Indoor radon exposure and risk of lung cancer: a nested case-control study in Finland.

BACKGROUND: Inhaled radon has been shown to cause lung cancer among underground miners exposed to very high radon concentrations, but the results regarding the effects of residential radon have been conflicting. PURPOSE: Our aim was to assess the effect of indoor radon exposure on the risk of lung cancer. METHODS: To investigate this effect, a nested case-control study was conducted in Finland. The subjects of the study were the 1973 lung cancer case patients (excluding patients with cancers of the pleura) diagnosed from January 1, 1986, until March 31, 1992, within a cohort of Finns residing in the same one-family house from January 1, 1967, or earlier, until the end of 1985 and 2885 control subjects identified from the same cohort and matched by age and sex. In September 1992, a letter was sent to all study subjects or proxy respondents explaining the purpose and methods of the study. After giving informed consent, the study participants were asked to fill out a questionnaire on smoking habits, occupational exposures, and other determinants of lung cancer risk and radon exposure. The odds ratio (OR) of lung cancer was estimated from matched and unmatched logistic regression analyses relative to indoor radon concentration assessed by use of a 12-month measurement with a passive alpha track detector. RESULTS. Five hundred seventeen case-control pairs were used in the matched analysis, and 1055 case subjects and 1544 control subjects were used in the unmatched analysis. The OR of lung cancer for indoor radon exposure obtained from matched analysis was 1.01 (95% confidence interval [CI] = 0.94-1.08) per 2.7 pCi/L (100 Bq m-3) after adjustment for the cigarette smoking status, intensity, duration, and age at commencement of smoking by subjects. For indoor radon concentrations 1.4-2.6, 2.7-5.3, 5.4-10.7, and 10.8-34.5 pCi/L (50-99, 100-199, 200-399, and 400-1277 Bq m-3, respectively), the matched ORs were 1.03 (95% CI = 0.84-1.26), 1.00 (95% CI = 0.78-1.29), 0.91 (95% CI = 0.61-1.35), and 1.15 (95% CI = 0.69-1.93), respectively, relative to the concentration below 1.4 pCi/L (0-49 Bq m-3). The unmatched analysis yielded similar results with somewhat smaller CIs. In the analyses stratified by age, sex, smoking status, or histologic type of lung cancer, no statistically significant indications of increased risk of lung cancer related to indoor radon concentration were observed for any of the subgroups. CONCLUSIONS: Our results do not indicate increased risk of lung cancer from indoor radon exposure. IMPLICATION: Indoor radon exposure does not appear to be an important cause of lung cancer.

Colposcopy in women with papillomavirus lesions of the uterine cervix.

Colposcopic examinations for human papillomavirus lesions were performed in 271 women, some of whom had developed concomitant cervical intraepithelial neoplasia since 1981. The colposcopic appearance was classified into one of the following categories: normal, punctate, mosaic, warty, leukoplakial, or combination, and was related to findings in Papanicolaou smears and punch biopsy specimens. There was a good correlation between the colposcopic appearance and the findings in the Papanicolaou smears and punch biopsy specimens, facilitating the diagnosis of the lesions. The accuracy of colposcopy in disclosing the atypias varied according to the growth pattern of the papillomavirus lesions, with the most accurate (100%) in cases of papillomatous condylomas, and the least accurate (50%) in the inverted lesions. White epithelium and combination patterns were most frequently associated with the papillomavirus lesions and cervical intraepithelial neoplasia, as evidenced by both cytology and biopsy. During the follow-up, normal colposcopic appearance increased from 32 to 50%, reflecting the established spontaneous regression of a certain percentage of the cervical lesions, or their regression as a result of biopsy. The results are discussed in terms of the mutually complementary roles of colposcopy, cytology, and biopsy, and in view of the clinical behavior of cervical papillomavirus lesions. Colposcopy is mandatory for adequate prospective follow-up of these patients but should not replace cytology and punch biopsy.

The in situ immunological reactivity and its significance in the clinical behavior of the cervical human papillomavirus lesions.

