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1.
Biol Blood Marrow Transplant ; 19(1): 75-81, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22871557

RESUMO

The value of prophylactic donor lymphocyte infusion (pDLI) is unclear and differs among diseases and transplantation protocols. Experience with this approach in patients with acute leukemia undergoing hematopoietic cell transplantation (HCT) with an alemtuzumab-incorporating conditioning protocol is lacking. We conducted a single-center prospective study to investigate the applicability and efficacy of prophylactic donor lymphocyte infusion (pDLI) in patients with leukemia undergoing HCT with a low-dose alemtuzumab-containing conditioning regimen. Inclusion criteria were high-risk acute myelogenous leukemia, acute lymphoblastic leukemia, or increasing mixed chimerism. All patients included were tapered off of immunotherapy. Exclusion criteria were a history of ≥ grade II or active graft-versus-host disease (GVHD). Of the 56 consecutive patients who underwent HCT with an alemtuzumab-containing regimen, 15 patients (8 with acute myelogenous leukemia and 7 with acute lymphoblastic leukemia) met the study inclusion criteria and received prophylactic DLI (total of 45 infusions) from 7 sibling donors and 8 unrelated donors. The first infusion was given at a median of 162 days posttransplantation. The median number of DLIs was 3, and the median cumulative CD3(+) cell dose was 2 × 10(6)cells/kg. Six of the 8 patients (75%) who received pDLI while in mixed chimerism converted to stable, complete donor chimerism. Some 47% of DLI recipients developed GVHD (4 acute GVHD and 3 with chronic GVHD) after a median cumulative dose of 2 × 10(6) CD3(+) cells/kg. After a median follow-up of 575 days, 11 (73%) pDLI recipients were alive. All 4 deaths were due to GVHD-related causes. None of the patients who received pDLIs relapsed. Patients with leukemia who received low-dose pDLI after conditioning with alemtuzumab are at low risk for relapse; however, this approach is associated with a relatively high incidence of severe GVHD.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Transfusão de Linfócitos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Irmãos , Condicionamento Pré-Transplante , Doadores não Relacionados , Adulto , Alemtuzumab , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Transplante Homólogo
2.
Biol Blood Marrow Transplant ; 17(3): 319-29, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20837151

RESUMO

Animal and human studies have shown that after allogeneic hematopoietic cell transplantation, epithelial cells containing donor-derived genome emerge. The mechanisms underlying this phenomenon are still unclear. We hypothesized that horizontal transfer of the hematopoietic donor-DNA to the host epithelium confers a possible operating mechanism. In an in vitro model mimicking the lymphocyte-epithelial interaction, we cocultivated keratinocyte HaCaT cells (Y-chromosome negative) with nonapoptotic or apoptotic, CMFDA, or BrdU-labeled hematopoietic Jurkat cells (Y+) and looked for the emergence of HaCaT cells bearing Jurkat genome. We found that DNA can be horizontally transferred from hematopoietic to epithelial cell lines through phagocytosis of apoptotic bodies. The ingested genomic material was also found within the nuclear compartment and in isolated chromosomes obtained from HaCaT metaphases. Both lysosomal inhibition in HaCaT cells and repetitive load of HaCaT cells with apoptotic bodies increased the intercellular and intranuclear DNA delivery. Although recipient cells remained viable and showed to express the foreign DNA, this expression was transient. Taking into consideration these findings of horizontal DNA transfer between hematopoietic and epithelial cells, we evaluated by quantitative microsatellite analysis the amount of donor DNA in 176 buccal swabs obtained from 71 patients after allogeneic transplantation. We found a high amount of donor-DNA (mean 26.6%) in the majority (89.7%) of them, although no donor hematopoietic cells were evident in the samples by immunofluorescence. We propose that the incessant charge of the transplant recipient with donor-DNA and its "inappropriate" intranuclear delivery in host epithelium may explain the emergence of epithelial cells with donor-derived genome.


