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The process of skin aging is currently recognized as a disease, and extracellular vesicles (EVs) are being used to care for it. While various EVs are present in the market, there is a growing need for research on improving skin conditions through microbial and plant-derived EVs. Edelweiss is a medicinal plant and is currently an endangered species. Callus culture is a method used to protect rare medicinal plants, and recently, research on EVs using callus culture has been underway. In this study, the researchers used LED light to increase the productivity of Edelweiss EVs and confirmed that productivity was enhanced by LED exposure. Additionally, improvements in skin anti-aging indicators were observed. Notably, M-LED significantly elevated callus fresh and dry weight, with a DW/FW ratio of 4.11%, indicating enhanced proliferation. Furthermore, M-LED boosted secondary metabolite production, including a 20% increase in total flavonoids and phenolics. The study explores the influence of M-LED on EV production, revealing a 2.6-fold increase in concentration compared to darkness. This effect is consistent across different plant species (Centella asiatica, Panax ginseng), demonstrating the universality of the phenomenon. M-LED-treated EVs exhibit a concentration-dependent inhibition of reactive oxygen species (ROS) production, surpassing dark-cultured EVs. Extracellular melanin content analysis reveals M-LED-cultured EVs’ efficacy in reducing melanin production. Additionally, the expression of key skin proteins (FLG, AQP3, COL1) is significantly higher in fibroblasts treated with M-LED-cultured EVs. These results are expected to provide valuable insights into research on improving the productivity of plant-derived EVs and enhancing skin treatment using plant-derived EVs.

Background/Aims Efficient anti-fibrotic therapies are required for the treatment of liver cirrhosis. Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) and cyclooxygenase-2 (COX-2) inhibitors have been reported to have anti-fibrotic effects. Here, we investigated whether combined treatment with a statin and a COX-2 inhibitor has synergistic anti-fibrotic effects. Methods The effects of treatment strategies incorporating both simvastatin and a COX-2 inhibitor, NS-398, were investigated using an immortalized human hepatic stellate cell line (LX-2) and a hepatic fibrosis mouse model developed using thioacetamide (TAA) in drinking water. Cellular proliferation was investigated via 5-bromo-2-deoxyuridine uptake. Pro- and anti-apoptotic factors were investigated through Western blotting and real-time polymerase chain reaction analysis. Results The evaluation of the anti-proliferative effects on LX-2 cells showed that the observed effects were more pronounced with combination therapy than with single-drug therapy. Moreover, hepatic fibrosis and collagen deposition decreased significantly in TAA-treated mice in response to the combined treatment strategy. The mechanisms underlying the anti-fibrotic effects of the combination therapy were investigated. The effects of the combination therapy were correlated with increased expression levels of extracellular signal-regulated kinase 1/2 signaling molecules, upregulation of the Bax/Bcl-2 signaling pathway, inhibition of the transforming growth factor-β signaling pathway, and inhibition of tissue inhibitor of matrix metalloproteinases 1 and 2. Conclusions The combination of simvastatin and NS-398 resulted in a synergistic anti-fibrotic effect through multiple pathways. These findings offer a theoretical insight into the possible clinical application of this strategy for the treatment of advanced liver diseases with hepatic fibrosis.

Objectives Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by recurrent epistaxis, telangiectasia, and visceral arteriovenous malformations (AVMs). Activin A receptor-like type 1 (ACVRL1/ALK1) and endoglin (ENG) are the principal genes whose mutations cause HHT. No multicenter study has yet investigated correlations between genetic variations and clinical outcomes in Korean HHT patients. Methods Seventy-two members from 40 families suspected to have HHT based on symptoms were genetically screened for pathogenic variants of ACVRL1 and ENG. Patients with genetically diagnosed HHT were also evaluated. Results In the HHT genetic screening, 42 patients from 24 of the 40 families had genetic variants that met the pathogenic criteria (pathogenic very strong, pathogenic strong, pathogenic moderate, or pathogenic supporting) based on the American College of Medical Genetics and Genomics Standards and Guidelines for either ENG or ACVRL1: 26 from 12 families (50%) for ENG, and 16 from 12 families (50%) for ACVRL1. Diagnostic screening of 42 genetically positive HHT patients based on the Curaçao criteria revealed that 24 patients (57%) were classified as having definite HHT, 17 (41%) as having probable HHT, and 1 (2%) as unlikely to have HHT. Epistaxis was the most common clinical presentation (38/42, 90%), followed by visceral AVMs (24/42, 57%) and telangiectasia (21/42, 50%). Five patients (12%) did not have a family history of HHT clinical symptoms. Conclusion Only approximately half of patients with ACVRL1 or ENG genetic variants could be clinically diagnosed as having definite HHT, suggesting that genetic screening is important to confirm the diagnosis.

