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.

Siderophore production as a biomarker for Klebsiella pneumoniae strains that cause sepsis: A pilot study.

BACKGROUND/PURPOSE: Klebsiella pneumoniae bacteremia-induced sepsis is a clinically important condition with a high mortality rate and various known virulence factors. However, studies on the association of these virulence factors with the occurrence of K. pneumoniae bacteremia-induced sepsis are scarce. We aimed to investigate clinical variables and virulence factors in patients with K. pneumoniae bacteremia-induced sepsis. METHODS: We retrospectively reviewed the medical records of 76 patients with K. pneumoniae bacteremia between January 2012 and July 2017. Patients were divided into sepsis (n = 25) and non-sepsis (n = 51) groups. Patient background characteristics, antimicrobial regimens, and prognosis were evaluated. We assessed the distribution of virulence factors related to K. pneumoniae, such as mucoviscosity, capsular polysaccharide, and siderophores. Siderophore production levels were determined by measuring the orange halo zone on chrome azurol S agar plate assay. RESULTS: There were no intergroup differences in male-to-female ratio and age. Multivariable analysis revealed that siderophore production level (p < 0.01) was an independent predictor of K. pneumoniae bacteremia-induced sepsis. Furthermore, the optimal cut-off point of siderophore production to predict sepsis was 9.6 mm (sensitivity, 86%; specificity, 76%; AUC, 0.81). CONCLUSION: Siderophore production was an independent predictor of sepsis caused by K. pneumoniae bacteremia. The optimal cut-off point for siderophore production for sepsis occurrence prediction was 9.6 mm. To improve outcomes, patients with K. pneumoniae bacteremia-induced sepsis with high siderophore production levels should be managed prudently.

Clinical and virulence factors related to the 30-day mortality of Klebsiella pneumoniae bacteremia at a tertiary hospital: a case-control study.

Klebsiella pneumoniae bacteremia is a critical clinical presentation that is associated with high mortality. However, extremely few studies have investigated the virulence factors related to mortality of K. pneumoniae bacteremia in patients. The present study elucidated clinical and virulence factors associated with the 30-day mortality of K. pneumoniae bacteremia at a tertiary hospital. The medical records of 129 patients with K. pneumoniae bacteremia admitted to Osaka City University Hospital between January 2012 and December 2018 were retrospectively reviewed. Patient background characteristics, antimicrobial regimens, and prognosis were evaluated. Additionally, virulence factors were assessed using multiplex polymerase chain reaction to elucidate their association with K. pneumoniae. The 30-day mortality was 10.9% in patients with K. pneumoniae bacteremia. The male-to-female ratio, age, and underlying disease did not differ between the non-survivor and survivor groups. Multivariate analysis showed that sepsis (odds ratio (OR), 7.46; p = 0.005) and iutA (OR, 4.47; p = 0.046) were independent predictors associated with the 30-day mortality of K. pneumoniae bacteremia. Despite the relatively low 30-day mortality of patients with K. pneumoniae bacteremia, the treatment of those with sepsis and those infected with K. pneumoniae harboring iutA may require careful management for improving their outcomes.

Preserving Mafa expression in diabetic islet ß-cells improves glycemic control in vivo.

The murine Mafa transcription factor is a key regulator of postnatal islet ß-cell activity, affecting insulin transcription, insulin secretion, and ß-cell mass. Human MAFA expression is also markedly decreased in islet ß-cells of type 2 diabetes mellitus (T2DM) patients. Moreover, levels are profoundly reduced in db/db islet ß-cells, a mouse model of T2DM. To examine the significance of this key islet ß-cell-enriched protein to glycemic control under diabetic conditions, we generated transgenic mice that conditionally and specifically produced Mafa in db/db islet ß-cells. Sustained expression of Mafa resulted in significantly lower plasma glucose levels, higher plasma insulin, and augmented islet ß-cell mass. In addition, there was increased expression of insulin, Slc2a2, and newly identified Mafa-regulated genes involved in reducing ß-cell stress, like Gsta1 and Gckr. Importantly, the levels of human GSTA1 were also compromised in T2DM islets. Collectively, these results illustrate how consequential the reduction in Mafa activity is to islet ß-cell function under pathophysiological conditions.

Two unusual cases of successful treatment of hypermucoviscous Klebsiella pneumoniae invasive syndrome.

