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Metabolic Disorders (metabolic + disorders)
Selected AbstractsLiver Transplantation in Children with Metabolic Disorders in the United StatesAMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2003Liise K. Kayler We studied pediatric liver transplantation for metabolic disease in a large national cohort to determine whether smaller studies suggesting a survival advantage for these recipients could be corroborated. We also hoped to determine whether higher survival rates in recipients with metabolic disease are associated with lack of structural liver disease, and to evaluate these recipients' risk factors for mortality. Data from the Scientific Registry of Transplant Recipients were used to analyze nationwide results (1990,99) of pediatric liver transplantation for patients with biliary atresia and metabolic disease. Adjusted patient survival rates for children with metabolic disease at 1 and 5 years were 94% and 92%, respectively, , significantly higher than for recipients with biliary atresia (90% and 86%) (p,=,0.008). Cox regression models identified recipient black race [relative risk (RR) = 5.1] and simultaneous transplantation of other organs (RR = 3.2) as significant risk factors for mortality in the metabolic group. Adjusted survival rates for metabolic patients with structural and nonstructural liver diseases were similar to each other at both 1 and 5 years. Children with metabolic disease had significantly higher adjusted short- and long-term post-transplant survival rates than those with biliary atresia. Structural disease was not a risk factor for worse outcomes. [source] The role of PAS kinase in regulating energy metabolismIUBMB LIFE, Issue 4 2008Huai-Xiang Hao Abstract Metabolic disorders, such as diabetes and obesity, are fundamentally caused by cellular energy imbalance and dysregulation. Therefore, understanding the regulation of cellular fuel and energy metabolism is of great importance to develop effective therapies for metabolic disease. The cellular nutrient and energy sensors, AMPK and TOR, play a key role in maintaining cellular energy homeostasis. Like AMPK and TOR, PAS kinase (PASK) is also a nutrient responsive protein kinase. In yeast, PAS kinase phosphorylates the enzyme Ugp1 and thereby shifts glucose partitioning toward cell wall glucan synthesis at the expense of glycogen synthesis. Consistent with this function, yeast PAS kinase is activated by both cell integrity stress and growth in non-fermentative carbon sources. PASK is also important for proper regulation of glucose metabolism in mammals at both the hormonal and cellular level. In cultured pancreatic ,-cells, PASK is activated by elevated glucose concentrations and is required for glucose-stimulated transcription of the insulin gene. PASK knockdown in cultured myoblasts causes increased glucose oxidation and elevated cellular ATP levels. Mice lacking PASK exhibit increased metabolic rate and resistance to diet-induced obesity. Interestingly, PGC-1 expression and AMPK and TOR activity were not affected in PASK deficient mice, suggesting PASK may exert its metabolic effects through a new mechanism. We propose that PASK plays a significant role in nutrient sensing, metabolic regulation, and energy homeostasis, and is a potential therapeutic target for metabolic disease. © 2008 IUBMB IUBMB Life, 60(4): 204,209, 2008 [source] Prevalence and etiology of elevated serum alanine aminotransferase level in an adult population in TaiwanJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 9 2007Chien-Hua Chen Abstract Background:, The prevalence and etiologies of elevated alanine aminotransferase (ALT) have geographic variations and they are rarely reported in Taiwan. Through a population-based screening study, the prevalence and etiologies of elevated ALT in an adult population of Taiwan were assessed. Methods:, A cross-sectional community study in a rural village of Taiwan was conducted in 3260 Chinese adults (age ,18 years) undergoing ultrasonography (US), blood tests, and interviews with a structured questionnaire. The diagnostic criteria of non-alcoholic fatty liver disease (NAFLD) included alcohol intake <20 g/week for women or <30 g/week for men, negative hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, no known etiologies of liver disease, and US consistent with fatty liver. Results:, The prevalence of elevated ALT was 11.4% (372/3260). The probable cause of this elevation was excess alcohol consumption in 0.8%, HBV in 28.5%, HCV in 13.2%, both HBV and HCV in 2.2%, NAFLD in 33.6%, and unexplained cause in 21.8%. The etiologic distribution of elevated ALT was similar in both genders, although elevation was more common in men compared to women (17.3%vs 6.1%, P < 0.05). The prevalence of elevated ALT in NAFLD was 18.1% (125/691), and the positive predictive value was 33.6% (125/372). The development of NAFLD was related to increasing age (age between 40 years and 64 years, odds ratio [OR] 1.59, 95% confidence interval [CI]: 1.25,2.01; age , 65 years, OR 1.46, 95%CI: 1.08,1.96), fasting plasma glucose (FPG) , 126 mg/dL (OR 1.54, 95%CI: 1.11,2.14), bodymass index (BMI) , 25 kg/m2 (OR 5.01, 95%CI: 4.13,6.26), triglyceridemia , 150 mg/dL (OR 1.96, 95%CI: 1.58,2.42), and hyperuricemia (OR 1.50, 95%CI: 1.22,1.84). Elevated ALT was related to male gender, BMI , 25 kg/m2, and triglyceridemia , 150 mg/dL in subjects without known etiologies of liver disease (all P < 0.05). Conclusions:, Non-alcoholic fatty liver disease appears to be the commonest cause of elevated ALT and presumed liver injury in Taiwan. The development of NAFLD is closely associated with many metabolic disorders. Metabolic disorders are also related to elevated ALT in subjects without known etiologies of liver disease. [source] AMPK-dependent hormonal regulation of whole-body energy metabolismACTA PHYSIOLOGICA, Issue 1 2009N. L. Dzamko Abstract AMP-dependent protein kinase (AMPK) is an evolutionarily conserved serine/threonine protein kinase central to the regulation of energy balance at both the cellular and whole-body levels. In its classical role as an intracellular metabolic stress-sensing kinase, AMPK switches on fatty acid oxidation and glucose uptake in muscle, while switching off hepatic gluconeogenesis. AMPK also has a broader role in metabolism through the control of appetite. Regulation of AMPK