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Biomedical subjects

E Bergamaschi

Publications and source records attributed to E Bergamaschi.

At least 19 recordsLinked to original sources

Motor function, olfactory threshold, and hematological indices in manganese-exposed ferroalloy workers.

A cross-sectional study was conducted in 35 male subjects randomly selected from workers of a ferroalloy production plant and exposed to manganese (Mn) oxides; the objective was to detect early signs of neurologic impairment. The subjects' mean age was 39.4 years (SD, 8. 4); the average exposure duration was 14.5 years (range, 5-29 years). A control group of industrial workers not exposed to neurotoxic chemicals and comparable in age and confounding factors was recruited. The intensity of Mn exposure was moderate, as reflected by airborne Mn concentrations in total dust averaging 193 [corrected] micro g/m3. Mn levels in blood (MnB) and urine (MnU) were significantly higher in the Mn-exposed workers than in control workers. A relationship (not found with MnU) was found between MnB and a cumulative exposure index calculated on the basis of air concentration and exposure history for each subject (r = 0.52; r2 = 0.27; P = 0.002). Psychomotor function scores were lower among Mn-exposed subjects. The Aiming score was negatively correlated with MnB in the exposed group. The olfactory threshold did not differ between the two groups, although it was negatively associated with MnU in the exposed group. The white blood cell count results were significantly higher in Mn-exposed subjects than in controls. These findings show that an increase in Mn body burden is associated with an impairment of motor functions, whereas the increased excretion of Mn is related to an increased olfactory perception. Changes in numbers of leukocytes could indicate possible interferences of Mn with the immunological system.

Air Pollutants, Occupational

The assessment of biomarkers to detect nephrotoxicity using an integrated database.

Groups of industrial workers exposed to heavy metals (cadmium, mercury, and lead) or solvents were studied together with corresponding control groups. The cohorts were collected from several European centers (countries). Eighty-one measurements were carried out on urine, blood, and serum samples and the results of these analyses together with questionnaire information on each individual were entered into a central database using the relational database package Rbase. After the completion of the database construction phase, the data were exported in a format suitable for analysis by the statistical package SAS. The potential value of each test as an indicator of nephrotoxicity was then assessed. Rigorous exclusion criteria were applied which resulted in the elimination of some tests and samples from the dataset. The measurable contributions of smoking, gender, metal exposure, and site were either singly or in combination assessed by biomarkers for nephrotoxicity. The parameters measured included three urinary enzymes, six specific proteins, total protein, two extracellular matrix markers, four prostaglandins and anti-GBM antibodies, and beta 2-microglobulin in serum. The most sensitive renal tests included the urinary enzymes N-acetyl-beta-D-glucosaminidase (NAG) and intestinal alkaline phosphatase (IAP), brush border antigens, and urinary low-molecular-weight proteins. Of the newer tests investigated the prostaglandins were the most promising. Different patterns of biomarker excretion were observed following exposure to lead, cadmium, or mercury. The dataset provides a unique repository of data which could provide the basis of an enlarging source of information on normal human reference ranges and on the effects of exposure to toxins and the use of biomarkers for monitoring nephrotoxicity.

Biomarkers

Peripheral markers of catecholaminergic dysfunction and symptoms of neurotoxicity among styrene-exposed workers.

