Human metabolic individuality in biomedical and pharmaceutical research.

Genome-wide association studies (GWAS) have identified many risk loci for complex diseases, but effect sizes are typically small and information on the underlying biological processes is often lacking. Associations with metabolic traits as functional intermediates can overcome these problems and potentially inform individualized therapy. Here we report a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with non-targeted metabolomics. We identified 37 genetic loci associated with blood metabolite concentrations, of which 25 show effect sizes that are unusually high for GWAS and account for 10-60% differences in metabolite levels per allele copy. Our associations provide new functional insights for many disease-related associations that have been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism and Crohn's disease. The study advances our knowledge of the genetic basis of metabolic individuality in humans and generates many new hypotheses for biomedical and pharmaceutical research.

Metabolic syndrome according to different definitions in a rapidly developing country of the African region

AIMS: We examined, in a country of the African region, i) the prevalence of the metabolic syndrome (MetS) according to three definitions (ATP, WHO and IDF); ii) the distribution of the MetS criteria; iii) the level of agreement between these three definitions and iv) we also examined these issues upon exclusion of people with diabetes. METHODS: We conducted an examination survey on a sample representative of the general population aged 25-64 years in the Seychelles (Indian Ocean, African region), attended by 1255 participants (participation rate of 80.3%). RESULTS: The prevalence of MetS increased markedly with age. According to the ATP, WHO and IDF definitions, the prevalence of MetS was, respectively, 24.0%, 25.0%, 25.1% in men and 32.2%, 24.6%, 35.4% in women. Approximately 80% of participants with diabetes also had MetS and the prevalence of MetS was approximately 7% lower upon exclusion of diabetic individuals. High blood pressure and adiposity were the criteria found most frequently among MetS holders irrespective of the MetS definitions. Among people with MetS based on any of the three definitions, 78% met both ATP and IDF criteria, 67% both WHO and IDF criteria, 54% both WHO and ATP criteria and only 37% met all three definitions. CONCLUSION: We identified a high prevalence of MetS in this population in epidemiological transition. The prevalence of MetS decreased by approximately 32% upon exclusion of persons with diabetes. Because of limited agreement between the MetS definitions, the fairly similar proportions of MetS based on any of the three MetS definitions classified, to a substantial extent, different subjects as having MetS.

A fully-automatic caudate nucleus segmentation of brain MRI: application in volumetric analysis of pediatric attention-deficit/hyperactivity disorder

Background Accurate automatic segmentation of the caudate nucleus in magnetic resonance images (MRI) of the brain is of great interest in the analysis of developmental disorders. Segmentation methods based on a single atlas or on multiple atlases have been shown to suitably localize caudate structure. However, the atlas prior information may not represent the structure of interest correctly. It may therefore be useful to introduce a more flexible technique for accurate segmentations. Method We present Cau-dateCut: a new fully-automatic method of segmenting the caudate nucleus in MRI. CaudateCut combines an atlas-based segmentation strategy with the Graph Cut energy-minimization framework. We adapt the Graph Cut model to make it suitable for segmenting small, low-contrast structures, such as the caudate nucleus, by defining new energy function data and boundary potentials. In particular, we exploit information concerning the intensity and geometry, and we add supervised energies based on contextual brain structures. Furthermore, we reinforce boundary detection using a new multi-scale edgeness measure. Results We apply the novel CaudateCut method to the segmentation of the caudate nucleus to a new set of 39 pediatric attention-deficit/hyperactivity disorder (ADHD) patients and 40 control children, as well as to a public database of 18 subjects. We evaluate the quality of the segmentation using several volumetric and voxel by voxel measures. Our results show improved performance in terms of segmentation compared to state-of-the-art approaches, obtaining a mean overlap of 80.75%. Moreover, we present a quantitative volumetric analysis of caudate abnormalities in pediatric ADHD, the results of which show strong correlation with expert manual analysis. Conclusion CaudateCut generates segmentation results that are comparable to gold-standard segmentations and which are reliable in the analysis of differentiating neuroanatomical abnormalities between healthy controls and pediatric ADHD.

Gestational diabetes mellitus and the risk of metabolic syndrome: a population-based study in Lausanne, Switzerland.

