[Show abstract][Hide abstract] ABSTRACT: Inflammatory conditions affecting the gut may cause motility disturbances, and ulcerative colitis - one of the main disorders among the inflammatory bowel diseases - may display abnormal colonic motility.
To review the abnormalities of the large bowel in ulcerative colitis, by considering the motility, laboratory (in vitro) and pathological studies dealing with this topic.
A comprehensive online search of Medline and the Science Citation Index was carried out.
Patients with ulcerative colitis frequently display colonic motor abnormalities, including lack of contractility, an increase of propulsive contractile waves, an excessive production of nitric oxide, vasoactive intestinal polypeptide nerves, interleukin 1 beta, neurotensin, tachykinins levels and the weaker action of substance P, likely related to a neuromuscular dysfunction due to the inflammatory process.
A better understanding of the pathophysiological grounds of altered colonic motility in ulcerative colitis may lead to a more in-depth knowledge of the accompanying symptoms and to better and more targeted therapeutic approaches.
United European Gastroenterology Journal 12/2014; 2(6):457-462. DOI:10.1177/2050640614548096 · 2.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Intestinal superinfections may occur in the setting of inflammatory bowel diseases (IBD), complicating the clinical picture and triggering flares of disease.
To report our experience with intestinal superinfections in IBD patients over a three-year period.
Charts of patients hospitalized for moderate-to-severe active disease during the observation period were reviewed, and data of patients with flares due to infections collected and analyzed.
Overall, 15 out of 113 IBD patients (13.3%) had flare-ups related to intestinal infections; 143 acute flare-ups were thus documented, with 17 episodes (12%) related to infective agents, represented by Campylobacter jejuni (3 infections), Clostridium difficile (7 infections), and Cytomegalovirus (7 infections). All but two infections occurred in ulcerative colitis patients, and all responded to appropriate treatment.
Intestinal superinfections may complicate the clinical picture of IBD patients, increasing the diagnostic and therapeutic burden. Appropriate early diagnostic and therapeutic measures are thus needed in these patients.
Journal of Crohn s and Colitis 03/2012; 6(2):154-9. DOI:10.1016/j.crohns.2011.07.012 · 6.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bowel ultrasound has been shown to be a useful tool to evaluate patients with inflammatory bowel disease, especially Crohn's disease. However, such data are still scarce in ulcerative colitis patients.
To establish the value of bowel ultrasound in moderate to severe ulcerative colitis patients, and compare these data with endoscopic findings.
Endoscopic, ultrasound and C-reactive protein data from 51 patients with moderate to severe ulcerative colitis observed during a 3-year period were retrospectively obtained and analysed.
All patients displayed pathological thickness (>4 mm) of the colon wall. This value strongly correlated with C-reactive protein values (p=0.0001) and the endoscopic score (p<0.0001). Also, a strong correlation (p<0.0001) was found between CRP values and endoscopic score.
Bowel ultrasound, in expert hands, may represent a useful adjunctive (or first line) tool for the evaluation of patients with moderate to severe ulcerative colitis.
[Show abstract][Hide abstract] ABSTRACT: The dose of warfarin needed to obtain a therapeutic anticoagulation level varies widely among patients and can undergo abrupt changes for unknown reasons. Drug interactions and genetic factors may partially explain these differences. Intestinal flora produces vitamin K2 (VK2) and patients with small intestinal bacterial overgrowth (SIBO) rarely present reduced INR values due to insufficient dietary vitamin K. The present study was undertaken to investigate whether SIBO occurrence may affect warfarin dose requirements in anticoagulated patients. Based on their mean weekly dose of warfarin while on stable anticoagulation, 3 groups of 10 patients each were defined: low dose (LD, <or=17.5 mg/wk of warfarin); high dose (HD, from 35-70 mg/wk); and very high dose (VHD>or=70 mg/wk). Each patient underwent a lactulose breath test to diagnose SIBO. Plasma levels of warfarin and vitamin K-analogues were also assessed. Patients with an altered breath test were 50% in the VHD group, 10% in the HD group, and none in the LD group (P=0.01). Predisposing factors to SIBO were more frequent in the VHD group, while warfarin interfering variables were not. VHD patients were younger and had a higher plasma vitamin K1 (VK1) concentration (P>0.05). On the contrary, the plasma VK2 levels tended to be lower. This pilot study suggests that SIBO may increase a patient's warfarin dose requirement by increasing dietary VK1 absorption through the potentially damaged intestinal mucosa rather than increasing intestinal VK2 biosynthesis. Larger studies are needed to confirm these preliminary data and to evaluate the effects of SIBO decontamination on warfarin dosage.
