Selective inhibition of phosphodiesterase-4 ameliorates chronic colitis and prevents intestinal fibrosis.

The phosphodiesterase-4 (PDE4) inhibitors may be an important target in the treatment of several inflammatory conditions. The anti-inflammatory effect of PDE4 inhibitors bears similarities with that of steroids, without interfering with the hypophysary-adrenal-axis. We compared the effect of rolipram, a selective PDE4 inhibitor, with steroids on the clinical course of experimental colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS). Three groups of rats (n = 20) received TNBS. One group received methylprednisolone from day 7, another group received rolipram from the same day, and control group received no further treatment. On days 14 and 21 after TNBS instillation, sets of 10 rats underwent colonic dialysis to measure eicosanoid release. Colonic lesions were blindly scored, and colons were homogenized for quantification of myeloperoxidase (MPO) activity and collagen content. Concentration of tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta1 (TGF-beta1) in colonic tissue was also measured. Both treatments reduced significantly the eicosanoid release and MPO activity. On day 14, both rolipram and methylprednisolone significantly reduced TNF-alpha content, but TGF-beta1 was only inhibited by rolipram. On day 21, lesion scores and collagen content were significantly reduced only in rolipram-treated group. In conclusion, PDE4 inhibition by rolipram markedly ameliorates the course of chronic colitis and it is superior to methylprednisolone in preventing late collagen deposition.

Pancreatitis and haemobilia due to arterioportal fistula after percutaneous liver biopsy resolved by selective arterial embolization.

Haemobilia and arterioportal fistula are uncommon complications secondary to percutaneous liver biopsy. We report the case of a patient who developed haemobilia and subsequently acute pancreatitis as a result of a liver biopsy. Selective hepatic angiogram showed an arterioportal fistula. Transcatheter arterial embolization successfully occluded the fistula. The patient remained asymptomatic 4 months later. We review the published literature concerning acute pancreatitis associated with haemobilia and draw conclusions for management of similar cases in the future.

Influence of inflammatory bowel disease on different dimensions of quality of life.

OBJECTIVE: To establish the impairment of different dimensions of quality of life in inflammatory bowel disease (IBD). DESIGN: Prospective observational study. PARTICIPANTS: 289 patients [160 with ulcerative colitis (UC) and 129 with Crohn's disease (CD)]. MEASURES: Health-related quality of life was assessed by means of the Inflammatory Bowel Disease Questionnaire (IBDQ) and the Psychological General Well Being Index (PGWBI). RESULTS: In active IBD, all dimensions of the quality of life scored significantly lower than in inactive IBD, indicating a poor quality of life. Social impairment was the least impaired dimension of the IBDQ in active UC and CD, compared with digestive and systemic symptoms. In inactive IBD, the systemic symptoms domain received the lowest score (P < 0.01). In a subgroup of 22 patients studied before and after remission, emotional function was the most impaired dimension after achieving remission. The Psychological General Well Being Index was significantly impaired in active UC [78.5 (range 64-89)] and CD [76.5 (range 69-97)] relative inactive IBD [104 (range 93-111)] vs 106 (95-113), respectively; P < 0.05]. CONCLUSIONS: Quality of life is impaired in IBD. During relapse, clinicians should pay attention to digestive symptoms and psychological distress. In remission, they should be sensitive to systemic symptoms.

Impact of surgery for Crohn's disease on health-related quality of life.

OBJECTIVE: When patients with Crohn's disease (CD) express concerns about their disease, they emphasize worries about surgery. However, most studies about the impact of surgery in CD on health-related quality of life (HRQOL) have compared postsurgical changes on HRQOL relative to HRQOL before surgery, not taking into account the influence of CD activity on HRQOL. Our aim was to assess whether surgical treatment of CD modifies HRQOL, compared with inactive CD, active CD, or healthy controls. METHODS: Outcomes of 29 CD patients in remission with a previous bowel resection were compared with those from 42 clinically active CD patients and 48 patients with medically induced remission. A reference control group of 63 healthy individuals was also studied. HRQOL was measured by the Inflammatory Bowel Disease Questionnaire (IBDQ), the Psychological General Well Being Index (PGWBI), and the EuroQol. RESULTS: Active CD patients scored the lowest on the IBDQ. Both operated and nonoperated inactive CD patients had lower HRQOL scores than controls in overall IBDQ and in all five domains. However, neither global score, digestive, systemic, emotional, social, or functional dimensions differed significantly between operated and nonoperated inactive CD patients. PGWBI and the visual analog scale of the EuroQol were also similar in both groups of inactive CD patients (103 [range, 94-107] vs. 103 [97-106] and 90 [73-87] vs. 82 [76-84]), but significantly higher than in active CD. CONCLUSIONS: HRQOL is impaired in active CD, and improves during remission irrespective of whether it had been achieved medically or surgically. Our results suggest that to improve HRQOL it is more important to achieve remission than the approach, drugs or surgery, chosen.

