Recurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism.

Recent studies have identified both recessive and dominant forms of mitochondrial disease that result from ATAD3A variants. The recessive form includes subjects with biallelic deletions mediated by non-allelic homologous recombination. We report five unrelated neonates with a lethal metabolic disorder characterized by cardiomyopathy, corneal opacities, encephalopathy, hypotonia, and seizures in whom a monoallelic reciprocal duplication at the ATAD3 locus was identified. Analysis of the breakpoint junction fragment indicated that these 67 kb heterozygous duplications were likely mediated by non-allelic homologous recombination at regions of high sequence identity in ATAD3A exon 11 and ATAD3C exon 7. At the recombinant junction, the duplication allele produces a fusion gene derived from ATAD3A and ATAD3C, the protein product of which lacks key functional residues. Analysis of fibroblasts derived from two affected individuals shows that the fusion gene product is expressed and stable. These cells display perturbed cholesterol and mitochondrial DNA organization similar to that observed for individuals with severe ATAD3A deficiency. We hypothesize that the fusion protein acts through a dominant-negative mechanism to cause this fatal mitochondrial disorder. Our data delineate a molecular diagnosis for this disorder, extend the clinical spectrum associated with structural variation at the ATAD3 locus, and identify a third mutational mechanism for ATAD3 gene cluster variants. These results further affirm structural variant mutagenesis mechanisms in sporadic disease traits, emphasize the importance of copy number analysis in molecular genomic diagnosis, and highlight some of the challenges of detecting and interpreting clinically relevant rare gene rearrangements from next-generation sequencing data

2-Deoxy-D-glucose couples mitochondrial DNA replication with mitochondrial fitness and promotes the selection of wild-type over mutant mitochondrial DNA

Pathological variants of human mitochondrial DNA (mtDNA) typically co-exist with wild-type molecules, but the factors driving the selection of each are not understood. Because mitochondrial fitness does not favour the propagation of functional mtDNAs in disease states, we sought to create conditions where it would be advantageous. Glucose and glutamine consumption are increased in mtDNA dysfunction, and so we targeted the use of both in cells carrying the pathogenic m.3243A>G variant with 2-Deoxy-D-glucose (2DG), or the related 5-thioglucose. Here, we show that both compounds selected wild-type over mutant mtDNA, restoring mtDNA expression and respiration. Mechanistically, 2DG selectively inhibits the replication of mutant mtDNA; and glutamine is the key target metabolite, as its withdrawal, too, suppresses mtDNA synthesis in mutant cells. Additionally, by restricting glucose utilization, 2DG supports functional mtDNAs, as glucose-fuelled respiration is critical for mtDNA replication in control cells, when glucose and glutamine are scarce. Hence, we demonstrate that mitochondrial fitness dictates metabolite preference for mtDNA replication; consequently, interventions that restrict metabolite availability can suppress pathological mtDNAs, by coupling mitochondrial fitness and replication

Four-year safety and effectiveness data from patients with multiple sclerosis treated with fingolimod : The Spanish GILENYA registry

Objective To describe the profile of patients with multiple sclerosis (MS) treated with fingolimod in Spain and to assess the effectiveness and safety of fingolimod after 4 years of inclusion in the Spanish Gilenya Registry. Methods An observational, retrospective/prospective, multicenter case registry, including all patients with relapsing-remitting MS (RRMS) starting treatment with fingolimod in 43 centers in Spain. Analyses were performed in the overall population and in subgroups according to prior disease-modifying therapy (DMT): glatiramer acetate/interferon beta-1 (BRACE), natalizumab, other treatment, or naïve. Results Six hundred and sixty-six evaluable patients were included (91.1% previously treated with at least one DMT). The mean annualized relapse rate (ARR) prior to fingolimod was 1.12, and the mean EDSS at fingolimod initiation was 3.03. Fingolimod reduced the ARR by 71.4%, 75%, 75.5%, and 80.3%, after 1, 2, 3 and 4 years, respectively (p<0.001). This significant reduction in the ARR continuedto be observed in all subgroups. After 4 years, the EDSS showed a minimal deterioration, with the EDSS scores from year 1 to year 4 remaining mostly stable. The percentage of patients without T1 Gd+ lesions progressively increased from 45.6% during the year prior to fingolimod initiation to 88.2% at year 4. The proportion of patients free from new/enlarged T2 lesions after 4 years of fingolimod treatment was 80.3%. This trend in both radiological measures was also observed in the subgroups. Adverse events (AEs) were experienced by up to 41.6% of patients (most commonly: lymphopenia [12.5%] and urinary tract infection [3.7%]). Most AEs were mild in severity, 3.6% of patients had serious AEs. Conclusions The patient profile was similar to other observational studies. The results obtained from the long-term use of fingolimod showed that it was effective, regardless of prior DMT, and it had adequate safety results, with a positive benefit-risk balance

