The Effects of Policy-Driven Air Quality Improvements on Children's Respiratory Health.

INTRODUCTION: Ambient air pollution causes substantial morbidity and mortality in the United States and worldwide. To reduce this burden of adverse health effects, a broad array of strategies to reduce ambient air pollution has been developed and applied over past decades to achieve substantial reductions in ambient air pollution levels. This has been especially true in California, where the improvement of air quality has been a major focus for more than 50 years. Direct links between regulatory policies, changes in ambient pollutant concentrations, and improvements in public health have not been extensively documented. Data from the Children's Health Study (CHS), a multiyear study of children's respiratory health development, offered a unique opportunity to evaluate the effects of long-term reductions in air pollution on children's health. METHODS: We assessed whether changes in ambient air quality and emissions were reflected in three important indices of children's respiratory health: lung-function growth, lung-function level, and bronchitic symptoms. To make the best use of available data, these analyses were performed across the longest chronological period and largest CHS population available for the respective lung-function or bronchitic symptoms data sets. During field study operations over the course of the CHS, children's health status was documented annually by testing lung-function performance and the completion of standardized questionnaires covering a broad range of respiratory symptoms. Air quality data for the periods of interest were obtained from community monitoring stations, which operated in collaboration with regional air monitoring networks over the 20-year study time frame. Over the 20-year sampling period, common protocols were applied to collect data across the three cohorts of children. Each cohort's data set was assessed to investigate the relationship between temporal changes in lung-function development, prevalence of bronchitic symptoms, and ambient air pollution concentrations during a similar, vulnerable adolescent growth period (age 11 to 15 years). Analyses were performed separately for particulate matter ≤10 µm in aerodynamic diameter (PM10), particulate matter ≤2.5 µm in aerodynamic diameter (PM2.5), ozone (O3), and nitrogen dioxide (NO2). Emissions data and regulatory policies were collected from the staff of state and regional regulatory agencies, modeling estimates, and archived reports. RESULTS: Emissions in the regions of California studied during the 20-year period decreased by 54% for oxides of nitrogen (NOₓ), 65% for reactive organic gases (ROG), 21% for PM2.5, and 15% for PM10. These reductions occurred despite a concurrent 22% increase in population and a 38% increase in motor vehicle miles driven during that time frame. Air quality improved over the same time frame, with reductions in NO2 and PM2.5 in virtually all of the CHS communities. Annual average NO2 decreased by about 53% (from ~41 to 19 ppb) in the highest NO2-reporting community (Upland) and by about 28% (from ~10 to 7 ppb) in one of the lowest NO2-reporting communities (Santa Maria). Reductions in annual average PM2.5 concentrations ranged from 54% (~33 to 15 µg/m³) in the community with the highest concentration (Mira Loma) to 13% (~9 to 8 µg/m³) in a community with one of the lowest concentrations (Santa Maria). Improvements in PM10 and O3 (measured during eight daytime hours, 10 AM to 6 PM) were most evident in the CHS communities that initially had the highest levels of PM and O3. Trends in annual average NO2, PM2.5, and PM10 ambient air concentrations in the communities with higher-pollution levels were generally consistent with observed trends in NOₓ, ROG, PM2.5, and PM10 emissions.Significant improvements in lung-function growth in progressive cohorts were observed as air quality improved over the study period. Improvements in four-year growth of both forced expiratory volume in the first second of exhalation (FEV1) and forced vital capacity (FVC) were associated with declining levels of NO2 (P < 0.0001), PM2.5 (P < 0.01), and PM10 (P < 0.001). These associations persisted after adjustment for important potential confounders. Further, significant improvements in lung-function growth were observed in both boys and girls and among asthmatic and non-asthmatic children. Within-community decreases in O3 exposure were not significantly associated with lung-function growth. The proportion of children with clinically low FEV1 (defined as <80% predicted) at age 15 declined significantly, from 7.9% to 3.6% across the study periods, respectively, as the air quality improved (P < 0.005). We found little evidence to suggest that improvements in lung-function development were attributable to temporal confounding.Reductions in outdoor levels of NO2, O3, PM10, and PM2.5 across the cohort years of participation were associated with significant reductions in the prevalence of bronchitic symptoms regardless of asthma status, but observed improvements were larger in children with asthma. Among asthmatic children, the reductions in prevalence of bronchitic symptoms at age 10 were 21% (P < 0.01) for NO2, 34% (P < 0.01) for O3, 39% (P < 0.01) for PM10, and 32% (P < 0.01) for PM2.5 for reductions of 4.9 ppb, 3.6 ppb, 5.8 µg/m³, and 6.8 µg/m³, respectively. Similar reductions in prevalence of bronchitic symptoms were observed at age 15 among these same asthmatic children. As in the lung-function analyses, we found little evidence that temporal confounding accounted for the observed associations of symptoms reduction with air quality improvement.The large number and breadth of regulatory activities, as well as the prolonged phase-in periods of several policy approaches to reduce emissions, precluded the close temporal linkage of specific policies with specific changes in health status. However, the combination of policies addressing motor vehicle emissions - from on-board diagnostics to emission controls, from low-sulfur fuels to vehicle smog-check recertification, and from re-formulated gasoline to the various strategies contained within the San Pedro Bay Ports Clean Air Plan (especially the Clean Truck Program) - all contributed to an impressive and substantial reduction in emissions. These reductions collectively improved local and regional air quality, and improvements in local and regional air quality were associated with improvements in respiratory health. CONCLUSIONS: This study provides evidence that multiyear improvements in air quality and emissions, primarily driven through a broad array of science-based regulatory policy initiatives, have resulted in improved public health outcomes. Our study demonstrates that improvements in air quality, brought about by science-based regulatory actions, are associated with improved respiratory health in children. These respiratory health metrics include reductions in respiratory symptoms and improvements in lung-function development in a population widely accepted to be at risk and highly vulnerable to the effects of air pollution. Our research findings underscore the importance of sustained air regulatory efforts as an effective means of achieving improved respiratory health in communities and regions affected by airborne pollution.