Assuntos
Quimerismo , Células Epiteliais/fisiologia , Transferência Genética Horizontal , Transplante de Células-Tronco Hematopoéticas , Linfócitos/metabolismo , Recombinação Genética , Apoptose , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Linhagem Celular , Células Cultivadas , Cromossomos Humanos Y/genética , Técnicas de Cocultura , Inibidores Enzimáticos/farmacologia , Células Epiteliais/citologia , Feminino , Humanos , Hibridização in Situ Fluorescente , Linfócitos/citologia , Lisossomos/efeitos dos fármacos , Lisossomos/fisiologia , Masculino , Repetições de Microssatélites/genética , Mucosa Bucal/metabolismo , Fagocitose , Células Estromais/citologia , Células Estromais/metabolismo
3.
Eur J Heart Fail ; 11(12): 1178-81, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19889689

RESUMO

AIMS: Cardiac death remains the principal cause of mortality in beta-thalassemia major (beta-TM). Echocardiography may provide additional information, incremental to haematological profile, both for guiding chelation therapy and to assess prognosis. METHODS AND RESULTS: Between 1993 and 1995, 36 patients with beta-TM and normal cardiac function and 25 normal volunteers underwent evaluation using resting and dobutamine stress echocardiography (DSE). Dobutamine stress echocardiography was performed at baseline and repeated after 2 years. The primary endpoint was cardiac mortality. During a 12-year observation period, seven patients (19%) died from heart failure. All seven deaths occurred among the cohort of 12 patients with median ferritin concentrations >or= 2800 ng/mg. In addition, a resting left ventricular ejection fraction (LVEF) < 60% was also associated with increased late mortality. In multivariate analysis, increased serum ferritin levels and reduced LVEF but not DSE or other haematological variables were independent survival determinants. CONCLUSION: Resting LVEF provides prognostic information that is additional to ferritin levels among patients with beta-TM.


Assuntos
Ecocardiografia sob Estresse , Cardiopatias/mortalidade , Talassemia beta/complicações , Adulto , Feminino , Ferritinas/sangue , Cardiopatias/complicações , Cardiopatias/diagnóstico por imagem , Cardiopatias/fisiopatologia , Humanos , Hipertrofia Ventricular Esquerda/complicações , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Estudos Longitudinais , Masculino , Prognóstico , Função Ventricular Esquerda , Adulto Jovem
4.
Acta Haematol ; 121(4): 187-95, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19468203

RESUMO

BACKGROUND/AIMS: Disease-related anemia in chronic lymphocytic leukemia (CLL) occurs when the obvious causes are excluded while its pathogenesis is still obscure. We investigated its underlying mechanisms in 56 untreated patients with CLL. METHODS: Bone marrow (BM) lymphocytic infiltration was estimated in trephine biopsies. Serum erythropoietin (EPO) and tumor necrosis factor-alpha (TNF-alpha) levels were measured by ELISA. The potential of BM CD34+ to differentiate into erythroid cells was evaluated by methylcellulose-based assays and in liquid cultures supplemented with EPO, SCF, IL-3 +/- TNF-alpha. The response of erythroid precursors to EPO +/- TNF-alpha was assessed by detecting activated key proteins of EPO-EPO receptor signalling pathway using Western Blot and EMSA. RESULTS: Bone marrow lymphocytic infiltration was not exclusively responsible for disease-related anemia and CD34+ cells were intrinsically capable of generating erythroid precursors. Also, no deficiency of serum erythropoietin (EPO) or defective intracellular response of erythroid precursors to EPO +/- TNF-alpha stimulation was observed. Serum TNF-alpha levels were found increased in anemic CLL patients and TNF-alpha appeared to directly inhibit the erythroid development in early stages of erythropoiesis. CONCLUSION: We concluded that CLL-related anemia was not due to intrinsic defects of erythroid precursors, but might result from the direct suppressive effect of TNF-alpha on the erythroid production.


Assuntos
Anemia/etiologia , Eritropoese/fisiologia , Leucemia Linfocítica Crônica de Células B/complicações , Proteínas de Neoplasias/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/fisiopatologia , Medula Óssea/patologia , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/patologia , Células Precursoras Eritroides/efeitos dos fármacos , Células Precursoras Eritroides/patologia , Eritropoetina/sangue , Feminino , Fatores de Crescimento de Células Hematopoéticas/farmacologia , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/fisiopatologia , Infiltração Leucêmica , Masculino , Pessoa de Meia-Idade
5.
J Mol Biol ; 387(5): 1239-49, 2009 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-19248788