AIM: A cross-sectional investigation was carried out to assess possible relations between styrene-induced changes in three peripheral markers of catecholaminergic dysfunction and self-reported symptoms of neurotoxicity. SUBJECTS: Male workers (n = 46) aged 14-60 (mean 29.5) years who had been exposed to styrene for an average of 6 (0.2-29) years were recruited in glassfiber reinforced plastics plants. A control group of 30 blue-collar workers aged 22-52 (mean 35) years and with no history of exposure to chemicals was recruited from local industries. Styrene exposure ranged from 5 to 120 ppm (8 h-TWA), the median level being relatively low (25 ppm, 8 h-TWA). Styrene metabolites, mandelic and phenylglycoxylic acids (MAPGA) in the "next morning" urine spot samples ranged from 32.0 to 931.1 mg/g creatinine (median 186.5). METHODS: Platelet monoamine oxidases B (MAO B) and dopamine beta-hydroxylase (DBH) activities were assessed using methods based on HPLC and electrochemical detection. Plasma prolactin (PRL) was measured by a commercially available immunoassay. Questionnaire 16 (Q16) was used to survey self-reported symptoms. RESULTS: Although there was no difference in DBH activity between exposed workers and controls, the most highly exposed workers had significantly lower activity than control subjects. A tendency to lower platelet MAO B activity in exposed than in control subjects was observed. The prevalence of plasma DBH and platelet MAO B values below the lower reference limit was similar in the two groups. PRL values exceeding the upper reference limit were higher (14/46 vs 2/30) among styrene-exposed workers, who also exhibited significantly higher median levels (10.0 vs 5.7 micrograms/l) than control subjects. Although the number of reported symptoms was similar among exposed and control subjects, in the exposed group it was positively associated with urinary MAPGA (Rho = 0.30, P = 0.04). Of the three peripheral markers of catecholaminergic dysfunction, plasma DBH was the only parameter negatively related to both urinary MAPGA (F = 9.56, P = 0.003) and the number of reported symptoms (Rho = 0.23, P = 0.05). CONCLUSIONS: Plasma PRL appears to be a sensitive marker of styrene-induced tubero-infundibular dopaminergic dysfunction in male subjects. DBH in plasma and MAO B in platelets seem to be less suitable markers for biomonitoring effect at the individual level, although DBH was related to the number of reported symptoms and to internal dose. Further studies on a larger and more exposed population are necessary to clarify the significance of these markers for health and their predictive value with regard to both subjective disturbances and concurrently administered performance tests.

Adolescent

Age-related changes in interstitial norepinephrine. A microdialysis study in spontaneously hypertensive rats.

This study was aimed at evaluating the time course of interstitial norepinephrine (NE) concentrations in the white adipose tissue and at assessing NE release after local perfusion with tyramine hydrochloride (TYR) in rats of different ages. Two groups of eight spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats, aged 14 to 16 weeks, were studied. The same animals were reexamined at the age of 52 to 54 weeks. A soft microdialysis probe was implanted subcutaneously in the parascapular region and was perfused with Ringer solution (flow rate: 2.0 microL/min). After an equilibration period, NE levels were monitored for 120 min, following which, TYR (0.1 nmol/min) was perfused for 90 min. Dialysates from each 30 min collection period were analyzed by HPLC using electrochemical detection. At 14 to 16 weeks, SHR showed higher NE concentrations in dialysates as compared to WKY (1124.0 pg/mL v 541.4 pg/mL; P < .001) and a blunted response to TYR challenge. The net output, estimated by subtracting basal values, was 86.0 pg NE/h in SHR as compared to 212.5 pg NE/ h in WKY (P = .005). Differences in basal NE levels persisted in the same aged groups (P < .001) as well as a blunted response to TYR. The net NE output was still lower in SHR as compared to WKY (320.4 pg NE/h v 414.7 pg NE/h in WKY; P = .023). Basal levels of NE in SHR could be accounted for by either a higher amount of the neurotransmitter stored into and released from vescicles or by an increased firing rate of the sympathetic fibers. Since TYR is known to deplete axoplasmic but not vesicular NE available for neurotransmission, the response of SHR to TYR challenge is consistent with an increased turnover rate of NE. Aging was associated with an increased response to TYR in both strains, thus suggesting an age-dependent decline in turnover rates or changes in NE reuptake mechanisms.

Adipose Tissue

Development and validation of new screening tests for nephrotoxic effects.

Within the framework of an European Commission-funded project, groups of industrial workers exposed to heavy metals (cadmium, mercury and lead) or solvents were studied together with corresponding control groups. Eighty-one measurements were carried out on urine and serum samples and the scientific results together with individual questionnaire information were entered into a central database. Data obtained was assessed centrally and individually in subsidiary studies. The measurable contributions were assessed either singly or in combination, of smoking, gender, metal exposure and site, to nephrotoxicity. The potential value of each test as an indicator of nephrotoxicity was then assessed on the basis of sensitivity and specificity. A number of new tests including prostaglandins and for extracellular matrix components were investigated as well as established tests for renal damage and dysfunction. The data obtained from this comprehensive study emphasises the value of noninvasive biomarkers for the early detection of nephrotoxicity due to environmental toxins. The urinary profile varied with the type of environmental/occupational toxin. By careful selection of a small panel of markers they can be used to indicate the presence of renal damage, the principal region affected, and to monitor the progress of disease and damage. Biomarkers were also used to confirm and tentatively establish safe exposure levels to nephrotoxins.

