Construction of a screening system for lipid-derived radical inhibitors and validation of hit compounds to target retinal and cerebrovascular diseases.

Recent studies have highlighted the indispensable role of oxidized lipids in inflammatory responses, cell death, and disease pathogenesis. Consequently, inhibitors targeting oxidized lipids, particularly lipid-derived radicals critical in lipid peroxidation, which are known as radical-trapping antioxidants (RTAs), have been actively pursued. We focused our investigation on nitroxide compounds that have rapid second-order reaction rate constants for reaction with lipid-derived radicals. A novel screening system was developed by employing competitive reactions between library compounds and a newly developed profluorescence nitroxide probe with lipid-derived radicals to identify RTA compounds. A PubMed search of the top hit compounds revealed their wide application as repositioned drugs. Notably, the inhibitory efficacy of methyldopa, selected from these compounds, against retinal damage and bilateral common carotid artery stenosis was confirmed in animal models. These findings underscore the efficacy of our screening system and suggest that it is an effective approach for the discovery of RTA compounds.

Ethoxyquin, a Lipid Peroxidation Inhibitor, Has Protective Effects against White Matter Lesions in a Mouse Model of Chronic Cerebral Hypoperfusion.

White matter lesions induced by chronic cerebral hypoperfusion can cause vascular dementia; however, no appropriate treatments are currently available for these diseases. In this study, we investigated lipid peroxidation, which has recently been pointed out to be associated with cerebrovascular disease and vascular dementia, as a therapeutic target for chronic cerebral hypoperfusion. We used ethoxyquin, a lipid-soluble antioxidant, in a neuronal cell line and mouse model of the disease. The cytoprotective effect of ethoxyquin on glutamate-stimulated HT-22 cells, a mouse hippocampal cell line, was comparable to that of a ferroptosis inhibitor. In addition, the administration of ethoxyquin to bilateral common carotid artery stenosis model mice suppressed white matter lesions, blood-brain barrier disruption, and glial cell activation. Taken together, we propose that the inhibition of lipid peroxidation may be a useful therapeutic approach for chronic cerebrovascular disease and the resulting white matter lesions.

Transcoronary mapping using a guidewire during transcoronary ethanol ablation for ventricular tachycardia with a deep intramural substrate: a case report.

Background: Transcoronary ethanol ablation is effective in treating ventricular tachycardia (VT) in the deep myocardium. The selection of the target coronary artery plays an important role in the success of transcoronary ethanol ablation. Transcoronary mapping, using a guidewire, may be effective for identifying the target coronary artery. Case summary: A 72-year-old man, who had undergone thrombolytic therapy for acute myocardial infarction 40 years ago, was admitted to the emergency department with a chief complaint of syncope. Five years ago, a cardiac resynchronization therapy defibrillator was implanted for a left bundle branch block (QRS duration 153 ms), with New York Heart Association Class Ⅲ and a left ventricular ejection fraction of 30%.Due to VT, he experienced a critical deterioration in his vital parameters, leading to shock. The first VT ablation was performed on the 3rd day of hospitalization. Activation mapping showed that the earliest activation site was located in the mid-anterior septum of the left ventricle. Mapping from the endocardial surface showed no mid-diastolic potential around the VT. Radiofrequency catheter ablation therapy was performed at the targeted site, resulting in transient termination of VT. However, the VT showed recurrence the next day. A transcoronary ethanol ablation was performed on the 10th day of hospitalization. A 0.014 inch guidewire and microcatheter were advanced into the target coronary septal branch, and the myocardial septum was mapped. The guidewire-assisted transcoronary mapping showed a potential 43 ms ahead of QRS onset during VT. The coronary septal artery branch was considered the target artery, and 0.5 mL of ethanol was injected. No further VT was observed for 12 months after the transcoronary ethanol ablation. Discussion: Transcoronary ethanol ablation is considered in cases where a deep intramural substrate is suspected or when early activation at the interventricular septum is identified. Guidewire-assisted transcoronary mapping allows mapping of VT with deep intramural substrates and may be useful in selecting target coronary arteries while performing transcoronary ethanol ablation.

Is a freeze-all strategy necessary for all embryo transfers†: Fresh embryo transfer without progesterone elevation results in an equivalent pregnancy rate to cryopreserved embryo transfer.

