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Arsenite inhibits mitotic division and perturbs spindle dynamics in HeLa S3 cells.

Arsenical compounds, known to be human carcinogens, were shown to disturb cell cycle progression and induce cytogenetic alterations in a variety of cell systems. We report here that a 24 h treatment of arsenite induced mitotic accumulation in human cell lines. HeLa S3 and KB cells were most susceptible: 35% of the total cell population was arrested at the mitotic stage after treatment with 5 microM sodium arsenite in HeLa S3 cells and after 10 microM in KB cells. Under a microscope, we observed abnormal mitotic figures in arsenite-arrested mitotic cells, including deranged chromosome congression, elongated polar distance of mitotic spindle, and enhanced microtubule immunofluorescence. The spindle microtubules of arsenite-arrested mitotic cells were more resistant to nocodazole-induced dissolution than those of control mitotic cells. According to turbidity assay, arsenite at concentrations below 100 microM significantly enhanced polymerization of tubulins. Since spindle dynamics play a crucial role in mitotic progression, our results suggest that arsenite-induced mitotic arrest may be due to arsenite's effects on attenuation of spindle dynamics.

Animals↗

Prevalence of the causes of fleece derangement among sheep flocks in New South Wales.

An investigation of sheep flocks with unknown histories of fleece derangement, selected at random from the main sheep raising areas of New South Wales, showed that Psorergates ovis was present in 53 of the 177 flocks surveyed and in 162 of the 3495 sheep examined. Of the single causes of fleece derangement, the most prevalent was grass seed contamination (15.7%) followed by infestation with sheep body lice, Bovicola ovis, (14.7%) and infestation with itch mite (7.8%). The prevalence of fleece derangement was significantly higher on sheep in which lice were the only ectoparasites found than on those in which itch mites were the only ectoparasites present. The greatest prevalence of P ovis was in flocks in the Young, Yass, Mudgee and Tenterfield districts. In most affected flocks, more than one potential cause of fleece derangement was present. Itch mite infestation was more prevalent in flocks that received no treatment for ectoparasites than in those that had been treated in the year preceding the survey. Our results did not support a commonly held belief among farmers that arsenical compounds control infestations of itch mites more effectively than other types of pesticides. There was no significant difference in prevalence of fleece derangement between flocks treated with different pesticide groups and those that received no treatment, but mean fleece derangement score was significantly lower in sheep treated with organophosphates than in untreated sheep. Infestations of lice were significantly more prevalent in sheep from flocks treated with synthetic pyrethroids than from those treated with organophosphates or those that received no treatment.

Animals↗

An immunological strategy To monitor In situ the phosphate starvation state in thiobacillus ferrooxidans

Thiobacillus ferrooxidans is one of the chemolithoautotrophic bacteria important in industrial biomining operations. During the process of ore bioleaching, the microorganisms are subjected to several stressing conditions, including the lack of some essential nutrients, which can affect the rates and yields of bioleaching. When T. ferrooxidans is starved for phosphate, the cells respond by inducing the synthesis of several proteins, some of which are outer membrane proteins of high molecular weight (70,000 to 80,000). These proteins were considered to be potential markers of the phosphate starvation state of these microorganisms. We developed a single-cell immunofluorescence assay that allowed monitoring of the phosphate starvation condition of this biomining microorganism by measuring the increased expression of the surface proteins. In the presence of low levels of arsenate (2 mM), the growth of phosphate-starved T. ferrooxidans cells was greatly inhibited compared to that of control nonstarved cells. Therefore, the determination of the phosphorus nutritional state is particularly relevant when arsenic compounds are solubilized during the bioleaching of different ores.

Journal Article↗

Phosphorylation of eukaryotic initiation factor 2 by heme-regulated inhibitor kinase-related protein kinases in Schizosaccharomyces pombe is important for fesistance to environmental stresses.

