Search

Autoimmune pancreatitis (AIP) is an autoimmune disorder of the pancreas characterized by enhanced IgG4 antibody responses and multiple organ involvement. AIP is a pancreatic manifestation of the systemic IgG4-related disease (IgG4-RD). Although AIP and IgG4-RD predominantly occur in middle-aged and elderly men, the roles of eating habits and lifestyle in the pathogenesis of these conditions are poorly understood. In this study, we examined whether a high-fat diet (HFD), preferred by middle-aged and elderly men, increases sensitivity to experimental AIP. We modeled AIP in MRL/MpJ mice by repeated injections of polyinosinic:polycytidylic acid. HFD exacerbated AIP development and promoted pancreatic accumulation of interferon (IFN)-α-producing plasmacytoid dendritic cells (pDCs). However, HFD did not increase the severity of autoimmune sialadenitis, another disorder associated with AIP and IgG4-RD. Neutralization of type I IFN signaling pathways prevented the development of severe AIP induced by HFD. In contrast, leaky gut was less likely to be associated with the HFD-induced exacerbation of AIP, as was evidenced by the lack of significant alterations in the jejunal or ileal expression of tight junction proteins. These data suggest that HFD exacerbates experimental AIP through the activation of pDCs producing IFN-α.

An 82-year-old man with fever and back pain was referred to our hospital and was thus found to be thrombocytopenic. A bone marrow biopsy revealed the diffuse infiltration of poorly differentiated neuroendocrine carcinoma (NEC). Computed tomography revealed a large hepatic mass. Considering the risk of bleeding due to thrombocytopenia, a needle biopsy was not performed. The patient rapidly deteriorated and died 10 days after presentation. An autopsy confirmed the diagnosis of primary hepatic NEC, with diffuse metastasis to the spleen, bone marrow, and systemic lymph nodes. This is an extremely rare case of NEC presenting with thrombocytopenia due to extensive bone marrow and splenic infiltration.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor expressed in hematopoietic and non-hematopoietic cells. Activation of the AhR by xenobiotics, microbial metabolites, and natural substances induces immunoregulatory responses. Autoimmune pancreatitis (AIP) is a chronic fibroinflammatory disorder of the pancreas driven by autoimmunity. Although AhR activation generally suppresses pathogenic autoimmune responses, the roles played by the AhR in AIP have been poorly defined. In this study, we examined how AhR activation affected the development of experimental AIP caused by the activation of plasmacytoid dendritic cells producing IFN-α and IL-33. Experimental AIP was induced in MRL/MpJ mice by repeated injections of polyinosinic-polycytidylic acid. Activation of the AhR by indole-3-pyruvic acid and indigo naturalis, which were supplemented in the diet, inhibited the development of experimental AIP, and these effects were independent of the activation of plasmacytoid dendritic cells producing IFN-α and IL-33. Interaction of indole-3-pyruvic acid and indigo naturalis with AhRs robustly augmented the production of IL-22 by pancreatic islet α cells. The blockade of IL-22 signaling pathways completely canceled the beneficial effects of AhR ligands on experimental AIP. Serum IL-22 concentrations were elevated in patients with type 1 AIP after the induction of remission with prednisolone. These data suggest that AhR activation suppresses chronic fibroinflammatory reactions that characterize AIP via IL-22 produced by pancreatic islet α cells.

Supporting force, that a rod receives from the ground, is increased when vibration gives to the ground. This phenomenon is effective to improve the running performance for the legged rovers. In this study, the flow of the ground particles when a rod is dragged is measured using PIV for improving the running performance of the legged rovers. As observed from the experimental result, the larger the supporting force is, the larger the area that the particles move is. Therefore, the supporting force is related to the movement of the ground particles. Moreover, the area that the particles move becomes large by providing vibration whose frequency is high. The reason is considered that density is increased in a wide range of the ground when the vibration whose frequency is high. It is considered that the supporting force is increased by providing vibration to the ground because the area, that the particles move, grows by increasing density of the ground. The findings of this study suggest facilitating further planetary exploration using legged rovers.

