hepatic sinusoidal resistance combined with portal hypertension leading to opening of intrahepatic portosystemic collateral vessels are NASH-related mechanical defects that alter the balance between splanchnic and systemic distributions of glucose, hormones and incretins.The model reveals the latent contribution of portosystemic shunting in development of metabolic disease. This diverts splanchnic blood content away from the hepatic sinuses to the systemic circulation, particularly during the glucose absorptive phase of digestion, resulting in inappropriate increases in insulin-dependent systemic glucose metabolism.  This hastens onset of hypoglycaemia and thence hyperglucagonaemia. The model reveals that low rates of GLP-1 secretion, frequently associated with T2DM and NASH, may be also be caused by splanchnic hypoglycaemia, rather than to intrinsic loss of incretin secretory capacity. These findings may have therapeutic implications on GLP

  8. The heart-liver metabolic axis: defective communication exacerbates disease.

    PubMed

    Baskin, Kedryn K; Bookout, Angie L; Olson, Eric N

    2014-04-01

    The heart has been recognized as an endocrine organ for over 30 years (de Bold, 2011); however, little is known about how the heart communicates with other organs in the body, and even less is known about this process in the diseased heart. In this issue of EMBO Molecular Medicine, Magida and Leinwand (2014) introduce the concept that a primary genetic defect in the heart results in aberrant hepatic lipid metabolism, which consequently exacerbates hypertrophic cardiomyopathy (HCM). This study provides evidence in support of the hypothesis that crosstalk occurs between the heart and liver, and that this becomes disrupted in the diseased state.

  9. Organelle pathology in metabolic neuromuscular disease: an overview.

    PubMed Central

    Becker, L E

    1990-01-01

    The spectrum of metabolic neuromuscular disorders is wide. Most inherited metabolic diseases are related to enzyme defects within lysosomes but recent advances emphasize abnormalities of mitochondria, peroxisomes and intermediate filaments. In this overview, organelle pathology is described in the context of both the clinical manifestations and the biochemical and/or molecular aspects of the disease. Among the many clinical presentations of mitochondrial disorders three emerge as distinctive entities: mitochondrial encephalopathy with lactic acidosis and stroke-like symptoms, mitochondrial encephalopathy with ragged-red fibers, and Kearns-Sayre syndrome. Peroxisomal disorders are associated with numerous biochemical defects, the most frequent of which are Zellweger's syndrome, neonatal adrenoleukodystrophy, and infantile Refsum's disease. Disorders of cytoskeletal proteins are associated with distinctive pathological accumulation of intermediate filaments but are without confirmed evidence of a biochemical defect. Understanding the role that organelle pathology plays in the pathogenesis of cellular disturbance or demise is essential to the elucidation of the pathogenesis of metabolic disorders. Images Fig. 1. Fig. 2. Fig. 3. Fig. 4. Fig. 5. Fig. 6. Fig. 7. Fig. 8. Fig. 9. Fig. 10. PMID:2407327

  10. Metabolic bone disease in home total parenteral nutrition.

    PubMed

    McCullough, M L; Hsu, N

    1987-07-01

    Home total parenteral nutrition (HTPN) is in its infancy but has proved to be lifesaving for patients unable to manage on enteral nutrition alone. However, this mode of nutrition therapy is not without problems. Aside from mechanical and other metabolic complications, a peculiar metabolic bone disease has been reported to occur in some HTPN recipients. The disease, characterized by abnormalities in calcium and phosphorus homeostasis, often results in osteomalacia, bone pain, and fractures. Reports of approximately 50 cases of metabolic bone disease have been published by centers in the United States and Canada. Factors that have been implicated as possible causes include infusion of excess vitamin D, aluminum, calcium, protein, or glucose; cyclic vs. continuous TPN administration; and the patient's previous nutritional state. Although removal of vitamin D or aluminum from the TPN solution and discontinuation of TPN altogether have been associated with improvement in symptoms, histology, and laboratory values, no single factor has been identified as the cause of this troubling phenomenon. PMID:3110249

  11. Integrative neurobiology of metabolic diseases, neuroinflammation, and neurodegeneration

    PubMed Central

    van Dijk, Gertjan; van Heijningen, Steffen; Reijne, Aaffien C.; Nyakas, Csaba; van der Zee, Eddy A.; Eisel, Ulrich L. M.

    2015-01-01

    Alzheimer's disease (AD) is a complex, multifactorial disease with a number of leading mechanisms, including neuroinflammation, processing of amyloid precursor protein (APP) to amyloid β peptide, tau protein hyperphosphorylation, relocalization, and deposition. These mechanisms are propagated by obesity, the metabolic syndrome and type-2 diabetes mellitus. Stress, sedentariness, dietary overconsumption of saturated fat and refined sugars, and circadian derangements/disturbed sleep contribute to obesity and related metabolic diseases, but also accelerate age-related damage and senescence that all feed the risk of developing AD too. The complex and interacting mechanisms are not yet completely understood and will require further analysis. Instead of investigating AD as a mono- or oligocausal disease we should address the disease by understanding the multiple underlying mechanisms and how these interact. Future research therefore might concentrate on integrating these by “systems biology” approaches, but also to regard them from an evolutionary medicine point of view. The current review addresses several of these interacting mechanisms in animal models and compares them with clinical data giving an overview about our current knowledge and puts them into an integrated framework. PMID:26041981

  12. The BioFIND study: Characteristics of a clinically typical Parkinson's disease biomarker cohort

    PubMed Central

    Goldman, Jennifer G.; Alcalay, Roy N.; Xie, Tao; Tuite, Paul; Henchcliffe, Claire; Hogarth, Penelope; Amara, Amy W.; Frank, Samuel; Rudolph, Alice; Casaceli, Cynthia; Andrews, Howard; Gwinn, Katrina; Sutherland, Margaret; Kopil, Catherine; Vincent, Lona; Frasier, Mark

    2016-01-01

    ABSTRACT Background Identifying PD‐specific biomarkers in biofluids will greatly aid in diagnosis, monitoring progression, and therapeutic interventions. PD biomarkers have been limited by poor discriminatory power, partly driven by heterogeneity of the disease, variability of collection protocols, and focus on de novo, unmedicated patients. Thus, a platform for biomarker discovery and validation in well‐characterized, clinically typical, moderate to advanced PD cohorts is critically needed. Methods BioFIND (Fox Investigation for New Discovery of Biomarkers in Parkinson's Disease) is a cross‐sectional, multicenter biomarker study that established a repository of clinical data, blood, DNA, RNA, CSF, saliva, and urine samples from 118 moderate to advanced PD and 88 healthy control subjects. Inclusion criteria were designed to maximize diagnostic specificity by selecting participants with clinically typical PD symptoms, and clinical data and biospecimen collection utilized standardized procedures to minimize variability across sites. Results We present the study methodology and data on the cohort's clinical characteristics. Motor scores and biospecimen samples including plasma are available for practically defined off and on states and thus enable testing the effects of PD medications on biomarkers. Other biospecimens are available from off state PD assessments and from controls. Conclusion Our cohort provides a valuable resource for biomarker discovery and validation in PD. Clinical data and biospecimens, available through The Michael J. Fox Foundation for Parkinson's Research and the National Institute of Neurological Disorders and Stroke, can serve as a platform for discovering biomarkers in clinically typical PD and comparisons across PD's broad and heterogeneous spectrum. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society PMID:27113479

  13. Danish cohort of monozygotic inflammatory bowel disease twins: Clinical characteristics and inflammatory activity

    PubMed Central

    Moller, Frederik Trier; Knudsen, Lina; Harbord, Marcus; Satsangi, Jack; Gordon, Hannah; Christiansen, Lene; Christensen, Kaare; Jess, Tine; Andersen, Vibeke

    2016-01-01

    AIM: To describe the establishment of a Danish inflammatory bowel diseases (IBD) twin cohort with focus on concordance of treatment and inflammatory markers. METHODS: We identified MZ twins, likely to be discordant or concordant for IBD, by merging information from the Danish Twin Register and the National Patient Register. The twins were asked to provide biological samples, questionnaires, and data access to patient files and public registries. Biological samples were collected via a mobile laboratory, which allowed for immediate centrifugation, fractionation, and storage of samples. The mean time from collection of samples to storage in the -80 °C mobile freezer was less than one hour. The diagnoses where validated using the Copenhagen diagnostic criteria. RESULTS: We identified 159 MZ IBD twin pairs, in a total of 62 (39%) pairs both twins agreed to participate. Of the supposed 62 IBD pairs, the IBD diagnosis could be confirmed in 54 pairs. The cohort included 10 concordant pairs, whereof some were discordant for either treatment or surgery. The 10 concordant pairs, where both pairs suffered from IBD, included eight CD/CD pairs, one UC/UC pair and one UC/IBDU pair. The discordant pairs comprised 31 UC, 5 IBDU (IBD unclassified), and 8 CD discordant pairs. In the co-twins not affected by IBD, calprotectin was above 100 μg/g in 2 participants, and above 50 μg/g in a further 5 participants. CONCLUSION: The presented IBD twin cohorts are an excellent resource for bioinformatics studies with proper adjustment for disease-associated exposures including medication and inflammatory activity in the co-twins. PMID:27275097

  14. Prospective observational cohort studies for studying rare diseases: the European PedNet Haemophilia Registry.

    PubMed

    Fischer, K; Ljung, R; Platokouki, H; Liesner, R; Claeyssens, S; Smink, E; van den Berg, H M

    2014-07-01

    Haemophilia is a rare disease. To improve knowledge, prospective studies of large numbers of subjects are needed. To establish a large well-documented birth cohort of patients with haemophilia enabling studies on early presentation, side effects and outcome of treatment. Twenty-one haemophilia treatment centres have been collecting data on all children with haemophilia with FVIII/IX levels up to 25% born from 2000 onwards. Another eight centres collected data on severe haemophilia A only. At baseline, details on delivery and diagnosis, gene mutation, family history of haemophilia and inhibitors are collected. For the first 75 exposure days, date, reason, dose and product are recorded for each infusion. Clinically relevant inhibitors are defined as follows: at least two positive inhibitor titres and a FVIII/IX recovery <66% of expected. For inhibitor patients, results of all inhibitor- and recovery tests are collected. For continued treatment, data on bleeding, surgery, prophylaxis and clotting factor consumption are collected annually. Data are downloaded for analysis annually. In May 2013, a total of 1094 patients were included: 701 with severe, 146 with moderate and 247 with mild haemophilia. Gene defect data were available for 87.6% of patients with severe haemophilia A. The first analysis, performed in May 2011, lead to two landmark publications. The outcome of this large collaborative research confirms its value for the improvement of haemophilia care. High-quality prospective observational cohorts form an ideal source to study natural history and treatment in rare diseases such as haemophilia.

  15. Vaccination and reduced cohort duration can drive virulence evolution: Marek's disease virus and industrialized agriculture.

    PubMed

    Atkins, Katherine E; Read, Andrew F; Savill, Nicholas J; Renz, Katrin G; Islam, A F M Fakhrul; Walkden-Brown, Stephen W; Woolhouse, Mark E J

    2013-03-01

    Marek's disease virus (MDV), a commercially important disease of poultry, has become substantially more virulent over the last 60 years. This evolution was presumably a consequence of changes in virus ecology associated with the intensification of the poultry industry. Here, we assess whether vaccination or reduced host life span could have generated natural selection, which favored more virulent strains. Using previously published experimental data, we estimated viral fitness under a range of cohort durations and vaccine treatments on broiler farms. We found that viral fitness maximized at intermediate virulence, as a result of a trade-off between virulence and transmission previously reported. Our results suggest that vaccination, acting on this trade-off, could have led to the evolution of increased virulence. By keeping the host alive, vaccination prolongs infectious periods of virulent strains. Improvements in host genetics and nutrition, which reduced broiler life spans below 50 days, could have also increased the virulence of the circulating MDV strains because shortened cohort duration reduces the impact of host death on viral fitness. These results illustrate the dramatic impact anthropogenic change can potentially have on pathogen virulence.

  16. The Cohort for Childhood Origin of Asthma and allergic diseases (COCOA) study: design, rationale and methods

    PubMed Central

    2014-01-01

    Background This paper describes the background, aim, and design of a prospective birth-cohort study in Korea called the COhort for Childhood Origin of Asthma and allergic diseases (COCOA). COCOA objectives are to investigate the individual and interactive effects of genetics, perinatal environment, maternal lifestyle, and psychosocial stress of mother and child on pediatric susceptibility to allergic diseases. Methods/Design The participants in COCOA represents a Korean inner-city population. Recruitment started on 19 November, 2007 and will continue until 31 December, 2015. Recruitment is performed at five medical centers and eight public-health centers for antenatal care located in Seoul. Participating mother-baby pairs are followed from before birth to adolescents. COCOA investigates whether the following five environmental variables contribute causally to the development and natural course of allergic diseases: (1) perinatal indoor factors (i.e. house-dust mite, bacterial endotoxin, tobacco smoking, and particulate matters 2.5 and 10), (2) perinatal outdoor pollutants, (3) maternal prenatal psychosocial stress and the child’s neurodevelopment, (4) perinatal nutrition, and (5) perinatal microbiome. Cord blood and blood samples from the child are used to assess whether the child’s genes and epigenetic changes influence allergic-disease susceptibility. Thus, COCOA aims to investigate the contributions of genetics, epigenetics, and various environmental factors in early life to allergic-disease susceptibility in later life. How these variables interact to shape allergic-disease susceptibility is also a key aim. The COCOA data collection schedule includes 11 routine standardized follow-up assessments of all children at 6 months and every year until 10 years of age, regardless of allergic-disease development. The mothers will complete multiple questionnaires to assess the baseline characteristics, the child’s exposure to environmental factors, maternal pre

  17. Metabolic bone disease in children : etiology and treatment options.

    PubMed

    Skowrońska-Jóźwiak, Elzbieta; Lorenc, Roman S

    2006-01-01

    Metabolic bone disease in children includes many hereditary and acquired conditions of diverse etiology that lead to disturbed metabolism of the bone tissue. Some of these processes primarily affect bone; others are secondary to nutritional deficiencies, a variety of chronic disorders, and/or treatment with some drugs. Some of these disorders are rare, but some present public health concerns (for instance, rickets) that have been well known for many years but still persist. The most important clinical consequences of bone metabolic diseases in the pediatric population include reduced linear growth, bone deformations, and non-traumatic fractures leading to bone pain, deterioration of motor development and disability. In this article, we analyze primary and secondary osteoporosis, rickets, osteomalacia (nutritional and hereditary vitamin D-dependent, hypophosphatemic and that due to renal tubular abnormalities), renal osteodystrophy, sclerosing bony disorders, and some genetic bone diseases (hypophosphatasia, fibrous dysplasia, skeletal dysplasia, juvenile Paget disease, familial expansile osteolysis, and osteoporosis pseudoglioma syndrome). Early identification and treatment of potential risk factors is essential for skeletal health in adulthood. In most conditions it is necessary to ensure an appropriate diet, with calcium and vitamin D, and an adequate amount of physical activity as a means of prevention. In secondary bone diseases, treatment of the primary disorder is crucial. Most genetic disorders await prospective gene therapies, while bone marrow transplantation has been attempted in other disorders. At present, affected patients are treated symptomatically, frequently by interdisciplinary teams. The role of exercise and pharmacologic therapy with calcium, vitamin D, phosphate, bisphosphonates, calcitonin, sex hormones, growth hormone, and thiazides is discussed. The perspectives on future therapy with insulin-like growth factor-1, new analogs of vitamin D

  18. Burden of neurodegenerative diseases in a cohort of medical examiner subjects.

    PubMed

    Uryu, Kunihiro; Haddix, Terri; Robinson, John; Nakashima-Yasuda, Hanae; Lee, Virginia M-Y; Trojanowski, John Q

    2010-05-01

    Here we report studies of the burden of neurodegenerative neuropathologies in a cohort of Medical Examiner (ME) subjects from the County of Santa Clara (California) to determine if this unique population of decedents manifested evidence of neurodegeneration that might underlie causes of death seen in an ME practice. We found that 13% of the brains from ME cases showed significant tau pathology, including 55% of those 65 years old and older and 63% of those 70 years old and older. The histochemical and immunohistochemical findings were consistent with Alzheimer's disease (AD) in 7 subjects and frontotemporal lobar degeneration (FTLD) tauopathy type in six cases. There were no cases of Parkinson's disease, dementia with Lewy Bodies or other neurodegenerative conditions. Our study suggests that decedents >65 years of age in an ME practice are afflicted by common causes of dementia such as AD and FTLD which could contribute wholly or in part to their causes of death.

  19. The emerging use of zebrafish to model metabolic disease

    PubMed Central

    Seth, Asha; Stemple, Derek L.; Barroso, Inês

    2013-01-01

    The zebrafish research community is celebrating! The zebrafish genome has recently been sequenced, the Zebrafish Mutation Project (launched by the Wellcome Trust Sanger Institute) has published the results of its first large-scale ethylnitrosourea (ENU) mutagenesis screen, and a host of new techniques, such as the genome editing technologies TALEN and CRISPR-Cas, are enabling specific mutations to be created in model organisms and investigated in vivo. The zebrafish truly seems to be coming of age. These powerful resources invoke the question of whether zebrafish can be increasingly used to model human disease, particularly common, chronic diseases of metabolism such as obesity and type 2 diabetes. In recent years, there has been considerable success, mainly from genomic approaches, in identifying genetic variants that are associated with these conditions in humans; however, mechanistic insights into the role of implicated disease loci are lacking. In this Review, we highlight some of the advantages and disadvantages of zebrafish to address the organism’s utility as a model system for human metabolic diseases. PMID:24046387

  20. Black leaf streak disease affects starch metabolism in banana fruit.

    PubMed

    Saraiva, Lorenzo de Amorim; Castelan, Florence Polegato; Shitakubo, Renata; Hassimotto, Neuza Mariko Aymoto; Purgatto, Eduardo; Chillet, Marc; Cordenunsi, Beatriz Rosana

    2013-06-12

    Black leaf streak disease (BLSD), also known as black sigatoka, represents the main foliar disease in Brazilian banana plantations. In addition to photosynthetic leaf area losses and yield losses, this disease causes an alteration in the pre- and postharvest behavior of the fruit. The aim of this work was to investigate the starch metabolism of fruits during fruit ripening from plants infected with BLSD by evaluating carbohydrate content (i.e., starch, soluble sugars, oligosaccharides, amylose), phenolic compound content, phytohormones, enzymatic activities (i.e., starch phosphorylases, α- and β-amylase), and starch granules. The results indicated that the starch metabolism in banana fruit ripening is affected by BLSD infection. Fruit from infested plots contained unusual amounts of soluble sugars in the green stage and smaller starch granules and showed a different pattern of superficial degradation. Enzymatic activities linked to starch degradation were also altered by the disease. Moreover, the levels of indole-acetic acid and phenolic compounds indicated an advanced fruit physiological age for fruits from infested plots. PMID:23692371

  1. Impact of DHA on Metabolic Diseases from Womb to Tomb

    PubMed Central

    Arnoldussen, Ilse A. C.; Kiliaan, Amanda J.

    2014-01-01

    Long chain polyunsaturated fatty acids (LC-PUFAs) are important mediators in improving and maintaining human health over the total lifespan. One topic we especially focus on in this review is omega-3 LC-PUFA docosahexaenoic acid (DHA). Adequate DHA levels are essential during neurodevelopment and, in addition, beneficial in cognitive processes throughout life. We review the impact of DHA on societal relevant metabolic diseases such as cardiovascular diseases, obesity, and diabetes mellitus type 2 (T2DM). All of these are risk factors for cognitive decline and dementia in later life. DHA supplementation is associated with a reduced incidence of both stroke and atherosclerosis, lower bodyweight and decreased T2DM prevalence. These findings are discussed in the light of different stages in the human life cycle: childhood, adolescence, adulthood and in later life. From this review, it can be concluded that DHA supplementation is able to inhibit pathologies like obesity and cardiovascular disease. DHA could be a dietary protector against these metabolic diseases during a person’s entire lifespan. However, supplementation of DHA in combination with other dietary factors is also effective. The efficacy of DHA depends on its dose as well as on the duration of supplementation, sex, and age. PMID:25528960

  2. Hemoglobin and Hematocrit Levels in the Prediction of Complicated Crohn's Disease Behavior – A Cohort Study

    PubMed Central

    Rieder, Florian; Paul, Gisela; Schnoy, Elisabeth; Schleder, Stephan; Wolf, Alexandra; Kamm, Florian; Dirmeier, Andrea; Strauch, Ulrike; Obermeier, Florian; Lopez, Rocio; Achkar, Jean-Paul; Rogler, Gerhard; Klebl, Frank

    2014-01-01

    Background Markers that predict the occurrence of a complicated disease behavior in patients with Crohn's disease (CD) can permit a more aggressive therapeutic regimen for patients at risk. The aim of this cohort study was to test the blood levels of hemoglobin (Hgb) and hematocrit (Hct) for the prediction of complicated CD behavior and CD related surgery in an adult patient population. Methods Blood samples of 62 CD patients of the German Inflammatory Bowel Disease-network “Kompetenznetz CED” were tested for the levels of Hgb and Hct prior to the occurrence of complicated disease behavior or CD related surgery. The relation of these markers and clinical events was studied using Kaplan-Meier survival analysis and adjusted COX-proportional hazard regression models. Results The median follow-up time was 55.8 months. Of the 62 CD patients without any previous complication or surgery 34% developed a complication and/or underwent CD related surgery. Low Hgb or Hct levels were independent predictors of a shorter time to occurrence of the first complication or CD related surgery. This was true for early as well as late occurring complications. Stable low Hgb or Hct during serial follow-up measurements had a higher frequency of complications compared to patients with a stable normal Hgb or Hct, respectively. Conclusions Determination of Hgb or Hct in complication and surgery naïve CD patients might serve as an additional tool for the prediction of complicated disease behavior. PMID:25116048

  3. Disorders of Iron Metabolism and Anemia in Chronic Kidney Disease.

    PubMed

    Panwar, Bhupesh; Gutiérrez, Orlando M

    2016-07-01

    Dysregulated iron homeostasis plays a central role in the development of anemia of chronic kidney disease (CKD) and is a major contributor toward resistance to treatment with erythropoiesis-stimulating agents. Understanding the underlying pathophysiology requires an in-depth understanding of normal iron physiology and regulation. Recent discoveries in the field of iron biology have greatly improved our understanding of the hormonal regulation of iron trafficking in human beings and how its alterations lead to the development of anemia of CKD. In addition, emerging evidence has suggested that iron homeostasis interacts with bone and mineral metabolism on multiple levels, opening up new avenues of investigation into the genesis of disordered iron metabolism in CKD. Building on recent advances in our understanding of normal iron physiology and abnormalities in iron homeostasis in CKD, this review characterizes how anemia related to disordered iron metabolism develops in the setting of CKD. In addition, this review explores our emerging recognition of the connections between iron homeostasis and mineral metabolism and their implications for the management of altered iron status and anemia of CKD.

  4. [Alteration of biological rhythms causes metabolic diseases and obesity].

    PubMed

    Saderi, Nadia; Escobar, Carolina; Salgado-Delgado, Roberto

    2013-07-16

    The incidence of obesity worldwide has become a serious, constantly growing public health issue that reaches alarming proportions in some countries. To date none of the strategies developed to combat obesity have proved to be decisive, and hence there is an urgent need to address the problem with new approaches. Today, studies in the field of chronobiology have shown that our physiology continually adapts itself to the cyclical changes in the environment, regard-less of whether they are daily or seasonal. This is possible thanks to the existence of a biological clock in our hypothalamus which regulates the expression and/or activity of enzymes and hormones involved in regulating our metabolism, as well as all the homeostatic functions. It has been observed that this clock can be upset as a result of today's modern lifestyle, which involves a drop in physical activity during the day and the abundant ingestion of food during the night, among other factors, which together promote metabolic syndrome and obesity. Hence, the aim of this review is to summarise the recent findings that show the effect that altering the circadian rhythms has on the metabolism and how this can play a part in the development of metabolic diseases.

  5. Disorders of Iron Metabolism and Anemia in Chronic Kidney Disease.

    PubMed

    Panwar, Bhupesh; Gutiérrez, Orlando M

    2016-07-01

    Dysregulated iron homeostasis plays a central role in the development of anemia of chronic kidney disease (CKD) and is a major contributor toward resistance to treatment with erythropoiesis-stimulating agents. Understanding the underlying pathophysiology requires an in-depth understanding of normal iron physiology and regulation. Recent discoveries in the field of iron biology have greatly improved our understanding of the hormonal regulation of iron trafficking in human beings and how its alterations lead to the development of anemia of CKD. In addition, emerging evidence has suggested that iron homeostasis interacts with bone and mineral metabolism on multiple levels, opening up new avenues of investigation into the genesis of disordered iron metabolism in CKD. Building on recent advances in our understanding of normal iron physiology and abnormalities in iron homeostasis in CKD, this review characterizes how anemia related to disordered iron metabolism develops in the setting of CKD. In addition, this review explores our emerging recognition of the connections between iron homeostasis and mineral metabolism and their implications for the management of altered iron status and anemia of CKD. PMID:27475656

  6. Evidence for treatable inborn errors of metabolism in a cohort of 187 Greek patients with autism spectrum disorder (ASD).

    PubMed

    Spilioti, Martha; Evangeliou, Athanasios E; Tramma, Despoina; Theodoridou, Zoe; Metaxas, Spyridon; Michailidi, Eleni; Bonti, Eleni; Frysira, Helen; Haidopoulou, A; Asprangathou, Despoina; Tsalkidis, Aggelos J; Kardaras, Panagiotis; Wevers, Ron A; Jakobs, Cornelis; Gibson, K Michael

    2013-01-01

    We screened for the presence of inborn errors of metabolism (IEM) in 187 children (105 males; 82 females, ages 4-14 years old) who presented with confirmed features of autism spectrum disorder (ASD). Twelve patients (7%) manifested increased 3-hydroxyisovaleric acid (3-OH-IVA) excretion in urine, and minor to significant improvement in autistic features was observed in seven patients following supplementation with biotin. Five diagnoses included: Lesch Nyhan syndrome (2), succinic semialdehyde dehydrogenase (SSADH) deficiency (2), and phenylketonuria (1) (2.7%). Additional metabolic disturbances suggestive of IEMs included two patients whose increased urine 3-OH-IVA was accompanied by elevated methylcitrate and lactate in sera, and 30 patients that showed abnormal glucose-loading tests. In the latter group, 16/30 patients manifested increased sera beta hydroxybutyrate (b-OH-b) production and 18/30 had a paradoxical increase of sera lactate. Six patients with elevated b-OH-b in sera showed improved autistic features following implementation of a ketogenic diet (KD). Five patients showed decreased serum ketone body production with glucose loading. Twelve of 187 patients demonstrated non-specific MRI pathology, while 25/187 had abnormal electroencephalogram (EEG) findings. Finally, family history was positive for 22/187 patients (1st or 2nd degree relative with comparable symptomatology) and consanguinity was documented for 12/187 patients. Our data provide evidence for a new biomarker (3-OH-IVA) and novel treatment approaches in ASD patients. Concise 1 sentence take-home message: Detailed metabolic screening in a Greek cohort of ASD patients revealed biomarkers (urine 3-hydroxyisovaleric acid and serum b-OH-b) in 7% (13/187) of patients for whom biotin supplementation or institution of a KD resulted in mild to significant clinical improvement in autistic features. PMID:24399946

  7. Evidence for treatable inborn errors of metabolism in a cohort of 187 Greek patients with autism spectrum disorder (ASD)

    PubMed Central

    Spilioti, Martha; Evangeliou, Athanasios E.; Tramma, Despoina; Theodoridou, Zoe; Metaxas, Spyridon; Michailidi, Eleni; Bonti, Eleni; Frysira, Helen; Haidopoulou, A.; Asprangathou, Despoina; Tsalkidis, Aggelos J.; Kardaras, Panagiotis; Wevers, Ron A.; Jakobs, Cornelis; Gibson, K. Michael

    2013-01-01

    We screened for the presence of inborn errors of metabolism (IEM) in 187 children (105 males; 82 females, ages 4–14 years old) who presented with confirmed features of autism spectrum disorder (ASD). Twelve patients (7%) manifested increased 3-hydroxyisovaleric acid (3-OH-IVA) excretion in urine, and minor to significant improvement in autistic features was observed in seven patients following supplementation with biotin. Five diagnoses included: Lesch Nyhan syndrome (2), succinic semialdehyde dehydrogenase (SSADH) deficiency (2), and phenylketonuria (1) (2.7%). Additional metabolic disturbances suggestive of IEMs included two patients whose increased urine 3-OH-IVA was accompanied by elevated methylcitrate and lactate in sera, and 30 patients that showed abnormal glucose-loading tests. In the latter group, 16/30 patients manifested increased sera beta hydroxybutyrate (b-OH-b) production and 18/30 had a paradoxical increase of sera lactate. Six patients with elevated b-OH-b in sera showed improved autistic features following implementation of a ketogenic diet (KD). Five patients showed decreased serum ketone body production with glucose loading. Twelve of 187 patients demonstrated non-specific MRI pathology, while 25/187 had abnormal electroencephalogram (EEG) findings. Finally, family history was positive for 22/187 patients (1st or 2nd degree relative with comparable symptomatology) and consanguinity was documented for 12/187 patients. Our data provide evidence for a new biomarker (3-OH-IVA) and novel treatment approaches in ASD patients. Concise 1 sentence take-home message: Detailed metabolic screening in a Greek cohort of ASD patients revealed biomarkers (urine 3-hydroxyisovaleric acid and serum b-OH-b) in 7% (13/187) of patients for whom biotin supplementation or institution of a KD resulted in mild to significant clinical improvement in autistic features. PMID:24399946

  8. Molecular links between early energy metabolism alterations and Alzheimer's disease.

    PubMed

    Pedros, Ignacio; Patraca, Ivan; Martinez, Nohora; Petrov, Dmitry; Sureda, Francesc X; Auladell, Carme; Beas-Zarate, Carlos; Folch, Jaume

    2016-01-01

    Recent studies suggest that the neurobiology of Alzheimer's disease (AD) pathology could not be explained solely by an increase in beta-amyloid levels. In fact, success with potential therapeutic drugs that inhibit the generation of beta amyloid has been low. Therefore, due to therapeutic failure in recent years, the scientists are looking for alternative hypotheses to explain the causes of the disease and the cognitive loss. Accordingly, alternative hypothesis propose a link between AD and peripheral metabolic alteration. Then, we review in depth changes related to insulin signalling and energy metabolism in the context of the APPSwe/PS1dE9 (APP/PS1) mice model of AD. We show an integrated view of the changes that occur in the early stages of the amyloidogenic process in the APP/PS1 double transgenic mice model. These early changes affect several key metabolic processes related to glucose uptake and insulin signalling, cellular energy homeostasis, mitochondrial biogenesis and increased Tau phosphorylation by kinase molecules like mTOR and Cdk5.

  9. Retinopathy and the risk of cardiovascular disease in patients with chronic kidney disease (from the Chronic Renal Insufficiency Cohort study).

    PubMed

    Grunwald, Juan E; Pistilli, Maxwell; Ying, Gui-Shuang; Maguire, Maureen; Daniel, Ebenezer; Whittock-Martin, Revell; Parker-Ostroff, Candace; Mohler, Emile; Lo, Joan C; Townsend, Raymond R; Gadegbeku, Crystal Ann; Lash, James Phillip; Fink, Jeffrey Craig; Rahman, Mahboob; Feldman, Harold; Kusek, John W; Xie, Dawei

    2015-11-15

    Patients with chronic kidney disease (CKD) experience other diseases such as cardiovascular disease (CVD) and retinopathy. The purpose of this study was to assess whether retinopathy predicts future CVD events in a subgroup of the participants of the Chronic Renal Insufficiency Cohort (CRIC) study. In this ancillary investigation, 2,605 participants of the CRIC study were invited to participate, and nonmydriatic fundus photographs were obtained in 1,936 subjects. Using standard protocols, presence and severity of retinopathy (diabetic, hypertensive, or other) and vessel diameter caliber were assessed at a central photograph reading center by trained graders masked to study participant's information. Patients with a self-reported history of cardiovascular disease were excluded. Incident CVD events were adjudicated using medical records. Kidney function measurements, traditional and nontraditional risk factors, for CVD were obtained. Presence and severity of retinopathy were associated with increased risk of development of any CVD in this population of CKD patients, and these associations persisted after adjustment for traditional risk factors for CVD. We also found a direct relation between increased venular diameter and risk of development of CVD; however, the relation was not statistically significant after adjustment for traditional risk factors. In conclusion, the presence of retinopathy was associated with future CVD events, suggesting that retinovascular pathology may be indicative of macrovascular disease even after adjustment for renal dysfunction and traditional CVD risk factors. Assessment of retinal morphology may be valuable in assessing risk of CVD in patients with CKD, both clinically and in research settings.

  10. Spectrum of cardiac disease in maternity in a low-resource cohort in South Africa

    PubMed Central

    Sliwa, Karen; Libhaber, Elena; Elliott, Catherine; Momberg, Zoe; Osman, Ayesha; Zühlke, Liesl; Lachmann, Tony; Nicholson, Lauren; Thienemann, Friedrich; Roos-Hesselink, Jolien; Anthony, John

    2014-01-01

    Background Lack of evidence-based data on the spectrum of cardiovascular disease (CVD) in pregnancy or in the postpartum period, as well as on maternal and fetal outcome, provides challenges for treating physicians, particularly in areas of low resources. The objectives of this study were to investigate the spectrum of disease, mode of presentation and maternal and fetal outcome of patients referred to a dedicated Cardiac Disease and Maternity Clinic (CDM). Methods The prospective cohort study was conducted at a single tertiary care centre in South Africa. Two hundred and twenty-five women presenting with CVD in pregnancy, or within 6 months postpartum, were studied over a period of 2 years. Clinical assessment, echocardiography and laboratory tests were performed at baseline and follow-up visits. Prepartum, peripartum and postpartum complications were grouped into cardiac, neonatal and obstetric events. Results Ethnicity was black African (45%), mixed ethnicity (32%), white (15%), Indian/others (8%) and 12% were HIV positive. Of the 225 consecutive women (mean age 28.8±6.4), 196 (86.7%) presented prepartum and 73 in modified WHO class I. The 152 women presenting in a higher risk group (modified WHO class II–IV) were offered close follow-up at the CDM clinic and were diagnosed with congenital heart disease (32%, 15 operated previously), valvular heart disease (26%, 15 operated previously), cardiomyopathy (27%) and other (15%). Women presenting with symptoms of CVD or heart failure postpartum (n=30) presented in a higher New York Heart Association, had higher heart rates (p<0.001) and NTproBNP levels (p<0.0005). Of the 152 patients, 9 (6%) died within the 6-month follow-up period. Eight of the nine patients died >42 days postpartum. Perinatal death occurred in 1/152 (0.7%)—translating to a perinatal mortality rate of 7/1000 live births. Conclusions Disease patterns were markedly different to that seen in the developed world. However, joint obstetric

  11. PREVALENCE OF FACTORS ASSOCIATED TO METABOLIC SYNDROME IN A COHORT OF CHILDREN IN SOUTH BRAZIL.

    PubMed

    Borges Pretto, Alessandra Doumid; Correa Kaufmann, Cristina; Ferreira Dutra, Gisele; Pinto Albernaz, Elaine

    2015-07-01

    Introducción: el síndrome metabólico es un grupo de enfermedades que ha ido ganando importancia debido a la asociación con el desarrollo posterior de enfermedades cardiovasculares. Objetivo: verificar la prevalencia de factores de riesgo asociados con el síndrome metabólico en niños de una cohorte del sur de Brasil. Métodos: estudio de cohorte prospectivo con el hospital de todos los nacimientos (2.741) que tuvieron lugar en el mes de septiembre/2002 a mayo/2003 y seguimiento de una muestra aleatoria de 30,0% con uno, tres y seis meses y ocho años de edad. En una visita a los ocho años de edad se utilizó un cuestionario con preguntas relacionadas con la nutrición, la actividad física y la historia familiar de enfermedades crónicas, y se midieron peso, talla y circunferencia de la cintura. Se realizaron análisis descriptivos y bivariados entre las variables independientes y los resultados obtenidos. Resultados y discusión: de 616 niños estudiados, el 51,3% fueron varones, el 70,3% blancos, cerca de la mitad pertenecían a la clase económica C, el 20,6% tenían sobrepeso y el 17,0% eran obesos. Mostró una alta prevalencia de historia familiar de hipertensión arterial (81,5%), y se observó que el 20,7% de los niños eutróficos tenían una circunferencia de cintura elevada. Conclusión: la alta prevalencia de factores de riesgo para el síndrome metabólico en los niños estudiados refuerza la importancia de una adecuada anamnesis: historia familiar. Se sugiere medir la circunferencia de la cintura en la rutina de cuidados pediátricos.

  12. Cytokine gene polymorphisms and atopic disease in two European cohorts. (ECRHS-Basel and SAPALDIA)

    PubMed Central

    Imboden, M; Nieters, A; Bircher, AJ; Brutsche, M; Becker, N; Wjst, M; Ackermann-Liebrich, U; Berger, W; Probst-Hensch, NM

    2006-01-01

    Background Atopy and allergic phenotypes are biologically characterized by an imbalanced T helper cell response skewed towards a type 2 (TH2) immune response associated with elevated serum immunoglobulin E (IgE) levels. Polymorphisms in cytokine genes might modulate regulation of the TH1/TH2 balance. We thus aimed at reproducing our previous findings from a European study population on the association of various cytokine polymorphisms with self-reported hay fever as well as increased total and specific IgE levels in two comparable study populations. Methods Two prospective Caucasian cohorts were used. In the Basel center of the European Community Respiratory Health Survey (ECRHS, n = 418) ten distinct cytokine polymorphisms of putative functional relevance were genotyped. In the Swiss cohort Study on Air Pollution And Lung Disease In Adults (SAPALDIA, n = 6003) two cytokine polymorphisms were genotyped. The associations of these polymorphisms with atopy were estimated by covariance and logistic regression analysis. Results We confirmed IL4, IL10, IL6 and IL18 as candidate genes for atopic health outcomes. In the large, well-characterized SAPALDIA cohort the IL6(-174G>C) and IL18(-137G>C) polymorphisms were associated with circulating total IgE concentrations in subjects with hay fever. The IL18(-137G>C) polymorphism was also associated with the prevalence of hay fever. Conclusion Comprehensive characterization of genetic variation in extended cytokine candidate gene regions is now needed. Large study networks must follow to investigate the association of risk patterns defined by genetic predisposing and environmental risk factors with specific atopic phenotypes. PMID:16759385

  13. Population Based Cohort Study for Pediatric Infectious Diseases Research in Vietnam

    PubMed Central

    Yoshida, Lay-Myint; Suzuki, Motoi; Thiem, Vu Dinh; Smith, Wolf Peter; Tsuzuki, Ataru; Huong, Vu Thi Thu; Takahashi, Kensuke; Miyakawa, Masami; Anh, Nguyen Thi Hien; Watanabe, Kiwao; Ai, Nguyen Thu Thuy; Tho, Le Huu; Kilgore, Paul; Yoshino, Hiroshi; Toizumi, Michiko; Yasunami, Michio; Moriuchi, Hiroyuki; Anh, Dang Duc; Ariyoshi, Koya

    2014-01-01

    A population-based cohort study on pediatric infectious diseases was established at Khanh Hoa Province, central Vietnam in 2006, to determine the etiology and risk factors for severe pediatric infectious diseases (SPID) such as acute respiratory infection (ARI), diarrhea and dengue which are the major causes of under 5 mortality. A population census survey was conducted in Nha-Trang and Ninh-Hoa to collect demographic, social-behavioral data and disease burden on SPID. The study site covered a population of 353,525 residing in 75,826 households with 24,781 children less than 5 years. Hospital databases from two hospitals covering the region were obtained. Linking the census and hospital databases, we were able to investigate on a variety of SPID such as environmental tobacco smoking exposure and increased risked of pediatric pneumonia hospitalization, population density, water supply and risk of dengue fever and animal livestock and risk of hospitalized diarrhea. To determine incidence, viral etiology and risk factors for pediatric ARI/pneumonia, we setup a population based prospective hospitalized Pediatric ARI surveillance at Khanh Hoa General Hospital, Nha-Trang in February 2007. The study has revealed RSV, rhinovirus and influenza A as major viral pathogens, role of multiple viral infection and its interaction with bacteria in the development of pneumonia. In addition, we are also conducting a birth cohort study to investigate the incidence of congenital infection and its impact on physical-neurological development, and role of host genetic polymorphism on SPID hospitalization in Vietnam. Population mobility, high cost of regular census update and low mortality are the challenges. PMID:25425951

  14. Disease progression by infecting HIV-1 subtype in a seroconverter cohort in sub-Saharan Africa

    PubMed Central

    Amornkul, Pauli N.; Karita, Etienne; Kamali, Anatoli; Rida, Wasima N.; Sanders, Eduard J.; Lakhi, Shabir; Price, Matt A.; Kilembe, William; Cormier, Emmanuel; Anzala, Omu; Latka, Mary H.; Bekker, Linda-Gail; Allen, Susan A.; Gilmour, Jill; Fast, Patricia E.

    2013-01-01

    Objective: To describe immunologic, virologic, and clinical HIV disease progression by HIV-1 subtype among Africans with well documented estimated dates of HIV infection (EDIs). Design: Prospective cohort. Methods: Adults and youth with documented HIV-1 infection in the past 12 months were recruited from seroincidence cohorts in East and Southern Africa and followed at 3–6 month intervals. Blood for lymphocyte subset and viral load determination was collected at each visit. Pol was sequenced from the first positive specimen to ascertain subtype. Preantiretroviral therapy disease progression was measured by three time-to-event endpoints: CD4+ cell count 350 cells/μl or less, viral load measurement at least 1 × 105 copies/ml, and clinical AIDS. Results: From 2006 to 2011, 615 participants were enrolled at nine research centers in Kenya, Rwanda, South Africa, Uganda, and Zambia; 579 (94.1%) had viral subtyping completed. Predominant subtypes were C (256, 44.2%), A (209, 36.1%), and D (84, 14.5%). After adjustment for age, sex, and human leukocyte antigen alleles in Cox regression analyses, subtype C-infected participants progressed faster than subtype A to all three endpoints [CD4+ hazard ratio 1.60, 95% (confidence interval) CI 1.16, 2.20; viral load hazard ratio 1.59, 95% CI 1.12, 2.25; and AIDS hazard ratio 1.60, 95% CI 1.11, 2.31). Subtype D-infected participants reached high viral load more rapidly (hazard ratio 1.61, 95% CI 1.01, 2.57) and progressed nearly twice as fast to AIDS compared to subtype A (hazard ratio 1.93, 95% CI 1.21, 3.09). Conclusion: Subtype-specific differences in HIV disease progression suggest that the local subtype distribution be considered when planning HIV programs and designing and defining clinical endpoints for HIV prevention trials. PMID:24113395

  15. Population based cohort study for pediatric infectious diseases research in Vietnam.

    PubMed

    Yoshida, Lay-Myint; Suzuki, Motoi; Thiem, Vu Dinh; Smith, Wolf Peter; Tsuzuki, Ataru; Huong, Vu Thi Thu; Takahashi, Kensuke; Miyakawa, Masami; Anh, Nguyen Thi Hien; Watanabe, Kiwao; Ai, Nguyen Thu Thuy; Tho, Le Huu; Kilgore, Paul; Yoshino, Hiroshi; Toizumi, Michiko; Yasunami, Michio; Moriuchi, Hiroyuki; Anh, Dang Duc; Ariyoshi, Koya

    2014-06-01

    A population-based cohort study on pediatric infectious diseases was established at Khanh Hoa Province, central Vietnam in 2006, to determine the etiology and risk factors for severe pediatric infectious diseases (SPID) such as acute respiratory infection (ARI), diarrhea and dengue which are the major causes of under 5 mortality. A population census survey was conducted in Nha-Trang and Ninh-Hoa to collect demographic, social-behavioral data and disease burden on SPID. The study site covered a population of 353,525 residing in 75,826 households with 24,781 children less than 5 years. Hospital databases from two hospitals covering the region were obtained. Linking the census and hospital databases, we were able to investigate on a variety of SPID such as environmental tobacco smoking exposure and increased risked of pediatric pneumonia hospitalization, population density, water supply and risk of dengue fever and animal livestock and risk of hospitalized diarrhea. To determine incidence, viral etiology and risk factors for pediatric ARI/pneumonia, we setup a population based prospective hospitalized Pediatric ARI surveillance at Khanh Hoa General Hospital, Nha-Trang in February 2007. The study has revealed RSV, rhinovirus and influenza A as major viral pathogens, role of multiple viral infection and its interaction with bacteria in the development of pneumonia. In addition, we are also conducting a birth cohort study to investigate the incidence of congenital infection and its impact on physical-neurological development, and role of host genetic polymorphism on SPID hospitalization in Vietnam. Population mobility, high cost of regular census update and low mortality are the challenges.

  16. Cross-sectional and longitudinal comparisons of metabolic profiles between vegetarian and non-vegetarian subjects: a matched cohort study.

