ABSTRACT
BACKGROUND: Chest x-ray is a basic, cost-effective, and widely available imaging method that is used for static assessments of organic diseases and anatomical abnormalities, but its ability to estimate dynamic measurements such as pulmonary function is unknown. We aimed to estimate two major pulmonary functions from chest x-rays. METHODS: In this retrospective model development and validation study, we trained, validated, and externally tested a deep learning-based artificial intelligence (AI) model to estimate forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) from chest x-rays. We included consecutively collected results of spirometry and any associated chest x-rays that had been obtained between July 1, 2003, and Dec 31, 2021, from five institutions in Japan (labelled institutions A-E). Eligible x-rays had been acquired within 14 days of spirometry and were labelled with the FVC and FEV1. X-rays from three institutions (A-C) were used for training, validation, and internal testing, with the testing dataset being independent of the training and validation datasets, and then x-rays from the two other institutions (D and E) were used for independent external testing. Performance for estimating FVC and FEV1 was evaluated by calculating the Pearson's correlation coefficient (r), intraclass correlation coefficient (ICC), mean square error (MSE), root mean square error (RMSE), and mean absolute error (MAE) compared with the results of spirometry. FINDINGS: We included 141 734 x-ray and spirometry pairs from 81 902 patients from the five institutions. The training, validation, and internal test datasets included 134 307 x-rays from 75 768 patients (37 718 [50%] female, 38 050 [50%] male; mean age 56 years [SD 18]), and the external test datasets included 2137 x-rays from 1861 patients (742 [40%] female, 1119 [60%] male; mean age 65 years [SD 17]) from institution D and 5290 x-rays from 4273 patients (1972 [46%] female, 2301 [54%] male; mean age 63 years [SD 17]) from institution E. External testing for FVC yielded r values of 0·91 (99% CI 0·90-0·92) for institution D and 0·90 (0·89-0·91) for institution E, ICC of 0·91 (99% CI 0·90-0·92) and 0·89 (0·88-0·90), MSE of 0·17 L2 (99% CI 0·15-0·19) and 0·17 L2 (0·16-0·19), RMSE of 0·41 L (99% CI 0·39-0·43) and 0·41 L (0·39-0·43), and MAE of 0·31 L (99% CI 0·29-0·32) and 0·31 L (0·30-0·32). External testing for FEV1 yielded r values of 0·91 (99% CI 0·90-0·92) for institution D and 0·91 (0·90-0·91) for institution E, ICC of 0·90 (99% CI 0·89-0·91) and 0·90 (0·90-0·91), MSE of 0·13 L2 (99% CI 0·12-0·15) and 0·11 L2 (0·10-0·12), RMSE of 0·37 L (99% CI 0·35-0·38) and 0·33 L (0·32-0·35), and MAE of 0·28 L (99% CI 0·27-0·29) and 0·25 L (0·25-0·26). INTERPRETATION: This deep learning model allowed estimation of FVC and FEV1 from chest x-rays, showing high agreement with spirometry. The model offers an alternative to spirometry for assessing pulmonary function, which is especially useful for patients who are unable to undergo spirometry, and might enhance the customisation of CT imaging protocols based on insights gained from chest x-rays, improving the diagnosis and management of lung diseases. Future studies should investigate the performance of this AI model in combination with clinical information to enable more appropriate and targeted use. FUNDING: None.