Using routinely collected growth data to assess a school-based obesity prevention strategy.

BACKGROUND: Studies of school-based anti-obesity interventions have yielded inconsistent results. Using growth screening data from a school administrative database, we re-evaluated an obesity prevention strategy that was previously reported to have a beneficial effect on weight status of a sample of students in grades 5-7. METHODS: Ten K-8 schools (five control and five intervention) participated in a 2-year cluster-randomized trial of a multi-component nutrition education intervention. We obtained student height and weight data for 6 consecutive school years and imputed missing baseline and follow-up measurements (53% and 55%, respectively) and defined the target population based on the intent-to-treat principle. We analyzed changes in body mass index (BMI) Z-scores via mixed-effects linear regression and in the prevalence of overweight/obesity via conditional logistic regression. We also assessed incidence and remission of overweight/obesity and long-term effects. RESULTS: We analyzed data for 8186 (96%) K-8 students in the 10 schools (4511 in intervention; 3675 in control). From baseline to the end of the intervention period, mean increases in BMI Z-score were 0.10 and 0.09 in the control and intervention groups, respectively (P=0.671). The prevalence of overweight/obesity increased by 3% in both groups (P=0.926). There was no significant intervention effect on the incidence or remission of overweight/obesity. Among 5469 students who attended study schools during both years of the intervention, there was no significant intervention effect. Furthermore, there was no long-term effect among students with up to 2 years of data beyond the end of the intervention. CONCLUSION: Using routinely collected data for the entire target population, we failed to confirm earlier findings of an intervention effect observed in a subset of students in grades 5-7. Volunteer bias in the prior evaluation and/or measurement error in the routinely collected data are potential reasons for the discrepant findings.

The effect of ambient air pollution on exhaled nitric oxide in the Children's Health Study.

We assessed the effect of daily variations in ambient air pollutants on exhaled nitric oxide fraction (F(eNO)) using data from a cohort of school children with large differences in air pollutant exposures from the Children's Health Study. Based on a cohort of 2,240 school children from 13 Southern Californian communities, cumulative lagged average regression models were fitted to determine the association between F(eNO) and ambient air pollution levels from central site monitors with lags of up to 30 days prior to F(eNO) testing. Daily 24-h cumulative lagged averages of particles with a 50% cut-off aerodynamic diameter of 2.5 µm (PM2.5; over 1-8 days) and particles with a 50% cut-off aerodynamic diameter of 10 µm (PM10; over 1-7 days), as well as 10:00-18:00 h cumulative lagged average of O3 (over 1-23 days) were significantly associated with 17.42% (p<0.01), 9.25% (p<0.05) and 14.25% (p<0.01) higher F(eNO) levels over the interquartile range of 7.5 µg·m⁻³, 12.97 µg·m⁻³ and 15.42 ppb, respectively. The effects of PM2.5, PM10 and O3 were higher in the warm season. The particulate matter effects were robust to adjustments for effects of O3 and temperature and did not vary by asthma or allergy status. In summary, short-term increases in PM2.5, PM10 and O3 were associated with airway inflammation independent of asthma and allergy status, with PM10 effects significantly higher in the warm season.

