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Autism spectrum disorder (ASD) has been associated with decreased coherent dot motion (CDM) performance, a task that measures magnocellular sensitivity as well as fronto-parietal attentional integration processing. In order to clarify the role of spatial attention in CDM tasks, we measured the perception of coherently moving dots displayed in the central or peripheral visual field in ASD and typically developing children. A dorsal-stream deficit in children with ASD should predict a generally poorer performance in both conditions. In our study, however, we show that in children with ASD, CDM perception was selectively impaired in the central condition. In addition, in the ASD group, CDM efficiency was correlated to the ability to zoom out the attentional focus. Importantly, autism symptoms severity was related to both the CDM and attentional zooming-out impairment. These findings suggest that a dysfunction in the attentional network might help to explain decreased CDM discrimination as well as the "core" social cognition deficits of ASD.

Platinum(IV) am(m)ine complexes are of interest as potential anticancer pro-drugs, but there are few reports of their acid-base properties. We have studied the acid-base properties of three photoactivatable anticancer platinum(IV)-diazidodiam(m)ine complexes (cis,trans,cis-[Pt(IV)(N(3))(2)(OH)(2)(NH(3))(2)], trans,trans,trans-[Pt(IV)(N(3))(2)(OH)(2)(NH(3))(2)], and cis,trans-[Pt(IV)(N(3))(2)(OH)(2)(en)]) using multinuclear NMR methods and potentiometry. In particular, the combination of both direct and indirect techniques for the detection of (15)N signals has allowed changes of the chemical shifts to be followed over the pH range 1-11; complementary (14)N NMR studies have been also carried out. A distinct pK(a) value of approximately 3.4 was determined for all the investigated complexes, involving protonation/deprotonation reactions of one of the axial hydroxido groups, whereas a second pH-dependent change for the three complexes at approximately pH 7.5 appears not to be associated with a loss of an am(m)ine or hydroxido proton from the complex. Our findings are discussed in comparison with the limited data available in the literature on related complexes., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Gold(III)-dithiocarbamato complexes have recently gained increasing attention as potential anticancer agents because of their strong tumor cell growth--inhibitory effects, generally achieved by exploiting non-cisplatin-like mechanisms of action. The rationale of our research work is to combine the antitumor properties of the gold(III) metal center with the potential chemoprotective function of coordinated dithiocarbamates in order to reduce toxic side effects (in particular nephrotoxicity) induced by clinically established platinum-based drugs. In this context, [Au(III) Br(2) (ESDT)] (AUL12) was proved to exert promising and outstanding antitumor activity in vitro and to overcome both acquired and intrinsic resistance showed by some types of tumors toward cisplatin. As a subsequent extension of our previous work, we here report on detailed in vivo studies in rodents, including antitumor activity toward three transplantable murine tumor models, toxicity, nephrotoxicity and histopathological investigations. Remarkably, the gold(III) complex AUL12 stands out for higher anticancer activity than cisplatin toward all the murine tumor models examined, inducing up to 80% inhibition of tumor growth. In addition, it shows low acute toxicity levels (lethal dose, LD(50) = 30 mg kg(-1) ) and reduced nephrotoxicity. Altogether, these results confirm the reliability of our drug design strategy and support the validation of this gold(III)-dithiocarbamato derivative as a suitable candidate for clinical trials., (Copyright © 2010 UICC.)

The photodecomposition of the anticancer complex trans,trans,trans-[Pt(N(3))(2)(OH)(2)(NH(3))(2)] in acidic aqueous solution, as well as in phosphate-buffered saline (PBS), induced by UVA light (centred at λ = 365 nm) has been studied by multinuclear NMR spectroscopy. We show that the photoreaction pathway in PBS, which involves azide release, differs from that in acidic aqueous conditions, under which N(2) is a major product. In both cases, a number of trans-{N-Pt(II/IV)-NH(3)} species were also observed as photoproducts, as well as the evolution of O(2) and release of free ammonia with a subsequent increase in pH. The results from this study illustrate that photoinduced reactions of Pt(IV)-diazido derivatives can lead to novel reaction pathways, and therefore potentially to new cytotoxic mechanisms in cancer cells.