Biomarkers

Biochemical markers of neurotoxicity. A review of mechanistic studies and applications.

Neurotoxicology presents major challenges to the development of biological markers in accordance to conventional research strategies. Because of the inaccessibility of the nervous system, one of the proposed alternatives is the study of biochemical signals in peripheral tissues which can easily and ethically be obtained in humans, and which could represent surrogate indicators of equivalent parameters in the nervous tissue. Considerable scientific support to this approach is provided by the results of recent investigations in major areas of pharmacology and psychobiology. Studies examining parameters of neurotransmission and second messenger systems in peripheral blood cells, and variations in the peripheral body fluid content of endogenous substances reflecting nervous tissue dysfunction or damage are presented in this paper as examples of efforts toward rational development and validation of novel indicators of nervous system toxicity. Cholinergic muscarinic receptors and calcium signalling in peripheral blood lymphocytes, myelin basic protein in cerebrospinal fluid, and blood polyamines are discussed as potential surrogate indicators based on the results of in vitro or in vivo animal studies of neurotoxic metals (mercury, triethyltin), pesticides (disulfoton), drugs of abuse (d-fenfluramine) and model epileptogenic compounds (kainic acid). Data from investigations examining serum prolactin, type B monoamine oxidase (MAO-B) and dopamine beta-hydroxylase (DBH) in workers occupationally exposed to manganese, lead or styrene are also presented. Although research in this field is still at its very early stage, current evidence suggests that (i) certain neurochemical markers may be valuably used in animal studies as a complement to conventional laboratory tests to augment their sensitivity or predictivity; (ii) a mechanistic research approach is required to establish which markers offer the greatest promise for application in human biomonitoring.

Animals

Effects of urinary macromolecules on the nucleation of calcium oxalate in idiopathic stone formers and healthy controls.

Urinary macromolecules have attracted great interest because of their possible role as both promoters and inhibitors of calcium oxalate (CaOx) crystallization and it remains unclear whether there is any difference, in their nucleating activity, between stone formers and controls. We selected 9 male idiopathic CaOx stone formers whose 24-h urines presented no evidence of common urinary stone risk factors such as hypercalciuria, hyperoxaluria, hyperuricosuria, hypocitraturia, hypomagnesiuria or low glycosaminoglycans excretion and 12 male controls (matched for age and body weight) whose 24-h urines did not differ from those of stone formers. The study of urinary CaOx nucleation was made in freshly voided overnight urines whose biochemical composition was almost identical in the two groups. In filtered (0.22 micron) and ultrafiltered (10 kDa) urine we performed an oxalate tolerance test to determine the permissible increment of oxalate, the oxalate level for nucleation and the permissible increment of CaOx relative supersaturation (CaOx RS). In filtered urine from stone formers the permissible increment of oxalate was lower than controls (30 +/- 10.2 vs. 46.7 +/- 9.7 mg/l, P = 0.001), the oxalate level for nucleation was lower (64.4 +/- 14.2 vs. 79.5 +/- 15.6 mg/l, P = 0.035) and the permissible increment of CaOx RS was also lower (9.71 +/- 2.59 vs. 13.39 +/- 3.62, P = 0.018). In ultrafiltered urine these differences disappeared because the removal of macromolecules in stone formers significantly enhanced the oxalate-tolerance values. The difference between the change of the oxalate permissible increment of filtered and ultrafiltered urine allowed a distinction to be made between stone formers and controls that was not feasible in other ways (7.6 +/- 5.3 vs. 3.3 +/- 5.9 mg/l, P < 0.0001). The study suggests that, in idiopathic CaOx stone formers free from common urinary risk factors of CaOx crystallization, there is an increased tendency for CaOx nucleation in urine, which is mediated by macromolecular components.

Adult

Immunological changes among workers occupationally exposed to styrene.

