162 research outputs found
A Replication Study of GWAS-Derived Lipid Genes in Asian Indians: The Chromosomal Region 11q23.3 Harbors Loci Contributing to Triglycerides
Recent genome-wide association scans (GWAS) and meta-analysis studies on European populations have identified many genes previously implicated in lipid regulation. Validation of these loci on different global populations is important in determining their clinical relevance, particularly for development of novel drug targets for treating and preventing diabetic dyslipidemia and coronary artery disease (CAD). In an attempt to replicate GWAS findings on a non-European sample, we examined the role of six of these loci (CELSR2-PSRC1-SORT1 rs599839; CDKN2A-2B rs1333049; BUD13-ZNF259 rs964184; ZNF259 rs12286037; CETP rs3764261; APOE-C1-C4-C2 rs4420638) in our Asian Indian cohort from the Sikh Diabetes Study (SDS) comprising 3,781 individuals (2,902 from Punjab and 879 from the US). Two of the six SNPs examined showed convincing replication in these populations of Asian Indian origin. Our study confirmed a strong association of CETP rs3764261 with high-density lipoprotein cholesterol (HDL-C) (pā=ā2.03Ć10ā26). Our results also showed significant associations of two GWAS SNPs (rs964184 and rs12286037) from BUD13-ZNF259 near the APOA5-A4-C3-A1 genes with triglyceride (TG) levels in this Asian Indian cohort (rs964184: pā=ā1.74Ć10ā17; rs12286037: pā=ā1.58Ć10ā2). We further explored 45 SNPs in a ā¼195 kb region within the chromosomal region 11q23.3 (encompassing the BUD13-ZNF259, APOA5-A4-C3-A1, and SIK3 genes) in 8,530 Asian Indians from the London Life Sciences Population (LOLIPOP) (UK) and SDS cohorts. Five more SNPs revealed significant associations with TG in both cohorts individually as well as in a joint meta-analysis. However, the strongest signal for TG remained with BUD13-ZNF259 (rs964184: pā=ā1.06Ć10ā39). Future targeted deep sequencing and functional studies should enhance our understanding of the clinical relevance of these genes in dyslipidemia and hypertriglyceridemia (HTG) and, consequently, diabetes and CAD
FRAX (R): Prediction of Major Osteoporotic Fractures in Women from the General Population: The OPUS Study
Purposes: The aim of this study was to analyse how well FRAXH predicts the risk of major osteoporotic and vertebral
fractures over 6 years in postmenopausal women from general population.
Patients and methods: The OPUS study was conducted in European women aged above 55 years, recruited in 5 centers
from random population samples and followed over 6 years. The population for this study consisted of 1748 women (mean
age 74.2 years) with information on incident fractures. 742 (43.1%) had a prevalent fracture; 769 (44%) and 155 (8.9%) of
them received an antiosteoporotic treatment before and during the study respectively. We compared FRAXH performance
with and without bone mineral density (BMD) using receiver operator characteristic (ROC) c-statistical analysis with ORs and
areas under receiver operating characteristics curves (AUCs) and net reclassification improvement (NRI).
Results: 85 (4.9%) patients had incident major fractures over 6 years. FRAXH with and without BMD predicted these
fractures with an AUC of 0.66 and 0.62 respectively. The AUC were 0.60, 0.66, 0.69 for history of low trauma fracture alone,
age and femoral neck (FN) BMD and combination of the 3 clinical risk factors, respectively. FRAXH with and without BMD
predicted incident radiographic vertebral fracture (n = 65) with an AUC of 0.67 and 0.65 respectively. NRI analysis showed a
significant improvement in risk assignment when BMD is added to FRAXH.
