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Autoimmune thyroid diseases (AITDs), such as Graves’ disease (GD) and Hashimoto’s disease (HD), are organ-specific autoimmune diseases. Histone acetylation, especially that of histone H3, is an epigenetic mechanism that regulates gene expression and is associated with the development of autoimmune diseases. However, physiological variations in histone acetylation are not yet clear, and we believe that physiological variations should be examined prior to analysis of the role of histone H3 in the pathogenesis of AITDs. In this study, we analyzed histone H3 acetylation levels in peripheral blood mononuclear cells (PBMCs) using a histone H3 total acetylation detection fast kit. Blood samples were collected before meals, between 8:30–9:00 am, daily for 10 weeks to evaluate the daily variation. At 4 days, blood was also collected before meals three times a day (at 8:30–9:00, 12:30–13:00, and 16:30–17:00) to evaluate circadian variation. Then, histone H3 acetylation levels were evaluated in AITD patients to clarify the association with the pathogenesis of AITD. Although we could not find a common pattern of circadian variance, we observed daily variation in histone H3 acetylation levels, and their coefficient of variances (CVs) were approximately 48.3%. Then, we found that histone H3 acetylation levels were significantly lower in GD and HD patients than in control subjects and these differences were larger than the daily variation in histone acetylation. In conclusion, histone H3 acetylation levels were associated with the development of AITD, even allowing for daily variation.

BackgroundThe fibrosis-4 (FIB-4) index has attracted attention as a predictive factor for cardiovascular events and mortality in patients with heart disease. However, its clinical value in patients with implanted pacemakers remains unclear.MethodsThis study included patients who underwent pacemaker implantation. The FIB-4 index was calculated based on blood tests performed during the procedure. The primary outcome was all-cause mortality, and the secondary outcomes included cardiovascular death, non-cardiovascular death, and major adverse cardiovascular events (MACE; composite of cardiovascular death, heart failure hospitalization, non-fatal myocardial infarction, and non-fatal stroke). The FIB-4 index was stratified into tertiles. Between-group comparisons were performed using log-rank tests and multivariate analysis using Cox proportional hazards. The predictive accuracy and cut-off value of the FIB-4 index were calculated from the receiver operating characteristic curve for all-cause mortality. Finally, based on the calculated cut-off values, the patients were divided into two groups for outcome validation and subgroup analysis.ResultsThis study included 201 participants, of whom 38 experienced death during the observation period (median: 1097 days). All-cause mortality, non-cardiovascular death, and MACE differed significantly between groups stratified by the FIB-4 index tertiles (log-rank test: PConclusionsIn patients with pacemakers, the FIB-4 index may be a predictor of early all-cause mortality, with a cut-off value of 3.75.

Cases of painful left bundle branch block syndrome have been reported; however, the pathophysiology of chest pain remains unclear. Here, we report a patient with left bundle branch block and chest pain. We evaluated coronary microvascular dysfunction using guide wire–based thermodilution. (Level of Difficulty: Intermediate.)

Leadless pacemakers, specifically Micra (Medtronic), have recently become a preferred alternative to transvenous pacemakers for use in bradyarrhythmia. Problems with conventional transvenous pacemakers include wound infection, lead disconnection, and tricuspid valve dysfunction. While Micra has the advantage of not being associated with the aforementioned complications, there have been reports of cardiac injury during Micra implantation, which have raised safety concerns. Many reports have evaluated Micra safety, but its effect on cardiac function remains unclear. In an 85-year-old man with bradycardic atrial fibrillation, a heart rate of approximately 35 bpm, and symptoms of dizziness, we analyzed ventricular workload, ejection fraction of the left and right ventricles, and inter/intraventricular synchrony using cardiac blood pool scintigraphy and myocardial work. Micra was successfully implanted into the right ventricular septum via the left femoral vein. A follow-up, 2 days later, showed no major complications associated with Micra pacing threshold and impedance. At this time, there was no apparent worsening of heart failure. Micra implantation for bradycardic atrial fibrillation has the potential to improve left ventricular work efficiency without the loss of ventricular synchrony.

