ABSTRACT
Proranolol has long been recommended to prevent variceal bleeding in patients with cirrhosis. However, the mechanisms of propranolol in liver fibrosis have not yet been thoroughly elucidated. Autophagic cell death (ACD) of activated hepatic stellate cells (HSCs) is important in the alleviation of liver fibrosis. Our study aims to assess the mechanisms of propranolol regulating HSC ACD and liver fibrosis. ACD of HSCs was investigated using lentivirus transfection. The molecular mechanism was determined using a PCR profiler array. The role of autophagy-related protein 9b (ATG9b) in HSC ACD was detected using co-immunoprecipitation and co-localization of immunofluorescence. Changes in the signalling pathway were detected by the Phospho Explorer antibody microarray. Propranolol induces ACD and apoptosis in HSCs. ATG9b upregulation was detected in propranolol-treated HSCs. ATG9b upregulation promoted ACD of HSCs and alleviated liver fibrosis in vivo. ATG9b enhanced the P62 recruitment to ATG5-ATG12-LC3 compartments and increased the co-localization of P62 with ubiquitinated proteins. The PI3K/AKT/mTOR pathway is responsible for ATG9b-induced ACD in activated HSCs, whereas the p38/JNK pathway is involved in apoptosis. This study provides evidence for ATG9b as a new target gene and propranolol as an agent to alleviate liver fibrosis by regulating ACD of activated HSCs.
Subject(s)
Autophagic Cell Death , Esophageal and Gastric Varices , Humans , Hepatic Stellate Cells/metabolism , Propranolol/pharmacology , Propranolol/metabolism , Up-Regulation , Phosphatidylinositol 3-Kinases/metabolism , Esophageal and Gastric Varices/metabolism , Esophageal and Gastric Varices/pathology , Gastrointestinal Hemorrhage/metabolism , Gastrointestinal Hemorrhage/pathology , Liver Cirrhosis/metabolism , Liver/metabolism , AutophagyABSTRACT
A new set of derivatives bearing pyrazole-methylenehydrazono-thiazolidinone scaffold 4-23 was designed, synthesized and confirmed by different spectroscopic means and elemental analyses. In-vivo anti-inflammatory and ulcerogenic evaluation was performed for all the newly synthesized derivatives using indomethacin, celecoxib and diclofenac as standard drugs. The compounds 5, 10, 15, 17, 21, 22 appeared to be the most promising candidates producing rapid onset and long duration of anti-inflammatory activity as well as promising GIT safety profile. Furthermore, analgesic evaluation revealed that the compounds 5, 10, 15 and 22 produced potent and long acting analgesia accompanied with significant inhibition of the inflammatory cytokine TNF-α level in comparison with the standard drugs. Molecular docking study of the latter derivatives was also carried out to rationalize their binding affinities and their modes of interactions with the active site of TNF-α.
Subject(s)
Analgesics/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Ulcer Agents/pharmacology , Pyrazoles/pharmacology , Thiazolidines/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Analgesics/chemical synthesis , Analgesics/chemistry , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Ulcer Agents/chemical synthesis , Anti-Ulcer Agents/chemistry , Dose-Response Relationship, Drug , Drug Design , Female , Gastrointestinal Hemorrhage/drug therapy , Gastrointestinal Hemorrhage/metabolism , Male , Mice , Molecular Docking Simulation , Molecular Structure , Pyrazoles/chemistry , Rats , Rats, Wistar , Structure-Activity Relationship , Thiazolidines/chemistry , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Shiga toxin-producing E. coli (STEC) is a common foodborne pathogen in developed countries. STEC generates "attaching and effacing" (AE) lesions on colonic epithelium, characterized by effacement of microvilli and the formation of actin "pedestals" beneath intimately attached bacteria. In addition, STEC are lysogenized with a phage that, upon induction, can produce potent Shiga toxins (Stx), potentially leading to both hemorrhagic colitis and hemolytic uremic syndrome. Investigation of the pathogenesis of this disease has been challenging because STEC does not readily colonize conventional mice.Citrobacter rodentium (CR) is a related mouse pathogen that also generates AE lesions. Whereas CR does not produce Stx, a murine model for STEC utilizes CR lysogenized with an E. coli-derived Stx phage, generating CR(Φstx), which both colonizes conventional mice and readily gives rise to systemic disease. We present here key methods for the use of CR(Φstx) infection as a highly predictable murine model for infection and disease by STEC. Importantly, we detail CR(Φstx) inoculation by feeding, determination of pathogen colonization, production of phage and toxin, and assessment of intestinal and renal pathology. These methods provide a framework for studying STEC-mediated systemic disease that may aid in the development of efficacious therapeutics.