BACKGROUND: A few Japanese cases of hypermucoviscous Klebsiella pneumoniae (K. pneumoniae) invasive syndrome have recently been reported. Although extrahepatic complications from bacteremic dissemination have been observed, infected aneurysms are rare. Furthermore, the primary source of infection is generally a liver abscess, and is rarely the prostate. Therefore, we report two atypical cases of hypermucoviscous K. pneumoniae invasive syndrome. CASE PRESENTATION: The first case was an 81-year-old Japanese man with no significant medical history, who was referred to our hospital for vision loss in his right eye. Contrast-enhanced whole-body computed tomography revealed abscesses in the liver and the prostate, and an infected left internal iliac artery aneurysm. Contrast-enhanced head magnetic resonance imaging revealed brain abscesses. Cultures of the liver abscess specimen and aqueous humor revealed K. pneumoniae with the hypermucoviscosity phenotype, which carried the magA gene (mucoviscosity-associated gene A) and the rmpA gene (regulator of mucoid phenotype A). We performed enucleation of the right eyeball, percutaneous transhepatic drainage, coil embolization of the aneurysm, and administered a 6-week course of antibiotic treatment. The second case was a 69-year-old Japanese man with diabetes mellitus, who was referred to our hospital with fever, pollakiuria, and pain on urination. Contrast-enhanced whole-body computed tomography revealed lung and prostate abscesses, but no liver abscesses. Contrast-enhanced head magnetic resonance imaging revealed brain abscesses. The sputum, urine, prostate abscess specimen, and aqueous humor cultures revealed K. pneumoniae with the hypermucoviscosity phenotype, which carried magA and rmpA. We performed enucleation of the left eyeball, percutaneous drainage of the prostate abscess, and administered a 5-week course of antibiotic treatment. CONCLUSIONS: Hypermucoviscous K. pneumoniae can cause infected aneurysms, and the prostate can be the primary site of infection. We suggest that a diagnosis of hvKP invasive syndrome should be considered in all patients who present with K. pneumoniae infection and multiple organ abscesses.

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.

Short-term selective alleviation of glucotoxicity and lipotoxicity ameliorates the suppressed expression of key ß-cell factors under diabetic conditions.

Alleviation of hyperglycaemia and hyperlipidemia improves pancreatic ß-cell function in type 2 diabetes. However, the underlying molecular mechanisms are still not well clarified. In this study, we aimed to elucidate how the expression alterations of key ß-cell factors are altered by the short-term selective alleviation of glucotoxicity or lipotoxicity. We treated db/db mice for one week with empagliflozin and/or bezafibrate to alleviate glucotoxicity and/or liptotoxicity, respectively. The gene expression levels of Pdx1 and Mafa, and their potential targets, insulin 1, Slc2a2, and Glp1r, were higher in the islets of empagliflozin-treated mice, and levels of insulin 2 were higher in mice treated with both reagents, than in untreated mice. Moreover, compared to the pretreatment levels, Mafa and insulin 1 expression increased in empagliflozin-treated mice, and Slc2a2 increased in combination-treated mice. In addition, empagliflozin treatment enhanced ß-cell proliferation assessed by Ki-67 immunostaining. Our date clearly demonstrated that the one-week selective alleviation of glucotoxicity led to the better expression levels of the key ß-cell factors critical for ß-cell function over pretreatment levels, and that the alleviation of lipotoxicity along with glucotoxicity augmented the favorable effects under diabetic conditions.

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.

Selective evaluation of high density lipoprotein from mouse small intestine by an in situ perfusion technique.

The small intestine (SI) is the second-greatest source of HDL in mice. However, the selective evaluation of SI-derived HDL (SI-HDL) has been difficult because even the origin of HDL obtained in vivo from the intestinal lymph duct of anesthetized rodents is doubtful. To shed light on this question, we have developed a novel in situ perfusion technique using surgically isolated mouse SI, with which the possible filtration of plasma HDL into the SI lymph duct can be prevented. With the developed method, we studied the characteristics of and mechanism for the production and regulation of SI-HDL. Nascent HDL particles were detected in SI lymph perfusates in WT mice, but not in ABCA1 KO mice. SI-HDL had a high protein content and was smaller than plasma HDL. SI-HDL was rich in TG and apo AIV compared with HDL in liver perfusates. SI-HDL was increased by high-fat diets and reduced in apo E KO mice. In conclusion, with our in situ perfusion model that enables the selective evaluation of SI-HDL, we demonstrated that ABCA1 plays an important role in intestinal HDL production, and SI-HDL is small, dense, rich in apo AIV, and regulated by nutritional and genetic factors.

Uric acid secretion from adipose tissue and its increase in obesity.

