Real-World Safety and Effectiveness of Benralizumab in Japanese Patients with Severe Asthma: A Multicenter Prospective Observational Study.

Introduction: This study aimed to demonstrate whether benralizumab maintained the safety and effectiveness profiles established in randomized controlled trials among all patients with severe uncontrolled asthma initially prescribed benralizumab in the real-world setting in Japan. Methods: This was a prospective, observational, multicenter post-marketing study (ClinicalTrial.gov, NCT03588546). The safety and tolerability of benralizumab over 1 year were assessed by the incidence of adverse events (AEs), serious AEs, adverse drug reactions (ADRs), and serious ADRs. Patient background characteristics indicating a more frequent onset of ADRs with benralizumab were explored. The main effectiveness assessment was the change in Asthma Control Questionnaire-5 (ACQ-5) score from baseline. Patients with baseline ACQ-5 scores ≥1.5 were defined as having severe uncontrolled asthma. Results: In total, 632 patients were evaluated for safety and 274 for effectiveness; 139 patients were included in the severe uncontrolled asthma subgroup. ADRs were reported in 12.7% and serious AEs in 13.0% of patients. Serious infections occurred in 3.8%, serious hypersensitivity in 0.3%, and malignancy in 0.3% of patients. No helminthic infections occurred. In the effectiveness population, benralizumab improved the mean (standard deviation [95% confidence interval]) ACQ-5 score by -1.16 (1.40 [-1.36, -0.96]) from baseline; forced expiratory volume in 1 second by 0.151 (0.440 [0.09, 0.21]) L; and Mini-Asthma Quality of Life questionnaire score by 1.16 (1.29 [0.94, 1.38]) at the last observation. The annual asthma exacerbation rate was 0.42. A greater ACQ-5 score improvement was observed among patients with eosinophilic asthma characteristics. Conclusion: No new safety concerns were raised, and patients experienced benefits consistent with previous studies of benralizumab, thus supporting the use of benralizumab for the add-on maintenance treatment of patients with eosinophilic severe uncontrolled asthma.

Prognostic Value of Coronary Sinus Flow Quantification by Cardiac Magnetic Resonance Imaging in Patients With Acute Myocardial Infarction.

Background This study aimed to evaluate the prognostic value of hyperemic coronary sinus flow (h-CSF) and global coronary flow reserve (g-CFR) obtained by phase-contrast cine-magnetic resonance imaging in patients with acute myocardial infarction (MI). Methods and Results This retrospective study analyzed patients with acute MI (n=523) who underwent primary (ST-segment-elevation MI) or urgent (non-ST-segment-elevation MI) percutaneous coronary intervention. Absolute coronary sinus blood flow (CSF) at rest and during vasodilator stress hyperemia was quantified at 30 days (24-36 days) after the index infarct-related lesion percutaneous coronary intervention and revascularization of functionally significant non-infarct-related lesions. We used Cox proportional hazards regression modeling to examine the association between h-CSF, g-CFR, and major adverse cardiac events defined as all-cause death, nonfatal MI, hospitalization for congestive heart failure, and stroke. Finally, 325 patients with ST-segment-elevation MI (62.1%) and 198 patients with non-ST-segment-elevation MI (37.9%) were studied over a median follow-up of 2.5 years. The rest CSF, h-CSF, and g-CFR were 0.94 (0.68-1.26) mL/min per g, 2.05 (1.42-2.73) mL/min per g, and 2.17 (1.54-3.03), respectively. Major adverse cardiac events occurred in 62 patients, and Cox proportional hazards analysis showed that h-CSF and g-CFR were independent predictors of major adverse cardiac events (h-CSF: hazard ratio [HR], 0.64; 95% CI, 0.47-0.88; P=0.005; g-CFR: HR, 0.62; 95% CI, 0.47-0.82; P=0.001). When stratified by h-CSF and g-CFR, cardiac event-free survival was the worst in patients with concordantly impaired h-CSF (<1.6 mL/min per g) and g-CFR (<1.7) (P<0.001). Conclusions Global coronary sinus flow quantification using phase-contrast cine-magnetic resonance imaging provided significant prognostic information independent of infarction size and conventional risk factors in patients with acute MI undergoing revascularization.

