Exercise-induced anaphylaxis: a serious form of physical allergy associated with mast cell degranulation

Exercise-induced anaphylaxis (EIA) is a unique and an increasingly recognized syndrome consisting of premonitory symptoms and signs of generalized body warmth, pruritus, and erythema, which progresses on continued exertion to confluent urticaria, laryngeal edema with stridor or hoarseness, and gastrointestinal colic and frequently culminates in vascular collapse. Previous studies of five individuals with this condition have demonstrated significant elevations of serum histamine concurrent with the early clinical manifestations after experimental exercise. To assess relevant morphologic alterations in the skin of these patients, cutaneous mast cells were examined by light and transmission electron microscopy before and during the initial erythema elicited by exertion. The marked alterations observed in mast cells immediately after exercise consisted of (1) loss of electron density and internal substructure of granules, (2) fusion of granule membranes with those of adjacent granules and with mast cell membranes creating conduits to the extracellular space, and (3) an apparent decrease in the number of intact granules per cell. Biopsy specimens obtained before exercise from patients with EIA and from two normal individuals who served as control subjects were identical, and the control subjects had normal mast cell morphology after exercise. Serum histamine levels were significantly elevated in patients with EIA after exercise at the time of biopsy, whereas control subjects had normal levels. These observations provide evidence that EIA is a distinct form of physical allergy associated with mast cell degranulation similar in morphology to that of human pulmonary mast cell IgE-Fc-dependent activation secretion. Characterization of this disorder is important because its prevalence may be underestimated, and its clinical consequences, which may include some morbidity, are not fully known.     

Evidence that most of the dopamine β-hydroxylase is not membrane bound in purified large dense cored noradrenergic vesicles

The compartmentalization of dopamine β-hydroxylase was studied in a purified fraction of large, dense-cored noradrenergic vesicles from bovine splenic nerve. A correlative biochemical and morphological approach was used to evaluate physical methods designed to produce more efficient vesicle lysis than has been accomplished previously with freeze-thawing, hypo-osmotic shocks or incubation at 37°C, all of which are relatively ineffective. Of the seven purely physical techniques tested, only those which subjected the vesicles to high pressures followed by rapid decompression produced effective lysis, unmasking of latent enzyme activity, and release of enzyme into the soluble phase. Based on results with the French Press, the best estimate for the percentage of dopamine β-hydroxylase which can be released into the soluble phase is 55–70% of the total enzyme activity produced by the addition of 0.05% v/v Triton X-100. This includes two-thirds of the enzyme which was originally in a latent form. The enzyme is considered to occur primarily, if not entirely, in a granular complex in the vesicle matrix. About one-third is thought to be oriented specifically at the inner surface of the vesicle membrane and is active enzymatically.Physical rupture of the vesicles causes redistribution of partially depleted vesicles and free matrix granules containing dopamine β-hydroxylase activity into less dense zones of a sucrose-D₂O density gradient. After French Press treatment, 30% of the enzyme lost from the heavy vesicle peak is found in the region of the light vesicle peak which is thought to be the equilibrium density of the smaller vesicles characteristic of nerve terminals.The data indicate that much more dopamine β-hydroxylase is potentially available for release from the large, dense-cored vesicles upon nerve stimulation than previously has been believed. This will affect interpretations of exocytotic release from the two vesicle populations in noradrenergic varicosities and will have a bearing on the origin of circulating dopamine β-hydroxylase in response to physiological stress and pharmacological intervention, as well as in neurological diseases.     

Hypermacroglobulinemia associated with heroin use in adolescents

Increases of serum 19S IgM globulin were detected in adolescent patients admitted for narcotic detoxification. The mean IgM level was 294 ± 130 mg. per cent compared to 164 ± 63 mg. per cent in a control group. Twenty-six of the 64 adolescent narcotic users (40.6 per cent) had IgM levels above 290 mg. per cent, the upper limit of normal. There was no evidence of cytomegalovirus infection, infectious mononucleosis, primary biliary cirrhosis, mixed cryoglobulinemia, or cold agglutinins. The presence of Australia antigen in 2 patients and elevated serum glutamic oxaloacetic transaminase (SGOT) levels in 19 suggests that the increased IgM levels may be related to the presence of chronic persistent hepatitis. Heroin use should be considered as an important cause of elevated serum IgM, especially in association with relatively normal levels of IgG and IgA.     

