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1.
Biomolecules ; 10(8)2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32751168

RESUMO

Red blood cell (RBC) deformability is altered in inherited RBC disorders but the mechanism behind this is poorly understood. Here, we explored the molecular, biophysical, morphological, and functional consequences of α-spectrin mutations in a patient with hereditary elliptocytosis (pEl) almost exclusively expressing the Pro260 variant of SPTA1 and her mother (pElm), heterozygous for this mutation. At the molecular level, the pEI RBC proteome was globally preserved but spectrin density at cell edges was increased. Decreased phosphatidylserine vs. increased lysophosphatidylserine species, and enhanced lipid peroxidation, methemoglobin, and plasma acid sphingomyelinase (aSMase) activity were observed. At the biophysical level, although membrane transversal asymmetry was preserved, curvature at RBC edges and rigidity were increased. Lipid domains were altered for membrane:cytoskeleton anchorage, cholesterol content and response to Ca2+ exchange stimulation. At the morphological and functional levels, pEl RBCs exhibited reduced size and circularity, increased fragility and impaired membrane Ca2+ exchanges. The contribution of increased membrane curvature to the pEl phenotype was shown by mechanistic experiments in healthy RBCs upon lysophosphatidylserine membrane insertion. The role of lipid domain defects was proved by cholesterol depletion and aSMase inhibition in pEl. The data indicate that aberrant membrane content and biophysical properties alter pEl RBC morphology and functionality.

2.
Open Forum Infect Dis ; 6(11): ofz229, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31700940

RESUMO

A 7-year-old child of Turkish origin presented with headache and vomiting in the context of prolonged fever of unknown source. At examination, oral candidiasis and chronic onychomycosis were noted. A Candida meningoencephalitis was diagnosed and intravenous Amphotericin B liposomal was given during 6 months relayed by oral Fluconazole after regression of CNS lesions was observed on MRI. A complete immune evaluation was performed, and genetic analysis detected homozygous CARD9 mutation. CARD9 deficiency have been associated with invasive candidiasis in otherwise healthy patients. Culture of the cerebrospinal fluid grew for multisensitive Candida albicans. Brain magnetic resonance (MRI) showed the presence of focal lesions in the left caudate nucleus and in the right cerebellar hemisphere. Medullar MRI showed diffuse meningeal nodular lesions. Treatment with intravenous amphotericin B liposomal was given during 6 months relayed by oral fluconazole after regression of CNS lesions was observed on MRI. A complete immune evaluation was performed and genetic analysis detected a homozygous CARD9 mutation. CARD9 deficiency have been associated with invasive candidiasis in otherwise healthy patients.

3.
Br J Haematol ; 187(4): 530-542, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31338833

RESUMO

Congenital sideroblastic anaemia (CSA) is a rare disease caused by germline mutations of genes involved in haem and iron-sulphur cluster formation, and mitochondrial protein biosynthesis. We performed a retrospective multicentre European study of a cohort of childhood-onset CSA patients to explore genotype/phenotype correlations. We studied 23 females and 20 males with symptoms of CSA. Among the patients, the most frequently mutated genes were ALAS2 (n = 10; 23·3%) and SLC25A38 (n = 8; 18·6%), causing isolated forms of microcytic anaemia of varying severity. Five patients with SLC19A2 mutations suffered from thiamine-responsive megaloblastic anaemia and three exhibited the 'anaemia, deafness and diabetes' triad. Three patients with TRNT1 mutations exhibited severe early onset microcytic anaemia associated with thrombocytosis, and two exhibited B-cell immunodeficiency, inflammatory syndrome and psychomotor delay. The prognoses of patients with TRNT1 and SLC2A38 mutations were generally dismal because of comorbidities or severe iron overload. No molecular diagnosis could be established in 14/43 cases. This study emphasizes the frequency of ALAS2 and SLC25A38 mutations and provides the largest comprehensive analysis to date of genotype/phenotype correlations in CSA. Further studies of CSA patients with data recorded in an international registry would be helpful to improve patient management and establish standardized guidelines.