Subject(s)
Deep Learning , Humans , Japan , Male , Female , Retrospective Studies , Middle Aged , Aged , Vital Capacity , Lung/diagnostic imaging , Lung/physiology , Forced Expiratory Volume , Radiography, Thoracic , Spirometry/methods , Adult , Respiratory Function Tests/methodsABSTRACT
The objective of the present study was to comprehensively evaluate whether body measurement traits, including body weight and body size, could be used as indicators of genetic selection for feed efficiency and carcass traits in Japanese Black steers. First, we estimated the genetic parameters for body measurements, feed efficiency, and carcass traits. Second, we estimated the correlated responses in feed efficiency and carcass traits when selection was applied to one or multiple-body measurement traits. In total, 4,578 Japanese Black steers with phenotypic values of residual feed intake (RFI) and residual body weight gain (RG) as feed efficiency traits and carcass weight (CWT) and beef marbling standard (BMS) as carcass traits were used. Eleven body measurement traits were measured at the start and finish of the fattening periods (BMT1 and BMT2, respectively), and their growth during the fattening period (BMT3) was used for genetic analyses. The results of genetic parameters showed that the heritability estimates were low to moderate (0.10 to 0.66), and the genetic correlations among body measurement traits were also estimated to be positively moderate to high in each measuring point (0.23 to 0.99). The genetic correlations of body measurement traits with RFI and BMS were estimated to be low (-0.14 to 0.30 and -0.17 to 0.35, respectively), but those with CWT were positively low to high (0.12 to 0.97). The genetic correlation estimates between BMT3 and RG were moderate to high (0.38 to 0.78). Second, correlated responses were estimated under positive selection for body measurement traits. Positive selection for BMT2 and BMT3 increased CWT and RG; however, positive selection for body measurement traits resulted in no change in RFI and BMS. Favorable directions of genetic gains, which were positive for RG, CWT, and BMS and negative for RFI, were obtained by selection indices, including multiple traits in BMT1. Our results suggest that using only one-body measurement trait as an indicator of genetic selection for RFI is difficult. However, body measurement traits can be indirect indicators of improved RG. Our results also suggest that genetic improvement of both RFI and RG without reducing CWT and BMS could be achieved using selection indices that account for a balance of body conformation using multiple-body measurement traits in Japanese Black cattle.
Improving feed efficiency is a key objective in the beef cattle industry. Still, high costs and logistical efforts make measuring daily feed intake per animal in many cattle difficult. Here, we focused on body measurement traits, including body weight and body size, as indirect indicators of feed efficiency in Japanese Black cattle, as measuring these traits is easy and inexpensive. When selection was applied to one- or multiple-body measurement traits, we estimated the correlated responses in feed efficiency and carcass traits. We also estimated the genetic relationships of body measurement traits with feed efficiency and carcass traits. Our results showed body measurement traits were heritable and had weak genetic relationships with residual feed intake. Regarding the possibility of genetic selection for residual feed intake using body measurement traits as indirect indicators, our results suggest that using a single body measurement trait as an indicator is difficult. However, our results also suggest that the genetic improvement of residual feed intake could be possible using selection indices that account for a balance of body conformation using multiple-body measurement traits in Japanese Black cattle.
Subject(s)
Selection, Genetic , Animals , Cattle/genetics , Cattle/physiology , Cattle/growth & development , Male , Weight Gain/genetics , Body Composition/genetics , Body Weight/genetics , Breeding , Phenotype , Animal Feed/analysis , Body Size/geneticsABSTRACT
We used standardized detection ratio to evaluate the quality of nasal upper gastrointestinal endoscopy screening for the secondary prevention of gastric cancer, and examined the gastric cancer risk in the era of total Helicobacter pylori (H. pylori) eradication. We performed 21,931 upper gastrointestinal endoscopies, 77 subjects were diagnosed with gastric cancer. Of these, 28 had gastric cancer after H. pylori eradication, 47 had gastric cancer with H. pylori-positive or others, and 2 had H. pylori-negative gastric cancer. The Standardized detection ratios for men and women were 5.33 and 4.82, respectively. Multivariable logistic regression analyses performed exclusively on first endoscopy subjects, excluding H. pylori-negative gastric cancer, revealed that smoking was a risk factor for developing gastric cancer (adjusted odds ratio, 3.31; 95% confidence interval, 1.65-6.64; pâ =â 0.001). A statistically significant interaction was found between daily alcohol consumpption and H. pylori eradication on gastric cancer development (pâ =â 0.005). In conclusion, relatively high standardized detection ratio values suggest that an appropriate endoscopic diagnosis of gastric cancer should be performed during a medical check-up. Smoking is a risk factor for developing gastric cancer, and continued alcohol consumption suggests a possible risk for developing gastric cancer after H. pylori eradication.
