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Background: Fulminant myocarditis presentation (FMP) is a rare and severe presentation of myocarditis. The natural history of FMP and its clinical features associated with poor outcomes are incompletely understood because there is a lack of generalizable evidence. Methods: This multicenter retrospective cohort study included patients hospitalized with histologically proven myocarditis who underwent catecholamine or mechanical support from 235 cardiovascular training hospitals across Japan between April 2012 and March 2017. Clinical features and the prognostic predictors of death or heart transplantation within 90 days on the basis of clinical and pathologic findings were determined using the Kaplan-Meier method, log-rank test, and Cox regression analysis. Results: This study included 344 patients with histologically proven FMP (median age, 54 years; 40% female). The median follow-up was 600 days (interquartile range, 36 to 1599 days) and the cumulative risk of death or heart transplantation at 90 days was 29% (n=98). Results from multivariable Cox regression analysis showed that older age, nonsinus rhythm, low left ventricular wall motion ( Conclusions: The results from analyses of data from this multicenter registry demonstrated that patients with FMP are at a higher risk of death or heart transplantation in real-world settings. These observations inform which clinical and pathologic findings may be useful for prognostication in FMP. Registration: URL: https://www.umin.ac.jp/ctr ; Unique identifier: UMIN000039763.

Aim Familial hypercholesterolemia (FH) is an underdiagnosed autosomal dominant genetic disorder characterized by high levels of plasma low-density lipoprotein cholesterol (LDL-C) from birth. This study aimed to assess the genetic identification of FH in children with high LDL-C levels who are identified in a universal pediatric FH screening in Kagawa, Japan. Method In 2018 and 2019, 15,665 children aged 9 or 10 years underwent the universal lipid screening as part of the annual health checkups for the prevention of lifestyle-related diseases in the Kagawa prefecture. After excluding secondary hyper-LDL cholesterolemia at the local medical institutions, 67 children with LDL-C levels of ≥ 140 mg/dL underwent genetic testing to detect FH causative mutations at four designated hospitals. Results The LDL-C levels of 140 and 180 mg/dL in 15,665 children corresponded to the 96.3 and 99.7 percentile values, respectively. Among 67 children who underwent genetic testing, 41 had FH causative mutations (36 in the LDL-receptor, 4 in proprotein convertase subtilisin/kexin type 9, and 1 in apolipoprotein B). The area under the curve of receiver operating characteristic curve predicting the presence of FH causative mutation by LDL-C level was 0.705, and FH causative mutations were found in all children with LDL-C levels of ≥ 250 mg/dL. Conclusion FH causative mutations were confirmed in almost 60% of the referred children, who were identified through the combination of the lipid universal screening as a part of the health checkup system and the exclusion of secondary hyper-LDL cholesterolemia at the local medical institutions.

Aims Interoception is the sensing function of physiological conditions and is crucial in self-regulation and decision-making. We examined the association of heartbeat tracking task performance, an indicator of interoceptive accuracy, with the degree of improvement in exercise tolerance in patients undergoing home-based cardiac rehabilitation. Methods and results Participants underwent baseline peak oxygen uptake (VO2) measurements and a heartbeat tracking task. The heartbeat tracking task score varies between 0 and 1, with higher scores indicating a better heartbeat perception. After 6 months of home-based exercise training, peak VO2 was measured again, and the percentage change (%Δ peak VO2) relative to the peak VO2 at baseline was calculated. Univariate regression analysis was performed to examine the association between %Δ peak VO2 and the heartbeat tracking task score. Multiple regression analysis was performed to determine the predictors of %Δ peak VO2. Of 120 participants, 100 patients (age 65.9 ± 11.9 years; 86% male) were included. There was a significant positive association between %Δ peak VO2 and the heartbeat tracking task score at baseline (R2 = 0.236, P < 0.001). In multiple regression analysis, the percentage of measured peak VO2 to the predicted value (%predicted peak VO2) (β = −0.248, P = 0.002), exercise adherence (β = 0.364, P < 0.001), and heartbeat tracking task score at baseline (β = 0.372, P < 0.001) were significantly associated with %Δ peak VO2. Conclusions Heartbeat tracking task performance, an indicator of interoceptive accuracy, at baseline is associated with the degree of improvement in exercise tolerance.