Assuntos
5-Aminolevulinato Sintetase/genética , Anemia Sideroblástica/genética , Estudos de Associação Genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Anemia Sideroblástica/patologia , Criança , Estudos de Coortes , Europa (Continente) , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Masculino , Mutação , Nucleotidiltransferases/genética , Estudos Retrospectivos
4.
Cell Physiol Biochem ; 48(6): 2563-2582, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30121671

RESUMO

BACKGROUND/AIMS: Transient nanometric cholesterol- and sphingolipid-enriched domains, called rafts, are characterized by higher lipid order as compared to surrounding lipids. Here, we asked whether the seminal concept of highly ordered rafts could be refined with the presence of lipid domains exhibiting different enrichment in cholesterol and sphingomyelin and association with erythrocyte curvature areas. We also investigated how differences in lipid order between domains and surrounding membrane (bulk) are regulated and whether changes in order differences could participate to erythrocyte deformation and vesiculation. METHODS: We used the fluorescent hydration- and membrane packing-sensitive probe Laurdan to determine by imaging mode the Generalized Polarization (GP) values of lipid domains vs the surrounding membrane. RESULTS: Laurdan revealed the majority of sphingomyelin-enriched domains associated to low erythrocyte curvature areas and part of the cholesterol-enriched domains associated with high curvature. Both lipid domains were less ordered than the surrounding lipids in erythrocytes at resting state. Upon erythrocyte deformation (elliptocytes and stimulation of calcium exchanges) or membrane vesiculation (storage at 4°C), lipid domains became more ordered than the bulk. Upon aging and in membrane fragility diseases (spherocytosis), an increase in the difference of lipid order between domains and the surrounding lipids contributed to the initiation of domain vesiculation. CONCLUSION: The critical role of domain-bulk differential lipid order modulation for erythrocyte reshaping is discussed in relation with the pressure exerted by the cytoskeleton on the membrane.


Assuntos
Eritrócitos/química , Microdomínios da Membrana/química , 2-Naftilamina/análogos & derivados , 2-Naftilamina/química , Colesterol/metabolismo , Deformação Eritrocítica , Eritrócitos/citologia , Eritrócitos/metabolismo , Humanos , Lauratos/química , Microdomínios da Membrana/metabolismo , Microscopia Confocal , Microscopia de Fluorescência por Excitação Multifotônica , Esfingomielinas/química , Esfingomielinas/metabolismo
5.
J Med Screen ; 25(2): 57-63, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-28686106

RESUMO

Objectives To compare the outcomes of sickle cell disease patients diagnosed through neonatal screening with those who were not. Methods In an observational multicenter study in Belgium, 167 screened and 93 unscreened sickle cell disease patients were analyzed for a total of 1116 and 958 patient-years of follow-up, respectively. Both groups were compared with propensity score analysis, with patients matched on three covariates (gender, genotype, and central Africa origin). Bonferroni correction was applied for all comparisons. Results Kaplan-Meier estimates of survival without bacteremia were significantly higher in the screened group than the unscreened group (94.47%; [95% CI, 88.64-97.36%] versus 83.78% [95% CI, 72.27-90.42%]), p = 0.032. Non-significant differences between both groups were reported for survival without acute chest syndrome, acute anemia, cerebral complication, severe infection, and vaso-occlusive crisis. Significantly lower hospitalization rate and days per 100 patient-years were observed in the screened compared with the unscreened group (0.27 vs. 0.63 and 1.25 vs. 2.82, p = 0.0006 and <0.0001). Conclusion These data confirm the benefit of a neonatal screening programme in reducing bacteremia and hospitalization.


Assuntos
Anemia Falciforme/mortalidade , Triagem Neonatal , Avaliação de Resultados em Cuidados de Saúde , Adolescente , Adulto , Anemia Falciforme/diagnóstico , Anemia Falciforme/etnologia , Bélgica/epidemiologia , Criança , Pré-Escolar , Grupos Étnicos , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Masculino , Pontuação de Propensão , Análise de Sobrevida , Adulto Jovem
6.
Blood Cells Mol Dis ; 66: 11-18, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28772256

RESUMO

The most frequent germline mutations responsible for non syndromic congenital sideroblastic anemia are identified in ALAS2 and SLC25A38 genes. Iron overload is a key issue and optimal chelation therapy should be used to limit its adverse effects on the development of children. Our multicentre retrospective descriptive study compared the strategies for diagnosis and management of congenital sideroblastic anemia during the follow-up of six patients with an ALAS2 mutation and seven patients with an SLC25A38 mutation. We described in depth the clinical, biological and radiological phenotype of these patients at diagnosis and during follow-up and highlighted our results with a review of available evidence and data on the management strategies for congenital sideroblastic anemia. This report confirms the considerable variability in manifestations among patients with ALAS2 or SLC25A38 mutations and draws attention to differences in the assessment and the monitoring of iron overload and its complications. The use of an international registry would certainly help defining recommendations for the management of these rare disorders to improve patient outcome.


