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Biomedical subjects

C A Paterson

Publications and source records attributed to C A Paterson.

At least 55 records · Page 3Linked to original sources
PubMed1994

EP2-receptor stimulated cyclic AMP synthesis in cultured human non-pigmented ciliary epithelium.

Prostaglandins are locally produced mediators of physiologic function which act through specific receptors to influence cellular response pathways. We have conducted a series of experiments designed to obtain a preliminary pharmacologic characterization of the prostaglandin E2 receptor subtype mediating increased synthesis of adenosine 3',5'-cyclic monophosphate (cyclic AMP) in an SV40 transformed line of human non-pigmented ciliary epithelium (ODMC2). Human non-pigmented epithelial (NPE) cells were grown to confluency, preincubated with indomethacin (to prevent endogenous PGE2 synthesis) and with isobutyl-methyl-xanthine (to prevent breakdown of cAMP), challenged with PGE2 or receptor-selective prostanoids and extracted. Prostanoid-stimulated cAMP synthesis was determined using a protein binding assay and normalized to cellular protein. Prostanoid agonists known to be relatively selective for the EP2 receptor subtype stimulated cAMP synthesis by human NPE cells. EP1 and EP3, IP, FP and DP selective prostanoids had negligible effects on stimulation of cAMP synthesis. The results of these studies lead us to conclude that human NPE cells express receptors of the EP2 subtype which mediate PGE2 stimulated synthesis of cyclic AMP.

Cell Line, Transformed↗
PubMed1994

Pneumatic reduction of intussusception using carbon dioxide.

Pneumatic reduction using air has recently become popular for the initial non-surgical management of intussusception. Since carbon dioxide (CO2) is rapidly absorbed from body surfaces, it should theoretically result in less cramping and distension following reduction. We reviewed our recent experience with the pneumatic reduction of intussusception using CO2 in 26 children. In 22 of these the intussusception was reduced (85%). There was one performation with CO2; the patient did not suffer any postoperative complications. Five additional children who had been treated unsuccessfully with barium had intussusception subsequently reduced with CO2. Following CO2 reduction, most children were fed within hours, and there were no instances of significant abdominal distension or cramping. We conclude that pneumatic reduction of intussusception using CO2 is safe and effective, and has the theoretical advantage of more rapid absorption from the gastrointestinal tract than air.

Carbon Dioxide↗
PubMed1994

Studies on prostanoid receptors in ocular tissues.

Cyclooxygenase products of arachidonic acid, for example prostaglandins (PGs), prostacyclin, and thromboxane A2, mediate a wide range of physiological actions. Vasodilation, increased vascular permeability, platelet aggregation and its inhibition, and immunomodulation are some of the important biological actions of cyclooxygenase products (1). Depending on type and dose, PGs cause vasodilation, increase or decrease intraocular pressure, and disrupt the blood-aqueous barrier (2, 3). These actions also vary qualitatively and quantitatively with the animal species. Prostaglandins, like any biological molecule, must act by binding with their specific receptors. Coleman and coworkers (4, 5), from a series of studies with PG agonists and antagonists in vascular and non-vascular smooth muscle preparations, classified PG receptors. This classification led to a greater appreciation of the relationship between PG actions and specific PG receptors in various tissues. Ocular actions of PGs linked with specific PG receptors are far from being clear. In this communication we will review our work on PG binding sites in ocular tissues and PG receptors coupled to adenylyl cyclase or phosphoinositidase C signal transduction pathways in ocular tissues of various animal species.

Adenylyl Cyclases↗
PubMed1994

Recombinant tissue inhibitor of metalloproteinases type 1 suppresses alkali-burn-induced corneal ulceration in rabbits.

PURPOSE: To test if recombinant tissue inhibitor of metalloproteinases (TIMP-1) was effective in reducing corneal ulceration after alkali injury to the rabbit cornea. The effect of TIMP-1 was compared with that of a proven synthetic metalloproteinase inhibitor. METHODS: After a defined alkali injury to the rabbit cornea, a topical treatment regimen was followed for 24 days; one group was treated with vehicle only, a second group with recombinant TIMP-1, and a third group with the synthetic metalloproteinase inhibitor. Corneas were scored for ulceration during the 24-day period and the scores for the three groups were compared. RESULTS: The incidence and progression of ulceration and perforation, in the alkali-burned corneas receiving treatment with recombinant TIMP-1 or the synthetic inhibitor, were significantly less than in corneas receiving vehicle treatment alone. CONCLUSION: Recombinant TIMP-1 is as effective as a proven synthetic inhibitor in ameliorating corneal ulceration and perforation after an alkali injury.

