Urinary volatile Organic compounds in non-alcoholic fatty liver disease (NAFLD), type two diabetes mellitus (T2DM) and NAFLD-T2DM coexistence.

INTRODUCTION: Accumulating evidence have shown a significant correlation between urinary volatile organic compounds (VOCs) profile and the manifestation of several physiological and pathological states, including liver diseases. Previous studies have investigated the urinary metabolic signature as a non-invasive tool for the early discrimination between non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), which nowadays represents one of the most important challenges in this context, feasible only by carrying out liver biopsy. OBJECTIVES: The aim of the study was to investigate the differences in the urinary VOCs profiles of non-alcoholic fatty liver disease (NAFLD) patients, diabetes mellitus (T2DM) subjects and NAFLD/T2DM patients. METHODS: Headspace solid-phase microextraction (HS-SPME) coupled with gas chromatography-mass spectrometry (GC-MS) was applied to profile the urinary VOCs. Urine samples were analysed both under acid and alkaline conditions, to obtain a range of urinary volatiles with different physicochemical properties. RESULTS: Urinary VOCs profiles of 13 NAFLD patients, 13 T2DM subjects and 13 NAFLD/T2DM patients were investigated by multivariate and univariate data analysis techniques which allowed to identify 21 volatiles under alkaline conditions able to describe the NAFLD/T2DM group concerning the other two groups. CONCLUSION: Our results suggest that VOCs signatures can improve the knowledge of the pathological condition where NAFLD coexists with T2DM and discovering new features that are not simply the sum of the two diseases. These preliminary findings may be considered as hypothesis-generating, to be clearly confirmed by larger prospective investigations.

The prognostic impact of the extent of ulceration in patients with clinical stage I-II melanoma: a multicentre study of the Italian Melanoma Intergroup (IMI).

BACKGROUND: The presence of ulceration has been recognized as an adverse prognostic factor in primary cutaneous melanoma (PCM). OBJECTIVES: To investigate whether the extent of ulceration (EoU) predicts relapse-free survival (RFS) and overall survival (OS) in PCM. MATERIALS AND METHODS: We retrieved data for 477 patients with ulcerated PCM from databases of the Italian Melanoma Intergroup. Univariate and multivariable Cox proportional hazard models were used to assess the independent prognostic impact of EoU. RESULTS: A significant interaction emerged between Breslow thickness (BT) and EoU, considering both RFS (P < 0·0001) and OS (P = 0·0006). At multivariable analysis, a significant negative impact of EoU on RFS [hazard ratio (HR) (1-mm increase) 1·26, 95% confidence interval (CI) 1·08-1·48, P = 0·0047] and OS [HR (1-mm increase) 1·25, 95% CI 1·05-1·48, P = 0·0120] was found in patients with BT ≤ 2 mm, after adjusting for BT, age, tumour-infiltrating lymphocytes, sentinel lymph node status and mitotic rate. No impact of EoU was found in patients with 2·01-4 mm and > 4 mm BT. CONCLUSIONS: This study demonstrates that EoU has an independent prognostic impact in PCM and should be recorded as a required element in pathology reports.

Association between anthropometric markers and asthma control, quality of life and pulmonary function in adults with asthma.

BACKGROUND: The role of abdominal fat and body fat (BF) in the evaluation of nutritional status in asthma has been considered recently. The present study aimed to evaluate the association between different anthropometric markers and asthma control, pulmonary function and quality of life. A secondary objective was to determine the agreement between the anthropometric markers with respect to assessing obesity in adults with asthma. METHODS: This cross-sectional study enrolled adult asthma patients attending an outpatient asthma clinic in southern Brazil. Patients were evaluated regarding sociodemographic data, lung function, asthma control, nutritional status and health-related quality of life (Asthma Quality of Life Questionnaire; AQLQ). Nutritional status was classified by body mass index (BMI), waist circumference (WC) and BF. RESULTS: The mean (SD) age of the 198 patients was 56.2 (14.8) years. The prevalence of uncontrolled asthma among subjects who were overweight as diagnosed by their BMI was 64.6% higher than in those who were normal weight. An increase in a measure of BMI (1 kg m-2 ) decreases approximately 44-59% of symptoms, activity limitations and emotional function domains of the AQLQ, whereas an increase in a measure in WC (1 cm) decreases approximately 24-30% of the same domains. Agreement between BMI and BF was 0.566 and that between BMI and WC was 0.597 by Kendall's Tau-b test. CONCLUSIONS: The prevalence of uncontrolled asthma is greater in overweight subjects than in normal weight subjects. WC and BMI were negatively associated with symptoms, activity limitations and emotional function domains of the AQLQ. BMI appears to be sufficient to diagnose the nutritional status of subjects with asthma in this population.

