A comparison of the effects of rapamycin and cyclosporine on kidney and heart morphology in a rabbit heterotopic heart transplant model

Rapamycin (RAPA) or cyclosporine (CsA) was administered intravenously, daily for 60 days, to rabbits with heterotopic heart transplants. Groups of 5 rabbits were randomly assigned to receive RAPA at 0.05,O. 1,0.5 or 1 .O mg/kglday or CsA at either 5 .O, 10.0 or 15 mg/kg/day. Dmg vehicle and saline controls were also included. Animals were examined daily and the cervical allografts assessed by palpation for viabilitylrejection. In those animals in which the heart stopped beating, the heart was removed and processed for light microscopic evaluation. The duration of the study was for 60 days at which time the animals were sacrificed and the transplanted heart and native kidneys removed and processed for light microscopic assessment of rejection and drug toxicity respectively. Biochemical and functional parameters in these animals were previously reported (Transplantation 5: 340-345, 1993). Animals that rejected their grafts were maintained on the dmg until the endpoint of the study to assess toxicity in the native kidneys. The rejected hearts from these animals were also harvested for microscopic evaluation. The results of the study revealed that heart rejection in drug treated animals was significantly lower than in corresponding controls but not different among the various drug treated groups. In the kidney, there were no differences in glomerular tuft area or tuft volume density amongst drug-treated or control animals. In contrast, tubule atrophy and interstitial fibrosis were markedl 3 greater in CsA-treated vs RAPA-treated animals (X 5.00, pe0.02). These data suggest that whereas drug efficacy with respect to heart allograft viability is similar between CsA and RAPA, renal toxicity is significantly less in those animals receiving RAPA

A comparison of cyclosporine A and cyclosporine G in a rabbit heterotopic cardiac transplant model: graft outcome and histological findings

Cervical heterotopic heart transplants were performed on 20 male New Zealand white rabbits comprising 4 treatment groups. Animals in each group were injected daily via the marginal ear vein and received one of the following regimes: Cyclosporine A, 10 mglkglday; Cyclosporine G, 15 mglkglday; cremophor-El, 3mllday; or normal saline. Measurement of 24 hour trough blood concentrations revealed no significant differences between the average concentrations of Cyclosporine A and Cyclosporine G. Animals were examined daily and the cervical allografts assessed by palpation for viabilitylrejection. The duration of the study ended for each animal when the graft stopped beating at which time the animals was euthanized and the transplanted heart and native kidneys harvested and processed for light microscopy evaluation of rejection and drug toxicity, respectively. Graft survival in the Cyclosporine A group significantly surpassed that seen in the Cyclosporine G group as well as the control groups, whereas in animals treated with Cyclosporine G, graft survival was not different from controls. In the native kidney, there were no differences in glomerular tuft area or volume density amongst drug-treated or control animals. In contrast, tubule atrophy and interstitial fibrosis were markedly greater in Cyclosporine A-treated vs Cyclosporine Gtreated animals. The results of this study indicate that, whereas Cyclosporine G is less nephrotoxic than Cyclosporine A, given equivalent blood concentrations Cyclosporine A delays rejection of a cardiac allograft significantly longer than Cyclosporine G in this animal species

Impact of Wnt/β-catenin signaling on ethanol-induced changes in brain endothelial cell permeability