Exhaled nitric oxide, susceptibility and new-onset asthma in the Children's Health Study.

A substantial body of evidence suggests an aetiological role of inflammation, and oxidative and nitrosative stress in asthma pathogenesis. Exhaled nitric oxide fraction (F(eNO)) may provide a noninvasive marker of oxidative and nitrosative stress, and aspects of airway inflammation. We examined whether children with elevated F(eNO) are at increased risk for new-onset asthma. We prospectively followed 2,206 asthma-free children (age 7-10 yrs) who participated in the Children's Health Study. We measured F(eNO) and followed these children for 3 yrs to ascertain incident asthma cases. Cox proportional hazard models were fitted to examine the association between F(eNO) and new-onset asthma. We found that F(eNO) was associated with increased risk of new-onset asthma. Children in the highest F(eNO) quartile had more than a two-fold increased risk of new-onset asthma compared to those with the lowest quartile (hazard ratio 2.1, 95% CI 1.3-3.5). This effect did not vary with the child's history of respiratory allergic symptoms. However, the effect of elevated F(eNO) on new-onset asthma was most apparent among those without a parental history of asthma. Our results indicate that children with elevated F(eNO) are at increased risk for new-onset asthma, especially if they have no parental history of asthma.

Genetic variations in nitric oxide synthase and arginase influence exhaled nitric oxide levels in children.

BACKGROUND: Exhaled nitric oxide (FeNO) is a biomarker of airway inflammation. In the nitric oxide (NO) synthesis pathway, nitric oxide synthases (encoded by NOS1, NOS2A, and NOS3) and arginases (encoded by ARG1 and ARG2) compete for L-arginine. Although FeNO levels are higher in children with asthma/allergy, influence of these conditions on the relationships between variations in these genes and FeNO remains unknown. The aims of the study were to evaluate the role of genetic variations in nitric oxide synthases and arginases on FeNO in children and to assess the influence of asthma and respiratory allergy on these genetic associations. METHODS: Among children (6-11 years) who participated in the southern California Children's Health Study, variations in these five genetic loci were characterized by tagSNPs. FeNO was measured in two consecutive years (N = 2298 and 2515 in Years 1 and 2, respectively). Repeated measures analysis of variance was used to evaluate the associations between these genetic variants and FeNO. RESULTS: Sequence variations in the NOS2A and ARG2 loci were globally associated with FeNO (P = 0.0002 and 0.01, respectively). The ARG2 association was tagged by intronic variant rs3742879 with stronger association with FeNO in asthmatic children (P-interaction = 0.01). The association of a NOS2A promoter haplotype with FeNO varied significantly by rs3742879 genotypes and by asthma. CONCLUSION: Variants in the NO synthesis pathway genes jointly contribute to differences in FeNO concentrations. Some of these genetic influences were stronger in children with asthma. Further studies are required to confirm our findings.

Heritable breast cancer in twins.

