Study of Langerhans cells after allogeneic bone marrow transplantation

We assessed the number of Langerhans cells (LC) before and after bone marrow transplantation (BMT) in 27 patients in order to study the fate and behavior of these dendritic antigen-presenting cells following allogeneic BMT. LC were identified using monoclonal antibody OKT6 on skin biopsies performed on days - 10, 0, 11, 25, 39, 120, and 365. In a control group composed of 15 healthy adults aged 20-37 yr, the mean number of LC (+/- SEM) was 25.6 +/- 1.17/0.1 sq mm of epidermal surface. Our study shows that pretransplant, the number of LC in patients with aplastic anemia or leukemia was lower than that of controls. The finding of low numbers of LC in patients with untreated aplastic anemia is suggestive of a medullary origin of LC in man. Moreover, during the early posttransplant period, nearly all patients present a severe deficit in LC. This deficit may delay the maturation of their immune system. The number of LC reaches nearly normal levels 4- 12 mo after BMT. Finally, we have noted a significant impairment of LC reconstitution in patients with acute graft-versus-host disease (GVHD), providing evidence that this defect may be an important mechanism involved in acute GVHD-related immunodeficiency.     

Acute effects and long-term sequelae of 1,3-dinitrobenzene on male reproduction in the rat. I. Sperm quality, quantity, and fertilizing ability

Groups of eight adult male rats were given a single oral dose of 0 or 48 mg/kg of 1,3-dinitrobenzene and sacrificed at 1, 2, 4, 8, 16, 24, 32, 72, and 175 days posttreatment. The groups killed at 175 days were bred to untreated females during weeks 3, 4, 6, 9, 13, and 24. Decreased testis weight and testicular sperm numbers were observed by day 4; decreased cauda sperm reserves and epididymis weight occurred by day 8 and day 16, respectively. Reduced numbers of motile spermatozoa and abnormal sperm morphology were seen in spermatozoa from the cauda epididymidis by day 16. Fertilizing ability, as indicated by the presence of two pronuclei and a sperm tail in eggs flushed from the oviducts of inseminated females, was slightly reduced by week 4 and declined to zero by week 6. Group means for reproductive organ weights, sperm production, and sperm reserves failed to return to control levels although some individual animals approached full recovery. Normal fertilizing ability was restored in most animals by week 13, but two of seven remained infertile. Occlusion of some efferent ductules was observed in three of seven animals at 175 days. This study indicates that 1,3-dinitrobenzene is a potent testicular toxicant in the rat, capable of producing marked testicular damage, infertility, and possibly sterility from a single exposure.     

Evaluation of Fc-dependent monocyte-macrophage function in bone marrow transplant recipients

Allogeneic bone marrow recipients exhibit a complex and multifactorial immunodeficiency affecting numerous effector functions for various periods of time. In order to evaluate their Fc-mediated monocyte-macrophage (MM) function we studied the clearance of IgG-coated Rh-positive erythrocytes (EA) in healthy control subjects and recipients of unmanipulated marrow. We measured the survival of radiolabeled EA prior to myeloablation and on days 0, +14, +38, +124, +368, and greater than or equal to +730 following bone marrow transplant (BMT). Simultaneously we evaluated the interaction of adherent peripheral blood monocytes (PBMs) with EA (in vitro phagocytosis and attachment). Fc-mediated function appeared normal prior to BMT despite the fact that most patients had received chemotherapy previously. We found no deficit in the Fc-dependent MM activity (in vivo and in vitro) at any time after transplantation. On the contrary we demonstrated an enhanced Fc-dependent clearance during the first month after BMT (p less than 0.001; Mann-Whitney test). These results suggest that we can expect efficient MM function to eliminate IgG-coated cells and particles in BMT recipients.     

Molecular activation of PPARgamma by angiotensin II type 1-receptor antagonists

OBJECTIVE AND DESIGN: Elevated blood pressure and insulin resistance are strongly associated in patients. We explored the potential for the anti-hypertensive angiotensin II type 1-receptor (ATR(1)) antagonists to improve insulin sensitivity through modulation of the nuclear receptor PPARgamma, in vitro and in vivo compared to the potent insulin sensitizer, rosiglitazone. METHODS: PPARgamma modulation by ATR(1) antagonists was measured first by direct recruitment of PGC-1, followed by trans-activation reporter assays in cells, and promotion of adipogenesis in fibroblast and pre-adipocyte cell lines. Improvement of insulin sensitivity was measured as changes in levels of glucose, insulin, and adiponectin in ob/ob mice. RESULTS: Telmisartan, candesartan, irbesartan, and losartan (but not valsartan or olmesartan) each served as bona fide PPARgamma ligands in vitro, with EC(50) values between 3 and 5 micro mol/l. However, only telmisartan, and to a lesser extent candesartan, resulted in significant PPARgamma agonism in cells. In vivo, although rosiglitazone significantly lowered both glucose (33%, p<0.01) and insulin (61%, p<0.01) levels and increased expression of adiponectin (74%, p<0.001), sartan treatment had no effect. CONCLUSIONS: Many members of the sartan family of ATR(1) antagonists are PPARgamma ligands in cell-free assays but their modulation of PPARgamma in cells is relatively weak. Furthermore, none appear to improve insulin sensitivity in a rodent model under conditions where other insulin sensitizers, including rosiglitazone, do. These results question whether reported effects of sartans on insulin sensitivity may be through other means, and should guide further efforts to develop dual agents to treat hypertension and insulin resistance.     

The influence of perturbation duration and velocity on the long-latency response to stretch in the biceps muscle

Different neural pathways are proposed to mediate the long-latency stretch reflex response (M2) in muscles spanning distal and proximal joints of the upper limb. The M2 at the wrist joint is present only if the duration of the perturbation exceeds a critical time. Lee and Tatton put forward a converging input hypothesis, requiring an interaction of excitatory volleys at the spinal cord, to account for this feature. The goal of the present study was to examine the influence of the duration of perturbation on M2 responses elicited in a muscle spanning the elbow joint. Reflex responses were induced in the biceps brachii muscle by applying ramp-and-hold position displacements to the elbow. It was found that the M2 was strongly dependent on the duration of the perturbation. On average, responses were not elicited following perturbations of less than 35±5 ms. Using a novel double-movement paradigm, we were unable to provide support for the converging input hypothesis. The effect of the duration of perturbation on the M2 may account for the conflicting characteristics of the M2 that have been provided by previous studies applying mechanical or electrical perturbations of varying time durations.