Search

This study aimed to evaluate the clinical significance of urine protein to creatinine ratio (uPCR) in relation to the cardiovascular risk associated with carotid artery intima-media thickness (cIMT) progression in subjects with type 2 diabetes (T2D) and normoalbuminuria.In this retrospective longitudinal study on T2D, we recruited 927 participants with normoalbuminuria (urine albumin to creatinine ratio [uACR] 30 mg/g) whose cIMT was measured at baseline and after at least 1 year, and whose initial uPCR and uACR data were available.Higher initial uPCR was positively correlated with a greater increment in maximal cIMT (β = 0.074, p = 0.028), and this correlation was significant even after adjusting for multiple confounding factors (β = 0.074, p = 0.046). High baseline uPCR was an independent predictive factor for the increased risk of maximal cIMT progression in a simple logistic regression model (OR, 1.41; 95% CI, [1.08-1.86]; p = 0.013). Even after adjusting for several confounding variables, higher uPCR was significantly associated with a higher risk of cIMT progression (OR, 1.48; 95% CI, [1.08-2.03]; p = 0.014).These results suggest that high uPCR may be a useful predictive marker for the progression of carotid artery atherosclerosis, even in subjects with T2D and without albuminuria.

Turbulence generator (Called turbulence generating plate or perforated plate) of a swirler in low-swirl combustion plays an important role in generating a stable lifted flame with an isotropic turbulence intensity and forming a uniform flow field. According to the previous experimental studies, the typical porosities of the generator in a low-swirl combustor have been reported between 25 % and 40 %. This study focused to confirm these results in terms of various porosities and hole patterns of a turbulence generator in a lab-scale based low swirl combustor. The pressure drop, the flame shapes, the velocity profiles and the emission performances were experimentally investigated to confirm the flame characteristics of low swirl combustion. The outer diameter(2R c) of the turbulence generator was taken to 2R c = 20 mm, and the porosity and the diameter of the circular hole pattern were varied in ranges of 15 - 35 % and 1.5 - 4.5 mm, respectively. The results show that as the porosity decreases, the occurrence of attached flame is encouraged, the lean flammable limit is extended, the flow rate through the turbulence generator decreases, the swirl intensity increases. The central velocity increases, so that the V-shaped flame changes into a flat flame. Also, the minimum velocity in the central low velocity zone increases and the flame liftoff height increases. As the axial velocity increases and the swirl intensity decreases, the effect of outer recirculation decreases, thereby, the temperature of the outer recirculation zone decreases and the exhaust gas temperature increases. Therefore, the NOx emission slightly increases because the flame temperature is increased due to the reduction of outer recirculation influence. As the hole pattern of the turbulence generator becomes a configuration with having more holes for the same porosity, the stable flame region is widened. Also, the velocity uniformity of the central low velocity zone is improved and the turbulence intensity is decreased. These results confirm that the factors of flame stabilization of low swirl combustor are velocity uniformity and turbulence intensity of the turbulence generator.

The combustion instability in a dual swirl combustor was investigated experimentally. The effects of thermal power and combustor length on combustion instability were evaluated. Pressure and heat release fluctuation were measured simultaneously. In a conventional combustor, the frequency was decreased with increasing combustor length and decreasing thermal power. However, it showed different results with a dual swirl combustor. In regime 1 where thermal power was relatively high, the results showed same tendency with a conventional combustor. In regime 2 where thermal power was relatively low, the frequency was almost constant with increasing combustor length. It was found that a beating phenomenon occurred with increased combustor length in regime 2 by measuring sound pressure fluctuation. By confirming that beating phenomenon occurs only in regime 2, it is considered that beating phenomenon is the dominant factor of combustion instability in regime 2. This beating phenomenon inside combustion chamber greatly affected to combustion instability. The reason of the beating phenomenon seemed to be the difference oscillating period between main flame and pilot flame.

