Discriminant Profiles of Volatile Compounds in the Alveolar Air of Patients with Squamous Cell Lung Cancer, Lung Adenocarcinoma or Colon Cancer.

The objective of the present work was to analyze volatile compounds in alveolar air in patients with squamous cell lung cancer, lung adenocarcinoma or colon cancer, to prepare algorithms able to discriminate such specific pathological conditions. The concentration of 95 volatile com-pounds was measured in the alveolar air of 45 control subjects, 36 patients with lung adenocarci-noma, 25 patients with squamous cell lung cancer and 52 patients with colon cancer. Volatile compounds were measured with ion molecule reaction mass spectrometry (IMR-MS). An iterat-ed least absolute shrinkage and selection operator multivariate logistic regression model was used to generate specific algorithms and discriminate control subjects from patients with differ-ent kinds of cancer. The final predictive models reached the following performance: by using 11 compounds, patients with lung adenocarcinoma were identified with a sensitivity of 86% and specificity of 84%; nine compounds allowed us to identify patients with lung squamous cell car-cinoma with a sensitivity of 88% and specificity of 84%; patients with colon adenocarcinoma could be identified with a sensitivity of 96% and a specificity of 73% using a model comprising 13 volatile compounds. The different alveolar profiles of volatile compounds, obtained from pa-tients with three different kinds of cancer, suggest dissimilar biological-biochemistry condi-tions; each kind of cancer has probably got a specific alveolar profile.

Health-related quality of life varies in different respiratory disorders: a multi-case control population based study.

BACKGROUND AND OBJECTIVE: Health-related quality of life (HRQL) in respiratory diseases has been generally investigated in clinical settings, focusing on a single disorder. In this study on a general population sample, we assessed the relationship between HRQL and several respiratory diseases studied simultaneously (COPD, current (CA) and past (PA) asthma, allergic (AR) and non-allergic (NAR) rhinitis and chronic bronchitis (CB). METHODS: Controls (n = 328) and cases of NAR (n = 95), AR (n = 163), CB (n = 48), CA (n = 224), PA (n = 126) and COPD (n = 28) were recruited in the centre of Verona in the frame of the Italian multi-case control GEIRD (Gene Environment Interactions in Respiratory Diseases) study; HRQL was measured through the SF-36 questionnaire. The relationships between HRQL (in terms of Physical (PCS) and Mental Component Scores (MCS)), respiratory diseases, and covariates were evaluated. RESULTS: With respect to controls, the adjusted PCS median score was worse in subjects suffering from current asthma (- 1.7; 95%CI:-2.8;-0.6), CB (- 3.8; 95%CI:-5.7;-1.9), and COPD (- 5.6; 95%CI:-8.1;-3.1). MCS was worse in current asthmatics (- 2.2; 95%CI:-4.1;-0.3), CB (- 5.5; 95%CI:-8.7;-2.2), and COPD cases (- 4.6; 95%CI:-8.8;-0.5) as well. CONCLUSIONS: To our knowledge, this is the first study in the general population that analyzed HRQL performing a simultaneous comparison of HRLQ in several respiratory disorders. We found that subjects suffering from COPD, CA, and CB had the poorest HRQL. Clinicians should carefully consider the possible impact of respiratory disorders as CB and not only that of CA and COPD.

Urinary levels of metal elements in the non-smoking general population in Italy: SIVR study 2012-2015.

The purpose of this study of the Italian Society of Reference Values (SIVR) was to provide the reference values for metals in the urine of the Italian general population. Thirteen sampling centres situated in the north, centre and south of Italy took part in this project. Each sampling centre selected 20 adult subjects. The sample was made up of 120 male and 140 female non-smokers or smokers who had abandoned the habit at least 5 years previously, aged between 18 and 60 years. Urine samples were obtained from the same subjects in June and again in November of the same year. During collection of these two samples, we administered an ad hoc questionnaire designed to assess factors that might influence exposure and the results of the study such as personal characteristics, occupational or extra-occupational activities, dietary habits, the presence of dental fillings containing amalgam, the frequency and mode of exposure to passive smoking and exhaust gases of motor vehicles (traffic). Therefore, the urinary levels of thirteen trace elements (Be, Cd, Co, Cr, Cu, In, Mn, Ni, Pb, Pt, Sb, Tl and V) were determined by Inductively Coupled Plasma Mass Spectrometry. The concentrations obtained (95th percentile) are in µg/L: 0.034, 0.900, 2.24, 0.600, 24.0, 0.013, 1.53, 4.44, 2.64, 0.022, 0.095, 0.759 and 0.855 for Be, Cd, Co, Cr, Cu, In, Mn, Ni, Pb, Pt, Sb, Tl and V, respectively. Further studies with a larger number of subjects are needed in order to continue the biomonitoring of the Italian general population and to monitor the modified levels over time.

