Toxic Chemicals

Catastrophic events such as the Bhopal, India tragedy and rising incidences of cancer in areas neighboring industrial facilities have heightened concern over the use of toxic chemicals in manufacturing and industry, particularly with respect to long-term exposure. While legislation and publicity have reduced the use of some chemicals, risks remain that continue to threaten the health of individuals worldwide. Based on the authors’ research conducted through their development of a program in Sao Paulo, Brazil, Toxic Chemicals: Risk Prevention Through Use Reduction examines various toxicity factors and proposes a plan to reduce the toxic impact of these hazardous substances. Explores all factors that contribute to toxicity The book begins by exploring the history of toxic chemical release reporting programs, a trend growing out of the Bhopal tragedy. It surveys their impact both in the United States through the Toxics Release Inventory (TRI) program and in the 29 other countries that maintain similar programs. Then, with the goal of developing a rational method of prioritizing toxic chemicals for reduction, the authors discuss mobility, persistence, and bioconcentration adjustment factors and present a method for integrating all of these factors to estimate the relative impact of chemical release. Compares alternate emphases in existing programs The book describes programs that concentrate on reducing the release of chemicals with the greatest adverse toxic impact and those that require companies to prepare pollution prevention plans and set goals for reducing use or release. It also examines technical assistance programs that help companies search for alternative chemicals to use or process changes that eliminate the use of toxic chemicals. In addition, it explores alternative market-based approaches for achieving environmental protection. Presents a workable plan for the future In the final chapters, the authors lay out their proposed program for reducing the use of toxic chemicals. This plan builds on the existing TRI program and uses lessons learned from this and other programs. The combined research assembled by the authors and their multifaceted approach to the issue of chemical toxicity enables companies and policy makers to move to the next level of toxic chemical use reduction, resulting in a safer environment for future generations

Anatomía comparada de la lámina foliar del género Distichlis (Poaceae)

Six species and 11 varieties of the genus Distichlis Raf. were compared anatomically. The taxa studied were: Distichlis australis (Speg.) Villamil; D. humilis Phil.; D. palmeri (Vasey) Fassett ex I.M. Johnst.; D. scoparia (Nees ex Kunth) Arechav. var. erinacea (Beetle) Nicora and var. scoparia; and D. spicata (L.) Greene, represented by the following eight varieties: var. borealis (J. Presl) Beetle, var. divaricata Beetle, var. mendocina (J. Presl) Hack., var. mexicana Beetle, var. nana Beetle, var. spicata, var. stolonifera Beetle and var. stricta (Torr.) Scribn. Also included were two taxa for which the anatomical information was taken from the literature: Distichlis laxiflora Hack. and Distichlis spicata var. distichophylla (Michx.) Beetle. Fourteen anatomical characters of taxonomic value were found, seven in cross section and seven in the epidermis as seen in surface view. Distichlis australis and D. palmeri were found to differ from all of the other species. Distichlis humilis, D. scoparia and D. spicata form an anatomically homogeneous group, but with characteristics that distinguish each of them. Within Distichlis spicata, no anatomical character or combination of characters was found that would justify the recognition of infraspecific taxa and/or segregate species. For this reason, these taxa are considered to be synonyms of D. spicata.Se hizo un estudio anatómico-sistemático de seis especies y 11 variedades del género Distichlis Raf. Los taxa incluidos fueron: D. australis (Speg.) Villamil; D. humilis Phil.; D. palmeri (Vasey) Fassett ex I. M. Johnst.; D. scoparia (Nees ex Kunth) Arechav. var. erinacea (Beetle) Nicora, y var. scoparia; y D. spicata (L.) Greene, esta última representada por las siguientes ocho variedades: var. borealis (J. Presl) Beetle, var. divaricata Beetle, var. mendocina (Phil.) Hack., var. mexicana Beetle, var. nana Beetle, var. spicata, var. stolonifera Beetle y var. stricta (Torr.) Scribn. Se incluyeron dos taxa cuya información anatómica fue extraída de la literatura: Distichlis laxiflora Hack. y Distichlis spicata var. distichophylla (Michx.) Beetle. Se encontraron 14 caracteres anatómicos considerados de valor taxonómico, siete en corte transversal y siete en vista superficial de la epidermis abaxial. Distichlis australis y D. palmeri difieren claramente del resto de las especies. Distichlis humilis, D. scoparia y D. spicata forman un grupo anatómicamente homogéneo pero con características que las hacen distintivas a cada una. Para Distichlis spicata, no se encontró ningún carácter o combinación de caracteres anatómicos con los cuales pueda separarse en distintos grupos. Por esta razón, las especies, subespecies y/o variedades propuestas por algunos autores para esta entidad se consideran sinónimos de D. spicata

The Interface of Pancreatic Cancer With Diabetes, Obesity, and Inflammation: Research Gaps and Opportunities: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop.

