| 1. |
- Assimes, Themistocles L., et al.
(författare)
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Lack of Association Between the Trp719Arg Polymorphism in Kinesin-Like Protein-6 and Coronary Artery Disease in 19 Case-Control Studies
- 2010
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 56:19, s. 1552-1563
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Tidskriftsartikel (refereegranskat)abstract
- Objectives We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD). Background Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers. Methods The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in 19 case-control studies of nonfatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports. Results A total of 17,000 cases and 39,369 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the 19 studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with noncarriers. Regression analyses and fixed-effects meta-analyses ruled out with high degree of confidence an increase of >= 2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early-onset disease (younger than 50 years of age for men and younger than 60 years of age for women) compared with similarly aged controls as well as all non-European subgroups. Conclusions The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study. (J Am Coll Cardiol 2010;56:1552-63) (C) 2010 by the American College of Cardiology Foundation
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| 2. |
- Eckhard, Andreas, et al.
(författare)
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Co-localisation of Kir4.1 and AQP4 in rat and human cochleae reveals a gap in water channel expression at the transduction sites of endocochlear K+ recycling routes
- 2012
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Ingår i: Cell and Tissue Research. - : Springer Science and Business Media LLC. - 0302-766X .- 1432-0878. ; 350:1, s. 27-43
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Tidskriftsartikel (refereegranskat)abstract
- Sensory transduction in the cochlea depends on perilymphatic-endolymphatic potassium (K+) recycling. It has been suggested that the epithelial supporting cells (SCs) of the cochlear duct may form the intracellular K+ recycling pathway. Thus, they must be endowed with molecular mechanisms that facilitate K+ uptake and release, along with concomitant osmotically driven water movements. As yet, no molecules have been described that would allow for volume-equilibrated transepithelial K+ fluxes across the SCs. This study describes the subcellular co-localisation of the Kir4.1 K+ channel (Kir4.1) and the aquaporin-4 water channel (AQP4) in SCs, on the basis of immunohistochemical double-labelling experiments in rat and human cochleae. The results of this study reveal the expression of Kir4.1 in the basal or basolateral membranes of the SCs in the sensory domain of the organ of Corti that are adjacent to hair cells and in the non-sensory domains of the inner and outer sulci that abut large extracellular fluid spaces. The SCs of the inner sulcus (interdental cells, inner sulcus cells) and the outer sulcus (Hensen’s cells, outer sulcus cells) display the co-localisation of Kir4.1 and AQP4 expression. However, the SCs in the sensory domain of the organ of Corti reveal a gap in the expression of AQP4. The outer pillar cell is devoid of both Kir4.1 and AQP4. The subcellular co-localisation of Kir4.1 and AQP4 in the SCs of the cochlea described in this study resembles that of the astroglia of the central nervous system and the glial Mueller cells in the retina.
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| 3. |
- Ellinghaus, David, et al.
(författare)
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Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies
- 2013
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 145:2, s. 339-347
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Genome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies.METHODS: We sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems.RESULTS: We identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 x 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 x 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor kappa B activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways.CONCLUSIONS: We have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.
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| 4. |
- van As, Dirk, et al.
(författare)
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Darkening of the Greenland ice sheet due to the melt-albedo feedback observed at PROMICE weather stations
- 2013
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Ingår i: Geological Survey of Denmark and Greenland Bulletin. - 1811-4598 .- 1604-8156. ; 28, s. 69-72
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Tidskriftsartikel (refereegranskat)abstract
- The Greenland ice sheet is losing mass (Barletta et al. 2012) and at least half of this loss is caused by an increase in surface melt (e.g. Tedesco et al. 2013). The other part is caused by increased dynamic mass loss, as marine-terminating glaciers lose resistive stresses (Nick et al. 2009) due to both retreat and meltwater lubrication at the bed (Sasgen et al. 2012).In 2007, the Programme for Monitoring of the Greenland Ice Sheet (PROMICE) was initiated with the aim of gaining an insight into the causes of the ice-mass budget changes based on quantitative observations. This is primarily done by assessing how much mass is gained as snow accumulation on the surface versus how much is lost by calving and surface ablation (Ahlstrøm et al. 2008). PROMICE monitors the surface mass balance by means of automatic weather stations (AWSs) designed to quantify accumulation and ablation, as well as the specific energy sources contributing to ablation. These observations are vital to interpreting the physical mechanisms for ice-sheet response to climate change and for the calibration and validation of both satellite observations and climate models.In the wake of several record-breaking warm summers – increasing surface melt rate and extent (Nghiem et al. 2012) – interest in Greenland’s surface mass balance has increased (Tedesco et al. 2013). Observations of net ablation at PROMICE stations provided in situ confirmation of extreme massloss events in 2010 (Fausto et al. 2012) and 2012, primarily documented by other workers through satellite data. In this paper, we present atmospheric temperatures and surface solar reflectivity (known as albedo) of the Greenland ice sheet in the PROMICE period. Albedo modulates the absorption of solar radiation, which is the primary source of melt energy. It is reported to be decreasing in Greenland in recent years (Box et al. 2012), causing the monitoring of albedo variability to be increasingly important. Air temperatures, besides being strongly correlated to surface melt rates, affect surface albedo by controlling the rate of snow-grain metamorphism and the fraction of summer precipitation falling as rain versus snow. To elucidate the so-called melt-albedo feedback, whereby increased melt darkens the ice sheet and further enhances melt, the relationship between albedo and air temperature, observed at PROMICE stations, is examined in this study.
