RESUMEN
Disruption of attention is an early and disabling symptom of Alzheimer's disease (AD). The underlying cellular mechanisms are poorly understood and treatment options for patients are limited. These early attention deficits are evident in the TgCRND8 mouse, a well-established murine model of AD that recapitulates several features of the disease. Here, we report severe impairment of the nicotinic receptor-mediated excitation of prefrontal attentional circuitry in TgCRND8 mice relative to wild-type littermate controls. We demonstrate that this impairment can be remedied by apamin, a bee venom neurotoxin peptide that acts as a selective antagonist to the SK family of calcium-sensitive potassium channels. We probe this seeming upregulation of calcium-sensitive inhibition and find that the attenuated nicotinic firing rates in TgCRND8 attention circuits are mediated neither by greater cellular calcium signals nor by elevated SK channel expression. Instead, we find that TgCRND8 mice show enhanced functional coupling of nicotinic calcium signals to inhibition. This SK-mediated inhibition exerts a powerful negative feedback on nicotinic excitation, dampening attention-relevant signaling in the TgCRND8 brain. These mechanistic findings identify a new cellular target involved in the modulation of attention and a novel therapeutic target for early attention deficits in AD.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Apamina/administración & dosificación , Corteza Prefrontal/fisiología , Células Piramidales/fisiología , Receptores Nicotínicos/fisiología , Animales , Modelos Animales de Enfermedad , Femenino , Masculino , Potenciales de la Membrana , Ratones Endogámicos C57BL , Ratones Transgénicos , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/antagonistas & inhibidoresRESUMEN
After allogeneic hematopoietic stem cell transplantation, risk factors for cytomegalovirus (CMV) reactivation include pretransplantation donor and recipient CMV serologic status and posttransplantation development of acute graft-vs-host disease (aGvHD). Human leukocyte antigen (HLA) allele type is an additional factor in CMV infection. The present study included 108 patients who received an allogeneic stem cell graft from an HLA-identical sibling between 1993 and 2004. All recipients and donors were typed for HLA-A, HLA-B, and HLA-DR alleles using serologic or molecular methods. All recipients received grafts because of a hematologic disease from HLA full-matched donors. In pretransplantation seropositive patients with aGvHD, no significant difference was observed in patients who developed CMV infection compared with those without CMV infection. Seropositive patients without aGvHD but with posttransplantation CMV infection demonstrated a higher incidence of HLA-A30, HLA-B40, and HLA-DRB1*15 compared with those without CMV infection. In conclusion, it seems that certain HLA alleles may have either a protective or predisposing role in CMV reactivation, which might be helpful in estimating the risk of aGvHD and designing individualized therapy.
Asunto(s)
Infecciones por Citomegalovirus/epidemiología , Enfermedad Injerto contra Huésped/epidemiología , Antígenos HLA/inmunología , Trasplante de Células Madre Hematopoyéticas/estadística & datos numéricos , Enfermedad Aguda , Adolescente , Adulto , Femenino , Enfermedad Injerto contra Huésped/genética , Antígenos HLA/genética , Antígenos HLA-A/inmunología , Antígenos HLA-B/inmunología , Antígenos HLA-DR/inmunología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Prueba de Histocompatibilidad , Humanos , Masculino , Persona de Mediana Edad , Medicina de Precisión/tendencias , Estudios Retrospectivos , Trasplante Homólogo , Adulto JovenRESUMEN
Inflammatory pseudotumor (IPT) is a rare tumor that occurs in various organs and tissues. The clinical picture varies from the more frequent benign lesions to the rare malignant tumors with distant metastases. IPT associated with hematopoietic stem cell transplantation (HSCT) is rarely reported. In this article, we review the reports of IPT after HSCT and describe the first case of bladder IPT. We also review the possible factors involved in the pathogenesis. IPT might be rare but it is a potentially serious complication of HSCT. It should be considered in patients with otherwise unexplained inflammatory symptoms or signs or with any mass lesion in the post-HSCT period. A knowledge of this entity and insistence on a definitive biopsy of mass lesions in the post-HSCT period can avoid unnecessary treatment such as radical surgery, chemotherapy or radiotherapy.