Lack of effect of an antifibrinolytic agent on cholesterol-induced aortic lesions in the rat, with observations on the independence of intimal foam cell lesions and extracellular medial lipid.

Hypercholesterolemic rats fed aminocaproic acid on alternate weeks for periods of 6 to 10 months did not show a difference in the character, extent or severity of aortic lesions, as compared to a control group with similar serum total cholesterol levels. It was noted that the early lesions in the rat are of two distinct types, an intimal foam cell lesion and an upper medial lesion consisting of intercellular accumulation of lipid. These two lesions appear to be unrelated spatially. They are also not related to proliferation of vascular smooth muscle, which does not occur in this experimental situation.     

Elevated serum immunoglobulin E in T cell-deficient infants fed cow's milk

Serum IgE levels at various ages during infancy were related to the number of T cells assessed at the age of 1 mo and type of feeding. Cow's milk-fed babies with low T cell counts had higher IgE at the ages of 3 and 6 mo than breast-fed babies with low T cell counts. Of the babies fed cow's milk, those with low T cell counts had higher IgE levels than those with normal T cell counts. Onset of cow's milk feeding before the age of 3 mo in babies with low T cell counts was associated with continuously elevated IgE during the first year of life, as compared with babies with normal T cell counts. However, when cow's milk feeding was instituted after the age of 3 mo such a difference was not noted. It is concluded that in T cell-deficient infants there might exist a critical period during which onset of cow's milk feeding is associated with subsequently increased IgE synthesis.     

Elevated serum immunoglobulin E in bronchial carcinoma: its relation to the histology and prognosis of the cancer

Total IgE and specific IgE antibodies against six common allergens were measured in the sera of 217 unselected patients with bronchial carcinoma. Their median total IgE level was significantly increased as compared to the median levels found in two control populations consisting of 246 individuals representing the adult general population and 143 patients with benign pulmonary disorders. The frequency of serological atopy, i.e., the presence of specific IgE antibodies, was also significantly increased in the cancer population as compared to the controls. In contrast, the incidence of possible clinical atopy was about five times higher in the general population than in the cancer group. Patients with bronchial carcinoma typed as adenocarcinoma had the best prognosis and also had nonelevated IgE levels in contrast to patients with bronchial carcinoma typed as squamous cell carcinoma, small or large cell carcinoma. The favourable prognosis with nonelevated IgE levels also was demonstrated in patients with squamous cell carcinoma. It is suggested that the elevated IgE levels in bronchial carcinoma reflect impaired cellular immunity.     

Antibodies to purified bee venom proteins and peptides. II. A detailed study of changes in IgE and IgG antibodies to individual bee venom antigens

Antibodies to individual bee venom antigens were studied in detail in nine bee sting-allergic patients who received venom immunotherapy without side effects, in two patients who failed to reach maintenance, and in two whose sensitivity returned. The study was confined to patients who had IgE antibodies to at least one of four purified bee venom antigens at the start of treatment. IgE and IgG antibodies to phospholipase A2 (PLA2), hyaluronidase (HYAL), and acid phosphatase (ACID P) and IgE antibodies to melittin (MEL) were measured, and changes in the antibody levels were followed during bee venom immunotherapy. Two contrasting patterns of antibody response were seen in the nine successfully treated patients. In five patients there was a rise in serum IgG antibodies to the same antigens as the IgE antibodies. In two patients' serum IgE antibody to HYAL or ACID P fell without a marked IgG antibody response to these antigens, although high levels of IgG antibody to PLA2 were present in both. Although the first pattern is consistent with a "blocking" role for IgG antibody, clearly the second is not. Not all patients can be conveniently divided into these two categories, and two patients did not show any significant change in either IgG or IgE antibody but were nevertheless able to tolerate the maintenance dose of 100 micrograms of venom. Two patients who failed to reach the maintenance dose of 100 micrograms because of their allergic reactions to the injections of venom were distinguished by (1) very high serum IgE antibody and (2) a low ratio of IgG/IgE antibody. Passive immunization with IgG antibody from a hyperimmune beekeeper was, however, protective in these patients, although it did not raise their overall serum IgG antibody level very much. We are unable to explain either the failure of conventional therapy or the beneficial effect of passive immunization in these two patients. Two bee sting--allergic beekeepers lost their sensitivity to stings, but later, when their sera contained IgE antibody to another bee venom antigen, they reacted to stings and inhalation of beehive dander. These data suggest that either falling IgE antibody or IgG- "blocking" antibody could be responsible for providing clinical protection to bee venom--allergic subjects. Renewed clinical sensitivity was observed when the IgE response was modulated, with patients making IgE antibody first to one antigen and then to another.     