Background: Pulmonary hypertension is a rare complication of sarcoidosis. The pathogenesis of sarcoidosis-related pulmonary hypertension is multifactorial, and patients with sarcoidosis-related pulmonary hypertension can have variable treatment responses and prognoses. While selexipag (Nippon Shinyaku / Kyoto / Japan) was recently approved in Japan for the treatment of pulmonary hypertension, the risk of cerebral infarction has not been clearly reported. Case report: A 63-year-old Asian female with a diagnosis of ocular and cutaneous sarcoidosis developed shortness of breath and was referred to our department to rule out cardiac sarcoidosis. Swan–Ganz catheterization was performed, and she was diagnosed with pulmonary arterial hypertension and started on selexipag. A few days after starting treatment, she presented with hemiplegia and was diagnosed with cardiogenic cerebral embolism by using magnetic resonance imaging. As there was no evidence of pre-existing intracardiac thrombosis, we suspected unusual cerebral embolism. Echocardiography revealed a deep venous thrombus and a bubble study revealed a right-left shunt through a patent foramen ovale. Conclusions: The initiation of selexipag improved pulmonary blood flow and caused cerebral embolism, which was an unusual and unexpected event. This report highlights the importance of confirming the presence of patent foramen ovale and a deep venous thrombus before starting treatment for pulmonary hypertension.

The programmed cell death-1 (PD-1)/PD ligand pathway plays a key role in the maintenance of peripheral tolerance by enhancing the suppressive activity of regulatory T (Treg) cells. The promoter activity of the A allele of PD1 rs36084323 G/A polymorphism is lower than that of the G allele. We examined the association of PD1 gene polymorphisms, PD-1 expression on Treg cells, and thyroid PD-1/PD-1 ligand (PD-L1) expression with the pathogenesis of autoimmune thyroid disease (AITD). We classified patients and genotyped PD-1 polymorphisms by using the PCR-RFLP method in a total of 176 Graves’ disease (GD) patients, 150 Hashimoto’s disease (HD) patients with different disease severities and 99 healthy controls. PD-1 expression on Treg cells was analysed by flow cytometry. Indirect immunofluorescence staining was performed in thyroid tissue to detect PD-1, PD-L1, and PD-L2. The frequencies of the A allele and the AA + AG genotypes of the PD1 rs36084323 polymorphism were lower in HD patients than in GD patients, and the frequencies of the AA genotype of the PD1 rs36084323 and of the TT genotype of the PD1 rs2227982 were lower in mild HD patients than in severe HD patients. In patients with severe HD, the titres of TgAb at the onset were higher in patients with the PD1 rs36084323 AA genotype than in patients with the GG genotype. Peripheral PD1+ Treg cells tended to decrease in individuals with the PD1 rs36084323 AA genotype than with the G carrier genotype. Peripheral PD-1+ Treg cells were increased in HD, especially in mild HD. PD-1, PD-L1, and PD-L2 were expressed in thyroid-infiltrating mononuclear cells (TIMCs), and PD-L1 and PD-L2 were expressed in thyroid epithelial cells (TECs) in AITD patients but not in normal controls. Expression of PD-L1 in TIMCs and expression of PD-L2 in TECs were predominant in HD and GD patients, respectively. In conclusion, the functional PD1 rs36084323 polymorphism and the thyroid PD-1/ PD-L1s expression which may enhance the suppressive activity of Treg cells differ between GD and HD, and the PD1 rs36084323 and rs2227982 polymorphisms and PD1+ Treg cells are related to the severity of HD.

