The selective estrogen receptor-beta agonist biochanin A shows vasculoprotective effects without uterotrophic activity

OBJECTIVE: Current hormone therapy in postmenopausal women is associated with uterotrophic activity and cancer-promoting effects. In this experimental study, we compared the effects of the selective estrogen-receptor (ER) beta agonist biochanin A, and the selective ERalpha agonist ethinylestradiol, on the development of intimal hyperplasia after balloon injury and on uterus morphology. DESIGN: Female F344 rats with or without prior ovariectomy were used for aortic denudations. Animals remained untreated or received oral biochanin A (100 mg/kg) or ethinylestradiol (100 microg/kg). After 14 days, aortas and uteri were harvested for histologic and immunohistochemical analyses. Computerized assessments of aortic adhesion molecule expression, and isometric relaxation experiments, and uteri were analyzed. In vitro studies with smooth muscle cells and endothelial cells were performed to further investigate the effects of hormone treatment on cell proliferation, migration and adhesion molecule expression. RESULTS: Among untreated rats, ovariectomized animals tended to show greater neointimal hyperplasia and increased expression of the adhesion molecules 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). Biochanin A treatment reduced neointima formation, inhibited VCAM-1 up-regulation, and improved the vascular relaxation response. No effect was observed on uterus growth or histology. Ethinylestradiol also reduced aortic neointima formation and inhibited VCAM-1 up-regulation, but failed to improve endothelial function and significantly induced uterus growth. Both agents showed antiproliferative and weak antimigratory effects on smooth muscle cells, and reduced VCAM-1 expression on stimulated endothelial cells in vitro. CONCLUSIONS: The ERbeta agonist biochanin A shows vasculoprotective effects without uterotrophic activity. Because hormone therapy may have cancer-promoting side effects, administration of ERbeta-selective agents might be alternatively used to reduce the risk of cardiovascular disease in postmenopausal women.     

Signal-dependent splicing of tissue factor pre-mRNA modulates the thrombogenicity of human platelets

Tissue factor (TF) is an essential cofactor for the activation of blood coagulation in vivo. We now report that quiescent human platelets express TF pre-mRNA and, in response to activation, splice this intronic-rich message into mature mRNA. Splicing of TF pre-mRNA is associated with increased TF protein expression, procoagulant activity, and accelerated formation of clots. Pre-mRNA splicing is controlled by Cdc2-like kinase (Clk)1, and interruption of Clk1 signaling prevents TF from accumulating in activated platelets. Elevated intravascular TF has been reported in a variety of prothrombotic diseases, but there is debate as to whether anucleate platelets-the key cellular effector of thrombosis-express TF. Our studies demonstrate that human platelets use Clk1-dependent splicing pathways to generate TF protein in response to cellular activation. We propose that platelet-derived TF contributes to the propagation and stabilization of a thrombus.     

Selective disruption of hippocampus-mediated recognition memory processes after episodes of transient global amnesia

Transient global amnesia (TGA) is characterized by the abrupt onset of severe amnesia without concomitant focal neurological symptoms. Recent studies revealed that small and punctate MR-signal diffusion-weighted imaging (DWI) lesions can be found within the hippocampus of TGA patients during the post-acute phase. On the basis of dual-process models of recognition memory, the present study examined the hypothesis that hippocampal dysfunction as suggested by these DWI lesions disrupts hippocampus-mediated recollection in patients with TGA, whereas familiarity-based recognition memory that is assumed to be supported by extra-hippocampal brain regions should be unaffected. We administered a recognition memory task for faces and words to eleven TGA patients during the post-acute phase and to eleven matched controls. Receiver operating characteristics (ROCs) were obtained in order to derive estimates of familiarity and recollection by applying a formal dual-process model of recognition memory. Analyses of ROC curves revealed a disruption of recollection in TGA patients’ memory for words [t(20) = 2.70, p < .05], but no difference in familiarity-based recognition memory between patients and controls [t(20) = −1.10, p = .284]. Post hoc analyses indicated that the deficit in recollection is more pronounced in TGA patients who show visible hippocampal lesions on diffusion-weighted MR imaging compared to those without detectable hippocampal lesions. In conclusion, consistent with recent neuroanatomical dual-process models of recognition memory, hippocampal dysfunction in patients with TGA is associated with a selective effect on specific recognition memory subprocesses.     

Assessment of long-term antihypertensive treatment by clinic and ambulatory blood pressure: data from the European Lacidipine Study on Atherosclerosis

OBJECTIVES: Information on the features of long-term modifications of clinic and 24-h ambulatory blood pressure (ABP) by treatment is limited. The present study aimed to address this issue. METHODS: Ambulatory BP monitoring and clinic BP (CBP) measurements were performed at baseline and at yearly intervals over a 4-year follow-up period in 1523 hypertensives (56.1 +/- 7.6 years) randomized to treatment with lacidipine or atenolol in the European Lacidipine Study on Atherosclerosis (ELSA). RESULTS: CBP was always greater than ABP, while reductions in all BP values (greater for CBP than for ABP) were on average maintained throughout 4 years, CBP changes showing limited relationship with ABP changes (r = 0.14-0.27). BP reductions by treatment during daytime and night-time were correlated (r = 0.63-0.73). BP normalization was achieved in a greater percentage of patients for CBP (41.7%) than for ABP (25.3%), with systolic BP control being always less common than diastolic BP control. BP normalization was more frequent at single yearly visits than throughout the 4 years. Twenty-four-hour BP variability was reduced by treatment over 4 years in absolute but not in normalized units. CONCLUSIONS: The present study provides the best evidence available on long-term effect of antihypertensive treatment on both ABP and CBP. On average, ABP was sustainedly reduced by treatment throughout the follow-up period, but 24-h BP was more difficult to control than CBP. In several patients, ABP control was unstable between visits, the percentage of patients under control over 4 years being much less than that of those controlled at each year. Treatment induced a reduction in absolute but not in normalized BP variability estimates. This has clinical implications because of the prognostic importance of ABP mean values and variability.     

