Development of an Artificial Intelligence Diagnostic System Using Linked Color Imaging for Barrett's Esophagus.

Background: Barrett's esophagus and esophageal adenocarcinoma cases are increasing as gastroesophageal reflux disease increases. Using artificial intelligence (AI) and linked color imaging (LCI), our aim was to establish a method of diagnosis for short-segment Barrett's esophagus (SSBE). Methods: We retrospectively selected 624 consecutive patients in total at our hospital, treated between May 2017 and March 2020, who experienced an esophagogastroduodenoscopy with white light imaging (WLI) and LCI. Images were randomly chosen as data for learning from WLI: 542 (SSBE+/- 348/194) of 696 (SSBE+/- 444/252); and LCI: 643 (SSBE+/- 446/197) of 805 (SSBE+/- 543/262). Using a Vision Transformer (Vit-B/16-384) to diagnose SSBE, we established two AI systems for WLI and LCI. Finally, 126 WLI (SSBE+/- 77/49) and 137 LCI (SSBE+/- 81/56) images were used for verification purposes. The accuracy of six endoscopists in making diagnoses was compared to that of AI. Results: Study participants were 68.2 ± 12.3 years, M/F 330/294, SSBE+/- 409/215. The accuracy/sensitivity/specificity (%) of AI were 84.1/89.6/75.5 for WLI and 90.5/90.1/91.1/for LCI, and those of experts and trainees were 88.6/88.7/88.4, 85.7/87.0/83.7 for WLI and 93.4/92.6/94.6, 84.7/88.1/79.8 for LCI, respectively. Conclusions: Using AI to diagnose SSBE was similar in accuracy to using a specialist. Our finding may aid the diagnosis of SSBE in the clinic.

Light-Touch-Induced Afterdischarge Firing in the Superficial Spinal Dorsal Horn Neurons in Hairless Mice with Irritant Contact Dermatitis.

The skin is an important barrier that protects against invasion by foreign substances, including irritants and harmful microorganisms, and holds water in the body. Washing the skin with cleansers and shampoos containing anionic surfactants, for example sodium dodecyl sulfate (SDS), is important for maintaining skin homeostasis. However, surfactants can cause dermatitis, cutaneous hypersensitivity (e.g., alloknesis), and pruritus in humans. Our previous studies revealed an alloknesis response in the skin with SDS-induced dermatitis in C57BL/6 mice. In addition, we found that alloknesis responses and afterdischarge responses following stimulation with light touch are related because they are observed contemporaneously. In this study, we used Hos:HR-1 hairless mice to establish a mouse model to evaluate long-term drug application for alloknesis responses. Alloknesis was observed in HR-1 mice with SDS-induced dermatitis. The mean number of c-Fos (a marker of neural activity) immunopositive neurons was increased in the lamina 1-2 (L1-2) spinal dorsal horn, but not in L3-4, of SDS-treated HR-1 mice compared to vehicle-treated mice. We also discovered that afterdischarge responses were observed in neurons in L1-2. There was also a correlation between the intensity of the afterdischarge responses and depth of the recording site. Thus, the following were suggested: 1) neurons that mediate these afterdischarge responses are located on the superficial layer of the spinal cord; 2) afterdischarge responses can be an index of alloknesis responses, and 3) the mouse model of SDS-induced dermatitis is an appropriate alloknesis model.

Histamine enhances ATP-induced itching and responsiveness to ATP in keratinocytes.

Mechanical stimulation of cultured keratinocytes and a living epidermis increases intracellular calcium ion concentrations ([Ca2+]i) in stimulated cells. This action propagates a Ca2+ wave to neighboring keratinocytes via ATP/P2Y2 receptors. Recent behavioral, pharmacological studies revealed that exogenous ATP induces itching via P2X3 receptors in mice. We previously showed that alloknesis occurs when an external stimulus is applied to the skin with increased epidermal histamine in the absence of spontaneous pruritus. Based on these results, we investigated the effects of histamine at a concentration that does not cause itching on ATP-induced itching. The mean number of scratching events induced by the mixture of ATP and histamine increased by 28% over the sum of that induced by histamine alone or ATP alone. A317491, a P2X3 receptor antagonist, suppressed the mixture-induced scratching more often than the ATP-induced scratching. Next, we examined the ATP-induced [Ca2+]i change before and after histamine stimulation using normal human epidermal keratinocytes. Some cells did not respond to ATP before histamine stimulation but responded to ATP afterward, the phenomenon suppressed by chlorpheniramine maleate. These findings suggest that histamine enhances ATP-induced itching and that a potential mechanism could involve increased responsiveness to ATP in keratinocytes.