    PubMed

    Chiu, Yen-Feng; Hsu, Chih-Cheng; Chiu, Tina H T; Lee, Chun-Yi; Liu, Ting-Ting; Tsao, Chwen Keng; Chuang, Su-Chun; Hsiung, Chao A

    2015-10-28

    Several previous cross-sectional studies have shown that vegetarians have a better metabolic profile than non-vegetarians, suggesting that a vegetarian dietary pattern may help prevent chronic degenerative diseases. However, longitudinal studies on the impact of vegetarian diets on metabolic traits are scarce. We studied how several sub-types of vegetarian diets affect metabolic traits, including waist circumference, BMI, systolic blood pressure (SBP), diastolic blood pressure, fasting blood glucose, total cholesterol (TC), HDL, LDL, TAG and TC:HDL ratio, through both cross-sectional and longitudinal study designs. The study used the MJ Health Screening database, with data collected from 1994 to 2008 in Taiwan, which included 4415 lacto-ovo-vegetarians, 1855 lacto-vegetarians and 1913 vegans; each vegetarian was matched with five non-vegetarians based on age, sex and study site. In the longitudinal follow-up, each additional year of vegan diet lowered the risk of obesity by 7 % (95 % CI 0·88, 0·99), whereas each additional year of lacto-vegetarian diet lowered the risk of elevated SBP by 8 % (95 % CI 0·85, 0·99) and elevated glucose by 7 % (95 % CI 0·87, 0·99), and each additional year of ovo-lacto-vegetarian diet increased abnormal HDL by 7 % (95 % CI 1·03, 1·12), compared with non-vegetarians. In the cross-sectional comparisons, all sub-types of vegetarians had lower likelihoods of abnormalities compared with non-vegetarians on all metabolic traits (P<0·001 for all comparisons), except for HDL and TAG. The better metabolic profile in vegetarians is partially attributable to lower BMI. With proper management of TAG and HDL, along with caution about the intake of refined carbohydrates and fructose, a plant-based diet may benefit all aspects of the metabolic profile.

  17. Cross-sectional and longitudinal comparisons of metabolic profiles between vegetarian and non-vegetarian subjects: a matched cohort study.

    PubMed

    Chiu, Yen-Feng; Hsu, Chih-Cheng; Chiu, Tina H T; Lee, Chun-Yi; Liu, Ting-Ting; Tsao, Chwen Keng; Chuang, Su-Chun; Hsiung, Chao A

    2015-10-28

    Several previous cross-sectional studies have shown that vegetarians have a better metabolic profile than non-vegetarians, suggesting that a vegetarian dietary pattern may help prevent chronic degenerative diseases. However, longitudinal studies on the impact of vegetarian diets on metabolic traits are scarce. We studied how several sub-types of vegetarian diets affect metabolic traits, including waist circumference, BMI, systolic blood pressure (SBP), diastolic blood pressure, fasting blood glucose, total cholesterol (TC), HDL, LDL, TAG and TC:HDL ratio, through both cross-sectional and longitudinal study designs. The study used the MJ Health Screening database, with data collected from 1994 to 2008 in Taiwan, which included 4415 lacto-ovo-vegetarians, 1855 lacto-vegetarians and 1913 vegans; each vegetarian was matched with five non-vegetarians based on age, sex and study site. In the longitudinal follow-up, each additional year of vegan diet lowered the risk of obesity by 7 % (95 % CI 0·88, 0·99), whereas each additional year of lacto-vegetarian diet lowered the risk of elevated SBP by 8 % (95 % CI 0·85, 0·99) and elevated glucose by 7 % (95 % CI 0·87, 0·99), and each additional year of ovo-lacto-vegetarian diet increased abnormal HDL by 7 % (95 % CI 1·03, 1·12), compared with non-vegetarians. In the cross-sectional comparisons, all sub-types of vegetarians had lower likelihoods of abnormalities compared with non-vegetarians on all metabolic traits (P<0·001 for all comparisons), except for HDL and TAG. The better metabolic profile in vegetarians is partially attributable to lower BMI. With proper management of TAG and HDL, along with caution about the intake of refined carbohydrates and fructose, a plant-based diet may benefit all aspects of the metabolic profile. PMID:26355190

  18. Carotid body, insulin, and metabolic diseases: unraveling the links

    PubMed Central

    Conde, Sílvia V.; Sacramento, Joana F.; Guarino, Maria P.; Gonzalez, Constancio; Obeso, Ana; Diogo, Lucilia N.; Monteiro, Emilia C.; Ribeiro, Maria J.

    2014-01-01

    The carotid bodies (CB) are peripheral chemoreceptors that sense changes in arterial blood O2, CO2, and pH levels. Hypoxia, hypercapnia, and acidosis activate the CB, which respond by increasing the action potential frequency in their sensory nerve, the carotid sinus nerve (CSN). CSN activity is integrated in the brain stem to induce a panoply of cardiorespiratory reflexes aimed, primarily, to normalize the altered blood gases, via hyperventilation, and to regulate blood pressure and cardiac performance, via sympathetic nervous system (SNS) activation. Besides its role in the cardiorespiratory control the CB has been proposed as a metabolic sensor implicated in the control of energy homeostasis and, more recently, in the regulation of whole body insulin sensitivity. Hypercaloric diets cause CB overactivation in rats, which seems to be at the origin of the development of insulin resistance and hypertension, core features of metabolic syndrome and type 2 diabetes. Consistent with this notion, CB sensory denervation prevents metabolic and hemodynamic alterations in hypercaloric feed animal. Obstructive sleep apnea (OSA) is another chronic disorder characterized by increased CB activity and intimately related with several metabolic and cardiovascular abnormalities. In this manuscript we review in a concise manner the putative pathways linking CB chemoreceptors deregulation with the pathogenesis of insulin resistance and arterial hypertension. Also, the link between chronic intermittent hypoxia (CIH) and insulin resistance is discussed. Then, a final section is devoted to debate strategies to reduce CB activity and its use for prevention and therapeutics of metabolic diseases with an emphasis on new exciting research in the modulation of bioelectronic signals, likely to be central in the future. PMID:25400585

  19. Hypergammaglobulinemia in the pediatric population as a marker for underlying autoimmune disease: a retrospective cohort study

    PubMed Central

    2013-01-01

    Background The significance of hypergammaglobulinemia as a marker of immune activation is unknown, as a differential diagnosis for hypergammaglobulinemia in children has not been adequately established. The goal of this study was to identify conditions associated with hypergammaglobulinemia in children, with the hypothesis that elevated immunoglobulin levels may precede or predict the development of autoimmune conditions. Methods We reviewed the medical records for all children with IgG level ≥2000 mg/dL treated at a tertiary care children’s hospital from January 1, 2000 through December 31, 2009. We compared clinical and laboratory features of these patients, and developed an algorithm to predict the likelihood of underlying autoimmunity based on these characteristics. Results After excluding children who had received IVIG, a total of 442 patients with hypergammaglobulinemia were identified. Of these, nearly half had autoimmune conditions, most frequently systemic lupus erythematosus and lupus-related disorders. Autoimmune gastrointestinal disorders such as inflammatory bowel disease were also common. Infectious diseases were the next largest category of diseases, followed with much less frequency by malignant, drug-related, and other conditions. In comparison with non-autoimmune conditions, patients with autoimmune disease had higher IgG levels, lower white blood cell counts, lower hemoglobin values, and lower C-reactive protein (CRP) levels. Multivariable logistic regression confirmed that CRP (P = 0.002), white blood cell count (P < 0.001), hemoglobin (P = 0.015), and female gender (P < 0.001) are independent risk factors for autoimmune disease in patients with high IgG levels. Conclusions In a cohort of pediatric patients at a tertiary care children’s hospital, hypergammaglobulinemia was most commonly associated with autoimmune diseases. In female patients with hypergammaglobulinemia, the presence of leukopenia, anemia, and normal CRP

  20. Analysis of Published Criteria for Clinically Inactive Disease in a Large Juvenile Dermatomyositis Cohort Shows That Skin Disease Is Underestimated

    PubMed Central

    Almeida, Beverley; Campanilho‐Marques, Raquel; Arnold, Katie; Pilkington, Clarissa A.; Wedderburn, Lucy R.; Armon, Kate; Briggs, Vanja; Ellis‐Gage, Joe; Roper, Holly; Watts, Joanna; Baildam, Eileen; Hanna, Louise; Lloyd, Olivia; McCann, Liza; Roberts, Ian; McGovern, Ann; Riley, Phil; Al‐Abadi, Eslam; Ryder, Clive; Scott, Janis; Southwood, Taunton; Thomas, Beverley; Amin, Tania; Burton, Deborah; Jackson, Gillian; Van Rooyen, Vanessa; Wood, Mark; Wyatt, Sue; Browne, Michael; Davidson, Joyce; Ferguson, Sue; Gardner‐Medwin, Janet; Martin, Neil; Waxman, Liz; Foster, Helen; Friswell, Mark; Jandial, Sharmila; Qiao, Lisa; Sen, Ethan; Smith, Eve; Stevenson, Vicky; Swift, Alison; Wade, Debbie; Watson, Stuart; Crate, Lindsay; Frost, Anna; Jordan, Mary; Mosley, Ellen; Satyapal, Rangaraj; Stretton, Elizabeth; Venning, Helen; Warrier, Kishore; Almeida, Beverley; Arnold, Katie; Beard, Laura; Brown, Virginia; Campanilho‐Marques, Raquel; Enayat, Elli; Glackin, Yvonne; Halkon, Elizabeth; Hasson, Nathan; Juggins, Audrey; Kassoumeri, Laura; Lunt, Sian; Maillard, Sue; Nistala, Kiran; Pilkington, Clarissa; Simou, Stephanie; Smith, Sally; Varsani, Hemlata; Wedderburn, Lucy; Murray, Kevin; Ioannou, John; Suffield, Linda; Al‐Obaidi, Muthana; Leach, Sam; Lee, Helen; Smith, Helen; Inness, Emma; Kendall, Eunice; Mayers, David; Wilkinson, Nick; Clinch, Jacqui; Pluess‐Hall, Helen

    2015-01-01

    Objective The Pediatric Rheumatology International Trials Organisation (PRINTO) recently published criteria for classification of patients with juvenile dermatomyositis (DM) as having clinically inactive disease. The criteria require that at least 3 of 4 conditions be met, i.e., creatine kinase level ≤150 units/liter, Childhood Myositis Assessment Scale score ≥48, Manual Muscle Testing in 8 muscles score ≥78, and physician's global assessment of overall disease activity (PGA) ≤0.2. The present study was undertaken to test these criteria in a UK cohort of patients with juvenile DM. Methods We assessed 1,114 patient visits for the 4 items in the PRINTO criteria for clinically inactive disease. Each visit was analyzed to determine whether skin disease was present. The Disease Activity Score (DAS) for juvenile DM was determined in 59 patients. Results At 307 of the 1,114 visits, clinically inactive disease was achieved based on the 3 muscle criteria (but with a PGA of >0.2); rash was present at 65.8% of these visits and nailfold capillary abnormalities at 35.2%. When PGA ≤0.2 was one of the 3 criteria that were met, the frequency of skin signs was significantly lower (rash in 23.1% and nailfold capillary abnormalities in 8.7%). If PGA was considered an essential criterion for clinically inactive disease (P‐CID), patients with active skin disease were less likely to be categorized as having clinically inactive disease (a median DAS skin score of 0 [of a possible maximum of 9] in visits where the PGA was ≤0.2, versus a median DAS skin score of 4 in patients meeting the 3 muscle criteria [with a PGA of >0.2]; P < 0.001). Use of the P‐CID led to improvements in the positive predictive value and the positive likelihood ratio (85.4% and 11.0, respectively, compared to 72.9% and 5.1 with the current criteria). Conclusion There was a high frequency of skin disease among patients with juvenile DM who did not meet the PGA criterion for inactive disease but met

  1. Peritoneal Dialysate Glucose Load and Systemic Glucose Metabolism in Non-Diabetics: Results from the GLOBAL Fluid Cohort Study

    PubMed Central

    Chess, James; Do, Jun-Young; Noh, Hyunjin; Lee, Hi-Bahl; Kim, Yong-Lim; Summers, Angela; Williams, Paul Ford; Davison, Sara; Dorval, Marc

    2016-01-01

    Background and Objectives Glucose control is a significant predictor of mortality in diabetic peritoneal dialysis (PD) patients. During PD, the local toxic effects of intra-peritoneal glucose are well recognized, but despite large amounts of glucose being absorbed, the systemic effects of this in non-diabetic patients are not clear. We sought to clarify whether dialysate glucose has an effect upon systemic glucose metabolism. Methods and Materials We analysed the Global Fluid Study cohort, a prospective, observational cohort study initiated in 2002. A subset of 10 centres from 3 countries with high data quality were selected (368 incident and 272 prevalent non-diabetic patients), with multilevel, multivariable analysis of the reciprocal of random glucose levels, and a stratified-by-centre Cox survival analysis. Results The median follow up was 5.6 and 6.4 years respectively in incident and prevalent patients. On multivariate analysis, serum glucose increased with age (β = -0.007, 95%CI -0.010, -0.004) and decreased with higher serum sodium (β = 0.002, 95%CI 0.0005, 0.003) in incident patients and increased with dialysate glucose (β = -0.0002, 95%CI -0.0004, -0.00006) in prevalent patients. Levels suggested undiagnosed diabetes in 5.4% of prevalent patients. Glucose levels predicted death in unadjusted analyses of both incident and prevalent groups but in an adjusted survival analysis they did not (for random glucose 6–10 compared with <6, Incident group HR 0.92, 95%CI 0.58, 1.46, Prevalent group HR 1.42, 95%CI 0.86, 2.34). Conclusions In prevalent non-diabetic patients, random glucose levels at a diabetic level are under-recognised and increase with dialysate glucose load. Random glucose levels predict mortality in unadjusted analyses, but this association has not been proven in adjusted analyses. PMID:27249020

  2. Cohort study of effect of vaccination on pancreas disease in Norwegian salmon aquaculture.

    PubMed

    Bang Jensen, Britt; Kristoffersen, Anja B; Myr, Camilla; Brun, Edgar

    2012-12-01

    Pancreas disease (PD) is an economically important viral disease in Norwegian aquaculture, with 75 to 89 annual outbreaks from 2009 to 2011. To hinder further spread of disease from an initial endemic area on the west coast of Norway, measures for surveillance and control are in place, and the disease is notifiable on a national level. Since 2008, the Norwegian coastline has been divided into 2 administrative zones separated by a production-free area of 10 nautical miles at approximately 63°N. At the same time, a vaccination program involving most marine salmonid farms was initiated by the industry, using a vaccine against PD that was made commercially available in 2007. The effects of the vaccine in the field have been questioned, since the annual number of PD outbreaks has not decreased as expected. However, other production parameters can be used for evaluation of vaccine effect, and in this study the effects of vaccination on cumulative mortality, growth rate, feed conversion factor and number of discarded fish were analyzed using data collected from fish cohorts with and without PD put to sea between spring 2007 and spring 2009. The results show that vaccination against PD has a positive effect in reducing the number of outbreaks, and decreasing cumulative mortality and the number of fish discarded at slaughter.

  3. Two patients with co-morbid myasthenia gravis in a Brazilian cohort of inflammatory bowel disease.

    PubMed

    Gondim, Francisco de A A; de Oliveira, Gisele R; Araújo, Davi F; Souza, Marcellus Henrique Loiola Ponte; Braga, Lúcia Libanez Bessa Campelo; Thomas, Florian P

    2014-11-01

    Co-morbid auto-immune disorders may affect 0.2% of the population. We present the clinical and electrodiagnostic findings of 2 patients with inflammatory bowel disease and myasthenia gravis from a Brazilian cohort of 218 inflammatory bowel disease patients. Patient 1: A 40year-old man was diagnosed with ulcerative colitis at age 37 and underwent total colectomy 3years later. After prednisone was tapered, he experienced a clinical relapse and was diagnosed with Crohn's disease. He then developed quadriparesis, bilateral ptosis, dysphagia and dysarthria. Patient 2: A 41year-old woman (diagnosed with ulcerative colitis and primary sclerosing cholangitis at age 35) developed speech impairment and ptosis. On both patients, symptoms quickly progressed over few weeks. Myasthenia gravis was diagnosed and confirmed by abnormal repetitive nerve stimulation and elevated anti-acetylcholine receptor antibody titers. Pyridostigmine and prednisone successfully treated both patients. Myasthenia gravis prevalence over 9years was 0.9%. Myasthenia gravis clinical course was not significantly modified by inflammatory bowel disease relapses and should be suspected with new onset weakness.

  4. Burden of dengue infection and disease in a pediatric cohort in urban Sri Lanka.

    PubMed

    Tissera, Hasitha; Amarasinghe, Ananda; De Silva, Aruna Dharshan; Kariyawasam, Pradeep; Corbett, Kizzmekia S; Katzelnick, Leah; Tam, Clarence; Letson, G William; Margolis, Harold S; de Silva, Aravinda M

    2014-07-01

    Dengue is the most significant arthropod-borne viral infection of humans. Persons infected with dengue viruses (DENV) have subclinical or clinically apparent infections ranging from undifferentiated fever to dengue hemorrhagic fever/shock syndrome. Although recent studies estimated that the Indian subcontinent has the greatest burden of DENV infection and disease worldwide, we do not have reliable, population-based estimates of the incidence of infection and disease in this region. The goal of this study was to follow-up a cohort of 800 children living in a heavily urbanized area of Colombo, Sri Lanka to obtain accurate estimates of the incidence of DENV infection and disease. Annual blood samples were obtained from all children to estimate dengue seroprevalence at enrollment and to identify children exposed to new DENV infections during the study year. Blood was also obtained from any child in whom fever developed over the course of the study year to identify clinically apparent DENV infections. At enrollment, dengue seroprevalence was 53.07%, which indicated high transmission in this population. Over the study year, the incidence of DENV infection and disease were 8.39 (95% confidence interval = 6.56-10.53) and 3.38 (95% confidence interval = 2.24-4.88), respectively, per 100 children per year. The ratio of clinically inapparent to apparent infections was 1.48. These results will be useful for obtaining more accurate estimates of the burden of dengue in the region and for making decisions about testing and introduction of vaccines.

  5. Disease surveillance methods used in the 8-site MAL-ED cohort study.

    PubMed

    Richard, Stephanie A; Barrett, Leah J; Guerrant, Richard L; Checkley, William; Miller, Mark A

    2014-11-01

    Describing the early life associations between infectious disease episodes and growth, cognitive development, and vaccine response in the first 2 years of life is one of the primary goals of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study. To collect high-resolution data during a critical early period of development, field staff visit each study participant at their house twice weekly from birth to 2 years of age to collect daily reported illness and treatment data from caregivers. Detailed infectious disease histories will not only allow us to relate the overall burden of infectious disease with the primary outcomes of the study, but will also allow us to describe the ages at which infectious diseases have the greatest effect on child health. In addition, twice-weekly visits allow for sample collection when diarrhea episodes are identified. This article describes the methods used to collect illness and treatment history data and discusses the a priori definitions of diarrhea and acute lower respiratory illness episodes. PMID:25305290

  6. Alterations in metabolic pathways and networks in Alzheimer's disease.

    PubMed

    Kaddurah-Daouk, R; Zhu, H; Sharma, S; Bogdanov, M; Rozen, S G; Matson, W; Oki, N O; Motsinger-Reif, A A; Churchill, E; Lei, Z; Appleby, D; Kling, M A; Trojanowski, J Q; Doraiswamy, P M; Arnold, S E

    2013-04-09

    The pathogenic mechanisms of Alzheimer's disease (AD) remain largely unknown and clinical trials have not demonstrated significant benefit. Biochemical characterization of AD and its prodromal phase may provide new diagnostic and therapeutic insights. We used targeted metabolomics platform to profile cerebrospinal fluid (CSF) from AD (n=40), mild cognitive impairment (MCI, n=36) and control (n=38) subjects; univariate and multivariate analyses to define between-group differences; and partial least square-discriminant analysis models to classify diagnostic groups using CSF metabolomic profiles. A partial correlation network was built to link metabolic markers, protein markers and disease severity. AD subjects had elevated methionine (MET), 5-hydroxyindoleacetic acid (5-HIAA), vanillylmandelic acid, xanthosine and glutathione versus controls. MCI subjects had elevated 5-HIAA, MET, hypoxanthine and other metabolites versus controls. Metabolite ratios revealed changes within tryptophan, MET and purine pathways. Initial pathway analyses identified steps in several pathways that appear altered in AD and MCI. A partial correlation network showed total tau most directly related to norepinephrine and purine pathways; amyloid-β (Ab42) was related directly to an unidentified metabolite and indirectly to 5-HIAA and MET. These findings indicate that MCI and AD are associated with an overlapping pattern of perturbations in tryptophan, tyrosine, MET and purine pathways, and suggest that profound biochemical alterations are linked to abnormal Ab42 and tau metabolism. Metabolomics provides powerful tools to map interlinked biochemical pathway perturbations and study AD as a disease of network failure.

  7. Sphingolipids in Obesity, Type 2 Diabetes, and Metabolic Disease

    PubMed Central

    Russo, S.B.; Ross, J.S.; Cowart, L.A.

    2014-01-01

    Metabolic disease, including obesity and type 2 diabetes, constitutes a major emerging health crisis in Western nations. Although the symptoms and clinical pathology and physiology of these conditions are well understood, the molecular mechanisms underlying the disease process have largely remained obscure. Sphingolipids, a lipid class with both signaling and structural properties, have recently emerged as key players in most major tissues affected by diabetes and are required components in the molecular etiology of this disease. Indeed, sphingolipids have been shown to mediate loss of insulin sensitivity, to promote the characteristic diabetic pro-inflammatory state, and to induce cell death and dysfunction in important organs such as the pancreas and heart. Furthermore, plasma sphingolipid levels are emerging as potential biomarkers for the decompensation of insulin resistance to frank type 2 diabetes. Despite these discoveries, the roles of specific sphingolipid species and sphingolipid metabolic pathways remain obscure, and newly developed experimental approaches must be employed to elucidate the detailed molecular mechanisms necessary for rational drug development and other clinical applications. PMID:23563667

  8. Endocrine manifestations related to inherited metabolic diseases in adults

    PubMed Central

    2012-01-01

    Most inborn errors of metabolism (IEM) are recessive, genetically transmitted diseases and are classified into 3 main groups according to their mechanisms: cellular intoxication, energy deficiency, and defects of complex molecules. They can be associated with endocrine manifestations, which may be complications from a previously diagnosed IEM of childhood onset. More rarely, endocrinopathies can signal an IEM in adulthood, which should be suspected when an endocrine disorder is associated with multisystemic involvement (neurological, muscular, hepatic features, etc.). IEM can affect all glands, but diabetes mellitus, thyroid dysfunction and hypogonadism are the most frequent disorders. A single IEM can present with multiple endocrine dysfunctions, especially those involving energy deficiency (respiratory chain defects), and metal (hemochromatosis) and storage disorders (cystinosis). Non-autoimmune diabetes mellitus, thyroid dysfunction and/or goiter and sometimes hypoparathyroidism should steer the diagnosis towards a respiratory chain defect. Hypogonadotropic hypogonadism is frequent in haemochromatosis (often associated with diabetes), whereas primary hypogonadism is reported in Alström disease and cystinosis (both associated with diabetes, the latter also with thyroid dysfunction) and galactosemia. Hypogonadism is also frequent in X-linked adrenoleukodystrophy (with adrenal failure), congenital disorders of glycosylation, and Fabry and glycogen storage diseases (along with thyroid dysfunction in the first 3 and diabetes in the last). This is a new and growing field and is not yet very well recognized in adulthood despite its consequences on growth, bone metabolism and fertility. For this reason, physicians managing adult patients should be aware of these diagnoses. PMID:22284844

  9. DIETARY HYPERGLYCEMIA, GLYCEMIC INDEX AND METABOLIC RETINAL DISEASES

    PubMed Central

    Chiu, Chung-Jung; Taylor, Allen

    2014-01-01

    The glycemic index (GI) indicates how fast blood glucose is raised after consuming a carbohydrate-containing food. Human metabolic studies indicate that GI is related to patho-physiological responses after meals. Compared with a low-GI meal, a high-GI meal is characterized with hyperglycemia during the early postprandial stage (0~2 h) and a compensatory hyperlipidemia associated with counter-regulatory hormone responses during late postprandial stage (4~6 h). Over the past three decades, several human health disorders have been related to GI. The strongest relationship suggests that consuming low-GI foods prevents diabetic complications. Diabetic retinopathy (DR) is a complication of diabetes. In this aspect, GI appears to be useful as a practical guideline to help diabetic people choose foods. Abundant epidemiological evidence also indicates positive associations between GI and risk for type 2 diabetes, cardiovascular disease, and more recently, age-related macular degeneration (AMD) in people without diabetes. Although data from randomized controlled intervention trials are scanty, these observations are strongly supported by evolving molecular mechanisms which explain the pathogenesis of hyperglycemia. This wide range of evidence implies that dietary hyperglycemia is etiologically related to human aging and diseases, including DR and AMD. In this context, these diseases can be considered metabolic retinal diseases. Molecular theories that explain hyperglycemic pathogenesis involve a mitochondria-associated pathway and four glycolysis-associated pathways, including advanced glycation end products formation, protein kinase C activation, polyol pathway, and hexosamine pathway. While the four glycolysis-associated pathways appear to be universal for both normoxic and hypoxic conditions, the mitochondria-associated mechanism appears to be most relevant to the hyperglycemic, normoxic pathogenesis. For diseases that affect tissues with highly active metabolism and that

  10. Dietary hyperglycemia, glycemic index and metabolic retinal diseases.

    PubMed

    Chiu, Chung-Jung; Taylor, Allen

    2011-01-01

    The glycemic index (GI) indicates how fast blood glucose is raised after consuming a carbohydrate-containing food. Human metabolic studies indicate that GI is related to patho-physiological responses after meals. Compared with a low-GI meal, a high-GI meal is characterized with hyperglycemia during the early postprandial stage (0-2h) and a compensatory hyperlipidemia associated with counter-regulatory hormone responses during late postprandial stage (4-6h). Over the past three decades, several human health disorders have been related to GI. The strongest relationship suggests that consuming low-GI foods prevents diabetic complications. Diabetic retinopathy (DR) is a complication of diabetes. In this aspect, GI appears to be useful as a practical guideline to help diabetic people choose foods. Abundant epidemiological evidence also indicates positive associations between GI and risk for type 2 diabetes, cardiovascular disease, and more recently, age-related macular degeneration (AMD) in people without diabetes. Although data from randomized controlled intervention trials are scanty, these observations are strongly supported by evolving molecular mechanisms which explain the pathogenesis of hyperglycemia. This wide range of evidence implies that dietary hyperglycemia is etiologically related to human aging and diseases, including DR and AMD. In this context, these diseases can be considered as metabolic retinal diseases. Molecular theories that explain hyperglycemic pathogenesis involve a mitochondria-associated pathway and four glycolysis-associated pathways, including advanced glycation end products formation, protein kinase C activation, polyol pathway, and hexosamine pathway. While the four glycolysis-associated pathways appear to be universal for both normoxic and hypoxic conditions, the mitochondria-associated mechanism appears to be most relevant to the hyperglycemic, normoxic pathogenesis. For diseases that affect tissues with highly active metabolism and

  11. Emerging pathways in genetic Parkinson's disease: Potential role of ceramide metabolism in Lewy body disease.

    PubMed

    Bras, Jose; Singleton, Andrew; Cookson, Mark R; Hardy, John

    2008-12-01

    Heterozygous loss-of-function mutations at the glucosecerebrosidase locus have recently been shown to be a potent risk factor for Lewy body disease. Based on this observation, we have re-evaluated the likelihood that the different PARK loci (defined using clinical criteria for disease) may be misleading attempts to find common pathways to pathogenesis. Rather, we suggest, grouping the different loci which lead to different Lewy body disease may be more revealing. Doing this, we suggest that several of the genes involved in disparate Lewy body diseases impinge on ceramide metabolism and we suggest that this may be a common theme for pathogenesis. PMID:19021754

  12. Arsenic exposure from drinking water and mortality from cardiovascular disease in Bangladesh: prospective cohort study

    PubMed Central

    Graziano, Joseph H; Parvez, Faruque; Liu, Mengling; Slavkovich, Vesna; Kalra, Tara; Argos, Maria; Islam, Tariqul; Ahmed, Alauddin; Rakibuz-Zaman, Muhammad; Hasan, Rabiul; Sarwar, Golam; Levy, Diane; van Geen, Alexander

    2011-01-01

    Objective To evaluate the association between arsenic exposure and mortality from cardiovascular disease and to assess whether cigarette smoking influences the association. Design Prospective cohort study with arsenic exposure measured in drinking water from wells and urine. Setting General population in Araihazar, Bangladesh. Participants 11 746 men and women who provided urine samples in 2000 and were followed up for an average of 6.6 years. Main outcome measure Death from cardiovascular disease. Results 198 people died from diseases of circulatory system, accounting for 43% of total mortality in the population. The mortality rate for cardiovascular disease was 214.3 per 100 000 person years in people drinking water containing <12.0 µg/L arsenic, compared with 271.1 per 100 000 person years in people drinking water with ≥12.0 µg/L arsenic. There was a dose-response relation between exposure to arsenic in well water assessed at baseline and mortality from ischaemic heart disease and other heart disease; the hazard ratios in increasing quarters of arsenic concentration in well water (0.1-12.0, 12.1-62.0, 62.1-148.0, and 148.1-864.0 µg/L) were 1.00 (reference), 1.22 (0.65 to 2.32), 1.35 (0.71 to 2.57), and 1.92 (1.07 to 3.43) (P=0.0019 for trend), respectively, after adjustment for potential confounders including age, sex, smoking status, educational attainment, body mass index (BMI), and changes in urinary arsenic concentration since baseline. Similar associations were observed when baseline total urinary arsenic was used as the exposure variable and for mortality from ischaemic heart disease specifically. The data indicate a significant synergistic interaction between arsenic exposure and cigarette smoking in mortality from ischaemic heart disease and other heart disease. In particular, the hazard ratio for the joint effect of a moderate level of arsenic exposure (middle third of well arsenic concentration 25.3-114.0 µg/L, mean 63.5 µg/L) and

  13. Diphosphonates in the evaluation of metabolic bone disease.

    PubMed

    Fogelman, I; Smith, M L

    1982-03-01

    The bone scan may be of value in the assessment of patients with metabolic bone disease. However the superiority of the bone scan when compared to radiology in conditions such as renal osteodystrophy, osteomalacia, primary hyperparathyroidism, and osteoporosis requires substantiation with the newer radiopharmaceuticals which have a higher affinity for bone. Two methods of quantitating skeletal uptake of tracer have been assessed to try to remove the subjective aspect of bone scan evaluation. Measurements of bone to soft tissue ratios have proved clinically disappointing, but 24 hour whole body retention of diphosphonate appears to provide a sensitive index of increased bone turnover.

  14. Metabolic Abnormalities Are Common among South American Hispanics Subjects with Normal Weight or Excess Body Weight: The CRONICAS Cohort Study

    PubMed Central

    Benziger, Catherine P.; Bernabé-Ortiz, Antonio; Gilman, Robert H.; Checkley, William; Smeeth, Liam; Málaga, Germán; Miranda, J. Jaime

    2015-01-01

    Objective We aimed to characterize metabolic status by body mass index (BMI) status. Methods The CRONICAS longitudinal study was performed in an age-and-sex stratified random sample of participants aged 35 years or older in four Peruvian settings: Lima (Peru’s capital, costal urban, highly urbanized), urban and rural Puno (both high-altitude), and Tumbes (costal semirural). Data from the baseline study, conducted in 2010, was used. Individuals were classified by BMI as normal weight (18.5–24.9 kg/m2), overweight (25.0–29.9 kg/m2), and obese (≥30 kg/m2), and as metabolically healthy (0–1 metabolic abnormality) or metabolically unhealthy (≥2 abnormalities). Abnormalities included individual components of the metabolic syndrome, high-sensitivity C-reactive protein, and insulin resistance. Results A total of 3088 (age 55.6±12.6 years, 51.3% females) had all measurements. Of these, 890 (28.8%), 1361 (44.1%) and 837 (27.1%) were normal weight, overweight and obese, respectively. Overall, 19.0% of normal weight in contrast to 54.9% of overweight and 77.7% of obese individuals had ≥3 risk factors (p<0.001). Among normal weight individuals, 43.1% were metabolically unhealthy, and age ≥65 years, female, and highest socioeconomic groups were more likely to have this pattern. In contrast, only 16.4% of overweight and 3.9% of obese individuals were metabolically healthy and, compared to Lima, the rural and urban sites in Puno were more likely to have a metabolically healthier profile. Conclusions Most Peruvians with overweight and obesity have additional risk factors for cardiovascular disease, as well as a majority of those with a healthy weight. Prevention programs aimed at individuals with a normal BMI, and those who are overweight and obese, are urgently needed, such as screening for elevated fasting cholesterol and glucose. PMID:26599322

  15. Vitamins and their derivatives in the prevention and treatment of metabolic syndrome diseases (diabetes).

    PubMed

    Dakshinamurti, Krishnamurti

    2015-05-01

    A cluster of inter-related conditions such as central obesity, dyslipidemia, impaired glucose metabolism, and hypertension is referred to as Metabolic Syndrome, which is a risk factor for the development of type-2 diabetes. The micro- and macro-vascular complications of diabetes contribute to its morbidity and mortality. In addition to its calcitropic effect, vitamin D is a regulator of gene expression as well as cell proliferation and differentiation. Various cross-sectional and longitudinal cohort studies have indicated a beneficial effect from vitamin D supplementation on the development of type-2 diabetes. Binding of retinol-bound retinol-binding protein to a membrane-binding protein suppresses insulin signaling. All-trans retinoic acid, a derivative of vitamin A, reverses these effects, resulting in increased insulin sensitivity, suppression of the phosphoenolpyruvate carboxy kinase (PEPCK) gene, and the induction of the glucokinase gene. Glucokinase and PEPCK are also regulated in opposite directions by the vitamin biotin, acting at the transcriptional level. Biotin also regulates the synthesis of insulin by the islet of Langerhans cells of the pancreas. The increase in advanced glycation end products (AGEs) is implicated in the initiation and progression of diabetes-associated microvascular diseases. Benfotiamine, a derivative of thiamine, and pyridoxamine, a vitamer of vitamin B6, both have anti-AGE properties, making them valuable therapeutic adjuvants in the treatment of diabetic complications. Thus, various vitamins and their derivatives have profound therapeutic potential in the prevention and treatment of type-2 diabetes. PMID:25929424

  16. Abnormal metabolic pattern associated with cognitive impairment in Parkinson's disease: a validation study.

    PubMed

    Meles, Sanne K; Tang, Chris C; Teune, Laura K; Dierckx, Rudi A; Dhawan, Vijay; Mattis, Paul J; Leenders, Klaus L; Eidelberg, David

    2015-09-01

    Cognitive deficits in Parkinson's disease (PD) have been associated with a specific metabolic covariance pattern. Although the expression of this PD cognition-related pattern (PDCP) correlates with neuropsychological performance, it is not known whether the PDCP topography is reproducible across PD populations. We therefore sought to identify a PDCP topography in a new sample comprised of 19 Dutch PD subjects. Network analysis of metabolic scans from these individuals revealed a significant PDCP that resembled the original network topography. Expression values for the new PDCP correlated (P=0.001) with executive dysfunction on the Frontal Assessment Battery (FAB). Subject scores for the new PDCP correlated (P<0.001) with corresponding values for the original pattern, which also correlated (P<0.005) with FAB scores in this patient group. For further validation, subject scores for the new PDCP were computed in an independent group of 86 American PD patients. In this cohort, subject scores for the new and original PDCP topographies were closely correlated (P<0.001); significant correlations between pattern expression and cognitive performance (P<0.05) were observed for both PDCP topographies. These findings suggest that the PDCP is a replicable imaging marker of PD cognitive dysfunction. PMID:26058693

  17. The Influence of Metabolic Factors for Nonalcoholic Fatty Liver Disease in Women

    PubMed Central

    Chung, Goh Eun; Yim, Jeong Yoon; Kim, Donghee; Lim, Seon Hee; Yang, Jong In; Kim, Young Sun; Yang, Sun Young; Kwak, Min-Sun; Kim, Joo Sung; Cho, Sang-Heon

    2015-01-01

    Background/Aims. Women after menopause have increased insulin resistance and visceral fat, which may increase the prevalence of nonalcoholic fatty liver disease (NAFLD). However, the pathogenesis of NAFLD in women has not been clearly defined. In this study, we aimed to determine the risk factors for NAFLD in women. Methods. A retrospective cohort study was conducted. Women who underwent abdominal ultrasonography and blood sampling for routine health check-ups were recruited. Results. Among 1,423 subjects, 695 women (48.9%) were in a menopausal state. The prevalence of NAFLD was higher in postmenopausal women than in premenopausal women (27.2% versus 14.4%, P < 0.001). In premenopausal women, low HDL-cholesterol, central obesity, and homeostasis model assessment-estimated insulin resistance showed a significant association with the increased risk of NAFLD in multivariate analysis. In postmenopausal women, the presence of diabetes, triglyceridemia, and central obesity showed a significant association with the risk of NAFLD. The presence of menopause and hormone replacement therapy in postmenopausal women were not risk factors for NAFLD. Conclusions. Our findings showed different metabolic factors for NAFLD in pre- and postmenopausal women. However, the key issues are the same: central obesity and insulin resistance. These results reemphasize the importance of metabolic factors irrespective of menopausal status in the pathogenesis of NAFLD in women. PMID:25973422

  18. Vitamins and their derivatives in the prevention and treatment of metabolic syndrome diseases (diabetes).

    PubMed

    Dakshinamurti, Krishnamurti

    2015-05-01

    A cluster of inter-related conditions such as central obesity, dyslipidemia, impaired glucose metabolism, and hypertension is referred to as Metabolic Syndrome, which is a risk factor for the development of type-2 diabetes. The micro- and macro-vascular complications of diabetes contribute to its morbidity and mortality. In addition to its calcitropic effect, vitamin D is a regulator of gene expression as well as cell proliferation and differentiation. Various cross-sectional and longitudinal cohort studies have indicated a beneficial effect from vitamin D supplementation on the development of type-2 diabetes. Binding of retinol-bound retinol-binding protein to a membrane-binding protein suppresses insulin signaling. All-trans retinoic acid, a derivative of vitamin A, reverses these effects, resulting in increased insulin sensitivity, suppression of the phosphoenolpyruvate carboxy kinase (PEPCK) gene, and the induction of the glucokinase gene. Glucokinase and PEPCK are also regulated in opposite directions by the vitamin biotin, acting at the transcriptional level. Biotin also regulates the synthesis of insulin by the islet of Langerhans cells of the pancreas. The increase in advanced glycation end products (AGEs) is implicated in the initiation and progression of diabetes-associated microvascular diseases. Benfotiamine, a derivative of thiamine, and pyridoxamine, a vitamer of vitamin B6, both have anti-AGE properties, making them valuable therapeutic adjuvants in the treatment of diabetic complications. Thus, various vitamins and their derivatives have profound therapeutic potential in the prevention and treatment of type-2 diabetes.

  19. Outcome of anthroposophic medication therapy in chronic disease: A 12-month prospective cohort study

    PubMed Central

    Hamre, Harald J; Witt, Claudia M; Glockmann, Anja; Ziegler, Renatus; Kienle, Gunver S; Willich, Stefan N; Kiene, Helmut

    2008-01-01

    Background Anthroposophic medications (AMED) are prescribed in 56 countries. Objective To study clinical outcomes in patients prescribed AMED for chronic disease. Design Prospective cohort study. Setting 110 medical practices in Germany. Participants 665 consecutive outpatients aged 1–71 years, prescribed AMED for mental, respiratory, musculoskeletal, neurological, genitourinary, and other chronic diseases. Main outcomes Disease and Symptom Scores (physicians’ and patients’ assessment, 0–10) and SF-36. Results During the first six months, an average of 1.5 AMED per patient was used, in total 652 different AMED. Origin of AMED was mineral (8.0% of 652 AMED), botanical (39.0%), zoological (7.2%), chemically defined (13.0%), and mixed (33.0%). From baseline to six-month-follow-up, all outcomes improved significantly: Disease Score improved by mean 3.15 points (95% confidence interval 2.97–3.34, p < 0.001), Symptom Score by 2.43 points (2.23–2.63, p < 0.001), SF-36 Physical Component Summary by 3.04 points (2.16–3.91, p < 0.001), and SF-36 Mental Component Summary by 5.75 points (4.59–6.92, p < 0.001). All improvements were maintained at 12-month follow-up. Improvements were similar in adult men and women, in children, and in patients not using adjunctive therapies. Conclusion Outpatients using AMED for chronic disease had long-term reduction of disease severity and improvement of quality of life. PMID:19920891

  20. Degeneration of Dopaminergic Neurons Due to Metabolic Alterations and Parkinson’s Disease

    PubMed Central

    Song, Juhyun; Kim, Jongpil

    2016-01-01

    The rates of metabolic diseases, such as type 2 diabetes mellitus (T2DM), obesity, and cardiovascular disease (CVD), markedly increase with age. In recent years, studies have reported an association between metabolic changes and various pathophysiological mechanisms in the central nervous system (CNS) in patients with metabolic diseases. Oxidative stress and hyperglycemia in metabolic diseases lead to adverse neurophysiological phenomena, including neuronal loss, synaptic dysfunction, and improper insulin signaling, resulting in Parkinson’s disease (PD). In addition, several lines of evidence suggest that alterations of CNS environments by metabolic changes influence the dopamine neuronal loss, eventually affecting the pathogenesis of PD. Thus, we reviewed recent findings relating to degeneration of dopaminergic neurons during metabolic diseases. We highlight the fact that using a metabolic approach to manipulate degeneration of dopaminergic neurons can serve as a therapeutic strategy to attenuate pathology of PD. PMID:27065205

  1. Childhood infectious disease and premature death from cancer: a prospective cohort study.

    PubMed

    Tennant, Peter W G; Parker, Louise; Thomas, Julian E; Craft, Sir Alan W; Pearce, Mark S

    2013-03-01

    Studies of the association between early life infections and cancer have produced inconsistent findings, possibly due to limited adjustment for confounding and retrospective designs. This study utilised data from the Newcastle Thousand Families Study, a prospective cohort of 1,142 individuals born in Newcastle-upon-Tyne in 1947, to assess the impact of various childhood infectious diseases on cancer mortality during ages 15-60 years. Detailed information was collected prospectively on a number of early life factors. Deaths from cancer during ages 15-60 years were analysed in relation to childhood infections, adjusting for potential early-life confounders, using Cox proportional-hazards regression. In a subsample who returned questionnaires at aged 49-51 years, additional adjustment was made for adult factors to predict death from cancer during ages 50-60 years. Childhood history of measles and influenza, were both independently associated with lower cancer mortality during ages 15-60 years (adjusted hazard ratios = 0.39, 95% CI 0.17-0.88 and 0.49, 95% CI 0.24-0.98 respectively). In contrast, childhood pertussis was associated with higher cancer mortality during ages 15-60 years (adjusted hazard ratio = 4.88, 95% CI 2.29-10.38). In the subsample with additional adjustment for adult variables, measles and pertussis remained significantly associated with cancer mortality during ages 50-60 years. In this pre-vaccination cohort, childhood infection with measles and influenza were associated with a reduced risk of death from cancer in adulthood, while pertussis was associated with an increased risk. While these results suggest some disease-specific associations between early-life infections and cancer, further studies are required to confirm the specific associations identified.

  2. Prevalence of CADASIL and Fabry Disease in a Cohort of MRI Defined Younger Onset Lacunar Stroke

    PubMed Central

    Kilarski, Laura L.; Rutten-Jacobs, Loes C. A.; Bevan, Steve; Baker, Rob; Hassan, Ahamad; Hughes, Derralynn A.; Markus, Hugh S.

    2015-01-01

    Background and Purpose Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), caused by mutations in the NOTCH3 gene, is the most common monogenic disorder causing lacunar stroke and cerebral small vessel disease (SVD). Fabry disease (FD) due to mutations in the GLA gene has been suggested as an underdiagnosed cause of stroke, and one feature is SVD. Previous studies reported varying prevalence of CADASIL and FD in stroke, likely due to varying subtypes studied; no studies have looked at a large cohort of younger onset SVD. We determined the prevalence in a well-defined, MRI-verified cohort of apparently sporadic patients with lacunar infarct. Methods Caucasian patients with lacunar infarction, aged ≤70 years (mean age 56.7 (SD8.6)), were recruited from 72 specialist stroke centres throughout the UK as part of the Young Lacunar Stroke DNA Resource. Patients with a previously confirmed monogenic cause of stroke were excluded. All MRI’s and clinical histories were reviewed centrally. Screening was performed for NOTCH3 and GLA mutations. Results Of 994 subjects five had pathogenic NOTCH3 mutations (R169C, R207C, R587C, C1222G and C323S) all resulting in loss or gain of a cysteine in the NOTCH3 protein. All five patients had confluent leukoaraiosis (Fazekas grade ≥2). CADASIL prevalence overall was 0.5% (95% CI 0.2%-1.1%) and among cases with confluent leukoaraiosis 1.5% (95% CI 0.6%-3.3%). No classic pathogenic FD mutations were found; one patient had a missense mutation (R118C), associated with late-onset FD. Conclusion CADASIL cases are rare and only detected in SVD patients with confluent leukoaraiosis. No definite FD cases were detected. PMID:26305465

  3. Relationship between chronic kidney disease and metabolic syndrome: current perspectives

    PubMed Central

    Nashar, Khaled; Egan, Brent M

    2014-01-01

    Both metabolic syndrome (MetS) and chronic kidney disease (CKD) are increasing in incidence and lead to significant cardiovascular morbidity and mortality. The relationship between these two entities is complex. Individual components of the MetS are known risk factors for incident kidney disease, but it is not clear how the clustering of these components is linked to the development and progression of kidney disease. Cross-sectional studies show an association of the MetS and prevalent CKD; however, one cannot draw conclusions as to which came first – the MetS or the kidney disease. Observational studies suggest a relationship between MetS and incident CKD, but they also demonstrate the development of MetS in patients with established CKD. These observations suggest a bidirectional relationship. A better understanding of the relationship between components of the MetS and whether and how these components contribute to progression of CKD and incident cardiovascular disease could inform more effective prevention strategies. PMID:25258547

  4. Obesity end stage renal disease and survival in an elderly cohort with cardiovascular disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Obesity is highly prevalent in African-Americans and is associated with increased risk of end stage renal disease (ESRD) and death. It is not known if the effect of obesity is similar among Blacks and whites. The aim of this study is to examine racial differences in the association of obesity with E...

