Zwinderman, A.H.

Psychometric evaluation of the subjective well-being under neuroleptic treatment scale (SWN) in patients with schizophrenia, their relatives and controls (Article)

2012-09-28T00:00:00Z

The objective of this study was to evaluate the psychometric properties of the Subjective Well-being under Neuroleptic treatment scale 20-item version (SWN) in patients, their siblings and parents and in healthy controls. In order to study heritability of subjective wellbeing, assessment in unaffected relatives and healthy controls is necessary. Data were obtained from the Dutch GROUP study (Genetic Risk and Outcome of Psychosis), a large cohort study on non-affective psychotic disorders incorporating patients, their relatives and healthy controls. 545 schizophrenia patients, 541 siblings, 75 parents and 280 healthy controls completed the SWN scale and relevant other assessments. Reliability within the four groups ranged between Cronbach's alpha 0.88 and 0.92. Factor analysis indicated a single factor structure of the SWN scale which makes only SWN total scores relevant. The WHO-QoL psychological domain correlated highly with SWN total scores in all groups. Subclinical psychotic experiences were found to be associated with SWN total scores in relatives and healthy controls, supporting the psychosis continuum concept. The 20-item SWN scale is a reliable measure for subjective wellbeing which can also be used in relatives and healthy controls to investigate genetic and psychological dispositions of subjective wellbeing.

The effect on mental health of a large scale psychosocial intervention for survivors of mass violence: A quasi-experimental study in Rwanda (Article)

2011-08-11T00:00:00Z

Background: War has serious and prolonged mental health consequences. It is argued that post-emergency mental health interventions should not only focus on psychological factors but also address the social environment. No controlled trials of such interventions exist. We studied the effect on mental health of a large scale psychosocial intervention primarily aimed at social bonding in post-genocide Rwanda. The programme is implemented at population level without diagnostic criteria for participation. It is open to any person older than 15 years, and enables participation of over 1500 individuals per year. We postulated that the mental health of programme participants would improve significantly relative to non-participants. Methods and Findings: We used a prospective quasi-experimental study design with measurement points pre and post intervention and at 8 months follow-up. 100 adults from both sexes in the experimental condition entered the study; follow-up measurements were taken from 81. We selected a control group of 100 respondents with similar age, sex and symptom score distribution from a random community sample in the same region; of these, 73 completed the study. Mental health was assessed by use of the Self Reporting Questionnaire (SRQ-20), a twenty item instrument to detect common mental disorders in primary health care settings. Mean SRQ-20 scores decreased by 2.3 points in the experimental group and 0.8 in the control group (p = 0.033). Women in the experimental group scoring above cut-off at baseline improved with 4.8 points to below cut-off (p<0.001). Men scoring above cut-off at baseline showed a similar trend which was statistically non-significant. No adverse events were observed. Conclusions: A large scale psychosocial intervention primarily aimed at social bonding caused a lasting improvement of mental health in survivors of mass violence in Rwanda. This approach may have a similar positive effect in other post-conflict settings. Trial Registration: Nederlands Trial Register 1120.

Upper and extra-motoneuron involvement in early motoneuron disease: A diffusion tensor imaging study (Article)

2011-04-01T00:00:00Z

Motoneuron disease is a term encompassing three phenotypes defined largely by the balance of upper versus lower motoneuron involvement, namely amyotrophic lateral sclerosis, primary lateral sclerosis and progressive muscular atrophy. However, neuroradiological and pathological findings in these phenotypes suggest that degeneration may exceed the neuronal system upon which clinical diagnosis is based. To further delineate the phenotypes within the motoneuron disease spectrum, this controlled study assessed the upper- and extra-motoneuron white matter involvement in cohorts of patients with motoneuron disease phenotypes shortly after diagnosis by comparing diffusion tensor imaging data of the different cohorts to those of healthy controls and directly between the motoneuron disease phenotypes (n=12 for each cohort). Furthermore, we acquired follow-up data 6 months later to evaluate fractional anisotropy changes over time. Combined use of diffusion tensor tractography of the corticospinal tract and whole-brain voxel-based analysis allowed for comparison of the sensitivity of these techniques to detect white matter involvement in motoneuron disease. The voxel-based analysis demonstrated varying extents of white matter involvement in different phenotypes of motoneuron disease, albeit in quite similar anatomical locations. In general, fractional anisotropy reductions were modest in progressive muscular atrophy and most extensive in primary lateral sclerosis. The most extensive patterns of fractional anisotropy reduction were observed over time in the voxel-based analysis, indicating progressive extra-motor white matter degeneration in limb- and bulbar onset amyotrophic lateral sclerosis and in progressive muscular atrophy. The observation of both upper motor and extra-motoneuron involvement in all phenotypes of motoneuron disease shortly after diagnosis suggests that these are all part of a single spectrum of multisystem neurodegenerative disease. Voxel-based analysis was more sensitive to detect longitudinal changes than diffusion tensor tractography of the corticospinal tract. Voxel-based analyses may be particularly valuable in the evaluation of motor and extra-motor white matter involvement in the early symptomatic stages of motoneuron disease, and for monitoring the spread of pathology over time.

