Besong, AA, Tipper, JL, Ingham, E, Stone, MH, Wroblewski, BM & Fisher, J 1998, 'Quantitative comparison of wear debris from UHMWPE that has and has not been sterilised by gamma irradiation', The Journal of Bone and Joint Surgery, vol. 80, no. 2, pp. 340-344.
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El-Ghundi, M, George, SR, Drago, J, Fletcher, PJ, Fan, T, Nguyen, T, Liu, C, Sibley, DR, Westphal, H & O'Dowd, BF 1998, 'Disruption of dopamine D1 receptor gene expression attenuates alcohol-seeking behavior', European Journal of Pharmacology, vol. 353, no. 2-3, pp. 149-158.
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The role of the dopamine D1 receptor subtype in alcohol-seeking behaviors was studied in mice genetically deficient in dopamine D1 receptors (D1-/-). In two-tube free choice limited (1-5 h) and continuous (24 h) access paradigms, mice were exposed to water and increasing concentrations of ethanol (3%, 6% and 12% w/v). Voluntary ethanol consumption and preference over water were markedly reduced in D1-/- mice as compared to heterozygous (D1+/-) and wild-type (D1+/+) controls, whereas overall fluid consumption was comparable. When offered a single drinking tube containing alcohol as their only source of fluid for 24 h, D1-/- mice continued to drink significantly less alcohol than D1+/+ and D1+/- mice. Dopamine D2 receptor blockade with sulpiride caused a small but significant reduction in alcohol intake and preference in D1+/+ mice and attenuated residual alcohol drinking in D1-/- mice. Dopamine D1 receptor blockade with SCH-23390 very effectively reduced alcohol intake in D1+/+ and D1+/- mice to the level seen in untreated D1-/- mice. These findings suggest involvement of both dopamine D1 and D2 receptor mechanisms in alcohol-seeking behavior in mice; however, these implicate D1 receptors as having a more important role in the motivation for alcohol consumption. Copyright (C) 1998 Elsevier Science B.V.
Gough, A, Sambrook, P, Devlin, J, Huissoon, A, Njeh, C, Robbins, S, Nguyen, T & Emery, P 1998, 'Osteoclastic activation is the principal mechanism leading to secondary osteoporosis in rheumatoid arthritis.', J Rheumatol, vol. 25, no. 7, pp. 1282-1289.
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OBJECTIVE: To use clinical measures and biochemical markers of bone turnover to investigate mechanisms of generalized bone loss in early rheumatoid arthritis (RA). METHODS: We studied 232 patients with RA of less than 2 years' duration and 72 healthy controls using serial dual x-ray absorptiometry scanning of lumbar spine and hips. Patients attended the clinic for clinical and laboratory assessment with storage of serum, urine, and plasma at each visit. Change in bone mineral density (BMD) was calculated for patients and controls and compared with baseline and mean serial values of bone markers over the same intervals. Serum was assayed for procollagen I carboxyterminal propeptide (PICP) and skeletal alkaline phosphatase (sALP); urine for pyridinoline and deoxypyridinoline corrected for creatinine; and plasma for interleukin 1 (IL-1) and IL-6. RESULTS: Patients lost bone significantly faster than controls at all sites (p < 0.01 for all). At first visit patients had significantly lower PICP levels than controls (p < 0.05) and sALP correlated with initial BMD in both patients (p < 0.01, r > 0.35, all sites) and controls (p < 0.0001, r > 0.50, all sites). We rescanned 167 patients at one year and 121 patients at 2 years. Mean urinary pyridinoline and deoxypyridinoline levels correlated strongly with BMD change at all sites, were increased in patients with active disease (p < 0.005), and correlated closely with mean C-reactive protein (CRP) (p < 0.005, r > 0.41 for both). CONCLUSION: This study suggests that osteoclastic activation, rather than suppression of bone formation, is the dominant process leading to bone loss in early RA. Although urinary pyridinoline and deoxypyridinoline were excellent markers of BMD change, CRP was found to be best overall. This provides a rational approach for selecting and treating patients with RA to reduce their established longterm risk of osteoporotic fracture.
Gough, A, Sambrook, P, Devlin, J, Lilley, J, Huisoon, A, Betteridge, J, Franklyn, J, Nguyen, T, Morrison, N, Eisman, J & Emery, P 1998, 'Effect of vitamin D receptor gene alleles on bone loss in early rheumatoid arthritis.', J Rheumatol, vol. 25, no. 5, pp. 864-868.
