A selective inhibitor of the elicitation of immune-mediated reactions.

6-Chloro-17 alpha-hydroxypregna-1,4,6-triene-3,20-dione (CHP), a steroid having a progestin-type structure yet not having progestational activity, was found to exhibit moderate anti-inflammatory activity in a number of conventional tests for corticoid potency (e.g., thymolytic, granuloma, carrageenin edema). CHP was essentially equipotent, however, with cortisol in models of inflammation mediated via delayed hypersensitivity such as experimental allergic encephalomyelitis, adjuvant-induced arthritis, mouse skin graft, and mouse skin delayed hypersensitivity. In contrast to cortisol, which inhibits both 19-s and 7-s antibody formation, CHP does not diminish the number of cells producing either antibody.     

Intranasal flunisolide in the treatment of perennial rhinitis: Correlation with immunologic parameters

The effectiveness and safety of 200 μg/day of intranasal flunisolide in the treatment of perennial rhinitis was studied in 56 patients in a 6 wk double-blind parallel vehicle controlled clinical trial. In addition, patients failing to respond to placebo were entered into a 6 wk open trial with the active drug. Forty-six percent of the flunisolide-treated patients achieved total or substantial control of their nasal symptoms compared to 11% of the placebo-treated group in the double-blind study (p = 0.031). Eighty percent of patients achieved total or substantial control of their nasal symptoms in the 6 wk open study. No adverse effects attributable to flunisolide were observed. Parameters of IgE-mediated reactivity, including immediate-type skin test reactivity, total serum and nasal secretion IgE, specific serum and nasal secretion IgE, and nasal eosinophilia, were also assessed in these patients. Although benefit from flunisolide significantly correlated with all of these parameters except specific serum IgE, the absence of these findings did not preclude significant benefit from the drug. This study demonstrates the efficacy and safety of intranasal flunisolide in the treatment of perennial rhinitis, especially but not exclusively in those patients with evidence of IgE-mediated reactivity.     

A method to evaluate the capacity of monocytes and macrophages to inhibit multiplication of an intracellular pathogen.

A new method to assess intracellular inhibition of multiplication or killing by normal and activated mouse peritoneal macrophages, human peripheral blood monocytes, and human monocyte-derived macrophages is described. This method involves measurement of incorporation of [3H]uracil into nucleic acids of the obligate intracellular parasite Toxoplasma gondii. The method utilizes the observation by Pfefferkorn and Pfefferkorn (1977) that [3H]uracil is incorporated in substantially greater amounts by T. gondii than by certain mammalian cell types. Differential uptake of [3H]uracil by Toxoplasma-infected and uninfected cultures allows for evaluation of the ability of macrophages or monocytes to inhibit or kill this organism. This method has been adapted to microsystem.     

Detection of platelet antibodies by anti-kappa light chain facilitation of C-FDA (KC-FDA) thrombocytotoxicity

Sensitivity of the carboxyfluorescein diacetate (C-FDA) thrombocytotoxicity technique for the detection of antiplatelet antibodies has been enhanced by the addition of an anti-Kappa light chain antibody facilitation step. This new technique, DC-FDA, was compared with the platelet suspension immunofluorescence test (PSIFT) by titering platelet-reactive allo-anti-PlAl and anti-HLA antibodies. The results show that compared to PSIFT, KC-FDA is more sensitive for detecting platelet specific antibodies (PlAl), is more or equally sensitive for detecting other antibodies (HLA), and is significantly faster and easier to perform.     

‘Second generation’ antidepressant drugs

After a long period of clinical use abroad, the “second generation” of antidepressant drugs has reached the United States. Although no claims are made that these new agents are more effective overall than the tricyclics, various advantages are claimed for them: more rapid onset of action, less sedative and anticholinergic side-effects, and less cardiotoxicity. The true test of their worth will await widespread clinical use. Some of these drugs may prove, because of their pharmacologic differences from conventivnai drugs, to be useful tools for testing various hypotheses about depression.     

A stable,sensitive assay for human fibronectin

A solid-phase radioimmunoassay system to quantitate human fibronectin has been developed. This assay utilizes ¹²⁵I-labeled affinity purified IgG directed against human plasma fibronectin. The sensitivity of this system is comparable to conventional (labeled antigen) radioimmunoassays having a detection limit of approximately 0.5 ng. This assay is relatively rapid (<24 h), the reagents are stable at 4°C (> 2 months), and the reproducibility is excellent. Both human plasma and cellular fibronectin react equivalently in this assay.     

