Maturation-dependent neurotoxicity of lead acetate in vitro: implication of glial reactions.

Despite a wealth of data on the neurotoxic effects of lead at the cellular and molecular levels, the reasons for its development-dependent neurotoxicity are still unclear. Here, the maturation-dependent effects of lead acetate were analyzed in immature and differentiated brain cells cultured in aggregates. Markers of general cytotoxicity as well as cell-type-specific markers of glial and neuronal cells showed that immature brain cells were more sensitive to lead than the differentiated counterparts, demonstrating that the development-dependent neurotoxicity of lead can be reproduced in aggregating brain cell cultures. After 10 days of treatment, astrocytes were found to be more affected by lead acetate than neurons in immature cultures, and microglial cells were strongly activated. Eleven days after cessation of the treatment, lead acetate caused a partial loss of astrocytes and an intense reactivity of the remaining ones. Furthermore, microglial cells expressed a macrophagic phenotype, and the loss of activity of neuron-specific enzymes was aggravated. In differentiated cultures, no reactive gliosis was found. It is hypothetized that the intense glial reactions (microgliosis and astrogliosis) observed in immature cultures contribute to the development-dependent neurotoxicity of lead.

An evaluation of the inorganic and organic geochemistry of the San Vicente Mississippi Valley-type zinc-lead district, central Peru: Implications for ore fluid composition, mixing processes, and sulfate reduction

Mississippi Tialley-type zinc-lead deposits and ore occurrences in the San Vicente belt are hosted in dolostones of the eastern Upper Triassic to Lower Jurassic Pucara basin, central Peru. Combined inorganic and organic geochemical data from 22 sites, including the main San Vicente deposit, minor ore occurrences, and barren localities, provide better understanding of fluid pathways and composition, ore precipitation mechanisms, Eh-pH changes during mineralization, and relationships between organic matter and ore formation. Ore-stage dark replacement dolomite and white sparry dolomite are Fe and rare earth element (REE) depleted, and Mn enriched, compared to the host dolomite. In the main deposit, they display significant negative Ce and probably Eu anomalies. Mixing of an incoming hot, slightly oxidizing, acidic brine (H2CO3 being the dominant dissolved carbon species), probably poor in REE and Fe, with local intraformational, alkaline, reducing waters explains the overall carbon and oxygen isotope variation and the distributions of REE and other trace elements in the different hydrothermal carbonate generations. The incoming ore fluid flowed through major aquifers, probably basal basin detrital units, with limited interaction with the carbonate host rocks. The hydrothermal carbonates show a strong regional chemical homogeneity, indicating access of the ore fluids by interconnected channelways near the ore occurrences. Negative Ce anomalies in the main deposit, that are absent at the district scale, indicate local ore-fluid chemical differences. Oxidation of both migrated and indigenous hydrocarbons by the incoming fluid provided the local reducing conditions necessary for sulfate reduction to H2S, pyrobitumen precipitation, and reduction of Eu3+ to Eu2+. Fe-Mn covariations, combined with the REE contents of the hydrothermal carbonates, are consistent with the mineralizing system shifting from reducing/rock-dominated to oxidizing/fluid-dominated conditions following ore deposition. Sulfate and sulfide sulfur isotopes support sulfide origin from evaporite-derived sulfate by thermochemical organic reduction; further evidence includes the presence of C-13-depleted calcite cements (similar to-12 parts per thousand delta(13)C) as sulfate pseudomorphs, elemental sulfur, altered organic matter in the host dolomite, and isotopically heavier, late, solid bitumen. Significant alteration of the indigenous and extrinsic hydrocarbons, with absent bacterial membrane biomarkers (hopanes) is observed. The light delta(34)S of sulfides from small mines and occurrences compared to the main deposit reflect a local contribution of isotopically light sulfur, evidence of local differences in the ore-fluid chemistry.