Impairment in macroautophagy/autophagy flux and inflammasome activation are common characteristics of nonalcoholic steatohepatitis (NASH). Considering the lack of approved agents for treating NASH, drugs that can enhance autophagy and modulate inflammasome pathways may be beneficial. Here, we investigated the novel mechanism of ezetimibe, a widely prescribed drug for hypercholesterolemia, as a therapeutic option for ameliorating NASH. Human liver samples with steatosis and NASH were analyzed. For in vitro studies of autophagy and inflammasomes, primary mouse hepatocytes, human hepatoma cells, mouse embryonic fibroblasts with Ampk or Tsc2 knockout, and human or primary mouse macrophages were treated with ezetimibe and palmitate. Steatohepatitis and fibrosis were induced by feeding Atg7 wild-type, haploinsufficient, and knockout mice a methionine- and choline-deficient diet with ezetimibe (10 mg/kg) for 4 wk. Human livers with steatosis or NASH presented impaired autophagy with decreased nuclear TFEB and increased SQSTM1, MAP1LC3-II, and NLRP3 expression. Ezetimibe increased autophagy flux and concomitantly ameliorated lipid accumulation and apoptosis in palmitate-exposed hepatocytes. Ezetimibe induced AMPK phosphorylation and subsequent TFEB nuclear translocation, related to MAPK/ERK. In macrophages, ezetimibe blocked the NLRP3 inflammasome-IL1B pathway in an autophagy-dependent manner and modulated hepatocyte-macrophage interaction via extracellular vesicles. Ezetimibe attenuated lipid accumulation, inflammation, and fibrosis in liver-specific Atg7 wild-type and haploinsufficient mice, but not in knockout mice. Ezetimibe ameliorates steatohepatitis by autophagy induction through AMPK activation and TFEB nuclear translocation, related to an independent MTOR ameliorative effect and the MAPK/ERK pathway. Ezetimibe dampens NLRP3 inflammasome activation in macrophages by modulating autophagy and a hepatocyte-driven exosome pathway.

We investigated the effect of long-term treatment with lobeglitazone, a novel thiazolidinedione-based activator of peroxisome proliferator-activated receptor gamma, on adipose tissue (AT), focusing on its effects on insulin resistance in obese db/db mice. Seven-week-old male db/db mice were assigned to either a vehicle-treated (n=8) or lobeglitazone-treated (n=8) group. Lobeglitazone (1 mg kg−1 daily) was injected intraperitoneally for 20 weeks. Lobeglitazone treatment for 20 weeks resulted in a remarkably improved glycemic index, including significantly decreased glucose levels, enhanced insulin sensitivity and preserved pancreatic beta cells. Both whole body and subcutaneous AT weight increased in the lobeglitazone-treated group. However, lobeglitazone induced an increase in the number of small adipocyte in both epididymal and subcutaneous AT, with a significant weight decrease in the epididymal AT of db/db mice. Using flow cytometry, the CD11c-positive M1 macrophages and CD206-positive M2 macrophages in the epididymal AT were observed to exhibit a decreased M1-to-M2 ratio in lobeglitazone-treated db/db mice. Furthermore, in the lobeglitazone-treated group, interscapular brown AT was clearly visualized by 18F-fluoro-2-deoxy-D-glucose positron emission tomography combined with computed tomography (18F-FDG-PET/CT) and its mass was significantly greater than that of the vehicle-treated group. In the lobeglitazone-treated group, beige-specific gene expression and the number of mitochondria in white AT were upregulated. Lobeglitazone, with upregulating interferon regulatory factor-4 (a key transcriptional regulator of thermogenesis), promoted the development of brown adipocytes and the differentiation of white adipocytes into beige adipocytes. Long-term lobeglitazone treatment has a beneficial role in remodeling and ameliorating inflammation in white AT and in glycemic control, in relation to insulin sensitivity in obese db/db mice. Moreover, lobeglitazone induced the differentiation of brown and beige adipocytes. Collectively, our data suggest that lobeglitazone treatment provides promising effects on white and brown AT as well as great improvement in glycemic control, as a potent insulin sensitizer.

We report that a Lewis acidic silane, Me2SiHCl, can mediate the direct cross-coupling of a wide range of carbonyl compounds with alcohols to form dialkyl ethers. The reaction is operationally simple, tolerates a range of polar functional groups, can be utilized to make sterically hindered ethers, and is extendable to sulfur and nitrogen nucleo­philes.

This study investigated the effect of a co-solvent on the lithium metal negative electrode to understand the growth of dendritic lithium and the battery performance. An electrolyte was prepared by adding a dimethyl carbonate (DMC) co-solvent in a propylene carbonate (PC) solvent. Adding DMC, considerably improved the unstable and low cyclic efficiency in the PC only electrolyte was considerably improved. Scanning electron microscopy showed that the growth of dendritic lithium was affected by the quantity of DMC. The more DMC was added, the more the dendritic lithium formation was suppressed. Fourier transform infrared spectroscopy revealed that the surface component of the deposited lithium was different, depending on the quantity of DMC added. This study successfully demonstrated that DMC co-solvent could suppress dendritic lithium.