[Management of a perforated duodenal diverticulum using an endoscopic nasobiliary drainage tube:a case report].

A man in his 70s visited our hospital for abdominal pain. Upon admission, abdominal computed tomography findings suggested a duodenal diverticular perforation. Upper gastrointestinal endoscopy revealed an incarcerated enterolith in the periampullary diverticulum. We achieved conservative management by inserting an endoscopic nasobiliary drainage tube into the duodenal diverticulum to aid drainage. The patient was discharged without serious complications 35 days after admission. We report a case of duodenal diverticular perforation with an incarcerated enterolith managed conservatively using endoscopic therapy.

Expression of histidine decarboxylase in melanocytes of the human skin.

Histamine-producing cells include storage-type cells (e.g., mast cells and basophils), which store histamine intracellularly, and inducible-type cells (e.g., keratinocytes and macrophages), which induce histidine decarboxylase (HDC, a key enzyme for histamine biosynthesis) activity but do not have a storage pool of histamine. Most of the studies focused on identifying HDC-expressing cells by using cultured cells, and few on investigating the localization of HDC by using skin tissues. Hence, this study conducted immunohistochemical studies using human healthy skin samples. HDC-positive and cytokeratin 14 (a marker of basal keratinocytes)-negative cells were present around the basal layer of the epidermis. These cells did not immunohistochemically react with mast cell tryptase but expressed tyrosinase (a key enzyme for melanin biosynthesis) and microphthalmia-associated transcription factor (MITF, a transcription factor controlling the expression of tyrosinase genes). Melanin granules were clearly observed around HDC-positive and MITF-positive cells. Moreover, HDC mRNA and protein were both detected in cultured normal human epidermal melanocytes. In conclusion, HDC-positive and cytokeratin 14-negative cells around the basal layer of the epidermis are melanocytes.

Association between the severity of constipation and sarcopenia in elderly adults: A single-center university hospital-based, cross-sectional study.

The aim of the present study was to investigate the association between the severity of constipation and sarcopenia in elderly adults. We conducted a single-center university hospital-based, retrospective cross-sectional study of consecutive outpatients aged ≥65 years from 2017 to 2020. Patients were included in the study if all of the following information were available from medical records: Patient's profile (age, sex, body mass index), laxative/prokinetics use, evaluation of sarcopenia, nutritional status, and questionnaires concerning the severity of constipation [Constipation Scoring System (CSS)], abdominal symptom-related quality of life (QOL) (Izumo scale) and stool shape [Bristol Stool Form Scale (BSFS)]. Multiple regression analysis of risk factors for high CSS score was performed. The results revealed that of the 310 eligible study subjects, [149 men (48.1%) and 161 women (51.9%); mean age, 75.7±6.1 years; mean body mass index, 23.0±3.6 kg/m2], sarcopenia was noted in 83 cases (26.8%). The CSS score was significantly higher in the sarcopenia group than that noted in the non-sarcopenia group (4.9±4.9 vs. 3.6±3.6, P=0.009). The CSS score was significantly associated with the albumin level (r=-0.148), lymphocyte count (r=-0.118), CONUT score (r=0.130), reflux-related QOL score (r=0.155), upper abdominal pain-related QOL score (r=0.171), fullness-related QOL score (r=0.299), constipation-related QOL score (r=0.615), diarrhea-related QOL score (r=0.235) and BSFS score (r=-0.114). In multiple regression analysis, independent predictors for CSS score were sarcopenia [standardized partial regression coefficient (ß)=0.107, P=0.032], constipation-related QOL score (ß=0.537, P<0.001), laxative/prokinetics use (ß=0.211, P<0.001) and BSFS score (ß=-0.098, P=0.031) (R2=0.436). In conclusion, sarcopenia, constipation-related QOL score, laxative/prokinetics use and BSFS score are associated with the severity of constipation in elderly adults.

