The function and affinity maturation of HIV-1 gp120-specific monoclonal antibodies derived from colostral B cells.

Despite the risk of transmitting HIV-1, mothers in resource-poor areas are encouraged to breastfeed their infants because of beneficial immunologic and nutritional factors in milk. Interestingly, in the absence of antiretroviral prophylaxis, the overwhelming majority of HIV-1-exposed, breastfeeding infants are naturally protected from infection. To understand the role of HIV-1 envelope (Env)-specific antibodies in breast milk in natural protection against infant virus transmission, we produced 19 HIV-1 Env-specific monoclonal antibodies (mAbs) isolated from colostrum B cells of HIV-1-infected mothers and investigated their specificity, evolution, and anti-HIV-1 functions. Despite the previously reported genetic compartmentalization and gp120-specific bias of colostrum HIV Env-specific B cells, the colostrum Env-specific mAbs described here demonstrated a broad range of gp120 epitope specificities and functions, including inhibition of epithelial cell binding and dendritic cell-mediated virus transfer, neutralization, and antibody-dependent cellular cytotoxicity. We also identified divergent patterns of colostrum Env-specific B-cell lineage evolution with respect to crossreactivity to gastrointestinal commensal bacteria, indicating that commensal bacterial antigens play a role in shaping the local breast milk immunoglobulin G (IgG) repertoire. Maternal vaccine strategies to specifically target this breast milk B-cell population may be necessary to achieve safe breastfeeding for all HIV-1-exposed infants.

Estimating lung cancer mortality from residential radon using data for low exposures of miners.

Some recent estimates of lung cancer risk from exposure to radon progeny in homes have been based on models developed from a pooled analysis of 11 cohorts of underground miners exposed to radon. While some miners were exposed to over 10,000 working level months (WLM), mean exposure among exposed miners was 162 WLM, about 10 times the exposure from lifetime residence in an average house and about three times the exposure from lifetime residence at the "action level" suggested by the U.S. Environmental Protection Agency. The extrapolation of lung cancer risk from the higher exposures in the miners to the generally lower exposures in the home is a substantial source of uncertainty in the assessment of the risk of indoor radon. Using the pooled data for the miners, analyses of lung cancer risk were carried out on data restricted to lower exposures, either <50 WLM or <100 WLM. In the pooled data, there were 115 lung cancer cases among workers with no occupational WLM exposure and 2,674 among exposed miners, with 353 and 562 lung cancer cases in miners with <50 WLM and <100 WLM, respectively. Relative risks (RRs) for categories of WLM based on deciles exhibited a statistically significant increasing trend with exposure in each of the restricted data sets. In the restricted data, there was little evidence of departures from a linear excess relative risk model in cumulative exposure, although power to assess alternative exposure-response trends was limited. The general patterns of declining excess RR per WLM with attained age, time since exposure and exposure rate seen in the unrestricted data were similar to the patterns found in the restricted data. Risk models based on the unrestricted data for miners provided an excellent fit to the restricted data, suggesting substantial internal validity in the projection of risk from miners with high exposures to those with low exposures. Estimates of attributable risk for lung cancer (10-14%) in the U.S. from residential radon based on models from the unrestricted data were similar to estimates based on the data for miners receiving low exposures.

Probability of causation for lung cancer after exposure to radon progeny: a comparison of models and data.

The estimates of lung cancer risk due to the exposure to radon decay products are based on different data sets from underground mining and on different mathematical models that are used to fit the data. Diagrams of the excess relative rate per 100 working level months in its dependence on age at exposure and age attained are shown to be a useful tool to elucidate the influence that is due to the choice of the model, and to assess the differences between the data from the major western cohorts and those from the Czech uranium miners. It is seen that the influence of the choice of the model is minor compared to the difference between the data sets. The results are used to derive attributable lifetime risks and probabilities of causation for lung cancer following radon progeny exposures.

Mortality in uranium miners in west Bohemia: a long-term cohort study.

