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- Blokland, G. A. M., et al.
(författare)
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Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 91:1, s. 102-117
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Results: Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels. © 2021 Society of Biological Psychiatry
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- Munn-Chernoff, M. A., et al.
(författare)
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Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies
- 2021
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Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 26:1
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Tidskriftsartikel (refereegranskat)abstract
- Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r(g)], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from similar to 2400 to similar to 537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r(g) = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r(g) = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r(g) = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r(gs) = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
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- Karasik, D., et al.
(författare)
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Disentangling the genetics of lean mass
- 2019
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Ingår i: American Journal of Clinical Nutrition. - : Elsevier BV. - 0002-9165 .- 1938-3207. ; 109:2, s. 276-287
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Tidskriftsartikel (refereegranskat)abstract
- Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age(2), and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms). Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LMwere termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection. Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.
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- de Jong, S, et al.
(författare)
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Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder
- 2018
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 1, s. 163-
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Tidskriftsartikel (refereegranskat)abstract
- Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
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- van de Sande-Bruinsma, Nienke, et al.
(författare)
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Antimicrobial drug use and resistance in Europe
- 2008
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Ingår i: Emerging Infectious Diseases. - : Centers for Disease Control and Prevention (CDC). - 1080-6040 .- 1080-6059. ; 14:11, s. 1722-30
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Tidskriftsartikel (refereegranskat)abstract
- Our study confronts the use of antimicrobial agents in ambulatory care with the resistance trends of 2 major pathogens, Streptococcus pneumoniae and Escherichia coli, in 21 European countries in 2000-2005 and explores whether the notion that antimicrobial drug use determines resistance can be supported by surveillance data at national aggregation levels. The data obtained from the European Surveillance of Antimicrobial Consumption and the European Antimicrobial Resistance Surveillance System suggest that variation of consumption coincides with the occurrence of resistance at the country level. Linear regression analysis showed that the association between antimicrobial drug use and resistance was specific and robust for 2 of 3 compound pathogen combinations, stable over time, but not sensitive enough to explain all of the observed variations. Ecologic studies based on routine surveillance data indicate a relation between use and resistance and support interventions designed to reduce antimicrobial drug consumption at a national level in Europe.
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14. |
- Estrada, Karol, et al.
(författare)
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Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
- 2012
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:5, s. 491-501
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Tidskriftsartikel (refereegranskat)abstract
- Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
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- Hou, Liping, et al.
(författare)
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Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder.
- 2016
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 25:15, s. 3383-94
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p=5.87×10(-9); odds ratio=1.12) and markers within ERBB2 (rs2517959, p=4.53×10(-9); odds ratio=1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
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21. |
- Mullins, Niamh, et al.
(författare)
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GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores
- 2019
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Ingår i: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 176:8, s. 651-660
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Tidskriftsartikel (refereegranskat)abstract
- Objective: More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium.Methods: The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders.Results: Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%).Conclusions: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.
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- Elks, Cathy E, et al.
(författare)
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Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:12, s. 1077-85
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Tidskriftsartikel (refereegranskat)abstract
- To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.
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- Stinner, B, et al.
(författare)
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Granulocyte-colony stimulating factor in the prevention of postoperative infectious complications and sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4) - Protocol of a controlled clinical trial developed by consensus of an international study group Part three : individual patient, complication algorithm and quality management
- 2001
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Ingår i: Inflammation Research. - 1023-3830 .- 1420-908X. ; 50:5, s. 233-248
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Forskningsöversikt (refereegranskat)abstract
- General design: Presentation of a new type of a study protocol for evaluation of the effectiveness of an immune modifier (rhG-CSF, filgrastim): prevention of postoperative infectious complications and of sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). A randomised placebo controlled, double-blinded, single-centre study is performed at an University Hospital (n = 40 patients for each group). This part presents the course of the individual patient and a complication algorithm for the management of anastomotic leakage and quality management. Objective: In part three of the protocol, the three major sections include: - The course of the individual patient using a comprehensive graphic display, including the perioperative period, hospital stay and post discharge outcome. - A center based clinical practice guideline for the management of the most important postoperative complication anastomotic leakage - including evidence based support for each step of the algorithm. - Data management, ethics and organisational structure. Conclusions: Future studies with immune modifiers will also fail if not better structured (reduction of variance) to achieve uniform patient management in a complex clinical scenario. This new type of a single-centre trial aims to reduce the gap between animal experiments and clinical trials or - if it fails - at least demonstrates new ways for explaining the failures.