In vitro efficacy of ARQ 092, an allosteric AKT inhibitor, on primary fibroblast cells derived from patients with PIK3CA-related overgrowth spectrum (PROS).

Postzygotic mutations of the PIK3CA [phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha] gene constitutively activate the PI3K/AKT/mTOR pathway in PIK3CA-related overgrowth spectrum (PROS) patients, causing congenital mosaic tissue overgrowth that even multiple surgeries cannot solve. mTOR inhibitors are empirically tested and given for compassionate use in these patients. PROS patients could be ideal candidates for enrolment in trials with PI3K/AKT pathway inhibitors, considering the "clean" cellular setting in which a unique driver, a PIK3CA mutation, is present. We aimed to assess the effects of blocking the upstream pathway of mTOR on PROS patient-derived cells by using ARQ 092, a potent, selective, allosteric, and experimental orally bioavailable and highly selective AKT-inhibitor with activity and long-term tolerability, currently under clinical development for treatment of cancer and Proteus syndrome. Cell samples (i.e., primary fibroblasts) were derived from cultured tissues obtained from six PROS patients [3 boys, 3 girls; aged 2 to 17 years] whose spectrum of PIK3A-related overgrowth included HHML [hemihyperplasia multiple lipomatosis; n = 1], CLOVES [congenital lipomatosis, overgrowth, vascular malformations, epidermal nevi, spinal/skeletal anomalies, scoliosis; n = 1], and MCAP [megalencephaly capillary malformation syndrome; n = 4]. We performed the following: (a) a deep sequencing assay of PI3K/AKT pathway genes in the six PROS patients' derived cells to identify the causative mutations and (b) a pathway analysis to assess the phosphorylation status of AKT [Ser473 and Thr308] and its downstream targets [pAKTS1 (Thr246), pRPS6 (Ser235/236), and pRPS6Kß1 (Ser371)]. The anti-proliferative effect of ARQ 092 was tested and compared to other PI3K/AKT/mTOR inhibitors [i.e., wortmannin, LY249002, and rapamycin] in the six PROS patient-derived cells. Using ARQ 092 to target AKT, a critical node connecting PI3K and mTOR pathways, we observed the following: (1) strong anti-proliferative activity [ARQ 092 at 0.5, 1, and 2.5 µM blunted phosphorylation of AKT and its downstream targets (in the presence or absence of serum) and inhibited proliferation after 72 h; rapamycin at 100 nM did not decrease AKT phosphorylation] and (2) less cytotoxicity as compared to rapamycin and wortmannin. We demonstrated the following: (a) that PROS cells are dependent on AKT; (b) the advantage of inhibiting the pathway immediately downstream of PI3K to circumventing problems depending on multiple classes a PI3K kinases; and (c) that PROS patients benefit from inhibition of AKT rather than mTOR. Clinical development of ARQ 092 in PROS patients is on going in these patients.

Neurotrophin-mimicking peptides at the biointerface with gold respond to copper ion stimuli.

The peptide fragments NGF1-14 and BDNF1-12, encompassing the N-terminal domains, respectively, of the proteins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were used in this study for the fabrication of a hybrid gold/peptide biointerface. These peptides mimic the Trk receptor activation of the respective whole protein - with a crucial role played by copper ions - and exhibit, in bulk solution, a pH-dependent capability to complex copper. We demonstrate here the maintenance of peptide-specific responses at different pH values as well as the copper binding also for the adlayers formed upon physisorption at the gold surface. The physicochemical properties, including viscoelastic behavior of the adlayer and competitive vs. synergic interactions in sequential adsorption processes, were addressed both experimentally, by quartz crystal microbalance with dissipation monitoring (QCM-D) and circular dichroism (CD), and theoretically, by molecular dynamics (MD) calculations. Proof-of work biological assays with the neuroblastoma SY-SH5H cell line demonstrated that the developed hybrid Au/peptide nanoplatforms are very promising for implementation in pH- and metal-responsive systems for application in nanomedicine.

