History and environmental impact of mining activity in Celtic Aeduan territory recorded in a peat bog (Morvan, France).

The present study aims to document historical mining and smelting activities by means of geochemical and pollen analyses performed in a peat bog core collected around the Bibracte oppidum (Morvan, France), the largest settlement of the great Aeduan Celtic tribe (ca. 180 B.C. to 25 A.D.). The anthropogenic Pb profile indicates local mining operations starting from the Late Bronze Age, ca. cal. 1300 B.C. Lead inputs peaked at the height of Aeduan civilization and then decreased after the Roman conquest of Gaul, when the site was abandoned. Other phases of mining are recognized from the 11th century to modern times. They have all led to modifications in plant cover, probably related in part to forest clearances necessary to supply energy for mining and smelting. Zn, Sb, Cd, and Cu distributions may result from diffusional and biological processes or from the influence of groundwater and underlying mineral soil, precluding their interpretation for historical reconstruction. The abundance of mineral resources, in addition to the strategic location, might explain why early settlers founded the city of Bibracte at that particular place. About 20% of the anthropogenic lead record was accumulated before our era and about 50% before the 18th century, which constitutes a troublesome heritage. Any attempts to develop control strategies in accumulating environments should take into account past human activities in order to not overestimate the impact of contemporary pollution.

Metachromatic leukodystrophy: identification of the first deletion in exon 1 and of nine novel point mutations in the arylsulfatase A gene.

Metachromatic leukodystrophy (MLD), a lysosomal storage disease caused by the deficiency of arylsulfatase A (ASA), is inherited as an autosomal recessive trait, and its frequency is estimated to be 1 in 40,000 live births. Genomic DNA from 21 MLD patients (14 late-infantile and 7 juvenile cases) was amplified in four overlapping PCR fragments and tested by allele-specific oligonucleotide (ASO) for the two common mutations 459 + 1G-->A and P426L. These mutations were found in only 28.6% of the alleles studied. The remaining alleles were analyzed by chemical mismatch cleavage (CMC) and automatic sequencing. In addition to five previously reported mutations (459 + 1G-->A, A212V, R244C, R390W, P426L), 10 novel mutations were identified: 9 missense mutations (S95N, G119R, D152Y, R244H, S250Y, A314T, R384C, R496H, K367N) and one 8 bp deletion in exon 1, the first mutation reported in this exon. These methods allowed us to identify 76% of the alleles tested. Genotype-phenotype correlations could be established for some of these mutations. These results confirm the heterogeneity of mutations causing MLD and suggest that CMC is a reliable and informative screening method for point mutation detection in the arylsulfatase A gene.

Technetium-99m-sestamibi uptake by human benign and malignant breast tumor cells: correlation with mdr gene expression.

UNLABELLED: Early diagnosis of multidrug-resistance (MDR) development is extremely important for the judicious choice of treatment protocols in breast cancer chemotherapy. In this study, the mechanism of 99mTc-sestamibi uptake by nine human breast tumor cell lines was analyzed as a function of P-glycoprotein (PgP) expression. METHODS: Technetium-99m-sestamibi radioactivity incorporation into the cells was determined after different times of incubation at 37 degrees C. We analyzed the mechanism of 99mTc-sestamibi uptake as follows: (a) effect of temperature (4 degrees C); (b) influence of extracellular 99mTc-sestamibi concentration; and (c) competitive inhibition of cell uptake with cold 99mTc-sestamibi. Technetium-99m-sestamibi uptake was compared to the level of PgP determined by Western blotting. The PgP reversing effect of verapamil was evaluated at different drug concentrations (50, 200, 500 microM). RESULTS: Technetium-99m-sestamibi uptake plateaued at 60 min, which was 14 times lower at 4 degrees C than at 37 degrees C and was directly proportional to the extracellular concentration between 0.3 and 10 nM. Technetium-99m-sestamibi percentage uptake by cells expressing nonimmunodetectable levels of PgP was significantly higher (7.3% +/- 0.6% (s.d.) to 14.9% +/- 1.9%) than that by cells expressing high PgP levels (0.7% +/- 0.4%, p < 0.001). In the presence of verapamil, a known reverser of PgP functions, 99mTc-sestamibi uptake was increased by a factor of 2 in cells expressing no detectable levels of PgP and by a factor of 12 in cells with high PgP levels. CONCLUSION: Technetium-99m-sestamibi uptake by these breast tumor cells is energy-dependent but not specific. These data suggest that 99mTc-sestamibi imaging may be used as a noninvasive technique to diagnose the presence of MDR in breast tumors in vivo.

