Deletion of Trps1 regulatory elements recapitulates postnatal hip joint abnormalities and growth retardation of Trichorhinophalangeal syndrome in mice.

Trichorhinophalangeal syndrome (TRPS) is a genetic disorder caused by point mutations or deletions in the gene-encoding transcription factor TRPS1. TRPS patients display a range of skeletal dysplasias, including reduced jaw size, short stature, and a cone-shaped digit epiphysis. Certain TRPS patients experience early onset coxarthrosis that leads to a devastating drop in their daily activities. The etiologies of congenital skeletal abnormalities of TRPS were revealed through the analysis of Trps1 mutant mouse strains. However, early postnatal lethality in Trps1 knockout mice has hampered the study of postnatal TRPS pathology. Here, through epigenomic analysis we identified two previously uncharacterized candidate gene regulatory regions in the first intron of Trps1. We deleted these regions, either individually or simultaneously, and examined their effects on skeletal morphogenesis. Animals that were deleted individually for either region displayed only modest phenotypes. In contrast, the Trps1Δint/Δint mouse strain with simultaneous deletion of both genomic regions exhibit postnatal growth retardation. This strain displayed delayed secondary ossification center formation in the long bones and misshaped hip joint development that resulted in acetabular dysplasia. Reducing one allele of the Trps1 gene in Trps1Δint mice resulted in medial patellar dislocation that has been observed in some patients with TRPS. Our novel Trps1 hypomorphic strain recapitulates many postnatal pathologies observed in human TRPS patients, thus positioning this strain as a useful animal model to study postnatal TRPS pathogenesis. Our observations also suggest that Trps1 gene expression is regulated through several regulatory elements, thus guaranteeing robust expression maintenance in skeletal cells.

The cell surface hyaluronidase TMEM2 plays an essential role in mouse neural crest cell development and survival.

Hyaluronan (HA) is a major extracellular matrix component whose tissue levels are dynamically regulated during embryonic development. Although the synthesis of HA has been shown to exert a substantial influence on embryonic morphogenesis, the functional importance of the catabolic aspect of HA turnover is poorly understood. Here, we demonstrate that the transmembrane hyaluronidase TMEM2 plays an essential role in neural crest development and the morphogenesis of neural crest derivatives, as evidenced by the presence of severe craniofacial abnormalities in Wnt1-Cre-mediated Tmem2 knockout (Tmem2CKO) mice. Neural crest cells (NCCs) are a migratory population of cells that gives rise to diverse cell lineages, including the craniofacial complex, the peripheral nervous system, and part of the heart. Analysis of Tmem2 expression during NCC formation and migration reveals that Tmem2 is expressed at the site of NCC delamination and in emigrating Sox9-positive NCCs. In Tmem2CKO embryos, the number of NCCs emigrating from the neural tube is greatly reduced. Furthermore, linage tracing reveals that the number of NCCs traversing the ventral migration pathway and the number of post-migratory neural crest derivatives are both significantly reduced in a Tmem2CKO background. In vitro studies using Tmem2-depleted mouse O9-1 neural crest cells demonstrate that Tmem2 expression is essential for the ability of these cells to form focal adhesions on and to migrate into HA-containing substrates. Additionally, we show that Tmem2-deficient NCCs exhibit increased apoptotic cell death in NCC-derived tissues, an observation that is corroborated by in vitro experiments using O9-1 cells. Collectively, our data demonstrate that TMEM2-mediated HA degradation plays an essential role in normal neural crest development. This study reveals the hitherto unrecognized functional importance of HA degradation in embryonic development and highlights the pivotal role of Tmem2 in the developmental process.

Methylation analysis of DCC gene in saliva samples is an efficient method for non-invasive detection of superficial hypopharyngeal cancer.

