Plasmepsin II inhibition and antiplasmodial activity of Primaquine-Statine 'double-drugs'

Statine-based inhibitors of Plasmepsin II (PLMII) coupled with Primaquine have been designed using the 'double-drug' approach. The IC50 values for PLMII inhibition ranged from 0.59 to 400 nM and the best IC50 value for inhibition of Plasmodium falciparum growth in vitro was 0.4 microM, which represent a remarkable improvement compared to other statine-based PLMII inhibitors.     

Inorganic raw materials economy and provenance of chipped industry in some stone age sites of northern and central Italy

An opportunistic and local choice of raw materials is typically attested in the Lower and Middle Paleolithic industries throughout Italy. The quality of the raw material usually affected the flaking technology and quality of the products. In the Upper Paleolithic and the Mesolithic, raw material procurement strategies were more complex. Flint was exploited both locally, in areas where abundant outcrops of raw materials were available (such as the Lessini mountains), and in distant localities, after which it was transported or exchanged over medium/long distances. Different routes of exchange were thus followed in the various periods; good reconstruction of these routes have been provided by a study of the Garfagnana sites in Northern Tuscany, and the Mesolithic deposit of Mondeval de Sora (Dolomites). An interesting example of a Late Upper Paleolithic flint quarry and workshop were found in Abruzzo, in the San Bartolomeo shelter. The extended trade of obsidian from Lipari, Palmarola and Sardinia to the Italian Peninsula is attested in the Neolithic, with some differences concerning the age and different areas.     

Apoptosis induction in DU-145 human prostate carcinoma cells

Due to the recent importance assumed by the apoptotic process as a tool in the therapeutic protocols, we investigated the onset and rate of drug-induced apoptosis in a cell model of prostatic tumor: the DU-145 cells. The human prostatic cancer cells, DU-145, have been treated with pro-apoptotic substances like puromycin (1 microg/ml for 4 and 6 h) and oxygen peroxide (1 mM for 1 h) or exposed to hyperthermic treatment (43 degrees C for 1 h followed by 2 h of recovery). The conventional techniques of preparation and observation of biological samples for electron scanning microscopy were used to estimate the sensitivity of these cells to the pro-apoptotic treatments and to establish their ability to undergo apoptosis. The ultrastructural changes occurring in the different phases of the phenomenon were characterized in parallel with the evaluation of the rate of apoptosis and in parallel with the evaluation of the expression levels of hsp-70 proteins.     

Post-continuous whole body exposure of rabbits to 650 MHz electromagnetic fields: effects on liver, spleen, and brain

This study deals with the effects of post (12 or 18 months) whole body continuous (2 years) exposure of rabbits to 650 MHz electromagnetic fields (EMF) that are characteristic of those produced by broadcasting stations, on body weight and body mass, on the morphology of liver, spleen and brain, and on apoptosis rates and glycogen distribution in the liver. Two groups of rabbits were continuously exposed for 2 years to EMF of 650 MHz followed by 12 months (group 1) or 18 months (group 2) of post-exposure; a third group (group 3) was sham exposed. It was shown that the changes in apoptosis rates were conditional during the time of exposure, but not on a specific organ and that the whole body continuous exposure gave rise to modifications whose types and intensities were related to the time of post-exposure (12 or 18 months, respectively), the type of organ, and the individual animal. A number of effects were observed only in group 1, and not in group 2, which suggests some kind of adaptive response or of long-term recovery in the rabbits following continuous exposure to 650 MHz EMF.     

Adalimumab clinical efficacy is associated with rheumatoid factor and anti-cyclic citrullinated peptide antibody titer reduction: a one-year prospective study