Cellular inhibitors of apoptosis proteins 1 (cIAP1) and 2 (cIAP2) are involved in signaling pathways mediated by Toll-like receptors (TLRs) and tumor necrosis factor (TNF)-α. Excessive activation of TLRs and TNF-α underlies the immunopathogenesis of Crohn’s disease (CD) and ulcerative colitis (UC). However, the roles played by cIAP1 and cIAP2 in the development of CD and UC remain poorly understood. In this study, we attempted to clarify the molecular link between cIAP1/cIAP2 and colonic inflammation. Human monocyte-derived dendritic cells (DCs) treated with siRNAs specific for cIAP1 or cIAP2 exhibited reduced pro-inflammatory cytokine responses upon stimulation with TLR ligands. Expression of cIAP1 and cIAP2 in human DCs was suppressed in the presence of interferon regulatory factor 4 (IRF4). This effect was associated with inhibition of cIAP1 and cIAP2 polyubiquitination. To verify these in vitro findings, we created mice overexpressing IRF4 in DCs and showed that these mice were resistant to trinitrobenzene sulfonic acid-induced colitis as compared with wild-type mice; these effects were accompanied by reduced expression levels of cIAP1 and cIAP2. Pro-inflammatory cytokine production by mesenteric lymph node cells upon stimulation with TLR ligands was reduced in mice with DC-specific IRF4 overexpression as compared with that in wild-type mice. Finally, in clinical samples of the colonic mucosa from patients with CD, there was a negative relationship between the percentage of IRF4+ DCs and percentages of cIAP1+ or cIAP2+ lamina propria mononuclear cells. These data suggest that the colitogenic roles of cIAP1 and cIAP2 are negatively regulated by IRF4.

Figure S2. Association between Cirp and IL-17, Bcl-2, Bcl-xL or Sox2 in the colonic mucosa of patients with Crohn's disease (CD). Scatter plot of relative mRNA levels of Cirp and respective genes in human colonic mucosa.

Supplementary Figure Legends

Figure S3. (A) Representative immunostaining images of colonic mucosa of controls and patients with refractory UC using anti-Sox2 antibody. Scale bar, 50 microm. (B) Representative immunostaining images of colonic mucosa of patients with refractory UC with anti-Cirp and anti-E-cadherin antibodies. (C) Representative immunostaining images of well-moderately differentiated colorectal cancer tissues with anti-Cirp antibody. Scale bar, 100 microm. (D) Representative immunostaining images of colonic mucosa of patients with refractory UC using anti-Dclk1 antibody. Scale bar, 20 microm.

Figure S6. (A) Representative images of immunohistochemical detection of E-cadherin, a marker for epithelial cells, and TUNEL staining of tumors from AOM + DSS-treated mice. (B) Representative immunostaining images of colonic mucosa of non-treated (DSS -), DSS-treated (DSS) and AOM + DSS-treated mice (AOM + DSS) using anti-PCNA antibody. Scale bar, 100 microm.

Supplementary Figure 1. Cdx2 expression in human gastric epithelial cell lines. Supplementary Figure 2. The expression of Cdx2 was enhanced by H. pylori infection in gastric epithelial cell. Supplementary Figure 3. Scheme of the Cdx2 prmoter-luciferase reporter plasmids used in this study. Supplementary Figure 4. BAY11-7082 inhibits NF-κB activation. Supplementary Figure 5. NOD1 siRNA reduced the expression of NOD1. Supplementary Figure 6. Cdx2 and MUC2 expression in GSM06 cells. Supplementary Figure 7. Pretreatment with iE-DAP reduces H. pylori infection-induced Cdx2 expression. Supplementary Figure 8. iE-DAP alone does not alter Cdx2 expression. Supplementary Figure 9. Inflammatory scores of the stomach did not differ between NOD1-intact and NOD1-deficient mice. Supplementary Figure 10. TNF-α was induced in the stomachs of H. pylori-infected mice.

Figure S4. (A) Colonic lysates from DSS-treated WT and Cirp-/- mice were immunoblotted with antibodies against the indicated proteins. (B) Relative mRNA levels in colonic tissues from mice treated with DSS, as determined by real-time qPCR (n = 4 per group). Expression level in colonic tissues from non-treated WT mice was set as 1. Results are expressed as means + SEM. *P < 0.05 compared with WT mice. (C) TNF-B mRNA level extracted from BM-derived macrophages was analyzed by real-time qPCR. (D) BM-derived macrophages were isolated from WT and Cirp-/- mice and cell lysates were immunoblotted with antibodies against the indicated proteins.

Figure S5. Representative immunostaining images of colonic mucosa of non-treated (DSS -), DSS-treated (DSS) and AOM+DSS-treated mice (AOM+DSS) using anti-Sox2 (A) and anti-Cirp(B) antibody. Scale bar, 100 microm.

Chronic infection with the bacterial Helicobacter pylori is a major cause of gastric and duodenal ulcer disease, gastric mucosal atrophy, and cancer. H. pylori–induced expression of the intestinal epithelial–specific transcription factor caudal-related homeobox 2 (Cdx2) contributes to intestinal metaplasia, a precursor event to gastric cancer. Given a role for the bacterial pattern recognition molecule nucleotide-binding oligomerization domain 1 (NOD1) in the innate immune response to bacterial infection, we investigated mechanisms used by NOD1 to regulate H. pylori infection and its propensity towards the development of intestinal metaplasia. We found that Cdx2 was induced by H. pylori infection in both normal and neoplastic gastric epithelial cells in a manner that was inversely related to NOD1 signaling. Mechanistic investigations revealed that Cdx2 induction relied upon activation of NF-κB but was suppressed by NOD1-mediated activation of TRAF3, a negative regulator of NF-κB. In vivo, prolonged infection of NOD1-deficient mice with H. pylori led to increased Cdx2 expression and intestinal metaplasia. Furthermore, gastric epithelial cells from these mice exhibited increased nuclear expression of the NF-κB p65 subunit and decreased expression of TRAF3. Overall, our findings illuminated a role for NOD1 signaling in attenuating H. pylori–induced Cdx2 expression in gastric epithelial cells, suggesting a rationale to augment NOD1 signaling in H. pylori–infected patients to limit their risks of accumulating precancerous gastric lesions. Cancer Res; 76(5); 1135–45. ©2016 AACR.

