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Background and Objectives Vocal fold (VF) scar is known to be the most common cause of dysphonia after laryngeal microsurgery (LMS). Steroids reduce postoperative scar formation by inhibiting inflammation and collagen deposition. However, the clinical evidence of whether steroids are helpful in reducing VF scar formation after LMS is still lacking. The purpose of this study is to determine whether intralesional VF steroid injection after LMS helps to reduce postoperative scar formation and voice quality.Materials and Method This study was conducted on 80 patients who underwent LMS for VF polyp, Reinke’s edema, and leukoplakia. Among them, 40 patients who underwent VF steroid injection after LMS were set as the injection group, and patients who had similar sex, age, and lesion size and who underwent LMS alone were set as the control group. In each group, stroboscopy, multi-dimensional voice program, Aerophone II, and voice handicap index (VHI) were performed before and 1 month after surgery, and the results were statistically analyzed.Results There were no statistically significant differences in the distribution of sex, age, symptom duration, occupation and smoking status between each group. Both groups consisted of VF polyp (n=21), Reinke’s edema (n=11), and leukoplakia (n=9). On stroboscopy, the lesion disappeared after surgery, and the amplitude and mucosal wave were symmetrical on both sides of the VFs in all patients. Acoustic parameters and VHI significantly improved after surgery in all patients. However, there was no significant difference between the injection and control group in most of the results.Conclusion There was no significant difference in the results of stroboscopy, acoustic, aerodynamic, and subjective evaluation before and after surgery in the injection group and the control group.

Systemic lupus erythematosus(SLE) is a multisystemic disorder of autoimmune etiology. SLE can occur commonly in young women, and the early symptoms include fever, myalgia, arthralgia, weight loss, lymphadenopathy and these nonspecific symptoms develop into skin rash, splenomegaly, serositis and encephalopathy. Diagnosis of SLE requires clinical and serologic criteria, and treatment choices are hydroxyquinolone and NSAIDs for mild disease, corticosteroids and immunosuppressant for severe disease.In lupus patient, the prevalence of lymphadenopathy is 12~59%. Although lymphadenopathy is common finding in SLE, it is hard to distinguish in early phase of SLE.A 38-year-old woman visited our hospital for cervical lymphadenopathy with polyarthritis and malaise. Multiple cervical lymph nodes enlargement was found on Neck CT, and serologic laboratory test including ANA, antiphospholipid antibody, and anti-dsDNA was positive. For excluding lymphoma, PET-CT and excisional biopsy were performed. The patient finally diagnosed with SLE, and got regular follow-up without complication.

A tree model with low time complexity can support the application of artificial intelligence to industrial systems. Variable selection based tree learning algorithms are more time efficient than existing Classification and Regression Tree (CART) algorithms. To our best knowledge, there is no attempt to deal with categorical input variable in variable selection based multi-output tree learning. Also, in the case of multi-output regression tree, a conventional variable selection based algorithm is not suitable to large datasets. We propose a mutual information-based multi-output tree learning algorithm that consists of variable selection and split optimization. The proposed method discretizes each variable based on k-means into 2–4 clusters and selects the variable for splitting based on the discretized variables using mutual information. This variable selection component has relatively low time complexity and can be applied regardless of output dimension and types. The proposed split optimization component is more efficient than an exhaustive search. The performance of the proposed tree learning algorithm is similar to or better than that of a multi-output version of CART algorithm on a specific dataset. In addition, with a large dataset, the time complexity of the proposed algorithm is significantly reduced compared to a CART algorithm.

The purpose of this study was to search for the methods that can contribute to be done the systematic the health education curriculum in the educational field by analyzing the core competencies, the change of characteristics and goal, the change of organization of contents, and academic achievement level of health education in the health education curriculum that was published in revised education curriculum in 2015. For this reason, this study focused on the ways how the health education curriculum can be performed effectively in the field based on the needs of next education curriculum by comparing the education curriculum, which were analyzed the materials of the health education and health education curriculum after Received (February 22, 2016), Review Result (March 8, 2016) Accepted (March 15, 2016), Published (April 30, 2016) 702-701Dept. Education, Kyungpook National Univ., 80 Daehak-ro, Buk-gu, Daegu, Korea email: barbara017@hanmail.net (Corresponding Author),702-701Dept. Education, Kyungpook National Univ., 80 Daehak-ro, Buk-gu, Daegu, Korea. email: hskang84@knu.ac.kr Analysis of the direction and features of Health Education curriculum under the 2015 revised curriculum Copyright c 2016 HSST 330 the first applied the health education curriculum at education curriculum from 2009, with the revised content and direction of curriculum appearing in the revised education curriculum in 2015. As the result of research, it were suggested that six core competencies of health education, personal competency, and the characteristics and goals of health education emphasized the balance of social responsibility, and also suggested the restructuring of the content domain by presenting health contents domain and the 11 key concepts, and proposed the education achievement standard in accordance with decrease of education achievement standard and the content elements at the revised health education curriculum. For the revised education curriculum in 2015 is carried out in a systemic ways, It is presented that it is necessary to notice the elementary school health curriculum including total number of lesson hours, to secure the health education class time in middle and high school for not selecting health education in their classes, to be more health education books, and to increase health education teachers at large schools as a policy.

Human ether-a-go-go-related gene (hERG) channels conduct delayed rectifier K+ current. However, little information is available on physiological situations affecting hERG channel protein and function. In the present study we examined the effects of intermittent hypoxia (IH), which is a hallmark manifestation of sleep apnea, on hERG channel protein and function. Experiments were performed on SH-SY5Y neuroblastoma cells, which express hERG protein. Cells were exposed to IH consisting of alternating cycles of 30 s of hypoxia (1.5% O2) and 5 min of 20% O2. IH decreased hERG protein expression in a stimulus-dependent manner. A similar reduction in hERG protein was also seen in adrenal medullary chromaffin cells from IH-exposed neonatal rats. The decreased hERG protein was associated with attenuated hERG K+ current. IH-evoked hERG protein degradation was not due to reduced transcription or increased proteosome/lysomal degradation. Rather it was mediated by calcium-activated calpain proteases. Both COOH- and NH2-terminal sequences of the hERG protein were the targets of calpain-dependent degradation. IH increased reactive oxygen species (ROS) levels, intracellular Ca2+ concentration ([Ca2+]i), calpain enzyme activity, and hERG protein degradation, and all these effects were prevented by manganese-(111)-tetrakis-(1-methyl-4-pyridyl)-porphyrin pentachloride, a membrane-permeable ROS scavenger. These results demonstrate that activation of calpains by ROS-dependent elevation of [Ca2+]i mediates hERG protein degradation by IH.

