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BACKGROUND & AIMS: Several medications have been suspected to contribute to the etiology of inflammatory bowel disease (IBD). This study assessed the association between medication use and the risk of developing IBD using the Prospective Urban Rural Epidemiology cohort. METHODS: This was a prospective cohort study of 133,137 individuals between the ages of 20 and 80 from 24 countries. Country-specific validated questionnaires documented baseline and follow-up medication use. Participants were followed up prospectively at least every 3 years. The main outcome was the development of IBD, including Crohn's disease (CD) and ulcerative colitis (UC). Short-term (baseline but not follow-up use) and long-term use (baseline and subsequent follow-up use) were evaluated. Results are presented as adjusted odds ratios (aORs) with 95% CIs. RESULTS: During a median follow-up period of 11.0 years (interquartile range, 9.2-12.2 y), there were 571 incident IBD cases (143 CD and 428 UC). Incident IBD was associated significantly with baseline antibiotic (aOR, 2.81; 95% CI, 1.67-4.73; P = .0001) and hormonal medication use (aOR, 4.43; 95% CI, 1.78-11.01; P = .001). Among females, previous or current oral contraceptive use also was associated with IBD development (aOR, 2.17; 95% CI, 1.70-2.77; P < .001). Nonsteroidal anti-inflammatory drug users also were observed to have increased odds of IBD (aOR, 1.80; 95% CI, 1.23-2.64; P = .002), which was driven by long-term use (aOR, 5.58; 95% CI, 2.26-13.80; P < .001). All significant results were consistent in direction for CD and UC with low heterogeneity. CONCLUSIONS: Antibiotics, hormonal medications, oral contraceptives, and long-term nonsteroidal anti-inflammatory drug use were associated with increased odds of incident IBD after adjustment for covariates.
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Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Feminino , Humanos , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Anticoncepcionais Orais , Estudos Prospectivos , Anti-Inflamatórios não Esteroides/efeitos adversos , Antibacterianos/efeitos adversos , Fatores de Risco , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/epidemiologia , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Inquéritos e QuestionáriosRESUMO
Background: Our study aims to comment on all ADPKD variants identified in our health area and explain how they are distributed geographically, to identify new variants, and relate the more frequent variants with their renal phenotype in terms of kidney survival. Materials and Methods: We identified patients suffering from ADPKD in a specialized consultation unit; genealogical trees were constructed from the proband. According to the ultrasound-defined modified Ravine-Pei criteria, relatives classified as at risk were offered participation in the genetic study. Socio-demographic, clinical, and genetic factors related to the impact of the variant on the survival of the kidney and the patient, such as age at RRT beginning and age of death, were recorded. Results: In 37 families, 33 new variants of the PKD1 gene were identified, which probably produce a truncated protein. These variants included 2 large deletions, 19 frameshifts, and 12 stop-codons, all of which had not been previously described in the databases. In 10 families, six new probably pathogenic variants in the PKD2 gene were identified. These included three substitutions; two deletions, one of which was intronic and not associated with any family; and one duplication. A total of 11 missense variants in the PKD1 gene were grouped in 14 families and classified as probably pathogenic. We found that 33 VUS were grouped into 18 families and were not described in the databases, while another 15 were without grouping, and there was only 1 in the PKD2 gene. Some of these variants were present in patients with a different pathogenic variant (described or not), and the variant was probably benign. Renal survival curves were compared to nonsense versus missense variants on the PKD1 gene to check if there were any differences. A group of 328 patients with a nonsense variant was compared with a group of 264 with a missense variant; mean renal survival for truncated variants was lower (53.1 ± 0.46 years versus non-truncated variant 59.1 ± 1.36 years; Log Rank, Breslow, and Tarone Ware, p < 0.05). Conclusions: To learn more about ADPKD, it is necessary to understand genetics. By describing new genetic variants, we are approaching creation of an accurate genetic map of the disease in our country, which could have prognostic and therapeutic implications in the future.
