Association of Sources of Worry and Stress with Smoking in Japan: Findings from the Comprehensive Survey of Living Conditions 2010.

Objectives: The purpose of this study is to examine which sources of worry and stress are associated with smoking behavior and if these associations are varied by gender. Methods: The anonymous data of 28,588 men and 30,813 women aged 20-79 years old in Japan were analyzed. We defined the subjects who chose "smoking everyday" as "smokers." We also assessed 20 sources of worry and stress. Multivariable odds ratios (ORs) and 95% confidence intervals (CIs) of smoking for each source of worry and stress were calculated using logistic regression analysis. Results: We found significant association of financial stress with smoking behavior in both genders. The multivariable OR (95% CI) of smoking according to stress from financial stress was 1.22 (1.15-1.31) in men and 1.66 (1.53-1.80) in women. Moreover, the OR of smoking according to stress from human relationships and job affairs was significantly higher for women. Conclusion: We found that some sources of worry and stress were related to smoking behavior and these associations were found to be gender-specific.

Dual interleukin-17A/F deficiency protects against acute and chronic response to cigarette smoke exposure in mice.

IL-17A and IL-17F are both involved in the pathogenesis of neutrophilic inflammation observed in COPD and severe asthma. To explore this, mice deficient in both Il17a and Il17f and wild type (WT) mice were exposed to cigarette smoke or environmental air for 5 to 28 days and changes in inflammatory cells in bronchoalveolar lavage (BAL) fluid were determined. We also measured the mRNA expression of keratinocyte derived chemokine (Kc), macrophage inflammatory protein-2 (Mip2), granulocyte-macrophage colony stimulating factor (Gmcsf) and matrix metalloproteinase-9 (Mmp9 ) in lung tissue after 8 days, and lung morphometric changes after 24 weeks of exposure to cigarette smoke compared to air-exposed control animals. Macrophage counts in BAL fluid initially peaked at day 8 and again on day 28, while neutrophil counts peaked between day 8 and 12 in WT mice. Mice dual deficient with Il17a and 1l17f showed similar kinetics with macrophages and neutrophils, but cell numbers at day 8 and mRNA expression of Kc, Gmcsf and Mmp9 were significantly reduced. Furthermore, airspaces in WT mice became larger after cigarette smoke exposure for 24 weeks, whereas this was not seen dual Il17a and 1l17f deficient mice. Combined Il17a and Il17f deficiency resulted in significant attenuation of neutrophilic inflammatory response and protection against structural lung changes after long term cigarette smoke exposure compared with WT mice. Dual IL-17A/F signalling plays an important role in pro-inflammatory responses associated with histological changes induced by cigarette smoke exposure.

Association of diagnostic delay with medical cost for patients with Crohn's disease: A Japanese claims-based cohort study.

BACKGROUND AND AIM: Longer diagnostic delay (DD) in Crohn's disease (CD) is associated with complications and related surgeries. However, the impact of DD on medical cost after CD diagnosis remains uncertain. METHODS: This was a claims-based cohort study. Our analysis used data from 2005 to 2018 from the Japanese Claims Database. We enrolled a total of 528 newly diagnosed CD patients (76.9% male) aged 31.5 ± 13.6 years. High medical cost was defined as the highest quartile of the average monthly medical cost. DD was defined as the interval between the first visit to a gastroenterologist and diagnosis with CD. In the multivariable logistic regression analysis, patients were stratified by the use of anti-tumor necrosis factor alpha (anti-TNFα) agents to exclude their influence on the observed effects. This study was approved by the ethics review board of the Juntendo University Faculty of Medicine (No. 2019178). RESULTS: The multivariable-adjusted odds ratios and 95% confidence intervals of high medical cost were 1.41 (0.81-2.43) and 0.91 (0.57-1.46), respectively, for a DD of >12 months and 1 to ≤12 months compared to <1 month. In patients receiving anti-TNFα agents, the multivariable-adjusted odds ratios for high medical cost were 2.63 (1.34-5.16) and 1.35 (0.79-2.28) for a DD of >12 months and 1 to ≤12 months, respectively, compared to <1 month. In patients without anti-TNFα, multivariable logistic regression analyses were not presented because of a small number of patients categorized into the high medical cost group. CONCLUSION: A delayed diagnosis of CD may incur high medical cost in patients who develop aggressive disease that requires treatment with anti-TNFα agents.

