[A case report:the progress of fascioliasis from hepatic phase to biliary phase].

This is a case report of fascioliasis that progressed from the hepatic to the biliary phases over 2 years. A woman in her late 60s ate Zingiber mioga from the field, which was followed by abdominal pain that occurred 1 month later. Although CT and MRI studies revealed an increase in blood eosinophils as well as multiple hepatic nodules, they vanished quickly. After 2 years, an MRCP study revealed multiple flat lesions, which were diagnosed as adult fascioliasis. Definitive diagnosis was provided by enzyme-labeled antibody method using fasciola-specific antigen. Triclabendazole was administered once to complete the treatment.

Demarcation Line Determination for Diagnosis of Gastric Cancer Disease Range Using Unsupervised Machine Learning in Magnifying Narrow-Band Imaging.

BACKGROUND AND AIMS: It is important to determine an accurate demarcation line (DL) between the cancerous lesions and background mucosa in magnifying narrow-band imaging (M-NBI)-based diagnosis. However, it is difficult for novice endoscopists. We aimed to automatically determine the accurate DL using a machine learning method. METHODS: We used an unsupervised machine learning approach to determine the DLs. Our method consists of the following four steps: (1) an M-NBI image is segmented into superpixels using simple linear iterative clustering; (2) the image features are extracted for each superpixel; (3) the superpixels are grouped into several clusters using the k-means method; and (4) the boundaries of the clusters are extracted as DL candidates. The 23 M-NBI images of 11 cases were used for performance evaluation. The evaluation investigated the similarity of the DLs identified by endoscopists and our method, and the Euclidean distance between the two DLs was calculated. For the single case of 11 cases, the histopathological examination was also conducted to evaluate the proposed system. RESULTS: The average Euclidean distances for the 11 cases were 10.65, 11.97, 7.82, 8.46, 8.59, 9.72, 12.20, 9.06, 22.86, 8.45, and 25.36. The results indicated that the proposed method could identify similar DLs to those identified by experienced doctors. Additionally, it was confirmed that the proposed system could generate pathologically valid DLs by increasing the number of clusters. CONCLUSIONS: Our proposed system can support the training of inexperienced doctors as well as enrich the knowledge of experienced doctors in endoscopy.

The persistence of interleukin-6 is regulated by a blood buffer system derived from dendritic cells.

The interleukin-6 (IL-6) membrane receptor and its circulating soluble form, sIL-6R, can be targeted by antibody therapy to reduce deleterious immune signaling caused by chronic overexpression of the pro-inflammatory cytokine IL-6. This strategy may also hold promise for treating acute hyperinflammation, such as observed in coronavirus disease 2019 (COVID-19), highlighting a need to define regulators of IL-6 homeostasis. We found that conventional dendritic cells (cDCs), defined in mice via expression of the transcription factor Zbtb46, were a major source of circulating sIL-6R and, thus, systemically regulated IL-6 signaling. This was uncovered through identification of a cDC-dependent but T cell-independent modality that naturally adjuvants plasma cell differentiation and antibody responses to protein antigens. This pathway was then revealed as part of a broader biological buffer system in which cDC-derived sIL-6R set the in-solution persistence of IL-6. This control axis may further inform the development of therapeutic agents to modulate pro-inflammatory immune reactions.

Benefits of linked color imaging for recognition of early differentiated-type gastric cancer: in comparison with indigo carmine contrast method and blue laser imaging.

