Bishop, LA, Nguyen, TV & Schofield, PR 1995, 'Both of the beta-subunit carbohydrate residues of follicle-stimulating hormone determine the metabolic clearance rate and in vivo potency.', Endocrinology, vol. 136, no. 6, pp. 2635-2640.
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FSH is a glycoprotein hormone required for the development and maturation of the ovarian follicle and for spermatogenesis. FSH is glycosylated at asparagine residues 52 and 78 on the α-subunit and residues 7 and 24 on the β-subunit. In vitro, the carbohydrate residue at position α 52 is required for signal transduction. To define the contribution of the carbohydrate residues to FSH potency in vivo, we assessed the MCR and in vivo bioactivity of site-specifically deglycosylated recombinant human FSH variants. The removal of the β-subunit carbohydrate residues significantly (P < 0.05) affected the MCR and resulted in significantly (P < 0.05) reduced in vivo bioactivity. For all recombinant human FSH variants, a strong correlation (r = 0.90; P < 0.01) was observed between MCR and in vivo potency, indicating that the circulatory half-life of the hormone appears to be the primary determinant of in vivo bioactivity. Although the β-subunit carbohydrate residues have the greatest effect in determining FSH potency in vivo; the α 52 residue, important in vitro, has no effect on either MCR or in vivo potency. This study highlights the difficulties of translating in vitro results to whole animal physiology. © 1995 by The Endocrine Society.
Dr. Menzies, GJ, Nguyen, T, Sambrook, PN & Eisman, JA 1995, 'Thiazide diuretics and fractures: Can meta-analysis help?', Journal of Bone and Mineral Research, vol. 10, no. 1, pp. 106-111.
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Abstract 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% Cl 0.73–0.91). Thiazide use of long duration may be protective (OR 0.82, 95% Cl 0.62–1.08) but not short duration (OR 1.23, 95% Cl 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 These results suggest, in the absence of a suitably designed large randomized controlled trial, that thiazides should be considered as part of an approach to osteoporotic fracture prevention, particularly in hypertensive subjects.
HEIBER, M, DOCHERTY, JM, SHAH, G, NGUYEN, T, CHENG, R, HENG, HHQ, MARCHESE, A, TSUI, L-C, SHI, X, GEORGE, SR & O'DOWD, BF 1995, 'Isolation of Three Novel Human Genes Encoding G Protein-Coupled Receptors', DNA and Cell Biology, vol. 14, no. 1, pp. 25-35.
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We have cloned and mapped the chromosomal location of three novel human genes encoding G protein-coupled receptors that we have named GPR6, GPR5, and GPR4. The entire coding region for each of these genes was contained on single exons. Gene GPR6 encoded a receptor that shared closest identity (71% in the transmembrane regions) with the human orphan receptor GPR3 and was localized to chromosome 6 (q21–q22.1). Northern blot analysis revealed that GPR6 transcripts were abundant in the human putamen and to a lesser extent in the frontal cortex, hippocampus, and hypothalamus. Gene GPR5 encoded a receptor that most closely resembled the orphan receptor RBS11 (48% in the transmembrane regions) and the MIP 1α/RANTES receptor (45% in the transmembrane regions) and was localized to chromosome 3 (p21.3–p21.1). Gene GPR4 shared identity (40% in the transmembrane regions) with the human platelet-activating factor receptor and was localized to chromosome 19 (q13.2–q13.3). © 1995, Mary Ann Liebert, Inc. All rights reserved.
Howard, G, Nguyen, T, Morrison, N, Watanabe, T, Sambrook, P, Eisman, J & Kelly, PJ 1995, 'Genetic influences on bone density: physiological correlates of vitamin D receptor gene alleles in premenopausal women.', J Clin Endocrinol Metab, vol. 80, no. 9, pp. 2800-2805.
