Hypermagnesemia does not increase brain intracellular magnesium in newborn swine.

Phosphorus-31 magnetic resonance spectroscopy was used in 2-day (n = 4) and 40-day (n = 4) miniswine to determine whether plasma hypermagnesemia alters brain intracellular magnesium concentration and if the plasma-brain intracellular magnesium relationship changes with age. At control, brain intracellular magnesium concentration was similar in the 2-day (0.24 +/- 0.04 mM) and 40-day groups (0.21 +/- 0.01 mM). Intravenous infusions of magnesium sulfate (MgSO(4), 60 minute) raised plasma magnesium concentration to 4-6 mM in both groups. During and for 3 hours after MgSO(4) infusions, there were no changes in brain intracellular magnesium concentration in either group and no correlation between plasma and brain intracellular magnesium (r = 0.11 and 0.08 for 2- and 40-day groups, respectively). Brain intracellular magnesium concentration appears to be tightly regulated.

Silica, silicosis, and lung cancer: a response to a recent working group report.

The relationship between crystalline silica and lung cancer has been the subject of many recent publications, conferences, and regulatory considerations. An influential, international body has determined that there was sufficient evidence to conclude that quartz and cristobalite are carcinogenic in humans. The present authors believe that the results of these studies are inconsistent and, when positive, only weakly positive. Other, methodologically strong, negative studies have not been considered, and several studies viewed as providing evidence supporting the carcinogenicity of silica have significant methodological weaknesses. Silica is not directly genotoxic and is a pulmonary carcinogen only in the rat, a species that seems to be inappropriate for assessing particulate carcinogenesis in humans. Data on humans demonstrate a lack of association between lung cancer and exposure to crystalline silica. Exposure-response relationships have generally not been found. Studies in which silicotic patients were not identified from compensation registries and in which enumeration was complete did not support a causal association between silicosis and lung cancer, which further argues against the carcinogenicity of crystalline silica.

Asbestos exposure and laryngeal cancer.

OBJECTIVE: To carry out a systematic review of the evidence relating asbestos exposure to the risk of laryngeal cancer. METHOD: All identified studies of asbestos workers providing data on laryngeal disease were reviewed, together with studies of laryngeal cancers giving epidemiological or experimental evidence of associated exposures. RESULTS: Confounding due to smoking and alcohol intake, and to a lesser extent diet and socio-economic factors, creates a major difficulty over the identification of any asbestos or other occupational effect. Not only are smoking and alcohol independently associated with large increases in relative risk (RR) of laryngeal cancer, but also have a synergistic effect with each other. Few of the studies provide details of either habit. Among 24 prospective studies for which a standardized mortality ratio (SMR) was available, nine had an SMR at or below unity, and among a further 11 without an SMR for comparison, in only one was there a clear excess risk. In 17 retrospective studies, only two showed a significantly increased RR. Evidence from animal experiments, studies of associations with pleural plaques, and autopsy findings also appear negative or inconclusive. CONCLUSION: The evidence does not indicate that asbestos exposure increases the RR of laryngeal cancer.

Age-dependent differences in the relationship between plasma and brain extracellular fluid concentrations of magnesium after MgSO4 infusions in miniswine.

