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1.
Cell Rep ; 42(11): 113411, 2023 11 28.
Artículo en Inglés | MEDLINE | ID: mdl-37952155

RESUMEN

Phenotypic heterogeneity in monogenic neurodevelopmental disorders can arise from differential severity of variants underlying disease, but how distinct alleles drive variable disease presentation is not well understood. Here, we investigate missense mutations in DNA methyltransferase 3A (DNMT3A), a DNA methyltransferase associated with overgrowth, intellectual disability, and autism, to uncover molecular correlates of phenotypic heterogeneity. We generate a Dnmt3aP900L/+ mouse mimicking a mutation with mild to moderate severity and compare phenotypic and epigenomic effects with a severe R878H mutation. P900L mutants exhibit core growth and behavioral phenotypes shared across models but show subtle epigenomic changes, while R878H mutants display extensive disruptions. We identify mutation-specific dysregulated genes that may contribute to variable disease severity. Shared transcriptomic disruption identified across mutations overlaps dysregulation observed in other developmental disorder models and likely drives common phenotypes. Together, our findings define central drivers of DNMT3A disorders and illustrate how variable epigenomic disruption contributes to phenotypic heterogeneity in neurodevelopmental disease.


Asunto(s)
ADN (Citosina-5-)-Metiltransferasas , ADN Metiltransferasa 3A , Animales , Ratones , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Epigénesis Genética , Epigenómica , Mutación/genética
2.
Mol Cell ; 83(9): 1412-1428.e7, 2023 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-37098340

RESUMEN

During postnatal development, the DNA methyltransferase DNMT3A deposits high levels of non-CG cytosine methylation in neurons. This methylation is critical for transcriptional regulation, and loss of this mark is implicated in DNMT3A-associated neurodevelopmental disorders (NDDs). Here, we show in mice that genome topology and gene expression converge to shape histone H3 lysine 36 dimethylation (H3K36me2) profiles, which in turn recruit DNMT3A and pattern neuronal non-CG methylation. We show that NSD1, an H3K36 methyltransferase mutated in NDD, is required for the patterning of megabase-scale H3K36me2 and non-CG methylation in neurons. We find that brain-specific deletion of NSD1 causes altered DNA methylation that overlaps with DNMT3A disorder models to drive convergent dysregulation of key neuronal genes that may underlie shared phenotypes in NSD1- and DNMT3A-associated NDDs. Our findings indicate that H3K36me2 deposited by NSD1 is important for neuronal non-CG DNA methylation and suggest that the H3K36me2-DNMT3A-non-CG-methylation pathway is likely disrupted in NSD1-associated NDDs.


Asunto(s)
Metilación de ADN , Histonas , Animales , Ratones , Histonas/genética , Histonas/metabolismo , Lisina/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Neuronas/metabolismo
3.
bioRxiv ; 2023 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-36909558

RESUMEN

Phenotypic heterogeneity is a common feature of monogenic neurodevelopmental disorders that can arise from differential severity of missense variants underlying disease, but how distinct alleles impact molecular mechanisms to drive variable disease presentation is not well understood. Here, we investigate missense mutations in the DNA methyltransferase DNMT3A associated with variable overgrowth, intellectual disability, and autism, to uncover molecular correlates of phenotypic heterogeneity in neurodevelopmental disease. We generate a DNMT3A P900L/+ mouse model mimicking a disease mutation with mild-to-moderate severity and compare phenotypic and epigenomic effects with a severe R878H mutation. We show that the P900L mutation leads to disease-relevant overgrowth, obesity, and social deficits shared across DNMT3A disorder models, while the R878H mutation causes more extensive epigenomic disruption leading to differential dysregulation of enhancers elements. We identify distinct gene sets disrupted in each mutant which may contribute to mild or severe disease, and detect shared transcriptomic disruption that likely drives common phenotypes across affected individuals. Finally, we demonstrate that core gene dysregulation detected in DNMT3A mutant mice overlaps effects in other developmental disorder models, highlighting the importance of DNMT3A-deposited methylation in neurodevelopment. Together, these findings define central drivers of DNMT3A disorders and illustrate how variable disruption of transcriptional mechanisms can drive the spectrum of phenotypes in neurodevelopmental disease.