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31. |
- Hsu, Y. H., et al.
(författare)
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Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry
- 2019
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431 .- 1523-4681. ; 34:7, s. 1284-1296
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Tidskriftsartikel (refereegranskat)abstract
- Hip geometry is an important predictor of fracture. We performed a meta-analysis of GWAS studies in adults to identify genetic variants that are associated with proximal femur geometry phenotypes. We analyzed four phenotypes: (i) femoral neck length; (ii) neck-shaft angle; (iii) femoral neck width, and (iv) femoral neck section modulus, estimated from DXA scans using algorithms of hip structure analysis. In the Discovery stage, 10 cohort studies were included in the fixed-effect meta-analysis, with up to 18,719 men and women ages 16 to 93 years. Association analyses were performed with similar to 2.5 million polymorphisms under an additive model adjusted for age, body mass index, and height. Replication analyses of meta-GWAS significant loci (at adjusted genomewide significance [GWS], threshold p <= 2.6 x 10(-8)) were performed in seven additional cohorts in silico. We looked up SNPs associated in our analysis, for association with height, bone mineral density (BMD), and fracture. In meta-analysis (combined Discovery and Replication stages), GWS associations were found at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several hip geometry signals overlapped with BMD, including LRP5 (chr. 11). Chr. 11 SNP rs7102273 was associated with any-type fracture (p = 7.5 x 10(-5)). We used bone transcriptome data and discovered several significant eQTLs, including rs7102273 and PPP6R3 expression (p = 0.0007), and rs6556301 (intergenic, chr.5 near FGFR4) and PDLIM7 expression (p = 0.005). In conclusion, we found associations between several genes and hip geometry measures that explained 12% to 22% of heritability at different sites. The results provide a defined set of genes related to biological pathways relevant to BMD and etiology of bone fragility. (c) 2019 American Society for Bone and Mineral Research.
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32. |
- Koller, Daniel L., et al.
(författare)
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Meta-analysis of genome-wide studies identifies WNT16 and ESR1 SNPs associated with bone mineral density in premenopausal women
- 2013
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 1523-4681 .- 0884-0431. ; 28:3, s. 547-558
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWAS) have identified common variants in genes associated with variation in bone mineral density (BMD), although most have been carried out in combined samples of older women and men. Meta-analyses of these results have identified numerous single-nucleotide polymorphisms (SNPs) of modest effect at genome-wide significance levels in genes involved in both bone formation and resorption, as well as other pathways. We performed a meta-analysis restricted to premenopausal white women from four cohorts (n=4061 women, aged 20 to 45 years) to identify genes influencing peak bone mass at the lumbar spine and femoral neck. After imputation, age- and weight-adjusted bone-mineral density (BMD) values were tested for association with each SNP. Association of an SNP in the WNT16 gene (rs3801387; p=1.7x109) and multiple SNPs in the ESR1/C6orf97 region (rs4870044; p=1.3x108) achieved genome-wide significance levels for lumbar spine BMD. These SNPs, along with others demonstrating suggestive evidence of association, were then tested for association in seven replication cohorts that included premenopausal women of European, Hispanic-American, and African-American descent (combined n=5597 for femoral neck; n=4744 for lumbar spine). When the data from the discovery and replication cohorts were analyzed jointly, the evidence was more significant (WNT16 joint p=1.3x1011; ESR1/C6orf97 joint p=1.4x1010). Multiple independent association signals were observed with spine BMD at the ESR1 region after conditioning on the primary signal. Analyses of femoral neck BMD also supported association with SNPs in WNT16 and ESR1/C6orf97 (p<1x105). Our results confirm that several of the genes contributing to BMD variation across a broad age range in both sexes have effects of similar magnitude on BMD of the spine in premenopausal women. These data support the hypothesis that variants in these genes of known skeletal function also affect BMD during the premenopausal period. (c) 2013 American Society for Bone and Mineral Research.
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- Niggemann, B., et al.
