Harvard T.H. Chan School of Public Health

Insidious neurotoxic effects of lead have been studied in a population of 42 lead-exposed workers and a reference group of 22 comparable workers with no lead exposure. The age of the individuals ranged from 18 to 50 years. The complete Wechler Adult Intelligence Scale, as well as psychomotor and memory tests, was included in the test battery. The exposure was assessed by means of the lead concentration in blood and hair and the ratio between zinc protoporphyrin and hemoglobin in the blood. Significant differences were found between the two groups of workers, especially concerning long-term memory, verbal and visuospatial abstraction, and psychomotor speed. Decreased performance in these tests was in most cases associated with indices of increased lead exposure, not only in the total population studied, but also within the lead-exposed group alone. Blood lead and zinc protoporphyrin appeared to correlate better with the intellectual impairment than did hair lead, and thus these analyses are probably better predictors for neurotoxic effects of lead. Age and exposure time were not found to be significant confounding factors in this study.

The federal government has increased its activities directed toward health promotion and disease prevention. We carried out a pilot survey of a random sample of Massachusetts physicians and lawyers to obtain a profile of the personal health-promoting behaviors in the two professional groups.

YOUNG female ballet dancers attending professional schools or dancing in companies in which thinness is much admired restrict their food intake and are highly active. The unusual eating habits and levels of activity of some of these dancers have been related to lack of menstrual cycles.1 Amenorrhea and late menarche among girls and women with average activity levels are associated with undernutrition and weight loss in the range of 10 to 15 per cent of the normal weight for height; such weight loss apparently reduces the fat/lean ratio to less than a critical level. We report here on 89 young ballet dancers among whom there was a high incidence of primary amenorrhea, secondary amenorrhea, irregular cycles, and delayed menarche — an incidence correlated with excessive thinness.

Simian T-lymphotropic retroviruses with structural, antigenic, and cytopathic features similar to the etiologic agent of human acquired immunodeficiency syndrome, human T-lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV), have been isolated from a variety of primate species including African green monkeys (STLV-IIIAGM). This report describes nucleic acid cross-reactivity between STLV-IIIAGM and HTLV-III/LAV, molecular cloning of the STLV-IIIAGM genome, and evaluation of its structure and genetic relationship to other retroviruses. Overlapping clones from a cell line infected with virus from a single animal were found to encompass the entire STLV-IIIAGM genome and exhibit a limited degree of restriction-site variability. Specific hybridizing fragments were detected in DNA from this and other STLV-IIIAGM-infected cell lines. A fraction of viral DNA present in at least two STLV-IIIAGM lines persists as unintegrated viral DNA, a characteristic of infection with cytopathic retroviruses. Strongest cross-reactivity was detected between HTLV-III/LAV pol- and gag- genes and STLV-IIIAGM, whereas no cross-reactivity was detected between STLV-IIIAGM and molecular clones of human T-lymphotropic virus types I and II (HTLV-I and -II), visna virus, bovine leukemia virus, or feline leukemia virus.

To identify possible barriers to women physicians who wish to combine parenting with medical careers, we studied 56 of 64 pregnancies from the past 10 years in 63 of 66 Harvard-affiliated residency programs. Pregnancies during residency were common (one in eight married women in 1983) and were usually planned (77 percent). Most institutions were unprepared for pregnancies among members of the house staff; four fifths of the programs had no maternity-leave policy. No one quit a residency program because of pregnancy, and pregnancy rarely affected achievement of board certification. Whether the pregnant women found pregnancy during residency a "pleasant" experience was determined largely by whether the program director was supportive, whether the issue of pregnancy was openly discussed within the program, and whether the woman was permitted to return to work on a part-time basis for the first weeks after maternity leave. We conclude that pregnancy within residency programs should be expected and planned for and that if proper arrangements are made, it need not be a major problem for either the training program or the pregnant resident. (N Engl J Med 1986; 314:418–23.)