The functional status of the immune system was investigated in a group of 71 workers exposed to styrene and in 65 control subjects, recruited according to the same selection criteria and comparable as to sex, age, and confounding variables. Air and biological monitoring were used to characterize styrene exposure (median of the main urinary metabolites in the "next-morning" spot samples: 106 mg/g creatinine). Phenotypic analysis of peripheral blood lymphocytes (PBL) by automated flow cytometry revealed a reduced proportion of T lymphocyte subsets (CD3+, CD4+ and CD4+45+), with no changes in CD8+, and a higher proportion of B lymphocytes (CD19+) among styrene-exposed workers. The exposed workers showed a higher proportion of activation markers, namely DR and interleukin-2 receptors (CD25). Immunoglobulin subclasses were comparable in the two groups. An increased prevalence of abnormally low values was apparent for CD2+, CD3+, CD4+, CD4+45+ and CD11b subsets among workers exposed to styrene, whereas CD19+, DR+ and CD25+ showed an increased prevalence of abnormally high values. Natural killer-related phenotypes (CD56+, CD56+16+, and CD56+16-) were more expressed among styrene workers, with average increase of 30%. However, the frequency distribution of the lytic activity of natural killer cells against K-562 target cells was shifted towards lower values in the exposed workers as compared to control subjects. Dose-response relationships between indices of internal dose and prevalence of abnormal values were detectable for T lymphocyte subsets, NK phenotypes, and activation markers. These findings suggest that moderate exposure to styrene is associated with an altered distribution of lymphocyte subsets.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult

Quality assurance for immunochemical methods.

Recently developed immunochemical methods offer many advantages, although they may suffer from problems in standardisation due to the difficulties in the characterisation of immunological reagents. The reliability of the results is influenced by the availability of reference materials, calibrators, reagent kits and instruments. Since inter-laboratory quality control programmes have been limited by the lack of standard reference materials, laboratories using immunoassays should, at least, implement an internal quality control programme aimed at avoiding systematic errors, and adhere to the rules for good laboratory practice. The exchange of home-made materials as well as the control over pre-analytical factors (selection, collection and storage of specimens) within collaborative studies could be useful to the harmonisation of the measurement procedures. This paper deals with whether such quality requirements are or can be fulfilled with regard to early markers of nephrotoxic effects based on the immunochemical determination of proteins and kidney-derived antigens in urine or serum.

Humans

The assay of laminin fragments in serum and urine as an indicator of renal damage induced by toxins.

An ELISA procedure for the assay of laminin fragments in serum and urine is described. Samples from solvent-exposed workers and diabetic patients were studied. In cohorts exposed to perchloroethylene serum and urine laminin fragments were elevated but the urinary N-acetyl-beta-D-glucosaminidase (NAG) was unaffected. The data indicate that the urinary assay may be more specific for renal damage than the serum method. Differences in the excretion of NAG and urinary laminin fragments were observed in the diabetic groups suggesting that the excretion of these two components reflects different stages of severity of the disease.

Acetylglucosaminidase

Peripheral markers of catecholamine metabolism among workers occupationally exposed to manganese (Mn).

In a preliminary study of 11 men randomly selected in a ferro-alloy plant and of 15 control subjects, platelet monoamine oxidase (MAO) and serum dopamine beta-hydroxylase (DBH) activities were measured. A tendency towards lower MAO-B activity in the exposed workers as compared to control subjects (t = 1.95; P = 0.06) was found whereas DBH activity was similar. In the exposed group, a dose-effect relationship was noted between a manganese (Mn) cumulative exposure index (CEI) and DBH activity (R2 = 0.40, P < 0.05). Since DBH is an expression of catecholamine release, the relative increase in such activity could be envisaged as a compensatory mechanism to a reduced turnover rate as reflected by MAO-B activity. Owing to the limited sample size, these findings should be confirmed by further epidemiological and experimental studies.

Adult

Monitoring norepinephrine levels by microdialysis in the white adipose tissue of spontaneously hypertensive rats.