Low BMI and weight loss aggravate COPD mortality in men, findings from a large prospective cohort: the JACC study.

To clarify how low BMI and weight loss were associated with risk of chronic obstructive pulmonary disease (COPD) mortality, in a large prospective cohort of the general population across Japan, the Japan Collaborative Cohort Study, conducted between 1988 and 2009. A total of 45,837 male residents were observed for a median period of 19.1 years. Self-administered questionnaires, collecting information on BMI, weight loss since the age of 20, lifestyles, history of diseases, as well as records of COPD mortality, were analysed at 2019. During follow-up, 268 participants died from COPD. The multivariate-adjusted hazard ratio (95% confidence interval) of COPD mortality associated with a 1-SD increment of body mass index (BMI) was 0.48 (0.41-0.57), while for weight change from age of 20 (+ 2.0 kg) it was 0.63 (0.59-0.68). These associations were persistently observed after stratifications with smoking status, excluding those having airway symptoms in the baseline survey, and excluding early COPD deaths within 5, 10 and 15 years. Our study suggests that BMI and weight change since the age of 20 could be markers for COPD prognosis, indicated by risk of COPD mortality.

Association of employment and company size with lung cancer screening participation among Japanese based on the socioeconomic conditions using the Comprehensive Survey of Living Conditions.

BACKGROUND: The proportion of non-regularly employed persons has increased in Japan, but few studies have examined the relationship between employment status and lung cancer screening (LCS) participation. METHODS: Authors analyzed data from the 2010 Comprehensive Survey of Living Conditions in Japan. The anonymous responses of 28,951 people aged 40-69 years old were analyzed. Authors defined nine employment status categories: unemployed, regularly employed in a large-, middle-, and small-scale company, non-regularly employed in a large-, middle-, and small-scale company, self-employed, and other. LCS participation in the past year was surveyed through a self-reported questionnaire. Sex-specific prevalence ratios (PRs) and 95% confidence intervals (CIs) for LCS participation for all employment status categories, using the regularly employed in a middle-scale company category as the reference, were calculated using multivariable Poisson regression analysis, after adjusting for potentially confounding factors. RESULTS: Multivariable-adjusted PRs (95% CI) for LCS participation for the regularly employed in a large-scale company were 1.33 (1.25-1.41) in men and 1.53 (1.38-1.71) in women. Multivariable-adjusted PRs (95% CI) for LCS participation for the non-regularly employed in a middle- and small-scale company compared with the regularly employed in a middle-scale company were 0.81 (0.72-0.92) and 0.62 (0.50-0.76) in men, and 0.89 (0.80-0.99) and 0.80 (0.71-0.91) in women, respectively. CONCLUSION: Regularly employed in a large-scale company had significantly higher LCS participation, and non-regularly employed in a middle- or small-scale company showed significantly lower LCS participation than those who were regularly employed in a middle-scale company.

Pseudomonas aeruginosa-derived flagellin stimulates IL-6 and IL-8 production in human bronchial epithelial cells: A potential mechanism for progression and exacerbation of COPD.

Background and purpose of the study:Pseudomonas aeruginosa commonly colonizes the airway of patients with chronic obstructive pulmonary disease (COPD) and exacerbates their symptoms. P. aeruginosa carries flagellin that stimulates toll-like receptor (TLR)-5; however, the role of flagellin in the pathogenesis of COPD remains unclear. The aim of the study was to evaluate the mechanisms of the flagellin-induced innate immune response in bronchial epithelial cells, and to assess the effects of anti-inflammatory agents for treatment. Materials and methods: We stimulated BEAS-2B cells with P. aeruginosa-derived flagellin, and assessed mRNA expression and protein secretion of interleukin (IL)-6 and IL-8. We also used mitogen-activated protein kinases (MAPK) inhibitors to assess the signaling pathways involved in flagellin stimulation, and investigated the effect of clinically available anti-inflammatory agents against flagellin-induced inflammation. Results: Flagellin promoted protein and mRNA expression of IL-6 and IL-8 in BEAS-2B cells and induced phosphorylation of p38, ERK, and JNK; p38 phosphorylation-induced IL-6 production, while IL-8 production resulted from p38 and ERK phosphorylation. Fluticasone propionate (FP) and dexamethasone (DEX) suppressed IL-6 and IL-8 production in BEAS-2B cells, but clarithromycin (CAM) failed to do so. Conclusions:P. aeruginosa-derived flagellin-induced IL-6 and IL-8 production in bronchial epithelial cells, which partially explains the mechanisms of progression and exacerbation of COPD. Corticosteroids are the most effective treatment for the suppression of flagellin-induced IL-6 and IL-8 production in the bronchial epithelial cells.

