Sensitivity and specificity of mammographic screening as practised in Vermont and Norway.

OBJECTIVE: The aim of this study was to examine the sensitivity and specificity of screening mammography as performed in Vermont, USA, and Norway. METHODS: Incident screening data from 1997 to 2003 for female patients aged 50-69 years from the Vermont Breast Cancer Surveillance System (116 996 subsequent screening examinations) and the Norwegian Breast Cancer Screening Program (360 872 subsequent screening examinations) were compared. Sensitivity and specificity estimates for the initial (based on screening mammogram only) and final (screening mammogram plus any further diagnostic imaging) interpretations were directly adjusted for age using 5-year age intervals for the combined Vermont and Norway population, and computed for 1 and 2 years of follow-up, which ended at the time of the next screening mammogram. RESULTS: For the 1-year follow-up, sensitivities for initial assessments were 82.0%, 88.2% and 92.5% for 1-, 2- and >2-year screening intervals, respectively, in Vermont (p=0.022). For final assessments, the values were 73.6%, 83.3% and 81.2% (p=0.047), respectively. For Norway, sensitivities for initial assessments were 91.0% and 91.3% (p=0.529) for 2- and >2-year intervals, and 90.7% and 91.3%, respectively, for final assessments (p=0.630). Specificity was lower in Vermont than in Norway for each screening interval and for all screening intervals combined, for both initial (90.6% vs 97.8% for all intervals; p<0.001) and final (98.8% vs 99.5% for all intervals; p<0.001) assessments. CONCLUSION: Our study showed higher sensitivity and specificity in a biennial screening programme with an independent double reading than in a predominantly annual screening program with a single reading. ADVANCES IN KNOWLEDGE: This study demonstrates that higher recall rates and lower specificity are not always associated with higher sensitivity of screening mammography. Differences in the screening processes in Norway and Vermont suggest potential areas for improvement in the latter.

Vermont granite mortality study: an update with an emphasis on lung cancer.

This mortality study extends the period of observation of an article published in 1988 of 5414 workers in Vermont granite sheds and quarries to assess whether previously reported reductions in silicosis and tuberculosis mortality were maintained. The relationship between lung cancer and quartz exposure is also examined by comparing mortality in workers hired before and after 1940, when dust controls were introduced and exposures were reduced by 80% to 90%. Before 1940, general stone shed air contained 20 million particles/cubic foot (mppcf) (approximately equivalent to 0.2 mg/m of quartz), and pneumatic chisel workers were exposed on average to 60 mppcf (approximately equivalent to 0.6 mg/m of quartz). Other workers had variable exposures. After 1940, a period of decline occurred in dust levels and then stabilized in approximately 1955, when average dust levels were 5 to 6 mppcf (equivalent to 0.05-.06 mg/m of quartz). Dust exposures in the Vermont industry is considered to be free of confounding occupational substances such as arsenic, although cigarette smoking was common. By the end of 1996, 2539 workers, or 46.9% of the cohort, had died. There were no silicosis deaths in workers hired after 1940 who were exposed only in the Vermont granite industry, illustrating the effect of lowering quartz exposures. Tuberculosis caused 2 deaths in those hired after 1940 (standardized mortality ratio [SMR] = 0.52; not significant). Overall lung cancer mortality was elevated in shed workers who had been exposed both to high levels of quartz before 1940 and to the lower levels prevailing after 1940 (SMR = 1.32; P < 0.01). Quarry workers did not show an excess of lung cancer (SMR = 0.73; not significant). When shed workers with high and low exposure histories (before and after 1940) but with comparable latency and tenure were contrasted, lung cancer mortality was similar. Differing levels of quartz exposure, which resulted in large differences in the mortality experience from silicosis, did not result in differences in lung cancer mortality. The results do not support the hypothesis that granite dust exposure has a causal association with lung cancer.

Factors associated with arm swelling after breast cancer surgery.