Factor VII Activating Protease Polymorphism (G534E) Is Associated with Increased Risk for Stroke and Mortality (Article)

2011-01-01T00:00:00Z

Matrix metalloproteinases 2 and 3 gene polymorphisms and the risk of target vessel revascularization after percutaneous coronary intervention: Is there still room for determining genetic variation of MMPs for assessment of an increased risk of restenosis? (Article)

2010-12-01T00:00:00Z

Objective: Mixed results have been reported of matrix metalloproteinases (MMP) and their association with restenosis after percutaneous coronary intervention (PCI). The current study examines whether multiple single nucleotide polymorphisms (SNPs), covering the full genomic region of MMP2 and MMP3, were associated with restenosis in the GENDER study population. Methods and results: The GENetic DEterminants of Restenosis (GENDER) study enrolled 3104 consecutive patients after successful PCI. The primary endpoint was clinical restenosis, defined as target vessel revascularization (TVR), occurring in 9.8% of the patients. From the Hapmap database, 19 polymorphisms of MMP2 and 11 of MMP3 were selected. Furthermore, in a subpopulation, a genome-wide association analysis (GWA) was performed. No significant association was found with any of the investigated SNPs, including the previously reported 5A/6A polymorphism (rs3025058), with regard to TVR using single SNP analysis or haplotype analysis. Conclusion: We found no significant association of MMP2 or MMP3 with TVR with this SNP-broad gene approach. Although we did not test all the known polymorphisms of these genes, using tagging analyses we examined those SNPs covering all known haplotypes of MMP2 and MMP3 to conclude that these genes do not correlate with a genetic risk of coronary restenosis after successful PCI.

Rationale and design of a trial on the effect of angiotensin II receptor blockers on the function of the systemic right ventricle (Article)

2010-11-01T00:00:00Z

Background: Angiotensin II receptor blockers have been proven to be beneficial in left ventricular failure. In patients with a morphologic right ventricle supporting the systemic circulation, its efficacy has not yet been established. Methods: We designed a multicenter, prospective, randomized, double-blind, placebo-controlled trial studying the effect of valsartan in patients with a systemic right ventricle due to a congenitally or surgically corrected transposition of the great arteries. The primary end point is the change in right ventricular ejection fraction as measured by cardiovascular magnetic resonance or multidetector row cardiac computed tomography in case of pacemaker patients. Conclusion: This large prospective, double-blind, randomized, placebo-controlled trial will establish the role of angiotensin II receptor blockers (valsartan) in the treatment of patients with a systemic right ventricle.

The association of the dopamine transporter gene and the dopamine receptor 2 gene with delirium, a meta-analysis (Article)

2010-03-01T00:00:00Z

Delirium is the most common neuropsychiatric syndrome in elderly ill patients. Previously, associations between delirium and the dopamine transporter gene (solute carrier family 6, member 3 (SLC6A3)) and dopamine receptor 2 gene (DRD2) were found. The aim of this study was to validate whether markers of the SLC6A3 and DRD2 genes are were associated with delirium in independent populations. Six European populations collected DNA of older delirious patients. Associations were determined per population and results were combined in a meta-analysis. In total 820 medical inpatients, 185 cardiac surgery patients, 134 non-cardiac surgery patients and 502 population-based elderly subjects were included. Mean age was 82 years (SD 7.5 years), 598 (36%) were male, 665 (41%) had pre-existing cognitive impairment, and 558 (34%) experienced delirium. The SLC6A3 rs393795 homozygous AA genotype was more frequent in patients without delirium in all populations. The meta-analysis showed an Odds Ratio (OR) for delirium of 0.4 (95% confidence interval (C.I.) 0.2-0.6, P=0.0003) for subjects with AA genotype compared to the AG and GG genotypes. SLC6A3 marker rs1042098 showed no association with delirium. In meta-analysis the DRD2 rs6276 homozygous GG genotype showed an OR of 0.8 for delirium (95% C.I. 0.6-1.1, P=0.24). When subjects were stratified for cognitive status the rs6276 GG genotype showed ORs of 0.6 (95% C.I. 0.4-1.0, P=0.06) and 0.8 (95% C.I. 0.5-1.5, P=0.51) for delirium in patients with and without cognitive impairment, respectively. In independent cohorts, a variation in the SLC6A3 gene and possibly the DRD2 gene were found to protect for delirium.