Recurrent sick leave and resignation rates among female cancer survivors after return to work: the Japan sickness absence and return to work (J-SAR) study.

BACKGROUND: To date, there have not been any workforce-based Japanese cohort studies investigating work sustainability after return to work (RTW). The objective of this study was to investigate the post-RTW cumulative recurrent sick leave rate and cumulative resignation rate among female cancer survivors. METHODS: Among Japanese employees who were registered in the Japan sickness absence and return to work (J-SAR) study, the subjects were those female employees who returned to work after sick leave due to newly clinically diagnosed cancer (C01-C99; ICD-10), based on a physician's certificate, between 2000 and 2011. The last day of the follow-up period was December 31, 2012. The recurrent sickness leave rate and resignation rate were calculated using competing risk survival analysis. RESULTS: Of 223 cancer survivors, 61 took further physician-certified sick leave after their RTW. The median duration of the post-RTW work period among all cancer survivors was 10.6 years. The work continuance rates of the female cancer survivors were 83.2 and 60.4% at 1 and 5 years after they returned to work, respectively. There was a steep reduction in the work continuance rate during the first post-RTW year. There were considerable differences in the work continuance rate according to the primary cancer site. Cumulative recurrent sick leave rates of 11.8 and 28.9% were seen at 1 and 5 years after the subjects returned to work. The cumulative resignation rate was 5.0 and 10.7% at 1 and 5 years after the subjects returned to work. Most recurrent sick leave occurred in the first year after the subjects returned to work, followed by the second year. CONCLUSIONS: Sixty percent of female cancer survivors were still working at 5 years after returning to work, although the work continuance rates for different types of cancer varied significantly.

Association between unemployment and insomnia-related symptoms based on the Comprehensive Survey of Living Conditions: a large cross-sectional Japanese population survey.

This study examined whether employment category was associated with insomnia-related symptoms (IRS). We analyzed the 2010 Comprehensive Survey of Living Conditions in Japan. The anonymous data of 43,865 people ranging from 20-59 yr of age were analyzed. We defined six employment categories: regularly employed, non-regularly employed, self-employed, others, unemployed and not in the labor force. Sex-specific odds ratios (ORs) and 95% confidence intervals (CIs) of IRS were calculated using multivariable logistic regression analysis, adjusted for confounding factors. We further conducted stratified analyses by mental illness, smoking status, and age. For men, the multivariable ORs (95% CI) of IRS for the unemployed and those who were not in the labor force were 2.5 (1.8-3.4) and 2.1 (1.2-3.7). For women, the multivariable ORs (95% CI) for the unemployed was 1.9 (1.5-2.5). After being stratified by mental illness, we found that the associations were not significant in persons with mental illness, and were more evident in persons without mental illness. Smoking and age did not modify the associations. In conclusion, we found a significantly higher OR of IRS for the unemployed, and men who were not in the labor force. These associations were particularly more evident for individuals without mental illness.

[Sleep-disordered breathing in occupational places: from screening to Health and Productivity Management].

BACKGROUND: Sleep-disordered breathing (SDB), represented by sleep apnea, is highly prevalent in the general population and is associated with alcohol intake and obesity. Since SDB is further associated with hypertension, diabetes, and future cardiovascular diseases, as well as accidents and injuries in workplaces, there is a need for complete SDB assessment in workers, including screening and the application of diagnostic and therapeutic approaches. RESULTS: Currently, it appears that SDB assessment is not sufficiently conducted, even among commercial motor vehicle (CMV) drivers, despite CMV drivers with SDB being at a high risk of serious traffic accidents. Based on a discussion conducted in The Study Group for Sleep Disordered Breathing in Work Places, we summarized the current situation in Japan and tried to elucidate the bottleneck of these approaches. Then, the situation in Japan was compared with that in South Korea; Professor Chol Shin substantiated that the situation in South Korea was similar to that in Japan. However, recently published data on CMV drivers in the United States showed that appropriate treatment of SDB reduced the risk of traffic accidents among CMV drivers. This will encourage the implementation of the required processes, from screening to maintenance of treatment. CONCLUSION: We propose a new approach based on "harmonizing work with treatment and prevention" and "Health and Productivity Management (HPM)" as a solution for implementing SDB programs.