(författare)
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Five-year follow-up on the PAT study : specific immunotherapy and long-term prevention of asthma in children
- 2006
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Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : Wiley. - 0105-4538 .- 1398-9995. ; 61:7, s. 855-859
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Tidskriftsartikel (refereegranskat)abstract
- Background: A 3-year course of specific immunotherapy (SIT) in children with hay fever to grass and/or birch pollen significantly reduced the risk of developing asthma. To investigate the long-term preventive effect, we performed a follow up – 2 years after termination of immunotherapy.Methods: A total of 183 children, aged 6–14 years with grass and/or birch pollen allergy could be investigated 2 years after discontinuation of SIT or no treatment. Conjunctival provocation tests (CPTs) and methacholine bronchial provocation tests were carried out during the season and winter after 5 years. The development of asthma was assessed by clinical evaluation.Results: The significant improvement in hay fever and CPT results observed after 3 years of SIT persisted at the 5-year follow-up. No difference in bronchial responsiveness to methacholine was found after 5 years because of spontaneous improvement during the follow-up period in the control patients. The immunotherapy-treated children had significantly less asthma after 5 years as evaluated by clinical symptoms [odds ratio 2.68 (1.3–5.7)] in favor of SIT for prevention of development of asthma and significantly less patients reported an increase in asthma scores (P < 0.01).Conclusion: Immunotherapy for 3 years with standardized allergen extracts of grass and/or birch shows long-term clinical effect and preventive effect on development of asthma in children with seasonal rhinoconjunctivitis.
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35. |
- Wang, Thomas J, et al.
(författare)
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Common genetic determinants of vitamin D insufficiency: a genome-wide association study.
- 2010
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Ingår i: Lancet. - 1474-547X. ; 376:9736, s. 180-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency. METHODS: We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants. FINDINGS: Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile. INTERPRETATION: Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency. FUNDING: Full funding sources listed at end of paper (see Acknowledgments).
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36. |
- Bauhofer, A., et al.
(författare)
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Granulocyte-colony stimulating factor in the prevention of postoperative infectious complications and sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). Protocol for a controlled clinical trial developed by consensus of an international study group : Part two
- 2001
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Ingår i: Inflammation Research. - : Springer Science and Business Media LLC. - 1023-3830 .- 1420-908X. ; 50:4, s. 187-205
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Forskningsöversikt (refereegranskat)abstract
- General design: Presentation of a new type of a study protocol for evaluation of the effectiveness of an immune modifier (rhG-CSF, filgrastim): prevention of postoperative infectious complications and of sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4) This part describes the design of the randomised, placebo controlled, double-blinded, single-centre study performed at an university hospital (n = 40 patients for each group). Objective: The trial design includes the following elements for a prototype protocol: - The study population is restricted to patients with colorectal cancer, including a left sided resection and an increased perioperative risk (ASA 3 and 4). - Patients are allocated by random to the control or treatment group. - The double blinding strategy of the trial is assessed by psychometric indices - An endpoint construct with quality of life (EORTC QLQ-C30) and a recovery index (modified Mc Peek index) are used as primary endpoints Qualitative analysis of clinical relevance of the endpoints is performed by both patients and doctors. - Statistical analysis uses an area under the curve (AUC) model for improvement of quality of life on leaving hospital and two and six months after operation. A confirmatory statistical model with quality of life as the first primary endpoint in the hierarchic test procedure is used. Expectations of patients and surgeons and the negative affect are analysed by social psychological scales. Conclusion: This study design differs from other trials on preoperative prophylaxis and postoperative recovery, and has been developed to try a new concept and avoid previous failures.
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- Gürdal, G., et al.
(författare)
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Measurements of g(41+,22+) in 70,72,74 ,76Ge: Systematics of low-lying structures in 30≤Z≤40 and 30≤N≤50 nuclei
- 2013
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Ingår i: Physical Review C - Nuclear Physics. - 2469-9985 .- 2469-9993. ; 88:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The interplay between single-particle and collective excitations in the 30 ≤Z≤ 40 and 30 ≤N≤ 50 even-even isotopes has been examined in light of recent new measurements of magnetic moments of 41+, 22+, and 21+ states. Purpose: The g factors of the 41+ and 22+ states in the 72,74,76Ge isotopes have been measured for the first time and the g(21+) values have been remeasured. Methods: The transient field (TF) technique in inverse kinematics with a variety of targets has been applied, following Coulomb excitation of the relevant states. The data have been analyzed within the framework of the IBA-II model. Large-scale shell-model calculations have been performed within the p3/2,p1/2,f 5/2,g9/2 orbital space for both protons and neutrons with the JUN45 and JJ4B interactions. Results: The measured Ge g factors were compared to the g factors of the low-lying states of the neighboring Zn, Ge, Se, Kr, and Sr isotopes. The results were evaluated in the context of the systematics of g factors in the A∼80 region. Conclusions: The predictions based on the classic collective model and the interacting boson model IBA-II agree with the experimental results. No evidence for shell closure was found for neutrons at N=38 or N=40. © 2013 American Physical Society.
