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1.
Nat Commun ; 10(1): 3902, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467281

RESUMO

Systemic lupus erythematous (SLE) is a heterogeneous autoimmune disease in which outcomes vary among different racial groups. Here, we aim to identify SLE subgroups within a multiethnic cohort using an unsupervised clustering approach based on the American College of Rheumatology (ACR) classification criteria. We identify three patient clusters that vary according to disease severity. Methylation association analysis identifies a set of 256 differentially methylated CpGs across clusters, including 101 CpGs in genes in the Type I Interferon pathway, and we validate these associations in an external cohort. A cis-methylation quantitative trait loci analysis identifies 744 significant CpG-SNP pairs. The methylation signature is enriched for ethnic-associated CpGs suggesting that genetic and non-genetic factors may drive outcomes and ethnic-associated methylation differences. Our computational approach highlights molecular differences associated with clusters rather than single outcome measures. This work demonstrates the utility of applying integrative methods to address clinical heterogeneity in multifactorial multi-ethnic disease settings.


Assuntos
Biologia Computacional , Grupos Étnicos/genética , Genômica , Lúpus Eritematoso Sistêmico/genética , Família Multigênica , Estudos de Coortes , Metilação de DNA , Epigenômica , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Locos de Características Quantitativas , Índice de Gravidade de Doença , Estados Unidos
2.
J Hosp Med ; 14(4): 246-250, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30933677
3.
Lupus Sci Med ; 5(1): e000285, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30094041

RESUMO

SLE is a complex autoimmune disease that results from the interplay of genetics, epigenetics and environmental exposures. DNA methylation is an epigenetic mechanism that regulates gene expression and tissue differentiation. Among all the epigenetic modifications, DNA methylation perturbations have been the most widely studied in SLE. It mediates processes relevant to SLE, including lymphocyte development, X-chromosome inactivation and the suppression of endogenous retroviruses. The establishment of most DNA methylation marks occurs in utero; however, a small percentage of epigenetic marks are dynamic and can change throughout a person's lifetime and in relation to exposures. In this review, we discuss the current understanding of the biology of DNA methylation and its regulators, the measurement and interpretation of methylation marks, the effects of genetics on DNA methylation and the role of environmental exposures with relevance to SLE. We also summarise research findings associated with SLE disease risk and heterogeneity. The robust finding of hypomethylation of interferon-responsive genes in patients with SLE and new associations beyond interferon-responsive genes such as cell-specific methylation abnormalities are described. We also discuss methylation changes associated with lupus nephritis, autoantibody status and disease activity. Lastly, we explore future research directions, emphasising the need for longitudinal studies, cell tissue and context-specific profiling, as well as integrative approaches. With new technologies, DNA methylation perturbations could be targeted and edited, offering novel therapeutic approaches.

4.
ERJ Open Res ; 4(2)2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29977900

RESUMO

The COPA syndrome is a monogenic, autoimmune lung and joint disorder first identified in 2015. This study sought to define the main pulmonary features of the COPA syndrome in an international cohort of patients, analyse patient responses to treatment and highlight when genetic testing should be considered. We established a cohort of subjects (N=14) with COPA syndrome seen at multiple centres including the University of California, San Francisco, CA, USA. All subjects had one of the previously established mutations in the COPA gene, and had clinically apparent lung disease and arthritis. We analysed cohort characteristics using descriptive statistics. All subjects manifested symptoms before the age of 12 years, had a family history of disease, and developed diffuse parenchymal lung disease and arthritis. 50% had diffuse alveolar haemorrhage. The most common pulmonary findings included cysts on chest computed tomography and evidence of follicular bronchiolitis on lung biopsy. All subjects were positive for anti-neutrophil cytoplasmic antibody, anti-nuclear antibody or both and 71% of subjects had rheumatoid factor positivity. All subjects received immunosuppressive therapy. COPA syndrome is an autoimmune disorder defined by diffuse parenchymal lung disease and arthritis. We analysed an international cohort of subjects with genetically confirmed COPA syndrome and found that common pulmonary features included cysts, follicular bronchiolitis and diffuse alveolar haemorrhage. Common extrapulmonary features included early age of onset, family history of disease, autoantibody positivity and arthritis. Longitudinal data demonstrated improvement on chest radiology but an overall decline in pulmonary function despite chronic treatment.

