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Find video protocols related to scientific articles indexed in Pubmed.
HIV transmission through breastfeeding: still possible in developed countries.
Pediatrics
PUBLISHED: 08-20-2014
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We describe here the case of a 13-month-old boy who acquired HIV infection postnatally through breastfeeding in a developed country in 2012. His mother had regular pregnancy follow-up and was found to be seronegative for HIV on 2 consecutive screening tests (during pregnancy and just after delivery). However, 1 year later, diagnosis of HIV infection arose in both of them after a pediatric emergency department visit for bronchitis when unexplained hepatosplenomegaly and inflammatory syndrome were noted. The negative maternal viral load found just after delivery confirmed that the mother's seroconversion occurred postnatally, which allowed for active HIV transmission during lactation and lack of the efficient preventive measures that have implemented in Belgium for years. We discuss this uncommon but still existing mode of HIV transmission in industrialized countries and highlight the importance of implementing new targeted health education interventions in addition to constant clinicians' awareness.
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A pilot study of manual chronic partial exchange transfusion in children with sickle disease.
Hematology
PUBLISHED: 08-18-2014
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Objective Red cell exchange transfusion is frequently used in the management of patients with sickle cell disease (SCD) either electively or chronically to maintain hemoglobin S (HbS) <30%. The purpose of this retrospective study was to evaluate the results of manual chronic partial exchange transfusion (MCPET) on level of Hb and HbS, on iron load and on the need for chelation, on risk of immunization, monitoring transfusion-transmitted viral infection, and clinical outcome. Methods We reviewed the long-term effect of MCPET in 10 children (six men and four women) with SCD and evaluated the iron balance during a median follow-up of 20 months (range: 6-36) in which 248 exchanges were performed. Results The pre-exchange median Hb value was 9.5 g/dl (range: 7.7-10.9 g/dl) and the median post-exchange value was 9.4 g/dl (range: 8.4-11.1 g/dl).The majority of patients reached an HbS of <50% with a median HbS value of 40.04% (range: 30-54). At start of the MCPET program, the median ferritin was 439 ng/ml (range: 80-1704 ng/ml). In the final evaluation, the median value of ferritin was 531 ng/ml (range: 84-3840 ng/ml). The annual calculated iron balance was 0. 28 ± 0.08 mg/kg/day. MCPET was well tolerated, and adverse effects were limited. Discussion MCPET in children with SCD is safe to prevent iron overload, and is effective and easy to use in our cohort. Conclusion Indication for chronic exchange blood transfusion is essential for patients with SCD with recurrent and frequent crises who do not respond to hydroxyurea. However, there is no consensual study for the period at which chronic transfusion can safely be stopped and further research in large population of patients with SCD will need to clarify this question.
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Detection of Herpesviridae in whole blood by multiplex PCR DNA-based microarray analysis after hematopoietic stem cell transplantation.
J. Clin. Microbiol.
PUBLISHED: 05-14-2014
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Viral infections are important causes of morbidity and mortality in patients after hematopoietic stem cell transplantation. The monitoring by PCR of Herpesviridae loads in blood samples has become a critical part of posttransplant follow-up, representing mounting costs for the laboratory. In this study, we assessed the clinical performance of the multiplex PCR DNA microarray Clart Entherpex kit for detection of cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus 6 (HHV-6) as a screening test for virological follow-up. Two hundred fifty-five blood samples from 16 transplanted patients, prospectively tested by routine PCR assays, were analyzed by microarray. Routine PCR detected single or multiple viruses in 42% and 10% of the samples, respectively. Microarray detected single or multiple viruses in 34% and 18% of the samples, respectively. Microarray results correlated well with CMV and EBV detections by routine PCR (kappa tests = 0.79 and 0.78, respectively), whereas a weak correlation was observed with HHV-6 (0.43). HHV-7 was also detected in 48 samples by microarray. In conclusion, the microarray is a reliable screening assay for a posttransplant virological follow-up to detect CMV and EBV infections in blood. However, positive samples must be subsequently confirmed and viral loads must be quantified by PCR assays. Limitations were identified regarding HHV-6 detection. Although it is promising, is easy to use as a first-line test, and allows a reduction in the cost of analysis without undue delay in the reporting of the final quantitative result to the clinician, some characteristics of this microarray should be improved, particularly regarding quality control and the targeted virus panel, such that it could then be used as a routine test.