PURPOSE: As life expectancy improves for women with breast cancer, more women will be living with symptoms of lymphedema. This study reports the incidence of arm or hand swelling and associated risk factors in women with invasive breast cancer following surgery. METHODS: Data were obtained from baseline and follow-up interviews of women with invasive breast cancer (n = 145), and mammography and pathology records. The Kaplan-Meier method was used to estimate the probability of developing arm or hand swelling over time. Univariate and multivariate logistic regression analyses were conducted to identify risk factors for arm or hand swelling. RESULTS: Of women in this study, 38% self-reported arm or hand swelling. There was a significantly increased risk of arm swelling if women were under 50 years of age, had axillary node dissection, received chemotherapy, worked outside the home, and had a high household income. There was no association of body weight with swelling. A significantly decreased risk of arm swelling was found in women who were on treatment for high blood pressure. After adjustment for nodal dissection, only age had a significant independent effect. CONCLUSIONS: Our study highlights two important areas of future research that could reduce the incidence of lymphedema. There is a need to better understand the role that treatment for high blood pressure may play in protecting women from arm edema. Second, the potential effect of weight as a modifiable lymphedema risk factor needs to be studied in more detail in light of the conflicting results of different studies.

High-risk human papillomavirus type does not predict grade of cervical intraepithelial neoplasia.

PURPOSE OF INVESTIGATION: The aim of this study was to examine whether HPV testing specificity for cervical intraepithelial neoplasia (CIN) grades 2 or 3 could be improved by restricting the range of HPV types classified as 'high-risk'. METHODS: DNA was extracted from 28 CIN I, nine CIN II and 13 CIN III formalin-fixed, paraffin-embedded biopsies. HPV type was determined by General Primer mediated 5+/6+ PCR assay. RESULTS: The prevalence of specific HPV types among the different grades of CIN and the relationship to the referral smear diagnosis was examined. HPV type-16 alone was more highly associated with CIN grade (p < 0.0001; Specificity = 0.93; Sensitivity = 0.68) than was the group of HPV types collectively classed as high-risk (p = 0.025; Specificity = 0.23; Sensitivity = 1.00). CONCLUSIONS: These data suggest HPV testing specificity could be improved simply by including a separate test for HPV-16. In conjunction with previous studies, the data also suggests redefinition of the high-risk HPV category to take into account the differing degrees of oncogenicity of high-risk HPV types.

Biomarkers for assessing occupational exposures to 1,3-butadiene.

The overall objective of this study was to evaluate a continuum of biomarkers in blood and urine for their sensitivities as indicators of low level occupational exposures to 1,3 butadiene (BD). The study design was largely cross-sectional, with biological samples collected within a short timeframe. Personal 8-h BD exposure measures were made on several occasions over a 60-day period for each potentially exposed worker in order provide maximum accuracy for this independent variable and to accommodate the different expression intervals of the several biomarkers. Co-exposures to styrene, toluene and benzene were also measured. The study included 24 BD monomer production workers (mean BD exposure=0.642 mg/m(3)), 34 polymerization workers (mean BD exposure=1.794 mg/m(3)) and 25 controls (mean BD exposure=0.023 mg/m(3)). The several biomarkers were measured by a consortium of investigators at different locations in the US and Europe. These biomarkers included: (1) metabolic genotypes (CYP2E1, EH, GST M1, GST T1, ADH2, ADH3), determined in Prague and Burlington, VT; (2) urinary M1 and M2 metabolites (1,2-dihydroxy-4-[N-acetylcysteinyl]-butane and 1-hydroxy-2-[N-acetylcysteinyl]-3-butene, respectively), determined in Albuquerque, NM and Leiden; (3) hemoglobin adducts (N-[2-dihydroxy-3-butenyl]valine=HBVal and N-[2,3,4-trihydroxybutyl]valine=THBVal), determined in Amsterdam and Chapel Hill, NC, respectively; (4) HPRT mutations determined by autoradiographic assay in Galveston, TX, with slides re-read in Burlington, VT; (6) hypoxanthine-guanine phosphoribosyltransferase (HPRT) mutations determined by cloning assay in Leiden with mutational spectra characterized in Burlington, VT; (7) sister chromatid exchanges and chromosome aberrations determined by standard methods and FISH analysis in Prague. Urinary M1 and M2 metabolites and HBVal and THBVal hemoglobin adducts were all significantly correlated with BD exposure levels, with adducts being the most highly associated. No significant relationships were observed between BD exposures and HPRT mutations or any of the cytogenetic endpoints, regardless of method of assay.