Subject(s)
Bacteriophages , Citrobacter rodentium , Colitis , Gastrointestinal Hemorrhage , Hemolytic-Uremic Syndrome , Intestinal Mucosa , Lysogeny , Shiga Toxins , Shiga-Toxigenic Escherichia coli , Animals , Bacteriophages/genetics , Bacteriophages/metabolism , Citrobacter rodentium/genetics , Citrobacter rodentium/metabolism , Citrobacter rodentium/pathogenicity , Citrobacter rodentium/virology , Colitis/genetics , Colitis/metabolism , Colitis/microbiology , Disease Models, Animal , Gastrointestinal Hemorrhage/genetics , Gastrointestinal Hemorrhage/metabolism , Gastrointestinal Hemorrhage/microbiology , Hemolytic-Uremic Syndrome/genetics , Hemolytic-Uremic Syndrome/metabolism , Hemolytic-Uremic Syndrome/microbiology , Intestinal Mucosa/metabolism , Intestinal Mucosa/microbiology , Mice , Shiga Toxins/biosynthesis , Shiga Toxins/geneticsABSTRACT
BACKGROUND: Colorectal polyps are reported in 6,1% of paediatric colonoscopies and in 12% of those performed for lower gastrointestinal bleeding. Although colonoscopy is widely used in paediatric patients, it requires bowel preparation and general anaesthesia or deep sedation, and in rare cases, it can cause complications. Non-invasive screening techniques able to predict polyps in children with isolated and sporadic rectal bleeding may play a key role in the selection of patients needing colonoscopy. METHODS: We enrolled all children undergoing colonoscopy for isolated and sporadic rectal bleeding to determine the diagnostic accuracy of faecal calprotectin, ultrasonography (US) and digital rectal examination as diagnostic methods for screening colorectal polyps. RESULTS: A total of 26 of 59 enrolled patients (44.1%) had colonic polyps, one patient had multiple polyps, and 23% of children had polyps proximal to the splenic flexure. The diagnostic accuracy of faecal calprotectin for detecting colorectal polyps was 96.6%, with a sensitivity of 100%. False-positive faecal calprotectin was shown in 2 patients with non-steroidal anti-inflammatory drug-related lesions. The diagnostic accuracy of ultrasound was 77.9%. Polyps not seen with ultrasound tended to be relatively smaller (1.5 vs 2.3, p = 0.001) and located in the rectum. The combined use of FC, US and digital rectal examination obtained a specificity and PPV of 100%. CONCLUSIONS: FC combined with US and digital rectal examination is a good and promising non-invasive screening test for detecting colorectal polyps in children with isolated and sporadic rectal bleeding.
Subject(s)
Colonic Polyps/diagnosis , Feces/chemistry , Gastrointestinal Hemorrhage/etiology , Leukocyte L1 Antigen Complex/metabolism , Ultrasonography , Adolescent , Child , Child, Preschool , Colonic Polyps/complications , Colonic Polyps/metabolism , Colonoscopy , Digital Rectal Examination , Female , Gastrointestinal Hemorrhage/diagnosis , Gastrointestinal Hemorrhage/metabolism , Humans , Male , Prospective Studies , Rectum , Sensitivity and SpecificityABSTRACT
This study investigated the effectiveness of new hemostatic adhesive powder (UI-EWD) in a swine mode of acute gastric bleeding. Gastric ulcer bleeding was induced endoscopically at two locations in each of eight heparinized mini-pigs. UI-EWD and saline were sprayed endoscopically in the experimental (n = 5) and control groups (n = 3), respectively. The hemostatic effect and hydrogel persistence on ulcers were periodically evaluated endoscopically. Initial hemostasis was achieved successfully in all lesions in the experimental group. Follow-up endoscopy showed minor delayed bleeding in 10% at 6 hours in the experimental group, whereas re-bleeding was observed in 50% at 6 hours in the control group. UI-EWD gel persisted at 90%, 80%, and 50% of ulcer bases at 6, 18, and 42 hours post-application, respectively. This study suggests that muco-adhesive UI-EWD may be effective in the endoscopic treatment of active ulcer bleeding.
Subject(s)
Drug Delivery Systems , Endoscopy , Gastric Mucosa/metabolism , Gastrointestinal Hemorrhage/drug therapy , Gastrointestinal Hemorrhage/physiopathology , Hemostatics/pharmacology , Adhesiveness , Animals , Disease Models, Animal , Gastrointestinal Hemorrhage/metabolism , Hemostasis/drug effects , Hemostatics/metabolism , Hemostatics/therapeutic use , Powders , SwineABSTRACT
Previously, we generated mouse models of Rack1 deficiency to identify key functions for Rack1 in regulating growth of intestinal epithelia: suppressing crypt cell proliferation and regeneration, promoting differentiation and apoptosis, and repressing development of neoplasia. However, other than low body weight, we did not detect an overt phenotype in mice constitutively deleted of Rack1 in intestinal epithelia ( vil-Cre: Rack1fl/fl mice), presumably because Rack1 was deleted in <10% of the total surface area of the epithelia. To assess the effect of Rack1 loss throughout the entire intestinal epithelia, we generated another mouse model of Rack1 deficiency, vil-Cre-ERT2: Rack1fl/fl. Within 5-10 days of the initial tamoxifen treatment, the mice lost over 20% of their body weight, developed severe diarrhea that for some was bloody, became critically ill, and died, if not euthanized. Necropsies revealed mildly distended, fluid-, gas-, and sometimes blood-filled loops of small and large bowel, inguinal lymphadenopathy, and thrombocytosis. Rack1 was deleted in nearly 100% of the epithelia in both the small intestine and colon when assessed by immunofluorescent or immunoblot analyses. Rack1 expression in other tissues and organs was not different than in control mice, indicating tissue specificity of the recombination. Histopathology revealed a patchy, erosive, hemorrhagic, inflammatory enterocolitis with denuded, sloughed off surface epithelium, and crypt hyperplasia. These results suggest a protective function for Rack1 in maintaining the integrity of intestinal epithelia and for survival. NEW & NOTEWORTHY Our findings reveal a novel function for Rack1 in maintaining intestinal homeostasis by protecting the epithelial barrier. Rack1 loss results in a patchy, erosive, hemorrhagic, inflammatory enterocolitis, which resembles that of inflammatory bowel diseases (IBD) in humans. Understanding mechanisms that protect barrier function in normal intestine and how loss of that protection contributes to the pathogenesis of IBD could lead to improved therapies for these and other erosive diseases of the gastrointestinal tract.