Understanding the problem of inadequately staging early ovarian cancer (Article)

2010-03-01T00:00:00Z

Background: Early ovarian cancer patients are often incompletely staged during initial surgery.1-3 This omission can have serious adverse consequences for the prognosis of patients as the completeness of surgical staging has been identified as an independent prognostic parameter for survival.4,5 The reasons for the problem of inadequate staging of early ovarian cancer are largely unknown. We have analysed the data of a large randomised trial in early ovarian cancer in which detailed information of the surgical staging procedure was monitored.5. Methods: Data of the EORTC Adjuvant ChemoTherapy In Ovarian Neoplasm (ACTION) Trial were used in which 448 early ovarian cancer patients were randomised between postoperative chemotherapy in one arm and observation following surgery in the other. In this trial strict criteria for surgical staging were advised but optimal, complete staging was performed in only 1/3 of patients. Staging characteristics of the incompletely staged patients were analysed and factors that could explain the failure to perform a complete staging were studied. Results: Sampling of para-aortic nodes was omitted in 78% of the incompletely staged patients, while 52% of these patients had no pelvic lymph node dissection. Taking blind biopsies from different peritoneal sites was not performed in more than 1/3 of the incompletely staged group. Omission of the staging steps ranged from 3% (infracolic omentectomy) to 55% (biopsy of the right hemi-diaphragm). A significant difference (p = 0.04) between the fraction of completely staged patients was found when comparing institutes who entered less than 5 patients (21%) versus those who included more than 20 patients (37%) in the trial. Conclusions: Even in a randomised trial in which comprehensive surgical staging was strongly advised in the study protocol the majority of patients (66%) were incompletely staged. Factors relating to a lack of surgical skills attributed most to the number of incompletely staged patients, but insufficient knowledge of the tumour behaviour and routes of spread of ovarian cancer also contributed substantially to this problem. Multicentre trials recruiting patients from many institutes with small volume contribution to the study, run the risk of inadequate adherence to the study protocol.

Vitamin D receptor: A new risk marker for clinical restenosis after percutaneous coronary intervention (Article)

2010-03-01T00:00:00Z

Objective: Restenosis is the main drawback of percutaneous coronary intervention (PCI). Inherited factors may explain part of the risk of restenosis. Recently, the vitamin D receptor (VDR) has been shown to be involved not only in bone metabolism but also in modulating immune responses and cell proliferation. Since the inflammatory response is implicated in restenosis, VDR-gene variants could therefore contribute to the risk of restenosis. Methods/results: Systematic genotyping for 15 haplotype tagging single-nucleotide polymorphisms (SNPs) of the VDR gene was performed with the high throughput TaqMan allelic discrimination assays in the Genetic Determinants of Restenosis (GENDER) population. A haplotype-based survival analysis revealed an association of haplotypes in blocks 2, 3 and 4 of the VDR-gene with the risk of clinical restenosis (p-values 0.01, 0.04 and 0.02 respectively). After adjustment for clinical risk factors for restenosis, the individual effect of the block 2 AA haplotype (p = 0.011) persisted. Conclusions: The present study indicates that VDR plays a role in restenosis after PCI. Therefore, VDR genotype may be used as risk marker for restenosis and may contribute to individual patient screening prior to PCI in clinical practice.

Genetic polymorphisms in the DRD2, DRD3, and SLC6A3 gene in elderly patients with delirium (Article)

2010-01-01T00:00:00Z

Dopamine excess appears to be critical in the final common pathway of delirium. The aim of this study was to investigate whether genetic polymorphisms in three dopamine-related genes (the dopamine receptor 2 (DRD2), dopamine receptor 3 (DRD3), and the dopamine transporter (SLC6A3) gene) were associated with delirium. Patients aged 65 years and older acutely admitted to the medical department or to the surgical department following hip fracture were included. Delirium was diagnosed by the Confusion Assessment Method. Sixteen single nucleotide polymorphisms (SNPs) and one variable number of tandem repeats in the SLC6A3 gene, nine SNPs in the DRD2 gene, and six SNPs in the DRD3 gene were genotyped. Fifty percent of the 115 surgical patients and 34% of the 605 medical patients experienced delirium. Delirious patients were older and had more frequently pre-existing functional and cognitive impairment (P<0.001). After correction for multiple testing, one SNP in the SLC6A3 gene (rs393795) was associated with reduced risk of delirium (P=0.032). Adjusted for age, cognitive impairment, and functional impairment, three SNPs in the DRD2 gene and seven SNPs in the SLC6A3 gene were associated with delirium; none of these associations was significant after correction for multiple testing. Variations in the SLC6A3 gene and possibly the DRD2 gene were associated with delirium. Although validation of these results is needed our results support a role for the dopamine transporter and dopamine receptor 2 in the pathogenesis of delirium.

Adaptive cognitive testing in cerebrovascular disease and vascular dementia (Article)

2009-12-01T00:00:00Z

Background/Aims: To examine whether brevity can be combined with precision in measuring global cognitive ability in patients with cerebrovascular disease (CVD) or vascular dementia (VaD). Longer tests (e.g. the CAMCOG) are precise but inefficient, whereas brief tests (e.g. the MMSE) are efficient but imprecise. Methods: A simulated computerized adaptive testing (CAT) algorithm using existing CAMCOG data from 284 patients with CVD of whom 55 were diagnosed with VaD. CAT was used to estimate each individual patient's total score on a large precise test (the CAMCOG). CAT repeatedly selected only items of appropriate difficulty, depending on whether the previous item was (in)correctly responded to. CAT estimates were compared with total scores on the whole CAMCOG. Results: Even though there was an average test reduction of more than 40%, CAT estimates were in very high agreement with the whole test results (intraclass correlation >0.97) and had similar accuracy for the diagnosis of dementia (area under the curve = 0.94). Conclusion: CAT combines efficiency with precision in the measurement of global cognitive ability in CVD patients.