Arf GTPase-Activating proteins (ArfGAPs) mediate the hydrolysis of GTP bound to ADP-ribosylation factors (Arfs), which are critical to form transport intermediates. ArfGAPs have been thought to be negative regulators of Arfs; however, accumulating evidence indicates that ArfGAPs are important for cargo sorting and promote membrane traffic. Weibel-Palade bodies (WPBs) are cigar-shaped secretory granules in endothelial cells that contain von Willebrand factor (vWF) as their main cargo. WPB biogenesis at the Golgi was reported to be regulated by Arf and their regulators, but the role of ArfGAPs has been unknown. In this study, we performed siRNA screening of ArfGAPs to investigate the role of ArfGAPs in the biogenesis of WPBs. We found two ArfGAPs, SMAP1 and AGFG2, to be involved in WPB size and vWF exocytosis, respectively. SMAP1 depletion resulted in small-sized WPBs, and the lysosomal inhibitor leupeptin recovered the size of WPBs. The results indicate that SMAP1 functions in preventing the degradation of cigar-shaped WPBs. On the other hand, AGFG2 downregulation resulted in the inhibition of vWF secretion upon Phorbol 12-myristate 13-acetate (PMA) or histamine stimulation, suggesting that AGFG2 plays a role in vWF exocytosis. Our study revealed unexpected roles of ArfGAPs in vWF transport.

Autoimmune thyroid diseases (AITDs), including Hashimoto’s disease (HD) and Graves’ disease (GD), are archetypes of organ-specific autoimmune diseases, but the prognosis of patients with AITD varies. Autoimmune diseases, including AITDs, are believed to develop in response to both genetic and environmental factors. Interleukin (IL)-6 plays a major role in B cell differentiation and T cell proliferation, and methylation of the IL6 gene is associated with IL-6 production. To clarify the role of IL6 gene methylation in the pathogenesis and prognosis of AITDs, we measured the methylation levels of −666, −664, −610, −491 and −426 CpG sites in the IL6 gene. We measured the methylation levels of 5 CpG sites in 29 patients with HD, 31 patients with GD and 16 healthy volunteers using pyrosequencing. The methylation level at each of the −664, −491 and −426 CpG sites was negatively correlated with the age at the time of sampling. Multiple regression analysis indicated that patients with HD, including severe or mild HD, showed higher methylation levels at the −426 CpG site than control subjects. Patients with intractable GD showed lower methylation levels at the −664 and −666 CpG sites than patients with GD in remission. In conclusion, IL6 gene methylation levels were related to the susceptibility to HD and the intractability of GD.

Introduction Pacing-induced cardiomyopathy occasionally occurs in patients undergoing pacemaker implantation. Although compared with right ventricular (RV) apical pacing, RV septal pacing can attenuate left ventricular dyssynchrony; the success rate of lead placement on the RV septum using the stylet system is low. Additionally, no randomised controlled trial has addressed the issue regarding the accuracy of RV lead placement on the RV septum using the stylet and delivery catheter systems. This study hypothesises that a newly available delivery catheter system can improve the accuracy of RV lead placement on the RV septum.Methods and analysis In a multicentre, prospective, randomised, single-blind, controlled trial, 70 patients with pacemaker indication owing to atrioventricular block will be randomised to either the delivery catheter or stylet group before the pacemaker implantation procedure. The position of the RV lead tip will be assessed using ECG-gated cardiac CT in all patients within 4 weeks after pacemaker implantation. Lead tip positions are classified into three groups: (1) RV septum, (2) anterior/posterior edge of the RV septal wall and (3) RV free wall. The primary endpoint will be the success rate of RV lead tip placement on the RV septum, which will be evaluated using cardiac CT.Ethics and dissemination This study will be conducted according to the stipulations of the Helsinki Declaration and the institutional review board of Hamamatsu University School of Medicine. The results of the study will be disseminated at several research conferences and will be published in peer-reviewed journals.Trial registration number jRCTs042200014; Pre-results.

The prognosis of autoimmune thyroid disease (AITD) including Graves’ disease (GD) and Hashimoto’s disease (HD) is difficult to predict. We previously suggested that Th17 cells may be associated with the pathogenesis of AITD. However, the association between gene polymorphisms in Th17-related genes and the prognosis of AITD was not clarified. To clarify this association, we genotyped 12 polymorphisms in 11 Th17-related genes (IL1Ra, IL6R, IL17R, IL21R, IL23R, CCR6, SOCS3, RORC, IL17A, IL17F and IL21) in 142 HD patients including 58 patients with severe HD and 48 patients with mild HD, 170 patients with GD including 81 patients with intractable GD and 49 patients with GD in remission, and 84 healthy volunteers. The frequency of the IL17F rs763780 T allele was higher in patients with severe HD than in patients with mild HD (p = .008). The frequency of the IL17R rs9606615 T allele was higher in patients with HD than in normal subjects (p = .011). The frequencies of the SOCS3 rs4969170 AA genotype, CCR6 rs3093024 AA genotype, and IL21 rs907715 AA genotype were higher in patients with intractable GD than in patients with GD in remission (p = .035, p = .002 and p = .030, respectively). In conclusion, IL17R rs9607715 and IL17F rs763780 polymorphisms are associated with the susceptibility and severity of HD, respectively. IL21 rs907715, SOCS3 rs4969170 and CCR6 rs3093024 polymorphisms are associated with the intractability of GD.

