Comments on council report.
Explore the source record for details and available documents.
Education, Veterinary↗
Biomedical subjects
D C Ferguson
Publications and source records attributed to D C Ferguson.
Glucose tolerance and insulin secretion in spontaneously hyperthyroid cats.
Glucose tolerance and insulin secretion after administration of a glucose load were determined in 11 clinically normal cats and 15 cats with spontaneous hyperthyroidism. In six hyperthyroid cats, a glucose tolerance test was repeated after treatment with radioactive iodine (131I). All cats had similar baseline glucose concentrations. However, the cats with hyperthyroidism had a significantly decreased glucose clearance, which was worse after treatment. Hyperthyroidism also caused a marked increase in basal and glucose-stimulated insulin secretion, which was not improved with treatment. It is concluded that hyperthyroidism in cats may lead to long-lasting alterations of glucose tolerance and insulin secretion which may not be reversed by treatment.
Animals↗
Na+/Ca2+ exchange in plasma membrane vesicles from a glucose-responsive insulinoma.
Plasma membrane vesicles from a glucose-responsive insulinoma exhibited properties consistent with the presence of a membrane Na+/Ca2+ exchange. The exchange was rapid, reversible, and was dependent on the external Ca2+ concentration (Km = 4.1 +/- 1.1 microM). External Na+ inhibited the uptake in a dose-dependent manner (IC50 = 15 mM). Dissipation of the Na+ gradient by 10 microM monensin decreased Na+/Ca2+ exchange from 0.74 +/- 0.17 nmoles/mg protein/s to 0.11 +/- 0.05 nmoles/mg protein/s. Exchange was not influenced by veratridine, tetrodotoxin and ouabain, or by modifiers of cAMP. No effect was seen using the calcium channel blockers, nitrendipine or nifedipine. Glucose had no direct effect on Na+/Ca2+ exchange, while glyceraldehyde, glyceraldehyde-3-phosphate and dihydroxyacetone inhibited the exchange. Na+ induced efflux of calcium was seen in Ca2+ loaded vesicles and was half maximal at [Na+] of 11.1 +/- 0.75 mM. Ca2+ efflux was dependent on [Na+], with a Hill coefficient of 2.7 +/- 0.07 indicating that activation of Ca2+ release involves a minimum of three sites. The electrogenicity of this exchange was demonstrated using the lipophilic cation tetraphenylphosphonium [( 3H]-TPP), a membrane potential sensitive probe. [3H]-TPP uptake increased transiently during Na+/Ca2+ exchange indicating that the exchange generated a membrane potential. These results show that Na+/Ca2+ exchange operates in the beta cell and may be an important regulator of intracellular free Ca2+ concentrations.
Animals↗
Use of ultrasound to detect intestinal wall ischemia in piglets.
To evaluate the use of ultrasound (US) to detect intestinal wall ischemia, we isolated segments of jejunum on single vascular pedicles in five piglets. We sequentially clamped these segments in intervals of 0 to 6 h, reperfused them for 24 h, and then examined them in vitro histologically and with an 8.5 MHz US scan. All segments were grossly viable except those with 6 h of ischemia. Histologically, mild submucosal edema developed after 1 to 2 h of ischemia; after 3 to 4 h, mucosal necrosis, loss of folds, worsening submucosal edema, and prominent neutrophilic infiltration occurred; after 5 to 6 h, severe mucosal necrosis with hemorrhage and submucosal edema was present. Ultrasonically, we saw five wall layers in the control group corresponding to mucosa, submucosa, muscularis propria, and subserosal fat. After mild (1 to 2 h) ischemia, all layers were present except for a discontinuity in layer 3. After moderate (3 to 4 h) ischemia, the five layers persisted but with a markedly thickened submucosal layer, reduced echogenicity, and flattened mucosal folds. With severe (5 to 6 h) ischemia, we observed a loss of all normal layers with no discernible architecture. Using these US criteria, blinded observers were able to differentiate normal/mild from moderate/severe ischemia with a sensitivity and specificity of 100%. These data suggest that US can differentiate, in vitro, normal from moderate and severe degrees of intestinal wall ischemia that correlates well with the histological appearance. Endoscopic US or surgically implantable US probes can potentially help diagnose clinical intestinal wall ischemia.