Minerais, métaux, isotopes : recherches archéométriques sur les mines de plomb et d'argent en Valais, Suisse

RESUME Les nombreuses mines de plomb et d'argent du Valais témoignent d'une activité minière importante par le passé, sans toutefois dévoiler ni l'importance des minéralisations, ni l'ancienneté de l'exploitation. La présente recherche a pour but de comprendre pourquoi les grandes mines sont concentrées dans une région, et de déterminer la chronologie de leur exploitation. L'originalité de ce travail réside dans son interdisciplinarité, plus précisément dans l'application des méthodes minéralogiques pour résoudre une problématique historique. Afin d'évaluer les ressources minières en plomb et en argent du Valais, 57 mines et indices ont été repérés et échantillonnés. Les signatures isotopiques du Pb (74 analyses) et les compositions chimiques élémentaires (45 analyses) ont été déterminées. Les plus grandes exploitations se situent dans la nappe de Siviez-Mischabel, au Sud d'une ligne Vallée du Rhône / Val de Bagnes ainsi que dans le Lötschental. Elles sont liées, d'après leur signature isotopique de plomb, à des minéralisations d'âge calédonien (408 à 387 Ma) ou tardi-hercynien (333 à 286 Ma). À ces périodes, l'ancien continent est très lourd et subit une subsidence thermique. Des premières fractures d'extrême importance se forment. Comme il s'agit d'accidents tectoniques majeurs, des gisements de grande extension peuvent se former dans ce contexte. D'autres minéralisations se situent dans les domaines helvétiques (Massif des Aiguilles Rouges, Massif du Mont Blanc et couverture sédimentaire), couvrant une région au Nord de la Vallée du Rhône et du Val d'Entremont. D'âge post-hercynien à tardi-alpin (notons qu'il n'y a pas de minéralisations d'âge tertiaire), elles sont pour la plupart liées à des intrusions granitiques, sources de plomb juvénile. Les mines situées dans ces unités tectoniques sont nettement moins étendues que celles de la nappe de Siviez-Mischabel, ce qui permet de penser que les minéralisations correspondantes le sont également. Les périodes d'exploitation des mines peuvent être déterminées par quatre approches différentes l'archéologie minière, la lecture des textes historiques, l'étude des déchets métallurgiques et la comparaison de la signature isotopique du plomb, que l'on mesure dans un objet archéologique bien daté (monnaie, bijoux etc.), avec celles des minerais. Cette dernière méthode a été appliquée et développée dans le cadre de la présente recherche. Pour ce faire, 221 échantillons d'objet en plomb ou en argent datés entre l'Âge du Fer et le Moyen Age ont été analysés par la méthode des isotopes de plomb et comparés à environ 1800 signatures isotopiques de minerais des gisements les plus importants en Suisse et en Europe. Avant l'époque romaine et jusqu'au 1 er siècle de cette époque, le plomb provient principalement des mines de la péninsule ibérique alors en pleine activité. Un apport des mines d'Europe tempérée, notamment des Vosges, reste à confirmer. A partir du 1" siècle de notre ère, le plomb a principalement été importé en Suisse occidentale de grands centres de productions situées en Allemagne du Nord (région d'Eifel). Les mines de plomb valaisannes, notamment celles de Siviez, débutent leur exploitation en même temps, principalement pour couvrir les besoins locaux, mais également pour l'exportation jusque dans l'arc lémanique et, dans une moindre importance, au-delà. À partir du 4ème siècle, le besoin en plomb a été couvert par un apport des mines locales et par la refonte d'objets anciens. Ce changement d'approvisionnement est probablement lié aux tensions créées par les invasions germaniques durant la seconde moitié du 3' siècle ; le marché suisse n'est dès lors plus approvisionné par le nord, c'est-à-dire par la vallée du Rhin. Quant à l'argent, l'exploitation de ce métal est attestée à partir de la fin du La Tène, peu après l'apparition de ce métal dans la région valaisanne. L'échantillonnage ne couvrant pas l'époque romaine, rien n'est connu pour cette période. A partir du 5" siècle, une exploitation d'argent est de nouveau attestée. Cependant, l'exploitation d'argent des mines locales ne gagne en importance qu'à partir du Moyen Âge avec les frappes monétaires, notamment les frappes carolingiennes et épiscopales valaisannes. Les sources d'argent sont différentes selon leur utilisation : à part quelques exceptions notamment vers la fin du La Tène et au tardo-antique, les