Publications by authors named "Atsushi Suzuki"

550 Publications

The prognostic value of the COPD Assessment Test in fibrotic interstitial lung disease.

Respir Investig 2021 Sep 18. Epub 2021 Sep 18.

Department of Respiratory Medicine and Allergy, Tosei General Hospital, Seto, Aichi, Japan.

Background: The COPD Assessment Test (CAT) has been studied as a measure of health status in idiopathic pulmonary fibrosis (IPF) and interstitial lung disease associated with connective tissue disease. However, its prognostic value is unknown. The present study explored the association between CAT score and mortality in fibrotic interstitial lung disease (FILD), including IPF and other forms of ILD.

Methods: We retrospectively analyzed 501 consecutive patients with FILD who underwent clinical assessment, including pulmonary function test and CAT. The association between CAT score and 3-year mortality was assessed using Cox proportional hazard analysis, Kaplan-Meier plots, and the log-rank test for trend. To handle missing data, the imputed method was used.

Results: The patients' median age was 68 years, and 320 were male (63.9%). Regarding CAT severity, 203 patients had a low impact level (score <10), 195 had a medium level (10-20), 80 had a high level (21-30), and 23 had a very high level (31-40). During the 3-year study period, 118 patients died. After adjusting for age, sex, forced vital capacity, diffusion capacity for carbon monoxide, IPF diagnosis, and usual interstitial pneumonia pattern on high-resolution computed tomography, the CAT score was significantly associated with 3-year mortality (hazard ratio in increments of 10 points: 1.458, 95% confidence interval 1.161-1.830; p < 0.001). In addition, patients with high and very high impact levels had twofold and threefold higher mortality risk than those with low levels, respectively.

Conclusion: The CAT has prognostic value in FILD.
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http://dx.doi.org/10.1016/j.resinv.2021.07.007DOI Listing
September 2021

Comparison of Microemboli Formation Between Irrigated Catheter Tip Architecture Using a Microemboli Monitoring System.

JACC Clin Electrophysiol 2021 Aug 17. Epub 2021 Aug 17.

Translational Interventional Electrophysiology Laboratory, Mayo Clinic, Rochester, Minnesota, USA. Electronic address:

Objectives: This study aimed to compare the efficacy and safety of ablation with high and low power settings using either a flexible tip or straight SF tip irrigated catheter in the left ventricle (LV) using a peripheral microemboli monitoring system.

Background: The microemboli risk of flexible and straight SF tip irrigated catheters in creating ablative lesions in the LV at variable power settings has not been adequately assessed.

Methods: Six pigs underwent catheter ablation in the LV using a flexible tip or straight SF tip catheter with 2 energy settings (30 or 50 W, 30 seconds, irrigation saline 17 mL/min).

Results: A total of 79 radiofrequency (RF) applications were assessed. High power settings via a flexible tip formed a significantly higher arterial microbubble volume in the extracorporeal circulation (P = 0.005). Notably, RF applications with a steam pop induced an exponential increase of microbubble volume with both catheters. A higher power setting induced a significantly higher number of microembolic signals on carotid artery Doppler ultrasound with a flexible tip irrigated catheter (P < 0.001). Similarly, the straight SF tip irrigated catheter tended to increase the number of microembolic signals with 50 W (P = 0.091).

Conclusions: RF ablation at high power settings in the LV carries a risk of microembolic events compared with lower power settings. When high power settings are used for creating ablative lesions for deep intramural foci in the LV, the risk of microembolic events induced by RF ablation should be carefully monitored.
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http://dx.doi.org/10.1016/j.jacep.2021.06.012DOI Listing
August 2021

Ketoacidosis, Hypertriglyceridemia and Acute Pancreatitis Induced by Soft Drink Polydipsia in a Patient with Occult Central Diabetes Insipidus.

Intern Med 2021 Aug 6. Epub 2021 Aug 6.

Department of Diabetes and Endocrinology, Akashi Medical Center Hospital, Japan.

A 21-year-old Japanese man without known diabetes mellitus had abdominal pain. The diagnosis was ketoacidosis and hypertriglyceridemia-induced acute pancreatitis. He had polydipsia and polyuria and had habitually drunk several soft drinks every day for two years. After hospitalization, despite adequate liquid intake, dehydration remained with hypotonic polyuria. Further examinations revealed the coexistence of central diabetes insipidus (CDI), possibly caused by lymphocytic infundibulo-neurohypophysitis, based on anti-rabphilin-3A antibody positivity. Although CDI had been undiagnosed for two years, over-consumption of sugar-rich soft drinks to ease thirst caused ketoacidosis, hypertriglyceridemia, and acute pancreatitis. There are no previous reports of this three-part combination of symptoms caused by CDI.
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http://dx.doi.org/10.2169/internalmedicine.7663-21DOI Listing
August 2021

De novo ARF3 variants cause neurodevelopmental disorder with brain abnormality.

Hum Mol Genet 2021 Aug 4. Epub 2021 Aug 4.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.

