Giacomo Muzi

Yellow nail syndrome: does protein leakage play a role?

Yellow nail syndrome is characterized by primary lymphoedema, recurrent pleural effusion and yellow discoloration of the nails. Although mechanical lymphatic obstruction is assumed to be the underlying pathology, it cannot explain the common finding of high albumin concentration in the pleural space. This paper describes a case of yellow nail syndrome presenting with the classical triad of lymphoedema, recurrent pleural effusion and yellow discoloration of the nails, associated with persistent hypoalbuminaemia and increased enteric loss of albumin. Based on the findings in this case and those in the literature, it is speculated that increased microvascular permeability may contribute to the pathogenesis of this syndrome.

Some Endocrine and Morphological Aspects of the Acute Toxicity of 2,3,7,8=Tetrachlorodibenzo=p=Dioxin (TCDD)*

Hormonal status was evaluated in TCDD-treated rats and in pair-fed and ad libitum- fed controls in order to separate hormonal changes resulting from the toxic insult of TCDD from those arising from progressive feed deprivation as it occurs in pair-fed controls. TCDD-treated rats received either a usually non-lethal (25 μg/kg) or a usually lethal (125 μg/kg) dose of TCDD whereas pair-fed and ad libitum- fed controls were given vehicle alone. Animals were terminated at predetermined time intervals and several hormones measured in serum or plasma. In addition, the morphology of the thyroid, pancreas, and pituitary was also examined. In both dosage groups, TCDD-treatment had the following effects: decreased TT4, FT4, insulin, and glucagon; mixed effects upon TT3, FT3, TSH, and GH. Pair-feeding to the non-lethal dose of TCDD had no effect on any of the hormones measured. Pair-feeding to the lethal dose of TCDD had the following effects: slightly decreased TT4, FT4, TT3, TSH, and insulin; no effect on FT3 and glucagon. It is concluded that the endocrine status of TCDD-treated rats was different from that of pair-fed rats suggesting that some hormonal changes represent responses to an insult other than that due to starvation stress alone. A differential response between TCDD-treated and pair-fed rats was also observable morphologically in the corresponding endocrine glands indicating the importance of this additional control for morphologic observations in instances when reduced-feed intake and body weight loss are prominent features of toxicity.

Assessment of primary, oxidative and excision repaired DNA damage in hospital personnel handling antineoplastic drugs

The International Agency for Research on Cancer has classified several antineoplastic drugs in Group 1 (human carcinogens), among which chlorambucil, cyclophosphamide (CP) and tamoxifen, Group 2A (probable human carcinogens), among which cisplatin, etoposide, N-ethyl- and N-methyl-N-nitrosourea, and Group 2B (possible human carcinogens), among which bleomycins, merphalan and mitomycin C. The widespread use of these mutagenic/carcinogenic drugs in the treatment of cancer has led to anxiety about possible genotoxic hazards to medical personnel handling these drugs. The aim of the present study was to evaluate work environment contamination by antineoplastic drugs in a hospital in Central Italy and to assess the genotoxic risks associated with antineoplastic drug handling. The study group comprised 52 exposed subjects and 52 controls. Environmental contamination was assessed by taking wipe samples from different surfaces in preparation and administration rooms and nonwoven swabs were used as pads for the surrogate evaluation of dermal exposure, 5-fluorouracil and cytarabine were chosen as markers of exposure to antineoplastic drugs in the working environment. The actual exposure to antineoplastic drugs was evaluated by determining the urinary excretion of CP. The extent of primary, oxidative and excision repaired DNA damage was measured in peripheral blood leukocytes with the alkaline comet assay. To evaluate the role, if any, of genetic variants in the extent of genotoxic effects related to antineoplastic drug occupational exposure, the study subjects were genotyped for GSTM1, GSTT1, GSTP1 and TP53 polymorphisms. Primary DNA damage significantly increased in leukocytes of exposed nurses compared to controls. The use of personal protective equipment (i.e. gloves and/mask) was associated with a decrease in the extent of primary DNA damage.