The association of coffee consumption and oxygen desaturation index during sleep among Japanese male workers.

BACKGROUND AND OBJECTIVE: Coffee is a major caffeine-containing food source that can be used for treatment of apnea in prematurity. However, few studies have examined the association between coffee consumption and sleep-disordered breathing (SDB). We investigated whether coffee consumption is associated with the oxygen desaturation index (ODI) as a marker of SDB among middle-aged Japanese male workers. METHODS: The subjects were 1126 male local government workers aged 22-59 who participated in SDB screening in 2011-2012. Daily coffee consumption was assessed by a self-administered questionnaire. We measured 3% oxygen desaturation (3%ODI) during a night's sleep using a pulse oximeter. A general linear model was used to calculate the multivariate-adjusted means of 3%ODI per quartile of coffee consumption. We further analyzed the data after stratifying by overweight and current smoking status. RESULTS: A inverse association between coffee consumption and 3%ODI was found. The multivariate-adjusted mean of 3%ODI for the lowest and highest coffee consumption groups were 11.9 times/h and 10.6 times/h (p for trend = 0.06), respectively; 14.6 and 11.5 times/h (p for trend = 0.01) in overweight participants; and 12.7 and 11.0 times/h (p for trend = 0.06) in non-smokers. No associations were found in non-overweight and smoking workers. CONCLUSIONS: Our results suggest that higher coffee consumption was associated with lower 3% ODI as a marker of SDB in overweight and non-smoking workers.

Changes in bone metabolism after gastric cancer surgery in male patients: a prospective observational study.

BACKGROUND: Several retrospective studies have shown that bone disorders occur after gastric cancer surgery. This study was designed to prospectively evaluate the changes in bone metabolism after gastrectomy for gastric cancer. METHODS: We prospectively enrolled 39 men with early gastric cancer who underwent gastrectomy. We excluded women to avoid the effects of menopause. We employed dual energy X-ray absorptiometry (DEXA) to measure bone mineral density (BMD) of the lumbar spine. DEXA was performed before and 1 and 2 years after surgery. The serum levels of alkaline phosphatase (ALP), 1,25-dihydroxy vitamin D [1,25(OH)2VD], 25-hydroxy vitamin D [25(OH)VD], and estradiol were measured before surgery and every 3 months until 2 years after surgery. RESULTS: DEXA revealed that BMD significantly decreased by 0.036 ± 0.033 g/cm2 12 months after gastrectomy (P < 0.001) and by 0.046 ± 0.040 g/cm2 24 months after gastrectomy (P < 0.001). The serum ALP level significantly increased by 38.31 ± 103.8 IU/L 24 months after surgery (P = 0.013). The serum 25(OH)VD level significantly decreased by 4.88 ± 6.42 ng/ml 24 months after surgery (P < 0.001), whereas the serum 1,25(OH)2VD levels were consistently in the normal range. The serum estradiol level significantly increased by 2.94 ± 7.49 pg/ml 12 months after gastrectomy (P = 0.035). A lower preoperative body mass index (BMI) significantly correlated with the reduction in BMD 12 months after surgery; the correlation coefficient was 0.37 (P = 0.025). CONCLUSIONS: This study showed that a significant decrease in BMD was observed for up to 24 months after gastrectomy, not only 12 months.

Toward the harmonization of work with treatment and prevention for patients with chronic respiratory failure.

