Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium.

Conventional major histocompatibility complex (MHC) class I genes encode molecules that present intracellular peptide antigens to T cells. They are ubiquitously expressed and regulated by interferon gamma. Two highly divergent human MHC class I genes, MICA and MICB, are regulated by promoter heat shock elements similar to those of HSP70 genes. MICA encodes a cell surface glycoprotein, which is not associated with beta 2-microglobulin, is conformationally stable independent of conventional class I peptide ligands, and almost exclusively expressed in gastrointestinal epithelium. Thus, this MHC class I molecule may function as an indicator of cell stress and may be recognized by a subset of gut mucosal T cells in an unusual interaction.

Parkinson's disease and gastrointestinal dysfunctions: morphological, neurochemical and functional modifications of the enteric nervous system associated with central dopaminergic impairment

Parkinson’s disease (PD) is frequently associated with gastrointestinal (GI) symptoms, mostly represented by abdominal distension, constipation and defecatory dysfunctions. Despite GI dysfunctions have a major impact on the clinical picture of PD, there is currently a lack of information on the neurochemical, pathological and functional correlates of GI dysmotility associated with PD. Moreover, there is a need of effective and safe pharmacological therapies for managing GI disturbances in PD patients. The present research project has been undertaken to investigate the relationships between PD and related GI dysfunctions by means of investigations in an animal model of PD induced by intranigral injection of 6-hydroxydopamine (6-OHDA). The use of the 6-OHDA experimental model of PD in the present program has allowed to pursue the following goals: 1) to examine the impact of central dopaminergic denervation on colonic excitatory cholinergic and tachykininergic neuromotility by means of molecular, histomorphologic and functional approaches; 2) to elucidate the role of gut inflammation in the onset and progression of colonic dysmotility associated with PD, characterizing the degree of inflammation and oxidative damage in colonic tissues, as well as identifying the immune cells involved in the production of pro-inflammatory cytokines in the gut; 3) to evaluate the impact of chronic treatment with L-DOPA plus benserazide on colonic neuromuscular activity both in control and PD animals. The results suggest that central nigrostriatal dopaminergic denervation is associated with an impaired excitatory cholinergic neurotransmission and an enhanced tachykininergic control, resulting in a dysregulated smooth muscle motor activity, which likely contributes to the concomitant decrease in colonic transit rate. These motor alterations might result from the occurrence of a condition of gut inflammation associated with central intranigral denervation. The treatment with L-DOPA/BE following central dopaminergic neurodegeneration can restore colonic motility, likely through a normalization of the cholinergic enteric neurotransmission, and it can also improve the colonic inflammation associated with central dopaminergic denervation.

Diagnosis and management of nonvariceal upper gastrointestinal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline

This Guideline is an official statement of the European Society of Gastrointestinal Endoscopy (ESGE). It addresses the diagnosis and management of nonvariceal upper gastrointestinal hemorrhage (NVUGIH). Main Recommendations MR1. ESGE recommends immediate assessment of hemodynamic status in patients who present with acute upper gastrointestinal hemorrhage (UGIH), with prompt intravascular volume replacement initially using crystalloid fluids if hemodynamic instability exists (strong recommendation, moderate quality evidence). MR2. ESGE recommends a restrictive red blood cell transfusion strategy that aims for a target hemoglobin between 7 g/dL and 9 g/dL. A higher target hemoglobin should be considered in patients with significant co-morbidity (e. g., ischemic cardiovascular disease) (strong recommendation, moderate quality evidence). MR3. ESGE recommends the use of the Glasgow-Blatchford Score (GBS) for pre-endoscopy risk stratification. Outpatients determined to be at very low risk, based upon a GBS score of 0 - 1, do not require early endoscopy nor hospital admission. Discharged patients should be informed of the risk of recurrent bleeding and be advised to maintain contact with the discharging hospital (strong recommendation, moderate quality evidence). MR4. ESGE recommends initiating high dose intravenous proton pump inhibitors (PPI), intravenous bolus followed by continuous infusion (80 mg then 8 mg/hour), in patients presenting with acute UGIH awaiting upper endoscopy. However, PPI infusion should not delay the performance of early endoscopy (strong recommendation, high quality evidence). MR5. ESGE does not recommend the routine use of nasogastric or orogastric aspiration/lavage in patients presenting with acute UGIH (strong recommendation, moderate quality evidence). MR6. ESGE recommends intravenous erythromycin (single dose, 250 mg given 30 - 120 minutes prior to upper gastrointestinal [GI] endoscopy) in patients with clinically severe or ongoing active UGIH. In selected patients, pre-endoscopic infusion of erythromycin significantly improves endoscopic visualization, reduces the need for second-look endoscopy, decreases the number of units of blood transfused, and reduces duration of hospital stay (strong recommendation, high quality evidence). MR7. Following hemodynamic resuscitation, ESGE recommends early (≤ 24 hours) upper GI endoscopy. Very early (< 12 hours) upper GI endoscopy may be considered in patients with high risk clinical features, namely: hemodynamic instability (tachycardia, hypotension) that persists despite ongoing attempts at volume resuscitation; in-hospital bloody emesis/nasogastric aspirate; or contraindication to the interruption of anticoagulation (strong recommendation, moderate quality evidence). MR8. ESGE recommends that peptic ulcers with spurting or oozing bleeding (Forrest classification Ia and Ib, respectively) or with a nonbleeding visible vessel (Forrest classification IIa) receive endoscopic hemostasis because these lesions are at high risk for persistent bleeding or rebleeding (strong recommendation, high quality evidence). MR9. ESGE recommends that peptic ulcers with an adherent clot (Forrest classification IIb) be considered for endoscopic clot removal. Once the clot is removed, any identified underlying active bleeding (Forrest classification Ia or Ib) or nonbleeding visible vessel (Forrest classification IIa) should receive endoscopic hemostasis (weak recommendation, moderate quality evidence). MR10. In patients with peptic ulcers having a flat pigmented spot (Forrest classification IIc) or clean base (Forrest classification III), ESGE does not recommend endoscopic hemostasis as these stigmata present a low risk of recurrent bleeding. In selected clinical settings, these patients may be discharged to home on standard PPI therapy, e. g., oral PPI once-daily (strong recommendation, moderate quality evidence). MR11. ESGE recommends that epinephrine injection therapy not be used as endoscopic monotherapy. If used, it should be combined with a second endoscopic hemostasis modality (strong recommendation, high quality evidence). MR12. ESGE recommends PPI therapy for patients who receive endoscopic hemostasis and for patients with adherent clot not receiving endoscopic hemostasis. PPI therapy should be high dose and administered as an intravenous bolus followed by continuous infusion (80 mg then 8 mg/hour) for 72 hours post endoscopy (strong recommendation, high quality evidence). MR13. ESGE does not recommend routine second-look endoscopy as part of the management of nonvariceal upper gastrointestinal hemorrhage (NVUGIH). However, in patients with clinical evidence of rebleeding following successful initial endoscopic hemostasis, ESGE recommends repeat upper endoscopy with hemostasis if indicated. In the case of failure of this second attempt at hemostasis, transcatheter angiographic embolization (TAE) or surgery should be considered (strong recommendation, high quality evidence). MR14. In patients with NVUGIH secondary to peptic ulcer, ESGE recommends investigating for the presence of Helicobacter pylori in the acute setting with initiation of appropriate antibiotic therapy when H. pylori is detected. Re-testing for H. pylori should be performed in those patients with a negative test in the acute setting. Documentation of successful H. pylori eradication is recommended (strong recommendation, high quality evidence). MR15. In patients receiving low dose aspirin for secondary cardiovascular prophylaxis who develop peptic ulcer bleeding, ESGE recommends aspirin be resumed immediately following index endoscopy if the risk of rebleeding is low (e. g., FIIc, FIII). In patients with high risk peptic ulcer (FIa, FIb, FIIa, FIIb), early reintroduction of aspirin by day 3 after index endoscopy is recommended, provided that adequate hemostasis has been established (strong recommendation, moderate quality evidence).

