Abstract Background Despite recent studies that suggested statins' beneficial effects on chronic obstructive pulmonary disease (COPD) outcomes, the impact, if any, of statins on COPD exacerbations ...remains unclear. This study aimed to examine the association between statin use and risk of hospitalized COPD exacerbation, and to assess whether the association varied by statin initiation, dose, or duration of use. Methods A retrospective nested case-control study among patients with COPD was conducted analyzing a nationwide health insurance claims database in Taiwan. Cases were subjects hospitalized for COPD exacerbations; each case was matched to 4 randomly selected controls on age, sex, cohort entry, and number of COPD-related outpatient visits by an incident-density sampling approach. Conditional logistic regressions were employed to quantify the COPD exacerbation risk associated with statin use. Results The study cohort comprised 14,316 COPD patients, from which 1584 cases with COPD exacerbations and 5950 matched controls were identified. Any use of statins was associated with a 30% decreased risk of COPD exacerbation (95% confidence interval CI, 0.56-0.88), and current use of statins was related to a greater reduced risk (adjusted odds ratio OR 0.60; 95% CI, 0.44-0.81). A dose-dependent reduced risk of COPD exacerbation by statins was observed (medium average daily dose: adjusted OR 0.60; 95% CI, 0.41-0.89; high daily dose: adjusted OR 0.33; 95% CI, 0.14-0.73). The reduced risk remained significant for either short or long duration of statin use. Conclusions Statin use was associated with a reduced risk of COPD exacerbation, with a further risk reduction for statins prescribed more recently or at high doses.
Background Total IgE is a therapeutic target in patients with allergic diseases. DNA methylation in white blood cells (WBCs) was associated with total IgE levels in an epigenome-wide association ...study of white subjects. Whether DNA methylation of eosinophils explains these findings is insufficiently understood. Methods We tested for association between genome-wide DNA methylation in WBCs and total IgE levels in 2 studies of Hispanic children: the Puerto Rico Genetics of Asthma and Lifestyle Study (PR-GOAL; n = 306) and the Genes-environments and Admixture in Latino Americans (GALA II) study (n = 573). Whole-genome methylation of DNA from WBCs was measured by using the Illumina Infinium HumanMethylation450 BeadChip. Total IgE levels were measured by using the UniCAP 100 system. In PR-GOAL WBC types (ie, neutrophils, eosinophils, basophils, lymphocytes, and monocytes) in peripheral blood were measured by using Coulter Counter techniques. In the GALA II study WBC types were imputed. Multivariable linear regression was used for the analysis of DNA methylation and total IgE levels, which was first conducted separately for each cohort, and then results from the 2 cohorts were combined in a meta-analysis. Results CpG sites in multiple genes, including novel findings and results previously reported in white subjects, were significantly associated with total IgE levels. However, adjustment for WBC types resulted in markedly fewer significant sites. Top findings from this adjusted meta-analysis were in the genes ZFPM1 ( P = 1.5 × 10−12 ), ACOT7 ( P = 2.5 × 10−11 ), and MND1 ( P = 1.4 × 10−9 ). Conclusions In an epigenome-wide association study adjusted for WBC types (including eosinophils), methylation changes in genes enriched in pathways relevant to asthma and immune responses were associated with total IgE levels among Hispanic children.
Objectives This study tested whether interleukin (IL)-17A is involved in the pathogenesis of mouse myocardial ischemia/reperfusion (I/R) injury and investigated the mechanisms. Background ...Inflammatory processes play a major role in myocardial I/R injury. We recently identified IL-17A as an important cytokine in inflammatory cardiovascular diseases such as atherosclerosis and viral myocarditis. However, its role in myocardial I/R injury remains unknown. Methods The involvement of IL-17A was assessed in functional assays in mouse myocardial I/R injury by neutralization/repletion or genetic deficiency of IL-17A, and its mechanism on cardiomyocyte apoptosis and neutrophil infiltration were further studied in vivo and in vitro. Results Interleukin-17A was elevated after murine left coronary artery ligation and reperfusion. Intracellular cytokine staining revealed that γδT lymphocytes but not CD4+ helper T cells were a major source of IL-17A. Anti–IL-17A monoclonal antibody treatment or IL-17A knockout markedly ameliorated I/R injury, as demonstrated by reduced infarct size, reduced cardiac troponin T levels, and improved cardiac function. This improvement was associated with a reduction in cardiomyocyte apoptosis and neutrophil infiltration. In contrast, repletion of exogenous IL-17A induced the opposite effect. In vitro study showed that IL-17A mediated cardiomyocyte apoptosis through regulating the Bax/Bcl-2 ratio, induced CXC chemokine-mediated neutrophil migration and promoted neutrophil-endothelial cell adherence through induction of endothelial cell E-selectin and inter-cellular adhesion molecule-1 expression. Conclusions IL-17A mainly produced by γδT cells plays a pathogenic role in myocardial I/R injury by inducing cardiomyocyte apoptosis and neutrophil infiltration.
