| 1. |
- Panneman, Daan M., et al.
(författare)
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Cost-effective sequence analysis of 113 genes in 1,192 probands with retinitis pigmentosa and Leber congenital amaurosis
- 2023
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Ingår i: Frontiers in Cell and Developmental Biology. - : Frontiers Media SA. - 2296-634X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are two groups of inherited retinal diseases (IRDs) where the rod photoreceptors degenerate followed by the cone photoreceptors of the retina. A genetic diagnosis for IRDs is challenging since >280 genes are associated with these conditions. While whole exome sequencing (WES) is commonly used by diagnostic facilities, the costs and required infrastructure prevent its global applicability. Previous studies have shown the cost-effectiveness of sequence analysis using single molecule Molecular Inversion Probes (smMIPs) in a cohort of patients diagnosed with Stargardt disease and other maculopathies. Methods: Here, we introduce a smMIPs panel that targets the exons and splice sites of all currently known genes associated with RP and LCA, the entire RPE65 gene, known causative deep-intronic variants leading to pseudo-exons, and part of the RP17 region associated with autosomal dominant RP, by using a total of 16,812 smMIPs. The RP-LCA smMIPs panel was used to screen 1,192 probands from an international cohort of predominantly RP and LCA cases. Results and discussion: After genetic analysis, a diagnostic yield of 56% was obtained which is on par with results from WES analysis. The effectiveness and the reduced costs compared to WES renders the RP-LCA smMIPs panel a competitive approach to provide IRD patients with a genetic diagnosis, especially in countries with restricted access to genetic testing.
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| 2. |
- Grüning, Björn, et al.
(författare)
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Bioconda: A sustainable and comprehensive software distribution for the life sciences
- 2017
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We present Bioconda (https://bioconda.github.io), a distribution of bioinformatics software for the lightweight, multi-platform and language-agnostic package manager Conda. Currently, Bioconda offers a collection of over 3000 software packages, which is continuously maintained, updated, and extended by a growing global community of more than 200 contributors. Bioconda improves analysis reproducibility by allowing users to define isolated environments with defined software versions, all of which are easily installed and managed without administrative privileges.
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| 3. |
- Freitag, Daniel F., et al.
(författare)
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Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis
- 2015
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Ingår i: The Lancet Diabetes & Endocrinology. - 2213-8595. ; 3:4, s. 243-253
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Tidskriftsartikel (refereegranskat)abstract
- Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND.
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| 4. |
- Escott-Price, Valentina, et al.
(författare)
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Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6, s. e94661-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-8)) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
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| 5. |
- Jones, Lesley, et al.
(författare)
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Convergent genetic and expression data implicate immunity in Alzheimer's disease
- 2015
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:6, s. 658-671
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Tidskriftsartikel (refereegranskat)abstract
- Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
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| 6. |
- van Doorn, Leni, et al.
(författare)
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Effect of Scalp Cooling on the Pharmacokinetics of Paclitaxel
- 2021
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 13:15
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary This study investigated the correlation between scalp cooling used to prevent chemotherapy-induced alopecia and the pharmacokinetics of paclitaxel in female cancer patients with a solid tumor. In a prospective cohort study, 14 patients who were treated with weekly paclitaxel and scalp cooling were able to undergo pharmacokinetic sampling of paclitaxel during one cycle of treatment. In comparison to a control cohort of 24 patients treated with weekly paclitaxel without scalp cooling, our data showed that scalp cooling used concomitantly with one course of paclitaxel did not reduce or increase the clearance of paclitaxel. Therefore, it is unlikely that scalp cooling influences paclitaxel efficacy or toxicity. Finally, despite scalp cooling, half of the patients in our study developed a form of hair loss. Importantly, neither an association with difference in paclitaxel clearance nor change in hair loss was found. Chemotherapy-induced alopecia (CIA), a side effect with high impact, can be prevented by cooling the scalp during the administration of some cytotoxic drugs. However, the effects of this prolonged scalp cooling on the pharmacokinetics of chemotherapy have never been investigated. In this study, we compared the pharmacokinetics of the widely used chemotherapeutic agent paclitaxel (weekly dose of 80-100 mg/m(2)) in female patients with solid tumors using concomitant scalp cooling (n = 14) or not (n = 24). Blood samples were collected in all patients for pharmacokinetic analyses up to 6 h after one course of paclitaxel administration. The primary endpoint was the clearance (L/h) of paclitaxel. Paclitaxel clearance-expressed as relative difference in geometric means-was 6.8% (90% CI: -16.7% to 4.4%) lower when paclitaxel was administered with concomitant scalp cooling versus paclitaxel infusions without scalp cooling. Within the subgroup of patients using scalp cooling, paclitaxel clearance was not statistically significantly different between patients with CIA (alopecia grade 1 or 2) and those without CIA. Hence, scalp cooling did not negatively influence the clearance of paclitaxel treatment.