The in situ immunocompetent cell (ICC) infiltrates in 286 cervical punch biopsies derived from the women prospectively followed-up since 1981 (16 +/- 14 months, M +/- SD) for an established human papillomavirus (HPV) infection with or without coexistent cervical intraepithelial neoplasia (CIN) were characterized using the histochemical ANAE (acid alpha-naphthyl acetate esterase) staining. Only minor fluctuations in the relative proportions of ANAE T+, ANAE M+, and ANAE- cells were found between the three types of HPV lesions (flat, inverted and papillomatous condylomas), as well as between the lesions with varying degree of HPV-CIN. The percentage of ANAE- cells (mediators of humoral immune response) increases in parallel with the increasing density of the ICC infiltrate. The intensity of the local infiltrate was inversely correlated with the progression, but not with regression or persistence of the HPV lesions. The percentage of ANAE T+ cells was highest in the 32 (18.7%) HPV lesions progressed during the follow up, almost identical in the 88 (51.5%) persistent lesions and lowest in those 51 (29.8%) lesions showing clinical regression. The results are discussed in terms of the proposed immune surveillance functions attributed to the local ICCs according to the MALT (mucosal-associated lymphatic tissue) concept. Conclusion is drawn that no major imbalance in the ANAE- definable main populations of ICCs exist in the cervical HPV lesions, which readily could explain their divergent clinical behavior. Other factors (like HPV type, synergistic action of cocarcinogens or a deranged balance between the ICC subsets) should be searched for to elucidate this issue.

Electron microscopy in assessment of the biological behavior of human papillomavirus infections in the uterine cervix.

To asses the natural history of human papillomavirus (HPV) infections in uterine cervix, currently implicated in etiology of cervical cancer, a prospective follow-up study has been conducted for 418 women at our clinic since 1981. The present communication summarized the current follow-up data of these patients, with special emphasis on detection of the virus in cervical punch biopsies, as correlated with other characteristics pertinent to the clinical behavior of cervical HPV infections. On each attendance, the patients are subjected to colposcopy accompanied either by Papanicolaou (PAP) smears or punch biopsies. The latter are analyzed for the cytopathic changes of HPV, for concomitant cervical intraepithelial neoplasia (CIN), for HPV structural proteins with IP-PAP technique as well as on transmission electron microscopy (TEM) for the presence of HPV particles. The local immunocompetent cell (ICC) infiltrates are analyzed using ANAE technique to define B cells, MPS cells and T cells and monoclonal antibodies (McAb) for T cell subsets, NK (natural killer) cells and Langerhans cells. HPV particles were disclosed with equal frequency (approx. 65%) in all three types of HPV lesions. Surprisingly, HPV particles were present in 70% of the biopsies derived from the regressed lesions (e. g. in those without histological evidence of HPV lesions), suggesting a possibility of a latent HPV infection. Presence of viral particles did not bear any direct correlations with the expression of HPV antigens, intensity or cellular composition of the ICC infiltrate, defined by ANAE or using McAb. Presence of HPV particles was not a major prognostic determinant, whereas the clinical course was most significantly influenced by the grade of HPV-associated CIN, to which regression was inversely and progression directly related. The results clearly confirm that cervical HPV infections are capable of progressing into carcinoma in situ and thus present with a natural history equivalent to that of classical CIN.

Lymphocyte beta 2-adrenoceptor density during menstrual cycle and pregnancy, in delivery and puerperium.

Lymphocyte beta 2-adrenoceptor density was determined in 11 women during the normal menstrual cycle and 15 women during normal pregnancy. No significant difference in lymphocyte beta 2-adrenoceptor density was established in this follow-up study during the menstrual cycle or pregnancy. Lower lymphocyte beta 2-adrenoceptor density was established just after delivery and in puerperium compared with that during pregnancy. It is likely that the high catecholamine concentration during parturition together with the duration of labour and delivery caused down-regulation of the beta 2-adrenoceptors. In puerperium the irregular day-rhythm and the stress of caring for the newborn may also have an effect.

Thyroid function during treatment with a new oral contraceptive combination containing desogestrel.

The present study was carried out to assess the effect of an oral contraceptive combination containing 0.075 mg desogestrel (Org 2969, 17 alpha-ethinyl-18-methyl-11-methylene-4-estren-17-ol) plus 0.050 mg ethinyloestradiol on thyroid function in healthy women. All 15 volunteers participated for three cycles; in each cycle they took 1 tablet daily for 21 consecutive days, followed by a 17-day tablet-free period. In total, 'treatment' lasted 3 months. After 3 months treatment serum thyroxine significantly increased (+ 43.9%), as did free thyroxine index (+ 20.0%) and thyroxine-binding globulin (+ 101%). Serum triiodothyronine uptake to Sephadex decreased (- 17.3%), corresponding to the decrease in thyroxine/thyroxine-binding globulin ratio (- 23.8%). Serum triiodothyronine and thyrotropin (TSH) concentrations did not change. After treatment had stopped, all values rapidly returned to initial levels. As a more specific parameter of thyroid function, serum free thyroxine concentration was measured. During treatment a slight decrease of - 125% (which was within normal limits) was observed. Moreover, the pituitary response to TSH-releasing hormone (TRH) was not changed. Thus, treatment with desogestrel plus ethinyloestradiol in the present combination did not alter thyroid function.

