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Lithium, generally, occurs in barely trace amounts in ground water with few major exceptions. One of these is the northern area of Chile where all potable water and many of the food stuffs contain high levels of lithium. Surface water can contain between 100 and 10,000 times more than most rivers in North America. Inevitably, food, both animal and vegetable, contains higher lithium levels than found elsewhere. In consequence, the local population has been exposed to high levels of lithium in their food and drinking water for as long as the region has been populated. The present report details lithium levels in a variety of food stuffs from several locations in Northern Chile and compares these with those found elsewhere. The implications for the local population have been discussed in our earlier paper.

Objective: A cost-effectiveness analysis was conducted to investigate the clinical and economic impact of teleophthalmology in evaluating diabetic retinopathy in prison inmates with type 2 diabetes., Research Design and Methods: Based on a hypothetical teleophthalmology system to evaluate diabetic retinopathy patients with type 2 diabetes in a prison care setting, a Markov decision model was developed with probability and cost data derived primarily from published epidemiological and outcome studies. A 40-year-old African-American man with type 2 diabetes was used as a reference case subject. The number of quality-adjusted life-years (QALYs) gained was used as the clinical outcome, and the cost in U.S. dollars from the year 2003 was used as the economic outcome. Teleophthalmology and nonteleophthalmology strategies were compared using an expected QALYs calculation and two types of sensitivity analyses: probabilistic and traditional n-way sensitivity analyses., Results: The teleophthalmology strategy dominates in the cost-effectiveness analysis for the reference case subject: 16,514/18.73 dollars QALYs for teleophthalmology and 17,590/18.58 dollars QALYs for nonteleophthalmology. Ninety percent of the Monte Carlo simulations showed cost effectiveness (annual cost/QALYs < or = 50,000 dollars) in the teleophthalmology strategy based on an assumed inmate population. Teleophthalmology is the better strategy if the number of diabetic inmates in the prison community is >500., Conclusions: Our cost-effectiveness analysis demonstrates that teleophthalmology holds great promise to reduce the cost of inmate care and reduce blindness caused by diabetic retinopathy in type 2 diabetic patients.

When the atomic bombing of Hiroshima and Nagasaki occurred in the summer of 1945, most members of the public presumed that many of the children conceived by the survivors would be grossly deformed or seriously damaged in other ways as a consequence of radiation-induced mutations. Although the experimental data then available, largely limited to studies of Drosophila melanogaster, the common fruit fly, did not support this perception, the limitations of the data and the depth of public concern warranted a careful follow-up of the children born to the survivors. To this end a surveillance was begun in 1947 of all pregnancy outcomes after 20 weeks of gestation in these two cities. Over the half century subsequent to the initiation of this surveillance, some 80-odd thousand pregnancy outcomes have been studied and a variety of potential indicators of mutational damage measured. This report summarises the findings of these studies and offers an estimate of the genetic risk based on these findings.

It has been postulated that paternal gonadal exposure would increase the sex ratio by inducing X-chromosomal dominant lethals but that maternal gonadal exposure would decrease the sex ratio by inducing recessive sex-linked lethals. We therefore evaluated the sex ratio (male-to-female ratio) of children born to survivors of childhood cancers in Denmark. Children with cancer were identified from the Danish Cancer Registry from 1943 to 1996 and their offspring from the Central Population Registry. Radiation treatments were determined from records within the Cancer Registry and gonadal radiation exposures were estimated based on the cancer being treated and the likely proximity of the radiation fields to the gonads. Overall, 1100 survivors of childhood cancer became the parents of 2130 children. The sex ratio for male (0.99) and female (1.00) cancer survivors was similar and did not differ significantly from the Danish population (1.06). Radiotherapy did not influence the sex ratio of the children of either male or female survivors, and there was no evidence for dose-related changes over categories of estimated dose to parental gonads. We saw no consistent association between the sex ratio and the interval between cancer diagnosis of the parent and birth of the child. This nationwide study provides no support for the hypothesis that radiation exposure to the gonads results in an inherited genetic effect that would be manifested by a change in the sex ratio of children born after exposure. It may be, however, that sex ratio alterations are not a good or even a valid indicator of possible genetic effects in humans.

James V. Neel was one of the leaders who developed human genetics into a predominant field of 20th-century science. Neel was originally trained in basic biology, and this fact was clearly reflected in the evolutionary, population perspective of his life's work. His interests were in the amount and burden of mutation in human populations. He studied this problem in clinical samples, survivors of the atomic bombings in Hiroshima and Nagasaki, and minimally acculturated indigenous populations in Amazonia. Because his perspective was populational, he cautioned that the most serious health problems faced by our species should not be approached as if they have a genetic solution.

Prior studies have implicated an involvement of the Msx1 homeobox gene in cleft palate in mice and its homolog in humans (called MSX1 in the HOX7 gene, located on chromosome 4). In this study we present evidence of a sex-dependent association between MSX1 and non-syndromic cleft lip/palate (NSCLP) in the Chilean population. The sample included 73 NSCLP cases, 37 from multiplex families (Mx), 36 from simplex families (Sx), and 87 controls. Polymerase chain reaction amplification of the MSX1 intragenic microsatellite (CA)n-sequence shows significant (p = 0.035) differences in the allele frequencies between NSCLP-Mx males and control males. These differences are mainly due to frequency differences in allele *2 (173 base pairs) among cases (21.9%) and controls (13.2%). When the NSCLP cases are subdivided by sex and positive family history (Mx versus Sx), the Mx males (27.8%) as well as the total NSCLP-Mx cases (25.7%) showed significantly higher frequencies of allele *2, compared to controls (11.4% and 13.2%, respectively). Analysis of the genotype data indicates that the relative risk for NSCLP is greater for persons carrying allele *2 (i.e., odds ratio [OR] larger than 1), reaching significance for all Mx cases (OR = 2.67; 95% confidence interval [CI], 1.10 to 6.52) and even more pronounced for Mx males (OR = 3.33; 95% CI, 1.08 to 10.32). Taken together, these findings support the hypothesis that the genetic variation at the MSX1 locus is a predisposing gene involved in sex-dependent susceptibility to clefting and that it also differentiates simplex from multiplex families.