Animals↗
The interaction of L-triiodothyronine and 2,3,7,8-tetrachlorodibenzo-p-dioxin on Ah-receptor-mediated hepatic Phase I and Phase II enzymes and iodothyronine 5'-deiodinase in thyroidectomized rats.
Across all levels of L-triiodothyronine (L-T3) treatment, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in increased hepatic cytochrome P-450-associated activities of 7-ethoxycoumarin O-deethylase (ECOD), 7-ethoxyresorufin O-dealkylase (EROD) and aryl hydrocarbon hydroxylase (AHH). The treatment of thyroidectomized rats with L-T3 at physiologic replacement levels in concert with TCDD produced an increase in ECOD, EROD and AHH activity above that seen with only TCDD. TCDD as well as L-T3 enhanced the activity of hepatic 1-naphthol glucuronyl transferase (NGT). In addition, the combined effect of L-T3 and TCDD resulted in similar levels of induction of NGT at both physiologic and supraphysiologic doses of L-T3. TCDD treatment resulted in elevated serum T3 levels at both physiologic and supraphysiologic levels of L-T3. One TCDD dose inhibited hepatic microsomal 3,3',5'-triiodothyronine (reverse T3) 5'-deiodinase activity by 61% in thyroidectomized, T3-untreated rats. The inhibition of 5'-deiodinase activity was partially overcome by increasing the T3 dose.
Animals↗
Leukotrienes and sensory innervation in blood-aqueous barrier disruption in the dog.
The effect of a specific 5-lipoxygenase inhibitor, PF5901 (5% in corn oil), on disruption of the blood-aqueous barrier (BAB) in the dog was investigated using a unilateral mild paracentesis model. BAB breakdown was quantitated using anterior chamber fluorophotometry. Fluorescence in the eyes of the PF5901 group was not statistically significantly different (P greater than 0.05) from that in the vehicle group. A tendency towards greater fluorescein concentrations was noted in the PF5901 treated eyes. It was concluded that leukotrienes are not important mediators of BAB disruption in this model and that leukotriene inhibitors may actually exacerbate disruption due to shunting of arachidonate metabolism towards the cyclooxygenase and/or epoxygenase pathways. In a second experiment, the effects of proparacaine and flurbiprofen were evaluated on blood-aqueous barrier disruption and pupil size following a more severe paracentesis. Flurbiprofen dampened both barrier disruption and the miotic response but proparacaine suppressed neither reaction, suggesting that, in the dog, prostaglandins are more important mediators of the ocular irritative response than are sensory neuropeptides.
Animals↗
The effects of stress on gastric ulceration, T3, T4, reverse T3 and cortisol in neonatal foals.
Sixteen neonatal foals stressed by disease underwent endoscopic examination of their stomachs and blood was assayed for triiodothyronine (T3), reverse T3 (rT3), thyroxine (T4) and cortisol, to determine the effects of severe physiological stress and the occurrence of gastric ulcers. compared with eight age-matched controls, six foals had abnormal cortisol, seven had abnormal T3 and 12 had abnormal T4. Eleven of 13 foals had rT3 outside the 95 per cent confidence interval for clinically normal foals of comparable ages. Gastric lesions were seen more frequently in stressed foals, and gastric glandular mucosal lesions were noted in 40 per cent of the stressed foals. Previous studies report low (3 per cent) occurrence of gastric mucosal lesions. The frequency of squamous mucosal lesions was not different from that reported previously, indicating that stress has little effect on the development of lesions at this site.
Animals↗
Effects of prednisone on thyroxine and 3,5,3'-triiodothyronine metabolism in normal dogs.
