Hepatic changes in patients with nonspecific ulcerative colitis

The presence of hepatic changes in ulcerative colitis ranges from 4.7% to 90% and the mechanisms are not clear. This study had the purpose to verify their frequency, observe the relation between clinical forms and hepatic lesions and identify the possible histological changes in the liver. We studied 21 patients with ulcerative colitis (Group 1, subdivided in Group 1A non-alcoholic and 1B alcoholic) and compared with 10 patients with irritable bowel syndrome (Group 2). The study involved clinical evaluation, ultrasonography liver function tests and needle biopsy of the liver, performed by laparoscopy, when necessary. Clinical alterations were present in three patients. The ultra-sonographic study was altered in 14.3% in Group 1A and in 57.1% in Group 1B. The albumin and cholinesterase levels were the most frequent abnormality in ulcerative colitis. In irritable bowel syndrome (Group 2), these exams were normal. Liver biopsy was performed in 15 patients and variable degrees of histologic changes were present in all.     

Listeria monocytogenes in the colon in a case of fulminant ulcerative colitis

A case of ulcerative colitis in which the presence of Listeria monocytogenes was confirmed in the resected colon with polymerase chain reaction and subsequent Southern blot analysis and immunohistochemistry using antibody against Listeria is presented. The patient developed ulcerative colitis at the age of 59 years. Prednisolone, 50 mg/day, was given for severe ulcerative colitis. Later the disease became fulminating, indicating colectomy 4 months after the onset. Multiple sealed colonic perforations were observed. Numerous L. monocytogenes were found at the site of perforation, in fissures, and in cracks in the submucosa. This case indicates the possibility that L. monocytogenes contributes to the exacerbation of colitis to fulminating and colonic perforation.     

Localized tumor-like lesions in ulcerative colitis and Crohn's disease of the colon

Ulcerative colitis and Crohn's disease of the colon may manifest roentgenographically as localized tumor-like lesions of the colon. Such lesions are often of inflammatory origin but are likely to be mistaken for polypoid carcinoma or infiltrating submucosal malignancy. Four patients with localized inflammatory lesions of the colon that mimicked a neoplastic process are reported. The clinical features and the radiological-pathological correlation of such lesions are presented.     

Pathophysiological role of nitric oxide in rat experimental colitis

Overproduction of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) may contribute to the pathophysiology of ulcerative colitis. A 2,4,6-trinitrobenzenesulfonic acid sodium salt (TNBS) colitis model was established to examine the effect of selective iNOS inhibition, by S-(2-aminoethyl) isothiouronium bromide (ITU), on colonic mucosal cell damage and inflammation. Rats, killed 7 days after TNBS, had increased colonic mucosal levels of iNOS and interleukin-8 (IL-8), in addition to severe colonic inflammation which was characterized by significantly increased colon weight, damage score and colonic myeloperoxidase activity (MPO) (a marker of neutrophil influx). TNBS-treated rats had markedly decreased body weight and thymus weight. Administration of colitic rats with ITU significantly inhibited iNOS activity/expression and tended to reduce mucosal levels of IL-8, but no effect on MPO activity was observed. Following ITU therapy, colitic rats had reduced colonic damage and losses in body weight and thymus weight were reversed. Improvement of TNBS colitis by ITU suggested that excess NO, produced by iNOS, may have contributed to the initiation/amplification of colonic disease, by mechanisms including enhancement of IL-8 release. NO-mediated enhancement of pro-inflammatory cytokine release was further investigated in vitro. Lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) stimulated release of nitrite, lactate dehydrogenase (LDH), TNF alpha, IL-1 beta and IL-8 from rat peritoneal macrophages, all of which were significantly reduced by ITU. This suggests that NO-mediated cell damage enhances pro-inflammatory mediator release from macrophages. In addition, enhancement of IL-8 and TNF alpha release was also partially NO-dependent in activated peritoneal neutrophils. Therefore, the amelioration of TNBS colitis by ITU could include inhibition of NO-mediated pro-inflammatory cytokine release.     