4.
bioRxiv ; 2023 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-36824816

RESUMEN

During postnatal development the DNA methyltransferase DNMT3A deposits high levels of non-CG cytosine methylation in neurons. This unique methylation is critical for transcriptional regulation in the mature mammalian brain, and loss of this mark is implicated in DNMT3A-associated neurodevelopmental disorders (NDDs). The mechanisms determining genomic non-CG methylation profiles are not well defined however, and it is unknown if this pathway is disrupted in additional NDDs. Here we show that genome topology and gene expression converge to shape histone H3 lysine 36 dimethylation (H3K36me2) profiles, which in turn recruit DNMT3A and pattern neuronal non-CG methylation. We show that NSD1, the H3K36 methyltransferase mutated in the NDD, Sotos syndrome, is required for megabase-scale patterning of H3K36me2 and non-CG methylation in neurons. We find that brain-specific deletion of NSD1 causes alterations in DNA methylation that overlap with models of DNMT3A disorders and define convergent disruption in the expression of key neuronal genes in these models that may contribute to shared phenotypes in NSD1- and DNMT3A-associated NDD. Our findings indicate that H3K36me2 deposited by NSD1 is an important determinant of neuronal non-CG DNA methylation and implicates disruption of this methylation in Sotos syndrome. Highlights: Topology-associated DNA methylation and gene expression independently contribute to neuronal gene body and enhancer non-CG DNA methylation patterns.Topology-associated H3K36me2 patterns and local enrichment of H3K4 methylation impact deposition of non-CG methylation by DNMT3A. Disruption of NSD1 in vivo leads to alterations in H3K36me2, DNA methylation, and gene expression that overlap with models of DNMT3A disorders.

5.
Mol Cell ; 82(1): 90-105.e13, 2022 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-34942119

RESUMEN

Neurodevelopmental cognitive disorders provide insights into mechanisms of human brain development. Here, we report an intellectual disability syndrome caused by the loss of APC7, a core component of the E3 ubiquitin ligase anaphase promoting complex (APC). In mechanistic studies, we uncover a critical role for APC7 during the recruitment and ubiquitination of APC substrates. In proteomics analyses of the brain from mice harboring the patient-specific APC7 mutation, we identify the chromatin-associated protein Ki-67 as an APC7-dependent substrate of the APC in neurons. Conditional knockout of the APC coactivator protein Cdh1, but not Cdc20, leads to the accumulation of Ki-67 protein in neurons in vivo, suggesting that APC7 is required for the function of Cdh1-APC in the brain. Deregulated neuronal Ki-67 upon APC7 loss localizes predominantly to constitutive heterochromatin. Our findings define an essential function for APC7 and Cdh1-APC in neuronal heterochromatin regulation, with implications for understanding human brain development and disease.


Asunto(s)
Subunidad Apc7 del Ciclosoma-Complejo Promotor de la Anafase/metabolismo , Encéfalo/enzimología , Heterocromatina/metabolismo , Discapacidad Intelectual/enzimología , Células-Madre Neurales/enzimología , Neurogénesis , Adolescente , Animales , Antígenos CD , Subunidad Apc7 del Ciclosoma-Complejo Promotor de la Anafase/genética , Conducta Animal , Encéfalo/crecimiento & desarrollo , Cadherinas/genética , Cadherinas/metabolismo , Línea Celular , Niño , Preescolar , Modelos Animales de Enfermedad , Femenino , Heterocromatina/genética , Humanos , Lactante , Discapacidad Intelectual/patología , Discapacidad Intelectual/fisiopatología , Discapacidad Intelectual/psicología , Inteligencia , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Mitosis , Mutación , Células-Madre Neurales/patología , Proteolisis , Transducción de Señal , Síndrome , Ubiquitinación , Adulto Joven
6.
Cell Rep ; 33(8): 108416, 2020 11 24.
Artículo en Inglés | MEDLINE | ID: mdl-33238114