Pancreatic ductal adenocarcinoma can be detected by analysis of volatile organic compounds (VOCs) in alveolar air.

BACKGROUND: In the last decade many studies showed that the exhaled breath of subjects suffering from several pathological conditions has a peculiar volatile organic compound (VOC) profile. The objective of the present work was to analyse the VOCs in alveolar air to build a diagnostic tool able to identify the presence of pancreatic ductal adenocarcinoma in patients with histologically confirmed disease. METHODS: The concentration of 92 compounds was measured in the end-tidal breath of 65 cases and 102 controls. VOCs were measured with an ion-molecule reaction mass spectrometry. To distinguish between subjects with pancreatic adenocarcinomas and controls, an iterated Least Absolute Shrinkage and Selection Operator multivariate Logistic Regression model was elaborated. RESULTS: The final predictive model, based on 10 VOCs, significantly and independently associated with the outcome had a sensitivity and specificity of 100 and 84% respectively, and an area under the ROC curve of 0.99. For further validation, the model was run on 50 other subjects: 24 cases and 26 controls; 23 patients with histological diagnosis of pancreatic adenocarcinomas and 25 controls were correctly identified by the model. CONCLUSIONS: Pancreatic cancer is able to alter the concentration of some molecules in the blood and hence of VOCs in the alveolar air in equilibrium. The detection and statistical rendering of alveolar VOC composition can be useful for the clinical diagnostic approach of pancreatic neoplasms with excellent sensitivity and specificity.

Hepcidin and DNA promoter methylation in hepatocellular carcinoma.

BACKGROUND: The liver hormone hepcidin regulates iron homoeostasis that is often altered in hepatocellular carcinoma (HCC). Epigenetic phenomena control gene expression through a dynamic fashion; therefore, considering the plasticity of both iron homoeostasis and epigenetic mechanisms and their role in liver carcinogenesis, we investigated whether hepcidin gene (HAMP) expression is modulated by DNA methylation, thus affecting iron status in human HCC. MATERIALS AND METHODS: Thirty-two patients affected by nonviral HCC were enrolled, and their main clinical and biochemical characteristics were obtained. Neoplastic and homologous non-neoplastic liver tissues were analysed for HAMP promoter DNA methylation, for HAMP gene expression and for iron content. An in vitro demethylation assay with a human hepatocarcinoma cell line was performed to evaluate the role of DNA methylation on HAMP transcriptional repression. RESULTS: Gene expression and DNA methylation analyses on tissues showed that HAMP was transcriptionally repressed in HCC tissues consensually with a promoter hypermethylation. Furthermore, patients with HCC had low serum hepcidin concentrations, and HCC tissues had relative iron depletion as compared to non-neoplastic liver tissues. The cell culture model showed the functional role of DNA hypermethylation by downregulating HAMP gene expression. Through a quantitative methylation analysis on HCC tissues, we then proved that methylation at definite CpG sites within consensus sequences for specific transcription factors is possibly the mechanism underlying HAMP repression. CONCLUSIONS: This study highlights a novel role for HAMP downregulation through DNA promoter hypermethylation and emphasises the significance of epigenetics in the regulation of iron metabolism in HCC.

Inflammatory bowel disease and patterns of volatile organic compounds in the exhaled breath of children: A case-control study using Ion Molecule Reaction-Mass Spectrometry.

