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1.
Pediatr Rheumatol Online J ; 16(1): 36, 2018 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-29914510

RESUMO

BACKGROUND: Bisphosphonates are recommended for use as first-line therapy for the prevention and treatment of glucocorticoid-induced osteoporosis in adults. However, the appropriate usage of bisphosphonates for the prevention or treatment of glucocorticoid-induced osteoporosis in children remains unclear. METHODS: We performed a cross-sectional study to clarify the factors associated with the development of glucocorticoid-induced bone loss and osteoporosis in patients with childhood-onset rheumatic disease and to investigate the impact of the early use of alendronate. We recruited 39 patients with childhood-onset rheumatic disease who were evaluated to detect bone loss or osteoporosis at 3 months to 1.5 years after the initiation of treatment. The primary outcome of the study was the presence of bone loss or osteoporosis at the initial evaluation of the bone mineral density after at least 3 months of glucocorticoid therapy. RESULTS: Bone loss and a history of fracture were found in 56 and 18% of the participants, respectively. Weekly oral alendronate therapy (median, 25.4 mg/m2) had been started by the time of the evaluation of osteoporosis in 46% of the participants and within 3 months after the start of glucocorticoid in 31% of the participants. There were no significant differences between the participants with bone loss (wBL group) and without bone loss (w/oBL group) in terms of gender, primary disease, or the age at the onset of primary disease. In terms of glucocorticoid use, there was no significant difference in the age at the start of glucocorticoid therapy, the length of glucocorticoid use, or the dose of glucocorticoids. The proportion of patients in the w/oBL group who received alendronate within 3 months after the start of glucocorticoid therapy was significantly greater than that in the wBL group. In the logistic regression analysis, only "alendronate therapy within 3 months after the start of glucocorticoid therapy" had a statistically significant effect on the development of bone loss (OR, 0.08; 95% CI, 0.02-0.43). The analysis did not reveal any factors associated with the development of osteoporosis. CONCLUSIONS: The early use of alendronate may have a preventive effect against the development of bone loss in glucocorticoid-treated patients with childhood-onset rheumatic disease.


Assuntos
Alendronato/administração & dosagem , Conservadores da Densidade Óssea/administração & dosagem , Glucocorticoides/efeitos adversos , Osteoporose/induzido quimicamente , Doenças Reumáticas/tratamento farmacológico , Adolescente , Adulto , Densidade Óssea , Criança , Estudos Transversais , Feminino , Glucocorticoides/uso terapêutico , Humanos , Japão , Masculino , Osteoporose/epidemiologia , Osteoporose/prevenção & controle , Fatores de Risco , Adulto Jovem
3.
Inflammation ; 39(3): 949-62, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26635116

RESUMO

Matrix metalloproteinases (MMPs) are a class of extra-cellular and membrane-bound proteases involved in a wide array of physiological and pathological processes including tissue remodeling, inflammation, and cytokine secretion and activation. MMP-13 has been shown to be involved in lung diseases such as acute lung injury, viral infections, and chronic obstructive pulmonary disease; however, the molecular pathogenesis of MMP-13 in these conditions is not well understood. In this study, we investigated the mechanisms and roles of MMP-13 secretion in human small airway epithelial cells (SAECs) and functional polymorphisms of the MMP13 gene. Polyinosinic-polycytidylic acid (poly(I:C)) and interferon ß (IFN-ß) stimulated the secretion of MMP-13 from SAECs by more than several hundred-fold. Stimulation of the secretion by poly(I:C) was abolished by SB304680 (p38 inhibitor), LY294002 (PI3K inhibitor), Janus kinase (JAK) inhibitor I, RNA-activated protein kinase (PKR) inhibitor, and Bay 11-7082 (NF-κB inhibitor), while stimulation by IFN-ß was inhibited by all except Bay 11-7082. These data suggested that the secretion of MMP-13 was mediated through IFN receptor pathways independently of nuclear factor kappa B (NF-κB) and that poly(I:C) stimulated IFN secretion in an NF-κB-dependent manner from SAECs, leading to IFN-stimulated MMP-13 secretion. Chemical MMP-13 inhibitors and MMP-13 small interfering RNA (siRNA) inhibited IFN-stimulated secretion of interferon gamma-inducible protein 10 (IP-10) and regulated on activation, normal T-cell expressed and secreted (RANTES), suggesting that MMP-13 is involved in the secretion of these virus-induced proinflammatory chemokines. We identified a novel functional polymorphism in the promoter region of the MMP13 gene. The MMP13 gene may play important roles in defense mechanisms of airway epithelial cells.