Known major mutations such as BRCA1/2 and TP53 only cause a small proportion of heritable breast cancers. Co-dominant genes of lower penetrance that regulate hormones have been thought responsible for most others. Incident breast cancer cases in the identical (monozygotic) twins of representative cases reflect the entire range of pertinent alleles, whether acting singly or in combination. Having reported the rate in twins and other relatives of cases to be high and nearly constant over age, we now examine the descriptive and histological characteristics of the concordant and discordant breast cancers occurring in 2310 affected pairs of monozygotic and fraternal (dizygotic) twins in relation to conventional expectations and hypotheses. Like other first-degree relatives, dizygotic co-twins of breast cancer cases are at higher than usual risk (standardised incidence ratio (SIR)=1.7, CI=1.1-2.6), but the additional cases among monozygotic co-twins of cases are much more numerous, both before and after menopause (SIR=4.4, CI=3.6-5.6), than the 100% genetic identity would predict. Monozygotic co-twin diagnoses following early proband cancers also occur more rapidly than expected (within 5 years, SIR=20.0, CI=7.5-53.3). Cases in concordant pairs represent heritable disease and are significantly more likely to be oestrogen receptor-positive than those of comparable age from discordant pairs. The increase in risk to the monozygotic co-twins of cases cannot be attributed to the common environment, to factors that cumulate with age, or to any aggregate of single autosomal dominant mutations. The genotype more plausibly consists of multiple co-existing susceptibility alleles acting through heightened susceptibility to hormones and/or defective tumour suppression. The resultant class of disease accounts for a larger proportion of all breast cancers than previously thought, with a rather high overall penetrance. Some of the biological characteristics differ from those of breast cancer generally.

Family history and the risk of early-onset persistent, early-onset transient, and late-onset asthma.

Family history of asthma and allergies strongly influences asthma risk in children, but the association may differ for early-onset persistent, early-onset transient, and late-onset asthma. We analyzed the relation between family history and these types of asthma using cross-sectional data from a school-based study of 5,046 Southern California children. Parental and/or sibling history of asthma and allergy were generally more strongly associated with early-onset persistent asthma compared with early-onset transient or late-onset asthma. For children with two asthmatic parents relative to those with none, the prevalence ratio for early-onset persistent asthma was 12.1 [95% confidence interval (CI) = 7.91-18.7] compared with 7.51 (95% CI = 2.62-21.5) for early-onset transient asthma and 5.38 (95% CI = 3.40-8.50) for late-onset asthma. Maternal smoking in pregnancy was predominantly related to the risk of early-onset persistent asthma in the presence of parental history of allergy and asthma, and the joint effects were more than additive (interaction contrast ratio = 3.10, 95% CI = 1.45-4.75). Our results confirm earlier data that parental history of asthma and allergy is most strongly associated with early-onset persistent asthma and suggest that among genetically predisposed children, an early-life environmental exposure, maternal smoking during pregnancy, favors the development of early-onset asthma that persists into later early childhood.

Rosiglitazone monotherapy is effective in patients with type 2 diabetes.

This study evaluated the efficacy and safety of rosiglitazone monotherapy in patients with type 2 diabetes. After a 4-week placebo run-in period, 493 patients with type 2 diabetes were randomized to receive rosiglitazone [2 or 4 mg twice daily (bd)] or placebo for 26 weeks. The primary end point was change in hemoglobin A(1c); other variables assessed included fasting plasma glucose, fructosamine, endogenous insulin secretion, urinary albumin excretion, serum lipids, and adverse events. Rosiglitazone (2 and 4 mg bd) decreased mean hemoglobin A(1c) relative to placebo by 1.2 and 1.5 percentage points, respectively, and reduced fasting plasma glucose concentrations relative to placebo by 3.22 and 4.22 mmol/L, respectively. Fasting plasma insulin and insulin precursor molecules decreased significantly. Homeostasis model assessment estimates indicate that rosiglitazone (2 and 4 mg bd) reduced insulin resistance by 16.0% and 24.6%, respectively, and improved ss-cell function over baseline by 49.5% and 60.0%, respectively. Urinary albumin excretion decreased significantly in the rosiglitazone (4 mg bd) group. There was no increase in adverse events with rosiglitazone. In the short-term, rosiglitazone is an insulin sensitizer that is effective and safe as monotherapy in patients with type 2 diabetes who are inadequately controlled by lifestyle interventions.

Once- and twice-daily dosing with rosiglitazone improves glycemic control in patients with type 2 diabetes.

