RESUMEN
Acute graft-versus-host disease (GvHD) limits the applicability of allogeneic hematopoietic cell transplantation for the treatment of leukemia. GvHD occurs as a consequence of multiple activating events in antigen-presenting cells (APCs) and T cells (Tcs). Spleen tyrosine kinase (Syk) is an intracellular non-receptor tyrosine kinase involved in multiple signaling events of immune cells. Therefore, we hypothesized that Syk may be a promising target to inhibit GvHD, which involves activation of different immune cell populations. In vivo expansion of luciferase(+) donor Tcs in mice developing GvHD was reduced by treatment with the Syk inhibitor Fostamatinib, which led to increased survival and reduced histologically confirmed GvHD severity. Importantly, in vivo and in vitro cytotoxicity against leukemia target cells and anti-murine cytomegalovirus immune responses were not impacted by Fostamatinib. In APCs Syk inhibition reduced the expression of costimulatory molecules and disrupted cytoskeletal organization with consecutive APC migratory defects in vitro and in vivo while phagocytic activity remained intact. On the basis of these immunomodulatory effects on different cell populations, we conclude that Syk targeting in alloantigen-activated Tcs and APCs with pharmacologic inhibitors, already applied successfully in anti-lymphoma therapy, has clinical potential to reduce GvHD, especially as anti-leukemia and anti-viral immunity were preserved.
Asunto(s)
Células Presentadoras de Antígenos/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Leucemia/terapia , Oxazinas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Piridinas/uso terapéutico , Bazo/enzimología , Aminopiridinas , Animales , Western Blotting , Trasplante de Médula Ósea , Movimiento Celular , Proliferación Celular , Citomegalovirus , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Células Dendríticas/inmunología , Femenino , Citometría de Flujo , Enfermedad Injerto contra Huésped/enzimología , Enfermedad Injerto contra Huésped/etiología , Efecto Injerto vs Leucemia , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Leucemia/inmunología , Activación de Linfocitos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Morfolinas , Fosforilación , Proteínas Tirosina Quinasas/metabolismo , Pirimidinas , Quinasa Syk , Linfocitos T/inmunología , Trasplante HomólogoRESUMEN
BACKGROUND: To determine whether reamed or unreamed intramedullary nailing of femoral fractures results in higher incidence of pulmonary fat embolism, three different methods of intramedullary nailing were compared in sheep. To analyze the presence of bone marrow fat embolism in pulmonary arteries, histological evaluation was undertaken using a quantitative computer-assisted measurement system. METHODS: In this experimental model of 27 female Swiss alpine sheep, an osteotomy of the proximal femur was conducted in each animal. Then, the animals were divided into three groups according to the method of treatment: two different reamed intramedullary nailing techniques and an unreamed nailing technique were used. In the first group "ER" (experimental reamer; n=9), the nail was inserted after reaming with an experimental reamer; in the second group "CR" (conventional reamer; n=7), the intramedullary nail was inserted after reaming with the conventional AO-reamer. In the third group "UN" (unreamed; n=8) unreamed nailing was performed. During the operation procedure intramedullary pressure was measured in the distal fragment. After sacrificing the animals, quantitative histological analyses of bone marrow fat embolism in pulmonary arteries were done using osmium tetroxide fixation and staining of the fat. RESULTS: The measurement of intramedullary pressure showed significantly lower values for reamed nailing than for the unreamed technique. The quantitative histological evaluation of lung vessels concerning bone marrow fat embolism revealed a statistically significant difference between reamed and unreamed insertion of the nail: 7.77%±6.93 (ER) and 6.66%±5.61 (CR) vs. 16.25%±10.05 (UN) (p<0.05) of the assessed lung vessels were filled with fat emboli. However, no difference was found between the traditional and experimental reamer. CONCLUSIONS: Intramedullary nailing after reaming is a safe procedure with low systemic embolisation when compared to the unreamed insertion of the nail.
Asunto(s)
Embolia Grasa/etiología , Fracturas del Fémur/complicaciones , Fijación Intramedular de Fracturas/efectos adversos , Embolia Pulmonar/etiología , Animales , Clavos Ortopédicos/efectos adversos , Embolia Grasa/cirugía , Femenino , Fracturas del Fémur/cirugía , Fijación Intramedular de Fracturas/métodos , Incidencia , Osteotomía , Embolia Pulmonar/cirugía , Ovinos/cirugíaRESUMEN
Benign fibrous histocytoma of bones is a very rare tumour and only a few cases have been reported. We report a case of 40-year-old patient with no significant previous medical history who presented with a painful lesion in his right wrist joint. Incision biopsy was done and there was a histological picture similar to a metaphyseal fibrous defect (non-ossifying fibroma). This was managed with excision of the lesion and filling the defect with cancellous and cortical bone grafts from the left iliac bone. To our knowledge, this is the second case report of a benign fibrous histocytoma involving the distal radius in adult. In this case report, we review similar cases in the literature and discuss the differential diagnoses of this lesion.
Asunto(s)
Neoplasias Óseas/diagnóstico , Histiocitoma Fibroso Benigno/diagnóstico , Radio (Anatomía) , Adulto , Biopsia , Neoplasias Óseas/patología , Neoplasias Óseas/cirugía , Histiocitoma Fibroso Benigno/patología , Histiocitoma Fibroso Benigno/cirugía , Humanos , Imagen por Resonancia MagnéticaRESUMEN
In a pilot experiment comparing four different modalities for inducing osteoporosis in the sheep, a combination of ovariectomy, calcium/vitamin D-restricted diet and steroid administration was found to generate the highest decrease in bone mineral density (BMD). The aim of the present study was to quantify the outcome of this triple treatment in an animal model of osteoporosis in terms of alteration in bone mass, bone structure and bone mechanics. A total of 32 sheep were divided into two equal groups. Group 1 (age 3-5 years) was used as a normal control. Group 2 (age 7-9 years) was ovariectomized, fed a calcium/vitamin D-restricted diet and injected with methylprednisolone (MP) over 7 months (22 weeks MP solution, 6 weeks MP suspension). The BMD at the distal radius and tibia was determined preoperatively and at repeated intervals bilaterally using quantitative computed tomography. Steroid blood levels were determined 4 and 24 h after selected injections. BMD was measured at L3 and L4 after 7 months. Biopsies were taken from iliac crests, vertebral bodies and femoral heads, and bone structure parameters investigated by three-dimensional micro-CT. Compressive mechanical properties of cancellous bone were determined from biopsies of vertebral bodies and femoral heads. After 7 months of osteoporosis induction the BMD of cancellous bone decreased 36 +/- 3% in the radius and 39 +/- 4% in the tibia. Steroid blood levels 24 h after injection of MP suspension were significantly higher than after injection of MP solution. Changes in structural parameters of cancellous bone from the iliac crest, lumbar spine and femoral head in group 2 indicated osteoporosis-associated changes. In group 2 there was a significant reduction in BMD of the lumbar spine and a significant reduction in stiffness and failure load in compression testing of biopsies of lumbar vertebrae. In sheep, changes in the structural parameters of bone such as trabecular number and separation during osteoporosis induction are comparable to the human situation. The sheep model presented seems to meet the criteria for an osteoporosis model for fracture treatment with respect to mechanical and morphometric bone properties.