Elevated Blood Lead Levels Among Fire Assay Workers and Their Children in Alaska, 2010-2011.

In October 2010, an employee at Facility A in Alaska that performs fire assay analysis, an industrial technique that uses lead-containing flux to obtain metals from pulverized rocks, was reported to the Alaska Section of Epidemiology (SOE) with an elevated blood lead level (BLL) ≥10 micrograms per deciliter (µg/dL). The SOE initiated an investigation; investigators interviewed employees, offered blood lead screening to employees and their families, and observed a visit to the industrial facility by the Alaska Occupational Safety and Health Section (AKOSH). Among the 15 employees with known work responsibilities, 12 had an elevated BLL at least once from October 2010 through February 2011. Of these 12 employees, 10 reported working in the fire assay room. Four children of employees had BLLs ≥5 µg/dL. Employees working in Facility A's fire assay room were likely exposed to lead at work and could have brought lead home. AKOSH inspectors reported that they could not share their consultative report with SOE investigators because of the confidentiality requirements of a federal regulation, which hampered Alaska SOE investigators from fully characterizing the lead exposure standards.

Brucella species survey in polar bears (ursus maritimus) of northern Alaska.

We report on the presence of specific antibodies to Brucella spp. and Yersinia enterocolitica in polar bears (Ursus maritimus) from northern Alaska (southern Beaufort Sea) during 2003-2006. Based on numerous known stressors (e.g., climate change and loss of sea ice habitat, contaminants), there is increased concern regarding the status of polar bears. Considering these changes, it is important to assess exposure to potentially pathogenic organisms and to improve understanding of transmission pathways. Brucella or specific antibodies to Brucella spp. has been reported in marine mammals. Various assays were used to elucidate the pathway or source of exposure (e.g., "marine" vs. "terrestrial" Brucella spp.) of northern Alaska polar bears to Brucella spp. The standard plate test (SPT) and the buffered Brucella antigen card test (BBA) were used for initial screening for antibodies specific to Brucella. We then evaluated positive reactors (presence of serum antibody specific for Brucella spp.) using immunoblots and competitive enzyme-linked immunosorbent assay (cELISA; based on pinniped-derived Brucella spp. antigen). Annual prevalence of antibody (BBA and SPT) for Brucella spp. ranged from 6.8% to 18.5% over 2003-2006, with an overall prevalence of 10.2%. Prevalence of Brucella spp. antibody did vary by age class. Western blot analyses indicated 17 samples were positive for Brucella spp. antibody; of these, 13 were negative by marine (pinniped) derived Brucella antigen cELISA and four were positive by marine cELISA. Of the four samples positive for Brucella antibody by marine cELISA, three cross-reacted with Y. enterocolitica and Brucella spp. (one sample was Brucella negative and Y. enterocolitica positive). It appears the polar bear antibody does not react with the antigens used on the marine cELISA assay, potentially indicating a terrestrial (nonpinniped) source of Brucella spp.

Hematology of southern Beaufort Sea polar bears (2005-2007): biomarker for an Arctic ecosystem health sentinel.

Declines in sea-ice habitats have resulted in declining stature, productivity, and survival of polar bears in some regions. With continuing sea-ice declines, negative population effects are projected to expand throughout the polar bear's range. Precise causes of diminished polar bear life history performance are unknown, however, climate and sea-ice condition change are expected to adversely impact polar bear (Ursus maritimus) health and population dynamics. As apex predators in the Arctic, polar bears integrate the status of lower trophic levels and are therefore sentinels of ecosystem health. Arctic residents feed at the apex of the ecosystem, thus polar bears can serve as indicators of human health in the Arctic. Despite their value as indicators of ecosystem welfare, population-level health data for U.S. polar bears are lacking. We present hematological reference ranges for southern Beaufort Sea polar bears. Hematological parameters in southern Beaufort Sea polar bears varied by age, geographic location, and reproductive status. Total leukocytes, lymphocytes, monocytes, eosinophils, and serum immunoglobulin G were significantly greater in males than females. These measures were greater in nonlactating females ages ≥5, than lactating adult females ages ≥5, suggesting that females encumbered by young may be less resilient to new immune system challenges that may accompany ongoing climate change. Hematological values established here provide a necessary baseline for anticipated changes in health as arctic temperatures warm and sea-ice declines accelerate. Data suggest that females with dependent young may be most vulnerable to these changes and should therefore be a targeted cohort for monitoring in this sentinel.