Galectin-9 (Gal-9) is a multifunctional lectin that moderates inflammation and organ damage. In this study, we tested whether Gal-9 has a protective role in the pathogenesis of endotoxemic acute kidney injury. We examined the levels of Gal-9 in control mice after lipopolysaccharide (LPS) administration. We developed Gal-9 knockout (KO) mice that lack Gal-9 systemically and evaluated the role of Gal-9 in LPS-induced proinflammatory cytokines, vascular permeability, and renal injury. Gal-9 levels were increased in the plasma, kidney, and spleen within 4 h after LPS administration to wild-type mice. Gal-9 deficiency did not affect the LPS-induced increase in plasma tumor necrosis factor-α levels at 1 h or vascular permeability at 6 h. Lower urine volume and reduced creatinine clearance were observed in Gal-9-KO mice compared with wild-type mice after LPS administration. Gal-9-KO mice had limited improvement in urine volume after fluid resuscitation compared with wild-type mice. LPS reduced the body temperature 12 h after its administration. Hypothermia had disappeared in wild-type mice by 24 h, whereas it was sustained until 24 h in Gal-9-KO mice. Importantly, maintaining body temperature in Gal-9-KO mice improved the response of urine flow to fluid resuscitation. Deficiency in Gal-9 worsened LPS-induced hypothermia and kidney injury in mice. The accelerated hypothermia induced by Gal-9 deficiency contributed to the blunted response to fluid resuscitation.

Background Immune checkpoint inhibitors are new immunotherapy drugs globally used for many malignancies, including renal cell carcinoma. Myocarditis as an immune-related adverse event is rare but highly fatal, suggesting that its frequency may be higher than reported. This paper describes a case of myocarditis that developed asymptomatically following ipilimumab and nivolumab combination therapy for renal cell carcinoma. Case presentation A 71-year-old Asian man who presented to hospital with fever, fatigue, and weight loss of approximately 10 kg within 2 months was diagnosed with Xp.11.2 translocation renal cell carcinoma. Computed tomography revealed multiple lung masses, mediastinal lymph node enlargement, and a level II tumor thrombus reaching the inferior vena cava (cT3bN0M1; International Metastatic Renal Cell Carcinoma Database Consortium, poor risk). Ipilimumab/nivolumab combination therapy was started as induction therapy. The patient experienced acute interstitial nephritis as an immune-related adverse event after treatment initiation; however, a good response to steroid therapy was observed. The antitumor effect of the immunotherapy was notable. Although he experienced pulmonary embolism, it seemed asymptomatic and harmless; thus, a second infusion was introduced. From the eighth day, he demonstrated rapidly worsening cardiogenic shock with asymptomatic electrocardiographic changes and drastic drop in cardiac biomarkers, and a diagnosis of myocarditis as an immune-related adverse event was made. Although immediate methylprednisolone mini-pulse therapy followed by tapered prednisolone prevented mortality, extensive myocardial fibrosis with marked ejection fraction decline persisted as a sequela. Consequently, follow-up without treatment was instituted; however, much of the tumor response initially observed was maintained over several months. Conclusion Physicians treating patients with immune checkpoint inhibitors should be aware of their potentially life-threatening cardiotoxic effects. This study emphasized the importance of a high index of suspicion, prompt diagnosis, and early intervention in patients who present with cardiac abnormalities and possible myocarditis after receiving immunotherapy.

Ivabradine is an established treatment for chronic heart failure with reduced ejection fraction (HFrEF) but not for acute heart failure. β-blocker up-titration is often not possible because of its negative inotropic effect (NIE). Ivabradine has no NIE; therefore, it may be preferred over β-blockers in patients with acute decompensated HFrEF.

