Effects of smoking cessation on endothelial function as assessed by flow-mediated total dilation.

BACKGROUND: In assessing the effects of smoking cessation on endothelial function, low-flow-mediated constriction (L-FMC) may provide complementary information to flow-mediated dilation (FMD). However, the value of flow-mediated total dilation (FMTD), an index that incorporates L-FMC into FMD, remains underreported. We aimed to evaluate the effect of smoking cessation on endothelial function, as assessed by FMD and FMTD, and clarify its associated clinical factors. METHODS: We enrolled 118 consecutive current smokers without previous coronary artery disease (72.9% were men; age: 59 ± 11 years) who underwent smoking cessation treatment. The clinical variables %FMD, %L-FMC, and %FMTD were examined before and 20 weeks after treatment initiation. A multivariate linear regression model was used to investigate the effects of smoking cessation on %FMD and %FMTD and the interaction between smoking cessation and baseline clinical variables. RESULTS: After 20 weeks, 85 smokers (69.4% were men; age: 59 ± 12 years) ceased smoking (abstainers), whereas 33 smokers (81.8% were men; age: 58 ± 11 years) did not (continued smokers). The estimated group differences (abstainers - continued smokers) in changes in the %FMD and %FMTD were 0.77% (95% confidence interval [CI], -0.22-1.77%; p = 0.129) and 1.17% (95% CI, 0.16-2.18%; p = 0.024), respectively. Smoking cessation-associated improvement in %FMTD was greater in women than in men (5.41% [95% CI, 3.15-7.67%] versus 0.24% [95% CI, -0.81-1.28%]; p-value for interaction, < 0.001). Additionally, a greater %FMTD improvement was observed in patients who smoked fewer cigarettes per day (p-value for interaction, 0.042) and those who had a smaller resting baseline lumen diameter (Dbase) (p-value for interaction, 0.023). CONCLUSIONS: Smoking cessation was associated with an improvement in %FMTD. Sex, cigarettes smoked per day, and Dbase significantly affected this improvement. The FMTD may help in risk stratification after smoking cessation.

Clopidogrel-induced Eosinophilia with Hypercalcemia.

There are few cases describing the association of eosinophilia with hypercalcemia, and drug-induced eosinophilia with hypercalcemia has not been reported. A 74-year-old man had been diagnosed with asthma 4 months earlier. He was admitted due to eosinophilia with hypercalcemia. Chest computed tomography showed a nodule in the left lung and mediastinal lymphadenopathy. By obtaining a detailed medical history, clopidogrel was suspected as the prime cause of eosinophilia. After the discontinuation of clopidogrel, the eosinophilia with hypercalcemia, lung nodule and mediastinal lymphadenopathy improved. Clopidogrel-induced eosinophilia can potentially cause hypercalcemia. Obtaining a detailed clinical history is important in diagnosing the cause of eosinophilia.

Predictors of the effects of smoking cessation on the endothelial function of conduit and digital vessels.

Smoking predisposes individuals to endothelial dysfunction. Flow-mediated dilation (FMD) and reactive hyperemia peripheral artery tonometry (RH-PAT) are used to assess endothelial function. However, whether smoking cessation demonstrates comparable effects on endothelial function evaluated by FMD and RH-PAT remains unclear. Thus, we aimed to evaluate the effects of smoking cessation on endothelial function evaluated simultaneously by FMD and RH-PAT and clarify the factors associated with these effects. Fifty-eight consecutive current smokers (mean ± standard deviation; age, 64 ± 11 years) who visited our smoking cessation outpatient department and succeeded with smoking cessation were enrolled. Twenty-one continued smokers were enrolled as age- and sex-matched controls. Clinical variables, FMD, and natural logarithmic transformation of the reactive hyperemia index (Ln-RHI) were examined before and 20 weeks after treatment initiation. In 58 smokers who succeeded with smoking cessation, FMD significantly improved (3.80 ± 2.24 to 4.60 ± 2.55%; p = 0.013), whereas Ln-RHI did not (0.59 ± 0.28 to 0.66 ± 0.22; p = 0.092). Spearman's rank correlation coefficient between changes in FMD and Ln-RHI was -0.004, and the intraclass correlation coefficient for a two-way mixed effects model was <0.001 (p = 0.499). In multivariate analysis, the presence of an increase in FMD was inversely correlated with the Brinkman index and changes in systolic blood pressure (SBP), whereas Ln-RHI was positively correlated with changes in SBP and inversely correlated with baseline body mass index. These factors may predict the varying effects of smoking cessation on the endothelial function of the conduit and digital vessels.