Subject(s)
Enterocolitis/metabolism , Epithelial Cells/metabolism , Intestinal Absorption , Intestinal Mucosa/metabolism , Receptors for Activated C Kinase/metabolism , Animals , Diarrhea/genetics , Diarrhea/metabolism , Diarrhea/pathology , Enterocolitis/genetics , Enterocolitis/pathology , Epithelial Cells/pathology , Gastrointestinal Hemorrhage/genetics , Gastrointestinal Hemorrhage/metabolism , Gastrointestinal Hemorrhage/pathology , Genetic Predisposition to Disease , Homeostasis , Intestinal Mucosa/pathology , Mice, Knockout , Permeability , Phenotype , Receptors for Activated C Kinase/deficiency , Receptors for Activated C Kinase/genetics , Signal Transduction , Weight LossABSTRACT
BACKGROUND: Oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC-ox) induces specific morbidity with hemorrhagic complications (HC). The aim of this study was to identify preoperative, intraoperative and postoperative HC predictive factors after HIPEC-ox. METHODS: A prospective single center study that included all consecutive patients treated with curative-intent HIPEC-ox, whatever the origin of peritoneal disease, was conducted. All patients underwent systematic blood tests exploring primary hemostasis and endothelial activation before surgical incision (D0) and on postoperative days 2 (POD2) and 5 (POD5). RESULTS: Between May 2012 and August 2015, 47 patients were enrolled in the study. The overall HC rate was 38%. Major morbidity was significantly higher in patients with HC. Patients presenting HC were significantly more often affected with pseudomyxoma peritonei and had less preoperative chemotherapy. Multivariate analysis showed that a higher plasmatic level of Von Willebrand factor antigen at D0 (D0 VWF:Ag) was a protective predictive factor for HC (p = 0.049, HR: 0.97 CI 95% [0.94-1.00]). A D0 VWF:Ag level below 138% had a sensitivity of 87.5%, a specificity of 67% and an area under the curve of 80.3% (CI 95% [66.5-94], p < 0.01) for predicting HC. CONCLUSIONS: Through the identification of prognostic factors, this study highlighted a subgroup of patients with low risk of HC after HIPEC-ox. Based on these results, we propose a routine preoperative dosage of VWF that would help the surgeon to select the most suitable patients for HIPEC-ox.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Cytoreduction Surgical Procedures , Hyperthermia, Induced/methods , Organoplatinum Compounds/administration & dosage , Peritoneal Neoplasms/therapy , Postoperative Hemorrhage/epidemiology , von Willebrand Factor/metabolism , Adult , Aged , Colorectal Neoplasms/pathology , Colorectal Neoplasms/therapy , Epistaxis/epidemiology , Epistaxis/metabolism , Epistaxis/prevention & control , Female , Gastrointestinal Hemorrhage/epidemiology , Gastrointestinal Hemorrhage/metabolism , Gastrointestinal Hemorrhage/prevention & control , Humans , Infusions, Parenteral , Intestinal Neoplasms/pathology , Intestinal Neoplasms/therapy , Male , Middle Aged , Multivariate Analysis , Oxaliplatin , Peritoneal Diseases/epidemiology , Peritoneal Diseases/metabolism , Peritoneal Diseases/prevention & control , Peritoneal Neoplasms/secondary , Postoperative Hemorrhage/metabolism , Postoperative Hemorrhage/prevention & control , Prognosis , Proportional Hazards Models , Prospective Studies , Uterine Neoplasms/pathology , Uterine Neoplasms/therapy , von Willebrand Factor/therapeutic useABSTRACT
Aspirin and P2Y12 receptor antagonists are widely used across the spectrum of cardiovascular diseases. Upper gastrointestinal complications, including ulcer and bleeding, are relatively common during antiplatelet treatment and, therefore, concomitant proton pump inhibitor (PPI) treatment is often prescribed.PPIs provide gastroprotection by changing the intragastric milieu, essentially by raising intragastric pH. In recent years, it has been heavily discussed whether PPIs may reduce the cardiovascular protection by aspirin and, even more so, clopidogrel. Pharmacodynamic and pharmacokinetic studies suggested an interaction between PPIs and clopidogrel, and subsequent clinical studies were conducted to evaluate the clinical impact of this interaction. More recently, it was reported that PPIs may also attenuate the antiplatelet effect of aspirin. This may be clinically important, because a fixed combination of aspirin and a PPI (esomeprazole) has recently been approved and because aspirin is the most widely used drug in patients with cardiovascular disease. The antiplatelet effect of the new P2Y12 receptor antagonists, ticagrelor and prasugrel, seems less influenced by PPI co-treatment.Given the large number of patients treated with antithrombotic drugs and PPIs, even a minor reduction of platelet inhibition potentially carries considerable clinical impact. The present book chapter summarizes the evidence regarding the widespread use of platelet inhibitors and PPIs in combination. Moreover, it outlines current evidence supporting or opposing drug interactions between these drugs and discusses clinical implications.
