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Biomedical subjects

J E Taylor

Publications and source records attributed to J E Taylor.

At least 55 records · Page 3Linked to original sources
PubMed1999

Increased platelet activation in renal transplant patients.

BACKGROUND: Patients with functioning renal transplants are at risk of graft thrombosis in the postoperative period, and of fistula thrombosis and other thrombotic events thereafter. Investigation and therapeutic manipulation of haemostasis in these patients offers a means to counter this thrombotic tendency. METHODS: Platelet aggregation in whole blood, plasma von Willebrand factor and plasma fibrinogen levels were measured in 32 stable renal transplant patients (creatinine <200 micromol/litre, age of graft >4 months) and in 32 age, sex and smoking-habit matched normal controls. RESULTS: In both patient and control groups, seven patients were smokers and the remaining 25 were non-smokers. There was no significant difference in age between patients and controls [patients, median: 39 (20-64) years; controls: 38 (24-60) years]. Spontaneous platelet aggregation was significantly higher in the patients at all time points studied [30s-6 min; at 4 min: patients median (interquartile range) 19.4 (11.3-27.3)%; controls, 8.0 (5.1-15.0)%, P < 0.0005]. ADP-induced aggregation was also increased at a concentration range of 0.1-3 microM (at 1 microM, 1 min, patients median (interquartile range) was 52.4 (30.5-70.0)%; controls was 16.5 (1.4-31.4)%, P < 0.0001). Transplant patients had significantly higher von Willebrand factor and fibrinogen levels compared with the controls (von Willebrand factor, patients median (range): 158 (13-269)%; controls: 85 (43-223)%, P < 0.00001; fibrinogen, patients: 3.29 (2.12-7.39) g/litre; controls: 2.81 (1.84-4.65) g/litre, P < 0.0002). CONCLUSION: Patients with stable renal transplants have in vitro evidence of enhanced platelet activation, and increased plasma von Willebrand factor and fibrinogen levels.

Journal Article↗
PubMed1999

Establishing efficient partner notification periods for patients with chlamydia.

OBJECTIVES: To delineate chlamydia partner notification periods with high proportions of infected, untreated sexual partners, and to evaluate relevant Centers for Disease Control (CDC) recommendations. METHODS: Disease Intervention Specialists (DIS) offered contact tracing services to all chlamydia patients (N = 1,309) reported in Colorado Springs between July 1996 and June 1997. Patients were asked to identify sexual partners during the 180 days preceding treatment. Partners were actively sought by DIS and offered DNA amplification testing. RESULTS: Of 1,309 patients, 1,109 were interviewed, resulting in 2,293 named partners. Two fifths of eligible partners were located; inability to examine partners was related to time of last exposure and to frequency of sexual exposure. Of located partners, 95% were tested with DNA amplification technology. Adherence to CDC criteria identified 88% of infected, untreated partners; the other 12% consisted mainly of epidemiologically important asymptomatic men whose infection is seldom identified by current public health interventions. CONCLUSIONS: The chlamydia partner notification recommendations of the CDC are adequate, but miss men with long-standing infection. These men contribute to entrenched chlamydia endemicity; targeted programs to screen high-risk men merit serious consideration.

Adult↗
PubMed1998

Design, synthesis, and biological activities of potent and selective somatostatin analogues incorporating novel peptoid residues.

We report the synthesis, bioactivity, and structure-activity relationship studies of compounds related to the Merck cyclic hexapeptide c[Pro6-Phe7-d-Trp8-Lys9-Thr10-Phe11], L-363,301 (the numbering in the sequence refers to the position of the residues in native somatostatin). The Pro residue in this compound is replaced with arylalkyl peptoid residues. We present a novel approach utilizing beta-methyl chiral substitutions to constrain the peptoid side-chain conformation. Our studies led to molecules which show potent binding and increased selectivity to the hsst2 receptor (weaker binding to the hsst3 and hsst5 receptors compared to L-363, 301). In vivo, these peptoid analogues selectively inhibit the release of growth hormone but have no effect on the inhibition of insulin. The biological assays which include binding to five recombinant human somatostatin receptors carried out in two independent laboratories and in vivo inhibition of growth hormone and insulin provide insight into the relationship between structure and biological activity of somatostatin analogues. Our results have important implications for the study of other peptide hormones and neurotransmitters.