The infection of susceptible mice with Theiler&rsquo, s murine encephalomyelitis virus (TMEV) induces a T cell-mediated demyelinating disease. This system has been studied as a relevant infection model for multiple sclerosis (MS). Therefore, defining the type of T cell responses and their functions is critically important for understanding the relevant pathogenic mechanisms. In this study, we adoptively transferred naive VP2-specific TCR-Tg CD4+ T cells into syngeneic susceptible SJL mice and monitored the development of the disease and the activation and proliferation of CD4+ T cells during the early stages of viral infection. The preexisting VP2-specific naive CD4+ T cells promoted the pathogenesis of the disease in a dose-dependent manner. The transferred VP2-specific CD4+ T cells proliferated rapidly in the CNS starting at 2&ndash, 3 dpi. High levels of FoxP3+CD4+ T cells were found in the CNS early in viral infection (3 dpi) and persisted throughout the infection. Activated VP2-specific FoxP3+CD4+ T cells inhibited the production of IFN-&gamma, but not IL-17, via the same VP2-specific CD4+ T cells without interfering in proliferation. Thus, the early presence of regulatory T cells in the CNS with viral infection may favor the induction of pathogenic Th17 cells over protective Th1 cells in susceptible mice, thereby establishing the pathogenesis of virus-induced demyelinating disease.

This paper presents a 300 W GaN power amplifier operating in the LTE band 7 (2.62∼2.69 GHz). From the loadpull simulation, optimum impedances of the GaN HEMT at the fundamental frequency and the second harmonic frequency are extracted for a maximum output power. The matching circuits that give the nearly optimum second harmonic impedances are implemented on a titanate substrate with a high dielectric constant and are integrated with a bare GaN transistor in a ceramic package. The fabricated power amplifier shows a saturated output power of 258∼324 W and a drain efficiency of 67∼73 % under the pulsed condition of 1 msec period and 10 % duty cycle. It also has an output power of 80∼85 W and a drain efficiency of 42∼49 % at ACLR of 30 dBc with the LTE input signal.

Interleukin-6 (IL-6) plays an important role in the development and progression of inflammatory responses, autoimmune diseases, and cancers. Many viral infections, including Theiler's murine encephalomyelitis virus (TMEV), result in the vigorous production of IL-6. However, the role of IL-6 in the development of virus-induced inflammatory responses is unclear. The infection of susceptible mice with TMEV induces the development of chronic demyelinating disease, which is considered a relevant infectious model for multiple sclerosis. In this study, we demonstrate that resistant C57BL/6 mice carrying an IL-6 transgene (IL-6 Tg) develop a TMEV-induced demyelinating disease accompanied by an increase in viral persistence and an elevated Th17 cell response in the central nervous system. Either IL-6 or IL-17 induced the expression of Bcl-2 and Bcl-xL at a high concentration. The upregulated expression of prosurvival molecules in turn inhibited target cell destruction by virus-specific CD8 + T cells. More interestingly, IL-6 and IL-17 synergistically promoted the expression of these prosurvival molecules, preventing cellular apoptosis at a much lower (+ T cell-mediated target destruction. These results suggest that blocking both IL-6 and IL-17 functions are important considerations for therapies of chronic viral diseases, autoimmune diseases, and cancers. IMPORTANCE This study indicates that an excessive level of IL-6 cytokine produced following viral infection promotes the development of IL-17-producing pathogenic helper T cells. We demonstrate here for the first time that IL-6 together with IL-17 synergistically enhances the expression of survival molecules to hinder critical host defense mechanisms removing virus-infected cells. This finding has an important implication in controlling not only chronic viral infections but also autoimmune diseases and cancers, which are associated with prolonged cell survival.

Key Words: Cold Rolling(냉간압연), Cluster Mill(다단압연기), Roll Slip(롤슬립), Slip Ratio(슬립률),Roll Slip State Observer(롤슬립상태관측기)초록: 이논문은냉간압연공정의다단압연기에서각롤간의슬립현상에대한상태공간모델을도출하고, 이를이용하여롤간슬립상태관측기설계에관한연구를수행한다. 먼저뉴튼의운동법칙을이용하여각롤들의회전운동방정식을1계비선형미분방정식으로기술한후, 테일러급수를이용하여임의의동작점에서상태공간방정식으로선형화한다. 다음에는선형화된상태공간방정식에기초하여Gopinath 구성법으로측정가능한구동롤을제외한종동롤의회전각속도를추정하는최소차원상태관측기를설계한다. 마지막으로컴퓨터시뮬레이션을통하여상태관측기로부터추정된각롤회전각속도와슬립률의유용성을고찰한다.Abstract: This study focuses on the state space model and the design of a state observer for the slip dynamicsbetween rolls in STS cold cluster mills. First, a mathematical model of the roll slip is given as a nonlineardifferential equation. Then, by using a Taylor series expansion, it is linearized as a state space model. Next, byusing Gopinath’s algorithm, a minimal-order state observer based on the state space model is designed to estimatethe angular speed of all idle rolls except for an actuated roll that is measureable. Finally, a computer simulation isused to validate that the proposed state space model very well describes slip dynamics between, and moreover, thestate observer very well estimates the angular speed of the idle roll.

