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Intestinal ischemia-reperfusion injury (IRI) is a common clinical entity, and its outcome is unpredictable due to the triad of inflammation, increased permeability and bacterial translocation. Polyethylene glycol (PEG) is a polyether compound that is extensively used in pharmacology as an excipient in various products. More recently, this class of products have shown to have potent anti-inflammatory, anti-apoptotic, immunosuppressive and cell-membrane-stabilizing properties. However, its effects on the outcome after intestinal IRI have not yet been investigated. We hypothesized that PEG administration would reduce the effects of intestinal IRI in rodents. In a previously described rat model of severe IRI (45 min of ischemia followed by 60 min of reperfusion), we evaluated the effect of IV PEG administration at different doses (50 and 100 mg/kg) before and after the onset of ischemia. In comparison to control animals, PEG administration stabilized the endothelial glycocalyx, leading to reduced reperfusion edema, bacterial translocation and inflammatory reaction as well as improved 7-day survival. These effects were seen both in a pretreatment and in a treatment setting. The fact that this product is readily available and safe should encourage further clinical investigations in settings of intestinal IRI, organ preservation and transplantation. [ABSTRACT FROM AUTHOR]

Animal research in intestinal ischemia-reperfusion injury (IRI) is mainly performed in rodent models. Previously, intraperitoneal (I.P.) injections with ketamine–xylazine mixtures were used. Nowadays, volatile anesthetics (isoflurane) are more common. However, the impact of the anesthetic method on intestinal IRI has not been investigated. We aim to analyze the different anesthetic methods and their influence on the extent of intestinal IRI in a rat model. Male Sprague–Dawley rats were used to investigate the effect of I.P. anesthesia on 60 min of intestinal ischemia and 60 min of reperfusion in comparison to hyperoxygenation (100% O2) and volatile isoflurane anesthesia. In comparison to I.P. anesthesia with room air (21% O2), supplying 100% O2 improved 7-day survival by cardiovascular stabilization, reducing lactic acidosis and preventing vascular leakage. However, this had no effect on the intestinal epithelial damage, permeability, and inflammatory response observed after intestinal IRI. In contrast to I.P. + 100% O2, isoflurane anesthesia reduced intestinal IRI by preventing ongoing low-flow reperfusion hypotension, limiting intestinal epithelial damage and permeability, and by having anti-inflammatory effects. When translating the aforementioned results of this study to clinical situations, such as intestinal ischemia or transplantation, the potential protective effects of hyperoxygenation and volatile anesthetics require further research. [ABSTRACT FROM AUTHOR]

Background: A complex interplay between a failing intestinal barrier and low‐grade inflammation leading to sensorimotor disturbances is an often‐cited mechanism in the pathogenesis of functional gastrointestinal disorders (FGID). However, the cause‐consequence relationship between these features has not been clearly established. We previously described jejunal alterations in the normoglycemic BB‐rat (BBDP‐N) model proposing this model as a suitable animal model to study FGID pathophysiology. The current study explores colonic permeability, inflammation, and sensitivity of the BB‐rat. Methods: Colonic tissue of BBDP‐N and control (BBDR) rats at 50, 90, 110, 160, and 220 days (n ≥ 7 per group) was used to assess intestinal permeability in Ussing chambers and inflammation, including infiltration by eosinophils, mast cells, and eosinophil peroxidase (EPO) activity. Anxiety‐like symptoms were evaluated at 50, 90, and 220 days and colonic sensitivity at 160 and 220 days by measuring the visceromotor response (VMR) to isobaric colorectal distensions. Keys results: Lamina propria eosinophil and mast cell infiltration and increased EPO activity were demonstrated from 90 days onward. Increased permeability and myenteric ganglionitis were observed in the oldest BBDP‐N rats. At 220 days, the VMR was significantly increased suggesting colonic hypersensitivity. At the same age, increased anxiety‐like behavior was observed. Conclusion and inferences: We demonstrated a lamina propria eosinophil and mast cell infiltration preceding visceral hypersensitivity in the colon of the BBDP‐N rat, reminiscent of patients with FGID. These findings help elucidating pathogenetic pathways in FGID and further validate the BBDP‐N rat as an attractive model to study pathophysiology and therapy of FGID. [ABSTRACT FROM AUTHOR]