5.
PLoS One ; 13(6): e0199003, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29953444

RESUMO

OBJECTIVE: African Americans, East Asians, and Hispanics with systemic lupus erythematous (SLE) are more likely to develop lupus nephritis (LN) than are SLE patients of European descent. The etiology of this difference is not clear, and this study was undertaken to investigate how genetic variants might explain this effect. METHODS: In this cross-sectional study, 1244 SLE patients from multiethnic case collections were genotyped for 817,810 single-nucleotide polymorphisms (SNPs) across the genome. Continental genetic ancestry was estimated utilizing the program ADMIXTURE. Gene-based testing and pathway analysis was performed within each ethnic group and meta-analyzed across ethnicities. We also performed candidate SNP association tests with SNPs previously established as risk alleles for SLE, LN, and chronic kidney disease (CKD). Association testing and logistic regression models were performed with LN as the outcome, adjusted for continental ancestries, sex, disease duration, and age. RESULTS: We studied 255 North European, 263 South European, 238 Hispanic, 224 African American and 264 East Asian SLE patients, of whom 606 had LN (48.7%). In genome-wide gene-based and candidate SNP analyses, we found distinct genes, pathways and established risk SNPs associated with LN for each ethnic group. Gene-based analyses showed significant associations between variation in ZNF546 (p = 1.0E-06), TRIM15 (p = 1.0E-06), and TRIMI0 (p = 1.0E-06) and LN among South Europeans, and TTC34 (p = 8.0E-06) was significantly associated with LN among Hispanics. The SNP rs8091180 in NFATC1 was associated with LN (OR 1.43, p = 3.3E-04) in the candidate SNP meta-analysis with the highest OR among African-Americans (OR 2.17, p = 0.0035). CONCLUSION: Distinct genetic factors are associated with the risk of LN in SLE patients of different ethnicities. CKD risk alleles may play a role in the development of LN in addition to SLE-associated risk variants. These findings may further explain the clinical heterogeneity of LN risk and response to therapy observed between different ethnic groups.


Assuntos
Nefrite Lúpica/etnologia , Nefrite Lúpica/genética , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Adulto , Estudos de Coortes , Feminino , Humanos , Nefrite Lúpica/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco
6.
J Child Adolesc Psychopharmacol ; 28(6): 395-401, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29741922

RESUMO

OBJECTIVE: Parasomnias are common in childhood but there is no established treatment for parasomnias. The aim of this study was to (1) report on the outcome of using L-tryptophan to manage parasomnias in children and (2) examine sleep architecture and subjective psychological/sleep symptoms in children with parasomnia. METHOD: A retrospective analysis was conducted of charts of children (3-18 years old) who underwent polysomnographic testing and were diagnosed with primary parasomnia. Study patients were either prescribed L-tryptophan (daily dose range: 500-4500 mg, mean dose of 2400 mg) to manage their parasomnias or administered no treatment whereby parents/guardians declined treatment. Questionnaires assessing sleep and psychosocial symptoms were administered at the initial clinical consultation and a follow-up parasomnia outcome questionnaire was administered over the phone to parents/guardians. RESULTS: One hundred and sixty-five children (106 boys, 59 girls) received a sleep diagnosis of primary parasomnia. A significantly (p < 0.001) higher proportion (84%) of children taking L-tryptophan experienced improvements in their parasomnia symptoms compared with those (47%) who chose not to use L-tryptophan. Polysomnography revealed that children with parasomnias had an altered sleep architecture based on age-related normative values. Children with a diagnosis of parasomnia were also subjectively more fatigued and endorsed more depressive symptoms. CONCLUSIONS: This study finds that parasomnias in children are not benign and that treatment with L-tryptophan provides a favorable outcome. Children diagnosed with parasomnia had altered sleep architecture, were more fatigued, and endorsed depressive symptoms. This study supports the need to diagnose and treat parasomnias in children.