Animals↗
PubMed1998

Potent antagonists of somatostatin: synthesis and biology.

The search for synthetic analogues of somatostatin (SRIF) which exhibit selective affinities for the five known receptor subtypes (sst1-5) has generated a large number of potent agonist analogues. Many of these agonists display good subtype selectivities and affinities for the subtypes 2, 3, and 5, with very few selective for sst1 or sst4. Until the recent report by Bass and co-workers (Mol. Pharmacol. 1996, 50, 709-715; erratum, Mol. Pharmacol. 1997, 51, 170), no true antagonists had been discovered, let alone any displaying differential receptor subtype selectivity. In this present study, we explore the effect of this putative L5,D6 antagonist motif on various series of somatostatin agonist analogues, both linear and cyclic. It was found that many D5,L6 agonists could be converted into competitive antagonists by applying this motif, the most potent of which was H-Nal-cyclo[DCys-Pal-DTrp-Lys-Val-Cys]-Nal-NH2 (32). This antagonist was selective for hsst2 with an affinity of 75 nM and an IC50 of 15.1 nM against SRIF-14 in a rat in vitro antagonist bioassay. Receptor-selective somatostatin antagonists should provide valuable tools for characterizing the many important physiological functions of this neuropeptide.

Animals↗
PubMed1998

Identification of a unique ligand which has high affinity for all four bombesin receptor subtypes.

Four subtypes of bombesin receptors are identified (gastrin-releasing peptide receptor, neuromedin B receptor, the orphan receptor bombesin receptor subtype 3 (BB3 or BRS-3) and bombesin receptor subtype 4 (BB4)), however, only the pharmacology of the gastrin-releasing peptide receptor has been well studied. This lack of data is due in part to the absence of a general ligand. Recently we have discovered a ligand, 125I-[D-Tyr6,betaAla11,Phe13,Nle14]bombesin-(6-1 4) that binds to BRS-3 receptors. In this study we investigate its ability to interact with all four bombesin receptor subtypes. In rat pancreatic acini containing only gastrin-releasing peptide receptor and in BB4 transfected BALB cells, this ligand and 125I-[Tyr4]bombesin, the conventional gastrin-releasing peptide receptor ligand, gave similar results for receptor number, affinity for bombesin and affinity for the unlabeled ligand. In neuromedin B receptor transfected BALB cells, this ligand and 125I-[D-Tyr0]neuromedin B, the generally used neuromedin B receptor ligand, gave similar results for receptor number, neuromedin B affinity or the unlabeled ligand affinity. Lastly, in BRS-3 transfected BALB cells, only this ligand had high affinity. For all four bombesin receptors this ligand had an affinity of 1-8 nM and was equal or greater in affinity than any other specific ligands for any receptor. The unlabeled ligand is specific for gastrin-releasing peptide receptors on rat pancreatic acini and did not inhibit binding of 125I-cholecystokinin octapeptide (125I-CCK-8), 125I-vasoactive intestinal peptide (125I-VIP) or 125I-endothelin to their receptors. The unlabeled ligand was an agonist only at the gastrin-releasing peptide receptor in rat acini and did not interact with CCK(A) receptors or muscarinic M3 acetylcholine receptors to increase [3H]inositol phosphates. These results demonstrate 125I-[D-Tyr6,betaAla11,Phe13,Nle14]bombesin-(6-1 4) is a unique ligand with high affinity for all subtypes of bombesin receptors. Because of the specificity for bombesin receptors, this ligand will be a valuable addition for such pharmacological studies as screening for bombesin receptor agonists or antagonists and, in particular, for investigating BRS-3 cell biology, a receptor for which no ligand currently exists.

3T3 Cells↗
PubMed1998

Osteoporotic fracture among older U.S. women: risk factors quantified.