A common complication of cisplatin-based chemotherapy is hearing loss. Here, Park et al. show that glutathione transferase α4 (GSTA4) contributes to reducing cisplatin toxicity in the inner ear of female mice by removing 4-hydroxynonenal (4-HNE).

Although ulcerative colitis (UC) is confined to colonic and rectal mucosa in a continuous fashion, recent studies have also demonstrated the involvement of upper gastrointestinal tract as diagnostic endoscopy becomes more available and technically advanced. The pathogenesis of UC is not well established yet. It might be associated with an inappropriate response of host mucosal immune system to gut microflora. Although continuous and symmetric distribution of mucosal inflammation from rectum to colon is a typical pattern of UC, clinical feature and course of atypically distributed lesions in UC might also help us understand the pathogenesis of UC. Herein, we report a case of duodenal involvement of UC which successfully remitted after infliximab therapy. Endoscopic and pathologic findings before and after administration of anti-tumor necrosis factor suggest that the pathogenesis of upper gastrointestinal involvement of UC may be similar to that of colon involvement.

Background: Parkinson's disease (PD) is a common neurodegenerative disorder, characterized by a clinical symptomatology involving both motor and non-motor symptoms. Motor complications associated with long-term dopaminergic treatment include motor fluctuations and levodopa-induced dyskinesia (LID), which may have a major impact on the quality of life. The clinical features and onset time of motor complications in the disease course are heterogeneous, and the etiology remains unknown.Objective: We aimed to identify genomic variants associated with the development of motor fluctuations and LID at 5 years after the onset of PD.Methods: Genomic data were obtained using Affymetrix Axiom KORV1.1 array, including an imputation genome-wide association study (GWAS) grid and other GWAS loci; functional variants of the non-synonymous exome; pharmacogenetic variants; variants in genes involved in absorption, distribution, metabolism, and excretion of drugs; and expression quantitative trait loci in 741 patients with PD.Results:FAM129B single-nucleotide polymorphism (SNP) rs10760490 was nominally associated with the occurrence of motor fluctuations at 5 years after the onset of PD [odds ratio (OR) = 2.9, 95% confidence interval (CI) = 1.8–4.8, P = 6.5 × 10−6]. GALNT14 SNP rs144125291 was significantly associated with the occurrence of LID (OR = 5.5, 95% CI = 2.9–10.3, P = 7.88 × 10−9) and was still significant after Bonferroni correction. Several other genetic variants were associated with the occurrence of motor fluctuations or LID, but the associations were not significant after Bonferroni correction.Conclusion: This study identified new loci associated with the occurrence of motor fluctuations and LID at 5 years after the onset of PD. However, further studies are needed to confirm our findings.

Objective To replace camera-based three-dimensional motion analyzers which are widely used to analyze body movements and gait but are also costly and require a large dedicated space, this study evaluates the validity and reliability of inertial measurement unit (IMU)-based systems by analyzing their spatio-temporal and kinematic measurement parameters. Methods The investigation was conducted in three separate hospitals with three healthy participants. IMUs were attached to the abdomen as well as the thigh, shank, and foot of both legs of each participant. Each participant then completed a 10-m gait course 10 times. During each gait cycle, the hips, knees, and ankle joints were observed from the sagittal, frontal, and transverse planes. The experiments were conducted with both a camerabased system and an IMU-based system. The measured gait analysis data were evaluated for validity and reliability using root mean square error (RMSE) and intraclass correlation coefficient (ICC) analyses. Results The differences between the RMSE values of the two systems determined through kinematic parameters ranged from a minimum of 1.83 to a maximum of 3.98 with a tolerance close to 1%. The results of this study also confirmed the reliability of the IMU-based system, and all of the variables showed a statistically high ICC. Conclusion These results confirmed that IMU-based systems can reliably replace camera-based systems for clinical body motion and gait analyses.

Background: The geographical origin of Panax ginseng Meyer, a valuable medicinal plant, is important to both ginseng producers and consumers in the context of economic profit and human health benefits. We, therefore, aimed to discriminate between the cultivation regions of ginseng using the stable isotope ratios of C, N, O, and S, which are abundant bioelements in living organisms. Methods: Six Korean ginseng cultivars (3-yr-old roots) were collected from five different regions in Korea. The C, N, O, and S stable isotope ratios in ginseng roots were measured by isotope ratio mass spectrometry, and then these isotope ratio profiles were statistically analyzed using chemometrics. Results: The various isotope ratios found in P. ginseng roots were significantly influenced by region, cultivar, and the interactions between these two factors (p ≤ 0.001). The variation in δ15N and δ13C in ginseng roots was significant for discriminating between different ginseng cultivation regions, and δ18O and δ34S were also affected by both altitude and proximity to coastal areas. Chemometric model results tested in this study provided discrimination between the majority of different cultivation regions. Based on the external validation, this chemometric model also showed good model performance (R2 = 0.853 and Q2 = 0.738). Conclusion: Our case study elucidates the variation of C, N, O, and S stable isotope ratios in ginseng root depending on cultivation region. Hence, the analysis of stable isotope ratios is a suitable tool for discrimination between the regional origins of ginseng samples from Korea, with potential application to other countries. Keywords: geographical origin, Panax ginseng, PCA, PLS-DA, stable isotope ratio

