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Biomedical subjects

G Jones

Publications and source records attributed to G Jones.

At least 253 records · Page 14Linked to original sources
PubMed1995

1 alpha,24(S)-dihydroxyvitamin D2: a biologically active product of 1 alpha-hydroxyvitamin D2 made in the human hepatoma, Hep3B.

A major metabolite of the vitamin D analogue 1 alpha-hydroxyvitamin D2 in human liver cells in culture has been identified as 1 alpha,24(S)-dihydroxyvitamin D2 [1 alpha,24(S)-(OH)2D2]. 1 alpha-Hydroxyvitamin D3 incubated with the same cells gives rise to predominantly 25- and 27-hydroxylated products. Our identification of 1 alpha,24(S)-dihydroxyvitamin D2 is based on comparisons of the liver cell metabolite with chemically synthesized 1 alpha,24(S)-(OH)2D2 and 1 alpha,24(R)-(OH)2D2 by using HPLC, GC and GC-MS techniques. The stereochemical orientation of the 24-hydroxyl group was inferred after X-ray-crystallographic analysis of the 24(R)-OH epimer. 1 alpha,24(S)-Dihydroxyvitamin D2 binds strongly to the vitamin D receptor and is biologically active in growth hormone and chloramphenicol acetyltransferase reporter gene expression systems in vitro, but binds poorly to rat vitamin D-binding globulin, DBP. We suggest that this metabolite, 1 alpha,24(S)-(OH)2D2, possesses the spectrum of biological properties to be useful as a drug in the treatment of psoriasis, metabolic bone disease and cancer.

Animals↗
PubMed1995

Different mechanisms of hydroxylation site selection by liver and kidney cytochrome P450 species (CYP27 and CYP24) involved in vitamin D metabolism.

A series of homologated 1 alpha-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 molecules with one to three extra carbons in the side chain were used to examine the substrate preferences and hydroxylation site selection mechanisms of the liver vitamin D3-25-hydroxylase (CYP27) and the target cell 25-hydroxyvitamin D3-24-hydroxylase (CYP24). Cultured and transfected cell models, used as sources of these hydroxylases, gave 23-, 24-, 25-, and 27-hydroxylated metabolites which were identified by their high performance liquid chromatography and GC-MS characteristics. Lengthening the side chain is tolerated by each cytochrome P450 isoform such that 25-hydroxylation or 24-hydroxylation continues to occur at the same rate as in the native side chain, while the site of hydroxylation remains the same for the liver enzyme in that CYP27 continues to hydroxylate at C-25 and C-27 (minor) despite the two-carbon-atom extension. Somewhat surprising is the finding that C-24 and C-23 (minor) hydroxylations also do not change as the side chain is extended by as much as three carbons. We conclude that CYP24 must be directed to its hydroxylation site(s) by the distance of carbon 24 from the vitamin D ring structure and not as in CYP27 by the distance of the hydroxylation site from the end of the side chain.

Calcitriol↗
PubMed1995

Involvement of extracellular matrix in acetylcholine receptor epsilon-subunit gene expression at the rat neuromuscular junction.

During neuromuscular development, the nerve induces the expression of acetylcholine receptor (AChR) epsilon-subunit gene selectively in synaptic myonuclei. Here we show that even after elimination of neural effects by denervation, synaptic expression of epsilon-subunit transcripts is maintained for > 4 months. In contrast, after damage of the extracellular matrix (ECM) by treatment with proteolytic enzymes, epsilon-subunit mRNA is significantly reduced within less than 1 day, indicating a role of ECM in the regulation of AChR subunit transcripts at the synapse.

Animals↗
PubMed1995

Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation.

Understanding the principles whereby macromolecular biological receptors can recognise small molecule substrates or inhibitors is the subject of a major effort. This is of paramount importance in rational drug design where the receptor structure is known (the "docking" problem). Current theoretical approaches utilise models of the steric and electrostatic interaction of bound ligands and recently conformational flexibility has been incorporated. We report results based on software using a genetic algorithm that uses an evolutionary strategy in exploring the full conformational flexibility of the ligand with partial flexibility of the protein, and which satisfies the fundamental requirement that the ligand must displace loosely bound water on binding. Results are reported on five test systems showing excellent agreement with experimental data. The design of the algorithm offers insight into the molecular recognition mechanism.