Immune thrombocytopenic purpura in three patients with preexisting ulcerative colitis

Ulcerative colitis (UC) is associated with extraintestinal diseases in numerous target tissues. Associated immune-mediated hematological diseases, however, are rarely described. We report three Caucasian adult patients with UC and immune thrombocytopenic purpura (ITP). Platelet-associated antibodies (IgG) were positive in two patients, and bone marrow examinations in two patients revealed normal to increased megakaryocyte numbers. ITP was treated with corticosteroids in all patients. Two patients eventually received intravenous immune gamma-globulin, and one patient required surgical splenectomy. Of particular interest, UC preceded the onset of ITP in all patients (by from 1 to 19 yr). This suggests that ITP in these patients is causally associated with UC, possibly secondary to immunostimulation from lumenal antigens and altered immunoregulation.     

Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension

BACKGROUND: Patients with essential hypertension have abnormal endothelium-dependent vasodilation. Because the endothelium exerts its action on the vascular smooth muscle through the release of several substances, it is important to identify which of these factors is involved in the abnormal response of hypertensive arteries. METHODS AND RESULTS: To investigate the role of endothelium-derived nitric oxide in this abnormality, we studied the vascular effect of the arginine analogue NG-monomethyl-L-arginine, an inhibitor of the endothelial synthesis of nitric oxide, under baseline conditions and during infusion of acetylcholine, an endothelium-dependent vasodilator, and sodium nitroprusside, a direct smooth muscle dilator. The study included 11 hypertensive patients (seven men; age, 46.5 +/- 9 years) and 10 normal control subjects (seven men; age, 45.7 +/- 7 years). Drugs were infused into the brachial artery, and the response of the forearm vasculature was measured by strain-gauge plethysmography. Basal blood flow was similar in normal control subjects and hypertensive patients (2.97 +/- 0.7 versus 2.86 +/- 1.1 mL.min-1.100 mL-1, respectively). NG-monomethyl-L-arginine produced a significantly greater decrease in blood flow in control subjects than in patients (1.08 +/- 0.6 versus 0.32 +/- 0.4 mL.min-1.100 mL-1; p < 0.004). The vasodilator response to acetylcholine was reduced in patients compared with control subjects (maximum flow, 8.2 +/- 4 versus 16.4 +/- 8 mL.min-1.100 mL-1; p < 0.001). NG-monomethyl-L-arginine blunted the vasodilator response to acetylcholine in control subjects (maximum flow decreased from 16.4 +/- 8 to 7.01 +/- 3 mL.min-1.100 mL-1; p < 0.004); however, the arginine analogue did not significantly alter the response to acetylcholine in hypertensive patients (maximum flow, 8.2 +/- 4 versus 8.01 +/- 5 mL.min-1.100 mL-1). NG-monomethyl-L-arginine did not modify the vasodilator response to sodium nitroprusside in either control subjects or patients. CONCLUSIONS: These findings indicate that patients with essential hypertension have a defect in the endothelium-derived nitric oxide system that may at least partly account for both the increased vascular resistance under basal conditions and the impaired response to endothelium-dependent vasodilators.     

Role of mast cells, neutrophils and nitric oxide in endotoxin-induced damage to the neonatal rat colon

PURPOSE: Twelve synthetic spider toxin analogs were prepared in an effort to better understand the structure-activity relationships of the polyamine portion of argiotoxin-636 (Arg-636), a noncompetitive NMDA receptor (NMDAR) antagonist. METHODS: The 1,13-diamino-4,8-diazatridecane portion of the side chain of Arg-636 was systematically modified in an effort to further our knowledge of the structural requirements for the alkyl linker spacing between the amine nitrogens. Systematic isosteric replacement of each of the amine nitrogens in the polyamine moiety with either oxygen or carbon provided a series of compounds which were evaluated in vitro for NMDAR antagonist activity. RESULTS: One-half of the heteroatoms found in Arg-636 were removed to provide analogs which maintained in vitro potency below 1 microM. However, these simplified analogs produced similar or more pronounced effects on the cardiovascular system than Arg-636 in vivo. CONCLUSIONS: In this set of analogs, a minimum of three basic nitrogens in the side chain was required for maximum potency as NMDAR antagonists. Isosteric nitrogen substitutions in the polyamine chain reduced the in vitro potency of these analogs. An analog binding-conformation model was proposed to rationalize the inactivity of these isosterically substituted analogs.     