Ankle ligament injury risk factors: a prospective study of college athletes.

Over two million individuals suffer ankle ligament trauma each year in the United States, more than half of these injuries are severe ligament sprains; however, very little is known about the factors that predispose individuals to these injuries. The purpose of this study was to determine the risk factors associated with ankle injury. We performed a prospective study of 118 Division I collegiate athletes who participated in soccer, lacrosse, or field hockey. Prior to the start of the athletic season, potential ankle injury risk factors were measured, subjects were monitored during the athletic season, and injuries documented. The number of ankle injuries per 1,000 person-days of exposure to sports was 1.6 for the men and 2.2 for the women. There were 13 injuries among the 68 women (19%) and seven injuries among the 50 men (13%), but these proportions were not significantly different. Women who played soccer had a higher incidence of ankle injury than those who played field hockey or lacrosse. Among men, there was no relationship between type of sport and incidence of injury. Factors associated with ankle ligament injury differ for men relative to women. Women with increased tibial varum and calcaneal eversion range of motion are at greater risk of suffering ankle ligament trauma, while men with increased talar tilt are at greater risk. Generalized joint laxity, strength, postural stability, and muscle reaction time were unrelated to injury.

In vivo mutant frequency of thioguanine-resistant T-cells in the peripheral blood and lymph nodes of melanoma patients.

T-cell activation by malignant melanoma would be anticipated to stimulate T-cell proliferation, which in turn has been associated with increasing the likelihood of somatic gene mutation. The purpose of this study was to test the hypothesis that in vivo hypoxanthine guanine phosphoribosyltransferase (hprt) mutant frequencies (MFs) are increased in peripheral blood T-cells from melanoma patients compared to normal controls. Assays were made of 48 peripheral blood samples from melanoma patients with stage 3 (13 patients) and stage 4 (35 patients) disease, 38 normal controls, and of nine tumor bearing lymph nodes. The mean hprt log(10)(MF) in patient peripheral blood was -4.77 (geometric mean hprt MF=17.0x10(-6)) compared to a mean hprt log(10)(MF) of -4.87 (geometric mean hprt MF=13.5x10(-6)) in controls. Although modest, this difference is statistically significant both by t-test (P=0.049) and after adjustment for covariates of age, gender, and cigarette smoking by regression analysis (P=0.001). Among the melanoma patients, the mean log(10)(MF) for the 17 patients who had received potentially genotoxic therapies was not significantly different from the mean log(10)(MF) for the 31 patients not receiving such therapies. The hprt MFs in the nine tumor bearing nodes were compared with MFs in peripheral blood from the same patients and revealed a non-significant (P=0.07) trend for increasing MFs in blood. Furthermore, analyses of T-cell receptor gene rearrangement patterns revealed hprt mutants originating from the same in vivo clone in both peripheral blood and a tumor-bearing node. The finding of elevated hprt MFs not entirely explained by genotoxic therapies in patients compared to controls can be explained either by hypermutability or in vivo T-cell activation. The similar MFs in peripheral blood and tumor bearing lymph nodes, as well as the finding of mutant representatives of the same in vivo T-cell clone in both locations, support monitoring peripheral blood to detect events in the nodes. If in vivo proliferation accounts for the current findings, the hprt deficient (hprt-) mutant fraction in blood may be enriched for T-cells that mediate the host immune response against malignant melanoma. Further studies will characterize the functional reactivity of hprt mutant isolates against melanoma-related antigens.

Radiographic abnormalities in long-tenure Vermont granite workers and the permissible exposure limit for crystalline silica.