Arabinose↗
PubMed1995

Thiazide diuretics and fractures: can meta-analysis help?

Published observational estimates of the effect of thiazide diuretics on osteoporotic fracture risk vary from a 70% reduction to a 60% increase but there have been no randomized controlled trials. The aims of this study were to use the technique of meta-analysis to attempt to resolve this conflict and to explore whether duration and/or dose of therapy has an effect on osteoporotic fracture risk. The data sources utilized were Medline and Excerpta Medica databases supplemented by reviews and back references. A total of 18 observational studies that looked at the relationship between diuretics and fracture were located, of which 13, involving 29,600 subjects, had extractable data on thiazides and fracture occurrence. Current thiazide users were protected against hip fracture (OR 0.82, 95% CI 0.73-0.91). Thiazide use of long duration may be protective (OR 0.82, 95% CI 0.62-1.08) but not short duration (OR 1.23, 95% CI 0.99-1.54). The size of this effect, which compares favorably to other interventions, indicates that a randomized controlled trial to resolve the problem of potential confounders and safety profile would require a minimum of 7000 person-years of observation in those at highest risk of fracture (women aged 80 or over) which is unlikely to be pursued at the present time. The results of this meta-analysis indicate that current thiazide users have a 20% reduction in fracture risk and that long-term use may reduce fractures by a similar amount.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1995

1,25(OH)2D3-dependent regulation of calbindin-D28k mRNA requires ongoing protein synthesis in chick duodenal organ culture.

Organ culture of 19-day-old chick embryo duodena was utilized to evaluate the mechanism of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)-dependent calbindin-D28k (CaBP) expression. Duodenal CaBP and 1,25(OH)2D3 receptor (VDR) expression were assessed by Western blot analysis, while CaBP and VDR mRNA levels were determined by Northern blot analysis. In untreated duodena, both VDR protein and mRNA were present, while CaBP protein and mRNA were undetectable. Treatment of cultured duodena with 25 nM 1,25(OH)2D3 resulted in detectable CaBP mRNA after 4 h which continued to increase during a 24 h time period. Under these conditions, localization of [3H-1 beta]1 alpha,25(OH)2D3 in duodenal chromatin is rapid (< or = 30 min). Thus, the delayed accumulation of detectable CaBP mRNA cannot be explained by slow nuclear binding of 1,25(OH)2D3. The inclusion of 1.6 microM actinomycin D in the organ culture partially inhibited the 1,25(OH)2D3-regulated increase in CaBP mRNA, which implies that there is a transcriptional component involved in the increased CaBP mRNA levels. Similarly, quantitative polymerase chain reaction studies allowed the detection of CaBP pre-mRNA and mRNA sequences 1 h after hormone treatment, suggesting that CaBP gene transcription is initiated rapidly. Treatment of cultures with 36 microM cycloheximide 1 h prior to 1,25(OH)2D3 addition resulted in superinduction of VDR mRNA levels but sharply reduced CaBP steady-state mRNA levels. This dramatic reduction in CaBP mRNA reveals that 1,25(OH)2D3-mediated CaBP expression is dependent on ongoing protein synthesis. Thus, we propose that a labile auxiliary protein or other cofactor, which may or may not be 1,25(OH)2D3-dependent, is necessary for 1,25(OH)2D3-mediated CaBP gene transcription in chick duodena.

Animals↗
PubMed1995

A genetic algorithm for flexible molecular overlay and pharmacophore elucidation.

A genetic algorithm (GA) has been developed for the superimposition of sets of flexible molecules. Molecules are represented by a chromosome that encodes angles of rotation about flexible bonds and mappings between hydrogen-bond donor proton, acceptor lone pair and ring centre features in pairs of molecules. The molecule with the smallest number of features in the data set is used as a template, onto which the remaining molecules are fitted with the objective of maximising structural equivalences. The fitness function of the GA is a weighted combination of: (i) the number and the similarity of the features that have been overlaid in this way; (ii) the volume integral of the overlay; and (iii) the van der Waals energy of the molecular conformations defined by the torsion angles encoded in the chromosomes. The algorithm has been applied to a number of pharmacophore elucidation problems, i.e., angiotensin II receptor antagonists, Leu-enkephalin and a hybrid morphine molecule, 5-HT1D agonists, benzodiazepine receptor ligands, 5-HT3 antagonists, dopamine D2 antagonists, dopamine reuptake blockers and FKBP12 ligands. The resulting pharmacophores are generated rapidly and are in good agreement with those derived from alternative means.