  5. The French Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort study

    PubMed Central

    Stengel, Bénédicte; Combe, Christian; Jacquelinet, Christian; Briançon, Serge; Fouque, Denis; Laville, Maurice; Frimat, Luc; Pascal, Christophe; Herpe, Yves-Edouard; Deleuze, Jean-François; Schanstra, Joost; Pisoni, Ron L.; Robinson, Bruce M.; Massy, Ziad A.

    2014-01-01

    Background While much has been learned about the epidemiology and treatment of end-stage renal disease (ESRD) in the last 30 years, chronic kidney disease (CKD) before the end-stage has been less investigated. Not enough is known about factors associated with CKD progression and complications, as well as its transition to ESRD. We designed the CKD-renal epidemiology and information network (REIN) cohort to provide a research platform to address these key questions and to assess clinical practices and costs in patients with moderate or advanced CKD. Methods A total of 46 clinic sites and 4 renal care networks participate in the cohort. A stratified selection of clinic sites yields a sample that represents a diversity of settings, e.g. geographic region, and public versus for-profit and non-for-profit private clinics. In each site, 60–90 patients with CKD are enrolled at a routine clinic visit during a 12-month enrolment phase: 3600 total, including 1800 with Stage 3 and 1800 with Stage 4 CKD. Follow-up will continue for 5 years, including after initiation of renal replacement therapy. Data will be collected from medical records at inclusion and at yearly intervals, as well as from self-administered patient questionnaires and provider-level questionnaires. Patients will also be interviewed at baseline, and at 1, 3 and 5 years. Healthcare costs will also be determined. Blood and urine samples will be collected and stored for future studies on all patients at enrolment and at study end, and at 1 and 3 years in a subsample of 1200. Conclusions The CKD-REIN cohort will serve to improve our understanding of the biological, clinical and healthcare system determinants associated with CKD progression and adverse outcomes as well as of international variations in collaboration with the CKD Outcome and Practice Pattern Study (CKDopps). It will foster CKD epidemiology and outcomes research and provide evidence to improve the health and quality of life of patients with CKD and

  6. Pathophysiology and therapeutics of cardiovascular disease in metabolic syndrome.

    PubMed

    Wang, Yabin; Yu, Qiujun; Chen, Yundai; Cao, Feng

    2013-01-01

    The metabolic syndrome (MetS) is characterized by a cluster of cardiovascular risk factors, including central obesity, hyperglycemia, dyslipidemia and hypertension, which are highly associated with increased morbidity and mortality of cardiovascular diseases (CVD). The association between these metabolic disorders and the development of CVD is believed to be multifactorial, where insulin resistance, oxidative stress, low-grade inflammation and vascular maladaptation act as the major contributors. Therefore, multipronged therapeutic strategies should be taken for the management of patients with MetS. Lifestyle changes including weight control, healthy heart diet and regular exercises have been proposed as first line treatment to decrease CVD risks in MetS individuals. In addition, improving insulin resistance and glucose metabolism, controlling blood pressure as well as modulating dyslipidemia can also delay or reverse the progression of CVD in MetS. This review will first address the complicated interactions between MetS and CVD¸ followed by discussion about the optimal strategy in the prevention and treatment of CVD in MetS patients and the updated results from newly released clinical trials.

  7. Cohort Profile: The Malaysian Cohort (TMC) project: a prospective study of non-communicable diseases in a multi-ethnic population

    PubMed Central

    Jamal, Rahman; Syed Zakaria, Syed Zulkifli; Kamaruddin, Mohd Arman; Abd Jalal, Nazihah; Ismail, Norliza; Mohd Kamil, Norkhamiwati; Abdullah, Noraidatulakma; Baharudin, Norhafizah; Hussin, Noor Hamidah; Othman, Hanita; Mahadi, Nor Muhammad

    2015-01-01

    The Malaysian Cohort study was initiated in 2005 by the Malaysian government. The top-down approach to this population-based cohort study ensured the allocation of sufficient funding for the project which aimed to recruit 100 000 individuals aged 35–70 years. Participants were recruited from rural and urban areas as well as from various socioeconomic groups. The main objectives of the study were to identify risk factors, to study gene-environment interaction and to discover biomarkers for the early detection of cancers and other diseases. At recruitment, a questionnaire-based interview was conducted, biophysical measurements were performed and biospecimens were collected, processed and stored. Baseline investigations included fasting blood sugar, fasting lipid profile, renal profile and full blood count. From April 2006 to the end of September 2012 we recruited a total of 106 527participants. The baseline prevalence data showed 16.6% participants with diabetes, 46.5% with hypertension, 44.9% with hypercholesterolaemia and 17.7% with obesity. The follow-up phase commenced in June 2013. This is the most comprehensive and biggest cohort study in Malaysia, and has become a valuable resource for epidemiological and biological research. For information on collaboration and also data access, investigators can contact the project leader at (rahmanj@ppukm.ukm.edu.my). PMID:24729425

  8. Cohort Profile: The Malaysian Cohort (TMC) project: a prospective study of non-communicable diseases in a multi-ethnic population.

    PubMed

    Jamal, Rahman; Syed Zakaria, Syed Zulkifli; Kamaruddin, Mohd Arman; Abd Jalal, Nazihah; Ismail, Norliza; Mohd Kamil, Norkhamiwati; Abdullah, Noraidatulakma; Baharudin, Norhafizah; Hussin, Noor Hamidah; Othman, Hanita; Mahadi, Nor Muhammad

    2015-04-01

    The Malaysian Cohort study was initiated in 2005 by the Malaysian government. The top-down approach to this population-based cohort study ensured the allocation of sufficient funding for the project which aimed to recruit 100,000 individuals aged 35-70 years. Participants were recruited from rural and urban areas as well as from various socioeconomic groups. The main objectives of the study were to identify risk factors, to study gene-environment interaction and to discover biomarkers for the early detection of cancers and other diseases. At recruitment, a questionnaire-based interview was conducted, biophysical measurements were performed and biospecimens were collected, processed and stored. Baseline investigations included fasting blood sugar, fasting lipid profile, renal profile and full blood count. From April 2006 to the end of September 2012 we recruited a total of 106,527 participants. The baseline prevalence data showed 16.6% participants with diabetes, 46.5% with hypertension, 44.9% with hypercholesterolaemia and 17.7% with obesity. The follow-up phase commenced in June 2013. This is the most comprehensive and biggest cohort study in Malaysia, and has become a valuable resource for epidemiological and biological research. For information on collaboration and also data access, investigators can contact the project leader at (rahmanj@ppukm.ukm.edu.my). PMID:24729425

  9. Central obesity measurements predict metabolic syndrome in a retrospective cohort study of postmenopausal women.

    PubMed

    Rosety-Rodríguez, Manuel; Fornieles, Gabriel; Rosety, Ignacio; Díaz, Antonio J; Rosety, Miguel A; Camacho-Molina, Alejandra; Rodríguez-Pareja, A; Tejerina, A; Alvero-Cruz, José Ramón; Ordonez, Francisco J

    2013-11-01

    Introducción: En la actualidad se acepta la importancia de la masa grasa abdominal en la fisiopatología del síndrome metabólico tal y como reconocen las diferentes clasificaciones diagnósticas disponibles. Nuestro objetivo fue analizar la utilidad como predictores de síndrome metabólico de marcadores de grasa abdominal obtenidos por DEXA en mujeres postmenopausicas aprovechando su participación en screening rutinarios para el estudio de la densidad mineral ósea. Material y método: El presente estudio de cohortes histórico incluyó a un total de 1326 mujeres post-menopausicas con edad > 45 años que se habían sometido rutinariamente a DEXA para conocer su densidad mineral ósea entre Enero de 2006 y Enero de 2011. Además del DEXA, se obtuvo de cada participante la correspondiente anamnesis, bioquímica, tensión arterial e índices de distribución de masa grasa mediante técnicas antropométricas convencionales. Se utilizó la clasificación NCEP-ATP-III para el diagnóstico de síndrome metabólico. Este protocolo fue aprobado por un Comité de Ética Institucional. Resultados: Durante el periodo de observación, 537 mujeres, el 40.5% del total de las estudiadas, cumplió los criterios diagnósticos de síndrome metabólico. Los parámetros de masa grasa abdominal obtenidos mediante DEXA fueron significativamente mayores en mujeres postmenopáusicas con síndrome metabólico. Finalmente, la masa grasa abdominal de regiones de interés L1-L4 y L3-L4 obtenidas por DEXA se relacionaron con el desarrollo de síndrome metabólico en los modelos de regresión ensayados. Conclusión: La masa grasa abdominal determinada por DEXA, especialmente la región L1-L4, podría recomendarse como predictor de síndrome metabólico en este grupo.

  10. Metabolic bone disease in chronic renal failure. I. Dialyzed uremics.

    PubMed Central

    Huffer, W. E.; Kuzela, D.; Popovtzer, M. M.

    1975-01-01

    Garner and ball's point counting technic was used to compare metabolic bone disease in dialyzed and nondialyzed uremic patients. Histologic measurements of bone from dialyzed and nondialyzed uremic patients dying between 1966 and 1971 showed that dialyzed patients have quantitatively more severe bone resorption, distortion of trabecular architecture and mineralization defects. Mineralization defects become more severe as the duration of dialysis increases but are not related to serum calcium and phosphorus levels. Bone volume in both groups is normal or increased and in dialysis patients increases in proportion to the elevation of serum phosphorus. Mean serum phosphorus and calcium levels, bone volume, and volume: surface ratios all decreased in dialysis patients between 1966 and 1971, while bone resorption and mineralization defects did not change. These results suggest that lowering of serum phosphorus without increasing serum calcium may aggrevate the uremic bone disease by reducing bone volume without improvement of mineralization and resorption defects. Images Fig 1 PMID:1119535

  11. Progression of carotid-artery disease in type 2 diabetic patients: a cohort prospective study.

    PubMed

    Bosevski, Marijan; Stojanovska, Lily

    2015-01-01

    In order to assess the progression of carotid-artery disease in type 2 diabetic cohort (n=207 patients), the dynamic change in carotid intima-media thickness (CIMT) and the occurrence of plaques were followed for a period of 31.35±10.59 months. The mean CIMT at the beginning of the study was 0.9178±0.1447 mm, with a maximal value of 1.1210±0.2366 mm. The maximal value of CIMT changed by 0.07 mm/year. Progression of CIMT was noted in 86.8% and its regression in 7.8% of patients. The occurrence of carotid plaques was detected in 41.8% of patients. Multiple regression analysis revealed the maximal value of CIMT to be associated with diastolic blood pressure, despite mean CIMT being predicted by body mass index. The presence of peripheral arterial disease and hypo-high-density lipoproteinemia were found to be predictors for the occurrence of carotid plaques. Our data have clinical implications in predicting risk factors for the progression of carotid-artery disease in type 2 diabetic patients for their appropriate management. PMID:26527880

  12. Clinical and Epidemiological Factors Associated with Mortality in Parkinson's Disease in a Brazilian Cohort

    PubMed Central

    Fernandes, Gustavo Costa; Socal, Mariana Peixoto; Schuh, Artur Francisco Schumacher; Rieder, Carlos R. M.

    2015-01-01

    Background. Prognosis of PD is variable. Most studies show higher mortality rates in PD patients compared to the general population. Clinical and epidemiologic factors predicting mortality are poorly understood. Methods. Clinical and epidemiologic features including patient history and physical, functional, and cognitive scores were collected from a hospital-based cohort of PD patients using standardized protocols and clinical scales. Data on comorbidities and mortality were collected on follow-up. Results. During a mean follow-up of 4.71 years (range 1–10), 43 (20.9%) of the 206 patients died. Those who died had higher mean age at disease onset than those still alive at the last follow-up (67.7 years versus 56.3 years; p < 0.01). In the univariate analysis, age at baseline was associated with decreased survival. In the adjusted Cox proportional hazards model, age at disease onset and race/ethnicity were predictors of mortality. Conclusions. Late age at disease onset and advanced chronological age are associated with decreased survival. Comorbidities and PD characteristics were not associated with decreased survival in our sample. Race/ethnicity was found in our study to be associated with increased hazard of mortality. Our findings indicate the importance of studying survival among different populations of PD patients. PMID:26819798

  13. Clinical and Epidemiological Factors Associated with Mortality in Parkinson's Disease in a Brazilian Cohort.

    PubMed

    Fernandes, Gustavo Costa; Socal, Mariana Peixoto; Schuh, Artur Francisco Schumacher; Rieder, Carlos R M

    2015-01-01

    Background. Prognosis of PD is variable. Most studies show higher mortality rates in PD patients compared to the general population. Clinical and epidemiologic factors predicting mortality are poorly understood. Methods. Clinical and epidemiologic features including patient history and physical, functional, and cognitive scores were collected from a hospital-based cohort of PD patients using standardized protocols and clinical scales. Data on comorbidities and mortality were collected on follow-up. Results. During a mean follow-up of 4.71 years (range 1-10), 43 (20.9%) of the 206 patients died. Those who died had higher mean age at disease onset than those still alive at the last follow-up (67.7 years versus 56.3 years; p < 0.01). In the univariate analysis, age at baseline was associated with decreased survival. In the adjusted Cox proportional hazards model, age at disease onset and race/ethnicity were predictors of mortality. Conclusions. Late age at disease onset and advanced chronological age are associated with decreased survival. Comorbidities and PD characteristics were not associated with decreased survival in our sample. Race/ethnicity was found in our study to be associated with increased hazard of mortality. Our findings indicate the importance of studying survival among different populations of PD patients. PMID:26819798

  14. Progression of carotid-artery disease in type 2 diabetic patients: a cohort prospective study

    PubMed Central

    Bosevski, Marijan; Stojanovska, Lily

    2015-01-01

    In order to assess the progression of carotid-artery disease in type 2 diabetic cohort (n=207 patients), the dynamic change in carotid intima-media thickness (CIMT) and the occurrence of plaques were followed for a period of 31.35±10.59 months. The mean CIMT at the beginning of the study was 0.9178±0.1447 mm, with a maximal value of 1.1210±0.2366 mm. The maximal value of CIMT changed by 0.07 mm/year. Progression of CIMT was noted in 86.8% and its regression in 7.8% of patients. The occurrence of carotid plaques was detected in 41.8% of patients. Multiple regression analysis revealed the maximal value of CIMT to be associated with diastolic blood pressure, despite mean CIMT being predicted by body mass index. The presence of peripheral arterial disease and hypo-high-density lipoproteinemia were found to be predictors for the occurrence of carotid plaques. Our data have clinical implications in predicting risk factors for the progression of carotid-artery disease in type 2 diabetic patients for their appropriate management. PMID:26527880

  15. Autoimmune thyroid disease in a cohort of Malaysian SLE patients: frequency, clinical and immunological associations.

    PubMed

    Ong, S G; Choy, C H

    2016-01-01

    Autoimmune thyroid disease (ATD) has been associated with other systemic autoimmune diseases. To date, there is limited data on thyroid disorders and autoimmune thyroid disease in Malaysia. The frequency of ATD among 189 systemic lupus erythematosus (SLE) patients was 6.3%, with 2.6% in the hyperthyroid group and 3.7% in the hypothyroid group. Hypothyroidism developed at a much younger mean age (24.3 years), suggesting that SLE might be a predisposing factor for the development of Hashimoto's thyroiditis. There was a higher rate of thyroid peroxidase antibody (TPO) positivity compared with anti-thyroglobulin antibody (Tg) in the hyperthyroid subgroup. This study also demonstrated a greater proportion of ATD patients who demonstrated high titres (≥ 1:6400) of TPO compared with high titres of Tg. Although there was an association between ATD and the presence of anti-Ro/SSA and/or anti-La/SSB antibodies, the absence of sicca symptoms and negative Schirmer's tests suggest a lack of association with secondary Sjogren's syndrome. A novel association between ATD and antiphospholipid syndrome (APS) was detected in our cohort. Hence we propose that patients affected by APS be routinely screened for ATD.

  16. Prospective cohort studies of dengue viral transmission and severity of disease.

    PubMed

    Endy, Timothy P; Yoon, In-Kyu; Mammen, Mammen P

    2010-01-01

    As the four serotypes of dengue virus (DENV) systematically spread throughout the tropical and subtropical regions globally, dengue is increasingly contributing to the overall morbidity and mortality sustained by populations and thereby challenging the health infrastructures of most endemic countries. DENV-human host-mosquito vector interactions are complex and cause in humans either asymptomatic or subclinical DENV infection, mild to severe dengue fever (DF), severe dengue hemorrhagic fever (DHF), or dengue shock syndrome (DSS). Over the past decade, we have seen an increase in research funding and public health efforts to offset the effects of this pandemic. Though multiple vaccine development efforts are underway, the need remains to further characterize the determinants of varying severities of clinical outcomes. Several long-term prospective studies on DENV transmission and dengue severity have sought to define the epidemiology and pathogenesis of this disease. Yet, more studies are required to quantify the disease burden on different populations, explore the impact of DENV serotype-specific transmission on host-responses and dengue severity and measure the economic impact of dengue on a population. In this section, we will review the critical past and recent findings of dengue prospective studies on our understanding of the disease and the potential role of future prospective cohort studies in advancing issues required for vaccine field evaluations.

  17. Is COPD a Progressive Disease? A Long Term Bode Cohort Observation

    PubMed Central

    de-Torres, Juan P.; Marín, Jose M.; Pinto-Plata, Víctor; Divo, Miguel; Sanchez-Salcedo, Pablo; Zagaceta, Jorge; Zulueta, Javier J.; Berto, Juan; Cabrera, Carlos; Celli, Bartolome R.; Casanova, Ciro

    2016-01-01

    Background The Global Initiative for Obstructive Lung Diseases (GOLD) defines COPD as a disease that is usually progressive. GOLD also provides a spirometric classification of airflow limitation. However, little is known about the long-term changes of patients in different GOLD grades. Objective Explore the proportion and characteristics of COPD patients that change their spirometric GOLD grade over long-term follow-up. Methods Patients alive for at least 8 years since recruitment and those who died with at least 4 years of repeated spirometric measurements were selected from the BODE cohort database. We purposely included the group of non survivors to avoid a “survival selection” bias. The proportion of patients that had a change (improvement or worsening) in their spirometric GOLD grading was calculated and their characteristics compared with those that remained in the same grade. Results A total of 318 patients were included in the survivor and 217 in the non-survivor groups. Nine percent of survivors and 11% of non survivors had an improvement of at least one GOLD grade. Seventy one percent of survivors and non-survivors remained in the same GOLD grade. Those that improved had a greater degree of airway obstruction at baseline. Conclusions In this selected population of COPD patients, a high proportion of patients remained in the same spirometric GOLD grade or improved in a long-term follow-up. These findings suggest that once diagnosed, COPD is usually a non-progressive disease. PMID:27100872

  18. Serum immune markers and disease progression in an incident Parkinson's disease cohort (ICICLE‐PD)

    PubMed Central

    Wijeyekoon, Ruwani; Yarnall, Alison J.; Lawson, Rachael A.; Breen, David P.; Evans, Jonathan R.; Cummins, Gemma A.; Duncan, Gordon W.; Khoo, Tien K.; Burn, David J.; Barker, Roger A.

    2016-01-01

    ABSTRACT Background The immune system is a promising therapeutic target for disease modification in Parkinson's disease (PD), but appropriate immune‐related biomarkers must be identified to allow patient stratification for trials and tracking of therapeutic effects. The objective of this study was to investigate whether immune markers in peripheral blood are candidate prognostic biomarkers through determining their relationship with disease progression in PD. Methods Serum samples were collected in incident PD cases and age‐matched controls. Subjects were clinically evaluated at baseline and 18 and 36 months. Ten cytokines and C‐reactive protein were measured, with data reduction using principal‐component analysis, and relationships between component scores and motor (MDS Unified Parkinson's Disease Rating Scale — part 3) and cognitive (Mini Mental State Examination [MMSE]) measures of disease severity/progression were investigated. Results TNF‐α, IL1‐β, IL‐2, and IL‐10 were higher in PD (n = 230) than in controls (n = 93), P ≤ 0.001). Principal‐component analysis of log‐transformed data resulted in a 3‐component solution explaining 51% of the variance. Higher “proinflammatory” and lower “anti‐inflammatory” component scores were associated with more rapid motor progression over 36 months (P < 0.05), and higher “proinflammatory” component scores were associated with lower MMSE at all times (P < 0.05). Multiple linear regression analysis with adjustment for covariates confirmed “anti‐inflammatory” component score was the strongest predictor of slower motor progression (β = −0.22, P = 0.002), whereas proinflammatory cytokines were associated with lower baseline MMSE (β = −0.175, P = 0.007). Conclusions Serum immune marker profile is predictive of disease progression in PD and hence a potential prognostic biomarker. However, interventional trials are needed to clarify whether peripheral immune changes

  19. Adipokines in Healthy Skeletal Muscle and Metabolic Disease.

    PubMed

    Coles, C A

    2016-01-01

    Adipose tissue not only functions as a reserve to store energy but has become of major interest as an endocrine organ, releasing signalling molecules termed adipokines which impact on other tissues, such as skeletal muscle. Adipocytes, within skeletal muscle and adipose tissue, secrete adipokines to finely maintain the balance between feed intake and energy expenditure. This book chapter focuses on the three adipokines, adiponectin, leptin and IL-6, which have potent effects on skeletal muscle during rest and exercise. Similarly, adiponectin, leptin and IL-6 enhance glucose uptake and increase fatty acid oxidation in skeletal muscle. Fatty acid oxidation is increased through activation of AMPK (adenosine monophosphate-activated protein kinase signalling) causing phosphorylation and inhibition of ACC (acetyl-coenzyme A carboxylase), decreasing availability of malonyl CoA. Leptin and adiponectin also control feed intake via AMPK signalling in the hypothalamus. Adipokines function to maintain energy homeostasis, however, when feed intake exceeds energy expenditure adipokines can become dysregulated causing lipotoxicity in skeletal muscle and metabolic disease can prevail. Cross-talk between adipocytes and skeletal muscle via correct control by adipokines is important in controlling energy homeostasis during rest and exercise and can help prevent metabolic disease. PMID:27003399

  20. Epicardial adipose tissue in endocrine and metabolic diseases.

    PubMed

    Iacobellis, Gianluca

    2014-05-01

    Epicardial adipose tissue has recently emerged as new risk factor and active player in metabolic and cardiovascular diseases. Albeit its physiological and pathological roles are not completely understood, a body of evidence indicates that epicardial adipose tissue is a fat depot with peculiar and unique features. Epicardial fat is able to synthesize, produce, and secrete bioactive molecules which are then transported into the adjacent myocardium through vasocrine and/or paracrine pathways. Based on these evidences, epicardial adipose tissue can be considered an endocrine organ. Epicardial fat is also thought to provide direct heating to the myocardium and protect the heart during unfavorable hemodynamic conditions, such as ischemia or hypoxia. Epicardial fat has been suggested to play an independent role in the development and progression of obesity- and diabetes-related cardiac abnormalities. Clinically, the thickness of epicardial fat can be easily and accurately measured. Epicardial fat thickness can serve as marker of visceral adiposity and visceral fat changes during weight loss interventions and treatments with drugs targeting the fat. The potential of modulating the epicardial fat with targeted pharmacological agents can open new avenues in the pharmacotherapy of endocrine and metabolic diseases. This review article will provide Endocrine's reader with a focus on epicardial adipose tissue in endocrinology. Novel, established, but also speculative findings on epicardial fat will be discussed from the unexplored perspective of both clinical and basic Endocrinologist.

  1. Understanding the role of gut microbiome in metabolic disease risk.

    PubMed

    Sanz, Yolanda; Olivares, Marta; Moya-Pérez, Ángela; Agostoni, Carlo

    2015-01-01

    The gut microbiota structure, dynamics, and function result from interactions with environmental and host factors, which jointly influence the communication between the gut and peripheral tissues, thereby contributing to health programming and disease risk. Incidence of both type-1 and type-2 diabetes has increased during the past decades, suggesting that there have been changes in the interactions between predisposing genetic and environmental factors. Animal studies show that gut microbiota and its genome (microbiome) influence alterations in energy balance (increased energy harvest) and immunity (inflammation and autoimmunity), leading to metabolic dysfunction (e.g., insulin resistance and deficiency). Thus, although they have different origins, both disorders are linked by the association of the gut microbiota with the immune-metabolic axis. Human studies have also revealed shifts in microbiome signatures in diseased subjects as compared with controls, and a few of them precede the development of these disorders. These studies contribute to pinpointing specific microbiome components and functions (e.g., butyrate-producing bacteria) that can protect against both disorders. These could exert protective roles by strengthening gut barrier function and regulating inflammation, as alterations in these are a pathophysiological feature of both disorders, constituting common targets for future preventive approaches.

  2. Roles of leptin in bone metabolism and bone diseases.

    PubMed

    Chen, Xu Xu; Yang, Tianfu

    2015-09-01

    Adipose tissue has been more accepted as an active contributor to whole body homeostasis, rather than just a fat depot, since leptin, a 16 kDa protein, was discovered as the product of the obese gene in 1994. With more and more studies conducted on this hormone, it has been shown that there is a close relationship between adipose tissue and bone, which have important effects on each other. Bone is the source of many hormones, such as osteocalcin, that can affect energy metabolism and then the anabolism or catabolism of fat tissue. In contrast, the adipose tissue synthesizes and releases a series of adipokines, which are involved in bone metabolism through direct or indirect effects on bone formation and resorption. Interestingly, leptin, one of the most important cytokines derived from fat tissue, seems to account for the largest part of effects on bone, through direct or indirect involvement in bone remodeling and by playing a significant role in many bone diseases, such as osteoporosis, osteoarthritis, rheumatic arthritis, bone tumors and even fractures. In this review, we will discuss the progress in leptin research, particularly focusing on the roles of leptin in bone diseases.

  3. Quantitative evaluation of disease progression in a longitudinal mild cognitive impairment cohort.

    PubMed

    Runtti, Hilkka; Mattila, Jussi; van Gils, Mark; Koikkalainen, Juha; Soininen, Hilkka; Lötjönen, Jyrki

    2014-01-01

    Several neuropsychological tests and biomarkers of Alzheimer's disease (AD) have been validated and their evolution over time has been explored. In this study, multiple heterogeneous predictors of AD were combined using a supervised learning method called Disease State Index (DSI). The behavior of DSI values over time was examined to study disease progression quantitatively in a mild cognitive impairment (MCI) cohort. The DSI method was applied to longitudinal data from 140 MCI cases that progressed to AD and 149 MCI cases that did not progress to AD during the follow-up. The data included neuropsychological tests, brain volumes from magnetic resonance imaging, cerebrospinal fluid samples, and apolipoprotein E from the Alzheimer's Disease Neuroimaging Initiative database. Linear regression of the longitudinal DSI values (including the DSI value at the point of MCI to AD conversion) was performed for each subject having at least three DSI values available (147 non-converters, 126 converters). Converters had five times higher slopes and almost three times higher intercepts than non-converters. Two subgroups were found in the group of non-converters: one group with stable DSI values over time and another group with clearly increasing DSI values suggesting possible progression to AD in the future. The regression parameters differentiated between the converters and the non-converters with classification accuracy of 76.9% for the slopes and 74.6% for the intercepts. In conclusion, this study demonstrated that quantifying longitudinal patient data using the DSI method provides valid information for follow-up of disease progression and support for decision making.

  4. NAD+ metabolism, a therapeutic target for age-related metabolic disease

    PubMed Central

    Auwerx, Johan

    2013-01-01

    Nicotinamide adenine dinucleotide (NAD) is a central metabolic cofactor by virtue of its redox capacity, and as such regulates a wealth of metabolic transformations. However, the identification of the longevity protein Sir2, the founding member of the sirtuin protein family, as being NAD+-dependent reignited interest in this metabolite. The sirtuins (SIRT1-7 in mammals) utilize NAD+ to deacetylate proteins in different subcellular compartments with a variety of functions, but with a strong convergence on optimizing mitochondrial function. Since cellular NAD+ levels are limiting for sirtuin activity, boosting its levels is a powerful means to activate sirtuins as a potential therapy for mitochondrial, often age-related, diseases. Indeed, supplying excess precursors, or blocking its utilization by PARP enzymes or CD38/CD157, boosts NAD+ levels, activates sirtuins and promotes healthy aging. Here, we discuss the current state of knowledge of NAD+ metabolism, primarily in relation to sirtuin function. We highlight how NAD+ levels change in diverse physiological conditions, and how this can be employed as a pharmacological strategy. PMID:23742622

  5. Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

    PubMed Central

    Ceni, Elisabetta; Mello, Tommaso; Galli, Andrea

    2014-01-01

    Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Although the pathogenesis of alcoholic liver disease (ALD) involves complex and still unclear biological processes, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species (ROS) play a preeminent role in the clinical and pathological spectrum of ALD. Ethanol oxidative metabolism influences intracellular signaling pathways and deranges the transcriptional control of several genes, leading to fat accumulation, fibrogenesis and activation of innate and adaptive immunity. Acetaldehyde is known to be toxic to the liver and alters lipid homeostasis, decreasing peroxisome proliferator-activated receptors and increasing sterol regulatory element binding protein activity via an AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK activation by ROS modulates autophagy, which has an important role in removing lipid droplets. Acetaldehyde and aldehydes generated from lipid peroxidation induce collagen synthesis by their ability to form protein adducts that activate transforming-growth-factor-β-dependent and independent profibrogenic pathways in activated hepatic stellate cells (HSCs). Furthermore, activation of innate and adaptive immunity in response to ethanol metabolism plays a key role in the development and progression of ALD. Acetaldehyde alters the intestinal barrier and promote lipopolysaccharide (LPS) translocation by disrupting tight and adherent junctions in human colonic mucosa. Acetaldehyde and LPS induce Kupffer cells to release ROS and proinflammatory cytokines and chemokines that contribute to neutrophils infiltration. In addition, alcohol consumption inhibits natural killer cells that are cytotoxic to HSCs and thus have an important antifibrotic function in the liver. Ethanol metabolism may also interfere with cell

  6. Sleep deficits but no metabolic deficits in premanifest Huntington's disease

    PubMed Central

    Panin, Francesca; Goodman, Anna O. G.; Lazic, Stanley E.; Lazar, Zsolt I.; Mason, Sarah L.; Rogers, Lorraine; Murgatroyd, Peter R.; Watson, Laura P. E.; Singh, Priya; Borowsky, Beth; Shneerson, John M.; Barker, Roger A.

    2015-01-01

    Objective Huntington disease (HD) is a fatal autosomal dominant, neurodegenerative condition characterized by progressively worsening motor and nonmotor problems including cognitive and neuropsychiatric disturbances, along with sleep abnormalities and weight loss. However, it is not known whether sleep disturbances and metabolic abnormalities underlying the weight loss are present at a premanifest stage. Methods We performed a comprehensive sleep and metabolic study in 38 premanifest gene carrier individuals and 36 age‐ and sex‐matched controls. The study consisted of 2 weeks of actigraphy at home, 2 nights of polysomnography and multiple sleep latency tests in the laboratory, and body composition assessment using dual energy x‐ray absorptiometry scanning with energy expenditure measured over 10 days at home by doubly labeled water and for 36 hours in the laboratory by indirect calorimetry along with detailed cognitive and clinical assessments. We performed a principal component analyses across all measures within each studied domain. Results Compared to controls, premanifest gene carriers had more disrupted sleep, which was best characterized by a fragmented sleep profile. These abnormalities, as well as a theta power (4–7Hz) decrease in rapid eye movement sleep, were associated with disease burden score. Objectively measured sleep problems coincided with the development of cognitive, affective, and subtle motor deficits and were not associated with any metabolic alterations. Interpretation The results show that among the earliest abnormalities in premanifest HD is sleep disturbances. This raises questions as to where the pathology in HD begins and also whether it could drive some of the early features and even possibly the pathology. Ann Neurol 2015;78:630–648 PMID:26224419

  7. Assessing inflammatory bowel disease-associated antibodies in Caucasian and First Nations cohorts

    PubMed Central

    Bernstein, Charles N; El-Gabalawy, Hani; Sargent, Michael; Landers, Carol J; Rawsthorne, Patricia; Elias, Brenda; Targan, Stephan R

    2011-01-01

    BACKGROUND: First Nation populations in Canada have a very low incidence of inflammatory bowel disease (IBD). Based on typical infections in this population, it is plausible that the First Nations react differently to microbial antigens with a different antibody response pattern, which may shed some light as to why they experience a low rate of IBD. OBJECTIVE: To compare the positivity rates of antibodies known to be associated with IBD in Canadian First Nations compared with a Canadian Caucasian population. METHODS: Subjects with Crohn’s disease, ulcerative colitis (UC), rheumatoid arthritis (RA) (as an immune disease control) and healthy controls without a personal or family history of chronic immune diseases, were enrolled in a cohort study aimed to determine differences between First Nations and Caucasians with IBD or RA. Serum from a random sample of these subjects (n=50 for each of First Nations with RA, First Nations controls, Caucasians with RA, Caucasians with Crohn’s disease, Caucasians with UC and Caucasians controls, and as many First Nations with either Crohn’s disease or UC as could be enrolled) was analyzed in the laboratory for the following antibodies: perinuclear antineutrophil cytoplasmic antibody (pANCA), and four Crohn’s disease-associated antibodies including anti-Saccharomyces cerevisiae, the outer membrane porin C of Escherichia coli, I2 – a fragment of bacterial DNA associated with Pseudomonas fluorescens, and the bacterial flagellin CBir-1. The rates of positive antibody responses and mean titres among positive results were compared. RESULTS: For pANCA, First Nations had a positivity rate of 55% in those with UC, 32% in healthy controls and 48% in those with RA. The pANCA positivity rate was 32% among Caucasians with RA. The rates of the Crohn’s disease-associated antibodies for the First Nations and Caucasians were comparable. Among First Nations, up to one in four healthy controls were positive for any one of the Crohn

  8. The appraisal of chronic stress and the development of the metabolic syndrome: a systematic review of prospective cohort studies.

    PubMed

    Bergmann, N; Gyntelberg, F; Faber, J

    2014-06-01

    Chronic psychosocial stress has been proposed as a risk factor for the development of the metabolic syndrome (MES). This review gives a systematic overview of prospective cohort studies investigating chronic psychosocial stress as a risk factor for incident MES and the individual elements of MES. Thirty-nine studies were included. An association between chronic psychosocial stress and the development of MES was generally supported. Regarding the four elements of MES: i) weight gain: the prospective studies supported etiological roles for relationship stress, perceived stress, and distress, while the studies on work-related stress (WS) showed conflicting results; ii) dyslipidemi: too few studies on psychosocial stress as a risk factor for dyslipidemia were available to draw a conclusion; however, a trend toward a positive association was present; iii) type 2 diabetes mellitus (DM2): prospective studies supported perceived stress and distress as risk factors for the development of DM2 among men, but not among women, while WS was generally not supported as a risk factor among neither men nor women; iv) hypertension: marital stress and perceived stress might have an influence on blood pressure (BP), while no association was found regarding distress. Evaluating WS the results were equivocal and indicated that different types of WS affected the BP differently between men and women. In conclusion, a longitudinal association between chronic psychosocial stress and the development of MES seems present. However, the number of studies with sufficient quality is limited and the design of the studies is substantially heterogeneous.

  9. Chronic Obstructive Pulmonary Disease is associated with risk of Chronic Kidney Disease: A Nationwide Case-Cohort Study

    PubMed Central

    Chen, Chung-Yu; Liao, Kuang-Ming

    2016-01-01

    Patients with chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD) share common risk factors. However, there is limited information about COPD and CKD. This is case-cohort study was carried out using the Taiwanese National Health Insurance Research Database to evaluate the correlation between COPD and CKD. We identified cases aged older than 40 years who had an inpatient hospitalization with a first-time COPD diagnosis between 1998 and 2008. Control were selected from hospitalized patients without COPD or CKD and were matched according to age, gender, and year of admission at a 2:1 ratio. Cox proportional hazards model was used to assess the association of CKD and COPD. The overall incidence of CKD was higher in the COPD group (470.9 per 104 person-years) than in the non-COPD group (287.52 per 104 person-years). The adjusted hazard ratio of case was 1.61 (P < 0.0001) times that of control. COPD was found to be associated with kidney disease from our follow-up. To detect CKD early, early diagnosis of CKD in patients with COPD and prompt initiation of monitoring and treatment are imperative. PMID:27166152

  10. Inhaled Corticosteroids Increase the Risk of Pneumonia in Patients With Chronic Obstructive Pulmonary Disease: A Nationwide Cohort Study.

    PubMed

    Lee, Ming-Chia; Lee, Chih-Hsin; Chien, Shu-Chen; Chang, Jer-Hwa; She, Han-Lin; Wang, Jann-Yuan; Yu, Ming-Chih

    2015-10-01

    The association of inhaled corticosteroids (ICS) and pneumonia in patients with chronic obstructive pulmonary disease (COPD) is still controversial.From the National Health Insurance Database of Taiwan, COPD cases with history of acute exacerbation (AE) were identified (COPD cohort). Time-dependent Cox regression analysis was applied to investigate the risk factors for pneumonia with COPD severity controlled by surrogate variables. Among the COPD cohort, those who continuously used ICS for more than 360 days without interruption were selected (ICS cohort). The incidence rate of pneumonia during ICS use was compared with those before ICS use and after ICS discontinuation by using pair t test.A total of 6034 and 842 cases were identified as the COPD and ICS cohorts, respectively. In the COPD cohort, recent ICS use was independently associated with pneumonia (hazard ratio: 1.06 [1.02-1.11] for per 80 mg of budesonide). Other independent risk factors included age, male, diabetes mellitus, malignancy, low income, baseline pneumonia event, and recent use of oral corticosteroids and aminophylline. In the ICS cohort, while AE rate gradually decreased, the incidence rate of pneumonia significantly increased after ICS use (from 0.10 to 0.21 event/person-year, P = 0.001).This study demonstrates the association between ICS use and pneumonia in patients with COPD and history of AE. ICS should be judiciously used in indicated COPD patients.

  11. Metabolic syndrome and the risk of bone fractures: A Meta-analysis of prospective cohort studies.

    PubMed

    Yang, Libo; Lv, Xiaohong; Wei, Dailin; Yue, Feng; Guo, Jinying; Zhang, Tie

    2016-03-01

    Increasing evidence has suggested an association between metabolic syndrome (MetS) and bone fractures. However, because of controversial results it is still not clear whether this effect is protective or detrimental. Therefore, we conducted a meta-analysis of prospective studies to assess the association between them. Pertinent studies were identified by searching PubMed and EMBASE databases until the end of July 2015. Summary relative risks (RRs) and 95% confidence intervals (CIs) for associations between MetS and fracture risk were estimated with random effects models. Our meta-analysis included five prospective studies. The summarized RRs of any type of fractures for MetS were 0.76 (95%CI: 0.59-0.97, P = 0.026) with moderate heterogeneity (I(2) = 63.80%, P = 0.064). Notably, subgroup analyses by gender showed that significant inverse associations were observed only in men (summarized RR = 0.66; 95%CI = 0.51-0.86, P = 0.002; I(2) = 27.90%, P = 0.235; n = 5) but not in women (summarized RR = 0.96, 95%CI: 0.60-1.54, P = 0.866; I(2) = 83.40%, P = 0.002; n = 3). However, the difference of the pooled RRs from the two subgroups did not reach statistical significance with a test of interaction (p = 0.179 for the interaction test). When pooling the RRs of non-vertebral fractures, significant inverse associations were similarly observed in men (RR = 0.72, 95%CI: 0.52-0.99, P = 0.048) but not in women (RR = 0.99, 95%CI: 0.60-1.64, P = 0.969). There was no evidence of publication bias. Our findings demonstrated that MetS was significantly associated with a lower fracture risk. There might be gender differences in the relationship of MetS with fractures, but further confirmation is needed.

  12. [Pathological and metabolic bone diseases: Clinical importance for fracture treatment].

    PubMed

    Oheim, R

    2015-12-01

    Pathological and metabolic bone diseases are common and relevant occurrences in orthopedics and trauma surgery; however, fractures are often treated as being the illness itself and not seen as the symptom of an underlying bone disease. This is why further diagnostics and systemic treatment options are often insufficiently considered in the routine treatment of fractures. This review focuses on osteoporosis, osteopetrosis, hypophosphatasia and Paget's disease of bone.In patients with osteoporotic vertebral or proximal femur fractures, pharmaceutical treatment to prevent subsequent fractures is an integral part of fracture therapy together with surgical treatment. Osteopetrosis is caused by compromised osteoclastic bone resorption; therefore, even in the face of an elevated bone mass, vitamin D3 supplementation is crucial to avoid clinically relevant hypocalcemia. Unspecific symptoms of the musculoskeletal system, especially together with stress fractures, are typically found in patients suffering from hypophosphatasia. In these patients measurement of alkaline phosphatase shows reduced enzyme activity. Elevated levels of alkaline phosphatase are found in Paget's disease of bone where bisphosphonates are still the treatment of choice.

  13. Relationships of physical fitness and obesity with metabolic risk factors in children and adolescents: Chungju city cohort study

    PubMed Central

    Kim, Hyo Jin; Lee, Kyu-Jin; Jeon, Yeon Jin; Ahn, Moon Bae; Jung, In Ah; Kim, Shin Hee; Cho, Won-Kyoung; Cho, Kyoung Soon; Park, So Hyun; Jung, Min Ho

    2016-01-01

    Purpose The purpose of this study was to investigate the relationships of physical fitness and obesity with metabolic risk factors in children and adolescents. Methods This cohort study was conducted in Chungju city, South Korea. Total 843 subjects were enrolled, including 193 elementary school 4th grade male (E4M), 189 elementary school 4th grade female (E4F) and 461 male-middle school students (M1M). The subjects were also classified into 2 groups by body mass index; normal weight (NW) group and overweight included obesity (OW/OB) group. Physical fitness was measured by shuttle run (cardiorespiratory fitness, CRF), sit and reach (flexibility), handgrip strength (muscular strength) and stand long jump (agility). Results The prevalence of OW/OB was respectively 33.7% (65 of 193) among E4M, 28.6% (54 of 189) among E4F, and 28.0% (129 of 461) among M1M. Hematocrit, white blood cell, triglyceride, low-density lipoprotein, insulin, homeostasis model assessment of insulin resistance, systolic and diastolic blood pressure were higher, while high-density lipoprotein were lower in the OW/OB group than in the NW group. The OW/OB group presented significantly lower CRF (P<0.01) and lower agility, but higher muscular strength compared with NW group. CRF was negatively correlated with obesity indices and metabolic risk factors. After adjustments for potential confounders, odds ratios for 4th–5th grade CRF of OW/OB compared NW in the E4M, E4F, M1M, were 7.38 (95 % CI, 3.24–16.83), 4.10 (95% CI, 1.83–9.18), 16.06 (95% CI, 8.23–31.00) (P<0.01). Conclusion Our study has shown that CRF has negative correlation with OW/OB in children and adolescents of Chungju city. We suggest that improvement of CRF through regular physical activity would be an important method for reducing the metabolic risks of childhood obesity. PMID:27104177

  14. Risk of Peripheral Arterial Occlusive Disease in Patients With Systemic Lupus Erythematosus: A Nationwide Population-Based Cohort Study.

    PubMed

    Chuang, Ya-Wen; Yu, Mei-Ching; Lin, Cheng-Li; Yu, Tung-Min; Shu, Kuo-Hsiung; Kao, Chia-Hung

    2015-11-01

    Systemic lupus erythematosus (SLE) is associated with atherosclerosis, but the relationship between SLE and peripheral arterial occlusive disease (PAOD) remains unclear. We sought to investigate this relationship by comparing cardiovascular complications in patients with and without SLE.Data on patients from 2000 to 2011 were collected from the National Health Insurance Research Database of Taiwan. The SLE cohort was frequency-matched according to age, sex, and history of diabetes mellitus (DM) with patients without SLE (control cohort). We evaluated the risk of cardiovascular complications, including hypertension, DM, stroke, chronic obstructive pulmonary disease, heart failure, coronary artery disease, and hyperlipidemia.The study included 10,144 patients with SLE and 10,144 control patients. The incidence of PAOD was 9.39-fold higher (95% confidence interval [CI] = 7.70-11.15) in the SLE cohort than in the non-SLE cohort. Moreover, SLE was an independent risk factor for PAOD. The adjusted risk of PAOD was highest in patients with SLE who were aged ≤34 years (hazard ratio = 47.6, 95% CI = 26.8-84.4). The risk of PAOD was highest during the first year of follow-up and decreased over time.Patients with SLE exhibit a higher incidence and an independently higher risk of PAOD compared with the general population. The PAOD risk is markedly elevated in patients with SLE who are young and in whom the disease is at an early stage. PMID:26579830

  15. Trends in U.S. Adult Chronic Disease Mortality, 1960–1999: Age, Period, and Cohort Variations

    PubMed Central

    YANG, YANG

    2008-01-01

    In this paper, I examine temporal changes in U.S. adult mortality by chronic disease cause of death and by sex over a 40-year period in the second half of the twentieth century. I apply age-period-cohort (APC) analyses that combine conventional approaches and a new method of model estimation to simultaneously account for age, period, and cohort variations in mortality rates for four leading causes of deaths, including heart disease, stroke, lung cancer, and breast cancer. The results show that large reductions in mortality since the late 1960s continued well into the late 1990s and that these reductions were predominately contributed by cohort effects. Cohort effects are found to differ by specific causes of death examined, but they generally show substantial survival improvements. Implications of these results are discussed with regard to demographic theories of mortality reductions, differential cohort accumulation of health capital and lifetime exposures to socioeconomic and behavioral risk factors, and period changes in diagnostic techniques and medical treatment. PMID:18613487

  16. Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes

    PubMed Central

    May, Patrick; Thiele, Holger; Lehesjoki, Anna-Elina; Schwarz, Günter; Riesch, Erik; Ikram, M. Arfan; van Duijn, Cornelia M.; Uitterlinden, Andre G.; Hofman, Albert; Steinböck, Hannelore; Gruber-Sedlmayr, Ursula; Neophytou, Birgit; Zara, Federico; Hahn, Andreas; Gormley, Padhraig; Becker, Felicitas; Weber, Yvonne G.; Cilio, Maria Roberta; Kunz, Wolfram S.; Krause, Roland; Zimprich, Fritz; Lemke, Johannes R.; Nürnberg, Peter; Sander, Thomas; Lerche, Holger; Neubauer, Bernd A.

