RESUMO
Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients' heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.
Assuntos
Receptor gp130 de Citocina/genética , Genes Dominantes , Síndrome de Job/genética , Mutação/genética , Adolescente , Alelos , Proteína C-Reativa/metabolismo , Membrana Celular/metabolismo , Células Cultivadas , Criança , Receptor gp130 de Citocina/deficiência , Citocinas/biossíntese , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Genética Populacional , Células HEK293 , Humanos , Síndrome de Job/sangue , Síndrome de Job/diagnóstico por imagem , Síndrome de Job/imunologia , Cinética , Mutação com Perda de Função/genética , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Linhagem , Fenótipo , Células Th2/metabolismo , Regulação para Cima , Adulto JovemRESUMO
OBJECTIVE: To assess whether antibiotic prescriptions in a department of pneumology are in accordance with the hospital conventions and whether documented prescriptions and probabilistic prescriptions are correctly adapted with regard to microbiological results and clinical progression of patients. METHOD: A 3-month prospective observational study was performed from november 1999 to january 2000 in a department of pneumology on all antibiotic prescriptions. The referential used for the conformity of probabilistic was the guide to pneumology antibiotic protocols regarding the most frequently encountered diseases. Treatment was considered adapted if the choice of the molecule and the dose administered were effective. Documented antibiotherapy was considered appropriate if the dose was correct and/or the micro-organisms were sensitive to at least one of the molecules administered. Probabilistic treatment was considered appropriated if progression was good without any change in the antibiotics. RESULTS: Among the 404 patients hospitalised in Pneumology, 132 (33%) received at least one antibiotherapy. There was a total of 163 treatments, 142 (87%) of which were probabilistic and 21 were documented. Seventy-two percent of the probabilistic prescriptions were in accordance with the protocols. The majority of those which did not conform (60.5%) was due to the dose rather than the choice of the antibiotic. More than three quarters of the probabilistic and documented treatments (79%) were clinically adapted. Treatment failures were more often due to a mistake in spectrum rather than an inappropriate dose. CONCLUSION: The use of antibiotics has become increasingly complex because of the need for therapeutic efficacy, limitation of the selection of microbial resistance, and the cost of treatment. Application of antibiotic protocols drawn-up by the clinicians, microbiologists and chemists concerned appears to be an efficient solution that is clearly acceptable to the various participants.