Subject(s)
Aspirin/pharmacokinetics , Cardiovascular Diseases/drug therapy , Esomeprazole/pharmacokinetics , Proton Pump Inhibitors/pharmacokinetics , Purinergic Antagonists/pharmacokinetics , Ticlopidine/analogs & derivatives , Adenosine/analogs & derivatives , Adenosine/therapeutic use , Aspirin/blood , Cardiovascular Diseases/genetics , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/pathology , Clopidogrel , Drug Administration Schedule , Drug Dosage Calculations , Drug Interactions , Esomeprazole/blood , Gastrointestinal Hemorrhage/chemically induced , Gastrointestinal Hemorrhage/metabolism , Gastrointestinal Hemorrhage/pathology , Gene Expression , Humans , Hydrogen-Ion Concentration/drug effects , Peptic Ulcer/chemically induced , Peptic Ulcer/metabolism , Peptic Ulcer/pathology , Prasugrel Hydrochloride/therapeutic use , Proton Pump Inhibitors/blood , Purinergic Antagonists/blood , Receptors, Purinergic P2Y12/genetics , Receptors, Purinergic P2Y12/metabolism , Ticagrelor , Ticlopidine/blood , Ticlopidine/pharmacokineticsABSTRACT
BACKGROUND: Angiogenesis is the formation of new blood vessels to supply nutrients to tumors. Vascular endothelial growth factor (VEGF) and cluster of differentiation 34 (CD34) are important signaling proteins involved in angiogenesis. Many studies have demonstrated that VEGF and CD34 are related to tumor progression. This study focused on the relationship between VEGF, CD34, and perioperative hemorrhage in patients with gastric cancer. METHODS: To observe the relationship between VEGF and CD34, we tracked 112 patients with advanced gastric cancer for 5 years to assess factors related to hemorrhage, using immunohistochemistry. The results were subjected to statistical analysis using a 2 × 2 contingency table, logistic regression, and receiver operating characteristic (ROC) test. RESULTS: The concentrations of VEGF and CD34 were critically correlated with perioperative hemorrhage and neural invasion in patients with gastric cancer (P < 0.05). Expression of VEGF and CD34 was related (P < 0.05, χ2 = 6.834). VEGF and CD34 co-expression strongly increased the risk of preoperative bleeding (area under the ROC curve >0.7, P < 0.05). CONCLUSIONS: Expression of VEGF and CD34 was critically correlated with perioperative hemorrhage in gastric cancer patients. Co-expression of VEGF and CD34 could be an effective indicator for evaluating the risk of perioperative bleeding in gastric cancer patients.
Subject(s)
Antigens, CD34/metabolism , Gastrointestinal Hemorrhage/metabolism , Neovascularization, Pathologic/metabolism , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , Vascular Endothelial Growth Factor A/metabolism , Adult , Aged , Aged, 80 and over , Female , Gastrointestinal Hemorrhage/etiology , Humans , Immunohistochemistry , Male , Middle Aged , Neovascularization, Pathologic/complications , Prognosis , Retrospective Studies , Risk Factors , Stomach Neoplasms/surgery , Young AdultABSTRACT
In this study we investigated the effect of free heme, the local level of which was increased by bleeding, on the intestinal barrier function, using human epithelial colorectal adenocarcinoma cells (Caco-2). Our results show that the addition of hemin to the culture medium markedly disrupted the barrier function, which was significantly improved by glutamine supplementation. Although hemin treatment caused the increased expression of heme oxygenase (HO)-1, the inhibition of HO activity resulted in the aggravation of hemin-induced barrier dysfunction. Up-regulation of HO-1 by pretreatment with a low concentration of hemin almost completely prevented hemin-induced barrier dysfunction. Taken together, these observations indicate that an abnormally high level of intracellular free heme causes barrier dysfunction, probably through the modulation of proteins forming tight junctions.
Subject(s)
Gastrointestinal Hemorrhage/metabolism , Heme Oxygenase-1/metabolism , Intestinal Mucosa/metabolism , Ascorbic Acid/pharmacology , Caco-2 Cells , Glutamine/pharmacology , Heme Oxygenase-1/antagonists & inhibitors , Hemin/pharmacology , Humans , Malondialdehyde/metabolism , Metalloporphyrins/pharmacologyABSTRACT
Thalidomide is used in clinical practice to treat gastrointestinal vascular malformation (GIVM), but the pathogenesis of GIVM is not clear. Hypoxia inducible factor 1 alpha (HIF-1α) and 2 alpha (HIF-2α/EPAS1) are in the same family and act as master regulators of the adaptive response to hypoxia. HIF-1α and HIF-2α are up-regulated in vascular malformations in intestinal tissues from GIVM patients, but not in adjacent normal vessels. Therefore, we investigated the role of HIF-1α and HIF-2α during angiogenesis and the mechanism of thalidomide action. In vitro experiments confirmed that vascular endothelial growth factor (VEGF) was a direct target of HIF-2α and that HIF-1α and HIF-2α regulated NOTCH1, Ang2, and DLL4, which enhanced vessel-forming of endothelial cells. Thalidomide down-regulated the expression of HIF-1α and HIF-2α and inhibited angiogenesis. In vivo zebrafish experiments suggested that HIF-2α overexpression was associated with abnormal subintestinal vascular (SIV) sprouting, which was reversed by thalidomide. This result indicated that thalidomide regulated angiogenesis via the inhibition of HIF-1α and HIF-2α expression, which further regulated downstream factors, including VEGF, NOTCH1, DLL4, and Ang2. The abnormally high expression of HIF-1α and HIF-2α may contribute to GIVM.
