Ronald D. Fairshter

Role of Altemaria and Penicillium spores in the pathogenesis of asthma

The ability to harvest spore-rich isolates of molds permitted quantitative studies of their role in the pathogenesis of asthma. Alternaria and Penicillium were selected as examples of ubiquitous molds that readily induce IgE antibodies and are of contrasting sizes. Extracts from those spores were prepared for skin tests and aerosol bronchial challenges. Intact spores were used in the same subjects in bronchial challenges delivered by a Spinhaler. Seven patients with a history of mild asthma received a total of 16 bronchial challenges with the mold to which they had been sensitized. Provocative doses in spore equivalents for a 35% drop in SGaw, 20% drop in FEV1, or 25% drop in PEFR were sought for each challenge. Density dependence-flow rates were also determined. Environmental spore survey data were obtained and compared with the challenge doses for these spores. It was found that immediate-type asthma was readily provoked by both whole spores and by their extracts, in some subjects fewer intact than extracted spores were required, delayed-type asthma occurred only after whole spore challenges, SGaw was the most sensitive and equally specific of the pulmonary function tests, and provocative doses of spore equivalents were within natural exposure ranges. The study confirmed that Alternaria and Penicillium spores in relatively natural states and numbers were potent immunopathogens for asthma.

Magnesium and potassium therapy in multifocal atrial tachycardia

Eight patients with multifocal atrial tachycardia received 7 to 12 gm of magnesium sulfate intravenously over a 5-hour period. Potassium supplements were given initially or added later. Initial arterial blood gases showed mean pH 7.48 +/- 0.03, PcO2 39.7 torr, PO2 72 torr, HCO-3 29.8 +/- 4.5 mEq/L, and base excess 6.84 +/- 3.78 mEq/L. Initial serum magnesium correlated well with initial serum potassium. Three patients had subnormal levels of magnesium and potassium. The level of serum magnesium rose with an intravenous injection magnesium and serum potassium levels tended to fall unless they were supplanted with potassium. There were seven patients who retained more than 20 mEq of the infused magnesium. Multifocal atrial tachycardia was successfully converted to sinus rhythm or sinus tachycardia in seven patients. Multifocal atrial rhythm (at slow rate) persisted in one patient. Two patients with falling serum potassium levels required potassium supplements. Results of this study confirm that patients with multifocal atrial tachycardia respond favorably to parenteral magnesium and potassium. We believe that serum magnesium administered together with serum potassium stabilizes the ionic balance of atrial cells and thus prevents spontaneous ectopy.

Postprandial exercise-induced anaphylaxis

A variety of systemic reactions associated with exercise are increasingly being recognized. We studied an atopic individual whose job-related activities involved strenuous running that often terminated in an episode of syncope and hypotension preceded by cutaneous pruritus, warmth, urticaria, and angioedema. These attacks occurred only after meals, but no foods appeared to elicit symptoms without subsequent exercise. The subject underwent three exercise challenges in the laboratory under the following conditions: (1) fasting state, with heat-dissipating clothing. (2) fasting, with heat-retention clothes, and (3) after a meal. Blood pressure decreases and minimum skin reactivity were observed for (1) and (2), and reproduction of syncope, hypotension, and further cutaneous manifestation were observed only after (3). Venous and arterial plasma determinations for complement activation (C4, C4d, and CH50) and histamine before, during, and after exercise were not abnormal. Although other vasodepressor mediators may have been liberated, at least part of the mechanism for postprandial exercise-related syncope may be attributed to a shift of blood flow to the splanchnic as well as skeletal muscle vasculature.

A comparison of incremental exercise tests during cycle and treadmill ergometry.

We evaluated a short-duration maximum exercise test by comparing a 15-s incremental exercise protocol with a 1-min incremental method. Twenty normal men and women were studied using cycle and/or treadmill ergometry. In subjects tested on both exercise devices, anaerobic threshold and maximal oxygen uptake (VO2max) were higher for both protocols on the treadmill than on the cycle ergometer (P less than 0.001). However, when the 15-s and 1-min tests were compared using the same device (treadmill or cycle), there were no significant differences between protocols in anaerobic threshold or maximum exercise values of minute ventilation, respiratory rate, tidal volume, VO2max, oxygen pulse, and peak expiratory flow rate. Linear regression analyses indicated differences between the 15-s and 1-min protocols when cardiopulmonary measurements were related to power; however, the two protocols were comparable when cardiopulmonary data were related to oxygen uptake. Comparisons between protocols or between exercise devices were not systematically different in large vs small individuals, or in men vs women. Short-duration incremental exercise tests appear to be reliable, practical methods for assessing exercise performance in normal individuals.

In vivo and in vitro cell-mediated immunity to tetanus toxoid in adults

The purpose of this study was to evaluate tetanus toxoid (TT) as an indicator of cutaneous delayed hypersensitivity (CDH) in adults. Fifty-two normal subjects, aged 25 to 64 yr, were skin tested with TT and streptokinase-streptodornase (SK/SD). Lymphocyte transformation was studied in seven normal TT reactors, four normal TT nonreactors, and seven hospitalized anergic patients. CDH was common with both TT and SK/SD; 90% of the adults, aged 25 to 39 yr, had CDH reactions to TT and 79% had CDH reactions to SK/SD. In adults aged 40 to 64 yr, 75% had DCH reactions to TT and 59% had CDH reactions to SK/SD. Lymphocyte transformation to TT correlated well with TT skin-test results. Punch biopsy specimens of TT reactions 48 hr after skin testing demonstrated DCH. We conclude that TT is an excellent antigen for assessing the presence or absence of CDH in adults aged 25 to 64 yr.