The hypothesis that an infection plays a role in the etiology of Hodgkin's disease (HD) is suggested by both its clinical and histologic features. Its bimodal age-incidence pattern also suggests an infectious process among younger persons. In economically advantaged populations, the first peak occurs among young adults, while in disadvantaged populations, it occurs among children at a much lower frequency. It appears that the age distribution of HD shadows that of susceptibility to common childhood infections, such as the Epstein-Barr virus (EBV); furthermore, that risk of HD is increased among those susceptible to a relatively late infection, in parallel with infectious mononucleosis (IM), and it has been found that people who have had IM have about three times the expected rate of HD. Serologically, there is a consistent association between EBV and HD. As a group, patients have an altered antibody pattern against EBV which suggests chronic reactivation, both following and preceding diagnosis. This altered pattern is common to all age groups. Severity of infection may alter host control among younger people, while diminished cellular immunity with aging may allow similar reactivation among older persons. Whether the EBV plays a direct role or simply reflects the action of a more primary factor is unknown.

Techniques for measuring acid aerosols in the ambient environment have been developed only recently. As part of the on-going Harvard Study on the Health Effects of Sulfur Dioxide and Respirable Particulates, we have developed monitoring equipment for acidic particles that can be used in multiple field settings. Preliminary data suggest that these strong acid aerosol measurements may correlate with respiratory symptoms more closely than similar measurements of particulate matter less than 15 microns in size. These results have led to the beginning of a U.S.-Canadian cooperative study to assess the chronic effects of acid aerosols on the health of North American children. Communities are being selected on the basis of anticipated levels of H2SO4 in ambient air along with predicted levels of ozone and nitrates. Each community will undergo a 1-year period of every other day, 24-hr monitoring with newly developed monitoring equipment that will allow for quantification of H+ ion concentrations, as well as for specific measures of ozone and acid fractions. At the end of the 1-year period, while measurements are still being made, approximately 600 children aged 7 to 11 in each of up to 24 communities will be assessed with standardized questionnaires completed by parents, and pulmonary function will be measured in the children while in school. By estimating chronic exposure from the year-long measurement of acid aerosols and consideration of specific criteria for selecting communities to study, we hope to minimize potential confounding to allow us to assess the chronic impact of strong acid in the atmosphere on the respiratory health of these children.

There has been considerable recent interest in the mechanisms by which recessive mutations involving cancer genes may be expressed. We have developed an in vitro model to study this phenomenon in an endogenous autosomal gene in human cells. We have analyzed the molecular structural changes that lead to loss of heterozygosity at the thymidine kinase (tk) locus. The results indicate that expression of a recessive allele frequently occurs by loss of heterozygosity at that locus. Over 90% of spontaneous mutants at the tk locus arose by allele loss. The fraction of induced mutants that arose by this mechanism depended upon the inducing agent. Loss of the active tk allele was often accompanied by loss of linked genetic loci on the long arm of chromosome 17. These results suggest that large-scale chromosomal mutations resulting from events such as deletion or mitotic recombination may be an important mechanism for the expression of activated or mutated recessive genes in human cells. Such recessive mutations could involve oncogenes or other growth regulatory genes important in carcinogenesis.

BACKGROUND: This study sought to resolve conflicting views about whether physicians are especially prone to alcohol abuse. METHODS: Using an anonymous, mailed questionnaire on substance use, we surveyed 500 physicians, 510 pharmacists, and 974 of their students. The physicians and pharmacists were selected randomly from the state society's membership lists, and students selected were from local school lists. Follow-up surveys were sent to nonresponders at two-week intervals. RESULTS: The physicians and medical students did not drink especially heavily and were no more vulnerable to alcoholism than were their counterparts in pharmacy and other professions. Physicians differed from pharmacists in their style of drinking (greater frequency, smaller quantity), but not in total amount of alcohol consumed. Drinking habits among physicians were not associated with medical specialty or type of practice, but were positively related to gender (males drank more than females) and to age (older doctors were more apt to qualify as heavy drinkers than were younger doctors). CONCLUSIONS: Physicians were no more likely to abuse substances nonmedically than were other professionals. Any group in which alcohol use is nearly universal incurs a risk of abuse and impairment that cannot be ignored.