BACKGROUND AND AIM: Linked color imaging (LCI) is a novel endoscopy system, which enhances slight differences in mucosal color. However, whether LCI is more useful than other kinds of image-enhanced endoscopy (IEE) in recognizing early gastric cancer remains unclear. This study aimed to evaluate LCI efficacy compared with the indigo carmine contrast method (IC), and blue laser imaging-bright (BLI-brt) in early differentiated-type gastric cancer recognition. METHODS: We retrospectively analyzed early differentiated-type gastric cancer, which were examined by all four imaging techniques (white light imaging, IC, LCI, BLI-brt) at Asahi University Hospital from June 2014 to November 2018. Both subjective evaluation (using ranking score: RS) and objective evaluation (using color difference score: CDS) were adopted to quantify early differentiated-type gastric cancer recognition. RESULTS: During this period, 87 lesions were enrolled in this study. Both RS and CDS of LCI were significantly higher (p < 0.01) than those of IC and BLI-brt. Both RS and CDS of BLI-brt had no significant difference compared with those of IC. Subgroup analysis revealed that LCI was especially useful in post-Helicobacter pylori eradication patients and flat or depressed lesions compared with IC and BLI-brt. CONCLUSIONS: LCI appears to be more beneficial for the recognition of early differentiated-type gastric cancer in endoscopic screenings than IC and BLI-brt from the middle to distant view.

Hemostatic radiotherapy for inoperable gastric cancer: a pilot study.

OBJECTIVE: Standard treatment for progressive gastric cancer with bleeding includes hemostatic radiotherapy (RT); however, the only prospective study using a fixed dose with fractions during hemostatic RT did not introduce re-irradiation. Therefore, we determined the utility of RT including re-irradiation for gastric cancer. METHODS: In this study, 31 patients with gastric cancer and bleeding were treated with an initial dose of 20 Gy/5 fractions for the whole stomach and a salvage dose of 15 Gy/5 fractions for the partial stomach. Patients achieving hemostasis, defined as a stable hemoglobin level within 30 days following irradiation, were considered responders, whereas those with no cessation of bleeding and those with re-bleeding within 30 days of irradiation were considered non-responders. We evaluated response rate, disease-free survival, overall survival (OS), re-irradiation, and adverse events (AEs). RESULTS: The response rate of initial RT was 80% (25/31). 6 of the 25 patients underwent re-irradiation, and all 6 were responders (100%). The median OS was significantly different among the entire cohort and one-time irradiation and re-irradiation groups (91, 76, and 112 days, respectively). No AEs of grade ≥3 were observed. Initial low-dose RT followed by reirradiation was effective in reducing AEs and did not cause any further AEs. CONCLUSION: Hemostatic RT was an effective approach with low toxicity, and re-irradiation was effective and tolerable, with no patients developing severe AEs. Further, randomized controlled studies are warranted to determine the ideal dose and number of fractions for initial RT in patients with gastric cancer and bleeding. ADVANCES IN KNOWLEDGE: In this prospective study on hemostatic radiotherapy for gastric cancer, the response rate was 80% using a fixed dose of 20 Gy/5 fractions and the salvage dose of 15 Gy for re-bleeding was effective. Future comparative studies should include other doses with 20 Gy as a control.

Recurrence of Cutaneous and Lymph Node Metastases 12 Years after Radical Total Gastrectomy for Stage IIA Gastric Cancer.

We herein report a rare case of cutaneous and lymph node metastases that recurred 12 years after radical total gastrectomy for stage IIA gastric cancer. A 62-year-old man had undergone total gastrectomy for stage IIA gastric cancer 12 years earlier without postoperative adjuvant chemotherapy. At 12 years after the surgery, he was admitted for left jugular swelling. Computed tomography revealed supraclavicular lymph node swelling and precordial subcutaneous edema. The lymph node specimens and cutaneous biopsies indicated late recurrence of the gastric cancer. Concurrent chemoradiotherapy was administered effectively, but after eight months, the patient died due to deterioration in his general condition.

Successful treatment of unresectable advanced rectal cancer with liver metastases by hemostasis re-irradiation of the rectal cancer and palliative low-dose whole-liver radiation therapy: a case report.

