Bioinformatic Identification of Potential RNA Alterations on the Atrial Fibrillation Remodeling from Human Pulmonary Veins.

Atrial fibrillation (AF) is the most frequent persistent arrhythmia. Many genes have been reported as a genetic background for AF. However, most transcriptome analyses of AF are limited to the atrial samples and have not been evaluated by multiple cardiac regions. In this study, we analyzed the expression levels of protein-coding and long noncoding RNAs (lncRNAs) in six cardiac regions by RNA-seq. Samples were donated from six subjects with or without persistent AF for left atria, left atrial appendages, right atria, sinoatrial nodes, left ventricles, right ventricles, and pulmonary veins (PVs), and additional four right atrial appendages samples were collected from patients undergoing mitral valve replacement. In total, 23 AF samples were compared to 23 non-AF samples. Surprisingly, the most influenced heart region in gene expression by AF was the PV, not the atria. The ion channel-related gene set was significantly enriched upon analysis of these significant genes. In addition, some significant genes are cancer-related lncRNAs in PV in AF. A co-expression network analysis could detect the functional gene clusters. In particular, the cancer-related lncRNA, such as SAMMSON and FOXCUT, belong to the gene network with the cancer-related transcription factor FOXC1. Thus, they may also play an aggravating role in the pathogenesis of AF, similar to carcinogenesis. In the least, this study suggests that (1) RNA alteration is most intense in PVs and (2) post-transcriptional gene regulation by lncRNA may contribute to the progression of AF. Through the screening analysis across the six cardiac regions, the possibility that the PV region can play a role other than paroxysmal triggering in the pathogenesis of AF was demonstrated for the first time. Future research with an increase in the number of PV samples will lead to a novel understanding of the pathophysiology of AF.

Enhanced strategy against mediastinitis with thoracic vascular graft infection: A combination of hydro-debridement with pulsed lavage and negative pressure wound therapies.

BACKGROUND: We investigated the effects of hydrodebridement with pulsed lavage (HDPL) and negative pressure (NP) wound therapies, instead of excising the prosthetic graft, in patients with postoperative thoracic vascular graft infection (TVGI). METHODS: Between 2020 and 2021, five TVGI patients aged 49.6 ± 19.4 years old underwent a combined therapy of HDPL and NP. The patients underwent a two-step procedure (first step: re-sternotomy and HDPL; second step: NP) every 3 or 4 days. After negative tissue culture, the patients underwent omentum flap wrapping and skin closure. RESULTS: No hospital death was observed. The time to skin closure was 10.8 ± 3.4 days. The time to the day in which bacteria were not cultured was 3.5 ± 2.4 days. No recurrent infections occurred for 241 ± 186 postoperative days. CONCLUSION: Our strategy for TVGI patients may contribute to (1) sufficient infection control, (2) physical rehabilitation, and (3) less invasiveness for high-risk patients.

Ruptured type A aortic dissection with saddle pulmonary embolism-like appearance on computed tomography angiography.

We present a case of ruptured type A acute aortic dissection with pulmonary trunk compression by mediastinal hematoma. This condition mimicked a pulmonary embolism on the early arterial phase of computed tomography angiography, whereas the correct diagnosis was determined from the late arterial phase and unenhanced computed tomography. We highlight the importance of carefully interpreting triphasic computed tomography angiography to assess the status of aortic dissection.

Endovascular rescue for malpositioned frozen elephant trunk into the false lumen.

We describe a case of frozen elephant trunk deployment unintentionally malpositioned into the false lumen. An 83-year-old man underwent total arch repair with a frozen elephant trunk for type A acute aortic dissection complicated by mesenteric malperfusion. However, intraoperative transesophageal echocardiography showed expansion of the false lumen in the descending aorta, suggesting a malpositioned frozen elephant trunk into the false lumen. Endovascular fenestration of the dissecting flap and subsequent endograft deployment from the inside of the malpositioned frozen elephant trunk graft to the true lumen of the descending aorta was successfully performed under intravascular ultrasound guidance.

Right coronary ostium occlusion by aortic valve tumor during systole.

Here, we present a case of acute myocardial infarction caused by an aortic valve tumor. Electrocardiography (ECG)-gated four-dimensional computed tomography revealed obstruction of the right coronary ostium by a mobile mass during systole. To ensure an accurate diagnosis of angina in patients without significant coronary artery disease, ECG-gated four-dimensional computed tomography is useful because it can simultaneously visualize the coronary ostium and arteries, aortic valve leaflets, and mass.

Discovery of novel histone lysine methyltransferase G9a/GLP (EHMT2/1) inhibitors: Design, synthesis, and structure-activity relationships of 2,4-diamino-6-methylpyrimidines.

The discovery and optimization of a novel series of G9a/GLP (EHMT2/1) inhibitors are described. Starting from known G9a/GLP inhibitor 5, efforts to explore the structure-activity relationship and optimize drug properties led to a novel compound 13, the side chain of which was converted to tetrahydroazepine. Compound 13 showed increased G9a/GLP inhibitory activity compared with compound 5. In addition, compound 13 exhibited improved human ether-a-go-go related gene (hERG) inhibitory activity over compound 5 and also improved pharmacokinetic profile in mice (oral bioavailability: 17 to 40%). Finally, the co-crystal structure of G9a in complex with compound 13 provides the basis for the further development of tetrahydroazepine-based G9a/GLP inhibitors.

