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1.
Artigo em Inglês | MEDLINE | ID: mdl-31483922

RESUMO

Metronidazole, a widely used drug for the treatment of infections with anaerobic and facultative anaerobic bacteria and protozoa, can frequently cause metronidazole-induced cutaneous adverse reactions (McADRs). The aim of the present study was to investigate the association between human leucocyte antigen (HLA) alleles and McADRs in a Chinese Han population. The frequency of HLA-B*24:02 carriers among the McADR patients was 73.3%, which was significantly higher than that of the population controls (32.16%, OR = 5.80, 95% CI = [1.80-18.72], Pc = 0.004) and of the metronidazole-tolerant patients (26.67%, OR = 7.56, 95% CI = [2.02-28.35], Pc = 0.004). Molecular docking showed that metronidazole and one of its major metabolites had the potential to bind in the HLA groove and that there was a relatively stable binding state of the HLA-B*24:02-metronidazole/the metabolite complex. The CDR3 repertoires of both T cell receptor (TCR)Vα and Vß of the patients showed a significantly skewed or an oligoclonal distribution. The TCRVß CDR3 of the patients shared a similar motif, "CASSxxxxxxQxF." The current study demonstrated that both the HLA-A*24:02 allele and TCR are involved in the pathogenesis of McADRs.

2.
Dermatol Ther ; 32(5): e13027, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31323168

RESUMO

We are the first to report on a new, safe, and effective treatment of infections induced by conditional pathogenic strains with local wet packing with hydrogen water. The new treatment method may also shed light on the therapy of chronic, inflammatory skin ulcers.

3.
Mol Immunol ; 106: 170-177, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30623817

RESUMO

Stevens-Johnson syndrome (SJS) /toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse drug reactions characterized by widespread epidermal necrosis. Recent studies have indicated that SJS/TEN is a specific immune reaction regulated by T cells. Certain drug serves as foreign antigens that are presented by major histocompatibility complex (MHC) and recognized by T cell receptors (TCRs), inducing adaptive immune responses. However, few studies have performed detailed characterization of TCR repertoire in SJS/TEN, and it remains unclear whether the particular types of TCRs expanded clonally are drug-specific, which would provide a potential underlying mechanism of SJS/TEN. In this study, using high-throughput sequencing, we comprehensively assessed the diversity, composition and molecular characteristics of the TCRß repertoires in 17 SJS/TEN patients associated with three different causative drugs including methazolamide (MZ), carbamazepine (CBZ) and allopurinol (ALP). Systematic analysis of the TCRß sequences revealed that SJS/TEN patients had more highly expanded clones and less TCR repertoire diversity, and the TCR repertoire diversity of these patients showed certain associations with the clinical severity of disease. Similar predominant clonotypes, shared-usage TRBV/TRBJ subtypes and combinations thereof were observed among different subjects with the same causative agent. Our observations provide enhanced understanding of the role of T lymphocytes in the pathogenesis of SJS/TEN and enumerate potential therapeutic targets.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Síndrome de Stevens-Johnson/genética , Alopurinol/administração & dosagem , Alopurinol/efeitos adversos , Carbamazepina/administração & dosagem , Carbamazepina/efeitos adversos , Feminino , Humanos , Masculino , Metazolamida/administração & dosagem , Metazolamida/efeitos adversos , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Síndrome de Stevens-Johnson/imunologia , Síndrome de Stevens-Johnson/patologia
4.
Pharmacogenomics J ; 2018 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-30237582

RESUMO

Xuesaitong (XST) is mainly used to treat cardiovascular and cerebrovascular diseases, sometimes causing cutaneous adverse drug reactions (cADRs) with unknown mechanisms of pathogenicity or risk factors. We aimed to verify whether human leukocyte antigen (HLA) alleles are associated with XST-related cADRs in Han Chinese population. We carried out an association study including 12 subjects with XST-induced cADRs, 283 controls, and 28 XST-tolerant subjects. Five out of 12 patients with XST-induced cADRs carried HLA-C*12:02, and all of them received XST via intravenous drip. The carrier frequency of HLA-C*12:02 was significantly high compare to that of the control population (Pc = 4.4 × 10-4, odds ratio (OR) = 21.75, 95% CI = 5.78-81.88). Compared with that of the XST-tolerant group, the patients who received XST through intravenous drip presented a higher OR of cADRs (Pc = 0.011, OR = 27.00, 95% CI = 2.58-282.98). The results suggest that HLA-C*12:02 is a potentially predictive marker of XST-induced cADRs in Han Chinese, especially when XST is administered via intravenous drip.

