Parkinson's Disease in Louisiana, 1999-2012: Based on Hospital Primary Discharge Diagnoses, Incidence, and Risk in Relation to Local Agricultural Crops, Pesticides, and Aquifer Recharge.

The two major causes of Parkinson's disease (PD) are genetic susceptibility and exposure to agricultural pesticides. Access to 23,224 individuals' hospital primary discharge diagnoses of PD allowed the mapping of cases against known crop distributions and pesticides. Our main objective was to map PD risks (cases per 10,000 people) against crops and their pesticides. The ZIP Code address locations, and the 2000 and 2010 census data, were used to map the risks of PD throughout Louisiana and in relation to United States Department of Agriculture (USDA)-recorded crops. The introduction of glyphosate-resistant crops appears to have initiated the PD disappearance from northeastern parishes on the west bank of the Mississippi river. Rice and sugar cane are seemingly unassociated with PD, as is the Mississippi itself, except for Jefferson and St. Charles Parishes, which are essentially urban or industrial. The present major PD-affected areas are associated with commercial forests, woodlands, and pastures, and thus with certain arbor-pastoral pesticides, 2,4-D, chlorpyrifos, and paraquat. Human populations at maximum risk are those living in areas of moderate and high aquifer-recharge potential. The levels of estimated pesticide exposure in these recharge areas we were able to access were of variable use, but significant amounts of 2,4-D were being used.

Computational feasibility of calculating the steady-state blood flow rate through the vasculature of the entire human body.

The human body contains approximately 20 billion individual blood vessels that deliver nutrients and oxygen to tissues. While blood flow is a well-developed field of research, no previous studies have calculated the blood flow rates through more than 5 million connected vessels. The goal of this study was to test if it is computationally feasible to calculate the blood flow rates through a vasculature equal in size to that of the human body. We designed and implemented a two-step algorithm to calculate the blood flow rates using principles of steady-state fluid dynamics. Steady-state fluid dynamics is an accurate approximation for the microvascular and venous structures in the human body. To determine the computational feasibility, we measured and evaluated the execution time, scalability, and memory usage to quantify the computational requirements. We demonstrated that it is computationally feasible to calculate the blood flow rate through 17 billion vessels in 6.5 hours using 256 compute nodes. The computational modeling of blood flow rate in entire organisms may find application in research on drug delivery, treatment of cancer metastases, and modulation of physiological performance.

Arsenic speciation driving risk based corrective action.

The toxicity of arsenic depends on a number of factors including its valence state. The more potent trivalent arsenic [arsenite (As3+)] inhibits a large number of cellular enzymatic pathways involved in energy production, while the less toxic pentavalent arsenic [arsenate (As5+)] interferes with phosphate metabolism, phosphoproteins and ATP formation (uncoupling of oxidative phosphorylation). Environmental risk based corrective action for arsenic contamination utilizes data derived from arsenite studies of toxicity to be conservative. However, depending upon environmental conditions, the arsenate species may predominate substantially, especially in well aerated surface soils. Analyses of soil concentrations of arsenic species at two sites in northeastern Texas historically contaminated with arsenical pesticides yielded mean arsenate concentrations above 90% of total arsenic with the majority of the remainder being the trivalent arsenite species. Ecological risk assessments based on the concentration of the trivalent arsenite species will lead to restrictive remediation requirements that do not adequately reflect the level of risk associated with the predominate species of arsenic found in the soil. The greater concentration of the pentavalent arsenate species in soils would be the more appropriate species to monitor remediation at sites that contain high arsenate to arsenite ratios.

Combustion products of 1,3-butadiene inhibit catalase activity and induce expression of oxidative DNA damage repair enzymes in human bronchial epithelial cells.

1,3-Butadiene, an important petrochemical, is commonly burned off when excess amounts need to be destroyed. This combustion process produces butadiene soot (BDS), which is composed of a complex mixture of polycyclic aromatic hydrocarbons in particulates ranging in size from <1 microm to 1 mm. An organic extract of BDS is both cytotoxic and genotoxic to normal human bronchial epithelial (NHBE) cells. Based on the oxidizing potential of BDS, we hypothesized that an organic extract of this particulate matter would (1) cause enzyme inactivation due to protein amino acid oxidation and (2) induce oxidative DNA damage in NHBE cells. Thus, our aims were to determine the effect of butadiene soot ethanol extract (BSEE) on both enzyme activity and the expression of proteins involved in the repair of oxidative DNA damage. Catalase was found to be sensitive to BDS as catalase activity was potently diminished in the presence of BSEE. Using Western analysis, both the alpha isoform of human 8-oxoguanine DNA glycosylase (alpha-hOGG1) and human apurinic/apyrimidinic endonuclease (APE-1) were shown to be significantly overexpressed as compared to untreated controls after exposure of NHBE cells to BSEE. Our results indicate that BSEE is capable of effectively inactivating the antioxidant enzyme catalase, presumably via oxidation of protein amino acids. The presence of oxidized biomolecules may partially explain the extranuclear fluorescence that is detected when NHBE cells are treated with an organic extract of BDS. Overexpression of both alpha-hOGG1 and APE-1 proteins following treatment of NHBE cells with BSEE suggests that this mixture causes oxidative DNA damage.

