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Revista Espanola de Enfermedades... Nov 2023Gastrointestinal bleeding of obscure origin accounts for less than 5% of gastrointestinal hemorrhages. It is typically difficult to diagnose due to limited accessibility...
Gastrointestinal bleeding of obscure origin accounts for less than 5% of gastrointestinal hemorrhages. It is typically difficult to diagnose due to limited accessibility through standard endoscopic techniques and generally requires a significant number of procedures to reach a diagnosis. The "blue rubber bleb nevus syndrome" is a rare condition, of a probably hereditary origin, characterized by the presence of multiple hemangiomatous lesions, which can manifest as gastrointestinal bleeding of obscure origin. These lesions are generally nodular, rubbery to the touch, and have a submucosal appearance, primarily affecting the skin and gastrointestinal tract. We present the case of a 72-year-old male who was investigated for iron deficiency anemia with upper and lower gastrointestinal endoscopies conducted on two occasions, without revealing any findings that could explain the condition. Subsequently, a study with video-capsule endoscopy was performed, which revealed multiple submucosal and vascular lesions, measuring between 3-5 mm, located in the distal duodenum and jejunum, consistent with "Blue rubber bleb nevus syndrome".
Topics: Male; Humans; Aged; Skin; Anemia, Iron-Deficiency; Capsule Endoscopy; Gastrointestinal Hemorrhage
PubMed: 37882205
DOI: 10.17235/reed.2023.9913/2023 -
Phytomedicine : International Journal... Dec 2023Tripterygium wilfordii has been widely used for the treatment of rheumatoid arthritis, which is frequently accompanied by severe gastrointestinal damage. The molecular...
Celastrol as an intestinal FXR inhibitor triggers tripolide-induced intestinal bleeding: Underlying mechanism of gastrointestinal injury induced by Tripterygium wilfordii.
BACKGROUND
Tripterygium wilfordii has been widely used for the treatment of rheumatoid arthritis, which is frequently accompanied by severe gastrointestinal damage. The molecular mechanism underlying the gastrointestinal injury of Tripterygium wilfordii are yet to be elucidated.
METHODS
Transmission electron microscopy, and pathological and biochemical analyses were applied to assess intestinal bleeding. Metabolic changes in the serum and intestine were determined by metabolomics. In vivo (time-dependent effect and dose-response) and in vitro (double luciferase reporter gene system, DRATs, molecular docking, HepG2 cells and small intestinal organoids) studies were used to identify the inhibitory role of celastrol on intestinal farnesoid X receptor (FXR) signaling. Fxr-knockout mice and FXR inhibitors and agonists were used to evaluate the role of FXR in the intestinal bleeding induced by Tripterygium wilfordii.
RESULTS
Co-treatment with triptolide + celastrol (from Tripterygium wilfordii) induced intestinal bleeding in mice. Metabolomic analysis indicated that celastrol suppressed intestinal FXR signaling, and further molecular studies revealed that celastrol was a novel intestinal FXR antagonist. In Fxr-knockout mice or the wild-type mice pre-treated with pharmacological inhibitors of FXR, triptolide alone could activate the duodenal JNK pathway and induce intestinal bleeding, which recapitulated the pathogenic features obtained by co-treatment with triptolide and celastrol. Lastly, intestinal bleeding induced by co-treatment with triptolide and celastrol could be effectively attenuated by the FXR or gut-restricted FXR agonist through downregulation of the duodenal JNK pathway.
CONCLUSIONS
The synergistic effect between triptolide and celastrol contributed to the gastrointestinal injury induced by Tripterygium wilfordii via dysregulation of the FXR-JNK axis, suggesting that celastrol should be included in the quality standards system for evaluation of Tripterygium wilfordii preparations. Determining the mechanism of the FXR-JNK axis in intestinal bleeding could aid in the identification of additional therapeutic targets for the treatment of gastrointestinal hemorrhage diseases. This study also provides a new standard for the quality assessment of Tripterygium wilfordii used in the treatment of gastrointestinal disorders.