Chronic exposure to ethanol is associated with enhanced leakiness in the brain microvessel endothelial cells that form the blood�brain barrier (BBB). As previous studies suggested Wnt/β-catenin signaling could improve the BBB phenotype of brain endothelial cells, we examined the extent to which Wnt signaling is altered following ethanol exposure, using both a cell culture model of the BBB and mice exposed to ethanol, and the ability of Wnt activation to reverse the permeability effects of ethanol. The human brain endothelial cells, hCMEC/D3, were exposed to ethanol (17�200 mM) for various periods of time (0�96 hr) and Wnt signaling, as well as expression of downstream genes influencing BBB integrity in the cell monolayers were monitored. Determination of Wnt signaling in both brain homogenates and brain microvessels from mice exposed to ethanol was also performed. The effects of ethanol on the permeability of the hCMEC/D3 monolayers were examined using both small molecular weight (sodium fluorescein) and large molecular weight (IRdye 800CW PEG) fluorescent markers. Exposure of hCMEC/D3 to ethanol (50 mM) caused a down-regulation of Wnt/β-catenin signaling, a reduction of tight junction protein expression and up-regulation of plasmalemma vesicle associated protein (PLVAP). A similar reduction in Wnt/β-catenin activity in both cortical brain homogenates and isolated cortical cerebral microvessels were observed in mice. Other areas such as cerebellum and striatum displayed as much as 3�6 fold increases in Dkk-1, an endogenous Wnt inhibitor. Ethanol exposure caused significant changes in both sodium fluorescein and IRdye 800CW PEG permeability (2-fold compared to control). The ethanol-induced increases in permeability were attenuated by treatment with known Wnt activators (i.e. LiCl or Wnt3a). Additional screens of CNS active agents with possible Wnt activity indicated fluoxetine could also prevent the permeability effects of ethanol. These studies suggest that ethanol-induced changes in brain microvessel permeability can be reversed through activation of Wnt signaling. (Figure presented.). © 2020 International Society for Neurochemistr

Functional status of the immune system after chronic administration of 2'-deoxycoformycin in the BB rat

Insulin-dependent diabetes mellitus (IDDM) is caused by autoimmune destruction of pancreatic beta cells with the primary mechanism being cell mediated. The BB rat develops insulitis and IDDM with many features analogous to the disease in man. In previous studies we reported that weekly administration of 2'- deoxycoformycin (dCF) for four months reduces significantly the incidence of IDDM in the BB rat by 70%, and that the animals remain free of diabetes for a minimum of two months after drug withdrawal. Since the diabetes-prone BB rat is lymphopenic, with a reduction of both CD4 and CD8 cells, the continuous failure of dCF treated animals to develop diabetes may have been due to generalized immunosuppression. To test this possibility, the ability of dCF treated diabetesfree BB rats to mount an immune response after challenge with Ovalbumin was examined five months after drug withdrawal. The results showed that the postimmunization levels of total IgG and specific IgG in these animals did not differ from those observed in nondCF treated controls nor those of control diabetesresistant non-lymphopenic BB rats. Moreover, FACS analysis indicated no change in the percentages or total numbers of CD4t or CD8+ cells between the two groups of animals. Histological assessment of the pancreata of the post-dCF treated animals showed varying degrees of mononuclear cell infiltrates in the islets. These data demonstrate that treatment by dCF is not permanent, and may require intermittent or continuous administration to prevent development of diabetes. Further studies are needed to determine the mechanism of action of dCF in this model of IDDM

Lung cancer : occurrence and new possibilities for detection

Lung cancer is the leading cause of death worldwide. Physical and chemical agents such as tobacco smoke are the leading cause of various lung cancers. The intrinsic heterogeneity of normal lung tissue may be affected in different ways, giving rise to different types of lung cancers classified as either small\u2010cell lung cancer (SCLC) or non\u2010small cell lung cancer (NSCLC). Adenocarcinoma, a NSCLC, accounts for 40 percent of all lung cancer cases and the incidence is increasing worldwide, especially among women. The survival rate and prognosis is poorest for adenocarcinoma. Therefore, diagnosis at the earliest stage (Stage I, localized) is critical for increasing survival rates of those suffering from lung cancer. However, many factors affect early diagnosis including the variable natural growth of tumors plus technological and human factors associated with manipulation of tissue samples and interpretation of results. This article reviews potential problems associated with diagnosing lung cancer and considers future directions of diagnostic technology.Peer reviewed: YesNRC publication: Ye