Supplementary Figure Legends

Figure S1. Association between Cirp and TNF-B, IL-17, IL-23, Bcl-xL or Dclk1 in the colonic mucosa of patients with ulcerative colitis (UC). Scatter plot of relative mRNA levels of Cirp and respective genes in human colonic mucosa.

Although concurrent occurrence of spondyloarthritis (SpA) and ulcerative colitis (UC) is sometimes seen, the profiles of cytokines have been poorly understood in UC-associated SpA. We herein report a case of UC-associated SpA successfully treated with infliximab. Profiles of cytokines in the serum and colonic mucosa were characterized by an enhanced expression of IL-6 but not TNF-α. Successful induction of remission by infliximab was associated with the downregulation of IL-6 expression but no significant alteration in TNF-α expression. These findings suggest that some cases of UC-associated SpA might be driven by IL-6, and infliximab might be effective in cases lacking enhanced TNF-α responses.

The present study focused on the siltation process at the navigation channel in the Port of Niigata, Japan. A part of the port is located at the mouth of the Shinano River, which is the longest one in the country. Due to the discharged sediments through the river and their deposition in the port area, frequent dredging works are required for the safety navigations in the waterway and turning basins. The purpose of the present study is to get a better understanding of the specific features of the sedimentary process in the target area for the consideration of any appropriate countermeasures for the optimization of the dredging works. In the present study, we especially focus on the sedimentation processes around the dredged navigation channel, which need frequent dredging to keep the planned depth from −5.5 to −12 m, under the complicated estuarine hydraulic conditions and several field measurements have been carried out, including current measurements, bathymetric surveys by acoustic soundings with a narrow multibeam sonar system.

Background The clinical characteristics of IgG4-related sclerosing cholangitis (IgG4-SC) especially without autoimmune pancreatitis (AIP) have not been investigated in a large cohort. Aims To clarify the clinical characteristics of IgG4-SC and IgG4-SC without AIP. Methods We retrospectively reviewed imaging, serology, other organ involvement (OOI) and histology of 872 patients with IgG4-SC who participated in a Japanese nationwide survey in 2019, and compared these items between IgG4-SC with and without AIP. Results AIP was present in 83.7% (730/872) of IgG4-SC. In IgG4-SC, bile duct wall thickening was observed on ultrasound (528/650; 81.2%), computed tomography (375/525; 71.4%) and magnetic resonance imaging or cholangiopancreatography (290/440; 65.9%). An elevated serum IgG4 level (≥ 135 mg/dL) was found in 88.0% (322/366). IgG4-related OOI other than AIP was observed in 25.2% (211/836). The proportion of females was significantly higher in IgG4-SC without AIP (28.9% vs. 20.1%; p = 0.025). Hilar stricture was the most common cholangiographic type in IgG4-SC without AIP (39/107; 36.4%).There were no significant differences between IgG4-SC with and without AIP in the rates of bile duct wall thickening, elevated serum IgG4 level, or IgG4-related OOI. Conclusions The clinical characteristics of IgG4-SC was similar between IgG4-SC with and without AIP in a large cohort.

To compare the behavioral roles of biogenic amines in the males of primitive and advanced eusocial bees, we determined the levels of dopamine- and octopamine-related substances in the brain, and the behavioral effects of these monoamines by drug injection in the primitive eusocial bumble bee, Bombus ignitus. The levels of dopamine and its precursors in the brain peaked at the late pupal stage, but the dopamine peak extended to adult emergence. The tyramine and octopamine levels increased from the mid-pupal to adult stages. The locomotor and flight activities, and light preference increased with age. Injection of octopamine and its receptor antagonist had significant effects on the locomotor and flight activities, whereas dopamine injection did not, indicating that these activities can be regulated by the octopaminergic system. We also determined the dynamics of dopamine-related substances in honey bee (Apis mellifera) drones. The changes in the dopamine level in the brains of honey bee drones exhibited two peaks from the pupal to adult stages, whereas the bumble bee males had only one peak. These are consistent with the behavioral functions of dopamine in honey bee drones and ineffectiveness of dopamine injection at the adult stage in bumble bee males.

