Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 111
Filtrar
1.
Cell ; 187(8): 1971-1989.e16, 2024 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-38521060

RESUMEN

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) share many clinical, pathological, and genetic features, but a detailed understanding of their associated transcriptional alterations across vulnerable cortical cell types is lacking. Here, we report a high-resolution, comparative single-cell molecular atlas of the human primary motor and dorsolateral prefrontal cortices and their transcriptional alterations in sporadic and familial ALS and FTLD. By integrating transcriptional and genetic information, we identify known and previously unidentified vulnerable populations in cortical layer 5 and show that ALS- and FTLD-implicated motor and spindle neurons possess a virtually indistinguishable molecular identity. We implicate potential disease mechanisms affecting these cell types as well as non-neuronal drivers of pathogenesis. Finally, we show that neuron loss in cortical layer 5 tracks more closely with transcriptional identity rather than cellular morphology and extends beyond previously reported vulnerable cell types.


Asunto(s)
Esclerosis Amiotrófica Lateral , Degeneración Lobar Frontotemporal , Corteza Prefrontal , Animales , Humanos , Ratones , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Demencia Frontotemporal/genética , Degeneración Lobar Frontotemporal/genética , Degeneración Lobar Frontotemporal/metabolismo , Degeneración Lobar Frontotemporal/patología , Perfilación de la Expresión Génica , Neuronas/metabolismo , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Análisis de Expresión Génica de una Sola Célula
2.
Nucleic Acids Res ; 52(D1): D138-D144, 2024 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-37933855

RESUMEN

The Gene Expression Omnibus (GEO) is an international public repository that archives gene expression and epigenomics data sets generated by next-generation sequencing and microarray technologies. Data are typically submitted to GEO by researchers in compliance with widespread journal and funder mandates to make generated data publicly accessible. The resource handles raw data files, processed data files and descriptive metadata for over 200 000 studies and 6.5 million samples, all of which are indexed, searchable and downloadable. Additionally, GEO offers web-based tools that facilitate analysis and visualization of differential gene expression. This article presents the current status and recent advancements in GEO, including the generation of consistently computed gene expression count matrices for thousands of RNA-seq studies, and new interactive graphical plots in GEO2R that help users identify differentially expressed genes and assess data set quality. The GEO repository is built and maintained by the National Center for Biotechnology Information (NCBI), a division of the National Library of Medicine (NLM), and is publicly accessible at https://www.ncbi.nlm.nih.gov/geo/.


Asunto(s)
Epigenómica , Perfilación de la Expresión Génica , Expresión Génica , Bases de Datos Genéticas , Análisis de Secuencia por Matrices de Oligonucleótidos
3.
J Korean Soc Radiol ; 84(6): 1339-1349, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-38107681

RESUMEN

Purpose: To determine the efficacy and safety of iliac branch device (IBD) implantation and to evaluate its limitations based on 7 years of experience in a single center. Materials and Methods: This single-center study included patients with bilateral common iliac artery aneurysms (CIAAs). We investigated follow-up CT and reviewed the internal iliac artery (IIA) patency and complications related to IBD. A retrospective analysis was performed and the overall survival rate and freedom from reintervention rate were reported according to the Kaplan-Meier method. Results: Of the 38 patients with CIAAs, only 10 (12 CIAAs) were suitable for IBD treatment. Five patients underwent unilateral IBD insertion with contralateral IIA embolization, and three (60%) showed claudication; however, symptoms resolved within 6 months. The 7-year freedom from IBD-related reintervention rate was 77.8%. No procedure-related deaths occurred. Conclusion: IBD has good technical success and long-term patency rates; however, anatomical factors frequently limit its application, particularly in Asians. Additionally, unilateral IIA embolization showed relatively mild complications and a good prognosis; therefore, it can be performed safely for anatomically complex aortoiliac aneurysms.

