Effect of adjusting the combination of budesonide/formoterol on the alleviation of asthma symptoms.

BACKGROUND: The combination of budesonide + formoterol (BFC) offers the advantages of dose adjustment in a single inhaler according to asthma symptoms. We analyzed the relationship between asthma symptoms in terms of peak expiratory flow (PEF) and dose adjustment by the patient. METHODS: Twenty-eight patients with asthma who used BFC for alleviation of their symptoms (12 men, 16 women; 60 years old) were instructed that the inhaled BFC dose could be increased to a maximum of 8 inhalations per day according to symptom severity. Patients measured and recorded PEF every morning and evening in their asthma diary along with their symptoms and the dose of drugs taken. RESULTS: Sixteen of the 28 patients increased their dose for asthma symptoms. The time to recovery from the asthma symptoms was significantly shorter when cough was the only symptom present compared with dyspnea or wheeze (1.4 vs. 5.3 or 6.6 days, p < 0.05) and when they had only one symptom compared with two or three symptoms (1.3 vs. 5.7 or 10.5, p < 0.01). The relationship between PEF (% of personal best) when the dose was increased (Y) and the days for the increased dose to achieve a PEF greater than PEF in the symptom-free state (X) was determined to be Y = - 0.591X + 89.2 (r2 = 0.299, p < 0.001). CONCLUSION: As a guide for increasing the BFC dose when patients with mild asthma have asthma symptoms, the dose should be increased when cough is present or PEF is decreased to 88.9% (i.e., X = 0.5).

Dipeptidyl peptidase-4 is highly expressed in bronchial epithelial cells of untreated asthma and it increases cell proliferation along with fibronectin production in airway constitutive cells.

BACKGROUND: Type 2 helper T-cell cytokines including IL-13 play a central role in the pathogenesis of bronchial asthma (BA). During the course of our research, our attention was drawn to dipeptidyl peptidase-4 (DPP4) as one of the molecules that were induced from bronchial epithelial cells (BECs) by IL-13 stimulation. DPP4 could become a new biomarker or therapeutic target. The aim of this study was to investigate the expression of DPP4 in the asthmatic airway, and its role in the pathophysiology of asthma. METHODS: BECs were isolated from patients with inhaled corticosteroid-treated asthma (stBA) and inhaled corticosteroid-naïve asthma (snBA) using bronchoscopy. DPP4 mRNA expression in freshly isolated BECs and primary cultured BECs with or without IL-13 stimulation was investigated by microarray analysis and quantitative real-time PCR (qPCR). The distribution of DPP4 protein was determined by immunostaining of transbronchial lung biopsy specimens from asthma patients. The effect of recombinant human (rh) DPP4 on the proliferation of lung fibroblasts (HFL-1) and bronchial smooth muscle cells (BSMCs) was examined, as well as its effect on the production of fibronectin (FN). RESULTS: DPP4 mRNA was strongly expressed in freshly isolated BECs in snBA, and its expression was significantly enhanced by IL-13 stimulation. DPP4 mRNA expression in BECs of snBA significantly correlated with exhaled nitric oxide. Biopsied tissues of the asthmatic airway revealed strong expression of DPP4 protein in BECs from snBA subjects. rhDPP4 stimulated the proliferation of HFL-1 and BSMCs, and it also enhanced production of FN from these airway cells. CONCLUSION: DPP4 may be involved in the pathologic features of asthmatic airway inflammation and cell proliferation and FN production.

Epidemiologic investigation of hornet and paper wasp stings in forest workers and electrical facility field workers in Japan.

BACKGROUND: Forestry and field workers who work outdoors are at high risk for Hymenoptera stings and may develop occupation-related allergies from being stung. However, clinical and immunological surveys of Hymenoptera stings in the occupational setting have rarely been reported. We surveyed the natural history of Hymenoptera stings in Japanese forestry workers (FWs) and electrical facility field workers (EFFWs), and we assessed the utility of measuring specific (s)IgE Ab to Hymenptera venom. METHODS: Questionnaires on hornet and paper wasp stings were completed by 999 FWs, 354 EFFWs, and 365 office workers as controls between July and November 2009. Sera from these participants were tested for sIgE Ab levels to Hymenptera venom with a CAP system using a fluoroenzyme immunoassay. RESULTS: Of the participants who had experienced Hymenoptera stings, 914 (91.5%) were FWs, 293 (82.8%) were EFFWs, and 295 (80.8%) were controls. Of the participants who had experienced systemic reactions, 210 (21.0%) were FWs, 51 (14.4%) were EFFWs, and 39 (10.7%) were controls. sIgE Ab in response to hornet and wasp venom was positive (≥ class 2) in 42.4% and 41.4% of FWs, 30.1% and 31.4% of EFFWs, and 15.1% and 18.1% of controls, respectively. The likelihood of being sIgE-positive to wasp and hornet venom was significantly higher in FWs and EFFWs than in controls (P < 0.05). CONCLUSIONS: 21% of FWs and 14% of EFFWs had experienced systemic reactions to Hymenoptera stings with a higher frequency compared with office workers in the same area. 40% of FWs and 30% of EFFWs had sera that were sIgE positive to Hymenoptera venom.