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OBJECTIVE: Rheumatoid arthritis (RA) is a polygenic disease characterized by localized joint destruction and generalized osteoporosis resulting in increased fracture risk. The pathogenetic mechanisms that determine the severity of generalized bone loss in RA are poorly understood. Polymorphisms in the vitamin D receptor (VDR) gene have been described as a significant determinant of bone turnover and mass. In this prospective study we describe VDR gene allele effects on bone loss in patients with early RA. METHODS: We recruited 232 patients with early RA. Bone mineral density measurements were repeated in 167 patients. Serial clinical and laboratory measures were recorded during the period of followup. DNA extraction, polymerase chain reaction amplification, and restriction fragment length polymorphism analysis of VDR alleles were performed using standard techniques. Presence of the Taq restriction site for both alleles was denoted 'tt', and absence 'TT'. RESULTS: In women with RA the tt genotype group lost bone more rapidly than subjects with TT genotype at both the lumbar spine (-0.1 vs -4.9% p.a, respectively; p < 0.05) and femoral neck (-3.9 vs -9.6%, respectively; p < 0.01). The effect was independent of other disease characteristics. CONCLUSION: The presence of the VDR gene 't' allele in female patients with RA was associated with accelerated bone loss.
Harris, M, Nguyen, TV, Howard, GM, Kelly, PJ & Eisman, JA 1998, 'Genetic and Environmental Correlations Between Bone Formation and Bone Mineral Density: A Twin Study', Bone, vol. 22, no. 2, pp. 141-145.
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Hoffman, DM, Pallasser, R, Duncan, M, Nguyen, TV & Ho, KKY 1998, 'How Is Whole Body Protein Turnover Perturbed in Growth Hormone-Deficient Adults?1', The Journal of Clinical Endocrinology & Metabolism, vol. 83, no. 12, pp. 4344-4349.
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Adult patients with GH deficiency have reduced lean body mass (LBM), muscle mass, and muscle strength, suggesting an underlying abnormality of protein metabolism. As acute GH administration has previously been reported to decrease protein oxidation and increase protein synthesis in GH-deficient (GHD) adults, we investigated whether the converse might occur in untreated GH deficiency by undertaking studies of whole body protein turnover in 10 GHD and 13 normal subjects using a 3-h primed constant infusion of 1-[13C]leucine. Dual energy x-ray absorptiometry was used to quantify LBM and fat mass (FM). In normal subjects, LBM was the major, independent determinant of leucine appearance (Ra; r = 0.80; P = 0.0009), leucine oxidation (r = 0.81; P = 0.0008), and leucine incorporation into protein (r = 0.75; P = 0.003). However, in an analysis of covariance, FM was also a significant independent determinant of leucine Ra (P = 0.002) and leucine incorporation into protein (P = 0.003). After correcting for LBM and FM, GHD patients had significantly reduced rates of leucine Ra (109.9 ± 4.4 vs. 125.5 ± 3.7 μmol/min, respectively; P = 0.02) and leucine incorporation into protein (87.0 ± 3.9 vs. 100.3 ± 3.3 mmol/min; P = 0.02) compared to normal subjects. There was no significant difference in the corrected rates of leucine oxidation between the two groups (22.9 ± 1.3 vs. 25.2± 1.0, GHD vs. normal; P = 0.20). In summary, GHD adults have reduced rates of protein synthesis and protein breakdown, but normal rates of irreversible oxidative loss; these findings are discordant with what was predicted from the acute changes in protein metabolism observed with GH administration. We conclude that normalization of protein oxidation may be a homeostatic mechanism that operates to constrain protein loss in GHD adults.
Howard, G, Nguyen, T, Morrison, N, Watanabe, T, Sambrook, P, Eisman, J & Kelly, P 1998, 'Genetic influences on bone density: physiological correlates of vitamin D receptor gene alleles in premenopausal women. Notification of genotype corrections.', J Clin Endocrinol Metab, vol. 83, no. 3, pp. 1043-1043.
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Howard, GM, Nguyen, TV, Harris, M, Kelly, PJ & Eisman, JA 1998, 'Genetic and Environmental Contributions to the Association Between Quantitative Ultrasound and Bone Mineral Density Measurements: A Twin Study', Journal of Bone and Mineral Research, vol. 13, no. 8, pp. 1318-1327.
