RESUMO
UNLABELLED: We report on four female adolescents, who presented with inflammatory symptoms. Extensive diagnostic workup revealed tumors on different locations. After surgical removal, clinical and laboratory signs of inflammation disappeared rapidly. On histology, the tumors showed a mixture of inflammatory cells characteristic of inflammatory pseudotumors in three of the patients. CONCLUSION: In patients with unclear inflammatory symptoms, inflammatory pseudotumor should be added to the differential diagnosis. WHAT IS KNOWN: ⢠The inflammatory pseudotumor (IPT) is a mostly benign myofibroblastic tumor of the soft tissue and causes inflammatory symptoms. What is new: ⢠IPTs have may wider than hitherto defined histologic features. Removal of IPT is curative.
Assuntos
Granuloma de Células Plasmáticas , Adolescente , Antibacterianos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Criança , Diagnóstico Diferencial , Feminino , Granuloma de Células Plasmáticas/diagnóstico , Granuloma de Células Plasmáticas/patologia , Granuloma de Células Plasmáticas/terapia , Humanos , Tomografia por Emissão de PósitronsRESUMO
BACKGROUND: Increased serum IgE levels are characteristic but not specific for allergic diseases. Particularly, severe atopic dermatitis (AD) overlaps with hyper-IgE syndromes (HIES) regarding eczema, eosinophilia, and increased serum IgE levels. HIES are primary immunodeficiencies due to monogenetic defects such as in the genes DOCK8 and STAT3. As it is not known to date why allergic manifestations are not present in all HIES entities, we assessed the specificity of serum IgE of AD and HIES patients in the context of clinical and immunological findings. METHODS: Clinical data, skin prick tests, specific IgE to aero- and food allergens, and T helper (Th) subpopulations were compared in AD and molecularly defined HIES patients. RESULTS: Total serum IgE levels were similarly increased in STAT3-HIES, DOCK8-HIES, and AD patients. The ratio of aeroallergen-specific IgE to total IgE was highest in AD, whereas DOCK8-HIES patients showed the highest specific serum IgE against food allergens. Overall, clinical allergy and skin prick test results complied with the specific IgE results. Th2-cell numbers were significantly increased in DOCK8-HIES and AD patients compared to STAT3-HIES patients and controls. AD patients showed significantly higher nTreg-cell counts compared to STAT3-HIES and control individuals. High Th17-cell counts were associated with asthma. Specific IgE values, skin prick test, and T-cell subsets of STAT3-HIES patients were comparable with those of healthy individuals except decreased Th17-cell counts. CONCLUSION: Hyper-IgE syndromes and atopic dermatitis patients showed different sensitization pattern of serum IgE corresponding to the allergic disease manifestations and Th-cell subset data, suggesting a key role of DOCK8 in the development of food allergy.
Assuntos
Dermatite Atópica/imunologia , Fatores de Troca do Nucleotídeo Guanina/imunologia , Imunoglobulina E/imunologia , Síndrome de Job/imunologia , Fator de Transcrição STAT3/imunologia , Adulto , Análise Mutacional de DNA , Dermatite Atópica/sangue , Feminino , Citometria de Fluxo , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Imunoglobulina E/sangue , Síndrome de Job/sangue , Síndrome de Job/genética , Masculino , Pessoa de Meia-Idade , Fator de Transcrição STAT3/genética , Testes Cutâneos , Linfócitos T Auxiliares-Indutores/imunologia , Adulto JovemRESUMO
X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was initially described in patients with X-linked lymphoproliferative syndrome (XLP) who had no mutations in SH2D1A. In the initial reports, EBV-associated hemophagocytic lymphohistiocytosis (HLH) was the predominant clinical phenotype. Among 25 symptomatic patients diagnosed with XIAP deficiency, we identified 17 patients who initially presented with manifestations other than HLH. These included Crohn-like bowel disease (n=6), severe infectious mononucleosis (n=4), isolated splenomegaly (n=3), uveitis (n=1), periodic fever (n=1), fistulating skin abscesses (n=1) and severe Giardia enteritis (n=1). Subsequent manifestations included celiac-like disease, antibody deficiency, splenomegaly and partial HLH. Screening by flow cytometry identified 14 of 17 patients in our cohort. However, neither genotype nor protein expression nor results from cell death studies were clearly associated with the clinical phenotype. Only mutation analysis can reliably identify affected patients. XIAP deficiency must be considered in a wide range of clinical presentations.