Background Chronic infection with Theiler’s murine encephalomyelitis virus (TMEV) in susceptible SJL/J mice induces an immune-mediated demyelinating disease and has extensively been used as a relevant infectious model for multiple sclerosis (MS). Infection of the host with many other viruses also leads to acute or chronic inflammatory diseases in the central nervous system (CNS). Levels of viral load in the host often play a critical role in the pathogenesis of virus-induced diseases. Thus, the inhibition of viral replication in the host against a broad spectrum of similar viruses is critically important for preventing the viral pathogenicity. Methods P2/P3-expressing transgenic (B6 X SJL)F1 founders were generated and bred onto the C57BL/6 and SJL/J backgrounds. Differences in the development of demyelinating disease were compared. Viral persistence, cytokine production, and immune responses in the CNS of infected control and P2/P3-Tg mice were analyzed after infection using quantitative PCR, ELISA, and flow cytometry. Various cell types from the control and P2/P3-Tg mice, as well as cells transfected in vitro with the P2 and/or P3 regions, were also analyzed for viral replication and innate cytokine production. Results P2/P3-transgenic (P2/P3-Tg) mice carrying the viral non-structural protein genes displayed significantly reduced virus-specific T cell responses in the CNS against both the structural and non-structural proteins. Consequently, viral loads in the CNS were greater in the Tg mice during the chronic infection. However, P2/P3-Tg SJL mice exhibited reduced disease incidence and less severe clinical symptoms than did their non-transgenic littermates. Interestingly, P2/P3-Tg mice showed low viral loads in the CNS at a very early period after infection (1–3 days) with TMEV and related EMCV but not unrelated VSV. Cells from P2/P3-Tg mice and cells transfected with the P2 and/or P3 regions in vitro yielded also lower viral replication but higher IFN-α/β production. Conclusions This study demonstrates that the expression of viral non-structural genes in mice inhibits initial viral replication and suppresses sustaining pathogenic anti-viral immune responses to broad viral determinants. It appears that the elevation of innate immune cytokines produced in the cells expressing the non-structural viral genes upon viral infection is responsible for the inhibitions. The inhibition is partially virus-specific as it is more efficient for a related virus compared to an unrelated virus, suggesting a role for the similarity in the viral genome structures. Therefore, the expression of viral non-structural genes may serve as a useful new method to prevent a broadly virus-specific pathogenesis in the hosts.

Background and Aims: Transient elastography (TE) is useful for predicting the fibrosis stage, but it is unsatisfactory as a substitute for liver biopsy, especially in patients with chronic hepatitis B (CHB). This study was performed to establish a reliable model for predicting significant fibrosis (SF) in patients with CHB. Methods: All CHB patients who were admitted to undergo liver biopsy were enrolled. They were randomly classified into either a training set (n = 139) or a validation set (n = 69). A model for predicting SF was established in the training set and validated in the validation set. Low and high cutoff values (COVs) were chosen for sensitivity ≥ 99% and specificity ≥ 99%, respectively. Results: A total of 208 patients were enrolled. Age was 39 ± 12 years and 149 (71.6%) were men. In the training set, liver stiffness values and serum haptoglobin, apolipoprotein A1, and α2-macroglobulin levels were independent predictors of SF on multivariate analysis. These variables were used to construct a novel model, called the HALF index. The area under the receiver operating characteristics curve of the HALF index for predicting SF was significantly higher than that of TE alone (0.915 vs 0.877, P = 0.010). Using low and high COVs of the HALF index, it appears that approximately half (47.1%) of patients could avoid liver biopsy, with an associated accuracy of 99.0%. Conclusion: A combination of liver stiffness and serum markers identified SF with a high degree of accuracy. Approximately half of all patients with CHB could avoid liver biopsy through the utilization of the HALF index.

Infection of the central nervous system (CNS) with Theiler’s murine encephalomyelitis virus (TMEV) induces an immune-mediated demyelinating disease in susceptible mouse strains such as SJL/J (H-2 s ) but not in strains such as C57BL/6 (H-2 b ). In addition, it has been shown that (C57BL/6 SJL/J)F1 mice (F1 mice), which carry both resistant and susceptible MHC haplotypes (H-2 b/s ), are resistant to both viral persistence and TMEV-induced demyelinating disease. In this study, we further analyzed the immune responses underlying the resistance of F1 mice. Our study shows that the resistance of F1 mice is associated with a higher level of the initial virus-specific H-2 b -restricted CD8 T cell responses than of the H-2 s -restricted CD8 T cell responses. In contrast, pathogenic Th17 responses to viral epitopes are lower in F1 mice than in susceptible SJL/J mice. Dominant effects of resistant genes expressed in antigen-presenting cells of F1 mice on regulation of viral replication and induction of protective T cell responses appear to play a crucial role in disease resistance. Although the F1 mice are resistant to disease, the level of viral RNA in the CNS was intermediate between those of SJL/J and C57BL/6 mice, indicating the presence of a threshold of viral expression for pathogenesis. Intracerebral infection of susceptible mice with Theiler’s murine encephalomyelitis virus (TMEV) induces a chronic, progressive demyelinating disease that is clinically and histopathologically similar to a form of human multiple sclerosis (MS) (25). In addition, the various immunological and genetic factors that affect disease outcome in TMEV-infected mice closely parallel those associated with the development of MS (23). Combined with a suspected viral etiology for MS (1, 13, 46), these similarities make TMEV-induced demyelinating disease (TMEV-IDD) an attractive and relevant infectious model for investigating this human demyelinating disease. Development of TMEV-IDD in highly susceptible SJL/J (H-2 s ) mice (SJL mice) is associated with chronic viral persistence in the central nervous system (CNS) (7, 26, 44), whereas resistant C57BL/6 (H-2 b ) mice (B6 mice) clear the virus within