bijoux et objets de cultes ont été souvent créés à partir d'argent refondu, contrairement aux monnaies pour lesquelles l'argent provient des mines locales. On note un approvisionnement différent de ce métal pour les objets, notamment les monnaies, selon leur lieu de fabrication : on peut clairement distinguer les objets valaisans de ceux du Plateau Suisse. SUMMARY The many lead and silver mines of the Valais testify of an important mining activity in the past, without however revealing neither the importance of the mineralizations, nor the era of the exploitation. The purpose of this research is to understand why the large mines are concentrated in one region, and to determine the history of their exploitation. The uniqueness of this work lies in its interdisciplinarity, more precisely in the application of mineralogical methods to solve historical problems. In order to evaluate the lead and silver mining resources of the Valais region, 57 mines and ore deposits were located and sampled. The isotope signatures of Pb (74 analyses) and the compositions of the chemical elements (45 analyses) were determined. The largest activities are in the Siviez-Mischabel area, located in the South of the boundary formed by the Rhone, Bagnes and Lotschental valleys. According to their lead isotope signatures, they are linked to mineralizations of the Caledonian (408 to 387 my) or tardi-Hercynian (333 to 286 my) orogenies. In those times, the old continent was very heavy and underwent a thermal subsidence. First fractures of great significance were formed. Through these major tectonic events, large extended ore deposits can be formed. Other mineralizations are found in the helvetic regions situated north of the Rhone and the Entremont valley (the Aiguilles Rouges basement, Mount Blanc basement and the covering sediment). Because they are from post-hercynien to tardi-alpine age (there are no mineralizations of tertiary age), they are mainly linked to granite intrusions, the sources of juvenile lead. The mines found in these tectonic units are significantly less extensive than those of the Siviez-Mischabel area, leading to the assumption that the respective mineralizations extend accordingly. The history of exploitation of the mines can be determined by four different sources: mining archaeology, historical texts, metallurgical waste, and the comparison of the isotope signature of the lead from accurately dated archaeological objects (currency, jewels etc), with those of the ores. This last approach was applied and developed within the framework of this research. The lead isotope signatures of 221 lead or silver objects from the Iron Age to the Middle Age were compared with approximately 1800 samples of ore of the most important ore deposits in Switzerland and Europe. Before the Roman time up to the 1st century, lead comes mainly from the mines of the Iberian Peninsula then in full activity. A contribution of the mines of Central Europe, in particular of the Vosges, remains to be confirmed. From the 1st century on, lead was mainly imported into Western Switzerland from Northern Germany (Eiffel region). The lead mines in the Valais region, in particular those of Siviez, begin their exploitation at the same time, mainly to meet the local needs, but also for export to the lemanic basin and of lesser importance, beyond. As from the 4th century, the need of lead was met by the production from local mines and the recycling of old objects. This change of supply is probably related to the tensions created by the Germanic invasions during second half of the 3rd century; as a consequence, the Swiss market is not supplied any more by the north, i.e. the Rhine valley. Silver production is confirmed starting from the end of La Tene, shortly after the appearance of this metal in the Valais region. Since no objects of Roman origin were analyzed, nothing is known for this period. From the 5th century on, silver production is again confirmed. However, significant silver production from local mines starts only in the Middle Age with the coinage, in particular Carolingian and Episcopal minting from the Valais region. The sources of silver differ according to their use: besides some exceptions in particular towards the end of La Tene and the tardi-Roman, the jewels and objects of worships were often created from recycled silver, contrary to the coins the silver for which comes from the local mines. A different source of silver is observed according to