Obesity is often accompanied by hyperuricemia. However, purine metabolism in various tissues, especially regarding uric acid production, has not been fully elucidated. Here we report, using mouse models, that adipose tissue could produce and secrete uric acid through xanthine oxidoreductase (XOR) and that the production was enhanced in obesity. Plasma uric acid was elevated in obese mice and attenuated by administration of the XOR inhibitor febuxostat. Adipose tissue was one of major organs that had abundant expression and activities of XOR, and adipose tissues in obese mice had higher XOR activities than those in control mice. 3T3-L1 and mouse primary mature adipocytes produced and secreted uric acid into culture medium. The secretion was inhibited by febuxostat in a dose-dependent manner or by gene knockdown of XOR. Surgical ischemia in adipose tissue increased local uric acid production and secretion via XOR, with a subsequent increase in circulating uric acid levels. Uric acid secretion from whole adipose tissue was increased in obese mice, and uric acid secretion from 3T3-L1 adipocytes was increased under hypoxia. Our results suggest that purine catabolism in adipose tissue could be enhanced in obesity.

Analysis of the contributing factors to airway hyperresponsiveness by a forced oscillation technique in patients with asthma.

BACKGROUND: Forced oscillation technique (FOT) is increasingly used to obtain much information on the state of the respiratory system. However, there are little data about FOT parameters on methacholine provocation test in adult asthma. This study was designed to determine the physiological implications of FOT parameters during methacholine provocation and analyze the major contributing factors to airway hyperresponsiveness (AHR) in asthma. METHODS: Spirometry and FOT were performed in 22 asthmatic patients and 21 normal control subjects before and after provocation with a maximal dose of methacholine. RESULTS: In asthmatic patients, the percent increase in resistance at 5 Hz (R5) and resistance at 20 Hz (R20) after the methacholine provocation was 70 [45-93] % and 16 [5-23] %. The percent change in R20 was not significantly correlated with the percent change in FVC or FEV1. Similarly, the percent change in R5 was not significantly correlated with the percent change in FEV1, but was significantly correlated with the percent change in FVC. Moreover, the percent change in R5 was significantly correlated with the closing index (r = 0.55, p = 0.01). In addition, AHR to methacholine was closely correlated with the percent change in R5 (r = -0.71, p = 0.001). CONCLUSIONS: Simultaneous measurement of FOT and bronchial challenge test provide meaningful information, and greater change in R5 may represent exaggerated response of small airways in asthmatic patients. This study will provide new insights into the physiological implications of each FOT parameter in asthmatic patients.

Predictors of mortality from extended-spectrum beta-lactamase-producing Enterobacteriaceae bacteremia.

ABSTRACTExtended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) bacteremia can have poor clinical outcomes. Thus, determining the predictors of mortality from ESBL-PE bacteremia is very important. The present systematic review and meta-analysis aimed to evaluate studies to determine predictors associated with ESBL-PE bacteremia mortality. We searched PubMed and Cochrane Library databases for all relevant publications from January 2000 to August 2022. The outcome measure was mortality rate. In this systematic review of 22 observational studies, 4607 patients with ESBL-PE bacteremia were evaluated, of whom 976 (21.2%) died. The meta-analysis showed that prior antimicrobial therapy (RR, 2.89; 95% CI, 1.22-6.85), neutropenia (RR, 5.58; 95% CI, 2.03-15.35), nosocomial infection (RR, 2.46; 95% CI, 1.22-4.95), rapidly fatal underlying disease (RR, 4.21; 95% CI, 2.19-8.08), respiratory tract infection (RR, 2.12; 95% CI, 1.33-3.36), Pitt bacteremia score (PBS) (per1) (RR, 1.35; 95% CI, 1.18-1.53), PBS ≥ 4 (RR, 4.02; 95% CI, 2.77-5.85), severe sepsis (RR, 11.74; 95% CI, 4.68-29.43), and severe sepsis or septic shock (RR, 4.19; 95% CI, 2.83-6.18) were found to be mortality predictors. Moreover, urinary tract infection (RR, 0.15; 95% CI, 0.04-0.57) and appropriate empirical therapy (RR, 0.39; 95% CI, 0.18-0.82) were found to be a protective factor against mortality. Patients with ESBL-PE bacteremia who have the aforementioned require prudent management for improved outcomes. This research will lead to better management and improvement of clinical outcomes of patients with bacteremia caused by ESBL-PE.

Mental health complaints among healthcare workers engaged in the care of COVID-19 patients: A prospective cohort study from Japan.