Validation of the spanish version of the inflammatory bowel disease questionnaire on ulcerative colitis and Crohn's disease.

The objective of this study is to validate the Spanish translation of the Inflammatory Bowel Disease Questionnaire (SIBDQ) on ulcerative colitis and Crohn's disease by assessing its convergence validity, discriminatory power, reliability and sensitivity to change. For that purpose, 211 patients with inflammatory bowel disease (116 with ulcerative colitis and 95 with Crohn's disease) completed the SIBDQ, the Psychological General Well-Being Index and the EuroQol. SIBDQ was repeated in those patients who remained in stable remission and in those with changes in clinical activity. Clinical activity was assessed by the Rachmilewitz and Harvey-Bradshaw indices. Correlations among scores of SIBDQ, EuroQol, Psychological General Well-Being Index and clinical indices of activity were all positive and comparable for both diseases (r = -0. 50 to r = -0.70, p < 0.01). Analysis of variance showed that SIBDQ discriminates between different clinical degrees of activity. Cronbach's alpha was 0.96 in ulcerative colitis and Crohn's disease. SIBDQ was also highly reliable when it was repeated in clinically stable patients with ulcerative colitis (intraclass correlation coefficient = 0.82) and Crohn's disease (intraclass correlation coefficient = 0.86). SIBDQ was sensitive to clinical changes in ulcerative colitis and in Crohn's disease, whether patients entered remission (effect size -1.88 and -1.81, respectively) or relapsed (effect size 1.70 and 8.04, respectively). In conclusion, the Spanish version of the IBDQ has proven to be a valid, reliable and sensitive instrument to detect clinical changes in patients with ulcerative colitis and Crohn's disease.

Antitumor necrosis factor therapy in rat chronic granulomatous colitis: critical dose-timing effects on outcome.

Inhibition of tumor necrosis fact (TNFalpha) is of potential benefit in the treatment of chronic inflammatory conditions. However, TNFalpha plays an important role in host defenses against infection, and blocking TNFalpha production may also have adverse effects. We tested the efficacy and safety of anti-TNFalpha therapy in experimental colitis induced by trinitrobenzenesulfonic acid. We cultured colonic wall specimens for bacterial growth and measured native TNFalpha protein synthesis in colonic tissue at days 0, 1, 4, 10 and 18 after induction of colitis. Anti-TNFalpha therapy (monoclonal g1 immunoglobulin, 15 mg/kg i.p., every third day) was started on either day 4 or day 10 after induction of colitis. On day 18, we measured the release of inflammatory mediators and scored colonic lesions. In acute lesions, several species of the common flora were grown, including Streptococcus, Staphylococcus, Bacteroides, clostridia and enterobacteria. In chronic lesions, only enterobacteria, clostridia and lactobacilli were isolated. TNFalpha production by inflamed colonic tissue was increased in both acute and chronic lesions. Anti-TNFalpha therapy induced a significant decrease in the release of inflammatory mediators and histopathological remission when treatment started on day 10. However, anti-TNFalpha therapy increased eicosanoid release and lesion scores when treatment started on day 4. In conclusion, acute colonic lesions showed polymicrobial infection. Anti-TNFalpha therapy induced remission of chronic intestinal inflammation, but early treatment did not prove effective.

Association between strong inflammatory response and low risk of developing visual loss and other cranial ischemic complications in giant cell (temporal) arteritis.

