Association between COVID-19 severity and relatively high serum adiponectin levels at the time of admission.

At the beginning of 2020, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to epidemics worldwide. Obesity and visceral fat accumulation have been reported to be independent risk factors for severe COVID-19. Several reports have focused on the levels of adipocytokines/adipokines, including adiponectin (APN), which is exclusively secreted from adipocytes, although the importance of these factors in acute disease conditions remains unclear. Therefore, we investigated the relationship between serum adiponectin levels and COVID-19 severity. Patients with COVID-19 who were admitted to Sumitomo Hospital (Osaka, Japan) from May through October 2021 were included. A total of 107 patients were enrolled in this study. We obtained the anthropometric and clinical laboratory data of the patients at the time of admission and examined the associations between various parameters and COVID-19 severity. The mean period from onset to admission was 6.5 ± 2.8 days. We divided the patients into "non-severe" (mild, moderate-I and moderate-II) (n = 80) and "severe" (n = 27) groups. The "severe" patients were significantly older than "non-severe" patients. Additionally, no significant differences were observed in BMI, sex, or the period from onset to admission. The serum adiponectin levels of "severe" patients at the time of admission were significantly greater than those of "non-severe" patients even after adjusting for age, sex, and BMI. These results suggest that the serum APN levels at the time of admission can predict COVID-19 severity. However, further investigations on the changes in APN levels in acute diseases are needed.

Restrictive annuloplasty or replacement on reverse remodeling for nonischemic dilated cardiomyopathy.

BACKGROUND: For patients with nonischemic dilated cardiomyopathy (NIDCM), the indications for and results of mitral surgery remain controversial. We reviewed a strategy of mitral repair and replacement for clinically relevant secondary mitral regurgitation (MR) in patients with NIDCM. METHODS: We retrospectively reviewed 65 patients with advanced NIDCM (LVEF < 40%) who underwent mitral surgery. Of them, 47 (72%) underwent mitral annuloplasty and 18 (28%) replacement for secondary MR. The primary endpoint was postoperative reduction in indexed LV end-systolic volume (LVESVI). RESULTS: At baseline, there was no intergroup difference in LVESVI (123 ± 47 vs. 147 ± 37 ml/m2, P = 0.055), LVEF (27 ± 8% vs. 25 ± 6%, P = 0.41), incidence of severe MR (57% (27/47) vs. 72% (13/18), P = 0.40), or EuroSCORE II score (6.2% vs. 7.6%, P = 0.90). At 6 months, the annuloplasty group reduced LVESVI to a greater degree than the replacement group (P < 0.001), yielding significantly smaller postoperative LVESVI (96 ± 59 vs. 154 ± 61 ml/m2, P < 0.001) and better LVEF (P < 0.001). The rates of moderate/severe recurrent MR were 17% (8/47) and 0%, respectively. Multivariable analysis demonstrated that mitral annuloplasty (OR 6.10, 95% CI 1.14-32.8, P = 0.035) was significantly associated with postoperative LV reverse remodeling. Cumulative survival was not different between the groups (P = 0.26). CONCLUSIONS: In patients with NIDCM, mitral annuloplasty reduced LV volume to a greater degree than did mitral replacement. These findings may assist with surgical options for secondary MR associated with NIDCM.

Safety confirmation of induced pluripotent stem cell-derived cardiomyocyte patch transplantation for ischemic cardiomyopathy: first three case reports.

Introduction: With the expected increase in patients with heart failure and ischemic 15 cardiomyopathy, the development of myocardial regenerative medicine using cell transplantation as a novel treatment method is progressing. This first-in-human clinical trial aimed to confirm the safety of cardiomyocyte patch transplantation derived from allogeneic induced pluripotent stem (iPS) cells based on the results of several preclinical studies. Study design: The inclusion criteria were left ventricular ejection fraction of 35% or less; heart failure symptoms of New York Heart Association class III or higher despite existing therapies such as revascularization; and a 1-year observation period that included a 3-month immunosuppressive drug administration period after transplantation of iPS cell-derived cardiomyocyte patches to evaluate adverse events, cardiac function, myocardial blood flow, heart failure symptoms, and immune response. Results: In the first three cases of this trial, no transplanted cell-related adverse events were observed during the 1-year observation period, and improvement in heart failure symptoms was observed. In addition, improvements in left ventricular contractility and myocardial blood flow were observed in two of the three patients. Regarding immune response, an increase in transplant cell-specific antibody titer was observed in all three patients after immunosuppressive drug administration. In one patient with poor improvement in cardiac function and myocardial blood flow, an increase in antibody titer against HLA-DQ was observed even before cell transplantation. Conclusions: Our case findings demonstrate that the transplantation of iPS cell-derived cardiomyocyte patches for ischemic cardiomyopathy can be safely performed; however, further investigation of the therapeutic effect and its relationship with an immune response is needed by accumulating the number of patients through continued clinical trials.