Topics: Animals; Mice; Triterpenes; Tripterygium; Molecular Docking Simulation; Gastrointestinal Hemorrhage; Mice, Knockout
PubMed: 37738906
DOI: 10.1016/j.phymed.2023.155054 -
The American Journal of Gastroenterology Jun 2024Gut microbiome changes are linked to obesity, but findings are based on stool data. In this article, we analyzed the duodenal microbiome and serum biomarkers in subjects...
INTRODUCTION
Gut microbiome changes are linked to obesity, but findings are based on stool data. In this article, we analyzed the duodenal microbiome and serum biomarkers in subjects with normal weight, overweight, and obesity.
METHODS
Duodenal aspirates and serum samples were obtained from subjects undergoing standard-of-care esophagogastroduodenoscopy without colon preparation. Aspirate DNAs were analyzed by 16S rRNA and shotgun sequencing. Predicted microbial metabolic functions and serum levels of metabolic and inflammatory biomarkers were also assessed.
RESULTS
Subjects with normal weight (N = 105), overweight (N = 67), and obesity (N = 42) were identified. Overweight-specific duodenal microbial features include lower relative abundance (RA) of Bifidobacterium species and Escherichia coli strain K-12 and higher Lactobacillus intestinalis , L. johnsonii , and Prevotella loescheii RA. Obesity-specific features include higher Lactobacillus gasseri RA and lower L. reuteri (subspecies rodentium ), Alloprevotella rava , and Leptotrichia spp RA. Escalation features (progressive changes from normal weight through obesity) include decreasing Bacteroides pyogenes , Staphylococcus hominis , and unknown Faecalibacterium species RA, increasing RA of unknown Lactobacillus and Mycobacterium species, and decreasing microbial potential for biogenic amines metabolism. De-escalation features (direction of change altered in normal to overweight and overweight to obesity) include Lactobacillus acidophilus , L. hominis , L. iners , and Bifidobacterium dentium . An unknown Lactobacillus species is associated with type IIa dyslipidemia and overweight, whereas Alloprevotella rava is associated with type IIb and IV dyslipidemias.
DISCUSSION
Direct analysis of the duodenal microbiome has identified key genera associated with overweight and obesity, including some previously identified in stool, e.g., Bifidobacterium and Lactobacillus . Specific species and strains exhibit differing associations with overweight and obesity, including escalation and de-escalation features that may represent targets for future study and therapeutics.
Topics: Humans; Obesity; Female; Male; Overweight; Middle Aged; Gastrointestinal Microbiome; Adult; Duodenum; RNA, Ribosomal, 16S; Biomarkers; Lactobacillus; Bifidobacterium; Aged
PubMed: 38578969
DOI: 10.14309/ajg.0000000000002790 -
Advanced Science (Weinheim,... Sep 2023Dermatitis herpetiformis (DH) is an inflammatory skin disorder often considered as an extra intestinal manifestation of celiac disease (CeD). Hallmarks of CeD and DH are...
Dermatitis herpetiformis (DH) is an inflammatory skin disorder often considered as an extra intestinal manifestation of celiac disease (CeD). Hallmarks of CeD and DH are auto-antibodies to transglutaminase 2 (TG2) and transglutaminase 3 (TG3), respectively. DH patients have auto-antibodies reactive with both transglutaminase enzymes. Here it is reported that in DH both gut plasma cells and serum auto-antibodies are specific for either TG2 or TG3 with no TG2-TG3 cross reactivity. By generating monoclonal antibodies from TG3-specific duodenal plasma cells of DH patients, three conformational epitope groups are defined. Both TG2-specific and TG3-specific gut plasma cells have few immunoglobulin (Ig) mutations, and the two transglutaminase-reactive populations show distinct selection of certain heavy and light chain V-genes. Mass spectrometry analysis of TG3-specific serum IgA corroborates preferential usage of IGHV2-5 in combination with IGKV4-1. Collectively, these results demonstrate parallel induction of anti-TG2 and anti-TG3 auto-antibody responses involving separate B-cell populations in DH patients.