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Abstract This study was designed to assess the relative contributions of genetic and environmental factors to the variation and covariation of quantitative ultrasound (QUS) measurements and their relationships to bone mineral density (BMD). Forty-nine monozygotic (MZ) and 44 dizygotic (DZ) female twins between 20 and 83 years of age (53 ± 13 years, mean ± SD) were studied. Digital (phalangeal) QUS (speed of sound [SOS]) and calcaneal QUS (broadband ultrasound attenuation [BUA] and velocity of sound [VOS]) were measured using a DBM Sonic 1200 ultrasound densitometer and a CUBA ultrasound densitometer, respectively. Femoral neck (FN), lumbar spine (LS), and total body (TB) BMD were measured using dual-energy X-ray absorptiometry. Familial resemblance and hence heritability (proportion of variance of a trait attributable to genetic factors) were assessed by analysis of variance, univariate, and multivariate model-fitting genetic analyses. In both QUS and BMD parameters, MZ twins were more alike than DZ pairs. Estimates of heritability for age- and weight-adjusted BUA, VOS, and SOS were 0.74, 0.55, and 0.82, respectively. Corresponding indices of heritability for LS, FN, and TB BMD were 0.79, 0.77, and 0.82, respectively. In cross-sectional analysis, both BUA and SOS, but not VOS, were independently associated with BMD measurements. However, analysis based on intrapair differences suggested that only BUA was related to BMD. Bivariate genetic analysis indicated that the genetic correlations between BUA and BMD ranged between 0.43 and 0.51 (p < 0.001), whereas the environmental correlations ranged between 0.20 and 0.28 (p < 0.01). While the genetic correlations within QUS and BMD measurements were significant, factor analysis indicates that common genes affect BMD at different sites. Also, individual QUS measurements appear to be influenced by some common sets of genes rather than by environmental ...
Kolakowski, LF, O'Neill, GP, Howard, AD, Broussard, SR, Sullivan, KA, Feighner, SD, Sawzdargo, M, Nguyen, T, Kargman, S, Shiao, L, Hreniuk, DL, Tan, CP, Evans, J, Abramovitz, M, Chateauneuf, A, Coulombe, N, Ng, G, Johnson, MP, Tharian, A, Khoshbouei, H, George, SR, Smith, RG & O'Dowd, BF 1998, 'Molecular Characterization and Expression of Cloned Human Galanin Receptors GALR2 and GALR3', Journal of Neurochemistry, vol. 71, no. 6, pp. 2239-2251.
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Abstract: Galanin is a 29‐ or 30‐amino acid peptide with wide‐ranging effects on hormone release, feeding behavior, smooth muscle contractility, and somatosensory neuronal function. Three distinct galanin receptor (GALR) subtypes, designated GALR1, 2, and 3, have been cloned from the rat. We report here the cloning of the human GALR2 and GALR3 genes, an initial characterization of their pharmacology with respect to radioligand binding and signal transduction pathways, and a profile of their expression in brain and peripheral tissues. Human GALR2 and GALR3 show, respectively, 92 and 89% amino acid sequence identity with their rat homologues. Radioligand binding studies with 125I‐galanin show that recombinant human GALR2 binds with high affinity to human galanin (KD = 0.3 nM). Human GALR3 binds galanin with less affinity (IC50 of 12 nM for porcine galanin and 75 nM for human galanin). Human GALR2 was shown to couple to phospholipase C and elevation of intracellular calcium levels as assessed by aequorin luminescence in HEK‐293 cells and by Xenopus melanophore pigment aggregation and dispersion assays, in contrast to human GALR1 and human GALR3, which signal predominantly through inhibition of adenylate cyclase. GALR2 mRNA shows a wide distribution in the brain (mammillary nuclei, dentate gyrus, cingulate gyrus, and posterior hypothalamic, supraoptic, and arcuate nuclei), and restricted peripheral tissue distribution with highest mRNA levels detected in human small intestine. In comparison, whereas GALR3 mRNA was expressed in many areas of the rat brain, there was abundant expression in the primary olfactory cortex, olfactory tubercle, the islands of Calleja, the hippocampal CA regions of Ammon's horn, and the dentate gyrus. GALR3 ...