Effect of percutaneous coronary intervention on global hemodynamics and the prevalence of residual microvascular dysfunction.

OBJECTIVES: We aimed to examine the changes in hyperemic coronary sinus flow (CSF) and global coronary flow reserve (g-CFR) after percutaneous coronary intervention (PCI) and investigate the predictors to improve these metrics and the prevalence of residual coronary microvascular dysfunction (CMD). METHODS: This prospective, single-center study included 118 patients with stable coronary artery disease undergoing PCI for a single proximal lesion. Phase-contrast cine-cardiac magnetic resonance (PC-CMR) was used to assess hyperemic CSF (HCSF) and g-CFR, before and after PCI. Residual CMD was defined as concordantly impaired post-PCI HCSF (<2.3 ml/min/g) and g-CFR (<2.0). RESULTS: HCSF significantly increased, although 38 (32.2%) patients showed a decrease. There was no significant change in g-CFR despite fractional flow reserve (FFR) improvement in all target territories. Concordantly increased HCSF and g-CFR were effectively discriminated by adding PC-CMR-derived information to pre-PCI FFR. Residual CMD was observed in 30 (25.4%) patients and was associated with pre-PCI renal dysfunction and lower pre-PCI rest and hyperemic CSF, but not with pre-PCI regional physiological indices. CONCLUSIONS: FFR-guided PCI was associated with increased HCSF, but not with increased g-CFR. After uncomplicated PCI, one-quarter of patients showed residual CMD. Our approach may help identify patients who may benefit from increased coronary perfusion or show residual CMD.

Association between pericoronary adipose tissue attenuation and outcome after second-generation cryoballoon ablation for atrial fibrillation.

OBJECTIVES: Previous studies reported the association between inflammation and atrial fibrillation (AF). Pericoronary adipose tissue (PCAT) attenuation, PCATA, on cardiac CT angiography (CTA) reflects pericoronary inflammation. We hypothesized that the PCATA predicts AF recurrence after cryoballoon ablation (CBA) for paroxysmal and persistent AF. METHODS: We studied 364 patients (median age, 65 years) with persistent (n = 41) and paroxysmal (n = 323) AF undergoing successful first-session second-generation CBA with pre-ablation cardiac CTA. Three-vessel (3V)-PCATA was defined as the mean CT attenuation value of PCAT of all three major coronary arteries. Predictors of AF recurrence during follow-up were evaluated. RESULTS: AF recurrence after the 3-month blanking period was detected in 90 patients (24.7%) during the median follow-up of 26 (interquartile range, 19-42) months. AF recurrence was associated with prior stroke and statin use, NT-proBNP and high-sensitivity cardiac troponin-I levels, left ventricular dimension, left atrial volume index (LAVI), 3V-PCATA, and early AF recurrence during the blanking period. On multivariable Cox proportional hazard analysis, prior stroke (hazard ratio [HR], 2.208, 95% confidence interval [CI], 1.166-4.180, p = 0.015), LAVI (HR, 1.030, 95% CI, 1.010-1.051, p = 0.003), 3V-PCATA (HR, 1.034, 95% CI, 1.001-1.069, p = 0.046), and early AF recurrence (HR, 2.858, 95% CI, 1.855-4.405, p < 0.001) remained statistically significant. CONCLUSION: Pre-ablation CTA-derived 3V-PCATA, representing pericoronary inflammation, was an independent predictor of recurrence after first-session AF ablation using a second-generation cryoballoon. ADVANCES IN KNOWLEDGE: Assessment of 3V-PCATA may identify patients at high risk of AF recurrence after CBA for AF.

Effect of contrast medium versus low-molecular-weight dextran for intracoronary optical coherence tomography in renal insufficiency.

