Severe Cerebral Venous and Sinus Thrombosis: Clinical Course,Imaging Correlates,and Prognosis

Background

Severe cerebral venous-sinus thrombosis (CVT) is a rare disease, and its clinical course, imaging correlates, as well as long-term prognosis have not yet been investigated systematically.

Methods

Multicenter retrospective study. Inclusion criteria were CVT, Glasgow coma scale ≤9, and treatment in the intensive care unit. Primary outcome was death or dependency, assessed by a modified Rankin Score (mRS) >2 at last follow-up.

Results

114 patients were included. At last follow-up (median 2.5 years), 38 patients (33.3 %) showed no or minor residual symptoms (mRS = 0 or 1), 12 (10.5 %) had a mild (mRS = 2), 13 (11.4 %) a moderate (mRS = 3), 12 (10.5 %) a severe disability (mRS = 4 or 5), and 39 (34.2 %) had died. In bivariate analysis, predictors of poor outcome were any signs of mass effect on imaging, clinical deterioration after admission, and age. In contrast, clinical symptoms on admission and parenchymal lesions per se, such as edema, infarction, or hemorrhage were not predictive. Multivariate predictors of poor outcome were an increase in National Institutes of Health Stroke Scale ≥3 after admission [odds ratio (OR) 6.7], bilateral motor signs in the further course (OR 9.2), and midline shift (OR 5.1).

Conclusion

The outcome of severe CVT is almost equally divided between severe impairment or death and survival with no or only mild handicap. Specifically, space-occupying mass effect and associated neurologic deterioration seem to determine a poor outcome. Therefore, early detection and treatment of mass effect should be the focus of critical care.

     

Antitumor activity of CTFB, a novel anticancer agent, is associated with the down-regulation of nuclear factor-kappaB expression and proteasome activation in head and neck squamous carcinoma cell lines

This study aimed to characterize the antitumor activity of 5-Chloro-N-[2-[2-(4-chloro-phenyl)-3-methyl-butoxy]-5-trifluoromethyl-phenyl]-2-hydroxy-benzamide (CTFB), a novel anticancer agent, in head and neck cancer cell lines, FaDu, SCC-25 and cisplatin-resistant CAL-27. CTFB was generated as a result of an extensive medicinal chemistry effort on a lead compound series discovered in a high-throughput screen for inducers of apoptosis. All cell lines showed significant growth delay in response to CTFB treatment at a concentration of 1 micromol/L with 17.16 +/- 2.08%, 10.92 +/- 1.22%, and 27.03 +/- 1.86% of cells surviving at 120 h in FaDu, CAL-27, and SCC-25, respectively. To define proteins involved in the mechanism of action of CTFB, we determined differences in the proteome profile of cell lines before and after treatment with CTFB using two-dimensional difference gel electrophoresis followed by computational image analysis and mass spectrometry. Eight proteins were found to be regulated by CTFB in all cell lines. All these proteins are involved in cytoskeleton formation and function and/or in cell cycle regulation. We showed that CTFB-induced cell growth delay was accompanied by cell cycle arrest at the G(0)-G(1) phase that was associated with the up-regulation of p21/WAF1 and p27/Kip1 expression and the down-regulation of cyclin D1. Furthermore, we showed that activity of CTFB depended on the down-regulation of nuclear factor-kappaB (NF-kappaB) and NF-kappaB p65 phosphorylated at Ser(536). The level of proteasome activity correlated with the response to CTFB treatment, and the down-regulation of NF-kappaB is accompanied by enhanced proteasome activity in all investigated head and neck cancer cell lines. In this report, we show that CTFB reveals multiple effects that lead to delayed cell growth. Our data suggest that this compound should be studied further in the treatment of head and neck cancer.     

Expression analyses for rheumatoid arthritis

Inflammatory rheumatic diseases with their unclear aetiology are a challenge for the routine clinical practice. The dominating inflammatory processes with many facets of autoimmune phenomena have been extensively studied during the last decades. Modern high throughput technologies provide for the first time the opportunity to obtain an insight into the many different molecular aspects in one patient in parallel. Step by step, concepts can be developed to understand the relationships and interdependencies of the molecular processes and to place them in order of importance for each individual separately. Thus, studies have demonstrated that the risk of disease severity can be estimated and the response to therapy can be objectified based on molecular investigations. Exemplarily, the potential has been demonstrated that the therapeutic outcome towards a defined treatment may be predicted. Despite the high cost, it is becoming more and more obvious that an extensive increase of knowledge depends on the detection of a multitude of parameters, a task which will need to be accomplished in the near future.     