Background Mesenchymal stem cells (MSCs) attenuate injury in various lung injury models through paracrine effects. We hypothesized that intratracheal transplantation of allogenic MSCs could attenuate lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice, mediated by anti-inflammatory responses. Methods Six-week-old male mice were randomized to either the control or the ALI group. ALI was induced by intratracheal LPS instillation. Four hours after LPS instillation, MSCs or phosphate-buffered saline was randomly intratracheally administered. Neutrophil count and protein concentration in bronchoalveolar lavage fluid (BALF); lung histology; levels of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and macrophage inflammatory protein-2; and the expression of proliferation cell nuclear antigen (PCNA), caspase-3, and caspase-9 were evaluated at 48 hours after injury. Results Treatment with MSCs attenuated lung injury in ALI mice by decreasing protein level and neutrophil recruitment into the BALF and improving the histologic change. MSCs also decreased the protein levels of proinflammatory cytokines including IL-1β, IL-6, and TNF-α, but had little effect on the protein expression of PCNA, caspase-3, and caspase-9. Conclusions Intratracheal injection of bone marrow-derived allogenic MSCs attenuates LPS-induced ALI via immunomodulatory effects.

Optimizing flowering time in crop plants is critical for maximizing yield and quality under target environments. While there is a wide range of heading date variation in Korean rice cultivars, the underlying gene mechanisms are unclear. Here, we sequenced the protein coding regions of Hd1, the major rice heading date gene, from 293 Korean rice cultivars and investigated the associations between Hd1 allele types and major agronomic traits under four different environments. There were four functional Hd1 and five nonfunctional hd1 alleles distributed among the 293 Korean rice cultivars. The effects of the Hd1 allele types were highly significant for days to heading in all four environments, explaining 51.4–65.8% of the phenotypic variation. On average, cultivars carrying nonfunctional hd1 headed 13.7 days earlier than those carrying functional Hd1. While the Hd1 allele types exhibited highly significant effects on culm length and protein content under all four environments, the differences between cultivars carrying Hd1 and hd1 were minimal. The effects of the Hd1 allele types on amylose content were significant in only one of the four environments. Our results provide useful information for fine-tuning rice heading dates by utilizing different Hd1 alleles in rice breeding programs.

Angelica polymorpha Maxim. (APM) is used in traditional medicine to treat chronic gastritis, rheumatic pain, and duodenal bulbar ulcers. However, it is not known whether APM has epidermis-associated biological activities. Here, we investigated the effects of APM flower absolute (APMFAb) on responses associated with skin wound healing and whitening using epidermal cells. APMFAb was obtained by solvent extraction and its composition was analyzed by GC/MS. Water-soluble tetrazolium salt, 5-bromo-2′-deoxyuridine incorporation, Boyden chamber, sprouting, and enzyme-linked immunosorbent assays and immunoblotting were used to examine the effects of APMFAb on HaCaT keratinocytes and B16BL6 melanoma cells. APMFAb contained five compounds and induced keratinocyte migration, proliferation, and type IV collagen synthesis. APMFAb also induced the phosphorylations of ERK1/2, JNK, p38 mitogen-activated protein kinase, and AKT in keratinocytes. In addition, APMFAb decreased serum-induced B16BL6 cell proliferation and inhibited tyrosinase expression, melanin contents, and microphthalmia-associated transcription factor expression in α-melanocyte-stimulating hormone-stimulated B16BL6 cells. These findings demonstrate that APMFAb has beneficial effects on skin wound healing by promoting the proliferation, migration, and collagen synthesis of keratinocytes and on skin whitening by inhibiting melanin synthesis in melanoma cells. Therefore, we suggest that APMFAb has potential use as a wound healing and skin whitening agent.