RESUMO

The scaffold/matrix attachment regions (S/MARs) are chromosomal elements that participate in the formation of chromatin domains and have origin of replication support functions. Because of all these functions, in recent years, they have been used as part of episomal vectors for gene transfer. The S/MAR of the human beta-interferon gene has been shown to support efficient episome retention and transgene expression in various mammalian cells. In Jurkat and other cells, DNA plasmid vectors containing Epstein-Barr virus origin of replication (EBV OriP) and the EBV nuclear antigen-1 gene mediate prolonged episome retention in the host cell nucleus, which, however, diminishes over time. In order to enhance retention, we combined this system with an S/MAR element. Unexpectedly, this completely eliminated the capacity of episomes to replicate. Calculation of the stress-induced DNA duplex destabilization profile of the vectors suggested that the S/MAR element had created an increase in molecular stability at the OriP site that may have disturbed replicative potential. In contrast, introduction of an alternative initiation of replication region from the beta-globin gene locus, instead of EBV OriP and the EBV nuclear antigen-1 gene, restored replicative capacity and enhanced episome retention mediated by the S/MAR. These effects were associated with a destabilization profile at the initiation of replication region. These data demonstrate a correlation between S/MAR-mediated vector retention and the presence of an unstable duplex at a replication origin, in this particular setting. We consider that the calculation of stress-induced duplex destabilization may be an informative first step in the design of units that replicate extrachromosomally, particularly as the latter present a safer and, therefore, attractive alternative to integrating viral vectors for gene therapy applications.


Assuntos
Vetores Genéticos , Regiões de Interação com a Matriz , Plasmídeos/genética , Sequência de Bases , Linhagem Celular Tumoral , Primers do DNA/genética , Antígenos Nucleares do Vírus Epstein-Barr/genética , Expressão Gênica , Técnicas de Transferência de Genes , Instabilidade Genômica , Proteínas de Fluorescência Verde/genética , Herpesvirus Humano 4/genética , Humanos , Interferon beta/genética , Células Jurkat , Células K562 , Origem de Replicação , Transfecção
6.
World J Gastroenterol ; 14(10): 1559-63, 2008 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-18330948

RESUMO

AIM: To detect the prevalence of anti-HAV IgG antibodies in adult multitransfused beta-thalassemic patients. METHODS: We studied 182 adult beta-thalassemic patients and 209 controls matched for age and sex from the same geographic area, at the same time. Anti-HAV IgG antibodies, viral markers of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection were evaluated. RESULTS: Anti-HAV IgG antibodies were detected more frequently in thalassemic patients (133/182; 73.1%) than in healthy controls (38/209; 18.2%, P < 0.0005). When we retrospectively evaluated the prevalence of anti-HAV IgG antibodies in 176/182 (96.7%) thalassemic patients, whose medical history was available for the previous ten years, it was found that 83 (47.2%) of them were continuously anti-HAV IgG positive, 16 (9.1%) acquired anti-HAV IgG antibody during the previous ten years, 49 (27.8%) presented anti-HAV positivity intermittently and 28 (15.9%) were anti-HAV negative continuously. CONCLUSION: Multitransfused adult beta-thalassemic patients present higher frequency of anti-HAV IgG antibodies than normal population of the same geographic area. This difference is difficult to explain, but it can be attributed to the higher vulnerability of thalassemics to HAV infection and to passive transfer of anti-HAV antibodies by blood transfusions.


Assuntos
Transfusão de Sangue , Anticorpos Anti-Hepatite A/sangue , Vírus da Hepatite A/imunologia , Imunoglobulina G/sangue , Talassemia beta/sangue , Talassemia beta/imunologia , Adulto , Estudos de Casos e Controles , Feminino , Anticorpos Anti-Hepatite B/sangue , Anticorpos Anti-Hepatite C/sangue , Humanos , Masculino , Prevalência , Talassemia beta/terapia
7.
BMC Bioinformatics ; 9: 99, 2008 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-18275602

RESUMO

BACKGROUND: The integration of biomedical information is essential for tackling medical problems. We describe a data model in the domain of flow cytometry (FC) allowing for massive management, analysis and integration with other laboratory and clinical information. The paper is concerned with the proper translation of the Flow Cytometry Standard (FCS) into a relational database schema, in a way that facilitates end users at either doing research on FC or studying specific cases of patients undergone FC analysis RESULTS: The proposed database schema provides integration of data originating from diverse acquisition settings, organized in a way that allows syntactically simple queries that provide results significantly faster than the conventional implementations of the FCS standard. The proposed schema can potentially achieve up to 8 orders of magnitude reduction in query complexity and up to 2 orders of magnitude reduction in response time for data originating from flow cytometers that record 256 colours. This is mainly achieved by managing to maintain an almost constant number of data-mining procedures regardless of the size and complexity of the stored information. CONCLUSION: It is evident that using single-file data storage standards for the design of databases without any structural transformations significantly limits the flexibility of databases. Analysis of the requirements of a specific domain for integration and massive data processing can provide the necessary schema modifications that will unlock the additional functionality of a relational database.