Assuntos
Brônquios/citologia , Células Epiteliais/enzimologia , Interferons/fisiologia , Metaloproteinase 13 da Matriz/genética , Polimorfismo Genético , Brônquios/patologia , Células Cultivadas , Quimiocinas , Células Epiteliais/citologia , Humanos , Interferon beta/farmacologia , Interferons/farmacologia , Metaloproteinase 13 da Matriz/metabolismo , NF-kappa B/metabolismo , Poli I-C/farmacologia , Regiões Promotoras Genéticas , Ativação Transcricional
4.
J Allergy Clin Immunol ; 134(5): 1131-41.e9, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24942515

RESUMO

BACKGROUND: Crohn disease is an inflammatory bowel disease (IBD) with a complex mode of inheritance. Although nucleotide binding and oligomerization domain containing 2 (NOD2) is the strongest risk factor, the cause of Crohn disease remains unknown in the majority of the cases. X-linked inhibitor of apoptosis (XIAP) deficiency causes X-linked lymphoproliferative syndrome type 2. IBD has been reported in some XIAP-deficient patients. OBJECTIVE: We characterize the IBD affecting a large cohort of patients with mutations in XIAP and examine the possible pathophysiologic mechanisms. METHODS: We performed a phenotypical and histologic analysis of the IBD affecting 17 patients with hemizygous mutations in XIAP, including 3 patients identified by screening 83 patients with pediatric-onset IBD. The X chromosome inactivation was analyzed in female carriers of heterozygous XIAP mutations, including 2 adults with IBD. The functional consequences of XIAP deficiency were analyzed. RESULTS: Clinical presentation and histology of IBD in patients with XIAP deficiency overlapped with those of patients with Crohn disease. The age at onset was variable (from 3 months to 41 years), and IBD was severe and difficult to treat. In 2 patients hematopoietic stem cell transplantation fully restored intestinal homeostasis. Monocytes of patients had impaired NOD2-mediated IL-8 and monocyte chemoattractant protein 1 (MCP-1) production, as well as IL-10, in response to NOD2 and Toll-like receptor 2/4 costimulation. Nucleotide binding and oligomerization domain containing 1 (NOD1)-mediated IL-6 and IL-8 production was defective in fibroblasts from XIAP-deficient patients. The 2 heterozygous female carriers of XIAP mutations with IBD displayed abnormal expression of the XIAP mutated allele, resulting in impaired activation of the NOD2 pathway. CONCLUSION: IBD in patients with XIAP deficiency is similar to Crohn disease and is associated with defective NOD2 function in monocytes. Importantly, we report that it is not restricted to male patients because we identified 2 symptomatic female heterozygous carriers of XIAP mutations.


Assuntos
Cromossomos Humanos X , Doença de Crohn , Doenças Genéticas Ligadas ao Cromossomo X , Hemizigoto , Heterozigoto , Transtornos Linfoproliferativos , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Cromossomos Humanos X/genética , Cromossomos Humanos X/metabolismo , Estudos de Coortes , Doença de Crohn/sangue , Doença de Crohn/genética , Doença de Crohn/patologia , Citocinas/sangue , Citocinas/genética , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/sangue , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Lactente , Transtornos Linfoproliferativos/sangue , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/patologia , Masculino , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Adaptadora de Sinalização NOD2/metabolismo
5.
Int Arch Allergy Immunol ; 160(3): 287-96, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23075521

RESUMO

BACKGROUND: Matrix metalloproteinase 12 gene (MMP12) has been shown to be associated with asthma in a Caucasian population. In this study, we investigate whether single-nucleotide polymorphisms (SNPs) of MMP12 are associated with a risk for asthma in a Japanese population. METHODS: We tested for an association between SNPs in MMP12 and asthma, including its severity, in a Japanese population (630 pediatric and 417 adult patients with atopic asthma and 336 children and 632 adults as controls). The rs652438 A and G variants (N357S) were generated by site-directed mutagenesis and an assay with artificial peptide substrates was used to compare two types of MMP12 activity. The effect of MMP12 inhibition with MMP12-specific small interfering RNA (siRNA) on chemokine secretion from airway epithelial cells was also tested in vitro. RESULTS: N357S showed a p value <0.05 for childhood and combined (adult plus childhood) asthma in the dominant model [odds ratio (OR) 1.60, 95% confidence interval (CI) 1.00-2.56, p = 0.047; OR 1.40, 95% CI 1.04-1.89, p = 0.028, respectively]. This risk variant is associated with asthma severity in adult patients. In the functional assay, the minor-allele enzyme showed significantly lower activity than the major-allele enzyme. MMP12-specific siRNA suppressed IP-10 secretion from airway epithelial cells upon stimulation with IFN-ß. CONCLUSIONS: Our results suggest that MMP12 confers susceptibility to asthma and is associated with asthma severity in a Japanese population. MMP12 may be associated with asthma through inappropriate attraction of leukocytes to the inflamed tissue.