Wasp venom allergy: effect of anti-IgE antibody on wasp venom anaphylaxis in a mouse model.

BACKGROUND: Although anti-IgE antibody (Ab) therapy was recently shown to be effective in patients with bronchial asthma, no study has reported the effect of IgE therapy in the prevention of wasp venom anaphylaxis. In this study, we used a mouse model of wasp venom allergy to investigate the effect of anti-IgE Ab on wasp venom anaphylaxis. METHODS: We developed a mouse model of wasp venom allergy by intraperitoneally (i.p.) injecting wasp venom into BALB/c mice twice on experimental day (day) 0 and 7. On day 20, a group of mice received an i.p. injection of mouse anti-IgE Ab as a pretreatment, and another group received rat anti-IgG1 Ab. On day 21, the animals were challenged by i.p. injection of wasp venom, and 30 min later, body temperature was measured and serum levels of leukotriene (LT) B4 and LTC4 were determined using enzyme immunoassay. RESULTS: The body temperature of mice treated with anti-IgE Ab and controls before and after wasp venom challenge was 37.8±0.2 vs 37.7± 0.3°C before challenge and 37.8±0.2 vs 37.1± 0.3°C after challenge, respectively, showing that anti-IgE Ab treatment significantly prevented body temperature from falling (p <0.05). Furthermore, anti-IgE Ab treatment reduced total serum IgE levels in the treated mice (42.2±15.9 pg/ml), compared with controls (105.9±23.1 pg/ml, p <0.05), and inhibited the secretion of LTC4 in the treated mice (32.0±18.8 pg/ml), but not in the controls (162.4±12.4 pg/ml, p <0.05), following challenge with wasp venom. CONCLUSION: The results of the present study indicate that anti-IgE Ab treatment is an effective preventive measure against wasp venom-induced anaphylaxis.

Comparative analysis of circulating dendritic cell subsets in patients with atopic diseases and sarcoidosis.

BACKGROUND: Dendritic cells (DCs) are professional antigen-presenting cells that play a crucial role in the initiation and modulation of immune responses. Human circulating blood DCs are divided into two major subsets: myeloid DCs (mDCs); and plasmacytoid DCs (pDCs). Furthermore, mDCs are subdivided into two subsets: Th1-promoting mDCs (mDC1s); and Th2-promoting mDCs (mDC2s). Although CD1a, CD1c, and CD141 are generally used for classifying mDC subsets, their adequacy as a specific marker remains unclear. We performed this study to compare circulating mDC, pDC, mDC1, and mDC2 subsets between Th1- and Th2-mediated diseases using CD1a and CD141, and to analyze the adequacy of CD1a and CD141 as a marker for mDC1s and mDC2s, respectively. METHODS: Thirty patients with sarcoidosis, 23 patients with atopic diseases, such as atopic bronchial asthma, and 23 healthy subjects as controls were enrolled in this study. Peripheral blood DC subsets were analyzed with flow cytometry according to expressions of CD11c, CD123, CD1a, and CD141. For functional analysis, we measured interleukin (IL) 12p40 levels produced by the sorted mDC subsets. RESULTS: The sarcoidosis group showed decreased total DC (P < 0.05) and mDC counts (P < 0.05) compared to controls. The atopy group showed decreased CD1a+mDC count (P < 0.05), and increased CD1a-mDC count (P < 0.05) compared to controls. CD141+mDC count in the atopy group was higher than controls (P < 0.05). Sorted CD1a+mDCs produced higher levels of IL-12p40 than CD1a-mDCs (P = 0.025) and CD141+mDCs (P = 0.018). CONCLUSIONS: We conclude that decreased count of CD1a+mDC and increased count of CD141+mDC may reflect the Th2-skewed immunity in atopic diseases. The results of IL-12 levels produced by the sorted mDC subsets suggested the adequacy of CD1a and CD141 as a marker for mDC1 and mDC2, respectively, in vivo.