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Common vitamin D receptor (VDR) gene alleles have recently been shown to contribute to the genetic variability in bone mass and bone turnover, however, the physiological mechanisms involved are unknown. To examine this, the response to 7 days of 2 micrograms oral 1,25-dihydroxyvitamin D[1,25-(OH)2D] (calcitriol) stimulation was assessed in 21 premenopausal women, homozygous for one or other of the common VDR alleles (bb, n = 11; BB, n = 10). Indices of bone turnover and calcium homeostasis were measured during 2 weeks. Baseline osteocalcin, 1,25-(OH)2D, type I collagen carboxyterminal telopeptide, and inorganic phosphate levels were significantly higher and spinal bone mineral density was significantly lower in the BB allelic group. After calcitriol administration, similar levels of 1,25-(OH)2D were attained throughout the study in both genotypic groups. The increase in serum osteocalcin levels in the BB group was significantly less than that in the bb group (11% vs. 32%, P = 0.01). The genotype-related baseline difference in osteocalcin levels was not apparent at the similar serum 1,25-(OH)2D levels. By contrast, the baseline differences in phosphate and type I collagen carboxyterminal telopeptide persisted throughout the study. Serum ionized calcium levels did not differ between genotypes, nor did it move out of normal range values. However, parathyroid hormone was less suppressed in the low bone density group (38% vs. 11%, P = 0.01). These data indicate that the VDR alleles are associated with differences in the vitamin D endocrine system and may have important implications in relation to the pathophysiology of osteoporosis.
Jones, G 1995, 'Cigarette smoking and vertebral body deformity', JAMA: The Journal of the American Medical Association, vol. 274, no. 23, pp. 1834-1835.
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Jones, G 1995, 'Cigarette Smoking and Vertebral Body Deformity', JAMA: The Journal of the American Medical Association, vol. 274, no. 23, pp. 1834-1834.
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Cigarette smoking has been consistently associated with osteoporosis1,2and both appendicular3and vertebral4fractures. The increase in fracture risk is thought to be mediated by a decrease in bone density, but this has not been directly assessed for spinal fractures. We studied the relationship between cigarette smoking, bone density, and vertebral deformity in 300 elderly men and women participating in the Dubbo Osteoporosis Epidemiology Study (DOES). The city of Dubbo has a population of approximately 32 000 people and is situated 400 km northwest of Sydney, New South Wales, Australia. This community includes approximately 1600 men and 2100 women aged 60 years or older (as of January 1, 1989), 98.6% of whom are white. Subjects were invited to participate in DOES, which commenced in 1989. By the end of 1993, 1950 subjects (62%) of a surviving total target population of 2900 were participating. Using. © 1995, American Medical Association. All rights reserved.
Jones, G, Nguyen, T, Sambrook, PN, Kelly, PJ & Eisman, JA 1995, 'A longitudinal study of the effect of spinal degenerative disease on bone density in the elderly.', J Rheumatol, vol. 22, no. 5, pp. 932-936.
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OBJECTIVE: To describe the relationship between spinal degenerative disease and bone density in the elderly both cross sectionally and longitudinally. METHODS: Random population based sample of 113 men and 187 women over 60 yrs of age participating in the Dubbo Osteoporosis Epidemiology Study (a longitudinal population based study of fracture risk factors) who had bone density measured on 2 occasions (average interval 2.5 yrs) and spinal radiographs on one occasion (performed according to a standardized approach). RESULTS: Spinal degenerative disease, of varying severity, was common in this population (osteophytes 69%, disc narrowing 67%, posterior element disease 99%). Scores for osteophytosis, disc narrowing, and posterior element disease (together with age and body mass index) independently explained 43% of the variation in spinal bone density in men (p < 0.00001) and 26% in women (p < 0.00001). The rate of change at the spine increased with increasing severity of osteophytosis in both men (p = 0.03) and women (p = 0.05), but not the other measures, and the total amount of variation explained by these measures was modest. In comparison, severity of spinal degenerative disease had only a modest but significant relationship with femoral neck bone density in both sexes, but not its rate of change. Subjects with any degree of osteophytosis had higher bone density compared to those without osteophytes at both the lumbar spine (men 21% higher, 95% CI 12-31; women 16% higher, 95% CI 9-23) and, to a lesser extent, femoral neck (men 12% higher, 95% CI 4-20; women 6% higher, 95% CI 1-13). Vascular calcification had no relationship with bone density at either spine or hip. CONCLUSION: Spinal bone density measurement and its sequential followup may be erroneous in the elderly due to concomitant degenerative disease. Bone density at the femoral neck was much less affected by spinal degenerative disease, which suggests that this site may be more efficacious for bo...
Jones, G, Nguyen, T, Sambrook, PN, Lord, SR, Kelly, PJ & Eisman, JA 1995, 'Osteoarthritis, bone density, postural stability, and osteoporotic fractures: a population based study.', J Rheumatol, vol. 22, no. 5, pp. 921-925.