Assuntos
Parassonias/tratamento farmacológico , Fases do Sono/fisiologia , Sono/fisiologia , Triptofano/administração & dosagem , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Polissonografia , Estudos Retrospectivos , Inquéritos e Questionários
7.
Can J Ophthalmol ; 53(1): 76-80, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29426446

RESUMO

OBJECTIVE: To compare the percentage of patients at risk for obstructive sleep apnea (OSA) in open-angle glaucoma (OAG) versus controls using the STOP-Bang questionnaire. METHODS: This study used a cross-sectional survey. Patients with OAG and controls completed the STOP-Bang questionnaire-a validated tool to identify patients at high risk for OSA. Patients were considered at risk if they scored 3 or more points or at high risk for moderate/severe OSA if they scored 5 or more out of the maximum 8 points. Demographic information, medical history, and previous diagnosis of OSA were recorded. Details regarding the patients' glaucoma were obtained from their medical records. RESULTS: A total of 437 patients with OAG and 441 controls were included. The mean STOP-Bang score was 3.01 ± 1.3 for the glaucoma group and 3.03 ± 1.4 for the control group (p = 0.92). There was no significant difference between the percentage of subjects considered at risk for OSA (62.7% OAG vs 59.4% controls, p = 0.37) or at high risk for moderate/severe OSA (12.6% OAG vs 16.5% controls, p = 0.1). Significantly more patients in the control group had a previous diagnosis of OSA (p = 0.01). More patients with OAG reported feeling tired compared with controls (p = 0.003). A risk/high risk for OSA was not associated with glaucoma severity, progression, intraocular pressure control, or glaucoma type. CONCLUSIONS: Our results indicate that a risk or high risk for moderate/severe OSA as measured by the STOP-Bang questionnaire is not correlated with the presence or absence of glaucoma (regardless of the type), glaucoma severity, glaucoma progression, or IOP control.


Assuntos
Glaucoma de Ângulo Aberto/complicações , Programas de Rastreamento/métodos , Apneia Obstrutiva do Sono/epidemiologia , Inquéritos e Questionários , Idoso , Estudos Transversais , Feminino , Glaucoma de Ângulo Aberto/fisiopatologia , Humanos , Incidência , Masculino , Ontário/epidemiologia , Polissonografia , Fatores de Risco , Apneia Obstrutiva do Sono/etiologia
8.
J Sleep Res ; 27(4): e12610, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-28944605

RESUMO

Untreated obstructive sleep apnea in children is associated with significant medical and psychological morbidities. Polysomnographic testing is the gold-standard method for diagnosis of obstructive sleep apnea. However, laboratory-based polysomnography is expensive and associated with a substantial healthcare burden. Thus, a simple valid tool to accurately identify those at high risk of obstructive sleep apnea is essential. We performed a retrospective cross-sectional study of children referred to the Youthdale Child and Adolescent Sleep Clinic. Data were collected from questionnaires and sleep studies reports of 395 children. A comparison between two screening tools for paediatric obstructive sleep apnea - a six-item (parent-response) and an eight-item IF-SLEEPY/IM-SLEEPY scales - was performed. The results showed that 42% of the children (n = 164) were diagnosed with obstructive sleep apnea. The six-item scale (score ≥3) exhibited a sensitivity of 17% and a specificity of 95% for diagnosing obstructive sleep apnea. The eight-item IF-SLEEPY scale displayed 82% sensitivity and 28% specificity. The IM-SLEEPY scale exhibited 79% sensitivity and 32% specificity. In children ≥7 years old, the IF-SLEEPY (parent-response) had a sensitivity of 82% and specificity of 28% compared with the child-response (66% and 37%, respectively). Logistic regression analysis revealed that age (odds ratio = 0.78), IF-SLEEPY/IM-SLEEPY score ≥3 (odds ratio = 1.78) and a score ≥2.72 on the six-item scale (odds ratio = 4.54) were predictors of obstructive sleep apnea. This study suggests that the eight-item scale is a better screening tool for paediatric obstructive sleep apnea, with a higher sensitivity and simple yes/no responses that are easy to complete and to score.