Assuntos
Síndromes de Imunodeficiência/genética , Linfo-Histiocitose Hemofagocítica/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/deficiência , Adolescente , Adulto , Criança , Pré-Escolar , Genótipo , Humanos , Síndromes de Imunodeficiência/imunologia , Linfo-Histiocitose Hemofagocítica/imunologia , Masculino , Mutação , Células T Matadoras Naturais/imunologia , Fenótipo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/imunologia , Adulto JovemRESUMO
In 2009, a federally funded clinical and research consortium (PID-NET, http://www.pid-net.org) established the first national registry for primary immunodeficiencies (PID) in Germany. The registry contains clinical and genetic information on PID patients and is set up within the framework of the existing European Database for Primary Immunodeficiencies, run by the European Society for Primary Immunodeficiencies. Following the example of other national registries, a central data entry clerk has been employed to support data entry at the participating centres. Regulations for ethics approvals have presented a major challenge for participation of individual centres and have led to a delay in data entry in some cases. Data on 630 patients, entered into the European registry between 2004 and 2009, were incorporated into the national registry. From April 2009 to March 2012, the number of contributing centres increased from seven to 21 and 738 additional patients were reported, leading to a total number of 1368 patients, of whom 1232 were alive. The age distribution of living patients differs significantly by gender, with twice as many males than females among children, but 15% more women than men in the age group 30 years and older. The diagnostic delay between onset of symptoms and diagnosis has decreased for some PID over the past 20 years, but remains particularly high at a median of 4 years in common variable immunodeficiency (CVID), the most prevalent PID.
Assuntos
Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/epidemiologia , Sistema de Registros , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Pré-Escolar , Bases de Dados Factuais , Feminino , Alemanha , Humanos , Síndromes de Imunodeficiência/genética , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Prevalência , Adulto JovemRESUMO
Nijmegen breakage syndrome (NBS), also known as ataxia-telangiectasia (AT) variant, is an autosomal recessive disorder characterized by microcephaly, growth retardation, severe combined immunodeficiency and a high incidence of lymphoid cancers. Cells from NBS patients display chromosome instability, hypersensitivity to ionizing radiation and abnormal cell-cycle regulation after irradiation, all of which are characteristics shared with AT. Recently, the NBS locus was mapped at 8q21 by two independent approaches, complementation studies and linkage analysis. Here, we report the positional cloning of the NBS gene, NBS1, from an 800-kb candidate region. The gene comprises 50 kb and encodes a protein of 754 amino acids. The amino-terminal region of the protein shows weak homology to the yeast XRS2, MEK1, CDS1 and SPK1 proteins. The gene is expressed at high levels in the testes, suggesting that it might be involved in meiotic recombination. We detected the same 5-bp deletion in 13 individuals, and conclude that it is likely to be a founder mutation.
Assuntos
Ataxia Telangiectasia/genética , Proteínas de Ciclo Celular/genética , Quebra Cromossômica/genética , Cromossomos Humanos Par 8 , Proteínas Nucleares , Sequência de Aminoácidos , Mapeamento Cromossômico , Clonagem Molecular , Bases de Dados Factuais , Transtornos do Crescimento/genética , Humanos , Microcefalia/genética , Dados de Sequência Molecular , Linhagem , Imunodeficiência Combinada Severa/genética , SíndromeRESUMO
The importance of serum immunoglobulin (Ig)G concentration in IgG replacement therapy for primary immunodeficiency diseases is established in certain settings. Generally, IgG is infused via the intravenous (IVIG) or subcutaneous (SCIG) route. For IVIG infusion, published data demonstrate that higher IgG doses and trough levels provide patients with improved protection from infection. The same conclusions are not yet accepted for SCIG; data from two recent Phase III studies and a recent post-hoc analysis, however, suggest the same correlation between higher SCIG dose and serum IgG concentration and decreased incidence of infection seen with IVIG. Other measures of clinical efficacy have not been considered similarly. Thus, combined analyses of these and other published SCIG studies were performed; a full comparison of the 13 studies was, however, limited by non-standardized definitions and reporting. Despite these limitations, our analyses indicate that certain clinical outcomes improve at higher SCIG doses and associated higher serum IgG concentrations, and suggest that there might be opportunity to improve patient outcomes via SCIG dose adjustment.