Graves’ disease (GD) and Hashimoto’s disease (HD) are different pathological types of autoimmune thyroid diseases (AITDs). However, the epigenetic differences between these diseases have not been elucidated. DNA methylation is one of the primary epigenetic modifications that reflect environmental influences on gene expression. In this study, we evaluated the methylation status of six CpG sites in the TNFA promoter using pyrosequencing and analyzed the data in combination with functional polymorphisms (−1031 T/C and +123 C/T) in the TNFA gene to clarify the role of gene methylation on the prognosis of AITDs. We examined the methylation pattern in 52 patients with GD, 60 patients with HD, and 29 healthy controls by pyrosequencing. Additionally, we also genotyped the polymorphisms from 163 patients with GD, 152 patients with HD, and 94 healthy controls using the restriction fragment length polymorphism (RFLP) method. Each proportion of subjects with low methylation of the −72 CpG site (≤11.9%), low methylation of the −49 CpG site (≤15.5%), and low methylation of the −38 CpG site (≤8.9%) was significantly increased in the groups with high concentration of TNF-α (≥0.134 pg/mL). The methylation level of the −72 CpG site was significantly higher in GD cases (10.7 ± 4.9%) than in healthy controls (6.8 ± 3.9%). The methylation level of the −49 and −38 CpG sites were significantly higher in patients with GD in remission (20.5 ± 9.5%, 17.6 ± 8.0%, respectively) than in healthy controls (13.0 ± 7.6%, 7.9 ± 7.3%, respectively). The frequency of the TNFA − 1031C carrier (CT + CC) is correlated with higher TNF-α production and was significantly higher in GD (35.0%) and HD (39.5%) cases than in controls (19.1%). In the subjects with the TNFA − 1031C carrier (CT + CC), the methylation level of the −72 CpG site was significantly higher in GD (11.5 ± 5.7%) than in HD (6.0 ± 3.4%). However, there was no difference between GD and HD in patients with the TT genotype. Cumulatively, our data indicate the methylation levels of CpG sites in the TNFA gene may be related to the difference between GD and HD in AITDs and may be influenced by the TNFA gene polymorphism.

The microRNA (miRNA) biogenesis pathway is regulated by specific proteins and enzymes, including Dicer, Drosha, DGCR8, Exportin 5 and the Argonaute (AGO) family. In this study, we investigated the AGO family, which is the primary component of RISC (RNA-induced silencing complex) and directly binds to microRNA. We examined the association of polymorphisms in AGO family genes with AGO expression and with the development and prognosis of autoimmune thyroid diseases. We genotyped AGO1 rs636832A/G, AGO2 rs7005286C/T, AGO2 rs11166985A/G and AGO2 rs2292779C/G polymorphisms in 184 Graves’ disease (GD) patients, 195 Hashimoto’s disease (HD) patients and 122 healthy volunteers using the polymerase chain reaction-restriction fragment length polymorphism method. We also examined the expression of AGO1 and AGO2 mRNAs in peripheral blood mononuclear cells (PBMC) obtained from 52 GD patients, 41 HD patients, and 25 healthy volunteers using quantitative RT-PCR methods. The G allele of AGO1 rs636832 and the A allele of AGO2 rs11166985 polymorphisms were significantly more frequent in GD patients than in healthy controls. The A allele of AGO2 rs11166985 was also significantly more frequent in intractable GD patients than in controls. The C carrier (CC + CG genotypes) and C allele of AGO2 rs2292779 polymorphism were significantly more frequent in intractable GD patients than in patients with GD in remission. Expression of AGO1 mRNA in PBMC was significantly higher in AITD patient than in controls, and that of AGO2 mRNA in PBMC was significantly higher in intractable GD patients than in patients with GD in remission. Furthermore, the expression levels of both the AGO1 and AGO2 genes were significantly correlated with the proportions of Th17 cells in PBMC. In conclusion, the polymorphisms of the AGO1 and AGO2 genes, the expression levels of which correlated with the proportion of Th17 cells, were associated with the development and prognosis of GD. The AGO2 rs2292779 C carrier and C allele were associated with the intractability of GD.