Metabolic background determines the importance of NOS3 polymorphisms in restenosis after percutaneous coronary intervention: A study in patients with and without the metabolic syndrome (Article)

2009-07-31T00:00:00Z

Variation in the NOS3 gene has been related to the development of restenosis. The Glu298Asp polymorphism has previously been investigated for its effect on NO levels and the development of restenosis. However, the variability of findings gave rise to the hypothesis that the functional significance of this polymorphism may only become manifest under conditions of endothelial dysfunction. Since patients with the metabolic syndrome are known to have endothelial dysfunction, we aimed to investigate if the significance of NOS3 polymorphisms may depend on the presence of the metabolic syndrome. We examined the impact of the -949 A/G, the -716 C/T and the Glu298Asp polymorphisms in the NOS3 gene on the risk of clinical restenosis in a previously described subpopulation of the GENDER-study, a multicenter prospective study design that enrolled consecutive patients after successful PCI. This subpopulation consisted of 901 patients of whom sufficient data were available to establish absence or presence of the metabolic syndrome. Of these patients, 448 had the metabolic syndrome. Clinical restenosis, defined as target vessel revascularization (TVR), was the primary endpoint. We demonstrated that the minor -949G, -716T and 298Asp alleles were associated with a significantly increased risk of TVR in patients with the metabolic syndrome (HR: 1.58 [95%CI: 1.04-2.40], HR: 1.95 [95%CI: 1.02-3.70] and HR: 1.67 [95%CI: 1.09-2.54], respectively). In the group without the metabolic syndrome we observed no association between the three polymorphisms and TVR.

The establishment of the GENEQOL consortium to investigate the genetic disposition of patient reported quality-of-life outcomes (Article)

2009-06-01T00:00:00Z

To our knowledge, no comprehensive, interdisciplinary initiatives have been taken to examine the role of genetic variants on patient-reported quality-of-life outcomes. The overall objective of this paper is to describe the establishment of an international and interdisciplinary consortium, the GENEQOL Consortium, which intends to investigate the genetic disposition of patient-reported quality-of-life outcomes. We have identified five primary patient-reported quality-of-life outcomes as initial targets: negative psychological affect, positive psychological affect, self-rated physical health, pain, and fatigue. The first tangible objective of the GENEQOL Consortium is to develop a list of potential biological pathways, genes and genetic variants involved in these quality-of-life outcomes, by reviewing current genetic knowledge. The second objective is to design a research agenda to investigate and validate those genes and genetic variants of patient-reported quality-of-life outcomes, by creating large datasets. During its first meeting, the Consortium has discussed draft summary documents addressing these questions for each patient-reported quality-of-life outcome. A summary of the primary pathways and robust findings of the genetic variants involved is presented here. The research agenda outlines possible research objectives and approaches to examine these and new quality-of-life domains. Intriguing questions arising from this endeavor are discussed. Insight into the genetic versus environmental components of patient-reported quality-of-life outcomes will ultimately allow us to explore new pathways for improving patient care. If we can identify patients who are susceptible to poor quality of life, we will be able to better target specific clinical interventions to enhance their quality of life and treatment outcomes

Clear cell carcinoma compared to serous carcinoma in early ovarian cancer: Same prognosis in a large randomized trial (Article)

2009-01-01T00:00:00Z

Background: An analysis was performed comparing survival of patients with clear cell carcinoma (CCC) to patients with serous adenocarcinoma (SAC) in early ovarian cancer. Furthermore, a literature search was done to clarify the clinical and histopathological features of clear cell tumors of the ovary. Methods: Between November 1990 and March 2000, 448 patients with ovarian cancer International Federation of Gynecology and Obstetrics stages I to IIa were enrolled in the European Organisation for Research and Treatment of CancerYAdjuvant Chemotherapy in Ovarian Neoplasm Trial, a randomized study comparing adjuvant platinumbased chemotherapy to observation after surgical treatment in patients with early ovarian cancer. Results: Sixty-three patients (14.1%) with CCC were compared with 156 patients (34.8%) with serous tumors. A significant difference was found in the International Federation of Gynecology and Obstetrics stage Ic with capsule rupture, 28 (44.4%) of 63 patients with CCC and 29 (18.6%) of 156 patients with SAC (P < 0.001). Recurrences occurred in 25% of the patients, and this was similar in the CCC and SAC groups. No significant difference was found in overall survival between patients with CCC and patients with SAC in both treatment arms together. In the observation arm, the 5-year disease-free survival was 71% in the CCC group versus 61% in the SAC group, whereas in the chemotherapy arm, the 5-year disease-free survival was higher in the SAC group compared with the CCC group (78% vs 60%). Both differences were not statistically significant. Conclusions: The present study showed no worse prognosis in patients with CCC as compared with patients with serous carcinoma in early ovarian cancer.

