Lean mass predicts asthma better than fat mass among females.

The obesity phenotype associated with asthma is not known. Our objective was to define the relative contribution of various distributions of fat and lean mass to asthma prevalence. Data were obtained from 2,525 participants (including 1,422 females) who underwent dual-energy X-ray absorptiometry (DEXA) at the year 20 examination in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. Total, truncal, arm and leg distributions of fat and lean mass were adjusted to the person's height. Self-reported asthma was the outcome. Asthma among females was associated with greater total fat mass, arm fat mass, total lean mass, truncal lean mass and arm lean mass. Among males, none of these mass measures were significantly associated with asthma. Among females, the association with asthma was stronger for total lean mass than for total fat mass. Further, among various regional distributions of lean and fat mass in females, truncal lean mass was the strongest predictor. Total lean mass is more strongly associated with asthma than total fat mass among females. These findings are contrary to the popular perception that excess physiological fat drives the obesity-asthma association. Rather, we hypothesise that ectopic fat within the "lean" tissues drives this association among females.

Association between asthma and serum adiponectin concentration in women.

BACKGROUND: The association of murine asthma with adiposity may be mediated by adiponectin, an anti-inflammatory adipokine with reduced serum concentrations in obese subjects. A study was undertaken to examine whether the serum adiponectin concentration is associated with human asthma and whether it explains the association between adiposity and asthma, particularly in women and in premenopausal women. METHODS: A cross-sectional analysis was performed of 2890 eligible subjects at year 15 of the Coronary Artery Risk Development in Young Adults (CARDIA) cohort and its YALTA ancillary study who had either current asthma or never asthma at that evaluation. Obesity was defined as body mass index (BMI) >or=30 kg/m(2). Multivariable logistic regression analysis was performed with current asthma status as the dependent variable. RESULTS: Women, but not men, with current asthma had a lower mean unadjusted serum adiponectin concentration than those with never asthma (p<0.001; p for sex interaction <0.001). Similarly, current asthma was related to obesity only in women (OR 3.31, 95% CI 2.00 to 5.46, p for sex interaction = 0.004); this association was little affected by adjusting for serum adiponectin. The prevalence of current asthma in premenopausal women was reduced in the highest compared with the lowest tertile of serum adiponectin concentration (OR 0.46, 95% CI 0.26 to 0.84, p = 0.03), after adjusting for BMI. However, the interaction between serum adiponectin concentration and BMI category on current asthma status was not significant in premenopausal women or women overall. CONCLUSIONS: A high serum adiponectin concentration may protect against current asthma in premenopausal women but does not explain the association between asthma and adiposity.

Web based listing of agents associated with new onset work-related asthma.

BACKGROUND: Work-related asthma is common and yet remains a challenge to diagnose. Access to a listing of agents associated with work-related asthma has been suggested as useful in assisting in the diagnosis. METHODS: The Association of Occupational and Environmental Clinics (AOEC) developed criteria that were used to review the peer-reviewed medical literature published in English. Based on this review, substances were designated either as a sensitizing agent or an irritant. The reviews were conducted by a board certified internist/pulmonologist/occupational medicine specialist from 2002 to 2007 and a board certified internist/occupational medicine physician from 2008- date. All reviews were then reviewed by the nine member AOEC board of directors. RESULTS: The original list of agents associated with new onset work-related asthma was derived from the tables of a text book on work-related asthma. After 13 years of review, there are 327 substances designated as asthma agents on the AOEC list; 173 (52.9%) coded as sensitizers, 35 (10.7%) as generally recognized as an asthma causing agent, four (1.2%) as irritants, two (0.6%) as both a sensitizer and an irritant and 113(34.6%) agents that still need to be reviewed. CONCLUSIONS: The AOEC has developed a readily available web based listing of agents associated with new onset work-related asthma in adults. The listing is based on peer-reviewed criteria. The listing is updated twice a year. Regular review of the peer-reviewed medical literature is conducted to determine whether new substances should be added to the list. Clinicians should find the list useful when considering the diagnosis of work-related asthma.