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| 5. |
- van As, Dirk, et al.
(författare)
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Katabatic winds and piteraq storms : observations from the Greenland ice sheet
- 2014
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Ingår i: Geological Survey of Denmark and Greenland Bulletin. - 1811-4598 .- 1604-8156. ; 31, s. 83-86
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Tidskriftsartikel (refereegranskat)abstract
- In 2007 the Programme for Monitoring the Greenland Ice Sheet (PROMICE) was initiated to observe and gain insight into the mass budget of Greenland ice masses. By means of in situ observations and remote sensing, PROMICE assesses how much mass is gained as snow accumulation on the surface versus how much is lost by iceberg calving and surface ablation (Ahlstrøm et al. 2008). A key element of PROMICE is a network of automatic weather stations (AWSs) designed to quantify components of the surface mass balance, including the energy exchanges contributing to surface ablation (Van As et al. 2013).The use of these AWS observations is not limited to studies of ice-sheet mass balance. PROMICE contributes to CryoNet (www.globalcryospherewatch.org/cryonet), the core network of surface measurement sites of the World Meteorological Organization (WMO) Global Cryosphere Watch. By real-time delivery through WMO, PROMICE observations contribute to improve both operational forecasting and climate analysis in the data-sparse Arctic. The Greenlandic population, highly dependent on accurate forecasting of weather conditions, benefits directly from these real-time observations. For instance, extreme surface wind speeds are a high-risk element in Greenland. The third-highest wind speed observed at the surface of the Earth (93 m/s or 333 km/h), was recorded in a 8–9 March 1972 storm at Thule in North-West Greenland (Stansfield 1972).In this paper, we discuss the extent to which the Greenland ice sheet generates its own near-surface wind field. We use PROMICE data to gain insight into the interaction between air temperature, radiation and gravity-driven katabatic winds. We focus on a particularly powerful spring storm in 2013 that contributed to a fatality on an ice-sheet ski traverse attempt (Linden 2013).
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| 6. |
- Andersen, Andreas, et al.
(författare)
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The immunological effect of revaccination with Bacille Calmette-Guerin vaccine at 19 months of age
- 2013
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Ingår i: Vaccine. - : Elsevier BV. - 1873-2518 .- 0264-410X. ; 31:17, s. 2137-2144
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Tidskriftsartikel (refereegranskat)abstract
- Background: Bacille Calmette-Guerin (BCG) vaccination has important non-specific immune effects. In a randomized trial in Guinea-Bissau, BCG revaccination was associated with significantly increased survival in children who received diphtheria-tetanus-pertussis (DTP)-booster vaccine before enrolment and in children who did not receive micronutrient supplementation (MN). Within the trial we assessed the immunological effects of BCG revaccination. Methods: Children were randomized to BCG or nothing. Blood was sampled 6-11 weeks after randomization (early sample group) or 5-9 months later (late sample group). In vitro cytokine responses (interferon (IFN)-gamma, interleukin (IL)-13, tumor-necrosis-factor (TNF)-alpha, and IL-10) were assessed in whole blood cultures stimulated with lipopolysaccharide (LPS), purified protein derivative (PPD) or phytohaemagglutinin (PHA). Effect-modification by sex, DTP-booster vaccination and MN was studied. Results: Cytokines were measured in 345 infants. BCG was associated with significantly increased IFN-gamma (geometric mean ratio (GMR) = 4.54 (95% confidence interval: 3.13-6.58)) and IL-13 (GMR = 1.43 (1.00-2.05)) PPD responses, the effect being strongest in the early sample group. Across all three conditions BCG tended to increase IL-10 (LPS, PHA, PPD: GMR = 1.20, 1.12, 1.20), most pronounced in the late sample group. BCG reduced the TNF-alpha/IL-10 ratio in boys with DTP-booster at bleeding and increased it in those without (interaction test: p = 0.03). In children without MN, BCG was associated with reduced TNF-alpha response in the early sample group (p = 0.006), and increased IL-10 in the late sample group (p = 0.03). Conclusion: BCG revaccination resulted in a strong IFN-gamma response to PPD, which waned slightly over time. BCG also affected the pro-/anti-inflammatory balance, with reduced TNF-alpha and increased IL-10 responses to LPS, PHA and PPD. This effect depended on sex, DTP-booster vaccination and micronutrient supplementation, being most pronounced in children who had received DTP-booster before enrolment and children who had not received MN, i.e. the group of children which also had lower mortality after BCG revaccination. (C) 2013 Elsevier Ltd. All rights reserved.