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Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia.
Haematologica
PUBLISHED: 04-24-2014
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Pregnancy in women with inherited thrombocytopenias is a major matter of concern as both the mothers and the newborns are potentially at risk of bleeding. However, medical management of this condition cannot be based on evidence because of the lack of consistent information in the literature. To advance knowledge on this matter, we performed a multicentric, retrospective study evaluating 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Neither the degree of thrombocytopenia nor the severity of bleeding tendency worsened during pregnancy and the course of pregnancy did not differ from that of healthy subjects in terms of miscarriages, fetal bleeding and pre-term births. The degree of thrombocytopenia in the babies was similar to that in the mother. Only 7 of 156 affected newborns had delivery-related bleeding, but 2 of them died of cerebral hemorrhage. The frequency of delivery-related maternal bleeding ranged from 6.8% to 14.2% depending on the definition of abnormal blood loss, suggesting that the risk of abnormal blood loss was increased with respect to the general population. However, no mother died or had to undergo hysterectomy to arrest bleeding. The search for parameters predicting delivery-related bleeding in the mother suggested that hemorrhages requiring blood transfusion were more frequent in women with history of severe bleedings before pregnancy and with platelet count at delivery below 50 × 10(9)/L.
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Dexamethasone (6 mg/m2/day) and prednisolone (60 mg/m2/day) were equally effective as induction therapy for childhood acute lymphoblastic leukemia in the EORTC CLG 58951 randomized trial.
Haematologica
PUBLISHED: 04-11-2014
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Dexamethasone could be more effective than prednisolone at similar anti-inflammatory doses in the treatment of childhood acute lymphoblastic leukemia. In order to check if this "superiority" of dexamethasone might be dose-dependent, we conducted a randomized phase III trial comparing dexamethasone (6 mg/m(2)/day) to prednisolone (60 mg/m(2)/day) in induction therapy. All newly diagnosed children and adolescents with acute lymphoblastic leukemia in the 58951 EORTC trial were randomized on prephase day 1 or day 8. The main endpoint was event-free survival; secondary endpoints were overall survival and toxicity. A total of 1947 patients with acute lymphoblastic leukemia were randomized. At a median follow-up of 6.9 years, the 8-year event-free survival rate was 81.5% in the dexamethasone arm and 81.2% in the prednisolone arm; the 8-year overall survival rates were 87.2% and 89.0% respectively. The 8-year incidences of isolated or combined central nervous system relapse were 2.9% and 4.5% in the dexamethasone and prednisolone arms, respectively. The incidence of grade 3-4 toxicities during induction and the frequency of osteonecrosis were similar in the two arms. In conclusion, dexamethasone and prednisolone, used respectively at the doses of 6 and 60 mg/m(2)/day during induction, were equally effective and had a similar toxicity profile. Dexamethasone decreased the 8-year central nervous system relapse incidence by 1.6%. This trial was registered at www.clinicaltrials.gov as #NCT00003728.
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Haematopoietic stem cell transplantation for severe sickle cell disease in childhood: a single centre experience of 50 patients.
Br. J. Haematol.
PUBLISHED: 01-16-2014
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Despite improvements in medical management, sickle cell disease (SCD) remains associated with severe morbidity and decreased survival. Allogeneic haematopoietic stem cell transplantation (HSCT) remains the only curative approach. We report the outcome of 50 consecutive children with severe SCD that received HSCT in our unit between November 1988 and April 2013. The stem cell source was bone marrow (n = 39), cord blood (n = 3), bone marrow and cord blood (n = 7) and peripheral blood stem cells (n = 1). All patients had ?1 severe manifestation: 37 presented with recurrent vaso-occlusive crises/acute chest syndrome, 27 cerebral vasculopathy and 1 nephropathy. The conditioning regimen consisted of busulfan + cyclophosphamide (BuCy) before November 1991 and BuCy + rabbit antithymocyte globulin after that date. Since 1995, all patients have been treated with hydroxycarbamide (HC) prior to transplantation for a median duration of 2·7 years. Median age at transplantation and median follow-up was 8·3 and 7·7 years, respectively. Acute graft-versus-host disease (GVHD) and chronic GVHD were observed in 11 and 10 patients, respectively. An excellent outcome was achieved, with 8-year overall survival and event-free survival (EFS) rates of 94·1% and 85·6%, respectively. Since HC introduction, no graft failure occurred and EFS reached 97·4%. Prior treatment with HC may have contributed to successful engraftment.