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There are limited data on individual risk factors for SARS-CoV-2 infection (including unrecognized infection). In this seroepidemiologic substudy of an ongoing prospective cohort study of community-dwelling adults, participants were thoroughly characterized pre-pandemic. The SARS-CoV-2 infection was ascertained by serology. Among 8,719 participants from 11 high-, middle-, and low-income countries, 3,009 (35%) were seropositive for SARS-CoV-2. Characteristics independently associated with seropositivity were younger age (odds ratio, OR; 95% confidence interval, CI, per five-year increase: 0.95; 0.91-0.98) and body mass index >25 kg/m2 (OR, 95% CI: 1.16, 1.01-1.34). Smoking (as compared with never smoking, OR, 95% CI: 0.83, 0.70-0.97) and COVID-19 vaccination (OR, 95% CI: 0.70, 0.60-0.82) were associated with a reduced risk of seropositivity. Among seropositive participants, 83% were unaware of having been infected with SARS-CoV-2. Seropositivity and a lack of awareness of infection were more common in lower-income countries. The COVID-19 vaccination reduces the risk of SARS-CoV-2 infection (including recognized and unrecognized infections). Overweight or obesity is an independent risk factor for SARS-CoV-2 infection. Infection and lack of infection awareness are more common in lower-income countries.IMPORTANCEIn this large, international study, evidence of SARS-CoV-2 infection was obtained by testing blood specimens from 8,719 community-dwelling adults from 11 countries. The key findings are that (i) the large majority (83%) of community-dwelling adults from several high-, middle-, and low-income countries with blood test evidence of SARS-CoV-2 infection were unaware of this infection-especially in lower-income countries; and (ii) overweight/obesity predisposes to SARS-CoV-2 infection, while COVID-19 vaccination is associated with a reduced risk of SARS-CoV-2 infection. These observations are not attributable to other individual characteristics, highlighting the importance of the COVID-19 vaccination to prevent not only severe infection but possibly any infection. Further research is needed to understand the mechanisms by which overweight/obesity might increase the risk of SARS-CoV-2 infection.
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COVID-19 , Adulto , Humanos , SARS-CoV-2 , Estudos Prospectivos , Sobrepeso , Vacinas contra COVID-19 , Estudos Soroepidemiológicos , Fatores de Risco , ObesidadeRESUMO
Mutations in BEST1 gene, encoding the bestrophin-1 (Best1) protein are associated with macular dystrophies. Best1 is predominantly expressed in the retinal pigment epithelium (RPE), and is inserted in its basolateral membrane. We investigated the cellular localization in polarized MDCKII cells of disease-associated Best1 mutant proteins to study specific sorting motifs of Best1. Real-time PCR and western blots for endogenous expression of BEST1 in MDCK cells were performed. Best1 mutant constructs were generated using site-directed mutagenesis and transfected in MDCK cells. For protein sorting, confocal microscopy studies, biotinylation assays and statistical methods for quantification of mislocalization were used. Analysis of endogenous expression of BEST1 in MDCK cells revealed the presence of BEST1 transcript but no protein. Confocal microscopy and quantitative analyses indicate that transfected normal human Best1 displays a basolateral localization in MDCK cells, while cell sorting of several Best1 mutants (Y85H, Q96R, L100R, Y227N, Y227E) was altered. In contrast to constitutively active Y227E, constitutively inactive Y227F Best1 mutant localized basolaterally similar to the normal Best1 protein. Our data suggest that at least three basolateral sorting motifs might be implicated in proper Best1 basolateral localization. In addition, non-phosphorylated tyrosine 227 could play a role for basolateral delivery.
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Canais de Cloreto/metabolismo , Proteínas do Olho/metabolismo , Animais , Bestrofinas , Linhagem Celular , Canais de Cloreto/análise , Canais de Cloreto/genética , Cães , Proteínas do Olho/análise , Proteínas do Olho/genética , Humanos , Hipoxantina Fosforribosiltransferase/genética , Hipoxantina Fosforribosiltransferase/metabolismo , Células Madin Darby de Rim Canino , Microscopia Confocal , Mutagênese Sítio-Dirigida , Fosforilação , Distrofia Macular Viteliforme/genética , Distrofia Macular Viteliforme/metabolismo , Distrofia Macular Viteliforme/patologiaRESUMO
Introduction: Precarious work is one of the most studied concepts related to work, and its effects have been analyzed in relation to variables such as mental health and wellbeing. However, there is a tendency to atomise the analysis of precarious work, without understanding that people's working life is intertwined with other areas of their life. Objective: Faced with this situation, this paper presents the concept of perceived precarious life, which is aligned with contemporary models of social inclusion and exclusion. Thus, perceived precarious life comprises variables of labor precariousness, social support and hopelessness in the family economic situation. Methods: To test this idea, a structural equation model (SEM) is presented, which tests the structure of the construct of perceived precarious life by relating it to mental health and coping strategies. Results: After testing the fit of the model in both men and women, a SEM path analysis is designed between the variables, observing that perceived precarious life has an effect on mental health (ß = 0.635, p < 0.01). This relationship is mediated by unproductive coping strategies (ß = 0.142, p < 0.01). Conclusion: This model exposes a broad and integrated conceptualization of precariousness, combining aspects of work, relationships and hopelessness, which allows for an understanding of the integral experience of precariousness.