The purpose of this study was to develop a predictive model for osteoporotic fracture among a national sample of 2,325 women ages 50 years and older. Predictors for examination included age, race, heredity, body mass index (BMI), physical activity, smoking status, alcohol use, and dairy product use. Analyses were conducted using Standard Analysis System (SAS) procedures. Strong risk factors predicting osteoporotic fracture included age, race, low BMI, and inactivity. Recommendations emphasize screening of high-risk women, achieving and maintaining health body weights for underweight women, and obtaining moderate physical activity. Promotion of healthy body weights for women of all ages is emphasized. Recommendations also include encouraging widespread physician, patient, and public education regarding osteoporotic fracture.

Activities of Daily Living↗
PubMed1998

Predictors for osteoporosis diagnosis among postmenopausal women: results from a national survey.

Osteoporosis is a serious health problem in the U.S. today resulting in premature mortality, deformity, pain, loss of function, and disability. Diagnosis of osteoporosis is key to obtaining treatment. The purpose of this study was to examine risk factors that are correlated with osteoporosis diagnosis among a national sample of postmenopausal women. Factors associated with osteoporosis diagnosis included age, race, and family history. Health care providers, including physicians, dietitians, nurses, physical therapists and social workers, can play a key role in improving diagnoses among at-risk women. They can work together to increase awareness and improve knowledge regarding the risk factors for osteoporosis including body mass index, physical activity, smoking and nutritional status.

Aged↗
PubMed1998

Novel somatostatin analogs for the treatment of acromegaly and cancer exhibit improved in vivo stability and distribution.

The biodistribution of several radiolabeled somatostatin (SRIF) analogs was determined in the rat. Newly developed analogs BIM-23190 and BIM-23197 attained higher plasma levels and much greater target tissue concentrations than the clinically used BIM-23014 analog. Highest tissue concentrations of BIM-23190 and BIM-23197 were found in adrenal, kidney, pituitary and pancreas, tissues that are known to be abundant in mRNA for the somatostatin subtype 2 receptor. BIM-23190 and BIM-23197 associated radioactivity in these tissues was prolonged compared with that of BIM-23014, especially in the SRIF-receptor-rich pituitary. BIM-23190 and BIM-23197 were more stable in vivo and much less subject to biliary excretion than BIM-23014. These properties account for the elevated plasma and target tissue concentrations of these new SRIF analogs. Based on higher plasma levels, greater distribution to target tissues and longer in vivo stability, BIM-23190 and BIM-23197 may prove to be superior to BIM-23014 for the treatment of acromegaly and some types of cancer.

Acromegaly↗
PubMed1997

Simultaneous determination of lamotrigine and its glucuronide and methylated metabolites in human plasma by automated sequential trace enrichment of dialysates and gradient high-performance liquid chromatography.

The use of the system, automated sequential trace enrichment of dialysates (ASTED), to prepare plasma samples for the estimation of lamotrigine, its glucuronide and methylated metabolites in plasma prior to gradient high-performance liquid chromatography (HPLC) is described. Using this technique the procedure was observed to be specific for all three compounds and linear over the range 0.04 to 10 microg/ml for lamotrigine and the glucuronide metabolite and 2 to 500 ng/ml for the methylated metabolite. The within-run precision (C.V.) at four different supplemented plasma lamotrigine concentrations of 0.04, 0.10, 2.5 and 10.0 microg/ml was 6.21, 5.17, 1.29 and 0.73%, respectively, and the between-run precision (C.V.) estimated to be 13.49, 6.08, 1.95 and 1.78%, respectively. The overall accuracy (% bias) of the procedure was estimated to be 12.50, 0.00, 2.80 and 1.80%, respectively. The glucuronide and methylated metabolites in plasma showed similar assay performance.

Anticonvulsants↗
PubMed1997

Development of an assay for the simultaneous determination of sildenafil (Viagra) and its metabolite (UK-103,320) using automated sequential trace enrichment of dialysates and high-performance liquid chromatography.