Asunto(s)
Granuloma de Células Plasmáticas/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedades de la Vejiga Urinaria/etiología , Adulto , Granuloma de Células Plasmáticas/patología , Humanos , Masculino , Enfermedades de la Vejiga Urinaria/patologíaRESUMEN
Renal insufficiency is a common complication early after hematopoietic stem cell transplantation (HSCT). Renal function as measured by creatinine clearance (CrCl) was prospectively evaluated in 47 patients undergoing allogeneic (n=22) or autologous (n=25) HSCT during the first 100 days. Renal dysfunction was classified as follows: Grade 0 (<25% decline in CrCl), Grade 1 (>or=25% decline in CrCl but <2 x increase in serum creatinine), Grade 2 (>or=2 x rise in serum creatinine but no need for dialysis) and Grade 3 (>or=2 x rise in serum creatinine and need for dialysis). Thirty-three patients (70%) had Grade 1-3 renal dysfunction. Renal dysfunction was more common after myeloablative allogeneic HSCT (91%) than autologous HSCT (52%) (P=0.004), and was associated with a high risk of mortality (P=0.039). Sepsis in autologous HSCT patients and cyclosporine toxicity in allogeneic HSCT patients were associated with renal dysfunction. We conclude that autologous and allogeneic HSCT differ in the likelihood and causes of renal dysfunction.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/efectos adversos , Agonistas Mieloablativos/efectos adversos , Insuficiencia Renal/etiología , Adulto , Presión Sanguínea , Femenino , Humanos , Masculino , Agonistas Mieloablativos/uso terapéutico , Estudios Prospectivos , Insuficiencia Renal/fisiopatología , Insuficiencia Renal/terapia , Acondicionamiento Pretrasplante/efectos adversos , Trasplante Autólogo , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Veno-occlusive disease (VOD) of the liver occurs in 10% to 50% of patients after hematopoietic stem cell transplantation (HSCT), ranging from a mild reversible disease to a fulminant course with a mortality rate close to 100%. We retrospectively evaluated the clinical signs, diagnosis, prognosis, therapy, and outcome of 13 hepatic VOD cases which developed after HSCT. A total of 193 consecutive patients (age: 15-62 years; median 33 years) with various hematologic diseases underwent 197 HSCT (allogeneic HSCT, n = 128; autologous HSCT, n = 69). In general, the conditioning regimen consisted of cyclophosphamide combined either with total body irradiation or busulfan. Since 2000, to reduce hepatic complications, all patients received ursodexycolic acid and discontinuation of norethisterone which inhibits ovulation. VOD diagnosed clinically was mainly managed in supportive fashion. Five patients received thrombolytic therapy (t-plasminogen activator [t-PA], n = 3; defibrotide [DF], n = 2). VOD developed in 13 of 197 cases (6.6%). All except one were in the allogeneic group who had received a busulfan-containing conditioning regimen; Ten (77%) were severe. Thirty-three of 197 (17%) cases died before day 100 with VOD as the cause in eight (24%). All of the t-PA administered patients died with significant hemorrhagic complications. DF patients improved completely, even after renal and respiratory failure, despite high total bilirubin levels. Only one patient who received DF became a long-term survivor; the other died with sepsis during the following days. The dramatic improvement with regard to VOD during DF therapy was encouraging.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Veno-Oclusiva Hepática/etiología , Adolescente , Adulto , Bilirrubina/sangre , Biomarcadores/sangre , Femenino , Enfermedad Veno-Oclusiva Hepática/epidemiología , Enfermedad Veno-Oclusiva Hepática/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de Supervivencia , Trasplante Autólogo , Trasplante Homólogo , Trasplante IsogénicoRESUMEN
Since transplantation cannot be performed immediately after the diagnosis of chronic myelogenous leukemia (CML), interferon treatment is usually required. This study aims to analyze the effects of interferon-alpha (IFN) treatment on allogeneic stem cell transplantation (SCT) outcome. A total of 106 patients aged 16-47 years and transplanted from HLA-identical sibling donors for CML in chronic phase (CP) were evaluated. In all, 48 had received IFN-alpha for a median duration of 5 months (1-18 months) until a median of 1 month prior to transplantation. Of the patients, 50 have received bone marrow transplant (BMT) whereas 56 have received peripheral blood stem cells (PBSCT) between 1991 and 1999 in three major transplant centers in Turkey. Patient characteristics in both groups were similar. More hematological responders were present in the IFN(+) patients (P=0.0001). No difference was found in engraftment kinetics. The incidences of acute or chronic graft-versus-host disease (GVHD), relapse and graft failure were similar in all patients regardless of stem cell source. Overall survival (OS) and disease-free survival (DFS) at 2 years were similar for both IFN(+) or (-) patients following SCT. With multivariate analysis, pretransplant IFN-alpha use, stem cell source, transplant year and CD34+ cell content were not found to be risk factors for OS. In conclusion, prior IFN exposure did not impair BMT or PBSCT outcome.
