Achuthan, A, Masendycz, P, Lopez, JA, Nguyen, T, James, DE, Sweet, MJ, Hamilton, JA & Scholz, GM 2008, 'Regulation of the Endosomal SNARE Protein Syntaxin 7 by Colony-Stimulating Factor 1 in Macrophages', Molecular and Cellular Biology, vol. 28, no. 20, pp. 6149-6159.
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ABSTRACT
Colony-stimulating factor 1 (CSF-1) is the main growth factor controlling the development of macrophages from myeloid progenitor cells. However, CSF-1 also regulates some of the key effector functions of macrophages (e.g., phagocytosis and cytokine secretion). The endosomal SNARE protein syntaxin 7 (Stx7) regulates vesicle trafficking events involved in phagocytosis and cytokine secretion. Therefore, we investigated the ability of CSF-1 to regulate Stx7. CSF-1 upregulated Stx7 expression in primary mouse macrophages; it also upregulated expression of its SNARE partners Vti1b and VAMP8 but not Stx8. Additionally, CSF-1 induced the rapid serine phosphorylation of Stx7 and enhanced its binding to Vti1b, Stx8, and VAMP8. Bioinformatics analysis and results from experiments with kinase inhibitors suggested the CSF-1-induced phosphorylation of Stx7 was mediated by protein kinase C and Akt in response to phosphatidylinositol 3-kinase activation. Based on mutagenesis studies, CSF-1 appeared to increase the binding of Stx7 to its SNARE partners by inducing the phosphorylation of serine residues in the Habc domain and/or “linker” region of Stx7. Thus, CSF-1 is a key regulator of Stx7 expression and function in macrophages. Furthermore, the effects of CSF-1 on Stx7 may provide a mechanism for the regulation of macrophage effector functions by CSF-1.
Ahlborg, HG, Nguyen, ND, Center, JR, Eisman, JA & Nguyen, TV 2008, 'Incidence and risk factors for low trauma fractures in men with prostate cancer', Bone, vol. 43, no. 3, pp. 556-560.
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Background: Men with prostate cancer on androgen deprivation therapy (ADT) are at increased risk of bone loss. The present study sought to determine the incidence of low trauma fracture in men with prostate cancer (PC), and to characterize the association between potential risk factors and fracture risk in these men. Methods: In the prospective, population-based Dubbo Osteoporosis Epidemiology Study, 43 men aged 60+ years reported a history of prostate cancer; among whom, 22 men received ADT, and 21 men did not. Low-trauma fractureswere ascertained between 1989 and 2004. Bone mineral density at the femoral neck (FNBMD), postural instability and lifestyle factors were obtained at baseline. Results: Men with prostate cancer had significantly higher lumbar spine BMD than those without cancer (p=0.013). During the follow-up period, 15 men with prostate cancer had sustained a fracture, yielding the ageadjusted incidence of fracture among this group was 31.6 per 1000 person-years, which was greater than those without cancer (22.1 per 1000 person-years). The age-adjusted incidence of fracture was more pronounced among those with prostate cancer on ADT (40.2 per 1000 person-years). After adjusting for age, the increase in fracture risk among prostate cancer patientswas associated with lower femoral neck BMD (hazard ratio [HR] per SD=1.8, 95% CI: 1.03.4) and increased rate of bone loss (HR 2.3, 1.24.6). Conclusions: Menwith prostate cancer, particularly those treated with ADT, had an increased fracture risk. Although the average BMD inmen with prostate cancerwas higher thanmen without cancer, a lowBMDprior to treatment or increased rate of bone loss after initiating ADT treatment was each a significant predictor of fracture in these.
Gentile, C, Fleming, PA, Mironov, V, Argraves, KM, Argraves, WS & Drake, CJ 2008, 'VEGF‐mediated fusion in the generation of uniluminal vascular spheroids', Developmental Dynamics, vol. 237, no. 10, pp. 2918-2925.
