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Uxbridge, United Kingdom

Hosang G.M.,Kings College London | Uher R.,Kings College London | Keers R.,Kings College London | Cohen-Woods S.,Kings College London | And 8 more authors.
Journal of Affective Disorders

Background: Gene-environment interactions may contribute to the high heritability of bipolar affective disorder. The aim of the present study was to examine the interplay between the BDNF Val66Met polymorphism and stressful life events (SLEs) in bipolar disorder. Method: A total of 1085 participants were recruited, including 487 bipolar I cases and 598 psychiatrically healthy controls. All participants completed the List of Threatening Life Events Questionnaire; bipolar subjects reported the events that occurred 6 months leading up to their worst manic episode and 6 months prior to their worst depressive episode, controls recorded events experienced 6 months before interview. The sample was genotyped for the BDNF Val66Met polymorphism (rs6265). Results: Both Met carrier BDNF genotype and SLEs were significantly associated with the worst depressive episode of bipolar disorder. For the worst depressive episodes the effects of SLEs were also significantly moderated by BDNF genotype (gene × environment interaction). Limitations: The use of a self report questionnaire to measure stressful life events may increase recall inaccuracies, therefore caution should be taken when interpreting these results. Discussion: The findings of this study highlight the importance of the interplay between genes and the environment in bipolar disorder. © 2010 Elsevier B.V. All rights reserved. Source

Wouters E.F.M.,Maastricht University | Pinto-Plata V.M.,University of Liverpool | Bakke P.S.,University of Bergen | Agusti A.,University of Barcelona | And 8 more authors.
Respiratory Medicine

In addition to the six-min walk distance (6 MWD), other six-min walk test (6 MWT) derived variables, such as mean walk-speed (6MWSpeed), 6-min walk-work (6 MWW), distance-saturation product (DSP), exercise-induced oxygen desaturation (EID), and unintended stops may be useful for the prediction of mortality and hospitalization in patients with chronic obstructive pulmonary disease (COPD). We studied the association between 6 MWT-derived variables and mortality as well as hospitalization in COPD patients and compared it with the BODE index. A three-year prospective study (ECLIPSE) to evaluate the prognostic value of 6 MWT-derived variables in 2010 COPD patients. Cox's proportional-hazard regressions were performed to estimate 3-year mortality and hospitalization. During the follow-up, 193 subjects died and 622 were hospitalized. An adjusted Cox's regression model of hazard ratio [HR] for impaired 6 MWT-derived variables was significant referring to: mortality (6 MWD ≤334 m [2.30], 6MWSpeed ≤0.9 m/sec [2.15], 6 MWW ≤20000 m kg [2.17], DSP ≤290 m% [2.70], EID ≤88% [1.75], unintended stops [1.99]; and hospitalization (6 MWW ≤27000 m kg [1.23], EID ≤88% [1.25], BODE index ≥3 points [1.40]; all p ≤ 0.05). The 6 MWT-derived variables have an additional predictive value of mortality in patients with COPD. The 6 MWW, EID and the BODE index refine the prognosis of hospitalization. © 2015 Elsevier Ltd. All rights reserved. Source

Nair S.C.,University Utrecht | Welsing P.M.J.,University Utrecht | Choi I.Y.K.,University of Amsterdam | Roth J.,University Hospital Muenster | And 10 more authors.

Objectives: Measurement of MRP8/14 serum levels has shown potential in predicting clinical response to different biological agents in rheumatoid arthritis (RA). We aimed to develop a treatment algorithm based on a prediction score using MRP8/14 measurements and clinical parameters predictive for response to different biological agents. Methods: Baseline serum levels of MRP8/14 were measured in 170 patients starting treatment with infliximab, adalimumab or rituximab. We used logistic regression analysis to develop a predictive score for clinical response at 16 weeks. MRP8/14 levels along with clinical variables at baseline were investigated. We also investigated how the predictive effect of MRP8/14 was modified by drug type. A treatment algorithm was developed based on categorizing the expected response per drug type as high, intermediate or low for each patient and optimal treatment was defined. Finally, we present the utility of using this treatment algorithm in clinical practice. Results: The probability of response increased with higher baseline MRP8/14 complex levels (OR = 1.39), differentially between the TNF-blockers and rituximab (OR of interaction term = 0.78), and also increased with higher DAS28 at baseline (OR = 1.28). Rheumatoid factor positivity, functional disability (a higher HAQ), and previous use of a TNF-inhibitor decreased the probability of response. Based on the treatment algorithm 80 patients would have been recommended for anti-TNF treatment, 8 for rituximab, 13 for another biological treatment (other than TNFi or rituximab) and for 69 no recommendation was made. The predicted response rates matched the observed response in the cohort well. On group level the predicted response based on the algorithm resulted in a modest 10% higher response rate in our cohort with much higher differences in response probability in individual patients treated contrary to treatment recommendation. Conclusions: Prediction of response using MRP8/14 levels along with clinical predictors has potential in personalizing treatment for RA patients starting biological anti-rheumatic treatment, and might increase cost-effectiveness. © 2016 Nair et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Source