We have recently reported that the yeast chromatin-remodeling factor Swi1 can exist as a prion, [SWI(+)], demonstrating a link between prionogenesis and global transcriptional regulation. To shed light on how the Swi1 conformational switch influences Swi1 function and to define the sequence and structural requirements for [SWI(+)] formation and propagation, we functionally dissected the Swi1 molecule. We show here that the [SWI(+)] prion features are solely attributable to the first 327 amino acid residues (N), a region that is asparagine rich. N was aggregated in [SWI(+)] cells but diffuse in [swi(-)] cells; chromosomal deletion of the N-coding region resulted in [SWI(+)] loss, and recombinant N peptide was able to form infectious amyloid fibers in vitro, enabling [SWI(+)] de novo formation through a simple transformation. Although the glutamine-rich middle region (Q) was not sufficient to aggregate in [SWI(+)] cells or essential for SWI/SNF function, it significantly modified the Swi1 aggregation pattern and Swi1 function. We also show that excessive Swi1 incurred Li(+)/Na(+) sensitivity and that the N/Q regions are important for this gain of sensitivity. Taken together, our results provide the final proof of "protein-only" transmission of [SWI(+)] and demonstrate that the widely distributed "dispensable" glutamine/asparagine-rich regions/motifs might have important and divergent biological functions.

Persistent viral infection and its associated chronic diseases are a global health concern. Interleukin (IL) 17–producing Th17 cells have been implicated in the pathogenesis of various autoimmune diseases, and in protection from bacterial or fungal infection. However, the role of Th17 cells in persistent viral infection remains unknown. We report that Th17 cells preferentially develop in vitro and in vivo in an IL-6–dependent manner after Theiler’s murine encephalomyelitis virus infection. Th17 cells promote persistent viral infection and induce the pathogenesis of chronic demyelinating disease. IL-17 up-regulates antiapoptotic molecules and, consequently, increases persistent infection by enhancing the survival of virus-infected cells and blocking target cell destruction by cytotoxic T cells. Neutralization of IL-17 augments virus clearance by eliminating virus-infected cells and boosting lytic function by cytotoxic T cells, leading to the prevention of disease development. Thus, these results indicate a novel pathogenic role of Th17 cells via IL-17 in persistent viral infection and its associated chronic inflammatory diseases.

Intracerebral infection with Theiler's murine encephalomyelitis virus (TMEV) induces immune-mediated demyelinating disease in susceptible SJL/J mice but not in resistant C57BL/6 mice. Previous studies have indicated that the major histocompatibility complex (MHC) genes play the most prominent role in the development of TMEV-induced demyelinating disease. In this study, we used C57BL/6.S (B6.S) congenic mice, which carry H-2 s MHC genes instead of H-2 b MHC genes in conjunction with the C57BL/6 (B6) background genes. Our data show that virus-infected B6.S mice are free from disease and have significantly lower viral loads than susceptible SJL mice, particularly in the spinal cord. A strong protective Th1-type T helper response with virtually no pathogenic Th17 response was detected in B6.S mice, in contrast to the reduced Th1- and robust Th17-type responses in SJL mice. Notably, lower levels of viral infectivity in B6.S antigen-presenting cells (APCs) correlated with the disease resistance and T-cell-type response. In vitro studies using APCs from B6.S and SJL mice show that TLR2, -3, -4, and -7, but not TLR9, signaling can replace viral infection and augment the effect of viral infection in the differentiation of the pathogenic Th17 cell type. Taken together, these results strongly suggest that the viral replication levels in APCs critically affect the induction of protective versus pathogenic Th cell types via the signaling of pattern recognition receptors for innate immune responses. Our current findings further imply that the levels of viral infectivity/replication and TLR-mediated signaling play critical roles in the pathogenesis of chronic viral diseases. IMPORTANCE This study indicates that innate immune cytokines produced in antigen-presenting cells stimulating the T cell immune responses during early viral infection play a critical role in determining the susceptibility of mice to the development of demyelinating disease. The level of innate immune cytokines reflects the level of initial viral infection in the antigen-presenting cells, and the level determines the development of T cell types, which are either protective or pathogenic. The level of initial viral infection to the cells is controlled by a gene or genes that are not associated with the major histocompatibility antigen complex genes. This finding has an important implication in controlling not only chronic viral infections but also infection-induced autoimmune-like diseases, which are closely associated with the pathogenic type of T cell responses.

We have investigated the potential effects of H-2 and T-cell receptor (TCR) V beta family genes on induction of T-cell immunity and susceptibility to virally induced demyelinating disease by using BALB.S (H-2K(s)A(s)D(s)) and BALB.S 3 R (H-2K(s)A(s)D(d)/L(d)) mice. These parameters were compared with those of highly susceptible SJL/J (H-2K(s)A(s)D(s)) mice that contain only one-half of TCR V beta family genes compared with the above-mentioned strains. Our results demonstrate that BALB.S but not BALB.S 3 R mice are susceptible similar to SJL/J mice. Although the level of CD4(+) T-cell infiltration to the CNS was elevated in susceptible mice, virus-specific immune responses restricted with H-2(s) were similar in these mice. No preferential use of V beta families associated with differences in the major histocompatibility complex (MHC) components was apparent. However, the pattern and sequence of CDR 3 distribution shows T-cell clonal accumulation in the CNS associated with the H-2 components. Further anti-CD8 antibody treatment of resistant BALB.S 3 R mice abrogated resistance to demyelinating disease, indicating that CD8(+) T cells restricted with H-2D(d)/L(d) are most likely to exert resistance in BALB.S 3 R mice. These studies indicated that TCR V beta and MHC class II genes are the secondary to a particular MHC class I gene expression in susceptibility to virally induced demyelinating disease.

Noise and vibration comfort is a critical design criterion for road machinery. An acoustic modal analysis provides useful insights to understanding interior acoustic characteristics and to developing noise mitigation strategies, to improve operator comfort. In this study, an acoustic cavity modal analysis of a compactor cabin is done by utilizing analytical solution, FEA and experimental measurements. While the analytical method and FEA calculate the normal modes of a rigid-walled acoustic cavity, the physical test measures the acoustic modes in-situ that account for the vibro-acoustic coupling effect between the interior cavity and flexible panels. The discrepancies of resultant modal parameters extracted by testing and simulation are discussed. In addition, the impacts of the seat and steering column assembly on the acoustic cavity modes are also investigated. Last but not least, a local vibro-acoustic behavior of the cab and its relation to the interior booming noise is deeply investigated. From the NVH development standpoint for a practical cabin, the findings of this investigation not only help troubleshooting cabin noise issues but also lead to improvement in virtual acoustical modal predictions and guide the design to achieve a robust NVH performance.

