Quantification of venous blood signal contribution to BOLD functional activation in the auditory cortex at 3 T

Most modern techniques for functional magnetic resonance imaging (fMRI) rely on blood-oxygen-level-dependent (BOLD) contrast as the basic principle for detecting neuronal activation. However, the measured BOLD effect depends on a transfer function related to neurophysiological changes accompanying electrical neural activation. The spatial accuracy and extension of the region of interest are determined by vascular effect, which introduces incertitude on real neuronal activation maps. Our efforts have been directed towards the development of a new methodology that is capable of combining morphological, vascular and functional information; obtaining new insight regarding foci of activation; and distinguishing the nature of activation on a pixel-by-pixel basis. Six healthy volunteers were studied in a parametric auditory functional experiment at 3 T; activation maps were overlaid on a high-resolution brain venography obtained through a novel technique. The BOLD signal intensities of vascular and nonvascular activated voxels were analyzed and compared: it was shown that nonvascular active voxels have lower values for signal peak (Pb10−7) and area (Pb10−8) with respect to vascular voxels. The analysis showed how venous blood influenced the measured BOLD signals, supplying a technique to filter possible venous artifacts that potentially can lead to misinterpretation of fMRI results. This methodology, although validated in the auditory cortex activation, maintains a general applicability to any cortical fMRI study, as the basic concepts on which it relies on are not limited to this cortical region. The results obtained in this study can represent the basis for new methodologies and tools that are capable of adding further characterization to the BOLD signal properties

Attilio Maseri, Italian cardiologist of universal value

Attilio Maseri, Italian cardiologist of universal valu

Does the combination with handgrip increase the sensitivity of dipyridamole-echocardiography test?

The aim of this study was to assess the possibility of increasing the sensitivity of dipyridamole-echocardiography testing (DET:2-D echo monitoring during dipyridamole infusion) by combining this procedure with handgrip testing. Dipyridamole-handgrip test (DHT) was therefore performed in 24 patients with rest/effort angina, negative DET, and negative handgrip-echo (without dipyridamole pretreatment). DHT consisted of 4.5 min of sustained 25% maximum grip strength, started 4 min after the end of dipyridamole infusion (0.56 mg/kg for 4 min). Interpretable studies were obtained in all patients. Of the 24 patients tested (10 without and 14 with significant coronary artery disease, CAD), only one CAD patient had a positive DHT, which indicates an increased sensitivity of 7% versus DET alone. In conclusion, DHT is feasible in all patients and--if compared to DET--has the same specificity. However, in spite of the theoretical premises, it provides only a modest step up in sensitivity

Short-term reproducibility of dipyridamole-echocardiography test.

The aim of this study was to assess the short-term reproducibility of dipyridamole-echocardiography test (DET) consisting of two-dimensional echo monitoring during dipyridamole infusion (up to 0.84 mg/kg in 10 min). The diagnostic end-point of the test is the detection of new onset or worsening regional asynergy. A group of 87 patients with rest and/or effort angina performed two DETS on two consecutive days. All 60 patients with a positive DET had a positive repeat test, and the 27 negative DETs were also negative on the following day. The timing of the asynergy was also very similar between the two tests, both in patients with angina on effort (r = .93, p less than 0.01) and at rest (r = .92, p less than 0.01). In conclusion, DET has a very high short-term reproducibility regarding the presence and timing of asynergy

OMEGA-3 fatty acids contribute to plaque stability differentially affecting the release of matrix metalloproteinases and tissue inhibitors of metalloproteinases by human monocytes/macrophages in culture

Objectives. High intakes of omega-3 fatty acids has been associated with protection from plaque rupture. The secretion of metalloproteinases (MMPs) by macrophages is believed to play a key role in matrix degradation underlying plaque instability. Conversely, tissue inhibitors of metalloproteinases (TIMPs) would contribute to plaque stability. We therefore studied the effects of omega-3 fatty acids on the release and activity of MMPs and TIMPs in cultured human monocytoid cells. Methods. Human U937 monocytoid cells were differentiated into macrophages by exposure for 24 h to 30 ng/mL phorbol myristate acetate (PMA) and 10 ng/mL tumor necrosis factor(TNF)-α. Both monocytes and macrophages were treated for 48 h with the DHA (22:6 n-3) or EPA (22:6 n-3) (25-100 μmol/L) before stimulation for 24 h with 10 ng/ml TNFα. Cell supernatates were used to test the release of gelatinase A (MMP-2), gelatinase-B (MMP-9), collagenase-1 (MMP-1), TIMP-1 and TIMP-2, by ELISAs, and total gelatinase and anti-gelatinase activities by zymography and retro-zymography techniques, respectively. Results. The long term exposure to 50 μmol/L EPA and DHA, but not to arachidonic acid (20:4 n-6), significantly reduced MMP-9 protein release without affecting the release of MMP-1, MMP-2 and TIMP-1. Conversely, TIMP-2 protein release was significantly increased by EPA and DHA (Table). Zymography for MMP-9 and retro-zymography for TIMP-1 and -2 reproduced the same results. Conclusions. The long term exposure to omega-3 fatty acids significantly reduces MMP-9 release without affecting the release of MMP-1 and -2. This effect, associated with the increase of TIMP-2 protein production and activity, may contribute to explaining the plaque-stabilizing effect by omega-3 fatty acid observed in humans

Peroxisome proliferator-activated receptory inhibits angiogenesis by suppressing creb-mediated cyclooxygenase-2 expression in human endothelium