Assuntos
5-Aminolevulinato Sintetase/genética , Anemia Sideroblástica/congênito , Proteínas de Transporte da Membrana Mitocondrial/genética , Anemia Sideroblástica/genética , Criança , Humanos , Sobrecarga de Ferro , Fenótipo , Estudos Retrospectivos
7.
Front Psychol ; 8: 704, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28539897

RESUMO

Haematopoietic stem cell transplantation (HSCT) improves the survival rate of children and adolescents with malignant and non-malignant conditions; however, the physical, psychological and social burden of such a procedure is considerable both during and after treatment. The present qualitative study investigated the long-term effects of HSCT after pediatric cancer. Thirty adolescent and young adult (AYA) survivors (Mage = 23.61 years, SD = 5.21) participated in individual interviews and were invited to speak about their life experiences following their treatment and strategies they use to deal with their past medical experiences and the long-term sequelae. Our results showed the presence of ongoing physical and psychosocial consequences of their past illness and its treatments with wide ranging psychosocial impacts, such as affected self-image, social withdrawal, sense of lack of choice, and need for specific attention. Different strategies were reported to overcome these consequences, such as talking about illness, giving a sense to their past medical experiences, and developing meaningful social relationships. Clinical and research implications are also discussed.

8.
J Allergy Clin Immunol ; 135(6): 1558-68.e2, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25702837

RESUMO

BACKGROUND: Invasive infections of the central nervous system (CNS) or digestive tract caused by commensal fungi of the genus Candida are rare and life-threatening. The known risk factors include acquired and inherited immunodeficiencies, with patients often displaying a history of multiple infections. Cases of meningoencephalitis, colitis, or both caused by Candida species remain unexplained. OBJECTIVE: We studied 5 previously healthy children and adults with unexplained invasive disease of the CNS, digestive tract, or both caused by Candida species. The patients were aged 39, 7, 17, 37, and 26 years at the time of infection and were unrelated, but each was born to consanguineous parents of Turkish (2 patients), Iranian, Moroccan, or Pakistani origin. Meningoencephalitis was reported in 3 patients, meningoencephalitis associated with colitis was reported in a fourth patient, and the fifth patient had colitis only. METHODS: Inherited caspase recruitment domain family, member 9 (CARD9) deficiency was recently reported in otherwise healthy patients with other forms of severe disease caused by Candida, Trichophyton, Phialophora, and Exophiala species, including meningoencephalitis but not colitis caused by Candida and Exophiala species. Therefore we sequenced CARD9 in the 5 patients. RESULTS: All patients were found to be homozygous for rare and deleterious mutant CARD9 alleles: R70W and Q289* for the 3 patients with Candida albicans-induced meningoencephalitis, R35Q for the patient with meningoencephalitis and colitis caused by Candida glabrata, and Q295* for the patient with Candida albicans-induced colitis. Regardless of their levels of mutant CARD9 protein, the patients' monocyte-derived dendritic cells responded poorly to CARD9-dependent fungal agonists (curdlan, heat-killed C albicans, Saccharomyces cerevisiae, and Exophiala dermatitidis). CONCLUSION: Invasive infections of the CNS or digestive tract caused by Candida species in previously healthy children and even adults might be caused by inherited CARD9 deficiency.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Candidíase Invasiva/genética , Sistema Nervoso Central/patologia , Colite/genética , Trato Gastrointestinal/patologia , Meningoencefalite/genética , Adolescente , Adulto , Proteínas Adaptadoras de Sinalização CARD/deficiência , Proteínas Adaptadoras de Sinalização CARD/imunologia , Candida/imunologia , Candidíase Invasiva/imunologia , Candidíase Invasiva/microbiologia , Candidíase Invasiva/patologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/microbiologia , Criança , Colite/imunologia , Colite/microbiologia , Colite/patologia , Consanguinidade , Feminino , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/microbiologia , Expressão Gênica , Loci Gênicos , Estudo de Associação Genômica Ampla , Homozigoto , Humanos , Masculino , Meningoencefalite/imunologia , Meningoencefalite/microbiologia , Meningoencefalite/patologia , Linhagem , Análise de Sequência de DNA
9.
Br J Clin Pharmacol ; 79(3): 429-40, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25099492

