Heparin-bridging therapy is associated with post-colorectal polypectomy bleeding in patients whose oral anticoagulation therapy is interrupted.

OBJECTIVES: The American and Japanese Societies for Gastrointestinal Endoscopy Guidelines recommend heparin-bridging therapy for patients whose oral anticoagulants are interrupted for endoscopic procedures. However, little is known about the potential association between heparin-bridging therapy and post-polypectomy bleeding (PPB). The aim was to investigate the incidence of PPB associated with heparin-bridging therapy administered to patients whose anticoagulants were interrupted. MATERIALS AND METHODS: This was a retrospective observational study using inverse propensity analysis. Between 2013 and 2015, 1004 patients with 2863 lesions were included. The primary outcomes were the rates of PPB and thromboembolism associated with heparin-bridging therapy. The risk factors associated with PPB were identified using multivariate logistic regression analysis involving probability of treatment weighting (IPTW). RESULTS: The patients were categorized into a heparin-bridging therapy group (78 patients with 255 lesions) or a control group (926 patients with 2608 lesions). The PPB rate in the heparin-bridging therapy group (10.2%, 8/78) was significantly higher than in the control group (1.1%, 11/926) (p <.01). Thromboembolism occurred in one patient in the control group. The multivariate analysis revealed that heparin-bridging therapy was an independent risk factor associated with PPB (odds ratio [OR], 8.21; 95% confidence interval [95% CI], 2.32-29.10; p <.01). IPTW showed heparin-bridging therapy increased PPB (OR, 7.68; 95% CI, 1.83-32.28; p <.01). CONCLUSIONS: Heparin-bridging therapy administered to patients whose oral anticoagulants were interrupted was associated with an increased PPB risk.

Persistent colonization of Candida albicans yeast on the tongue in NOD/SCID.e2f1-/- mice.

Candida albicans is a commensal fungus that commonly colonizes as opportunistic pathogens human mucosal surfaces. Our aim was to observe persistent infection of C. albicans on the tongue in NOD/SCID.e2f1(-/-) mice, which naturally was decreased saliva and undeveloped T and B cells. Using a cotton swab, a C. albicans suspension was applied to the tongue of wild type and mutant mice after disinfection using 0.2% Chlorhexidine (CHX). In our earlier report, it was found that many times inoculation per day and consecutive day inoculations without disinfection of indigenous microorganisms did not induce significant C. albicans infection for 48 h in the oral cavity. In this study, using inoculation of four sets {one inoculation after disinfection by CHX + interval (3 or 4 d)} induced longer term and higher numbers infection for 4 days on the tongue than results in a previous report in both NOD/SCID.e2f1(+/+) and NOD/SCID.e2f1(-/-) mice. Repeat of disinfection to indigenous microorganisms and inoculation with interval established and realized a new model for persistent infection of C. albicans yeast. However, decreased saliva and consecutive inoculations per day did not contribute to the persistent colonization on the tongue in the mice. It is suggested that the interaction between C. albicans and indigenous microorganisms is important for persistent colonization of C. albicans yeast on the tongue rather than decreased saliva in the oral cavity.

[An investigation of oral colonization by Candida albicans in immunodeficient animal with decreasing saliva volume].

Candida albicans is a commensal fungus that commonly colonizes human mucosal surfaces. When the host immune defenses are impaired, C. albicans triggers recurrent infections of the oral mucosa and tongue. We previously reported that the characteristics in NOD/SCID. e2f1(-/-) mice that have naturally decreased saliva and T and B cells that do not develop increase the susceptibility of oral bacterial infection in the oral cavity. Next, we sought to establish a C. albicans infection model in NOD/SCID. e2f1(-/-) mice. C. albicans yeast forms were introduced by wiping a cotton swab moistened with C. albicans solution on the tongue after disinfection by 0.2 Chlorhexidine for the first time. After an interval of 60 min, the inoculation was performed by pipette 2 or 4 times at an interval of 60 min. The number of C. albicans colonized on the tongue significantly increased but there were no significant difference between NOD/SCID. e2f1(+/+) mice and NOD/SCID. e2f1(-/-) mice at 120-240 minutes. However, a significant difference between these mice was observed at 24 hours after the last inoculation. Moreover, 5 inoculations/day were also performed for 2-4 days and significant differences between mice arose, and the maximum level of infection was found at 24 hours after consecutive inoculation for 3, 4 and 5 days, but the levels were reduced after 48 h. It is suggested that the saliva volume and flow are important for preventing 24-hour colonization of C. albicans. NOD/SCID. e2f1(-/-) mice are a relevant mouse model for 24-hour colonization on the tongue.

