Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiac allograft vasculopathy is the major long-term problem after heart transplantation. However, the assumption, mostly based on experimental animal data, that human CAV is an immune-mediated diffuse concentric intimal proliferation with progressive, homogenous vessel narrowing, involving equally epicardial arteries and the microcirculation, leading inevitably to ischemic organ failure and death, does not adequately reflect the complexity of the clinical setting. CAV in humans is much more characterized by a very heterogeneous pattern concerning pathogenetic mechanisms (e.g., immune activation, ischemia-reperfusion injury, CMV infection, hyperlipoproteinemia), protective mechanisms (e.g., remodeling, endothelium-derived vasodilators), endothelial dysfunction, morphological manifestations, involvement of the microcirculation, temporal appearance, disease progression and prognosis. Thus, clinicians have to deal with several clinical dilemmas of the disease, which can be summarized in three simple questions: how can CAV be detected/diagnosed, how can CAV and related events be predicted, and finally how can CAV be prevented and treated. Initial and promising answers to these pivotal questions have been found in recent years, and continuing progress is under way.
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PMID:The clinical dilemma of cardiac allograft vasculopathy--an introduction to the clinical session. 1115 91

We investigated whether enhanced expression of alphaB crystallin, a stress-inducible molecular chaperone of the small heat shock family, can protect myocardial contractile apparatus against ischemia reperfusion (I/R) injury. Transgenic mice overexpressing alphaB crystallin were generated using the 0.76 kb rat alphaB crystallin cDNA cloned into a pCAGGS plasmid driven by a human cytomegalovirus expression system. Southern analysis confirmed transgene integration and Northern and Western blotting characterized expression (3.1-fold and 6.9-fold elevations in myocardial mRNA and protein levels, respectively). Extent of functional recovery over a 3 h reperfusion period following a 20 min ischemic period in transgenic and wild-type mouse hearts was assessed using an ex vivo work-performing heart preparation. The transgenic group displayed significantly higher values of DP at R45 min (29.14+/-1.9 mm Hg vs. 17.6+/-0.7 mm Hg), R60 min (31.56+/-1.7 mm Hg vs. 17.8+/-0.8 mm Hg), and R75 min (32.5+/-2.2 mm Hg vs. 16.9+/-0.9 mm Hg), and of dLVP/dt at R45 min (1740.2+/-111.5 mm Hg.s-1 vs. 548.7+/-82.2 mm Hg.s-1) and R60 min (1199.8+/-104.6 mm Hg.s-1 vs. 466.9+/-61.1 mm Hg.s-1). The transgenic group also displayed development of less oxidative stress, decreased extent of infarction, and attenuated cardiomyocyte apoptotic cell death. Transgene overexpression of alphaB crystallin was therefore successful in diminishing the independent contributory effects of both necrosis and apoptosis on I/R-induced cell death.
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PMID:Transgene overexpression of alphaB crystallin confers simultaneous protection against cardiomyocyte apoptosis and necrosis during myocardial ischemia and reperfusion. 1115 55

Islet transplantation offers the prospect of good glycemic control without major surgical risks. After our initial report of successful islet transplantation, we now provide further data on 12 type 1 diabetic patients with brittle diabetes or problems with hypoglycemia previous to 1 November 2000. Details of metabolic control, acute complications associated with islet transplantation, and long-term complications related to immunosuppression therapy and diabetes were noted. Insulin secretion, both acute and over 30 min, was determined after intravenous glucose tolerance tests (IVGTTs). The median follow-up was 10.2 months (CI 6.5-17.4), and the longest was 20 months. Glucose control was stable, with pretransplant fasting and meal tolerance-stimulated glucose levels of 12.5+/-1.9 and 20.0+/-2.7 mmol/l, respectively, but decreased significantly, with posttransplant levels of 6.3+/-0.3 and 7.5+/-0.6 mmol/l, respectively (P < 0.006). All patients have sustained insulin production, as evidenced by the most current baseline C-peptide levels 0.66+/-0.06 nmol/l, increasing to 1.29+/-0.25 nmol/l 90 min after the meal-tolerance test. The mean HbA1c level decreased from 8.3+/-0.5% to the current level of 5.8+/-0.1% (P < 0.001). Presently, four patients have normal glucose tolerance, five have impaired glucose tolerance, and three have post-islet transplant diabetes (two of whom need oral hypoglycemic agents and low-dose insulin (<10 U/day). Three patients had a temporary increase in their liver-function tests. One patient had a thrombosis of a peripheral branch of the right portal vein, and two of the early patients had bleeding from the hepatic needle puncture site; but these technical problems were resolved. Two patients had transient vitreous hemorrhages. The two patients with elevated creatinine levels pretransplant had a significant increase in serum creatinine in the long term, although the mean serum creatinine of the group was unchanged. The cholesterol increased in five patients, and lipid-lowering therapy was required for three patients. No patient has developed cytomegalovirus infection or disease, posttransplant lymphoproliferative disorder, malignancies, or serious infection to date. None of the patients have been sensitized to donor antigen. In 11 of the 12 patients, insulin independence was achieved after 9,000 islet equivalents (IEs) per kilogram were transplanted. The acute insulin response and the insulin area under the curve (AUC) after IVGTT were consistently maintained over time. The insulin AUC from the IVGTT correlated to the number of islets transplanted, but more closely correlated when the cold ischemia time was taken into consideration (r = 0.83, P < 0.001). Islet transplantation has successfully corrected labile type 1 diabetes and problems with hypoglycemia, and our results show persistent insulin secretion. After a minimum of 9,000 IEs per kilogram are provided, insulin independence is usually attained. An elevation of creatinine appears to be a contraindication to this immunosuppressive regimen. For the subjects who had labile type 1 diabetes that was difficult to control, the risk-to-benefit ratio is in favor of islet transplantation.
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PMID:Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. 1128 33