AIMS: To investigate the relationships between gestational diabetes mellitus (GDM) and the metabolic syndrome (MS), as it was suggested that insulin resistance was the hallmark of both conditions. To analyse post-partum screening in order to identify risk factors for the subsequent development of type 2 diabetes mellitus (DM). METHODS: A retrospective analysis of all singleton pregnancies diagnosed with GDM at the Lausanne University Hospital for 3 consecutive years. Pre-pregnancy obesity, hypertension and dyslipidaemia were recorded as constituents of the MS. RESULTS: For 5788 deliveries, 159 women (2.7%) with GDM were identified. Constituents of the MS were present before GDM pregnancy in 26% (n = 37/144): 84% (n = 31/37) were obese, 38% (n = 14/37) had hypertension and 22% (n = 8/37) had dyslipidaemia. Gestational hypertension was associated with obesity (OR = 3.2, P = 0.02) and dyslipidaemia (OR = 5.4, P=0.002). Seventy-four women (47%) returned for post-partum OGTT, which was abnormal in 20 women (27%): 11% (n = 8) had type 2 diabetes and 16% (n = 12) had impaired glucose tolerance. Independent predictors of abnormal glucose tolerance in the post-partum were: having > 2 abnormal values on the diagnostic OGTT during pregnancy and presenting MS constituents (OR = 5.2, CI 1.8-23.2 and OR = 5.3, CI 1.3-22.2). CONCLUSIONS: In one fourth of GDM pregnancies, metabolic abnormalities precede the appearance of glucose intolerance. These women have a high risk of developing the MS and type 2 diabetes in later years. Where GDM screening is not universal, practitioners should be aware of those metabolic risks in every pregnant woman presenting with obesity, hypertension or dyslipidaemia, in order to achieve better diagnosis and especially better post-partum follow-up and treatment.

Utilization of dietary glucose in the metabolic syndrome

This review is focused on the fate of dietary glucose under conditions of chronically high energy (largely fat) intake, evolving into the metabolic syndrome. We are adapted to carbohydrate-rich diets similar to those of our ancestors. Glucose is the main energy staple, but fats are our main energy reserves. Starvation drastically reduces glucose availability, forcing the body to shift to fatty acids as main energy substrate, sparing glucose and amino acids. We are not prepared for excess dietary energy, our main defenses being decreased food intake and increased energy expenditure, largely enhanced metabolic activity and thermogenesis. High lipid availability is a powerful factor decreasing glucose and amino acid oxidation. Present-day diets are often hyperenergetic, high on lipids, with abundant protein and limited amounts of starchy carbohydrates. Dietary lipids favor their metabolic processing, saving glucose, which additionally spares amino acids. The glucose excess elicits hyperinsulinemia, which may derive, in the end, into insulin resistance. The available systems of energy disposal could not cope with the excess of substrates, since they are geared for saving not for spendthrift, which results in an unbearable overload of the storage mechanisms. Adipose tissue is the last energy sink, it has to store the energy that cannot be used otherwise. However, adipose tissue growth also has limits, and the excess of energy induces inflammation, helped by the ineffective intervention of the immune system. However, even under this acute situation, the excess of glucose remains, favoring its final conversion to fat. The sum of inflammatory signals and deranged substrate handling induce most of the metabolic syndrome traits: insulin resistance, obesity, diabetes, liver steatosis, hyperlipidemia and their compounded combined effects. Thus, a maintained excess of energy in the diet may result in difficulties in the disposal of glucose, eliciting inflammation and the development of the metabolic syndrome

Metabolic effects of a mixed and a high-carbohydrate low-fat diet in man, measured over 24 h in a respiration chamber.

1. The relation between dietary carbohydrate: lipid ratio and the fuel mixture oxidized during 24 h was investigated in eleven healthy volunteers (six females, and five males) in a respiration chamber. Values of the fuel mixture oxidized were estimated by continuous indirect calorimetry and urinary nitrogen measurements. 2. The subjects, were first given a mixed diet for 7 d and spent the last 24 h of the 7 d period in a respiration chamber for continuous gas-exchange measurement. The fuels oxidized during 2.5 h or moderate exercise were also measured in the respiration chamber. After an interval of 2 weeks from the end of the mixed-diet period, the same subjects were given an isoenergetic high-carbohydrate low-fat diet for 7 d, and the same experimental regimen was repeated. 3. Dietary composition markedly influenced the fuel mixture oxidized during 24 h and this effect was still present 12 h after the last meal in the postabsorptive state. However, the diets had no influence on the substrates oxidized above resting levels during exercise. With both diets, the 24 h energy balance was slightly negative and the energy deficit was covered by lipid oxidation. 4. With the high-carbohydrate low-fat diet, the energy expenditure during sleep was found to be higher than that with the mixed diet. 5. It is concluded that: (a) the composition of the diet did not influence the fuel mixture utilized for moderate exercise, (b) the energy deficit calculated for a 24 h period was compensated by lipid oxidation irrespective of the carbohydrate content of the diet, (c) energy expenditure during sleep was found to be higher with the high-carbohydrate low-fat diet than with the mixed diet.

