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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. As long-term survival improves after liver transplantation, cardiovascular complications are emerging as a major cause of late morbidity and mortality. It seems reasonable to correct the potentially reversible cardiovascular risk factors of diabetes, hyperlipidemia, and obesity, in addition to hypertension. 2. The results of liver transplantation in diabetics are acceptable in terms of morbidity, mortality, and prevalence of posttransplant diabetes, but the poor outcomes described in some series suggest that more extensive testing for macro- and microvascular disease may become necessary. 3. The management of diabetes in liver transplant recipients is not substantially different from its management in non-transplant patients, except that steroid reduction or withdrawal and minimizing doses of calcineurin inhibitors are beneficial. 4. Hyperlipidemia occurs in all solid-organ transplantation, with prevalence rates the lowest for liver transplant recipients. Following liver transplantation, between 15% and 40% of recipients on average have increased plasma cholesterol levels and about 40% have hypertriglyceridemia. Dietary changes, weight reduction, exercise and statins are the mainstays of therapy. 5. Retrospective studies suggest that long-term survival of obese recipients after liver transplantation does not differ from nonobese recipients. Posttransplant weight gain occurs in most recipients, and approximately two thirds become overweight. The management of posttransplant obesity is similar to that in non-transplant settings.
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PMID:Long-term management of the liver transplant patient: diabetes, hyperlipidemia, and obesity. 1168 72

The identification of genetic mutations underlying familial structural heart disease has provided exciting new insights into how alterations in structural components of the cardiomyocyte lead to different forms of cardiomyopathy. Specifically, mutations in components of the sarcomere are frequently associated with hypertrophic cardiomyopathy, whereas mutations in cytoskeletal proteins lead to dilated cardiomyopathy. In addition, extrinsic stresses such as hypertension and valvular disease can produce myocardial remodeling that is very similar to that observed in genetic cardiomyopathy. For myocardial remodeling to occur, changes in gene expression must occur; therefore, changes in contractile function or wall stress must be communicated to the nucleus via signal transduction pathways. The identity of these signaling pathways has become a key question in molecular biology. Numerous signaling molecules have been implicated in the development of hypertrophy and failure, including the beta-adrenergic receptor, G alpha(q) and downstream effectors, mitogen-activated protein kinase pathways, and the Ca(2+)-regulated phosphatase, calcineurin. In the past it has been difficult to discern which signaling molecules actually contributed to disease progression in vivo; however, the development of numerous transgenic and knockout mouse models of cardiomyopathy is now allowing the direct testing of stimulatory and inhibitory molecules in the mouse heart. From this work it has been possible to identify signaling molecules and pathways that are required for different aspects of disease progression in vivo. In particular, a number of signaling pathways have now been identified that may be key regulators of changes in myocardial structure and function in response to mutations in structural components of the cardiomyocyte. Myocardial structure and signal transduction are now merging into a common field of research that will lead to a more complete understanding of the molecular mechanisms that underly heart disease.
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PMID:From the sarcomere to the nucleus: role of genetics and signaling in structural heart disease. 1170 29

Although only very few new immunosuppressive drugs have been approved over the past two decades, the introduction of each new drug has progressively reduced the incidence of acute rejection and raised hopes that there would be an increase in long-term allograft survival. It is now consistently possible to achieve acute rejection rates of between 10 and 20%, and in many studies the rate has fallen below 10%. This is important, as acute rejection is one of the most important factors reducing the long-term survival of the allograft as a consequence of the development of chronic allograft nephropathy. The availability of these new agents has allowed experimentation with diverse protocols that explore the possibility of reduced exposure to calcineurin inhibitors and corticosteroids. These include both 'avoidance' and 'withdrawal' protocols. The target of rapamycin inhibitors, sirolimus and everolimus, have extended this paradigm. It is possible, but not yet proved, that their antiproliferative effect on smooth muscle will retard the vascular remodelling characteristic of chronic allograft nephropathy, atherosclerosis and hypertension. This review concentrates on the current progress being made in clinical immunosuppression, and includes data presented at the Transplant 2001 meeting of the American Society of Transplantation and the American Society of Transplant Surgeons, held in May 2001.
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PMID:Progress in the clinical application of immunosuppressive drugs in renal transplantation. 1170 3

