The association between hyperuricemia and atrial fibrillation recurrence after catheter ablation.

Background: Hyperuricemia (HU) has been reported to be associated with a high incidence of atrial fibrillation (AF). However, the relationship between HUA and recurrent AF after catheter ablation (CA) is unclear. Methods: Four hundred consecutive AF patients (paroxysmal/persistent AF [PAF/PsAF]: 200/200) who underwent the initial CA were retrospectively enrolled. HU was defined as serum uric acid (SUA) level >7.0 mg/dL. We measured SUA levels 1 day before (pre-CA) and 1 month after CA (post-CA). A second-generation 28 mm cryoballoon was used for pulmonary vein isolation (PVI) for PAF, while PVI plus linear ablation (roof and mitral isthmus lines) by radiofrequency catheter was conducted for PsAF. Results: During 57 ± 24 months of follow-up, AF recurred in 16% and 42% in PAF and PsAF patients (p < .0001). Pre-CA SUA level in PsAF was significantly higher than that in PAF (6.5 ± 1.3 vs. 5.8 ± 1.3 mg/dL, p < .001). SUA level was significantly decreased after CA in both PAF and PsAF (5.8 ± 1.3 vs. 5.6 ± 1.3 mg/dL; p < .01 and 6.5 ± 1.3 vs. 6.1 ± 1.2 mg/dL; p < .0001, respectively). The association between pre-/post-CA HU and recurrent AF was not identified in PAF, while the incidence of post-CA HU was significantly higher in patients with recurrent AF than those without in PsAF (36% vs. 15%, p < .001). In multivariable analysis, longer AF duration and the presence of post-CA HU were identified as independent predictors of AF recurrence in PsAF (OR:1.01, 95%CI:1.003-1.011, p = .0001 and OR:2.77, 95%CI:1.333-5.755, p = .007, respectively). Conclusions: SUA level was significantly higher in PsAF than PAF patients. The presence of post-CA HU was strongly related to AF recurrence in PsAF patients.

Multiple gastric neuroendocrine tumors in a patient with parietal cell dysfunction and adenosine triphosphatase H+/K+ transporting subunit alpha gene variant.

A 47-year-old woman presented with multiple gastric tumors, each up to 10 mm in diameter, in the gastric body and fundus without mucosal atrophy. White spots and numerous transparent, light-brownish, small, and rounded spots were observed in the background gastric mucosa. Biopsy specimens obtained from the tumors revealed gastric neuroendocrine tumors. The patient exhibited hypergastrinemia and achlorhydria and tested negative for serum parietal cell antibody, intrinsic factor antibody, and Helicobacter pylori infection. Moreover, no additional lesions were detected on imaging. These findings were inconsistent with Rindi's classification. The tumor was resected via endoscopic submucosal resection. Histopathological examination revealed gastric neuroendocrine tumors G2 infiltrating the submucosa with no atrophy of the gastric mucosa, dilated fundic glands, parietal cell protrusions, and hyperplasia of enterochromaffin-like cells. Immunohistochemically, the parietal cells were negative for both α- and ß-subunits of H+/K+ ATPase, suggesting parietal cell dysfunction. A genomic variant was identified in adenosine triphosphatase H+/K+ transporting subunit alpha. After 7 years of treatment, there was no evidence of residual or metastatic lesions. Modification of adenosine triphosphatase H+/K+ transporting subunit alpha may be a significant factor in the pathogenesis of multiple gastric neuroendocrine tumors in the context of gastric parietal cell dysfunction.

[A pedigree of myotonia congenita with a novel mutation p.F343C of the CLCN1 gene].