A cohort of 4320 uranium miners in West Bohemia who started work at the mines during 1948 to 1959 and worked there for at least four years were followed up to the end of 1990 to determine cause specific mortality risks in relation to exposures in the mines. The miners had experienced high radon exposures, on average 219 working level months during their uranium mining careers, for which detailed measurements were available. They had also been exposed to high arsenic levels in one of the two major mines, and to dust. New follow up methods, not previously used for occupational cohorts in Czechoslovakia, were utilised. By the end of follow up 2415 (56%) of the cohort were known to have died. Overall mortality was significantly raised compared with that in the general population (relative risk (RR) = 1.56, 95% confidence interval (95% CI) 1.50-1.63), with significantly raised risks of lung cancer (RR = 5.08, 95% CI 4.71-5.47), accidents (RR = 1.59, 95% CI 1.34-1.87), homicide (RR = 5.57, 95% CI 2.66-10.21), mental disorders (RR = 5.18, 95% CI 2.83-8.70), cirrhosis (RR = 1.51, 95% CI 1.16-1.94), and non-rheumatic circulatory diseases (RR = 1.16, 95% CI 1.08-1.25). The relative risk of lung cancer was greatest four to 14 years after entry to the mines. Relative risks for homicide and accidents were raised up to 25 years from entry but not after this. Substantial significantly raised risks at 15 to 24 years after entry occurred for cirrhosis, non-rheumatic circulatory diseases,a nd pneumonia and other respiratory infections. Sizeable significantly raised risks at 25 and more years after entry, but not earlier, were present for mental disorders, tuberculosis, and non-malignant non-infectious respiratory conditions. No specific causes showed risks significantly related to age at entry to mining. Risk of lung cancer was significantly positively related to radon exposure, estimated arsenic exposure, and duration of work in the mines, but no other cause was significantly positively related to these variables. The raised risk of lung cancer in uranium miners, which is well established, is related aetiologically to radon exposure, and in the present cohort it may also in part have been due to exposure to arsenic. The raised risks of accidents, tuberculosis, and non-infectious respiratory diseases have also been seen in other uranium mining cohorts, and are likely to reflect the dangerous and dusty working conditions and the confined spaces in which work occurred. The cirrhosis and homicide deaths probably related to the lifestyle associated with mining. The raised risk of circulatory diseases does not seem to be related to radon or arsenic exposure; its causes are unclear. The use of multiple follow up methods was found to be mortality in the cohort.

Patterns of lung cancer mortality among uranium miners in West Bohemia with varying rates of exposure to radon and its progeny.

Lung cancer mortality in a cohort of 4320 miners first employed during 1948-1959 at the Jáchymov and Horní Slavkov uranium mines in West Bohemia and followed until 1 January 1991 has been studied to gain a greater understanding of the consequences of exposure to radon and its progeny. Among men whose exposure rates never exceeded 10 working levels, excess relative risks per unit exposure were greater in younger men, and exposures received in the periods 15-24, 25-34 and 35+ years previously were found to have 47, 24 and 0% of the effect of exposures 5-14 years previously. Within this low-exposure-rate group excess relative risk increased linearly with time-weighted cumulative exposure and did not depend on exposure rate or duration of exposure. For men who spent less than 20% of their employment at the Jáchymov mine the excess relative risk per working level month was 1.36% (95% confidence interval 0.52-3.54) in the baseline category (age group 55+ and exposure received 5-14 years previously). For men who spent more than 20% of their employment at Jáchymov, the corresponding excess relative risk per working level month was higher by a factor of 1.80 (95% confidence interval 1.27-2.97). The difference may be due to the fact that men who spent more than 20% of their employment at Jáchymov were exposed to the much higher levels of arsenic in the dust at the Jáchymov mine than at other mines. When men with exposure rates above 10 working levels were included in the analysis, patterns of risk were complex and depended on both exposure rate and duration of exposure in addition to the factors mentioned above. If these findings are confirmed elsewhere, calculation of risk estimates for extrapolation to modern occupational or environmental exposures should be based on miners with exposure rates below about 10 working levels. Further investigation is desirable of the influence of dusts containing arsenic on lung cancer risk in miners exposed to radon.

A survey of the Czechoslovak follow-up of lung cancer mortality in uranium miners.

The major Czechoslovak cohort of uranium miners (S-cohort) is surveyed in terms of diagrams illustrating dependences on calendar year, age, and exposure to radon and radon progeny. An analysis of the dose dependence of lung cancer mortality is performed by nonparametric and, subsequently, by parametric methods. In the first step, two-dimensional isotonic regression is employed to derive the lung cancer mortality rate and the relative excess risk as functions of age attained and of lagged cumulated exposure. In a second step, analytical fits in terms of relative risk models are derived. The treatment is largely analogous to the methods applied by the BEIR IV Committee to other major cohorts of uranium miners. There is a marked dependence of the excess risk on age attained and on time since exposure. A specific characteristic of the Czechoslovak data is the nonlinearity of the dependence of the lung cancer excess risk on the cumulated exposure; exposures on the order of 100 working level months or less appear to be more effective per working level month than larger exposures but, in the absence of an internal control group, this cannot be excluded to be due to confounders such as smoking or environmental exposures. A further notable observation is the association of larger excess risks with longer protraction of the exposures.