Role of nitric oxide in ventricular dysfunction

In this study a semi-automated and observer-independent algorithm for quantifying post-stenotic signal loss (PSL) in three-dimensional phase-contrast (PC) magnetic resonance angiography (MRA) of patients with renal artery stenosis is presented. This algorithm was developed on MRA datasets of stenotic phantoms, included in a flow circuit with stationary flows. The length and the severity of the PSL (incorporating both the length and the degree of PSL) in the MRA datasets were proposed for quantifying the stenoses. The algorithm was tested in renal arteries; ten patients with renal artery stenosis and seven healthy volunteers were investigated. Digital subtraction angiography was performed in the patients and served as the gold standard. Stenosis severity showed better correlation with the severity of the PSL than with the length, both for in vitro and in vivo measurements. Spearman correlation coefficients (rs) showed statistically significant correlations between the severity of the PSL and parameters determined by digital subtraction angiography, i.e., percent diameter stenosis (rs = 0.90). The length of the PSL showed no correlation with the diameter stenosis (rs = 0.37). In conclusion, this study presents a semi-automated and observer-independent way of quantifying signal loss, and the severity of the PSL is proposed for quantifying stenoses, rather than the length of PSL.     

Clinical status of ulcerative colitis in patients who smoke

OBJECTIVES: Ulcerative colitis (UC) is largely a disease of nonsmokers. There are few patients who are current smokers, but we have identified a group and reviewed their clinical status, disease activity, and nicotine exposure to examine whether they remain well controlled while smoking. METHODS: Fifty-one patients from three centers with verified UC were reviewed. RESULTS: Thirty of the group were men; mean age 50 yr, with a mean age of onset of 37 yr. Twenty-two patients had proctosigmoid disease, 12 involvement of left colon, and 17 total colitis. All were current smokers; 41 were cigarette smokers averaging 17 daily. At the onset of colitis 30 were nonsmokers, 25 of them were ex-smokers and 19 developed colitis within 2 yr of stopping smoking. Twenty-eight believed smoking improved disease activity and none felt smoking had a detrimental effect on their UC. Eleven were receiving no medication for UC, 40 were receiving 5-ASA (5-aminosalicylic acid) preparations, and only two took oral steroids. All were in clinical remission, with the exception of one patient; mean St. Marks score was 1.5, out of a possible total of 22. Sigmoidoscopic grades were inactive in all patients except three. Histological assessment showed significant activity in only five. Median serum nicotine was 8 ng/ml (range, 0.4-24.4), median serum cotinine 180 ng/ml (range, 20-453), with corresponding salivary cotinine of 255 ng/ml (range, 34-683). Median rise in nicotine 2 min after a cigarette in 35 patients was 12.1 ng/ml (range, 0.4-44). CONCLUSIONS: Because most current smokers with UC have inactive disease, smoking may contribute to the clinical remission in these patients.     

HLA association and occurrence of autoantibodies in Asian-Indian patients with ulcerative colitis

OBJECTIVES: The purpose of the present study was to determine the profile of HLA class I antigens, antinuclear antibodies (ANA), and antineutrophil cytoplasmic antibodies (ANCA) in ulcerative colitis (UC) patients from Northern India. METHODS: The study consisted of 100 UC patients with or without extraintestinal manifestations. Data on HLA, ANA, and ANCA were analyzed with respect to age at onset, sex, duration of disease, and occurrence of extraintestinal manifestations, and data were correlated with those of healthy controls from the same population. RESULTS: The most common extraintestinal manifestations in order of occurrence were arthralgia (53.8%), ocular lesions (18%), sacroiliitis (12.7%), hepatobiliary (7.7%), cutaneous (5%), and vascular (2.6%). ANA and ANCA were positive in only 3% of cases. Of the HLA class I antigens, HLA-A19 was significantly increased in UC patients compared with controls (63.4% vs. 33.5%, p < 0.001, RR = 3.4), particularly its subtype HLA-A33 (20.7% vs. 4%, p < 0.001, RR = 6.3). There was no deviation in the frequency of HLA-B locus antigens, whereas HLA-Cw6 was increased significantly in patients compared with controls (14.6% vs. 3.5%, p < 0.001, RR = 4.4). CONCLUSIONS: The occurrence of extraintestinal manifestations in Indian patients with UC is similar to that reported elsewhere, although ANA and ANCA positivity is lower. HLA studies revealed that A19(33) and Cw6 are associated with UC.     