    2016-01-01

    Objective The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic. Methods We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients. Results and Interpretation We identified 8 known missense mutations, previously reported as pathogenic, in a total of 17 unrelated epilepsy patients (17/448; 3.80%). Our re-evaluation indicates that 7 out of these 8 variants (p.R27T; p.R28C; p.R542Q; p.R604H; p.T1250M; p.E1308D; p.R1928G; NP_001159435.1) are not pathogenic. Only the p.T1174S mutation may be considered as a genetic risk factor for epilepsy of small effect size based on the enrichment in patients (P = 6.60 x 10−4; OR = 0.32, fishers exact test), previous functional studies but incomplete penetrance. Thus, incorporation of previous studies in genetic counseling of SCN1A sequencing results is challenging and may produce incorrect conclusions. PMID:26990884

  17. Food environment, walkability, and public open spaces are associated with incident development of cardio-metabolic risk factors in a biomedical cohort.

    PubMed

    Paquet, Catherine; Coffee, Neil T; Haren, Matthew T; Howard, Natasha J; Adams, Robert J; Taylor, Anne W; Daniel, Mark

    2014-07-01

    We investigated whether residential environment characteristics related to food (unhealthful/healthful food sources ratio), walkability and public open spaces (POS; number, median size, greenness and type) were associated with incidence of four cardio-metabolic risk factors (pre-diabetes/diabetes, hypertension, dyslipidaemia, abdominal obesity) in a biomedical cohort (n=3205). Results revealed that the risk of developing pre-diabetes/diabetes was lower for participants in areas with larger POS and greater walkability. Incident abdominal obesity was positively associated with the unhealthful food environment index. No associations were found with hypertension or dyslipidaemia. Results provide new evidence for specific, prospective associations between the built environment and cardio-metabolic risk factors.

  18. Peptic Ulcer Disease in Healthcare Workers: A Nationwide Population-Based Cohort Study.

    PubMed

    Lin, Hong-Yue; Weng, Shih-Feng; Lin, Hung-Jung; Hsu, Chien-Chin; Wang, Jhi-Joung; Su, Shih-Bin; Guo, How-Ran; Huang, Chien-Cheng

    2015-01-01

    Health care workers (HCWs) in Taiwan have heavy, stressful workloads, are on-call, and have rotating nightshifts, all of which might contribute to peptic ulcer disease (PUD). We wanted to evaluate the PUD risk in HCWs, which is not clear. Using Taiwan's National Health Insurance Research Database, we identified 50,226 physicians, 122,357 nurses, 20,677 pharmacists, and 25,059 other HCWs (dieticians, technicians, rehabilitation therapists, and social workers) as the study cohort, and randomly selected an identical number of non-HCW patients (i.e., general population) as the comparison cohort. Conditional logistical regression analysis was used to compare the PUD risk between them. Subgroup analysis for physician specialties was also done. Nurses and other HCWs had a significantly higher PUD risk than did the general population (odds ratio [OR]: 1.477; 95% confidence interval [CI]: 1.433-1.521 and OR: 1.328; 95% CI: 1.245-1.418, respectively); pharmacists had a lower risk (OR: 0.884; 95% CI: 0.828-0.945); physicians had a nonsignificantly different risk (OR: 1.029; 95% CI: 0.987-1.072). In the physician specialty subgroup analysis, internal medicine, surgery, Ob/Gyn, and family medicine specialists had a higher PUD risk than other physicians (OR: 1.579; 95% CI: 1.441-1.731, OR: 1.734; 95% CI: 1.565-1.922, OR: 1.336; 95% CI: 1.151-1.550, and OR: 1.615; 95% CI: 1.425-1.831, respectively). In contrast, emergency physicians had a lower risk (OR: 0.544; 95% CI: 0.359-0.822). Heavy workloads, long working hours, workplace stress, rotating nightshifts, and coping skills may explain our epidemiological findings of higher risks for PUD in some HCWs, which might help us improve our health policies for HCWs. PMID:26301861

  19. Sex differences in the outcomes of peripheral arterial disease: a population-based cohort study

    PubMed Central

    Hussain, Mohamad A.; Lindsay, Thomas F.; Mamdani, Muhammad; Wang, Xuesong; Verma, Subodh; Al-Omran, Mohammed

    2016-01-01

    Background: The role of sex in the outcomes of patients with peripheral arterial disease (PAD) has been poorly studied. We sought to investigate differences in the long-term adverse cardiovascular and limb outcomes between men and women with PAD. Methods: We conducted a population-based cohort study with up to 7 years of follow-up using linked administrative databases in Ontario, Canada. Patients aged 40 years or older who visited a vascular surgeon between Apr. 1, 2004, and Mar. 31, 2007 (index date), and carried a diagnosis of PAD comprised the study cohort. The primary outcome was a composite of death or hospital admission for stroke or myocardial infarction. Secondary outcomes included lower limb amputation or revascularization. We used Cox proportional hazards modelling to compute unadjusted hazard ratios (HRs) and HRs adjusted for baseline covariates. Results: A total of 6915 patients were studied, of whom 2461 (35.6%) were women. No significant differences in the risk of the primary outcome were observed between men and women (adjusted HR 0.99 [95% confidence interval (CI) 0.92-1.05]). Women were less likely than men to undergo minor amputation (adjusted HR 0.73 [95% CI 0.62-0.85]) and arterial bypass surgery (adjusted HR 0.82 [95% CI 0.71-0.94]) but were more likely to be admitted to hospital for acute myocardial infarction (adjusted HR 1.15 [95% CI 1.00-1.31]). There were no sex differences in the rates of major amputation or transluminal percutaneous angioplasty. Interpretation: We identified no significant differences in the composite risk of major adverse cardiovascular events between women and men with PAD, although our findings suggest men may be at increased risk for adverse limb events compared with women. Cardiovascular health campaigns should focus on both women and men to promote early diagnosis and management of PAD. PMID:27280110

  20. Metabolic Effects Associated with ICS in Patients with COPD and Comorbid Type 2 Diabetes: A Historical Matched Cohort Study

    PubMed Central

    Price, David B.; Burden, Anne; Skinner, Derek; Mikkelsen, Helga; Ding, Cherlyn; Brice, Richard; Chavannes, Niels H.; Kocks, Janwillem W. H.; Stephens, Jeffrey W.; Haughney, John

    2016-01-01

    Background Management guidelines for chronic obstructive pulmonary disease (COPD) recommend that inhaled corticosteroids (ICS) are prescribed to patients with the most severe symptoms. However, these guidelines have not been widely implemented by physicians, leading to widespread use of ICS in patients with mild-to-moderate COPD. Of particular concern is the potential risk of worsening diabetic control associated with ICS use. Here we investigate whether ICS therapy in patients with COPD and comorbid type 2 diabetes mellitus (T2DM) has a negative impact on diabetic control, and whether these negative effects are dose-dependent. Methods and Findings This was a historical matched cohort study utilising primary care medical record data from two large UK databases. We selected patients aged ≥40 years with COPD and T2DM, prescribed ICS (n = 1360) or non-ICS therapy (n = 2642) between 2008 and 2012. The primary endpoint was change in HbA1c between the baseline and outcome periods. After 1:1 matching, each cohort consisted of 682 patients. Over the 12–18-month outcome period, patients prescribed ICS had significantly greater increases in HbA1c values compared with those prescribed non-ICS therapies; adjusted difference 0.16% (95% confidence interval [CI]: 0.05–0.27%) in all COPD patients, and 0.25% (95% CI: 0.10–0.40%) in mild-to-moderate COPD patients. Patients in the ICS cohort also had significantly more diabetes-related general practice visits per year and received more frequent glucose strip prescriptions, compared with those prescribed non-ICS therapies. Patients prescribed higher cumulative doses of ICS (>250 mg) had greater odds of increased HbA1c and/or receiving additional antidiabetic medication, and increased odds of being above the Quality and Outcomes Framework (QOF) target for HbA1c levels, compared with those prescribed lower cumulative doses (≤125 mg). Conclusion For patients with COPD and comorbid T2DM, ICS therapy may have a negative impact on

  1. Bone metabolism status and associated risk factors in elderly patients with chronic obstructive pulmonary disease (COPD).

    PubMed

    Xiaomei, Wang; Hang, Xiao; Lingling, Liu; Xuejun, Li

    2014-09-01

    The prevalence of osteoporosis in older patients with chronic obstructive pulmonary disease (COPD) is higher than in the age-matched elderly patients, but the exact cause in relation to COPD is not clear. We hypothesized that the underlying causes for this difference are related to bone metabolism with the possible risk factors that include the duration of COPD, GOLD grade, cor pulmonale, the frequencies of acute exacerbations within the past year, smoking and inhaled corticosteroid therapy. We conducted a matched-pair study of 100 patients aged older than 65 years at the Southwest Hospital from May to November 2012. The enrolled patients with COPD were matched to controls for age and gender. Clinical characteristics of cohorts were recorded. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry and osteoporosis was diagnosed according to the definition of WHO. All cohorts accepted bone metabolism marker measurement, including Procollagen type 1 aminoterminal propeptide (P1NP), β-C-telopeptides of type I collagen (βCTX), and N-terminal midmolecule fragment osteocalcin (N-MID OC). Statistical analysis was calculated using the student's t test, ANOVA and multiple regression analysis at a significance level set at a p < 0.05. Circulating biochemical markers of bone formation (P1NP), resorption (βCTX) and turnover (N-MID OC) were significantly lower in the COPD group than control group, while mean 25-OH Vitamin D was similar in two groups. The P1NP, βCTX, and N-MID OC were still lower in men with COPD, but only P1NP was lower in women with COPD compared to that of controls. Multiple regression analysis in COPD group suggests that age, the frequency of acute exacerbation, and BMD are independent risk factors for P1NP. The frequency of acute exacerbation within the past one year and 25-OH D level are independent risk factors for βCTX; the frequency of acute exacerbation is the only independent risk factor for N-MID OC. These were significant

  2. Can We Prevent Obesity-Related Metabolic Diseases by Dietary Modulation of the Gut Microbiota?

    PubMed

    Brahe, Lena K; Astrup, Arne; Larsen, Lesli H

    2016-01-01

    Obesity increases the risk of type 2 diabetes, cardiovascular diseases, and certain cancers, which are among the leading causes of death worldwide. Obesity and obesity-related metabolic diseases are characterized by specific alterations in the human gut microbiota. Experimental studies with gut microbiota transplantations in mice and in humans indicate that a specific gut microbiota composition can be the cause and not just the consequence of the obese state and metabolic disease, which suggests a potential for gut microbiota modulation in prevention and treatment of obesity-related metabolic diseases. In addition, dietary intervention studies have suggested that modulation of the gut microbiota can improve metabolic risk markers in humans, but a causal role of the gut microbiota in such studies has not yet been established. Here, we review and discuss the role of the gut microbiota in obesity-related metabolic diseases and the potential of dietary modulation of the gut microbiota in metabolic disease prevention and treatment. PMID:26773017

  3. Can We Prevent Obesity-Related Metabolic Diseases by Dietary Modulation of the Gut Microbiota?

    PubMed

    Brahe, Lena K; Astrup, Arne; Larsen, Lesli H

    2016-01-01

    Obesity increases the risk of type 2 diabetes, cardiovascular diseases, and certain cancers, which are among the leading causes of death worldwide. Obesity and obesity-related metabolic diseases are characterized by specific alterations in the human gut microbiota. Experimental studies with gut microbiota transplantations in mice and in humans indicate that a specific gut microbiota composition can be the cause and not just the consequence of the obese state and metabolic disease, which suggests a potential for gut microbiota modulation in prevention and treatment of obesity-related metabolic diseases. In addition, dietary intervention studies have suggested that modulation of the gut microbiota can improve metabolic risk markers in humans, but a causal role of the gut microbiota in such studies has not yet been established. Here, we review and discuss the role of the gut microbiota in obesity-related metabolic diseases and the potential of dietary modulation of the gut microbiota in metabolic disease prevention and treatment.

  4. Pyoderma gangrenosum among patients with inflammatory bowel disease: a descriptive cohort study

    PubMed Central

    Weizman, Adam V.; Huang, Brian; Targan, Stephan; Dubinsky, Marla; Fleshner, Phillip; Kaur, Manreet; Ippoliti, Andrew; Panikkath, Deepa; Vasiliauskas, Eric; Shih, David; McGovern, Dermot P.B.; Melmed, Gil Y.

    2016-01-01

    BACKGROUND Pyoderma gangrenosum (PG) is a severe extra-intestinal manifestation of inflammatory bowel disease (IBD). OBJECTIVE To better characterize PG features and management among an IBD cohort. METHODS Subjects with PG were identified using a large database at a tertiary center. Patient demographics and clinical characteristics were summarized using descriptive statistics. RESULTS 80 patients with an episode(s) of PG were identified, yielding an overall prevalence of 1.9%. Overall, 93% of patients with PG had some degree of colonic involvement. Thirty-one (39%) patients required hospitalization for PG. Underlying bowel disease was active at the time of PG episode(s) in 52 (65%) patients. PG location was variable, with the lower extremity being the most common. Most patients (71.3%) required multiple therapies to achieve PG healing. CONCLUSIONS We have described one of the largest case series of PG among patients with IBD. The variety of treatment strategies used highlights the lack of clear guidelines in managing this complex group of patients. PMID:25277124

  5. Prevalence of mental health disorders in inflammatory bowel disease: an Australian outpatient cohort

    PubMed Central

    Tribbick, Davina; Salzberg, Michael; Ftanou, Maria; Connell, William R; Macrae, Finlay; Kamm, Michael A; Bates, Glen W; Cunningham, Georgina; Austin, David W; Knowles, Simon R

    2015-01-01

    Background This study aimed to characterize prevalence of anxiety and depressive conditions and uptake of mental health services in an Australian inflammatory bowel disease (IBD) outpatient setting. Methods Eighty-one IBD patients (39 males, mean age 35 years) attending a tertiary hospital IBD outpatient clinic participated in this study. Disease severity was evaluated according to the Manitoba Index. Diagnosis of an anxiety or depressive condition was based upon the Mini-International Neuropsychiatric Interview and the Hospital Anxiety and Depression Scale. Results Based on Hospital Anxiety and Depression Scale subscale scores >8 and meeting Mini-International Neuropsychiatric Interview criteria, 16 (19.8%) participants had at least one anxiety condition, while nine (11.1%) had a depressive disorder present. Active IBD status was associated with higher prevalence rates across all anxiety and depressive conditions. Generalized anxiety was the most common (12 participants, 14.8%) anxiety condition, and major depressive disorder (recurrent) was the most common depressive condition reported (five participants, 6.2%). Seventeen participants (21%) reported currently seeking help for mental health issues while 12.4% were identified has having at least one psychological condition but not seeking treatment. Conclusion We conclude that rates of anxiety and depression are high in this cohort, and that IBD-focused psychological services should be a key component of any holistic IBD service, especially for those identified as having active IBD. PMID:26213474

  6. Systematic validation of disease models for pharmacoeconomic evaluations. Swiss HIV Cohort Study.

    PubMed

    Sendi, P P; Craig, B A; Pfluger, D; Gafni, A; Bucher, H C

    1999-08-01

    Pharmacoeconomic evaluations are often based on computer models which simulate the course of disease with and without medical interventions. The purpose of this study is to propose and illustrate a rigorous approach for validating such disease models. For illustrative purposes, we applied this approach to a computer-based model we developed to mimic the history of HIV-infected subjects at the greatest risk for Mycobacterium avium complex (MAC) infection in Switzerland. The drugs included as a prophylactic intervention against MAC infection were azithromycin and clarithromycin. We used a homogenous Markov chain to describe the progression of an HIV-infected patient through six MAC-free states, one MAC state, and death. Probability estimates were extracted from the Swiss HIV Cohort Study database (1993-95) and randomized controlled trials. The model was validated testing for (1) technical validity (2) predictive validity (3) face validity and (4) modelling process validity. Sensitivity analysis and independent model implementation in DATA (PPS) and self-written Fortran 90 code (BAC) assured technical validity. Agreement between modelled and observed MAC incidence confirmed predictive validity. Modelled MAC prophylaxis at different starting conditions affirmed face validity. Published articles by other authors supported modelling process validity. The proposed validation procedure is a useful approach to improve the validity of the model. PMID:10461580

  7. Unfavourable cardiovascular disease risk profiles in a cohort of Dutch and British haemophilia patients.

    PubMed

    Fransen van de Putte, Dietje E; Fischer, Kathelijn; Makris, Michael; Tait, R Campbell; Chowdary, Pratima; Collins, Peter W; Meijer, Karina; Roosendaal, Goris; Schutgens, Roger E G; Mauser-Bunschoten, Eveline P

    2013-01-01

    Cardiovascular disease (CVD) mortality is reported to be decreased in haemophilia patients, but reports on the prevalence of CVD risk factors are conflicting. A cross-sectional assessment of CVD risk profiles was performed in a large cohort of haemophilia patients. Baseline data on CVD risk factors of 709 Dutch and UK haemophilia patients aged ≥30 years were analysed and compared with the general age-matched male population. CVD risk profiles were assessed using the QRISK®2-2011 and SCORE algorithms. Although QRISK® 2 was only validated in the UK, comparison with SCORE indicated similar properties of QRISK®2 in both Dutch and UK patients (correlation 0.86). Mean age was 49.8 years. Hypertension was more common in haemophilia patients than in the general population (49% vs. 40%), while the prevalences of obesity and hypercholesterolaemia were lower (15 vs. 20% and 44 vs. 68%, respectively), and those of diabetes and smoking were similar. The predicted 10-year QRISK®2 risk was significantly higher in haemophilia patients than in the general population (8.9 vs. 6.7%), indicating more unfavourable cardiovascular disease risk profiles. This increased risk became apparent after the age of 40 years. Our results indicate an increased prevalence of hypertension and overall more unfavourable CVD risk profiles in haemophilia patients compared with the general age-matched male population.

  8. Dietary Inflammatory Index and Incidence of Cardiovascular Disease in the SUN Cohort

    PubMed Central

    Ramallal, Raúl; Toledo, Estefanía; Martínez-González, Miguel A.; Hernández-Hernández, Aitor; García-Arellano, Ana; Shivappa, Nitin; Hébert, James R.; Ruiz-Canela, Miguel

    2015-01-01

    Background Diet is known to play a key role in atherogenesis and in the development of cardiovascular events. Dietary factors may mediate these processes acting as potential modulators of inflammation. Potential Links between inflammatory properties of diet and the occurrence of cardiovascular events have not been tested previously. Objective We aimed to assess the association between the dietary inflammatory index (DII), a method to assess the inflammatory potential of the diet, and incident cardiovascular disease. Methods In the prospective, dynamic SUN cohort, 18,794 middle-aged, Spanish university graduates were followed up for 8.9 years (median). A validated 136-item food-frequency questionnaire was used to calculate the DII. The DII is based on scientific evidence about the relationship between diet and inflammatory biomarkers (C-reactive protein, IL-1β, IL-4, IL-6, IL-10 and TNF-α). Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between the DII and incident cardiovascular disease (myocardial infarction, stroke or cardiovascular death). Results The risk for cardiovascular events progressively increased with each increasing quartile of DII (ptrend = 0.017). The multivariable-adjusted HR for participants in the highest (most pro-inflammatory) vs. the lowest quartile of the DII was 2.03 (95% CI 1.06–3.88). Conclusions A pro-inflammatory diet was associated with a significantly higher risk for developing cardiovascular events. PMID:26340022

  9. Proteinuria as a Therapeutic Target in Advanced Chronic Kidney Disease: a Retrospective Multicenter Cohort Study

    PubMed Central

    Chen, Chang-Hsu; Wu, Hon-Yen; Wang, Chieh-Li; Yang, Feng-Jung; Wu, Pei-Chen; Hung, Szu-Chun; Kan, Wei-Chih; Yang, Chung-Wei; Chiang, Chih-Kang; Huang, Jenq-Wen; Hung, Kuan-Yu

    2016-01-01

    Current evidence of proteinuria reduction as a surrogate target in advanced chronic kidney disease (CKD) is incomplete due to lack of patient-pooled database. We retrospectively studied a multicenter cohort of 1891 patients who were enrolled in the nationwide multidisciplinary pre-end stage renal disease care program with a baseline glomerular filtration rate (GFR) <45 mL/min/1.73 m2 and followed longitudinally to investigate the effect of the change in proteinuria on renal death (defined as composite of dialysis and death occurring before initiation of dialysis). The group with a change in proteinuria ≤0.30 g/g (n = 1261) had lower cumulative probabilities of renal death (p < 0.001). In a linear regression model, a higher baseline proteinuria and a greater increase in proteinuria were associated with faster annual GFR decline. Cox’s analysis showed that every 1 unit increase in natural log(baseline proteinuria, 10 g/g) and every 0.1 g/g increase in the change in proteinuria resulted in 67% (HR = 1.67, 95% CI: 1.46–1.91) and 1% (HR = 1.01, 95% CI: 1.01–1.01) greater risk of renal death respectively after adjusting for the effects of the other covariates. Our study provided a patient-based evidence to support proteinuria as a therapeutic target in advanced CKD. PMID:27198863

  10. Pneumococcal Serotypes and Mortality following Invasive Pneumococcal Disease: A Population-Based Cohort Study

    PubMed Central

    Harboe, Zitta B.; Thomsen, Reimar W.; Riis, Anders; Valentiner-Branth, Palle; Christensen, Jens Jørgen; Lambertsen, Lotte; Krogfelt, Karen A.; Konradsen, Helle B.; Benfield, Thomas L.

    2009-01-01

    Background Pneumococcal disease is a leading cause of morbidity and mortality worldwide. The aim of this study was to investigate the association between specific pneumococcal serotypes and mortality from invasive pneumococcal disease (IPD). Methods and Findings In a nationwide population-based cohort study of IPD in Denmark during 1977–2007, 30-d mortality associated with pneumococcal serotypes was examined by multivariate logistic regression analysis after controlling for potential confounders. A total of 18,858 IPD patients were included. Overall 30-d mortality was 18%, and 3% in children younger than age 5 y. Age, male sex, meningitis, high comorbidity level, alcoholism, and early decade of diagnosis were significantly associated with mortality. Among individuals aged 5 y and older, serotypes 31, 11A, 35F, 17F, 3, 16F, 19F, 15B, and 10A were associated with highly increased mortality as compared with serotype 1 (all: adjusted odds ratio ≥3, p<0.001). In children younger than 5 y, associations between serotypes and mortality were different than in adults but statistical precision was limited because of low overall childhood-related mortality. Conclusions Specific pneumococcal serotypes strongly and independently affect IPD associated mortality. PMID:19468297

  11. Frequency distribution of gastro esophageal reflux disease in inhalation injury: A historical cohort study

    PubMed Central

    Karbasi, Ashraf; Aliannejad, Rasoul; Ghanei, Mostafa; Sanamy, Mehran Noory; Alaeddini, Farshid; Harandi, Ali Amini

    2015-01-01

    Background: There is no data on the prevalence and the association of gastro esophageal reflux disease (GERD) with toxic fume inhalation. Therefore, we aimed to evaluate the frequency distribution of GERD symptoms among the individuals with mild respiratory disorder due to the past history of toxic fume exposure to sulfur mustard (SM). Materials and Methods: In a historical cohort study, subjects were randomly selected from 7000 patients in a database of all those who had a history of previous exposure to a single high dose of SM gas during war. The control group was randomly selected from adjacent neighbors of the patients, and two healthy male subjects were chosen per patient. In this study, we used the validated Persian translation of Mayo Gastroesophageal Reflux Questionnaire to assess the frequency distribution of reflux disease. Results: Relative frequency of GERD symptoms, was found to be significantly higher in the inhalation injury patients with an odds ratio of 8.30 (95% confidence interval [CI]: 4.73-14.55), and after adjustment for cigarette smoking, tea consumption, age, and body mass index, aspirin and chronic cough the odds ratio was found to be 4.41 (95% CI: 1.61-12.07). Conclusion: The most important finding of our study was the major GERD symptoms (heartburn and/or acid regurgitation once or more per week) among the individuals with the past history of exposure to SM toxic gas is substantially higher (4.4-fold) than normal populations. PMID:26622251

  12. Obesity, end-stage renal disease, and survival in an elderly cohort with cardiovascular disease.

    PubMed

    Lea, Janice P; Crenshaw, Daryl O; Onufrak, Stephen J; Newsome, Britt B; McClellan, William M

    2009-12-01

    Obesity is highly prevalent in African Americans and is associated with increased risk of End-Stage Renal Disease (ESRD) and death. It is not known if the effect of obesity is similar among blacks and whites. The aim of this study is to examine racial differences in the association of obesity with ESRD and survival in elderly patients (age >65). Data were obtained for 74,167 Medicare patients with acute myocardial infarction (AMI) between February 1994 and July 1995. BMI was calculated as weight (kg) divided by height (m(2)). We evaluated the association of BMI class with ESRD incidence and death using multivariable Cox proportional hazards models, testing for race-BMI interactions. Compared to whites, African Americans had higher BMI (26.9 vs. 26.0, P < 0.0001) and estimated glomerular filtration rate (72.4 ml/min/1.73 m(2) vs. 66.6 ml/min/1.73 m(2), P < 0.0001). Crude ESRD rates increased with increasing obesity among whites but not among blacks. However, after adjusting for age, sex, and other comorbidities, obesity was not associated with increased ESRD rate among blacks or whites and the interaction between race and BMI was not significant. Furthermore, for both races, patients classified as overweight, class 1 obese, or class 2 obese had similar, significantly better survival abilities compared to normal weight patients and the race BMI interaction was not significant. In conclusion, obesity does not increase risk of ESRD among black or white elderly subjects with cardiovascular disease (CVD). However, both obese blacks and whites, in this population, experience a survival benefit. Further studies need to explore this obesity paradox. PMID:19325542

  13. Understanding the Causes and Implications of Endothelial Metabolic Variation in Cardiovascular Disease through Genome-Scale Metabolic Modeling

    PubMed Central

    McGarrity, Sarah; Halldórsson, Haraldur; Palsson, Sirus; Johansson, Pär I.; Rolfsson, Óttar

    2016-01-01

    High-throughput biochemical profiling has led to a requirement for advanced data interpretation techniques capable of integrating the analysis of gene, protein, and metabolic profiles to shed light on genotype–phenotype relationships. Herein, we consider the current state of knowledge of endothelial cell (EC) metabolism and its connections to cardiovascular disease (CVD) and explore the use of genome-scale metabolic models (GEMs) for integrating metabolic and genomic data. GEMs combine gene expression and metabolic data acting as frameworks for their analysis and, ultimately, afford mechanistic understanding of how genetic variation impacts metabolism. We demonstrate how GEMs can be used to investigate CVD-related genetic variation, drug resistance mechanisms, and novel metabolic pathways in ECs. The application of GEMs in personalized medicine is also highlighted. Particularly, we focus on the potential of GEMs to identify metabolic biomarkers of endothelial dysfunction and to discover methods of stratifying treatments for CVDs based on individual genetic markers. Recent advances in systems biology methodology, and how these methodologies can be applied to understand EC metabolism in both health and disease, are thus highlighted. PMID:27148541

  14. Protein and leucine metabolism in maple syrup urine disease

    SciTech Connect

    Thompson, G.N.; Bresson, J.L.; Pacy, P.J.; Bonnefont, J.P.; Walter, J.H.; Leonard, J.V.; Saudubray, J.M.; Halliday, D. )

    1990-04-01

    Constant infusions of (13C)leucine and (2H5)phenylalanine were used to trace leucine and protein kinetics, respectively, in seven children with maple syrup urine disease (MSUD) and eleven controls matched for age and dietary protein intake. Despite significant elevations of plasma leucine (mean 351 mumol/l, range 224-477) in MSUD subjects, mean whole body protein synthesis (3.78 +/- 0.42 (SD) g.kg-1. 24 h-1) and catabolism (4.07 +/- 0.46) were similar to control values (3.69 +/- 0.50 and 4.09 +/- 0.50, respectively). The relationship between phenylalanine and leucine fluxes was also similar in MSUD subjects (mean phenylalanine-leucine flux ratio 0.35 +/- 0.07) and previously reported adult controls (0.33 +/- 0.02). Leucine oxidation was undetectable in four of the MSUD subjects and very low in the other three (less than 4 mumol.kg-1.h-1; controls 13-20). These results show that persistent elevation in leucine concentration has no effect on protein synthesis. The marked disturbance in leucine metabolism in MSUD did not alter the relationship between rates of catabolism of protein to phenylalanine and leucine, which provides further support for the validity of the use of a single amino acid to trace whole body protein metabolism. The minimal leucine oxidation in MSUD differs from findings in other inborn metabolic errors and indicates that in patients with classical MSUD there is no significant route of leucine disposal other than through protein synthesis.

  15. Microvesicles and exosomes: new players in metabolic and cardiovascular disease.

    PubMed

    Lawson, Charlotte; Vicencio, Jose M; Yellon, Derek M; Davidson, Sean M

    2016-02-01

    The past decade has witnessed an exponential increase in the number of publications referring to extracellular vesicles (EVs). For many years considered to be extracellular debris, EVs are now seen as novel mediators of endocrine signalling via cell-to-cell communication. With the capability of transferring proteins and nucleic acids from one cell to another, they have become an attractive focus of research for different pathological settings and are now regarded as both mediators and biomarkers of disease including cardio-metabolic disease. They also offer therapeutic potential as signalling agents capable of targeting tissues or cells with specific peptides or miRNAs. In this review, we focus on the role that microvesicles (MVs) and exosomes, the two most studied classes of EV, have in diabetes, cardiovascular disease, endothelial dysfunction, coagulopathies, and polycystic ovary syndrome. We also provide an overview of current developments in MV/exosome isolation techniques from plasma and other fluids, comparing different available commercial and non-commercial methods. We describe different techniques for their optical/biochemical characterization and quantitation. We also review the signalling pathways that exosomes and MVs activate in target cells and provide some insight into their use as biomarkers or potential therapeutic agents. In summary, we give an updated focus on the role that these exciting novel nanoparticles offer for the endocrine community.

  16. Does metabolic failure at the synapse cause Alzheimer's disease?

    PubMed

    Engel, Peter A

    2014-12-01

    Alzheimer's disease (AD) a neurodegenerative disorder of widely distributed cortical networks evolves over years while A beta (Aβ) oligomer neurotoxicity occurs within seconds to minutes. This disparity combined with disappointing outcomes of anti-amyloid clinical trials challenges the centrality of Aβ as principal mediator of neurodegeneration. Reconsideration of late life AD as the end-product of intermittent regional failure of the neuronal support system to meet the needs of vulnerable brain areas offers an alternative point of view. This model introduces four ideas: (1) That Aβ is a synaptic signaling peptide that becomes toxic in circumstances of metabolic stress. (2) That intense synaptic energy and maintenance requirements of cortical hubs may exceed resources during peak demand initiating a neurotoxic cascade in these selectively vulnerable regions. (3) That axonal transport to and from neuron soma cannot account fully for high mitochondrial densities and other requirements of distant terminal axons. (4) That neurons as specialists in information management, delegate generic support functions to astrocytes and other cell types. Astrocytes use intercellular transport by exosomes and tunneling nanotubes (TNTs) to deliver mitochondria, substrates and protein reprocessing services to axonal sites distant from neuronal soma. This viewpoint implicates the brain's support system and its disruption by various age and disease-related insults as significant mediators of neurodegenerative disease. A better understanding of this system should broaden concepts of neurodegeneration and facilitate development of effective treatments.

  17. Role of NADPH Oxidase in Metabolic Disease-Related Renal Injury: An Update

    PubMed Central

    Su, Hua

    2016-01-01

    Metabolic syndrome has been linked to an increased risk of chronic kidney disease. The underlying pathogenesis of metabolic disease-related renal injury remains obscure. Accumulating evidence has shown that NADPH oxidase is a major source of intrarenal oxidative stress and is upregulated by metabolic factors leading to overproduction of ROS in podocytes, endothelial cells, and mesangial cells in glomeruli, which is closely associated with the initiation and progression of glomerular diseases. This review focuses on the role of NADPH oxidase-induced oxidative stress in the pathogenesis of metabolic disease-related renal injury. Understanding of the mechanism may help find potential therapeutic strategies.

  18. Role of NADPH Oxidase in Metabolic Disease-Related Renal Injury: An Update.

    PubMed

    Wan, Cheng; Su, Hua; Zhang, Chun

    2016-01-01

    Metabolic syndrome has been linked to an increased risk of chronic kidney disease. The underlying pathogenesis of metabolic disease-related renal injury remains obscure. Accumulating evidence has shown that NADPH oxidase is a major source of intrarenal oxidative stress and is upregulated by metabolic factors leading to overproduction of ROS in podocytes, endothelial cells, and mesangial cells in glomeruli, which is closely associated with the initiation and progression of glomerular diseases. This review focuses on the role of NADPH oxidase-induced oxidative stress in the pathogenesis of metabolic disease-related renal injury. Understanding of the mechanism may help find potential therapeutic strategies. PMID:27597884

  19. Role of NADPH Oxidase in Metabolic Disease-Related Renal Injury: An Update

    PubMed Central

    Su, Hua

    2016-01-01

    Metabolic syndrome has been linked to an increased risk of chronic kidney disease. The underlying pathogenesis of metabolic disease-related renal injury remains obscure. Accumulating evidence has shown that NADPH oxidase is a major source of intrarenal oxidative stress and is upregulated by metabolic factors leading to overproduction of ROS in podocytes, endothelial cells, and mesangial cells in glomeruli, which is closely associated with the initiation and progression of glomerular diseases. This review focuses on the role of NADPH oxidase-induced oxidative stress in the pathogenesis of metabolic disease-related renal injury. Understanding of the mechanism may help find potential therapeutic strategies. PMID:27597884

  20. Alterations in metabolic properties in fibroblasts in Alzheimer disease.

    PubMed

    Sorbi, S; Piacentini, S; Latorraca, S; Piersanti, P; Amaducci, L

    1995-01-01

    Alzheimer disease (AD) leads to alterations in several biochemical properties in cultured skin fibroblasts. Because abnormal glucose metabolism has been reported in both in vivo and in vitro studies of the brain, we examined glucose and glutamine oxidation and lactate production in cultured skin fibroblasts from nine patients with familial AD, 19 with sporadic AD, and 20 age-matched controls. The production of CO2 from glucose and glutamine was significantly lower in both groups of Alzheimer fibroblasts compared to controls after 10 min or 1, 2, and 4 h of incubation. The reduction in CO2 production was most evident after 1 h of incubation with either (U-14C)-glucose or (U-14C)-glutamine. Lactate concentration was comparable in all groups at any time of incubation. These findings suggest that processes that require mitochondrial function as glucose or glutamine oxidation are altered in AD and provide evidence that complex metabolic differences are expressed in cultured nonneuronal cells from Alzheimer patients. PMID:7662326

  1. Evidence of altered phosphatidylcholine metabolism in Alzheimer's disease.

    PubMed

    Whiley, Luke; Sen, Arundhuti; Heaton, James; Proitsi, Petroula; García-Gómez, Diego; Leung, Rufina; Smith, Norman; Thambisetty, Madhav; Kloszewska, Iwona; Mecocci, Patrizia; Soininen, Hilkka; Tsolaki, Magda; Vellas, Bruno; Lovestone, Simon; Legido-Quigley, Cristina

    2014-02-01

    Abberant lipid metabolism is implicated in Alzheimer's disease (AD) pathophysiology, but the connections between AD and lipid metabolic pathways are not fully understood. To investigate plasma lipids in AD, a multiplatform screen (n = 35 by liquid chromatography-mass spectrometry and n = 35 by nuclear magnetic resonance) was developed, which enabled the comprehensive analysis of plasma from 3 groups (individuals with AD, individuals with mild cognitive impairment (MCI), and age-matched controls). This screen identified 3 phosphatidylcholine (PC) molecules that were significantly diminished in AD cases. In a subsequent validation study (n = 141), PC variation in a bigger sample set was investigated, and the same 3 PCs were found to be significantly lower in AD patients: PC 16:0/20:5 (p < 0.001), 16:0/22:6 (p < 0.05), and 18:0/22:6 (p < 0.01). A receiver operating characteristic (ROC) analysis of the PCs, combined with apolipoprotein E (ApoE) data, produced an area under the curve predictive value of 0.828. Confirmatory investigations into the background biochemistry indiciated no significant change in plasma levels of 3 additional PCs of similar structure, total choline containing compounds or total plasma omega fatty acids, adding to the evidence that specific PCs play a role in AD pathology. PMID:24041970

  2. Sirtuins: Novel targets for metabolic disease in drug development

    SciTech Connect

    Jiang Weijian

    2008-08-29

    Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases such as type 2 diabetes. SIRT1, an NAD{sup +}-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produces beneficial effects on glucose homeostasis and insulin sensitivity. Activation of SIRT1 leads to enhanced activity of multiple proteins, including peroxisome proliferator-activated receptor coactivator-1{alpha} (PGC-1{alpha}) and FOXO which helps to mediate some of the in vitro and in vivo effects of sirtuins. Resveratrol, a polyphenolic SIRT1 activator, mimics the effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance. In this review, we summarize recent research advances in unveiling the molecular mechanisms that underpin sirtuin as therapeutic candidates and discuss the possibility of using resveratrol as potential drug for treatment of diabetes.

  3. Traffic air pollution and mortality from cardiovascular disease and all causes: a Danish cohort study

    PubMed Central

    2012-01-01

    Background Traffic air pollution has been linked to cardiovascular mortality, which might be due to co-exposure to road traffic noise. Further, personal and lifestyle characteristics might modify any association. Methods We followed up 52 061 participants in a Danish cohort for mortality in the nationwide Register of Causes of Death, from enrollment in 1993–1997 through 2009, and traced their residential addresses from 1971 onwards in the Central Population Registry. We used dispersion-modelled concentration of nitrogen dioxide (NO2) since 1971 as indicator of traffic air pollution and used Cox regression models to estimate mortality rate ratios (MRRs) with adjustment for potential confounders. Results Mean levels of NO2 at the residence since 1971 were significantly associated with mortality from cardiovascular disease (MRR, 1.26; 95% confidence interval [CI], 1.06–1.51, per doubling of NO2 concentration) and all causes (MRR, 1.13; 95% CI, 1.04–1.23, per doubling of NO2 concentration) after adjustment for potential confounders. For participants who ate < 200 g of fruit and vegetables per day, the MRR was 1.45 (95% CI, 1.13–1.87) for mortality from cardiovascular disease and 1.25 (95% CI, 1.11–1.42) for mortality from all causes. Conclusions Traffic air pollution is associated with mortality from cardiovascular diseases and all causes, after adjustment for traffic noise. The association was strongest for people with a low fruit and vegetable intake. PMID:22950554

  4. Cardiovascular Disease Among Hispanics and Non-Hispanics in the Chronic Renal Insufficiency Cohort (CRIC) Study

    PubMed Central

    Ricardo, Ana C.; Fischer, Michael J.; Lora, Claudia M.; Budoff, Matthew; Keane, Martin G.; Kusek, John W.; Martinez, Monica; Nessel, Lisa; Stamos, Thomas; Ojo, Akinlolu; Rahman, Mahboob; Soliman, Elsayed Z.; Yang, Wei; Feldman, Harold I.; Go, Alan S.

    2011-01-01

    Summary Background and objectives Hispanics are the largest minority group in the United States. The leading cause of death in patients with chronic kidney disease (CKD) is cardiovascular disease (CVD), yet little is known about its prevalence among Hispanics with CKD. Design, setting, participants, & measurements We conducted cross-sectional analyses of prevalent self-reported clinical and subclinical measures of CVD among 497 Hispanics, 1638 non-Hispanic Caucasians, and 1650 non-Hispanic African Americans, aged 21 to 74 years, with mild-to-moderate CKD at enrollment in the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic CRIC (HCRIC) studies. Measures of subclinical CVD included left ventricular hypertrophy (LVH), coronary artery calcification (CAC), and ankle-brachial index. Results Self-reported coronary heart disease (CHD) was lower in Hispanics compared with non-Hispanic Caucasians (18% versus 23%, P = 0.02). Compared with non-Hispanic Caucasians, Hispanics had a lower prevalence of CAC >100 (41% versus 34%, P = 0.03) and CAC >400 (26% versus 19%, P = 0.02). However, after adjusting for sociodemographic factors, these differences were no longer significant. In adjusted analyses, Hispanics had a higher odds of LVH compared with non-Hispanic Caucasians (odds ratio 1.97, 95% confidence interval, 1.22 to 3.17, P = 0.005), and a higher odds of CAC >400 compared with non-Hispanic African Americans (odds ratio, 2.49, 95% confidence interval, 1.11 to 5.58, P = 0.03). Hispanic ethnicity was not independently associated with any other CVD measures. Conclusions Prevalent LVH was more common among Hispanics than non-Hispanic Caucasians, and elevated CAC score was more common among Hispanics than non-Hispanic African Americans. Understanding reasons for these racial/ethnic differences and their association with long-term clinical outcomes is needed. PMID:21896829

  5. Sleep Characteristics in Early Stages of Chronic Kidney Disease in the HypnoLaus Cohort

    PubMed Central

    Ogna, Adam; Forni Ogna, Valentina; Haba Rubio, José; Tobback, Nadia; Andries, Dana; Preisig, Martin; Tafti, Mehdi; Vollenweider, Peter; Waeber, Gerard; Marques-Vidal, Pedro; Heinzer, Raphaël

    2016-01-01

    Study Objectives: To evaluate the association between early stages of chronic kidney disease (CKD) and sleep disordered breathing (SDB), restless legs syndrome (RLS), and subjective and objective sleep quality (SQ). Methods: Cross-sectional analysis of a general population-based cohort (HypnoLaus). 1,760 adults (862 men, 898 women; age 59.3 (± 11.4) y) underwent complete polysomnography at home. Results: 8.2% of participants had mild CKD (stage 1–2, estimated glomerular filtration rate [eGFR] ≥ 60 mL/min/1.73 m2 with albuminuria) and 7.8% moderate CKD (stage 3, eGFR 30–60 mL/min/1.73 m2). 37.3% of our sample had moderate-to-severe SDB (apnea-hypopnea index [AHI] ≥ 15/h) and 15.3% had severe SDB (AHI ≥ 30/h). SDB prevalence was positively associated with CKD stages and negatively with eGFR. In multivariate analysis, age, male sex, and body mass index were independently associated with SDB (all P < 0.001), but kidney function was not. The prevalence of RLS was 17.5%, without difference between CKD stages. Periodic leg movements index (PLMI) was independently associated with CKD stages. Subjective and objective SQ decreased and the use of sleep medication was more frequent with declining kidney function. Older age, female sex, and the severity of SDB were the strongest predictors of poor SQ in multivariate regression analysis but CKD stage was also independently associated with reduced objective SQ. Conclusions: Patients with early stages of CKD have impaired SQ, use more hypnotic drugs, and have an increased prevalence of SDB and PLM. After controlling for confounders, objective SQ and PLMI were still independently associated with declining kidney function. Citation: Ogna A, Forni Ogna V, Haba Rubio J, Tobback N, Andries D, Preisig M, Tafti M, Vollenweider P, Waeber G, Marques-Vidal P, Heinzer R. Sleep characteristics in early stages of chronic kidney disease in the HypnoLaus cohort. SLEEP 2016;39(4):945–953. PMID:26715230

  6. Triheptanoin improves brain energy metabolism in patients with Huntington disease

    PubMed Central

    Adanyeguh, Isaac Mawusi; Rinaldi, Daisy; Henry, Pierre-Gilles; Caillet, Samantha; Valabregue, Romain; Durr, Alexandra

    2015-01-01

    Objective: Based on our previous work in Huntington disease (HD) showing improved energy metabolism in muscle by providing substrates to the Krebs cycle, we wished to obtain a proof-of-concept of the therapeutic benefit of triheptanoin using a functional biomarker of brain energy metabolism validated in HD. Methods: We performed an open-label study using 31P brain magnetic resonance spectroscopy (MRS) to measure the levels of phosphocreatine (PCr) and inorganic phosphate (Pi) before (rest), during (activation), and after (recovery) a visual stimulus. We performed 31P brain MRS in 10 patients at an early stage of HD and 13 controls. Patients with HD were then treated for 1 month with triheptanoin after which they returned for follow-up including 31P brain MRS scan. Results: At baseline, we confirmed an increase in Pi/PCr ratio during brain activation in controls—reflecting increased adenosine triphosphate synthesis—followed by a return to baseline levels during recovery (p = 0.013). In patients with HD, we validated the existence of an abnormal brain energy profile as previously reported. After 1 month, this profile remained abnormal in patients with HD who did not receive treatment. Conversely, the MRS profile was improved in patients with HD treated with triheptanoin for 1 month with the restoration of an increased Pi/PCr ratio during visual stimulation (p = 0.005). Conclusion: This study suggests that triheptanoin is able to correct the bioenergetic profile in the brain of patients with HD at an early stage of the disease. Classification of evidence: This study provides Class III evidence that, for patients with HD, treatment with triheptanoin for 1 month restores an increased MRS Pi/PCr ratio during visual stimulation. PMID:25568297

  7. Resting metabolic connectivity in prodromal Alzheimer's disease. A European Alzheimer Disease Consortium (EADC) project.