4.
J Pers Med ; 13(4)2023 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-37109037

RESUMEN

The hemolysis rate in the emergency department (ED) is higher compared to that in other departments. We propose a new blood sampling technique without repeated venipuncture to reduce hemolysis and compare the hemolysis rate between blood collected by this method and that collected with an intravenous (IV) catheter. This prospective study included a nonconsecutive sample of patients visiting the ED (aged ≥ 18 years) of a tertiary urban university hospital. The intravenous catheterization was performed by three pre-trained nurses. The new blood collection technique involved sample collection without removing the catheter needle, performed immediately before the conventional method (through an IV catheter), without additional venipuncture. Two blood samples were collected from each patient using both the new and conventional methods, and the hemolysis index was evaluated. We compared the hemolysis rate between the two methods. From the 260 patients enrolled in this study, 147 (56.5%) were male, and the mean age was 58.3 years. The hemolysis rate of the new blood collection method was 1.9% (5/260), which was significantly lower than that of the conventional method (7.3%; 19/260) (p = 0.001). The new blood collection method can reduce the hemolysis rate as compared to the conventional blood collection method.

5.
Ren Fail ; 45(1): 2177086, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36876658

RESUMEN

BACKGROUND: Acute kidney injury (AKI) in COVID-19 patients is associated with poor prognosis. Characterization of AKI by timing and trajectory and early prediction of AKI progression is required for better preventive management and the prediction of patient outcomes. METHODS: A total of 858 patients who were hospitalized due to coronavirus disease 2019 (COVID-19) were retrospectively enrolled from December 2020 to August 2021. The occurrence of AKI was evaluated throughout hospitalization. The hazard ratios (HRs) of mortality outcomes according to the trajectory of AKI were measured using Cox regression models after adjustment for multiple variables. RESULTS: Among 858 patients, 226 (26.3%) presented AKI at admission, and 44 (5.1%) developed AKI during hospitalization. Patients with AKI at admission or hospital-acquired AKI had a higher risk of mortality than those without AKI, with HRs of 9.87 (2.81-34.67) and 13.74 (3.57-52.84), respectively. Of 226 patients with AKI at admission, 104 (46.0%) recovered within 48 hr, 83 (36.7%) had AKI beyond 48 hr and recovered in 7 days, and 39 (17.3%) showed no recovery from AKI on Day 7. Delayed recovery and persistent AKI were significantly associated with an increased risk of mortality, with HRs of 4.39 (1.06-18.24) and 24.33 (7.10-83.36), respectively. CONCLUSIONS: The onset and progression of AKI was significantly associated with in-hospital mortality in patients with COVID-19. A thorough observation of the recovery trajectory of early AKI after infection is necessary.


Asunto(s)
Lesión Renal Aguda , COVID-19 , Humanos , Mortalidad Hospitalaria , Estudios Retrospectivos , Hospitalización
6.
Nat Commun ; 14(1): 282, 2023 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-36650127

RESUMEN

Striatal projection neurons (SPNs), which progressively degenerate in human patients with Huntington's disease (HD), are classified along two axes: the canonical direct-indirect pathway division and the striosome-matrix compartmentation. It is well established that the indirect-pathway SPNs are susceptible to neurodegeneration and transcriptomic disturbances, but less is known about how the striosome-matrix axis is compromised in HD in relation to the canonical axis. Here we show, using single-nucleus RNA-sequencing data from male Grade 1 HD patient post-mortem brain samples and male zQ175 and R6/2 mouse models, that the two axes are multiplexed and differentially compromised in HD. In human HD, striosomal indirect-pathway SPNs are the most depleted SPN population. In mouse HD models, the transcriptomic distinctiveness of striosome-matrix SPNs is diminished more than that of direct-indirect pathway SPNs. Furthermore, the loss of striosome-matrix distinction is more prominent within indirect-pathway SPNs. These results open the possibility that the canonical direct-indirect pathway and striosome-matrix compartments are differentially compromised in late and early stages of disease progression, respectively, differentially contributing to the symptoms, thus calling for distinct therapeutic strategies.


Asunto(s)
Enfermedad de Huntington , Ratones , Animales , Humanos , Masculino , Enfermedad de Huntington/genética , Enfermedad de Huntington/metabolismo , Roedores , Cuerpo Estriado/metabolismo , Neuronas/metabolismo , Ganglios Basales/metabolismo , Modelos Animales de Enfermedad , Ratones Transgénicos
7.
Kidney360 ; 3(9): 1494-1501, 2022 09 29.
Artículo en Inglés | MEDLINE | ID: mdl-36245653