Objectives : It has been suggested that the clinical outcomes of frozen-thawed embryo transfer (ET) are superior to those of fresh embryo transfer. We examined whether a freeze-all strategy is necessary for all embryo transfers, and, if not, to evaluate the conditions in which the pregnancy rates of fresh embryo transfer and frozen-thawed ET did not differ. Methods : Patients who underwent blastocyst transfer at Tokushima University Hospital between 2008 and 2019 were enrolled. The clinical outcomes and clinical characteristics of 1,022 patients that underwent fresh embryo transfer and 1,728 patients that underwent frozen-thawed ET were examined retrospectively. We considered the factors that influenced the pregnancy outcomes of fresh embryo transfer. Results : The frozen-thawed ET group exhibited significantly higher pregnancy, live-birth, and miscarriage rates than the fresh embryo transfer group. In the fresh embryo transfer group, a high progesterone level on the day of the human chorionic gonadotropin (hCG) trigger and lower grade embryos were risk factors for a low pregnancy rate. However, in the cases in which the progesterone level was < 1.0 ng / mL the pregnancy rate was equal to that of frozen-thawed ET. Conclusions : A freeze-all strategy is not necessary for embryo transfers, but should be employed in cases involving pre-ovulatory progesterone elevation. J. Med. Invest. 69 : 224-229, August, 2022.

Real-World Data on Ramucirumab Therapy including Patients Who Experienced Two or More Systemic Treatments: A Multicenter Study.

BACKGROUND: The present study aimed to clarify the efficacy and safety of ramucirumab in a real-world setting, including patients who experienced two or more systemic treatments or whose hepatic reserve was deteriorated. METHODS: In total, 79 patients with hepatocellular carcinoma (HCC) from 14 institutes throughout Japan were retrospectively analyzed. The response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and AEs were recorded according to the Common Terminology Criteria for AEs (CTCAE) version 5.0. RESULTS: Median overall survival (OS) in the total cohort was 7.5 months (m). Median OS was 8.8 m in patients who were administered ramucirumab as a second-line treatment, while it was 7.3 m in third- or later-line treatment. Progression-free survival rates in the second- and third- or later-line therapies were 3.2 m and 3.2 m, respectively. The disease control rate (DCR) in the study was 43%. There were no statistically significant differences in DCR between the treatment courses. Regarding adverse events (AEs), the development of ascites was observed significantly more frequently in modified albumin-bilirubin (mALBI) 2b/3 patients than in mALBI 1/2a patients (54.5% vs. 25.0%, p = 0.03). CONCLUSIONS: Ramucirumab is useful as a second-line therapy and feasible as a third- or later-line treatment for HCC.

Realization of Low-wax Lipstick by Rubber Molding Technology.

Reducing the quantity of wax in lipstick can improve the properties of the lipstick, including the glossiness, moisturizing capability, and longevity. However, lipsticks with less wax tend to break more easily. Therefore, to prevent breakage while reducing the wax content, we focused on the crystal structure of the wax gel and strain generated during the cooling and solidification processes as they are structural factors that affect fragility. Generally, if the crystals and strain are small, the structure is less easily broken. However, because the tip of the lipstick cools more rapidly from below than the root, the strain of the root against the tip increases owing to poor heat transmission. This creates large shrink holes in the root. While reheating from above can suppress the generation of shrink holes, it also causes the crystals to grow larger and the structure to become weak owing to slow cooling. Therefore, we adopted a rubber-molding technology generally used to form logos and complicated shapes as a strategy to mitigate these issues. This successfully reduced the strain generated inside the lipstick during the cooling process, as the rubber mold shrunk along with the lipstick, making it possible to quench the root. Therefore, we were able to realize a small crystal structure and low strain on the root of the lipstick. Our results demonstrate that it is possible to realize a lipstick with excellent features by reducing the quantity of wax.

Long-term wheel-running prevents reduction of grip strength in type 2 diabetic rats.