Depression and African Americans in the First Decade of Midlife: The Consequences of Social Roles and Gender

ObjectiveThis study examined gender differences in how three social roles – marriage, parenthood, and employment – impact depressive symptoms and clinically significant depression for African Americans in the first decade of midlife, from 40 to 50 years old. Specifically, we sought to understand the associations between roles configurations (e.g., married parent versus employed only) and depressed mood as well as diagnosable depression.MethodThe data for this study were extracted from the National Longitudinal Survey of Youth 1979 cohort (NLSY79). Constituting a representative sample of non-institutionalized Americans, NLSY respondents were interviewed each year from 1979 to 1994 and biennially thereafter. Our study included 2372 African Americans. We used ordinary least squares regression to estimate depressive symptoms and logistic regression to model the probability of clinically significant depression.ResultsAfrican American men who were married/cohabiting only, employed only, or married/cohabiting, employed parents experienced lower levels of depressed mood, compared to African American women. Holding none of the roles under consideration in this study resulted in higher levels of depressive symptoms for African American women than for African American men. For diagnosable depression, the role combinations of married/cohabiting, employed and married/cohabiting, employed parent resulted in a lower probability of depression for African American men, compared to their female counterparts. Regardless of gender, role configurations that included employment produced the lowest levels of depressive symptoms and the lowest likelihood of clinically significant depression.ConclusionsOverall, the pattern of findings showed that role configurations are important in shaping mental health for both African American men and women. Multiple role combinations that included employment make individuals less vulnerable to depressive symptoms and clinically significant depression. Having no roles (e.g., unmarried, unemployed, non-parent) was more problematic for the well-being of African American women compared to African American men, but not as detrimental to African American mental health as prior studies focused on other racial and ethnic groups have suggested.     

Oropharyngeal candidiasis in patients treated with triamcinolone acetonide aerosol

Thirty asthmatic patients participating in a trial of triamcinolone acetonide aerosol were evaluated to determine the relationships among symptoms of sore throat or hoarseness, the appearance of the throat on physical examination, and the presence of yeasts on pharyngeal culture. Observations were recorded prior to aerosol therapy and repeated after 2 wk, 4 wk, 6 wk, 4 mo, and 6 mo of therapy. A total of 15 patients (50%) experienced sore throat or hoarseness, 15 (50%) had yeasts cultured from the pharynx on at least one occasion, and 11 (37%) at some point had an abnormal throat examination; however, there was no predictable relationship between symptoms or abnormal physical examinations and the presence of a positive culture. The frequency of positive cultures did not change significantly during the observation period. Twelve patients had positive yeast cultures on 50% or more of their samples. The incidence of symptoms was not sigficantly increased in these chronically colonized patients. Symptoms were usually transient, and discontinuation of the aerosol or antifungal therapy was unnecessary. Triamcinolone aerosol was not associated with significantly increased pharyngeal colonization with yeasts in this 6-mo study. Existing chronic colonization is not necessarily a contraindication to triamcinolone therapy. Sore throat and hoarseness are usually unrelated to yeast infection in patients using triamcinolone acetonide aerosol.     

The effect of ranitidine, alone and in combination with clemastine, on allergen-induced cutaneous wheal-and-flare reactions in human skin

The effect of intradermal ranitidine (administered alone and in combination with clemastine) on allergen-mediated wheal-and-flare reactions has been evaluated in a double-blind study on 10 healthy atopic volunteers. Ranitidine alone, administered in doses over a 10(4)-fold concentration range, had no effect on the size either of allergen-induced wheal or flare reactions. Clemastine alone evoked a dose-related inhibition of both wheal and flare. Compared to the inhibition achieved by clemastine alone, the combination of ranitidine with clemastine produced a small but significant increase in inhibition of allergen-induced flare at ranitidine concentrations of 10(-5) mol/L (p less than 0.001) and 10(-6) mol/L (p less than 0.01), and of allergen-induced wheal at ranitidine concentration 10(-5) mol/L (p less than 0.01). Our results provide further evidence for the presence of cutaneous histamine H2 receptors and their participation in the formation of allergen-mediated skin reactions but indicate that the contribution of cutaneous histamine H2-receptor stimulation to the production of immediate wheal-and-flare reactions evoked by allergen is only modest.     

