High myopia is the most severe and pathological form of myopia. It occurs when the spherical refractive error exceeds –6.00 spherical diopters (SDs) or the axial length (AL) of the eye is greater ...than 26 mm. This article focuses on early-onset high myopia, an increasingly common condition that affects children under 10 years of age and can lead to other serious ocular pathologies. Through the genetic analysis of 21 families with early-onset high myopia, this study seeks to contribute to a better understanding of the role of genetics in this disease and to propose candidate genes. Whole-exome sequencing studies with a panel of genes known to be involved in the pathology were performed in families with inconclusive results: 3% of the variants found were classified as pathogenic, 6% were likely pathogenic and the remaining 91% were variants of uncertain significance. Most of the families in this study were found to have alterations in several of the proposed genes. This suggests a polygenic inheritance of the pathology due to the cumulative effect of the alterations. Further studies are needed to validate and confirm the role of these alterations in the development of early-onset high myopia and its polygenic inheritance.
CLAPO syndrome is a rare vascular disorder characterized by capillary malformation of the lower lip, lymphatic malformation predominant on the face and neck, asymmetry, and partial/generalized ...overgrowth. Here we tested the hypothesis that, although the genetic cause is not known, the tissue distribution of the clinical manifestations in CLAPO seems to follow a pattern of somatic mosaicism.
We clinically evaluated a cohort of 13 patients with CLAPO and screened 20 DNA blood/tissue samples from 9 patients using high-throughput, deep sequencing.
We identified five activating mutations in the PIK3CA gene in affected tissues from 6 of the 9 patients studied; one of the variants (NM_006218.2:c.248T>C; p.Phe83Ser) has not been previously described in developmental disorders.
We describe for the first time the presence of somatic activating PIK3CA mutations in patients with CLAPO. We also report an update of the phenotype and natural history of the syndrome.
Abstract Most survival outcomes in out-of-hospital cardiac arrest (OHCA) are provided by emergency medical services (EMS) without a doctor on board. Our objective was to determine such outcomes in a ...whole country with public physician-led EMS. Methods We analyzed data from a nationwide prospective registry of OHCA cases attended by emergency medical teams (EMS) of 19 Public EMS in Spain, covering the period from 1 October, 2013 to 30-October, 2014 (13 months). Results Advanced life support (ALS) was initiated in 9347 cases (incidence of 18.6 cases per 105 inhabitants per year). Resuscitation was considered futile in 558 cases (5.9%), and ALS was continued in 8789 cases (94.1%); mean age 63.5 ± 17 years, 72.1% men. Initial rhythm was shockable in 22.1% of cases. Basic life support (BLS) was provided by bystanders in 1602 (24%) cases (635 of them with telephone assistance from the dispatch center). Of 8789 patients receiving ALS, 72.1% men, 2669 (30.4%) patients had return of spontaneous circulation (ROSC) on hospital arrival, a figure that reached 50.6% when the initial rhythm was shockable. Hospital discharge with good neurological status (CPC1-2) was found in 11.1% of the study population. Survival at discharge was 27.6% in the Utstein comparator group of patients. A total of 216 (2.5%) patients arrived at the hospital with ongoing resuscitation, of whom only one survived with CPC1-2, and 165 (1.9%) patients were included in non-heart-beating donation programs. Conclusions In Spain with physician-led EMS, OHCA survival with good neurologic status reached 11.1%, and 27.65% in the case of our Utstein comparator group, despite only a modest contribution of bystander BLS. In these services, the ongoing resuscitation strategy seems to be of little use except when considering non-heart beating donation programs
Genetic Alzheimer's disease (AD) risk factors associate with reduced defensive amyloid β plaque-associated microglia (AβAM), but the contribution of modifiable AD risk factors to microglial ...dysfunction is unknown. In AD mouse models, we observe concomitant activation of the hypoxia-inducible factor 1 (HIF1) pathway and transcription of mitochondrial-related genes in AβAM, and elongation of mitochondria, a cellular response to maintain aerobic respiration under low nutrient and oxygen conditions. Overactivation of HIF1 induces microglial quiescence in cellulo, with lower mitochondrial respiration and proliferation. In vivo, overstabilization of HIF1, either genetically or by exposure to systemic hypoxia, reduces AβAM clustering and proliferation and increases Aβ neuropathology. In the human AD hippocampus, upregulation of HIF1α and HIF1 target genes correlates with reduced Aβ plaque microglial coverage and an increase of Aβ plaque-associated neuropathology. Thus, hypoxia (a modifiable AD risk factor) hijacks microglial mitochondrial metabolism and converges with genetic susceptibility to cause AD microglial dysfunction.