Resilience Management for Healthy Cities in a Changing Climate

Cities are experiencing multiple impacts from global environmental change, and the degree to which they will need to cope with and adapt to these challenges will continue to increase. We argue that a ‘complex systems and resilience management’ view may significantly help guide future urban development through innovative integration of, for example, grey, blue and green infrastructure embedded in flexible institutions (both formal and informal) for multi-functionality and improved health. For instance, the urban heat island effect will further increase city-centre temperatures during projected more frequent and intense heat waves. The elderly and people with chronic cardiovascular and respiratory diseases are particularly vulnerable to heat. Integrating vegetation and especially trees in the urban infrastructure helps reduce temperatures by shading and evapotranspiration. Great complexity and uncertainty of urban social-ecological systems are behind this heatwave-health nexus, and they need to be addressed in a more comprehensive manner. We argue that a systems perspective can lead to innovative designs of new urban infrastructure and the redesign of existing structures. Particularly to promoting the integration of grey, green and blue infrastructure in urban planning through institutional innovation and structural reorganization of knowledge-action systems may significantly enhance prospects for improved urban health and greater resilience under various scenarios of climate change.info:eu-repo/semantics/publishedVersio

Dietary inflammatory index and all-cause mortality in large cohorts: The SUN and PREDIMED studies

[Background]: Inflammation is known to be related to the leading causes of death including cardiovascular disease, several types of cancer, obesity, type 2 diabetes, depression-suicide and other chronic diseases. In the context of whole dietary patterns, the Dietary Inflammatory Index (DII®) was developed to appraise the inflammatory potential of the diet. [Objective]: We prospectively assessed the association between DII scores and all-cause mortality in two large Spanish cohorts and valuated the consistency of findings across these two cohorts and results published based on other cohorts.[Design]: We assessed 18,566 participants in the “Seguimiento Universidad de Navarra” (SUN) cohort followed-up during 188,891 person-years and 6790 participants in the “PREvencion con DIeta MEDiterránea” (PREDIMED) randomized trial representing 30,233 person-years of follow-up. DII scores were calculated in both cohorts from validated FFQs. Higher DII scores corresponded to more proinflammatory diets. A total of 230 and 302 deaths occurred in SUN and PREDIMED, respectively. In a random-effect meta-analysis we included 12 prospective studies (SUN, PREDIMED and 10 additional studies) that assessed the association between DII scores and all-cause mortality.[Results]: After adjusting for a wide array of potential confounders, the comparison between extreme quartiles of the DII showed a positive and significant association with all-cause mortality in both the SUN (hazard ratio [HR] = 1.85; 95% CI: 1.15, 2.98; P-trend = 0.004) and the PREDIMED cohort (HR = 1.42; 95% CI: 1.00, 2.02; P-trend = 0.009). In the meta-analysis of 12 cohorts, the DII was significantly associated with an increase of 23% in all-cause mortality (95% CI: 16%–32%, for the highest vs lowest category of DII).[Conclusion]: Our results provide strong and consistent support for the hypothesis that a pro-inflammatory diet is associated with increased all-cause mortality. The SUN cohort and PREDIMED trial were registered at clinicaltrials.gov as NCT02669602 and at isrctn.com as ISRCTN35739639, respectively.Supported by the official funding agency for biomedical research of the Spanish Government, Instituto de Salud Carlos III (ISCIII), through grants provided to research networks specifically developed for the trial (RTIC G03/140, to R.E.; RTIC RD 06/0045, to Miguel A. Martínez-González) and through Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), and by grants from Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007), Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional (Proyecto de Investigación (PI) 04-2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, PI13/00462, PI13/00615, PI13/01090, PI14/01668, PI14/01798, PI14/01764), Ministerio de Ciencia e Innovación (Recursos y teconologia agroalimentarias(AGL)-2009-13906-C02 and AGL2010-22319-C03 and AGL2013-49083-C3-1- R), Fundación Mapfre 2010, the Consejería de Salud de la Junta de Andalucía (PI0105/2007), the Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana (Generalitat Valenciana Ayuda Complementaria (GVACOMP) 06109, GVACOMP2010-181, GVACOMP2011-151), Conselleria de Sanitat y, PI14/01764 AP; Atención Primaria (CS) 2010-AP-111, and CS2011-AP-042), and Regional Government of Navarra (P27/2011).). Drs. Shivappa and Hébert were supported by grant number R44DK103377 from the United States National Institute of Diabetes and Digestive and Kidney Diseases