Algorithms↗
PubMed1995

Direct clinical and welfare costs of osteoporotic fractures in elderly men and women.

Osteoporosis is an increasing health care problem in all aging populations, but overall direct costs associated with the total fracture burden of osteoporosis remain uncertain. We have examined direct costs associated with 151 osteoporotic fractures occurring between 1989 and 1992 in a large cohort of elderly men and women followed prospectively as part of the Dubbo Osteoporosis Epidemiology Study. The median cost of hospital treated fractures was $A10,511 per fracture and for fractures treated on an outpatient basis $A455 in 1992 Australian dollars. Femoral neck fractures were the most expensive fractures ($15,984 median cost). There was no significant difference in costs between men and women for either hospital- or outpatient-treated fractures. Rehabilitation hospital costs comprised the largest proportion of costs (49%) for hospital-treated fractures. Community services comprised the major cost (40%) of outpatient-treated fractures. Univariate predictors of costs were quadriceps strength and bone density, although multivariate analysis showed quadriceps strength to be the best overall predictor of costs. The predicted annual treatment costs in Australia for atraumatic fractures occurring in subjects > or = 60 years was $A779 million or approximately $A44 million per million of population per annum. Estimated total osteoporotic fracture-related costs for the Australian population were much higher than previously reported. The majority of direct costs (95%) were incurred by hospitalized patients and related to hospital and rehabilitation costs. Extrapolation of these data suggests that the direct costs for hip fracture alone will increase approximately twofold in most Western countries by 2025. Improving the cost-effectiveness of treating osteoporotic fractures should involve reduced hospitalization and/or greater efficiency in community rehabilitation services. The costs of various approaches to osteoporosis prevention must be placed into the context of these direct costs and prevention should target men as well as women.

Aged↗
PubMed1995

Changes in protein C and protein S levels in normal pregnancy.

OBJECTIVE: The objective of the study was to determine the normal changes in the plasma concentrations of protein C and protein S that occur during each trimester of pregnancy. STUDY DESIGN: The study was a prospective cross-sectional study of 91 normal pregnant women who had plasma concentrations of protein C and protein S measured during the first, second, and third trimesters. RESULTS: There was no statistically significant change in antigenic or functional protein C levels during normal pregnancy. Total protein S levels also remained unchanged. Free protein S levels fell significantly from first to second trimesters (0.45 U/ml mean to 0.26 U/ml mean, p < 0.001), but no further fall occurred during the third trimester. CONCLUSIONS: The second-trimester fall in free protein S levels is a physiologic pregnancy adaptation. Women with a thromboembolic event appearing for the first time during pregnancy should have investigations for protein S deficiency delayed until the postpartum period, to avoid misdiagnosis and treatment.

Cross-Sectional Studies↗
PubMed1995

Docking small-molecule ligands into active sites.

Docking involves the development of computer algorithms that evaluate the binding modes of putative ligands in receptor sites. The principal advances of the past year have been the development of new algorithmic approaches, several of which incorporate conformational flexibility, and the increased use of docking to identify leads in drug-discovery programmes.

Algorithms↗
PubMed1995

Women and eugenics in Britain: the case of Mary Scharlieb, Elizabeth Sloan Chesser, and Stella Browne.

Existing literature on eugenics only touches briefly upon the role played by women. This article sets out to examine the reason for the high participation of women in the British eugenics movement by focusing on the role of three individuals in the early part of the twentieth century. It concludes that an important objective of women in eugenics was the 'feminization' of its social agenda.

Eugenics↗
PubMed1995

Effects of goal-setting interventions on selected basketball skills: a single-subject design.