Purpose: To examine the pattern and spurt in growth and development of prenatally exposed atomic-bomb survivors and to determine whether a statistically significant radiation-related growth retardation exists., Materials and Methods: The stature of 1566 individuals exposed prenatally to the atomic bombings has been employed to study the effect of such exposure on growth. Among these survivors, 30 were severely mentally retarded, and 66 individuals on whom no physical measurements between ages 9 and 19 exist were excluded from this study. Thus this analysis rests on the measurements obtained on 1470 survivors 9 to 19 years of age at the time of examination., Results: When the > or =0.50 Sv group was compared to the other two prenatally exposed groups, a significant retardation of growth was observed only among those survivors exposed in the first trimester of gestation. The onset of the growth spurt among males in the three exposure groups was at approximately the same age, 11.34 years, but this was not true in females. The maximum velocity in growth for males was at 14.38 years of age, but for females no clear peak velocity was demonstrable., Conclusion: A radiation-related growth retardation was demonstrable in this longitudinal study of the stature of individuals prenatally exposed. It is further demonstrated that among these survivors the growth velocity was faster in the high-dose group than in the low-dose group for both males and females.

It is clear from the many studies of the prenatally exposed survivors of the atomic bombing of Hiroshima and Nagasaki that exposure to ionizing radiation during gestation has harmful effects on the developing human brain, particularly if that exposure occurs at critical stages in the development of the neocortex. Data on a variety of measures of cognitive function, including the occurrence of severe mental retardation as well as variation in the intelligence quotient (IQ) and school performance, show significant effects on those survivors exposed 8-15 weeks and 16-25 weeks after ovulation. Studies of seizures, primarily those without known precipitating cause, also exhibit a radiation effect on those individuals exposed in the first 16 weeks after ovulation. The cellular and molecular events that subtend these abnormalities are still largely unknown although some progress toward an understanding has occurred. For example, magnetic resonance imaging of the brain of some of the mentally retarded survivors has revealed a large region of abnormally situated gray matter, suggesting an abnormality in neuronal migration, but cell killing could also contribute importantly to the effects on cognitive function that have been seen. The retardation of growth in stature observed in individuals exposed in the first and second trimesters of pregnancy suggests that the development of an atypically small head size, without conspicuously impaired cognitive function, may reflect a generalized retardation of growth.

Many studies of prenatally exposed survivors of the atomic bombings of Hiroshima and Nagasaki have shown that exposure to ionizing radiation during gestation has harmful effects on the developing human brain. Data on the occurrence of severe mental retardation as well as variation in intelligence quotient (IQ) and school performance show significant effects on those survivors exposed 8-15 and 16-25 weeks after ovulation. Studies of seizures, especially those without a known precipitating cause, also exhibit a radiation effect in survivors exposed 8-15 weeks after ovulation. The biologic events that subtend these abnormalities are still unclear. However, magnetic resonance imaging of the brains of some mentally retarded survivors has revealed a large region of abnormally situated gray matter, suggesting an abnormality in neuronal migration. Radiation can induce small head size as well as mental retardation, and a review of the relationship between small head size and anthropometric measurements, such as height, weight, sitting height and chest circumference, shows that individuals with small head size have smaller anthropometric measurements than normocephalics. This suggests that radiation-related small head size is related to a generalized growth retardation. Finally, the issue of a threshold in the occurrence of one or more of these effects, both heuristically and from a regulatory perspective, remains uncertain. Simple inspection of the data often suggests that a threshold may exist, but little statistical support for this impression can be advanced, except in the instance of mental retardation.

Mental retardation as a result of prenatal exposure to ionizing radiation is not a common phenomenon when compared to the incidence of cancer, but it has nevertheless been well-documented. This article describes results from studies of individuals who were exposed prenatally to radiation in Hiroshima and Nagasaki. The critical time of exposure, when the most significant damage was done, was during the 8th-15th week of gestation, with a lesser effect at 16-25 weeks. Individuals in the study were assessed by measurement of an intelligence quotient and by examination of school performance. Studies show that the period of 8-15 weeks of gestation coincides with a key time for neuronal cell migration in the developing brain. There is continuing investigation of the mechanism of this migration and how it might be disrupted by ionizing radiation.