Assuntos
Imunização Passiva , Imunoglobulina G/administração & dosagem , Síndromes de Imunodeficiência/terapia , Infecções Bacterianas/etiologia , Humanos , Imunização Passiva/efeitos adversos , Imunoglobulina G/sangue , Síndromes de Imunodeficiência/complicações , Infusões Subcutâneas , Resultado do TratamentoRESUMO
A prospective, open-label, multicenter, single-arm, Phase III study evaluated the efficacy and safety of Hizentra(®), a 20% human IgG for subcutaneous administration, in 51 primary immunodeficiency patients over 40 weeks. Patients previously on intravenous or subcutaneous IgG were switched to weekly subcutaneous infusions of Hizentra(®) at doses equivalent to their previous treatment. IgG levels achieved with Hizentra(®) were similar to pre-study levels with subcutaneous, and higher by 17.7% than pre-study levels with intravenous IgG. No serious bacterial infections were reported in the efficacy period. The rate of all infections was 5.18/year/patient, the rates of days missed from work/school, and days spent in hospital were 8.00/year/patient and 3.48/year/patient, respectively. Local reactions (rate 0.060/infusion) were mostly mild (87.3%). No serious, Hizentra(®)-related adverse events were reported. Individual median infusion durations ranged between 1.14 and 1.27 h. Hizentra(®) maintained or improved serum IgG levels without dose increases and effectively protected patients against infections.
Assuntos
Imunoglobulina G/administração & dosagem , Síndromes de Imunodeficiência/terapia , Adolescente , Adulto , Agamaglobulinemia/sangue , Agamaglobulinemia/imunologia , Agamaglobulinemia/terapia , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/sangue , Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/terapia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/sangue , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Imunoglobulina G/efeitos adversos , Imunoglobulina G/sangue , Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/efeitos adversos , Imunoglobulinas Intravenosas/sangue , Síndromes de Imunodeficiência/sangue , Síndromes de Imunodeficiência/imunologia , Infusões Intravenosas , Infusões Subcutâneas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Subcutaneous immunoglobulin (SCIG) therapy is an alternative to intravenous immunoglobulin (IVIG) therapy. METHODS: We evaluated the efficacy and safety of the SCIG Vivaglobin(formerly known as Beriglobin SC) under real-life conditions in a post-marketing observational study in 82 patients with primary or secondary antibody deficiencies. Health-related quality of life (HRQoL) was evaluated in a subset of 30 patients previously treated with IVIG (including 11 children <14 years) using the Short Form 36 (SF-36) for patients > or = 14 years of age (adults) and the Child Health Questionnaire - Parental Form 50 (CHQ-PF50) for children <14 years of age. Treatment preferences were assessed in adults. RESULTS: The mean serum immunoglobulin G (IgG) trough level during SCIG treatment (7.5 g/L) was higher than during previous IVIG treatment (6.6 g/L; p<0.01). The investigators assessed the efficacy of SCIG therapy as "excellent" in 89% of patients. No systemic adverse drug reactions were observed. Improvements by > or = 5 points were observed in 5 of 8 SF-36 subscales and in 6 of 12 CHQ-PF50 subscales. Statistically significant improvements (p< or =0.05) were observed for the SF-36 subscales of bodily pain, general health perceptions, and vitality (adults), and for the CHQ-PF50 subscales of general health perceptions, parental impact - time, parental impact - emotional, and family activities (children). Patients preferred SCIG over IVIG therapy (92%) and home therapy over therapy at the clinic/physician (83%). CONCLUSION: This study confirms that therapy with Vivaglobin at home is effective, safe, well tolerated, and improves quality of life in patients with antibody deficiency.