activity at the whole-body level is coordinated by a growing number of hormones and cytokines secreted from adipose tissue, skeletal muscle, pancreas and the gut including leptin, adiponectin, insulin, interluekin-6, resistin, TNF-, and ghrelin. Understanding how these secreted signalling proteins regulate AMPK activity to control fatty acid oxidation, glucose uptake, gluconeogenesis and appetite may yield therapeutic treatments for metabolic disorders such as diabetes, insulin resistance and obesity. [source] AMPK activators , potential therapeutics for metabolic and other diseasesACTA PHYSIOLOGICA, Issue 1 2009G. Zhou Abstract AMP-activated protein kinase (AMPK)-mediated cellular metabolic responses to tissue-specific and whole-body stimuli play a vital role in the control of energy homeostasis. As a cellular energy-sensing mechanism, AMPK activation stimulates glucose uptake and fat oxidation, while it suppresses lipogenesis and gluconeogenesis. The cumulative effects of AMPK activation lead to beneficial metabolic states in liver, muscle and other peripheral tissues that are critical in the pathogenesis of obesity, type 2 diabetes and related metabolic disorders. Activators of AMPK that target selected tissues hold potential as novel therapeutics for diseases in which altered energy metabolism contributes to aetiology. [source] Genetic variation in D7S1875 repeat polymorphism of leptin gene is associated with increased risk for depression: a case-control study from IndiaDEPRESSION AND ANXIETY, Issue 9 2009Manav Kapoor M.Sc. Abstract Background: Epidemiologic data suggest an association between obesity and depression, however findings vary considerably across different studies. Both depression and obesity are disabling disorders associated with loss over appetite control, influenced by genetic and environmental factors and are risk factors for diseases like hypertension, cardiovascular disorders, etc. This study attempts to establish a link between the symptoms of depression, metabolic disorders, and obesity, to unravel the underlying association/s. Methods: This exploratory case,control study comprises 133 clinically diagnosed depressed individuals and 136 age matched controls. DNA from all 269 subjects was genotyped for D7S1875 repeat polymorphism in the promoter region of Leptin (LEP) gene using polymerase chain reaction. Results: Frequency of the shorter allele of D7S1875 (<208,bp) was 0.73 in the depressive group versus 0.67 in the control group (P=.01). Cases homozygous for D7S1875,208,bp alleles had significantly higher value of systolic (130 versus 122; P<.009) and diastolic (85.4 versus 81; P=.01) blood pressure (SBP and DBP) than the individuals homozygous for<208,bp allele. A similar trend was observed for SBP (127.8 versus 123.6; P=.03) among controls homozygous for the longer or the shorter allele. Thus, the LEP gene appears to be an important genetic determinant for susceptibility to depression in the Indian population (OR=1.4913, 95% CI=1.0334,2.1522; P=.04). Conclusions: Our findings suggest that LEP gene variants could be related to depression and associated co-morbidities such as hypertension. Depression and Anxiety, 2009. © 2009 Wiley-Liss, Inc. [source] Sanfilippo B in an elderly female psychiatric patient: a rare but relevant diagnosis in presenile dementiaACTA PSYCHIATRICA SCANDINAVICA, Issue 2 2010W. M. A. Verhoeven Verhoeven WMA, Csepán R, Marcelis CLM, Lefeber DJ, Egger JIM, Tuinier S. Sanfilippo B in an elderly female psychiatric patient: a rare but relevant diagnosis in presenile dementia. Objective:, Sanfilippo B is a rare autosomal recessive mucopolysaccharidosis (MPS IIIB) caused by a deficiency of N -acetyl-,-D-glucosaminidase (NAGLU). Method:, A mild mentally retarded elderly female patient is described with a slowly progressive dementia who had given birth to a daughter who developed normally. Results:, Metabolic screening revealed an enhanced concentration of heparan sulfate in urine. Enzymatic assay demonstrated deficiency of N -acetyl-,-D-glucosaminidase. Mutations in the NAGLU gene were found. One mentally retarded and hospitalized elder brother was also found to have MPS IIIB, whereas a second brother, who had died earlier, is suspected to have had the same metabolic disorder. Prior to the development of dementia, both the patient and her brother showed autistic like features, signs of ideomotor apraxia and weakness in verbal comprehension. Conclusion:, Screening for metabolic disorders, in particular MPSes, should always be considered in patients with a history of mental deficit and dementia or progressive functional decline. [source] Serum adiponectin and resistin levels in major depressive disorderACTA PSYCHIATRICA SCANDINAVICA, Issue 3 2010S. M. Lehto Lehto SM, Huotari A, Niskanen L, Tolmunen T, Koivumaa-Honkanen H, Honkalampi K, Ruotsalainen H, Herzig K-H, Viinamäki H, Hintikka J. Serum adiponectin and resistin levels in major depressive disorder. Objective:, To examine the role of the adipose-tissue-derived low-grade inflammation markers adiponectin and resistin in major depressive disorder (MDD) in a population-based sample. Method:, Serum levels of adiponectin and resistin were measured from 70 DSM-IV MDD subjects and 70 healthy controls. Depression severity was assessed with the 29-item Hamilton Depression Rating Scale. Results:, The MDD group had lowered serum adiponectin levels. Regression modelling with adjustments for age, gender, overweight, several socioeconomic and lifestyle factors, coronary heart disease and metabolic syndrome showed that each 5.0 ,g/ml decrease in serum adiponectin increased the likelihood of MDD by approximately 20% (P = 0.01). The resistin levels correlated with atypical (P = 0.02), but not with typical depressive symptoms (P = 0.12). Conclusion:, Our findings suggest that the lowered adiponectin levels in MDD are depression-specific and not explained by conventional low adiponectin-related factors such as such as coronary heart disease and metabolic disorders. [source] Universal newborn screening and adverse medical outcomes: A historical noteDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 4 2006Jeffrey P. Brosco Abstract Universal newborn screening programs for metabolic disorders are typically described as a triumph of medicine and public policy in the US over the last 50 years. Advances in science and technology, including the