Conclusions: This study shows that FRAXH with BMD and to a lesser extent also without FN BMD predict major osteoporotic
and vertebral fractures in the general population
Opposing effects of D-aspartic acid and nitric oxide on tuning of testosterone production in mallard testis during the reproductive cycle
<p>Abstract</p> <p>Background</p> <p>D-Aspartic acid (D-Asp) and nitric oxide (NO) play an important role in tuning testosterone production in the gonads of male vertebrates. In particular, D-Asp promotes either the synthesis or the release of testosterone, whereas NO inhibits it. In this study, we have investigated for the first time in birds the putative effects of D-Asp and NO on testicular testosterone production in relation to two phases of the reproductive cycle of the adult captive wild-strain mallard (Anas platyrhynchos) drake. It is a typical seasonal breeder and its cycle consists of a short reproductive period (RP) in the spring (April-May) and a non reproductive period (NRP) in the summer (July), a time when the gonads are quiescent. The presence and the localization of D-Asp and NO in the testis and the trends of D-Asp, NO and testosterone levels were assessed during the main phases of the bird's reproductive cycle. Furthermore, in vitro experiments revealed the direct effect of exogenously administered D-Asp and NO on testosterone steroidogenesis.</p> <p>Methods</p> <p>By using immunohistochemical (IHC) techniques, we studied the presence and the distributional pattern of D-Asp and NO in the testes of RP and NRP drakes. D-Asp levels were evaluated by an enzymatic method, whereas NO content, via nitrite, was assessed using biochemical measurements. Finally, immunoenzymatic techniques determined testicular testosterone levels.</p> <p>Results</p> <p>IHC analyses revealed the presence of D-Asp and NO in Leydig cells. The distributional pattern of both molecules was in some way correlated to the steroidogenic pathway, which is involved in autocrine testosterone production. Indeed, whereas NO was present only during the NRP, D-Asp was almost exclusively present during the RP. Consistently, the high testosterone testicular content occurring during RP was coupled to a high D-Asp level and a low NO content in the gonad. By contrast, in sexually inactive drakes (NRP), the low testosterone content in the gonad was coupled to a low D-Asp content and to a relatively high NO level. Consequently, to determine the exogenous effects of the two amino acids on testosterone synthesis, we carried out in vitro experiments using testis sections deriving from both the RP and NRP. When testis slices were incubated for 60 or 120 min with D-Asp, testosterone was enhanced, whereas in the presence of L-Arg, a precursor of NO, it was inhibited.</p> <p>Conclusion</p> <p>Our results provide new insights into the involvement of D-Asp and NO in testicular testosterone production in the adult captive wild-strain mallard drake. The localization of these two molecules in the Leydig cells in different periods of the reproductive cycle demonstrates that they play a potential role in regulating local testosterone production.</p
Association analysis of 31 common polymorphisms with type 2 diabetes and its related traits in Indian sib pairs
: AIMS/HYPOTHESIS: Evaluation of the association of 31 common single nucleotide polymorphisms (SNPs) with fasting glucose, fasting insulin, HOMA-beta cell function (HOMA-?), HOMA-insulin resistance (HOMA-IR) and type 2 diabetes in the Indian population. METHODS: We genotyped 3,089 sib pairs recruited in the Indian Migration Study from four cities in India (Lucknow, Nagpur, Hyderabad and Bangalore) for 31 SNPs in 24 genes previously associated with type 2 diabetes in European populations. We conducted within-sib-pair analysis for type 2 diabetes and its related quantitative traits. RESULTS: The risk-allele frequencies of all the SNPs were comparable with those reported in western populations. We demonstrated significant associations of CXCR4 (rs932206), CDKAL1 (rs7756992) and TCF7L2 (rs7903146, rs12255372) with fasting glucose, with ? values of 0.007 (p?=?0.05), 0.01 (p?=?0.01), 0.007 (p?=?0.05), 0.01 (p?=?0.003) and 0.08 (p?=?0.01), respectively. Variants in NOTCH2 (rs10923931), TCF-2 (also known as HNF1B) (rs757210), ADAM30 (rs2641348) and CDKN2A/B (rs10811661) significantly predicted fasting insulin, with ? values of -0.06 (p?=?0.04), 0.05 (p?=?0.05), -0.08 (p?=?0.01) and -0.08 (p?=?0.02), respectively. For HOMA-IR, we detected associations with TCF-2, ADAM30 and CDKN2A/B, with ? values of 0.05 (p?=?0.04), -0.07 (p?=?0.03) and -0.08 (p?=?0.02), respectively. We also found significant associations of ADAM30 (??=?-0.05; p?=?0.01) and CDKN2A/B (??=?-0.05; p?=?0.03) with HOMA-?. THADA variant (rs7578597) was associated with type 2 diabetes (OR 1.5; 95% CI 1.04, 2.22; p?=?0.03). CONCLUSIONS/INTERPRETATION: We validated the association of seven established loci with intermediate traits related to type 2 diabetes in an Indian population using a design resistant to population stratification
Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector
The inclusive and dijet production cross-sections have been measured for jets
containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass
energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The
measurements use data corresponding to an integrated luminosity of 34 pb^-1.