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| 7. |
- Bagnoud, Alexandre, et al.
(författare)
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Reconstructing a hydrogen-driven microbial metabolic network in Opalinus Clay rock
- 2016
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- The Opalinus Clay formation will host geological nuclear waste repositories in Switzerland. It is expected that gas pressure will build-up due to hydrogen production from steel corrosion, jeopardizing the integrity of the engineered barriers. In an in situ experiment located in the Mont Terri Underground Rock Laboratory, we demonstrate that hydrogen is consumed by microorganisms, fuelling a microbial community. Metagenomic binning and metaproteomic analysis of this deep subsurface community reveals a carbon cycle driven by autotrophic hydrogen oxidizers belonging to novel genera. Necromass is then processed by fermenters, followed by complete oxidation to carbon dioxide by heterotrophic sulfate-reducing bacteria, which closes the cycle. This microbial metabolic web can be integrated in the design of geological repositories to reduce pressure build-up. This study shows that Opalinus Clay harbours the potential for chemolithoautotrophic-based system, and provides a model of microbial carbon cycle in deep subsurface environments where hydrogen and sulfate are present.
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| 8. |
- Calon, Tim G A, et al.
(författare)
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Minimally Invasive Ponto Surgery compared to the linear incision technique without soft tissue reduction for bone conduction hearing implants: study protocol for a randomized controlled trial.
- 2016
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Ingår i: Trials. - : Springer Science and Business Media LLC. - 1745-6215. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Over the last years, less invasive surgical techniques with soft tissue preservation for bone conduction hearing implants (BCHI) have been introduced such as the linear incision technique combined with a punch. Results using this technique seem favorable in terms of rate of peri-abutment dermatitis (PAD), esthetics, and preservation of skin sensibility. Recently, a new standardized surgical technique for BCHI placement, the Minimally Invasive Ponto Surgery (MIPS) technique has been developed by Oticon Medical AB (Askim, Sweden). This technique aims to standardize surgery by using a novel surgical instrumentation kit and minimize soft tissue trauma.A multicenter randomized controlled trial is designed to compare the MIPS technique to the linear incision technique with soft tissue preservation. The primary investigation center is Maastricht University Medical Center. Sixty-two participants will be included with a 2-year follow-up period. Parameters are introduced to quantify factors such as loss of skin sensibility, dehiscence of the skin next to the abutment, skin overgrowth, and cosmetic results. A new type of sampling method is incorporated to aid in the estimation of complications. To gain further understanding of PAD, swabs and skin biopsies are collected during follow-up visits for evaluation of the bacterial profile and inflammatory cytokine expression. The primary objective of the study is to compare the incidence of PAD during the first 3 months after BCHI placement. Secondary objectives include the assessment of parameters related to surgery, wound healing, pain, loss of sensibility of the skin around the implant, implant extrusion rate, implant stability measurements, dehiscence of the skin next to the abutment, and esthetic appeal. Tertiary objectives include assessment of other factors related to PAD and a health economic evaluation.This is the first trial to compare the recently developed MIPS technique to the linear incision technique with soft tissue preservation for BCHI surgery. Newly introduced parameters and sampling method will aid in the prediction of results and complications after BCHI placement.Registered at the CCMO register in the Netherlands on 24 November 2014: NL50072.068.14 . Retrospectively registered on 21 April 2015 at ClinicalTrials.gov: NCT02438618 . This trial is sponsored by Oticon Medical AB.