Does Endoscopic Retrograde Cholangiopancreatography Carry Higher Risk for Patients 90 Years and Older? A Single-Institution Retrospective Study.

BACKGROUND Endoscopic retrograde cholangiography (ERCP) for patients aged ≥90 years is often required. The safety of ERCP for super-elderly patients is a major concern for gastrointestinal endoscopists. We retrospectively examined the safety of ERCP for super-elderly patients by comparison with patients in their 70s. MATERIAL AND METHODS We reviewed 66 patients aged ≥90 years (Group A) and 43 patients in their 70s (Group B) who underwent ERCP in our institution from January 2012 to October 2019. Data were collected on patients' backgrounds, corresponding procedures, and clinical outcomes, including adverse events. RESULTS Patients in Group A (mean age: 92.3±2.1 years) had significantly poorer performance status (median: 3 vs. 0; P<0.001) and American Society of Anesthesiologists classification (median: III vs. II; P<0.001) when compared to Group B (mean age: 75.1±2.7 years). Underlying cardiovascular, cerebrovascular, renal, and orthopedic comorbidity occurrence was significantly higher in Group A than in Group B (87.88% vs. 67.44%; P=0.0094). Group A comprised more patients with benign disease than Group B (90.91% vs. 76.74%; P=0.040). Group B comprised more patients with malignant disease (31.82% vs. 53.54%; P=0.041). Emergency ERCP was higher in Group A than in Group B (71.70% vs. 29.73%; P<0.0001). No significant between-group differences in adverse events (15.15% vs. 11.63%; P=0.602) and mortality rate (1.52% vs. 2.33%; P=0.758) were noted. CONCLUSIONS Indications for ERCP should not be determined simply based on the super-elderly age of patients. ERCP may not necessarily carry higher risks if endoscopists practice maximal caution against gastrointestinal perforation.

Linked color imaging improves visibility of reflux esophagitis.

BACKGROUND: With more prevalent gastroesophageal reflux disease comes increased cases of Barrett's esophagus and esophageal adenocarcinoma. Image-enhanced endoscopy using linked-color imaging (LCI) differentiates between mucosal colors. We compared LCI, white light imaging (WLI), and blue LASER imaging (BLI) in diagnosing reflux esophagitis (RE). METHODS: Consecutive RE patients (modified Los Angeles [LA] classification system) who underwent esophagogastroduodenoscopy using WLI, LCI, and BLI between April 2017 and March 2019 were selected retrospectively. Ten endoscopists compared WLI with LCI or BLI using 142 images from 142 patients. Visibility changes were scored by endoscopists as follows: 5, improved; 4, somewhat improved; 3, equivalent; 2, somewhat decreased; and 1, decreased. For total scores, 40 points was considered improved visibility, 21-39 points was comparable to white light, and < 20 points equaled decreased visibility. Inter- and intra-rater reliabilities (Intra-class Correlation Coefficient [ICC]) were also evaluated. Images showing color differences (ΔE*) and L* a* b* color values in RE and adjacent esophageal mucosae were assessed using CIELAB, a color space system. RESULTS: The mean age of patients was 67.1 years (range: 27-89; 63 males, 79 females). RE LA grades observed included 52 M, 52 A, 24 B, 11 C, and 3 D. Compared with WLI, all RE cases showed improved visibility: 28.2% (40/142), LA grade M: 19.2% (10/52), LA grade A: 34.6% (18/52), LA grade B: 37.5% (9/24), LA grade C: 27.3% (3/11), and LA grade D: 0% (0/3) in LCI, and for all RE cases: 0% in BLI. LCI was not associated with decreased visibility. The LCI inter-rater reliability was "moderate" for LA grade M and "substantial" for erosive RE. The LCI intra-rater reliability was "moderate-substantial" for trainees and experts. Color differences were WLI: 12.3, LCI: 22.7 in LA grade M; and WLI: 18.2, LCI: 31.9 in erosive RE (P < 0.001 for WLI vs. LCI). CONCLUSION: LCI versus WLI and BLI led to improved visibility for RE after subjective and objective evaluations. Visibility and the ICC for minimal change esophagitis were lower than for erosive RE for LCI. With LCI, RE images contrasting better with the surrounding esophageal mucosa were more clearly viewed.

