| 1. |
- Szatmari, Peter, et al.
(author)
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Mapping autism risk loci using genetic linkage and chromosomal rearrangements.
- 2007
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 39:3, s. 319-328
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Journal article (peer-reviewed)abstract
- Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,168 families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.
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| 2. |
- van der Bol, Jessica M., et al.
(author)
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Cigarette smoking and irinotecan treatment : Pharmacokinetic interaction and effects on neutropenia
- 2007
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In: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 25:19, s. 2719-2726
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Journal article (peer-reviewed)abstract
- Purpose Several constituents of cigarette smoke are known to interact with drug metabolizing enzymes and potentially affect treatment outcome with substrate drugs. The purpose of this study was to determine the effects of cigarette smoking on the pharmacokinetics and adverse effects of irinotecan. Patients and Methods A total of 190 patients (49 smokers, 141 nonsmokers) treated with irinotecan (90-minute intravenous administration on a 3-week schedule) were evaluated for pharmacokinetics. Complete toxicity data were available in a subset of 134 patients receiving 350 mg/m(2) or 600 mg flat-fixed dose irinotecan. Results In smokers, the dose-normalized area under the plasma concentration-time curve of irinotecan was significantly lower (median, 28.7 v 33.9 ng . h/mL/mg; P = .001) compared with nonsmokers. In addition, smokers showed an almost 40% lower exposure to SN-38 (median, 0.54 v 0.87 ng . h/mL/mg; P < .001) and a higher relative extent of glucuronidation of SN-38 into SN-38G (median, 6.6 v 4.5; P = .006). Smokers experienced considerably less hematologic toxicity. In particular, the incidence of grade 3 to 4 neutropenia was 6% in smokers versus 38% in nonsmokers (odds ratio [OR], 0.10; 95% CI, 0.02 to 0.43; P < .001). There was no significant difference in incidence of delayed-onset diarrhea (6% v 15%; OR, 0.34; 95% CI, 0.07 to 1.57; P = .149). Conclusion This study indicates that smoking significantly lowers both the exposure to irinotecan and treatment-induced neutropenia, indicating a potential risk of treatment failure. Although the underlying mechanism is not entirely clear, modulation of CYP3A and uridine diphosphate glucuronosyltransferase isoform 1A1 may be part of the explanation. The data suggest that additional investigation is warranted to determine whether smokers are at increased risk for treatment failure.
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| 3. |
- Van Holsbeke, C., et al.
(author)
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Ultrasound methods to distinguish between malignant and benign adnexal masses in the hands of examiners with different levels of experience
- 2009
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In: Ultrasound in Obstetrics & Gynecology. - : Wiley. - 1469-0705 .- 0960-7692. ; 34:4, s. 454-461
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Journal article (peer-reviewed)abstract
- Objectives To determine the effect of an ultrasound training course on the performance of pattern recognition when used by less experienced examiners and to compare the performance of pattern recognition, a logistic regression model and a scoring system to estimate the risk of malignancy between examiners with different levels of experience. Methods Using ultrasound images of selected adnexal masses, two trainees classified the masses as benign or malignant by using pattern recognition both before and after they bad attended a theoretical gynecological ultrasound course. They also classified the masses by using a logistic regression model and a scoring system, but only after they bad attended the course. The performance of these three methods when they were used by the trainees was then compared with that when they were used by experts. Results One hundred and sixty-five adnexal masses were included, of which 42% were malignant (21% invasive tumors and 21% borderline tumors). The area under the receiver- operating characteristics curve of pattern recognition when used by the trainees was similar before and after they had attended the course. Training decreased sensitivity (84% vs. 70% for Trainee 1, P = 0.004; 70% vs. 61% for Trainee2, P = 0.08) and increased specificity (77% vs. 92% for Trainee 1, P = 0.001; 89% vs. 95% for Trainee 2, P = 0.058). The performance of pattern recognition was poorer in the hands of the trainees than in the bands of the experts. The sensitivities of the logistic regression model were 70% and 54% for the trainees vs. 83% for an expert (P = 0.020 and < 0.001, respectively) and the specificities were 84% and 94% vs. 89% (P = 0.25 and 0.59, respectively). The sensitivities of the scoring system were 59% and 54% for the trainees vs. 75% for the expert (P = 0.002 and < 0.001, respectively), and the specificities were 90% and 93% vs. 85% (P = 0.103 and 0.008, respectively). Conclusion Theoretical ultrasound teaching did not seem to improve the performance of pattern recognition in the bands of trainees. A logistic regression model and a scoring system to classify adnexal masses as benign or malignant perform less well when they were used by inexperienced examiners than when used by an expert. Before using a model or a scoring system, experience and/or proper training are likely to be of paramount importance if diagnostic performance is to be optimized. Copyright (C) 2009 ISUOG. Published by John Wiley & Sons, Ltd.
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| 4. |
- Chijimatsu, M., et al.
(author)
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Numerical study of the THM effects on the near-field safety of a hypothetical nuclear waste repository - BMT1 of the DECOVALEX III project. Part 1 : Conceptualization and characterization of the problems and summary of results
- 2005
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In: International Journal of Rock Mechanics And Mining Sciences. - : Elsevier BV. - 1365-1609 .- 1873-4545. ; 42:5-6, s. 720-730
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Journal article (peer-reviewed)abstract
- Geological disposal of the spent nuclear fuel often uses the concept of multiple barrier systems. In order to predict the performance of these barriers, mathematical models have been developed, verified and validated against analytical solutions, laboratory tests and field experiments within the international DECOVALEX III project. These models in general consider the full coupling of thermal (T), hydraulic (H) and mechanical (M) processes that would prevail in the geological media around the repository. For Bench Mark Test no. 1 (BMTI) of the DECOVALEX III project, seven multinational research teams studied the implications of coupled THM processes on the safety of a hypothetical nuclear waste repository at the near-field and are presented in three accompanying papers in this issue. This paper is the first of the three companion papers, which provides the conceptualization and characterization of the BMT1 as well as some general conclusions based on the findings of the numerical studies. It also shows the process of building confidence in the mathematical models by calibration with a reference T-H-M experiment with realistic rock mass conditions and bentonite properties and measured outputs of thermal, hydraulic and mechanical variables.