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Afeto , Saúde Mental , Masculino , Humanos , Feminino , Capacidades de Enfrentamento , Autoimagem , Apoio SocialRESUMO
In-work poverty reflects situations of income below the poverty threshold among employed people, involving a deterioration of wellbeing. The International Labour Organization prioritises this situation, which in countries such as Spain, Germany or Italy reaches rates of 11.8%, 10.6% and 11.8%, respectively. Within a context of flexibility, the occupational situation tends to be understood as an individual responsibility, which is why this study analyses the increase in self-criticism in these situations, and the role of social support in this relationship. The mediation of social support in the manifestation of self-criticism among people experiencing in-work poverty is analysed. The participants were 1430 employed people, grouped into those in a situation of poverty and those who are not. The results show that people in a situation of in-work poverty present a higher score in self-criticism and lower in social support. Social support is a mediating variable that prevents the manifestation of self-criticism. Lastly, a gender analysis shows that women experience this relationship more intensely. These findings enable a critical assessment of the activation policies that only take an individual approach. As an alternative, we propose strengthening interventions that foster social support, particularly among women.
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Pobreza , Autoavaliação (Psicologia) , Feminino , Alemanha , Humanos , Renda , Apoio SocialRESUMO
Our group identified two pathogenic variants on the PKD1 gene, c.10527_10528delGA and c.7292T>A, from unrelated families. They came from two small counties in Granada, with 61 and 26 autosomal dominant polycystic kidney disease (ADPKD) individuals affected. To determine a common ancestor, healthy and ADPKD individuals from these families were genotyped by analysing four microsatellites located on chromosome 16. Our study identified a common haplotype in all ADPKD individuals. These findings underpin our hypothesis of the founder effect and explain why there is a high frequency of ADPKD in small regions. Determining hotspots of ADPKD will help to better plan healthcare in the future.
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[This corrects the article DOI: 10.1093/ckj/sfaa261.].
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Importance: Hospitalized patients with COVID-19 pneumonia have high rates of morbidity and mortality. Objective: To assess the efficacy of colchicine in hospitalized patients with COVID-19 pneumonia. Design, Setting, and Participants: The Estudios Clínicos Latino América (ECLA) Population Health Research Institute (PHRI) COLCOVID trial was a multicenter, open-label, randomized clinical trial performed from April 17, 2020, to March 28, 2021, in adults with confirmed or suspected SARS-CoV-2 infection followed for up to 28 days. Participants received colchicine vs usual care if they were hospitalized with COVID-19 symptoms and had severe acute respiratory syndrome or oxygen desaturation. The main exclusion criteria were clear indications or contraindications for colchicine, chronic kidney disease, and negative results on a reverse transcription-polymerase chain reaction test for SARS-CoV-2 before randomization. Data were analyzed from June 20 to July 25, 2021. Interventions: Patients were assigned in a 1:1 ratio to usual care or usual care plus colchicine. Colchicine was administered orally in a loading dose of 1.5 mg immediately after randomization, followed by 0.5 mg orally within 2 hours of the initial dose and 0.5 mg orally twice a day for 14 days or discharge, whichever occurred first. Main Outcomes and Measures: The first coprimary outcome was the composite of a new requirement for mechanical ventilation or death evaluated at 28 days. The second coprimary outcome was death at 28 days. Results: A total of 1279 hospitalized patients (mean [SD] age, 61.8 [14.6] years; 449 [35.1%] women and 830 [64.9%] men) were randomized, including 639 patients in the usual care group and 640 patients in the colchicine group. Corticosteroids were used in 1171 patients (91.5%). The coprimary outcome of mechanical ventilation or 28-day death occurred in 160 patients (25.0%) in the colchicine group and 184 patients (28.8%) in the usual care group (hazard ratio [HR], 0.83; 95% CI, 0.67-1.02; P = .08). The second coprimary outcome, 28-day death, occurred in 131 patients (20.5%) in the colchicine group and 142 patients (22.2%) in the usual care group (HR, 0.88; 95% CI, 0.70-1.12). Diarrhea was the most frequent adverse effect of colchicine, reported in 68 patients (11.3%). Conclusions and Relevance: This randomized clinical trial found that compared with usual care, colchicine did not significantly reduce mechanical ventilation or 28-day mortality in patients hospitalized with COVID-19 pneumonia. Trial Registration: ClinicalTrials.gov Identifier: NCT04328480.