Assuntos
Programas de Rastreamento/normas , Pais , Apneia Obstrutiva do Sono/diagnóstico , Inquéritos e Questionários/normas , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Masculino , Programas de Rastreamento/métodos , Pais/psicologia , Polissonografia/métodos , Estudos Retrospectivos , Sono/fisiologia , Apneia Obstrutiva do Sono/fisiopatologia , Apneia Obstrutiva do Sono/psicologia , Vigília/fisiologia
9.
Rheum Dis Clin North Am ; 43(4): 503-518, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29061238

RESUMO

Primary angiitis of the central nervous system (PACNS) is rare but often included in the differential diagnosis for unusual or unexplained neurologic symptoms owing to its array of clinical manifestations. PACNS is not a single entity, but rather an umbrella term for distinct subtypes of disease affecting different parts of the CNS, different sized vessels, and with different histologic and pathologic findings. Although brain biopsy is considered the gold standard test, it is neither highly sensitive nor specific. One must always pursue a workup for mimics of PACNS. Treatment consists of prednisone monotherapy or combination therapy with prednisone and cyclophosphamide.


Assuntos
Vasculite do Sistema Nervoso Central/diagnóstico , Vasculite do Sistema Nervoso Central/terapia , Anti-Inflamatórios/uso terapêutico , Antirreumáticos/uso terapêutico , Humanos , Imagem por Ressonância Magnética , Vasculite do Sistema Nervoso Central/complicações
10.
Curr Opin Rheumatol ; 28(4): 346-51, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27224741

RESUMO

PURPOSE OF REVIEW: We review select studies of newly discovered rare variants in autoimmune diseases with a focus on newly described monogenic disorders, rheumatoid arthritis, and systemic lupus erythematosus. RECENT FINDINGS: Two new monogenic syndromes of inflammatory arthritis were discovered using whole exome sequencing: the coatomer subunit alpha syndrome because of rare mutations in coatomer subunit alpha and haploinsufficiency of A20 resulting from rare mutations in TNFAIP3. Targeted exon sequencing identified rare variants in IL2RA and IL2RB associated with rheumatoid arthritis. Rare variants in TREX1 and other genes associated with monogenic interferonopathies are also associated with systemic lupus erythematosus. SUMMARY: Rare genetic variants contribute to the heritability of autoimmunity and provide key insight into both novel and previously implicated immunological pathways that are disrupted in autoimmune diseases.


Assuntos
Artrite Reumatoide/genética , Doenças Autoimunes/genética , Lúpus Eritematoso Sistêmico/genética , Artrite Reumatoide/imunologia , Doenças Autoimunes/imunologia , Autoimunidade/genética , Exodesoxirribonucleases/genética , Predisposição Genética para Doença , Variação Genética/imunologia , Humanos , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade beta de Receptor de Interleucina-2/genética , Lúpus Eritematoso Sistêmico/imunologia , Fosfoproteínas/genética
11.
Nat Sci Sleep ; 8: 41-5, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26855603

RESUMO

OBJECTIVE: The Toronto Hospital Alertness Test (THAT) scale was designed to measure alertness, defined as the capacity of the mind to respond appropriately to external and internal stimuli. The present study's aim is to determine normative values of alertness on the THAT and to explore the relationship among excessive daytime sleepiness, fatigue, depressive symptoms, and alertness. METHODS: Normative data were collected from 60 healthy males and females. To explore the relationship among alertness, daytime sleepiness, fatigue, depression, and anxiety, data were collected from charts of sleep clinic patients. All study subjects completed measures for fatigue, sleepiness, depressive symptoms, and anxiety. RESULTS: The average score on the THAT was 34.9±7.2 (range 22-50) for the control group. The cutoff score for the THAT, indicative of clinically significant reduced alertness, was determined to be ≤20.5 (mean -2 SD). THAT alertness scores were found to be modestly, significantly, and negatively correlated with fatigue levels (r=-0.39, P<0.001), depressive symptoms (r=-0.53, P<0.001), and anxiety symptoms (r=-0.41, P<0.001). No correlations were found between alertness levels and daytime sleepiness. Regression analyses revealed a significant model (F=19.9, P<0.001, adjusted R (2)=0.35) with depressive symptoms (P<0.001) and fatigue (P=0.006) emerging as the only significant predictors of scores on the THAT. CONCLUSION: The findings of this study support that sleepiness is not the same as poor alertness. Depressive symptoms and fatigue, but not sleepiness, were found to have a strong and significant impact on levels of alertness. This is the first study to link poor alertness to depressive symptoms.

