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Biomedical subjects

C Guijarro

Publications and source records attributed to C Guijarro.

At least 55 records · Page 3Linked to original sources
PubMed1995

Early glomerular changes in rats with dietary-induced hypercholesterolemia.

Increasing evidence suggests that lipids may be important modulators of progressive glomerular injury. We previously reported the long-term glomerular changes in rats with dietary-induced hypercholesterolemia. In this work, we evaluated the early glomerular changes induced by hypercholesterolemia that precede the development of glomerulosclerosis. In cholesterol-fed rats, an early macrophage influx was observed. This was associated with an increase in glomerular size, mesangial matrix expansion, lipid deposits, and foam cell formation. Immunohistochemical techniques showed that type IV collagen, fibronectin, and laminin were increased in cholesterol-fed rats. The mRNA expression for the alpha 1 chain of type IV collagen and an inhibitor of type IV collagenase were increased, suggesting that both increased synthesis and reduced degradation may be involved in cholesterol-induced mesangial matrix accumulation. The glomerular mRNA expression of transforming growth factor-beta 1 was also upregulated, suggesting that transforming growth factor-beta 1 could be an important mediator for mesangial matrix accumulation in hypercholesterolemic states. The early cholesterol-induced changes in the glomerulus are reminiscent in many respects to the process leading to glomerulosclerosis in the vessel wall.

Animals↗
PubMed1995

Human mesangial cell production of monocyte chemoattractant protein-1: modulation by lovastatin.

Macrophages play a critical role in the progression of clinical and experimental glomerular injury. Serum-stimulated human fetal mesangial cells in culture produce a chemotactic factor that is monocyte-selective. This chemotactic factor is most likely monocyte chemoattractant protein-1 (MCP-1) as a monoclonal antibody directed against MCP-1, but not an irrelevant antibody, suppressed the mesangial cell-derived chemotactic activity. Inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase by lovastatin resulted in a reduction of the mesangial cell-derived chemotactic activity as well as MCP-1 mRNA expression. The inhibitory effects of lovastatin in the presence of exogenous cholesterol were reversed by mevalonate, suggesting a role for isoprenoid intermediates of the mevalonate pathway and/or isoprenylated proteins in mesangial cell MCP-1 regulation. These findings suggest an additional mechanism by which HMG-CoA reductase inhibition in vivo may reduce glomerular injury.

Cells, Cultured↗
PubMed1995

Chronic renal allograft rejection and clinical trial design.

Both the choice of endpoints and the selection of patients will be critical study design features in randomized controlled trials needed to test the effectiveness of treatments for chronic renal allograft rejection. We examined the feasibility of carrying out clinical trials with different endpoints and patient inclusion criteria by analyzing data from a population of 627 cadaveric kidney transplant recipients who survived with a functioning allograft for at least six months. Among those who lost grafts to chronic rejection, decreases in renal function of 30% and 60% preceded graft loss by a median of only 1.1 and 0.7 years, respectively, suggesting that little would be gained in a clinical trial that used a predetermined reduction in renal function as a surrogate endpoint. Less clear is whether histologic changes could be used as a surrogate endpoint. At present, graft loss to chronic rejection and graft failure from any cause are the most reliable endpoints. Unfortunately, large numbers of patients are needed to demonstrate clinically relevant therapeutic effects on these endpoints. Limiting enrollment to patients who are at high risk for developing chronic rejection, by selecting patients who already have a decline in renal function, for example, may reduce the number of patients needed in a clinical trial. On the other hand, selecting patients with disease that is too advanced may diminish the effectiveness of therapy. In any case, it is impossible to accurately determine the number of patients needed for a definitive clinical trial without preliminary data demonstrating the expected magnitude of the treatment effect. Thus, well-designed pilot studies are needed to measure possible treatment effects before conducting large-scale clinical trials for chronic renal allograft rejection.

Clinical Trials as Topic↗
PubMed1995

Isoprenoids and Ras: potential role in chronic rejection.