This study was undertaken to assess the prevalence of radiographic abnormalities consistent with silicosis in a group of 600 retired granite workers who were receiving pensions. Files of regional clinics and hospitals were searched for chest radiographs taken on these men, and 470 x-ray films suitable for interpretation were located. After exclusions (women, and men who had worked in the granite industry elsewhere), 408 x-ray films were independently read by three experienced readers using the 1980 International Labour Office scheme. Dust exposures were estimated for workers hired after 1940, when the dust-control standard of 10 million particles per cubic foot (mppcf) (equivalent to 0.1 mg/m3) was put in place and monitored by the Vermont Division of Industrial Hygiene. Dust levels were initially high but were gradually reduced from 1940 to 1954, after which average quartz exposures stabilized to a mean of approximately 0.05 to 0.06 mg/m3; however, about 10% to 15% of samples after 1954 exceeded 0.1 mg/m3. Of the 408 x-ray films, 58 were taken on workers hired before dust controls were instituted in 1940, and 25.9% showed abnormalities (a profusion score of 1/0 or greater). A total of 350 x-ray films were taken on workers hired in 1940 or after, and the prevalence in this group was 5.7%. The radiographic changes in workers hired after 1940 are likely due to excessive exposures during the first 15 years of dust control. We conclude that if the exposure standard of 0.1 mg/m3 is rigorously observed in the workplace, radiographic abnormalities caused by quartz dust in long-term workers will be rare.

Gestational age and gender-specific in utero V(D)J recombinase-mediated deletions.

Recent studies have brought to the forefront the importance of somatic mutations during human fetal development and malignant transformation in children, specifically leukemia. Therefore, a better understanding of the frequency and mutational spectrum of spontaneous in utero mutations is essential for understanding the genetic mechanisms associated with pediatric malignancies. Previously we reported that the frequency of somatic mutations during the late stages of fetal development was dependent on both gestational age and gender. Here we present the hypoxanthine-guanine phosphoribosyltransferase (HPRT) reporter gene mutational spectra analysis for 60 T-cell mutant isolates from the umbilical cord blood of preterm newborns to gain insight into background mutational events during the late stages of fetal development. Logistic regression analyses showed a significant increase in HPRT deletions mediated by V(D)J recombinase in preterm newborns compared with full-term newborns (P = 0.009). A comparative analysis of deletion mutations also revealed that V(D)J recombinase-mediated HPRT deletions increased with decreasing gestational age (P = 0.012) and were significantly higher in females than males of the same developmental status (P = 0.031). Developmental and gender-specific differences in HPRT deletions mediated by V(D)J recombinase provide insight into the gender-specific differences seen in infant leukemia.

The association of increased weight, body mass index, and tissue density with the risk of breast carcinoma in Vermont.

BACKGROUND: Etiologic studies of breast carcinoma have indicated that weight, body mass index (BMI), and breast tissue density are important determinants of a woman's risk for the disease. This study looked at the independent effects of these risk factors. METHODS: Data from the Vermont Breast Cancer Surveillance System (VBCSS), collected between May 1996 and November 1997, were used to identify 529 breast carcinoma cases with no prior history of the disease. Each case was matched to four randomly chosen women of the same age who had mammograms during the same time period and had no biopsy-confirmed breast carcinoma. Logistic regression was used to assess the effects of weight, BMI, and breast tissue density on breast carcinoma risk for pre- and postmenopausal women. RESULTS: Weight and BMI were found to be significantly associated with postmenopausal breast carcinoma after adjustment for breast density, and vice versa. The density-adjusted odds ratio for women weighing over 81 kg, relative to women weighing under 63 kg, was 2.1, with a 95% confidence interval (CI) of 1.3-3.2. Relative to women with breasts consisting entirely of fat, the weight-adjusted odds ratios for women with heterogeneously dense and extremely dense breasts were 2.3 (CI: 1.3-4.3) and 4.5 (CI: 1.9-10.6), respectively. CONCLUSIONS: Among postmenopausal Vermont women, weight, BMI, and breast density were independently associated with breast carcinoma risk. Because breast density and weight or BMI are inversely related, estimates of their independent effects should be used when evaluating a woman's risk for breast carcinoma.

Azathioprine associated T-cell mutations in insulin-dependent diabetes mellitus.