Background: Healthcare workers (HCWs) caring for patients with coronavirus disease-2019 (COVID-19) can experience physical and mental health burdens. It is imperative that hospitals reduce such burdens on frontline HCWs, protect them, and support their healthcare. This study aimed to investigate the association between occupation and the manifestation of physical or psychological symptoms among HCWs during the current COVID-19 pandemic. Methods: A twice-weekly survey using questionnaires targeting HCWs who care for COVID-19 patients was performed at Osaka Metropolitan University Hospital (tertiary hospital). The demographic characteristics of the participants, exposure level, and physical and psychological complaints were evaluated. Results: Seventy-one HCWs participated in this study, of whom 27 (38.0%) were doctors, 25 (35.2%) were nurses, and 19 (26.8%) were technicians. Among the HCWs, the proportions of those who experienced any physical or psychological symptoms were 28.2% and 31.0%, respectively. The frequency of depression and anxiety was obviously higher among the nurses than that among the doctors (both p < 0.01). Multivariate analysis revealed that being a nurse (odds ratio 4.90; p = 0.04) and having physical complaints (odds ratio 4.66; p = 0.02) might be independent predictors of the manifestation of psychological symptoms. Conclusion: Our results indicate that the follow-up of HCWs experiencing physical symptoms, especially nurses engaged in the care of COVID-19 patients, may require more careful management to improve the psychological outcomes. We believe that this study is the first step toward establishing a psychological health management strategy for HCWs caring for COVID-19 patients.

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.

Potential roles of pentosidine in age-related and disease-related impairment of pulmonary functions in patients with asthma.

BACKGROUND: Pentosidine is well established as an intermolecular cross-linking type of advanced glycation end products, and it accumulates with aging in various connective tissues. OBJECTIVE: To determine whether pentosidine contributes to age-related and disease-related impairment of pulmonary functions in patients with asthma. METHODS: We measured pentosidine levels in induced sputum from young to elderly patients with asthma and assessed the slope of the nitrogen (N(2)) alveolar plateau (delta N(2)), closing volume (CV), and closing capacity (CC) from a nitrogen washout curve in a single breath. RESULTS: Pentosidine levels in induced sputum were significantly higher in patients with asthma than in normal controls (patients with asthma: median, 20.1, interquartile range, 16.7-26.5 ng/mL; normal controls: median, 3.0, interquartile range, 0.7-7.5 ng/mL; P < .001). The levels were closely correlated with age in both normal controls and patients with asthma. However, the slope of age-related increase in pentosidine levels was markedly steeper in patients with asthma than in normal controls. CV/vital capacity, CC/total lung capacity, and delta N(2) increased with aging in both normal controls and patients with asthma. Moreover, in each range of age (21-40, 41-60, 61-80 years), CV/vital capacity, CC/total lung capacity, and delta N(2) were significantly higher in patients with asthma than in normal controls. In addition, pentosidine levels in patients with asthma were closely correlated with each of these variables. CONCLUSION: Our results demonstrated the association between sputum levels of pentosidine and age-related small airways function in both normal controls and patients with asthma. Moreover, the age-related increase in pentosidine levels was more pronounced in patients with asthma. These findings will herald new era in the pathophysiology of elderly asthma.

Combined online and offline basic life support workshop with infection prevention and control for COVID-19.

The coronavirus disease 2019 outbreak has made it difficult to hold face-to-face BLS training sessions at university. Even in this limited situation, the effective use of combined online video course and offline training can contribute to gaining participants' confidence in conducting BLS and improving mindset than before.

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.

Effect of alogliptin, pioglitazone and glargine on pancreatic ß-cells in diabetic db/db mice.

OBJECTIVE: Progressive ß-cell dysfunction and loss of ß-cell mass are fundamental pathogenic features of type 2 diabetes. To examine if anti-diabetic reagents, such as insulin, pioglitazone (pio), and alogliptin (alo), have protective effects on ß-cell mass and function in vivo, we treated obese diabetic db/db mice with these reagents. METHODS: Male db/db mice were treated with a chow including pio, alo, or both of them from 8 to 16 weeks of age. Insulin glargine (gla) was daily injected subcutaneously during the same period. RESULTS: At 16 weeks of age, untreated db/db mice revealed marked increase of HbA1c level, whereas those treated with pio, pio+alo, or insulin revealed the almost same HbA1c levels as non-diabetic db/m mice. Islet mass evaluated by direct counting in the whole pancreas and insulin content in isolated islets were preserved in pio, pio+alo and gla groups compared with untreated or alo groups, and there was no difference among pio, pio+alo and gla groups. To precisely evaluate islet ß-cell functions, islet perifusion analysis was performed. In pio, pio+alo and gla groups, biphasic insulin secretion was preserved compared with untreated or alo groups. In particular, pio+alo as well as gla therapy preserved almost normal insulin secretion, although pio therapy improved partially. To examine the mechanism how these reagents exerted beneficial effects on ß-cells, we evaluated expression levels of various factors which are potentially important for ß-cell functions by real-time RT-PCR and immunohistochemistry. The results showed that expression levels of MafA and GLP-1 receptor were markedly decreased in untreated and alo groups, but not in pio, pio+alo and gla groups. CONCLUSION: Combination therapy with pio and alo almost completely normalized ß-cell functions in vivo, which was comparable with gla treatment.