Identification of concealed cardiomyopathy using next-generation sequencing-based genetic testing in Korean patients initially diagnosed with idiopathic ventricular fibrillation.

AIMS: Idiopathic ventricular fibrillation (IVF) is a disease in which the cause of ventricular fibrillation cannot be identified despite comprehensive clinical evaluation. This study aimed to investigate the clinical yield and implications of genetic testing for IVF. METHODS AND RESULTS: This study was based on the multi-centre inherited arrhythmia syndrome registry in South Korea from 2014 to 2017. Next-generation sequencing-based genetic testing was performed that included 174 genes previously linked to cardiovascular disease. A total of 96 patients were clinically diagnosed with IVF. The mean age of the onset was 41.2 ± 12.7 years, and 79 patients were males (82.3%). Of these, 74 underwent genetic testing and four (5.4%) of the IVF probands had pathogenic or likely pathogenic variants (each having one of MYBPC3, MYH7, DSP, and TNNI3). All pathogenic or likely pathogenic variants were located in genes with definite evidence of a cardiomyopathy phenotype, either hypertrophic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy. CONCLUSION: Next-generation sequencing-based genetic testing identified pathogenic or likely pathogenic variants in 5.4% of patients initially diagnosed with IVF, suggesting that genetic testing with definite evidence genes of cardiomyopathy may enable molecular diagnosis in a minority of patients with IVF. Further clinical evaluation and follow-up of patients with IVF with positive genotypes are needed to unveil concealed phenotypes, such as the pre-clinical phase of cardiomyopathy.

Comparison of Factors Associated With Direct Versus Transferred-in Admission to Government-Designated Regional Centers Between Acute Ischemic Stroke and Myocardial Infarction in Korea.

BACKGROUND: There has been no comparison of the determinants of admission route between acute ischemic stroke (AIS) and acute myocardial infarction (AMI). We examined whether factors associated with direct versus transferred-in admission to regional cardiocerebrovascular centers (RCVCs) differed between AIS and AMI. METHODS: Using a nationwide RCVC registry, we identified consecutive patients presenting with AMI and AIS between July 2016 and December 2018. We explored factors associated with direct admission to RCVCs in patients with AIS and AMI and examined whether those associations differed between AIS and AMI, including interaction terms between each factor and disease type in multivariable models. To explore the influence of emergency medical service (EMS) paramedics on hospital selection, stratified analyses according to use of EMS were also performed. RESULTS: Among the 17,897 and 8,927 AIS and AMI patients, 66.6% and 48.2% were directly admitted to RCVCs, respectively. Multivariable analysis showed that previous coronary heart disease, prehospital awareness, higher education level, and EMS use increased the odds of direct admission to RCVCs, but the odds ratio (OR) was different between AIS and AMI (for the first 3 factors, AMI > AIS; for EMS use, AMI < AIS). EMS use was the single most important factor for both AIS and AMI (OR, 4.72 vs. 3.90). Hypertension and hyperlipidemia increased, while living alone decreased the odds of direct admission only in AMI; additionally, age (65-74 years), previous stroke, and presentation during non-working hours increased the odds only in AIS. EMS use weakened the associations between direct admission and most factors in both AIS and AMI. CONCLUSIONS: Various patient factors were differentially associated with direct admission to RCVCs between AIS and AMI. Public education for symptom awareness and use of EMS is essential in optimizing the transportation and hospitalization of patients with AMI and AIS.

A Trade-Off Analysis between Sensor Quality and Data Intervals for Prognostics Performance.

