Search

Objective: We retrospectively investigated whether the dosage of prednisolone (PSL) affects the response rate in patients with idiopathic sudden sensorineural hearing loss (ISSNHL). Design: Retrospective. Methods: A total of 159 patients diagnosed with initial ISSNHL and hospitalized between April 2007 and March 2021 at Yokosuka Kyosai Hospital were treated with systemic steroid therapy (SST) as a primary therapy and evaluated by pure-tone audiometry once a month. The cohort was comprised of 82 males and 77 females, with a mean age of 60.9 years old (range 16-83), consisting of 76 and 83 right and left ears, respectively. A total of 135 and 24 patients received SST with PSL dosage at 200 mg/day for 3 days with a 6-day taper and at 100 mg/day for 3 days with a 6-day taper, respectively. Results: In grades 1-2, there were no significant differences in the therapeutic response rates between the 2 groups; however, in grades 3-4, the response rate in the 200 mg PSL dosage group was significantly higher. We extracted dosage of PSL, age, time from onset to treatment, and vertigo as variables affecting the recovery rate, which was defined as the sum of the rate of complete recovery and marked improvement. Multivariate logistic regression analysis identified age and vertigo as significant variables influencing the recovery rate. Conclusion: Systemic steroid therapy with more than 100 mg/day of PSL with a taper for ISSNHL may not increase therapeutic efficacy in a dose-dependent manner

Advanced glycation end-products (AGEs) have recently been implicated in the onset/progression of lifestyle-related diseases (LSRDs); therefore, the suppression of AGE-induced effects may be used in both the prevention and treatment of these diseases. Various AGEs are produced by different biological pathways in the body. Glyceraldehyde (GA) is an intermediate of glucose and fructose metabolism, and GA-derived AGEs (GA-AGEs), cytotoxic compounds that accumulate and induce damage in mammalian cells, contribute to the onset/progression of LSRDs. The following GA-AGE structures have been detected to date: triosidines, GA-derived pyridinium compounds, GA-derived pyrrolopyridinium lysine dimers, methylglyoxal-derived hydroimidazolone 1, and argpyrimidine. GA-AGEs are a key contributor to the formation of toxic AGEs (TAGE) in many cells. The extracellular leakage of TAGE affects the surrounding cells via interactions with the receptor for AGEs. Elevated serum levels of TAGE, which trigger different types of cell damage, may be used as a novel biomarker for the prevention and early diagnosis of LSRDs as well as in evaluations of treatment efficacy. This review provides an overview of the structures of GA-AGEs.

Superconducting (SC) tokamak JT-60SA plays an essential role in fusion research and development by supporting and complementing the ITER project, providing directions to the DEMO design activity and fostering next generation scientists and engineers. Since the short circuit incident at the terminal joints of equilibrium field coil #1 during the integrated commissioning (IC) in March 2021, both EU and JA implementing agencies (IAs) have examined how to ensure safe operation of JT-60SA by mitigating the risk of possible discharge occurrence inside the cryostat. Based on the experience of the global Paschen tests, the IAs have established a strategy of risk mitigation measures, which is a combination of (i) reinforcement of insulation, (ii) avoiding unnecessary voltage application to the coil systems and (iii) immediate de-energization of the coils when deteriorated vacuum conditions are detected. Thanks to the considerable efforts of the Integrated Project Team members, the IC restarted in May 2023. After confirmation of the SC state of the coil systems (TF, EF and CS), the coil energization test and the plasma operation phase 1 (OP-1) started. The first plasma was successfully achieved on 23 October 2023 with a limited value of voltage and current applied to the coils. The plasma configuration control was also confirmed with low plasma current and low auxiliary heating power conditions. Based on the IO–F4E–QST collaboration, activities of JT-60SA have been shared with the IO and provided an important lesson for ITER assembly and commissioning, and will provide an outstanding contribution to fusion research at large. After OP-1, maintenance & enhancement phase 1 (M/E-1) starts from January 2024, in which in-vessel components are installed, and heating and diagnostic systems are extensively upgraded to allow a high power heating experiment planned in OP-2. In order to make the best use of JT-60SA, a newly organized JT-60SA experiment team will refine the research plan for the future high heating power operation phase.