Somatic mutations arise regularly in human T lymphocytes. As these events occur at increased frequencies in several autoimmune disorders, presumably because of increased T-cell proliferation, we investigated if this is also true for insulin-dependent diabetes mellitus (IDDM). Mutations of the hypoxanthine guanine phosphoribosyltransferase (hprt) gene measured by 6-thioguanine (TG) selection were studied in 28 patients (60 determinations) enrolled in a prospective double-blinded placebo-controlled study of azathioprine immunosuppression: 17 patients (34 determinations) were receiving azathioprine and 11 (26 determinations) placebo. Mean hprt T-cell mutant frequencies (MFs) were elevated in both patient groups, but only in the azathioprine group were elevations large and statistically correlated with the duration of the therapy. These results suggest that the organ-specific antigenic stimulus of the T-cell proliferation in IDDM does increase mutant cells in the peripheral blood, but this increase is relatively small. However, azathioprine, which is converted to 6-mercaptopurine in vivo, selects and amplifies the hprt mutants that do arise. Clinical azathioprine resistance may be explained by hprt mutations arising in T cells relevant to the underlying autoimmune process. Monitoring for these mutations should allow more effective use of this immunosuppressive agent.

Screening for breast cancer: time, travel, and out-of-pocket expenses.

BACKGROUND: We estimated the personal costs to women found to have a breast problem (either breast cancer or benign breast disease) in terms of time spent, miles traveled, and cash payments made for detection, diagnosis, initial treatment, and follow-up. METHODS: We analyzed data from personal interviews with 465 women from four communities in Florida. These women were randomly selected from those with a recent breast biopsy (within 6-8 months) that indicated either breast cancer (208 women) or benign breast disease (257 women). One community was the site of a multifaceted intervention to promote breast screening, and the other three communities were comparison sites for evaluation of that intervention. All P values are two-sided. RESULTS: In comparison with time spent and travel distance for women with benign breast disease (13 hours away from home and 56 miles traveled), time spent and travel distance were statistically significantly higher (P<.001) for treatment and follow-up of women with breast cancer (89 hours and 369 miles). Personal financial costs for treatment of women with breast cancer were also statistically significantly higher (breast cancer = $604; benign breast disease = $76; P < .001) but were statistically significantly lower for detection and diagnosis (breast cancer = $170; benign breast disease = $310; P < .001). Among women with breast cancer, time spent for treatment was statistically significantly lower (P = .013) when their breast cancer was detected by screening (68.9 hours) than when it was detected because of symptoms (84.2 hours). Personal cash payments for detection, diagnosis, and treatment were statistically significantly lower among women whose breast problems were detected by screening than among women whose breast problems were detected because of symptoms (screening detected = $453; symptom detected = $749; P = .045). CONCLUSION: There are substantial personal costs for women who are found to have a breast problem, whether the costs are associated with problems identified through screening or because of symptoms.

Gender-specific frequency of background somatic mutations at the hypoxanthine phosphoribosyltransferase locus in cord blood T lymphocytes from preterm newborns.

Limited information is available regarding the frequency, spectrum, and clinical relevance of somatic mutations in the developing fetus. The goal of this study was to determine somatic mutant frequencies (Mfs) at the hypoxanthine phosphoribosyltransferase (HPRT) reporter gene in cord blood T lymphocytes from preterm infants to gain insight into in utero mutational events. Mf determinations were made by using the HPRT T cell cloning assay on cord blood samples from 52 preterm infants. Natural logarithm Mfs (lnMfs) from preterm infants were compared with results from our database for full-term infants. Our analysis revealed higher lnMfs in cord blood T lymphocytes from preterm compared with full-term infants (P = 0.008). In addition, preterm females had significantly higher lnMfs compared with full-term females (P < 0.001), whereas preterm males were found to have significantly lower lnMfs than preterm females (P = 0.005). Regression analyses also demonstrate a significant relationship between lnMf and gestational age for preterm females that does not exist for preterm males. These results demonstrate the gender-specific association between Mf and age in humans.

Estimated gains in birth weight associated with reductions in smoking during pregnancy.

