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PubMed1994

Twenty-six-week oral toxicity study of benzalazine in rats.

A 26-week toxicity study by oral gavage administration was performed in Sprague-Dawley rats with benzalazine (2-hydroxy-5-[(4-carboxyphenyl) azo] benzoic acid, CAS 64896-26-0), a new agent for the treatment of ulcerative colitis and Crohn's disease of the large intestine, as a part of a safety evaluation program. Dosages of 0 (control), 300, 900 and 2700 mg/kg b.w./d were selected for this study. Except slight changes in the urinary status (decreased pH value and increased specific gravity) from 900 mg/kg b.w./d p.o. onwards, which were probably substance related, no further intolerance reactions were observed. The urine had a dark-yellow colour which was probably an indication of metabolites of benzalazine or benzalazine itself which were excreted via the urine. Behaviour, external appearance, body weight gain, food and water consumption, haematology, clinical biochemistry, organ weight analysis, macroscopic and microscopic examinations revealed no substance-related influence. Therefore, on the basis of the results obtained, it is concluded that the non-toxic dose level in this study is considered to be 300 mg benzalazine/kg b.w./d p.o. following daily administration for 26 weeks.

Animals↗
PubMed1983

Decreased incorporation of 14C-glucosamine relative to 3H-N-acetyl glucosamine in the intestinal mucosa of patients with inflammatory bowel disease.

The synthesis of glycoproteins was investigated in intestinal mucosa from patients with inflammatory bowel disease (IBD) and from those with various other conditions. The incorporation into acid-insoluble macromolecules of the amino sugar glucosamine, the first and committed metabolite in the biosynthetic sequence, and its immediate derivative, N-acetyl glucosamine was determined. Tissue was incubated with 1-2 nmol 14C-glucosamine and 3H-N-acetyl glucosamine and the simultaneous incorporation of both isotopes was measured. Bowel tissue from areas microscopically uninvolved in active disease process was examined. Values for the incorporation of both substrates into acid-soluble constituents were similar for both IBD and non-IBD groups, as was also the incorporation of 3H into acid-insoluble constituents. The incorporation of 14C, however, when expressed relative to that of 3H in each individual patient, i.e., 14C/3H, was distinctly different in IBD cases. In 26 non-IBD samples this ratio ranged from 0.04-0.26 with a mean of 0.097 +/- 0.009. In nine cases of Crohn's disease values ranged from 0.013-0.06 with a mean of 0.039 +/- 0.011 (p less than 0.01); in nine cases of ulcerative colitis values were 0.007-0.06 with a mean of 0.031 +/- 0.006 (p less than 0.01). It is concluded that the step involving the N-acetylation of the amino sugar is relatively deficient in patients with IBD and this could reduce the synthesis of the glycoprotein cover which protects the mucosa from damage by bowel contents.

Acetylglucosamine↗
PubMed1997

Lower extremity arterial occlusions in young patients with Crohn's colitis and premature atherosclerosis: report of six cases.

Arterial occlusive disease (AOD) which is rarely described in patients with inflammatory bowel disease, is mainly associated with Crohn's disease (CD), and its etiology and natural course are unknown. We studied six patients (five women, one man) with CD and major lower extremity AOD who were treated at the Cleveland Clinic between 1985 and 1994. These were relatively young patients (age range 24-48 years) with steroid-dependent Crohn' colitis. On their presentation, five had acute onset of severe ischemic symptoms ("blue toe" syndrome in three) and one had rapid progression of claudication. All the patients had active CD and/or prior extensive bowel resections, and had no evidence of extraintestinal manifestation. Cardiovascular risk factors were smoking (n = 5), dyslipidemia (n = 3), family history of coronary artery disease (n = 3), premature menopause (n = 2), diabetes mellitus (n = 1). Arteriograms showed iliac artery involvement in all six patients and bilateral AOD in three. None of the patients had arteriographic or clinical signs of vasculitis. Five patients required arterial revascularizations, i.e., endovascular (n = 2), surgical (n = 2), and combined in one. Three patients had microscopic evidence of atherosclerosis. Lower extremity AOD in patients less than 50 yr of age and with CD may be partially related to premature atherosclerosis. Prospective screening for cardiovascular risk factors, subclinical disease, and hypercoagulability might be indicated in patients with active CD to prevent major arterial complications.