Among the nonplatinum antitumor drugs, gold(III)-dithiocarbamato derivatives have recently attracted considerable attention due to their strong in vitro and in vivo antiproliferative activity and reduced renal toxicity. Some of them, namely [AuCl(2) (DMDT)] (compound 1) and [AuBr(2) (ESDT)] (compound 2), have shown to be highly active against the androgen-resistant prostate cancer cell lines PC3 and DU145, both inhibiting cell proliferation in a dose-dependent way, and are more active than the reference drug cisplatin (cis-[PtCl(2) (NH(3) )(2) ]). In particular, [AuCl(2) (DMDT)] was proved cytotoxic against cisplatin-resistant R-PC3 cells, with activity levels comparable to those induced on the parent cisplatin-sensitive PC3 cells, ruling out the occurrence of cross-resistance phenomena. Moreover, it causes early cell damage, slightly affecting the cell cycle, thus suggesting a different mechanism of action from clinically established platinum-based drugs. In fact, the investigated gold(III) complex alters mitochondrial functions, promoting mitochondrial membrane permeabilization and Cyt-c release, stimulating ROS generation, and strongly inhibiting the activity of the selenoenzyme TrxR, which is overexpressed in prostate cancer and associated with the onset of drug resistance. In addition, it induces apoptosis, caspase activation, Bcl-2 downregulation and Bax upregulation, reduces the expression of the phosphorylated form of the EGFR, and it inhibits PC3 cell migration. Finally, the treatment of PC3 prostate tumor-bearing nude mice with [AuCl(2) (DMDT)] significantly inhibited tumor growth in vivo, causing minimal systemic toxicity. Altogether, our results confirm that these gold(III)-dithiocarbamato derivatives have potential for the treatment of prostate cancer., (Copyright © 2010 UICC.)

Since ancient times, many cultures worldwide found out independently that the topical administration of some photoactive natural products (mainly extracted from plants) followed by exposure to sunlight, might be an effective treatment of some skin diseases, thus accidently giving birth to the so-called photochemotherapy. In the attempt to resemble nature by exploiting its teaching, during the last two centuries, scientists tried to rationalize this knowledge in order to develop more effective therapeutic strategies and to understand in depth the mechanisms of action involved, expanding the potential application of this therapy to pathologies other than skin diseases, such as some types of tumors. In this paper we aim at giving an overview on results achieved to date on state-of-the-art photochemotherapy related to the treatment of cancer. The script is organized in three sections. Subsequent to a general introduction describing the origin and basic principles of photochemotherapy, the first section deals with the issue concerning the choice of the proper light sources for each type of therapeutic application, stressing the technological advances in the field (e.g. fiber optics). The second and the third sections provide an overview of the two clinically-established phototherapies to date, that is, PUVA photochemotherapy and PDT, respectively. Both sections are further subdivided into sub-paragraphs emphasizing specific relate topics such as principles and applications, employed light sources, and available data concerning anticancer activity. The third section also provides examples of non-conventional metal-based photosensitizers for PDT.

In this review paper we aim at giving a detailed overview on our research work devoted to the design of gold-based anticancer agents. In particular, during the last decade, we have been developing some gold(III)-dithiocarbamato derivates showing outstanding in vitro and in vivo antitumor properties and reduced, or even no, systemic and renal toxicity, compared to the reference clinically-established anticancer drug cisplatin. Starting from the rationale behind our investigations, we here summarize the results achieved so far, focusing on the latest in-depth mechanistic studies that have recently provided insights into their mechanism of action, thus opening up new prospects for further pharmacological testing and, hopefully, to enter clinical trials.

We have previously reported on a gold(III) complex, namely [AuBr(2)(DMDT)] (N,N-dimethyldithiocarbamate) showing potent in vitro and in vivo growth inhibitory activities toward human cancer cells and identifying the cellular proteasome as one of the major targets. However, the importance of the oxidation state of the gold center and the involved mechanism of action has yet to be established. Here we show that both gold(III)- and gold(I)-dithiocarbamato species, namely [AuBr(2)(ESDT)] (AUL12) and [Au(ESDT)](2) (AUL15), could inhibit the chymotrypsin-like activity of purified 20S proteasome and 26S proteasome in human breast cancer MDA-MB-231 cells, resulting in accumulation of ubiquitinated proteins and proteasome target proteins, and induction of cell death, but at significantly different levels. Gold(I)- and gold(III)-compound-mediated proteasome inhibition and cell death induction were completely reversed by the addition of a reducing agent, dithiothreitol or N-acetyl-L-cysteine, suggesting the involvement of redox processes. Furthermore, treatment of MDA-MB-231 cells with gold(III) compound (AUL12), but not the gold(I) analog (AUL15), resulted in the production of significant levels of reactive oxygen species. Our study provides strong evidence that the cellular proteasome is an important target of both gold(I) and gold(III)-dithiocarbamates, but distinct cellular mechanisms of action are responsible for their different overall effect.