Introduction: The combination of a fluoropyrimidine [5-fluorouracil (5-FU), capecitabine, or S-1] with a platinum analog (cisplatin or oxaliplatin) is the most widely accepted first-line chemotherapy regimen for metastatic or recurrent advanced gastric cancer (AGC), based on the results of clinical trials. However, there is little evidence to guide chemotherapy for elderly patients with AGC because of under-representation of this age group in clinical trials. Thus, the aim of this study is to determine the optimal chemotherapy regimen for elderly patients with AGC by comparing the efficacies and safeties of combination therapy versus monotherapy as first-line chemotherapy. Methods: This study is a randomized, controlled, multicenter, phase III trial. A total of 246 elderly patients (≥70 years old) with metastatic or recurrent AGC who have not received previous palliative chemotherapy will be randomly allocated to a combination therapy group or a monotherapy group. Patients randomized to the combination therapy group will receive fluoropyrimidine plus platinum combination chemotherapy (capecitabine/cisplatin, S-1/cisplatin, capecitabine/oxaliplatin, or 5-FU/oxaliplatin), and those randomized to the monotherapy group will receive fluoropyrimidine monotherapy (capecitabine, S-1, or 5-FU). The primary outcome is the overall survival of patients in each treatment group. The secondary outcomes include progression-free survival, response rate, quality of life, and safety. Discussion: We are conducting this pragmatic trial to determine whether elderly patients with AGC will obtain the same benefit from chemotherapy as younger patients. We expect that this study will help guide decision-making for the optimal treatment of elderly patients with AGC.

Abstract Background Composite intestinal adenoma-microcarcinoid (CIAM) is a rare colorectal lesion that mostly comprises a conventional adenomatous component with a minute proportion of neuroendocrine (NE) component. Although microcarcinoids are well-recognized in the setting of chronic inflammatory disorders of the gastrointestinal tract, large intestinal microcarcinoids associated with intestinal adenoma are exceedingly rare and their clinicopathologic characteristics are yet to be elucidated. This study was performed to clarify their clinicopathologic characteristics and to review the relevant literature. Methods In total, 24 cases of CIAM in which tumors were excised endoscopically (n = 22) or surgically (n = 2) were retrieved from the Department of Pathology, Daehang Hospital. We analyzed their clinicopathologic characteristics and performed immunohistochemical staining for NE markers to determine their endocrine nature. Results CIAM usually developed in middle-aged and elderly patients, with a mean age of 62.0 years (range, 44–81 years). Thirteen patients were men and 11 were women, indicating a nearly equal sex ratio. Unlike classic carcinoid tumors, CIAMs occurred mostly in the colon (83.3% of cases), particularly in the proximal colon. Histologically, the microcarcinoid component consisted of low-grade NE cells arranged in small nests, glands or cords interspersed with glandular elements or less frequently resembled squamous morules. There was no expansile nodular or organoid growth pattern, which is typical of carcinoid tumors. The microcarcinoids were 1–20 mm in size (mean size, 4.7 mm) and were mostly situated in the basal lamina propria with no submucosal layer involvement; none showed desmoplastic reaction or increased proliferative activity. Follow-up data (mean, 23.1 months) were available for 18 patients; all patients are alive and well. Conclusions To the best of our knowledge, ours is the largest series of patients with CIAM in the English-language literature. Microcarcinoids found in CIAMs appear to show favorable clinical outcomes regardless of their size, likely due to the absence of submucosal extension and/or increased proliferative activity. We recommend avoiding additional radical surgeries in patients who have endoscopically undergone complete CIAM excision unless they exhibit ominous histologic features such as submucosal extension or increased proliferative activity.

Objective Gait disturbance is the main factor contributing to a negative impact on quality of life in patients with Huntington’s disease (HD). Understanding gait features in patients with HD is essential for planning a successful gait strategy. The aim of this study was to investigate temporospatial gait parameters in patients with HD compared with healthy controls. Methods We investigated 7 patients with HD. Diagnosis was confirmed by genetic analysis, and patients were evaluated with the Unified Huntington’s Disease Rating Scale (UHDRS). Gait features were assessed with a gait analyzer. We compared the results of patients with HD to those of 7 age- and sex-matched normal controls. Results Step length and stride length were decreased and base of support was increased in the HD group compared to the control group. In addition, coefficients of variability for step and stride length were increased in the HD group. The HD group showed slower walking velocity, an increased stance/swing phase in the gait cycle and a decreased proportion of single support time compared to the control group. Cadence did not differ significantly between groups. Among the UHDRS subscores, total motor score and total behavior score were positively correlated with step length, and total behavior score was positively correlated with walking velocity in patients with HD. Conclusion Increased variability in step and stride length, slower walking velocity, increased stance phase, and decreased swing phase and single support time with preserved cadence suggest that HD gait patterns are slow, ataxic and ineffective. This study suggests that quantitative gait analysis is needed to assess gait problems in HD.