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| 5. |
- Clarke, A. L., et al.
(author)
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Long-Term Trends in Eutrophication and Nutrients in the Coastal Zone
- 2006
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In: Limnology and Oceanography. - 0024-3590 .- 1939-5590. ; 51:1, s. 385-397
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Journal article (peer-reviewed)abstract
- We used high-resolution paleoecological records of environmental change to study the rate and magnitude of eutrophication over the last century in two contrasting coastal ecosystems. A multiproxy approach using geochemical and biological indicators and diatom-based transfer functions provides a long-term perspective on changes in nutrient concentrations and the corresponding biological and sedimentary responses. In Roskilde Fjord, Denmark, total nitrogen (TN) increased 85% during the last century, with the most rapid increase occurring after the 1950s, corresponding to the postwar increase in N fertilizer use. In Laajalahti Bay, an urban embayment near Helsinki, Finland, total dissolved nitrogen (TDN) increased with growing wastewater inputs and decreased with the remedial actions taken to reduce these discharges. These changes are small relative to the order of magnitude increases in nutrient loading that have occurred in northwestern Europe, where the dissolved inorganic nitrogen (DIN) load has increased more than threefold in certain areas.
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| 6. |
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| 7. |
- Millard, A., et al.
(author)
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Numerical study of the THM effects on the near-field safety of a hypothetical nuclear waste repository - BMT1 of the DECOVALEX III project. Part 2 : Effects of THM coupling in continuous and homogeneous rocks
- 2005
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In: International Journal of Rock Mechanics And Mining Sciences. - : Elsevier BV. - 1365-1609 .- 1873-4545. ; 42:5-6, s. 731-744
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Journal article (peer-reviewed)abstract
- An evaluation of the importance of the thermo-hydro-mechanical couplings (THM) on the performance assessment of a deep underground radioactive waste repository has been made as a part of the international DECOVALEX III project. It is a numerical study that simulates a generic repository configuration in the near field in a continuous and homogeneous hard rock. A periodic repository configuration comprises a single vertical borehole, containing a canister surrounded by an over-pack and a bentonite layer, and the backfilled upper portion of the gallery. The thermo-hydro-mechanical evolution of the whole configuration is simulated over a period of 100 years. The importance of the rock mass's intrinsic permeability has been investigated through scoping calculations with three values: 10(-17), 10(-18) and 10(-19) m(2). Comparison of the results predicted by fully coupled THM analysis as well as partially coupled TH, TM and HM analyses, in terms of several predefined indicators of importance for performance assessment, enables us to identify the effects of the different combinations of couplings, which play a crucial role with respect to safety issues. The results demonstrate that temperature is hardly affected by the couplings. In contrast, the influence of the couplings on the mechanical stresses is considerable.
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| 8. |
- Tsutsumi, A, et al.
(author)
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Application of item response theory to achieve cross-cultural comparability of occupational stress measurement
- 2009
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In: International Journal of Methods in Psychiatric Research. - : Wiley. - 1049-8931 .- 1557-0657. ; 18:1, s. 58-67
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Journal article (peer-reviewed)abstract
- Our objective was to examine cross-cultural comparability of standard scales of the Effort-Reward Imbalance occupational stress scales by item response theory (IRT) analyses. Data were from 20,256 Japanese employees, 1464 Dutch nurses and nurses' aides, 2128 representative employees from post-communist countries, 963 Swedish representative employees, 421 Chinese female employees, 10,175 employees of the French national gas and electric company and 734 Spanish railroad employees, sanitary personnel and telephone operators. The IRT likelihood ratio model was used for differential item functioning (DIF) and differential test functioning (DTF) analyses. Despite the existence of DIF, most comparisons did not show discernible differences in the relations between Effort-Reward total score and level of the underlying trait across cultural groups. In the case that DTF was suspected, excluding an item with significant DIF improved the comparability. The full cross-cultural comparability of Effort-Reward Imbalance scores can be achieved with the help of IRT analysis.
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| 9. |
- van de Pavert, Serge A., et al.
(author)
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Chemokine CXCL13 is essential for lymph node initiation and is induced by retinoic acid and neuronal stimulation
- 2009
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In: Nature Immunology. - : Springer Science and Business Media LLC. - 1529-2908 .- 1529-2916. ; 10:11, s. 78-1193
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Journal article (peer-reviewed)abstract
- The location of embryonic lymph node development is determined by the initial clustering of lymphoid tissue-inducer (LTi) cells. Here we demonstrate that both the chemokine CXCL13 and the chemokine CCL21 attracted LTi cells at embryonic days 12.5-14.5 and that initial clustering depended exclusively on CXCL13. Retinoic acid (RA) induced early CXCL13 expression in stromal organizer cells independently of lymphotoxin signaling. Notably, neurons adjacent to the lymph node anlagen expressed enzymes essential for RA synthesis. Furthermore, stimulation of parasymphathetic neural output in adults led to RA receptor (RAR)-dependent induction of CXCL13 in the gut. Therefore, our data show that the initiation of lymph node development is controlled by RA-mediated expression of CXCL13 and suggest that RA may be provided by adjacent neurons.
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