Methylglyoxal (MG) is a reactive dicarbonyl intermediate and a precursor of advanced glycation end products (AGEs). The authors investigated the role played by AGEs in muscle myopathy and the amelioration of its effects by curcumin and gingerol. In addition to producing phenotypical changes, MG increased oxidative stress and reduced myotube formation in C2C12 cells. RAGE (receptor for AGEs) expression was up-regulated and MYOD and myogenin (MYOG) expressions were concomitantly down-regulated in MG-treated cells. Interestingly, AGE levels were higher in plasma (~32 fold) and muscle (~26 fold) of diabetic mice than in control mice. RAGE knock-down (RAGEkd) reduced the expressions of MYOD and MYOG and myotube formation in C2C12 cells. In silico studies of interactions between curcumin or gingerol and myostatin (MSTN; an inhibitor of myogenesis) and their observed affinities for activin receptor type IIB (ACVRIIB) suggested curcumin and gingerol reduce the interaction between MSTN and ACVRIIB. The findings of this study suggest enhanced AGE production and subsequent RAGE-AGE interaction obstruct the muscle development program, and that curcumin and gingerol attenuate the effect of AGEs on myoblasts.

Sodium glucose co-transporter 2 (SGLT2) inhibitors increase urinary glucose excretion (UGE) by reducing the renal threshold for glucose excretion, which results in decreased serum glucose concentrations in patients with type 2 diabetes mellitus (T2D). However, no study to date has determined whether larger increases in UGE after SGLT2 inhibitor treatment correspond to larger reductions in glycated hemoglobin (HbA1C). We enrolled participants who were newly prescribed an SGLT2 inhibitor (dapagliflozin 10 mg or ipragliflozin 50 mg, once daily) as an add-on therapy. Patients were tested for HbA1C and first morning spot urinary-creatinine and -glucose concentrations immediately prior to administration of the SGLT2 inhibitor and at a 12-week follow-up appointment. We investigated the relationship between increases in morning spot UGE and decreases in HbA1C. A total of 101 participants with T2D were enrolled. The median age and diabetes duration were 61.0 and 12.8 years, respectively, and the median HbA1C was 8.10%. SGLT2 inhibitors significantly lowered the HbA1C level, with a median change from baseline to week 12 of −0.60% (p

Impaired diastolic heart function has been observed in persons with non-alcoholic fatty liver disease (NAFLD) and/or with type 2 diabetes mellitus (T2DM). However, it is unclear whether NAFLD fibrotic progression, i.e., non-alcoholic steatohepatitis, poses an independent risk for diastolic dysfunction in T2DM. We investigated the association between liver fibrosis and left ventricular (LV) diastolic dysfunction in T2DM.We analyzed 606 patients with T2DM, aged ≥50 years, who had undergone liver ultrasonography and pulsed-wave Doppler echocardiography. Insulin sensitivity was measured by short insulin tolerance test. Presence of NAFLD and/or advanced liver fibrosis was determined by abdominal ultrasonography and NAFLD fibrosis score (NFS). LV diastolic dysfunction was defined according to transmitral peak early to late ventricular filling (E/A) ratio and deceleration time, using echocardiography.LV diastolic dysfunction was significantly more prevalent in the NAFLD versus non-NAFLD group (59.7% vs. 49.0%,Liver fibrosis was associated with LV diastolic dysfunction in patients with T2DM and may be an independent risk factor for diastolic dysfunction, especially in patients without systemic insulin resistance.

Skeletal muscle, the largest part of the total body mass, influences energy and protein metabolism as well as maintaining homeostasis. Herein, we demonstrate that during murine muscle satellite cell and myoblast differentiation, transthyretin (TTR) can exocytose via exosomes and enter cells as TTR- thyroxine (T4) complex, which consecutively induces the intracellular triiodothyronine (T3) level, followed by T3 secretion out of the cell through the exosomes. The decrease in T3 with the TTR level in 26-week-old mouse muscle, compared to that in 16-week-old muscle, suggests an association of TTR with old muscle. Subsequent studies, including microarray analysis, demonstrated that T3-regulated genes, such as FNDC5 (Fibronectin type III domain containing 5, irisin) and RXR&gamma, (Retinoid X receptor gamma), are influenced by TTR knockdown, implying that thyroid hormones and TTR coordinate with each other with respect to muscle growth and development. These results suggest that, in addition to utilizing T4, skeletal muscle also distributes generated T3 to other tissues and has a vital role in sensing the intracellular T4 level. Furthermore, the results of TTR function with T4 in differentiation will be highly useful in the strategic development of novel therapeutics related to muscle homeostasis and regeneration.