The first reaction of the methanogenic pathway from carbon dioxide (CO2) is the reduction and condensation of CO2 to formyl-methanofuran, catalyzed by formyl-methanofuran dehydrogenase (Fmd). Strongly reducing electrons for this reaction are generated by heterodisulfide reductase (Hdr) in complex with hydrogenase or formate dehydrogenase (Fdh) using a flavin-based electron-bifurcation mechanism. Here, we report enzymological and structural characterizations of Fdh-Hdr-Fmd complexes from Methanospirillum hungatei. The complexes catalyze this reaction using electrons from formate and the reduced form of the electron carrier F420. Conformational changes in HdrA mediate electron bifurcation, and polyferredoxin FmdF directly transfers electrons to the CO2 reduction site, as evidenced by methanofuran-dependent flavin-based electron bifurcation even without free ferredoxin, a diffusible electron carrier between Hdr and Fmd. Conservation of Hdr and Fmd structures suggests that this complex is common among hydrogenotrophic methanogens.

Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular receptor for muramyl dipeptide derived from the intestinal microbiota. Loss-of-function mutations in Nod2 are associated with the development of Crohn's disease, suggesting that NOD2 signaling plays critical roles in the maintenance of intestinal immune homeostasis. Although NOD2 activation prevents the development of short-term experimental colitis, it remains unknown whether the sensitivity to long-term experimental colitis is influenced by NOD2. In this study, we explored the roles played by NOD2 in the development of long-term adoptive transfer colitis. Unexpectedly, we found that Rag1-/-Nod2-/- mice were more resistant to adoptive transfer colitis than Rag1-/- mice and had reduced proinflammatory cytokine responses and enhanced accumulation of regulatory T cells (Tregs) expressing forkhead box P3 in the colonic mucosa. Prevention of colitis in Rag1-/-Nod2-/- mice was mediated by TGF-β1 because neutralization of TGF-β1 resulted in the development of more severe colitis due to reduced accumulation of Tregs. Such paradoxical Treg responses in the absence of NOD2 could explain why Nod2 mutations in humans are not sufficient to cause Crohn's disease.

The value of contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) for T-staging in patients with extrahepatic bile duct cancer was evaluated. This single-center, retrospective study included consecutive patients with extrahepatic bile duct cancer who underwent surgical resection after preoperative EUS, CH-EUS, and contrast-enhanced CT (CE-CT) examinations between June 2014 and August 2017. The capacity of these modalities for T-staging of extrahepatic bile duct cancer was evaluated by assessing invasion beyond the biliary wall into the surrounding tissue, gallbladder, liver, pancreas, duodenum, portal vein system (portal vein and/or superior mesenteric vein), inferior vena cava, and hepatic arteries (proper hepatic artery, right. and/or left. hepatic artery). Blind reading of EUS, CH-EUS, and CE-CT images was performed by two expert reviewers each. 38 patients were eligible for analysis, of which eight had perihilar bile duct cancer and 30 had distal bile duct cancer. Postoperative T-staging was T1 in 6, T2 in 16, and T3 in 16 cases. CH-EUS was superior to CE-CT for diagnosing invasion beyond the biliary wall into surrounding tissue (92.1% vs. 45.9%, P = 0.0002); the ability to detect invasion to other organs did not differ significantly between the two modalities. The accuracy of CH-EUS for T-staging of tumors was better than that of CE-CT (73.7% vs. 39.5%, P = 0.0059). CH-EUS tended to have a better accuracy than EUS for the diagnosis of invasion beyond the biliary wall into the surrounding tissue (92.1% vs. 78.9%, P = 0.074) and T-staging (73.7% vs. 60.5%, P = 0.074). CH-EUS is useful for T-staging of extra hepatic bile duct cancer, especially in terms of invasion beyond the biliary wall into the surrounding tissue.