12.
Lupus Sci Med ; 3(1): e000183, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28074145

RESUMO

OBJECTIVE: Previous studies have shown that differential DNA methylation is associated with SLE susceptibility. How DNA methylation affects the clinical heterogeneity of SLE has not been fully defined. We conducted this study to identify differentially methylated CpG sites associated with nephritis among women with SLE. METHODS: The methylation status of 428 229 CpG sites across the genome was characterised for peripheral blood cells from 322 women of European descent with SLE, 80 of whom had lupus nephritis, using the Illumina HumanMethylation450 BeadChip. Multivariable linear regression adjusting for population substructure and leucocyte cell proportions was used to identify differentially methylated sites associated with lupus nephritis. The influence of genetic variation on methylation status was investigated using data from a genome-wide association study of SLE. Pathway analyses were used to identify biological processes associated with lupus nephritis. RESULTS: We identified differential methylation of 19 sites in 18 genomic regions that was associated with nephritis among patients with SLE (false discovery rate q<0.05). Associations for four sites in HIF3A, IFI44 and PRR4 were replicated when examining methylation data derived from CD4+ T cells collected from an independent set of patients with SLE. These associations were not driven by genetic variation within or around the genomic regions. In addition, genes associated with lupus nephritis in a prior genome-wide association study were not differentially methylated in this epigenome-wide study. Pathway analysis indicated that biological processes involving type 1 interferon responses and the development of the immune system were associated with nephritis in patients with SLE. CONCLUSIONS: Differential methylation of genes regulating the response to tissue hypoxia and interferon-mediated signalling is associated with lupus nephritis among women with SLE. These findings have not been identified in genetic studies of lupus nephritis, suggesting that epigenome-wide association studies can help identify the genomic differences that underlie the clinical heterogeneity of SLE.

13.
Case Rep Neurol Med ; 2015: 278287, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26613054

RESUMO

Prader-Willi syndrome (PWS) is a genetic disorder characterized by short stature, mental retardation, hypotonia, functionally deficient gonads, and uncontrolled appetite leading to extreme obesity at an early age. Patients with this condition require multidisciplinary medical care, which facilitates a significant improvement in quality of life. PWS is the first human disorder to be attributed to genomic imprinting. Prevalence varies in the literature, ranging from 1 in 8,000 in the Swedish population to 1 in 54,000 in the United Kingdom. Rarely, the genetic mechanism responsible for Prader-Willi syndrome can be inherited. We report a highly unique case of three siblings who share this condition. This report describes a case of two brothers and one half sister with PWS. All three siblings have sleep-related complaints. The sister died at the age of 24 years in her sleep, with the cause of death reported as obstructive sleep apnea. The outcome was positive in both of the brothers' cases as a result of professional medical care and specific tailored recommendations implemented by their mother. A review of the relevant literature vis-à-vis sleep and PWS is provided.

14.
PLoS One ; 10(7): e0129813, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26192630

RESUMO

Systemic lupus erythematosus (SLE) is characterized by the development of autoantibodies associated with specific clinical manifestations. Previous studies have shown an association between differential DNA methylation and SLE susceptibility, but have not investigated SLE-related autoantibodies. Our goal was to determine whether DNA methylation is associated with production of clinically relevant SLE-related autoantibodies, with an emphasis on the anti-dsDNA autoantibody. In this study, we characterized the methylation status of 467,314 CpG sites in 326 women with SLE. Using a discovery and replication study design, we identified and replicated significant associations between anti-dsDNA autoantibody production and the methylation status of 16 CpG sites (pdiscovery<1.07E-07 and preplication<0.0029) in 11 genes. Associations were further investigated using multivariable regression to adjust for estimated leukocyte cell proportions and population substructure. The adjusted mean DNA methylation difference between anti-dsDNA positive and negative cases ranged from 1.2% to 19%, and the adjusted odds ratio for anti-dsDNA autoantibody production comparing the lowest and highest methylation tertiles ranged from 6.8 to 18.2. Differential methylation for these CpG sites was also associated with anti-SSA, anti-Sm, and anti-RNP autoantibody production. Overall, associated CpG sites were hypomethylated in autoantibody positive compared to autoantibody negative cases. Differential methylation of CpG sites within the major histocompatibility region was not strongly associated with autoantibody production. Genes with differentially methylated CpG sites represent multiple biologic pathways, and have not been associated with autoantibody production in genetic association studies. In conclusion, hypomethylation of CpG sites within genes from different pathways is associated with anti-dsDNA, anti-SSA, anti-Sm, and anti-RNP production in SLE, and these associations are not explained by genetic variation. Thus, studies of epigenetic mechanisms such as DNA methylation represent a complementary method to genetic association studies to identify biologic pathways that may contribute to the clinical heterogeneity of autoimmune diseases.