Subject(s)
Angiogenesis Inhibitors/administration & dosage , Basic Helix-Loop-Helix Transcription Factors/genetics , Gastrointestinal Hemorrhage/drug therapy , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Thalidomide/administration & dosage , Vascular Malformations/drug therapy , Adaptor Proteins, Signal Transducing , Adult , Aged , Angiogenesis Inhibitors/pharmacology , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , Calcium-Binding Proteins , Disease Models, Animal , Female , Gastrointestinal Hemorrhage/genetics , Gastrointestinal Hemorrhage/metabolism , Human Umbilical Vein Endothelial Cells , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Intercellular Signaling Peptides and Proteins/metabolism , Male , Mice , Middle Aged , Receptor, Notch1/metabolism , Thalidomide/pharmacology , Up-Regulation/drug effects , Vascular Endothelial Growth Factor A/metabolism , Vascular Malformations/genetics , Vascular Malformations/metabolism , Vesicular Transport Proteins/metabolism , ZebrafishABSTRACT
NSAIDuse is limited due to the drugs' toxicity to the gastrointestinal mucosa, an action incompletely understood. Lower gut injury induced byNSAIDs is dependent on bile secretion and is reported to increase the growth of a number of bacterial species, including an enterococcal species,Enterococcus faecalis This study examined the relationships between indomethacin (INDO)-induced intestinal injury/bleeding, small bowel overgrowth (SBO) and dissemination of enterococci, and the contribution of bile secretion to these pathological responses. Rats received either a sham operation (SO) or bile duct ligation (BDL) prior to administration of two daily subcutaneous doses of saline orINDO, and 24 h later, biopsies of ileum and liver were collected for plating on selective bacterial media. Fecal hemoglobin (Hb) and blood hematocrit (Hct) were measured to assess intestinal bleeding. Of the four treatment groups, onlySO/INDOrats experienced a significant 10- to 30-fold increase in fecal Hb and reduction in Hct, indicating thatBDLattenuatedINDO-induced intestinal injury/bleeding. Ileal enterococcal colony-forming units were significantly increased (500- to 1000-fold) inSO/INDOrats. Of all groups, only theSO/INDOrats demonstrated gut injury, and this was associated with enterococcal overgrowth of the gut and dissemination to the liver. We also demonstrated thatINDO-induced intestinal injury andE. faecalisovergrowth was independent of the route of administration of the drug, as similar findings were observed in rats orally dosed with theNSAID Bile secretion plays an important role inINDO-induced gut injury and appears to support enterococcal overgrowth of the intestine.NSAID-induced enterococcalSBOmay be involved either as a compensatory response to gut injury or with the pathogenic process itself and the subsequent development of sepsis.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal , Bile Ducts/metabolism , Bile/metabolism , Enterococcus faecalis/growth & development , Gastrointestinal Hemorrhage/microbiology , Ileal Diseases/microbiology , Ileum/microbiology , Indomethacin , Animals , Bacterial Translocation , Bile Ducts/surgery , Disease Models, Animal , Enterococcus faecalis/metabolism , Feces/chemistry , Gastrointestinal Hemorrhage/chemically induced , Gastrointestinal Hemorrhage/metabolism , Gastrointestinal Hemorrhage/pathology , Hemoglobins/metabolism , Ileal Diseases/chemically induced , Ileal Diseases/metabolism , Ileal Diseases/pathology , Ileum/metabolism , Ileum/pathology , Ligation , Liver/microbiology , Male , Rats, Sprague-DawleyABSTRACT
OBJECTIVE: Meckel's diverticulum (MD) is the most common congenital anomaly of the gastrointestinal tract. Although a majority of patients remain asymptomatic, complications may occur in a subset of patients. MD is a rare cause of gastrointestinal bleeding (GIB) in adults. We aimed to clarify the possible role of capsule endoscopy (CE) in the identification of Meckel's diverticulum. PATIENTS AND METHODS: From October 2004 to December 2010, 157 CEs were performed (83 male individuals, mean age 51±20 years; range 3-83 years) for obscure GIB. Before CE, all patients underwent nonconclusive upper and lower endoscopy at least two times and barium follow-through. RESULTS: CE identified the source of bleeding in 70/157 patients (44.6%). MD was diagnosed in 13/70 (18.6%) patients (11 male individuals, mean age 35±20 years, range, 3-69 years) after CE. Nine patients presented with obscure overt and four with obscure occult bleeding. The mean duration of obscure GIB history was 13 months (range 1-72 months). The mean hemoglobin concentration at the time of the procedure was 115±12 g/l. The findings of MD on CE were double lumen sign (13/13), visible blood (7/13), and diaphragm sign (6/13). All patients were operated upon, and MD histologically verified in 11. In two patients CE was false-positive and in two patients, false-negative. Capsule endoscopy had a positive predictive value of 84.6% for the diagnosis of MD. CONCLUSION: MD should be considered in the differential diagnosis of obscure GIB in adults. CE is an effective and promising modality for diagnosing MD in patients with obscure GIB.