OBJECTIVE: To determine the efficacy of rosiglitazone compared with placebo in reducing hyperglycemia. RESEARCH DESIGN AND METHODS: After a 4-week placebo run-in period, 959 patients were randomized to placebo or rosiglitazone (total daily dose 4 or 8 mg) for 26 weeks. The primary measure of efficacy was change in the HbA1c concentration. RESULTS: Rosiglitazone produced dosage-dependent reductions in HbA1c of 0.8, 0.9, 1.1, and 1.5% in the 4 mg o.d., 2 mg b.i.d., 8 mg o.d., and 4 mg b.i.d. groups, respectively, compared with placebo. Clinically significant decreases from baseline in HbA1c were observed in drug-naive patients at all rosiglitazone doses and in patients previously treated with oral monotherapy at rosiglitazone 8 mg o.d. and 4 mg b.i.d. Clinically significant decreases from baseline in HbA1c were also observed with rosiglitazone 4 mg b.i.d. in patients previously treated with combination oral therapy. Approximately 33% of drug-naive patients treated with rosiglitazone achieved HbA1c < or =7% at study end. The proportions of patients with at least one adverse event were comparable among the rosiglitazone and placebo groups. There was no evidence of hepatotoxicity in any treatment group. There were statistically significant increases in weight and serum lipids in all rosiglitazone treatment groups compared with placebo. For LDL and HDL cholesterol, the observed increase appeared to be dose related. CONCLUSIONS: Rosiglitazone at total daily doses of 4 and 8 mg significantly improved glycemic control in patients with type 2 diabetes and was well tolerated.

The effects of ambient air pollution on school absenteeism due to respiratory illnesses.

We investigated the relations between ozone (O3), nitrogen dioxide (NO2), and respirable particles less than 10 microm in diameter (PM10) and school absenteeism in a cohort of 4th-grade school children who resided in 12 southern California communities. An active surveillance system ascertained the numbers and types of absences during the first 6 months of 1996. Pollutants were measured hourly at central-site monitors in each of the 12 communities. To examine acute effects of air pollution on absence rates, we fitted a two-stage time-series model to the absence count data that included distributed lag effects of exposure adjusted for long-term pollutant levels. Short-term change in O3, but not NO2 or PM10, was associated with a substantial increase in school absences from both upper and lower respiratory illness. An increase of 20 ppb of O3 was associated with an increase of 62.9% [95% confidence interval (95% CI) = 18.4-124.1%] for illness-related absence rates, 82.9% (95% CI = 3.9-222.0%) for respiratory illnesses, 45.1% (95% CI = 21.3-73.7%) for upper respiratory illnesses, and 173.9% (95% CI = 91.3-292.3%) for lower respiratory illnesses with wet cough. The short-term effects of a 20-ppb change of O3 on illness-related absenteeism were larger in communities with lower long-term average PM10 [223.5% (95% CI = 90.4-449.7)] compared with communities with high average levels [38.1% (95% CI = 8.5-75.8)]. Increased school absenteeism from O3 exposure in children is an important adverse effect of ambient air pollution worthy of public policy consideration.

Effects of in utero and environmental tobacco smoke exposure on lung function in boys and girls with and without asthma.

To investigate whether the effects of in utero exposure to maternal smoking and environmental tobacco smoke (ETS) exposure on lung function vary by sex or asthma status, we examined medical history and tobacco smoke exposure data for 5,263 participants in the Children's Health Study. At study enrollment, parents or guardians of each subject completed a questionnaire, and lung function was measured spirometrically with maximum forced expiratory flow-volume maneuvers. To assess the in utero effects of maternal smoking and ETS exposure on lung function, we used regression splines that accounted for the nonlinear relationship between pulmonary function, height, and age. In utero exposure to maternal smoking was independently associated with deficits in lung function that were larger for children with asthma. Boys and girls with a history of in utero exposure to maternal smoking showed deficits in maximum midexpiratory flow (MMEF) and a decrease in the FEV(1)/FVC ratio. As compared with children without asthma, boys with asthma had significantly larger deficits from in utero exposure in FVC, MMEF, and FEV(1)/FVC, and girls with asthma had larger decreases in FEV(1)/FVC. The effect of ETS exposure varied by children's gender and asthma status. Deficits in flows associated with current ETS exposure were present in children with and without asthma but were significant only among children without asthma. Past ETS exposure was associated with reduced FEV(1), MMEF, and FEV(1)/FVC among boys with asthma. In contrast, past ETS exposure was associated with decreased flow rates in girls without asthma. In summary, both in utero exposure to maternal smoking and ETS exposure were associated with persistent deficits in lung function. The effects of in utero exposure were greatest among children with asthma.

Association between air pollution and lung function growth in southern California children.

