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Biomedical subjects

A D Watson

Publications and source records attributed to A D Watson.

At least 19 recordsLinked to original sources
PubMed2001

Dimeric W3SO3 cluster complexes: synthesis, characterization, and potential applications as X-ray contrast agents.

Our continued research on the use of heavy metal cluster complexes as a new class of X-ray contrast agents in medical diagnostic imaging is described. A series of 2:3 cluster-ligand complexes, [(W(IV)3SO3)2L3]4- (L = linear polyaminopolycarboxylate ligands), were isolated from the reaction of aqua ion [W(IV)3SO3(H2O)9]4- (prepared in large quantities through an improved literature process) with respective ligands in refluxing DMF. The salts of [(W(IV)3SO3)2L3]4- complex anions were fully characterized using routine techniques such as elemental analysis, MS, HPLC, UV-vis, IR, and NMR. The solid structures of two complex anions, [(W(IV)3SO3)2(PDTA)3]4- and [(W(IV)3SO3)2(HO-PDTA)3]4-, were determined by X-ray crystallography. They are the first examples wherein two W(IV)3SO3 clusters are complexed and linked by three ligands that contain two terminal iminodiacetate (bis-IDA) groups. Complexation of the unstable aqua ion [W(IV)3SO3(H2O)9]4- with ligands has imparted desired biological compatibility to the tungsten metal cluster. These complexes are stable and highly soluble in H2O. The potential utility of such tungsten cluster complexes as X-ray contrast agents was evaluated in both in vitro and in vivo animal studies. In addition, the syntheses of several new linear polyaminopolycarboxylate ligands used in this study are reported.

Animals↗
PubMed2001

Systemic antibacterial drug use in dogs in Australia.

A survey of veterinarians' use of antibacterial drugs was conducted by distributing a questionnaire to Australian practitioners. Respondents were asked to indicate their general patterns of use of various systemic antibacterial drugs and drug combinations in dogs and their approach to certain specified clinical disorders. Overall, antibacterials of the beta-lactam type (penicillins and cephalosporins) were most commonly used. Other antibacterials with substantial use were doxycycline, sulphonamide-trimethoprim, metronidazole, fluoroquinolones and clindamycin. Drug selection for different disorders was generally appropriate when compared with recommendations in recent texts, although inappropriate use was evident in some circumstances.

Animals↗
PubMed2001

Small bowel motility and colonic transit are altered in dogs with moderate renal failure.

Although gastrointestinal complications are common in patients with renal disease, the effects of renal dysfunction on bowel motility and gut transit times are not well known. We assessed gastrointestinal electromyographic activity, gastric emptying rate, orocolonic transit time, oroanal transit time, and xylose absorption before and after surgically inducing a 66% decrease in glomerular filtration rate in dogs. Moderate renal failure induced no gross or microscopic gastrointestinal lesions but caused a 16-42% increase in gastrointestinal motility indexes. We found a 24% decrease in the propagation velocity of the myoelectrical migrating complex in the duodenojejunal segment, a 30% decrease in phase I duration in duodenal and jejunal regions, a 20% increase in the total irregular electrical activity of the small intestine, and a 22% increase in duration of the meal response in the duodenum and jejunum. Renal failure did not change xylose absorption, gastric emptying rate, and orocolonic transit time but decreased colonic transit time by 38%. The mean weight of feces was increased. These results indicate that moderate renal failure alters duodenojejunal motility and decreases colonic transit time.

Animals↗
PubMed2001

HDL and the inflammatory response induced by LDL-derived oxidized phospholipids.

Oxidation of low density lipoprotein (LDL) phospholipids containing arachidonic acid at the sn-2 position occurs when a critical concentration of "seeding molecules" derived from the lipoxygenase pathway is reached in LDL. When this critical concentration is reached, the nonenzymatic oxidation of LDL phospholipids produces a series of biologically active, oxidized phospholipids that mediate the cellular events seen in the developing fatty streak. Normal high density lipoprotein (HDL) contains at least 4 enzymes as well as apolipoproteins that can prevent the formation of the LDL-derived oxidized phospholipids or inactivate them after they are formed. In the sense that normal HDL can prevent the formation of or inactivate these inflammatory LDL-derived oxidized phospholipids, normal HDL is anti-inflammatory. HDL from mice that are genetically predisposed to diet-induced atherosclerosis became proinflammatory when the mice are fed an atherogenic diet, injected with LDL-derived oxidized phospholipids, or infected with influenza A virus. Mice that were genetically engineered to be hyperlipidemic on a chow diet and patients with coronary atherosclerosis, despite normal lipid levels, also had proinflammatory HDL. It is proposed that LDL-derived oxidized phospholipids and HDL may be part of a system of nonspecific innate immunity and that the detection of proinflammatory HDL may be a useful marker of susceptibility to atherosclerosis.