OBJECTIVE: To compare the estimated effect on birth weight of reductions in maternal cigarette consumption and urinary cotinine during pregnancy. STUDY DESIGN: An observational study of 641 women with complete data on cigarette consumption, urinary cotinine and infant birth weight. Correlation and regression analyses were used to examine relationships between birth weight, cigarette consumption and urinary cotinine at first and last prenatal visits. RESULTS: Correlations of cigarette consumption and urinary cotinine with infant birth weight were -.23 and -.30 (first visit) and -.26 and -.31 (last visit); all P values were < .001. The regression equation relating urinary cotinine concentrations at first and last visits to infant birth weight explained a significantly larger proportion of the variability in birth weight than the equation relating cigarette consumption at these visits to infant birth weight, 11% vs. 7%, P = .04. Among continuing smokers, both equations predicted gains in birth weight in association with reductions in cigarette consumption, but quitting smoking before the first visit was associated with the most weight gain. As compared to the average infant birth weight of a woman who smoked 20 cigarettes per day throughout pregnancy, the estimated gain in birth weight would be 105 g if she cut down by 10 cigarettes per day after the first visit, 210 g if she quit after this visit and 310 g if she quit before the first visit. CONCLUSION: For women still smoking at their first prenatal visit, infant birth weight is already compromised, but subsequent reductions in cigarette consumption are associated with gains in birth weight. For women who cannot quit smoking, these reductions need to be substantial if increases in birth weight of > 100 g are to be achieved.

Gene mutations with characteristic deletions in cord blood T lymphocytes associated with passive maternal exposure to tobacco smoke.

We have investigated the molecular effects of passive maternal cigarette exposure in a newborn population and consider the possible implications of the observed genetic changes in the development of neoplastic diseases in children. We present a distribution analysis of somatic mutational events in a reporter gene, HPRT, in cord blood T lymphocytes from newborns after transplacental exposure to cigarette smoke. Analysis of 30 HPRT mutant isolates from 12 newborn infants born to mothers with no evidence of environmental exposure to cigarette smoke and 37 HPRT mutant isolates from 12 infants born to mothers exposed to passive cigarette smoke showed a significant difference in the HPRT mutational spectrum in those exposed in utero to cigarette smoke. The most notable change was an increase in 'illegitimate' genomic deletions mediated by V(D)J recombinase, a recombination event associated with hematopoietic malignancies in early childhood. Recent epidemiological studies of maternal and paternal cigarette smoke exposure and childhood cancers may need to be re-interpreted, given these results.

Effects of the intensity and timing of asbestos exposure on lung cancer risk at two mining areas in Quebec.

Mortality data from 9609 workers at two asbestos mining areas in Quebec were analyzed to assess the effects of the intensity and timing of exposure on lung cancer risk. Summary exposure measures based on differing assumption were computed for lung cancer cases and matched controls and were fitted to the data using conditional logistic regression. A non-linear relationship between intensity and risk fit both mining areas, but risk was greater at one area than the other. At the mine with lower risk, exposure occurring more than 30 years prior to death had little effect, while at the other mine risk did not vary with time since exposure and men starting employment before 1924 were at elevated risk. The results point to differences in dust composition at the two areas and illustrate the difficulties in estimating risk.

Estrogen-receptor-related protein p29 in primary nonsmall cell lung carcinoma: pathologic and prognostic correlations.

BACKGROUND: Estrogen-dependent intracellular processes are important in the growth regulation of normal tissue and may play a role in the regulation of malignancies. Utilization of estrogen receptor assays in breast carcinoma is well established, but the role of such evaluation in other cancers largely is unknown. In this study, immunohistochemical expression of estrogen receptor (ER) and the ER-related protein p29 was correlated with survival of patients with nonsmall cell carcinoma of the lung. METHODS: All patients with a tissue diagnosis of primary nonsmall cell bronchogenic carcinoma diagnosed over a 6-year period at the Medical Center Hospital of Vermont were reviewed. Assays for p29 and ER using a streptavidin-biotin immunoperoxidase method were performed on each tumor. Results were correlated with clinical data, including survival. RESULTS: Of 111 tumors examined, 109 (98%) were positive for p29 whereas none of the tumors reacted with ER (ER1D5). The relation between p29 expression and survival time was different for men and women. A statistically significant negative relation for women was observed; this relation was most pronounced in patients with Stage I and II tumors. A positive but not statistically significant relation was observed for men. CONCLUSIONS: The ER-related protein p29 commonly is expressed in nonsmall cell carcinomas of the lung. The relation between p29 and survival time is different for males and females, suggesting the presence of gender specific factors that may influence tumor growth and overall patient survival, especially in patients with early stage lung carcinoma.