Tissue warming and regulatory responses induced by radio frequency energy deposition on a whole-body 3-Tesla magnetic resonance imager

PURPOSE: To quantify the B1-field induced tissue warming on a 3T-whole-body scanner, to test whether the patient is able to sense the temperature change, and to evaluate whether the imaging procedure constitutes a significant cardiovascular stress. MATERIALS AND METHODS: A total of 18 volunteers were divided into three equal groups for 3.0T MRI of the pelvis, the head, or the knee. An imaging protocol operating at first level mode was applied, allowing radio frequency (RF) irradiation up to the legal specific absorption rate (SAR) limits. An identical placebo protocol with active gradient switching but without RF transmission was used. Temperature changes were measured with a fiber-optic thermometer (FO) and an infrared camera (IR). RESULTS: Temperature differences to the placebo were highest for imaging of the pelvis (FO: DeltaT = 0.88 +/- 0.13 degrees C, IR: DeltaT = 1.01 +/- 0.15 degrees C) as compared to the head (FO: DeltaT = 0.46 +/- 0.12 degrees C, IR: DeltaT = 0.47 +/- 0.10 degrees C) and the knee (FO: DeltaT = 0.33 +/- 0.11 degrees C, IR: DeltaT = 0.37 +/- 0.09 degrees C). The volunteers were able to discriminate between imaging and placebo for pelvic (P < 0.0001) and head (P = 0.0005) imaging but not for knee imaging (P = 0.209). No changes in heart rate or blood pressure were detected. CONCLUSION: The 3.0T MRI in the first operational mode may lead to measurable and perceptible thermal energy deposition. However, it may be regarded as safe concerning the thermoregulatory cardiovascular stress.     

Heating of metallic implants and instruments induced by gradient switching in a 1.5-Tesla whole-body unit

PURPOSE: To examine gradient switching-induced heating of metallic parts. MATERIALS AND METHODS: Copper and titanium frames and sheets ( approximately 50 x 50 mm(2), 1.5 mm thick, frame width = 3 mm) surrounded by air were positioned in the scanner perpendicular to the static field horizontally 20 cm off-center. During the execution of a sequence (three-dimensional [3D] true fast imaging with steady precession [True-FISP], TR = 6.4 msec) exploiting the gradient capabilities (maximum gradient = 40 mT/m, maximum slew rate = 200 T/m/second), heating was measured with an infrared camera. Radio frequency (RF) amplitude was set to zero volts. Heating of a copper frame with a narrowing to 1 mm over 20 mm at one side was examined in air and in addition surrounded by several liters of gelled saline using fiber-optic thermography. Further heating studies were performed using an artificial hip made of titanium, and an aluminum replica of the hip prosthesis with the same geometry. RESULTS: For the copper specimens, considerable heating (>10 degrees C) in air and in gelled saline (>1.2 degrees C) could be observed. Heating of the titanium specimens was markedly less ( approximately 1 degrees C in air). For the titanium artificial hip no heating could be detected, while the rise in temperature for the aluminum replica was approximately 2.2 degrees C. CONCLUSION: Heating of more than 10 degrees C solely due to gradient switching without any RF irradiation was demonstrated in isolated copper wire frames. Under specific conditions (high gradient duty cycle, metallic loop of sufficient inductance and low resistance, power matching) gradient switching-induced heating of conductive specimens must be considered.     

Magnetic susceptibility effects on the accuracy of MR temperature monitoring by the proton resonance frequency method

PURPOSE: To evaluate the error of MR temperature assessment based on the temperature-dependent Larmor frequency shift of water protons, which can result from susceptibility effects caused by the radiofrequency (RF) applicator. MATERIALS AND METHODS: Local frequency shifts due to RF applicator displacements were simulated numerically by means of a three-dimensional elementary dipole model. Experimental examinations using a water tank phantom equipped with a high-precision screw thread were applied to examine temperature and movement effects for five commercially available, MR-compatible RF applicators. Measurements were performed at 1.5 Tesla. RESULTS: For single-needle electrodes perpendicular to the external field, a distortion of 0.1 ppm and 0.2 ppm was recorded at a distance of 17.5 mm and 12.5 mm, respectively, to the needle shaft. Cluster applicators and umbrella-shaped applicators caused distortions of 0.1 ppm up to distances of 36 mm. Sinusoidal dependence on applicator orientation was found with the highest values for perpendicular orientation and the lowest values for orientation parallel to the magnetic field. With a single electrode oriented perpendicular to the field at a distance of 1.5 cm and 2.0 cm, a needle displacement of 5 mm led to an error in temperature measurement of 16.3 degrees C and 7.5 degrees C, respectively. CONCLUSION: In MR temperature measurement, displacement of the RF applicator by patient movement or breathing leads to significant errors that have to be taken into account when PRF temperature maps are used to monitor tumor ablation in the presence of paramagnetic applicators.