Possible role of airway microvascular permeability on airway obstruction in patients with chronic obstructive pulmonary disease.

BACKGROUND: Airway microvascular system participates in the airway inflammation that is central to the pathophysiology of inflammatory lung disorders. OBJECTIVE: To examine the role of airway microvascular permeability on airway obstruction in patients with chronic obstructive pulmonary disease (COPD). METHODS: We measured the airway microvascular permeability index (AMPI) separately in the central or peripheral airways using a bronchoscopic microsampling technique in 9 non-smokers, 18 smokers without COPD (10 former smokers and 8 current smokers), and 26 smokers with COPD (12 former smokers and 14 current smokers). RESULTS: AMPI in the central airways was relatively low, and this index was comparable among the five groups. In contrast, AMPI in the peripheral airways was significantly higher in smokers with or without COPD compared with non-smokers. Moreover, AMPI in the peripheral airways was significantly higher in current smokers than in former smokers with COPD. Especially, AMPI in the peripheral airways, but not in the central airways, showed a significant correlation with the degree of airway obstruction in former or current smokers with COPD. However, AMPI in the peripheral airways was not correlated with the diffusing capacity of the lung in former or current smokers with COPD. CONCLUSION: Airway microvascular permeability in the peripheral airways is increased in patients with COPD, and is associated with the severity of airway obstruction. We may need to consider this characteristic feature as a target in any therapeutic strategy for the treatment of the disease. (237 words).

Evaluation of the severity of small airways obstruction and alveolar destruction in chronic obstructive pulmonary disease.

BACKGROUND: Airflow limitation in COPD is caused by a mixture of small airways obstruction and alveolar destruction. OBJECTIVE: To evaluate the contributions of these factors to airflow limitation through measurement of two biomarkers, pentosidine and vascular endothelial growth factor (VEGF), which reflect pathology or function of the lower respiratory tract of COPD. METHODS: We measured pentosidine and VEGF levels in induced sputum from 23 non-smokers, 26 smokers without COPD, and 43 smokers with COPD. We evaluated the correlations of two biomarkers levels with the grade of low attenuation area (LAA) in high-resolution computed tomographic scans and the Δ N2 from the nitrogen washout curve. RESULTS: Pentosidine levels were significantly higher in smokers with COPD than in non-smokers and smokers without COPD. In contrast, VEGF levels were significantly lower in smokers without COPD than in non-smokers, and further decreased in smokers with COPD. In the four-stage classification of LAA grading, pentosidine levels steeply increased from grade I to Ⅳ, while VEGF levels decreased with increasing severity of LAA grade. Pentosidine levels were positively correlated with Δ N2 in COPD patients with mild emphysema. In contrast, VEGF levels were inversely correlated with Δ N2 in COPD patients with severe emphysema. CONCLUSION: Pentosidine level is responsible for the severity of small airways obstruction, while VEGF level reflects the magnitude of alveolar destruction. Thus, simultaneous measurement of pentosidine and VEGF levels may be a promising approach to discriminate the severity of small airways obstruction and alveolar destruction in the lower respiratory tract of COPD.

Asthma-COPD overlap syndrome-Coexistence of chronic obstructive pulmonary disease and asthma in elderly patients and parameters for their differentiation.

Japan is an aging society, and the number of elderly patients with asthma and chronic obstructive pulmonary disease (COPD) is consequently increasing, with an estimated incidence of approximately 5 million. In 2014, asthma-COPD overlap syndrome (ACOS) was defined by a joint project of Global Initiative for Asthma (GINA) committee and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) committee. The main aims of this consensus-based document are to assist clinicians, especially those in primary care or nonpulmonary specialties. In this article, we discussed parameters to differentiate asthma and COPD in elderly patients and showed prevalence, clinical features and treatment of ACOS on the basis of the guidelines of GINA and GOLD. Furthermore, we showed also referral for specialized investigations.

Down-Regulation of Soluble α-Klotho is Associated with Reduction in Serum Irisin Levels in Chronic Obstructive Pulmonary Disease.

