Control of metabolic acidosis after pancreas transplantation using acetazolamide.
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Biomedical subjects
Publications and source records attributed to R J Tesi.
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Successful heterotopic and denervated pancreas allograft transplantation (PAT) often results in normoglycemia and peripheral hyperinsulinemia in insulin-dependent (type I) diabetic recipients. The contribution of altered hepatic insulin extraction (HIE) to the resulting hyperinsulinemia in such patients remains uncertain. Furthermore, whether the denervated pancreas allografts exhibit beta-cell hyperresponsiveness to physiological and pharmacological stimulation is controversial. We evaluated beta-cell function and HIE after successful whole cadaveric PAT with systemic venous drainage in 13 type I diabetic patients before and after mixed-meal and intravenous glucose and glucagon administration. The results were compared with those of 5 nondiabetic patients with kidney transplantation only, who had native innervated pancreases with portal insulin delivery and were receiving an equivalent triple immunosuppressive therapy (cyclosporin, azathioprine, and prednisone), and 7 healthy control subjects with no family history of diabetes. After PAT, fasting and poststimulation serum glucose concentrations were normalized. PAT was associated with marked basal hyperinsulinemia (3- to 8-fold) as assessed by immunoreactive insulin (IRI) levels in type I diabetic patients (mean +/- SE 345 +/- 43 pM) compared with control subjects (43 +/- 14 pM) and nondiabetic kidney-transplantation patients (129 +/- 38 pM). After mixed-meal ingestion, the mean incremental integrated insulin area was similar in PAT patients (18 +/- 3 nM.min) compared with kidney-transplantation patients (20 +/- 4 nM.min) and healthy control subjects (21 +/- 3 nM.min). Basal serum C-peptide levels were significantly greater in PAT (1.72 +/- 0.13 nM) and kidney-transplantation (2.15 +/- 0.33 nM) patients than in healthy control subjects (0.50 +/- 0.10 nM; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
At our center, KPT is the treatment of choice for diabetics with ESRD who are not irreversibly disabled by their secondary complications of diabetes. Mortality, as a result of cardiovascular complications, has a significant impact on the outcome of patients in both the KPT and KTA groups. Metabolic complications are problematic in the early posttransplant period. Infectious complications are frequent but not life threatening in the combined recipients. Excellent graft outcome (pancreas and kidney) can be achieved in those patients selected to undergo the KPT procedure.
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Verapamil has been shown to potentiate cyclosporine's effect in inhibiting lectin-stimulated proliferation of murine and human lymphocytes, and in prolonging graft survival in experimental heterotopic cardiac transplantation in rats. A series of experiments were designed to determine whether verapamil's effect occurred by increasing cyclosporine uptake or decreasing cyclosporine's clearance by lymphocytes utilizing human peripheral blood lymphocytes and radiolabeled cyclosporine. Verapamil had no effect. The distribution of radiolabeled cyclosporine was also studied in mice that had been given verapamil (10 mg/kg) 1 hr prior to cyclosporine injection. No significant changes in organ distribution occurred. Lectin-stimulated release of intracellular ionized calcium was studied using a flurometric technique (Quin-2 and Fura-2). Neither cyclosporine nor verapamil had any effect on either lectin-stimulated or phorbol ester-stimulated release of intracellular ionized calcium. Phorbol ester and subproliferative doses of lectin were used to determine the effect of cyclosporine and verapamil on protein kinase C-mediated lymphocyte activation. Cyclosporine inhibited phorbol ester stimulated proliferation and verapamil potentiated this inhibition. Verapamil does not change cell or organ uptake of cyclosporine, and it does not affect the initial increase in intracellular ionized calcium that occurs with lymphocyte activation. Verapamil potentiates cyclosporine in inhibiting protein kinase C-mediated events in lymphocyte activation.
We have shown that the addition of verapamil, a calcium channel blocking agent, or trifluoperazine, a phenothiazine, to a regiment using the immunosuppressive agent Cs significantly enhances heterotopic cardiac allograft survival in an ACI to Lewis transplant model. This work verifies previous in vitro work from our laboratory and offers a potential therapeutic strategy to decrease the dose of Cs needed for effective immunosuppression while perhaps lessening its dose-related side effects.
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The mammalian testes have several mechanisms to propel the nonmotile spermatozoa in the seminiferous tubules through the rete testis into the epididymis. These include (a) contractions of the testicular capsule and the seminiferous tubules and (b) fluid flow through the excurrent ducts resulting from active transport of fluids and electrolyte into the seminiferous tubules from the extracellular space. The efflux of fluids and sperm from the testis appears to closely parallel spermiation. An increased output of fluid may result from prostaglandins (PGF2 alpha) and possibly oxytocin (not all species respond to oxytocin) as a result of capsular contractions compressing and expelling the fluid from the tubules. Seminiferous tubular contractions do not result from nervous stimulation but are linked to PGs and cyclic nucleotide generation. They are regulated to some extent by androgens and the lesser response of the tubules to 5 alpha-dihydrotestosterone compared to testosterone can be explained by their interaction with androgen binding protein and their action on phospholipase A2 activity for PG synthesis.
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