Administration, Topical↗
PubMed1993

Collagen shields exacerbate ulceration of alkali-burned rabbit corneas.

OBJECTIVE: To determine the impact of collagen shields on ulceration of rabbit corneas after alkali burn. METHODS: After a 60-second 2N sodium hydroxide burn to rabbit corneas, 24-hour collagen shields were placed on the corneas daily for 21 days; control corneas did not receive collagen shields. The extent of corneal ulceration was documented daily for 21 days by slit-lamp examination of treated and control eyes. Three separate studies were performed using collagen shields from two commercial sources. RESULTS: In the three studies, corneas in the collagen shield-treated eyes began to ulcerate sooner than those in the control group; the corneas in collagen shield-treated eyes also began to perforate sooner. At 21 days after alkali injury, the mean (+/- SE) corneal ulceration score in the collagen shield-treated rabbits was 4.1 +/- 0.17 (descemetocele formation) compared with 2.7 +/- 0.28 (midstromal ulceration) in controls. This difference was significant at P < .005. CONCLUSION: Collagen shield treatment results in marked acceleration of corneal ulceration and perforation after alkali injury.

Animals↗
PubMed1993

Prostaglandin receptors coupled to adenylyl cyclase in the iris-ciliary body of rabbits, cats and cows.

Stimulation of adenylyl cyclase by prostaglandin (PG) receptor agonists was examined in the iris-ciliary body of rabbits, cats and cows. Iris-ciliary bodies were incubated with or without agonists in Krebs pyruvate buffer containing protease and cyclooxygenase inhibitors. The formation of cAMP in a 15-min period in response to the agonists was measured. In the rabbit iris-ciliary body, all PG receptor agonists at concentrations of 0.062-10.0 microM with the exception of sulprostone stimulated adenylyl cyclase. In this species, 17-phenyl trinor PGE2 and PGF2 alpha stimulated adenylyl cyclase but only at high concentrations (> 5 microM). The order of potency of the agonists was dimethyl PGE2 > PGE2 > 11-deoxy PGE1 = PGD2 > iloprost > PGF2 alpha. The DP receptor antagonist BWA868C had no effect on EP agonist responses, indicating that PGE2, dimethyl PGE2 and 11-deoxy PGE1 were not stimulating DP receptors. In the cat, PGE2, dimethyl PGE2 and 11-deoxy PGE1, were all equally potent in stimulating adenylyl cyclase. The order of potency in the cow was PGE2 > dimethyl PGE2 > 11-deoxy PGE1. However, PGD2, iloprost, 17-phenyl trinor PGE2 and PGF2 alpha were inactive in this species. The results of this study indicate that EP receptor agonists stimulate adenylyl cyclase in the iris-ciliary body of the three species; stimulation by other agonists depends on the species. In the rabbit, the EP2 receptor subtype appears to predominate; such a predominance of EP2 receptors was not observed in the cat and cow.

Adenylyl Cyclases↗
PubMed1993

Late anastomotic ulceration after ileocolic resection in childhood [corrected].

Anastomotic ulcers are a rare late complication of ileocolic resection in children. The authors describe the cases of two patients who presented 10 and 8 years, respectively, after ileocolic resection. Both had suffered from iron-deficiency anemia caused by an anastomotic ulcer. In one patient the anemia improved after resection of the ulcer; in the second patient cholestyramine and a lactose-free diet resolved the problems of anemia and diarrhea. Anastomotic ulceration should be suspected in any child who has undergone an ileocolic anastomosis and subsequently presents with persistent iron-deficiency anemia and occult blood in the stool.

Anastomosis, Surgical↗
PubMed1993

The influence of calcium on the rabbit lens sodium pump.