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OBJECTIVE: Osteoarthritis (OA) is associated with an increase in bone density both locally and at distant sites. Prospective data are limited on the relationship between OA and fracture. We studied the possible relationship between self-reported OA, bone density, postural stability measures, and atraumatic fractures as part of a study of men and women over 60 years of age. METHODS: Subjects were part of the Dubbo Osteoporosis Epidemiology Study (a longitudinal population based study of fracture risk factors). Bone density was measured by dual energy x-ray absorptiometry. Postural stability was assessed by the validated measures of quadriceps strength and sway. Medication use and self-reported arthritis were assessed by a structured personal interview. Fractures were ascertained retrospectively by interview and prospectively by viewing radiographic reports for fracture. RESULTS: Among a study population of 1101 women and 720 men (mean age 69) there were 462 subjects (25%) who reported a diagnosis of OA. In both sexes, subjects with OA had higher bone density (adjusted for age and body mass index) at both the femoral neck (men, p = 0.026; women, p = 0.048) and lumbar spine (men, p = 0.0007; women, p = 0.0007). However, in both sexes, those with self-reported OA also had higher body sway and lower quadriceps strength. The combination of these observed differences in fracture risk factors led to no predicted change in fracture risk overall when using established nomograms for this population [men, OR = 1.11 (95% CI 0.83-1.45); women, OR = 1.08 (95% CI 0.83-1.39)]. This paralleled our observational finding that self-reported OA was not associated with a decrease in fracture incidence compared to those not reporting OA in both men (RR 0.64, 95% CI 0.29-1.39) and women (RR 1.00, 95% CI 0.66-1.51). CONCLUSION: Individuals with self-reported OA, despite higher bone density, are not protected against nonvertebral osteoporotic fracture, apparently due to worsened ...
Kelly, PJ, Morrison, NA, Sambrook, PN, Nguyen, TV & Eisman, JA 1995, 'Genetic Influences on Bone Density and Bone Turnover', Physical Medicine and Rehabilitation Clinics of North America, vol. 6, no. 3, pp. 539-550.
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Twin and family studies provide strong evidence for a genetic affect on bone density and bone turnover, but identifying the sources of this variance is a major challenge. Understanding of this topic can provide insight into the pathogenesis of osteoporosis and allow a more tailored treatment and prevention of this disorder.
Kelly, PJ, Morrison, NA, Sambrook, PN, Nguyen, TV & Eisman, JA 1995, 'Genetic influences on bone turnover, bone density and fracture', European Journal of Endocrinology, vol. 133, no. 3, pp. 265-271.
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Marchese, A, Beischlag, TV, Nguyen, T, Niznik, HB, Weinshank, RL, George, SR & O'Dowd, BF 1995, 'Two gene duplication events in the human and primate dopamine D5 receptor gene family', Gene, vol. 154, no. 2, pp. 153-158.
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The human dopamine D5 receptor (DRD5) gene family consists of the DRD5-encoding gene (DRD5) and the pseudogenes Ψ DRD5-1 and ΨDRD5-2. Analysis of the 5′ UTR of DRD5 and homologous regions in the pseudogenes revealed that the nucleotide identity (approx. 95%) extended for 1.9 kb and terminated at a monomeric Alu sequence in each of the pseudogenes. The presence of Alu sequences in the pseudogenes, at this point of divergence with DRD5, suggests that Alu sequences were involved in the evolution of the DRD5 family. This report is the first to describe a possible mechanism involved in the duplication of genes in the G-protein-coupled receptor (GPCR) family. The pseudogenes continue to share identity (approx. 98%) beyond this 5′ UTR point of divergence with DRD5 for at least another 6 kb. Analysis of the 3′ UTR of DRD5 and homologous regions in the pseudogenes revealed that the identity (approx. 95%) extends at least 14 kb, and the identity between the pseudogenes (approx. 98%) extends for at least 18 kb. Thus, the duplication unit that produced the first pseudogene was at least 16 kb, whereas the second pseudogene was at least 28 kb. We have also located two DRD5 pseudogenes in gorilla demonstrating that these closely related pseudogenes were present in a common ancestor of human and gorilla. © 1995.
MARCHESE, A, HEIBER, M, NGUYEN, T, HENG, HHQ, SALDIVIA, VR, CHENG, R, MURPHY, PM, TSUI, L-C, SHI, X, GREGOR, P, GEORGE, SR, O'DOWD, BF & DOCHERTY, JM 1995, 'Cloning and Chromosomal Mapping of Three Novel Genes, GPR9, GPR10, and GPR14, Encoding Receptors Related to Interleukin 8, Neuropeptide Y, and Somatostatin Receptors', Genomics, vol. 29, no. 2, pp. 335-344.