Human germline and somatic cells have similar TP53 and Kirsten-RAS gene single base mutation frequencies.

Understanding the risk of offspring inheriting rare mutations, and the frequencies at which these mutations are present in germ cells can be explored with direct analysis of human semen samples. The present work utilized the ultrasensitive PCR/RE/LCR mutation assay to detect, identify and determine the prevalence single base substitution mutations in the TP53 and KRAS genes in human sperm. Four disease-associated base sites in the TP53 and KRAS genes, three of which are known to be heritable to live, term offspring, were studied in sperm from eleven human semen specimens. Eight of the specimens (73%) displayed single base substitution mutations, and 30% of all base sites tested were found to harbor mutations ranging in prevalence from 1 x 10(-6) to 1 x 10(-5) wild type sperm. These germ cell single base substitution mutation frequencies are very similar to somatic tissue TP53 and KRAS mutation frequencies. Equivalent single base mutation frequencies in both germ and somatic cells suggest that there is no unusual selection or mutation protective process operating premeiotically in the germline, and that a selection bias at the level of sperm viability, conception, early cleavage, implantation, and/or embryogenesis operates to exclude the majority of these TP53 mutations and all of the activating KRAS mutations.

'HPV vulvitis' revisited: frequent and persistent detection of novel epidermodysplasia verruciformis-associated HPV genotypes.

BACKGROUND: 'Human papillomavirus (HPV) vulvitis' is a disputed entity where most studies examining for genital-mucosal (GM) HPV have been negative. METHODS: Using degenerate and type specific primers for cutaneous (CU), GM and epidermodysplasia verruciformis (EV) HPV types, the prevalence of specific HPV types was investigated in biopsy specimens from 19 women with 'HPV vulvitis', seven with asymptomatic vulvar squamous papillomatosis (ASxVSP), and controls of vulvar fibroepithelial polyps (FEP) (15), vulvar condyloma (10) and normal vulva (NV) (10). RESULTS: HPV DNA/EV HPV/GM HPV/CU HPV were detected in 84/74/47/5% of vulvitis patients, 78/71/0/28% of ASxVSP, 47/20/20/7% of FEP, 10/10%/0/0 of NV and 100/0/100/10% of condyloma. Fourteen putatively novel HPV genotypes were detected in vulvitis and ASxVSP patients, but not in controls. The two most frequent novel EV HPV, Alb-4 and DL285, were detected in 9/19 (47%) and 5/19 (26%) of vulvitis cases and were persistently identified in serial biopsies. HPV co-infection and Alb-4 infection occurred significantly more frequently in vulvitis patients, particularly those complaining of 'burning' (62/62% vs. 17/7%, p < or = 0.004). Koilocytosis was identified significantly more frequently in vulvitis compared with non-condyloma controls (81% vs. 40%, p = 0.0001), and its presence correlated with detection of HPV DNA (r = 0.3, p = 0.002). CONCLUSION: The high frequency of novel EV HPV in HPV vulvitis and correlation of clinicopathologic findings with HPV DNA suggests that HPV vulvitis may indeed exist.

Single base instability is promoted in vulvar lichen sclerosus.

Single base substitution mutations in codons 248 and 273 of TP53 and codon 12 Kirsten-ras (KRAS) are commonly found in human carcinomas. To determine whether these mutations also occur in normal and inflamed tissues from which carcinomas arise, we utilized the ultra-sensitive polymerase chain reaction/restriction endonuclease/ligase chain reaction mutation assay. Ninety samples of genital skin, including lichen sclerosus (LS) affected skin, adjacent normal and non-adjacent normal, were assayed. Mutations were detected in 103 of 349 assays and consisted of KRAS G34A, G34T, G35A, and TP53 C742T, G818C, C817T, and G818A mutations. Mutant prevalence varied from 1 to 20 per 10(6) wild-type cells. Mutations occurred significantly more frequently in LS (78/224 (35%)) than adjacent normal (20/88 (23%)) and non-adjacent normal genital skin (5/38 (13%)). KRAS G34A mutation was relatively common to all classes of specimen, whereas TP53 gene C742T and G818C mutations were significantly more frequent in LS than normal genital skin. In matched samples, immunohistochemistry evaluation of p53 protein expression revealed the presence of epidermal p53 clones in LS whose presence and number significantly correlated with the presence of TP53 C742T and G818C mutations. Based on these results, it appears oncogenic point mutations occur in normal genital skin, and are selected for in LS.