Tetrameric complexes of human histocompatibility leukocyte antigen (HLA)-G bind to peripheral blood myelomonocytic cells.

The nonclassical MHC class I molecule human histocompatibility leukocyte antigen (HLA)-G is selectively expressed on fetal trophoblast tissue at the maternal-fetal interface in pregnancy. It has long been suggested that HLA-G may inhibit maternal natural killer (NK) cells through interaction with particular NK cell receptors (KIRs). To investigate interactions of HLA-G, we constructed phycoerythrin-labeled tetrameric complexes of HLA-G refolded with a self-peptide. These HLA-G tetramers failed to bind to NK cells and cells transfected with CD94/NKG2 and killer immunoglobulin-like NK receptors. In contrast, HLA-G tetramers did bind to peripheral blood monocytes, staining a CD16(+)CD14(mid) subset with greater intensity. On transfectants, HLA-G tetramers bound to inhibitory immunoglobulin-like transcript (ILT)2 and ILT4 receptors. However, staining in the presence of antibodies reactive with ILT receptors revealed that the interaction of HLA-G tetramers with blood monocytes was largely due to binding to ILT4. These results suggest that the primary role of HLA-G may be the modulation of myelomonocytic cell behavior in pregnancy.

Cancer mortality among rubber workers: an epidemiologic study.

Several previous epidemiologic studies of the rubber industry--an industry that uses many chemicals--have identified excess mortality from certain specific cancers. In this study, four cohorts of active and retired workers, at four major rubber-tire plants, were identified historically and followed for the ten-year period from 1964 to 1973. The cancer mortality of these four population was compared, separately and combined, with that of the general community. For all cancers combined, there was a slight excess above the expected number of deaths, whereas for some specific cancers (stomach, colon, prostate, and neoplasms of the lymphatic and hematopoietic system) there was a marked excess of deaths. Proportional mortality analysis at other small plants revealed similar excesses for these cancers, and some excess for lung, bladder, and CNS cancers. Analysis of detailed individual work histories reveals an association of certain cancers with specific job exposures; in particular, lymphatic leukemia and solvent exposure, and lung cancer and curing-room exposure. For both bladder cancer and stomach cancer, preliminary analyses indicate an association with groups of jobs in adjacent production stages (handling and mixing raw ingredients, and processing the "green" precured rubber, respectively). Further analytic studies are currently under way to identify groups of rubber workers at increased risk of other specific cancers.

Teratogenic effect of extended administration of N-nitrosoethylurea and ethylurea/nitrite in rats.

N-Nitrosoethylurea (ENU) and ethylurea (EU) with sodium nitrite (NaNO2) were administered daily by mouth to Hooded Wistar rats. Doses ranged from 1-50 mg ENU/kg body weight (day-1) and from 20-70 mg EU/kg body weight day-1 and extended over days 7 to 16 inclusive of pregnancy. Severe teratogenesis occurred in animals which received from 10 mg ENU/kg day-1. Fetal death predominated at intakes above 12.5 mg ENU/kg body wt. Many organ systems were affected by ENU, but developmental anomalies of the nervous system were most common, especially anophthalmia and hydrocephalus. With EU and nitrite severe teratogenesis was noted at levels above 50 mg EU/kg body weight. Maximum teratogenic potency was obtained when nitrite was administered at approximately 50% of the level of the EU dose. Terata arising from treatment with EU/nitrite were similar to those caused by ENU. However, unlike ENU-treated animals, litters from the EU/nitrite study were either severely malformed or barely affected at all. The erratic nature of the teratogenesis following treatment with EU/nitrite was not influenced by the presence of food in the stomach at the time of dosing. For both substances administered over a 10-day period, the threshold dose needed for obvious teratogenicity was considerably less than in all previously reported single-dose studies.

Plasma membranes from influenza virus-infected cells induce in vitro human secondary virus-specific cytotoxic T lymphocyte responses.

Influenza A virus-specific cytotoxic T lymphocytes (CTL) were induced by incubating human peripheral blood mononuclear cells with membranes prepared from influenza A virus-infected cells. The response obtained was equivalent to that given after sensitization in vitro with influenza A virus-infected lymphocytes. It was shown that this response was only obtained when stimulating membrane fragments and responding cells shared HLA-A or -B locus antigens. In order to analyse further the nature of the activating antigen, the membrane fragments were solubilized with detergent and then reconstituted by dialysing it out. This treatment destroyed their ability to stimulate virus-specific CTL although similar treatment of membranes from uninfected cells did not affect their capacity to stimulate a xenogeneic mouse CTL response. Liposomes constructed to contain defined virus and cell surface antigens also failed to stimulate CTL. These findings suggest that secondary induction of influenza virus-specific CTL in vitro requires the presence of the correct HLA antigen and that the virus-membrane association is irreversibly destroyed by detergent treatment.