the location of coin manufacture: Objects originating from the Valais region are clearly distinguished from those from the Plateau Suisse. ZUSAMMENFASSUNG Die grosse Zahl von Blei- und Silberminen im Wallis ist Zeugnis einer bedeutenden Bergbautätigkeit, es fehlen aber Hinweise über ihren Umfang und den Zeitraum ihrer Ausbeutung. Die vorliegende Arbeit sucht zu ergründen, warum grosse Minen sich in einer eng begrenzten Region häufen und in welchem Zeitraum sie genutzt wurden. Die Besonderheit der Studie liegt in ihrer Interdisziplinarität, genauer in der Anwendung von mineralogischen Methoden zur Beantwortung historischer Fragestellungen. Zur Beurteilung der Lagerstätten wurden von 57 Minen und Aufschlüssen Proben entnommen oder Nachweise erbracht und mittels 74 Isotopen-Analysen von Blei und 45 chemischen Gesamtanalysen ausgewertet. Die wichtigsten Vorkommen liegen in der Siviez- Mischabel- Decke südlich der Linie Rhonetal- Val de Bagnes, sowie im Lötschental. Die Bleiisotopen- Alter weisen ihre Entstehung der kaledonischen (408 - 387 Mio. J.) oder der spät- herzynischen (333 - 286 Mio. J.) Gebirgsbildungsphase zu. In dieser Periode ist die kompakte Landmasse sehr schwer und erfairt eine thermische Absenkung. Es bilden sich tektonische Brüche von kontinentaler Ausdehnung. Die grossen tektonischen Bewegungen ermöglichen die Bildung von ausgedehnten Lagerstätten. Andere Vorkommen finden sich im Bereich der Helvetischen Alpen (Aiguilles Rouges Massiv, Mont-Blanc-Massiv und Sediment-Decken) im Gebiet nördlich des Rhonetales bis zum Val d'Entremont. Altersmässig sind sie der nach-hercynischen bis zur spät-alpidischen Orogenese zuzuweisen (auffällig ist das Fehlen von Vorkommen im Tertiär) und haben sich meist in der Folge von Granit- Intrusion, dem Ursprung von primärem Blei ausgebildet. Die Bergwerke in diesem Bereich sind deutlich weniger ausgedehnt als jene in der Siviez-Mischabel-Decke und entsprechen wahrscheinlich dem geringen Umfang der zugehörigen Vorkommen. Die Nutzungsperioden der Minen können mit vier verschiedenen Methoden bestimmt werden: Minenarchäologie, Historische Quellen, Auswertung von metallischen Abfällen (Schlacken) und Vergleich der Bleiisotopen-Zusammensetzung von Erzen mit jener von zeitlich gut datierbaren archäologischen Gegenständen (Münzen, Schmuckstücke). Die letztere Methode wurde im Rahmen der vorliegenden Forschungsarbeit entwickelt und angewendet. Zu diesem Zweck wurden an 221 Proben von Blei- oder Silberobjekten, die in die Periode zwischen Eisenzeit und Mittelalter eingestuft werden können, Bleiisotopen- Analysen durchgeführt und mit ca. 1800 Proben aus den wichtigsten Lagerstätten der Schweiz und Europas verglichen. Vor der Römerzeit und bis ins 1. Jahrh. stammt das Blei vornehmlich aus den in jener Zeit in voller Ausbeutung begriffenen Minen der Iberischen Halbinsel. Der Beitrag von Mitteleuropa, besonders der Vogesen, muss noch bestätigt werden. Ab dem 1. Jahrh. nach Chr. wurde die Westschweiz hauptschlich mit Blei aus den grossen Produktionszentren Norddeutschlands, vorwiegend der Eifel, versorgt. In dieser Periode setzt die Ausbeutung der Bleiminen des Wallis, besonders von Siviez, ein. Sie dienen der Deckung des örtlichen Bedarfs aber auch der Ausfuhr in das Gebiet des Genfersees und in einem bescheidenen Rahmen sogar darüber hinaus. Ab dem 4. Jahrhundert wurden vermehrt alte Objekte eingeschmolzen. Dieser Wechsel der Versorgungsquellen war vermutlich eine Folge der Wölkerwanderung in der zweiten Hälfte des 3. Jahrhunderts. Ab diesem Zeitpunkt war Helvetien der Zugang zu den Versorgungsquellen des Nordens, besonders des Rheinlandes, verwehrt. Der Abbau von Silber ist ab dem Ende des La Tène nachgewiesen, nur wenig nach dem Auftreten dieses Metalls im Wallis. Über die Römerzeit können wegen dem Fehlen entsprechender Proben keine Aussagen gemacht werden. Eine erneute Abbauperiode ist ab dem 5. Jahrhundert nachgewiesen. Die Produktion der örtlichen Minen erreicht aber erst im Mittelalter eine gewisse Bedeutung mit der Prägung von Mnzen durch die Karolinger und die Walliser Bischöfe. Die Herkunft des Silbers ist abhängig von dessen Verwendung. Mit wenigen Ausnahmen in der Zeit des La Tène und der späteren Römerzeit wurde für Kunst- und Kult- Gegenstände rezykliertes Silber verwendet, für Münzprägungen neues Silber aus den örtlichen Minen. Von Einfluss auf die Herkunft war auch der Produktionsstandort: Die Objekte aus dem Wallis unterscheiden sich deutlich von jenen des Mittellandes.