Mitochondrial function and coronary flow reserve improvement after autologous myoblast patch transplantation for ischaemic cardiomyopathy: a case report.

Background: Autologous myoblast patch (AMP) transplantation has resulted in good clinical outcomes for end-stage ischaemic cardiomyopathy, but the mechanisms behind them are unclear. Herein, we report the relationship between mitochondrial function and coronary flow reserve (CFR) before and after AMP transplantation. Case summary: The patient was a 73-year-old man who underwent coronary artery bypass grafting (CABG). At that time, the left ventricular ejection fraction (LVEF) was 53%, but it declined to 25% after 6 years. He was diagnosed with ischaemic cardiomyopathy (ICM). Coronary flow reserve in NH3-positron emission tomography (NH3-PET) was impaired to 1.69. In Tc-99m MIBI scintigraphy, the washout rate (WR) was 17%, suggestive of impaired mitochondrial function. He was not a candidate for heart transplantation, and we performed AMP transplantation 6 years after CABG. One year after AMP transplantation, LVEF, CFR, and Tc-99m MIBI WR improved to 36%, 2.07, and 7%, respectively. The Tc-99m MIBI WR improved especially in the anterolateral region, and the CFR increased in almost all segments. Discussion: In this case, AMP transplantation for ICM improved cardiac function, CFR, and mitochondrial function. The mitochondrial transfer from the transplanted myoblasts to the damaged myocardium may have contributed to the mitochondrial function improvement. This probably induced myocardial energy metabolism recovery and decreased oxygen demand. AMP transplantation also has the potential to improve microvascular dysfunction, due to angiogenesis induction. These effects can lead to improved prognoses of ICM after AMP transplantation, highlighting its potential to cure refractory heart failure.

RhoA rescues cardiac senescence by regulating Parkin-mediated mitophagy.

Heart failure is one of the leading causes of death worldwide. RhoA, a small GTPase, governs actin dynamics in various tissue and cell types, including cardiomyocytes; however, its involvement in cardiac function has not been fully elucidated. Here, we generated cardiomyocyte-specific RhoA conditional knockout (cKO) mice, which demonstrated a significantly shorter lifespan with left ventricular dilation and severely impaired ejection fraction. We found that the cardiac tissues of the cKO mice exhibited structural disorganization with fibrosis and also exhibited enhanced senescence compared with control mice. In addition, we show that cardiomyocyte mitochondria were structurally abnormal in the aged cKO hearts. Clearance of damaged mitochondria by mitophagy was remarkably inhibited in both cKO cardiomyocytes and RhoA-knockdown HL-1 cultured cardiomyocytes. In RhoA-depleted cardiomyocytes, we reveal that the expression of Parkin, an E3 ubiquitin ligase that plays a crucial role in mitophagy, was reduced, and expression of N-Myc, a negative regulator of Parkin, was increased. We further reveal that the RhoA-Rho kinase axis induced N-Myc phosphorylation, which led to N-Myc degradation and Parkin upregulation. Re-expression of Parkin in RhoA-depleted cardiomyocytes restored mitophagy, reduced mitochondrial damage, attenuated cardiomyocyte senescence, and rescued cardiac function both in vitro and in vivo. Finally, we found that patients with idiopathic dilated cardiomyopathy without causal mutations for dilated cardiomyopathy showed reduced cardiac expression of RhoA and Parkin. These results suggest that RhoA promotes Parkin-mediated mitophagy as an indispensable mechanism contributing to cardioprotection in the aging heart.