Central venulitis (CV), a distinct histologic lesion described in adult liver transplants, can occur with acute portal tract rejection or in isolation (ICV). Possible etiologies include immunosuppressive drug toxicity, acute cellular rejection, viral hepatitis, ischemic injury, and recurrent disease. This study was designed to characterize ICV and to assess its potential etiology in pediatric liver recipients because this population generally does not develop recurrent disease or viral hepatitis. All posttransplantation liver biopsy specimens that were obtained from children who received liver allografts over a 4-year period were reviewed. ICV was identified in 12 of 127 posttransplantation biopsies and in 7 of 45 allograft recipients. Only 4 liver transplantations were performed for potentially recurrent diseases (primary sclerosing cholangitis). ICV first appeared in posttransplantation biopsy specimens significantly later than did portal rejection alone. The finding of CV was not significantly correlated with elevation of Tacrolimus levels, reason for transplantation, donor/recipient cytomegalovirus (CMV) status or blood type, cold ischemic times, or the incidence of outflow obstruction. The responses of CV to therapy were variable and, although the majority of cases resolved, several episodes persisted or recurred. In conclusion, ICV occurs in 16% of pediatric liver allograft recipients and does not appear to be related to recurrent disease, viral hepatitis, drug toxicity, or graft ischemia. CV may be a variant of acute rejection, but longer follow-up is required to determine the most adequate therapy for this entity.
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PMID:Central venulitis in pediatric liver allografts. 1134 63

Cholestasis is a common finding after liver transplantation and usually signifies graft dysfunction. The most important factor in the evaluation of patients with cholestasis is an awareness of the disorders that commonly arise along a time continuum post-transplant. Therefore, the approach to cholestasis requires a systematic review of biochemical, histological, and radiographic data. This article considers the causes of cholestasis in liver transplant recipients, excluding those associated with biliary anastomotic stricturing. These causes include conditions as diverse as ischemia reperfusion injury, ABO blood group incompatibility, hepatic arterial thrombosis, cytomegalovirus infection, fibrosing cholestatic hepatitis secondary to hepatitis B and C viruses, recurrent primary sclerosing cholangitis, recurrent primary biliary cirrhosis, and chronic rejection. Also examined are management issues pertinent to these conditions and strategies used in preventing or diminishing the effects of cholestasis once established.
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PMID:Cholestatic diseases of liver transplantation. 1135 20