Inflammatory bowel diseases (IBD) profoundly affect quality of life and have been gradually increasing in incidence, prevalence and severity in many areas of the world, and in children in particular. Patients with suspected IBD require careful history and clinical examination, while definitive diagnosis relies on endoscopic and histological findings. The aim of the present study was to investigate whether the alveolar air of pediatric patients with IBD presents a specific volatile organic compounds' (VOCs) pattern when compared to controls. Patients 10-17 years of age, were divided into four groups: Crohn's disease (CD), ulcerative colitis (UC), controls with gastrointestinal symptomatology, and surgical controls with no evidence of gastrointestinal problems. Alveolar breath was analyzed by ion molecule reaction mass spectrometry. Four models were built starting from 81 molecules plus the age of subjects as independent variables, adopting a penalizing LASSO logistic regression approach: 1) IBDs vs. controls, finally based on 18 VOCs plus age (sensitivity = 95%, specificity = 69%, AUC = 0.925); 2) CD vs. UC, finally based on 13 VOCs plus age (sensitivity = 94%, specificity = 76%, AUC = 0.934); 3) IBDs vs. gastroenterological controls, finally based on 15 VOCs plus age (sensitivity = 94%, specificity = 65%, AUC = 0.918); 4) IBDs vs. controls, built starting from the 21 directly or indirectly calibrated molecules only, and finally based on 12 VOCs plus age (sensitivity = 94%, specificity = 71%, AUC = 0.888). The molecules identified by the models were carefully studied in relation to the concerned outcomes. This study, with the creation of models based on VOCs profiles, precise instrumentation and advanced statistical methods, can contribute to the development of new non-invasive, fast and relatively inexpensive diagnostic tools, with high sensitivity and specificity. It also represents a crucial step towards gaining further insights on the etiology of IBD through the analysis of specific molecules which are the expression of the particular metabolism that characterizes these patients.

Methodology to define biological reference values in the environmental and occupational fields: the contribution of the Italian Society for Reference Values (SIVR).

BACKGROUND: Biological reference values (RVs) explore the relationships between humans and their environment and habits. RVs are fundamental in the environmental field for assessing illnesses possibly associated with environmental pollution, and also in the occupational field, especially in the absence of established biological or environmental limits. OBJECTIVES: The Italian Society for Reference Values (SIVR) determined to test criteria and procedures for the definition of RVs to be used in the environmental and occupational fields. METHODS: The paper describes the SIVR methodology for defining RVs of xenobiotics and their metabolites. Aspects regarding the choice of population sample, the quality of analytical data, statistical analysis and control of variability factors are considered. The simultaneous interlaboratory circuits involved can be expected to increasingly improve the quality of the analytical data. RESULTS: Examples of RVs produced by SIVR are presented. In particular, levels of chromium, mercury, ethylenethiourea, 3,5,6-trichloro-2-pyridinol, 2,5-hexanedione, 1-hydroxypyrene and t,t-muconic acid measured in urine and expressed in micrograms/g creatinine (µg/g creat) or micrograms/L (µg/L) are reported. CONCLUSIONS: With the proposed procedure, SIVR intends to make its activities known to the scientific community in order to increase the number of laboratories involved in the definition of RVs for the Italian population. More research is needed to obtain further RVs in different biological matrices, such as hair, nails and exhaled breath. It is also necessary to update and improve the present reference values and broaden the portfolio of chemicals for which RVs are available. In the near future, SIVR intends to expand its scientific activity by using a multivariate approach for xenobiotics that may have a common origin, and to define RVs separately for children who may be exposed more than adults and be more vulnerable.

Biological monitoring of cobalt in hard metal factory workers.

PURPOSE: The main aim of this study was to investigate the cobalt (Co) concentrations in urine along 4 months and their relationship with Co concentrations in blood and haemoglobin (adducts) in 34 workers from a hard metal manufacturing plant where metallic Co and Co oxide were used. Furthermore, the excretion kinetics of Co was investigated and the half-lives of Co in blood, plasma and urine were calculated along 18 days of non-exposure in the same workers. METHODS: Co was analysed, in all biological samples, by ICP/MS. RESULTS: Wide fluctuations in the urinary Co concentration were observed throughout the work shift and during the work week. A highly significant linear correlation was found between Co concentration (geometrical mean) in urine samples provided each Thursday (end shift) during 16 subsequent weeks and levels of Co-haemoglobin adducts or blood Co concentrations at the end of the same period. The Co elimination kinetics in globin calculated along 18 days without Co exposure was slow, being related to the physiological metabolism of haemoglobin, while in blood, plasma and urine Co half-lives were 12.3, 9.1 and 5.3 days, respectively. CONCLUSION: Co concentrations in haemoglobin or blood are highly related to the geometrical mean concentration of urinary Co when samples are collected weekly for several subsequent weeks. The biological monitoring of occupational exposure to Co in hard metal facilities provides reliable results by using the Co concentrations in haemoglobin or in whole blood. The urinary findings, though, do not show the same reliability because of their wide daily and weekly fluctuations.