Lakatos, L, Hutvágner, G & Bánfalvi, Z 1998, 'Potato protein kinase StCPK1: a putative evolutionary link between CDPKs and CRKs', Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression, vol. 1442, no. 2-3, pp. 101-108.
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Calcium-dependent protein kinases (CDPKs) in plants are characterized by a four-domain structure including conserved sequences in the catalytic domain, and in the C-terminal calmodulin-like domain. Based on this conservation we have PCR amplified and iso
Marchese, A, Nguyen, T, Malik, P, Xu, S, Cheng, R, Xie, Z, Heng, HHQ, George, SR, Kolakowski, LF & O'Dowd, BF 1998, 'Cloning Genes Encoding Receptors Related to Chemoattractant Receptors', Genomics, vol. 50, no. 2, pp. 281-286.
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We report the cloning of a novel human gene (GPR32) encoding a putative G-protein-coupled receptor (GPCR) of 356 amino acids and a related pseudogene ψGPR32. The deduced amino acid sequence of GPR32 shares 35-39% identity with members of the chemoattractant receptor family. ψGPR32 shares 93% nucleotide identity with GPR32. We identified a mouse EST encoding a putative GPCR (GPR33) of 309 amino acids. The deduced amino acid sequence of GPR33 shares 30-35% identity with members of the chemoattractant receptor family and 36% identity with the receptor encoded by GPR32. The human orthologue of GPR33 contains a single basepair substitution with respect to the mouse, resulting in the presence of an in-frame stop codon within the predicted second intracellular loop, demonstrating that it is a pseudogene. Through fluorescence in situ hybridization and physical mapping of YACs, both GPR32 and ψGPR32 were mapped to chromosomal 19, region q13.3, while ψGPR33 was mapped to chromosome 14q12.
Nguyen, TV 1998, 'Science in Vietnam', Science, vol. 280, no. 5366, pp. 983-983.
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Nguyen, TV, Eisman, JA, Mizunuma, H & Okano, H 1998, 'Does Postmenopausal Bone Loss Occur in Two Phases?', Journal of Bone and Mineral Research, vol. 13, no. 8, pp. 1350-1351.
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Nguyen, TV, Howard, GM, Kelly, PJ & Eisman, JA 1998, 'Bone Mass, Lean Mass, and Fat Mass: Same Genes or Same Environments?', American Journal of Epidemiology, vol. 147, no. 1, pp. 3-16.
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Nguyen, TV, Sambrook, PN & Eisman, JA 1998, 'Bone Loss, Physical Activity, and Weight Change in Elderly Women: The Dubbo Osteoporosis Epidemiology Study', Journal of Bone and Mineral Research, vol. 13, no. 9, pp. 1458-1467.
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Abstract The present study examined the effects of physical activity, weight, and weight change on femoral bone loss in relation to age in elderly women. Baseline and follow-up measurements at an average interval of 2.7 years of femoral neck bone mineral density (BMD) were reanalyzed for 827 women who were part of the Dubbo Osteoporosis Epidemiology Study. Physical activity was assessed based on hours per day spent in each of various activities according to its expected oxygen consumption. The rate of loss of BMD progressively increased with age, i.e., −0.6 ± 0.1, −1.1 ± 0.2, and −2.1 ± 0.6% per year (mean ± SEM) for the 60–69, 70–79, and ≥80 age groups, respectively (p < 0.001). After adjustment for age, physically inactive women lost more (−1.4 ± 0.2% per year; p < 0.001), compared with physically active women (−0.5 ± 0.3% per year; p = 0.15). Thinner women experienced more rapid bone loss, and women whose weight decreased (≥5%) over the study period lost more bone (−1.7 ± 0.4% per year) than those whose weight was stable (−0.8 ± 0.1% per year) or increased (+0.1 ± 0.3% per year; p < 0.01, analysis of variance). Furthermore, women whose BMD was high (>0.81 g/cm2) at baseline experienced greater loss (−1.1 ± 0.2%) compared with those in the middle tertile (1.0 ± 0.2%) or lowest tertile (−0.5 ± 0.3%). Independent predictors of rate of bone loss included age, baseline BMD, weight, weight change, and physical activity; collectively these factors accounted for 13% of total variance of bone loss by multiple regression analysis. It is concluded that a physically active lifestyle and stable weight in the later decades of life may retard proximal femur bone loss and thus contribute to reduction of fracture risk.
