RESUMO
Ataxia-telangiectasia (A-T) is a recessive disorder caused by biallelic pathogenic variants of ataxia-telangiectasia mutated (ATM). This disease is characterized by progressive ataxia, telangiectasia, immune deficiency, predisposition to malignancies, and radiosensitivity. However, hypomorphic variants may be discovered associated with very atypical phenotypes, raising the importance of evaluating their pathogenic effects. In this study, multiple functional analyses were performed on lymphoblastoid cell lines from 36 patients, comprising 49 ATM variants, 24 being of uncertain significance. Thirteen patients with atypical phenotype and presumably hypomorphic variants were of particular interest to test strength of functional analyses and to highlight discrepancies with typical patients. Western-blot combined with transcript analyses allowed the identification of one missing variant, confirmed suspected splice defects and revealed unsuspected minor transcripts. Subcellular localization analyses confirmed the low level and abnormal cytoplasmic localization of ATM for most A-T cell lines. Interestingly, atypical patients had lower kinase defect and less altered cell-cycle distribution after genotoxic stress than typical patients. In conclusion, this study demonstrated the pathogenic effects of the 49 variants, highlighted the strength of KAP1 phosphorylation test for pathogenicity assessment and allowed the establishment of the Ataxia-TeLangiectasia Atypical Score to predict atypical phenotype. Altogether, we propose strategies for ATM variant detection and classification.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Processamento Alternativo , Ciclo Celular , Linhagem Celular , Análise Mutacional de DNA , Estudos de Associação Genética/métodos , Genótipo , Humanos , Mutação , FenótipoRESUMO
Smoking cessation is possible for individuals with schizophrenia but the relapse rate is high. It is necessary to develop more flexible approaches to help these patients. The aim of this study was to examine the feasibility of an intervention approach that integrates counseling and exercise for participants with schizophrenia or schizoaffective disorder. A single group prospective design was used in this study. A sample of inpatients with schizophrenia or schizoaffective disorder participated in a program called "oxygen group", a program combining five sessions of smoking reduction counseling and three sessions of moderate intensity exercise over an 8-week period. Tobacco consumption, motivation, carbon monoxide level, anxiety and depression, smoking self-efficacy, nicotine dependence and waist circumference were measured pre- and post-intervention. Participants reported their satisfaction with the study characteristics after completion of the intervention. Smoking consumption and CO level were assessed at 6-week post-intervention follow-up. Twelve individuals (mean age 45.7±10.8years) were recruited. Participant attendance was 81.3%. There were no dropouts. Significant decreases were found for tobacco consumption (P=.04) and CO rate (P=.003) at the end of the intervention and were maintained at 6-week follow-up. Compared to baseline levels, there were no changes in depression and anxiety. Smoking cessation motivation increased significantly. This intervention appears feasible and acceptable to patients with schizophrenia and there were promising findings regarding smoking reduction. Larger trials to test the intervention are warranted.
Assuntos
Aconselhamento/métodos , Exercício Físico/psicologia , Transtornos Psicóticos , Esquizofrenia , Abandono do Hábito de Fumar/métodos , Fumar/psicologia , Tabagismo/terapia , Adulto , Monóxido de Carbono/análise , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Psicologia do Esquizofrênico , Fumar/fisiopatologia , Abandono do Hábito de Fumar/psicologia , Tabagismo/psicologiaRESUMO
Invasive aspergillosis (IA) is an increasingly common and often fatal fungal infection in children with haematological disorders. To describe the epidemiology, diagnosis, treatment and outcome of IA in children, retrospective review of the medical records of proven and probable IA between January 1986 and December 2000 was used. Twenty-four patients with IA were identified (10 proven and 14 probable) with a median age of 8.5 years. The incidence of IA was particularly high in acute myeloblastic leukaemia (5.35%) and leukaemia relapse (4%). Twenty-two patients presented with lung involvement. Broncho-alveolar lavage led to a diagnosis in 11 cases, but diagnosis was difficult and repeated invasive explorations were required. Antifungal therapy mainly consisted of amphotericin B. Eight patients underwent open-thorax surgery without any complication. Nine patients (37.5%) were cured of IA and three are still alive. The mortality was 87.5%. Three patients died of massive haemoptysis, including two before neutropenia recovery. Four patients presented with IA recurrence and three were cured again. Despite significant progress having been made in the treatment and diagnosis of IA, it is still a devastating complication in children with haematological disorders. New antifungal therapies and strategies are promising, but objective data are still lacking.