Blood cadmium concentrations in the general population of Umbria, Central Italy

The aims of this study were (a) to assess blood cadmium (B-Cd) concentrations and to establish a tentative reference interval; (b) to identify significant determinants of B-Cd, in a population from Umbria, Central Italy, which was not occupationally exposed to cadmium (Cd). Four hundred and thirty-four healthy blood-donors volunteered to answer a questionnaire and provide a blood sample for B-Cd analysis, which was performed by graphite furnace atomic absorption spectrophotometry. Blood Cd concentrations ranged from non-detectable values, i.e. below 0.1 microgram/l up to 3.4 micrograms/l and were not normally distributed. The median values and the 95th percentiles were 0.7 and 2.0 micrograms/l, respectively. Concentrations of B-Cd were more than double in smokers than in non-smokers, median values being 1.1 micrograms/l and 0.5 microgram/l, respectively. In current smokers, B-Cd values correlated with the number of cigarettes smoked daily (rs = 0.40, P = 0.0001) and with the cumulative exposure to cigarette smoke (rs = 0.35, P = 0.0001). Concentrations of B-Cd correlated with age in the non-smokers, but not in the smokers and were significantly higher in women than in men only in the non-smokers. Both in smokers and non-smokers, B-Cd concentrations were similar in subjects living in urban or in rural areas. In the whole study population the lower and the upper tentative reference limit were < 0.1 and 2.2 micrograms/l, respectively, as computed by a non-parametric rank-based method. The upper limit was approximately double in smokers than in non-smokers (3.1 micrograms/l and 1.6 micrograms/l, respectively). Our results show that B-Cd concentrations in a general population from Umbria are in the range reported for general populations in Northern Italy and other European Countries. Smoking was the strongest determinant of B-Cd concentrations and age had a lesser effect.

Parkinsonism and cognitive impairment following chronic exposure to potassium cyanide

1. Zhou B, Westaway SK, Levinson B, Johnson MA, Gitschier J, Hayflick SJ. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat Genet 2001;28:345–349. 2. Thomas M, Hayflick SJ, Jankovic J. Clinical heterogeneity of neurodegeneration with brain iron accumulation (HallervordenSpatz syndrome) and pantothenate kinase-associated neurodegeneration. Mov Disord 2004;19:36–42. 3. Ng PC, Henikoff S. Predicting deleterious amino acid substitutions. Genome Res 2001;11:863–874. 4. Ramensky V, Bork P, Sunyaev S. Human non-synonymous SNPs: server and survey. Nucleic Acids Res 2002;30:3894–3900. 5. Hayflick SJ, Westaway SK, Levinson B, et al. Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. N Engl J Med 2003;348:33–40. 6. Hayflick SJ, Hartman M, Coryell J, Gitschier J, Rowley H. Brain MRI in neurodegeneration with brain iron accumulation with and without PANK2 mutations. AJNR Am J Neuroradiol 2006;27:1230–1233. 7. Zolkipli Z, Dahmoush H, Saunders DE, Chong WK, Surtees R. Pantothenate kinase 2 mutation with classic pantothenate-kinaseassociated neurodegeneration without ‘eye-of-the-tiger’ sign on MRI in a pair of siblings. Pediatr Radiol 2006;36:884–886. 8. Valentino P, Annesi G, Ciro Candiano IC, et al. Genetic heterogeneity in patients with pantothenate kinase-associated neurodegeneration and classic magnetic resonance imaging eye-of-thetiger pattern. Mov Disord 2006;21:252–254. 9. Kumar N, Boes CJ, Babovic-Vuksanovic D, Boeve BF. The “eyeof-the-tiger” sign is not pathognomonic of the PANK2 mutation. Arch Neurol 2006;63:292–293. 10. Thomas M, Jankovic J. Neurodegenerative disease and iron storage in the brain. Curr Opin Neurol 2004;17:437–442. 11. Hartig MB, Hortnagel K, Garavaglia B, et al. Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation. Ann Neurol 2006;59: 248–256. Parkinsonism and Cognitive Impairment Following Chronic Exposure to Potassium Cyanide