Diabetic skeletal muscles show reduced contractile force and increased fatigability. Hands are a target for several diabetes-induced complications. Therefore, reduced handgrip strength often occurs as a consequence of diabetes. The aim of this study was to examine whether long-term exercise can prevent reduction of grip strength in type 2 diabetes mellitus (T2DM) model OLETF rats, and to explore the mechanisms underlying diabetes-induced grip strength reduction. Ten 5-week-old OLETF rats were used as experimental animals, and five non-diabetic LETO rats as controls of OLETF rats. Half OLETF rats performed daily voluntary wheel-running for 17 months (OLETF + EXE), and the rest of OLETF and LETO rats were sedentary. Grip strength was higher in OLETF + EXE and LETO groups than in OLETF group. OLETF group with hyperglycemia showed an increase in HbA1c, serum TNF-α, and muscle SERCA activity, but a decrease in circulating insulin. Each fiber area, total fiber area, and % total fiber area in type IIb fibers of extensor digitorum longus muscles were larger in OLETF + EXE and LETO groups than in OLETF group. There was a positive correlation between grip strength and the above three parameters concerning type IIb fiber area. Therefore, type IIb fiber atrophy may be the major direct cause of grip strength reduction in OLETF group, although there seems multiple etiological mechanisms. Long-term wheel-running may have blocked the diabetes-induced reduction of grip strength by preventing type IIb fiber atrophy. Regular exercise may be a potent modality for preventing not only the progression of diabetes but muscle dysfunction in T2DM patients.

Paroxysmal Atrioventricular Block in a Relatively Young Patient with COVID-19.

Cardiac involvement has been reported in patients with coronavirus disease 2019 (COVID-19). We herein report a 41-year-old man who presented with recurrent paroxysmal atrioventricular block without showing significant cardiac injuries or comorbidities. The patient was diagnosed with COVID-19 and admitted to our hospital, where he was noted to have paroxysmal atrioventricular block. Cardiac biomarkers, echocardiography, and cardiac magnetic resonance imaging findings were fairly normal. An endomyocardial biopsy performed before the implantation of a permanent pacemaker revealed mild myocardial fibrosis without inflammatory infiltrates. The unusual myocardial involvement of the novel coronavirus was suspected.

Eccentric Resistance Training Ameliorates Muscle Weakness in a Mouse Model of Idiopathic Inflammatory Myopathies.

OBJECTIVE: High-force eccentric contractions (ECCs) have traditionally been excluded from rehabilitation programs that include patients with idiopathic inflammatory myopathies (IIMs) due to unverified fear of causing muscle damage and inflammation. In an IIM animal model that used mice with experimental autoimmune myositis (EAM), we undertook this study to investigate whether ECC training can safely and effectively be used to counteract muscle weakness in IIM. METHODS: EAM was induced in BALB/c mice by immunization with 3 injections of myosin emulsified in Freund's complete adjuvant. Controls (n = 12) and mice with EAM (n = 12) were exposed to either an acute bout of 100 ECCs or 4 weeks of ECC training (20 ECCs every other day). To induce ECCs, plantar flexor muscles were electrically stimulated while the ankle was forcibly dorsiflexed. RESULTS: Less cell damage, as assessed by Evans blue dye uptake, was observed in the muscles of mice with EAM, compared to controls, after an acute bout of 100 ECCs (P < 0.05). Maximum Ca2+ -activated force was decreased in skinned gastrocnemius muscle fibers from mice with EAM, and this was accompanied by increased expression of endoplasmic reticulum (ER) stress proteins, including Gsp78 and Gsp94 (P < 0.05). ECC training prevented the decrease in force and the increase in ER stress proteins and also enhanced the expression and myofibrillar binding of small heat-shock proteins (HSPs) (P < 0.05), which can stabilize myofibrillar structure and function. CONCLUSION: ECC training protected against the reduction in myofibrillar force-generating capacity in an IIM mouse model, and this occurred via inhibition of ER stress responses and small HSP-mediated myofibrillar stabilization.

Cancer Cachexia Induces Preferential Skeletal Muscle Myosin Loss When Combined With Denervation.

Patients with cancer cachexia (CCX) suffer from muscle wasting, which is often but not always accompanied by selective loss of myosin. Here we examined the effects of CCX on muscle mass and myosin heavy chain (MyHC) expression in denervated (DEN) muscles, especially focusing on the protein synthesis and degradation pathways. Male CD2F1 mice were randomly divided into control (CNT) and CCX groups and their left sciatic nerve was transected. CCX was induced by an intraperitoneal injection of colon 26 cells. After 14 days, the serum concentration of IL-6 and corticosteroid was higher in CCX mice than in CNT mice. The combination of CCX with DEN (CCX + DEN) resulted in a marked reduction of the gastrocnemius muscle weight (-69%) that was significantly lower than DEN (-53%) or CCX (-36%) alone. CCX had no effect on MyHC content, but it elicited a preferential MyHC loss when combined with DEN. The expression levels of autophagy markers cathepsin D and LC3BII/I ratio were markedly higher in the CCX + DEN group than in the CNT + DEN and the CCX groups. Paradoxically, there was an increase in protein synthesis rate and phosphorylation levels of p70S6K and rpS6, markers of mTORC1 signaling, in the CNT + DEN group, and these molecular alterations were inhibited in the CCX + DEN group. Our data indicate that CCX aggravates muscle atrophy in DEN muscles by inducing seletive loss of myosin, which involves inactivity dependent mechanisms that is likely to be a consequence of increased autophagy-mediated protein breakdown coupled with impaired protein synthesis.

