Mobilization of lead from human bone tissue during pregnancy and lactation--a summary of long-term research

The skeleton is potential endogenous source of lead during pregnancy and lactation. We have undertaken a longitudinal investigation into the mobilization of lead from the human maternal skeleton to determine whether lead is mobilized from the maternal skeleton during pregnancy and lactation, and if so, when and how much is released. Subjects in the study were migrants to Australia (n=15) whose skeletal lead isotopic composition (endogenous lead) was different to that prevailing in the Australian environment (exogenous lead). This migrant cohort was compared with 6 multi-generational Australian controls. Biological and environmental samples were taken pre-pregnancy where possible, throughout pregnancy and postpartum for at least 6 months. Newly-born infants of the migrant and Australian mothers were monitored for 6 months. Blood lead concentrations for the migrant mothers ranged from 1.5 to 20 microg/dl (geometric mean 2.8) and for Australian mothers ranged from 1.9 to 4.3 microg/dl (geometric mean 2.9). There was minimal change in lead isotopic composition of the Australian pregnant controls although there were increases of approximately 40% in blood lead concentration in 3 of 6 cases during the postpartum period and from 0 to 12% in the other 3. In the migrant pregnant subjects, the geometric mean skeletal lead contribution to blood lead using the isotopic composition was approximately 33% (range 10-88%) for 14 subjects using a revised estimate for exogenous lead. Skeletal contribution to blood lead during the postpartum period was significantly greater than during pregnancy (P<0.001). The skeletal contributions to blood lead are higher and the changes are more consistent in those subjects who conceived within 100 days of arrival in Australia compared with those who conceived longer than 100 days. In the migrant subjects, changes in blood lead concentration during pregnancy and postpartum varied from subject to subject with an overall 20% increase; the increases during the postpartum period were greater than during pregnancy (P<0.001). It was estimated that the amount of maternal skeletal lead mobilized during pregnancy and transferred to the infant via cord blood averaged approximately 79%. The increased skeletal contribution to blood lead is attributed to a low daily calcium intake of approximately 500 mgCa/day, a condition which was present in both migrant and Australian subjects. An ongoing clinical trial is providing a new cohort with calcium supplements. A summary of other aspects of the study is included and covers: additional flux released from the skeleton during pregnancy and postpartum; XRF bone lead results; urinary excretion of lead during pregnancy and postpartum; dietary contribution to blood lead in female adults and children; comparison of rates of exchange of lead in blood of newly-born infants and mothers; relationships of lead in breast milk to lead in blood, urine and diet of the infant and mother; changes in blood lead after cessation of breastfeeding; urinary lead isotopes during pregnancy and postpartum indicate no preferential partitioning of endogenous lead into plasma; a comparison of some aspects of the nonhuman primate and human pregnancy studies.     

The effect of exposure to employees from mining and milling operations in a uranium mine on lead isotopes--a pilot study

Potential exposure during mining and milling of uranium ore has resulted in the industry being highly regulated. Exposure can arise from inhalation of the daughter product radioactive gas radon (222Rn), inhalation of radioactive dust particles from mining and milling, direct irradiation from outside the body, and ingestion of radionuclides (e.g. uranium or radium) in food or water. Making use of the highly unusual lead isotopic signature for uranium ores (high 206Pb/204Pb from the high uranium content, low 208Pb/204Pb from the low Th/U ratio), we undertook a pilot study of nine male mine employees and three controls from the Ranger uranium mine in the Northern Territory Australia to determine if it was feasible to use lead isotopes in blood to identify exposure to uranium-derived materials. The lead isotopic data for the mine employees and controls plot in two distinct fields which are consistent with predicted isotopic patterns. Assuming retention of 10% of the ingested lead, then the increases seen in 206Pb represent intakes of between 0.9 and 15 mg, integrated over the years of exposure. The small amount of lead does not affect blood lead concentrations, but appears to be sufficient to be detectable with sensitive isotopic methods. Further studies, including those on urine, should be undertaken to confirm the veracity of the lead isotope method in monitoring exposure of uranium industry employees.     