Objective To compare the therapeutic and adverse effects of globus pallidus interna (GPi) and subthalamic nucleus (STN) deep brain stimulation (DBS) for the treatment of advanced Parkinson’s disease (PD). Methods We retrospectively analyzed the clinical data of patients with PD who underwent GPi (n = 14) or STN (n = 28) DBS surgery between April 2002 and May 2014. The subjects were matched for age at surgery and disease duration. The Unified Parkinson’s Disease Rating Scale (UPDRS) scores and levodopa equivalent dose (LED) at baseline and 12 months after surgery were used to assess the therapeutic effects of DBS. Adverse effects were also compared between the two groups. Results At 12 months, the mean changes in the UPDRS total and part I–IV scores did not differ significantly between the two groups. However, the subscores for gait disturbance/postural instability and dyskinesia were significantly more improved after GPi DBS than those after STN DBS (p = 0.024 and 0.016, respectively). The LED was significantly more reduced in patients after STN DBS than that after GPi DBS (p = 0.004). Serious adverse effects did not differ between the two groups (p = 0.697). Conclusion The patients with PD showed greater improvement in gait disturbance/postural instability and dyskinesia after GPi DBS compared with those after STN DBS, although the patients had a greater reduction in LED after STN DBS. These results may provide useful information for optimal target selection for DBS in PD.

Objective Autonomic symptoms are commonly observed in patients with Parkinson’s disease (PD) and often limit the activities of daily living. The Scale for Outcomes in Parkinson’s disease-Autonomic (SCOPA-AUT) was developed to evaluate and quantify autonomic symptoms in PD. The goal of this study was to translate the original SCOPA-AUT, which was written in English, into Korean and to evaluate its reliability and validity for Korean PD patients. Methods For the translation, the following processes were performed: forward translation, backward translation, expert review, pretest of the pre-final version and development of the final Korean version of SCOPA-AUT (K-SCOPA-AUT). In total, 127 patients with PD from 31 movement disorder clinics of university-affiliated hospitals in Korea were enrolled in this study. All patients were assessed using the K-SCOPA-AUT and other motor, non-motor, and quality of life scores. Test-retest reliability for the K-SCOPA-AUT was assessed over a time interval of 10−14 days. Results The internal consistency and reliability of the K-SCOPA-AUT was 0.727 as measured by the mean Cronbach’s α-coefficient. The test-retest correlation reliability was 0.859 by the Guttman split-half coefficient. The total K-SCOPA-AUT score showed a positive correlation with other non-motor symptoms [the Korean version of non-motor symptom scale (K-NMSS)], activities of daily living (Unified Parkinson’s Disease Rating Scale part II) and quality of life [the Korean version of Parkinson’s Disease Quality of Life 39 (K-PDQ39)]. Conclusion The K-SCOPA-AUT had good reliability and validity for the assessment of autonomic dysfunction in Korean PD patients. Autonomic symptom severities were associated with many other motor and non-motor impairments and influenced quality of life.

Usher’s syndrome is the most common combined blindness–deafness disorder with USH1B, caused by mutations in MYO7A, resulting in the most severe phenotype. The existence of numerous, naturally occurring shaker1 mice harboring variable MYO7A mutations on different genetic backgrounds has complicated the characterization of MYO7A knockout (KO) and heterozygote mice. We generated a novel MYO7A KO mouse (Myo7a–/–) that is easily genotyped, maintained, and confirmed to be null for MYO7A in both the eye and inner ear. Like USH1B patients, Myo7a–/– mice are profoundly deaf, and display near complete loss of inner and outer cochlear hair cells (HCs). No gross structural changes were observed in vestibular HCs. Myo7a–/– mice exhibited modest declines in retinal function but, unlike patients, no loss of retinal structure. We attribute the latter to differential expression of MYO7A in mouse vs. primate retina. Interestingly, heterozygous Myo7a+/– mice had reduced numbers of cochlear HCs and concomitant reductions in auditory function relative to Myo7a+/+ controls. Notably, this is the first report that loss of a single Myo7a allele significantly alters auditory structure and function and suggests that audiological characterization of USH1B carriers is warranted. Maintenance of vestibular HCs in Myo7a–/– mice suggests that gene replacement could be used to correct the vestibular dysfunction in USH1B patients. While Myo7a–/– mice do not exhibit sufficiently robust retinal phenotypes to be used as a therapeutic outcome measure, they can be used to assess expression of vectored MYO7A on a null background and generate valuable pre-clinical data toward the treatment of USH1B.