Hesketh P.J.,Lahey Clinic Medical Center | Wright O.,GSK Research and Development | Rosati G.,Medical Oncology Unit | Russo M.,GSK Research and Development | And 6 more authors.
Supportive Care in Cancer

Purpose The primary objective was to determine if a single dose of casopitant 90 mg added to ondansetron and dexamethasone would improve the control of chemotherapy-induced nausea and vomiting (CINV) over 0-120 h following initiation of oxaliplatin-based moderately emetic chemotherapy (MEC) compared to ondansetron and dexamethasone alone. Methods Patients with colorectal cancer received either casopitant or placebo intravenously (IV) added to ondansetron 8 mg bid oral on study days 1 to 3 and one dose of dexamethasone 8 mg IV given prior to starting the oxaliplatin on day 1. The primary endpoint was the percentage of subjects achieving complete response (CR; no vomiting/retching or use of rescue medication) during 120 h after initiation of chemotherapy in cycle 1. Results No difference in the rate of CR was noted in the casopitant group compared to the placebo group for the overall (placebo 85%, casopitant 86%, p=0.7273), acute (placebo 96%, casopitant 97%), or delayed phases (placebo 85%, casopitant 86%). The average area under curve (0-∞) of casopitant after a single 90-mg IV dose was 8,390 ng h/mL. At 24 h after casopitant 90-mg IV dosing, the plasma casopitant concentration was 24% lower than the values noted in prior studies with 150 mg oral administration, and the plasma exposure of the major metabolite (GSK525060) was 18% lower. Conclusions Addition of single-dose casopitant 90 mg IV did not improve the control of CINV at any time during 120 h following initiation of oxaliplatin-based MEC. Excellent control of CINV was achieved in this study population with the combination of ondansetron and dexamethasone alone. © 2011 Springer-Verlag. Source

Xu W.,University of Toronto | Cohen-Woods S.,Kings College London | Noor A.,Campbell Family Mental Health Research Institute | Knight J.,Campbell Family Mental Health Research Institute | And 20 more authors.
BMC Medical Genetics

Background: Recently, genome-wide association studies (GWAS) for cases versus controls using single nucleotide polymorphism microarray data have shown promising findings for complex neuropsychiatric disorders, including bipolar disorder (BD).Methods: Here we describe a comprehensive genome-wide study of bipolar disorder (BD), cross-referencing analysis from a family-based study of 229 small families with association analysis from over 950 cases and 950 ethnicity-matched controls from the UK and Canada. Further, loci identified in these analyses were supported by pathways identified through pathway analysis on the samples.Results: Although no genome-wide significant markers were identified, the combined GWAS findings have pointed to several genes of interest that support GWAS findings for BD from other groups or consortia, such as at SYNE1 on 6q25, PPP2R2C on 4p16.1, ZNF659 on 3p24.3, CNTNAP5 (2q14.3), and CDH13 (16q23.3). This apparent corroboration across multiple sites gives much confidence to the likelihood of genetic involvement in BD at these loci. In particular, our two-stage strategy found association in both our combined case/control analysis and the family-based analysis on 1q21.2 (closest gene: sphingosine-1-phosphate receptor 1 gene, S1PR1) and on 1q24.1 near the gene TMCO1, and at CSMD1 on 8p23.2, supporting several previous GWAS reports for BD and for schizophrenia. Pathway analysis suggests association of pathways involved in calcium signalling, neuropathic pain signalling, CREB signalling in neurons, glutamate receptor signalling and axonal guidance signalling.Conclusions: The findings presented here show support for a number of genes previously implicated genes in the etiology of BD, including CSMD1 and SYNE1, as well as evidence for previously unreported genes such as the brain-expressed genes ADCY2, NCALD, WDR60, SCN7A and SPAG16. © 2014 Xu et al.; licensee BioMed Central Ltd. Source

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