TRANSFAC: an integrated system for gene expression regulation.

TRANSFAC is a database on transcription factors, their genomic binding sites and DNA-binding profiles (http://transfac.gbf.de/TRANSFAC/). Its content has been enhanced, in particular by information about training sequences used for the construction of nucleotide matrices as well as by data on plant sites and factors. Moreover, TRANSFAC has been extended by two new modules: PathoDB provides data on pathologically relevant mutations in regulatory regions and transcription factor genes, whereas S/MARt DB compiles features of scaffold/matrix attached regions (S/MARs) and the proteins binding to them. Additionally, the databases TRANSPATH, about signal transduction, and CYTOMER, about organs and cell types, have been extended and are increasingly integrated with the TRANSFAC data sources.

Resistance of young gelatinase B-deficient mice to experimental autoimmune encephalomyelitis and necrotizing tail lesions.

Regulated expression of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) plays a role in various physiological processes. To determine in vivo how unbalanced expression of these factors can promote or affect the course of pathologies, we knocked out the mouse gelatinase B gene by replacing the catalytic and zinc-binding domains with an antisense-oriented neomycin resistance gene. Adult gelatinase B-deficient mice and wild-type controls could be induced to develop experimental autoimmune encephalomyelitis (EAE) with similar scores for neurologic disease, blood-brain barrier permeability, and central nervous system histopathology. However, whereas diseased control animals showed necrotizing tail lesions with hyperplasia of osteocartilaginous tissue, adult gelatinase B-deficient mice were resistant to this tail pathology. Gelatinase B-deficient mice younger than 4 weeks of age were significantly less susceptible to the development of EAE than were age matched controls and, even as they aged, they remained resistant to tail lesions. These data illustrate that gelatinase B expression plays a role in the development of the immune system and that, in ontogenesis, the propensity to develop autoimmunity is altered by the absence of this MMP.

Expanding the TRANSFAC database towards an expert system of regulatory molecular mechanisms.

TRANSFAC is a database on transcription factors, their genomic binding sites and DNA-binding profiles. In addition to being updated and extended by new features, it has been complemented now by a series of additional database modules. Among them, modules which provide data about signal transduction pathways (TRANSPATH) or about cell types/organs/developmental stages (CYTOMER) are available as well as an updated version of the previously described COMPEL database. The databases are available on the WWW at http://transfac.gbf.de/

Guidelines for medical screening in the workplace.

This chapter deals with general principles of conducting medical examinations to detect adverse health effects of workplace exposures and thereby prevent occupational disease or slow its progression. Much of the discussion is most relevant to screening for effects of chemical hazards, but many of the principles presented apply to physical and biological hazards as well. Procedural and administrative aspects of workplace medical examinations that are not "exposure specific" and are applicable to all medical programs are reviewed.

Environmental epidemiologic investigations in the styrene-butadiene rubber production industry.

A review of the literature and an update that is in progress of a previous retrospective cohort mortality study of the styrene-1,3-butadiene industry are discussed. The follow-up has now been extended from April 1, 1976, through December 31, 1981, for plant B and December 31, 1982, for plant A. The person-years at risk of death have gone from 34,187 to 43,341 in plant A and from 19,742 to 26,314 in plant B. Among the death certificates received to date, observed deaths have increased in both plants, with increases in cancers of the trachea, bronchus and lung and in lymphosarcomas, reticulosarcomas, and cancers of the overall lymphatic and hematopoietic system.

Quantitative risk assessment of lung cancer in U.S. uranium miners.

The National Institute for Occupational Safety and Health (NIOSH) has recently updated the vital status of the U.S. cohort of U miners through the end of 1982. This represents 69 additional lung cancer deaths since the last published follow-up through 1977. This more recent data was used to generate quantitative risk estimates of lung cancer after exposure to Rn daughters. Relative risks were estimated through use of the Cox proportional hazards model with an internal referent group. Results indicated that the exposure-response relationship was a slightly convex curve, predicting excess relative risks between 0.9 and 1.4 per 100 working level months (WLM) in the lower cumulative exposure range. Other findings of interest include a significant exposure-rate effect with low exposure rates more harmful per unit of cumulative exposure (WLM). Two temporal effects which modify relative risk estimates were also found. Relative risk increased with age at initial exposure to underground U mining. However, relative risk of lung cancer fell dramatically in the years following cessation of exposure.

A cytogenetic study of papaya workers exposed to ethylene dibromide.