Comparison of Clinical Effects and Pharmacokinetics of Once- Daily Uniphyl and Twice-Daily Theo-Dur in Asthmatic Patients

A pharmacokinetic study using theophylline syrup in adult asthmatic patients demonstrated a mean apparent volume of distribution of 0.38 liters/kg, mean elimination rate constant of 0.10 hours-1, and variable rates of clearance of theophylline (total body clearance of 0.38 to 0.96 ml/kg per minute). Subsequently, the asthmatic patients were compared using a cross-over design after maintenance Uniphyl (once daily at 8 a.m. or at 8 p.m.) and Theo-Dur (twice daily at 8 a.m. and 8 p.m.). Total daily maintenance theophylline dosage, calculated from the pharmacokinetic data, was identical in all three cross-over phases. At the end of each phase, plasma theophylline levels were measured every two hours and spirometric determinations were made every four hours (excluding 4 a.m.) for 24 hours. The following results were observed: highest peak and mean plasma theophylline concentration and area under the concentration-time curves with evening Uniphyl (p less than 0.05); prolonged time-to-peak theophylline concentration after nocturnal compared with daytime dosing; diurnal variation in pulmonary function and plasma theophylline concentrations; no significant differences between the three maintenance treatments in asthmatic symptoms or spirometric results.

Ultrastructural evidence of pulmonary capillary endothelial damage from paraquat.

Because of lack of agreement concerning the toxicity of paraquat to the pulmonary microvasculature, we have undertaken an electron microscopic study of lungs of paraquat-treated rats. Rats were injected with paraquat or sterile water (controls) intraperitoneally; the animals were then killed at 24-h intervals for 10 days post-injection. In the control animals, lung ultrastructure remained normal throughout the study. In treated animals, the initial evidence of alveolar epithelial injury occurred 24 h post-paraquat. By 48 h, severe fragmentation and desquamation of membranous pneumocytes occurred, and both alveolar and interstitial edema were present. Epithelial damage was maximal 72-96 h post-paraquat. Pulmonary capillary endothelial abnormalities were less extensive than the alveolar epithelial lesions. Endothelial damage was first observed 48 h post-paraquat. In endothelial cells on the septal (thick) side of the capillaries, the number of pinocytotic vesicles was significantly increased (P less than 0.05) from 48 to 96 h post-paraquat. In endothelium adjacent to damaged epithelium, abnormalities included hydration, fragmentation, discontinuity, and widened intercellular junctions; these were maximal 72-96 h post-paraquat. Although other mechanisms are probably important, damaged pulmonary capillary endothelium seems to be a factor favoring paraquat-induced pulmonary edema.

Paraquat poisoning: An analytical toxicologic study of three cases

Paraquat concentrations were measured in tissue, serum, urine and hemodialysate obtained from 3 patients who died 16.5 h, 22 days and 23 days after ingestion. In the patient who died 16.5 h post-ingestion, tissue paraquat levels were high. Kidney and liver had paraquat concentrations of 14 micrograms/g and 13.2 micrograms/g respectively, whereas lung tissue had a paraquat level of 3.8 micrograms/g. Low concentrations of paraquat were detectable in the tissues of the patients who died 22 and 23 days post-ingestion. Early in the poisoning, serum paraquat levels were high and large quantities of paraquat could be removed by both hemodialysis and forced diuresis. During an 8-h period, 713 mg of paraquat were removed by hemodialysis and 340 mg by forced diuresis. After the day of ingestion, little paraquat could be removed by hemodialysis or by forced diuresis; however, at all stages of the poisoning studied, hemodialysis was more effective than forced diuresis in removing paraquat from the blood.

P pulmonale in status asthmaticus

We studied 129 patients during acute, severe asthmatic attacks. Electrocardiograms showed P pulmonale in 49% of patients who had an arterial carbon dioxide tension (PaCo2) greater than or equal to 45 mm Hg and an arterial pH less than or equal to 7.37, whereas P pulmonale was present in only 2.5% of asthmatics who had a PaCO2 less than or equal to 44 mm Hg and a pH greater than or equal to 7.38 (p less than 0.001). P wave and QRS axes were 79 +/- 8 degrees and 80 +/- 20 degrees, respectively, in the presence of P pulmonale. When P pulmonale disappeared, the P wave and QRS axes shifted significantly to the left (p less than 0.001). Electrocardiographic P pulmonale persisted 12 to 60 hr after correction of hypoxemia, hypercapnia, and acidosis. In 7 patients with P pulmonale and respiratory acidosis, cardiac catheterization demonstrated normal artery pressures (PAPs) measured relative to atmospheric pressure. In 12 of these peak inspiratory pulmonary artery transmural pressures (PATPs) were increased. Since increased right heart transumural pressures could result in chamber distention, these data are consistent with the hypothesis that reversible P pulmonale in status asthmaticus is explainable on the basis of markedly negative tidal pleural pressures and increased right heart transmural pressures.

Effect of dimethylthiourea on paraquat toxicity in rats

We evaluated the utility of dimethylthiourea ( DMTU ), a hydroxyl radical scavenger, as potential therapy for paraquat poisoning. Seventy-five male Sprague-Dawley rats were divided into four groups ( DMTU -paraquat, paraquat, DMTU , control) and studied for up to 10 days. Clinical observations (dyspnea, weakness), mortality, hepatic and renal function tests, body weights, and histologic studies were performed. There was no mortality in the DMTU and control groups although various histologic and biochemical studies suggested that DMTU may be both hepatotoxic and nephrotoxic. In contrast, 74% of DMTU -paraquat rats and 39% of paraquat rats died (p less than 0.01). In addition, toxicity was clearly earlier in the DMTU -paraquat group than in the paraquat group. Hence, rather than being protective, treatment with dimethylthiourea was associated with increased mortality in paraquat-poisoned rats.