5.
J Invest Dermatol ; 138(11): 2307-2314, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29857070

RESUMO

To identify possible additional genetic susceptibility loci for pemphigus vulgaris (PV), we performed a genome-wide association study of 240 PV patients and 1,031 control individuals, and we selected the top single nucleotide polymorphisms for replication in independent samples, with 252 patient samples and 1,852 control samples. We identified rs11218708 (P = 3.1 × 10-8, odds ratio = 1.54) at chromosome locus 11q24.1 as significantly associated with PV. A fine-mapping analysis of PV risk in the major histocompatibility complex region showed three independent variants predisposed to PV using stepwise analysis: HLA-DRB1*14:04 (P = 2.47 × 10-38, odds ratio = 6.28), rs7454108 at the TAP2 gene (P = 2.78 × 10-12, odds ratio = 3.25), and rs1051336 at the HLA-DRA gene (P = 3.06 × 10-6, odds ratio = 0.33). A systematic evaluation using gene- and pathway-based analyses showed a high tendency for PV susceptibility genes to be associated with autoimmunity. Our study highlights the involvement of immune-mediated processes in the pathophysiology of PV and illustrates the value of imputation to identify variants in the major histocompatibility complex region.

6.
Sci Rep ; 8(1): 8051, 2018 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-29795283

RESUMO

Psoriasis and parapsoriasis en plaques are chronic inflammatory skin diseases, both representing therapeutic challenge in daily practice and adversely affecting the quality of life. Reactive oxygen species (ROS) has been evidenced to be involved in the pathogenesis of the chronic inflammatory diseases. We now report that hydrogen water, an effective ROS scavenger, has significant and rapid improvement in disease severity and quality of life for patients with psoriasis and parapsoriasis en plaques. At week 8, our parallel-controlled trial revealed 24.4% of patients (10/41) receiving hydrogen-water bathing achieved at least 75% improvement in Psoriasis Area Severity Index (PASI) score compared with 2.9% of patients (1/34) of the control group (Pc = 0.022, OR = 0.094, 95%CI = [0.011, 0.777]). Of patients, 56.1% (23/41) who received bathing achieved at least 50% improvement in PASI score compared with only 17.7%(6/34) of the control group (P = 0.001, OR = 0.168, 95%CI = [0.057, 0.492]). The significant improvement of pruritus was also observed (P = 3.94 × 10-4). Besides, complete response was observed in 33.3% of patients (2/6) of parapsoriasis en plaques and partial response in 66.7% (4/6) at week 8. Our findings suggested that hydrogen-water bathing therapy could fulfill the unmet need for these chronic inflammatory skin diseases.

7.
Basic Clin Pharmacol Toxicol ; 123(3): 308-313, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29575644

RESUMO

Genetic risk factors could cause cutaneous adverse drug reactions (cADRs) in patients after treatment with clarithromycin. This study explored the association of HLA class I genes with clarithromycin-cADRs in Han Chinese patients. A total of 12 clarithromycin-cADR patients and 34 clarithromycin-tolerant controls were recruited for the high-resolution genotyping of HLA class I genes (HLA-A, HLA-B and HLA-C). The population controls consisted of 283 Han Chinese retrieved from the MHC database for validated comparison. A molecular docking analysis of HLA-A*02:07 protein and clarithromycin was conducted using glide module with Schrödinger Suite. Among all tested HLA alleles, the carrier frequencies of HLA-A*02:07 (58% versus 5.9%, OR = 22.40, 95% CI = 3.58-139.98, p = 8.20 × 10E-5, pc = 1.1 × 10E-3) and HLA-B*46:01 (50% versus 5.9%, OR = 16.00, 95% CI = 2.59-98.99, p = 0.002, pc = 0.03) were significantly higher in clarithromycin-cADRs than in clarithromycin-tolerant controls. However, when compared to population controls, only HLA-A*02:07, and not HLA-B*46:01, reached statistical significance (58% versus 15.5%, OR = 7.61, 95% CI = 2.31-25.04, p = 1.2 × 10E-4, pc = 1.7 × 10E-3). Furthermore, molecular docking data revealed that clarithromycin could bind to and interact with HLA-A*02:07 in two possible binding situations. These data suggest that HLA-A*02:07 might be a genetic risk factor for developing clarithromycin-cADRs in Han Chinese and serve as a useful biomarker for personalized medicine to prevent clarithromycin-cADRs.