Serum lipids and proteins during treatment with a new oral contraceptive combination containing desogestrel.

The present study was carried out to measure lipid and protein levels in serum of healthy women during treatment with a new oral contraceptive combination containing 0.075 mg desogestrel (Org 2969, 17 alpha-ethinyl-18-methyl-11-methylene-4-estren-17-ol) plus 0.050 mg ethinyloestradiol per tablet. All 30 volunteers took 1 tablet daily for 21 consecutive days, followed by a tablet-free period of 7 days. Treatment lasted 3 months. At the end of treatment serum total cholesterol had increased by 0.26 mmol/l (5.0%), high-density lipoprotein-cholesterol by 0.22 mmol/l (15.2%) and triglycerides by 0.43 mmol/l (50%); the calculated low-density lipoprotein cholesterol had decreased by 0.16 mmol/l (4.9%). All lipid concentrations had returned to initial levels 2 months after treatment stopped. After 3 months treatment serum ceruloplasmin, cortisol-binding globulin capacity, sex-hormone-binding globulin capacity and thyroxine-binding globulin had significantly increased by 85.2, 133, 206 and 101%, respectively. All protein levels returned to normal 2 months after treatment stopped. The relationship between serum lipids and hormone-binding proteins has been discussed, as well as the significance of the high-density lipoprotein level with regard to contraceptive treatment.

Studies of high indoor radon areas in Finland.

Solid state nuclear track detectors were used in a regional survey of radon in indoor air. The study area comprises seven rural municipalities and two towns in an area of 80 X 50 km2 with a population of about 65,000. Measurements were made in 754 houses in 31 subareas. The highest and lowest subarea means were 1,200 Bq/m3 and 95 Bq/m3, respectively. The estimated mean for the whole area was 370 Bq/m3. The concentrations 2,000 Bq/m3 and 800 Bq/m3 were exceeded in 32 and 90 houses, respectively. The present lung cancer incidence does not differ significantly from the national mean.

Ritodrine hydrochloride induced cardiopulmonary and placental hemodynamic changes in normal and hypertensive late pregnancy.

Cardiopulmonary parameters (minute volume, heart rate, stroke volume, right heart, pulmonary and left heart blood volumes), blood pressure and placental blood flow were evaluated in 20 normal patients, nine patients with preeclamptic disease and 12 with essential hypertension in late pregnancy before and 60 minutes after a single i.m. dose of 10 mg of ritodrine hydrochloride. The drug caused a statistically significant increase in heart rate in all the patient groups, while the systolic and diastolic blood pressures were only slightly affected. Minute volume was unchanged in the group of normal patients, but in both hypertensive groups there was a significant increase. The placental perfusion index was statistically nearly significantly decreased in the group of uncomplicated pregnancies, statistically significantly increased in preeclamptic patients, and not affected in the group with essential hypertension. Ritodrine hydrochloride medication can be expected to have a positive effect on placental blood flow only in preeclamptic disease, and then probably in the milder forms of the disease.

Verrucous squamous cell carcinoma of the female genital tract. Report of three cases and survey of the literature.

Three new cases of gynecological verrucous squamous cell carcinomas are reported; one in the uterine cervix, and two in the vulva. The English literature covering the 49 cases reported previously is surveyed with special reference to the diagnostic and therapeutic aspects of these tumors, as well as with their clinical behavior and possible relationship to viral (HPV) lesions (Condylomas) of the genital tract. It was concluded that so far the exact relationship between the different verrucous squamous cell lesions in the genital tract remains obscure, all such lesions should be regarded as potentially malignant, and treated accordingly by radical surgery.

Langerhans cells in human papillomavirus (HPV) lesions of the uterine cervix identified by the monoclonal antibody OKT-6.