An optimal Golgi transport system is important for mammalian cells. The adenosine diphosphate (ADP) ribosylation factors (ARF) are key proteins for regulating cargo sorting at the Golgi network. In this family, ARF3 mainly works at the trans-Golgi network (TGN), and no ARF3-related phenotypes have yet been described in humans. We here report the clinical and genetic evaluations of two unrelated children with de novo pathogenic variants in the ARF3 gene: c.200A > T (p.Asp67Val) and c.296G > T (p.Arg99Leu). Although the affected individuals presented commonly with developmental delay, epilepsy, and brain abnormalities, there were differences in severity, clinical course, and brain lesions. In vitro subcellular localization assays revealed that the p.Arg99Leu mutant localized to Golgi apparatus, similar to the wild-type, whereas the p.Asp67Val mutant tended to show a disperse cytosolic pattern together with abnormally dispersed Golgi localization, similar to that observed in a known dominant negative variant (p.Thr31Asn). Pull-down assays revealed that the p.Asp67Val had a loss-of-function effect and the p.Arg99Leu variant had increased binding of the adaptor protein, Golgi-localized, γ-adaptin ear-containing, ARF-binding protein 1 (GGA1), supporting the gain of function. Furthermore, in vivo studies revealed that p.Asp67Val transfection led to lethality in flies. In contrast, flies expressing p.Arg99Leu had abnormal rough eye, as observed in the gain-of-function variant p.Gln71Leu. These data indicate that two ARF3 variants, the possibly loss-of-function p.Asp67Val and the gain-of-function p.Arg99Leu, both impair the Golgi transport system. Therefore, it may not be unreasonable that they showed different clinical features like diffuse brain atrophy (p.Asp67Val) and cerebellar hypoplasia (p.Arg99Leu).
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http://dx.doi.org/10.1093/hmg/ddab224DOI Listing
August 2021

Peri-Balloon Leak Flow Velocity Assessed by Intra-Cardiac Echography Predicts Pulmonary Vein Electrical Gap - Intra-Cardiac Echography-Guided Contrast-Free Cryoballoon Ablation.

Circ J 2021 Jul 30. Epub 2021 Jul 30.

Department of Cardiology, Osaka Saiseikai Nakatsu Hospital.

Background: The use of iodine contrast agents is one possible limitation in cryoballoon ablation (CBA) for atrial fibrillation (AF). This study investigated intracardiac echography (ICE)-guided contrast-free CBA.Methods and Results:The study was divided into 2 phases. First, 25 paroxysmal AF patients (Group 1) underwent CBA, and peri-balloon leak flow velocity (PLFV) was assessed using ICE and electrical pulmonary vein (PV) lesion gaps were assessed by high-density electroanatomical mapping. Then, 24 patients (Group 2) underwent ICE-guided CBA and were compared with 25 patients who underwent conventional CBA (historical controls). In Group 1, there was a significant correlation between PLFV and electrical PV gap diameter (r=-0.715, P<0.001). PLFV was higher without than with an electrical gap (mean [±SD] 127.0±28.6 vs. 66.6±21.0 cm/s; P<0.001) and the cut-off value of PLFV to predict electrical isolation was 105.7 cm/s (sensitivity 0.700, specificity 0.929). In Group 2, ICE-guided CBA was successfully performed with acute electrical isolation of all PVs and without the need for "rescue" contrast injection. Atrial tachyarrhythmia recurrence at 6 months did not differ between ICE-guided and conventional CBA (3/24 [12.5%] vs. 5/25 [20.0%], respectively; P=0.973, log-rank test).

Conclusions: PLFV predicted the presence of an electrical PV gap after CBA. ICE-guided CBA was feasible and safe, and could potentially be performed completely contrast-free without a decrease in ablation efficacy.
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http://dx.doi.org/10.1253/circj.CJ-21-0423DOI Listing
July 2021

Eating whole fruit, not drinking fruit juice, may reduce the risk of type 2 diabetes mellitus.

J Diabetes Investig 2021 Jul 28. Epub 2021 Jul 28.

Departments of Endocrinology, Diabetes and Metabolism, Fujita Health University Graduate School of Medicine, Toyoake, Japan.

Fruit intake may reduce the risk of type 2 diabetes by probably four factors: dietary fiber, phytochemicals (flavonoids), fructose, and chewing.
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http://dx.doi.org/10.1111/jdi.13639DOI Listing
July 2021

Patient-centered Outcomes Research in Interstitial Lung Disease: An Official American Thoracic Society Research Statement.

Am J Respir Crit Care Med 2021 07;204(2):e3-e23

In the past two decades, many advances have been made to our understanding of interstitial lung disease (ILD) and the way we approach its treatment. Despite this, many questions remain unanswered, particularly those related to how the disease and its therapies impact outcomes that are most important to patients. There is currently a lack of guidance on how to best define and incorporate these patient-centered outcomes in ILD research. To summarize the current state of patient-centered outcomes research in ILD, identify gaps in knowledge and research, and highlight opportunities and methods for future patient-centered research agendas in ILD. An international interdisciplinary group of experts was assembled. The group identified top patient-centered outcomes in ILD, reviewed available literature for each outcome, highlighted important discoveries and knowledge gaps, and formulated research recommendations. The committee identified seven themes around patient-centered outcomes as the focus of the statement. After a review of the literature and expert committee discussion, we developed 28 research recommendations. Patient-centered outcomes are key to ascertaining whether and how ILD and interventions used to treat it affect the way patients feel and function in their daily lives. Ample opportunities exist to conduct additional work dedicated to elevating and incorporating patient-centered outcomes in ILD research.
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http://dx.doi.org/10.1164/rccm.202105-1193STDOI Listing
July 2021

Features Suggesting Preferential Conduction in Pulmonary Artery Ventricular Arrhythmia for Identification of Successful Ablation Sites.

Int Heart J 2021 Jul 17;62(4):771-778. Epub 2021 Jul 17.

Department of Cardiology, Tsuchiura Kyodo Hospital.