    PubMed

    Morbelli, Silvia; Drzezga, Alex; Perneczky, Robert; Frisoni, Giovanni B; Caroli, Anna; van Berckel, Bart N M; Ossenkoppele, Rik; Guedj, Eric; Didic, Mira; Brugnolo, Andrea; Sambuceti, Gianmario; Pagani, Marco; Salmon, Eric; Nobili, Flavio

    2012-11-01

    We explored resting-state metabolic connectivity in prodromal Alzheimer's disease (pAD) patients and in healthy controls (CTR), through a voxel-wise interregional correlation analysis of 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) by means of statistical parametric mapping. Baseline 18F-fluorodeoxyglucose-positron emission tomography of 36 patients with amnestic mild cognitive impairment who converted to Alzheimer's disease (AD) dementia after an average time of 2 years (pAD) and of 105 CTR were processed. The area of hypometabolism in pAD showed less metabolic connectivity in patients than in CTR (autocorrelation and correlation with large temporal and frontal areas, respectively). pAD patients showed limited correlation even in selected nonhypometabolic areas, including the hippocampi and the dorsolateral prefrontal cortex (DLFC). On the contrary, in CTR group correlation was highlighted between hippocampi and precuneus/posterior cingulate and frontal cortex, and between dorsolateral prefrontal cortex and caudate nuclei and parietal cortex. The reduced metabolic connections both in hypometabolic and nonhypometabolic areas in pAD patients suggest that metabolic disconnection (reflecting early diaschisis) may antedate remote hypometabolism (early sign of synaptic degeneration).

  8. ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism.

    PubMed

    Peters, Heidi; Buck, Nicole; Wanders, Ronald; Ruiter, Jos; Waterham, Hans; Koster, Janet; Yaplito-Lee, Joy; Ferdinandusse, Sacha; Pitt, James

    2014-11-01

    Two siblings with fatal Leigh disease had increased excretion of S-(2-carboxypropyl)cysteine and several other metabolites that are features of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, a rare defect in the valine catabolic pathway associated with Leigh-like disease. However, this diagnosis was excluded by HIBCH sequencing and normal enzyme activity. In contrast to HIBCH deficiency, the excretion of 3-hydroxyisobutyryl-carnitine was normal in the children, suggesting deficiency of short-chain enoyl-CoA hydratase (ECHS1 gene). This mitochondrial enzyme is active in several metabolic pathways involving fatty acids and amino acids, including valine, and is immediately upstream of HIBCH in the valine pathway. Both children were compound heterozygous for a c.473C > A (p.A158D) missense mutation and a c.414+3G>C splicing mutation in ECHS1. ECHS1 activity was markedly decreased in cultured fibroblasts from both siblings, ECHS1 protein was undetectable by immunoblot analysis and transfection of patient cells with wild-type ECHS1 rescued ECHS1 activity. The highly reactive metabolites methacrylyl-CoA and acryloyl-CoA accumulate in deficiencies of both ECHS1 and HIBCH and are probably responsible for the brain pathology in both disorders. Deficiency of ECHS1 or HIBCH should be considered in children with Leigh disease. Urine metabolite testing can detect and distinguish between these two disorders.

  9. Atrial Fibrillation Increases the Risk of Peripheral Arterial Disease With Relative Complications and Mortality: A Population-Based Cohort Study.

    PubMed

    Chang, Chia-Jung; Chen, Yen-Ting; Liu, Chiu-Shong; Lin, Wen-Yuan; Lin, Cheng-Li; Lin, Ming-Chia; Kao, Chia-Hung

    2016-03-01

    Atrial fibrillation (AF), an increasing prevalent cardiac arrhythmia due to aging general population, has many common risk factors with peripheral arterial disease (PAD). However, it is unclear whether AF is associated with a risk of PAD. We investigated the prevalence of AF and PAD in the general population and the risk of PAD among the AF population. This longitudinal, nationwide, population-based cohort study was conducted using data from the Taiwan National Health Insurance Research Database recorded during 2000 to 2011. In total, 3814 and 15,364 patients were included in the AF and non-AF cohorts, respectively. Univariate and multivariate Cox proportional hazard regression models were used for examining the effects of AF on the risk of outcomes. The average follow-up periods of PAD were 4.96 ± 3.28 and 5.29 ± 3.35 years for the AF and non-AF cohorts, respectively. Overall, the risk of PAD showed a significantly higher risk in the AF cohort (adjusted HR=1.31, 95% CI=1.19-1.45) compared with the non-AF cohort. Similar results were observed for heart failure and stroke, where the AF cohort had a 1.83-fold and 2.53-fold higher risk of developing heart failure and stroke. The AF cohort also had a significant increased risk for mortality (adjusted HR=1.66, 95% CI=1.49-1.84). The present study indicated that the incidence of PAD, heart failure, stroke, and overall mortality is higher in patients with AF than in those without it. PMID:26945422

  10. Snippets From the Past: Cohort Analysis of Disease Rates—Another Piece in a Seemingly Still Incomplete Puzzle

    PubMed Central

    Morabia, Alfredo

    2014-01-01

    For almost a century, epidemiologists have stratified age-specific disease rates by year of birth to better understand the distribution of a disease in a population and its evolution across time. In the present article, I review the contributions of John Brownlee, Kristian Feyer Andvord, and Wade Hampton Frost and, to accentuate the similarities of their approaches, redraw their original graphs of age-specific death rates of tuberculosis organized either by year of death or year of birth. In addition, this article reports on an apparently universally forgotten publication in the American Journal of Hygiene published in 1929, which both upsets the conventional history of the earliest reports of disease rates stratified by birth cohorts and challenges the theory that Frost discovered cohort analysis independently and gave it its name. PMID:24920785

  11. Dietary components and risk of total, cancer and cardiovascular disease mortality in the Linxian Nutrition Intervention Trials cohort in China

    PubMed Central

    Wang, Jian-Bing; Fan, Jin-Hu; Dawsey, Sanford M.; Sinha, Rashmi; Freedman, Neal D.; Taylor, Philip R.; Qiao, You-Lin; Abnet, Christian C.

    2016-01-01

    Although previous studies have shown that dietary consumption of certain food groups is associated with a lower risk of cancer, heart disease and stroke mortality in western populations, limited prospective data are available from China. We prospectively examined the association between dietary intake of different food groups at baseline and risk of total, cancer, heart disease and stroke mortality outcomes in the Linxian Nutrition Intervention Trials(NIT) cohort. In 1984–1991, 2445 subjects aged 40–69 years from the Linxian NIT cohort completed a food frequency questionnaire. Deaths from esophageal and gastric cancer, heart disease and stroke were identified through up to 26 years of follow-up. We used Cox proportional hazard models to calculate hazard ratios and 95% confidence intervals for associations between intake of groups of food items and these mortality endpoints. We concluded that higher intake of certain food groups was associated with lower risk of gastric cancer, heart disease and stroke mortality in a prospective cohort in rural China. Our findings provide additional evidence that increasing intake of grains, vegetables, beans, fruits and nuts may help reduce mortality from these diseases. PMID:26939909

  12. The possible importance of income and education as covariates in cohort studies that investigate the relationship between diet and disease

    PubMed Central

    Temple, Norman

    2016-01-01

    Background:  Many cohort studies have been carried out that have provided information on the relationship between diet and health-related outcomes. Omission of important covariates during multivariate analysis may give rise to error due to residual confounding. A possibly important covariate is socioeconomic status (SES) as this is related to both diet and health. Objective: To determine the frequency with which different measures of SES are included as covariates during multivariate analysis of cohort studies that investigated the relationship between diet and health. Methodology:  An analysis was carried out of 76 randomly selected papers from 66 cohort studies. The papers covered many dietary variables and a wide variety of diseases/health-related outcomes. The cohort studies were carried out in many different locations and the subjects varied widely in age. Results:  Approximately two-thirds of the papers (65.8%) used at least one measure of SES as a covariate. Education was used most often (60.5% of papers), followed by income (14.4%) and social class (2.6%). More than one measure of SES was used in 11.8% of papers. Conclusions:  Failure to include income (or another measure of present SES, such as occupation) may be a common source of error in cohort studies. Over-reliance on education may be particularly important as it is likely to be a weaker measure of present SES than is income. There is a need for more research on this question. SES in childhood is almost never included in multivariate analysis in cohort studies carried out on adults. This could also play a significant role in disease risk in middle age or later. Very little is known regarding whether this is also a source of residual confounding. PMID:27303622

  13. Mortality rates for chronic lower respiratory diseases in Italy from 1979 to 2010: an age–period–cohort analysis

    PubMed Central

    2016-01-01

    Chronic lower respiratory diseases (CLRDs) are a major cause of morbidity and mortality worldwide. The objectives of this study were to estimate the trends in CLRD mortality in Italy, and the specific contributions of age, time period and birth cohort in driving these trends. Population and cause-of-death data in Italy between 1979 and 2010 were collected from the World Health Organization website. Age-specific mortality rates for CLRDs, and effects for age, time period and birth cohort on mortality trends were estimated using age–period–cohort models. Chronic obstructive pulmonary disease (COPD) and chronic bronchitis represent nearly 98% of the deaths from CLRDs. Despite the overall number of deaths have been stable (in men) or increasing (in women), the age-standardised rates have been steadily decreasing from 1979 to 2010, passing from 104.3 to 55.4 per 100 000 person-years in men and from 32.2 to 19.6 per 100 000 person-years in women. The average relative annual decrease was −3.6% in men and −2.7% in women. Since the end of the 1990s, the decreasing trend of CLRD mortality has started to level off, in particular in women. The decrease in CLRD mortality rates has been more accentuated in more recent cohorts and in younger age groups. Both birth cohort and time period significantly affected the CLRD mortality rates, suggesting that changes in the spread of risk factors (smoking habits, early-life and occupational exposures) across different birth cohorts, as well as in advanced in healthcare and medical practice, may have played a major role in secular changes in COPD mortality rates in Italy. PMID:27730182

  14. Urinary Metabolic Phenotyping Reveals Differences in the Metabolic Status of Healthy and Inflammatory Bowel Disease (IBD) Children in Relation to Growth and Disease Activity

    PubMed Central

    Martin, Francois-Pierre; Ezri, Jessica; Cominetti, Ornella; Da Silva, Laeticia; Kussmann, Martin; Godin, Jean-Philippe; Nydegger, Andreas

    2016-01-01

    Background: Growth failure and delayed puberty are well known features of children and adolescents with inflammatory bowel disease (IBD), in addition to the chronic course of the disease. Urinary metabonomics was applied in order to better understand metabolic changes between healthy and IBD children. Methods: 21 Pediatric patients with IBD (mean age 14.8 years, 8 males) were enrolled from the Pediatric Gastroenterology Outpatient Clinic over two years. Clinical and biological data were collected at baseline, 6, and 12 months. 27 healthy children (mean age 12.9 years, 16 males) were assessed at baseline. Urine samples were collected at each visit and subjected to 1H Nuclear Magnetic Resonance (NMR) spectroscopy. Results: Using 1H NMR metabonomics, we determined that urine metabolic profiles of IBD children differ significantly from healthy controls. Metabolic differences include central energy metabolism, amino acid, and gut microbial metabolic pathways. The analysis described that combined urinary urea and phenylacetylglutamine—two readouts of nitrogen metabolism—may be relevant to monitor metabolic status in the course of disease. Conclusion: Non-invasive sampling of urine followed by metabonomic profiling can elucidate and monitor the metabolic status of children in relation to disease status. Further developments of omic-approaches in pediatric research might deliver novel nutritional and metabolic hypotheses. PMID:27529220

  15. Dicarbonyl proteome and genome damage in metabolic and vascular disease.

    PubMed

    Rabbani, Naila; Thornalley, Paul J

    2014-04-01

    Methylglyoxal is a potent protein-glycating agent. It is an arginine-directed glycating agent and often modifies functionally important sites in proteins. Glycation forms mainly MG-H1 [Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine] residues. MG-H1 content of proteins is quantified by stable isotopic dilution analysis-MS/MS and also by immunoblotting with specific monoclonal antibodies. Methylglyoxal-modified proteins undergo cellular proteolysis and release MG-H1 free adduct for excretion. MG-H1 residues have been found in proteins of animals, plants, bacteria, fungi and protoctista. MG-H1 is often the major advanced glycation end-product in proteins of tissues and body fluids, increasing in diabetes and associated vascular complications, renal failure, cirrhosis, Alzheimer's disease, arthritis, Parkinson's disease and aging. Proteins susceptible to methylglyoxal modification with related functional impairment are called the DCP (dicarbonyl proteome). The DCP includes albumin, haemoglobin, transcription factors, mitochondrial proteins, extracellular matrix proteins, lens crystallins and others. DCP component proteins are linked to mitochondrial dysfunction in diabetes and aging, oxidative stress, dyslipidaemia, cell detachment and anoikis and apoptosis. Methylglyoxal also modifies DNA where deoxyguanosine residues are modified to imidazopurinone MGdG {3-(2'-deoxyribosyl)-6,7-dihydro-6,7-dihydroxy-6/7-methylimidazo-[2,3-b]purine-9(8)one} isomers. MGdG was the major quantitative adduct detected in vivo. It was linked to frequency of DNA strand breaks and increased markedly during apoptosis induced by a cell-permeant glyoxalase I inhibitor. Glyoxalase I metabolizes >99% methylglyoxal and thereby protects the proteome and genome. Gene deletion of GLO1 is embryonically lethal and GLO1 silencing increases methylglyoxal concentration, MG-H1 and MGdG, premature aging and disease. Studies of methylglyoxal glycation have importance for human health, longevity and

  16. Dicarbonyl proteome and genome damage in metabolic and vascular disease.

    PubMed

    Rabbani, Naila; Thornalley, Paul J

    2014-04-01

    Methylglyoxal is a potent protein-glycating agent. It is an arginine-directed glycating agent and often modifies functionally important sites in proteins. Glycation forms mainly MG-H1 [Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine] residues. MG-H1 content of proteins is quantified by stable isotopic dilution analysis-MS/MS and also by immunoblotting with specific monoclonal antibodies. Methylglyoxal-modified proteins undergo cellular proteolysis and release MG-H1 free adduct for excretion. MG-H1 residues have been found in proteins of animals, plants, bacteria, fungi and protoctista. MG-H1 is often the major advanced glycation end-product in proteins of tissues and body fluids, increasing in diabetes and associated vascular complications, renal failure, cirrhosis, Alzheimer's disease, arthritis, Parkinson's disease and aging. Proteins susceptible to methylglyoxal modification with related functional impairment are called the DCP (dicarbonyl proteome). The DCP includes albumin, haemoglobin, transcription factors, mitochondrial proteins, extracellular matrix proteins, lens crystallins and others. DCP component proteins are linked to mitochondrial dysfunction in diabetes and aging, oxidative stress, dyslipidaemia, cell detachment and anoikis and apoptosis. Methylglyoxal also modifies DNA where deoxyguanosine residues are modified to imidazopurinone MGdG {3-(2'-deoxyribosyl)-6,7-dihydro-6,7-dihydroxy-6/7-methylimidazo-[2,3-b]purine-9(8)one} isomers. MGdG was the major quantitative adduct detected in vivo. It was linked to frequency of DNA strand breaks and increased markedly during apoptosis induced by a cell-permeant glyoxalase I inhibitor. Glyoxalase I metabolizes >99% methylglyoxal and thereby protects the proteome and genome. Gene deletion of GLO1 is embryonically lethal and GLO1 silencing increases methylglyoxal concentration, MG-H1 and MGdG, premature aging and disease. Studies of methylglyoxal glycation have importance for human health, longevity and

  17. Influenza Vaccination Reduces Dementia Risk in Chronic Kidney Disease Patients: A Population-Based Cohort Study.

    PubMed

    Liu, Ju-Chi; Hsu, Yi-Ping; Kao, Pai-Feng; Hao, Wen-Rui; Liu, Shing-Hwa; Lin, Chao-Feng; Sung, Li-Chin; Wu, Szu-Yuan

    2016-03-01

    Taiwan has the highest prevalence of chronic kidney disease (CKD) worldwide. CKD, a manifestation of vascular diseases, is associated with a high risk of dementia. Here, we estimated the association between influenza vaccination and dementia risk in patients with CKD. Data from the National Health Insurance Research Database of Taiwan were used in this study. The study cohort included all patients diagnosed with CKD (according to International Classification of Disease, Ninth Revision, Clinical Modification codes) at healthcare facilities in Taiwan (n = 32,844) from January 1, 2000, to December 31, 2007. Each patient was followed up to assess dementia risk or protective factors: demographic characteristics of age and sex; comorbidities of diabetes, hypertension, dyslipidemia, cerebrovascular diseases, parkinsonism, epilepsy, substance and alcohol use disorders, mood disorder, anxiety disorder, psychotic disorder, and sleep disorder; urbanization level; monthly income; and statin, metformin, aspirin, and angiotensin-converting enzyme inhibitor (ACEI) use. A propensity score was derived using a logistic regression model for estimating the effect of vaccination by accounting for covariates that predict receiving the intervention (vaccine). A time-dependent Cox proportional hazard model was used to calculate the hazard ratios (HRs) of dementia among vaccinated and unvaccinated CKD patients. The study population comprised 11,943 eligible patients with CKD; 5745 (48%) received influenza vaccination and the remaining 6198 (52%) did not. The adjusted HRs (aHRs) of dementia decreased in vaccinated patients compared with those in unvaccinated patients (influenza season, noninfluenza season, and all seasons: aHRs = 0.68, 0.58, and 0.64; P < 0.0001, P < 0.0001, and P < 0.0001, respectively). In the sensitivity analysis, adjustments were made to estimate the association of age and sex; diabetes, dyslipidemia, hypertension, cerebrovascular diseases, anxiety

  18. Influenza Vaccination Reduces Dementia Risk in Chronic Kidney Disease Patients: A Population-Based Cohort Study.

    PubMed

    Liu, Ju-Chi; Hsu, Yi-Ping; Kao, Pai-Feng; Hao, Wen-Rui; Liu, Shing-Hwa; Lin, Chao-Feng; Sung, Li-Chin; Wu, Szu-Yuan

    2016-03-01

    Taiwan has the highest prevalence of chronic kidney disease (CKD) worldwide. CKD, a manifestation of vascular diseases, is associated with a high risk of dementia. Here, we estimated the association between influenza vaccination and dementia risk in patients with CKD. Data from the National Health Insurance Research Database of Taiwan were used in this study. The study cohort included all patients diagnosed with CKD (according to International Classification of Disease, Ninth Revision, Clinical Modification codes) at healthcare facilities in Taiwan (n = 32,844) from January 1, 2000, to December 31, 2007. Each patient was followed up to assess dementia risk or protective factors: demographic characteristics of age and sex; comorbidities of diabetes, hypertension, dyslipidemia, cerebrovascular diseases, parkinsonism, epilepsy, substance and alcohol use disorders, mood disorder, anxiety disorder, psychotic disorder, and sleep disorder; urbanization level; monthly income; and statin, metformin, aspirin, and angiotensin-converting enzyme inhibitor (ACEI) use. A propensity score was derived using a logistic regression model for estimating the effect of vaccination by accounting for covariates that predict receiving the intervention (vaccine). A time-dependent Cox proportional hazard model was used to calculate the hazard ratios (HRs) of dementia among vaccinated and unvaccinated CKD patients. The study population comprised 11,943 eligible patients with CKD; 5745 (48%) received influenza vaccination and the remaining 6198 (52%) did not. The adjusted HRs (aHRs) of dementia decreased in vaccinated patients compared with those in unvaccinated patients (influenza season, noninfluenza season, and all seasons: aHRs = 0.68, 0.58, and 0.64; P < 0.0001, P < 0.0001, and P < 0.0001, respectively). In the sensitivity analysis, adjustments were made to estimate the association of age and sex; diabetes, dyslipidemia, hypertension, cerebrovascular diseases, anxiety

  19. Incidence of and risk factors for cognitive impairment in an early Parkinson disease clinical trial cohort

    PubMed Central

    Uc, E Y.; McDermott, M P.; Marder, K S.; Anderson, S W.; Litvan, I; Como, P G.; Auinger, P; Chou, K L.; Growdon, J C.

    2009-01-01

    Objective: To investigate the incidence of and risk factors for cognitive impairment in a large, well-defined clinical trial cohort of patients with early Parkinson disease (PD). Methods: The Mini-Mental State Examination (MMSE) was administered periodically over a median follow-up period of 6.5 years to participants in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism trial and its extension studies. Cognitive impairment was defined as scoring 2 standard deviations below age- and education-adjusted MMSE norms. Results: Cumulative incidence of cognitive impairment in the 740 participants with clinically confirmed PD (baseline age 61.0 ± 9.6 years, Hoehn-Yahr stage 1–2.5) was 2.4% (95% confidence interval: 1.2%–3.5%) at 2 years and 5.8% (3.7%–7.7%) at 5 years. Subjects who developed cognitive impairment (n = 46) showed significant progressive decline on neuropsychological tests measuring verbal learning and memory, visuospatial working memory, visuomotor speed, and attention, while the performance of the nonimpaired subjects (n = 694) stayed stable. Cognitive impairment was associated with older age, hallucinations, male gender, increased symmetry of parkinsonism, increased severity of motor impairment (except for tremor), speech and swallowing impairments, dexterity loss, and presence of gastroenterologic/urologic disorders at baseline. Conclusions: The relatively low incidence of cognitive impairment in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism study may reflect recruitment bias inherent to clinical trial volunteers (e.g., younger age) or limitations of the Mini-Mental State Examination–based criterion. Besides confirming known risk factors for cognitive impairment, we identified potentially novel predictors such as bulbar dysfunction and gastroenterologic/urologic disorders (suggestive of autonomic dysfunction) early in the course of the disease. GLOSSARY CI = confidence interval; COWA = Controlled Word Association

  20. The association between renal stone disease and cholesterol gallstones: the easy to believe and not hard to retrieve theory of the metabolic syndrome.

    PubMed

    Ahmed, Mohamed H; Barakat, Salma; Almobarak, Ahmed O

    2014-07-01

    Renal stone disease and gallstone disease are widely prevalent and costly disease across the globe. Both renal stone disease and gallstone disease are associated with a variety of diseases including obesity, metabolic syndrome, dyslipidemia, hypertension, insulin resistance diabetes and gout. Importantly, the presence of either renal stone disease or gallstone disease is associated with an increased risk of cardiovascular disease. In a recent study of the Atherosclerosis Risk in Communities (ARIC), individuals with a history of gallstones were 54% more likely to report a history of nephrolithiasis after adjusting for age, gender, body size and other factors. Furthermore, in three large cohorts including over 240,000 subjects: the Nurses' Health Studies (NHS) I and II and the Health Professionals Follow-up Study (HPFS), showed that gallstone disease is independently associated with nephrolithiasis. The mechanisms linking gallstone disease and renal stone disease are complex and not yet established. Insulin resistance, lithogenic diets, alterations of transporters in gallbladder and urinary system, and pH are possible potential mechanisms for future exploration. How the liver communicates with kidney in individuals with renal stone disease and gallstone disease is not well known and whether this communication is similar as in hepto-renal syndrome is subject for future research. Further research is needed to determine: (i) the underlying mechanisms of renal stone disease and gallstone disease; (ii) the potential treatment of renal stone disease and gallstone disease.

  1. [Cohort studies].

    PubMed

    Mathis, Stefan; Gartlehner, Gerald

    2008-01-01

    This article about cohort studies is part of a methods series about study designs and their critical evaluation by the Ludwig Boltzmann Institute for Health Technology assessment. This article aims to describe the theoretical concept of cohort studies and their typical characteristics. Furthermore, it strives to highlight advantages and disadvantages of this study type and to make suggestions for the critical evaluation of the significance and validity of cohort studies. The article gives an account about characteristics due to the observational design and ways of acquiring control groups. Problems of blurring results by selection bias and confounding are also discussed. Cohort studies are applied in situations where the effects of environmental exposures are measured and rare side effects are identified but randomised controlled studies did not show significant results because of limitations. They are also used to assess the incidence of a disease or a condition.

  2. Periodontal disease and some adverse perinatal outcomes in a cohort of low risk pregnant women

    PubMed Central

    2010-01-01

    Objective To evaluate the association of periodontal disease (PD) in pregnancy with some adverse perinatal outcomes. Method This cohort study included 327 pregnant women divided in groups with or without PD. Indexes of plaque and gingival bleeding on probing, probing pocket depth, clinical attachment level and gingival recession were evaluated at one periodontal examination below 32 weeks of gestation. The rates of preterm birth (PTB), low birth weight (LBW), small for gestational age (SGA) neonates and prelabor rupture of membranes (PROM) were evaluated using Risk Ratios (95%CI) and Population Attributable Risk Fractions. Results PD was associated with a higher risk of PTB (RRadj. 3.47 95%CI 1.62-7.43), LBW (RRadj. 2.93 95%CI 1.36-6.34) and PROM (RRadj. 2.48 95%CI 1.35-4.56), but not with SGA neonates (RR 2.38 95%CI 0.93 - 6.10). Conclusions PD was a risk factor for PT, LBW and PROM among Brazilian low risk pregnant women. PMID:21047427

  3. Incident Ischemic Heart Disease and Recent Occupational Exposure to Particulate Matter in an Aluminum Cohort

    PubMed Central

    Costello, Sadie; Brown, Daniel M.; Noth, Elizabeth M.; Cantley, Linda; Slade, Martin D; Tessier-Sherman, Baylah; Hammond, S. Katharine; Eisen, Ellen A.; Cullen, Mark R.

    2014-01-01

    Fine particulate matter (PM2.5) in air pollution, primarily from combustion sources, is recognized as an important risk factor for cardiovascular events but studies of workplace PM2.5 exposure are rare. We conducted a prospective study of exposure to PM2.5 and incidence of ischemic heart disease (IHD) in a cohort of 11,966 US aluminum workers. Incident IHD was identified from medical claims data from 1998 to 2008. Quantitative metrics were developed for recent exposure (within the last year) and cumulative exposure; however, we emphasize recent exposure in the absence of interpretable work histories prior to follow-up. IHD was modestly associated with recent PM2.5 overall. In analysis restricted to recent exposures estimated with the highest confidence, the hazard ratio (HR) increased to 1.78 (95%CI: 1.02, 3.11) in the second quartile and remained elevated. When the analysis was stratified by work process, the HR rose monotonically to 1.5 in both smelter and fabrication facilities, though exposure was almost an order of magnitude higher in smelters. The differential exposure-response may be due to differences in exposure composition or healthy worker survivor effect. These results are consistent with the air pollution and cigarette smoke literature; recent exposure to PM2.5 in the workplace appears to increase the risk of IHD incidence. PMID:23982120

  4. Antibiotic exposure in pregnancy and risk of coeliac disease in offspring: a cohort study

    PubMed Central

    2014-01-01

    Background The infant microbiota may play a pathogenic role in coeliac disease (CD). Antibiotic treatment in pregnancy is common and could significantly impact the infant microbiota. In this study, we aimed to investigate the association between antibiotic exposure during pregnancy and CD in offspring. Methods Prospective questionnaire data on antibiotic exposure in pregnancy were available in 8729 children participating in the All Babies in Southeast Sweden (ABIS) cohort study, and of these 46 developed CD until December 2006. Cox regression estimated hazard ratios (HRs) for CD in the offspring among mothers exposed to antibiotics during pregnancy, with adjustment for parent-reported diary data on breastfeeding, age at gluten introduction and number of infections in the child’s first year of life. Results Of the 1836 children exposed to antibiotics during pregnancy, 12 (0.7%) children developed CD as compared with 34/6893 (0.5%) unexposed children (HR = 1.33; 95% CI = 0.69-2.56). Risk estimates remained unchanged after adjustment for breastfeeding, age at gluten introduction and infection load in the child’s first year of life (HR = 1.28; 95% CI = 0.66-2.48). Conclusions We found no statistically significant association between antibiotic exposure during pregnancy and CD in offspring. This lack of association may either be true or the result of limited statistical power. PMID:24731164

  5. ERα Variants Affect Age at Onset of Alzheimer's Disease in a Multiethnic Female Cohort

    PubMed Central

    Janicki, S.C.; Park, N.; Cheng, R.; Clark, L.N.; Lee, J. H.; Schupf, N.

    2014-01-01

    Background/Aims Few studies of gene variants that affect estrogen activity investigate their association with age at onset of Alzheimer's disease (AD) in women of different ethnicities. We investigated the influence of ESR1 polymorphisms on age at onset of AD in a multiethnic cohort of women. Methods Among 1,436 women participating in the Washington Heights Inwood Columbia Aging Project (WHICAP), association with age at AD onset was assessed for 41 single-nucleotide polymorphisms (SNPs) on the ESR1 gene using Cox proportional hazard models, adjusting for presence of an APOE ε4 allele, years of education, and body mass index (BMI). Results Six SNPs in self-identified White women were protectively associated with delayed age of AD onset in this self-identified group, including the two restriction fragment length polymorphisms (RFLPs) PvuII (rs2234693) and XbaI (rs9340799) (HR range 0.420 – 0.483). Two separate SNPs were found to affect age of AD onset in self-identified Black women. Conclusions ESR1 polymorphisms affect age of onset for AD in women, and risk alleles vary by ethnicity. These effects are possibly due to different linkage disequilibrium patterns or differences in comorbid environmental or cultural risk factors mediating SNP effect on risk for AD. PMID:24732579

  6. Analysis of DNAJC13 mutations in French-Canadian/French cohort of Parkinson's disease.

    PubMed

    Ross, Jay P; Dupre, Nicolas; Dauvilliers, Yves; Strong, Stephanie; Ambalavanan, Amirthagowri; Spiegelman, Dan; Dionne-Laporte, Alexandre; Pourcher, Emanuelle; Langlois, Melanie; Boivin, Michel; Leblond, Claire S; Dion, Patrick A; Rouleau, Guy A; Gan-Or, Ziv

    2016-09-01

    DNAJC13 mutations have been suggested to cause Parkinson's disease (PD), yet subsequent studies reported conflicting results on this association. In the present study, we sequenced the coding region of DNAJC13 in a French-Canadian/French cohort of 528 PD patients and 692 controls. A total of 62 (11.7%) carriers of rare DNAJC13 variants were identified among the PD patients compared with 82 (11.8%) among controls (p = 1.0). Two variants that were previously suggested to be associated with PD, p.R1516H and p.L2170W, were identified with similar directions of association as previously reported. The p.R1516H was found in 2 (0.4%) patients versus 6 (0.9%, nonsignificant) controls and the p.L2170W variant was found in 9 (1.7%) patients and 5 (0.7%, nonsignificant) controls. Meta-analysis with previous reports resulted in odds ratios of 0.32 (95% confidence interval = 0.15-0.68, p = 0.0037) and 2.68 (95% confidence interval = 1.32-5.42, p = 0.007), respectively. Our results provide some support for the possibility that specific DNAJC13 variants may play a minor role in PD susceptibility, although studies in additional populations are necessary. PMID:27236598

  7. Isotretinoin use and the risk of inflammatory bowel disease: a population-based cohort study.

    PubMed

    Alhusayen, Raed O; Juurlink, David N; Mamdani, Muhammad M; Morrow, Richard L; Shear, Neil H; Dormuth, Colin R

    2013-04-01

    Limited evidence suggests that isotretinoin may be associated with inflammatory bowel disease (IBD). To explore this association, we conducted a retrospective population-based cohort study in British Columbia, Canada, among participants who were newly treated with isotretinoin or topical acne medications. The entire population of untreated provincial residents aged 12-29 years served as the reference group. During the 12-year study period, we identified 46,922 participants treated with isotretinoin, 184,824 treated with a topical acne medication, and 1,526,946 untreated individuals. Compared with untreated individuals, we observed no significant association between isotretinoin use and IBD (rate ratio (RR) 1.14; 95% confidence interval (CI) 0.92-1.41). As expected, we found no association with topical acne medications (RR 1.11; 95% CI 0.99-1.24). In prespecified secondary analyses, isotretinoin was associated with IBD among individuals aged 12-19 years (RR 1.39; 95% CI 1.03-1.87) and topical acne medications were associated with ulcerative colitis (RR 1.19; 95% CI 1.00-1.42). Our primary analyses found no association between isotretinoin and IBD. In prespecified secondary analyses, some evidence was found of associations with isotretinoin as well as topical acne medications, suggesting a possible association between IBD and acne itself. Additional research is needed to explore this possibility.

  8. Venous thromboembolism and subsequent risk of cancer in patients with liver disease: a population-based cohort study

    PubMed Central

    Montomoli, Jonathan; Erichsen, Rune; Søgaard, Kirstine Kobberøe; Körmendiné Farkas, Dóra; Bloch Münster, Anna-Marie; Sørensen, Henrik Toft

    2015-01-01

    Objective Venous thromboembolism (VTE) may be a marker of occult cancer in the general population. While liver disease is known to increase the risk of VTE and cancer, it is unclear whether VTE in patients with liver disease is also a marker of occult cancer. Design A population-based cohort study. Setting Denmark. Participants We used population-based health registries to identify all patients with liver disease in Denmark with a first-time diagnosis of VTE (including superficial or deep venous thrombosis and pulmonary embolism) during 1980–2010. Patients with non-cirrhotic liver disease and patients with liver cirrhosis were followed as two separate cohorts from the date of their VTE. Measures For each cohort, we computed the absolute and relative risk (standardised incidence ratio; SIR) of cancer after VTE. Results During the study period, 1867 patients with non-cirrhotic liver disease and 888 with liver cirrhosis were diagnosed with incident VTE. In the first year following VTE, the absolute risk of cancer was 2.7% among patients with non-cirrhotic liver disease and 4.3% among those with liver cirrhosis. The SIR for the first 90 days of follow-up was 9.96 (95% CI 6.85 to 13.99) among patients with non-cirrhotic liver disease and 13.11 (95% CI 8.31 to 19.67) among patients with liver cirrhosis. After 1 year of follow-up, SIRs declined, but remained elevated in patients with non-cirrhotic liver disease (SIR=1.50, 95% CI 1.23 to 1.81) and patients with liver cirrhosis (SIR=1.95, 95% CI 1.45 to 2.57). Conclusions VTE may be a marker of occult cancer in patients with liver disease. PMID:26462285

  9. Posttraumatic Stress Disorder, Cardiovascular and Metabolic Disease: A Review of the Evidence

    PubMed Central

    Dedert, Eric A.; Calhoun, Patrick S.; Watkins, Lana L.; Sherwood, Andrew; Beckham, Jean C.

    2011-01-01

    Background Posttraumatic stress disorder (PTSD) is a significant risk factor for cardiovascular and metabolic disease. Purpose The purpose of the current review is to evaluate the evidence suggesting that PTSD increases cardiovascular and metabolic risk factors, and to identify possible biomarkers and psychosocial characteristics and behavioral variables that are associated with these outcomes. Methods A systematic literature search in the period of 2002–2009 for PTSD, cardiovascular disease, and metabolic disease was conducted. Results The literature search yielded 78 studies on PTSD and cardiovascular/metabolic disease and biomarkers. Conclusions Although the available literature suggests an association of PTSD with cardiovascular disease and biomarkers, further research must consider potential confounds, incorporate longitudinal designs, and conduct careful PTSD assessments in diverse samples to address gaps in the research literature. Research on metabolic disease and biomarkers suggests an association with PTSD, but has not progressed as far as the cardiovascular research. PMID:20174903

  10. Exploring the metabolic syndrome: Nonalcoholic fatty pancreas disease.

    PubMed

    Catanzaro, Roberto; Cuffari, Biagio; Italia, Angelo; Marotta, Francesco

    2016-09-14

    After the first description of fatty pancreas in 1933, the effects of pancreatic steatosis have been poorly investigated, compared with that of the liver. However, the interest of research is increasing. Fat accumulation, associated with obesity and the metabolic syndrome (MetS), has been defined as "fatty infiltration" or "nonalcoholic fatty pancreas disease" (NAFPD). The term "fatty replacement" describes a distinct phenomenon characterized by death of acinar cells and replacement by adipose tissue. Risk factors for developing NAFPD include obesity, increasing age, male sex, hypertension, dyslipidemia, alcohol and hyperferritinemia. Increasing evidence support the role of pancreatic fat in the development of type 2 diabetes mellitus, MetS, atherosclerosis, severe acute pancreatitis and even pancreatic cancer. Evidence exists that fatty pancreas could be used as the initial indicator of "ectopic fat deposition", which is a key element of nonalcoholic fatty liver disease and/or MetS. Moreover, in patients with fatty pancreas, pancreaticoduodenectomy is associated with an increased risk of intraoperative blood loss and post-operative pancreatic fistula.

  11. Gender differences in glutathione metabolism in Alzheimer's disease.

    PubMed

    Liu, Honglei; Harrell, Lindy E; Shenvi, Swapna; Hagen, Tory; Liu, Rui-Ming

    2005-03-15

    The mechanism underlying Alzheimer's disease (AD), an age-related neurodegenerative disease, is still an area of significant controversy. Oxidative damage of macromolecules has been suggested to play an important role in the development of AD; however, the underlying mechanism is still unclear. In this study, we showed that the concentration of glutathione (GSH), the most abundant intracellular free thiol and an important antioxidant, was decreased in red blood cells from male AD patients compared with age- and gender-matched controls. However, there was no difference in blood GSH concentration between the female patients and female controls. The decrease in GSH content in red blood cells from male AD patients was associated with reduced activities of glutamate cysteine ligase and glutathione synthase, the two enzymes involved in de novo GSH synthesis, with no change in the amount of oxidized glutathione or the activity of glutathione reductase, suggesting that a decreased de novo GSH synthetic capacity is responsible for the decline in GSH content in AD. These results showed for the first time that GSH metabolism was regulated differently in male and female AD patients. PMID:15693022

  12. Enzymology of mammalian NAD metabolism in health and disease.

    PubMed

    Magni, Giulio; Orsomando, Giuseppe; Raffelli, Nadia; Ruggieri, Silverio

    2008-01-01

    Mounting evidence attests to the paramount importance of the non-redox NAD functions. Indeed, NAD homeostasis is related to the free radicals-mediated production of reactive oxygen species responsible for irreversible cellular damage in infectious disease, diabetes, inflammatory syndromes, neurodegeneration and cancer. Because the cellular redox status depends on both the absolute concentration of pyridine dinucleotides and their respective ratios of oxidized and reduced forms (i.e., NAD/NADH and NADP/NADPH), it is conceivable that an altered regulation of the synthesis and degradation of NAD impairs the cell redox state and likely contributes to the mechanisms underlying the pathogenesis of the above mentioned diseases. Taking into account the recent appearance in the literature of comprehensive reviews covering different aspects of the significance of NAD metabolism, with particular attention to the enzymes involved in NAD cleavage, this monograph includes the most recent results on NAD biosynthesis in mammals and humans. Due to recent findings on nicotinamide riboside as a nutrient, its inclusion under "niacins" is proposed. Here, the enzymes involved in the de novo and reutilization pathways are overviewed. PMID:18508649

  13. Exploring the metabolic syndrome: Nonalcoholic fatty pancreas disease.

    PubMed

    Catanzaro, Roberto; Cuffari, Biagio; Italia, Angelo; Marotta, Francesco

    2016-09-14

    After the first description of fatty pancreas in 1933, the effects of pancreatic steatosis have been poorly investigated, compared with that of the liver. However, the interest of research is increasing. Fat accumulation, associated with obesity and the metabolic syndrome (MetS), has been defined as "fatty infiltration" or "nonalcoholic fatty pancreas disease" (NAFPD). The term "fatty replacement" describes a distinct phenomenon characterized by death of acinar cells and replacement by adipose tissue. Risk factors for developing NAFPD include obesity, increasing age, male sex, hypertension, dyslipidemia, alcohol and hyperferritinemia. Increasing evidence support the role of pancreatic fat in the development of type 2 diabetes mellitus, MetS, atherosclerosis, severe acute pancreatitis and even pancreatic cancer. Evidence exists that fatty pancreas could be used as the initial indicator of "ectopic fat deposition", which is a key element of nonalcoholic fatty liver disease and/or MetS. Moreover, in patients with fatty pancreas, pancreaticoduodenectomy is associated with an increased risk of intraoperative blood loss and post-operative pancreatic fistula. PMID:27678349

  14. Hepatitis C in Special Patient Cohorts: New Opportunities in Decompensated Liver Cirrhosis, End-Stage Renal Disease and Transplant Medicine

    PubMed Central

    Hüsing, Anna; Kabar, Iyad; Schmidt, Hartmut H.; Heinzow, Hauke S.

    2015-01-01

    Worldwide, hepatitis C virus (HCV) is a common infection. Due to new antiviral approaches and the approval of direct-acting antiviral agents (DAA), HCV therapy has become more comfortable. Nevertheless, there are special patient groups, in whom treatment of HCV is still challenging. Due to only few data available, tolerability and efficacy of DAAs in special patient cohorts still remain unclear. Such special patient cohorts comprise HCV in patients with decompensated liver disease (Child-Pugh Class B or C), patients with chronic kidney disease, and patients on waiting lists to renal/liver transplantation or those with HCV recurrence after liver transplantation. HCV infection in these patient cohorts has been shown to be associated with increased morbidity and mortality and may lead to reduced graft survival after transplantation. Successful eradication of HCV results in a better outcome concerning liver-related complications and in a better clinical outcome of these patients. In this review, we analyze available data and results from recently published literature and provide an overview of current recommendations of HCV-therapy regimen in these special patient cohorts. PMID:26251895

  15. Hepatitis C in Special Patient Cohorts: New Opportunities in Decompensated Liver Cirrhosis, End-Stage Renal Disease and Transplant Medicine.

    PubMed

    Hüsing, Anna; Kabar, Iyad; Schmidt, Hartmut H; Heinzow, Hauke S

    2015-01-01

    Worldwide, hepatitis C virus (HCV) is a common infection. Due to new antiviral approaches and the approval of direct-acting antiviral agents (DAA), HCV therapy has become more comfortable. Nevertheless, there are special patient groups, in whom treatment of HCV is still challenging. Due to only few data available, tolerability and efficacy of DAAs in special patient cohorts still remain unclear. Such special patient cohorts comprise HCV in patients with decompensated liver disease (Child-Pugh Class B or C), patients with chronic kidney disease, and patients on waiting lists to renal/liver transplantation or those with HCV recurrence after liver transplantation. HCV infection in these patient cohorts has been shown to be associated with increased morbidity and mortality and may lead to reduced graft survival after transplantation. Successful eradication of HCV results in a better outcome concerning liver-related complications and in a better clinical outcome of these patients. In this review, we analyze available data and results from recently published literature and provide an overview of current recommendations of HCV-therapy regimen in these special patient cohorts. PMID:26251895

  16. Elevated Bathing-Associated Disease Risks Despite Certified Water Quality: A Cohort Study

    PubMed Central

    Papastergiou, Panagiotis; Mouchtouri, Varvara; Pinaka, Ourania; Katsiaflaka, Anna; Rachiotis, George; Hadjichristodoulou, Christos

    2012-01-01

    Bacteriological water quality criteria have been recommended to ensure bathers’ health. However, this risk-assessment approach is based mainly on routine measurements of fecal pollution indicator bacteria in seawater, and may not be adequate to protect bathers effectively. The aim of this study was to assess the risks of symptoms related to infectious diseases among bathers after exposure to seawater which was of excellent quality according to EU guidelines. This study is a cohort study recruiting bathers and non-bathers. Water samples were collected for estimating bacterial indicators. Univariable and multivariable analysis was performed to compare the risks of developing symptoms/diseases between bathers and non-bathers. A total of 3805 bathers and 572 non-bathers were included in the study. Water analysis results demonstrated excellent quality of bathing water. Significantly increased risks of symptoms related to gastrointestinal infections (OR = 3.60, 95% CI 1.28–10.13), respiratory infections (OR = 1.92, 95% CI 1.00–3.67), eye infections (OR = 2.43, 95% CI 1.27–4.63) and ear infections (OR = 17.21, 95% CI 2.42–122.34) were observed among bathers compared with non-bathers. Increased rates of medical consultation and medication use were also observed among bathers. There was evidence that bathers experienced increased morbidity compared with non-bathers though the bathing waters met bacteriological water quality criteria. These results suggest that risk assessments of recreational seawaters should not only focus on bacteriological water quality criteria. PMID:22754456

  17. Fruit intake and cardiovascular disease mortality in the UK Women's Cohort Study.

    PubMed

    Lai, Heidi Tsz Mung; Threapleton, Diane Erin; Day, Andrea Jill; Williamson, Gary; Cade, Janet Elizabeth; Burley, Victoria Jane

    2015-09-01

    In observational studies, fruit intake is associated with a reduced risk of cardiovascular disease (CVD), though fruit type has been less frequently explored. The aim of the current study was to explore the association between total fruit and fruit subgroup intake according to polyphenol content and CVD mortality in the UK Women's Cohort Study. Total fruit intake (g/day) derived from a 217-item food frequency questionnaire was obtained from 30,458 women (aged 35-69 years) at baseline from 1995-1998. Fruit intakes were sub-categorised according to similarities in polyphenol profile from Phenol Explorer, including berries, citrus, drupes, pomes and tropical fruits. Mortality events were derived from the NHS Central Register. During the mean follow-up period of 16.7 years, 286 fatal CVD deaths [138 coronary heart disease (CHD), 148 stroke] were observed. Survival analysis was conducted using participants free from history of CVD at baseline. Total fruit intake was associated with lower risk of CVD and CHD mortality, with a 6-7 % reduction in risk for each 80 g/day portion consumed (99 % CI 0.89, 1.00 and 0.85, 1.01 respectively). Concerning particular fruit types, the direction of the associations tended to be inverse, but point estimates and tests for trend were not generally statistically significant. However, women in the highest intake group of grapes and citrus experienced a significant reduction in risk of CVD and stroke respectively compared with non-consumers [HR 0.56 (99 % CI 0.32, 0.98) and 0.34 (0.14, 0.82) respectively]. These findings support promoted guidelines encouraging fruit consumption for health in women, but do not provide strong evidence to suggest that fruit type is as important.