Potato consumption does not increase blood pressure or incident hypertension in 2 cohorts of Spanish adults

5 TablasBackground: Potatoes have a high glycemic load but also antioxidants, vitamins, and minerals. It is unclear what mechanisms are involved in relation to their effect on blood pressure (BP) and hypertension. Objectives: This study aimed to assess the association between potato consumption, BP changes, and the risk of hypertension in 2 Spanish populations. Methods: Separate analyses were performed in PREDIMED (PREvención con DIeta MEDiterránea), a multicenter nutrition intervention trial of adults aged 55-80 y, and the SUN (Seguimiento Universidad de Navarra) project, a prospective cohort made up of university graduates and educated adults with ages (means±SDs) of 42.7±13.3 y for men and 35.1± 10.7 y for women. In PREDIMED, generalized estimating equations adjusted for lifestyle and dietary characteristics were used to assess changes in BP across quintiles of total potato consumption during a 4-y follow-up. Controlled BP values (systolic BP < 140 mm Hg and diastolic BP < 90 mm Hg) during follow-up were also assessed. For SUN, multivariateadjusted HRs for incident hypertension during a mean 6.7-y follow-up were calculated. Results: In PREDIMED, the total potato intake was 81.9 ± 40.6 g/d. No overall differences in systolic or diastolic BP changes were detected based on consumption of potatoes. For total potatoes, the mean difference in change between quintile 5 (highest intake) and quintile 1 (lowest intake) in systolic BP after multivariate adjustment was 20.90 mm Hg (95% CI: -2.56, 0.76 mm Hg; P-trend = 0.1) and for diastolic BP was 20.02 mm Hg (95% CI: -0.93, 0.89 mm Hg; P-trend = 0.8). In SUN, the total potato consumption was 52.7 ± 33.6 g/d, and no significant association between potato consumption and hypertension incidence was observed in the fully adjusted HR for total potato consumption (quintile 5 compared with quintile 1: 0.98; 95% CI: 0.80, 1.19; P-trend = 0.8). Conclusions: Potato consumption is not associated with changes over 4 y in blood pressure among older adults in Spain or with the risk of hypertension among Spanish adults.Supported by the official funding agency for biomedical research of the Spanish Government, Instituto de Salud Carlos III through grants provided to research networks specifically developed for the trial (RTIC G03/140, to RE; RTIC RD 06/0045, to MAM-G) and through Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), and by grants from Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007), Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional [Proyecto de Investigación (PI) 04-2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505 and PI13/00462], Ministerio de Ciencia e Innovación [Recursos y teconologia agroalimentarias (AGL)-2009-13906-C02 and AGL2010-22319-C03 and AGL2013-49083-C3-1-R], Fundación Mapfre 2010, the Consejería de Salud de la Junta de Andalucía (PI0105/2007), the Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana [Generalitat Valenciana Ayuda Complementaria (GVACOMP) 06109, GVACOMP2010-181, GVACOMP2011-151], Conselleria de Sanitat y AP; Atención Primaria (CS) 2010-AP-111 and CS2011-AP-042, and Regional Government of Navarra (P27/2011)