Thrombosis Research 07/2010; 126(1):12-7. DOI:10.1016/j.thromres.2009.11.032 · 2.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Anal endosonography (AES) is able to reliably visualize and identify anal sphincter abnormalities. However, dedicated probes are quite expensive.
We describe a simple and less costly method to perform AES in a unit that already has echoendoscopes available by inserting the endoscope through a disposable anoscope filled with standard ultrasound gel.
Subjects without anal abnormalities and patients with anal disease (abscesses, fistulas) were evaluated.
Good-quality images were obtained in both controls and patients, with optimal visualization of the anatomic structures and pathologic features. The latter (abscesses, fistulas) were always confirmed by magnetic resonance imaging.
This simple and less costly method allows to perform good-quality AES in units having echoendoscopes availability, without the need of a more expensive dedicated probe.
[Show abstract][Hide abstract] ABSTRACT: Most studies of soy and cholesterol have tested foods made from purified soy proteins containing mainly isoflavone glycosides. Fermented soy foods have mainly isoflavone aglycons and account for a high proportion of the soy protein source in Asia, where there is an inverse relationship between soy intake and serum cholesterol. The aim of this study was to compare a novel soy germ pasta, naturally enriched in isoflavone aglycons as a result of the manufacturing process, with conventional pasta for effects on serum lipids and other cardiovascular risk markers. In this randomized, controlled, parallel study design of 62 adults with hypercholesterolemia who consumed a Step II diet that included one 80-g serving/d of pasta, we measured serum lipids, high sensitivity C-reactive protein (hsCRP), urinary isoprostanes, and brachial artery flow-mediated vasodilatation at baseline and after 4 and 8 wk. The pasta delivered 33 mg of isoflavones and negligible soy protein and led to a serum isoflavone concentration of 222 +/- 21 nmol/L; 69% of subjects were equol producers. Soy germ pasta reduced serum total and LDL cholesterol by 0.47 +/- 0.13 mmol/L (P = 0.001) and 0.36 +/- 0.10 mmol/L (P = 0.002) more than conventional pasta, representing reductions from baseline of 7.3% (P = 0.001) and 8.6% (P = 0.002), respectively. Arterial stiffness (P = 0.003) and hsCRP (P = 0.03) decreased and improvements in all the above risk markers were greatest in equol producers. All measures returned to baseline when patients were switched to conventional pasta. In conclusion, pasta naturally enriched with isoflavone aglycons and lacking soy protein had a significant hypocholesterolemic effect beyond a Step II diet and improved other cardiovascular risk markers.
Journal of Nutrition 11/2007; 137(10):2270-8. · 3.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Uncontrolled T cell activation and abnormal function of the innate immune system against normal enteric bacterial flora play a critical part in the pathogenesis of inflammatory bowel disease (IBD). Therefore, pharmacological strategies directed to restore the normal responsiveness of the immune system could be efficacious in the treatment of these pathological conditions. Glucocorticoid-induced tumour necrosis factor receptor (GITR)-related gene is a member of the tumour necrosis factor receptor superfamily that is constitutively expressed at high levels on regulatory T cells and at low levels on unstimulated T cells, B cells and macrophages. GITR triggering leads to activation of T effectors and reversal of suppressive function of regulatory T cells.
To investigate the role of GITR in the development of experimental colitis in mice.
Using GITR(-/-) mice, GITR deletion protected against 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis by reducing innate immune responses and effector T cell activity. Effector T cells isolated from GITR(-/-) mice were less effective than T cells isolated from GITR(+/+) mice to transfer colitis in immunodeficient mice. Blocking the GITR/ligand for GITR (GITRL) signal by giving soluble GITR prevented TNBS-induced colitis in normal GITR(+/+) and also in lymphocyte-deficient SCID mice.