Adult↗
PubMed1988

Extraintestinal manifestations in patients with diverticulitis.

Three patients had diverticulitis and extraintestinal manifestations of arthritis and pyoderma gangrenosum. In each, a mistaken diagnosis of idiopathic inflammatory bowel disease was first made because of extraintestinal complaints associated with the gastrointestinal symptoms of diverticular disease. The joint and skin manifestations were refractory to various treatments, including oral and intradermal steroids, immunosuppressive agents, and hyperbaric oxygen. Segmental resection of the involved colon promptly and completely resolved all symptoms, without recurrence 26 to 38 months after surgery. Microscopic examination of the resected specimens showed only diverticulitis without any evidence of chronic idiopathic inflammatory bowel disease. Patients with diverticulitis may have extraintestinal manifestations as do patients with other inflammatory diseases of the colon. The failure to recognize this relationship may result in misdiagnosis and prolonged medical therapy, whereas segmental colonic resection may be curative.

Aged↗
PubMed1999

Nitroxide stable radical suppresses autoimmune uveitis in rats.

Free radicals have been implicated in the pathogenesis of experimental autoimmune uveoretinitis (EAU). Nitroxides are stable radicals with a superoxide-dismutase-mimicking activity, which exert an anti-inflammatory effect in various animal models of oxidative damage and inflammation, such as experimental colitis and head trauma. We examined the use of the SOD mimic nitroxide 4-hydroxy-2,2,6,6,-tetramethylpiperidine-1-N-oxyl (TPL) to suppress EAU. Adult male Lewis rats were immunized with 125 microg/rat synthetic human retinal S-Ag, emulsified with Freund's adjuvant. Intravenous pertussis toxin was simultaneously injected. Beginning on Day 6, rats were injected with a daily intraperitoneal dose of 35, 175 or 350 micromol/rat of the nitroxide TPL. Control rats received intraperitoneal normal saline. The animals were examined daily, and on the 19th day the eyes were enucleated. Aqueous protein concentrations and retinal lipid peroxidation product levels (ketodienes and conjugated dienes) were determined. Histological sections were stained and examined microscopically. TPL was found to penetrate the aqueous humor readily. Beginning on day 12, rats developed a severe pan-uveitis. Rats in the treatment group had a lower mean clinical and histological score than that of controls. Levels of aqueous humor protein, retinal conjugated diens and ketodiens were all significantly lower in the treatment group. This effect was more pronounced with the lower TPL concentration. We conclude that TPL reduces clinical, biochemical and histopathological severity of S-Ag induced EAU in Lewis rats. This effect is probably mediated by removal of superoxide radicals, but other mechanisms may also be involved.

Amino Acid Sequence↗
PubMed2005

Advances in colonic imaging: new endoscopic imaging methods.

There is a need for better endoscopic visualization in specific circumstances like detection of flat colorectal lesions and dysplasia-screening in ulcerative colitis. Chromoendoscopy is a technique with proven success, but many more, novel endoscopic techniques are currently under investigation. In this article different point measurement and still imaging methods are discussed: Raman spectroscopy, elastic (light) scattering spectroscopy, fluorescence spectroscopy, optical coherence tomography and confocal laser microscopy. Furthermore, real-time endoscopic imaging methods are discussed. These include narrow band imaging, fluorescence imaging and endocytoscopy. The results of fluoroscence imaging might be improved by application of photosensitizers or coupling of fluorescent dyes to tumour-related antigens (immunoscopy). Most of these techniques still have to be developed further and are not yet available for routine use. In our opinion, a combination of a red-flag technique and a microscopic technique carries an enormous potential.