Radiofrequency catheter ablation (RFCA) for pulmonary artery ventricular arrhythmia (PAVA) can be difficult because of the occasional existence of PAVA with preferential conduction.This study described the characteristics of PAVA that demonstrate preferential conduction.We analyzed electrocardiographic and electrophysiological data from 8 patients found to have PAVAs with preferential conduction out of 183 patients (4.4%) with right ventricular outflow tract (RVOT) arrhythmias who underwent RFCA at our hospitals. The PAVA with preferential conduction were classified into two types. In type 1 PAVA, successful ablation sites (success-sites) exhibited discrete prepotentials with an isoelectric line, in which the activation time (AT) was ≥ 50 milliseconds. In type 2 PAVA, excellent pace mapping was achieved at two sites separated by ≥ 20 mm: one in the RVOT free wall and the other at the success-site in the pulmonary artery. Type 1 and 2 PAVA features were considered signs of a short and long preferential conduction pathway, respectively.There were four patients each with type 1 and 2 PAVA. Type 1 PAVA was distinguished by the isoelectric line at success-sites with the mean AT of 78 ± 25.1 milliseconds. In type 2 PAVAs, although the AT at RVOT sites was very short (18.5 ± 10.1 milliseconds), the AT at success-sites was longer than that at the RVOT by 42.3 ± 36.2 milliseconds. Type 2 PAVAs displayed distinct electrocardiogram (ECG) features (R wave in lead I, RR' in inferior leads, and transitional zone in V4) not found in typical PAVA ECGs.PAVA with preferential conduction can manifest in distinct ways on the ECG and intracardiac mapping. Knowledge of these features may facilitate successful RFCA of such PAVA cases.
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http://dx.doi.org/10.1536/ihj.20-785DOI Listing
July 2021

Strictly regulated agonist-dependent activation of AMPA-R is the key characteristic of TAK-653 for robust synaptic responses and cognitive improvement.

Sci Rep 2021 Jul 15;11(1):14532. Epub 2021 Jul 15.

Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Kanagawa, 251-8555, Fujisawa, Japan.

Agonistic profiles of AMPA receptor (AMPA-R) potentiators may be associated with seizure risk and bell-shaped dose-response effects. Here, we report the pharmacological characteristics of a novel AMPA-R potentiator, TAK-653, which exhibits minimal agonistic properties. TAK-653 bound to the ligand binding domain of recombinant AMPA-R in a glutamate-dependent manner. TAK-653 strictly potentiated a glutamate-induced Ca influx in hGluA1i-expressing CHO cells through structural interference at Ser743 in GluA1. In primary neurons, TAK-653 augmented AMPA-induced Ca influx and AMPA-elicited currents via physiological AMPA-R with little agonistic effects. Interestingly, TAK-653 enhanced electrically evoked AMPA-R-mediated EPSPs more potently than AMPA (agonist) or LY451646 (AMPA-R potentiator with a prominent agonistic effect) in brain slices. Moreover, TAK-653 improved cognition for both working memory and recognition memory, while LY451646 did so only for recognition memory, and AMPA did not improve either. These data suggest that the facilitation of phasic AMPA-R activation by physiologically-released glutamate is the key to enhancing synaptic and cognitive functions, and nonselective activation of resting AMPA-Rs may negatively affect this process. Importantly, TAK-653 had a wide safety margin against convulsion; TAK-653 showed a 419-fold (plasma C) and 1017-fold (AUC ) margin in rats. These findings provide insight into a therapeutically important aspect of AMPA-R potentiation.
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http://dx.doi.org/10.1038/s41598-021-93888-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282797PMC
July 2021

Impact of beta-blocker use on the long-term outcomes of heart failure patients with chronic obstructive pulmonary disease.

ESC Heart Fail 2021 Jun 29. Epub 2021 Jun 29.

Department of Cardiovascular Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-0022, Japan.

Aims: The number of patients with both chronic obstructive pulmonary disease (COPD) and heart failure (HF) is increasing in Asia, and these conditions often coexist. We previously revealed a tendency of beta-blocker underuse among patients with HF with reduced ejection fraction (HFrEF) and COPD in Asian countries other than Japan. Here, we evaluated the impact of cardio-selective beta-blocker use on the long-term outcomes of patients with HF and COPD.

Methods And Results: Among the 5232 patients with HFrEF (left ventricular ejection fraction of <40%) prospectively enrolled from 11 Asian regions in the ASIAN-HF registry, 412 (7.9%) had a history of COPD. We compared the clinical characteristics and long-term outcomes of the patients with HF and COPD according to the use and type of beta-blockers used: cardio-selective beta-blockers (n = 149) vs. non-cardio-selective beta-blockers (n = 124) vs. no beta-blockers (n = 139). The heart rate was higher, and the outcome was poorer in the no beta-blocker group than in the beta-blocker groups. The 2 year all-cause mortality was significantly lower in the non-cardio-selective beta-blocker group than in the no beta-blocker group. Further, the cardiovascular mortality significantly decreased in the non-cardio-selective beta-blocker group before (hazard ratio: 0.36; 95% confidence interval: 0.18-0.73; P = 0.004) and after adjustments (hazard ratio: 0.37; 95% confidence interval: 0.19-0.73; P = 0.005), but not in the cardio-selective beta-blocker group.

Conclusions: Beta-blockers reduced the all-cause mortality of patients with HFrEF and COPD after adjusting for age and heart rate, although the possibility of selection bias could not be completely excluded due to multinational prospective registry.
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http://dx.doi.org/10.1002/ehf2.13489DOI Listing
June 2021

The dual-specificity protein kinase Clk3 is essential for Xenopus neural development.

Biochem Biophys Res Commun 2021 Aug 16;567:99-105. Epub 2021 Jun 16.