Protein synthesis is regulated by the phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha) in response to different environmental stresses. One member of the eIF2alpha kinase family, heme-regulated inhibitor kinase (HRI), is activated under heme-deficient conditions and blocks protein synthesis, principally globin, in mammalian erythroid cells. We identified two HRI-related kinases from Schizosaccharomyces pombe which have full-length homology with mammalian HRI. The two HRI-related kinases, named Hri1p and Hri2p, exhibit autokinase and kinase activity specific for Ser-51 of eIF2alpha, and both activities were inhibited in vitro by hemin, as previously described for mammalian HRI. Overexpression of Hri1p, Hri2p, or the human eIF2alpha kinase, double-stranded-RNA-dependent protein kinase (PKR), impeded growth of S. pombe due to elevated phosphorylation of eIF2alpha. Cells from strains with deletions of the hri1(+) and hri2(+) genes, individually or in combination, exhibited a reduced growth rate when exposed to heat shock or to arsenic compounds. Measurements of in vivo phosphorylation of eIF2alpha suggest that Hri1p and Hri2p differentially phosphorylate eIF2alpha in response to these stress conditions. These results demonstrate that HRI-related enzymes are not unique to vertebrates and suggest that these eIF2alpha kinases are important participants in diverse stress response pathways in some lower eukaryotes.

Amino Acid Sequence↗

The virulence plasmid of Yersinia, an antihost genome.

The 70-kb virulence plasmid enables Yersinia spp. (Yersinia pestis, Y. pseudotuberculosis, and Y. enterocolitica) to survive and multiply in the lymphoid tissues of their host. It encodes the Yop virulon, an integrated system allowing extracellular bacteria to disarm the cells involved in the immune response, to disrupt their communications, or even to induce their apoptosis by the injection of bacterial effector proteins. This system consists of the Yop proteins and their dedicated type III secretion apparatus, called Ysc. The Ysc apparatus is composed of some 25 proteins including a secretin. Most of the Yops fall into two groups. Some of them are the intracellular effectors (YopE, YopH, YpkA/YopO, YopP/YopJ, YopM, and YopT), while the others (YopB, YopD, and LcrV) form the translocation apparatus that is deployed at the bacterial surface to deliver the effectors into the eukaryotic cells, across their plasma membrane. Yop secretion is triggered by contact with eukaryotic cells and controlled by proteins of the virulon including YopN, TyeA, and LcrG, which are thought to form a plug complex closing the bacterial secretion channel. The proper operation of the system also requires small individual chaperones, called the Syc proteins, in the bacterial cytosol. Transcription of the genes is controlled both by temperature and by the activity of the secretion apparatus. The virulence plasmid of Y. enterocolitica and Y. pseudotuberculosis also encodes the adhesin YadA. The virulence plasmid contains some evolutionary remnants including, in Y. enterocolitica, an operon encoding resistance to arsenic compounds.

Animals↗

Paul Ehrlich: pioneer of chemotherapy and cure by arsenic (1854-1915).

Paul Ehrlich's experiments in staining techniques at the end of the nineteenth century resulted in many discoveries which help to form the basis of present research work. Ehrlich's chemotherapy research led to his formulating the arsenic compound, Salvarsan, which was used in the treatment of syphilis during the first half of this century until it was superseded by penicillin.

Animals↗

Ham-Wasserman lecture: treatment of acute leukemia by inducing differentiation and apoptosis.

Conventional treatment of acute leukemia involves the use of cytotoxic agents (chemotherapy), but other strategies have been explored. All-trans retinoic acid (ATRA) and arsenic have clearly been effective in the treatment of acute promyelocytic leukemia (APL), which creates the possibility that other types of acute leukemia can be conquered by selectively inducing differentiation and/or apoptosis. A great number of investigations have been performed to elucidate the mechanisms and search for effective agents in the treatment of other types of acute leukemia by these new strategies. Progress at the molecular level has been achieved in explaining the mechanisms of action of ATRA and arsenic compounds, and several new agents have emerged, although their clinical effectiveness remains to be confirmed. Mechanism-/gene-based targeted therapy and a combination of different strategies will improve the treatment of acute leukemia.

Acute Disease↗

Interference by toxic metal ions with DNA repair processes and cell cycle control: molecular mechanisms.