Reactive oxygen species induce apoptosis in bronchial epithelial BEAS-2B cells by inhibiting the antiglycation glyoxalase I defence: involvement of superoxide anion, hydrogen peroxide and NF-κB

Reactive oxygen species (ROS) are implicated in the regulation of apoptosis through a number of distinct mechanisms depending on cell type and stimulation conditions. Glyoxalase I (GI) metabolizes methylglyoxal (MG) and MG-derived advanced glycation end products (AGEs) known to cause apoptosis. This study examined the possible role of GI among the mechanisms of ROS-driven apoptosis in human bronchial epithelial BEAS-2B cells exposed to wood dust and signaling pathways by which these reactive species regulate GI expression. Our results showed that wood dust generated distinct ROS (superoxide anion, and hydrogen peroxide) by selectively inhibiting the enzymatic activity of superoxide dismutase or glutathione peroxidase and catalase enzymes. These ROS caused a dramatic inhibition of the antiglycation GI enzyme, leading to the intracellular accumulation of the pro-apoptotic AGE, argpyrimidine (AP) and programmed cell death via a mitochondrial pathway. Pre-treatment with N-acetyl-l-cysteine (NAC), a ROS scavenger, prevented these events. Hence, ROS-induced apoptosis in BEAS-2B cells occurred via a novel mechanism relying on GI inhibition and AP accumulation. We interestingly found that superoxide anion and hydrogen peroxide induced a diverse apoptosis level by differently inhibiting GI via NF-κB pathway. Since maintenance of an intact epithelium is a critically important determinant of normal respiratory function, the knowledge of the mechanisms underlying its disruption may provide insight into the genesis of a number of pathological conditions commonly occurring in wood dust occupational exposure. Our findings suggest that the antioxidant NAC may merit investigation as a potential preventive agent in wood dust exposure-induced respiratory diseases.

Silica and Its Antagonistic Effects on Transforming Growth Factor-β in Lung Fibroblast Extracellular Matrix Production

Background Silicosis, a pneumoconiosis marked by interstitial pulmonary fibrosis, is caused by inhalation of free crystalline silica particles. When silica particles are injected into the lower lung, they are translocated across the epithelium into the interstitial space, where macrophage-derived growth factors affect lung fibroblast proliferation and collagen deposition. We hypothesized that silica may act directly on pulmonary fibroblasts modifying extracellular matrix (ECM) synthesis and that the effects of silica may be mediated by transforming growth factor-β (TGFβ) overproduction. Methods To test this hypothesis, we studied a human lung fibroblast cell line (WI-1003) exposed to silica in vitro. We investigated cell morphology by electron microscopic procedure, cell growth, collagen production, and glycosaminoglycans (GAG) composition by radiolabeled precursors. Cytokine and growth factor synthesis were evaluated by specific enzyme-linked immunoadsorbent assay kits and Northern blotting analysis. Results Pulmonary fibroblasts internalized silica particles without detectable cell damage. Silica directly stimulated collagen synthesis and decreased the amount of 3H-glucosamine-labeled GAG. Silica-treated fibroblasts secreted less TGFβ than untreated controls, antagonized the stimulatory effect of TGFβ on ECM synthesis, and reversed TGFβ-induced inhibition of cell proliferation. Northern blotting analysis showed increased interleukin-1α (IL-1α) mRNA after silica treatment. IL-1α had no influence on collagen synthesis but increased the number of WI-1003 fibroblasts. Conclusions These results support our hypothesis that lung fibroblasts are direct silica targets. However, contradicting our hypothesis, silica antagonized TGFβ activities through a TGFβ downregulation and an IL-1α upregulation. The complex pattern of TGFβ and IL-1α regulation in pulmonary fibroblasts is imbalanced by silica exposure and might play a key role in silica-mediated pulmonary fibrosis.