BACKGROUND: Advances in upper gastrointestinal endoscopic technology have enabled early detection and treatment of hypopharyngeal cancer. However, in-depth pharyngeal observations require sedation and are invasive. It is important to establish a minimally invasive and simple evaluation method to identify high-risk patients. METHODS: Eighty-seven patients with superficial hypopharyngeal cancer and 51 healthy controls were recruited. We assessed the methylation status of DCC, PTGDR1, EDNRB, and ECAD, in tissue and saliva samples and verified the diagnostic accuracy by methylation analyses of their promoter regions using quantitative methylation-specific PCR. RESULTS: Significant differences between cancer and their surrounding non-cancerous tissues were observed in the methylation values of DCC (p = 0.003), EDNRB (p = 0.001), and ECAD (p = 0.043). Using receiver operating characteristic analyses of the methylation values in saliva samples, DCC showed the highest area under the curve values for the detection of superficial hypopharyngeal cancer (0.917, 95% confidence interval = 0.864-0.970), compared with those for EDNRB (0.680) and ECAD (0.639). When the cutoff for the methylation values of DCC was set at ≥0.163, the sensitivity to detect hypopharyngeal cancer was 82.8% and the specificity was 90.2%. CONCLUSIONS: DCC methylation in saliva samples could be a non-invasive and efficient tool for early detection of hypopharyngeal cancer in high-risk patients.

GATA3 is essential for separating patterning domains during facial morphogenesis.

Neural crest cells (NCCs) within the mandibular and maxillary prominences of the first pharyngeal arch are initially competent to respond to signals from either region. However, mechanisms that are only partially understood establish developmental tissue boundaries to ensure spatially correct patterning. In the 'hinge and caps' model of facial development, signals from both ventral prominences (the caps) pattern the adjacent tissues whereas the intervening region, referred to as the maxillomandibular junction (the hinge), maintains separation of the mandibular and maxillary domains. One cap signal is GATA3, a member of the GATA family of zinc-finger transcription factors with a distinct expression pattern in the ventral-most part of the mandibular and maxillary portions of the first arch. Here, we show that disruption of Gata3 in mouse embryos leads to craniofacial microsomia and syngnathia (bony fusion of the upper and lower jaws) that results from changes in BMP4 and FGF8 gene regulatory networks within NCCs near the maxillomandibular junction. GATA3 is thus a crucial component in establishing the network of factors that functionally separate the upper and lower jaws during development.

Mixed hepatocellular carcinoma and high-grade neuroendocrine neoplasm with ambiguous histopathological features: a case report.

Well-differentiated neuroendocrine tumor (NET) and poorly differentiated neuroendocrine carcinoma (NEC) are distinct entities with different biological behavior. However, difficult cases showing equivocal morphology have been reported in some organs. Herein, we report a case of primary hepatic neuroendocrine neoplasm (NEN) with ambiguous histopathological features admixed with conventional hepatocellular carcinoma (HCC). A 70-year-old man with untreated chronic hepatitis B underwent left medial sectionectomy because of two incidental liver masses. On pathological examination, one of the resected tumors had intermingling NEN and HCC components. The NEN component consisted of relatively uniform tumor cells proliferating in trabecular, cord-like, or solid patterns with peripheral nuclear palisading. The tumor cells were immunopositive for synaptophysin, chromogranin A, cluster of differentiation 56 (CD56), and focally hepatocyte paraffin 1. p53 showed wild-type expression. The Ki-67 labeling index was 27% at the hot spot. Eleven months after the surgery, he died of a cerebral hemorrhage without evidence of recurrent liver cancer. The intermediate degree of differentiation and the modest proliferative activity can challenge the distinction between NEC and NET G3. While the coexisting HCC indicates NEC rather than NET in a pathogenetic viewpoint, such ambiguous tumor may not be as aggressive as typical NECs.

Inference of core needle biopsy whole slide images requiring definitive therapy for prostate cancer.

BACKGROUND: Prostate cancer is often a slowly progressive indolent disease. Unnecessary treatments from overdiagnosis are a significant concern, particularly low-grade disease. Active surveillance has being considered as a risk management strategy to avoid potential side effects by unnecessary radical treatment. In 2016, American Society of Clinical Oncology (ASCO) endorsed the Cancer Care Ontario (CCO) Clinical Practice Guideline on active surveillance for the management of localized prostate cancer. METHODS: Based on this guideline, we developed a deep learning model to classify prostate adenocarcinoma into indolent (applicable for active surveillance) and aggressive (necessary for definitive therapy) on core needle biopsy whole slide images (WSIs). In this study, we trained deep learning models using a combination of transfer, weakly supervised, and fully supervised learning approaches using a dataset of core needle biopsy WSIs (n=1300). In addition, we performed an inter-rater reliability evaluation on the WSI classification. RESULTS: We evaluated the models on a test set (n=645), achieving ROC-AUCs of 0.846 for indolent and 0.980 for aggressive. The inter-rater reliability evaluation showed s-scores in the range of 0.10 to 0.95, with the lowest being on the WSIs with both indolent and aggressive classification by the model, and the highest on benign WSIs. CONCLUSION: The results demonstrate the promising potential of deployment in a practical prostate adenocarcinoma histopathological diagnostic workflow system.