RESUMEN

Background: Predicting the risk of death in patients admitted to the critical care unit facilitates appropriate management. In particular, among patients who are critically ill, patients with continuous RRT (CRRT) have high mortality, and predicting the mortality risk of these patients is difficult. The purpose of this study was to develop models for predicting the mortality risk of patients on CRRT and to validate the models externally. Methods: A total of 699 adult patients with CRRT who participated in the VolumE maNagement Under body composition monitoring in critically ill patientS on CRRT (VENUS) trial and 1515 adult patients with CRRT in Seoul National University Hospital were selected as the development and validation cohorts, respectively. Using 11 predictor variables selected by the Cox proportional hazards model and clinical importance, equations predicting mortality within 7, 14, and 28 days were developed with development cohort data. Results: The equation using 11 variables had area under the time-dependent receiver operating characteristic curve (AUROC) values of 0.75, 0.74, and 0.73 for predicting 7-, 14-, and 28-day mortality, respectively. All equations had significantly higher AUROCs than the Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores. The 11-variable equation was superior to the SOFA and APACHE II scores in the integrated discrimination index and net reclassification improvement analyses. Conclusions: The newly developed equations for predicting CRRT patient mortality showed superior performance to the previous scoring systems, and they can help physicians manage patients.


Asunto(s)
Terapia de Reemplazo Renal Continuo , Adulto , Humanos , APACHE , Estudios de Cohortes , Enfermedad Crítica/terapia , Unidades de Cuidados Intensivos , Ensayos Clínicos como Asunto
8.
Neuron ; 110(7): 1087-1089, 2022 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-35390285

RESUMEN

In this issue of Neuron, Gu et al. (2022) describe a new BAC mouse model that faithfully recapitulates various aspects of Huntington's disease pathobiology and reveals important insights into the relative toxicities of mHTT-derived products.


Asunto(s)
Enfermedad de Huntington , Animales , Modelos Animales de Enfermedad , Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Ratones , Neuronas/fisiología
9.
Nature ; 603(7903): 893-899, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35158371

RESUMEN

Despite the importance of the cerebrovasculature in maintaining normal brain physiology and in understanding neurodegeneration and drug delivery to the central nervous system1, human cerebrovascular cells remain poorly characterized owing to their sparsity and dispersion. Here we perform single-cell characterization of the human cerebrovasculature using both ex vivo fresh tissue experimental enrichment and post mortem in silico sorting of human cortical tissue samples. We capture 16,681 cerebrovascular nuclei across 11 subtypes, including endothelial cells, mural cells and three distinct subtypes of perivascular fibroblast along the vasculature. We uncover human-specific expression patterns along the arteriovenous axis and determine previously uncharacterized cell-type-specific markers. We use these human-specific signatures to study changes in 3,945 cerebrovascular cells from patients with Huntington's disease, which reveal activation of innate immune signalling in vascular and glial cell types and a concomitant reduction in the levels of proteins critical for maintenance of blood-brain barrier integrity. Finally, our study provides a comprehensive molecular atlas of the human cerebrovasculature to guide future biological and therapeutic studies.


Asunto(s)
Células Endoteliales , Enfermedad de Huntington , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Células Endoteliales/metabolismo , Humanos , Enfermedad de Huntington/metabolismo , Sistema Inmunológico , Neuroglía , Proteínas/metabolismo
10.
Pediatr Neurol ; 123: 30-37, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34388423

RESUMEN

BACKGROUND: Adequate sleep is important for proper neurodevelopment and positive health outcomes. Sleep disturbances are more prevalent in children with genetically determined neurodevelopmental syndromes compared with typically developing counterparts. We characterize sleep behavior in Rett (RTT), Angelman (AS), and Prader-Willi (PWS) syndromes to identify effective approaches for treating sleep problems in these populations. We compared sleep-related symptoms across individuals with these different syndromes with each other, and with typically developing controls. METHODS: Children were recruited from the Rare Diseases Clinical Research Network consortium registries; unaffected siblings were enrolled as related controls. For each participant, a parent completed multiple sleep questionnaires including Pediatric Sleep Questionnaire (Sleep-Disordered Breathing), Children's Sleep Habits Questionnaire (CSHQ), and Pediatric Daytime Sleepiness Scale. RESULTS: Sleep data were analyzed from 714 participants, aged two to 18 years. Young children with AS had more reported sleep problems than children with RTT or PWS. Older children with RTT had more reported daytime sleepiness than those with AS or PWS. Finally, all individuals with RTT had more evidence of sleep-disordered breathing when compared with individuals with PWS. Notably, typically developing siblings were also reported to have sleep problems, except for sleep-related breathing disturbances, which were associated with each of the genetic syndromes. CONCLUSIONS: Individuals with RTT, AS, and PWS frequently experience sleep problems, including sleep-disordered breathing. Screening for sleep problems in individuals with these and other neurogenetic disorders should be included in clinical assessment and managements. These data may also be useful in developing treatment strategies and in clinical trials.