SDZ RAD (everolimus, Certican is a novel macrolide immunosuppressant that blocks growth factor-driven transduction signals in the T-cell response to alloantigen. After stimulation of the IL-2 receptor on the activated T-cell, SDZ RAD inhibits p70S6 kinase, acting at a later stage in the T-cell mediated response than do cyclosporine and other calcineurin inhibitors (CNIs). Unlike the CNIs, SDZ RAD is a proliferation signal inhibitor, blocking growth factor-driven proliferation of both hematopoietic and nonhematopoietic cells. These activities are complementary to those of cyclosporine and provide a rationale for the addition of SDZ RAD to cyclosporine-based immunosuppression, with the potential for minimizing CNI nephrotoxicity, reducing the incidence of acute rejection, and favoring long-term graft survival. Potential also exists for beneficial effects on other factors that may influence the development of chronic rejection. These factors include comorbid diseases such as hypertension, which may affect transplant vasculopathy, and opportunistic infection with cytomegalovirus (CMV) and other viruses, which may increase the risk of chronic rejection. The synergistic effect of SDZ RAD and cyclosporine has been confirmed in preclinical models, with graft survival being significantly prolonged in rat models of kidney and heart allotransplantation. Clinical experience with SDZ RAD in cyclosporine-based immunosuppression, including low-dose cyclosporine regimens, has also resulted in predictable and favorable clinical outcomes. Low rates of acute rejection, excellent rates of patient and graft survival, lower incidence of CMV infections, better cholesterol, triglyceride and creatinine profiles, and better renal function have been demonstrated with SDZ RAD and lower doses of cyclosporine (Neoral; Novartis) in recipients of renal transplants. These findings, combined with good tolerability rates and an acceptable side-effect profile, indicate that the synergistic profile of SDZ RAD in combination with nontoxic dosages of CNI's and IL2 inhibitors will further improve longterm results in renal transplantation.
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PMID:Early clinical experience with a novel rapamycin derivative. 1180 23

Success in solid organ transplantation with minimal complications can now be achieved for most patients, and a remarkable rate of graft and patient survival can also be expected. However, the potential for adverse events and comorbid conditions increases with longer graft survival. Although the immunosuppressive regimen is central to the outcome of the transplant recipient and directly impacts the survival of the graft, chronic use of immunosuppressive agents is associated with metabolic disturbances such as hypertension, hyperlipidemia, loss of bone density, nephrotoxicity, and diabetes, which may contribute to other comorbid conditions. In addition, changes in appearance, gingival hyperplasia, hirsutism, alopecia, and weight gain disrupt quality of life and may lead to noncompliance with the immunosuppressive regimen. New immunosuppressive medications, including mycophenolate mofetil, sirolimus, basiliximab, and daclizumab, have allowed for experimentation with new regimens designed to reduce or allow discontinuation of corticosteroids and calcineurin inhibitors. This review highlights the impact and cost of immunosuppressive side effects and the potential for new immunosuppressive regimens to reduce this substantial clinical burden in transplantation.
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PMID:Reducing adverse effects of immunosuppressive agents in kidney transplant recipients. 1187 Dec 76

Ongoing improvements in immunosuppression and posttransplantation care have dramatically improved patient and graft outcomes after transplantation. The frequency of graft loss due to acute rejection has declined considerably as a result of the availability of a variety of more potent immunosuppressive agents and probably also because of refined clinical care and follow-up. Complications of long-term administration of corticosteroids (steroids) and calcineurin inhibitors, however, have become increasingly apparent as patients live longer with their transplant, and attention is shifting to long-term issues. Use of both steroids and calcineurin inhibitors is associated with metabolic toxicities such as hypertension, hyperlipidemia, diabetes, bone loss, and cataracts. These contribute to posttransplantation morbidity and may negatively affect patient and allograft survival. A variety of troublesome cosmetic side effects, such as hirsutism, gingival hyperplasia, alopecia, obesity, and cushingoid appearance, also are associated with these drugs. These effects can detract from patient self-esteem and compliance with the immunosuppressive regimen. In the past 2 decades, the introduction of second-generation immunosuppressive drugs, such as tacrolimus, mycophenolate mofetil, sirolimus, and anti-interleukin-2 receptor monoclonal antibodies, has provided some alternatives to classic immunosuppressant choices. Patients experiencing undesirable adverse events now can be converted to another immunosuppressive regimen that ultimately will improve graft and patient survival rates and improve quality of life after transplantation.
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PMID:Strategies to reduce toxicities and improve outcomes in renal transplant recipients. 1189 90

Sarco/endoplasmic reticulum Ca2+-ATPases (SERCAs) pump Ca2+ into the endoplasmic reticulum. Recently, three human SERCA3 (h3a-c) proteins and a previously unknown rat SERCA3 (r3b/c) mRNA have been described. Here, we (i) document two novel human SERCA3 splice variants h3d and h3e, (ii) provide data for the expression and mechanisms regulating the expression of all known SERCA3 variants (r3a, r3b/c, and h3a-e), and (iii) show functional characteristics of the SERCA3 isoforms. h3d and h3e are issued from the insertion of an additional penultimate exon 22 resulting in different carboxyl termini for these variants. Distinct distribution patterns of the SERCA3 gene products were observed in a series of cell lines of hematopoietic, epithelial, embryonic origin, and several cancerous types, as well as in panels of rat and human tissues. Hypertension and protein kinase C, calcineurin, or retinoic acid receptor signaling pathways were found to differently control rat and human splice variant expression, respectively. Stable overexpression of each variant was performed in human embryonic kidney 293 cells, and the SERCA3 isoforms were fully characterized. All SERCA3 isoforms were found to pump Ca2+ with similar affinities. However, they modulated the cytosolic Ca2+ concentration ([Ca2+]c) and the endoplasmic reticulum Ca2+ content ([Ca2+]er) in different manners. A newly generated polyclonal antibody and a pan-SERCA3 antibody proved the endogenous expression of the three novel SERCA3 proteins, h3d, h3e, and r3b/c. All these data suggest that the SERCA3 gene products have a more widespread role in cellular Ca2+ signaling than previously appreciated.
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PMID:Three novel sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) 3 isoforms. Expression, regulation, and function of the membranes of the SERCA3 family. 1195 12