A total of 73,707 primary renal transplants reported to the USRDS between 1988 and 1997 were examined to investigate the cause-specific risk for patient death associated with anti-lymphocyte antibody induction therapy (ABI). Cox proportional hazard models were used to estimate the relative risk of the use of ABI and patient death. All Cox models were corrected for potential confounding variables, such as age, gender, race, HLA mismatch, panel reactive antibody, delayed graft function, cold ischemia time, time since start of dialysis, etiology of end-stage renal disease, cytomegalovirus risk group, donor source (living or cadaveric), era effect, and immunosuppressive therapy. Primary study end points were patient death with functioning graft (DWFG) and overall patient death, including death after graft loss. Early patient death (deaths within the first 6 mo after renal transplantation) and late death (deaths after 6 mo post-renal transplantation) were investigated separately. Additionally, specific causes of death were investigated. ABI was associated with a significant risk for late death after renal transplantation (relative risk [RR] = 1.1; P < 0.001) but not for DWFG (RR = 0.94; P = 0.10). ABI conferred the highest RR for late malignancy-related death (RR = 1.35; P < 0.001). ABI was significantly associated with early deaths due to infection and cardiovascular causes (RR = 1.32 [P < 0.001] and RR = 1.27 [P < 0.001], respectively). Kaplan Meier plots confirmed that the risk of ABI for patient death secondary to infectious complications was increased predominately early after transplantation as opposed to late for malignancy-related death. ABI was associated with a significant relative risk for patient death secondary to cardiovascular causes and infectious complications early in the posttransplant period. In addition, ABI was associated with a significant risk for long-term malignancy-related death. The risk of ABI should be taken in context with potential benefits of this therapy.
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PMID:Association of antibody induction with short- and long-term cause-specific mortality in renal transplant recipients. 1185 83

Repeated bouts of ischemia in the heart lead to fibrosis and eventually to heart failure. Although certain genes, such as SOD or hemoxygenase and antisense to AT(1)R, ACE, and (beta(1)-AR can provide short-term protection of the heart from ischemia, there is no known mechanism for constantly responding to repeated incidences of ischemia. We hypothesized that a "vigilant vector," designed to be expressed specifically in the heart and switch on therapeutic genes only during hypoxia, would provide cardioprotection. To attain cardiac specificity, we inserted an MLC2v promoter into an adeno-associated virus (AAV) designed to deliver AS to AT(1)R and gfp. In in vitro experiments in cardiomyocytes (H9C2 cells), the MLC2v-AAV-gfp drove gene expression in all cells at levels comparable to a cytomegalovirus (CMV) promoter. In in vivo experiments, the rAAV-MLC2v-gfp was injected intravenously into mice or rats. Green fluorescence protein (GFP) DNA was located in kidney, heart (right and left ventricle), lung, adrenal and spleen. GFP mRNA, however, was expressed only in the heart and absent in other tissues. To switch on the rAAV transgene during ischemia, we inserted a hypoxia response element (HRE). This upregulates transcription when O(2) levels are low. Thus, there are 4 components to the vigilant vector; a gene switch (HRE), a heart-specific promoter (MLC2v), a therapeutic gene (AS-AT(1)R) and a reporter gene (gfp). To silence or lower basal level of expression while retaining specificity, we have reduced the length of the MLC2v promoter from 3 kb to 1775 bp or 281 bp. The truncated promoter is equally effective in heart specific expression. Preliminary studies with the rAAV-HRE-gfp in vitro show an increased expression in 1% O(2) in 4 to 6 hours. By adding additional hypoxia-inducible factor (HIFalpha) (5 microg), the MLC2v-gfp expression is increased by 4-fold in 1% O(2). Further amplification of the gene to 400-fold in 1% O(2) can be achieved with a double plasmid. The construct may serve as a prototype "vigilant vector" to switch on therapeutic genes in specific tissue with physiological signals.
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PMID:Vigilant vector: heart-specific promoter in an adeno-associated virus vector for cardioprotection. 1188 25

Acute cerebral ischemia causes hypoxic neuronal cell death by necrosis and apoptosis. Expression of anti-apoptotic transgenes in ischemic brain may provide a useful therapeutic strategy for alleviation of postischemic damage. The present study investigates liposome-mediated transfer of the human bcl-2 protein in a rat model of focal transient ischemia due to middle cerebral artery (MCA) occlusion. Two different types of plasmid vectors were used for bcl-2 expression: one driven by the constitutive cytomegalovirus promoter (pCMV) and another based on the hypoxia-inducible human vascular endothelial growth factor promoter (pHRE). Cationic liposome/plasmid DNA complexes (lipoplexes) were injected directly into the cerebrospinal fluid (CSF) of rats immediately after MCA occlusion. The brains of treated and control animals were analyzed 48 h later. Infarct volumes and numbers of apoptotic cells were quantified. Occlusion of the MCA resulted in ipsilateral cerebral infarcts in all study animals. Transfer of the bcl-2 gene resulted in high level widespread protein expression in the case of the pCMV-bcl2 plasmid, while animals treated with the pHRE-bcl2 vector showed lower expression levels of bcl2 which were in addition limited to the ischemic area. Treatment with pCMV-bcl2, but not with pHRE-bcl2, was able to significantly reduce the infarct volume, which was 109 +/- 8 mm(3) for pCMV-bcl2, 152 +/- 29 mm(3) for pHRE-bcl2, and 155 +/- 18 mm(3) for control animals. Animals transfected with either vector showed a significant reduction in numbers of apoptotic cells in the infarct and penumbra area compared with controls. There were no short-term neurological side-effects of the CSF injection of lipoplexes or of bcl-2 expression. In conclusion, the hypoxia-inducible bcl-2 expression mediated by intrathecal lipoplexes may represent a novel, biologically safe and lesion-selective therapeutic approach for neuroprotection after acute cerebral ischemia. DOI: 10.1038/sj/gt/3301676
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PMID:Liposome-mediated transfer of the bcl-2 gene results in neuroprotection after in vivo transient focal cerebral ischemia in an animal model. 1196 Mar 18