Human Genome Project, offer the opportunity to expand universal newborn screening programs to include many additional metabolic and genetic conditions. Although the benefits of such screening programs appear to outweigh their costs, some critics have claimed that historical examples of inadvertent harm ensuing from false-positive screening results and subsequent inappropriate medical treatment should make us wary of expanding universal newborn screening. In this essay, we report the results of a review of the published literature to assess whether the extension of screening from at risk populations to all newborns led to substantial morbidity and mortality from misguided medical treatment. We provide a historical overview of universal newborn screening programs in the United States, and then focus on six early NBS programs: congenital hypothyroidism, phenylketonuria, congenital adrenal hyperplasia, galactosemia, sickle cell disease, and maple syrup urine disease. Our comprehensive search of published sources did not reveal a widespread problem of harm ensuing from medical treatment of children with false positive screening test results. © 2006 Wiley-Liss, Inc. MRDD Research Reviews 2006;12:262,269. [source] Autophagic pathways and metabolic stressDIABETES OBESITY & METABOLISM, Issue 2010S. Kaushik Autophagy is an essential intracellular process that mediates degradation of intracellular proteins and organelles in lysosomes. Autophagy was initially identified for its role as alternative source of energy when nutrients are scarce but, in recent years, a previously unknown role for this degradative pathway in the cellular response to stress has gained considerable attention. In this review, we focus on the novel findings linking autophagic function with metabolic stress resulting either from proteins or lipids. Proper autophagic activity is required in the cellular defense against proteotoxicity arising in the cytosol and also in the endoplasmic reticulum, where a vast amount of proteins are synthesized and folded. In addition, autophagy contributes to mobilization of intracellular lipid stores and may be central to lipid metabolism in certain cellular conditions. In this review, we focus on the interrelation between autophagy and different types of metabolic stress, specifically the stress resulting from the presence of misbehaving proteins within the cytosol or in the endoplasmic reticulum and the stress following a lipogenic challenge. We also comment on the consequences that chronic exposure to these metabolic stressors could have on autophagic function and on how this effect may underlie the basis of some common metabolic disorders. [source] Acupuncture: is it effective for treatment of insulin resistance?DIABETES OBESITY & METABOLISM, Issue 7 2010F. Liang Insulin resistance (IR) is closely associated with obesity, type 2 diabetes mellitus (T2DM), hypertension, polycystic ovary syndrome (PCOS), non-alcohol fatty liver diseases (NAFLD) and metabolic syndrome and is also a risk factor for serious diseases such as cardiovascular diseases. Pharmacological treatments available for IR are limited by drug adverse effects. Because acupuncture has been practiced for thousands of years in China, it has been increasingly used worldwide for IR-related diseases. This review analyses 234 English publications listed on the PubMed database between 1979 and 2009 on the effectiveness of acupuncture as a treatment for IR. These publications provide clinical evidence, although limited, in support of the effectiveness of acupuncture in IR. At this stage, well-designed, evidence-based clinical randomized controlled trial studies are therefore needed to confirm the effects of acupuncture on IR. Numerous experimental studies have demonstrated that acupuncture can correct various metabolic disorders such as hyperglycemia, overweight, hyperphagia, hyperlipidemia, inflammation, altered activity of the sympathetic nervous system and insulin signal defect, all of which contribute to the development of IR. In addition, acupuncture has the potential to improve insulin sensitivity. The evidence has revealed the mechanisms responsible for the beneficial effects of acupuncture, though further investigations are warranted. [source] Cardiovascular metabolic syndrome , an interplay of, obesity, inflammation, diabetes and coronary heart diseaseDIABETES OBESITY & METABOLISM, Issue 3 2007J. S. Rana Cardiovascular disease is currently one of the biggest causes of morbidity and mortality facing humanity. Such a paradigm shift of disease pattern over the last century has only worsened due to the alarming global prevalence of obesity and type 2 diabetes. In recent years there is increasing focus on inflammation as one of the key players in the patho-physiology of these disorders. In addition to these overt risk factors new research is unraveling the significance of a constellation of early metabolic abnormalities that include weight gain, insulin resistance, prehypertension and a specific pattern of dyslipidaemia. There exists a complex interrelationship of these various metabolic disorders and their effect on cardiovascular system. Simplified explanation can be that inflammation increases insulin resistance, which in turn leads to obesity while perpetuating diabetes, high blood pressure, prothrombotic state and dyslipidaemia. While inflammation and insulin resistance have direct adverse effects on cardiac muscle, these metabolic abnormalities as a whole cause causes cardiovascular complications; warranting a multi pronged therapeutic and preventive approach for the ,Cardiovascular Metabolic Syndrome' as an entity. [source] Type 2 diabetes mellitus and obesity in sub-Saharan AfricaDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 6 2010Vivian C. Tuei Abstract While communicable diseases such as human immunodeficiency virus/acquired immune deficiency syndrome, malaria, and tuberculosis have continued to pose greater threats to the public health system in sub-Saharan Africa (SSA), it is now apparent that non-communicable diseases such as diabetes mellitus are undoubtedly adding to the multiple burdens the peoples in this region suffer. Type 2 diabetes mellitus (T2DM) is the most common form of diabetes (90,95%), exhibiting an alarming prevalence among peoples of this region. Its main risk factors include obesity, rapid urbanization, physical