  18. Peptic Ulcer Disease in Healthcare Workers: A Nationwide Population-Based Cohort Study

    PubMed Central

    Lin, Hong-Yue; Weng, Shih-Feng; Lin, Hung-Jung; Hsu, Chien-Chin; Wang, Jhi-Joung; Su, Shih-Bin; Guo, How-Ran; Huang, Chien-Cheng

    2015-01-01

    Health care workers (HCWs) in Taiwan have heavy, stressful workloads, are on-call, and have rotating nightshifts, all of which might contribute to peptic ulcer disease (PUD). We wanted to evaluate the PUD risk in HCWs, which is not clear. Using Taiwan’s National Health Insurance Research Database, we identified 50,226 physicians, 122,357 nurses, 20,677 pharmacists, and 25,059 other HCWs (dieticians, technicians, rehabilitation therapists, and social workers) as the study cohort, and randomly selected an identical number of non-HCW patients (i.e., general population) as the comparison cohort. Conditional logistical regression analysis was used to compare the PUD risk between them. Subgroup analysis for physician specialties was also done. Nurses and other HCWs had a significantly higher PUD risk than did the general population (odds ratio [OR]: 1.477; 95% confidence interval [CI]: 1.433–1.521 and OR: 1.328; 95% CI: 1.245–1.418, respectively); pharmacists had a lower risk (OR: 0.884; 95% CI: 0.828–0.945); physicians had a nonsignificantly different risk (OR: 1.029; 95% CI: 0.987–1.072). In the physician specialty subgroup analysis, internal medicine, surgery, Ob/Gyn, and family medicine specialists had a higher PUD risk than other physicians (OR: 1.579; 95% CI: 1.441–1.731, OR: 1.734; 95% CI: 1.565–1.922, OR: 1.336; 95% CI: 1.151–1.550, and OR: 1.615; 95% CI: 1.425–1.831, respectively). In contrast, emergency physicians had a lower risk (OR: 0.544; 95% CI: 0.359–0.822). Heavy workloads, long working hours, workplace stress, rotating nightshifts, and coping skills may explain our epidemiological findings of higher risks for PUD in some HCWs, which might help us improve our health policies for HCWs. PMID:26301861

  19. The Metabolic Role of Gut Microbiota in the Development of Nonalcoholic Fatty Liver Disease and Cardiovascular Disease.

    PubMed

    Sanduzzi Zamparelli, Marco; Compare, Debora; Coccoli, Pietro; Rocco, Alba; Nardone, Olga Maria; Marrone, Giuseppe; Gasbarrini, Antonio; Grieco, Antonio; Nardone, Gerardo; Miele, Luca

    2016-01-01

    The prevalence of metabolic disorders, such as type 2 diabetes (T2D), obesity, and non-alcoholic fatty liver disease (NAFLD), which are common risk factors for cardiovascular disease (CVD), has dramatically increased worldwide over the last decades. Although dietary habit is the main etiologic factor, there is an imperfect correlation between dietary habits and the development of metabolic disease. Recently, research has focused on the role of the microbiome in the development of these disorders. Indeed, gut microbiota is implicated in many metabolic functions and an altered gut microbiota is reported in metabolic disorders. Here we provide evidence linking gut microbiota and metabolic diseases, focusing on the pathogenetic mechanisms underlying this association. PMID:27483246

  20. The Metabolic Role of Gut Microbiota in the Development of Nonalcoholic Fatty Liver Disease and Cardiovascular Disease

    PubMed Central

    Sanduzzi Zamparelli, Marco; Compare, Debora; Coccoli, Pietro; Rocco, Alba; Nardone, Olga Maria; Marrone, Giuseppe; Gasbarrini, Antonio; Grieco, Antonio; Nardone, Gerardo; Miele, Luca

    2016-01-01

    The prevalence of metabolic disorders, such as type 2 diabetes (T2D), obesity, and non-alcoholic fatty liver disease (NAFLD), which are common risk factors for cardiovascular disease (CVD), has dramatically increased worldwide over the last decades. Although dietary habit is the main etiologic factor, there is an imperfect correlation between dietary habits and the development of metabolic disease. Recently, research has focused on the role of the microbiome in the development of these disorders. Indeed, gut microbiota is implicated in many metabolic functions and an altered gut microbiota is reported in metabolic disorders. Here we provide evidence linking gut microbiota and metabolic diseases, focusing on the pathogenetic mechanisms underlying this association. PMID:27483246

  1. Therapeutic manipulation of glucocorticoid metabolism in cardiovascular disease

    PubMed Central

    Hadoke, Patrick WF; Iqbal, Javaid; Walker, Brian R

    2009-01-01

    The therapeutic potential for manipulation of glucocorticoid metabolism in cardiovascular disease was revolutionized by the recognition that access of glucocorticoids to their receptors is regulated in a tissue-specific manner by the isozymes of 11β-hydroxysteroid dehydrogenase. Selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 have been shown recently to ameliorate cardiovascular risk factors and inhibit the development of atherosclerosis. This article addresses the possibility that inhibition of 11β-hydroxsteroid dehydrogenase type 1 activity in cells of the cardiovascular system contributes to this beneficial action. The link between glucocorticoids and cardiovascular disease is complex as glucocorticoid excess is linked with increased cardiovascular events but glucocorticoid administration can reduce atherogenesis and restenosis in animal models. There is considerable evidence that glucocorticoids can interact directly with cells of the cardiovascular system to alter their function and structure and the inflammatory response to injury. These actions may be regulated by glucocorticoid and/or mineralocorticoid receptors but are also dependent on the 11β-hydroxysteroid dehydrogenases which may be expressed in cardiac, vascular (endothelial, smooth muscle) and inflammatory (macrophages, neutrophils) cells. The activity of 11β-hydroxysteroid dehydrogenases in these cells is dependent upon differentiation state, the action of pro-inflammaotory cytokines and the influence of endogenous inhibitors (oxysterols, bile acids). Further investigations are required to clarify the link between glucocorticoid excess and cardiovascular events and to determine the mechanism through which glucocorticoid treatment inhibits atherosclerosis/restenosis. This will provide greater insights into the potential benefit of selective 11β-hydroxysteroid dehydrogenase inhibitors in treatment of cardiovascular disease. PMID:19239478

  2. Baseline characteristics of patients with chronic kidney disease stage 3 and stage 4 in spain: the MERENA observational cohort study

    PubMed Central

    2011-01-01

    Background To obtain information on cardiovascular morbidity, hypertension control, anemia and mineral metabolism based on the analysis of the baseline characteristics of a large cohort of Spanish patients enrolled in an ongoing prospective, observational, multicenter study of patients with stages 3 and 4 chronic kidney diseases (CKD). Methods Multicenter study from Spanish government hospital-based Nephrology outpatient clinics involving 1129 patients with CKD stages 3 (n = 434) and 4 (n = 695) defined by GFR calculated by the MDRD formula. Additional analysis was performed with GFR calculated using the CKD-EPI and Cockcroft-Gault formula. Results In the cohort as a whole, median age 70.9 years, morbidity from all cardiovascular disease (CVD) was very high (39.1%). In CKD stage 4, CVD prevalence was higher than in stage 3 (42.2 vs 35.6% p < 0.024). Subdividing stage 3 in 3a and 3b and after adjusting for age, CVD increased with declining GFR with the hierarchy (stage 3a < stage 3b < stage 4) when calculated by CKD-EPI (31.8, 35.4, 42.1%, p 0.039) and Cockcroft-Gault formula (30.9, 35.6, 43.4%, p 0.010) and MDRD formula (32.5, 36.2, 42.2%,) but with the latter, it did not reach statistical significance (p 0.882). Hypertension was almost universal among those with stages 3 and 4 CKD (91.2% and 94.1%, respectively) despite the use of more than 3 anti-hypertensive agents including widespread use of RAS blockers. Proteinuria (> 300 mg/day) was present in more than 60% of patients and there was no significant differences between stages 3 and 4 CKD (1.2 ± 1.8 and 1.3 ± 1.8 g/day, respectively). A majority of the patients had hemoglobin levels greater than 11 g/dL (91.1 and 85.5% in stages 3 and 4 CKD respectively p < 0.001) while the use of erythropoiesis-stimulating agents (ESA) was limited to 16 and 34.1% in stages 3 and 4 CKD respectively. Intact parathyroid hormone (i-PTH) was elevated in stage 3 and stage 4 CKD patients (121 ± 99 and 166 ± 125 pg/mL p 0

  3. Case-cohort study of styrene exposure and ischemic heart disease.

    PubMed

    Matanoski, Genevieve M; Tao, Xuguang

    2002-05-01

    Recent epidemiologic studies have consistently reported increased daily mortalities and hospital admissions associated with exposure to particulate air pollution. Ischemic heart disease (IHD*, International Classification of Diseases, Eighth Revision [ICD-8], codes 410-414) is among those diseases that contribute in large measure to this excess mortality. Some occupational studies have suggested elevated risk of IHD among workers exposed for short periods to styrene, which can be emitted from fossil fuel combustion, aircraft exhausts, and motor vehicle exhausts. Styrene is found in ambient air at average concentrations of a few micrograms per cubic meter or less but may reach very high concentrations at particular locations and times. Unmeasured aerosols of styrene may also increase population exposures. This case-cohort study explored a possible association and dose-response relation between styrene exposure and risk of acute IHD in an occupational setting. The population under study was 6587 male workers employed between 1943 and 1982 in two US plants manufacturing styrene-butadiene polymers used in synthetic rubber. The study assessed all 498 subjects who died from IHD along with a subcohort of twice that size, 997 subjects, selected as a 15% random sample of the full target cohort. IHD deaths during the study led to some overlap between cases and the subcohort, leaving 1424 unique subjects. Job histories were collected for all subjects. Industrial hygienists and engineers from the industry estimated relative exposures for all jobs. Exposure data were collected for many of the jobs from different sources. For any job with no available exposure measurements, z scores were used to estimate job exposure in each plant from the relative exposure level for that job in similar plants and the measurement distribution parameters of the study plant. Standardized mortality ratio (SMR) analyses were used to examine the overall risk of dying from IHD among study subjects

  4. HLA correlates in a cohort of slow progressors from China: effects on HIV-1 disease progression.

    PubMed

    Rai, Mohammad A; Zhang, Yonghong; Yindom, Louis-M; Holmes, Jane; Yu, Ly-Mee; Hao, Chun; Rostron, Tim; Yan, Huiping; Zhang, Yong Li; Cai, Chao; McMichael, Andrew J; Dong, Tao; Rowland-Jones, Sarah L; Blais, Marie-E; Xu, Ke Yi

    2013-11-13

    We looked at our HIV + slow progressors cohort to determine if there were any human leukocyte antigen (HLA) correlates for protection. No statistically significant allelic differences were found between the HIV + and control cohorts using regression analysis, though trends were noted. Data for Elite Controllers showed an increased frequency of B*57. Likewise, no correlation was inferred with the clinical data of the HIV + cohort. We hypothesize that the protective effect of HLA alleles may have been lost over time. PMID:23942057

  5. Effect of Natural Polyphenols on CYP Metabolism: Implications for Diseases.

    PubMed

    Korobkova, Ekaterina A

    2015-07-20

    Cytochromes P450 (CYPs) are a large group of hemeproteins located on mitochondrial membranes or the endoplasmic reticulum. They play a crucial role in the metabolism of endogenous and exogenous molecules. The activity of CYP is associated with a number of factors including redox potential, protein conformation, the accessibility of the active site by substrates, and others. This activity may be potentially modulated by a variety of small molecules. Extensive experimental data collected over the past decade point at the active role of natural polyphenols in modulating the catalytic activity of CYP. Polyphenols are widespread micronutrients present in human diets of plant origin and in medicinal herbs. These compounds may alter the activity of CYP either via direct interactions with the enzymes or by affecting CYP gene expression. The polyphenol-CYP interactions may significantly alter the pharmacokinetics of drugs and thus influence the effectiveness of chemical therapies used in the treatment of different types of cancers, diabetes, obesity, and cardiovascular diseases (CVD). CYPs are involved in the oxidation and activation of external carcinogenic agents, in which case the inhibition of the CYP activity is beneficial for health. CYPs also support detoxification processes. In this case, it is the upregulation of CYP genes that would be favorable for the organism. A CYP enzyme aromatase catalyzes the formation of estrone and estradiol from their precursors. CYPs also catalyze multiple reactions leading to the oxidation of estrogen. Estrogen signaling and oxidative metabolism of estrogen are associated with the development of cancer. Thus, polyphenol-mediated modulation of the CYP's activity also plays a vital role in estrogen carcinogenesis. The aim of the present review is to summarize the data collected over the last five to six years on the following topics: (1) the mechanisms of the interactions of CYP with food constituents that occur via the direct binding of

  6. Brain lipoprotein metabolism and its relation to neurodegenerative disease.

    PubMed

    Danik, M; Champagne, D; Petit-Turcotte, C; Beffert, U; Poirier, J

    1999-01-01

    notion and suggests that the isolated brain possesses its own system to maintain local lipid homeostasis. This is further exemplified by the salvage and recycling of lipids shown to occur following a lesion in order to allow surviving neurons to sprout and reestablish lost synapses. Not much is currently known about lipoprotein metabolism in neurodegenerative diseases, but lipid alterations have been repeatedly reported in Alzheimer brains in which neuronal loss and deafferentation are major features. Although the mechanism underlying the link between the epsilon4 allele of the apolipoprotein E gene and Alzheimer's disease is presently unclear, it may well be postulated that it is related to disturbances in brain lipoprotein metabolism. PMID:11028681

  7. Effect of Natural Polyphenols on CYP Metabolism: Implications for Diseases.

    PubMed

    Korobkova, Ekaterina A

    2015-07-20

    Cytochromes P450 (CYPs) are a large group of hemeproteins located on mitochondrial membranes or the endoplasmic reticulum. They play a crucial role in the metabolism of endogenous and exogenous molecules. The activity of CYP is associated with a number of factors including redox potential, protein conformation, the accessibility of the active site by substrates, and others. This activity may be potentially modulated by a variety of small molecules. Extensive experimental data collected over the past decade point at the active role of natural polyphenols in modulating the catalytic activity of CYP. Polyphenols are widespread micronutrients present in human diets of plant origin and in medicinal herbs. These compounds may alter the activity of CYP either via direct interactions with the enzymes or by affecting CYP gene expression. The polyphenol-CYP interactions may significantly alter the pharmacokinetics of drugs and thus influence the effectiveness of chemical therapies used in the treatment of different types of cancers, diabetes, obesity, and cardiovascular diseases (CVD). CYPs are involved in the oxidation and activation of external carcinogenic agents, in which case the inhibition of the CYP activity is beneficial for health. CYPs also support detoxification processes. In this case, it is the upregulation of CYP genes that would be favorable for the organism. A CYP enzyme aromatase catalyzes the formation of estrone and estradiol from their precursors. CYPs also catalyze multiple reactions leading to the oxidation of estrogen. Estrogen signaling and oxidative metabolism of estrogen are associated with the development of cancer. Thus, polyphenol-mediated modulation of the CYP's activity also plays a vital role in estrogen carcinogenesis. The aim of the present review is to summarize the data collected over the last five to six years on the following topics: (1) the mechanisms of the interactions of CYP with food constituents that occur via the direct binding of

  8. Heart Failure in a Cohort of Patients with Chronic Kidney Disease: The GCKD Study

    PubMed Central

    Beck, Hanna; Titze, Stephanie I.; Hübner, Silvia; Busch, Martin; Schlieper, Georg; Schultheiss, Ulla T.; Wanner, Christoph; Kronenberg, Florian; Krane, Vera; Eckardt, Kai-Uwe; Köttgen, Anna

    2015-01-01

    Background and Aims Chronic kidney disease (CKD) is a risk factor for development and progression of heart failure (HF). CKD and HF share common risk factors, but few data exist on the prevalence, signs and symptoms as well as correlates of HF in populations with CKD of moderate severity. We therefore aimed to examine the prevalence and correlates of HF in the German Chronic Kidney Disease (GCKD) study, a large observational prospective study. Methods and Results We analyzed data from 5,015 GCKD patients aged 18–74 years with an estimated glomerular filtration rate (eGFR) of <60 ml/min/1.73m² or with an eGFR ≥60 and overt proteinuria (>500 mg/d). We evaluated a definition of HF based on the Gothenburg score, a clinical HF score used in epidemiological studies (Gothenburg HF), and self-reported HF. Factors associated with HF were identified using multivariable adjusted logistic regression. The prevalence of Gothenburg HF was 43% (ranging from 24% in those with eGFR >90 to 59% in those with eGFR<30 ml/min/1.73m2). The corresponding estimate for self-reported HF was 18% (range 5%-24%). Lower eGFR was significantly and independently associated with the Gothenburg definition of HF (p-trend <0.001). Additional significantly associated correlates included older age, female gender, higher BMI, hypertension, diabetes mellitus, valvular heart disease, anemia, sleep apnea, and lower educational status. Conclusions The burden of self-reported and Gothenburg HF among patients with CKD is high. The proportion of patients who meet the criteria for Gothenburg HF in a European cohort of patients with moderate CKD is more than twice as high as the prevalence of self-reported HF. However, because of the shared signs, symptoms and medications of HF and CKD, the Gothenburg score cannot be used to reliably define HF in CKD patients. Our results emphasize the need for early screening for HF in patients with CKD. PMID:25874373

  9. Is schizophrenia associated with an increased risk of chronic kidney disease? A nationwide matched-cohort study

    PubMed Central

    Tzeng, Nian-Sheng; Hsu, Yung-Ho; Ho, Shinn-Ying; Kuo, Yu-Ching; Lee, Hua-Chin; Yin, Yun-Ju; Chen, Hong-An; Chen, Wen-Liang; Chu, William Cheng-Chung; Huang, Hui-Ling

    2015-01-01

    Objective The impact of schizophrenia on vital diseases, such as chronic kidney disease (CKD), has not as yet been verified. This study aims to establish whether there is an association between schizophrenia and CKD. Design A nationwide matched cohort study. Setting Taiwan's National Health Insurance Research Database. Participants A total of 2338 patients with schizophrenia, and 7014 controls without schizophrenia (1:3), matched cohort for sex, age group, geography, urbanisation and monthly income, between 1 January 2003 and 31 December 2007, based on the International Classifications of Disease Ninth Edition (ICD-9), Clinical Modification codes. Primary and secondary outcome measures After making adjustments for confounding risk factors, a Cox proportional hazards model was used to compare the risk of developing CKD during a 3-year follow-up period from the index date. Results Of the 2338-subject case cohort, 163 (6.97%) developed a CKD, as did 365 (5.20%) of the 7014 control participants. Cox proportional hazards regression analysis revealed that patients with schizophrenia were more likely to develop CKD (HR=1.36, 95% CI 1.13 to 1.63; p<0.001). After adjusting for gender, age group, hypertension, diabetes mellitus, hyperlipidaemia, heart disease and non-steroid anti-inflammatory drugs (NSAIDs) usage, the HR for patients with schizophrenia was 1.25 (95% CI 1.04 to 1.50; p<0.05). Neither typical nor atypical antipsychotics was associated an increased risk of CKD in patients with schizophrenia. Conclusions The findings from this population-based retrospective cohort study suggest that schizophrenia is associated with a 25% increase in the risk of developing CKD within only a 3-year follow-up period. PMID:25628048

  10. Association between sexually transmitted disease and church membership. A retrospective cohort study of two Danish religious minorities

    PubMed Central

    Kørup, Alex Kappel; Thygesen, Lau Caspar; Christensen, René dePont; Johansen, Christoffer; Søndergaard, Jens; Hvidt, Niels Christian

    2016-01-01

    Objectives Studies comprising Danish Seventh-day Adventists (SDAs) and Danish Baptists found that members have a lower risk of chronic diseases including cancer. Explanations have pointed to differences in lifestyle, but detailed aetiology has only been sparsely examined. Our objective was to investigate the incidence of sexually transmitted diseases (STDs) among Danish SDAs and Baptists as a proxy for cancers related to sexual behaviour. Methods We followed the Danish Cohort of Religious Societies from 1977 to 2009, and linked it with national registers of all inpatient and outpatient care contacts using the National Patient Register. We compared the incidence of syphilis, gonorrhoea and chlamydia among members of the cohort with the general population. Results The cohort comprised 3119 SDA females, 1856 SDA males, 2056 Baptist females and 1467 Baptist males. For the entire cohort, we expected a total of 32.4 events of STD, and observed only 9. Female SDAs and Baptists aged 20–39 years had significant lower incidence of chlamydia (both p<0.001). Male SDAs and Baptists aged 20–39 years also had significant lower incidence of chlamydia (p<0.01 and p<0.05, respectively). No SDA members were diagnosed with gonorrhoea, when 3.4 events were expected, which, according to Hanley's ‘rule of three’, is a significant difference. No SDA or Baptist was diagnosed with syphilis. Conclusions The cohort shows significant lower incidence of STD, most likely including human papillomavirus, which may partly explain the lower incidence of cancers of the cervix, rectum, anus, head and neck. PMID:27016243

  11. MRI biomarker assessment of neuromuscular disease progression: a prospective observational cohort study

    PubMed Central

    Morrow, Jasper M; Sinclair, Christopher D J; Fischmann, Arne; Machado, Pedro M; Reilly, Mary M; Yousry, Tarek A; Thornton, John S; Hanna, Michael G

    2016-01-01

    Summary Background A substantial impediment to progress in trials of new therapies in neuromuscular disorders is the absence of responsive outcome measures that correlate with patient functional deficits and are sensitive to early disease processes. Irrespective of the primary molecular defect, neuromuscular disorder pathological processes include disturbance of intramuscular water distribution followed by intramuscular fat accumulation, both quantifiable by MRI. In pathologically distinct neuromuscular disorders, we aimed to determine the comparative responsiveness of MRI outcome measures over 1 year, the validity of MRI outcome measures by cross-sectional correlation against functionally relevant clinical measures, and the sensitivity of specific MRI indices to early muscle water changes before intramuscular fat accumulation beyond the healthy control range. Methods We did a prospective observational cohort study of patients with either Charcot-Marie-Tooth disease 1A or inclusion body myositis who were attending the inherited neuropathy or muscle clinics at the Medical Research Council (MRC) Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, London, UK. Genetic confirmation of the chromosome 17p11·2 duplication was required for Charcot-Marie-Tooth disease 1A, and classification as pathologically or clinically definite by MRC criteria was required for inclusion body myositis. Exclusion criteria were concomitant diseases and safety-related MRI contraindications. Healthy age-matched and sex-matched controls were also recruited. Assessments were done at baseline and 1 year. The MRI outcomes—fat fraction, transverse relaxation time (T2), and magnetisation transfer ratio (MTR)—were analysed during the 12-month follow-up, by measuring correlation with functionally relevant clinical measures, and for T2 and MTR, sensitivity in muscles with fat fraction less than the 95th percentile of the control group. Findings Between Jan 19, 2010

  12. The general population cohort in rural south-western Uganda: a platform for communicable and non-communicable disease studies

    PubMed Central

    Asiki, Gershim; Murphy, Georgina; Nakiyingi-Miiro, Jessica; Seeley, Janet; Nsubuga, Rebecca N; Karabarinde, Alex; Waswa, Laban; Biraro, Sam; Kasamba, Ivan; Pomilla, Cristina; Maher, Dermot; Young, Elizabeth H; Kamali, Anatoli; Sandhu, Manjinder S

    2013-01-01

    The General Population Cohort (GPC) was set up in 1989 to examine trends in HIV prevalence and incidence, and their determinants in rural south-western Uganda. Recently, the research questions have included the epidemiology and genetics of communicable and non-communicable diseases (NCDs) to address the limited data on the burden and risk factors for NCDs in sub-Saharan Africa. The cohort comprises all residents (52% aged ≥13years, men and women in equal proportions) within one-half of a rural sub-county, residing in scattered houses, and largely farmers of three major ethnic groups. Data collected through annual surveys include; mapping for spatial analysis and participant location; census for individual socio-demographic and household socioeconomic status assessment; and a medical survey for health, lifestyle and biophysical and blood measurements to ascertain disease outcomes and risk factors for selected participants. This cohort offers a rich platform to investigate the interplay between communicable diseases and NCDs. There is robust infrastructure for data management, sample processing and storage, and diverse expertise in epidemiology, social and basic sciences. For any data access enquiries you may contact the director, MRC/UVRI, Uganda Research Unit on AIDS by email to mrc@mrcuganda.org or the corresponding author. PMID:23364209

  13. Rare Variants in PLD3 Do Not Affect Risk for Early-Onset Alzheimer Disease in a European Consortium Cohort.

    PubMed

    Cacace, Rita; Van den Bossche, Tobi; Engelborghs, Sebastiaan; Geerts, Nathalie; Laureys, Annelies; Dillen, Lubina; Graff, Caroline; Thonberg, Håkan; Chiang, Huei-Hsin; Pastor, Pau; Ortega-Cubero, Sara; Pastor, Maria A; Diehl-Schmid, Janine; Alexopoulos, Panagiotis; Benussi, Luisa; Ghidoni, Roberta; Binetti, Giuliano; Nacmias, Benedetta; Sorbi, Sandro; Sanchez-Valle, Raquel; Lladó, Albert; Gelpi, Ellen; Almeida, Maria Rosário; Santana, Isabel; Tsolaki, Magda; Koutroumani, Maria; Clarimon, Jordi; Lleó, Alberto; Fortea, Juan; de Mendonça, Alexandre; Martins, Madalena; Borroni, Barbara; Padovani, Alessandro; Matej, Radoslav; Rohan, Zdenek; Vandenbulcke, Mathieu; Vandenberghe, Rik; De Deyn, Peter P; Cras, Patrick; van der Zee, Julie; Sleegers, Kristel; Van Broeckhoven, Christine

    2015-12-01

    Rare variants in the phospholipase D3 gene (PLD3) were associated with increased risk for late-onset Alzheimer disease (LOAD). We identified a missense mutation in PLD3 in whole-genome sequence data of a patient with autopsy confirmed Alzheimer disease (AD) and onset age of 50 years. Subsequently, we sequenced PLD3 in a Belgian early-onset Alzheimer disease (EOAD) patient (N = 261) and control (N = 319) cohort, as well as in European EOAD patients (N = 946) and control individuals (N = 1,209) ascertained in different European countries. Overall, we identified 22 rare variants with a minor allele frequency <1%, 20 missense and two splicing mutations. Burden analysis did not provide significant evidence for an enrichment of rare PLD3 variants in EOAD patients in any of the patient/control cohorts. Also, meta-analysis of the PLD3 data, including a published dataset of a German EOAD cohort, was not significant (P = 0.43; OR = 1.53, 95% CI 0.60-3.31). Consequently, our data do not support a role for PLD3 rare variants in the genetic etiology of EOAD in European EOAD patients. Our data corroborate the negative replication data obtained in LOAD studies and therefore a genetic role of PLD3 in AD remains to be demonstrated.

  14. Rare Variants in PLD3 Do Not Affect Risk for Early‐Onset Alzheimer Disease in a European Consortium Cohort

    PubMed Central

    Cacace, Rita; Van den Bossche, Tobi; Engelborghs, Sebastiaan; Geerts, Nathalie; Laureys, Annelies; Dillen, Lubina; Graff, Caroline; Thonberg, Håkan; Chiang, Huei‐Hsin; Pastor, Pau; Ortega‐Cubero, Sara; Pastor, Maria A.; Diehl‐Schmid, Janine; Alexopoulos, Panagiotis; Benussi, Luisa; Ghidoni, Roberta; Binetti, Giuliano; Nacmias, Benedetta; Sorbi, Sandro; Sanchez‐Valle, Raquel; Lladó, Albert; Gelpi, Ellen; Almeida, Maria Rosário; Santana, Isabel; Tsolaki, Magda; Koutroumani, Maria; Clarimon, Jordi; Lleó, Alberto; Fortea, Juan; de Mendonça, Alexandre; Martins, Madalena; Borroni, Barbara; Padovani, Alessandro; Matej, Radoslav; Rohan, Zdenek; Vandenbulcke, Mathieu; Vandenberghe, Rik; De Deyn, Peter P.; Cras, Patrick; van der Zee, Julie; Sleegers, Kristel

    2015-01-01

    ABSTRACT Rare variants in the phospholipase D3 gene (PLD3) were associated with increased risk for late‐onset Alzheimer disease (LOAD). We identified a missense mutation in PLD3 in whole‐genome sequence data of a patient with autopsy confirmed Alzheimer disease (AD) and onset age of 50 years. Subsequently, we sequenced PLD3 in a Belgian early‐onset Alzheimer disease (EOAD) patient (N = 261) and control (N = 319) cohort, as well as in European EOAD patients (N = 946) and control individuals (N = 1,209) ascertained in different European countries. Overall, we identified 22 rare variants with a minor allele frequency <1%, 20 missense and two splicing mutations. Burden analysis did not provide significant evidence for an enrichment of rare PLD3 variants in EOAD patients in any of the patient/control cohorts. Also, meta‐analysis of the PLD3 data, including a published dataset of a German EOAD cohort, was not significant (P = 0.43; OR = 1.53, 95% CI 0.60–3.31). Consequently, our data do not support a role for PLD3 rare variants in the genetic etiology of EOAD in European EOAD patients. Our data corroborate the negative replication data obtained in LOAD studies and therefore a genetic role of PLD3 in AD remains to be demonstrated. PMID:26411346

  15. Dietary fatty acids in metabolic syndrome, diabetes and cardiovascular diseases.

    PubMed

    Cascio, Giuseppe; Schiera, Gabriella; Di Liegro, Italia

    2012-01-01

    In the last few decades, the prevalence of overweight and essential obesity has been undergoing a fast and progressive worldwide increase. Obesity has been in turn linked to type II diabetes, with the total number of diabetic patients worryingly increasing, in the last fifteen years, suggesting a pandemic phenomenon. At the same time, an increase in the prevalence of cardiovascular diseases has been also recorded. Increasing evidence suggests that the diet is involved in such escalation. In particular, the progressive globalization of food industry allowed massive supply, at a relatively low price, of a great variety of pre-packed food and bakery products, with very high energy content. Most of this food contains high amounts of saturated fatty acids (SFA) and of hydrogenated or trans fatty acids (TFA), that probably represent the prominent risk factors in the diet. Herein we will report diffusion and possible impact on health of such molecules, with reference to coronary heart disease, insulin resistance, metabolic syndrome and diabetes. We will also discuss the cellular and molecular mechanisms of action of fatty acids and fatty acid-derivatives which have been involved either in promoting or in preventing human pathologies. Free fatty acids (FFA) are not indeed only essential fuels for the organism. They also act as ligands for both membrane and nuclear receptors involved in different signaling pathways. Notably, some of these pathways can induce cell stress and apoptosis. Most important, FFA can affect glucose-induced insulin secretion and activate β-cell death. These events can be at least in part counteracted by polyunsaturated fatty acids. PMID:22414056

  16. Effectiveness of a multidisciplinary heart failure disease management programme on 1-year mortality: Prospective cohort study.

    PubMed

    Laborde-Castérot, Hervé; Agrinier, Nelly; Zannad, Faiez; Mebazaa, Alexandre; Rossignol, Patrick; Girerd, Nicolas; Alla, François; Thilly, Nathalie

    2016-09-01

    We performed a multicenter prospective observational cohort study (Epidémiologie et Pronostic de l'Insuffisance Cardiaque Aiguë en Lorraine, Epidemiology and Prognosis of Acute Heart Failure in Lorraine [EPICAL2]) to evaluate the effectiveness on mortality of a community-based multidisciplinary disease management programme (DMP) for heart failure (HF) patients.Between October 2011 and October 2012, 1816 patients, who were hospitalized for acute HF or who developed acute HF during a hospitalization, were included from 21 hospitals in a northeast region of France. At hospital admission, their mean age was 77.3 (standard deviation [SD] 11.6) years and mean left ventricular ejection fraction was 45.0 (SD 16.0)%. A subset of patients were enrolled in a multidimensional DMP for HF (n = 312, 17.2%), based on structured patient education, home monitoring visits by HF-trained nurses, and automatic alerts triggered by significant clinical and biological changes to the patient. The DMP involved general practitioners, nurses, and cardiologists collaborating via an individual web-based medical electronic record. The outcome was all-cause mortality from the 3rd to the 12th month after discharge. During the follow-up, a total of 377 (20.8%) patients died: 321 (21.3%) in the control group and 56 (17.9%) in the DMP group. In a propensity score analysis, DMP was associated with lower 1-year all-cause mortality (hazard ratio 0.65, 95% CI 0.46-0.92). Instrumental variable analysis gave similar results (hazard ratio 0.56, 0.27-1.16).In a real world setting, a multidimensional DMP for HF with structured patient education, home nurse monitoring, and appropriate physician alerts may improve survival when implemented after discharge from hospitalization due to worsening HF.

  17. Role of Cilostazol Therapy in Hemodialysis Patients with Asymptomatic Peripheral Arterial Disease: A Retrospective Cohort Study

    PubMed Central

    Wu, Ming Ying; Pai, Mei-Ann; Wu, Tsai-Kun; Chen, Chang Hsu

    2016-01-01

    Background. Peripheral arterial disease (PAD) and its relevant complications are more common in hemodialysis (HD) patients, while the evidence regarding antiplatelet therapy in CKD patients is scarce. We retrospectively analyzed the efficacy of cilostazol on outcomes in HD patients with asymptomatic PAD (aPAD). Methods. This cohort study enrolled 217 HD patients (median follow-up time: 5.75 years). Associations between cilostazol use and the outcomes were evaluated by time-dependent Cox regression analysis. Results. During follow-up, 39.5% (47/119) patients used cilostazol for aPAD and 31.8% (69/217) patients died. Cilostazol users had significantly lower CVD and all-cause mortalities (adjusted HR [95% CI]: 0.11 [0.03, 0.51] and 0.2 [0.08, 0.52]) than nonusers. Both death risks were nonsignificantly higher in cilostazol users than in HD patients without aPAD. The unadjusted and adjusted HR [95% CI] of CVD death risk were 0.4 [0.07, 2.12] and 0.14 [0.02, 0.8] for patients with aPAD during follow-up and were 0.74 [0.16, 3.36] and 0.19 [0.04, 0.93] for those with aPAD at initial. Conclusions. In HD patients with aPAD, lower CVD and all-cause mortality rates were observed in low-dose cilostazol user. Further evidences from large-scale prospective study and randomization trial are desired to confirm the effect of cilostazol. PMID:27747241

  18. Effectiveness of a multidisciplinary heart failure disease management programme on 1-year mortality: Prospective cohort study.

    PubMed

    Laborde-Castérot, Hervé; Agrinier, Nelly; Zannad, Faiez; Mebazaa, Alexandre; Rossignol, Patrick; Girerd, Nicolas; Alla, François; Thilly, Nathalie

    2016-09-01

    We performed a multicenter prospective observational cohort study (Epidémiologie et Pronostic de l'Insuffisance Cardiaque Aiguë en Lorraine, Epidemiology and Prognosis of Acute Heart Failure in Lorraine [EPICAL2]) to evaluate the effectiveness on mortality of a community-based multidisciplinary disease management programme (DMP) for heart failure (HF) patients.Between October 2011 and October 2012, 1816 patients, who were hospitalized for acute HF or who developed acute HF during a hospitalization, were included from 21 hospitals in a northeast region of France. At hospital admission, their mean age was 77.3 (standard deviation [SD] 11.6) years and mean left ventricular ejection fraction was 45.0 (SD 16.0)%. A subset of patients were enrolled in a multidimensional DMP for HF (n = 312, 17.2%), based on structured patient education, home monitoring visits by HF-trained nurses, and automatic alerts triggered by significant clinical and biological changes to the patient. The DMP involved general practitioners, nurses, and cardiologists collaborating via an individual web-based medical electronic record. The outcome was all-cause mortality from the 3rd to the 12th month after discharge. During the follow-up, a total of 377 (20.8%) patients died: 321 (21.3%) in the control group and 56 (17.9%) in the DMP group. In a propensity score analysis, DMP was associated with lower 1-year all-cause mortality (hazard ratio 0.65, 95% CI 0.46-0.92). Instrumental variable analysis gave similar results (hazard ratio 0.56, 0.27-1.16).In a real world setting, a multidimensional DMP for HF with structured patient education, home nurse monitoring, and appropriate physician alerts may improve survival when implemented after discharge from hospitalization due to worsening HF. PMID:27631204

  19. Contaminated Small Drinking Water Supplies and Risk of Infectious Intestinal Disease: A Prospective Cohort Study

    PubMed Central

    Risebro, Helen L.; Breton, Lynette; Aird, Heather; Hooper, Alan; Hunter, Paul R.

    2012-01-01

    Background This study sought to identify whether elevated risk of infectious intestinal disease (IID) exists in contaminated small water supply consumers compared with consumers drinking from small supplies complying with current standards and whether this effect is modified by age. Methodology and Principal Findings A prospective cohort study of 611 individuals receiving small supplies in England was conducted. Water supplies received sanitary inspection and examination for indicator bacteria and participants maintained a daily record of IID. Regression modeling with generalized estimating equations that included interaction terms between age and indicators of fecal pollution was performed. Crude IID prevalence was 9·3 days with symptoms/1000 person days (95%CI: 8·4, 10·1) and incidence was 3·2 episodes/1000 person days (95%CI, 2·7, 3·7) or 1·2 episodes per person year. Although there was no overall association between IID risk and indicator presence, there was strong interaction between age and indicator presence. In children under ten, relative risk (RR) of IID in those drinking from enterococci contaminated supplies was 4.8 (95%CI: 1.5, 15.3) for incidence and 8.9 (95%CI: 2.8, 27.5) for prevalence. In those aged 10 to 59, IID risk was lower but not statistically significant. Conclusions Contaminated small water supplies pose a substantial risk of IID to young children who live in homes reliant on these supplies. By contrast older children and adults do not appear to be at increased risk. Health care professionals with responsibility for children living in homes provided by very small water supplies should make parents aware of the risk. PMID:22936989

  20. Mortality rate in children born to mothers and fathers with celiac disease: a nationwide cohort study.

    PubMed

    Zugna, Daniela; Richiardi, Lorenzo; Stephansson, Olof; Cnattingius, Sven; Ludvigsson, Jonas F

    2013-06-15

    Celiac disease (CD) is associated with increased mortality rate and adverse pregnancy outcome, but little is known about offspring mortality rate. In this nationwide retrospective cohort study, we identified persons whose biopsy-verified CD was diagnosed in Sweden in 1969-2008. We compared mortality rates in children born to mothers with and without CD (n = 16,121 vs. n = 61,782) and children born to fathers with and without CD (n = 9,289 vs. n = 32,984). Median age of offspring at end of follow-up was 28.7 (range, 16.7-39.7) years. We also examined mortality rates in children born to mothers with undiagnosed CD (later CD diagnosis; n = 12,919) and diagnosed CD (n = 3,202) to determine if intrauterine exposures associated with CD could affect offspring mortality rate. We estimated hazard ratios for death by using Cox regression. Death rates were independent of maternal CD (60 deaths per 100,000 person-years in children of mothers with CD, vs. 54 in controls) and paternal CD (53 deaths per 100,000 person-years in children of fathers with CD, vs. 53 in controls). Corresponding adjusted hazard ratios were 1.09 (95% confidence interval: 0.95, 1.26) for maternal CD and 1.02 (95% confidence interval: 0.85, 1.23) for paternal CD. Death rates were similar in children born to mothers with undiagnosed CD and in children whose mothers had diagnosed CD during pregnancy. Parental CD does not seem to influence mortality rate in offspring, which suggests that neither genetic influences of CD nor intrauterine conditions have adverse effects on offspring mortality rate.

  1. Hormone replacement therapy is associated with gastro-oesophageal reflux disease: a retrospective cohort study

    PubMed Central

    2012-01-01

    Background Oestrogen and progestogen have the potential to influence gastro-intestinal motility; both are key components of hormone replacement therapy (HRT). Results of observational studies in women taking HRT rely on self-reporting of gastro-oesophageal symptoms and the aetiology of gastro-oesophageal reflux disease (GORD) remains unclear. This study investigated the association between HRT and GORD in menopausal women using validated general practice records. Methods 51,182 menopausal women were identified using the UK General Practice Research Database between 1995–2004. Of these, 8,831 were matched with and without hormone use. Odds ratios (ORs) were calculated for GORD and proton-pump inhibitor (PPI) use in hormone and non-hormone users, adjusting for age, co-morbidities, and co-pharmacy. Results In unadjusted analysis, all forms of hormone use (oestrogen-only, tibolone, combined HRT and progestogen) were statistically significantly associated with GORD. In adjusted models, this association remained statistically significant for oestrogen-only treatment (OR 1.49; 1.18–1.89). Unadjusted analysis showed a statistically significant association between PPI use and oestrogen-only and combined HRT treatment. When adjusted for covariates, oestrogen-only treatment was significant (OR 1.34; 95% CI 1.03–1.74). Findings from the adjusted model demonstrated the greater use of PPI by progestogen users (OR 1.50; 1.01–2.22). Conclusions This first large cohort study of the association between GORD and HRT found a statistically significant association between oestrogen-only hormone and GORD and PPI use. This should be further investigated using prospective follow-up to validate the strength of association and describe its clinical significance. PMID:22642788

  2. Increased incidence of coronary heart disease associated with "double burden" in a cohort of Italian women.

    PubMed

    D'Ovidio, Fabrizio; d'Errico, Angelo; Scarinzi, Cecilia; Costa, Giuseppe

    2015-06-01

    Objective of this study was to assess the risk of coronary heart disease (CHD) associated with the combination of employment status and child care among women of working age, also examining the sex of the offspring. Only two previous studies investigated the effect of double burden on CHD, observing an increased risk among employed women with high domestic burden or providing child care, although the relative risks were marginally or not significant. The study population was composed of all women 25-50 years old at 2001 census, living in Turin in families composed only by individuals or couples, with or without children (N = 109,358). Subjects were followed up during 2002-2010 for CHD incidence and mortality through record-linkage of the cohort with the local archives of mortality and hospital admissions. CHD risk was estimated by multivariate Poisson regression models. Among employed women, CHD risk increased significantly by 29% for each child in the household (IRR = 1.29) and by 39% for each son (IRR = 1.39), whereas no association with the presence of children was found among non-employed women or among employed women with daughters. When categorized, the presence of two or more sons significantly increased CHD risk among employed women (IRR = 2.23), compared to those without children. The study found a significant increase in CHD risk associated with the presence of two or more sons in the household, but not daughters, among employed women. This is a new finding, which should be confirmed in other studies, conducted also in countries where the division of domestic duties between males and females is more balanced, such as the European Nordic countries.