The Association between Frailty and Abdominal Symptoms: A Hospital-based Cross-sectional Study.

Objective The association between frailty and abdominal symptoms has not been evaluated. Methods We conducted a hospital-based, retrospective cross-sectional study of consecutive outpatients ≥65 years old at the Department of Gastroenterology, Juntendo Tokyo Koto Geriatric Medical Center from 2017 to 2019. Patients were included in the study if all of the following information was available from their medical records: patient's profile, the evaluation of osteoporosis, sarcopenia, frailty, nutritional status, findings of upper gastrointestinal endoscopy, and questionnaire results for abdominal symptoms [Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (FSSG) and Constipation Scoring System (CSS)]. We divided the subjects into frailty and non-frailty groups and investigated the risk factors for frailty. Results Of the 313 eligible study subjects [134 men (42.8%) and 179 women (57.2%); mean age, 75.7±6.0 years; mean body mass index, 22.8±3.6 kg/m2], frailty was noted in 71 cases (22.7%). In a univariate analysis, an older age (p<0.001), female gender (p=0.010), successful eradication of Helicobacter pylori (p=0.049), proton pump inhibitor (PPI) use (p<0.001), laxative/prokinetics use (p=0.008), sarcopenia (p<0.001), osteoporosis (p<0.001), hypozincemia (p=0.002), hypoalbuminemia (p<0.001), low lymphocytes (p=0.004), a high CONUT score (p<0.001), a high FSSG score (p=0.001), and a high CSS score (p<0.001) were significantly associated with frailty. A multivariate logistic regression analysis showed that an older age [odds ratio (OR) 1.16; 95% confidence interval (CI) 1.08-1.24, p<0.001], PPI use (OR 2.42; 95% CI 1.18-4.98, p=0.016), sarcopenia (OR 7.35; 95% CI 3.30-16.40, p<0.001), hypozincemia (OR 0.96; 95% CI 0.92-0.99, p=0.027), a high FSSG score (OR 1.08; 95% CI 1.01-1.16, p=0.021), and a high CSS score (OR 1.13; 95% CI 1.03-1.23, p=0.007) were significantly associated with frailty. Conclusion Advanced age, PPI user, sarcopenia, hypozincemia, a high FSSG score, and high CSS score are associated with frailty.

Neuronal hyperexcitability and astrocyte activation in spinal dorsal horn of a dermatitis mouse model with cutaneous hypersensitivity.

Cleaning products such as soaps, shampoos, and detergents are comprised mainly of surfactants, agents known to cause dermatitis and cutaneous hypersensitivity characterized by itching, stinging, and burning of the skin and scalp. However, the mechanisms underlying surfactant-induced cutaneous hypersensitivity remain unclear. In the present study, we investigated the mechanisms of cutaneous hypersensitivity in mice treated with the detergent sodium dodecyl sulfate (SDS). Repeated SDS application to the skin induced inflammation, xeroderma, and elongation of peripheral nerves into the epidermis. The number of neurons immunopositive for c-Fos, a well known marker of neural activity, was substantially higher (+441%) in spinal dorsal horn (SDH) lamina I-II (but not lamina III-VI) of SDS-treated mice compared to vehicle-treated mice. In vivo extracellular recording revealed enhanced spontaneous (+64%) and non-noxious mechanical stimulation-evoked firing (+139%) of SDH lamina I-II neurons in SDS-treated mice, and stimulation-evoked neuronal firing was sustained (+5333%) even after stimulation. The number of GFAP-positive (activated) astrocytes, but not Iba1-positive microglia, was also elevated (+137%) in SDH lamina I-II of SDS-treated mice compared to vehicle-treated mice. Peripheral nerve elongation and hyperexcitability of afferent or SDH neurons, possible associated with the activation of spinal astrocytes, may underlie cutaneous hypersensitivity induced by surfactants.

Inhibition of glycogen synthase kinase-3 reduces extension of the axonal leading process by destabilizing microtubules in cerebellar granule neurons.

