Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease.

PURPOSE: To understand the role of the mitochondrial oxodicarboxylate carrier (SLC25A21) in the development of spinal muscular atrophy-like disease. METHODS: We identified a novel pathogenic variant in a patient by whole-exome sequencing. The pathogenicity of the mutation was studied by transport assays, computer modeling, followed by targeted metabolic testing and in vitro studies in human fibroblasts and neurons. RESULTS: The patient carries a homozygous pathogenic variant c.695A>G; p.(Lys232Arg) in the SLC25A21 gene, encoding the mitochondrial oxodicarboxylate carrier, and developed spinal muscular atrophy and mitochondrial myopathy. Transport assays show that the mutation renders SLC25A21 dysfunctional and 2-oxoadipate cannot be imported into the mitochondrial matrix. Computer models of central metabolism predicted that impaired transport of oxodicarboxylate disrupts the pathways of lysine and tryptophan degradation, and causes accumulation of 2-oxoadipate, pipecolic acid, and quinolinic acid, which was confirmed in the patient's urine by targeted metabolomics. Exposure to 2-oxoadipate and quinolinic acid decreased the level of mitochondrial complexes in neuronal cells (SH-SY5Y) and induced apoptosis. CONCLUSION: Mitochondrial oxodicarboxylate carrier deficiency leads to mitochondrial dysfunction and the accumulation of oxoadipate and quinolinic acid, which in turn cause toxicity in spinal motor neurons leading to spinal muscular atrophy-like disease

Gender, school and academic year differences among Spanish university students at high-risk for developing an eating disorder: An epidemiologic study

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to assess the magnitude of the university population at high-risk of developing an eating disorder and the prevalence of unhealthy eating attitudes and behaviours amongst groups at risk; gender, school or academic year differences were also explored.</p> <p>Methods</p> <p>A cross-sectional study based on self-report was used to screen university students at high-risk for an eating disorder. The sample size was of 2551 university students enrolled in 13 schools between the ages of 18 and 26 years. The instruments included: a social-demographic questionnaire, the Eating Disorders Inventory (EDI), the Body Shape Questionnaire (BSQ), the Symptom Check List 90-R (SCL-90-R), and the Self-Esteem Scale (RSE). The sample design is a non-proportional stratified sample by academic year and school. The prevalence rate was estimated controlling academic year and school. Logistic regression analysis was used to investigate adjusted associations between gender, school and academic year.</p> <p>Results</p> <p>Female students presented unhealthy weight-control behaviours as dieting, laxatives use or self-induced vomiting to lose weight than males. A total of 6% of the females had a BMI of 17.5 or less or 2.5% had amenorrhea for 3 or more months. In contrast, a higher proportion of males (11.6%) reported binge eating behaviour. The prevalence rate of students at high-risk for an eating disorder was 14.9% (11.6–18) for males and 20.8% (18.7–22.8) for females, according to an overall cut-off point on the EDI questionnaire. Prevalence rates presented statistically significant differences by gender (p < 0.001) but not by school or academic year.</p> <p>Conclusion</p> <p>The prevalence of eating disorder risk in university students is high and is associated with unhealthy weight-control practices, similar results have been found in previous studies using cut-off points in questionnaires. These results may be taken into account to encourage early detection and a greater awareness for seeking treatment in order to improve the diagnosis, among students on university campuses.</p

Transmission of Mitochondrial DNA Diseases and Ways to Prevent Them

Recent reports of strong selection of mitochondrial DNA (mtDNA) during transmission in animal models of mtDNA disease, and of nuclear transfer in both animal models and humans, have important scientific implications. These are directly applicable to the genetic management of mtDNA disease. The risk that a mitochondrial disorder will be transmitted is difficult to estimate due to heteroplasmy—the existence of normal and mutant mtDNA in the same individual, tissue, or cell. In addition, the mtDNA bottleneck during oogenesis frequently results in dramatic and unpredictable inter-generational fluctuations in the proportions of mutant and wild-type mtDNA. Pre-implantation genetic diagnosis (PGD) for mtDNA disease enables embryos produced by in vitro fertilization (IVF) to be screened for mtDNA mutations. Embryos determined to be at low risk (i.e., those having low mutant mtDNA load) can be preferentially transferred to the uterus with the aim of initiating unaffected pregnancies. New evidence that some types of deleterious mtDNA mutations are eliminated within a few generations suggests that women undergoing PGD have a reasonable chance of generating embryos with a lower mutant load than their own. While nuclear transfer may become an alternative approach in future, there might be more difficulties, ethical as well as technical. This Review outlines the implications of recent advances for genetic management of these potentially devastating disorders

Year in review in Intensive Care Medicine 2010: I. Acute renal failure, outcome, risk assessment and ICU performance, sepsis, neuro intensive care and experimentals

SCOPUS: re.jinfo:eu-repo/semantics/publishe

Biodiversity and Health: Implications for Conservation

The human health and well-being benefits of contact with nature are becoming increasingly recognised and well understood, yet the implications of nature experiences for biodiversity conservation are far less clear. Theoretically, there are two plausible pathways that could lead to positive conservation outcomes. The first is a direct win-win scenario where biodiverse areas of high conservation value are also disproportionately beneficial to human health and well-being, meaning that the two sets of objectives can be simultaneously and directly achieved, as long as such green spaces are safeguarded appropriately. The second is that experiencing nature can stimulate people’s interest in biodiversity, concern for its fate, and willingness to take action to protect it, therefore generating conservation gains indirectly. To date, the two pathways have rarely been distinguished and scarcely studied. Here we consider how they may potentially operate in practice, while acknowledging that the mechanisms by which biodiversity might underpin human health and well-being benefits are still being determined

Germline selection shapes human mitochondrial DNA diversity.

Approximately 2.4% of the human mitochondrial DNA (mtDNA) genome exhibits common homoplasmic genetic variation. We analyzed 12,975 whole-genome sequences to show that 45.1% of individuals from 1526 mother-offspring pairs harbor a mixed population of mtDNA (heteroplasmy), but the propensity for maternal transmission differs across the mitochondrial genome. Over one generation, we observed selection both for and against variants in specific genomic regions; known variants were more likely to be transmitted than previously unknown variants. However, new heteroplasmies were more likely to match the nuclear genetic ancestry as opposed to the ancestry of the mitochondrial genome on which the mutations occurred, validating our findings in 40,325 individuals. Thus, human mtDNA at the population level is shaped by selective forces within the female germ line under nuclear genetic control, which ensures consistency between the two independent genetic lineages.NIHR, Wellcome Trust, MRC, Genomics Englan