Short communication: ultrasonographic assessment of the thorax as a fast technique to assess pulmonary lesions in dairy calves with bovine respiratory disease.

The aim of this study was to assess inter- and intraoperator agreement when assessing lung consolidation secondary to bovine respiratory disease (BRD) by thoracic ultrasonography. Ten calves were blindly assessed by 3 operators with varying expertise in thoracic ultrasound to look for lung consolidation and the presence of comet-tail artifacts (COMT). Systematic ultrasonography of the thorax was performed using an 18-site per side assessment with a linear 8.5-MHz probe. The status of the calves [healthy (n=4) vs. treated for BRD (n=6)] was not known by the operators. The interoperator kappa agreement for detecting consolidation was moderate to almost perfect (from 0.6 to 1.0) depending on the operator's experience (diagnosis of consolidation if depth ≥1cm). The intraclass correlation coefficient for consistency was 0.71 for a single measurement and 0.88 for average measurement. The intraclass correlation coefficient for agreement was 0.73 for single measurements and 0.89 for average measurements. These values were considered good for single measurements and excellent for average measurements. Systematic ultrasonography of the thorax can be used routinely to assess lung consolidation in dairy calves and can therefore be of importance, especially for assessment of subclinical BRD.

Increased frequency of 20q gain and copy-neutral loss of heterozygosity in mismatch repair proficient familial colorectal carcinomas.

Many hereditary nonpolyposis colorectal cancers (CRCs) cannot be explained by Lynch syndrome. Other high penetrance genetic risk factors are likely to play a role in these mismatch repair (MMR)-proficient CRC families. Because genomic profiles of CRC tend to vary with CRC susceptibility syndromes, our aim is to analyze the genomic profile of MMR-proficient familial CRC to obtain insight into the biological basis of MMR-proficient familial CRC. We studied 30 MMR-proficient familial colorectal carcinomas, from 15 families, for genomic aberrations, including gains, physical losses, and copy-neutral loss of heterozygosity LOH (cnLOH) using SNP array comparative genomic hybridization. In addition, we performed somatic mutation analysis for KRAS, BRAF, PIK3CA and GNAS. The frequency of 20q gain (77%) is remarkably increased when compared with sporadic CRC, suggesting that 20q gain is involved in tumor progression of familial CRC. There is also a significant increase in the frequency of cnLOH and, as a consequence, a reduced frequency of physical loss compared with sporadic CRC. The most frequent aberrations observed included gains of 7p, 7q, 8q, 13q, 20p and 20q as well as physical losses of 17p, 18p and 18q. Most of these changes are also observed in sporadic CRC. Mutations in KRAS were identified in 37% of the MMR-proficient CRCs, and mutations in BRAF were identified in 16%. No mutations were identified in PIK3CA or chromosome 20 candidate gene GNAS. We show that the patterns of chromosomal instability of MMR-proficient familial CRC are clearly distinct from those from sporadic CRC. Both the increased gain on chromosome 20 and the increased levels of cnLOH suggest the presence of yet undiscovered germline defects that can, in part, underlie the cancer risk in these families.

Unopposed estrogens: current and future perspectives.

Estrogens and progestogens act on female reproductive tissues in opposite ways. As they counteract each other actions, the correct balance between these two classes of hormones is pivotal to avoid dangerous states. Unopposed estrogens occur when progestogen levels do not balance estrogens, primarily deriving from overproduction of estrogens via aromatase enzyme. In the endometrium, unopposed estrogens induce proliferative or invasive phenomena, which represent the first step toward different diseases. These pathologies include endometrial hyperplasia, endometrial polyps, endometriosis and adenomyosis. Endometrial hyperplasia and polyps are proliferative pathologies, while endometriosis and adenomyosis are characterized by the invasion of other tissues by endometrial cells. Current pharmacological treatments include Gonadotropin-Releasing-Hormone analogs, aromatase inhibitors and progestogens, either alone or in combination with estrogens. As these drugs usually lead to burdensome undesired effects, researchers seek to find new therapeutical molecules. Recent literature highlights the positive effects of metformin, an insulin sensitizing drug that reduces the insulin proliferative stimulus on the endometrium. d-chiro-inositol is an insulin second messenger with insulin sensitizing and mimetic properties, recently described as an aromatase down-regulator. Based on current evidence, d-chiro-inositol may be useful to treat the pathologies responsive to unopposed estrogens.