BACKGROUND Preparation for colon capsule endoscopy (CCE) requires a large liquid laxative volume for capsule excretion, which compromises the procedure's tolerability. AIM To assess the safety and utility of castor oil-boosted bowel preparation. METHODS This prospective cohort study including 20 patients (age range, 16-80 years; six men and 14 women) suspected of having colorectal disease was conducted at Kindai University Hospital from September 2017 to August 2019. All patients underwent CCE because of the following inclusion criteria: previous incomplete colonoscopy in other facility (n = 20), history of abdominal surgery (n = 7), or organ abnormalities such as multiple diverticulum (n = 4) and adhesion after surgery (n = 6). The exclusion criteria were as follows: Dysphagia, history of allergic reactions to the drugs used in this study (magnesium citrate, polyethylene glycol, metoclopramide, and castor oil), possibility of pregnancy, possibility of bowel obstruction or stenosis based on symptoms, or scheduled magnetic resonance imaging within 2 wk after CCE. The primary outcome was the capsule excretion rate within the battery life, as evaluated by the total large bowel observation rate, large bowel transit time, and bowel creasing level using a five-grade scale in different colorectal segments. The secondary outcomes were complications, colorectal lesion detection rates, and patients’ tolerability. RESULTS The castor oil-based regimen was implemented in 17 patients. Three patients cancelled CCE because they could tolerate castor oil, but not liquid laxatives. The capsule excretion rate within the battery life was 88% (15/17). The mean large bowel transit time was 236 min. Approximately 70% of patients had satisfactory colon cleansing levels. CCE detected colon polyps (14/17, 82%) and colonic diverticulum (4/12, 33%). The sensitivity, specificity, and diagnostic accuracy rates for detecting colorectal polyps (size ≥ 6 mm) were 76.9%, 75.0%, and 76.4%, respectively. The sensitivity, specificity, and diagnostic accuracy rates for detection of diverticulum were 100% each. Twelve patients (71%) rated CCE as more than “good”, confirming the new regimen’s tolerability. No serious adverse events occurred during this study. CONCLUSION The castor oil-based regimen could reduce bowel preparation dose and improve CCE tolerability.

A novel chemolithoautotrophic bacterium, strain H1576T, was isolated from water of a brackish lake. Strain H1576T grew aerobically on inorganic sulfur compounds. Hydrogen gas did not support autotrophic growth, and heterotrophic growth was not observed. Cells were rod-shaped, motile, 1.5–2.7 µm in length and 0.6–0.7 µm in width. Growth was observed at 3–22°C with an optimum growth temperature of 13–15°C. The pH range for growth was 6.0–7.4 with an optimum pH of 6.6–6.8. Major fatty acids were summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c). The complete genome of strain H1576T consists of a circular chromosome and a plasmid, with total length of 2.8 Mbp and G + C content of 46.4 mol%. Phylogenetic analyses indicated that strain H1576T belongs to the genus Sulfurimonas but distinct from representatives of existing species. On the basis of genomic and phenotypic characteristics, a new species named Sulfurimonas aquatica sp. nov. is proposed with the type strain of strain H1576T (= BCRC 81254T = JCM 35004T).

Hepatocytes and liver-resident antigen-presenting cells are exposed to microbe-associated molecular patterns (MAMPs) and microbial metabolites, which reach the liver from the gut via the portal vein. MAMPs induce innate immune responses via the activation of pattern recognition receptors (PRRs), such as toll-like receptors (TLRs), nucleotide-binding oligomerization domain 1 (NOD1), and NOD2. Such proinflammatory cytokine responses mediated by PRRs likely contribute to the development of chronic liver diseases and hepatocellular carcinoma (HCC), as shown by the fact that activation of TLRs and subsequent production of IL-6 and TNF-α is required for the generation of chronic fibroinflammatory responses and hepatocarcinogenesis. Similar to TLRs, NOD1 and NOD2 recognize MAMPs derived from the intestinal bacteria. The association between the activation of NOD1/NOD2 and chronic liver diseases is poorly understood. Given that NOD1 and NOD2 can regulate proinflammatory cytokine responses mediated by TLRs both positively and negatively, it is likely that sensing of MAMPs by NOD1 and NOD2 affects the development of chronic liver diseases, including HCC. Indeed, recent studies have highlighted the importance of NOD1 and NOD2 activation in chronic liver disorders. Here, we summarize the roles of NOD1 and NOD2 in hepatocarcinogenesis and liver injury.

The value of contrast-enhanced harmonic EUS (CH-EUS) for diagnosis of portal vein invasion in patients with pancreatic cancer was evaluated.This single-center, retrospective study included consecutive patients with pancreatic cancer who underwent both surgical resection after preoperative EUS, CH-EUS, and contrast-enhanced computed tomography (CE-CT) examinations between April 2015 and August 2017. CH-EUS evaluation was performed during the late phase. Portal vein invasion on EUS and CH-EUS was defined as no continuity in the line of the vessel wall. Definition of portal vein invasion on CE-CT was based on the Loyer's criteria. The accuracy of three modalities for diagnosis of invasion into the portal vein was compared using the McNemar's test.Eighty-eight patients (mean age: 71.0 years, ratio of male to female: 48:40) were eligible. Postoperative pathological results were as follows: seven cases of portal vein invasion; 81 cases without. Diagnostic accuracy of EUS, CH-EUS, and CE-CT for diagnosing invasion into the portal vein was 72.7%, 93.2%, and 81.8%, respectively. The differences between CH-EUS and CE-CT (P = 0.0094) and CH-EUS and EUS (P = 0.0022) were significant. EUS and CE-CT were comparable.CH-EUS is useful for diagnosis of portal vein invasion by pancreatic cancer.

