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1.
Front Pediatr ; 7: 483, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31803701

RESUMO

Background: Familial Mediterranean fever (FMF) is an inherited auto-inflammatory disorder and is extremely rare in Chinese. This study aimed to investigate the demographic, clinical, and genetic features of FMF in a series of Chinese pediatric patients. Methods: This was a retrospective case series of children with recurrent febrile or inflammatory episodes and referred to the Peking Union Medical College Hospital between 06/2013 and 06/2018. All suspected patients were genetically diagnosed and met the Tel-Hashomer criteria for FMF. Demographic, clinical, genetic, and treatment characteristics were collected. Descriptive statistics were used. Results: Eleven patients were included (seven boys and four girls). The median age at the time of disease onset was 7.1 (range, 3-12) years, while the median age at diagnosis was 10.9 (range, 6-15) years. The median delay in diagnosis was 2.1 years (range, 6 months to 6.7 years). Fever (100%, 11/11) was the most common symptom, followed by joint pain (63.6%, 7/11), rash (54.5%, 6/11), abdominal pain (36.4%, 4/11), and oral ulcers (18.2%, 2/11), without evidence of amyloidosis. C-reactive protein (81.8%, 9/11) and erythrocyte sedimentation (90.9%, 10/11) were increased during attacks. All patients harbored one to five different MEFV mutations, with E148Q and L110P being the most frequent. A novel non-synonymous mutation F636Y in exon 10 was discovered. Favorable responses to colchicine was observed in all six treated patients. Conclusion: The most common variants in our study were E148Q and L110P. F636Y may found for the first time. Colchicine led to favorable responses in all treated patients.

2.
World J Pediatr ; 2019 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-31377974

RESUMO

BACKGROUNDS: Type I interferonopathy is a group of autoinflammatory disorders associated with prominent enhanced type I interferon signaling. The mechanisms are complex, and the clinical phenotypes are diverse. This review briefly summarized the recent progresses of type I interferonopathy focusing on the clinical and molecular features, pathogeneses, diagnoses and potential therapies. DATA SOURCES: Original research articles and literature reviews published in PubMed-indexed journals. RESULTS: Type I interferonopathies include Aicardi-Goutières syndrome, spondyloenchondro-dysplasia with immune dysregulation, stimulator of interferon genes-associated vasculopathy with onset in infancy, X-linked reticulate pigmentary disorder, ubiquitin-specific peptidase 18 deficiency, chronic atypical neutrophilic dermatitis with lipodystrophy, and Singleton-Merten syndrome originally. Other disorders including interferon-stimulated gene 15 deficiency and DNAse II deficiency are believed to be interferonopathies as well. Intracranial calcification, skin vasculopathy, interstitial lung disease, failure to thrive, skeletal development problems and autoimmune features are common. Abnormal responses to nucleic acid stimuli and defective regulation of protein degradation are main mechanisms in disease pathogenesis. First generation Janus kinase inhibitors including baricitinib, tofacitinib and ruxolitinib are useful for disease control. Reverse transcriptase inhibitors seem to be another option for Aicardi-Goutières syndrome. CONCLUSIONS: Tremendous progress has been made for the discovery of type I interferonopathies and responsible genes. Janus kinase inhibitors and other agents have potential therapeutic roles. Future basic, translational and clinical studies towards disease monitoring and powerful therapies are warranted.

3.
Steroids ; 150: 108448, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31302112

RESUMO

Aldosterone synthase deficiency (ASD) is a rare autosomal recessive disorder characterized by severe hyperkalemia, salt loss, vomiting, severe dehydration and failure to thrive. ASD is a life-threatening electrolyte imbalance in infants resulting from mutations in CYP11B2. We described ASD in a Chinese male infant with vomiting, poor feeding and failure to thrive. He was mildly dehydrated, with a weight of 6 kg (-3.45 SDS) and length of 67 cm (-3.10 SDS). Laboratory tests showed hyponatremia (119 mmol/L), serum potassium 5.4 mmol/L, low plasma aldosterone and plasma renin activity (PRA) levels. Next-generation sequencing of his DNA revealed compound heterozygous mutations in CYP11B2, a known variant c.1391_1393delTGC (p.Leu464del, rs776404064) and a novel variant c.1294delA (p.Arg432Glyfs*37). The HEK-293T expression system was used to investigate the variants, demonstrating negligible aldosterone synthesis compared with WT CYP11B2. The patient started fludrocortisone and subsequently gained 3.2 kg of weight and normalized serum sodium (137 mmol/L). We further reviewed reported cases of ASD, summarizing clinical features and CYP11B2 mutations; missense and nonsense mutations are most frequent. Fludrocortisone treatment is essential for ASD, and the need for mineralocorticoid replacement wanes with age; eventually, therapy can be discontinued for many affected children. Our study broadens the ASD phenotypic spectrum and shows the efficiency of next-generation sequencing for patients with atypical clinical manifestations.

