8 research outputs found
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