Alpha-Tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance.

BACKGROUND: Experimental and epidemiologic investigations suggest that alpha-tocopherol (the most prevalent chemical form of vitamin E found in vegetable oils, seeds, grains, nuts, and other foods) and beta-carotene (a plant pigment and major precursor of vitamin A found in many yellow, orange, and dark-green, leafy vegetables and some fruit) might reduce the risk of cancer, particularly lung cancer. The initial findings of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study) indicated, however, that lung cancer incidence was increased among participants who received beta-carotene as a supplement. Similar results were recently reported by the Beta-Carotene and Retinol Efficacy Trial (CARET), which tested a combination of beta-carotene and vitamin A. PURPOSE: We examined the effects of alpha-tocopherol and beta-carotene supplementation on the incidence of lung cancer across subgroups of participants in the ATBC Study defined by base-line characteristics (e.g., age, number of cigarettes smoked, dietary or serum vitamin status, and alcohol consumption), by study compliance, and in relation to clinical factors, such as disease stage and histologic type. Our primary purpose was to determine whether the pattern of intervention effects across subgroups could facilitate further interpretation of the main ATBC Study results and shed light on potential mechanisms of action and relevance to other populations. METHODS: A total of 29,133 men aged 50-69 years who smoked five or more cigarettes daily were randomly assigned to receive alpha-tocopherol (50 mg), beta-carotene (20 mg), alpha-tocopherol and beta-carotene, or a placebo daily for 5-8 years (median, 6.1 years). Data regarding smoking and other risk factors for lung cancer and dietary factors were obtained at study entry, along with measurements of serum levels of alpha-tocopherol and beta-carotene. Incident cases of lung cancer (n = 894) were identified through the Finnish Cancer Registry and death certificates. Each lung cancer diagnosis was independently confirmed, and histology or cytology was available for 94% of the cases. Intervention effects were evaluated by use of survival analysis and proportional hazards models. All P values were derived from two-sided statistical tests. RESULTS: No overall effect was observed for lung cancer from alpha-tocopherol supplementation (relative risk [RR] = 0.99; 95% confidence interval [CI] = 0.87-1.13; P = .86, logrank test). beta-Carotene supplementation was associated with increased lung cancer risk (RR = 1.16; 95% CI = 1.02-1.33; P = .02, logrank test). The beta-carotene effect appeared stronger, but not substantially different, in participants who smoked at least 20 cigarettes daily (RR = 1.25; 95% CI = 1.07-1.46) compared with those who smoked five to 19 cigarettes daily (RR = 0.97; 95% CI = 0.76-1.23) and in those with a higher alcohol intake (> or = 11 g of ethanol/day [just under one drink per day]; RR = 1.35; 95% CI = 1.01-1.81) compared with those with a lower intake (RR = 1.03; 95% CI = 0.85-1.24). CONCLUSIONS: Supplementation with alpha-tocopherol or beta-carotene does not prevent lung cancer in older men who smoke. beta-Carotene supplementation at pharmacologic levels may modestly increase lung cancer incidence in cigarette smokers, and this effect may be associated with heavier smoking and higher alcohol intake. IMPLICATIONS: While the most direct way to reduce lung cancer risk is not to smoke tobacco, smokers should avoid high-dose beta-carotene supplementation.

Inhaled beclomethasone decreases serum osteocalcin in postmenopausal asthmatic women.

There are very few data as yet to quantify the effect of inhaled corticosteroids on bone metabolism, although the use of these drugs as a first-line treatment in bronchial asthma has widened. We determined the effect of three dose levels (200, 1000, 2000 micrograms/day, three weeks each) of inhaled beclomethasone on specific characteristics of bone metabolism in nine postmenopausal women with new asthma without any previous corticosteroid therapy. Significant decrease was noted in the mean serum morning osteocalcin concentration between the baseline and after nine weeks of beclomethasone (from 4.4 to 3.1 micrograms/l, p = 0.005). Significant increase in serum total and ionised calcium was found, although the parameters measuring bone resorption itself did not change. The results show that especially high-dose inhaled beclomethasone decreases serum osteocalcin in post-menopausal asthmatic women. Further studies are needed to assess the effects of inhaled beclomethasone, both on the ability of the osteoblasts to form bone matrix and on the density of bone during a longer treatment period on inhaled corticosteroids.

Bone mineral density in asthmatic women on high-dose inhaled beclomethasone dipropionate.