Recent studies have uncovered various molecules that play key roles in neuronal morphogenesis. Nevertheless, the mechanisms underlying the neuron-type-dependent regulation of morphogenesis remain unknown. We have previously reported that inhibition of glycogen synthase kinase-3 (GSK3) markedly reduced axonal length of cerebellar granule neurons (CGNs) in a neuron-type-dependent manner. In the present study, we investigated the mechanisms by which the growth of CGN axons was severely suppressed upon GSK3 inhibition. Using time-lapse imaging of cultured CGNs at early morphogenesis, we found that extension of the leading process was severely inhibited by the pharmacological inhibition of GSK3. The rate of somal migration was also reduced with a GSK3 inhibitor in dissociated culture as well as in microexplant culture. In addition, CGNs ectopically expressed with a catalytically inactive mutant of GSK3 exhibited a migration defect in vivo. In axonal leading processes of CGNs, detyrosination and acetylation of α-tubulin, which are known to correlate with microtubule stability, were decreased by GSK3 inhibition. A photoconversion analysis found that inhibition of GSK3 increases the turnover of microtubules. Furthermore, in the presence of paclitaxel, a microtubule-stabilizing reagent, inhibition of GSK3 recovered the axonal leading process extension that was reduced by paclitaxel. Our results suggest that GSK3 supports the extension of axonal processes by stabilizing microtubules, contrary to its function in other neuron-types, lending mechanical insight into neuron-type-dependent morphological regulation.

Continuation of antithrombotic therapy may be associated with a high incidence of colonic post-polypectomy bleeding.

BACKGROUND AND AIM: Post-polypectomy bleeding (PPB) is the most common complication of endoscopic procedures. To reduce the risk of thromboembolic incidents, Japanese guidelines for gastroenterological endoscopy were revised to indicate that antithrombotic agents were not to be discontinued for endoscopic treatment. However, carrying out endoscopic procedures under antithrombotic medication potentially increases the incidence of hemorrhagic complications. The present study investigated the impact of the revised guidelines on the frequency of complications after colonoscopic procedures. METHODS: The surveillance period comprised the year before the initiation of the new guidelines (2012), which served as a control period, and 2 years after initiation of the new guidelines (2013 and 2014). During the control period, 3955 cases were examined colonoscopically and 1601 lesions were treated endoscopically. During the 2-year period under the new guidelines, 8749 colonoscopies and 3768 endoscopic treatments were carried out. Changes in treatment methods and rates of complications were compared. RESULTS: PPB rate was not significantly different before and after the revision (0.87% vs 1.01%). With the new guidelines, PPB rates in antithrombotic non-users and users were 0.60% and 3.13%, respectively (OR 5.11, P = 0.000). Multivariable analysis showed that the risks for PPB were as follows: heparin bridging therapy (OR 6.34, P = 0.0002); low-dose aspirin (LDA) continuation (OR 5.30, P = 0.0079); and lesion size (OR 1.06, P < 0.0001). CONCLUSION: The present study showed that the overall PPB rate under the new guidelines was not significantly higher when compared with the previous data obtained before the new guidelines were introduced.

Inhibition of mTOR improves the impairment of acidification in autophagic vesicles caused by hepatic steatosis.

Recent investigations revealed that dysfunction of autophagy involved in the progression of chronic liver diseases such as alcoholic and nonalcoholic steatohepatitis and hepatocellular neoplasia. Previously, it was reported that hepatic steatosis disturbs autophagic proteolysis via suppression of both autophagic induction and lysosomal function. Here, we demonstrate that autophagic acidification was altered by a decrease in lysosomal proton pump vacuolar-ATPase (V-ATPase) in steatohepatitis. The number of autophagic vesicles was increased in hepatocytes from obese KKAy mice as compared to control. Similarly, autophagic membrane protein LC3-II and lysosomal protein LAMP-2 expression were enhanced in KKAy mice liver. Nevertheless, both phospho-mTOR and p62 expression were augmented in KKAy mice liver. More than 70% of autophagosomes were stained by LysoTracker Red (LTR) in hepatocytes from control mice; however, the percentage of acidic autolysosomes was decreased in hepatocytes from KKAy mice significantly (40.1 ± 3.48%). Both protein and RNA level of V-ATPase subunits ATP6v1a, ATP6v1b, ATP6v1d in isolated lysosomes were suppressed in KKAy mice as compared to control. Interestingly, incubation with mTOR inhibitor rapamycin increased in the rate of LTR-positive autolysosomes in hepatocytes from KKAy mice and suppressed p62 accumulation in the liver from KKAy mice which correlated to an increase in the V-ATPase subunits expression. These results indicate that down-regulation of V-ATPase due to hepatic steatosis causes autophagic dysfunction via disruption of lysosomal and autophagic acidification. Moreover, activation of mTOR plays a pivotal role on dysregulation of lysosomal and autophagic acidification by modulation of V-ATPase expression and could therefore be a useful therapeutic target to ameliorate dysfunction of autophagy in NAFLD.