Asunto(s)
Síndrome de Angelman/fisiopatología , Trastornos del Neurodesarrollo/fisiopatología , Síndrome de Prader-Willi/fisiopatología , Síndrome de Rett/fisiopatología , Trastornos del Sueño-Vigilia/diagnóstico , Trastornos del Sueño-Vigilia/fisiopatología , Adolescente , Síndrome de Angelman/complicaciones , Niño , Preescolar , Humanos , Trastornos del Neurodesarrollo/complicaciones , Síndrome de Prader-Willi/complicaciones , Enfermedades Raras , Síndrome de Rett/complicaciones , Trastornos del Sueño-Vigilia/etiología
11.
Nature ; 593(7857): 114-118, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33790466

RESUMEN

Innate social behaviours, such as mating and fighting, are fundamental to animal reproduction and survival1. However, social engagements can also put an individual at risk2. Little is known about the neural mechanisms that enable appropriate risk assessment and the suppression of hazardous social interactions. Here we identify the posteromedial nucleus of the cortical amygdala (COApm) as a locus required for the suppression of male mating when a female mouse is unhealthy. Using anatomical tracing, functional imaging and circuit-level epistatic analyses, we show that suppression of mating with an unhealthy female is mediated by the COApm projections onto the glutamatergic population of the medial amygdalar nucleus (MEA). We further show that the role of the COApm-to-MEA connection in regulating male mating behaviour relies on the neuromodulator thyrotropin-releasing hormone (TRH). TRH is expressed in the COApm, whereas the TRH receptor (TRHR) is found in the postsynaptic MEA glutamatergic neurons. Manipulating neural activity of TRH-expressing neurons in the COApm modulated male mating behaviour. In the MEA, activation of the TRHR pathway by ligand infusion inhibited mating even towards healthy female mice, whereas genetic ablation of TRHR facilitated mating with unhealthy individuals. In summary, we reveal a neural pathway that relies on the neuromodulator TRH to modulate social interactions according to the health status of the reciprocating individual. Individuals must balance the cost of social interactions relative to the benefit, as deficits in the ability to select healthy mates may lead to the spread of disease.


Asunto(s)
Amígdala del Cerebelo/citología , Amígdala del Cerebelo/fisiología , Preferencia en el Apareamiento Animal/fisiología , Vías Nerviosas/fisiología , Conducta Social , Animales , Copulación/fisiología , Complejo Nuclear Corticomedial/citología , Complejo Nuclear Corticomedial/metabolismo , Femenino , Ácido Glutámico/metabolismo , Salud , Ligandos , Lipopolisacáridos/farmacología , Masculino , Ratones , Neuronas/metabolismo , Receptores de Hormona Liberadora de Tirotropina/metabolismo , Hormona Liberadora de Tirotropina/metabolismo
12.
Sci Rep ; 11(1): 3627, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33574451

RESUMEN

Our aim was to investigate the associations between erythrocyte fatty acids and the risk of islet autoimmunity in children. The Environmental Determinants of Diabetes in the Young Study (TEDDY) is a longitudinal cohort study of children at high genetic risk for type 1 diabetes (n = 8676) born between 2004 and 2010 in the U.S., Finland, Sweden, and Germany. A nested case-control design comprised 398 cases with islet autoimmunity and 1178 sero-negative controls matched for clinical site, family history, and gender. Fatty acids composition was measured in erythrocytes collected at the age of 3, 6, and 12 months and then annually up to 6 years of age. Conditional logistic regression models were adjusted for HLA risk genotype, ancestry, and weight z-score. Higher eicosapentaenoic and docosapentaenoic acid (n - 3 polyunsaturated fatty acids) levels during infancy and conjugated linoleic acid after infancy were associated with a lower risk of islet autoimmunity. Furthermore, higher levels of some even-chain saturated (SFA) and monounsaturated fatty acids (MUFA) were associated with increased risk. Fatty acid status in early life may signal the risk for islet autoimmunity, especially n - 3 fatty acids may be protective, while increased levels of some SFAs and MUFAs may precede islet autoimmunity.


