ࡱ> Y bjbjWW =={]DXXXX4 dX#||@"""""""$#%b##`|```"XX"`:` ""p V~XX>"" OHES Literature Review 1/2000 Introduction The OHES Committee of IMnI has accepted the advice of its Scientific Advisory Group (SAG) that a regular review be made of the scientific literature dealing with issues relevant to occupational health and environmental issues affecting the world-wide manganese industry (producers and users). The objective of the publication is to draw attention to specific articles which merit reading and further study by individuals with responsibility for OHES matters. An initial survey of the literature indicates that more than 2000 articles dealing with all aspects of Mn are published annually with approximately 10/15% relating to some aspect of OHES affairs, whether it be human health, animal studies, vegetation or environmental matters. It is not always easy to judge the importance of any one paper and each paper has to be seen against the background of prior publications and the best available current understanding of a large number of scientific topics. The review will not therefore (in the first instance) critically analyse each individual paper, rather, it will draw attention to papers dealing with topics which the SAG have judged to be of current and future relevance to our industry. Our current plan is to publish this review bi-annually.  We plan to publish abstracts along with any necessary commentary on each abstract by the SAG members. A copy of each paper will be held by IMnIs secretariat so that members can request copies, should they so wish, of specific papers. During the course of the next 12 months we intend to make these papers available in electronic form, provided that our new web-site has the capacity to store this information and that it can be accessed without difficulty. We would appreciate all feedback on the publication, preferably as constructive criticism, so that we can improve the service and make it more pertinent to member companies and other interested parties. C.D. DesForges Executive Director, IMnI P. Rousseau Chairman, SAG January 2000 1/00 Bright basal ganglia in T1-weighted magnetic resonance images are frequent in patients with portal vein thrombosis without liver cirrhosis and not suggestive of hepatic encephalopathy Nolte (W) Wiltfang (J) Schindler (C) Unterberg (K) Finkenstaedt (M) Niedmann (P) Hartmann (H) Ramadori (G) Journal of Hepatology 1998; 29; 443-449 Background/Aims: Deposition of paramagnetic substances in basal ganglia, resulting in increased signals in T1-weighted magnetic resonance images (bright basal ganglia), is frequently seen in liver cirrhosis. The present study describes the prevalence of bright basal ganglia and its clinical significance in patients with long-standing portal vein thrombosis in the absence of liver cirrhosis. Methods: Six patients with angiographically proven complete portal vein thrombosis and cavernomatous transformation without signs of acute or chronic liver disease were studied by magnetic resonance imaging of the brain, neuropsychiatric evaluation, psychometric tests, electroencephalography, and determination of arterial ammonia levels and of scrum manganese concentrations from peripheral venous blood. Results: Five out of six patients demonstrated increased signal intensity in the basal ganglia. Overt portal-systemic encephalopathy was not noted prior to or at the time of evaluation. Normal EEG results were recorded in all patients. Only one of the six patients had pathological results in at least two out of four psychometric tests. This latter patient had had a large right-sided brain infarction. Arterial ammonia concentrations were normal in four of the six patients; one patient with increased ammonia levels had concomitant renal insufficiency with azotemia. The other four patients had no relevant concomitant diseases. Serum manganese levels were non-significantly increased compared with a control group (p=0.06), but they were significantly correlated to basal ganglia signal intensity (R=0.88; p=0.02). Conclusions: Our results demonstrate that bright basal ganglia primarily represent shunt-induced alterations. They are not directly associated with disturbed liver function nor with portal-systemic encephalopathy.  2/00 Long-term progression in chronic manganism. Ten years of follow-up Huang (C.-C.) N.-S. Chu (N.-S.) Lu (C.-S.) Chen (R.-S.) Calne (D.B.) Neurology 1998; 50; 698-700 We studied the long-term clinical course of five patients with chronic manganese intoxication. The mean scores of the King's College Hospital Rating Scale for Parkinson's disease increased from 15.0 4.2 in 1987 to 28.3 6.70 in 1991 and then to 38.1 12.9 in 1995. The deterioration was most prominent in gait, rigidity, speed of foot tapping, and writing. Tissue concentrations of manganese in blood, urine, scalp hair, and pubic hair returned to normal. Follow-up MRIs did not show paramagnetic high-signal intensity on T1-weighted images. The data indicate that clinical progression in patients with manganese parkinsonism continues even 10 years after cessation of exposure. 