The establishment of the GENEQOL consortium to investigate the genetic disposition of patient reported quality-of-life outcomes (Article)

2009-01-01T00:00:00Z

Analysis of gene expression identifies differentially expressed genes and pathways associated with lymphatic dissemination in patients with adenocarcinoma of the esophagus (Article)

2008-12-01T00:00:00Z

Introduction: The presence of lymphatic dissemination is an important predictor of survival in esophageal adenocarcinoma (EA). The aim of this study was to discover a prognostic gene expression profile for lymphatic dissemination in EA and to identify genes and pathways that provide oncological insight in lymphatic dissemination. Methods: Patients who had lymphatic dissemination (N = 55) were compared with patients without lymphatic dissemination (N = 22). Whole-genome oligonucleotide microarrays were used to evaluate the genetic signature of 77 esophageal cancers. Multiple random validation was used to analyze the stability of the molecular signature and predictive power. Gene set enrichment analysis (GSEA) was applied to elucidate oncogenetic pathways. Results: Lymphatic dissemination was correctly predicted in 75 ± 14% of lymph node positive patients. The absence of lymphatic dissemination was correctly predicted in 41 ± 23% of lymph-node-negative patients. Argininosuccinate synthetase (ASS) was selected for validation on the protein level because it was present in most prognostic signatures as well as the list of differentially expressed genes. ASS expression was lower (P = 0.048) in patients with lymphatic dissemination than in patients without. GSEA identified that arginine metabolism pathways and lipid metabolism pathways are related to less chance of developing lymphatic dissemination. The predictive profile does not outperform current clinical practice to predict the presence of lymphatic dissemination in patients with EA. Several genes, including ASS, and genetic pathways which are important in the development of lymphatic dissemination in EA, were identified.

High HDL cholesterol does not protect against coronary artery disease when associated with combined cholesteryl ester transfer protein and hepatic lipase gene variants (Article)

2008-09-01T00:00:00Z

Cholesteryl ester transfer protein (CETP) and hepatic lipase (HL) are two HDL modifying proteins that have both pro- and anti-atherogenic properties. We hypothesized that CETP and HL synergistically affect HDL cholesterol and atherosclerotic risk. To test our hypothesis, we analysed the genotype frequencies of CETP Taq1B (rs708272) and LIPC-514C/T (rs1800588) polymorphisms in male coronary artery disease patients (CAD; n = 792) and non-symptomatic controls (n = 539). Cases and controls had similar allele frequencies, but the occurrence of the combined genotypes differed (p = 0.027). In CAD patients, 1.3% had the CETP-B2B2/LIPC-TT genotype, with only 0.2% in controls (p = 0.033). The presence of the CETP lowering B2 allele and the HL lowering LIPC-T allele synergistically increased HDL cholesterol from 0.87 ± 0.19 mmol/L in the B1B1/CC (n = 183) to 1.21 ± 0.25 mmol/L in the B2B2/TT carriers (n = 10). The B1B1/CC carriers had an increased CAD risk (OR 1.4; p = 0.025). Despite their high HDL cholesterol, the B2B2/TT individuals also had an increased CAD risk (OR 3.7; p = 0.033). In a 2-year follow up, the loss of coronary artery lumen diameter in these patients was higher than in all other patients combined (0.34 ± 0.70 versus 0.10 ± 0.29 mm; p = 0.044). We conclude that a high HDL cholesterol does not protect against coronary artery disease when associated with combined CETP- and HL-lowering gene variants.

Value of serum cartilage oligomeric matrix protein as a prognostic marker of large-joint damage in rheumatoid arthritis - Data from the RAPIT study (Article)

2008-06-01T00:00:00Z

Objective. To investigate the utility of serum COMP level measurements as a predictor of future damage of the weight-bearing (large) joints in RA patients participating in intensive exercise. Methods. Data of the 281 completers of a 2-yr randomized controlled trial (Rheumatoid Arthritis Patients In Training; RAPIT) comparing the effects of usual care physical therapy with high-intensity weight-bearing exercises were analysed. The primary outcome variable was defined as the change in radiological joint damage (Larsen score) of the large joints. Potential predictors of outcome were defined: baseline and change in serum level of COMP after 3 months, baseline radiological damage of the large and small joints, number of months on glucocorticoids, change in disease activity and in physical capacity (aerobic fitness and muscle strength) after 2 yrs, and participation in the exercise group. Results. In cross-sectional evaluation of baseline data, we found strong association between the high serum COMP level and current damage of the large joints. Serum COMP level at baseline, however, was not associated with an increased rate of radiological joint damage after 2 yrs of follow-up. Furthermore, neither interaction between baseline COMP level and participation in exercises, nor change in COMP level after 3 months of exercising were associated with future damage of the large joints. Conclusion. Neither baseline serum COMP level nor its individual change after 3 months from start of intensive exercise predict longitudinal progression of damage of the large joints in this population.