Background Among the different mechanisms involved in irritable bowel syndrome ( IBS) physiopathology, visceral hypersensitivity seems to play a key role. It involves sensitization of the colonic primary afferent fibers, especially through an overexpression of ion channels. The aims of this translational study were to investigate the colonic expression of Cav3.2 calcium channels and their involvement in an animal model of colonic hypersensitivity, and to assess their expression in the colonic mucosa of symptomatic IBS patients. Methods This bench-to-bed study combined a preclinical experimental study on mice and a case-control clinical study. Preclinical studies were performed on wild-type and Cav3.2- KO mice. Colonic sensitivity and Cav3.2 expression were studied after a low-dose treatment of dextran sodium sulfate ( DSS 0.5%). Regarding the clinical study, colonic biopsies were performed in 14 IBS patients and 16 controls during a colonoscopy to analyze the mucosal Cav3.2 expression. Key results Wild-type, but not Cav3.2- KO, mice developed visceral hypersensitivity without colonic inflammation, after 0.5% DSS treatment. A significant increase of Cav3.2 mRNA ( p = 0.04) was found in the colon of low-dose DSS-treated wild-type ( WT) mice compared to their controls. In human colonic biopsies, the Cav3.2 mRNA level was significantly higher in the IBS group compared to the control group ( p = 0.01). The immunofluorescence staining revealed their protein expression in colonic mucosa, particularly in nerve fibers. Conclusions & inferences This translational study supports the involvement of the calcium channels Cav3.2 in abdominal pain, as observed in IBS patients. It opens new therapeutic perspectives based on molecules specifically blocking these channels. [ABSTRACT FROM AUTHOR]

Intestinal ischemia is a potentially catastrophic emergency, with a high rate of morbidity and mortality. Currently, no specific pharmacological treatments are available. Previous work demonstrated that pre-treatment with obeticholic acid (OCA) protected against ischemia reperfusion injury (IRI). Recently, a more potent and water-soluble version has been synthesized: Intercept 767 (INT-767). The aim of this study was to investigate if intravenous treatment with INT-767 can improve outcomes after IRI. In a validated rat model of IRI (60 min ischemia + 60 min reperfusion), three groups were investigated (n = 6/group): (i) sham: surgery without ischemia; (ii) IRI + vehicle; and (iii) IRI + INT-767. The vehicle (0.9% NaCl) or INT-767 (10 mg/kg) were administered intravenously 15 min after start of ischemia. Endpoints were 7-day survival, serum injury markers (L-lactate and I-FABP), histology (Park–Chiu and villus length), permeability (transepithelial electrical resistance and endotoxin translocation), and cytokine expression. Untreated, IRI was uniformly lethal by provoking severe inflammation and structural damage, leading to translocation and sepsis. INT-767 treatment significantly improved survival by reducing inflammation and preserving intestinal structural integrity. This study demonstrates that treatment with INT-767 15 min after onset of intestinal ischemia significantly decreases IRI and improves survival. The ability to administer INT-767 intravenously greatly enhances its clinical potential. [ABSTRACT FROM AUTHOR]

Although sport and physical activity are generally considered as positive factors for bone metabolism some endurance trainings such as running and bicycling have few or no beneficial or even deleterious effects on bone mineral density. The present study was designed to investigate the acute effect of an intensive endurance cycling exercise on biochemical bone markers. Futrthermore, the effect of the oral intake of 1g calcium load, by drinking high-calcium mineral water, just prior to and during the exercise was checked. Twelve well-trained elite male triathletes aged 23-37 years were explored. The serum concentrations of calcium, phosphate, PTH, bone alkaline phosphatase (BALP) and C-terminal cross-linking telopeptide of type 1 collagen (CTX) were measured before, during and after a 60 min 80% VO2max cycle ergometer exercise. Since cycling exercise was accompanied by a reduction in plasma volume the total amount of biochemical bone markers was calculated. When the exercise was performed without calcium load both serum concentrations and total amount of CTX began to increase progressively 30 min after the start of the exericse and were still significantly elevated, by 45-50%, 2h after the end of the exercise. Ingestion of high-calcium mineral water completely suppressed the CTX reponse. By contrast serum concentrations and total amount of BALP fluctuated and showed no significant difference with or without calcium load. The present study demonstrates that the burst of osteoclastic activity acutely induced by an endurance cycling exercise can be suppressed by the previous intake of a calcium load afforded by drinking high-calcium mineral water. [ABSTRACT FROM AUTHOR]