The development of the ASTED (automated sequential trace enrichment of dialysates) system to prepare plasma samples prior to high-performance liquid chromatography (HPLC) of sildenafil and its demethylated metabolite (UK-103,320) is described. Investigations to elucidate potential pitfalls of the ASTED on-line sample preparation system prior to separation of the analytes by HPLC are presented. The procedure is shown to be selective for sildenafil and UK-103,320, and linear over the range 1.00-250 ng/ml. The intra-batch imprecision (C.V.) of the method at plasma analyte concentrations of 1.00, 5.00, 50.0 and 200 ng/ml was 11.2, 3.10, 1.50, and 1.30%, respectively, and the corresponding inter-batch imprecision was estimated to be 13.5, 7.09, 3.69, and 5.43%. At these plasma analyte concentrations the overall inaccuracy (% bias) of the procedure ranged from 3.6 to 8.4%. The method showed similar assay performance for the estimation of the metabolite, UK-103,320. The application of the assay to a pharmacokinetic investigation during a clinical study is presented.

Chromatography, High Pressure Liquid↗
PubMed1997

Somatostatin receptor (SSTR) subtype-selective analogues differentially suppress in vitro growth hormone and prolactin in human pituitary adenomas. Novel potential therapy for functional pituitary tumors.

Previously, we have shown somatostatin receptor (SSTR) subtype-specific regulation of growth hormone (GH), thyroid-stimulating hormone, and prolactin (PRL) secretion in human fetal pituitary cultures, where GH and thyroid-stimulating hormone are mediated by both SSTR2 and SSTR5, whereas SSTR2 preferentially mediates PRL secretion. We now tested SSTR subtype-selective analogues in primary human GH- and PRL-secreting pituitary adenoma cultures. Analogue affinities determined by membrane radioligand binding in cells stably expressing human SSTR forms were either SSTR2 or SSTR5-selective. Analogues preferential either for SSTR2, including octreotide, lanreotide, and novel compounds with improved affinity for SSTR2, or new SSTR5-selective compounds suppressed GH in tumor cell cultures (up to 44% of control; P < 0.0005). However, novel analogues from both groups were 30-40% more potent than octreotide and lanreotide in suppressing GH (P < 0.05). Heterologous analogue combinations containing both SSTR2- and SSTR5-selective compounds were more potent in decreasing GH than analogues used alone (P < 0.05), or than combinations of compounds specific for the same receptor subtype (P < 0.005). In contrast, SSTR2-selective analogues did not suppress PRL release from six cultured prolactinomas studied. However, new SSTR5-selective analogues suppressed in vitro PRL secretion (30-40%; P < 0.05) in four of six prolactinomas. These results suggest that both SSTR2 and SSTR5 are involved in GH regulation in somatotroph adenoma cells, whereas SSTR5 exclusively regulates PRL secretion from prolactinoma cells. Thus, somatostatin analogues with improved selective binding affinity for these receptor subtypes may be effective in the treatment of either GH- or PRL-secreting adenomas.

Adenoma↗
PubMed1997

Somatostatin receptor subtype specificity in human fetal pituitary cultures. Differential role of SSTR2 and SSTR5 for growth hormone, thyroid-stimulating hormone, and prolactin regulation.

Somatostatin (SRIF), a hypothalamic inhibitor of pituitary growth hormone (GH) and thyroid-stimulating hormone (TSH) secretion, binds to five distinct receptor (SSTR) subtypes. We therefore tested SSTR subtype-specific SRIF analogs in primary human fetal pituitary cultures (23-25-wk gestation) to elucidate their role in regulating human pituitary function. Using reverse transcription-PCR, mRNA expression of SSTR2 and SSTR5 were detected in fetal pituitary by 25 wk. SRIF analog affinities were determined by membrane radioligand binding in cells stably expressing the human SSTR forms. GH secretion was suppressed equally (40-60%, P < 0.005) by analogs preferential for either SSTR2 (IC50 for receptor binding affinity, 0.19-0.42 nM) or SSTR5 (IC50, 0.37 nM), and compounds with enhanced affinity for SSTR2 were more potent (EC50 for GH suppression, 0.05-0.09 nM) than Lanreotide (EC50, 2.30 nM) and SRIF (EC50, 0.19 nM). Similarly, analogs with high affinity for SSTR2 or SSTR5 decreased TSH secretion (30-40%, P < 0.005). However, prolactin was effectively inhibited only by compounds preferentially bound to SSTR2 (20-30%, P < 0.05). Luteinizing hormone was modestly decreased (15-20%) by SSTR2- or SSTR5-specific analogs. An SSTR5-specific analog also exclusively inhibited GH in acromegalic tumor cells. Thus, SRIF regulation of GH and TSH in primary human fetal pituitary cells is mediated by both SSTR2 and SSTR5, both of which are abundantly expressed by 25 wk. In contrast, suppression of prolactin is mediated mainly by SSTR2. These results indicate that SSTR5 is critical for physiologic regulation of GH and TSH. SRIF analogs with selective affinity for this receptor may therefore be more effective in the treatment of hormone-secreting pituitary adenomas.