Hypersensitivity pneumonitis from ordinary residential exposures.

A previously healthy woman developed hypersensitivity pneumonitis of such severity that she required chronic systemic corticosteroid therapy for symptom control. Detailed investigation of her workplace and home environments revealed fungi in her typical suburban home, to which she had specific serum precipitating antibodies. Efforts to remove mold from the home were unsuccessful in relieving symptoms, and moving to another residence was the only intervention that allowed her to be withdrawn from corticosteroid therapy. Hypersensitivity pneumonitis is commonly associated with occupational or avocational exposures, such as moldy hay in farmers or bird antigen in bird breeders. We propose that hypersensitivity pneumonitis may occur in North America, as it does in Japan, from domestic exposures alone.

Effect of nitrous acid on lung function in asthmatics: a chamber study.

Nitrous acid, a component of photochemical smog and a common indoor air pollutant, may reach levels of 100 ppb where gas stoves and unvented portable kerosene heaters are used. Nitrous acid is a primary product of combustion and may also be a secondary product by reaction of nitrogen dioxide with water. Because the usual assays for nitrogen dioxide measure several oxides of nitrogen (including nitrous acid) together, previous studies of indoor nitrogen dioxide may have included exposure to and health effects of nitrous acid. To assess the respiratory effects of nitrous acid exposure alone, we carried out a double-blinded crossover chamber exposure study with 11 mildly asthmatic adult subjects. Each underwent 3-hr exposures to 650 ppb nitrous acid and to filtered room air with three 20-min periods of moderate cycle exercise. Symptoms, respiratory parameters during exercise, and spirometry after exercise were measured. A statistically significant decrease in forced vital capacity was seen on days when subjects were exposed to nitrous acid. This effect was most marked at 25 min and 85 min after exposure began. Aggregate respiratory and mucous membrane symptoms were also significantly higher with nitrous acid. We conclude that this concentration and duration of exposure to nitrous acid alters lung mechanics slightly, does not induce significant airflow obstruction, and produces mild irritant symptoms in asthmatics.

Indomethacin and methacholine tolerance in normal subjects. Role of prostaglandin synthesis in the attenuation of methacholine's effect during repeated inhalation challenges.

Within hours, tolerance occurs to repeated methacholine challenge in normal subjects, and this study examines whether prostaglandin synthesis produces this phenomenon. On two separate study days, ten nonasthmatic non-smoking subjects with measurable baseline responsiveness to methacholine performed five sequential methacholine challenge tests over 6 h. Pretreatment before each day consisted of either placebo tablets or 50-mg tablets of indomethacin given three times daily for 48 h prior to testing. Medications were administered in a single-blind crossover fashion, with study days assigned in random order and separated by at least 1 wk. Methacholine challenge tests were summarized by the PD20FEV1 (the provocative dose in cumulative breath units [cbu] required to produce a 20 percent fall in FEV1). Indomethacin pretreatment had no effect on baseline spirometry between the two study days; however, the baseline geometric mean PD20FEV1 fell from 145 +/- 2 cbu (+/- percent SD) after placebo pretreatment to 65 +/- 1 cbu (+/- percent SD) on the indomethacin day (p = 0.046). This effect of indomethacin on baseline airway responsiveness persisted when an additional ten subjects were studied to further investigate this finding. Significant tolerance to repeated methacholine challenges occurred on both study days, with geometric mean PD20FEV1 rising approximately 16-fold (p less than 0.0001) regardless of pretreatment received. This study demonstrates that the attenuation of methacholine's effect with repeated testing is not due solely to prostaglandin synthesis and must involve, in part, other mechanisms, such as changes in methacholine deposition, agonist-receptor interactions, or postreceptor responses. In addition, prostaglandin inhibitors may increase baseline methacholine responsiveness in healthy nonasthmatic subjects.

Repeated methacholine challenge produces tolerance in normal but not in asthmatic subjects.