Intraperitoneal bevacizumab for control of malignant ascites due to advanced-stage gastrointestinal cancers: A multicentre double-blind, placebo-controlled phase II study - AIO SUP-0108

PURPOSE: Malignant ascites is debilitating for patients with advanced cancer. As shown previously, tumour cell production of vascular endothelial growth factor might be a major cause of the formation of malignant ascites. Intraperitoneal bevacizumab could therefore be an option for symptom control in refractory ascites. PATIENTS AND METHODS: Patients with advanced gastrointestinal cancer and malignant ascites who had undergone paracentesis at least twice within the past 4 weeks were randomly assigned in a 2:1 ratio to intraperitoneal bevacizumab (400 mg absolute) or placebo after paracentesis. During the 8-week treatment period, a minimum interval of 14 d was kept between the applications of the study drug. Primary end-point was paracentesis-free survival (ParFS). RESULTS: Fifty-three patients (median age 63 years) were randomised. Forty-nine patients received at least one study drug application and qualified for the main analysis. The proportion of patients with at least one common toxicity criteria grade III-V event was similar with 20/33 (61%) on bevacizumab and 11/16 (69%) on placebo. Median ParFS was 14 d (95% confidence interval [CI]: 11-17) in the bevacizumab arm and 10.5 d (95% CI: 7-21) on placebo (hazard ratio 0.74, 95% CI: 0.40-1.37; P = 0.16). The longest paracentesis-free period was 19 d on bevacizumab (range 6-66 d) and 17.5 d in the placebo arm (range 4-42) (P = 0.85). Median overall survival was 64 d (95% CI: 45-103) on bevacizumab compared to 31.5 d (95% CI: 20-117) on placebo (P = 0.31). CONCLUSION: Intraperitoneal bevacizumab was well tolerated. Overall, treatment did not result in a significantly better symptom control of malignant ascites. However, patients defined by specific immune characteristics may benefit.

Second St. Gallen European Organisation for Research and Treatment of Cancer Gastrointestinal Cancer Conference: consensus recommendations on controversial issues in the primary treatment of rectal cancer

Primary treatment of rectal cancer was the focus of the second St. Gallen European Organisation for Research and Treatment of Cancer (EORTC) Gastrointestinal Cancer Conference. In the context of the conference, a multidisciplinary international expert panel discussed and voted on controversial issues which could not be easily answered using published evidence. Main topics included optimal pretherapeutic imaging, indication and type of neoadjuvant treatment, and the treatment strategies in advanced tumours. Here we report the key recommendations and summarise the related evidence. The treatment strategy for localised rectal cancer varies from local excision in early tumours to neoadjuvant radiochemotherapy (RCT) in combination with extended surgery in locally advanced disease. Optimal pretherapeutic staging is a key to any treatment decision. The panel recommended magnetic resonance imaging (MRI) or MRI + endoscopic ultrasonography (EUS) as mandatory staging modalities, except for early T1 cancers with an option for local excision, where EUS in addition to MRI was considered to be most important because of its superior near-field resolution. Primary surgery with total mesorectal excision was recommended by most panellists for some early tumours with limited risk of recurrence (i.e. cT1-2 or cT3a N0 with clear mesorectal fascia on MRI and clearly above the levator muscles), whereas all other stages were considered for multimodal treatment. The consensus panel recommended long-course RCT over short-course radiotherapy for most clinical situations where neoadjuvant treatment is indicated, with the exception of T3a/b N0 tumours where short-course radiotherapy or even no neoadjuvant therapy were regarded to be an option. In patients with potentially resectable tumours and synchronous liver metastases, most panel members did not see an indication to start with classical fluoropyrimidine-based RCT but rather favoured preoperative short-course radiotherapy with systemic combination chemotherapy or alternatively a liver-first resection approach in resectable metastases, which both allow optimal systemic therapy for the metastatic disease. In general, proper patient selection and discussion in an experienced multidisciplinary team was considered as crucial component of care.

Treatment approach in patients with hyperbilirubinemia secondary to liver metastases in gastrointestinal malignancies: a case series and review of literature

