RNA-Sequencing Highlights Inflammation and Impaired Integrity of the Vascular Wall in Brain Arteriovenous Malformations.

Background and Purpose- Interventional treatment of unruptured brain arteriovenous malformations (BAVMs) has become increasingly controversial. Because medical therapy is still lacking, we aimed to obtain insight into the disease mechanisms implicated in BAVMs and to identify potential targets for medical treatment to prevent rupture of a BAVM. Methods- We used next-generation RNA sequencing to identify differential expression on a transcriptome-wide level comparing tissue samples of 12 BAVMs to 16 intracranial control arteries. We identified differentially expressed genes by negative binominal generalized log-linear regression (false discovery rate corrected P<0.05). We selected 10 genes for validation using droplet digital polymerase chain reaction. We performed functional pathway analysis accounting for potential gene-length bias, to establish enhancement of biological pathways involved in BAVMs. We further assessed which Gene Ontology terms were enriched. Results- We found 736 upregulated genes in BAVMs including genes implicated in the cytoskeletal machinery and cell-migration and genes encoding for inflammatory cytokines and secretory products of neutrophils and macrophages. Furthermore, we found 498 genes downregulated including genes implicated in extracellular matrix composition, the binary angiopoietin-TIE system, and TGF (transforming growth factor)-ß signaling. We confirmed the differential expression of top 10 ranked genes. Functional pathway analysis showed enrichment of the protein digestion and absorption pathway (false discovery rate-adjusted P=1.70×10-2). We identified 47 enriched Gene Ontology terms (false discovery rate-adjusted P<0.05) implicated in cytoskeleton network, cell-migration, endoplasmic reticulum, transmembrane transport, and extracellular matrix composition. Conclusions- Our genome-wide RNA-sequencing study points to involvement of inflammatory mediators, loss of cerebrovascular quiescence, and impaired integrity of the vascular wall in the pathophysiology of BAVMs. Our study may lend support to potential receptivity of BAVMs to medical therapeutics, including those promoting vessel maturation, and anti-inflammatory and immune-modifying drugs.

Author Correction: A replication study of genetic risk loci for ischemic stroke in a Dutch population: a case-control study.

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A replication study of genetic risk loci for ischemic stroke in a Dutch population: a case-control study.

We aimed to replicate reported associations of 10 SNPs at eight distinct loci with overall ischemic stroke (IS) and its subtypes in an independent cohort of Dutch IS patients. We included 1,375 IS patients enrolled in a prospective multicenter hospital-based cohort in the Netherlands, and 1,533 population-level controls of Dutch descent. We tested these SNPs for association with overall IS and its subtypes (large artery atherosclerosis, small vessel disease and cardioembolic stroke (CE), as classified by TOAST) using an additive multivariable logistic regression model, adjusting for age and sex. We obtained odds ratios (OR) with 95% confidence intervals (95% CI) for the risk allele of each SNP analyzed and exact p-values by permutation. We confirmed the association at 4q25 (PITX2) (OR 1.43; 95% CI, 1.13-1.81, p = 0.029) and 16q22 (ZFHX3) (OR 1.62; 95% CI, 1.26-2.07, p = 0.001) as risk loci for CE. Locus 16q22 was also associated with overall IS (OR 1.24; 95% CI, 1.08-1.42, p = 0.016). Other loci previously associated with IS and/or its subtypes were not confirmed. In conclusion, we validated two loci (4q25, 16q22) associated with CE. In addition, our study may suggest that the association of locus 16q22 may not be limited to CE, but also includes overall IS.

A systematic comparison of cardiovascular magnetic resonance and high resolution histological fibrosis quantification in a chronic porcine infarct model.