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Reduction of the six-minute walk distance in children with sickle cell disease is correlated with silent infarct: results from a cross-sectional evaluation in a single center in Belgium.
PLoS ONE
PUBLISHED: 01-01-2014
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The 6-minute walk test (6 MWT) is used in adults and children affected by a wide range of chronic diseases to evaluate their sub-maximal exercise capacity. It reflects the global response of various physiological systems in a situation simulating a daily life activity.
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Pneumococcal Antibody Levels in Children With PID Receiving Immunoglobulin.
Pediatrics
PUBLISHED: 12-23-2013
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Clinical data are lacking on optimal levels of specific antipneumococcal antibodies (PnPsAbs) in patients with primary immunodeficiency (PID) receiving intravenous immunoglobulin (IVIG) replacement. Objectives were to conduct a prospective multicenter study providing data on total immunoglobulin G (IgG) and peak/trough levels of PnPsAbs specifically targeting the 16 most prevalent pneumococcal serotypes in IVIG-treated children with PID; to compare trough PnPsAb levels with those measured in healthy adults and the IVIG product; and to evaluate PnPsAb protection correlates with thresholds based on World Health Organization.
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Transient leukemia in a newborn without Down syndrome: case report and review of the literature.
Eur. J. Pediatr.
PUBLISHED: 07-04-2013
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Transient neonatal leukemia occurs almost exclusively in Down syndrome babies. We report here the unusual case of a newborn without Down syndrome who presented neonatal transient leukemia and who achieved spontaneously complete remission. Trisomy 21 and GATA1 mutation were both present in leukemic cells. While close follow-up is advised since true leukemia may develop later, the patient is still in remission for 2.5 years. We performed a literature review of 15 other similar cases. Conclusion: Our case of transient leukemia without Down syndrome and the literature review highlight the important role of trisomy 21 and GATA1 mutation in the development of transient neonatal leukemia.
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Thrombin generation in children with sickle cell disease: relationship with age, hemolysis, transcranial Doppler velocity, and hydroxyurea treatment.
Eur. J. Haematol.
PUBLISHED: 02-01-2013
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Increased thrombin generation (TG) was described in sickle cell disease (SCD) children. The aim of this study was to characterize TG at the individual level and assess its relationship with age, hemolysis, transcranial Doppler velocity (TCD), and hydroxyurea treatment.
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Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects.
Eur. J. Hum. Genet.
PUBLISHED: 01-30-2013
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Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a primary immunodeficiency, predominantly characterized by agammaglobulinemia or hypoimmunoglobulinemia, centromere instability and facial anomalies. Mutations in two genes have been discovered to cause ICF syndrome: DNMT3B and ZBTB24. To characterize the clinical features of this syndrome, as well as genotype-phenotype correlations, we compared clinical and genetic data of 44 ICF patients. Of them, 23 had mutations in DNMT3B (ICF1), 13 patients had mutations in ZBTB24 (ICF2), whereas for 8 patients, the gene defect has not yet been identified (ICFX). While at first sight these patients share the same immunological, morphological and epigenetic hallmarks of the disease, systematic evaluation of all reported informative cases shows that: (1) the humoral immunodeficiency is generally more pronounced in ICF1 patients, (2) B- and T-cell compartments are both involved in ICF1 and ICF2, (3) ICF2 patients have a significantly higher incidence of intellectual disability and (4) congenital malformations can be observed in some ICF1 and ICF2 cases. It is expected that these observations on prevalence and clinical presentation will facilitate mutation-screening strategies and help in diagnostic counseling.
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Thrombin generation reveals high procoagulant potential in the plasma of sickle cell disease children.
Am. J. Hematol.