PURPOSE: The klotho gene was originally identified as a putative aging-suppressor gene. Klotho-depleted mice display a shortened life span and exhibit a variety of premature aging-related phenotypes such as pulmonary emphysema and sarcopenia. This study was designed to determine the roles of secreted-type klotho protein on lung and skeletal muscle in chronic obstructive pulmonary disease (COPD). METHODS: Serum α-klotho and irisin levels were assayed in 16 non-smokers, 13 smokers without COPD, and 24 smokers with COPD. Moreover, we examined correlations between soluble α-klotho levels and the results of lung function test, cardiopulmonary exercise test (CPET), and skeletal muscle function in smokers with COPD. RESULTS: Soluble α-klotho levels were significantly lower in smokers with COPD compared to non-smokers and smokers without COPD. In smokers with COPD, those levels did not significantly correlate with any parameters of lung function test. In CPET, peak VO2 significantly correlated with FEV1 (% predicted) (r = 0.76, p = 0.0003) and DLCO (% predicted) (r = 0.62, p = 0.003). In contrast, soluble α-klotho levels did not significantly correlate with peak VO2. Irisin levels were also significantly lower in smokers with COPD. Moreover, there was a significant correlation between soluble α-klotho and serum irisin levels (r = 0.61, p = 0.004). CONCLUSIONS: Our findings could provide a critical first step to understanding the impacts of soluble α-klotho on skeletal muscle in COPD and may lead to the identification of new molecular targets for the treatment of COPD.

Impaired nuclear factor erythroid 2-related factor 2 expression increases apoptosis of airway epithelial cells in patients with chronic obstructive pulmonary disease due to cigarette smoking.

BACKGROUND: Cigarette smoking-induced oxidative stress is known to be a key mechanism in COPD pathogenesis. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a central transcription factor that regulates the antioxidant defense system. The aim of this study was to compare Nrf2 expression in COPD subjects and control subjects, and to determine the role of Nrf2 in protecting against oxidative stress-induced apoptosis. METHODS: We enrolled 8 COPD subjects and 7 control subjects in this study. We performed bronchial brushing by bronchoscopy and obtained bronchial epithelial cells from the airways. Nrf2 expression in bronchial epithelial cells was evaluated by real-time PCR and Western blotting. We examined the effect of 10 or 15 % cigarette smoke extract (CSE) induced A549 cells apoptosis using a time-lapse cell imaging assay with caspase-3/7 activation detecting reagent and performed Terminal deoxynucleotidyltransferase-mediated dUTP nick end labelling assay for confirming A549 cells apoptosis. We also examined the effects of Nrf2 knockdown and, 0.1, 0.5, and 1.0 mM N-acetyl cysteine on CSE-induced apoptosis. Statistical analyses were performed using t-test, paired t-test or an analysis of variance followed by the Tukey-Kramer method. RESULTS: Nrf2 mRNA expression in COPD subjects was significantly lower than that in control subjects and Nrf2 mRNA were negatively correlated with pack year. Nrf2 protein in COPD subjects was significantly lower than that in control subjects. CSE-induced A549 cells apoptosis was increased in a time-, concentration-dependent manner, and was significantly increased by Nrf2 knockdown. N-acetyl cysteine significantly ameliorated CSE-induced apoptosis. CONCLUSIONS: Nrf2 expression was lower in COPD patients than in control subjects. Nrf2 might have a protective role against apoptosis caused by CSE-induced oxidative stress. These results suggest an involvement of Nrf2 in COPD and administration of antioxidants to patients with COPD might be a basic therapeutic option.

Up-regulation of the MicroRNA miR-30c Induced by High Mobility Group Box 1 in A549 Cells Used as an Alveolar Epithelial Model.