1. To investigate whether microdialysis is suitable to monitor catecholamine in white adipose tissue of conscious rat and to assess eventual differences in norepinephrine (NE) interstitial levels, two groups of 12 male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats, 14-16 weeks old, were compared. 2. A flexible microdialysis probe was implanted subcutaneously in the parascapular region, and perfused with Ringer solution (flow rate: 2.0 mu L/min). After a 20 min equilibration period, NE levels were monitored over a 120 min period; then, tyramine hydrochloride (0.1 nmol/min) was perfused for 80 min. Dialysates from each 20 min collection period were analysed by HPLC with electrochemical detection for NE. 3. Basal levels of NE (adjusted for the recovery) were higher in SHR compared to WKY (1210.0 +/- 140.5 pg/mL dialysate vs 573.3 +/- 75.8 pg/mL dialysate; P < 0.001, ANOVA). In both strains tyramine perfusion increased NE concentration in dialysates; the net (i.e. baseline subtracted) NE output was lower (76.3 pg/h, s.e.m. 22.3) in SHR compared with that shown by WKY rats (201.0 pg/h, s.e.m 18.4, P < 0.01). 4. The increased basal levels of NE observed in SHR are associated with a blunted response to tyramine challenge. Since tyramine is known to cause NE release from the cytosol but not from vesicle stores, such a blunted response is consistent with an increased turnover rate of NE or with an accelerated uptake in pre-synaptic vesicles which, together with the higher basal levels, would suggest increased noradrenergic activity.

Adipose Tissue

Microdialysis as a tool to assess interstitial norepinephrine levels in adipose tissue of spontaneously hypertensive rats.

The microdialysis technique was applied to the study of norepinephrine (NE) metabolism in white adipose tissue of spontaneously hypertensive (SHR, n = 6) and normotensive Wistar-Kyoto (WKY, n = 6) rats. Mean concentrations of interstitial NE were much higher in SHR as compared to WKY (mean +/- SEM: 980.9 +/- 125.6 pg/ml vs 520.7 +/- 96.1 pg/ml; p = 0.01) over the 180 min experimental period. These results are consistent with the hypothesis that sustained outflow from nerve endings of the peripheral sympathetic system may play a role in the maintenance of arterial hypertension. Owing to its low invasiveness, the microdialysis technique allows to continuously monitor NE extracellular levels in conscious and freely-moving animals.

Adipose Tissue

Does occupational cobalt exposure determine early renal changes?

A cohort of workers occupationally exposed to cobalt (Co) dusts was examined to assess possible subclinical renal effects attributable to Co. Cross-sectional investigations involved 26 workers with a mean age of 34.2 (S.D., 8.3), chronically-exposed (median, 3.5 years; range, 0.9-11) to Co dusts in hard-metal manufacturing factories. Thirty-five healthy control workers, with a mean age of 32.4 (S.D., 4.6) were also examined. Individual interviews were used to exclude subjects with renal or systemic diseases, intake of nephrotoxic drugs, and exposure to known nephrotoxins. Exposure levels, assessed by ambient and biological monitoring, showed an estimated exposure approaching the ACGIH-recommended TLV of 50 micrograms/m3. Immunochemical methods were used to measure urinary albumin, retinol-binding protein (RBP), beta 2-microglobulin (beta 2m), and tubular brush-border antigens. The prevalence of abnormal values for early markers of renal dysfunction was similar in Co-exposed workers and in controls. However, within the reference interval, the cumulated frequency distribution for beta 2m was shifted towards higher values in the exposed group. No relationship was detected between renal markers and either intensity or duration of exposure. In spite of a limited number of observations, these findings suggest that the kidney is not a target organ during occupational exposure to Co.

Adult

Protracted high-dose interferon gamma therapy for chronic experimental nephropathy.

This study focused on the utility of interferon gamma (IFN gamma) as an anti-fibrotic drug in renal experimental fibrosis; the nephropathy was induced by two doses of Adriamycin (ADR) in 20 Sprague Dawley rats, 10 of which were randomly assigned to receive IFN gamma (45,000 UI) on alternate day for 16 weeks. At the end of the follow up, ADR rats treated with IFN gamma developed massive proteinuria, slight renal insufficiency, and presented diffuse glomerulosclerosis, tubulo interstitial infiltration and fibrosis. No difference was found in the composition of tubulo-interstitial infiltrates, mainly consisting in CD4+T lymphocytes with a minor component of CD8+T cells, in comparison with rats treated with ADR alone. These observations demonstrate the inefficacy of a protracted high-dose treatment with IFN gamma in chronic experimental nephropathy with interstitial fibrosis.