PUBLISHED: 09-20-2011
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Changes in several components of the clotting system are well documented in sickle cell disease (SCD) patients. However, whether the global hemostatic potential of these patients is altered is still unclear. Calibrated automated thrombogram(®) method of thrombin generation (TG) was used to characterize the hemostatic potential of 83 SCD children (75 SS, 6 SC, and 2 S? (thal)) at steady-state as compared with 50 controls of the same range of age. TG was triggered using 1 pM tissue factor and 4 ?M phospholipids with and without thrombomodulin. Thirteen SCD children were also evaluated during vaso-occlusive crisis. Protein C activity, free protein S and D-dimers levels were measured in parallel. SCD patients showed higher rates of thrombin formation, higher thrombin peak height (with and without thrombomodulin), and higher endogenous thrombin potential (ETP) than controls in the presence of thrombomodulin. Reduction of ETP (RETP) in the presence of thrombomodulin was lower in SCD group compared with controls and correlated both with protein C and protein S levels. ETP, RETP, peak height, and velocity index of TG correlated with D-dimers. Compound heterozygous patients showed an intermediate hemostatic phenotype at steady-state. No significant difference was observed when comparing TG parameters during vaso-occlusive crisis to those obtained at steady-state in the same patients. The global hemostatic potential is increased and reflects the hypercoagulable state of SCD patients even at steady-state. The relevance of this finding with respect to the risk of thrombotic complications of the disease needs further investigation.
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Vitamin B12 deficiency in a 9-month-old boy.
Eur. J. Pediatr.
PUBLISHED: 06-28-2011
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We present a 9-month-old boy with megaloblastic anaemia, neutropenia and hypogammaglobulinaemia due to vitamin B12 deficiency. The deficiency was secondary to prolonged exclusive breastfeeding with inadequate nutritional amounts of vitamin B12 from the mother. There were no clinical or biological signs of maternal anaemia or macrocytosis. Treatment with oral vitamin B12 rapidly improved the biological findings of the child. Vitamin B12 deficiency should be considered in infants older than 2 months presenting with failure to thrive, neurocognitive retardation or even pancytopenia and hypogammaglobulinaemia, even in the absence of any signs of maternal anaemia or macrocytosis. Therefore, evaluation of vitamin B12 status during pregnancy and lactation is necessary in order to prevent B12 deficiency and its possible long-term effects in infants.
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Effects of disodium cromoglycate on cationic exchange of deoxygenated sickle cells.
Eur. J. Pharmacol.
PUBLISHED: 03-21-2011
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In the present work, we explored the way in which cromoglycate, a drug used to treat allergies acts on ion movements in sickle cells. Cells were either slowly deoxygenated by overnight exposure to nitrogen or acutely deoxygenated by exposure to metabisulfite, a strong reducing agent which induces sickling of red blood sickle cells. Flushing the cells with nitrogen increased the intracellular concentration of Na(+) and decreased the intracellular concentration of K(+) and the sum of the concentrations of the two cations. One hundred nM cromoglycate inhibited the decrease of intracellular K(+) and the increase of intracellular Na(+) induced by deoxygenation (n=17). Metabisulfite (100mM) increased the intracellular concentration of Ca(2+) (measured by Fura Red) (n=15) and the shape of the cells (measured by light scattering) (n=9). One ?M cromoglycate partially inhibited these two responses. In conclusion, cromoglycate partially inhibits abnormal K(+) loss, Ca(2+) entry pathways or Ca(2+) channels opened by cell deoxygenation and ensuing membrane modifications and prevents cell sickling.
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Malignancies after hematopoietic cell transplantation for primary immune deficiencies: a report from the Center for International Blood and Marrow Transplant Research.
Biol. Blood Marrow Transplant.
PUBLISHED: 03-16-2011
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We describe the incidence of malignancy in patients with primary immunodeficiency disorders (PIDD) following hematopoietic cell transplantation (HCT). From the Center for International Blood and Marrow Transplant Research, 2266 PIDD patients who had undergone allogeneic HCT between 1968 and 2003 were identified. Patient, disease, and transplant factors for development of malignancy were examined and pathology reports for reported malignancies reviewed independently by a pathologist for confirmation. The incidence of malignancy was highest for Wiskott-Aldrich syndrome (3.3%), with an overall incidence of 2.3% for PIDD. Post-HCT malignancy was confirmed for 52 of 63 reported cases. Forty-five of 52 patients developed posttransplant lymphoproliferative disorders (PTLD) at a median of 3 months post-HCT. Of these, 26 had received T cell-depleted (TCD) bone marrow. Three patients who developed myelodysplastic syndrome had received TCD marrow and total body irradiation. Three patients developed a solid tumor. Patients with PIDD are at a relatively low risk of developing malignancies post-HCT compared with their historic risk of cancer. The most frequent malignancy or lymphoproliferative disorder was early-onset PTLD. As in other HCT recipients, TCD appears to correlate with PTLD development. Our results lend support to the hypothesis that immune reconstitution in PIDD following HCT leads to a decrease in cancer risk.