4.
Clin Immunol ; 198: 11-18, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30445156

RESUMO

BACKGROUND: Several complications like calcinosis, interstitial lung disease (ILD) or malignancy, are primary causes leading to poor outcomes in idiopathic inflammatory myopathies (IIM) patients. Specific antibodies might help to indicate the occurrence or absence of these complications. OBJECTIVE: The aim of this study was to evaluate the association of anti-nuclear matrix protein 2 antibody (anti-NXP2) with calcinosis, ILD and malignancy in IIM patients. METHODS: Two investigators independently searched literature about the relation of anti-NXP2 with calcinosis, ILD, malignancy in IIM patients in PubMed, EMBASE, Web of Science databases, then selected eligible articles and extracted data from the included studies. The association between anti-NXP2 and these complications was assessed by odds ratios (OR) and 95% confidence intervals (95% CI). Further quantitative meta-analysis, subgroup analysis, sensitivity analysis and publication bias analysis were conducted with STATA 14.0 software (Stata Corp.; College Station, Texas, USA). A fixed-effects model (the Mantel-Haenszel method) was employed when I2 < 25%, otherwise a random-effects model (the Mantel-Haenszel method) was used. RESULTS: Twenty cohorts with 3064 IIM patients were included in this meta-analysis, among which 9 were about calcinosis in adults, 6 about calcinosis in juvenile patients, 9 about ILD in adults, 3 about ILD in juvenile patients, while 13 about malignancy in adult patients. Anti-NXP2 was more common in patients with calcinosis than those without calcinosis (pooled OR = 4.00, 95% CI: 2.65-6.06 in adults; pooled OR = 1.62, 95% CI: 1.14-2.30 in juvenile patients). On the contrary, this antibody was less common in adult patients with ILD than those without ILD (pooled OR: 0.33, 95% CI: 0.19-0.56). No significant difference concerning the incidence of anti-NXP2 antibody was found in IIM patients between those with and without cancer (pooled OR = 1.42, 95% CI: 0.69-2.91). CONCLUSION: The present study indicates that anti-NXP2 autoantibody is a risk factor for development into calcinosis both in adult and juvenile patients, while a protective factor for ILD in adult patients. Anti-NXP2 had no relation with malignancy in adult patients.


Assuntos
Adenosina Trifosfatases/imunologia , Autoanticorpos/imunologia , Proteínas de Ligação a DNA/imunologia , Miosite/imunologia , Calcinose/etiologia , Humanos , Doenças Pulmonares Intersticiais/imunologia , Miosite/complicações , Viés de Publicação
5.
Nucleic Acids Res ; 44(17): 8199-215, 2016 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-27298254

RESUMO

Here, we investigate the role of the budding yeast Shu complex in promoting homologous recombination (HR) upon replication fork damage. We recently found that the Shu complex stimulates Rad51 filament formation during HR through its physical interactions with Rad55-Rad57. Unlike other HR factors, Shu complex mutants are primarily sensitive to replicative stress caused by MMS and not to more direct DNA breaks. Here, we uncover a novel role for the Shu complex in the repair of specific MMS-induced DNA lesions and elucidate the interplay between HR and translesion DNA synthesis. We find that the Shu complex promotes high-fidelity bypass of MMS-induced alkylation damage, such as N3-methyladenine, as well as bypassing the abasic sites generated after Mag1 removes N3-methyladenine lesions. Furthermore, we find that the Shu complex responds to ssDNA breaks generated in cells lacking the abasic site endonucleases. At each lesion, the Shu complex promotes Rad51-dependent HR as the primary repair/tolerance mechanism over error-prone translesion DNA polymerases. Together, our work demonstrates that the Shu complex's promotion of Rad51 pre-synaptic filaments is critical for high-fidelity bypass of multiple replication-blocking lesion.


