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Biomedical subjects

R McArthur

Publications and source records attributed to R McArthur.

At least 19 recordsLinked to original sources
PubMed1997

Phenylimidazolidin-2-one derivatives as selective 5-HT3 receptor antagonists and refinement of the pharmacophore model for 5-HT3 receptor binding.

A possible bioisosterism between the benzamido and the phenylimidazolidin-2-one moieties has been suggested on the basis of the similarity between the molecular electrostatic potential (MEP) of metoclopramide, a D2 receptor antagonist with weak 5-HT3 receptor antagonist properties, and zetidoline, a D2 receptor antagonist. Starting from this premise, a series of phenylimidazolidin-2-one derivatives bearing a basic azabicycloalkyl or an imidazolylalkyl moiety were synthesized and evaluated for 5-HT3 receptor radioligand binding affinity ([3H]-GR 43,694). In vitro 5-HT3 receptor antagonist activity was tested in the guinea pig ileum assay (GPI). A number of high-affinity ligands were shown to be potent 5-HT3 receptor antagonists in vivo as determined by inhibition of the Bezold--Jarisch reflex in the anesthetized rat. In general, the imidazolylalkyl derivatives were found to be more active than azabicycloalkyls. 1-(3,5-Dichlorophenyl)-3-[(5-methyl-1H-imidazol-4-yl)methyl]imidazoli din-2-one (58), in particular, displayed very high affinity for the 5-HT3 receptor (Ki of 0.038 nM) with a Kb of 5.62 nM in the GPI assay, being more potent than the reference compounds (ondansetron, tropisetron, granisetron, and BRL 46,470) tested. 58 showed an ID50 comparable to that of ondansetron (2.2 micrograms/kg i.v.) in the Bezold--Jarisch reflex. A molecular modeling study based on this structurally novel series of compounds allowed the refinement of previously reported 5-HT3 receptor antagonist pharmacophore models.

Animals↗
PubMed1996

Characterization of the reductase domain of rat neuronal nitric oxide synthase generated in the methylotrophic yeast Pichia pastoris. Calmodulin response is complete within the reductase domain itself.

Rat neuronal NO synthase (nNOS) is comprised of a flavin-containing reductase domain and a heme-containing oxygenase domain. Calmodulin binding to nNOS increases the rate of electron transfer from NADPH into its flavins, triggers electron transfer from flavins to the heme, activates NO synthesis, and increases reduction of artificial electron acceptors such as cytochrome c. To investigate what role the reductase domain plays in calmodulin's activation of these functions, we overexpressed a form of the nNOS reductase domain (amino acids 724-1429) in the yeast Pichia pastoris that for the first time exhibits a complete calmodulin response. The reductase domain was purified by 2',5'-ADP affinity chromatography yielding 25 mg of pure protein per liter of culture. It contained 1 FAD and 0.8 FMN per molecule. Most of the protein as isolated contained an air-stable flavin semiquinone radical that was sensitive to FeCN6 oxidation. Anaerobic titration of the FeCN6-oxidized reductase domain with NADPH indicated the flavin semiquinone re-formed after addition of 1-electron equivalent and the flavins could accept up to 3 electrons from NADPH. Calmodulin binding to the recombinant reductase protein increased its rate of NADPH-dependent flavin reduction and its rate of electron transfer to cytochrome c, FeCN6, or dichlorophenolindophenol to fully match the rate increases achieved when calmodulin bound to native full-length nNOS. Calmodulin's activation of the reductase protein was associated with an increase in domain tryptophan and flavin fluorescence. We conclude that many of calmodulin's actions on native nNOS can be fully accounted for through its interaction with the nNOS reductase domain itself.

Animals↗
PubMed1995

Effect on plasma lipids of interesterifying a mix of edible oils.