Protein prenylation, the post-translational attachment of isoprenoids to certain cellular proteins, increases protein hydrophobicity and promotes protein-membrane interactions. Of the many cellular proteins that undergo protein prenylation, particular attention has been paid to the protooncogene product Ras. Prenylated Ras protein localizes to the inner cell membrane and appears to function as a "molecular switch" through which peptide growth factors such as PDGF, IGF-1, and FGF, and cytokines such as IL-2, IL-6, and GM-CSF stimulate intracellular events. Binding of these substances to their respective receptors on target cells can activate Ras, triggering intracellular signaling cascades which culminate in processes such as cell proliferation, differentiation, and T-cell activation. Protein prenylation inhibitors block Ras prenylation, prevent membrane localization of Ras, and inhibit growth and proliferation of a variety of cell types. Recent studies in our laboratory have begun to examine the possible role of Ras in chronic allograft rejection. Abdominal aorta segments from donor Lewis rats were transplanted into Buffalo recipient rats. Recipients treated with the HMG-CoA reductase inhibitor lovastatin, which inhibits isoprenoid production, showed significantly decreased allograft intimal area after 12 weeks, when compared with untreated recipients. In a separate study, recipients treated with the agent leflunomide, which inhibits growth factor receptor tyrosine kinases that can activate Ras, had significantly decreased allograft intimal area after 12 weeks. These results suggest that Ras may be important in chronic allograft rejection, and that agents that interfere with Ras protein prenylation or activation by growth factor receptors may ameliorate chronic rejection.

Animals↗
PubMed1995

Clinical correlation between renal allograft failure and hyperlipidemia.

Chronic rejection is the leading cause of late allograft failure, but its pathogenesis is poorly understood. The prominence of the vascular lesions and certain similarities with the pathological features of atherosclerosis suggest that lipids may be involved in the pathogenesis of chronic rejection. Studies have reported an association between different lipid abnormalities and several indicators of chronic renal allograft damage. However, other potential risk factors for the development of chronic rejection were present in most cases, and an independent association between lipids and chronic rejection has not been convincingly demonstrated. In our series of 706 consecutive renal transplants with long-term follow-up, increased post-transplant serum triglycerides, but not total cholesterol, were strong predictors of graft loss to chronic rejection. This effect was independent of other risk factors for chronic rejection such as age, acute rejections, proteinuria and hypoalbuminemia. These results add to existing evidence suggesting that lipid abnormalities may be involved in the pathogenesis of chronic renal allograft rejection.

Animals↗
PubMed1995

Clinical predictors of chronic renal allograft rejection.

Among both immune and nonimmune factors implicated in the pathogenesis of chronic renal allograft rejection, acute rejection episodes represent a strong and consistent predictor. However, all acute rejection episodes are not equally predictive of chronic renal allograft rejection. Early and mild acute rejection episodes do not usually cause chronic renal allograft rejection. On the other hand, late and severe acute rejection episodes occurring more than one year after transplantation are particularly strong predictors of chronic renal allograft rejection. The number of HLA mismatches is a risk factor, but its influence may not be independent of acute rejection and other risk factors. Proteinuria and recently hypoalbuminemia are also independent risk factors for chronic renal allograft rejection. However, whether these nonimmune factors are merely the result of chronic renal allograft rejection, or whether they contribute to the pathogenesis of renal injury in chronic renal allograft rejection is yet unclear. Better HLA matching, new strategies to decrease the severity of acute rejection, and measures to prevent late acute rejection, as well as prospective evaluation of the therapies to reduce proteinuria and other nonimmune risk factors for chronic renal allograft rejection are needed.

Graft Rejection↗
PubMed1994

[Effect of pravastatin on hypercholesterolemia associated with proteinuria].

BASIS: Hyperlipidemia associated to nephrotic syndrome has been involved in the deterioration of the renal function in these patients. The reduction in the synthesis of cholesterol with pravastatin, an hydrophilic inhibitor of such synthesis, may improve both the dyslipemia, the renal function and the proteinuria. METHODS: We conducted a controlled open randomized study in 16 patients with proteinuria greater than 2 g/day, creatinine clearance greater than 0.5 ml/s (30 ml/min) and hypercholesterolemia with LDL cholesterol greater than 4.9 mmol/l (190 mg/dl) distributed in two groups. One of these groups received hypolipemiant dietetic treatment and 20-40 mg of pravastatin and the other group, only the dietetic treatment. RESULTS: The patients receiving pravastatin showed a 27% decrease in total plasmatic cholesterol, compared to a 6.7% in the control group (p < 0.01). This decrease was more evident in the LDL cholesterol fraction (44 vs 9%; p < 0.01). No significant modifications were observed in the HDL cholesterol fraction, triglycerides, renal function or proteinuria. Neither clinical nor enzymatiz adverse effects from hepatic or muscular origin were observed.

Female↗
PubMed1993

Neoplasms of unknown primary site: a clinicopathological study of autopsied patients.