Prognostic Impact of Early Changes in Serum Chloride Concentrations Among Hospitalized Acute Heart Failure Patients　- A Retrospective Cohort Study.

Background: Serum electrolyte concentrations on admission and after the administration of loop diuretics may be associated with prognosis in patients hospitalized due to acute heart failure (AHF). This study investigated the prognostic impact of early changes in chloride (Cl) concentrations after diuretic administration, according to stratified Cl concentrations on admission, in AHF. Methods and Results: In all, 355 consecutive patients hospitalized due to AHF were included in this single-center retrospective cohort study. Patients were divided into 2 groups based on whether Cl decreased (n=196) or not (n=159) during the first 5 days in hospital. These 2 groups were further stratified according to Cl on admission into 4 groups: Group 1, decrease in Cl and no hypochloremia (n=127); Group 2, decrease in Cl and hypochloremia (n=69); Group 3, no decrease in Cl and no hypochloremia (n=50); and Group 4, no decrease in Cl and hypochloremia (n=109). The risk of death was significantly higher in the group without than with a decrease in Cl (all-cause death hazard ratio [HR] 1.79; 95% confidence interval [CI] 1.15-2.78; P=0.009). Group 4 had the worst prognosis and a significantly higher risk of death (all-cause death [vs. Group 1 as a reference], HR 2.51; 95% CI 1.45-4.32; P=0.001). Conclusions: The absence of an early decline in Cl was associated with poor prognosis in AHF, especially in patients with hypochloremia on admission.

Prognostic Value of Lactate Dehydrogenase for Mid-Term Mortality in Acute Decompensated Heart Failure: A Comparison to Established Biomarkers and Brain Natriuretic Peptide.

BACKGROUND: Enzyme biomarkers-such as creatine phosphokinase, aspartate aminotransferase, and alanine aminotransferase-are associated with acute decompensated heart failure (ADHF) severity and, therefore, have a prognostic value in ADHF. However, the prognostic value of lactate dehydrogenase (LDH) is unclear. This study aimed to investigate the prognostic value of LDH in ADHF. METHODS: This single-centre observational retrospective study enrolled 396 patients with ADHF between June 2014 and July 2016. The patients were categorised into groups based on the tertile values of serum LDH (LDH-low [<196 U/L], LDH-intermediate [196≤ LDH <239 U/L] and LDH-high [LDH ≥239 U/L]). Survival analysis for all-cause mortality was performed. This study also examined the ability of adding log-transformed LDH (LogLDH) on Get With The Guideline score, which is an established risk score to predict 90-day, 180-day and 365-day mortality using time-dependent receiver operating characteristic curves. RESULTS: During the follow-up (median, 204 days), 100 (25%) patients died. The LDH-intermediate and LDH-high groups had worse survival (LDH-low vs LDH-intermediate, log-rank p=0.019; LDH-low vs LDH-high, log-rank p<0.001). Log LDH improved the ability to predict 90-day, 180-day and 365-day all-cause mortality, which was statistically significant (90 days, area under curve [AUC] = 0.79, p=0.012; 180 days, AUC = 0.79, p=0.017; and 365 days, AUC = 0.79, p=0.025). CONCLUSIONS: Lactate dehydrogenase may be an important predictor of 90-day, 180-day and 365-day all-cause mortality in ADHF patients; however, further studies are needed to confirm these findings.

Comparison of the prognostic values of three calculation methods for echocardiographic relative wall thickness in acute decompensated heart failure.