OBJECTIVE: To identify clinical and biochemical parameters that have good predictive value for identifying giant cell (temporal) arteritis (GCA) patients who are at high or low risk of developing cranial ischemic events. METHODS: In this multicenter study, records of patients at 3 university hospitals in Barcelona were reviewed retrospectively. Two hundred consecutive patients with biopsy-proven GCA were studied. RESULTS: Thirty-two patients developed irreversible cranial ischemic complications. The duration of clinical symptoms before diagnosis was similar in patients with and those without ischemic events. Patients with ischemic complications less frequently had fever (18.8% versus 56.9%) and weight loss (21.9% versus 62%) and more frequently had amaurosis fugax (32.3% versus 6%) and transient diplopia (15.6% versus 3.6%). Patients with ischemic events had lower erythrocyte sedimentation rates (ESR) (82.7 mm/hour versus 104.4 mm/hour) and higher concentrations of hemoglobin (12.2 gm/dl versus 10.9 gm/dl) and albumin (37.4 gm/liter versus 32.7 gm/liter). Clinical inflammatory status and biologic inflammatory status were defined empirically (clinical: fever and weight loss; biologic: ESR > or =85 mm/hour and hemoglobin < 11.0 gm/dl). Patients not showing a clinical and biologic inflammatory response were at high risk of developing ischemic events (odds ratio [OR] 5, 95% confidence interval [95% CI] 2.05-12.2). The risk was greatly reduced among patients with either a clinical (OR 0.177, 95% CI 0.052-0.605) or a biologic (OR 0.226, 95% CI 0.076-0.675) inflammatory reaction. No patient with both a clinical and a biologic response developed ischemic events. CONCLUSION: The presence of a strong acute-phase response defines a subgroup of patients at very low risk of developing cranial ischemic complications. Our findings provide a rationale for testing less aggressive treatment schedules in these individuals. Conversely, a low inflammatory response and the presence of transient cranial ischemic events provide a high risk of developing irreversible ischemic complications and require a prompt therapeutic intervention.

Monoclonal antibodies raised to the dengue-2 virus (Cuban: A15 strain) which recognize viral structural proteins.

Mouse monoclonal antibodies (MAbs) were raised to dengue-2 virus (D-2V) Cuban (A15) strain and the cell culture supernatants were screened by ELISA using the homologous virus. Three MAb-secreting lines were further characterized using immunoblot, haemaglutination, complement-fixation, and neutralization assays. One of these, MAb 8H8, weakly reacted with the viral nonstructural-1 protein (NS1) but more specifically identified the capsid protein (C), MAb 3E1 recognized in serological assays D-2V A15 but it had a weak reaction to C protein by immunodetection whereas another, MAb 4G3, weakly neutralized the homologous virus isolate and blocked the binding of specific anti-envelope (E) Mab, and its reaction with this protein could not be confirmed using immunoblot assays. These reagents are now being used to compare virulent plus avirulent Caribbean viruses antibody dependent enhancement (ADE) assays.

[Evaluation of a mouse anti-IgG-fluorescein conjugate using indirect immunofluorescence and flow cytometry techniques]. / Evaluación de un conjugado anti-IgG de ratón-fluoresceína mediante técnicas de inmunofluorescencia indirecta y citometría de flujo.

An immunoglobulin G of mouse was purified from sera by affinity chromatography in protein A. The rabbits whose sera were able to recognize the antigen injected by double immunodiffusion were immunized with this preparation. The antibodies were precipitated from the rabbit's serum and purified by ion exchange chromatography. This preparation was conjugated to fluorescin isothiocyanate according to the conventional technique. The conjugated obtained was evaluated with the reference strains of Parainfluenza virus 1, 2, 3; Adenovirus; respiratory syncytial virus; and influenza virus A and B, by an indirect immunofluorescence technique and HIV positive samples by flow citometry. Specific monoclonal antibodies were used in both cases. Clinical specimens of patients with acute respiratory infection were evaluated.

Von Willebrand factor in the outcome of temporal arteritis.