Fatal myocardial toxicity during continuous infusion intravenous isoproterenol therapy of asthma

We recently utilized continuous infusion intravenous isoproterenol in the treatment of respiratory failure in an 18-yr-old steroid-dependent asthmatic female. Aminophylline, hydrocortisone, aerosolized isoetharine, and oxygen were also administrered. The patient responded to this therapy, with PaCO2 falling from 70 torr to 33 torr in 18 hr. The maximum isoproterenol dosage administered was 0.32 microgram/kg/min. Thirty-six hours following the institution of therapy, while the isoproterenol was being tapered, the patient experienced an increase in respiratory distress followed by cardiac arrest. Postmortem examination revealed multiple small areas of myocardial necrosis. These findings, unusual in asthma, probably were related to the effects of isoproterenol or the combination of isoproterenol and aminophylline on the stressed myocardium. The vulnerability of the hypoxic myocardium to the effects of isoproterenol suggests that careful cardiac monitoring is essential in the management of patients receiving this medication for treatment of respiratory failure secondary to severe asthma.     

Microtiter solid-phase radioimmunoassay for specific immunoglobulin E

A microtiter solid phase-radioimmunoassay (MSPRIA) for perennial rye grass-specific IgE is described. The assay is carried out in flexible polyvinyl chloride "u" microtiter plates by sequentially incubating antigen, albumin, test sera, and finally radiolabeled antihuman IgE. Wells are cut free of the plate with a hot wire-cutting apparatus and counted individually in a gamma counter. The amount of radioactivity bound is proportional to the amount of specific IgE in the serum. The MSPRIA is shown to be antigen and antibody specific, reproducible, and easily done. Rye-specific IgE levels assayed with the MSPRIA correlated with quantitative end point titration skin testing using perennial rye grass antigen performed on 31 volunteers with a maximum correlation coefficient of 0.92. The MSPRIA was compared with the radioallergosorbent test (RAST) method using sera from the same 31 volunteers. The rye-specific IgE levels assayed by MSPRIA correlated with those assayed by RAST with a correlation coefficient of 0.95. The MSPRIA is well suited for mass screening and represents a useful method for measuring specific IgE.     

Electron microscopy of synapses in reptile spinal cord

The spinal cord of the reptile Anolis carolinensis was examined by electron microscopy. Motor neurons appear as multipolar cells 30-60 micrometer in diameter. Two types of synaptic endings are endings are present on motor neurons. The first type is characterized by distinct synaptic clefts measuring 15-20 nm between pre- and postsynaptic membranes, and by clear presynaptic vesicles. The second type of synapse, which is less common, is characterized by gap junctions between pre- and postsynaptic membranes. At these synapses, there are also clusters of clear vesicles close to the presynaptic membrane adjacent to the gap junction. These findings indicate that both chemical and electrical synaptic transmission are present in the spinal cord of Anolis.     

Induction of immunologic tolerance to the trimellitate haptenic group in mice: Model for a therapeutic approach to trimellitic anhydride-induced hypersensitivity syndromes in humans?

IgE and IgG antibody responses to the trimellitate (TM) hapten group were elicited in mice by the intraperitoneal injection of the hapten coupled with keyhole limpet hemocyanin (KLH). Treatment of such previously sensitized mice with the same hapten coupled to synthetic copolymer of d-glutamic acid and d-lysine (d-GL) after primary immunization resulted in significant and specific suppression of anti-TM antibody responses in both IgE and IgG classes. These results provide direct evidence for the potential clinical usefulness of the d-GL immunotherapeutic approach to TMA sensitivity in humans.     

Magnitude and site of airway response to exercise in asthmatics in relation to arterial histamine levels

In order to determine if there is a relationship among arterial histamine levels, state of disease activity, and the magnitude and site of obstruction in exercise-induced asthma, we recorded airway resistance, lung volumes, spirometry, and density dependence of maximum expiratory flow before and after an exercise challenge in 17 asymptomatic individuals. These observations were then related to the concentration of histamine in systemic arterial blood. This study demonstrates that those individuals whose disease process was the most active at the time of investigation had more depressed lung function and higher baseline histamine levels, and responded to the challenge with severe obstruction that involved the airways in the periphery of the lung. In contrast, those subjects whose underlying disease was more quiescent had lower histamine values and the response to provocation was less severe and predominated in the larger airways. In neither group did the postchallenge values for histamine increase. It is suggested that the factor that determines these patterns of response is the state of inflammation of the airways, for which histamine may serve as a marker.     