Assuntos
Antibacterianos/efeitos adversos , Claritromicina/efeitos adversos , Erupção por Droga/etiologia , Antígenos HLA-A/genética , Adulto , Idoso , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Erupção por Droga/genética , Feminino , Predisposição Genética para Doença , Genótipo , Antígenos HLA-B/genética , Humanos , Masculino , Pessoa de Meia-Idade , Simulação de Acoplamento Molecular , Fatores de Risco , Adulto Jovem
8.
Eur J Dermatol ; 28(1): 13-25, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29521632

RESUMO

Drug reaction with eosinophilia and systemic symptoms (DRESS) is characterised by skin rash and multivisceral involvement. The liver is the organ most frequently affected and the degree of liver function impairment often correlates with the mortality rate of DRESS. We aimed to examine the expression of cytotoxic proteins, including soluble Fas ligand (sFasL), TNF-α, granulysin, perforin, and granzyme B in the sera and skin lesions of patients with DRESS and evaluate their clinical significance. Our cohort consisted of 21 patients with DRESS and control groups including 39 patients with Stevens-Johnson syndrome/toxic epidermal necrolysis, 21 patients with maculopapular eruption, and 29 normal controls. Concentrations of cytotoxic proteins in the sera were measured using enzyme-linked immunosorbent assays. Tissue samples were also obtained from typical skin lesions, and immunohistochemical staining was conducted to assess the local expression of cytotoxic proteins. We found that sFasL and granzyme B were significantly overexpressed in the sera of DRESS patients compared to normal controls. Furthermore, the levels of sFasL, perforin, and granzyme B significantly correlated with the serum level of liver enzymes in DRESS patients. Immunohistochemical examination also showed overexpressed cytotoxic proteins in cutaneous DRESS lesions. Cytotoxic proteins may play a vital role in the pathogenesis of DRESS, and serum sFasL, perforin, and granzyme B may also be involved in liver function impairment in DRESS patients.


Assuntos
Citotoxinas/metabolismo , Síndrome de Hipersensibilidade a Medicamentos/metabolismo , Eosinofilia/metabolismo , Fígado/metabolismo , Síndrome de Stevens-Johnson/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Diferenciação de Linfócitos T/metabolismo , Estudos de Casos e Controles , Síndrome de Hipersensibilidade a Medicamentos/complicações , Eosinofilia/complicações , Exantema/complicações , Exantema/metabolismo , Proteína Ligante Fas/metabolismo , Feminino , Granzimas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Perforina/metabolismo , Pele/metabolismo , Síndrome de Stevens-Johnson/complicações , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
10.
Acta Derm Venereol ; 98(4): 401-405, 2018 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-29242946

RESUMO

DRESS is one of the most severe drug reactions. The aim of this retrospective study was to summarize the clinical presentation, genetic predisposition and prognostic factors of DRESS. A total of 52 patients with DRESS, who were inpatients at a medical referral centre in Shanghai, China, from January 2011 to December 2016, were analysed retrospectively. All the patients had skin eruption, 83% had liver involvement, and ≤10% had other organ involvement. Mean cost of hospitalization was US$5,511±3,050. The 3 most common causative agents were allopurinol (18/52; 35%), salazosulphapyridine (11/52; 21%) and carbamazepine (5/52; 10%). HLA-B*5801 and HLA-B*1302 were associated with allopurinol-induced DRESS. HLA-B*1301 was related to salazosulphapyridine-induced DRESS. The mortality rate was 6% (3/52). Epstein-Barr virus DNA was found in 10 patients (19%) and indicated a poor prognosis. Human herpes virus 6 DNA was detected in 17 patients (33%) and was associated with autoimmune sequelae. Due to its high medical cost and sometimes poor prognosis, prevention of DRESS should be a high priority.