Low-molecular-weight dextran (LMWD) is considered a safe alternative to contrast media to displace blood during optical coherence tomography (OCT) imaging, but concerns remain. The purpose of this study was to investigate whether using LMWD for OCT protects against kidney injury in patients with renal insufficiency compared with contrast media. We retrospectively identified 474 patients with renal insufficiency (estimated glomerular filtration rate < 60 ml/min/1.73 m2) who underwent OCT during coronary angiography or percutaneous coronary intervention; 110 patients with LMWD plus contrast medium (LMWD group) and 364 patients with contrast medium exclusively (Contrast group). We evaluated differences between the two groups and performed propensity score-matched subgroup comparisons. Compared with the Contrast group, the LMWD group had worse baseline renal function, higher prevalence of diabetes mellitus and percutaneous coronary intervention history, higher C-reactive protein and N-terminal pro B-type natriuretic peptide levels, lower hemoglobin levels, and lower left ventricular ejection fraction. The median total volume of contrast medium in the Contrast group was 230.0 ml vs. 61.8 ml of LMWD in addition to 164.0 ml of contrast medium in the LMWD group. Renal function was consistently impaired in the LMWD group within 5 days, at 1-month, and 1-year follow-up (P < 0.001). Two propensity score-matched analyses adjusted for either total volume used or contrast media volume consistently indicated a trend toward worsening renal function in the LMWD group at the 1-year follow-up. No protective benefit for renal function from using LMWD instead of contrast media for OCT was observed in patients with renal insufficiency.

Japanese guidelines for occupational allergic diseases 2020.

Occupational allergic diseases are likely to worsen or become intractable as a result of continuous exposure to high concentrations of causative allergens. These are socioeconomically important diseases that can lead to work interruptions for patients and potentially job loss. We published the first guideline for managing occupational allergic diseases in Japan. The original document was published in Japanese in 2013, and the following year (2014) it was published in English. This guideline consists of six chapters about occupational asthma, occupational allergic rhinitis, occupational skin diseases, hypersensitivity pneumonitis, occupational anaphylaxis shock, and the legal aspects of these diseases. Providing general doctors with the knowledge to make evidence-based diagnoses and to understand the occupational allergic disease treatment policies, was a breakthrough in allergic disease treatment. Due to the discovery of new occupational allergens and the accumulation of additional evidence, we published a revised version of our original article in 2016, and it was published in English in 2017. In addition to including new knowledge of allergens and evidence, the 2016 revision contains a "Flowchart to Diagnosis" for the convenience of general doctors. We report the essence of the revised guidelines in this paper.

Drug hypersensitivity reactions in Asia: regional issues and challenges.

There are geographical, regional, and ethnic differences in the phenotypes and endotypes of patients with drug hypersensitivity reactions (DHRs) in different parts of the world. In Asia, aspects of drug hypersensitivity of regional importance include IgE-mediated allergies and T-cell-mediated reactions, including severe cutaneous adverse reactions (SCARs), to beta-lactam antibiotics, antituberculous drugs, nonsteroidal anti-inflammatory drugs (NSAIDs) and radiocontrast agents. Delabeling of low-risk penicillin allergy using direct oral provocation tests without skin tests have been found to be useful where the drug plausibility of the index reaction is low. Genetic risk associations of relevance to Asia include human leucocyte antigen (HLA)-B*1502 with carbamazepine SCAR, and HLA-B*5801 with allopurinol SCAR in some Asian ethnic groups. There remains a lack of safe and accurate diagnostic tests for antituberculous drug allergy, other than relatively high-risk desensitization regimes to first-line antituberculous therapy. NSAID hypersensitivity is common among both adults and children in Asia, with regional differences in phenotype especially among adults. Low dose aspirin desensitization is an important therapeutic modality in individuals with cross-reactive NSAID hypersensitivity and coronary artery disease following percutaneous coronary intervention. Skin testing allows patients with radiocontrast media hypersensitivity to confirm the suspected agent and test for alternatives, especially when contrasted scans are needed for future monitoring of disease relapse or progression, especially cancers.

Clinical significance of the presence of puff-chandelier ruptures detected by nonobstructive aortic angioscopy.