Background: MicroRNAs (miRNAs) have been reported to be involved in multiple diseases, including chronic obstructive pulmonary disease (COPD), a progressive disease in which alveolar apoptosis may play a role. We hypothesized that miRNAs are associated with the response to injury. induced by high mobility group box 1 (HMGB1), a cytokine crucial for the development of COPD, and studied the potential link between HMGB1 and miRNAs. Materials and Methods: A549 cells were stimulated with recombinant HMGB1. RNA and protein were extracted and culture supernatants were collected. Molecules downstream of HMGB1 signaling were analyzed by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Expression levels of miRNA were analyzed by quantitative RT-PCR. Cellular injury was evaluated by western blotting of relevant proteins. Apoptosis was evaluated by in situ terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL). Results: HMGB1 treatment of A549 cells resulted in the up-regulation of tumor necrosis factor (TNF)-α and macrophage inflammatory protein (MIP)-2 mRNAs and over expression of matrix metalloprotease (MMP)-7 protein in the supernatant. The miRNA miR-30c was also up-regulated in response to HMGB1 treatment. Cellular injury and apoptosis were observed following HMGB1 treatment, as demonstrated by the oyerexpression of cyclin A2 (CCNA2) and phosphatase and tensin homolog (PTEN) proteins and-b'y decreased levels of pro-caspase-7 protein. The TUNEL assay showed that A549 cells with HMGB1 stimulation underwent apoptosis. Conclusions: Up-regulation of miR-30c and apoptosis of A549 cells were observed following HMGB1 stimulation. Our model demonstrates the potential for utilization of HMGB1 and miR-30c in further studies of alveolar apoptosis in COPD.

Phase II study of a combination regimen of gefitinib and pemetrexed as first-line treatment in patients with advanced non-small cell lung cancer harboring a sensitive EGFR mutation.

PURPOSE: Patients with advanced non-small cell lung cancer (NSCLC) harboring a sensitive epidermal growth factor receptor (EGFR) mutation have been shown to exhibit a marked response to EGFR-tyrosine kinase inhibitor (TKI) treatment. Pemetrexed and gefitinib were reported to have a schedule-dependent cytotoxic synergism. We evaluated the efficacy and safety of a combination regimen of gefitinib and pemetrexed as first-line chemotherapy in EGFR-mutated NSCLC patients. PATIENTS AND METHODS: Systemic therapy-naïve patients with advanced non-squamous NSCLC harboring a sensitive EGFR mutation were included in this study. Pemetrexed was administered on day 1 at a dose of 500 mg/m(2), and gefitinib was sequentially administered on days 2-16. This treatment regimen was repeated every 3 weeks until disease progression. RESULTS: Twenty-six patients were enrolled in this study. The median number of treatment cycles was 16 (range, 1-35). The overall response rate (ORR) was 84.6% (95% confidence interval [CI], 70.7-98.5%), and the disease control rate (DCR) was 96.2% (95% CI, 88.9-100%). Grade 3/4 hematological toxicities included neutropenia (15.4%), leukopenia (7.7%), and anemia (3.8%). No grade 4 non-hematological toxicities were observed. The main grade 3 non-hematological toxicities were infection (11.5%), increased alanine aminotransferase (11.5%) and aspartate aminotransferase (7.7%) levels, fatigue (3.8%), diarrhea (3.8%), and pneumonitis (3.8%). We observed a median progression-free survival (PFS) of 18.0 months (95% CI, 15.0-21.0 months) and a median survival time (MST) of 32.0 months (95% CI, 28.5-35.5 months). There were no treatment-related deaths. CONCLUSIONS: The combination regimen used in this study showed a high ORR, long median PFS, and acceptable toxicity. A future randomized trial on pemetrexed plus gefitinib compared with gefitinib alone is warranted.

The Macroscopic Appearance of Computed Tomography-guided Needle Biopsy Specimens Correlates with Tumor Metastasis in Non-small Cell Lung Cancer.

BACKGROUND: Computed tomography (CT)-guided needle biopsy is a well-established and dependable procedure for the diagnosis of pulmonary lesions. Some tissue biopsy samples have loose cohesion and disintegrate into tiny pieces before formalin fixation. The purpose of this study was to assess the association between the fresh macroscopic appearance of samples obtained using CT-guided needle biopsy and the clinicopathological features of non-small cell lung cancer (NSCLC). METHODS: A total of 111 patients who underwent CT-guided lung needle biopsy at Osaka City University Hospital between May 2009 and May 2013 were enrolled. Macroscopic appearance was categorized as either loose or tight cohesion. Samples were evaluated using Azan staining to detect collagen fibers. The staining intensity was multiplied by the percentage of positive cells, and the specimen was categorized as having either low (<100) or high expression ( ≥100). Univariate and multivariate logistic regression models were used to evaluate significant covariates for tumor metastasis. RESULTS: In the cohort of 111 patients, the diagnostic rates in loose and tight cohesions were 82.6% and 87.5%, respectively (p=0.509). In 60 patients diagnosed with NSCLC, Azan staining of collagen fibers was positive in 93.5% of the samples with tight cohesion and 28.6% of the samples with loose cohesion (p<0.001). In the multivariate logistic regression models, distant metastasis was significantly associated with loose cohesion (p=0.026). CONCLUSIONS: These results suggest that the macroscopic appearance of CT-guided biopsy samples correlates with tumor metastasis in NSCLC.