PURPOSE: Left ventricular (LV) wall thickness can be measured at the posterior wall (PW) and the intraventricular septum (IVS) in a parasternal long axis view by transthoracic echocardiography. Thus, there are three methods to calculate relative wall thickness as follows: RWTPW = 2 × PWth/LVDd; RWTIVS + PW = (IVSth + PWth) /LVDd; and RWTIVS = 2 × IVSth/LVDd (IVSth = interventricular septum thickness; LVDd = LV internal dimension at end--diastole; PWth = posterior wall thickness). The aim was to compare the prognostic values of these RWTs in patients with acute decompensated heart failure (ADHF). METHOD: This was a single-center, retrospective, observational study at a Japanese community hospital. A total of 389 hospitalized ADHF patients were divided into two groups based on the three median RWT values. The primary outcome was all-cause death. Survival analysis was performed, and Cox proportional hazard models unadjusted and adjusted by Get With The Guideline score were used. RESULTS: High-RWTPW had poor survival (log-rank, P = 0.009) and was a significant risk (unadjusted HR (95%CI), 1.72 (1.14-2.61), P = 0.01; adjusted HR, 1.95 (1.28-2.98), P = 0.02). High-RWTIVS + PW was not associated with poor survival on survival analysis or the unadjusted Cox model. Only the adjusted Cox model showed that High-RWTIVS + PW was associated with a significant risk of the primary outcome (unadjusted HR (95%CI), 1.45 (0.96-2.17), P = 0.07; adjusted HR, 1.53 (1.01-2.32), P = 0.045). High-RWTIVS did not have significant prognostic value. CONCLUSIONS: When calculating RWT, RWTPW should be recommended for evaluating the mortality risk in ADHF.

Safety and efficacy of glecaprevir and pibrentasvir in Japanese hemodialysis patients with genotype 2 hepatitis C virus infection.

BACKGROUND: Until recently, interferon-free anti-hepatitis C virus (HCV) therapy for genotype 2 (GT2) HCV-infected hemodialysis patients was an unfulfilled medical need. Recent clinical trials of glecaprevir and pibrentasvir (G/P) for hemodialysis patients showed high efficacy and safety; however, the number of GT2 HCV-infected patients, especially Asian patients, was limited and most of them were treated with a 12-week regimen. In this prospective multicenter study, we aimed to investigate the efficacy and safety of G/P in Japanese hemodialysis patients with GT2 HCV infection. METHODS: Twenty-seven Japanese hemodialysis patients with GT2 HCV infection who were started on with 8- or 12-week G/P regimen between November 2017 and June 2018 were included and followed up for around 12 weeks after treatment completion. RESULTS: Among the 27 included patients, 13 non-liver cirrhosis (LC) and direct-acting antivirals (DAAs)-naïve patients were treated with 8 weeks of G/P and 14 patients with LC (n = 13) or history of failure of DAAs (n = 1) were treated with a 12-week regimen. The overall sustained virological response at 12 weeks after treatment completion (SVR 12) was 96.3% (26/27). All patients with 8 weeks of treatment achieved SVR12. Two patients discontinued the therapy at 2 and 11 weeks after treatment initiation. The patient who discontinued at 2 weeks due to pruritus alone failed to respond to G/P. No patients experienced lethal adverse events during the therapy, and the most common adverse event was pruritus. CONCLUSIONS: An 8- or 12-week G/P regimen is highly effective and safe in GT2 HCV-infected hemodialysis patients.

Membrane hyperpolarization and depolarization of rat thymocytes by azoxystrobin, a post harvest fungicide.

Azoxystrobin, a broad-spectrum fungicide, has been increasingly used in the agricultural industry. In Japan in 2018, azoxystrobin at five times the normal limit was detected in a shipment of Australian barley that had been used in food products. Therefore, the effects of azoxystrobin need to be carefully examined to predict potential adverse reactions in humans. In this study, the effects of azoxystrobin on the membrane potential and intracellular Ca2+ levels of thymocytes have been photochemically examined using flow cytometry. Azoxystrobin hyperpolarized plasma membrane potential. This hyperpolarization appeared to be due to the activation of Ca2+-dependent K+ channels, as both the removal of extracellular Ca2+ and addition of charybdotoxin attenuated the observed hyperpolarization. In the presence of quinine, an anti-malarial drug that blocks Ca2+-dependent K+ channels, azoxystrobin depolarized the membranes instead. Azoxystrobin increased intracellular Ca2+ levels in a concentration-dependent manner through the influx of extracellular Ca2+ and intracellular release of Ca2+, as confirmed by reduction in azoxystrobin-induced response in the absence of extracellular Ca2+. It appears likely that azoxystrobin at micromolar concentrations modifies membrane ion permeability in thymocytes. Since changes in membrane potential and intracellular Ca2+ levels occur during typical physiological lymphocyte responses, azoxystrobin may disturb lymphocyte function.