Home oxygen therapy (HOT), also known as long-term oxygen therapy, is prescribed to patients with chronic respiratory failure (CRF) due to advanced respiratory diseases, as it has been shown to improve the prognosis of patients with chronic obstructive pulmonary disease (COPD). However, the therapeutic impact of HOT does not fully reflect the "socialization" of patients, which is one of the final goals of "comprehensive pulmonary rehabilitation", proposed by the Japanese Respiratory Society. Since working is one form of socialization, we evaluated a 55-yr-old worker prescribed with HOT for the management of advanced COPD to elucidate and assess the social barriers experienced by HOT users. This case demonstrates a variety of factors affecting patients, respiratory physicians, occupational physicians, and management teams, which prevents patients from working. By elucidating these factors and seeking solutions, the promotion of the "harmonization of work with treatment and prevention" will both improve working environments and encourage CRF patients to continue working, leading to better socialization. Thus, the "harmonization of working with treatment and prevention" for CRF patients is a core goal for the promotion of both "health and productivity management" and "comprehensive pulmonary rehabilitation."

Bronchial epithelial cells produce CXCL1 in response to LPS and TNFα: A potential role in the pathogenesis of COPD.

RATIONALE: Neutrophilic airway inflammation plays a central role in chronic obstructive pulmonary disease (COPD). CXC chemokine ligand (CXCL)1 is a neutrophil chemokine involved in the pathogenesis of COPD. However, its clinical significance in COPD patients is poorly understood. AIM OF THE STUDY: To assess the production of CXCL1 by bronchial epithelial cells in response to lipopolysaccharide (LPS) and tumor necrosis factor (TNF)α. MATERIALS AND METHODS: We measured sputum CXCL1 and CXCL8 levels in patients with COPD, asthma, and asthma-COPD overlap (ACO), and compared them to those of patients with interstitial pneumonia (IP). Using primary human bronchial epithelial cells and BEAS-2B cells, CXCL1 protein release and mRNA expression were measured after LPS or TNFα stimulation. We evaluated signal transduction mechanisms for CXCL1 production using nuclear factor-κ B (NF-kB) and mitogen-activated protein kinase (MAPK) inhibitors, and examined the effects of anti-inflammatory agents on CXCL1 production in BEAS-2B cells. RESULTS: Sputum CXCL1 levels in COPD and ACO patients were higher than in IP patients, whereas sputum CXCL8 levels were not. Sputum CXCL1 levels were not affected by inhaled corticosteroid usage, whereas sputum CXCL8 levels tended to be affected. LPS and TNFα stimulated CXCL1 production and mRNA expression in bronchial epithelial cells. NF-kB and MAPK p38 were involved in LPS-induced CXCL1 production. Therapeutic anti-inflammatory agents minimally attenuated CXCL1 production and considerably inhibited CXCL8 production in BEAS-2B cells. CONCLUSIONS: Sputum CXCL1 levels is a potentially better diagnostic marker for COPD than sputum CXCL8 levels, which is explained by that CXCL1 production in bronchial epithelial cells is less affected by therapeutic anti-inflammatory agents than CXCL8 production.

Serum Reactive Oxygen Metabolite Levels Predict Severe Exacerbations of Asthma.

BACKGROUND AND PURPOSE: Bronchial asthma (BA) is a chronic airway disease characterized by airway hyperresponsiveness and remodeling, which are intimately linked to chronic airway inflammation. Reactive oxygen species (ROS) such as hydrogen peroxide are generated by inflammatory cells that are involved in the pathogenesis of BA. However, the role of ROS in the management of BA patients is not yet clear. We attempted to determine the role of ROS as a biomarker in the clinical setting of BA. SUBJECTS AND METHODS: We enrolled patients with BA from 2013 through 2015 and studied the degrees of asthma control, anti-asthma treatment, pulmonary function test results, fractional exhaled nitric oxide (FeNO), serum reactive oxygen metabolite (ROM) levels, and serum levels of interleukin (IL)-6 and IL-8. RESULTS: We recruited 110 patients with BA. Serum ROM levels correlated with white blood cell (WBC) count (rs = 0.273, p = 0.004), neutrophil count (rs = 0.235, p = 0.014), CRP (rs = 0.403, p < 0.001), and IL-6 (rs = 0.339, p < 0.001). Serum ROM levels and IL-8 and CRP levels negatively correlated with %FEV1 (rs = -0.240, p = 0.012, rs = -0.362, p < 0.001, rs = -0.197, p = 0.039, respectively). Serum ROM levels were significantly higher in patients who experienced severe exacerbation within 3 months than in patients who did not (339 [302-381] vs. 376 [352-414] CARR U, p < 0.025). Receiver-operating characteristics analysis showed that ROM levels correlated significantly with the occurrence of severe exacerbation (area under the curve: 0.699, 95% CI: 0.597-0.801, p = 0.025). CONCLUSIONS: Serum levels of ROM were significantly associated with the degrees of airway obstruction, WBC counts, neutrophil counts, IL-6, and severe exacerbations. This biomarker may be useful in predicting severe exacerbations of BA.

