The exposure metric: does including time since exposure in the calculation of working lifetime exposure provide a better understanding of disease risk than the cumulative exposure?

BACKGROUND: When exposure measurements are available for occupational epidemiology studies, the cumulative exposure (the sum of the products of duration and exposure intensity at all jobs) is generally selected as the summary metric for chronic diseases. For silica exposures, a metric that weights each exposure by the number of years since it occurred has been suggested as more biologically relevant. Comparative reports of analyses using both metrics have not been found in the literature, however. METHODS: We calculated both metrics for silica exposure, and evaluated exposure-response relations for lung cancer and silicosis in two separate case-control studies. RESULTS: Generally the results were consistent, due to the high correlation between the two metrics and the fact that the rate of time away from work during the employment years was low. CONCLUSION: The significant relation between exposure and silicosis using the weighted metric provides additional point estimates of risk, adding to the understanding of exposure-response.

Impact of differential cyclin D1 expression and localisation in prostate cancer.

Cyclin D1 is a critical regulator of androgen-dependent transcription and cell cycle progression in prostate cancer cells. Despite the influence of D-type cyclins on prostate cancer proliferation, few studies have examined the expression of cyclin D1 in localised tumours or challenged its relevance to disease progression. Cyclin D1 status was characterised using immunohistochemistry in 38 non-neoplastic prostate samples, 138 primary human prostate carcinomas, and three lymph node metastatic specimens. Relevance of cyclin D1 to preoperative prostate-specific antigen (PSA) levels, Ki-67 index, and p21Cip1 status was also examined. Cyclin D1-positive phenotype was increased in primary carcinoma compared to non-neoplastic tissue, and was evident in all lymph node metastases cases. Interestingly, at least three distinct localisation patterns were observed in the cyclin D1-positive cohort, wherein cytoplasmic localisation was identified in a large fraction, and this pattern was predominant in lower grade tumours. Relevance of altered cyclin D1 status was observed, wherein cyclin D1-positive tumours were associated with low preoperative PSA levels, consistent with in vitro reports that cyclin D1 may alter the expression of this tumour marker. Moreover, tumours with predominantly cytoplasmic cyclin D1 showed the lowest Ki-67 index, whereas nuclear cyclin D1 was associated with higher grade, elevated Ki-67, and increased nuclear p21Cip1. These data demonstrate that differential cyclin D1 status may influence clinicopathological parameters, and reveal new insight as to the regulation and potential consequence of cyclin D1 expression in prostate cancer.

Consequences of smoking and caffeine consumption during pregnancy in women with type 1 diabetes.

OBJECTIVE: To test the hypothesis that, in women with type 1 diabetes, prenatal smoking and caffeine consumption during pregnancy are associated with an increased risk of adverse maternal and perinatal outcomes. METHODS: A secondary analysis of data on pregnant women with type 1 diabetes from an interdisciplinary program of Diabetes in Pregnancy. Women were interviewed monthly, by a trained non-medical member of the research team, using a standardized questionnaire, to ascertain daily smoking habits and caffeine consumption. RESULTS: Smoking and caffeine information were available on 191 pregnancies, 168 progressing beyond 20 weeks of gestation. Early pregnancy smoking (OR 3.3, 95% CI 1.2, 8.7) and caffeine consumption (OR 4.5, 95% CI 1.2, 16.8) were associated with increased risk of spontaneous abortion when controlling for age, years since diagnosis of diabetes, previous spontaneous abortion, nephropathy and retinopathy. Smoking throughout pregnancy was significantly associated with decreased birth weight and prolonged neonatal hospital stay. Smoking throughout pregnancy (OR 0.2, 95% 0.1, 1.0) and caffeine consumption after 20 weeks (OR 0.3, 95% CI 0.1, 1.0) were associated with reduced risk of pre-eclampsia. CONCLUSIONS: Caffeine consumption during early pregnancy, regardless of glycemic control, increases the risk of spontaneous abortion. Smoking throughout pregnancy and caffeine consumption are associated with reduced risk of pre-eclampsia.

Relationship between socioeconomic factors and severe childhood injuries.