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Mutations in ZBTB24 are associated with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2.
Am. J. Hum. Genet.
PUBLISHED: 03-13-2011
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Autosomal-recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is mainly characterized by recurrent, often fatal, respiratory and gastrointestinal infections. About 50% of patients carry mutations in the DNA methyltransferase 3B gene (DNMT3B) (ICF1). The remaining patients carry unknown genetic defects (ICF2) but share with ICF1 patients the same immunological and epigenetic features, including hypomethylation of juxtacentromeric repeat sequences. We performed homozygosity mapping in five unrelated ICF2 patients with consanguineous parents and then performed whole-exome sequencing in one of these patients and Sanger sequencing in all to identify mutations in the zinc-finger- and BTB (bric-a-bric, tramtrack, broad complex)-domain-containing 24 (ZBTB24) gene in four consanguineously descended ICF2 patients. Additionally, we found ZBTB24 mutations in an affected sibling pair and in one patient for whom it was not known whether his parents were consanguineous. ZBTB24 belongs to a large family of transcriptional repressors that include members, such as BCL6 and PATZ1, with prominent regulatory roles in hematopoietic development and malignancy. These data thus indicate that ZBTB24 is involved in DNA methylation of juxtacentromeric DNA and in B cell development and/or B and T cell interactions. Because ZBTB24 is a putative DNA-binding protein highly expressed in the lymphoid lineage, we predict that by studying the molecular function of ZBTB24, we will improve our understanding of the molecular pathophysiology of ICF syndrome and of lymphocyte biology in general.
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Antibody deficiency due to a missense mutation in CD19 demonstrates the importance of the conserved tryptophan 41 in immunoglobulin superfamily domain formation.
Hum. Mol. Genet.
PUBLISHED: 02-17-2011
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Immunoglobulin superfamily (IgSF) domains are conserved structures present in many proteins in eukaryotes and prokaryotes. These domains are well-capable of facilitating sequence variation, which is most clearly illustrated by the variable regions in immunoglobulins (Igs) and T cell receptors (TRs). We studied an antibody-deficient patient suffering from recurrent respiratory infections and with impaired antibody responses to vaccinations. Patients B cells showed impaired Ca(2+) influx upon stimulation with anti-IgM and lacked detectable CD19 membrane expression. CD19 sequence analysis revealed a homozygous missense mutation resulting in a tryptophan to cystein (W52C) amino acid change. The affected tryptophan is CONSERVED-TRP 41 located on the C-strand of the first extracellular IgSF domain of CD19 and was found to be highly conserved, not only in mammalian CD19 proteins, but in nearly all characterized IgSF domains. Furthermore, the tryptophan is present in all variable domains in Ig and TR and was not mutated in 117 Ig class-switched transcripts of B cells from controls, despite an overall 10% amino acid change frequency. In vitro complementation studies and CD19 western blotting of patients B cells demonstrated that the mutated protein remained immaturely glycosylated. This first missense mutation resulting in a CD19 deficiency demonstrates the crucial role of a highly conserved tryptophan in proper folding or stability of IgSF domains.
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ENERCA clinical recommendations for disease management and prevention of complications of sickle cell disease in children.
Am. J. Hematol.
PUBLISHED: 02-12-2011
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Universal neonatal screening is performed in the United States, England, the Netherlands, and several cities in Belgium, with selective screening targeted on "high-risk" population in France (globally, one quarter of all the babies born in France are screened). Newborns diagnosed with a major sickle cell syndrome (SCD) should be referred to a designated pediatric sickle cell centre, and the parents are informed that their child has SCD; this may be in the sickle cell centre by an expert physician or in the community by an experienced nurse counsellor. The pediatric sickle cell centre should organize the care of the baby.
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Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of infants with mixed-lineage-leukemia (MLL)-rearranged acute lymphoblastic leukemia: results from the Interfant-99 Study.