Investigating site-selection mechanisms of retroviral integration in supercoiled DNA braids.

We theoretically study the integration of short viral DNA in a DNA braid made up by two entwined double-stranded DNA molecules. We show that the statistics of single integration events substantially differ in the straight and buckled, or plectonemic, phase of the braid and are more likely in the latter. We further discover that integration is most likely close to plectoneme tips, where the larger bending energy helps overcome the associated energy barrier and that successive integration events are spatio-temporally correlated, suggesting a potential mechanistic explanation of clustered integration sites in host genomes. The braid geometry we consider provides a novel experimental set-up to quantify integration in a supercoiled substrate in vitro, and to better understand the role of double-stranded DNA topology during this process.

The use of D-chiro-Inositol in clinical practice.

OBJECTIVE: D-chiro-Inositol has been widely used in clinical practice to induce ovulation in women with polycystic ovary syndrome. Only recent evidence established that this molecule acts through two different mechanisms, with potentially different outcomes. On the one hand, under a metabolic perspective, D-chiro-Inositol improves insulin signaling, thus restoring physiological insulin levels in resistant subjects. On the other hand, at a cellular level, it downregulates the expression of steroidogenic enzyme aromatase, which is responsible for the conversion of androgens to estrogens. MATERIALS AND METHODS: We reviewed current literature in different databases, searching for D-chiro-Inositol in relation with one of the following keywords: myo-inositol, PCOS, infertility, insulin resistance, aromatase, androgen and inositol, testosterone, estrogen and inositol, estradiol, hypogonadotropic hypogonadism, fat tissue, estrogens and cancer, anovulation, uterine myoma, endometriosis, endometrial hyperplasia. RESULTS: D-Chiro-Inositol treatment may be helpful in restoring physiological hormonal levels in various clinical disorders. However, D-Chiro-Inositol intervention should be carefully designed to avoid possible undesired side effects stemming from its multiple mechanisms of action. CONCLUSIONS: We evaluated the optimal D Chiro-Inositol administration for different pathologies, defining dosages and timing. Even though further studies are required to validate our preliminary results, this paper is primarily intended to guide researchers through some of the pathways of D-Chiro-Inositol.

Interfacing Sca-1(pos) mesenchymal stem cells with biocompatible scaffolds with different chemical composition and geometry.

An immortalized murine mesenchymal stem cell line (mTERT-MSC) enriched for Lin(neg)/Sca-1(pos) fraction has been obtained through the transfection of MSC with murine TERT and single-cell isolation. Such cell line maintained the typical MSC self-renewal capacity and continuously expressed MSC phenotype. Moreover, mTERT-MSC retained the functional features of freshly isolated MSC in culture without evidence of senescence or spontaneous differentiation events. Thus, mTERT-MSC have been cultured onto PLA films, 30 and 100 microm PLA microbeads, and onto unpressed and pressed HYAFF-11 scaffolds. While the cells adhered preserving their morphology on PLA films, clusters of mTERT-MSC were detected on PLA beads and unpressed fibrous scaffolds. Finally, mTERT-MSC were not able to colonize the inner layers of pressed HYAFF-11. Nevertheless, such cell line displayed the ability to preserve Sca-1 expression and to retain multilineage potential when appropriately stimulated on all the scaffolds tested.

Radiobiological quantities in proton-therapy: Estimation and validation using Geant4-based Monte Carlo simulations.