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| 9. |
- Bergmann, Troels K., et al.
(författare)
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Retrospective study of the impact of pharmacogenetic variants on paclitaxel toxicity and survival in patients with ovarian cancer
- 2011
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Ingår i: European Journal of Clinical Pharmacology. - : Springer Science Business Media. - 0031-6970 .- 1432-1041. ; 67:7, s. 693-700
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Tidskriftsartikel (refereegranskat)abstract
- Paclitaxel has a broad spectrum of anti-tumor activity and is useful in the treatment of ovarian, breast, and lung cancer. Paclitaxel is metabolized in the liver by CYP2C8 and CYP3A4 and transported by P-glycoprotein. The dose-limiting toxicities are neuropathy and neutropenia, but the interindividual variability in toxicity and also survival is large. The main purpose of this study was to investigate the impact of genetic variants in CYP2C8 and ABCB1 on toxicity and survival. The 182 patients previously treated for ovarian cancer with carboplatin and paclitaxel in either the AGO-OVAR-9 or the NSGO-OC9804 trial in Denmark or Sweden were eligible for this study. Genotyping was carried out on formalin-fixed tissue. The patients toxicity profiles and survival data were derived from retrospective data. CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T were chosen a priori for primary analysis; a host of other variants were entered into an exploratory analysis. Clinical data and tissue were available from a total of 119 patients. Twenty-two single nucleotide polymorphisms (SNPs) in 10 genes were determined. Toxicity registration was available from 710 treatment cycles. In the primary analysis, no statistically significant correlation was found between CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T and neutropenia, sensoric neuropathy, and overall survival. CYP2C8*3 and the ABCB1 SNPs C1236T, G2677T/A, and C3435T were not statistically significantly correlated to overall survival, sensoric neuropathy, and neutropenia in 119 patients treated for ovarian cancer with paclitaxel/carboplatin.
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| 10. |
- Birve, Anna, et al.
(författare)
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A novel SOD1 splice site mutation associated with familial ALS revealed by SOD activity analysis
- 2010
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 19:21, s. 4201-4206
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Tidskriftsartikel (refereegranskat)abstract
- More than 145 mutations have been found in the gene CuZn-Superoxide dismutase (SOD1) in patients with amyotrophic lateral sclerosis (ALS). The vast majority are easily detected nucleotide mutations in the coding region. In a patient from a Swiss ALS family with half-normal erythrocyte SOD1 activity, exon flanking sequence analysis revealed a novel thymine to guanine mutation 7 bp upstream of exon 4 (c.240-7T>G). The results of splicing algorithm analyses were ambiguous, but five out of seven analysis tools suggested a potential novel splice site that would add six new base pairs to the mRNA. If translated, this mRNA would insert Ser and Ile between Glu78 and Arg79 in the SOD1 protein. In fibroblasts from the patient, the predicted mutant transcript and the mutant protein were both highly expressed, and despite the location of the insertion into the metal ion-binding loop IV, the SOD1 activity appeared high. In erythrocytes, which lack protein synthesis and are old compared with cultured fibroblasts, both SOD1 protein and enzymic activity was 50% of controls. Thus, the usage of the novel splice site is near 100%, and the mutant SOD1 shows the reduced stability typical of ALS-associated mutant SOD1s. The findings suggests that this novel intronic mutation is causing the disease and highlights the importance of wide exon-flanking sequencing and transcript analysis combined with erythrocyte SOD1 activity analysis in comprehensive search for SOD1 mutations in ALS. We find that there are potentially more SOD1 mutations than previously reported.
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