Titanium (Ti) is widely used in dentistry. Fluorides at acid pH could destabilize Ti oxide and make it susceptible to corrosion. The behaviour of IV grade machined Ti disks in 5 electrolytic solutions: Fusayama artificial saliva (Fas), ammine fluoride-stannous fluoride (Am-SnF2), 0.2 percent Chlorexidine (CHX) 0.20 percent, Fas with 20 percent Am-SnF2, and Fas with 20 percent CHX, was evaluated. Open circuit potential Ecorr was determined by immersing Ti disks for 24 hours in an electrochemical cell containing the solutions, potential changes were measured until a stable value was obtained. Examination by Scanning Electronic Microscope and Energy Dispersive X-ray Analysis were then performed. One way ANOVA analysis showed a significant difference of Ecorr values regarding the 5 solutions (p less than 0.001). The highest values were observed for Fas (-37.6 mV), intermediate for Am-SnF2 (-81mV) and lowest for CHX (-87.6mV). SEM analysis of disks after polarization curve in CHX showed a marked localized corrosion, while the other solutions showed no considerable corrosive action on Ti surface. When considering corrosive potential range in oral cavity, Ti had an excellent behaviour on both antiseptics evaluated. The results obtained in this study will enable us to recommend the use of Am-SnF2 mouthwash for patients with dental implants.

The unquestionable therapeutic success of the anticancer drug cisplatin and its second- and third-generation analogues has triggered, in the past forty years, the development of several metal-based potential chemotherapeutic agents, most of which have failed to enter clinical trials. In this context, during the last decade, our research group has been making quite an effort to design a number of metal-dithiocarbamato derivatives that were expected, at least in principle, to resemble the main features of cisplatin together with higher activity, improved selectivity and bioavailability, and lower side-effects. Among all, gold(III) complexes have shown outstanding in vitro and in vivo antitumour properties and reduced or no systemic and renal toxicity, compared to the reference drug. Here, we summarize the results achieved to date, focusing on the mechanistic studies and the potential future developments opened up by our research work.

The photodecomposition of cis,trans,cis-[Pt(IV)(N(3))(2)(OH)(2)(NH(3))(2)] in phosphate buffered saline (PBS), as well as in the presence of 1-methylimidazole (1-MeIm), induced by UVA light (centred at lambda=365 nm) has been studied by multinuclear NMR spectroscopy. We show that photoreduction, photoisomerisation and trans-labilisation pathways are involved. The photodecomposition pathway in PBS, which involves azide release, as detected by (14)N NMR spectroscopy, appears to differ from that in acidic aqueous conditions, under which N(2) is a product. A number of trans-{N-Pt(II)-NH(3)} species were also observed as photoproducts, as well as the release of free ammonia with a corresponding increase in pH. Oxygen was also detected as a product in solution. In the presence of 1-methylimidazole, surprisingly the major photoproduct was the tetra-substituted Pt(II) complex [Pt(II)(1-MeIm-N(3))(4)](2+) (structure confirmed by crystallography), even at a Pt/1-MeIm molar ratio of 1:1, together with cis- and trans-[Pt(II)(NH(3))(2)(1-MeIm-N(3))(2)](2+) as minor products. In these photoinduced 1-MeIm reactions, free ammonia, azide and oxygen were also detected. The results from this study illustrate that photoinduced reactions of platinum complexes can lead to novel reaction pathways, and therefore to new cytotoxic mechanisms in cancer cells.

There is a wide range of potential applications of inorganic compounds, and metal coordination complexes in particular, in medicine but progress is hampered by a lack of methods to study their speciation. The biological activity of metal complexes is determined by the metal itself, its oxidation state, the types and number of coordinated ligands and their strength of binding, the geometry of the complex, redox potential and ligand exchange rates. For organic drugs a variety of readily observed spin I  = 1/2 nuclei can be used ( 1 H, 13 C, 15 N, 19 F, 31 P), but only a few metals fall into this category. Most are quadrupolar nuclei giving rise to broad lines with low detection sensitivity (for biological systems). However we show that, in some cases, heteronuclear NMR studies can provide new insights into the biological and medicinal chemistry of a range of elements and these data will stimulate further advances in this area., (Copyright © 2008 Elsevier B.V. All rights reserved.)