Pharmacological doses of glucocorticoids may reduce serum T4 and T3 levels in normal dogs and humans due to hypothalamic-pituitary suppression and/or altered peripheral hormone metabolism. To evaluate the chronic effects of antiinflammatory doses of glucocorticoids on peripheral thyroid hormone metabolism, serum T4 and T3 kinetic studies were performed in five thyroidectomized L-T4-replaced (5 micrograms/kg, sc, daily) normocalcemic male dogs at baseline and after 35 days of oral prednisone (0.55 mg/kg every 12 h). Data were analyzed in a three-pool model, with rapidly (liver and kidney) and slowly (muscle and skin) equilibrating pools exchanging with serum and rapid pool losses. Prednisone lowered the percent free fraction of T4 (to 70% of baseline) and total T3 (to 60%) and free T3 (to 51%) levels without significantly changing total or free T4 or percent free fraction of T3. This was associated with reduced T4 fractional transfer rates from serum rapid (to 39%) and slow (42%) pools and from rapid (to 25%) and slow pools (to 7%) to serum, and increased serum free T4 clearance rates (to 144%) as well as binding in the rapid (162%) and slow (710%) pools. Total T4 clearance and degradation rates were not significantly altered. Significant correlations included T4 binding in the rapid pool with percent free fractions of T4 (r = -0.86), T4 fractional transfer rates from rapid pool to serum with rapid pool T4 binding (r = -0.75), and fractional T4 transfer rates from slow pool to serum with slow pool T4 binding (r = -0.88). In contrast, prednisone increased fractional T3 transfer rates from serum to the slow pool (to 289%) and reduced serum (to 42%) and maximum total body degradation and production rates (to 41%) without altering total or free T3 clearance rates. Fractional T3 transfer rates from the slow pool to serum correlated with slow pool T3 binding (r = -0.84). Prednisone redistributed T4 and T3 from the serum and rapid pools to the slowly equilibrating pool. Thus, the peripheral effects of chronic antiinflammatory doses of prednisone on thyroid hormone metabolism include 1) increased T4 binding to serum carrier proteins, which may contribute to lower T4 transfer rates from serum to extravascular sites and increased extravascular T4 binding; 2) reduced fractional transfer rates of T4 from extravascular sites to serum, which may relate to increased tissue binding of T4; 3) redistribution of T4 and T3 from the serum and rapid pools to the slow pool; and 4) decreased T3 production from T4, resulting in reduced serum total and free T3 levels.
Administration, Oral↗
Poly-L-aspartic acid does but triiodothyronine does not protect against gentamicin-induced cytotoxicity in the porcine kidney cell line LLC-PK1.
This study investigated the protective effect of thyroid hormone and poly-L-aspartic acid (PAA) in an in vitro model of gentamicin nephrotoxicity. LLC-PK1 porcine renal cells were grown in Medium 199 supplemented with either fetal bovine serum or thyroid hormone-depleted fetal bovine serum. After a preincubation with or without 30 nM L-triiodothyronine for 3 days, or 0.1 mM PAA for 1 hr, cells were coincubated with 1 mM gentamicin for an additional 3 days. Determinations were made of the following indicators of cell damage and/or viability: the numbers of detached dead cells, the total lactate dehydrogenase activity and its percentage release and gamma-glutamyl transpeptidase activity. Preincubation with L-triiodothyronine did not protect from gentamicin-induced cell death but did reduce cellular accumulation of gentamicin (3.2 +/- 0.8 micrograms/mg of protein vs. 5.2 +/- 1.8 micrograms/mg of protein in controls; P less than .05). In contrast, preincubation with 0.1 mM PAA decreased gentamicin-induced cell death (gentamicin: 685 +/- 416% of control dead cells and 487 +/- 48% of control lactate dehydrogenase release; PAA + gentamicin: 164 +/- 63% of control dead cells and 257 +/- 85% of control lactate dehydrogenase release; P less than .05) but failed to attenuate inhibition by gentamicin of gamma-glutamyl transpeptidase activity (gentamicin: 69 +/- 7% of control; PAA+gentamicin: 76 +/- 3% of control) and failed to alter cellular gentamicin levels. Protection against gentamicin nephrotoxicity by L-triiodothyronine was not demonstrated in LLC-PK1 cells, indicating that its protective effect in vivo is likely due to a systemic effect of the hormone.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Serum free and total iodothyronine concentrations in dogs with hyperadrenocorticism.