Repeated methacholine challenge in normal nonasthmatic subjects (who require higher doses of methacholine than do asthmatic subjects to produce a 20 percent decrease in FEV1) can produce progressively diminishing methacholine responsiveness (or tolerance) with serial challenges. To determine whether tolerance to methacholine occurs in asthmatic subjects as it does in nonasthmatic subjects, we studied eight young (mean age, 24 years) mild asthmatic patients (occasional but not regular use of bronchodilator medications, PC20 methacholine range 0.1 to 7.0 mg/ml) who underwent five sequential methacholine challenges at 1.5-h intervals. Serially increasing concentrations of methacholine were given until FEV1 fell by 20 percent. Results were compared with those in seven nonasthmatic control subjects who underwent an identical protocol. As seen in previous studies, the normal subjects demonstrated significant tolerance to methacholine when each of five challenges was compared to the first. By contrast, in the asthmatic group, the mean cumulative dose of methacholine producing a 20 percent fall in FEV1 in the fifth challenge was not significantly different from the dose required in the first challenge. These results indicate that marked tolerance to methacholine does not occur in mild asthmatic patients with multiple repeated challenges over 6 h. The lower cumulative dose of methacholine required by asthmatic patients may be insufficient to produce tolerance.

A new index of prognostic severity for chronic asthma.

OBJECTIVE: To develop a prognostic clinical index for adults with chronic stable asthma. DESIGN: Analysis of data from a 48-week randomized, crossover trial of regular vs as-needed inhaled beta-agonist therapy. PATIENTS: Eligible patients included 70 men and women between the ages of 15 and 64 years with asthma for > 1 year. OUTCOME MEASURE: Asthma deterioration within 20 weeks, defined as either a marked decline in FEV1 (> or = 1.0 L or > or = 30% from baseline) or initiation of systemic corticosteroid therapy for asthma exacerbation. RESULTS: Three baseline factors independently predicted asthma deterioration: frequent symptoms on waking in the 4 weeks before baseline, past hospitalization for asthma, and age 35 years or older. Based on cross-stratification and consolidation of these prognostic factors, an index was developed that stratified subjects into four risk groups with distinctive deterioration rates of 9%, 21%, 39%, and 67% (p<0.001). CONCLUSION: For adults with chronic stable asthma, three simple clinical factors can be combined to stratify effectively for risk of subsequent asthma deterioration.

Effect of normobaric hyperoxia on airways of normal subjects.

Airway responsiveness to inhaled cholinergic agonist during the early stage of pulmonary O2 toxicity was examined to determine whether normobaric hyperoxia alters airway function. Eight healthy nonsmoking males with moderate base-line methacholine responsiveness breathed normobaric O2 (greater than or equal to 95%) over 12 h and on another occasion breathed air in an identical protocol. Vital capacity, expiratory flow, airway responsiveness to methacholine, and respiratory symptoms were measured at 0, 4, 8, and 12 h while subjects breathed O2 and 12 h afterwards. After 12 h, forced vital capacity was significantly decreased with O2 breathing but not with air breathing. At 4, 8, or 12 h of exposure and 12 h after exposure, there was no difference in methacholine sensitivity or reactivity between O2 and air-exposure trials. The earliest manifestations of pulmonary normobaric O2 toxicity in normal adults include diminished vital capacity and the onset of respiratory symptoms, but early O2 toxicity does not produce altered responsiveness to inhaled methacholine.

Effect of positive-pressure breathing on cardiovascular and thermoregulatory responses to exercise.

Five healthy male volunteers performed 20 min of both seated and supine cycle-ergometer exercise (intensity, 50% maximal O2 uptake) in a warm environment (Tdb = 30 degrees C, relative humidity = 40-50%) with and without breathing 10 cmH2O of continuous positive airway pressure (CPAP). The final esophageal temperature (Tes) at the end of 20 min of seated exercise was significantly higher during CPAP (mean difference = 0.18 +/- 0.04 degree C, P less than 0.05) compared with control breathing (C). The Tes threshold for forearm vasodilation was significantly higher (P less than 0.05) during seated CPAP exercise than C (C = 37.16 +/- 0.13 degrees C, CPAP = 37.38 + 0.12 degree C). The highest forearm blood flow (FBF) at the end of exercise was significantly lower (P less than 0.05) during seated exercise with CPAP (mean +/- SE % difference from C = -30.8 +/- 5.8%). During supine exercise, there were no significant differences in the Tes threshold, highest FBF, or final Tes with CPAP compared with C. The added strain on the cardiovascular system produced by CPAP during seated exercise in the heat interacts with body thermoregulation as evidenced by elevated vasodilation thresholds, reduced peak FBF, and slightly higher final esophageal temperatures.