Assuntos
Algoritmos , Sistemas de Gerenciamento de Base de Dados , Bases de Dados Factuais , Citometria de Fluxo/métodos , Armazenamento e Recuperação da Informação/métodos , Software , Interface Usuário-Computador , Integração de Sistemas
8.
Atherosclerosis ; 198(2): 448-57, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17988670

RESUMO

BACKGROUND: Patients with beta-thalassemia major (beta-TM) demonstrate an increased incidence of vascular complications, which are thought to result from a procoagulant/proinflammatory environment. We investigated the arterial vasorelaxing capacity and sought for early carotid atherosclerosis and underlying pathophysiological correlates in these transfusion-dependent patients. METHODS AND RESULTS: The vasodilatory properties of the brachial artery and the carotid intima-media thickness (IMT) were examined with ultrasonography in 35 non-diabetic young adults with beta-TM (patient group) and 35 control subjects (control group). Among thalassemic patients, both endothelium-dependent (FMD) and -independent dilatation (FID) as well as their ratio was impaired, whereas IMT was increased (p<0.01). Patients on optimal, as compared with those on non-optimal chelation treatment had a non-significantly lower IMT. Vasodilatory capacity in the patient group was inversely correlated with IMT and independently associated either with the quality of chelation therapy (FMD) or serum ferritin levels (FID). Plasma concentrations of D-dimers, circulating markers of endothelial activation, inflammation and apoptosis were higher, while plasma cholesterol and fibrinogen levels were lower-than-normal in the patient group. Independent predictors of IMT among thalassemic patients were tumor necrosis factor-alpha levels and age. CONCLUSIONS: Young adults with beta-TM exhibit both a global impairment of arterial vasorelaxation and early carotid atherosclerosis. A procoagulant/proinflammatory state in these transfusion-dependent patients may overwhelm atheroprotective mechanisms, including an optimal chelation regimen, and promote vascular injury and atherogenesis.


Assuntos
Artérias Carótidas/fisiopatologia , Doenças das Artérias Carótidas/etiologia , Vasodilatação , Sistema Vasomotor/fisiopatologia , Talassemia beta/fisiopatologia , Adulto , Biomarcadores/sangue , Artéria Braquial/diagnóstico por imagem , Artéria Braquial/patologia , Artéria Braquial/fisiopatologia , Artérias Carótidas/diagnóstico por imagem , Artérias Carótidas/patologia , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/patologia , Feminino , Humanos , Masculino , Túnica Íntima/diagnóstico por imagem , Túnica Íntima/patologia , Túnica Íntima/fisiopatologia , Túnica Média/diagnóstico por imagem , Túnica Média/patologia , Túnica Média/fisiopatologia , Ultrassonografia , Talassemia beta/complicações , Talassemia beta/patologia
9.
Nucleic Acids Res ; 35(4): e23, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17251199

RESUMO

We report the first dry-reagent, disposable, dipstick test for molecular screening of seven chromosomal translocations associated with acute and chronic leukemia. The dipstick assay offers about 10 times higher detectability than agarose gel electrophoresis and, contrary to electrophoresis, allows confirmation of the sequence of the polymerase chain reaction (PCR) product by hybridization within a few minutes without the need of instrumentation. Biotinylated amplified DNA is hybridized with a dA-tailed probe and applied to the strip, which contains oligo(dT)-conjugated gold nanoparticles in dry form. Upon immersion of the strip in the appropriate buffer, the solution migrates and the hybrids are captured by immobilized streptavidin at the test zone generating a characteristic red line. The excess nanoparticles are captured by oligo(dA) strands immobilized at the control zone of the strip producing a second red line. We studied the: t(9;22)(q34;q11), t(15;17)(q22;q21), t(11;17)(q23;q21), t(5;17)(q32;q21), t(11;17)(q13;q21), t(8,21)(q22;q22) and inv(16)(p13;q22) that generate the BCR-ABL, PML-RARa, PLZF-RARa, NPM-RARa, NuMA-RARa, AML1-ETO and CBFbeta-MYH11 fusion genes, respectively. A single K562 cell was detectable amidst 10(6) normal leukocytes. A dipstick test was developed for actin, as a reference gene. The dipstick assay with appropriate probes can be used for identification of the fusion transcripts involved in the translocation.