PURPOSE: The Geant4 Monte Carlo simulation toolkit was used to reproduce radiobiological parameters measured by irradiating three different cancerous cell lines with monochromatic and clinical proton beams. METHODS: The experimental set-up adopted for irradiations was fully simulated with a dedicated open-source Geant4 application. Cells survival fractions was calculated coupling the Geant4 simulations with two analytical radiobiological models: one based on the LEM (Local Effect Model) approach and the other on a semi-empirical parameterisation. Results was evaluated and compared with experimental data. RESULTS AND CONCLUSIONS: The results demonstrated the Geant4 ability to reproduce radiobiological quantities for different cell lines.

Sub-cellular localization of manganese in the basal ganglia of normal and manganese-treated rats An electron spectroscopy imaging and electron energy-loss spectroscopy study.

We have studied at the ultrastructural level the presence of manganese (Mn) in rat basal ganglia, which are target regions of the brain for Mn toxicity. The rats underwent a moderate level of Mn exposure induced per os for 13 weeks. Mn was detected by means of electron spectroscopy imaging (ESI) and electron energy-loss spectroscopy (EELS) analyses on perfusion fixed samples embedded in resin. While no significant contamination by exogenous Mn occurred during the processing procedures, less than 50% of endogenous Mn was lost during fixation and dehydration of the brain samples. The residual Mn ions in the samples appeared as discrete particles, localized in selected sub-cellular organelles in a cell, suggesting that no significant translocation had occurred in the surrounding area. In control rats, the Mn sub-cellular localization and relative content were the same in neurons and astrocytes of rat striatum and globus pallidus: the Mn level was highest in the heterochromatin and in the nucleolus, intermediate in the cytoplasm, and lowest in the mitochondria (p<0.001). After chronic Mn treatment, while no ultrastructural damage was detected in the neurons and glial cells, the largest rate of Mn increase was noted in the mitochondria of astrocytes (+700%), an intermediate rate in the mitochondria of neurons (+200%), and the lowest rate in the nuclei (+100%) of neurons and astrocytes; the Mn level in the cytoplasm appeared unchanged. EELS analysis detected the specific spectra of Mn L(2,3) (peak at DeltaE = 665 eV) in such organelles, confirming the findings of ESI. Although a consistent loss of Mn occurred during the processing of tissue samples, ESI and EELS can be useful methods for localization of endogenous Mn in embedded tissues. The high rate of Mn sequestration in the mitochondria of astrocytes in vivo may partly explain the outstanding capacity of astrocytes to accumulate Mn, and their early dysfunction in Mn neurotoxicity. The high level of Mn in the heterochromatin and nucleoli of neurons and astrocytes in basal conditions and its further increase after Mn overload should provide insight into new avenues of investigating the role of Mn in the normal brain and a baseline for future Mn toxicity studies.

Determination of mercury in hair of children.

Although high or repeated exposure to different forms of Hg can have serious health consequences, the most important toxicity risk for humans is as methylmercury (MeHg) which exposure is mainly through consumption of fish. Generally, more than the 80% of Hg in hair is as MeHg, which is taken up by hair follicles as MeHg-cysteine complexes. In this context, hair samples were collected from 200 children (7 years) living in a coastal site in the North-East (A) of Italy and from 299 children (6-11 years) living in a urban area of South of Italy (B) to determine the levels of MeHg. Considering the neurotoxicity of MeHg, children were subjected to cognitive and neuropsychological tests. The hair values of Hg in the children population groups were comparable with data reported in other international surveys. On the other hand, combining results of the neurological tests with Hg levels, a possible relationship between Hg and an increase of the errors average reported in some neurological tests has been noted. Although the Hg levels were not elevated, a possible neurological influence in children, a population more susceptible than adults, might not be excluded, but the influence on neurological performances of the children could be also due to the family environment (socio economic status, educational level, etc.).

Surface-driven first-step events of nanoscale self-assembly for molecular peptide fibers: An experimental and theoretical study.