The objective was to determine the effects of prebiotics and synbiotics on adults with functional constipation (FC). Medline, Embase and the Cochrane Library were searched for literature published up ...to February 2015. We selected randomized controlled trials (RCTs) that reported administration of prebiotics or synbiotics to adults with FC. The end points included stool frequency, stool consistency and other symptoms related to constipation. Mean differences (MD) or standard mean differences (SMD) were used for continuous outcomes and risk ratios for discontinuous outcomes using a random-effects model. The Cochrane Risk of Bias Tool was used to determine the quality of the trials. Funnel plots and Egger's test were used to analyze for publication bias. We included 5 RCTs involving 199 patients who were administered prebiotics and 8 RCTs involving 825 patients who were administered synbiotics. Prebiotics increased weekly stool frequency (MD: 1.01bowel movements/week, 95% CI: 0.04-1.99) and improved stool consistency (SMD: -0.59, 95% CI: -1.16 to -0.02). Subgroup analysis showed specific effects for galacto-oligosaccharides on stool frequency, consistency, ease of defecation and abdominal pain. Synbiotics significantly improved stool frequency (MD: 1.15bowel movements/week, 95% CI: 0.58-1.71), consistency (SMD: 0.63, 95% CI: 0.33-0.92) and reduced whole-gut transit time (MD: 13.52, 95% CI: -26.56 to -0.49) in patients with FC. Subgroup analysis showed specific effects for fructo-oligosaccharides and probiotic combinations on stool frequency, consistency, straining defecation and bloating. Galacto-oligosaccharides and synbiotics made up of fructo-oligosaccharides with probiotic combinations may improve stool frequency, consistency and some other symptoms related to constipation.
This study evaluated the efficacy of a targeted social skills training group in school-aged children with autism spectrum disorder (ASD). The intervention, Seaver-NETT (Nonverbal communication, ...Emotion recognition, and Theory of mind Training), is a 12-session cognitive-behavioral intervention (CBI) for verbal, school-aged children targeting ASD-specific social behavioral impairments.
Sixty-nine children with ASD, 8 to 11 years of age, with verbal IQs greater than 70, participated in a randomized comparative trial to examine the efficacy of NETT relative to a facilitated play group. Treatment outcomes included caregiver reports of social behavior and neuropsychological assessments of social cognition conducted by blinded raters. Outcomes were collected at baseline, endpoint, and 3 months posttreatment.
Significant improvements were found on social behavior outcomes such as nonverbal communication, empathic responding, and social relations in the NETT condition relative to the active control at endpoint. Verbal IQ moderated the interaction effect on social behavior, with higher verbal IQ associated with improvements in the CBI condition. No significant improvements were found on social cognitive outcomes. No significant group differences were found at 3-month follow-up conducted with approximately half the sample (n = 34).
These data indicate that targeted CBI social skills groups such as NETT improve social communication deficits in verbal, school-aged children with ASD. The moderating effects of high verbal IQ suggest a need to consider participant and treatment characteristics associated with outcomes in future studies. Clinical trial registration information-Neural and Behavioral Outcomes of Social Skills Groups in Children With Autism Spectrum Disorder; https://clinicaltrials.gov; NCT01190917.