Asunto(s)
Autoinmunidad , Eritrocitos/metabolismo , Ácidos Grasos/metabolismo , Islotes Pancreáticos/inmunología , Lactancia Materna , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Factores de Riesgo
13.
Neuron ; 107(5): 891-908.e8, 2020 09 09.
Artículo en Inglés | MEDLINE | ID: mdl-32681824

RESUMEN

The mechanisms by which mutant huntingtin (mHTT) leads to neuronal cell death in Huntington's disease (HD) are not fully understood. To gain new molecular insights, we used single nuclear RNA sequencing (snRNA-seq) and translating ribosome affinity purification (TRAP) to conduct transcriptomic analyses of caudate/putamen (striatal) cell type-specific gene expression changes in human HD and mouse models of HD. In striatal spiny projection neurons, the most vulnerable cell type in HD, we observe a release of mitochondrial RNA (mtRNA) (a potent mitochondrial-derived innate immunogen) and a concomitant upregulation of innate immune signaling in spiny projection neurons. Further, we observe that the released mtRNAs can directly bind to the innate immune sensor protein kinase R (PKR). We highlight the importance of studying cell type-specific gene expression dysregulation in HD pathogenesis and reveal that the activation of innate immune signaling in the most vulnerable HD neurons provides a novel framework to understand the basis of mHTT toxicity and raises new therapeutic opportunities.


Asunto(s)
Proteína Huntingtina/inmunología , Enfermedad de Huntington/inmunología , Inmunidad Innata/inmunología , Neuronas/inmunología , ARN Mitocondrial/inmunología , Animales , Humanos , Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Enfermedad de Huntington/patología , Ratones , Mutación , Neuronas/patología , Transcriptoma
14.
Mol Neurodegener ; 15(1): 29, 2020 05 24.
Artículo en Inglés | MEDLINE | ID: mdl-32448329

RESUMEN

Huntington's disease (HD) is an incurable neurodegenerative disorder caused by CAG trinucleotide expansions in the huntingtin gene. Markers of both systemic and CNS immune activation and inflammation have been widely noted in HD and mouse models of HD. In particular, elevation of the pro-inflammatory cytokine interleukin-6 (IL-6) is the earliest reported marker of immune activation in HD, and this elevation has been suggested to contribute to HD pathogenesis. To test the hypothesis that IL-6 deficiency would be protective against the effects of mutant huntingtin, we generated R6/2 HD model mice that lacked IL-6. Contrary to our prediction, IL-6 deficiency exacerbated HD-model associated behavioral phenotypes. Single nuclear RNA Sequencing (snRNA-seq) analysis of striatal cell types revealed that IL-6 deficiency led to the dysregulation of various genes associated with synaptic function, as well as the BDNF receptor Ntrk2. These data suggest that IL-6 deficiency exacerbates the effects of mutant huntingtin through dysregulation of genes of known relevance to HD pathobiology in striatal neurons, and further suggest that modulation of IL-6 to a level that promotes proper regulation of genes associated with synaptic function may hold promise as an HD therapeutic target.


Asunto(s)
Encéfalo/metabolismo , Enfermedad de Huntington/metabolismo , Interleucina-6/deficiencia , Fenotipo , Animales , Encéfalo/fisiopatología , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Enfermedad de Huntington/genética , Interleucina-6/metabolismo , Ratones Transgénicos
15.
Neuron ; 106(1): 76-89.e8, 2020 04 08.
Artículo en Inglés | MEDLINE | ID: mdl-32004439

RESUMEN

Unbiased in vivo genome-wide genetic screening is a powerful approach to elucidate new molecular mechanisms, but such screening has not been possible to perform in the mammalian central nervous system (CNS). Here, we report the results of the first genome-wide genetic screens in the CNS using both short hairpin RNA (shRNA) and CRISPR libraries. Our screens identify many classes of CNS neuronal essential genes and demonstrate that CNS neurons are particularly sensitive not only to perturbations to synaptic processes but also autophagy, proteostasis, mRNA processing, and mitochondrial function. These results reveal a molecular logic for the common implication of these pathways across multiple neurodegenerative diseases. To further identify disease-relevant genetic modifiers, we applied our screening approach to two mouse models of Huntington's disease (HD). Top mutant huntingtin toxicity modifier genes included several Nme genes and several genes involved in methylation-dependent chromatin silencing and dopamine signaling, results that reveal new HD therapeutic target pathways.