Background: N- and C-terminal fragments of type I collagen such as NTX, CTX and ICTP are released into circulation during bone resorption and can be quantified in serum. Their respective sensitivity as indices of osteoclastic activity was compared after a short-term inhibition of resorption induced by repeated drinking of calcium-fortified water. Methods: Serum NTX, CTX and ICTP were measured by specific immunoassays in one group of 15 subjects sampled at 08.00, 11.00, 14.00 and 17.00 (referred to as T0, T3h, T6h and T9h) and having ingested in two experimental periods 660 ml of either low-calcium mineral water or the same low-calcium mineral water fortified with calcium (300 mg/l) at three times (08.00, 11.00 and 14.00). Results: Oral intake of calcium-fortified water resulted in progressive decrease in serum CTX (by 38.7% at T3h, 61.0% at T6h and 60.4% at T9h) and NTX (by 19.0% at T3h, 24.1% at T6h and 25.2% at T9h) while serum ICTP concentrations were not significantly affected. Since ingestion of low-calcium water induced a modest but significant decrease in both CTX (−19.4%) and NTX (−10.6%) we compared the two sets of assays with repeated-measures two-factor analysis of variance with interaction. Ingestion of calcium-fortified water vs. low-calcium water resulted in a significant decrease in both serum CTX (time, P<0.0001; treatment, P<0.0001; time-by treatment, P<0.0001) and NTX (time, P<0.0001; treatment, P=0.0001; time-by treatment, P=0.0066). Conclusions: CTX is more sensitive than NTX while ICTP is not sensitive to calcium-induced acute changes in osteoclastic activity. The present results stress the importance of choosing appropriate biochemical bone markers to demonstrate the effects of calcium on bone resorption. [Copyright &y& Elsevier]

The present study was designed to measure the effects, on parathyroid function and bone metabolism, of ingestion of high-calcium mineral water and of a calcium salt bringing the same dose (600 mg) of calcium as a reference. Fifteen healthy young men (mean ± SD age : 23.3 ± 1.2) ingested, during 3 different experimental periods chosen at random, a) high-calcium mineral water (596 mg/L), b) low-calcium mineral water as a control assay, c) one bag of tricalcium phosphate powder containing 600 mg of calcium. Serum concentrations of ionized calcium (iCa), intact parathyroid hormone (iPTH) and of a biochemical marker of bone resorption, type I collagen cross-linked C telopeptide (CTX), were measured before 08.00 and every hour from 09.00 to 17.00. Serum iCa concentrations were significantly (P < 0.0001) higher and serum iPTH concentrations were significantly (P < 0.01) lower after oral intake of both high-calcium water and tricalcium phosphate than in control period. Serum concentrations of CTX were significantly lower after either high-calcium water (P < 0.0001) or tricalcium phosphate (P = 0.011) than in the control period and a statistically significant difference (P < 0.05) using Bonferroni t test between the effects of high-calcium mineral water and of tricalcium phosphate was observed from 14.00 to 17.00. The same total amount of calcium (# 600 mg) from one liter of high-calcium mineral water, divided into three intakes, at 3 hours intervals, resulted in a more prolonged suppression of serum CTX, than from the ingestion of a calcium salt. [Copyright &y& Elsevier]