Effect of long-term piceatannol treatment on eNOS levels in cultured endothelial cells.

Piceatannol (3, 3', 4, 5'-tetrahydroxy-trans-stilbene) is a naturally occurring phytochemical found in passion fruit (Passiflora edulis) seeds. Previously, we demonstrated that piceatannol has acute vasorelaxant effects in rat thoracic aorta. It was suggested that endothelial NO synthase (eNOS) might be involved in piceatannol-induced acute vasorelaxation. Here, we investigated the expression of eNOS in EA.hy926 human umbilical vein cells after long-term treatment with piceatannol, and compared this effect with that of resveratrol, an analog of piceatannol. Long-term treatment with piceatannol up-regulated eNOS mRNA expression and increased eNOS protein expression in a dose-dependent manner. Moreover, piceatannol increased the levels of phosphorylated eNOS. Treatment with resveratrol also increased eNOS expression, but to a lesser degree than piceatannol. These findings indicate that piceatannol may improve vascular function by up-regulating eNOS expression.

Effects of salivary protein flow and indigenous microorganisms on initial colonization of Candida albicans in an in vivo model.

BACKGROUND: Candida albicans is a dimorphic fungus that is part of the commensal microbial flora of the oral cavity. When the host immune defenses are impaired or when the normal microbial flora is disturbed, C. albicans triggers recurrent infections of the oral mucosa and tongue. Recently, we produced NOD/SCID.e2f1-/- mice that show hyposalivation, decrease of salivary protein flow, lack IgA and IgG in saliva, and have decreased NK cells. Our objective was to characterize C. albicans infection and biofilm formation in mice. METHODS: NOD/SCID.e2f1-/- mice were used as an animal model for C. albicans infection. C. albicans yeast and hyphal forms solutions were introduced in the oral cavity after disinfection by Chlorhexidine. RESULTS: The numbers of C. albicans colonized and decreased in a time-dependent manner in NOD/SCID.e2f1+/+ after inoculation. However, the colonization levels were higher in NOD/SCID.e2f1+/+ than NOD/SCID.e2f1-/- mice. In the mice fed 1% sucrose water before inoculation, C. albicans sample was highly contaminated by indigenous microorganisms in the oral cavity; and was not in the mice fed no sucrose water. The colonization of C. albicans was not influenced by the contamination of indigenous microorganisms. The hyphal form of C. albicans restricted the restoration of indigenous microorganisms. The decreased saliva in NOD/SCID.e2f1-/- did not increase the colonization of C. albicans in comparison to NOD/SCID.e2f1+/+ mice. We suggest that the receptor in saliva to C. albicans may not be sufficiently provided in the oral cavity of NOD/SCID.e2f1-/- mice. CONCLUSION: The saliva protein flow may be very important for C. albicans initial colonization, where the indigenous microorganisms do not affect colonization in the oral cavity.

Angle of covered self-expandable metallic stents after placement is a risk factor for recurrent biliary obstruction.

BACKGROUND: Studies have shown that covered self-expandable metallic stents (CSEMS) with a low axial forces after placement can cause early recurrent biliary obstruction (RBO) due to precipitating sludge formation. AIM: To ascertain whether the angle of CSEMS after placement is a risk factor for RBO in unresectable distal malignant biliary obstruction (MBO). METHODS: Between January 2010 and March 2019, 261 consecutive patients underwent self-expandable metallic stent insertion by endoscopic retrograde cholangiopancreatography at our facility, and 87 patients were included in this study. We evaluated the risk factors for RBO, including the angle of CSEMS after placement as the primary outcome. We measured the obtuse angle of CSEMS after placement on an abdominal radiograph using the SYNAPSE PACS system. We also evaluated technical and functional success, adverse events, time to RBO (TRBO), non-RBO rate, survival time, cause of RBO, and reintervention procedure as secondary outcomes. RESULTS: We divided the patients into two cohorts based on the presence or absence of RBO. The angle of CSEMS after placement (per 1° and per 10°) was evaluated using the multivariate Cox proportional hazard analysis, which was an independent risk factor for RBO in unresectable distal MBO [hazard ratio, 0.97 and 0.71; 95% confidence interval (CI): 0.94-0.99 and 0.54-0.92; P = 0.01 and 0.01, respectively]. For early diagnosis of RBO, the cut-off value of the angle of CSEMS after placement using the receiver operating characteristic curve was 130° [sensitivity, 50.0%; specificity 85.5%; area under the curve 0.70 (95%CI: 0.57-0.84)]. TRBO in the < 130° angle group was significantly shorter than that in the ≥ 130° angle group (P < 0.01). CONCLUSION: This study suggests that the angle of the CSEMS after placement for unresectable distal MBO is a risk factor for RBO. These novel results provide pertinent information for future stent management.