Synthesis of 4-Amino-1-Hydroxy-Butane-1,1-Diphosphonate (AHBDP) - Stannous Complexes for the Preparation of Ahbdp-Sn(II)-Tc and its Biodistribution in Rats.

The new potential tracer of bone imaging, AHBDP-Sn(II)-TcO.3H(2)O was synthesized by reducing the TcO(4) (-) to TcO(2) (+) in the presence of AHBDP and Sn(ll)'s reducing agent. We found that tin rapidly forms a stable complex with AHBDP, giving AHBDP-Sn(II).3H(2)O. In the excess of AHBDP-Sn(ll).3H(2)O, the AHBDP-Sn(II).3H(2)O coordinates with TcO(2) (+) to give AHBDP-Sn(II)-TcO.3H(2)O which could polymerise or oligomerise to give hydrophobic species. The overall process appears as a first-order reaction (K= 0.67 +/- 0.005s(-1)). In rats, the fixation of AHBDP-Sn(II)-(99m)TcO. 3H(2)O on bone is homogeneous and the scintigraphic images have the same quality as those of 1-hydroxymethane-1,1-diphosphonate-Technetium (HMDP-(99m)Tc). The activity in non-target organs was neglible.

Kinetics of a new iodolabeled MAO-B inhibitor in the rat brain and in cultured astrocytes.

3-Bromobenzyloxy phenyloxy hydroxymethyl propanol was labelled with iodine-125. Labeling yield was approximately 92%. Using HPLC and an RP18 column, Iodo*MD (MW = 412) was obtained at no-carrier-added conditions (specific activity 125 Ci/mmole). Biochemical experiments were carried out in vitro and showed a Ki for MAO-B of 5.4 nM and of 5000 for MAO-A (RA/B = 926). Using ex vivo kinetic inhibition in rat (dose: 5 mg/kg p.o.), the results demonstrated a strong similarity of action with BromoMD and IodoMD, with an inhibition percentage that decreased with time (91% at 1 hour, 48% at 8 hours, 2% at 24 hours). The rat brain Iodo*MD concentration was maximal after the first pass and inhibition decreased slowly with time (T1/2 = 1.8 hours). Uptake and wash-out of Iodo*MD was studied on two-day-old rat astrocytes in culture. Half-times of uptake and efflux were respectively 2.5 minutes and 7.5 minutes. The use of metabolic inhibitors (KCN and Digoxin) suggested the absence of any active transport. Binding studies with various concentration of cold MD 360194 showed that at 10(-8) M the uptake decreased significantly. Rats were dissected at different times post i.v. injection (0-2 hours), and the principal organs and brain were obtained (the brain was separated into 7 pieces). Radioactivity was concentrated mainly in the liver (24.6 +/- 4%), fat (12.4 +/- 3.4%) and muscles (18.4 +/- 3%). In the brain the concentration was approximately 1.2 +/- 0.3% within 30 minutes post i.v. injection and 0.84 +/- 0.15% thereafter. The hypothalamus and striatum were two-fold more active than the cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Control of erythropoiesis in humans during prolonged exposure to the altitude of 6,542 m.

Altitude hypoxia induces an increase in erythropoiesis. Some of the factors involved in the control of altitude polycythemia were studied. Ten subjects (4 women, 6 men) were exposed for 3 wk to extreme altitude (6,542 m). Blood was withdrawn in normoxia (N) and after 1 wk (H1), 2 wk (H2), or 3 wk (H3) at 6,542 m for the measurement of serum erythropoietin (EPO), blood hemoglobin (Hb), hematocrit (Hct), intraerythrocyte folate (Fol), and plasma ferritin (Fer) concentrations. Renal blood flow (RBF) and absolute proximal reabsorption rate (APR) were measured by the p-aminohippuric acid and lithium clearance, respectively, in N and H2 conditions. O2 supply to the kidneys was calculated using RBF and arterial O2 content (CaO2). After an initial sharp increase in EPO, it decreased at H2 and H3. Hct and Hb increased from N to H1 and H2 and then unexpectedly decreased from H2 to H3. Mean corpuscular Hb content (MCHC = Hb/Hct) was lower in all H than in N conditions. Increase in EPO at H1 varied from 3- to 134-fold among individuals. Women showed a smaller increase in Hct and Hb and a greater decrease in MCHC. Two women showed a large increase in EPO without increase in Hb. Fol was not modified by altitude hypoxia. Fer showed a marked decrease in H1 and H3 compared with N. Hb was positively related to Fer in hypoxia. Iron intake in food was markedly decreased during the 2-wk ascent to 6,542 m. EPO was inversely related to CaO2 and positively related to APR.(ABSTRACT TRUNCATED AT 250 WORDS)