O'Dowd, BF, Nguyen, T, Marchese, A, Cheng, R, Lynch, KR, Heng, HHQ, Kolakowski, LF & George, SR 1998, 'Discovery of Three Novel G-Protein-Coupled Receptor Genes', Genomics, vol. 47, no. 2, pp. 310-313.
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We report here the molecular cloning, tissue distribution, and chromosomal localization of novel genes encoding G-protein-coupled receptors (GPCRs). A search of a mouse database of expressed sequence tags revealed an EST partially encoding a GPCR, which was used to screen a mouse genomic library to obtain the translational open reading frame (ORF). The resultant clone, GPR27, contained an intronless ORF, encoding a receptor of 379 amino acids. In an alternate strategy, human genomic DNA was subjected to polymerase chain reaction (PCR) amplification, using degenerate oligonucleotides based on GPR1. Two PCR products partially encoding GPCRs were isolated and used to screen a genomic library to obtain the translational ORF. One of the resultant clones, GPR30, contained an intronless ORF encoding a receptor of 375 amino acids. The other clone, GPR35, also contained an intronless ORF encoding a receptor of 309 amino acids. Transcripts corresponding to GPR27 and GPR30 were detected in several areas of human and rat CNS, while GPR35 expression was detected only in the rat intestine. Through fluorescence in situ hybridization analysis the gene encoding GPR30 was localized to chromosome 7p22 and GPR35 to chromosome 2q37.3.
Randell, AG, Bhalerao, N, Nguyen, TV, Sambrook, PN, Eisman, JA & Silverman, SL 1998, 'Quality of life in osteoporosis: reliability, consistency, and validity of the Osteoporosis Assessment Questionnaire.', J Rheumatol, vol. 25, no. 6, pp. 1171-1179.
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OBJECTIVE: To determine the reliability, consistency, and clinical utility of the Osteoporosis Assessment Questionnaire (OPAQ), an AIMS2 based self-assessment questionnaire. METHODS: Reliability of individual questions, scales, and domains were evaluated in 40 subjects by test-retest and intraclass correlation coefficients and internal consistency by Cronbach's alpha. Construct validity was evaluated by disease state. The relationships between domains and scales were modeled by confirmatory factor analysis. RESULTS: Mean kappa (79 questions) and intraclass correlation (18 health scales) coefficients were 0.58+/-0.16 (mean+/-SD) and 0.82+/-0.07, respectively. Internal consistency was greater than 0.8 in all but 3 scales. Construct validity was confirmed. Patients with hip fracture recorded lower OPAQ scores than patients with vertebral fracture. Correlation and confirmatory factor analyses grouped the 18 health scales into 7 domains. CONCLUSION: These findings suggest that OPAQ is a reliable, consistent, and valid instrument capable of distinguishing hierarchy of functional loss in disease states in osteoporosis.
Tipper, JL, Ingham, E, Cove, JH, Todd, NJ & Kerr, KG 1998, 'Survival and multiplication of Burkholderia cepacia within respiratory epithelial cells', Clinical Microbiology and Infection, vol. 4, no. 8, pp. 450-459.
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Objective: To investigate the ability of both clinical and environmental strains of Burkholderia cepacia, along with control strains of Pseudomonas aeruginosa and Escherichia coli, to invade a respiratory epithelial cell line, A549. Methods and Results: Using a double immunofluorescence labeling technique, a clinical strain of B. cepacia, C1359, and the clonally related strains A509 and J2315, were shown to invade A549 cells at a high level (2-8% A549 cells invaded) compared to environmental strains of B. cepacia NCTC 10661 and NCTC 10743 (0.5-1% of A549 cells invaded). Control strains of P. aeruginosa PAO1 and E. coli C600 did not appear to be able to invade respiratory epithelial cells using this method. Ceftazidime protection assays revealed that B. cepacia C1359 and NCTC 10743 were able to survive and multiply within A549 cells for > 24 h. In contrast, B. cepacia NCTC 10661, P. aeruginosa PAO1 and E. coli C600 failed to multiply within A549 cells, showing a significant decrease in numbers after 24 h. Conclusions: The ability to survive and multiply within respiratory epithelial cells may be an important virulence factor of B. cepacia infection in cystic fibrosis.