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AbstractEmbryonic mouse allantoic tissue (E8.5) was cultured in hanging drops to generate a three‐dimensional vascular micro‐tissue. The resulting tissue spheroids had an inner network of small diameter vessels expressing platelet endothelial cell adhesion molecule‐1 (PECAM‐1) and an outer layer of cells expressing SMαA, SM22‐α, and SM‐MHC. In a subsequent phase of culture, the fusion‐promoting activity of vascular endothelial growth factor (VEGF) was used to transform the inner network of small diameter endothelial tubes into a contiguous layer of cells expressing PECAM‐1, CD34, and VE‐cadherin that circumscribed a central lumen‐like cavity. The blood vessel‐like character of the VEGF‐treated spheroids was further demonstrated by their physiologically relevant vasodilatory and contractile responses, including contraction induced by KCl and relaxation stimulated by high‐density lipoproteins and acetylcholine‐induced nitric oxide production. Developmental Dynamics 237:2918–2925, 2008. © 2008 Wiley‐Liss, Inc.
Hutvagner, G & Simard, MJ 2008, 'Argonaute proteins: key players in RNA silencing', Nature Reviews Molecular Cell Biology, vol. 9, no. 1, pp. 22-32.
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During the past decade, small non-coding RNAs have rapidly emerged as important contributors to gene regulation. To carry out their biological functions, these small RNAs require a unique class of proteins called Argonautes. The discovery and our comprehension of this highly conserved protein family is closely linked to the study of RNA-based gene silencing mechanisms. With their functional domains, Argonaute proteins can bind small non-coding RNAs and control protein synthesis, affect messenger RNA stability and even participate in the production of a new class of small RNAs, Piwi-interacting RNAs. © 2008 Nature Publishing Group.
Khosroshahi, ME, Mahmoodi, M, Tavakoli, J & Tahriri, M 2008, 'Effect of Nd:Yttrium-aluminum-garnet laser radiation on Ti6Al4V alloy properties for biomedical applications', Journal of Laser Applications, vol. 20, no. 4, pp. 209-217.
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The effect of Nd:yttrium-aluminum-garnet laser on the microtopography and physicochemical properties of Ti6Al4V alloy are investigated in the view of biomedical applications. The surface roughness and hardness for laser treated samples (LTS) at 140 J cm−2 were measured 7±0.02 and 825 vickers hardness number, respectively. This superior microhardness value is attributed to grain refinement associated with laser melting and rapid solidification. The electrochemical property, mainly pitting corrosion resistance, has been carried out in Hanks salt balanced physiological solution using standard potentiodynamic polarization testing. A higher corrosion potential of −0.21 V was achieved for LTS. At the optimium treating value of laser fluence (140 J cm−2), the energy dispersive x-ray analysis showed about a 30% decrease of vanadium. The contact angle measurements also indicated an improved surface wettability (i.e., hydrophilicity) characteristic at 35°. Finally, the cell culture studies provided a useful tool to investigate the morphology and cell cytotoxicity.
Meier, C 2008, 'Endogenous Sex Hormones and Incident Fracture Risk in Older Men<subtitle>The Dubbo Osteoporosis Epidemiology Study</subtitle>', Archives of Internal Medicine, vol. 168, no. 1, pp. 47-47.
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Background: Data on the influence of gonadal hormones on incident fracture risk in elderly men are limited. We prospectively examined the relationship between serum levels of testosterone and estradiol and future fracture risk in community-dwelling men. Methods: A total of 609 men older than 60 years had been observed between January 1989 and December 2005, with the median duration being 5.8 years (up to 13 years). Clinical risk factors, including bone mineral density and lifestyle factors, were assessed at baseline. Serum testosterone and estradiol levels were measured by tandem mass spectrometry. The incidence of a low-trauma fracture was ascertained during follow-up. Results: During follow-up, 113 men had at least 1 low-trauma fracture. The risk of fracture was significantly increased in men with reduced testosterone levels (hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.09-1.62). After adjustment for sex hormone-binding globulin, serum testosterone (HR, 1.48; 95% CI, 1.22-1.78) and serum estradiol (HR, 1.21; 95% CI, 1.00-1.47) levels were associated with overall fracture risk. After further adjustment for major risk factors of fractures (age, weight or bone mineral density, fracture history, smoking status, calcium intake, and sex hormone-binding globulin), lower testosterone was still associated with increased risk of fracture, particularly with hip (HR, 1.88; 95% CI, 1.24-2.82) and nonvertebral (HR, 1.32; 95% CI, 1.03-1.68) fractures. Conclusion: in community-dwelling men older than 60 years, serum testosterone is independently associated with the risk of osteoporotic fracture and its measurement may provide additional clinical information for the assessment of fracture risk in elderly men.
