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1.
J Med Chem ; 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33417443

RESUMO

Tryptophan hydroxylase 1 (TPH1) has been recently suggested as a promising therapeutic target for treating obesity and fatty liver disease. A new series of 1,2,4-oxadiazolylphenyl alanine derivatives were identified as TPH1 inhibitors. Among them, compound 23a was the most active in vitro, with an IC50 (half-maximal inhibitory concentration) value of 42 nM, showed good liver microsomal stability, and showed no significant inhibition of CYP and hERG. Compound 23a inhibited TPH1 in the peripheral tissue with limited BBB penetration. In high-fat diet-fed mice, 23a reduced body weight gain, body fat, and hepatic lipid accumulation. Also, 23a improved glucose intolerance and energy expenditure. Taken together, compound 23a shows promise as a therapeutic agent for the treatment of obesity and fatty liver diseases.

2.
PLoS One ; 15(12): e0244114, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33332430

RESUMO

Disease progression (DP) in interstitial lung disease (ILD) is variable and difficult to predict. In previous reports, serum Krebs von den Lungen-6 (KL-6) was suggested to be useful in diagnosing and predicting survival in ILD. The aim of our study was to investigate the usefulness of serum KL-6 as a predictor of DP in ILD. Clinical data of 199 patients with ILD (idiopathic pulmonary fibrosis: 22.8%) were prospectively collected and serum KL-6 levels were measured. DP was defined as a relative decline in forced vital capacity (FVC) ≥ 10%, acute exacerbation, or death during follow-up. The median follow-up period was 11.1 months. The mean age of the subjects was 62.2 years, and 59.8% were male. DP occurred in 21.6% of patients. The progressed group showed lower FVC, lower diffusing capacity for carbon monoxide, lower the minimum oxygen saturation during the 6-minute walk test, higher fibrosis scores on high-resolution computed tomography, and higher KL-6 levels (826.3 vs. 629.0 U/mL; p < 0.001) than those of the non-progressed group. In receiver operating characteristic curve analysis, serum KL-6 levels were a significant predictor of DP in ILD (area under the curve = 0.629, p = 0.009, and the optimal cut-off level was 811 U/mL). In multivariable Cox analysis, high serum KL-6 levels (≥ 800 U/mL) were only independently associated with DP in ILD (HR 2.689, 95% CI 1.445-5.004, P = 0.002). Serum KL-6 levels might be useful to predict DP in patients with ILD.

3.
Ann Am Thorac Soc ; 2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33270528

RESUMO

RATIONALE: In recent decades, diagnosis and treatment recommendations for idiopathic pulmonary fibrosis (IPF) have changed. In Korea, the average life expectancy has increased, unmet healthcare needs have been reduced, and the number of computed tomography (CT) examinations performed has nearly doubled. The Korean Interstitial Lung Disease (ILD) Study Group conducted a nationwide cohort study for idiopathic interstitial pneumonia, including IPF, and established a registry for IPF. OBJECTIVE: Using study data collected by the study group, this study aimed to evaluate longitudinal changes in clinical features, diagnosis, treatment, and mortality and analyze the extent to which changes in medication usage affected IPF-associated mortality. METHODS: The study population included newly diagnosed IPF patients from a cohort study (January 2002-September 2008, n=1839, 2008 group) and prospective registry (January 2012-August 2018, n=1345, 2018 group). Survival curves were estimated using the Kaplan-Meier method, and Cox regression models were used to identify mortality-associated risk factors in each group. RESULTS: The 2018 group was younger, had fewer symptoms, had less honeycombing, underwent more serologic autoimmune marker and pulmonary function tests, had higher oxygen partial pressure and lower carbon dioxide partial pressure values, was less frequently diagnosed by surgical biopsy, and had better survival than the 2008 group. Steroid use and conservative care declined, while N-acetylcysteine use increased in this group. Antifibrotic agents were used in only the 2018 group. In the 2008 group, N-acetylcysteine was associated with lower mortality, whereas conservative care was associated with higher mortality. In the 2018 group, the use of antifibrotic agents was associated with lower mortality, and steroid use was associated with higher mortality. The survival rates in the 2008 and 2018 non-antifibrotic agent subgroups were similar. CONCLUSIONS: This study analyzed national IPF cohort data spanning 17 years. In clinical practice, the IPF diagnosis was made earlier, steroid and immunosuppressive agent use was reduced, and antifibrotic agents were administered. The survival of IPF patients has improved over the decades, and antifibrotic use was consistently associated with improved survival. Clinical trial registered with ClinicalTrials.gov (NCT04160715).