Solitary organ autoimmune disorders, formerly known as autoimmune pancreatitis (AIP), autoimmune sialadenitis, and autoimmune sclerosing cholangitis, are now considered organ-specific manifestations of systemic immunoglobulin G4-related disease (IgG4-RD). AIP and IgG4-RD are characterized by elevated serum concentration of IgG4 antibody (Ab), accumulation of IgG4-expressing plasmacytes in the affected organs, and involvement of multiple organs. It is well established that enhanced IgG4 Ab responses are a hallmark of AIP and IgG4-RD for diagnosis and monitoring disease activity. However, a significant fraction of patients with AIP and IgG4-RD who develop chronic fibroinflammatory responses have normal serum concentrations of this IgG subtype. In addition, disease flare-up is sometimes seen even in the presence of normalized serum concentrations of IgG4 Ab after successful induction of remission by prednisolone. Therefore, it is necessary to identify new biomarkers based on the understanding of the pathophysiology of AIP and IgG4-RD. Recently, we found that activation of plasmacytoid dendritic cells producing both interferon-α (IFN-α) and interleukin-33 (IL-33) mediate murine AIP and human IgG4-RD. More importantly, we provided evidence that serum concentrations of IFN-α and IL-33 could be useful biomarkers for the diagnosis and monitoring of AIP and IgG4-RD activity after induction of remission in these autoimmune disorders. In this Frontier article, we have summarized and discussed biomarkers of AIP and IgG4-RD, including Igs, autoAbs, and cytokines to provide useful information not only for clinicians but also for researchers.

Ferredoxin is a type of electron carrier protein involved in many biological redox reactions and also incorporated as an electron transfer domain and subunit in redox enzyme complexes. MvhB-type po...

Background and Aims Kupffer-phase imaging visualized by perfluorobutane (Sonazoid) distribution into normal liver tissues upon phagocytosis by Kupffer cells potentially aids in improving detection of liver metastasis compared with fundamental B-mode EUS (FB-EUS). However, the diagnostic performance of Kupffer-phase imaging in contrast-enhanced harmonic EUS (CH-EUS) remains unclear. Hence, this study aimed to evaluate the usefulness of CH-EUS-based Kupffer-phase imaging for diagnosing liver metastasis from pancreatic cancer. Methods We retrospectively analyzed consecutive patients with pancreatic cancer who underwent contrast-enhanced CT (CE-CT) and FB-EUS, followed by CH-EUS, from 2011 to 2017. The diagnostic ability of CH-EUS against that of CE-CT and FB-EUS for metastasis in the left liver lobe was compared. Subsequently, the influences of CH-EUS on the determination of clinical stage and patient management for pancreatic cancer were assessed. Results We enrolled 426 patients with pancreatic cancer. Metastasis in the left liver lobe was present in 27.2% of patients. The diagnostic accuracy of CE-CT, FB-EUS, and CH-EUS was 90.6%, 93.4%, and 98.4%, respectively. The sensitivity and diagnostic accuracy of CH-EUS for metastasis in the left liver lobe were significantly higher than those of FB-EUS or CE-CT. The sensitivity of CH-EUS for detecting small liver metastasis ( Conclusions CH-EUS-based Kupffer-phase imaging increased the detectability of metastasis in the left liver lobe. This technique could be a reliable pretreatment imaging modality for clinical decision-making in patients with pancreatic cancer.

Efficient protection against coronavirus disease 2019 (COVID-19) has been achieved by immunization with mRNA-based vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, efficient immune responses against this novel virus by vaccination are accompanied by a wide variety of side effects. Indeed, flares or new-onset of autoimmune disorders have been reported soon after the COVID-19 vaccination. Although pro-inflammatory cytokine responses play pathogenic roles in the development of autoimmunity, cytokines charactering COVID-19 vaccination-related autoimmune responses have been poorly understood. Given that mRNA derived from COVID-19 vaccine is a potent inducer for pro-inflammatory cytokine responses, these cytokines might mediate autoimmune responses after COVID-19 vaccination. Here we report a case with new-onset rheumatoid arthritis (RA) following COVID-19 vaccination. Serum concentrations not only of arthrogenic cytokines, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), but also of type I interferon (IFN) were elevated at the active phase in this case. Induction of remission by methotrexate and tocilizumab was accompanied by a marked reduction in serum concentrations of type I IFN, IL-6, and TNF-α. These results suggest that production of type I IFN, IL-6, and TNF-α induced by COVID-19 vaccination might be involved in this case with new-onset RA.