Assuntos
Autoanticorpos/biossíntese , Metilação de DNA , Genômica , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Autoanticorpos/sangue , Epigênese Genética , Feminino , Humanos , Lúpus Eritematoso Sistêmico/sangue , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
15.
Sleep Breath ; 19(4): 1285-92, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25813356

RESUMO

PURPOSE: Opioid treatment of non-malignant chronic pain can result in hypoxemia, hypercarbia, and central sleep apnea. The aim of this study was to determine the initial efficacy of auto servo-ventilation (ASV) and after 3 months of home use. METHODS: This prospective multicenter interventional study recruited chronic pain patients prescribed ≥100 morphine equivalents for at least 4 months. PARTICIPANTS: Following full-night polysomnography (PSG) to confirm the presence of sleep-disordered breathing, patients were randomized to three additional full-night-attended PSGs with continuous positive airway pressure (CPAP), ASV, and servo-ventilation with an initial mandatory pressure support of 6 cm H2O (ASV manual PSmin 6). Following the PSGs, patients were sent home with EncoreAnywhere and ASV with or without mandatory pressure support. RESULTS: Based on the initial PSG studies, CPAP improved but did not normalize the apnea-hypopnea index (AHI), central apnea index (CAI), or hypopnea index (HI), as all remained elevated. Clinically significant reductions were noted after just one night of ASV and ASV manual (PSmin 6). After 3 months of ASV home use, the AHI, CAI, and obstructive apnea index (OAI) were significantly reduced when compared to baseline diagnostic levels and even when compared to respiratory disturbance indices with CPAP treatment. CONCLUSIONS: Initial and home use of ASV for 3 months resulted in significantly lower AHI, CAI, and OAI. This reduction attests to the efficacy of ASV treatment in chronic pain patients on high doses of opioids.


Assuntos
Analgésicos Opioides/efeitos adversos , Dor Crônica/tratamento farmacológico , Serviços Hospitalares de Assistência Domiciliar , Respiração com Pressão Positiva/métodos , Apneia do Sono Tipo Central/induzido quimicamente , Apneia do Sono Tipo Central/terapia , Adulto , Idoso , Analgésicos Opioides/uso terapêutico , Dor Crônica/diagnóstico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Polissonografia/efeitos dos fármacos , Respiração com Pressão Positiva/instrumentação , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
16.
Int J Pediatr Otorhinolaryngol ; 78(12): 2116-20, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25305064

RESUMO

BACKGROUND: Pediatric obstructive sleep apnea (OSA) is a prevalent but under-diagnosed disease. The importance of screening for OSA has been emphasized in the recently published guidelines for the diagnosis and management of childhood OSA. Several pediatric OSA questionnaires are available, but are complicated to use or not sensitive enough for screening. METHODS: In this study we developed an 8-item (IF SLEEPY) screening tool for pediatric OSA. One hundred and fifty children referred for evaluation at a pediatric sleep clinic and their parents completed the questionnaire and had a polysomnography. Two further questionnaires were developed: I SLEEPY and I'M SLEEPY versions. The questionnaires' scores were compared to the apnea hypopnea index (AHI) and the validity of each questionnaire was evaluated. RESULTS: The I'M SLEEPY version was found to have the highest sensitivity (82%) and a modest specificity (50%) for OSA diagnosis. CONCLUSION: I'M SLEEPY is a sensitive and easy-to-use screening tool for pediatric OSA. It is intended to be used by the primary physician in every suspected case of OSA. Larger studies are needed in the primary care setting for the validation of this tool.