Nickel, cadmium, cobalt, and arsenic compounds are well-known carcinogens to humans and experimental animals. Even though their DNA-damaging potentials are rather weak, they interfere with the nucleotide and base excision repair at low, noncytotoxic concentrations. For example, both water-soluble Ni(II) and particulate black NiO greatly reduced the repair of DNA adducts induced by benzo[a]pyrene, an important environmental pollutant. Furthermore, Ni(II), As(III), and Co(II) interfered with cell cycle progression and cell cycle control in response to ultraviolet C radiation. As potential molecular targets, interactions with so-called zinc finger proteins involved in DNA repair and/or DNA damage signaling were investigated. We observed an inactivation of the bacterial formamidopyrimidine-DNA glycosylase (Fpg), the mammalian xeroderma pigmentosum group A protein (XPA), and the poly(adenosine diphosphate-ribose)polymerase (PARP). Although all proteins were inhibited by Cd(II) and Cu(II), XPA and PARP but not Fpg were inhibited by Co(II) and Ni(II). As(III) deserves special attention, as it inactivated only PARP, but did so at very low concentrations starting from 10 nM. Because DNA is permanently damaged by endogenous and environmental factors, functioning processing of DNA lesions is an important prerequisite for maintaining genomic integrity; its inactivation by metal compounds may therefore constitute an important mechanism of metal-related carcinogenicity.

Animals↗

Leukemias resembling acute promyelocytic leukemia, microgranular variant.

Acute promyelocytic leukemia (APL) should be distinguished from other subtypes of acute myeloid leukemia (AML) because of the increased risk of disseminated intravascular coagulation (DIC) and its response to arsenic compounds and retinoids. Some cases of AML seem morphologically similar to the microgranular variant of APL (French-American-British [FAB] AML-M3v) but lack the t(15;17). We evaluated 8 cases of APL-like leukemias for subtle morphologic, cytochemical, immunophenotypic, and cytogenetic differences compared with 5 cases of promyelocytic leukemia/retinoic receptor alpha (PML/RARalpha)-positive APL (FAB AML-M3v). We also evaluated both groups for the presence of DIC. No differences among the groups were noted in blast size, chromatin pattern, nuclear morphologic features, intensity of myeloperoxidase staining, or presence of Auer rods. Immunophenotypes were similar; both types of cases lacked CD34 and HLA-DR and were CD13+ and CD33+. Two cases of APL-like leukemias also were CD56+. DIC was present in 2 patients with M3v. Our study shows that there are no definitive morphologic, cytochemical, or immunophenotypic findings that can distinguish these cases from PML/RARalpha-positive APL.

Antigens, CD↗

[Physicians, prostitution, and venereal disease in Colombia (1886-1951)].

The article examines the Colombian medical field's fight against so-called venereal diseases between 1886 and 1951, a period when the country was undergoing processes of urbanization, population growth, and the emergence both of industry as well as of a middle class and an urban proletariat. Physicians found a close connection between the spread of syphilis and gonorrhea and the rise of prostitution in cities. At the close of the 19th century, doctors and public health bodies assumed prostitution was inevitable. In 1907 they managed to have it legalized and they opened clinics to dispense mercury therapy and treatment with arsenic compounds. Starting in the 1930s amd 1940s, treatment of venereal diseases was viewed as the State's duty, necessary to protect "la raza" and safeguard progress and civilization. As of 1950, the efficient use of penicillin once again caused the question of prostitution to be posed in more moral and aesthetic terms and brought an end to the regulations groverning its practice, at least in Bogota.

Colombia↗

Genetically determined susceptibility markers in skin cancer and their application to chemoprevention.

Development of skin cancer is a result of interactions between genetic and environmental factors. Exposure to sunlight is an established cause of non-melanoma skin cancer as well as of melanoma. Other additional factors such as exposure to environmental chemicals (e.g., chimney soot, arsenic compounds), chronic irritation of the skin, viral infections and the immune status of the host may predispose to skin cancer. The high incidence of skin cancer highlights the need for development of more effective chemopreventive agents. This requires a better understanding of genetically determined host susceptibility, which is increasingly acknowledged as a major factor in the causation of skin tumours.

Albinism↗

[Morphological peculiarities of rat liver reaction to chronic xenobiotic exposure].

The data of the morphological studies of liver of animals subjected to chronic (3 months long) intoxication with different chemical substances (ammonium nitrogen, nitrite nitrogen, fluorine, chromium, arsenic) are presented. The xenobiotics tested induced stereotyped responses in liver which differed in their intensity and the extent of hemomicrocirculatory and inflammatory-destructive alterations. Most pronounced reactive changes were found in animals exposed to arsenic compounds, while sodium nitrate caused practically no destructive changes in hepatocytes.