Ethylene dibromide (EDB) has been shown to be carcinogenic in animal studies and mutagenic in vitro. One cytogenetic study of workers exposed to low levels of EDB for short durations was negative. To test whether exposure to low levels of EDB over long periods caused cytogenetic changes, we have assessed the frequencies of sister-chromatid exchanges (SCE) and chromosomal aberrations (CA) in the peripheral blood lymphocytes of 60 men occupationally exposed to EDB. These men worked in papaya-packing plants where EDB was used to fumigate the fruit after harvest to kill fruit-fly larvae. 42 other men who worked at a nearby sugar mill served as controls. The average duration of exposure of the papaya workers was 5 years. 82 full shift personal breathing-zone air samples indicated that the papaya workers were exposed to a geometric mean of 88 ppb of EDB, as an 8-h time weighted average (TWA). Peaks up to 262 ppb were measured. The proposed OSHA 8-h TWA for EDB is 100 ppb, while NIOSH recommends 45 ppb. No differences in SCE levels were found between exposed and nonexposed workers. No differences were found in the total CA frequency between exposed and nonexposed workers. SCE levels were significantly increased in men who smoked cigarettes (p = 0.0001) and in men who smoked marijuana (p = 0.01). CA levels showed a significant increasing trend with age (p = 0.03).

Arritmia cardíaca fetal antenatal: comunicación de un caso y revisión de la literatura / Fetal antenatal cardiac arrhytmia: report of a case and review of the literature

Se preasenta un caso de arritmia cardíaca fetal por extrasístoles, diagnosticada durante auscultación con estetoscopio de Pinard y, posteriormente, confirmada por ecocardiografía modo M. La literatura revisada reporta que la incidencia de extrasístoles fetales es de 1,7%, que pueden presentarse auscultatoriamente como ritmo irregular y como bradicardia cuando no son conducidas, que bajo la mayoría de las circunstancias son inocuas y han sido asociadas a acción de epinefrina; sin embargo, ha sido reportada coexistencia de cardiopatía congénita; la mayoría cesa antes del nacimiento. Su diagnóstico correcto evita cesárea innecesaria. Pueden producir taquicardia paroxística supraventricular (SVT), lo que constituye una verdadera emergencia médica, por lo que se requiere reevaluación ecocardiográfica semanal en su búsqueda y, de instalarse SVT, si el feto no está maduro, debe tratarse in útero y no realizar cesárea de entrada para evitar las dificultades inherentes al tratamiento de neonato inmaduro con arritmia, edema pulmonar, membrana hialiana e hidrops fetalis. La obtención, en el caso presentado, de bebé sano por parto normal post-inducción luego de haber alcanzado la madurez pulmonar, confirma que el ecocardiograma fetal modo M tipificó la arritmia y permitió pronosticar su evolución natural benigna, tranquilizando al obstetra, a la madre y al neonatólogo, por lo que estas patologías deben manejarse en equipo

Cytogenetic studies in humans after short-term exposure to ethylene dibromide.

Ethylene dibromide (EDB) has been shown to increase sister chromatid exchange in animal cells in vitro, but its cytogenetic effects in humans have not been previously studied. A solution containing EDB is used in the summer months in Colorado to spray felled pine trees to kill pine beetles. We have assessed the frequencies of sister chromatid exchanges and chromosomal aberrations in the peripheral blood lymphocytes of 14 sprayers both before and after exposure. Six nonexposed individuals also were tested. Full-shift personal breathing-zone air samples indicated that the sprayers were exposed to an average of 60 ppb of EDB, as an eight-hour time weighted average. The range of exposure was from 5 to 281 ppb. Workers sprayed EDB for only five to 26 days during the summer, with an average of 14 days. After adjusting for smoking and the use of prescription medicine, there was no statistically significant difference between the frequencies of either sister chromatid exchange or chromosomal aberrations before and after spraying.

A retrospective cohort mortality study of a phosphate fertilizer production facility.

A retrospective cohort mortality study of phosphate fertilizer production workers was undertaken to determine whether this group is at increased risk of dying from any cause, particularly from lung cancer. A total of 3,199 workers who had ever been employed at one facility were included in this investigation. These workers were followed for vital status ascertainment from their first date of employment up to December 1, 1977, or the date of death, whichever occurred first. Overall, no statistically significant elevations in cause-specific mortality were observed for the entire study population. However, when the analysis was stratified by duration of employment, and length of follow-up, a statistically significant (P less than .05) excess in lung cancer mortality was observed among workers with more than 10 yr of employment and follow-up (standardized mortality ratio = 411). Because of the small number of deaths involved, and because we had prior knowledge of a lung cancer cluster at this plant, we believe that these findings should be viewed as suggestive, and that other investigations in plants with similar exposures are needed to clarify whether an occupationally related lung cancer excess truly exists.

Mortality patterns among styrene-exposed boatbuilders.

In order to test the hypothesis that leukemia and lymphoma may be associated with exposure to styrene, cause-of-death patterns were studied at two reinforced plastic boatbuilding facilities. There were 5,021 workers who met the criterion of having worked at the two plants between 1959 and 1978. Based on industrial hygiene surveys conducted at the two plants, 2,060 individuals were determined to have worked in departments classified as having high exposure to styrene. There were 176 deaths observed among the total cohort, in comparison to 195.3 deaths expected (standardized mortality ratio [SMR] = 90). Among the high styrene exposure group, 47 deaths were observed in comparison to 41.5 deaths expected (SMR = 113). No leukemia or lymphoma deaths were observed in either the high exposure group or the total cohort. An excess of accidental deaths among the high exposure group (18 observed vs 12.4 expected) did not appear to be due to styrene's acute central nervous system effects, since none of the individuals were employed at the facilities at the time of their death. However, the possibility of a chronic effect could not be dismissed. While leukemia and lymphoma did not appear to be related to styrene exposure, the study had little statistical power to detect excesses of these diseases, due to the short length of observation and the young age of most cohort members. It was concluded that the cohort should provide increasingly useful information on chronic styrene toxicity as the population ages and the observation period increases.