Assuntos
Leucemia/diagnóstico , Hibridização de Ácido Nucleico/métodos , Proteínas de Fusão Oncogênica/genética , Translocação Genética , Doença Aguda , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Proteínas de Fusão bcr-abl/genética , Humanos , Indicadores e Reagentes , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mieloide/diagnóstico , Leucemia Promielocítica Aguda/diagnóstico , Reação em Cadeia da Polimerase , Proteína 1 Parceira de Translocação de RUNX1 , Reprodutibilidade dos Testes
10.
Haematologica ; 91(12): 1714-6, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17145614

RESUMO

We determined the intracellular expression and inducibility of heat shock proteins (Hsps) 72, 73 and 27 in the bone marrow of patients with myelodysplastic syndrome (MDS) and controls. Hsps were overexpressed in MDS marrow especially in advanced disease, providing resistance to induction of apoptosis. These data suggest that Hsps could be implicated in the progression of MDS to acute myeloid leukemia.


Assuntos
Medula Óssea/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Proteínas de Choque Térmico/biossíntese , Proteínas de Choque Térmico/genética , Síndromes Mielodisplásicas/metabolismo , Medula Óssea/patologia , Progressão da Doença , Humanos , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia
11.
Transplantation ; 82(2): 218-26, 2006 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-16858285

RESUMO

BACKGROUND: Increased risk of transplant related mortality in male recipients of female hematopoietic stem cell grafts and in vitro reactivity of lymphocytes against H-Y encoded gene products in females with rejected male grafts have been documented. An increased rejection of male grafts in female recipients is not reported for solid organ or stem cell transplants and the role of H-Y as transplantation antigen has been controversial. METHODS: Data from 1481 patients with a hematopoietic stem cell transplant for aplastic anemia reported from 154 centers in 28 countries were analyzed. Outcome was compared between patients with donors of the same or opposite sex. RESULTS: Survival at 5 years was significantly better in patients with donors from the same sex: 68% vs. 60% (P = 0.001). Male patients with female donors had a decreased survival (relative risk of death 1.52, P < 0.001) and an increased risk of severe graft-versus-host disease (relative risk 1.33, P = 0.03) compared to recipients of sex-matched grafts. Female patients with male donors had a decreased survival (relative risk of death 1.44, P = 0.01) and an increased risk of rejection (relative risk 2.20, P = 0.01) compared to recipients of sex-matched grafts. In a subgroup analysis, the negative effects of donor/recipient sex-mismatching appeared confined to patients receiving conditioning regimens not containing antithymocyte globulin. CONCLUSIONS: These data confirm H-Y as a clinically relevant transplantation antigen, in both the graft-versus-host and the host-versus-graft direction. Wherever possible, donor-recipient sex-matching should be integrated into donor selection algorithms.


Assuntos
Anemia Aplástica/terapia , Transplante de Células-Tronco/métodos , Adolescente , Adulto , Criança , Estudos de Coortes , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Teste de Histocompatibilidade , Humanos , Masculino , Estudos Retrospectivos , Fatores Sexuais , Transplante de Células-Tronco/efeitos adversos , Transplante de Células-Tronco/mortalidade , Análise de Sobrevida , Fatores de Tempo , Transplante Homólogo , Resultado do Tratamento
12.
Ann Hematol ; 85(2): 79-85, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16132904

RESUMO

We investigated erythropoietin (Epo) response in a cohort of diabetic patients with various types of anemia to approach the pathogenesis of some cases of "unexplained" anemia encountered among diabetics. Serum Epo levels were determined totally in 747 evaluable subjects with normal renal and hepatic function, of whom 694 had anemia. Among anemic patients, 237 were diabetics, while among the 53 nonanemic persons, there were also 21 diabetics. Diabetic and nondiabetic subjects were uniformly balanced in relation to their demographic features and were categorized according to the etiology of their anemia. Hemoglobin (Hb) did not differ between diabetic and nondiabetic subjects in all the etiological groups and in the whole population. Diabetic patients had significantly lower serum Epo levels as compared to nondiabetics (36.5+/-61 vs 69.4+/-191 IU/ml, p<0.0001), and this was true for all etiologic groups of anemia with the exception of patients with myeloproliferative disorders and those with megaloblastic anemia. The natural logarithmic (ln)-EpoxHb component was used as an index of response to anemia and was found to be significantly decreased in almost all subgroups of diabetic patients. Serum Epo levels were also negatively correlated with the percentage of glycosylated Hb, HbA1(C) (r=-0.446), and the correlation was stronger with the ln of serum Epo (r=-0.638, p<0.001). Inappropriately low serum Epo level is a uniform feature in patients with type II diabetes mellitus and may represent a constitutive blunted response to anemia or an altered metabolic rate of Epo, probably as a result of abnormal glycosylation of the cytokine.