The local inflammatory cell infiltrates in 263 cervical punch biopsies of the women followed-up since 1981 (16 +/- 14 months, mean +/- S.D.) for an established human papillomavirus (HPV) lesion with or without concomitant cervical intraepithelial neoplasia (CIN) were analysed for occurrence of Langerhans cells, defined by the monoclonal antibody OKT-6 using the avidin-biotin peroxidase complex (ABC) technique. OKT-6+ cells remained at the constant low level (1.5-1.9% of the inflammatory cells) in the different types of HPV lesions (flat, inverted or papillomatous condylomas), their percentages (range 0.8-2.1% of the cells) being slightly affected by the grade of HPV-associated CIN, however, (P less than 0.05 between HPV-CIN I and HPV-CIS). Although cervical HPV lesions characteristically are a disease of young females, the relative levels of in situ Langerhans cells did not show any age-dependence. Furthermore, the intensity of the inflammatory cell infiltrate did not correlate with the relative levels of OKT-6+ cells in the biopsies. Practically identical (1.6%) levels of OKT-6+ cells were found in the first biopsies of the HPV lesions shown to regress during the follow-up period (28.8% of cases), when compared with those (1.7%) in the lesions persisted (52.1% of cases) or progressed (19.1% of lesions). The results are discussed in terms of the proposed immune surveillance function against viral infections, attributed to Langerhans cells in the SALT/MALT concept.(ABSTRACT TRUNCATED AT 250 WORDS)

Morphological and immunohistochemical evidence of human papilloma virus (HPV) involvement in the dysplastic lesions of the uterine cervix.

A series of 110 biopsies of the uterine cervix containing dysplastic and/or in situ changes were assessed morphologiccally with reference to presence or absence of the coexistent condylomatous lesions, and using the immunoperoxidase-PAP technique to disclose the HPV (human papilloma virus) antigens in the cells. Morphologically, 79 biopsies contained condylomatous (CO) lesions (63 flat, 12 inverted and 4 papillomatous ones), and 31 were non-condylomatous (NCO) dysplasias/in situ carcinomas. The mean age of the CO group was more than 10 years less than that of NCO women (P less than 0.0001). Of the papillomatous COs, 75% were associated with mild or moderate dysplasia only, whereas 42% of the inverted ones contained an associated in situ carcinoma. Most of the flat lesions were found in very young women (10-39 years of age). HPV antigens were demonstrated in all papillomatous lesions (100%), in 83% of the inverted ones, and in 67% of the flat COs. In generally, the frequency of the HPV-positive cases decreased when epithelial atypia increased. None of the NCO lesions showed HPV positive cells. The results support earlier morphological findings on the frequent association of cervical condylomas and epithelial dysplasias, as well as those on the HPV as the etiologic agent of the former. The role of HPV as a possible etiologic agent of the cervical squamous cell neoplasia deserves further attention.

Cervical smears in assessment of the natural history of human papillomavirus infections in prospectively followed women.

The value of cervical (Papanicolaou) smears in monitoring the natural history of cervical human papillomavirus (HPV) infections was assessed in a series of 513 women prospectively followed since 1981. On each clinic visit, the patients were subjected to colposcopy accompanied by cervical smears and/or punch biopsies. The latter were analyzed by light microscopy for concomitant cervical intraepithelial neoplasia (CIN) and by transmission electron microscopy (TEM) for HPV particles as well as for HPV structural proteins. The stromal immunocompetent cell (ICC) infiltrates were phenotypically characterized using monoclonal antibodies for T-cell subsets, NK and K cells and Langerhans cells. HPV DNA typing was accomplished by Southern blot, spot and in situ hybridization using probes for HPV 6, 11, 16, 18 and 31. Lesions showing only changes consistent with HPV infection (HPV-NCIN) were associated with less severe atypia in cervical smears than were lesions with coexistent CIN (HPV-CIN). Normal smears were observed, however, in 24.7% of the cases with HPV-NCIN lesions, in 11.5% of cases with HPV-CIN I lesions but only exceptionally in cases with HPV-CIN II and III lesions (2.2% and 3.3%). The percentages of the different ICC phenotypes did not correlate with the atypia in cervical smears, but there was a shift towards the lower values of the T-helper/T-suppressor (OKT4+/OKT8+) cell ratio in parallel with increasing atypia. The possibility of latent HPV infection was suggested by the detection of viral particles, HPV antigens and HPV DNA in lesions shedding normal cells in the smears. The high-risk HPV types 16 and 18 were associated with the highest frequency of severely atypical cells; in the majority of cases, the low-risk types HPV 6 and 11 presented with less severe atypia. The first cervical smear seems to be of value as a predictor of the natural history of HPV lesions, as indicated by the fact that regression was inversely and progression directly related to initial cellular atypia. The present results confirm the intimate association between HPV infections and CIN. Although the biologic potential of the HPV infections seems to be dependent on multiple factors, routine cervical smears, because of their potential value in monitoring the natural history of this infection, should constitute an important means in the prospective follow-up of these patients.