Serum concentrations of total and free thyroxine (T4 and FT4, respectively), 3,5,3'-triiodothyronine (T3), 3,3',5'-triiodothyronine (reverse T3) were measured in 42 dogs with hyperadrenocorticism, and were compared with values determined in clinically normal dogs. Mean total T4 concentration in dogs with hyperadrenocorticism (14.3 nmol/L) was significantly (P less than 0.001) lower than the normal value (25.7 nmol/L), with 38% of the dogs having low serum T4 concentration. Although 16 (38%) of the 42 dogs with hyperadrenocorticism had a high FT4 fraction, indicative of diminished serum T4 binding, normal FT4 concentration was found in only 6 of the 16 dogs (38%) with low total T4 values. Mean serum T3 concentration in dogs with hyperadrenocorticism (0.79 nmol/L) was also significantly (P less than 0.001) lower than the normal value (1.16 nmol/L), with 39% of the dogs having T3 values below the normal range. Individual T3-to-T4 and T3-to-FT4 ratios, indices of T3 production and/or clearance, were above the normal range in 29 and 24% of dogs with hyperadrenocorticism, respectively. Mean reverse T3 concentration in dogs with hyperadrenocorticism (0.17 nmol/L) was also significantly (P less than 0.001) lower than the normal mean value (0.39 nmol/L), with 48% of the dogs having reverse T3 values below the normal range. Of the 21 dogs in which all iodothyronines were measured, 6 (29%) had undetectable values for all hormones.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenocortical Hyperfunction↗
High-frequency ultrasound detects abnormal bowel wall after porcine small bowel transplantation.
Explore the source record for details and available documents.
Animals↗
Characterization of Na(+)-Ca2+ exchange in the beta cell.
Explore the source record for details and available documents.
Animals↗
Calcium transport by plasma membranes from a glucose-responsive rat insulinoma.
Inside-out plasma membrane vesicles from a glucose-responsive rat insulinoma showed an ATP- and Mg2(+)-dependent uptake of Ca2+. The Km (concentration giving half-maximal activity) for Ca2+ was 60 nM. In the presence of 0.4 microM free Ca2+, the Km for ATP was 15 microM, and the Km for Mg2+ was 4 microM. Glucose (30 mM) decreased Ca2+ uptake by 50%, while other insulin secretagogues had no effect, except for glyceraldehyde, which stimulated Ca2+ uptake. Calmodulin increased the uptake of Ca2+, while trifluoperazine and vanadate inhibited the uptake. The Ca2(+)- and Mg2(+)-dependent ATPase from this tumor has a 10- to 20-fold higher requirement for Ca2+, which suggests that this enzyme is not responsible for Ca2+ transport, rather, Ca2+ transport activity represents only a small fraction of the total Ca2(+)-ATPase activity. The physiological importance of Ca2+ transport in insulin secretion is evident from the inhibition of Ca2+ uptake by glucose, which leads to a decrease in Ca2+ efflux from the cell. This inhibition would lead to an increase in intracellular free Ca2+ and insulin release.
Animals↗
Fluorophotometric evaluation of experimental blood-aqueous barrier disruption in dogs.
A protocol for performing slit-lamp fluorophotometry of the anterior chamber in dogs was established. The technique was then used to develop a model of blood-aqueous barrier disruption that can be used for comparative testing of ophthalmic anti-inflammatory drugs. It was determined that barrier disruption induced by a slow, controlled paracentesis of a small volume of aqueous humor may provide the most reliable model for drug testing. Additionally, fluorophotometry proved to be a sensitive and accurate means of detecting breakdown of the blood-aqueous barrier.
Animals↗
Glucose inhibits the high-affinity (Ca2+ + Mg2+)-ATPase in the plasma membrane of a glucose-responsive insulinoma.
