The Ile164 beta2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure.

The beta2-adrenergic receptor (beta2AR), an important modulator of cardiac inotropy and chronotropy, has significant genetic heterogeneity in the population. Because dysfunctional betaARs play a role in the pathogenesis of the failing ventricle, we tested the hypothesis that beta2AR polymorphisms alter the outcome of congestive heart failure. 259 patients with NYHA functional class II-IV heart failure due to ischemic or dilated cardiomyopathy were genotyped and prospectively followed, with the endpoint defined as death or cardiac transplantation. The allele frequencies between this group and those of 212 healthy controls also were compared and did not differ between the groups. However, those with the Ile164 polymorphism displayed a striking difference in survival with a relative risk of death or cardiac transplant of 4.81 (P < 0.001) compared with those with the wild-type Thr at this position. Age, race, gender, functional class, etiology, ejection fraction, and medication use did not differ between these individuals and those with the wild-type beta2AR, and thus the beta2AR genotype at position 164 was the only clear distinguishing feature between the two groups. The 1-yr survival for Ile164 patients was 42% compared with 76% for patients harboring wild-type beta2AR. In contrast, polymorphisms at amino acid positions 16 (Arg or Gly) or 27 (Gln or Glu), which also alter receptor phenotype, did not appear to have an influence on the course of heart failure. Taken together with cell-based and transgenic mouse results, this study establishes a paradigm whereby genetic variants of key signaling elements can have pathophysiologic consequences within the context of a disease. Furthermore, patients with the Ile164 polymorphism and heart failure may be candidates for earlier aggressive intervention or cardiac transplantation.

Lung cancer in radon-exposed miners and estimation of risk from indoor exposure.

BACKGROUND: Radioactive radon is an inert gas that can migrate from soils and rocks and accumulate in enclosed areas, such as homes and underground mines. Studies of miners show that exposure to radon decay products causes lung cancer. Consequently, it is of public health interest to estimate accurately the consequences of daily, low-level exposure in homes to this known carcinogen. Epidemiologic studies of residential radon exposure are burdened by an inability to estimate exposure accurately, low total exposure, and subsequent small excess risks. As a result, the studies have been inconclusive to date. Estimates of the hazard posed by residential radon have been based on analyses of data on miners, with recent estimates based on a pooling of four occupational cohort studies of miners, including 360 lung cancer deaths. PURPOSE: To more fully describe the lung cancer risk in radon-exposed miners, we pooled original data from 11 studies of radon-exposed underground miners, conducted a comprehensive analysis, and developed models for estimating radon-associated lung cancer risk. METHODS: We pooled original data from 11 cohort studies of radon-exposed underground miners, including 65,000 men and more than 2700 lung cancer deaths, and fit various relative risk (RR) regression models. RESULTS: The RR relationship for cumulative radon progeny exposure was consistently linear in the range of miner exposures, suggesting that exposures at lower levels, such as in homes, would carry some risk. The exposure-response trend for never-smokers was threefold the trend for smokers, indicating a greater RR for exposure in never-smokers. The RR from exposure diminished with time since the exposure occurred. For equal total exposure, exposures of long duration (and low rate) were more harmful than exposures of short duration (and high rate). CONCLUSIONS: In the miners, about 40% of all lung cancer deaths may be due to radon progeny exposure, 70% of lung cancer deaths in never-smokers, and 39% of lung cancer deaths in smokers. In the United States, 10% of all lung cancer deaths might be due to indoor radon exposure, 11% of lung cancer deaths in smokers, and 30% of lung cancer deaths in never-smokers. This risk model estimates that reducing radon in all homes exceeding the U. S. Environmental Protection Agency's recommended action level may reduce lung cancer deaths about 2%-4%. These estimates should be interpreted with caution, because concomitant exposures of miners to agents such as arsenic or diesel exhaust may modify the radon effect and, when considered together with other differences between homes and mines, might reduce the generalizability of findings in miners.

Modifiers of exposure-response estimates for lung cancer among miners exposed to radon progeny.