Assuntos
Imunoglobulinas/administração & dosagem , Síndromes de Imunodeficiência/terapia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Nível de Saúde , Humanos , Imunoglobulinas/sangue , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/fisiopatologia , Imunoterapia/métodos , Lactente , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Vigilância de Produtos Comercializados , Estudos Prospectivos , Qualidade de Vida , Índice de Gravidade de Doença , Adulto JovemRESUMO
Autosomal dominant hyper-IgE syndrome (AD-HIES), characterised by eczema, increased susceptibility to skin and lung infections, elevated IgE and skeletal abnormalities is associated with heterozygous STAT3 mutations. The autosomal recessive variant (AR-HIES) has similar immunological findings but mainly lacks extraimmune manifestations. Several AR-HIES patients have recently been shown to harbour mutations in the gene for dedicator of cytokinesis 8 (DOCK8). Here, we present the long-term outcome of a girl having received a hematopoietic stem cell graft for an at that time genetically undefined combined immunodeficiency associated with severe eczema, multiple food allergies, excessively elevated serum IgE levels and eosinophilia. She was recently found to carry a homozygous nonsense mutation in the DOCK8 gene. HSCT resulted in complete immunological correction, even though mixed donor chimerism occurred. Clinically, the outcome was characterised by disappearance of skin manifestations and severe infections, improvement of pulmonary function and constant decline of IgE levels. Outcome in untransplanted DOCK8 deficient patients is poor because of frequent life-threatening infections, CNS bleeding and infarction, and increased susceptibility to malignancy. This argues for early curative therapeutic approaches, supported by this report of successful long-term outcome after HSCT.
Assuntos
Fatores de Troca do Nucleotídeo Guanina/deficiência , Fatores de Troca do Nucleotídeo Guanina/genética , Transplante de Células-Tronco Hematopoéticas , Síndrome de Job/genética , Síndrome de Job/terapia , Fator de Transcrição STAT3/genética , Criança , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Feminino , Seguimentos , HumanosRESUMO
BACKGROUND: Immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome) is a rare autosomal recessive disease characterised by facial dysmorphism, immunoglobulin deficiency and branching of chromosomes 1, 9 and 16 after PHA stimulation of lymphocytes. Hypomethylation of DNA of a small fraction of the genome is an unusual feature of ICF patients which is explained by mutations in the DNA methyltransferase gene DNMT3B in some, but not all, ICF patients. OBJECTIVE: To obtain a comprehensive description of the clinical features of this syndrome as well as genotype-phenotype correlations in ICF patients. METHODS: Data on ICF patients were obtained by literature search and additional information by means of questionnaires to corresponding authors. RESULTS AND CONCLUSIONS: 45 patients all with proven centromeric instability were included in this study. Facial dysmorphism was found to be a common characteristic (n = 41/42), especially epicanthic folds, hypertelorism, flat nasal bridge and low set ears. Hypo- or agammaglobulinaemia was demonstrated in nearly all patients (n = 39/44). Opportunistic infections were seen in several patients, pointing to a T cell dysfunction. Haematological malignancy was documented in two patients. Life expectancy of ICF patients is poor, especially those with severe infections in infancy or chronic gastrointestinal problems and failure to thrive. Early diagnosis of ICF is important since early introduction of immunoglobulin supplementation can improve the course of the disease. Allogeneic stem cell transplantation should be considered as a therapeutic option in patients with severe infections or failure to thrive. Only 19 of 34 patients showed mutations in DNMT3B, suggesting genetic heterogeneity. No genotype-phenotype correlation was found between patients with and without DNMT3B mutations.
