Asthma is a chronic, inflammatory disease of the airways that exacts a large burden of illness among patients, their families, and the health-care system. Yet advances in research have generated the means for addressing this public health problem. The challenge is to bridge the gap between excessive asthma morbidity and the science that holds the promise of reducing it; that is, to translate the scientific advances into meaningful recommendations for clinical care and to promote adoption of the recommendations. This paper will demonstrate how national asthma education programs, founded on science-based clinical practice guidelines, meet this challenge and help reduce illness and improve the quality of life for people with asthma.

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Three factors in recent medical research and treatment (advances in the field of psychoneuroimmunology, epidemiological evidence regarding important interaction between psychosocial factors and development of disease, and the recognition of the importance of patient education for self-management of asthma) have led clinicians and researchers to reconsider the role of psychosocial stress in asthma. There are many reports suggesting that stressful life events, family problems and a behavior pattern that increases psychological conflict may influence the development or relapse of asthma and influence its clinical course. Depression is known as one of the risk factors of fatal asthmatic attack. In laboratory studies, about 20% of asthmatics were considered reactors who showed an airway change after exposure to emotional stress. Studies regarding the pathway of stress effect on allergy and asthma are reviewed and discussed from the standpoint of psychoneuroimmunology; for example, the enhancement of IgE production and increased susceptibility to respiratory infection by stress, conditioned anaphylaxis and nerve/mast cell interaction, the effect of stress on various bronchial responses and the inhibition of the immediate and late asthmatic response by anterior hypothalamic lesioning.

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To investigate the possible involvement of cytoskeletal components in antigen (Ag)-mediated activation of phospholipase D (PLD) in rat basophilic leukemia (RBL-2H3) cells, the effects of cytochalasin D, which is known to interfere with actin organization in various cells, on Ag-induced PLD activity were examined. Cytochalasin D, at concentrations that induced distinct shape changes of RBL-2H3 cells, enhanced the Ag-induced 5-HT (serotonin) release and formation of phosphatidylbutanol (PBut), a specific and stable metabolite produced by PLD activity in a concentration-dependent manner. Concomitantly, Ag-induced 1,2-diacylglycerol (DG) accumulation as well as phosphatidic acid (PA) production were increased by the drug. In contrast, cytochalasin D had no effect on PLD activation in response to phorbolmyristate acetate, an activator of protein kinase C (PKC), and Ca²⁺ ionophore A23187. These results suggest that cytoskeletal components may modulate Ag-induced PLD activation upstream of PKC and Ca²⁺ in RBL-2H3 cells.

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An allergic response to foreign intestinal antigens such as those contained in food has been implicated as a causative factor in the development of inflammatory bowel disease (IBD). In this study, we investigated the incidence of food allergy and other allergic disorders in Japanese patients with IBD. In addition, levels of serum IgE and IgG4 antibodies specific to various food antigens were measured. Twenty-six patients with Crohn's disease (CD) and 32 patients with ulcerative colitis (UC) were studied. Two sex- and age-matched controls were selected for each patient. The incidence of food allergy (29.2%), drug allergy (28.0%), and atopic dermatitis (28.0%) in patients with CD was significantly higher than in their matched controls (P < 0.05); however, no significant association was observed in UC patients. Levels of serum IgE specific to food allergens were similar among the groups, but the levels of IgG4 antibody specific to soybean, were significantly higher in patients with CD than in UC patients or controls. Our observations suggest that allergic disorders or dysregulation of immune responses to certain intestinal antigens can be found in CD patients in Japan in association with their disease.