OBJECTIVE: This study aimed to investigate the prevalence and prognostic significance of atherosclerotic aortic plaques (AAPs) or specific AAP types detected by nonobstructive angioscopy (NOA) in patients who underwent percutaneous coronary intervention (PCI). BACKGROUND: Although recent studies have reported the presence of various patterns of AAPs, identified by NOA, the clinical significance of the presence of AAPs remains elusive. METHODS: In this retrospective, multicenter cohort study, a total of 167 patients who underwent PCI and intra-aortic scans with NOA were studied. The association between AAPs and the incidence of major adverse cardiac events (MACEs), including cardiac death, myocardial infarction, stroke, and clinically driven unplanned revascularizations, was assessed. RESULTS: AAPs were detected in 126 patients (75%) who underwent NOA. MACEs occurred in 28 (17%) patients during the follow-up (median 2.9 years [range 2.1-3.8]). Among all types of AAPs, only puff-chandelier rupture (PCR) showed a significant difference in frequency between patients with and those without MACEs: 21 (75%) and 49 (35%), respectively (p < .001). Multivariable Cox proportional hazard analysis revealed that PCR (hazard ratio [HR] 3.73, 95% confidence interval [CI] 1.57-8.87, p = .004) and chronic kidney disease (HR 2.97, 95% CI 1.37-6.44, p = .010) were independent predictors of MACEs. Kaplan-Meier analysis revealed that PCR was significantly associated with more frequent MACEs. CONCLUSION: The detection of PCR in the aorta using NOA was significantly associated with an increased risk of subsequent adverse events after PCI.

Methotrexate-associated Lymphoproliferative Disorder: A Rare Differential Diagnosis of Wheezes.

A 70-year-old woman was admitted for the evaluation of wheezes and a nodular lesion in the left lung field. She had been diagnosed with rheumatoid arthritis at 45 years of age and was continuously treated with methotrexate (MTX) at 8 mg/week. Bronchoscopic aspiration histology of a hilar lymph node suggested a lymphoproliferative disorder (LPD). After discontinuation of MTX, the lung nodule and wheezes disappeared. Although wheezes are not a usual manifestation of LPD, her clinical course clearly demonstrated an obvious relationship between LPD-induced airway narrowing and wheezes.

Silent cerebral events/lesions after second-generation cryoballoon ablation: How can we reduce the risk of silent strokes?

BACKGROUND: Atrial fibrillation (AF) ablation is associated with a substantial risk of silent cerebral events/lesions (SCEs/SCLs) detected on magnetic resonance imaging (MRI). OBJECTIVE: The purpose of this study was to investigate the factors associated with the incidence of SCEs/SCLs during second-generation cryoballoon ablation. METHODS: Two hundred fifty-six AF patients underwent brain MRI 1 day after pulmonary vein (PV) isolation using second-generation cryoballoons with a single 28-mm balloon and short freeze strategy. RESULTS: Overall, 991 of 1016 PVs (97.5%) were successfully isolated by 4.9 ± 1.3 cryoballoon applications per patient, and 25 PVs required touch-up radiofrequency ablation. The total procedure time was 72.7 ± 26.1 minutes. SCEs and SCLs were detected in 68 (26.5%) and 27 (10.5%) patients, respectively. None of the patients reported any neurologic symptoms. Reinsertion of once withdrawn cryoballoons and subsequent applications significantly increased the incidence of SCEs (odds ratio [OR] 2.057; 95% confidential interval [CI] 1.051-4.028; P = .035), and additional left atrial mapping with a multielectrode catheter significantly increased the incidence of SCLs (OR 3.317; 95% CI 1.365-8.056; P = .008). Transient coronary air embolisms were significantly associated with the incidence of SCLs (OR 3.447; 95% CI 1.015-11.702; P = 0.047). On the contrary, an uninterrupted anticoagulation regimen, use of radiofrequency deliveries for transseptal access, cryoballoon air removal with extracorporeal balloon inflations, strength of the MRI magnet, internal electrical cardioversion, and touch-up ablation were not associated with the incidence of SCEs/SCLs. CONCLUSION: A significant number of SCE/SCL occurrences was observed after second-generation cryoballoon ablation procedures. These results suggest that air embolisms are the main mechanism of SCEs/SCLs, and the injected air volume might determine the lesion type.