Mudhasani, R, Zhu, Z, Hutvagner, G, Eischen, CM, Lyle, S, Hall, LL, Lawrence, JB, Imbalzano, AN & Jones, SN 2008, 'Loss of miRNA biogenesis induces p19Arf-p53 signaling and senescence in primary cells', The Journal of Cell Biology, vol. 181, no. 7, pp. 1055-1063.
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Dicer, an enzyme involved in microRNA (miRNA) maturation, is required for proper cell differentiation and embryogenesis in mammals. Recent evidence indicates that Dicer and miRNA may also regulate tumorigenesis. To better characterize the role of miRNA in primary cell growth, we generated Dicer-conditional mice. Ablation of Dicer and loss of mature miRNAs in embryonic fibroblasts up-regulated p19Arf and p53 levels, inhibited cell proliferation, and induced a premature senescence phenotype that was also observed in vivo after Dicer ablation in the developing limb and in adult skin. Furthermore, deletion of the Ink4a/Arf or p53 locus could rescue fibroblasts from premature senescence induced by Dicer ablation. Although levels of Ras and Myc oncoproteins appeared unaltered, loss of Dicer resulted in increased DNA damage and p53 activity in these cells. These results reveal that loss of miRNA biogenesis activates a DNA damage checkpoint, up-regulates p19Arf-p53 signaling, and induces senescence in primary cells.
Nguyen, ND, Frost, SA, Center, JR, Eisman, JA & Nguyen, TV 2008, 'Development of prognostic nomograms for individualizing 5-year and 10-year fracture risks', Osteoporosis International, vol. 19, no. 10, pp. 1431-1444.
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Summary: We have developed clinical nomograms for predicting 5-year and 10-year fracture risks for any elderly man or woman. The nomograms used age and information concerning fracture history, fall history, and BMD T-score or body weight. Introduction: Although many fracture risk factors have been identified, the translation of these risk factors into a prognostic model that can be used in primary care setting has not been well realized. The present study sought to develop a nomogram that incorporates non-invasive risk factors to predict 5-year and 10-year absolute fracture risks for an individual man and woman. Methods: The Dubbo Osteoporosis Epidemiology Study was designed as a community-based prospective study, with 1358 women and 858 men aged 60+ years as at 1989. Baseline measurements included femoral neck bone mineral density (FNBMD), prior fracture, a history of falls and body weight. Between 1989 and 2004, 426 women and 149 men had sustained a low-trauma fracture (not including morphometric vertebral fractures). Two prognostic models based on the Cox's proportional hazards analysis were considered: model I included age, BMD, prior fracture and falls; and model II included age, weight, prior fracture and fall. Results: Analysis of the area under the receiver operating characteristic curve (AUC) suggested that model I (AUC=0.75 for both sexes) performed better than model II (AUC=0.72 for women and 0.74 for men). Using the models' estimates, we constructred various nomograms for individualizing the risk of fracture for men and women. If the 5-year risk of 10% or greater is considered 'high risk', then virtually all 80-year-old men with BMD T-scores <-1.0 or 80-year-old women with T-scores <-2.0 were predicted to be in the high risk group. A 60-year-old woman's risk was considered high risk only if her BMD T-scores ≤-2.5 and with a prior fracture; however, no 60-year-old men would be in the high risk regardless of their BMD and risk profile. Conclus...
NGUYEN, TV 2008, 'Mapping translational research into individualized prognosis of fracture risk', International Journal of Rheumatic Diseases, vol. 11, no. 4, pp. 347-358.