Human papillomavirus (HPV) infections involved in the neoplastic process of the uterine cervix as established by prospective follow-up of 513 women for two years.

A total of 513 women with cervical HPV infections have been followed-up since 1981 (mean 25.6 months) to establish the biological potential of HPV in cervical carcinogenesis. On each attendance, the patients were subjected to colposcopy accompanied by Papanicolaou (PAP) smears and/or punch biopsies. The latter were analysed for HPV particles on TEM, for the cytopathic changes of HPV, as well as for HPV structural proteins. The local immunocompetent cell (ICC) infiltrates are enumerated using ANAE-technique to define B-, MPS- and T cells, and monoclonal antibodies for T cell subsets, NK and K cells and Langerhans cells. HPV DNA typing was accomplished by Southern blot and spot hybridization using the DNA probes for HPV 6, 11, 16 and 18. Antibody titres for HSV were measured, and Chlamydia trachomatis isolations completed in cervical swabs. No correlation with the clinical course, e.g. regression (RE), persistence (PE), progression (PR) or recurrence (RC) of the HPV lesions could be established for the following factors; expression of HPV antigens, presence of HPV particles on TEM, Chlamydia in cervical swabs, the levels of HSV antibodies, and the levels of the ICCs. The OKT4+/OKT8+ cell ratio, however, was inversely correlated with PR, being most markedly reduced in recurrent lesions. Of the 513 lesions, 24.8% regressed, 59.8% remained persistent, and 14.1% progressed, 11.9% having been coned due to progression into CIS. So far, 1.1% of lesions have recurred after such a treatment. The progression rate was highest (45.5%) in HPV 16 lesions, followed by that (27.3%) in HPV 18 lesions, as contrasted to 0% and 13.3% for HPV 6 and 11, respectively. The results clearly confirm that cervical HPV infections are capable of progressing into CIS and thus show a natural history equivalent to that of classical CIN. The inherent potential of HPV 16 and HPV 18 lesions for clinical progression was clearly established, supporting the concept on HPV 16 and HPV 18 as the high risk HPV types in cervical carcinogenesis.

Implications of a two-stage clonal expansion model to indoor radon risk assessment.

Spreadsheet macro programs for calculations of exact hazard and probability of having contracted cancer were used to study the implications of the lung cancer model of Moolgavkar et al. Excess lifetime risk ELR and loss of life expectancy LLE were calculated from the annual values of hazard and probability, using published life tables. The influence of various factors on ELR and LLE was studied, as well as the lifetime risk projection in epidemiological studies. At indoor concentrations, ELR and LLE are coarsely proportional to lifetime exposure. The main factors determining the proportionality coefficient are 1. Smoking status, 2. General life expectancy, 3. Exposure schedule, and 4. Sex. For constant domestic exposure, the sex is less important, because the longer life of women is compensated by the lower hazard. ELR and LLE for a population with 30% smokers and life expectancies of 72.1 y and 79.5 y for men and women, respectively, are 56 per million per WLM and 860 y per million per WLM, respectively. For an exposure schedule with one high radon period, the mean age during the period becomes important, and the age-specific values for men and women differ from each other. Furthermore, the model predicts that case-control epidemiological studies overestimate the lifetime risk by an amount which may arise to several tens of percent.

Treatment of imminent premature labour.

In this study, 194 imminent premature deliveries were treated. The pregnancies were in the 28th to 36th week. Uterine contractions were demonstrable in all patients and amniotic membranes were intact. All patients were treated with bedrest. Two betasympathomimetics were used in a double-blind study: Nyldrin hydrochloride (43 cases) and Isoxuprine hydrochloride (60 cases). A placebo was given to 41 patients, and ethyl alcohol to 50 patients. Intravenous and intramuscular treatment given in the hospital was continued with oral administration at home, and follow-up examinations were repeated at short intervals. Taking a minimum birth weight of 2500 g as the criteria of successful treatment, the success rate in the placebo group was 71%, in the Nylidrin hydrochloride group 86%, the Isoxuprine hydrochloride group 75% and the alcohol group 70%. When premature delivery was postponed 7 days, the pregnancy advanced., to the 37th week or later in 73, 77, 62 and 56% in their respective groups. The beta-sympathomimetics, especially the Nylidrin hydrochloride, were in every respect more efficient than placebo or alcohol. The therapeutic effect of alcohol was no better than that obtained with placebo. From the fetal point of view, the drugs used in the present study showed no adverse-effects.