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38. |
- Kalman, Janos L, et al.
(författare)
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Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study.
- 2019
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Ingår i: Bipolar disorders. - : Wiley. - 1399-5618 .- 1398-5647. ; 21:1, s. 68-75
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients.A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18years] vs adulthood [>18years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models.BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment.The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.
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39. |
- Kirnbauer, A., et al.
(författare)
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Mechanical properties and thermal stability of reactively sputtered multi-principal-metal Hf-Ta-Ti-V-Zr nitrides
- 2020
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Ingår i: Surface & Coatings Technology. - : ELSEVIER SCIENCE SA. - 0257-8972 .- 1879-3347. ; 389
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Tidskriftsartikel (refereegranskat)abstract
- Crystalline (Hf,Ta,Ti,V,Zr)N nitride thin films, with a high-entropy metal-sublattice, were synthesized at 440 degrees C by reactive magnetron sputtering using an equimolar Hf-Ta-Ti-V-Zr-compound target. The coatings are single-phase fcc structured mono-nitrides for N-2/(Ar + N-2) flow-rate-ratios (f(N2)) between 30 and 45%. For higher f(N2) a small fraction of a second phase (next to the fcc matrix) can be detected by X-ray diffraction (XRD) and selected area electron diffraction (SAED). All coatings studied (prepared with f(N2) between 30 and 60%) show similar chemical compositions and hardness (H) values between 30.0 and 34.0 GPa with indentation moduli of similar to 460 GPa. Atom probe tomography (APT) indicates a homogenous distribution of all elements within our fcc-(Hf,Ta,Ti,V,Zr)N even after vacuum-annealing at 1300 degrees C. While H decreased from 32.5 to 28.1 GPa by this annealing treatment, the coating is still single-phase fcc structured with a defect density (expressed by XRD and SAED features, transmission electron microscopy contrast, and grain sizes) comparable to the as-deposited state. Only after vacuum-annealing at 1500 degrees C, XRD and APT reveal the formation of hexagonal structured (Ta,V)(2)N. The onset of nitrogen-loss - detected by thermogravimetric analysis - is similar to 1350 degrees C. Based on our results we can conclude that the sluggish diffusion within our fcc-(Hf,Ta,Ti,V,Zr)N warrants the single-phase fcc structure up to 1300 degrees C, although ab initio based calculations would suggest the lower-entropy products [fcc-(Hf,Zr)N, fcc-(Ta,V)N, and fcc-TiN] and [fcc-(Hf,Zr)N and fcc-(Ta,Ti,V)N] to be energetically more stable up to 1302 K.
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40. |
- Koller-Smith, Louise I. M., et al.
(författare)
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Comparing very low birth weight versus very low gestation cohort methods for outcome analysis of high risk preterm infants
- 2017
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Ingår i: BMC Pediatrics. - : Springer Science and Business Media LLC. - 1471-2431. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- Background: Compared to very low gestational age (<32 weeks, VLGA) cohorts, very low birth weight (<1500 g; VLBW) cohorts are more prone to selection bias toward small-for-gestational age (SGA) infants, which may impact upon the validity of data for benchmarking purposes. Method: Data from all VLGA or VLBW infants admitted in the 3 Networks between 2008 and 2011 were used. Two-thirds of each network cohort was randomly selected to develop prediction models for mortality and composite adverse outcome (CAO: mortality or cerebral injuries, chronic lung disease, severe retinopathy or necrotizing enterocolitis) and the remaining for internal validation. Areas under the ROC curves (AUC) of themodels were compared. Results: VLBW cohort (24,335 infants) had twice more SGA infants (20.4% vs. 9.3%) than the VLGA cohort (29,180 infants) and had a higher rate of CAO (36.5% vs. 32.6%). The two models had equal prediction power for mortality and CAO (AUC 0.83), and similarly for all other cross-cohort validations (AUC 0.81-0.85). Neither model performed well for the extremes of birth weight for gestation (<1500 g and >= 32 weeks, AUC 0.50-0.65; >= 1500 g and >= 32 weeks, AUC 0.60-0.62). Conclusion: There was no difference in prediction power for adverse outcome between cohorting VLGA or VLBW despite substantial bias in SGA population. Either cohorting practises are suitable for international benchmarking.