Continuous warfarin administration versus heparin bridging therapy in post colorectal polypectomy haemorrhage: a study protocol for a multicentre randomised controlled trial (WHICH study).

BACKGROUND: Endoscopic removal of colorectal adenoma is considered an effective treatment for reducing the mortality rates associated with colorectal cancer. Warfarin, a type of anticoagulant, is widely used for the treatment and prevention of thromboembolism; however, bleeding may increase with its administration after polypectomy. In recent times, a high incidence of bleeding after endoscopic polypectomy has been reported in patients receiving heparin bridge therapy. However, previous studies have not compared the bleeding rate after endoscopic colorectal polypectomy between patients who continued with anticoagulant therapy and those who received heparin bridge therapy. We hypothesised that endoscopic colorectal polypectomy under the novel treatment with continuous warfarin is not inferior to endoscopic colorectal polypectomy under standard treatment with heparin bridge therapy with respect to the rate of postoperative bleeding. This study aims to compare the efficacy of endoscopic colorectal polypectomy with continuous warfarin administration and endoscopic colorectal polypectomy with heparin bridge therapy with respect to the rate of postoperative bleeding. METHODS: We will conduct a prospective multicentre randomised controlled non-inferiority trial of two parallel groups. We will compare patients scheduled to undergo colorectal polypectomy under anticoagulant therapy with warfarin. There will be 2 groups, namely, a standard treatment group (heparin bridge therapy) and the experimental treatment group (continued anticoagulant therapy). The primary outcome measure is the rate of postoperative bleeding. On the contrary, the secondary outcomes include the rate of cumulative bleeding, rate of overt haemorrhage (that does not qualify for the definition of haemorrhage after endoscopic polypectomy), incidence of haemorrhage requiring haemostasis during endoscopic polypectomy, intraoperative bleeding during endoscopic colorectal polypectomy requiring angiography, abdominal surgery and/or blood transfusion, total rate of bleeding, risk factors for postoperative bleeding, length of hospital stay, incidence of thromboembolism, prothrombin time-international ratio (PT-INR) 28 days after the surgery, and incidence of serious adverse events. DISCUSSION: The results of this randomised controlled trial will provide valuable information for the standardisation of management of anticoagulants in patients scheduled to undergo colorectal polypectomy. TRIAL REGISTRATION: UMIN-CTR UMIN000023720 . Registered on 22 August 2016.

The usefulness of serial pancreatic juice aspiration cytological examination for pancreatic cancer not diagnosed by EUS-FNAB.

Endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) is safe and useful for the diagnosis of pancreatic cancer. However, sometimes a diagnosis cannot be established by EUS-FNAB. The efficacy of serial pancreatic juice aspiration cytological examination (SPACE) for pancreatic cancer was reported. SPACE may be useful in cases in which diagnosis by EUS-FNAB is difficult; however, this has not been reported previously. We herein report two cases of pancreatic cancer diagnosed by SPACE when diagnosis by EUS-FNAB was difficult. Case 1 was a 77-year-old female. She was suspected of pancreatic cancer because of new-onset diabetes. We performed EUS-FNAB to the lesion in the pancreatic body; however, diagnosis failed. We performed SPACE and diagnosed pancreatic cancer finally. Case 2 was 72 years old female. She was suspected of having pancreatic cancer because of the dilatation of the pancreatic duct. We performed EUS-FNAB twice to the lesion in the pancreatic head, however, diagnosis failed. Therefore, we performed SPACE and got final diagnosis as pancreatic cancer. From our experience, we suggest that SPACE is a useful diagnostic method for patients with pancreatic cancer that are difficult to diagnose.

Effects of Cot expression on the nuclear translocation of NF-kappaB in RBL-2H3 cells.