Amphibian Research Center, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima, 739-8526, Japan; Amphibian Research Center, Graduate School of Integrated Sciences for Life, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima, 739-8526, Japan. Electronic address:

During vertebrate development, the formation of the central nervous system (CNS) is initiated by neural induction and patterning of the embryonic ectoderm. We previously reported that Cdc2-like kinase 2 (Clk2) promotes neural development in Xenopus embryos by regulating morphogen signaling. However, the functions of other Clk family members and their roles in early embryonic development remain unknown. Here, we show that in addition to Clk2, Clk1 and Clk3 play a role in the formation of neural tissue in Xenopus. clk1 and clk3 are co-expressed in the developing neural tissue during early Xenopus embryogenesis. We found that overexpression of clk1 and clk3 increases the expression of neural marker genes in ectodermal explants. Furthermore, knockdown experiments showed that clk3 is required for the formation of neural tissues. These results suggest that Xenopus Clk3 plays an essential role in promoting neural development during early embryogenesis.
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http://dx.doi.org/10.1016/j.bbrc.2021.06.005DOI Listing
August 2021

Size and surface modification of silica nanoparticles affect the severity of lung toxicity by modulating endosomal ROS generation in macrophages.

Part Fibre Toxicol 2021 06 17;18(1):21. Epub 2021 Jun 17.

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Background: As the application of silica nanomaterials continues to expand, increasing chances of its exposure to the human body and potential harm are anticipated. Although the toxicity of silica nanomaterials is assumed to be affected by their physio-chemical properties, including size and surface functionalization, its molecular mechanisms remain unclear. We hypothesized that analysis of intracellular localization of the particles and subsequent intracellular signaling could reveal a novel determinant of inflammatory response against silica particles with different physico-chemical properties.

Results: We employed a murine intratracheal instillation model of amorphous silica nanoparticles (NPs) exposure to compare their in vivo toxicities in the respiratory system. Pristine silica-NPs of 50 nm diameters (50 nm-plain) induced airway-centered lung injury with marked neutrophilic infiltration. By contrast, instillation of pristine silica particles of a larger diameter (3 μm; 3 μm-plain) significantly reduced the severity of lung injury and neutrophilic infiltration, possibly through attenuated induction of neutrophil chemotactic chemokines including MIP2. Ex vivo analysis of alveolar macrophages as well as in vitro assessment using RAW264.7 cells revealed a remarkably lower cellular uptake of 3 μm-plain particles compared with 50 nm-plain, which is assumed to be the underlying mechanism of attenuated immune response. The severity of lung injury and neutrophilic infiltration was also significantly reduced after intratracheal instillation of silica NPs with an amine surface modification (50 nm-NH) when compared with 50 nm-plain. Despite unchanged efficacy in cellular uptake, treatment with 50 nm-NH induced a significantly attenuated immune response in RAW264.7 cells. Assessment of intracellular redox signaling revealed increased reactive oxygen species (ROS) in endosomal compartments of RAW264.7 cells treated with 50 nm-plain when compared with vehicle-treated control. In contrast, augmentation of endosomal ROS signals in cells treated with 50 nm-NH was significantly lower. Moreover, selective inhibition of NADPH oxidase 2 (NOX2) was sufficient to inhibit endosomal ROS bursts and induction of chemokine expressions in cells treated with silica NPs, suggesting the central role of endosomal ROS generated by NOX2 in the regulation of the inflammatory response in macrophages that endocytosed silica NPs.

Conclusions: Our murine model suggested that the pulmonary toxicity of silica NPs depended on their physico-chemical properties through distinct mechanisms. Cellular uptake of larger particles by macrophages decreased, while surface amine modification modulated endosomal ROS signaling via NOX2, both of which are assumed to be involved in mitigating immune response in macrophages and resulting lung injury.
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http://dx.doi.org/10.1186/s12989-021-00415-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210371PMC
June 2021

TGF-β1 signaling is essential for tissue regeneration in the Xenopus tadpole tail.

Biochem Biophys Res Commun 2021 Aug 5;565:91-96. Epub 2021 Jun 5.

Amphibian Research Center, Graduate School of Integrated Sciences for Life, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima, 739-8526, Japan. Electronic address:

Amphibians such as Xenopus tropicalis exhibit a remarkable capacity for tissue regeneration after traumatic injury. Although transforming growth factor-β (TGF-β) receptor signaling is known to be essential for tissue regeneration in fish and amphibians, the role of TGF-β ligands in this process is not well understood. Here, we show that inhibition of TGF-β1 function prevents tail regeneration in Xenopus tropicalis tadpoles. We found that expression of tgfb1 is present before tail amputation and is sustained throughout the regeneration process. CRISPR-mediated knock-out (KO) of tgfb1 retards tail regeneration; the phenotype of tgfb1 KO tadpoles can be rescued by injection of tgfb1 mRNA. Cell proliferation, a critical event for the success of tissue regeneration, is downregulated in tgfb1 KO tadpoles. In addition, tgfb1 KO reduces the expression of phosphorylated Smad2/3 (pSmad2/3) which is important for TGF-β signal-mediated cell proliferation. Collectively, our results show that TGF-β1 regulates cell proliferation through the activation of Smad2/3. We therefore propose that TGF-β1 plays a critical role in TGF-β receptor-dependent tadpole tail regeneration in Xenopus.
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http://dx.doi.org/10.1016/j.bbrc.2021.05.082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255271PMC
August 2021

Meiosis-specific ZFP541 repressor complex promotes developmental progression of meiotic prophase towards completion during mouse spermatogenesis.

Nat Commun 2021 06 1;12(1):3184. Epub 2021 Jun 1.

Department of Chromosome Biology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, Kumamoto, Japan.