Background: Human exposure to high doses of radiation resulting in acute radiation syndrome and death can rapidly escalate to a mass casualty catastrophe in the event of nuclear accidents or terrorism. The primary reason is that there is presently no effective treatment option, especially for radiation-induced gastrointestinal syndrome. This syndrome results from disruption of mucosal barrier integrity leading to severe dehydration, blood loss, and sepsis. In this study, we tested whether extracellular vesicles derived from mesenchymal stromal cells (MSC) could reduce radiation-related mucosal barrier damage and reduce radiation-induced animal mortality. Methods: Human MSC-derived extracellular vesicles were intravenously administered to NUDE mice, 3, 24, and 48 h after lethal whole-body irradiation (10 Gy). Integrity of the small intestine epithelial barrier was assessed by morphologic analysis, immunostaining for tight junction protein (claudin-3), and in vivo permeability to 4 kDa FITC-labeled dextran. Renewal of the small intestinal epithelium was determined by quantifying epithelial cell apoptosis (TUNEL staining) and proliferation (Ki67 immunostaining). Statistical analyses were performed using one-way ANOVA followed by a Tukey test. Statistical analyses of mouse survival were performed using Kaplan-Meier and Cox methods. Results: We demonstrated that MSC-derived extracellular vesicle treatment reduced by 85% the instantaneous mortality risk in mice subjected to 10 Gy whole-body irradiation and so increased their survival time. This effect could be attributed to the efficacy of MSC-derived extracellular vesicles in reducing mucosal barrier disruption. We showed that the MSC-derived extracellular vesicles improved the renewal of the small intestinal epithelium by stimulating proliferation and inhibiting apoptosis of the epithelial crypt cells. The MSC-derived extracellular vesicles also reduced radiation-induced mucosal permeability as evidenced by the preservation of claudin-3 immunostaining at the tight junctions of the epithelium. Conclusions: MSC-derived extracellular vesicles promote epithelial repair and regeneration and preserve structural integrity of the intestinal epithelium in mice exposed to radiation-induced gastrointestinal toxicity. Our results suggest that the administration of MSC-derived extracellular vesicles could be an effective therapy for limiting acute radiation syndrome. [ABSTRACT FROM AUTHOR]

Background Irritable bowel syndrome ( IBS) is a functional gastrointestinal disorder associated with idiopathic colonic hypersensitivity ( CHS). However, recent studies suggest that low-grade inflammation could underlie CHS in IBS. The pro-inflammatory mediator nerve growth factor ( NGF) plays a key role in the sensitization of peripheral pain pathways and several studies have reported its contribution to visceral pain development. NGF modulates the expression of Acid-Sensing Ion Channels ( ASICs), which are proton sensors involved in sensory neurons sensitization. This study examined the peripheral contribution of NGF and ASICs to IBS-like CHS induced by butyrate enemas in the rat colon. Methods Colorectal distension and immunohistochemical staining of sensory neurons were used to evaluate NGF and ASICs contribution to the development of butyrate-induced CHS. Key Results Systemic injection of anti- NGF antibodies or the ASICs inhibitor amiloride prevented the development of butyrate-induced CHS. A significant increase in NGF and ASIC1a protein expression levels was observed in sensory neurons of rats displaying butyrate-induced CHS. This increase was specific of small- and medium-diameter L1 + S1 sensory neurons, where ASIC1a was co-expressed with NGF or trkA in CGRP-immunoreactive somas. ASIC1a was also overexpressed in retrogradely labeled colon sensory neurons. Interestingly, anti- NGF antibody administration prevented ASIC1a overexpression in sensory neurons of butyrate-treated rats. Conclusions & Inferences Our data suggest that peripheral NGF and ASIC1a concomitantly contribute to the development of butyrate-induced CHS NGF- ASIC1a interplay may have a pivotal role in the sensitization of colonic sensory neurons and as such, could be considered as a potential new therapeutic target for IBS treatment. [ABSTRACT FROM AUTHOR]