Radon exposure and cancers other than lung cancer among uranium miners in West Bohemia.

Recent observations have suggested that radon in the ambient air may cause cancers at sites other than the lung, but the evidence is indirect. We have studied site-specific cancer mortality in 4320 uranium miners in West Bohemia who have been followed-up for an average of 25 years, and in whom a four-fold radon-related excess of lung cancer has already been established. For all cancers other than lung cancer the number of deaths observed was slightly greater than that expected from national rates, but the increase was not significant statistically (ratio of observed to expected deaths [O/E] = 1.11, 95% confidence interval [CI] = 0.98-1.24) and mortality did not increase with duration of employment underground or with cumulative exposure to radon. Non-lung cancer mortality was significantly raised among men who started mining work aged under 25 but the increase was not related to cumulative radon exposure. When twenty-eight individual sites and types of cancer were examined, significantly increased risks were found for cancers of the liver (O/E = 1.67) and gallbladder and extrahepatic bile ducts (O/E = 2.26). For liver cancer, mortality did not increase with duration of employment underground or with cumulative radon exposure. For cancer of the gallbladder and extrahepatic bile ducts, mortality did not increase with duration of employment, but increased with cumulative exposure to radon. Mortality from multiple myeloma, although not significantly increased overall (O/E = 1.08), increased with cumulative exposure to radon. Mortality from leukaemia was not increased overall (O/E = 0.91) and was not related to cumulative radon exposure, but did increase with increasing duration of employment in the mines. There is no evidence in these miners that a radon-rich atmosphere increases the risk of any cancer other than lung cancer. Possible exceptions are cancer of the gallbladder and extrahepatic bile ducts and multiple myeloma but further study is needed before it can be concluded that the associations found are causal.

[Subjective sequelae of splenectomy]. / Die subjektiven Folgen des Milzverlustes.

111 of 806 former patients splenectomized at the Würzburg university hospital during the years 1968-1983 were interviewed for their complaints since their operation. Investigations included the use of Beck's inventory for measuring depression and the Giessen questionnaire for the evaluation of general complaints used in psychosomatic medicine. There was a significant increase of symptoms after splenectomy as compared to the normal population. A special list of 18 questions to investigate typical postsplenectomy complaints was answered by 95 of these 111 persons and by a control group of "statistical twins" with similar upper abdominal surgery without splenectomy. The leading difference was the highly significant increase of the susceptibility to infections after splenic loss followed by accelerated exhaustion and increased physical and mental weakness. The distribution of other complaints like for instance the intolerance to alcohol hitherto judged as typical sequelae of splenectomy was not statistically different in both splenectomy was not statistically different in both groups. Since the symptoms listed above as significantly increased in the splenectomized patient were closely correlated with the susceptibility to infection they seem to be rather the expression of the decreased resistance than direct consequences of the loss of the spleen.

Cancer in man after exposure to Rn daughters.

Results are reported of epidemiological studies in six groups of miners, who work in U mines, Fe mines and shale clay mines. A significant excess of lung cancer was proved in exposure categories below 50 WLM, the first significant excess of lung cancer rate was found in the sixth year following the start of exposure, and a significant difference between the observed and expected rate was found in miners even before the fortieth year of age. The mean attributable annual cancer risk after about 30 y of observation in the whole study was approximately 20.0 and in persons starting exposure after 30 y of age the risk was approximately 30.0 per year per 1 WLM per 10(6) persons. The dose-effect relationship and the attributable lung cancer risk per 1 WLM were significantly influenced by the age at the first exposure by total accumulated exposure and by the character of the accumulation of exposure. The observed effects of smoking and exposure to alpha radiation from Rn daughters were nearly additive. The lung cancer risk per 1 WLM at low levels of exposure (not including the contribution from natural sources in the living environment) in U as well as Fe mines indicated a certain elevation compared with the risk at higher accumulated exposure.