Animals

Renal effects of nifedipine and captopril in patients with essential hypertension and reduced renal reserve.

In this study we investigated the short-term effects of calcium channel blockers and angiotensin-converting enzyme inhibitors on renal hemodynamics and the urinary excretion of proteins with different relative mass in subjects with mild to moderate essential hypertension and apparently normal glomerular filtration rate but reduced renal functional reserve. Sixteen subjects underwent the following four treatments: (1) low-protein meal (0.2 g protein/kg body wt), (2) high-protein meal (1.3 g protein/kg body wt), (3) high-protein meal plus oral nifedipine (20 mg), and (4) high-protein meal plus oral captopril (50 mg). Two urine samples were obtained after meals. Blood samples were drawn at the midpoint of each 120-minute urine collection period. Urine and serum were tested for total protein, immunoglobulin G, albumin, alpha 1-microglobulin, retinol binding protein, and beta 2-microglobulin. Glomerular filtration rate and renal plasma flow were assessed by iothalamate and p-aminohippuric clearance, respectively. Compared with the high-protein meal alone, nifedipine elicited a clear-cut increase in the urinary excretion of total protein (+60%, P < .01), immunoglobulin G (+58%, P < .01), albumin (+25%, P < .05), retinol binding protein (+47%, P < .05), and beta 2-microglobulin (+52%, P < .05); captopril decreased the urinary excretion rate of immunoglobulin G (-26%, P < .05), albumin (-22%, P < .05), and beta 2-microglobulin (-34%, P < .05). The ratio between the clearances of immunoglobulin G and albumin was higher after nifedipine (+21%, P < .01) and unchanged after captopril (-9%, P = NS) compared with the high-protein meal alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult

Multiple interferences on catecholamine metabolism by tetrahydroisoquinolines (TIQs).

TIQs are thought to be formed by condensation between dopamine and certain metabolites of ethanol, organic solvents and anesthetic gases. Described here are experiments aimed at evaluating TIQs interference with catecholamine synthesis. Rat adrenal pheochromocytoma (PC12) cell lysates were exposed to benzyl-TIQ and phenyl-TIQ. The activities of tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) were measured by HPLC-based methods following exposure to variable concentrations of TIQs. The effects of TIQs on DBH activity were also assessed in human serum. Dixon plot analyses revealed that TIQs act on TH as competitive inhibitors with different affinity. Ki for benzyl- and phenyl-TIQ were 5 and 3 microM respectively. DBH activity in serum exposed to benzyl- and phenyl-TIQ ranging from 0.2 to 20 microM rose respectively by 12.5% to 58% for benzyl- and by 7.8% to 26% for phenyl-TIQ. Such TIQs interferences with catecholamine metabolism seem to account for dopamine (DA) depletion observed in parallel in vitro experiments on PC12 cells. The dose-dependent inhibition of TH and the increased activity of DBH together with the relatively low effective doses of TIQs suggest this mechanism as a possible explanation of the selective toxicity of styrene and other solvents to dopaminergic systems observed in rabbits following experimental exposure and suspected to occur in occupationally-exposed workers.

Animals

A case of asymptomatic giant aneurysm of the common hepatic artery.

The authors are presenting a case of asymptomatic giant aneurysm of the common hepatic artery in a 72 year-old woman. The patient came under our observation with a complete, recent diagnosis. However, two years earlier in another clinic, a para-hilar hepatic mass with partially calcified walls was incidentally found during an abdominal ultrasound. An abdominal TC without contrast medium showed the mass to be hepatic hydatid cysts. TC images after 2 years showed a growth in diameter from 7 to 12 cm. Having undergone an hysterectomy and a rectal prosthesis, technical difficulties occurred because of the aneurysm's characteristics. The authors would like to emphasize that the rarity of the lesion must not exclude it from the diagnostic protocol of abdominal masses: ultrasound must be accompanied by a Doppler and the TC must be made using a contrast medium. Furthermore, revascularization surgery may create difficulties that cannot be previously prevented.

Aged