Prolonged increased responsiveness of canine peripheral airways after exposure to O3.

Because it is relatively insoluble, the oxidant gas O3 may penetrate to small peripheral airways when it is inhaled. Increased responsiveness in large airways after O3 breathing has been associated with the presence of inflammatory cells. To determine whether O3 produces prolonged hyperresponsiveness of small airways associated with the presence of inflammatory cells, we exposed the peripheral lungs of anesthetized dogs to 1.0 ppm O3 for 2 h using a wedged bronchoscope technique. A contralateral sublobar segment was simultaneously exposed to air as a control. In the O3-exposed segments, collateral resistance (Rcs) was increased within 15 min and remained elevated approximately 150% throughout the 2-h exposure period. Fifteen hours later, the base-line Rcs of the O3-exposed sublobar segments was significantly elevated, and these segments demonstrated increased responsiveness to aerosolized acetylcholine (100 and 500 micrograms/ml). There were no differences in neutrophils, mononuclear cells, or mast cells (numbers or degree of mast cell degranulation) between O3 and air-exposed airways at 15 h. The small airways of the lung periphery thus are capable of remaining hyperresponsive hours after cessation of localized exposure to O3, but this does not appear to be dependent on the presence of inflammatory cells in the small airway wall.

Role of the parasympathetic nervous system in acute lung response to ozone.

We conducted an ozone (O3) exposure study using atropine, a muscarinic receptor blocker, to determine the role of the parasympathetic nervous system in the acute response to O3. Eight normal subjects with predetermined O3 responsiveness were randomly assigned an order for four experimental exposures. For each exposure a subject inhaled either buffered saline or atropine aerosol followed by exposure either to clean air or 0.4 ppm O3. Measurements of lung mechanics, ventilatory response to exercise, and symptoms were obtained before and after exposure. O3 exposure alone resulted in significant changes in specific airway resistance, forced vital capacity (FVC), forced expiratory flow rates, tidal volume (VT), and respiratory rate (f). Atropine pretreatment prevented the significant increase in airway resistance with O3 exposure and partially blocked the decrease in forced expiratory flow rates but did not prevent a significant fall in FVC, changes in f and VT, or the frequency of reported respiratory symptoms after O3. These results suggest that the increase in pulmonary resistance during O3 exposure is mediated by a parasympathetic mechanism and that changes in other measured variables are mediated, at least partially, by mechanisms not dependent on muscarinic cholinergic receptors of the parasympathetic nervous system.

Effect of exercise hemoconcentration and hyperosmolality on exercise responses.

We investigated the effects of a decrease in plasma volume (PV) and an increase in plasma osmolality during exercise on circulatory and thermoregulatory responses. Six subjects cycled at approximately 65% of their maximum O2 uptake in a warm environment (30 degrees C, 40% relative humidity). After 30 min of control (C) exercise (no infusion), PV decreased 13.0%, or 419 +/- 106 (SD) ml, heart rate (HR) increased to 167 +/- 3 beats/min, and esophageal temperature (Tes) rose to 38.19 +/- 0.09 degrees C (SE). During infusion studies (INF), infusates were started after 10 min of exercise. The infusates contained 5% albumin suspended in 0.45, 0.9, or 3.0% saline. The volume of each infusate was adjusted so that during the last 10 min of exercise PV was maintained at the preexercise level and osmolality was allowed to differ. HR was significantly lower (10-16 beats/min) during INF than during C. Tes was reduced significantly during INF, with trends for increased skin blood flow and decreased sweating rates. No significant differences in HR, Tes, or sweating rate occurred between the three infusion conditions. We conclude that the decrease in PV, which normally accompanies moderate cycle exercise, compromises circulatory and thermal regulations. Increases in osmolality appear to have small if any effects during such short-term exercise.