Aim: Patients with dental implants need optimal plaque control. Peri-implantitis is an inflammation of soft and hard tissues around implants characterized by bone loss mediated by proinflammatory molecules such as IL-1beta, PGE(2), vascular endothelial growth factor (VEGF). The aim of this study was to evaluate the influence of amine fluoride/stannous fluoride (AmF-SnF(2)) vs chlorhexidine 0.12% (CHX) combined with Am-SnF(2) on IL-1beta, PGE(2) and EGF secretion by cells of crevicular peri-implant fluid., Methods: Thirty patients with dental implants were included in this study. The test group used AmF-SnF(2) rinsing for 14 days, the control group used CHX rinsing during the first 7 days and AmF-SnF(2) during the following 7 days. Crevicular samples were collected using filter paper strips and assayed for level of IL-1beta, PGE(2) and VEGF with ELISA test. Data were analyzed with paired and unpaired t test., Results: IL-1beta, VEGF and PGE(2) levels were significantly lower in test compared to control group. Comparing first with second week of treatment, a greater decrease of IL-1beta and VEGF was evident in sample group during the second week. There was a lower decrease of IL-1beta and VEGF during the entire treatment in control group. Differences of PGE(2) levels after 7 days in both the groups were not significant while there was a significant difference during the second week., Conclusion: The following data suggest that the use of AmF-SnF(2) could decrease the production of IL-1beta, PGE(2) and VEGF by inflammatory cells.AmF-SnF(2) could be an alternative to CHX mouth rinses in plaque control of patients with implants.

UVA-induced photodecomposition of a Pt(IV)-diazido complex involves not only reduction to Pt(II) and N(2) release, but also O(2) evolution and formation of nitrene intermediates, whose trapping with (CH(3))(2)S gives rise to an unusual N,N'-bis(ethyl)sulfurousdiamide ligand in an apparently unprecedented process involving C-C bond formation.

Although gold compounds are now recognized as promising anticancer agents, so far only gold(I) derivatives have been investigated for this purpose, whereas the use of gold(III) complexes has been hampered by their poor stability under physiological conditions. We have therefore carried out studies on selected gold(III) anticancer agents, showing enhanced stability due to the presence of chelating dithiocarbamato ligands. We found that they induce cancer cell death through both apoptotic and nonapoptotic mechanisms. They also inhibit thioredoxin reductase activity, generate free radicals, modify some mitochondrial functions, and increase ERK1/2 phosphorylation. Based on our results, we propose and discuss a working model suggesting that deregulation of the thioredoxin reductase/thioredoxin redox system is a major mechanism involved in the anticancer activity of the investigated gold(III)-dithiocarbamato complexes.

Although cisplatin has been used for decades to treat human cancer, some toxic side effects and resistance are observed. It has been suggested that gold(III) complexes, containing metal centers isoelectronic and isostructural to cisplatin, are promising anticancer drugs. Gold(III) dithiocarbamate complexes were shown to exhibit in vitro cytotoxicity, comparable with and even greater than cisplatin; however, the involved mechanism of action remained unknown. Because we previously reported that copper(II) dithiocarbamates are potent proteasome inhibitors, we hypothesized that gold(III) dithiocarbamate complexes could suppress tumor growth via direct inhibition of the proteasome activity. Here, for the first time, we report that a synthetic gold(III) dithiocarbamate (compound 2) potently inhibits the activity of a purified rabbit 20S proteasome and 26S proteasome in intact highly metastatic MDA-MB-231 breast cancer cells, resulting in the accumulation of ubiquitinated proteins and the proteasome target protein p27 and induction of apoptosis. The compound 2-mediated proteasome inhibition and apoptosis induction were completely blocked by addition of a reducing agent DTT or N-acetyl-L-cysteine, showing that process of oxidation is required for proteasome inhibition by compound 2. Treatment of MDA-MB-231 breast tumor-bearing nude mice with compound 2 resulted in significant inhibition of tumor growth, associated with proteasome inhibition and massive apoptosis induction in vivo. Our findings reveal the proteasome as a primary target for gold(III) dithiocarbamates and support the idea for their potential use as anticancer therapeutics.

Objective: To identify coping strategies used by patients with systemic lupus erythematosus (SLE), and to assess the influence of main clinical and coping variables on health-related quality of life (HRQOL)., Methods: We administered the Coping Orientation to Problems Experienced and the Short Form 36 questionnaire to a group of 144 patients with SLE and a group of 129 healthy controls. At the time of the psychological assessment, all patients underwent a complete clinical and laboratory evaluation., Results: SLE patients had higher scores in acceptance (P < 0.001) and turning to religion (P = 0.05) and lower scores in planning (P = 0.001), suppression of competing activities (P = 0.010), restraint coping (P = 0.031), focusing on and venting of emotion (P = 0.009), and strategies focused on problem (P = 0.012) compared with controls. By means of linear regression analysis, HRQOL in SLE patients seemed to be influenced positively by restraint coping and positive reinterpretation and growth, and negatively by focusing on and venting of emotion, behavioral disengagement, and mental disengagement. When clinical variables were added to the multivariate analysis for coping strategies, more significant regression models that included joint pain were obtained., Conclusion: In facing stressful situations, patients with SLE tend to use coping skills that are generally adopted for events perceived as nonmodifiable. Strategies that show a passive attitude and joint pain seem to impair these patients' HRQOL.