Summary Growing evidence illustrates that aberrant activation of the epithelial-mesenchymal transition plays a key role in tumor cell invasion and metastasis. Transcription factors SNAI1 and ZEB1 ...regulate the epithelial-mesenchymal transition. To determine if SNAI1 and ZEB1 are involved in the metastasis of cervical cancer, we used immunohistochemistry to evaluate the expression of SNAI1, ZEB1, and vimentin in tumor and stromal compartments for a large set of cervical carcinoma samples. Results were evaluated using an H score (percentage × intensity). Of 70 samples, 64 cases (91.43%) were positive for SNAI1 expression. The median SNAI1 H score was 174.00 (range, 5-285). Sixty-seven cases (95.71%) were positive for ZEB1, with a median H score of 165.77 (range, 5-260). Nuclear expression of SNAI1 and ZEB1 in tumor cells was positively associated with International Federation of Gynecology and Obstetrics (FIGO) stages ( P = .015 and P = .008, respectively) and lymph node metastasis ( P = .007 and P = .007, respectively); meanwhile, expression of vimentin in tumor cells was positively associated with lymph node metastasis ( P = .019). According to negative vimentin expression, nuclear expression of ZEB1 in tumor cells was positively associated with FIGO stages ( P = .04). According to positive vimentin expression, nuclear expression of SNAI1 in tumor cells was positively associated with FIGO stages ( P = .018) and pN ( P = .029). In light of these findings, we propose that SNAI1 and ZEB1 have the potential to be used as a novel predictor of pelvic lymph node metastasis and represent promising therapeutic targets in patients with cervical cancer.
Abstract Purpose There is growing evidence supporting incorporating multiparametric (mp) magnetic resonance imaging (MRI) scans into risk stratification, active surveillance, and treatment paradigms ...for prostate cancer. The purpose of our study was to determine whether demographic disparities exist in staging MRI utilization for prostate cancer patients. Methods and materials An institutional database of 705 nonmetastatic prostate cancer patients treated with radiation therapy from 2005 through 2013 was used to identify patients undergoing versus not undergoing pretreatment diagnostic prostate mpMRI. Uni- and multivariable logistic regression evaluated the relationship of clinical and demographic characteristics with MRI utilization. Results All demographic variables assessed, except the other race category, were significantly associated with MRI utilization (all P < .05), including age (odds ratio OR, 0.92), black race (OR, 0.51), poverty (OR, 0.53), closer distance to radiation facility (OR, 1.79), and nonprivate primary insurance (OR, 0.57) on univariable analysis, while clinical stage T3 (OR, 3.37) was the only clinical characteristic. On multivariable analysis stratified by D'Amico risk group, age remained significant across all risk groups, whereas the black versus white racial (OR, 0.21; 95% confidence interval, 0.08-0.55) and nonprivate versus private insurance type (OR, 0.37; 95% confidence interval, 0.16-0.86) disparities persisted in the low-risk group. Clinical stage T3 remained associated in the high-risk group. For race specifically, the percentages of whites, blacks, and others undergoing MRI in the overall cohort and by risk group were, respectively: overall, 80% (343/427), 68% (156/231), and 85% (40/47); low risk, 86%, 56%, and 63%; intermediate risk, 79%, 72%, and 95%; and high risk, 72%, 72%, and 100%. Conclusions In this urban, academic center cohort, older patients across all risk groups and black or nonprivate insurance patients in the low risk group were less likely to undergo staging prostate MRI scans. Further research should investigate these differences to ensure equitable utilization across all demographic groups considering the burden of prostate cancer disparities.
Abstract Purpose Despite increasing use, proton therapy (PT) remains a relatively limited resource. The purpose of this study was to assess clinical and demographic differences in PT use for prostate ...cancer compared to intensity modulated radiation therapy (IMRT) at a single institution. Methods and materials All patients with low- and intermediate-risk prostate cancer (N = 633) who underwent definitive radiation therapy between 2010 and 2015 were divided into PT (n = 508) and IMRT (n = 125) comparison groups and compared using χ2 and independent sample t tests. Univariable and multivariable logistic regression analyses were conducted to assess the associations between PT use and demographic, clinical, and treatment characteristics. Results The PT and IMRT cohorts varied by age, race, poverty, distance, treatment year, and treating physician. Patients who underwent IMRT were more likely to be older (mean age, 66 vs. 68 years), black (51% vs. 75%), and living in poverty or close to the facility (mean distance between residence and facility, 90 vs. 21 miles; P < .05). Prostate-specific antigen, prostate volume, and International Index of Erectile Function were significantly higher in the IMRT cohort ( P < .05), but insurance type, risk group, tumor stage, Gleason score, and patient-reported urinary and bowel scores did not differ significantly ( P > .05). Patients who underwent PT were more likely to receive hypofractionated therapy and less likely to receive androgen deprivation therapy ( P < .01). On multivariable analysis, black (odds ratio OR, 0.29; 95% confidence interval CI, 0.15-0.57) and other race (OR, 0.42; 95% CI, 0.20-0.90); distance (OR, 1.14; 95% CI, 1.06-1.24); treatment years 2011 (OR, 4.87; 95% CI, 2.23-10.6), 2012 (OR, 8.27; 95% CI, 3.43-19.9), and 2014 (OR, 4.44; 95% CI, 1.94-10.2) relative to 2010; and a single treating physician (OR, 0.38; 95% CI, 0.18-0.81) relative to the reference physician with the highest rate of use were associated with PT use, whereas clinical factors such as prostate-specific antigen, prostate volume, International Index of Erectile Function, and androgen deprivation therapy were not. Conclusion Sociodemographic disparities exist in PT use for prostate cancer at an urban academic institution. Further investigation of potential barriers to access is warranted to ensure equitable distribution across all demographic groups.
Summary During infection and host defense, nuclear factor, erythroid 2-like 2 (Nrf2) dependent signaling is an efficient antioxidant defensive mechanism used by host cells to control the destructive ...effects of reactive oxygen species. This allows for effective defense responses against microbes while minimizing oxidative injury to the host cell itself. As a central regulator of antioxidant genes, Nrf2 has gained great attention in its pivotal role in infection, especially in tuberculosis (TB), the top infectious disease killer worldwide. To elucidate the genes potentially regulated by Nrf2 in TB, we conducted a meta-analysis on published gene expression datasets. Firstly, we compared the global gene expression profiles between control and Nrf2-deficient human cells. The differentially expressed genes were deemed as “Nrf2-mediated genes”. Next, the whole blood gene expression pattern of TB patients was compared with that of healthy controls, pneumonia patients, and lung cancer patients. We found that the genes deregulated in TB significantly overlap with the Nrf2-mediated genes. Based on the intersection of Nrf2-mediated and TB-regulated genes, we identified an Nrf2-mediated 17-gene signature, which reflects a cluster of gene ontology terms highly related to TB physiology. We demonstrated that the 17-gene signature can be used to distinguish TB patients from healthy controls and patients with latent TB infection, pneumonia, or lung cancer. Also, the Nrf2-mediated gene signature can be used as an indicator of the anti-TB therapeutic response. More importantly, we confirmed that the predictive power of the Nrf2-mediated 17-gene signature is significantly better than the random gene sets selected from the human transcriptome. Also, the 17-gene signature performs even better than the random gene signatures selected from TB-associated genes. Our study confirms the central role of Nrf2 in TB pathogenesis and provides a novel and useful diagnostic method to differentiate TB patients from other human subjects.
Abstract Background Esculentoside A (EsA) is a saponin isolated from the Chinese herb Phytolacca esculenta . In our study, we sought to investigate the protective effects of EsA on lipopolysaccharide ...(LPS)-induced acute lung injury (ALI) in mice. Materials and methods To determine the effects of EsA on the reduction of histopathologic changes in mice with ALI, inflammatory cell count in bronchoalveolar lavage fluid (BALF) and lung wet-to-dry weight ratio were measured in LPS-challenged mice, and lung histopathologic changes observed via paraffin section were assessed. Next, cytokine production induced by LPS in BALF was measured by enzyme-linked immunosorbent assay. To further study the mechanism of EsA protective effects on ALI, IκBa, p38, and extracellular signal receptor-activated kinase pathways were investigated in lung tissue of mice with ALI. Results In the present investigation, EsA showed marked effects by reducing inflammatory infiltration, thickening of the alveolar wall, and pulmonary congestion. Levels of tumor necrosis factor α and interleukin 6 elevated by LPS were significantly decreased in BALF in EsA-pretreated ALI model. Furthermore, EsA significantly suppressed phosphorylation of IκBa, p38, and extracellular signal receptor-activated kinase. Conclusions Taken together, our results suggest that EsA suppressed inflammatory responses in LPS-induced ALI through inhibition of the nuclear factor kappa B and mitogen activated protein kinase signaling pathways. EsA may be a promising potential preventive agent for ALI treatment.
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