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Anti-Inflamatórios/uso terapêutico , COVID-19/terapia , Colchicina/uso terapêutico , Hospitalização , Intubação Intratraqueal , Respiração Artificial , Corticosteroides/uso terapêutico , Adulto , Idoso , Anti-Inflamatórios/efeitos adversos , COVID-19/mortalidade , COVID-19/patologia , Colchicina/efeitos adversos , Feminino , Humanos , Inflamação/tratamento farmacológico , Inflamação/etiologia , Masculino , Pessoa de Meia-Idade , SARS-CoV-2 , Padrão de CuidadoRESUMO
OBJECTIVE: To demonstrate that the variant not described in PKD1 gene c.7292T> A, identified in four families from the Alpujarra in Granada, is the cause of autosomal dominant polycystic kidney disease (ADPKD). This variant consists of a transversion of thymine (T) by adenine (A) that at the level of the Polycystin 1 protein produces a change of leucine (Leu / L) by Glutamine (Gln / Q) in position 2431 (p.Leu2431Gln). METHOD: Sociodemographic and clinical variables were registered using clinical histories, genealogical trees, ultrasounds and genetic analysis to ADPKD and healthy individuals belonging to these families in the context of segregation study. RESULTS: All PKD individuals carried the c.7292T>A variant in heterozygosis, whereas healthy ones did not. Among all ADPKD patients, 62.9% were women. ADPKD diagnosis was made at 29.3 ± 15.82 years, after having the first child in 64.8%. The main reasons for diagnosis were family history and hematuria episodes. The onset of renal replacement therapy (RRT) occurred at 55.8 ± 7.62 years (range 44-67), and death at 63 ± 92.2 years (range 48-76), being the cause unknown, cardiovascular and insufficiency kidney the most frequent; the median of renal survival was established at 58.5 ± 0.77 years and the median survival of patients at 67.2 ± 3.54 years. No differences in kidney and patient survivals were observed according to sex. Among deceased patients, 52.2% required RRT and 94.4% suffered from renal failure. CONCLUSIONS: The variant c.7292T>A in PKD1 gene is responsible for the disease, and its distribution in the Alpujarra region of Granada suggests a founder effect. In ADPKD it is necessary to perform segregation studies that help us to reclassify genetic variants, in this case from indeterminate to pathogenic.
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Mutação , Rim Policístico Autossômico Dominante/genética , Canais de Cátion TRPP/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Espanha , Adulto JovemRESUMO
BACKGROUND: Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC) is a rare type of leukodystrophy characterized by astrocyte and myelin vacuolization, epilepsy and early-onset macrocephaly. MLC is caused by mutations in MLC1 or GLIALCAM, coding for two membrane proteins with an unknown function that form a complex specifically expressed in astrocytes at cell-cell junctions. Recent studies in Mlc1-/- or Glialcam-/- mice and mlc1-/- zebrafish have shown that MLC1 regulates glial surface levels of GlialCAM in vivo and that GlialCAM is also required for MLC1 expression and localization at cell-cell junctions. METHODS: We have generated and analysed glialcama-/- zebrafish. We also generated zebrafish glialcama-/- mlc1-/- and mice double KO for both genes and performed magnetic resonance imaging, histological studies and biochemical analyses. RESULTS: glialcama-/- shows megalencephaly and increased fluid accumulation. In both zebrafish and mice, this phenotype is not aggravated by additional elimination of mlc1. Unlike mice, mlc1 protein expression and localization are unaltered in glialcama-/- zebrafish, possibly because there is an up-regulation of mlc1 mRNA. In line with these results, MLC1 overexpressed in Glialcam-/- mouse primary astrocytes is located at cell-cell junctions. CONCLUSIONS: This work indicates that the two proteins involved in the pathogenesis of MLC, GlialCAM and MLC1, form a functional unit, and thus, that loss-of-function mutations in these genes cause leukodystrophy through a common pathway.
