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Biomedical subjects

D J Tiller

Publications and source records attributed to D J Tiller.

At least 37 records · Page 2Linked to original sources
PubMed1990

Essential hypertension--investigations and management.

When one is faced with the problem of essential hypertension it is prudent to pay attention to lifestyle factors, especially alcohol, smoking and obesity. Modification of salt intake in the diet is a simple measure. Drug therapy will need to be long-term therapy and ease of treatment is important, which means that drugs given once a day or at most twice a day should be used. Diuretics and beta-blockers are inexpensive and well proven but have many side-effects. Newer agents may have fewer side-effects but are more expensive. The choice will be an individual one.

Clinical Protocols↗
PubMed1990

Body protein of patients undergoing haemodialysis.

The total body protein status of 18 patients undergoing regular haemodialysis was assessed by measuring total body nitrogen (TBN) using in vivo neutron activation analysis (NAA). Eighteen healthy controls, who were selected according to their height, age and sex match with the patients were also measured. The male and female patients were both found to have lower mean values for total body protein (P less than 0.01, P less than 0.025 respectively) although they had similar weights compared with their matched controls. Seven patients were measured on further occasions and only two patients showed a change in their body protein. One female showed an increase of 11 per cent in body protein (with an increase of 25 per cent in body weight) after intensive nutritional repletion therapy. In vivo NAA provides a direct means of measuring body protein and is a reliable method to monitor changes with treatment regimes.

Adult↗
PubMed1989

Comparison of doxazosin and atenolol in mild hypertension, and effects on exercise capacity, hemodynamics and left ventricular function.

The effects of once-daily therapy with doxazosin (1 to 8 mg/day) on exercise capacity, left ventricular performance and hemodynamics (radionuclide ventriculography) were compared with those of atenolol (50 to 100 mg/day) and placebo in a randomized, double-blind crossover trial in 16 patients (9 men) with mild hypertension. Both medications controlled blood pressure (BP) to a similar degree (mean BP was 150 +/- 12, 137 +/- 17 and 141 +/- 14 mm Hg for placebo, atenolol and doxazosin, respectively) but by different mechanisms. Changes during maximal semierect bicycle exercise were similar to those seen at rest. Doxazosin decreased total peripheral resistance and maintained cardiac output, whereas atenolol decreased cardiac output. Exercise capacity (136 +/- 56 watts with placebo) was maintained by doxazosin (135 +/- 56 watts) but decreased with atenolol (122 +/- 55 watts). Compared with atenolol, doxazosin slightly increased the left ventricular ejection fraction at rest and during exercise. The significance of this study is in the choice of a first-line antihypertensive agent. Both are once-a-day medications that control BP. However, doxazosin does so by improving the abnormal physiology of essential hypertension and, consequently, does not adversely affect exercise performance.

Antihypertensive Agents↗
PubMed1989

Cyclosporin A inhibits protein kinase C activity: a contributing mechanism in the development of nephrotoxicity?

Cyclosporin A modifies many intracellular functions in a variety of different cells. This study investigated the potential interaction between cyclosporin A and protein kinase C, as a possible mechanism for the development of nephrotoxicity. The activity of protein kinase C, in the cytosol of renal epithelial cells, was shown to be significantly inhibited in a dose-dependent manner by CSA. Activation of protein kinase C by 12-O-tetradecanoylphorbol-13-acetate (phorbol ester) in rat mesangial cells in culture leads to an increase in PGE2 release. Phorbol ester stimulated PGE2 release was significantly inhibited by cyclosporin A. These results would suggest that intracellular site of action of cyclosporin A, in producing alterations in intracellular function and toxicity, may be at the level of protein kinase C.

Animals↗
PubMed1989

Vitamin supplementation of patients receiving haemodialysis.