Pregnane X receptor (PXR) represses osteoblast differentiation through repression of the Hedgehog signaling pathway.

The pregnane X receptor (PXR, NR1I2) belongs to the nuclear receptor family and functions as a xenobiotic and endobiotic sensor by binding to various molecules through its relatively flexible ligand-binding domain. In addition to these well-known canonical roles, we previously reported that PXR represses osteoblast differentiation. However, the mechanisms underlying the PXR-mediated repression of osteoblast differentiation remains unknown. In this study, we analyzed the changes in global gene expression profiles induced by PXR in calvarial osteoblasts cultured in standard fetal bovine serum (in which PXR induces repression of differentiation), and in those cultured in charcoal-stripped fetal bovine serum (in which PXR does not induce repression of differentiation). The comparison revealed that PXR attenuated the Hedgehog-mediated signaling in culture conditions that induced PXR-mediated repression of differentiation. Real-time PCR analysis showed that PXR repressed the Hedgehog signaling-induced genes such as Gli1 and Hhip, and conversely induced the Hedgehog signaling-repressed genes such as Cdon, Boc, and Gas1. Activation of Smo-mediated signaling in osteoblasts following treatment with a Smo agonist (SAG) significantly restored Gli-mediated transcriptional activity and osteoblast differentiation. Our results demonstrate the osteoblast-autonomous effects of PXR and identify a novel regulation of Hedgehog signaling by nuclear receptors.

Direct observation of epoxy resin blocks for renal biopsy by low-vacuum scanning electron microscopy.

To improve the resolution of low-vacuum scanning electron microscopy (LVSEM), the epoxy resin block for the transmission electron microscopy (TEM) was observed directly with LVSEM. After observing ultrathin sections from renal biopsies of IgA nephropathy, membranous nephropathy, lupus nephritis, diabetic nephropathy (DM), thin basement membrane disease (TBMD), Alport's syndrome, Fabry's disease, and renal amyloidosis, the epoxy resin blocks of the same sites were observed by LVSEM and compared. The LVSEM image of the epoxy resin block corresponds to the negative of the TEM image, and when the gradation is reversed, the LVSEM image was comparable to the TEM image. At a low magnification of 100 ×, the entire specimen, including the glomerulus, was obtained. LVSEM at 5000 × magnification was sufficient to identify paramesangial deposits in IgA nephropathy and subepithelial electron-dense deposits (EDD) and spikes in membranous nephropathy. Glomerular basement membrane thickening in DM and thinning in TBMD could be sufficiently diagnosed with LVSEM at 6000 ×. Accumulation of ceramide in Fabry's disease was easily identified, but amyloid fibril could not be identified by LVSEM. LVSEM of renal biopsy epoxy resin blocks can replace TEM up to moderate magnification.

Application of convolutional neural networks for evaluating the depth of invasion of early gastric cancer based on endoscopic images.

BACKGROUND AND AIM: Recently, artificial intelligence (AI) has been used in endoscopic examination and is expected to help in endoscopic diagnosis. We evaluated the feasibility of AI using convolutional neural network (CNN) systems for evaluating the depth of invasion of early gastric cancer (EGC), based on endoscopic images. METHODS: This study used a deep CNN model, ResNet152. From patients who underwent treatment for EGC at our hospital between January 2012 and December 2016, we selected 100 consecutive patients with mucosal (M) cancers and 100 consecutive patients with cancers invading the submucosa (SM cancers). A total of 3508 non-magnifying endoscopic images of EGCs, including white-light imaging, linked color imaging, blue laser imaging-bright, and indigo-carmine dye contrast imaging, were included in this study. A total of 2288 images from 132 patients served as the development dataset, and 1220 images from 68 patients served as the testing dataset. Invasion depth was evaluated for each image and lesion. The majority vote was applied to lesion-based evaluation. RESULTS: The sensitivity, specificity, and accuracy for diagnosing M cancer were 84.9% (95% confidence interval [CI] 82.3%-87.5%), 70.7% (95% CI 66.8%-74.6%), and 78.9% (95% CI 76.6%-81.2%), respectively, for image-based evaluation, and 85.3% (95% CI 73.4%-97.2%), 82.4% (95% CI 69.5%-95.2%), and 83.8% (95% CI 75.1%-92.6%), respectively, for lesion-based evaluation. CONCLUSIONS: The application of AI using CNN to evaluate the depth of invasion of EGCs based on endoscopic images is feasible, and it is worth investing more effort to put this new technology into practical use.