Simvastatin with or without ezetimibe in familial hypercholesterolemia (Article)

2008-04-03T00:00:00Z

Background: Ezetimibe, a cholesterol-absorption inhibitor, reduces levels of low-density lipoprotein (LDL) cholesterol when added to statin treatment. However, the effect of ezetimibe on the progression of atherosclerosis remains unknown. Methods: We conducted a double-blind, randomized, 24-month trial comparing the effects of daily therapy with 80 mg of simvastatin either with placebo or with 10 mg of ezetimibe in 720 patients with familial hypercholesterolemia. Patients underwent B-mode ultrasonography to assess the intima-media thickness of the walls of the carotid and femoral arteries. The primary outcome measure was the change in the mean carotid-artery intima-media thickness, which was defined as the average of the means of the far-wall intima-media thickness of the right and left common carotid arteries, carotid bulbs, and internal carotid arteries. Results: The primary outcome, the mean (±SE) change in the carotid-artery intima-media thickness, was 0.0058±0.0037 mm in the simvastatin-only group and 0.0111±0.0038 mm in the simvastatin-plus-ezetimibe (combined-therapy) group (P = 0.29). Secondary outcomes (consisting of other variables regarding the intima-media thickness of the carotid and femoral arteries) did not differ significantly between the two groups. At the end of the study, the mean (±SD) LDL cholesterol level was 192.7±60.3 mg per deciliter (4.98±1.56 mmol per liter) in the simvastatin group and 141.3±52.6 mg per deciliter (3.65±1.36 mmol per liter) in the combined-therapy group (a between-group difference of 16.5%, P<0.01). The differences between the two groups in reductions in levels of triglycerides and C-reactive protein were 6.6% and 25.7%, respectively, with greater reductions in the combined-therapy group (P<0.01 for both comparisons). Side-effect and safety profiles were similar in the two groups. Conclusions: In patients with familial hypercholesterolemia, combined therapy with ezetimibe and simvastatin did not result in a significant difference in changes in intima-media thickness, as compared with simvastatin alone, despite decreases in levels of LDL cholesterol and C-reactive protein. (ClinicalTrials.gov number, NCT00552097.) Copyright

Platelet receptor P2RY12 haplotypes predict restenosis after percutaneous coronary interventions (Article)

2008-03-01T00:00:00Z

The platelet receptor P2Y12 (gene symbol P2RY12) is involved in several processes that contribute to restenosis after percutaneous coronary interventions (PCI). Therefore, common variation in the P2Y12 gene may serve as a useful marker for risk stratification. We studied whether common variation in the platelet receptor P2Y12 gene affects the risk of restenosis after PCI. Comprehensive coverage of common variation in the P2Y12 gene was obtained by genotyping five haplotype-tagging SNPs (ht-SNPs) in 2,062 PCI-treated patients who received a stent and participated in the GENetic DEterminants of Restenosis (GENDER) Study. Haplotypes were inferred and their association with target vessel revascularization (TVR) was studied. Seven P2Y12 haplotypes were identified with an allelic frequency above 5% (designated here H1 to H7) of which two (H5 and H7) were associated with a higher risk of TVR (hazard ratios [HR] = 1.4, 95% confidence interval [CI] = 1.0-2.0; and HR = 1.6, 95% CI = 1.2-2.0, respectively) than the reference P2Y12 haplotype (H1), which contains the common alleles of all five P2Y12 ht-SNPs. Our study shows that common variation in the P2Y12 gene predicts restenosis in PCI-treated patients.

The influence of established genetic variation in the haemostatic system on clinical restenosis after percutaneous coronary interventions (Article)

2007-12-01T00:00:00Z

Since activation of the haemostatic system is an important feature of the wound healing response triggered by arterial injury, variations in genes involved in thrombus formation may play a role in restenosis after percutaneous coronary interventions (PCI). Therefore, our aim was to examine the relationship between polymorphisms that are known to play a role in the haemostatic system and the risk of clinical restenosis in the GENetic DEterminants of Restenosis (GENDER) studya multicenter prospective study design that enrolled 3,104 consecutive patients after successful PCI.Target vessel revascularization (TVR) was the primary endpoint.All patients were genotyped for six polymorphisms in the Factor II, Factor V, Factor VII and PAI-1 genes. The PAI-1 4G variant was associated with an increased risk ofTVR.When compared to 5G/5G homozygotes, heterozygous patients were at higher risk for TVR (HR: 1.46, 95%Cl: 1.05-2.03), whereas patients with the 4G/4G genotype had an even further increased risk (HR: 1.69, 95%Cl: 1.19-2.41). In contrast, the factor V 506GIn (factor V Leiden) amino acid substitution was associated with a decreased risk ofTVR (HR: 0.41, 95%Cl: 0.19-0.86). Our findings indicate that polymorphisms in the factor V and PAI-1 genes may play a role in the process of restenosis.