Assuntos
Alopurinol/efeitos adversos , Carbamazepina/efeitos adversos , DNA Viral/genética , Síndrome de Hipersensibilidade a Medicamentos/genética , Síndrome de Hipersensibilidade a Medicamentos/virologia , Antígenos HLA-B/genética , Herpesvirus Humano 4/genética , Herpesvirus Humano 6/genética , Sulfassalazina/efeitos adversos , Corticosteroides/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , China , Síndrome de Hipersensibilidade a Medicamentos/tratamento farmacológico , Síndrome de Hipersensibilidade a Medicamentos/mortalidade , Feminino , Predisposição Genética para Doença , Cadeias HLA-DRB1/genética , Herpesvirus Humano 4/patogenicidade , Herpesvirus Humano 6/patogenicidade , Custos Hospitalares , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Tempo de Internação/economia , Masculino , Pessoa de Meia-Idade , Admissão do Paciente/economia , Fenótipo , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Ativação Viral , Adulto Jovem
11.
Dermatol Ther ; 30(6)2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29047198

RESUMO

Few studies have been conducted in chronic actinic dermatitis (CAD) treated with narrowband ultraviolet B (NB UVB) phototherapy, especially in Asian patients. We aim to evaluate the efficacy and safety of NB UVB phototherapy in Chinese patients with CAD. 19 CAD patients of Fitzpatrick skin phototype IV received NB UVB phototherapy in spring and treatments were given 3 times weekly with incremental dose and maintenance therapy was given twice weekly for 3-4 weeks. The mean initial, endpoint, and cumulative dose of NB UVB was 0.08, 0.33, and 6.0 J/cm2 , respectively. Patients totally received 27 times of treatments in average. 87.5% of previously ultraviolet B(UVB) sensitive patients and 75% of previously ultraviolet A(UVA) sensitive patients had normal or improved MED after phototherapy. The percentage of patients returned to normal UVB phototesting was higher than that of patients returned to normal UVA phototesting (68.8% vs. 37.5%). The mean 1-week DLQI and the need for using immunosuppressive agents and antihistamines were significantly reduced after treatment (p < .01 or p < .05). In conclusion, prophylactic NB UVB phototherapy is effective and safe in treatment of CAD in Chinese patients with Fitzpatrick skin phototype IV.


Assuntos
Transtornos de Fotossensibilidade/radioterapia , Terapia Ultravioleta/métodos , Idoso , China , Feminino , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Transtornos de Fotossensibilidade/diagnóstico , Indução de Remissão , Fatores de Tempo , Resultado do Tratamento , Terapia Ultravioleta/efeitos adversos
12.
Australas J Dermatol ; 58(3): e61-e67, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27040133

RESUMO

BACKGROUND/OBJECTIVES: Keratinocyte death is a hallmark of Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN). Apoptotic signal-associated cytokines, such as TNF-α, sFasL, granulysin, sTRAIL and IFN-γ have been reported to participate in keratinocyte apoptosis. However, their levels are variable, which hampers the elucidation of the role of these cytokines. We sought to determine whether cytokine levels vary with disease course. METHODS: The serum cytokine levels of 24 patients and blister fluid of 10 were analysed by enzyme-linked immunosorbent assay on the first day of their admission to hospital and were evaluated at different time points in the disease course. Meanwhile, surface markers (CD3, CD4, CD8, CD1a, CD14, CD16+56 and CD68) of blister fluid cells were measured by flow cytometry. RESULTS: The concentrations of all cytokines in the serum and blister fluid were higher than those in the controls and were more elevated in the blister fluid than in the serum. Moreover, sTRAIL, IFN-γ and TNF-α quantities were relatively stable, while those of sFasL and granulysin decreased rapidly in the disease course. On the first day, CD8+ T and natural killer cells were predominant in the blister fluid but their relative percentage diminished gradually, while that of CD14+ cells increased. CONCLUSION: Our study confirmed there are high but variable levels of these cytokines in SJS/TEN, especially in the early phase and different tendencies are manifested in the disease course.