Asunto(s)
Supervivencia Celular/genética , Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Neostriado/metabolismo , Neuronas/metabolismo , Animales , Conducta Animal , Sistemas CRISPR-Cas , Técnicas de Silenciamiento del Gen , Biblioteca de Genes , Genes Esenciales/genética , Ratones , Ratones Transgénicos , Nucleósido Difosfato Quinasas NM23/genética , Nucleósido Difosfato Quinasa D/genética , Agregado de Proteínas , Interferencia de ARN , ARN Guía de Kinetoplastida , ARN Interferente Pequeño , Receptores de Dopamina D2/genética , Análisis de Secuencia de ARN
16.
Diabetes Metab Res Rev ; 36(1): e3204, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31322810

RESUMEN

BACKGROUND: A nested case-control (NCC) design within a prospective cohort study can realize substantial benefits for biomarker studies. In this context, it is natural to consider the sample availability in the selection of controls to minimize data loss when implementing the design. However, this violates the randomness required for selection, and it leads to biased analyses. An inverse probability weighting may improve the analysis, but the current approach using weighted Cox regression fails to maintain the benefits of NCC design. METHODS: This paper introduces weighted conditional logistic regression. We illustrate our proposed analysis using data recently investigated in The Environmental Determinants of Diabetes in the Young (TEDDY). Considering the potential data loss, the TEDDY NCC design was moderately selective in its selection of controls. A data-driven simulation study was performed to present the bias correction when a nonrandom control selection was ignored in the analysis. RESULTS: The TEDDY data analysis showed that the standard analysis using conditional logistic regression estimated the parameter: -0.015 (-0.023, -0.007). The biased estimate using Cox regression was -0.011 (95% confidence interval: -0.019, -0.003). Weighted Cox regression estimated -0.013 (-0.026, 0.0004). The proposed weighted conditional logistic regression estimated -0.020 (-0.033, -0.007), showing a stronger negative effect size than the one using conditional logistic regression. The simulation study also showed that the standard estimate of ß ignoring the nonrandom control selection tends to be greater than the true ß (ie, positive relative biases). CONCLUSION: Weighted conditional logistic regression can enhance the analysis by offering flexibility in the selection of controls, while maintaining the matching.


Asunto(s)
Diabetes Mellitus/epidemiología , Diabetes Mellitus/fisiopatología , Ambiente , Modelos Estadísticos , Determinantes Sociales de la Salud , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Simulación por Computador , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Selección de Paciente , Pronóstico , Estudios Prospectivos , Análisis de Regresión
17.
Diabetologia ; 63(2): 278-286, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31728565

RESUMEN

AIMS/HYPOTHESIS: We studied the association of plasma ascorbic acid with the risk of developing islet autoimmunity and type 1 diabetes and examined whether SNPs in vitamin C transport genes modify these associations. Furthermore, we aimed to determine whether the SNPs themselves are associated with the risk of islet autoimmunity or type 1 diabetes. METHODS: We used a risk set sampled nested case-control design within an ongoing international multicentre observational study: The Environmental Determinants of Diabetes in the Young (TEDDY). The TEDDY study followed children with increased genetic risk from birth to endpoints of islet autoantibodies (350 cases, 974 controls) and type 1 diabetes (102 cases, 282 controls) in six clinical centres. Control participants were matched for family history of type 1 diabetes, clinical centre and sex. Plasma ascorbic acid concentration was measured at ages 6 and 12 months and then annually up to age 6 years. SNPs in vitamin C transport genes were genotyped using the ImmunoChip custom microarray. Comparisons were adjusted for HLA genotypes and for background population stratification. RESULTS: Childhood plasma ascorbic acid (mean ± SD 10.76 ± 3.54 mg/l in controls) was inversely associated with islet autoimmunity risk (adjusted OR 0.96 [95% CI 0.92, 0.99] per +1 mg/l), particularly islet autoimmunity, starting with insulin autoantibodies (OR 0.94 [95% CI 0.88, 0.99]), but not with type 1 diabetes risk (OR 0.93 [95% Cl 0.86, 1.02]). The SLC2A2 rs5400 SNP was associated with increased risk of type 1 diabetes (OR 1.77 [95% CI 1.12, 2.80]), independent of plasma ascorbic acid (OR 0.92 [95% CI 0.84, 1.00]). CONCLUSIONS/INTERPRETATION: Higher plasma ascorbic acid levels may protect against islet autoimmunity in children genetically at risk for type 1 diabetes. Further studies are warranted to confirm these findings. DATA AVAILABILITY: The datasets generated and analysed during the current study will be made available in the NIDDK Central Repository at https://www.niddkrepository.org/studies/teddy.