In safety-critical systems such as industrial plants or aircraft, failure occurs inevitably during operation, and it is important to prevent it in order to maintain high availability. To reduce this risk, a lot of efforts are directed from developing sensing technologies to failure prognosis algorithms to enable predictive maintenance. The success of effective and reliable predictive maintenance not only relies on robust prognosis algorithms but also on the selection of sensors or data acquisition strategy. However, there are not many in-depth studies on a trade-off between sensor quality and data storage in the view of prognosis performance. The information about (1) how often data should be measured and (2) how good sensor quality should be for reliable failure prediction can be highly impactful for practitioners. In this paper, the authors evaluate the efficacy of the two factors in terms of remaining useful life (RUL) prediction accuracy and its uncertainty. In addition, since knowing true degradation information is almost impossible in practice, the authors validated the use of the prognosis metric without requiring the true degradation information. A numerical case study is conducted to identify the relationship between sensor quality and data storage. Then, real bearing run-to-failure (RTF) datasets acquired from accelerometer (contact type) and microphone (non-contact type) sensors are evaluated based on the prognosis performance metric and compared in terms of the sensors' cost-effectiveness for predictive maintenance.

Sulforaphane Suppresses the Nicotine-Induced Expression of the Matrix Metalloproteinase-9 via Inhibiting ROS-Mediated AP-1 and NF-κB Signaling in Human Gastric Cancer Cells.

Sulforaphane, a natural phytochemical compound found in various cruciferous vegetables, has been discovered to present anti-cancer properties. Matrix metalloproteinase-9 (MMP-9) plays a crucial role in gastric cancer metastasis. However, the role of sulforaphane in MMP-9 expression in gastric cancer is not yet defined. Nicotine, a psychoactive alkaloid found in tobacco, is associated with the development of gastric cancer. Here, we found that sulforaphane suppresses the nicotine-mediated induction of MMP-9 in human gastric cancer cells. We discovered that reactive oxygen species (ROS) and MAPKs (p38 MAPK, Erk1/2) are involved in nicotine-induced MMP-9 expression. AP-1 and NF-κB are the critical transcription factors in MMP-9 expression. ROS/MAPK (p38 MAPK, Erk1/2) and ROS functioned as upstream signaling of AP-1 and NF-κB, respectively. Sulforaphane suppresses the nicotine-induced MMP-9 by inhibiting ROS-mediated MAPK (p38 MAPK, Erk1/2)/AP-1 and ROS-mediated NF-κB signaling axes, which in turn inhibit cell invasion in human gastric cancer AGS cells. Therefore, the current study provides valuable evidence for developing sulforaphane as a new anti-invasion strategy for human gastric cancer therapy.

The effects of vascular access types on the survival and quality of life and depression in the incident hemodialysis patients.

Background: Although arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis (HD), the association between vascular access types and quality of life is not well-known. We investigated the relationships between HD vascular access types and all-cause mortality, health-related quality of life (HRQOL) and the degree of depression in a large prospective cohort.Methods: A total of 1461 patients who newly initiated HD were included. The initial vascular access types were classified into AVF, arteriovenous graft (AVG), and central venous catheter (CVC). The primary outcomes were all-cause mortality and HRQOL and depression. The secondary outcome was all-cause hospitalization. Kidney Disease Quality of Life Short Form 36 (KDQOL-36) and Beck's depression inventory (BDI) scores were measured to assess HRQOL and depression.Results: Among 1461 patients, we identified 314 patients who started HD via AVF, 76 via AVG, and 1071 via CVC. In the survival analysis, patients with AVF showed significantly better survival compared with patients with other accesses (p < .001). The AVF and AVG group had higher KDQOL-36 score and lower BDI score than CVC group at 3 months and 12 months after the initiation of HD. The frequency of hospitalization was higher in patients with AVG compared to those with AVF (AVF 0.7 vs. AVG 1.1 times per year) (p = .024).Conclusions: The patients with AVF had better survival rate and low hospitalization rate, and the patients with AVF or AVG showed both higher HRQOL and lower depression scores than those with CVC.

Information Value-Based Fault Diagnosis of Train Door System under Multiple Operating Conditions.

While there are many data-driven diagnosis algorithms for fault isolation of complex systems, a new challenge arises in the case of multiple operating regimes. In this case, the diagnosis is usually carried out for each regime for better accuracy. However, the problem is that different results can be derived from each regime and they can conflict with each other, which may invalidate the performance of fault diagnosis. To address this challenge, a methodology for selecting the most reliable one among the different diagnostic results is proposed, which combines the Bayesian network (BN) and the information value (IV). The BN is trained for each regime and a conditional probability table is obtained for probabilistic fault diagnosis. The IV is then employed to evaluate the value of several diagnostic results. The proposed approach is applied to the fault diagnosis of a train door system and its effectiveness is proven.