inactivity, ageing, nutrition transitions, and socioeconomic changes. Patients in sub-Saharan Africa also show manifestations of ,-cell dysfunction and insulin resistance. However, because of strained economic resources and a poor health care system, most of the patients are diagnosed only after they have overt symptoms and complications. Microvascular complications are the most prevalent, but metabolic disorders and acute infections cause significant mortality. The high cost of treatment of T2DM and its comorbidities, the increasing prevalence of its risk factors, and the gaps in health care system necessitate that solutions be planned and implemented urgently. Aggressive actions and positive responses from well-informed governments appear to be needed for the conducive interplay of all forces required to curb the threat of T2DM in sub-Saharan Africa. Despite the varied ethnic and transitional factors and the limited population data on T2DM in sub-Saharan Africa, this review provides an extensive discussion of the literature on the epidemiology, risk factors, pathogenesis, complications, treatment, and care challenges of T2DM in this region. Copyright © 2010 John Wiley & Sons, Ltd. [source] An adipocentric view of signaling and intracellular traffickingDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 5 2002Silvia Mora Abstract Adipocytes have traditionally been considered to be the primary site for whole body energy storage mainly in the form of triglycerides and fatty acids. This occurs through the ability of insulin to markedly stimulate both glucose uptake and lipogenesis. Conventional wisdom held that defects in fuel partitioning into adipocytes either because of increased adipose tissue mass and/or increased lipolysis and circulating free fatty acids resulted in dyslipidemia, obesity, insulin resistance and perhaps diabetes. However, it has become increasingly apparent that loss of adipose tissue (lipodystrophies) in both animal models and humans also leads to metabolic disorders that result in severe states of insulin resistance and potential diabetes. These apparently opposite functions can be resolved by the establishment of adipocytes not only as a fuel storage depot but also as a critical endocrine organ that secretes a variety of signaling molecules into the circulation. Although the molecular function of these adipocyte-derived signals are poorly understood, they play a central role in the maintenance of energy homeostasis by regulating insulin secretion, insulin action, glucose and lipid metabolism, energy balance, host defense and reproduction. The diversity of these secretory factors include enzymes (lipoprotein lipase (LPL) and adipsin), growth factors [vascular endothelial growth factor (VEGF)], cytokines (tumor necrosis factor-,, interleukin 6) and several other hormones involved in fatty acid and glucose metabolism (leptin, Acrp30, resistin and acylation stimulation protein). Despite the large number of molecules secreted by adipocytes, our understanding of the pathways and mechanisms controlling intracellular trafficking and exocytosis in adipocytes is poorly understood. In this article, we will review the current knowledge of the trafficking and secretion processes that take place in adipocytes, focusing our attention on two of the best characterized adipokine molecules (leptin and adiponectin) and on one of the most intensively studied regulated membrane proteins, the GLUT4 glucose transporter. Copyright © 2002 John Wiley & Sons, Ltd. [source] Continuous glucose monitoring in managing diabetes in childrenDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 4 2002Phyllis W. Speiser Abstract Continuous glucose monitoring (CGM) devices have now been added to the repertoire of technological devices useful in the management of patients with diabetes. In this issue, Schiaffini and colleagues confirm and extend published data describing the benefits of CGM in diabetic children. Specifically, such monitoring enables clinicians to detect occult hypoglycemia not otherwise discernable with intermittent testing of blood glucose. Although results of monitoring are not yet available in real time, the data can be used to adjust insulin regimens to allow more effective glycemic control. This is especially important in the pediatric population for whom strict glycemic control has traditionally been limited owing to concerns about the negative effects of hypoglycemia on the developing central nervous system. Additionally, postprandial hyperglycemia can be more readily detected and controlled. CGM provides new and important informaton not necessarily provided by measurement of HbA1c, and will likely prove an indispensable adjunct to diabetes care. Finally, this procedure has potential applications in the diagnosis and management of patients with other metabolic disorders. Copyright © 2002 John Wiley & Sons, Ltd. [source] Targeting of the central histaminergic system for treatment of obesity and associated metabolic disordersDRUG DEVELOPMENT RESEARCH, Issue 8 2006Kjell Malmlöf Abstract There is currently a need for effective pharmacological therapies for treatment of obesity. In this communication, the involvement of the neurotransmitter histamine in the regulation of food intake is reviewed, together with results obtained in animals with pharmacologically increased brain histamine levels. A survey of the literature reveals that histaminergic circuits, arising from nerve cell bodies in the tuberomammillary nucleus and projecting into the paraventricular nucleus, the arcuate nucleus, and the ventromedial hypothalamus, are strongly involved in regulation of food intake and possibly also energy expenditure. Current literature also suggests the histaminergic circuits connect to other neuronal pathways involved in the regulation of energy balance and body weight. Studies performed in rodents demonstrate that H3 receptor antagonists increase hypothalamic histamine and decrease food intake, which result in decreased body weight. Lipid oxidation is increased and, at higher doses, body fat is also decreased. These changes are associated with lower circulating levels of insulin during an oral glucose challenge suggesting an increase in insulin sensitivity. The effects on food intake have also been confirmed in pigs and rhesus monkeys. It can thus be concluded that results obtained with H3 antagonist in animals warrant