Total arch and descending thoracic aortic replacement for massive hemoptysis requiring CPR caused by intrapulmonary penetration of chronic dissecting aortic aneurysm: a case report.

BACKGROUND: Intrapulmonary penetration of the thoracic aorta is a rare, life-threatening complication of a chronic dissecting aortic aneurysm. It causes massive hemoptysis requiring prompt intervention to prevent fatal airway bleeding. A surgical approach that enables diverse surgical maneuvers and intraoperative organ protection is crucial. CASE PRESENTATION: A 62-year-old man, who underwent graft replacement of the ascending aorta for an acute type A aortic dissection 20 months before, developed massive hemoptysis and cardiac arrest. The hemoptysis was secondary to an aortopulmonary fistula from a rapidly expanding dissecting aortic aneurysm. However, a successful return of spontaneous circulation was achieved with cardiopulmonary resuscitation, including establishment of veno-arterial extracorporeal membrane oxygenation. The patient successfully underwent a total arch and descending thoracic aortic replacement. This was achieved by a median sternotomy combined with a left thoracotomy using a straight incision with a rib-cross (SIRC) approach. The patient was uneventfully discharged and remained well for the following 2 years. CONCLUSIONS: When performing a surgical graft replacement for an aortopulmonary fistula with a thoracic aortic aneurysm, the surgical approach chosen is critical. A surgical procedure using a median sternotomy combined with a left thoracotomy and a SIRC approach can be an effective therapeutic option.

Case report: Transplantation of human induced pluripotent stem cell-derived cardiomyocyte patches for ischemic cardiomyopathy.

Despite major therapeutic advances, heart failure, as a non-communicable disease, remains a life-threatening disorder, with 26 million patients worldwide, causing more deaths than cancer. Therefore, novel strategies for the treatment of heart failure continue to be an important clinical need. Based on preclinical studies, allogenic human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) patches have been proposed as a potential therapeutic candidate for heart failure. We report the implantation of allogeneic hiPSC-CM patches in a patient with ischemic cardiomyopathy (ClinicalTrials.gov, #jRCT2053190081). The patches were produced under clinical-grade conditions and displayed cardiogenic phenotypes and safety in vivo (severe immunodeficient mice) without any genetic mutations in cancer-related genes. The patches were then implanted via thoracotomy into the left ventricle epicardium of the patient under immunosuppressive agents. Positron emission tomography and computed tomography confirmed the potential efficacy and did not detect tumorigenesis in either the heart or other organs. The clinical symptoms improved 6 months after surgery, without any major adverse events, suggesting that the patches were well-tolerated. Furthermore, changes in the wall motion in the transplanted site were recovered, suggesting a favorable prognosis and the potential tolerance to exercise. This study is the first report of a successful transplant of hiPSC-CMs for severe ischemic cardiomyopathy.

Increase in glycemic set point, alongside a decrease in waist circumference, in the non-diabetic population during the Japanese National Intervention Program for metabolic syndrome: A single-center, large-scale, matched-pair analysis.

BACKGROUND: In 2008, the Japanese government implemented a National Intervention Program for metabolic syndrome. Low-risk individuals were not direct targets of this intervention. Nevertheless, they were indirectly enlightened by this massive campaign. Documentation of the metabolic shifts in low-risk individuals following the program launch may inform public health policy regarding approaches to metabolic risks in the general population. METHODS: We conducted a cross-sectional analysis of data from non-diabetic participants who underwent general health check-ups at the Physical Check-up Center of Sumitomo Hospital. Participants during 2007-2008 were pair-matched with those during 2015-2016 with respect to sex, age, smoking status, hemoglobin level, and red blood cell (RBC) count. Each participant was included only once in the study. RESULTS: Totals of 3,140 men and 2,048 women were pair-matched. The non-diabetic participants showed lower waist circumference, blood pressure, heart rate, and serum lipid concentrations during the second study period. In contrast, the entire distributions of fasting plasma glucose (FPG) concentration in both sexes and glycated hemoglobin (HbA1c) in women were shifted upwards. In men, Δ FPG was +1.6 mg/dL (P < 0.001) and Δ HbA1c was ±0% (P = 0.6). In women, Δ FPG was +3.0 mg/dL (P < 0.001), and Δ HbA1c was +0.1% (P < 0.001). Δ Homeostasis model assessment of ß-cell function was -6.6 in men (P < 0.001) and -10.3 in women (P < 0.001). The homeostasis model assessment of insulin resistance did not change significantly. CONCLUSIONS: The "glycemic set point" has increased in non-diabetic people in Japan during recent years. Lifestyle or environmental changes may have caused this metabolic shift through obesity-independent pathways, possibly through effects on pancreatic ß-cell function. The underlying mechanism awaits further investigation.

