Nonalcoholic fatty liver disease (NAFLD) is an important health concern worldwide and progresses into nonalcoholic steatohepatitis (NASH). Although prevalence and severity of NAFLD/NASH are higher in ...men than premenopausal women, it remains unclear how sex affects NAFLD/NASH pathophysiology. Formyl peptide receptor 2 (FPR2) modulates inflammatory responses in several organs; however, its role in the liver is unknown. Here we show that FPR2 mediates sex-specific responses to diet-induced NAFLD/NASH. NASH-like liver injury was induced in both sexes during choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) feeding, but compared with females, male mice had more severe hepatic damage. Fpr2 was more highly expressed in hepatocytes and healthy livers from females than males, and FPR2 deletion exacerbated liver damage in CDAHFD-fed female mice. Estradiol induced Fpr2 expression, which protected hepatocytes and the liver from damage. In conclusion, our results demonstrate that FPR2 mediates sex-specific responses to diet-induced NAFLD/NASH, suggesting a novel therapeutic target for NAFLD/NASH.
Mediation models have been widely used in many disciplines to better understand the underlying processes between independent and dependent variables. Despite their popularity and importance, the ...appropriate sample sizes for estimating those models are not well known. Although several approaches (such as Monte Carlo methods) exist, applied researchers tend to use insufficient sample sizes to estimate their models of interest, which might result in unstable and inaccurate estimation of the model parameters including mediation effects. In the present study, sample size requirements were investigated for four frequently used mediation models: one simple mediation model and three complex mediation models. For each model, path and structural equation modeling approaches were examined, and partial and complete mediation conditions were considered. Both the percentile bootstrap method and the multivariate delta method were compared for testing mediation effects. A series of Monte Carlo simulations was conducted under various simulation conditions, including those concerning the level of effect sizes, the number of indicators, the magnitude of factor loadings, and the proportion of missing data. The results not only present practical and general guidelines for substantive researchers to determine minimum required sample sizes but also improve understanding of which factors are related to sample size requirements in mediation models.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK, VSZLJ
Bisphenol A (BPA) exposure during the perinatal and postnatal periods increases the susceptibility to disease over the life cycle. However, information on the BPA delivered to fetuses or infants via ...the placenta and breastfeeding is limited. We determined the BPA exposure levels in various bodily fluids and tissues of pregnant women and described fetus and infant exposures to BPA based on associations and BPA ratios in mother–neonate paired samples. Maternal serum, urine, placenta, breast milk, cord serum, and neonatal urine samples were collected from 318 mother–neonate pairs at six university hospitals in Korea. BPA levels were detected using liquid chromatography tandem mass spectrometry. The ratios of the BPA levels in the other sample types to the levels in maternal serum were calculated. BPA was detected in 79.5–100% of the maternal and fetal samples. The median BPA concentration in the samples decreased in the order of neonatal urine (4.75ng/mL), maternal urine (2.86ng/mL), cord serum (1.71ng/mL), maternal serum (1.56ng/mL), breast milk (0.74ng/mL), and the placenta (0.53ng/g). We estimated the ratios of BPA levels in the other sample types to those in maternal serum. The median (95th percentile) cord serum-to-maternal serum ratio was 1.12 (15.2) for 160 mother–fetal pairs, in which BPA was detected in both samples. The placenta-, maternal urine-, neonatal urine-, and breast milk-to-maternal serum ratios were 0.28 (5.31), 1.79 (29.9), 1.98 (28.2), and 0.51 (10.5), respectively. In addition, the median (95th percentile) cord serum-to-placenta ratio was 4.03 (45.8), and the neonatal urine-to-cord serum ratio was 1.95 (25.6). The 95th percentile values were 14–20-fold greater than the medians. Urine contained the highest BPA concentrations, followed by serum, breast milk, and the placenta. The variations of BPA ratio show individual differences in the amounts of BPA delivered from mother to fetus.
