Comparing cryoballoon and contact-force guided radiofrequency ablation in pulmonary vein isolation for atrial fibrillation in patients with hypertrophic cardiomyopathy.

BACKGROUND: Pulmonary vein isolation (PVI) employing cryoballoon (CB) or contact force-guided radiofrequency (CF-RF) catheter ablation has been established as an effective strategy for managing atrial fibrillation (AF). However, its efficacy in hypertrophic cardiomyopathy (HCM) remains to be further explored. METHODS: This retrospective study analyzed 60 consecutive AF patients with HCM (average age 67 ± 10 years; 41 men) who were consecutively admitted to our hospital from January 2014 to December 2022 and underwent initial PVI. RESULTS: The patients were treated with CB (26 patients) or CF-RF (34 patients). Successful PVI was achieved in both groups without significant complications. In the CF-RF group, additional ablations were performed on the cavotricuspid isthmus (14.7% of patients) and the anterior line (2.9%). The CB group benefited from reduced procedural times (93 ± 31 vs. 165 ± 60 min, p < 0.05) and decreased saline irrigation requirements (77.5 ± 31.4 vs. 870 ± 281.9 mL, p < 0.0001). Using a contrast medium was exclusive to the CB group (33.8 ± 4.2 mL). In a 12-month follow-up, the atrial tachyarrhythmia recurrence-free rates in the CB and CF-RF groups were comparable (77% and 76%, respectively; p = 0.63 according to the log-rank test). Notably, pulmonary vein reconnection was prevalent in most (7 out of 8) patients requiring a secondary ablation procedure. CONCLUSION: PVI is feasible as a strategy for AF in patients with HCM employing either CB or CF-RF techniques. While the recurrence-free rates were comparable in both groups, differences were noted in procedure duration, saline usage, and the need for a contrast medium.

Hepatitis B virus-specific human stem cell memory T cells differentiate into cytotoxic T cells and eradicate HBV-infected hepatocytes in mice.

Chronic infection with the hepatitis B virus (HBV) induces progressive hepatic impairment. Achieving complete eradication of the virus remains a formidable challenge. Cytotoxic T lymphocytes, specific to viral antigens, either exhibit a numerical deficiency or succumb to an exhausted state in individuals chronically afflicted with HBV. The comprehension of the genesis and dissemination of stem cell memory T cells (TSCMs) targeting HBV remains inadequately elucidated. We identified TSCMs in subjects with chronic HBV infection and scrutinized their efficacy in a murine model with human hepatocyte transplants, specifically the TK-NOG mice. TSCMs were discerned in all subjects under examination. Introduction of TSCMs into the HBV mouse model precipitated a severe necro-inflammatory response, resulting in the elimination of human hepatocytes. TSCMs may constitute a valuable tool in the pursuit of a remedial therapy for HBV infection.

Multi-omics analysis of a fatty liver model using human hepatocyte chimeric mice.

We developed a fatty liver mouse model using human hepatocyte chimeric mice. As transplanted human hepatocytes do not respond to mouse growth hormone (GH) and tend to accumulate fat, we hypothesized that addition of human GH would alter lipid metabolism and reduce accumulation of fat in the liver even when fed a high-fat diet. Six uPA/SCID chimeric mice were fed a high-fat GAN diet to induce fatty liver while six were fed a normal CRF1 diet, and GH was administered to three mice in each group. The mice were euthanized at 8 weeks, and human hepatocytes were extracted for RNA-Seq, DIA proteomics, and metabolomics analysis. Abdominal echocardiography revealed that the degree of fatty liver increased significantly in mice fed GAN diet (p < 0.001) and decreased significantly in mice treated with GH (p = 0.026). Weighted gene correlation network analysis identified IGF1 and SEMA7A as eigengenes. Administration of GH significantly reduced triglyceride levels and was strongly associated with metabolism of amino acids. MiBiOmics analysis identified perilipin-2 as a co-inertia driver. Results from multi-omics analysis revealed distinct gene expression and protein/metabolite profiles in each treatment group when mice were fed a high-fat or normal diet with or without administration of GH.