future clinical studies to evaluate whether this principle is effective in the treatment of human obesity. Drug Dev. Res. 67:651,665, 2006. © 2006 Wiley-Liss, Inc. [source] Exenatide effects on glucose metabolism and metabolic disorders common to overweight and obese patients with type 2 diabetesDRUG DEVELOPMENT RESEARCH, Issue 8 2006David M. Webb Abstract The risks of cardiovascular disease (CVD) and type 2 diabetes increase as body mass index increases in overweight (25,30,kg/m2) and obese (>30,kg/m2) individuals. However, these risks can be reduced with even modest weight loss. In patients with established type 2 diabetes, control of both glycemia and body weight are important to minimize the risk of future diabetic complications. Exenatide is a 39-amino-acid peptide incretin mimetic currently approved in the United States for the treatment of type 2 diabetes as an adjunct to sulfonylurea and/or metformin. Phase-3 clinical studies showed exenatide therapy for 30 weeks significantly reduced glycosylated hemoglobin (HbA1c), and fasting and postprandial plasma glucose, while significantly reducing body weight. Open-label extensions from these pivotal trials demonstrated patients treated with exenatide for 2 years had sustained reductions in glycemic control at 30 weeks and a progressive reduction in body weight. Patients treated with exenatide also had improvement in blood pressure, inflammatory markers, and lipid profiles. The glucoregulatory and weight-reducing effects of exenatide are the result of multiple modes of action that mimic several of the glucoregulatory actions of the naturally occurring peptide, glucagon-like peptide-1 (GLP-1). These include restoration of first phase insulin response, enhancement of glucose-dependent insulin secretion, suppression of inappropriate glucagon secretion, slowing of gastric emptying, and affects on satiety leading to reduced food intake. Further research is required to fully understand the role for exenatide to potentially alleviate metabolic disorders associated with type 2 diabetes, including CVD and obesity. Drug Dev. Res. 67:666,676, 2006. © 2006 Wiley-Liss, Inc. [source] Microfluidic chip-capillary electrophoresis for two orders extension of adjustable upper working range for profiling of inorganic and organic anions in urineELECTROPHORESIS, Issue 18 2010Wen Peng Guo Abstract To meet the need for onsite monitoring of urine anions, a microfluidic chip-capillary electrophoresis device was designed, fabricated and tested to extend the upper CE working range for an enhancement up to 500 fold (100 fold for sample dilution and 5 folds for CE injection) in order to analyze highly variable anionic metabolites in urine samples. Capillaries were embedded between two PMMA plates with laser-fabricated microchannel patterns to produce the microfluidic chip-capillary electrophoresis to perform standard/sample dilution and CE injection with adjustable dilution ratios. A circular ferrofluid valve was incorporated on-chip to perform cleanup and conditioning, mixing and dilution, injection and CE separation. Under optimized conditions, a complete assay for four samples can be achieved within an hour for 15 anions commonly found in urines. Satisfactory working ranges (0.005,500,mM) and low detection limits (0.5,6.5,,M based on S/N =2) are obtained with satisfactory repeatability (RSD, n=5) 0.52,0.87% and 4.1,6.5% for migration time and peak area, respectively. The working ranges with two orders adjustable upper extension are adequate to cover all analytes concentrations commonly found in human urine samples. The device fabricated shows sufficiently large experimentally verifiable enhancement factor to meet the application requirements. Its reliability was established by more than 94% recoveries of spiked standards and agreeable results from parallel method comparison with conventional ion chromatography method. The extension of the upper CE working range enables flexible onsite dilution on demand, a quick turn-around of results, and a low-cost device suitable for bedside monitoring of patients under critical conditions for metabolic disorders. [source] Nonepileptic Disorders Imitating Generalized Idiopathic EpilepsiesEPILEPSIA, Issue 2005Natalio Fejerman Summary:, Differential diagnosis between epileptic and nonepileptic paroxysmal disorders is fundamental not only to allow correct management of patients but also to avoid the burden of unnecessary antiepileptic medication. The focus of this chapter is limited to imitators of idiopathic generalized epilepsies (IGE) which are expressed through myoclonic, tonic,clonic, tonic, atonic, and absence seizures. Apparent losses of consciousness and drop attacks also have to be considered. Benign myoclonus of early infancy is the main nonepileptic disorder in the differential diagnosis of infantile spasms, but is not dealt with here because West syndrome is not an IGE. Hyperekplexia, metabolic disorders, hypnagogic myoclonus, and disturbed responsiveness caused by the use of drugs are listed in Table 1. Other conditions that may imitate more focal epileptic seizures are omitted. Benign neonatal sleep myoclonus, apnea and apparent life-threatening events in infants, cyanotic and pallid breath-holding spells, syncope, staring spells, psychogenic seizures, hyperventilation syndrome, and narcolepsy have been selected based on frequency or difficulties in differential diagnosis with the intention to cover the most conspicuous imitators of IGE in different ages. Table 1. Nonepileptic disorders imitating idiopathic generalized epilepsies [source] Symptomatic Epilepsies Imitating Idiopathic Generalized EpilepsiesEPILEPSIA, Issue 2005Hirokazu Oguni Summary:, The diagnosis of idiopathic generalized epilepsies (IGEs) is not generally difficult if one follows the clinical and electroencephalogram (EEG) definitions of each subsyndrome that constitutes IGEs. In contrast, symptomatic epilepsies develop based on organic brain lesions and are easily diagnosed by the presence of developmental delay, neurologic abnormalities, and a characteristic seizure and EEG pattern. However, in clinical practice, it is sometimes difficult to differentiate IGEs from symptomatic epilepsies, especially when the clinical course from the onset of epilepsy is too short to exhibit typical clinical and EEG findings of either epilepsy type, or when patients with symptomatic epilepsies