Pulmonary vein isolation in patients with a left common pulmonary vein: Comparison between second-generation cryoballoon and radiofrequency ablation.

BACKGROUND: Adaptability of cryoballoons to anatomic pulmonary vein (PV) variations is limited due to the fixed geometrical shape, and use for left common PVs (LCPVs) is controversial. We compared the procedural and clinical outcomes in patients with LCPVs after cryoballoon and radiofrequency ablation, and explored the morphological parameters associated with procedural difficulty in LCPV isolations using cryoballoons. METHODS AND RESULTS: Eighty-nine consecutive atrial fibrillation patients with LCPVs undergoing PV isolation using either 28-mm second-generation cryoballoons (n=30) or irrigated-tip catheters (n=59) were included. The patient characteristics except for the left atrial diameter (p=0.05) or morphological parameters obtained from cardiac computed tomography were similar between the two groups. The number needed to disconnect the LCPVs (NND) in the cryoballoon-group was ≦3 applications in 22 patients, but ≧4 in the remaining 8, including 1 requiring touch-up ablation. The PV isolation procedure time was significantly shorter in the cryoballoon-group than radiofrequency-group (43.0±19.5min vs. 68.2±31.4min, p<0.001), whereas the single procedure 1-year atrial fibrillation freedom was similar between the groups (74% vs. 67%, p=0.73). A multivariate logistic regression analysis revealed that the ovality index in the cryoballoon-group (odds ratio=1.474; 95%confidence interval=1.020-2.128; p=0.039) and orientation difference between the LCPV and lower branch in the frontal plane (odds ratio=1.071; 95%confidence interval=1.008-1.137; p=0.026) were independent predictors of an NND≧4. The incidence of LCPV reconnections was similar between the cryoballoon- and radiofrequency-groups during the second procedure (50.0% vs. 58.3%, p=0.73). CONCLUSIONS: Cryoballoon ablation was similarly as effective as radiofrequency ablation in patients with LCPVs, and morphological evaluations aided in predicting procedural difficulty in LCPV isolations.

Utility and effectiveness of Symbicort® Turbuhaler® (oral inhalation containing budesonide and formoterol) in a patient with severe asthma after permanent tracheostomy.

BACKGROUND: The utility and effectiveness of inhalational asthma therapy in patients with a permanent tracheostomy has not been established. Previously, a few studies reported the use of nebulizer-type inhalers for treating these patients. Symbicort® Turbuhaler® (Symbicort) is an orally inhaled dry powder containing the corticosteroid budesonide and the bronchodilator formoterol. There are no reports describing the successful use of Symbicort in patients with a permanent tracheostomy. CASE PRESENTATION: We describe the case of a woman with poorly controlled severe asthma after a permanent tracheostomy. She had developed thyroid cancer with tracheal invasion for which right thyroid lobectomy and tracheal and esophageal resection were performed, with subsequent construction of a permanent tracheostomy. In our case, prior to surgery, asthma control had been improved by adding a bronchodilator-the long-acting muscarinic antagonist tiotropium-and the anti-IgE antibody agent omalizumab to single maintenance and reliever therapy (SMART) using Symbicort; surgery was then performed. After surgery, asthma control worsened as a result of a change from Symbicort to budesonide nebulizer and a tulobuterol patch. In order to resume SMART therapy, an In-Check® inspiratory flow meter was used to measure and assess whether the inspiratory flow rate was sufficient for a dry-powder inhaler. Inhalation guidance was provided. On inhalation with the tracheostomy closed at the same time, the inspiratory flow rate was 43 L/min at the maximum. This was judged to be sufficient for the effect of Symbicort, and thus the inhaler was changed to Symbicort. Asthma symptoms promptly improved, and the patient was subsequently discharged. CONCLUSIONS: The use of Symbicort resulted in improved asthma control in a patient with severe asthma following a permanent tracheostomy. Thus, it is suggested that inhalation powder could be an option for patients with permanent tracheostomy.