3/00 Effects of lead and manganese on the release of lysosomal enzymes in vitro and in vivo Bairati (C) Goi (G), Bollini (D) Roggi (C) Luca (M) Apostoli (P) Lombardo (A) Clinica Chimica Acta 1997; 261; 91-101 In this study we evaluated the effects of two heavy metals, lead and manganese on the release of some glycohydrolases of lysosomal origin. N-acetyl-(--glucosaminidase and its major isoenzymes. (--glucuronidase and (--galactosidase. We have studied release of these enzymes in vitro from peripheral mitogen-activated lymphocytes from healthy subjects after addition of Pb or Mn to the medium and their plasma levels in individuals exposed at work to Pb (31 subjects) or to manganese (36 subjects). versus matched controls. We also determined the plasma levels in a general population (417 subjects). The enzymatic activities were assayed fluorimetrically with 4-methyl -umbelliferyl-glycosides as substrates. Particular attention was given to some technical aspects: enzymatic activity was preserved by addition of ethylene glycol and stable liquid material was employed for calibration purposes. N-acetyl-(--gluco- saminidase iso -enzymes were separated by a routine chromatofocusing procedure on PBE 94. The addition of both metals to lymphocytes inhibits lysosomal enzyme release. These data were supported by the plasma levels for the exposed subjects, in which enzyme levels were significantly decreased after either type of exposure. In the general population of subjects not professionally exposed, the effect of lead appears to be. masked by. concomitant effects of alcohol consumption. Undoubtedly. some heavy metals can alter distribution of glycohydrolases of lysosomal origin between the intra-and extracellular environment, probably interfering with membrane mechanisms. Lysosomal enzymes seem to behave as sensitive biomarkers for early subclinical changes that might later lead to clinical disease. 4/00 Ammonia and Manganese Increase Arginine Uptake in Cultured Astrocytes Hazell (A) Norenberg (M) Neurochemical Research 1998; 23; 6, 869-873 Recent work has suggested a possible role for nitric oxide (NO) in the development of hepatic encephalopathy (HE). In this study, we examined the effect of ammonia and manganese, factors implicated in the pathogenesis of HE, on the transport of arginine (a precursor of NO) into primary cultures of astrocytes. Treatment with 5 mM ammonia for 1-4 days produced a maximal (53%) increase in L-arginine uptake at 3 days when compared to untreated cells. Kinetic analysis following 4-day treatment with 5 mM ammonia revealed an 82% increase in the Vmax and a 61% increase in the Km value. Similar analysis with 100 (M manganese showed a 101 % increase in Vmax and a 131% increase in the Km value. These results suggest that both manganese and ammonia alter L-arginine uptake by modifying the transporter for arginine. A decrease of 32% in the non-saturable component of L-arginine transport was also observed following treatment with ammonia. When cultures were treated separately with 5 mM ammonia and 100 (M manganese for 2 days, the uptake of L-arginine increased by 41 % and 57%, respectively. Combined exposure led to no further increase in uptake. Our results suggest that ammonia and manganese may contribute to the pathogenesis of HE by influencing arginine transport and thus possibly NO synthesis in astrocytes. 5/00 Determination of aluminium and manganese in human scalp hair by electrothermal atomic absorption spectrometry using slurry sampling Bermejo-Barrera (P) Moreda-Pieiro (A) Moreda-Pieiro (J) Bermejo-Barrera (A) Talanta 1998; 45; 1147 - 1154 Methods for the determination of aluminium and manganese in human scalp hair samples by electrothermal atomic absorption spectrometry using the slurry sampling technique were developed. Palladium and magnesium nitrate were used as chemical modifiers. Hair samples were pulverized using a zirconia vibrational mill ball, and were prepared as aqueous slurries. Determinations can be performed in the linear ranges of 1.9- 150 (g 1-1 Al3+ and 0.03- 10.0 (g 1-1 Mn2+ . Limits of detection of 0.9 mg kg-1 and 27.6 (g kg-1 were obtained for aluminium and manganese respectively. The analytical recoveries were between 99.6 and 101.8% for aluminium and in the 98.3-101.3% range for manganese. The repeatability of the methods (n = 11), slurry preparation procedure and ETAAS measurement, was 16.0 and 7.9%, for aluminium and manganese, respectively. The methods were finally applied to the aluminium and manganese determination in 25 scalp hair samples from healthy adults. The levels for aluminium were between 8.21 and 74.08 mg kg-1 while concentrations between 0.03 and 1.20 mg kg-1 were found for manganese. 