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| 9. |
- de Bruijn, Robert
(författare)
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Cardiovascular and hematological responses to voluntary apnea in humans
- 2007
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis deals with cardiovascular and hematological responses to voluntary apnea in humans, with a special focus on O2 usage and storage. Humans, and many other air‐breathing animals, respond to apnea (breath holding) with a collection of interacting cardiovascular reflexes, which are collectively called the diving response. In humans, the main characteristics of the diving response are a reduction in heart rate (bradycardia), decreased cardiac output, peripheral vasoconstriction and increased arterial blood pressure. Another response during apnea in mammals, more recently also observed in man, is a transient increase in hemoglobin concentration across a series of apneas, probably due a reduction in spleen size. There may also be long‐term effects on erythropoiesis in the apneic diver, as suggested by high hemoglobin levels observed in divers. The focus of the included studies are the short transient diving response (I), the more slowly occurring transient hematological changes to apnea, most likely related to a reduction in spleen size (II), and the possible effects of repeated apnea on serum erythropoietin concentration (III). I) The aim was to study the effects of body immersion on the O2‐conserving effect of the human diving response. The results showed that, regardless of body immersion, apnea with face immersion causes a stronger cardiovascular diving response compared to during apnea alone, leading to a smaller reduction in arterial oxygen saturation levels. Thus the diving response is triggered and conserves O2 even during whole‐body immersion, which has previously only been observed during apnea without whole‐body immersion. II) The aim was to study hematological responses to voluntary repeated maximal‐duration apneas in divers and non‐divers. Increases in hemoglobin concentration were found across a series of 3 apneas in elite breath‐hold divers, elite cross‐country skiers and untrained subjects. However a larger increase in hemoglobin was found in divers compared to non‐divers, which suggests a possible training effect of their extensive apnea‐specific training. In contrast, physical endurance training does not appear to affect the hematological response to apnea. III) The aim was to study the effects of serial voluntary apnea on the serum erythropoietin concentration. In a comparison between elite breath‐hold divers and subjects untrained in apnea, divers were found to have a 5% higher resting hemoglobin concentration. An average maximum increase in erythropoietin of 24 % was found in untrained subjects after 15 maximal duration apneas, preceded by 1 min of hyperventilation. This suggests a possible erythropoietic effect of apnea‐induced hypoxia, which may connect the increased resting hemoglobin found in divers to their apnea‐specific training. It was concluded from these studies that man responds to apnea with a series of different adjustments in order to limit O2 usage and increase O2 storage: The classical diving response is effectively restricting O2‐consumption also during full immersion, the spleen related hemoglobin increase occurs in both divers and non‐divers with different levels of physiological training, but is more prominent in divers, and finally, the observed high levels of hemoglobin concentration in divers may be related to enhanced erythropoiesis during dive training.
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| 10. |
- de Bruijn, Robert, et al.
(författare)
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Erythropoietin production as a result of repeated apneas
- 2004
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Konferensbidrag (refereegranskat)abstract
- Background: It has been known for decades that high altitude hypoxia will lead to increased erythropoiesis. Hypoxia in mainly the kidney results in an increased production of erythropoietin (EPO) stimulating erythropoiesis. High altitude natives display a higher haemoglobin concentration than sea level residents, which in turn increase their haemoglobin concentration as part of the adaptation to altitude. Another group of humans exposed to hypoxia is apneic divers, which may endure transient acute hypoxia, spaced by periods of normal breathing. We recently found higher haemoglobin levels in elite apneic divers, compared to groups of elite skiers and untrained subjects, suggesting that apnea training may induce erythropoiesis in humans. It is well known that diving mammals display high haemoglobin concentrations, and the beneficial effects are obvious: A larger oxygen store before diving prolongs the aerobic dive limit, and a higher haemoglobin concentration may speed up recovery after apneas and act as a buffer against acidosis during the dive. Although our group comparisons reveal a higher haemoglobin concentration in divers, it cannot be determined whether this is a training effect or genetically determined i.e. if individuals with higher concentrations of haemoglobin are more prone to take up apneic diving. Methods: To investigate if apnea training can induce EPO production, 5 previously untrained volunteers (3 men and 2 women, mean ageSD 28 5.5 years) performed 15 maximal apneas in a horizontal position in air. The apneas were grouped in 3 series of 5 apneas and spaced by 2 minutes of which 1 minute was spent slightly hyperventilating, to produce apneas sufficiently long to induce hypoxia. Series were spaced by 10 minutes resting periods. To determine EPO levels, venous blood samples were taken before apneas and directly after the last apnea series, followed by samples 1, 2, 3 and 5 hours after the apneas. Results: Mean baseline EPO before the apneas was 10.2 U/L. In all subjects EPO levels increased during the 5 hours period after the apneas. The time for EPO-peak values were different among individuals. The mean peak value occurred after 3 h, where the mean increase was 12 % of the pre apnea reference value. Conclusion: The results suggest that apnea induced intermittent hypoxia could lead to increased erythropoiesis. The evaluation of these findings in a larger group of subjects, including measurements of the individual circadian variations in EPO production, is in progress.
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