Linked Color Imaging (LCI) Emphasizes the Color Changes in the Gastric Mucosa After Helicobacter pylori Eradication.

BACKGROUND: Diffuse redness is a characteristic endoscopic finding that indicates current infection of Helicobacter pylori, which is reduced after successful eradication. Linked color imaging (LCI) has been reported to improve the visibility of diffuse redness compared to white light imaging (WLI); however, quantitative evaluation has not been reported. AIMS: This study aimed to objectively evaluate the color change of the gastric mucosa after H. pylori eradication. METHODS: Images of the greater curvature of the antrum and corpus were captured, and the sites were biopsied during esophagogastroduodenoscopy (EGD) before and 1 year after eradication. The region of interest (ROI) was set around the biopsied area on the images. The color difference (ΔE) before and after eradication was calculated using the CIE L*a*b* color space. The association between the histological evaluation and the color value of the corresponding ROI was determined. RESULTS: At the antrum, there was no significant color change with either mode. At the corpus, the a* value, which reflected redness, decreased significantly after eradication with both modes (WLI: 41.2 to 36.0, LCI: 37.5 to 25.5); the b* value, reflecting yellowish, decreased with WLI, but increased significantly with LCI (WLI: 44.6 to 41.6, LCI: 23.9 to 29.2). The ΔE was significantly larger with LCI than with WLI (16.5 vs. 8.6). The a* values at the corpus were generally associated with histological neutrophil infiltration. CONCLUSIONS: Quantitative evaluation revealed that LCI emphasizes the change in color of the gastric mucosa due to the reduction in diffuse redness.

A prospective multicenter study of the magnifying endoscopic evaluation of the invasion depth of superficial esophageal cancers.

BACKGROUND: Treatment strategies for superficial esophageal squamous cell carcinoma (SESCC) are determined mainly on the basis of the invasion depth. The Japan Esophageal Society (JES) developed a simplified magnifying endoscopic classification for estimating the invasion depth of SESCC. We aimed to evaluate its accuracy. METHODS: We prospectively applied the JES classification for estimating the invasion depth of SESCC to 204 consecutive lesions from 6 hospitals in Japan between April 2016 and October 2018. We analyzed the accuracy of the endoscopic diagnosis by adding the following two categories to the JES classification: ≥ 7 mm lesion in B2 vessels (defined as B2 ≥ 7 mm) and B2 vessels with inflammation (defined as B2i). RESULTS: After applying the exclusion criteria, 201 lesions remained in the analysis. The diagnostic value of type B1, B2, B3 vessels were as follows: sensitivity, 93.9%, 68.0%, 25.0%; specificity, 81.1%, 89.2%, 99.4%; positive predictive value (PPV), 95.6%, 47.2%, 75.0%; negative predictive value (NPV), 75.0%, 95.1%, 95.4%; and accuracy, 91.5%, 86.5%, 95.0%, respectively. A retrospective analysis showed that the diagnostic accuracy was higher in type B2 vessels (86.5% to 92.0%). An avascular area (AVA) was found in 55 (27%) of the 201 lesions, which tended to be associated with a deeper pathological diagnosis of each Type B vessel. In an additional analysis, B2 ≥ 7 mm and B2i improved the diagnostic accuracy of type B2 vessels from 86.5% to 92.0%. CONCLUSIONS: The JES classification is useful for estimating the invasion depth of SESCC. The diagnostic accuracy for type B2 vessels was low, which may be improved by using B2 ≥ 7 mm and B2i.

Kruppel-like Factors in Skeletal Physiology and Pathologies.

Kruppel-like factors (KLFs) belong to a large group of zinc finger-containing transcription factors with amino acid sequences resembling the Drosophila gap gene Krüppel. Since the first report of molecular cloning of the KLF family gene, the number of KLFs has increased rapidly. Currently, 17 murine and human KLFs are known to play crucial roles in the regulation of transcription, cell proliferation, cellular differentiation, stem cell maintenance, and tissue and organ pathogenesis. Recent evidence has shown that many KLF family molecules affect skeletal cells and regulate their differentiation and function. This review summarizes the current understanding of the unique roles of each KLF in skeletal cells during normal development and skeletal pathologies.

