Center, JR, Nguyen, TV, Sambrook, PN & Eisman, JA 1999, 'Hormonal and Biochemical Parameters in the Determination of Osteoporosis in Elderly Men*', The Journal of Clinical Endocrinology & Metabolism, vol. 84, no. 10, pp. 3626-3635.
View/Download from: Publisher's site
View description>>
Abstract The extent to which changes in several hormonal and biochemical parameters are involved in the pathogenesis of osteoporosis in men remains controversial. This study examined the roles of free testosterone (T), estradiol (E2), sex hormone-binding globulin (SHBG), 25-hydroxyvitamin D, PTH, and insulin-like growth factor I in the determination of bone mineral density (BMD) in 437 community-dwelling elderly men. Age, height, weight, quadriceps strength, and femoral neck (FN) and lumbar spine (LS) BMD were also obtained. In multiple regression analysis, after adjusting for age and weight, low E2 (P = 0.01), and high SHBG (P = 0.0002) levels were common determinants of FN and LS BMD. In addition, high PTH (P = 0.03) was an independent predictor of FN BMD, and low free T (P = 0.02) was an independent predictor of LS BMD. Low free T was associated with FN BMD in univariate analysis only. The hormonal measurements collectively accounted for 5% and 7% of the age- and weight-adjusted variance of FN and LS BMD, respectively. The sex steroids, SHBG and insulin-like growth-I were found to be interrelated using a technique of path analysis that examines the intercorrelation between these variables. A subject with any one abnormal serum parameter had a 4-fold increase in the risk of osteoporosis, whereas three abnormal parameters were associated with an 11-fold increased risk, although the latter group only applied to 1% of the study population. Although the precise causal effects these biochemical parameters may have on the development of osteoporosis remains to be determined, the present findings support an important interrelated role for these hormonal and biochemical parameters on changes in bone density in elderly men.
Center, JR, Nguyen, TV, Schneider, D, Sambrook, PN & Eisman, JA 1999, 'Mortality after all major types of osteoporotic fracture in men and women: an observational study', The Lancet, vol. 353, no. 9156, pp. 878-882.
View/Download from: Publisher's site
Endo, MM, Barbour, PS, Barton, DC, Wroblewski, BM, Fisher, J, Tipper, JL, Ingham, E & Stone, MH 1999, 'A comparison of the wear and debris generation of GUR 1120 (compression moulded) and GUR 4150HP (ram extruded) ultra high molecular weight polyethylene.', Biomed Mater Eng, vol. 9, no. 2, pp. 113-124.
View description>>
The wear debris generated from UHMWPE (ultra high molecular weight polyethylene) has been recognised as one of the major causes of failure in THR (total hip replacement). GUR 1120 (compression moulded) and GUR 4150HP (ram extruded) which are currently the most frequently used materials in THR were studied in pin-on-plate wear test. The wear particles generated from this test were observed by scanning electron micrograph and analysed by image analysis. The results from this study showed that GUR 4150HP had superior wear resistance than GUR 1120 under relatively high wear factor conditions. These results also highlighted the importance of multidirectional motion and its effect on the wear rates of UHMWPE. The multidirectional motion tended to show a higher wear factor than previous studies using unidirectional motion conducted under otherwise similar conditions. The wear debris analysis conducted with the wear particles collected from unidirectional (relatively rough) pin-on-plate wear tests (GUR 1120 and GUR 4150HP) showed that the greatest number of particles had a size range of 0.1-0.5 micron followed by 0.5-1.0 micron, 1.0-5.0 microns and 5.0-10.0 microns, in both GUR 1120 and GUR 4150HP. However, comparing the masses of the wear particles, the bigger size range of greater than 10 microns, had the highest percent mass followed by 1.0-5.0 microns, 0.5-1.0 micron, 0.1-0.5 micron and 5.0-10.0 microns.
Ensrud, KE, Stone, K, Cauley, JA, White, C, Zmuda, JM, Nguyen, TV, Eisman, JA & Cummings, SR 1999, 'Vitamin D Receptor Gene Polymorphisms and the Risk of Fractures in Older Women', Journal of Bone and Mineral Research, vol. 14, no. 10, pp. 1637-1645.
View/Download from: Publisher's site
Lee, DK, Nguyen, T, O'Neill, GP, Cheng, R, Liu, Y, Howard, AD, Coulombe, N, Tan, CP, Tang-Nguyen, A-T, George, SR & O'Dowd, BF 1999, 'Discovery of a receptor related to the galanin receptors', FEBS Letters, vol. 446, no. 1, pp. 103-107.