6/00 Role of oxidative stress in the manganese and 1-methyl-4-(2-ethylphenyl)-1,2,3,6- tetra-hydropyridine-induced apoptosis in PC12 cells Desole (MS) Sciola (L) Delogu (MR) Sircana (S) Migheli (R) Miele (E) Neurochem. Int. 1997; 31; 2; 169 176 Oxidative stress is thought to play a key role in the apoptotic death of several cellular systems, including neurons. Oxidative stress is proposed also as a mechanism of the neurotoxin 1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- and manganese (Mn)-induced neuronal death. We have recently shown that Mn and the MPTP analogue 1-methyl-4-(2'-ethylphenyl)-1,2,3,6-tetrahydropyridine (2Et-MPTP), which is metabolized by MAO-A to 1-methyl-4-(2'- ethylphenyl)-pyridinium ion, induce apoptosis in PC12 cells. In the present study, we evaluated the effects of deprenyl and the antioxidant drugs N-acetylcysteine (NAC) and ascorbic acid (AA) on Mn- and 2'Et-MPTP-induced apoptosis in PC12 cells. Apoptosis was tested by terminal deoxynucleotidyl transferase-mediated 2'-deoxy-uridine-5'-triphosphate nick end labelling (TUNEL) technique, flow cytometry and fluorescence microscopy. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Mn-induced apoptosis and decrease in cell viability was inhibited by the antioxidants NAC and AA. Deprenyl failed to inhibit the above Mn effects. Neither NAC, AA nor deprenyl were able to inhibit both 2'Et-MPTP-induced apoptosis and decrease in cell viability. These results confirm that apoptosis may be an important mechanism of cell death in MPTP- and Mn-induced parkinsonism. However, an oxidative stress mechanism may be recognized, at least in vitro, only in the Mn-induced apoptosis. 7/00 Immunodetection of manganese superoxide dismutase in cultured human retroocular fibroblasts using sera directed against the thyrotropin receptor Burch (H.B.) Barnes (S) Nagy (E.V.) Sellitti (D) Burman (K.D.) Bahn (R.S.) Lahiri (S) J. Endocrinol. Invest. 1998; 21; 48-55 The identification of antigenic targets in the retroocular autoimmune response of Graves' ophthalmopathy is likely to increase our understanding of mechanisms underlying this disorder. While a number of putative autoantigens have been identified on the basis of molecular weight or cell of origin, a determination of the significance of these antigens is contingent upon an identification of the amino acid sequence. Our group has previously identified immunoreactive retroocular fibroblast (ROF) proteins recognized by thyrotropin receptor (hTSH-R) antisera (anti-p1), at molecular weights of 95, 71, 41, and 14-25 kDa. In the present study, proteins detected by anti-p1 and visualized by Ponceau staining were isolated and processed for microsequencing. Ponceau staining revealed dense bands at molecular weights of 14 and 23 kDa, and a weak band at 41 kDa. N-terminal sequencing was performed on the prominent band at approximately 23 kDa, showing it to be manganese superoxide dismutase (MnSOD), a mitochondrial enzyme responsible for protection against oxygen free radical-associated cellular damage. Sequence comparison of MnSOD to the hTSH-R peptide, p1, revealed a linear segment of amino acid homology. Preincubation of anti-p1 with p1 blocked immunodetection of the 23 kDa band corresponding to MnSOD, and immunoprecipitation of ROF protein using anti-p1 yielded protein recognized by anti-MnSOD. Autoimmunity against human recombinant MnSOD was further assessed by ELISA. Patients with Graves' disease (n = 53) had significantly higher ELISA indices than normal control subjects (n = 29), while patients with Hashimoto's thyroiditis had intermediate values. These results document MnSOD autoantibodies in patients with Graves' disease and suggest that this may result from an immune cross-reactivity between MnSOD and the TSH-receptor. 