Nicotine stimulates IL-6 expression by activating the AP-1 and STAT-3 pathways in human endothelial EA.hy926 cells.

Interleukin-6 (IL-6), a pleiotropic cytokine, plays a key role in endothelial injury and atherosclerosis. In this study, we investigated the effects of nicotine, a major psychoactive compound in cigarette smoke, on IL-6 expression and EA.hy926 endothelial cell invasion. Nicotine stimulated IL-6 expression via the activator protein 1 (AP-1) transcription factor. Pharmacological inhibition and mutagenesis studies indicated that p38 mitogen-activated protein kinase (MAPK) mediated the IL-6-induced upregulation of nicotine in EA.hy926 cells. Furthermore, the antioxidant compound N-acetyl-cysteine eliminated the nicotine-activated production of reactive oxygen species (ROS) and inhibited signal transducer and activator of transcription 3 (STAT-3) phosphorylation; these two mechanisms mediated the upregulation of IL-6 expression by nicotine. In addition, the EA.hy926 cells treated with nicotine displayed markedly enhanced invasiveness due to IL-6 upregulation. Our data demonstrate that nicotine induced IL-6 expression, which, in turn, enhanced the invasiveness of endothelial EA.hy926 cells, via activation of the p38 MAPK/AP-1 and ROS/STAT-3 signaling pathways.

Comparative efficacy and safety of gemigliptin versus linagliptin in type 2 diabetes patients with renal impairment: A 40-week extension of the GUARD randomized study.

AIMS: The long-term safety and efficacy of gemigliptin was evaluated in the present extension study after a 12-week study during a 40-week follow-up period. METHODS: The main study was a randomized, placebo-controlled, double-blinded, phase IIIb study in which 50 mg of gemigliptin (N = 66) or placebo (N = 66) was administered to patients with type 2 diabetes mellitus (T2DM) and moderate or severe renal impairment over a 12-week period. Patients with a glycated haemoglobin (HbA1c) level of 7% to 11% and an estimated glomerular filtration rate (eGFR) of 15 to 59 mL/min/1.73 m2 were enrolled in the main study. After 12 weeks, patients in the gemigliptin group continued to receive gemigliptin (N = 50), whereas patients in the placebo group were transitioned from placebo to linagliptin (N = 52). Each group received the indicated treatment over the subsequent 40-week period. A total of 102 patients consented to participate in the extension study, and 79 patients ultimately completed the study. RESULTS: The HbA1c levels of both groups were significantly reduced at week 52 compared with baseline. Specifically, the adjusted mean change ± standard error in HbA1c level in the gemigliptin and placebo/linagliptin groups was 1.00% ± 0.21% and 0.65% ± 0.22% lower at week 52 than at baseline (P < .001 and P = .003), respectively. No significant difference in the change in HbA1c level was found between the 2 groups (P = .148). Trends in fasting plasma glucose, fructosamine and glycated albumin levels in the 2 groups were similar to trends in HbA1c levels. The eGFR of both groups was also significantly lower at week 52 than at baseline, and no significant difference in change in eGFR was found between the 2 groups. In contrast, both drugs had little effect on urinary albumin excretion, although both drugs significantly reduced the urinary type IV collagen level. The overall rates of adverse events were similar between the 2 groups. CONCLUSIONS: Gemigliptin and linagliptin did not differ with respect to safety and efficacy in patients with T2DM and renal impairment. The 2 drugs had similar glucose-lowering effects, and the changes in eGFR and albuminuria were also similar. Additionally, the risk of side effects, including hypoglycaemia, was similar between the 2 groups.

Quality of Anticoagulation and Treatment Satisfaction in Patients with Non-Valvular Atrial Fibrillation Treated with Vitamin K Antagonist: Result from the KORean Atrial Fibrillation Investigation II.