  3. Dissecting the Genetic Susceptibility to Graves’ Disease in a Cohort of Patients of Italian Origin

    PubMed Central

    Lombardi, Angela; Menconi, Francesca; Greenberg, David; Concepcion, Erlinda; Leo, Marenza; Rocchi, Roberto; Marinó, Michele; Keddache, Mehdi; Tomer, Yaron

    2016-01-01

    Graves’ disease (GD) is an autoimmune oligogenic disorder with a strong hereditary component. Several GD susceptibility genes have been identified and confirmed during the last two decades. However, there are very few studies that evaluated susceptibility genes for GD in specific geographic subsets. Previously, we mapped a new locus on chromosome 3q that was unique to GD families of Italian origin. In the present study, we used association analysis of single-nucleotide polymorphism (SNPs) at the 3q locus in a cohort of GD patients of Italian origin in order to prioritize the best candidates among the known genes in this locus to choose the one(s) best supported by the association. DNA samples were genotyped using the Illumina GoldenGate genotyping assay analyzing 690 SNP in the linked 3q locus covering all 124 linkage disequilibrium blocks in this locus. Candidate non-HLA (human-leukocyte-antigen) genes previously reported to be associated with GD and/or other autoimmune disorders were analyzed separately. Three SNPs in the 3q locus showed a nominal association (p < 0.05): rs13097181, rs763313, and rs6792646. Albeit these could not be further validated by multiple comparison correction, we were prioritizing candidate genes at a locus already known to harbor a GD-related gene, not hypothesis testing. Moreover, we found significant associations with the thyroid-stimulating hormone receptor (TSHR) gene, the cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene, and the thyroglobulin (TG) gene. In conclusion, we identified three SNPs on chromosome 3q that may map a new GD susceptibility gene in this region which is unique to the Italian population. Furthermore, we confirmed that the TSHR, the CTLA-4, and the TG genes are associated with GD in Italians. Our findings highlight the influence of ethnicity and geographic variations on the genetic susceptibility to GD. PMID:27014188

  4. Factors Affecting Hemodialysis Adequacy in Cohort of Iranian Patient with End Stage Renal Disease

    PubMed Central

    Shahdadi, Hosein; Balouchi, Abbas; Sepehri, Zahra; Rafiemanesh, Hosein; Magbri, Awad; Keikhaie, Fereshteh; Shahakzehi, Ahmad; Sarjou, Azizullah Arbabi

    2016-01-01

    Background: There are many factors that can affect dialysis adequacy; such as the type of vascular access, filter type, device used, and the dose, and rout of erythropoietin stimulation agents (ESA) used. The aim of this study was investigating factors affecting Hemodialysis adequacy in cohort of Iranian patient with end stage renal disease (ESRD). Methods: This is a cross-sectional study conducted on 133 Hemodialysis patients referred to two dialysis units in Sistan-Baluchistan province in the cities of Zabol and Iranshahr, Iran. We have looked at, (the effects of the type of vascular access, the filter type, the device used, and the dose, route of delivery, and the type of ESA used) on Hemodialysis adequacy. Dialysis adequacy was calculated using kt/v formula, two-part information questionnaire including demographic data which also including access type, filter type, device used for hemodialysis (HD), type of Eprex injection, route of administration, blood groups and hemoglobin response to ESA were utilized. The data was analyzed using the SPSS v16 statistical software. Descriptive statistical methods, Mann-Whitney statistical test, and multiple regressions were used when applicable. Results: The range of calculated dialysis adequacy is 0.28 to 2.39 (units of adequacy of dialysis). 76.7% of patients are being dialyzed via AVF and 23.3% of patients used central venous catheters (CVC). There was no statistical significant difference between dialysis adequacy, vascular access type, device used for HD (Fresenius and B. Braun), and the filter used for HD (p> 0.05). However, a significant difference was observed between the adequacy of dialysis and Eprex injection and patients’ time of dialysis (p <0.05). Conclusion: Subcutaneous ESA (Eprex) injection and dialysis shift (being dialyzed in the morning) can have positive impact on dialysis adequacy. Patients should be educated on the facts that the type of device used for HD and the vascular access used has no

  5. Fibrosis and coronary perfusion - a cardiovascular disease risk in an African male cohort: The SABPA study.

    PubMed

    Jansen van Vuren, Esmé; Malan, Leoné; Cockeran, Marike; Scheepers, Jacobus D; Oosthuizen, Woudri; Malan, Nicolaas T

    2016-01-01

    Low-grade inflammation has been correlated with risk factors of cardiovascular diseases (CVD). Whether the pro-inflammatory and thrombotic ratio (fibrosis) may contribute to CVD is not known. We therefore aimed to assess whether Cornell Product left ventricular hypertrophy (LVH) is associated with fibrosis and coronary perfusion (silent ischemia) in a bi-ethnic male cohort from South Africa. A cross sectional study was conducted including 165 African and Caucasian men between the ages of 20-65. Fasting blood samples were obtained to measure fibrinogen, C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor (TNF-α). Ambulatory blood pressure, ECG and 12 lead ECG measures were obtained to determine silent ischemic events (ST events) and LVH, respectively. Africans revealed more silent ischemia, higher 24 h blood pressure, inflammatory, coagulation as well as fibrosis levels than Caucasians. In a low-grade inflammatory state (CRP > 3 mg/l), Africans revealed higher fibrosis (p ≤ 0.01) values, but lower IL-6 and TNF-α values than Caucasians. Linear regression analyses in several models demonstrated positive associations between silent ischemia and fibrosis [Adj. R(2) 0.23; ß 0.35 (95% CI 0.13, 0.58), p ≤ 0.01]. In a low-grade inflammatory state (CRP>3mg/l), fibrinogen predicted AV-block in African men [OR 3.38 (95% CI 2.24, 4.53); p = 0.04]. Low-grade inflammation may induce AV-block through mechanisms involving fibrosis and ischemia to increase the burden on the heart in African men. PMID:27380493

  6. Exploring the metabolic syndrome: Nonalcoholic fatty pancreas disease

    PubMed Central

    Catanzaro, Roberto; Cuffari, Biagio; Italia, Angelo; Marotta, Francesco

    2016-01-01

    After the first description of fatty pancreas in 1933, the effects of pancreatic steatosis have been poorly investigated, compared with that of the liver. However, the interest of research is increasing. Fat accumulation, associated with obesity and the metabolic syndrome (MetS), has been defined as “fatty infiltration” or “nonalcoholic fatty pancreas disease” (NAFPD). The term “fatty replacement” describes a distinct phenomenon characterized by death of acinar cells and replacement by adipose tissue. Risk factors for developing NAFPD include obesity, increasing age, male sex, hypertension, dyslipidemia, alcohol and hyperferritinemia. Increasing evidence support the role of pancreatic fat in the development of type 2 diabetes mellitus, MetS, atherosclerosis, severe acute pancreatitis and even pancreatic cancer. Evidence exists that fatty pancreas could be used as the initial indicator of “ectopic fat deposition”, which is a key element of nonalcoholic fatty liver disease and/or MetS. Moreover, in patients with fatty pancreas, pancreaticoduodenectomy is associated with an increased risk of intraoperative blood loss and post-operative pancreatic fistula. PMID:27678349

  7. Glycolipid and Ganglioside Metabolism Imbalances In Huntington’s Disease

    PubMed Central

    Desplats, Paula A.; Denny, Christine A.; Kass, Kristi E.; Gilmartin, Tim; Head, Steven R.; Sutcliffe, J. Gregor; Seyfried, Thomas N.; Thomas, Elizabeth A.

    2007-01-01

    We have explored genome-wide expression of genes related to glycobiology in exon 1 transgenic Huntington’s disease (HD) mice using a custom designed GLYCOv2 chip and Affymetrix microarray analyses. We validated, using quantitative real-time PCR, abnormal expression levels of genes encoding glycosyltransferases in the striatum of R6/1 transgenic mice, as well as in postmortem caudate from human HD patients. Many of these genes show differential regional expression within the CNS, as indicated by in situ hybridization analysis, suggesting region-specific regulation of this system in the brain. We further show disrupted patterns of glycolipids (acidic and neutral lipids) and/or ganglioside levels in both the forebrain of the R6/1 transgenic mice and caudate samples from human HD subjects. These findings reveal novel disruptions in glycolipid/ganglioside metabolic pathways in the pathology of HD and suggest that the development of new targets to restore glycosphingolipid balance may act to ameliorate some symptoms in HD. PMID:17600724

  8. Exploring the metabolic syndrome: Nonalcoholic fatty pancreas disease

    PubMed Central

    Catanzaro, Roberto; Cuffari, Biagio; Italia, Angelo; Marotta, Francesco

    2016-01-01

    After the first description of fatty pancreas in 1933, the effects of pancreatic steatosis have been poorly investigated, compared with that of the liver. However, the interest of research is increasing. Fat accumulation, associated with obesity and the metabolic syndrome (MetS), has been defined as “fatty infiltration” or “nonalcoholic fatty pancreas disease” (NAFPD). The term “fatty replacement” describes a distinct phenomenon characterized by death of acinar cells and replacement by adipose tissue. Risk factors for developing NAFPD include obesity, increasing age, male sex, hypertension, dyslipidemia, alcohol and hyperferritinemia. Increasing evidence support the role of pancreatic fat in the development of type 2 diabetes mellitus, MetS, atherosclerosis, severe acute pancreatitis and even pancreatic cancer. Evidence exists that fatty pancreas could be used as the initial indicator of “ectopic fat deposition”, which is a key element of nonalcoholic fatty liver disease and/or MetS. Moreover, in patients with fatty pancreas, pancreaticoduodenectomy is associated with an increased risk of intraoperative blood loss and post-operative pancreatic fistula.

  9. Coronary Heart Disease (CHD) Risk Factors and Metabolic Syndrome in HIV-Positive Drug Users in Miami.

    PubMed

    Baum, Marianna K; Rafie, Carlin; Lai, Shenghan; Xue, Lihua; Sales, Sabrina; Page, J Bryan; Berkman, Ronald; Karas, Linden; Campa, Adriana

    2006-01-01

    The frequency of coronary heart disease (CHD) is increasing among HIV seropositive persons. This phenomenon may be related to HIV disease itself, the use of antiretroviral medications and increased length of survival, or the synergism of these factors. In this study we have calculated the 10-year CHD risk estimate and the prevalence of metabolic syndrome in a cohort of 118 HIV seropositive chronic drug users, including those who are on HAART with or without protease inhibitors (PI). The results showed that the 10-year coronary heart disease risk among the HIV seropositive drug users was 4.8 ± 5.7, which is within the range of results published for other HIV infected cohorts. The 10-year CHD risk was significantly higher in men (5.9±6.1, p<0.001) than in women (1.7±2.4), due to their gender and the pre-menopausal mean age of the women (39.4±7.3 years of age), despite a significantly higher rate of abdominal obesity (54.8% in women vs. 8.1% in men, p<0.001) and lower HDL (61.3% in women vs. 40% in men, p=0.042). The rate of metabolic syndrome among our female HIV seropositive drug users was significantly higher (29% vs 10.3%, p=0.013) compared to men (10.3%). Participants with metabolic syndrome had a significantly higher 10-year CHD risk (27.8% vs. 10.2%, p=0.041) and higher mean BMI (28.6 ± 4.1 vs. 24.2±4, p<0.001) than those without the syndrome. The predominant proportion of the cohort had a high viral load, suggesting that their use of illicit drugs has an influence on either adherence or effectiveness of antiretroviral medication. Increased viral load was significantly associated with metabolic syndrome (OR=2.23, 95% CI:1.12, 4.47; p=0.023), high fasting glucose (OR=1.61, 95% CI: 1.02, 2.55; p=0.042) and low HDL levels (OR=1.41, 95% CI: 1.01, 1.98; p=0.046), after controlling for age gender, smoking, PI exposure, BMI and CD4. HAART with or without PI did not significantly impact the 10-year CHD risk estimate or metabolic syndrome in this cohort. The

  10. Mitochondrial response to nutrient availability and its role in metabolic disease.

    PubMed

    Gao, Arwen W; Cantó, Carles; Houtkooper, Riekelt H

    2014-05-01

    Metabolic inflexibility is defined as an impaired capacity to switch between different energy substrates and is a hallmark of insulin resistance and type 2 diabetes mellitus (T2DM). Hence, understanding the mechanisms underlying proper metabolic flexibility is key to prevent the development of metabolic disease and physiological deterioration. An important downstream player in the effects of metabolic flexibility is the mitochondrion. The objective of this review was to describe how mitochondrial metabolism adapts to limited nutrient situations or caloric excess by changes in mitochondrial function or biogenesis, as well as to define the mechanisms propelling these changes. Altogether, this should pinpoint key regulatory points by which metabolic flexibility might be ameliorated in situations of metabolic disease. PMID:24623376

  11. Mitochondrial response to nutrient availability and its role in metabolic disease

    PubMed Central

    Gao, Arwen W; Cantó, Carles; Houtkooper, Riekelt H

    2014-01-01

    Metabolic inflexibility is defined as an impaired capacity to switch between different energy substrates and is a hallmark of insulin resistance and type 2 diabetes mellitus (T2DM). Hence, understanding the mechanisms underlying proper metabolic flexibility is key to prevent the development of metabolic disease and physiological deterioration. An important downstream player in the effects of metabolic flexibility is the mitochondrion. The objective of this review was to describe how mitochondrial metabolism adapts to limited nutrient situations or caloric excess by changes in mitochondrial function or biogenesis, as well as to define the mechanisms propelling these changes. Altogether, this should pinpoint key regulatory points by which metabolic flexibility might be ameliorated in situations of metabolic disease. PMID:24623376

  12. Membrane transporters in a human genome-scale metabolic knowledgebase and their implications for disease

    PubMed Central

    Sahoo, Swagatika; Aurich, Maike K.; Jonsson, Jon J.; Thiele, Ines

    2014-01-01

    Membrane transporters enable efficient cellular metabolism, aid in nutrient sensing, and have been associated with various diseases, such as obesity and cancer. Genome-scale metabolic network reconstructions capture genomic, physiological, and biochemical knowledge of a target organism, along with a detailed representation of the cellular metabolite transport mechanisms. Since the first reconstruction of human metabolism, Recon 1, published in 2007, progress has been made in the field of metabolite transport. Recently, we published an updated reconstruction, Recon 2, which significantly improved the metabolic coverage and functionality. Human metabolic reconstructions have been used to investigate the role of metabolism in disease and to predict biomarkers and drug targets. Given the importance of cellular transport systems in understanding human metabolism in health and disease, we analyzed the coverage of transport systems for various metabolite classes in Recon 2. We will review the current knowledge on transporters (i.e., their preferred substrates, transport mechanisms, metabolic relevance, and disease association for each metabolite class). We will assess missing coverage and propose modifications and additions through a transport module that is functional when combined with Recon 2. This information will be valuable for further refinements. These data will also provide starting points for further experiments by highlighting areas of incomplete knowledge. This review represents the first comprehensive overview of the transporters involved in central metabolism and their transport mechanisms, thus serving as a compendium of metabolite transporters specific for human metabolic reconstructions. PMID:24653705

  13. The Ophthalmic Branch of the Gutenberg Health Study: Study Design, Cohort Profile and Self-Reported Diseases

    PubMed Central

    Höhn, René; Kottler, Ulrike; Peto, Tunde; Blettner, Maria; Münzel, Thomas; Blankenberg, Stefan; Lackner, Karl J.; Beutel, Manfred

    2015-01-01

    Purpose This paper describes the study design, methodology, cohort profile and self-reported diseases in the ophthalmological branch of the Gutenberg Health Study (GHS). Methods The GHS is an ongoing, prospective, interdisciplinary, single-center, population-based cohort study in Germany. The main goals of the ophthalmological section are to assess the prevalence and incidence of ocular diseases and to explore risk factors, genetic determinants and associations with systemic diseases and conditions. The eye examination at baseline included a medical history, self-reported eye diseases, visual acuity, refractive errors, intraocular pressure, visual field, pachymetry, keratometry, fundus photography and tear sampling. The 5-year follow-up visit additionally encompassed optical coherence tomography, anterior segment imaging and optical biometry. The general examination included anthropometry; blood pressure measurement; carotid artery ultrasound; electrocardiogram; echocardiography; spirometry; cognitive tests; questionnaires; assessment of mental conditions; and DNA, RNA, blood and urine sampling. Results Of 15,010 participants (aged 35-74 years at the time of inclusion), ocular data are available for 14,700 subjects (97.9%). The mean visual acuity (standard deviation), mean spherical equivalent, median decimal visual acuity, and mean intraocular pressure were 0.08 (0.17) logMar, -0.42 (2.43) diopters, 0.9 and 14.24 (2.79) mm Hg, respectively. The frequencies of self-reported strabismus, glaucoma, surgery for retinal detachment and retinal vascular occlusions were 2.7%, 2.3%, 0.2% and 0.4%, respectively. Conclusions The GHS is the most extensive dataset of ophthalmic diseases and conditions and their risk factors in Germany and one of the largest cohorts worldwide. This dataset will provide new insight in the epidemiology of ophthalmic diseases and related medical specialties. PMID:25775251

  14. Evolution of prodromal clinical markers of Parkinson disease in a glucocerebrosidase mutation positive cohort

    PubMed Central

    Beavan, Michelle; McNeill, Alisdair; Proukakis, Christos; Hughes, Derralynn A; Mehta, Atul; Schapira, Anthony H V

    2015-01-01

    Importance Numerically, the most important genetic risk factor for the development of Parkinson disease (PD) is the presence of a glucocerebrosidase gene (GBA) mutation. Objective The purpose of this study was the longitudinal clinical evaluation of a GBA mutation positive cohort and the evolution of the prodromal features of PD. Design Individuals were participants in a study of the aetiology and prodrome of PD and have been re-evaluated in this 2 year follow-up report. Setting Clinic-based. Participants Type 1 GD patients and heterozygous GBA mutation positive carriers were recruited in 2010 from the Lysosomal Storage Disorder Unit at the Royal Free Hospital, London. Thirty previously diagnosed Type 1 GD patients, twenty-eight heterozygous GBA mutation carriers and twenty-six genetically unrelated controls were included. For both GD and carrier subjects, exclusion criteria included a diagnosis of PD or dementia and for controls, any existing neurological disease. Main Outcome(s) and Measure(s) Assessment was performed for clinical markers including hyposmia, rapid eye movement sleep behaviour disorder (RBD), depression, autonomic dysfunction, cognitive function and parkinsonian motor signs (UPDRS part III). Results Over 2 years, depression scores were significantly worse in heterozygotes (P = ·01), RBD scores were significantly worse in GD patients (P < ·001) and heterozygotes (P < ·001), and UPDRS III scores were significantly worse in GD patients (P < ·001) and heterozygotes (P < ·001). In controls, there was a small but significant deterioration in the UPDRS II score (P = ·006). At 2 years, olfactory and cognitive assessment scores were lower in GD patients and heterozygotes compared to controls, but did not differ significantly from baseline. When the results from GD patients and heterozygotes were combined, there was a significant deterioration from baseline in RBD, BDI, UPDRS II and III scores (in all, P < ·01), and at 2 years, significant

  15. Masked Hypertension and Cardiovascular Disease Events in a Prospective Cohort of Blacks: The Jackson Heart Study.

    PubMed

    Booth, John N; Diaz, Keith M; Seals, Samantha R; Sims, Mario; Ravenell, Joseph; Muntner, Paul; Shimbo, Daichi

    2016-08-01

    Masked hypertension, defined as nonelevated clinic blood pressure (BP) with elevated out-of-clinic BP, has been associated with increased cardiovascular disease (CVD) risk in Europeans and Asians. Few data are available on masked hypertension and CVD and mortality risk among blacks. We analyzed data from the Jackson Heart Study, a prospective cohort study of blacks. Analyses included participants with clinic-measured systolic/diastolic BP <140/90 mm Hg who completed ambulatory BP monitoring after the baseline examination in 2000 to 2004 (n=738). Masked daytime (10:00 am-8:00 pm) hypertension was defined as mean ambulatory systolic/diastolic BP ≥135/85 mm Hg. Masked nighttime (midnight to 6:00 am) hypertension was defined as mean ambulatory systolic/diastolic BP ≥120/70 mm Hg. Masked 24-hour hypertension was defined as mean systolic/diastolic BP ≥130/80 mm Hg. CVD events (nonfatal/fatal stroke, nonfatal myocardial infarction, or fatal coronary heart disease) and deaths identified through December 2010 were adjudicated. Any masked hypertension (masked daytime, nighttime, or 24-hour hypertension) was present in 52.2% of participants; 28.2%, 48.2% and 31.7% had masked daytime, nighttime, and 24-hour hypertension, respectively. There were 51 CVD events and 44 deaths during a median follow-up of 8.2 and 8.5 years, respectively. CVD rates per 1000 person-years (95% confidence interval) in participants with and without any masked hypertension were 13.5 (9.9-18.4) and 3.9 (2.2-7.1), respectively. The multivariable adjusted hazard ratio (95% confidence interval) for CVD was 2.49 (1.26-4.93) for any masked hypertension and 2.86 (1.59-5.13), 2.35 (1.23-4.50), and 2.52 (1.39-4.58) for masked daytime, nighttime, and 24-hour hypertension, respectively. Masked hypertension was not associated with all-cause mortality. Masked hypertension is common and associated with increased risk for CVD events in blacks. PMID:27354424

  16. Perinatal Risk Factors for Development of Celiac Disease in Children Based on the Prospective Norwegian Mother and Child Cohort Study

    PubMed Central

    Emilsson, Louise; Magnus, Maria; Størdal, Ketil

    2014-01-01

    Background & Aims There have been inconsistent reports of pre- and perinatal factors that affect risk for development of celiac disease. We assessed the association of fetal growth, birth weight, and mode of delivery with development of celiac disease within the Norwegian Mother and Child (MoBa) cohort study. Methods The MoBa cohort contains pregnancy information on 95,200 women and data on their 114,500 children, collected in Norway from 1999 through 2008; it is linked to the Medical Birth Registry. Women and children with celiac disease were identified from the National Patient Register and from women's responses to MoBa questionnaires. We calculated odds ratios (ORs) for celiac disease using a multivariable logistic regression model, adjusting for maternal celiac disease, sex of children, and children's age (model 1); in a second model, we adjusted for age of gluten introduction and duration of breastfeeding (model 2). Results We identified 650 children with celiac disease and 107,828 controls in the MoBa database. We found no association between birth weight or height with celiac disease (born small for gestational age was not associated). Celiac disease was not associated with mode of delivery (Cesarean section, model 1: OR=0.84; 95% confidence interval [CI], 0.65–1.09 and model 2: OR=0.83; 95% CI, 0.63−1.09). Maternal celiac disease, adjusted for age and sex of the children (OR=12.45; 95% CI, 8.29−18.71) and type 1 diabetes (model I: OR=2.58; 95% CI, 1.19−5.53 and model 2: OR=2.61; 95% CI, 1.14−5.98) were associated with development of celiac disease in children, whereas maternal type 2 diabetes and gestational diabetes were not. Conclusion Based on analysis of the Norwegian MoBa cohort, development of celiac disease in children is significantly associated with sex of the child, maternal celiac disease and type 1 diabetes, but not with intrauterine growth. PMID:25459557

  17. Prevalence of chronic kidney disease in adults with metabolic syndrome.

    PubMed

    Emem-Chioma, P C; Siminialayi, I M; Wokoma, F S

    2011-09-01

    The burden of chronic kidney disease (CKD) and other non- communicable diseases continues to rise globally, and recent studies suggest that metabolic syndrome (MS) may add to this burden by contributing to the development of CKD. Given that reports on the prevalence of CKD in patients with MS in this environment are scanty, this study was undertaken with the sole aim of determining the prevalence of CKD in subjects with MS as defined by the International Diabetes Federation (IDF) and the National Cholesterol Education Project Adult Treatment Panel III (NCEP ATP III). A total of 240 consenting adults (18-70 years) attending the general out- patient clinic of the General Hospital Okrika for various ailments were studied. Subjects were screened for MS as per the above- mentioned criteria. Estimated GFR (eGFR) was determined with Modification of Diet for Renal Disease (MDRD) formula and CKD was defined as eGFR less than 60 mL/min/1.73 m2 . Data was analyzed using SPSS version 12.0 and Epi info version 4.06d; P <0.05 was considered as significant. A total of 88 males and 152 females were screened for MS by both criteria. Eighty- four (35.0%) of 240 subjects had MS as defined by NCEP ATP III, while 85 (35.4%) had MS as defined by the IDF. The subjects were predominantly females, and mean age was between 54.74 ± 15.30 and 55.60 ± 14.81 years. Four of the 84 (4.8%) subjects with MS by NCEP ATP III definition had CKD while three of the 85 (3.5%) subjects with MS by IDF definition had CKD. Among subjects without MS by either definition, the prevalence of CKD was four of 140 (2.9%). Although the prevalence of CKD was higher among subjects with MS by ATP III compared with those with MS as defined by IDF and subjects without MS, the differences were not statistically significant (X2 = 0.14; P = 0.710). A comparison of MS subjects without CKD and those with CKD did not show any significant difference in age, waist circumference, body mass index, blood pressure, fasting blood

  18. Influence of Coding Variability in APP-Aβ Metabolism Genes in Sporadic Alzheimer's Disease.

    PubMed

    Sassi, Celeste; Ridge, Perry G; Nalls, Michael A; Gibbs, Raphael; Ding, Jinhui; Lupton, Michelle K; Troakes, Claire; Lunnon, Katie; Al-Sarraj, Safa; Brown, Kristelle S; Medway, Christopher; Lord, Jenny; Turton, James; Morgan, Kevin; Powell, John F; Kauwe, John S; Cruchaga, Carlos; Bras, Jose; Goate, Alison M; Singleton, Andrew B; Guerreiro, Rita; Hardy, John

    2016-01-01

    The cerebral deposition of Aβ42, a neurotoxic proteolytic derivate of amyloid precursor protein (APP), is a central event in Alzheimer's disease (AD)(Amyloid hypothesis). Given the key role of APP-Aβ metabolism in AD pathogenesis, we selected 29 genes involved in APP processing, Aβ degradation and clearance. We then used exome and genome sequencing to investigate the single independent (single-variant association test) and cumulative (gene-based association test) effect of coding variants in these genes as potential susceptibility factors for AD, in a cohort composed of 332 sporadic and mainly late-onset AD cases and 676 elderly controls from North America and the UK. Our study shows that common coding variability in these genes does not play a major role for the disease development. In the single-variant association analysis, the main hits, none of which statistically significant after multiple testing correction (1.9e-4

  19. Influence of Coding Variability in APP-Aβ Metabolism Genes in Sporadic Alzheimer’s Disease

    PubMed Central

    Sassi, Celeste; Ridge, Perry G.; Nalls, Michael A.; Gibbs, Raphael; Ding, Jinhui; Lupton, Michelle K.; Troakes, Claire; Lunnon, Katie; Al-Sarraj, Safa; Brown, Kristelle S.; Medway, Christopher; Lord, Jenny; Turton, James; Morgan, Kevin; Powell, John F.; Kauwe, John S.; Cruchaga, Carlos; Bras, Jose; Goate, Alison M.; Singleton, Andrew B.; Guerreiro, Rita; Hardy, John

    2016-01-01

    The cerebral deposition of Aβ42, a neurotoxic proteolytic derivate of amyloid precursor protein (APP), is a central event in Alzheimer’s disease (AD)(Amyloid hypothesis). Given the key role of APP-Aβ metabolism in AD pathogenesis, we selected 29 genes involved in APP processing, Aβ degradation and clearance. We then used exome and genome sequencing to investigate the single independent (single-variant association test) and cumulative (gene-based association test) effect of coding variants in these genes as potential susceptibility factors for AD, in a cohort composed of 332 sporadic and mainly late-onset AD cases and 676 elderly controls from North America and the UK. Our study shows that common coding variability in these genes does not play a major role for the disease development. In the single-variant association analysis, the main hits, none of which statistically significant after multiple testing correction (1.9e-4

  20. Adverse Renal, Endocrine, Hepatic, and Metabolic Events during Maintenance Mood Stabilizer Treatment for Bipolar Disorder: A Population-Based Cohort Study

    PubMed Central

    Marston, Louise; Walters, Kate; Geddes, John R.; King, Michael; Osborn, David P. J.

    2016-01-01

    Background There is limited, poorly characterized information about adverse events occurring during maintenance treatment of bipolar disorder. We aimed to determine adverse event rates during treatment with lithium, valproate, olanzapine, and quetiapine. Methods and Findings We conducted a propensity score adjusted cohort study using nationally representative United Kingdom electronic health records from January 1, 1995, until December 31, 2013. We included patients who had a diagnosis of bipolar disorder and were prescribed lithium (n = 2148), valproate (n = 1670), olanzapine (n = 1477), or quetiapine (n = 1376) as maintenance mood stabilizer treatment. Adverse outcomes were chronic kidney disease, thyroid disease, hypercalcemia, weight gain, hypertension, type 2 diabetes mellitus, cardiovascular disease, and hepatotoxicity. The propensity score included important demographic, physical health, and mental health predictors of drug treatment allocation. The median duration of drug treatment was 1.48 y (interquartile range 0.64–3.43). Compared to patients prescribed lithium, those taking valproate, olanzapine, and quetiapine had reduced rates of chronic kidney disease stage 3 or more severe, following adjustment for propensity score, age, and calendar year, and accounting for clustering by primary care practice (valproate hazard ratio [HR] 0.56; 95% confidence interval [CI] 0.45–0.69; p < 0.001, olanzapine HR 0.57; 95% CI 0.45–0.71; p < 0.001, quetiapine HR 0.62; 95% CI 0.47–0.80; p < 0.001). Hypothyroidism was reduced in those taking valproate (HR 0.60; 95% CI 0.40–0.89; p = 0.012) and olanzapine (HR 0.48; 95% CI 0.29–0.77; p = 0.003), compared to those taking lithium. Rates of new onset hyperthyroidism (valproate HR 0.24; 95% CI 0.09–0.61; p = 0.003, olanzapine HR 0.31; 95% CI 0.13–0.73; p = 0.007) and hypercalcemia (valproate HR 0.25; 95% CI 0.10–0.60; p = 0.002, olanzapine HR 0.32; 95% CI 0.14–0.76; p = 0.008, quetiapine HR 0.23; 95% CI 0.07

  1. Metabolic bone disease associated with total parenteral nutrition.

    PubMed

    Klein, G L; Coburn, J W

    1984-01-01

    Patients receiving long-term treatment with total parenteral nutrition often develop bony abnormalities characterized by patchy osteomalacia and low bone turnover. The patients present evidence of physiologic hypoparathyroidism, although low levels of iPTH cannot entirely explain the osteomalacia. Abnormally low serum levels of 1,25(OH)2-vitamin D have been demonstrated, but the significance of these reduced levels in the pathogenesis of the bone lesions is not defined. Aluminum has been detected in large quantities in the plasma, urine, and bone of some patients treated with TPN, and there is mounting evidence that aluminum may be associated with skeletal pathology, particularly osteomalacia. There is, however, no clear documentation that aluminum accumulation produces the skeletal lesions observed, although it could be a contributing factor. There has been the unusual empiric observation that the removal of vitamin D2 from the infusate is associated with a decrease in the quantity of unmineralized osteoid in TPN patients. A possible role of vitamin D2 in producing osteomalacia is not easy to understand since normal serum levels of 25(OH)-D2, the circulating form of vitamin D2, have been reported. The long-term consequences of intravenous nutritional support for many aspects of metabolism remain unknown. Administration into the systemic circulation of predetermined quantities of calcium and phosphorus via a route that bypasses their passage across the intestinal mucosa, the portal system and the liver may have adverse consequences. It is possible that bypassing homeostatic mechanisms may affect bone formation and metabolism or lead to alterations in vitamin D sterols. Alternatively, a deficiency of an essential trace metal or the accumulation of a toxic trace substance could be responsible for the bony abnormalities. Much remains to be clarified concerning calcium homeostasis and bone disease during total parenteral nutrition. Among various possible factors, it

  2. Ascertainment and Verification of End-Stage Renal Disease and End-Stage Liver Disease in the North American AIDS Cohort Collaboration on Research and Design

    PubMed Central

    Kitahata, Mari M.; Drozd, Daniel R.; Crane, Heidi M.; Van Rompaey, Stephen E.; Althoff, Keri N.; Gange, Stephen J.; Klein, Marina B.; Lucas, Gregory M.; Abraham, Alison G.; Lo Re, Vincent; McReynolds, Justin; Lober, William B.; Mendes, Adell; Modur, Sharada P.; Jing, Yuezhou; Morton, Elizabeth J.; Griffith, Margaret A.; Freeman, Aimee M.; Moore, Richard D.

    2015-01-01

    The burden of HIV disease has shifted from traditional AIDS-defining illnesses to serious non-AIDS-defining comorbid conditions. Research aimed at improving HIV-related comorbid disease outcomes requires well-defined, verified clinical endpoints. We developed methods to ascertain and verify end-stage renal disease (ESRD) and end-stage liver disease (ESLD) and validated screening algorithms within the largest HIV cohort collaboration in North America (NA-ACCORD). Individuals who screened positive among all participants in twelve cohorts enrolled between January 1996 and December 2009 underwent medical record review to verify incident ESRD or ESLD using standardized protocols. We randomly sampled 6% of contributing cohorts to determine the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ESLD and ESRD screening algorithms in a validation subcohort. Among 43,433 patients screened for ESRD, 822 screened positive of which 620 met clinical criteria for ESRD. The algorithm had 100% sensitivity, 99% specificity, 82% PPV, and 100% NPV for ESRD. Among 41,463 patients screened for ESLD, 2,024 screened positive of which 645 met diagnostic criteria for ESLD. The algorithm had 100% sensitivity, 95% specificity, 27% PPV, and 100% NPV for ESLD. Our methods proved robust for ascertainment of ESRD and ESLD in persons infected with HIV. PMID:25789171

  3. ICE COLD ERIC – International collaborative effort on chronic obstructive lung disease: exacerbation risk index cohorts – Study protocol for an international COPD cohort study

    PubMed Central

    Siebeling, Lara; ter Riet, Gerben; van der Wal, Willem M; Geskus, Ronald B; Zoller, Marco; Muggensturm, Patrick; Joleska, Irena; Puhan, Milo A

    2009-01-01

    Background Chronic Obstructive Pulmonary Disease (COPD) is a systemic disease; morbidity and mortality due to COPD are on the increase, and it has great impact on patients' lives. Most COPD patients are managed by general practitioners (GP). Too often, GPs base their initial assessment of patient's disease severity mainly on lung function. However, lung function correlates poorly with COPD-specific health-related quality of life and exacerbation frequency. A validated COPD disease risk index that better represents the clinical manifestations of COPD and is feasible in primary care seems to be useful. The objective of this study is to develop and validate a practical COPD disease risk index that predicts the clinical course of COPD in primary care patients with GOLD stages 2–4. Methods/Design We will conduct 2 linked prospective cohort studies with COPD patients from GPs in Switzerland and the Netherlands. We will perform a baseline assessment including detailed patient history, questionnaires, lung function, history of exacerbations, measurement of exercise capacity and blood sampling. During the follow-up of at least 2 years, we will update the patients' profile by registering exacerbations, health-related quality of life and any changes in the use of medication. The primary outcome will be health-related quality of life. Secondary outcomes will be exacerbation frequency and mortality. Using multivariable regression analysis, we will identify the best combination of variables predicting these outcomes over one and two years and, depending on funding, even more years. Discussion Despite the diversity of clinical manifestations and available treatments, assessment and management today do not reflect the multifaceted character of the disease. This is in contrast to preventive cardiology where, nowadays, the treatment in primary care is based on patient-specific and fairly refined cardiovascular risk profile corresponding to differences in prognosis. After

  4. Interorgan ammonia metabolism in health and disease: a surgeon's view.

    PubMed

    Souba, W W

    1987-01-01

    Ammonia is a toxic molecule that is the principal by-product of amino acid metabolism. Although the transport of ammonia in a nontoxic form protects the brain against high circulating levels, the interorgan transport of this molecule and the orchestration between tissues that has evolved is related primarily to the fact that the nitrogen molecule is an essential molecule for the maintenance of the body's nutrition economy and overall metabolic homeostasis. Efficient handling and disposal of ammonia requires a cooperative effort between tissues in order to maintain nitrogen homeostasis. The liver is the central organ of ammonia metabolism, but other organs also play a key role in the interorgan exchange of this molecule. Alterations in ammonia metabolism occur during critical illness. These changes are adaptive and are designed to maintain metabolic homeostasis. Interorgan cooperation in ammonia metabolism is necessary to insure the proper integration of the metabolic processes which contribute to and are essential for survival during critical illness. An understanding of these processes improves our knowledge of metabolic regulation and will lead to a rational approach to the nutritional and metabolic support provided to critically ill patients. PMID:3323556

  5. The clinical application of metabolic therapy for cardiovascular disease.

    PubMed

    Hadj, Anthony; Pepe, Salvatore; Rosenfeldt, Franklin

    2007-01-01

    Metabolic therapy involves the administration of a substance normally found in the body to enhance a metabolic reaction within the cell. This may be achieved in two ways. Firstly, for some systems a substance can be given to achieve greater than normal levels in the body so as to drive an enzymic reaction in a preferred direction. Secondly, metabolic therapy may be used to correct an absolute or relative deficiency of a cellular component. Thus, metabolic therapy differs greatly from most standard cardiovascular pharmacologic therapies such as the use of ACE Inhibitors, beta-blockers, statins and calcium channel antagonists that are given to block rather than enhance cellular processes.

  6. The clinical application of metabolic therapy for cardiovascular disease.

    PubMed

    Hadj, Anthony; Pepe, Salvatore; Rosenfeldt, Franklin

    2007-01-01

    Metabolic therapy involves the administration of a substance normally found in the body to enhance a metabolic reaction within the cell. This may be achieved in two ways. Firstly, for some systems a substance can be given to achieve greater than normal levels in the body so as to drive an enzymic reaction in a preferred direction. Secondly, metabolic therapy may be used to correct an absolute or relative deficiency of a cellular component. Thus, metabolic therapy differs greatly from most standard cardiovascular pharmacologic therapies such as the use of ACE Inhibitors, beta-blockers, statins and calcium channel antagonists that are given to block rather than enhance cellular processes. PMID:17618830

  7. Information system for the support of research, diagnosis and therapy of inborn metabolic diseases.

    PubMed

    Kauert, R; Töpel, T; Scholz, U; Hofestädt, R

    2001-01-01

    We developed an information system for inborn metabolic diseases. The system consists of three parts. The first part is the MD-Cave for information on laboratory findings, genes, enzymes and metabolic pathways. The second part (ASDB) concerns with active agents and their different mechanisms of action inside the metabolic pathway and possible therapeutic treatment of these illnesses. The third part deals with the integration of these and other data bases for easy access to different information. This information system can be helpful for scientists and physicians working in the field of inborn metabolic diseases.

  8. Does skeletal muscle have an 'epi'-memory? The role of epigenetics in nutritional programming, metabolic disease, aging and exercise.

    PubMed

    Sharples, Adam P; Stewart, Claire E; Seaborne, Robert A

    2016-08-01

    Skeletal muscle mass, quality and adaptability are fundamental in promoting muscle performance, maintaining metabolic function and supporting longevity and healthspan. Skeletal muscle is programmable and can 'remember' early-life metabolic stimuli affecting its function in adult life. In this review, the authors pose the question as to whether skeletal muscle has an 'epi'-memory? Following an initial encounter with an environmental stimulus, we discuss the underlying molecular and epigenetic mechanisms enabling skeletal muscle to adapt, should it re-encounter the stimulus in later life. We also define skeletal muscle memory and outline the scientific literature contributing to this field. Furthermore, we review the evidence for early-life nutrient stress and low birth weight in animals and human cohort studies, respectively, and discuss the underlying molecular mechanisms culminating in skeletal muscle dysfunction, metabolic disease and loss of skeletal muscle mass across the lifespan. We also summarize and discuss studies that isolate muscle stem cells from different environmental niches in vivo (physically active, diabetic, cachectic, aged) and how they reportedly remember this environment once isolated in vitro. Finally, we will outline the molecular and epigenetic mechanisms underlying skeletal muscle memory and review the epigenetic regulation of exercise-induced skeletal muscle adaptation, highlighting exercise interventions as suitable models to investigate skeletal muscle memory in humans. We believe that understanding the 'epi'-memory of skeletal muscle will enable the next generation of targeted therapies to promote muscle growth and reduce muscle loss to enable healthy aging.

  9. Chronic Kidney Disease in Primary Care: Outcomes after Five Years in a Prospective Cohort Study

    PubMed Central

    Shardlow, Adam; McIntyre, Natasha J.; Fluck, Richard J.; McIntyre, Christopher W.; Taal, Maarten W.

    2016-01-01

    Background Chronic kidney disease (CKD) is commonly managed in primary care, but most guidelines have a secondary care perspective emphasizing the risk of end-stage kidney disease (ESKD) and need for renal replacement therapy. In this prospective cohort study, we sought to study in detail the natural history of CKD in primary care to better inform the appropriate emphasis for future guidance. Methods and Findings In this study, 1,741 people with CKD stage 3 were individually recruited from 32 primary care practices in Derbyshire, United Kingdom. Study visits were undertaken at baseline, year 1, and year 5. Binomial logistic regression and Cox proportional hazards models were used to model progression, CKD remission, and all-cause mortality. We used Kidney Disease: Improving Global Outcomes (KDIGO) criteria to define CKD progression and defined CKD remission as the absence of diagnostic criteria (estimated glomerular filtration rate [eGFR] >60 ml/min/1.73 m2 and urine albumin-to-creatinine ratio [uACR] <3 mg/mmol) at any study visit. Participants were predominantly elderly (mean ± standard deviation (SD) age 72.9 ± 9.0 y), with relatively mild reduction in GFR (mean ± SD eGFR 53.5 ± 11.8 mL/min/1,73 m2) and a low prevalence of albuminuria (16.9%). After 5 y, 247 participants (14.2%) had died, most of cardiovascular causes. Only 4 (0.2%) developed ESKD, but 308 (17.7%) evidenced CKD progression by KDIGO criteria. Stable CKD was observed in 593 participants (34.1%), and 336 (19.3%) met the criteria for remission. Remission at baseline and year 1 was associated with a high likelihood of remission at year 5 (odds ratio [OR] = 23.6, 95% CI 16.5–33.9 relative to participants with no remission at baseline and year 1 study visits). Multivariable analyses confirmed eGFR and albuminuria as key risk factors for predicting adverse as well as positive outcomes. Limitations of this study include reliance on GFR estimated using the Modification of Diet in Renal Disease study

  10. Radiation-epidemiological Study of Cerebrovascular Diseases in the Cohort of Russian Recovery Operation Workers of the Chernobyl Accident.

    PubMed

    Kashcheev, V V; Chekin, S Yu; Maksioutov, M A; Tumanov, K A; Menyaylo, A N; Kochergina, E V; Kashcheeva, P V; Gorsky, A I; Shchukina, N V; Karpenko, S V; Ivanov, V K

    2016-08-01

    The paper presents an analysis of the incidence of cerebrovascular diseases (CeVD) in the cohort of Russian workers involved in recovery tasks after the Chernobyl accident. The studied cohort consists of 53,772 recovery operation workers (liquidators) who arrived in the zone of the Chernobyl accident within the first year after this accident (26 April 1986-26 April 1987). The mean external whole body dose in the cohort was 0.161 Gy, while individual doses varied from 0.0001 Gy to 1.42 Gy. During the follow-up period 1986-2012, a total of 23,264 cases of CeVD were diagnosed as a result of annual health examinations. A Poisson regression model was applied for estimation of radiation risks and for an assessment of other risk factors of CeVD. The following factors were considered as risk factors for CeVD: the dose, duration of the liquidators' work in the Chernobyl zone, and the concomitant diseases (hypertension, ischemic heart disease, atherosclerosis, and diabetes). The baseline incidence of CeVD is statistically significantly (p < 0.001) associated with all studied concomitant diseases. The incidence of CeVD has revealed a statistically significant dose response with the lack of a latent period and with the average ERR/Gy = 0.45, 95% CI: (0.28, 0.62), p < 0.001. Radiation risks of CeVD statistically significantly (p = 0.03) varied with the duration of liquidators' stay in the Chernobyl zone; for those who stayed in the Chernobyl zone less than 6 wk, ERR/Gy = 0.64, 95% CI = (0.38; 0.93), p < 0.001. Among studied concomitant diseases, diabetes mellitus statistically significantly (p = 0.002) increases the radiation risk of CeVD: for liquidators with diagnosed diabetes, ERR/Gy = 1.29. PMID:27356064

  11. The Natural Progression of Parkinson's Disease in a Small Cohort with 15 Drug-naïve Patients

    PubMed Central

    Liu, Ying; Fan, Jin-Hu; Gao, Xiang; Ma, Li; Qiao, You-Lin; Zhang, Lin

    2015-01-01

    Background: The studies of the natural progression of Parkinson's disease (PD) in Chinese populations have been lacking. To address this issue and obtain a preliminary data, we conducted a PD progression assessment in 15 adults with de novo PD from a nutritional intervention trial (NIT) cohort in Lin County China. Methods: Using the Copiah County screening questionnaire and United Kingdom Parkinson's Disease Society Brain Bank diagnostic criteria, we surveyed the available NIT cohort members in 2000 and diagnosed 86 patients as PD. In 2010, we resurveyed all PD patients and confirmed definite PD diagnosis in 15 cases with the rest of them being dead (54); having probable (10) PD or vascular Parkinsonism (3); refusing to participate (2); or being away (2). In both surveys, we used Hoehn and Yahr (HY) scale and assessed the disease progression. Unified Parkinson's Disease Rating Scale (UPDRS) was added to the second survey. Results: In 2010, the average disease duration for 15 definite PD patients was 13.6 ± 7.3 years. Over a 10-year time span, 9 out of 15 patients remained at the same HY stage while the remaining 6 progressed. Rigidity (47% vs. 100%; P = 0.002) and postural instability (7% vs. 47%; P = 0.005) worsened significantly. The mean UPDRS motor scores in 2010 were 39.4 ± 23.7. Conclusions: Overall worsening of motor function in PD seems to be the rule in this untreated cohort, and their rate of progression seemed to be slower than those reported in the western populations. PMID:26112717

  12. Radiation-epidemiological Study of Cerebrovascular Diseases in the Cohort of Russian Recovery Operation Workers of the Chernobyl Accident.

    PubMed

    Kashcheev, V V; Chekin, S Yu; Maksioutov, M A; Tumanov, K A; Menyaylo, A N; Kochergina, E V; Kashcheeva, P V; Gorsky, A I; Shchukina, N V; Karpenko, S V; Ivanov, V K

    2016-08-01

    The paper presents an analysis of the incidence of cerebrovascular diseases (CeVD) in the cohort of Russian workers involved in recovery tasks after the Chernobyl accident. The studied cohort consists of 53,772 recovery operation workers (liquidators) who arrived in the zone of the Chernobyl accident within the first year after this accident (26 April 1986-26 April 1987). The mean external whole body dose in the cohort was 0.161 Gy, while individual doses varied from 0.0001 Gy to 1.42 Gy. During the follow-up period 1986-2012, a total of 23,264 cases of CeVD were diagnosed as a result of annual health examinations. A Poisson regression model was applied for estimation of radiation risks and for an assessment of other risk factors of CeVD. The following factors were considered as risk factors for CeVD: the dose, duration of the liquidators' work in the Chernobyl zone, and the concomitant diseases (hypertension, ischemic heart disease, atherosclerosis, and diabetes). The baseline incidence of CeVD is statistically significantly (p < 0.001) associated with all studied concomitant diseases. The incidence of CeVD has revealed a statistically significant dose response with the lack of a latent period and with the average ERR/Gy = 0.45, 95% CI: (0.28, 0.62), p < 0.001. Radiation risks of CeVD statistically significantly (p = 0.03) varied with the duration of liquidators' stay in the Chernobyl zone; for those who stayed in the Chernobyl zone less than 6 wk, ERR/Gy = 0.64, 95% CI = (0.38; 0.93), p < 0.001. Among studied concomitant diseases, diabetes mellitus statistically significantly (p = 0.002) increases the radiation risk of CeVD: for liquidators with diagnosed diabetes, ERR/Gy = 1.29.

  13. Food environment, walkability, and public open spaces are associated with incident development of cardio-metabolic risk factors in a biomedical cohort.

    PubMed

    Paquet, Catherine; Coffee, Neil T; Haren, Matthew T; Howard, Natasha J; Adams, Robert J; Taylor, Anne W; Daniel, Mark

    2014-07-01

    We investigated whether residential environment characteristics related to food (unhealthful/healthful food sources ratio), walkability and public open spaces (POS; number, median size, greenness and type) were associated with incidence of four cardio-metabolic risk factors (pre-diabetes/diabetes, hypertension, dyslipidaemia, abdominal obesity) in a biomedical cohort (n=3205). Results revealed that the risk of developing pre-diabetes/diabetes was lower for participants in areas with larger POS and greater walkability. Incident abdominal obesity was positively associated with the unhealthful food environment index. No associations were found with hypertension or dyslipidaemia. Results provide new evidence for specific, prospective associations between the built environment and cardio-metabolic risk factors. PMID:24880234

  14. Integrated analysis of transcript-level regulation of metabolism reveals disease-relevant nodes of the human metabolic network.