RESUMEN

Mutations in DNA methyltransferase 3A (DNMT3A) have been detected in autism and related disorders, but how these mutations disrupt nervous system function is unknown. Here, we define the effects of DNMT3A mutations associated with neurodevelopmental disease. We show that diverse mutations affect different aspects of protein activity but lead to shared deficiencies in neuronal DNA methylation. Heterozygous DNMT3A knockout mice mimicking DNMT3A disruption in disease display growth and behavioral alterations consistent with human phenotypes. Strikingly, in these mice, we detect global disruption of neuron-enriched non-CG DNA methylation, a binding site for the Rett syndrome protein MeCP2. Loss of this methylation leads to enhancer and gene dysregulation that overlaps with models of Rett syndrome and autism. These findings define the effects of DNMT3A haploinsufficiency in the brain and uncover disruption of the non-CG methylation pathway as a convergence point across neurodevelopmental disorders.


Asunto(s)
ADN Metiltransferasa 3A/metabolismo , Epigenómica/métodos , Trastornos del Neurodesarrollo/genética , Animales , Haploinsuficiencia , Humanos , Ratones
7.
Nat Commun ; 11(1): 3419, 2020 07 09.
Artículo en Inglés | MEDLINE | ID: mdl-32647123

RESUMEN

The development and function of the brain require tight control of gene expression. Genome architecture is thought to play a critical regulatory role in gene expression, but the mechanisms governing genome architecture in the brain in vivo remain poorly understood. Here, we report that conditional knockout of the chromatin remodeling enzyme Chd4 in granule neurons of the mouse cerebellum increases accessibility of gene regulatory sites genome-wide in vivo. Conditional knockout of Chd4 promotes recruitment of the architectural protein complex cohesin preferentially to gene enhancers in granule neurons in vivo. Importantly, in vivo profiling of genome architecture reveals that conditional knockout of Chd4 strengthens interactions among developmentally repressed contact domains as well as genomic loops in a manner that tightly correlates with increased accessibility, enhancer activity, and cohesin occupancy at these sites. Collectively, our findings define a role for chromatin remodeling in the control of genome architecture organization in the mammalian brain.


Asunto(s)
Encéfalo/metabolismo , Ensamble y Desensamble de Cromatina , ADN Helicasas/metabolismo , Genoma , Animales , Proteínas de Ciclo Celular/metabolismo , Cromatina/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Cromosomas de los Mamíferos/metabolismo , ADN Helicasas/genética , Elementos de Facilitación Genéticos/genética , Epigénesis Genética , Ratones Noqueados , Modelos Genéticos , Unión Proteica , Cohesinas
8.
Mol Cell ; 77(2): 279-293.e8, 2020 01 16.
Artículo en Inglés | MEDLINE | ID: mdl-31784360

RESUMEN

The genomes of mammalian neurons contain uniquely high levels of non-CG DNA methylation that can be bound by the Rett syndrome protein, MeCP2, to regulate gene expression. How patterns of non-CG methylation are established in neurons and the mechanism by which this methylation works with MeCP2 to control gene expression is unclear. Here, we find that genes repressed by MeCP2 are often located within megabase-scale regions of high non-CG methylation that correspond with topologically associating domains of chromatin folding. MeCP2 represses enhancers found in these domains that are enriched for non-CG and CG methylation, with the strongest repression occurring for enhancers located within MeCP2-repressed genes. These alterations in enhancer activity provide a mechanism for how MeCP2 disruption in disease can lead to widespread changes in gene expression. Hence, we find that DNA topology can shape non-CG DNA methylation across the genome to dictate MeCP2-mediated enhancer regulation in the brain.