Assuntos
Instabilidade Cromossômica , Anormalidades Craniofaciais/genética , Síndromes de Imunodeficiência/genética , Adolescente , Adulto , Centrômero/genética , Criança , Pré-Escolar , Anormalidades Craniofaciais/patologia , DNA (Citosina-5-)-Metiltransferases/genética , Feminino , Genótipo , Humanos , Lactente , Masculino , Mutação , Fenótipo , Síndrome , DNA Metiltransferase 3BRESUMO
OBJECTIVES: To study the clinical outcome, treatment response, T-cell subsets and functional consequences of a novel tumour necrosis factor (TNF) receptor type 1 (TNFRSF1A) mutation affecting the receptor cleavage site. METHODS: Patients with symptoms suggestive of tumour necrosis factor receptor-associated periodic syndrome (TRAPS) and 22 healthy controls (HC) were screened for mutations in the TNFRSF1A gene. Soluble TNFRSF1A and inflammatory cytokines were measured by ELISAs. TNFRSF1A shedding was examined by stimulation of peripheral blood mononuclear cells (PBMCs) with phorbol 12-myristate 13-acetate followed by flow cytometric analysis (FACS). Apoptosis of PBMCs was studied by stimulation with TNFalpha in the presence of cycloheximide and annexin V staining. T cell phenotypes were monitored by FACS. RESULTS: TNFRSF1A sequencing disclosed a novel V173D/p.Val202Asp substitution encoded by exon 6 in one family, the c.194-14G>A splice variant in another and the R92Q/p.Arg121Gln substitution in two families. Cardiovascular complications (lethal heart attack and peripheral arterial thrombosis) developed in two V173D patients. Subsequent etanercept treatment of the V173D carriers was highly effective over an 18-month follow-up period. Serum TNFRSF1A levels did not differ between TRAPS patients and HC, while TNFRSF1A cleavage from monocytes was significantly reduced in V173D and R92Q patients. TNFalpha-induced apoptosis of PBMCs and T-cell senescence were comparable between V173D patients and HC. CONCLUSIONS: The TNFRSF1A V173D cleavage site mutation may be associated with an increased risk for cardiovascular complications and shows a strong response to etanercept. T-cell senescence does not seem to have a pathogenetic role in affected patients.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Febre Familiar do Mediterrâneo/genética , Imunoglobulina G/uso terapêutico , Mutação , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/uso terapêutico , Adolescente , Adulto , Sequência de Aminoácidos , Apoptose/imunologia , Sequência de Bases , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/imunologia , Células Cultivadas , Senescência Celular/imunologia , Análise Mutacional de DNA/métodos , Etanercepte , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Monócitos/imunologia , Linhagem , Receptores Tipo I de Fatores de Necrose Tumoral/sangue , Receptores Tipo II do Fator de Necrose Tumoral/sangue , Subpopulações de Linfócitos T/imunologia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Human T-cell function is dependent on T-cell antigen receptor (TCR) and co-signalling as evidenced by immunodeficiencies affecting TCR-dependent signalling pathways. Here, we show four human patients with EBV+ disseminated smooth muscle tumours that carry two homozygous loss-of-function mutations in the CARMIL2 (RLTPR) gene encoding the capping protein regulator and myosin 1 linker 2. These patients lack regulatory T cells without evidence of organ-specific autoimmunity, and have defective CD28 co-signalling associated with impaired T-cell activation, differentiation and function, as well as perturbed cytoskeletal organization associated with T-cell polarity and migration disorders. Human CARMIL2-deficiency is therefore an autosomal recessive primary immunodeficiency disorder associated with defective CD28-mediated TCR co-signalling and impaired cytoskeletal dynamics.
Assuntos
Síndromes de Imunodeficiência/genética , Proteínas dos Microfilamentos/metabolismo , Antígenos CD28/genética , Antígenos CD28/metabolismo , Criança , Pré-Escolar , Genótipo , Homozigoto , Humanos , Proteínas dos Microfilamentos/genética , Mutação , Transdução de SinaisRESUMO
Five male patients from four different families presented with a clinical record of chronic granulomatous disease (CGD): recurrent infections of the skin and/or respiratory tract with catalase-positive microorganisms, sometimes in combination with granulomata and/or abscesses in various organs. These patients differed from "classical" forms of the disease in that their neutrophils, although deficient in killing in vitro of Staphylococcus aureus, contained a decreased but measurable amount of cytochrome b558 (10-60% of normal on a heme basis), causing weak staining in the nitroblue tetrazolium dye test and a depressed respiratory burst after contact of the cells with fluid or particulate activators of the NADPH:O2 oxidoreductase. In the cell-free activation system, the defect in the patients' cells was localized in the membrane fraction. In each of the four families, the cellular abnormalities showed an X-linked inheritance. Fusion experiments performed with the monocytes from these patients and those from patients with classical X-linked, cytochrome b558-negative (Xb(0)) or autosomal, cytochrome b558-positive (Ab+) CGD showed complementation of NADPH:O2 oxidoreductase activity in the latter but not in the former combination. Thus, the unusual CGD patients represent variant forms of Xb(0) CGD, with mutations in the gene coding for the beta subunit of cytochrome b558 that do not cause complete loss of this protein.