Collectively, these data suggest that GITR plays a critical part in regulating both acquired and innate mucosal immune responses during the development of experimental colitis in mice. Therefore, targeting the GITR/GITRL system signalling may represent a potential pharmacological tool for the treatment of IBD.
Gut 02/2007; 56(1):52-60. DOI:10.1136/gut.2006.091181 · 14.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Signet-ring cell carcinoma is a relatively rare neoplasm that rarely occurs in the urinary bladder. We report a case of a 60-year-old man who presented with gross haematuria. Cystoscopy revealed a white sessile tumour of the anterior bladder wall. The histological diagnosis showed a primary signet-ring cell carcinoma of the bladder (T3bN0M0). Eighteen months after radical cystectomy, the patient developed colon and stomach metastases. This case represents the first description of a primary signet-ring cell carcinoma of the urinary bladder with gastrointestinal metastases.
[Show abstract][Hide abstract] ABSTRACT: 3alpha-6alpha-Dihydroxy-7alpha-fluoro-5beta-cholanoate (UPF-680), the 7alpha-fluorine analog of hyodeoxycholic acid (HDCA), was synthesized to improve bioavailability and stability of ursodeoxycholic acid (UDCA). Acute rat biliary fistula and chronic cholestasis induced by 17alpha-ethynyl-estradiol (17EE) models were used to study and compare the effects of UPF-680 (dose range 0.6-6.0 micromol/kg min) with UDCA on bile flow, biliary bicarbonate (HCO(3)(-)), lipid output, biliary bile acid composition, hepatic enzymes and organic anion pumps. In acute infusion, UPF-680 increased bile flow in a dose-related manner, by up to 40.9%. Biliary HCO(3)(-) output was similarly increased. Changes were observed in phospholipid secretion only at the highest doses. Treatment with UDCA and UPF-680 reversed chronic cholestasis induced by 17EE; in this model, UDCA had no effect on bile flow in contrast to UPF-680, which significantly increased bile flow. With acute administration of UPF-680, the biliary bile acid pool became enriched with unconjugated and conjugated UPF-680 (71.7%) at the expense of endogenous cholic acid and muricholic isomers. With chronic administration of UPF-680 or UDCA, the main biliary bile acids were tauro conjugates, but modification of biliary bile acid pool was greater with UPF-680. UPF-680 increased the mRNA for cytochrome P450 7A1 (CYP7A1) and cytochrome P450 8B (CYP8B). Both UDCA and UPF-680 increased the mRNA for Na(+) taurocholate co-transporting polypeptide (NCTP). In conclusion, UPF-680 prevented 17EE-induced cholestasis and enriched the biliary bile acid pool with less detergent and cytotoxic bile acids. This novel fluorinated bile acid may have potential in the treatment of cholestatic liver disease.
[Show abstract][Hide abstract] ABSTRACT: Glucocorticoids, widely used therapeutic agents for several pathologies, act upon diverse cells and tissues, including the lympho-haemopoietic system. Glucocorticoid-mediated apoptosis has been described as one of the mechanisms underlying their pharmacological and physiological effects. Glucocorticoids induce apoptosis in thymocytes through genomic and non-genomic signals. We tested thymocyte apoptosis rates as induced by a panel of glucocorticoids. Using four glucocorticoids that are widely adopted in clinical practice we compared their induction of thymocyte apoptosis and activation of non-genomic and genomic signals, including phosphatidylinositol-specific phospholipase C (PI-PLC), caspase-8, -9 and -3, and Glucocorticoid-Induced Leucine Zipper (GILZ). GILZ is a protein that is rapidly induced by glucocorticoids treatment and involved in apoptosis modulation. Results indicate different glucocorticoids have different apoptotic activity which is related to their ability to induce both genomic, evaluated as caspases activation and GILZ expression, and non-genomic effects, evaluated as PI-PLC phosphorylation.