Adrenocorticotropic Hormone↗
PubMed1997

Characterization of bombesin binding sites in the rat stomach.

We characterized the bombesin receptor population in the rat stomach and determined the receptor subtype mediating the contractile effect of bombesin in the gastric fundus. Using in vitro receptor autoradiography, we evaluated the ability of the specific gastrin-releasing peptide-preferring receptor antagonist [D-F5,Phe6,D-Ala11]bombesin-(6-13) methyl ester to inhibit binding of 125I-[Tyr4]bombesin to the gastric fundus, corpus and antrum. Binding to these regions was completely inhibited by [D-F5,Phe6,D-Ala11]bombesin-(6-13) methyl ester suggesting that these receptors are the gastrin-releasing peptide-preferring subtype. We found that the rank order of potency for the contractile effect of bombesin, and the related mammalian peptides neuromedin C and neuromedin B, was bombesin > neuromedin C > neuromedin B. [D-F5,Phe6,D-Ala11]bombesin-(6-13) methyl ester was equipotent in antagonizing contractions produced by all three peptides. Furthermore, receptor tachyphylaxis to either neuromedin C or neuromedin B abolished the subsequent contractile response elicited by neuromedin C and neuromedin B, suggesting that one bombesin receptor subtype mediates rat gastric fundal contractions. Together, these results demonstrate that the bombesin receptor subtype in the rat stomach is gastrin-releasing peptide-preferring subtype and that this subtype is responsible for the effects of bombesin-like peptides on fundal smooth muscle contraction.

Animals↗
PubMed1997

Caudal hindbrain neuromedin B-preferring receptors participate in the control of food intake.

Recent studies have identified two subtypes of bombesin (BN) receptors in the rat central nervous system: gastrin releasing-peptide (GRP) preferring and neuromedin B (NMB) preferring. To investigate a role for the NMB-preferring receptor subtype in feeding suppression elicited by fourth ventricular (4V) BN administration, we evaluated the ability of a selective NMB-preferring receptor antagonist, BIM-23127, to block suppression of glucose intake produced by 4V BN (10 pmol). Our results showed that 4V administration of BIM-23127 dose dependently antagonized the suppression of glucose intake produced by 4V BN. In addition, 4V administration of BIM-23127 alone increased glucose intake above that observed in the baseline condition. These results support a role for the NMB-preferring BN receptor subtype in the suppression of intake produced by 4V BN administration and suggest that endogenously released NMB participates in ingestive control.

Animals↗
PubMed1997

The interaction of culture with general job stressors in air traffic controllers.

Elements of the job of Air Traffic Controllers perceived as being stressful were rated for degree of stressfulness by a group of Singaporean controllers. The results were compared with those from earlier studies in Canada and New Zealand. It was hypothesized that the international nature of the job would be reflected in findings from all three groups of controllers. It was further hypothesized, however, that environmental and cultural factors would produce differences among the groups and that these would be greater between the Asian and the two "Western" cultures than between the two earlier samples studied. Results showed that the two Western cultures share 56% common variance in their perceptions of stressfulness, but this changes to 35% between the New Zealand and Singapore groups and only 21% between Canada and Singapore. Although comparison of the factor structure of the stress ratings of the Singapore and New Zealand samples again confirmed a general pattern of underlying stressors related to air traffic control (which fits general occupational models of stress), it also revealed culturally specific components. The nature of these suggests that they are emhedded in the context of Asian environments and cultures. The conclusion is that stress in Air Traffic Controllers is related both to generic occupation stressors and to others that are both organizationally and culturally specific.

Adult↗