Prevalence of Bladder and Bowel Dysfunction in Duchenne Muscular Dystrophy Using the Childhood Bladder and Bowel Dysfunction Questionnaire.

INTRODUCTION: Lower urinary tract symptoms (LUTS) and gastrointestinal (GI) problems are common in Duchenne muscular dystrophy (DMD), but not systematically assessed in regular care. We aimed to determine the prevalence of bladder and bowel dysfunction (BBD) in DMD patients compared with healthy controls (HC). METHODS: The Childhood Bladder and Bowel Dysfunction Questionnaire (CBBDQ) based on the International Rome III criteria and the International Children's Continence Society was filled out by 57 DMD patients and 56 HC. Additionally, possible associations of BBD with, for example, medication use or quality of life were evaluated in an additional questionnaire developed by experts. RESULTS: In 74% of patients versus 56% of HC ≥ 1 LUTS (n.s.) were reported, 68% of patients versus 39% of HC reported ≥1 bowel symptom (p = 0.002) and 53% of patients versus 30% of HC reported combined LUTS and bowel symptoms (p = 0.019). A negative impact of BBD on daily life functioning was reported by 42% of patients. CONCLUSIONS: These data underscore that standard screening for BBD is needed and that the CBBDQ could be of added value to optimize DMD care.

Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection.

Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year). Minor cervical traumas, infection, migraine and hypertension are putative risk factors, and inverse associations with obesity and hypercholesterolemia are described. No confirmed genetic susceptibility factors have been identified using candidate gene approaches. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69-0.82; P = 4.46 × 10(-10)), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 × 10(-3); combined P = 1.00 × 10(-11)). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions.

Relationship of Von Willebrand Factor with carotid artery and aortic arch calcification in ischemic stroke patients.

BACKGROUND: Large population studies have revealed that increased von Willebrand Factor (VWF) levels are associated with an increased risk of ischemic stroke. In previous studies VWF was associated with atherosclerosis in healthy individuals. However, it is yet unknown what the association is between atherosclerosis and VWF levels in patients with ischemic stroke. OBJECTIVES: The aim of our study was to determine the association of atherosclerosis, measured with recent developed techniques, and VWF levels in a large, well characterized, cohort of ischemic stroke patients and to determine the prognostic value. METHODS: We included 925 consecutive patients with transient ischemic attack (TIA) or ischemic stroke. Calcification volumes (mm(3)) were scored in the aortic arch and both carotid arteries using multidetector computed tomography (CT) angiography. VWF antigen (VWF:Ag) levels were measured using ELISA. RESULTS: Mean VWF:Ag levels were significantly higher in the presence of calcification in either the aortic arch (1.47 vs. 1.37 IU/ml [P = 0.039]) or the carotid arteries (1.49 vs. 1.34 IU/ml [P = 0.001]). Patients with a large artery atherosclerosis ischemic stroke had significantly higher VWF:Ag levels then the other TOAST subtypes (P < 0.0001). High VWF:Ag levels were associated with an unfavorable outcome (modified Rankin Scale >2 vs. ≤2; 1.64 vs. 1.41 IU/ml, [P < 0.0001]). CONCLUSION: Our study showed a strong association between the extent of atherosclerosis in both the aortic arch and the carotid arteries and VWF levels in patients with TIA or ischemic stroke. Higher VWF levels are found in large artery atherosclerosis and are associated with a poor outcome.

Association of two single nucleotide polymorphisms from genomewide association studies with clinical phenotypes of cerebral ischemia.