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BACKGROUND AND AIM: Nonsteroidal anti-inflammatory drugs (NSAIDs) damage the small intestine via neutrophil infiltration driven by the mucosal invasion of enterobacteria. The antimicrobial function of neutrophils is partially dependent on neutrophil extracellular traps (NETs). Excessive NET formation has been associated with several inflammatory diseases. Here, we aimed to investigate the role of NETs in NSAID-induced small intestinal damage using human samples and an experimental mouse model. METHODS: Human small intestine specimens were obtained from NSAID users during double-balloon enteroscopy. Wild-type, protein arginine deiminase 4 (PAD4) knockout, and antibiotic-treated mice were administered indomethacin to induce small intestinal injury. The expression of NET-associated proteins, including PAD4, citrullinated histone H3 (CitH3), cell-free DNA, and myeloperoxidase (MPO), was evaluated. RESULTS: The double-positive stained area with CitH3 and MPO, which is specific for neutrophil-derived extracellular traps, was significantly high in the injured small intestinal mucosa of NSAID users. In a mouse model, small intestinal damage developed at 6 h after indomethacin administration, accompanied by increased mRNA levels of interleukin-1ß and keratinocyte chemoattractant and elevated NET-associated protein levels of PAD4, CitH3, and MPO in small intestine and serum levels of cell-free DNA. Both genetic deletion and pharmacological inhibition of PAD4 attenuated this damage by reducing the mRNA expression of inflammatory cytokines and NET-associated proteins. Furthermore, mice pretreated with antibiotics showed resistance to indomethacin-induced small intestinal damage, with less NET formation. CONCLUSION: These results suggest that NETs aggravate NSAID-induced small intestinal injury. Therefore, NET inhibition could be a potential treatment for NSAID-induced small intestinal injury.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal , Disease Models, Animal , Extracellular Traps , Indomethacin , Intestine, Small , Peroxidase , Protein-Arginine Deiminase Type 4 , Animals , Extracellular Traps/metabolism , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Intestine, Small/pathology , Intestine, Small/metabolism , Protein-Arginine Deiminase Type 4/metabolism , Humans , Indomethacin/adverse effects , Peroxidase/metabolism , Male , Neutrophils/metabolism , Histones/metabolism , Mice , Mice, Inbred C57BL , Intestinal Diseases/chemically induced , Intestinal Diseases/pathology , Interleukin-1beta/metabolism , Intestinal Mucosa/pathology , Intestinal Mucosa/drug effects , Intestinal Mucosa/metabolism , Mice, Knockout , Female , Cell-Free Nucleic Acids/blood , CitrullinationABSTRACT
Reactive oxygen species (ROS) are associated with oocyte maturation inhibition, and N-acetyl-l-cysteine (NAC) partially reduces their harmful effects. Mitochondrial E3 ubiquitin ligase 1 (Mul1) localizes to the mitochondrial outer membrane. We found that female Mul1-deficient mice are infertile, and their oocytes contain high ROS concentrations. After fertilization, Mul1-deficient embryos showed a DNA damage response (DDR) and abnormal preimplantation embryogenesis, which was rescued by NAC addition and ROS depletion. These observations clearly demonstrate that loss of Mul1 in oocytes increases ROS concentrations and triggers DDR, resulting in abnormal preimplantation embryogenesis. We conclude that manipulating the mitochondrial ROS levels in oocytes may be a potential therapeutic approach to target infertility.
Subject(s)
Embryonic Development , Oocytes , Reactive Oxygen Species , Ubiquitin-Protein Ligases , Animals , Oocytes/metabolism , Reactive Oxygen Species/metabolism , Female , Embryonic Development/genetics , Mice , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/deficiency , DNA Damage , Acetylcysteine/pharmacology , Blastocyst/metabolism , Mitochondrial Membranes/metabolism , Mice, Knockout , Mitochondrial Proteins/metabolism , Mitochondrial Proteins/genetics , Mitochondrial Proteins/deficiency , Mitochondria/metabolismABSTRACT
Esophageal submucosal hematoma is a rare, often incidental complication of therapeutic endoscopic procedures marked by disrupted blood vessels beneath the esophageal mucosa, forming a hematoma. We report the unique case of a severely thin and alcoholic 38-year-old woman with a history of reflux esophagitis who developed an esophageal submucosal hematoma during an unsedated transnasal endoscopy for health check-up. During the procedure, the patient experienced strong vomiting reflexes and vomited blood, leading to the initial suspicion of either Mallory-Weiss syndrome or epistaxis. However, subsequent sedated endoscopy revealed an esophageal submucosal tumor-like lesion and a mucosal laceration with blood clots, prompting a dual diagnosis of esophageal submucosal hematoma and Mallory-Weiss syndrome. The bleeding was not severe enough to require hemostatic intervention. The patient opted for conservative treatment with vonoprazan, which resulted in the improvement and healing of the hematoma within 28 days. This is the first report of an esophageal submucosal hematoma during transnasal endoscopy and emphasizes the importance of including an esophageal submucosal hematoma and Mallory-Weiss syndrome in the differential diagnosis of hematemesis encountered in similar scenarios. Factors such as severe thinness, daily alcohol consumption, and reflux esophagitis may have possibly contributed to the development of the esophageal submucosal hematoma in this patient.