Antigens, Neoplasm↗
PubMed1999

Mycophenolate mofetil for maintenance therapy of Wegener's granulomatosis and microscopic polyangiitis: a pilot study in 11 patients with renal involvement.

Successful maintenance therapy with mycophenolate mofetil (MMF) 2 g/d and low-dose oral corticosteroids (OCS) over a period of 15 mo was given to patients with Wegener's granulomatosis (WG) (n = 9) and microscopic polyangiitis (MPA) (n = 2). All patients had severe generalized disease with pauci-immune necrotizing glomerulonephritis and received standard induction therapy with oral cyclophosphamide and OCS for a mean of 14 wk until remission was achieved. Of 11 patients, only one WG patient relapsed in the 14th month of maintenance therapy. Maintenance therapy with MMF was able to further reduce grumbling disease activity as measured by the Birmingham vasculitis activity score (BVAS2) and proteinuria that were still present by the end of induction therapy. OCS could be reduced to a median daily dose of 5 mg and discontinued in three patients. Possible drug-related adverse effects were transient and included abdominal pain, respiratory infection, diarrhea, leukopenia, and a cytomegalovirus-colitis in one patient that was successfully treated with ganciclovir. It is concluded that MMF in combination with low-dose OCS is well tolerated and effective for maintenance therapy of WG and MPA. Long-term treatment with MMF in these diseases is attractive because of its low toxicity. MMF will have to be studied further and compared with cyclophosphamide or azathioprine maintenance therapy in randomized trials.

Adrenal Cortex Hormones↗
PubMed1995

Elevation of interleukin-6 in inflammatory bowel disease is macrophage- and epithelial cell-dependent.

Local interleukin-6 (IL-6) activity was studied using colonic mucosal tissues in inflammatory bowel disease (IBD) and inflammatory control patients. Active IBD specimens exhibited significantly higher IL-6 activity than control specimens in both cultures of isolated lamina propria mononuclear cells (LPMC) and mucosal tissues with an increased number of IL-6-producing cells. However, the activity in inactive IBD or inflammatory controls did not differ from controls. Northern blot analysis demonstrated IL-6 messenger RNA in LPMC and colonic epithelial cells isolated from active IBD specimens but not in control cells. Furthermore, immunofluorescent microscopic study of active IBD specimens showed more conspicuous staining of IL-6 in infiltrating LPMC (mostly CD68+ cells) and colonic epithelial cells. These results suggest that elevation of local IL-6 activity may be a characteristic feature of active IBD and both macrophages and colonic epithelial cells are the major cell types responsible for this phenomenon.

Adenocarcinoma↗
PubMed1998

[The establishment of TNBS-induced experimental colitis].

OBJECTIVE: To explore the pathogenesis of inflammatory bowel disease (IBD) and to establish some indices monitoring the activity and severity of IBD. METHODS: A rat model of experimental colitis was induced by administration of the hapten 2, 4, 6-trinitrobenzenesulfonic acid (TNBS, 30 mg) in 50% ethanol 0.25 ml as the "barrier breaker". And it then recurs only after 10 mg TNBS administration. Inflammation was assessed by gross appearance using a grading scale and by histology. Myeloperoxidase(MPO) and superioxide dismutase(SOD) activities were also measured to evaluate the severity of inflammation. RESULTS: An acute inflammation with ulcers and neutrophil infiltration developed that evolved into a chronic inflammation with luminol narrowing and abundant fibrous connective tissue hypertrophy at 21 days. Crypt abcess were observed in some rats killed in 1 week. MPO activity was significantly elevated, while SOD decreased, in mucosa from all treated groups at all time intervals when macroscopic and microscopic mucosal injury was evident. CONCLUSIONS: These results indicate that this model affords an opportunity to study the pathogenesis of colonic inflammatory disease and may be used to evaluate new treatments potentially applicable to IBD in humans. In addition, MPO and SOD activities could be regarded as two markers which may evaluate the severity of colonic inflammation.