A workshop on "The Interface of Pancreatic Cancer with Diabetes, Obesity, and Inflammation: Research Gaps and Opportunities" was held by the National Institute of Diabetes and Digestive and Kidney Diseases on October 12, 2017. The purpose of the workshop was to explore the relationship and possible mechanisms of the increased risk of pancreatic ductal adenocarcinoma (PDAC) related to diabetes, the role of altered intracellular energy metabolism in PDAC, the mechanisms and biomarkers of diabetes caused by PDAC, the mechanisms of the increased risk of PDAC associated with obesity, and the role of inflammatory events and mediators as contributing causes of the development of PDAC. Workshop faculty reviewed the state of the current knowledge in these areas and made recommendations for future research efforts. Further knowledge is needed to elucidate the basic mechanisms contributing to the role of hyperinsulinemia, hyperglycemia, adipokines, and acute and chronic inflammatory events on the development of PDAC

Elite Suppressors Harbor Low Levels of Integrated HIV DNA and High Levels of 2-LTR Circular HIV DNA Compared to HIV+ Patients On and Off HAART

Elite suppressors (ES) are a rare population of HIV-infected individuals that are capable of naturally controlling the infection without the use of highly active anti-retroviral therapy (HAART). Patients on HAART often achieve viral control to similar (undetectable) levels. Accurate and sensitive methods to measure viral burden are needed to elucidate important differences between these two patient populations in order to better understand their mechanisms of control. Viral burden quantification in ES patients has been limited to measurements of total DNA in PBMC, and estimates of Infectious Units per Million cells (IUPM). There appears to be no significant difference in the level of total HIV DNA between cells from ES patients and patients on HAART. However, recovering infectious virus from ES patient samples is much more difficult, suggesting their reservoir size should be much smaller than that in patients on HAART. Here we find that there is a significant difference in the level of integrated HIV DNA in ES patients compared to patients on HAART, providing an explanation for the previous results. When comparing the level of total to integrated HIV DNA in these samples we find ES patients have large excesses of unintegrated HIV DNA. To determine the composition of unintegrated HIV DNA in these samples, we measured circular 2-LTR HIV DNA forms and found ES patients frequently have high levels of 2-LTR circles in PBMC. We further show that these high levels of 2-LTR circles are not the result of inefficient integration in ES cells, since HIV integrates with similar efficiency in ES and normal donor cells. Our findings suggest that measuring integration provides a better surrogate of viral burden than total HIV DNA in ES patients. Moreover, they add significantly to our understanding of the mechanisms that allow viral control and reservoir maintenance in this unique patient population

Alteration of AKT Activity Increases Chemotherapeutic Drug and Hormonal Resistance in Breast Cancer yet Confers an Achilles Heel by Sensitization to Targeted Therapy

The PI3K/PTEN/Akt/mTOR pathway plays critical roles in the regulation of cell growth. The effects of this pathway on drug resistance and cellular senescence of breast cancer cells has been a focus of our laboratory. Introduction of activated Akt or mutant PTEN constructs which lack lipid phosphatase [PTEN(G129E)] or lipid and protein phosphatase [PTEN(C124S)] activity increased the resistance of the cells to the chemotherapeutic drug doxorubicin, and the hormonal drug tamoxifen. Activated Akt and PTEN genes also inhibited the induction of senescence after doxorubicin treatment; a phenomenon associated with unrestrained proliferation and tumorigenesis. Interference with the lipid phosphatase domain of PTEN was sufficient to activate Akt/mTOR/p70S6K as MCF-7 cells transfected with the mutant PTEN gene lacking the lipid phosphatase activity [PTEN(G129E)] displayed elevated levels of activated Akt and p70S6K compared to empty vector transfected cells. Cells transfected with mutant PTEN or Akt constructs were hypersensitive to mTOR inhibitors when compared with the parental or empty vector transfected cells. Akt-transfected cells were cultured for over two months in tamoxifen from which tamoxifen and doxorubicin resistant cells were isolated that were >10-fold more resistant to tamoxifen and doxorubicin than the original Akt-transfected cells. These cells had a decreased induction of both activated p53 and total p21Cip1 upon doxorubicin treatment. Furthermore, these cells had an increased inactivation of GSK-3β and decreased expression of the estrogen receptor-α. In these drug resistant cells, there was an increased activation of ERK which is associated with proliferation. These drug resistant cells were hypersensitive to mTOR inhibitors and also sensitive to MEK inhibitors, indicating that the enhanced p70S6K and ERK expression was relevant to their drug and hormonal resistance. Given that Akt is overexpressed in greater than 50% of breast cancers, our results point to potential therapeutic targets, mTOR and MEK. These studies indicate that activation of the Akt kinase or disruption of the normal activity of the PTEN phosphatase can have dramatic effects on activity of p70S6K and other downstream substrates and thereby altering the therapeutic sensitivity of breast cancer cells. The effects of doxorubicin and tamoxifen on induction of the Raf/MEK/ERK and PI3K/Akt survival pathways were examined in unmodified MCF-7 breast cells. Doxorubicin was a potent inducer of activated ERK and to a lesser extent Akt. Tamoxifen also induced ERK. Thus a consequence of doxorubicin and tamoxifen therapy of breast cancer is the induction of a pro-survival pathway which may contribute to the development of drug resistance. Unmodified MCF-7 cells were also sensitive to MEK and mTOR inhibitors which synergized with both tamoxifen and doxorubicin to induce death. In summary, our results point to the key interactions between the PI3K/PTEN/Akt/mTOR and Raf/ MEK/ERK pathways in regulating chemotherapeutic drug resistance/sensitivity in breast cancer and indicate that targeting these pathways may prevent drug and hormonal resistance. Orignally published Advances in Enzyme Regulation, Vol. 48, No. 1, 2008