The effects of an intermittent fasting diet (IFD) in the general population are still controversial. In this study, we aimed to systematically evaluate the effectiveness of an IFD to reduce body mass index and glucose metabolism in the general population without diabetes mellitus. Cochrane, PubMed, and Embase databases were searched to identify randomized controlled trials and controlled clinical trials that compared an IFD with a regular diet or a continuous calorie restriction diet. The effectiveness of an IFD was estimated by the weighted mean difference (WMD) for several variables associated with glucometabolic parameters including body mass index (BMI) and fasting glucose. The pooled mean differences of outcomes were calculated using a random effects model. From 2814 studies identified through a literature search, we finally selected 12 articles (545 participants). Compared with a control diet, an IFD was associated with a significant decline in BMI (WMD, &minus, 0.75 kg/m2, 95% CI, &minus, 1.44 to &minus, 0.06), fasting glucose level (WMD, &minus, 4.16 mg/dL, 6.92 to &minus, 1.40), and homeostatic model assessment of insulin resistance (WMD, &minus, 0.54, 1.05 to &minus, 0.03). Fat mass (WMD, &minus, 0.98 kg, 2.32 to 0.36) tended to decrease in the IFD group with a significant increase in adiponectin (WMD, 1008.9 ng/mL, 95% CI, 140.5 to 1877.3) and a decrease in leptin (WMD, &minus, 0.51 ng/mL, 0.77 to &minus, 0.24) levels. An IFD may provide a significant metabolic benefit by improving glycemic control, insulin resistance, and adipokine concentration with a reduction of BMI in adults.

Two spotted spider mite, Tetranychus urticae, is a polyphagous pest to a variety of plants and they are hard to be controlled due to occurrence of resistance to acaricides. In this study, biochemical evaluation after ethyl formate (EF) and phosphine (PH3) fumigation towards T. urticae might help officials to control them in quarantine purposes. PH3 fumigation controlled eggs (LC50; 0.158 mg/L), nymphs (LC50; 0.030 mg/L), and adults (LC50; 0.059 mg/L) of T. urticae, and EF effectively affected nymphs (LC50; 2.826 mg/L) rather than eggs (LC50; 6.797 mg/L) and adults (LC50; 5.836 mg/L). In a longer exposure time of 20 h, PH3 fumigation was 94.2-fold more effective tool for control of T. urticae than EF fumigant. EF and PH3 inhibited cytochrome c oxidase (COX) activity differently in both nymphs and adults of T. urticae. It confirmed COX is one of target sites of these fumigants in T. urticae and COX is involved in the respiratory chain as complex IV. Molecular approaches showed that EF fumigation completely down-regulated the expression of cox11 gene at the concentration of LC10 value, while PH3 up-regulated several genes greater than twofold in T. urticae nymphs treated with the concentration of LC50 value. These increased genes by PH3 fumigation are ndufv1, atpB, para, and ace, responsible for the expression of NADH dehydrogenase [ubiquinone] flavoprotein 1, ATP synthase, and acetylcholinesterase in insects, respectively. Lipidomic analyses exhibited a significant difference between two fumigants-exposed groups and the control, especially an ion with 815.46 m/z was analyzed less than twofold in the fumigants-treated group. It was identified as PI(15:1/18:3) and it may be used as a biomarker to EF and PH3 toxicity. These findings may contribute to set an effective control strategy on T. urticae by methyl bromide alternatives such as EF and PH3 because they have shared target sites on the respiratory chain in the pest.

BACKGROUND AND OBJECTIVES We sought to investigate an anti-atherosclerotic and anti-inflammatory effect of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in normoglycemic atherosclerotic rabbit model. METHODS Male New Zealand white rabbits (n=26) were fed with a 1% high-cholesterol diet for 7 weeks followed by normal diet for 2 weeks. After balloon catheter injury, the rabbits were administered with the Dapagliflozin (1mg/kg/day) or control-medium for 8 weeks (n=13 for each group). All lesions were assessed with angiography, optical coherence tomography (OCT), and histological assessment. RESULTS Atheroma burden (38.51±3.16% vs. 21.91±1.22%, p