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Moléculas de Adesão Celular Neurônio-Glia/metabolismo , Proteínas de Membrana/metabolismo , Bainha de Mielina/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Animais , Astrócitos/metabolismo , Moléculas de Adesão Celular Neurônio-Glia/genética , Mutação com Perda de Função/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Mutação , Bainha de Mielina/genética , Proteínas do Tecido Nervoso/genética , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismoRESUMO
The distribution of thyrotropin-releasing hormone (TRH) in the brain of the adult zebrafish was studied with immunohistochemical techniques. In the telencephalon, abundant TRH-immunoreactive (TRHir) neurons were observed in the central, ventral, and supra- and postcommissural regions of the ventral telencephalic area. In the diencephalon, TRHir neurons were observed in the anterior parvocellular preoptic nucleus, the suprachiasmatic nucleus, the lateral hypothalamic nucleus, the rostral parts of the anterior tuberal nucleus and torus lateralis, and the posterior tuberal nucleus. Some TRHir neurons were also observed in the central posterior thalamic nucleus and in the habenula. The mesencephalon contained TRHir cells in the rostrodorsal tegmentum, the Edinger-Westphal nucleus, the torus semicircularis, and the nucleus of the lateral lemniscus. Further TRHir neurons were observed in the interpeduncular nucleus. In the rhombencephalon, TRHir cells were observed in the nucleus isthmi and the locus coeruleus, rostrally, and in the vagal lobe and vagal motor nucleus, caudally. In the forebrain, TRHir fibers were abundant in several regions, including the medial and caudodorsal parts of the dorsal telencephalic area, the ventral and commissural parts of the ventral telencephalic area, the preoptic area, the posterior tubercle, the anterior tuberal nucleus, and the posterior hypothalamic lobe. The dorsal thalamus exhibited moderate TRHir innervation. In the mesencephalon, the optic tectum received a rich TRHir innervation between the periventricular gray zone and the stratum griseum centrale. A conspicuous TRHir longitudinal tract traversed the tegmentum and extended to the rhombencephalon. The medial and lateral mesencephalic reticular areas and the interpeduncular nucleus were richly innervated by TRHir fibers. In the rhombencephalon, the secondary gustatory nucleus received abundant TRHir fibers. TRHir fibers moderately innervated the ventrolateral and ventromedial reticular area and richly innervated the vagal lobe and Cajal's commissural nucleus. Some TRHir fibers coursed in the lateral funiculus of the spinal cord. Some TRHir amacrine cells were observed in the retina. The wide distribution of TRHir neurons and fibers observed in the zebrafish brain suggests that TRH plays different roles. These results in the adult zebrafish reveal a number of differences with respect to the TRHir systems reported in other adult teleosts but were similar to those found during late developmental stages of trout (Díaz et al., 2001).
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Axônios/metabolismo , Encéfalo/metabolismo , Vias Neurais/metabolismo , Hormônio Liberador de Tireotropina/metabolismo , Peixe-Zebra/metabolismo , Animais , Axônios/ultraestrutura , Encéfalo/citologia , Cerebelo/citologia , Cerebelo/metabolismo , Epitálamo/citologia , Epitálamo/metabolismo , Imuno-Histoquímica , Mesencéfalo/citologia , Mesencéfalo/metabolismo , Vias Neurais/citologia , Área Pré-Óptica/citologia , Área Pré-Óptica/metabolismo , Retina/citologia , Retina/metabolismo , Rombencéfalo/citologia , Rombencéfalo/metabolismo , Telencéfalo/citologia , Telencéfalo/metabolismo , Tálamo/citologia , Tálamo/metabolismo , Peixe-Zebra/anatomia & histologiaRESUMO
La apoptosis es un tipo de muerte celular caracterizado por un conjunto de cambios citoplasmáticos y nucleares inducidos por estímulos, que originan la desnutrición de células aisladas dentro de un determinado tejido afectar a las células vecinas. Durante el desarrollo, este proceso actúa en la modulación, diferenciación y eliminación de poblaciones celulares, para mantener la integridad de muchos órganos. Interviene en circunstancias normales como la embriogénesis, la metamorfosis o el recambio celular; y también en situaciones patológicas como enfermedades neoplásicas o autoinmunes. En muchos órganos entre ellos la piel, la apoptosis es un factor importante para mantener la homeostasis del tejido por lo tanto, alteraciones en este proceso favorecerían la sobrevida de células malignas o trastornos del sistema inmune