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.

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.

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.

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.

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.

Augmented hepatic Toll-like receptors by fatty acids trigger the pro-inflammatory state of non-alcoholic fatty liver disease in mice.

AIM: There is considerable evidence that intestinal microbiota are involved in the development of metabolic syndromes and, consequently, with the development of non-alcoholic fatty liver disease (NAFLD). Toll-like receptors (TLRs) are essential for the recognition of microbiota. However, the induction mechanism of TLR signals through the gut-liver axis for triggering the development of non-alcoholic steatohepatitis (NASH) or NAFLD remains unclear. In this study, we investigated the role of palmitic acid (PA) in triggering the development of a pro-inflammatory state of NAFLD. METHODS: Non-alcoholic fatty liver disease was induced in mice fed a high fat diet (HFD). The mice were killed and the expression of TLRs, tumor necrosis factor (TNF), interleukin (IL)-1ß, and phospho-interleukin-1 receptor-associated kinase 1 in the liver and small intestine were assessed. In addition, primary hepatocytes and Kupffer cells were treated with PA, and the direct effects of PA on TLRs induction by these cells were evaluated. RESULTS: The expression of inflammatory cytokines such as TNF, IL-1ß, and TLR-2, -4, -5, and -9 was increased in the liver, but decreased in the small intestine of HFD-fed mice in vivo. In addition, the expression of TLRs in primary hepatocytes and Kupffer cells was increased by treatment with PA. CONCLUSION: In the development of the pro-inflammatory state of NAFLD, PA triggers the expression of TLRs, which contribute to the induction of inflammatory cytokines through TLR signals by intestinal microbiota.

Impact of stentablation with rotational atherectomy in coronary microcirculatory function.

Key Clinical Message: Stentablation (SA) has been used as a bailout method for undilated, under-expanded stents, but one reason that SA is associated with a high rate of major adverse cardiac events may be its adverse effect on microcirculation. Consequently, appropriate lesion preparation should always be considered for heavily calcified lesions to avoid such complications. Abstract: Under-expansion of the coronary stent is associated with increased rates of in-stent restenosis and thrombosis. Stentablation (SA) with rotational atherectomy is used in the treatment of undilatable, under-expanded coronary stents; however, its effect on coronary microcirculatory function remains unclear. This novel report compares microcirculation indices before and after SA.

Early and short-term use of proprotein convertase anti-subtilisin-kexin type 9 inhibitors on coronary plaque stability in acute coronary syndrome.

Aims: Proprotein convertase anti-subtilisin-kexin type 9 inhibitors (PCSK9Is) improve plaque volume and composition and reduce major adverse coronary events in chronic coronary artery disease. We evaluated the effects of the short-term use of PCSK9Is on coronary plaque stability in patients with acute coronary syndrome (ACS) using optical coherence tomography (OCT). Methods and results: This is a multicentre, open-label randomized controlled trial. The enrolled 80 subjects met the inclusion criteria. Of these, 52 patients (age 60 ± 11 years, 38 men, 14 women) with ST-elevated ACS had undergone successful primary percutaneous coronary intervention with LDL-cholesterol (LDL-C) levels > 70 mg/dL while receiving high-intensity statins. Participants were randomly assigned to the PCSK9I group (evolocumab 420 mg for 3 months, n = 29) or the standard of care (SoC) group (n = 23). Optical coherence tomography was performed at baseline (BL) and 3 and 9 months after randomization to assess lipid-rich plaques in non-culprit lesions. The change in the minimum fibrous cap thickness (MFCT) from BL to 9 months was the primary endpoint. The percentage change in LDL-C levels from BL to 3 months was significantly greater in the PCSK9I group (-67.8 ± 21.5% in the PCSK9I group vs. -16.3 ± 21.8% in the SoC group; P < 0.0001), and the difference between the two groups disappeared from BL to 9 months (-20.0 ± 37.8% in the PCSK9I group vs. -6.7 ± 34.2% in the SoC group; P = 0.20). The changes in MFCT from BL to 9 months were significantly greater in the PCSK9I group, even after PCSK9I discontinuation {100 µm [interquartile range (IQR): 45-180 µm] vs. 50 µm [IQR: 0-110 µm]; P = 0.032}. Conclusion: Combination treatment with PCSK9Is and statins resulted in more marked plaque stabilization after ACS than SoC alone, and this effect persisted for 6 months after PCSK9I discontinuation. Registration: Adage-Joto study, UMIN ID No. 26516.

Implementation of the kissing balloon technique using a perfusion balloon in acute myocardial infarction: a case report.