Animals↗
PubMed2003

Colonic spirochetosis of colony-raised rhesus macaques associated with Brachyspira and Helicobacter.

Colonic spirochetosis is an inflammatory bowel disease that affects a broad range of hosts, including human and non-human primates. The disease in humans and non-human primates is characterized by intimate attachment of the anaerobic spirochetes Brachyspira aalborgi and B. pilosicoli, and some unclassified flagellated microbes along the apical membrane of colonic enterocytes. Although the presence of spiral-shaped bacteria with single polar flagella and blunted ends in colonic spirochetosis is well established, the identities of many of these organisms is still unknown. Recently, Helicobacter species with a morphology similar to the flagellated bacteria present in colonic spirochetosis have been cultured from intestinal specimens obtained from rhesus macaques, some with idiopathic colitis. The purpose of the present study was to determine whether or not the flagellated bacteria seen in the colons of rhesus macaques with colonic spirochetosis are Helicobacter. The presence of flagellated bacteria alone (n=2) or together with spirochetes (n=1) in formalin-fixed and paraffin-embedded colons of three rhesus macaques with the naturally occurring disease was demonstrated by immunohistochemical staining and ultrastructural examination. Total DNA extracted from affected and control intestinal specimens was amplified by polymerase chain reaction (PCR) using Helicobacter 16S rRNA gene-specific primers. Comparative nucleotide sequence analysis of PCR products cloned from positive reactions indicated that two distinct Helicobacter genomospecies were present either alone or in combination with Brachyspira in the colons of rhesus macaques with microscopic lesions indicative of colonic spirochetosis.

Journal Article↗
PubMed2000

Pathogenesis of intestinal amebiasis: from molecules to disease.

In spite of a wealth of knowledge on the biochemistry and cellular and molecular biology of Entamoeba histolytica, little has been done to apply these advances to our understanding of the lesions observed in patients with intestinal amebiasis. In this review, the pathological and histological findings in acute amebic colitis are related to the molecular mechanisms of E. histolytica pathogenicity described to date. Infection of the human colon by E. histolytica produces focal ulceration of the intestinal mucosa, resulting in dysentery (diarrhea with blood and mucus). Although a complete picture has not yet been achieved, the basic mechanisms involved in the production of focal lytic lesions include complex multifactorial processes in which lectins facilitate adhesion, proteases degrade extracellular matrix components, porins help nourish the parasite and may also kill incoming polymorphonuclear leukocytes and macrophages, and motility is used by the parasite to invade deeper layers of the colon. In addition, E. histolytica has developed mechanisms to modulate the immune response during acute infection. Nevertheless, much still needs to be unraveled to understand how this microscopic parasite has earned its well-deserved histolytic name.

Animals↗
PubMed2000

Liver transplantation for primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology that is progressive in most symptomatic patients, advancing toward cirrhosis and liver failure. Liver transplantation is the only therapeutic option for patients with end stage liver disease resulting from this disorder. The results of transplantation for PSC are excellent with one-year survival rates of 90-97% and five-year survival rates of 80-85%, but are closely related to pre-transplant Child-Pugh stage. Recurrence of PSC after liver transplantation is common, occurring in up to 20% of patients, but it appears to have little effect on patient survival, as survival of patients with recurrent PSC is similar to that of those without evidence of recurrence. Cholangiocarcinoma is a catastrophic complication of PSC and as yet no reliable screening method exists. The results of liver transplantation for patients with clinically apparent cholangiocarcinoma are extremely poor, however in patients in whom a microscopic tumour is detected in the explanted liver, survival is similar to those transplanted with PSC without cholangiocarcinoma. Activity of inflammatory bowel disease (IBD) appears to be more severe after transplantation, especially in units where steroid immunosuppression is withdrawn early. Colon cancer appears within the first few years after transplantation in approximately 7% of patients with IBD who are transplanted for PSC. Annual colonoscopy in this population seems prudent.