Mutations of the Serine Protease CAP1/Prss8 Lead to Reduced Embryonic Viability, Skin Defects, and Decreased ENaC Activity.

CAP1/Prss8 is a membrane-bound serine protease involved in the regulation of several different effectors, such as the epithelial sodium channel ENaC, the protease-activated receptor PAR2, the tight junction proteins, and the profilaggrin polypeptide. Recently, the V170D and the G54-P57 deletion mutations within the CAP1/Prss8 gene, identified in mouse frizzy (fr) and rat hairless (fr(CR)) animals, respectively, have been proposed to be responsible for their skin phenotypes. In the present study, we analyzed those mutations, revealing a change in the protein structure, a modification of the glycosylation state, and an overall reduction in the activation of ENaC of the two mutant proteins. In vivo analyses demonstrated that both fr and fr(CR) mutant animals present analogous reduction of embryonic viability, similar histologic aberrations at the level of the skin, and a significant decrease in the activity of ENaC in the distal colon compared with their control littermates. Hairless rats additionally had dehydration defects in skin and intestine and significant reduction in the body weight. In conclusion, we provided molecular and functional evidence that CAP1/Prss8 mutations are accountable for the defects in fr and fr(CR) animals, and we furthermore demonstrate a decreased function of the CAP1/Prss8 mutant proteins. Therefore, fr and fr(CR) animals are suitable models to investigate the consequences of CAP1/Prss8 action on its target proteins in the whole organism.

Problèmes d'échantillonnage lors d'une enquête sur la plombémie d'enfants citadin [Sampling problems in a survey of blood lead levels in city children].

A study on lead pollution was carried out on a sample of ca. 300 city children. This paper presents the errors producing bias in the sample. It is emphasized that, in Switzerland, the difference between the Swiss and the migrant population (the latter being mainly Italian and Spanish) must be taken into account.

Hydrocarbon biomarkers in the Topla-Mezica zinc-lead deposits, northern Karavanke/Drau Range, Slovenia: Paleoenvironment at the site of ore formation

The Mississippi Valley-type zinc and lead deposits at Topla (250,150 metric tons (t) of ore grading 1.0 wt % Zn and 3.3 wt % Pb) and Mezica (19 million metric tons (Mt) of ore grading 5.3 wt % Pb and 2.7 wt % Zn) occur within the Middle to Upper Triassic platform carbonate rocks of the northern Karavanke/Drau Range geotectonic units of the Eastern Alps, Slovenia. The ore and host rocks of these deposits have been investigated by a combination of inorganic and organic geochemical methods to determine major, trace, and rare earth element (REE) concentrations, hydrocarbon distribution, and stable isotope ratios of carbonates, kerogen, extractable organic matter, and individual hydrocarbons. These data combined with sedimentological evidence provide insight into the paleoenvironmental conditions at the site of ore formation. The carbonate isotope composition, the REE patterns, and the distribution of hydrocarbon biomarkers (normal alkanes and steranes) suggest a marine depositional environment. At Topla, a relatively high concentration of redox sensitive trace elements (V, Mo, U) in the host dolostones and REE patterns parallel to that of the North American shale composite suggest that sediments were deposited in a reducing environment. Anoxic conditions enhanced the preservation of organic matter and resulted in relatively higher total organic carbon contents (up to 0.4 wt %). The isotopic composition of the kerogen (delta C-13(kerogon) = -29.4 to -25.0 parts per thousand, delta N-15(kerogen) = -.13.6 to 6.8 parts per thousand) suggests that marine algae and/or bacteria were the main source of organic carbon with a very minor contribution from detrital continental plants and a varying degree of alteration. Extractable organic matter from Topla ore is generally depleted in C-13 compared to the associated kerogen, which is consistent with an indigenous source of the bitumens. The mineralization correlates with delta N-15(kerogen) values around 0 per mil, C-13 depleted kerogen, C-13 enriched n-heptadecane, and relatively high concentrations of bacteria] hydrocarbon biomarkers, indicating a high cyanobacterial biomass at the site of ore formation. Abundant dissimilatory sulfate-reducing bacteria, feeding on the cyanobacterial remains, led to accumulation of biogenic H2S in the pore water of the sediments. This biogenic H2S was mainly incorporated into sedimentary organic matter and diagenetic pyrite. Higher bacterial activity at the ore site also is indicated by specific concentration ratios of hydrocarbons, which are roughly correlated with total Pb plus Zn contents. This correlation is consistent with mixing of hydrothermal metal-rich, fluids and local bacteriogenic sulfide sulfur. The new geochemical data provide supporting evidence that Topla is a low-temperature Mississippi Valley-type deposit formed in an anoxic supratidal saline to hypersaline environment. A laminated cyanobacterial mat, with abundant sulfate-reducing bacteria was the main site of sulfate reduction.

Minority quasispecies of drug-resistant HIV-1 that lead to early therapy failure in treatment-naive and -adherent patients.