Significant effects on the developing human brain of exposure to ionizing radiation are seen among individuals exposed in the 8th-25th week after ovulation. These effects, particularly in the highly vulnerable period of 8-15 weeks after ovulation, manifest themselves most dramatically as an increased frequency of severe mental retardation. However, the distribution of cases of severe mental retardation suggests a threshold in the low-dose region. The 95% lower bound of the threshold in those survivors exposed 8-15 weeks after ovulation was zero for the individual data based on the simple linear model, and 0.15 Gy based on the exponential linear model used in our previous report (1987), but the 95% lower bound of the threshold based on all of the data including 21 additional cases with known doses appears to be 0.05 Gy using the maximum likelihood estimates derived from an exponential-linear model. The latter model was selected because it provides the best fit from the standpoint of the stableness and reasonableness of the estimates among the five models applied to the data. When two probably non-radiation-related cases of Down's syndrome are excluded from the 19 mentally retarded cases exposed 8-15 weeks post ovulation, the 95% lower bound of the threshold is in the range of 0.15-0.25 Gy based on the exponential-linear model used in 1987, but is in the range of 0.06-0.31 Gy when the more reasonable and better model applied here is used. For exposure in the 16-25-week period based on the same model, the 95% lower bound of the threshold changed from 0.25 to 0.28 Gy, both with and without inclusion of the two probable non-radiation-related mentally retarded cases; one of these cases was probably familial in origin since there was a retarded sibling, and the other due to infection, since the individual had Japanese B encephalitis at age 4 years.

This report re-examines the relationship of radiation dose to the occurrence of cataracts among 1742 atomic bomb survivors seen in the years 1963-1964 for whom the degree of epilation and Dosimetry System 1986 (DS86) doses are known. Of these individuals, 67 had cataracts. A relative risk model with two thresholds, one for the epilation group and the other for the no-epilation group, has been fitted to the data using a binomial odds regression approach and a constant relative biological effectiveness (RBE) for neutrons of 10. Among these models, a linear-linear (L-L) dose-response relationship with two thresholds presents the best fit. Under the L-L threshold model based on DS86 eye organ dose estimates for the epilation and no-epilation groups, the slope estimate for the epilation group was 1.6-2.0 times greater than that for the no-epilation group, but no statistical difference between the two slope estimates was noted. The estimated threshold for the epilation group was 0.86 Sv and 1.54 Sv for the no-epilation group, but again the difference between the two threshold estimates is not statistically significant. When an L-L relative risk model with two thresholds was fitted to the data assuming the dose estimates to be in error by 35%, or when the data were restricted to the 1105 individuals exposed in Japanese houses at distances of less than 2500 m, where the DS86 doses are thought to be most reliable, the results were almost the same as those for the individuals for whom unadjusted DS86 eye organ dose estimates were used.

In order to elucidate the possible mechanisms for the effects of low doses of ionizing radiation on the developing rat cerebral cortex we studied how neuronal migration can be affected by prenatal in utero irradiation. We have demonstrated an effect of ionizing radiation on neuronal migration at doses as low as 15 cGy together with a changing pattern of expression of the neural cell adhesion molecule N-CAM. After a dose of 15 cGy or more there was a reduction in N-CAM immunoreactivity in the matrix cell zone which became apparent about 24 h after exposure and continued until 48 h after exposure. Normal reactivity occurred 3 days after exposure to radiation. However, there was no obvious change in the immunoreactivity for L1, MAP2, tau protein or neurofilament. Our findings suggest the possible role of N-CAM in neuronal migration and also suggest the presence of a threshold in terms of the effects of small radiation doses on the developing cerebral cortex.

Estimation of the risk of cancer and other health effects following exposure to the atomic bombing of Hiroshima and Nagasaki remains largely empirical, and the models used to adduce risk incorporate few, if any, of the advances in molecular biology of the past decade or so. These facts compromise the estimation of risk where the epidemiologic data are weakest, namely, at low doses and dose rates. Although the risk estimates may be sufficient for regulatory purposes, without a better understanding of the molecular and cellular events ionizing radiation initiates or promotes, it seems unlikely that the estimates will be as intellectually satisfying as they might be. Nor will the situation improve further without attention to the identification and estimation of the effects of those host and environmental factors that enhance or diminish risk of cancer or the effects on the developing brain.

Boron is a ubiquitous constituent of man's external environment. Levels of the element in human blood reflect both acute and chronic exposure, usually as dietary intake (food and drinking water). There is an absolute requirement for boron in vascular plants but evidence for biological essentiality in animals (including man) is limited. A high body burden of the element may be harmful, especially to young animals (including human neonates). Information on boron deficiency is scanty. It has been proposed that boron contributes to living systems by acting indirectly as a proton donor and that it exerts a particular influence on cell membrane structure and function. The present study examines the variation in blood levels within and between human sibships and provides some support for the possibility that boron metabolism is subject to genetic regulation.

The health status of approximately 1 million immigrants in the United States and Israel may have been adversely affected by radiation exposure as a result of the Chernobyl nuclear power plant disaster and cleanup efforts. Many of these immigrants suffer from significant psychological distress, fearing that they have a radiation-induced illness. Based on a review of the literature and our experience from the US National Chernobyl Registry Coordinating Center, we recommend that medical management of these immigrants include routine physical examination, with particular attention to the thyroid gland. Adults should receive regular cancer screening as well as routine blood chemistry tests, thyroid function tests, complete blood cell count, and urinalysis. Children should be examined regularly, with attention to the thyroid and overall body growth. It is reasonable for children to undergo thyroid studies, a complete blood cell count, or neuropsychiatric testing if there is clinical suspicion of a disorder. Given the long latency period for disease induction by radiation exposure, it is still too early to fully assess and draw conclusions concerning the possible health effects of the Chernobyl disaster, and long-term follow-up of all potentially affected individuals is important.