The b-jets are identified using either a lifetime-based method, where secondary
decay vertices of b-hadrons in jets are reconstructed using information from
the tracking detectors, or a muon-based method where the presence of a muon is
used to identify semileptonic decays of b-hadrons inside jets. The inclusive
b-jet cross-section is measured as a function of transverse momentum in the
range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet
cross-section is measured as a function of the dijet invariant mass in the
range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets
and the angular variable chi in two dijet mass regions. The results are
compared with next-to-leading-order QCD predictions. Good agreement is observed
between the measured cross-sections and the predictions obtained using POWHEG +
Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet
cross-section. However, it does not reproduce the measured inclusive
cross-section well, particularly for central b-jets with large transverse
momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final
version published in European Physical Journal
Decreased Functional Diversity and Biological Pest Control in Conventional Compared to Organic Crop Fields
Organic farming is one of the most successful agri-environmental schemes, as humans benefit from high quality food, farmers from higher prices for their products and it often successfully protects biodiversity. However there is little knowledge if organic farming also increases ecosystem services like pest control. We assessed 30 triticale fields (15 organic vs. 15 conventional) and recorded vascular plants, pollinators, aphids and their predators. Further, five conventional fields which were treated with insecticides were compared with 10 non-treated conventional fields. Organic fields had five times higher plant species richness and about twenty times higher pollinator species richness compared to conventional fields. Abundance of pollinators was even more than one-hundred times higher on organic fields. In contrast, the abundance of cereal aphids was five times lower in organic fields, while predator abundances were three times higher and predator-prey ratios twenty times higher in organic fields, indicating a significantly higher potential for biological pest control in organic fields. Insecticide treatment in conventional fields had only a short-term effect on aphid densities while later in the season aphid abundances were even higher and predator abundances lower in treated compared to untreated conventional fields. Our data indicate that insecticide treatment kept aphid predators at low abundances throughout the season, thereby significantly reducing top-down control of aphid populations. Plant and pollinator species richness as well as predator abundances and predator-prey ratios were higher at field edges compared to field centres, highlighting the importance of field edges for ecosystem services. In conclusion organic farming increases biodiversity, including important functional groups like plants, pollinators and predators which enhance natural pest control. Preventative insecticide application in conventional fields has only short-term effects on aphid densities but long-term negative effects on biological pest control. Therefore conventional farmers should restrict insecticide applications to situations where thresholds for pest densities are reached
Forty-Three Loci Associated with Plasma Lipoprotein Size, Concentration, and Cholesterol Content in Genome-Wide Analysis
While conventional LDL-C, HDL-C, and triglyceride measurements reflect aggregate properties of plasma lipoprotein fractions, NMR-based measurements more accurately reflect lipoprotein particle concentrations according to class (LDL, HDL, and VLDL) and particle size (small, medium, and large). The concentrations of these lipoprotein sub-fractions may be related to risk of cardiovascular disease and related metabolic disorders. We performed a genome-wide association study of 17 lipoprotein measures determined by NMR together with LDL-C, HDL-C, triglycerides, ApoA1, and ApoB in 17,296 women from the Women's Genome Health Study (WGHS). Among 36 loci with genome-wide significance (P<5Ć10ā8) in primary and secondary analysis, ten (PCCB/STAG1 (3q22.3), GMPR/MYLIP (6p22.3), BTNL2 (6p21.32), KLF14 (7q32.2), 8p23.1, JMJD1C (10q21.3), SBF2 (11p15.4), 12q23.2, CCDC92/DNAH10/ZNF664 (12q24.31.B), and WIPI1 (17q24.2)) have not been reported in prior genome-wide association studies for plasma lipid concentration. Associations with mean lipoprotein particle size but not cholesterol content were found for LDL at four loci (7q11.23, LPL (8p21.3), 12q24.31.B, and