RESUMEN
The simultaneous typing of five-HLA loci at high resolution and the availability of pedigree data allowed us to characterize extended five-locus phased haplotypes in 124 Nigerian families and to compare the observed frequencies with those expected by an expectation-maximization algorithm for unphased data. Despite the occurrence of some frequent alleles at each locus (e.g. B*53:01, which is assumed to protect against Plasmodium falciparum), as many as 82% of the sampled individuals carry two unique five-locus haplotypes and only three extended haplotypes with frequency above 1% exhibit significant linkage disequilibrium. Although preliminary, these results reveal an extreme level of HLA diversity in the Nigerian population, which reflects both its multi-ethnic composition and the very ancient demographic history of African populations.
Asunto(s)
Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Cadenas beta de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Haplotipos , Desequilibrio de Ligamiento , Alelos , Familia , Expresión Génica , Frecuencia de los Genes , Variación Genética , Genética de Población , Antígenos HLA-A/inmunología , Antígenos HLA-B/inmunología , Antígenos HLA-C/inmunología , Cadenas beta de HLA-DQ/inmunología , Cadenas HLA-DRB1/inmunología , Prueba de Histocompatibilidad , Humanos , Nigeria , LinajeRESUMEN
The mechanisms responsible for the hematopoietic failure in human immunodeficiency virus type 1 (HIV-1)-infected patients are still unknown. Several findings indicate that the in vitro proliferative potential of precursor cells from AIDS patients is reduced. The changes seen in bone marrow (BM) morphology and the defective BM functions associated with cytopenias have both been proposed as potential explanations. In patients treated with highly active antiretroviral therapy (HAART) an immune reconstitution associated with increased whole blood cell counts has been described. We have investigated the effects of HAART on the number of colony-forming cells (CFCs) and long-term culture-initiating cells (LTC-ICs), using long-term BM cell cultures (LTBMC) in a group of subjects with HIV-1 infection enrolled in an open study to evaluate the mechanisms of immune reconstitution during HAART. In each patient, the increase in colony growth was homogeneous, regardless of the type of hematopoietic progenitor cells assayed; in four subjects an increase in the most primitive progenitor cells (LTC-ICs) was observed. These findings were associated with the in vivo data showing increased numbers of BM mononuclear cells (BMMCs) after HAART and with a rise in peripheral CD4(+) T cell counts and decreased levels of plasma HIV-1 RNA. A decreased number of hematopoietic progenitor cells and/or a defective modulation of progenitor cell growth might be the cause of the hematological abnormalities in AIDS patients. Controlling HIV-1 replication by HAART could determine a restoration of stem cell activity, probably because of the suppression of factors that inhibit normal hematopoiesis.
Asunto(s)
Médula Ósea , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , VIH-1 , Hematopoyesis , Adulto , Terapia Antirretroviral Altamente Activa , Médula Ósea/inmunología , Células Cultivadas , ADN Viral/análisis , Femenino , Citometría de Flujo , Infecciones por VIH/sangre , VIH-1/genética , VIH-1/inmunología , Hematología , Hematopoyesis/inmunología , Humanos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/inmunología , Masculino , Metilcelulosa , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa/métodos , Factores de TiempoRESUMEN
Neurologic abnormalities are common in HIV-1 infected patients and often represent the dominant clinical manifestation of pediatric AIDS. Although the neurological dysfunction has been directly related to CNS invasion by HIV-1, the pathogenesis of neurologic disorders remains unclear. This review will first discuss the spectrum of potential interactions between HIV-1 and neural (neuronal and glial) cells, in the face of experimental data. Next, we will focus on the role of immune-derived cytokines and other soluble compounds which have been proposed to act as neurotoxic mediators and appear to play a role in the pathogenesis of AIDS-associated neurodegeneration.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/inmunología , Encéfalo/inmunología , VIH-1/inmunología , Enfermedades del Sistema Nervioso/inmunología , Neurotoxinas/biosíntesis , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Difusión , Humanos , Enfermedades del Sistema Nervioso/complicaciones , Neuroglía/inmunología , Neuronas/inmunologíaRESUMEN
Authors report a rare case of testicular metastasis from carcinoma of the prostate in a patient treated with anti-androgen therapy. The report of this kind of testicular metastasis was more frequent in the past years, when the neoplasm was often treated with bilateral orchiectomy. Metastatic carcinoma of the prostate to the testis is commonly accepted as a sign of advanced disease and it is usually accompanied by multiple metastases to other organs. The prognostic significance of testicular localization is still unknown.
Asunto(s)
Carcinoma/secundario , Neoplasias de la Próstata/patología , Neoplasias Testiculares/secundario , Anciano , Anciano de 80 o más Años , Carcinoma/cirugía , Humanos , Masculino , Neoplasias de la Próstata/cirugía , Neoplasias Testiculares/patología , Neoplasias Testiculares/cirugíaRESUMEN
Sickle cell anemia (SCA) remains associated with high risks of morbidity and early death. Allogeneic hematopoietic SCT (HSCT) is the only curative treatment for SCA. We report our experience with transplantation in a group of patients with the non-Black African variant and the Black African variant of SCA. This study included 40 consecutive SCA patients (13 patients with the non-Black African variant and 27 with the Black African variant) who underwent BM transplantation from HLA-identical sibling donors between June 2004 and May 2013, following a myeloablative-conditioning regimen. All patients obtained sustained engraftment. One patient (non-Black African variant) became a stable mixed chimera with 25% donor cells more than 6 years after transplantation. The probabilities of survival, SCA-free survival and TRM at 5 years after transplant were 91%, 91% and 9%, respectively. All surviving patients remained free of any SCA-related events after transplantation. Our results confirm that it is possible to offer a greater than 90% chance of cure to children with SCA. HSCT should be considered the standard of care for who have an HLA-identical donor, before complications result from the sickling of RBC.