The pervasiveness of abnormal brain development caused by prenatal exposure to ionizing radiation is still largely unknown. The relationship between A-bomb radiation dose and two measures of neuromuscular performance, one of grip strength and the other of the fine motor coordination required in repetitive action, is described. A multivariate analysis of covariance was used to evaluate the effect of several covariates, such as prenatal radiation exposure and some physical measurements or IQ adding city and sex as categorical factors. When mentally retarded cases were included, a statistically significant effect of radiation exposure on the grip strength and repetitive-action test scores was seen in the 8-15-week postovulation period, and a statistically suggestive effect at 16-25 weeks postovulation. No effect of radiation exposure on the two test scores was noted for prenatal exposure in either of the aforementioned periods when mentally retarded cases were excluded, but a statistically significant diminution of IQ was noted for exposures > or = 16 weeks postovulation. We discuss, from the biological perspective, the projected standard scores for exposures > or = 16 weeks postovulation, and the possibility of lower IQ, small head and mild mental retardation related to radiation exposures < or = 15 weeks postovulation with mentally retarded cases excluded.

Skinfolds at five anatomic sites were measured on 47 subjects in a study of gallbladder disease in Starr County, Texas, by two methods, one and two handed. A comparison was made of the two methods as to bias and precision. There were statistically significant but biologically unimportant differences (on the order of 1-2 mm) at four of the five sites. At three of these, the two-handed method gave larger values (lower thigh, triceps, and subscapular), and at the other site (medial calf) this method produced smaller values on average. Measurement precision was improved using the two-handed method at three of the five sites, significantly so for the triceps skinfold. Measuring skinfolds with two hands improves the precision of measurement for some skinfold sites in obese individuals. It does not introduce important and systematic biases across skinfold sites. Adoption of this technique should be used when circumstances outweigh the cost of involving an extra observer in the measurement of skinfold thickness, such as when precision is very important and when subjects are obese. © 1995 Wiley-Liss, Inc., (Copyright © 1995 Wiley-Liss, Inc., A Wiley Company.)

Reduction of growth from exposure to atomic bomb radiation has been examined using individuals under 10 years old at the time of the bombing (ATB) and a growth curve analysis based on measurements of height and weight made in the course of the 4th-7th cycles of the Adult Health Study examinations (1964-1972). As expected, the largest difference in growth to emerge is between males and females. However, a highly significant reduction of growth associated with dose (DS86) was observed among those survivors for whom four repeated measurements of height and weight were available. Longitudinal analysis of a more extended data set (n = 821), using expected values based on simple linear regression models fitted to the three available sets of measurements of height and weight on the 254 individuals with a missing measurement, also indicates a significant radiation-related growth reduction. The possible contribution of such factors as poor nutrition and disruption of normal family life in the years immediately after the war is difficult to evaluate, but the effects of socioeconomic factors on the analysis of these data are discussed.

We describe a newly devised explant culture system employing rat neocortex in which neurones migrate in a fashion similar to that seen in vivo. Using neocortical explant culture we have demonstrated an effect of ionizing radiation on neuronal migration at doses as low as 10 cGy together with a changing pattern of expression of the neural cell adhesion molecule N-CAM. After a dose of more than 10 cGy there was a significant reduction in N-CAM immunoreactivity in the matrix cell zone. We do not know the reason why the reduction in N-CAM immunoreactivity is so localized, although it is not unlikely that the most active site in terms of N-CAM synthesis is significantly affected by radiation.

We performed two studies to investigate environmental factors in relation to neurological development in infants. The first, a field study, examined the elementary school performance of 929 children who were born from mothers exposed to the atomic bombing of Hiroshima, Japan, August 6, 1945. The most severe mental retardation was observed in the group exposed between 8 and 15 weeks following fertilization, and the second most severely damaged group was exposed between 16 and 25 weeks. The second, a clinical investigation, examined infants in the perinatal center who survived intrauterine growth retardation (IUGR). Those who survived with abnormal neurological development had a mean growth arrest corresponding to a uterine height of 27 weeks of gestation. This was at an earlier stage than those who survived with normal neurological development and had a mean growth arrest corresponding to 29-30 weeks of gestation. A smaller head circumference at birth was closely correlated with abnormal neurological sequelae. These results indicate that the brain development of the fetuses may have been affected by neurotoxic events similar to ionizing radiation. We emphasize the importance of avoiding neurotoxic stress to pregnant women when the fetus is in the critical period of neuronal development, before 27 weeks of gestational age.

Growth retardation due to exposure to the atomic bomb has been evaluated using repeated measurements of stature from 10 to 18 years of age. A highly significant growth retardation due to the DS86 uterine dose was observed in all trimesters combined and in the first and second trimesters of pregnancy. In the first trimester, all parameter estimates based on a linear (L) or linear-quadratic (L-Q) dose-response relationship were negative in relation to the DS86 uterine dose. The positive dose estimate in the second trimester is small and close to the control level. Statistically significant difference was determined by a multivariate test statistic examining whether or not a set of two- or three-parameter estimates including a constant term related to an L or L-Q dose-response relationship was different from zero. A radiation-related growth retardation was demonstrable as a longitudinal result of the repeated measurements of stature. The dose effect in the third trimester was not significant under either the L or the L-Q model. The relationship between birth weights and repeated measurements of stature in adolescence is discussed based on the results obtained by a growth curve analysis.