Objetives. Neoangiogenesis contributes to diabetic vasculopathy and intraplaque hemorrhage in atherosclerosis. The activation of Peroxisome Proliferator-Activated Receptor(PPAR)γ is known to inhibit angiogenesis. We therefore examined the effects of PPARγ agonists on the pro-angiogenic enzyme cyclooxygenase(COX)-2 in human umbilical vein endothelial cells challenged with vascular endothelial growth factor (VEGF) and phorbol 12-myristate 13-acetate (PMA). Methods and Results.A 24 h exposure of HUVEC to the PPARγ agonists rosiglitazone (RSG) and GW1929 significantly attenuated VEGF- and PMA-stimulated COX-2 activity (by 30%, immunoassay for 6-keto-PGF1α), as well as protein (by 50%, Western analysis) and mRNA expression (by 50%, RT-PCR). This effect was abolished by the PPARγ antagonists bisphenol A diglycidyl ether and GW9662. COX-2 promoter activity experiments revealed that the induction of COX-2 promoter was significantly inhibited by RSG through an interference with the cAMP response element (CRE) site. COX-2 downregulation after siRNA knockdown of the transcription factor CRE binding protein (CREB) confirmed the role of CREB in mediating COX-2 transcription. Correspondingly, PPARγ agonists also attenuated CREB phosphorylation/activation. Since Protein Kinase(PK)C is involved in VEGF-induced COX-2 expression and CREB activation, we also investigated which isoforms of PKC were affected by RSG. While the inhibition of both conventional PKCα and β suppressed VEGF- and PMA-stimulated CREB activation and COX-2 expression, RGS only reduced VEGF- and PMA-stimulated PKCα membrane translocation. Conclusions. The anti-angiogenic effect of PPARγ agonists is due, at least in part, to their interference with the PKCα-mediated activation of CREB and the related expression of COX-2. PKCα may therefore be a novel therapeutic target for antidiabetic drugs in atherosclerosis

Hydroxytyrosol suppresses MMP-9 activity and expression in human monocytes. A mechanism for plaque stabilization by an olive oil component of Mediterranean diets

Purpose: Mediterranean diets, of which olive oil is an important component, are associated with low prevalence of cardiovascular diseases. The production of inflammatory mediators, such as prostaglandin (PG) E2, the overexpression of the inducible cyclooxygenase (COX)- 2 isoform and the activation of matrix metalloproteinase(MMP)-9 by macrophages likely contributes to plaque instability leading to acute coronary events. We studied the effects of the olive oil phenolic antioxidant hydroxytyrosol (HT) on MMP-9 and COX-2 activity and expression in human monocytes and explored underlying mechanisms. Methods: Human monocytes were treated either with 1-50 &#956;mol/L HT for 60 min or with selective inhibitors of PKC or COX isoenzymes for 30 min before stimulation with 30 nmol/L phorbol myristate acetate (PMA) for 24 h. Cell supernatants were tested for the release of MMP-9, PGE2 and TIMP-1 and -2 by ELISA and MMP-9 activity by zymography. Cell protein extracts were analyzed by Western analysis for COX-2 expression and for membrane translocation of PKCs and the NADPH oxidase p47phox subunit. We analyzed the activity of COX-2 promoter by transient transfection experiments and the.activation of the transcription factor Nuclear Factor(NF)-kappaB by EMSA. Results: PMA and, to a lesser extent, PGE2, induced the release of MMP-9 in monocytes. Cell exposure to HT before PMA stimulation reduced MMP-9 activity and expression (IC50 for HT of 10 micromol/L p < 0.01) without affecting the release of TIMP-1 and -2. Correspondingly, HT inhibited PMA-induced PGE2 production (by 54 ? 7%) and COX-2 expression (by 43 ? 5%) without affecting COX-1. Inhibition by HT was mediated by the suppression of NF-kappaB and the NADPH oxidase p47phox and PKC&#945;/&#946;1 activation. Conclusions: Our findings show that HT, at concentrations nutritionally achievable, inhibits the expression and the release of MMP-9 at least in part by the suppression of COX-2 dependent PGE2 pathway. Such effect occurs through the attenuation of PKC&#945;/&#946;1 and NADPH oxidase activation. Overall, such results contribute to explaining the vascular protective effects exerted by olive oil in Mediterranean diets

Personalized paths for physical activity: developing a person-centered quantitative function to determine a customized amount of exercise and enhancing individual commitment

Background: Non-Communicable Diseases (NCDs) are leading causes of mortality. These conditions are also known as chronic diseases of long duration and generally slow progression. Physical activity (PA) is a main factor to delay symptoms and consequences of NCDs. In last decades, reduced physical exercise has been observed across all ages. Despite educational campaigns aimed at modifying unhealthy habits, it is difficult to promote healthy lifestyles in general population. Poor interest, lack of motivation, as well as career and family commitments hinder people’s participation in regular PA programs. In this study we propose a theoretical person-centred approach to actively involve general population in enhancing their opportunity to perform PA based on personalized needs and targets. Methods: We defined four profiles of baseline PA levels (inactive, moderately inactive, moderately active, and active people) by referring to Metabolic equivalents (METs) based on individual answers to General Practice Physical Activity Questionnaire (GPPAQ). Results: Based on the answers to the GPPAQ and by computing the related METs for each profile of baseline exercise levels, we developed an innovative person-centered web-based algorithm/function for enhancing and measuring PA participation in community settings. This function can compute evidence-based standardized profiles of participants, personalized goals of PA being functional to the purpose of maintaining or gaining health benefits, as well as the type and duration of PA needed to reach these goals. Conclusion: It might be speculated that this approach would be a reliable method for increasing people’s self-efficacy and population adherence to recommended levels of PA. However, this theoretical proposal requires to be implemented in further research