The objective was to examine the relationship between injury rates and socioeconomic factors for children in Hamilton County, Ohio, using small-area analysis. The subjects were county residents less than 15 years old who were hospitalized or died of injuries between January 1, 1993, and December 31, 1995; they were identified through a population-based trauma registry. The census tract was the unit of analysis; the rate of injury per 100,000 population was the dependent variable. Risk factors included median income, level of education, percentage below the poverty level, percentage unemployment, percentage non-Caucasian, and percentage families headed by females. There were 2,437 children meeting the case definition; injuries per census tract ranged from 0 to 2,020.2 per 100,000 per year. Census tracts with higher injury rates had lower median incomes, more people with less than a high school education, more unemployment, more families headed by females, more people living below the poverty level, and more non-Caucasians than those with lower rates. In a regression model, percentage of people living below the poverty level, percentage of those who did not graduate from high school, and percentage unemployment were significant risk factors for injuries, P < .001. Since small-area analysis examines associations on an ecological level rather than an individual level, these studies should always be interpreted with caution because an association found at the level of the census tract may not apply at the individual level. Interventions to reduce injuries should target socioeconomically disadvantaged children living below the poverty level and those in areas with fewer high school graduates and more unemployment.

Prospective analysis of strength in spinal muscular atrophy. DCN/Spinal Muscular Atrophy Group.

Spinal muscular atrophy is a genetic disorder of the motor neurons that causes profound hypotonia, severe weakness, and often fatal restrictive lung disease. Patients with spinal muscular atrophy present a spectrum of disease from the most severe infantile-onset type, called Werdnig-Hoffmann disease (type 1), associated with a mortality rate of up to 90%, to a late-onset mild form (type 3), wherein patients remain independently ambulatory throughout adult life. Although many clinicians agree that patients with spinal muscular atrophy lose motor abilities with age, it is unknown whether progressive weakness occurs in all patients with spinal muscular atrophy. We present here results of the first prospective study of muscle strength in patients with spinal muscular atrophy. There was no loss in muscle strength as determined by a quantitative muscle test during the observation period. However, motor function diminished dramatically in some patients with spinal muscular atrophy. Explanations for this loss of function could not be determined from our data. Decrease in motor function could be caused by factors other than loss of strength. Therefore, it is not clear from our results whether spinal muscular atrophy is a neurodegenerative disease. We conclude that treatment trials in spinal muscular atrophy should be designed with consideration of the natural history of strength and motor function in this disorder.

An EEG should not be obtained routinely after first unprovoked seizure in childhood.

OBJECTIVE: To quantify and analyze the value of expected information from an EEG after first unprovoked seizure in childhood. BACKGROUND: An EEG is often recommended as part of the standard diagnostic evaluation after first seizure. METHODS: A MEDLINE search from 1980 to 1998 was performed. From eligible studies, data on EEG results and seizure recurrence risk in children were abstracted, and sensitivity, specificity, and positive and negative predictive values of EEG in predicting recurrence were calculated. Linear information theory was used to quantify and compare the expected information from the EEG in all studies. Standard test-treat decision analysis with a treatment threshold at 80% recurrence risk was used to determine the range of pretest recurrence probabilities over which testing affects treatment decisions. RESULTS: Four studies involving 831 children were eligible for analysis. At best, the EEG had a sensitivity of 61%, a specificity of 71%, and an expected information of 0.16 out of a possible 0.50. The pretest probability of recurrence was less than the lower limit of the range for rational testing in all studies. CONCLUSIONS: In this analysis, the quantity of expected information from the EEG was too low to affect treatment recommendations in most patients. EEG should be ordered selectively, not routinely, after first unprovoked seizure in childhood.

Cluster analysis applied to building-related illness.

Identifying remediable causes of occupant symptoms in building-related illness is frequently difficult. This is particularly true when the building-wide prevalence of symptoms is comparable to that reported in non-problem buildings. This analysis applied an epidemiological approach to an assessment of a problem building, allowing investigators to visually identify an area of apparent increased symptom density. A cluster analysis approach permitted biostatistical confirmation of the visual cluster. Building-related symptom reporting was statistically significantly associated with a prior physician diagnosis of dust and/or mold allergy. The likely etiology of building occupant symptoms was identified within the region implicated by the cluster analysis. This approach may be useful to focus building evaluations on both the likely physical source and general characteristics of suspect etiologic agents.

Function changes in spinal muscular atrophy II and III. The DCN/SMA Group.

The course of spinal muscular atrophy (SMA) is not well established except for those patients whose age of onset is before 6 months and who achieve only "sit with support" as their maximum function (Werdnig-Hoffmann disease or SMA I). This study shows that there is another group of SMA patients whose age of onset and maximum function achieved can be used as prognostic guides. Fifty percent of SMA patients who could walk without assistance and whose onset was prior to age 2 years lost the ability to walk independently by age 12. Fifty percent of SMA patients who walked and whose onset was between 2 and 6 years of age lost walking ability by age 44 years. Fifty percent of SMA patients who could walk with assistance as their best function ever achieved lost this ability by age 7 years, unrelated to age of onset; none could walk with assistance after age 14 years. Seventy-five percent of SMA patients who developed the ability to sit independently as their best function were still sitting after age 7 years independent of age of onset; 50% of this group could sit independently after age 14 years. Eighty-five percent of SMA patients who could walk could not negotiate stairs without holding onto a rail. They could raise their hands above the head; however, as they lost walking ability, they lost this function as well. Only one SMA patient whose maximum function was sitting independently could get to the sitting position on his own. Only two of these patients could hold their hands above their heads. All patients with SMA lose function over time. This function loss occurs slowly and is related primarily to maximum function achieved; knowledge of age of onset provides helpful information, especially for predicting the loss of independent walking.