Role of nitric oxide in cyclosporine A-induced hypertension

Cyclosporine A (CsA) is an immunosuppressive agent that also causes hypertension. The effect of CsA on vascular responses was determined in Sprague-Dawley rats and isolated rat aortic rings. Male rats weighing 250 to 300 g were given either CsA (25 mg. kg-1. d-1) in olive oil or vehicle by intraperitoneal injection for 7 days. CsA administration produced a 42% increase (P<0.001) in mean arterial pressure (MAP) that reached a plateau after 3 days. Conversely, the levels of both nitrate/nitrite, metabolites of nitric oxide (NO), and cGMP, which mediates NO action, decreased by 50% (P<0.001) and 35% (P<0.001), respectively, in the urine. Thoracic aortic rings from rats treated with CsA and precontracted with endothelin (10(-9) mol/L) showed a 35% increase (P<0.001) in tension, whereas endothelium-dependent relaxation induced by acetylcholine (ACh, 10(-9) mol/L) was inhibited 65% (P<0.001) compared with that in untreated rats. This response was similar to that of endothelium-denuded aortic rings from untreated rats in which ACh-induced relaxation was completely abolished (P<0.001), but relaxation induced by S-nitroso-N-acetylpenicillamine (SNAP, 10(-8) mol/L) was unaffected (P<0.001). ACh-induced formation of both nitrate/nitrite and cGMP by both denuded and CsA-treated aortic rings was inhibited 95% (P<0.001) and 65% (P<0.001), respectively, compared with intact aortic rings. The effects of CsA were reversed both in vivo and in vitro by pretreatment with L-arginine (10 mg. kg-1. d-1 IP), the precursor of NO. There were no changes in MAP and tension in rats treated with L-arginine alone. In summary, CsA inhibits endothelial NO activity, with resulting increases in MAP and tension, and this inhibition can be overcome by parenteral administration of L-arginine.     

Role of nitric oxide in sepsis-associated pulmonary edema

Transient pulmonary hypertension after inhibition of nitric oxide synthase (NOS) does not alter pulmonary reflection coefficients or lymph flows in endotoxemic sheep. To test the effects of persistent pulmonary hypertension induced by N omega-nitro-L-arginine methylester (L-NAME) and of inhaled NO on pulmonary edema, 18 sheep (three groups) were chronically instrumented with pulmonary artery catheters, femoral arterial fiberoptic thermistor catheters, and tracheostomy. The awake, spontaneously breathing animals received Salmonella typhi endotoxin (lipopolysaccharide; LPS) (10 ng/kg/ min) for 28 h. After 24 h, an airflow of 6 L/min was delivered through the tracheostomy. One group of animals (L-NAME/air) received L-NAME intravenously (25 mg/kg + 5 mg/kg/h) and breathed air. The second group (L-NAME/NO) was given L-NAME and NO (40 ppm) was added to the airflow. The third group was given NaCl 0.9% and breathed air (NaCl/air). Extravascular lung water was measured through the double-indicator dilution technique. Endotoxemia caused pulmonary edema, which was aggravated by L-NAME. Breathing of NO normalized pulmonary artery pressure (Ppa) and ameliorated pulmonary edema. Inhalation of NO may therefore be a therapeutic option for pulmonary edema associated with pulmonary hypertension.     