Assuntos
Antígenos de Diferenciação/metabolismo , Apoptose , Vesícula/metabolismo , Citocinas/sangue , Síndrome de Stevens-Johnson/sangue , Adulto , Estudos de Casos e Controles , Citocinas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transdução de Sinais , Síndrome de Stevens-Johnson/metabolismo , Adulto Jovem
13.
Pharmacogenet Genomics ; 26(12): 538-546, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27749688

RESUMO

OBJECTIVE: Tetanus antitoxin (TAT) is an effective antitetanus medicine, but may sometimes cause adverse drug reactions such as rapid-onset anaphylactic shock and late-onset cutaneous adverse drug reactions, including exanthematous drug eruptions (EDE). Human leukocyte antigen (HLA) class I alleles are strongly associated with different types of cutaneous adverse drug reactions. This study aimed to assess whether there is an association between TAT-induced EDE and HLA-A, HLA-B, and HLA-C alleles in the Chinese Han population. PATIENTS AND METHODS: We carried out an association study in 15 patients with TAT-induced EDE and two groups of general Han Chinese patients. Allele-level genotypes of the HLA-A, HLA-B, and HLA-C genes of each patient were determined using the PCR-sequence-specific oligonucleotides method. RESULTS: The carrier frequency of HLA serotype A2 was significantly higher in the TAT-induced EDE patients than in the general Han Chinese study participants from the human major histocompatibility complex database [n=283, odds ratio (OR)=6.93; P=0.0061]. Particularly, the carrier frequency of three A2 alleles, including HLA-A*02:01, HLA-A*02:06, and HLA-A*02:07, is significantly higher than that of the control group (OR=14.40; P=2.4×10). Furthermore, HLA-B*39:01 was in complete linkage disequilibrium with HLA-A*02:06 in the case patients. Consequently, the distribution of the HLA-A*02:06/-B*39:01 haplotype was also significantly different in the cases and the controls (OR=105.00; P=0.0024). CONCLUSION: The HLA-A*02:06/-B*39:01 haplotype is a potential genetic marker for the TAT-induced EDE. Furthermore, the HLA-A2 serotype, especially three alleles A*02:01, A*02:06, and A*02:07, was identified to be associated with the TAT-induced EDE in the Han Chinese population for the first time.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Exantema/genética , Antígenos HLA-A/genética , Antitoxina Tetânica/toxicidade , Adulto , Grupo com Ancestrais do Continente Asiático/etnologia , China/etnologia , Exantema/induzido quimicamente , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade
14.
J Investig Dermatol Symp Proc ; 17(1): 29-31, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26067314

RESUMO

Cutaneous adverse drug reactions (cADRs) include mild maculopapular exanthems (MPE), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP). We used HLA high-resolution genotyping and genome wide association analysis (GWAS) to identify the genetic markers for cADRs induced by common culprit drugs in Han Chinese population. To further understand the immunopathogenesis of cADRs, and with the goal of developing treatment strategies, we compared the expression of cytoxic cytokines between the patients with cADRs and normal controls. Our data suggested that the carbamazepine induced SJS/TEN, allopurinol induced CADRs, methazolamide induced SJS/TEN and SASP induced DRESS were respectively strongly associated with HLA-B*15:02, HLA-B*58:01, HLA-B*59:01 and HLA-B*13:01. In addition, increased expression of cytotoxic cytokines in sera and tissues of cADRs patients were found, compared with healthy controls. Our findings may shed light on prediction and prevention of cADRs, provide clues to pathogenesis, and guide treatment strategies of these reactions.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Erupção por Droga/genética , Erupção por Droga/imunologia , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Alopurinol/efeitos adversos , Alopurinol/imunologia , Amoxicilina/efeitos adversos , Antibacterianos/efeitos adversos , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/imunologia , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/imunologia , Biomarcadores , Carbamazepina/efeitos adversos , Carbamazepina/imunologia , Inibidores da Anidrase Carbônica/efeitos adversos , Inibidores da Anidrase Carbônica/imunologia , Estudos de Casos e Controles , Cefalosporinas/efeitos adversos , China/etnologia , Citocinas/imunologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Supressores da Gota/efeitos adversos , Supressores da Gota/imunologia , Humanos , Metazolamida/efeitos adversos , Metazolamida/imunologia , Polimorfismo de Nucleotídeo Único , Sulfassalazina/efeitos adversos , Sulfassalazina/imunologia
15.
Int J Clin Exp Med ; 8(10): 19701-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26770634