Measurement of Hymenoptera venom specific IgE by the IMMULITE 3gAllergy in subjects with negative or positive results by ImmunoCAP.

BACKGROUND: Patients may receive negative results from a specific IgE (sIgE) test such as the ImmunoCAP (CAP) despite a documented history of systemic reaction to a Hymenoptera sting. Thus, further testing may be required using another serological method or venom skin prick tests to confirm allergy diagnosis and correct species. OBJECTIVE: To evaluate the sensitivity and the specificity of CAP and IMMULITE 3gAllergy (IMMULITE) for detecting sIgE to Paper wasp (WA) and Yellow Jacket (YJ) venoms using patient clinical history as the comparator. METHODS: Sera from 70 participants with a history of systemic reactions (SR) to WA and/or YJ stings were tested using CAP and IMMULITE. Fifty participants from this group had negative results on CAP. To assess specificity, sera from 71 participants who had never experienced either a WA or YJ sting were tested using CAP and IMMULITE. Fifty participants from this group tested positive using CAP. RESULTS: In participants with a history of systemic reaction to a Hymenoptera sting, yet who tested negative for WA and/or YJ sIgE according to CAP, the positivity rate according to IMMULITE was 20-42% using 0.10 IU(A)/mL as the limit of detection (LoD), per the manufacturer's specification. When the LoD for CAP (0.35 IU(A)/mL) was applied to the IMMULITE results, positivity according to IMMULITE was 14-26%. Overall, sensitivity, specificity, and agreement with SR were greater for IMMULITE than for CAP. For YJ: sensitivity (IMMULITE:CAP), 42.8%:28.5%; specificity, 53.5%:39.4%; agreement, 48.2%:34%. For WA, sensitivity (IMMULITE:CAP), 58.6%:28.5%; specificity, 49.3%:47.8%; agreement, 43.9%:38.3%. CONCLUSION: The IMMULITE performed well for detecting sIgE to Hymenoptera venom.

[Clinical investigation of weekly cisplatin and vinorelbine with concurrent radiation therapy for locally advanced non-small cell lung cancer].

Concurrent combination therapy with chemotherapy(cisplatin(CDDP)and vinorelbine(VNR))and thoracic radiotherapy was administered to patients with unresectable locally advanced non-small cell lung cancer. The subjects were 19 patients with stage III non-small cell lung cancer, PS 0-1. They were able to undergo thoracic radiotherapy, had not received previous therapy, and had maintained main organ functions. CDDP(40mg/m / 2)and VNR(20mg/m2)were administered on days 1, 8, 22, and 29, and thoracic radiotherapy was performed every day except for those on which chemotherapy was conducted, 5 days a week at 2 Gy/day(total: 60 Gy). Four subjects were stage III A, 15 were stage III B, and their ages ranged from 42 to 75 years(median age: 65 years). The subjects were 18 males and 1 female, and concerning their histological types, 12, 5, and 2 were diagnosed squamous cell, adeno- and adenosquamous carcinoma, respectively. Regarding the therapeutic efficacy, 0, 14, and 5 subjects were clinically CR, cPR, and cSD, respectively, and their response rate was 73. 7%. The median survival time was 27. 2 months, and the one-year survival rate was 71. 2%. Concerning≥grade 3 adverse effects, 14 and 12 cases had leukocytopenia and neutropenia, respectively. However, no esophagitis was observed, and only one case experienced≥grade 3 nausea and vomiting. Radiation pneumonitis(≥grade 3)was observed in one case, but there was no severe liver or renal dysfunction, and no treatment-related death. It was suggested that this treatment reduces the occurrence of renal toxicity and digestive symptoms, and that a marked antitumor effect can be expected from its administration.

Relation between the antimicrobial susceptibility of clinical isolates of Pseudomonas aeruginosa from respiratory specimens and antimicrobial use density (AUD) from 2005 through 2008.