Topics: Humans; Celiac Disease; Dermatitis Herpetiformis; Immunoglobulin A; Plasma Cells; Protein Glutamine gamma Glutamyltransferase 2; Transglutaminases
PubMed: 37424036
DOI: 10.1002/advs.202300401 -
The Lancet. Oncology Dec 2023Stereotactic body radiotherapy (SBRT) has the potential to ablate localised pancreatic ductal adenocarcinoma. Selective dismutase mimetics sensitise tumours while... (Randomized Controlled Trial)
Randomized Controlled Trial
Stereotactic body radiotherapy with or without selective dismutase mimetic in pancreatic adenocarcinoma: an adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial.
BACKGROUND
Stereotactic body radiotherapy (SBRT) has the potential to ablate localised pancreatic ductal adenocarcinoma. Selective dismutase mimetics sensitise tumours while reducing normal tissue toxicity. This trial was designed to establish the efficacy and toxicity afforded by the selective dismutase mimetic avasopasem manganese when combined with ablative SBRT for localised pancreatic ductal adenocarcinoma.
METHODS
In this adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial, patients aged 18 years or older with borderline resectable or locally advanced pancreatic cancer who had received at least 3 months of chemotherapy and had an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at six academic sites in the USA. Eligible patients were randomly assigned (1:1), with block randomisation (block sizes of 6-12) with a maximum of 24 patients per group, to receive daily avasopasem (90 mg) or placebo intravenously directly before (ie, within 180 min) SBRT (50, 55, or 60 Gy in five fractions, adaptively assigned in real time by Bayesian estimates of 90-day safety and efficacy). Patients and physicians were masked to treatment group allocation, but not to SBRT dose. The primary objective was to find the optimal dose of SBRT with avasopasem or placebo as determined by the late onset EffTox method. All analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT03340974, and is complete.
FINDINGS
Between Jan 25, 2018, and April 29, 2020, 47 patients were screened, of whom 42 were enrolled (median age was 71 years [IQR 63-75], 23 [55%] were male, 19 [45%] were female, 37 [88%] were White, three [7%] were Black, and one [2%] each were unknown or other races) and randomly assigned to avasopasem (n=24) or placebo (n=18); the placebo group was terminated early after failing to meet prespecified efficacy parameters. At data cutoff (June 28, 2021), the avasopasem group satisfied boundaries for both efficacy and toxicity. Late onset EffTox efficacy response was observed in 16 (89%) of 18 patients at 50 Gy and six (100%) of six patients at 55 Gy in the avasopasem group, and was observed in three (50%) of six patients at 50 Gy and nine (75%) of 12 patients at 55 Gy in the placebo group, and the Bayesian model recommended 50 Gy or 55 Gy in five fractions with avasopasem for further study. Serious adverse events of any cause were reported in three (17%) of 18 patients in the placebo group and six (25%) of 24 in the avasopasem group. In the placebo group, grade 3 adverse events within 90 days of SBRT were abdominal pain, acute cholangitis, pyrexia, increased blood lactic acid, and increased lipase (one [6%] each); no grade 4 events occurred. In the avasopasem group, grade 3-4 adverse events within 90 days of SBRT were acute kidney injury, increased blood alkaline phosphatase, haematoma, colitis, gastric obstruction, lung infection, abdominal abscess, post-surgical atrial fibrillation, and pneumonia leading to respiratory failure (one [4%] each).There were no treatment-related deaths but one late death in the avasopasem group due to sepsis in the setting of duodenal obstruction after off-study treatment was reported as potentially related to SBRT.
INTERPRETATION
SBRT that uses 50 or 55 Gy in five fractions can be considered for patients with localised pancreatic ductal adenocarcinoma. The addition of avasopasem might further enhance disease outcomes. A larger phase 2 trial (GRECO-2, NCT04698915) is underway to validate these results.
FUNDING
Galera Therapeutics.