BACKGROUND: Treatment of patients with severe liver dysfunction including hyperbilirubinemia secondary to liver metastases of gastrointestinal (GI) cancer is challenging. Regimen of oxaliplatin and fluoropyrimidine (FP)/folinic acid (FA) ± a monoclonal antibody (moAb), represents a feasible option considering the pharmacokinetics. Clinical data on the respective dosage and tolerability are limited and no recommendations are available. METHODS: Consecutive patients with severe hyperbilirubinemia [>2 × upper limit of the normal range (ULN) and >2.4 mg/dl] due to liver metastases of GI cancer without options for drainage receiving oxaliplatin, FP/FA ± moAb were analyzed. To collect further data a review of the literature was performed. RESULTS: A total of 12 patients were identified between 2011 and 2015. At treatment start, median bilirubin level was 6.1 mg/dl (>5 × ULN, range 2.7-13.6). The majority of patients (n = 11) received dose-reduced regimen with oxaliplatin (60-76%) and FP/FA (0-77%), rapidly escalating to full dose regimen. During treatment, bilirubin levels dropped more than 50% within 8 weeks or normalized within 12 weeks in 6 patients (responders). Median overall survival was 5.75 months (range 1.0-16.0 months) but was significantly prolonged in responders compared to nonresponders [9.7 and 3.0 months, p = 0.026 (two-sided test); 95% confidence interval (CI): 1.10-10.22]. In addition, case reports or series comprising a further 26 patients could be identified. Based on the obtained data a treatment algorithm was developed. CONCLUSION: Treatment with oxaliplatin, FP/FA ± moAb is feasible and may derive relevant benefits in patients with severe liver dysfunction caused by GI cancer liver metastases without further options of drainage.

Medicinal plants - prophylactic and therapeutic options for gastrointestinal and respiratory diseases in calves and piglets? A systematic review.

BACKGROUND Gastrointestinal and respiratory diseases in calves and piglets lead to significant economic losses in livestock husbandry. A high morbidity has been reported for diarrhea (calves ≤ 35 %; piglets ≤ 50 %) and for respiratory diseases (calves ≤ 80 %; piglets ≤ 40 %). Despite a highly diverse etiology and pathophysiology of these diseases, treatment with antimicrobials is often the first-line therapy. Multi-antimicrobial resistance in pathogens results in international accordance to strengthen the research in novel treatment options. Medicinal plants bear a potential as alternative or additional treatment. Based on the versatile effects of their plant specific multi-component-compositions, medicinal plants can potentially act as 'multi-target drugs'. Regarding the plurality of medicinal plants, the aim of this systematic review was to identify potential medicinal plant species for prevention and treatment of gastrointestinal and respiratory diseases and for modulation of the immune system and inflammation in calves and piglets. RESULTS Based on nine initial sources including standard textbooks and European ethnoveterinary studies, a total of 223 medicinal plant species related to the treatment of gastrointestinal and respiratory diseases was identified. A defined search strategy was established using the PRISMA statement to evaluate 30 medicinal plant species starting from 20'000 peer-reviewed articles published in the last 20 years (1994-2014). This strategy led to 418 references (257 in vitro, 84 in vivo and 77 clinical trials, thereof 48 clinical trials in veterinary medicine) to evaluate effects of medicinal plants and their efficacy in detail. The findings indicate that the most promising candidates for gastrointestinal diseases are Allium sativum L., Mentha x piperita L. and Salvia officinalis L.; for diseases of the respiratory tract Echinacea purpurea (L.) MOENCH, Thymus vulgaris L. and Althea officinalis L. were found most promising, and Echinacea purpurea (L.) MOENCH, Camellia sinensis (L.) KUNTZE, Glycyrrhiza glabra L. and Origanum vulgare L. were identified as best candidates for modulation of the immune system and inflammation. CONCLUSIONS Several medicinal plants bear a potential for novel treatment strategies for young livestock. There is a need for further research focused on gastrointestinal and respiratory diseases in calves and piglets, and the findings of this review provide a basis on plant selection for future studies.

Impact of a Potassium-enriched, Chloride-depleted 5% Glucose Solution on Gastrointestinal Function after Major Abdominopelvic Surgery: Results of a Randomized Controlled Trial.

BACKGROUND Gastrointestinal (GI) complications often delay recovery after radical cystectomy with urinary diversion. The authors investigated if perioperative administration of a potassium-enriched, chloride-depleted 5% glucose solution (G5K) accelerates recovery of GI function. METHODS This randomized, parallel-group, single-center double-blind trial included 44 consecutive patients undergoing radical cystectomy and pelvic lymph node dissection with urinary diversion. Patients were randomized to receive either a G5K (G5K group) solution or a Ringer's maleate solution (control group). Fluid management aimed for a zero fluid balance. Primary endpoint was time to first defecation. Secondary endpoints were time to normal GI function, need for electrolyte substitution, and renal dysfunction. RESULTS Time to first defecation was not significantly different between groups (G5K group, 93 h [19 to 168 h] and control group, 120 h [43 to 241 h]); estimator of the group difference, -16 (95% CI, -38 to 6); P = 0.173. Return of normal GI function occurred faster in the G5K group than in the control group (median, 138 h [range, 54 to 262 h] vs. 169 h [108 to 318 h]); estimator of the group difference, -38 (95% CI, -74 to -12); P = 0.004. Potassium and magnesium were less frequently substituted in the G5K group (13.6 vs. 54.5% [P = 0.010] and 18.2 vs. 77.3% [P < 0.001]), respectively. The incidence of renal dysfunction (Risk, Injury, Failure, Loss and End-stage kidney disease stage "risk") at discharge was 9.1% in the G5K group and 4.5% in the control group; P = 1.000. CONCLUSIONS Perioperative administration of a G5K did not enhance first defecation, but may accelerate recovery of normal GI function, and reduces potassium and magnesium substitution after radical cystectomy and urinary diversion.