4.
Sci Rep ; 10(1): 21137, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33273612

RESUMO

Some patients with idiopathic pulmonary fibrosis (IPF) have histopathologic features suggesting connective tissue disease (CTD); however, their clinical course and prognosis remain unclear. Thus, we aimed to investigate the clinical course and prognosis of these patients with histologic autoimmune features. Among 114 patients with biopsy-proven IPF, the histologic features were semi-quantitatively graded, and CTD scores (range: 0-9) were calculated as the sum of each score of plasma cell infiltration, lymphoid aggregates, and germinal centres. Patients with high CTD scores (≥ 4) were classified into the interstitial pneumonia with histologic autoimmune features (IP-hAF) group. The mean age of the patients was 60.0 years; 74.6% were men, 69.3% were ever-smokers, and 35.1% had IP-hAF. During follow-up, the IP-hAF group showed slower decline in lung function, and better prognosis (median survival, 48.7 vs. 40.4 months; p = 0.015) than the no-IP-hAF group. On multivariate Cox analysis, IP-hAF was an independent prognostic factor (hazard ratio, 0.522; p = 0.016), along with the lower diffusing capacity for carbon monoxide, higher scores of reticulation and honeycombing, and usual interstitial pneumonia pattern on high-resolution computed tomography. Patients with IPF having histologic autoimmune features show distinct clinical characteristics and better outcome than those without histologic autoimmune features.

5.
PLoS Negl Trop Dis ; 14(12): e0008952, 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33284789

RESUMO

The liver fluke Clonorchis sinensis inhabits the bile ducts, where bile concentration disparities across the fluke cell membrane can cause bile intoxication. Sodium-bile acid co-transporter (SBAT) plays a crucial role in bile acid recycling. The process by which SBAT imports bile acids is electrically coupled to sodium ion co-transportation. Here, we report that the SBAT of C. sinensis (CsSBAT) is involved in bile acid transportation. CsSBAT cDNA encoded a putative polypeptide of 546 amino acid residues. Furthermore, CsSBAT consisted of ten putative transmembrane domains, and its 3D structure was predicted to form panel and core domains. The CsSBAT had one bile acid- and three Na+-binding sites, enabling coordination of a symport process. CsSBAT was mainly localized in the mesenchymal tissue throughout the fluke body and sparsely localized in the basement of the tegument, intestinal epithelium, and excretory bladder wall. Bile acid permeated into the adult flukes in a short time and remained at a low concentration level. Bile acid accumulated inside the mesenchymal tissue when CsSBAT was inhibited using polyacrylic acid-tetradeoxycholic acid conjugate. The accumulated bile acid deteriorated the C. sinensis adults leading to death. CsSBAT silencing shortened the lifespan of the fluke when it was placed into bile. Taken together, we propose that CsSBAT transports bile acids in the mesenchymal tissue and coordinate with outward transporters to maintain bile acid homeostasis of C. sinensis adults, contributing to C. sinensis survival in the bile environment.

6.
PLoS Negl Trop Dis ; 14(12): e0008998, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33370333

RESUMO

Clonorchiasis caused by Clonorchis sinensis is endemic in East Asia; approximately 15 million people have been infected thus far. To diagnose the infection, serodiagnostic tests with excellent functionality should be performed. First, 607 expressed sequence tags encoding polypeptides with a secretory signal were expressed into recombinant proteins using an in vitro translation system. By protein array-based screening using C. sinensis-infected sera, 18 antigen candidate proteins were selected and assayed for cross-reactivity against Opisthorchis viverrini-infected sera. Of the six antigenic proteins selected, four were synthesized on large scale in vitro and evaluated for antigenicity against the flukes-infected human sera using ELISA. CsAg17 antigen showed the highest sensitivity (77.1%) and specificity (71.2%). The sensitivity and specificity of the bacterially produced CsAg17-28GST fusion antigen was similar to those of CsAg17 antigen. CsAg17 antigen can be used to develop point-of-care serodiagnostic tests for clonorchiasis.

7.
Chem Commun (Camb) ; 2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33350413

RESUMO

In the presence of multiple electrophiles, the reaction sequence is a critical mechanistic problem. Here, we report a theoretical study on the mechanism of phosphine-catalyzed [8+2] cycloaddition of heptafulvenes and allenoate. DFT calculations showed that electrophilicity is the barrier for nucleophilic attack, while it fails in the prediction of priority.

8.
World J Clin Cases ; 8(20): 4753-4762, 2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33195643

RESUMO

BACKGROUND: Horseshoe kidney (HK) with renal stones is challenging for urologists. Although both retroperitoneal and transperitoneal laparoscopic approaches have been reported in some case reports, the therapeutic outcome of retroperitoneal compared with transperitoneal laparoscopic lithotripsy is unknown. AIM: To assess the efficacy of laparoscopic lithotripsy for renal stones in patients with HK. METHODS: This was a retrospective study of 12 patients with HK and a limited number (n ≤ 3) of 20-40 mm renal stones treated with either retroperitoneal or transperitoneal laparoscopic lithotripsy (June 2012 to May 2019). The perioperative data of both groups were compared including operation time, estimated blood loss, postoperative fasting time, perioperative complications and stone-free rate (SFR). RESULTS: No significant difference was observed for age, gender, preoperative symptoms, body mass index, preoperative infection, hydronephrosis degree, largest stone diameter, stone number and isthmus thickness. The mean postoperative fasting time of the patients in the retroperitoneal group and the transperitoneal group was 1.29 ± 0.49 and 2.40 ± 0.89 d, respectively (P = 0.019). There was no significant difference in operation time (194.29 ± 102.48 min vs 151.40 ± 39.54 min, P = 0.399), estimated blood loss (48.57 ± 31.85 mL vs 72.00 ± 41.47 mL, P = 0.292) and length of hospital stay (12.14 ± 2.61 d vs 12.40 ± 3.21 d, P = 0.881) between the retroperitoneal and transperitoneal groups. All patients in both groups had a complete SFR and postoperative renal function was within the normal range. The change in estimated glomerular filtration rate (eGFR) from the preoperative stage to postoperative day 1 in the retroperitoneal group and the transperitoneal group was -3.86 ± 0.69 and -2.20 ± 2.17 mL/(min·1.73 m2), respectively (P = 0.176). From the preoperative stage to the 3-mo follow-up, the absolute change in eGFR values for patients in the retroperitoneal group and the transperitoneal group was -3.29 ± 1.11 and -2.40 ± 2.07 mL/(min·1.73 m2), respectively (P = 0.581). CONCLUSION: Both retroperitoneal and transperitoneal laparoscopic lithotripsy seem to be safe and effective for HK patients with a limited number of 20-40 mm renal stones.

9.
Eur Respir J ; 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33184121

RESUMO

Ambient air pollution is associated with prognosis of idiopathic pulmonary fibrosis (IPF) patients. We aimed to identify the impacts of individual exposure to particulate matter with aerodynamic diameter ≤10 µm (PM10) and nitrogen dioxide (NO2) on IPF patients' mortality.Total 1114 patients (mean age, 65.7 years; male, 80.5%) diagnosed with IPF between 1995 and 2016 were included in this study. Individual-level long-term concentrations of PM10 and NO2 at residential addresses of patients were estimated using a national-scale exposure prediction model. The effect of PM10 and NO2 on mortality was estimated using a Cox proportional hazards model adjusted for individual- and area-level covariates.The median follow-up period was 3.8 years, and 69.5% of all the patients died or underwent lung transplantation. When adjusted for individual- and area-level covariates, a 10-ppb increase in NO2 concentration was associated with a 17% increase in mortality (hazard ratio [HR], 1.172 [95% CI: 1.030-1.344, p=0.016]). When IPF patients were stratified by age (≥65 years versus <65 years) or by sex, NO2 was a significant prognostic factor for mortality in the elderly (HR, 1.331 [95% CI: 1.010-1.598, p=0.010]). When stratified by age and sex jointly, NO2 showed the stronger association with mortality in elderly male (HR, 1.305 [95% CI: 1.072-1.598, p=0.008]) than in other groups. PM10 was not associated with IPF mortality in all patients and in subgroups stratified by age or sex.Our findings suggest that increased exposure to NO2 can increase risk of mortality in patients with IPF, specifically in elderly men.

10.
Top Stroke Rehabil ; : 1-11, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33156735

RESUMO

Background and Purpose: Up to 40% of stroke patients with paresis develop post-stroke spasticity (PSS), which induces difficult complications including pain, contracture, posture disorder. The most important factor for PSS management is its early initiation, so that early recognition of PSS is required in clinical practice. Methods: This prospective observational cohort study was conducted with a high standard of PSS assessment and a comprehensive protocol investigating possible predictive factors to identify early predictors of PSS already in the acute phase following stroke (<7 days). PSS was assessed with the Resistance to Passive movement Scale (REPAS) for major joint movements in upper- and lower limbs, based on Ashworth scale, within 7 days following stroke and after 3 months. Binary logistic regression analysis with significant clinical parameters was applied with 95% of confidence intervals (CI) to find predictors of PSS. Results: Of 145 consecutive first-ever stroke patients, 34 patients (23.4%) exhibited PSS. The Modified Rankin Scale (MRS), National Institutes of Health Stroke Scale (NIHSS), and Mini-Mental State Examination (MMSE) were revealed as strong clinical predictors of PSS. The combination of an MRS >2 (Odds Ratio (OR): 56.538, 95% CI: 17.150-186.394), NIHSS >2 (OR: 57.137, 95% CI:15.685-208.142) and MMSE <27 (OR: 6.133, 95% CI:2.653-14.178) showed positive predictive (95.2%) value for prediction of PSS (sensitivity 94.4%, specificity 93.3%). Conclusions: Besides evaluating PSS itself with a reliable and valid rating scale the common clinical scales in stroke units practice (NIHSS, MRS, MMSE) allow early identification of patients at high risk for PSS.

11.
Respir Res ; 21(1): 295, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33172463

RESUMO

BACKGROUND: A new clinical guideline for idiopathic pulmonary fibrosis (IPF) uses high-resolution computed tomography (HRCT) patterns for diagnostic purposes. However, it is unknown how they relate to the IPF clinical course. We aimed to investigate whether HRCT patterns could be used to predict lung function changes and survival in patients with IPF. METHODS: Clinical data were retrospectively reviewed in 337 patients with IPF (all biopsy-proven cases). HRCT patterns were classified according to the 2018 IPF diagnostic criteria. RESULTS: The median follow-up was 46.9 months. The mean age was 62.5 years, and 74.2% were men. Among the HRCT patterns, usual interstitial pneumonia (UIP), probable UIP, indeterminate for UIP, and an alternative diagnosis were identified in 163 (48.4%), 110 (32.6%), 33 (9.8%), and 31 (9.2%) patients, respectively. The indeterminate for UIP group showed higher lung function and exercise capacity and better prognosis than the other groups. They also had a lesser decline in lung function than the other groups during follow-up. In the multivariate Cox analysis, which was adjusted by age, smoking status, lung function, exercise capacity, and use of antifibrotic agents, indeterminate for UIP pattern was found to be an independent prognostic factor (hazard ratio 0.559, 95% confidence interval 0.335-0.933, P = 0.026). However, the probable UIP group had similar lung function changes and prognosis when compared the UIP group. CONCLUSIONS: Our results suggest that indeterminate for UIP pattern on HRCT may predict a more favorable clinical course in patients with IPF, supporting the validity of the new IPF diagnostic guidelines.

12.
Eur Radiol ; 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33241510

RESUMO

OBJECTIVES: To evaluate the longitudinal changes of chest CT findings in patients with chronic hypersensitivity pneumonitis (HP) and identify risk factors for fibrotic progression and acute exacerbation (AE). METHODS: This retrospective study included patients with chronic HP with follow-up CT. Baseline and serial follow-up CT were evaluated semi-quantitatively. Fibrosis score was defined as the sum of the area with reticulation and honeycombing. The modified CT pattern of Fleischner Society idiopathic pulmonary fibrosis diagnostic guidelines was evaluated. Cox proportional hazards regression was performed to determine significant variables associated with fibrotic progression and AEs. RESULTS: Of 91 patients, mean age was 59.1 years and 61.5% were women. The median follow-up period was 4.9 years. Seventy-nine patients (86.8%) showed fibrotic progression with persistent areas of mosaic attenuation, finally replaced by fibrosis, and 20 (22.0%) developed AE. Baseline fibrosis score and CT pattern of usual interstitial pneumonia (UIP)/probable UIP were independent risk factors for predicting fibrotic progression (hazard ratio [HR] = 1.05, 95% confidence interval [CI] = 1.02-1.09, p < 0.001, for fibrosis score; HR = 2.50, CI = 1.50-4.16, p < 0.001, for CT pattern) and AEs (HR = 1.07, CI = 1.01-1.13, p = 0.019, for fibrosis score; HR = 5.47, CI = 1.23-24.45, p = 0.026, for CT pattern) after adjusting clinical covariables. CONCLUSION: Fibrotic progression and AE were identified in 86.8% and 22.0% of patients with chronic HP. Fibrosis score and CT pattern of UIP/probable UIP on baseline chest CT may predict fibrotic progression and AE. KEY POINTS: • Most patients (87%) showed fibrotic progression on long-term follow-up with persistent areas of mosaic attenuation that were finally replaced by fibrosis at a later stage. • One-fifth of patients (22%) experienced acute exacerbation associated with worse prognosis. • Fibrosis score (sum of reticulation and honeycombing) and CT pattern of UIP/probable UIP on baseline CT were independent predictors for predicting fibrotic progression and acute exacerbation.

13.
Eur Respir J ; 2020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-33243842

RESUMO

RATIONALE: The SARS-CoV-2/COVID-19 pandemic has highlighted the serious unmet need for effective therapies that reduce ARDS mortality. We explored whether extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a ligand for Toll-like receptor 4 and a master regulator of innate immunity and inflammation, is a potential ARDS therapeutic target. METHODS: Wild type C57BL/6J or endothelial cell (EC)-cNAMPT -/- knockout mice (targeted EC NAMPT deletion) were exposed to either a lipopolysaccharide (LPS)-induced ("one-hit") or a combined LPS/ventilator ("two-hit")-induced acute inflammatory lung injury model. A NAMPT-specific mAb imaging probe (99mTc-ProNamptorTM) was used to detect NAMPT expression in lung tissues. Either an eNAMPT-neutralising goat polyclonal antibody (pAb) or a humanised monoclonal antibody (ALT-100 mAb) were utilised in vitro and in vivo. RESULTS: Immunohistochemical, biochemical, and imaging studies validated time-dependent increases in NAMPT lung tissue expression in both preclinical ARDS models. Intravenous delivery of either eNAMPT-neutralising pAb/mAb significantly attenuated inflammatory lung injury (H & E staining, BAL protein, BAL PMNs, plasma IL-6) in both preclinical models. In vitro human lung EC studies demonstrated eNAMPT-neutralising antibodies (pAb, mAb) to strongly abrogate eNAMPT-induced TLR4 pathway activation and EC barrier disruption. In vivo studies in wild type and EC-cNAMPT -/- mice confirmed a highly significant contribution of EC-derived NAMPT to the severity of inflammatory lung injury in both preclinical ARDS models. CONCLUSIONS: These findings highlight both the role of EC-derived eNAMPT and the potential for biologic targeting of the eNAMPT/TLR4 inflammatory pathway. In combination with predictive eNAMPT biomarker and NAMPT genotyping assays, this offers the opportunity to identify high-risk ARDS subjects for delivery of personalised medicine.

14.
Cancer Res Treat ; 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33070561

RESUMO

Purpose: Colorectal cancer (CRC) is increasing in South Korea due to westernized eating habits and regular health check-ups. The Korean Health Insurance Review and Assessment Service (HIRA) has conducted a national quality assessment of the treatment of CRC. This study examined the quality assessment report of the Korean HIRA and analyzed the status of practice pattern and the epidemiology of CRC in South Korea. Materials and Methods: The number of subjects was determined based on the number of surgical procedures in each institution during 2012-2017. The institution types were classified according to the number of beds and the composition of oncologic specialists. Twenty-one indicators for diagnosis, chemotherapy, radiotherapy, surgery, pathology, and mortality were analyzed and the inter-institutional variation for each indicator was calculated. Results: Among 21 evaluation indices, indicators related to medical records, receipt of chemotherapy with a high coefficient of variation of ≥ 0.1% were improved over 6 years until the survey in 2017. In the analysis of indices affecting surgical mortality, the regional lymph node resection and examination rate (p=0.022) showed a negative correlation with surgical mortality. Hospitalization stay (p < 0.001) and hospitalization cost (p=0.002) were positively correlated with surgical mortality. Conclusion: This study showed that the treatment quality and examination status for CRC in South Korea were appropriate for improving relevant medical records, receipt of chemotherapy, maintaining the quality of treatment, and mortality. These analyses could be the basis for developing an improved quality assessment program worldwide.

15.
Artigo em Inglês | MEDLINE | ID: mdl-33103824

RESUMO

Catalytic kinetic resolution (KR) and dynamic kinetic asymmetric transformation (DyKAT) are alternative and complementary avenues to access chiral stereoisomers of both starting materials and reaction products. The development of highly efficient chiral catalytic systems for kinetically controlled processes has therefore been one of the linchpins in asymmetric synthesis. N-heterocyclic carbene (NHC)/copper cooperative catalysis has enabled highly efficient KR and DyKAT of racemic N-tosylaziridines by [3+3] annulation with isatin-derived enals, leading to highly enantioenriched N-tosylaziridine derivatives (up to >99 % ee) and a large library of spirooxindole derivatives with high structural diversity and stereoselectivity (up to >95:5 d.r., >99 % ee). Mechanistic studies suggest that the NHC can bind reversibly to the copper catalyst without compromising its catalytic activity and regulate the catalytic activity of the copper complex to switch the chemoselection between KR and DyKAT.

16.
Acta Histochem ; 122(7): 151614, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33066836

RESUMO

Neonatal calvarial bone has been widely used for investigating the biological behaviour of intramembranous bones. This work evaluated the bone formation of neonatal calvarial bone by microcomputed tomography (micro-CT) and histomorphometry. Moreover, the viability of neonatal calvarial bone and the effect of micro-CT radiation exposure on neonatal calvarial bone viability were investigated. The calvarial bones of 4-day-old CD-1 mice were cultured in Dulbecco's modified Eagle's medium (DMEM) or osteogenic medium (OM) for 23 days. Micro-CT scanning and histological analysis were performed on days 2, 9, 16 and 23. An "OM-control" group was scanned only on days 2 and 23 to evaluate the effect of a single micro-CT radiation dose on calvarial bones. Histomorphometric measurements revealed that the number of osteoblasts per unit bone surface area (N. Ob/BS, /mm2) (days 9, 16 and 23) and the number of osteoclasts per unit bone surface area (N. Oc/BS, /mm2) (days 9 and 16) were higher and lower, respectively, in the OM group than in the DMEM group. Moreover, the calvarial bone survived for at least 16 days in vitro, as indicated by tartrate-resistant acid phosphatase (TRAP)-positive staining. Micro-CT assessment revealed that the bone surface (BS), bone volume (BV), bone surface density (BS/TV(Tissue volume)) and percent bone volume (BV/TV) were greater in the OM group than in the DMEM group except at baseline on day 2. All bone parameters of calvariae cultured in OM and OM-control conditions were not significantly different on days 2 and 23. Thus, the radiation dose from micro-CT in our study design had no perceptible effect on the formation of mouse calvarial bone in vitro.

17.
PLoS Negl Trop Dis ; 14(10): e0008714, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33035222

RESUMO

BACKGROUND: Hantaan orthohantavirus (Hantaan virus, HTNV), harbored by Apodemus agrarius (the striped field mouse), causes hemorrhagic fever with renal syndrome (HFRS) in humans. Viral genome-based surveillance at new expansion sites to identify HFRS risks plays a critical role in tracking the infection source of orthohantavirus outbreak. In the Republic of Korea (ROK), most studies demonstrated the serological prevalence and genetic diversity of orthohantaviruses collected from HFRS patients or rodents in Gyeonggi Province. Gangwon Province is a HFRS-endemic area with a high incidence of patients and prevalence of infected rodents, ROK. However, the continued epidemiology and surveillance of orthohantavirus remain to be investigated. METHODOLOGY/PRINCIPAL FINDINGS: Whole-genome sequencing of HTNV was accomplished in small mammals collected in Gangwon Province during 2015-2018 by multiplex PCR-based next-generation sequencing. To elucidate the geographic distribution and molecular diversity of viruses, we conducted phylogenetic analyses of HTNV tripartite genomes. We inferred the hybrid zone using cline analysis to estimate the geographic contact between two different HTNV lineages in the ROK. The graph incompatibility based reassortment finder performed reassortment analysis. A total of 12 HTNV genome sequences were completely obtained from A. agrarius newly collected in Gangwon Province. The phylogenetic and cline analyses demonstrated the genetic diversity and hybrid zone of HTNV in the ROK. Genetic exchange analysis suggested the possibility of reassortments in Cheorwon-gun, a highly HFRS-endemic area. CONCLUSIONS/SIGNIFICANCE: The prevalence and distribution of HTNV in HFRS-endemic areas of Gangwon Province enhanced the phylogeographic map for orthohantavirus outbreak monitoring in ROK. This study revealed the hybrid zone reflecting the genetic diversity and evolutionary dynamics of HTNV circulating in Gangwon Province. The results arise awareness of rodent-borne orthohantavirus diseases for physicians in the endemic area of ROK.

18.
Respir Res ; 21(1): 273, 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33076916

RESUMO

BACKGROUND: Immunoglobulin G4-related lung disease (IgG4-RLD) is the pulmonary manifestation of a systemic fibroinflammatory disease characterized by lymphoplasmacytic infiltration with an abundance of IgG4-positive plasma cells. Long-term clinical course and outcomes of IgG4-RLD remain unclear. We aimed to identify clinical characteristics, treatment outcomes, and longitudinal pulmonary function changes in patients with IgG4-RLD according to the radiologic classification. METHODS: Chest computed tomography findings of 37 subjects were classified into five subtypes: solid nodular, bronchovascular, alveolar interstitial, round ground glass opacity, and alveolar consolidative. Radiologic treatment outcomes and longitudinal pulmonary function changes were compared among the different radiologic subtypes. RESULTS: The mean age of the subjects was 55.6 years, and 78.4% were male. Among the five radiologic subtypes, alveolar consolidative and solid nodular type were most common, accounting for approximately 29.7% each of the total cases. Prednisone with or without azathioprine was administered to 31 patients (median treatment duration 14 months). In the treated patients, serial images showed complete response or partial response in 77.4%. However, relapse was documented in 25.0% of those who showed complete or partial response. In patients whose longitudinal lung function data were available (n = 20), the lung function was found to be stable during follow-up. Alveolar consolidative type showed the highest complete response rate, whereas alveolar interstitial type showed the lowest response rate, either complete or partial. CONCLUSIONS: Most patients showed a favorable outcome with regards to radiologic improvement and maintenance of pulmonary function; however, the response differed according to the radiologic subtype.

19.
Respirology ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33025706

RESUMO

BACKGROUND AND OBJECTIVE: Lipid metabolism dysregulation has been implicated in the pathogenesis of IPF; however, the roles of most lipid metabolites in lung fibrosis remain unexplored. Therefore, we aimed to identify changes in lipid metabolites in the lung tissues of IPF patients and determine their roles in pulmonary fibrosis. METHODS: Free fatty acids in the lung tissues of IPF patients and controls were quantified using a metabolomic approach. The roles of free fatty acids in fibroblasts or epithelial cells treated with TGF-ß1 were evaluated using fibrotic markers. The antifibrotic role of stearic acid was also assessed in a bleomycin-induced lung fibrosis mouse model. Protein levels in cell lysates or tissues were measured by western blotting. RESULTS: The levels of stearic acid were lower in IPF lung tissues than in control lung tissues. Stearic acid significantly reduced TGF-ß1-induced α-SMA and collagen type 1 expression in MRC-5 cells. Furthermore, stearic acid decreased the levels of p-Smad2/3 and ROS in MRC-5 cells treated with TGF-ß1 and disrupted TGF-ß1-induced EMT in Beas-2B cells. Stearic acid reduced the levels of bleomycin-induced hydroxyproline in a mouse model. CONCLUSION: Changes in the free fatty acid profile, including low levels of stearic acid, were observed in IPF patients. Stearic acid may exert antifibrotic activity by regulating profibrotic signalling.

20.
PLoS One ; 15(10): e0239963, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33017401

RESUMO

Interstitial lung diseases (ILDs) are chronic, progressive, parenchymal lung diseases with high morbidity and mortality. In recent studies, the prevalence of obstructive sleep apnea (OSA) in patients with ILD has been reported to be high. However, the prevalence and predictive factors of OSA in Korean ILD patients are not well defined. Therefore, the aim of this study was to evaluate the prevalence and predictive factors of OSA in Korean patients with ILD. Clinical data from 86 patients with ILD enrolled from December 2017 to April 2019 at Haeundae-Paik Hospital, Busan, South Korea, were retrospectively analyzed. OSA was monitored with a level 4 portable device and defined as an apnea-hypopnea index of more than 5 per hour of sleep. The median follow-up period was 7 months. The mean age was 69.8 years, and 64% of participants were men. Among the ILDs, idiopathic pulmonary fibrosis (IPF) was the most common (66.3%), followed by connective tissue disease-associated ILD (16.3%) and cryptogenic organizing pneumonia (5.8%). Forty-six ILD patients (53.5%) were diagnosed with OSA, and IPF patients had OSA more frequently (64.9% vs. 31.0%, p = 0.003) than those with other ILDs. Older age (odds ratio [OR], 1.11, 95% CI 1.04-1.19, p = 0.002), higher body weight (OR 1.05, 95% CI 1.01-1.10, p = 0.012), and diabetes mellitus (OR 4.03, 95% CI 1.26-12.91, p = 0.019) were independent risk factors for OSA in the multivariable logistic regression analysis. In the multivariable Cox analysis, an IPF diagnosis was a significant risk factor for one-year mortality (hazard ratio [HR] 7.92, 95% CI: 1.01-61.83, p = 0.048) in ILD patients; however, OSA was not. In conclusion, half of Korean patients with ILD had OSA. Older age, higher body weight, and diabetes mellitus were risk factors for OSA in patients with ILD.


Assuntos
Doenças Pulmonares Intersticiais/epidemiologia , Apneia Obstrutiva do Sono/epidemiologia , Idoso , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de Risco
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