Assuntos
Grupo dos Citocromos b/deficiência , Doença Granulomatosa Crônica/fisiopatologia , NADH NADPH Oxirredutases/deficiência , Explosão Respiratória , Atividade Bactericida do Sangue , Western Blotting , Expressão Gênica , Teste de Complementação Genética , Doença Granulomatosa Crônica/genética , Humanos , Masculino , NADPH Oxidases , RNA Mensageiro/genética , Cromossomo XRESUMO
Focal viral encephalitis in childhood is a rare but life-threatening disease. Animal experiments and case reports suggest a positive effect of an additional therapy with interferon-beta on the course of the disease. Therefore, we initiated a prospective, double-blind placebo-controlled study to investigate the benefit of a combination therapy of Aciclovir (ACV) and recombinant interferon-beta (rIFN-beta) in juvenile focal viral encephalitis. - Initial inclusion criterium was suspicion of focal viral encephalitis. Diagnosis was proven by demonstration of characteristic focal lesions in cerebral imaging or virological evidence of HSV in cerebrospinal fluid. Patients were treated with ACV plus rIFN-beta or ACV plus placebo. Neurological outcome was determined 21 days and 3 months after onset of the disease. - Initially 59 patients were enrolled in the study. Encephalitis was proven in 14 patients (7 ACV + rIFN-beta, 7 ACV + placebo). The study groups were balanced in terms of important prognostic criteria. 10 patients (5 ACV + rIFN-beta, 5 ACV + placebo) were cured or had slight defects, 4 patients (2 ACV + rIFN-beta, 2 ACV + placebo) showed moderate to severe defects. There was no significant difference in favour of the additive therapy with rIFN-beta.
Assuntos
Aciclovir/uso terapêutico , Antivirais/uso terapêutico , Encefalite Viral/tratamento farmacológico , Infecção Focal/tratamento farmacológico , Herpes Simples/tratamento farmacológico , Interferon beta/uso terapêutico , Adolescente , Criança , Pré-Escolar , Método Duplo-Cego , Quimioterapia Combinada , Encefalite Viral/patologia , Encefalite Viral/fisiopatologia , Feminino , Infecção Focal/patologia , Herpes Simples/patologia , Humanos , Lactente , Masculino , Sistema Nervoso/patologia , Sistema Nervoso/fisiopatologia , Proteínas Recombinantes/uso terapêutico , Recuperação de Função Fisiológica/efeitos dos fármacos , Resultado do TratamentoRESUMO
Five heavily pretreated HIV-infected children were put on amprenavir and delavirdine plus two nucleoside inhibitors to reverse transcriptase to boost amprenavir levels and to use the antiretroviral activity of a non-nucleoside reverse transcriptase inhibitor. No data are available about this combination in children. It w;as well tolerated, and the median reduction in viral load was 1.5 log after 18 months. Delavirdine boosted amprenavir trough levels more than 10-fold, and delavirdine trough levels remained i several fold above susceptible HIV strains.
Assuntos
Fármacos Anti-HIV/farmacocinética , Delavirdina/farmacocinética , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/farmacocinética , Sulfonamidas/farmacocinética , Adolescente , Área Sob a Curva , Carbamatos , Criança , Combinação de Medicamentos , Furanos , HumanosRESUMO
To facilitate studies of the pharmacokinetic properties of zidovudine, the relationship between plasma and salivary concentrations of the drug was studied, after oral dosage, in 10 HIV-infected patients. Zidovudine concentrations were determined in plasma, unstimulated mixed saliva and citric-acid-stimulated mixed saliva over a period of 3 1/2 hours by high-performance liquid chromatography. Correlation coefficients were r = 0.97 (P less than 0.0001) for stimulated saliva compared with plasma and r = 0.89 (P less than 0.0001) for unstimulated saliva, with average values in unstimulated saliva being 113.8 +/- 44.6% in plasma and 67.8 +/- 25.4% in stimulated saliva. Stimulated saliva values found to be 70% of the total reflected the concentration of the unbound drug in plasma. Except for a shorter half-life time (t1/2) in saliva, pharmacokinetic parameters showed a good correlation in the three types of specimen. These findings and the convenience of sample collection suggest that citric-acid-stimulated saliva might be an appropriate specimen for monitoring zidovudine therapy.