Histoplasmosis, protecting workers at risk /

"September 1997."

Current cancer research on etiology, epidemilogy and related biology of gastrointestinal, oral, esophageal and pancreatic cancers.

Includes index.

Histoplasmosis in Australia: A report of a case with a review of the literature

Histoplasmosis is a rare but serious fungal infection commonly presenting as mucosal ulceration of the oral cavity. It is increasingly recognized in Australia but the source of infection remains obscure and it is likely to be under-diagnosed. We report a case of chronic mucosal ulceration which failed to fully respond to periodontal therapy. Histology and culture of a gingival biopsy was consistent with histoplasmosis, and the patient responded favourably to treatment with oral itraconazole. Histoplasmosis may present to general dental practitioners as chronic mucosal ulceration and should be considered in the differential diagnosis of such lesions. Diagnosis is best made by culture and histology of biopsy specimens.

Gastrointestinal transit in the common brushtail possum measured by gamma scintigraphy

This paper reports an example of the application of pharmaceutical technology to wildlife management, specifically the design of an oral delivery system for the common brushtail possum in New Zealand. Designing an oral delivery system requires a knowledge of the time taken for particulates to reach target sites within the gastrointestinal tract (GIT). The transit time for fluid and indigestible particles of two different size ranges was determined in the common brushtail possum (Trichosurus vulpecula). Technetium-labelled (Tc-99m) anion exchange resin particles (75-125 or 500-700 mu m diameter) or solution (Tc-99m-labelled diethylenetriamine pentaacetic acid, Tc-99m-DTPA) was administered orally. At predetermined times after dosing (3, 6, 12, 24 or 32 h), the distribution of radioactivity throughout excised gastrointestinal tracts was determined by gamma scintigraphy. The transit profile was similar for the three formulations investigated. Unlike other closely related hindgut fermenting marsupials, there was no evidence to support the presence of a colonic separating mechanism in the common brushtail possum. Gastrointestinal transit was independent of body mass, gender and time of day that the dose is given. To target the hindgut for oral delivery of protein and peptide biocontrol agents, the formulation Would need to protect the bioactive for approximately 12 h prior to release. (c) 2005 Elsevier B.V. All rights reserved.

The genetic diversity of lactic acid producing bacteria in the equine gastrointestinal tract

Seventy-two lactic acid producing bacterial isolates (excluding streptococci) were cultured from the gastrointestinal tract of six horses. Two of the horses were orally dosed with raftilose to induce lactic acidosis and laminitis while the remaining four were maintained on a roughage diet. Near complete 16S rDNA was amplified by PCR from the genomic DNA of each isolate. Following RFLP analysis with the restriction enzymes MboI, HhaI and HinfI, the PCR products from the IS isolates that produced L- and/or D-lactate were subsequently cloned and sequenced. DNA sequence analysis indicated that the majority of the isolates were closely related to species within the genus Lactobacillus, including Lactobacillus salivarius, Lactobacillus mucosae and Lactobacillus delbrueckii. Four isolates were closely related to Mitsuokella jalaludinii. Lactic acid producing bacteria (LAB) from the equine gastrointestinal tract was dominated by representatives from the genus Lactobacillus, but also included D-lactate-producing bacteria closely related to M. jalaludinii. Identification and characterization of LAB from the equine gastrointestinal tract should contribute to our understanding and management of fermentative acidosis, ulceration of the stomach and laminitis. (c) 2005 Federation of European Microbiological Societies. Published by Elsevier B.V. All rights reserved.