Induction of persistent tolerance to urushiol in humans

Young nonimmune subjects were injected intramuscularly multiple times with small amounts of urushiol oil derived from poison oak. One week after the last injection this group and another group of age-matched controls were exposed to a sensitizing dose of the oil painted on the skin. All were challenged at 1 mo, then each year for 7 yr. Initially all experimental subjects were tolerant to high challenge doses; this persisted for 1 yr, at which time experimental subjects were no longer completely tolerant but were clinically tolerant (hyporeactive). This state persisted for at least 4 yr, and this represents complete tolerance followed by long-lasting hyposensitization.     

The relative merits of cromolyn sodium and high-dose theophylline therapy in childhood asthma

The use of cromolyn sodium (SCG) and high-dose theophylline (HDT) in the treatment of chronic perennial asthma in children is reviewed. It is noted that the regimens are only suitable for children with persistent symptoms uncontrolled by simpler forms of treatment. The methods of administration and dosage based on pharmacologic data are considered, and the potential importance of long-acting theophylline and nebulized cromolyn preparations is noted. Short-term studies have confirmed the efficacy of both drugs, and a comparative study showed little difference between them. Long-term studies of SCG have demonstrated its value to some 66% of children without serious side effects. No formal long-term studies have been carried out on HDT. Side effects from theophylline can often be eliminated by careful control of blood levels. From published evidence, neither SCG nor HDT is effective in steroid-dependent asthmatic children, and they contribute little, if anything, to management in such cases. The difference in cost of the drugs is small when all factors are considered, and either regimen is justified by the saving in medical expenses when used for carefully selected patients.     

A technique for intense radiolabelling of pollen and pollen extract with 99mTc

Methods for radiolabelling Poa praetensis whole pollen grains and pollen extract with ^99mTc are described. Structurally intact and antigenically potent dry pollen grains with specific activities as high as 4.2 mc. per milligram pollen were obtained. The radiolabel is apparently confined to the nucleophilic groups of pollen outer wall. An almost identical procedure may be used for radiolabelling pollen extract.     

Sensitivity to ingested metabisulfites in asthmatic subjects

While ingesting selected foods and drinks in restaurants, four asthmatic patients reported the sudden onset of severe wheezing and associated anaphylactoid symptoms and signs. Single-blind placebo and potassium metabisulfite (K₂S₂O₅) oral challenges documented asthmatic responses 15 to 30 min after ingestion of K₂S₂O₅. Laboratory investigations failed to demonstrate specific reaginic antibody recognition of K₂S₂O₅ in these patients. Furthermore, their peripheral basophils did not release histamine during in vitro challenges with K₂S₂O₅. It seems likely that additional asthmatic subjects have such sensitivities but are currently assumed to have “food allergies.” Such individuals can be suspected of having this sensitivity by history, and oral K₂S₂O₅ challenges can identify asthmatics who are sensitive.     

Large airway constriction in allergic rhinitis: Response to inhalation of helium-oxygen

Pulmonary function results were compared in 15 allergic rhinitis and 30 normal subjects. Airways resistance (R_AW) was higher (p < 0.01) and specific conductance (SG_AW) was lower (p < 0.01) in the rhinitis group. Maximal expiratory flow (V?_EMax), lung volumes, and results of tests measuring airways closure, distribution of ventilation, diffusing capacity, volume of isoflow, and density-dependence of V?_EMax at 50% of vital capacity (ΔV?_EMax₅₀) significantly between the two groups. Following inhalation of isoproterenol, R_AW decreased and SG_AW and V?_EMax increased significantly in both groups. On the other hand, ΔV?_E decreased significantly in the rhinitis group (p < 0.01) and increased significantly in the control group (p < 0.05). In addition to comparing pulmonary function in rhinitis patients and control subjects, physiologic measurements were also made on two separate occasions in the rhinitis subjects (minimal or no symptoms; very symptomatic). Although rhinitis symptomatology varied considerably (p < 0.001), pulmonary function results were not significantly different. Hence we conclude that: (1) Rhinitis subjects have large airway constriction which does not vary with season or symptoms. (2) As in normal control subjects, airflow limitation occurs in the large airways of rhinitis subjects. (3) The predominant site of isoproterenol-associated bronchodilatation differs between allergic rhinitis and normal subjects.     

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 CDH 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 CDH. We conclude that TT is an excellent antigen for assessing the presence or absence of CDH in adults aged 25 to 64 yr.