A Japanese woman experienced slowness of movement in her early teens and difficulty in opening her hands during pregnancy. On admission to our hospital at 42 years of age, she showed grip myotonia with warm-up phenomenon. However, she had neither muscle weakness, muscle atrophy, cold-induced symptomatic worsening nor episodes of transient weakness of the extremities. Needle electromyography of the first dorsal interosseous and anterior tibial muscles demonstrated myotonic discharges. Whole exome sequencing of the patient revealed a heterozygous single-base substitution in the CLCN1 gene (c.1028T>G, p.F343C). The same substitution was identified in affected members of her family (mother and brother) by Sanger sequencing, but not in healthy family members (father and a different brother). We diagnosed myotonia congenita (Thomsen disease) with a novel CLCN1 mutation in this pedigree. This mutation causes a single amino acid substitution in the I-J extracellular loop region of CLCN1. Amino acid changes in the I-J loop region are rare in an autosomal-dominantly inherited form of myotonia congenita. We think that this pedigree is precious to understand the pathogenesis of myotonia congenita.

Identification of causative gene variants for patients with known monogenic diabetes using a targeted next-generation sequencing panel in a single-center study.

Aims: We aimed to verify the usefulness of targeted next-generation sequencing (NGS) technology for diagnosing monogenic diabetes in a single center. Methods: We designed an amplicon-based NGS panel targeting 34 genes associated with known monogenic diabetes and performed resequencing in 56 patients with autoantibody-negative diabetes mellitus diagnosed at < 50 years who had not been highly obese. By bioinformatic analysis, we filtered significant variants based on allele frequency (< 0.005 in East Asians) and functional prediction. We estimated the pathogenicity of each variant upon considering the family history. Results: Overall, 16 candidate causative variants were identified in 16 patients. Among them, two previously known heterozygous nonsynonymous single-nucleotide variants associated with monogenic diabetes were confirmed as causative variants: one each in the GCK and WFS1 genes. The former was found in two independent diabetes-affected families. Two novel putatively deleterious heterozygous variants were also assumed to be causative from the family history: one frameshift and one nonsynonymous single-nucleotide variant in the HNF4A gene. Twelve variants remained as candidates associated with the development of diabetes. Conclusion: Targeted NGS panel testing was useful to diagnose various forms of monogenic diabetes in combination with familial analysis, but additional ingenuity would be needed for practice. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-023-00669-3.

Familial Intraductal Papillary Mucinous Neoplasm Associated With the Germline MSH6 Missense Variant and Progression of Pancreatic cancer.

OBJECTIVES: Intraductal papillary mucinous neoplasm (IPMN) in individuals with at least one first-degree relative with IPMN is defined as familial IPMN. However, few studies have reported on familial IPMN, its clinical characteristics, or the associated genetic factors. MATERIALS AND METHODS: We report the case of a 58-year-old woman with multifocal IPMN and a mural nodule in the pancreatic body. The patient underwent a distal pancreatectomy and developed pancreatic head cancer 1 year and 6 months postoperatively. The patient had a family history of multifocal IPMN in her father. Therefore, a genetic predisposition to IPMN and pancreatic cancer was suspected. The patient was analyzed for germline variants, and the resected IPMN was subjected to immunohistochemical and somatic variant analyses. RESULTS: Next-generation sequencing revealed a heterozygous germline missense variant in exon 5 of MSH6 (c.3197A>G; Tyr1066Cys). The pathogenicity of this variant of uncertain significance was suspected based on multiple in silico analyses, and the same MSH6 variant was identified in the patient's father's colonic adenoma. The mural nodule in the pancreatic body was pathologically diagnosed as a high-grade IPMN with ossification and somatic KRAS and PIK3CA variants. CONCLUSIONS: This case revealed a possible genetic factor for familial IPMN development and presented interesting clinicopathological findings.

Clinical Relevance of Patient-Derived Organoid of Surgically Resected Lung Cancer as an In Vitro Model for Biomarker and Drug Testing.