IL-17A synergistically stimulates TNF-α-induced IL-8 production in human airway epithelial cells: A potential role in amplifying airway inflammation.

BACKGROUND: Recent reports have suggested an involvement of neutrophilic inflammation driven by interleukin (IL)-17 from Th17 cells, especially in severe, refractory asthma. It remains unknown about the possible interactions of this cytokine and other proinflammatory cytokines to direct neutrophilic airway inflammation. MATERIALS AND METHODS: We evaluated the effects of IL-17A, IL-17E, and IL-17F in combination with other stimuli such as tumor necrosis factor (TNF) -α on the production and expression of IL-8 in human bronchial epithelial cells. We also studied their effects on other cytokine production. The possible role of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways was evaluated by specific inhibitors. We examined the effects of anti-asthma drugs, such as steroids or salmeterol. RESULTS: IL-17A alone induced only a minimal effect on IL-8 expression. IL-17A, but not IL-17E or IL-17F, in combination with TNF-α showed a synergistic effect on IL-8 expression. Similar findings were found when combination with IL-1ß and IL-17A were used, but such was not the case with lipopolysaccharide (LPS). In addition, we further found such synergy on GM-CSF production. The synergy with TNF-α and IL-17A was significantly inhibited by MAPKs inhibitors. Corticosteroids such as fluticasone propionate and dexamethasone, but not salmeterol, partially suppressed the IL-17A and TNF-α-induced IL-8 production. CONCLUSIONS: IL-17A in the combination with TNF-α or IL-1ß showed a synergistic augmenting effect on IL-8 and GM-CSF production in human airway epithelial cells.

Interleukin-10 modulates pulmonary neutrophilic inflammation induced by cigarette smoke exposure.

AIM OF THE STUDY: Interleukin (IL)-10 is an anti-inflammatory cytokine, but its role in cigarette smoke (CS)-induced inflammation and chronic obstructive pulmonary disease (COPD) has not been fully elucidated. The purpose of this study was to investigate the effect of IL-10 deficiency on CS-induced pulmonary inflammation in mice in vivo and in vitro. MATERIALS AND METHODS: IL-10-deficient and wild-type control mice with a C57BL6/J genetic background were exposed to CS, and inflammatory cells in bronchoalveolar lavage fluid (BALF) and mRNA of cytokines in lung were evaluated with enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR). RESULTS: During 12 days of daily CS exposure to wild-type mice, neutrophil counts in BAL fluid and tumor necrosis factor (TNF)-α mRNA expression were increased, peaked at day 8, and then declined on day 12 when the level of IL-10 reached its peak. In IL-10-deficient mice, neutrophil recruitment and TNF-α mRNA levels induced by CS exposure were significantly greater than those in wild-type mice. Keratinocyte-derived chemokine (KC; murine ortholog of human CXCL8) and granulocyte macrophage colony-stimulating factor (GM-CSF) mRNA levels or matrix metalloproteinase(MMP)-9 protein levels were not correlated with neutrophil count. CONCLUSIONS: IL-10 had a modulatory effect on CS-induced pulmonary neutrophilic inflammation and TNF-α expression in mice in vivo and therefore appears to be an important endogenous suppressor of airway neutrophilic inflammation.

Clarithromycin ameliorates pulmonary inflammation induced by short term cigarette smoke exposure in mice.