Asunto(s)
Cromosomas/genética , Metilación de ADN/genética , Elementos de Facilitación Genéticos/genética , Proteína 2 de Unión a Metil-CpG/genética , Proteínas Represoras/genética , Animales , Encéfalo/fisiología , Femenino , Regulación de la Expresión Génica/genética , Genoma/genética , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratas
9.
Nucleic Acids Res ; 47(5): e28, 2019 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-30649543

RESUMEN

Since the discovery of 5-hydroxymethylcytosine (5hmC) as a prominent DNA modification found in mammalian genomes, an emergent question has been what role this mark plays in gene regulation. 5hmC is hypothesized to function as an intermediate in the demethylation of 5-methylcytosine (5mC) and in the reactivation of silenced promoters and enhancers. Further, weak positive correlations are observed between gene body 5hmC and gene expression. We previously demonstrated that ME-Class is an effective tool to understand relationships between whole-genome bisulfite sequencing data and expression. In this work, we present ME-Class2, a machine-learning based tool to perform integrative 5mCG, 5hmCG and expression analysis. Using ME-Class2 we analyze whole-genome single-base resolution 5mCG and 5hmCG datasets from 20 primary tissue and cell samples to reveal relationships between 5hmCG and expression. Our analysis indicates that conversion of 5mCG to 5hmCG within 2 kb of the transcription start site associates with distinct functions depending on the summed level of 5mCG + 5hmCG. Unchanged levels of 5mCG + 5hmCG (conversion from 5mCG to stable 5hmCG) associate with repression. Meanwhile, decreases in 5mCG + 5hmCG (5hmCG-mediated demethylation) associate with gene activation. Our results demonstrate that ME-Class2 will prove invaluable to interpret genome-wide 5mC and 5hmC datasets and guide mechanistic studies into the function of 5hmCG.


Asunto(s)
5-Metilcitosina/análogos & derivados , Aprendizaje Automático , Análisis de Secuencia de ARN/métodos , 5-Metilcitosina/metabolismo , Animales , Encéfalo/metabolismo , Bases de Datos Genéticas , Conjuntos de Datos como Asunto , Genes/genética , Genoma/genética , Humanos , Metilación , Ratones , Especificidad de Órganos/genética , Regiones Promotoras Genéticas/genética , Sulfitos/química , Sulfitos/metabolismo
10.
J Neurosci ; 39(1): 44-62, 2019 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-30425119

RESUMEN

Control of neuronal precursor cell proliferation is essential for normal brain development, and deregulation of this fundamental developmental event contributes to brain diseases. Typically, neuronal precursor cell proliferation extends over long periods of time during brain development. However, how neuronal precursor proliferation is regulated in a temporally specific manner remains to be elucidated. Here, we report that conditional KO of the transcriptional regulator SnoN in cerebellar granule neuron precursors robustly inhibits the proliferation of these cells and promotes their cell cycle exit at later stages of cerebellar development in the postnatal male and female mouse brain. In laser capture microdissection followed by RNA-Seq, designed to profile gene expression specifically in the external granule layer of the cerebellum, we find that SnoN promotes the expression of cell proliferation genes and concomitantly represses differentiation genes in granule neuron precursors in vivo Remarkably, bioinformatics analyses reveal that SnoN-regulated genes contain binding sites for the transcription factors N-myc and Pax6, which promote the proliferation and differentiation of granule neuron precursors, respectively. Accordingly, we uncover novel physical interactions of SnoN with N-myc and Pax6 in cells. In behavior analyses, conditional KO of SnoN impairs cerebellar-dependent learning in a delayed eye-blink conditioning paradigm, suggesting that SnoN-regulation of granule neuron precursor proliferation bears functional consequences at the organismal level. Our findings define a novel function and mechanism for the major transcriptional regulator SnoN in the control of granule neuron precursor proliferation in the mammalian brain.SIGNIFICANCE STATEMENT This study reports the discovery that the transcriptional regulator SnoN plays a crucial role in the proliferation of cerebellar granule neuron precursors in the postnatal mouse brain. Conditional KO of SnoN in granule neuron precursors robustly inhibits the proliferation of these cells and promotes their cycle exit specifically at later stages of cerebellar development, with biological consequences of impaired cerebellar-dependent learning. Genomics and bioinformatics analyses reveal that SnoN promotes the expression of cell proliferation genes and concomitantly represses cell differentiation genes in vivo Although SnoN has been implicated in distinct aspects of the development of postmitotic neurons, this study identifies a novel function for SnoN in neuronal precursors in the mammalian brain.