Infection with Theiler's murine encephalomyelitis virus (TMEV) in the central nervous system (CNS) of susceptible mice results in an immune-mediated demyelinating disease which is considered a relevant viral model of human multiple sclerosis. We previously demonstrated that the expression of positive costimulatory molecules (CD40, CD80, and CD86) is higher on the microglia of TMEV-resistant C57BL/6 (B6) mice than the microglia of TMEV-susceptible SJL/J (SJL) mice. In this study, we analyzed the expression levels of the negative costimulatory molecules PD-1 and PDL-1 in the CNS of TMEV-infected SJL mice and B6 mice. Our results indicated that TMEV infection induces the expression of both PD-1 and PDL-1 on microglia and macrophages in the CNS but not in the periphery. The expression of PD-1 only on CNS-infiltrating macrophages and not on resident microglia was considerably higher (>4-fold) in TMEV-infected SJL mice than TMEV-infected B6 mice. We further demonstrated that interleukn-6 (IL-6) is necessary to induce the maximal expression of PDL-1 but not PD-1 after TMEV infection using IL-6-deficient mice and IL-6-transgenic mice in conjunction with recombinant IL-6. In addition, cells from type I interferon (IFN) receptor knockout mice failed to upregulate PD-1 and PDL-1 expression after TMEV infection in vitro , indicating that type I IFN signaling is associated with the upregulation. However, other IFN signaling may also participate in the upregulation. Taken together, these results strongly suggest that the expression of PD-1 and PDL-1 in the CNS is primarily upregulated following TMEV infection via type I IFN signaling and the maximal expression of PDL-1 additionally requires IL-6 signaling.

Theiler's virus-induced demyelinating disease has been extensively investigated as a model for persistent viral infection and multiple sclerosis (MS). However, the role of CD8 + T cells in the development of disease remains unclear. To assess the role of virus-specific CD8 + T cells in the pathogenesis of demyelinating disease, a single amino acid substitution was introduced into the predominant viral epitope (VP3 from residues 159 to 166 [VP3 159-166 ]) and/or a subdominant viral epitope (VP3 173-181 ) of susceptible SJL/J mice by site-directed mutagenesis. The resulting variant viruses (N160V, P179A, and N160V/P179A) failed to induce CD8 + T cell responses to the respective epitopes. Surprisingly, mice infected with N160V or N160V/P179A virus, which lacks CD8 + T cells against VP3 159-166 , did not develop demyelinating disease, in contrast to wild-type virus or P179A virus lacking VP3 173-181 -specific CD8 + T cells. Our findings clearly show that the presence of VP3 159-166 -specific CD8 + T cells, rather than viral persistence itself, is strongly correlated with disease development. VP3 173-181 -specific CD8 + T cells in the central nervous system (CNS) of these virus-infected mice expressed higher levels of transforming growth factor β, forkhead box P3, interleukin-22 (IL-22), and IL-17 mRNA but caused minimal cytotoxicity compared to that caused by VP3 159-166 -specific CD8 + T cells. VP3 159-166 -specific CD8 + T cells exhibited high functional avidity for gamma interferon production, whereas VP3 173-181 -specific CD8 + T cells showed low avidity. To our knowledge, this is the first report indicating that the induction of the IL-17-producing CD8 + T cell type is largely epitope specific and that this specificity apparently plays a differential role in the pathogenicity of virus-induced demyelinating disease. These results strongly advocate for the careful consideration of CD8 + T cell-mediated intervention of virus-induced inflammatory diseases.

Background Theiler’s virus infection induces chronic demyelinating disease in mice and has been investigated as an infectious model for multiple sclerosis (MS). IL-1 plays an important role in the pathogenesis of both the autoimmune disease model (EAE) and this viral model for MS. However, IL-1 is known to play an important protective role against certain viral infections. Therefore, it is unclear whether IL-1-mediated signaling plays a protective or pathogenic role in the development of TMEV-induced demyelinating disease. Methods Female C57BL/6 mice and B6.129S7-Il1r1tm1Imx/J mice (IL-1R KO) were infected with Theiler’s murine encephalomyelitis virus (1 x 106 PFU). Differences in the development of demyelinating disease and changes in the histopathology were compared. Viral persistence, cytokine production, and immune responses in the CNS of infected mice were analyzed using quantitative PCR, ELISA, and flow cytometry. Results Administration of IL-1β, thereby rending resistant B6 mice susceptible to TMEV-induced demyelinating disease, induced a high level of Th17 response. Interestingly, infection of TMEV into IL-1R-deficient resistant C57BL/6 (B6) mice also induced TMEV-induced demyelinating disease. High viral persistence was found in the late stage of viral infection in IL-1R-deficient mice, although there were few differences in the initial anti-viral immune responses and viral persistent levels between the WT B6 and IL-1R-deficiecent mice. The initial type I IFN responses and the expression of PDL-1 and Tim-3 were higher in the CNS of TMEV-infected IL-1R-deficient mice, leading to deficiencies in T cell function that permit viral persistence. Conclusions These results suggest that the presence of high IL-1 level exerts the pathogenic role by elevating pathogenic Th17 responses, whereas the lack of IL-1 signals promotes viral persistence in the spinal cord due to insufficient T cell activation by elevating the production of inhibitory cytokines and regulatory molecules. Therefore, the balance of IL-1 signaling appears to be extremely important for the protection from TMEV-induced demyelinating disease, and either too much or too little signaling promotes the development of disease.