Leptin enhances ICAM-1 expression, induces migration and cytokine synthesis, and prolongs survival of human airway epithelial cells.

There is rising interest in how obesity affects respiratory diseases, since epidemiological findings indicate a strong relationship between the two conditions. Leptin is a potent adipokine produced mainly by adipocytes. It regulates energy storage and expenditure and also induces inflammation. Previous studies have shown that leptin is able to activate inflammatory cells such as lymphocytes and granulocytes, but little is known about its effect on lung structural cells. The present study investigated the effects of leptin on human airway epithelial cells by using human primary airway epithelial cells and a human airway epithelial cell line, BEAS-2B. Flow cytometry showed enhanced ICAM-1 expression by both of those cells in response to leptin, and that effect was abrogated by dexamethasone or NF-κB inhibitor. Flow cytometry and quantitative PCR showed that airway epithelial cells expressed leptin receptor (Ob-R), whose expression level was downregulated by leptin itself. Multiplex cytokine analysis demonstrated enhanced production of CCL11, G-CSF, VEGF, and IL-6 by BEAS-2B cells stimulated with leptin. Furthermore, transfection of Ob-R small interference RNA decreased the effect of leptin on CCL11 production as assessed by quantitative PCR. Finally, leptin induced migration of primary airway epithelial cells toward leptin, suppressed BEAS-2B apoptosis induced with TNF-α and IFN-γ, and enhanced proliferation of primary airway epithelial cells. In summary, leptin was able to directly activate human airway epithelial cells by binding to Ob-R and by NF-κB activation, resulting in upregulation of ICAM-1 expression, induction of CCL11, VEGF, G-CSF, and IL-6 synthesis, induction of migration, inhibition of apoptosis, and enhancement of proliferation.

Allergy to formaldehyde: basophil histamine-release test is useful for diagnosis.

We describe a case of formaldehyde-induced urticaria with a positive test result for serum IgE antibody against this substance. Formaldehyde's slow protein-binding property may explain why basophil histamine-release tests using fresh formaldehyde solutions are not diagnostic, whereas the tests are useful if formaldehyde that had been stored with albumin is used.

Impact of four loci on serum tamsulosin hydrochloride concentration.

Tamsulosin hydrochloride is one of the most potent drugs for treatment of benign prostatic hyperplasia (BPH), however, the efficacy of tamsulosin hydrochloride varies among individuals. In this study, we measured the maximum serum concentration (Cmax) of tamsulosin hydrochloride in 182 of BPH patients and found remarkable individual variability. To investigate the genetic factors that regulate pharmacokinetics of tamsulosin hydrochloride, we conducted a genome-wide association study in these 182 BPH patients. As a result, rs16902947 on chromosome 5p13.2, rs7779057 on 7q22.3, rs35681285 on 7p21.2 and rs2122469 on 8p21.3 indicated possible associations with Cmax of tamsulosin hydrochloride (P=1.29 × 10(-7), 2.15 × 10(-7), 4.35 × 10(-7) and 7.03 × 10(-7), respectively), although these single-nucleotide polymorphisms (SNPs) did not reach the genome-wide significance threshold after Bonferroni correction. As these associated SNPs showed additive effects on serum tamsulosin hydrochloride concentration, we defined the 'Cmax prediction index' based on genotypes of these SNPs. This index clearly associated with Cmax values (P=4.5 × 10(-6)), indicating the possible roles of these four variants in tamsulosin hydrochloride pharmacokinetics. Our findings would partially explain the variability of the response to the tamsulosin hydrochloride treatment.

Japanese Orthopaedic Association Hip Disease Evaluation Questionnaire (JHEQ): a patient-based evaluation tool for hip-joint disease. The Subcommittee on Hip Disease Evaluation of the Clinical Outcome Committee of the Japanese Orthopaedic Association.