The association between lung cancer and exposure to radon decay products has been well established. Despite agreement on this point, there is still some degree of uncertainty regarding characteristics of the exposure-response relationship. The use of studies of underground miners to estimate lung cancer risks due to residential radon exposure depends upon a better understanding of factors potentially modifying the exposure-response relationship. Given the diversity in study populations regarding smoking status, mining conditions, risk analysis methodology, and referent populations, the risk estimates across studies are quite similar. However, several factors partially contributing to differences in risk estimates are modified by attained age, time since last exposure, exposure rate, and cigarette smoking patterns. There is growing agreement across studies that relative risk decreases with attained age and time since last exposure. Several studies have also found an inverse exposure-rate effect, i.e., low exposure rates for protracted duration of exposure are more hazardous than equivalent cumulative exposures received at higher rates for shorter periods of time. Additionally, the interaction between radon exposure and cigarette smoking appears to be intermediate between additive and multiplicative in a growing number of studies. Quantitative estimates of these modifying factors are given using a new analysis of data from the latest update of the Colorado Plateau uranium miners cohort.

Effects of aging on the induction of angiosarcoma.

Adult, Sprague-Dawley albino rats of four different ages (6, 18, 32 and 52 weeks) were exposed to 940 ppm vinyl chloride by inhalation for 24 weeks, 5 days/week, 7 hr/day. In each age group, there were 110 to 128 males and the same number of females. The similarly housed control group, which was not exposed to vinyl chloride, consisted of the same number of males and females in each age group. All animals that died spontaneously, or were sacrificed moribund, or were killed at scheduled times (3, 6 and 9 months after initial exposure) were autopsied. All organs were examined grossly, and several tissues from each animal were examined microscopically. The older the rats were when they were first exposed, the greater the incidence of angiosarcomas. The incidences of angiosarcomas in the four age groups (from youngest to oldest) in the exposed males in the nonscheduled sacrifice groups were: 0/37 (0%); 0/44 (0%); 3/45 (6.7%); and 13/55 (24%). Similarly, for the females, these incidences were: 2/38 (5.3%); 7/47 (15%); 23/49 (47%); and 11/54 (20%). Most of the angiosarcomas were highly anaplastic, primary tumors in the livers that metastasized to the lungs. Only one angiosarcoma was seen in all the control rats; that occurred in subcutaneous tissue. This study demonstrated that older adult animals and females are more susceptible to the angiosarcoma-inducing effects of vinyl chloride than young adult animals and males, respectively.

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

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

Ethoxyethanol behavioral teratology in rats.

2-ethoxyethanol, a solvent developed for nitrocellulose and also used in lacquers, dyes, varnish removers, and in numerous industrial processes, was evaluated for possible functional effects in offspring of rats exposed during gestation. A dose finding study revealed that no offspring survived inhalation exposure (7 hours/day) from gestation days 7-13 or 14-20 at 900 ppm, and there were approximately 34 percent neonatal deaths even after prenatal exposure to 200 ppm-the current Federal occupational standard. Consequently, pregnant Sprague-Dawley rats were exposed to 100 ppm ethoxyethanol for 7 hours/day on gestation days 7-13 or 14-20. The only effect observed in the mothers was slightly prolonged gestation in he mothers exposed on days 14-20 of gestation (p less than .001). Behavioral testing of offspring from dams exposed to ethoxyethanol on gestation days 7-13 revealed: (a) impaired performance on a rotorod test of neuromuscular ability (p = .002); (b) prolonged latency of leaving the start area of an open field (p = .009); and (c) marginal superiority in avoidance conditioning begun on day 34 of age (p = 061). Offspring from dams exposed to ethoxyethanol on gestation days 14-20: (a) were less active than controls in a running wheel (p = 0.32), and (b) received an increased number and duration of shocks in avoidance conditioning begun on day 60 of age (p = .004). Neurochemical evaluation of whole-brain samples from newborn pups revealed significantly decreased levels of norepinephrine in offspring from both exposure periods (p less than .01). In regional analyses of brains from 21-day-old offspring of dams exposed to 100 ppm ethoxyethanol on gestation days 7-13, the cerebrum had significant elevations in acetylcholine (p less than .01), norepinephrine ( p less than .01), and dopamine (p less than .05), the cerebellum had nearly a 3-fold increase in acetylcholine (p less than .01); the brainstem had an increase in norepinephrine (p less than 0.01); and the midbrain had excesses of acetylcholine (p less than .01), norepinephrine (p less than .05) and protein (p less than .05). In brains from 21-day-old offspring of dams exposed to ethoxyethanol on gestation days 14-20, the cerebrum had significant elevations in acetylcholine, dopamine, and 5-hydroxytryptamine (p less than .05). Overall, the results indicate that there are behavioral and neurochemical alterations in offspring of rats following prenatal exposure to 100 ppm ethoxyethanol.