ABSTRACT
Protein phosphatase 6 (PP6) is a serine/threonine (Ser/Thr) protein phosphatase, and its catalytic subunit is Ppp6c. PP6 forms the PP2A subfamily with PP2A and PP4. The diverse phenotypes observed following small interfering RNA (siRNA)-based knockdown of Ppp6c in cultured mammalian cells suggest that PP6 plays roles in cell growth and DNA repair. There is also evidence that PP6 regulates nuclear factor kappa B (NF-κB) signaling and mitogen-activated protein kinases and inactivates transforming growth factor-ß-activated kinase 1 (TAK1). Loss of Ppp6c causes several abnormalities, including those of T cell and regulatory T cell function, neurogenesis, oogenesis, and spermatogenesis. PP2A has been reported to play an important role in erythropoiesis. However, the roles of PP6 in other hematopoietic cells have not been investigated. We generated Ppp6cfl/fl;Tie2-Cre (Ppp6cTKO) mice, in which Ppp6c was specifically deleted in hematopoietic and vascular endothelial cells. Ppp6cTKO mice displayed embryonic lethality. Ppp6c deficiency increased the number of dead cells and decreased the percentages of erythroid and monocytic cells during fetal hematopoiesis. By contrast, the number of Lin-Sca-1+c-Kit+ cells, which give rise to all hematopoietic cells, was slightly increased, but their colony-forming cell activity was markedly decreased. Ppp6c deficiency also increased phosphorylation of extracellular signal-regulated kinase 1/2 and c-Jun amino (N)-terminal kinase in fetal liver hematopoietic cells.
Subject(s)
Hematopoiesis , Phosphoprotein Phosphatases , Animals , Female , Mice , Embryo Loss/genetics , Embryo Loss/pathology , Endothelial Cells/metabolism , Endothelial Cells/pathology , Hematopoietic Stem Cells/metabolism , MAP Kinase Kinase Kinases/genetics , MAP Kinase Kinase Kinases/metabolism , Mice, Knockout , Phosphoprotein Phosphatases/genetics , Phosphoprotein Phosphatases/metabolism , Phosphoprotein Phosphatases/deficiencyABSTRACT
Obg-like ATPase 1 (OLA1) is a binding protein of Breast cancer gene 1 (BRCA1), germline pathogenic variants of which cause hereditary breast cancer. Cancer-associated variants of BRCA1 and OLA1 are deficient in the regulation of centrosome number. Although OLA1 might function as a tumor suppressor, the relevance of OLA1 deficiency to carcinogenesis is unclear. Here, we generated Ola1 knockout mice. Aged female Ola1+/- mice developed lymphoproliferative diseases, including malignant lymphoma. The lymphoma tissues had low expression of Ola1 and an increase in the number of cells with centrosome amplification. Interestingly, the proportion of cells with centrosome amplification in normal spleen from Ola1+/- mice was higher in male mice than in female mice. In human cells, estrogen stimulation attenuated centrosome amplification induced by OLA1 knockdown. Previous reports indicate that prominent centrosome amplification causes cell death but does not promote tumorigenesis. Thus, in the current study, the mild centrosome amplification observed under estrogen stimulation in Ola1+/- female mice is likely more tumorigenic than the prominent centrosome amplification observed in Ola1+/- male mice. Our findings provide a possible sex-dependent mechanism of the tumor suppressor function of OLA1.