Prior research has shown that the total amount of white matter ischemia had no significant correlation with cognitive deficits. We compared the association of white matter hyperintensities (WMHs) of total as well as cholinergic pathways with clinical dementia severity and investigated whether cholinergic ischemic burden had an independent predictive value with respect to cognitive decline in subcortical vascular cognitive impairment (SVCI). Forty-eight patients underwent detailed neuropsychological tests and brain magnetic resonance imaging. Quantification of WMH in the total white matter and in cholinergic pathways was achieved using the visual Scheltens scale and Cholinergic Pathway HyperIntensity Scale (CHIPS), respectively. We explored the association between WMH scores and clinical dementia rating scale (CDR). To assess the relation between WMH and cognitive scores, multiple linear regression analysis was used. The CHIPS score was higher in subcortical vascular dementia compared to subcortical vascular MCI, while this difference was not found with the total TMHs (TWMH) score. The TWMH score had a positive correlation with CHIPS, however only CHIPS scores positively correlated with sum of box scores of CDR scale (CDR SB; ρ = .474, P = .001). Higher CHIPS scores were associated with lower performance on the semantic word fluency test (β = -.447, P = .036), whereas the TWMH scores had no independent predictive value with respect to cognitive impairment, after controlling for CHIPS score. Our data confirmed the association of ischemic damage within cholinergic pathways with dementia severity, independent of TWMH in SVCI. In addition, this cholinergic deficit is clinically relevant to cognitive deterioration, especially with frontal dysfunction.

Background: We have previously shown that toll-like receptor 3 (TLR3)-mediated signaling plays an important role in the induction of innate cytokine responses to Theiler's murine encephalomyelitis virus (TMEV) infection. In addition, cytokine levels produced after TMEV infection are significantly higher in the glial cells of susceptible SJL mice compared to those of resistant C57BL/6 mice. However, it is not known whether TLR3-mediated signaling plays a protective or pathogenic role in the development of demyelinating disease. Methods: SJL/J and B6; 129S-Tlr3(tm1Flv)/J (TLR3KO-B6) mice, and TLR3KO-SJL mice that TLR3KO-B6 mice were backcrossed to SJL/J mice for 6 generations were infected with Theiler's murine encephalomyelitis virus (2 x 10(5) PFU) with or without treatment with 50 mu g of poly IC. Cytokine production and immune responses in the CNS and periphery of infected mice were analyzed. Results: We investigated the role of TLR3-mediated signaling in the protection and pathogenesis of TMEV-induced demyelinating disease. TLR3KO-B6 mice did not develop demyelinating disease although they displayed elevated viral loads in the CNS. However, TLR3KO-SJL mice displayed increased viral loads and cellular infiltration in the CNS, accompanied by exacerbated development of demyelinating disease, compared to the normal littermate mice. Late, but not early, anti-viral CD4(+) and CD8(+) T cell responses in the CNS were compromised in TLR3KO-SJL mice. However, activation of TLR3 with poly IC prior to viral infection also exacerbated disease development, whereas such activation after viral infection restrained disease development. Activation of TLR3 signaling prior to viral infection hindered the induction of protective IFN-gamma-producing CD4(+) and CD8(+) T cell populations. In contrast, activation of these signals after viral infection improved the induction of IFN-gamma-producing CD4(+) and CD8(+) T cells. In addition, poly IC-pretreated mice displayed elevated PDL-1 and regulatory FoxP3(+) CD4+ T cells in the CNS, while poly IC-post-treated mice expressed reduced levels of PDL-1 and FoxP3(+) CD4(+) T cells. Conclusions: These results suggest that TLR3-mediated signaling during viral infection protects against demyelinating disease by reducing the viral load and modulating immune responses. In contrast, premature activation of TLR3 signal transduction prior to viral infection leads to pathogenesis via over-activation of the pathogenic immune response., Article, JOURNAL OF NEUROINFLAMMATION. 8:178 (2011)

It remains unclear whether the currently-used normal range for serum alanine aminotransferase (ALT) levels really reflects a healthy liver. The present study was conducted to evaluate the healthy range of serum ALT in the Korean adult population and to determine the clinical significance of unhealthy levels.We reviewed the medical records, including questionnaires and the results of laboratory and radiological tests conducted at the Health Promotion Center at Korea University Anam Hospital between March 2005 and February 2007. The records, written in questionnaire form, included baseline data, such as physical status, social behaviors, medication history, and past and present disease histories.The mean age of the 7403 enrolled patients was 48 years, and 49.9% of these patients were male. A healthy cohort was selected after excluding patients who showed any abnormalities of the factors that were significantly associated with the serum ALT level upon multivariate regression analysis. The upper limit of the healthy range of the serum ALT level (i.e. 95th percentile) in the healthy population was 31 IU/L for males and 23 IU/L for females. The prevalence of metabolic syndrome and insulin resistance (IR) were significantly higher in patients with an 'unhealthy' normal ALT level than in those with a healthy ALT level.In our study, the upper limit of the healthy range of the serum ALT level was 31 IU/L for males and 23 IU/L for females. An unhealthy normal ALT level was associated with a higher prevalence of metabolic syndrome and IR.

Transient elastography (TE) is useful for predicting the fibrosis stage, but it is unsatisfactory as a substitute for liver biopsy, especially in patients with chronic hepatitis B (CHB). This study was performed to establish a reliable model for predicting significant fibrosis (SF) in patients with CHB.All CHB patients who were admitted to undergo liver biopsy were enrolled. They were randomly classified into either a training set (n = 139) or a validation set (n = 69). A model for predicting SF was established in the training set and validated in the validation set. Low and high cutoff values (COVs) were chosen for sensitivity ≥ 99% and specificity ≥ 99%, respectively.A total of 208 patients were enrolled. Age was 39 ± 12 years and 149 (71.6%) were men. In the training set, liver stiffness values and serum haptoglobin, apolipoprotein A1, and α2-macroglobulin levels were independent predictors of SF on multivariate analysis. These variables were used to construct a novel model, called the HALF index. The area under the receiver operating characteristics curve of the HALF index for predicting SF was significantly higher than that of TE alone (0.915 vs 0.877, P = 0.010). Using low and high COVs of the HALF index, it appears that approximately half (47.1%) of patients could avoid liver biopsy, with an associated accuracy of 99.0%.A combination of liver stiffness and serum markers identified SF with a high degree of accuracy. Approximately half of all patients with CHB could avoid liver biopsy through the utilization of the HALF index.