RESUMO

AIMS: Acute lymphoblastic leukemia (ALL) is the most common of all paediatric cancers. Aside from predisposing to ALL, polymorphisms could also be associated with poor outcome. Indeed, genetic variations involved in drug metabolism could, at least partially, be responsible for heterogeneous responses to standardized leukemia treatments, hence requiring more personalized therapy. The aims of this study were to (a) to determine the prevalence of seven common genetic polymorphisms including those that affect the folate and/or thiopurine metabolic pathways, i.e. cyclin D1 (CCND1-G870A), γ-glutamyl hydrolase (GGH-C452T), methylenetetrahydrofolate reductase (MTHFR-C677T and MTHFR-A1298C), thymidylate synthase promoter (TYMS-TSER), thiopurine methyltransferase (TPMT*3A and TPMT*3C) and inosine triphosphate pyrophosphatase (ITPA-C94A), in Caucasian (n = 94, age < 20) and Vietnamese (n = 141, age < 16 years) childhood ALL and (b) to assess the impact of a multilocus genetic risk score (MGRS) on relapse-free survival (RFS) using a Cox proportional-hazards regression model. RESULTS: The prevalence of MTHFR-677TT genotype was significantly higher in Caucasians (P = 0.008), in contrast to the prevalence of TYMS-TSER*3R/3R and ITPA-94AA/AC genotypes which were significantly higher in Vietnamese (P < 0.001 and P = 0.02, respectively). Compared with children with a low MGRS (≤ 3), those with a high MGRS (≥ 4) were 2.06 (95% CI = 1.01, 4.22; P = 0.04) times more likely to relapse. Adding MGRS into a multivariate Cox regression model with race/ethnicity and four clinical variables improved the predictive accuracy of the model (AUC from 0.682 to 0.709 at 24 months). CONCLUSION: Including MGRS into a clinical model improved the predictive accuracy of short and medium term prognosis, hence confirming the association between well determined pharmacogenotypes and outcome of paediatric ALL. Whether variants on other genes associated with folate metabolism can substantially improve the predictive value of current MGRS is not known but deserves further evaluation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Farmacogenética , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Criança , Pré-Escolar , Intervalo Livre de Doença , Frequência do Gene , Humanos , Lactente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Adulto Jovem
10.
Haematologica ; 99(8): 1395-402, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24997149

RESUMO

Long-term granulocyte-colony stimulating factor treatment has been shown to be safe and effective in severe chronic neutropenia patients. However, data on its use during pregnancy are limited. To address this issue, we analyzed all pregnancies reported to the European branch of the Severe Chronic Neutropenia International Registry since 1994. A total of 38 pregnancies in 21 women with chronic neutropenia (16 pregnancies in 10 women with congenital, 10 in 6 women with cyclic, 12 in 5 women with idiopathic neutropenia) were reported. Granulocyte-colony stimulating factor was administered throughout pregnancy in 16 women and for at least one trimester in a further 5 women. No major differences were seen between treated and untreated women with respect to pregnancy outcome, newborn complications and infections. In addition, we evaluated the genetic transmission of known or suspected genetic defects in 16 mothers having 22 newborns as well as in 8 men fathering 15 children. As a proof of inheritance, neutropenia was passed on to the newborn in 58% from female and in 62% from male patients with ELANE mutations, but also to some newborns from parents with unknown gene mutation. Based on our results, granulocyte-colony stimulating factor therapy has been shown to be safe for mothers throughout pregnancies and for newborns without any signs of teratogenicity. With an increasing number of adult patients, genetic counseling prior to conception and supportive care of mothers during pregnancy are crucial. The acceptance of having affected children may reflect the high quality of life obtained due to this treatment.


Assuntos
Neutropenia/diagnóstico , Neutropenia/terapia , Complicações Hematológicas na Gravidez/diagnóstico , Complicações Hematológicas na Gravidez/terapia , Sistema de Registros , Adulto , Estudos de Coortes , Gerenciamento Clínico , Europa (Continente)/epidemiologia , Feminino , Humanos , Recém-Nascido , Masculino , Neutropenia/epidemiologia , Gravidez , Complicações Hematológicas na Gravidez/epidemiologia , Resultado da Gravidez/epidemiologia , Resultado do Tratamento , Adulto Jovem
11.
J Pediatr Hematol Oncol ; 36(7): 534-40, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24322500