Intravenous gamma globulin in the management of patients with hypogammaglobulinemia

The safety and efficacy of plasmin-treated gamma globulin (PG-GG), an intravenous preparation with low anticomplementary activity, was assessed as an antibody replacement therapy in 14 patients with hypogammaglobulinemia. Seven were studied in 2 treatment periods of 6 and 15 mo on PT-GG with an intervening control period of intramuscular gamma globulin (IM-ISG). Frequency of infusions ranged from 2 to 4 wk to maintain a serum IgG concentration of less than 2.5 mg/ml. Three patients with severe chronic pulmonary disease were removed from the study because of lack of clinical improvement and were placed on single-donor plasma. The remaining 11 patients had a decrease in the number of hospitalizations or severe infections. Five patients had one or more systemic reactions (21/240 infusions). Symptoms abated rapidly with temporary interruption of the infusion. From these results, we conclude that PT-GG represents a relatively safe, efficacious mode of replacement therapy which has had uniformly high acceptance in patients with hypogammaglobulinemia.     

Difference between lung and spleen susceptibility of beta-adrenergic receptors to desensitization by terbutaline

There are many reports about a marked down-regulation of beta-adrenergic receptors by beta agonists in human leukocytes. To determine whether beta receptors in lung tissue are down regulated by the long-term administration of beta agonists, as are those in the spleen (which consists largely of lymphocytes), we injected terbutaline (0.1 mg/kg, t.i.d.) intramuscularly into rats for either 3 or 6 days. We observed a significant decrease in beta-receptor density in spleen tissue but not in lung parenchyma, associated with terbutaline injection. The affinity for an antagonist did not change significantly in any group in either tissue. We did not observe any change in alpha 1-adrenergic receptors in the lung after this treatment. In in vitro studies, we also observed reduced beta-receptor density in spleen cells but not in lung parenchyma after incubation of these tissues with terbutaline. However, there was agonist-specific alteration in lung beta receptors. It was found that the isoproterenol competition curve for 3H-dihydroalprenolol binding shifted to the right and steepened, suggesting reduced affinity of the receptors for isoproterenol. We used whole lung and did not examine bronchial smooth muscle per se, nor were functional studies performed. Our results show a difference between lung parenchyma and spleen tissue in the susceptibility of beta receptors to desensitization by an adrenergic agonist and suggest that there may be such a difference in sensitivity between beta receptors in human lung and leukocytes.     

Selective subsensitization of beta-adrenergic receptors in central airways of asthmatics and normal subjects during long-term therapy with inhaled salbutamol

In five subjects with mild asthma and in five normal subjects, we determined the effect of a 4 wk course of inhaled salbutamol (albuterol), 200 μg q.i.d., on (I) acute bronchodilator responsiveness, (2) bronchial sensitivity to inhaled histamine, (3) beta-adrenergic protection against histamine-induced bronchospasm, and (4) beta-receptor density of peripheral blood lymphocytes. We observed a diminution in central airway bronchodilator responsiveness (as measured by airway conductance responses) to acutely inhaled salbutamol and to subcutaneous terbutaline in both groups of subjects, although only the response to subcutaneous terbutaline was statistically significant (p < 0.02). On the other hand, no impairment of small airway bronchodilator responsiveness was noted in either group of subjects when responses were measured as partial expiratory flow rates at 60% below total lung capacity. These findings suggest the development of selective subsensitization of beta-receptors in the larger central airways, where a proportionately greater amount of the inhaled beta-agonist aerosol would necessarily be deposited. A greater loss of protection against histamine-induced bronchospasm was seen in asthmatics than in normals (approximately twofold), although the difference was not significant. A modest but not significant reduction in peripheral blood lymphocyte beta-receptor density was observed by the end of the 4 wk treatment period. The possibility that the observed changes in bronchodilator responsiveness might influence the morbidity and mortality associated with bronchial asthma is discussed.