New experimental results are reported on the self-assembling behavior of EAK16-II, the first discovered ionic self-complementary peptide, incubated at ultralow concentration (10-6 M) at neutral pH onto differently charged surfaces. It is found that strongly negatively charged surfaces promote the self-assembly of flat, micrometer-long mono-molecular fibers of side-on assembled sequences, lying onto a continuous monolayer of flat-on EAK16-II molecules. These results suggest that the monomolecular EAK16-II self-assembly is driven by the peculiar matching condition between peptide and surface electrostatic properties. Molecular Mechanics simulations of the basic bimolecular interactions confirmed the experimental inferences, showing that the flat-on state is the most stable arrangement for two interacting EAK16-II sequences onto strongly negatively charged surfaces, where indeed EAK16-II ß-sheet conformation is stabilized, while the weak electrostatic interactions with mildly charged substrates promote an "entangled" EAK16-II geometry. Molecular Dynamics simulations further showed that the mobility and diffusional freedom of the peptides from the surfaces are ruled by the relative strength of peptide-surface electrostatic interactions, so that desorption probability for the peptide sequences is negligible from strongly-charged surfaces and high from mildly-charged surfaces. Furthermore, it has been found that an oligopeptide sequence lying onto two flat-on EAK16-II molecules, gains a remarkable lateral mobility, while remaining weakly bound to the surface, thus allowing the further molecular self-alignment responsible for the micrometer-long fiber formation. The reported results pave the way to the understanding and control of the subtle peptide-surface structural motifs matching enabling the formation of micrometer-long, but nanometer-wide monomolecular fibers.

Monte Carlo GEANT4-based application for in vivo RBE study using small animals at LNS-INFN preclinical hadrontherapy facility.

Preclinical studies represent an important step towards a deep understanding of the biological response to ionizing radiations. The effectiveness of proton therapy is higher than photons and, for clinical purposes, a fixed value of 1.1 is used for the relative biological effectiveness (RBE) of protons considered 1.1. Recent in vitro studies have reported that the RBE along the spread-out Bragg peak (SOBP) is not constant and, in particular, the RBE value increases on the distal part of SOBP. The present work has been carried-out in the perspective of a preclinical hadrontherapy facility at LNS-INFN and was focused on the experimental preparation of an in vivo study concerning the RBE variation along the SOBP. The main purpose of this work was to determine, using GEANT4-based Monte Carlo simulations, the best configuration for small animal treatments. The developed GEANT4 application simulates the proton-therapy beam line of LNS-INFN (CATANA facility) and allows to import the DICOM-CT images as targets. The RBE will be evaluated using a deterministic radiation damage like myelopathy as end-point. In fact, the dose at which the 50% of animals will show the myelopathy is supposed to be LET-dependent. In this work, we studied different treatment configurations in order to choose the best two that maximize the LET difference reducing as much as possible the dose released to healthy tissue. The results will be useful to plan hadrontherapy treatments for preclinical in vivo studies and, in particular, for the future in vivo RBE studies.

Levels of nickel and other potentially allergenic metals in Ni-tested commercial body creams.

It is extensively well-known that Ni and other metals occurring as impurities in cosmetic products might give rise to contact dermatitis in subjects with pre-existing allergy. The present study on the content of 13 metals (Cd, Co, Cr, Cu, Hg, Ir, Mn, Ni, Pb, Pd, Pt, Rh, and V) in moisturizing creams, labelled as "Ni-tested" (i.e., Ni content <100 ng g(-1)) and available on the Italian market, provides a basis for assessing their safety for consumers. Quantification of metals was performed by sector field inductively coupled plasma mass spectrometry after microwave-assisted acid digestion of products. The developed method had limits of quantification less than 0.8 ng g(-1) for all the elements; recovery was in the interval 88% (Cd, Co) to 110% (Hg), and precision was always under 7%. Nickel was present in all the products with levels between 17.5 and 153 ng g(-1); three skin creams were slightly above the concentration reported on the label. The other elements were at levels below 1 microg g(-1). The highest concentrations, in ng g(-1), of Co, Cr, Cu, and Mn were 222, 303, 51.2, and 59.9, respectively. Mean Cd, Pb, and V were below 5 ng g(-1), while Hg was absent in all the samples. Among the new emergent allergens, Ir and Rh were in traces or even undetectable, while Pt had levels of 2.65 and 6.28 ng g(-1) in two creams and Pd was equal to 1.07 ng g(-1) in one product. The overall results are below the sensitizing limit proposed for consumer products and, thus, probably have no significant toxicological effects. Nevertheless, some creams presented amounts of Co and Cr comparable to those of Ni and therefore they have to be monitored in consideration of their cross-reactivity as well.