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•Not enough data on tissue distribution of BPA in mother‑neonate (or fetus) pair•The order of BPA concentrations in examined tissue or bio-samples are urine in mother and neonates>cord serum>maternal serum>breast milk>placenta.•BPA in cord serum, significantly associated with in maternal serum and urine but not in others.•The variations of BPA ratio show individual differences in the amounts of BPA delivered from mother to fetus.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Stage-sequential (or multiphase) growth mixture models are useful for delineating potentially different growth processes across multiple phases over time and for determining whether latent subgroups ...exist within a population. These models are increasingly important as social behavioral scientists are interested in better understanding change processes across distinctively different phases, such as before and after an intervention. One of the less understood issues related to the use of growth mixture models is how to decide on the optimal number of latent classes. The performance of several traditionally used information criteria for determining the number of classes is examined through a Monte Carlo simulation study in single- and multiphase growth mixture models. For thorough examination, the simulation was carried out in 2 perspectives: the models and the factors. The simulation in terms of the models was carried out to see the overall performance of the information criteria within and across the models, whereas the simulation in terms of the factors was carried out to see the effect of each simulation factor on the performance of the information criteria holding the other factors constant. The findings not only support that sample size adjusted Bayesian Information Criterion would be a good choice under more realistic conditions, such as low class separation, smaller sample size, or missing data, but also increase understanding of the performance of information criteria in single- and multiphase growth mixture models.
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BFBNIB, NUK, PILJ, SAZU, UL, UM, UPUK
Previous cross-sectional studies demonstrated the close relationship between visceral obesity and the increased prevalence of proteinuria. But, little is known about the role of changes in visceral ...fat mass (∆VFM) over several years in the development of proteinuria. In this longitudinal cohort study with the general population, the changes in ∆VFM as well as baseline VFM on proteinuria development were evaluated.
Healthy individuals (n = 2393) who participated in two health screening exams were analyzed. Subjects were divided into three groups based on gender-specific tertiles of baseline VFM and ∆VFM. Each patient was tested for proteinuria using a dipstick, and proteinuria was defined as 1+ or greater.
The mean age was 51.9±7.7 years, and the incidence of proteinuria was 3.9% (n = 93). During the 4 years, 52.5% of the subjects experienced a decline in ∆VFM. However, subjects who developed proteinuria exhibited a significant increase in ∆VFM. Even after adjustment for age, smoking, systolic and diastolic BP, serum creatinine, and hs-CRP levels, the highest tertiles for baseline VFM men, odds ratio (OR) 3.43, 95% confidence interval (CI) 1.22-9.67; women, OR 2.01, 95% CI 1.05-4.15 and ∆VFM (men, OR 2.92, 95% CI 1.22-6.99; women, OR 3.16, 95% CI 1.56-6.39) were independent predictors of proteinuria development. Following adjustment of both parameters, subjects in the highest baseline VFM and ∆VFM tertiles exhibited the greatest risk of proteinuria development, which suggested the additive harmful effects of the two factors.
Baseline VFM and greater increase in ∆VFM were both important risk factors for developing proteinuria in the general population. Appropriate education and interventions to prevent accumulation of VFM should be the major focus of preemptive strategies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Protection of endothelial integrity has been recognized as a frontline approach to alleviating sepsis progression, yet no effective agent for preserving endothelial integrity is available. Using an ...unusual anti-angiopoietin 2 (ANG2) antibody, ABTAA (ANG2-binding and TIE2-activating antibody), we show that activation of the endothelial receptor TIE2 protects the vasculature from septic damage and provides survival benefit in three sepsis mouse models. Upon binding to ANG2, ABTAA triggers clustering of ANG2, assembling an ABTAA/ANG2 complex that can subsequently bind and activate TIE2. Compared with a conventional ANG2-blocking antibody, ABTAA was highly effective in augmenting survival from sepsis by strengthening the endothelial glycocalyx, reducing cytokine storms, vascular leakage, and rarefaction, and mitigating organ damage. Together, our data advance the role of TIE2 activation in ameliorating sepsis progression and open a potential therapeutic avenue for sepsis to address the lack of sepsis-specific treatment.