Introduction: Lung tumor organoids (LTOs) have attracted attention as in vitro preclinical models; however, their clinical and experimental applications have not been fully established. Methods: We attempted to establish LTOs from resected specimens of patients with lung cancer who underwent lung resection. Clinicopathologic characteristics related to the establishment of LTOs were evaluated. Histologic assessment and genetic analysis were conducted for both LTOs and their parental tumors. Organoid-derived xenografts were generated in immunocompetent mice. Drug sensitivity was assessed using cell proliferation assays. Results: We established 53 LTOs from 79 lung cancer samples, including 10 long-term culture models. The establishment rate was significantly lower in squamous cell carcinomas than in other histologic types (48% versus 75%, p = 0.034). Histologic similarities were confirmed among LTOs, the parental tumors, and organoid-derived xenografts. Seven mutations, including two EGFR L858R and one EGFR exon 20 H773delinsYNPY mutations, were detected in both LTO and parental tumors; the other four mutations were detected in either LTO or parental tumors. The extensive culture ability of LTO (passaged >10 times) correlated with poor patient prognosis. LTO9 cells harboring EGFR H773delinsYNPY were sensitive to osimertinib. The parental patient, who had new metastatic lesions, was treated with osimertinib and exhibited a remarkable response. Conclusions: The establishment and growth rates of LTOs were associated with the histologic subtype and tumor size. LTOs derived from resected specimens have become preclinical models that can be used to predict drug responses and accelerate the development of treatment strategies for patients with rare mutations.

Role of Bile-Derived Extracellular Vesicles in Hepatocellular Proliferation after Partial Hepatectomy in Rats.

Although liver regeneration has been extensively studied, the effects of bile-derived extracellular vesicles (bile EVs) on hepatocytes has not been elucidated. We examined the influence of bile EVs, collected from a rat model of 70% partial hepatectomy (PH), on hepatocytes. We produced bile-duct-cannulated rats. Bile was collected over time through an extracorporeal bile duct cannulation tube. Bile EVs were extracted via size exclusion chromatography. The number of EVs released into the bile per liver weight 12 h after PH significantly increased. Bile EVs collected 12 and 24 h post-PH, and after sham surgery (PH12-EVs, PH24-EVs, sham-EVs) were added to the rat hepatocyte cell line, and 24 h later, RNA was extracted and transcriptome analysis performed. The analysis revealed that more upregulated/downregulated genes were observed in the group with PH24-EVs. Moreover, the gene ontology (GO) analysis focusing on the cell cycle revealed an upregulation of 28 types of genes in the PH-24 group, including genes that promote cell cycle progression, compared to the sham group. PH24-EVs induced hepatocyte proliferation in a dose-dependent manner in vitro, whereas sham-Evs showed no significant difference compared to the controls. This study revealed that post-PH bile Evs promote the proliferation of the hepatocytes, and genes promoting cell cycles are upregulated in hepatocytes.

Direct Observation of Palladium Leaching from Pd/C by a Simple Method: X-ray Absorption Spectroscopy of Heterogeneous Mixtures.

Herein, we show the detailed behavior of palladium leaching from palladium on charcoal by aqueous HCl, directly observed by X-ray absorption spectroscopy measurement employing a simplified reaction setup. While Pd0 is not affected by the addition of HCl, palladium oxide in nanoparticles readily reacts with HCl to form the ionic species [PdIICl4]2-, even though these ions mostly remain adsorbed on the surface of activated charcoal and can only be detected at a low level in the solution phase. This finding provides a new aspect for control of the leaching behavior and robust usage of palladium on charcoal in organic reactions.

Pulmonary Vein Stenosis After Catheter Ablation of Atrial Fibrillation Using a Cryoballoon, Hot Balloon, or Laser Balloon.

BACKGROUND: Pulmonary vein stenosis (PVS) after PV isolation (PVI) for atrial fibrillation (AF) is a severe complication that requires angioplasty. This study aimed to compare the reduction of the cross-sectional PV area (PVA) and the incidence of PVS after cryoballoon (CB)-PVI, hot balloon (HB)-PVI, or laser balloon (LB)-PVI.Methods and Results: A total of 320 patients who underwent an initial catheter ablation procedure for AF using a CB, HB, or LB in 2 hospitals were included. They underwent contrast-enhanced multidetector CT before and 3 months after the procedure. In all 4 PVs, the reduction in PVA was more significant in the LB group than in the CB or HB groups, respectively. Moderate (50-75%) and severe (>75%) PVS were observed in 5.3% and 0.5% of the PVs, respectively. Although moderate PVS was more frequently observed in the LB group than in the CB or HB groups (8.2%, 3.8%, and 5.0%; P=0.03), the incidence of severe PVS was similar in the LB, CB, and HB groups (0.3%, 0.5%, and 1.0%; P=0.46). Symptomatic PVS requiring intervention occurred in 1 (0.3%) patient. CONCLUSIONS: Although the reduction in cross-sectional PVA and the incidence of moderate PVS after LB-PVI was more significant than after CB-PVI or HB-PVI, it rarely led to severe PVS. Symptomatic PVS requiring intervention was rare after the balloon ablation of AF.