Subject(s)
Capsule Endoscopy , Gastrointestinal Hemorrhage/diagnosis , Meckel Diverticulum/diagnosis , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Female , Gastrointestinal Hemorrhage/etiology , Gastrointestinal Hemorrhage/metabolism , Hemoglobins/metabolism , Humans , Male , Meckel Diverticulum/complications , Middle Aged , Predictive Value of Tests , Young AdultABSTRACT
PRO304186, a humanized monoclonal antibody targeting soluble interleukin-17 A and F, was developed for autoimmune and inflammatory disease indications. When administered to cynomolgus monkeys PRO304186 induced unexpected adverse effects characterized by clinical signs of hematemesis, hematochezia, and moribundity. Pathology findings included hemorrhage throughout the gastrointestinal tract without any evidence of vascular wall damage or inflammatory cellular infiltration. Mechanistic investigation of these effects revealed mild elevations of serum MCP-1 and IL-12/23 but without a classical proinflammatory profile in PRO304186-treated animals. In vitro studies demonstrated off-target effects on vascular endothelial cells including activation of nitric oxide synthase leading to production of nitric oxide (NO) accompanied by increased mitochondrial membrane depolarization, glutathione depletion, and increased paracellular permeability. Additionally, endothelial cell-PRO304186-conditioned medium reduced myosin light chain phosphorylation in vascular smooth muscle cells. Furthermore, an ex vivo study utilizing segments from cynomolgus aorta and femoral artery confirmed PRO304186-induced endothelium-dependent smooth muscle relaxation and vasodilation mediated via NO. Finally, a single dose of PRO304186 in cynomolgus monkeys induced a rapid and pronounced increase in NO in the portal circulation that preceded a milder elevation of NO in the systemic circulation and corresponded temporally with systemic hypotension; findings consistent with NO-mediated vasodilation leading to hypotension. These changes were associated with non-inflammatory, localized hemorrhage in the gastrointestinal tract consistent with hemodynamic vascular injury associated with intense local vasodilation. Together, these data demonstrate that PRO304186-associated toxicity in monkeys was due to an off-target effect on endothelium that involved regional NO release resulting in severe systemic vasodilation, hypotension, and hemorrhage.
Subject(s)
Antibodies, Monoclonal, Humanized/toxicity , Arteries/drug effects , Endothelium, Vascular/drug effects , Gastrointestinal Hemorrhage/chemically induced , Hypotension/chemically induced , Nitric Oxide/metabolism , Vasodilation/drug effects , Animals , Antibodies, Monoclonal, Humanized/metabolism , Arteries/metabolism , Arteries/physiopathology , Cells, Cultured , Endothelium, Vascular/metabolism , Endothelium, Vascular/physiopathology , Female , Gastrointestinal Hemorrhage/metabolism , Gastrointestinal Hemorrhage/physiopathology , Hematemesis/chemically induced , Hematemesis/metabolism , Hematemesis/physiopathology , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Hypotension/metabolism , Hypotension/physiopathology , Interleukin-17/antagonists & inhibitors , Interleukin-17/immunology , Interleukin-17/metabolism , Macaca fascicularis , Male , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/metabolism , Myosin Light Chains/metabolism , Nitric Oxide Synthase Type III/metabolism , Phosphorylation , Time FactorsABSTRACT
ANTECEDENTES Y PROPÓSITO DEL ESTUDIO: la hemorragia digestiva alta es una causa importante de ingreso hospitalario y constituye la principal emergencia gastroenterológica, con una tasa de mortalidad de hasta el 14%. En el Perú no existen estudios sobre el uso de la escala de Glasgow-Blatchford para predecir mortalidad por hemorragia digestiva alta. El objetivo de este estudio es realizar la validación externa de la escala de Glasgow-Blatchford y establecer su mejor punto de corte para predecir mortalidad por hemorragia digestiva alta en un hospital de Lima, Perú. Métodos: estudio de validación diagnóstica, analítico, longitudinal, de tipo retrospectivo, con datos de pacientes con diagnóstico clínico y endoscópico de hemorragia digestiva alta atendidos en la Unidad de Hemorragia Digestiva del Hospital Nacional Edgardo Rebagliati Martins, entre junio de 2012 y diciembre de 2013. Calculamos el área bajo la curva ROC (receiver operating characteristic) de la escala de Glasgow-Blatchford para predecir mortalidad, con un intervalo de confianza al 95%. Resultados: un total de 339 registros fueron analizados. El 57,5% fueron varones y la edad media (desviación estándar) fue de 67,0 (15,7) años. La mediana de la escala de Glasgow-Blatchford obtenida en la población fue de 12. El análisis ROC para mortalidad dio un área bajo la curva de 0,59 (IC95% 0,5-0,7). Se estratificó por tipo de hemorragia digestiva alta, obteniendo un área bajo la curva de 0,66 (IC95% 0,53-0,78) para el tipo no variceal. Conclusiones: en la población estudiada, la escala de Glasgow-Blatchford no posee una validez diagnóstica adecuada para predecir mortalidad