Impact of a school-based intervention on access to healthcare for underserved youth.

PURPOSE: To determine whether a multidimensional school-based intervention, which included physical and mental health services, increased adolescents' use of needed medical care and preventive care and decreased emergency room use. METHODS: A total of 2832 seventh- through twelfth-grade students in six public urban intervention schools and 2036 students in six demographically matched comparison schools completed a previously validated survey regarding health status and healthcare utilization in spring 1998 and 1999. Bivariate analyses examined the association between intervention status and Year 1/Year 2 outcomes. The multifaceted intervention included programs such as anger management groups, substance abuse prevention, tutoring, home visits, and enhanced school health services. Stepwise multivariate logistic models tested differences between the intervention and comparison groups across years, controlling for potential confounding variables [gender, age, race/ethnicity, maternal education, grade in school, school district (city or county), health status, and chronic health problems]. The interaction term for Group x Year was used to test the effect of the intervention. Multivariable modeling was also used to determine student factors independently associated with healthcare utilization. RESULTS: Respondents had a median age of 15 years, 56% were female, 51% were white, 42% were black, and 34% reported chronic health problems. In both years, over 45% of students in both groups reported not seeking medical care they believed they needed. The proportion with missed care in the intervention schools did not change, whereas the proportion with missed care in the comparison schools increased. Emergency room use decreased slightly in the intervention schools and increased slightly in the comparison schools between Year 1 and Year 2. There were no major changes in healthcare delivery in this area during the year, demonstrating the volatility of adolescents' perceived access to care. Among the student factors, health status, having a chronic condition, and being in a higher grade were independently associated with students' report of not seeking care they believed they needed. CONCLUSION: These results confirm that many adolescents have unmet healthcare needs. Those with poor health status are most likely to report underutilization and unmet needs. These findings underscore the need for comparison groups when evaluating interventions and suggest the need for better understanding of community level changes in perceived healthcare access and use.

Silicosis in a grey iron foundry. The persistence of an ancient disease.

An industrial hygiene and medical survey was conducted in an iron foundry to study the occurrence of silicosis. Breathing zone exposures to respirable crystalline silica had been very high in 1977 [1 045 micrograms/m3 (geometric mean) for coremakers and 198 micrograms/m3 for fettlers]; exposures in 1980 and 1982 were substantially lower. A radiographic evaluation of 188 workers revealed silicosis in 18 (9.6%). Eight had category 1 profusion of small rounded pulmonary lesions (by the 1980 classification of the International Labour Office); two had category 2; and eight had category 3. Two had progressive massive fibrosis. Four workers without silicosis in 1977 had developed lesions by 1980. The prevalence increased from 1.5% among workers employed less than 20 years to 53% among longer term workers. No association was found between the prevalence of silicosis and cigarette smoking. Chronic cough was more common in workers with heavy current dust exposure than in those with light exposure, more common in smokers than in nonsmokers, and more common in silicotics than in nonsilicotics. A multiplicative interaction existed between dust exposure and smoking in the etiology of cough. Silicosis continues to exist in American foundries. Cigarette smoking does not contribute to the causation of silicosis, but it aggravates the attendant respiratory symptoms.

Differential markers for regionalization.

OBJECTIVE: To examine the site of delivery for very low birth weight (VLBW) infants and infants with major congenital malformations (MCM) within an established system of perinatal regionalization. STUDY DESIGN: A retrospective study of site of delivery for VLBW infants and infants born with MCM (tracheoesophageal fistula/esophageal atresia, diaphragmatic hernia, or gastroschisis/omphalocele) from 1990 through 1995 in Ohio. RESULTS: A total of 59.8% of VLBW infants and 36.1% of MCM infants were born in a level III hospital. There was a significant trend toward a decrease in VLBW infants (p < 0.01) and an increase in MCM infants (p < 0.05) born in a level III hospital between 1990 and 1995. There were significant regional variations among the six perinatal regions in Ohio in the proportion of both VLBW and MCM infants born in a tertiary center. CONCLUSION: Using the traditional marker of VLBW to assess regionalization in one state, we found significant variation in site of delivery among the perinatal regions and over the time course of the study. The delivery of infants with MCM at level III centers may be an alternative measure of regionalization.