Citrate-stabilized lanthanide-doped nanoparticles: brain penetration and interaction with immune cells and neurons.

AIM: To unravel key aspects of the use of lanthanide-doped nanoparticles (NPs) in biomedicine, the interaction with immune and brain cells. MATERIALS & METHODS: Effects of citrate-stabilized CaF2 and SrF2: Yb, Er NPs (13-15 nm) on human dendritic cells and neurons were assessed in vitro. In vivo distribution was analyzed in mice at tissue and ultrastructural levels, and with glia immunophenotyping. RESULTS: The NPs did not elicit dendritic cell activation and were internalized by cultured neurons, without viability changes. After intravenous injection, NPs were found in the brain parenchyma, without features of glial neuroinflammatory response. CONCLUSION: Lanthanide-doped NPs do not activate cells protagonists of systemic and brain immune responses, are endocytosed by neurons and can cross an intact blood-brain barrier.

An Interleukin 13 Polymorphism Is Associated with Symptom Severity in Adult Subjects with Ever Asthma.

Different genes are associated with categorical classifications of asthma severity. However, continuous outcomes should be used to catch the heterogeneity of asthma phenotypes and to increase the power in association studies. Accordingly, the aim of this study was to evaluate the association between single nucleotide polymorphisms (SNPs) in candidate gene regions and continuous measures of asthma severity, in adult patients from the general population. In the Gene Environment Interactions in Respiratory Diseases (GEIRD) study (www.geird.org), 326 subjects (aged 20-64) with ever asthma were identified from the general population in Verona (Italy) between 2007 and 2010. A panel of 236 SNPs tagging 51 candidate gene regions (including one or more genes) was analysed. A symptom and treatment score (STS) and pre-bronchodilator FEV1% predicted were used as continuous measures of asthma severity. The association of each SNP with STS and FEV1% predicted was tested by fitting quasi-gamma and linear regression models, respectively, with gender, body mass index and smoking habits as potential confounders. The Simes multiple-test procedure was used for controlling the false discovery rate (FDR). SNP rs848 in the IL13 gene region (IL5/RAD50/IL13/IL4) was associated with STS (TG/GG vs TT genotype: uncorrected p-value = 0.00006, FDR-corrected p-value = 0.04), whereas rs20541 in the same gene region, in linkage disequilibrium with rs848 (r(2) = 0.94) in our sample, did not reach the statistical significance after adjusting for multiple testing (TC/CC vs TT: uncorrected p-value = 0.0003, FDR-corrected p-value = 0.09). Polymorphisms in other gene regions showed a non-significant moderate association with STS (IL12B, TNS1) or lung function (SERPINE2, GATA3, IL5, NPNT, FAM13A) only. After adjusting for multiple testing and potential confounders, SNP rs848 in the IL13 gene region is significantly associated with a continuous measure of symptom severity in adult subjects with ever asthma.

Hypoxia-reperfusion affects osteogenic lineage and promotes sickle cell bone disease.

Sickle cell disease (SCD) is a worldwide distributed hereditary red cell disorder, characterized by severe organ complication. Sickle bone disease (SBD) affects a large part of the SCD patient population, and its pathogenesis has been only partially investigated. Here, we studied bone homeostasis in a humanized mouse model for SCD. Under normoxia, SCD mice display bone loss and bone impairment, with increased osteoclast and reduced osteoblast activity. Hypoxia/reperfusion (H/R) stress, mimicking acute vaso-occlusive crises (VOCs), increased bone turnover, osteoclast activity (RankL), and osteoclast recruitment (Rank) with upregulation of IL-6 as proresorptive cytokine. This was associated with further suppression of osteogenic lineage (Runx2, Sparc). To interfere with the development of SBD, zoledronic acid (Zol), a potent inhibitor of osteoclast activity/osteoclastogenesis and promoter of osteogenic lineage, was used in H/R-exposed mice. Zol markedly inhibited osteoclast activity and recruitment, promoting osteogenic lineage. The recurrent H/R stress further worsened bone structure, increased bone turnover, depressed osteoblastogenesis (Runx2, Sparc), and increased both osteoclast activity (RankL, Cathepsin k) and osteoclast recruitment (Rank) in SCD mice compared with either normoxic or single-H/R-episode SCD mice. Zol used before recurrent VOCs prevented bone impairment and promoted osteogenic lineage. Our findings support the view that SBD is related to osteoblast impairment, and increased osteoclast activity resulted from local hypoxia, oxidative stress, and the release of proresorptive cytokine such as IL-6. Zol might act on both the osteoclast and osteoblast compartments as multimodal therapy to prevent SBD.