Abstract: A high-resolution stratigraphy has been developed for the interval encompassing the Cenomanian–Turonian boundary (CTBI), by means of several lithological, biological and geochemical events. This work entails the study of two sections selected on the base of the completeness of their sedimentary record and their contrasting paleogeographical setting: (1) The Rock Canyon Anticline section west of Pueblo, Colorado, (US Western Interior Basin), which is the Global Boundary Stratotype Section and Point (GSSP) candidate for the base of the Turonian stage, as well as the reference section for the ammonite biostratigraphy of the CTBI; and (2) The wadi Bahloul section in Central Tunisia which is the best and complete section spanning this time interval in the southern Tethyan Margin. These sections record similar biogeochemical events that can be correlated over a great distance. Several important biological and geochemical events determined in these sections relative to the ammonite zonation of the CTBI are listed below in chronological order from old to young: 1. FO (first occurrence) of Sciponoceras gracile-Metoicoceras geslinianum ammonite Assemblage-Zone, 2. δ13C peak I, 3. LO (last occurrence) of Rotalipora cushmani, 4. “Heterohelix shift”, 5. FO of the ammonites Pseudaspidoceras pseudonodosoides and Neocardioceras juddii, 6. δ13C peak II, 7. δ13C peak III, 8. LO of Cenomanian ammonites (Ps. pseudonodosoides and N. juddii), 9. LO of Anaticinella, 10. FO of Turonian ammonites (Watinoceras devonense, base of the Turonian stage), 11. “filament event”, 12. FO of Pseudaspidoceras flexuosum, 13. FO of the Tethyan Helvetoglobotruncana helvetica, 14. FO of Mammites nodosoides, 15. FO of the Western Interior H. helvetica. In the two sections, the Cenomanian–Turonian (C/T) boundary, as defined by the ammonite biostratigraphy, is placed within an interval about 50 cm thick. This interval is termed here as the C/T boundary “precision interval”. The δ13C peak III slightly precedes the precision interval. The genus Anaticinella planktic foraminifer disappears in the middle part of this interval. The “filament event” occurs just above it and is coeval with the first occurrence of Turonian ammonites. These events are useful for placing the C/T boundary precision interval in absence of ammonite markers. Comparing ammonite and planktic foraminiferal biostratigraphy we have dated and correlated changes occurring in planktic foraminiferal assemblages. On this base, as an important result, we have demonstrated the diachroneity of the FO of Helvetoglobotruncana helvetica and the variable duration of the Whiteinella archaeocretacea PRZ. [Copyright &y& Elsevier]

Proton pump inhibitors (PPI) may improve symptoms in functional dyspepsia (FD) through duodenal eosinophil-reducing effects. However, the contribution of the microbiome to FD symptoms and its interaction with PPI remains elusive. Aseptic duodenal brushings and biopsies were performed before and after PPI intake (4 weeks Pantoprazole 40 mg daily, FD-starters and controls) or withdrawal (2 months, FD-stoppers) for 16S-rRNA sequencing. Between- and within-group changes in genera or diversity and associations with symptoms or duodenal factors were analyzed. In total, 30 controls, 28 FD-starters and 19 FD-stoppers were followed. Mucus-associated Porphyromonas was lower in FD-starters vs. controls and correlated with symptoms in FD and duodenal eosinophils in both groups, while Streptococcus correlated with eosinophils in controls. Although clinical and eosinophil-reducing effects of PPI therapy were unrelated to microbiota changes in FD-starters, increased Streptococcus was associated with duodenal PPI effects in controls and remained higher despite withdrawal of long-term PPI therapy in FD-stoppers. Thus, duodenal microbiome analysis demonstrated differential mucus-associated genera, with a potential role of Porphyromonas in FD pathophysiology. While beneficial effects of short-term PPI therapy were not associated with microbial changes in FD-starters, increased Streptococcus and its association with PPIeffects in controls suggest a role for duodenal dysbiosis after long-term PPI therapy. [ABSTRACT FROM AUTHOR]

Duodenal hyperpermeability and low-grade inflammation in functional dyspepsia is potentially related to duodenal acid exposure. We aimed to evaluate in healthy volunteers the involvement of mast cell activation on the duodenogastric reflex and epithelial integrity during duodenal acidification. This study consisted of 2 parts: (1) Duodenal infusion of acid or saline during thirty minutes in a randomized, double-blind cross-over manner with measurement of intragastric pressure (IGP) using high resolution manometry and collection of duodenal biopsies to measure epithelial barrier function and the expression of cell-to-cell adhesion proteins. Mast cells and eosinophils were counted and activation and degranulation status were assessed. (2) Oral treatment with placebo or mast cell stabilizer disodiumcromoglycate (DSCG) prior to duodenal perfusion with acid, followed by the procedures described above. Compared with saline, acidification resulted in lower IGP (P < 0.01), increased duodenal permeability (P < 0.01) and lower protein expression of claudin-3 (P < 0.001). Protein expression of tryptase (P < 0.001) was increased after acid perfusion. Nevertheless, an ultrastructural examination did not reveal degranulation of mast cells. DSCG did not modify the drop in IGP and barrier dysfunction induced by acid. Duodenal acidification activates an inhibitory duodenogastric motor reflex and, impairs epithelial integrity in healthy volunteers. However, these acid mediated effects occur independently from mast cell activation. [ABSTRACT FROM AUTHOR]