Summary
The effects of NCX 4050, a drug belonging to a new class of NO donors, was investigated in isolated preparations of human and rabbit corpus cavernosum (CC) and in human foetal corpora ...cavernosa (hfCC) smooth muscle cells. In strips of rabbit CC, NCX 4050 (0.001–100 μM) induced a concentration‐dependent relaxation which was influenced neither by Nw‐nitro‐l‐arginine‐methyl‐ester (l‐NAME; 100 μm) nor by endothelium deprivation. The NCX 4050‐induced relaxation was significantly reduced by the guanylate cyclase inhibitor 1H‐1,2,4‐oxadiazolo4,3‐aquinoxalin‐1‐one (ODQ; 1 μm) and enhanced by a specific phosphodiesterase 5 inhibitor, sildenafil (300 nm). Moreover, NCX 4050 (0.01–1 μm), induced a concentration‐dependent potentiation of the relaxant response induced by electrical field stimulation (EFS) in rabbit preparations pre‐treated with guanethidine and indomethacin. The relaxant effect of NCX 4050 was similar to that obtained by increasing concentrations (0.001–100 μm) of sodium nitroprusside (SNP) in either rabbit or human preparations. To further investigate the activity of NCX 4050 on human corpora cavernosa, we exposed cultured hfCC smooth muscle cells to increasing concentrations of NCX 4050 and SNP. We found that both compounds dose‐dependently reduced cell proliferation. The antiproliferative effect of all the concentration tested of NCX 4050 was completely blocked by ODQ (1 μm). These results suggest that in rabbit and human corpora cavernosa NCX 4050 acts by activating guanylate cyclase activity, induces smooth muscle relaxation and quiescence. Our results provide a rationale for a possible future use of NCX 4050 in the pharmacotherapy of erectile dysfunction linked to an impaired release of NO from the endothelium.
IgE monoclonal antibodies hold great potential for cancer therapy. Preclinical in vivo systems, particularly those in which the antibody recognizes the host species target antigen and binds to ...cognate Fc receptors, are often the closest approximation to human exposure and represent a key challenge for evaluating the safety of antibody-based therapies. We sought to develop an immunocompetent rat system to assess the safety of a rodent anti-tumor IgE, as a surrogate for the human therapeutic candidate. We generated a rat IgE against the human tumor-associated antigen chondroitin sulfate proteoglycan 4 (CSPG4) and cross-reactive for the rat antigen. We analyzed CSPG4 distribution in normal rat and human tissues and investigated the in vivo safety of the antibody by monitoring clinical signs and molecular biomarkers after systemic administration to immunocompetent rats. Human and rat CSPG4 expression in normal tissues were comparable. Animals receiving antibody exhibited transient mild to moderate adverse events accompanied by mild elevation of serum tryptase, but not of angiotensin II or cytokines implicated in allergic reactions or cytokine storm. In the long term, repeated antibody administration was well tolerated, with no changes in animal body weight, liver and kidney functions or blood cell counts. This model provides preclinical support for the safety profiling of IgE therapeutic antibodies. Due to the comparable antigen tissue distribution in human and rat, this model may also comprise an appropriate tool for proof-of-concept safety evaluations of different treatment approaches targeting CSPG4.
125IAtrial natriuretic peptide (ANP) was used to identify ANP receptors on a clonal line of bovine bone endothelial (BBE) cells. Specific binding of 125IANP was saturable and of high affinity. ...Computer analysis of the equilibrium binding data indicated that the Scatchard plots are best fit by a straight line (Kd = 69.3 +/- 20.9 pM; binding capacity = 37.9 fmol/10(6) cells). The order of potency for competing with 125IANP binding was human ANP (hANP) > rat atriopeptin-1 (rAP-1) > porcine brain natriuretic peptide (pBNP) > porcine C-type natriuretic peptide. Affinity cross-linking studies indicated the presence of two major 130- and 70-kilodalton bands that specifically bound to hANP, rAP-1, pBNP, and porcine C-type natriuretic peptide. The binding of natriuretic peptides to BBE cells resulted in an increase in cGMP production and a significant decrease in Na+/K+/Cl- cotransport, without effects on cAMP intracellular accumulation. hANP, rAP-1, and pBNP at 100-nM concentrations, significantly inhibited PTH-induced cAMP production. Treatment with natriuretic hormones was also associated with an increase in 6-keto-prostaglandin F1 alpha levels in the culture medium of BBE cells and a higher cell growth rate. These studies demonstrate that bone endothelial cells bear receptors for natriuretic hormones associated with changes in PTH-induced cAMP production, prostaglandin production, and cell proliferation.
A large multicenter cohort study, the DAI study, is being performed on patients with type 2 diabetes mellitus who are followed by diabetic care units in Italy, to study the prevalence and incidence ...of myocardial infarction, ischemic heart disease, coronary artery bypass, coronary angioplasty, cerebral thromboembolism, and amputations. The reference population consists of all patients visited at the participating units in the period September-December 1998 or March-June 1999. Patients were randomly chosen so as to create a sample representative of the diabetic population visited at the units. Overall, 201 of the approximately 650 Italian diabetic care units participated in the study and 24,094 patients were included in the study. The paper presents the protocol and the characteristics of the DAI study population.
Provider: - Institution: - Data provided by Europeana Collections- This paper describes a database management system created for organising the data which emerged during an investigation conducted by ...a team from the University of Florence in Petra, Jordan. The subject of the research are Crusader settlements in Transjordan and, in particular, the castle system of the Petra valley; the study employed a methodological approach based on so-called “light archaeology”, that is a set of methods typical of European Medieval archaeology like “landscape archaeology” and “standing structure archaeology”. The study, which is still in progress, has revealed the key role of Petra in the territorial organisation of Transjordan during the Crusader period. By focusing on Wu’ayra, the most important fortress of the Petra valley, by means of a series of trial trenches, the project has documented the different settlement stages of the site. It is now apparent that the site was defended by a double wall overhanging the surrounding wadi with a single access and fourteen square towers on the outer ring and the inner walls, and an extreme defence nucleus, the fortified church, inside the cassero, in the centre of the system. Of the nine stages studied so far, three concern the Crusader settlement, one a very short occupation by the Ayyubids, and five correspond to the phase of abandonment of the castle with subsequent occasional use by Bedouin communities. The investigation will eventually evolve into a wide ranging study of the Crusader border, from Antioch to Aqaba. The computer project consists of a database management system, which is based on a Java servlet, a software which uses the HTTP protocol to generate and submit HTML pages “on demand”, and which can be viewed using a common Internet browser. This helps communication and simplifies access to data, which can also be shared on-line. Future developments will include spatial information, based on freely available GIS software. A particular feature of this investigation is the close connection which is maintained between computer technology and archaeological methods, which envisages new forms of co-operation in interdisciplinary research and new skills that draw from both disciplines.- All metadata published by Europeana are available free of restriction under the Creative Commons CC0 1.0 Universal Public Domain Dedication. However, Europeana requests that you actively acknowledge and give attribution to all metadata sources including Europeana
PDF