AIM Skeletal muscle mass is associated with exercise tolerance in patients with chronic heart failure (CHF). Anthropometric indicators are used to evaluate skeletal muscle mass, as these can be easily assessed in clinical practice. However, the association between anthropometric indicators and exercise tolerance is unclear. This study aimed to investigate the association between anthropometric indicators and exercise tolerance in CHF patients. METHODS We evaluated 69 patients with CHF. Mid-arm circumference, mid-arm muscle circumference (MAMC), calf circumference and body mass index were measured as the anthropometric indicators. Exercise tolerance was evaluated according to the peak oxygen uptake (VO2 ). Correlation analyses were carried out to determine the association between peak VO2 and anthropometric indicators. Furthermore, univariate and multiple regression analyses were carried out using peak VO2 as the dependent variable, and age, male, left ventricular ejection fraction, angiotensin II receptor blocker or angiotensin converting enzyme inhibitor, diuretics, B-type natriuretic peptide, estimated glomerular filtration rate, hemoglobin and anthropometric indicators as the independent variables. RESULTS There were significant positive correlations between the peak VO2 and mid-arm circumference (rs = 0.378, P = 0.001), MAMC (r = 0.634, P

Cardiogenesis requires the orchestrated spatiotemporal tuning of BMP signalling upon the balance between induction and counter-acting suppression of the differentiation of the cardiac tissue. SMADs are key intracellular transducers and the selective degradation of SMADs by the ubiquitin–proteasome system is pivotal in the spatiotemporal tuning of BMP signalling. However, among three SMADs for BMP signalling, SMAD1/5/9, only the specific E3 ligase of SMAD9 remains poorly investigated. Here, we report for the first time that SMAD9, but not the other SMADs, is ubiquitylated by the E3 ligase ASB2 and targeted for proteasomal degradation. ASB2, as well as Smad9, is conserved among vertebrates. ASB2 expression was specific to the cardiac region from the very early stage of cardiac differentiation in embryogenesis of mouse. Knockdown of Asb2 in zebrafish resulted in a thinned ventricular wall and dilated ventricle, which were rescued by simultaneous knockdown of Smad9. Abundant Smad9 protein leads to dysregulated cardiac differentiation through a mechanism involving Tbx2, and the BMP signal conducted by Smad9 was downregulated under quantitative suppression of Smad9 by Asb2. Our findings demonstrate that ASB2 is the E3 ligase of SMAD9 and plays a pivotal role in cardiogenesis through regulating BMP signalling.

Mycophenolate mofetil is a key immunosuppressant that is metabolized into mycophenolic acid (MPA). The prognostic impact of MPA-focused therapeutic drug monitoring on allograft prognosis has not been determined in kidney transplant recipients with diabetes. In this study, we assessed the pharmacokinetics of MPA and allograft prognosis in recipients with diabetes. This study retrospectively analyzed 64 adult kidney transplant recipients. MPA blood concentration data (e.g., the time to the maximum concentration (Tmax), and the area under the concentration–time curve from 0 to 12 h (AUC0–12)) were collected at 3 weeks and 3 months after kidney transplantation. Of the 64 recipients, 15 had pre-existing diabetes. At 3 months after kidney transplantation, the Tmax of MPA was significantly longer in recipients with diabetes (mean (standard deviation): 2.8 (2.1) h) than in recipients without diabetes (1.9 (1.1) h, p = 0.02). However, the allograft estimated glomerular filtration rate and acute rejection rate, including borderline change, did not differ according to the diabetes status in patients with adjusted AUC0–12 of MPA within the target range. In conclusion, a longer Tmax of MPA was observed in recipients with diabetes, however, acceptable allograft prognosis was observed in kidney transplant recipients with diabetes and a sufficient AUC0–12 of MPA.

The National Health Insurance (NHI) special health checkup system in Japan targets the NHI population aged 40–74 years. Since 2015, the Kagawa NHI special health checkup was initiated in a prefecture-wide chronic kidney disease (CKD) initiative, including renal examination as an essential item in NHI health checkups. Here, we aimed to investigate the effects of the prefecture-wide CKD initiative. We conducted a retrospective cohort survey using the Kagawa National Health Insurance database created by the Kagawa National Health Insurance Organization. Results of the NHI health checkup (2015–2019) and prefecture-wide outcomes (2013–2019) were analyzed. The prevalence of CKD among examinees who underwent the NHI health checkup increased from 17.7% in 2015 to 23.2% in 2019. The percentage of examinees who completed a medical visit was 29.4% in 2015. After initiation of the initiative, the NHI health checkup coverage rate increased significantly, from a mean (standard deviation) of 40.8% (0.4%) to 43.2% (1.1%) (p = 0.04). After the start of the CKD initiative, we found an increase in the prevalence of CKD and the NHI health checkup coverage rate.