Role of nitric oxide in the control of glomerular microcirculation

1. Nitric oxide (NO) plays an important role in the control of glomerular haemodynamics and is synthesized from the amino acid L-arginine by a family of enzymes, NO synthase (NOS). 2. Nitric oxide synthase is present in the endothelium and also in the macula densa, a plaque of specialized tubular epithelial cells. Endothelial NOS is known to be stimulated by shear stress and hormones, while the factor that regulates the activity of macula densa NOS remains undefined. 3. Studies with the in vitro microperfusion of glomerular arterioles have shown that the constriction of afferent arterioles (Af-Art) induced by myogenic responses and angiotensin II (AngII) is stronger in the absence rather than in the presence of luminal flow. Furthermore, endothelial disruption or NOS inhibition abolishes such differences, suggesting that flow through the lumen stimulates the endothelium to synthesize and release NO, which in turn attenuates both the myogenic response and the action of AngII in the Af-Art. 4. In contrast, NOS inhibitors have no effect on efferent arteriolar (Ef-Art) constriction induced by AngII. 5. In preparations in which Af-Art and the macula densa are simultaneously microperfused, selective inhibition of macula densa NOS has been shown to augment Af-Art constriction when the NaCl concentration at the macula densa is high, suggesting that the macula densa produces NO, which in turn modulates tubuloglomerular feedback. 6. Thus, the differential actions of NO in the Af-Art, Ef-Art and the macula densa may be important in the control of glomerular haemodynamics under various physiological and pathological conditions.     

Performing a cost-effectiveness analysis: surveillance of patients with ulcerative colitis

OBJECTIVE: To illustrate the principles of cost-effectiveness analysis, this third article in the "Primer on Economic Analysis for the Gastroenterologist" applies published criteria for appraising an economic analysis to a study of the cost-effectiveness of surveillance of patients with ulcerative colitis. METHODS: We review and apply the 10 standard criteria for critical appraisal and evaluation of cost-effectiveness analyses. SUMMARY: We outlined the development and critique of a decision analytic model that examines the cost-effectiveness of surveillance of patients with ulcerative colitis, and we compared the cost-effectiveness of surveillance of patients with ulcerative colitis to other well-accepted medical practices.     

Carbonic anhydrase I reduction in colonic mucosa of patients with active ulcerative colitis

Ulcerative colitis (UC) is associated with low intracolonic pH and unbalanced transmucosal ionic exchanges. Along the gastrointestinal tract carbonic anhydrase isoenzyme I (CA-I) is specifically expressed in colon epithelium and is involved in mucosal control of ion, fluid, and acid-base balance. Since altered CA-I expression may play some role in UC, CA-I was measured at the mRNA and protein level and carbonic anhydrase (CA) enzyme activity was determined in colon biopsies of 14 UC patients (6 remission, 4 mild, 4 moderate UC) and of 12 healthy subjects. Patients with mild or moderate UC showed a significant reduction of CA-I mRNA and protein and of total CA activity in the inflamed mucosa compared to controls. Patients with UC in remission showed a pattern of CA-I expression and CA activity similar to controls. This is the first report showing a reduction in the expression of CA-I in active UC.     

Recurrent polychondritis associated with ulcerative colitis

Relapsing polychondritis and Ulcerative Colitis is an uncommon association that has been described only ten times in medical literature. We report a new case of this association in which it was necessary to treat with azathriopine to stop disease progression. Relapsing Polichondritis is a disorder to be considered in patients with Ulcerative Colitis and inflammation of the cartilagenous structures.     

Elevated exhaled nitric oxide in patients with hepatopulmonary syndrome

The hypoxaemia of hepatopulmonary syndrome, seen in severe chronic liver dysfunction, occurs as a result of precapillary pulmonary arterial dilatation and arteriovenous communications. These abnormalities contribute to the mismatch between ventilation and perfusion, and the right to left blood flow shunting. Nitric oxide (NO) is a powerful vasodilator concerned with the regulation of pulmonary vascular tone in man. Using a chemiluminescence analyser, we have measured endogenously produced NO in the exhaled air of three patients with the hepatopulmonary syndrome, six normoxaemic cirrhotic patients and six healthy volunteers. The subjects breathed NO-free air throughout the measurements. The molar rate of production of exhaled NO was raised almost threefold in the patients with hepatopulmonary syndrome compared with normal volunteers and with normoxaemic cirrhotic patients. Hypoxia per se, achieved in the normal volunteers by breathing a hypoxic gas mixture, reduced rather than increased the exhaled NO. One hepatopulmonary syndrome patient received an orthotopic liver transplant and achieved normoxaemia after 3 months. The exhaled NO also returned to normal. Increased pulmonary production of NO could contribute to the development of the hepatopulmonary syndrome.     