Subject(s)
BRCA1 Protein , Centrosome , Estrogens , Mice, Knockout , Animals , Female , Humans , Male , Mice , BRCA1 Protein/genetics , BRCA1 Protein/metabolism , Centrosome/metabolism , Estrogens/metabolism , Lymphoma/metabolism , Lymphoma/genetics , Lymphoma/pathologyABSTRACT
Protein phosphatase 6 is a Ser/Thr protein phosphatase and its catalytic subunit is Ppp6c. Ppp6c is thought to be indispensable for proper growth of normal cells. On the other hand, loss of Ppp6c accelerates growth of oncogenic Ras-expressing cells. Although it has been studied in multiple contexts, the role(s) of Ppp6c in cell proliferation remains controversial. It is unclear how oncogenic K-Ras overcomes cell proliferation failure induced by Ppp6c deficiency; therefore, in this study, we attempted to shed light on how oncogenic K-Ras modulates tumor cell growth. Contrary to our expectations, loss of Ppp6c decreased proliferation, anchorage-independent growth in soft agar, and tumor formation of oncogenic Ras-expressing mouse embryonic fibroblasts (MEFs). These findings show that oncogenic K-RasG12V cannot overcome proliferation failure caused by loss of Ppp6c in MEFs.
Subject(s)
Fibroblasts , Phosphoprotein Phosphatases , Proto-Oncogene Proteins p21(ras) , Animals , Mice , Cell Proliferation/genetics , Fibroblasts/metabolism , Phosphoprotein Phosphatases/genetics , Phosphoprotein Phosphatases/metabolism , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolismABSTRACT
OBJECTIVE: The main goal of our current study was to improve the growth curve of meat animals by decreasing the birth weight while achieving a finishing weight that is the same as that before selection but at younger age. METHODS: Random regression model was developed to derive various selection indices to achieve desired gains in body weight at target time points throughout the fattening process. We considered absolute and proportional gains at specific ages (in weeks) and for various stages (i.e., early, middle, late) during the fattening process. RESULTS: The point gain index was particularly easy to use because breeders can assign a specific age (in weeks) as a time point and model either the actual weight gain desired or a scaled percentage gain in body weight. CONCLUSION: The point gain index we developed can achieve the desired weight gain at any given postnatal week of the growing process and is an easy-to-use and practical option for improving the growth curve.
ABSTRACT
Protein phosphatase 6 (PP6) is a Ser/Thr protein phosphatase with the catalytic subunit Ppp6c. Recent cell-level studies have revealed that Ppp6c knockdown suppresses neurite outgrowth, suggesting that Ppp6c is involved in the development of the nervous system. We found that the function of PP6 in neurons is essential for mouse survival after birth, as all neural-stem-cell-specific KO (Ppp6cNKO) and neuron-specific KO mice died within 2 days of birth. By contrast, approximately 40 % of oligodendrocyte-specific KO mice died within 2 days of birth, whereas others survived until weaning or later, suggesting that the lethality of PP6 loss differs between neurons and oligodendrocytes. Furthermore, the fetal brain of Ppp6cNKO mice exhibited decreased numbers of neurons in layers V-VI and interneurons in layer I of the neocortex. These results suggest for the first time that Ppp6c is essential for neonatal survival and proper development of neurons and interneurons in the neocortex.