METHODS We reviewed 30,121 randomly selected records from 51 randomly selected acute care, nonpsychiatric hospitals in New York State in 1984. We then developed population estimates of injuries and computed rates according to the age and sex of the patients as well as the specialties of the physicians.

RESULTS Adverse events occurred in 3.7 percent of the hospitalizations (95 percent confidence interval, 3.2 to 4.2), and 27.6 percent of the adverse events were due to negligence (95 percent confidence interval, 22.5 to 32.6). Although 70.5 percent of the adverse events gave rise to disability lasting less than six months, 2.6 percent caused permanently disabling injuries and 13.6 percent led to death. The percentage of adverse events attributable to negligence increased in the categories of more severe injuries (Wald test χ2 = 21.04, P<0.0001). Using weighted totals, we estimated that among the 2,671,863 patients discharged from New York hospitals in 1984 there were 98,609 adverse events and 27,179 adverse events involving negligence. Rates of adverse events rose with age (P<0.0001). The percentage of adverse events due to negligence was markedly higher among the elderly (P<0.01). There were significant differences in rates of adverse events among categories of clinical specialties (P<0.0001), but no differences in the percentage due to negligence.

CONCLUSIONS There is a substantial amount of injury to patients from medical management, and many injuries are the result of substandard care.

Background: In a sample of 30,195 randomly selected hospital records, we identified 1133 patients (3.7 percent) with disabling injuries caused by medical treatment. We report here an analysis of these adverse events and their relation to error, negligence, and disability.

Methods: Two physician-reviewers independently identified the adverse events and evaluated them with respect to negligence, errors in management, and extent of disability. One of the authors classified each event according to type of injury. We tested the significance of differences in rates of negligence and disability among categories with at least 30 adverse events.

Results: Drug complications were the most common type of adverse event (19 percent), followed by wound infections (14 percent) and technical complications (13 percent). Nearly half the adverse events (48 percent) were associated with an operation. Adverse events during surgery were less likely to be caused by negligence (17 percent) than nonsurgical ones (37 percent). The proportion of adverse events due to negligence was highest for diagnostic mishaps (75 percent), noninvasive therapeutic mishaps ("errors of omission") (77 percent), and events occurring in the emergency room (70 percent). Errors in management were identified for 58 percent of the adverse events, among which nearly half were attributed to negligence.

Conclusions: Although the prevention of many adverse events must await improvements in medical knowledge, the high proportion that are due to management errors suggests that many others are potentially preventable now. Reducing the incidence of these events will require identifying their causes and developing methods to prevent error or reduce its effects.

Macrophages exist throughout the body. They have critical roles in the peritoneal cavity, bone marrow, skin, spleen, liver, and elsewhere. Their migratory patterns, phagocytic behavior, immunologic roles, and secretory potential are pivotal to both defense mechanisms and to the pathogenesis of disease. Macrophages have been implicated recently in such diverse disease processes as arthritis, AIDS, and juvenile onset diabetes. It is important to recognize the existence of other lung macrophages besides alveolar macrophages. Macrophages exist in small and large airways above and below the mucus. They may release chemotactic factors and a variety of mediators. They ingest and degrade antigens and are microbicidal. Interstitial macrophages are in direct contact with the extracellular matrix as well as other cells in pulmonary connective tissue such as fibroblasts. Thus, release of mediators or enzymes by interstitial macrophages can have a profound effect. Pulmonary intravascular macrophages are resident cells within the pulmonary capillaries of some species. They avidly remove particles and pathogens from circulating blood and secrete inflammatory mediators. Finally, pleural macrophages are involved in the fate and consequences of inhaled particles, especially fibers. A key attribute of macrophages is motility. Movement is an essential step in phagocytosis. There can be no particle binding or ingestion unless macrophage-particle contact occurs. To what extent and by what mechanisms do alveolar macrophages move on the alveolar epithelium? We have used optical methods as well as magnetometry to describe macrophage motility. Lung macrophages express an array of contractile proteins that are responsible for spreading, migration, phagocytosis, and the controlled intracellular motions of phagosomes and lysosomes. We have used magnetometric probing of cytoplasmic motion and rheology for both in vivo studies of macrophage function in animals and humans as well as in vitro studies of macrophages. The cytoskeleton of macrophages and resulting motile events are key in understanding the role of macrophages in relation to particle phagocytosis, translocation, and solubilization.