Adenovirus-mediated gene transfer is augmented in basilar and carotid arteries of heritable hyperlipidemic rabbits

OBJECTIVE: Regional presynaptic dopaminergic function and its regulation by dopamine agonists in different stages of PD can be measured by L-[11C]dopa and PET. In the current investigation, we studied the effects of therapeutic apomorphine on L-[11C]dopa uptake in patients with early and advanced PD. BACKGROUND: With disease progression and chronic dopamine agonist treatment, motor response complications supervene in a majority of PD patients. It is assumed that both presynaptic and postsynaptic changes in the dopaminergic system act to modify dopaminergic efficacy. METHODS: Patients with early and advanced stages of PD were included in the study. All patients were investigated twice with PET and L-[11C]dopa drug free and during a subsequent standardized therapeutic apomorphine infusion. RESULTS: Subregional analysis of the striatum showed differences in the effects of apomorphine infusion on the L-[11C]dopa influx rate in the two patient categories. In patients with early and uncomplicated PD, apomorphine infusion decreased the L-[11C]dopa influx rate. This decrease was most pronounced in the dorsal part of the putamen. In advanced PD patients, apomorphine did not affect the striatal L-[11C]dopa influx rate. CONCLUSIONS: We suggest that in mild and stable PD an upregulated presynaptic inhibitory feedback regulation, particularly in the dorsal putamen, acts to maintain congruity within the dopaminergic system in response to antiparkinsonian medication. However, this inhibitory feedback regulation is diminished with the progression of nigrostriatal degeneration and chronic dopamine agonist treatment.     

The effect of exercise and rehabilitation on anterior-posterior knee displacements after anterior cruciate ligament autograft reconstruction

We studied the effect of rehabilitation strength training and return to activities on anterior-posterior knee displacements after patellar tendon autogenous anterior cruciate ligament reconstruction. A total of 938 measurements were sequentially collected for 142 patients with the KT-2000 arthrometer. Rehabilitation included immediate knee motion and early weightbearing, light sports at 6 months, and competitive sports at 8 months or later. At a minimum of 2 years after surgery, 121 patients (85%) had normal displacements (less than 3 mm of increase at 134 N), 14 (10%) had 3 to 5.5 mm of increase (partial function), and 7 (5%) had more than 5.5 mm of increase (failed). There was no association found between the initial onset of the abnormal displacements in the 21 knees and either the amount of time after surgery or the rehabilitation program. Six of the seven grafts that failed did so in the 1st postoperative year. Serial displacement measurements allow early detection of graft stretching and subsequent modification of rehabilitation or delay in return to strenuous activities. These measurements showed that the rehabilitation program used in this study was not itself injurious and resulted in an acceptable failure rate of 5%.     

Regional variation in the lamina propria T cell receptor V beta repertoire in normal human colon

The Ewing's sarcoma cell line RD-ES, which carries the EWS/FLI-1 fusion gene, responded to the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor lovastatin with growth arrest. Replenishment of mevalonate (MVA) to the arrested cells restored cell growth. However, if tunicamycin (TM), which is an inhibitor of N-linked glycosylation, was present together with MVA the cells remained arrested, indicating that N-linked glycosylation is of importance for growth of Ewing's sarcoma cells. Inhibition of the biosynthesis of EWS/FLI-1 fusion protein by treatment with antisense oligonucleotides also led to growth arrest, suggesting that this protein is of importance for cell growth. We investigated whether MVA synthesis and N-linked glycosylation could be involved in regulation of the expression of the EWS/FLI-1 fusion protein, which in fact contains four potential sites for N-linked glycosylation. We found that inhibition of both HMG-CoA reductase and N-linked glycosylation drastically decreased the expression of the fusion protein, which mainly appears in the cell nuclei. There was no significant difference in the inhibitory effect on the fusion protein between the cytoplasm and the cell nuclei, indicating that the transport of the fusion protein to the cell nucleus is not affected. The fusion protein did not exhibit any gel electrophoretic mobility shift after treatment of the cells with lovastatin or TM, and it did not incorporate [3H]glucosamine. Therefore we can conclude that the fusion protein is not a glycoprotein. The decreased expression of the fusion protein following lovastatin or TM treatment was found to be due to a lowered stability of de novo-synthesized fusion protein. The down-regulation of the fusion protein was correlated to growth arrest. Furthermore, the kinetics between the expression of EWS/FLI-1 fusion protein and the initiation of DNA synthesis in MVA-stimulated cells were similar. Taken together, our data suggest that the regulatory role of N-linked glycosylation in the expression of the EWS/FLI-1 fusion protein is important for growth of Ewing's sarcoma cells. Possible mechanisms underlying TM-induced decrease in EWS/FLI-1 expression may involve the breaking of growth factor receptor pathways.