Effect of valsartan on angiotensin II-induced plasminogen activator inhibitor-1 biosynthesis in arterial smooth muscle cells

Previous studies have shown that angiotensin II stimulates the synthesis of plasminogen activator inhibitor-1 in cultured vascular cells, which suggests that activation of the renin-angiotensin system may impair fibrinolysis. We have investigated the effects of angiotensin II and of valsartan, a recently developed angiotensin II antagonist that is highly specific and selective for the angiotensin II subtype 1 receptor, on plasminogen activator inhibitor-1 secretion by smooth muscle cells isolated from rat and human vessels. Angiotensin II induced a time- and concentration-dependent increase of plasminogen activator inhibitor activity in supernatants of rat aortic cells, which reached a plateau after 6 hours of incubation with 100 nmol/L angiotensin II (2.4+/-0.6-fold over control value; P:<0.001). The angiotensin II-induced plasminogen activator inhibitor activity was inhibited, in a concentration-dependent manner, by valsartan with an IC(50) value of 21 nmol/L. Valsartan fully prevented the angiotensin II-induced increase in plasminogen activator inhibitor-1 protein and mRNA. Furthermore, angiotensin II doubled the secretion of plasminogen activator inhibitor-1 by smooth muscle cells obtained from human umbilical and internal mammary arteries, and valsartan fully prevented it. Angiotensin II did not affect the secretion of tissue plasminogen activator antigen by any of the cell systems tested. Thus, valsartan effectively inhibits angiotensin II-induced plasminogen activator inhibitor-1 secretion without affecting that of tissue plasminogen activator in arterial rat and human smooth muscle cells

Increased prothrombotic state lasting as long as one month after on-pump and off-pump coronary surgery

OBJECTIVE: This study investigated whether the activation of coagulation, fibrinolysis, and endothelium occurring during the first postoperative month after on-pump coronary artery bypass surgery differs from that after off-pump coronary artery bypass grafting. METHODS: Thirty-five patients candidates to coronary surgery were randomized to undergo on-pump (n = 18) or off-pump (n = 17) coronary artery bypass grafting. Blood samples were collected before the intervention and to 1 month after surgery. RESULTS: Prothrombin fragment F1.2, thrombin-antithrombin complex, and D-dimer increased after surgery and were persistently higher than preoperative values as late as 30 postoperative days in both on- and off-pump groups; higher levels of these variables were detected after on-pump surgery relative to off-pump surgery only at the time point after termination of cardiopulmonary bypass (fragment F1.2 and thrombin-antithrombin complex) or from bypass end to 8 postoperative days (D-dimer). Fibrinogen levels decreased after surgery and then increased in parallel in both groups to 8 days after surgery. The von Willebrand factor level increased postoperatively in both groups and returned to baseline 30 days after surgery; it was higher after on-pump surgery from bypass end to 8 postoperative days. Soluble vascular cell adhesion molecule 1 was increased significantly from baseline in both groups 30 days after surgery, with no difference between groups. CONCLUSION: Patients undergoing off-pump surgery showed protection against activation of coagulation and fibrinolysis and against endothelial injury only during the intraoperative period; this was followed by the development of a prothrombotic pattern comparable to that of patients undergoing on-pump surgery lasting at least as late as 30 days after surgery

The Calabrian Arc subduction complex in the Ionian Sea: Regional architecture, active deformation, and seismic hazard

We analyzed the structure and evolution of the external Calabrian Arc (CA) subduction complex through an integrated geophysical approach involving multichannel and single‐channel seismic data at different scales. Pre‐stack depth migrated crustal‐scale seismic profiles have been used to reconstruct the overall geometry of the subduction complex, i.e., depth of the basal detachment, geometry and structural style of different tectonic domains, and location and geometry of major faults. High‐resolution multichannel seismic (MCS) and sub‐bottom CHIRP profiles acquired in key areas during a recent cruise, as well as multibeam data, integrate deep data and constrain the fine structure of the accretionary wedge as well as the activity of individual fault strands. We identified four main morpho‐structural domains in the subduction complex: 1) the post‐Messinian accretionary wedge; 2) a slope terrace; 3) the pre‐Messinian accretionary wedge and 4) the inner plateau. Variation of structural style and seafloor morphology in these domains are related to different tectonic processes, such as frontal accretion, out‐of-sequence thrusting, underplating and complex faulting. The CA subduction complex is segmented longitudinally into two different lobes characterized by different structural style, deformation rates and basal detachment depths. They are delimited by a NW/SE deformation zone that accommodates differential movements of the Calabrian and the Peloritan portions of CA and represent a recent phase of plate re‐organization in the central Mediterranean. Although shallow thrust‐type seismicity along the CA is lacking, we identified active deformation of the shallowest sedimentary units at the wedge front and in the inner portions of the subduction complex. This implies that subduction could be active but aseismic or with a locked fault plane. On the other hand, if underthrusting of the African plate has stopped recently, active shortening may be accommodated through more distributed deformation. Our findings have consequences on seismic hazard, since we identified tectonic structures likely to have caused large earthquakes in the past and to be the source regions for future events