Graves’ disease (GD) and Hashimoto’s disease (HD) are autoimmune thyroid diseases (AITDs), and the prognosis of AITDs is different for each patient. We examined the association of polymorphisms in the Thyroglobulin (TG) gene with the pathogenesis of AITD. We genotyped TG rs180195G/A, rs853326G/A, rs2076740C/T, rs2703013G/T, rs2958692C/T and rs733735A/G polymorphisms in 137 HD patients, 131 GD patients and 89 healthy controls and also examined the levels of TG mRNA expression and serum TG. The TG rs180195 GG genotype was more frequent in HD patients (p = .0277), and the proportion of CD4+ cells with high levels of TG mRNA was greater in individuals with the GG genotype than in A carriers (p = .0107). The TG rs2703013 TT genotype was less frequent in AITD (p = .0186), and serum TG levels were lower in individuals with the TT genotype than in G carriers (p = .0170). In the TG rs2958692 polymorphism, the T allele was more frequent in intractable GD than in GD in remission (p = .0055), and serum titres of anti-thyroglobulin antibody (TgAb) were lower in GD patients with the TT genotype than in C carriers (p = .0151). In the TG rs2076740 polymorphism, serum titres of TgAb were higher in HD patients who were T carriers than in those with the CC genotype (p = .0359). SNPs in the TG gene were associated with the development of HD and GD, the intractability of GD, and the levels of TG mRNA expression, serum TG, and serum TgAb.

Graves’ disease (GD) and Hashimoto’s disease (HD) are autoimmune thyroid diseases (AITDs). Prognosis of AITDs varies in each patient. Toll-like receptors (TLRs) are pattern-recognition receptors that activate signaling pathways involved in the production of proinflammatory cytokines. UNC93B1 is a transcription factor of TLR7 and TLR9. In this study, we examined the association of TLR expression and TLR and UNC93B1 polymorphisms with the development and prognosis of AITDs. The ratio of intracellular TLR7 (iTLR7) and iTLR9 intensities in B cells was lower in patients with GD in remission than in patients with intractable GD (p = 0.0007). The frequency of G allele of TLR7 rs3853839 G/C polymorphism was significantly higher in male patients with GD and intractable GD than in control subjects (p = 0.0062 and 0.0173, respectively). The frequencies of T allele of TLR9 rs187084 C/T polymorphism and C allele of TLR9 rs352140 C/T polymorphism were significantly higher in patients with intractable GD who had GG genotype of TLR7 rs3853839 polymorphism, which is associated with higher TLR7 expression, than in patients with GD in remission (p = 0.0334 and 0.0023, respectively). The frequencies of AA genotype and A allele of UNC93B1 rs308328 polymorphism were significantly higher in patients with GD than in patients with HD (p = 0.0406 and 0.0316, respectively). These results suggested that the ratio of iTLR7 and iTLR9 intensities was associated with the development and intractability of GD and that TLR7 and UNC93B1 polymorphisms were associated with the development of GD.

In this study, we investigated the possibilities of using activated carbon fibre (ACF) as a carbon capture and storage (CCS) technology. The CO 2 adsorption isotherms of ACFs with different porosities were systematically examined at 273 and 298 K under ambient pressure conditions. The porosities of the ACFs were characterized by the adsorption of nitrogen at 77 K. We analyzed the adsorption capabilities of three types of ACFs (A5, A10 and A20) having different slit-shaped pore widths, specific surface areas and micropore volumes. Our results reveal that A5 had ultramicropores and achieved a higher adsorption of CO 2 at low relative pressure (