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We employed the polymerase chain reaction and genomic DNA library screening to clone novel human genes, GPR9 and GPR10, and a rat gene, GPR14. GPR9, GPR10, and GPR14 each encode G protein-coupled receptors. GPR10 and GPR14 are intronless within their coding regions, while GPR9 contains at least one intron. The receptor encoded by GPR9 shares the highest identity with human IL-8 receptor type B (38% overall and 53% in the transmembrane regions), followed by IL-8 receptor type A (36% overall and 51% in the transmembrane domains). GPR10 encodes a receptor that shares highest identity with the neuropeptide Y receptor (31% overall and 46% in the transmembrane domains). The receptor encoded by GPR14 shares highest identity with the somatostatin receptor SSTR 4 (27% overall and 41% in the transmembrane domains). Fluorescencein situhybridization analysis localized GPR9 to chromosome 8p11.2-p12 and GPR10 to chromosome 10q25.3-q26. © 1995 by Academic Press, Inc.
McBride, AJ & Thomas, H 1995, 'Psychosis is also common in users of 'normal' cannabis', BMJ, vol. 311, no. 7009, pp. 875-875.
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Nguyen, T, Erb, L, Weisman, GA, Marchese, A, Heng, HHQ, Garrad, RC, George, SR, Turner, JT & O'Dowd, BF 1995, 'Cloning, Expression, and Chromosomal Localization of the Human Uridine Nucleotide Receptor Gene', Journal of Biological Chemistry, vol. 270, no. 52, pp. 30845-30848.
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Extracellular ATP and ADP mediate diverse physiological responses in mammalian cells, in part through the activation of G protein-coupled P2 purinoceptors. The cloning and expression of cDNAs encoding several P2 purinoceptor subtypes have enabled rapid advances in our understanding of the structural and functional properties of these receptors. The current report describes the isolation of a gene from a human genomic library that encodes a protein with the greatest similarity to the human P(2U) purinoceptor, a subtype that is distinguished by its ability to be activated by uridine nucleotides as well as adenine nucleotides. When expressed in a mammalian cell line, this novel receptor is activated specifically by UTP and UDP but not by ATP and ADP. Activation of this uridine nucleotide receptor resulted in increased inositol phosphate formation and calcium mobilization. Fluorescence in situ hybridization revealed that the gene encoding the uridine nucleotide receptor is located in region q13 of the X chromosome. Dendrogram analysis of the G protein-coupled P2 purinoceptors and the uridine nucleotide receptor indicates that these receptors belong to a family that may be more aptly named nucleotide receptors.
Nguyen, TV 1995, 'Effects of estrogen exposure and reproductive factors on bone mineral density and osteoporotic fractures', Journal of Clinical Endocrinology & Metabolism, vol. 80, no. 9, pp. 2709-2714.
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Nguyen, TV, Jones, G, Sambrook, PN, White, CP, Kelly, PJ & Eisman, JA 1995, 'Effects of estrogen exposure and reproductive factors on bone mineral density and osteoporotic fractures.', The Journal of Clinical Endocrinology & Metabolism, vol. 80, no. 9, pp. 2709-2714.
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The risk of osteoporotic fracture is related to peak bone mass achieved at skeletal maturity and subsequent bone loss. Although premature menopause is a risk factor for osteoporosis, the effect of exposure to endogenous estrogen during a woman’s reproductive years is poorly characterized. We analyzed the relationship between reproductive factors and estrogen exposure on bone mineral density (BMD) and incidence of atraumatic fracture in data from 1091 women (age: 70 ± 7.2 yr; mean ± SD) participating in the Dubbo Osteoporosis Epidemiology Study. Age- and weight-adjusted BMD among women who had used estrogen replacement therapy (ERT) for more than 5 yr was higher at the lumbar spine and femoral neck by 13.7% and 10.2% (P < 0.001), respectively, compared with women who had used ERT for less than 5 yr or nonusers. Duration of exposure to estrogen (years of menstruation plus postmenopausal ERT use) was associated with higher BMD, such that BMD increased by 2-3% for every 10-yr increase in years of estrogen exposure; thus women who menstruated for more than 40 yr had a 6-8% higher BMD than did women who menstruated for less than 30 yr. Higher BMD was also significantly associated with high parity, such that nulliparous women had 5-6% lower BMD than did their peers of the same age and weight. The incidence of atraumatic fractures among non-ERT users was higher than that of ERT-users [odds ratio (OR): 1.06; 95% confidence interval (CI): 0.94-1.16] and was significantly lower among parous women than among nulliparous women (OR 0.94; 95% CI: 0.84-0.98) in univariate analysis. Longer duration of menstruation was associated with lower fracture incidence (OR for 1 SD = 6.6 yr: 0.93; 95% CI: 0.86-1.02). Moreover, when all of these factors were considered simultaneously, parity remained a significant determinant of fracture as well as femoral neck BMD. We conclude that high parity and longer duration of exposure to estrogen, either through natural menstruation or postmenopausal...