Exhaled carbon monoxide and urinary cotinine as measures of smoking in pregnancy.

We examined the relationships among self-reported cigarette consumption, exhaled carbon monoxide, and urinary cotinine/creatinine ratio in pregnant women. Information on these measures of smoking was collected at first and 36th week prenatal visits. Correlations between cigarette consumption and exhaled carbon monoxide were .65 at the first visit and .70 at the 36th-week visit. For urinary cotinine/creatinine ratio, the correlations were .61 and .65, respectively, at these visits. Correlations with change in cigarette consumption between the two visits were .37 for change in carbon monoxide and .33 for change in urinary cotinine/creatinine ratio. Urinary cotinine/creatinine ratio had slightly higher overall agreement with self-reported smoking status and was less likely to misclassify smokers than carbon monoxide. We conclude that urinary cotinine/creatinine ratio is the more accurate measure for validating smoking status among pregnant women, but exhaled carbon monoxide is the better measure of cigarette consumption and of changes in consumption.

Effects of low dose methotrexate on the bone mineral density of patients with rheumatoid arthritis.

OBJECTIVE: To determine the effects of low dose methotrexate (MTX) on bone mineral density (BMD) of patients with rheumatoid arthritis (RA). METHODS: We examined the relationship between BMD and disease modifying antirheumatic drug (DMARD) use with data from a prospective, randomized, placebo controlled trial assessing the effects of calcium and vitamin D3 supplementation on BMD of patients with RA. Measurements of BMD of the lumbar spine and femoral neck were performed at baseline and at yearly followup visits over 3 years. RESULTS: Information about DMARD use and BMD was available for 133 patients at baseline, and for 95 patients at Year 3. Lumbar spine and femoral neck BMD of MTX and non-MTX treated patients were similar at the start of the study. At the end of 3 years of followup, there was no significant differences in the change in BMD of the femoral neck and lumbar spine in MTX and non-MTX treated patients, in general. However, patients treated with prednisone > or = 5 mg/day plus MTX had greater loss of BMD in the lumbar spine than patients treated with a similar dose of prednisone without MTX (difference -8.08% over 3 years; p = 0.004). CONCLUSION: At the end of 3 years, low dose MTX use was not associated with change in femoral neck or lumbar spine BMD in patients who were not treated with corticosteroids. However, among patients treated with prednisone > or = 5 mg/day, combined treatment with MTX and prednisone was associated with greater bone loss in the lumbar spine than treatment with prednisone without MTX.

The effects of maternal cigarette smoke exposure on somatic mutant frequencies at the hprt locus in healthy newborns.

We utilized the hprt T-cell cloning assay to prospectively determined the somatic mutant frequency at the hprt locus of fetal T-lymphocytes exposed in utero to maternal active and passive cigarette smoke. In addition, a maternal questionnaire was administered to evaluate a number of social and medical parameters that may effect hprt mutant frequency. Newborn cord blood plasma cotinine levels were determined on all subjects to compare in utero tobacco metabolite levels with maternal smoking histories. A total of 63 newborns were enrolled and placed into four groups: Group I (n = 21), newborns whose mothers had no history of active or passive cigarette exposure during the pregnancy; Group II (n = 12), newborns whose mothers actively smoked cigarettes throughout the pregnancy; Group III (n = 8), newborns whose mothers actively smoked cigarettes during first trimester only; and Group IV (n = 22), newborns whose mothers were exposed only to passive cigarette smoke. Our analysis showed no statistically significant difference in hprt mutation frequency between any of the four groups. A significant increase in plasma cord blood cotinine was detected in Group II, newborns whose mothers were active cigarette smokers throughout the pregnancy. Our data indicate that exposure to active and passive maternal cigarette smoke in utero does not result in a significant increase in somatic mutant frequency as determined by the hprt T-cell cloning assay.