Multifunctional nanoprobes based on upconverting lanthanide doped CaF2: towards biocompatible materials for biomedical imaging.

Water dispersible Gd3+,Yb3+,Er3+ and Gd3+,Yb3+,Tm3+ doped CaF2 nanoparticles (NPs) were prepared by one-pot hydrothermal synthesis using citrate ions as capping agents without the need for any post-synthesis reaction. UC emissions are easily observed in the visible and infrared regions upon NIR diode laser excitation at 980 nm. EPR spectroscopy confirms the substitutional nature of the rare-earth doping, while magnetometric studies reveal that the NPs have a useful magnetization. MRI experiments conducted in vivo show that after 40 min from the injection, the NPs localize in the liver and spleen. Electron microscopy images of liver tissue reveal that the NPs are located in the Kupffer cells, although a small amount is also found in the hepatocytes. An excitation with a 980 nm emission on the excised liver and epithelial tissue induces clearly visible UC emission. The local temperature upon 980 nm irradiation was monitored in situ and it was found to increase slowly with the exposure time, maintaining under 1-2 °C for less than 60 second exposure. The NPs show a low toxicity towards cultured HeLa cells and human primary dendritic cells (DCs), and did not induce pro-inflammatory cytokine secretion by cultured human DCs, indicating that the NPs do not cause relevant adverse reactions in immune cells. Therefore, the present NPs are suitable candidates to be efficiently used in surgery applications, where spatial resolution and lack of harmful effects on human health are important issues.

Serum hepcidin levels and muscle iron proteins in humans injected with low- or high-dose erythropoietin.

Inhibition of hepcidin expression by erythropoietic signals is of great physiological importance; however, the inhibitory pathways remain poorly understood. To investigate (i) the direct effect of erythropoietin (Epo) and (ii) the contribution of putative mediators on hepcidin repression, healthy volunteers were injected with a single dose of Epo, either low (63 IU/kg, n = 8) or high (400 IU/kg, n = 6). Low-dose Epo provoked hepcidin down-modulation within 24 h; the effect was not immediate as hepcidin circadian variations were still present following injection. High-dose Epo induced no additional effect on the hepcidin response, that is hepcidin diurnal fluctuations were not abolished in spite of extremely high Epo levels. We did not find significant changes in putative mediators of hepcidin repression, such as transferrin saturation, soluble transferrin receptor, or growth differentiation factor 15. Furthermore, the potential hepcidin inhibitor, soluble hemojuvelin, was found unaltered by Epo stimulation. This finding was consistent with the absence of signs of iron deficiency observed at the level of skeletal muscle tissue. Our data suggest that hepcidin repression by erythropoietic signals in humans may not be controlled directly by Epo, but mediated by a still undefined factor.

Mild asthma and chronic bronchitis seem to influence functional exercise capacity: a multi-case control study.

BACKGROUND: In the Genes Environment Interaction in Respiratory Diseases population-based multi-case control study, we investigated whether asthma, chronic bronchitis (CB) and rhinitis were associated with a reduced 6-minute walk distance (6MWD), and whether the 6MWD determinants were similar for subjects with/without respiratory diseases. METHODS: Cases of asthma (n = 360), CB (n = 120), rhinitis (n = 203) and controls (no respiratory diseases: n = 302) were recruited. The variation in the 6MWD across the groups was analyzed by ANCOVA, adjusting for gender, age, height, weight and comorbidity. The 6MWD determinants were studied by linear regression, and heterogeneity across the cases and controls was investigated. RESULTS: The 6MWD differed across cases and controls (p = 0.01). It was shorter for cases of asthma (-17.1, 95% CI -28.3 to -5.8 m) and CB (-20.7, 95% CI: -36.6 to -4.8 m) than for controls (604 ± 68 m on average), but not for cases of rhinitis. The negative association between age and the 6MWD was significant for cases of CB, but not for the other groups (p = 0.001). CONCLUSIONS: Even at the level of severity found in the general population, asthma and CB could influence the 6MWD, which seems to reflect the functional exercise level for daily physical activities. The negative association between ageing and the 6MWD was particularly strong in subjects with CB. Our report adds to the mounting evidence that CB is not a trivial condition, especially in the ageing adult population, and it supports the importance of monitoring functional capacity and of physical reconditioning in mild asthma.