PurposeIntensive care unit (ICU)-related mortality for lung cancer is ranked highest among the solid tumors and little information exists on the role of intensivists on clinical outcomes. This study aimed to elucidate the intensivist's contribution toward clinical outcomes.Materials and methodsData of advanced lung cancer patients, including stage IIIB or IV non-small cell lung cancer and extensive-stage small cell lung cancer, admitted to the ICU from 2005 to 2016 were analyzed. Multivariate logistic regression was performed to determine variables associated with ICU and in-hospital mortality. Autoregressive integrated moving average (ARIMA) for time-series was used to assess the intensivist's impact.ResultsOf 264 patients, 85 (32.2%) were admitted to the ICU before and 179 (67.8%) after organized intensive care introduction in 2011. Before and after 2011, the changes observed were as follows: ICU mortality rate, 43.5% to 40.2%, respectively (p = 0.610); hospital mortality rate, 82.4% to 65. 9% (p = 0.006). The duration of ICU and hospital stay decreased after 2011 (14.5±16.5 vs. 8.3 ± 8.6, p < 0.001; 36.6 ± 37.2 vs. 22.0 ± 19.6, p < 0.001). On multivariate analysis, admission after 2011 was independently associated with decreased hospital mortality (Odds ratio 0.42, 95% confidence interval 0.21-0.77, p = 0.006). In ARIMA models, intensivist involvement was associated with significantly reduced hospital mortality. (Estimate -17.95, standard error 5.31, p = 0.001).ConclusionIn patients with advanced lung cancer, organized intensive care could contribute to improved clinical outcomes.

Glutathione reductase (GSR), a key member of the glutathione antioxidant defense system, converts oxidized glutathione (GSSG) to reduced glutathione (GSH) and maintains the intracellular glutathione redox state to protect the cells from oxidative damage. Previous reports have shown that Gsr deficiency results in defects in host defense against bacterial infection, while diquat induces renal injury in Gsr hypomorphic mice. In flies, overexpression of GSR extended lifespan under hyperoxia. In the current study, we investigated the roles of GSR in cochlear antioxidant defense using Gsr homozygous knockout mice that were backcrossed onto the CBA/CaJ mouse strain, a normal-hearing strain that does not carry a specific Cdh23 mutation that causes progressive hair cell degeneration and early onset of hearing loss. Gsr-/- mice displayed a significant decrease in GSR activity and GSH/GSSG ratios in the cytosol of the inner ears. However, Gsr deficiency did not affect ABR (auditory brainstem response) hearing thresholds, wave I amplitudes or wave I latencies in young mice. No histological abnormalities were observed in the cochlea of Gsr-/- mice. Furthermore, there were no differences in the activities of cytosolic glutathione-related enzymes, including glutathione peroxidase and glutamate-cysteine ligase, or the levels of oxidative damage markers in the inner ears between WT and Gsr-/- mice. In contrast, Gsr deficiency resulted in increased activities of cytosolic thioredoxin and thioredoxin reductase in the inner ears. Therefore, under normal physiological conditions, GSR is not essential for the maintenance of antioxidant defenses in mouse cochlea. Given that the thioredoxin system is known to reduce GSSG to GSH in multiple species, our findings suggest that the thioredoxin system can support GSSG reduction in the mouse peripheral auditory system.

Mitochondrial DNA (mtDNA) mutations are thought to have a causative role in age-related pathologies. We have shown previously that mitochondrial mutator mice (PolgD257A/D257A), harboring a proofreading-deficient version of the mtDNA polymerase gamma (POLG), accumulate mtDNA mutations in multiple tissues and display several features of accelerated aging. Calorie restriction (CR) is known to delay the onset of age-related diseases and to extend the lifespan of a variety of species, including rodents. In the current study we investigated the effects of CR on the lifespan and healthspan of mitochondrial mutator mice. Long-term CR did not increase the median or maximum lifespan of PolgD257A/D257A mice. Furthermore, CR did not reduce mtDNA deletions in the heart and muscle, accelerated sarcopenia, testicular atrophy, nor improve the alterations in cardiac parameters that are present in aged mitochondrial mutator mice. Therefore, our findings suggest that accumulation of mtDNA mutations may interfere with the beneficial action of CR in aging retardation.

Multiple system atrophy (MSA) is a sporadic, adult-onset disease characterized by progressive degeneration of nervous systems including cerebellar, pyramidal, extrapyramidal, and autonomic system. Although a few recent studies reported that cognitive impairments could occur in patients with MSA, prominent dementia with progressive decline is not a typical clinical manifestation of MSA. In particular, dementia with MSA-cerebellar type is very rare. We have experienced a patient with 2-year history of severe cognitive impairment, who was finally diagnosed as MSA-cerebellar type.