Assuntos
Anemia/complicações , Anemia/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Eritropoetina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Citocinas/metabolismo , Eritropoetina/metabolismo , Feminino , Hemoglobinas Glicadas/metabolismo , Glicosilação , Hemoglobinas/metabolismo , Humanos , Hipóxia , Masculino , Pessoa de Meia-Idade
13.
Leuk Res ; 30(6): 713-21, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16310248

RESUMO

Aplastic anemia (AA) is a syndrome of hematopoietic failure involving increased apoptosis of stem cells. In order to investigate the molecular mechanisms participated in the process of marrow failure, we created an in vitro model of hematopoietic cell suppression, by continuous addition of TNF-alpha and IFN-gamma in an vitro long-term bone marrow culture system. An up-regulation of Fas expression was observed in CD34+ cells in cytokine treated cultures, compared to controls. This was accompanied by significant TRAIL and decreased caspase 3 mRNA expression, whereas the expression of Bcl-2 family members was low (Bcl-xl) or absent (Bcl-2, Bax). The expression of these apoptotic genes was also investigated in aplastic anemia patients. Apart from Fas mRNA expression in total marrow and/or CD34+ cells, TRAIL mRNA expression was found only in CD34+ cells in active disease while in total marrow cell compartment this remains a constant finding even in patients in remission. The above data are in agreement with previous studies proposing a major role for the extrinsic apoptosis pathway in the pathogenesis of aplastic anemia and additionally introduce TRAIL as a probable important molecule in the process.


Assuntos
Anemia Aplástica/metabolismo , Proteínas Reguladoras de Apoptose/biossíntese , Apoptose , Células-Tronco Hematopoéticas/metabolismo , Glicoproteínas de Membrana/biossíntese , Transdução de Sinais , Fator de Necrose Tumoral alfa/biossíntese , Regulação para Cima , Adulto , Idoso , Anemia Aplástica/patologia , Antígenos CD34/biossíntese , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Células Cultivadas , Feminino , Células-Tronco Hematopoéticas/patologia , Humanos , Interferon gama/farmacologia , Masculino , Pessoa de Meia-Idade , Transdução de Sinais/efeitos dos fármacos , Ligante Indutor de Apoptose Relacionado a TNF , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima/efeitos dos fármacos , Proteína X Associada a bcl-2/biossíntese , Proteína bcl-X/biossíntese , Receptor fas/biossíntese
15.
Am J Med ; 118(9): 957-67, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16164878

RESUMO

The thalassemias are common monogenic disorders of hemoglobin synthesis. beta-thalassemias are the most important among the thalassemia syndromes and have become a worldwide clinical problem due to an increasing immigrant population. In beta-thalassemia major, regular blood transfusions are necessary early in life. Beta-thalassemia intermedia refers to a less severe phenotype, whereas beta-thalassemia/hemoglobin E disease encompasses a broad phenotypic spectrum. Blood transfusions and increased gastrointestinal iron absorption result in iron overload and tissue damage. Among patients with beta-thalassemia major, biventricular, dilated cardiomyopathy remains the leading cause of mortality. In some patients, a restrictive type of left ventricular cardiomyopathy or pulmonary hypertension is noted. The clinical course, although variable and occasionally fulminant, is more benign in recent than in older series. Myocarditis has been described as a cause of left-sided heart failure in younger patients. Pulmonary arterial hypertension is the principal cause of heart failure in beta-thalassemia intermedia. Chelation therapy has improved prognosis in beta-thalassemia major both by reducing the incidence of heart failure and by reversing cardiomyopathy. Estimation of the patient's cardiac risk is mainly based on clinical criteria and serial echocardiography. A new cardiovascular magnetic resonance technique will probably fulfill the need for more precise risk stratification in beta-thalassemia syndromes. By increasing the proportion of patients on optimal chelation, survival in beta-thalassemia major may further improve. Recent advances in gene therapy are expected to result in the long-awaited cure of this disease.