Asunto(s)
Encéfalo/citología , Proliferación Celular , Cerebelo/fisiología , Células-Madre Neurales/fisiología , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/fisiología , Animales , Conducta Animal , Parpadeo/fisiología , Encéfalo/crecimiento & desarrollo , Diferenciación Celular/genética , Cerebelo/citología , Biología Computacional , Gránulos Citoplasmáticos/fisiología , Femenino , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/fisiología , Genes myc/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor de Transcripción PAX6/genética , Factor de Transcripción PAX6/fisiología
11.
Proc Natl Acad Sci U S A ; 113(52): 15114-15119, 2016 12 27.
Artículo en Inglés | MEDLINE | ID: mdl-27965390

RESUMEN

Rett syndrome is a severe neurodevelopmental disorder caused by mutations in the methyl-CpG binding protein gene (MECP2). MeCP2 is a methyl-cytosine binding protein that is proposed to function as a transcriptional repressor. However, multiple gene expression studies comparing wild-type and MeCP2-deficient neurons have failed to identify gene expression changes consistent with loss of a classical transcriptional repressor. Recent work suggests that one function of MeCP2 in neurons is to temper the expression of the longest genes in the genome by binding to methylated CA dinucleotides (mCA) within transcribed regions of these genes. Here we explore the mechanism of mCA and MeCP2 in fine tuning the expression of long genes. We find that mCA is not only highly enriched within the body of genes normally repressed by MeCP2, but also enriched within extended megabase-scale regions surrounding MeCP2-repressed genes. Whereas enrichment of mCA exists in a broad region around these genes, mCA together with mCG within gene bodies appears to be the primary driver of gene repression by MeCP2. Disruption of methylation at CA sites within the brain results in depletion of MeCP2 across genes that normally contain a high density of gene-body mCA. We further find that the degree of gene repression by MeCP2 is proportional to the total number of methylated cytosine MeCP2 binding sites across the body of a gene. These findings suggest a model in which MeCP2 tunes gene expression in neurons by binding within the transcribed regions of genes to impede the elongation of RNA polymerase.


Asunto(s)
Metilación de ADN , Regulación de la Expresión Génica , Proteína 2 de Unión a Metil-CpG/genética , Proteínas Represoras/genética , Síndrome de Rett/genética , Animales , Sitios de Unión , Encéfalo/metabolismo , Islas de CpG , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Proteína 2 de Unión a Metil-CpG/metabolismo , Ratones , Ratones Noqueados , Mutación , Neuronas/metabolismo , Unión Proteica , Proteínas Represoras/metabolismo , Transcripción Genética
12.
Am J Clin Nutr ; 83(2): 202-10, 2006 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-16469976

RESUMEN

BACKGROUND: In maintenance hemodialysis (MHD) patients, a larger body size is associated with better survival but a worse self-reported quality of life (QoL). It is not clear whether muscle mass or body fat confers the survival advantage. OBJECTIVE: We hypothesized that both a low baseline body fat percentage and a loss of fat over time were independently associated with higher mortality but with a better QoL score. DESIGN: In 535 adult MHD patients, body fat was measured directly with the use of near infrared interactance and QoL was measured with a Short Form 36 questionnaire. The patients were followed for < or =30 mo. RESULTS: Across four 12% increments of body fat at baseline, the reported QoL scores were progressively lower (P < 0.01). After a multivariate adjustment for demographics and surrogates of muscle mass and inflammation (ie, midarm muscle circumference, serum creatinine, and proinflammatory cytokines), 46 patients with body fat of <12% had a death hazard ratio (HR) 4 times that of 199 patients with body fat content between 24% and 36% (HR: 4.01; 95% CI: 1.61, 9.99; P = 0.003). In 411 MHD patients whose body fat was remeasured after 6 mo, a fat loss (< or =-1%) was associated with a death risk 2 times that of patients who gained fat (> or =1%) after a multivariate adjustment (HR: 2.06; 95% CI: 1.05, 4.05; P = 0.04). CONCLUSIONS: A low baseline body fat percentage and fat loss over time are independently associated with higher mortality in MHD patients even after adjustment for demographics and surrogates of muscle mass and inflammation, whereas a tendency toward a worse QoL is reported by MHD patients with a higher body fat percentage. Obesity management in dialysis patients may need reconsideration.