Administration, Oral↗

Fire-air and dephlogistication. Revisionisms of oxygen's discovery.

Americans are taught that Joseph Priestley discovered oxygen in 1774 and promptly brought that news to Lavoisier. Lavoisier proved that air contained a new element, oxygen, which combined with hydrogen to make water. He disproved the phlogiston theory but Priestley called it dephlogisticated air until his death 30 years later. Scandanavians learn that a Swedish apothecary Carl Wilhelm Scheele beat Priestley by 2 years but was deprived of credit because Lavoisier denied receiving a letter Scheele later claimed to have sent in September 1774 describing his 1772 discovery of "fire air". His claim was unconfirmed because Scheele first published his work in 1777. However, Scheele's missing letter was made public in 1992 in Paris, 218 years late, and now resides at the French Academie de Sciences. Lavoisier received it on Oct 15, 1774. His guilt was kept secret in the effects of Madame Lavoisier. He failed on several occasions to credit either Priestley or Scheele for contributing to the most important discovery in the history of science. Priestley was a teacher, political philosopher, essayist, Unitarian minister and pioneer in chemical and electrical science. He discovered 9 gases including nitrous oxide. He invented soda water, refrigeration, and gum erasers for which he coined the term "rubber". He discovered photosynthesis. He was humorless, argumentative, brilliant and passionate, called a "furious free-thinker". While his liberal colleagues Josiah Wedgwood, Erasmus Darwin, James Watts, and others of the Lunar Society were celebrating the 2nd anniversary of the French revolution, a Birmingham mob, supported by the royalists and the established church, destroyed Priestley's home, laboratory and church. Driven from England, he emigrated to Pennsylvania where he built a home and laboratory and collected a 1600 volume library, then among the largest in America. He is regarded as a founder of liberal Unitarian thinking. He was friend and correspondent of Thomas Jefferson. His philosophy and insight persuaded Jefferson to initiate what Americans call a liberal arts education. Scheele was later recognized as a brilliant and productive pioneer in chemistry although he died at age 44 of tasting his own arsenic compounds. In the new time-lapse play "Oxygen" set in Stockholm in both 18th and 21st centuries, in 1774, blame falls on Lavoisier's wife who hid Scheele's letter in hopes of giving her husband sole credit for discovering oxygen. In 2001, four Nobel committee panelists cannot agree which should receive the first "Retro-Nobel Prize" for the greatest discovery of all time: Priestley, Scheele or Lavoisier or all three. The audience is asked to choose.

Drama↗

[Effect of metals, benzene, pesticides and ethylene oxide on the haematopoietic system].

The hematopoietic system, due to intensive cells proliferation, is very sensitive to toxic substances. Many chemicals, including benzene, pesticides (dithiocarbamines), ethylene oxide and metals (mercury, cadmium, chrome, cobalt, lead, aluminum) exert their toxic effect on the hematopoietic system. Exposure to each of these substances may occur in the work place due to environmental pollution and in municipal or residential areas. Exposure to lead, aluminum, cadmium, and benzene results in the incidence of anemia. In addition, exposure to benzene and its metabolites leads to myelodysplastic syndromes, leukemia, lymphomas and bone marrow aplasia. Ethylene oxide induces neoplasm of the hematopoietic system and lymphomas, especially non-Hodgkin lymphoma. Arsenic compounds act like immunosuppressants. Mercury and chrome affect the immune system by immunosuppression and by evoking autoimmune reactions. Dithiocarbamates are suspected to induce leukemia. An analysis of the pathophysiology of individual substances reveal universal toxic mechanisms. In this paper, the authors discuss the pathomechanism of toxic effects of the aforesaid chemicals on the haematopoietic system and peripheral blood cells from the viewpoint of mutagenesis, apoptosis, myelotoxicity, anemia, immunomodulation, and individual sensitivity.

Benzene↗

Syphilis during 1900-1910: similarities to present-day AIDS.

