A Few Considerations on Structural and Logical Composition in Specification Theories

Over the last 20 years a large number of automata-based specification theories have been proposed for modeling of discrete,real-time and probabilistic systems. We have observed a lot of shared algebraic structure between these formalisms. In this short abstract, we collect results of our work in progress on describing and systematizing the algebraic assumptions in specification theories.Comment: In Proceedings FIT 2010, arXiv:1101.426

Association of Cardiometabolic Genes with Arsenic Metabolism Biomarkers in American Indian Communities: The Strong Heart Family Study (SHFS)

Background: Metabolism of inorganic arsenic (iAs) is subject to inter-individual variability, which is explained partly by genetic determinants. Objectives: We investigated the association of genetic variants with arsenic species and principal components of arsenic species in the Strong Heart Family Study (SHFS). Methods: We examined variants previously associated with cardiometabolic traits (~ 200,000 from Illumina Cardio MetaboChip) or arsenic metabolism and toxicity (670) among 2,428 American Indian participants in the SHFS. Urine arsenic species were measured by high performance liquid chromatography–inductively coupled plasma mass spectrometry (HPLC-ICP-MS), and percent arsenic species [iAs, monomethylarsonate (MMA), and dimethylarsinate (DMA), divided by their sum × 100] were logit transformed. We created two orthogonal principal components that summarized iAs, MMA, and DMA and were also phenotypes for genetic analyses. Linear regression was performed for each phenotype, dependent on allele dosage of the variant. Models accounted for familial relatedness and were adjusted for age, sex, total arsenic levels, and population stratification. Single nucleotide polymorphism (SNP) associations were stratified by study site and were meta-analyzed. Bonferroni correction was used to account for multiple testing. Results: Variants at 10q24 were statistically significant for all percent arsenic species and principal components of arsenic species. The index SNP for iAs%, MMA%, and DMA% (rs12768205) and for the principal components (rs3740394, rs3740393) were located near AS3MT, whose gene product catalyzes methylation of iAs to MMA and DMA. Among the candidate arsenic variant associations, functional SNPs in AS3MT and 10q24 were most significant (p \u3c 9.33 × 10–5). Conclusions: This hypothesis-driven association study supports the role of common variants in arsenic metabolism, particularly AS3MT and 10q24

Dietary determinants of cadmium exposure in the Strong Heart Family Study

Urinary cadmium (Cd) concentrations in the Strong Heart Family Study (SHFS) participants are higher than in the general US population. This difference is unlikely to be related to tobacco smoking. We evaluated the association of consumption of processed meats and other dietary products with urinary Cd concentrations in the SHFS, a family-based study conducted in American Indian communities. We included 1725 participants with urine Cd concentrations (standardized to urine creatinine) and food frequency questionnaire data grouped in 24 categories, including processed meat. Median (IQR) urinary Cd concentrations were 0.42 (0.20–0.85) μg/g creatinine. The age, sex, smoking, education, center, body mass index, and total kcal adjusted geometric mean ratio (GMR) (95%CI) of urinary cadmium concentrations per IQR increase in each dietary category was 1.16 (1.04–1.29) for processed meat, 1.10 (1.00–1.21) for fries and chips, 0.87 (0.80–0.95) for dairy products, and 0.89 (0.82–0.97) for fruit juices. The results remained similar after further adjustment for the dietary categories associated with urinary Cd in the previous model except for fries and chips, which was no longer statistically significant. These findings revealed the potential importance of processed meat products as a dietary source of cadmium

Association of Cardiometabolic Genes with Arsenic Metabolism Biomarkers in American Indian Communities: The Strong Heart Family Study (SHFS)