A 72-year-old man was admitted to the hospital with fatigue. Colonoscopy revealed a 50 × 50 mm rectal tumor with bleeding. Based on close inspection, he was diagnosed with unresectable advanced rectal cancer with multiple liver metastases. Chemotherapy was administered as 10 cycles of bevacizumab + mFOLFOX6 and 7 cycles of bevacizumab + FOLFIRI. Nine months later, he presented with hematochezia and progression of anemia. It was difficult to stop the bleeding via endoscopy. He underwent radiation therapy (39 Gy in 13 fractions), and hemostasis was confirmed. Then, further chemotherapy was performed with 3 cycles of bevacizumab + FOLFIRI and 2 cycles of TAS102. However 14 months after the initial visit, he presented with right hypochondralgia and abdominal fullness due to the progression of multiple liver metastases. Palliative low-dose whole-liver radiation therapy (WLRT) (30 Gy in 10 fractions) was performed. He developed Grade 2 nausea, but his right hypochondralgia reduced, liver dysfunction improved, and he successfully completed radiotherapy. At approximately the same time his anemia progressed, and colonoscopy revealed recurrent bleeding from the tumor. Re-irradiation (15 Gy in 5 fractions) of the rectal tumor was carried out and a blood transfusion was performed for the bleeding. He was discharged after confirmation the anemia had not progressed. Few reports have been published on the use of both palliative re-irradiation to stop bleeding from rectal cancer and palliative low-dose WLRT. Based on our experience with this case, we believe that palliative radiotherapy can be useful in treating patients with a poor prognosis.

Potential of automatic diagnosis system with linked color imaging for diagnosis of Helicobacter pylori infection.

BACKGROUND AND AIM: It is necessary to establish universal methods for endoscopic diagnosis of Helicobacter pylori (HP) infection, such as computer-aided diagnosis. In the present study, we propose a multistage diagnosis algorithm for HP infection. METHODS: The aims of this study are to: (i) to construct an interpretable automatic diagnostic system using a support vector machine for HP infection; and (ii) to compare the diagnosis capability of our artificial intelligence (AI) system with that of endoscopists. Presence of an HP infection determined through linked color imaging (LCI) was learned through machine learning. Trained classifiers automatically diagnosed HP-positive and -negative patients examined using LCI. We retrospectively analyzed the new images from 105 consecutive patients; 42 were HP positive, 46 were post-eradication, and 17 were uninfected. Five endoscopic images per case taken from different areas were read into the AI system, and used in the HP diagnosis. RESULTS: Accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the diagnosis of HP infection using the AI system were 87.6%, 90.4%, 85.7%, 80.9%, and 93.1%, respectively. Accuracy of the AI system was higher than that of an inexperienced doctor, but there was no significant difference between the diagnosis of experienced physicians and the AI system. CONCLUSIONS: The AI system can diagnose an HP infection with significant accuracy. There remains room for improvement, particularly for the diagnosis of post-eradication patients. By learning more images and considering a diagnosis algorithm for post-eradication patients, our new AI system will provide diagnostic support, particularly to inexperienced physicians.

A case of phlegmonous gastritis with hepatic portal venous gas caused by Aeromonas hydrophila successfully treated with medication.

A 74-year-old woman was admitted to the hospital with epigastric pain, severe nausea and vomiting, and diarrhea that had started 3 days previously. She had eaten raw Ayu fish 4 days before admission. An abdominal contrast-enhanced computed tomography scan revealed the presence of gas in the portal vein and remarkable thickening of the gastric wall. In many cases, the gas in the portal vein indicates the existence of intestinal necrosis. Esophagogastroduodenoscopy showed a submucosal tumor-like elevation in the gastric corpus. She was diagnosed with sepsis and phlegmonous gastritis (PG) with hepatic portal venous gas (HPVG) caused by Aeromonas hydrophila, which was detected in her stool. The patient was treated with antibiotics and discharged from the hospital 23 days after admission in a stable condition. When caused by PG, HPVG is not necessarily considered a poor prognostic factor and is expected to be treatable with medication. However, patients should be closely monitored for signs of a life-threatening pathology such as intestinal necrosis.

T cell fate following Salmonella infection is determined by a STING-IRF1 signaling axis in mice.