Successful surgical treatment of delayed left ventricular pseudoaneurysm related to Candida albicans infection after repair of ventricular septal rupture complicating acute myocardial infarction.

Left ventricular (LV) pseudoaneurysm is a rare complication after postinfarction repair of ventricular septal rupture (VSR), and surgical treatment of this condition due to mycosis has rarely been reported. We report a rare case of successful surgical treatment of delayed LV pseudoaneurysm related to Candida albicans infection after repair of VSR due to myocardial infarction. A 75-year-old woman was admitted for fever and severe inflammatory reaction. Two and a half years previously, she had undergone postinfarct VSR repair and was treated for mycotic infective endocarditis due to C. albicans. Transthoracic echocardiography and computed tomography revealed a LV pseudoaneurysm (maximum transverse diameter 6.2 cm). The cause of the LV pseudoaneurysm was suspected to be infectious, and broad-spectrum antibiotic treatment was started. Fourteen days after admission, she developed acute abdominal pain and an elevated ß-D-glucan level because the LV pseudoaneurysm ruptured. Emergency surgical treatment was performed with antimycotic drug therapy. The LV wall defect was reconstructed using bovine pericardium under cardiopulmonary support. Her postoperative course was good, and she was discharged to home. Echocardiography revealed no recurrence of the LV pseudoaneurysm at 4 months postoperatively. During 1 year of follow-up, the patient had been doing well without any infection or adverse event. .

Unusual Case of Giant Nonthrombosed Right Coronary Artery Pseudoaneurysm With Coronary Artery Fistula.

Coronary artery aneurysm and pseudoaneurysm are rare and mainly result from atherosclerosis. We present a successfully treated case of a giant right coronary artery aneurysm and pseudoaneurysm with a coronary artery fistula, which might have developed after cardiac surgery for a right ventricular tumor 35 years earlier. (Level of Difficulty: Advanced.).

Long-term outcomes of autologous skeletal myoblast cell-sheet transplantation for end-stage ischemic cardiomyopathy.

We evaluated the cardiac function recovery following skeletal myoblast cell-sheet transplantation and the long-term outcomes after applying this treatment in 23 patients with ischemic cardiomyopathy. We defined patients as "responders" when their left ventricular ejection fraction remained unchanged or improved at 6 months after treatment. At 6 months, 16 (69.6%) patients were defined as responders, and the average increase in left ventricular ejection fraction was 4.9%. The responders achieved greater improvement degrees in left ventricular and hemodynamic function parameters, and they presented improved exercise capacity. During the follow-up period (56 ± 28 months), there were four deaths and the overall 5-year survival rate was 95%. Although the responders showed higher freedom from mortality and/or heart failure admission (5-year, 81% versus 0%; p = 0.0002), both groups presented an excellent 5-year survival rate (5-year, 93% versus 100%; p = 0.297) that was higher than that predicted using the Seattle Heart Failure Model. The stepwise logistic regression analysis showed that the preoperative estimated glomerular filtration rate and the left ventricular end-systolic volume index were independently associated with the recovery progress. Approximately 70% of patients with "no-option" ischemic cardiomyopathy responded well to the cell-sheet transplantation. Preoperative renal and left ventricular function might predict the patients' response to this treatment.

Increase in Adiponectin Level Prevents the Development of Type 2 Diabetes in Japanese Men With Low Adiponectin Levels.