Structural Variants of Midnolin, a Genetic Risk Factor for Parkinson's Disease, in a Yamagata Cohort.

Parkinson's disease (PD) is a common neurodegenerative disease. We previously identified Midnolin (MIDN) to be a genetic risk factor for PD in both Yamagata (Japan) and British populations. However, the scale of our previous study was not sufficient to identify MIDN structural variants in the ascertained control of Yamagata Prefecture. We, therefore, reanalyzed MIDN variants in 3021 individuals from Yamagata Prefecture to compare with that in our previous British cohort study. MIDN copy number loss was only found in two cases (0.0662%), which was a lower frequency than that (1.64%) of the previously studied British cohort. Between the Yamagata and British groups, there was significant difference for rs3746106, located in the 5'-UTR of MIDN mRNA (p = 0.0003344, odds ratio 1.143), and for rs3746107, which corresponds to Ala34 (p < 2.2 × 10-16, odds ratio 5.89401). This study indicates that MIDN loss is relatively rare in the general Japanese population. Considering our previous studies that the frequency of MIDN loss is high among patients with PD (10.5 and 6.55% in Yamagata and Britain, respectively), the MIDN variants are much higher genetic risk factors for PD in a Japanese population than in a British population.

Using the pre-freezing technique results in a wider area of antral isolation during cryoballoon pulmonary vein isolation in patients with atrial fibrillation.

The "pre-freezing" technique was a method in which a fully inflated balloon after the start of freezing was pressed against the pulmonary vein (PV) during cryoballoon ablation and has been applied especially in large-size PVs. Of 556 patients who underwent cryoballoon ablation for atrial fibrillation (AF), the pre-freezing technique was applied to 48 patients. The resulting 2:1 propensity score-matched data set included 120 patients. Using the pre-freezing technique, all left-superior PVs, all left-inferior PVs, and 95% of right-superior PVs were successfully isolated. In most right-inferior PVs, complete sealing using the pre-freezing technique was challenging, and this technique was not applied. Procedure time was similar between the two groups. In the pre-freezing group, the percentage of the left atrial posterior wall isolated was larger (47.6 ± 10.3 vs. 42.8 ± 15.7%, P = 0.006), and the postoperative reduction of diaphragmatic compound motor action potentials tended to occur less frequently (2.5 vs. 12.5%, P = 0.07), and the reduction of the cross-sectional LSPV area was smaller (17.5 ± 12.2 vs. 27.2 ± 19.8%, P = 0.03) than the conventional group. The AF-free rate of the two groups was similar between the two groups (P = 0.15). The pre-freezing technique was a simple method that can isolate a wider surface area during cryoballoon PV isolation. While the postoperative AF recurrence was comparable, the postoperative reduction in the cross-sectional PV area was less than that of the conventional method, which may reduce the risk of PV stenosis.

Combination of photodynamic therapy and endoscopic mucosal resection for recurrent esophageal squamous cell carcinoma after chemoradiotherapy.