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Inhaled corticosteroids are potent and effective treatment agents for controlling symptoms of childhood asthma. However, there are no predictive factors that help to determine which patients with asthma are likely to be tapered off inhaled corticosteroids successfully. We examined whether any factor or combination of factors could help the clinician safely discontinue inhaled steroid therapy. Thirty-six asthmatic children whose symptoms were stable on low-dose beclomethasone dipropionate (BDP) were divided by parental choice into two groups: maintenance BDP (n = 11) and no BDP (n = 25). Methacholine inhalation tests were performed at the beginning of the study and after 1 month. Twelve children (48%) who had BDP discontinued developed exacerbations after 2-3 months, whereas there were no problems in the maintenance group. The no BDP group was retrospectively divided into two subgroups: exacerbation (+) and (-). The threshold to methacholine in the exacerbation (+) subgroup decreased significantly in advance of clinical symptoms. The two subgroups were analyzed statistically by two-group discriminant function analysis. The change in threshold to methacholine, the dose and potency of drugs, duration of asthma and gender (female) correlated with exacerbation. These results suggest that discontinuation of inhaled steroids should be done carefully, even in stable asthmatic children. The methacholine inhalation test, gender, drugs and history may be used as references for discontinuing inhaled steroids.

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Agents that increase intracellular cyclic 3',5'-adenosine monophosphate (cAMP), such as forskolin, prostaglandin (PG)E₂, salbutamol and 8-bromo-cAMP, have been shownto inhibit the proliferation of airway smooth-muscle (ASM) cells in vitro. However, it has not yet been determined whether selective inhibitors of phosphodiesterase (PDE) isoenzymes III and IV that catalyze cAMPto 5'-adenosine monophosphate have the ability to inhibit ASM cell proliferation. To evaluate the effectsof PDE inhibitors on ASM cell proliferation, ASM cells isolated from bovine tracheae were cultured in the presence of fetal bovine serum (FBS), with or without a non-selective PDE inhibitor (theophylline), a selective PDE III inhibitor (cilostazol), and a selective PDE IV inhibitor (rolipram). The number of ASM cells cultured with 5% FBS was significantly reduced by the presence of theophylline at 10^-3 and 3 × 10^-4 mol/L, cilostazol at 10^-5, 10^-6 and 10^-7 mol/L, and rolipram at 10^-4 and 10^-5 mol/L. The release of lactic dehydrogenase from ASM cells cultured with any concentration of these agents was not significantly different from that with medium alone. Inhibitors of PDE III and IV were demonstrated to have an inhibitory effect on ASM cell proliferation induced by FBS. Our results suggest the value of the further development of PDE inhibitors for the treatment of hyperplasia of ASM cells characteristic of airway remodeling, in addition to bronchospasm and airway inflammation, in bronchial asthma.

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Previous studies have reported that the mice passively sensitized with anti-dinitrophenol (DNP) IgE antibody exhibited IgE-mediated cutaneous reaction with an immediate phase response (IPR) at 1 h and a late phase response (LPR) at 24 h after the challenge of dinitrofluorobenzene (DNFB). We found that the third-phase inflammatory reaction with intense and persisting infiltration of eosinophils, named 'very late phase reaction (vLPR)', was induced following IPR and LPR in response to DNFB in actively and passively sensitized mice, and that the peak response of vLPR was at 8 days after the challenge. This reaction was slightly observed in non-sensitized mice. Since the accumulation of eosinophils in vLPR was markedly observed when compared with that of LPR at 24 h, the vLPR may be an important reaction in allergic diseases. The development of vLPR was partly decreased in mast cell-deficient WBB6F1-W/W^v mice and was absent in T cell-deficient BALB/c-nu/nu mice in passive sensitization. These results indicate that the vLPR in the triphasic cutaneous reaction may be mainly mediated by T cells and partially by mast cells and/or IgE antibody, and consequently lead to an intense ear swelling accompanying massive infiltration of eosinophils.