8/00 Enhancement of cytotoxicity and clastogenicity Of L-DOPA and doparnine by manganese and copper ' Snyder (R.D.) Friedman (M.B.) Mutation Research 1998; 405; 1-8 It is an increasingly popular hypothesis that the continued degeneration of dopaminergic neurons in Parkinson's disease (PD) may be the consequence of aberrant oxidation of dopamine and resultant generation of DNA reactive species in PD patients receiving levodopa (L-DOPA) therapy. Occupational metal exposure, particularly to manganese, is a risk factor for Parkinsonism and manganese has been shown to be a true catalyst for dopamine oxidation lending support to this hypothesis. In the present studies, we demonstrate that the antiproliferative activity of L-DOPA and dopamine on Chinese Hamster V79 cells is enhanced by at least an order of magnitude by concomitant exposure to manganese chloride or copper sulfate (500 (M), but not to iron(III) or zinc. Moreover, manganese and copper confer strong clastogenic properties to both compounds as detected in an in vitro micronucleus assay in V79 cells. Metal catalyzed oxidation of drug was associated with the development of a brown-black particulate substance presumed to be a melanin precursor formation. The extent of formation of this precursor paralleled clastogenicity. Metal-enhanced effects were completely antagonized by the concurrent addition of cysteine or reduced glutathione to the cultures. These findings are in support of the hypothesis that aberrant oxidation of dopamine resulting from non-physiological levels of catalytic metals may contribute to the death of dopaminergic neurons and further suggest that oxidation-dependent DNA damage may be the basis for this cell death. 9/00 Manganese inhibits mitochondrial aconitase: a mechanism of manganese neurotoxicity Zheng (W) Ren (S) Graziano (J.H.) Brain Research 1998; 799; 334-342 The symptoms of Mn-induced neurotoxicity resemble those of Parkinson's diseases. Since iron (Fe) appears to play a pivotal role in pathophysiology of Parkinson's disease, we set out to test the hypothesis that alterations in Fe-requiring enzymes such as aconitase contribute to Mn-induced neurotoxicity. Mitochondrial fractions prepared from rat brain were preincubated with MnCl2 in vitro, followed by the enzyme assay. Mn treatment significantly inhibited mitochondrial aconitase activity (24% inhibition at 625 (M to 81% at 2.5 mM, p < 0.05). The inhibitory effect was reversible and Mn-concentration dependent, and was reversed by the addition of Fe (0.05- 1 mM) to the reaction mixture. In an in vivo chronic Mn exposure model, rats received intraperitoneal injection of 6 mg/kg Mn as MnCI2 once daily for 30 consecutive days. Mn exposure led to a region-specific alteration in total aconitase (i.e., mitochondrial + cytoplasmic): 48.5% reduction of the enzyme activity in frontal cortex ( p < 0.01), 33.7% in striatum ( p < 0.0963), and 20.6% in substantia nigra (p < 0.139). Chronic Mn exposure increased Mn concentrations in serum, CSF and brain tissues. The elevation of Mn in all selected brain regions (range between 3.1 and 3.9 fold) was similar in magnitude to that in CSF (3.1 fold) rather than serum (6.1 fold). The present results suggest that Mn alters brain aconitase activity, which may lead to the disruption of mitochondrial energy production and cellular Fe metabolism in the brain. 10/00 Relative and Combined Effects of Ethanol and Protein Deficiency on Zinc, Iron, Copper, and Manganese Contents in Different Organs and Urinary and Fecal Excretion Gonzales-Reimers (E) Martinez-Riera (A) Santolaria-Fernandez (F) Mas-Pascual (A) Rodriguez-Moreno (F) Galindo-Martin (L) Molina-Perez (M) Barros-Lopez (N) Alcohol 1998; 16; 1; 7-12 The relative contribution of protein deficiency to the altered metabolism of certain trace elements in chronic alcoholics is not well defined, so this study was performed to analyse the relative and combined effects of ethanol and protein deficiency on liver, bone, muscle, and blood cell content of copper, zinc, iron and manganese. and also on serum levels and urinary and fecal excretion of these elements in four groups of eight animals each that were pair-fed during 8 weeks with a nutritionally adequate diet, a 36% (as energy) ethanol-containing isocaloric diet, a 2% protein isocaloric diet, and a 36% ethanol 2% protein isocaloric diet, respectively, following the Lieber-DeCarli model. Five additional rats were fed ad lib the control diet. Protein malnutrition. but not ethanol. leads to liver zinc depletion. Both ethanol and protein malnutrition cause muscle zinc depletion and increase urinary zinc and manganese excretion, whereas ethanol also increases urinary iron excretion and liver manganese content. No differences were observed regarding copper metabolism. 11/00 Alteration of lipid composition of hepatic membranes associated with manganese-bilirubin induced cholestasis Duguay (A) Yousef (I.M.) Tuchweber (B) Plaa (G.L.) Fundam. Clin. Pharmacol. 