Simultaneous assessment of hepatocyte growth factor and vascular endothelial growth factor in epithelial lining fluid from patients with COPD.

BACKGROUND: Hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) are involved in the pathogenesis of various lung diseases. This study was designed to determine the possible interactions of these growth factors in the development of COPD. METHODS: We measured the levels of HGF and VEGF in epithelial lining fluid obtained from central or peripheral airways using a bronchoscopic microsampling technique in 10 never smokers, 14 smokers without COPD, and 24 smokers with COPD. We also evaluated whether their levels were correlated with pulmonary function parameters and the grade of low attenuation area (LAA) observed in high-resolution CT scans. RESULTS: HGF and VEGF levels in the peripheral airways of smokers with COPD were significantly lower than those in never smokers and smokers without COPD. In smokers with COPD, HGF and VEGF levels of the peripheral airways inversely correlated with the degree of airway obstruction and diffusing capacity of the lung. The HGF and VEGF levels also correlated with the grade of LAA. Although the VEGF levels of smokers with and without COPD overlapped considerably, HGF levels were markedly higher in smokers without COPD. CONCLUSIONS: Upregulated HGF probably compensated for the reduced levels of VEGF and preserved the pulmonary function in smokers without COPD. By contrast, both HGF and VEGF levels were decreased in smokers with COPD, which likely led to the development of COPD. Thus, the level of HGF relative to that of VEGF may be a reliable indicator of the risk for COPD.

Potential role of pentosidine on susceptibility to small airway closure in elderly and smoking asthma.

BACKGROUND: Small airway closure in asthma is determined by a complex interaction of structural and functional characteristics including lung elastic recoil. Recently, we determined that loss of elastic recoil might be attributable to pentosidine level in the airways. This study was designed to investigate the influences of aging and smoking on small airway closure in asthma. METHODS: Sixty-one patients with asthma (20 non-smoking young adult, 23 non-smoking elderly, and 18 smoking young adult) and 36 control subjects (12 non-smoking young adult, 11 non-smoking elderly, and 13 smoking young adult) were included. We assessed airway responses during methacholine provocation and calculated the closing index. In addition, we measured pentosidine levels in induced sputum from all study subjects. RESULTS: Pentosidine levels in induced sputum were markedly higher in asthmatic patients than in controls. In control subjects, the intergroup differences in pentosidine level among 3 subgroups were significant. Similarly, pentosidine levels were significantly higher in non-smoking elderly and smoking young adult asthmatics than in non-smoking young adult asthmatics. There was no significant difference in pentosidine levels between non-smoking elderly and smoking young adult asthmatics. The closing index was also significantly higher in non-smoking elderly and smoking young adult asthmatics than in non-smoking young adult asthmatics. Moreover, pentosidine levels in non-smoking elderly and smoking young adult asthmatics were closely correlated with closing index. CONCLUSIONS: We determined the correlation of pentosidine level with susceptibility to small airway closure in elderly and smoking asthmatics. Our results might facilitate the understanding of elderly and smoking asthma.

Dose escalation and feasibility study of amrubicin combined with cisplatin in previously untreated patients with advanced non-small cell lung cancer.

