Association between cardiovagal baroreflex sensitivity and baseline cerebral perfusion of the hippocampus.

PURPOSE: A failure to control perfusion pressure due to impaired baroreflex sensitivity (BRS) could potentially cause chronic brain hypoperfusion, leading to cognitive dysfunction. The primary aim of this study was to determine whether BRS was associated with regional cerebral blood flow as measured by MRI arterial spin labeling (ASL) technique. METHODS: Baroreflex sensitivity was measured using the Valsalva maneuver technique in 52 middle-aged normotensive adults (49 ± 1 years), and phase IV of the Valsalva maneuver was used for analyses. Cerebral perfusion was measured using the ASL MRI technique in 10 pre-determined brain regions of interest. RESULTS: Hippocampal perfusion was correlated with BRS (R (2) = 0.17, P = 0.01). No association was observed between BRS and cerebral perfusion in the other brain regions of interest. Partial correlational analyses revealed that BRS was an important predictor of hippocampal perfusion, explaining 11 % of the variability independent of other covariates. When participants were divided into tertiles of BRS (11.8 ± 1.9 and 3.5 ± 0.1 ms/mmHg for the highest and lowest tertiles), regional cerebral perfusion of the hippocampus was significantly lower in the lowest BRS tertile than in the highest tertile (39.1 ± 4.3 and 60.5 ± 8.4 ml/100 g/min). CONCLUSIONS: Baroreflex sensitivity in midlife is positively associated with regional cerebral perfusion of the hippocampus, and impaired BRS appears to be related to brain hypoperfusion even in apparently healthy middle-aged adults. Future longitudinal studies based on the present cross-sectional findings may help to further define the relationship between BRS to cognitive dysfunction.

Factor Xa inhibitors: new anti-thrombotic agents and their characteristics.

Factor Xa (FXa) is a key enzyme that is positioned at the convergence of the intrinsic and extrinsic pathways in the blood coagulation cascade, and inactivation by a specific FXa inhibitor effectively prevents the generation of thrombin. Various types of low molecular weight (LMW) heparin, which function as semi-selective and indirect FXa inhibitors, are replacing unfractionated heparin (UFH) as agents for the prevention and treatment of venous thromboembolism (VTE), as well as in initial treatment for coronary events. Of those, heparinoid has been shown to be safer and more effective for the prevention of postoperative VTE than UFH, especially for treatment of heparin-induced thrombocytopenia (HIT). Further, synthetic pentasaccharide has been found to offer advantages over current thromboprophylactic regimens in a number of patients undergoing major orthopedic surgery. Other studies have shown that pentasaccharide is more effective for overall VTE in comparison with LMW heparin, though it was also associated with an increased rate of major bleeding. Synthetic, selective, and direct inhibitors to FXa, such as DX-9065a, are highly potent and orally bioavailable antithrombotic agents that have demonstrated an improved side effect profile, probably by allowing sufficient thrombin to remain for platelet activation and normal hemostasis, while preventing pathological thrombus formation. For thrombosis therapy, the most desirable type of antithrombotic agent is an orally active drug that has a broad range of effective doses and no hemorrhagic side effects. Presently, many types of direct inhibitors are in various stages of clinical trials and expected to provide significant benefits as compared to currently utilized therapy strategies.

Cloning and characterization of the human factor XI gene promoter: transcription factor hepatocyte nuclear factor 4alpha (HNF-4alpha ) is required for hepatocyte-specific expression of factor XI.

Factor XI is the zymogen of a plasma protease produced primarily in liver that is required for normal blood coagulation. We cloned approximately 2600 base pairs of the human factor XI gene upstream of exon one, identified transcription start sites, and conducted a functional analysis. Luciferase reporter assays demonstrate that the 381 base pairs upstream of exon one are sufficient for maximum promoter activity in HepG2 hepatocellular carcinoma cells. The removal of 19 base pairs between -381 and -363 results in a nearly complete loss of promoter activity. This region contains the sequence ACTTTG, a motif required for binding of the transcription factor hepatocyte nuclear factor 4alpha (HNF-4alpha) to the promoters of several genes. Gel mobility shift assays using HepG2 or rat hepatocyte nuclear extract confirm HNF-4alpha binds between bp -375 and -360. Scrambling the ACTTTG motif completely abolishes promoter activity in luciferase assays. The factor XI promoter functions poorly when transfected into HeLa carcinoma cells, and gel mobility shift experiments with HeLa nuclear extracts demonstrate no HNF-4alpha binding to the ACTTTG sequence. When a rat HNF-4alpha expression construct is co-transfected into HeLa cells, factor XI promoter activity is enhanced approximately 10-fold. We conclude that HNF-4alpha is required for hepatocyte-specific expression of factor XI.