BACKGROUND: Vitamin K antagonist (VKA) to prevent thromboembolism in non-valvular atrial fibrillation (NVAF) patients has limitations such as drug interaction. This study investigated the clinical characteristics of Korean patients treated with VKA for stroke prevention and assessed quality of VKA therapy and treatment satisfaction. METHODS: We conducted a multicenter, prospective, non-interventional study. Patients with CHADS2 ≥ 1 and treated with VKA (started within the last 3 months) were enrolled from April 2013 to March 2014. Demographic and clinical features including risk factors of stroke and VKA treatment information was collected at baseline. Treatment patterns and international normalized ratio (INR) level were evaluated during follow-up. Time in therapeutic range (TTR) > 60% indicated well-controlled INR. Treatment satisfaction on the VKA use was measured by Treatment Satisfaction Questionnaire for Medication (TSQM) after 3 months of follow-up. RESULTS: A total of 877 patients (age, 67; male, 60%) were enrolled and followed up for one year. More than half of patients (56%) had CHADS2 ≥ 2 and 83.6% had CHA2DS2-VASc ≥ 2. A total of 852 patients had one or more INR measurement during their follow-up period. Among those patients, 25.5% discontinued VKA treatment during follow-up. Of all patients, 626 patients (73%) had poor-controlled INR (TTR < 60%) measure. Patients' treatment satisfaction measured with TSQM was 55.6 in global satisfaction domain. CONCLUSION: INR was poorly controlled in Korean NVAF patients treated with VKA. VKA users also showed low treatment satisfaction.

Comparison of outcomes between the incremental and thrice-weekly initiation of hemodialysis: a propensity-matched study of a prospective cohort in Korea.

Background: Recent reports have suggested the possible benefit of beginning hemodialysis (HD) at a rate less frequent than three times weekly and incrementally increasing the dialysis dose. However, the data regarding the benefits and safety of incremental HD are insufficient. Methods: We analyzed 927 patients with newly initiated HD from the Clinical Research Center for End-Stage Renal Disease cohort from 2008 to 2014. The patients were classified into a thrice-weekly initiation group or an incremental initiation group (one to two sessions per week) according to the frequency of HD per week at baseline. We compared health-related quality of life (HRQOL), daily urine volume at 12 months and all-cause mortality between the groups. We matched the thrice-weekly and incremental groups at a 1:2 ratio using propensity score matching. Results: A total of 312 patients (207 in the thrice-weekly group and 105 in the incremental group) were selected. All-cause mortality was comparable between the two groups before and after propensity score matching. The HRQOL tended to be better in the incremental group for the majority of domains of the Kidney Disease Quality of Life Short Form and Beck's Depression Inventory; however, only the symptoms and problems domain was significantly better in the incremental group at 3 months after HD. At 12 months after HD, there were no differences between the groups. The daily urine volume at 12 months after HD was similar between the two groups. Conclusions: Incremental HD initiation showed comparable results to thrice-weekly initiation for HRQOL, residual renal function and all-cause mortality. Incremental HD may be considered an additional option for HD initiation in selected patients.

Nonincisional Conjoint Fascial Sheath Suspension: A Novel Technique for Minimally Invasive Blepharoptosis Correction.

BACKGROUND: Mild to moderate blepharoptosis, or ptosis, is relatively common among Asians, and it is not uncommon to offer ptosis correction at the time of double-eyelid surgery in this patient population. The traditional open approaches to ptosis correction are subject to scarring and prolonged recovery time, whereas the newer nonincisional approaches are marred by issues of incomplete correction or recurrence. This study describes a new nonincisional technique that overcomes the limitations of current methods by using conjoint fascial sheath (CFS) for suspension. METHODS: From January 2014 to April 2015, a retrospective review was conducted on 21 patients (41 eyelids) who underwent simultaneous nonincisional ptosis correction and double-eyelid surgery. All patients had either mild or moderate ptosis without excess skin hooding and excellent or good levator palpebrae function. RESULTS: Mild ptosis correction (1-loop CFS suspension) was performed in 25 eyelids, and moderate ptosis correction (2-loop CFS suspension) was performed in 16 eyelids. At 6 months of follow-up, 23 eyelids (56.1 %) improved to "normal" with overall improvement seen in 33 eyelids (80.0%). The mean marginal reflex distance 1 increased from 3.16 ± 0.61 mm preoperatively to 4.11 ± 0.61 mm postoperatively, which was statistically significant (P < 0.001). CONCLUSIONS: Mild to moderate ptosis correction with nonincisional CFS suspension technique is a safe and effective method that combines the benefits of nonincisional procedure with longevity and precision seen in the traditional open approaches. The procedure is easy to perform with minimal recovery time and high patient satisfaction and can be combined with nonincisional double-eyelid surgery.

