Effect of theophylline on cortisol secretion

Theophylline is thought to improve asthma by increasing intracellular cyclic adenosine 3'-5'-monophosphate (cAMP) levels. It has been demonstrated in experimental animals that elevation of intracellular cAMP in the adrenal cortex causes an increased secretion of cortisol. We studied whether therapeutic doses of theophylline given intravenously and orally to human subjects over 3 days would increase cortisol secretion. A single-blind, 6-day protocol was employed in five normal and five asthmatic volunteers. Adrenal function was monitored by 8 A.M. and 4 P.M. serum cortisol and adrenocorticotropic hormone (ACTH) levels; daily 24-hr urine for urinary-free cortisol (UFF), 17-hydroxysteroids (17-OH), and 17-ketosteroids (17-KS); and alternate-day cortisol secretory rates (FSR) measured by isotope dilution after intravenous 14C-cortisol. Serum theophylline concentration also was monitored. Results in normal and asthmatic subjects were similar. Theophylline caused a significant but transient increase in UFF and 17-OH excretion. Urine volumes also increased significantly, suggesting that the renal effect of theophylline accounted for the increased UFF and 17-OH excretion. FSR increased during the first 24 hr after theophylline in eight of nine cases (p < 0.05 by sign test), mean values increasing from 14.2 to 19.3 mg, but this effect had dissipated by day 3 of theophylline administration. In contrast to these findings, theophylline had no effect on serum cortisol or ACTH or urinary 17-KS. It is likely that serum cortisol and ACTH remained unchanged because the increase in cortisol secretion was offset by a concomitant increase in cortisol clearance. It is concluded that theophylline produces a small, transient increase in cortisol secretion and clearance, and this effect is similar in asthmatic and normal subjects.     

Effect of histamine and methacholine on nasal airway resistance in atopic and nonatopic subjects: Comparison with bronchial challenge and skin test responses

Serial nasal, intracutaneous, or bronchial challenges were carried out with solutions containing 2- or 3-fold increments in histamine (H) or methacholine (Meth) concentration until nasal airway resistance (NAR) increased by more than 100%, a large intracutaneous reaction was elicited, or FEV₁ decreased by 20% or more. Thirty nonatopic and 48 asymptomatic atopic subjects were studied, the latter group divided into rhinitic patients with and without asthma. Several types of data analysis demonstrated there was no significant difference in the nasal or cutaneous effects of H or Meth between the atopic and nonatopic groups. Comparable results were obtained in a subgroup of 39 subjects (13 normal, 13 atopic, and 13 atopic with asthma) who underwent all six test sequences (i.e., nasal, cutaneous, and bronchial with both drugs). As expected, the asthmatics showed significantly increased bronchial reactivity to both agents. In comparison with Meth, H had a much greater effect on the nasal mucosa and skin than on the bronchi. It is concluded that, contrary to bronchial responses, but in accord with cutaneous reactivity, the nasal responses of nonatopic subjects, atopic persons with allergic rhinitis alone, and subjects with both allergic rhinitis and asthma show no intergroup differences on testing with H or Meth.     

Calculation of secretory antibodies and immunoglobulins

There is increasing evidence for the secretion of IgG and IgE, as well as IgA, antibodies by the nasal mucosa. Because the former immunoglobulins lack an identifiable secretory piece, estimates of their secretion have been based on their ratio to albumin or to total immunoglobulin of the same type in the nasal secretion as compared with serum. It is shown, however, that use of the ratio to albumin will result in large errors if the amount of antibody secreted by the nose is relatively small, and ratios based on total secretory Ig will, at least hypothetically, lead to error if antibodies with multiple specificities are being secreted. It is suggested that a more valid quantitation will be obtained from the expression

$INS=\frac{{Ab}_N}{{Alb}_N}-\frac{{Al}_S}{{Alb}_S}$

where INS is an index of nasal secretion, Ab = antibody, Alb = albumin, N = nasal secretion, and S = serum.     