BACKGROUND: Early virological failure of antiretroviral therapy associated with the selection of drug-resistant human immunodeficiency virus type 1 in treatment-naive patients is very critical, because virological failure significantly increases the risk of subsequent failures. Therefore, we evaluated the possible role of minority quasispecies of drug-resistant human immunodeficiency virus type 1, which are undetectable at baseline by population sequencing, with regard to early virological failure. METHODS: We studied 4 patients who experienced early virological failure of a first-line regimen of lamivudine, tenofovir, and either efavirenz or nevirapine and 18 control patients undergoing similar treatment without virological failure. The key mutations K65R, K103N, Y181C, M184V, and M184I in the reverse transcriptase were quantified by allele-specific real-time polymerase chain reaction performed on plasma samples before and during early virological treatment failure. RESULTS: Before treatment, none of the viruses showed any evidence of drug resistance in the standard genotype analysis. Minority quasispecies with either the M184V mutation or the M184I mutation were detected in 3 of 18 control patients. In contrast, all 4 patients whose treatment was failing had harbored drug-resistant viruses at low frequencies before treatment, with a frequency range of 0.07%-2.0%. A range of 1-4 mutations was detected in viruses from each patient. Most of the minority quasispecies were rapidly selected and represented the major virus population within weeks after the patients started antiretroviral therapy. All 4 patients showed good adherence to treatment. Nonnucleoside reverse-transcriptase inhibitor plasma concentrations were in normal ranges for all 4 patients at 2 separate assessment times. CONCLUSIONS: Minority quasispecies of drug-resistant viruses, detected at baseline, can rapidly outgrow and become the major virus population and subsequently lead to early therapy failure in treatment-naive patients who receive antiretroviral therapy regimens with a low genetic resistance barrier.

Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human.

Neuronal migration disorders such as lissencephaly and subcortical band heterotopia are associated with epilepsy and intellectual disability. DCX, PAFAH1B1 and TUBA1A are mutated in these disorders; however, corresponding mouse mutants do not show heterotopic neurons in the neocortex. In contrast, spontaneously arisen HeCo mice display this phenotype, and our study revealed that misplaced apical progenitors contribute to heterotopia formation. While HeCo neurons migrated at the same speed as wild type, abnormally distributed dividing progenitors were found throughout the cortical wall from embryonic day 13. We identified Eml1, encoding a microtubule-associated protein, as the gene mutated in HeCo mice. Full-length transcripts were lacking as a result of a retrotransposon insertion in an intron. Eml1 knockdown mimicked the HeCo progenitor phenotype and reexpression rescued it. We further found EML1 to be mutated in ribbon-like heterotopia in humans. Our data link abnormal spindle orientations, ectopic progenitors and severe heterotopia in mouse and human.

Involvement of environmental mercury and lead in the etiology of neurodegenerative diseases.

The incidence of neurodegenerative disease like Parkinson's disease and Alzheimer's disease (AD) increases dramatically with age; only a small percentage is directly related to familial forms. The etiology of the most abundant, sporadic forms is complex and multifactorial, involving both genetic and environmental factors. Several environmental pollutants have been associated with neurodegenerative disorders. The present article focuses on results obtained in experimental neurotoxicology studies that indicate a potential pathogenic role of lead and mercury in the development of neurodegenerative diseases. Both heavy metals have been shown to interfere with a multitude of intracellular targets, thereby contributing to several pathogenic processes typical of neurodegenerative disorders, including mitochondrial dysfunction, oxidative stress, deregulation of protein turnover, and brain inflammation. Exposure to heavy metals early in development can precondition the brain for developing a neurodegenerative disease later in life. Alternatively, heavy metals can exert their adverse effects through acute neurotoxicity or through slow accumulation during prolonged periods of life. The pro-oxidant effects of heavy metals can exacerbate the age-related increase in oxidative stress that is related to the decline of the antioxidant defense systems. Brain inflammatory reactions also generate oxidative stress. Chronic inflammation can contribute to the formation of the senile plaques that are typical for AD. In accord with this view, nonsteroidal anti-inflammatory drugs and antioxidants suppress early pathogenic processes leading to Alzheimer's disease, thus decreasing the risk of developing the disease. The effects of lead and mercury were also tested in aggregating brain-cell cultures of fetal rat telencephalon, a three-dimensional brain-cell culture system. The continuous application for 10 to 50 days of non-cytotoxic concentrations of heavy metals resulted in their accumulation in brain cells and the occurrence of delayed toxic effects. When applied at non-toxic concentrations, methylmercury, the most common environmental form of mercury, becomes neurotoxic under pro-oxidant conditions. Furthermore, lead and mercury induce glial cell reactivity, a hallmark of brain inflammation. Both mercury and lead increase the expression of the amyloid precursor protein; mercury also stimulates the formation of insoluble beta-amyloid, which plays a crucial role in the pathogenesis of AD and causes oxidative stress and neurotoxicity in vitro. Taken together, a considerable body of evidence suggests that the heavy metals lead and mercury contribute to the etiology of neurodegenerative diseases and emphasizes the importance of taking preventive measures in this regard.