Of 1566 individuals prenatally exposed to the atomic bombings of Hiroshima and Nagasaki, 1473 had the circumference of their head measured at least once between ages 9 and 19. Among these 1473 individuals, 62 had small heads--the circumference of the heads was two standard deviations or more below the observed specific-age-at measurement mean. Of 26 cases with severe mental retardation, 15 (58%) had small heads. Most (86%) of the individuals with small heads were exposed in the first trimester (about < 12 weeks postovulation) or second trimester (about 12-24 weeks postovulation)--55% in the former period and 31% in the latter. Various dose-response relationships, with and without a threshold, have been fitted to the data grouped by the trimester or postovulatory age (weeks after ovulation) at which exposure occurred. A significant effect of radiation on the frequency of individuals with atypically small heads is observed only in the first and second trimesters and for the intervals postovulation of 0-7 weeks and 8-15 weeks. Although the risk of a small head at 0-7 weeks postovulation increases significantly with increasing dose, no increase in risk for severe mental retardation is noted in this period. No excess risk of a small head was seen in the third trimester (about > or = 25 weeks postovulation) or among individuals exposed at 16 weeks or more postovulation. The mean IQ values of mentally retarded cases with and without small heads were 63.8 and 68.9, respectively. No significant difference exists between these two IQ means, but both were significantly smaller than 96.4, the IQ value for individuals with small heads without severe mental retardation and 107.8, the value for the overall sample.

Objective: To determine the rate and risk factors of mortality in a cohort of Mexican Americans with NIDDM., Research Design and Methods: A cohort of 353 Mexican Americans with NIDDM were identified between 1981 and 1986. All individuals underwent extensive evaluations that included physical, historical, ophthalmological, and laboratory assessments. This cohort was followed prospectively for a mean of 8 yr. Follow-up included mortality surveillance, death certificate extraction, and a combination of annual and intermediate examinations., Results: The cohort experienced 67 mortality events. One-third of all deaths were premature < 65 yr of age) and most often were attributed to diseases of the heart (60.0%). In no case was diabetes listed as the cause of death, although it was listed as a contributing cause in 25.5% of cases. Men had a higher mortality rate than women. In both sexes, baseline retinopathy was identified as an important predictor of subsequent mortality. Mortality was significantly elevated in those with nonproliferative retinopathy and even further elevated in those with proliferative disease (relative risks of > or = 4 for proliferative disease)., Conclusions: Mexican Americans with NIDDM are experiencing premature and excessive mortality compared with the general population. The results clearly link microvascular complications with macrovascular disease, but this link is not explained by a more untoward profile of traditional cardiovascular risk factors. Retinopathy appears to serve as an important monitor of the progression of diabetes and when identified would warrant aggressive action to inhibit or slow the processes leading to subsequent mortality.

It has long been recognized that the prevalence of many, possibly most diseases differs among different ethnic groups, and it is further known that cultural differences among people affect the acceptability of measures to prevent or ameliorate a given disease process. Major public health challenges of our time are the delineation and understanding of how these differences in prevalence arise, and the fashioning of acceptable and effective intervention strategies. The web of causation is undoubtedly complex and in the unraveling there will be a need to examine new paradigms, new models of how genes and environments interact in the evolution of disease. These models must recognize the levels within the disease process where interactions can occur. This will demand a holistic rather than the reductionist approach that has obtained in the past. However, there are promising developments at the molecular and cellular levels, and the methods of data analysis grow progressively more sophisticated. This presentation briefly describes the methods of and problems confronted by genetic epidemiology in the context of studies of ethnic differences in disease. © 1993 Wiley-Liss, Inc., (Copyright © 1993 Wiley-Liss, Inc., A Wiley Company.)

Upper and centralized body fat distribution is associated with non-insulin dependent diabetes mellitus (NIDDM). Few studies have focused on anthropometric characteristics of preadults from families in which there is a diabetic (NIDDM) proband. This study explores the prevalence of upper and centralized body fatness in Mexican American children from the Diabetes Alert study (1981-1983) in Starr County, Texas. Anthropometric data on 165 males and 224 females 9-19 years include measures of adiposity such as skinfold thicknesses and the body mass index (BMI), a measure of overweight. They show rates of obesity two to three times that of White children of comparable age and sex from National Health Surveys. In comparison with U.S. White subjects, Mexican American adults are shorter, have more adiposity and arm muscle mass and have sitting heights and body breadths at the mean of these dimensions for the U.S., Population: Children from Diabetes Alert families show only marginal excess of severe obesity (> 95th percentile of BMI) when compared to the general population of children surveyed in Starr County schools. Girls from these families, but not boys, have excess fatness in the BMI compared to Mexican American children from the Hispanic Health and Nutrition Examination Survey (HHANES); suprailiac skinfold thicknesses are also greater in children of the Diabetes Alert study than in HHANES children. From 1972 through 1982, Mexican American children in South Texas showed an increase in average stature, weight, and the BMI. These data together suggest that excessive obesity exists and may be increasing in children in populations at risk for NIDDM. The prevention of NIDDM in the Mexican American population may be more effective if educational and promotional interventions include the school aged population. © 1993 Wiley-Liss, Inc., (Copyright © 1993 Wiley-Liss, Inc., A Wiley Company.)

Estimation of the risk of cancer following exposure to ionizing radiation remains largely empirical, and the models used to adduce risk incorporate few, if any, of the advances in molecular biology of the past decade or so. These facts compromise the estimation of risk where the epidemiological data are weakest, namely, at low doses and dose rates. Without a better understanding of the molecular and cellular events ionizing radiation initiates or promotes, it seems unlikely that this situation will improve. Nor will the situation improve without further attention to the identification and quantitative estimation of the effects of those host and environmental factors that enhance or attenuate risk.