At the beginning of the 20th century, despite 20 years of intensive bacteriologic research, the cause of syphilis was unknown; no diagnostic test and no treatment had been found. Syphilis was one of the leading causes of morbidity and mortality, and those who had the disease were burdened with a social stigma. It was considered a disease of "bad blood." But success was soon to follow. In only 10 years, from 1900 to 1910, the Treponema pallidum was discovered as the cause of syphilis. Animal models were developed for research. The Wassermann test was "invented" for serologic diagnosis, and Paul Ehrlich proved that salvarsan, or 606, was effective for the treatment of syphilis. This success was preceded by 300 failures with related arsenical compounds. The scientific, medical, social, ethical, and economic issues of that day have recurred again with the AIDS epidemic. This earlier drama, therefore, is reflected in the current decade, but the success of Ehrlich, Wassermann, and others in the fight against syphilis is an optimistic omen that researchers will be equally successful in the fight against acquired immune deficiency syndrome (AIDS).

History, 20th Century↗

Incidence and etiology of lung cancer in the Pacific Basin.

Incidence of lung cancer in the Pacific Basin was either compiled from published reports or computed by the authors. The results showed a great variation in age-standardized annual incidence rates of lung cancer among 10 countries and 17 areas in the Pacific Basin where tumor registry statistics are available. For males the incidence rates ranged from 10 to over 70 and for females from less than 5 to over 30/100,000 population. The reason(s) for the great variation is unclear. Ionizing radiation, carcinogenic chemical substances (e.g., chromium, arsenic compounds, asbestos, etc.), or air pollution are unlikely to be responsible. Because cigarette smoking is known to be a major cause of lung cancer, the authors have suggested that surveys on cigarette smoking be conducted among various populations in the Pacific Basin so that etiologic significance of cigarette smoking for the noted variation can be assessed. In Hawaii such a survey is underway, and a preliminary analysis was made to examine the association between lung cancer and cigarette smoking among five races.

Australia↗

Agriculturally-related carcinogenic risk.

Although all people are exposed throughout life to pesticides (during manufacture and use, in the environment, via the food chain), with the exception of vinyl chloride and the arsenic compounds, no human carcinogen pesticide is known. In experimental animals and short-term tests, however, many pesticides have proved to be carcinogenic or genotoxic. In order to elucidate possible modes of action related to genotoxicity (short-term tests) and carcinogenicity, data on 83 pesticides were analysed. A definitive promoter effect was demonstrated for five compounds, and a suspected promoter effect could be attributed to 16 compounds. Almost all were organohalogens. Ethylenthiourea and aminotriazole are also carcinogens, which induce tumours through hormonal imbalance. Ethylenthiourea is the degradation product and metabolite of certain ethylene-bisdithiocarbamate pesticides. Chlorphenol and chlorophenoxyacetic acid-type pesticides contain 2,3,7,8-tetrachlorodibenzo-paradioxin (TCDD) as a contaminant. TCDD has definite promoter action. Seventeen tumorigenic pesticides could be regarded as genotoxic, and similar activity could be suspected in three other carcinogenic pesticides. Many pesticides contain N-nitroso impurities in various amounts. Nitrosation of the original pesticide or its derivative, such as dialkylamines, alkyl-arylamines, methyleneimines, gives rise to the formation of N-nitroso compounds. Amides containing secondary amines, such as ethylcarbamate and alkylurea, could be nitrosated in vivo and in vitro. Most nitrosated pesticides are strong genotoxic carcinogens.

Agricultural Workers' Diseases↗

A cohort study on mortality among long-time employed Swedish chimney sweeps.

A cohort study on mortality among all members of the Swedish Chimney Sweeps Union who were active in 1950 or later and have been members for at least 10 a has been performed; 2,071 chimney sweeps fulfilled the criteria and the loss in the follow-up was less than 1 %. The observed numbers of death before the age of 80 were compared with sex-, calendar year-, and age class specific expectancy values from the national statistics of 1951-1979. Two hundred and thirty deaths were observed versus 197.6 expected. This result was due to a significant excess of deaths from tumors, particularly lung and esophageal cancer, and from nonmalignant chronic respiratory diseases. The multifold increased risk from these diseases could hardly be explained by extreme smoking or alcohol habits but rather by exposure to polycyclic aromatic hydrocarbons, nitrogen compounds, arsenic, and asbestos in combination with exposure to sulfur dioxide. The excess mortality had occurred in spite of favorable selection factors as demonstrated in different subcohorts. Preventive actions to diminish inhalation of soot and combustion gases should be taken.

Adult↗