Effect of prolonged bed rest on lung volume in normal individuals.

Pulmonary function was assessed in supine subjects before, during, and after three separate bed-rest studies of 11 and 12 days duration. Forced vital capacity (FVC) increased during bed rest in each subject. Total lung capacity (TLC) was measured by helium dilution in one bed-rest study and increased in each subject, while residual volume and functional residual capacity of the respiratory system did not change. No change in FVC was found in an ambulatory control group using identical measurement techniques. Maintaining base-line plasma volume during one bed rest by the use of exogenous estrogen did not prevent an increase in FVC, and decreasing plasma volume with diuretics in ambulatory subjects to the same degree as seen in the bed rests did not cause an increase in FVC. We conclude that prolonged bed rest results in a small significant increase in TLC and that this change is not dependent on alterations in plasma volume.

Changes in plasma volume during bed rest: effects of menstrual cycle and estrogen administration.

Bed rest (BR) is associated with a decrease in plasma volume (PV), which may contribute to the impaired orthostatic and exercise tolerances seen immediately after BR. The purpose of this study was to determine whether increases in blood estrogen concentration, either during normal menstrual cycles or during exogenous estrogen administration, would attenuate this loss of PV. Nineteen healthy women (21-39 yr of age) completed the study. Twelve women underwent duplicate 11-day BR without estrogen supplementation. PV decreased significantly (P less than or equal to 0.01) during both BR's, from 2,531 +/- 113 to 2,027 +/- 102 ml during BR1 and from 2,445 +/- 115 to 2,244 +/- 96 ml during BR2. The women who began BR in the periovulatory stage of the menstrual cycle (n = 3), a time of elevated endogenous estrogens, had a transient delay in loss of PV during the first 5 days of BR. Women who began BR during other stages of the menstrual cycle (n = 17) showed the established trend to decrease PV primarily during the first few days of BR. Seven additional women underwent a single 12-day BR while taking estrogen supplementation (1.25 mg/day premarin). PV decreased during the first 4-5 days of BR, then returned toward the pre-BR level during the remainder of the BR (pre-BR PV, 2,525 +/- 149 ml; post-BR PV, 2,519 +/- 162 ml). Thus menstrual fluctuations in endogenous estrogens appear to have only small transient effects on the loss of PV during BR, whereas exogenous estrogen supplementation significantly attenuates PV loss.

Epidemiology and etiology of lung cancer.

Lung cancer incidence and mortality have increased sharply during this century, making it a common cause of death and the most frequent fatal cancer in men and women. The known behavioral and environmental causes--cigarette smoking, asbestos and other occupational carcinogens, radon, and environmental tobacco smoke--are responsible for the majority of cases. Although the proportion of adults who smoke in the United States has dropped since the mid-1960s, the incidence of lung cancer in the United States is expected to continue to rise through the 1990s because of the long latency between initiation of smoking and the occurrence of the disease. Efforts to alter lung cancer mortality by early detection and better therapy have not yet succeeded in reversing this trend. The modification of risk factors is currently the most effective approach to reducing future lung cancer deaths.

Determination of disability for patients with advanced lung disease.

To conclude, impairment ratings differ among various diseases and compensation programs. It therefore is important to note, at the outset, which compensation program the patient is eligible for because the requirements of the different programs may vary. The physician report must clearly state an opinion using terminology understandable to lay people. It should include the diagnosis, whether the condition is work-related or not, the evidence of impairment, and the severity of impairment. It should also state whether the resultant disability is temporary or permanent. In the case of work-related diseases, apportionment should be addressed. Finally, patients with advanced lung disease may be totally disabled from certain types of employment and yet may be eligible for vocational training. It is appropriate to describe the types of jobs and work the patient physically can and cannot do.