Analysis of purple urine bag syndrome by low vacuum scanning electron microscopy.

Purple urine bag syndrome (PUBS) is seen in the prolonged indwelling bladder catheters, and the mechanism of its onset was investigated using low vacuum scanning electron microscopy (LVSEM), which enables us to study the 3D structure of urinary sediments and urine bag walls. The urinary sediment and urine bags of 2 cases of PUBS were observed by LVSEM. The urine was brown turbid urine with a pH of 8.5, and magnesium phosphate stones and granules were observed in the urinary sediment together with Gram-positive and Gram-negative bacilli. Bacteria that moved by Brownian motion were observed with a dark-field microscope. LVSEM showed granular crystals around the bacilli, cocci, or mycelium that adhered to the walls of the bag. Granular crystals were dissolved in chloroform and presumed to be a mixture of the bacterial metabolites indigo blue and indirubin red. LVSEM also detected unusual tubular and honeycomb-like graphene in the urinary sediments, which were derived from the inner layer of the silicon elastomer-coated rubber catheter. LVSEM revealed purple crystals produced by bacteria or fungi attached to the urine bag that caused PUBS.

Intracellular density is a novel indicator of differentiation stages of murine osteoblast lineage cells.

Osteoblasts are primary bone-making cells originating from mesenchymal stem cells (MSCs) in the bone marrow. The differentiation of MSCs to mature osteoblasts involves an intermediate stage called preosteoblasts, but the details of this process remain unclear. This study focused on the intracellular density of immature osteoblast lineage cells and hypothesized that the density might vary during differentiation and might be associated with the differentiation stages of osteoblast lineage cells. This study aimed to clarify the relationship between intracellular density and differentiation stages using density gradient centrifugation. Primary murine bone marrow stromal cell cultures were prepared in an osteogenic induction medium, and cells were separated into three fractions (low, intermediate, and high-density). The high-density fraction showed elevated expression of osteoblast differentiation markers (Sp7, Col1a1, Spp1, and Bglap) and low expression of MSC surface markers (Sca-1, CD73, CD105, and CD106). In contrast, the low-density fraction showed a high expression of MSC surface markers. These results indicated that intracellular density increased during differentiation from preosteoblasts to committed osteoblasts. Intracellular density may be a novel indicator for osteoblast differentiation stages. Density gradient centrifugation is a novel technique to study the process by which preosteoblasts transform into bone-forming cells.

Renal Dysfunction as a Predictor of Slow-Flow/No-Reflow Phenomenon and Impaired ST Segment Resolution After Percutaneous Coronary Intervention in ST-Elevation Myocardial Infarction With Initial Thrombolysis in Myocardial Infarction Grade 0.

BACKGROUND: The slow-flow/no-reflow phenomenon and impaired ST segment resolution (STR) following primary percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction (STEMI) predict unfavorable prognosis and are characterized by obstruction of the coronary microvascular. Several predictors of slow-flow/no-reflow have been revealed, but few studies have investigated predictors of slow-flow/no-reflow and STR exclusively in acute myocardial infarction patients with initial Thrombolysis in Myocardial Infarction (TIMI) Grade 0.Methods and Results:In all, 279 STEMI patients with initial TIMI Grade 0 were enrolled in the study. Slow-flow/no-reflow was defined as TIMI Grade <3 by angiography after PCI, and impaired STR was defined as STR <50% on an electrocardiogram after PCI. Slow-flow/no-reflow was observed in 31 patients. In multivariate analysis, estimated glomerular filtration rate (eGFR; odds ratio [OR] 0.97; P=0.007), a history of cerebrovascular disease (OR 4.65, P=0.007), time to recanalization ≥4 h (OR 2.76, P=0.023), and systolic blood pressure ≤90 mmHg (OR 3.45, P=0.046) were independent predictors of slow-flow/no-reflow. Impaired STR was observed in 102 of 248 patients with TIMI Grade 3. In multivariate analysis, eGFR (OR 0.94, P<0.001) and occlusion of the left anterior descending artery (OR 4.48, P<0.001) were independent predictors of impaired STR; eGFR was the only independent predictor of both slow-flow/no-reflow and impaired STR. CONCLUSIONS: Renal dysfunction may be related to coronary microvascular dysfunction and obstruction.

Effects of empagliflozin in different phases of diabetes mellitus-related cardiomyopathy: a prospective observational study.