RESUMO

AIM OF THIS STUDY: To compare the relapse-free survival (RFS) in Vietnamese (n=141) and white (n=94) children living in Vietnam and Belgium, respectively, and treated in their own country for acute lymphoblastic leukemia according to the same FRALLE 2000 protocol. RESULTS: RFS was significantly worse in Vietnamese children (hazards ratio=4.48; 95% confidence interval [CI], 2.16-9.3; P<0.01). The 5-year RFS was 83.8% (95% CI, 76.3%-92.0%) and 47.8% (95% CI, 35.6%-64.2%) for white and Vietnamese children, respectively. In the latter group, relapses occurred in bone marrow and cerebrospinal fluid at a much earlier stage. The outcome was compared at first relapse only because of different treatments afterward, according to the country. Both series were similar for sex, age at diagnosis, initial white blood cell count, cytogenetic abnormalities, and corticosensitivity at day 8. Higher frequency of L2-acute lymphoblastic leukemia (P<0.001) but lower frequency of T-acute lymphoblastic leukemia (P=0.004) were observed in Vietnamese children. CONCLUSIONS: Several factors may contribute to the poor RFS in Vietnamese children, which include the time interval before the first intrathecal therapy and differences in the management of drug-related toxicity. However, additional contribution of socioeconomic factors and/or variations in pharmacogenetic polymorphisms in Vietnamese patients cannot currently be ruled out.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Antimetabólitos Antineoplásicos/uso terapêutico , Bélgica/epidemiologia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Mercaptopurina/uso terapêutico , Metotrexato/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/etnologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Modelos de Riscos Proporcionais , Resultado do Tratamento , Vietnã/epidemiologia , Adulto Jovem
12.
Transfus Apher Sci ; 49(2): 151-4, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23954416

RESUMO

Tremendous progress has been made in the treatment of patients with sickle cell anaemia. This paper emphasises the benefit of early therapy with hydroxyurea, the indication for blood transfusions including iron chelation and the role of hematopoietic stem cell transplantation. In order to offer transplantation to a larger number of patients including adolescents and young adults, it is important to find less toxic, but still effective conditioning therapy and to evaluate the feasability of using alternative donors.


Assuntos
Anemia Falciforme/terapia , Antidrepanocíticos/uso terapêutico , Transfusão de Sangue , Transplante de Células-Tronco Hematopoéticas , Hidroxiureia/uso terapêutico , Quelantes de Ferro/uso terapêutico , Adolescente , Adulto , Aloenxertos , Criança , Pré-Escolar , Feminino , Humanos , Masculino
13.
Pediatr Blood Cancer ; 60(12): 1982-7, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23897631

RESUMO

BACKGROUND: Iron overload is responsible for severe morbidity and mortality in polytransfused patients. Although repeated blood transfusions are needed during the treatment of most cancers, pediatric patients are not routinely screened for subsequent iron overload. PROCEDURE: Seventy-five patients were identified as candidates for cancer treatment and enrolled prospectively in a yearly protocol including a cardiac and liver magnetic resonance imaging coupled with ferritin level measurements. Patients were divided into four groups using the intensity of treatment rating (ITR-3). RESULTS: Fifty-nine patients reached 1-year of follow-up and liver iron overload was found in up to 66% of them. Such overload correlated with the total volume of red blood cells transfused and persisted at least 2 years after the initiation of therapy. Moderate myocardial overload was also, but less frequently (14%), observed in these patients. CONCLUSIONS: Our study demonstrated that severe liver iron overload as well as moderate myocardial iron overload can be found 1 year after cancer treatment and that this overload persists overtime. The patients with higher ITR and those who have received more than a liter of blood red cells per square meter, regardless of their diagnosis or ITR, are at risk of iron overload and should be screened carefully.


Assuntos
Sobrecarga de Ferro/epidemiologia , Sobrecarga de Ferro/etiologia , Neoplasias/terapia , Reação Transfusional , Adolescente , Criança , Pré-Escolar , Feminino , Ferritinas/sangue , Humanos , Lactente , Masculino , Estudos Prospectivos
14.
Blood ; 122(6): 1072-8, 2013 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-23692854