To develop an experimental model of adult T‐cell leukemia/lymphoma in small animals, severe combined immunodeficiency (SCID) mice treated with anti‐asialo GM‐1 antibody were inoculated with MT‐2 cells, a cell line transformed by the human T‐cell leukemia virus (HTLV–I). Three mice injected with 4 × 107 cells subcutaneously or intramuscularly developed tumors at or near inoculation sites. Immunofluorescent antibody (IFA) staining for HTLV–I structural protein, p19, revealed the specific antigen in the cytoplasm of most cells from tumors and the DNA signals of HTLV–I proviral DNA were also positive in cellular DNA by polymerase chain reaction assay with HTLV–I tax gene primers, SK43/SK44. The MT–2 cells did not invade in mouse organs.

We examined the association between oral contraceptive use and incidence of Type 2 (non-insulin-dependent) diabetes mellitus among 115117 female nurses free of diabetes, cardiovascular disease and cancer in 1976 and followed-up for 12 years. During 1237 440 person years of follow-up, 2276 women who provided information on oral contraceptive use were clinically diagnosed with Type 2 diabetes. Women who used oral contraceptives in the past had only a slight and marginally increased relative risk of 1.10 (95% confidence interval 1.01, 1.21) compared to those women who had never used oral contraceptives after controlling for known risk factors of disease. We found no evidence of increased risk with longer duration of use or with shorter interval since last use. Current users did not have an increased risk of Type 2 diabetes (relative risk = 0.86, 95 % confidence interval 0.46, 1.61) when compared to women who had never used the drug. There was no effect modification by obesity, family history of diabetes, or physical activity. These data suggest that past or current oral contraceptive use does not substantially influence subsequent risk of Type 2 diabetes.

Frequently, covariates used in a logistic regression are measured with error. The authors Previously described the correction of logistic regression relative risk estimates for measurement error in one or more covariates when a ''gold standard'' is available for exposure assessment. For some exposures (e.g., serum cholesterol), no gold standard exists, and one must assess measurement error via a reproducibility substudy. In this paper, the authors present measurement error methods for logistic regression when there is error (possibly correlated) in one or more covariates and one has data from both a main study and a reproducibility substudy. Confidence intervals from this procedure reflect error in parameter estimates from both studies. These methods are applied to the Framingham Heart Study. where the 10-year incidence of coronary heart disease is related to several coronary risk factors among 1,731 men disease-free at examination 4. Reproducibility data are obtained from the subgroup of 1,346 men seen at examinations 2 and 3. Estimated odds ratios comparing extreme quintiles for risk factors with substantial error were increased after correction for measurement error (serum cholesterol, 2.2 vs. 2.9; serum glucose, 1.3 vs. 1.5; systolic blood pressure, 2.8 vs. 3.8). but were generally decreased or unchanged for risk factors with little or no error (body mass index, 1 .6 vs 1.6. age 65-69 years vs. 35-44 years, 4.3 vs. 3.8; smoking, 1.7 vs. 1.7).

Epidemiologic studies of the respiratory health effects of air pollution are intrinsically difficult because exposure is common, expected effects at concentrations found in developed countries are weak, random misclassification of exposure is common, and the respiratory health indicators have multiple etiologies. Exposures to air pollutants also are multidimensional, generally consisting of a mixture of gases and particles. In this paper, epidemiologic study designs are described, and their potential for evaluating effects of complex pollutant mixtures are discussed. Power to detect the independent effects of individual pollutants in a complex pollutant mixture or to measure their interactions is in general very weak unless the study is specifically designed to test such hypotheses. However, with innovative and creative design, the independent and joint effects of multiple pollutants should be estimable in epidemiologic studies.