Recent epidemiological studies have suggested an association between sarcopenia and non-alcoholic fatty liver disease (NAFLD) in the general population, prompting our investigation into the gender-specific association between sarcopenia and NAFLD in patients with type 2 diabetes mellitus (T2DM).In this cross-sectional study, 4210 patients with T2DM were recruited from the Seoul Metabolic Syndrome Cohort. Appendicular skeletal muscle mass (ASM) was estimated from bioimpedance analysis measurements, and the skeletal muscle mass index (SMI) was calculated by dividing the sum of ASM by body weight. Sarcopenia was defined as a gender-specific SMI value2 standard deviations (SDs) below the mean for healthy young adults. NAFLD was defined as the presence of hepatic steatosis on ultrasonography with no other causes of chronic liver disease.Among the entire study population (mean age: 57.4±10.8 years), 1278 (30.4%) had NAFLD and 1240 (29.5%) had sarcopenia, and the prevalence of NAFLD was significantly higher in those with sarcopenia: 46.2% vs 25.1% (P0.001) in men; 38.3% vs 25.4% (P0.001) in women. Sarcopenia was significantly associated with higher risk of NAFLD in men (adjusted odds ratio [OR]: 1.58, 95% confidence interval [CI]: 1.15-2.17), whereas the association was attenuated in women after adjusting for clinical risk factors.Sarcopenia is independently associated with NAFLD in men with T2DM, which suggests that sarcopenia may be a risk factor for NAFLD in men with T2DM.

The proton electric dipole moment (pEDM) experiment is proposed to be done with two counter-rotating beams in an all-electric storage ring. Radial magnetic field is one of the most critical systematic errors in the experiment as it mimics the EDM signal. Its secondary effect is a vertical split between the counter-rotating beams. According to the proposal of the pEDM experiment, that split should be monitored and compensated to picometer level by the beam position monitoring systems (BPM). We propose a BPM using Superconducting QUantum Interference Devices or SQUIDs to measure the beam splitting with such resolution that corresponds to magnetic field measurement with $10^{-18}$ T (aT) resolution. In this paper we experimentally demonstrate that the white noise of such magnetometers and SQUID read-out electronics can be decreased by more than two orders of magnitude down to 25 aT$\sqrt{\text{Hz}}$ by using 5 hour signal averaging. It demonstrates very high long-time stability and low intrinsic fluctuation level in the instrument. We expect that our next BPM version will be able to reach

In this paper, we propose a mixed-reality system that provides an immersive interaction space for both real and virtual objects. Using a custom-made video-see-thru (VST) HMD, the system streams high-resolution stereo images of what the user is currently looking at. Also, the proposed system includes a rotating 2D LiDAR that configures a geometry of the user's surrounding space. Based on the triangle mesh approach, the proposed system creates an interaction space from the point cloud data. With the constructed interaction space, the user experiences various interactions using both real and virtual objects in the mixed-reality environment. We demonstrate the feasibility and effectiveness of our system with a real-time application.

Objective: Ketones may be regarded as a thrifty fuel for peripheral tissues, but their clinical prognostic significance still remains unclear. We investigated the association between spontaneous fasting ketonuria and incident diabetes in conjunction with changes in metabolic parameters in a large population-based, observational study. Research Design and Methods: We analyzed a total of 8,703 individuals free of diabetes at baseline in the Korean Genome and Epidemiology Study, a community-based, 12-year prospective study. Subjects with (n=195) or without fasting ketonuria were 1:4 matched by propensity score. Incident diabetes was defined as: fasting plasma glucose ≥126 mg/dL, 2-hour glucose ≥200 mg/dL on biennial 75g oral glucose tolerance test, or current antidiabetic medication. Using Cox regression models, hazard ratios for developing diabetes associated with the presence of ketonuria at baseline were analyzed. Results: Over 12 years, of the 925 subjects in the propensity score matched cohort, 190 (20.5%) developed diabetes. The incidence rate of diabetes was significantly lower in subjects with spontaneous ketonuria compared to those without ketonuria (adjusted hazard ratio 0.64 [95% confidence interval=0.42-0.99]. This result was replicated in the whole cohort (HR 0.67 [95% CI: 0.46-0.98] after multivariate adjustment). During follow-up, subjects with ketonuria at baseline maintained lower 1-hour and 2-hour glucose levels, and a higher insulinogenic index during follow-up despite comparable baseline values. Conclusions: The presence of spontaneous fasting ketonuria was significantly associated with a reduced incidence rate of diabetes, independently of metabolic parameters. Our findings suggest spontaneous fasting ketonuria is a stable phenotype and a novel signature in the modulation of glucose metabolism. Disclosure S.J. Cho: None. I. Lee: None. S. Lee: None. E. Kang: None. E. Ferrannini: None. Y. Lee: None. G. Kim: None. B. Cha: None.