PURPOSE: Experiments were conducted to examine how elevation of calcium in the lens impairs the lens sodium pump. METHODS: Rabbit lenses were incubated in the presence or absence of calcium ionophore A23187. 86Rb uptake by the intact lens was measured as an index of sodium pump activity. Na,K-ATPase (ouabain-sensitive adenosine triphosphate [ATP] hydrolysis) activity was determined in membrane material isolated from the lens. Lens ion content and ATP content also were determined. RESULTS: Rabbit lenses gained calcium after exposure to calcium ionophore A23187 or ionomycin. Ionophore-treated lenses also gained sodium and lost potassium. A diminished rate of 86Rb uptake observed in ionophore-treated lenses suggests that elevation of lens calcium leads to sodium pump inhibition. In contrast, the rate of 86Rb efflux was not altered by A23187, indicating that elevated lens calcium causes little change in passive cation permeability. Membranes isolated from A23187-treated lenses were found to have normal Na,K-ATPase activity. However, calcium had a small direct inhibitory effect upon the Na,K-ATPase activity measured in freshly prepared lens membranes isolated from control (nonionophore-treated) lenses. Using a luciferase assay, A23187-treated lenses were found to have a normal ATP content. CONCLUSIONS: Calcium may impair the ability of the lens, Na,K-ATPase to pump ions in the intact lens, but appears to leave the ATP-hydrolyzing capability of the isolated enzyme unchanged.

Adenosine Triphosphate↗
PubMed1993

Prostaglandin E2 and F2 alpha binding sites in the bovine iris ciliary body.

PURPOSE: To determine the regional distribution and selectivity of prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha) specific binding sites in membrane preparations from bovine iris ciliary body. METHODS: Bovine eyes were obtained fresh from a local abattoir. Whole irides were separated into sphincter muscle, ciliary body, and remaining iris tissue then homogenized in 50 mM tris buffer, pH 7.5, containing cyclooxygenase, protease, and soybean trypsin inhibitors. Membranes were obtained after three-stage high-speed centrifugation then reconstituted in buffer. Aliquot portions were incubated with 3H-PGE2 or 3H-PGF2 alpha at 37 degrees C for 30 min in a final volume of 500 microliters. Competition studies were performed in the presence of up to 1000-fold excess unlabeled ligand. At the end of a 30-min incubation period, free and membrane bound ligand were separated by rapid filtration through a type HA millipore filter preequilibrated with buffer. The radioactivity bound to the membranes retained on the filter was quantitated in a scintillation counter. RESULTS: The equilibrium dissociation constant and maximum number 3H-PGE2 saturable binding sites were determined by Scatchard analysis. The data best fit to a single binding site model for all three membrane preparations. The majority of the 3H-PGE2 specific binding sites were in sphincter muscle (65%), followed by iris (17%), and ciliary body (18%). 3H-PGE2 alpha binding sites were not measurable in either iris or ciliary body and PGF2 alpha was less competitive than PGE2 in all tissues. The rank order of potency for agonist displacement by both 3H-PGE2 and 3H-PGF2 in sphincter muscle membrane was PGE2 > PGF2 alpha > PGD2 > Iloprost. It was determined that 3H-PGE2 and 3H-PGF2 alpha binding in the bovine sphincter was primarily to EP not FP, DP, or IP prostaglandin receptor types. CONCLUSIONS: The characteristics of PGE2 and PGF2 alpha specific binding sites in the bovine sphincter correlate with its in vitro contractile response to these prostanoids. The inability of PGF2 alpha to effectively compete with PGE2 for specific binding sites in the sphincter and lack of high affinity PGF2 alpha specific binding sites in the iris and ciliary body suggests that this prostaglandin may exert its in vivo effects through PGE2 specific binding sites.

Animals↗
PubMed1992

Prostaglandin E2 binding site distribution and subtype classification in the rabbit iris-ciliary body.

The distribution and characteristics of specific binding sites for tritium labeled prostaglandin E2 (3H-PGE2) were examined in membrane preparations from rabbit iris-sphincter, iris and ciliary body. The majority of 3H-PGE2 specific binding sites were found in the ciliary body (46%) followed by the iris (37%) and the iris-sphincter muscle (5%). Scatchard analysis of saturable 3H-PGE2 binding sites in the ciliary body indicated a single binding site with a Kd of 2.81 nM and Bmax value of 84 fmoles bound/mg protein. Competition by agonists selective for the EP1, EP2 and EP3 receptor subtypes of the EP (PGE2) prostanoid receptor indicated that the majority of rabbit ciliary body 3H-PGE2 binding sites are of the EP2 subtype. Incomplete displacement of labeled 3H-PGE2 from its binding sites by the EP2 selective agonist 11-deoxy PGE1 suggests the presence of additional EP or non-EP binding sites. There was essentially no binding to EP1 receptor sites as defined by the displacement of 3H-PGE2 by 17-phenyl-trinor PGE2. A weak displacement of 3H-PGE2 by the EP3/EP1 specific agonist, sulprostone, may account for the presence of a small number of EP3 specific binding sites in this tissue. The predominant distribution of PGE2 binding sites in the ciliary body and their identification as EP2 selective, supports recent functional studies where topical application of prostanoids with EP2 but not EP1 or EP3 agonist activity resulted in breakdown of the blood-aqueous barrier.