European Journal of Pharmacology 02/2006; 529(1-3):63-70. DOI:10.1016/j.ejphar.2005.10.053 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The 2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester (NCX-4016) is a NO-releasing derivative of aspirin. In this study, we provide evidence that NCX-4016 delivered to PMBC-derived T lymphocytes and monocytes causes a transitory inhibition of cell respiration and approximately 50% reduction of cellular ATP, which translates in a time-reversible inhibition of cell proliferation and IL-2, IL-4, IL-5, and IFN-gamma secretion. Exposure of lymphocytes and monocytes to aspirin, 2-(acetyloxy)benzoic acid 3-(hydroxymethyl)phenyl ester (NCX-4017), a non-NO-releasing analog of NCX-4016, and cyclooxygenase inhibitors, reduced PG formation, but has no effect on cytokine/chemokine release. In contrast, delivering NO with (z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino] diazen-1-ium-1,2 diolate (DETA-NO) reproduced most of the metabolic and anti-cytokine activities of NCX-4016. Scavenging NO with hemoglobin or adding selective substrates of complex II, III, and IV of the mitochondrial respiratory chain reverses NCX-4016' inhibitory activities. Exposure to DETA-NO and NCX-4016 enhances glucose uptake, glycolytic rate, and lactate generation in CD3/CD28-costimulated lymphocytes, while reduced citric acid cycle intermediates. These effects were not reproduced by selective and nonselective cyclooxygenase 2 inhibitors. In summary, we demonstrated that exposure of lymphocytes to NCX-4016 causes a metabolic hypoxia that inhibits lymphocyte reactivity to costimulatory molecules, providing a potential counteregulatory mechanism to control activated immune system.
The Journal of Immunology 08/2004; 173(2):874-82. DOI:10.4049/jimmunol.173.2.874 · 4.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 2-(Acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester (NCX-4016) is a nitric oxide (NO)-releasing derivative of aspirin that inhibits cyclooxygenase (COX) activity and releases NO. Acetylation of COX-2 by aspirin activates a transcellular biosynthetic pathway that switches eicosanoid biosynthesis from prostaglandin E(2) to 15-epi-lipoxin (LX)A(4) or aspirin-triggered lipoxin (ATL). Here, we demonstrate that exposure of neutrophil (PMN)/human umbilical vein endothelial cell (HUVEC) cocultures to aspirin and NCX-4016 triggers ATL formation and inhibits cell-to-cell adhesion induced by endotoxin (LPS) and interleukin (IL)-1beta by 70 to 90%. However, although selective and nonselective COX-2 inhibitors (celecoxib, rofecoxib, and naproxen) or N-t-butoxycarbonylmethionine-leucine-phenylalanine (Boc-1), an LXA(4) receptor antagonist, reduced the antiadhesive properties of aspirin by approximately 70%, antiadhesive effects of NCX-4016 were only marginally affected ( approximately 30%) by COX inhibitors and Boc-1, implying that COX-independent mechanisms mediate the antiadhesive properties of NCX-4016. Indeed, NCX-4016 causes a long-lasting (up to 12 h) release of NO and cGMP accumulation in HUVEC. Scavenging NO with 10 mM hemoglobin, in the presence of celecoxib, reduced the antiadhesive properties of NCX-4016 by approximately 80%. Confirming a role for NO, the NO donor diethylenetriamine-NO also inhibited PMN/HUVEC adhesion by approximately 80%. NCX-4016, but not aspirin, decreased DNA binding of nuclear factor-kappaB (NF-kappaB) on gel shift analysis and HUVEC's overexpression of CD54 and CD62E induced by LPS/IL-1beta. Reduction of binding of the two NF-kappaB subunits p50-p50 and p50-p65 was reversed by dithiothreitol, implying S-nitrosylation as mechanism of inhibition. In summary, our results support that ATL and NO are formed at the PMN/HUVEC interface after exposure to NCX-4016 and mediate the antiadhesive properties of this compound.