Asunto(s)
Anemia de Células Falciformes/terapia , Población Negra , Trasplante de Células Madre Hematopoyéticas , Adolescente , Adulto , Aloinjertos , Anemia de Células Falciformes/etnología , Anemia de Células Falciformes/mortalidad , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Estudios Retrospectivos , Hermanos , Tasa de SupervivenciaRESUMEN
Many patients with thalassemia have been cured with BMT since the first successful transplant in 1981. Allogeneic stem cell gene therapy is the only treatment option for patients with sickle cell anemia (SCA). A total of 11 patients with a median age of 12 years (range, 2-16), affected by SCA, received hematopoietic SCT from HLA-identical, related donors following a myeloablative-conditioning regimen. Indications for transplantation were vaso-occlusive crisis, acute chest syndrome, avascular bone necrosis, chronic RBC transfusions, or hemorrhagic stroke. All patients had sustained engraftment. One patient became a stable mixed chimera with 25% of donor cells at 4 years after transplantation. One patient died at 1 year after transplantation. The probability of survival, SCA-free survival and TRM at 5 years after transplant were 90, 90 and 10%, respectively. All 10 surviving patients remained free of any SCA-related events after transplantation. In conclusion, these data confirm SCT from a suitable HLA-matched, related donor should become the primary option for curing children with SCA. There is an excellent survival rate and a return to normal life, free of SCA-related events.
Asunto(s)
Anemia de Células Falciformes/terapia , Terapia Genética/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Adolescente , Anemia de Células Falciformes/genética , Anemia de Células Falciformes/cirugía , Niño , Preescolar , Femenino , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Masculino , Estudios Prospectivos , Tasa de Supervivencia , Quimera por Trasplante , Trasplante HomólogoRESUMEN
We evaluated the incidence of GVHD, risk factors and the impact of graft composition on acute GVHD (aGVHD) in 92 children who underwent BMT for thalassemia following busulfan/cyclophosphamide (BUCY)-based conditioning regimens and GVHD prophylaxis with CSA/short-MTX and methylprednisolone. The incidence of grade 2-4 and 3-4 aGVHD was 35% (95% confidence interval (CI) 25-44) and 9% (95% CI 4-16), respectively. We found that CD3(+) and CD34(+) cell doses above the median were associated with high incidence of grade 2-4 aGVHD (49 vs 20%, P=0.005 and 46 vs 23%, P=0.021, respectively). In multivariate analysis, high CD3(+) (hazard ratio (HR) 4.6; 95% CI 1.4-14.7; P=0.010) and CD34(+) (HR 4.3; 95% CI 1.4-12.7; P=0.011) cell doses were associated with grade 2-4 aGVHD. We further examined the effect of CD3(+) and CD34(+) cell doses on aGVHD using quartile cutoff points and found a minimum threshold for CD3(+) (38 × 10(6)/kg) and CD34(+) (4 × 10(6)/kg) cells above which the incidence of grade 2-4 aGVHD is significantly increased. This study shows for the first time a positive correlation between the number of CD3(+) and CD34(+) cells and aGVHD in children receiving sibling BMT, and indicates that using tailored and more intensive post transplant immunosuppression may permit to better control aGVHD.
Asunto(s)
Antígenos CD34 , Trasplante de Médula Ósea , Complejo CD3 , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/prevención & control , Talasemia/terapia , Acondicionamiento Pretrasplante , Enfermedad Aguda , Adolescente , Antiinflamatorios/administración & dosificación , Busulfano/administración & dosificación , Niño , Preescolar , Ciclofosfamida/administración & dosificación , Femenino , Humanos , Terapia de Inmunosupresión/métodos , Inmunosupresores/administración & dosificación , Incidencia , Lactante , Masculino , Metotrexato/administración & dosificación , Metilprednisolona/administración & dosificación , Agonistas Mieloablativos/administración & dosificación , Hermanos , Trasplante HomólogoAsunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Hematopoyesis/efectos de los fármacos , Adulto , Ensayo de Unidades Formadoras de Colonias , Infecciones por VIH/patología , VIH-1 , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/patología , Humanos , MasculinoRESUMEN
There is a substantial incidence of graft failure in patients with thalassemia after myeloablative conditioning regimens especially in class 3 patients in whom its incidence could be as high as 8-38.5%. Most patients with graft failure have recurrence of thalassemic marrow. Historically, results of second transplants for thalassemia were poor because of a high rejection rate and/or increased TRM. Sixteen patients with thalassemia recurrence following rejection of the first graft and with a median age of 9 years (range, 4-20) were given second transplants using BM (n=7) or PBSC (n=9) after preparation with a new treatment protocol. All but two patients received stem cells from the same donor. The median interval between two transplants was 28 months (range, 8-204). The sustained engraftment rate was high (94%) with only one patient having primary graft failure. The probability of overall survival, event-free survival, TRM and graft failure were 79, 79, 16 and 6%, respectively. There were three transplant-related deaths. Thirteen patients are alive with Lansky/Karnofsky score of 100. This intensified treatment protocol was well tolerated with no significant increase in toxicity. The excellent results obtained with this new preparative regimen allow us to recommend it for second transplantation for patients with thalassemia recurrence.