Average growth of lung function over a 4-yr period, in three cohorts of southern California children who were in the fourth, seventh, or tenth grade in 1993, was modeled as a function of average exposure to ambient air pollutants. In the fourth-grade cohort, significant deficits in growth of lung function (FEV(1), FVC, maximal midexpiratory flow [MMEF], and FEF(75)) were associated with exposure to particles with aerodynamic diameter less than 10 micrometer (PM(10)), PM(2.5), PM(10)-PM(2.5), NO(2), and inorganic acid vapor (p < 0.05). No significant associations were observed with ozone. The estimated growth rate for children in the most polluted of the communities as compared with the least polluted was predicted to result in a cumulative reduction of 3.4% in FEV(1) and 5.0% in MMEF over the 4-yr study period. The estimated deficits were generally larger for children spending more time outdoors. In the seventh- and tenth-grade cohorts, the estimated pollutant effects were also negative for most lung function measures, but sample sizes were lower in these groups and none achieved statistical significance. The results suggest that significant negative effects on lung function growth in children occur at current ambient concentrations of particles, NO(2), and inorganic acid vapor.

Rosiglitazone short-term monotherapy lowers fasting and post-prandial glucose in patients with type II diabetes.

AIMS/HYPOTHESIS: The short-term efficacy, safety and tolerability of rosiglitazone were compared with placebo in patients with Type II (non-insulin-dependent) diabetes mellitus in a dose-ranging study. METHODS: After a 2-week placebo run-in phase, 303 patients were randomly assigned to 8 weeks of treatment with twice-daily placebo or 2, 4 or 6 mg of rosiglitazone. RESULTS: All rosiglitazone doses significantly reduced fasting plasma glucose compared with baseline. All rosiglitazone treatment groups showed significantly reduced peak postprandial glucose concentrations compared with baseline (p < 0.001) and with placebo (p < 0.0001) and reduced postprandial glucose excursion, without an increase in the area under the postprandial insulin concentration-time curve. Rosiglitazone at 4 and 6 mg twice daily prevented the increase in HbA1c observed in the placebo group. C peptide and serum insulin concentrations were significantly reduced from baseline in all rosiglitazone treatment groups. In all rosiglitazone treatment groups, nonesterified fatty acids decreased significantly (p < 0.0001) and triglycerides did not change. Although total LDL and HDL cholesterol increased significantly in the rosiglitazone treatment groups, total cholesterol/HDL ratios did not change significantly. The proportion of patients with one or more adverse event was similar in all four treatment groups. No patient showed evidence of hepatotoxicity. CONCLUSION/INTERPRETATION: Rosiglitazone given twice daily significantly reduced fasting and postprandial glucose concentrations, C peptide, insulin and nonesterified fatty acids in Type II diabetic patients. The glucose-lowering effect of the 4-mg twice-daily dose of rosiglitazone was similar to that of 6-mg twice daily, suggesting that 4 mg twice daily should be the maximum clinical dose.

Maternal smoking during pregnancy, environmental tobacco smoke exposure and childhood lung function.

BACKGROUND: Exposure to environmental tobacco smoke (ETS) during childhood and in utero exposure to maternal smoking are associated with adverse effects on lung growth and development. METHODS: A study was undertaken of the associations between maternal smoking during pregnancy, exposure to ETS, and pulmonary function in 3357 school children residing in 12 Southern California communities. Current and past exposure to household ETS and exposure to maternal smoking in utero were assessed by a self-administered questionnaire completed by parents of 4th, 7th, and 10th grade students in 1993. Standard linear regression techniques were used to estimate the effects of in utero and ETS exposure on lung function, adjusting for age, sex, race, Hispanic ethnicity, height, weight, asthma, personal smoking, and selected household characteristics. RESULTS: In utero exposure to maternal smoking was associated with reduced peak expiratory flow rate (PEFR) (-3.0%, 95% CI -4.4 to -1.4), mean mid expiratory flow (MMEF) (-4.6%, 95% CI -7.0 to -2.3), and forced expiratory flow (FEF(75)) (-6.2%, 95% CI -9.1 to -3.1), but not forced expiratory volume in one second (FEV(1)). Adjusting for household ETS exposure did not substantially change these estimates. The reductions in flows associated with in utero exposure did not significantly vary with sex, race, grade, income, parental education, or personal smoking. Exposure to two or more current household smokers was associated with reduced MMEF (-4.1%, 95% CI -7.6 to -0. 4) and FEF(75) (-4.4%, 95% CI -9.0 to 0.4). Current or past maternal smoking was associated with reductions in PEFR and MMEF; however, after adjustment for in utero exposure, deficits in MMEF and FEF(75) associated with all measurements of ETS were substantially reduced and were not statistically significant. CONCLUSIONS: In utero exposure to maternal smoking is independently associated with decreased lung function in children of school age, especially for small airway flows.