LIPG (18q21.1)) and for HDL at one locus (GCKR (2p23.3)). In addition, genetic determinants of total IDL and total VLDL concentration were found at many loci, most strongly at LIPC (15q22.1) and APOC-APOE complex (19q13.32), respectively. Associations at seven more loci previously known for effects on conventional plasma lipid measures reveal additional genetic influences on lipoprotein profiles and bring the total number of loci to 43. Thus, genome-wide associations identified novel loci involved with lipoprotein metabolismāincluding loci that affect the NMR-based measures of concentration or size of LDL, HDL, and VLDL particlesāall characteristics of lipoprotein profiles that may impact disease risk but are not available by conventional assay
Transferability of Type 2 Diabetes Implicated Loci in Multi-Ethnic Cohorts from Southeast Asia
Recent large genome-wide association studies (GWAS) have identified multiple loci
which harbor genetic variants associated with type 2 diabetes mellitus (T2D),
many of which encode proteins not previously suspected to be involved in the
pathogenesis of T2D. Most GWAS for T2D have focused on populations of European
descent, and GWAS conducted in other populations with different ancestry offer a
unique opportunity to study the genetic architecture of T2D. We performed
genome-wide association scans for T2D in 3,955 Chinese (2,010 cases, 1,945
controls), 2,034 Malays (794 cases, 1,240 controls), and 2,146 Asian Indians
(977 cases, 1,169 controls). In addition to the search for novel variants
implicated in T2D, these multi-ethnic cohorts serve to assess the
transferability and relevance of the previous findings from European descent
populations in the three major ethnic populations of Asia, comprising half of
the world's population. Of the SNPs associated with T2D in previous GWAS,
only variants at CDKAL1 and
HHEX/IDE/KIF11 showed the strongest
association with T2D in the meta-analysis including all three ethnic groups.
However, consistent direction of effect was observed for many of the other SNPs
in our study and in those carried out in European populations. Close examination
of the associations at both the CDKAL1 and
HHEX/IDE/KIF11 loci provided some evidence of locus and
allelic heterogeneity in relation to the associations with T2D. We also detected
variation in linkage disequilibrium between populations for most of these loci
that have been previously identified. These factors, combined with limited
statistical power, may contribute to the failure to detect associations across
populations of diverse ethnicity. These findings highlight the value of
surveying across diverse racial/ethnic groups towards the fine-mapping efforts
for the casual variants and also of the search for variants, which may be
population-specific
Microstructure and biomechanical characteristics of bone substitutes for trauma and orthopaedic surgery
Abstract.
BACKGROUND: Many (artificial) bone substitute materials are currently available for use in orthopaedic trauma surgery. Objective data on their biological and biomechanical characteristics, which determine their clinical application, is mostly lacking. The aim of this study was to investigate structural and in vitro mechanical properties of nine bone substitute cements registered for use in orthopaedic trauma surgery in the Netherlands.
METHODS: Seven calcium phosphate cements (BoneSourceĀ®, CalcibonĀ®, ChronOSĀ®, EuroboneĀ®, HydroSetā¢, Norian SRSĀ®, and OstimĀ®), one calcium sulphate cement (MIIGĀ® X3), and one bioactive glass cement (CortossĀ®) were tested. Structural characteristics were measured by micro-CT scanning. Compression strength and stiffness were determined following unconfined compression tests.
RESULTS: Each bone substitute had unique characteristics. Mean total porosity ranged from 53% (OstimĀ®) to 0.5% (Norian SRSĀ®). Mean pore size exceeded 100 Ī¼m only in EuroboneĀ® and CortossĀ® (162.2 Ā± 107.1 Ī¼m and 148.4 Ā± 70.6 Ī¼m, respectively). However, 230 Ī¼m pores were found in CalcibonĀ®, Norian SRSĀ®, HydroSetā¢, and MIIGĀ® X3. Connectivity density ranged from 27/cm3 for HydroSetā¢ to 0.03/cm3 for CalcibonĀ®. The ultimate compression strength was highest in CortossĀ® (47.32 MPa) and lowest in OstimĀ® (0.24 MPa). Young's Modulus was highest in CalcibonĀ® (790 MPa) and lowest in OstimĀ® (6 MPa).
CONCLUSIONS: The bone substitutes tested display a wide range in structural properties and compression strength, indicating that they will be suitable for different clinical indications. The data outlined here will help surgeons to select the most suitable products currently available for specific clinical indications
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