RESUMO

OBJECTIVE: To study the effect of DNMT1 on CD4(+) T cells in the peripheral blood of systemic lupus erythematosus (SLE) patients. METHODS: To investigate the differential expression of DNMT1 in CD4(+) T cells of SLE patients and healthy individuals, a DNMT1 lentiviral plasmid (pLenti6.3/V5-DNMT1) and a control plasmid (pLenti6.3/V5-GW/LacZ) were constructed and transfected into CD4(+) T cells from the peripheral blood of SLE patients. The transcriptional and translational expression of DNMT1, global genomic DNA methylation, and the production of IgG antibody in the CD4(+) T cells in the peripheral blood of SLE patients were assessed using qPCR analysis, western blotting, flow cytometry, and ELISA, respectively. RESULTS: The expression level of DNMT1 in SLE patients was significantly lower than that in normal humans. The expression of DNMT1 was found to be positively correlated with the methylation level of genomic DNA and negatively correlated with the IgG titration level. DNA sequencing results confirmed that the DNMT1 lentiviral plasmid was successfully constructed. After the CD4(+) T cells from the peripheral blood of SLE patients were transfected with the pLenti6.3/V5-DNMT1 plasmid, the transcription level of the DNMT1 gene was upregulated and abundance of DNMT1 protein significantly increased. Global genomic DNA methylation was enhanced, while the production of IgG antibody was reduced. CONCLUSION: DNMT1 can inhibit the autoimmune response in SLE patients by reversing the abnormally low DNA methylation level in the CD4(+) T cells.

16.
Clin Chem Lab Med ; 53(3): 383-90, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25257159

RESUMO

BACKGROUND: The HLA-B*58:01 allele is associated with allopurinol-induced severe cutaneous adverse drug reactions (sCADR) in certain geographic regions, but the diversity of the correlation is large. In addition, the currently available HLA-B*58:01 testing methods are too laborious for use in routine clinical detection. The objective of this study was to develop a new, convenient method for the detection of HLA-B*58:01 and to investigate the association of HLA-B*58:01 with allopurinol-induced sCADR in a Han Chinese population. METHODS: A new method combining sequence-specific primers (SSP) and TaqMan probe amplification was developed in this study and was used to detect the HLA-B*58:01 in 48 allopurinol-induced sCADR, 133 allopurinol-tolerant, and 280 healthy individuals. The accuracy, sensitivity, and specificity were assessed by a commercial PCR-SSP HLA-B typing kit. The low limit of detection was detected by serial dilution of an HLA-B*58:01-positive DNA template. RESULTS: The new method successfully identified HLA-B*58:01 in thousands of HLA-B alleles, and the results for 344 DNA samples were perfectly concordant with the results of the commercial PCR-SSP HLA-B kit. The analytical sensitivity is 100% and the specificity is over 99%. The low limit of detection of this assay is 100 pg DNA, which was 10 times more sensitive than the commercial PCR-SSP kit. HLA-B*58:01 was present in 93.8% of the patients with sCADR, 7.5% of the allopurinol-tolerant patients, and 12.1% of the healthy controls. The frequency of HLA-B*58:01 was significantly higher in the sCADR group than in the control group (p<0.0001). However, there was no significant difference between the allopurinol-tolerant and control groups (p=0.1547). CONCLUSIONS: HLA-B*58:01 has a strong association with allopurinol-induced sCADR in Han Chinese. The newly developed method is reliable for HLA-B*58:01 detection prior to allopurinol therapy.