Galectin-9 (Gal-9) is a multifunctional lectin that moderates inflammation and organ damage. In this study, we tested whether Gal-9 has a protective role in the pathogenesis of endotoxemic acute kidney injury.We examined the levels of Gal-9 in control mice after lipopolysaccharide (LPS) administration. We developed Gal-9 knockout (KO) mice that lack Gal-9 systemically and evaluated the role of Gal-9 in LPS-induced proinflammatory cytokines, vascular permeability, and renal injury.Gal-9 levels were increased in the plasma, kidney, and spleen within 4 h after LPS administration to wild-type mice. Gal-9 deficiency did not affect the LPS-induced increase in plasma tumor necrosis factor-α levels at 1 h or vascular permeability at 6 h. Lower urine volume and reduced creatinine clearance were observed in Gal-9-KO mice compared with wild-type mice after LPS administration. Gal-9-KO mice had limited improvement in urine volume after fluid resuscitation compared with wild-type mice. LPS reduced the body temperature 12 h after its administration. Hypothermia had disappeared in wild-type mice by 24 h, whereas it was sustained until 24 h in Gal-9-KO mice. Importantly, maintaining body temperature in Gal-9-KO mice improved the response of urine flow to fluid resuscitation.Deficiency in Gal-9 worsened LPS-induced hypothermia and kidney injury in mice. The accelerated hypothermia induced by Gal-9 deficiency contributed to the blunted response to fluid resuscitation.

Twelve-lead electrocardiography provides us the clue about the differential diagnosis between atrioventricular nodal reentrant tachycardia and atrioventricular reentrant tachycardia.

Clinical Introduction A 69-year-old woman with hypertension and dyslipidemia developed sudden onset of substernal chest pain at night and was admitted to our hospital the following day. A 12-lead and 18-lead ECG (Nihon Kohden, Japan) was done (figure 1A,B). Question Which is the most likely diagnosis? Reperfused anterior acute myocardial infarction Takotsubo (stressed) cardiomyopathy Pericarditis Apical hypertrophic cardiomyopathy For answer see page 2.

Background Atrial fibrillation (AF), which contributes to an increased risk of stroke, frequently remains undetected, suggesting an unmet need for easier and more reliable AF screening. The reports on screening AF using an Omron blood pressure (BP) monitor with an irregular heartbeat (IHB) detector show inconsistent results, so the aim of this study was to develop a novel algorithm to accurately diagnose AF with 3 BP measurements using an Omron automated BP monitor with IHB detector.Methods and Results:In total, 303 general cardiac patients were included. Real-time single-lead ECG revealed AF in 44 patients. BP measurement was performed 3 times per patient using the Omron BP monitor HEM-907, and the number of IHBs detected was recorded. Based on these data, we developed the following algorithm: ≥1 IHB is detected during at least 2 of 3 BP measurements and the maximum number of IHBs detected is ≥2. Using this algorithm, we achieved a sensitivity of 95.5% and specificity of 96.5%, for diagnosing AF. Conclusions The novel algorithm with 3 BP measurements using the Omron automated BP monitor with IHB detector showed high sensitivity and specificity for diagnosing AF in general cardiac patients.

The type of lifestyle guidance that is effective for preventing development of chronic kidney disease (CKD) is unknown. Here, we aim to investigate the effects of a participatory structured group education (SGE) program on the development of CKD in a population-based study. We retrospectively analyzed 1060 adult special health check-up examinees with CKD. Examinees with an estimated glomerular filtration rate (eGFR) from 50 to 60 mL/min/1.73 m2 and/or proteinuria 1+ were encouraged to attend an SGE program. The SGE program included participatory small group discussions on the attendees’ remaining risk factors. The primary outcome of this study was the change in eGFR per year. The changes in eGFR in examinees who attended the SGE program (n = 209, + 2.9 mL/min/1.73 m2 [95% confidence interval (CI) + 1.9 to + 3.9]) significantly improved compared with control (n = 383, + 1.2 mL/min/1.73 m2 [95% CI + 0.5 to + 1.9], p = 0.006). Attending an SGE program was independently and positively related to the changes in eGFR at 1 year after attendance, after adjusting for classical covariates (β = 1.55 [95% CI 0.37–2.73], p = 0.01). Attending an SGE program was effective for the examinees with a lower eGFR compared with those with only proteinuria. Our SGE program showed the beneficial effects of preventing the development of CKD, independent of classical factors. The type of SGE program that is more effective for preventing development of CKD should be investigated in a long-term analysis.