Cot is a serine/threonine protein kinase and is classified as a mitogen-activated protein (MAP) kinase kinase kinase. Overexpression of this protein has been shown to activate the extracellular signal-regulated kinase, the c-Jun N-terminal kinase, and the p38 MAP kinase pathways and to stimulate NF-AT and NF-kappaB-dependent transcription. Here we have shown that Cot kinase activity is intimately involved in the high affinity receptor for IgE (FcvarepsilonRI)-mediated nuclear translocation of NF-kappaB1 independent of NF-kappaB-inducing kinase (NIK) in rat basophilic leukemia (RBL-2H3) cells. A transfected green fluorescent protein-tagged NF-kappaB1 (GFP-NF-kappaB1) resided in the cytoplasm in RBL-2H3 cells and it remained in the cytoplasm even when Cot tagged with red fluorescent protein (Cot-RFP) was co-expressed. Western blotting analysis showed that IkappaB kinases (IKKs) were expressed in RBL-2H3 cells but NIK was not. GFP-NF-kappaB1 translocated from the cytoplasm to the nucleus after the aggregation of FcvarepsilonRI in Cot-transfected cells but not in kinase-deficient Cot-transfected cells. This finding gives a new insight into the role of Cot in the FcvarepsilonRI-mediated NF-kappaB activation in mast cells.

Piceatannol and its metabolite, isorhapontigenin, induce SIRT1 expression in THP-1 human monocytic cell line.

Piceatannol is a phytochemical that is present in large amounts in passion fruit (Passiflora edulis) seeds, and is an analog of resveratrol. Recently, the absorption and metabolism of piceatannol were investigated in rats, and isorhapontigenin, O-methyl piceatannol, was detected as a piceatannol metabolite in rat plasma. To elucidate the function of piceatannol and its metabolites, we investigated the expression of sirtuin 1 (SIRT1) in THP-1 monocytic cells after treatment with piceatannol and its metabolites, and compared their effects with those of resveratrol and its metabolites. Piceatannol and resveratrol upregulated the expression levels of SIRT1 mRNA and SIRT1 protein. An extract of passion fruit seeds, which contained high levels of piceatannol, also upregulated SIRT1 mRNA expression. As for the metabolites, isorhapontigenin upregulated SIRT1 mRNA expression, whereas resveratrol glucuronides and sulfate did not affect SIRT1 expression. These findings indicate that after intake of piceatannol, not only piceatannol itself, but also its metabolite, isorhapontigenin, contributed to the upregulation of SIRT1 expression.

Primary small intestinal mucosa-associated lymphoid tissue lymphoma diagnosed by balloon-assisted enteroscopy.

A 78-year-old Japanese woman presented with anemia. Oral double-balloon endoscopy (DBE) detected multiple ulcerative lesions covered with coagula extending up to approximately 20 cm from the mid-jejunum. Based on the histopathological findings, the patient's condition was diagnosed as mucosa-associated lymphoid tissue (MALT) lymphoma of the small intestine. During the second DBE examination, a small intestinal perforation occurred in one of the ulcerative lesions, and an emergency segmental small intestinal resection was performed. The present case suggests that in MALT lymphoma, intestinal wall fragility may lead to perforation even though the lesion may appear to be a superficial ulcer on endoscopy.

Hydroxylation of (-)-epigallocatechin-3-O-gallate at 3'', but not 4'', is essential for the PI3-kinase/Akt-dependent phosphorylation of endothelial NO synthase in endothelial cells and relaxation of coronary artery rings.

(-)-Epigallocatechin-3-O-gallate (EGCg) has been shown to induce endothelium-dependent nitric oxide (NO)-mediated relaxation via the redox-sensitive Src/PI3-kinase/Akt-dependent phosphorylation of endothelial NO synthase (eNOS). Although the presence of 8 hydroxyl functions, mainly on B and D rings, is essential for the EGCg-induced activation of eNOS, the relative role of each individual hydroxyl function still remains unclear. This study examined the effect of selective replacement of hydroxyl functions by methoxy moieties on either the B or D ring on the EGCg-induced phosphorylation of Akt and eNOS, formation of reactive oxygen species (ROS) and NO in cultured coronary artery endothelial cells, and endothelium-dependent relaxation of coronary artery rings. Replacement of a single hydroxyl by the methoxy group on position 3', 4' or 4'' affected little the EGCg-induced phosphorylation of Akt and eNOS, formation of ROS and NO in endothelial cells, and induction of endothelium-dependent relaxations. In contrast, the single methylation at position 3'' and the double methylation at both positions 3' and 4' reduced markedly the phosphorylation of Akt and eNOS, the formation of ROS and NO in endothelial cells and the relaxation of artery rings. These findings suggest that the hydroxyl group at the 3'' position of the gallate ring is essential and, also, to some extent, the two hydroxyl groups at positions 3' and 4', for the EGCg-induced redox-sensitive activation of eNOS leading to the subsequent NO-mediated vascular relaxation.