Animals↗
PubMed2000

Ssn6-Tup1 interacts with class I histone deacetylases required for repression.

Ssn6-Tup1 regulates multiple genes in yeast, providing a paradigm for corepressor functions. Tup1 interacts directly with histones H3 and H4, and mutation of these histones synergistically compromises Ssn6-Tup1-mediated repression. In vitro, Tup1 interacts preferentially with underacetylated isoforms of H3 and H4, suggesting that histone acetylation may modulate Tup1 functions in vivo. Here we report that histone hyperacetylation caused by combined mutations in genes encoding the histone deacetylases (HDACs) Rpd3, Hos1, and Hos2 abolishes Ssn6-Tup1 repression. Unlike HDAC mutations that do not affect repression, this combination of mutations causes concomitant hyperacetylation of both H3 and H4. Strikingly, two of these class I HDACs interact physically with Ssn6-Tup1. These findings suggest that Ssn6-Tup1 actively recruits deacetylase activities to deacetylate adjacent nucleosomes and promote Tup1-histone interactions.

Acetylation↗
PubMed2000

Bioactive products of phospholipid oxidation: isolation, identification, measurement and activities.

There is considerable evidence to suggest that oxidation of LDL plays an important role in atherogenesis. Polyunsaturated fatty acids, a major oxidative target, are present as phospholipids in the outer core of the lipoprotein particle. Studies from several laboratories have shown an increase in the levels of phospholipid oxidation products in atherosclerotic lesions and of antibodies to oxidized phospholipids in mice and humans with lesions. Significantly, phospholipid oxidation products have been demonstrated (in vitro) to selectively activate processes in vascular wall cells that may contribute to atherogenesis. This review discusses activities, methods for isolation, identification and measurement of bioactive phospholipids. Past studies suggest that defined and relatively simple current technologies allow identification of bioactive phospholipid oxidation products and measurement of their levels in tissue.

Animals↗
PubMed2000

Effect of phenobarbitone on the low-dose dexamethasone suppression test and the urinary corticoid: creatinine ratio in dogs.

OBJECTIVES: To investigate potential effects of phenobarbitone on the low-dose dexamethasone suppression (LDDS) test and urinary corticoid to creatinine ratio in dogs in a controlled prospective study and in a clinical setting. ANIMALS: Ten crossbreed experimental dogs and 10 client-owned dogs of mixed breeds treated chronically with phenobarbitone to control seizures. PROCEDURES: Experimental dogs were allocated to treatment (6 mg/kg oral phenobarbitone, n = 6) and control (n = 4) groups. LDDS tests (dexamethasone 0.01 mg/kg intravenously, cortisol concentration determined at 0, 2, 4, 6 and 8 h) were conducted repeatedly over a 3-month period. Urinary corticoid to creatinine ratios were measured before LDDS tests. A single LDDS test was performed on 10 epileptic dogs. RESULTS: LDDS and urinary corticoid to creatinine ratios in dogs were not affected by treatment with phenobarbitone. CONCLUSIONS: Phenobarbitone does not interfere with LDDS testing regardless of dosage or treatment time. Urinary corticoid to creatinine ratios are also unaffected.

Adrenal Cortex Function Tests↗
PubMed2000

Effects of phenobarbitone on serum biochemical tests in dogs.

OBJECTIVES: To investigate effects of phenobarbitone on serum activities of alanine aminotransferase, alkaline phosphatase and gamma-glutamyl transferase and concentrations of bilirubin, albumin, cholesterol and total protein in dogs. ANIMALS: Ten crossbreed experimental dogs and 10 client-owned dogs of mixed breeds treated chronically with phenobarbitone to control seizures. PROCEDURES: Experimental dogs were allocated to treatment (6 mg/kg oral phenobarbitone, n = 6) and control (no treatment, n = 4) groups in which serum biochemical tests were performed at intervals during a 3-month period. Biochemical tests were performed once on the 10 epileptic dogs. RESULTS: Phenobarbitone caused increased serum alkaline phosphatase activity but did not affect gamma-glutamyl transferase activity or bilirubin, cholesterol, albumin and total protein concentrations. Phenobarbitone had minimal effect on alanine aminotransferase activity. CONCLUSIONS: Individual dogs treated with phenobarbitone may have small increases in serum alanine aminotransferase activity and variable increases in alkaline phosphatase activity but are unlikely to have alterations in gamma-glutamyl transferase activity or bilirubin, cholesterol, albumin or total protein concentrations.

Alanine Transaminase↗
PubMed2000

Determinants of bioactivity of oxidized phospholipids. Specific oxidized fatty acyl groups at the sn-2 position.