Comparison of Outcomes with Arteriovenous Fistula and Arteriovenous Graft for Vascular Access in Hemodialysis: A Prospective Cohort Study.

BACKGROUND: Poor vessel quality and limited life expectancy in the elderly may make arteriovenous fistula (AVF) less ideal than arteriovenous graft (AVG) or catheter for vascular access (VA) in hemodialysis (HD). METHODS: A total of 946 adult incident HD patients from clinical research center registry for end-stage renal disease prospective cohort in South Korea were analyzed for outcomes with AVF and AVG. RESULTS: Overall, AVF was associated with better patient survival only in male (p < 0.001) and diabetic (p = 0.004) patients, although it was superior to AVG in access patency, regardless of diabetes mellitus status and gender. AVG (vs. AVF; hazard ratio (HR) 2.282; 95% CI 1.071-4.861; p = 0.032) was associated with poor patient survival. In elderly patients (≥65 years), AVF was associated with survival benefit only in male (p < 0.001) and diabetic (p = 0.04) patients, and with better access patency only in female (p = 0.05) and diabetic (p = 0.04) patients. AVG (vs. AVF; HR 3.158; 95% CI 1.080-9.238; p = 0.036) was associated with poor patient survival. In septuagenarian patients, AVF was associated only with survival benefit (p = 0.01) and there was no advantage in access patency (p = 0.12). However, AVF was superior to AVG in both access patency (p = 0.001) and patient survival (p = 0.03) even with propensity matching. CONCLUSION: AVF is the more desirable VA and its survival benefits warrant its consideration in septuagenarian patients although a prolonged life expectancy is essential to realize the potential benefits of AVF.

Serum ß2-Microglobulin Predicts Mortality in Peritoneal Dialysis Patients: A Prospective Cohort Study.

BACKGROUND/AIMS: ß2-Microglobulin (ß2-M) is a surrogate marker of middle-molecule uremic toxins and is associated with mortality in chronic hemodialysis patients. However, the impact of serum ß2-M levels on mortality in peritoneal dialysis (PD) patients is uncertain. The purpose of this study was to examine the association of serum ß2-M levels with all-cause mortality in PD patients. METHODS: A total of 771 PD patients were selected from the Clinical Research Center registry for end-stage renal disease cohort in Korea. Patients were categorized into 3 groups by tertiles of serum ß2-M levels. The primary outcome was all-cause mortality. RESULTS: The median value of serum ß2-M was 23.6 mg/l (interquartile range 14.8-33.4 mg/l), and the median follow-up period was 39 months. The Kaplan-Meier analysis showed that the all-cause mortality rate was significantly different according to tertiles of serum ß2-M in PD patients (p=0.03, log-rank). Multivariate Cox proportional analysis showed that the hazards ratio for all-cause mortality was 1.02 (95% CI 1.01-1.04, p=0.006) per 1 mg/l increase in ß2-M after adjustment for multiple confounding factors that relate to malnutrition and inflammation marker. However, serum ß2-M was not associated with all-cause mortality after adjustment for residual renal clearance. CONCLUSIONS: These results are supportive of the potential role of the serum ß2-M level as a predictor of mortality in PD patients.

Serum Ferritin Predicts Mortality Regardless of Inflammatory and Nutritional Status in Patients Starting Dialysis: A Prospective Cohort Study.