Pancreatitis occurs in two forms defined by its chronicity. Acute pancreatitis (AP) occurs suddenly and only lasts for several days. Consequently, most patients with AP recover without permanent damage to the pancreas, and about 20% of patients with AP have severe disease. In contrast, chronic pancreatitis (CP) is a long-lasting inflammation that causes permanent damage to pancreatic tissue; consequently, this form is marked by the emergence of persistent endocrine and exocrine pancreatic insufficiency. Despite these differences, AP and CP share central mechanisms of disease: in both forms, inflammation is initiated and/or sustained by the intrapancreatic activation of pancreatic digestive enzymes followed by the autodigestion of pancreatic tissues. In addition, in both forms enzymatic damage is accompanied by changes in intestinal permeability and entry of commensal organisms into the pancreas where they elicit innate immune responses that ultimately dominate and define pancreatic inflammation. In the murine models of AP and CP described here, both of these elements of pancreatitis pathogenesis are taken into account. Thus, in one approach mice are administered high doses of cerulein, a cholecystokinin analog with the ability at this dose to induce excessive activation of the cholecystokinin receptor expressed in pancreatic acinar cells and the release of active trypsin that causes both direct and indirect acinar damages due to entry of commensal organisms and stimulation of innate immune responses. In a second approach mice are administered low doses of cerulein, which causes little or no damage to the pancreas unless given along with nucleotide-binding oligomerization domain 1 (NOD1) ligand, which in the presence of low-dose cerulein administration induces a pathologic innate immune response mediated by NOD1. These approaches are adopted to produce AP when cerulein or cerulein plus NOD1 ligand is applied only once or to produce CP when a similar regimen is applied multiple times. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Cerulein-induced acute pancreatitis Alternate Protocol 1: Acute pancreatitis induced by cerulein and NOD1 ligand Basic Protocol 2: Cerulein-induced chronic pancreatitis Alternate Protocol 2: Chronic pancreatitis induced by cerulein and NOD1 ligand Support Protocol: Isolation of pancreatic mononuclear cells.

BACKGROUND AND AIMS Pancreatic neuroendocrine neoplasms (PanNENs), including Grade 1 (G1) or G2 tumors, can have a poor prognosis. This study investigated the value of contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) for predicting the prognosis of PanNENs. METHODS This single-center, retrospective study included 47 consecutive patients who underwent CH-EUS and were diagnosed with PanNEN by surgical resection or EUS-guided fine needle aspiration between December 2011 and February 2016. Patients were divided into aggressive and non-aggressive groups according to the degree of clinical malignancy. CH-EUS was assessed regarding its capacity for diagnosing aggressive PanNEN, the correspondence between contrast patterns and pathological features, and its ability to predict the prognosis of PanNEN. RESULTS There were 19 cases of aggressive PanNEN and 28 cases of non-aggressive PanNEN. The aggressive group included three G1, four G2, three G3 tumors, three mixed neuroendocrine non-neuroendocrine neoplasms, and six neuroendocrine carcinomas. CH-EUS was superior to contrast-enhanced computed tomography for the diagnosis of aggressive PanNEN (P

Summary Although increasing evidence demonstrates the association between intestinal dysbiosis and pancreatic diseases such as chronic pancreatitis and pancreatic cancer, it remains largely unknown whether intestinal dysbiosis is involved in the immunopathogenesis of autoimmune pancreatitis (AIP). Recently, we found that intestinal dysbiosis mediates experimental AIP via the activation of plasmacytoid dendritic cells (pDCs), which can produce interferon (IFN)-α and interleukin (IL)-33. However, candidate intestinal bacteria, which promote the development of AIP, have not been identified. Fecal samples were obtained from type 1 AIP patients before and after prednisolone (PSL) treatment and subjected to 16S ribosomal RNA sequencing to evaluate the composition of intestinal bacteria. Induction of remission by PSL was associated with the complete disappearance of Klebsiella species from feces in two of the three analyzed patients with type 1 AIP. To assess the pathogenicity of Klebsiella species, mild experimental AIP was induced in MRL/MpJ mice by repeated injections of 10 μg of polyinosinic–polycytidylic acid [poly(I:C)], in combination with oral administration of heat-killed Klebsiella pneumoniae. The AIP pathology score was significantly higher in MRL/MpJ mice that received both oral administration of heat-killed K. pneumoniae and intraperitoneal injections of poly(I:C) than in those administered either agent alone. Pancreatic accumulation of pDCs capable of producing large amounts of IFN-α and IL-33 was also significantly higher in mice that received both treatments. These data suggest that intestinal colonization by K. pneumoniae may play an intensifying role in the development of type 1 AIP.