O'Dowd, BF, Scheideler, MA, Nguyen, T, Cheng, R, Rasmussen, JS, Marchese, A, Zastawny, R, Heng, HHQ, Tsui, L-C, Shi, X, Asa, S, Puy, L & George, SR 1995, 'The Cloning and Chromosomal Mapping of Two Novel Human Opioid-Somatostatin-like Receptor Genes, GPR7 and GPR8, Expressed in Discrete Areas of the Brain', Genomics, vol. 28, no. 1, pp. 84-91.
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Following the cloning of the opioid receptors μ, κ, and δ, we conducted a search for related receptors. Using oligonucleotides based on the opioid and also the structurally related somatostatin receptors, we amplified genomic DNA using the polymerase chain reaction and isolated fragments of novel G protein-coupled receptor genes. Two of these gene fragments designated clones 12 and 11 were used to isolate the full-length genes. The intronless coding sequences of these genes, named GPR7 and GPR8, shared 70% identity with each other, and each shared significant similarity with the sequences encoding transmembrane regions of the opioid and somatostatin receptors. GPR7 was mapped to chromosome 10q11.2-q21.1 and GPR8 chromosome 20q13.3. Northern blot analysis using human mRNA demonstrated expression of GPR7 mainly in cerebellum and frontal cortex, while GPR8 was located mainly in the frontal cortex. In situ hybridization revealed expression of GPR7 in the human pituitary. A partial sequence of the mouse orthologue of GPR7 was obtained, and in situ hybridization demonstrated expression in discrete nuclei of brain, namely suprachiasmatic, arcuate, and ventromedial nuclei of hypothalamus. A stable cell line expressing the GPR7 gene was created, but expression levels of the receptor were low. The available pharmacology indicated binding to several opioid drugs such as bremazocine, levorphanol, and β-FNA, but not to the opioid receptor subtype-selective μ, δ, or κ agonists. © 1995 Academic Press, Inc.
Peacock, M, Hustmyer, FG, Hui, S, Johnston, CC & Christian, J 1995, 'Vitamin D receptor genotype and bone mineral density', BMJ, vol. 311, no. 7009, pp. 874-875.
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Silhavy, DN, Hutv�gner, GR, Barta, E & B�nfalvi, ZF 1995, 'Isolation and characterization of a water-stress-inducible cDNA clone from Solanum chacoense', Plant Molecular Biology, vol. 27, no. 3, pp. 587-595.
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A rich source of valuable genes are wild species. Solanum chacoense Bitter with its extreme resistance to viruses, insects and drought, is a good example. In the present study, a stress gene, designated DS2, has been isolated from S. chacoense. We have shown that the expression of the gene is organ-specific being detected in leaf, stem and stolon, but not in root, tuber or flower. Treatment of detached leaves with abscisic acid (ABA), salicylic acid or methyl jasmonate resulted in only very moderate accumulation of DS2 mRNA. Thus, DS2 represents a very rare type of the water-stress-inducible genes whose signalling pathway is not primarily related to ABA. Based on DNA sequence analysis, DS2 encodes a putative protein starting with 20 amino acids homologous to the ABA- and water-stress-inducible, ripening-related (ASR) proteins of tomato continued by an insert of 155 amino acids structurally similar to certain LEAs (late embryogenesis-abundant proteins) and ending in 88 amino acids homologous again to the ASR sequences and to an unpublished partial cDNA fragment isolated from the root of rice. The N-terminal region of the DS2 protein is hydrophilic with ten 13-mer amino acid motifs and random coil structure. In contrast, the C-terminus predicts an α-helix and possesses a bipartite nuclear targeting sequence motif. These data suggest that the function of the DS2 may be the protection of the nuclear DNA from desiccation. © 1995 Kluwer Academic Publishers.
Spector, TD, Keen, RW, Arden, NK, Morrison, NA, Major, PJ, Nguyen, TV, Kelly, PJ, Baker, JR, Sambrook, PN, Lanchbury, JS & Eisman, JA 1995, 'Influence of vitamin D receptor genotype on bone mineral density in postmenopausal women: a twin study in Britain', BMJ, vol. 310, no. 6991, pp. 1357-1360.
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