Dual tachyarrhythmia: Ventricular fibrillation induced by atrial tachyarrhythmia in a patient with hypertrophic cardiomyopathy.

A patient with hypertrophic cardiomyopathy experienced cardiopulmonary arrest. An automated external defibrillator administered defibrillation for ventricular fibrillation (A). The pacemaker recorded atrial tachycardia with a rapid ventricular response before the patient collapsed (B). After a few minutes, the pacemaker records dual tachyarrhythmia, characterized by the simultaneous presence of ventricular fibrillation (VF) and atrial fibrillation (AF) (C). This case demonstrates that VF induced by atrial tachyarrhythmia could contribute to AF-related sudden cardiac death.

SDF-1 involvement in orthodontic tooth movement after tooth extraction.

The stromal cell-derived factor 1 (SDF-1)/chemokine receptor type 4 (CXCR4) axis plays a key role in alveolar bone metabolism during orthodontic tooth movement (OTM). Herein, the effects of the SDF-1/CXCR4 axis on the regional acceleratory phenomenon (RAP) in OTM velocity and on changes in the surrounding periodontium after adjacent tooth extraction in rats were investigated. Six-week-old male Wistar/ST rats underwent left maxillary first molar (M1) extraction and mesial OTM of the left maxillary second molar (M2) with a 10-g force closed-coil spring. Phosphate-buffered saline, immunoglobulin G (IgG) isotype control antibody, or anti-SDF-1 neutralizing monoclonal antibody were injected at the M1 and M2 interproximal areas (10 µg/0.1 mL) for the first three days. Analyses were performed after 1, 3, and 7 days (n = 7). The results demonstrated a significant increase in SDF-1 expression from day 1, which was effectively blocked via anti-SDF-1 neutralizing monoclonal antibody injection. On day 3, the M2 OTM distance and the number of positively stained osteoclasts significantly reduced alongside a reduction in inflammatory markers in the experimental group. Our results demonstrated that serial local injection of the anti-SDF-1 neutralizing monoclonal antibody reduces M2 OTM, osteoclast accumulation, and localized inflammatory responses in an OTM model with tooth extraction-induced RAP.

Landiolol, an intravenous ß1-selective blocker, is useful for dissociating a fusion of atrial activation via accessory pathway and atrioventricular node.

Introduction: During ventricular pacing, a fusion of atrial activation may occur owing to the simultaneous retrograde conduction of the atrioventricular (AV) node and accessory pathway (AP), potentially leading to an inaccurate mapping of the atrial AP insertion site. Objective: We tested the hypothesis that landiolol, an ultra-short-acting intravenous ß1-blocker, could dissociate a fusion of atrial activation. Methods: We conducted a prospective before-and-after study to investigate the effect of landiolol on retrograde conduction via the AV node and AP. We enrolled 21 consecutive patients with orthodromic AV reciprocating tachycardia who underwent electrophysiological studies at our hospital between January 1, 2018, and August 31, 2020. Results: Six patients exhibited a fusion of atrial activation. After landiolol administration (10 µg/kg/min), the effective refractory period was unchanged in AP (280 [240-290] ms vs. 280 [245-295] ms, p = .91), whereas that of the AV node was prolonged (275 [215-380] ms vs. 332 [278-445] ms, p = .03). The Wenckebach pacing rate via retrograde AV node decreased after landiolol administration (180 [140-200] beats per minute [bpm] vs. 140 [120-180] bpm, p = .02). Thus, landiolol decreased the minimum ventricular pacing rate required to dissociate a fusion of atrial activation (180 [160-200] bpm vs. 140 [128-155] bpm, p = .007). Radiofrequency catheter ablation under landiolol administration successfully eliminated AP in all patients during ventricular pacing without complications or recurrence. Conclusion: Landiolol inhibited the AV node without affecting the AP and helped dissociate a fusion of atrial activation at a lower ventricular pacing rate.