A case-control study of prostate cancer within a cohort of rubber and tire workers.

A matched case-control study was conducted to test the hypothesis that prostate cancer is associated with employment in the compounding area of a rubber and tire manufacturing plant. A search of death certificates from the years 1964 to 1975 led to the identification of 88 cases of prostate cancer. These were individually matched with 258 controls on the factors of age, race, and date of entry into the plant. To eliminate possible confounding by sociodemographic differences, several variables were assessed but none differed significantly between cases and controls. The batch preparation work area showed statistically significant (p < 0.025) risk ratios over three exposure periods -- more than one month, more than 24 months, and more than 60 months. The service to batch preparation and shipping and receiving work areas showed significant risks for blacks. The data were used to assess a latent period or etilogic fraction for prostate cancer for those employed in batch preparation. Twenty-nine years was estimated to be the latent period while the period of greatest risk occurred during the years 1940 to 1947.

Amalgam fillings, diagnostic dental x-rays and tumours of the brain and meninges.

A population-based case-control study of incident brain tumours in adults in Adelaide, South Australia considered possible associations of exposures to amalgam fillings and diagnostic dental X-rays with subsequent development of glioma and meningioma. The study, conducted in 1987-1990, recorded data from 110 subjects with glioma, 60 with meningioma and 417 controls. Principal findings were unexplained decreased risks for glioma associated with both exposure to amalgam fillings (age- and sex adjusted relative risk = 0.47, 95% confidence interval: 0.25-0.91; P = 0.02) and to diagnostic dental X-rays (adjusted relative risk = 0.42; 95% confidence interval: 0.24-0.76; P = 0.004), and a possible increased risk for meningioma in males exposed to dental X-rays. The choice of the unexposed comparison group is important in determining if an increased risk is associated with panoramic or full-mouth X-rays in glioma.

Effect of occupational and nonoccupational factors on the respiratory system of vinyl chloride and other workers.

There are suggestions in the literature that vinyl chloride (VC) acts as a lung irritant. Respiratory questionnaires and lung function tests were administered to 174 chemical (VC) workers, 81 polyvinyl chloride (PVC) workers, 72 former VC workers, and 136 rubber workers, and 68 maintenance workers with exposure to VC, PVC, and rubber. Except for small airways obstruction associated with rubber, increased respiratory symptoms and decreased pulmonary function were not associated with working in chemicals, plastics, or rubber. Some increases in baseline pulmonary function were associated with VC exposure. Acute reductions in pulmonary function were observed in smokers working in chemicals, plastics, and rubber. Heavier cigarette smokers over 40 years of age had the most adversely affected respiratory system. Work was not associated with chronic respiratory effects, but all exposure groups experienced some acute respiratory insult.

Chronic respiratory symptoms and job type within the rubber industry.

Associations between the presence of chronic respiratory symptoms and a history of working in certain production job categories within the rubber industry are presented. Environmental explanations for these associations are discussed. Particular attention is also paid to the methodologic diffculties in analyzing cross-sectional health data in relation to the mobile and environmentally varied work-histories of individual workers within the rubber industry.

Respiratory function and symptoms: an environmental-epidemiological study of rubber workers exposed to a phenolformaldehyde type resin.

Rubber workers exposed to a hexamethylenetetramine-resorcinol (HR) adhesive system reported an excess of acute symptoms and significant reductions in expiratory flow rates at low lung volumes. Smokers exhibited greater reductions in flow rates than nonsmokers. The greatest reductions in ventilatory capacity were associated with HR exposure. There was a moderate association of reduced flow rates with respirable particulate in the HR exposed workers only.

The association of vinyl chloride exposures with morbidity symptoms.

A mail-out questionnaire examined symptoms previously associated with vinyl chloride exposure. Assessment of exposure levels was made by analytical measurement and observation. The resulting statistical analysis revealed a dose-response type of relationship between exposure and certain morbidity symptoms.

The occupational determinants of chronic disabling pulmonary disease in rubber workers.