Familial hypercholesterolemia (FH) is an inherited disorder with retarded clearance of plasma LDL caused by mutations of the genes involved in the LDL receptor-mediated pathway and most of them exhibit autosomal dominant inheritance. Homozygotes of FH (HoFH) may have plasma LDL-C levels, which are at least twice as high as those of heterozygous FH (HeFH) and therefore four times higher than normal levels. Prevalence of HoFH had been estimated as 1 in 1,000,000 before but more recent genetic analysis surveys predict 1 in 170,000 to 300,000. Since LDL receptor activity is severely impaired, HoFH patients do not or very poorly respond to medications to enhance activity, such as statins, and have a poorer prognosis compared to HeFH. HoFH should therefore be clinically distinguished from HeFH. Thorough family studies and genetic analysis are recommended for their accurate diagnosis. Fatal cardiovascular complications could develop even in the first decade of life for HoFH, so aggressive lipid-lowering therapy should be initiated as early as possible. Direct removal of plasma LDL by lipoprotein apheresis has been the principal measure for these patients. However, this treatment alone may not achieve stable LDL-C target levels and combination with drugs should be considered. The lipid-lowering effects of statins and PCSK9 inhibitors substantially vary depending on the remaining LDL receptor activity of individual patients. On the other hand, the action an MTP inhibitor is independent of LDL receptor activity, and it is effective in most HoFH cases. This review summarizes the key clinical issues of HoFH as well as insurance coverage available under the Japanese public healthcare system.

Introduction: Familial hypercholesterolemia (FH) is an autosomal hereditary disease found in patients who have elevated low-density lipoprotein cholesterol (LDL-C) levels from birth. Early detection and treatment of FH during childhood potentially reduces the risk of premature cardiovascular events. In Kagawa prefecture, a unique community health system, involving three steps, has been conducted to prevent lifestyle-related diseases for 10-year-old children. This system includes universal lipid screening, selection by pediatricians, and next-generation sequencing (NGS) of FH-related genes in the hospitals. The aim of this study is to investigate whether this system can be effective in detection of FH. Methods: In Kagawa prefecture, the universal lipid screening of children at 10 years of age is performed annually at school, covering over 90% of the target group. After excluding secondary hypercholesterolemia, pediatric clinics introduced children with LDL-C levels >140 mg/dL to four hospitals to perform NGS to detect FH. Results: In 2017, 279 children (3.7%) showed elevated LDL-C >140mg/dL among 7,647 ones who received the screening. We performed NGS for 46 children after excluding secondary hypercholesterolemia by pediatricians (LDL-C 186.0±50.3 mg/dL; M/F 27/19) and 26 children (57%) had FH genetic mutations (23 LDL-R, 3 PCSK9). The children with LDL-C >180mg/dL are recommended to receive statin therapy according to the guideline from the Japanese Atherosclerosis Society (JAS). Children with LDL-C levels ≥180 mg/dL have 74% of positive genetic mutations, and even those with 140-180 mg/dl LDL-C levels have as much as 44%, respectively (Table). Conclusions: The unique community health system in Kagawa can efficiently detect FH of children. Further investigation will be required for the effective prevention of future atherosclerotic cardiovascular diseases.