BACKGROUND: Recent genomewide association studies have revealed an association between two single nucleotide polymorphisms, rs11833579 and rs12425791, and ischemic stroke. AIM: To gain more insight in pathophysiological mechanisms underlying the found associations by exploring relationships between these single nucleotide polymorphisms and clinical and radiological characteristics of patients with cerebral ischemia. METHODS: Our cohort consisted of 660 Caucasian patients with cerebral ischemia; from all patients detailed clinical and radiological data were available. Etiologic subtype of cerebral ischemia was determined according to the TOAST classification and an alternative classification. We studied associations between risk alleles and etiologic subtype, duration of ischemia, occurrence of multiple events, functional outcome and findings on CT-angiography by means of logistic regression analysis. RESULTS: The risk allele of rs11833579 was associated with an atherothrombotic etiology of cerebral ischemia, but not with other etiologic subtypes. Risk alleles of both single nucleotide polymorphisms were related to events of shorter duration (<24 h), the risk allele of rs11833579 with occurrence of multiple events. There was no association between single nucleotide polymorphism and clinical outcome. Both single nucleotide polymorphismswere associated with presence of stenotic calcifications and stenosis >30% in a symptomatic artery on CT-angiography. CONCLUSIONS: This is the first study to show an association of rs11833579 with multiple episodes of cerebral ischemia of atherothrombotic origin, and of rs11833579 and rs12425791 with short duration of ischemia. Also, we found an association of both single nucleotide polymorphisms with atherosclerotic lesions in the extracranial vessels on CT-angiography. Together this suggests a relationship between the two single nucleotide polymorphisms and large artery pathology.

γ'/total fibrinogen ratio is associated with short-term outcome in ischaemic stroke.

Fibrinogen γ' (γ') is a natural isoform of fibrinogen, and alters the rate of formation and the properties of clots. It could therefore affect outcome after ischaemic stroke. The prognostic significance of γ' fibrinogen levels is, however, still unclear. It was the objective of this study to assess levels of γ' in ischaemic stroke, and its association with short-term outcome. We included 200 ischaemic stroke patients and 156 control persons. Total fibrinogen and γ' levels were measured; outcome at discharge was assessed by means of the modified Rankin Scale score (defined as unfavourable when >2). We compared levels between patients and controls using multiple linear regression analysis, and logistic regression analysis was used to assess the relationship between levels and outcome. All analyses were adjusted for age and sex. Mean γ' levels were significantly higher in patients with ischaemic stroke than in controls (0.37 vs. 0.32 g/l, p<0.001), and patients also had a higher γ'/total fibrinogen ratio (0.102 vs. 0.096, p=0.19). The γ'/total fibrinogen ratio is associated with unfavourable outcome in patients with ischaemic stroke (odds ratio per unit increase of γ'/total fibrinogen ratio 1.27, 95% confidence interval 1.09-1.47). Our study shows that patients with ischaemic stroke have increased levels of fibrinogen γ' and suggests a trend towards an increased γ'/total fibrinogen ratio in ischaemic stroke. Increased fibrinogen γ' relative to total fibrinogen levels are associated with unfavourable outcome in the early phase after stroke.

Variation in the C-reactive protein gene is associated with serum levels of CRP in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: Elevated levels of C-reactive protein (CRP) are found in up to three quarters of patients with acute ischemic stroke and are associated with poor outcome. We investigated whether haplotypes representing common variations in the CRP gene are associated with levels of CRP in patients with acute ischemic stroke. METHODS: We included 185 patients with ischemic stroke in whom CRP was measured within 24 h of symptom onset. Common haplotypes within the CRP gene were determined by 3 genotype-tagging single-nucleotide polymorphisms (SNPs). RESULTS: Four haplotypes with frequencies >5% covered 99.2% of the genetic variation. Haplotype 4 (CCG, frequency 8.3%) was associated with a 20.6 mg/l (95% CI, 9.8-30.4) stronger increase in CRP level as compared with haplotype 1 (CTC, frequency 33.7%). CONCLUSION: Variation in the CRP gene is associated with levels of CRP in acute ischemic stroke.

Predicting and preventing stroke after transient ischemic attack.

The prognosis of transient ischemic attacks (TIAs) is not as favorable as previously thought. Given a risk of stroke of approximately 10% in the first week following a TIA, urgent evaluation and initiation of treatment are required. Recently developed scores to predict the early risk of subsequent stroke in individual patients may guide treatment decisions in the acute phase. Lately it has become clear that transient attacks with nonfocal symptoms are not benign either, as these were found to be associated with an increased risk of vascular disease. The significance of this finding and its implications for treatment are not yet clear. There is substantial evidence from a number of clinical trials that adequate secondary prevention therapies can reduce the risk of stroke after TIA. In addition to the conventional vascular risk factors, interest has grown in less strong but more prevalent lifestyle factors, but trials evaluating the effect of modifying these factors are as yet lacking.

Genomewide association studies of stroke.

BACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined. METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons. RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P=0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P=0.03) and 1.19 (95% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant. CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.