(Ca2+ + Mg2+)-ATPase enzyme activity of a purified plasma membrane preparation from a glucose responsive rat insulinoma, was characterized as Ca2(+)-dependent dephosphorylation of [gamma-32P]ATP. A high-affinity enzyme with a Km(ATP) ranging from 20 to 30 microM and a Km(Ca2+) of 1 microM was identified. Glucose inhibited this high-affinity enzyme in a dose-dependent manner, with no significant inhibition at a concentration between 0 and 5 mM, 50% inhibition at 13.3 mM and 94.5% inhibition at 30 mM. The inhibitory effect of glucose was immediate and rapidly reversible. The effect was stereospecific for the alpha-anomer. These findings support the concept that glucose acts directly at the beta-cell plasma membrane and is involved in the maintenance of elevated intracellular free calcium concentrations associated with insulin release by directly or indirectly inhibiting energy-dependent calcium efflux. Glyceraldehyde (20 mM) increased enzyme activity 3-fold, while other metabolic fuels had no effect. This suggests that inhibition of the enzyme is not an obligatory requirement for insulin release. Calmodulin stimulated the enzyme activity in calmodulin-depleted but not in undepleted membranes. Trifluoperazine (30-100 microM) inhibited (Ca2+ + Mg2+)-ATPase in a dose-dependent manner (14-61% activity) and the activity was also inhibited by vanadate (0.1-1.0 mM) and NaCl (150 mM).
Adenoma, Islet Cell↗
Evidence that the soluble interleukin 2 receptor level may determine the optimal time for cystoscopically-directed biopsy in pancreaticoduodenal allograft recipients.
In 18 consecutive pancreaticoduodenal allograft recipients (15 combined kidney/pancreas and 3 pancreas only after a prior successful kidney transplantation) operated on between December 1987 and February 1989, we studied the soluble interleukin 2 receptor (SIL-2R) level over time. All pancreaticoduodenal allografts were transplanted with exocrine drainage via a duodenocystostomy that allowed for cystoscopically directed needle biopsies of the pancreas. Of these 18 recipients, at 6 weeks after transplantation, 6 had had no rejection episodes or cytomegalovirus disease (control group), an acute allograft rejection had developed in 7, CMV disease developed in 4, and both rejection and CMV disease developed in 1 by 12 days after transplantation. SIL-2R level increased in all patients during immunosuppressive induction therapy (preoperative mean +/- SE, 1637 +/- 284 U/mL; maximum, 4367 +/- 687 U/mL). After induction therapy, the mean was 2768 +/- 432 U/mL. In all 6 recipients in the control group, SIL-2R level continued to decrease. However, SIL-2R level was significantly higher compared with controls, in those who had CMV disease (levels were increased at a mean of 7 days before diagnosis of CMV disease) and in those who had acute rejection episodes (levels were increased a mean of 7 days before the clinical diagnosis of rejection). Factors that did not cause an increase in SIL-2R level included acute pancreatitis, wound infection, operative procedures, and CsA nephrotoxicity. SIL-2R level can be useful for monitoring pancreaticoduodenal allograft recipients. Increases predict impending rejection or CMV disease, prior to the onset of organ dysfunction. When SIL-2R level increases, we recommend cultures of blood and urine to exclude CMV and pancreaticoduodenal allograft biopsy to confirm early rejection prior to the initiation of potentially dangerous antirejection therapy.
Biopsy↗
Comparison of reverse triiodothyronine distribution and metabolism in normal dogs and humans.