BACKGROUND: Diabetes mellitus-related cardiomyopathy (DMCMP), defined as left ventricular (LV) dysfunction caused by hyperglycemia in the absence of coronary artery disease, leads to heart failure (HF). Previous studies have shown that treatment with sodium-glucose co-transporter 2 inhibitor (SGLT2i) reduces the risk of exacerbation of HF. The beneficial effects of SGLT2i on HF depend not only on indirect actions such as osmotic diuresis but also on direct actions on the myocardium, leading to improvements in LV function. However, it remains unclear whether SGLT2i treatment is equally effective in any phase of DMCMP. The aim of this observational study was to compare the efficacy of SGLT2i treatment on LV dysfunction between early and advanced DMCMP. METHODS: Thirty-five symptomatic non-ischemic HF patients with LV ejection fraction > 40% and type 2 diabetes mellitus (T2DM) treated with empagliflozin (EMPA group) and 20 controls treated without SGLT2i were enrolled. According to the myocardial extracellular volume fraction (ECV), a reliable marker of cardiac fibrosis quantified by cardiac magnetic resonance, the EMPA group was further divided into early DMCMP (n = 16, ECV ≤ 30%) and advanced DMCMP (n = 19, ECV > 30%) groups and followed up prospectively. Echocardiography was performed at baseline and after 12 months. LV function assessed as LV global longitudinal strain (LVGLS) and the ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E/e') were compared. RESULTS: ECV was strongly correlated with T2DM duration (r2 = 0.65, p < 0.001). At baseline, each group had a similar background. After 12 months, the EMPA group, especially the early DMCMP group, showed remarkable improvements in LVGLS (ΔLVGLS: 2.9 ± 3.0% (EMPA) vs. 0.6 ± 2.2% (controls), p = 0.005, and 4.6 ± 1.5% (early DMCMP) vs. 1.6 ± 3.3% (advanced DMCMP), p = 0.003) and E/e' (ΔE/e': - 1.5 ± 4.7 vs. - 0.3 ± 3.0, p = 0.253, and - 3.4 ± 5.5 vs. - 0.1 ± 3.5, p = 0.043). CONCLUSIONS: The positive effects of empagliflozin on LV dysfunction were more remarkable in early than in advanced DMCMP. Early intervention of SGLT2i for DMCMP may be preferable.

Gastric Adenoma: A High Incidence Rate of Developing Carcinoma and Risk of Metachronous Gastric Cancer according to Long-Term Follow-Up.

INTRODUCTION: Gastric adenomas are histologically defined as benign epithelial tumors. While some of them remain adenomas for a long time, others progress to carcinomas. However, long-term outcomes of such cases are not entirely clear. Here, we explored the risk factors and incidence of developing carcinoma from gastric adenoma as well as metachronous gastric cancer. METHODS: This study was conducted at a facility that adopted a follow-up strategy for gastric adenoma. Lesions histologically diagnosed as gastric intestinal-type adenomas between January 2004 and December 2016 were analyzed. Clinicopathological data were collected from patients' medical records, and histological changes from adenoma to carcinoma during endoscopic follow-up and risk factors of cancer development were evaluated. RESULTS: This study involved 409 lesions from 376 patients. The analysis of the development of gastric cancer from adenoma and metachronous gastric cancer was ultimately performed for 282 lesions from 258 patients and 269 lesions from 246 patients, respectively, due to different follow-up periods. The 5-year rate of carcinoma development was 34.0%. Risk factors for carcinoma development upon multivariate analysis were lesion size ≥15 mm and morphological depression. All cases with both factors developed gastric carcinoma, and 50.5% of those with either factor developed carcinoma within 5 years. Gastric adenoma was accompanied by metachronous gastric cancer in 1.5% of the patients annually. The only risk factor for metachronous gastric carcinoma was primary adenoma progressing to carcinoma during the follow-up period. DISCUSSION/CONCLUSION: Given the high rate of carcinoma development in patients with risk factors, resection of gastric adenoma should be considered during the initial examination. Careful observation and follow-up should also be conducted to detect not only changes in the primary adenoma but also the occurrence of metachronous carcinoma, especially in cases of adenoma progressing to carcinoma.

Rate Versus Rhythm Control in Tachycardia-Induced Cardiomyopathy Patients with Persistent Atrial Flutter.