MMPI-2 personality profiles and suicidal ideation and behavior in victims of bullying at work: a follow-up study.

The main aim of this study was to investigate longitudinally the personality profile and suicidal ideation and behavior in victims of bullying at work in relation to the evolution of the victimization. Forty-eight victims were evaluated by means of medical and psychological assessment including the Minnesota Multiphasic Personality Inventory-2 (MMPI-2). A follow up session was carried out after an average of 22 months. At first evaluation, the average MMPI-2 personality profile of victims showed abnormal elevations on scales Hs (Hypochondria), D (Depression), Hy (Hysteria), and Pa (Paranoia), which were strikingly similar to that found in previous studies. Furthermore, suicidal ideation and behavior were common among victims. At follow-up, 26 victims reported that the degree of bullying had remained the same or had even worsened, whereas 22 said that the situation had improved or had been resolved. Although there was a trend toward normalization in the MMPI-2 profile for all victims, the profile of the "static" group was still abnormal at follow up. On the contrary, the profile of the "improved" group was entirely within normal range. Suicidal ideation and behavior decreased in all victims, but only to a significant degree in the improved group. Results are discussed in the light of the bullying process.

[New varnishing techniques and health risk assessment]. / Le nuove tecniche di verniciatura e rischi per la salute.

The first part of the report signals the significant changes coating processes have endured over the last twenty years. The shift from traditional "solvent-based" paints to "water-based" paints marked a very important toxicological evolution, to reduce the possible toxic effects, to improve the products quality and to limit environmental pollution, Old and new recipes for preparation of paints and enamels are compared and discussed. The second part of the report summarizes the international literature concerning epidemiological data on painters and describes the toxic effects in experimental area that are reported for several solvents of water-based paints.

In vivo effect of alpha-bisabolol, a nontoxic sesquiterpene alcohol, on the induction of spontaneous mammary tumors in HER-2/neu transgenic mice.

Breast cancer represents the most commonly diagnosed invasive malignancy in pre- and postmenopausal women in both developed and underdeveloped countries. Taking into account that treatment options, including surgery, have not been able to deal with the growing incidence of breast malignancy, it is required to develop mechanism-based novel agents for its prevention. Wide interest in some natural compounds as antiinflammatory agents and as alternative to the traditional medicines is increasing because they do not provoke any adverse effects and are effective in multiple organs, alpha-Bisabolol (BISA), a small oily sesquiterpene alcohol, was reported as chemopreventive agent in induced rat mammary carcinogenesis. The aim of the present study is to investigate the role played by two doses of BISA (via intramammary infusion) on the induction and development of mammary tumor in HER-2/neu transgenic mice as well as the BISA effect after tumor surgical resection. The main data show that (a) optimal dosage of BISA is 10 mg/mouse rather than 3.6 mg/mouse with no adverse effects (e.g., alopecia); (b) the number of the palpable tumor masses decreases in mice treated with 10 mg/mouse of BISA; (c) mice after surgical resection of the primary tumor and treatment with BISA (10 mg) are free from tumor for more weeks, after the surgical treatment; (d) using array analysis, some genes implicated in carcinogenesis mechanisms (NF-kappaBia, Map2k, Mapkl4, and HER2/ neu), angiogenesis process (Fgf), and inhibition of apoptosis (Birc5) are differently regulated after BISA treatment, with a downregulation of the HER2/neu as well as of Fgf and Birc5 genes; (e) the NK cell cytotoxicity increases in tumor-treated mice, especially after the removal of the first tumor mass. Such effectiveness could be important to achieve goals for a possible combination of BISA to conventional therapies in breast cancer and to tumor surgical removal (adjuvant therapy), as suggested for other sesquiterpene analogs.

S-(acetamidomethyl)mercapturic acid (AMMA): a new biomarker for occupational exposure to N,N-dimethylacetamide.