Background and purpose: Online magnetic resonance-guided adaptive radiotherapy (MRgART) is a new technology of radiotherapy and requires a new quality control program in many aspects. This study aimed to gain a deeper understanding of risks in online MRgART through the application of failure mode and effect analysis (FMEA) for more enhanced and effective quality assurance (QA) programs. Materials and methods: We present an FMEA conducted by a multidisciplinary team with more than two years of experience. A process map describing the whole process of online MRgART was developed and potential failure modes were identified. High-risk failure modes and their potential causes and corrective measures were also identified. Failure modes were classified into three categories, MRgRT, online ART, and conventional RT, to investigate their features. A comparison with previous studies was also conducted to gain a general perspective. Results: In total, 153 failure modes and 49 high risks were identified. Among all failure modes, 51, 63, and 66 were related to MRgRT, online ART, and conventional RT, respectively. The hazardous processes were structure segmentation, treatment planning, and treatment beam delivery. Lists of failure modes identified in this study and previous studies were presented. Based on the results, characteristics and general aspects of the risks were discussed. Conclusion: Exploring the results of the FMEA enhanced our understanding of risk characteristics to improve QA program of online MRgART.

Advanced glycation end-products (AGEs), formed through glyceraldehyde (GA) as an intermediate in non-enzymatic reactions with intracellular proteins, are cytotoxic and have been implicated in the pathogenesis of various diseases. Despite their significance, the mechanisms underlying the degradation of GA-derived AGEs (GA-AGEs) remain unclear. In the present study, we found that N-terminal checkpoint kinase 1 cleavage products (CHK1-CPs) and their mimic protein, d270WT, were degraded intracellularly post-GA exposure. Notably, a kinase-dead d270WT variant (d270KD) underwent rapid GA-induced degradation, primarily via the ubiquitin–proteasome pathway. The high-molecular-weight complexes formed by the GA stimulation of d270KD were abundant in the RIPA-insoluble fraction, which also contained high levels of GA-AGEs. Immunoprecipitation experiments indicated that the high-molecular-weight complexes of d270KD were modified by GA-AGEs and that p62/SQSTM1 was one of its components. The knockdown of p62 or treatment with chloroquine reduced the amount of high-molecular-weight complexes in the RIPA-insoluble fraction, indicating its involvement in the formation of GA-AGE aggregates. The present results suggest that the ubiquitin–proteasome pathway and p62 play a role in the degradation and aggregation of intracellular GA-AGEs. This study provides novel insights into the mechanisms underlying GA-AGE metabolism and may lead to the development of novel therapeutic strategies for diseases associated with the accumulation of GA-AGEs.

Abstract Non-alcoholic fatty liver disease (NAFLD) constitutes a metabolic disorder with high worldwide prevalence and increasing incidence. The inflammatory progressive state, non-alcoholic steatohepatitis (NASH), leads to liver fibrosis and carcinogenesis. Here, we evaluated whether tyrosinase mutation underlies NASH pathophysiology. Tyrosinase point-mutated B6 (Cg)-Tyr c-2J /J mice (B6 albino) and C57BL/6J black mice (B6 black) were fed with high cholesterol diet (HCD) for 10 weeks. Normal diet-fed mice served as controls. HCD-fed B6 albino exhibited high NASH susceptibility compared to B6 black, a phenotype not previously reported. Liver injury occurred in approximately 50% of B6 albino from one post HCD feeding, with elevated serum alanine aminotransferase and aspartate aminotransferase levels. NASH was induced following 2 weeks in severe-phenotypic B6 albino (sB6), but B6 black exhibited no symptoms, even after 10 weeks. HCD-fed sB6 albino showed significantly higher mortality rate. Histological analysis of the liver revealed significant inflammatory cell and lipid infiltration and severe fibrosis. Serum lipoprotein analysis revealed significantly higher chylomicron and very low-density lipoprotein levels in sB6 albino. Moreover, significantly higher small intestinal lipid absorption and lower fecal lipid excretion occurred together with elevated intestinal NPC1L1 expression. As the tyrosinase point mutation represents the only genetic difference between B6 albino and B6 black, our work will facilitate the identification of susceptible genetic factors for NASH development and expand the understanding of NASH pathophysiology.