Asunto(s)
Trasplante de Médula Ósea/fisiología , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Trasplante de Células Madre/métodos , Acondicionamiento Pretrasplante/métodos , Factor de Necrosis Tumoral alfa/uso terapéutico , Adolescente , Adulto , Trasplante de Médula Ósea/efectos adversos , Trasplante de Médula Ósea/mortalidad , Familia , Femenino , Enfermedad Injerto contra Huésped/epidemiología , Prueba de Histocompatibilidad , Humanos , Lactante , Donadores Vivos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Hermanos , Trasplante de Células Madre/efectos adversos , Trasplante de Células Madre/mortalidad , Tasa de Supervivencia , Trasplante Homólogo/inmunología , Trasplante Homólogo/fisiología , Insuficiencia del Tratamiento , Resultado del Tratamiento , TurquíaRESUMEN
Between July 1992 and July 2001, 81 patients with de novo adult acute lymphoblastic leukemia (ALL) treated according to the German Multicenter Study Group for Adult ALL (GMALL) 01/81 protocol were evaluated in order to analyze the effect of aberrant myeloid antigen expression on prognosis. We observed myeloid antigen aberrant expression in 21 of the adult ALL cases. We did not observe any effect of aberrant myeloid antigen expression on the time to achieve remission, relapse rate, and death rate. After 5 years of follow-up, cumulative disease-free survival of myeloid antigen (My) (+) and My (-) adult ALL patients was 67% and 43%, respectively. These data were not found to be statistically significant (P=0.29), but we did find a statistically significant difference in overall survivals between these two groups (85% vs 50%) (P=0.05). Twenty-nine patients died and the remaining 52 patients were followed for a median of 31 months. We could not find any special effect of the known prognostic factors on prediction of relapse in multivariate analysis. However, myeloid antigen expression was the most significant factor, which affected long-term survival in our patients (P=0.01). These data indicate that myeloid antigen expression is useful for predicting a favorable outcome of adult patients with ALL.
Asunto(s)
Antígenos de Superficie/metabolismo , Células Mieloides/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Adolescente , Adulto , Análisis de Varianza , Biomarcadores/análisis , Femenino , Estudios de Seguimiento , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Pronóstico , Factores de Riesgo , Análisis de Supervivencia , Resultado del TratamientoAsunto(s)
Transfusión Sanguínea , Cuidados Intraoperatorios , Trasplante de Hígado/métodos , Adulto , Análisis de Varianza , Bilirrubina/sangre , Pérdida de Sangre Quirúrgica , Peso Corporal , Femenino , Humanos , Hepatopatías/clasificación , Hepatopatías/cirugía , Pruebas de Función Hepática , Masculino , Registros Médicos , Tiempo de Tromboplastina Parcial , Transfusión de Plaquetas , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Donantes de Tejidos/estadística & datos numéricosAsunto(s)
Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante Homólogo/efectos adversos , Adolescente , Adulto , Enfermedad Crónica , Femenino , Enfermedad Injerto contra Huésped/epidemiología , Neoplasias Hematológicas/terapia , Humanos , Terapia de Inmunosupresión/efectos adversos , Incidencia , Masculino , Persona de Mediana Edad , RiesgoAsunto(s)
Ciclosporina/efectos adversos , Inmunosupresores/efectos adversos , Músculos/efectos de los fármacos , Adulto , Creatina Quinasa/sangre , Relación Dosis-Respuesta a Droga , Trasplante de Células Madre Hematopoyéticas , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Masculino , Músculos/enzimologíaRESUMEN
Various chronic pulmonary diseases can cause hypoxia mediated erythrocytosis. We report on a 46 year old male patient presenting with erythrocytosis, in whom a pulmonary arteriovenous fistula on the basis of a vascular malformation was identified as a rare cause of hypoxic erythrocytosis. Thus, congenital pulmonary vascular malformations can become clinically manifest in advanced age.
Asunto(s)
Fístula Arteriovenosa/diagnóstico , Hipoxia/etiología , Pulmón/irrigación sanguínea , Policitemia/etiología , Fístula Arteriovenosa/sangre , Diagnóstico Diferencial , Hematócrito , Humanos , Hipoxia/sangre , Masculino , Persona de Mediana Edad , Policitemia/sangreRESUMEN
Evaluation of chimeric status following allogenic BMT is an important tool for monitoring the replacement of host cells with donor cells and for determining the risk of relapse. Polymorphic DNA sequences can be used as powerful markers in identification of donor/recipient genotype differences, even between close relatives. Polymerase chain reaction (PCR) amplification of three variable number of tandem repeat (VNTR) loci and five single-locus polymorphisms (SLP) was used to identify chimerism in 40 recipient-donor pairs. Mixed chimerism was present in 11 patients, and complete chimerism in 29. This PCR method is a rapid and sensitive assay to detect engraftment and evaluate relapse potential, and thus is very useful in the clinical management of BMT patients.
Asunto(s)
Trasplante de Médula Ósea , Quimera/genética , Polimorfismo Genético , Adolescente , Adulto , Niño , Preescolar , Femenino , Marcadores Genéticos , Humanos , Masculino , Repeticiones de Minisatélite , Reacción en Cadena de la PolimerasaRESUMEN
The incidence of aplastic anemia among hospitalized adult patients was prospectively determined in this first study in Turkey. New cases of aplastic anemia among patients 14 years and older who were admitted to the study centers were included in a 3 year survey. Seventy-three patients fulfilled the diagnostic criteria, yielding a mean annual incidence rate of 1.14 cases in 10(3) admissions. The male-to-female ratio of the cases (1.6:1) differed from the almost equal ratio of the larger population of Turkey. The median age was 30 years and females were younger at diagnosis. The age distribution of the cases was different from that of the population; showing two incidence peaks in both sexes. The majority of the patients (89%) had severe disease.