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41. |
- Lorenz, W., et al.
(författare)
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Granulocyte-colony stimulating factor in the prevention of postoperative infectious complications and sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4) : Part one
- 2001
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Ingår i: Inflammation Research. - : Springer Science and Business Media LLC. - 1023-3830 .- 1420-908X. ; 50:3, s. 115-122
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Forskningsöversikt (refereegranskat)abstract
- General design: Presentation of a novel study protocol to evalue the effectiveness of an immune modifier (rhG-CSF, filgrastim): prevention of postoperative infectious complications and sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). The rationale and hypothesis are presented in this part of the protocol of the randomised, placebo controlled, double-blinded, single-centre study performed at an - university hospital (n = 40 patients for each group). Objective: Part one of this protocol describes the concepts of three major sections of the study: - Definition of optimum and sub-optimal recovery after operation. Recovery, as an outcome, is not a simple univariate endpoint, but a complex construction of mechanistic variables (i. e. death, complications and health status assessed by the surgeon), quality of life expressed by the patient, and finally a weighted outcome judgement by both the patient and the surgeon (true endpoint). Its conventional early assessment within 14-28 days is artificial: longer periods (such as 6 months) are needed for the patient to state: "I am now as well as I was before". Identification of suitable target patients: - the use of biological response modifiers (immune modulators) in addition to traditional prophylaxes (i. e. antibiotics, heparin, volume substitutes) may improve postoperative outcome in appropriate selected patients with reduced host defence and increased immunological stress response, but these have to be defined. Patients classified as ASA 3 and 4 (American Society for Anaesthesiologists) and with colorectal cancer will be studied to prove this hypothesis. Choice of biological response modifier: - Filgrastim has been chosen as an example of a biological response modifier because it was effective in a new study type, clinic-modelling randomised trials in rodents, and has shown promise in some clinical trials for indications other than preoperative prophylaxis. It has also enhanced host defence and has been anti-inflammatory in basic research. Conclusion: The following hypothesis will be tested in patients with operations for colorectal cancer and increased preoperative risk (ASA 3 and 4): is the outcome as evaluated by the hermeneutic endpoint (quality of life expressed by the patient) and mechanistic endpoints (mortality rate, complication rate, relative hospital stay, assessed by the doctor) improved in the group receiving filgrastim prophylaxis in comparison with the placebo group? Quality of life will be the first primary endpoint in the hierarchical, statistical testing of confirmatory analysis.
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44. |
- Rinne, Juha O, et al.
(författare)
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11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study.
