Morphological and Chemical Mechanisms of Elongated Mineral Particle Toxicities

Much of our understanding regarding the mechanisms for induction of disease following inhalation of respirable elongated mineral particles (REMP) is based on studies involving the biological effects of asbestos fibers. The factors governing the disease potential of an exposure include duration and frequency of exposures; tissue-specific dose over time; impacts on dose persistence from in vivo REMP dissolution, comminution, and clearance; individual susceptibility; and the mineral type and surface characteristics. The mechanisms associated with asbestos particle toxicity involve two facets for each particle's contribution: (1) the physical features of the inhaled REMP, which include width, length, aspect ratio, and effective surface area available for cell contact; and (2) the surface chemical composition and reactivity of the individual fiber/elongated particle. Studies in cell-free systems and with cultured cells suggest an important way in which REMP from asbestos damage cellular molecules or influence cellular processes. This may involve an unfortunate combination of the ability of REMP to chemically generate potentially damaging reactive oxygen species, through surface iron, and the interaction of the unique surfaces with cell membranes to trigger membrane receptor activation. Together these events appear to lead to a cascade of cellular events, including the production of damaging reactive nitrogen species, which may contribute to the disease process. Thus, there is a need to be more cognizant of the potential impact that the total surface area of REMP contributes to the generation of events resulting in pathological changes in biological systems. The information presented has applicability to inhaled dusts, in general, and specifically to respirable elongated mineral particles

Degradation of Internalized αvβ5 Integrin Is Controlled by uPAR Bound uPA: Effect on β1 Integrin Activity and α-SMA Stress Fiber Assembly

Myofibroblasts (Mfs) that persist in a healing wound promote extracellular matrix (ECM) accumulation and excessive tissue contraction. Increased levels of integrin αvβ5 promote the Mf phenotype and other fibrotic markers. Previously we reported that maintaining uPA (urokinase plasminogen activator) bound to its cell-surface receptor, uPAR prevented TGFβ-induced Mf differentiation. We now demonstrate that uPA/uPAR controls integrin β5 protein levels and in turn, the Mf phenotype. When cell-surface uPA was increased, integrin β5 levels were reduced (61%). In contrast, when uPA/uPAR was silenced, integrin β5 total and cell-surface levels were increased (2–4 fold). Integrin β5 accumulation resulted from a significant decrease in β5 ubiquitination leading to a decrease in the degradation rate of internalized β5. uPA-silencing also induced α-SMA stress fiber organization in cells that were seeded on collagen, increased cell area (1.7 fold), and increased integrin β1 binding to the collagen matrix, with reduced activation of β1. Elevated cell-surface integrin β5 was necessary for these changes after uPA-silencing since blocking αvβ5 function reversed these effects. Our data support a novel mechanism by which downregulation of uPA/uPAR results in increased integrin αvβ5 cell-surface protein levels that regulate the activity of β1 integrins, promoting characteristics of the persistent Mf

Association of kidney disease measures with risk of renal function worsening in patients with type 1 diabetes

Background: Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage 653 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage 653 CKD in a large cohort of patients affected by T1DM. Methods: A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage 653 CKD (eGFR < 60 mL/min/1.73 m2) or eGFR reduction > 30% from baseline was evaluated. Results: The mean estimated GFR was 98 \ub1 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR < 90 ml/min/m2 were independent risk factors for stage 653 CKD and renal function worsening. When compared to patients with eGFR > 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions: Albuminuria and eGFR reduction represent independent risk factors for incident stage 653 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening

Air embolism: diagnosis with single-photon emission tomography and successful hyperbaric oxygen therapy

Venous air embolism may occur when the surgical ®eld is above the level of the heart. We present a case of venous air embolism in a patient undergoing percutaneous nephrolithotripsy in the prone position and presenting with blindness and neurological de®cits 8 h later. The clinical diagnosis of paradoxical air embolism was con®rmed by early single-photon emission tomography (SPET), whereas magnetic resonance imaging including diffusion-weighted imaging (DWMRI) was diagnostic only 30 h later. Hyperbaric oxygen therapy was successful. In this case, early DW-MRI scan was inconclusive, but a SPET study of the brain appeared to be useful in con®rming the clinical diagnosis. Early hyperbaric oxygen was demonstrated to be a successful therapy

Tipicit\ue0 e atipicit\ue0 nei contratti pubblici

Gli scritti pubblicati in questo volume costituiscono la trasposizione delle relazioni, opportunamente rivisitate e per lo pi\uf9 arricchite di ogni necessario riferimento dottrinale e giurisprudenziale, tenute nell\u2019ambito del Convegno organizzato il 6 febbraio 2006 dal Centro Ricerca e Formazione sugli Appalti Pubblici della Spisa. Il tema della tipicit\ue0-atipicit\ue0 dei contratti pubblici costituisce da sempre uno dei nodi essenziali da sciogliere, se si vuole predicare una effettiva autonomia negoziale della Pubblica Amministrazione; in mancanza di ci\uf2 la pur conclamata capacit\ue0 di diritto privato risulterebbe lettera morta e uno dei tanti proclami diretti a soddisfare la politica del momento, ma non ad identificare strumenti dell\u2019azione idonei a valorizzarla in termini di efficienza, efficacia ed economicit\ue0. Ne \ue8 derivata, grazie alle qualit\ue0 scientifiche e professionali dei relatori, una riflessione approfondita, che si segnala, anche per la sistematicit\ue0 degli argomenti trattati, all\u2019attenzione degli studiosi

Balloon-borne measurements of the atmospheric emission near 94 GHz

We report on a balloon-borne experiment to measure high altitude atmospheric emission in the 90 GHz spectral window. The experiment was carried out with a monolithic microwave integrated circuit (MMIC) Dicke-switched radiometer based on high electron mobility transistor (HEMT) low noise amplifiers. The instrument broad bandpass (87-101 GHz) includes strong ozone lines. The atmospheric emission profile was measured from 6 to 15 km altitude. In addition, zenith-scan measurements at about 38 km altitude have been obtained, yielding an atmospheric antenna temperature T-A,T-atm = 15+/-6 mK. The results are in good agreement with model predictions which take into account the contribution of O-3, spectral lines. Ozone emission contributes significantly to the signal of balloon-borne Cosmic Microwave Background experiments unless the instrument bands are carefully selected. (C) 1998 Elsevier Science Ltd. All rights reserved