have atypical features that imitate the clinical characteristics of IGEs. The neurodegenerative or metabolic disorders at times start during the clinical course with epileptic seizures and later show typical neurologic abnormalities. The newly recognized metabolic disorder of glucose transporter type 1 deficiency syndrome (Glut-1 DS) may start with myoclonic seizures at an age of less than 1 year and imitate benign myoclonic epilepsy in infancy early in the clinical course. Progressive myoclonus epilepsies (PMEs) that develop at 1,4 years of age at times imitate epilepsy with myoclonic-astatic seizures with respect to the presence of astatic seizures and an epileptic encephalopathic EEG pattern. In addition, young children with focal cortical dysplasia may also have similar clinical and EEG patterns, although the latter may become localized after treatment. Approximately 15% of patients with juvenile myoclonic epilepsy (JME) are resistant to antiepileptic drugs (AEDs) and may require extensive study to make a differential diagnosis from symptomatic epilepsies. PMEs that develop during adolescence may imitate JME early in the clinical course; however, a detailed history and the differentiation between myoclonic seizures and myoclonus would help to distinguish both conditions. The diagnosis of IGEs is very demanding for patients with atypical features with regard to seizure type, EEG findings, and response to appropriate AEDs. [source] Vitamin D and calcium deficits predispose for multiple chronic diseasesEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 5 2005M. Peterlik Abstract There is evidence from both observational studies and clinical trials that calcium malnutrition and hypovitaminosis D are predisposing conditions for various common chronic diseases. In addition to skeletal disorders, calcium and vitamin D deficits increase the risk of malignancies, particularly of colon, breast and prostate gland, of chronic inflammatory and autoimmune diseases (e.g. insulin-dependent diabetes mellitus, inflammatory bowel disease, multiple sclerosis), as well as of metabolic disorders (metabolic syndrome, hypertension). The aim of the present review was to provide improved understanding of the molecular and cellular processes by which deficits in calcium and vitamin D cause specific changes in cell and organ functions and thereby increase the risk for chronic diseases of different aetiology. 1,25-dihydroxyvitamin D3 and extracellular Ca++ are both key regulators of proliferation, differentiation and function at the cellular level. However, the efficiency of vitamin D receptor-mediated intracellular signalling is limited by the negative effects of hypovitaminosis D on extrarenal 25-hydroxyvitamin D-1,-hydroxylase activity and thus on the production of 1,25-dihydroxyvitamin D3. Calcium malnutrition eventually causes a decrease in calcium concentration in extracellular fluid compartments, resulting in organ-specific modulation of calcium-sensing receptor activity. Hence, attenuation of signal transduction from the ligand-activated vitamin D receptor and calcium-sensing receptor seems to be the prime mechanism by which calcium and vitamin D insufficiencies cause perturbation of cellular functions in bone, kidney, intestine, mammary and prostate glands, endocrine pancreas, vascular endothelium, and, importantly, in the immune system. The wide range of diseases associated with deficits in calcium and vitamin D in combination with the high prevalence of these conditions represents a special challenge for preventive medicine. [source] Differential alteration of lipid antigen presentation to NKT cells due to imbalances in lipid metabolismEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2007Jens Schümann Abstract Deficiencies in enzymes of the lysosomal glycosphingolipid degradation pathway or in lysosomal lipid transfer proteins cause an imbalance in lipid metabolism and induce accumulation of certain lipids. A possible impact of such an imbalance on the presentation of lipid antigens to lipid-reactive T cells has only been hypothesized but not extensively studied so far. Here we demonstrate that presentation of lipid antigens to, and development of, lipid-reactive CD1d-restricted NKT cells, are impaired in mice deficient in the lysosomal enzyme ,-galactosidase (,Gal) or the lysosomal lipid transfer protein Niemann-Pick C (NPC) 2. Importantly, the residual populations of NKT cells selected in ,Gal,/, and NPC2,/, mice showed differential TCR and CD4 repertoire characteristics, suggesting that differential selecting CD1d:lipid antigen complexes are formed. Furthermore, we provide direct evidence that accumulation of lipids impairs lipid antigen presentation in both cases. However, the mechanisms by which imbalanced lipid metabolism affected lipid antigen presentation were different. Based on these results, the impact of lipid accumulation should be generally considered in the interpretation of immunological deficiencies found in mice suffering from lipid metabolic disorders. [source] Peroxisome proliferator-activated receptors (PPARs) in the control of bone metabolismFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2007Costas Giaginis Abstract Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors that regulate the storage and catabolism of dietary fats. PPARs constitute molecular targets for the treatment of human metabolic disorders, and also play a crucial role in inflammatory-related disease and cancer. Recent evidence has revealed the presence of three different PPAR isotypes (,, ,/,, and ,) in different cells of the bone tissue, as well as the possible role of PPAR ligands in bone turnover. In the present review, the latest knowledge of the expression of PPARs in bone tissue and the diverse effects of PPAR ligands on bone metabolism is summarized. PPARs, especially of the , isotype, could be targets for the treatment of diverse bone diseases such as osteoporosis and osteopenia related to either diabetes or aging. [source] Genetic background of Japanese patients with adult-onset storage diseases in the liverHEPATOLOGY RESEARCH, Issue 10 2007Hisao Hayashi In contrast to primary lysosomal diseases in young subjects, adult-onset liver storage disorders may be explained by non-lysosomal genetic defects. The aim of the present review is to summarize the genetic backgrounds of Japanese patients with hemochromatosis