For a significant proportion of patients with inflammatory bowel disease (IBD), primary non-response and secondary loss of response to treatment remain significant issues. Anti-tumor necrosis factor ...therapies have been licensed for use in IBD. Other disease-related pathways have been targeted as well, including the interleukin 12/23 axis and lymphocyte tracking. However, the need for parenteral administration and the associated costs of dispensing and monitoring all biologics remain a burden on healthcare systems and patients. Janus kinase inhibitors are small-molecule drugs that can be administered orally and are relatively inexpensive, thus offering an additional option for treating IBD. They have been shown to be effective in patients with ulcerative colitis (UC), but they are less effective in those with Crohn's disease (CD). Nonetheless, given the immune-system-based mechanism of these drugs, their safety profile remains a cause for concern. This article provides an overview of Janus kinase (JAK) inhibitors and new trends in the treatment of IBD.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Panax ginseng is one of the most universally used herbal medicines in Asian and Western countries. Most of the biological activities of ginseng are derived from its main constituents, ginsenosides. ...Interestingly, a number of studies have reported that ginsenosides and their metabolites/derivatives—including ginsenoside (G)-Rb1, compound K, G-Rb2, G-Rd, G-Re, G-Rg1, G-Rg3, G-Rg5, G-Rh1, G-Rh2, and G-Rp1—exert anti-inflammatory activities in inflammatory responses by suppressing the production of proinflammatory cytokines and regulating the activities of inflammatory signaling pathways, such as nuclear factor-κB and activator protein-1. This review discusses recent studies regarding molecular mechanisms by which ginsenosides play critical roles in inflammatory responses and diseases, and provides evidence showing their potential to prevent and treat inflammatory diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background. Treatment outcomes of patients with Mycobacterium abscessus subspecies abscessus lung disease are poor, and the microbial characteristics associated with treatment outcomes have not been ...studied systematically. The purpose of this study was to identify associations between microbial characteristics and treatment outcomes in patients with M. abscessus lung disease. Methods. Sixty-seven consecutive patients with M. abscessus lung disease undergoing antibiotic treatment for ≥12 months between January 2002 and December 2012 were included. Morphotypic and genetic analyses were performed on isolates from 44 patients. Results. Final sputum conversion to culture negative occurred in 34 (51%) patients. Compared to isolates from 24 patients with persistently positive cultures, pretreatment isolates from 20 patients with final negative conversion were more likely to exhibit smooth colonies (9/20, 45% vs 2/24, 8%; P = .020), susceptibility to clarithromycin (7/20, 35% vs 1/24, 4%; P = .015), and be of the C28 sequevar with regard to the erm(41) gene (6/20, 30% vs 1/24, 4%; P = .035). Mycobacterium abscessus lung disease recurred in 5 (15%) patients after successful completion of antibiotic therapy. Genotypic analysis revealed that most episodes (22/24, 92%) of persistently positive cultures during antibiotic treatment and all cases of microbiologic recurrence after treatment completion were caused by different M. abscessus genotypes within a patient. Conclusions. Precise identification to the subspecies level and analysis of mycobacterial characteristics could help predict treatment outcomes in patients with M. abscessus lung disease. Treatment failures and recurrences are frequently associated with multiple genotypes, suggesting reinfection. Clinical Trials Registration. NCT00970801.
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BFBNIB, NUK, PNG, UL, UM, UPUK
The role of bacterial microbiota in the pathogenesis of nontuberculous mycobacterial pulmonary disease (NTM-PD) is unclear. We aimed to compare the bacterial microbiome of disease-invaded lesions and ...non-invaded lung tissue from NTM-PD patients.
We analyzed lung tissues from 23 NTM-PD patients who underwent surgical lung resection. Lung tissues were collected in pairs from each patient, with one sample from a disease-involved site and the other from a non-involved site. Lung tissue microbiome libraries were constructed using 16S rRNA gene sequences (V3-V4 regions).
Sixteen (70%) patients had Mycobacterium avium complex (MAC)-PD, and the remaining seven (30%) had Mycobacterium abscessus-PD. Compared to non-involved sites, involved sites showed greater species richness (ACE, Chao1, and Jackknife analyses, all p = 0.001); greater diversity on the Shannon index (p = 0.007); and genus-level differences (Jensen-Shannon, PERMANOVA p = 0.001). Analysis of taxonomic biomarkers using linear discriminant analysis (LDA) effect sizes (LEfSe) demonstrated that several genera, including Limnohabitans, Rahnella, Lachnospira, Flavobacterium, Megamonas, Gaiella, Subdoligranulum, Rheinheimera, Dorea, Collinsella, and Phascolarctobacterium, had significantly greater abundance in involved sites (LDA >3.00, p <0.05, and q <0.05). In contrast, Acinetobacter had significantly greater abundance at non-involved sites (LDA = 4.27, p<0.001, and q = 0.002). Several genera were differentially distributed between lung tissues from MAC-PD (n = 16) and M. abscessus-PD (n = 7), and between nodular bronchiectatic form (n = 12) and fibrocavitary form (n = 11) patients. However, there was no genus with a significant q-value.
We identified differential microbial distributions between disease-invaded and normal lung tissues from NTM-PD patients, and microbial diversity was significantly higher in disease-invaded tissues.
Clinical Trial registration number: NCT00970801.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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