Induction of antigen-specific CD8+T cells bearing a high-avidity T-cell receptor (TCR) is thought to be an important factor in antiviral and antitumor immune responses. However, the relationship between TCR diversity and functional avidity of epitope-specific CD8+T cells accumulating in the central nervous system (CNS) during viral infection is unknown. Hence, analysis of T-cell diversity at the clonal level is important to understand the fate and function of virus-specific CD8+T cells. In this study, we examined the Vβ diversity and avidity of CD8+T cells specific to the predominant epitope (VP2121-130) of Theiler's murine encephalomyelitis virus. We found that Vβ6+CD8+T cells, associated with epitope specificity, predominantly expanded in the CNS during viral infection. Further investigations of antigen-specific Vβ6+CD8+T cells by CDR3 spectratyping and sequencing indicated that distinct T-cell clonotypes are preferentially increased in the CNS compared to the periphery. Among the epitope-specific Vβ6+CD8+T cells, MGX-Jβ1.1 motif-bearing cells, which could be found at a high precursor frequency in naïve mice, were expanded in the CNS and tightly associated with gamma interferon production. These T cells displayed moderate avidity for the cognate epitope rather than the high avidity normally observed in memory/effector T cells. Therefore, our findings provide new insights into the CD8+T-cell repertoire during immune responses to viral infection in the CNS.

Herbs are widely used as treatments for various symptoms. However, several herbs have been reported to be inducers of liver injury. We report herein a case of hepatotoxicity induced by Corydalis speciosa Max. A 37-year-old male complained of jaundice and mild abdominal discomfort. A thorough history was taken, and laboratory investigation, diagnostic imaging studies, and percutaneous liver biopsy sampling were conducted to determine the cause of liver injury. An accurate cause was not revealed. We administered supportive management for acute cholestatic hepatitis of unknown origin, after which his symptoms disappeared and serum aminotransferase levels decreased gradually to near normal levels. However, at 2 months after discharge, the symptoms and the elevation of aminotransferase levels recurred. At that time he told us that he had repeatedly but unintentionally eaten a herb called "Hwang-geun cho"(Corydalis speciosa Max.). Thus, we diagnosed his case as herbal hepatotoxicity.

Intracranial infection of Theiler’s murine encephalomyelitis virus (TMEV) induces demyelination and a neurological disease in susceptible SJL/J (SJL) mice that resembles multiple sclerosis. While the virus is cleared from the central nervous system (CNS) of resistant C57BL/6 (B6) mice, it persists in SJL mice. To investigate the role of viral persistence and its accompanying immune responses in the development of demyelinating disease, transgenic mice expressing the P1 region of the TMEV genome (P1-Tg) were employed. Interestingly, P1-Tg mice with the B6 background showed severe reductions in both CD4 and CD8 T-cell responses to capsid epitopes, while P1-Tg mice with the SJL background displayed transient reductions following viral infection. Reduced antiviral immune responses in P1-Tg mice led to >100- to 1,000-fold increases in viral persistence at 120 days postinfection in the CNS of mice with both backgrounds. Despite the increased CNS TMEV levels in these P1-Tg mice, B6 P1-Tg mice developed neither neuropathological symptoms nor demyelinating lesions, and SJL P1-Tg mice developed significantly less severe TMEV-induced demyelinating disease. These results strongly suggest that viral persistence alone is not sufficient to induce disease and that the level of T-cell immunity to viral capsid epitopes is critical for the development of demyelinating disease in SJL mice. Theiler’s murine encephalomyelitis virus (TMEV) is a member of the Cardiovirus genus within the Picornaviridae family. TMEV is a common enteric pathogen among wild mice and rarely causes a neurological disease. However, intracerebral (i.c.) infection in susceptible mice, e.g., SJL/J (SJL) mice, reproducibly induces a chronic immune-mediated demyelinating disease, providing an excellent infectious model for multiple sclerosis (10, 25). The precise mechanism of TMEV-induced demyelinating disease (TMEV-IDD) is unknown. However, virus-specific T cells, various proinflammatory chemokines (e.g., monocyte chemoattractant protein 1 and interferon-inducible protein 10), and cytokines (e.g., gamma interferon [IFN-] and tumor necrosis factor alpha) in the central nervous system (CNS) are believed to play a critical role (reviewed in references 26 and 44) in this disease process. In addition, the presence of persistent viral infection may lead to demyelinating disease by directly causing host cell lysis (51), which releases sequestrated CNS autoantigens, resulting in the activation of autoreactive T cells (39). The persistence of viral antigens also is believed to perpetuate a massive inflammatory milieu in the CNS by continuously activating virus-specific T cells (25, 33). Thus, it is conceivable that viral persistence is essential for the development of TMEV-IDD. This possibility is consistent with the observation that spontaneously occurring variant viruses with relatively low pathogenicity display reduced levels of viral persistence in the CNS (27), implying that viral persistence is a critical susceptibility factor. Furthermore, genetic studies show that viral persistence levels in the CNS correlate with demyelinating disease levels (7, 34).

Simian virus 40 (SV40) contains an essential protein, large tumor antigen (Tag), which assists in viral replication and causes cell transformation and immortalization. Our laboratory has examined plasmid DNA, expressing SV40 Tag under two different promoters, for use in potential cancer vaccination strategies. One plasmid, pSV3-neo, failed to induce SV40 Tag antibody, produced a weak cell-mediated response, and only partial protection in murine experimental tumor challenge systems. The second plasmid, pCMV-Tag, induced antibodies to SV40 Tag, produced a robust cell-mediated response, and invoked complete tumor immunity in vivo. The induction of CD4+ and CD8+ T cell responses following plasmid DNA immunization and tumor cell challenge reflected a type 1 cytokine secretion profile. Our hypothesis for this differential immune response is that pCMV-Tag exhibits a higher level of transgene expression due to a more efficient promoter. We determined that pCMV-Tag levels of SV40 Tag mRNA and protein expression were higher when compared to pSV3-neo. A threshold amount of SV40 Tag may be required to stimulate antibody production and provide complete systemic tumor immunity.