Dose-response studies of the suppression of whole blood histamine and basophil counts by prednisone

If some clinical problems (e.g., radiographic contrast media reactions) arise from mediator release by circulating basophils, prednisone's capacity to prevent such is likely to be at least partly related to its suppressive effects on whole blood histamine and basophil levels. To establish an optimal dosage schedule, 15 healthy male volunteers entered a two-phased study to determine (1) the single dose of prednisone required to produce maximal suppression of histamine and basophil levels and (2) the effects of repeated prednisone doses. Parameters monitored were whole blood histamine, quantitative basophil counts, white blood cell (WBC) and differential counts, and plasma prednisone, prednisolone, and cortisol levels. Fifty milligrams prednisone suppressed whole blood histamine levels as much as a larger dose and also showed a marked effect on circulating basophils and other leukocytes. Three 50-mg prednisone doses given at 6-hr intervals had a greater effect on whole blood histamine and circulating leukocytes than fewer doses. Thus, the commonly used empirical prednisone dosage regimen is supported. One implication of the results of this study is that greater suppression of blood basophils and histamine levels might be obtained by administering the last prednisone dose about 6 hr before procedures in which a very rapid release of mediators from basophils is anticipated.     

Inhalant allergy due to crickets

Two employees developed allergic rhinitis and bronchial asthma which was occupationally related to raising crickets. Skin tests, bronchial challenge, radioallergosorbent test (RAST), in vitro histamine release and a passive transfer test supported the presence of type I hypersensitivity to cricket allergens. Skin tests of other employees and patients of an allergy clinic suggested that cricket emanations are potent allergens.     

Immediate-type hypersensitivity to a bean lectin source with commentary on occupational allergy in allergy-immunology laboratory and research workers.

A case of acute, severe allergic conjunctivitis is reported in a biochemist who had been grinding Bandeiraea simplicifolia, the source of an anti-B lectin. A crude extract of these beans produced immediate-type skin test reactivity, and reaginic antibodies were demonstrated in her serum. Several other examples of occupationally induced allergy in laboratory and research workers in the field of allergy-immunology are briefly cited. Exposure to potential allergens in a dry, powdered form seems particularly hazardous.     

Hypersensitivity to phenylglycine acid chloride

Twenty-four industrial workers, some of whom had respiratory symptoms on exposure to phenylglycine add chloride (PG-AC), were evaluated. A univalent and several polyvalent conjugates of PG-AC were synthesized for skin testing. Based on history, skin testing, Prausnitz-Küstner (P-K) studies, and inhalation challenge, evidence is presented that in some instances the respiratory symptoms elicited by PG-AC are immunologically mediated, apparently via a Type I immediate hypersensitivity reaction involving reaginic antibody.     

Comparative nasal absorption of allergens in atopic and nonatopic subjects.

Based on sensitization following intranasal antigen administration, previous investigations have suggested greater absorption of allergens through the nasal mucous membranes of atopic than of nonatopic subjects. In this study mucosal absorption was assessed more directly by determining the capacity of allergens applied intranasally to elicit cutaneous Prausnitz-Küstner (P-K) reactions in nonatopic persons as compared with asymptomatic atopic subjects sensitive to other allergens. Two series of reaginic human serum dilutions were injected intracutaneously in recipients backs, and 48 hours later one series was challenged intracutaneously with test allergen. After the responses had been recorded, concentrated allergenic extract was sprayed into the nose and the second series of P-K sites observed for reactivity. Sometimes these P-K sites were rechallenged intracutaneously the following day to determine passive transfer neutralization. Two allergens were studied: bovine ribonuclease (RNase) and peanut extract. Two sera containing peanut reagins and one with RNase antibodies were each used in 10 to 11 atopic and 9 to 11 nonatopic recipients. The atopic group failed to show greater or more rapid absorption of either allergen through the nose based on the highest serum dilution reacting after nasal challenge. the speed of the reaction, the ratio of the titer by nasal challenge to the intracutaneous titer, or passive transfer neutralization. Controls showed that the results were not influenced by systemic absorption of allergen employed for intracutaneous tests. Drinking the amount of peanut extract applied intranasally did not elicit P-K reactions.     

Assessing fungus prevalence in domestic interiors.

Single-plate, Andersen sampler collections of mesonphilic imperfect fungi were made at three points in and immediately outside a series of midwestern homes. During frost-free periods, emanations of dark-spored form genera predominated at both points with indoor levels averaging 25% of those in outside air. At these times, volumetric recoveries and those by 30-min exposure of open culture plates have correlated tenuously (r = 0.29) in bedroom air of 20 homes. During winter, form species of Penicillium, Aspergillus, Oospora, Sporothrix, yeasts, etc. predominated indoors, with levels exceeding 1,000 particles/M3 noted in over 18% of homes; outdoor concentrations never exceeded 230 particles/M3. Comparisons of volumetric and open-plate recoveries from 50 homes during winter have revealed an almost random relationship (r = 0.06). These findings reflect the case with which outdoor spore clouds may penetrate structures and obscure evidence of internal fungus cources. The data also imply that, because of size-related undersampling, open plates often seriously misrepresent prevalence levels and occasionally can exclude abundant types from recovery. The fungus flora of enclosed spaces merits further critical study by volumetric techniques of calculable efficiency in a setting that minimizes contamination from without.     