BACKGROUND: The Japanese Orthopaedic Association Hip Score is widely used in Japan, but this tool is designed to reflect the viewpoint of health-care providers rather than that of patients. In gauging the effect of medical therapies in addition to clinical results, it is necessary to assess quality of life (QOL) from the viewpoint of patients. However, there is no tool evaluating QOL for Japanese patients with hip-joint disease. METHODS: With the aim of more accurately classifying QOL for Japanese patients with hip-joint disease, we prepared a questionnaire with 58 items for the survey derived from 464 opinions obtained from approximately 100 Japanese patients with hip-joint disease and previously devised evaluation criteria. In the survey, we collected information on 501 cases, and 402 were subjected to factor analysis. From this, we formulated three categories-movement, mental, and pain-each comprising 7 items, for a total of 21 items to be used as evaluation criteria for hip-joint function. RESULTS: The Cronbach's α coefficients for the three categories were 0.93, 0.93, and 0.95, respectively, indicating the high reliability of the evaluation criteria. The 21 items included some related to the Asian lifestyle, such as use of a Japanese-style toilet and rising from the floor, which are not included in other evaluation tools. CONCLUSIONS: This self-administered questionnaire may become a useful tool in the evaluation of not only Japanese patients, but also of members of other ethnic groups who engage in deep flexion of the hip joint during daily activities.

The in vitro effects of advanced glycation end products on basophil functions.

BACKGROUND: Basophils are thought to play pivotal roles in the pathogenesis of allergic reactions, but their roles in inflammation associated with systemic abnormalities such as metabolic disorders remain largely unknown. Advanced glycation end products (AGEs) are potentially important substances produced in high-glucose disease conditions. In this in vitro study, we investigated whether the biological functions of human basophils can be influenced by AGEs. METHODS: We analyzed the effects of AGEs on various functions and markers of human basophils, including CD11b expression, apoptosis, degranulation, and cytokine production. RESULTS: Flow cytometric analysis indicated that the level of the receptor for AGEs (RAGE) on the surface of freshly isolated basophils was very low but was clearly upregulated by IL-3. Apoptosis of basophils was induced by high concentrations of glycated albumin. Although glycated albumin failed to affect the level of surface CD11b expression or to trigger degranulation or production of IL-4 and IL-13 in basophils, it dose-dependently induced IL-6 and IL-8 secretion. CONCLUSIONS: AGEs seem to act on human basophils; they suppress the cells' longevity but elicit secretion of inflammatory cytokines. Through these biological changes, basophils might play some roles in inflammatory conditions associated with metabolic disorders presenting elevated levels of AGEs.

Leptin enhances survival and induces migration, degranulation, and cytokine synthesis of human basophils.

Basophils are the rarest leukocytes in human blood, but they are now recognized as one of the most important immunomodulatory as well as effector cells in allergic inflammation. Leptin, a member of the IL-6 cytokine family, has metabolic effects as an adipokine, and it is also known to participate in the pathogenesis of inflammatory reactions. Because there is an epidemiologic relationship between obesity and allergy, we examined whether basophil functions are modified by leptin. We found that human basophils express leptin receptor (LepR) at both the mRNA and surface protein levels, which were upregulated by IL-33. Leptin exerted strong effects on multiple basophil functions. It induced a strong migratory response in human basophils, similar in potency to that of basophil-active chemokines. Also, leptin enhanced survival of human basophils, although its potency was less than that of IL-3. Additionally, CD63, a basophil activation marker expressed on the cell surface, was upregulated by leptin, an effect that was neutralized by blocking of LepR. Assessments of basophil degranulation and cytokine synthesis found that leptin showed a strong priming effect on human basophil degranulation in response to FcεRI aggregation and induced Th2, but not Th1, cytokine production by the cells. In summary, the present findings indicate that leptin may be a key molecule mediating the effects of adipocytes on inflammatory cells such as basophils by binding to LepR and activating the cellular functions, presumably exacerbating allergic inflammation.