Introduction: Familial hypercholesterolemia (FH) is an autosomal hereditary disease found in patients who have elevated low-density lipoprotein cholesterol (LDL-C) from birth. Early detection and treatment of FH during childhood potentially reduces the risk of premature cardiovascular events. In Kagawa prefecture, a unique community health system, involving three steps, has been conducted to prevent lifestyle-related diseases for 10-year-old children. This system includes universal lipid screening, selection by pediatricians, and next-generation sequencing (NGS) of FH-related genes in hospitals. The aim of this study is to compare 3 international guidelines to detect pediatric FH with this unique community health system in Kagawa. Methods: In Kagawa prefecture, the universal lipid screening of approximately 8,000 children at 10 years of age is performed annually, covering over 90% of the target group. After excluding secondary hypercholesterolemia, pediatric clinics introduced children with LDL-C >140mg/dL to 4 designated hospitals to perform NGS. We applied the guidelines of the Dutch Lipid Clinic Network (DLCN), Simon Broome (SB), and the Japanese Atherosclerosis Society (JAS) to children who received NGS in the unique community health system in Kagawa. Results: We performed NGS for 46 children from January 2018 to February 2020 (LDL-C 186.0±50.3 mg/dL; Male/F 27/19) and 26 (57%) had FH genetic mutations (23 LDL-R and 3 PCSK9 mutations). Seventeen children met FH criteria for DLCN (35%), 10 for Simon Broome (22%), and 11 for JAS (24%), respectively. The combination of NGS and either of the 3 guidelines increased the number of children diagnosed as FH up to 31 (67%). Conclusion: International guidelines detected only half of pediatric FH who were diagnosed by the unique community health system in Kagawa. Further investigation will be required to build an effective universal screening system for pediatric FH.

Objective Home care is important in patients with heart failure (HF) in order to maintain their quality of life. A biomarker that can be measured noninvasively is needed to optimize the home care of patients with HF. Urinary angiotensinogen (uAGT) is an indicator of the intrarenal renin-angiotensin system activity, which may be augmented in HF. We hypothesized that uAGT might be a urinary biomarker in HF. Methods We measured uAGT by an enzyme-linked immunosorbent assay and uAGT normalized by urinary creatinine (uCr)-designated uAGT/uCr-at admission and discharge in 45 patients hospitalized for HF. Results We found that both uAGT/uCr [median (interquartile range): 65.5 (17.1-127.7) μg/g Cr at admission; 12.1 (6.0-37.0) μg/g Cr at discharge; p

Left ventricular hypertrophy (LVH) is a cardiovascular complication highly prevalent in patients with chronic kidney disease (CKD). Previous studies analyzing 1α-hydroxylase or vitamin D receptor (Vdr) knockout mice revealed active vitamin D as a promising agent inhibiting LVH progression. Paricalcitol, an active vitamin D analog, failed to suppress the progression of LV mass index (LVMI) in pre-dialysis patients with CKD. As target genes of activated VDR differ depending on its agonists, we examined the effects of maxacalcitol (22-oxacalcitriol: OCT), a less calcemic active vitamin D analog, on LVH in hemodialysis patients and animal LVH models with renal insufficiency. In retrospective cohort study, patients treated with OCT who underwent hemodialysis were enrolled. Using cardiac echocardiography, LV mass was evaluated by the area-length method. In animal study, angiotensin II (Ang II)-infused Wister rats with heminephrectomy or Ang II-stimulated neonatal rat ventricular myocytes (NRVM) were treated with OCT. OCT significantly inhibited the progression of LVMI in hemodialysis patients. In Ang II-infused heminephrectomized rats, OCT suppressed the progression of LVH in a blood pressure-independent manner. OCT also suppressed the activity of calcineurin in the left ventricle of model rats. Specifically, OCT reduced the protein levels of calcineurin A, but not the mRNA levels of Ppp3ca (calcineurin Aα). Luciferase assays showed that OCT increased the promoter activity of Fbxo32 (atrogin1), an E3 ubiquitin ligase targeting calcineurin A. Finally, OCT promoted ubiquitination and degradation of calcineurin A. Our works indicated that OCT retards progression of LVH through calcineurin-NFAT pathway, which reveal a novel aspect of OCT in attenuating pathological LVH.