Photodynamic therapy (PDT) was developed for residual or recurrent esophageal cancer after radiotherapy. Here, we report a case of successful treatment of highly elevated esophageal squamous cell carcinoma (ESCC) that recurred after definitive chemoradiotherapy (dCRT) using PDT combined with endoscopic resection (ER). An 86-year-old man was found to have an ESCC in the mid-thoracic esophagus. One year and two months after dCRT, a local recurrence was seen. The recurrent ESCC had a highly elevated component. The ESCC was estimated to have invaded the deep submucosa at the highly elevated component. PDT was selected as a treatment option since no lymph node or distant metastases were found. However, there was concern that the laser would not be able to penetrate deep into the ESCC due to its high elevated component. Therefore, ER was performed to remove the highly elevated component, and PDT was performed later. However, after the ER, the circumference of the recurrent ESCC was found to be approximately half the circumference, and post-PDT stenosis was also a concern due to the wide circumference of the ESCC. Therefore, we limited the area of laser irradiation in one session of PDT. Four sessions of PDT were needed over 13 months, but a local complete response was achieved without adverse events.

A 15-year follow-up study of radiofrequency catheter ablation for atrial fibrillation in patients with tachycardia-bradycardia syndrome.

INTRODUCTION: Catheter ablation for atrial fibrillation (AF) in patients with tachycardia-bradycardia syndrome (TBS) can be a major therapeutic option to replace permanent pacemaker implantation (PMI). However, the very long-term outcome of more than 15 years in these patients has not been elucidated. METHODS: From 2002 to 2008, 25 consecutive TBS patients (62 ± 7.9 years old, 68% male) with both AF and symptomatic sinus pauses (>3.0 s) were performed radiofrequency AF ablation. These patients were followed for 15 ± 2.7 years. RESULTS: The median longest sinus pause before the ablation procedure was 6.0 s (4.4-8.0). Following 1.6± 0.8 ablation procedures, 18 (72%) patients remained free from AF. Three (12%) patients died due to noncardiovascular causes, and seven (28%) patients underwent PMI due to symptomatic sinus pause after recurrent AF in five patients and progression of sinus node dysfunction in two patients. The median duration from the first AF ablation to PMI was 6.3 years (range: 9 days to 11.0 years). Five and two patients required PMI more than 5 and 10 years after the first ablation procedure, respectively. CONCLUSION: AF ablation prevented PMI in 72% of TBS patients for a 15-year follow-up. However, in consideration of the long duration of PMI, a continuous careful long-term follow-up was warranted.

Case Report: Coexistence of Multiple Myeloma and Auricular Chondritis in VEXAS Syndrome.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an inflammatory disorder caused by somatic UBA1 variants, which are sometimes associated with hematological disorders, including myelodysplastic syndrome (MDS). VEXAS syndrome often overlaps with rheumatic diseases, including relapsing polychondritis. Here, we describe a case of VEXAS syndrome with auricular chondritis and exceptional multiple myeloma (MM). An 83-year-old man was diagnosed with MM, which was treated once by lenalidomide hydrate obtaining a partial response, but the patient did not desire further aggressive therapy. Although the treatment was effective, progressive macrocytic anemia and inflammation of both the ears emerged over the following 2 months. The histological examination of the auricle skin revealed that the perichondrial area was infiltrated by inflammatory cells, leading to the diagnosis of auricular chondritis. He was treated with oral prednisolone 40 mg/day, and his symptoms rapidly resolved. The re-evaluation of the histopathological bone marrow findings revealed vacuoles in the myeloid precursor cells without myelodysplasia-related changes. Sanger sequencing of UBA1 was performed using genomic DNA from peripheral blood leukocytes and revealed a somatic variant (c.122T>C:p.Met41Thr) consistent with VEXAS syndrome. This demonstrates that patients with chondritis can have complications with MM despite the absence of underlying MDS. A strong association exists between UBA1 variants and the risk of MDS; however, it remains elusive whether somatic UBA1 variants contribute to the development of plasma cell dyscrasia without MDS. Hence, we discuss the possible relationship between auricular chondritis and MM on a background of VEXAS syndrome.

Effect of air removal with extracorporeal balloon inflation on incidence of asymptomatic cerebral embolism during cryoballoon ablation of atrial fibrillation: A prospective randomized study.