Ragweed immunotherapy in adult asthma.

BACKGROUND: Although allergen immunotherapy is effective for allergic rhinitis, its role in treating asthma is unclear. METHODS: We examined the efficacy of immunotherapy for asthma exacerbated by seasonal ragweed exposure. During an observation phase, adults with asthma who were sensitive to ragweed kept daily diaries and recorded peak expiratory flow rates between July and October. Those who reported seasonal asthma symptoms and medication use as well as decreased peak expiratory flow were randomly assigned to receive placebo or ragweed-extract immunotherapy in doses that increased weekly for an additional two years. RESULTS: During the observation phase, the mean (+/- SE) peak expiratory flow rate measured in the morning during the three weeks representing the height of the pollination season was 454 +/- 20 liters per minute in the immunotherapy group and 444 +/- 16 liters per minute in the placebo group. Of the 77 patients who began the treatment phase, 64 completed one year of the study treatment and 53 completed two years. During the two treatment years, the mean peak expiratory flow rate was higher in the immunotherapy group (489 +/- 16 liters per minute, vs. 453 +/- 17 in the placebo group [P = 0.06] during the first year, and 480 +/- 12 liters per minute, vs. 461 +/- 13 in the placebo group [P = 0.03] during the second). Medication use was higher in the immunotherapy group than in the placebo group during observation and lower during the first treatment year (P = 0.01) but did not differ in the two groups during the second year (P = 0.7). Asthma-symptom scores were similar in the two groups (P = 0.08 in year 1 and P = 0.3 in year 2). The immunotherapy group had reduced hay-fever symptoms, skin-test sensitivity to ragweed, and sensitivity to bronchial challenges and increased IgG antibodies to ragweed as compared with the placebo group; there was no longer a seasonal increase in IgE antibodies to ragweed allergen in the immunotherapy group after two years of treatment. Reduced medication costs were counterbalanced by the costs of immunotherapy. CONCLUSIONS: Although immunotherapy for adults with asthma exacerbated by seasonal ragweed exposure had positive effects on objective measures of asthma and allergy, the clinical effects were limited and many were not sustained for two years.

A prospective 15-year follow up of 154 consecutive patients with trigeminal neuralgia treated by percutaneous stereotactic radiofrequency thermal rhizotomy.

There is a lack of prospective studies for the long-term results of percutaneous stereotactic radiofrequency rhizotomy (PSR) in the treatment of patients with trigeminal neuralgia. The authors present results in 154 consecutive patients with trigeminal neuralgia treated by PSR and prospectively followed for 15 years. Ninety-nine percent of the patients obtained initial pain relief after one PSR. Dysesthesia occurred in 31 patients (23%): in 7% with mild initial hypalgesia; in 15% with dense hypalgesia; and in 36% with analgesia. Dysesthesia was mild and did not require treatment in most patients. The corneal reflex was absent or depressed in 29 patients, and keratitis developed in three patients. In 19 of 22 patients with trigeminal motor weakness, the paresis resolved within 1 year. Of 33 patients who had pain recurrence, 10 patients had pain that was mild or controlled with medications, and 23 patients required additional surgical treatment. The authors estimated using Kaplan-Meier analysis that the 14-year recurrence rate was 25% in the total group: 60% in patients with mild hypalgesia, 25% in those with dense hypalgesia, and 20% in those with analgesia. Timing of pain recurrence varied according to the degree of sensory loss. All pain recurrences in patients with mild hypalgesia occurred within 4 years after surgery; 10% more of the patients with dense hypalgesia had pain recurrences within the first 10 years compared with patients with analgesia. The median pain-free survival rate was 32 months for patients with mild hypalgesia and more than 15 years for patients with either analgesia or dense hypalgesia. Of the 100 patients followed for 15 years after one or two PSR procedures, 95 patients (95%) rated the procedure excellent (77 patients) or good (18 patients). The authors conclude that PSR is an effective, safe treatment for trigeminal neuralgia. Dense hypalgesia in the painful trigger zone, rather than analgesia, should be the target lesion.