CONTEXT: Low serum adiponectin (Ad) level is an important risk factor for the development of type 2 diabetes mellitus (T2DM). OBJECTIVE: To determine whether the changes in Ad in subjects with low baseline serum Ad levels can reduce the rate of development of T2DM. DESIGN/SETTING/PARTICIPANTS: We performed a large-scale longitudinal study of 7052 healthy Japanese men who underwent general health checkups more than twice between April 2007 and May 2015 at the Physical Check up Center, Sumitomo Hospital. The participants were divided into quartile groups according to baseline Ad level. Subjects of the lowest baseline Ad group (≤5.2 µg/mL) were subdivided into quartile subgroups according to the percent change in Ad (%ΔAd) and into two subgroups according to endpoint Ad (>5.2 and ≤5.2 µg/mL). MAIN OUTCOME MEASURES: The cumulative incidence rate of T2DM. RESULTS: The cumulative incidence rate of T2DM of the lowest baseline Ad group (≤5.2 µg/mL) was significantly higher than the other quartile groups. The cumulative incidence rates of T2DM were significantly lower in the largest (≥21.5%) and the second largest (9.3% to 21.4%) %ΔAd-increased subgroups compared with the %ΔAd-decreased subgroup (P < 0.001 and P = 0.005, respectively). The cumulative incidence rates of T2DM were significantly lower in the endpoint Ad >5.2 µg/mL subgroup than in the ≤5.2 µg/mL subgroup (P < 0.001). CONCLUSIONS: Increases in serum Ad levels of at least ~10% or >5.2 µg/mL can potentially reduce the risk of development of T2DM in Japanese men with low baseline Ad levels who are at a high risk of developing T2DM.

Near-Infrared photoluminescence in the femtosecond time region in monolayer graphene on SiO2.

We investigate the dynamical properties of photoexcited carriers in a single monolayer of graphene at room temperature in air using femtosecond time-resolved luminescence spectroscopy. The luminescence kinetics are observed in the near-infrared region of 0.7-1.4 eV and analyzed based on the two-temperature model describing the cooling of thermalized carriers via the carrier-optical phonon interaction. The observed luminescence in the range 0.7-0.9 eV is well reproduced by the model. In the range 1.0-1.4 eV, however, the luminescence, which decays in ∼300 fs, cannot be reproduced by this model. These results indicate that the carrier system is not completely thermalized in ∼300 fs. We also show the importance of the carrier-doping effect induced by the substrate and surrounding environment in the carrier cooling dynamics and the predominance of optical phonons over acoustic phonons in the carrier-phonon interactions even at a temperature of ∼400 K.

Step-templated CVD growth of aligned graphene nanoribbons supported by a single-layer graphene film.

We present chemical vapor deposition (CVD) growth of a hybrid structure of aligned graphene nanoribbons (GNRs) supported by a single-layer graphene sheet. The step structure created on the epitaxial Co film is used to segregate arrays of aligned GNRs. Reflecting the highly ordered step structure of the Co catalyst, straight nanoribbons with high aspect ratio (>100) are formed. Analysis suggests that a large-area, single-layer graphene film also grows over the aligned GNRs, making a GNR-graphene hybrid structure. We also demonstrate the isolation of aligned GNRs by oxygen plasma treatment or partial transfer of the hybrid film. These findings on the formation of highly aligned GNRs give new insights into the formation mechanism of graphene and can be applied for more advanced graphene structure for future electronics.

Difference in serum complement component C4a levels between hepatitis C virus carriers with persistently normal alanine aminotransferase levels or chronic hepatitis C.

Certain hepatitis C virus (HCV) carriers exhibit persistently normal alanine aminotransferase (ALT) levels (PNALT) (≤ 30 IU/l) accompanied by normal platelet counts (≥ 15 x 10(4)/µl); these individuals show milder disease activity and slower progression to cirrhosis. This study aimed to elucidate the characteristics of HCV carriers with PNALT using serum proteomics. The first group of subjects, who underwent clinical evaluation in the hospital, consisted of 19 HCV carriers with PNALT (PNALT-1) and 20 chronic hepatitis C (CHC-1) patients. The second group of subjects was part of a cohort study on the natural history of liver disease, and included 37 PNALT (PNALT-2) and 30 CHC (CHC-2) patients. Affinity bead-purified serum protein was subjected to matrix-assisted laser desorption ionization time-of-flight mass spectrometry analysis. Serum proteomics showed that 6 protein peaks with mass-to-charge ratios ranging from 1,000 to 3,000 differed significantly between the PNALT-1 and CHC-1 groups. Among these peaks, a 1738-m/z peak protein was identified as a fragment of complement component 4 (C4) and correlated significantly with serum C4a concentrations as determined by enzyme immunoassay. Serum C4a levels were also significantly higher in the PNALT-2 group compared to the CHC-2 group and healthy volunteers. Furthermore, in the PNALT-2 group, serum C4a levels negatively correlated with transaminase levels, but not with other biochemical tests, HCV core antigen levels, peripheral blood cell counts or serum hepatic fibrosis markers. This study indicates that host factors such as C4a not only differ between HCV carriers with PNALT and CHC, but that proteomic approaches could also contribute to the elucidation of factors in PNALT as more differences are discovered.