In order to assess the necessity of vitamin supplementation for patients who are receiving haemodialysis, measurements of vitamin status were made, and both dietary and supplementary intakes were assessed, in 26 patients who were undergoing haemodialysis. Blood samples were collected from these patients before they underwent haemodialysis, after an overnight fast, for the measurement of plasma retinol, alpha-tocopherol and ascorbate levels. Serum and erythrocyte folate levels were measured also. Thiamin status was assessed by the effect of added thiamin pyrophosphate on erythrocyte transketolase activity and pyridoxine status was assessed by the effect of added pyridoxal-5'-phosphate on erythrocyte aminotransferase activity. All patients had elevated plasma retinol levels; 48% of patients had elevated plasma alpha-tocopherol levels; the plasma ascorbate level was low in 50% of patients but was elevated in 25% of patients; and plasma and erythrocyte folate levels were elevated in 76% and 91% of patients, respectively. Thiamin status was normal in all but one patient and the pyridoxine level appeared to be low in two other patients. Many patients had low dietary intakes of vitamin C, folate and vitamin B6. We conclude that supplements of vitamins A and E are not required and, when dietary intakes of water-soluble vitamins are marginal, these should be supplemented at a dose as near as possible to the recommended dietary intake.

Ascorbic Acid↗
PubMed1989

Structure-activity relationships of cyclosporines. Toxicity in cultured renal tubular epithelial cells.

Proximal (LLC-PK1) and distal (MDCK) renal epithelial cell cultures were used to investigate early biochemical changes in cellular metabolism following exposure to cyclosporine A (CsA). 3H-thymidine and 3H-leucine incorporation into the cells were used as indices of DNA and protein synthesis. The cells were exposed to concentrations of CsA ranging from 0.2 microgram/ml to 20 micrograms/ml. By 20 hr there was a decrease in the total cell count at concentrations of 10 and 20 micrograms/ml that was more pronounced by 5 days of exposure. At 5 days there was also a reduction in cell count at the lower concentrations of CsA. There was an initial increase in DNA and protein synthesis at 2 hr with inhibition of DNA synthesis evident by 20 hr. Protein synthesis was increased in the LLC-PK1 cells and decreased in the MDCK cells. At 5 days there was evidence of increased DNA and protein synthesis, most marked in the remaining viable cells exposed to the higher concentrations of CsA. Similar alterations in cellular metabolism were evident when the cells were exposed to the immunologically inert cyclosporine H (D-N-MeVal11-Cs). These studies demonstrate that cyclosporine produces alterations in cellular function as early as 2 hr after exposure to the drug. At the lower concentrations there is evidence of sublethal cellular toxicity and cellular regeneration. The toxicity appears to be related to the molecular structure of cyclosporine and its incorporation into cell membranes. We postulate that cyclosporine nephrotoxicity is the summation of several subtoxic alterations in cellular function the final expression of which is modified by other factors affecting renal function.

Animals↗
PubMed1989

Malignant lymphoma in a renal transplant patient on cyclosporin A therapy.

Cyclosporin A has been associated with an apparent increased incidence of non Hodgkins lymphoma, most often in conjunction with multiple immunosuppressive agents. We report a patient who developed a non Hodgkins lymphoma arising in the right tonsillar fossa six months following renal transplantation. The development of the lymphoma was associated with seroconversion for the Epstein Barr capsid antigen and nuclear antigen. The patient was receiving cyclosporin A alone as immunosuppression.

Adult↗
PubMed1989

Dietary eicosapentaenoic acid does not modify cyclosporin-induced inhibition of angiotensin II-stimulated prostaglandin synthesis in mesangial cells.