Volumetric studies of aeroallergen prevalence. I. Pollens of weedy forbs at a midwestern station

Volumetric levels of pollens derived from broad-leaved herbaceous plant species have been determined at a midwestern urban site with suction and rotating arm samplers. The resulting data confirm an abundance of ragweed and nettle emanations but suggest that those of plantains, chenopods, and amaranths achieve modest levels, at best, despite their prominence in gravity slide recoveries. Regular seasonal occurrence periods for pollens, including those of entemophilous composites, the hophemp group, wild grape, and the mustard and pea families, were evident in volumetric recoveries. In general, prevalence peaks of the most prominent pollen types correlated with intermediate, rather than extreme, values for air speed and relative humidity.     

Priming of the nasal mucosa by ragweed extract or by an irritant (ammonia)

Confirming previous work by Connell, it was shown that challenging nine subjects intranasally on successive days with short ragweed extract (SRW) resulted in a priming effect manifested by significantly augmented increases in nasal airways resistance as well as in increasing subjective symptoms. Priming was reproducible and transient. In contrast, significant priming to an irritant, ammonia gas (NH₃), could not be unequivocally demonstrated over a similar period of time in these same subjects under the conditions employed. Also, priming these subjects with SRW extract failed to enhance responsiveness to NH₃.     

An improved technique for nasal inhalation challenge tests.

An improved technique for nasal inhalation challenge tests is described. It includes an improved delivery system utilizing a Maxi-Myst air compressor delivering a flow of room air controlled by an in-line, electroncially timed solenoid which precisely controls the duration of compressor activity. A No. 251 DeVilbiss atomizer will deliver 0.1 + 0.01 gm/spray when the flow rate is 11.5 L/min, the duration of atomizer activity is approximately 0.1 sec, and the amount of liquid in the atomizer insert is kept between 0.75 and 2.0 ml. Nasal aerosol challenge of 0.1 ml of isotonic phosphate-buffered saline per nostril produced less variability in nasal airway resistance (NAR) response than 0.2 ml, and the smaller volume proved satisfactory for 6 consecutive saline challenges at 15-min intervals. A new face mask, which did not impinge on the bridge of the nose or paranasal structures, yielded lower baseline values of nasal airway resistance and much less variability in these measurements. Techniques employed in objectively quantitating nasal responses to various exogenous substances are briefly but critically reviewed.     

The effects of topical saline and isoproterenol on nasal airway resistance

Following determination of baseline nasal airway resistance (NAR) in human subjects, phosphate-buffered saline (PBS) was aerosolized into each nostril and NAR measurements repeated 8 times in 15 minutes. The mean maximal NAR increase in 102 subjects was 22.5% (SD ± 24.5%) with no significant difference between atopic and nonatopic persons. Hay fever patients did not show significantly increased responsiveness to PBS while symptomatic. During 242 repeat challenges with PBS in 67 asymptomatic subjects, NAR increased over 50% in 24 tests. Following a series of 6 PBS challenges at 15-minute intervals, 10 of 71 subjects had more than a 100% increase in NAR over initial baseline values. Administration of PBS on cotton pledgets, pipetting PBS into the nose, or even just inserting a nasal speculum produced greater increases in NAR than the usual aerosol method. Intranasal atropine effectively blocked PBS-induced increases in NAR, suggesting parasympathetic stimulation as a mechanism. Isoproterenol increased NAR over 100% in 27 of 53 subjects, with no significant difference among rhinitic, asthmatic, and nonatopic individuals. This effect was inhibited by propranolol. Isoproterenol administration to 12 ragweed-sensitive subjects 15 minutes prior to ragweed challenge produced a variable inhibition in NAR responses or no protection at all. Thus the direct effects of isoproterenol on the nasal vasculature tend to outweigh those expected from inhibition of mediator release under the conditions of this study.     

Airborne Aspergillus fumigatus levels outside and within a large clinical center.