The innate immune response following infection with entero-invasive bacterial species is triggered upon release of cyclic di-guanylate monophosphate (c-di-GMP) into the host cell cytosol. Bacterial c-di-GMP activates the intracellular Sensor Stimulator of Interferon Genes (STING), encoded by Tmem173 in mice. Here we identify Interferon Regulatory Factor (IRF) 1 as a critical effector of STING-mediated microbial DNA sensing that is responsible for TH17 cell generation in the mucosal immune system. We find that STING activation induces IRF1-dependent transcriptional programs in dendritic cells (DCs) that define T cell fate determination, including induction of Gasdermin D, IL-1 family member cytokines, and enzymes for eicosanoid synthesis. Our results show that IRF1-dependent transcriptional programs in DCs are a prerequisite for antigen-specific TH17 subspecification in response to microbial c-di-GMP and Salmonella typhimurium infection. Our identification of a STING-IRF1 signaling axis for adaptive host defense control will aid further understanding of infectious disease mechanisms.

Usefulness of diffusion-weighted magnetic resonance imaging for evaluating the effect of hemostatic radiotherapy for unresectable gastric cancer.

There are several reports that vouch for the usefulness of diffusion-weighted image (DWI) in making a diagnosis before treatment. However, no study has evaluated the effect of radiotherapy (RT) for unresectable gastric cancer. In the present case report, we evaluated the effectiveness of RT using DWI. An 81-year-old man was hospitalized with a broken bone and then diagnosed with advanced gastric cancer with breeding. He had chorionic renal failure and surgery was impossible. Further, contrast-enhanced computed tomography and magnetic resonance imaging (MRI) were not performed due to renal failure, whereas palliative RT was performed. We followed up the patient using blood test and MRI (DWI) to estimate whether bleeding had stopped or not after radiotherapy. Hemostasis effect was found after 2 weeks of RT. In DWI examination, there was a decrease in the tumor signal intensity 30 days after RT. Similarly, at day 60, the tumor signal intensity further decreased on DWI and the blood test results indicated no progression of anemia. At 4 months after the RT, the patient died because of respiratory failure without any bleeding. DWI is useful not only for the initial diagnosis but also for evaluating the effectiveness of RT.Trial registration: National clinical study registered number: UMIN000026362.

A review of the mechanism and prophylaxis of acetyl salicylic acid-induced injury of the small intestine.

Besides the preventive effect of aspirin on cerebrocardiovascular diseases, aspirin has adverse effects, especially on the gastrointestinal system and kidneys. Especially, a recent advancement in endoscopy revealed that aspirin-induced small intestinal mucosal injury is considerably higher than previously believed. However, the mechanism of this phenomenon is not clear yet. Moreover, effective prophylaxis does not exist. First, we investigated the cytotoxic effect of aspirin on the intestinal epithelial cell line in rats at a high concentration, and found that aspirin significantly decreased heat shock protein 70 expression, increased reactive oxygen species production, and increased epithelial cell apoptosis. These phenomena were prevented by the increment of heat shock protein 70 expression. Next, we investigated the effect of a lower concentration of aspirin on epithelial cell permeability, and found that aspirin significantly increased reactive oxygen species production, decreased tight junction protein expression, and increased epithelial permeability. These phenomena were suppressed by an antioxidant. Finally, we investigated the role of intestinal mucus on aspirin-induced mucosal damage using an in vivo model, and found that mucus prevented a high concentration of aspirin-induced mucosal damage. The investigation of chronic users of aspirin revealed that mucus-increasing therapy might be useful for preventing aspirin-induced small intestinal mucosal injury.

Dynamic regulation of plasma matrix metalloproteinases in human diabetic ketoacidosis.