Tachycardia-induced cardiomyopathy (TIC) is a potentially reversible cardiomyopathy caused by tachyarrhythmia. For atrial flutter (AFL) -induced TIC, a rhythm control strategy, such as catheter ablation, has been recommended. However, the efficacy of rate control has remained unclear due to the difficulty of achieving control using arrhythmic medications.We prospectively assessed 47 symptomatic heart failure (HF) patients with left ventricular ejection fraction (LVEF) < 50% and suspected persistent AFL-induced TIC. Patients were divided into the rhythm control strategy (n = 22; treatment with catheter ablation or electrical cardioversion) and rate control strategy (n = 25; treatment with bisoprolol) groups. The latter was further divided into the strict rate control strategy (average heart rate < 80 bpm) and lenient rate control strategy (average heart rate < 110 bpm) subgroups. The primary outcome was left ventricular (LV) function recovery, which was defined as an increase in LVEF ≥ 20% or to a value of ≥ 55% after 6 months.In the rhythm control strategy group, more patients achieved LV function recovery after 6 months (95.2% versus 60.9%, P = 0.010). The cumulative incidence of worsening HF events was significantly higher in the rate control strategy group than in the rhythm control strategy group (hazard ratio, 4.66; 95% confidence interval, 1.01-21.57). The subgroup study revealed the advantage of the strict rate control strategy for achieving LV function recovery (83.3% versus 36.4%, P = 0.036).The rate control strategy was significantly inferior to the rhythm control strategy for the LV function recovery in TIC patients with persistent AFL. Our findings suggest that the strict rate control strategy should be aimed if the rhythm control strategy cannot be performed.

[Clinical characteristics of five patients with gastric emphysema].

Gastric emphysema is a rare condition in which gas from a nonbacterial source accumulates within the gastric wall. In this study, we retrospectively analyzed the cases of five patients who were diagnosed with gastric emphysema at the Okayama University Hospital between January 2010 and April 2021, to reveal the clinical features of the disease. Based on their reviews, we revealed that:i) gastric emphysema occurred in hospitalized bedridden patients (n=5), such as those during/after endotracheal intubation (n=3), those undergoing gastric tube placement (n=3), those undergoing percutaneous endoscopic gastrostomy (n=1), and those undergoing treatment for cerebral infarction (n=1);ii) gastric emphysema was accompanied by the accumulation of gas in the portal (n=4) or gastric veins (n=1);iii) gastric emphysema was accompanied by colon wall thickness increase (n=4);iv) esophagogastroduodenoscopy showed redness, erosions, coarse mucosa, and/or ulcers (n=5);v) a clear boundary between the damaged area and the intact mucosa was observed (n=5);vi) the anterior wall of the stomach was less affected (n=4);vii) mucosal damage was predominant in the gastric folds, whereas the furrow of the mucosa was less affected;and viii) treatment with enteral nutrition suspension and the administration of proton pump inhibitors and antibiotics resulted in the recovery of patients from gastric emphysema (n=5). These results indicate that patients with gastric emphysema have distinct clinical, endoscopic, and radiological features. Furthermore, our results show that these patients can be conservatively managed.

Kruppel-like factor 4 upregulates matrix metalloproteinase 13 expression in chondrocytes via mRNA stabilization.

Matrix metalloproteinase 13 (MMP13) is indispensable for normal skeletal development and is also a principal proteinase responsible for articular joint pathologies. MMP13 mRNA level needs to be tightly regulated in both positive and negative manners to achieve normal development and also to prevent joint destruction. We showed previously that Kruppel-like factor 4 (KLF4) strongly induces the expression of members of the MMP family of genes including that for MMP13 in cultured chondrocytes. Through expression-based screening of approximately 400 compounds, we identified several that efficiently downregulated MMP13 gene expression induced by KLF4. Compounds grouped as topoisomerase inhibitors (transcriptional inhibitors) downregulated MMP13 expression levels, which proved the validity of our screening method. In this screening, trichostatin A (TSA) was identified as one of the most potent repressors. Mechanistically, increased MMP13 mRNA levels induced by KLF4 were not mainly caused by increased rates of RNA polymerase II-mediated MMP13 transcription, but arose from escaping mRNA decay. TSA treatment almost completely blunted the effect of KLF4. Importantly, KLF4 was detected in chondrocytes at the joint destruction sites in a rodent model of osteoarthritis. Our results partially explain how KLF4 regulates numerous proteinase gene expressions simultaneously in chondrocytes. Also, these observations suggest that modulation of KLF4 activity or expression could be a novel therapeutic target for osteoarthritis.