Quantitative risk assessment of lung cancer in U.S. uranium miners.

The National Institute for Occupational Safety and Health (NIOSH) has recently updated the vital status of the U.S. cohort of U miners through the end of 1982. This represents 69 additional lung cancer deaths since the last published follow-up through 1977. This more recent data was used to generate quantitative risk estimates of lung cancer after exposure to Rn daughters. Relative risks were estimated through use of the Cox proportional hazards model with an internal referent group. Results indicated that the exposure-response relationship was a slightly convex curve, predicting excess relative risks between 0.9 and 1.4 per 100 working level months (WLM) in the lower cumulative exposure range. Other findings of interest include a significant exposure-rate effect with low exposure rates more harmful per unit of cumulative exposure (WLM). Two temporal effects which modify relative risk estimates were also found. Relative risk increased with age at initial exposure to underground U mining. However, relative risk of lung cancer fell dramatically in the years following cessation of exposure.

Modifiers of lung cancer risk in uranium miners from the Colorado Plateau.

Given the scientific consensus that exposure to radon decay products causes lung cancer, most recent studies have focused on the nature of the exposure-response relationship. Since residential radon exposure is now a primary public health issue, a better understanding of the effects of low levels of radon as well as factors modifying risk estimates has become very important. Several factors are shown to affect risk estimates in the latest update of the vital status follow-up (through 1990) and smoking history for the cohort of underground uranium miners in the Colorado Plateau. This analysis confirms earlier results indicating a strong dependence of relative risk estimates upon attained age. Quantitative estimates of relative risk as a function of cumulative exposure to radon decay products (WLM) are provided for three age strata. The non-linearity often reported in the Colorado Plateau data is shown to be at least partially due to an inverse exposure-rate effect, i.e., low exposure rates for long periods are more hazardous than equivalent cumulative exposure received at higher rates for shorter periods of time. However, this effect is shown to diminish at lower exposure rates and cumulative exposures. In addition, use of the new smoking data indicates that the radon/smoking interaction is submultiplicative and may depend upon attained age.

Radon-exposed underground miners and inverse dose-rate (protraction enhancement) effects.

Recent models for radon-induced lung cancer assume that at high levels of cumulative exposure, as experienced historically by many underground miners of uranium and other ores, the risk of lung cancer follows an inverse dose-rate (protraction enhancement) pattern. That is, for equal total dose, a greater risk is incurred by those whose total dose is accumulated at a lower rate over a longer duration than at a higher rate over a shorter duration. This inverse dose-rate effect is hypothesized to be the consequence of multiple traversals of the nucleus of a target cell by alpha particles. It has recently been concluded, however, that for low total doses, as in most residential settings, the inverse dose-rate effect should diminish and perhaps even disappear, since at very low doses the probability that more than one alpha particle would traverse a cell is small and there would be no possibility for interactions from multiple hits. Pooling original data from 11 cohort studies of underground miners, including nearly 1.2 million person-y of observation and 2,701 lung cancer deaths, we evaluate the presence of an inverse dose-rate effect and its modification by total dose. An inverse dose-rate effect was confirmed in each cohort, except one, and overall in the pooled data. There also appears to be a diminution of the inverse dose-rate effect below 50 Working Level Months (WLM), although analyses were necessarily hampered by a limited range of exposure rates at low total WLM. These data support both the presence of an inverse dose-rate effect, as well as its diminution at low total dose. As a consequence, assessment of risks of radon progeny exposure in homes (on average 15-20 WLM for a lifetime) using miner-based models should not assume an ever-increasing risk per unit dose. Rather, it is more appropriate to apply risk models that take into account protraction enhancement and its diminution.

[Severe roller crush injuries of the upper extremities]. / Die schweren Walzenquetschverletzungen der oberen Extremitäten.

During the past ten years, 57 patients with severe roller-crush injuries of the upper extremities were treated. The surgical intervention, duration of therapy, vocational rehabilitation, and residual disabilities are described and results of 39 patients from this collective are presented.