OBJECTIVES: Cisplatin is a key drug used in the treatment of non-small cell lung cancer (NSCLC), and amrubicin is one of the new active agents for NSCLC. The objective of this study was to determine the recommended dose (RD) of amrubicin in combination with a fixed dose of cisplatin, and to assess the toxicity profile and feasibility of this regimen. METHODS: We conducted a dose escalation study of amrubicin and cisplatin in previously untreated patients with stage IIIB or IV NSCLC. Dose level 1 of amrubicin was 30 mg/m on days 1 to 3 and level 2 was 35 mg/m. Cisplatin was administered at a fixed dose of 80 mg/m on day 1. Chemotherapy was given in a 3-week cycle. RESULTS: Twenty patients were enrolled. Dose-limiting toxicities were neutropenia, febrile neutropenia, thrombocytopenia, and creatinine elevation. Level 1 (30 mg/m) was determined to be the RD, and 35 mg/m exceeded the RD. In 17 patients treated with the RD, the overall response rate was 41.2% (95% confidence interval, 17.7-64.7) and the median survival time was 16.4 months (95% confidence interval, 13.1-19.5). CONCLUSIONS: This amrubicin and cisplatin regimen may be feasible and promising against advanced NSCLC. The efficacy and safety of this regimen should be confirmed in a phase II study.

Validity of HMGB1 measurement in epithelial lining fluid in patients with COPD.

BACKGROUND: It has been known that high-mobility group box 1 (HMGB1) plays an important role in the pathogenesis of various inflammatory disorders in the lung. We attempted to determine the validity of measurement of HMGB1 levels in epithelial lining fluid (ELF) from patients with chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: We measured HMGB1 levels in ELF separately obtained from central or peripheral airways using a bronchoscopic microsampling technique in 14 non-smokers, 13 smokers without COPD and 30 smokers with COPD. We also evaluated whether those levels were correlated with the indexes of pulmonary function and grade of low-attenuation area (LAA) on high-resolution computed tomographic scans. RESULTS: HMGB1 levels in ELF from central airways did not significantly differ among the three groups. However, HMGB1 levels in peripheral airways were significantly higher in COPD patients than in non-smokers and smokers without COPD. Both the concentrations of interleukin-8 and human polymorphonuclear elastase in peripheral airways were also significantly higher in COPD patients. Moreover, those levels were significantly correlated with HMGB1 level. In addition, HMGB1 level in peripheral airways was closely correlated with the degree of airflow obstruction and grade of LAA in COPD patients. CONCLUSIONS: HMGB1 levels in peripheral airways were elevated in smokers without COPD, as compared with non-smokers, and those levels were further augmented in COPD patients. Those levels were associated with the severity of COPD. Therefore, HMGB1 in peripheral airways may be a potentially interesting target for new pharmacological treatments in COPD patients.

Measurement of soluble perforin, a marker of CD8+ T lymphocyte activation in epithelial lining fluid.

BACKGROUND: CD8(+) T lymphocytes in the peripheral airways have been suggested to be involved in the pathogenesis of COPD. However, the significance of CD8(+) T lymphocyte activation in COPD is not well understood. A biomarker of CD8(+) T lymphocyte activation in patients with COPD is required. METHODS: Thirty COPD patients and twenty-one healthy controls (eleven ex-smokers and ten who had never smoked or were light ex-smokers) were included in this study. We separately obtained epithelial lining fluid (ELF) from central and peripheral airways using a bronchoscopic microsampling technique. Levels of perforin in ELF were measured and we examined correlations between its values and patients characteristics including pulmonary function. RESULTS: Perforin levels in both the central and peripheral airways in COPD patients were significantly higher than those in the healthy control groups. In the healthy control groups, there was no significant difference in perforin levels between central and peripheral airways. However, in COPD patients, perforin levels in peripheral airways were significantly higher than those in central airways. Perforin levels in peripheral airways were significantly correlated with FEV(1) (percent predicted), FEV(1)/FVC, and DLco (percent predicted) in COPD patients. CONCLUSION: The microsampling technique is safe and useful for separately obtaining ELF from central and peripheral airways. Levels of perforin in ELF from peripheral airways were significantly increased and correlated with the degree of pulmonary dysfunction. Perforin might reflect inflammation involving CD8(+) T-lymphocytes. This novel biomarker might enable better understanding of the pathogenesis of COPD.

Lack of adiponectin promotes formation of cholesterol gallstones in mice.

Plasma adiponectin levels are reduced in obese people, and hypoadiponectinemia is recently reported to associate with cholesterol gallstone formation in human. The aim of this study was to examine the role of adiponectin in gallstone formation using adiponectin knockout mice. We analyzed male knockout and C57BL6J mice fed normal or lithogenic diet for 6 weeks. On lithogenic diet, the prevalence rate of gallstone was significantly greater in knockout mice than C57BL6J mice. The molar percentages of beta and omega-muricholic acid were significantly higher and hepatic sterol 12 alpha-hydroxylase expression (cyp8b1) was significantly lower in knockout mice than C57BL6J mice fed normal diet. The bile apolipoprotein A-I protein levels were decreased in knockout mice. Histological examination showed gallbladder wall thickening and accumulation of glycoprotein in the gallbladder of knockout mice. Gallbladder phospholipase A2-IVA expression was significantly higher in knockout mice than in C57BL6J mice fed lithogenic diet. Our results indicate that lack of adiponectin promotes gallstone formation in mice.