Network-based scoring system for genome-scale metabolic reconstructions

Background: Network reconstructions at the cell level are a major development in Systems Biology. However, we are far from fully exploiting its potentialities. Often, the incremental complexity of the pursued systems overrides experimental capabilities, or increasingly sophisticated protocols are underutilized to merely refine confidence levels of already established interactions. For metabolic networks, the currently employed confidence scoring system rates reactions discretely according to nested categories of experimental evidence or model-based likelihood. Results: Here, we propose a complementary network-based scoring system that exploits the statistical regularities of a metabolic network as a bipartite graph. As an illustration, we apply it to the metabolism of Escherichia coli. The model is adjusted to the observations to derive connection probabilities between individual metabolite-reaction pairs and, after validation, to assess the reliability of each reaction in probabilistic terms. This network-based scoring system uncovers very specific reactions that could be functionally or evolutionary important, identifies prominent experimental targets, and enables further confirmation of modeling results. Conclusions: We foresee a wide range of potential applications at different sub-cellular or supra-cellular levels of biological interactions given the natural bipartivity of many biological networks.

AMCHP Issue Brief: Environmental Scan: State Title V Program Response to Autism Spectrum Disorder and Other Developmental Disabilities, December 2009

The increasing incidence of children identified and diagnosed with Autism Spectrum Disorders (ASD) and other developmental disabilities (DD) poses a major challenge to Title V and other programs as they try to meet the diverse and sometimes complex needs of these children. However, those state that have initiated coordinated efforts to meet the needs of these children cross systems have had the opportunity to form and/or strengthen relationships with new partners. In addition, these coordinated efforts will allow states to develop new policies, programs and financing mechanisms addressing the health of children with ASD, which may also strengthen the system of care for all Children and Youth with Special Health Care Needs.

Apports de la médecine nucléaire en cardiologie préventive: l'exemple du syndrome métabolique [Value of nuclear medicine in preventive cardiology: the metabolic syndrome example]

Metabolic syndrome represents a grouping of risk factors closely linked to cardiovascular diseases and diabetes. At first, nuclear medicine has no direct application in cardiology at the level of primary prevention, but positron emission tomography is a non invasive imaging technique that can assess myocardial perfusion as well as the endothelium-dependent coronary vasomotion--a surrogate marker of cardiovascular event rate--thus finding an application in studying coronary physiopathology. As the prevalence of the metabolic syndrome is still unknown in Switzerland, we will estimate it from data available in the frame of a health promotion program. Based on the deleterious effect on the endothelium already observed with two components, we will estimate the number of persons at risk in Switzerland.

Le syndrome métabolique: des spécialistes au médecin de premier recours [Metabolic syndrome: from specialists to the first aid physician]

Numerous algorithms originating from evidence-based medicine already exist; in spite of this, metabolic syndrome management remains problematical and needs to be improved. Specialists, working interactively and referring to clinical scenarios, pooled their specific areas of expertise in a transverse perspective of the metabolic syndrome management by the primary care physician. This concerted multidisciplinary approach has clearly revealed that a bio-psycho-social approach is absolutely essential in the management of this type of patients.

Public health significance of bipolar disorder: implications for early intervention and prevention.

OBJECTIVES: Early intervention and preventive strategies have become major targets of research and service development in psychiatry over the last few years. Compared to schizophrenia, bipolar disorder (BD) has received limited attention in this regard. In this paper, we review the available literature in order to explore the public health significance of BD and the extent to which this may justify the development of early intervention strategies for this disorder. METHODS: The main computerized psychiatric literature databases were accessed. This included Medline and PsychInfo, using the following keywords: bipolar, early intervention, staging model, burden, caregiver, public health, and manic depression. RESULTS: BD is often recurrent and has an impact that goes well beyond symptomatic pathology. The burden it incurs is linked not only to its cardinal clinical features, but also to cognitive dysfunction, poor functional outcome, poor physical health, high rate of comorbidities, and suicide. At a societal level, BD induces enormous direct and indirect costs and has a major impact on caregivers. The available literature reveals a usually long delay between illness onset and the start of treatment, and the absence of specific guidelines for the treatment of the early phase of BD. CONCLUSIONS: Considering the major impact of BD on patients and society, there is an urgent need for the development of early intervention strategies aimed at earlier detection and more specific treatment of the early phase of the disorder.