[Case of computed tomography (CT) gastrography for the detection of multiple gastric submucosal tumors: a case report].

A 66-year-old female underwent esophagogastroduodenoscopy, which revealed a 17-mm gastric submucosal tumor (SMT) located in the posterior wall of the upper area of the stomach. She was referred to our hospital for further investigation because of accumulation of radioactive substance in the gastric wall by PET-CT. CT gastrography (CTG) revealed three gastric SMTs in total. Partial gastrectomy was performed; histopathologically, they were diagnosed as gastrointestinal stromal tumor (GIST), benign schwannoma, and necrotic tissue. Gastric schwannoma is very rare, and we could find no cases with both GIST and schwannoma. Additionally, the three gastric SMTs were only detected clearly via CTG. We report on the details of this case and the usefulness of CTG for the detection of gastric SMT.

Inhibitory activity of the flower buds of Lonicera japonica Thunb. against histamine production and L-histidine decarboxylase in human keratinocytes.

In previous studies we found that anionic surfactants such as sodium laurate (SL) and/or sodium dodecylsulfate (SDS) exert actions on epidermal keratinocytes rather than mast cells to give rise of histamine production and skin itching through increasing the expression of the 53-kDa active form of L-histidine decarboxylase (HDC). In addition, with treatment of SL in a three-dimensional human keratinocyte culture, increases in both the 53-kDa HDC and histamine production are detected and thus this culture assay is applied to screen anti-itching materials from natural resources. In this study, the inhibitory activity of "Kin-gin-ka" (flower buds of Lonicera japonica Thunb., FLJ) against histamine production and expression of the active form of HDC were examined in this culture assay. FLJ is a well-known traditional Chinese medicine, being used to treat fevers, coughs and some infectious diseases. The result showed both FLJ and chlorogenic acid had inhibitory activities against the expression of 53-kDa HDC and histamine production. However, chlorogenic acid showed a weaker effect on histamine production than that of FLJ, suggesting that other chemical constituents besides chlorogenic acid could contribute to the inhibitory activities. Thus, a further chemical study of FLJ is now under investigation.

Surfactant-induced chronic pruritus: Role of L-histidine decarboxylase expression and histamine production in epidermis.

Shampoo and cleansers containing anionic surfactants including sodium dodecyl sulphate (SDS) often cause pruritus in humans. Daily application of 1-10% SDS for 4 days induced hind-paw scratching (an itch-related behaviour) in a concentration-dependent manner, and 10% SDS also caused dermatitis, skin dryness, barrier disruption, and an increase in skin surface pH in mice. SDS-induced scratching was inhibited by the opioid receptor antagonist naloxone and the H histamine receptor antagonist terfenadine. Mast-cell deficiency did not inhibit SDS-induced scratching, although it almost completely depleted histamine in the dermis. Treatment with SDS increased the histamine content of the epidermis, but not that of the dermis. SDS treatment increased the gene expression and post-translation processing of L-histidine decarboxylase in the epidermis. The present results suggest that repeated application of SDS induces itch through increased production of epidermal histamine, which results from an increase in the gene expression and post-translation processing of L-histidine decarboxylase.

Prevention of topical surfactant-induced itch-related responses by chlorogenic acid through the inhibition of increased histamine production in the epidermis.

Effects of chlorogenic acid on surfactant-induced itching were studied in mice. Topical application of sodium laurate increased hind-paw scratching, an itch-related response, 2 h after application, which was inhibited by topical post-treatment with chlorogenic acid. Sodium laurate increased the histamine content and 53-kDa L-histidine decarboxylase in the epidermis, which were also inhibited by post-treatment with chlorogenic acid. These results suggest that topical chlorogenic acid is effective in the prevention of itching induced by anionic surfactants. The inhibitory activity of chlorogenic acid may be due to the inhibition of an increase in histamine in the epidermis.