Ethylene oxide: an overview of toxicologic and epidemiologic research.

Ethylene oxide (EtO) is a reactive epoxide and potent biocide. It is used widely in gas sterilization of hospital equipment. An estimated 75,000 health care workers in the United States have potential exposure. EtO binds covalently to deoxyribonucleic acid (DNA) and has been shown in 13 species to cause point mutations. Apparently, as a consequence of its alkylating ability, EtO exposure can result in chromosomal damage. In monkeys EtO exposure produces increased frequencies of sister chromatid exchanges (SCEs) and chromosomal aberrations. In man, five cytogenetic studies have shown dose-related increased frequencies of either SCE or chromosomal aberrations; in one study SCEs developed after regular exposures lasting less than five minutes per day. EtO is a reproductive toxin. In adult male rats, exposure produces decreased fertility, increased fetal deaths, and heritable chromosomal translocations. In pregnant female rats and rabbits, exposure causes increased fetal losses, and in one study in pregnant mice exposure was associated with increased numbers of malformed fetuses. In male monkeys EtO causes dose-related reductions in sperm count and sperm motility. In pregnant women, one study suggests that brief occupational exposure twice daily in concentrations of 20 ppm or above was associated with increased spontaneous abortions. EtO is carcinogenic to animals. In rats it causes dose-related increases in mononuclear cell leukemias, peritoneal mesotheliomas, and cerebral gliomas. In man, exposure has been associated in two epidemiologic studies with increased leukemias: 3 leukemias observed versus 0.2 expected in one study, and 2 observed versus 0.14 expected in the other; two additional small studies of limited power found no excess leukemias. Quantitative risk assessment indicates that from 634 to 1,093 excess deaths from cancer will occur per 10,000 workers exposed to EtO at 50 ppm over a working lifetime, and that 12 to 23 excess cancer deaths will occur per 10,000 workers exposed at 1 ppm. The National Institute for Occupational Safety and Health (NIOSH) recommends that EtO be regarded as a potential human carcinogen. NIOSH has recommended that eight-hour time-weighted average exposure to EtO be less than 0.1 ppm and that short-term peak exposure not exceed 5 ppm for more than ten minutes per working day.

Environmental epidemiologic investigation of the styrene-butadiene rubber industry. Mortality patterns with discussion of the hematopoietic and lymphatic malignancies.

A retrospective cohort mortality study and an industrial hygiene assessment were undertaken in two styrene-butadiene rubber producing facilities in eastern Texas. Occupational history records were available from 1943 at plant A and from 1950 at plant B to the study cut-off date of 31 March 1976. With a two-sided test statistic, no statistically significant excesses in total or cause-specific mortality were observed for the overall worker population of either plant. However, the plant A study group demonstrated a nonsignificant statistical excess [standardized mortality ratio (SMR) of 203] for the cause-specific category of leukemia and aleukemia. Additional analyses were performed on a subgroup consisting of all white males with at least six months of employment at plant A between the beginning of 1943 and the end of 1945, a time which coincided with process and operational changes. An SMR of 278, also not statistically significant, was demonstrated for the leukemia and aleukemia cause-specific category. Due to the relative modest study population sizes, the power of this study to detect statistically significant excesses in leukemias or other malignancies of the hematopoietic and lymphatic tissues is not very large unless one is interested in substantial excesses, such as those that would correspond to a fourfold increase in risk.

Epidemiologic investigations of styrene-butadiene rubber production and reinforced plastics production.

The United States National Institute for Occupational Safety and Health (NIOSH) began an epidemiologic study of workers employed in the styrene-butadiene rubber (SBR) industry during 1976. This study was prompted by reports of relatively high numbers of leukemia deaths occurring within SBR production work populations. Simultaneous with the initiation of this investigation, the University of North Carolina released a report associating an excess risk of death due to hematopoietic and lymphatic malignancies among workers producing several synthetic rubbers, including SBR. This report presents NIOSH's preliminary mortality observations and a discussion of progress made on the analyses of contaminants found in two SBR production facilities. Currently, NIOSH is determining the feasibility of doing an epidemiologic study in the reinforced plastics industry. Interest in this study developed as part of an effort to determine health hazards associated with occupational exposure to styrene. Most of the technology for the reinforced plastics industry developed in the 1950s, and therefore this process represents a relatively new industry. This report also includes information on environmental conditions observed in the reinforced plastics industry and enumerates some of the complicating characteristics of this industry which increase the complexity of this study.