View/Download from: Publisher's site
View description>>
We report the isolation of a cDNA clone named GPR54, which encodes a novel G protein‐coupled receptor (GPCR). A PCR search of rat brain cDNA retrieved a clone partially encoding a GPCR. In a library screening this clone was used to isolate a cDNA with an open reading frame (ORF) encoding a receptor of 396 amino acids long which shared significant identities in the transmembrane regions with rat galanin receptors GalR1 (45%), GalR3 (45%) and GalR2 (44%). Northern blot and in situ hybridization analyses revealed that GPR54 is expressed in brain regions (pons, midbrain, thalamus, hypothalamus, hippocampus, amygdala, cortex, frontal cortex, and striatum) as well as peripheral regions (liver and intestine). In COS cell expression of GPR54 no specific binding was observed for 125I‐galanin. A recent BLAST search with the rat GPR54 ORF nucleotide sequence recovered the human orthologue of GPR54 in a 3.5 Mb contig localized to chromosome 19p13.3.
Lee, DK, Nguyen, T, Porter, CA, Cheng, R, George, SR & O'Dowd, BF 1999, 'Two related G protein-coupled receptors: The distribution of GPR7 in rat brain and the absence of GPR8 in rodents', Molecular Brain Research, vol. 71, no. 1, pp. 96-103.
View/Download from: Publisher's site
View description>>
GPR7 and GPR8, orphan G protein-coupled receptor (GPCR) genes, expressed in the brain and periphery share highest sequence identity to each other and significant similarity with opioid and somatostatin receptors. To further our knowledge of GPR7's physiological function, we performed in situ hybridization analyses of rat brain to reveal specific patterns of expression in the brain. GPR7 mRNA was found to be discretely localized in areas of the amygdala, hippocampus, hypothalamus and cortex. We previously reported that GPR7 was highly conserved in both human and rodent orthologs while GPR8 was not found in the rodent . We speculated that GPR8 originated after the divergence of the human and rodent. Using primers designed from human GPR8, we isolated lemur GPR8 and subsequently aligned human, monkey, and lemur GPR8 orthologs to design primers recognizing highly conserved regions of GPR8. Using these primers, orthologs of GPR7 and GPR8 were isolated by the PCR from rabbit, tree shrew, and flying lemur, as well as GPR7 in the rat. Subsequent analysis of the clones obtained demonstrated that both GPR7 and GPR8 sequences were highly conserved amongst the species studied, but a rodent GPR8 was not isolated. The absence of a GPR8 gene in the rodent suggests that GPR8 originated from gene duplication of GPR7 after the rodent line diverged from the rabbit, tree shrew, flying lemur, lemur, monkey and human lines. In addition, the taxonomic distribution of GPR8 is consistent with molecular studies grouping rabbits with primates, tree shrews and flying lemurs rather than with rodents. Copyright (C) 1999 Elsevier Science B.V.
Marchese, A, Sawzdargo, M, Nguyen, T, Cheng, R, Heng, HHQ, Nowak, T, Im, D-S, Lynch, KR, George, SR & O'Dowd, BF 1999, 'Discovery of Three Novel Orphan G-Protein-Coupled Receptors', Genomics, vol. 56, no. 1, pp. 12-21.
View/Download from: Publisher's site
View description>>
We have discovered three novel human genes, GPR34, GPR44, and GPR45, encoding family A G-protein-coupled receptors (GPCRs). The receptor encoded by GPR34 is most similar to the P2Y receptor subfamily, while the receptor encoded by GPR44 is most similar to chemoattractant receptors. The receptor encoded by GPR45 is the mammalian orthologue of a putative lysophosphatidic acid receptor from Xenopus laevis. Partial sequence of GPR34 was discovered during a search of the GenBank database of expressed sequence tags (ESTs). This sequence information was used both to isolate the full-length translational open reading frame from a human genomic library and to assemble a contig from additional GPR34 EST cDNAs. Northern blot and in situ hybridization analyses revealed GPR34 mRNA transcripts in several human and rat brain regions. Also, we used polymerase chain reaction (PCR) to amplify human genomic DNA using degenerate oligonucieotides designed from sequences encoding transmembrane domains 3 and 7 of opioid and somatostatin receptors. Two PCR products partially encoding novel GPCRs, named GPR44 and GPR45, were discovered and used to isolate the full-length translational open reading frames from a human genomic library. Both GPR44 and GPR45 are expressed in the central nervous system and periphery. For chromosomal localization, fluorescence in situ hybridization analysis was performed to assign GPR34 to chromosomes 4p12 and Xp11.3, GPR44 to chromosome 11q12-q13.3, and GPR45 to chromosome 2q11.1-q12.
O'Dowd, BF, Marchese, A, Lee, D, Nguyen, T & George, SR 1999, 'Novel orphan g protein-coupled receptors', Proceedings of the Western Pharmacology Society, vol. 42, p. 135.