Role for the Salmonella flavohemoglobin in protection from nitric oxide

Hemoglobin homologs are being identified in an expanding number of unicellular prokaryotic and eukaryotic organisms. Many of these hemoglobins are twodomain proteins that possess a flavin-containing reductase in their C terminus. Determination of a function for these flavohemoglobins has been elusive. A Salmonella typhimurium strain harboring a deletion in the flavohemoglobin gene shows no difference in growth under oxidative stress conditions but displays an increased sensitivity to acidified nitrite and S-nitrosothiols, both of which produce nitric oxide. The effect is seen aerobically or anaerobically, indicating that oxygen is not required for flavohemoglobin function. These results suggest a role for the bacterial flavohemoglobins that is independent of oxygen metabolism and provide evidence for a bacterial route of protection from nitric oxide that is distinct from oxidative stress responses.     

Effects of chronic nitric oxide synthase inhibition on TNB-induced colitis in rats

Nitric oxide (NO) synthesis is increased in ulcerative colitis, but the role of NO in colitis is poorly understood. The present study employed Nw-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, in rats to evaluate the effect of NO on 2,4,6-trinitrobenzenesulphonic acid (TNB)-induced colitis. L-NAME solutions were placed in subcutaneous, osmotic mini-pumps which continuously released L-NAME at 0.042, 0.208, 0.417, or 1.667 mg kg-1 h-1. L-NAME dose-dependently enhanced lesions in TNB-induced colitis. The two higher doses of L-NAME significantly increased colonic mucosal damage, although there was slight, nonsignificant reduced lesion formation with the lowest dose of L-NAME. 0.042 mg kg-1 h-1. A single dose of L-NAME at 100 mg kg-1 subcutaneously injected daily in TNB-treated rats also increased lesions, and these ulcerogenic actions of L-NAME were reversed by L-arginine but not by D-arginine (both at 500 mg kg-1, s.c.). Only the highest dose of L-NAME (mini-pump) significantly depressed myeloperoxidase (MPO) activity. Faecal occult bleeding showed a close relationship with severity of colitis. These findings suggest that there may exist a balance between NO protective and aggressive effects. In TNB-induced colitis, antagonism of endogenous NO generation was intensified, whereas slight inhibition of NO synthesis reduced lesions. Variations in responses, related to timing or dose changes in L-NAME, may reflect the differences in inducible vs constitutive NO synthase isoforms.     

A case report of ulcerative colitis complicated with protein losing enteropathy and colon cancer in a young female

AIMS: To assess the ability of dobutamine echocardiography to detect multivessel coronary artery disease and to determine predictive factors for multivessel disease with or without beta-blockers. PATIENTS AND METHODS: A total of 101 patients underwent dobutamine stress echocardiography and coronary angiography (evaluation of chest pain 76, extent of coronary disease after myocardial infarction 19, other indications 6). RESULTS: Ten patients in whom the test was prematurely terminated were excluded. Out of 91 patients who underwent dobutamine echocardiography, 54 patients had multivessel disease (sensitivity of dobutamine test 93%, specificity 46%). Heart rate at the maximum dose of dobutamine or atropine was 88 +/- 21 beats/min for multivessel diseases and 104 +/- 21 beats/min without multivessel disease (p < 0.001). A cut-off value < 94 beats/min discriminated patients at risk for multivessel disease. After adjusting for treatment with beta-blockers, heart rate < 94 beats/min, ECG signs of ischemia, and abnormalities on baseline echocardiogram with remote asynergies during dobutamine testing were independent predictors of multivessel disease in the multivariate analysis (probability > 90% when at least two factors were present). CONCLUSION: A heart rate < 94 beats/min at peak dose of dobutamine or after atropine, ECG signs of ischemia, and the presence of abnormalities on echocardiogram at rest with remote asynergies during dobutamine stress testing were independent predictive factors of multivessel coronary artery disease.