Epitaxial chemical vapor deposition growth of single-layer graphene over cobalt film crystallized on sapphire.

Epitaxial chemical vapor deposition (CVD) growth of uniform single-layer graphene is demonstrated over Co film crystallized on c-plane sapphire. The single crystalline Co film is realized on the sapphire substrate by optimized high-temperature sputtering and successive H(2) annealing. This crystalline Co film enables the formation of uniform single-layer graphene, while a polycrystalline Co film deposited on a SiO(2)/Si substrate gives a number of graphene flakes with various thicknesses. Moreover, an epitaxial relationship between the as-grown graphene and Co lattice is observed when synthesis occurs at 1000 °C; the direction of the hexagonal lattice of the single-layer graphene completely matches with that of the underneath Co/sapphire substrate. The orientation of graphene depends on the growth temperature and, at 900 °C, the graphene lattice is rotated at 22 ± 8° with respect to the Co lattice direction. Our work expands a possibility of synthesizing single-layer graphene over various metal catalysts. Moreover, our CVD growth gives a graphene film with predefined orientation, and thus can be applied to graphene engineering, such as cutting along a specific crystallographic direction, for future electronics applications.

Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C.

The recommended treatment for patients with chronic hepatitis C, pegylated interferon-alpha (PEG-IFN-alpha) plus ribavirin (RBV), does not provide sustained virologic response (SVR) in all patients. We report a genome-wide association study (GWAS) to null virological response (NVR) in the treatment of patients with hepatitis C virus (HCV) genotype 1 within a Japanese population. We found two SNPs near the gene IL28B on chromosome 19 to be strongly associated with NVR (rs12980275, P = 1.93 x 10(-13), and rs8099917, 3.11 x 10(-15)). We replicated these associations in an independent cohort (combined P values, 2.84 x 10(-27) (OR = 17.7; 95% CI = 10.0-31.3) and 2.68 x 10(-32) (OR = 27.1; 95% CI = 14.6-50.3), respectively). Compared to NVR, these SNPs were also associated with SVR (rs12980275, P = 3.99 x 10(-24), and rs8099917, P = 1.11 x 10(-27)). In further fine mapping of the region, seven SNPs (rs8105790, rs11881222, rs8103142, rs28416813, rs4803219, rs8099917 and rs7248668) located in the IL28B region showed the most significant associations (P = 5.52 x 10(-28)-2.68 x 10(-32); OR = 22.3-27.1). Real-time quantitative PCR assays in peripheral blood mononuclear cells showed lower IL28B expression levels in individuals carrying the minor alleles (P = 0.015).

Novel single nucleotide polymorphisms of the cytokeratin 19 pseudogene are associated with primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is characterized by chronic inflammation and destruction of intra-hepatic bile ducts. However, the pathogenesis of PBC has not been fully delineated. We examined whether patients with PBC harbor genomic mutations of the cytokeratin 19 (CK19) gene since that gene is specifically expressed in biliary epithelial cells. Thirty-six patients with PBC, 26 patients with other liver diseases, and 36 healthy volunteers were enrolled in this study, but there were no significant differences in the genomic sequence of the CK19 gene between those groups. On the other hand, novel single nucleotide polymorphisms (SNPs) of the CK19 pseudogene, C341T, T524G and A754G, were frequently detected in PBC patients. These results suggest that those novel SNPs of the CK19 pseudogene may be associated with PBC and may prove useful for predicting susceptibility to PBC.