Animals↗
PubMed1992

Modulation of immune responses by cyclo-oxygenase inhibitors during intraocular inflammation.

The effects of cyclooxygenase inhibitors flurbiprofen and indomethacin on the inflammatory response and immune reactions induced by S-antigen in the rat eye were studied. The treatment with flurbiprofen and indomethacin administered subcutaneously every 12 hours, commenced on the day of S-antigen injection and was continued until the termination of the experiment (12 days). Flurbiprofen reduced vasodilation and the inflammatory exudate into the anterior chamber by 38% and 36% respectively while inhibiting polymorphonuclear leukocytes infiltration by 57% without affecting monocytes infiltration. Indomethacin had similar but greater effects than flurbiprofen on all these parameters. However, the differences between the mean values of the two compounds were not significant. Both compounds also attenuated spleen cell proliferation, serum IgG levels to S-antigen and interferon-gamma levels in the aqueous humor. The level of prostaglandin E2, but not of leukotriene B4, was increased in the untreated inflamed uveal tissues and this increase was significantly inhibited by flurbiprofen and indomethacin. The results of this study suggest that cyclooxygenase products are involved in the normal development of both humoral and cellular immune response in the experimental uveitis.

Animals↗
PubMed1992

Effect of a metalloproteinase inhibitor on established corneal ulcers after an alkali burn.

Proteinase inhibitors have been shown to prevent corneal ulceration and perforation when used immediately after an experimental alkali burn injury. To evaluate the clinical efficacy of a synthetic metalloproteinase inhibitor, HSCH2CH[CH2CH(CH3)2]CO-Phe-Ala-NH2(SIMP), treatment with inhibitor was withheld until corneal ulceration ensued after a standard alkali injury to the rabbit eye. When topical therapy with a 1 mmol/l solution of SIMP was initiated after corneal ulceration had progressed to a mid-stromal level (clinical score of 2), there was no significant difference in the progression of corneal ulceration between the treated vs. control group after 6 d of therapy. In the second study in which treatment was initiated earlier at the onset of superficial ulceration (clinical score of 1), there was a significant difference in clinical scores between the two groups after 1 day of treatment until termination of the experiment at 21 d (P less than 0.005). In the inhibitor-treated group, 88.9% of the corneas showed a reversal or cessation of progression of the ulceration process. Eighty-seven-and-a-half percent of the control corneas progressed to descemetocele formation or perforation by day 14 of treatment. This study suggests that SIMP may be used for effective treatment of corneal ulcers resulting from an alkali burn injury in the human eye. It also shows that early and aggressive initiation of therapy is critical.

Administration, Topical↗
PubMed1991

Metformin increases insulin sensitivity and basal glucose clearance in type 2 (non-insulin dependent) diabetes mellitus.

The effects of metformin on glycaemia, insulin and c-peptide levels, hepatic glucose production and insulin sensitivity (using the euglycaemic, hyperinsulinaemic clamp) were evaluated at fortnightly intervals in 9 Type 2 diabetic patients using a stepwise dosing protocol: Stage 1--no metformin for four weeks; stage 2--metformin 500mg mane; stage 3--metformin 500mg thrice daily; stage 4--metformin 1000mg thrice daily. Results are expressed as Mean +/- SEM. Fasting blood glucose decreased from basal values (9.7 +/- 1.0 mmol/L) by 13% at stage 2, 34% at stage 3 and 41% at stage 4 (p less than 0.02 vs basal for all stages; p less than 0.02 stage 2 vs stage 3). Post-prandial glycaemia was significantly improved only with metformin 3000mg/day (p less than 0.05). Fasting, meal-stimulated and total insulin and c-peptide levels showed no change. Hepatic glucose output did not change significantly with metformin. Insulin sensitivity, measured as total glucose utilisation during hyperinsulinaemia, increased from stage 1 (10.3 +/- 2.1 mumoL/kg/min) by 23% at stage 3 (p less than 0.05) and by 29% at stage 4 (p less than 0.02). Basal metabolic clearance of glucose increased compared to stage 1 (1.69 +/- 0.16 mL/kg/min) by 30% at stage 2, 53% at stage 3 and 44% at stage 4 (all p less than 0.02). This study demonstrates that improved efficiency of glucose utilisation, both basally and under conditions of euglycaemic hyperinsulinaemia, is the basis of metformin's antihyperglycaemic action.