Studies on autoantibody production in patients treated with tumor necrosis factor-α (TNF-α) inhibitors reported contradictory results. We investigated in a prospective study the efficacy of a treatment with human monoclonal anti-TNF-α antibody (adalimumab) in patients with rheumatoid arthritis (RA) and we evaluated the relationship between treatment efficacy and the incidence and titers of disease-associated and non-organ-specific autoantibodies. Fifty-seven patients with RA not responsive to methotrexate and treated with adalimumab were enrolled. Antinuclear, anti-double-stranded(ds)DNA, anti-extractable nuclear antigens, anti-cardiolipin (aCL), anti-β₂ glycoprotein I (anti-β₂GPI) autoantibodies, rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) autoantibodies were investigated at baseline and after 6 and 12 months of follow-up. Comparable parameters were evaluated in a further 55 patients treated with methotrexate only. Treatment with adalimumab induced a significant decrease in RF and anti-CCP serum levels, and the decrease in antibody titers correlated with the clinical response to the therapy. A significant induction of antinuclear autoantibodies (ANA) and IgG/IgM anti-dsDNA autoantibodies were also found in 28% and 14.6% patients, respectively, whereas aCL and anti-β₂GPI autoantibodies were not detected in significant quantities. No association between ANA, anti-dsDNA, aCL and anti-β₂GPI autoantibodies and clinical manifestations was found. Clinical efficacy of adalimumab is associated with the decrease in RF and anti-CCP serum levels that was detected after 24 weeks and remained stable until the 48th week of treatment. Antinuclear and anti-dsDNA autoantibodies, but not anti-phospholipid autoantibodies, can be induced by adalimumab but to a lower extent than in studies with other anti-TNF blocking agents.     

Role of the Multidrug Resistance Protein 1 in protection from heavy metal oxyanions: investigations in vitro and in MRP1-deficient mice

The Multidrug Resistance Protein 1 (MRP1) is a membrane pump that mediates the efflux of a wide variety of xenobiotics, including arsenical and antimonial compounds, as demonstrated by the study of MRP1-transfected cell lines. We have previously shown that mrp1(-/-) cells are hypersensitive to sodium arsenite, sodium arsenate, and antimony potassium tartrate. We now report that the retroviral vector-mediated overexpression of MRP1 and of the two subunits of gamma-GCS (heavy and light) resulted in higher intracellular glutathione levels and in a greater level of resistance to sodium arsenite and antimony potassium tartrate, compared to the overexpression of MRP1 and gamma-GCS heavy alone. These observations further demonstrate that glutathione is an important component of MRP1-mediated cellular resistance to arsenite and antimony. However, the constitutive expression of MRP1 did not protect mice from the lethality of sodium arsenite and antimony potassium tartrate nor reduced the tissue accumulation of arsenic in mice injected i.p. with sodium arsenite. It is conceivable that, in vivo, other pump(s) effectively vicariate for MRP1-mediated transport of heavy metal oxyanions.     

On the characterization of the heterogeneous mechanical response of human brain tissue

The mechanical characterization of brain tissue is a complex task that scientists have tried to accomplish for over 50 years. The results in the literature often differ by orders of magnitude because of the lack of a standard testing protocol. Different testing conditions (including humidity, temperature, strain rate), the methodology adopted, and the variety of the species analysed are all potential sources of discrepancies in the measurements. In this work, we present a rigorous experimental investigation on the mechanical properties of human brain, covering both grey and white matter. The influence of testing conditions is also shown and thoroughly discussed. The material characterization performed is finally adopted to provide inputs to a mathematical formulation suitable for numerical simulations of brain deformation during surgical procedures.     

Involvement of glycosaminoglycans in detachment of early myeloid precusors from bone-marrow stromal cells

Fibroblast-like cells were obtained by in vitro cultivation of needle aspirations of human bone-marrow. These cells show a unique composition of coat-associated glycosaminoglycans: 10% chondroitin 4-sulfate, 30% hyaluronic acid and 60% heparan sulfate which were resolved and characterized by electrophoresis, nitrous acid treatment and enzymatic degradation. Chondroitin 4-sulfate is the only glycoaminoglycan detectable on the surface of mature granulocytes, whereas the immature cells do not seem to possess surface glycoaminoglycans. Immature hemopoietic cells can adhere on to marrow-derived fibroblast cells, whereas mature granulocytes cannot. Treatment with mucopolysaccharidases of both mature leukocytes and marrow stromal cells can interfere in these adhesive relationships, suggesting a role of glycoaminoglycans in regulating short-range interactions during hematopoiesis.