Background: Sarcopenia, an age-related decline in skeletal muscle mass, leads to metabolic and vascular abnormalities. However, little is known regarding the independent relationship between skeletal muscle mass and atherosclerosis in patients with type 2 diabetes mellitus (T2DM). The purpose of this study was to evaluate the association of skeletal muscle mass with markers of carotid atherosclerosis, carotid intima-media thickness (CIMT) and carotid artery plaque, in men and women with T2DM. Methods: In this cross-sectional study, a total of 8,918 patients (4,520 men and 4,398 women) with T2DM were recruited from the outpatient clinic of Huh’s Diabetes Center from 2003 to 2016. Skeletal muscle mass was estimated from bioimpedance analysis measurements and skeletal muscle mass index (SMI, %) was defined as skeletal muscle mass (kg)/total body weight (kg) × 100. Carotid ultrasonography was performed to measure mean CIMT of both common carotid arteries. Carotid artery plaque was defined as a focal structure protruding into the lumen of the vessel of ≥50% than the surrounding area. Results: In both men and women, the presence of carotid artery plaque was higher with decreasing SMI quartiles. In men, this association remained significant after adjustment for additional risk factors (ptrend Conclusion: Low muscle mass is associated with the presence of carotid artery plaque in men with T2DM. Disclosure M. Nam: None. D. Seo: None. M. Jung: None. S. Ahn: None. S. Hong: None. Y. Lee: None. Y. Choi: None. B. Huh: None. K. Huh: None. S. Kim: None. Funding National Research Foundation of Korea (2017R1D-1A1B03034581)

Background: Obese individuals with normal metabolic profiles, so-called “metabolically healthy obese (MHO)” status has shown better clinical outcomes via previous studies. However, studies dealing with the association between MHO and dementia, which is deeply associated with metabolic disorders, were still insufficient. We designed this study to assess the association between MHO and the risk of incident dementia. Methods: The present study is a retrospective cohort study, including 5,669,488 patients aged 60 years old or over without any history of dementia, by using the National Health Insurance System of South Korea. Subjects were divided into 4 groups based on their metabolic health and obesity status. Metabolic health was determined based on the criteria of metabolic syndrome by Adult Treatment Panel-III. Obesity was judged based on the baseline body mass index. The incidence of dementia was checked and compared longitudinally between 4 groups. Results: When we put the metabolically healthy non-obese group to the reference value (hazard ratio (HR) = 1), MHO group showed the lowest incidence of dementia (HR 0.87, 95% confidence interval (CI) 0.86-0.88). This trend was more prominent when we followed up the risk of Alzheimer’s disease as a subgroup analysis (HR 0.85, 95% CI 0.83-0.86). Non-obese subjects with metabolic syndrome showed significantly increased risk for overall dementia (HR 1.20, 95% CI 1.19-1.21), especially for vascular dementia (HR 1.41, 95% CI 1.38-1.45). Conclusion: MHO status was associated with lower risk for dementia, especially for Alzheimer’s disease. Disclosure J. Bae: None. J. Lee: None. Y. Cho: None. M. Lee: None. S. Lee: None. I. Lee: None. E. Kang: None. S.J. Cho: None. K. Han: None. B. Cha: None. Y. Lee: None.

Caspase 8 is a central player in the apoptotic cell death pathway and is also essential for cytokine processing. The critical role of this protease in cell death pathways has generated research interest because its activation has also been linked with neural cell death. Thus, blocking the activity of caspase 8 is considered a potential therapy for neurodegenerative diseases. To extend the repertoire of caspase 8 inhibitors, we employed several computational approaches to identify potential caspase 8 inhibitors. Based on the structural information of reported inhibitors, we designed several individual and consensus pharmacophore models and then screened the ZINC database, which contains 105,480 compounds. Screening generated 5332 candidates, but after applying stringent criteria only two candidate compounds, ZINC19370490 and ZINC04534268, were evaluated by molecular dynamics simulations and subjected to Molecular Mechanics/Poisson Boltzmann Surface Area (MM-PBSA) analysis. These compounds were stable throughout simulations and interacted with targeted protein by forming hydrogen and van der Waal bonds. MM-PBSA analysis showed that these compounds were comparable or better than reported caspase 8 inhibitors. Furthermore, their physical properties were found to be acceptable, and they are non-toxic according to the ADMET online server. We suggest that the inhibitory efficacies of ZINC19370490 and ZINC04534268 be subjected to experimental validation.