Assuntos
Apneia Obstrutiva do Sono/diagnóstico , Inquéritos e Questionários , Criança , Feminino , Humanos , Masculino , Polissonografia , Sensibilidade e Especificidade
17.
J Am Soc Nephrol ; 25(12): 2859-70, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24925725

RESUMO

Lupus nephritis is a manifestation of SLE resulting from glomerular immune complex deposition and inflammation. Lupus nephritis demonstrates familial aggregation and accounts for significant morbidity and mortality. We completed a meta-analysis of three genome-wide association studies of SLE to identify lupus nephritis-predisposing loci. Through genotyping and imputation, >1.6 million markers were assessed in 2000 unrelated women of European descent with SLE (588 patients with lupus nephritis and 1412 patients with lupus without nephritis). Tests of association were computed using logistic regression adjusting for population substructure. The strongest evidence for association was observed outside the MHC and included markers localized to 4q11-q13 (PDGFRA, GSX2; P=4.5×10(-7)), 16p12 (SLC5A11; P=5.1×10(-7)), 6p22 (ID4; P=7.4×10(-7)), and 8q24.12 (HAS2, SNTB1; P=1.1×10(-6)). Both HLA-DR2 and HLA-DR3, two well established lupus susceptibility loci, showed evidence of association with lupus nephritis (P=0.06 and P=3.7×10(-5), respectively). Within the class I region, rs9263871 (C6orf15-HCG22) had the strongest evidence of association with lupus nephritis independent of HLA-DR2 and HLA-DR3 (P=8.5×10(-6)). Consistent with a functional role in lupus nephritis, intra-renal mRNA levels of PDGFRA and associated pathway members showed significant enrichment in patients with lupus nephritis (n=32) compared with controls (n=15). Results from this large-scale genome-wide investigation of lupus nephritis provide evidence of multiple biologically relevant lupus nephritis susceptibility loci.


Assuntos
Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Nefrite Lúpica/genética , Adolescente , Adulto , Idoso , Criança , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Antígeno HLA-DR2/genética , Antígeno HLA-DR3/genética , Humanos , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/fisiopatologia , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/metabolismo , Adulto Jovem
18.
Br J Pain ; 8(3): 107-18, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26516542

RESUMO

Pain and sleep share a bidirectional relationship, with each influencing the other. Several excellent reviews have explored this relationship. In this article, we revisit the evidence and explore existing research on this complex inter-relationship. The primary focus of the article is on the pharmacological treatment of chronic non-malignant pain and the main purpose is to review the effect of various pharmacological agents used in the management of chronic pain on sleep. This has not been comprehensively done before. We explore the clinical use of these agents, their impact on sleep architecture and sleep physiology, the mechanism of action on sleep parameters and sleep disorders associated with these agents. Pharmacological classes reviewed include antidepressants, opioid analgesics, anti-epileptics, cannabinoids and non-steroidal anti-inflammatory agents, drugs most commonly used to manage chronic pain. The objective is to help health professionals gain better insight into the complex effect that commonly used analgesics have on an individual's sleep and how this could impact on the effectiveness of the drug as an analgesic. We conclude that antidepressants have both positive and negative effects on sleep, so do opioids, but in the latter case the evidence shifts towards the counterproductive side. Some anticonvulsants are sleep sparing and non-steroidal anti-inflammatory drugs (NSAIDs) are sleep neutral. Cannabinoids remain an underexplored and researched group.