BACKGROUND: Metabolism of inorganic arsenic (iAs) is subject to inter-individual variability, which is explained partly by genetic determinants. OBJECTIVES: We investigated the association of genetic variants with arsenic species and principal components of arsenic species in the Strong Heart Family Study (SHFS). METHODS: We examined variants previously associated with cardiometabolic traits (~ 200,000 from Illumina Cardio MetaboChip) or arsenic metabolism and toxicity (670) among 2,428 American Indian participants in the SHFS. Urine arsenic species were measured by high performance liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICP-MS), and percent arsenic species [iAs, monomethylarsonate (MMA), and dimethylarsinate (DMA), divided by their sum × 100] were logit transformed. We created two orthogonal principal components that summarized iAs, MMA, and DMA and were also phenotypes for genetic analyses. Linear regression was performed for each phenotype, dependent on allele dosage of the variant. Models accounted for familial relatedness and were adjusted for age, sex, total arsenic levels, and population stratification. Single nucleotide polymorphism (SNP) associations were stratified by study site and were meta-analyzed. Bonferroni correction was used to account for multiple testing. RESULTS: Variants at 10q24 were statistically significant for all percent arsenic species and principal components of arsenic species. The index SNP for iAs%, MMA%, and DMA% (rs12768205) and for the principal components (rs3740394, rs3740393) were located near AS3MT, whose gene product catalyzes methylation of iAs to MMA and DMA. Among the candidate arsenic variant associations, functional SNPs in AS3MT and 10q24 were most significant (p < 9.33 × 10-5). CONCLUSIONS: This hypothesis-driven association study supports the role of common variants in arsenic metabolism, particularly AS3MT and 10q24. Citation: Balakrishnan P, Vaidya D, Franceschini N, Voruganti VS, Gribble MO, Haack K, Laston S, Umans JG, Francesconi KA, Goessler W, North KE, Lee E, Yracheta J, Best LG, MacCluer JW, Kent J Jr., Cole SA, Navas-Acien A. 2017. Association of cardiometabolic genes with arsenic metabolism biomarkers in American Indian communities: the Strong Heart Family Study (SHFS). Environ Health Perspect 125:15-22; http://dx.doi.org/10.1289/EHP251

Associations of maternal arsenic exposure with adult fasting glucose and insulin resistance in the Strong Heart Study and Strong Heart Family Study

Experimental and prospective epidemiologic evidence suggest that arsenic exposure has diabetogenic effects. However, little is known about how family exposure to arsenic may affect risk for type 2 diabetes (T2D)-related outcomes in adulthood. We evaluated the association of both maternal and offspring arsenic exposure with fasting glucose and incident T2D in 466 participants of the Strong Heart Family Study. Total arsenic (ΣAs) exposure was calculated as the sum of inorganic arsenic (iAs) and methylated (MMA, DMA) arsenic species in maternal and offspring baseline urine. Median maternal ΣAs at baseline (1989-91) was 7.6 µg/g creatinine, while median offspring ΣAs at baseline (2001-03) was 4.5 µg/g creatinine. Median offspring glucose in 2006-2009 was 94 mg/dL, and 79 participants developed T2D. The fully adjusted mean difference (95% CI) for offspring glucose was 4.40 (-3.46, 12.26) mg/dL per IQR increase in maternal ΣAs vs. 2.72 (-4.91 to 10.34) mg/dL per IQR increase in offspring ΣAs. The fully adjusted odds ratio (95%CI) of incident T2D was 1.35 (1.07, 1.69) for an IQR increase in maternal ΣAs and 1.15 (0.92, 1.43) for offspring ΣAs. The association of maternal ΣAs with T2D outcomes were attenuated with adjustment for offspring adiposity markers. Familial exposure to arsenic, as measured in mothers 15-20 years before offspring follow-up, is associated with increased odds of offspring T2D. More research is needed to confirm findings and better understand the importance of family exposure to arsenic in adult-onset diabetes.This study was supported by the National Institute of EnvironmentalHealth Sciences, Unites States (P42ES010349, P30ES009089,R01ES028758, R01ES025216).N.T., P.F.-L., and A.N.-A. contributed to the preparation of researchdata and writing of the manuscript. N.T, M.J.S, A.D.-R., M.T.-P., M.G.-P., and A.N.-A. contributed to the statistical analysis. B.V.H., J.M., K.N.,J.G.U., and S.C. contributed as the primary investigators of the SHS andSHFS, and to the preparation of the research data. K.A.F. and W.G.contributed to the arsenic measurements in the SHS and SHFS partici-pants. A.N.-A. is the guarantor of this work and, as such, had full accessto all the data in the study and takes responsibility for the integrity ofthe data and the accuracy of the data analysis.S

Low-moderate arsenic exposure and respiratory in American Indian communities in the Strong Heart Study