- 2010
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Ingår i: Lancet neurology. - 1474-4465. ; 9:4, s. 363-72
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Carbon-11-labelled Pittsburgh compound B ((11)C-PiB) PET is a marker of cortical fibrillar amyloid-beta load in vivo. We used (11)C-PiB PET to investigate whether bapineuzumab, a humanised anti-amyloid-beta monoclonal antibody, would reduce cortical fibrillar amyloid-beta load in patients with Alzheimer's disease. METHODS: Patients with mild-to-moderate Alzheimer's disease were randomly assigned to receive intravenous bapineuzumab or placebo in a ratio of seven to three in three ascending dose groups (0.5, 1.0, or 2.0 mg/kg). Each dose group was enrolled after safety review of the previous group. Randomisation was by interactive voice response system; masking was achieved with numbered kit allocation. Patients, investigators, study site personnel, sponsor staff, and carers were masked to treatment. Patients received up to six infusions, 13 weeks apart, and had (11)C-PiB PET scans at baseline and at weeks 20, 45, and 78. The primary outcome was the difference between the pooled bapineuzumab group and the pooled placebo group in mean change from screening to week 78 in (11)C-PiB cortical to cerebellar retention ratio averaged across six cortical regions of interest. Analysis was by modified intention to treat. This study is registered with EudraCT, number 2004-004120-12; ISRCTN17517446. FINDINGS: 28 patients were assigned to bapineuzumab (n=20) or placebo (n=8). 19 patients in the bapineuzumab group and seven in the placebo group were included in the modified intention-to-treat analysis. Estimated mean (11)C-PiB retention ratio change from baseline to week 78 was -0.09 (95% CI -0.16 to -0.02; p=0.014) in the bapineuzumab group and 0.15 (95% CI 0.02 to 0.28; p=0.022) in the placebo group. Estimated mean difference in (11)C-PiB retention ratio change from baseline to week 78 between the bapineuzumab group and the placebo group was -0.24 (95% CI -0.39 to -0.09; p=0.003). Differences between the bapineuzumab group and the placebo group in the individual regions of interest were similar to the overall mean difference. Adverse events were typically mild to moderate in severity and transient. Two patients in the 2.0 mg/kg bapineuzumab group had transient cerebral vasogenic oedema. INTERPRETATION: Treatment with bapineuzumab for 78 weeks reduced cortical (11)C-PiB retention compared with both baseline and placebo. (11)C-PiB PET seems to be useful in assessing the effects of potential Alzheimer's disease treatments on cortical fibrillar amyloid-beta load in vivo. FUNDING: Elan Pharmaceuticals and Wyeth Research.
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45. |
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46. |
- Alturki, M, et al.
(författare)
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Biochemical characterisation of carious dentine zones using Raman spectroscopy.
- 2021
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Ingår i: Journal of dentistry. - : Elsevier BV. - 1879-176X .- 0300-5712. ; 105
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Tidskriftsartikel (refereegranskat)abstract
- Carious tissue discrimination in clinical operative caries management relies traditionally on the subjective hardness of carious dentine. Biochemical alterations within the lesion have the potential to discriminate the lesion zones objectively. This study aimed to determine the correlation between the biochemical proportions of amide I and phosphate moieties as these are the most prominent peaks found in dentine with the Knoop microhardness of carious dentine zones, using non-contact Raman spectroscopy. The null hypothesis investigated was that there was no correlation between Raman peak ratios, amide I: phosphateν1, and the Knoop microhardness within specific zones of a carious lesion.423 scan points from 20 carious dentine lesion samples examined using high-resolution Raman spectroscopy. The peak ratio of the characteristic vibration mode of amide I (1650 cm-1) and phosphate (960 cm-1) bands were calculated, following a straight line path through the lesion to the pulp and correlated to corresponding Knoop microhardness measurements.Using logistic regression analysis, clear correlations were found between the Knoop microhardness and Raman peak ratio cut-off values between caries-infected and caries-affected dentine (81.5 % sensitivity / 92.7 % specificity), with a lower specificity (2.7 %) found between caries-affected and sound dentine.This study concluded that non-contact Raman spectroscopy can be used in vitro to discriminate objectively between the different zones of a carious dentine lesion at high resolution, using the Raman peak ratios, amide I : phosphate ν1.Specific biochemical alterations have the potential to be used in-vitro and in-vivo to identify the end-point of selective carious lesion excavation.
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47. |
- Alturki, M., et al.
(författare)
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Chemo-mechanical characterization of carious dentine using Raman microscopy and Knoop microhardness
- 2020
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Ingår i: Royal Society Open Science. - : The Royal Society. - 2054-5703. ; 7:5
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Tidskriftsartikel (refereegranskat)abstract
- One of the aims in the clinical operative management of dental carious lesions is to remove selectively the highly infected and structurally denatured dentine tissue, while retaining the deeper, repairable affected and intact, healthy tissues for long-term mechanical strength. The present study examined the correlation of chemical functional groups and the microhardness through the different depths of a carious lesion using Raman spectroscopy and Knoop microhardness testing. The null hypothesis investigated was that there was no correlation between Raman peak ratios (amide I : phosphate (nu 1)) and equivalent Knoop microhardness measurements. Ten freshly extracted human permanent teeth with carious dentine lesions were sectioned and examined using high-resolution Raman microscopy. The ratio of absorbency at the amide I and phosphate bands were calculated from 139 scan points through the depth of the lesions and correlated with 139 juxtaposed Knoop microhardness indentations. The results indicated a high correlation (p < 0.01) between the peak ratio and the equivalent Knoop hardness within carious dentine lesions. This study concluded that Raman spectroscopy can be used as a non-invasive analytical technology for in vitro studies to discriminate the hardness of carious dentine layers using the peak ratio as an alternative to the invasive, mechanical Knoop hardness test.