    PubMed

    Galhardo, Mafalda; Sinkkonen, Lasse; Berninger, Philipp; Lin, Jake; Sauter, Thomas; Heinäniemi, Merja

    2014-02-01

    Metabolic diseases and comorbidities represent an ever-growing epidemic where multiple cell types impact tissue homeostasis. Here, the link between the metabolic and gene regulatory networks was studied through experimental and computational analysis. Integrating gene regulation data with a human metabolic network prompted the establishment of an open-sourced web portal, IDARE (Integrated Data Nodes of Regulation), for visualizing various gene-related data in context of metabolic pathways. Motivated by increasing availability of deep sequencing studies, we obtained ChIP-seq data from widely studied human umbilical vein endothelial cells. Interestingly, we found that association of metabolic genes with multiple transcription factors (TFs) enriched disease-associated genes. To demonstrate further extensions enabled by examining these networks together, constraint-based modeling was applied to data from human preadipocyte differentiation. In parallel, data on gene expression, genome-wide ChIP-seq profiles for peroxisome proliferator-activated receptor (PPAR) γ, CCAAT/enhancer binding protein (CEBP) α, liver X receptor (LXR) and H3K4me3 and microRNA target identification for miR-27a, miR-29a and miR-222 were collected. Disease-relevant key nodes, including mitochondrial glycerol-3-phosphate acyltransferase (GPAM), were exposed from metabolic pathways predicted to change activity by focusing on association with multiple regulators. In both cell types, our analysis reveals the convergence of microRNAs and TFs within the branched chain amino acid (BCAA) metabolic pathway, possibly providing an explanation for its downregulation in obese and diabetic conditions.

  15. Integrated analysis of transcript-level regulation of metabolism reveals disease-relevant nodes of the human metabolic network

    PubMed Central

    Galhardo, Mafalda; Sinkkonen, Lasse; Berninger, Philipp; Lin, Jake; Sauter, Thomas; Heinäniemi, Merja

    2014-01-01

    Metabolic diseases and comorbidities represent an ever-growing epidemic where multiple cell types impact tissue homeostasis. Here, the link between the metabolic and gene regulatory networks was studied through experimental and computational analysis. Integrating gene regulation data with a human metabolic network prompted the establishment of an open-sourced web portal, IDARE (Integrated Data Nodes of Regulation), for visualizing various gene-related data in context of metabolic pathways. Motivated by increasing availability of deep sequencing studies, we obtained ChIP-seq data from widely studied human umbilical vein endothelial cells. Interestingly, we found that association of metabolic genes with multiple transcription factors (TFs) enriched disease-associated genes. To demonstrate further extensions enabled by examining these networks together, constraint-based modeling was applied to data from human preadipocyte differentiation. In parallel, data on gene expression, genome-wide ChIP-seq profiles for peroxisome proliferator-activated receptor (PPAR) γ, CCAAT/enhancer binding protein (CEBP) α, liver X receptor (LXR) and H3K4me3 and microRNA target identification for miR-27a, miR-29a and miR-222 were collected. Disease-relevant key nodes, including mitochondrial glycerol-3-phosphate acyltransferase (GPAM), were exposed from metabolic pathways predicted to change activity by focusing on association with multiple regulators. In both cell types, our analysis reveals the convergence of microRNAs and TFs within the branched chain amino acid (BCAA) metabolic pathway, possibly providing an explanation for its downregulation in obese and diabetic conditions. PMID:24198249

  16. Redox metabolism abnormalities in autistic children associated with mitochondrial disease.

    PubMed

    Frye, R E; Delatorre, R; Taylor, H; Slattery, J; Melnyk, S; Chowdhury, N; James, S J

    2013-06-18

    Research studies have uncovered several metabolic abnormalities associated with autism spectrum disorder (ASD), including mitochondrial disease (MD) and abnormal redox metabolism. Despite the close connection between mitochondrial dysfunction and oxidative stress, the relation between MD and oxidative stress in children with ASD has not been studied. Plasma markers of oxidative stress and measures of cognitive and language development and ASD behavior were obtained from 18 children diagnosed with ASD who met criteria for probable or definite MD per the Morava et al. criteria (ASD/MD) and 18 age and gender-matched ASD children without any biological markers or symptoms of MD (ASD/NoMD). Plasma measures of redox metabolism included reduced free glutathione (fGSH), oxidized glutathione (GSSG), the fGSH/GSSG ratio and 3-nitrotyrosine (3NT). In addition, a plasma measure of chronic immune activation, 3-chlorotyrosine (3CT), was also measured. Language was measured using the preschool language scale or the expressive one-word vocabulary test (depending on the age), adaptive behaviour was measured using the Vineland Adaptive Behavior Scale (VABS) and core autism symptoms were measured using the Autism Symptoms Questionnaire and the Social Responsiveness Scale. Children with ASD/MD were found to have lower scores on the communication and daily living skill subscales of the VABS despite having similar language and ASD symptoms. Children with ASD/MD demonstrated significantly higher levels of fGSH/GSSG and lower levels of GSSG as compared with children with ASD/NoMD, suggesting an overall more favourable glutathione redox status in the ASD/MD group. However, compare with controls, both ASD groups demonstrated lower fGSH and fGSH/GSSG, demonstrating that both groups suffer from redox abnormalities. Younger ASD/MD children had higher levels of 3CT than younger ASD/NoMD children because of an age-related effect in the ASD/MD group. Both ASD groups demonstrated significantly

  17. The Age-Specific Quantitative Effects of Metabolic Risk Factors on Cardiovascular Diseases and Diabetes: A Pooled Analysis

    PubMed Central

    Farzadfar, Farshad; Stevens, Gretchen A.; Woodward, Mark; Wormser, David; Kaptoge, Stephen; Whitlock, Gary; Qiao, Qing; Lewington, Sarah; Di Angelantonio, Emanuele; vander Hoorn, Stephen; Lawes, Carlene M. M.; Ali, Mohammed K.; Mozaffarian, Dariush; Ezzati, Majid

    2013-01-01

    Background The effects of systolic blood pressure (SBP), serum total cholesterol (TC), fasting plasma glucose (FPG), and body mass index (BMI) on the risk of cardiovascular diseases (CVD) have been established in epidemiological studies, but consistent estimates of effect sizes by age and sex are not available. Methods We reviewed large cohort pooling projects, evaluating effects of baseline or usual exposure to metabolic risks on ischemic heart disease (IHD), hypertensive heart disease (HHD), stroke, diabetes, and, as relevant selected other CVDs, after adjusting for important confounders. We pooled all data to estimate relative risks (RRs) for each risk factor and examined effect modification by age or other factors, using random effects models. Results Across all risk factors, an average of 123 cohorts provided data on 1.4 million individuals and 52,000 CVD events. Each metabolic risk factor was robustly related to CVD. At the baseline age of 55–64 years, the RR for 10 mmHg higher SBP was largest for HHD (2.16; 95% CI 2.09–2.24), followed by effects on both stroke subtypes (1.66; 1.39–1.98 for hemorrhagic stroke and 1.63; 1.57–1.69 for ischemic stroke). In the same age group, RRs for 1 mmol/L higher TC were 1.44 (1.29–1.61) for IHD and 1.20 (1.15–1.25) for ischemic stroke. The RRs for 5 kg/m2 higher BMI for ages 55–64 ranged from 2.32 (2.04–2.63) for diabetes, to 1.44 (1.40–1.48) for IHD. For 1 mmol/L higher FPG, RRs in this age group were 1.18 (1.08–1.29) for IHD and 1.14 (1.01–1.29) for total stroke. For all risk factors, proportional effects declined with age, were generally consistent by sex, and differed by region in only a few age groups for certain risk factor-disease pairs. Conclusion Our results provide robust, comparable and precise estimates of the effects of major metabolic risk factors on CVD and diabetes by age group. PMID:23935815

  18. Dysregulation of hepatic fatty acid metabolism in chronic kidney disease

    PubMed Central

    Jin, Kyubok; Norris, Keith; Vaziri, Nosratola D.

    2013-01-01

    Background Chronic kidney disease (CKD) results in hypertriglyceridemia which is largely due to impaired clearance of triglyceride-rich lipoproteins occasioned by downregulation of lipoprotein lipase and very low-density lipoprotein (LDL) receptor in the skeletal muscle and adipose tissue and of hepatic lipase and LDL receptor-related protein in the liver. However, data on the effect of CKD on fatty acid metabolism in the liver is limited and was investigated here. Methods Male Sprague-Dawley rats were randomized to undergo 5/6 nephrectomy (CRF) or sham operation (control) and observed for 12 weeks. The animals were then euthanized and their liver tissue tested for nuclear translocation (activation) of carbohydrate-responsive element binding protein (ChREBP) and sterol-responsive element binding protein-1 (SREBP-1) which independently regulate the expression of key enzyme in fatty acid synthesis, i.e. fatty acid synthase (FAS) and acyl-CoA carboxylase (ACC) as well as nuclear Peroxisome proliferator-activated receptor alpha (PPARα) which regulates the expression of enzymes involved in fatty acid oxidation and transport, i.e. L-FABP and CPT1A. In addition, the expression of ATP synthase α, ATP synthase β, glycogen synthase and diglyceride acyltransferase 1 (DGAT1) and DGAT2 were determined. Results Compared with controls, the CKD rats exhibited hypertriglyceridemia, elevated plasma and liver tissue free fatty acids, increased nuclear ChREBP and reduced nuclear SREBP-1 and PPARα, upregulation of ACC and FAS and downregulation of L-FABP, CPT1A, ATP synthase α, glycogen synthase and DGAT in the liver tissue. Conclusion Liver in animals with advanced CKD exhibits ChREBP-mediated upregulation of enzymes involved in fatty acid synthesis, downregulation of PPARα-regulated fatty acid oxidation system and reduction of DGAT resulting in reduced fatty acid incorporation in triglyceride. PMID:23045433

  19. East Mediterranean region sickle cell disease mortality trial: retrospective multicenter cohort analysis of 735 patients.

    PubMed

    Karacaoglu, Pelin Kardaş; Asma, Suheyl; Korur, Aslı; Solmaz, Soner; Buyukkurt, Nurhilal Turgut; Gereklioglu, Cigdem; Kasar, Mutlu; Ozbalcı, Demircan; Unal, Selma; Kaya, Hasan; Gurkan, Emel; Yeral, Mahmut; Sariturk, Çagla; Boga, Can; Ozdogu, Hakan

    2016-05-01

    Sickle cell disease (SCD), one of the most common genetic disorders worldwide, is characterized by hemolytic anemia and tissue damage from the rigid red blood cells. Although hydroxyurea and transfusion therapy are administered to treat the accompanying tissue injury, whether either one prolongs the lifespan of patients with SCD is unknown. SCD-related mortality data are available, but there are few studies on mortality-related factors based on evaluations of surviving patients. In addition, ethnic variability in patient registries has complicated detailed analyses. The aim of this study was to investigate mortality and mortality-related factors among an ethnically homogeneous population of patients with SCD. The 735 patients (102 children and 633 adults) included in this retrospective cohort study were of Eti-Turk origin and selected from 1367 patients seen at 5 regional hospitals. A central population management system was used to control for records of patient mortality. Data reliability was checked by a data supervision group. Mortality-related factors and predictors were identified in univariate and multivariate analyses using a Cox regression model with stepwise forward selection. The study group included patients with homozygous hemoglobin S (Hgb S) disease (67 %), Hb S-β(0) thalassemia (17 %), Hgb S-β(+) thalassemia (15 %), and Hb S-α thalassemia (1 %). They were followed for a median of 66 ± 44 (3-148) months. Overall mortality at 5 years was 6.1 %. Of the 45 patients who died, 44 (6 %) were adults and 1 (0.1 %) was a child. The mean age at death was 34.1 ± 10 (18-54) years for males, 40.1 ± 15 (17-64) years for females, and 36.6 ± 13 (17-64) years overall. Hydroxyurea was found to have a notable positive effect on mortality (p = 0.009). Mortality was also significantly related to hypertension and renal damage in a univariate analysis (p = 0.015 and p = 0.000, respectively). Acute chest syndrome

  20. East Mediterranean region sickle cell disease mortality trial: retrospective multicenter cohort analysis of 735 patients.

    PubMed

    Karacaoglu, Pelin Kardaş; Asma, Suheyl; Korur, Aslı; Solmaz, Soner; Buyukkurt, Nurhilal Turgut; Gereklioglu, Cigdem; Kasar, Mutlu; Ozbalcı, Demircan; Unal, Selma; Kaya, Hasan; Gurkan, Emel; Yeral, Mahmut; Sariturk, Çagla; Boga, Can; Ozdogu, Hakan

    2016-05-01

    Sickle cell disease (SCD), one of the most common genetic disorders worldwide, is characterized by hemolytic anemia and tissue damage from the rigid red blood cells. Although hydroxyurea and transfusion therapy are administered to treat the accompanying tissue injury, whether either one prolongs the lifespan of patients with SCD is unknown. SCD-related mortality data are available, but there are few studies on mortality-related factors based on evaluations of surviving patients. In addition, ethnic variability in patient registries has complicated detailed analyses. The aim of this study was to investigate mortality and mortality-related factors among an ethnically homogeneous population of patients with SCD. The 735 patients (102 children and 633 adults) included in this retrospective cohort study were of Eti-Turk origin and selected from 1367 patients seen at 5 regional hospitals. A central population management system was used to control for records of patient mortality. Data reliability was checked by a data supervision group. Mortality-related factors and predictors were identified in univariate and multivariate analyses using a Cox regression model with stepwise forward selection. The study group included patients with homozygous hemoglobin S (Hgb S) disease (67 %), Hb S-β(0) thalassemia (17 %), Hgb S-β(+) thalassemia (15 %), and Hb S-α thalassemia (1 %). They were followed for a median of 66 ± 44 (3-148) months. Overall mortality at 5 years was 6.1 %. Of the 45 patients who died, 44 (6 %) were adults and 1 (0.1 %) was a child. The mean age at death was 34.1 ± 10 (18-54) years for males, 40.1 ± 15 (17-64) years for females, and 36.6 ± 13 (17-64) years overall. Hydroxyurea was found to have a notable positive effect on mortality (p = 0.009). Mortality was also significantly related to hypertension and renal damage in a univariate analysis (p = 0.015 and p = 0.000, respectively). Acute chest syndrome

  1. Risk of lower extremity arterial disease in a cohort of workers occupationally exposed to ionizing radiation over a prolonged period.

    PubMed

    Azizova, Tamara V; Bannikova, Maria V; Grigorieva, Evgenia S; Bagaeva, Yaroslava P; Azizova, Elena V

    2016-05-01

    In this study the incidence risk of lower extremity arterial disease (LEAD; international classification of diseases version 9 code 440.2) was assessed in a cohort of workers occupationally exposed to radiation over a prolonged period. The study cohort includes 22,377 workers of the Mayak Production Association (25% of whom are females) first employed at one of the main facilities in 1948-1982 and followed up to the end of 2008. Dose estimates used in the study are provided by Mayak Worker Dosimetry System 2008. The mean total dose from external gamma-rays is 0.54 Gy for males and 0.44 Gy for females. The mean absorbed liver dose from internal alpha-radiation due to incorporated plutonium is 0.23 Gy in males and 0.44 Gy in females. Relative risks and excess relative risks per unit dose (ERR/Gy) are calculated based on maximum likelihood. A total of 943 cases of LEAD are registered in the study cohort during the follow-up of 512,801 person-years. A significant association of LEAD incidence with total dose from external gamma-rays (based on a linear model) was revealed, and the ERR/Gy is 0.27 (95% confidence interval (CI) 0.11; 0.48). It turned out that a linear-exponential model provides a better fit of the data (∆AIC = 9.957). Inclusion of an adjustment for internal alpha-radiation dose resulted in the reduction of the ERR/Gy to 0.19 (95% CI 0.05; 0.39), but the risk remains significant. No association of LEAD incidence with dose from internal alpha-radiation was found in the study worker cohort. It is concluded that this study provides evidence for an association of LEAD incidence with dose from external gamma-rays taking non-radiation factors into account. PMID:26994996

  2. Risk of lower extremity arterial disease in a cohort of workers occupationally exposed to ionizing radiation over a prolonged period.

    PubMed

    Azizova, Tamara V; Bannikova, Maria V; Grigorieva, Evgenia S; Bagaeva, Yaroslava P; Azizova, Elena V

    2016-05-01

    In this study the incidence risk of lower extremity arterial disease (LEAD; international classification of diseases version 9 code 440.2) was assessed in a cohort of workers occupationally exposed to radiation over a prolonged period. The study cohort includes 22,377 workers of the Mayak Production Association (25% of whom are females) first employed at one of the main facilities in 1948-1982 and followed up to the end of 2008. Dose estimates used in the study are provided by Mayak Worker Dosimetry System 2008. The mean total dose from external gamma-rays is 0.54 Gy for males and 0.44 Gy for females. The mean absorbed liver dose from internal alpha-radiation due to incorporated plutonium is 0.23 Gy in males and 0.44 Gy in females. Relative risks and excess relative risks per unit dose (ERR/Gy) are calculated based on maximum likelihood. A total of 943 cases of LEAD are registered in the study cohort during the follow-up of 512,801 person-years. A significant association of LEAD incidence with total dose from external gamma-rays (based on a linear model) was revealed, and the ERR/Gy is 0.27 (95% confidence interval (CI) 0.11; 0.48). It turned out that a linear-exponential model provides a better fit of the data (∆AIC = 9.957). Inclusion of an adjustment for internal alpha-radiation dose resulted in the reduction of the ERR/Gy to 0.19 (95% CI 0.05; 0.39), but the risk remains significant. No association of LEAD incidence with dose from internal alpha-radiation was found in the study worker cohort. It is concluded that this study provides evidence for an association of LEAD incidence with dose from external gamma-rays taking non-radiation factors into account.

  3. Congenital heart disease in men – birth characteristics and reproduction: a national cohort study

    PubMed Central

    2014-01-01

    Background Women with congenital heart disease (CHD) are more often born preterm or small-for-gestational age and with a caesarean section. This pattern together with an increased risk of congenital anomalies seems to be repeated in the next generation. Information on the effect of paternal CHD on their offspring is sparse. In this study we investigated if men with CHD differ from those who do not have CHD with respect to characteristics related to their own births, their reproductive patterns and the neonatal outcomes of their children. Methods In this national cohort study data were derived from Swedish population-based registries. The population consists of all men born in 1973-1983 who were alive and living in Sweden at 13 years of age (n = 522 216). The index group is men with CHD (n = 2689). Men diagnosed with CHD were compared with men without CHD. The CHD were also divided into two groups, complex and simple CHD and comparisons between the groups were made. Results Men with CHD are more likely to have been born preterm (p < 0.001), small-for gestational-age (p < 0.001) or large-for-gestational-age (p < 0.001) than men without CHD. They are also more likely to have been the result of a twin pregnancy (p < 0.001) and to have been delivered by caesarean section (p < 0.001). Men with CHD have a decreased likelihood to become fathers compared to non-CHD men and in this study their offspring do not have a higher incidence of CHD than offspring to non-CHD fathers. The neonatal outcomes of children of men with CHD do not differ from the outcomes of children of non-CHD men. Conclusions Men with CHD were more often born with non-optimal characteristics compared to men without the condition. However, the increased risk does not repeat itself in the next generation. This knowledge can lead to improved preconception counselling for couples in which the father has a CHD. PMID:24890365

  4. Markers of Bone Metabolism Are Affected by Renal Function and Growth Hormone Therapy in Children with Chronic Kidney Disease

    PubMed Central

    Doyon, Anke; Fischer, Dagmar-Christiane; Bayazit, Aysun Karabay; Canpolat, Nur; Duzova, Ali; Sözeri, Betül; Bacchetta, Justine; Balat, Ayse; Büscher, Anja; Candan, Cengiz; Cakar, Nilgun; Donmez, Osman; Dusek, Jiri; Heckel, Martina; Klaus, Günter; Mir, Sevgi; Özcelik, Gül; Sever, Lale; Shroff, Rukshana; Vidal, Enrico; Wühl, Elke; Gondan, Matthias; Melk, Anette; Querfeld, Uwe; Haffner, Dieter; Schaefer, Franz

    2015-01-01

    Objectives The extent and relevance of altered bone metabolism for statural growth in children with chronic kidney disease is controversial. We analyzed the impact of renal dysfunction and recombinant growth hormone therapy on a panel of serum markers of bone metabolism in a large pediatric chronic kidney disease cohort. Methods Bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase 5b (TRAP5b), sclerostin and C-terminal FGF-23 (cFGF23) normalized for age and sex were analyzed in 556 children aged 6–18 years with an estimated glomerular filtration rate (eGFR) of 10–60 ml/min/1.73m2. 41 children receiving recombinant growth hormone therapy were compared to an untreated matched control group. Results Standardized levels of BAP, TRAP5b and cFGF-23 were increased whereas sclerostin was reduced. BAP was correlated positively and cFGF-23 inversely with eGFR. Intact serum parathormone was an independent positive predictor of BAP and TRAP5b and negatively associated with sclerostin. BAP and TRAP5B were negatively affected by increased C-reactive protein levels. In children receiving recombinant growth hormone, BAP was higher and TRAP5b lower than in untreated controls. Sclerostin levels were in the normal range and higher than in untreated controls. Serum sclerostin and cFGF-23 independently predicted height standard deviation score, and BAP and TRAP5b the prospective change in height standard deviation score. Conclusion Markers of bone metabolism indicate a high-bone turnover state in children with chronic kidney disease. Growth hormone induces an osteoanabolic pattern and normalizes osteocyte activity. The osteocyte markers cFGF23 and sclerostin are associated with standardized height, and the markers of bone turnover predict height velocity. PMID:25659076

  5. General anesthesia exposure in early life reduces the risk of allergic diseases: A nationwide population-based cohort study.

    PubMed

    Kuo, Ho-Chang; Yang, Ya-Ling; Ho, Shu-Chen; Guo, Mindy Ming-Huey; Jiang, Jyun-Hong; Huang, Ying-Hsien

    2016-07-01

    General anesthesia (GA) has been used for second line treatment strategy for status asthmaticus in pediatric patients. The association between GA in children and risk of followed-up allergic diseases is unclear. This study aims to assess the risk of allergic diseases after GA in children.We did a nationwide retrospective cohort study by analyzing data from the National Health Insurance Research Database (NHIRD) in Taiwan. The subsequent risks for allergic diseases, including asthma (ICD-9: 493.X), allergic rhinitis (AR; ICD-9 CM code 477.X), and atopic dermatitis (AD; ICD-9-CM code 691.X), were compared between exposure to GA and none before 1 year of age throughout the follow-up period using the Cox proportional hazards model.Insurance claims data for 32,742 children younger than 1 year old from all insured children in the NHIRD. Of those, 2358 subjects were exposed to GA; 414 and 1944 children exposed to mask and intubation ventilation, respectively, served as the study cohort, whereas the remaining 30,384 children made up the comparison cohort. Children in the GA group were at a lower risk of developing asthma, AR and AD, with adjusted hazard ratios of 0.67 (0.62-0.72, 95%CI), 0.72 (0.68-0.77, 95%CI), 0.60 (0.56-0.64, 95%CI), respectively.Children who were exposed to GA in early life before 1 year of age had reduced risk of subsequently developing allergic diseases such as asthma, AD, and AR, when compared with general population. PMID:27428241

  6. Skipping Breakfast and Risk of Mortality from Cancer, Circulatory Diseases and All Causes: Findings from the Japan Collaborative Cohort Study

    PubMed Central

    Yokoyama, Yae; Onishi, Kazunari; Hosoda, Takenobu; Amano, Hiroki; Otani, Shinji; Kurozawa, Youichi; Tamakoshi, Akiko

    2016-01-01

    Background Breakfast eating habits are a dietary pattern marker and appear to be a useful predictor of a healthy lifestyle. Many studies have reported the unhealthy effects of skipping breakfast. However, there are few studies on the association between skipping breakfast and mortality. In the present study, we examined the association between skipping breakfast and mortality from cancer, circulatory diseases and all causes using data from a large-scale cohort study, the Japan Collaborative Cohort Study (JACC) Study. Methods A cohort study of 34,128 men and 49,282 women aged 40–79 years was conducted, to explore the association between lifestyle and cancer in Japan. Participants completed a baseline survey during 1988 to 1990 and were followed until the end of 2009. We classified participants into two groups according to dietary habits with respect to eating or skipping breakfast and carried out intergroup comparisons of lifestyle. Multivariate analysis was performed using the Cox proportional hazard regression model. Results There were 5,768 deaths from cancer and 5,133 cases of death owing to circulatory diseases and 17,112 cases for all causes of mortality during the median 19.4 years follow-up. Skipping breakfast was related to unhealthy lifestyle habits. After adjusting for confounding factors, skipping breakfast significantly increased the risk of mortality from circulatory diseases [hazard ratio (HR) = 1.42] and all causes (HR = 1.43) in men and all causes mortality (HR = 1.34) in women. Conclusion Our findings showed that skipping breakfast is associated with increasing risk of mortality from circulatory diseases and all causes among men and all causes mortality among women in Japan. PMID:27046951

  7. The role of the complement system in metabolic organs and metabolic diseases.

    PubMed

    Phieler, Julia; Garcia-Martin, Ruben; Lambris, John D; Chavakis, Triantafyllos

    2013-02-01

    Emerging evidence points to a close crosstalk between metabolic organs and innate immunity in the course of metabolic disorders. In particular, cellular and humoral factors of innate immunity are thought to contribute to metabolic dysregulation of the adipose tissue or the liver, as well as to dysfunction of the pancreas; all these conditions are linked to the development of insulin resistance and diabetes mellitus. A central component of innate immunity is the complement system. Interestingly, the classical view of complement as a major system of host defense that copes with infections is changing to that of a multi-functional player in tissue homeostasis, degeneration, and regeneration. In the present review, we will discuss the link between complement and metabolic organs, focusing on the pancreas, adipose tissue, and liver and the diverse effects of complement system on metabolic disorders.

  8. Is cancer a disease of abnormal cellular metabolism?

    PubMed Central

    DeBerardinis, Ralph J.

    2009-01-01

    In the 1920s, Otto Warburg observed that tumor cells consume a large amount of glucose, much more than normal cells, and convert most of it to lactic acid. This phenomenon, now known as the ‘Warburg effect,’ is the foundation of one of the earliest general concepts of cancer: that a fundamental disturbance of cellular metabolic activity is at the root of tumor formation and growth. In the ensuing decades, as it became apparent that abnormalities in chromosomes and eventually individual genes caused cancer, the ‘metabolic’ model of cancer lost a good deal of its appeal, even as emerging technologies were exploiting the Warburg effect clinically to detect tumors in vivo. We now know that tumor suppressors and proto-oncogenes influence metabolism, and that mutations in these genes can promote a metabolic phenotype supporting cell growth and proliferation. Thus, these advances have unified aspects of the metabolic and genetic models of cancer, and have stimulated a renewed interest in the role of cellular metabolism in tumorigenesis. This review reappraises the notion that dysregulated cellular metabolism is a key feature of cancer, and discusses some metabolic issues that have escaped scrutiny over the years and now deserve closer attention. PMID:18941420

  9. Is the Mouse a Good Model of Human PPARγ-Related Metabolic Diseases?

    PubMed

    Pap, Attila; Cuaranta-Monroy, Ixchelt; Peloquin, Matthew; Nagy, Laszlo

    2016-01-01

    With the increasing number of patients affected with metabolic diseases such as type 2 diabetes, obesity, atherosclerosis and insulin resistance, academic researchers and pharmaceutical companies are eager to better understand metabolic syndrome and develop new drugs for its treatment. Many studies have focused on the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ), which plays a crucial role in adipogenesis and lipid metabolism. These studies have been able to connect this transcription factor to several human metabolic diseases. Due to obvious limitations concerning experimentation in humans, animal models-mainly mouse models-have been generated to investigate the role of PPARγ in different tissues. This review focuses on the metabolic features of human and mouse PPARγ-related diseases and the utility of the mouse as a model. PMID:27483259

  10. Is the Mouse a Good Model of Human PPARγ-Related Metabolic Diseases?

    PubMed Central

    Pap, Attila; Cuaranta-Monroy, Ixchelt; Peloquin, Matthew; Nagy, Laszlo

    2016-01-01

    With the increasing number of patients affected with metabolic diseases such as type 2 diabetes, obesity, atherosclerosis and insulin resistance, academic researchers and pharmaceutical companies are eager to better understand metabolic syndrome and develop new drugs for its treatment. Many studies have focused on the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ), which plays a crucial role in adipogenesis and lipid metabolism. These studies have been able to connect this transcription factor to several human metabolic diseases. Due to obvious limitations concerning experimentation in humans, animal models—mainly mouse models—have been generated to investigate the role of PPARγ in different tissues. This review focuses on the metabolic features of human and mouse PPARγ-related diseases and the utility of the mouse as a model. PMID:27483259

  11. The Impact of Dietary and Metabolic Risk Factors on Cardiovascular Diseases and Type 2 Diabetes Mortality in Brazil

    PubMed Central

    de Oliveira Otto, Marcia C.; Afshin, Ashkan; Micha, Renata; Khatibzadeh, Shahab; Fahimi, Saman; Singh, Gitanjali; Danaei, Goodarz; Sichieri, Rosely; Monteiro, Carlos A; Louzada, Maria L. C.; Ezzati, Majid; Mozaffarian, Dariush

    2016-01-01

    Background Trends in food availability and metabolic risk factors in Brazil suggest a shift toward unhealthy dietary patterns and increased cardiometabolic disease risk, yet little is known about the impact of dietary and metabolic risk factors on cardiometabolic mortality in Brazil. Methods Based on data from Global Burden of Disease (GBD) Study, we used comparative risk assessment to estimate the burden of 11 dietary and 4 metabolic risk factors on mortality due to cardiovascular diseases and diabetes in Brazil in 2010. Information on national diets and metabolic risks were obtained from the Brazilian Household Budget Survey, the Food and Agriculture Organization database, and large observational studies including Brazilian adults. Relative risks for each risk factor were obtained from meta-analyses of randomized trials or prospective cohort studies; and disease-specific mortality from the GBD 2010 database. We quantified uncertainty using probabilistic simulation analyses, incorporating uncertainty in dietary and metabolic data and relative risks by age and sex. Robustness of findings was evaluated by sensitivity to varying feasible optimal levels of each risk factor. Results In 2010, high systolic blood pressure (SBP) and suboptimal diet were the largest contributors to cardiometabolic deaths in Brazil, responsible for 214,263 deaths (95% uncertainty interval [UI]: 195,073 to 233,936) and 202,949 deaths (95% UI: 194,322 to 211,747), respectively. Among individual dietary factors, low intakes of fruits and whole grains and high intakes of sodium were the largest contributors to cardiometabolic deaths. For premature cardiometabolic deaths (before age 70 years, representing 40% of cardiometabolic deaths), the leading risk factors were suboptimal diet (104,169 deaths; 95% UI: 99,964 to 108,002), high SBP (98,923 deaths; 95%UI: 92,912 to 104,609) and high body-mass index (BMI) (42,643 deaths; 95%UI: 40,161 to 45,111). Conclusion suboptimal diet, high SBP, and high

  12. Race and Ethnicity, Obesity, Metabolic Health, and Risk of Cardiovascular Disease in Postmenopausal Women

    PubMed Central

    Schmiegelow, Michelle D; Hedlin, Haley; Mackey, Rachel H; Martin, Lisa W; Vitolins, Mara Z; Stefanick, Marcia L; Perez, Marco V; Allison, Matthew; Hlatky, Mark A

    2015-01-01

    Background It is unclear whether obesity unaccompanied by metabolic abnormalities is associated with increased cardiovascular disease risk across racial and ethnic subgroups. Methods and Results We identified 14 364 postmenopausal women from the Women's Health Initiative who had data on fasting serum lipids and serum glucose and no history of cardiovascular disease or diabetes at baseline. We categorized women by body mass index (in kg/m2) as normal weight (body mass index 18.5 to <25), overweight (body mass index 25 to <30), or obese (body mass index ≥30) and by metabolic health, defined first as the metabolic syndrome (metabolically unhealthy: ≥3 metabolic abnormalities) and second as the number of metabolic abnormalities. We used Cox proportional hazards regression to assess associations between baseline characteristics and cardiovascular risk. Over 13 years of follow-up, 1101 women had a first cardiovascular disease event (coronary heart disease or ischemic stroke). Among black women without metabolic syndrome, overweight women had higher adjusted cardiovascular risk than normal weight women (hazard ratio [HR] 1.49), whereas among white women without metabolic syndrome, overweight women had similar risk to normal weight women (HR 0.92, interaction P=0.05). Obese black women without metabolic syndrome had higher adjusted risk (HR 1.95) than obese white women (HR 1.07; interaction P=0.02). Among women with only 2 metabolic abnormalities, cardiovascular risk was increased in black women who were overweight (HR 1.77) or obese (HR 2.17) but not in white women who were overweight (HR 0.98) or obese (HR 1.06). Overweight and obese women with ≤1 metabolic abnormality did not have increased cardiovascular risk, regardless of race or ethnicity. Conclusions Metabolic abnormalities appeared to convey more cardiovascular risk among black women. PMID:25994446

  13. Pre-treatment evaluation of 5-fluorouracil degradation rate: association of poor and ultra-rapid metabolism with severe toxicity in a colorectal cancer patients cohort

    PubMed Central

    Mazzuca, Federica; Borro, Marina; Botticelli, Andrea; Mazzotti, Eva; Marchetti, Luca; Gentile, Giovanna; La Torre, Marco; Lionetto, Luana; Simmaco, Maurizio; Marchetti, Paolo

    2016-01-01

    Despite the wide use of 5-fluorouracil-based chemotherapy, development of severe toxicity that follow the treatment is not a rare event. The efforts to establish pretreatment tools for toxicity prediction, led to the development of various pharmacogenetic and biochemical assays, mainly targeted to assess the activity level of dihydropyrimidine dehydrogenase (DPD), the main metabolizing enzyme for 5-fluorouracil. Using peripheral blood mononuclear cells, we developed a biochemical assay, that is not limited to the evaluation of DPD activity, but determines the net result of all the enzymatic transformation of 5FU, in terms of the amount of drug consumed by the cells in a time unit. This parameter, named 5-fluorauracil degradation rate, presents a normal distribution inside the population and highlight the presence of an ultra-rapid metabolizers class of subjects, besides the expected poor metabolizers class. Here we will show that, in a colorectal cancer patient cohort, both poor and ultra-rapid metabolizers have significantly increased the risk of developing severe toxicity (grade3–4). Patient stratification depending on the individual 5-fluorouracil degradation rate allows to identify a 10% of the overall population at high risk of developing severe toxicity, compared to the 1.3% (as assessed in the Italian population) identified by the most commonly employed pharmacogenetic test, including the DPD polymorphism IVS14+1G>A. PMID:26967565

  14. Triad of metabolic syndrome, chronic kidney disease, and coronary heart disease with a focus on microalbuminuria death by overeating.

    PubMed

    Gobal, Freij; Deshmukh, Abhishek; Shah, Sudhir; Mehta, Jawahar L

    2011-06-01

    Coronary heart disease remains a major cause of morbidity and mortality in the United States, and its incidence is rising worldwide. Because atherosclerosis is a chronic process, and it is often associated with certain lifestyle and risk factors such as hypertension, dyslipidemia, and insulin resistance, much emphasis is being placed on lifestyle modification and control of risk factors. It is being recognized that some lifestyle patterns such as overeating result in metabolic syndrome, which may play a role in the development of chronic kidney disease and coronary heart disease. Here, we focus on an important relationship between these 3 conditions, and we provide evidence that microalbuminuria develops in many patients with metabolic syndrome, may be an important correlate of chronic kidney disease and coronary heart disease, and may represent an important prognostic marker. Although the pathogenesis of microalbuminuria in metabolic syndrome is not clear, we suggest that microalbuminuria, chronic kidney disease, and coronary heart disease share common pathways involving inflammation and oxidative stress. We also discuss that a healthy lifestyle is essential for preventing and treating chronic kidney disease and coronary heart disease seen in patients with metabolic syndrome.

  15. The effect of a low-fat, plant-based lifestyle intervention (CHIP) on serum HDL levels and the implications for metabolic syndrome status – a cohort study

    PubMed Central

    2013-01-01

    Background Low levels of high-density lipoproteins (HDL) are considered an important risk factor for cardiovascular disease and constitute one of the criteria for the Metabolic Syndrome (MetS). Lifestyle interventions promoting a low-fat, plant-based eating pattern appear to paradoxically reduce cardiovascular risk but also HDL levels. This study examined the changes in MetS risk factors, in particular HDL, in a large cohort participating in a 30-day lifestyle intervention that promoted a low-fat, plant-based eating pattern. Methods Individuals (n = 5,046; mean age = 57.3 ± 12.9 years; 33.5% men, 66.5% women) participating in a in a Complete Health Improvement Program (CHIP) lifestyle intervention within the United States were assessed at baseline and 30 days for changes in body mass index (BMI), blood pressure (BP), lipid profile and fasting plasma glucose (FPG). Results HDL levels decreased by 8.7% (p<0.001) despite significant reductions (p<0.001) in BMI (-3.2%), systolic BP (-5.2%), diastolic BP (-5.2%), triglycerides (TG; -7.7%), FPG (-6.3%), LDL (-13.0%), total cholesterol (TC, -11.1%), TC: HDL ratio (-3.2%), and LDL: HDL ratio (-5.3%). While 323 participants classified as having MetS at program entry no longer had this status after the 30 days, 112 participants acquired the MetS classification as a result of reduction in their HDL levels. Conclusions When people move towards a low-fat, plant-based diet, HDL levels decrease while other indicators of cardiovascular risk improve. This observation raises questions regarding the value of using HDL levels as a predictor of cardiovascular risk in populations who do not consume a typical western diet. As HDL is part of the assemblage of risk factors that constitute MetS, classifying individuals with MetS may not be appropriate in clinical practice or research when applying lifestyle interventions that promote a plant-based eating pattern. PMID:24283215

  16. Metabolic Abnormalities, Cardiovascular Disease Risk Factors, and GFR Decline in Children with Chronic Kidney Disease

    PubMed Central

    Abraham, Alison G.; Jerry-Fluker, Judith; Schwartz, George J.; Benfield, Mark; Kaskel, Frederick; Wong, Craig; Mak, Robert H.; Moxey-Mims, Marva; Warady, Bradley A.

    2011-01-01

    Summary Background and objectives Metabolic abnormalities and cardiovascular disease (CVD) risk factors have rarely been systematically assessed in children with chronic kidney disease (CKD). We examined the prevalence of various CKD sequelae across the GFR spectrum. Design, setting, participants, & measurements Data were used from 586 children participating in the Chronic Kidney Disease in Children (CKiD) study (United States and Canada) with GFR measured by iohexol plasma disappearance. Laboratory values and CVD risk factors were compared across GFR categories and with an age-, gender-, and race-matched community sample. Results CKiD participants were 62% male, 66% Caucasian, 23% African American, and 15% Hispanic with a median age of 11 years and a median GFR of 44 ml/min per 1.73 m2. Compared with those with a GFR ≥ 50 ml/min per 1.73 m2, having a GFR < 30 ml/min per 1.73 m2 was associated with a three-fold higher risk of acidosis and growth failure and a four- to five-fold higher risk of anemia and elevated potassium and phosphate. Median GFR change was −4.3 ml/min per 1.73 m2 and −1.5 ml/min per 1.73 m2 per year in children with glomerular and nonglomerular diagnoses, respectively. Despite medication and access to nephrology care, uncontrolled systolic hypertension was present in 14%, and 16% had left ventricular hypertrophy. Children with CKD frequently were also shorter and had lower birth weight, on average, compared with norms. Conclusions Growth failure, metabolic abnormalities, and CVD risk factors are present at GFR >50 ml/min per 1.73 m2 in children with CKD and, despite therapy, increase in prevalence two- to four-fold with decreasing GFR. PMID:21841064

  17. Decomposing Black-White Disparities in Heart Disease Mortality in the United States, 1973-2010: An Age-Period-Cohort Analysis.

    PubMed

    Kramer, Michael R; Valderrama, Amy L; Casper, Michele L

    2015-08-15

    Against the backdrop of late 20th century declines in heart disease mortality in the United States, race-specific rates diverged because of slower declines among blacks compared with whites. To characterize the temporal dynamics of emerging black-white racial disparities in heart disease mortality, we decomposed race-sex-specific trends in an age-period-cohort (APC) analysis of US mortality data for all diseases of the heart among adults aged ≥35 years from 1973 to 2010. The black-white gap was largest among adults aged 35-59 years (rate ratios ranged from 1.2 to 2.7 for men and from 2.3 to 4.0 for women) and widened with successive birth cohorts, particularly for men. APC model estimates suggested strong independent trends across generations ("cohort effects") but only modest period changes. Among men, cohort-specific black-white racial differences emerged in the 1920-1960 birth cohorts. The apparent strength of the cohort trends raises questions about life-course inequalities in the social and health environments experienced by blacks and whites which could have affected their biomedical and behavioral risk factors for heart disease. The APC results suggest that the genesis of racial disparities is neither static nor restricted to a single time scale such as age or period, and they support the importance of equity in life-course exposures for reducing racial disparities in heart disease.

  18. Effect of peripheral circadian dysfunction on metabolic disease in response to a diabetogenic diet.

    PubMed

    Pijut, Sonja S; Corbett, Danielle E; Wang, Yuhuan; Li, Jianing; Charnigo, Richard J; Graf, Gregory A

    2016-06-01

    BMAL1 is a core component of the transcription/translation machinery that regulates central and peripheral circadian rhythms that coordinate behavior and metabolism, respectively. Our objective was to determine the impact of BMAL1 in adipose alone or in combination with liver on metabolic phenotypes. Control, adipose-Bmal1 knockout (ABKO), and liver- and adipose-Bmal1 knockout (LABKO) female mice were placed in TSE System metabolic chambers for metabolic phenotyping. A second cohort of male mice was fed a control or diabetogenic diet, and body weight and composition, glucose tolerance, insulin sensitivity, and serum and hepatic lipids were measured. Both female ABKO and LABKO mice exhibited increased food consumption compared with control mice. ABKO mice also exhibited increased overall activity predominantly during the light phase compared with both control and LABKO mice and were protected from increased weight gain. When the male cohort was challenged with a diabetogenic diet, LABKO mice had increased body weight due to increased fat mass compared with control and ABKO mice. However, these mice did not present further impairments in glycemic control, adipose inflammation, or liver injury. LABKO mice had increased hepatic cholesterol and elevated expression of cholesterol synthesis and uptake genes. Our data indicate that deletion of this allele in adipose or in combination with liver alters feeding behavior and locomotor activity. However, obesity is exacerbated only with the combination of liver and adipose deletion. PMID:27048996

  19. Metabolic syndrome: is equine disease comparable to what we know in humans?

    PubMed Central

    Ertelt, Antonia; Barton, Ann-Kristin; Schmitz, Robert R; Gehlen, Heidrun

    2014-01-01

    This review summarizes similarities and differences between the metabolic syndromes in humans and equines, concerning the anatomy, symptoms, and pathophysiological mechanisms. In particular, it discusses the structure and distribution of adipose tissue and its specific metabolic pathways. Furthermore, this article provides insights and focuses on issues concerning laminitis in horses and cardiovascular diseases in humans, as well as their overlap. PMID:24894908

  20. "Design Your Own Disease" Assignment: Teaching Students to Apply Metabolic Pathways

    ERIC Educational Resources Information Center

    Flynn, Nick

    2010-01-01

    One of the major focuses of biochemistry courses is metabolic pathways. Although certain aspects of this content may require a rote approach, more applied techniques make these subject areas more interesting. This article describes the use of an assignment, "Design Your Own Disease" to teach students metabolic regulation and biosignaling…

  1. Metabolic syndrome: is equine disease comparable to what we know in humans?

    PubMed

    Ertelt, Antonia; Barton, Ann-Kristin; Schmitz, Robert R; Gehlen, Heidrun

    2014-09-01

    This review summarizes similarities and differences between the metabolic syndromes in humans and equines, concerning the anatomy, symptoms, and pathophysiological mechanisms. In particular, it discusses the structure and distribution of adipose tissue and its specific metabolic pathways. Furthermore, this article provides insights and focuses on issues concerning laminitis in horses and cardiovascular diseases in humans, as well as their overlap. PMID:24894908

  2. A Risk Score with Additional Four Independent Factors to Predict the Incidence and Recovery from Metabolic Syndrome: Development and Validation in Large Japanese Cohorts

    PubMed Central

    Obokata, Masaru; Negishi, Kazuaki; Ohyama, Yoshiaki; Okada, Haruka; Imai, Kunihiko; Kurabayashi, Masahiko

    2015-01-01

    Background Although many risk factors for Metabolic syndrome (MetS) have been reported, there is no clinical score that predicts its incidence. The purposes of this study were to create and validate a risk score for predicting both incidence and recovery from MetS in a large cohort. Methods Subjects without MetS at enrollment (n = 13,634) were randomly divided into 2 groups and followed to record incidence of MetS. We also examined recovery from it in rest 2,743 individuals with prevalent MetS. Results During median follow-up of 3.0 years, 878 subjects in the derivation and 757 in validation cohorts developed MetS. Multiple logistic regression analysis identified 12 independent variables from the derivation cohort and initial score for subsequent MetS was created, which showed good discrimination both in the derivation (c-statistics 0.82) and validation cohorts (0.83). The predictability of the initial score for recovery from MetS was tested in the 2,743 MetS population (906 subjects recovered from MetS), where nine