Blood
PUBLISHED: 06-30-2010
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To define a role for hematopoietic stem cell transplantation (HSCT) in infants with acute lymphoblastic leukemia and rearrangements of the mixed-lineage-leukemia gene (MLL(+)), we compared the outcome of MLL(+) patients from trial Interfant-99 who either received chemotherapy only or HSCT. Of 376 patients with a known MLL status in the trial, 297 (79%) were MLL(+). Among the 277 of 297 MLL(+) patients (93%) in first remission (CR), there appeared to be a significant difference in disease-free survival (adjusted by waiting time to HSCT) between the 37 (13%) who received HSCT and the 240 (87%) who received chemotherapy only (P = .03). However, the advantage was restricted to a subgroup with 2 additional unfavorable prognostic features: age less than 6 months and either poor response to steroids at day 8 or leukocytes more than or equal to 300 g/L. Ninety-seven of 297 MLL(+) patients (33%) had such high-risk criteria, with 87 achieving CR. In this group, HSCT was associated with a 64% reduction in the risk of failure resulting from relapse or death in CR (hazard ratio = 0.36, 95% confidence interval, 0.15-0.86). In the remaining patients, there was no advantage for HSCT over chemotherapy only. In summary, HSCT seems to be a valuable option for a subgroup of infant MLL(+) acute lymphoblastic leukemia carrying further poor prognostic factors. The trial was registered at www.clinicaltrials.gov as #NCT00015873 and at www.controlled-trials.com as #ISRCTN24251487.
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CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency.
J. Clin. Invest.
PUBLISHED: 01-13-2010
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Antibody deficiencies constitute the largest group of symptomatic primary immunodeficiency diseases. In several patients, mutations in CD19 have been found to underlie disease, demonstrating the critical role for the protein encoded by this gene in antibody responses; CD19 functions in a complex with CD21, CD81, and CD225 to signal with the B cell receptor upon antigen recognition. We report here a patient with severe nephropathy and profound hypogammaglobulinemia. The immunodeficiency was characterized by decreased memory B cell numbers, impaired specific antibody responses, and an absence of CD19 expression on B cells. The patient had normal CD19 alleles but carried a homozygous CD81 mutation resulting in a complete lack of CD81 expression on blood leukocytes. Retroviral transduction and glycosylation experiments on EBV-transformed B cells from the patient revealed that CD19 membrane expression critically depended on CD81. Similar to CD19-deficient patients, CD81-deficient patients had B cells that showed impaired activation upon stimulation via the B cell antigen receptor but no overt T cell subset or function defects. In this study, we present what we believe to be the first antibody deficiency syndrome caused by a mutation in the CD81 gene and consequent disruption of the CD19 complex on B cells. These findings may contribute to unraveling the genetic basis of antibody deficiency syndromes and the nonredundant functions of CD81 in humans.
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Outcome of congenital acute lymphoblastic leukemia treated on the Interfant-99 protocol.
Blood
PUBLISHED: 08-05-2009
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Acute lymphoblastic leukemia (ALL) diagnosed in the first month of life (congenital ALL) is very rare. Although congenital ALL is often assumed to be fatal, no studies have been published on outcome except for case reports. The present study reports the outcome of 30 patients with congenital ALL treated with the uniform Interfant-99 protocol, a hybrid regimen combining ALL treatment with elements designed for treatment of acute myeloid leukemia. Congenital ALL was characterized by a higher white blood cell count and a strong trend for higher incidence of MLL rearrangements and CD10-negative B-lineage ALL compared with older infants. Induction failure rate was 13% and not significantly different from that in older infants (7%, P = .14), but relapse rate was significantly higher in congenital ALL patients (2-year cumulative incidence [SE] was 60.0 [9.3] vs 34.2 [2.3], P < .001). Two-year event-free survival and survival of congenital ALL patients treated with this protocol was 20% (SE 9.1%). Early death in complete remission and treatment delays resulting from toxicity were not different. The survival of 17% after last follow-up, combined with a toxicity profile comparable with that in older infants, justifies treating congenital ALL with curative intent. This trial was registered at www.clinicaltrials.gov as no. NCT 00015873, and at www.controlled-trials.com as no. ISRCTN24251487.