Rosiglitazone monotherapy improves glycaemic control in patients with type 2 diabetes: a twelve-week, randomized, placebo-controlled study.

AIM: Rosiglitazone is the most potent of the thiazolidinediones, a novel class of oral antidiabetic agents that reduce blood glucose levels by sensitizing peripheral tissues to insulin. This study was designed to identify doses of rosiglitazone that would lower fasting plasma glucose (FPG) in patients with type 2 diabetes. METHODS: In this 12-week, double-blind, multicentre study, 380 patients with FPG values > or =7.8 mmol/L (140 mg/dL) and < or =13.3 mmol/L (240 mg/dL) were randomly assigned to receive treatment with placebo or rosiglitazone, 0.05, 0.25, 1.0, or 2.0 mg twice daily. The primary efficacy parameter was changed in FPG from baseline after 12 weeks of treatment. Secondary endpoints were changes in HbA1c, fructosamine, C peptide, insulin, lipid levels, and body weight (b.w.). Safety monitoring included clinical laboratory evaluations, electrocardiography, and echocardiography. RESULTS: Rosiglitazone 1.0 and 2.0 mg b.i.d. produced significant decreases in FPG (p=0.0001). Fructosamine also decreased in patients treated with these two dosages (p=0.003 in the 2.0 mg b.i.d. group). Rosiglitazone 2.0 mg b.i.d. significantly reduced plasma insulin levels (p=0.0044) and free fatty acids (p=0.0014) compared with placebo. Total cholesterol (p=0.0001), HDL (p=0.0009), and LDL (p=0.0001) increased in the rosiglitazone 2.0 mg b.i.d. group, but there was no significant change in the total cholesterol/HDL ratio or triglyceride levels in any rosiglitazone treatment group. Clinically insignificant dose-dependent increases in b.w. were observed in the rosiglitazone 1.0 and 2.0 mg b.i.d. treatment groups. CONCLUSIONS: Twelve weeks of treatment with rosiglitazone 2.0 mg b.i.d. significantly decreases fasting plasma glucose, fructosamine, plasma insulin, and free fatty acids in patients with type 2 diabetes. Longer studies using higher doses will be needed to assess the efficacy and safety of rosiglitazone in patients with type 2 diabetes mellitus.

Acute effects of ambient ozone on asthmatic, wheezy, and healthy children.

Southern California children (10 to 12 years old) participated in a two-season study to assess the potential acute respiratory effects of ambient ozone (O3). Asthmatic (n = 49), wheezy (n = 53), and healthy (n = 93) children completed a four-day (Friday through Monday) study protocol, once in spring and again in summer, that included the use of daily activity and symptom diaries, heart rate recording devices, personal O3 samplers, and maximal effort spirometry several times per day. Data from regional monitoring stations were used to establish ambient hourly O3 concentrations. Analyses revealed that the children spent more time outdoors and were more physically active in the spring. Girls spent less time outdoors and were less physically active than boys. Personal O3 samplers correlated poorly with, and generally gave lower readings than, outdoor ambient monitors. Higher personal O3 exposures were associated generally with increased inhaler use, more outdoor time, and more physical activity. Children with asthma spent more time outdoors and were more active in the spring on high-O3 days (measured by personal sampler), and had the most trouble breathing, the most wheezing, and the most inhaler use on these days. Activity pattern data suggested that children with asthma protected themselves by being less physically active outdoors during the summer on high-O3 days. Wheezy children had the most trouble breathing during the summer on low-O3 days (measured by personal sampler). Observed relationships between O3 and pulmonary function were erratic and difficult to reconcile with existing knowledge about the acute respiratory effects of air pollution. We conclude that although asthmatic and wheezy children behave differently from their healthy peers with regard to symptoms and patterns of activity when challenged by ambient ozone, the nature of these changes remains inconsistent and ill-defined.

Concordance for Hodgkin's disease in identical twins suggesting genetic susceptibility to the young-adult form of the disease.