Bile Duct Neoplasms↗
PubMed2002

Malakoplakia in association with colorectal carcinoma: a series of four cases.

AIMS: Malakoplakia is a characteristic inflammatory condition which is usually seen in the urogenital tract. Gastrointestinal malakoplakia is seen in association with a variety of conditions such as ulcerative colitis, diverticular disease, adenomatous polyps and carcinoma. The purpose of this paper is to report four additional cases of colorectal cancer associated with malakoplakia and review the literature on this association. METHODS: All specimens were colectomies for cancer. Routine handling of the specimen with lymph node harvesting was performed. In addition to H&E stains, PAS, Perls' Prussian Blue and von Kossa stains were performed. RESULTS: Three of the cases were encountered in males and the patients ranged in age from 55 to 64 years. One case each occurred in the caecum/ascending colon and descending colon, while the remaining two were located in the rectum. All four cases were Dukes' stage B tumours. Furthermore, all four cases had spread to pericolic fat and two had perforated. Microscopic examination showed the malakoplakia to be present at the infiltrating edge of the tumours. The draining lymph nodes were involved by malakoplakia to varying degrees in all cases. CONCLUSIONS: From this series and the literature review, malakoplakia associated with colorectal cancer tends to occur in elderly males in the rectum. The malakoplakia is found at the infiltrating front of the tumour and is not admixed with the neoplastic glands. Although lymph node involvement by malakoplakia has been reported only once previously, all four cases in this series showed evidence of involvement. The association does not appear to have any prognostic significance.

Carcinoma, Ductal, Breast↗
PubMed1995

Intestinal pseudo-obstruction and ischemia secondary to both beta 2-microglobulin and serum A amyloid deposition.

We present the case of a 61-year-old man on long-term hemodialysis in whom early colonic ischemia and pseudo- obstruction were caused by amyloid deposition of both the beta 2-microglobulin and AA type. The light microscopic diagnosis of amyloidosis was confirmed by Congo red birefringence, immunohistochemistry, and electron microscopy. The two types of amyloid had separate distributions within the colon. While both types affected submucosal and serosal blood vessels, the beta 2- microglobulin amyloid also formed large masses that displaced smooth muscle cells and was associated with Class II major histocompatibility-positive multinucleated giant cells. The pathogenesis of this uncommon occurrence of two amyloids and the role of chronic inflammation in amyloidogenesis are discussed.

Colitis, Ischemic↗
PubMedDate not supplied

Antineutrophil cytoplasmic antibodies (ANCA) and small vessel vasculitis.

We report on one patient with Wegener's granulomatosis (WG) and two patients with microscopic polyangiitis (MPA). The patient with WG had signs of a respiratory infection and showed a c-ANCA pattern with proteinase 3 (PR3) specificity. The patients with MPA presented with pulmonary haemorrhage and signs of renal damage and showed a p-ANCA pattern with myeloperoxidase (MPO) specificity. In the three patients histopathological findings confirmed the diagnosis. We discuss the clinical indications of ANCA testing and the current terminology for reporting ANCA results (c-ANCA, p-ANCA, c-ANCA (atypical) and atypical ANCA). The target antigens and diseases associated with these different patterns are considered. Finally we focus on the value of ANCA and more specific PR3-ANCA and MPO-ANCA in the diagnosis of WG and MPA. The new application domain of ANCA in Crohn's disease and ulcerative colitis is also discussed.

Adolescent↗
PubMed2006

[Parasitic fauna and the frequency of Entamoeba histolytica/Entamoeba dispar detected by ELISA in stool samples in Sanliurfa, Turkey].