of unknown etiology, Wilson disease of primary copper toxicosis, and the black liver of Dubin,Johnson syndrome. Three patients with middle-age onset hemochromatosis were homozygous for mutations of HJV and two patients were homozygous for mutations of TFR2. Minor genes other than HJV and TFR2 might be involved in Japanese patients. Five of the six patients with Wilson disease were compound heterozygous, while the remaining patient was heterozygous for the mutation in ATP7B responsible for copper toxicosis. Involvement of MURR1 was not proved in the heterozygote of ATP7B. Because of ferroxidase deficiency,most patients had secondary lysosomes shared by cuprothioneins and iron complex. Six patients with Dubin,Johnson syndrome were homozygous or compound heterozygous for mutant MRP2. Despite complex metabolic disorders, the syndrome had a single genetic background. Thus, most patients with adult-onset lysosomal proliferation in the liver had genetic defects in non-lysosomal organelles, named the secondary lysosomal diseases. The proliferating lysosomes in these conditions seemed to be heterogeneous in their matrices. [source] Mutation analysis in mitochondrial fatty acid oxidation defects: Exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype,phenotype relationshipHUMAN MUTATION, Issue 3 2001Niels Gregersen Abstract Mutation analysis of metabolic disorders, such as the fatty acid oxidation defects, offers an additional, and often superior, tool for specific diagnosis compared to traditional enzymatic assays. With the advancement of the structural part of the Human Genome Project and the creation of mutation databases, procedures for convenient and reliable genetic analyses are being developed. The most straightforward application of mutation analysis is to specific diagnoses in suspected patients, particularly in the context of family studies and for prenatal/preimplantation analysis. In addition, from these practical uses emerges the possibility to study genotype,phenotype relationships and investigate the molecular pathogenesis resulting from specific mutations or groups of mutations. In the present review we summarize current knowledge regarding genotype,phenotype relationships in three disorders of mitochondrial fatty acid oxidation: very-long chain acyl-CoA dehydrogenase (VLCAD, also ACADVL), medium-chain acyl-CoA dehydrogenase (MCAD, also ACADM), and short-chain acyl-CoA dehydrogenase (SCAD, also ACADS) deficiencies. On the basis of this knowledge we discuss current understanding of the structural implications of mutation type, as well as the modulating effect of the mitochondrial protein quality control systems, composed of molecular chaperones and intracellular proteases. We propose that the unraveling of the genetic and cellular determinants of the modulating effects of protein quality control systems may help to assess the balance between genetic and environmental factors in the clinical expression of a given mutation. The realization that the effect of the monogene, such as disease-causing mutations in the VLCAD, MCAD, and SCAD genes, may be modified by variations in other genes presages the need for profile analyses of additional genetic variations. The rapid development of mutation detection systems, such as the chip technologies, makes such profile analyses feasible. However, it remains to be seen to what extent mutation analysis will be used for diagnosis of fatty acid oxidation defects and other metabolic disorders. Hum Mutat 18:169,189, 2001. © 2001 Wiley-Liss, Inc. [source] Impact of selected inborn errors of metabolism on prenatal and neonatal developmentIUBMB LIFE, Issue 6 2010Sabine Illsinger Abstract In general, data regarding maturational processes of different metabolic pathways in the very vulnerable fetal and neonatal period are rare. This review is to substantiate the impact of selected inborn errors of metabolism on this critical period of life and their clinical manifestation. Significant adaptation of mitochondrial/energy-, carbohydrate-, lysosomal-, and amino acid-metabolism occurs during early prenatal and neonatal development. In utero, metabolic environment has an impact on the development of the fetus as well as fetal organ maturation. Defects of distinct metabolic pathways could therefore already be of significant relevance in utero and for clinical manifestations in the early fetal and neonatal period. Disturbances of these pathways may influence intrauterine growth and health. Production of a toxic intrauterine milieu, energy-deficiency, modification of membrane function, or disturbance of the normal intrauterine expression of genes may be responsible for fetal compromise and developmental disorders. Three categories of metabolic disorders will be discussed: the "intoxication type" (classical galactosemia, ornithine transcarbamylase deficiency, and "maternal phenylketonuria"), the "storage type" (Morbus Niemann Pick type C), and the "energy deficient type" (including long-chain fatty acid oxidation disorders, pyruvate dehydrogenase deficiency, and respiratory chain defects). For these disorders, the pathophysiology of early manifestation, special aspects regarding the prenatal and neonatal period, and diagnostic as well as therapeutic options are presented. © 2010 IUBMB IUBMB Life, 62(6): 403,413, 2010 [source] The impact of nutrient density in terms of energy and/or protein on live performance, metabolism and carcass composition of female and male broiler chickens of two commercial broiler strainsJOURNAL OF ANIMAL PHYSIOLOGY AND NUTRITION, Issue 4 2010E. Delezie Summary The objective of this study was to investigate the effects of diet composition on performance, slaughter yield and plasma metabolites, as different modern broiler strains show different responses to feed intake. Broilers of two commercial strains and of both sexes received one of three diets being different in energy and/or protein level [control diet, low energy/low protein diet (LM/LP) and low protein diet (LP)]. Low energy/low protein diet chickens were characterized by significantly lower body weights and feed intake compared with their LP and control counterparts. Broilers of the Cobb strain or broilers that were fed the control diet were most efficient in converting energy to body weight. No significant differences in plasma metabolites were detected due to diet composition or genotype. The diet