Background: Prolonged antiplatelet-agent administration associated with stenting for acute myocardial infarction is not ideal in young patients. We successfully performed a perfusion balloon-based kissing balloon technique in the left anterior descending artery ostium in a young patient with acute myocardial infarction. Case summary: A 34-year-old female presenting with recurrent chest pain was diagnosed with ST-segment elevation acute myocardial infarction. Emergency coronary angiography revealed 90% stenosis of the left anterior descending artery ostium. Considering her age, lesion dilation using a perfusion balloon was preferred. This inadvertently impinged the left circumflex artery, causing chest pain and ischaemia-related hypotension with only a 10 s perfusion dilation balloon. We transitioned to an alternative 7 Fr guiding catheter and performed the kissing balloon technique using a perfusion balloon. This allowed prolonged inflation for 120 s, without complications. Optical coherence tomography of the lesion revealed layered plaques. Based on the patient's age and medical history, coronary spasm may be the aetiological factor underlying acute ST-segment elevation myocardial infarction. Coronary angiography 3 months post-discharge revealed no restenosis. Discussion: Regarding acute myocardial infarction, prolonged inflation with a perfusion balloon had higher frequency of non-stent-related interventions than that of semi-compliant or non-compliant balloons. In this case, the perfusion balloon resulted in chest pain and hypotension. Perfusion balloon-based kissing balloon technique was useful in this setting. Optical coherence tomography revealing the responsible lesions can help determine the cause of acute myocardial infarction in young patients; in our case, a layered plaque was observed. Layered plaques are associated with coronary spasm; therefore, initiating treatment of coronary spasm was considered herein.

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.

Prognostic implications of chronic kidney disease and anemia after percutaneous coronary intervention in acute myocardial infarction patients.

Anemia is a common complication of chronic kidney disease (CKD), and a few studies suggest that both CKD and anemia have a marked impact on the prognosis of patients with cardiovascular disease. We retrospectively analyzed the prevalence of CKD and anemia in 312 patients with acute myocardial infarction (AMI). The patients were divided into four groups according to the presence of CKD and anemia. Chronic kidney disease was defined as estimated glomerular filtration rate <60 ml/min/1.73 m(2), and anemia was defined according to the World Health Organization definition. Of 312 AMI patients, 166 (53.2%) had CKD and 87 (27.8%) had anemia. A powerful relationship was observed between both CKD and anemia and major adverse cardiac and cerebrovascular events (MACCE) or death by any cause. After adjustment for comorbidities, the hazard ratio (HR) for MACCE was significantly higher in the anemia-only group (HR 5.42, 95% confidence interval (CI) 1.38-21.27, P = 0.015), the CKD-only group (HR 6.4, 95% CI 2.09-19.58, P = 0.001), and the CKD and anemia group (HR 11.61, 95% CI 3.65-36.89, P < 0.001). With respect to death by any cause, the HR was significantly higher in the CKD-only group (HR 2.68, 95% CI 1.02-7.02, P = 0.045) and the CKD and anemia group (HR 4.40, 95% CI 1.56-12.43, P = 0.005). One-half of the patients with AMI had CKD as well. Furthermore, when anemia coexisted with CKD, these conditions had a multiplicative amplification effect on the risk of MACCE and death by any cause in patients with AMI.

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.

Prevalence and prognostic implications of pre-diabetic state in patients with heart failure.

BACKGROUND: Diabetes mellitus (DM) is a risk factor of poor prognosis in patients with heart failure (HF). The prevalence and prognostic impact of the pre-diabetic state, however, are not well understood. METHODS AND RESULTS: One hundred and thirty-six consecutive patients admitted due to HF were included in this prospective study. The 75-g oral glucose tolerance test (OGTT) was performed in all patients without known DM, and patients were classified into normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and DM groups. Forty-two of the 136 patients had previously been diagnosed with diabetes. Of the remaining 94 patients without known diabetes, 35 (37.2%) patients were classified as NGT, 9 (9.6%) as having IFG, 37 (39.4%) were classified as having IGT, and 13 (13.8%) were newly diagnosed with DM. During follow-up, patients with DM or IGT had significantly lower major adverse cardiac and cerebrovascular event (MACCE)-free rates than NGT patients (P=0.006, P=0.036, respectively). IFG, however, was not significantly related to increased MACCE risk. The presence of IGT (hazard ratio [HR], 4.51; P=0.011) and DM (HR, 4.74; P=0.005) were independent predictors of MACCE even after multivariate analysis. CONCLUSIONS: IGT and DM contribute to adverse prognosis in patients with HF. It is feasible to perform diabetes screening using OGTT in patients with HF for risk stratification.

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.

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.

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.

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.

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.