Assuntos
Reparo do DNA , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Adenina/análogos & derivados , Adenina/metabolismo , Alquilação , Camptotecina/farmacologia , Cisplatino/farmacologia , Dano ao DNA/genética , DNA Polimerase beta/metabolismo , Reparo do DNA/efeitos dos fármacos , DNA Fúngico/biossíntese , Epistasia Genética/efeitos dos fármacos , Etoposídeo/farmacologia , Genes Fúngicos , Loci Gênicos , Recombinação Homóloga/genética , Humanos , Peróxido de Hidrogênio/farmacologia , Hidroxiureia/farmacologia , Metanossulfonato de Metila/farmacologia , Modelos Biológicos , Mutação/genética , Taxa de Mutação , Ligação Proteica/efeitos dos fármacos , Radiação Ionizante , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/crescimento & desenvolvimento , Saccharomyces cerevisiae/efeitos da radiação , Proteínas de Saccharomyces cerevisiae/genética , Raios Ultravioleta
6.
World J Gastrointest Surg ; 8(3): 202-11, 2016 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-27022447

RESUMO

Pancreatic cystic neoplasms have been increasingly recognized recently. Comprising about 16% of all resected pancreatic cystic neoplasms, serous cystic neoplasms are uncommon benign lesions that are usually asymptomatic and found incidentally. Despite overall low risk of malignancy, these pancreatic cysts still generate anxiety, leading to intensive medical investigations with considerable financial cost to health care systems. This review discusses the general background of serous cystic neoplasms, including epidemiology and clinical characteristics, and provides an updated overview of diagnostic approaches based on clinical features, relevant imaging studies and new findings that are being discovered pertaining to diagnostic evaluation. We also concisely discuss and propose management strategies for better quality of life.

7.
Cell Rep ; 8(6): 1819-1831, 2014 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-25220464

RESUMO

ARTD1 (PARP1) is a key enzyme involved in DNA repair through the synthesis of poly(ADP-ribose) (PAR) in response to strand breaks, and it plays an important role in cell death following excessive DNA damage. ARTD1-induced cell death is associated with NAD(+) depletion and ATP loss; however, the molecular mechanism of ARTD1-mediated energy collapse remains elusive. Using real-time metabolic measurements, we compared the effects of ARTD1 activation and direct NAD(+) depletion. We found that ARTD1-mediated PAR synthesis, but not direct NAD(+) depletion, resulted in a block to glycolysis and ATP loss. We then established a proteomics-based PAR interactome after DNA damage and identified hexokinase 1 (HK1) as a PAR binding protein. HK1 activity is suppressed following nuclear ARTD1 activation and binding by PAR. These findings help explain how prolonged activation of ARTD1 triggers energy collapse and cell death, revealing insight into the importance of nucleus-to-mitochondria communication via ARTD1 activation.


Assuntos
Glicólise/fisiologia , Hexoquinase/metabolismo , NAD/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Trifosfato de Adenosina/metabolismo , Sequência de Aminoácidos , Linhagem Celular Tumoral , Dano ao DNA , Reparo do DNA , Metabolismo Energético , Glicosídeo Hidrolases/antagonistas & inibidores , Glicosídeo Hidrolases/metabolismo , Hexoquinase/química , Humanos , Mitocôndrias/metabolismo , Dados de Sequência Molecular , Domínios e Motivos de Interação entre Proteínas , Proteômica , Alinhamento de Sequência
8.
Di Yi Jun Yi Da Xue Xue Bao ; 23(3): 219-21, 227, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12651233

RESUMO

OBJECTIVE: To investigate the effects of angiotensin II (AngII) and AT1a blocker losartan on growth and proliferation of rat hepatic stellate cells (HSCs). METHODS: Rat HSCs were isolated, cultured and identified, followed by incubation with AngII or losartan at different concentrations. The cell growth and proliferation were assessed via cell counting and MTT assay, and the effects of the agents on HSC DNA synthesis evaluated by way of (3)H-thymidine incorporation ((3)H-TDR). RESULTS: AngII (1 x 10(-9) to 1 x 10(-7) mol/L) stimulated HSC proliferation as demonstrated by cell counting, MTT assay and thymidine incorporation test (P < 0.05), but such effect was not observed at lower doses (<1 x 10(-9) mol/L). Losartan had significant inhibitory effect on HSC growth at the concentration of 1 x 10(-8) to 1 x 10(-6) mol/L (P < 0.05), but not at lower doses (<1 x 10(-8) mol/L). Co-stimulation of the cells with losartan and AngII did not result in a significant increase in cell number as compared with the control group (P > 0.05). CONCLUSION: Rapid proliferation of rat HSCs occurs in response to AngII treatment, but is inhibited after AT1a receptor is blocked with the antagonist losartan.


Assuntos
Angiotensina II/farmacologia , Hepatócitos/efeitos dos fármacos , Losartan/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II , Animais , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Combinação de Medicamentos , Hepatócitos/patologia , Cirrose Hepática/patologia , Masculino , Ratos , Ratos Sprague-Dawley
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