OBJECTIVE: To determine fluctuation in circulating von Willebrand factor (vWF) in the outcome of patients with temporal arteritis. METHODS: Plasma vWF antigen concentrations were measured in 65 patients with biopsy proven temporal arteritis at different disease activity stages, in 12 with isolated polymyalgia rheumatica, and in 16 controls. Fourteen temporal arteritis patients underwent serial determinations during the course of their disease. RESULTS: vWF concentrations were significantly raised in temporal arteritis (mean 220 [arbitrary units], range 96 to 720) and in polymyalgia rheumatica (mean 196, range 103 to 266) compared with healthy controls (mean 98, range 75 to 137) (P < 0.05). Although vWF values tended to be higher in temporal arteritis, no significant differences were found between temporal arteritis and polymyalgia rheumatica patients nor between temporal arteritis patients with ischaemic complications (mean 269, range 130 to 720) and those who presented with polymyalgia rheumatica or constitutional symptoms only (mean 179, range 140 to 220). The highest levels were obtained in patients with associated, mainly infectious, diseases (mean 631, range 240 to 1680). Raised vWF values found in active temporal arteritis patients (mean 220, range 96 to 720) persisted within the first two years after the beginning of treatment (mean 244, range 102 to 510) but tended to normalise in patients in long term remission (mean 143, range 50 to 260). CONCLUSIONS: Persistent elevation of vWF during early remission of temporal arteritis might represent an endothelial activation status induced by a remaining inflammatory microenvironment rather than a marker of endothelial cell injury. In long term remission, decreasing vWF concentrations might reflect progression of inflammatory lesions to a healing stage.

Eosinophilic gastroenteritis presenting as ascites and splenomegaly.

A 25-year-old man with a 1 year history of episodic abdominal pain presented with splenomegaly, eosinophilic ascites and peripheral eosinophilia. Full-thickness biopsies from his gastrointestinal tract revealed intense eosinophilic infiltration involving both muscular and serosal layers and extending from his stomach to his ileum. When given oral steroids, the patient's condition improved and he was discharged without symptoms. Eighteen months later, he remains asymptomatic and without recurrence of ascites or splenomegaly. This report adds to the scarce data on extraintestinal involvement in eosinophilic gastroenteritis. Special attention is drawn to the differential diagnosis of eosinophilic ascites and to the optimal approach to its management.

Efficacy of intravenous cyclosporine for steroid refractory attacks of ulcerative colitis.

The use of cyclosporine in refractory ulcerative colitis (UC) is still controversial. An 8-year-long retrospective review open-label treatment with intravenous cyclosporine in 21 patients with steroid-refractory UC is therefore in order. Intravenous cyclosporine, 5 mg/kg-1 day, was added to ongoing drug therapy. Those who responded were switched to oral cyclosporine for a mean 8.4-month period, and steroids were discontinued when possible. Sixteen out of 21 patients improved (76%). Mean latency time to onset of improvement was 9 days. Five did not improve: three underwent urgent surgery, one was switched to methotrexate, and the remainder died. While on oral cyclosporine, 10 out of 16 maintained remission and seven could discontinue steroids, five relapsed, and one went on continuous mild activity. One patient died of a Pneumocystis carinii pneumonia, while in remission. Five reversible episodes of hepatobiliary toxicity were recorded. Intravenous cyclosporine effectively and rapidly induces improvement of acute steroid-refractory flare-ups of UC and helps to prevent urgent surgery. However, major adverse events may limit its usefulness.

Intravenous cyclosporine for steroid-refractory attacks of Crohn's disease. Short- and long-term results.

A prospective, open trial was conducted to test whether i.v. cyclosporine was effective in the treatment of refractory Crohn's disease. Eight patients with acute steroid-refractory attacks were included. Intravenous cyclosporine, 5 mg/kg/day, was added to ongoing drug therapy. Patients who responded were then switched to oral cyclosporine for a mean 2.6-month period, and steroids were discontinued when possible. Six patients improved, with a mean latency time to onset of improvement of 9 days. Two did not improve, and both underwent urgent operation. On oral cyclosporine, five patients maintained remission and discontinued steroids, whereas one relapsed and underwent surgery. After discontinuation of oral cyclosporine, the five remaining patients relapsed, and two underwent surgery. One reversible episode of hepatobiliary toxicity and one of gastrointestinal intolerance were recorded. We conclude that i.v. cyclosporine effectively and rapidly induces improvement of acute steroid-refractory flare-ups of Crohn's disease, but after discontinuation relapse is to be expected.

Role of intestinal microflora in chronic inflammation and ulceration of the rat colon.