Long-term outcome of juvenile idiopathic arthritis following a placebo-controlled trial: Sustained benefits of early sulfasalazine treatment (Article)

2007-11-01T00:00:00Z

Objectives: A previous 24-week randomised trial demonstrated that sulfasalazine (SSZ) treatment was superior to placebo (PLAC) in suppressing disease activity in patients with oligo- and polyarticular onset juvenile idiopathic arthritis (JIA). The current study determines the long-term outcome of the trial participants and evaluates whether the benefits of SSZ allocation are sustained over time. Methods: Between 2001 and 2003, 32 SSZ and 29 PLAC patients (90% of all patients) were prospectively examined clinically and by chart review, median 9 years (range 7 to 10) after trial inclusion. In the follow-up assessment, variables of the American College of Rheumatology Pediatric 30 (ACR Pedi 30) criteria were collected. The assessor was blinded to trial treatment allocation. Results: After the trial, patients had been routinely followed in rheumatology referral centres, and treated at the discretion of the attending physician. Almost all patients continued or started disease-modifying antirheumatic drugs (DMARDs) (SSZ 91%, PLAC 93%; SSZ treatment in about 80%). DAAARD treatment appeared less intensive in the SSZ group as evidenced by a significantly shorter duration of SSZ use (median 2.5 vs 5.2 years; p = 0.02) and a trend towards less use of methotrexate and other DMARDs. More than one-third of the patients reported long periods of non-compliance with DMARD treatment in both groups. At follow-up, 74% of the patients had active joints, and 30% showed active polyarthritis. Almost all outcome scores were better for SSZ compared with PLAC patients. Differences (often exceeding 50%) were significant for the number of active joints, patients' overall well-being, number of patients with episodes of clinical remission off medication (CROM) and duration of these episodes, patients in CROM and ACR Pedi 30 response at follow-up. Additional exploratory analyses performed to detect potential confounders related to patient characteristics or follow-up treatment showed that DMARD treatment compliance was positively correlated with an ACR Pedi 30 response (odds ratio 3.8, 95% confidence interval (CI) 1.1 to 13.4; p = 0.03). Adjusted for compliance, an SSZ patient was 4.2 times as likely as a PLAC patient to be an ACR Pedi 30 responder at follow-up (95% CI 1.3 to 14.3; p = 0.02). Conclusions: This follow-up study shows that effective suppression of disease activity by SSZ treatment early in active disease in JIA patients has beneficial effects that persist for many years. Given these results, compliance with DMARD treatment deserves serious attention.

The M235T polymorphism in the angiotensinogen gene is associated with the risk of malignant hypertension in white patients (Article)

2007-11-01T00:00:00Z

BACKGROUND: Malignant hypertension can be considered an extreme phenotype of renin-mediated hypertension. Therefore, we compared the allelic frequencies of the angiotensinogen (AGT) M235T, angiotensin-converting enzyme insertion/deletion (ACE I/D) and angiotensin II-type I receptor (AT1R) A1166C polymorphisms in malignant hypertensive patients with hypertensive and normotensive controls. METHODS: A total of 101 consecutive patients between 1995 and 2005 admitted to a large university hospital fulfilled the criteria for malignant hypertension. Seventy-five patients (74%) were compared with 150 hypertensive and 150 normotensive controls, randomly selected from a population study and individually matched on age, sex and ethnicity. RESULTS: The odds of malignant hypertension in white subjects with the TT genotype of the AGT M235T polymorphism was 14.3 (5.5-37) compared to hypertensive controls, and 9.4 (3.8-23.2) compared to normotensive controls. Adjustment for age, sex, smoking and antihypertensive therapy did not affect this association. The association of AGT M235T with malignant hypertension was not significant in blacks. In patients with malignant hypertension, the TT genotype was associated with more severe renal dysfunction and microangiopathic haemolysis. No differences were found in allele frequencies of the ACE I/D or the AT1R A1166C polymorphisms between study groups. CONCLUSIONS: The TT genotype of AGT M235T is associated with malignant hypertension in whites, carriers having an odds of approximately 10 to 1 compared to hypertensive and normotensive controls. These observations may provide a better understanding of the pathophysiology of malignant hypertension and offer possibilities for identifying patients at risk. Larger association or linkage studies are needed for a more detailed risk assessment.

Preoperative thresholds for pulmonary valve replacement in patients with corrected tetralogy of Fallot using cardiovascular magnetic resonance (Article)

2007-07-01T00:00:00Z

BACKGROUND - To facilitate the optimal timing of pulmonary valve replacement, we analyzed preoperative thresholds of right ventricular (RV) volumes above which no decrease or normalization of RV size takes place after surgery. METHODS AND RESULTS - Between 1993 and 2006, 71 adult patients with corrected tetralogy of Fallot underwent pulmonary valve replacement in a nationwide, prospective follow-up study. Patients were evaluated with cardiovascular magnetic resonance both preoperatively and postoperatively. Changes in RV volumes were expressed as relative change from baseline. RV volumes decreased with a mean of 28%. RV ejection fraction did not change significantly after surgery (from 42±10% to 43±10%; P=0.34). Concomitant RV outflow tract reduction resulted in a 25% larger decrease of RV volumes. After correction for surgical RV outflow tract reduction, higher preoperative RV volumes (mL/m) were independently associated with a larger decrease of RV volumes (RV end-diastolic volume: β=0.41; P<0.001). Receiver operating characteristic analysis revealed a cutoff value of 160 mL/m for normalization of RV end-diastolic volume or 82 mL/m for RV end-systolic volume. CONCLUSIONS - Overall, we could not find a threshold above which RV volumes did not decrease after surgery. Preoperative RV volumes were independently associated with RV remodeling and also when corrected for a surgical reduction of the RV outflow tract. However, normalization could be achieved when preoperative RV end-diastolic volume was <160 mL/m or RV end-systolic volume was <82 mL/m.