Clinical and experimental cyclosporin A (CSA) nephrotoxicity is characterized by alterations in renal hemodynamics and a reduction in glomerular filtration rate (GFR). The mesangial cell may be a target for the actions of CSA. CSA has been shown to activate the renin angiotensin system and to increase the excretion of TXB2 (the stable metabolite of TXA2). This study investigated the role of CSA and mesangial cell prostaglandin release in mediating some of the alterations in renal hemodynamics. Primary rat mesangial cell cultures (first passage) were exposed to CSA followed by stimulation with angiotensin II (AII) 10(-7) M. PGE2 and TXB2 release was measured after 5 and 15 minutes incubation. Experimental CSA nephrotoxicity in rats has been shown to be reduced by the use of MaxEPA fish oil (containing eicosapentaenoic acid) as the vehicle for CSA. Therefore, the experiments were repeated using mesangial cells obtained from rats fed an enriched eicosapentaenoic acid (MaxEPA) diet for 3 weeks. CSA significantly inhibited AII stimulated PGE2 release in both experiments. There was no increase in TXB2 release. Alterations in membrane fatty acid composition, available for prostaglandin synthesis, did not alter the results. This study demonstrated that CSA significantly inhibits AII-stimulated prostaglandin release. The increased excretion of TXB2, seen with CSA treatment, does not arise from the mesangial cells, and the protective effect of MaxEPA, as a vehicle for CSA, is not due to its effects on mesangial cell prostaglandin release.

Angiotensin II↗
PubMed1988

Comparison of three immunosuppressive regimens in cadaver renal transplantation: long-term cyclosporine, short-term cyclosporine followed by azathioprine and prednisolone, and azathioprine and prednisolone without cyclosporine.

We conducted a randomized trial in seven Australian hospitals of the efficacy and safety of three immunosuppressive regimens after first transplantation of a cadaver kidney: long-term cyclosporine, short-term (three months) cyclosporine followed by azathioprine and prednisolone, and azathioprine and prednisolone without cyclosporine. Patients assigned to long-term cyclosporine (n = 138) or short-term cyclosporine followed by azathioprine and prednisolone (n = 141) had similar actuarial 12-month survival (98.4 vs. 96.4 percent) and graft survival (83.9 vs. 82.1 percent). Patients assigned to receive only azathioprine and prednisolone (n = 138), with optional use of antithymocyte globulin, had a significantly poorer survival rate (91.3 percent, P = 0.015) because of deaths from cardiac causes and infection, but their graft survival of 76.0 percent (P = 0.31) did not differ significantly from that of either group receiving cyclosporine. After the switch from cyclosporine to azathioprine and prednisolone, 15 percent of patients had reversible rejection episodes, but the frequency of rejection and graft loss did not differ from that in the long-term cyclosporine group. After the change to azathioprine and prednisolone, serum creatinine levels declined in nearly all patients, so that after three months they were comparable to those in the group receiving azathioprine and prednisolone only, and significantly lower than those in the group receiving long-term cyclosporine therapy (P less than 0.003). We conclude that the two cyclosporine regimens result in comparable patient and graft survival, but that changing to azathioprine and prednisolone at three months improves graft function.

Adult↗
PubMed1988

Synergistic toxicity of cyclosporin A and streptomycin in renal epithelial cell cultures.

Cyclosporin A (CSA) nephrotoxicity was examined in two renal epithelial cell cultures, the LLC-PK1 cell line and the MDCK cell line. Acute changes in cell growth and cellular DNA and protein synthesis were investigated at 2 hours, 20 hours and 5 days. The potential synergistic interaction between streptomycin (a standard additive to most culture media) and CSA was examined. CSA produced significant alterations in cell function as early as 2 hours after exposure and this became more noticeable with increased exposure to CSA. Streptomycin potentiated the toxicity effects on cellular metabolism that was seen with CSA. The use of cell culture models to investigate CSA toxicity must avoid the use of potential agents which may have a synergistic effect on the development of toxicity.

Animals↗
PubMed1987

Effect of angiotensin II on baroreceptor reflex control of heart rate in conscious baboons.