Abstract Background 1,5-anhydroglucitol is a reduction product of 1,5-anhydrofructose. Circulating 1,5-anhydroglucitol is usually excreted by the kidneys and is reabsorbed via sodium-glucose co-transporter 4 in the renal tubules. In patients on hemodialysis, serum levels of 1,5-anhydroglucitol have been reported to be low; however, the underlying mechanism remains unclear. Methods We measured inter-dialysis changes in the levels of serum 1,5-anhydroglucitol and 1,5-anhydrofructose-derived advanced glycation end products (AGEs) in 78 patients on hemodialysis. Serum levels of 1,5-anhydrofructose-derived AGEs were also determined using a polyclonal antibody. Results The serum 1,5-anhydroglucitol level was decreased to as low as 2.0 μg/mL in the regular hemodialysis group; however, we could not verify changes in the serum 1,5-anhydroglucitol level during inter-dialysis days because of undetectable levels in 29 patients. The measured serum level of 1,5-anhydrofructose-derived AGEs was significantly increased in both patient groups. In addition, the 1,5-anhydrofructose-derived AGEs/1,5-anhydroglucitol ratio was higher in patients on hemodialysis than in controls. Conclusions Accelerated glycation of 1,5-anhydrofructose is one possible mechanism by which serum 1,5-anhydroglucitol levels are lowered in patients on HD, and we propose that the 1,5-anhydrofructose-derived AGEs/1,5-anhydroglucitol ratio should be measured in clinical settings in which patients have low serum levels of 1,5-AG.

Abstract Background Sarcopenia is a progressive condition that is characterized by decreases in skeletal muscle mass and function. Although sarcopenia is associated with lifestyle-related diseases (LSRD), the mechanisms underlying cell death in myoblasts, which differentiate to myotubes, remain unclear. We previously designated glyceraldehyde (an intermediate of glucose/fructose metabolism)-derived advanced glycation end-products (AGEs) as toxic AGEs (TAGE) because of their cytotoxicity and involvement in LSRD, and hypothesized that TAGE contribute to cell death in myoblasts. Methods C2C12 cells, which are murine myoblasts, were treated with 0, 0.5, 1, 1.5, and 2 mM glyceraldehyde for 24 h. Cell viability and intracellular TAGE were then assessed using 5-[2,4,-bis(sodioxysulfonyl)phenyl]-3-(2-methoxy-4-nitrophenyl)-2-(4-nitrophenyl)-2H-tetrazole-3-ium (WST-8) and slot blot assays. Cells were pretreated with 8 mM aminoguanidine, an inhibitor of AGE production, for 2 h, followed by 0, 1.5, and 2 mM glyceraldehyde for 24 h. Cell viability and intracellular TAGE levels were then assessed. Serum TAGE levels in STAM mice, in which there were four stages (no steatosis, simple steatosis, steatohepatitis, and fibrosis), were measured using a competitive enzyme-linked immunosorbent assay. Results were expressed as TAGE units (U) per milliliter of serum, with 1 U corresponding to 1.0 μg of glyceraldehyde-derived AGE-bovine serum albumin (BSA) (TAGE-BSA). The viability of cells treated with 20, 50, and 100 μg/mL non-glycated BSA and TAGE-BSA for 24 h was assessed using the WST-8 assay. Results In C2C12 cells treated with 1.5 and 2 mM glyceraldehyde, cell viability decreased to 47.7% (p = 0.0021) and 5.0% (p = 0.0001) and intracellular TAGE levels increased to 6.0 and 15.9 μg/mg protein, respectively. Changes in cell viability and TAGE production were completely inhibited by 8 mM aminoguanidine. Serum TAGE levels at the steatohepatitis and fibrosis stages were 10.51 ± 1.16 and 10.44 ± 0.95 U/mL, respectively, and were higher than those at the no steatosis stage (7.27 ± 0.18 U/mL). Cell death was not induced by 20 or 50 μg/mL TAGE-BSA. The viabilities of C2C12 cells treated with 100 μg/mL non-glycated BSA and TAGE-BSA were 105.0% (p = 0.2890) and 85.3% (p = 0.0217), respectively. Conclusion Intracellular TAGE strongly induced cell death in C2C12 cells and may also induce myoblast cell death in LSRD model mice.