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AbstractThe assessment of fracture risk has until now been based on the measurement of bone mineral density (BMD) and/or a prior fracture. Individuals with BMD T‐scores < –2.5 (e.g. osteoporosis) or with prior fractures are indicated for treatment. However, recent data have suggested that 55% of women and 74% of men who sustained a fracture did not have osteoporosis. Therefore, the current strategy reduces a small number of fractures in the general population, and new thinking is required for that majority of individuals whose BMD measurements are at or near (both sides) the current threshold of osteoporosis. An individual's absolute risk of fracture can be estimated from the individual risk profile, which includes age, BMD, weight or body mass index, prior fracture, comorbidities, corticosteroid use, lifestyle factors, and falls. Therefore, risk assessment must simultaneously consider all risk factors to which the individual is exposed. A number of prognostic models and predictive nomograms have been developed to estimate an individual's absolute risk of fracture, but they have not been externally validated. Nevertheless, these prognostic models can be effective tools for individualizing short‐term and long‐term risks of fracture, which can help patient counseling and selecting appropriate patients for intervention to maximize the benefit of fracture reduction in the general population.
Nguyen, TV, Center, JR & Eisman, JA 2008, 'Pharmacogenetics of osteoporosis and the prospect of individualized prognosis and individualized therapy', Current Opinion in Endocrinology, Diabetes & Obesity, vol. 15, no. 6, pp. 481-488.
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Purpose of review Description of recent progress in genetics and pharmacogenetics of osteoporosis. Recent findings Osteoporosis and its consequence of fragility fracture are characterized by highly complex phenotypes, which include bone mineral density,
Nguyen, TV, Nelson, AE, Howe, CJ, Seibel, MJ, Baxter, RC, Handelsman, DJ, Kazlauskas, R & Ho, KK 2008, 'Within-Subject Variability and Analytic Imprecision of Insulinlike Growth Factor Axis and Collagen Markers: Implications for Clinical Diagnosis and Doping Tests', Clinical Chemistry, vol. 54, no. 8, pp. 1268-1276.
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AbstractBackground: The utility of insulinlike growth factor (IGF) axis and collagen markers for a growth hormone (GH) doping test in sport depends on their stability and reproducibility. We sought to determine short-term within-subject variability of these markers in a large cohort of healthy individuals.Methods: We measured IGF-I, IGF binding protein 3 (IGFBP-3), acid labile subunit (ALS), and the collagen markers N-terminal propeptide of type I procollagen (PINP), C-terminal telopeptide of type I collagen (ICTP), and N-terminal propeptide of type III procollagen (PIIINP) in serum samples obtained on multiple occasions (median 3 per participant) over a 2- to 3-week period from 1103 elite athletes (699 men, 404 women) ages 22.2 (5.2) years [mean (SD)]. We estimated between-subject and within-subject variances by mixed–effects ANOVA.Results: Within-subject variance accounted for 32% to 36% and 4% to 13% of the total variance in IGF markers and collagen markers, respectively. The within-subject CV ranged from 11% to 21% for the IGF axis markers and from 13% to 15% for the collagen markers. The index of individuality for the IGF axis markers was 0.66–0.76, and for the collagen markers, 0.26–0.45. For each marker, individuals with initial extreme measured values tended to regress toward the population mean in subsequent repeated measurements. We developed a Bayesian model to estimate the long-term probable value for each marker.Conclusions: These results indicate that in healthy individuals the within-subject variability was greater for IGF-I than for the collagen markers, and that where a single measurement is available, it is possible to estimate the long-term probable value of each of the markers by applying the Bayesian approach. Such an application can increase the reliability and decrease the cost of detecting GH doping.
Pham, TD, Honghui Wang, Xiaobo Zhou, Dominik Beck, Brandl, M, Hoehn, G, Azok, J, Brennan, M-L, Hazen, SL, Li, K & Wong, STC 2008, 'Computational Prediction Models for Early Detection of Risk of Cardiovascular Events Using Mass Spectrometry Data', IEEE Transactions on Information Technology in Biomedicine, vol. 12, no. 5, pp. 636-643.
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Early prediction of the risk of cardiovascular events in patients with chest pain is critical in order to provide appropriate medical care for those with positive diagnosis. This paper introduces a computational methodology for predicting such events in the context of robust computerized classification using mass spectrometry data of blood samples collected from patients in emergency departments. We applied the computational theories of statistical and geostatistical linear prediction models to extract effective features of the mass spectra and a simple decision logic to classify disease and control samples for the purpose of early detection. While the statistical and geostatistical techniques provide better results than those obtained from some other methods, the geostatistical approach yields superior results in terms of sensitivity and specificity in various designs of the data set for validation, training, and testing. The proposed computational strategies are very promising for predicting major adverse cardiac events within six months. © 2008 IEEE.