Journal of Pharmacology and Experimental Therapeutics 07/2004; 309(3):1174-82. DOI:10.1124/jpet.103.063651 · 3.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Low serum retinol and hepatic tocopherol levels correlate with hepatocellular carcinoma (HCC) risk. Antiestrogen tamoxifen seems useful in HCC patients. A pilot study was performed to evaluate the effect of all-trans retinoic acid associated with tamoxifen and vitamin E on patients with advanced HCC.
Fifteen consecutive patients with advanced HCC were included in the study. Patients were evaluated for survival, quality of life, liver function, tumor mass, toxicity related to the treatment and retinoid receptors in liver biopsies.
The median survival of our patients was 22 months. Pain and asthenia were improved in the majority of patients. Every patient with baseline elevated liver enzymes showed an improvement in liver function. RAR-alpha, RXR-alpha, RAR-beta and RAR-gamma receptors were demonstrated in 100%, 73%, 47% and 40%, respectively.
A combination therapy of all-trans retinoic acid, tamoxifen and vitamin E increases the survival rate and ameliorates the clinical outcome in patients with inoperable HCC.
Anticancer research 03/2004; 24(2C):1255-60. · 1.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In fibroblasts, thrombin induces collagen deposition through activation of a G-protein-coupled receptor, proteinase-activated receptor 1 (PAR(1)). In the current study, we examined whether PAR(1) antagonism inhibits hepatic stellate cell (HSC) activation in vitro and whether it protects against fibrosis development in a rodent model of cirrhosis. A rat HSC line was used for in vitro studies whereas cirrhosis was induced by bile duct ligation (BDL). The current results demonstrated that HSCs express PAR(1), as well as proteinase-activated receptors 2 (PAR(2)) and 4 (PAR(4)), and that all three PARs were up-regulated in response to exposure to growth factor in vitro. Exposure to thrombin and to SFLLRN-(SF)-NH(2), a PAR(1) agonist, and GYPGKF (GY)-NH(2), a PAR(4) agonist, triggered HSC proliferation and contraction, as well as monocyte chemotactic protein-1 (MCP-1) production and collagen I synthesis and release. These effects were inhibited by the PAR(1) antagonist. Administration of this antagonist, 1.5 mg/kg/d, to BDL rats reduced liver type I collagen messenger RNA (mRNA) expression and surface collagen by 63%, as measured by quantitative morphometric analysis. Similarly, hepatic and urinary excretion of hydroxyproline was reduced significantly by the PAR(1) antagonist. In conclusion, PAR(s) regulates HSC activity; development of PAR antagonists might be a feasible therapeutic strategy for protecting against fibrosis in patients with chronic liver diseases.
[Show abstract][Hide abstract] ABSTRACT: We studied whether acute administration of NCX-1000, a nitric oxide (NO)-releasing derivative of ursodeoxycholic acid (UDCA), to animals with established liver cirrhosis decreases intrahepatic resistance and modulates hepatic vascular hypereactivity to norepinephrine (NE).
Four-week bile duct ligated (BDL) cirrhotic and control, sham-operated, rats were treated orally with 28 mg/kg per day NCX-1000 or 15 mg/kg per day UDCA for 5 days. Isolated normal and cirrhotic livers were perfused with NE, from 10 nM to 30 microM, in a recirculating system.
NCX-1000 administration to BDL cirrhotic rats decreased portal pressure (P<0.01) without affecting mean arterial pressure and heart rate. In the isolated perfused liver system, administration of NE resulted in a dose-dependent increase of intrahepatic resistance. Vasoconstriction caused by 30 microM NE was reduced by 60% in animals treated with NCX-1000 (P<0.001), while UDCA was uneffective. The same portal pressure lowering effect was documented in cirrhotic and sham operated rats. Administration of NCX-1000 to BDL and sham operated rats resulted in a similar increase of nitrite/nitrate and cGMP concentrations in the liver.
By selectively delivering NO to the liver, NCX-1000 increases cGMP concentrations and effectively counteracts the effect of endogenous vasoconstrictors on the hepatic vascular tone.
Journal of Hepatology 12/2003; 39(6):932-9. DOI:10.1016/S0168-8278(03)00393-3 · 11.34 Impact Factor