Cerebral vein thrombosis: clinical manifestation and diagnosis

BACKGROUND: Cerebral venous thrombosis (CVT) is a disease with a wide spectrum of symptoms and severity. In this study we analysed the predictive value of clinical signs and symptoms and the contribution of D-dimer measurements for diagnosis. METHODS: We evaluated consecutive patients admitted with suspected CVT receiving non-invasive imaging. Symptoms and symptom combination as well as D-dimer levels were evaluated regarding their diagnostic value. RESULTS: 239 patients were included in this study, 170 (71%) were females. In 39 patients (16%) a CVT was found. For identifying a CVT patients underwent either a venous CT-angiography or MR-angiography or both. No combination of symptoms either alone or together with the D-dimer measurements had a sensitivity and positive predictive value as well as negative predictive value and specificity high enough to serve as red flag. D-dimer testing produced rates of 9% false positive and of 24% false negative results. For D-dimer values a Receiver Operating Characteristic curve (ROC) and the area under the curve (AUC = 0.921; CI: 0.864 - 0.977) were calculated. An increase of sensitivity above 0.9 results in a relevant decrease in specificity; a sensitivity of 0.9 matches a specificity value of 0.9. This corresponds to a D-dimer cut-off level of 0.16 μg/ml. CONCLUSION: Imaging as performed by venous CT-angiography or MR-angiography has a 1 to 2 in 10 chance to detect CVT when typical symptoms are present. D-dimer measurements are of limited clinical value because of false positive and negative results

Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase.

Notch signalling is a key intercellular communication mechanism that is essential for cell specification and tissue patterning, and which coordinates critical steps of blood vessel growth. Although subtle alterations in Notch activity suffice to elicit profound differences in endothelial behaviour and blood vessel formation, little is known about the regulation and adaptation of endothelial Notch responses. Here we report that the NAD(+)-dependent deacetylase SIRT1 acts as an intrinsic negative modulator of Notch signalling in endothelial cells. We show that acetylation of the Notch1 intracellular domain (NICD) on conserved lysines controls the amplitude and duration of Notch responses by altering NICD protein turnover. SIRT1 associates with NICD and functions as a NICD deacetylase, which opposes the acetylation-induced NICD stabilization. Consequently, endothelial cells lacking SIRT1 activity are sensitized to Notch signalling, resulting in impaired growth, sprout elongation and enhanced Notch target gene expression in response to DLL4 stimulation, thereby promoting a non-sprouting, stalk-cell-like phenotype. In vivo, inactivation of Sirt1 in zebrafish and mice causes reduced vascular branching and density as a consequence of enhanced Notch signalling. Our findings identify reversible acetylation of the NICD as a molecular mechanism to adapt the dynamics of Notch signalling, and indicate that SIRT1 acts as rheostat to fine-tune endothelial Notch responses