1998; 12; 213-219 One hypothesis concerning the pathogenesis of manganese-bilirubin (Mn-BR)-induced cholestasis is that the molecular organization of the bile canalicular membrane is altered. The purpose of the present study was to evaluate lipid composition and fluidity of hepatic membranes during cholestasis in male Sprague-Dawley rats. To induce cholestasis, manganese (Mn, 4.5 mg/kg, intravenously [iv]) was given 15 min before billrubin (BR, 25 mg/kg. iv). The rats were killed 30 min after BR injection, at which time bile flow was decreased by approximately 40% compared to control values. Liver cell plasma membranes enriched in canalicular fractions (BCM) and plasma membranes enriched in sinusoidal and lateral fractions (PM), microsomes, mitochondria and cytosol were isolated by differential centrifugation. Total lipids were extracted and measured colori -metrically. To assess fluidity, membranes were incubated in vitro with fluorescent probes [1,6-diphenyl-1,3,5-hexatriene and 1-(4'-trimethyl-ammonium-phenyl)-6-phenyl-1,3,5-hex -atriene]. After Mn-DR treatment BCM cholesterol incorporation increased markedly (about 3-fold) accompanied by a decrease in fluidity. BCM phospholipid content was unaltered by the cholestatic challenge. In PM-enriched fractions, the changes in cholesterol and phospholipid content after Mn-BR treatment were not statistically significant (P > 0.05) compared to controls. Furthermore, the biochemical alterations in PM were not accompanied by changes in membrane fluidity. These results support the hypothesis that altered lipid composition and fluidity of BCM are involved in the pathogenesis of Mn-BR cholestasis. 12/00 Distribution of mitochondrial man -ganese superoxide dismutase among rat glial cells in culture Pinteaux (E) Perraut (M) Tholey (G) GLIA 1998; 22; 408-414 Enzymatic antioxidant defense systems, like superoxide dismutase (SOD), may protect neuronal and glial cells from reactive oxygen species (ROS) damage. Beside the cytosolic constitutive CuZn SOD, mitochondrial manganese SOD (Mn SOD) represents a ROS inducible enzyme which should allow the adaptation of brain cells to variation in ROS concentrations resulting from their oxidative metabolism. Using immunocytochemistry, the distribution of Mn SOD among the various representatives of the rat brain glial population (astroglia and microglia in primary culture as well as oligodendroglia in secondary culture) has been examined. Among astroglial cells, only a population of flat polygonal-shaped astrocytes, highly immunostained for glial fibrillary acid protein (GFAP) express Mn SOD immunoreactivity. Microglial cells defined by their shape and OX-42 immunoreactivity also express an intense Mn SOD signal. Exposure of the primary culture to reactive oxygen species generated by a xanthine/xanthine oxidase mixture (X/XO) accentuates the Mn SOD signal in astroglial and microglial cells. On the contrary, oligodendroglial cells grown in secondary culture in a serum-free chemically defined or a serum-containing medium and well characterized by their 2,3-cyclic nucleotide 3'-phosphodiesterase (CNPase) immunoreactivity never express any immunostaining for Mn SOD, even in response to an extracellular reactive oxygen species generating source like X/XO. Likewise, a population of A2B5-positive glial cells which may represent bipotential 0-2A progenitor precursors does not express Mn SOD immunostaining. These results point out that in addition to the well known ability of microglial and astroglial cells to secrete ROS, they also express a high mitochondrial oxygen superoxide decomposition potential. On the contrary, the absence of any observable Mn SOD signal in precursors and in more differentiated oligodendroglial cells could be related to their great sensitivity to ROS damage and could therefore play an important role in the development of various dysmyelinating disorders. 13/00 Manganese concentration in rat brain: manganese transport from the peripheral tissues Takeda (A) Sawashita (J) Okada (S) Neuroscience Letters 1998; 242; 45-48 Mn distribution In the brain and peripheral tissues was studied with the course of time after intravenous injection of 54MnCl2 to see manganese (Mn) transport from the peripheral tissues, i.e. the liver, to the brain. One hour after injection, 54Mn concentratons In the brain were 0.15-0.25% dose/g, and 54Mn was largely concentrated in the choroid plexus. One day after injection, 54Mn in the choroid plexus decreased remarkably. 54Mn in other brain regions increased gradually after then, and reached 0.300.40% dose/g 6 days after injection. This increase of 54Mn was due to the redistribution from the peripheral tissues such as liver and pancreas, in which 54Mn was maintained at high levels (2.0-4.0% dose/g). The increment of 54Mn 1 h to 6 days after injection was the largest in the hippocampus, but not in the striatum. These results suggest that the delivery of Mn from the liver to the brain is not involved In preferential Mn accumulation in the basal nuclei under physiological condition. This delivery may be important for brain function. 