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The gamma-trifluoromethyl gamma-sulfone hydroxamate 1 was synthesized both in racemic and enantiomerically pure forms by means of a thia-Michael reaction of p-methoxythiophenol on achiral and chiral 3,3,3-trifluorocrotonoyl Michael acceptors. The (R)-1 enantiomer was the most potent inhibitor of MMP-3 (stromelysin-1), showing an IC50 = 3.2 nM, as well as the most selective with respect to MMP-9 (65-fold). (c) 2005 Elsevier Ltd. All rights reserved.

The racemic alpha-trifluoromethyl-alpha-amino-beta-sulfone hydroxamates 1 were synthesized by means of a nucleophilic addition of sulfur-stabilized carbanions to a N-Cbz imine of trifluoropyruvate (4). The free amino derivative 1a was the most potent inhibitor of both MMP-3 (stromelysin-1) and MMP-9 (gelatinase-B), showing an IC50 = 14 nM and 1 nM, respectively, and excellent selectivity versus MMP- 1 (>5000-fold difference in inhibitory capacity). The N-Me derivative 1b was the most selective for MMP-3 with respect to MMP-9 (62-fold difference).

Proliferative lesions, known as Von Brunn nests, cystitis cystica and glandularis, and squamous epithelium of vaginal type are not uncommon in the lamina propria of the vesical trigone. The former have been considered reactive to chronic irritants and may represent glandular metaplasia of the transitional epithelium; the latter looks like much more sensitive to hormones. These lesions have been thought to play a role in the pathogenesis of abacteric cystitis: but this has not been confirmed at all by our series of 27 cases. Nevertheless the extension of these lesions should be evaluated with both cystoscopy and biopsies in a large series of sintomatic and asintomatic women.

By interview with several women a dramatic problem for the doctors: how to give doomed patients something more than mere medical help.

Very high ground level concentrations of PM in winter and of ozone in summer often occur in Northern Italy, due to the high anthropogenic emissions and frequent stagnant meteorological conditions that characterize the area. These problems are not only related to urban, but also to suburban areas through the entire Po Valley. In such a situation it is important to use deterministic Chemical Transport Models, that allows to evaluate the effect of different air quality control policies on secondary pollution concentrations. Chemical Transport Models generally are part of more complex deterministic modelling systems, encompassing also emission models, meteorological models, and initial and boundary condition processors. Meteorological models are an important module of deterministic modelling systems and, due to their complexity, require high computational costs to perform simulations. In fact they solve a full set of non-hydrostatic equations that describe atmospheric dynamics and thermodynamics, and conservation equations, usually considering two-way interacting nested domains. Within the HPC-EUROPA (Pan-European Research Infrastructure on High Performance Computing) cooperation project, that allows to use clusters of CPUs all around Europe, the meteorological fields over Northern Italy were simulated using RAMS4.4 in parallel mode, creating a database for future air quality assessments. In the present work a CPUs cluster of the Italian computing centre CINECA have been used. The meteorological simulations have been performed considering three nested grids. The first grid covers an area that encompasses the entire Europe, the second grid is focused on Mediterranean sea, while the third one is limited to the Po Valley area. The spatial resolution of the three grids is respectively 128 km, 32 km and 8 km. The number of cells for the three grids is respectively 40x40, 86x86 and 102x102, with 33 vertical levels covering the domain from surface to roughly 20 km height. The entire 2004 year has been simulated through 72 simulations of 126 hours each, considering a spin-up time of 6 hours and 16 CPUs each simulation. In this paper the model configuration and the validation of the simulated meteorological fields are presented.

The pro-inflammatory cytokine, tumor necrosis factor alpha (TNF alpha), in concert with neurohormones, contributes to chronic heart failure (CHF) progression. This implies that TNF a antagonism may constitute an important target for CHF therapy. However, clinical trials in CHF patients using compounds that trap TNF alpha, comprising infliximab, an antibody directed to TNF alpha, and etanercept, a soluble recombinant receptor of TNF alpha, gave disappointing results bringing back to light the dual, short-term beneficial and long-term harmful effect of TNF alpha. This review focuses on the dual, concentration- and time-related effects of TNF alpha, the yin and yang action of TNF alpha in cardiac ischemia/reperfusion and contraction. Importantly, the harmful effects of TNF a are related to glutathione deficiency, a common hallmark to several other chronic inflammatory diseases. Recently, in rat models of CHF, oral administration of the glutathione precursor, N-acetylcysteine (NAC), was shown to hinder pathways of TNF alpha harmful signalling and to rescue cardiac structure and function. These results suggest that glutathione deficiency in association with TNF alpha activation may play a role in the pathophysiology of CHF and that NAC may represent a potential therapy in CHF.