RESUMO

We analyzed the outcomes of 485 patients with thalassemia major (TM) or sickle cell disease (SCD) receiving HLA-identical sibling cord blood transplantation (CBT, n = 96) or bone marrow transplantation (BMT, n = 389). Compared with patients given BMT, CBT recipients were significantly younger (median age 6 vs 8 years, P = .02), and were treated more recently (median year 2001 vs 1999, P < .01). A higher proportion of patients with TM belonging to classes II-III of the Pesaro classification received BMT (44%) compared with CBT (39%, P < .01). In comparison with patients receiving BMT (n = 259, TM; n = 130, SCD), those given CBT (n = 66, TM; n = 30, SCD) had slower neutrophil recovery, less acute graft-versus-host disease (GVHD) and none had extensive chronic GVHD. With a median follow-up of 70 months, the 6-year overall survival was 95% and 97% after BMT and CBT, respectively (P = .92). The 6-year disease-free survival (DFS) was 86% and 80% in TM patients after BMT and CBT, respectively, whereas DFS in SCD patients was 92% and 90%, respectively. The cell dose infused did not influence outcome of patients given CBT. In multivariate analysis, DFS did not differ between CBT and BMT recipients. Patients with TM or SCD have excellent outcomes after both HLA-identical sibling CBT and BMT.


Assuntos
Transplante de Medula Óssea/métodos , Sangue Fetal/transplante , Antígenos HLA/imunologia , Hemoglobinopatias/imunologia , Hemoglobinopatias/terapia , Adolescente , Adulto , Plaquetas/citologia , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/terapia , Humanos , Lactente , Masculino , Análise Multivariada , Neutrófilos/citologia , Neutrófilos/metabolismo , Irmãos , Resultado do Tratamento , Adulto Jovem
15.
Eur J Pediatr ; 172(5): 613-22, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23315050

RESUMO

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterised by skeletal dysplasia, exocrine pancreatic insufficiency and bone marrow failure. Various other conditions, such as hepatopathy and failure to thrive have been associated with SDS. A retrospective study was conducted to describe mutations, clinical features, and the immunological profile of 11 Belgian patients with genetically confirmed diagnosis of SDS. This study confirms the existing understanding of the classical features of SDS although the typical triad was present in only six out of nine fully studied patients. The following important observations are made in this cohort. Four out of eleven patients were misdiagnosed as having Asphyxiating Thoracic Dystrophy (Jeune syndrome) because of severe thoracic dystrophy. Another two patients presented with unexplained episodes of symptomatic hypoglycaemia. The immunological phenotype was heterogeneous although laboratory abnormalities were noticed in eight out of ten patients assessed. Three patients experienced a life threatening viral infection (respiratory syncytial virus, cytomegalovirus (CMV) and rotavirus). In one patient, CMV infection caused an episode of haemophagocytic lymphohistiocytosis. One patient has bronchiectasis at the age of 3 years due to recurrent respiratory tract infections. These findings strengthen the suspicion of an abnormal immune system in SDS. Liver anomalies, usually described as benign and transitory in SDS patients, were severe in two patients of the cohort. One patient developed hepatopulmonary syndrome. The findings in this national cohort of SDS patients could contribute to the prevention of misdiagnosis in the future and enable more rapid recognition of certain severe complications.


Assuntos
Doenças da Medula Óssea/diagnóstico , Infecções por Citomegalovirus/diagnóstico , Erros de Diagnóstico , Síndrome de Ellis-Van Creveld/diagnóstico , Insuficiência Pancreática Exócrina/diagnóstico , Lipomatose/diagnóstico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Adulto , Bélgica , Doenças da Medula Óssea/complicações , Infecções por Citomegalovirus/complicações , Diagnóstico Diferencial , Insuficiência Pancreática Exócrina/complicações , Feminino , Humanos , Lipomatose/complicações , Masculino , Estudos Retrospectivos , Síndrome de Shwachman-Diamond
16.
J Lipid Res ; 54(4): 1066-76, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23322884

RESUMO

Micrometric membrane lipid segregation is controversial. We addressed this issue in attached erythrocytes and found that fluorescent boron dipyrromethene (BODIPY) analogs of glycosphingolipids (GSLs) [glucosylceramide (BODIPY-GlcCer) and monosialotetrahexosylganglioside (GM1BODIPY)], sphingomyelin (BODIPY-SM), and phosphatidylcholine (BODIPY-PC inserted into the plasma membrane spontaneously gathered into distinct submicrometric domains. GM1BODIPY domains colocalized with endogenous GM1 labeled by cholera toxin. All BODIPY-lipid domains disappeared upon erythrocyte stretching, indicating control by membrane tension. Minor cholesterol depletion suppressed BODIPY-SM and BODIPY-PC but preserved BODIPY-GlcCer domains. Each type of domain exchanged constituents but assumed fixed positions, suggesting self-clustering and anchorage to spectrin. Domains showed differential association with 4.1R versus ankyrin complexes upon antibody patching. BODIPY-lipid domains also responded differentially to uncoupling at 4.1R complexes [protein kinase C (PKC) activation] and ankyrin complexes (in spherocytosis, a membrane fragility disease). These data point to micrometric compartmentation of polar BODIPY-lipids modulated by membrane tension, cholesterol, and differential association to the two nonredundant membrane:spectrin anchorage complexes. Micrometric compartmentation might play a role in erythrocyte membrane deformability and fragility.