During spermatogenesis, meiosis is accompanied by a robust alteration in gene expression and chromatin status. However, it remains elusive how the meiotic transcriptional program is established to ensure completion of meiotic prophase. Here, we identify a protein complex that consists of germ-cell-specific zinc-finger protein ZFP541 and its interactor KCTD19 as the key transcriptional regulators in mouse meiotic prophase progression. Our genetic study shows that ZFP541 and KCTD19 are co-expressed from pachytene onward and play an essential role in the completion of the meiotic prophase program in the testis. Furthermore, our ChIP-seq and transcriptome analyses identify that ZFP541 binds to and suppresses a broad range of genes whose function is associated with biological processes of transcriptional regulation and covalent chromatin modification. The present study demonstrates that a germ-cell specific complex that contains ZFP541 and KCTD19 promotes the progression of meiotic prophase towards completion in male mice, and triggers the reconstruction of the transcriptional network and chromatin organization leading to post-meiotic development.
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http://dx.doi.org/10.1038/s41467-021-23378-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169937PMC
June 2021

Fibroblasts positive for meflin have anti-fibrotic property in pulmonary fibrosis.

Eur Respir J 2021 May 28. Epub 2021 May 28.

National Hospital Organization Nagoya Medical Center, Nagoya, Japan.

The prognosis of elderly individuals with idiopathic pulmonary fibrosis (IPF) remains poor. Fibroblastic foci, in which aggregates of proliferating fibroblasts and myofibroblasts are involved, are the pathological hallmark lesions in IPF to represent focal areas of active fibrogenesis. Fibroblast heterogeneity in fibrotic lesions hampers the discovery of the pathogenesis of pulmonary fibrosis. Therefore, to determine of the pathogenesis of IPF, identification of functional fibroblasts is warranted. This study was aimed to determine the role of fibroblasts positive for meflin, identified as a potential marker for mesenchymal stromal cells, during the development of pulmonary fibrosis. We characterised meflin-positive cells in a single cell atlas established by single-cell RNA sequencing (scRNA-seq)-based profiling of 243 472 cells from 32 IPF lungs and 29 normal lung samples. scRNA-seq combined with RNA hybridisation identified proliferating fibroblasts positive for meflin in fibroblastic foci, not dense fibrosis, of fibrotic lungs in IPF patients. We determined the role of fibroblasts positive for meflin using bleomycin (BLM)-induced pulmonary fibrosis. A BLM-induced lung fibrosis model for meflin-deficient mice showed that fibroblasts positive for meflin had anti-fibrotic property to prevent pulmonary fibrosis. Although transforming growth factor-β-induced fibrogenesis and cell senescence with senescence-associated secretory phenotype were exacerbated in fibroblasts the repression or lack of meflin, these were inhibited in meflin-deficient fibroblasts with meflin reconstitution. These findings provide evidence to show the biological importance of meflin expression on fibroblasts and myofibroblasts in the active fibrotic region of pulmonary fibrosis.
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http://dx.doi.org/10.1183/13993003.03397-2020DOI Listing
May 2021

Real-time intracardiac echocardiography validation of saline-enhanced radiofrequency needle-tip ablation: lesion characteristics and gross pathology correlation.

Europace 2021 May 16. Epub 2021 May 16.

Translational Interventional Electrophysiology Laboratory, Mayo Clinic, 1216 2nd St. SW, Rochester, MN 55905, USA.

Aims: With the implementation of saline-enhanced radiofrequency (SERF) needle-tip ablation, real-time validation of lesion formation is needed for the controllable creation of transmural lesions. The aim of the study was to analyse the ability of two-dimensional intracardiac echocardiography (2D-ICE) to guide and validate SERF ablation in real-time.

Methods And Results: Fifty-six SERF energy deliveries at left ventricular sites of 11 dogs guided by 2D-ICE were analysed (power: 15-50 W; time: 25-120 s; irrigation saline: 60°C with 10 mL/min flow rate). Catheter tip/tissue orientation and lesion formation could be well detected by 2D-ICE in 49 (87.5%) energy deliveries. Gross pathology analysis confirmed excellent 2D-ICE lesion localization, the ability to detect transmural lesions (70% sensitivity, 47% specificity) and positive correlation between 2D-ICE and the corresponding gross pathology measurements of 'maximal lesion depth'; (repeated measures correlation: rrm = 0.43, P = 0.012) and 'depth at maximal lesion width' ([email protected]; rrm = 0.51, P = 0.003). The median angle between SERF catheter tip and endocardium was 76° [interquartile range (IQR) 58-83°]. The more perpendicular the catheter tip/tissue orientation was the deeper [email protected] (rrm = 0.32, P = 0.045). Grade 3 microbubbles on 2D-ICE during ablation, indicating inadequate catheter tip/tissue contact, was associated with smaller lesion volumes than with Grade 1 microbubbles (284.8 mm3 [IQR 151.3-343.1] vs. 2114.1 mm3 [IQR 1437.0-3026.3], P < 0.001).

Conclusion: With excellent lesion localization and a 70% detection rate of transmural lesions, 2D-ICE is well suited to validate SERF ablation lesion formation in real-time. The catheter tip/tissue angle impacts the lesion formation and through perpendicular catheter positioning, deeper intramural areas of the myocardium can be reached.
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http://dx.doi.org/10.1093/europace/euab121DOI Listing
May 2021

Beneficial effects of oral supplementation with ferulic acid, a plant phenolic compound, on the human skin barrier in healthy men.

Int J Vitam Nutr Res 2021 May 11:1-7. Epub 2021 May 11.

Research & Development, Kao Corporation, Sumida-ku, Tokyo, Japan.