The aim was to establish whether interesterification of oils, an alternative to the use of trans fatty acids in margarine manufacture, adversely affects plasma lipids. Twenty-seven hypercholesterolemic men participated in a double-blind, crossover trial of three margarines: 1) high-linoleic acid, moderate trans fatty acids; 2) high-palm oil blend (predominantly lauric, myristic, palmitic, oleic, and linoleic acids); and 3) an interesterified form of the high-palm oil margarine. Both high-palm oil margarines led to similar low-density-lipoprotein (LDL) cholesterol concentrations (4.43 +/- 0.94 and 4.54 +/- 0.88 mmol/L, respectively), which were significantly higher than the LDL concentrations after the high-linoleic acid margarine (4.02 +/- 0.85 mmol/L, P < 0.001). Interesterification transferred substantial proportions of palmitic acid into the sn-2 position of glycerides and unsaturated fatty acids into the sn-1,3 positions, and this was reflected in plasma chylomicrons. This study shows that interesterification of oils used to harden margarines does not raise plasma cholesterol more than does the margarine's constituent fatty acids.

Cholesterol, HDL↗
PubMed1994

Cooperative association of T cell beta receptor and HLA-DQ alleles in the production of anti-Ro in systemic lupus erythematosus.

The immunogenetics of the autoantibody response to Ro (or SS-A) have been explored in patients with systemic lupus erythematous. Data show that alleles of the T cell beta receptor and HLA-DQ loci are cooperatively associated with the presence of anti-Ro autoantibodies in systemic lupus erythematosus. Identification of HLA-DQ by oligonucleotide probe binding to polymerase chain reaction products demonstrates that the combination of DQB1*0201 and one of DQA1*0101, DQA1*0102, or DQA1*0103 is associated with anti-Ro. Patients possessing a particular pair of T cell receptor beta restriction enzyme polymorphisms along with these specific HLA-DQ alleles produce quantitatively more anti-Ro as measured by a sensitive solid-phase immunoassay than patients without these T cell receptor and DQ alleles. Other work has shown that the autoimmune response is directed against the human Ro antigen. These results are consistent with a central role in the disregulation of autoimmunity involving a trimolecular complex composed of the autoantigen bound by a HLA-DQ molecule which, together, are bound in turn by T cells which express a particular subset of T cell receptors.

Alleles↗
PubMed1993

Enhanced blood pressure response to dietary salt in elderly women, especially those with small waist: hip ratio.

OBJECTIVE: To determine the blood pressure responses in elderly normotensive men and women to dietary sodium and to the diunsaturated fatty acid dihomogammalinolenic acid (DGLA), which is derived from linoleic acid. DESIGN: Blood pressure responses were assessed in 66 subjects (36 male, 30 female; mean age 65 years) on two diets differing by approximately 70 mmol/day sodium, combined with daily supplements of either 1 g DGLA or 1 g safflower oil, giving a four-group parallel design. After a common period of salt restriction and salt supplementation, two sets of parallel groups continued with either salt or placebo tablets. The study was blinded, except for dietary adjustments based on 24-h urinary sodium excretion values measured once every 2 weeks. Blood pressures were also measured automatically once every 2 weeks. RESULTS: Urinary sodium excretion (sodium intake) correlated significantly with systolic and diastolic blood pressures. A strong interaction with sex (P < 0.001 for systolic blood pressure) reflected greater responsiveness in women to changing sodium intake. A second major determinant of blood pressure responsiveness was the waist: hip ratio, an index of central obesity; this correlation was independent of the initial sodium intake, initial blood pressure or body mass index. The waist: hip ratio was a powerful predictor of blood pressure changes with sodium intake in women only; women with android fat distribution were, similarly to men, less sensitive to dietary sodium. Daily supplements of 1 g DGLA doubled the concentration of DGLA in plasma but did not influence blood pressure. CONCLUSIONS: Among elderly normotensive subjects, women responded to changes in sodium intake with greater changes in blood pressure than men did. Furthermore, this response was strongly related to the gynaecoid distribution of body fat.

8,11,14-Eicosatrienoic Acid↗
PubMed1992

Plasma cholesterol-lowering potential of edible-oil blends suitable for commercial use.