OBJECTIVE: To examine the relation between annual trends in the antimicrobial susceptibility of Pseudomonas aeruginosa and drug usage, we compared annual changes in the susceptibility rates of P. aeruginosa clinical isolates during a 4-year period and annual trends in the overall usage of antimicrobials during the same period. METHODS: We studied annual trends in MIC(90)/MIC(50), antimicrobial use density (AUD), and antimicrobial susceptibility rates based on clinical breakpoints for 150 strains of P. aeruginosa isolated from respiratory specimens at Dokkyo Medical University Hospital from 2005 through 2008. RESULTS: The MIC(90)/MIC(50) of antimicrobials effective against P. aeruginosa in years 2005, 2006, 2007, and 2008 were as follows: imipenem, 32/2, 32/1, 8/2, and 16/1 microg/mL; meropenem, 8/1, 8/1, 4/0.5, and 4/0.5 microg/mL; and biapenem, 16/1, 32/0.5, 4/0.5, and 8/0.5 microg/mL, indicating that susceptibility to carbapenems increased slightly. The MIC(90)/MIC(50) was 4/0.25, 2/0.125, 1/0.125, and 2/0.25 microg/mL for ciprofloxacin, 8/4, 8/4, 4/4, and 8/4 microg/mL for amikacin, 64/16, 64/16, 64/16, and 64/16 microg/mL for sulbactam/cefoperazone, 8/2, 16/2, 32/2, and 8/2 microg/mL for ceftazidime, indicating little change. The AUDs of fourth-generation cephalosporins increased from 2005 to 2008 (16.2, 18.4, 28.0, and 23.0), while the AUDs of carbapenems decreased (25.7, 23.7, 10.9, and 12.5). CONCLUSION: The decrease in the AUDs of carbapenems was associated with increased susceptibility rates of P. aeruginosa to carbapenem derivatives. A continuous understanding of trends in the resistance of P. aeruginosa and various other pathogens is essential for designing countermeasures against nosocomial infections, including the proper and effective use of antimicrobials.

An analysis of characteristics of patients with exacerbation of asthma in a large university hospital in Japan.

BACKGROUND: Considerable progress has been made in the management of asthma with the increasing use of inhaled corticosteroids. However, asthma exacerbation remains a problem. To analyze the characteristics of patients with exacerbation of asthma who visited our hospital in order to better understand the risk factors for fatal asthma. OBJECTIVES: We studied 100 patients who presented at Dokkyo Medical University Hospital (DMUH) with asthma exacerbation. METHODS: Entry sheets were completed by physicians and questionnaires by patients. RESULTS: Before the exacerbation, the severity was assessed as Step 1 in 46% of patients, Step 2 in 15%, Step 3 in 11%, and Step 4 in 18%. With regard to primary care physicians, 45% were treated at DMUH and 36% had no primary care physicians. Among the DMUH group, the largest proportion was aged 60-69 years and was in Step 4 category. According to asthma control test (ACT) scores, disease was poorly controlled in 83%. Patients with no primary care physician were most often aged 20-39 years (p < 0.01), and severity was assessed as Step 1 in 86% (p < 0.01). However, 44% were poorly controlled according to ACT (p < 0.05). CONCLUSION: Patients could be classified into two groups: older patients with severe intractable asthma, treated by a specialist and younger patients considered to have mild asthma, half of whom had poorly controlled asthma and no primary care physician. Systems are needed that allow the emergency physicians to evaluate the need for regular treatment in patients with exacerbation because such patients often visit the hospital at night or on a non-working day.

[A case of group G Streptococcus sepsis, chest wall abscess, and vertebral osteomyelitis mimicking a primary lung cancer with bone metastasis].

A 73-year-old woman who had been followed in our department of gynecology because of ovarian cancer since 2002, was admitted with liver dysfunction and complaining of back pain and light precordial chest pain. The chest radiograph on admission revealed a tumor in her left upper lung field, and chest CT revealed a tumor adjacent to the chest wall and mediastinum. FDG-positron emission tomography (PET) showed abnormal uptake in the tumor and Th6/7, and the subaortic lymph nodes. On the basis of these findings, primary lung cancer with bone metastasis was suspected. She had a high grade fever on admission, and blood cultures were positive for group G streptococcus. The treatment with intravenous penicillin was started. Percutaneous biopsy of the tumor in her left chest showed an abscess wall in the chest wall, but no evidence of malignancy. Transbronchial lung biopsy and CT-guided biopsy also showed no malignant cells. Since the tumor decreased in size and back pain improved gradually by only antibiotic treatment, a diagnosis of sepsis of group G streptococcus, chest wall abscess, and vertebral osteomyelitis was made. She was treated with intravenous penicillin for 4 weeks and oral amoxicillin for another 4 weeks. After 60 days of antibiotic treatment, the tumor vanished.