Assuntos
Alopurinol/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Antígenos HLA-B/genética , Reação em Cadeia da Polimerase , Dermatopatias/induzido quimicamente , Dermatopatias/genética , China , Humanos , Dados de Sequência Molecular
17.
Pharmacogenomics ; 15(11): 1461-9, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25303297

RESUMO

AIM: Salazosulfapyridine (SASP) frequently causes several adverse reactions, such as drug rash with eosinophilia and systemic symptoms (DRESS). This study aims to assess whether there is an association between SASP-induced DRESS and HLA-A, -B and -C alleles in the Chinese Han population. SUBJECTS & METHODS: We performed an association study of six subjects with SASP-induced DRESS, 30 SASP-tolerant patients and 283 general subjects from the human MHC database, all of whom are Han Chinese. RESULTS: The frequency of the SASP-induced DRESS patients carrying the HLA-B*13:01 allele is 66.67% (4/6). It is significantly higher compared with the general Chinese Han population (15.19%, 43/283; odds ratio: 11.16; p = 0.007) or with the SASP-tolerant patients (13.33%, 4/30; odds ratio: 13.00; p = 0.004). CONCLUSION: These findings show for the first time that in the Chinese Han population, HLA-B*13:01 is associated with SASP-induced DRESS. HLA-B*13:01 might serve as a potential genetic marker for reducing the prevalence of SASP-induced DRESS.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Eosinofilia/induzido quimicamente , Exantema/induzido quimicamente , Predisposição Genética para Doença/genética , Antígeno HLA-B13/genética , Sulfassalazina/efeitos adversos , Adulto , Alelos , Erupção por Droga/genética , Eosinofilia/genética , Exantema/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
PLoS One ; 8(5): e62653, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23650522

RESUMO

BACKGROUND: Mycobacterium tuberculosis (MTB) infection has been suggested to contribute to the pathogenesis of erythema nodosum (EN) and nodular vasculitis (NV), the classic forms of panniculitis. However, there is little evidence to demonstrate the presence of MTB in the skin lesions. This study is aimed at evaluating the association between MTB infection and the development of EN and NV in a Chinese population. METHODS: A total of 107 patients (36 EN, 27 NV, and 44 others) with vasculitis and 40 control cases with other skin diseases were recruited and their skin lesion samples were subjected to real time polymerase chain reaction (PCR) analysis of the IS6110 and mpt64 gene fragments of MTB. Their blood mononuclear cells were tested for MTB antigen-specific IFN-γ responses by QuantiFERON®-TB Gold In-Tube (IT) assays. RESULTS: PCR analysis revealed that 7/23 (30.4%) and 7/18 (38.9%) of the EN and NV samples were positive for the IS6110 DNA, respectively, which were significantly higher than 3/34 (8.8%) of other vasculitis (OV) and 3/40 (7.5%) of the control samples (p<0.05). The nested Real-Time PCR assay indicated that 6/7 (86%) of the IS6110-positive EN samples, all of the IS6110-positive NV and control samples, but only 1/3 of the IS6110-positive OV samples, were positive for the mpt64 gene. Similarly, 19/32 (59.4%) of the EN patients, 20/26 (76.9%) of the NV patients, and 17/36 (47.2%) of the OV patients were positive for MTB antigen-specific IFN-γ responses, which were significantly higher than 6/40 (15%) of the controls (p<0.05). CONCLUSION: Our data strongly suggest that MTB infection and active TB are associated with the development of NV and EN in Chinese.


Assuntos
Eritema Nodoso/microbiologia , Mycobacterium tuberculosis/genética , Tuberculose Cutânea/complicações , Vasculite/microbiologia , Adolescente , Adulto , Idoso , Antígenos de Bactérias/genética , Antígenos de Bactérias/imunologia , Estudos de Casos e Controles , Criança , Feminino , Genes Bacterianos , Humanos , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Reação em Cadeia da Polimerase em Tempo Real , Tuberculose Cutânea/diagnóstico , Tuberculose Cutânea/imunologia , Adulto Jovem
19.
J Burn Care Res ; 33(6): e295-308, 2012 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22955159