Incremental Prognostic Value of Platelet Count in Patients With Acute Heart Failure　- A Retrospective Observational Study.

BACKGROUND: Acute heart failure (AHF) triggers platelet aggregation and platelet markers are associated with the severity of AHF. The present study aimed to investigate the prognostic value of platelet count (PLT) in patients with AHF. Methods and Results: This single-center retrospective observational study analyzed 425 consecutive patients with AHF. The patients were divided into groups based on tertiles of PLT: low (PLT1 <170,000/µL), intermediate (170,000/µL≤PLT<230,000/µL), and high (PLT3 ≥230,000/µL). The endpoint was all-cause death with a composite endpoint of all-cause death and HF rehospitalization. Survival analysis was performed, and Cox proportional hazard models adjusted by an established risk score (Get With The Guidelines score) were generated. The PLT1 group had the worst survival for all-cause death (log-rank, P=0.003) and the composite endpoint (P=0.009). A significant trend of increasing survival was observed for all-cause death (log-rank trend, P<0.001) and the composite endpoint (P=0.002) in the following order: PLT1, PLT2, and PLT3. Adjusted Cox proportional hazard models demonstrated that low PLT was a risk factor of all-cause death and the composite endpoint. CONCLUSIONS: Low PLT was associated with risk for all-cause death and HF rehospitalization in patients with AHF.

Safety and efficacy of elbasvir and grazoprevir in Japanese hemodialysis patients with genotype 1b hepatitis C virus infection.

BACKGROUND: The prevalence of hepatitis C virus (HCV) infection in hemodialysis patients is high and results in a poor prognosis. Thus, safer and more effective treatment regimens are required. In this prospective multicenter study, we investigated the efficacy and safety of the novel HCV-NS5A-inhibitor, elbasvir, and protease inhibitor, grazoprevir in Japanese hemodialysis patients with genotype 1b HCV infection. METHODS: This study is registered at the UMIN Clinical Trials Registry as UMIN00002578. A total of 23 Japanese dialysis patients with genotype 1b HCV infection who were treated with elbasvir and grazoprevir between January 2017 and March 2018 and followed for more than 12 weeks after treatment completion were included. We evaluated the sustained virologic response at 12 weeks after treatment completion (SVR12) and safety during treatment. RESULTS: Of the 23 patients, 7 had advanced liver fibrosis and 2 had a signature resistance-associated variant of NS5A (NS5A RAVs)-L31M/V or Y93H at baseline. All patients completed therapy, and 96.7% (22/23) of the patients achieved SVR12. All patients with advanced liver fibrosis and signature NS5A RAVs at baseline achieved SVR12 with a high safety profile. No patient experienced lethal or severe adverse events during therapy, and the most common adverse event was anemia. One patient, who was a non-responder to this therapy, had a history of failure with daclatasvir and asunaprevir therapies and had NS5A RAVs of A92K at baseline, but not signature NS5A RAVs. CONCLUSIONS: Grazoprevir and elbasvir combination is highly effective and safe for hemodialysis patients with genotype 1b HCV infection.

The prognostic impact of a concentric left ventricular structure evaluated by transthoracic echocardiography in patients with acute decompensated heart failure: A retrospective study.

BACKGROUND: Left ventricular (LV) wall thickening relative to the LV radius, known as a concentric LV structure, is a mechanism that compensates for pressure overload and is related to the risk of cardiovascular events and heart failure. The prognostic value of a concentric LV structure, however, has not been examined in acute decompensated heart failure (ADHF). METHODS: This single-center, observational, retrospective, cohort study analyzed 385 consecutive patients hospitalized due to ADHF. On hospital admission, relative wall thickness (RWT) and the ratio of LV mass to LV end-diastolic volume (LVM/LVEDV) were measured by transthoracic echocardiography as markers of a concentric LV structure. The association of either RWT or LVM/LVEDV with all-cause death as the primary outcome was analyzed. RESULTS: During the follow-up period (median, 235 days), 95 (25%) patients died. The high-RWT group had a poorer prognosis than the low-RWT group (log-rank test, P = 0.009). High RWT was a significant risk (HR: 1.95, 95% CI: 1.28-2.97, P = 0.002) in the Cox proportional hazard model analysis adjusted by the Get With The Guideline score, which is an established risk score. In contrast, there was no significant difference in survival between the low and high-LVM/LVEDV groups (P = 0.42). In the non-severe valvular disease subgroup, patients with high RWT consistently showed worse survival than the low-RWT group (P = 0.028 by log-rank test, HR: 1.96, 95% CI: 1.24-3.11, P = 0.004). There was no significant difference in survival between the low and high-LVM/LVEDV groups (P = 0.42). CONCLUSIONS: A concentric LV structure represented by a high RWT was associated with a poor prognosis in ADHF. The lack of association between LVM/LVEDV and mortality may result from methodological issues.