Background Arsenic exposure through drinking water is an established lung carcinogen. Evidence on non-malignant lung outcomes is less conclusive and suggests arsenic is associated with lower lung function. Studies examining low-moderate arsenic (< 50 μg/L), the level relevant for most populations, are limited. We evaluated the association of arsenic exposure with respiratory health in American Indians from the Northern Plains, the Southern Plains and the Southwest United States, communities with environmental exposure to inorganic arsenic through drinking water. Methods The Strong Heart Study is a prospective study of American Indian adults. This analysis used urinary arsenic measurements at baseline (1989–1991) and spirometry at Visit 2 (1993–1995) from 2132 participants to evaluate associations of arsenic exposure with airflow obstruction, restrictive pattern, self-reported respiratory disease, and symptoms. Results Airflow obstruction was present in 21.5% and restrictive pattern was present in 14.4%. The odds ratio (95% confidence interval) for obstruction and restrictive patterns, based on the fixed ratio definition, comparing the 75th to 25th percentile of arsenic, was 1.17 (0.99, 1.38) and 1.27 (1.01, 1.60), respectively, after adjustments, and 1.28 (1.02, 1.60) and 1.33 (0.90, 1.50), respectively, based on the lower limit of normal definition. Arsenic was associated with lower percent predicted FEV1 and FVC, self-reported emphysema and stopping for breath. Conclusion Low-moderate arsenic exposure was positively associated with restrictive pattern, airflow obstruction, lower lung function, self-reported emphysema and stopping for breath, independent of smoking and other lung disease risk factors. Findings suggest that low-moderate arsenic exposure may contribute to restrictive lung disease

Correction to: Low-moderate arsenic exposure and respiratory health in American Indian communities in the Strong Heart Study

The original version of this article [1], published on 28 November 2019, contained incorrect title. In this Correction the affected part of the article is shown

Mutation analysis of "Endoglin" and "Activin receptor-like kinase" genes in German patients with hereditary hemorrhagic telangiectasia and the value of rapid genotyping using an allele-specific PCR-technique

<p>Abstract</p> <p>Background</p> <p>Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is an autosomal dominant disorder which is clinically characterised by recurrent epistaxis, mucocutaneous telangiectasia and visceral arteriovenous malformations. Genetic linkage studies identified two genes primarily related to HHT: endoglin (<it>ENG</it>) on chromosome 9q33-34 and activin receptor-like kinase1 (<it>ACVRL1</it>) on chromosome 12q13. We have screened a total of 41 unselected German patients with the suspected diagnosis of HHT. Mutation analysis for the <it>ENG </it>and <it>ACVRL1 </it>genes in all patients was performed by PCR amplification. Sequences were then compared to the HHT database <url>http://www.hhtmutation.org</url> sequences of the <it>ENG </it>mRNA (accession no. BC014271.2) and the <it>ACVRL1 </it>mRNA (accession no. NM000020.1).</p> <p>Results</p> <p>We identified 15 different mutations in 18 cases by direct sequencing. Among these mutations, one novel <it>ENG </it>mutation could be detected which has not yet been described in the literature before. The genotype-phenotype correlation was consistent with a higher frequency of pulmonary arteriovenous malformations in patients with <it>ENG </it>mutations than in patients with <it>ACVRL1 </it>mutations in our collective.</p> <p>Conclusion</p> <p>For rapid genotyping of mutations and SNPs (single nucleotide polymorphisms) in <it>ENG </it>and <it>ACVRL1</it>, allele-specific PCR methods with sequence-specific primers (PCR-SSP) were established and their value analysed.</p

Plasmapheresis reverses all side-effects of a cisplatin overdose – a case report and treatment recommendation

BACKGROUND: Cisplatin is widely used as an antineoplastic agent since it is effective against a broad spectrum of different tumours. Nevertheless, it has several potential side effects affecting different organ systems and an overdose may lead to life-threatening complications and even death. CASE PRESENTATION: We report on a 46-year old woman with non-small cell lung cancer who accidentally received 225 mg/m(2 )of cisplatin, which was threefold the dose as scheduled, within a 3-day period. Two days later, the patient presented with hearing loss, severe nausea and vomiting, acute renal failure as well as elevated liver enzymes. In addition, she developed a severe myelodepression. After plasmapheresis on two consecutive days and vigorous supportive treatment, the toxicity-related symptoms improved and the patient recovered without any sequelae. CONCLUSION: To date, no general accepted guidelines for the treatment of cisplatin overdoses are available. Along with the experience from other published cases, our report shows that plasmapheresis is capable of lowering cisplatin plasma and serum levels efficiently. Therefore, plasma exchange performed as soon as possible can ameliorate all side effects of a cisplatin overdose and be a potential tool for clinicians for treatment. However, additional intensive supportive treatment-modalities are necessary to control all occurring side effects