We previously described 3 bioactive oxidation products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (PAPC) containing oxovaleroyl (POVPC), glutaroyl (PGPC), and epoxyisoprostane (PEIPC) groups at the sn-2 position that were increased in minimally modified/oxidized low density lipoprotein (MM-LDL) and rabbit atherosclerotic lesions. We demonstrated specific and contrasting effects of POVPC and PGPC on leukocyte-endothelial interactions and described an effect of PEIPC on monocyte binding. The major purpose of the present study was to determine the effects of structural changes on the bioactivities of these 3 lipids. We demonstrate herein that the group at the sn-2 position determines the specific bioactivity and that the substitution of stearoyl for palmitoyl at the sn-1 position or ethanolamine for choline at the sn-3 position of the phospholipid did not alter bioactivity. Oxidized PAPC, oxidized 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine, and oxidized 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphorylethanolamine stimulated monocyte binding and inhibited lipopolysaccharide-induced expression of the neutrophil-binding molecule E-selectin. Furthermore, all oxovaleroyl phospholipids but not the glutaroyl phospholipids induced monocyte binding without an increase in vascular cell adhesion molecule-1 (VCAM-1) expression and inhibited lipopolysaccharide-induced E-selectin expression. In contrast, glutaroyl phospholipids but not oxovaleroyl phospholipids stimulated E-selectin and VCAM-1 expression. We further demonstrate that all parts of the phospholipid molecules are required for these bioactivities. Hydrolysis with phospholipase (PL) A(1), PLA(2), and PLC strongly reduced the bioactivities of POVPC, PGPC, and mixed isomers of PEIPC. PLD had a smaller but still significant effect. The effects of POVPC and PEIPC could be abolished by sodium borohydride treatment, indicating the importance of the reducible groups (carbonyl and epoxide) in these molecules. In summary, these studies identify 6 new bioactive, oxidized phospholipids that are increased in MM-LDL and, where measured, in atherosclerotic lesions. They thus suggest that a family of phospholipid oxidation products containing oxovaleroyl, glutaroyl, and epoxyisoprostane at the sn-2 position play an important role in the regulation of leukocyte-endothelial interactions, bioactivity being in part controlled by several types of phospholipid hydrolases.

Animals↗
PubMed2000

Comparison of results of retrocalcaneal decompression for retrocalcaneal bursitis and insertional achilles tendinosis with calcific spur.

Sixteen feet with retrocalcaneal bursitis (RB) and twenty-two feet with calcific Achilles insertional tendinosis (IAT-CS) underwent retrocalcaneal decompression after failure of nonoperative treatment. Follow-up evaluation at least two years after surgery included AOFAS Ankle-Hindfoot subscale scores, satisfaction, time until maximum symptomatic improvement, and radiographs. Statistically significant differences between the groups include the following: IAT-CS patients were older, required nearly twice the time to reach maximum symptomatic improvement, had lower satisfaction rates, had a lower pain score, and more frequently had shoewear restrictions. Radiographic recurrence did not correlate with outcome or symptomatic recurrence.

Achilles Tendon↗
PubMed2000

Regulation of insulin-like growth factor-binding protein-3 ternary complex in feline diabetes mellitus.

The 140 kDa ternary complex of insulin-like growth factor-binding protein-3 (IGFBP-3), IGFs and an acid-labile subunit (ALS) has previously been shown to be decreased in diabetes mellitus in humans and rats. We have studied IGF-I levels and ternary complex formation in normal and diabetic cats. Total IGF-I concentrations, measured by RIA using des(1-3)-IGF-I as tracer were (+/-s.e.m.) 54+/-13 nmol/l in eight normal and 227+/-57 nmol/l in eight diabetic cats (P<0.01). The size-distribution of IGFBPs in the cat circulation was determined by incubation with (125)I-IGF-II and Superose 12 chromatography. In normal animals 26+/-2% of the (125)I-IGF-II were in a 140 kDa form compared with 48+/-5% in diabetic cats (P<0.01). When samples from normal and diabetic animals were co-incubated 52+/-3% were at 140 kDa. A similar shift was seen when normal cat and normal human serum were co-incubated. A 2-fold increase in the 140 kDa form in diabetic cats was confirmed first by size-fractionating samples and then performing a ligand-binding assay with (125)I-IGF-I or -II and charcoal separation. SDS-PAGE and Western ligand blotting demonstrated a 45 kDa doublet (presumably IGFBP-3) and 30-35 kDa forms. There were no apparent differences between normal and diabetic profiles on SDS-PAGE, suggesting that a proportion of IGFBP-3 which circulates 'free' in normal cats forms a ternary complex in the diabetic circulation. We conclude that (i) in contrast to humans and rats, ALS is the limiting factor for ternary complex formation in normal cats, (ii) ALS concentrations increase in feline diabetes mellitus and, by promoting ternary complex formation, this leads to an increase in total IGF-I concentrations, and (iii) total IGF-I concentrations may not be reliable in the diagnosis of acromegaly in diabetic cats.