Asunto(s)
Ácido Ascórbico/sangre , Autoinmunidad/fisiología , Diabetes Mellitus Tipo 1/sangre , Estudios de Casos y Controles , Niño , Preescolar , Diabetes Mellitus Tipo 1/genética , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Transportador de Glucosa de Tipo 2/genética , Humanos , Lactante , Masculino , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo
18.
Gut ; 69(8): 1416-1422, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-31744911

RESUMEN

OBJECTIVE: Higher gluten intake, frequent gastrointestinal infections and adenovirus, enterovirus, rotavirus and reovirus have been proposed as environmental triggers for coeliac disease. However, it is not known whether an interaction exists between the ingested gluten amount and viral exposures in the development of coeliac disease. This study investigated whether distinct viral exposures alone or together with gluten increase the risk of coeliac disease autoimmunity (CDA) in genetically predisposed children. DESIGN: The Environmental Determinants of Diabetes in the Young study prospectively followed children carrying the HLA risk haplotypes DQ2 and/or DQ8 and constructed a nested case-control design. From this design, 83 CDA case-control pairs were identified. Median age of CDA was 31 months. Stool samples collected monthly up to the age of 2 years were analysed for virome composition by Illumina next-generation sequencing followed by comprehensive computational virus profiling. RESULTS: The cumulative number of stool enteroviral exposures between 1 and 2 years of age was associated with an increased risk for CDA. In addition, there was a significant interaction between cumulative stool enteroviral exposures and gluten consumption. The risk conferred by stool enteroviruses was increased in cases reporting higher gluten intake. CONCLUSIONS: Frequent exposure to enterovirus between 1 and 2 years of age was associated with increased risk of CDA. The increased risk conferred by the interaction between enteroviruses and higher gluten intake indicate a cumulative effect of these factors in the development of CDA.


Asunto(s)
Enfermedades Autoinmunes/etiología , Enfermedad Celíaca/etiología , Enterovirus/aislamiento & purificación , Heces/virología , Glútenes/administración & dosificación , Adenoviridae/aislamiento & purificación , Autoanticuerpos/sangre , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/genética , Autoinmunidad , Estudios de Casos y Controles , Enfermedad Celíaca/sangre , Enfermedad Celíaca/genética , Preescolar , Dieta , Femenino , Proteínas de Unión al GTP/inmunología , Predisposición Genética a la Enfermedad , Antígenos HLA-DQ/genética , Humanos , Lactante , Masculino , Metagenómica , Proteína Glutamina Gamma Glutamiltransferasa 2 , Factores de Riesgo , Transglutaminasas/inmunología
19.
JAMA ; 322(6): 514-523, 2019 08 13.
Artículo en Inglés | MEDLINE | ID: mdl-31408136

RESUMEN

Importance: High gluten intake during childhood may confer risk of celiac disease. Objectives: To investigate if the amount of gluten intake is associated with celiac disease autoimmunity and celiac disease in genetically at-risk children. Design, Setting, and Participants: The participants in The Environmental Determinants of Diabetes in the Young (TEDDY), a prospective observational birth cohort study designed to identify environmental triggers of type 1 diabetes and celiac disease, were followed up at 6 clinical centers in Finland, Germany, Sweden, and the United States. Between 2004 and 2010, 8676 newborns carrying HLA antigen genotypes associated with type 1 diabetes and celiac disease were enrolled. Screening for celiac disease with tissue transglutaminase autoantibodies was performed annually in 6757 children from the age of 2 years. Data on gluten intake were available in 6605 children (98%) by September 30, 2017. Exposures: Gluten intake was estimated from 3-day food records collected at ages 6, 9, and 12 months and biannually thereafter until the age of 5 years. Main Outcomes and Measures: The primary outcome was celiac disease autoimmunity, defined as positive tissue transglutaminase autoantibodies found in 2 consecutive serum samples. The secondary outcome was celiac disease confirmed by intestinal biopsy or persistently high tissue transglutaminase autoantibody levels. Results: Of the 6605 children (49% females; median follow-up: 9.0 years [interquartile range, 8.0-10.0 years]), 1216 (18%) developed celiac disease autoimmunity and 447 (7%) developed celiac disease. The incidence for both outcomes peaked at the age of 2 to 3 years. Daily gluten intake was associated with higher risk of celiac disease autoimmunity for every 1-g/d increase in gluten consumption (hazard ratio [HR], 1.30 [95% CI, 1.22-1.38]; absolute risk by the age of 3 years if the reference amount of gluten was consumed, 28.1%; absolute risk if gluten intake was 1-g/d higher than the reference amount, 34.2%; absolute risk difference, 6.1% [95% CI, 4.5%-7.7%]). Daily gluten intake was associated with higher risk of celiac disease for every 1-g/d increase in gluten consumption (HR, 1.50 [95% CI, 1.35-1.66]; absolute risk by age of 3 years if the reference amount of gluten was consumed, 20.7%; absolute risk if gluten intake was 1-g/d higher than the reference amount, 27.9%; absolute risk difference, 7.2% [95% CI, 6.1%-8.3%]). Conclusions and Relevance: Higher gluten intake during the first 5 years of life was associated with increased risk of celiac disease autoimmunity and celiac disease among genetically predisposed children.