Whole-genome sequence analysis of mutations in rice plants regenerated from zygotes, mature embryos, and immature embryos.

Somaclonal variation was studied by whole-genome sequencing in rice plants (Oryza sativa L., 'Nipponbare') regenerated from the zygotes, mature embryos, and immature embryos of a single mother plant. The mother plant and its seed-propagated progeny were also sequenced. A total of 338 variants of the mother plant sequence were detected in the progeny, and mean values ranged from 9.0 of the seed-propagated plants to 37.4 of regenerants from mature embryos. The natural mutation rate of 1.2 × 10-8 calculated using the variants in the seed-propagated plants was consistent with the values reported previously. The ratio of single nucleotide variants (SNVs) among the variants in the seed-propagated plants was 91.1%, which is higher than 56.1% previously reported, and not significantly different from those in the regenerants. Overall, the ratio of transitions to transversions of SNVs was lower in the regenerants as shown previously. Plants regenerated from mature embryos had significantly more variants than different progeny types. Therefore, using zygotes and immature embryos can reduce somaclonal variation during the genetic manipulation of rice.

Modeling suggests that virion production cycles within individual cells is key to understanding acute hepatitis B virus infection kinetics.

Hepatitis B virus (HBV) infection kinetics in immunodeficient mice reconstituted with humanized livers from inoculation to steady state is highly dynamic despite the absence of an adaptive immune response. To recapitulate the multiphasic viral kinetic patterns, we developed an agent-based model that includes intracellular virion production cycles reflecting the cyclic nature of each individual virus lifecycle. The model fits the data well predicting an increase in production cycles initially starting with a long production cycle of 1 virion per 20 hours that gradually reaches 1 virion per hour after approximately 3-4 days before virion production increases dramatically to reach to a steady state rate of 4 virions per hour per cell. Together, modeling suggests that it is the cyclic nature of the virus lifecycle combined with an initial slow but increasing rate of HBV production from each cell that plays a role in generating the observed multiphasic HBV kinetic patterns in humanized mice.

Guiding Hepatic Differentiation of Pluripotent Stem Cells Using 3D Microfluidic Co-Cultures with Human Hepatocytes.

Human pluripotent stem cells (hPSCs) are capable of unlimited proliferation and can undergo differentiation to give rise to cells and tissues of the three primary germ layers. While directing lineage selection of hPSCs has been an active area of research, improving the efficiency of differentiation remains an important objective. In this study, we describe a two-compartment microfluidic device for co-cultivation of adult human hepatocytes and stem cells. Both cell types were cultured in a 3D or spheroid format. Adult hepatocytes remained highly functional in the microfluidic device over the course of 4 weeks and served as a source of instructive paracrine cues to drive hepatic differentiation of stem cells cultured in the neighboring compartment. The differentiation of stem cells was more pronounced in microfluidic co-cultures compared to a standard hepatic differentiation protocol. In addition to improving stem cell differentiation outcomes, the microfluidic co-culture system described here may be used for parsing signals and mechanisms controlling hepatic cell fate.

Function of hepatocyte spheroids in bioactive microcapsules is enhanced by endogenous and exogenous hepatocyte growth factor.