We tested semihardened blends of edible oils, suitable for commercial food manufacture, with a lower-than-conventional saturated fatty acid content, for their effects on plasma cholesterol. Twenty-six mildly hypercholesterolemic men took part in a double-blind crossover experiment in which two test blends were compared with two control dietary periods [which resembled the Australian fat intake: proportions of polyunsaturated, monounsaturated, and saturated fatty acids (PMS) 0.4:0.9:1]. PMS in the test diets was approximately 0.8:1.3:1 and resulted in significantly lower LDL-cholesterol concentrations (reductions of less than or equal to 7.7%). HDL cholesterol and plasma triglyceride were unchanged. The trans fatty acid (mainly elaidic) content of the blends was 16%, raising its contribution to energy by 4% but without apparent effect on LDL and HDL concentrations. Provided the overall ratio of linoleic acid to palmitic acid in commercial edible-oil blends exceeds that in the prevailing national diet, partial hydrogenation will not negate the LDL-lowering potential.

Adult↗
PubMed1992

Oat bran lowers plasma cholesterol levels in mildly hypercholesterolemic men.

The effects of oat bran and wheat bran on plasma lipid concentrations were compared in a crossover study. Each bran (123 g oat bran or 54 g wheat bran) added nearly 18 g of nonstarch polysaccharide to a background diet containing about 10 g nonstarch polysaccharide. Twenty-three men (average plasma cholesterol level = 5.84 mmol/L, and low-density-lipoprotein (LDL) cholesterol level = 4.11 mmol/L) were randomly assigned to either the oat or wheat bran diet for 4 weeks and then changed to the alternate bran diet for a similar period. The oat bran diet produced significantly lower levels of plasma total cholesterol and LDL cholesterol: 5.65 +/- 0.16 and 3.88 +/- 0.15 mmol/L (mean +/- standard error) for oat bran vs 5.89 +/- 0.16 and 4.11 +/- 0.16 mmol/L for wheat bran. Food intake diaries showed that average consumption of total fat and saturated fat was identical during the two test periods, which excluded displacement of fat as an explanation for lowering of plasma cholesterol by oat bran. Our results indicate that in mildly hypercholesterolemic men, a diet high in soluble oat fiber can significantly lower plasma total cholesterol and LDL cholesterol and thus potentially lower the risk of coronary heart disease.

Adult↗
PubMed1992

Plasma lipoprotein lipid and Lp[a] changes with substitution of elaidic acid for oleic acid in the diet.

The effect of additional dietary trans fatty acids (7% energy) on plasma lipids was assessed in a double-blind comparison of four separate diets: 1, enriched with butter fat (lauric-myristic-palmitic); 2, oleic acid-rich; 3, elaidic acid-rich; 4, palmitic acid-rich. The total dietary period was 11 weeks and comprised normal foods plus specific fat supplements. In 27 mildly hypercholesterolemic men, total and LDL cholesterol were significantly lower during the 3-week oleic acid-rich diet, and were similar during the other three diets. For the four diets LDL cholesterol levels were in mg/dl: 1, 163; 2, 151; 3, 165; 4, 161. HDL cholesterol was significantly higher with the palmitic acid-rich diet, 42 mg/dl, compared with elaidic acid, 38 mg/dl, which in turn was not lower than with oleic acid, 38 mg/dl. Plasma elaidic acid concentration rose seven-fold with the trans fatty acid diet but did not increase the vulnerability of LDL to oxidative change. The elaidic acid-rich diet led to significant elevations in the level of Lp[a] compared to all the other test diets. The Lp[a] level increased to 296 +/- 220 U/l in the elaidic acid-rich period from 235 +/- 182 (mean +/- SD) in the first ("butter") period (P less than 0.001) compared with 249 +/- 204 in the palmitic acid period (P less than 0.001) and 236 +/- 201 in the oleic acid period (NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Follow-up of cyclosporin A treatment in type 1 (insulin-dependent) diabetes mellitus: lack of long-term effects.