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48. |
- Alturki, M., et al.
(författare)
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In Vitro Analysis of Organic Ester Functional Groups in Carious Dentine
- 2022
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Ingår i: Applied Sciences (Switzerland). - : MDPI AG. - 2076-3417. ; 12:3
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Tidskriftsartikel (refereegranskat)abstract
- Background: With the implementation of minimally invasive selective caries removal protocols to treat cavitated, deep carious dentine lesions, there is a need to investigate specific biochemical moiety distributions to help characterise and distinguish between infected (contaminated) and affected (demineralised) zones within the dentine lesion. The present in vitro investigation aimed to compare the distribution of ester functional groups (1740 cm−1) within carious dentine tissue (infected and affected dentine). The null hypothesis stipulated that there are no differences in ester function intensity/distribution within carious dentine lesions. Materials and Methods: From a total of five extracted human molar teeth with carious dentine lesions, 246 points from 10 sections of carious dentine were examined using high‐resolution Raman spectroscopy and characterised into infected, affected and sound dentine. The peak intensity of the characteristic vibration mode of the ester function was calculated from sample scans. Results: Analyses indicated a statistically significant difference in the spectroscopic vibration bands of esters between the infected and affected dentine zones. Conclusion: The ester functional group is higher in intensity in the caries‐infected dentine zone compared to the affected tissue. This finding could be used to develop an objective indicator for the selective operative management of carious dentine. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
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50. |
- Kemp, John P, et al.
(författare)
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Phenotypic dissection of bone mineral density reveals skeletal site specificity and facilitates the identification of novel loci in the genetic regulation of bone mass attainment.
- 2014
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 10:6
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Tidskriftsartikel (refereegranskat)abstract
- Heritability of bone mineral density (BMD) varies across skeletal sites, reflecting different relative contributions of genetic and environmental influences. To quantify the degree to which common genetic variants tag and environmental factors influence BMD, at different sites, we estimated the genetic (rg) and residual (re) correlations between BMD measured at the upper limbs (UL-BMD), lower limbs (LL-BMD) and skull (SK-BMD), using total-body DXA scans of ∼ 4,890 participants recruited by the Avon Longitudinal Study of Parents and their Children (ALSPAC). Point estimates of rg indicated that appendicular sites have a greater proportion of shared genetic architecture (LL-/UL-BMD rg = 0.78) between them, than with the skull (UL-/SK-BMD rg = 0.58 and LL-/SK-BMD rg = 0.43). Likewise, the residual correlation between BMD at appendicular sites (r(e) = 0.55) was higher than the residual correlation between SK-BMD and BMD at appendicular sites (r(e) = 0.20-0.24). To explore the basis for the observed differences in rg and re, genome-wide association meta-analyses were performed (n ∼ 9,395), combining data from ALSPAC and the Generation R Study identifying 15 independent signals from 13 loci associated at genome-wide significant level across different skeletal regions. Results suggested that previously identified BMD-associated variants may exert site-specific effects (i.e. differ in the strength of their association and magnitude of effect across different skeletal sites). In particular, variants at CPED1 exerted a larger influence on SK-BMD and UL-BMD when compared to LL-BMD (P = 2.01 × 10(-37)), whilst variants at WNT16 influenced UL-BMD to a greater degree when compared to SK- and LL-BMD (P = 2.31 × 10(-14)). In addition, we report a novel association between RIN3 (previously associated with Paget's disease) and LL-BMD (rs754388: β = 0.13, SE = 0.02, P = 1.4 × 10(-10)). Our results suggest that BMD at different skeletal sites is under a mixture of shared and specific genetic and environmental influences. Allowing for these differences by performing genome-wide association at different skeletal sites may help uncover new genetic influences on BMD.
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