BACKGROUND: Diabetic ketoacidosis (DKA) in children is associated with cerebrovascular-related complications. We recently reported that DKA facilitates leukocyte adherence to the brain microvascular endothelium. Adhered leukocytes can release enzymes that instigate vascular dysfunction. Our aims were to measure plasma levels of leukocyte-derived matrix metalloproteinases (MMPs) from DKA patients and to correlate plasma MMP concentrations with DKA severity. METHODS: Plasma was obtained from children with type 1 diabetes, either in DKA (n = 16) or insulin controlled (CON; n = 16). Antibody microarray and gelatin zymography were used to quantify plasma MMPs and their endogenous tissue inhibitors (TIMPs). MMP concentrations were correlated with DKA severity (blood pH). Quantitative PCR of leukocyte mRNA was used to help determine the origin of plasma MMPs. RESULTS: DKA was associated with altered plasma levels of ↓MMP-2 (P < 0.001), ↑MMP-8 (P < 0.001), ↑MMP-9 (P < 0.05), and ↑TIMP-4 (P < 0.001), as compared with CON. Elevated MMP-8 and MMP-9 were both positively correlated with DKA severity (P < 0.05). DKA was associated with increased leukocyte mRNA for MMP-8, MMP-9, and TIMP-4 (P < 0.005). CONCLUSION: MMPs are dynamically regulated during DKA. Plasma MMP-8 and MMP-9 concentrations correlate with DKA severity and are known to degrade brain microvascular endothelial cell tight junctions. Thus, leukocyte-derived MMPs might contribute to DKA-associated cerebrovascular complications.

Gliadin Induces Neutrophil Migration via Engagement of the Formyl Peptide Receptor, FPR1.

BACKGROUND: Gliadin, the immunogenic component within gluten and trigger of celiac disease, is known to induce the production of Interleukin-8, a potent neutrophil-activating and chemoattractant chemokine. We sought to study the involvement of neutrophils in the early immunological changes following gliadin exposure. METHODS: Utilizing immunofluorescence microscopy and flow cytometry, the redistribution of major tight junction protein, Zonula occludens (ZO)-1, and neutrophil recruitment were assessed in duodenal tissues of gliadin-gavaged C57BL/6 wild-type and Lys-GFP reporter mice, respectively. Intravital microscopy with Lys-GFP mice allowed monitoring of neutrophil recruitment in response to luminal gliadin exposure in real time. In vitro chemotaxis assays were used to study murine and human neutrophil chemotaxis to gliadin, synthetic alpha-gliadin peptides and the neutrophil chemoattractant, fMet-Leu-Phe, in the presence or absence of a specific inhibitor of the fMet-Leu-Phe receptor-1 (FPR1), cyclosporine H. An irrelevant protein, zein, served as a control. RESULTS: Redistribution of ZO-1 and an influx of CD11b+Lys6G+ cells in the lamina propria of the small intestine were observed upon oral gavage of gliadin. In vivo intravital microscopy revealed a slowing down of GFP+ cells within the vessels and influx in the mucosal tissue within 2 hours after challenge. In vitro chemotaxis assays showed that gliadin strongly induced neutrophil migration, similar to fMet-Leu-Phe. We identified thirteen synthetic gliadin peptide motifs that induced cell migration. Blocking of FPR1 completely abrogated the fMet-Leu-Phe-, gliadin- and synthetic peptide-induced migration. CONCLUSIONS: Gliadin possesses neutrophil chemoattractant properties similar to the classical neutrophil chemoattractant, fMet-Leu-Phe, and likewise uses FPR1 in the process.

CXCL1/CXCL8 (GROα/IL-8) in human diabetic ketoacidosis plasma facilitates leukocyte recruitment to cerebrovascular endothelium in vitro.