BACKGROUND AND AIM: Upper gastrointestinal bleeding is a major cause of hospitalization and the most prevalent emergency worldwide, with a mortality rate of up to 14%. In Peru, there have not been any studies on the use of the Glasgow-Blatchford Scoring System to predict mortality in upper gastrointestinal bleeding. The aim of this study is to perform an external validation of the Glasgow-Blatchford Scoring System and to establish the best cutoff for predicting mortality in upper gastrointestinal bleeding in a hospital of Lima, Peru. METHODS: This was a longitudinal, retrospective, analytical validation study, with data from patients with a clinical and endoscopic diagnosis of upper gastrointestinal bleeding treated at the Gastrointestinal Hemorrhage Unit of the Hospital Nacional Edgardo Rebagliati Martins between June 2012 and December 2013. We calculated the area under the curve for the receiver operating characteristic of the Glasgow-Blatchford Scoring System to predict mortality with a 95% confidence interval. RESULTS: A total of 339 records were analyzed. 57.5% were male and the mean age (standard deviation) was 67.0 (15.7) years. The median of the Glasgow-Blatchford Scoring System obtained in the population was 12. The ROC analysis for death gave an area under the curve of 0.59 (95% CI 0.5-0.7). Stratifying by type of upper gastrointestinal bleeding resulted in an area under the curve of 0.66 (95% CI 0.53-0.78) for non-variceal type. CONCLUSIONS: In this population, the Glasgow-Blatchford Scoring System has no diagnostic validity for predicting mortality
Subject(s)
Female , Humans , Male , Gastrointestinal Hemorrhage/blood , Gastrointestinal Hemorrhage/pathology , Glasgow Outcome Scale/standards , Gastrointestinal Tract/abnormalities , Gastrointestinal Tract/injuries , Liver Diseases/pathology , Gastrointestinal Hemorrhage/complications , Gastrointestinal Hemorrhage/metabolism , Glasgow Outcome Scale , Gastrointestinal Tract/metabolism , Gastrointestinal Tract , Liver Diseases/metabolism , Retrospective StudiesABSTRACT
Critically ill children can develop bleeding complications when treated with heparin-like drugs. These events are usually attributed to the anticoagulant activity of these drugs. However, previous studies showed that fibroblast growth factor-2 (FGF-2), a heparin-binding growth factor released in the circulation of these patients, could precipitate intestinal hemorrhages in mice treated with the heparin-like drug pentosan polysulfate (PPS). Yet very little is known about how FGF-2 induces bleeding complications in combination with heparin-like drugs. Here, we examined the mechanisms by which circulating FGF-2 induces intestinal hemorrhages in mice treated with PPS. We used a well-characterized mouse model of intestinal hemorrhages induced by FGF-2 plus PPS. Adult FVB/N mice were infected with adenovirus carrying Lac-Z or a secreted form of recombinant human FGF-2, and injected with PPS, at doses that do not induce bleeding complications per se. Mice treated with FGF-2 in combination with PPS developed an intestinal inflammatory reaction that increased the permeability and disrupted the integrity of submucosal intestinal vessels. These changes, together with the anticoagulant activity of PPS, induced lethal hemorrhages. Moreover, a genetically modified form of the endothelial ligand angiopoietin-1 (Ang-1*), which has powerful antipermeability and anti-inflammatory activity, prevented the lethal bleeding complications without correcting the anticoagulant status of these mice. These findings define new mechanisms through which FGF-2 and Ang-1* modulate the outcome of intestinal bleeding complications induced by PPS in mice and may have wider clinical implications for critically ill children treated with heparin-like drugs.
Subject(s)
Angiopoietin-1/biosynthesis , Fibroblast Growth Factor 2/biosynthesis , Gastrointestinal Hemorrhage/prevention & control , Genetic Therapy/methods , Intestine, Small/metabolism , Adenoviridae/genetics , Angiopoietin-1/genetics , Animals , Blood Coagulation , Capillary Permeability , Disease Models, Animal , Fibroblast Growth Factor 2/genetics , Gastrointestinal Hemorrhage/chemically induced , Gastrointestinal Hemorrhage/genetics , Gastrointestinal Hemorrhage/metabolism , Gastrointestinal Hemorrhage/pathology , Gene Transfer Techniques , Genetic Vectors , Inflammation Mediators/metabolism , Inflammatory Bowel Diseases/chemically induced , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/metabolism , Inflammatory Bowel Diseases/prevention & control , Intestine, Small/blood supply , Intestine, Small/pathology , Macrophages/metabolism , Male , Matrix Metalloproteinases/metabolism , Mice , Pentosan Sulfuric PolyesterABSTRACT
OBJECTIVE: to study the expression of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) in the gastric mucosal (GM) vascular endothelium and epithelial cells of patients with portal hypertensive gastropathy (PHG) and those with portal hypertension (PH) without signs of PHG as compared to a control group. MATERIAL AND METHODS: GM biopsy specimens from patients with PHG, those with PH without signs of PHG, and controls with the normal gastric mucosa were immunohistochemically examined. RESULTS: Comparison of the expression of uPA in the GM vascular endothelium and epithelial vessels revealed no significant differences in the patient groups. The level of PAI-1 in the GM vessels was statistically significantly higher in the control group than in the groups of patients with PHG and PH without PHG. PAI-1 expression in the GM epithelial cells was significantly more commonly absent in the PHG group than in the control group. An analysis of an uPA and PAI-1 expression ratio showed a statistically significant predominance of the expression of uPA over its inhibitor in the GM vascular endothelium of the patients with PHG and those with PH without PHG as compared to the controls. CONCLUSION: The predominance of uPA over PAI-1 in the GM vessels and epithelial cells can play a role in the development of GM bleeding.