A 49-year-old woman was admitted with suspicion of acute myocarditis. On the next day after admission, her serum troponin I level continued to rise, indicating progression of myocardial damage. Moreover, her symptoms persisted, and left ventricular ejection fraction did not improve. Because of a predominant infiltration of lymphocytes in the myocardial specimens, lymphocytic myocarditis was diagnosed. However, a close observation of the specimens revealed eosinophil degranulation. Based on this finding, intravenous steroid therapy was initiated. High-dose methylprednisolone led to rapid and appreciable improvements in symptoms and left ventricular function within 12 hours after the first administration, which was followed by normalization of serum troponin I level. Steroid therapy was switched to oral administration and tapered carefully. There was no recurrence of left ventricular dysfunction or elevation of serum troponin I level. In eosinophilic myocarditis, eosinophil degranulation has been recognized as an important finding associated with progression of inflammation and myocardial damage. However, no attention has been paid to the presence and clinical implications of eosinophil degranulation in lymphocytic myocarditis. This case indicates that eosinophil degranulation in lymphocytic myocarditis may be an important finding associated with a high therapeutic response to steroid therapy.

Background In patients with aneurysmal subarachnoid hemorrhage (SAH), an association between hypocapnia and poor clinical outcomes has been reported. However, the optimal arterial carbon dioxide tension (PaCO2) remains unknown. The present retrospective study aimed to examine the association of abnormal PaCO2 levels with neurological outcomes and investigate the optimal target PaCO2 level in patients with SAH. Methods We retrospectively selected consecutive adult patients hospitalized in the intensive care unit (ICU) for SAH between January 2009 and April 2017. Univariate and multivariate analyses were performed to identify the independent predictors of unfavorable neurological outcomes (i.e., modified Rankin scale score of 3–6 on hospital discharge). Results Among 158 patients with SAH, 73 had unfavorable neurological outcomes. During the first 2 weeks in the ICU, the median number of PaCO2 measurements per patient was 43. The factors significantly associated with unfavorable neurological outcomes were age, Hunt and Kosnik grade, maximum lactate levels during the first 24 h, and maximum (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.03–1.21; p

Post-transplant immunoglobulin A (IgA) nephropathy (IgAN) in the allograft is the major cause of allograft loss. Using a protocol biopsy, latent mesangial IgA deposition (IgAD) can be detected in the allograft. Latent IgAD is distinguished from IgAN by the absence of urinary abnormalities, although IgA is observed in the mesangium. However, the pathophysiology and most appropriate treatment strategy for latent mesangial IgAD in the allograft remain to be fully determined. Importantly, it is unknown whether all cases of post-transplant asymptomatic IgAD progress to symptomatic IgAN; indeed, IgA deposits disappear in some cases. The differences in allograft prognosis between asymptomatic IgAD and IgAN have also not been determined. Non-invasive methods of diagnosis of IgAD in the allograft using serological and pathological biomarkers are being developed. Possible serum biomarkers include serum galactose-deficient IgA1 (Gd-IgA1), Gd-IgA1-specific IgG and Gd-IgA1-specific IgA, and its immune complexes. Immunofluorescence analysis using Gd-IgA1 monoclonal antibody may provide a pathological biomarker. These serological and pathological biomarkers may be suitable for the characterization of the stage of IgAD. However, there is insufficient information regarding whether serological and pathological biomarkers can predict the progression of asymptomatic IgAD to symptomatic IgAN. We propose that the pathogenesis of IgAN can be defined through the clinical study of IgAD in the allograft using protocol biopsies conducted by nephrologists involved in clinical kidney transplantation.

BACKGROUND Erythropoietin (EPO) has antiapoptotic and tissue-protective effects, but previous clinical studies using high-dose EPO have not shown cardioprotective effects, probably because of platelet activation and a lack of knowledge regarding the optimal dose. In contrast, a small pilot study using low-dose EPO has shown improvement in left ventricular function without adverse cardiovascular events.Methods and Results:We performed a multicenter (25 hospitals), prospective, randomized, double-blind, placebo-controlled, dose-finding study to clarify the efficacy and safety of low-dose EPO in patients with ST-segment elevation myocardial infarction (STEMI) under the Evaluation System of Investigational Medical Care of the Ministry of Health, Labor and Welfare of Japan. In total, 198 STEMI patients with low left ventricular ejection fraction (LVEF