Magnesium is a potential neuroprotective agent in the treatment of head injury and ischemia whose efficacy is likely determined by increases in brain extracellular fluid (ECF) magnesium, which in turn depends on its concentration in plasma. The objectives of this study were to: 1) examine the effects of increasing plasma magnesium concentration ([Mg]plasma) to 4-6 mM on brain ECF magnesium concentration ([Mg]ECF) and 2) determine whether maturational changes occur in the transfer of magnesium into brain ECF for newborn and more mature (approximately 1 month old) miniswine. Increases in [Mg]plasma by systemic administration of MgSO4 resulted in similar maximal elevations in brain [Mg]ECF for both age groups (193+/-76% versus 253+/-106% of control for newborn and 1-month-old miniswine, respectively). Calculations of half-lives (t1/2) for the increase and decrease in magnesium concentration (t1/2 uptake and t1/2 clearance) were used to characterize magnesium kinetics in plasma and brain ECF. Plasma magnesium uptake was shorter in 1-month-old (t1/2 = 11.1+/-0.9 min) compared with newborns (12.9+/-1.7 min, p < 0.05). The faster increase in [Mg]plasma probably contributed to a faster uptake of brain [Mg]ECF in 1-month-old compared with newborn swine (t1/2 uptake = 27.9+/-12.8 versus 46.0+/-20.9 min, respectively, p < 0.05). Although plasma magnesium clearance was shorter in 1-month-old swine compared with newborn (t1/2 = 34.3+/-7.0 versus 74.7+/-33.7 min, respectively, p < 0.05), the clearance of magnesium from the brain ECF was similar for each age group. Reductions in blood pressure and heart rate occurred during hypermagnesemia and were similar in each age group. This study shows that acute elevations in [Mg]plasma to 4-6 mM result in similar relative increases in brain [Mg]ECF for both newborn and 1-month-old miniswine. However, there are maturational differences, as demonstrated by the faster rate of magnesium uptake into the ECF observed in the older miniswine.

Pregnancy-induced hypertension and reduced intraventricular hemorrhage in preterm infants.

Increasing evidence suggests that the incidence of periventricular intraventricular hemorrhage (PV-IVH) is lower in infants born to mothers with pregnancy-induced hypertension (PIH). The mechanism or mechanisms accounting for this reduction remain unclear but may be related to PIH itself, medications used to treat the mother (e.g., magnesium sulfate), or to obstetrical management. In this retrospective analysis, we determined the incidence of PV-IVH in singleton preterm infants weighing less than 1,500 gm born to mothers with PIH who were also administered magnesium sulfate. Between January 1988 and December 1994, 254 singleton infants born to mothers with PIH and 1,083 born to mothers without PIH were studied. PV-IVH developed in 360 (26.9%) of the 1,337 infants; 977 (74.1%) infants did not exhibit PV-IVH. The incidence of total as well as severe PV-IVH was lower in infants born to mothers with PIH than in those without PIH [i.e., 16% vs 30% (total) and 8.2% vs 14.5% (severe), P < .001] with an odds ratio (OR) estimate of 0.43 [95% confidence interval (CI) 0.30, 0.61]. Infants born to mothers with PIH weighed more, (1,152 +/- 250 gm vs 1,058 +/- 283 gm, P < .001) and were more mature (30.1 +/- 2.9 vs 27.7 +/- 31 weeks, P < .001) than infants born to mothers without PIH. These infants were also less likely to be exposed to labor (57% vs 93%), to be delivered by cesarean section (81% vs 35%), and to require intubation (49% vs 58%), but more likely to exhibit respiratory distress syndrome (RDS) (47% vs 38%, P < .01). By logistic regression analysis, after seven variables (i.e., PIH, gestational age, and birthweight, both modeled as cubic polynomials; labor; intubation; RDS; and race) were included in the analytic model, PIH remained a significant predictor of IVH: P = .006, OR = 0.54 (95% CI 0.349, 0.847). These data indicate a significantly lower incidence of PV-IVH of approximately 50% in infants born to mothers with PIH as compared with the incidence in infants born to mothers without PIH, despite their higher incidence of RDS. The reduction in PV-IVH may be directly related to the PIH; however, the independent role of antenatal magnesium sulfate administration requires further study.

Asbestos in New York City public school buildings--public policy: is there a scientific basis?

The most recent of New York City's asbestos emergencies occurred in the late summer of 1993. It prevented schools from opening that fall, precipitated much media excitement, and caused a flurry of widespread abatement activities. This resulted in large measure from the U.S. Environmental Protection Agency's subjective school building inspection policy concerning identification of asbestos hazards in buildings and the subsequent Asbestos Hazard Emergency Response Act mandate for inspection. Data on concentrations of asbestos in the air, important for the calculation of risk to building occupants, were not required and therefore not obtained, as part of the abatement strategy or priority setting. Based on fiber-in-air measurements obtained elsewhere, the calculated risk to NYC school children, using the most pessimistic models, was less than six excess cancer deaths per million lifetimes equivalent to smoking less than a dozen cigarettes in a lifetime. The NYC administration responded to pressure from parent groups concerned with perceived asbestos risks to their children by closing the schools. The hysteria occurred because much of EPA's policy lacked a scientific basis for risk evaluation and assessment.