Bacteria and their products stimulate inflammatory responses. The effects of different antimicrobial regimens (amoxicillin/clavulanic acid, tobramycin, imipenem, vancomycin, metronidazole) were investigated on the course of experimental colitis induced by trinitrobenzenesulphonic acid (TNB) in the rat. On day 7 and 21 after the induction of colitis, matched groups of control and antibiotic treated rats were subjected to colonic dialysis to measure eicosanoid release, and killed for morphological assessment of the colonic lesions (macro and microscopic scores). Stool samples were cultured. Selective antibiotic treatment against Gram positive, Gram negative or anaerobic bacteria had no effect on colonic lesion scores. By contrast, certain broad spectrum antibiotics (amoxicillin/clavulanic acid or the association of imipenem plus vancomycin) significantly reduced macro and microscopic scores. Rats receiving these antibiotics did not develop chronic colitis as shown by the virtual absence of colonic strictures, adhesions, fibrosis, and granulomas. On day 21 after TNB, the intracolonic release of prostaglandin E2, thromboxane B2, and leukotriene B4 was significantly higher in control than in antibiotic treated rats. Control stool cultures showed abundant colony forming units of both aerobic and anaerobic bacteria. Amoxicillin/clavulanic acid and imipenem plus vancomycin induced appreciable reductions in luminal bacteria. In conclusion, certain broad spectrum antibiotics prevent chronic colitis. The normal colonic flora seems to play an important pathogenetic part in the progression of inflammatory colonic lesions to chronicity.

[The percutaneous dissolution treatment of gallstones. Our initial experience]. / Tratamiento disolutivo percutáneo de la litiasis vesicular. Experiencia inicial.

OBJECTIVE: To describe our initial experience in direct contact dissolution of cholesterol gallstones with methyl-tert-butyl ether, a non surgical approach for high risk patients. PATIENTS: Twenty symptomatic patients were preselected. They all had radiolucent stones in functioning gallbladders. Patients rejected elective surgery or were considered to be of high risk for anesthesia. Computerized tomography scan was performed to evaluate stone calcium content and liver-gallbladder anatomy. In selected patients, contact stone dissolution was carried out after transhepatic gallbladder catheterization. RESULTS: Ten patients were excluded due to poor gallbladder contact to the liver (two patients) or stone density greater than 70 Hounsfield Units. Percutaneous transhepatic positioning of the catheter into the gallbladder was achieved in seven patients. Stone dissolution was complete in five patients and partial in one. Mean perfusion time was 6.15 hours (3.45-7.5); however, mean hospitalization stay was 7 days (4-10) mainly due to inexperienced management coordination. While on treatment, all patients experienced nausea, burning or abdominal discomfort that were easily controlled. Complications were related to catheter placement (intraperitoneal biliary leakage, external fistula) and in five patients to the dissolution procedure (severe abdominal pain, biliary colic, cholecystopancreatitis). Complications were all handled with non surgical treatment. CONCLUSIONS: Percutaneous gallstone dissolution with methyl-tert-butyl ether is a rapid and efficacious procedure that can, nevertheless, induce relevant secondary effects and complications.

Dietary manipulation in experimental inflammatory bowel disease.

Eicosanoids are major mediators of defensive and inflammatory processes of the gut mucosa. The activity of the eicosanoid system is modulated by neural and hormonal pathways, but local factors acting within the gastrointestinal lumen may also be involved. We have studied the influence of dietary fatty acids on eicosanoid synthesis by the gastrointestinal mucosa. Since omega-3 fatty acids compete with the omega-6 as precursors of eicosanoid synthesis, we compared the effects of dietary supplementation with either sunflower or cod liver oil as sources of omega-6 or omega-3 fatty acids, respectively. Rats fed with the cod-liver-oil-supplemented diet for four weeks showed high omega-3 and low omega-6 plasma fatty acid levels compared to rats fed with the sunflower oil diet. Synthesis of arachidonic-acid-derived eicosanoids (6-keto-PGF1 alpha, PGE2, TXB2, LTB4, and LTC4) by gastric and intestinal mucosa was found to be lower in the cod liver group as compared to the sunflower group. However, significant generation of eicosapentaenoic-acid-derived eicosanoids (PGE3 and LTC5) was observed only in the cod liver group. We used the (trinitrobenzenesulphonic acid) TNBS model of inflammatory colitis to test the effect of the dietary fat on the development of inflammatory lesions of the bowel. A single intracolonic instillation of the hapten TNBS dissolved in 10% ethanol induces chronic granulomatous lesions of the colonic mucosa that persist for up to 8 weeks. Luminal release of eicosanoid mediators, as measured by intracolonic dialysis, was lower in the cod liver group than in the sunflower group, particularly during the chronic stage of the disease.(ABSTRACT TRUNCATED AT 250 WORDS)