Ramírez de Molina, A, Gallego-Ortega, D, Sarmentero-Estrada, J, Lagares, D, Gómez del Pulgar, T, Bandrés, E, García-Foncillas, J & Lacal, JC 2008, 'Choline kinase as a link connecting phospholipid metabolism and cell cycle regulation: Implications in cancer therapy', The International Journal of Biochemistry & Cell Biology, vol. 40, no. 9, pp. 1753-1763.
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Richards, L, Brown, C, Stone, MH, Fisher, J, Ingham, E & Tipper, JL 2008, 'Identification of nanometre-sized ultra-high molecular weight polyethylene wear particles in samples retrieved in vivo', The Journal of Bone and Joint Surgery. British volume, vol. 90-B, no. 8, pp. 1106-1113.
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Nanometre-sized particles of ultra-high molecular weight polyethylene have been identified in the lubricants retrieved from hip simulators. Tissue samples were taken from seven failed Charnley total hip replacements, digested using strong alkali and analysed using high-resolution field emission gun-scanning electron microscopy to determine whether nanometre-sized particles of polyethylene debris were generated in vivo. A randomised method of analysis was used to quantify and characterise all the polyethylene particles isolated. We isolated nanometre-sized particles from the retrieved tissue samples. The smallest identified was 30 nm and the majority were in the 0.1 μm to 0.99 μm size range. Particles in the 1.0 μm to 9.99 μm size range represented the highest proportion of the wear volume of the tissue samples, with 35% to 98% of the total wear volume comprised of particles of this size. The number of nanometre-sized particles isolated from the tissues accounted for only a small proportion of the total wear volume. Further work is required to assess the biological response to nanometre-sized polyethylene particles.
Stanton, C & Ronsmans, C 2008, 'Recommendations for Routine Reporting on Indications for Cesarean Delivery in Developing Countries', Birth, vol. 35, no. 3, pp. 204-211.
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ABSTRACT: Background: Cesarean delivery rates are increasing rapidly in many developing countries, particularly among wealthy women. Poor women have lower rates, often so low that they do not reach the minimum rate of 1 percent. Little data are available on clinical indications for cesarean section, information that could assist in understanding why cesarean delivery rates have changed. This paper presents recommendations for routine reporting on indications for cesarean delivery in developing countries. These recommendations resulted from an international consultation of researchers held in February 2006 to promote the collection of comparable data to understand change in, or composition of, the cesarean delivery rate in developing countries. Methods: Data are presented from selected countries, categorizing cesareans by three classification systems. Results: A single classification system was recommended for use in both high and low cesarean delivery rate settings, given that underuse and overuse of cesarean section are evident within many populations. The group recommended a hierarchical categorization, prioritizing cesareans performed for absolute maternal indications. Categorization among the remaining nonabsolute indications is based on the primary indication for the procedure and include maternal and fetal indications and psychosocial indications, required for high cesarean delivery rate settings. Conclusions: Data on indications for cesarean sections are available everywhere the procedure is performed. All that is required is compilation and review at facility and at higher levels. Advocacy within ministries of health and medical professional organizations...
Styrkarsdottir, U, Halldorsson, BV, Gretarsdottir, S, Gudbjartsson, DF, Walters, GB, Ingvarsson, T, Jonsdottir, T, Saemundsdottir, J, Center, JR, Nguyen, TV, Bagger, Y, Gulcher, JR, Eisman, JA, Christiansen, C, Sigurdsson, G, Kong, A, Thorsteinsdottir, U & Stefansson, K 2008, 'Multiple Genetic Loci for Bone Mineral Density and Fractures', New England Journal of Medicine, vol. 358, no. 22, pp. 2355-2365.