19.
J Dev Behav Pediatr ; 34(9): 688-96, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24247912

RESUMO

OBJECTIVE: To describe the relationship between sleep architecture and behavioral measures in unmedicated children and adolescents with Tourette syndrome (TS), attention-deficit hyperactivity disorder (ADHD), TS and comorbid ADHD (TS + ADHD), and healthy controls. The study also set out to examine differences in sleep architecture with each diagnosis. METHOD: A cross-sectional, 2-night consecutive polysomnographic sleep study was conducted in 90 children. All participants were matched for age, gender, and level of intelligence. RESULTS: Scores on the Child Behavior Checklist delinquency measure were modestly but significantly correlated with the number of movements during REM sleep (r = .36, p = .003). Significant correlations were also noted among the number of total arousals and arousals from slow wave sleep (SWS), and scores on the measures of conduct disorder, hyperactivity/immaturity, and restless/disorganized behaviors. There were a few significant differences in sleep architecture among the diagnostic groups. The ADHD-only group exhibited a significantly higher number of total arousals (p < .01) and arousals from SWS (p < .01) compared with the other three study groups. DISCUSSION: Our findings indicate that children with TS and/or ADHD and who have more arousals from sleep are significantly more likely to have issues with conduct disorder, hyperactivity/immaturity, and restless/disorganized behavior. It was also noted that having ADHD, alone or comorbid with TS, is associated with a significantly greater number of movements during both non-REM and REM sleep. This study underscores the compelling need for the diagnosis and treatment of any sleep disorders in children with TS and/or ADHD so as to facilitate better management of problem behaviors.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtornos do Comportamento Infantil/fisiopatologia , Polissonografia/métodos , Transtornos do Sono-Vigília/fisiopatologia , Síndrome de Tourette/fisiopatologia , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Criança , Transtornos do Comportamento Infantil/diagnóstico , Transtornos do Comportamento Infantil/epidemiologia , Comorbidade , Estudos Transversais , Feminino , Humanos , Masculino , Polissonografia/instrumentação , Transtornos do Sono-Vigília/diagnóstico , Transtornos do Sono-Vigília/epidemiologia , Síndrome de Tourette/diagnóstico , Síndrome de Tourette/epidemiologia
20.
PLoS One ; 8(8): e69404, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23950893

RESUMO

Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a negative regulator of T-cell activation associated with several autoimmune diseases, including systemic lupus erythematosus (SLE). Missense rs2476601 is associated with SLE in individuals with European ancestry. Since the rs2476601 risk allele frequency differs dramatically across ethnicities, we assessed robustness of PTPN22 association with SLE and its clinical sub-phenotypes across four ethnically diverse populations. Ten SNPs were genotyped in 8220 SLE cases and 7369 controls from in European-Americans (EA), African-Americans (AA), Asians (AS), and Hispanics (HS). We performed imputation-based association followed by conditional analysis to identify independent associations. Significantly associated SNPs were tested for association with SLE clinical sub-phenotypes, including autoantibody profiles. Multiple testing was accounted for by using false discovery rate. We successfully imputed and tested allelic association for 107 SNPs within the PTPN22 region and detected evidence of ethnic-specific associations from EA and HS. In EA, the strongest association was at rs2476601 (P = 4.7 × 10(-9), OR = 1.40 (95% CI = 1.25-1.56)). Independent association with rs1217414 was also observed in EA, and both SNPs are correlated with increased European ancestry. For HS imputed intronic SNP, rs3765598, predicted to be a cis-eQTL, was associated (P = 0.007, OR = 0.79 and 95% CI = 0.67-0.94). No significant associations were observed in AA or AS. Case-only analysis using lupus-related clinical criteria revealed differences between EA SLE patients positive for moderate to high titers of IgG anti-cardiolipin (aCL IgG >20) versus negative aCL IgG at rs2476601 (P = 0.012, OR = 1.65). Association was reinforced when these cases were compared to controls (P = 2.7 × 10(-5), OR = 2.11). Our results validate that rs2476601 is the most significantly associated SNP in individuals with European ancestry. Additionally, rs1217414 and rs3765598 may be associated with SLE. Further studies are required to confirm the involvement of rs2476601 with aCL IgG.


Assuntos
Predisposição Genética para Doença/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Afro-Americanos/genética , Anticorpos Anticardiolipina/imunologia , Americanos Asiáticos/genética , Grupo com Ancestrais do Continente Europeu/genética , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Haplótipos , Hispano-Americanos/genética , Humanos , Imunoglobulina G/imunologia , Desequilíbrio de Ligação , Modelos Logísticos , Lúpus Eritematoso Sistêmico/etnologia , Lúpus Eritematoso Sistêmico/imunologia , Fenótipo
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