Adult↗
PubMed1991

Calcium transport, Ca2(+)-ATPase, and lipid order in rabbit ocular lens membranes.

Calcium transport was monitored by measuring ATP-dependent 45Ca uptake into membrane vesicles prepared from rabbit lens cortex. Calcium-stimulated adenosinetriphosphatase (Ca2(+)-ATPase) activity was also measured in the same membrane preparation. Both uptake and Ca2(+)-ATPase activity were inhibited by vanadate. Calcium activation of the uptake process was similar to that of the Ca2(+)-ATPase. Calcium uptake was prevented by calcium ionophore A23187, suggesting that the calcium transported into the vesicles remains diffusible. The ATP-dependent calcium uptake probably represents the transport of calcium into "inside-out" membrane vesicles by the Ca2(+)-ATPase mechanism that normally shifts calcium outward from the lens cytoplasm. The temperature dependence of the Ca2(+)-ATPase and the calcium uptake process was determined. Because lipid order can influence Ca2(+)-ATPase function, we attempted to correlate calcium transport with the physical state of the membrane lipids. Infrared spectroscopy was used to determine the temperature dependence of the CH2 symmetric stretching frequency (an order parameter) in the lipids. A similarity was noted between the temperature-dependence curves for lipid order, Ca2(+)-ATPase, and calcium uptake rate. Entropy, enthalpy, and transition temperature calculated for the Ca2(+)-ATPase and calcium uptake process were in the same range as those parameters calculated for the lipid-phase transition.

Adenosine Triphosphate↗
PubMed1991

Prostaglandin E2 effects on corneal endothelial cyclic adenosine monophosphate synthesis and cell shape are mediated by a receptor of the EP2 subtype.

Corneal endothelial cells synthesize prostaglandin E2 (PGE2), and this synthesis is necessary for the maintenance of the normal polygonal shape of these cells. A series of experiments was done to examine the receptor-effector mechanism responsible for PGE2-mediated effects on cultured rabbit corneal endothelium. When challenged with exogenous PGE2, endothelial cells synthesized cyclic adenosine monophosphate (AMP) in a dose-dependent manner, and this synthesis was not antagonized by AH6809. The synthetic agonist 11-deoxy-PGE1, but not sulprostone, stimulated increased cyclic AMP synthesis. The pharmacologic profile of the endothelial PGE2 receptor is therefore consistent with that of an EP2 receptor linked to activation of adenylate cyclase. The prostaglandin agonists were also tested for their ability to prevent cellular elongation in response to indomethacin. The PGE2, 11-deoxy-PGE1, and 16,16-dimethyl PGE1 prevented elongation, but sulprostone and PGF2 alpha did not. The authors conclude that rabbit corneal endothelium in culture expresses a specific PG receptor of the EP2 subtype which is coupled to cyclic AMP synthesis and is involved in the regulation of cell shape.

Animals↗
PubMed1990

Further investigation into the ocular effects of prostaglandin E2, leukotriene B4 and formyl-methionyl-leucyl phenylalanine.

The effect of indomethacin and dexamethasone on the inflammatory response to intraocularly injected prostaglandin E2 (PGE2), leukotriene B4 (LTB4), and formyl-methionyl-leucyl phenylalanine (FMLP) has been examined in rabbits. PGE2, in nanogram quantities, dose-dependently increased intraocular pressure and protein concentration in the aqueous humor. These responses were not affected by an anti-inflammatory dose of dexamethasone, but indomethacin had a small insignificant inhibitory effect. LTB4 and FMLP caused substantial leukocyte accumulation in the anterior chamber and did not disrupt the blood-aqueous barrier. Neither indomethacin nor dexamethasone had any effect on the leukocyte response to LTB4 However, dexamethasone significantly reduced the FMLP-induced leukocyte response. These results suggest that PGE2 and LTB4 do not elicit a further release of AA metabolites and that their actions are direct. However, the chemofactic response of polymorphonuclear leukocytes to FMLP appears to be mediated by lipoxygenase products.

Animals↗