BACKGROUND: The impact of serum ferritin on prognosis in patients starting hemodialysis (HD) is not fully elucidated. METHODS: A prospective cohort of 946 incident HD patients from 26 dialysis centers in Korea was selected for this study. Patients were divided into tertiles according to natural logarithm (Ln) ferritin concentrations. RESULTS: During a median follow-up of 39 months, 88 (9.3%) patients died. Multivariate Cox proportional hazard analysis demonstrated that Ln ferritin was independently associated with an increase in cardiovascular mortality risk (hazard ratio (HR) 1.604, 95% CI 1.040-2.474, p = 0.033), infection-related mortality risk (HR 1.916, 95% CI 1.056-3.476, p = 0.032), and all-cause mortality risk (HR 1.547, 95% CI 1.156-2.069, p = 0.003). CONCLUSION: Serum ferritin levels at the time of HD commencement were a significant independent risk factor for mortality regardless of systemic inflammation and nutritional status. Therefore, elevated serum ferritin levels could be an effective indicator for prognosis.

Structural studies of the spinosyn forosaminyltransferase, SpnP.

Spinosyns A and D (spinosad) are complex polyketide natural products biosynthesized through the cooperation of a modular polyketide synthase and several tailoring enzymes. SpnP catalyzes the final tailoring step, transferring forosamine from a TDP-D-forosamine donor substrate to a spinosyn pseudoaglycone acceptor substrate. Sequence analysis indicated that SpnP belongs to a small group of glycosyltransferases (GTs) that require an auxiliary protein for activation. However, unlike other GTs in this subgroup, no putative auxiliary protein gene could be located in the biosynthetic gene cluster. To learn more about SpnP, the structures of SpnP and its complex with TDP were determined to 2.50 and 3.15 Å resolution, respectively. Binding of TDP causes the reordering of several residues in the donor substrate pocket. SpnP possesses a structural feature that has only been previously observed in the related glycosyltransferase EryCIII, in which it mediates association with the auxiliary protein EryCII. This motif, H-X-R-X5-D-X5-R-X12-20-D-P-X3-W-L-X12-18-E-X4-G, may be predictive of glycosyltransferases that interact with an auxiliary protein. A reverse glycosyl transfer assay demonstrated that SpnP possesses measurable activity in the absence of an auxiliary protein. Our data suggest that SpnP can bind its donor substrate by itself but that the glycosyl transfer reaction is facilitated by an auxiliary protein that aids in the correct folding of a flexible loop surrounding the pseudoaglycone acceptor substrate-binding pocket.

Interdialytic weight gain and cardiovascular outcome in incident hemodialysis patients.

BACKGROUND: Interdialytic weight gain (IDWG) has been regarded as a surrogate of volume overload, but also as a marker of a better nutritional status in end-stage renal disease (ESRD) patients on hemodialysis (HD). This paradoxical meaning of IDWG requires further investigation, particularly in adverse cardiovascular outcomes. METHODS: A prospective cohort of 1,013 incident HD patients from 36 HD centers of the Clinical Research Center for ESRD in Korea was included. Patients were categorized into five groups according to the IDWG%, a ratio of absolute IDWG to dry weight: <1.0, ≥4.0, and every 1.0 increment in between. Primary outcome was major adverse cardiac and cerebrovascular events (MACCE). RESULTS: During a mean follow-up of 18.7 months, primary outcome was observed in 104 patients (10.3%). In multivariate analysis, compared to patients with IDWG% of 1.0-1.9 (reference group), the hazard ratios (HRs) for primary outcome in the IDWG% <1.0, 2.0-2.9, 3.0-3.9, and ≥4.0 groups were 1.10 [95% confidence interval (CI) 0.55-2.20, p = 0.80], 1.15 (95% CI 0.59-2.27, p = 0.68), 1.80 (95% CI 0.95-3.41, p = 0.07), and 1.93 (95% CI 1.02-3.64, p = 0.04), respectively. Furthermore, even when residual renal function and 24-hour urine volume were adjusted, IDWG% ≥4.0 remained as a significant predictor of primary outcome (HR 2.03, 95% CI 1.02-4.02, p = 0.04). CONCLUSION: Increased IDWG% is a significant independent predictor of MACCE in incident HD patients. It could be helpful to prevent excessive IDWG for improving clinical outcomes in incident HD patients.