Subject(s)
Gastric Mucosa/metabolism , Gastrointestinal Hemorrhage/etiology , Gastrointestinal Hemorrhage/metabolism , Hypertension, Portal/metabolism , Plasminogen Activator Inhibitor 1/biosynthesis , Stomach Diseases/metabolism , Urokinase-Type Plasminogen Activator/biosynthesis , Case-Control Studies , Endothelium, Vascular/metabolism , Endothelium, Vascular/pathology , Epithelial Cells/metabolism , Epithelial Cells/pathology , Female , Gastric Mucosa/blood supply , Gastric Mucosa/pathology , Gastrointestinal Hemorrhage/pathology , Gastroscopy , Humans , Hypertension, Portal/complications , Hypertension, Portal/pathology , Immunohistochemistry , Male , Middle Aged , Portal Pressure , Severity of Illness Index , Stomach Diseases/etiology , Stomach Diseases/pathologyABSTRACT
No disponible
Subject(s)
Humans , Male , Aneurysm, False/blood , Aneurysm, False/pathology , Gastrointestinal Hemorrhage/blood , Gastrointestinal Hemorrhage/genetics , Cholecystitis/pathology , Hemobilia/blood , Magnetic Resonance Spectroscopy , Aneurysm, False/genetics , Aneurysm, False/metabolism , Gastrointestinal Hemorrhage/metabolism , Gastrointestinal Hemorrhage/pathology , Cholecystitis/metabolism , Hemobilia/pathology , Magnetic Resonance Spectroscopy/instrumentationABSTRACT
Isolated metachronous gastrointestinal metastases from advanced-stage lung cancer are rarely diagnosed on the basis of symptoms and resected. In this report, we present a case of resectable metachronous gallbladder and small intestinal metastases of lung cancer. An 86-year-old woman was treated for lung cancer with resection of the right inferior lobe. Five months after the surgery, she was re-admitted because of melena and anemia. Ultrasonography showed a gallbladder tumor with gastrointestinal hemorrhage, and laparoscopic-assisted cholecystectomy was subsequently performed. However, 2 months after this event, the patient presented again with melena and anemia and was diagnosed with a small intestinal tumor. Therefore, laparoscopic-assisted partial resection of the small intestine was performed. Immunohistochemical staining for thyroid transcription factor-1 and cytokeratin 7 confirmed that the two resected tumors were metachronous metastases of the primary lung cancer. The patient died of liver metastases 5 months after the last surgery. Our experience with this case suggests that surgical resection might not be curative but palliative for patients with isolated gallbladder and small intestinal metastases diagnosed on the basis of melena that is resistant to conservative treatment.
Subject(s)
Gallbladder Neoplasms/pathology , Gastrointestinal Hemorrhage/pathology , Intestinal Neoplasms/secondary , Intestine, Small/pathology , Liver Neoplasms/secondary , Lung Neoplasms/pathology , Neoplasms, Second Primary/pathology , Aged, 80 and over , Biomarkers, Tumor , Cholecystectomy, Laparoscopic , Female , Gallbladder Neoplasms/metabolism , Gallbladder Neoplasms/surgery , Gastrointestinal Hemorrhage/metabolism , Gastrointestinal Hemorrhage/surgery , Humans , Immunoenzyme Techniques , Intestinal Neoplasms/metabolism , Intestinal Neoplasms/surgery , Liver Neoplasms/metabolism , Liver Neoplasms/surgery , Lung Neoplasms/metabolism , Lung Neoplasms/surgery , Neoplasms, Second Primary/metabolism , Neoplasms, Second Primary/surgery , PrognosisABSTRACT
BACKGROUND AND PURPOSE: Hydrogen sulphide is an important mediator of gastrointestinal mucosal defence. The use of non-steroidal anti-inflammatory drugs (NSAIDs) is significantly limited by their toxicity in the gastrointestinal tract. Particularly concerning is the lack of effective preventative or curative treatments for NSAID-induced intestinal damage and bleeding. We evaluated the ability of a hydrogen sulphide donor to protect against NSAID-induced enteropathy. EXPERIMENTAL APPROACH: Intestinal ulceration and bleeding were induced in Wistar rats by oral administration of naproxen. The effects of suppression of endogenous hydrogen sulphide synthesis or administration of a hydrogen sulphide donor (diallyl disulphide) on naproxen-induced enteropathy was examined. Effects of diallyl disulphide on small intestinal inflammation and intestinal microbiota were also assessed. Bile collected after in vivo naproxen and diallyl disulphide administration was evaluated for cytotoxicity in vitro using cultured intestinal epithelial cells. KEY RESULTS: Suppression of endogenous hydrogen sulphide synthesis by ß-cyano-L-alanine exacerbated naproxen-induced enteropathy. Diallyl disulphide co-administration dose-dependently reduced the severity of naproxen-induced small intestinal damage, inflammation and bleeding. Diallyl disulphide administration attenuated naproxen-induced increases in the cytotoxicity of bile on cultured enterocytes, and prevented or reversed naproxen-induced changes in the intestinal microbiota. CONCLUSIONS AND IMPLICATIONS: Hydrogen sulphide protects against NSAID-enteropathy in rats, in part reducing the cytotoxicity of bile and preventing NSAID-induced dysbiosis.