RESUMO

Toxic epidermal necrolysis (TEN) represents the most severe drug-related skin condition that is potentially life-threatening with no well-established treatments. The application of corticosteroid therapy is controversial, whereas recently intravenous immunoglobulin (IVIG) therapy is emerging as a promising new method. A severity-of-illness score for TEN (SCORTEN) has gained acceptance in some western countries. In this study, our objectives were to assess the applicability of SCORTEN in Chinese patients with TEN and to evaluate the efficacy of the combination therapy of IVIG and corticosteroid in these patients. We performed a retrospective review of data from 61 patients with TEN treated at our intensive care unit from 2000 to 2010 to assess the performance of SCORTEN. In particular, 55 patients between 2002 and 2010 were grouped as a series to compare the therapeutic effects of corticosteroid therapy and IVIG combined therapy contemporaneously. During this period, 16 patients were administered with corticosteroid therapy and 39 were treated with the combination therapy. An initial dose of 1.5 mg/kg/day of methylprednisolone was given to all TEN patients. The combination therapy was combined with a total dose of 2 g/kg IVIG within 5 days. Areas under receiver operating characteristic curves and Hosmer-Lemeshow statistic were analyzed to illustrate the performance of SCORTEN. The comparison of the efficacy of the two therapies was conducted on the basis of clinical outcomes, standardized mortality ratio (SMR), and survival analysis. The overall actual mortality of patients between 2000 and 2010 was 16% (10/61), statistically insignificantly lower than predicted (24%, SMR = 67.98). Excellent discriminatory power (the areas under the receiver operating characteristic curves: 88.9, 88.2, 90.6%) and good calibration (P = .637, .833, .530) were found in all the groups. In patients admitted between 2002 and 2010, IVIG combined therapy showed a trend toward reducing the mortality rate (13%, SMR = 52.35), whereas corticosteroid monotherapy suggested no such difference (31%, SMR = 123.92). Besides, the cumulative survival rates of the combination therapy were higher at almost all the levels of SCORTEN (P = .002), especially at the score of 5 (P = 3.10 × 10⁻7). Compared with corticosteroid alone, the combination therapy arrested progression earlier (P = .013), although it did not significantly lead to a tapering of corticosteroid or a reduction of the time of hospitalization. We concluded that SCORTEN was generally applicable to Chinese patients with TEN. The comparison of the effect indicated that the combination therapy might achieve a better therapeutic effect than the administration of corticosteroid alone, especially in severe TEN patients.


Assuntos
Corticosteroides/uso terapêutico , Imunização Passiva/métodos , Imunoglobulinas Intravenosas/uso terapêutico , Metilprednisolona/uso terapêutico , Índice de Gravidade de Doença , Síndrome de Stevens-Johnson/tratamento farmacológico , Adulto , Área Sob a Curva , Biópsia , Distribuição de Qui-Quadrado , China , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Curva ROC , Estudos Retrospectivos , Síndrome de Stevens-Johnson/mortalidade , Análise de Sobrevida , Resultado do Tratamento
20.
Pharmacogenomics ; 13(10): 1193-201, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22909208

RESUMO

AIM: Allopurinol is widely used as an effective urate-lowering drug and is one of the most frequent causes of cutaneous adverse drug reactions (cADRs). Recently, a strong association of HLA-B*58:01 with allopurinol-induced severe cADRs was identified. This study investigated the predisposition to different types of allopurinol-cADRs conferred by HLA-B*5801 in a Han population from mainland China. PATIENTS & METHODS: HLA-B genotyping was performed on 38 Chinese patients with different types of allopurinol-cADRs from 2008 to 2011. RESULTS: All the allopurinol-cADR patients carried HLA-B*58:01, in contrast with only 11.11% (7/63) in the allopurinol-tolerant patients (odds ratio [OR] = 580.07; p < 0.0001) and 13.99% (80/572) in a Han Chinese population from the human MHC database (dbMHC; OR: 471.09; p < 0.0001) carried the genotype. Each type of allopurinol cADRs revealed a statistically significant association with HLA-B*58:01. In particular, the risk of allopurinol-induced maculopapular eruption was significantly higher in patients with HLA-B*58:01 (OR: 339.00; p < 0.0001). CONCLUSION: The strong association of both the mild and severe types of allopurinol cADRs with the HLA-B*58:01 allele were observed. The results indicated that the prospective use of a genetic test of HLA-B*58:01 might reduce the prevalence of allopurinol-induced cADRs. Original submitted 7 March 2012; Revision submitted 21 May 2012.


Assuntos
Alopurinol , Antígenos HLA-B/genética , Síndrome de Stevens-Johnson/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Alopurinol/administração & dosagem , Alopurinol/toxicidade , China , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Exantema/induzido quimicamente , Exantema/genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Risco , Síndrome de Stevens-Johnson/induzido quimicamente
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