It was identified as a sharp eyespot (Rhizoctonia cerealis) that the isolates from abnormal symptoms in wheat that showed yellowing leaves, necrotic spot on stem base and dead tillers. These isolates have slower growth property and fewer mycelia than Rhizoctonia solani AG-1(1A) (KACC 40106). They showed binuclear cell, same media cultural and DNA characteristics to R. cerealis. They caused same symptoms on leaves and stem base appeared in artificial inoculation test, comparing to diseased wheat fields and also affect to maturing of kernels. They have optimal growth temperature and acidity on the artificial media as 20~25℃ and pH 5~7, respectively. In the investigation of varietal resistance of Korean winter cereal crops to sharp eyespot, there was no resistant in wheat cultivars that all materials infected over 20% diseased ratio. 12 cultivars including ``Anbaekmil``, however, considered to moderate resistance with 20 to 30% infection ratio. The others crops using in feeding, whole crop barley, oat, rye and triticale were resistant below 15% diseased degree except the rye that showed over 50% infection rate. It was the first evaluation to sharp eyespot resistance for the Korean feeding crop cultivars. Most tested Korean barley cultivars for malting and food were moderate and susceptible to the sharp eyespot. Only 3 hulled barley, ``Tapgolbori``, ``Albori`` and ``Seodunchalbori``, showed resistance with less than 10% diseased ratio. All tested naked barley cultivars showed susceptible response to the disease.

The phenolic compounds (PC) of soybeans (Glycine max (L.) Merrill) varies mainly based on factors like genetics, the environment, and also the food processing techniques used. The effect of storage time and temperature on the phenolic acids and isoflavones composition of raw soybean flour (RWSF) and roasted soybean flour (RSF) were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Based on the analysis results, 56 PC and free amino acids were detected in the RWSF and RSF. The total phenolic content (TPC) was 301.59 µg/g in the control RWSF and 257.47 µg/g in the control RSF. In the analysis, eight types of phenolic acids and one flavonoid group belonging to the isoflavone group were detected. When comparing storage conditions of RWSF, 24 and 48 weeks of storage showed higher concentration of phenolic acids. In RSF, the percentage of total acetyl glucosides was high, but the outcome was reversed after 2 weeks. This study had identified that the composition of PC in RWSF and RSF were affected when the storage temperature increased and the storage time lengthened.

BackgroundRecently, non-motor symptoms of Parkinson's disease (PD) have been considered crucial factors in determining a patient's quality of life and have been proposed as the predominant features of the premotor phase. Researchers have investigated the relationship between non-motor symptoms and the motor laterality; however, this relationship remains disputed. This study investigated the neural connectivity correlates of non-motor and motor symptoms of PD with respect to motor laterality.MethodsEight-seven patients with PD were recruited and classified into left-more-affected PD (n = 44) and right-more affected PD (n = 37) based on their MDS-UPDRS (Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale) motor examination scores. The patients underwent MRI scanning, which included resting fMRI. Brain regions were labeled as ipsilateral and contralateral to the more-affected body side. Correlation analysis between the functional connectivity across brain regions and the scores of various symptoms was performed to identify the neural connectivity correlates of each symptom.ResultsThe resting functional connectivity centered on the ipsilateral inferior orbito-frontal area was negatively correlated with the severity of non-motor symptoms, and the connectivity of the contralateral inferior parietal area was positively correlated with the severity of motor symptoms (p < 0.001, |r| > 0.3).ConclusionsThese results suggest that the inferior orbito-frontal area may play a crucial role in non-motor dysfunctions, and that the connectivity information may be utilized as a neuroimaging biomarker for the early diagnosis of PD.

Mefloquine is widely used for the treatment of malaria. However, this drug is known to induce neurological side effects including depression, anxiety, balance disorder, and sensorineural hearing loss. Yet, there is currently no treatment for these side effects.In this study, we show that the coenzyme NAD(+), known to play a critical role in maintaining the appropriate cellular redox environment, protects cochlear axons and sensory hair cells from mefloquine-induced degeneration in cultured rat cochleae. Mefloquine alone destroyed hair cells and nerve fiber axons in rat cochlear organotypics cultures in a dose-dependent manner, while treatment with NAD(+) protected axons and hair cells from mefloquine-induced degeneration. Furthermore, cochlear organs treated with mefloquine showed increased oxidative stress marker levels, including superoxide and protein carbonyl, and increased apoptosis marker levels, including TUNEL-positive nuclei and caspases-3. Treatment with NAD(+) reduced the levels of these oxidative stress and apoptosis markers.Taken together, our findings suggest that that mefloquine disrupts the cellular redox environment and induces oxidative stress in cochlear hair cells and nerve fibers leading to caspases-3-mediated apoptosis of these structures. Exogenous NAD(+) suppresses mefloquine-induced oxidative stress and prevents the degeneration of cochlear axons and sensory hair cells caused by mefloquine treatment.

