RESUMEN
The mammalian target of rapamycin (mTOR) inhibitor sirolimus is effective in reducing incidence of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Agents that inhibit the mTOR pathway are known to be associated with significant and potentially dose-limiting toxicities, including stomatitis. The objective of this study was to report the clinical features and management outcomes of sirolimus-associated oral ulcers in the context of post-HSCT prophylaxis of GVHD. Seventeen patients, from a study cohort of 967, who were treated with sirolimus as prophylaxis for GVHD after allogeneic HSCT at the Dana-Farber/Brigham and Women's Cancer Center developed oral ulcers and were referred to the oral medicine clinic for evaluation and treatment over a period of 6 years. Clinical characteristics (appearance, anatomic site, size) and therapeutic outcomes (time to complete resolution) were documented. Median time to onset of oral ulceration was 55 days after allogeneic HSCT (range, 6 to 387 days); 92.9% of ulcers were located on nonkeratinized mucosa, with the ventrolateral tongue the most common site of involvement. Thirteen patients were treated with topical corticosteroid therapy; 12 of these patients also required intralesional corticosteroid injections. Clinical improvement (resolution of the lesions and improvement of symptoms) was noted in all cases, with no reported adverse events. Median time to complete resolution after onset of therapy was 14 days (range, 2 to 70 days). Patients receiving sirolimus for GVHD prophylaxis may develop painful oral ulcerations, which can be effectively managed with topical steroid treatment. Further prospective studies are needed to better elucidate the incidence of this complication, identify risk factors, and evaluate the effectiveness of interventions.
Asunto(s)
Enfermedad Injerto contra Huésped/prevención & control , Células Madre Hematopoyéticas , Inmunosupresores/efectos adversos , Sirolimus/efectos adversos , Estomatitis , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Adulto , Anciano , Aloinjertos , Femenino , Enfermedad Injerto contra Huésped/patología , Humanos , Inmunosupresores/administración & dosificación , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sirolimus/administración & dosificación , Estomatitis/inducido químicamente , Estomatitis/epidemiología , Estomatitis/patología , Estomatitis/terapia , Factores de TiempoRESUMEN
Exposing young rats to particles of high energy and charge, such as (56)Fe, enhances indices of oxidative stress and inflammation and disrupts behavior, including spatial learning and memory. In the present study, we examined whether gene expression in the hippocampus, an area of the brain important in memory, is affected by exposure to 1.5 Gy or 2.5 Gy of 1 GeV/n high-energy (56)Fe particles 36 hours after irradiation. We also determined if 8 weeks of pre-feeding with 2% blueberry or 2% strawberry antioxidant diets could ameliorate irradiation-induced changes in gene expression. Alterations in gene expression profile were analyzed by pathway-focused microarrays for inflammatory cytokines and genes involved in nuclear factor-kappa B (NF-κB) signal transduction pathways. We found that genes that are directly or indirectly involved in the regulation of growth and differentiation of neurons were changed following irradiation. Genes that regulate apoptosis were up-regulated whereas genes that modulate cellular proliferation were down-regulated. The brains of animals supplemented with berry diets demonstrated an up-regulation of some protective stress signal genes. Therefore, these data suggest that (56)Fe particle irradiation causes changes in gene expression in rats that are ameliorated by berry fruit diets.
Asunto(s)
Frutas , Regulación de la Expresión Génica , Hipocampo/efectos de los fármacos , Hipocampo/efectos de la radiación , Compuestos de Hierro/toxicidad , Extractos Vegetales/farmacología , Animales , Antioxidantes/administración & dosificación , Arándanos Azules (Planta) , Fragaria , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/efectos de la radiación , Hipocampo/metabolismo , Compuestos de Hierro/antagonistas & inhibidores , Masculino , Extractos Vegetales/aislamiento & purificación , Ratas , Ratas Sprague-DawleyRESUMEN
A body of evidence supports the idea that the mesolimbic dopamine (DA) system modulates the natural increase in responsiveness female rats show toward offspring (biological or foster) at birth. In the absence of the full hormonal changes associated with pregnancy and birth, female rats do not show immediate responsiveness toward foster offspring. Activation of the mesolimbic DA system can produce an immediate onset of maternal behavior in these females. For example, female rats that are hysterectomized and ovariectomized on day 15 of pregnancy (15HO) and presented with pups 48 hours later normally show maternal behavior after 2-3 days of pup exposure, but will show maternal behavior on day 0 of testing after microinjection of the DA D(1) receptor agonist, SKF 38393, into the nucleus accumbens (NA) at the time of pup presentation. DA D(1) receptor stimulation is known to activate cAMP intracellular signaling cascades via its stimulation of adenylyl cyclase (AC). However, some DA D(1) receptors are also linked to phospholipase C (PLC) and are capable of activating phosphatidylinositol signaling cascades. SKF 38393 stimulates both types of D(1) receptors. Here we provide evidence that the facilitatory effects of DA D(1) receptor stimulation in the NA on maternal behavior are mediated by AC-linked DA D(1) receptors. By examining the effects of intra-NA application of SKF 83822, a drug which selectively binds DA D(1)-AC receptors, or SKF 83959, a drug which selectively activates D(1)-PLC-linked receptors, we find that only SKF 83822 facilitates maternal behavior onset.
Asunto(s)
Adenilil Ciclasas/metabolismo , Conducta Materna/fisiología , Núcleo Accumbens/metabolismo , Receptores de Dopamina D1/fisiología , Sistemas de Mensajero Secundario/fisiología , Fosfolipasas de Tipo C/metabolismo , Animales , Dopaminérgicos/farmacología , Femenino , Conducta Materna/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Ratas , Receptores de Dopamina D1/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Estadísticas no ParamétricasRESUMEN
Female rats that are hysterectomized and ovariectomized on day 15 of pregnancy (15HO) and presented with pups 48 h later show maternal behavior after 2 or 3 days of pup exposure. In contrast, if 15HO females are administered (sc) 20 microg/kg of estradiol benzoate (EB) on day 15 of pregnancy after HO, they show near immediate maternal behavior when pups are presented 48 h later. EB has typically been administered on day 15 because of the underlying assumption that EB exerts genomic effects which require a long duration before being expressed in changes in neuronal phenotype. In light of the more recent evidence that estradiol can generate rapid changes in cellular function, we examined whether injection of a water-soluble form of 17beta-estradiol (E(2)) can facilitate maternal behavior in pregnancy-terminated females when it is administered at the time of pup presentation rather than at the time of HO. Female rats treated with 100 microg/kg of E(2) showed a robust facilitation of maternal behavior, requiring a median of 1 day of pup exposure before showing maternal behavior, compared with 3 days in vehicle-treated rats.