[Possibilities for using the first dorsal metacarpal artery in acute management of severe hand injuries]. / Zwei Einsatzmöglichkeiten der ersten dorsalen Metakarpalarterie in der Akutversorgung schwerer Handverletzungen.

Two new indications for the first dorsal metacarpal artery are demonstrated in two cases with severe hand injuries. In the first case, an index pollicization was performed on the dorsal pedicle, in the second case a "kite" flap from the index finger was successfully microsurgically anastomosed.

[Functional results following surgical management of palmar fibrocartilagenous injuries]. / Funktionelle Ergebnisse nach operativer Versorgung von Verletzungen der Fibrocartilago palmaris.

Lesions of the palmar plate of PIP-joints were treated surgically during the past ten years in cases of dislocation of the PIP-joint, lesions to the collateral ligaments, or lesions to the extensor apparatus (according to types 3, 4 and 5 of Hintringer's classification). A followup of 97 patients showed nearly 90% good results in cases of ligamentous injuries, comparable to results after conservative treatment in other centres. In cases of fracture dislocation and open injuries, results were only fair. Conservative treatment is now preferred in most cases.

[Washington regime after-care of flexor tendon injuries in zone 2]. / Die Nachbehandlung von Beugesehnenverletzungen in Zone 2 nach dem Washington-Regime.

The Washington-regimen for the rehabilitation of flexor tendon injuries (Chow et al., 1987) represents a combination of the established Kleinert-method and the controlled passive motion of Duran and Houser. This paper presents the results of a study which was carried out in 99 patients with 113 injured fingers treated in the Department of Burns, Plastic and Hand Surgery of the Accident Hospital Ludwigshafen. 55 patients with injuries of the fingers and 29 patients with injuries of the thumb were evaluated according to functional and subjective criteria and compared to a group of 15 patients treated by the Kleinert-method. The results showed that the Washington-regimen yielded an improvement of up to 27% of very good and good results in injured fingers compared to the Kleinert-method. The improvement of results in thumb injuries was 8%. The subjective estimation of the results by the patients corresponded generally with the functional outcome. In cases with additional laceration of digital nerves, the subjective evaluation of two thirds of the patients was significantly worse than the objective functional results.

Increased suicide risk among workers following toxic metal exposure at the Paducah gaseous diffusion plant from 1952 to 2003: a cohort study.

BACKGROUND: Suicide is a problem worldwide and occupation is an important risk factor. In the last decade, 55 200 deaths in the US were attributed to occupational risk factors. OBJECTIVE: To determine if toxic metal exposure was associated with suicide risk among Paducah gaseous diffusion plant (PGDP) workers. METHODS: We assembled a cohort of 6820 nuclear industry workers employed from 1952 to 2003. A job-specific exposure matrix (JEM) was used to determine metal exposure likelihood. Uranium exposure was also assessed by urinalysis. All suicide/self-injury International Classification for Disease (ICD) codes were used to identify suicides. Standardized mortality ratios (SMR), odds ratios (OR), and hazard ratios (HR) were used to estimate suicide risk. RESULTS: PGDP suicide victims typically were younger white men. Within exposure likelihood categories, several suicide SMRs were typically elevated for several metals. Only beryllium exposure likelihood was associated with an increased HR. Uranium urine concentration was associated with an elevated suicide risk after stratification by urinalysis frequency. CONCLUSION: Suicide risk is associated with uranium exposure.

Health effects in underground uranium miners.

The health effects associated with uranium miners have received much attention in the last 30 years. Although mortality rates are elevated for such causes as accidents and nonmalignant respiratory disease, lung cancer caused by exposure to radon decay products is the primary hazard to underground uranium miners. This review summarizes studies of eight cohorts of radium miners, and examines several pooled analyses that provide the best understanding of the radon/lung cancer relationship. The relative risk of lung cancer is linearly related to cumulative exposure to radon decay products. The excess relative risk decreases with attained age and time since exposure. An inverse exposure-rate effect exists, such that prolonged exposure at low levels of radon is more hazardous than shorter exposures to higher levels. The linear no-threshold model used in most epidemiologic studies has been attacked by some as overestimating risk at indoor radon levels. These arguments are rejected by this reviewer.