Topics: Humans; Male; Female; Aged; Adenocarcinoma; Pancreatic Neoplasms; Radiosurgery; Bayes Theorem; Carcinoma, Pancreatic Ductal; Double-Blind Method; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38039992
DOI: 10.1016/S1470-2045(23)00478-3 -
Allergy, Asthma, and Clinical... Dec 2023Non-esophageal eosinophilic gastrointestinal disorder (non-EoE-EGID) is a rare disease in which eosinophils infiltrate parts of the gastrointestinal tract other than the...
BACKGROUND
Non-esophageal eosinophilic gastrointestinal disorder (non-EoE-EGID) is a rare disease in which eosinophils infiltrate parts of the gastrointestinal tract other than the esophagus; however, the number of patients with non-EoE-EGID has been increasing in recent years. Owing to its chronic course with repeated relapses, it can lead to developmental delays due to malnutrition, especially in pediatric patients. No established treatment exists for non-EoE-EGID, necessitating long-term systemic corticosteroid administration. Although the efficacy of dupilumab, an anti-IL-4/13 receptor monoclonal antibody, for eosinophilic esophagitis, has been reported, only few reports have demonstrated its efficacy in non-EoE EGIDs.
CASE PRESENTATION
A 13-year-old boy developed non-EoE-EGID with duodenal ulcers, with chicken eggs as the trigger. He was successfully treated with an egg-free diet, proton pump inhibitors, and leukotriene receptor antagonists. However, at age 15, he developed worsening upper abdominal pain and difficulty eating. Blood analysis revealed eosinophilia; elevated erythrocyte sedimentation rate; and elevated levels of C-reactive protein, total immunoglobulin E, and thymic and activation-regulated chemokines. Upper gastrointestinal endoscopy revealed a duodenal ulcer with marked mucosal eosinophilic infiltration. Gastrointestinal symptoms persisted even after starting systemic steroids, making it difficult to reduce the steroid dose. Subcutaneous injection of dupilumab was initiated because of comorbid atopic dermatitis exacerbation. After 3 months, the gastrointestinal symptoms disappeared, and after 5 months, the duodenal ulcer disappeared and the eosinophil count decreased in the mucosa. Six months later, systemic steroids were discontinued, and the duodenal ulcer remained recurrence-free. The egg challenge test result was negative; therefore, the egg-free diet was discontinued. Blood eosinophil count and serum IL-5, IL-13, and eotaxin-3 levels decreased after dupilumab treatment. The serum levels of IL-5 and eotaxin-3 remained within normal ranges, although the blood eosinophil counts increased again after discontinuation of oral prednisolone.
CONCLUSIONS
Suppression of IL-4R/IL-13R-mediated signaling by dupilumab may improve abdominal symptoms and endoscopic and histologic findings in patients with non-EoE-EGID, leading to the discontinuation of systemic steroid administration and tolerance of causative foods.
PubMed: 38053199
DOI: 10.1186/s13223-023-00859-3 -
Gastrointestinal Endoscopy Apr 2024Ampullary lesions (ALs) of the minor duodenal papilla are extremely rare. Endoscopic papillectomy (EP) is a routinely used treatment for AL of the major duodenal...
BACKGROUND AND AIMS
Ampullary lesions (ALs) of the minor duodenal papilla are extremely rare. Endoscopic papillectomy (EP) is a routinely used treatment for AL of the major duodenal papilla, but the role of EP for minor AL has not been accurately studied.
METHODS
We identified 20 patients with ALs of minor duodenal papilla in the multicentric database from the Endoscopic Papillectomy vs Surgical Ampullectomy vs Pancreatitcoduodenectomy for Ampullary Neoplasm study, which included 1422 EPs. We used propensity score matching (nearest-neighbor method) to match these cases with ALs of the major duodenal papilla based on age, sex, histologic subtype, and size of the lesion in a 1:2 ratio. Cohorts were compared by means of chi-square or Fisher exact test as well as Mann-Whitney U test.