14/00 Iron-manganese interactions in the evolution of iron deficiency Rodriguez-Matas (M.C.) Camposa (M.S.) Lopez-Aliagaa (L) Gomez-Ayala (A.E.) Lisbonaa (F) Ann Nutr Metab 1998; 42; 96-109 This article examines the evolution of nutritional iron deficiency and the possible interactions with other minerals, such as manganese, in control and iron-deficient rats. The evolution of iron deficiency was studied at 0, 10, 20, 30 and 40 days of providing the animals with an iron-free diet (diet 0). It was found that the critical period in the development of nutritional iron deficiency occurs after 30-40 days without iron, at which moment the organism is unable to maintain hemoglobin levels without endangering the iron-dependent enzymatic groups which, in turn, are essential for life. It was also demonstrated that in a situation of iron deficiency, there occurs a greater absorption of manganese. It should be noted that this greater absorption of manganese is not reflected in the concentration of the mineral in the organs. Therefore, it is evident that the interactions of iron with manganese take place at the digestive level with no apparent consequences being observed at the metabolic level. 15/00 Decrease of manganese superoxide dismutase activity in rats fed high levels of iron during colon carcinogenesis Kuratko (C.N.) Food and Chemical Toxicology 1998; 36; 819-824 Diets high in fat or iron have been associated with an increased risk for development of colon cancer. These two dietary factors are known to decrease manganese superoxide dismutase (MnSOD) activity in colonic mucosa. MnSOD is an antioxidant enzyme that protects mitochondria from oxygen radical-damage. MnSOD has tumour suppressive activity and is absent or decreased in most tumours, including those from the colon. This study was designed to determine the effects of high dietary lipid and iron levels on MnSOD activity during the early weeks of colon carcinogenesis. Male Fischer-344 rats were fed 20% lipid diets of either corn oil or menhaden oil containing adequate iron (35 mg:kg) or supplemental iron (535 mg:kg). Rats from each diet were divided into carcinogen treatment groups and given two weekly injections of either azoxymethane (AOM) at a dose of 12 mg:kg. or saline. Mucosal tissue was collected 1, 6 and 12 wk following injections and analysed for MnSOD activity. mineral concentration and nuclear aberrations. Results showed that iron supplementation increased nuclear aberrations, and decreased manganese concentration and MnSOD activity in colonic mucosa of control animals. AOM. and interaction of iron and AOM. also decreased MnSOD activity. A decrease in the activity of this enzyme during carcinogenesis may be one mechanism whereby these dietary factors ultimately increase tumour risk. 16/00 Suppression of intracellular resistance factors by adriamycin augments heat-induced apoptosis via interleukin-1(-converting enzyme activation in pancreatic carcinoma cells Koboyashi (D) Watanabe (N) Sasaki (H) Okamoto (T) Tsuji (N) Sato (T) Yamauchi (N) Niitsu (Y) Int. J. Cancer 1998; 76; 552~555 Combination of heat and various anticancer drugs can exert a synergistic antitumor effect in vitro and in vivo, though the mechanism is not clear. We have previously shown that endogenous tumor necrosis factor (enTNF) acts as an intracellular resistance factor to inhibit the cytotoxic effect of heat by scavenging oxygen-free radicals via the induction of manganous superoxide dismutase (MnSOD). Consequently, we examined whether the suppression of these resistance factors by combining anticancer drugs and heat causes an augmentation of heat-induced cytotoxicity. The human pancreatic carcinoma cell line PANC-1, constitutively expresses appreciable amounts of enTNF and also demonstrates heat resistance. After treatment of these cells for 15 hr with adriamycin (ADM), the expression of enTNF was decreased by 43%, and MnSOD activity was suppressed by 55%. The cytotoxic effects of the treatment of PANC-1 cells with ADM followed by heat were greater than the sum of those observed with the agents administrated individually. Heat-induced apoptosis was also augmented by pretreatment with ADM. Furthermore, the interleukin. I(-converting enzyme inhibitor, AcYVAD-CMK, reversed the augmented cytotoxicity. Our results indicate that suppression of intracellular resistance factors such as enTNF and MnSOD plays an important role in apoptosis seen after heat and ADM combined therapy. 