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Biomedical subjects

G G Duggin

Publications and source records attributed to G G Duggin.

At least 55 records · Page 3Linked to original sources
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↗
PubMed1986

Sex-dependent activities of quinone reductases in rabbits indicate higher risk of bladder cancer in the male.

The distribution of NADPH-dependent quinone reductase and NADPH-cytochrome P-450 reductase activities was determined in the urinary bladders of male and female rabbits. In urinary bladder transitional epithelium (UBTE) and in urinary bladder non-transitional tissue (UBNT) microsomal quinone reductases demonstrated significant (P less than 0.05) sex-dependent differences in the case of both dicoumarol-insensitive (male greater than female) and dicoumarol-sensitive or DT-diaphorase (female greater than male) activities. Microsomal NADPH-cytochrome P-450 reductase activities in UBTE and in UBNT were found to be similar in male and female rabbits. The activities of microsomal and cytosolic quinone reductases and the activity of microsomal NADPH-cytochrome P-450 reductase in UBNT were much lower than those in UBTE. NADPH-cytochrome P-450 reductase and similar flavo-enzymes activate quinones via one-electron reduction into semiquinone free radicals, which then react with molecular oxygen, forming superoxide anions. DT-diaphorase acts as a detoxifying enzyme by converting many quinones via a unique two-electron reduction into less reactive hydroquinones, enabling their excretion as water-soluble conjugates. Since UBTE contains substantial activities of prostaglandin H synthase (PHS) and NADPH-cytochrome P-450 reductase, unlike UBNT, the toxicity and carcinogenicity of xenobiotics which are either quinones or form quinones in situ through the mediation of PHS would be high in UBTE. The risk of carcinogenicity of quinones in UBTE would be higher in male rabbits than in female rabbits due to sex-dependent differences in the relative proportions of the one-electron reduction pathway, represented by NADPH-cytochrome P-450 reductase, and the two-electron reduction pathway, represented by DT-diaphorase (female greater than male).

Animals↗
PubMed1986

Circulatory adaptation to pregnancy--serial studies of haemodynamics, blood volume, renin and aldosterone in the baboon (Papio hamadryas).

To test the hypothesis that haemodynamic changes in pregnancy precede any significant increase in circulating blood volume, serial haemodynamic studies were performed in eight baboon pregnancies using Swan-Ganz catheterization and arterial cannulation. Simultaneous measurements were made of red cell and plasma volumes, and of plasma renin activity and aldosterone concentration. Haemodynamic changes identified by 4 weeks gestation included significant (P less than 0.01) reductions in right atrial pressure, systemic and pulmonary arterial pressures, and systemic and pulmonary vascular resistance. Stroke volume increased in early pregnancy (P less than 0.01), with a consequent increase in cardiac output. Plasma renin activity and aldosterone concentration were elevated by 4 weeks (P less than 0.01), but plasma volume did not expand until 12 weeks. At no stage in middle or late pregnancy was cardiac filling pressure increased. These results provide the first haemodynamic evidence that pregnancy is a state of reduced effective blood volume associated with vasodilatation from the early weeks.

Aldosterone↗
PubMed1986

Expression of HLA antigens on renal tubular cells in culture. I. Evidence that mixed lymphocyte culture supernatants and gamma interferon increase both class I and class II HLA antigens.

The altered expression of HLA antigens on tissues during rejection is of potential importance to both the initiation and effector arms of the alloimmune response. Associated with rejection episodes, renal tubular cell expression of HLA DR (class II) antigens has been observed to be markedly increased. In this study an in vitro assay using cultured renal tubular cells from normal human kidneys was developed. Monoclonal antibodies to detect HLA DR and HLA A,B,C (class I) molecules were used to identify these antigens on cultured tubular cells either by indirect immunofluorescence stains and flow cytometric analysis or by immunoperoxidase stains with cytological analysis. With these techniques normal cultured cells had little membrane or cytoplasmic HLA DR but did have membrane HLA A,B,C. Culture of renal tubular cells with either supernatants from mixed lymphocyte cultures or purified gamma interferon induced expression of HLA DR, with maximum expression occurring between day 4 and day 6. Increased HLA A,B,C expression was also observed. This increased expression of HLA antigens was shown not to be dependent upon increased cell division of the cultured cells, and removal of gamma interferon from the cultures resulted in a decay in both HLA DR and A,B,C expression within days. HLA expression was inhibited by addition of protein synthesis inhibitor cycloheximide, but not by the addition of puromycin, mitomycin C, or actinomycin D--which suggested that tubular cells had transcribed m RNA for both HLA DR and A,B,C antigens. Expression of HLA antigens was not inhibited by cyclosporine, corticosteroids, or azathioprine. These studies demonstrate that the increased expression of HLA antigens seen in renal allografts at the time of rejection episodes can be explained by the release of lymphokines, especially gamma interferon, by infiltrating cells, and that reduced HLA DR expression of transplanted kidneys in patients treated with cyclosporine is not due to the drug directly inhibiting HLA expression by graft cells.