Evaluation of a possible association of urban air toxics and asthma.

The prevalence of asthma, measured either as the frequency of hospital admissions or number of deaths attributed to asthma, has increased over the last 15 to 20 years. Rapid increases in disease prevalence are more likely to be attributable to environmental than genetic factors. Inferring from past associations between air pollution and asthma, it is feasible that changes in the ambient environment could contribute to this increase in morbidity and mortality. Scientific evaluation of the links between air pollution and the exacerbation of asthma is incomplete, however. Currently, criteria pollutants [SOx, NOx, O3, CO, Pb, particulate matter (PM10)] and other risk factors (exposure to environmental tobacco smoke, volatile organic compounds, etc.) are constantly being evaluated as to their possible contributions to this situation. Data from these studies suggest that increases in respiratory disease are associated with exposures to ambient concentrations of particulate and gaseous pollutants. Similarly, exposure to environmental tobacco smoke, also a mixture of particulate and gaseous air toxics, has been associated with an increase in asthma among children. In addition, current associations of adverse health effects with existing pollution measurements are often noted at concentrations below those that produce effects in controlled animal and human exposures to each pollutant alone. These findings imply that adverse responses are augmented when persons are exposed to irritant mixtures of particles and gases and that current measurements of air pollution are, in part, indirect in that the concentrations of criteria pollutants are acting as surrogates of our exposure to a complex mixture. Other irritant air pollutants, including certain urban air toxics, are associated with asthma in occupational settings and may interact with criteria pollutants in ambient air to exacerbate asthma. An evaluation of dose-response information for urban air toxics and biological feasibility as possible contributors to asthma is therefore needed. However, this evaluation is compounded by a lack of information on the concentrations of these compounds in the ambient air and their effects on asthma morbidity and mortality. Through an initial review of the current toxicological literature, we propose a tentative list of 30 compounds that could have the highest impact on asthma and respiratory health. These compounds were selected based on their ability to induce or exacerbate asthma in occupational and nonoccupational settings, their allergic potential and ability to react with biological macromolecules, and lastly, their ability to irritate the respiratory passages. We recommend better documentation of exposure to these compounds through routine air sampling and evaluation of total exposure and further evaluation of biological mechanisms through laboratory and epidemiological studies directed specifically at the role these substances play in the induction and exacerbation of asthma.

Exposure-response analysis of mortality among coal miners in the United States.

The quantitative relationship between exposure to respirable coal mine dust and mortality from nonmalignant respiratory diseases was investigated in a study of 8,878 working male coal miners who were medically examined from 1969 to 1971 and followed to 1979. Exposure-related mortality was evaluated using Cox proportional hazards modeling for underlying or contributing causes of death and modified lifetable methods for underlying causes. For pneumoconiosis mortality, the lifetable analyses showed increasing standardized mortality ratios (SMRs) with increasing cumulative exposure category. Significant exposure-response relationships for mortality from pneumoconiosis (p < 0.001) and from chronic bronchitis or emphysema (p < 0.05) were observed in the proportional hazards models after controlling for age and smoking. No exposure-related increases in lung cancer or stomach cancer were observed. Pneumoconiosis mortality was found to vary significantly by the rank of coal dust to which miners were exposed. Miners exposed at or below the current U.S. coal dust standard of 2 mg/m3 over a working lifetime, based on these analyses, have an elevated risk of dying from pneumoconiosis or from chronic bronchitis or emphysema.

On prediction of future observation in growth curve model.

Rao proposed and compared several approaches for predicting future observations in a growth curve model. The assessment of associated prediction efficiency for different prediction methods were evaluated by Cross-Validation Assessment Error (CVAE). He used three data sets, each with a limited number of subjects (13-27) and also with a limited number of repeated measurements (4-7) per subject, to illustrate the prediction methods. In the present paper, we applied four of the prediction methods discussed by Rao, on a data set with a relatively large number of subjects (174) and also with a larger number of measurements (21) per subject, using the polynomial function and log-linear function. We propose to use the restricted cubic spline function as an alternative growth curve model and compare its performance with the polynomial function and log-linear function. It turns out that, at least for larger data sets such as that used in this paper, the prediction methods perform somewhat better when the growth is described by restricted cubic spline function than when the growth is described by polynomial function and log-linear function.

Pulmonary function in spinal muscular atrophy.