•Association between colorectal cancer and proximity to industries was investigated.•Colorectal cancer was detected near industries overall for all distances.•Excess risk was higher near industries ...releasing pollution to air than water.•Industry of metal, glass, chemical, food and organic solvents showed excess risks.•Risk found near plants releasing nonylphenol, antimony, naphthalene, and manganese.
Colorectal cancer is the third most frequent tumor in males and the second in females worldwide. In Spain, it is an important and growing health problem, and epidemiologic research focused on potential risk factors, such as environmental exposures, is necessary.
To analyze the association between colorectal cancer risk and residential proximity to industries, according to pollution discharge route, industrial groups, categories of carcinogens and other toxic substances, and specific pollutants released, in the context of a population-based multicase-control study of incident cancer carried out in Spain (MCC-Spain).
MCC-Spain included 557 colorectal cancer cases and 2948 controls in 11 provinces, frequency matched by sex, age, and region of residence. Distances were computed from subjects’ residences to each of the 134 industries located in the study area. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance (from 1 km to 3 km) to industrial facilities, adjusting for matching variables and other confounders.
Excess risk (OR; 95%CI) of colorectal cancer was detected near industries overall for all distances analyzed, from 1 km (2.03; 1.44–2.87) to 3 km (1.26; 1.00–1.59). In general, industries releasing pollutants to air showed higher excess risks than facilities releasing pollution to water. By industrial sector, excess risk (OR; 95%CI) was found near (≤3 km) production of metals (2.66; 1.77–4.00), surface treatment of metals (1.48; 1.08–2.02), glass and mineral fibers (2.06; 1.39–3.07), organic chemical industry (4.80; 3.20–7.20), inorganic chemical industry (6.74; 4.38–10.36), food/beverage sector (3.34; 2.38–4.68), and surface treatment using organic solvents (6.16; 4.06–9.36). By pollutants, the main excess risks (OR; 95%CI) were found near (≤3 km) industries releasing nonylphenol (9.19; 5.91–14.28), antimony (5.30; 3.45–8.15), naphthalene (3.11; 2.16–4.49), organotin compounds (2.64; 1.76–3.98), manganese (2.53; 1.63–3.93), dichloromethane (2.52; 1.74–3.66), and vanadium (2.49; 1.59–3.91).
Our results support the hypothesis that residing in the proximity of industries may be a risk factor for colorectal cancer.
Background & Aims The signaling mechanisms that regulate trypsinogen activation and inflammation in acute pancreatitis (AP) are unclear. We explored the involvement of the calcium- and ...calcineurin-dependent transcription factor nuclear factor of activated T cells (NFAT) in development of AP in mice. Methods We measured levels of myeloperoxidase and macrophage inflammatory protein 2 (CXCL2), trypsinogen activation, and tissue damage in the pancreas 24 hours after induction of AP by retrograde infusion of taurocholate into the pancreatic ducts of wild-type, NFAT luciferase reporter (NFAT-luc), and NFATc3-deficient mice. We isolated acinar cells and measured NFAT nuclear accumulation, trypsin activity, and expression of NFAT-regulated genes. Results Infusion of taurocholate increased the transcriptional activity of NFAT in the pancreas, aorta, lung, and spleen of NFAT-luc mice. Inhibition of NFAT with A-285222 blocked taurocholate-induced activation of NFAT in all organs. A-285222 also reduced taurocholate-induced increases in levels of amylase, myeloperoxidase, and CXCL2; activation of trypsinogen; necrosis of acinar cells; edema; leukocyte infiltration; and hemorrhage in the pancreas. NFATc3-deficient mice were protected from these effects of taurocholate. Similar results were obtained using an l -arginine–induced model of AP. Reverse-transcription polymerase chain reaction and confocal immunofluorescence analyses showed that NFATc3 is expressed by acinar cells. NFATc3 expression was activated by stimuli that increase intracellular calcium levels, and activation was prevented by the calcineurin blocker cyclosporin A or A-285222. Activation of trypsinogen by secretagogues in acinar cells was prevented by pharmacologic inhibition of NFAT signaling or lack of NFATc3. A-285222 also reduced expression of inflammatory cytokines such as CXCL2 in acinar cells. Conclusions NFATc3 regulates trypsinogen activation, inflammation, and pancreatic tissue damage during development of AP in mice and might be a therapeutic target.