Assuntos
Asma/genética , Metaloproteinase 12 da Matriz/genética , Mucosa Respiratória/imunologia , Adolescente , Adulto , Idoso , Asma/imunologia , Quimiocina CXCL10/metabolismo , Criança , Pré-Escolar , Análise Mutacional de DNA , Progressão da Doença , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Interferon beta/imunologia , Japão , Pessoa de Meia-Idade , Mutação/genética , Polimorfismo de Nucleotídeo Único , RNA Interferente Pequeno/genética , Risco , Adulto Jovem
6.
J Clin Immunol ; 32(3): 411-20, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22228567

RESUMO

Deficiency of X-linked inhibitor of apoptosis (XIAP) caused by XIAP/BIRC4 gene mutations is an inherited immune defect recognized as X-linked lymphoproliferative syndrome type 2. This disease is mainly observed in patients with hemophagocytic lymphohistiocytosis (HLH) often associated with Epstein-Barr virus infection. We described nine Japanese patients from six unrelated families with XIAP deficiency and studied XIAP protein expression, XIAP gene analysis, invariant natural killer T (iNKT) cell counts, and the cytotoxic activity of CD8(+) alloantigen-specific cytotoxic T lymphocytes. Of the nine patients, eight patients presented with symptoms in infancy or early childhood. Five patients presented with recurrent HLH, one of whom had severe HLH and died after cord blood transplantation. One patient presented with colitis, as did another patient's maternal uncle, who died of colitis at 4 years of age prior to diagnosis with XIAP deficiency. Interestingly, a 17-year-old patient was asymptomatic, while his younger brother suffered from recurrent HLH and EBV infection. Seven out of eight patients showed decreased XIAP protein expression. iNKT cells from patients with XIAP deficiency were significantly decreased as compared with age-matched healthy controls. These results in our Japanese cohort are compatible with previous studies, confirming the clinical characteristics of XIAP deficiency.


Assuntos
Linfo-Histiocitose Hemofagocítica/diagnóstico , Transtornos Linfoproliferativos/diagnóstico , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/deficiência , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Japão , Leucócitos Mononucleares/imunologia , Contagem de Linfócitos , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/imunologia , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/imunologia , Masculino , Mutação , Células T Matadoras Naturais/imunologia , Linfócitos T Citotóxicos/imunologia , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/imunologia
7.
Arerugi ; 58(6): 648-56, 2009 Jun.
Artigo em Japonês | MEDLINE | ID: mdl-19571658

RESUMO

BACKGROUND AND OBJECT: Two major convenient questionnaires of asthma control in childhood, Japanese Pediatric Asthma Control Program (JPAC) and Childhood Asthma Control Test (C-ACT) have been available in Japan. The aim of this study is comparison of utilities of these questionnaires by means of respiratory function and fractional nitric oxide (FENO). SUBJECT AND METHODS: The 154 samples from patients with asthma and their parents answered to two questionnaires at regular visits. At the same time, respiratory function and FENO were measured. The patients were divided into two groups according to the control levels defined by JPAC and C-ACT. The correlation of each total scores and respiratory function and FENO were examined. RESULTS: The total scores of JPAC and C-ACT strongly correlated each other. Among 3 groups in JPAC the score of JPAC weakly correlated with %FEV1, FEV1/FVC and %MMF. In contrast there was no correlation between 2 groups C-ACT. FEV1/FVC and %MMF were significantly different among the groups identified by the JPAC, but not among those by the C-ACT. Neither of the total scores of JPAC nor C-ACT correlated with FENO. CONCLUSION: JPAC and C-ACT may partially reflect the respiratory function, with preference to JPAC. In contrast, these questionnaires did not reflect FENO. Thus, physician should use these questionnaires with consideration of these points.


Assuntos
Asma/diagnóstico , Testes Respiratórios , Óxido Nítrico/análise , Testes de Função Respiratória , Inquéritos e Questionários , Criança , Pré-Escolar , Feminino , Humanos , Masculino
8.
Pediatr Allergy Immunol ; 19(8): 716-21, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18208460

RESUMO

The regulatory IL-10 and TGF-beta1 cytokine gene polymorphisms have been associated with allergic diseases in different populations, like Caucasian, Chinese and Indians. We investigated the association between the polymorphisms IL-10 A-1082G, C-819T, C-627A and TGF-beta1 T+869C, G+915C, C-509T and food allergy in Japanese children. One hundred and eleven children with food allergy and 115 atopic control children without food allergy were recruited. DNA samples from these subjects were genotyped by using PCR. The odds ratio of IL-10 -1082 AA genotype was 2.5 (95% CI, 1.0-6.4) for food allergy risk when compared with atopic control subjects (p = 0.03). There were no significative differences in the frequency of TGF-beta1 gene polymorphisms between both groups. Our results indicate that IL-10 A-1082G gene polymorphism is associated with food allergy susceptibility in atopic Japanese children.