Ferulic acid (FA) is a phytochemical compound with various physiologic functions. To clarify the effect of FA intake on skin barrier function (SBF), we conducted a placebo-controlled double-blind pilot trial. Sixteen healthy subjects were divided into 2 groups (n = 8) and ingested capsules containing either FA (200 mg) or placebo daily for 2 weeks. Two measures of SBF, transepidermal water loss and stratum corneum hydration, were assessed before and 2 weeks after the start of the study. Autonomic nervous activity, which is suggested to be related to SBF, was also measured. Compared with the values obtained before the start of the study, FA intake significantly reduced transepidermal water loss (from 6.1 ± 1.1 to 4.8 ± 1.0 g/m/h, p = 0.005) and increased stratum corneum hydration (from 30.1 ± 7.6 to 32.3 ± 8.1 a.u., p = 0.027) after 2 weeks. In addition, the amount change in sympathetic nervous activity was significantly reduced after ingesting the FA capsules compared with the placebo capsules (-0.7 ± 1.6 vs. 1.1 ± 1.4, p = 0.035). These findings suggest that FA supplementation decreases sympathetic nervous activity and strengthens SBF in healthy men.
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http://dx.doi.org/10.1024/0300-9831/a000699DOI Listing
May 2021

Phosphate bound to calcareous sediments hampers skeletal development of juvenile coral.

R Soc Open Sci 2021 Mar 17;8(3):201214. Epub 2021 Mar 17.

School of Marine Biosciences, Kitasato University, 1-15-1 Kitasato, Minami, Sagamihara, Kanagawa 252-0373, Japan.

To test the hypothesis that terrestrial runoff affects the functions of calcareous sediments in coral reefs and hampers the development of corals, we analysed calcareous sediments with different levels of bound phosphate, collected from reef areas of Okinawajima, Japan. We confirmed that phosphate bound to calcareous sediments was readily released into ambient seawater, resulting in much higher concentrations of phosphorous in seawater from heavily polluted areas (4.3-19.0 µM as compared with less than 0.096 µM in natural ambient seawater). Additionally, we examined the effect of phosphate released from calcareous sediments on the development of coral juveniles. We found that high phosphate concentrations in seawater clearly inhibit the skeletal formation of coral juveniles. Our results demonstrate that calcareous sediments in reef areas play a crucial role in mediating the impact of terrestrial runoff on corals by storing and releasing phosphate in seawater.
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http://dx.doi.org/10.1098/rsos.201214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074908PMC
March 2021

Clinical Effect of Adaptive Servo-Ventilation on Left Atrial Pressure During Catheter Ablation in Sedated Patients With Atrial Fibrillation.

Circ J 2021 Jul 13;85(8):1321-1328. Epub 2021 Apr 13.

Department of Cardiology, Tokyo Medical and Dental University.

Background: Sedation during pulmonary vein isolation (PVI) for atrial fibrillation often provokes a decline in left atrial (LA) pressure (LAP) under atmospheric pressure and increases the risk of systemic air embolisms. This study aimed to investigate the efficacy of adaptive servo-ventilation (ASV) on the LAP in sedated patients.Methods and Results:Fifty-one consecutive patients undergoing cryoballoon PVI were enrolled. All patients underwent sedation using propofol throughout the procedure. After the transseptal puncture and the insertion of a long sheath into the LA, the LAP was measured. Then, the ASV treatment was started, and the LAP was re-measured. The LAP before and after the ASV support was investigated. Before ASV, the LAP during the inspiratory phase was significantly smaller than that during the expiratory phase (4.9±5.4 mmHg vs. 14.0±5.2 mmHg, P<0.01). The lowest LAP was -2.2±5.1 mmHg and was under 0 mmHg in 37 (73%) patients. After the ASV, the LAP during the inspiratory phase significantly increased to 8.9±4.1 mmHg (P<0.01), and lowest LAP increased to 4.7±5.9 mmHg (P<0.01). The negative lowest LAP value became positive in 30/37 (81%) patients. There were no statistical differences regarding obstructive sleep apnea (OSA), obesity, gender, or other comorbidities between patients with and without a negative lowest LAP after ASV support.

Conclusions: ASV is effective for increasing the LAP above 0 mmHg and might prevent air embolisms during PVI.
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http://dx.doi.org/10.1253/circj.CJ-20-1263DOI Listing
July 2021

Predictor analysis of 1-year restenosis after percutaneous transluminal angioplasty for femoropopliteal stenotic lesions using intravascular ultrasound.

Heart Vessels 2021 Apr 8. Epub 2021 Apr 8.

Department of Cardiology, Osaka Saiseikai Nakatsu Hospital, 2-10-39 Shibata, Kita-ku, Osaka, Osaka, 530-0012, Japan.

This retrospective, single-center study evaluated the patency rate and predictors of restenosis after percutaneous transluminal angioplasty (PTA) for femoropopliteal stenotic lesions using intravascular ultrasound. We assessed 78 de novo femoropopliteal stenotic lesions (64 patients; mean age, 73.6 ± 9.4 years; average lesion length, 59.8 mm) that underwent PTA under intravascular ultrasound guidance. The primary endpoint was 1-year primary patency. The 1-year primary patency rate was 63%. The frequency of insulin use was significantly greater (44% vs. 12%, p = 0.005), and lesions were significantly longer (77.8 mm vs. 49.2 mm, p = 0.047) in the restenosis group than in the non-restenosis group. The pre-intervention reference lumen area and minimum lumen area (MLA) were significantly smaller in the restenosis group (reference lumen area: 19.7 ± 6.7 mm vs. 23.7 ± 7.4 mm, p = 0.017; MLA 3.9 ± 2.8 mm vs. 5.7 ± 3.9 mm, p = 0.026; respectively). The MLA was significantly smaller and the maximum angle of dissection was significantly larger in the restenosis group (MLA 9.3 mm vs. 12.3 mm, p = 0.013; maximum angle of dissection: 104.1° vs. 69.6°, p = 0.003; respectively) among post-intervention parameters. Multivariate analysis revealed that the independent predictors of 1-year restenosis were the large post-intervention maximum angle of dissection and insulin use. Per receiver operating curve analysis, the best cut-off value of the post-intervention maximum angle of dissection that predicted 1-year restenosis was 70.2° (sensitivity 72.4%, specificity 63.3%, area under the curve 0.70, p = 0.004). In conclusion, the 1-year primary patency rate after PTA for relatively short stenotic femoropopliteal lesions was 63%. The large post-intervention maximum angle of dissection, measured using intravascular ultrasound, and insulin use were independent predictors of restenosis after PTA.
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http://dx.doi.org/10.1007/s00380-021-01845-8DOI Listing
April 2021

De novo ATP1A3 variants cause polymicrogyria.