The ability to maintain functional hepatocytes has important implications for bioartificial liver development, cell-based therapies, drug screening, and tissue engineering. Several approaches can be used to restore hepatocyte function in vitro, including coating a culture substrate with extracellular matrix (ECM), encapsulating cells within biomimetic gels (Collagen- or Matrigel-based), or co-cultivation with other cells. This paper describes the use of bioactive heparin-based core-shell microcapsules to form and cultivate hepatocyte spheroids. These microcapsules are comprised of an aqueous core that facilitates hepatocyte aggregation into spheroids and a heparin hydrogel shell that binds and releases growth factors. We demonstrate that bioactive microcapsules retain and release endogenous signals thus enhancing the function of encapsulated hepatocytes. We also demonstrate that hepatic function may be further enhanced by loading exogenous hepatocyte growth factor (HGF) into microcapsules and inhibiting transforming growth factor (TGF)-ß1 signaling. Overall, bioactive microcapsules described here represent a promising new strategy for the encapsulation and maintenance of primary hepatocytes and will be beneficial for liver tissue engineering, regenerative medicine, and drug testing applications.

Use of a QDOT MICRO catheter to identify a premature ventricular contraction origin in the right ventricular anterior papillary muscle in a repaired truncus arteriosus.

The ventricular papillary muscles (VPMs) can be a source of premature ventricular contractions (PVCs). Catheter ablation of VPM PVCs is challenging because of the anatomical complexity, such as the apical structures in proximity to the ventricular walls. The QDOT MICRO catheter (Biosense Webster, Diamond Bar, CA, USA) has microelectrodes embedded along the circumference of its distal tip and can provide information on which side of its tip myocardial activation is earlier. This repaired truncus arteriosus case demonstrates the usefulness of the microelectrode recording in identifying a PVC origin in a right VPM apex close to the right ventricular anterior wall.

Persistent hepatic IFN system activation in HBV-HDV infection determines viral replication dynamics and therapeutic response.

Hepatitis delta virus (HDV), a satellite virus of HBV, is regarded as the most severe type of hepatitis virus because of the substantial morbidity and mortality. The IFN system is the first line of defense against viral infections and an essential element of antiviral immunity; however, the role of the hepatic IFN system in controlling HBV-HDV infection remains poorly understood. Herein, we showed that HDV infection of human hepatocytes induced a potent and persistent activation of the IFN system whereas HBV was inert in triggering hepatic antiviral response. Moreover, we demonstrated that HDV-induced constitutive activation of the hepatic IFN system resulted in a potent suppression of HBV while modestly inhibiting HDV. Thus, these pathogens are equipped with distinctive immunogenicity and varying sensitivity to the antiviral effectors of IFN, leading to the establishment of a paradoxical mode of viral interference wherein HDV, the superinfectant, outcompetes HBV, the primary pathogen. Furthermore, our study revealed that HDV-induced constitutive IFN system activation led to a state of IFN refractoriness, rendering therapeutic IFNs ineffective. The present study provides potentially novel insights into the role of the hepatic IFN system in regulating HBV-HDV infection dynamics and its therapeutic implications through elucidating the molecular basis underlying the inefficacy of IFN-based antiviral strategies against HBV-HDV infection.

Periostin splice variants affect craniofacial growth by influencing chondrocyte hypertrophy.

INTRODUCTION: Periostin, an extracellular matrix protein, plays an important role in osteogenesis and is also known to activate several signals that contribute to chondrogenesis. The absence of periostin in periostin knockout mice leads to several disorders such as craniosynostosis and periostitis. There are several splice variants with different roles in heart disease and myocardial infarction. However, little is known about each variant's role in chondrogenesis, followed by bone formation. Therefore, the aim of this study is to investigate the role of several variants in chondrogenesis differentiation and bone formation in the craniofacial region. Periostin splice variants included a full-length variant (Control), a variant lacking exon 17 (ΔEx17), a variant lacking exon 21 (ΔEx21), and another variant lacking both exon 17 and 21 ***(ΔEx17&21). MATERIALS AND METHODS: We used C56BL6/N mice (n = 6) for the wild type (Control)*** and the three variant type mice (n = 6 each) to identify the effect of each variant morphologically and histologically. Micro-computed tomography demonstrated a smaller craniofacial skeleton in ΔEx17s, ΔEx21s, and ΔEx17&21s compared to Controls, especially the mandibular bone. We, thus, focused on the mandibular condyle. RESULTS: The most distinctive histological observation was that each defected mouse appeared to have more hypertrophic chondrocytes than Controls. Real-time PCR demonstrated the differences among the group. Moreover, the lack of exon 17 or exon 21 in periostin leads to inadequate chondrocyte differentiation and presents in a diminutive craniofacial skeleton. DISCUSSION: Therefore, these findings suggested that each variant has a significant role in chondrocyte hypertrophy, leading to suppression of bone formation.