N,N-dimethylacetamide (DMA) is used in the textile and plastics industry as a solvent alternative to more toxic N,N-dimethylformamide. Here we studied toxicokinetics of two major urinary metabolites of DMA, namely, S-(acetamidomethyl)mercapturic acid (AMMA) and N-methylacetamide (NMA). Urine samples were collected from workers exposed to DMA in a factory manufacturing acrylic fibers. AMMA and NMA were determined by HPLC/MS and GC/MS, respectively. The working scheme in the factory consisted of periods of three consecutive working shifts alternated regularly with two days off work. In the first stage of the study, NMA and AMMA were determined in urine samples collected before, in the middle, and at the end of one working shift. In the second stage, urine was collected five times during three consecutive days after a two-day rest: before and at the end of the first and second working shifts and before the third shift. It was found that the end-of-shift NMA levels were several folds higher than the pre-shift levels of the same day and dropped significantly until the next shift. On the other hand, there were no significant differences in AMMA levels before and at the end of the same shift but a continuous rise during the three-day working period was observed. Median values of NMA concentrations at the end of working shifts were between 10.1 and 17.3 mg/g creatinine, median AMMA concentrations in the second or third day of the working period varied between 12.4 and 38.1 mg/g creatinine. The approximate half-lives of NMA and AMMA (means) in the exposed workers were about 9 and 29 h, respectively. Thus, while NMA in the end-of-shift urine samples remains a preferential biomarker of DMA exposure during that shift, AMMA determined at the end of a work-week reflects cumulative exposure over the last few days. Further studies are needed to determine AMMA concentrations corresponding to the threshold limit value of DMA.

Respiratory health effects and immunological response to Thermoactinomyces among sugar cane workers in Nicaragua.

Specific sensitization and respiratory effects associated with the inhalation of sugar cane dust were evaluated in a group of 51 Nicaraguan workers exposed to bagasse. A questionnaire interview, lung function test, serum precipitin tests for Thermoactinomyces sacchari and T. vulgaris, and immunoglobulin E tests for specific environmental allergens were performed for each worker. Twenty-one workers reported at least one respiratory symptom and 16 reported possible symptoms of bagassosis. Six workers demonstrated acute symptoms, 1 had chronic symptoms, and 9 had the reacutized form of the disease. A higher proportion of precipitin response to T. sacchari and T. vulgaris was found in workers reporting symptoms suggestive of acute bagassosis. A possible restrictive ventilatory pattern was observed in 8 subjects and a mild airway obstruction in 1 subject. Priority must be given to a surveillance and exposure prevention program for workers employed in sugar cane production and processing.

Involvement of mitochondrial permeability transition pore opening in alpha-bisabolol induced apoptosis.

Alpha-bisabolol is a natural monocyclic sesquiterpene alcohol. It has been used in cosmetics for hundreds of years because of its perceived skin-healing properties. Alpha-bisabolol is known to have anti-irritant, anti-inflammatory and antimicrobial properties. In precedent studies, we described how alpha-bisabolol exerts a selective pro-apoptotic action towards transformed cells [Cavalieri E et al. (2004) Biochem Biophys Res Commun 315, 589-594] and its uptake is mediated by lipid rafts on the plasma membrane [Darra E et al. (2008) Arch Biochem Biophys 476, 113-123]. In this study, we hypothesize that the intracellular target of alpha-bisabolol may be the mitochondrial permeability transition pore (mPTP). To evaluate this hypothesis, we used one transformed cell line (human glioma T67) in comparison with a nontransformed one (human fibroblasts). We assessed the effect of a specific mPTP inhibitor (cyclosporine A) on the toxic action of alpha-bisabolol. Results show that the alpha-bisabolol-induced decrease in oxygen consumption is abolished by the addition of cyclosporine A in T67 cells, indicating that alpha-bisabolol may target mPTP. The central role of mitochondria was also demonstrated by using galactose to force cells to a more aerobic metabolism. In this condition, we observed higher alpha-bisabolol toxicity. Furthermore, we studied the effect of alpha-bisabolol on isolated rat liver mitochondria. This study expands the notion of the specific action of alpha-bisabolol on transformed cells and suggests that it may act by disturbing the structure and function of the mPTP. Alpha-bisabolol toxicity is clearly related to its cellular uptake, which is higher in transformed cell lines.