Polymorphism of receptor-type tyrosine-protein phosphatase delta gene in the development of non-alcoholic fatty liver disease.

BACKGROUND AND AIM: Some single-nucleotide polymorphisms (SNPs) are associated with the development of non-alcoholic fatty liver disease (NAFLD). As one of the genetic factors, PNPLA3 rs738409 (I148M) is important to associate with pathogenesis of NAFLD. Because other SNPs remain unclear in Japan, we performed a high-throughput sequencing that targeted more than 1000 genes to identify a novel genetic variant in Japanese patients with NAFLD. METHODS: The present study in 36 NAFLD patients and 27 healthy volunteers was performed. A high-throughput sequencer was used to detect the gene variations. Candidate genes were validated by TaqMan SNP genotyping assay in 53 NAFLD patients and 41 healthy volunteers. To investigate the function of candidate gene, we performed biochemical analyses in cultured hepatocytes and liver tissues. RESULTS: EXO1 rs1047840, PTPRD rs35929428, IFNAR2 rs2229207, CPOX rs1131857, IL23R rs1884444, IL10RA rs2228055, and FAM3B rs111988437 were identified as candidate genetic variants, and PTPRD rs35929428 was only extracted as a SNP predicting to cause protein dysfunction. In validation analysis, PTPRD rs35929428 associated with the development of NAFLD (P = 0.015, odds ratio = 5.00, 95% confidence interval: 1.33-18.70). In addition, PTPRD rs35929428 was associated with Fib-4 index and with hepatic fat droplets. Biochemical analyses indicated that PTPRD rs35929428 promoted dephosphorylation of tyrosine 705 signal transducer and activator of transcription 3 (Tyr 705) in hepatocytes. CONCLUSION: PTPRD rs35929428 was a novel SNP in patients with NAFLD. Through exacerbation of the dephosphorylation of signal transducer and activator of transcription 3 (Tyr 705) in hepatocytes, PTPRD rs35929428 might play a role in hepatic lipid accumulation and fibrosis, followed by the development of NAFLD.

Supplementary Administration of Everolimus Reduces Cardiac Systolic Function in Kidney Transplant Recipients.

BACKGROUND The effect of everolimus, one of the mammalian targets of rapamycin inhibitors, on cardiac function was evaluated in kidney transplant recipients. MATERIAL AND METHODS Seventy-six participants who underwent kidney transplant between March 2009 and May 2016 were retrospectively reviewed. To standardize everolimus administration, the following criteria were used: (1) the recipient did not have a donor-specific antigen before kidney transplantation; (2) the recipient did not have proteinuria and uncontrollable hyperlipidemia after kidney transplantation; and (3) acute rejection was not observed on protocol biopsy 3 months after kidney transplantation. According to these criteria, everolimus administration for maintenance immunosuppression after kidney transplantation was included. Cardiac function was compared between the treatment group (n=30) and non-treatment group (n=46). RESULTS The mean observation periods of the treatment and non-treatment groups were 41.3±12.6 and 43.9±19.8 months, respectively (p=0.573). The mean ejection fraction and fractional shortening of the treatment and non-treatment groups after kidney transplant were 66.5±7.9% vs. 69.6±5.5% (p=0.024) and 37.1±6.2% vs. 39.3±4.7% (p=0.045), respectively. In the treatment group, the mean ejection fraction and fractional shortening before and after kidney transplantation did not differ significantly (p=0.604 and 0.606, respectively). In the non-treatment group, the mean ejection fraction and fractional shortening before and after kidney transplantation differed significantly (p=0.004 and 0.006, respectively). CONCLUSIONS Supplementary administration of everolimus after kidney transplantation can reduce cardiac systolic function.