Subject(s)
Perinatal Death , Humans , Female , Mice , Animals , Neurons/metabolism , Interneurons/metabolism , Phosphoprotein Phosphatases/metabolismABSTRACT
Background: Xanthine oxidoreductase (XOR) inhibitor administration, known to reduce uric acid and reactive oxygen species (ROS) production, also improves vascular endothelial function (VEF). This cross-sectional study examined our hypothesis that XOR contributes to impaired VEF through ROS but not uric acid production. Methods: In 395 subjects (196 males, 199 females) without urate-lowering agent administration who underwent a health examination, plasma XOR activity was determined using our highly sensitive assay based on [13C2,15N2] xanthine and liquid chromatography/triple quadrupole mass spectrometry. For VEF evaluation, flow-mediated dilatation (FMD) in the brachial artery was determined by ultrasound, with physical and laboratory measurements also obtained. Results: The median values for plasma XOR activity, serum uric acid, and FMD were 26.6 pmol/h/mL, 5.4 mg/dL, and 6.2%, respectively. Simple regression analysis showed weak correlations of both log plasma XOR activity and serum uric acid level with FMD (r = -0.213, p < 0.001 and r = -0.139, p = 0.006, respectively). However, multivariable linear regression analyses revealed that log plasma XOR activity but not serum uric acid level remained associated with FMD (ß = -0.116, p = 0.037 and ß = 0.041, p = 0.549, respectively) after adjustments for various clinical parameters, with no remarkable inconsistencies for the association observed in subgroups divided based on sex or uric acid level. Finally, a series of mediation analyses showed that serum uric acid level did not meet the criteria for mediator of the association of plasma XOR activity with FMD (p = 0.538). Conclusions: These findings suggest the possibility that XOR contributes to the pathophysiology of impaired VEF through ROS but not uric acid production.
ABSTRACT
BACKGROUND: Chest radiographs are widely available and cost-effective; however, their usefulness as a biomarker of ageing using multi-institutional data remains underexplored. The aim of this study was to develop a biomarker of ageing from chest radiography and examine the correlation between the biomarker and diseases. METHODS: In this retrospective, multi-institutional study, we trained, tuned, and externally tested an artificial intelligence (AI) model to estimate the age of healthy individuals using chest radiographs as a biomarker. For the biomarker modelling phase of the study, we used healthy chest radiographs consecutively collected between May 22, 2008, and Dec 28, 2021, from three institutions in Japan. Data from two institutions were used for training, tuning, and internal testing, and data from the third institution were used for external testing. To evaluate the performance of the AI model in estimating ages, we calculated the correlation coefficient, mean square error, root mean square error, and mean absolute error. The correlation investigation phase of the study included chest radiographs from individuals with a known disease that were consecutively collected between Jan 1, 2018, and Dec 31, 2021, from an additional two institutions in Japan. We investigated the odds ratios (ORs) for various diseases given the difference between the AI-estimated age and chronological age (ie, the difference-age). FINDINGS: We included 101â296 chest radiographs from 70â248 participants across five institutions. In the biomarker modelling phase, the external test dataset from 3467 healthy participants included 8046 radiographs. Between the AI-estimated age and chronological age, the correlation coefficient was 0·95 (99% CI 0·95-0·95), the mean square error was 15·0 years (99% CI 14·0-15·0), the root mean square error was 3·8 years (99% CI 3·8-3·9), and the mean absolute error was 3·0 years (99% CI 3·0-3·1). In the correlation investigation phase, the external test datasets from 34â197 participants with a known disease included 34â197 radiographs. The ORs for difference-age were as follows: 1·04 (99% CI 1·04-1·05) for hypertension; 1·02 (1·01-1·03) for hyperuricaemia; 1·05 (1·03-1·06) for chronic obstructive pulmonary disease; 1·08 (1·06-1·09) for interstitial lung disease; 1·05 (1·03-1·06) for chronic renal failure; 1·04 (1·03-1·06) for atrial fibrillation; 1·03 (1·02-1·04) for osteoporosis; and 1·05 (1·03-1·06) for liver cirrhosis. INTERPRETATION: The AI-estimated age using chest radiographs showed a strong correlation with chronological age in the healthy cohorts. Furthermore, in cohorts of individuals with known diseases, the difference between estimated age and chronological age correlated with various chronic diseases. The use of this biomarker might pave the way for enhanced risk stratification methodologies, individualised therapeutic interventions, and innovative early diagnostic and preventive approaches towards age-associated pathologies. FUNDING: None. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.