Gold(III) compounds are emerging as a new class of metal complexes with outstanding cytotoxic properties and are presently being evaluated as potential antitumor agents. We report here on the solution and electrochemical properties, and the biological behavior of some gold(III) dithiocarbamate derivatives which have been recently proved to be one to 4 orders of magnitude more cytotoxic in vitro than the reference drug (cisplatin) and to be able to overcome to a large extent both intrinsic and acquired resistance to cisplatin itself. Their solution properties have been monitored in order to study their stability under physiological conditions; remarkably, they have shown to undergo complete hydrolysis within 1 h, the metal center remaining in the +3 oxidation state. Their DNA binding properties and ability in hemolyzing red blood cells have been also evaluated. These gold(III) complexes show high reactivity toward some biologically important isolated macromolecules, resulting in a dramatic inhibition of both DNA and RNA synthesis and inducing DNA lesions with a faster kinetics than cisplatin. Nevertheless, they also induce a strong and fast hemolytic effect (compared to cisplatin), suggesting that intracellular DNA might not represent their primary or exclusive biological target.

At present, cisplatin (cis-diamminodichloroplatinum(II)) is one of the most largely employed anticancer drugs as it is effective in the treatment of 70-90% of testicular and, in combination with other drugs, of ovarian, small cell lung, bladder, brain, and breast tumors. Anyway, despite its high effectiveness, it exhibits some clinical problems related to its use in the curative therapy, such as a severe normal tissue toxicity (in particular, nephrotoxicity) and the frequent occurrence of initial and acquired resistance to the treatment. To obtain compounds with superior chemotherapeutic index in terms of increased bioavailability, higher cytotoxicity, and lower side effects than cisplatin, we report here on some gold(I) and gold(III) complexes with dithiocarbamate ligands (DMDT = N,N-dimethyldithiocarbamate; DMDTM = S-methyl-N,N-dimethyldithiocarbamate; ESDT = ethylsarcosinedithiocarbamate), which have been synthesized, purified, and characterized by means of elemental analyses, conductivity measurements, mono- and bidimensional NMR, FT-IR, and UV-vis spectroscopy, and thermal analyses. Moreover, the electrochemical properties of the designed compounds have been studied through cyclic voltammetry. All the synthesized gold complexes have been tested for their in vitro cytotoxic activity. Remarkably, most of them, in particular gold(III) derivatives of N,N-dimethyldithiocarbamate and ethylsarcosinedithiocarbamate, have been proved to be much more cytotoxic in vitro than cisplatin, with IC50 values about 1- to 4-fold lower than that of the reference drug, even toward human tumor cell lines intrinsically resistant to cisplatin itself. Moreover, they appeared to be much more cytotoxic also on the cisplatin-resistant cell lines, with activity levels comparable to those on the corresponding cisplatin-sensitive cell lines, ruling out the occurrence of cross-resistance phenomena and supporting the hypothesis of a different antitumor activity mechanism of action.

Aim: The aim of this study was to evaluate the behaviour of titanium (Ti) in precipitant condition, and more precisely the resistance against corrosion of Ti in presence of fluorides and the electrochemical interaction between Ti- amalgam couples in fluorinated solution., Methods: The experimental test was made with the use of an electrochemical cell. The following materials were tested: commercially pure Ti and 2 types of amalgams, the Persistalloy (Prs) and the IQC. Palladium (IQC.P). The free corrosion potential of Ti and the amalgams, the polarization curves of both amalgams and the corrosion current of the Ti-amalgam couples in the measurements were performed in 3 different electrolytic solutions: Ringer solution, fluorinated neutral Ringer solution and acid fluorinated solution. The three corrosive media are described., Results: The results showed that Ti could be damaged by the presence of fluorides with an acid pH: Ti potential becomes more negative in acid fluorinated solution. The corrosion currents between Ti and amalgam couples were considered: the amalgams underwent anodic oxidation in neutral Ringer, but a reversal phenomenon occurred in the fluorinated acid solution: Ti was damaged and the amalgams both Prs and IQC.P became the cathodic partner of the couple. In neutral fluorinated solution the IQC.P amalgam induced a significantly higher corrosion of Ti, when compared to the Prs one., Conclusion: Results clearly show the dependence of the Ti corrosion behaviour on the pH and composition of the solution and that the outcome of the damage is affected by the composition of other metals.