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In vitro inhibitory effects of disodium cromoglycate on ionic transports involved in sickle cell dehydration.
Pharmacology
PUBLISHED: 02-24-2009
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The antiallergic and antiasthmatic drug disodium cromoglycate (DSCG) has also demonstrated an activity against sickle cell disease, but the mechanism of this action still remains unknown.
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FAS-L, IL-10, and double-negative CD4- CD8- TCR alpha/beta+ T cells are reliable markers of autoimmune lymphoproliferative syndrome (ALPS) associated with FAS loss of function.
Blood
PUBLISHED: 01-27-2009
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Autoimmune lymphoproliferative syndrome (ALPS) is characterized by splenomegaly, lymphadenopathy, hypergammaglobulinemia, accumulation of double-negative TCRalphabeta(+) CD4(-)CD8(-) T cells (DNT cells), and autoimmunity. Previously, DNT cell detection and a functional defect of T cells in a FAS-induced apoptosis test in vitro had been used for ALPS diagnosis. However, a functional defect can also be detected in mutation-positive relatives (MPRs) who remain free of any ALPS-related disease. In contrast, lymphocytes from patients carrying a somatic mutation of FAS exhibit normal sensitivity to FAS-induced apoptosis in vitro. We assessed the soluble FAS-L concentration in the plasma of ALPS patients carrying FAS mutations. Overall, we showed that determination of the FAS-L represents, together with the IL-10 concentration and the DNT cell percentage, a reliable tool for the diagnosis of ALPS.
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Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness.
Nat. Genet.
PUBLISHED: 01-24-2009
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Reticular dysgenesis is an autosomal recessive form of human severe combined immunodeficiency characterized by an early differentiation arrest in the myeloid lineage and impaired lymphoid maturation. In addition, affected newborns have bilateral sensorineural deafness. Here we identify biallelic mutations in AK2 (adenylate kinase 2) in seven individuals affected with reticular dysgenesis. These mutations result in absent or strongly decreased protein expression. We then demonstrate that restoration of AK2 expression in the bone marrow cells of individuals with reticular dysgenesis overcomes the neutrophil differentiation arrest, underlining its specific requirement in the development of a restricted set of hematopoietic lineages. Last, we establish that AK2 is specifically expressed in the stria vascularis region of the inner ear, which provides an explanation of the sensorineural deafness in these individuals. These results identify a previously unknown mechanism involved in regulation of hematopoietic cell differentiation and in one of the most severe human immunodeficiency syndromes.
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Plasma hydroxyurea determined by gas chromatography-mass spectrometry.
J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.
PUBLISHED: 01-16-2009
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Hydroxyurea treatment is efficiently used to ameliorate the clinical course of patients affected with sickle cell disease. To understand the patients wide variation in the clinical response to that drug and monitor its plasma levels, a new method was developed and validated. Fifty microL plasmatic samples containing hydroxyurea are added with internal standard, deproteinized, evaporated to dryness, silanized, and analyzed by gas chromatography-mass spectrometry, which operates in the selected ion mode after electron impact fragmentation. Linearity was found to extend to at least 100mg/L. Over a 1-25mg/L concentration range, coefficients of variation for intra-day and inter-day precision are 5.3% and 7.7%, respectively. Plasma blank-samples reveal endogenous hydroxyurea at a level
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Two assays to evaluate potential genotoxic effects of hydroxyurea in sickle cell disease patients.
Hemoglobin
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Hydroxycarbamide, well known in clinical settings as hydroxyurea (HU), is an antineoplastic agent inhibiting the ribonucleotide reductase enzyme, and thus, the conversion of ribonucleotides into deoxyribonucleotides. A concern about long term side effects of HU treatment in sickle cell disease patients, particularly genotoxicity, has often been evoked. The present study assessed two suitable methods to evaluate oxidative DNA damage associated with HU: the comet assay on blood lymphocytes and the quantification of urinary excretion of 8-oxodeoxyguanosine (8-oxodG). Both methods were applied in a preliminary study including seven sickle cell disease patients treated with HU, seven untreated sickle cell disease patients and five healthy volunteers. Concerning DNA damage, the comet assay and the 8-oxodG assay did not reveal any significant differences among the three groups. Methodologies used in this pilot study could be suitable to carry out further research in this area including a larger size sample setting.
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