In the Canadian/European randomized controlled study on cyclosporin A (CsA) in recent onset Type 1 (insulin-dependent) diabetes, treatment with the immunosuppressive drug had increased and maintained Beta-cell function and clinical remission during the first 12 months. Following discontinuation of the study drug and double-blinding after a mean of 13.8 months former CsA patients doubled the daily insulin dose within 6 months reaching the level of former placebo patients. The difference in Beta-cell function between the two groups was also lost. Metabolic control (HbA1c) was transiently worse in the former CsA group. Adverse effects of cyclosporin A on systolic blood pressure, haemoglobin levels, serum potassium and creatinine levels also remitted during that time. We conclude that treatment with cyclosporin A for a mean of 13.8 months had no long-lasting effect on the course of Type 1 diabetes persisting beyond drug discontinuation.

Adolescent↗
PubMed1991

Barley and wheat foods: influence on plasma cholesterol concentrations in hypercholesterolemic men.

Twenty-one mildly hypercholesterolemic men aged 30-59 y were provided with comparable barley and wheat foods for each of 4 wk in a crossover-designed experiment. The purpose of the study was to examine the influence of two sources of dietary fiber (nonstarch polysaccharides, NSP) on blood lipids and glucose concentrations. Barley contains beta-glucan as a source of soluble dietary fiber (DF) whereas wheat contains the largely insoluble cellulose and hemicellulose fiber. Total dietary fiber increased from a previous intake of 21-38 g/d during the period of study for the two groups. Consumption of barley relative to wheat foods was associated with a significant fall in both plasma total cholesterol (6%, P less than 0.05) and in low-density-lipoprotein cholesterol (7%, P less than 0.02) whereas triglyceride and glucose concentrations did not change significantly. It is concluded that barley dietary fiber is more effective than wheat dietary fiber at lowering blood cholesterol in hypercholesterolemic men.

Blood Glucose↗
PubMed1990

Anti-Ro(SSA) autoantibodies are associated with T cell receptor beta genes in systemic lupus erythematosus patients.

Several of the heterogeneous clinical manifestations of systemic lupus erythematosus have been associated with specific autoantibodies. Associations between HLA class II antigens and autoantibodies to the ribonucleoproteins Ro(SSA) and La(SSB) have been reported in these patients. Because HLA class II molecules present antigen to T cell receptors (TCRs), we have searched for a TCR gene associated with the production of anti-Ro(SSA) antibodies. A pair of restriction fragment length polymorphisms (RFLPs), one of which hybridizes to the TCR constant region C beta 1 and the other to the C beta 2 gene, has been identified, suggesting these may be genotypic markers for an extended region of the TCR beta locus. This RFLP pair occurs in 76% of patients with Ro(SSA) precipitins, 84% of anti-Ro(SSA)-positive patients lacking La(SSB) precipitins, but only 41% of the patients lacking both precipitins (P = 0.0004). This disproportionate occurrence in a subset of lupus patients indicates that these RFLPs are not disease susceptibility markers, but rather are important markers for TCR genes whose products are involved in the production of anti-Ro(SSA) antibodies. The majority of patients who have these RFLPs and HLA class II antigens previously associated with the anti-Ro(SSA) response make this antibody, suggesting that interactions between products of these loci occur in response to Ro(SSA).

Adult↗
PubMed1990

Can eating baked beans lower plasma cholesterol?

The plasma cholesterol lowering potential of canned baked beans was examined in a cross-over comparison with canned spaghetti. The difference in total dietary non-starch polysaccharide (NSP) of 12 g daily (6.6 g difference in soluble NSP), was insufficient to alter the plasma cholesterol, HDL cholesterol, triglyceride and glucose concentrations in 20 mildly hyper-cholesterolaemic men. Thus, eating an average of six 440 g cans of this source of baked beans per week, large servings, does not lower the plasma cholesterol when dietary fat is not displaced.

Adult↗