Polymorphisms in the autophagy-related protein 16 like 1 (ATG16L1) and nucleotide-binding oligomerization domain 2 (NOD2) genes are associated with Crohn’s disease (CD). Impaired interaction between ATG16L1 and NOD2 underlies CD immunopathogenesis. Although activation of the receptor-interacting serine–threonine kinase (RICK, also known as RIP2), a downstream signaling molecule for NOD2 and multiple toll-like receptors (TLRs), plays a pathogenic role in the development of inflammatory bowel disease, the molecular interaction between ATG16L1 and RICK/RIP2 remains poorly understood. In this study, we examined the physical interaction between ATG16L1 and RICK/RIP2 in human embryonic kidney 293 cells and human monocyte-derived dendritic cells (DCs) expressing excessive and endogenous levels of these proteins, respectively. We established that ATG16L1 binds to RICK/RIP2 kinase domain and negatively regulates TLR2-mediated nuclear factor-kappa B (NF-κB) activation and pro-inflammatory cytokine responses by inhibiting the interaction between TLR2 and RICK/RIP2. Binding of ATG16L1 to RICK/RIP2 suppressed NF-κB activation by down-regulating RICK/RIP2 polyubiquitination. Notably, the percentage of colonic DCs expressing ATG16L1 inversely correlated with IL-6 and TNF-α expression levels in the colon of CD patients. These data suggest that the interaction between ATG16L1 and RICK/RIP2 maintains intestinal homeostasis via the down-regulation of TLR-mediated pro-inflammatory cytokine responses.

Background Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the early-onset epileptic encephalopathies resistant to antiepileptic drugs, therefore carrying an extremely poor neurodevelopmental outcome. KCNT1, encoding for a sodium-activated potassium channel (KCa4.1 channel), has recently been reported as the major gene responsible for EIMFS. Since gain of function is the only type of mutation identified in patients with EIMFS, quinidine, a partial antagonist of KCa4.1 channel, is considered as a potential candidate for targeted treatment of EIMFS. However, treatment results reported so far vary from seizure-free state to no response, and cardiac side effect remains a challenge for dose titration and long-term treatment. Case report Our case was an infant diagnosed with EIMFS with confirmed mutation in KCNT1 gene. Quinidine therapy was started as early as 9 months old. Within the first month of treatment, the number of seizures reduced to about one third. However, seizure-free state was not obtained and his neuropsychological development remained severely delayed. After 16 months of treatment, quinidine had to be discontinued because of cardiac side effects. At 27 months of age, however, his seizures suddenly stopped and he remained seizure-free for five days. This coincided with the prescription of tipepidine, a commonly used antitussive, administered for his persistent cough. Reduction in seizure frequency was also observed with dextromethorphan, another conventional antitussive drug. Although the relation between these treatments and his symptom improvement is a matter of elucidation, there is a possibility that these nonnarcotic antitussive drugs might play a role in the treatment of EIFMS.

Nephroptosis is a benign disorder defined as a significant descent of the affected kidney as the patient moves from supine to erect. Patients with nephroptosis sometimes manifest symptoms including abdominal pain, back pain, nausea and hematuria, while the majority of those are asymptomatic. Downward migration of the affected kidney induced by a postural change from the supine to the upright position underlies the pathophysiology of nephroptosis. The diagnosis of nephroptosis is difficult since routine imaging examinations are conducted in the supine position alone. Here, we report a case presenting recurrent abdominal pain due to unknown causes. This patient was successfully diagnosed as nephroptosis by ultrasonography and drip infusion pyelography, both of which were performed in both supine and upright positions. This case report strongly suggests that we need to take into consideration a possibility of nephroptosis when we encounter with patients complaining abdominal and/or back pain due to unknown causes.

Excessive type I IFN (IFN-I) production by plasmacytoid dendritic cells (pDCs) promotes autoimmunity. Recently, we reported that a prominent feature of both experimental autoimmune pancreatitis (AIP) and human type 1 AIP is pDC activation followed by enhanced production of IFN-I and IL-33. However, the roles played by interferon regulatory factor 7 (IRF7), a critical transcription factor for IFN-I production in pDCs, in these disorders have not been clarified. Whole and nuclear extracts were isolated from pancreatic mononuclear cells (PMNCs) from MRL/MpJ mice exhibiting AIP. Expression of phospho-IRF7 and nuclear translocation of IRF7 was examined in these extracts by immunoblotting. Pancreatic expression of IRF7 was assessed by immunofluorescence analysis in experimental AIP. Nuclear translocation of IRF7 upon exposure to neutrophil extracellular traps (NETs) was assessed in peripheral blood pDCs from type 1 AIP patients. Pancreatic IRF7 expression was examined in surgically operated specimens from type 1 AIP patients. IRF7 activation was induced in pancreatic pDCs in experimental AIP. siRNA-mediated knockdown of IRF7 expression prevented AIP development, which was accompanied by a marked reduction in both pancreatic accumulation of pDCs and production of IFN-α and IL-33. Notably, in peripheral blood pDCs isolated from patients with type 1 AIP, nuclear translocation of IRF7 was enhanced as compared with the translocation in pDCs from healthy controls. Furthermore, IRF7-expressing pDCs were detected in the pancreas of patients with type 1 AIP. These findings suggest that the IRF7-IFN-I-IL-33 axis activated in pDCs drives pathogenic innate immune responses associated with type 1 AIP.