HBV with precore and basal core promoter mutations exhibits a high replication phenotype and causes ER stress-mediated cell death in humanized liver chimeric mice.

BACKGROUND AND AIMS: Mutations within the precore (PC) and basal core promoter (BCP) regions of the HBV genome are associated with fulminant hepatitis and HBV reactivation. These mutations may enhance viral replication, but little is known about whether they directly induce damage to the liver. We investigated mechanisms of direct cytopathic effects induced by the infection with PC/BCP mutants in the absence of immune response in vitro and in vivo . APPROACH AND RESULTS: Mice with humanized livers and hepatocytes derived from humanized mice were infected with either wild-type or mutant-type PC/BCP HBV, and the HBV replication and human hepatocyte damage were evaluated. HBV proliferated vigorously in mice with PC/BCP-mutant infection, and the severe loss of human hepatocytes with a slight human ALT elevation subsequently occurred only in PC/BCP mutant mice. In PC/BCP mutant infection, the accumulation of HBsAg in humanized livers colocalized with the endoplasmic reticulum, leading to apoptosis through unfolded protein response in HBV-infected hepatocytes. RNA-sequencing revealed the molecular characteristics of the phenotype of PC/BCP mutant infection in a humanized mouse model. Reduced ALT elevation and higher HBV DNA levels in this model are consistent with characteristics of HBV reactivation, indicating that the hepatocyte damage in this model might mimic HBV reactivation followed by hepatocyte damage under immunosuppressive conditions. CONCLUSION: PC and BCP mutations were associated with enhanced viral replication and cell death induced by ER stress using HBV infection models. These mutations might be associated with liver damage in patients with fulminant hepatitis or HBV reactivation.

NF-κB Decoy ODN-Loaded Poly(Lactic-co-glycolic Acid) Nanospheres Inhibit Alveolar Ridge Resorption.

Residual ridge resorption combined with dimensional loss resulting from tooth extraction has a prolonged correlation with early excessive inflammation. Nuclear factor-kappa B (NF-κB) decoy oligodeoxynucleotides (ODNs) are double-stranded DNA sequences capable of downregulating the expression of downstream genes of the NF-κB pathway, which is recognized for regulating prototypical proinflammatory signals, physiological bone metabolism, pathologic bone destruction, and bone regeneration. The aim of this study was to investigate the therapeutic effect of NF-κB decoy ODNs on the extraction sockets of Wistar/ST rats when delivered by poly(lactic-co-glycolic acid) (PLGA) nanospheres. Microcomputed tomography and trabecular bone analysis following treatment with NF-κB decoy ODN-loaded PLGA nanospheres (PLGA-NfDs) demonstrated inhibition of vertical alveolar bone loss with increased bone volume, smoother trabecular bone surface, thicker trabecular bone, larger trabecular number and separation, and fewer bone porosities. Histomorphometric and reverse transcription-quantitative polymerase chain reaction analysis revealed reduced tartrate-resistant acid phosphatase-expressing osteoclasts, interleukin-1ß, tumor necrosis factor-α, receptor activator of NF-κB ligand, turnover rate, and increased transforming growth factor-ß1 immunopositive reactions and relative gene expression. These data demonstrate that local NF-κB decoy ODN transfection via PLGA-NfD can be used to effectively suppress inflammation in a tooth-extraction socket during the healing process, with the potential to accelerate new bone formation.