Tacrolimus and cyclosporine in the microemulsion formulation Neoral have demonstrated improvements in acute rejection rates after renal transplantation compared with conventional cyclosporine formulation, Sandimmune. To evaluate whether these drugs are also associated with improvements in chronic allograft failure (CAF) rates, we retrospectively analyzed 32,040 primary renal allograft recipients reported to the United States Renal Data System (USRDS) between 1994 and 1997. Graft loss secondary to CAF was defined as graft loss beyond 6 months post-transplant, censored for death, acute rejection, thrombosis, infections and noncompliance. A Cox proportional hazard model was used to investigate the relationship between graft loss secondary to CAF and the use of conventional cyclosporine formulation, as opposed to cyclosporine microemulsion and tacrolimus (Prograf). The analysis was corrected for confounding variables, such as acute rejection, sex, race, human leukocyte antigen (HLA) mismatch, % panel reactive antibodies (PRA), delayed graft function (DGF), cold ischemia time, induction therapy, dialysis time, etiology of end-stage renal disease, cytomegalovirus (CMV) risk group, donor source, era effect, and mycophenolate mofetil (MMF) use. Cyclosporine microemulsion use was associated with a significantly lower relative risk (RR = 0.6, Cl = 0.5-0.7) for CAF as opposed to conventional cyclosporine formulation. Likewise tacrolimus as compared with conventional cyclosporine formulation was associated with a significantly lower relative risk (RR = 0.7, CI = 0.6-0.8) for CAF. Conventional cyclosporine formulation treatment was associated with a 87.6% adjusted CAF-free survival rate at 4 years. Both tacrolimus and cyclosporine microemulsion were associated with a significantly better adjusted CAF-free survival at 4years (91.4 and 92.4%, respectively). Both cyclosporine microemulsion and tacrolimus are associated with improved graft survival and a decreased relative risk for CAF when compared with the older conventional cyclosporine formulation. This association is independent of the use of MMF or changes in era.
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PMID:Cyclosporine microemulsion and tacrolimus are associated with decreased chronic allograft failure and improved long-term graft survival as compared with sandimmune. 1209 48

Although the precise mechanisms are unclear, not only alloantigen-dependent but also antigen-independent factors are generally thought to influence the development of chronic allograft nephropathy (CAN). Among the non-immunological determinants, there are various factors related with donor, recipient and graft procurement. As donor factors, age and cause of death were demonstrated to be significantly independent in long-term graft survival of cadaveric kidney transplantation. Grafts from aged donors and from donors with athelosclerosis showed poor prognosis on graft survival. Regarding recipient factors, cardiovascular complications, as hypertension and hyperlipidemia, were responsible for graft as well as patient survival. In addition, CMV infection and drug nephrotoxicity were also shown to affect graft survival. For procurement factors, warm ischemia was determined to possess the strongest impact on long-term graft survival in our series of kidney transplant using grafts from non-heart beating donors (NHBDs). Delayed graft function, which correlated well with length of warm ischemia, also influenced long-term graft survival. These results proved that the supply of viable donor nephrons and the physiologic demands of the recipient are important determinants of long-term graft survival. So far there seems to be neither definitive nor specific treatment for CAN. It is basically essential to avoid graft damage before transplant and keep recipients from risk factors after transplant as much as possible. To improve long-term graft survival in cadaveric kidney transplantation, recipient selection is greatly important in terms of not only immunological compatibility but also body to nephron mass imbalance and ischemic time, which might cause fatal damage to grafts before engraftment.
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PMID:[Non-immunological risk factors associated with chronic allograft nephropathy following kidney transplantation]. 1251 44


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