BACKGROUND: Malignant neoplasms of an unknown primary site (NUPS) remain a diagnostic and therapeutic challenge in clinical practice. With this in mind, we have reviewed all autopsies performed in patients with NUPS in a single institution. PATIENTS AND METHODS: By reviewing 1656 autopsies performed on adults in our institution (1974-1990), 43 cases of NUPS were found. (NUPS was defined as histologically proven malignant tumor for which a primary site could not be found after anamnesis, complete physical examination, chest X-ray and routine chemistries.) RESULTS: There were 24 men (56%) and 19 women. Mean age was 62 years (76% of patients were aged 40-75). Clinical presentation included general deterioration (73%), digestive symptoms (58%), liver enlargement (58%) abdominal pain (56%), respiratory symptoms (45%), ascites (26%) and node enlargement (16%). Abnormalities in analysis and image tests were frequent but nonspecific. Median time from admission to death was 42 days (range, 4-135). Pathologic diagnoses at autopsy were: 23 adenocarcinomas (53%), arising from pancreas (6), biliary tree (6), lung (3), prostate (2), stomach (1), kidney (1) and unknown (4); 3 squamous carcinomas (5%) (1 renal pelvis, 1 biliary tree, 1 stomach); 5 undifferentiated carcinomas (1 lung, 4 unknown); and 12 miscellaneous tumors (including 3 lymphomas, 3 neuroendocrine tumors, 3 hepatocarcinomas, 2 mesotheliomas and 1 melanoma). There was a tendency towards a metastatic pattern different from that expected from the primary tumor. Image tests were of little usefulness in the search for the primary tumor. CONCLUSIONS: 1) Adenocarcinomas were the most frequent tumor presenting as NUPS, especially from the pancreas and biliary tree. 2) In this series, at least 11% of patients were amenable to standard systemic therapies (3 lymphomas and 2 prostatic adenocarcinomas) if a correct pathologic diagnosis could have been established when alive. 3) Presenting symptoms and metastatic pattern differed from those expected for the primary neoplasm eventually found. 4) Image tests were often misleading as regards the primary site, although they were useful to quantify the dissemination of the tumor.

Adult↗
PubMed1993

Sulfonylureas activate glycogen phosphorylase and increase cytosolic free-Ca2+ levels in isolated rat hepatocytes.

Without causing significant changes in cellular levels of cyclic adenosine monophosphate (cAMP), the addition of either glibenclamide or gliquidone to isolated rat hepatocytes caused a transient dose- and Ca(2+)-dependent activation of glycogen phosphorylase. The calculated concentrations corresponding to half-maximal activation were 5 and 2 mumol/L, respectively. In connection with this, it was observed that glibenclamide provoked a dose-dependent increase in cytosolic free-calcium concentration ([Ca2+]i) in Fura-2-loaded hepatocytes. Moreover, the presence of glibenclamide in the incubation medium accelerated the rate of Ca2+ uptake by Ca(2+)-depleted hepatocytes. These findings suggest that an increase in [Ca2+]i could mediate some of the effects of sulfonylureas in liver metabolism.

Animals↗
PubMed1993

Lipid abnormalities and changes in plasma proteins in glomerular diseases and chronic renal failure.

Lipid abnormalities are almost a constant feature of kidney disease. However, the contribution of deranged lipid metabolism to the increased incidence of cardiovascular disease among renal patients has not been definitely established. Conversely, the role of lipid abnormalities in the progression of renal disease has gained considerable experimental support. Both dietary and pharmacologic interventions, which reduce circulating lipid levels, have been proven to decrease the incidence of glomerulosclerosis in various animal models. Whether similar results can be achieved in renal patients is, at present, unknown. If the new lipid-lowering drugs prove useful in preventing the progression of both glomerulosclerosis and atherosclerosis, a major advance in the therapy for renal patients will be achieved.

Animals↗
PubMed1990

Modulation of glucose metabolism by sulfonylureas in primary cultures of adult rat hepatocytes.

Addition of tolbutamide (0.1-5 microM) or glipizide (0.05-5 microM) to primary cultures of adult rat hepatocytes caused a dose-dependent increase of fructose 2,6-bisphosphate concentration. This effect was accompanied by a stimulation of the rate of L-lactate production and by an acceleration of the metabolic flux through the reaction catalysed by 6-phosphofructo 1-kinase. Moreover, the continuous presence of tolbutamide during the first 26 hours of culture mimicked long-term insulin effects by raising fructose 2,6-bisphosphate levels and the rate of L-lactate formation. Glucokinase, 6-phosphofructo 1-kinase and total 6-phosphofructo 2-kinase activities were not found to be significantly different in hepatocytes cultured either in the presence or in the absence of sulfonylurea.

Animals↗