Deaths in the RERF Life Span Study (LSS) sample have been determined for the years 1950-1985 and an analysis of cancer mortality with the revised DS86 doses has been described separately. In this report, we examine the relationship to dose of deaths from all diseases other than cancer. Although the evidence is still limited, there seems to be an excess risk from noncancer death at high doses (2 or 3 Gy and over). Statistically, a pure quadratic or a linear-threshold model [the estimated threshold dose is 1.4 Gy (0.6-2.8 Gy)] is found to fit better than a simple linear or linear-quadratic model. This increase in noncancer mortality is statistically demonstrable, generally, after 1965 and among the younger survivors (less than 40 at the time of the bombing), suggesting a sensitivity for this age group. For specific causes of death, an excess in relative risk at the high dose level, that is, 2 Gy or more, is seen in circulatory and digestive diseases. The relative risk is, however, much smaller than that for cancer. These findings, based as they are on death certificates, have their limitations. Most significant, perhaps, is the possible erroneous attribution of radiation-related cancer deaths to other causes. At present, the contribution such errors may make to the apparent increase in non-cancer deaths at the higher doses cannot be estimated as rigorously as is obviously desirable. However, even now, this increase does not appear to be fully explicable in terms of errors in classification. Further follow-up of mortality in this LSS cohort as well as disease revealed by the biennial physical examinations of the morbidity subsample (Adult Health Study) of the LSS cohort will be needed to confirm this suggestion of a radiation-related increase in mortality from causes other than cancer, and to determine whether it results in a demonstrable life shortening among the heavily exposed A-bomb survivors.

This report describes the risk of cancer and in particular cancers other than leukemia among the survivors of the atomic bombing of Hiroshima and Nagasaki. Attention focuses primarily on the risk of death from cancer among individuals in the Life Span Study sample of the Radiation Effect Research Foundation in the period 1950-1985 based on the recently revised dosimetry, termed the DS86 doses. Mortality from malignant tumors is increased among A-bomb survivors as a late effect of A-bomb radiation. Besides the well-known increase of leukemia, there also has been demonstrated increase of cancer of the lung, breast, esophagus, stomach, colon, ovary, urinary bladder, thyroid, and of multiple myeloma, but no increase has yet been observed in mortality from cancer of the rectum, gallbladder, pancreas, prostate and uterus, and of malignant lymphoma. The pattern of appearance over time of radiation-induced cancer other than leukemia differs from that of leukemia. In general, radiation-induced solid cancer begins to appear after attaining the age at which the cancer is normally prone to develop (so-called cancer age), and continues to increase proportionately with the increase in mortality of the control group as it ages. Sensitivity to radiation, in terms of cancer induction, is higher for persons who were young at the time of the bomb (ATB) in general than for those who were older ATB. Furthermore, susceptibility to radiation-induced cancer tends to be higher in pre- than in post-natally exposed survivors (at least those exposed as adults). Other radiation effect modifiers and the shape of the dose response curve will also be discussed.

We compare the mortality in the years 1946-85 in a cohort of 31,159 children born to parents one or both of whom were exposed to the atomic bombing of Hiroshima and Nagasaki (a parental gonadal dose greater than or equal to 0.01 Sv) with that in a control group of 41,069 children. The average gonadal dose for the exposed parents was 0.435 Sv. The mean age of the cohorts was 28.8 years. In the greater than or equal to 0.01 Sv dose group 1,253 deaths were observed in the subset of children both of whose parents have been assigned DS86 doses. 3.2% were attributed to cancers, 72.9% to all diseases except neoplasms. These proportions in the 0 Sv dose group were about the same. Based on a linear relative risk model, no statistically significant increase in the mortality attributable to diseases other than neoplasms is noted following parental exposure, the excess relative risk being 0.030 (+/- 0.046) per sievert based on the DS86 doses (RBE of neutrons = 20). For fatal cancer, no statistically significant effect of parental radiation dose was also observed. An analysis based on the full sample, using not only the DS86 dose group but also ad hoc dose group, yields essentially the same results as the analysis restricted to the DS86 dose group.

As a part of the continuing assessment of the effects on the developing embryonic and fetal brain of exposure to ionizing radiation, the school performance of prenatally exposed survivors of the atomic bombing of Hiroshima and a suitable comparison group have been studied. In this report, the changes in performance in seven school subjects according to dose are compared under the dosimetry system (DS86) instituted in 1986 at the Radiation Effects Research Foundation. The sample involves 929 children whose fetal absorbed dose are known and includes 14 severely mentally retarded persons. The findings can be summarized as follows: 1) Damage to the 8-15 week fetal brain appears to be linearly related to the absorbed dose, as judged by the simple regression of average school-performance score on dose. Damage to the fetus exposed at 16-25 weeks after fertilization appears similar to that seen in the 8-15 week group. Canonical and multiple correlations also show a highly significant relationship of exposure 8-15 weeks and 16-25 weeks after fertilization to achievement in school. This trend is stronger, however, in the earliest years of schooling. 2) In the group exposed within 0-7 weeks following fertilization, or 26 or more weeks after fertilization, there was no evidence of a radiation-related effect on scholastic performance. 3) These results parallel those previously found in prenatally exposed survivors with respect to achievement in standard intelligence tests in childhood and development of severe mental retardation.