Inhaled corticosteroids are the cornerstone of the modern therapy for asthma. In recent years, inhaled corticosteroids have been used in higher doses than previously. This has caused concern about possible osteoporotic side-effects. We studied bone mineral densities (BMDs) in 19 non-smoking women (mean age 53 years, range 40-63) with newly diagnosed bronchial asthma and 19 voluntary healthy non-smoking women (mean age 53 years, range 43-67). In both groups, 13 subjects were postmenopausal. Patients started beclomethasone dipropionate from the spacer 500 micrograms twice daily as the sole corticosteroid therapy. BMDs were measured with dual-energy x-ray absorptiometry (DEXA) at the lumbar spine (L2-4) and at the left proximal femur (the neck, Ward's triangle and the trochanteric region). The measurements were made at baseline and 6 and 12 months thereafter. No significant changes were observed in the measured BMDs in either study group. The results show that inhaled beclomethasone dipropionate therapy 1000 micrograms/day for one year does not affect BMD. Further studies are needed to assess the effects of inhaled corticosteroid on BMD during a longer treatment period.

Clodronate is effective in preventing corticosteroid-induced bone loss among asthmatic patients.

Clodronate is a novel drug used for inhibiting osteoclastic activity. The aim of the present double-blind study was to evaluate the efficacy and tolerability of clodronate (Leiras, Finland) in corticosteroid-induced bone loss among asthmatic patients. Seventy-four adult patients (41 women and 33 men, mean age 57.3 years) having a long history (mean 8.1 years) of oral and inhaled corticosteroid therapy were randomized to four parallel treatment groups: clodronate 800, 1600, or 2400 mg/day, or an identical placebo. The bone mineral density (BMD) of the lumbar spine (L2-4), femoral neck, and trochanter were assessed using dual-energy X-ray absortiometry at entry, 6 months, and 12 months. The baseline BMDs did not differ significantly between the study groups. In the lumbar spine, the mean BMD increased significantly between the baseline and 12-month visit in the clodronate groups of 1600 and 2400 mg/day, 2.6% (0.02 g/cm2, p < 0.02) and 3.0% (0.03 g/cm2, p < 0.01), respectively, but not in the placebo and clodronate 800 mg/day groups. The test for a linear trend (BMD percent change for L2-4) at 12 months was significant (p < 0.02), indicating a dose response to clodronate. The mean BMD values of the femoral neck increased significantly in the 2400 mg/day group, 4.3% (0.03 g/cm2, p < 0.0001), as well as in the trochanter region 2.8% (0.02 g/cm2, p < 0.02). Gastric irritation was the most common adverse effect noted on a clodronate dose of 2400 mg/day. We conclude that oral clodronate is effective in preventing bone loss or increasing bone mass in asthmatic patients having a long history of continuous peroral and inhaled corticosteroid administration.

Prevalence of asthma in elderly Finns.

There is uncertainty about the prevalence of asthma even in countries in which extensive epidemiological surveys have been carried out and attention has been drawn to a probable increase in prevalence. A cross-sectional epidemiological survey of asthma in the population aged 64 years or over was carried out in the rural district of Lieto, Finland. All 1196 participants (488 men and 708 women, 93% of those eligible) were examined and individually assessed using a set of criteria for asthma. The prevalence of current asthma was 2.9% in the men and 3.8% in the women and it accounted for about 40% of the cumulative (life-time) prevalence of self-reported asthma. Current asthma was uncommon in men aged 75 years or over and no cases were found in men who smoked. Current asthma in women was associated with low social status, smoking and dusty working conditions in the past. The difference in prevalence between the men and women was greatest among the smokers, which may be due to a previous high mortality among elderly asthmatic men who had been smoking, or a lack of the typical characteristics of asthma in men with long histories of smoking. The prevalence of asthma was similar to that obtained earlier in Finland and elsewhere.

Periodic breathing imitating hyperventilation syndrome.

We report a male patient who developed an unusual periodic breathing. At presentation, the differential diagnosis at bedside between Cheyne-Stokes and primary hyperventilation syndrome was laborious, and the final verification was based on the result of capnography.

Pros and cons of BCG vaccination in countries with low incidence of tuberculosis.

Preventive bacille Calmette-Guérin (BCG) vaccination, together with case finding and effective chemotherapy, has formed an integral part of the tuberculosis (TB) control program in most countries. In some low-incidence countries the balance of prevention has been more on the side of chemoprophylaxis than of BCG vaccination. The time clearly has come when the strategy of mass BCG vaccination no longer is indicated medically, nor is it cost-effective. The pros and cons of the programs need to be critically evaluated against the present epidemiological background, taking into account the facts that TB, the killer disease, is recovering strength, human immunodeficiency virus infection is on the increase, and multidrug-resistant TB has changed the outcome of this previously fully curable disease. Although no longer appropriate for mass programs, BCG vaccination still should be considered for the protection of selected risk groups in low-incidence countries. The overall efficacy may be of the order 50% to 80%, but the variation is great. Therefore, further research urgently is needed on the effectiveness of BCG as an intervention in local TB programs.