View description>>
G protein-coupled receptors (GPCRs) belong to the gene family that forms 80% of all receptors. Cloning experiments have demonstrated a multiplicity of receptors which exceeds the number predicted on the basis of the pharmacological data alone. Using various strategies, novel receptor systems not known to exist previously have been identified. These receptors are known as orphans (oGPCRs), and over 70 have been identified. Recently, the natural ligands for four orphan receptors have been discovered, namely nociceptin, orexin, prolactin-releasing peptide and apelin. In our laboratory we isolated DNA encoding 36 novel oGPCRs, many of which are expressed in the CNS. We searched the expressed sequence tag (EST) DNA collections and also used degenerate oligos in the polymerase chain reaction, to identify partial cDNA or genomic clones. These clones were used to isolate DNAs that encompass the open reading frame of the novel GPCRs. Our approach combines bioinformatics expertise, molecular characterization and anatomic mapping, as well as a systematic approach to generating full-length, expressible GPCRs to generate novel receptor targets suitable for candidate ligand screening. Our interest is the discovery of novel cellular signaling systems, as well as developing a broad view of the evolution and genetics of these diverse gene families. The pursuit of cloning and identifying an individual receptor as a therapeutic target is a challenging task. However, the combined approach and expertise from our laboratory and collaborating scientists utilizing these technologies with many novel receptors has a high probability of identifying ligands for these targets and thus will allow the receptors to be used in the development of novel therapeutic agents.
Samaras, K, Nguyen, TV, Jenkins, AB, Eisman, JA, Howard, GM, Kelly, PJ & Campbell, LV 1999, 'Clustering of insulin resistance, total and central abdominal fat: same genes or same environment?', Twin Research, vol. 2, no. 3, pp. 218-225.
View/Download from: Publisher's site
View description>>
AbstractObesity, insulin resistance and disturbed glucose metabolism cluster within the Insulin Resistance Syndrome (IRS). Whether this reflects shared genetic or environmental factors detectable in ‘normal’ populations (not selected for IRS features) is unknown. This study estimated (i) genetic influences on IRS traits and (ii) shared and specific genetic and environmental factors on the relationships between these traits in healthy female twins. Fasting insulin, glucose, total and central fat were measured in 59 monozygotic (MZ) and 51 dizygotic (DZ) female twin pairs aged ( ± SD) 52 ± 13 years. Body fat was measured by dual-energy X-ray absorptiometry, insulin resistance and secretion by a modified homeostasis model assessment. Using intraclass correlation coefficients and univariate model-fitting analyses, genetic influences were found in total fat, central fat, insulin resistance, fasting glucose and insulin secretion, with genetic factors explaining 64, 57, 59, 75 and 68% of their variance, respectively, using the latter technique. In matched analysis intra-pair differences in total and central fat related to intra-pair differences in insulin resistance (r2 = 0.19, P < 0.001). Multivariate model-fitting showed a close genetic relationship between total and central fat (r = 0.88). The genetic correlation between IR and central fat (0.41) was significantly greater than that for total fat (0.24), suggesting that central fat is not only a predictor of, but shares considerable genetic influence with, insulin resistance. In Cholesky analysis, these genetic influences were separate from those shared between central and total fat. In conclusion, both shared and specific genetic factors regulate components of the IRS in healthy females. However, there were discrete genetic influences on -cell insulin secretion, not shared with other IRS components, suggesting that a separate genetic propensity exists for Type2 diabetes. ...
Sawzdargo, M, Nguyen, T, Lee, DK, Lynch, KR, Cheng, R, Heng, HHQ, George, SR & O'Dowd, BF 1999, 'Identification and cloning of three novel human G protein-coupled receptor genes GPR52, ΨGPR53 and GPR55: GPR55 is extensively expressed in human brain', Molecular Brain Research, vol. 64, no. 2, pp. 193-198.
View/Download from: Publisher's site
View description>>
The G protein-coupled receptor (GPCR) family share a structural motif of seven transmembrane segments with large numbers of conserved residues in those regions. Here, we report the identification and cloning of two novel human intronless GPCR genes, GPR52, GPR55 and a pseudogene ΨGPR53. GPR55 was identified from the expressed sequence tags (EST) database whereas GPR52 and pseudogene ΨGPR53 originated from the high throughput genome (HTG) database. A partial cDNA clone obtained from the IMAGE Consortium of GPR55 was used to screen a human genomic library to acquire the full length gene. GPR52 and ΨGPR53 were amplified from human genomic DNA using primers based on the HTG sequences. GPR55 and GPR52 encode receptors of 319 and 361 amino acids, respectively. GPR55 gene was mapped to chromosome 2q37, using fluorescence in situ hybridization (FISH), and its mRNA transcripts have been detected in the caudate nucleus and putamen, but not in five other brain regions. Human receptors showing the highest amino acid identity to GPR55 include P2Y5 (29%), GPR23 (30%), GPR35 (27%) and CCR4 (23%). GPR52 gene localized to chromosome 1q24 shares the highest identity with GPR21 (71%), histamine H2 (27%) and 5-HT4 (26%) human receptors. ΨGPR53 is a pseudogene mapped to chromosome 6p21 that demonstrates the highest similarity to the MRG (35%), MAS (28%) and C5a (24%) human receptor genes.
Tipper, JL 1999, 'Quantitative analysis of the wear and wear debris from low and high carbon content cobalt chrome alloys used in metal on metal total hip replacements', Journal of Materials Science: Materials in Medicine, vol. 10, no. 6, pp. 353-362.
View/Download from: Publisher's site