A pilot study on the content and the release of Ni and other allergenic metals from cheap earrings available on the Italian market.

The capability of alloys used in cheap jewellery to release metal ions on contact with the skin causing allergic contact dermatitis (ACD) is generally acknowledged. To reduce the diffusion of the Ni-induced ACD the Council Directive 94/27/EC [Council Directive 94/27/EC of 30 June 1994. Official Journal L 188, 22/07/1994, 1.] limited the total Ni content in alloys and its release rate in artificial sweat. In this work, three different aspects were explored: i) the frequency of skin sensitization to Ni-containing earrings in patients before and after the introduction of the Directive's limit; ii) metal composition of alloys by X-ray analysis; iii) metal leaching in artificial sweat followed by Sector Field Inductively Coupled Plasma Mass Spectrometry (SF-ICP-MS) quantification. Well-known allergenic metals, as Ni, Cr and Co, and possible emergent allergens, as Al, Ag, Au, Cd, Cu, Fe, Ir, Mn, Pb, Pd, Pt, Rh, Sn, V and Zn, were studied. Results showed that the frequency of allergy due to earrings did not decrease after the introduction of the Ni limit: in 1994 and in 2005 patients positive to Ni patch tests were 54.3% and 53.5%, respectively. The earring components analyzed were Fe-based or alloys of Cu/Zn or Fe/Cr/Ni, plated with a thin film of precious metal (Ag, Au) which, in several cases, was combined with a Ni layer beneath. Five out of 10 items were not in compliance with the Ni Directive 94/27/EC having a total Ni content >0.05%. In three cases the release of Ni concentrations was higher than the safe sensitizing limit given by the above mentioned Regulation (i.e., <0.5 microg/cm(2)/week). The release of Cu and Zn was very variable among the different pieces (Cu: 0.134-30.9 microg/cm(2)/week; Zn: 0.141-160 microg/cm(2)/week); two objects released high amounts of Fe (358 and 586 microg/cm(2)/week) and one released considerable Mn (21 microg/cm(2)/week). Lead was released from 70% of the objects, while Ag, Al, Cd, Co, Cr and Sn from ca. 30% of the items and concentrations of these elements were well below 0.5 microg/cm(2)/week. Vanadium was released by only one item whereas Au, Ir, Pd, Pt and Rh were never leached.

Iterative control strategies for nonlinear systems.

In this paper, we focus on the control of the mean-field equilibrium of nonlinear networks of the Langevin type in the limit of small noise. Using iterative linear approximations, we derive a formula that prescribes a control strategy in order to displace the equilibrium state of a given system and remarkably find that the control function has a "universal" form under certain physical conditions. This result can be employed to define universal protocols useful, for example, in the optimal work extraction from a given reservoir. Generalizations and limits of application of the method are discussed.

Metal changes in CSF and peripheral compartments of parkinsonian patients.

BACKGROUND: Involvement of metals in the risk of developing Parkinson's disease (PD) has been suggested. In the present study, concentration of metals in cerebrospinal fluid (CSF), blood, serum, urine and hair of 91 PD patients and 18 controls were compared. METHODS: Blood and hair were microwave digested, while CSF, serum and urine were water-diluted. Elements quantification was achieved by Inductively Coupled Plasma Atomic Emission Spectrometry and Sector Field Inductively Coupled Plasma Mass Spectrometry. RESULTS: Some metal imbalances in PD were observed: i), in CSF, lower Fe and Si; ii), in blood, higher Ca, Cu, Fe, Mg and Zn; iii), in serum, lower Al and Cu; iv), in urine, lower Al and Mn, higher Ca and Fe; and v), in hair, lower Fe. The ROC analysis suggested that blood Ca, Fe, Mg and Zn were the best discriminators between PD and controls. In addition, hair Ca and Mg were at least 1.5 times higher in females than in males of patients and controls. A decrement with age of patients in hair and urine Ca and, with less extent, in urine Si was observed. Magnesium concentration in CSF decreased with the duration and severity of the disease. Elements were not influenced by the type of antiparkinsonian therapy. CONCLUSIONS: Variation in elements with the disease do not exclude their involvement in the neurodegeneration of PD.