Is the risk of occupational tuberculosis higher for young health care workers?

SETTING: Health care workers in Finland. OBJECTIVE: Occupational tuberculosis (TB) was studied separately in nurses, assistant nurses, physicians, psychiatric nurses, medical laboratory workers and radiographers during the period 1971-1995. DESIGN: All 447 notified cases between 20 and 59 years of age were included. Incidence ratios by age and occupation were compared to the corresponding general population. RESULTS: A common profile, with a higher rate of TB towards older age, was seen in the general population but not among health care workers. Among nurses, assistant nurses and physicians, the incidence ratio was higher among those aged 20-39 than among those aged 40-59 years. Compared to the controls, the risk of TB was significantly smaller in the older group of nurses during 1971-1990 and in assistant nurses during 1971-1995. The risk among the older group of physicians was significantly lower during 1971-1980, and among the younger group it was significantly higher during 1976-1990. CONCLUSIONS: We speculate that in certain fields of health care, young workers are at the greatest risk of TB.

A cost-effectiveness analysis of universal versus selective immunization with Mycobacterium bovis bacille Calmette-Guérin in Finland.

SETTING: Mycobacterium bovis bacille Calmette-Guerin (BCG) is provided to all infants born in Finland. OBJECTIVE: To analyze the cost-effectiveness of universal versus selective BCG immunization. DESIGN: A Markov model was developed to simulate rates of tuberculosis (TB) and non-tuberculous mycobacterial disease (NTM), and to examine the cost-effectiveness in terms of cost per case averted of three different strategies: universal BCG, selective BCG (10% of infants at higher TB risk than other infants) or no BCG immunization. RESULTS: In a cohort of 60,000 infants over 15 years, the model predicts five cases each of TB and NTM disease with universal immunization, 8-21 TB and 31 NTM cases with various strategies of selective immunization, and 25 TB and 34 NTM cases with no BCG immunization. BCG side-effects are predicted in 5, 0.5 and 0 infants, respectively. The cost per case averted for immunization strategies ranges from a cost of 38,311 US dollars to a savings of 323 dollars as selective immunization becomes more efficient at targeting infants at highest risk of TB. CONCLUSIONS: In a country with a low incidence of pediatric tuberculosis, selective BCG immunization is a more cost-effective strategy than universal BCG immunization for the prevention of tuberculosis, but results in an increase in NTM cases.

Prevalence of chronic obstructive pulmonary disease in elderly Finns.

The prevalence of chronic obstructive pulmonary disease (COPD) in the elderly is poorly known. The aim of this study was to determine the prevalence of COPD and to analyse the factors associated with it in an elderly Finnish population. The population consisted of persons resident in Lieto, Finland, born in or before 1926. One thousand one hundred and ninety-six individuals (488 men and 708 women, 93% of those eligible) participated in the survey, which was carried out in 1990-91 at the Lieto Health Centre. The methods included a nurse's interview and spirometry with a bronchodilator test. The participants were also clinically examined, and the number of subjects with COPD was determined using simple diagnostic criteria. Sixty-one men and 21 women with COPD were found. Thus the prevalence was 12.5% for the men and 3.0% for the women. In both sexes only about 2% of those who had never smoked suffered from COPD, but among the current smokers the prevalence was 35% for the men and 13% for the women. In a stratified analysis COPD was commonest among those with a low social status and histories of smoking and working in dusty occupations. In a majority the obstruction was only minimally reversible when tested with salbutamol inhalation. The study confirmed that the prevalence of COPD in the elderly with negative histories of smoking is low, and emphasizes the importance of reducing smoking as the only effective preventive measure.

A comparative study of dirithromycin and erythromycin in bacterial pneumonia.

Dirithromycin, a new once-daily macrolide, was studied in a multicentre, randomised, double-blind trial in community-acquired bacterial pneumonia. A total of 591 patients received either a single daily dose of dirithromycin, 500 mg, or erythromycin, 250 mg, four times daily. Clinical response rates were similar in both treatment groups (127 dirithromycin-treated and 118 erythromycin-treated patients): at the time of the final consultation, the clinical and bacteriological response rates for dirithromycin-treated patients were 94.5% and 93.0%, while for erythromycin-treated patients, they were 92.1% and 90.3%, respectively. The nature and frequency of treatment-emergent events were comparable. We conclude that dirithromycin, 500 mg, once daily, is safe and effective in the treatment of community-acquired bacterial pneumonia. The once daily dose is likely to improve compliance, making it preferable to erythromycin.