Antibodies, Monoclonal↗
PubMed1986

Nonocclusive chronic vascular catheterization of conscious unrestrained baboons.

A surgical technique is described for chronic arterial and venous catheterization of unrestrained adult baboons. Vascular access was achieved through a small (5 cm) abdominal incision and an extraperitoneal approach to the iliac vessels, which minimizes postoperative morbidity, discomfort, and restriction of movement. The method permits secure but nonocclusive catheterization, confirmed by angiography. Catheters were removed without further surgery, leaving the baboons intact for reuse. Catheters placed in the distal common or proximal external iliac vessels were all patent when removed at 46-61 days. The results demonstrate arterial pressure, pulse rates, drug administration, blood sampling, and plasma volume measurement as examples of the technique's application in conscious unrestrained baboons.

Animals↗
PubMed1986

Renal tubular transport of cyclosporine A (CSA) and associated changes in renal function.

In an effort to understand the mechanisms of nephrotoxicity of cyclosporine A (CSA), this study has been undertaken to evaluate the CSA clearance by the kidney and its tubular transport, with simultaneous studies on the multiple renal functional parameters. New Zealand white rabbits weighing approximately 2.5 kg were used in the study. Rabbits were infused with 14C labelled inulin to determine GFR. Blood pressure was monitored throughout the study via ear artery cannula. The rabbits were catheterized by the bladder and remained conscious throughout the entire study. When an infusional steady state was achieved, three clearance periods of 15 minutes were undertaken, followed then by a bolus of 10 mg/kg CSA, followed by an infusion of 1 mg/kg. A further three clearance periods were undertaken, studying the clearance of CSA at the same time as the GFR. Additional studies were made of plasma renin activity, aldosterone, 6-keto-PGF1 alpha, urinary sodium excretion and urinary potassium excretion rate. CSA was determined in whole blood and urine by HPLC. The results indicate that CSA, as determined by HPLC, has a whole blood renal clearance of 0.029 +/- 0.011 ml/min/kg body weight. Glomerular filtration rate showed no difference in animals pretreated with an infusion of mannitol when comparing pre- and post-CSA administration. Without mannitol, there was a significant decrease in the GFR following administration of CSA. CSA administration was accompanied by a rise in plasma renin activity in animals treated with mannitol and without mannitol. The rate of 6-keto-PGF1 alpha excretion without pretreatment with mannitol showed a significant rise following CSA administration.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Influence of cyclosporine A (CSA) on intrarenal control of GFR.

In the acute clinical situation, CSA produces reversible renal impairment. Studies by Morris et al. [1982] and others indicate that this is rapidly reversible when the drug is ceased. A series of studies have been performed in rats with the aim of examining changes in GFR, together with changes in the intrarenal renin-angiotensin system and renal release of prostaglandins. Rats were treated for 3-7 days with CSA and at the end of the experiment kidneys were removed and renal cortical slices prepared. There was increased renin secretion from the CSA-treated rats, compared to controls, and the response was dose-dependent. There was an increase in renal cortical renin content paralleling the renin release. Determinations of plasma renin in these animals also indicated a rise in plasma renin activity associated with time. In animals not pretreated with CSA, the renal cortical slices incubated with CSA demonstrated a stimulation of renin release. A further group of rats pretreated with 100 mg/kg/day of CSA for 3-7 days showed no change in renal slice release of 6-keto-PGF1 alpha, thromboxane B2, PGE2 and PGF2 alpha. This data indicates that the renal renin-angiotensin system is activated by CSA and produces a dissociation of the linkage between renal slice prostaglandin release and the renin angiotensin system. This would indicate that CSA affects the intrarenal control of GFR. However, the exact site of the modulation remains to be determined.

Animals↗
PubMed1985

Hypertension in pregnancy. A study of 142 women presenting before 32 weeks' gestation.