BACKGROUND: Relatives of young adults with Hodgkin's disease are at increased risk of Hodgkin's disease, and lines of evidence implicate both inheritance and environment. METHODS: We have identified and followed 432 sets of twins affected by Hodgkin's disease. The number of cases of Hodgkin's disease observed before the age of 50 years in the healthy monozygotic and dizygotic twins of the patients with Hodgkin's disease was compared with the number expected from national age-specific incidence rates. RESULTS: None of the 187 pairs of dizygotic twins became concordant for Hodgkin's disease, whereas 10 of the 179 pairs of monozygotic twins did; in 5 of these pairs, the second case appeared after the original ascertainment. During the observation period, 0.1 (monozygotic) and 0.1 (dizygotic) cases in the unaffected twins were expected. Monozygotic twins of patients with Hodgkin's disease thus had a greatly increased risk (standardized incidence ratio, 99; 95 percent confidence interval, 48 to 182), whereas no increase in the risk for dizygotic twins of patients with Hodgkin's was observed. CONCLUSIONS: Genetic susceptibility underlies Hodgkin's disease in young adulthood.

Reproductive outcomes in relation to malathion spraying in the San Francisco Bay Area, 1981-1982.

We studied reproductive outcomes in a cohort of 7,450 pregnancies identified through three Kaiser-Permanente facilities in the San Francisco Bay Area, in relation to exposure to the pesticide malathion, applied aerially to control an infestation by the Mediterranean fruit fly. We included in the cohort all women over age 17 who were registered at these facilities and who were confirmed as pregnant during the spraying period. Residence histories throughout the pregnancy were obtained by mailed questionnaire or telephone interview from 933 women with adverse outcomes and a sample of 1,000 women with normal outcomes, and were converted to geographical coordinates. We linked the coordinates for malathion spraying corridors with the residence coordinates to create individual exposure indices for each week of pregnancy. The statistical analysis compared each of the adverse pregnancy outcome groups against an appropriate control group using logistic regression or survival time regression approaches. After adjustment for various confounders, no important association was found between malathion exposure and spontaneous abortion, intrauterine growth retardation, stillbirth, or most categories of congenital anomalies. Gastrointestinal anomalies were related to second trimester exposure (odds ratio = 2.6), based on 13 cases and not specific to any particular International Classification of Diseases code.

Isotretinoin embryopathy--a continuing problem.

First trimester exposure to isotretinoin is associated with an estimated 20% risk of major fetal malformations. Product labeling in force up to August 1988 included a statement that the drug is contraindicated in pregnancy and suggested procedures for prescribing physicians to follow to prevent inadvertent first trimester exposure to the product. This limited educational intervention did not prevent the continued occurrence of isotretinoin-related birth defects. The effectiveness of recent changes in the package labeling in preventing such birth defects remains to be demonstrated. Two infants with major birth defects associated with first trimester exposure to isotretinoin (Accutane, Roche Laboratories) were reported to the New Jersey Birth Defects Registry within 6 months. Stimulated by these reports, we sought additional cases in New Jersey and found three. We here describe these five cases of isotretinoin embryopathy, including available information on the circumstances which led to maternal use of isotretinoin during the first trimester of pregnancy. In response to a preliminary report of these cases and to investigations by epidemiologists at the U.S. Food and Drug Administration (FDA), the manufacturer altered the package labeling. The revised product information includes a more prominent "contraindication and warning" section and a new "patient information/consent" section. The effectiveness of this educational intervention should be evaluated.

Iatrogenic Creutzfeldt-Jakob disease.

Over the past 2 years, Creutzfeldt-Jakob disease (CJD) has affected several patients who received cadaver pituitary-derived growth hormone (pit-hGH) and one patient who received a cadaveric dura mater graft. The risk of iatrogenic transmission of CJD has long been recognized, but until recently, the low prevalence of the disorder and minimal use of therapeutic products derived from human tissues may have limited the risk. From 1963 to 1985, approximately 10,000 children received pit-hGH. These patients, exposed to pooled products potentially contaminated with the CJD agent, may have significantly increased the number of individuals whose blood and tissues could transmit CJD. This possibility as well as data on the pathophysiology of CJD and scrapie, a related disease of animals, should guide the development of practices that would limit iatrogenic spread of CJD.