Sci Adv 2021 Mar 24;7(13). Epub 2021 Mar 24.

Department of Pediatrics, Tottori Prefectural Central Hospital, Tottori 680-0901, Japan.

Polymicrogyria is a common malformation of cortical development whose etiology remains elusive. We conducted whole-exome sequencing for 124 patients with polymicrogyria and identified de novo variants in eight patients. Mutated causes functional brain diseases, including alternating hemiplegia of childhood (AHC), rapid-onset dystonia parkinsonism (RDP), and cerebellar ataxia, areflexia, pes cavus, optic nerve atrophy, and sensorineural deafness (CAPOS). However, our patients showed no clinical features of AHC, RDP, or CAPOS and had a completely different phenotype: a severe form of polymicrogyria with epilepsy and developmental delay. Detected variants had different locations in and different functional properties compared with AHC-, RDP-, or CAPOS-associated variants. In the developing cerebral cortex of mice, radial neuronal migration was impaired in neurons overexpressing the variant of the most severe patients, suggesting that this variant is involved in cortical malformation pathogenesis. We propose a previously unidentified category of polymicrogyria associated with abnormalities.
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http://dx.doi.org/10.1126/sciadv.abd2368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990330PMC
March 2021

Prognosis and recurrence in cardiac sarcoidosis: Serial assessment of BMIPP SPECT and FDG-PET.

J Nucl Cardiol 2021 Jun 16;28(3):919-929. Epub 2021 Mar 16.

Department of Cardiology, Tokyo Women's Medical University, Tokyo, Japan.

Background: We analyzed F-Fludeoxyglucose positron emission tomography (FDG-PET) and I-betamethyl-p-iodophenyl-pentadecanoic acid (BMIPP) single-photon emission computed tomography (SPECT) performed for cardiac sarcoidosis (CS) patients taking prednisolone, identified recurrence by FDG-PET, and investigated BMIPP as a recurrence and prognostic factor in CS.

Methods And Results: CS patients who underwent BMIPP and FDG-PET within 2 months were enrolled. The recurrence-free group included patients with standardized uptake value (SUVmax) < 4 in the myocardium consecutively for ≥ 2 years. The total BMIPP SPECT defect score (BDS) was used to estimate myocardial damage. The predictability of the initial BDS and SUVmax for major adverse cardiac events (MACE) was analyzed using Kaplan-Meier analysis. Overall, 73 patients and 250 BMIPP and FDG-PET sets were analyzed retrospectively (mean follow-up, 3.5 years). The BDS was significantly greater for the recurrence group (N = 21) vs recurrence-free group (20 ± 13 vs 14 ± 12, P = 0.041). Patients with BDS ≥16 had a significantly higher MACE rate than patients with BDS < 16 (log-rank test, P = 0.016). However, MACE occurrence was comparable between patients with SUVmax ≥ 4 and < 4.

Conclusions: BDS is a predictive marker of recurrence and MACE. SUV is not related to MACE. Recurrence, defined by prednisolone treatment-induced SUV variability, was observed in approximately 30% of CS patients.
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http://dx.doi.org/10.1007/s12350-021-02567-0DOI Listing
June 2021

Deactivation of implantable cardioverter defibrillator in Japanese patients with end-stage heart failure.

J Arrhythm 2021 Feb 24;37(1):196-202. Epub 2020 Nov 24.

Department of Cardiology Tokyo Women's Medical University Tokyo Japan.

Background: Despite the effectiveness of implantable cardioverter defibrillators (ICDs) in the prevention of sudden cardiac death, shock therapy causes patients to experience pain and psychological distress, which contradicts the purpose of palliative care. It is difficult to predict the time course for heart failure (HF) patients, unlike that for cancer patients. The aim of this study was to evaluate the deactivation status of ICD therapy in Japanese patients with end-stage HF.

Methods: We retrospectively studied 51 ICD patients who died due to worsening HF at Tokyo Women's Medical University Hospital from 2010 to 2019. The frequency of ICD therapy delivered before death and information about the discussion of deactivation and do not attempt resuscitation (DNAR) decisions were reviewed using medical charts.

Results: Of 51 patients, 12 (24%) patients deactivated ICD therapy and seven patients underwent deactivation within 24 hours of a DNAR order. The median time from deactivation to death was 3 days (range, 0-56). Of 39 patients with DNAR orders, 27 (69%) did not undergo deactivation. A relatively high proportion of patients (n = 14, 27%) experienced ICD shocks within 1 month of death. The frequency of electrical storms within 1 month of death was also high (n = 12, 24%).

Conclusions: Our study showed that only one-fourth of Japanese patients with end-stage HF underwent deactivation of ICD therapy. A relatively high frequency of shock therapy was observed in the last month before death.
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http://dx.doi.org/10.1002/joa3.12465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896444PMC
February 2021

Left intraventricular pressure gradient in hypertrophic cardiomyopathy patients receiving implantable cardioverter-defibrillators for primary prevention.