The purpose of this article was to characterize the origins of the United States Hispanic population and discuss the implications of these origins in the context of diabetes risk. Particular attention was focused on the genetic origins of the three major U.S. Hispanic groups, i.e., Mexican Americans, Puerto Ricans, and Cubans. The U.S. Census figures provided basic demographic information. Genetic marker data for ancestral populations were taken from a review of the literature and compendia. Genetic marker data for the Puerto Rican and Cuban populations were extracted from the literature. Genetic markers determined on approximately 1000 randomly selected Mexican Americans from Starr County, Texas, were taken as representative of the Mexican-American population. The Hispanic population is the second largest and fastest growing minority in the U.S. Estimates of the Hispanic population in 1988 indicated some 19.4 million residents, of whom 62% were classified as Mexican, 13% as Puerto Rican, and the remaining 25% as Cubans and others. Various lines of evidence can be used to characterize the Hispanic population and its origins. These include ethnohistory, self-assessment of ancestry, surname distributions, speech and cultural characteristics, quantitative traits, and genetic structure. Genetic data were used to estimate the contribution of putative ancestral populations to the contemporary gene pool. For Mexican Americans, 31% of the contemporary gene pool is estimated to be Native American derived, whereas 61 and 8% are Spanish and African derived, respectively. In Puerto Rico, the percentage of contributions of Spanish, Native American, and African admixture to the population are 45, 18, and 37%, respectively. For Cuba, the parallel estimates are 62, 18, and 20%. The high frequency of Native American-derived genes in the contemporary Hispanic population predict a higher frequency of non-insulin-dependent diabetes mellitus (NIDDM) under the assumption that genes are important in NIDDM etiology. Our results are consistent with the finding of the significant role of genes in determining risk.

The Mexicans residing in the Monterrey metropolitan area in Nuevo León, Mexico, were grouped by generation and birthplace [Monterrey Metropolitan Area (MMA), San Luis Potosi (SLP), and Zacatecas (ZAC)] of the four grandparents to determine the extent of genetic variation within this population and the genetic differences, if any, between the natives living in the MMA and the immigrant populations from SLP and ZAC. Nine genetic marker systems were analyzed. The genetic distance analysis indicates that SLP and ZAC are similar to the MMA, irrespective of birthplace and generation. Gene diversity analysis (GST) suggests that more than 96% of the total gene diversity (HT) can be attributed to individual variation within the population. The genetic admixture analysis suggests that the Mexicans of the MMA, SLP, and ZAC, stratified by birthplace and generation, have received a predominantly Spanish contribution (78.5%), followed by a Mexican Indian contribution (21.5%). Similarly, admixture analysis, conducted on the population of Nuevo León and stratified by generation, indicates a substantial contribution from the MMA (64.6%), followed by ZAC (22.1%) and SLP (13.3%). Finally, we demonstrate that there is no nonrandom association of alleles among the genetic marker systems (i.e., no evidence of gametic disequilibrium) despite the Mestizo origin of this population.

Multivariate associations were sought between risk factor levels (total cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides, glucose, and systolic and diastolic blood pressures) and two sets of anthropometric variables (four circumferences and six skinfolds) to select a set of anthropometric indicators of body fat distribution that correlate most highly with risk of disease. Subjects were men (n = 285) and women (n = 672) from a study of gallbladder disease in a Mexican American population in Starr County, Texas, 1985-1986. The canonical correlations showed that circumferences (0.49-0.61) and skinfolds (0.42-0.60) were equally well correlated to risk factor levels independently of sex and age. Weights from the canonical analyses suggest that measurements at or above the waist and on the lower limb (thigh) are most heavily loaded toward risk (waist = highest risk; thigh = lowest risk). The simplest and most reliable index of body fat distribution for both sexes is the ratio of waist to thigh circumferences. The more commonly used waist/hip ratio proved more valid in women, but not in men. Simple skinfold indices of body fat distribution were more poorly correlated to risk factor levels than the corresponding circumference ratios. In women, body mass index and waist circumference by themselves did as well as body fat distribution indices in explaining variation in risk factors, suggesting the involvement of visceral fat in the body fat/body fat distribution disease relation.

Cancer can arise through genetic damage of a variety of sorts, including recessive and dominant mutations, large chromosomal rearrangements, and the inability of cells to repair damaged DNA. Many of these events can be studied by standard methods of genetic analysis and thereby furnish the means to localize the gene to a specific region in the human genome. However, conventional methods of segregation analysis cannot provide the molecular and cellular understanding of the process of gene action essential to informed intervention. Here, recent advances in molecular biology, immunology and biochemistry hold promise of providing the understanding of how normal cells control their replication and why cancer cells do not. Heretofore these techniques have been largely restricted to modest-sized studies, but the requisite assays have now reached a level of development that makes practicable large clinical and population-based studies. Collectively, through these rapidly evolving techniques, we may eventually achieve the acquisition of new methods of prevention, diagnosis and therapy, and a better awareness of the events that order the lives of our cells.