Subject(s)
Aging , Artificial Intelligence , Humans , Japan , Retrospective Studies , BiomarkersABSTRACT
AIM: The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. The aim of this study was to determine the recent prevalence and clinical characteristics of NAFLD in Japan. METHODS: This study initially included 410 061 retrospectively enrolled adults from the medical health checkup registry for metabolic syndrome, chronic kidney disease, and fatty liver in Japan (MIRACLE-J; UMIN-CTR no. UMIN000049419), who were evaluated between 2014 and 2018 at 13 health centers in Japan. Individuals consuming >20 g of alcohol/day or with chronic liver disease were excluded. Fatty liver was diagnosed by ultrasonography. The probability of NAFLD with advanced fibrosis was estimated based on the fibrosis-4 index and NAFLD fibrosis score. RESULTS: A total of 71 254 participants were included in the final analysis. The overall prevalence of NAFLD was 25.8%. There was a significant, twofold difference in NAFLD prevalence between men (37.4%) and women (18.1%). Nonalcoholic fatty liver disease prevalence increased linearly with body mass index, triglycerides, and low-density lipoprotein cholesterol regardless of threshold values, even in the absence of obesity. Among patients with NAFLD, 14% had diabetes mellitus, 31% had hypertension, and 48% had dyslipidemia. The estimated prevalence of NAFLD with advanced fibrosis was 1.7% and 1.0% according to the fibrosis-4 index and NAFLD fibrosis score, respectively. CONCLUSIONS: The prevalence of NAFLD was approximately one-quarter of the general population in Japan. There was a linear relationship between NAFLD prevalence and various metabolic parameters, even in nonobese participants. The prevalence of NAFLD with advanced fibrosis was estimated to be 1%-2%.
ABSTRACT
BACKGROUND: The Rome IV criteria have been established as an international standard for diagnosing disorders of gut-brain interaction. In this study, we aimed to examine the upper gastrointestinal (GI) endoscopic findings and symptoms of subjects with functional constipation (FC) and irritable bowel syndrome (IBS) of individuals undergoing a medical check-up. METHODS: A total of 13,729 subjects underwent a medical check-up at Osaka City University-affiliated clinic, MedCity21, between April 2018 and March 2019. Among the 5,840 subjects who underwent screening upper GI endoscopy and completed a questionnaire based on the Rome IV criteria, 5,402 subjects were consecutively enrolled after excluding subjects with a large amount of gastric residue (n = 6), those who had previously undergone partial or total gastrectomy (n = 40), or those with daily use of low-dose aspirin (n = 82), nonsteroidal anti-inflammatory drugs (n = 63), or acid secretion inhibitors (n = 308). RESULTS: Robust Poisson regression analyses adjusted for age, sex, Helicobacter pylori infection status, alcohol intake, and smoking habits showed a significant association between FC and corpus erosion (adjusted prevalence ratio [aPR], 2.93; 95% confidence interval [CI], 1.51-5.67; p < 0.01) and red streaks (aPR, 3.83; 95% CI, 2.53-5.79; p < 0.01), whereas IBS was significantly associated with erosive gastritis (aPR, 8.46; 95% CI, 4.89-14.67; p < 0.01) and duodenitis (aPR, 7.28; 95% CI, 3.64-14.59; p < 0.01). Red streaks tended to be associated with IBS (aPR, 1.96; 95% CI, 1.00-3.83; p = 0.05). Subjects with IBS were the most to complain of both upper and lower GI symptoms and psychological symptoms, followed by those with FC and controls. IBS subjects with erosive gastritis or duodenitis had significantly more complaints of stomachache and feeling stressed than those without erosive gastritis or duodenitis (54.5% vs. 18.8%; p = 0.03 and 66.7% vs. 25.0%; p = 0.01). CONCLUSIONS: Subjects with FC and IBS had a variety of upper GI and psychological symptoms. In the upper GI endoscopic findings, corpus erosion and red streaks were associated with FC, and erosive gastritis, duodenitis, and possibly red streaks were associated with IBS.