An analysis of the inter-relationships among multiple bronchoalveolar lavage and serum determinations, physiologic tests, and clinical disease activity in patients with sarcoidosis.

Analysis of epithelial lining fluid from the lungs of patients with sarcoidosis frequently suggests the presence of an alveolitis. Several markers of this inflammatory response were quantitated in bronchoalveolar lavage fluid and serum from 45 non-smoking patients with sarcoidosis. All markers were elevated significantly compared to those from 19 normal controls. The degree of statistical correlation among all data was assessed. Pulmonary function tests, 67Gallium lung scans, and a clinical index of disease activity also were quantitated. When patients were grouped by the number of abnormal BAL lavage and serum markers, those patients with elevated values of five or more of these markers had significantly worse clinical disease and lower carbon monoxide diffusing capacities. These results indicate that pulmonary sarcoidosis is an immunologically heterogeneous disease and that measurement of several markers of disease activity may be required to accurately estimate the activity of the lung disease.

Phagocyte enzymes in bronchoalveolar lavage from patients with pulmonary sarcoidosis and collagen vascular disorders.

The balance between proteases and antiproteases in the lower respiratory tract is believed to play a role in the outcome of interstitial lung diseases. In this cross-sectional study, we measure several phagocyte derived enzymes, namely plasminogen activator, neutrophil elastase and an ill-defined protease active on the trialanine chromophore substrate succinyl-alanine3-nitroanilide (SLAPN) in bronchoalveolar lavage (BAL) fluid from 42 patients with pulmonary sarcoidosis and from 43 patients with collagen vascular disease (CVD), 22 without lung disease (group I) and 21 associated with parenchymal lung disease (group II). The results show: a) that sarcoidosis is associated with increased plasminogen activator activity and with the presence of enzymatic activity against SLAPN corresponding at least in part to a metalloprotease; b) that CVD in the absence of radiographic lung disease is associated with an increase of plasminogen activator activity and increased levels of alpha 1-antiprotease-neutrophil elastase complexes; c) that the majority of untreated CVD (group II) patients have detectable levels of neutrophil elastase activity. These data show that patients with pulmonary sarcoidosis and CVD have different enzymatic profiles in their lower respiratory tract as assessed by BAL. Thus, sarcoidosis (mostly lymphocytic) is associated with enhanced macrophage-derived proteolytic activity in BAL, while CVD patients both with and without lung disease have increased neutrophil counts and neutrophil elastase complexed to alpha 1-protease inhibitor and presumably inactive in BAL. Finally, only BAL from untreated CVD patients with interstitial lung disease contain neutrophil elastase activity. This latter activity could contribute to the lung lesions frequently observed in these disorders.

Asbestos: scientific developments and implications for public policy.

Asbestos is a commercial term for a group of fibrous minerals often associated with the development of pulmonary interstitial fibrosis (asbestosis), lung cancer, and malignant mesothelioma in occupationally exposed individuals. The pathogenicity of different forms of asbestos varies--long, thin amphibole fibers are most pathogenic, particularly in the induction of mesothelioma. Available data do not support the concept that low-level exposure to asbestos is a health hazard in buildings and schools. The concentration of asbestos fibers in air, type of asbestos, and size of fibers must be considered in evaluation of potential health risks.

Mepacrine impairs neutrophil response after acute lung injury in rats. Effects on neutrophil migration.