Amyloid-β (Aβ) accumulation in the brain is a pathological feature of Alzheimer’s disease (AD) and enhancing Aβ clearance is a potential therapeutic strategy. Pioglitazone is a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist and is widely used to treat type 2 diabetes. We previously reported that low-dose pioglitazone increased the expression of low-density lipoprotein receptor-related protein 1 (LRP1), which upregulates the clearance of Aβ, using human brain microvascular endothelial cells. We investigated whether low-dose pioglitazone can rescue the pathological phenotype and memory impairment in senescence-accelerated mouse prone-8 (SAMP8) mice by increasing LRP1 levels. SAMP8 mice were treated with vehicle or pioglitazone in dosages of 2 or 5 mg/kg/day for 7 weeks. In the water maze test, 2 mg/kg/day of pioglitazone significantly attenuated the increased escape latency in SAMP8 mice (p = 0.026), while 5 mg/kg/day of treatment did not. Compared with vehicle treatment, the hippocampi of SAMP8 mice with 2 mg/kg/day of pioglitazone exhibited fewer Aβ deposits and reduced Aβ1–40 levels, along with elevated LRP1 expression (p = 0.005). Collectively, our results proposed that a new therapeutic application of the PPAR-γ agonist for AD treatment should be considered at a lower dose than the conventional dose used to treat diabetes.

Nonalcoholic fatty liver disease (NAFLD) and diabetes are common metabolic disorders whose prevalence rates are expected to rise worldwide, corresponding to aging and increasingly obese populations. Compared to the general population (around 25%), 50% to 70% of people with diabetes have NAFLD, and NAFLD severity (including fibrosis) tends to be worsened by the presence of diabetes. NAFLD is considered an emerging risk factor for type 2 diabetes mellitus and a contributor to the development of chronic diabetes-related complications. This reciprocal relationship demonstrates the importance of confirming suspected NAFLD in patients with diabetes. Due to the invasive nature of liver biopsy to assess NAFLD status, various alternative non-invasive modalities have been developed and validated. Here, we summarized the epidemiology of NAFLD in patients with diabetes and reviewed currently available imaging modalities and biomarker-based prediction models for their ability to detect liver steatosis and/or fibrosis.

Diabetes is associated with cognitive impairment and greater risk for dementia, but the role of gamma-glutamyltransferase (γ-GT) in dementia has not been elucidated. We determined incident dementia including Alzheimer’s disease and vascular dementia, analyzing data from participants aged 40 years or older in the National Health Insurance Database, collected by the National Health Insurance Service in Korea, from January 2009 to December 2015. During a median follow-up of 7.6 years, 272,657 participants were diagnosed as having dementia. Higher serum γ-GT was associated with increased risk of dementia (HR = 1.22, 95% CI = 1.20–1.24), and had a strong positive association with early onset dementia (HR = 1.32, 95% CI = 1.24–1.40). An additive impact of higher γ-GT on dementia was observed regardless of glycemic status, and prevalent diabetes with the highest γ-GT quartile had a 1.8-fold increased dementia risk (HR = 1.82, 95% CI = 1.78–1.85). This effect of γ-GT concentration in diabetes was more prominent in individuals with vascular dementia (HR = 1.94, 95% CI = 1.84–2.04). In subgroup analysis, young age, male sex, and relatively healthy subjects with a higher γ-GT quartile had more increased dementia risk. In conclusion, γ-GT concentration as well as glycemic status could be a future risk factor for dementia in the general population.

Background The objective of this study was to identify a consensus on definition, diagnosis, treatment, and prognosis of frozen shoulder (FS) among shoulder specialists. Methods A questionnaire composed of 18 questions about FS-definition, classification, utilization of diagnostic modalities, the propriety of treatment at each stage, and prognosis-was sent to 95 shoulder specialists in Korea. Most questions (15 questions) required an answer on a 5-point analog scale (1, strongly disagree; 5, strongly agree); three questions about the propriety of treatment were binary. Results We received 71 responses (74.7%). Of the 71 respondents, 84.5% agreed with the proposed definition of FS, and 88.8% agreed that FS should be divided into primary and secondary types according to the proposed definition. Only 43.7% of the respondents agreed that FS in patients with systemic disease should be classified as secondary FS. For the diagnosis of FS, 71.9% agreed that plain radiography should be used and 64.8% agreed ultrasonography should be used. There was a high consensus on proper treatment of FS: 97.2% agreed on education, 94.4%, on the use of nonsteroidal anti-inflammatory drugs; 76.1%, on intra-articular steroid injections; and 97.2%, on stretching exercise. Among all respondents, 22.5% answered that more than 10% of the patients with FS do not respond to conservative treatment. Conclusions The survey revealed a general consensus among shoulder specialists on the definition and treatment of FS. However, classification of FS was found controversial.