LDL cholesterol affects clinical outcomes in incident hemodialysis patients during the early stages of dialysis.

BACKGROUND/AIMS: Using a cohort of incident hemodialysis (HD) patients, this study investigated the impact of lipid profiles on clinical outcomes, especially in the early period of dialysis. METHODS: A prospective cohort of 867 incident HD patients was selected. In order to determine the impact of cholesterol level on primary outcome, Cox regression analyses were performed for LDL and non-HDL (NHDL) variables. RESULTS: Univariate analysis revealed an increase in primary outcome risk with an LDL cholesterol level of 100 mg/dl or higher compared to an LDL cholesterol level lower than 100 mg/dl. High LDL cholesterol remained a significant independent predictor of the composite outcome, even after adjusting for age, gender, diabetes mellitus, preexisting CV disease, albumin, and hs-CRP. CONCLUSION: Serum LDL cholesterol at the time of HD commencement was a significant independent risk factor for the composite outcome of all-cause mortality and CV events in incident HD patients during the early stages of dialysis.

Lys1110 of TRPM2 is critical for channel activation.

TRPM2 (transient receptor potential melastatin 2) is a non-selective Ca2+-permeable cation channel activated by ADPR (adenosine diphosphoribose) and H2O2. It is widely expressed in mammalian cells and plays an important role in the regulation of various cell functions. However, the mechanisms of TRPM2 channel activation are not fully understood. Previously, we reported that TRPM2 channel activation is induced by high intracellular Cl- concentration. In the present study, we investigated the functional role of Lys1110 in the membrane-proximal C-terminal region by site-directed mutagenesis. Replacement of the positively charged amino acid lysine (Lys1110) with the neutrally charged amino acid asparagine (K1110N) or the negatively charged amino acid glutamic acid (K1110E) generated mutants that failed to induce an increase in free cytosolic calcium concentration ([Ca2+]i) not only by intracellular injection of Cl-, but also by H2O2 or ADPR. However, a mutant generated by replacing the lysine residue with a positively charged amino acid arginine (K1110R) displayed channel activity similar to wild-type TRPM2. Interestingly, in the K1107N/K1110N double-point mutant, the impaired function of the K1110N mutant in response to ADPR and H2O2, but not to Cl-, was recovered. There were no changes in protein expression, membrane trafficking and oligomerization of the mutant channels. The extent of [Ca2+]i increase by H2O2 in HEK (human embryonic kidney)-293 cells expressing TRPM2 mutants was well correlated with the degree of susceptibility to H2O2-induced cell death. These results display the crucial role of a positively charged amino acid residue at position 1110 for TRPM2 channel activity.

Metabolically Abnormal Non-Obese Phenotype Is Significantly Associated with All-Cause Mortality in Hemodialysis Patients.

The association between obesity and all-cause mortality in patients undergoing kidney failure with replacement therapy (KFRT) has shown conflicting results. This study aimed to evaluate whether metabolic abnormalities (MA) increase the risk of all-cause mortality in these patients. Between 2009 and 2015, 1141 patients undergoing KFRT were recruited from the Clinical Research Center for End-Stage Renal Disease dataset. Patients were divided into four groups according to the presence of obesity and MA. Multivariate Cox proportional hazard analysis was performed to determine the association between the phenotypes and all-cause mortality. During a mean follow-up of 4.2 years, all-cause mortality was observed in 491 (43.0%) patients. Obesity had a 24% decreased risk of all-cause mortality compared with non-obesity. In contrast, the presence of MA showed a 1.53-fold increased risk of all-cause mortality. There was a significant interaction between obesity and MA (p = 0.006). In Cox proportional hazard analyses after adjustment of confounding factors, the metabolically abnormal non-obesity (MANO) phenotype showed a 1.63-fold increased risk of all-cause mortality compared with the metabolically healthy non-obesity phenotype. In subgroup analysis, the risk of all-cause mortality was higher in the MANO phenotype; this phenotype was significantly associated with a higher all-cause mortality in patients undergoing KFRT.