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Asthma therapy including inhaled corticosteroids (ICS) has been shown to be effective in many parts of the world, but its use is still limited in Japan. A 6-week, randomized, placebo-controlled, clinical trial was therefore undertaken to assess the efficacy of the ICS budesonide Turbuhaler (budesonide administered via the dry-powder inhaler Turbuhaler) in patients in Japan with mild-to-moderate asthma. Prior to, and during, the study, all concomitant medications, except corticosteroid preparations, were allowed (i.e. all prestudy medication was to be maintained throughout the study). In total, 218 patients randomized to receive budesonide Turbuhaler 200 µg/day (n = 53), 400 µg/ day (n = 55), 800 µg/day (n = 57) or placebo (n = 53) were included in the analysis. Due to the increased demand and interest for health economic data in Japan, this retrospective cost-effectiveness analysis reports on the economic impact of budesonide Turbuhaler compared with placebo (i.e. usual care), based on this clinical trial. At each dosage, budesonide Turbuhaler was significantly more effective than the placebo, according to the number of symptom-free and episode-free days. The number of emergency visits, days of lost production and days of hospitalization were all lower in the budesonide Turbuhaler groups, leading to significantly (P < 0.05) reduced total health-care and productivity costs compared with placebo. These findings were generally stable to sensitivity analysis. However, this reduction in costs will obviously have to be compared with the acquisition cost of budesonide Turbuhaler (which was excluded in the analysis as a price had not been determined) when it becomes available on the market. Budesonide Turbuhaler, while improving the health of patients, could thus have a considerable impact on the costs of treating asthma in Japan, by shifting large hospital care costs towards relatively small out-patient medication costs.

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Although adrenergic β₂-agonist-induced smooth muscle relaxation has been attributed to increased intracellular cyclic AMP (cAMP), a relaxation response has been observed at low β₂-agonist concentrations that do not cause increased cAMP. To elucidate the mechanism of tracheal muscle relaxation induced by low concentrations of β₂-agonists, we used a guinea-pig skinned tracheal smooth muscle preparation to examine the effects on the contractile protein system. The isotonic contraction of β-escin-treated skinned tracheal muscle from guinea-pig was measured. When the intracellular Ca²⁺ concentration was maintained at 1 µmol/L in the presence of guanosine 5'-triphosphate (GTP; 100 µmol/L), neither isoproterenol (10 nmol/L) nor salbutamol (60 nmol/L) affected Ca²⁺ sensitivity, but a significant decrease in Ca²⁺ sensitivity was observed in the presence of okadaic acid (1 µmol/L). The decrease in Ca²⁺ sensitivity was a slow response and was blocked by pretreatment with propranolol (1 µmol/L). Forskolin (1 µmol/L) did not affect Ca²⁺ sensitivity. These results suggest that adrenergic β₂-agonists may activate protein phosphatase through an unknown pathway involving the β₂-receptor, which enhances dephosphorylation of the myosin light chain and/or thin filament proteins, resulting in relaxation of the tracheal smooth muscle.

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The case history of a 27-year-old man with Matsutake mushroom-dependent anaphylactoid reaction is reported. The patient suffered from general cutaneous erythema, with itching, urticaria angiedema to his face and body, and with inspiratory dyspnea, soon after consuming a meal of Matsutake mushrooms. A challenge test with about 100 g grilled Matsutake mushrooms resulted in irritation of the throat, inspiratory dyspnea and lowering of peak flow rate, all of which were observed after about 30 min. These symptoms disappeared spontaneously 4 h later, without treatment. About 5 h after the challenge, the patient suffered from dyspnea and general cutaneous erythema, with urticaria of his face and body. Hydrocortisone was given and next morning he had no more symptoms. Laboratory data showed elevation of neutrophils and myeloperoxidase after the challenge, but no elevation of serum histamine. This is the second case of anaphylaxis or anaphylactoid reaction to Matsutake mushrooms for which IgE antibody to Matsutake may not be the cause.

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It is well known that allergic reactions may sometimes occur in patients under treatment with β-lactam antibiotics. For the detection of antidrug antibodies in vitro, conjugation with human serum albumin has been considered to be essential. In this study, we found that cefotiam, cefpirome, and ceftazidime could be immobilized without conjugation to carrier protein to construct a solid-phase enzyme-linked immunosorbent assay (ELISA) system. We describe a patient (26-year-old female nurse) with contact urticaria induced by antibiotics. Using the serum of this patient, we successfully detected IgE antibody directed to the aminothiazolyl group of cephalosporins, which has not previously been reported. Results suggest that the simple ELISA using unconjugated antibiotics could be applicable to patients with allergy to some cephalosporins and the aminothiazole side chain of the cephalosporins could cause an IgE-mediated allergic reaction.

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