Background: It was previously reported, based on a retrospective study, that preliminary removal of air bubbles in heparinized saline water with extracorporeal balloon inflation reduced the incidence of asymptomatic cerebral embolism (ACE). The present study aims to compare the incidence of ACE between a conventional and pre-inflation method during cryoballoon ablation in a prospective randomized controlled study. Methods: A total of 98 atrial fibrillation patients were enrolled and randomized into conventional and pre-inflation groups. Patients in the pre-inflation group received balloon massaging with preliminary extracorporeal balloon inflation in saline water before the cryoballoon was inserted into the body. Results: The baseline characteristics were similar between the two groups. Post-procedural 3-Tesla MRI revealed CE in 27.6% of patients. Symptomatic CE only occurred in two patients in the pre-inflation group. One patient had transient dysarthria and mild muscle weakness in one hand; the other patient complained of transient left upper limb weakness, left lower limb paresthesia and dysarthria. The incidence of ACE detected by cerebral MRI did not differ between the two groups to a statistically significant extent (conventional vs. pre-inflation; 22.9% vs. 29.2%; P = 0.49). In the multivariable analysis, eGFR was independently associated with the presence of ACE (odds ratio 0.95; 95% confidence interval 0.907-0.995; P = 0.03). Conclusion: In this prospective randomized study, the preliminary removal of air bubbles in heparinized saline water with extracorporeal balloon inflation had no impact on the incidence of ACE.

Primary mucoepidermoid carcinoma of the intrahepatic bile duct: A case report.

Mucoepidermoid carcinoma (MEC) is the most common salivary gland carcinoma; however, hepatobiliary MEC is extremely rare. A 74-year-old patient was diagnosed with hepatobiliary MEC after hepatectomy. We considered its origin could be the peribiliary glands. Its genome profile was similar to salivary MEC rather than standard biliary tract carcinoma.

Ten-year longitudinal investigation of astigmatism: The Yamagata Study (Funagata).

Despite numerous investigations into ocular or corneal astigmatism, the dynamic nature of astigmatism remains poorly understood. To reveal potential associations between age and astigmatism, 264 Japanese participants who underwent systemic and ophthalmological examinations in Funagata Town (Yamagata Prefecture, Japan) were evaluated over a 10-year period. Astigmatism was evaluated with regard to the cylinder power, cylinder axis, and vector analyses. Whereas the refractive cylinders showed age-related increases in patients in their 40s to 60s, the corneal cylinders did not change over 10 years. Nevertheless, cylindrical axis of the cornea demonstrated a continuous shift toward against-the-rule (ATR) astigmatism. Vector analyses revealed that the astigmatic shift toward ATR progressed continually after patients reached their 40s, although the shift did not accelerate with age. These novel insights may pave the way for the development of potential strategies for vision correction, including refractive surgeries, and vision-quality maintenance in the elderly.

Complete mitochondrial genomes of three fairy shrimps from snowmelt pools in Japan.

BACKGROUND: Fairy shrimps belong to order Anostraca, class Branchiopoda, subphylum Crustacea, and phylum Arthropoda. Three fairy shrimp species (Eubranchipus uchidai, E. asanumai, and E. hatanakai) that inhabit snowmelt pools are currently known in Japan. Whole mitochondrial genomes are useful genetic information for conducting phylogenetic analyses. Mitochondrial genome sequences for Branchiopoda members are gradually being collated. RESULTS: Six whole mitochondrial genomes from the three Eubranchipus species are presented here. Eubranchipus species share the anostracan pattern of gene arrangement in their mitochondrial genomes. The mitochondrial genomes of the Eubranchipus species have a higher GC content than those of other anostracans. Accelerated substitution rates in the lineage of Eubranchipus species were observed. CONCLUSION: This study is the first to obtain whole mitochondrial genomes for Far Eastern Eubranchipus species. We show that the nucleotide sequences of cytochrome oxidase subunit I and the 16S ribosomal RNA of E. asanumai presented in a previous study were nuclear mitochondrial DNA segments. Higher GC contents and accelerated substitution rates are specific characteristics of the mitochondrial genomes of Far Eastern Eubranchipus. The results will be useful for further investigations of the evolution of Anostraca as well as Branchiopoda.