Morbillivirus and Toxoplasma exposure and association with hematological parameters for southern Beaufort Sea polar bears: potential response to infectious agents in a sentinel species.

Arctic temperatures are increasing in response to greenhouse gas forcing and polar bears have already responded to changing conditions. Declines in body stature and vital rates have been linked to warming-induced loss of sea-ice. As food webs change and human activities respond to a milder Arctic, exposure of polar bears and other arctic marine organisms to infectious agents may increase. Because of the polar bear's status as arctic ecosystem sentinel, polar bear health could provide an index of changing pathogen occurrence throughout the Arctic, however, exposure and monitoring protocols have yet to be established. We examine prevalence of antibodies to Toxoplasma gondii, and four morbilliviruses (canine distemper [CDV], phocine distemper [PDV], dolphin morbillivirus [DMV], porpoise morbillivirus [PMV]) including risk factors for exposure. We also examine the relationships between antibody levels and hematologic values established in the previous companion article. Antibodies to Toxoplasma gondii and morbilliviruses were found in both sample years. We found a significant inverse relationship between CDV titer and total leukocytes, neutrophils, monocytes, and eosinophils, and a significant positive relationship between eosinophils and Toxoplasma gondii antibodies. Morbilliviral prevalence varied significantly among age cohorts, with 1-2 year olds least likely to be seropositive and bears aged 5-7 most likely. Data suggest that the presence of CDV and Toxoplasma gondii antibodies is associated with polar bear hematologic values. We conclude that exposure to CDV-like antigen is not randomly distributed among age classes and suggest that differing behaviors among life history stages may drive probability of specific antibody presence.

Orally bioavailable anti-HBV dinucleotide acyloxyalkyl prodrugs.

The acyloxyalkyl derivatives of a model anti-HBV dinucleotide were synthesized and evaluated as orally bioavailable prodrugs. Our studies have led to the identification of the first orally bioavailable dinucleotide prodrugs for further therapeutic development against the hepatitis B virus (HBV).

Metallothioneins and zinc dysregulation contribute to neurodevelopmental damage in a model of perinatal viral infection.

Neonatal Borna disease (NBD) virus infection in the Lewis rat results in life-long viral persistence and causes behavioral and neurodevelopmental abnormalities. A hallmark of the disorder is progressive loss of cerebellar Purkinje and dentate gyrus granule cells. Findings of increased brain metallothionein-I and -II (MT-I/-II) mRNA expression in cDNA microarray experiments led us to investigate MT isoforms and their relationship to brain zinc metabolism, cellular toxicity, and neurodevelopmental abnormalities in this model. Real-time PCR confirmed marked induction of MT-I/-II mRNA expression in the brains of NBD rats (40.5-fold increase in cerebellum, p<0.0001; 6.8-fold increase in hippocampus, p=0.003; and 9.5-fold increase in striatum, p=0.0012), whereas a trend toward decreased MT-III mRNA was found in hippocampus (1.25-fold decrease, p=0.0841). Double label immunofluorescence revealed prominent MT-I/-II expression in astrocytes throughout the brain; MT-III protein was decreased in granule cell neurons and increased in astrocytes, with differential subcellular distribution from cytoplasmic to nuclear compartments in NBD rat hippocampus. Modified Timm staining of hippocampus revealed reduced zinc in mossy fiber projections to the hilus and CA3, accumulation of zinc in glial cells and degenerating granule cell somata, and robust mossy fiber sprouting into the inner molecular layer of the dentate gyrus. Zinc Transporter 3 (ZnT-3) mRNA expression was decreased in hippocampus (2.3-fold decrease, p= 0.0065); staining for its correlate protein was reduced in hippocampal mossy fibers. Furthermore, 2 molecules implicated in axonal pathfinding and mossy fiber sprouting, the extracellular matrix glycoprotein, tenascin-R (TN-R), and the hyaluronan receptor CD44, were increased in NBD hippocampal neuropil. Abnormal zinc metabolism and mechanisms of neuroplasticity may contribute to the pathogenesis of disease in this model, raising more general implications for neurodevelopmental damage following viral infections in early life.

Anti-HBV nucleotide prodrug analogs: synthesis, bioreversibility, and cytotoxicity studies.

Several pronucleotide analogs of the model anti-HBV dinucleotide 3'-dA-U(2'OMe) have been synthesized and evaluated for stability, bioreversibility and cytotoxicity. These studies have helped identify potential candidates for further evaluation.