Assuntos
Eritrócitos/metabolismo , Lipídeos de Membrana/química , Western Blotting , Compostos de Boro/química , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Células Cultivadas , Colesterol/química , Cromatografia em Camada Delgada , Eritrócitos/efeitos dos fármacos , Eritrócitos/ultraestrutura , Glicoesfingolipídeos/química , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Microscopia Eletrônica de Varredura , Fosfatidilcolinas/química , Esfingomielinas/química , beta-Ciclodextrinas/farmacologia
17.
Clin Endocrinol (Oxf) ; 78(5): 790-8, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-22967316

RESUMO

INTRODUCTION: An increased prevalence of metabolic disorders and cardiovascular (CV) disease has been reported in childhood acute lymphoblastic leukaemia (ALL)/non-Hodgkin lymphoma (NHL) cancer survivors. OBJECTIVE: To characterize the determinants of insulin resistance (IR) observed in this population, according to the treatment received. METHODS: Ninety one patients (45 men, mean age: 24 ± 5 years; mean follow-up: 15 ± 5 years) previously treated for a childhood ALL (n = 76) or NHL (n = 15) were grouped according to their previous treatment: chemotherapy only (Group I; n = 43), chemotherapy + cranial irradiation (CI) (Group II; n = 32) and chemotherapy + bone marrow transplant (BMT)/total body irradiation (TBI) (Group III, n = 16). RESULTS: A high prevalence of IR (HOMA-S < 60%) was observed in the BMT/TBI group (88%) compared to groups I (9%) and II (16%). The IR patients from groups [I+II] (12% of these groups) showed higher BMI, fat mass (FM) and visceral fat when compared with the non-IR patients. In contrast, the IR patients from group III had mean BMI and total FM similar to those of non-IR patients but showed a reduction of lean body mass and an increase in the relative proportion of trunk FM similar to the IR patients from groups [I + II]. This was associated with an altered lipid profile, high TNF-α and IL-6 levels, and reduced adiponectin levels compared to IR patients from group [I + II] and non-IR patients. CONCLUSION: Childhood ALL/NHL survivors treated by BMT/TBI frequently develop severe insulin resistance associated with peripheral-to-central fat redistribution, rather than increased total FM, and low adiponectin levels which may contribute to their increased CV risk.


Assuntos
Resistência à Insulina/fisiologia , Linfoma não Hodgkin/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Adulto , Feminino , Humanos , Masculino , Adulto Jovem
18.
Haematologica ; 97(11): 1743-50, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22580999

RESUMO

BACKGROUND: The prognosis of patients with relapses of ETV6/RUNX1-positive acute lymphoblastic leukemia remains to be evaluated, particularly with regards to the frequency of late relapses. We performed a long-term, follow-up retrospective study to address the outcome of patients with ETV6/RUNX1-positive leukemia relapses. DESIGN AND METHODS: Among the 713 children tested for ETV6/RUNX1 enrolled into the FRALLE 93 protocol, 43 ETV6/RUNX1-positive patients relapsed (19.4%). Most were initially stratified in the low or intermediate risk groups. The median follow-up after relapse was 54.2 months. All but three received second-line salvage therapy and 16 underwent allogeneic transplantation. RESULTS: ETV6/RUNX1 had a strong effect on overall survival after relapse (3-year survival= 64.7% for positive cases versus 46.5% for negative cases) (P=0.007). The 5-year cumulative incidence of relapse was 19.4% and testes were more frequently involved in ETV6/RUNX1-positive relapses (P=0.04). In 81.4% of cases the relapses were late, early combined or isolated extramedullary relapses. The 5-year survival rate of patients with ETV6-RUNX1-positive acute lymphoblastic leukemia relapses reached 80.8% when the relapse occurred after 36 months (versus 31.2% when the relapse occurred earlier). In univariate analysis, female gender was associated with a poor survival, whereas site of relapse, age at diagnosis, leukocytosis and consolidation strategy had no effect. In multivariate analysis, only the duration of first remission remained associated with outcome. CONCLUSIONS: We found an excellent outcome for patients with ETV6/RUNX1-positive leukemia relapses that occurred more than 36 months after diagnosis. The duration of first complete remission may, therefore, be a guide to define the treatment strategy for patients with relapsed ETV6/RUNX1- positive leukemia.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Subunidade alfa 2 de Fator de Ligação ao Core , Transplante de Células-Tronco Hematopoéticas , Proteínas de Fusão Oncogênica , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Antraciclinas/administração & dosagem , Asparaginase/administração & dosagem , Criança , Pré-Escolar , Cortisona/administração & dosagem , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Recidiva , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Transplante Homólogo , Vincristina/administração & dosagem
19.
Blood ; 119(12): 2935-42, 2012 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-22160619