The repeated excessive intake of sugar, a factor that contributes to the onset of nonalcoholic fatty liver disease (NAFLD) and its progression to the chronic form of nonalcoholic steatohepatitis (NASH), markedly increases the hepatocyte content of glyceraldehyde (GA), a glucose/fructose metabolic intermediate. Toxic advanced glycation end-products (toxic AGEs, TAGE) are synthesized by cross-linking reactions between the aldehyde group of GA and the amino group of proteins, and their accumulation has been implicated in the development of NAFLD/NASH and hepatocellular carcinoma (HCC). Our previous findings not only showed that hepatocyte disorders were induced by the intracellular accumulation of TAGE, but they also indicated that extracellular leakage resulted in elevated TAGE concentrations in circulating fluids. Interactions between extracellular TAGE and receptor for AGEs (RAGE) affect intracellular signaling and reactive oxygen species (ROS) production, which may, in turn, contribute to the pathological changes observed in NAFLD/NASH. RAGE plays a role in the effects of the extracellular leakage of TAGE on the surrounding cells, which ultimately promote the onset and progression of NAFLD/NASH. This review describes the relationships between intracellular TAGE levels and hepatocyte and hepatic stellate cell (HSC) damage as well as the TAGE–RAGE–ROS axis in hepatocytes, HSC, and HCC cells. The “TAGE theory” will provide novel insights for future research on NAFLD/NASH.

The habitual and excessive consumption of sugar (i.e., sucrose and high-fructose corn syrup, HFCS) is associated with the onset and progression of lifestyle-related diseases (LSRD). Advanced glycation end-products (AGEs) have recently been the focus of research on the factors contributing to LSRD. Approaches that inhibit the effects of AGEs may be used to prevent and/or treat LSRD; however, since the structures of AGEs vary depending on the type of reducing sugars or carbonyl compounds to which they respond, difficulties are associated with verifying that AGEs are an etiological factor. Cytotoxic AGEs derived from glyceraldehyde, a triose intermediate in the metabolism of glucose and fructose, have been implicated in LSRD and are called toxic AGEs (TAGE). A dietary imbalance (the habitual and excessive intake of sucrose, HFCS, or dietary AGEs) promotes the generation/accumulation of TAGE in vivo. Elevated circulating levels of TAGE have been detected in non-diabetics and diabetics, indicating a strong relationship between the generation/accumulation of TAGE in vivo and the onset and progression of LSRD. We herein outline current findings on “TAGE as a new target” for human health.

Cardiovascular disease (CVD) is a lifestyle-related disease (LSRD) induced by the dysfunction and cell death of cardiomyocytes. Cardiac fibroblasts are activated and differentiate in response to specific signals, such as transforming growth factor-β released from injured cardiomyocytes, and are crucial for the protection of cardiomyocytes, cardiac tissue repair, and remodeling. In contrast, cardiac fibroblasts have been shown to induce injury or death of cardiomyocytes and are implicated in the pathogenesis of diseases such as cardiac hypertrophy. We designated glyceraldehyde-derived advanced glycation end-products (AGEs) as toxic AGEs (TAGE) due to their cytotoxicity and association with LSRD. Intracellular TAGE in cardiomyocytes decreased their beating rate and induced cell death in the absence of myocardial ischemia. The TAGE levels in blood were elevated in patients with CVD and were associated with myocardial ischemia along with increased risk of atherosclerosis in vascular endothelial cells in vitro. The relationships between the dysfunction or cell death of cardiac fibroblasts and intracellular and extracellular TAGE, which are secreted from certain organs, remain unclear. We examined the cytotoxicity of intracellular TAGE by a slot blot analysis, and TAGE-modified bovine serum albumin (TAGE-BSA), a model of extracellular TAGE, in normal human cardiac fibroblasts (HCF). Intracellular TAGE induced cell death in normal HCF, whereas TAGE-BSA did not, even at aberrantly high non-physiological levels. Therefore, only intracellular TAGE induced cell death in HCF under physiological conditions, possibly inhibiting the role of HCF.