Most considerations of Aspergillus fumigatus prevalence have implied that patterns of occurrence observed within London hospitals are generally applicable. Since prevalence data are almost nonexistent elsewhere, this assumption remains untested. To provide a comparison relevant to North America, we have monitored thermotolerant fungi outside as well as at two sites within the University Hospital, Ann Arbor, Michigan, during one year. Collections were made with paired Andersen samplers and malt agar for 30- to 40-min periods in a hallway adjacent to 6W, a general medical ward (47 days), and 2W, a lower level service and supply area (40 days); in addition, 10-min outdoor samples (44 days) were taken on an unobstructed hospital rooftop (out). Recoveries were analyzed after 3 and 7 days of 37 degrees C aerobic incubation. Virtually complete suppression of Cladosporium form species at 37 degrees left a mycoflora with A. fumigatus, A. niger, Paecilomyces spp., Mucor spp., and yeast/bacteria predominating. Although the proportions of samples yielding A. fumigatus were 76% for 6W, 57% for 2W, and 56% (out), levels exceeded 40 isolates/m3 only twice and were over 10 isolates/m3 on only 10 of 131 total samples. For 6W, 2W and out, respectively, means were 4.78, 1.97, and 6.25 isolates/m3; medians were 1.20, 1.05 and 1.75/m3 without annual trends indoors and with only a limited outdoor summer increase. Our data fail entirely to show the fall-winter abundance observed in the London report and suggest substantially lower indoor exposure levels of A. fumigatus than those noted in London.     

Comparative merits of eight popular media in aerometric studies of fungi

Although cultural surveys of airborne fungi are pursued widely, the comparative virtues of popular media have not been systematically tested. To facilitate an informed choice, eight different agar media were compared using paired single-plate exposures of identical, wind-oriented, Andersen samplers. Modified Mehrlich's (MM), Sabouraud's dextrose (SAB), malt extract (MALT), V8 juice (V8), and potato dextrose-rose bengal (PDAR) agar were compared initially; potato dextrose (PDA), MALT, rose bengal streptomycin (RBS), and casein hydrolysate (CH) agar were compared during a subsequent series, as were PDA and PDAR. Overall, SAB, MALT, V8, and PDA total recoveries were similar, while MM, CH, PDAR, and RBS were significantly low in paired comparisons with one or more media. MALT and SAB produced the highest frequencies of recovery of most colony types. Bacteria were infrequently recovered on any of the media. CH and MM excluded Epicoccum but are of potential use in surveys that focus sharply on high concentrations of Cladosporium. Rose bengal-containing media performed poorly in this study and must be approached with caution and under properly controlled conditions.     

Modifications of the Wright Dust Feed Mechanism permitting stable dispersion of native ragweed pollen.

Conventional methods have not provided aerosols of suitable constancy. The Wright Dust Feed Mechanism was adapted to provide tractable pollen dispersion.     

A volumetric study of winter fungus prevalence in the air of midwestern homes

Volumetric recoveries of airborne, mesophilic microfungi were made during winter months at three specific points in 150 single-family dwellings in southeastern Michigan. Mean levels of total isolates/m³ comprised a range of from less than 10 to over 20,000, although concurrent outdoor levels never exceeded 230/m³. Form species of Penicillium, Aspergillus, Cladosporium, and Rhodotorula as well as non-pigmented yeasts were the types encountered most widely indoors. Certain homes showed high recoveries of other types, including Cephalosporium, Sporobolomyces, Verticillium, and Sporothrix form species. A positive association between indoor fungus prevalence and bedroom relative humidity was strongly suggested, and high levels were observed in well-humidified homes despite the presence of electrostatic air cleaners. The data indicate characteristic patterns of (winter) air spora in specific homes and suggest that humidifying devices may serve as dispersion sources in addition to their permissive role in facilitating fungus growth.     

Possible role of IgE-mediated reaction in immunity

The effect of a local IgE-mediated hypersensitivity reaction on the neutralization of diphtheria, toxin at skin sites was studied in monkeys passively immunized with human IgG antitoxin. When a mixture of toxin with ragweed allergen was injected intracutaneously into skin sites that had been sensitized with serum from ragweedsensitive patients, the sensitized sites tolerated a significantly greater dose of toxin than did unsensitized sites. An injection of anti-IgE, which induced reversed-type reaginic hypersensitivity reaction, together with the challenging toxin, similarly increased the toxin-neutralizing capacity of the skin sites. In nonimmunized animals, however, IgE-mediated reactions did not show any effect on local resistance. The results indicated that an increased toxin-neutralizing capacity of the local skin sites in passively immunized animals was due to translocation of serum IgG antibody into the skin sites rather than a possible dilution of the toxin by edema fluid. A possible “gatekeeper” role of IgE antibody system in local immunity of mucosal systems was discussed.