Assuntos
Hipersensibilidade Alimentar/genética , Predisposição Genética para Doença , Interleucina-10/genética , Polimorfismo de Nucleotídeo Único , Fator de Crescimento Transformador beta1/genética , Alelos , Criança , Feminino , Hipersensibilidade Alimentar/epidemiologia , Hipersensibilidade Alimentar/imunologia , Frequência do Gene , Genótipo , Humanos , Imunoglobulina E/sangue , Japão/epidemiologia , Masculino
9.
J Infect Dis ; 195(11): 1618-24, 2007 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-17471431

RESUMO

BACKGROUND: The contribution that genetic polymorphisms of Toll-like receptor (TLR) 4 and of CD14--both of which recognize respiratory syncytial virus (RSV) in the innate immune response--make to RSV bronchiolitis in the Japanese population has not yet been clarified. METHODS: This study genotyped 2 TLR4 mutations, Asp299Gly and Thr399Ile, and 2 single-nucleotide polymorphisms (SNPs) of CD14, -550 C/T and -159 C/T, in 54 children with RSV bronchiolitis and in 203 control subjects. CD14 SNPs and the serum level of soluble CD14 (sCD14) also were examined in 67 cord-blood specimens and in serum samples from 73 6-year-old children. RESULTS: No TLR4 mutations were found. The frequencies of both the CC genotype and the C allele of CD14 -550 C/T were significantly higher in children with RSV bronchiolitis than in the control subjects. The serum level of sCD14 was significantly higher in children with the CC genotype of CD14 -550 C/T than in those with the CT and TT genotypes. CONCLUSIONS: CD14 -550 C/T, which is related to the serum level of sCD14, is associated with the development of RSV bronchiolitis in the Japanese population. This study's results indicate that, in different ethnic groups, different genetic factors contribute to the development of RSV bronchiolitis.


Assuntos
Bronquiolite Viral/genética , Predisposição Genética para Doença , Receptores de Lipopolissacarídeos/sangue , Receptores de Lipopolissacarídeos/genética , Infecções por Vírus Respiratório Sincicial/genética , Vírus Sincicial Respiratório Humano/patogenicidade , Bronquiolite Viral/epidemiologia , Bronquiolite Viral/imunologia , Bronquiolite Viral/virologia , Criança , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Japão/epidemiologia , Masculino , Mutação , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único , Infecções por Vírus Respiratório Sincicial/epidemiologia , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/virologia , Receptor 4 Toll-Like/genética
10.
Int Arch Allergy Immunol ; 127(3): 191-7, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11979044

RESUMO

BACKGROUND: Imbalances of IL-4 and IFN-gamma production are widely known to increase IgE synthesis in allergic individuals, and IL-5 is known to play a critical role in the pathogenesis of various allergic diseases. However, little is known about how Th cells specific to house dust mite (HDM) develop the capacity to produce these cytokines in children with atopic dermatitis (AD). OBJECTIVE: This study aims to clarify when HDM-specific Th cells develop the capacity to produce IL-4, IL-5 and IFN-gamma in children with AD. METHODS: The production of IL-4, IL-5 and IFN-gamma by peripheral blood mononuclear cells (PBMCs) upon stimulation with HDM was measured in 91 children with AD and 37 control subjects. The changes in the cytokine production with age were analyzed transectionally and longitudinally. RESULTS: IL-4 production by HDM-stimulated PBMCs in children with AD was already increased before age 1. Thereafter, it continuously rose until reaching a near-maximum level at age 2. Growth-related changes in the production of IL-5 resembled those in the production of IL-4 and peaked at age 1. The production of these cytokines was very low in control subjects up to age 2 and then gradually increased, albeit never above the levels measured in AD children. The production of IFN-gamma in children with AD reached a near-maximum level during the first year of life and diminished after age 3. Although IFN-gamma production in controls was lower than that in AD children during infancy, it continuously rose even after age 3 and surpassed the levels measured in AD children. The level of serum HDM-specific IgE antibody began to increase after age 1 following the rise of IL-4 production. Essentially the same relationship among IL-4, IFN-gamma and IgE synthesis was seen in a longitudinal study of 6 AD infants, in whom HDM-specific IgE was initially negative but later turned positive. CONCLUSIONS: These findings suggest that the capacity of HDM-specific Th cells to produce IL-4, IL-5 and IFN-gamma develops and effectively matures during the first 3 years of life in children with AD.


Assuntos
Citocinas/biossíntese , Dermatite Atópica/imunologia , Ácaros/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adolescente , Fatores Etários , Animais , Células Cultivadas , Criança , Pré-Escolar , Poeira , Humanos , Lactente , Recém-Nascido , Interferon gama/biossíntese , Interleucina-4/biossíntese , Interleucina-5/biossíntese , Estudos Longitudinais
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