Metal fume fever: characterization of clinical and plasma IL-6 responses in controlled human exposures to zinc oxide fume at and below the threshold limit value.

Results from animal and preliminary human exposure studies have called into question whether the 5 mg/m3 8-hour time-weighted average threshold limit value (TLV) for zinc oxide fume is sufficient to protect workers against metal fume fever. The objectives of this study were to determine the clinical effects of exposures to low concentrations of zinc oxide and to ascertain whether these exposures elevated circulating levels of specific cytokines, which could account for the symptoms of the metal fume fever syndrome. Thirteen resting naive subjects inhaled, on separate days, air and 2.5 and 5 mg/m3 of furnace-generated zinc oxide fume for 2 hours. Subjects recorded symptoms and temperature and had blood drawn before and after each exposure. The mean (+/- SE) maximum rise in oral temperature at 6 to 12 hours after exposure was 1.4 +/- 0.3 degrees F after 5 mg/m3, compared with 0.6 +/- 0.5 degrees F after air exposure (P < 0.05). Mean temperature was also elevated after exposure to 2.5 mg/m3 zinc oxide (1.2 +/- 0.3 degrees F). In a parallel fashion, plasma levels of interleukin 6 (IL-6), a pyrogen, were significantly elevated after exposure to 5 mg/m3 zinc oxide. Mean IL-6 values (pg/mL) at pre-exposure and at 3 and 6 hours post-exposure were 1.9 (+/- 0.6), 2.8 (+/- 0.7), and 2.9 (+/- 0.6), respectively, on the air day and 1.6 (+/- 0.6), 4.4 (+/- 1.2), and 6.4 (+/- 1.1) on the 5 mg/m3 zinc oxide day. Zinc oxide exposure did not significantly affect plasma levels of tumor necrosis factor. Total symptom scores peaked 9 hours after the 5 mg/m3 zinc oxide exposure. Myalgias, cough, and fatigue were the predominant symptoms reported. Inhalation of zinc oxide for 2 hours at the current TLV of 5 mg/m3 produces fever and symptoms along with elevation in plasma IL-6 levels.

Airway reactivity in welders: a controlled prospective cohort study.

In a 3-year survey, respiratory symptoms, spirometry, and methacholine reactivity were measured annually in welders (n = 51) and non-welder controls subjects (n = 54) to determine whether welding-related symptoms are associated with accelerated decline in lung function or changes in airway reactivity. In the cross-workshift study, maximal midexpiratory flow rate declined reversibly during a welding day, whereas 1-second forced expiratory volume and forced-vital capacity were unchanged. In the longitudinal study, the welders had significantly more reversible work-related symptoms of cough, phlegm, wheeze, and chest tightness than the non-welder shipyard control subjects. In this group of actively working welders, across-workshift changes in midflow and reversible symptoms were related to the welding occupation, but evidence for chronic irreversible effects on spirometry or airway reactivity was not seen over the 3 years of observation. The short period of observation was not optimal for detecting a chronic effect on lung function. Work practices and engineering controls may be successfully preventing irreversible respiratory effects, but not mild reversible effects, in this group of welders.

Hearing conservation for farmers: source apportionment of occupational and environmental factors contributing to hearing loss.

Those who work on farms continue to have a strikingly high prevalence of hearing loss, despite efforts to promote hearing conservation in agriculture. To develop improved hearing conservation programs, we performed a source apportionment analysis for hearing loss in a large, multiphasic health survey, the New York Farm Family Health and Hazard Survey. We used information from audiometric, otoscopic, and tympanometric examinations; detailed general health and farm exposure interviews; and a second interview that focused on additional potential determinants of hearing loss. Hearing loss on audiometry was significantly associated with increased age, male gender, education through high school or less, lifetime years of hunting with guns, lifetime years of use of a grain dryer, and a history of spraying crops during the previous year. Hearing conservation programs for farmers should thus be directed toward reduction in noise exposure, both from occupational and non-occupational sources. Additional study is needed to evaluate the association seen between crop spraying and hearing loss.