Systemic nicotine exposure in tobacco harvesters

Abstract Several epidemics of nicotine intoxication have been described among tobacco harvesters; however, little is known about nicotine absorption under typical working conditions. To assess systemic nicotine absorption during a regular working shift, the authors performed an observational field study. Included in the study were 10 healthy, nonsmoking, female tobacco harvesters and a control group of 5 healthy, nonsmoking, female hospital workers. Nicotine and cotinine were measured in sequential samples of blood and urine during a regular workshift. Blood nicotine levels rose from a nadir value of 0.79 ± 0.12 ng/ml to a peak value of 3.45 ± 0.84 ng/ml (p < .05 [Tukeys modified t test]) in the exposed group. In the control group, levels were stable at 0.1 ± 0.1 ng/ml (p < .01). Moreover, the mean blood nicotine level measured 3 mo following the end of exposure in 6 of 10 exposed subjects was 0.24 ± 0.12 ng/ml (p < .01). Corresponding higher values of urine nicotine and urine cotinine were observed in the exposed versus control group (comparative P values were < .01 and < .05, respectively). Overall, tobacco harvesters absorbed approximately 0.8 mg of nicotine daily. Given that nicotine can induce adverse health effects, the authors believe that prevention of nicotine absorption in tobacco harvesters should be sought and that workers should be informed about occupational risks.

Long-term pulmonary and systemic toxicity following intravenous mercury injection

Abstract Long-term pulmonary and systemic toxicity following mercury intravenous injection has rarely been assessed. We present the results of a detailed investigation assessing pulmonary and systemic long-term toxic effects in a subject who had pulmonary and systemic mercury microembolism diagnosed more than 11 years previously. Radiographic examination showed the persistence of mercury microemboli in both lungs and elsewhere␣in the body. Lung function tests revealed a decreased diffusing capacity for carbon monoxide and Po2 probably indicative of microscopic inflammation of lung interstitium. Electroneuromyography showed signs of mild axonopathy in both legs. At semen analysis, a high proportion of motionless spermatozoa was present. Urinary excretion of mercury was high. Signs of interstitial lung impairment, peripheral axonopathy and asthenozoospermia in a subject who had mercury microembolism persisting for more than 11 years might be evidence of long-term mercury toxicity.

Primary DNA damage and genetic polymorphisms for CYP1A1, EPHX and GSTM1 in workers at a graphite electrode manufacturing plant

BackgroundThe results of a cross-sectional study aimed to evaluate whether genetic polymorphisms (biomarkers of susceptibility) for CYP1A1, EPHX and GSTM1 genes that affect polycyclic aromatic hydrocarbons (PAH) activation and detoxification might influence the extent of primary DNA damage (biomarker of biologically effective dose) in PAH exposed workers are presented. PAH-exposure of the study populations was assessed by determining the concentration of 1-hydroxypyrene (1OHP) in urine samples (biomarker of exposure dose).MethodsThe exposed group consisted of workers (n = 109) at a graphite electrode manufacturing plant, occupationally exposed to PAH. Urinary 1OHP was measured by HPLC. Primary DNA damage was evaluated by the alkaline comet assay in peripheral blood leukocytes. Genetic polymorphisms for CYP1A1, EPHX and GSTM1 were determined by PCR or PCR/RFLP analysis.Results1OHP and primary DNA damage were significantly higher in electrode workers compared to reference subjects. Moreover, categorization of subjects as normal or outlier highlighted an increased genotoxic risk OR = 2.59 (CI95% 1.32–5.05) associated to exposure to PAH. Polymorphisms in EPHX exons 3 and 4 was associated to higher urinary concentrations of 1OHP, whereas none of the genotypes analyzed (CYP1A1, EPHX, and GSTM1) had any significant influence on primary DNA damage as evaluated by the comet assay.ConclusionThe outcomes of the present study show that molecular epidemiology approaches (i.e. cross-sectional studies of genotoxicity biomarkers) can play a role in identifying common genetic risk factors, also attempting to associate the effects with measured exposure data. Moreover, categorization of subjects as normal or outlier allowed the evaluation of the association between occupational exposure to PAH and DNA damage highlighting an increased genotoxic risk.