Facile synthesis of the cyclohexane fragment of enacloxins, a series of antibiotics isolated from Frateuria sp. W-315.

An efficient and good yield synthesis of the cyclohexane moiety of enacyloxins, a series of antibiotics isolated from Frateuria sp. W-315, was achieved from d-quinic acid using a successive Barton-McCombie deoxygenation.

Hospital-acquired pneumonia in Japan may have a better mortality profile than HAP in the United States: a retrospective study.

The characteristics of hospital-acquired pneumonia (HAP) are not well documented. In the present study we investigated the severity and mortality, microbiological profile, and the value of Gram staining in culture-confirmed HAP in a Japanese hospital by retrospective review conducted at a Japanese university hospital. Only culture-confirmed cases with good specimen quality were included in the analysis. The clinical characteristics of HAP, as well as the causative organisms, were investigated. Furthermore, the prognostic ability of existing prediction rules were evaluated for prediction of overall mortality. Forty-two cases were enrolled in this analysis. The majority of patients were admitted to the ICU (61.9 %), and 40.5 % had ventilator-associated pneumonia (VAP). The 30-day mortality was 23.8 %, which is less than that reported in the United States. Factors commonly known to be associated with worse outcome in the USA did not appear to influence the mortality from HAP in Japan. The most frequent causative organisms were methicillin-resistant Staphylococcus aureus (MRSA), followed by Pseudomonas spp. Sensitivity and negative predictive value of Gram staining were 89.4 and 85.7 %, respectively. SMART-COP predicted 30-day mortality with an area under the ROC curve (AUC) >0.7. The characteristics of HAP in Japan differ from HAP reported in the USA. In addition to lower mortality, we found both fewer ICU cases and VAP. Gram staining of good-quality specimens demonstrated promising sensitivity to predict the causative organisms. SMART-COP predicted mortality with appropriate ROC curve (AUC).

Preferential Expression of Ca2+-Stimulable Adenylyl Cyclase III in the Supraventricular Area, including Arrhythmogenic Pulmonary Vein of the Rat Heart.

Ectopic excitability in pulmonary veins (PVs) is the major cause of atrial fibrillation. We previously reported that the inositol trisphosphate receptor in rat PV cardiomyocytes cooperates with the Na+-Ca2+ exchanger to provoke ectopic automaticity in response to norepinephrine. Here, we focused on adenylyl cyclase (AC) as another effector of norepinephrine stimulation. RT-PCR, immunohistochemistry, and Western blotting revealed that the abundant expression of Ca2+-stimulable AC3 was restricted to the supraventricular area, including the PVs. All the other AC isotypes hardly displayed any region-specific expressions. Immunostaining of isolated cardiomyocytes showed an enriched expression of AC3 along the t-tubules in PV myocytes. The cAMP-dependent response of L-type Ca2+ currents in the PV and LA cells is strengthened by the 0.1 mM intracellular Ca2+ condition, unlike in the ventricular cells. The norepinephrine-induced automaticity of PV cardiomyocytes was reversibly suppressed by 100 µM SQ22536, an adenine-like AC inhibitor. These findings suggest that the specific expression of AC3 along t-tubules may contribute to arrhythmogenic automaticity in rat PV cardiomyocytes.

Synthetic studies of enacyloxins: a series of antibiotics isolated from Frateuria sp. W-315: C1'-C8' and C9'-C15' fragments.

Synthetic studies of enacyloxins (ENXs), a series of yellow-colored, polyene-polyol antibiotics produced by Frateuria sp. W-315, are described. The C1'-C8' polyene fragments were prepared using successive Wittig reactions. The C9'-C15' and C10'-C15' fragments were constructed from (S)-isopropylideneglyceraldehyde using Yamaguchi's nucleophilic substitution reaction of acetylide to epoxide, and/or Marshall's allenylindium mediated reaction as the key steps.

Effect of neutrophil elastase inhibitor (sivelestat sodium) in the treatment of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS): a systematic review and meta-analysis.

INTRODUCTION: Sivelestat is neutrophil elastase inhibitor, which is widely used in Japan for the treatment of acute lung injury. However, the clinical efficacy of the medication has not been convincingly demonstrated. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials on sivelestat for the treatment of acute lung injury and acute respiratory distress syndrome. Studies were identified using MEDLINE, EMBASE, Cochrane library, conference proceedings, and references of included studies. Authors were contacted if necessary. ICHUSHI, the Japanese database for medical literature and conference proceedings was also used for the search, since many studies on sivelestat were published in Japanese language and not registered in major databases such as MEDLINE. The primary outcome was mortality within 28-30 days after randomization. Relative risks were pooled with the random effect model. RESULTS: 8 trials were included in the analysis. There was no difference in mortality within 28-30 days after randomization (relative risk 0.95, 95% confidence interval 0.72 to 1.26). Subgroup analysis conducted only on studies conducted in Japan showed the same result (0.59, 0.28 to 1.28). There was no difference in mechanical ventilation days (standardized mean difference -0.43, -1.12 to 0.27), but sivelestat was associated with a better short term PaO(2)/FiO(2) ratio (0.30, 0.05 to 0.56). Heterogeneity was not significant for the main analysis and funnel plot did not suggest publication bias. CONCLUSION: Sivelestat was not associated with decreased mortality, even when including studies published in Japanese language.