Theiler’s murine encephalomyelitis virus (TMEV) infection in the central nervous system (CNS) of susceptible mice results in an immune-mediated demyelinating disease, which is considered as a relevant viral model for human multiple sclerosis. We previously showed that the expression of positive costimulatory molecules is higher on microglia of TMEV-resistant B6 mice compared to TMEV-susceptible SJL mice. In this study, we analyzed the expression levels of negative costimulatory molecules, PD-1 and PDL-1, in the CNS of TMEV infected SJL and B6 mice. Our results indicated that TMEV infection induces the expression of both PD-1 and PDL-1 on microglia and macrophages in the CNS but not in the periphery. The expression of only PD-1 on CNS-infiltrating macrophages, but not on resident microglia, was considerably higher in TMEV-infected SJL mice compared to TMEV-infected B6 mice. We further showed that the presence of IL-6 is necessary to induce the upregulated expression of PDL-1 after TMEV infection. TMEV infection appears to provide both IL-6 and other undefined signal(s) for the upregulation. The expression of PD-1 and PDL-1 in the CNS of TMEV-infected mice was increased in the absence of signaling by type I IFNs, TLR3 or MDA5-mediated pathway. Taken together, these results strongly suggest that the expression of PD-1 and PDL-1 in the CNS is upregulated by IL-6 plus an unknown signal(s) following TMEV infection, and downregulated type I IFNs induced via TLRs and MDA5 pathways.

We have previously shown that toll-like receptor 3 (TLR3)-mediated signaling plays an important role in the induction of innate cytokine responses to Theiler’s murine encephalomyelitis virus (TMEV) infection. In addition, cytokine levels produced after TMEV infection are significantly higher in the glial cells of susceptible SJL mice compared to those of resistant C57BL/6 mice. However, it is not known whether TLR3-mediated signaling plays a protective or pathogenic role in the development of demyelinating disease. In this study, we investigated the role of TLR3-mediated signaling in the protection and pathogenesis of TMEV-induced demyelinating disease. Our results indicate that TLR3-mediated signaling plays an important role in protecting mice from the development of disease during viral infection, as a lack of TLR3 signals in TLR3-deficient mice exacerbates the disease. However, activation of TLR3 with poly IC prior to viral infection also exacerbated disease development, whereas administration of poly IC after viral infection restrained disease development. These results suggest that TLR3-mediated signaling during viral infection protects against demyelinating disease by reducing the viral load and modulating immune responses. In contrast, premature activation of TLR3 signal transduction during early viral infection may lead to pathogenesis via over-activation of the pathogenic immune response.

Infection of the CNS with Theiler's murine encephalomyelitis virus (TMEV) induces an immune-mediated demyelinating disease in susceptible mouse strains such as SJL/J (H-2(s)), but not in strains such as C57BL/6 (H-2(b)). In addition, it has been shown that (SJL/J x C57BL/6)F1 mice, which carry both resistant and susceptible MHC haplotypes (H-2(b/s)), are resistant to both viral persistence and TMEV-induced demyelinating disease. In this study, we further analyzed the immune responses underlying resistance of F1 mice. Our study shows that the resistance of F1 mice is associated with a higher level of the initial virus-specific H-2(b)-restricted CD8(+) T cell responses vs. the H-2(s)-restricted CD8(+) T cell responses. In contrast, pathogenic Th17 responses to viral epitopes are lower in F1 mice compared to that in susceptible SJL mice. Dominant effects of resistant genes expressed in antigen-presenting cells of F1 mice on regulating viral replication and inducing protective T cell responses appear to play a crucial role in disease resistance. Although the F1 mice are resistant to disease, the level of viral RNA in the CNS was intermediate between those of SJL/J and C57BL/6 mice, indicating the presence of a threshold of viral expression for pathogenesis.

Background/Aims Several studies suggested that serum cystatin C (CysC) is more useful than serum creatinine (Cr) for the assessment of renal function in patients with liver cirrhosis. This study evaluated the clinical significance of CysC in patients with cirrhotic ascites and normal Cr level. Methods We enrolled patients with cirrhotic ascites and a normal serum Cr level (

Background: Monitoring of anesthetic depth is important for successful general anesthesia, yet no such a monitor is widespread. Recently, anesthesia-monitoring device based on time-frequency balanced spectral entropy of electroencephalogram monitoring was developed and available in clinical practices. This study was performed to evaluate the effectiveness of this monitor on the consumption of anesthetic drugs and recovery time in general inhalational anesthesia. Methods: Patients scheduled for elective operation under inhalational anesthesia were randomly allocated to entropy (E) group (with entropy monitoring) or non-entropy (NE) group (without entropy monitoring). Anesthesia was maintained with sevoflurane, air, and remifentanil in all patients. In E group, the concentration of sevoflurane was adjusted to keep the state entropy (SE) value between 40 and 60. The concentration of sevoflurane in NE group was controlled to keep heart rate and blood pressure within ± 20% of the baseline value without the information of SE. After the operation, entropy values, end-tidal sevoflurane concentration, and recovery time were compared with each other. Results: A total of 60 patients were studied. Entropy values were higher during anesthesia period in the E group (P ＜ 0.05). Consequently, mean end-tidal sevoflurane concentration was lower in the E group during anesthesia period (P ＜ 0.05). And all recovery time was shorter in the E group (P ＜ 0.05). Conclusions: Entropy monitoring assisted titration of sevoflurane, as indicated by higher entropy values, decreased mean end-tidal sevoflurane concentration, and shorter recovery times in the entropy group. (Korean J Anesthesiol 2007; 53: 298～303)