RESUMO

We investigated prospectively factors influencing the safety of hematopoietic stem cell (HSC) collection in 453 pediatric donors. The children in the study donated either BM or peripheral blood stem cells (PBSCs) according to center policy. A large variability in approach to donor issues was observed between the participating centers. Significant differences were observed between BM and PBSC donors regarding pain, blood allotransfusion, duration of hospital stay, and iron supplementation; however, differences between the groups undergoing BM vs PBSC donation preclude direct risk comparisons between the 2 procedures. The most common adverse event was pain, reported mainly by older children after BM harvest, but also observed after central venous catheter (CVC) placement for PBSC collection. With regard to severe adverse events, one patient (0.7%) developed a pneumothorax with hydrothorax after CVC placement for PBSC collection. The risk of allotransfusion after BM harvest was associated with a donor age of < 4 years and a BM harvest volume of > 20 mL/kg. Children < 4 years were at higher risk than older children for allotransfusion after BM harvest and there was a higher risk of complications from CVC placement before apheresis. We conclude that PBSC and BM collection are safe procedures in children.


Assuntos
Coleta de Amostras Sanguíneas/efeitos adversos , Coleta de Amostras Sanguíneas/métodos , Transplante de Células-Tronco Hematopoéticas , Doadores de Tecidos , Adolescente , Transplante de Medula Óssea , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Transplante de Células-Tronco de Sangue Periférico , Irmãos , Doadores de Tecidos/psicologia
20.
Fertil Steril ; 96(1): 126-133.e3, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21550046

RESUMO

OBJECTIVE: To evaluate which factors determine premature ovarian failure after bone marrow transplantation (BMT) during childhood and adolescence. DESIGN: Cross-sectional study. SETTING: Academic teaching hospital. PATIENT(S): Thirty-five women with previous allogeneic (n = 19) or autologous (n = 16) BMT for benign (n = 12) or malignant disease (n = 23). Mean age at BMT was 9.8 ± 5.2 years. Eighteen patients had received total body irradiation (TBI). Twenty-three (66%) were premenarchal at the time of BMT. INTERVENTION(S): Evaluation of ovarian function. MAIN OUTCOME MEASURE(S): Retrospective analysis of gynecologic history and hormone measurements (FSH, E(2), and antimüllerian hormone [AMH]) in relation to initial pathology, treatment protocols, age, and menarchal status at the time of BMT and time elapsed since BMT. RESULT(S): Clinical evidence of persistent ovarian function after BMT was found in 46% of patients (16/35), but low AMH concentrations (<1.2 µg/L) were observed in 85% of patients, including a large subset (2/3) of clinically eugonadal subjects. Age ≤10 years at the time of BMT and absence of TBI were significantly and independently associated with higher rates of clinically proven persistent ovarian function at the time of evaluation. CONCLUSION(S): After BMT, ovarian function is impaired in the majority of women, even without clinical signs of premature ovarian failure. This impairment is mostly related to older age at the time of treatment and conditioning treatment with TBI.


Assuntos
Transplante de Medula Óssea/efeitos adversos , Ovário/fisiologia , Insuficiência Ovariana Primária/diagnóstico , Insuficiência Ovariana Primária/fisiopatologia , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Pessoa de Meia-Idade , Ovário/efeitos da radiação , Insuficiência Ovariana Primária/cirurgia , Estudos Retrospectivos , Irradiação Corporal Total/efeitos adversos , Adulto Jovem
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