Free fatty acids and insulin secretion in humans

Acute increases in plasma levels of long-chain fatty acids raise plasma insulin levels by stimulating insulin secretion or by decreasing insulin clearance. In normal subjects, longterm elevations of fatty acids also stimulate insulin secretion. In fact, they increase insulin precisely to the degree needed to compensate for the fatty acid-induced insulin resistance. In contrast, in individuals who are genetically predisposed to develop type 2 diabetes (prediabetic subjects), the free fatty acid (FFA) stimulation of insulin secretion is not sufficient to fully compensate for the FFAinduced insulin resistance. Therefore, obesity, if associated with elevated fatty acid levels, may lead to hyperglycemia in prediabetic but not in normal individuals.     

Modulation of granule cell migration by a glia-derived protein.

Cultured explants from early postnatal mouse cerebellum were used to examine the influence of a 43-kDa glia-derived neurite-promoting factor (GdNPF) on the migration of [3H]thymidine-labeled granule cell neurons. GdNPF, which is a potent serine protease inhibitor, significantly reduced the extent of granule cell migration in a dose-dependent manner. This effect could be neutralized by addition of thrombin, which binds GdNPF. Other protease inhibitors such as aprotinin, hirudin, soybean trypsin inhibitor, leupeptin, 6-aminocaproic acid, and D-Phe-Pro-ArgCH2Cl do not show this inhibitory effect. These results demonstrate that a glia-derived protein can regulate the migration of postmitotic neurons, an important cellular event in the development of the nervous system.     

No clinically relevant CYP3A induction after St. John’s wort with low hyperforin content in healthy volunteers

Objective  Induction of CYP3A by St. John’s wort (SJW) products with high hyperforin content is well described. Since CYP3A induction is mediated by hyperforin in a concentration-dependent manner, and SJW preparations differ significantly in hyperforin content, the aim of the study was to evaluate the effect of an SJW powder with low hyperforin content on CYP3A function. Methods  Twenty healthy male volunteers received an SJW powder with low hyperforin content for 2 weeks. Midazolam plasma concentration time profiles were characterized after a single oral dose of 7.5 mg midazolam on the day before and on the 14th day of SJW medication. Results  Midazolam AUC_0–∞ slightly decreased from 124.0 ± 62.5 ng/ml·h at baseline to 105.6 ± 53.2 ng/ml·h after SJW (P < 0.05), representing a mean 11.3% decrease (95% CI: −22.8 to 0.21). No significant change in midazolam C_max, t_1/2 and t_max was observed. For all pharmacokinetic parameters, the 90% CI for the geometric mean ratio of treatment over baseline were within the no-effect boundaries of 0.70–1.43. Conclusion  Administration of an SJW product with low hyperforin content resulted in a mild induction of CYP3A not considered clinically relevant.     

Imaging mesial temporal lobe activation during scene encoding: comparison of fMRI using BOLD and arterial spin labeling

Memory encoding is a critical brain function subserved by the hippocampus (HP) and mesial temporal lobe (mTL) structures. Visualization of mTL memory activation with BOLD fMRI is complicated by the presence of static susceptibility gradients in this region. Arterial spin labeled (ASL) perfusion fMRI offers an alternative approach not dependent on susceptibility contrast that instead suffers from lower intrinsic signal-to-noise ratio. An improved ASL perfusion fMRI approach combining pseudo-continuous ASL and a T(2)*-insensitive sequence (GRASE) with background suppression was compared to BOLD fMRI at 3 T during a scene encoding task known to activate the HP. Overall, an approximate sixfold sensitivity increase of ASL fMRI was achieved, with improved coverage in the anterior mTL, while suppression of the static tissue enhanced the stability of the ASL series by a factor of 2.4. Perfusion fMRI using this approach with 4 mm isotropic resolution yielded better localized and stronger group activation maps than BOLD fMRI at a standard resolution of 3 mm isotropic voxels. Increasing the resolution for BOLD to 2.5 mm isotropic produced stronger mTL and hippocampal activation in the group and individual subjects than the ASL technique, due to superior temporal resolution and reduced partial volume effects. Future improvements in ASL spatial and temporal resolution would allow the benefits of both approaches to be combined to further enhance the sensitivity for detecting mTL activation during memory encoding.