Heterozygous variants in ZBTB7A cause a neurodevelopmental disorder associated with symptomatic overgrowth of pharyngeal lymphoid tissue, macrocephaly, and elevated fetal hemoglobin

By clinical whole exome sequencing, we identified 12 individuals with ages 3 to 37 years, including three individuals from the same family, with a consistent phenotype of intellectual disability (ID), macrocephaly, and overgrowth of adenoid tissue. All 12 individuals harbored a rare heterozygous variant in ZBTB7A which encodes the transcription factor Zinc finger and BTB-domain containing protein 7A, known to play a role in lympho- and hematopoiesis. ID was generally mild. Fetal hemoglobin (HbF) fraction was elevated 2.2%–11.2% (reference value  6 months) in four of the five individuals for whom results were available. Ten of twelve individuals had undergone surgery at least once for lymphoid hypertrophy limited to the pharynx. In the most severely affected individual (individual 1), airway obstruction resulted in 17 surgical procedures before the age of 13 years. Sleep apnea was present in 8 of 10 individuals. In the nine unrelated individuals, ZBTB7A variants were novel and de novo. The six frameshift/nonsense and four missense variants were spread throughout the gene. This is the first report of a cohort of individuals with this novel syndromic neurodevelopmental disorder

Economic aspects of health education

Economic aspects of health education have, to date, received inadequate attention. An economic framework for discussing and evaluating health education is offered, with health education being placed in the already well established economic framework for assessing both health and education respectively. Health education is shown to yield both consumption and investment benefits. The application of cost-benefit analysis and cost-effectiveness analysis to health education activities is explored, and the reasons for the absence of successful applications of the cost-benefit technique to health education programmes are described. The somewhat greater scope for the application of cost-effectiveness analysis is then discussed. A detailed economic evaluation is provided of the North Karelia Project which was concerned with the prevention of cardiovascular disease. The inadequacy of the limited economic evaluation of that project is described and an attempt made to assess the true economic consequences of the project.

Toxic Chemicals

Catastrophic events such as the Bhopal, India tragedy and rising incidences of cancer in areas neighboring industrial facilities have heightened concern over the use of toxic chemicals in manufacturing and industry, particularly with respect to long-term exposure. While legislation and publicity have reduced the use of some chemicals, risks remain that continue to threaten the health of individuals worldwide. Based on the authors’ research conducted through their development of a program in Sao Paulo, Brazil, Toxic Chemicals: Risk Prevention Through Use Reduction examines various toxicity factors and proposes a plan to reduce the toxic impact of these hazardous substances. Explores all factors that contribute to toxicity The book begins by exploring the history of toxic chemical release reporting programs, a trend growing out of the Bhopal tragedy. It surveys their impact both in the United States through the Toxics Release Inventory (TRI) program and in the 29 other countries that maintain similar programs. Then, with the goal of developing a rational method of prioritizing toxic chemicals for reduction, the authors discuss mobility, persistence, and bioconcentration adjustment factors and present a method for integrating all of these factors to estimate the relative impact of chemical release. Compares alternate emphases in existing programs The book describes programs that concentrate on reducing the release of chemicals with the greatest adverse toxic impact and those that require companies to prepare pollution prevention plans and set goals for reducing use or release. It also examines technical assistance programs that help companies search for alternative chemicals to use or process changes that eliminate the use of toxic chemicals. In addition, it explores alternative market-based approaches for achieving environmental protection. Presents a workable plan for the future In the final chapters, the authors lay out their proposed program for reducing the use of toxic chemicals. This plan builds on the existing TRI program and uses lessons learned from this and other programs. The combined research assembled by the authors and their multifaceted approach to the issue of chemical toxicity enables companies and policy makers to move to the next level of toxic chemical use reduction, resulting in a safer environment for future generations