Amoebiasis is a significant health problem in developing countries. Humans are infected by two morphologically identical species of Entamoeba. Entamoeba histolytica causes amebic colitis and liver abscess, and Entamoeba dispar is noninvasive. The aim of this study was to determine the prevalence of the E. histolytica/E. dispar complex using the ELISA method on stools of patients. A total of 1600 stool specimens were examined using Lugol preparations and the modified Ritchie method. A total of 583 (36.4%) of the stool specimens were found to be positive for one or more than one parasite. Twenty two subjects (3.8%) of the study population with intestinal parasites harbored two parasites and one subject (0.2%), three parasites. A total of 87 stool specimens that were doubtful using the Lugol method were examined by the E. histolytica specific sensu-lato antigen based ELISA test and the trichrome staining method. Of these 87 specimens, 23 (26.4%) specimens were positive for E. histolytica/E. dispar trophozoites/cysts microscopically using trichrome staining and 19 (21.7%) of the stool specimens were found to be positive for the E. histolytica/E. dispar complex by the ELISA test.

Adolescent↗
PubMed2000

Release of membrane vesicles containing endotoxic lipopolysaccharide in Escherichia coli O157:H7 clinical isolates.

Membrane vesicles released by E. coli O157:H7 strains were investigated by immuno-electron microscopy using anti-O157 antibody. Anti-O157 antibody enhanced the negative-staining of vesicles and we found numerous small vesicles clearly formed around bacterial cells. An immunogold-electron microscopic examination confirmed that lipopolysaccharide (LPS) including the O-side chain is present on the surface of the vesicles. Sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis of the purified vesicles showed that the vesicles contained LPS consisting of a lipid-A and an O polysaccharide. In addition, the endotoxic activity of the vesicle was confirmed by a limulus test. These results suggest that the vesicles may play an important role in the pathogenesis of Escherichia coli O157:H7.

Animals↗
PubMed1987

The fundamental hemodynamic mechanism underlying gastric "stress ulceration" in cardiogenic shock.

Acute hemorrhagic ulceration of the gastric mucosa is seen frequently in patients with hypovolemic or cardiogenic shock. Although such lesions clearly are related to regional gastric ischemia, little attention has been directed at the underlying mechanism(s) mediating the ischemia itself. To this end, anesthetized pigs were subjected to sustained cardiogenic shock (mild hemorrhage and pericardial tamponade) such that cardiac output was reduced to 38 +/- 1% of the baseline level for 4 hours, followed by release of the tamponade, reinfusion of the shed blood, and resuscitation for 2 hours. During the period of shock, there was profound regional gastric ischemia, resulting from severe and disproportionate gastric vasoconstriction. "Blinded" gross and microscopic evaluation of the stomachs removed after the experiment revealed severe mucosal ischemic necrosis, hemorrhage, and ulceration, whereas sham-operated pigs showed no lesions. The characteristics of this model therefore mimic the essential features of the gastric "stress ulceration" syndrome. Prior confirmed total alpha-adrenergic blockade with phenoxybenzamine failed to alter these features significantly. In contrast, prior ablation of the renin-angiotensin axis, whether by angiotensin-converting enzyme inhibition with teprotide or by bilateral nephrectomy, significantly and substantially ameliorated the ischemia, vasospasm, and mucosal injury. In this model of cardiogenic shock, acute gastric mucosal "stress ulceration" is caused by a disproportionately severe regional gastric ischemia resulting from selective splanchnic vasospasm that is unaffected by sympathetic blockade but abolished by prior ablation of the renin-angiotensin axis. Like nonocclusive small bowel ischemia, ischemic colitis, and the "shock liver" syndrome, gastric "stress ulceration" is yet another component of the multiple splanchnic organ failure syndrome that appears to be mediated primarily by the remarkable sensitivity of the splanchnic vascular bed to the renin-angiotensin axis.

Animals↗