To measure weak magnetoencephalography (MEG) signals, two basic technical requirements are sensitive magnetic sensors and reduction of environmental noises. Until now, magnetic field sensors based on superconducting quantum interference devices (SQUIDs) made from low-temperature superconductors are the main sensors used for measuring MEG signals. For effective reduction of strong environmental magnetic noise, combination of magnetic shielding and gradiometers (hardware and/or software) are typically used. Since SQUIDs are very sensitive devices, care should be taken in handling them and in using them for multichannel MEG sensor arrays. Electrostatic shocks or strong magnetic fields can damage the normal operation of SQUIDs. Cooling of the SQUIDs needs a helmet-shape dewar which should provide reliable operation for longer than 1 year in vacuum tightness, and boil-off of the liquid He should be optimized to have refill interval longer than 1 week. For economic MEG systems, the SQUID array should be simple in the manufacturing process, and the structure of the sensor array should be compact. For the MEG system to be operated easily, the process for signal acquisition and signal processing devices needs to be simple, using a single personal computer. A magnetically shielded room (MSR) is mandatory for urban hospitals or downtown laboratory environments. Considering the high cost of magnetic alloy used in the construction of a MSR, optimization and cost-effective construction is needed. Even if the MEG measurements are done in a quiet or well-shielded environment, the signal-to-noise ratio of MEG signals are not sufficiently high, and signal processing is needed to remove some artifacts generated from the human body. This chapter presents basic technical issues for MEG instrumentation, especially in fabricating and operating economic MEG systems. In the later part of this chapter, atomic magnetometers for future non-cryogenic MEG systems, and brain magnetic resonance based on low-field nuclear magnetic resonance for visualizing brain functional activity are described.

Interactions between myoblasts and the surrounding microenvironment led us to explore the role of fibromodulin (FMOD), an extracellular matrix protein, in the maintenance of myoblast stemness and function. Microarray analysis of FMODkd myoblasts and in silico studies were used to identify the top most differentially expressed genes in FMODkd, and helped establish that FMOD-based regulations of integral membrane protein 2a and clusterin are essential components of the myogenic program. Studies in knockout, obese, and diabetic mouse models helped characterize the operation of a novel FMOD-based regulatory circuit that controls myoblast switching from a myogenic to a lipid accumulation fate. FMOD regulation of myoblasts is an essential part of the myogenic program, and it offers opportunities for the development of therapeutics for the treatment of different muscle diseases.-Lee, E. J., Jan, A. T., Baig, M. H., Ahmad, K., Malik, A., Rabbani, G., Kim, T., Lee, I.-K., Lee, Y. H., Park, S.-Y., Choi, I. Fibromodulin and regulation of the intricate balance between myoblast differentiation to myocytes or adipocyte-like cells.

Rationale: Transverse myelitis (TM) is a spinal cord inflammatory myelopathy that causes motor/sensory loss and urinary retention below the level of the affected spinal cord. Although a few case reports have described the control of neuropathic pain in patients with TM via spinal cord stimulation, no documented case regarding the control of severe allodynia following TM via intrathecal pump has been described. Patient concerns: A 37-year-old woman was referred to a pain clinic for severe intractable pain below the T5 level followed by Sjögren's syndrome-induced TM. Diagnoses: A neurological examination revealed paresthesia and allodynia below the T5 level. The sensory evaluation was limited by extreme pain and jerking movements. The muscle strength of both lower limbs was grade 3. Interventions: Intrathecal pump was inserted into the left lower abdomen. Catheter tip was placed at the midline of the T8 level. Outcomes: The numeric rating scale (NRS) for pain score decreased from 10 to 5. Functional Independence Measure score increased from 67 before implantation to 92 at the time of discharge, while the patient's Barthel score increased from 31 to 46. Lessons: Neuropathic pain due to Sjögren's syndrome-related TM could be controlled effectively using the intrathecal morphine pump.