Assuntos
Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Talassemia beta/complicações , Talassemia beta/fisiopatologia , Quelantes/uso terapêutico , Insuficiência Cardíaca/prevenção & controle , Hemoglobina E/fisiologia , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/prevenção & controle , Sobrecarga de Ferro/etiologia , Sobrecarga de Ferro/fisiopatologia , Sobrecarga de Ferro/prevenção & controle , Miocardite/etiologia , Miocardite/fisiopatologia , Miocardite/prevenção & controle , Pericardite/etiologia , Pericardite/fisiopatologia , Pericardite/prevenção & controle , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/prevenção & controle , Talassemia beta/terapia
17.
Eur J Gastroenterol Hepatol ; 17(3): 345-50, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15716660

RESUMO

OBJECTIVES: The aim of this study was to evaluate the serum lipid profile and to assess the prevalence of hepatic steatosis in adult beta-thalassaemic patients with chronic hepatitis C virus (HCV) infection. METHODS: Thirty-five adult HCV infected, multi-transfused, beta-thalassaemia patients (beta-HCV patients), 63 otherwise normal patients with chronic HCV infection (HCV patients) and 54 beta-thalassaemia patients without chronic viral hepatitis (beta patients) were studied. Total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, viral markers and liver histology were evaluated. RESULTS: Serum total cholesterol, HDL-C and LDL-C were found at significantly lower levels in beta-HCV and beta patients than in HCV patients. Triglyceride levels were significantly lower in the HCV group compared with the beta group. Nine (25.7%) of the 35 beta-HCV patients had mild hepatic steatosis. Thirteen (23.6%) of 55 HCV patients presented mild and 4/55 (7.3%) moderate hepatic steatosis. None of the beta group presented steatosis. When we compared beta-HCV and HCV patients with steatosis, we found that beta-HCV patients had a lower degree of steatosis (11.1+/-7% vs 22.9+/-17.2%, P=0.021). Multivariate logistic regression analysis showed that the only independent predictor associated with hepatic steatosis in beta-HCV and HCV patients was genotype 3a (OR, 3.61; 95% CI, 1.22-10.71, P=0.021). CONCLUSIONS: Adult beta-thalassaemia patients, compared to other patients with chronic HCV infection, present lower cholesterol levels (total cholesterol, HDL, LDL) and similar frequency but a lower degree of hepatic steatosis. This difference in the degree of steatosis is most likely due to the higher prevalence of genotype 3a in the non-beta-thalassaemia group.


Assuntos
Fígado Gorduroso/sangue , Hepatite C Crônica/sangue , Lipídeos/sangue , Talassemia beta/sangue , Adulto , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Fígado Gorduroso/complicações , Fígado Gorduroso/genética , Feminino , Genótipo , Hepatite C Crônica/complicações , Hepatite C Crônica/genética , Humanos , Masculino , Triglicerídeos/sangue , Talassemia beta/complicações , Talassemia beta/genética
18.
Clin Immunol ; 113(3): 310-7, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15507396

RESUMO

Myelodysplastic syndromes (MDS) are clonal stem cell disorders, characterized by ineffective and dysplastic hematopoiesis. MDS patients have a defective immune response manifested by increased susceptibility to bacterial infections, autoimmune phenomena, and high incidence of lymphoid malignancies. Presently, we investigated the phenotype and function of monocyte-derived dendritic cells (MoDC) in 23 MDS patients and 15 controls at different stages of differentiation using the maturation stimuli tumor necrosis factor-alpha (TNF-alpha) and LPS. Monocytes from MDS patients showed low potential to differentiate into dendritic cells (DC), as determined by low cell yield and CD1a expression. MDS-MoDCs exhibited low expression of mannose receptor and reduced endocytic capacity. MDS-MoDCs showed a diminished response to TNF-alpha with low CD83, CD80, and CD54 expression and allostimulatory capacity. In patients with 5q syndrome, monocytes and MoDCs were positive for the 5q deletion, suggesting their origin from the malignant clone. Our data indicate that MoDCs in MDS display quantitative and functional abnormalities that may contribute to the defective immune response of these patients.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/patologia , Monócitos/efeitos dos fármacos , Monócitos/patologia , Síndromes Mielodisplásicas/patologia , Fator de Necrose Tumoral alfa/farmacologia , Idoso , Idoso de 80 Anos ou mais , Antígenos/metabolismo , Células Cultivadas , Células Dendríticas/metabolismo , Endocitose , Feminino , Citometria de Fluxo , Humanos , Lectinas Tipo C/metabolismo , Masculino , Receptor de Manose , Lectinas de Ligação a Manose/metabolismo , Pessoa de Meia-Idade , Monócitos/metabolismo , Fenótipo , Receptores de Superfície Celular/metabolismo
19.
Br J Haematol ; 126(6): 806-14, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15352984