Genetic variability has been implicated as a significant contributor to the variation in levels of lipids, lipoproteins, and apolipoproteins (apos) through a variety of direct and indirect investigations. Among the direct investigations, apo E has been shown to be polymorphic and to explain a small but statistically significant proportion of the variability in cholesterol. The apo E polymorphism was typed in 964 randomly selected Mexican-Americans from Starr County, Tex., and its effects determined on levels of cholesterol, triglycerides, total high density lipoprotein (HDL) cholesterol, subfractions (HDL2 and HDL3), alpha- and beta-lipoprotein cholesterol, low density lipoprotein (LDL) cholesterol, and apos A-I, A-II, B, C-II, C-III, and E. Effects are reported for the entire sample and in each of three groups, namely, premenopausal females, postmenopausal women, and males. In the entire sample, significant effects were observed on cholesterol, beta-lipoprotein cholesterol, LDL, apo B, and apo E. There is evidence for significant physiological interaction of the apo E polymorphism effect in females by menopausal status. This is most evident for apo E levels, in which 5.9% of the variability in the entire sample is explained by the apo E polymorphism. In premenopausal females, however, the polymorphism accounts for 27.5% of the variability. In postmenopausal women and males, there is no significant effect. It is shown that the apo E polymorphism can be treated as a two-locus, two-allele system. Doing so identifies substitutions in amino acid position 158 as the mediators of most of the observed effects of this polymorphism.

This report reviews the relationship of ionizing radiation to the occurrence of cataracts (posterior lenticular opacities) among the A-bomb survivors in Hiroshima and Nagasaki. The new DS86 doses are available for 1,983 (93.4%) of the 2,124 A-bomb survivors analyzed in 1982. The DS86 kerma neutron component for Hiroshima is much smaller than its comparable T65DR component, but still 4.2 fold higher (0.38 Gy at 6 Gy) than that in Nagasaki (0.09 Gy at 6 Gy). Thus, if the eye is especially sensitive to neutrons, there may yet be some useful information on their effects, particularly in Hiroshima. Under the best fitting dose-response model, an L(gamma)-L(neutron) with two thresholds, both the gamma and neutron regression coefficients of the occurrence of cataracts on dose are positive and highly significant for the DS86 eye organ doses. The DS86 gamma coefficient is almost the same as that associated with the T65DR gamma dose, the ratio of the two coefficients being 1.1 (95% confidence limits: 0.5-2.3) for DS86 kerma in the individual dose data, and if the risks based on the DS86 eye organ dose and DS86 kerma are compared, the ratio is 1.3 (0.6-2.8). However, the risk estimates associated with neutron exposure are 6.4 (2.2-19.2) fold higher for the DS86 kerma than the T65DR kerma and 1.6 (0.5-2.3) fold higher for the DS86 eye organ dose than for the DS86 kerma.

The Radiation Effects Research Foundation (RERF) continues to conduct a follow-up study initiated some years ago of cancer mortality and incidence among the survivors of the atomic bombing of Hiroshima and Nagasaki exposed in utero. Although only 18 incident cases of cancer were identified in the years 1950-1984 (of which 5 cases were in the 0 dose group), cancer risk appears to increase significantly as maternal uterine dose increases. Only two cases of childhood cancer were observed among these individuals in the first 14 years of life; both had been exposed to greater than or equal to 0.30 Gy. All other cases developed cancer in adulthood, and the cancers they developed are, in the main, the ones known to be elevated in frequency among the postnatally exposed survivors. The estimated relative risk for cancer at 1 Gy (uterine dose) is 3.77. The results suggest that the in utero group may have a higher risk than that seen among exposed adults because the individuals exposed in utero have not reached the major cancer prone age. However, since the observed cases are too few to allow a site-specific review, further follow-up studies are required to determine if the observed increased cancer risk can definitely be attributed to A-bomb radiation, although there appears to be a significant dose-related cancer response.

Numerous attempts have been made to estimate the distance at which 50% of the individuals exposed to the A-bombing of Hiroshima and Nagasaki died, ostensibly from their exposure to ionizing radiation. It is difficult to convert most of these distance estimates to a dose-related LD50, since radiation shielding was ignored. The recent reassessment of the atomic bomb radiation dosimetry has provided an opportunity for the estimation of the bone marrow LD50. There is a surprising concordance in the various estimates that have been made given the different groups of survivors involved and the methods used to estimate the LD50/60.

Significant effects on the developing brain of exposure to ionizing radiation are seen among those individuals exposed in the 8th through the 25th week after fertilization. These effects, particularly in the most sensitive period, 8-15 weeks after fertilization, manifest themselves as an increased frequency of severe mental retardation (SMR), a diminution in IQ score and in school performance, and an increase in the occurrence of seizures. Of 30 SMR cases, 18 (60%) had small heads. About 10% of the individuals with small head sizes observed among the in utero clinical sample were mentally retarded. When all of the cases of mental retardation are included in the analysis, a linear dose-response model fits the data adequately and no evidence of a threshold emerges; however, if the two probable nonradiation-related cases of Down's syndrome are excluded from the 19 SMR cases exposed 8-15 weeks after fertilization, the evidence of a threshold is stronger. The 95% lower bound of the threshold based on the new dosimetry system appears to be in the range of 0.12-0.23 Gy. In the 16-25 week period, the 95% lower bound of the threshold is 0.21 Gy both with and without inclusion of two probable nonradiation-related retarded cases. In a regression analysis of IQ scores and school performance data, a greater linearity is suggested with the new dosimetry (DS86) than with the old (T65DR), but the mean IQ score and the mean school performance of those exposed in utero to doses under 0.10 Gy are similar, and not statistically different from the means in the control group. The risk ratios for unprovoked seizures, following exposure during the 8th through the 15th week after fertilization, are 4.4 (90% confidence interval: 0.5-40.9) after 0.10-0.49 Gy and 24.9 (4.1-191.6) after 0.50 Gy or more when the mentally retarded are included and 4.4 (0.5-40.9) and 14.5 (0.4-199.6), respectively, when they are excluded.