Increment and impairment of adiponectin in renal failure.

AIMS: Patients with chronic renal failure are at high risk of cardiovascular diseases. Previous studies in healthy population showed that hypoadiponectinemia was associated with high cardiovascular disease risk. However, plasma adiponectin (APN) levels are increased in renal dysfunction. Therefore, the clinical significance of plasma APN level in patients with moderate renal dysfunction is controversial. The aim of this study was to determine the change of plasma APN levels in a mouse model of renal failure and the loss of vasculo-protective function of APN in the presence of high cystatin C levels. METHODS AND RESULTS: Subtotal (5/6) nephrectomy was performed in APN-knockout (KO) mice and wild-type (WT) mice. The procedure in WT mice resulted in the significant increase of plasma APN and cystatin C levels. The clearance rate of APN was measured by injecting plasma from WT mice into KO mice. The clearance rate was significantly decreased in subtotal nephrectomized KO mice compared with sham-operated KO mice. Adiponectin protein and mRNA levels in adipose tissue were similar to subtotal nephrectomized and sham-operated mice. In cultured endothelial cells, at a high concentration corresponding to renal failure, cystatin C abolished the suppressive effects of APN on tumour necrosis factor alpha-induced expression of monocyte adhesion molecules. CONCLUSION: Plasma APN increases in chronic renal failure, at least in part due to low clearance rate. High concentrations of cystatin C abolish the vasculo-protective effect of APN.

[A case of Churg-Strauss syndrome following corticosteroid withdrawal].

A 56-year-old man with bilateral hearing impairment who had taken betamethasone combined with dexchlorpheniramine maleate for 7 years to treat chronic sinusitis developed a dry cough after discontinuing this medication and was diagnosed with asthma, and after which he sensed impaired bilateral hearing. Based on the presence of numerous eosinophilic leukocytes in otorrehea, we made a diagnosis of eosinophilic otitis media, and he was prescribed predonisolone to control the asthma, but discontinued it on his own. He then developed fever, maniphalanx stiffness, testicular pain, and facial hyperesthesia, eruptions, and the lower-limb numbness. The detection of a positive serum reaction for MPO-ANCA and evaluated of eosinophilic leukocyte levels yielded a definitive diagnosis of CSS, for which the man was treated with predonisolone and cyclophosphamide. His symptoms were relieved, even though the onset of neutropenia, necessitated the discontinuation of cyclophosphamade administration.

[Potential mechanisms of airway remodeling initiated by activated thrombin in asthma].

BACKGROUND: High expression of vascular endothelial growth factor (VEGF) induces subepithelial fibrosis associated with angiogenesis in asthma. Thrombin is recognized as a new candidate mediating airway remodeling. Therefore, this study was designed to determine the potential mechanisms of airway remodeling initiated by activated thrombin in asthma. METHODS: Levels of biochemical parameters in induced sputum were examined in 21 asthmatic patients and 11 normal controls. RESULTS: Thrombin activity in induced sputum was significantly higher in asthmatic patients than in normal controls (normal controls: median [range] 1.26 (0.93-2.42) U/mL; asthmatic patients: 3.67 (1.15-10.2) U/mL, p < 0.0001). VEGF level in induced sputum was positively correlated with thrombin activity in all study subjects. Levels of basic fibroblast growth factor (bFGF), which is a major profibrotic factor, were also significantly higher in asthmatic patients than in normal controls. Moreover, thrombin activity was significantly correlated with bFGF level in all study subjects. We also observed a significant correlation between bFGF and procollagen type III peptide level. CONCLUSION: Increase in VEGF level leads to up-regulation of thrombin activity in asthmatic airways, and this elevated thrombin activity induces elevation of bFGF level. It will become to be a new strategy of asthma therapy to attenuate thrombin activity for the regulation of airway remodeling.