The purpose of this investigation was to examine the effects of a goal-setting intervention program on selected components of basketball performance over the course of a competitive season. A multiple-baseline, single-subject design was used with baseline observations on various performance components (e.g., turnovers, rebounds), collected for four elite college basketball players during their first eight games of the season. At the midseason break, these players selected one aspect of their play that they felt would benefit from improvement. A goal-setting program was designed based on the goal attainment scaling procedure recommended by Smith (1988), whereby subjects generated numerical targets for their chosen components. Performance components were then assessed for the next eight games as they had been in the preintervention phase. Following the intervention, 3 of the 4 subjects showed consistent improvements in their targeted areas of performance. Also, there were no outcome changes in the performance components that weren't targeted by the subjects. The findings suggest that future studies may benefit from achieving greater ecological validity and utilizing alternative designs to the traditional nomothetic approaches which may tend to mask positive intervention effects on certain individuals.

Adult↗
PubMed1995

Food processing and maize variety affects amounts of starch escaping digestion in the small intestine.

Two meals which differed greatly in resistant starch (RS) concentration, but otherwise had similar macronutrient composition (including nonstarch polysaccharides), were fed for breakfast to five subjects with ileostomies. The high-RS meal included bread made from high-amylose maize, uncooked green banana flour, and coarsely ground uncooked wheat. The low-RS meal contained bread made from low-amylose maize, cooked green banana flour, and cooked wheat. The effluent produced over 14 h was analyzed for the total amount of starch escaping digestion. In the low-RS meal 51.8 +/- 6.2 g (mean +/- SD) starch was consumed and 2.4 +/- 0.6 g recovered in the effluent, while for the high-RS meal a total of 52.7 +/- 8.8 g starch was fed and 19.9 +/- 5.2 g recovered in the effluent. The ileostomy results provided additional validation of an in vitro resistant starch assay. Scanning electron micrographs of effluent from one subject who consumed the high-amylose bread revealed that many intact starch granules escaped digestion in the small intestine.

Adult↗
PubMed1995

Effect of i.v. diamorphine on the regression of spinal block.

Twenty patients undergoing transurethral prostatectomy under spinal anaesthesia were allocated randomly in one of two groups. After operation dermatomal levels to cold were measured every 30 min until they had receded to T10. Patients in group 1 were then given diamorphine 5 mg in 0.9% saline 5 ml i.v. and in group 2 0.9% saline 5 ml i.v. Block level to cold and degree of motor block were assessed at 15-min intervals for 1 h after injection. Block regression continued in the control group while there was no decrease in the diamorphine group for 30 min (P < 0.01) after which it then receded at a similar rate as the control group. There was no significant difference in motor block between the two groups.

Aged↗
PubMed1995

Preoperative oral naproxen for pain relief after day-case laparoscopic sterilization.

Analgesia with preoperative naproxen after laparoscopic sterilization was assessed in a prospective, double-blind, randomized study of 80 women; 42 women received oral naproxen 1 g, approximately 90 min before surgery, and 38 received placebo. Preoperative naproxen did not significantly influence postoperative pain scores, but was associated with a reduction in parenteral opioid administration (P = 0.04).

Adult↗
PubMed1995

Distribution of metoprolol enantiomers in a fatal overdose.

The distribution of the racemic and the enantiomeric content of (+/-)-metoprolol was compared after ingestion of a massive fatal overdose of the racemic drug. Postmortem concentrations of the racemate in different tissues were assayed by gas chromatography after derivatization with trifluoroacetic acid anhydride. The distribution of the R- and S-enantiomers of metoprolol was analyzed by reversed-phase high-performance liquid chromatography. Metoprolol was extracted from postmortem specimens and derivatized with the chiral reagent 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate. The concentrations of active S(-)-isomer in blood, liver, and stomach contents were 33 mg/L, 224 mg/kg, and 56 mg/61 g, respectively. The concentrations of inactive R(-)-enantiomer in blood, liver, and stomach contents were 33 mg/L, 222 mg/kg, and 55 mg/61 g, respectively. These results indicate that half the total postmortem tissue concentration of metoprolol is the R-enantiomer, which is devoid of any beta-blocker activity.

Adolescent↗