BACKGROUND: Cigarette smoking is considered to be one of major causes of acute worsening of asthma as well as chronic obstructive pulmonary disease (COPD). Macrolide antibiotics have been reported to reduce the risk of exacerbations of COPD, and possibly neutrophilic asthma. However, the effect of clarithromycin (CAM) on pulmonary inflammation caused by short term exposure to cigarette smoke still remains to be investigated. METHODS: C57BL/6J female mice were daily exposed to tobacco smoke using a tobacco smoke exposure system, or clean air for 8 days, while simultaneously treated with either oral CAM or vehicles. Twenty four hours after the last exposure, mice were anaesthetized and sacrificed, and bronchoalveolar lavage (BAL) fluids were collected. Cellular responses in BAL fluids were evaluated. Levels of cytokine mRNA in the lung tissues were measured by quantitative RT-PCR. Paraffin-embedded lung tissues were evaluated to quantitate degree of neutrophil infiltration. RESULTS: The numbers of total cells, macrophages and neutrophils in the BAL fluid of smoke-exposed mice were significantly increased as compared to clean air group. These changes were significantly ameliorated in CAM-treated mice. The lung morphological analysis confirmed decrease of neutrophils by CAM treatment. Studies by quantitative PCR demonstrated CAM treatment significantly reduced lung expression levels of IL-17A, keratinocyte-derived chemokine (KC), granulocyte-macrophage colony stimulating factor (GM-CSF) and MMP-9 induced by cigarette smoke. CONCLUSION: We demonstrate that CAM administration resolves enhanced pulmonary inflammation induced by short term cigarette smoke exposure in mice.

Systematic review and meta-analysis of histopathological predictive factors for lymph node metastasis in T1 colorectal cancer.

BACKGROUND: In this study we examined whether histopathological findings, specifically lymphatic vessel invasion identified by an anti-human podoplanin antibody, and several other factors are associated with lymph node metastasis in T1 colorectal cancer. METHODS: We searched PubMed and Cochrane Library, and also handsearched relevant journals, for reports written in English and published between 1998 and 2012, utilizing combination headings, such as 'colorectal cancer,' 'lymph node metastasis,' and 'risk factors.' For the report to be included in our study, the following criteria had to be met: (1) data on the frequency of lymph node metastasis in T1 colorectal cancer in relation to histopathological factors were reported; (2) patients had undergone bowel resection and had histologically diagnosed T1 colorectal cancer; (3) lymphatic vessel invasion was identified by immunohistochemistry with an anti-human podoplanin antibody rather than by hematoxylin and eosin staining; (4) univariate and multivariate analyses were conducted. Studies investigating molecular markers were excluded. The independent predictive factors were confirmed in at least one study included in the meta-analysis in the present systematic review. Microsoft Excel 2013 for Windows was used for the statistical analysis. RESULTS: Initially, 369 publications were identified in the database searches and handsearches, of which five ultimately met all of the inclusion criteria and selected for this systematic review. The meta-analysis revealed that only two factors were significantly associated with T1 colorectal cancer lymph node metastasis: (1) lymphatic vessel invasion identified by an anti-human podoplanin antibody [Mantel-Haenszel odds ratio (OR) 5.19; (95% confidence interval (CI) 3.31-8.15; P = 0.01]; (2) tumor budding (OR 7.45; 95 % CI 4.27-13.02; P = 0.0077). CONCLUSION: Our meta-analysis revealed that lymphatic vessel invasion identified by an anti-human podoplanin antibody and tumor budding were significantly associated with T1 colorectal cancer lymph node metastasis.

Soluble ST2 as a prognostic marker in community-acquired pneumonia.

OBJECTIVES: Community-acquired pneumonia (CAP) is associated with high mortality when initial treatment fails. Early identification of these patients allows physicians to modify treatments earlier, increasing survival. METHODS: Ninety-one hospitalized patients with CAP were studied. Serum soluble ST2 levels were measured at diagnosis and at 3, 7, and 14 days (days 0, 3, 7, and 14) after the initiation of antimicrobial treatment. The predictive value of all-cause in-hospital mortality and the additive effect of soluble ST2 on the pneumonia severity index (PSI) were evaluated. RESULTS: In univariate analysis, high serum levels of soluble ST2 at days 0, 3, 7, and 14 were predictive of death (hazard ratios: 3.1, 10.0, 12.0, and 22.6, respectively). In multivariate analysis, a combination of soluble ST2 at day 3 (above 2700 pg/ml) and PSI were predictive of death with higher accuracy than PSI alone (net reclassification improvement, 0.44; integrated discrimination improvement, 0.17; P = 0.001 for both). Specifically, simultaneous presence of high soluble ST2 (day 3) and a PSI of 5 was suggestive of higher mortality risk than a PSI of 5 alone (mortality 78% vs. 39%, respectively). CONCLUSIONS: Soluble ST2 is prognostic indicator of CAP and can add to the predictive value of the PSI.