RESULTS
Propensity score-based matching identified a cohort of 60 (minor papilla 20, major papilla 40) patients with similar baseline characteristics. The most common histologic subtype of lesions of minor papilla was an ampullary adenoma in 12 patients (3 low-grade dysplasia and 9 high-grade dysplasia). Five patients revealed nonneoplastic lesions. Invasive cancer (T1a), adenomyoma, and neuroendocrine neoplasia were each found in 1 case. The rate of complete resection, en-bloc resection, and recurrences were similar between the groups. There were no severe adverse events after EP of lesions of minor papilla. One patient had delayed bleeding that could be treated by endoscopic hemostasis, and 2 patients showed a recurrence in surveillance endoscopy after a median follow-up of 21 months (interquartile range, 12-50 months).
CONCLUSIONS
EP is safe and effective in ALs of the minor duodenal papilla. Such lesions could be managed according to guidelines for EP of major duodenal papilla.
Topics: Humans; Treatment Outcome; Ampulla of Vater; Endoscopy, Gastrointestinal; Pancreatic Ducts; Pancreatic Neoplasms; Duodenal Neoplasms; Common Bile Duct Neoplasms; Retrospective Studies
PubMed: 37951279
DOI: 10.1016/j.gie.2023.10.040 -
The American Journal of Clinical... Sep 2023Intestinal nutrient sensing regulates food intake and energy metabolism by acting locally and relaying nutritional status to the brain. It is unclear whether these... (Clinical Trial)
Clinical Trial
BACKGROUND
Intestinal nutrient sensing regulates food intake and energy metabolism by acting locally and relaying nutritional status to the brain. It is unclear whether these mechanisms are altered in obese humans.
OBJECTIVES
We aimed to investigate differences in duodenal nutrient sensing in humans with or without obesity and the effects of transiently blocking vagal transmission on nutrient sensing, hunger, and appetite.
METHODS
In a single-blinded, randomized, cross-over design, subjects with or without obesity (n = 14 and n = 11, respectively) were infused intraduodenally with saline or a combination of glucose and oleic acid for 90 min (glucose load: 22.5 g, 1 kcal/min; oleic acid load: 10 g, 1 kcal/min) in the presence or absence of local anesthetic (benzocaine). Blood was sampled at 10-min intervals (120-240 min) and 15-min intervals until termination of the study for measurements of gut hormones, insulin, leptin, and C-peptide. Hunger and satiety sensations were scored using the visual analog scale, and hepatic glucose production and glucose oxidation rates were measured.
RESULTS
Duodenal nutrient infusion in lean subjects led to a 65% drop in acyl ghrelin release and robustly increased cholecystokinin 8 (CCK-8) release (65%; P = 0.023); benzocaine infusion delayed this response (2-factor repeated-measures analysis of variance, P = 0.0065). In contrast, subjects with obesity had significantly blunted response to nutrient infusion, and no further effects were observed with benzocaine. Additionally, significant delays were observed in peptide YY (3-36), pancreatic polypeptide, glucose inhibitory peptide, and glucagon-like peptide 1 (7-36) response. No significant interactions were found between body mass index (BMI) or baseline hormone levels and areas under the curve for hormones except CCK-8 (BMI, P = 0.018; baseline CCK, P = 0.013). Nutrient-induced hunger and satiety sensations were impeded by benzocaine only in the lean cohort. Hunger and satiety sensations in subjects with obesity were not responsive to nutrient entry into the duodenum, and no additional effects were observed by blocking neural signaling.
CONCLUSION
Nutrient-induced gut hormone release and response to transient vagal blockade are significantly blunted in subjects with obesity. This trial was registered at clinicaltrials.org as NCT02537314.
Topics: Humans; Male; Female; Adult; Nutrients; Duodenum; Appetite; Satiety Response; Obesity; Thinness
PubMed: 37661107
DOI: 10.1016/j.ajcnut.2023.06.011 -
Oncology Letters Aug 2023The first part of the duodenum consists of the intraperitoneal segment, called the duodenal bulb, and the retroperitoneal segment. Regarding the blood supplying the... (Review)
Review
Intracorporeal linear‑stapled gastroduodenostomy in totally laparoscopic distal gastrectomy for gastric cancer: Consideration of the intraoperative management of the duodenal wall between the transecting staple line and anastomotic staple line (Review).