Diabetic ketoacidosis (DKA) in children is associated with intracranial vascular complications, possibly due to leukocyte-endothelial interactions. Our aim was to determine whether DKA-induced inflammation promoted leukocyte adhesion to activated human cerebrovascular endothelium. Plasma was obtained from children with type 1 diabetes either in acute DKA or in an insulin-controlled state (CON). Plasma concentrations of 21 inflammatory analytes were compared between groups. DKA was associated with altered circulating levels of ↑CXCL1 (GROα), ↑CXCL8 (IL-8), ↑IL-6, ↑IFNα2, and ↓CXCL10 (IP-10) compared with CON. These plasma analyte measurements were then used to create physiologically relevant cytokine mixtures (CM). Human cerebral microvascular endothelial cells (hCMEC/D3) were stimulated with either plasma (DKA-P or CON-P) or CM (DKA-CM or CON-CM) and assessed for polymorphonuclear leukocyte (PMN) adhesion. Stimulation of hCMEC/D3 with DKA-P or DKA-CM increased PMN adhesion to hCMEC/D3 under "flow" conditions. PMN adhesion to hCMEC/D3 was suppressed with neutralizing antibodies to CXCL1/CXCL8 or their hCMEC/D3 receptors CXCR1/CXCR2. DKA-P, but not DKA-CM, initiated oxidative stress in hCMEC/D3. Expression of ICAM-1, VCAM-1, and E-selectin were unaltered on hCMEC/D3 by either DKA-P or DKA-CM. In summary, DKA elicits inflammation in children associated with changes in circulating cytokines/chemokines. Increased CXCL1/CXCL8 instigated PMN adhesion to hCMEC/D3, possibly contributing to DKA-associated intracranial vascular complications.

The impact of non-steroidal anti-inflammatory drugs on the small intestinal epithelium.

The small intestine has been called as a dark continent of digestive tract and it had been very difficult to diagnose or treat the disease of small intestine. However recent technological development including video capsule endoscopy or balloon-assisted endoscopy has made us to aware the various diseases of small intestine. By using capsule endoscopy, many researchers reported that more than 70% of patients treated continuously with non-steroidal anti-inflammatory drugs (NSAID) exhibit the mucosal damage of small intestine. In some cases, NSAID not only causes mucosal damage but also results in life threatening bleeding from small intestine, which had not been prevented or cured by gastro-protective drug or anti-gastric acid secretion drug administration. Therefore to investigate and identify the effective drug that protects small intestine from mucosal damage is urgently expected. In spite of extensive investigation in clinical field, only a few drugs such as misoprostol, a synthetic prostaglandin E1 analogue, has been reported as an effective one but is not satisfactory enough to fulfill the requirement of patients who suffer from NSAID-induced mucosal damage of small intestine. And now, extensive study is being performed using several gastro-mucoprotective drugs by many researchers. In this review, we introduce the current clinical situation in small intestinal injury of patients under NSAID treatment, and to summarize the molecular mechanism by which NSAID, including acetyl salicylic acid, cause small intestinal damage. In addition, we present results of clinical trials performed so far, and refer the possible preventive method or treatment in the near future.

Diabetic ketoacidosis elicits systemic inflammation associated with cerebrovascular endothelial cell dysfunction.

OBJECTIVE: To determine if the DKA-induced inflammation in juvenile mice provokes activation and dysfunction of CVECs. METHODS: DKA in juvenile mice was induced with administration of STZ and ALX. Blood from DKA mice was assessed for cytokines and soluble cell adhesion proteins, and either DKA plasma or exogenous compounds were applied to immortalized bEND3. RESULTS: DKA increased circulating levels of IL-6, IL-8(KC), MCP-1, IL-10, sE-selectin, sICAM-1, and sVCAM-1. Stimulation of bEND3 with DKA plasma caused cellular activation (increased ROS and activation of NF-κΒ), upregulation of a proadhesive phenotype (E-selectin, ICAM-1, and VCAM-1), and increased leukocyte-bEND3 interaction (leukocyte rolling/adhesion). TEER, a measure of bEND3 monolayer integrity, was decreased by DKA plasma. Activation and dysfunction of bEND3 with DKA plasma were suppressed by plasma heat treatment (56°C, 1 hour) and replicated with the application of DKA recombinant cytomix (IL-6, IL-8[KC], MCP-1, and IL-10), implicating circulating inflammatory protein(s) as mediators. Treatment of bEND3 with ß-OH-butyrate, the main ketone elevated in DKA, failed to mimic the DKA plasma-induced activation and dysfunction of bEND3. CONCLUSIONS: DKA elicits systemic inflammation associated with CVEC activation and dysfunction, possibly contributing to DKA-associated intracranial microvascular complications.