Appropriate cristae remodeling is a determinant of mitochondrial function and bioenergetics and thus represents a crucial process for cellular metabolic adaptations. Here, we show that mitochondrial ...cristae architecture and expression of the master cristae-remodeling protein OPA1 in proopiomelanocortin (POMC) neurons, which are key metabolic sensors implicated in energy balance control, is affected by fluctuations in nutrient availability. Genetic inactivation of OPA1 in POMC neurons causes dramatic alterations in cristae topology, mitochondrial Ca2+ handling, reduction in alpha-melanocyte stimulating hormone (α-MSH) in target areas, hyperphagia, and attenuated white adipose tissue (WAT) lipolysis resulting in obesity. Pharmacological blockade of mitochondrial Ca2+ influx restores α-MSH and the lipolytic program, while improving the metabolic defects of mutant mice. Chemogenetic manipulation of POMC neurons confirms a role in lipolysis control. Our results unveil a novel axis that connects OPA1 in POMC neurons with mitochondrial cristae, Ca2+ homeostasis, and WAT lipolysis in the regulation of energy balance.
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•Nutritional state shapes mitochondrial cristae and OPA1 expression in POMC neurons•OPA1 deletion in POMC neurons alters mitochondrial Ca2+ handling and α-MSH release•POMC OPA1-deficient mice show impaired fat lipolysis and metabolic health•Pharmacological restoration of Ca2+ recovered molecular and metabolic alterations
Gómez-Valadés et al. report that mitochondrial cristae dynamically reshape in POMC neurons in response to nutritional state. With genetic targeting, they reveal that the cristae-remodeling protein OPA1 is essential to sustain cristae structure and mitochondrial Ca2+ homeostasis in POMC neurons, ensuring appropriate modulation of α-MSH release, the lipolytic program in adipose tissue and metabolic health.
Objective: The objective of this paper is to examine the role of place of residency in the expression and outcomes of systemic lupus erythematosus (SLE) in a multi-ethnic Latin American cohort. ...Patients and methods: SLE patients (<two years of diagnosis) from 34 centers constitute this cohort. Residency was dichotomized into rural and urban, cut-off: 10,000 inhabitants. Socio-demographic, clinical/laboratory and mortality rates were compared between them using descriptive tests. The influence of place of residency on disease activity at diagnosis and renal disease was examined by multivariable regression analyses. Results: Of 1426 patients, 122 (8.6%) were rural residents. Their median ages (onset, diagnosis) were 23.5 and 25.5 years; 85 (69.7%) patients were Mestizos, 28 (22.9%) Caucasians and 9 (7.4%) were African-Latin Americans. Rural residents were more frequently younger at diagnosis, Mestizo and uninsured; they also had fewer years of education and lower socioeconomic status, exhibited hypertension and renal disease more frequently, and had higher levels of disease activity at diagnosis; they used methotrexate, cyclophosphamide pulses and hemodialysis more frequently than urban patients. Disease activity over time, renal damage, overall damage and the proportion of deceased patients were comparable in rural and urban patients. In multivariable analyses, rural residency was associated with high levels of disease activity at diagnosis (OR 1.65, 95% CI 1.06–2.57) and renal disease occurrence (OR 1.77, 95% CI 1.00–3.11). Conclusions: Rural residency associates with Mestizo ethnicity, lower socioeconomic status and renal disease occurrence. It also plays a role in disease activity at diagnosis and kidney involvement but not on the other end-points examined.