Assuntos
Antifúngicos/uso terapêutico , Aspergilose , Neoplasias Hematológicas/complicações , Adolescente , Aspergilose/diagnóstico , Aspergilose/tratamento farmacológico , Aspergilose/epidemiologia , Aspergilose/cirurgia , Criança , Pré-Escolar , Feminino , Hematologia , Departamentos Hospitalares , Humanos , Incidência , Lactente , Leucemia/complicações , Leucemia Mieloide Aguda/complicações , Pneumopatias Fúngicas/diagnóstico , Pneumopatias Fúngicas/tratamento farmacológico , Pneumopatias Fúngicas/epidemiologia , Pneumopatias Fúngicas/cirurgia , Masculino , Pediatria , Prognóstico , Resultado do TratamentoRESUMO
The association between a familial history of autoimmune disease and childhood acute leukemia was investigated in a French case-control study that, overall, was designed to assess the role of perinatal, infectious, environmental, and genetic factors in the etiology of childhood acute leukemia. Familial histories of autoimmune disease in first- and second-degree relatives were compared in 279 incident cases, 240 cases of acute lymphocytic leukemia (ALL) and 39 cases of acute non-lymphoblastic leukemia (ANLL), and 285 controls. Recruitment was frequency matched by age, gender, hospital, and ethnic origin. Odds ratios (OR) were estimated using an unconditional regression model taking into account the stratification variables, socioeconomic status, and familial structure. A statistically significant association between a history of autoimmune disease in first- or second-degree relatives and ALL (OR, 1.7; 95% confidence interval (CI), 1.0-2.8) was found. A relationship between thyroid diseases overall and ALL (OR, 2.0; 95% CI, 1.0-3.9) was observed. This association was more pronounced for potentially autoimmune thyroid diseases (Grave's disease and/or hyperthyroidism and Hashimoto's disease and/or hypothyroidism) (OR, 3.5; 95% CI, 1.1-10.7 and OR, 5.6; 95% CI, 1.0-31.1, respectively for ALL and ANLL), whereas it was not statistically significant for the other thyroid diseases (thyroid goiter, thyroid nodule, and unspecified thyroid disorders) (OR, 1.6; 95% CI, 0.7-3.5 and OR, 1.3; 95% CI, 0.2-7.0, respectively, for ALL and ANLL). The results suggest that a familial history of autoimmune thyroid disease may be associated with childhood acute leukemia.
Assuntos
Doenças Autoimunes/genética , Saúde da Família , Leucemia Mieloide Aguda/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Doenças Autoimunes/epidemiologia , Criança , Pré-Escolar , Feminino , França/epidemiologia , Humanos , Leucemia Mieloide Aguda/epidemiologia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Tireoidite Autoimune/epidemiologia , Tireoidite Autoimune/genéticaRESUMO
UNLABELLED: Congenital erythropoietic porphyria (CEP; Gunther disease; OMIM 263700) is a rare autosomal recessive disorder caused by a deficiency of uroporphyrinogen III synthase (UROS). The deficiency of this enzyme is associated with lifelong overproduction of series I porphyrins which circulate and are deposited in many tissues, causing light-sensitisation and severe damage to skin beginning in childhood. Blistering and scarring of exposed areas may lead to mutilating deformities. We describe two cases: a 4-year-old boy and his first cousin who were cured of CEP by matched unrelated donor bone marrow transplants. Both are alive and disease-free 3 and 2 years post-transplant, respectively. Cutaneous lesions improved dramatically. The correction of the enzyme deficiency was confirmed by measuring erythrocyte UROS activity and urinary porphyrin excretion. Chimerism was complete for both children. Both patients were homoallelic for a novel mutation of the UROS gene, the missense mutation A69T. CONCLUSION: Considering the severity of the disease, if HLA-matched sibling donor is not available, haematopoietic stem cell transplantation using a matched unrelated donor should be strongly considered for treating congenital erythropoietic porphyria since this is currently the only known curative therapy.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Porfiria Eritropoética/terapia , Pré-Escolar , Quimerismo , Consanguinidade , Éxons , Feminino , Humanos , Masculino , Mutação de Sentido Incorreto , Porfiria Eritropoética/diagnóstico , Porfiria Eritropoética/genética , Uroporfirinogênio III Sintetase/genéticaRESUMO
INTRODUCTION: We investigated the role of maternal alcohol and coffee drinking and parental smoking on the risk of childhood acute leukemia in a multicenter case-control study. METHODS: The study included 280 incident cases and 288 hospitalized controls, frequency matched with the cases by age, gender and center. Data collection was completed by face-to-face standardized interviews of the case and control mothers. RESULTS: An association with maternal alcohol consumption during pregnancy was observed with acute lymphoid leukemia (ALL) (OR=2.0 [1.4-3.0]) and acute non-lymphoid leukemia (ANLL) (OR=2.6 [1.2-5.8]). Maternal coffee consumption during pregnancy was associated with childhood acute leukemia, ORs increasing in ALL with coffee consumption (OR=1.1 [0.7-1.8], OR=2.4 [1.3-4.7] and OR=3.1 [1.0-9.5], respectively, for < or =3, 4-8 and >8 cups/day). No association with maternal smoking during pregnancy or parental smoking before or after the index child's birth was observed. DISCUSSION: Our results suggest an association with maternal alcohol and coffee drinking during pregnancy and call for further investigations. Besides, the present study does not support the hypothesis of an increase in the risk of childhood leukemia related to parental smoking.
Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Café/efeitos adversos , Leucemia/epidemiologia , Leucemia/etiologia , Exposição Materna/efeitos adversos , Poluição por Fumaça de Tabaco/efeitos adversos , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Mães , Gravidez , Fatores de Risco , Fatores SocioeconômicosRESUMO
Asparaginase is an enzyme used in the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma in children. It has minimal bone marrow toxicity. Its major side effects are anaphylaxis, pancreatitis, diabetes, coagulation abnormalities, and thrombosis, especially intracranial. It is derived from 2 different sources: Escherichia coli and Erwinia chrysanthemi. Nonrandomized clinical studies have suggested a similar efficacy of these 2 types of asparaginases and a lower toxicity for Erwinia-asparaginase. The European Organisation for Research and Treatment of Cancer-Children's Leukemia Group (EORTC-CLG) 58881 trial randomized 700 children with acute lymphoblastic leukemia or lymphoblastic lymphoma to either E coli- or Erwinia-asparaginase at the same dosage of 10 000 IU/m(2) twice weekly to compare toxicity and efficacy. Coagulation abnormalities were more frequent in the E coli-asparaginase than in the Erwinia-asparaginase arm of the study (30.2% versus 11.9%, P <.0001). The incidence of other toxicity was not significantly different. In the Erwinia-asparaginase arm, more patients failed to achieve complete remission (4.9% versus 2.0%; P =.038) and the relapse rate was higher, leading to shorter event-free survival (hazard ratio,1.59; 95% CI, 1.23-2.06; P =.0004). The estimate of event-free survival rate (SE) at 6 years was 59.8% (2.6%) versus 73.4% (2.4%). Overall survival rate at 6 years was also lower in the Erwinia-asparaginase arm at 75.1% (2.3%) versus 83.9% (2.0%), P =.002. With the dose scheduling used in this protocol, E coli-asparaginase induced more coagulation abnormalities but was superior to Erwinia-asparaginase for the treatment of childhood lymphoid malignancies.
Assuntos
Antineoplásicos/administração & dosagem , Asparaginase/administração & dosagem , Erwinia/enzimologia , Escherichia coli/enzimologia , Adolescente , Antineoplásicos/normas , Antineoplásicos/toxicidade , Asparaginase/normas , Asparaginase/toxicidade , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Indução de Remissão/métodos , Equivalência TerapêuticaRESUMO
BACKGROUND: Philadelphia chromosome-positive chronic myelogenous leukemia (CML) is a rare disease in children, and the optimal therapy is not clearly defined in these patients when a human leukocyte antigen-identical donor is not available. The present work focuses on the therapeutic efficacy and the toxicity of interferon (IFN) alpha 2b in combination with cytosine arabinosine (Ara-C) in patients younger than age 18 years enrolled in the randomized trial CML 91, which compared the efficacy of IFN and cytosine arabinoside (Ara-C) with IFN alone in 810 patients with CML in the chronic phase. PATIENTS AND METHODS: Twelve patients younger than age 18 years were enrolled in the randomized trial CML 91. Hydroxyurea and IFN (5 million units/m2, once a day) were given as initial treatment in all patients. After randomization, six patients received IFN (5 million units/m2, once per day) and Ara-C (20 mg/m2 for 10 days each month) (IFN plus Ara-C group), and six patients received IFN alone (5 million units/m2 once per day) (IFN group). RESULTS: Six months after the beginning of the treatment, a complete hematologic response was obtained in all the patients in the IFN plus Ara-C group and in four patients in the IFN group. A major cytogenetic response was observed in three patients in the IFN plus Ara-C group and in two patients in the IFN group. Five patients from the IFN group who crossed over to receive Ara-C did not experience additional hematologic toxicity. Three patients in the IFN plus Ara-C group and two from the IFN group are alive, in major cytogenetic response, with a follow-up of 18 to 48 months. CONCLUSION: The combination of IFN and Ara-C induces complete hematologic and major cytogenetic responses and is well tolerated in patients younger than age 18 years with CML. This combination may offer an alternative to bone marrow transplantation in children in the chronic phase of CML without a histocompatible donor.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Criança , Citarabina/administração & dosagem , Humanos , Interferon-alfa/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Contagem de Leucócitos , Metáfase , Baço/patologia , Resultado do TratamentoRESUMO
Viral infections remain a major complication of allogeneic bone marrow transplantation. A population of children who underwent unrelated allogeneic bone marrow transplantation in a single centre has been followed-up for viral infections and diseases. We describe the detection of cytomegalovirus (CMV) and adenovirus among 75 children transplanted between 1989 and 2000. CMV was detected among 22 patients (29%) and adenovirus among 19 patients (25%); they were associated with clinical diseases in 10 and 8 patients, respectively. Four patients had adenovirus and CMV coinfection. The obvious risk factor for CMV infection is seropositivity of the recipient prior to transplantation. Adenovirus is detected significantly more frequently when conditioning regimen includes anti-thymocyte or anti-lymphocyte globulin. Diseases associated with adenovirus have been correlated with a significantly higher mortality rate, stressing the need for the implementation of a systematic virological survey for this virus and for the evaluation of therapeutic protocols including new molecules.