BMC Cardiovasc Disord 2021 02 19;21(1):106. Epub 2021 Feb 19.

Department of Cardiology, Tokyo Women's Medical University, Tokyo, Japan.

Background: Conventional risk factors for sudden cardiac death (SCD) justify primary prevention through implantable cardioverter-defibrillator (ICD) implantation in hypertrophic cardiomyopathy (HCM) patients. However, the positive predictive values for these conventional SCD risk factors are low. Left ventricular outflow tract obstruction (LVOTO) and midventricular obstruction (MVO) are potential risk modifiers for SCD. The aims of this study were to evaluate whether an elevated intraventricular pressure gradient (IVPG), including LVOTO or MVO, is a potential risk modifier for SCD and ventricular arrhythmias requiring ICD interventions in addition to the conventional risk factors among HCM patients receiving ICDs for primary prevention.

Methods: We retrospectively studied 60 HCM patients who received ICDs for primary prevention. An elevated IVPG was defined as a peak instantaneous gradient ≥ 30 mmHg at rest, as detected by continuous-wave Doppler echocardiography. The main outcome was a composite of SCD and appropriate ICD interventions, which were defined as an antitachycardia pacing or shock therapy for ventricular tachycardia or fibrillation. The Cox proportional hazards model was used to assess the relationships between risk factors and the occurrence of SCD and appropriate ICD interventions.

Results: Thirty patients met the criteria of elevated IVPG (50%). During the median follow-up period of 66 months, 2 patients experienced SCD, and 10 patients received appropriate ICD interventions. Kaplan-Meier curves showed that the incidence of the main outcome was higher in patients with an IVPG ≥ 30 mmHg than in those without an IVPG ≥ 30 mmHg (log-rank P = 0.03). There were no differences in the main outcome between patients with LVOTO and patients with MVO. The combination of nonsustained ventricular tachycardia (NSVT) and IVPG ≥ 30 mmHg was found to significantly increase the risk of the main outcome (HR 6.31, 95% CI 1.36-29.25, P = 0.02). Five patients experienced ICD implant-related complications.

Conclusions: Our findings showed that a baseline IVPG ≥ 30 mmHg was associated with an increased risk of experiencing SCD or appropriate ICD interventions among HCM patients who received ICDs for primary prevention. Combined with NSVT, which is a conventional risk factor, a baseline IVPG ≥ 30 mmHg may be a potential modifier of SCD risk in HCM patients.
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http://dx.doi.org/10.1186/s12872-021-01910-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893864PMC
February 2021

Impact of anatomical position of the inflow cannula on stroke in patients with left ventricular assist devices.

Int J Artif Organs 2021 Jan 21:391398820988297. Epub 2021 Jan 21.

Department of Cardiovascular Surgery, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan.

Objectives: Stroke is a substantial complication of left ventricular assist device (LVAD) implantation. The relationship between stroke and the anatomical position of the inflow cannula of patients who underwent LVAD implantation was investigated.

Methods: We enrolled 15 patients with advanced-stage heart failure who underwent implantation of continuous-flow-LVAD. Data of patients who suffered a stroke within 6 months after LVAD implantation were retrospectively compared to those who remained free of stroke. The distance between the inflow duct and left ventricular (LV) septum (duct-sep distance) and its ratio to LV diastolic diameter (LVDd) were measured from echocardiography at 1 month after LVAD implantation. Receiver operating characteristic curves for the endpoint of stroke using the duct-sep distance to LVDd ratio was created and the cut-off value was calculated. The incidence of stroke during the 6 months after LVAD implantation according to this ratio was estimated using the Kaplan-Meier method.

Results: At 1 month after LVAD implantation, there were no significant differences in baseline characteristics and echocardiography parameters between the stroke and stroke-free groups. Receiver operating characteristic curve analysis for the endpoint of stroke using the duct-sep distance to LVDd ratio revealed 0.217 as a cut-off value (sensitivity: 80%, specificity: 80%, area under the curve: 0.72). Stroke was more frequent in patients with a duct-sep distance to LVDd ratio ⩾0.217 at 1 month than in those with a lower ratio.

Conclusion: The duct-sep distance to LVDd ratio was associated with the occurrence of stroke, suggesting that inflow cannula position influences the incidence of stroke.
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http://dx.doi.org/10.1177/0391398820988297DOI Listing
January 2021

Identification of biomarkers for drug-resistant endometriosis using clinical proteomics.

Hum Cell 2021 Mar 2;34(2):394-399. Epub 2021 Jan 2.

Department of Obstetrics and Gynecology, Kosei Hospital, Tokyo, Japan.

Dienogest (DNG), is an effective and widely used progestin used in the treatment of endometriosis, yet clinically, a subset of cases show resistance to DNG treatment. During a previous investigation on the effect of DNG of cytokines and growth factor production, we incidentally found that endometriotic cyst fluid did not demonstrate inhibitory effects to DNG in a subset of cases. To clarify the mechanisms of this resistance to DNG, we performed proteomics analysis to compare the protein expression between DNG-sensitive and resistant cases. Based upon our results, several proteins were extracted that relate to neutrophil granulocyte activation marker (myeloperoxidase, lactotransferrin), inflammation (azurocidin, neutrophil gelatinase-associated lipocalin, etc.), and others biological processes reflecting the clinical environment of the endometriotic cyst. Among these proteins, azurocidin (AZU) is perhaps most interesting one as azurocidin is a protease that cleaves insulin-like growth factor-1 (IGFBP-1) associated with clear cell carcinoma of the ovary. We propose that the proteins extracted in the present study warrant further investigation in their relationship to carcinogenesis of endometrioma.
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http://dx.doi.org/10.1007/s13577-020-00465-0DOI Listing
March 2021
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