RESUMO

Myelodysplastic syndrome (MDS) is a stem cell disorder characterized by ineffective haematopoiesis and blood cytopenias. The present study investigated the potential of bone marrow CD34(+) progenitors in MDS patients to proliferate and differentiate into dendritic cells (DCs) in a cytokine-supplemented liquid culture system and analysed the status of blood DC subsets in these patients. CD34(+) progenitors had low potential to generate DCs in vitro, as the number of DCs obtained from one CD34(+) cell was significantly lower compared with controls (median value 0.2 vs. 4, P = 0.003). In patients, the survival and proliferation of CD34(+) cells in culture was not correlated to the degree of apoptosis. Phenotypically and functionally CD34(+)-derived DCs were similar in MDS patients and normal subjects. The percentage of both circulating DC subsets in patients was extremely diminished compared with controls (myeloid DC: 0.10 +/- 0.10% vs. 0.35 +/- 0.13%, P < 0.001; plasmacytoid DC: 0.11 +/- 0.10% vs. 0.37 +/- 0.14%, P < 0.001). In cases with the 5q deletion both CD34-derived DCs and blood DCs harboured the cytogenetic abnormality. Our results indicate that, in MDS, the production of DCs is affected by the neoplastic process resulting in ineffective 'dendritopoiesis' with low blood DC precursor numbers. This quantitative DC defect probably contributes to the poor immune response against infectious agents and to the escape of the malignant clone from immune recognition with disease progression towards acute leukaemia.


Assuntos
Antígenos CD34/análise , Células Dendríticas/patologia , Células-Tronco Hematopoéticas/patologia , Síndromes Mielodisplásicas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Diferenciação Celular , Divisão Celular , Células Cultivadas , Células Clonais/patologia , Células Dendríticas/imunologia , Feminino , Células-Tronco Hematopoéticas/imunologia , Humanos , Imunofenotipagem , Teste de Cultura Mista de Linfócitos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/imunologia
20.
Int J Hematol ; 79(3): 253-9, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15168594

RESUMO

We investigated endothelial and in vivo platelet activation in a cohort of 52 patients with essential thrombocythemia (ET) and polycythemia vera (PV) before and after cytoreductive treatment, 22 healthy controls, and 17 patients with acute cerebrovascular ischemia (ACVI) and normal platelet counts. We measured platelet expression of CD62P and CD63 antigens and levels of soluble vascular cell adhesion molecule 1 (sVCAM-1). We found increased in vivo platelet activation in all patients with ET and PV, both before and after cytoreductive treatment, compared with controls. In patients with arterial thrombosis, platelet expression of CD62P, and in patients with erythromelalgia, expression of both markers was higher compared with expression in patients without thrombotic complications. In patients with ET and PV before and after treatment, sVCAM-1 expression was increased compared with expression in controls but also compared with expression in patients with ACVI and normal platelet counts. In patients with arterial thrombosis and erythromelalgia, in vivo platelet activation correlated with the level of sVCAM-1. Our findings indicated that in vivo platelet activation reflects intrinsic platelet defects in patients with ET and PV, persists after cytoreductive treatment, and results in endothelial damage, probably through release of angiogenic factors and/or activation of white blood cells.


Assuntos
Endotélio Vascular/patologia , Ativação Plaquetária , Policitemia Vera/sangue , Trombocitemia Essencial/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/sangue , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores/sangue , Isquemia Encefálica/sangue , Isquemia Encefálica/tratamento farmacológico , Estudos de Casos e Controles , Endotélio Vascular/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Selectina-P/sangue , Glicoproteínas da Membrana de Plaquetas , Policitemia Vera/complicações , Policitemia Vera/tratamento farmacológico , Tetraspanina 30 , Trombocitemia Essencial/complicações , Trombocitemia Essencial/tratamento farmacológico , Trombose/etiologia , Molécula 1 de Adesão de Célula Vascular/sangue
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