Assuntos
Infecções por HIV/tratamento farmacológico , Saliva/metabolismo , Zidovudina/farmacocinética , Adulto , Estudos de Avaliação como Assunto , Infecções por HIV/diagnóstico , Infecções por HIV/metabolismo , Humanos , Masculino , Análise de Regressão , Zidovudina/uso terapêuticoRESUMO
ICF syndrome is a rare autosomal recessive immunoglobulin deficiency, sometimes combined with defective cellular immunity. Other features that are frequently observed in ICF syndrome patients include facial dysmorphism, developmental delay, and recurrent infections. The most diagnostic feature of ICF syndrome is the branching of chromosomes 1, 9, and 16 due to pericentromeric instability. Positional candidate cloning recently discovered the de novo DNA methyltransferase 3B (DNMT3B) as the responsible gene by identifying seven different mutations in nine ICF patients. DNMT3B specifically methylates repeat sequences adjacent to the centromeres of chromosome 1, 9, and 16. Our panel of 14 ICF patients was subjected to mutation analysis in the DNMT3B gene. Mutations in DNMT3B were discovered in only nine of our 14 ICF patients. Moreover, two ICF patients from consanguineous families who did not show autozygosity (i.e. homozygosity by descent) for the DNMT3B locus did not reveal DNMT3B mutations, suggesting genetic heterogeneity for this disease. Mutation analysis revealed 11 different mutations, including seven novel ones: eight different missense mutations, two different nonsense mutations, and a splice-site mutation leading to the insertion of three aa's. The missense mutations occurred in or near the catalytic domain of DNMT3B protein, indicating a possible interference with the normal functioning of the enzyme. However, none of the ICF patients was homozygous for a nonsense allele, suggesting that absence of this enzyme is not compatible with life. Compound heterozygosity for a missense and a nonsense mutation did not seem to correlate with a more severe phenotype.
Assuntos
Heterogeneidade Genética , Variação Genética , Síndromes de Imunodeficiência/genética , Anormalidades Múltiplas/genética , Adulto , Criança , Pré-Escolar , DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA , Análise Mutacional de DNA , Feminino , Haplótipos , Humanos , Síndromes de Imunodeficiência/epidemiologia , Lactente , Masculino , Mutação de Sentido Incorreto , DNA Metiltransferase 3BRESUMO
The effect of sulfite on the oxidative metabolism of human neutrophils was studied in vitro. Superoxide anion production of PMN was determined using superoxide dismutase-inhibitable lucigenin-dependent CL. The addition of sulfite in concentrations of 0.01 mM-1 mM results in an up to 6-fold increase in CL of nonstimulated neutrophils at 37 degrees C and pH 7. Neutrophils stimulated with zymosan or PMA have an additional 2-fold stimulation when sulfite is added. Higher sulfite concentrations (2 mM-10 mM) decrease the CL of both nonstimulated and stimulated cells. The activity of NADPH oxidase, responsible for O2.- production, is significantly increased in neutrophils incubated with 1 mM sulfite. Neutrophils from patients with chronic granulomatous disease, which are cytochrome b558 negative or have p47phox deficiency, exhibit no significant NADPH oxidase activity and show no increase in CL by sulfite. Inhibitors of protein kinase C, H7, and calphostin C, as well as inhibitors of Ca(2+)- and calmodulin-dependent processes, W7, and R 24 571, completely inhibited the increased CL of sulfite-treated neutrophils. These findings indicate that sulfite in low concentrations stimulates neutrophils to produce superoxide anions by activation of NADPH oxidase through a signal transduction pathway involving protein kinase C and Ca2+/calmodulin.