Serum rT3 tracer kinetic studies were performed in 14 normal dogs and 9 normal human subjects. A number of models were used to evaluate the data. Relative rates of hormone degradation by rapidly equilibrating tissues such as liver and kidney and slowly equilibrating tissues such as muscle, skin, and brain could not be determined using serum data alone. Based on known physiology, all hormone losses were confined to rapidly equilibrating sites. Dogs had significantly higher mean serum total rT3 (175% that in man), free fraction of rT3 (437%), and free rT3 levels (765%). Total rT3 values were determined in different assays, due to species differences, which had similar anti-rT3 antiserum characteristics and rT3 standards. Fractional rates of rT3 transfer from serum to both rapidly and slowly equilibrating pools in dogs were not significantly different from those in man, while the fractional transfer rate from the rapid pool to serum was increased (288%). This was associated with significantly smaller rapid and slow pool extravascular binding (rapid, 3.8%; slow, 2.8%), mass (29% and 21%, respectively), and volume (17% and 12%, respectively) in dogs compared to man. In dogs, 31% of the total 0.791 micrograms rT3 was in serum, 29% was in the rapid pool, and 40% was in the slow pool compared to 16% of 2.677 micrograms in serum, 29% in the rapid pool, and 55% in the slow pool in man (P less than 0.01). Further, 89% of the total unidirectional transfer from serum was to the rapid pool, and 11% to the slow pool in dogs compared to 82% and 18%, respectively, in man. Serum clearance (22%) and appearance rates (39%) as well as maximum total body production rates (34%) of rT3 were lower in the dogs. Serum appearance and maximum production rates, and hormone masses in the rapid and slow pools were no longer significantly different between dogs and man when normalized for either body weight or body surface area. Serum volume was no longer significant when normalized for body surface area. Noncompartmental analysis resulted in a significant underestimation of the mean total fraction rate of hormone exit from serum (by 20%), total volume of distribution (10%), extravascular binding (18%), and mean residence time (11%) in dogs and of extravascular binding (22%) in man. The serum appearance rate of rT3 was 78% of the maximum total body production rate in dogs and 69% in man.(ABSTRACT TRUNCATED AT 400 WORDS)
Adult↗
Kinetics of triiodothyronine dissociation from bovine serum albumin: modification of the resin capture method with subsequent computer modeling.
There has been much debate about the mechanism by which thyroid hormone leaves the circulation and enters cells. Critical to the development of theoretical models of thyroid hormone uptake are precise estimates of the kinetic constants describing the reversible binding of the hormone to its binding proteins. A resin capture method was modified to permit the collection of dissociation data at intervals of 0.12 sec. Columns (30 X 0.6 cm) of Amberlite IRA 400 anion exchange resin were perfused at 30 ml/min with 3.5% dextran in modified Krebs Henseleit bicarbonate buffer at pH 7.4 and 37 C. Injection of [125I]triiodothyronine (T3) tracer in BSA-free medium established the rate constant for resin capture of free T3 in this system: kRes = 0.89 +/- 0.04 sec-1 (mean +/- SD, n = 4). [125I]T3 preequilibrated with BSA was infused to achieve final BSA concentrations of 2.3, 48, 120, 290, 507, and 725 microM, yielding apparent uptake rate constants (kapp) of 0.77 +/- 0.12 (n = 6), 0.23 +/- 0.01 (n = 4), 0.17 +/- 0.04 (n = 4), 0.057 +/- 0.005 (n = 4), 0.039 +/- 0.003 (n = 4), 0.020 +/- 0.002 (n = 4) sec-1 (SSE less than 9.4 X 10(-2), respectively, when fitted by nonlinear methods. Solving the equation kapp = kRes/(1 + [BSA]/KD') gave KD' = 1.80 +/- 0.07 X 10(-5) M (r2 = 0.96, P less than 0.001, n = 26) where KD' is the apparent or flow equilibrium constant. In a further experiment T3:BSA reassociation was eliminated by BSA dilution. This resulted in determination of the dissociation rate constant kdissoc = 0.63 +/- 0.16 sec-1 (n = 8) and therefore, the association rate constant kassoc = 3.5 X 10(4) M-1 sec-1. Mathematical modeling predicted that 14.4 microM BSA would decrease the rate of T3 uptake by the resin system by 65%. The free fraction of T3 during a single pass extraction was predicted to be greater than that measured by equilibrium dialysis, suggesting that dissociation of T3 from BSA is favored in the flux model relative to that measured at equilibrium in vitro.
Animals↗