Chondrosarcoma (CHS) is a malignant cartilage-forming tumor and usually occurs within the medullary canal of long bones and pelvic bones. Based on the morphologic feature alone, a correct diangosis of CHS may be difficult, Therefore, correlation of radiological and clinicopathological features is mandatory in the diagnosis of CHS. The prognosis of CHS is closely related to histologic grading, however, histologic grading may be subjective with high inter-observer variability. In this paper, we present histologic grading system and clinicopathological and radiological findings of conventional CHS. Subtypes of CHSs, such as dedifferentiated, mesenchymal, and clear cell CHSs are also presented. In addition, we introduce updated cytogenetic and molecular genetic findings to expand our understanding of CHS biology. New markers of cell differentiation, proliferation, and cell signaling might offer important therapeutic and prognostic information in near future.

The aquaporins (AQP) are water channel proteins playing a major role in transcellular and transepithelial water movement. Recently, the role of AQPs in human carcinogenesis has become an area of great interest. Here, by immunohistochemistry (IHC), we have found an expression of AQP5 protein in 35.3% (IHC-score: > or = 1, 144/408) of the resected NSCLC tissue samples. Cases with AQP5-positive status (IHC-score: > or = 2) displayed a higher rate of tumor recurrence than negative ones in NSCLC (54.7% vs. 35.1%, p = 0.005) and worse disease-free survival (p = 0.033; OR = 1.52; 95%CI: 1.04-2.23). Further in vitro invasion assay using BEAS-2B and NIH3T3 cells stably transfected with overexpression constructs for full length wild-type AQP5 (AQP5) and its two mutants, N185D which blocks membrane trafficking and S156A which blocks phosphorylation on Ser156, showed that AQP5 induced cell invasions while both mutants did not. In BEAS-2B cells, the expression of AQP5 caused a spindle-like and fibroblastic morphologic change and losses of cell-cell contacts and cell polarity. Only cells with AQP5, not either of two mutants, exhibited a loss of epithelial cell markers and a gain of mesenchymal cell markers. In a human SH3-domains protein array, cellular extracts from BEAS-2B with AQP5 showed a robust binding activity to SH3-domains of the c-Src, Lyn, and Grap2 C-terminal. Furthermore, in immunoprecipitation assay, activated c-Src, phosphorylated on Tyr416, showed a stronger binding activity to cellular extracts from BEAS-2B with AQP5 compared with N185D or S156A mutant. Fluorescence in situ hybridization (FISH) analysis failed to show evidence of genomic amplification, suggesting AQP5 expression as a secondary event. Based on these clinical and molecular observations, we conclude that AQP5, through its phosphorylation on Ser156 and subsequent interaction with c-Src, plays an important role in NSCLC invasion and, therefore, may provide a unique opportunity for developing a novel therapeutic target as well as a prognostic marker in NSCLC.

Purpose This study evaluated whether combination therapy is more effective than monotherapy in elderly patients with metastatic or recurrent gastric cancer (MRGC) as first-line chemotherapy. Materials and Methods Elderly (≥ 70 years) chemo-naïve patients with MRGC were allocated to receive either combination therapy (group A: 5-fluorouracil [5-FU]/oxaliplatin, capecitabine/oxaliplatin, capecitabine/cisplatin, or S-1/cisplatin) or monotherapy (group B: 5-FU, capecitabine, or S-1). In group A, starting doses were 80% of standard doses, and they could be escalated to 100% at the discretion of the investigator. Primary endpoint was to confirm superior overall survival (OS) of combination therapy vs. monotherapy. Results After 111 of the planned 238 patients were randomized, enrollment was terminated due to poor accrual. In the full-analysis population (group A [n=53] and group B [n=51]), median OS of combination therapy vs. monotherapy was 11.5 vs. 7.5 months (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.56 to 1.30; p=0.231). Median progression-free survival (PFS) was 5.6 vs. 3.7 months (HR, 0.53; 95% CI, 0.34 to 0.83; p=0.005). In subgroup analyses, patients aged 70-74 years tended to have superior OS with combination therapy (15.9 vs. 7.2 months, p=0.056). Treatment-related adverse events (TRAEs) occurred more frequently in group A vs. group B. However, among severe TRAEs (≥ grade 3), there were no TRAEs with a frequency difference of > 5%. Conclusion Combination therapy was associated with numerically improved OS, although statistically insignificant, and a significant PFS benefit compared with monotherapy. Although combination therapy showed more frequent TRAEs, there was no difference in the frequency of severe TRAEs. [ABSTRACT FROM AUTHOR]