Subject(s)
Duodenitis , Gastritis , Helicobacter Infections , Helicobacter pylori , Irritable Bowel Syndrome , Humans , Irritable Bowel Syndrome/complications , Irritable Bowel Syndrome/diagnosis , Cross-Sectional Studies , Japan/epidemiology , Duodenitis/complications , Helicobacter Infections/complications , Helicobacter Infections/diagnosis , Rome , Constipation/diagnosis , Surveys and Questionnaires , Gastritis/complications , Gastritis/diagnosisABSTRACT
Maternal factors present in oocytes and surrounding granulosa cells influence early development of embryos. In this study, we searched for epigenetic regulators that are expressed in oocytes and/or granulosa cells. Some of the 120 epigenetic regulators examined were expressed specifically in oocytes and/or granulosa cells. When their expression was examined in young versus aged oocytes or granulosa cells, many were significantly up- or downregulated in aged cells. The maternal role of six genes in development was investigated by generating oocyte-specific knock-out (MKO) mice. Two genes (Mllt10, Kdm2b) did not show maternal effects on later development, whereas maternal effects were evident for Kdm6a, Kdm4a, Prdm3, and Prdm16 for MKO female mice. Offspring from Kdm6a MKO mice underwent perinatal lethality at a higher rate. Pups derived from Prdm3;Prdm16 double MKO showed a higher incidence of postnatal death. Finally, embryos derived from Kdm4a MKO mice showed early developmental defects as early as the peri-implantation stage. These results suggest that many of maternal epigenetic regulators undergo differential expression upon aging. Some, such as Kdm4a, Kdm6a, Prdm3, and Prdm16, have maternal role in later embryonic or postnatal development.
Subject(s)
Oocytes , Transcription Factors , Pregnancy , Female , Animals , Mice , Oocytes/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Histone Demethylases/genetics , Histone Demethylases/metabolism , Epigenesis, Genetic , Embryonic Development/geneticsABSTRACT
BACKGROUND: Eosinophilic esophagitis (EoE) is a type 2 helper T-cell (Th2)-mediated allergic disease that involves mast cells. This study aimed to clarify the relationship between perception of symptoms and mast cell levels in patients with EoE. METHODS: We enrolled patients with asymptomatic esophageal eosinophilia (aEE) and those with symptomatic EoE. Immunofluorescence staining was performed on esophageal biopsy specimens to quantify mast cell-related molecules, such as tryptase, proteinase-activated receptor (PAR)-2, and vasoactive intestinal peptide receptor (VPAC)-1. RESULTS: We evaluated 28 and 58 patients with aEE and EoE, respectively. There were no significant differences in clinical and endoscopic features and peak eosinophil counts between both groups. Mast cell tryptase-positive areas were significantly higher in EoE than in aEE (4.9 [3.5-6.2] vs. 2.0 [1.2-3.4] %, p < 0.01). The number of PAR-2-positive cells was significantly higher in EoE than in aEE (14 [8.8-20.0] vs. 4 [2.8-8.0] cells/high-power field [HPF], p < 0.01). The number of VPAC-1-positive cells was significantly higher in the EoE group than in the aEE group (13 [8.8-16.0] vs. 6 [3.0-9.3] cells/HPF, p < 0.01). A positive correlation was observed between the numbers of PAR-2-positive cells and VPAC-1-positive cells (r = 0.851, p < 0.01). Moreover, mast cell tryptase-positive areas positively correlated with the number of PAR-2- and VPAC-1-positive cells (r = 0.352, p < 0.01; r = 0.355, p < 0.01, respectively). CONCLUSIONS: Esophageal mast cells and their receptors, PAR-2 and VPAC-1, may contribute to the perception of symptoms in patients with EoE.
Subject(s)
Eosinophilic Esophagitis , Humans , Mast Cells/pathology , Tryptases , PerceptionABSTRACT
Mast cells are one of major players in allergic responses. Mast cell activation via the high affinity IgE receptor (FcεRI) causes degranulation and release of de novo synthesized proinflammatory cytokines in a process that involves vesicle trafficking. Considering that the GTPase ADP-ribosylation factor 1 (Arf1) orchestrates and maintains membrane traffic and organelle structure, it seems likely that Arf1 contributes to mast cell activation. Actually, it has been reported that pharmaceutical blockade of the Arf1 pathway suppresses cytokine secretion and mast cell degranulation. However, physiological roles of Arf1 in mast cells remain elusive. Here, by using a genetic approach, we demonstrate that Arf1 is required for optimal mTORC1 activation upon IL-3 and facilitates mast cell proliferation. On the other hand, contrary to our expectation, Arf1-deficiency had little impact on FcεRI-induced degranulation nor cytokine secretion. Our findings reveal an unexpected role of Arf1 in mast cell expansion and its potential as a therapeutic target in the mast cell proliferative disorders.