Resumen: El ámbito municipal, y con él el municipalismo, se configura como un elemento fundamental para el impulso de políticas públicas que mejoren la salud de las poblaciones, incidan sobre los ...determinantes sociales de la salud y tengan en cuenta de forma transversal la equidad, la participación ciudadana y la intersectorialidad. El objetivo de este artículo es analizar las dificultades y las oportunidades que ofrece el ámbito municipal para poner en marcha iniciativas locales e incidir en la salud de las poblaciones. En él se describe la evolución de los ayuntamientos y de sus marcos competenciales en el contexto sociopolítico actual. Se proponen tres herramientas clave para la acción local: la intersectorialidad, la participación comunitaria, y las redes y el trabajo conjunto con otras administraciones. Se ahonda en la puesta en marcha de estrategias globales como la implementación del enfoque de «salud comunitaria» y «salud en todas políticas» mediante mesas intersectoriales, la formación de estructuras o procesos formales e informales de participación comunitaria, y la realización de planes de salud local en cooperación con otras administraciones. Como medidas para seguir avanzando se propone adaptar las administraciones locales a las nuevas realidades sociales, crear modelos de organización más horizontales y flexibles, recuperar la autonomía local, dotar a los ayuntamientos de recursos, incorporar la evaluación y la búsqueda de la eficiencia, y construir redes y alianzas de gobernanza local. Abstract: Municipalities and local government are an essential element to promote public policies that improve people's health, and impact the social determinants of health, through developing approaches which incorporate equity, community engagement and intersectoral partnership at their core. The objective of this article is to analyze the barriers and opportunities that can be encountered within local governments when interventions aimed at improving people's health are developed and implemented. The evolution of the city councils, their competence frameworks and the current socio-political context are described, and three key tools for local action are proposed: intersectorality, community engagement and working in partnership with other administrations. Global strategies such as the implementation of the “community health” and “health in all policies” approach through cross-sectoral networks/partnerships are described, emphasizing the importance of developing formal and informal structures or processes of community engagement and designing local health action plans in cooperation with other administrations, such as regional and national governing bodies. To continue supporting these forms of local governance, we propose adapting the local administrations to the new social realities, with more horizontal and flexible organization models and resource allocation, integrating efficiency and evaluation processes, reclaiming local autonomy, and building local governance through networks and alliances. Palabras clave: Redes comunitarias, Ayuntamiento, Salud urbana, Ciudades, Participación comunitaria, Equidad, Determinantes sociales, Promoción de la salud, Keywords: Community networks, Local government, Urban health, Cites, Community participation, Equity, Social determinants, Health promotion
We assessed the real‐life use of direct oral anticoagulants (DOACs) in patients with venous thromboembolism (VTE) and exclusion criteria for randomized trials. From 2013 to 2016, 3,578 of 18,853 ...patients (19%) had exclusion criteria. Irrespective of which anticoagulant was chosen, they had more VTE recurrences (hazard ratio (HR): 3.10; 95% confidence interval (CI): 2.47–3.88), major bleeds (HR: 4.10; 95% CI: 3.38–4.96), and deaths (HR: 9.47; 95% CI: 8.46–10.6) than those without exclusion criteria. During initial therapy, no patient with exclusion criteria on DOACs (n = 115) recurred, but those on rivaroxaban bled less often (adjusted HR: 0.18; 95% CI: 0.04–0.79) than those on unfractionated heparin (n = 224) and similar to those (n = 3,172) on low‐molecular‐weight (LMWH) heparin. For long‐term therapy, patients on rivaroxaban (n = 151) had nonsignificantly fewer VTE recurrences (adjusted HR: 0.74; 95% CI: 0.08–1.32) and major bleeds (adjusted HR: 0.41; 95% CI: 0.15–1.15) than those on LMWH (n = 2,071). The efficacy and safety of DOACs were similar to standard therapy.
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