The first part of the duodenum consists of the intraperitoneal segment, called the duodenal bulb, and the retroperitoneal segment. Regarding the blood supplying the duodenal bulb, which is the portion utilized in anastomosing the duodenum and remnant stomach following distal gastrectomy, the arterial pedicles branching off from the gastroduodenal artery are reported to reach the posterior wall first and then spread over the anterior wall, where they anastomose. When performing intracorporeal linear-stapled gastroduodenostomy following totally laparoscopic distal gastrectomy, the blood supply of the duodenal wall between the transecting staple line and anastomotic staple line needs to be considered because both transection of the duodenal bulb and the gastroduodenostomy are performed using an endoscopic linear stapler and the duodenal wall between the staple lines can be ischemic after the anastomosis. Since it needs to be decided intraoperatively whether this duodenal site is preserved or removed, the present review discusses the technical differences among several procedures for intracorporeal linear-stapled gastroduodenostomy, classifying them into two groups on the basis of the intraoperative management of this duodenal site. When this site is preserved, the blood supply of the duodenal wall needs to be retained with certainty. On the other hand, when this site is removed, the ischemic portion of the duodenal wall needs to be identified and removed. Furthermore, in both groups, an adequate anastomotic area needs to be secured. In conclusion, surgeons need to be familiar with the anatomical features of the duodenal bulb, including its blood perfusion and shape, when carrying out intracorporeal linear-stapled gastroduodenostomy.
PubMed: 37545615
DOI: 10.3892/ol.2023.13940 -
Diabetologia Jul 2024Protein kinase CK2 acts as a negative regulator of insulin expression in pancreatic beta cells. This action is mainly mediated by phosphorylation of the transcription...
AIMS/HYPOTHESIS
Protein kinase CK2 acts as a negative regulator of insulin expression in pancreatic beta cells. This action is mainly mediated by phosphorylation of the transcription factor pancreatic and duodenal homeobox protein 1 (PDX1). In pancreatic alpha cells, PDX1 acts in a reciprocal fashion on glucagon (GCG) expression. Therefore, we hypothesised that CK2 might positively regulate GCG expression in pancreatic alpha cells.
METHODS
We suppressed CK2 kinase activity in αTC1 cells by two pharmacological inhibitors and by the CRISPR/Cas9 technique. Subsequently, we analysed GCG expression and secretion by real-time quantitative RT-PCR, western blot, luciferase assay, ELISA and DNA pull-down assays. We additionally studied paracrine effects on GCG secretion in pseudoislets, isolated murine islets and human islets. In vivo, we examined the effect of CK2 inhibition on blood glucose levels by systemic and alpha cell-specific CK2 inhibition.
RESULTS
We found that CK2 downregulation reduces GCG secretion in the murine alpha cell line αTC1 (e.g. from 1094±124 ng/l to 459±110 ng/l) by the use of the CK2-inhibitor SGC-CK2-1. This was due to a marked decrease in Gcg gene expression through alteration of the binding of paired box protein 6 (PAX6) and transcription factor MafB to the Gcg promoter. The analysis of the underlying mechanisms revealed that both transcription factors are displaced by PDX1. Ex vivo experiments in isolated murine islets and pseudoislets further demonstrated that CK2-mediated reduction in GCG secretion was only slightly affected by the higher insulin secretion after CK2 inhibition. The kidney capsule transplantation model showed the significance of CK2 for GCG expression and secretion in vivo. Finally, CK2 downregulation also reduced the GCG secretion in islets isolated from humans.
CONCLUSIONS/INTERPRETATION
These novel findings not only indicate an important function of protein kinase CK2 for proper GCG expression but also demonstrate that CK2 may be a promising target for the development of novel glucose-lowering drugs.
Topics: Casein Kinase II; Animals; Glucagon; Mice; Humans; Glucagon-Secreting Cells; Homeodomain Proteins; Trans-Activators; Male; Cell Line; Insulin
PubMed: 38503901
DOI: 10.1007/s00125-024-06128-1