Chronic respiratory disease is among the three leading causes of premature retirement due to work disability. The association of occupational exposure and smoking history as potential determinants of pulmonary disability retirement were examined. A cohort of 4302 male, hourly rubber workers actively employed at the Akron plant of a large rubber company on January 1, 1964 was identified and followed for ten years. During the period, 1964-1973, 73 workers terminated gainful employment with a pulmonary disability retirement. Work and smoking histories for these cases and two age-race-sex matched control groups were ascertained. Cases spent significantly greater durations of time employed in curing preparation, curing and finishing and inspection work areas. Each of these areas involves exposures to particulate material and/or solvents. Significant risk of developing a pulmonary disability was associated with smoking and exposure to dust and fumes, generally, and talc and carbon black more specifically. Smoking and occupational exposures were found to interact in their association with pulmonary disability retirement among these rubber workers.

Tooth lead levels and IQ in school-age children: the Port Pirie Cohort Study.

The relation between lead concentration in deciduous central upper incisor teeth and intellectual functioning was examined in 262 children who were followed from birth to age 7 years in the lead smelter town of Port Pirie, South Australia, and its environs. Intellectual functioning of the children was assessed over the 3-year period from 1986 to 1989 with the revised Wechsler Intelligence Scale for Children (WISC-R) while each child was in his or her eighth year. There was an inverse relation between tooth lead concentration and intellectual development; the intelligence quotient declined by 2.6 points (90% confidence interval (CI) 0.13-4.9) for each natural-log unit increase in tooth lead concentration, expressed in parts per million. Some WISC-R subscales were more strongly associated with lead exposure than others. In particular, tooth lead was significantly negatively associated with scores for the "Block Design" test (partial regression coefficient -1.25 points per unit of natural-log tooth lead; 90% CI -0.61 to -1.89). No statistically significant interaction between a child's sex and tooth lead concentration was found for any of the WISC-R scales. These findings are in agreement with previously published results from this cohort for which serial blood lead concentrations were used to estimate lifetime lead burden.

A case-control study of bladder cancer in the United States rubber and tyre industry.

A case-control study of bladder cancer was conducted in five United States rubber and tyre companies to determine if there were high-risk jobs and work areas within the industry. The study included 220 male cases of bladder cancer, of whom 107 were identified from hospital record reviews and 113 from death certificates. Each case was matched individually with two industry controls by sex, race, year of birth, and company. One control was matched additionally by year of hire and duration of employment. Comparisons of cases and controls not matched by year of hire and age of hire showed no differences for those variables, which suggests that age and calendar period of first exposure to the industry were not risk determinants. When the work histories of both cases and controls were contrasted it was found that cases were more likely than controls to have worked in milling (odds ratio (OR) = 1.91) and calender operation (OR = 2.21) jobs. The relative risk estimates for milling and calender operation both exhibited linear trends of increase with duration of exposure. Milling and calender operation jobs entail potential exposures to volatilised reaction products from heated rubber stock. A better understanding of aetiological associations with job type will require more detailed characterisation of the work environment with regard to the sources and levels of aromatic amines and other suspected bladder carcinogens.

Direct ex vivo analysis of hepatitis B virus-specific CD8(+) T cells associated with the control of infection.

BACKGROUND & AIMS: Cytotoxic T cells have been suggested to be responsible for lysis of hepatitis B virus (HBV)-infected hepatocytes and control of virus infection. The frequency, kinetics, phenotype, and capacity for clonal expansion of circulating HBV-specific CD8 cells were analyzed directly in patients with acute HBV infection to clarify their pathogenetic role. METHODS: Three HLA-A2 peptide tetramers able to visualize HBV core, envelope, and polymerase epitope-specific cytotoxic T lymphocytes were synthesized and used for flow cytometric analysis of antigen-specific populations. RESULTS: Tetramer-positive cells specific for the core 18-27 epitope were found at a higher frequency than those specific for polymerase 575-583 and envelope 335-343 epitopes in most patients with acute HBV. The number of HBV-specific CD8 cells was highest during the clinically acute stage of infection and decreased after recovery. These cells expressed an activated phenotype and had an impaired capacity to expand in vitro and to display cytolytic activity in response to peptide stimulation. Recovery of these functions was observed when the frequency of specific CD8 cells decreased, coincident with a progressive decrease in their expression of activation markers. CONCLUSIONS: This study provides the first ex vivo evidence that the highest frequency of circulating HBV-specific CD8 cells coincides with the clinically acute phase of hepatitis B. These cells exhibit an activated phenotype with limited further proliferative capacity that is restored during recovery.