Risky single occasion drinking frequency and alcohol-related consequences: can abstinence during early adulthood lead to alcohol problems?

QUESTIONS UNDER STUDY: the main purpose of this longitudinal study was to determine the impact of risky single occasion drinking (RSOD) frequency on alcohol dependence and drinking consequences reported 15 months later. METHODS: As a baseline sample, 5,990 young men were assessed on their drinking habits including the frequency of RSOD. Of them, 5,196 were reassessed at follow-up 15 months later on RSOD frequency, alcohol dependence and alcohol related consequences in thze interceding year. Drop out biases were investigated. RESULTS: Around 45% of the baseline participants reported regular RSOD (every month or more frequently). Despite the fact that RSOD distribution was generally stable during the initial sample, 47.4% reported a variation of their RSOD frequency 15 months later. Around 25% of the sample reported reduced RSOD frequency. Nonetheless, occasional RS drinkers were more likely to become regular (monthly) RSO drinkers at follow up. Daily and weekly RSOD were associated with high proportions of alcohol dependence and detrimental consequences of drinking. Surprisingly, abstainers at baseline were more likely to be at risk of alcohol dependence and consequences at follow up than non-RSO drinkers. CONCLUSIONS: Despite the fact that alcohol abstinence is logically the best way to avoid the detrimental consequences of alcohol drinking, abstainers at baseline reported as many problems due to alcohol use at follow up as occasional or monthly RSO drinkers. The few participants who had become RSO drinkers during the follow up period were indeed likely to engage in detrimental behaviour. Non-RSO drinkers had the fewest problems due to alcohol use. This substantiates the early occurrence of drinking consequences among inexperienced RSO drinkers.

Palaeoenvironment and palaeoclimate of the Middle Miocene lake in the Steinheim basin, SW Germany: A reconstruction from C, O, and Sr isotopes of fossil remains

A differentiated reconstruction of palaeolimnologic, -environmental, and -climatic conditions is presented for the Middle Miocene long-term freshwater lake (14.3 to 13.5 Ma) of the Steinheim basin, on the basis of a combined C, 0, and Sr isotope study of sympatric skeletal fossils of aquatic and terrestrial organisms from the lake sediments. The oxygen isotope composition for lake water of the Steinheim basin (delta O-18(H2O) = +2.0 +/- 0.4 parts per thousand VSMOW, n = 6) was reconstructed from measurements of delta O-18(PO4) of aquatic turtle bones. The drinking water calculated from the enamel of large mammals (proboscideans, rhinocerotids, equids, cervids, suids) has delta O-18(H2O) values (delta(OH2O)-O-18 = -5.9 +/- 1.7 parts per thousand VSMOW, n = 31) typical for Middle Miocene meteoric water of the area. This delta O-18(H2O) value corresponds to a mean annual air temperature (MAT) of 18.8 +/- 3.8 degrees C, calculated using a modem-day delta(OH2O)-O-18-MAT relation. Hence, large mammals did not use the lake water as principal drinking water. In contrast, small mammals, especially the then abundant pika Prolagus oeningensis drank from O-18-enriched water sources (delta O-18(H2O) = +2.7 +/- 2.3 parts per thousand VSMOW, n = 7), such as the lake water. Differences in Sr and 0 isotopic compositions between large and small mammal teeth indicate different home ranges and drinking behaviour and support migration of some large mammals between the Swabian Alb plateau and the nearby Molasse basin, while small mammals ingested their food and water locally. Changes in the lake level, water chemistry, and temperature were inferred using isotopic compositions of ostracod and gastropod shells from a composite lake sediment profile. Calcitic ostracod valves (Ilyocypris binocularis; delta O-18 = +1.7 +/- 1.2 parts per thousand VPDB, delta C-18 = -0.5 +/- 0.9 parts per thousand, VPDB, n = 68) and aragonitic, gastropod shells (Gyraulus spp.; delta O-18 = +2.0 +/- 13 parts per thousand VPDB, delta C-13 = -1.1 +/- 1.3 parts per thousand VPDB, n = 89) have delta O-18 and delta C-13 values similar to or even higher than those of marine, carbonates. delta C-13 values:of the biogenic carbonates parallel lake level fluctuations while delta O-18 values scatter around +2 +/- 2 parts per thousand and reflect the short term variability of meteoric water inflow vs. longer term evaporation. Sr-87/Sr-86 ratios of aragonitic Gyraulus spp. gastropod shells parallel the lake level fluctuations, reflecting variable inputs of groundwater and surface waters. Using a water delta O-18(H2O) value of +2.0 parts per thousand VSMOW, water temperatures calculated from skeletal tissue delta O-18 values of ostracods are 16.7 +/- 5.0 degrees C, gastropods 20.6 +/- 5.6 degrees C, otoliths 21.8 +/- 1.4 degrees C, and fish teeth 17.0 +/- 2.7 degrees C. The calculated MAT (similar to 19 degrees C), lake water temperatures (similar to 17 to 22 degrees C) and the O-18-enriched water compositions are indicative of warm-temperate climatic conditions, possibly with a high humidity during this period. Vegetation in the area surrounding the basin was largely of the C-3-type, as indicated by carbon isotopic compositions of tooth enamel from large mammals (delta C-13 = -11.1 +/- 1.1 parts per thousand VPDB, n = 40). (c) 2006 Elsevier B.V. All rights reserved.