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Background: Bone mineral density influences the risk of osteoporosis later in life and is useful in the evaluation of the risk of fracture. We aimed to identify sequence variants associated with bone mineral density and fracture. Methods: We performed a quantitative trait analysis of data from 5861 Icelandic subjects (the discovery set), testing for an association between 301,019 single-nucleotide polymorphisms (SNPs) and bone mineral density of the hip and lumbar spine. We then tested for an association between 74 SNPs (most of which were implicated in the discovery set) at 32 loci in replication sets of Icelandic, Danish, and Australian subjects (4165, 2269, and 1491 subjects, respectively). Results: Sequence variants in five genomic regions were significantly associated with bone mineral density in the discovery set and were confirmed in the replication sets (combined P values, 1.2x10-7 to 2.0x10-21). Three regions are close to or within genes previously shown to be important to the biologic characteristics of bone: the receptor activator of nuclear factor-κB ligand gene (RANKL) (chromosomal location, 13q14), the osteoprotegerin gene (OPG) (8q24), and the estrogen receptor 1 gene (ESR1) (6q25). The two other regions are close to the zinc finger and BTB domain containing 40 gene (ZBTB40) (1p36) and the major histocompatibility complex region (6p21). The 1p36, 8q24, and 6p21 loci were also associated with osteoporotic fractures, as were loci at 18q21, close to the receptor activator of the nuclear factor-κB gene (RANK), and loci at 2p16 and 11p11. Conclusions: We have discovered common sequence variants that are consistently associated with bone mineral density and with low-trauma fractures in three populations of European descent. Although these variants alone are not clinically useful in the prediction of risk to the individual person, they provide insight into the biochemical pathways underlying osteoporosis. Copyright © 2008 Massachusetts Medical Society.
Tran, BNH, Nguyen, ND, Eisman, JA & Nguyen, TV 2008, 'Association between LRP5 polymorphism and bone mineral density: a Bayesian meta-analysis', BMC Medical Genetics, vol. 9, no. 1.
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Abstract Background The low-density lipoprotein receptor-related protein 5 gene (LRP5) was identified to be linked to the variation in BMD in high bone mass pedigrees. Subsequent population-based studies of the association between the LRP5 gene and BMD have yielded conflicting results. The present study was aimed at examining the association between LRP5 gene and BMD by using meta-analysis. Methods A systematic electronic search of literature was conducted to identify all published studies in English on the association between LRP5 gene and osteoporosis-related phenotypes, including bone mineral density and fracture. BMD data were summarized from individual studies by LRP5 genotype, and a synthesis of data was performed with random-effects meta-analyses. After excluding studies on animal and review papers, there were 19 studies for the synthesis. Among these studies, 10 studies used the rs3736228 (A1330V) polymorphism and reported BMD values. Results The 10 eligible studies comprised 16,705 individuals, with the majority being women (n = 8444), aged between 18 – 81 years. The overall distribution of genotype frequencies was: AA, 68%, AV and VV, 32%. However, the genotype frequency varied significantly within as well as between ethnic populations. On random-effects meta-analysis, lumbar spine BMD among individuals with the AA genotype was on average 0.018 (95% confidence interval [CI]: 0.012 to 0.023) g/cm2 higher than those with either AV or VV genotype. Similarly, femoral neck BMD among carriers of the AA genotype was 0.011 (95%CI: 0.004 to 0.017) g/cm2 higher than those without the genotype. Whi...
VanLandingham, M, Nguyen, TV, Abdul-Rahman, OA, Parent, A & Zhang, J 2008, 'Phenotypical manifestations of partial trisomy 9 and monosomy 4 in two siblings', Neurological Sciences, vol. 29, no. 6, pp. 467-470.
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In this case report, we describe two siblings with a previously unreported partial monosomy 4q and partial trisomy 9q. The sibling karyotypes were determined to be 46,XX,der(4)t(4;9)(q33;q33)pat and 46,XY,der(4)t(4;9)-(q33;q33)pat. The siblings share sev
Xu, XX, Li, L & Zheng, YF 2008, 'Preparation and surface modification of magnetic nanoparticles for biomedical applications', Cailiao Kexue yu Gongyi/Material Science and Technology, vol. 16, no. 4, pp. 562-568.
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Magnetic nanoparticle is one of the hot research directions in the field of nano-biomedical materials. The magnetic nanoparticles prepared by different methods and modified with different polymers are used in various fields. In this paper, we synthetically summarize its preparation methods including co-precipitation, sol-gel, microemulsion, generalize the surface modification technique with different polymers, and report the biomedical applications of magnetic nanoparticles involving target drug delivery, cell separation hyperthermic treatment for malignant cells and MRI contrast enhancement. Magnetic nanoparticles still have great potentials for development and application in the future.