Assuntos
NADH NADPH Oxirredutases/metabolismo , Neutrófilos/metabolismo , Cálcio/metabolismo , Calmodulina/metabolismo , Radicais Livres/metabolismo , Humanos , Técnicas In Vitro , NADPH Oxidases , Neutrófilos/efeitos dos fármacos , Proteína Quinase C/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Sulfitos/farmacologia , Superóxidos/metabolismo , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
BACKGROUND: In this retrospective study we compared the antiretroviral effect of regimens consisting of simultaneous administration of two protease inhibitors (PI) with at least one nucleoside reverse transcriptase inhibitor on plasma viral load (VL) and CD4 cell count in HIV-infected children intensively pretreated with nucleoside reverse transcriptase inhibitors and PIs. METHODS: Eleven HIV-infected children were changed to antiretroviral combination regimens including two PIs and followed for a median time of 24 weeks. Group A comprised six patients who were given ritonavir + saquinavir (SQV) and Group B consists of five patients who were changed to nelfinavir + SQV. Patients were treated with these combinations with 2 PIs because of treatment failure (increasing viral load) of prior PI therapy or clinical signs of disease progression. OUTCOME MEASURES: Serial determinations of plasma viral load (Amplicor, Roche) and CD4 cells were performed every 4 to 8 weeks. The detection limit of the Amplicor-reverse transcriptase-PCR assay was 50 copies/ml (1.7 log10). RESULTS: In Group A the median VL reduction was 1.1 log10 after 3 months and 1.4 log10 after 6 months. In Group B median VL decreased 0.1 and 0.2 log10 after 3 and 6 months. In both groups during the study period none of the patients reached undetectable VL. The relative changes of CD4 cells above baseline in Group A showed a median increase of 7% after 3 months and 23% after 6 months. In Group B after 3 months CD4 cells did not increase, and after 6 months the median relative increase was only 7%. Both combination therapies were well tolerated, not necessitating any drug interruption during study period. CONCLUSIONS: In children with intensive prior antiretroviral treatment, a salvage therapy including two PIs demonstrated antiretroviral efficacy in some patients. In this study the reduction of the VL as well as the increase of CD4 cells was more pronounced with ritonavir + SQV than with nelfinavir + SQV. With both combinations complete suppression of HIV replication was not achieved. Therefore the long term effect of these combinations may be limited by the emergence of resistant HIV strains.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/administração & dosagem , HIV-1/efeitos dos fármacos , Nelfinavir/administração & dosagem , Ritonavir/administração & dosagem , Terapia de Salvação , Saquinavir/administração & dosagem , Adolescente , Criança , Quimioterapia Combinada , Feminino , Infecções por HIV/diagnóstico , Inibidores da Protease de HIV/efeitos adversos , Humanos , Masculino , Nelfinavir/efeitos adversos , Prognóstico , Estudos Retrospectivos , Ritonavir/efeitos adversos , Saquinavir/efeitos adversos , Resultado do TratamentoRESUMO
OBJECTIVES: To evaluate the safety and immunogenicity of Biken acellular pertussis vaccine in combination with diphtheria and tetanus toxoid (Biken DTaP) vaccine administered to children 4 to 6 years of age who had previously received four doses of Biken DTaP. METHODS: 580 children were enrolled to receive one dose of Biken DTaP. Local and systemic reactions were collected by parent diary for all subjects within 3 days after vaccination and in a subset for 14 days. All adverse events occurring within 30 days after vaccination were recorded. RESULTS: Any redness and swelling occurred in 59.8 and 61.4%, respectively. Redness or swelling larger than 5 cm/10 cm occurred in 31%/6.1% and 25%/6.5% of the children, respectively. Any pain was reported in 58.8%, but clinically significant pain occurred in 2.1% of the children. Fever >38.0 degrees C occurred in 3.8% of the children. Fussiness, drowsiness, anorexia and vomiting were experienced by 19.7, 15.5, 7.3 and 2.2%, respectively. Sixty-three of 247 adverse events (25%) occurring within 30 days after vaccination were assessed to possibly be vaccine-related. Fifty-eight of the 63 possibly related events (92%) were caused by local reactions as redness, swelling or itchiness. The remaining 5 events included hematoma, headache, stomachache and sleep disturbance. All local and systemic reactions and adverse events resolved without sequelae. Immunogenicity analysis showed a 4-fold antibody increase to pertussis toxin in 97% of subjects and to filamentous hemagglutinin in 82%. All subjects had postvaccination antibody titers of 0.1 IU/ml or greater against diphtheria and tetanus. Higher prevaccination antibody titers against diphtheria toxoid, pertussis toxin and filamentous hemagglutinin were associated with a higher frequency of large local reactions. CONCLUSION: In comparison with a fourth dose of Biken DTaP administered at 18 to 24 months of age in the same population, the rate of local reactions increased after the fifth dose, whereas systemic reactions remained similarly low or decreased.