Acromegaly↗
PubMed2000

Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: steps 2 and 3.

Treatment of human artery wall cells with apolipoprotein A-I (apoA-I), but not apoA-II, with an apoA-I peptide mimetic, or with high density lipoprotein (HDL), or paraoxonase, rendered the cells unable to oxidize low density lipoprotein (LDL). Human aortic wall cells were found to contain 12-lipoxygenase (12-LO) protein. Transfection of the cells with antisense to 12-LO (but not sense) eliminated the 12-LO protein and prevented LDL-induced monocyte chemotactic activity. Addition of 13(S)-hydroperoxyoctadecadienoic acid [13(S)-HPODE] and 15(S)-hydroperoxyeicosatetraenoic acid [15(S)-HPETE] dramatically enhanced the nonenzymatic oxidation of both 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PAPC) and cholesteryl linoleate. On a molar basis 13(S)-HPODE and 15(S)-HPETE were approximately two orders of magnitude greater in potency than hydrogen peroxide in causing the formation of biologically active oxidized phospholipids (m/z 594, 610, and 828) from PAPC. Purified paraoxonase inhibited the biologic activity of these oxidized phospholipids. HDL from 10 of 10 normolipidemic patients with coronary artery disease, who were neither diabetic nor receiving hypolipidemic medications, failed to inhibit LDL oxidation by artery wall cells and failed to inhibit the biologic activity of oxidized PAPC, whereas HDL from 10 of 10 age- and sex-matched control subjects did. We conclude that a) mildly oxidized LDL is formed in three steps, one of which involves 12-LO and each of which can be inhibited by normal HDL, and b) HDL from at least some coronary artery disease patients with normal blood lipid levels is defective both in its ability to prevent LDL oxidation by artery wall cells and in its ability to inhibit the biologic activity of oxidized PAPC.

Aorta↗
PubMed1999

Structural identification of a novel pro-inflammatory epoxyisoprostane phospholipid in mildly oxidized low density lipoprotein.

One of the earliest steps in the development of the atherosclerotic lesion is the accumulation of monocyte/macrophages within the vessel wall. Oxidized lipids present in minimally modified-low density lipoproteins (MM-LDL) contribute to this process by activating endothelial cells to express monocyte-specific adhesion molecules and chemoattractant factors. A major focus of our group has been the isolation and characterization of the biologically active oxidized lipids in MM-LDL. We have previously characterized three oxidized phospholipids present in MM-LDL, atherosclerotic lesions of fat fed rabbits, and autoxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (Ox-PAPC) that induced human aortic endothelial cells to adhere human monocytes in vitro. We have used sequential normal and reverse phase-high performance liquid chromatography to isolate various isomers of an oxidized phospholipid from autoxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine. The fatty acid in the sn-2 position of this biologically active isomer and its dehydration product was released by phospholipase A(2) and characterized. Hydrogenation with platinum(IV) oxide/hydrogen suggested a cyclic moiety, and reduction with sodium borohydride suggested two reducible oxygen-containing groups in the molecule. The fragmentation pattern produced by electrospray ionization-collision induced dissociation-tandem mass spectrometry was consistent with a molecule resembling an E-ring prostaglandin with an epoxide at the 5,6 position. The structure of this lipid was confirmed by proton nuclear magnetic resonance spectroscopy analysis of the free fatty acid isolated from the dehydration product of m/z 828.5. Based on these studies, we arrived at the structure of the biologically active oxidized phospholipids as 1-palmitoyl-2-(5, 6-epoxyisoprostane E(2))-sn-glycero-3-phosphocholine. The identification of this molecule adds epoxyisoprostanes to the growing list of biologically active isoprostanes.

Arachidonic Acids↗
PubMed1999

Plasma cortisol concentrations following cortisone infusion in dogs before and after treatment with cortisone acetate.

OBJECTIVE: To evaluate effects of iatrogenic hyperadrenocorticism on plasma cortisol concentrations produced by an infusion of hydrocortisone in dogs. PROCEDURE: Plasma cortisol concentrations were measured regularly during a 6 h infusion of hydrocortisone sodium succinate at two dose rates. The infusions were performed before and after treatment for 30 d with oral cortisone acetate at 10 mg/kg/24 h, divided thrice daily. Adrenal activity during the experimental period was assessed by weekly ACTH stimulation tests. RESULTS: Both infusion rates produced lower plasma cortisol concentrations after treatment for 30 d with cortisone. CONCLUSION: Prior exposure to high concentrations of glucocorticoids may result in accelerated metabolism of glucocorticoids administered subsequently. This may necessitate increased dosages when using glucocorticoids to support inadequate adrenal function.

Administration, Oral↗