Studies of the baroreceptor-heart rate reflex were performed in four conscious, unrestrained male baboons to determine whether changes in circulating angiotensin II within the physiological range are associated with alterations in baroreceptor reflex sensitivity. With the animals on a high sodium intake, studies were performed before and during graded angiotensin II infusion (10 and 20 ng/kg/min). To separate effects on baroreceptor reflex function mediated by angiotensin II-induced increases in arterial pressure, these studies were repeated on a different day with simultaneous glyceryl trinitrate infusion to prevent increases in pressure during angiotensin II infusion. With the animals on a low sodium intake, studies were performed before and after angiotensin converting enzyme inhibition with captopril (1 and 5 mg/kg). These studies were also repeated on a separate day during simultaneous phenylephrine infusion to prevent a decrease in pressure with captopril. Reduction in sodium intake had no significant effect on arterial pressure, heart rate, or plasma volume, although arterial plasma angiotensin II concentration and renin activity were significantly increased (p less than 0.01). Infusion of angiotensin II produced a significant reduction in baroreceptor reflex sensitivity (p less than 0.01), and converting enzyme inhibition produced a significant increase (p less than 0.05). These effects accompanied significant increases and decreases in arterial angiotensin II concentration, respectively (p less than 0.01), but were independent of angiotensin II-related changes in arterial pressure. The data indicate that physiological variations in circulating angiotensin II have a direct effect on sensitivity of the baroreceptor-heart rate reflex.

Angiotensin II↗
PubMed1987

Group housing of hamadryas baboons: a new cage design based upon field studies of social organization.

The hamadryas subspecies, which is utilized extensively for laboratory research, has a social structure unique among baboons. Field studies have shown that small one male units are the basic grouping in a complex multi-level social system. A housing design for a research colony of hamadryas baboons was conceived to reflect this unique social organization and related behavioral patterns. The outcome of combining such ethological considerations with practical dictates for housing large laboratory primates has been assessed in terms of reproductive performance, animal health and utilization for research. Various benefits of this approach to cage design for hamadryas baboons are identified in this report.

Animals↗
PubMed1986

Diagnosis of renal allograft rejection by analysis of fine-needle aspiration biopsy specimens with immunostains and simple cytology.

Fine-needle aspiration biopsy specimens of renal transplants were analysed by means of commercially available monoclonal antibodies and an immunoperoxidase stain. Three cellular features associated with acute cellular rejection were identified--heavy infiltrates of activated T cells or large mononuclear cells strongly expressing HLA-DR antigens, and HLA-DR expression by renal tubular cells. A combination of semiquantitative scores for these features correctly identified rejection in 32 of 34 cases, with no false positives in cases of cyclosporin nephrotoxicity or stable graft function.

Antibodies, Monoclonal↗
PubMed1986

Immunopathology of renal allograft rejection analyzed with monoclonal antibodies to mononuclear cell markers.

The composition of the mononuclear cell infiltrate in rejecting renal allografts was determined on 96 renal biopsies and 22 nephrectomy specimens by the use of monoclonal antibodies to mononuclear cell surface markers and an indirect immunoperoxidase staining technique. During rejection the composition of the infiltrate was heterogeneous, with T cells (T11), monocytes (OKM1) and HLA-DR expressing mononuclear cells the most frequent sub-populations. B cells (B1) and activated T cells, identified by OKT10, were always in the minority. The T cells infiltrate usually included the helper/inducer (T4) and cytotoxic (T8) subclasses, which suggests that both may contribute to the mediation of rejection. Whether T4 or T8 predominated in the graft did not relate to the ratio of T4:T8 in blood, the HLA A, B or DR incompatibilities of the graft, or the immunosuppressive used. The frequency of T11, T4, T8, HLA-DR positive cells and monocytes, but not B cells, increased with the severity of rejection and was similar in biopsies from patients immunosuppressed with Cyclosporine (CSA) to those given a combination of azathioprine, prednisone and antilymphocyte globulin (AZA). Severe rejection episodes which did not respond to treatment with corticosteroids were more often characterized by a predominance of T8 over T4 cells and T cells infiltrating the glomeruli. In grafts with evidence of cellular rejection, renal tubular cells were shown to have a marked increase in their expression of HLA-DR antigens compared to normal kidneys or grafts with minimal rejection. The expression of HLA-DR antigens on graft tubular cells correlated with the presence of T cells in the interstitium and the severity of rejection, except for moderate rejection in CSA treated biopsies, in which HLA-DR expression was lower than in AZA biopsies. These immunopathological studies have demonstrated that a variety of potential effector cells exist within the graft, and several features have been identified which may assist in assessing the prognosis of the rejection episode.

Antibodies, Monoclonal↗