Biomedical subjects

K A Robinson

Publications and source records attributed to K A Robinson.

104 records · Page 6Linked to original sources

PubMed1990

Growth factor binding and bioactivity in human kidney epithelial cell cultures.

Insulinlike growth factors (IGF) and epidermal growth factor (EGF) are produced in renal tissue, as are specific receptors for these hormones. To evaluate the significance of these observations to regulation of renal tubular cell proliferation, we have examined the interaction of IGF and EGF with cultured human proximal tubular epithelial cells (HPT). HPT cells showed specific binding of IGF-1, insulin, and EGF. IGF-1 binding was inhibited by antibody to the type 1 IGF receptor (alpha-IR3). Insulin receptors and type 1 IGF receptors were identified by bifunctional cross-linking. IGF-1, insulin, and EGF stimulated [3H]thymidine incorporation by 77, 73, and 87%, respectively. Half maximal stimulation by IGF-1, insulin, and EGF were produced with 4 X 10(-9) M, 2.5 X 10(-8) M, and 8 X 10(-10) M concentrations of these hormones. Alpha-IR3 inhibited stimulation of thymidine incorporation by IGF-1 and insulin but had no effect in EGF-stimulated thymidine incorporation. EGF and high concentrations of insulin both stimulated cell proliferation by 83 and 79%, respectively. These data are consistent with regulation of tubular epithelial proliferation by IGF-1, insulin, and EGF and suggest that the mitogenic activity of both insulin and IGF-1 is mediated by the type 1 IGF receptor.

Cells, Cultured↗

PubMed1990

Efficacy of ampicillin versus trimethoprim-sulfamethoxazole in a mouse model of lethal enterococcal peritonitis.

Lethal enterococcal peritonitis in mice was used to compare trimethoprim-sulfamethoxazole (TMP-SMX) therapy with ampicillin therapy. Peritoneal fluid showed a 10(3)-CFU decrease in enterococci with ampicillin compared with TMP-SMX. Mortality of the untreated mice was 100%, compared with 40% for ampicillin and 95% for TMP-SMX, despite adequately measured levels in serum and peritoneal fluid.

Ampicillin↗

PubMed1990

Metabolic effects of exposure to hypoxia plus cold at rest and during exercise in humans.

To determine effects on metabolic responses, subjects were exposed to four environmental conditions for 90 min at rest followed by 30 min of exercise: breathing room air with an ambient temperature of 25 degrees C (NN); breathing room air with an ambient temperature of 8 degrees C (NC); hypoxia (induced by breathing 12% O2 in N2) with a neutral temperature (HN); and hypoxia in the cold (HC). Hypoxia increased heart rate (HR), systolic blood pressure (SBP), pulmonary ventilation (VE), respiratory exchange ratio (R), blood lactate, and perceived exertion during exercise while depressing rectal temperature (Tre) and O2 uptake (VO2). Cold exposure elevated SBP, diastolic blood pressure (DBP), VE, VO2, blood glucose, and blood glycerol but decreased HR, Tre, and R. Shivering and DBP were higher and Tre was lower in HC compared with NC. HR, SBP, VE, R, and lactate tended to be higher in HC compared with NC, whereas VO2 and blood glycerol tended to be depressed. These results suggest that cold exposure during hypoxia results in an increased reliance on shivering for thermogenesis at rest whereas, during exercise, heat loss is accelerated.

Adult↗

PubMed1990

Trapidil in preventing restenosis after balloon angioplasty in the atherosclerotic rabbit.

Trapidil (triazolopyrimidine) possesses activity against platelet-derived growth factor-induced cellular proliferation in vitro and intimal proliferation in vivo. The objective of this study was to determine if trapidil could prevent restenosis in experimentally induced atherosclerotic rabbits. New Zealand White rabbits with preexisting iliac arterial lesions induced by balloon deendothelialization underwent balloon angioplasty. Arteriography was performed before, immediately after, and 4 weeks after the balloon dilatation. Tissue sections of the dilated arterial segment were also analyzed morphometrically. Seventeen rabbits were randomized to two groups: a control group (n = 8) and a trapidil-treated group (n = 9). The treatment group received 30 mg/kg s.c. trapidil twice daily. The angiographic luminal diameters before and after dilatation were similar. At the 4-week restudy, there was a significant preservation of luminal diameter in the trapidil group compared with the control group (1.27 +/- 0.20 vs. 0.94 +/- 0.48 mm, respectively; p less than 0.005). When luminal diameters immediately after dilatation were compared with diameters at the 4-week restudy (i.e., when the degree of restenosis was assessed), there was a greater luminal diameter reduction in the control group than in the trapidil group (0.70 +/- 0.44 vs. 0.30 +/- 0.25 mm, respectively; p = 0.005). By morphometric analyses, the luminal areas were also greater in the trapidil group than the control group (0.80 +/- 0.25 vs. 0.57 +/- 0.33 mm2, respectively; p = 0.03). Intimal thickness was significantly less for the trapidil group than for the control group (0.33 +/- 0.15 vs. 0.44 +/- 0.15 mm, respectively; p = 0.01), as well as medial thickness (0.09 +/- 0.03 vs. 0.11 +/- 0.03 mm, respectively; p = 0.01). In this study, trapidil significantly increased the luminal area and reduced the intimal thickness in the atherosclerotic rabbit iliac artery after balloon angioplasty.

Angioplasty, Balloon↗

PubMed1990

Intracoronary stenting during percutaneous transluminal coronary angioplasty.

A flexible, balloon-mounted, coil stent was developed to address the problems of acute closure and long-term restenosis, which currently limit the safety and efficacy of percutaneous transluminal coronary angioplasty. The device is made of 0.006-in. stainless steel suture material and is mounted on balloons, 2.5-4.5 mm in diameter, for use in the coronary circulation. Results of studies in canine coronary arteries have demonstrated long-term patency and stability, and studies in the atherosclerotic arteries of rabbits have suggested late results with stenting that might be superior to those obtained with balloon angioplasty alone. Initial clinical studies have focused on the use of the device as a "bridge" to surgery if closure occurs. The stent appears to have been successful in this application. A phase 2 study is now examining the stent as definitive therapy for acute closure in certain anatomic subsets of patients. Information on long-term patency is pending. If this is favorable, the device will be studied to see if it reduces the incidence of restenosis in the subset of patients in whom balloon dilatation alone fails to produce an optimal hemodynamic result.

Angioplasty, Balloon, Coronary↗

PubMed1989

Marine lipid concentrate and atherosclerosis in the rabbit model.

Twenty-seven New Zealand white rabbits underwent balloon de-endothelialization of the aorta and iliac arteries while consuming a 2% cholesterol, 10% peanut oil rabbit chow. Ten of these rabbits were fed 1 ml of concentrated marine fish lipid (MaxEpaTm) daily. Six weeks after de-endothelialization, angiography of the treated arteries was performed and histologic cross-sections of the terminal aorta were measured with a planimeter. Iliac artery luminal diameters were also measured at consecutive 3-mm divisions from the aortic bifurcation and found to have a mean lumen diameter of 1.60 +/- 0.08 mm in the marine lipid-supplemented group (M) and 1.38 +/- 0.12 mm in the control group (C) (P less than 0.001). Analysis of variance on individual segmental diameters confirmed this difference. However, neither the angiographic diameters nor histologic, cross-sectional, luminal areas of the terminal aorta were different between groups. Instead, the mean cross-sectional area of the terminal aortic wall was significantly greater in the marine lipid-fed group (4.4 +/- 1.2 mm2 in M and 3.1 +/- 0.6 mm2 in C, P less than 0.01). In addition, the vessel wall area showed a positive correlation with red blood cell (RBC) incorporation of docosahexaenoic acid (r = 0.82, P less than 0.005) in both groups. In the M group, RBC eicosapentaenoic acid and docosahexaenoic acids increased 100% and 650%, respectively, over baseline.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Insulin-stimulated phosphorylation of a 195K protein from muscle and liver in the presence of poly-L-lysine.

Substrates of the insulin receptor tyrosine kinase have not been identified in skeletal muscle, a major target organ of insulin action. We observed the insulin-stimulated phosphorylation of a 195K protein (pp195) in extracts prepared from rat skeletal muscle and liver. pp195 copurifies with the insulin receptor on wheat germ agglutinin affinity chromatography. pp195 is not related to the insulin receptor, as assessed by lack of recognition by antinsulin receptor antibodies and by phosphopeptide mapping. Reduction of sulfhydryl bonds does not affect its apparent mol wt. Phosphorylation of pp195 has an absolute requirement in vitro for Mn2+ or Mg2+ and for certain basic poly-amino acids, i.e. poly-L-lysine or poly-L-ornithine. In the presence of 1 microM poly-L-lysine insulin stimulates pp195 phosphorylation in a dose-dependent manner (k0.5, approximately 5 x 10(-10) M; maximum approximately 10(-8) M insulin); pp195 phosphorylation by insulin-like growth factor-I requires about 100-fold higher doses. By phosphoamino acid analysis, pp195 is predominantly phosphorylated on tyrosine, and it is recognized by antiphosphotyrosine antibodies. Insulin receptors isolated from rat muscles 5 min after insulin injection induce about 2-fold greater phosphorylation of pp195 in vitro than receptors isolated from saline-injected controls. Streptozotocin-induced diabetes results in marked diminution of insulin-stimulated pp195 phosphorylation in extracts of muscle and liver (approximately 50% when normalized to protein content of wheat germ agglutinin eluates or approximately 80% reduction when normalized to equal receptor number). The defect is reversible by insulin therapy in vivo.

Animals↗

PubMed1989

Antibody to type I insulinlike growth factor receptor inhibits growth of Wilms' tumor in culture and in athymic mice.

The role of the type I insulinlike growth factor (IGF) receptor in regulating growth of Wilms' tumor (WT) was evaluated by examining the effect of antibody-mediated inhibition of this receptor on tumor growth in cell cultures and as heterotransplants in athymic mice. An antibody to the human type I IGF receptor (alpha IR-3) inhibited 125I-IGF-1 binding and prevented stimulation of thymidine incorporation by IGF-1 in vitro. Intraperitoneal administration of alpha IR-3 to nude mice bearing WT heterotransplants prevented tumor growth for 4 weeks and resulted in partial regression of established tumors. These data indicate the importance of IGF action in control of WT growth in vivo, and suggest potential therapeutic application using antigrowth factor receptor antibodies to block growth factor action.

Animals↗

PubMed1989

Correlated microscopic observations of arterial responses to intravascular stenting.

Percutaneous catheter implantation of intravascular stent prostheses has emerged as a novel clinical adjunct to balloon angioplasty in the treatment of obstructive atherosclerotic vascular disease. We have examined the cellular and subcellular responses to stenting in the coronary arteries of the dog and pig (both normal and atherosclerotic), and in the iliac arteries and aorta of the atherosclerotic rabbit, using scanning electron, transmission electron, and light microscopies. Stenting in these models resulted in a thrombotic reaction ranging from mild to severe, depending on species and antithrombotic therapy. Subsequent organization of thrombotic material with hyperplasia of smooth muscle and inflammatory cells, luminal recovering with endothelial or pseudoendothelial cells, and atrophy of the tunica media led to incorporation of the prosthesis into the arterial wall. Endothelial or pseudoendothelial cells were observed adherent to the prosthesis as early as one day after placement, and regeneration of a confluent periluminal cell layer occurred within 2 to 4 weeks. Persistent ultrastructural abnormalities of the periluminal cell layer were seen as late as 2 years after stenting, but the intimal hyperplastic response appeared limited.

Animals↗

PubMed1988

Phenylarsine oxide and denervation effects on hormone-stimulated glucose transport.

Insulin and insulin-like growth factor I (IGF-I) stimulate glucose transport in skeletal muscle through separate receptors. The proximal postreceptor events in coupling insulin and IGF-I receptors to glucose transport have been suggested to differ. Denervation of skeletal muscle produces a postreceptor insulin resistance presumably at an early step in the signaling cascade. We examined the effects of denervation and phenylarsine oxide (PAO), an agent believed to block insulin action on transport at a postreceptor step, on insulin and IGF-I stimulated 2-deoxy-D-glucose transport in isolated solei. Denervation (24 h) produced severe IGF-I resistance without affecting IGF-I receptor number or affinity. PAO inhibited insulin and IGF-I stimulation of transport in control muscles by approximately 90 and approximately 70%, respectively. In denervated muscle PAO inhibited transport stimulation by both hormones less than in controls. Conclusions are that 1) skeletal muscle insulin and IGF-I receptors signal transport mainly through a PAO-sensitive mechanism, but IGF-I's action involves a larger PAO-resistant component; 2) the denervation-induced postreceptor resistance of glucose transport to both hormones involves primarily the PAO-sensitive pathway.

Adenosine Triphosphate↗

PubMed1988

Intra-arterial stenting in the atherosclerotic rabbit.

The major problem associated with percutaneous transluminal coronary angioplasty is recurrence of the stenotic lesion. Balloon catheter-mounted intracoronary stent devices may reduce restenosis by improving luminal morphology and flow characteristics. This study assessed the effects of a stainless steel wire, interdigitating coil stent on restenosis in the atherosclerotic rabbit model. Fifteen cholesterol-fed rabbits with preexisting iliac arterial lesions induced by balloon deendothelialization were instrumented in one iliac artery with a 2.0-mm diameter stent after balloon dilatation; the contralateral iliac lesion was treated by dilatation only to serve as a control. The animals were given heparin with aspirin (60 mg) and aspirin every 3rd day until death. Arteriography was repeated 4 weeks after stenting, just before death. Tissue sections from stented and control arterial segments were analyzed morphometrically. Stented arteries had a significantly larger luminal diameter at restudy, whether measured by arteriography (1.38 +/- 0.19 vs. 0.94 +/- 0.35 mm, p less than 0.01) or from tissue sections (1.26 +/- 0.18 vs. 0.81 +/- 0.30 mm, p = 0.0001). Wall thickness of the stented segment was slightly, but significantly, less than the control segment (436 +/- 143 vs. 532 +/- 221 microns, p less than 0.05). Scanning electron microscopy of five stented atherosclerotic rabbit aortas revealed regeneration of a nonthrombogenic, confluent, flow-directed endothelium by 4 weeks after placement. Intra-arterial stenting may be of benefit in the prevention of restenosis by the preservation of a larger functional lumen and by a decrease in the neointimal hyperplastic response to arterial injury.

Angiography↗

PubMed1987

Early and late results of intracoronary arterial stenting after coronary angioplasty in dogs.

Intimal dissection with acute closure represents the major complication associated with percutaneous transluminal coronary angioplasty (PTCA). Intracoronary stent devices offer the possibility of treatment for this sequela. We developed a balloon catheter-mounted, flexible coil stent for use in such cases. To determine the utility of this device and its immediate and long-term influence on arterial patency, 39 mongrel dogs had the stent placed after PTCA of the left circumflex or left anterior descending coronary arteries. Thirteen animals were treated before and after the procedure with warfarin. In this group there were three early deaths associated with stent thrombosis. Twenty-six animals were subsequently treated before and after with aspirin and dipyridamole. There were no early thrombotic events associated with stent placement in these animals. Late arteriographic examination revealed patent vessels in all dogs. Diameter stenosis for warfarin-treated dogs was 8 +/- 5% (mean +/- SD) at 2 months (n = 9), 6 +/- 4% at 6 months (n = 5), and 11 +/- 7% at 12 months (n = 3). Diameter stenosis for aspirin/dipyridamole-treated dogs was 9 +/- 3% at 2 months (n = 8), 8 +/- 5% at 6 months (n = 12), and 5% at 12 months (n = 1). Light and scanning electron microscopic analyses of stented arteries demonstrated incorporation of the stent wires into the arterial wall. Early findings included mild thrombosis localized to areas of wire entrenchment followed by rapid regrowth of endothelial and/or pseudoendothelial cells over trenches, exposed wires, and elastica.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiography↗

PubMedDate not supplied

Contrast echocardiographic quantification of regional myocardial perfusion: validation with an isolated rabbit heart model.

Quantification of regional myocardial tissue blood flow (RMBF) based on contrast echocardiography has yet to be achieved. This study validated our recently proposed algorithm for quantification of RMBF with colored microspheres. Experiments were carried out in an isolated rabbit heart preparation (n = 11). Aortic root injections of perfluoropropane-filled albumin microsphere solution (FS069) and colored microspheres were performed at five levels of coronary flow achieved by altering perfusion pressure. During each injection of contrast material, consecutive end-diastolic images of the heart and an extracardiac reference chamber were acquired with a 7.5 MHz transducer and digitized. Time-intensity curves from the reference chamber and myocardial regions of interest, corresponding to the anatomic segments used for colored microsphere analysis, were analyzed for RMBF. Blood flow was calculated as the intravascular volume fraction (ratio of areas under myocardial and reference curves) divided by mean transit time (deconvolution of impulse response) and compared with those obtained with colored microspheres. Injections of FS069 resulted in highly reproducible enhancement of myocardial contrast. Analysis of time-intensity curves provided consistent measurements of RMBF (r = 0.91), which correlated highly with microsphere data (r = 0.84). The use of this new algorithm allows accurate quantification of RMBF in the isolated heart model. Further validation of this approach in an animal model with peripheral intravenous injections of contrast material will allow noninvasive clinical measurements of RMBF.

Albumins↗

PubMedDate not supplied

Echocardiographic contrast agents and left ventricular contractility: evaluation using an isolated rabbit heart model.

The effects of Albunex (Molecular Biosystems, Inc., San Diego, Calif.) and a second generation contrast agent, FS069, on left ventricular (LV) contractility were evaluated using an isolated rabbit heart model under constant loading conditions and heart rate. Contrast injections (2 ml total volume) were performed in two separate protocols (N1 = 6, N2 = 6). In protocol 1, various doses of Albunex (0.1 to 2.0 ml in saline solution) were used, and paired control injections of a matched dose of 5% solution of human albumin in saline solution were administered. In protocol 2, LV contractility was assessed during injections of the following solutions: (1) 1:250 suspension of FS069 in saline solution, which caused optimal myocardial contrast enhancement; (2) a 1:25 suspension of FS069; (3) a 1:25 suspension of FS069 prefiltered using an 8 microns pore filter; and (4) 2 ml saline solution as a control. Instantaneous LV pressure was analyzed for variations in peak systolic pressure (peak P) and maximum pressure derivative (peak P'), both indices of LV contractility under conditions of fixed heart rate and chamber volume. Albumin alone caused a transient, dose-dependent depression of LV contractility, reflected by decreases in both peak P and peak P' values. These decreases presumably were caused by the decreasing availability of ionized calcium as a result of calcium binding. No further decrease in contractility was noted when Albunex microspheres were present in the solution. Saline injections caused a transient minor increase in LV contractility, reflected by increases of 4.5% +/- 1.1% and 10.6% +/- 3.8% in peak P and peak P' values, respectively. These levels returned to baseline levels within 2 minutes. A similar response was observed when a 1:250 suspension of FS069 was used. The 1:25 suspension of FS069 caused a bimodal response, with initial rises in peak P and peak P' levels (5.2% +/- 3.6% and 12.8% +/- 6.5%, respectively), followed by minor reductions in contractility (2.0% +/- 2.4% and 1.7% +/- 2.1%, respectively). The latter decrease in contractility caused by the 1:25 suspension of FS069 was eliminated by filtering. The isolated rabbit heart model is a highly sensitive tool that allows accurate and direct assessment of possible adverse effects of intravascular contrast agents on LV contractility. Using this model, we showed that neither Albunex microspheres nor FS069 microspheres impaired myocardial contractility.

Albumins↗