Asunto(s)
Autoanticuerpos/sangre , Enfermedad Celíaca/etiología , Proteínas en la Dieta/efectos adversos , Predisposición Genética a la Enfermedad , Glútenes/efectos adversos , Transglutaminasas/inmunología , Autoinmunidad , Enfermedad Celíaca/epidemiología , Enfermedad Celíaca/genética , Enfermedad Celíaca/inmunología , Preescolar , Diabetes Mellitus Tipo 1/etiología , Diabetes Mellitus Tipo 1/genética , Registros de Dieta , Femenino , Glútenes/administración & dosificación , Humanos , Incidencia , Lactante , Masculino , Estudios Prospectivos , Riesgo
20.
Eur Respir J ; 53(4)2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30846465

RESUMEN

INTRODUCTION: The Multicenter International Lymphangioleiomyomatosis (LAM) Efficacy of Sirolimus (MILES) trial revealed that sirolimus stabilised lung function in patients with moderately severe LAM. The purpose of this study was to further examine the MILES cohort for the effects of racial, demographic, clinical and physiological patient characteristics on disease progression and treatment response in LAM. METHODS: MILES subjects were stratified on the basis of menopausal status (pre-menopausal/post-menopausal), race (Asian/Caucasian), bronchodilator responsiveness (present/absent), initial forced expiratory volume in 1 s (FEV1; 51-70% versus ≤50% predicted) and tuberous sclerosis complex (TSC) association (yes/no). A linear mixed effects model was used to compare slope differences, and nonparametric tests were used to compare medians and proportions between treatment groups in each stratum. RESULTS: In the MILES placebo group, pre-menopausal patients declined 5-fold faster than post-menopausal patients (mean±se FEV1 slope -17±3 versus -3±3 mL·month-1; p=0.003). Upon treatment with sirolimus, both the pre-menopausal (-17±3 versus -1±2 mL·month-1; p<0.0001) and post-menopausal patients (-3±3 versus 6±3 mL·month-1; p=0.04) exhibited a beneficial response in mean±se FEV1 slope compared with the placebo group. Race, LAM subtype, bronchodilator responsiveness or baseline FEV1 did not impact the rate of disease progression in the placebo group or treatment response in the sirolimus group. Menopausal status and race had differential effects on the adverse event profile of sirolimus. Baseline serum vascular endothelial growth factor (VEGF)-D >600 pg·mL-1 identified subgroups of patients who were more likely to decline on placebo and respond to treatment with sirolimus. CONCLUSIONS: In LAM patients, treatment with sirolimus is beneficial regardless of menopausal status, race, bronchodilator responsiveness, baseline FEV1 or TSC association. Serum VEGF-D and menopausal status can help inform therapeutic decisions.


Asunto(s)
Antibióticos Antineoplásicos/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Linfangioleiomiomatosis/tratamiento farmacológico , Sirolimus/uso terapéutico , Adulto , Pueblo Asiatico , Broncodilatadores/uso terapéutico , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Volumen Espiratorio Forzado , Humanos , Neoplasias Pulmonares/fisiopatología , Linfangioleiomiomatosis/fisiopatología , Persona de Mediana Edad , Posmenopausia , Premenopausia , Resultado del Tratamiento , Población Blanca
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA