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Nitric oxide (NO) promotes angiogenesis via various mechanisms; however, the effective transmission of NO in ischemic diseases is unclear. Herein, we tested whether NO-releasing nanofibers modulate therapeutic angiogenesis in an animal hindlimb ischemia model. Male wild-type C57BL/6 mice with surgically-induced hindlimb ischemia were treated with NO-releasing 3-methylaminopropyltrimethoxysilane (MAP3)-derived or control (i.e., non-NO-releasing) nanofibers, by applying them to the wound for 20 min, three times every two days. The amount of NO from the nanofiber into tissues was assessed by NO fluorometric assay. The activity of cGMP-dependent protein kinase (PKG) was determined by western blot analysis. Perfusion ratios were measured 2, 4, and 14 days after inducing ischemia using laser doppler imaging. On day 4, Immunohistochemistry (IHC) with F4/80 and gelatin zymography were performed. IHC with CD31 was performed on day 14. To determine the angiogenic potential of NO-releasing nanofibers, aorta-ring explants were treated with MAP3 or control fiber for 20 min, and the sprout lengths were examined after 6 days. As per either LDPI (Laser doppler perfusion image) ratio or CD31 capillary density measurement, angiogenesis in the ischemic hindlimb was improved in the MAP3 nanofiber group; further, the total nitrate/nitrite concentration in the adduct muscle increased. The number of macrophage infiltrations and matrix metalloproteinase-9 (MMP-9) activity decreased. Vasodilator-stimulated phosphoprotein (VASP), one of the major substrates for PKG, increased phosphorylation in the MAP3 group. MAP3 nanofiber or NO donor SNAP (s-nitroso-n-acetyl penicillamine)-treated aortic explants showed enhanced sprouting in an ex vivo aortic ring assay, which was partially abrogated by KT5823, a potent inhibitor of PKG. These findings suggest that the novel NO-releasing nanofiber, MAP3 activates PKG and promotes therapeutic angiogenesis in response to hindlimb ischemia., (Copyright: © 2024 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Euonymus hamiltonianus and its relatives (Celastraceae family) are used for ornamental and medicinal purposes. However, species identification in Euonymus is difficult due to their morphological diversity. Using plastid genome (plastome) data, we attempt to reveal phylogenetic relationship among Euonymus species and develop useful markers for molecular identification. We assembled the plastome and nuclear ribosomal DNA (nrDNA) sequences from five Euonymus lines collected from South Korea: three Euonymus hamiltonianus accessions, E. europaeus, and E. japonicus. We conducted an in-depth comparative analysis using ten plastomes, including other publicly available plastome data for this genus. The genome structures, gene contents, and gene orders were similar in all Euonymus plastomes in this study. Analysis of nucleotide diversity revealed six divergence hotspots in their plastomes. We identified 339 single nucleotide polymorphisms and 293 insertion or deletions among the four E. hamiltonianus plastomes, pointing to abundant diversity even within the same species. Among 77 commonly shared genes, 9 and 33 were identified as conserved genes in the genus Euonymus and E. hamiltonianus, respectively. Phylogenetic analysis based on plastome and nrDNA sequences revealed the overall consensus and relationships between plastomes and nrDNAs. Finally, we developed six barcoding markers and successfully applied them to 31 E. hamiltonianus lines collected from South Korea. Our findings provide the molecular basis for the classification and molecular taxonomic criteria for the genus Euonymus (at least in Korea), which should aid in more objective classification within this genus. Moreover, the newly developed markers will be useful for understanding the species delimitation of E. hamiltonianus and closely related species., Competing Interests: The authors declare that there are no competing interests.

Objectives: The pathologic nodal stage of human papillomavirus (HPV)-related oropharyngeal cancer (OPC) patients is classified according to the number of lymph nodes (LNs), as revised in 2018. Previous studies showed that the LN ratio (LNR) could be also a significant prognostic factor in head and neck cancer, but there are few studies on the LNR in HPV-related [HPV(+)] OPC. The aim of the present study was to analyze the predictive value of the LNR for survival and recurrence in HPV(+) OPC patients., Materials and Methods: HPV(+) OPC patients treated with surgery with or without postoperative radiotherapy from January 2000 to March 2019 were evaluated. The patients were divided into two sets of three groups, according to LN numbers based on pathologic nodal stages, and LNRs by a cutoff value of 0.05. The medical records were reviewed, and the overall survival (OS), disease-free survival, locoregional recurrence, and distant metastasis incidence were analyzed., Results: Ninty patients were included and the median follow-up period was 38.2 months. There were no significant differences in OS in the LN number groups. However, there was a significant difference in OS in the LNR groups (P = 0.010). The incidence of distant metastasis in the LNR groups was significantly different (P = 0.005)., Conclusion: The LNR in HPV(+) OPC patients may be a more useful tool to predict survival and distant metastasis than the LN number. Additional research and consensus on surgical pathology are needed before applying the LNR to adjuvant treatment decisions and pathologic nodal staging., Competing Interests: The authors have declared that no competing interests exist.

The aim of the present study was to reveal the associations between skeletal and soft tissue features of the nasomaxillary complex and development and severity of obstructive sleep apnea (OSA) in adolescents. A total of 100 adolescents (mean age, 14.9 ± 1.4 years; age range, 13-17 years) were enrolled. All participants underwent full-night polysomnography and had an assessment of size and position of the tongue, tonsillar size, body mass index (BMI), and circumference of the waist, neck, and hip. The skeletal features of the nasomaxillary complex, including the zygomatic arch width, nasal cavity width, nasal base width, intercanine width, intermolar width, maxillary dental arch length, palatal vault angle, palatal depth, and SNA were measured on the three-dimensional images constructed with computed tomography data. Participants with an apnea and hypopnea index (AHI) of lower than 5 (AHI ≤ 5) were classified as control and participants while those with an AHI of greater than 5 were classified as OSA group. Each variable with a significant outcome in the independent T-test and age and sex factors were integrated into the multivariate linear regression and the dependent variable was AHI. There were significant differences in the BMI and hip circumference between two groups. The width of nasal base, palatal vault angle and SNA also showed significant differences between groups. The results from multivariate linear regression demonstrated that the BMI, width of the nasal base, and SNA showed significant contributions to the severity of OSA in adolescents. The features of the nasomaxillary complex seemed to have significant influences on development and severity of OSA., Competing Interests: The authors have declared that no competing interests exist.

The genus Artemisia is an important source of medicines in both traditional and modern pharmaceutics, particularly in East Asia. Despite the great benefits of herbal medicine, quality assessment methods for these medicinal herbs are lacking. The young leaves from Artemisia species are generally used, and most of the species have similar morphology, which often leads to adulteration and misuse. This study assembled five complete chloroplast genomes of three Artemisia species, two accessions of A. gmelinii and A. capillaris, and one A. fukudo. Through comparative analysis, we revealed genomic variations and phylogenetic relationships between these species and developed seven InDel-based barcode markers which discriminated the tested species from each other. Additionally, we analyzed specialized metabolites from the species using LC-MS and suggested chemical markers for the identification and authentication of these herbs. We expect that this integrated and complementary authentication method would aid in reducing the misuse of Artemisia species., Competing Interests: The authors have declared that no competing interests exist.

We examined the association between serum miRNA (-192-5p, -122-3p, -320a and -6126-5p) levels and the efficacy of pegylated interferon (Peg-IFN) monotherapy for chronic hepatitis B (CHB) patients. We enrolled 61 CHB patients treated with Peg-IFNα-2a weekly for 48 weeks, of whom 12 had a virological response (VR) and 49 did not VR (non-VR). A VR was defined as HBV DNA < 2,000 IU/ml, hepatitis B e antigen (HBeAg)-negative, and nucleos(t)ide analogue free at 48 weeks after the end of treatment. The non-VR group showed a significantly higher HBeAg-positivity rate, ALT, HBV DNA, and serum miR-192-5p levels at baseline (P = 0.024, P = 0.020, P = 0.007, P = 0.021, respectively). Serum miR-192-5p levels at 24-weeks after the start of treatment were also significantly higher in the non-VR than the VR group (P = 0.011). Multivariate logistic regression analysis for predicting VR showed that miR-192-5p level at baseline was an independent factor (Odds 4.5, P = 0.041). Serum miR-192-5p levels were significantly correlated with the levels of HBV DNA, hepatitis B core-related antigen, and hepatitis B surface antigen (r = 0.484, 0.384 and 0.759, respectively). The serum miR-192-5p level was useful as a biomarker for the therapeutic efficacy of Peg-IFN in CHB treatment., Competing Interests: Regarding COI of Yasuhito Tanaka: Research funding from C Fujifilim Corp., Janssen Pharmaceutical K.K, Gilead Sciences, GlaxoSmithKline Pharmaceuticals Ltd, and Stanford Junior University, and lecture fees from Fujirebio, Inc. and Gilead Sciences, these do not relate to employment, consultancy, patents, products in development, and marketed products. Therefore, these do not alter our adherence to PLOS ONE policies on sharing data and materials.

The purpose of the present study was to reveal the relationship between degenerative changes in the cervical spine, head and neck postures, neck pain, and bone mineral density (BMD) of the total hip, femoral neck, and lumbar spine in post-menopausal females. In total, 116 females (mean age 60.4 ± 7.1 years; age range 50-80 years) were included. Participants were classified into three groups based on the T-score criteria of the total hip, femoral neck, and lumbar spine set by World Health Organization, respectively. The degree of neck pain was assessed using self-administered questionnaire, the Neck Disability Index. Cervical spine degeneration and head and neck postures were identified using the lateral cephalograms. Grading system for cervical degeneration included three categories of the radiographic alterations including disc height loss, osteophyte formation, and diffuse sclerosis. The areal BMD of the total hip, femoral neck, and lumbar spine were determined using dual-energy x-ray absorptiometry. Females with lower BMD exhibited lesser degree of neck pain and forward head posture (FHP) compared to those with normal BMD. Higher BMD seemed to be associated with more notable loss of the disc height at the level of C4-5. More prominent degenerative changes in the cervical spine were associated with higher areal BMD of the hip, femoral neck, and lumbar spine, altered head posture, and development of neck pain., Competing Interests: The authors have declared that no competing interests exist.

Objectives: Mechanical and biochemical bone properties are influenced by muscles. However, the muscle-bone interaction has not been fully elucidated regarding the upper extremities. The objective of the present study was to evaluate the mechanical muscle-bone interaction at the forearm by evaluating the relationship between the properties of three-dimensional (3D) forearm cortical bone models derived from conventional computed tomography (CT) images and handgrip strength (HGS)., Methods: A total of 108 women (mean age, 75.2 ± 9.4 years; range, 62-101 years) with a distal radius fracture who took conventional CT scans for the assessment of the fracture were included in this study. Distal radius 3D models were reconstructed and the average cortical bone density (Cd) and thickness (Ct) of the region of interest (ROI), which might be affected by the forearm flexor muscles, were calculated using a 3D modeling software. Clinical parameters including HGS, lumbar and hip bone mineral densities (BMDs), and other demographic factors were also obtained. A multivariate linear regression analysis was performed to identify relevant factors associated with HGS., Results: HGS was found to be independently associated with height and Cd, but no significant difference was found between HGS and Ct, age, weight, as well as lumber and hip BMDs., Conclusions: Cortical bone density might be associated with HGS, which is generated by the forearm flexor muscles. Hence, the mechanical muscle-bone interaction in the upper extremities could be supported by the present study., Competing Interests: Seok Woo Hong, Jeong-Hyun Kang, Jong Seop Kim and Hyun Sik Gong declare that they have no conflicts of interests in the present study.

Takifugu rubripes is more expensive than other species of the genus because of its high protein content and special flavor. However, it is easily confused with imported T. chinensis and T. pseudommus because they have similar morphological characteristics. We identified single nucleotide polymorphism (SNP) markers of T. rubripes by genotyping-by-sequencing (GBS) and evaluated their ability to distinguish among T. rubripes, T. chinensis, and T. pseudommus. In all, 18 polymorphic SNPs were subjected to phylogenetic analyses of the three Takifugu species. Additionally, we subjected a second set of samples to Sanger sequencing to verify that the polymorphic SNPs could be used to evaluate the genetic variation among the three Takifugu species. A phylogenetic tree that included the analyzed sequence of set A, which is referred to as the reference sequence, and a validation sequence of set B with 18 SNPs were produced. Based on this phylogenetic tree and STRUCTURE analyses, T. rubripes, T. chinensis and T. pseudommus have low genetic variation and should be considered the same gene pool. Our findings suggest that further studies are needed to estimate the genetic association of the three Takifugu species., Competing Interests: No authors have competing interests.

Objective: To examine the interaction between APOE genotypes and both treated and untreated hypertension on cognitive function in an updated analysis of Nurses' Health Study (NHS) data., Design: At baseline (1995-2001) and 3 biennial follow-up assessments over ~6 years, cognitive function was assessed., Setting and Participants: 8300 NHS participants aged 70+ years underwent a cognitive battery, which comprised 6 tests including the Telephone Interview for Cognitive Status (TICS) and tests of verbal memory, category fluency, and working memory., Measures: We estimated the mean differences in average cognitive scores across up to 4 assessments using multiple linear regression. We also tested for interaction between APOE e4 allele carrier status and hypertension overall, as well as for apparently untreated and treated hypertension., Results: We confirmed that, compared with those with APOE e3/3 genotype, APOE e4 allele carriers scored lower by 0.55 units on the average TICS score (95%CI:-0.67,-0.43). We also observed a significantly worse average TICS score among women with untreated hypertension compared with women without hypertension (difference = -0.23, 95%CI:-0.37,-0.09), while no significant difference was observed for women with treated hypertension. Significant interaction was detected between the APOE e4 allele and untreated hypertension (p-int = 0.02 for the TICS; p-int = 0.045 for global score), but not with treated hypertension. Specifically, compared with normotensive women with the APOE e3/3 genotype, APOE e4 allele carriers with treated hypertension scored lower by 0.50 units (95%CI:-0.69,-0.31); however, the APOE e4 allele carriers with untreated hypertension scored lower by 1.02 units on the TICS score (95%CI:-1.29, -0.76). This interaction of APOE e4 and untreated hypertension was also consistently observed for the global score., Conclusions: Women with hypertension and at least one APOE e4 allele had worse average cognitive function compared with women without hypertension with the e3/3 genotype; this difference was amplified among APOE e4 allele carriers with untreated hypertension., Competing Interests: Dr. Gary Curhan reports grants and personal fees from Allena Pharmaceuticals, personal fees from Shire, royalties for his work as an author and section editor from UpToDate, and personal fees from RenalGuard, outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors have completed the ICMJE uniform disclosure form and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

B7-1 proteins are routinely expressed on the surface of antigen presenting cells (APC) and within the innate immune system. They function to establish a biologically optimal and dynamic balance between immune activation and inhibition or self-tolerance. Interactions between B7-1 and its receptors, which include CD28, CTLA4 and PD-L1, contribute to both stimulatory as well as inhibitory or homeostatic regulation. In the current study, we investigated whether the tumor-promoting actions of transforming growth factor beta (TGF-β) disrupted this equilibrium in pancreatic cancer to promote malignant progression and an enhanced means to evade immune detection. The data show that B7-1 is (i) upregulated following treatment of pancreatic carcinoma cells with TGF-β; (ii) induced by TGF-β via both Smad2/3-dependent and independent pathways; (iii) required for pancreatic tumor cell in vitro migration/invasion; and (iv) necessary for TGF-β regulated epithelial-mesenchymal transition (EMT) through induction of Snail family members. Results from the proposed studies provide valuable insights into mechanisms whereby TGF-β regulates both the innate immune response and intrinsic properties of pancreatic tumor growth., Competing Interests: The authors have declared that no competing interests exist.

Species diversity in the genus Ulva remains understudied worldwide. Using molecular analyses we investigated the species composition, diversity, distribution, and relative frequencies of the genus Ulva along the entire coast of Jeju Island, off the southern tip of Korea. Species identification was performed for 215 samples collected from 23 sites, based on comprehensive phylogenetic and model-based species delimitation analyses using the sequences of two molecular markers, chloroplast elongation factor Tu (tufA) and nuclear rDNA internal transcribed spacer (ITS). We identified 193 specimens as nine Ulva species, 14 specimens as Blidingia spp., and eight samples undetermined, based on the combined analysis of tufA and ITS phylogenies. Two model-based approaches generally supported nine groups of Ulva species. Previously documented species complex, such as U. ohnoi-U. spinulosa and U. procera-U. linza showed discordant relationships between the two phylogenies. The occurrence of U. torta on Jeju Island was first observed, despite its existence on the mainland previously reported. Ulva australis [16 of 23 sites; 34.4% (relative frequency)], U. ohnoi (16; 21.9%), and U. procera (11; 14%) were found to be the predominant species. Our study highlights that molecular analysis is critical for species delimitation in the genus Ulva and provides fundamental information for an understanding of green-tide assemblages on the "biological hotspot" coastal ecosystem, Jeju Island in Korea. This study will also help to monitor and manage local green tides at the areas that are currently encountering rapid climate changes., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Jae Hwan Kim is employed by Gencube, Gimpo. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Failure to deliver the standard stroke care is suspected to be a potential reason for disproportionately high mortality among patients with co-morbid bipolar disorder (BD). Few studies have explored adverse outcomes and medical care costs concurrently (as a proxy for care intensity) among patients with BD admitted for stroke. Data for this nationwide population-based study were extracted from the Taiwan National Health Insurance Research Database, on 580 patients with BD hospitalized for stroke (the study group) and a comparison group consisting of randomly selected 1740 stroke patients without BD matched by propensity scores. Conditional logistic regression was used to estimate odds ratios (OR) for adverse in-hospital outcomes between study group and comparison group. We found that stroke patients with BD had significantly lower in-hospital mortality (3.28% vs. 5.63%), acute respiratory failure (2.59% vs. 5.57%), and use of mechanical ventilation (6.55% vs. 10.23%) than the comparison group. After adjusting for geographical location, urbanization level, monthly income, hypertension, diabetes, hyperlipidemia, and coronary heart disease, the odds of in-hospital mortality, acute respiratory failure, and use of mechanical ventilation in the BD group were 0.56 (95% CI: 0.34-0.92), 0.46 (95% CI: 0.26-0.80), and 0.63 (95% CI: 0.44-0.91), respectively. No differences were found in hospitalization costs and the length of hospital stay. With comparable hospitalization costs and length of hospital stay, we concluded that stroke patients with BD had lower in-hospital mortality and serious adverse events compared to stroke patients without BD., Competing Interests: The authors have declared that no competing interests exist.

Aim: Health-related quality of life is impaired in patients with autoimmune hepatitis, but the association between health-related quality of life and patients' backgrounds remains unknown. We assessed health-related quality of life in patients with autoimmune hepatitis and identified factors associated with its impairment., Methods: We assessed health-related quality of life in patients with autoimmune hepatitis, patients with chronic hepatitis C, and healthy subjects using the Japanese version of the Chronic Liver Disease Questionnaire and the 36-Item Short Form Survey. We compared health-related quality of life in patients with autoimmune hepatitis with that of patients with chronic hepatitis C and healthy subjects., Results: A total of 265 patients with autoimmune hepatitis, 88 patients with chronic hepatitis C, and 97 healthy subjects were enrolled; most patients were women. The median ages of patients were 65, 66, and 57 years, respectively. Of these patients with autoimmune hepatitis, 10.6% and 57.0% had cirrhosis and comorbid diseases, respectively. The overall Chronic Liver Disease Questionnaire scores (5.5 vs. 6.2, P < 0.001) and physical (48.1 vs. 54.2, P < 0.001) and mental (51.8 vs. 55.0, P = 0.004) component summaries of 36-Item Short Form Survey were significantly lower in patients with autoimmune hepatitis than in healthy subjects, and similar to scores in patients with chronic hepatitis C. Having cirrhosis, comorbid diseases, and treatment for autoimmune hepatitis were associated with impaired health-related quality of life among patients with autoimmune hepatitis. In particular, prednisolone use was associated with lower scores on the worry domain of the Chronic Liver Disease Questionnaire., Conclusions: Patients with autoimmune hepatitis showed impairment in health-related quality of life, which was associated with not only disease progression, but also comorbid diseases and treatment. Ways to improve health-related quality of life should be considered in patients with AIH when disease outcome is not favorable and when using prednisolone., Competing Interests: Yoshiyuki Suzuki received lecture fees from Abbvie GK and Bristol-Myers Squibb. Zobair M. Younossi received lecture fees from Gilead Sciences and Intercept. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The other authors declare no conflict of interest.

Whether statins and an angiotensin-converting enzyme inhibitors (ACEIs) / angiotensin receptor blockors (ARBs) are associated with reduced risks of infection events is still inconclusive. This study aimed to explore the risk of hospitalization for pneumonia among patients who had received treatment with ACEIs/ARBs and/or statins using a population-based dataset. This study included 19,281 patients as cases who were hospitalized for pneumonia and 19,281 controls. We used a logistic regression to compute the odds ratio (OR) and 95% confidence interval (CI) for having previously used statins or an ACEI/ ARB between patients who were hospitalized for pneumonia treatment and controls. We found there were significant associations between hospitalization for pneumonia and statin-only users (p<0.001), ACEI/ARB-only users (p<0.001), and statin and ACEI/ARB users (p<0.001). The logistic regression analysis suggested that statin-only users (adjusted OR = 0.38, 95% CI = 0.34~0.43), ACEI/ARB-only users (adjusted OR = 0.86, 95% CI = 0.82~0.91), and statin and ACEI/ARB users (adjusted OR = 0.47, 95% CI = 0.44~0.50) were all less likely to be hospitalized for pneumonia treatment than were non-users. Furthermore, we found that statin-only users (adjusted OR = 0.44, 95% CI = 0.40~0.50) and statin and ACEI/ARB users (adjusted OR = 0.55, 95% CI = 0.52~0.58) were less likely to be hospitalized for pneumonia treatment compared to ACEI-only users. However, combined statin and ACEI/ARB users (adjusted OR = 1.24, 95% CI = 1.10~1.40) were more likely to have been hospitalized for pneumonia treatment compared to statin-only users. Although we found use of both statins and ACEI/ARB were significantly associated with a lower risk of pneumonia, the combination of the two medications did not provide additional protection against pneumonia risk., Competing Interests: The authors have declared that no competing interests exist.

Objectives: We assessed whether grip strength was related to various types of radiographic damage in Korean adults with osteoarthritis (OA)., Methods: Data from 2,251 subjects enrolled in the Dong-gu study, who had no hand joint pain, were analyzed to investigate the relationship between grip strength and OA. Hand grip strength was measured using a hand-held dynamometer, and radiographs of the hand and knee were scored according to a semi-quantitative grading system. Multiple linear regressions were used to explore associations between grip strength and radiographic features of OA., Results: Grip strength in men and women was negatively related to hand (both p < 0.001) and knee (men, p < 0.001; women, p = 0.010) OA after adjusting for confounders. Hand (men, p < 0.001; women, p = 0.001) and knee (both p < 0.001) joint space narrowing (JSN) showed the strongest associations with low grip strength, regardless of gender. Moreover, the severity of hand osteophytes in women (p = 0.001), and subchondral cysts (men, p < 0.001) was correlated with low grip strength in both genders., Conclusions: Among subjects without hand joint pain, low grip strength was associated significantly with hand and knee radiographic OA, regardless of gender. Among all types of OA radiographic damage, low grip strength showed the strongest association with JSN.

Objectives: Fourteen-day rehospitalization with new traumatic spinal cord injury (tSCI) diagnosis is used as an indicator for the diagnostic quality of the first hospitalization. In this nationwide population-based cohort study, we identified risk factors for this indicator., Methods: We conducted a nested case-control study by using the data of patients who received a first hospitalization for trauma between 2001 and 2011. The data were retrieved from Taiwan's National Health Insurance Research Database. Variables including demographic and trauma characteristics were compared between patients diagnosed with tSCI at the first hospitalization and those receiving a 14-day rehospitalization with new tSCI diagnosis., Results: Of the 23 617 tSCI patients, 997 had 14-day rehospitalization with new tSCI diagnosis (incidence rate, 4.22%). The risk of 14-day rehospitalization with new tSCI diagnosis was significantly lower in patients with severe (injury severity score [ISS] = 16-24; odds ratio [OR], 0.17; 95% confidence interval [CI], 0.13-0.21) and profound (ISS > 24; OR, 0.11; 95% CI, 0.07-0.18) injuries. Interhospital transfer (OR, 8.20; 95% CI, 6.48-10.38) was a significant risk factor, along with injuries at the thoracic (OR, 1.62; 95% CI, 1.21-2.18), lumbar (OR, 1.30; 95% CI, 1.02-1.65), and multiple (OR, 3.23; 95% CI, 1.86-5.61) levels. Brain (OR, 2.82), chest (OR, 2.99), and abdominal (OR, 2.74) injuries were also identified as risk factors. In addition, the risk was higher in patients treated at the orthopedic department (OR, 2.26; 95% CI, 1.78-2.87) and those of other surgical disciplines (OR, 1.89; 95% CI, 1.57-2.28) than in those treated at the neurosurgery department., Conclusions: Delayed tSCI diagnoses are not uncommon, particularly among trauma patients with ISSs < 16 or those who are transferred from lower-level hospitals. Further validation and implementation of evidence-based decision rules is essential for improving the diagnostic quality of traumatic thoracolumbar SCI.

Myotis rufoniger is a vesper bat in the genus Myotis. Here we report the whole genome sequence and analyses of the M. rufoniger. We generated 124 Gb of short-read DNA sequences with an estimated genome size of 1.88 Gb at a sequencing depth of 66× fold. The sequences were aligned to M. brandtii bat reference genome at a mapping rate of 96.50% covering 95.71% coding sequence region at 10× coverage. The divergence time of Myotis bat family is estimated to be 11.5 million years, and the divergence time between M. rufoniger and its closest species M. davidii is estimated to be 10.4 million years. We found 1,239 function-altering M. rufoniger specific amino acid sequences from 929 genes compared to other Myotis bat and mammalian genomes. The functional enrichment test of the 929 genes detected amino acid changes in melanin associated DCT, SLC45A2, TYRP1, and OCA2 genes possibly responsible for the M. rufoniger's red fur color and a general coloration in Myotis. N6AMT1 gene, associated with arsenic resistance, showed a high degree of function alteration in M. rufoniger. We further confirmed that the M. rufoniger also has bat-specific sequences within FSHB, GHR, IGF1R, TP53, MDM2, SLC45A2, RGS7BP, RHO, OPN1SW, and CNGB3 genes that have already been published to be related to bat's reproduction, lifespan, flight, low vision, and echolocation. Additionally, our demographic history analysis found that the effective population size of Myotis clade has been consistently decreasing since ~30k years ago. M. rufoniger's effective population size was the lowest in Myotis bats, confirming its relatively low genetic diversity.

Soluble guanylate cyclase (sGC) has been suggested as a therapeutic target for cardiac ischemia-reperfusion (IR) injury. Until now, the molecular mechanism of BAY 60-2770, a sGC activator, in cardiac IR injury has not been assessed. To identify the cardioprotective effects of BAY 60-2770 in IR-injured rat hearts, IR injury was established by occlusion of LAD for 40 min and reperfusion for 7 days, and the effects of BAY 60-2770 on myocardial protection were assessed by echocardiography and TTC staining. 5 nM and 5 μM of BAY 60-2770 were perfused into isolated rat hearts in a Langendorff system. After 10- or 30-min reperfusion with BAY 60-2770, cGMP and cAMP concentrations and PKG activation status were examined. Hearts were also perfused with 1 μM KT5823 or 100 μM 5-HD in conjunction with 5 nM Bay 60-2770 to evaluate the protective role of PKG. Mitochondrial oxidative stress was investigated under hypoxia-reoxygenation in H9c2 cells. In IR-injured rat hearts, BAY 60-2770 oral administration reduced infarct size by TTC staining and improved left ventricular function by echocardiography. Tissue samples from BAY 60-2770-perfused hearts had approximately two-fold higher cGMP levels. BAY 60-2770 increased PKG activity in the myocardium, and the reduced infarct area by BAY 60-2770 was abrogated by KT-5823 in isolated myocardium. In H9c2 cardiac myoblasts, hypoxia-reoxygenation-mediated mitochondrial ROS generation was diminished with BAY 60-2770 treatment, but was recovered by pretreatment with KT-5823. BAY 60-2770 demonstrated a protective effect against cardiac IR injury via mitoKATP opening and decreased mitoROS by PKG activation. BAY 60-2770 has a protective effect against cardiac IR injury via mitoKATP opening and decreased mitoROS by PKG activation. These results demonstrated that BAY 60-2770 may be used as a therapeutic agent for cardiac IR injury.

Purpose: To assess the effect of computer-aided detection (CAD) of brain metastasis (BM) on radiologists' diagnostic performance in interpreting three-dimensional brain magnetic resonance (MR) imaging using follow-up imaging and consensus as the reference standard., Materials and Methods: The institutional review board approved this retrospective study. The study cohort consisted of 110 consecutive patients with BM and 30 patients without BM. The training data set included MR images of 80 patients with 450 BM nodules. The test set included MR images of 30 patients with 134 BM nodules and 30 patients without BM. We developed a CAD system for BM detection using template-matching and K-means clustering algorithms for candidate detection and an artificial neural network for false-positive reduction. Four reviewers (two neuroradiologists and two radiology residents) interpreted the test set images before and after the use of CAD in a sequential manner. The sensitivity, false positive (FP) per case, and reading time were analyzed. A jackknife free-response receiver operating characteristic (JAFROC) method was used to determine the improvement in the diagnostic accuracy., Results: The sensitivity of CAD was 87.3% with an FP per case of 302.4. CAD significantly improved the diagnostic performance of the four reviewers with a figure-of-merit (FOM) of 0.874 (without CAD) vs. 0.898 (with CAD) according to JAFROC analysis (p < 0.01). Statistically significant improvement was noted only for less-experienced reviewers (FOM without vs. with CAD, 0.834 vs. 0.877, p < 0.01). The additional time required to review the CAD results was approximately 72 sec (40% of the total review time)., Conclusion: CAD as a second reader helps radiologists improve their diagnostic performance in the detection of BM on MR imaging, particularly for less-experienced reviewers.

Objectives: To assess the neurobiological substrate of initial cognitive decline in Parkinson's disease (PD) to inform patient management, clinical trial design, and development of treatments., Methods: We longitudinally assessed, up to 3 years, 423 newly diagnosed patients with idiopathic PD, untreated at baseline, from 33 international movement disorder centers. Study outcomes were four determinations of cognitive impairment or decline, and biomarker predictors were baseline dopamine transporter (DAT) single photon emission computed tomography (SPECT) scan, structural magnetic resonance imaging (MRI; volume and thickness), diffusion tensor imaging (mean diffusivity and fractional anisotropy), cerebrospinal fluid (CSF; amyloid beta [Aβ], tau and alpha synuclein), and 11 single nucleotide polymorphisms (SNPs) previously associated with PD cognition. Additionally, longitudinal structural MRI and DAT scan data were included. Univariate analyses were run initially, with false discovery rate = 0.2, to select biomarker variables for inclusion in multivariable longitudinal mixed-effect models., Results: By year 3, cognitive impairment was diagnosed in 15-38% participants depending on the criteria applied. Biomarkers, some longitudinal, predicting cognitive impairment in multivariable models were: (1) dopamine deficiency (decreased caudate and putamen DAT availability); (2) diffuse, cortical decreased brain volume or thickness (frontal, temporal, parietal, and occipital lobe regions); (3) co-morbid Alzheimer's disease Aβ amyloid pathology (lower CSF Aβ 1-42); and (4) genes (COMT val/val and BDNF val/val genotypes)., Conclusions: Cognitive impairment in PD increases in frequency 50-200% in the first several years of disease, and is independently predicted by biomarker changes related to nigrostriatal or cortical dopaminergic deficits, global atrophy due to possible widespread effects of neurodegenerative disease, co-morbid Alzheimer's disease plaque pathology, and genetic factors.

Objective: To validate preoperative dynamic CT and fecal elastase-1 level in predicting the development of pancreatic fistulae after pancreatoduodenectomy., Materials and Methods: For 146 consecutive patients, CT attenuation values of the nontumorous pancreatic parenchyma were retrospectively measured on precontrast, arterial and equilibrium phase images for calculation of enhancement ratios. CT enhancement ratios and preoperative fecal elastase-1 levels were correlated with the development of pancreatic fistulae using independent t-test, logistic regression models, ROC analysis, Youden method and tree analysis., Results: The mean value of enhancement ratio on equilibrium phase was significantly higher (p = 0.001) in the patients without pancreatic fistula (n = 107; 2.26±3.63) than in the patients with pancreatic fistula (n = 39; 1.04±0.51); in the logistic regression analyses, it was significant predictor for the development of pancreatic fistulae (odds ratio = 0.243, p = 0.002). The mean preoperative fecal elastase-1 levels were higher (odds ratio = 1.003, p = 0.034) in the pancreatic fistula patients than other patients, but there were no significant differences in the areas under the curve between the prediction values of CT enhancement ratios and fecal elastase-1 combined and those of CT enhancement ratios alone (P = 0.897, p = 0.917) on ROC curve analysis. Tree analysis revealed that the CT enhancement ratio was more powerful predictor of pancreatic fistula than fecal elastase-1 levels., Conclusion: The preoperative CT enhancement ratio of pancreas acquired at equilibrium phase regardless of combination with fecal elastase-1 levels might be a useful predictor of the risk of developing a pancreatic fistula following pancreatoduodenectomy.

Identification of the structure-function relationship of heparin, particularly between 2-O-, 6-O-, and N-sulfation and its anticoagulant or anti-inflammatory activities, is critical in order to evaluate the biological effects of heparin, especially in conjunction with modifications for oral formulation. In this study, we demonstrated that removal of 2-O, 6-O, or N-desulfation and their hydrophobic modifications have differential effects on the blocking of interactions between sLeX and P-and L-selectins, with highest inhibition by 6-O desulfation, which was consistent with their in vivo therapeutic efficacies on CIA mice. The 6-O desulfation of lower molecular weight heparin (LMWH) retained the ability of LMWH to interfere with T cell adhesion via selectin-sLeX interactions. Furthermore, 6DSHbD coated on the apical surface of inflamed endothelium directly blocked the adhesive interactions of circulating T cells, which was confirmed in vivo by suppressing T cell adhesion at post-capillary venular endothelium. Thus, in series with our previous study demonstrating inhibition of transendothelial migration, oral delivery of low anticoagulant LMWH to venular endothelium of inflamed joint tissues ameliorated arthritis by the stepwise inhibition of T cell recruitment and provides a rationale for the development of modified oral heparins as innovative agents for the treatment of chronic inflammatory arthritis.

Seagrasses provide numerous ecosystem services for coastal and estuarine environments, such as nursery functions, erosion protection, pollution filtration, and carbon sequestration. Zostera marina (common name "eelgrass") is one of the seagrass bed-forming species distributed widely in the northern hemisphere, including the Korean Peninsula. Recently, however, there has been a drastic decline in the population size of Z. marina worldwide, including Korea. We examined the current population genetic status of this species on the southern coast of Korea by estimating the levels of genetic diversity and genetic structure of 10 geographic populations using eight nuclear microsatellite markers. The level of genetic diversity was found to be significantly lower for populations on Jeju Island [mean allelic richness (AR) = 1.92, clonal diversity (R) = 0.51], which is located approximately 155 km off the southernmost region of the Korean Peninsula, than for those in the South Sea (mean AR = 2.69, R = 0.82), which is on the southern coast of the mainland. South Korean eelgrass populations were substantially genetically divergent from one another (FST = 0.061-0.573), suggesting that limited contemporary gene flow has been taking place among populations. We also found weak but detectable temporal variation in genetic structure within a site over 10 years. In additional depth comparisons, statistically significant genetic differentiation was observed between shallow (or middle) and deep zones in two of three sites tested. Depleted genetic diversity, small effective population sizes (Ne) and limited connectivity for populations on Jeju Island indicate that these populations may be vulnerable to local extinction under changing environmental conditions, especially given that Jeju Island is one of the fastest warming regions around the world. Overall, our work will inform conservation and restoration efforts, including transplantation for eelgrass populations at the southern tip of the Korean Peninsula, for this ecologically important species.

The Nurses' Health Study (NHS), Nurses' Health Study II (NHSII), Health Professionals Follow Up Study (HPFS) and the Physicians Health Study (PHS) have collected detailed longitudinal data on multiple exposures and traits for approximately 310,000 study participants over the last 35 years. Over 160,000 study participants across the cohorts have donated a DNA sample and to date, 20,691 subjects have been genotyped as part of genome-wide association studies (GWAS) of twelve primary outcomes. However, these studies utilized six different GWAS arrays making it difficult to conduct analyses of secondary phenotypes or share controls across studies. To allow for secondary analyses of these data, we have created three new datasets merged by platform family and performed imputation using a common reference panel, the 1,000 Genomes Phase I release. Here, we describe the methodology behind the data merging and imputation and present imputation quality statistics and association results from two GWAS of secondary phenotypes (body mass index (BMI) and venous thromboembolism (VTE)). We observed the strongest BMI association for the FTO SNP rs55872725 (β = 0.45, p = 3.48x10-22), and using a significance level of p = 0.05, we replicated 19 out of 32 known BMI SNPs. For VTE, we observed the strongest association for the rs2040445 SNP (OR = 2.17, 95% CI: 1.79-2.63, p = 2.70x10-15), located downstream of F5 and also observed significant associations for the known ABO and F11 regions. This pooled resource can be used to maximize power in GWAS of phenotypes collected across the cohorts and for studying gene-environment interactions as well as rare phenotypes and genotypes.

Purpose: To find differential CT features of colorectal schwannomas from gastrointestinal stromal tumors (GISTs)., Materials and Methods: CT features of 13 pathologically proven colorectal schwannomas and 21 GISTs were retrospectively reviewed. The following CT items were analyzed: size, longitudinal and transverse location, shape, margin, homogeneity, necrosis, surface ulceration, calcification, degree of attenuation, the presence of enlarged lymph node (LN), and metastasis. Among the features, significant variables were evaluated using univariate statistical tests. The optimal cut-off point of tumor size was obtained by ROC analysis. Binary logistic regression analysis was used to find the most independent CT variables., Results: Small size, non-rectum location, smooth margin, homogeneous high attenuation without necrosis, and the presence of enlarged LNs were found to be significant variables to differentiate schwannomas from GISTs (P<0.05). The optimized cut-off point for tumor size in distinguishing GISTs from schwannomas was 3.9 cm (AUC = 0.808, sensitivity = 66.7%, specificity = 92.3%, P<0.0001). Binary regression analysis revealed that only non-rectum location remained independent predictor for schwannomas differentiated from GISTs (odds ratio = 31.667, P = 0.001)., Conclusion: Colorectal schwannomas usually located in non-rectum and appear as small subepithelial nodules showing homogeneous high attenuation and smooth margin. Schwannomas exclusively accompany with enlarged LNs., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Baicalin, a Chinese herbal medicine, has anti-fibrotic and anti-inflammatory effects. The aims of present study were to investigate the effects of baicalin on the myofibroblast differentiation, extracellular matrix production, migration, and collagen contraction of interleukin (IL)-1β-stimulated nasal fibroblasts and to determine the molecular mechanism of baicalin in nasal fibroblasts., Methods: Nasal fibroblasts were isolated from the inferior turbinate of patients. Baicalin was used to treat IL-1β-stimulated nasal fibroblasts. To evaluate cytotoxicity, a 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide assay was used. The expression levels of α-smooth muscle actin (SMA), fibronectin, phospho-mitogen-activated protein kinase (p-MAPK), p-Akt, p-p50, p-p65, and p-IκBα were measured by western blotting, reverse transcription-polymerase chain reaction (RT-PCR),or immunofluorescence staining. Fibroblast migration was analyzed with scratch assays and transwell migration assays. Total collagen was evaluated with the Sircol collagen assay. Contractile activity was measured with a collagen gel contraction assay., Results: Baicalin (0-50 μM) had no significant cytotoxic effects in nasal fibroblasts. The expression of α-SMA and fibronectin were significantly down-regulated in baicalin-treated nasal fibroblasts. Migration, collagen production, and contraction of IL-1β-stimulated nasal fibroblasts were significantly inhibited by baicalin treatment. Baicalin also significantly down-regulated p-MAPK, p-Akt, p-p50, p-p65, and p-IκBα in IL-1β-stimulated nasal fibroblasts., Conclusions: We showed that baicalin down-regulated myofibroblast differentiation, extracellular matrix production, migration, and collagen contraction via the MAPK and Akt/ NF-κB pathways in IL-1β-stimulated nasal fibroblasts., Competing Interests: The authors have declared that no competing interests exist.

Some of the prior literature investigated the potential association between rheumatoid arthritis (RA) and Alzheimer's disease (AD) because these two diseases may share similar inflammatory mechanisms. Nevertheless, to date, findings of the previous literature are still controversial, and some methodological limitations were observed in those studies. The aim of this case-control study was to investigate the relationship between prior RA and AD using a large population-based dataset. This study used the Taiwan Longitudinal Health Insurance Database 2005. We included 2271 patients with AD who had received prescriptions for acetylcholinesterase inhibitors (AChEIs) as cases and 6813 patients without AD as controls in this study. In addition, we performed a conditional logistic regression to examine the odds ratio (OR) and 95% confidence interval (CI) for prior RA between cases and controls. The study found that 330 (3.63%) of the total sampled patients had an RA diagnosis before the index date. Additionally, prior RA was found in 60 (2.64%) cases and in 270 (3.96%) controls. The conditional logistic regression analysis showed that the crude OR of prior RA for cases was 0.66 (95% confidence interval (CI): 0.49~0.87) compared to controls. After adjusting for patients' geographic location, urbanization level, and comorbidities, the adjusted OR of prior RA for patients with AD was 0.73 (95% CI: 0.55~0.98) compared to those without AD. We concluded that there was an inverse association between prior RA and AD even after adjusting for potential confounders., Competing Interests: The authors have declared that no competing interests exist.

Objective: Therapeutic agents that are transformable via introducing cleavable linkage by locally enriched MMP-2 within inflamed synovium would enhance therapeutic efficacy on chronic inflammatory arthritis. Transforming growth factor-β-inducible gene-h3 (βig-h3), which consists of four fas-1 domains and an Arg-Gly-Asp (RGD) motif, intensifies inflammatory processes by facilitating adhesion and migration of fibroblast-like synoviocyte in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to investigate whether a MMP-2-cleavable peptide complex consisting of a fas-1 domain and an RGD peptide blocks the interaction between βig-h3 and resident cells and leads to the amelioration of inflammatory arthritis., Methods: We designed βig-h3-derivatives, including the fourth fas-1 domain truncated for H1 and H2 sequences of mouse (MFK00) and MMP-2-cleavable peptide complex (MFK902). MMP-2 selectivity was examined by treatment with a series of proteases. MFK902 efficacy was determined by the adhesion and migration assay with NIH3T3 cells in vitro and collagen-induced arthritis (CIA) model using male DBA/1J mice in vivo. The mice were treated intraperitoneally with MFK902 at different dosages., Results: MFK902 was specifically cleaved by active MMP-2 in a concentration-dependent manner, and βig-h3-mediated adhesion and migration were more effectively inhibited by MFK902, compared with RGD or MFK00 peptides. The arthritis activity of murine CIA, measured by clinical arthritis index and incidence of arthritic paws, was significantly ameliorated after treatment with all dosages of MFK902 (1, 10, and 30 mg/kg). MFK902 ameliorated histopathologic deterioration and reduced the expression of inflammatory mediators simultaneously with improvement of clinical features. In addition, a favorable safety profile of MFK902 was demonstrated in vivo., Conclusion: The present study revealed that MMP-2-cleavable peptide complex based on βig-h3 structure is a potent and safe therapeutic agent for chronic inflammatory arthritis, thus providing reliable evidence for a MMP-2-cleavable mechanism as a tissue-targeted strategy for treatment of RA., Competing Interests: The authors have declared that no competing interests exist.

Despite the clinical impact of non-motor symptoms (NMS) in Parkinson's disease (PD), the characteristic NMS in relation to the motor subtypes of PD is not well elucidated. In this study, we enrolled drug-naïve PD patients and compared NMS between PD subtypes. We enrolled 136 drug-naïve, early PD patients and 50 normal controls. All the enrolled PD patients were divided into tremor dominant (TD) and non-tremor dominant (NTD) subtypes. The Non-Motor Symptom Scale and scales for each NMS were completed. We compared NMS and the relationship of NMS with quality of life between normal controls and PD patients, and between the PD subtypes. Comparing with normal controls, PD patients complained of more NMS, especially mood/cognitive symptoms, gastrointestinal symptoms, unexplained pain, weight change, and change in taste or smell. Between the PD subtypes, the NTD subtype showed higher total NMS scale score and sub-score about weight change. Weight change was the characteristic NMS related to NTD subtype even after controlled other variables with logistic regression analysis. Even from the early stage, PD patients suffer from various NMS regardless of dopaminergic medication. Among the various NMS, weight change is the characteristic NMS associated with NTD subtype in PD patients., Competing Interests: The authors have declared that no competing interests exist.

Background and Objectives: Tissue remodeling is believed to cause recalcitrant chronic rhinosinusitis (CRS). Epithelial-mesenchymal transition (EMT) is a novel clinical therapeutic target in many chronic airway diseases related with tissue remodeling. The aim of this study was to investigate the effect of trichostatin A (TSA) on transforming growth factor (TGF)-β1-induced EMT in airway epithelium and nasal tissue., Materials and Methods: A549 cells, primary nasal epithelial cells (PNECs), or inferior nasal turbinate organ culture were exposed to TSA prior to stimulation with TGF-β1. Expression levels of E-cadherin, vimentin, fibronectin, α-smooth muscle actin (SMA), histone deacetylase 2 (HDAC2), and HDAC4 were determined by western blotting and/or immunofluorescent staining. Hyperacetylation of histone H2 and H4 by TSA was measured by western blotting. After siHDAC transfection, the effects of HDAC2 and HDAC4 silencing on expression of E-cadherin, vimentin, fibronectin, α-SMA, HDAC2, and HDAC4 in TGF-β1-induced A549 were determined by RT-PCR and/or western blotting. We assessed the change in migration capacity of A549 cells by using cell migration assay and transwell invasion assay., Results: TGF-β1 altered mRNA and protein expression levels of EMT markers including E-cadherin, vimentin, fibronectin, α-SMA, slug, and snail in A549 cells. Inhibition and silencing of HDAC2 and HDAC4 by TSA and siRNA enhanced TGF-β1-induced EMT in A549 cells. TSA blocked the effect of TGF-β1 on the migratory ability of A549 cells. In experiments using PNECs and inferior turbinate organ cultures, TSA suppressed expression of EMT markers induced by TGF-β1., Conclusions: We showed that EMT is induced by TGF-β1 in airway epithelial cells and nasal tissue via activation of HDAC2 and HDAC4, and that inhibition of HDAC2 and HDAC4 by TSA reduces TGF-β1-induced EMT. This observation indicates that histone deacetylase inhibitors such as TSA could be potential candidates for treatment of recalcitrant CRS related with tissue remodeling., Competing Interests: The authors have declared that no competing interests exist.

Objectives: Recurrent falls not only have risk factors different from those of single falls but also have less favorable outcomes. The aim of our study was to determine the association between the injury characteristics of a first fall and the likelihood of recurrent injurious falls in a cohort of hospitalized patients., Methods: We designed a nationwide retrospective cohort study and selected hospitalized patients who had injurious falls between 2001 and 2010. Cox proportional hazards models were used to estimate the hazard ratios (HRs) of recurrent injurious falls requiring hospitalization in the following year on the basis of the patients' demographic characteristics, comorbidities, and the characteristics of injuries from the first injurious fall requiring hospitalization., Results: Among the 504 512 patients hospitalized for injurious falls, 19 442 experienced recurrent injurious falls requiring hospitalization. The 1-year incidence of recurrent injurious falls requiring hospitalization was 3.85%. The incidence density was the highest within the 3-month period after the first injurious fall. The risk of recurrent injurious falls among patients aged 40 to 64, 65 to 74, and ≥ 75 years increased progressively (HR: 2.11, 95% confidence interval [CI]: 1.90-2.34; HR: 2.80, 95% CI: 2.51-3.11; and HR: 3.80, 95% CI: 3.42-4.23, respectively). The length of hospitalization (LOH) ≥ 15 or ≥ 31 days (HR: 1.39, 95% CI: 1.30-1.48; and HR: 1.59, 95% CI: 1.43-1.77, respectively) and injury to the head (HR: 1.59, 95% CI: 1.53-1.65) or spine (HR: 1.66, 95% CI: 1.59-1.74) were also found to be major risk factors., Conclusions: Our findings show that the LOH and head and spine injuries are associated with an increased risk of recurrent injurious falls leading to hospitalization. The risk of recurrent injurious falls requiring hospitalization increased significantly among adults older than 40 years. We suggest further research on the effects of injury characteristics associated with the first injurious fall requiring hospitalization and resultant anatomical damages on the risk of recurrent injurious falls requiring hospitalization. High-risk patients should receive tailored rehabilitation addressing their respective injuries within 3 months after hospital discharge.

Background: Gastric cancer with undifferentiated histology has different clinicopathologic characteristics compared to differentiated type gastric cancer. We aimed to compare the risk of synchronous or metachronous tumors after curative resection of early gastric cancer (EGC) via endoscopic submucosal dissection (ESD), according to the histologic differentiation of the primary lesion., Methods: Clinicopathological data of patients with initial-onset EGC curatively resected via ESD between January 2007 and November 2014 in a single institution were reviewed. We analyzed the incidence of synchronous or metachronous tumors after ESD with special reference to the differentiation status of the primary lesion., Results: Of 1,560 patients with EGC who underwent curative resection via ESD, 1,447 had differentiated type cancers, and 113 had undifferentiated type cancers. The cumulative incidence of metachronous or synchronous tumor after ESD was higher in the differentiated cancer group than in the undifferentiated cancer group (P = 0.008). Incidence of metachronous or synchronous tumor was 4.8% and 1.2% per person-year in the differentiated and undifferentiated cancer groups, respectively. The Cox proportional hazard model revealed that undifferentiated cancers were associated with a low risk of synchronous or metachronous tumors after adjusting for confounding variables (hazard ratio [95% confidence interval] = 0.287 [0.090-0.918])., Conclusions: The rate of synchronous or metachronous tumors after curative ESD was significantly lower for undifferentiated cancers compare to differentiated cancers. These findings suggest that ESD should be actively considered as a possible treatment for undifferentiated type EGCs.

Rosiglitazone is a well-known anti-diabetic drug that increases insulin sensitivity via peroxisome proliferator-activated receptor γ (PPARγ) activation, but unfortunately it causes bone loss in animals and humans. A previous study showed that prolyl hydroxylase domain protein (PHD) plays a role in rosiglitazone-induced adipocyte differentiation. Based on the inverse relationship between adipocyte and osteoblast differentiation, we investigated whether PHD is involved in the effects of rosiglitazone on osteoblast differentiation. Rosiglitazone inhibited osteoblast differentiation in a concentration-dependent manner, and in parallel induced three PHD isoforms (PHD1, 2, and 3). PHD inhibitors and knockdown of each isoform prevented the inhibitory effects of rosiglitazone on osteoblast differentiation and increased the expression of Runx2, a transcription factor essential for osteoblastogenesis. MG-132, a proteasomal inhibitor also prevented the rosiglitazone-induced degradation of Runx2. Furthermore, both increased PHD isoform expressions and reduced osteoblast differentiation by rosiglitazone were prevented by PPARγ antagonists, indicating these effects were mediated via PPARγ activation. In vivo oral administration of rosiglitazone to female ICR mice for 8 weeks reduced bone mineral densities and plasma alkaline phosphatase (ALP) activity, and increased PHD expression in femoral primary bone marrow cells and the ubiquitination of Runx2. Together, this suggests that the rosiglitazone-induced suppression of osteoblast differentiation is at least partly induced via PPARγ-mediated PHD induction and subsequent promotion of the ubiquitination and degradation of Runx2.

Facial preference that results from the processing of facial information plays an important role in social interactions as well as the selection of a mate, friend, candidate, or favorite actor. However, it still remains elusive which brain regions are implicated in the neural mechanisms underlying facial preference, and how neural activities in these regions are modulated during the formation of facial preference. In the present study, we investigated the modulation of electroencephalography (EEG) oscillatory power with facial preference. For the reliable assessments of facial preference, we designed a series of passive viewing and active choice tasks. In the former task, twenty-four face stimuli were passively viewed by participants for multiple times in random order. In the latter task, the same stimuli were then evaluated by participants for their facial preference judgments. In both tasks, significant differences between the preferred and non-preferred faces groups were found in alpha band power (8-13 Hz) but not in other frequency bands. The preferred faces generated more decreases in alpha power. During the passive viewing task, significant differences in alpha power between the preferred and non-preferred face groups were observed at the left frontal regions in the early (0.15-0.4 s) period during the 1-s presentation. By contrast, during the active choice task when participants consecutively watched the first and second face for 1 s and then selected the preferred one, an alpha power difference was found for the late (0.65-0.8 s) period over the whole brain during the first face presentation and over the posterior regions during the second face presentation. These results demonstrate that the modulation of alpha activity by facial preference is a top-down process, which requires additional cognitive resources to facilitate information processing of the preferred faces that capture more visual attention than the non-preferred faces.

Obesity is an increasing public health concern worldwide. According to the latest Organization for Economic Co-operation and Development (OECD) report (2014), the incidence of child obesity in Korea has exceeded the OECD average. To better understand and control this condition, the present study examined the composition of the gut microbial community in normal and obese adolescents. Fecal samples were collected from 67 obese (body mass index [BMI] ≥ 30 kg/m2, or ≥ 99th BMI percentile) and 67 normal (BMI < 25 kg/m2 or < 85th BMI percentile) Korean adolescents aged 13-16 years and subjected to 16S rRNA gene sequencing. Analysis of bacterial composition according to taxonomic rank (genus, family, and phylum) revealed marked differences in the Bacteroides and Prevotella populations in normal and obese samples (p < 0.005) at the genus and family levels; however, there was no difference in the Firmicutes-to-Bacteroidetes (F/B) ratio between normal and obese adolescents samples at the phylum level (F/B normal = 0.50 ± 0.53; F/B obese = 0.56 ± 0.86; p = 0.384). Statistical analysis revealed a significant association between the compositions of several bacterial taxa and child obesity. Among these, Bacteroides and Prevotella showed the most significant association with BMI (p < 0.0001 and 0.0001, respectively). We also found that the composition of Bacteroides was negatively associated with triglycerides (TG), total cholesterol, and high-sensitive C-reactive protein (hs-crp) (p = 0.0049, 0.0023, and 0.0038, respectively) levels, whereas that of Prevotella was positively associated with TG and hs-crp levels (p = 0.0394 and 0.0150, respectively). We then applied the association rule mining algorithm to generate "rules" to identify the association between the populations of multiple bacterial taxa and obesity; these rules were able to discriminate obese from normal states. Therefore, the present study describes a systemic approach to identify the association between bacterial populations in the gut and childhood obesity.

Objectives: We aimed to compare tissue-specific expression profiles and biological pathways of RNA from amniocytes and amniotic fluid supernatant (AFS) from second-trimester pregnancies by using transcriptome analysis. Additionally, we wanted to explore whether cell-free RNA from AFS exhibits a unique gene expression signature that more adequately reflects the fetal developmental process than amniocyte RNA., Methods: Amniotic fluid samples were prospectively collected in the second trimester of pregnancy from euploid fetuses. Total RNA was extracted from amniocytes and AFS and hybridized to Affymetrix GeneChip Human Arrays. Significantly differentially expressed transcripts between amniocytes and AFS were obtained by using Welch's t-test. Unsupervised hierarchical clustering was used to visualize overall expression characteristics and differences in transcripts between AFS and amniocytes. The biological functions of selected genes were analyzed using various online Gene Ontology databases., Results: A total of 3,072 and 15,633 transcripts were detected in the second-trimester AFS and amniocytes, respectively. Hierarchical clustering revealed differential transcript expression between AFS and amniocytes. We found 353 genes that were specifically enriched in the AFS only, and tissue expression analysis showed enrichment of brain-specific genes in the AFS. Biological pathway analysis revealed that AFS-specific transcripts were mainly involved in embryonic development, cardiovascular development, and cellular morphology pathways., Conclusion: This study demonstrated differential tissue-specific gene expression profiles and biological pathways between AFS and amniocytes. The results suggested that AFS is the preferred RNA source to investigate potential biomarkers of fetal neurodevelopment.

The aim of this study was to investigate the potential predictors of switching tumor necrosis factor (TNF)-α inhibitors in Korean patients with ankylosing spondylitis (AS). The patients who had been treated with TNF-α inhibitors were divided into two groups depending on whether they had switched TNF-α inhibitors. Demographic, clinical, laboratory, and treatment data at the time of initiation of TNF-α inhibitor treatment were compared between switchers and non-switchers, and within switchers according to the reasons for switching. Of the 269 patients, 70 (23%) had switched TNF-α inhibitors once; of these, 11 switched again. The median follow-up time was 52.7 months. Three- and five-year drug survival rates were 52%/48% for infliximab, 62%/42% for etanercept, and 71%/51% for adalimumab, respectively. Switchers were more likely to be prescribed disease-modifying anti-rheumatic drugs than non-switchers. A history of joint surgery and complete ankylosis of the sacroiliac joint was more frequent in switchers. Multivariate Cox's proportional hazard analysis showed that the use of adalimumab as the first TNF-α inhibitor was less likely to lead to switching and complete ankylosis of the sacroiliac joints was more likely to lead to switching. The principal reasons for switching were drug inefficacy and adverse events, but the differences in the clinical data of these two groups of switchers were not significant. In AS patients who are candidates for TNF-α inhibitor therapy, switching may improve the therapeutic outcome based on clinical information.

The eukaryotic translation elongation factor 1 (eEF1) has two components: the G-protein eEF1A and the nucleotide exchange factor eEF1B. In plants, eEF1B is itself composed of a structural protein (eEF1Bγ) and two nucleotide exchange subunits (eEF1Bα and eEF1Bβ). To test the effects of elongation factors on virus infection, we isolated eEF1A and eEF1B genes from pepper (Capsicum annuum) and suppressed their homologs in Nicotiana benthamiana using virus-induced gene silencing (VIGS). The accumulation of a green fluorescent protein (GFP)-tagged Potato virus X (PVX) was significantly reduced in the eEF1Bβ- or eEF1Bɣ-silenced plants as well as in eEF1A-silenced plants. Yeast two-hybrid and co-immunoprecipitation analyses revealed that eEF1Bα and eEF1Bβ interacted with eEF1A and that eEF1A and eEF1Bβ interacted with triple gene block protein 1 (TGBp1) of PVX. These results suggest that both eEF1A and eEF1Bβ play essential roles in the multiplication of PVX by physically interacting with TGBp1. Furthermore, using eEF1Bβ deletion constructs, we found that both N- (1-64 amino acids) and C-terminal (150-195 amino acids) domains of eEF1Bβ are important for the interaction with PVX TGBp1 and that the C-terminal domain of eEF1Bβ is involved in the interaction with eEF1A. These results suggest that eEF1Bβ could be a potential target for engineering virus-resistant plants.

Objective: Tumor Necrosis Factor (TNF) mediates retinal ganglion cell death in glaucoma. Anti-TNF drugs are neuroprotective in an animal model of glaucoma. It is unclear whether medications with anti-TNF properties such as bupropion have an impact on the risk of developing open-angle glaucoma (OAG) in humans. The purpose of this study is to determine whether bupropion use alters the risk of developing OAG., Methods: Claims data for beneficiaries age ≥35 years with no pre-existing OAG enrolled in a large nationwide U.S. managed care network continuously for ≥4 years between 2001-2011 was analyzed to identify patients who had been newly-diagnosed with OAG. The amount of bupropion use as captured from outpatient pharmacy claims over a four-year period was also quantified for each beneficiary. Multivariable Cox regression modeling assessed the impact of bupropion and other antidepressant medications on the risk of developing OAG with adjustment for sociodemographic characteristics of the enrollees along with medical and ocular comorbidities., Results: Of 638,481 eligible enrollees, 15,292 (2.4%) developed OAG. After adjustment for confounding factors including use of other antidepressant medication classes, each additional month of bupropion use was associated with a 0.6% reduced risk of OAG (HR = 0.994, (95% CI: 0.989-0.998), p = 0.007). Compared to nonusers, those with 24-48 months of bupropion use had a 21% reduced hazard (HR=0.79, (CI: 0.65-0.94), p = 0.0099) of OAG. This association did not differ among persons taking bupropion for depression or for other reasons (p-interaction = 0.82). There was no significant association between use of tricyclic antidepressants (HR = 1.000, (CI: 0.997-1.004), p = 0.95) or selective serotonin reuptake inhibitors (HR = 0.999, (CI: 0.997-1.001), p = 0.39) and development of OAG., Conclusion: These findings suggest bupropion use may be beneficial in reducing the risk of OAG. If prospective studies confirm the findings of this analysis, this may identify a novel therapeutic target for OAG.

The mechanisms underlying the progression of simple steatosis to steatohepatitis are yet to be elucidated. To identify the proteins involved in the development of liver tissue inflammation, we performed comparative proteomic analysis of non-alcoholic steatohepatitis (NASH). Mice fed a methionine and choline deficient diet (MCD) developed hepatic steatosis characterized by increased free fatty acid (FFA) and triglyceride levels as well as alpha-SMA. Two-dimensional proteomic analysis revealed that the change from the normal diet to the MCD diet affected the expressions of 50 proteins. The most-pronounced changes were observed in the expression of proteins involved in Met metabolism and oxidative stress, most of which were significantly downregulated in NASH model animals. Peroxiredoxin (Prx) is the most interesting among the modulated proteins identified in this study. In particular, cross-regulated Prx1 and Prx6 are likely to participate in cellular defense against the development of hepatitis. Thus, these Prx isoforms may be a useful new marker for early stage steatohepatitis. Moreover, curcumin treatment results in alleviation of the severity of hepatic inflammation in steatohepatitis. Notably, curcumin administration in MCD-fed mice dramatically reduced CYP2E1 as well as Prx1 expression, while upregulating Prx6 expression. These findings suggest that curcumin may have a protective role against MCD fed-induced oxidative stress.

Introduction: The purpose of this research is to evaluate the prospects for the use of 4-(trans-18F-fluoranylmethyl)-N-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-pyridin-2-ylcyclohexane-1-carboxamide (18F-Mefway) in comparison to 18F-trans-4-fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide (18F-FCWAY) for the quantification of 5-HT1A receptors in human subjects., Method: Five healthy male controls were included for two positron emission tomography (PET) studies: 18F-FCWAY PET after the pretreatment with 500 mg of disulfiram and two months later, 18F-Mefway PET without disulfiram. Regional time-activity curves (TACs) were extracted from nine cortical and subcortical regions in dynamic PET images. Using cerebellar cortex without vermis as reference tissue, in vivo kinetics for both radioligands were compared based on the distribution volume ratio (DVR) calculated by non-invasive Logan graphical analysis and area under the curve ratio of the TACs (AUC ratio)., Result: Although the pattern of regional uptakes in the 18F-Mefway PET was similar to that of the 18F-FCWAY PET (highest in the hippocampus and lowest in the cerebellar cortex), the amount of regional uptake in 18F-Mefway PET was almost half of that in 18F-FCWAY PET. The skull uptake in 18F-Mefway PET was only 25% of that in 18F-FCWAY PET with disulfiram pretreatment. The regional DVR values and AUC ratio values for 18F-Mefway were 17-40% lower than those of 18F-FCWAY. In contrast to a small overestimation of DVR values by AUC ratio values (< 10%) in 18F-FCWAY PET, the overestimation bias of AUC ratio values was much higher (up to 21%) in 18F-Mefway PET., Conclusion: As 18F-Mefway showed lower DVR values and greater overestimation bias of AUC ratio values, 18F-Mefway may appear less favorable than 18F-FCWAY. However, in contrast to 18F-FCWAY, the resistance to in vivo defluorination of 18F-Mefway obviates the need for the use of a defluorination inhibitor. Thus, 18F-Mefway may be a good candidate PET radioligand for 5-HT1A receptor imaging in human.

Recently, numerous efforts have been made to understand the neural mechanisms underlying cognitive regulation of emotion, such as cognitive reappraisal. Many studies have reported that cognitive control of emotion induces increases in neural activity of the control system, including the prefrontal cortex and the dorsal anterior cingulate cortex, and increases or decreases (depending upon the regulation goal) in neural activity of the appraisal system, including the amygdala and the insula. It has been hypothesized that information about regulation goals needs to be processed through interactions between the control and appraisal systems in order to support cognitive reappraisal. However, how this information is represented in the dynamics of cortical activity remains largely unknown. To address this, we investigated temporal changes in gamma band activity (35-55 Hz) in human electroencephalograms during a cognitive reappraisal task that was comprised of three reappraisal goals: to decease, maintain, or increase emotional responses modulated by affect-laden pictures. We examined how the characteristics of gamma oscillations, such as spectral power and large-scale phase synchronization, represented cognitive reappraisal goals. We found that left frontal gamma power decreased, was sustained, or increased when the participants suppressed, maintained, or amplified their emotions, respectively. This change in left frontal gamma power appeared during an interval of 1926 to 2453 ms after stimulus onset. We also found that the number of phase-synchronized pairs of gamma oscillations over the entire brain increased when participants regulated their emotions compared to when they maintained their emotions. These results suggest that left frontal gamma power may reflect cortical representation of emotional states modulated by cognitive reappraisal goals and gamma phase synchronization across whole brain regions may reflect emotional regulatory efforts to achieve these goals. Our study may provide the basis for an electroencephalogram-based neurofeedback system for the cognitive regulation of emotion.

Nasal polyposis is characterized by persistent inflammation and remodeling in sinonasal mucosa. Toll-like receptors (TLRs) play a role in the innate immune response to microbes in the sinonasal cavity. The aim of this study was to evaluate whether nasal polyp-derived fibroblasts (NPDFs) and organ-cultured nasal polyps can synthesize pro-inflammatory cytokines and matrix metalloproteinases (MMPs) after exposure to lipopolysaccharide (LPS), a TLR4 agonist. NPDFs and organ-cultured nasal polyps were isolated from nasal polyps of 8 patients and exposed to LPS. The mRNA and protein expression levels of TLRs, cytokines, and MMPs were determined using a gene expression microarray, real-time RT-PCR, western blot analysis, enzyme-linked immunosorbent assay, and immunofluorescence staining. The enzymatic activities of MMPs were analyzed using collagen or gelatin zymography. The protein expression level of MMP-1 increased in nasal polyp tissues compared to inferior turbinate tissues. LPS induced mRNA expression of TLR4, IL-6, IL-8, and MMP-1 and activated MAPK signaling in NPDFs. LPS promoted the release of interleukin (IL)-6 through extracellular signal-related kinase (ERK) and IL-8 through ERK and c-Jun N-terminal kinases (JNK). Production of IL-6 and IL-8 was induced by PI3K/Akt signaling in LPS-stimulated NPDFs. LPS increased the transcript and protein expression levels of MMP-1 and induced collagenase activity of MMP-1 via ERK and p38, but did not induce gelatinase activity of MMP-2 and MMP-9. LPS from Rhodobacter sphaeroides (LPS-RS) inhibited the stimulatory effects of LPS in NPDFs as well as in organ culture of nasal polyp. LPS triggers immune response via TLR 4 and activates MAPK and PI3K/Akt signaling pathway, which is involved in remodeling of nasal polyps.

Metabolic surgery has been shown to provide better glycemic control for type 2 diabetes than conventional therapies. Still, the outcomes of the surgery are variable, and prognostic markers reflecting the metabolic changes by the surgery are yet to be established. NMR-based plasma metabolomics followed by multivariate regression was used to test the correlation between the metabolomic profile at 7-days after surgery and glycated hemoglobin (HbA1c) levels at 3-months (and up to 12 months with less patients), and to identify the relevant markers. Metabolomic profiles at 7-days could differentiate the patients according to the HbA1c improvement status at 3-months. The HbA1c values were predicted based on the metabolomics profile with partial least square regression, and found to be correlated with the observed values. Metabolite analysis suggested that 3-Hydroxybutyrate (3-HB) and glucose contributes to this prediction, and the [3-HB]/[glucose] exhibited a modest to good correlation with the HbA1c level at 3-months. The prediction of 3-month HbA1c using 7-day metabolomic profile and the suggested new criterion [3-HB]/[glucose] could augment current prognostic modalities and help clinicians decide if drug therapy is necessary.

Background: This study investigated the association between statin use and herpes zoster (HZ) occurrence in a population-based case-control study., Methods: Study subjects were retrieved from the Taiwan Longitudinal Health Insurance Database 2000. This study included 47,359 cases with HZ and 142,077 controls. We performed conditional logistic regression analyses to calculate the odds ratio (OR) to present the association between HZ and having previously been prescribed statin., Results: We found that 13.0% of the sampled subjects had used statins, at 15.5% and 12.1% for cases and controls, respectively (p<0.001). A conditional logistic regression analysis suggested that the adjusted OR of being a statin user before the index date for cases was 1.28 (95% confidence interval (CI): 1.24∼1.32) compared to controls. Subjects aged 18∼44 years had the highest adjusted OR for prior statin use among cases compared to controls (OR: 1.69; 95% CI: 1.45∼1.92). Furthermore, we found that the ORs of being a regular and irregular statin user before the index date for cases were 1.32 (95% CI: 1.27∼1.38) and 1.23 (95% CI: 1.181.29), respectively, compared to controls., Conclusions: We concluded that prior statin use was associated with HZ occurrence.