Randomized trial of pacemaker and lead system for safe scanning at 1.5 Tesla.

BACKGROUND: Magnetic resonance imaging (MRI) of pacemakers is a relative contraindication because of the risks to the patient from potentially hazardous interactions between the MRI and the pacemaker system. Chest scans (ie, cardiac magnetic resonance scans) are of particular importance and higher risk. The previously Food and Drug Administration-approved magnetic resonance conditional system includes positioning restrictions, limiting the powerful utility of MRI. OBJECTIVE: To confirm the safety and effectiveness of a pacemaker system designed for safe whole body MRI without MRI scan positioning restrictions. METHODS: Primary eligibility criteria included standard dual-chamber pacing indications. Patients (n = 263) were randomized in a 2:1 ratio to undergo 16 chest and head scans at 1.5 T between 9 and 12 weeks postimplant (n = 177) or to not undergo MRI (n = 86) post-implant. Evaluation of the pacemaker system occurred immediately before, during (monitoring), and after MRI, 1-week post-MRI, and 1-month post-MRI, and similarly for controls. Primary end points measured the MRI-related complication-free rate for safety and compared pacing capture threshold between MRI and control subjects for effectiveness. RESULTS: There were no MRI-related complications during or after MRI in subjects undergoing MRI (n = 148). Differences in pacing capture threshold values from pre-MRI to 1-month post-MRI were minimal and similar between the MRI and control groups. CONCLUSIONS: This randomized trial demonstrates that the Advisa MRI pulse generator and CapSureFix MRI 5086MRI lead system is safe and effective in the 1.5 T MRI environment without positioning restrictions for MRI scans or limitations of body parts scanned.

Characterization of lead-recycling facility emissions at various workplaces : major insights for sanitary risks assessment

Most available studies on lead smelter emissions deal with the environmental impact of outdoor particles, but only a few focus on air quality at workplaces. The objective of this study is to physically and chemically characterize the Pb-rich particles emitted at different workplaces in a lead recycling plant. A multi-scale characterization was conducted from bulk analysis to the level of individual particles, to assess the particles properties in relation with Pb speciation and availability. Process PM from various origins were sampled and then compared; namely Furnace and Refining PM respectively present in the smelter and at refinery workplaces, Emissions PM present in channeled emissions.These particles first differed by their morphology and size distribution, with finer particles found in emissions. Differences observed in chemical composition could be explained by the industrial processes. All PM contained the same major phases (Pb, PbS, PbO, PbSO4 and PbO·PbSO4) but differed on the nature and amount of minor phases. Due to high content in PM, Pb concentrations in the CaCl2 extractant reached relatively high values (40 mg.L-1). However, the ratios (soluble/total) of CaCl2 exchangeable Pb were relatively low (< 0.02%) in comparison with Cd (up to 18%). These results highlight the interest to assess the soluble fractions of all metals (minor and major) and discuss both total metal concentrations and ratios for risk evaluations. In most cases metal extractability increased with decreasing size of particles, in particular, lead exchangeability was highest for channeled emissions. Such type of study could help in the choice of targeted sanitary protection procedures and for further toxicological investigations. In the present context, particular attention is given to Emissions and Furnace PM. Moreover, exposure to other metals than Pb should be considered. [Authors]