Asunto(s)
Tejido Adiposo/fisiología , Composición Corporal/fisiología , Calidad de Vida , Diálisis Renal/mortalidad , Tejido Adiposo/metabolismo , Adulto , Antropometría , Constitución Corporal/fisiología , Femenino , Predicción , Hospitalización , Humanos , Inflamación , Masculino , Persona de Mediana Edad , Análisis Multivariante , Espectroscopía Infrarroja Corta/métodos , Encuestas y Cuestionarios , Pérdida de Peso
13.
Clin J Am Soc Nephrol ; 1(1): 70-8, 2006 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17699193

RESUMEN

The optimal acid-base status for survival in maintenance hemodialysis (MHD) patients remains controversial. According to recent reports, acidosis is associated with improved survival in MHD patients. It was hypothesized that this inverse association is due to a confounding effect of the malnutrition-inflammation complex syndrome (MICS). Associations between baseline (first 3 mo averaged) predialysis serum bicarbonate (HCO3(-)) and 2-yr mortality were examined in 56,385 MHD patients who were treated in virtually all DaVita dialysis clinics across the United States. The range of HCO3(-) was divided into 12 categories (< 17, > or = 27, and 10 groups in between). Three sets of Cox regression models were evaluated to estimate hazard ratios of all-cause and cardiovascular death in both incident and prevalent patients: (1) Unadjusted, (2) multivariate case mix adjusted (which also included dialysate HCO3(-) and Kt/V), and (3) adjusted for case mix and nine markers of MICS (body mass index; erythropoietin dose; protein intake; serum albumin; creatinine; phosphorus; calcium; ferritin and total iron binding capacity; and blood hemoglobin, WBC, and lymphocytes). There were significant inverse associations between serum HCO3(-) and serum phosphorus and estimated protein intake. The lowest unadjusted mortality was associated with predialysis HCO3(-) in the 17- to 23-mEq/L range, whereas values > or = 23 mEq/L were associated with progressively higher all-cause and cardiovascular death rates. This association, however, reversed after case-mix and MICS multivariate adjustment, so that HCO3(-) values >22 mEq/L had lower death risk. Although previous epidemiologic studies indicated an association between high serum HCO3(-) and increased mortality in MHD patients, this effect seems to be due substantially to the effect of MICS on survival.


Asunto(s)
Equilibrio Ácido-Base , Bicarbonatos/sangre , Diálisis Renal/mortalidad , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad
14.
Blood Purif ; 23(1): 57-63, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-15627738

RESUMEN

In maintenance hemodialysis (MHD) patients, associations between demographic, clinical and laboratory values and mortality, including cardiovascular death, are significantly different and, in some cases, in the opposite direction of those derived from the general population. This phenomenon, termed 'reverse epidemiology', is not limited to MHD patients but is also observed in populations that encompass an estimated 20 million Americans including those with an advanced age, heart failure, malignancies, and AIDS. A significant portion of this reversal may be due to the overwhelming effect of the malnutrition-inflammation complex syndrome (MICS). Since two thirds of MHD patients die within 5 years of initiation of dialysis treatment, traditional cardiovascular risk factors such as obesity, hypercholesterolemia and hypertension cannot exert a long-term deleterious impact, and instead, their short-term beneficial effects on MICS provides a survival advantage. In order to improve survival and quality of life in MHD patients, extrapolated ideal norms derived from the general population should be substituted with novel norms obtained from outcome-oriented epidemiologic analyses while accounting for the differential effect of MICS in different case-mix subgroups.


Asunto(s)
Fallo Renal Crónico/epidemiología , Diálisis Renal , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/mortalidad , Humanos , Inflamación/epidemiología , Fallo Renal Crónico/mortalidad , Fallo Renal Crónico/terapia , Desnutrición Proteico-Calórica/epidemiología , Diálisis Renal/efectos adversos , Análisis de Supervivencia , Síndrome , Estados Unidos/epidemiología
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