With current immunosuppression, elevated blood pressure is found in almost 90% of renal graft recipients. Major causes of this are impairment of renal function, secondary to chronic allograft nephropathy or less frequently recurrence of primary renal disease, the use of calcineurin inhibitors as immunosuppressants, uncontrolled renin secretion by the shrunken kidneys of the recipient, stenosing lesions of the transplant artery (or the upstream arteries of the recipient), polycytemia and (genetic predisposition) to hypertension of the graft donor. Even minor degrees of blood pressure elevation have a significant impact on survival of the recipient and on graft survival, presumably by amplifying vascular injury to the graft. In this respect elevation of systolic blood pressure and an abnormal circadian blood pressure profile are of particular relevance. In contrast to previous opinion, ACE inhibitors are indicated in the treatment, but, given the causal role of sodium retention and graft vasoconstriction, diuretics and calcium channel blockers remain mainstays of antihypertensive treatment in the renal allograft recipient.
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PMID:Hypertension after renal transplantation. 1203 55

The endothelial isoform of nitric-oxide synthase (eNOS) is a key determinant of vascular tone. eNOS, a Ca(2+)/camodulin-dependent enzyme, is also regulated by a variety of agonist-activated protein kinases, but the role and regulation of the protein phosphatase pathways involved in eNOS dephosphorylation are much less well understood. Treatment of endothelial cells with vascular endothelial growth factor (VEGF), a potent eNOS agonist, leads to the activation of calcineurin, a Ca(2+)/camodulin-dependent protein phosphatase. In these studies, we used a phosphorylation state-specific antibody to show that VEGF promotes dephosphorylation of eNOS at serine residue 116 in cultured endothelial cells. Cyclosporin A, an inhibitor of calcineurin, completely blocks VEGF-induced eNOS dephosphorylation; under identical conditions, cyclosporin A also inhibits VEGF-induced eNOS activation. VEGF-induced eNOS dephosphorylation shows an EC(50) of 2 ng/ml and is maximal 30 min after agonist addition. eNOS phosphorylation at serine 116 is completely blocked by the protein kinase C inhibitor calphostin but is blocked by neither wortmannin (an inhibitor of phosphatidylinositide 3-kinase) nor the MAP kinase pathway inhibitor U0126. A phosphorylation-deficient mutant of eNOS in which serine 116 is changed to an alanine residue (S116A) shows significantly enhanced enzyme activity compared with the wild-type enzyme. Taken together, these findings indicated that VEGF-induced eNOS dephosphorylation at serine 116 leads to enzyme activation. Cyclosporin A is widely used as an immunosuppressive drug for which hypertension is an important dose-limiting side effect. Our results suggest that cyclosporin A-induced hypertension may involve, at least in part, the attenuation of endothelium-derived NO production through a calcineurin-sensitive pathway regulating eNOS dephosphorylation.
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PMID:Dephosphorylation of endothelial nitric-oxide synthase by vascular endothelial growth factor. Implications for the vascular responses to cyclosporin A. 1205 Jan 71

The introduction of new immunosuppressive agents and protocols has improved outcomes for renal transplant recipients by decreasing the risk of rejection and by increasing the function and lifespan of the allograft. This article reviews the major changes in the combinations of therapies used: calcineurin inhibitors, target of rapamycin inhibitors, mycophenolate mofetil, non-depleting monoclonal versus depleting monoclonal and polyclonal antibodies for induction and increasing emphasis on protocols for reduction or avoidance of steroids and calcineurin inhibitors. The new agents with novel immunological targets such as anti-CD40 ligand, LEA29Y, FTY720, anti-CD20 (rituximab, Rituxan, Mabthera) and anti-CH52 (alemtuzumab, Campath), which are under development but have yet to survive the rigors of clinical trials are also discussed. In the presence of low early rejection rates, immunosuppressive therapy is setting new goals such as better graft function (glomerular filtration rates), reduction in adverse effects such as hypertension, hyperlipidaemia and drug toxicity and, above all, the prevention of late graft deterioration.
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PMID:New developments in immunosuppressive therapy in renal transplantation. 1207 85


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