17/00 Speciation of manganese in tea leaves and tea infusions zdemir (Y) Gcer (S) Analytical Letters 1998; 31; 4; 679-689 A speciation scheme was developed for identification of the chemical forms of manganese in tea leaves and tea infusions. The range of manganese in five different groups of tea leaves was found to be 1107 - 2205 (g/g on a dry basis. It was noted that 30.0 % of Mn was passed into the water that was present in the form of Mn(II), and also 2.5% of Mn was found as the total organic bound fraction and passed into the various solvents, 18/00 Inducible nitric oxide synthase (iNOS)-like immunoreactivity in argyrophilic, tau-positive astrocytes in progressive supranuclear palsy Komori (T) Shibata (N) Kobayashi (M) Sasaki (S) Iwata (M) Acta Neuropathol. 1998; 95; 338-344 The immunoreactivily to the free radical-related enzymes, nitric oxide synthase (NOS) and superoxide dismutase (SOD), was examined in brain tissue in progressive supranuclear palsy (PSP). To determine the relationship between the immunoexpression of these enzymes and tau-positive, argyrophilic cytoplasmic inclusions, which are constantly present in PSP brains, double-label immunohistochemistry was applied. We demonstrated for the first time that strong inducible NOS-like immunoreactivity (iNOS-ir) was detected in tau-positive astrocytes that bore tufts of abnormal fibers (TAF), but not in oligodendrocytes containing argyrophilic/tau-positive coiled bodies nor in microglia. No brain NOS-ir was detected in neurons with neurofibrillary tangles. MnSOD-ir was also detected in tau-positive astrocytes and oligodendrocytes. Nitrotyrosine-ir of variable intensity was observed in astrocytes, oligodendrocytes and neurons. Our results indicate: (1) that TAF-bearing astrocytes may be a major source of excessive NO in PSP brains; (2) that after the induction of iNOS by unknown stimulating factors, TAF-bearing astrocytes produce an excessive amount of NO that exceeds the detoxification capability of SOD, and (3) that peroxynitrite and excessive NO, both cytotoxic, may be present in astrocytes, oligodendrocytes and neurons. Although the precise relationship between NO production and neuronal cell death in PSP remained uncertain, based on the specificity of TAF for PSP brains, our results indicated a possible mechanism of NO-mediated cytotoxicity that may contribute to the neuronal and glial cell damage followed by abnormal tau accumulation in this disease. 19/00 Determination of cobalt, manganese and alcohol content in beers Camean (A) Lopez-Artiguez (M) Roca (I) Herce-Pagliai (C ) Menendez (M) Repetto (M) Journal of Food Protection 1998; 61; 1 129-131 The purpose of this study was to investigate the degree of exposure to cobalt and manganese through the consumption of different brands of commercial beers widely consumed in Spain, considered as two groups according to their alcohol content. The Mn and Co concentrations in beer samples ranged from 25.29 to 228.60 (g/litre and 0.16 to 0.56 (g/litre respectively. These contents do not differ from those found in other countries, and all comply with the maximum levels permitted by law. Significant differences occurred only in Mn content between beers with and without alcohol. The consumption of alcoholic beers contributes to an increased body burden of Mn among heavy consumers. According to the low levels of Co found in both types of beers, we can suggest that there is no risk of suffering cardiomyopathies and there is no significant contribution to the total intake of the element in heavy beer drinkers. 20/00 Use of manganese in ripe olive processing Romero (C) Garcia (P) Brenes (M) Garrido (A) Z Lebensm Unters Forsch A 1998; 206; 297 - 302 The use of manganese (Mn) salts in various steps of the processing of ripe olives of the Manzanilla cultivar can increase their oxidation rate and produce darker olives. The best results were obtained by adding a Mn concentration of 40 mg/l to the storage brine and allowing a period of contact of at least 15 days. Good results were also obtained when using a Mn concentration of 100-250 mg/l in a "desalting" step before darkening, as well as variable periods of contact and temperatures. When Mn was added to the washing waters after any of the lye treatments of the darkening step, especially the first one, the effect was also appreciable, although varying degrees of Mn residues in the flesh were found. Addition of Mn to the storage brine and application of the usual darkening process produced more uniform and darker ripe olives with Mn residue levels at below 30 mg/kg, which is approximately 15% of the recommended daily intake for this metal. Results suggest that this cation, recognized as GRAS in the USA, may be used as a catalyst in the darkening of ripe olives if authorized as a processing aid. 21/00 Removal of Mn and simultaneous removal of NH3, Fe and Mn from potable water using a trickling filter Gouzinis (A) Kosmidis (N) Vayenas (D.V.) Lyberatos (G) Wat. Res. 1998; 32; 8; 2442-2450 Manganese removal using a biological trickling