Cholesteryl ester transfer protein and hyperalphalipoproteinemia in Caucasians (Article)

2007-03-01T00:00:00Z

It is unclear whether cholesteryl ester transfer protein (CETP) contributes to high density lipoprotein cholesterol (HDL-C) levels in hyperalphalipoproteinemia (HALP) in Caucasians. Moreover, even less is known about the effects of hereditary CETP deficiency in non-Japanese. We studied 95 unrelated Caucasian individuals with HALP. No correlations between CETP concentration or activity and HDL-C were identified. Screening for CETP gene defects led to the identification of heterozygosity for a novel splice site mutation in one individual. Twenty-five heterozygotes for this mutation showed reduced CETP concentration (-40%) and activity (-50%) and a 35% increase of HDL-C compared with family controls. The heterozygotes presented with an isolated high HDL-C, whereas the remaining subjects exhibited a typical high HDL-C/low-triglyceride phenotype. The increase of HDL-C in the CETP-deficient heterozygotes was primarily attributable to increased high density lipoprotein containing apolipoprotein A-I and A-II (LpAI:AII) levels, contrasting with an increase in both high density lipoprotein containing apolipoprotein A-I only and LpAI:AII in the other group. This study suggests the absence of a relationship between CETP and HDL-C levels in Caucasians with HALP. The data furthermore indicate that genetic CETP deficiency is rare among Caucasians and that this disorder presents with a phenotype that is different from that of subjects with HALP who have no mutation in the CETP gene. Copyright

Interleukin 10: A new risk marker for the development of restenosis after percutaneous coronary intervention (Article)

2007-01-01T00:00:00Z

Genetic factors appear to be important in the process of restenosis after percutaneous coronary intervention (PCI), as well as in inflammation, a pivotal factor in restenosis. An important mediator in the inflammatory response is interleukin (IL)-10. Our aim was to study whether genetic variants in IL-10 predispose to the risk of restenosis. The GENetic DEterminants of Restenosis (GENDER) study included 3104 patients treated with successful PCI. Target vessel revascularization (TVR) was chosen as primary end point. Genotyping of the -2849G/A, -1082G/A, -592C/A and +4259A/G polymorphisms of the IL-10 gene was performed by MassArray platform. After adjusting for clinical variables, three polymorphisms significantly increased the risk of restenosis (-2849AA: relative risk (RR), 1.7, 95% confidence interval (CI), 1.2-2.5; -1082AA: RR, 1.4, 95% CI, 1.1-1.8 and +4259GG: RR, 2.0, 95% CI, 1.4-2.8). To further exclude possible involvement of neighboring genes due to LD in the IL-10 locus, additional polymorphisms were genotyped. The results reveal that association of the IL-10 gene with restenosis is independent of flanking genes. Our findings demonstrate that IL-10 is associated with restenosis and therefore support the hypothesis that anti-inflammatory genes also may be involved in developing restenosis. Furthermore, they may provide a new targeting gene for drug-eluting stents.

Atypical HNPCC owing to MSH6 germline mutations: analysis of a large Dutch pedigree (Article)

2001-01-01T00:00:00Z

Hereditary non-polyposis colorectal cancer (HNPCC) is the most common genetic susceptibility syndrome for colorectal cancer. HNPCC is most frequently caused by germline mutations in the DNA mismatch repair (MMR) genes MSH2 and MLH1. Recently, mutations in another MMR gene, MSH6 (also known as GTBP), have also been shown to result in HNPCC. Preliminary data indicate that the phenotype related to MSH6 mutations may differ from the classical HNPCC caused by defects in MSH2 and MLH1. Here, we describe an extended Dutch HNPCC family not fulfilling the Amsterdam criteria II and resulting from a MSH6 mutation. Overall, the penetrance of colorectal cancer appears to be significantly decreased (p<0.001) among the MSH6 mutation carriers in this family when compared with MSH2 and MLH1 carriers (32% by the age of 80 v >80%). Endometrial cancer is a frequent manifestation among female carriers (six out of 13 malignant tumours). Transitional cell carcinoma of the urinary tract is also relatively common in both male and female carriers (10% of the carriers). Moreover, the mean age of onset of both colorectal cancer (MSH6 v MSH2/MLH1 = 55 years v 44/41 years) and endometrial carcinomas (MSH6 v MSH2/MLH1 = 55 years v 49/48 years) is delayed. As previously reported, we confirm that the pattern of microsatellite instability, in combination with immunohistochemical analysis, can predict the presence of a MSH6 germline defect. The detailed characterisation of the clinical phenotype of this kindred contributes to the establishment of genotype-phenotype correlations in HNPCC owing to mutations in specific mismatch repair genes.