This study evaluates the outcome of 142 consecutive pregnancies in women in whom hypertension was diagnosed before 32 weeks' gestation and who were managed by a team comprising obstetricians, physicians and perinatologists. Arterial pressure was lowered to 140/90 mmHg or lower with clonidine hydrochloride or methyldopa therapy to which, in most cases, a vasodilator, hydralazine or diazoxide was added. The outcome of patients who were managed by the multidisciplinary team from the clinical onset of their disease was compared to the outcome of those who were transferred after the onset of hypertension from other centres. A greater perinatal mortality rate was found among the infants of patients with pre-eclampsia and patients with essential hypertension in pregnancy when the mothers were referred late for management. Reasons for the difference in pregnancy outcome are not clear. Possible explanations are discussed which emphasize the need for further study to establish optimal management of this common complication of pregnancy.

Antihypertensive Agents↗
PubMed1985

Stimulation of renin secretion by 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8).

The intracellular calcium antagonist 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) prevents the release of Ca2+ from cell storage sites. The effect of this compound on renin secretion from rat renal cortical slices in vitro was investigated. TMB-8 was a potent stimulant of renin secretion within the concentration range 10(-5)M to 5 X 10(-4)M with an optimum concentration of 2 X 10(-4)M. TMB-8 overcame the inhibition of renin secretion by angiotensin II, ouabain, 60 mM KCl and A23187. The results add to the existing evidence that Ca2+ is a common inhibitory messenger for a number of compounds which affect renin release and suggest a role for intracellular calcium stores in the regulation of juxtaglomerular cell Ca2+ levels.

Animals↗
PubMed1985

Treatment of renal transplantation rejection. Cyclosporin A versus conventional treatment with azathioprine, prednisone and antithymocyte immunoglobulin in primary cadaveric renal transplantation.

In a prospective randomized clinical trial to compare treatment with cyclosporin A to conventional treatment with azathioprine, prednisone and antithymocyte immunoglobulin in cadaveric renal transplantation, 34 patients were entered into both treatment groups and were examined regularly for seven to 43 months. Renal graft survival at one year was 72% among patients receiving cyclosporin A therapy and 75% among those receiving conventional therapy. Rejection was a frequent complication of both treatments; irreversible rejection occurred in six patients receiving treatment with cyclosporin A and in 10 patients receiving conventional therapy. The nephrotoxicity of cyclosporin A was its main side-effect. A similar proportion of kidneys in both groups (65% and 69%) were initially affected with post-transplant oliguria, but recovery of function took significantly longer in the group receiving cyclosporin A therapy (median, 29 days versus 11 days, P less than 0.001). The results of this pilot study suggest that cyclosporin A can be used safely in patients with post-transplantation oliguria, and indicate that long-term graft survival with cyclosporin A is comparable to that achieved with azathioprine, prednisone and antithymocyte immunoglobulin.

Adolescent↗
PubMed1985

Post-transplant acute renal failure in cadaver renal recipients treated with cyclosporine.

The outcome of patients with acute renal failure following cadaveric renal transplant has been evaluated in a prospective, controlled trial, comparing treatment with cyclosporine (CSA) to prednisone, azathioprine, and antilymphocyte globulin (AZA). There was a high incidence of acute post-transplant renal failure in both groups: 37 of 51 CSA and 31 of 45 AZA patients, due to the long exposure of kidneys to warm and cold ischemia. Onset of adequate renal function was delayed for three or more weeks in 27 (53%) CSA and only nine (20%) AZA patients, and the only predisposing factor found was donor hypotension. All nine AZA and 18 of the 27 CSA patients with prolonged oliguria subsequently had a spontaneous diuresis. Nine of the CSA patients were changed to azathioprine and prednisone because of suspected CSA toxicity, and eight of these kidneys began functioning within days, even though they had been oliguric for 21 to 83 days. Of these nine patients, five had adequate long-term function on AZA, three developed CMV infections that were fatal to two individuals, and two rejected their grafts. Plasma CSA levels fluctuated widely in all patients, but were not higher in any group, including those with prolonged oliguria. During the oliguric period, biopsy specimens proved rejection was more common in the nine patients who had their CSA stopped than in the other CSA patients, and seven of these nine developed a diffuse interstitial fibrosis that was thought to be a manifestation of CSA toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1985

Blood volume measurement in baboons: simultaneous estimation of red cell volume and plasma volume.

A method is described for frequent sequential blood volume estimation in baboons using 32P for red cell volume measurements and 125I-albumin for simultaneous plasma volume measurements. Values for red cell, plasma, and total blood volumes are reported. Close correlations of the volumes to bodyweight were demonstrated. Circulatory half-lives of the isotopes, determined from disappearance curves, confirmed their suitability for serial measurements in these baboons.

Animals↗