filter was investigated. Manganese removal was found to be caused by both biological and chemical manganese oxidation. The extent of each oxidation type was assessed. The performance of the trickling filter was tested under both continuous and sequencing batch reactor operation. The effectiveness and throughput for each operational mode were determined as a function of retention time and the advantages of each operational mode were investigated. It was found that the continuous operational mode leads to higher percentage of manganese removal but lower throughput rates when compared with a sequencing batch reactor operation with the same feed concentration and retention time. A series of experiments was also performed in order to investigate the interactions between ammonia, iron and manganese removal when simultaneously present in a biological filter. For low ammonia concentrations there is no serious inhibition of manganese removal. For higher ammonia concentrations inhibition of manganese removal becomes substantial. The presence of iron affects both ammonia and manganese removal negatively, while ammonia and manganese do not significantly affect iron removal. 22/00 Status report on proposed changes to permissible airborne emission exposure limits for US shipyard workers Castner (H.R.) Journal of Ship Production 1997; 13; 3; 153-170 The Occupational Safety and Health Administration of the U. S. Department of Labor (OSHA) and the American Conference of Governmental Industrial Hygienists (ACGIH) are making or considering reductions in worker exposure limits for nickel, manganese, and chromium compounds, including hexavalent chromium. These changes will have an impact on the operations and processes used by Navy facilities and public and private shipyards for construction, maintenance, and repair of ships. A Navy/Industry Task Group led by the Naval Sea Systems Command is addressing these concerns and has gathered data on current worker exposure levels to nickel (Ni), manganese (Mn), total chromium (Cr), and hexavalent chromium (Cr(VI)). This paper reports the data gathered to date from literature, the Navy Environmental Health database, shipyard worker sampling, and controlled laboratory welding tests. 23/00 Hepatic cirrhosis: magnetisation transfer contrast in the globus pallidus Iwasa (M) Kinosada (V) Watanabe (S) Furuta (M) Yuda (H) Kawamura (N) Nakayabu (M) Esaki (A) Sato (T) Deguchi (T) Nakatsuka (A) Adachi (Y) Neuroradiology 1998; 40; 3; 145-149 The magnetisation transfer ratio (MTR), a quantitative tissue characteristic, and the palladium index, were measured in the globus pallidus of 37 patients with hepatic cirrhosis and 37 control subjects. The MTR decreased with severity of the disease, as indicated by the serum total bilirubin, indocyanine green 15-min retention rate, and plasma ammonia. The pallidal index correlated significantly with haematological parameters, although the correlation coefficients tended to be lower than those between MTR and haematological parameters. This change in MTR corresponded to the results of the manganese chloride experiments. T1 shortening in the palladium of patients with cirrhosis is presumably caused by paramagnetic effects, and possibly attributed to manganese deposition. 24/00 Dietary standards for manganese: overlap between nutritional and toxicological studies. Greger (J.L.) Jesse (B.W.) McFarland (D.C.) Hoffer (L.J.) Davis (T.A.) J. of Nutrition 1998; 128; 2; 368S-371S The estimated safe and adequate daily dietary intake (ESADDI) for adults for manganese is 2-5 mg Mn/D. The LOAEL (lowest observable adverse effect level) for manganese in water is 0.06 mg Mn/(Kg D) or 4.2 mg Mn/D for a 70 kg individual. The inconsistency in these standards reflects limitations in available data as well as differences in the way in which the standards are calculated. Manganese balance and excretion data are not useful biomarkers of manganese exposure but do demonstrate that the body is protected against manganese toxicity primarily by low absorption and/or rapid presystemic elimination of manganese by the liver. Serum manganese concentrations in combination with lymphocyte manganese-dependent superoxide dismutase (MnSOD) activity and perhaps blood arginase activity, seem to be the best way to monitor ingestion of insufficient manganese. Serum manganese concentrations, in combination with brain magnetic resonance imaging (MRI) scans, and perhaps a battery of neurofunctional tests, seem to be the best way to monitor excessive exposure to manganese. Copyright IMnI January 2000 No part of this publication may be reproduced in any form whatsoever without obtaining IMnI's prior written consent. 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