Intraalveolar leukocytosis is integral in initiating and perpetuating airspace inflammatory reactions. We used intratracheal instillation of silica suspensions in adult male rats to cause neutrophil flux (32% increase over saline controls) without creating a protein leak, so simulating an early inflammatory response. We examined the in vivo effects of a known phospholipase A2 inhibitor (mepacrine) and the two mast cell active agents (cyproheptadine and reserpine) on lung lavage fluid chemotactic capability, alveolar macrophage (AM) production of chemotactic factor(s), and neutrophil diapedesis. Only mepacrine significantly depressed the leukocytosis (from 32% to 8% of total cells), with a similar diminution in AM chemotaxin production. Separate in vitro experiments using mepacrine-pretreated neutrophils and macrophages gave evidence that mepacrine: (1) diminishes neutrophil response to chemotaxin(s), (2) inhibits spontaneous, random neutrophil movement, and (3) diminishes macrophage-derived chemotactic factor production. These observations suggest that the earliest events in alveolar inflammatory reactions probably involve local production of chemotactic factors by AM, and that mepacrine's anti-inflammatory action results from inhibitory influences on both macrophage and neutrophil populations.

Asbestos exposure and laryngeal cancer: an analysis of the epidemiologic evidence.

We conducted a critical analysis of the available epidemiologic investigations on the causal relationship between asbestos exposure and laryngeal cancer. A review of nine case-control studies indicates that the estimated risk (odds ratio) attributable to asbestos exposure alone is negligible when smoking and ethanol intake are appropriately controlled for. Six of the 12 cohort studies demonstrated no significant increase in the standardized mortality ratio due to asbestos exposure. The remaining six longitudinal studies showed an increased standardized mortality ratio from 1.91 to 5.41 but no adjustment was made for the confounding effects of smoking and ethanol consumption. In conclusion, the available epidemiologic evidence does not support a causal association between asbestos exposure and laryngeal cancer.

The neutrophil, friend or foe: pharmacologic manipulation.

We describe some features of neutrophil migration and their defense or injury mechanism in the lung. Employing an intratracheal silica instillation model in rats, we examined the effects on the silica-induced neutrophil migration of mepacrine, colchicine and reserpine on such migration in vivo and of mepacrine on phorbol-stimulated elastase release and superoxide anion generation by human neutrophils in vitro. Mepacrine sharply diminished neutrophil migration, O2 and elastase release. Colchicine produced variable effects on neutrophil migration which was unaffected by the mast cell agent reserpine. The implications for lung injury and therapy are discussed.

Acute effect of nitrogen dioxide exposure on the functional activity of alpha-1-protease inhibitor in bronchoalveolar lavage fluid of normal subjects.

Nitrogen dioxide is one form of an oxidizing free radical that is sufficiently stable to exist in relatively high concentrations in ambient air and cigarette smoke. We examined the effect of NO2 exposure on the functional activity against pancreatic elastase of alpha-1-protease inhibitor (alpha 1PI) in bronchoalveolar lavage (BAL) fluid of nonsmoking subjects. Ten nonsmokers (mean age, 25 +/- 2 SE yr) were exposed to NO2 (3 or 4 ppm) for 3 h with intermittent exercise. Seven nonsmokers (mean age, 24 +/- 2 SE yr) underwent a similar protocol but were exposed to NO2-free air and served as control subjects. Bronchoalveolar lavage was performed 3.5 to 4 h after the end of exposure. Exposure to NO2 caused a 45% decrease in functional activity of alpha 1PI in BAL. There was no significant difference in immunoreactive alpha 1PI between the groups whether expressed as micrograms per 100 ml of recovered fluid or per milligram of albumin. This inactivation of alpha 1PI was not associated with any neutrophil migration into the air spaces of the lung. The "elastaselike" activity of BAL using synthetic elastinlike chromophore substrate succinyl-trialanine-nitroanilide showed no significant difference between the NO2-exposed group (221 +/- 39 SE ng/dl BAL) and the control group (196 +/- 61 SE ng/dl BAL). Assay for human leukocyte elastase (HLE) in concentrated BAL using the synthetic substrate Methoxysuc-Ala3-Pro-Val-aminomethylcoumarin did not detect any HLE activity in the BAL. These results showed that nonsmoking subjects exposed to relatively low concentrations of NO2 for a short time have a significant inactivation of alpha 1PI in the lower respiratory tract fluid than did nonsmoking control subjects.