with the lower energy and crude protein levels reached the lowest slaughter yield but the highest drumstick and wing percentages. The lowest mortality percentages were observed for broilers fed the LM/LP diet, and Cobb birds appeared to be more sensitive for metabolic disorders resulting in death. It is obvious from this study that different genotypes respond differently to changes in diet composition and therefore have adjusted nutritional requirements. [source] The Roles of Osteoprotegerin and Osteoprotegerin Ligand in the Paracrine Regulation of Bone ResorptionJOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2000Lorenz C. Hofbauer Abstract Although multiple hormones and cytokines regulate various aspects of osteoclast formation, the final two effectors are osteoprotegerin ligand (OPG-L)/osteoclast differentiation factor (ODF), a recently cloned member of the tumor necrosis factor superfamily, and macrophage colony,stimulating factor. OPG-L/ODF is produced by osteoblast lineage cells and exerts its biological effects through binding to its receptor, osteoclast differentiation and activation receptor (ODAR)/receptor activator of NF-,B (RANK), on osteoclast lineage cells, in either a soluble or a membrane-bound form, the latter of which requires cell-to-cell contact. Binding results in rapid differentiation of osteoclast precursors in bone marrow to mature osteoclasts and, at higher concentrations, in increased functional activity and reduced apoptosis of mature osteoclasts. The biological activity of OPG-L/ODF is neutralized by binding to osteoprotegerin (OPG)/osteoclastogenesis inhibitory factor (OCIF), a member of the TNF-receptor superfamily that also is secreted by osteoblast lineage cells. The biological importance of this system is underscored by the induction in mice of severe osteoporosis by targeted ablation of OPG/OCIF and by the induction of osteopetrosis by targeted ablation of OPG-L/ODF or overexpression of OPG/OCIF. Thus, osteoclast formation may be determined principally by the relative ratio of OPG-L/ODF to OPG/OCIF in the bone marrow microenvironment, and alterations in this ratio may be a major cause of bone loss in many metabolic disorders, including estrogen deficiency and glucocorticoid excess. That changes in but two downstream cytokines mediate the effects of large numbers of upstream hormones and cytokines suggests a regulatory mechanism for osteoclastogenesis of great efficiency and elegance. [source] Aging alters PPAR, in rodent and human adipose tissue by modulating the balance in steroid receptor coactivator-1AGING CELL, Issue 4 2009Stéphanie Miard Summary Age is an important risk factor for the development of metabolic diseases (e.g. obesity, diabetes and atherosclerosis). Yet, little is known about the molecular mechanisms occurring upon aging that affect energy metabolism. Although visceral white adipose tissue (vWAT) is known for its key impact on metabolism, recent studies have indicated it could also be a key regulator of lifespan, suggesting that it can serve as a node for age-associated fat accretion. Here we show that aging triggers changes in the transcriptional milieu of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR,) in vWAT, which leads to a modified potential for transactivation of target genes upon ligand treatment. We found that in vWAT of mice, rats and men, aging induced a specific decrease in the expression of steroid receptor coactivator-1 (SRC-1), whose recruitment to PPAR, is associated with improved insulin sensitivity and low adipogenic activity. In contrast, aging and oxidative stress did not impact on PPAR, expression and PPAR, ligand production. Age-induced loss of PPAR,/SRC-1 interactions increased the binding of PPAR, to the promoter of the adipogenic gene aP2. These findings suggest that strategies aimed at increasing SRC-1 expression and recruitment to PPAR, upon aging might help improve age-associated metabolic disorders. [source] Prevalence and etiology of elevated serum alanine aminotransferase level in an adult population in TaiwanJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 9 2007Chien-Hua Chen Abstract Background:, The prevalence and etiologies of elevated alanine aminotransferase (ALT) have geographic variations and they are rarely reported in Taiwan. Through a population-based screening study, the prevalence and etiologies of elevated ALT in an adult population of Taiwan were assessed. Methods:, A cross-sectional community study in a rural village of Taiwan was conducted in 3260 Chinese adults (age ,18 years) undergoing ultrasonography (US), blood tests, and interviews with a structured questionnaire. The diagnostic criteria of non-alcoholic fatty liver disease (NAFLD) included alcohol intake <20 g/week for women or <30 g/week for men, negative hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, no known etiologies of liver disease, and US consistent with fatty liver. Results:, The prevalence of elevated ALT was 11.4% (372/3260). The probable cause of this elevation was excess alcohol consumption in 0.8%, HBV in 28.5%, HCV in 13.2%, both HBV and HCV in 2.2%, NAFLD in 33.6%, and unexplained cause in 21.8%. The etiologic distribution of elevated ALT was similar in both genders, although elevation was more common in men compared to women (17.3%vs 6.1%, P < 0.05). The prevalence of elevated ALT in NAFLD was 18.1% (125/691), and the positive predictive value was 33.6% (125/372). The development of NAFLD was related to increasing age (age between 40 years and 64 years, odds ratio [OR] 1.59, 95% confidence interval [CI]: 1.25,2.01; age , 65 years, OR 1.46, 95%CI: 1.08,1.96), fasting plasma glucose (FPG) , 126 mg/dL (OR 1.54, 95%CI: 1.11,2.14), bodymass index (BMI) , 25 kg/m2 (OR 5.01, 95%CI: 4.13,6.26), triglyceridemia , 150 mg/dL (OR 1.96, 95%CI: 1.58,2.42), and hyperuricemia (OR 1.50, 95%CI: 1.22,1.84). Elevated ALT was related to male gender, BMI , 25 kg/m2, and triglyceridemia , 150 mg/dL in subjects without known etiologies of liver disease (all P < 0.05). Conclusions:, Non-alcoholic fatty liver disease appears to be the commonest cause of elevated ALT and presumed liver injury in Taiwan. The development of NAFLD is closely associated with many metabolic disorders. Metabolic disorders are also related to elevated ALT in subjects without known etiologies of liver disease. [source] | ||||||||||||||||||||||||||||||||||||||||