The noninvasive reference standard for myocardial fibrosis detection on cardiovascular magnetic resonance imaging (CMR) is late gadolinium enhancement (LGE). Currently there is no consensus on the preferred method for LGE quantification. Moreover myocardial wall thickening (WT) and strain are measures of regional deformation and function. The aim of this research was to systematically compare in vivo CMR parameters, such as LGE, WT and strain, with histological fibrosis quantification. Eight weeks after 90 min ischemia/reperfusion of the LAD artery, 16 pigs underwent in vivo Cine and LGE CMR. Histological sections from transverse heart slices were digitally analysed for fibrosis quantification. Mean fibrosis percentage of analysed sections was related to the different CMR techniques (using segmentation or feature tracking software) for each slice using a linear mixed model analysis. The full width at half maximum (FWHM) technique for quantification of LGE yielded the highest R2 of 60%. Cine derived myocardial WT explained 16-36% of the histological myocardial fibrosis. The peak circumferential and radial strain measured by feature tracking could explain 15 and 10% of the variance of myocardial fibrosis, respectively. The used method to systematically compare CMR image data with digital histological images is novel and feasible. Myocardial WT and strain were only modestly related with the amount of fibrosis. The fully automatic FWHM analysis technique is the preferred method to detect myocardial fibrosis.

Age-Specific Vascular Risk Factor Profiles According to Stroke Subtype.

BACKGROUND: Ischemic and hemorrhagic stroke are increasingly recognized as heterogeneous diseases with distinct subtypes and etiologies. Information on variation in distribution of vascular risk factors according to age in stroke subtypes is limited. We investigated the prevalence of vascular risk factors in stroke subtypes in relation to age. METHODS AND RESULTS: We studied a prospective multicenter university hospital-based cohort of 4033 patients. For patients with ischemic stroke caused by large artery atherosclerosis, small vessel disease, or cardioembolism and for patients with spontaneous intracerebral hemorrhage or aneurysmal subarachnoid hemorrhage, we calculated prevalences of vascular risk factors in 4 age groups: <55, 55 to 65, 65 to 75, and ≥75 years, and mean differences with 95% CIs in relation to the reference age group. Patients aged <55 years were significantly more often of non-white origin (in particular in spontaneous intracerebral hemorrhage and aneurysmal subarachnoid hemorrhage patients) and most often smoked (most prominent for aneurysmal subarachnoid hemorrhage patients). Patients aged <55 years with ischemic stroke caused by large artery atherosclerosis or small vessel disease more often had hypertension, hyperlipidemia, and diabetes mellitus than patients with ischemic stroke of cardiac origin. Overall, the frequency of hypertension, hyperlipidemia, and diabetes mellitus increased with age among all stroke subtypes, whereas smoking decreased with age. Regardless of age, accumulation of potentially modifiable risk factors was most pronounced in patients with ischemic stroke caused by large artery atherosclerosis or small vessel disease. CONCLUSIONS: The prevalence of common cardiovascular risk factors shows different age-specific patterns among various stroke subtypes. Recognition of these patterns may guide tailored stroke prevention efforts aimed at specific risk groups.

No evidence for distinguishing bacterial from viral acute rhinosinusitis using fever and facial/dental pain: a systematic review of the evidence base.

OBJECTIVE: To assess the diagnostic value of fever and facial and dental pain in adults suspected of acute bacterial rhinosinusitis. DATA SOURCES: PubMed, EMBASE, and the Cochrane Library. REVIEW METHODS: A comprehensive systematic search was performed on March 18, 2013. We included articles reporting studies on the diagnostic value of fever or facial and dental pain in patients suspected of acute bacterial rhinosinusitis. For included articles, the reported study design was assessed for directness of evidence and risk of bias. Prevalences, positive predictive values, and negative predictive values were extracted. RESULTS: Of 3171 unique records, we included 1 study with a high directness of evidence and a moderate risk of bias. The prior probability of bacterial rhinosinusitis was 0.29 (95% confidence interval: 0.24 to 0.35). We could not extract posterior probabilities with accompanying positive and negative predictive values. The study reported an odds ratio from univariate analysis for fever of 1.02 (0.52 to 2.00) and 1.65 (0.83 to 3.28) for facial and dental pain. In subsequent multivariate analysis, the odds ratio of facial and dental pain was 1.86 (1.06 to 3.29). CONCLUSION AND RECOMMENDATION: There is 1 study with moderate risk of bias, reporting data in such a manner that we could not assess the value of fever and facial and dental pain in adults suspected of an acute bacterial rhinosinusitis. Therefore, these symptoms should not be used in clinical practice to distinguish between a bacterial and viral source of acute rhinosinusitis or for decision making about prescribing antibiotic treatment.