Familial aggregation of MATRICS Consensus Cognitive Battery scores in a large sample of outpatients with schizophrenia and their unaffected relatives

Background The increased use of the MATRICS Consensus Cognitive Battery (MCCB) to investigate cognitive dysfunctions in schizophrenia fostered interest in its sensitivity in the context of family studies. As various measures of the same cognitive domains may have different power to distinguish between unaffected relatives of patients and controls, the relative sensitivity of MCCB tests for relative-control differences has to be established. We compared MCCB scores of 852 outpatients with schizophrenia (SCZ) with those of 342 unaffected relatives (REL) and a normative Italian sample of 774 healthy subjects (HCS). We examined familial aggregation of cognitive impairment by investigating within-family prediction of MCCB scores based on probands' scores.Methods Multivariate analysis of variance was used to analyze group differences in adjusted MCCB scores. Weighted least-squares analysis was used to investigate whether probands' MCCB scores predicted REL neurocognitive performance.Results SCZ were significantly impaired on all MCCB domains. REL had intermediate scores between SCZ and HCS, showing a similar pattern of impairment, except for social cognition. Proband's scores significantly predicted REL MCCB scores on all domains except for visual learning.Conclusions In a large sample of stable patients with schizophrenia, living in the community, and in their unaffected relatives, MCCB demonstrated sensitivity to cognitive deficits in both groups. Our findings of significant within-family prediction of MCCB scores might reflect disease-related genetic or environmental factors

Rapid Quantitative Prediction of Ionization Energies and Electron Affinities of Polycyclic Aromatic Hydrocarbons.

Quantitative structure activity relationship (QSAR) studies of polycyclic aromatic hydrocarbons (PAHs) often employ rapid semiempirical calculations to evaluate ionization energy (IE) and electron affinity (EA) values, assuming they are equal (but of opposite sign) to the energies of the highest occupied and lowest unoccupied molecular orbitals (HOMO and LUMO), respectively. However, regardless of the assumption of validity of Koopmans’ theorem, the reliability of this simple theoretical approach for reproducing the experimental IE and EA trends has not been tested, except for a few linear PAHs. Here the measured IEs and EAs of 17 PAHs are plotted vs. the HOMO and LUMO energies obtained with semiempirical AM1 calculations and, for comparison, HF/6-31G calculations. Good linear relationships are obtained with both methods, with correlation coefficients r >0.98 for the IEs and r >0.96 for the EAs. The IEs and EAs predicted by scaling the corresponding MO energies with the appropriate empirical linear equation are compared with experimental values available in the literature for PAHs (28 IEs and 22 EAs). The average (absolute) difference between evaluated and measured IEs is found to be 0.07 eV (s.d.=0.05 eV), while for the EAs the average difference is slightly larger. The accuracy of both AM1 and HF/6-31G methods are essentially equal, the former having the significant advantage of being 60 times faster. The present study demonstrates the ability of rapid semiempirical calculations carried out on the neutral molecules to parallel the experimental IE and EA values of PAHs, and provides simple linear equations which can be routinely employed for their quantitative prediction in this class of compounds

Electron affinities of polycyclic aromatic hydrocarbons by means of B3LYP/6-31+G* calculations.

The gas-phase experimental adiabatic electron affinities (AEAs) of the polycyclic aromatic hydrocarbons (PAHs) anthracene, tetracene, pentacene, chrysene, pyrene, benzo[a]pyrene, benzo[e]pyrene and fluoranthene are well reproduced using the hybrid density functional method B3LYP with the 6-31+G* basis set, indicating that the smallest addition of diffuse functions to the basis set is suitable for a correct description of the stable PAH anion states. The calculated AEAs also give a very good linear correlation with available reduction potentials measured in solution. The AEAs (not experimentally available) of the isomeric benzo[ghi]fluoranthene and cyclopenta[cd]pyrene, commonly found in the environment, are predicted to be 0.817 and 1.108 eV, respectively, confirming the enhancement of the electron-acceptor properties associated with fusion of a peripheral cyclopenta ring. The calculated localization properties of the lowest unoccupied MO of cyclopenta[cd]pyrene, together with its relatively high electron affinity, account for a high reactivity at the ethene double bond of this PAH in reductive processes

Refractory semantic access dysphasia resulting from resection of a left frontal glioma

The existence of semantic access disorders is now well established, however the precise cognitive and anatomical underpinnings are still debated. Here we describe the case of a patient that became aphasic after the resection of a left frontal glioma. Detailed lesion reconstruction indicates that the lesion was mostly restricted to the left dorsal and ventral prefrontal cortices and the underlying white matter, but sparing temporal lobes. Critically, the patient showed all the signs of refractory semantic access dysphasia, supporting the association between this syndrome and damage to left prefrontal areas likely to subserve retrieval and selection mechanisms for verbal materia