We often observe patients with antiphospholipid syndrome (APS) presenting with both venous and arterial thrombi. Anticoagulant therapy is effective for venous and peripheral arterial embolisms in these patients; however, it has opposite effects when applied for thoracic aortic mural thrombosis because of the risk of new arterial embolisms. Recently, thoracic endovascular aortic repair (TEVAR) has been used to prevent arterial embolisms due to aortic thrombosis. However, we generally hesitate to implant artificial materials in patients in a hypercoagulable state because this can cause new thrombi to develop. Here, we present a case of successful treatment by anticoagulant therapy and TEVAR in an APS patient presenting with pulmonary embolisms (PEs) and multiple arterial embolisms due to thoracic aortic mural thrombosis. A 46-year-old man was referred to our hospital due to dyspnea and leg pain. Since contrast-enhanced computed tomography revealed PEs, thoracic aortic mural thrombosis, and lower limb arterial embolisms, we administered anticoagulation therapy. Three days later, contrast-enhanced computed tomography revealed new arterial embolisms in the right kidney. To prevent further arterial embolisms due to thoracic aortic mural thrombosis, we performed emergent TEVAR in addition to anticoagulant therapy. Thereafter, no venous or arterial embolisms recurred during the 13-month follow-up period.

Background: It is uncertain whether kidneys from marginal donors are suitable for live kidney transplantation. In deceased donor kidneys, tubular cell senescence affects allograft function. However, the degree of cell senescence in a living donor kidney with marginal factors has not been reported. In this study, we assessed the association of tubular cell senescence with allograft and remnant kidney function by a prospective observational clinical study. Methods: Thirty-eight living donor kidney transplantations were analyzed prospectively. Tissue sections obtained from preimplantation kidney biopsies were immunostained for p16INK4a to indicate cell senescence. Various kidney biomarkers were analyzed in urine and blood samples. Results: Of the 38 donors, 21 had marginal factors. Severe tubular senescence was found in living donors with overlapping marginal criteria. Tubular senescence in living donor kidneys was significantly related to donor age and lower recipient kidney function at 1 year after transplantation independently of donor age (β = –0.281; p = 0.050) but did not affect remnant kidney function after donation. Pretransplantation donor pre-estimated glomerular filtration rate and hypertension did not show a significant area under the curve (AUC) for prediction of high tubular senescence. High plasma levels of soluble αKlotho were associated with a higher predictive value for low tubular cell senescence with an AUC of 0.78 (95% CI 0.62–0.93; p < 0.01). Conclusions: The nuclear p16-staining rate in donated kidney tubules is a predictor for allograft kidney function but not donor remnant kidney function. Detection of tubular cell senescence may facilitate selection of appropriate living donor candidates.

Summary Background Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the EGF family and is involved in various diseases including cancers. Aptamers are synthetic oligonucleotides (RNA or DNA) that fold into unique three-dimensional structures and specifically bind to their targets with high affinity. We aimed to generate an aptamer with high affinity and specificity for HB-EGF. Methods Recombinant human HB-EGF (rhHB-EGF), comprised of the extracellular EGF-like and heparin-binding domains of HB-EGF, was used as the target. The aptamer against HB-EGF (the anti-HB-EGF aptamer) was obtained by systematic evolution of ligands by exponential enrichment (SELEX). Results After the 10th round of SELEX, aptamers were reverse-transcribed and PCR-amplified. Within obtained forty-six clones, twenty-three were identical (the anti-HB-EGF aptamer). The analysis using wireless-electrodeless quartz crystal microbalance revealed that the anti-HB-EGF aptamer had high affinity for rhHB-EGF (KD value: 12.2 ± 1.1 nmol/L). The dot-blot analysis revealed that the anti-HB-EGF aptamer specifically bound to rhHB-EGF. The analysis using confocal microscopy indicated that the anti-HB-EGF aptamer also bound to membrane-bound HB-EGF. Western-blot assay indicated that the anti-HB-EGF aptamer inhibited the phosphorylation of rhHB-EGF-mediated EGF receptor (EGFR). Conclusion We identified a novel RNA aptamer that bound with high affinity and specificity to rhHB-EGF and potently inhibited the rhHB-EGF-mediated phosphorylation of EGFR. The anti-HB-EGF aptamer may be a promising therapeutic agent for specifically neutralizing HB-EGF signaling.