We present the first prospective study on pulmonary function in spinal muscular atrophy patients. Seventy-seven spinal muscular atrophy patients, ages 5 to 18 years, from three centers, were studied with regard to forced vital capacity, using height as a predictor. Patients were categorized into four motor function categories. The highest-functioning group had normal or near-normal values, and those who sat with support had the lowest values. Those with intermediate function had intermediate values. Forced vital capacity was studied longitudinally in 40 spinal muscular atrophy patients for 1.1 to 4.4 years. Eighty-eight percent of patients grew in height, but only 35% showed an increase in height-adjusted forced vital capacity percent. In those patients with the least function, 100% lost height-adjusted forced vital capacity over time. In those patients with the highest function, 57% lost height-adjusted forced vital capacity. In addition, the basic forced vital capacity, not correlated to height, decreased in 43% of cases. These pulmonary function alterations appear to be important determinants for function and survival in spinal muscular atrophy patients.

Proportional mortality analysis of wastewater treatment system workers by birthplace with comments on amyotrophic lateral sclerosis.

There is concern that wastewater treatment system workers are at risk for cancers and diseases affecting the neurological and digestive systems. However, these diseases have also been linked to early exposures. A proportional mortality study was conducted on a large cohort of wastewater treatment system workers who were divided into two groups, migrants and nonmigrants, by place of birth as reported on their death certificates. The migrant worker group was significantly higher than the US white male population for cancer of the stomach, leukemia, and all lymphopoietic cancers. Migrant workers also had an elevated ratio for all diseases of the nervous system and sense organs. No cases of amyotrophic lateral sclerosis were found. The American-born workers had an elevated rate of death for arteriosclerotic heart disease compared with the US white male population. We suggest that place of birth may present a confounding factor when evaluating exposures in employee groups.

Retrieval of p53 protein in paraffin-embedded head and neck tumor tissues.

OBJECTIVES: To improve the detection of p53 protein in formalin-fixed, paraffin-embedded head and neck tumor tissues. DESIGN: Cohort. SETTING: University and Veterans Administration medical centers. PATIENTS OR OTHER PARTICIPANTS: Retrospective samples. INTERVENTION: Surgery for head and neck carcinoma. MAIN OUTCOME MEASURES: Retrieval of p53 antigen. Hypothesis formulated after data collection. RESULTS: An antigen retrieval method facilitated the unmasking of previously inaccessible p53 antigenic determinants in formalin-fixed, paraffin-embedded tissues. This approach has made possible a much more reliable and sensitive immunohistochemical detection of p53 antigen. The procedure is simple, requiring only microwave heating of tissue sections to 100 degrees C in the presence of a zinc sulfate solution. CONCLUSIONS: Antigen retrieval method in formalin-fixed, paraffin-embedded tissue demonstrated a significant increase in p53 immunostaining.

Birthplace as a risk factor in motor neurone disease and Parkinson's disease.

A proportional mortality study was conducted to determine if state of birth is a risk factor associated with motor neurone disease (MND) and Parkinson's disease (PD) using US death certificate information for 1981. State of birth was used as a surrogate variable for location of early childhood environment. A gradient of risk by geographical area in the US was found for MND and PD. Cerebral vascular accident (CVA) deaths served as a comparison group. Multiple sclerosis (MS) deaths were analysed to validate the methods used. A geographical relationship between latitude proportional mortality ratios for MND, PD and MS by state of birth, and a geographical relationship between latitude and proportional mortality ratios for MND and MS by state of birth were found. Statistical modelling was used to compare the deaths from MND, PD, MS, CVA to all other deaths in the US by state of birth. The resulting models were evaluated to determine if any individual states were not well represented by the model for each disease. As predicted, no pattern was evident for CVA. The geographical gradient observed for MS was as predicted by other studies. The geographical pattern found for MND has a northwest to southeast gradient and the pattern found for PD has a west to east gradient.

Prospective study of spinal muscular atrophy before age 6 years. DCN/SMA Group.

Spinal muscular atrophy (SMA) is a common neuromuscular disorder of childhood, associated with a high mortality rate during the first 2 years of life. Most practitioners expect patients with SMA to follow a progressive course with loss of muscle strength and function over 2-10 years. Counselling sessions with parents frequently emphasize the high mortality rate and risk for respiratory failure. The progressive nature of SMA has been attributed to the loss of motor neurons. Fifty-eight children, ages 6 years and younger, were examined between January, 1987, and April, 1992, as part of a large, multicenter collaborative study of SMA. Muscle function was evaluated at regular intervals using a standardized protocol that was demonstrated to be reliable. We determined a prevalence of 56% for tongue fasciculations, a prevalence of 22% for facial weakness, and persistent deep tendon reflexes in one patient. Improved motor function and acquired milestones during the study were documented. This work should contribute toward a better understanding of the natural history of SMA.