Apolipoprotein A-I inhibits experimental colitis and colitis-propelled carcinogenesis.

In both humans with long-standing ulcerative colitis and mouse models of colitis-associated carcinogenesis (CAC), tumors develop predominantly in the distal part of the large intestine but the biological basis of this intriguing pathology remains unknown. Herein we report intrinsic differences in gene expression between proximal and distal colon in the mouse, which are augmented during dextran sodium sulfate (DSS)/azoxymethane (AOM)-induced CAC. Functional enrichment of differentially expressed genes identified discrete biological pathways operating in proximal vs distal intestine and revealed a cluster of genes involved in lipid metabolism to be associated with the disease-resistant proximal colon. Guided by this finding, we have further interrogated the expression and function of one of these genes, apolipoprotein A-I (ApoA-I), a major component of high-density lipoprotein. We show that ApoA-I is expressed at higher levels in the proximal compared with the distal part of the colon and its ablation in mice results in exaggerated DSS-induced colitis and disruption of epithelial architecture in larger areas of the large intestine. Conversely, treatment with an ApoA-I mimetic peptide ameliorated the phenotypic, histopathological and inflammatory manifestations of the disease. Genetic interference with ApoA-I levels in vivo impacted on the number, size and distribution of AOM/DSS-induced colon tumors. Mechanistically, ApoA-I was found to modulate signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB activation in response to the bacterial product lipopolysaccharide with concomitant impairment in the production of the pathogenic cytokine interleukin-6. Collectively, these data demonstrate a novel protective role for ApoA-I in colitis and CAC and unravel an unprecedented link between lipid metabolic processes and intestinal pathologies.

Treatment of experimental murine colitis with CD40 antisense oligonucleotides delivered in amphoteric liposomes.

BACKGROUND AND AIMS: CD40-CD40L interactions appear to play an important role in the pathogenesis of experimental colitis. We tested the effect and investigated the underlying mechanism of action of systemically administered antisense oligonucleotide (ASO) targeting CD40 formulated in amphoteric liposomes (nov038/CD40). The charge characteristics of the amphoteric liposomes (anionic surface charge at physiological pH that becomes cationic at low pH), facilitate efficient sequestration of the ASO inside the liposomes at low pH and the direction of the carriers towards macrophages and dendritic cells under physiological conditions. METHODS: Colitis was induced in Balb/c mice using 2,4,6-Trinitrobenzene sulphonic acid (TNBS) and treated with nov038/CD40. Disease was monitored by body weight, histology, cytokine profiling and changes in immune cell populations. CD40 expression on different cell subsets was analyzed by flow cytometry. An antigen challenge model was used to determine neoimmunity under CD40 modulation. RESULTS: Administration of nov038/CD40 inhibited the development of TNBS colitis as assessed by weight loss, histology and cytokine profiles; unformulated CD40 ASO or nov038 encapsulating an unrelated ASO (nov038/SCR) were ineffective. The novel agent is potent as it completely suppressed even established colitis with a single treatment and significantly reduced T-cell activation as well as levels of pro-inflammatory mediators in serum. The inhibition of CD40 specifically occurred in macrophages, but not in B-cells. In contrast to prednisolone, standard treatment for inflammatory bowel diseases (IBD) that is effective in a single administration and involves extensive immunosuppression, nov038/CD40 did not affect the number of B- or Treg cells. Eventually, we observed a largely intact neoimmunity under conditions of a CD40 inhibition. CONCLUSIONS: Administration of nov038/CD40, but neither naked CD40 ASO nor nov038/SCR, prevents the development and treats established colitis in mice. Delivery of CD40 ASO in nov038 is highly cell-specific as it selectively suppresses CD40 on macrophages, but not on B-cells; the novel agent has strong anti-inflammatory characteristics without being immunosuppressive.

Thiopurine methyltransferase activity combined with 6-thioguanine metabolite levels predicts clinical response to thiopurines in patients with inflammatory bowel disease.

BACKGROUND/AIMS: 6-Mercaptopurine and its prodrug azathioprine are effective for the treatment of inflammatory bowel disease. Thiopurine methyltransferase is important for the metabolism of thiopurines. However, there is controversy as to the clinical utility of measuring thiopurine methyltransferase enzyme activity and 6-thioguanine nucleotide levels. Our aim was to determine if thiopurine methyltransferase enzyme activity and 6-thioguanine nucleotide level monitoring would predict response to therapy with thiopurines in patients with inflammatory bowel disease. METHODS: Baseline thiopurine methyltransferase enzyme activity prior to initiation of therapy with either 6-mercaptopurine or azathioprine was determined in 39 patients with inflammatory bowel disease. The association between clinical response and thiopurine methyltransferase activity and 6-thioguanine nucleotide levels singly or in combination were analysed. RESULTS: Seventeen of 39 patients (44%) responded to 6-mercaptopurine or azathioprine therapy. Thiopurine methyltransferase enzyme activity below the mean of 30.5 U was significantly associated with clinical response. The thiopurine methyltransferase low phenotype was associated with response in 65% vs. 29% in individuals with thiopurine methyltransferase enzyme activity above 30.5 U (p = 0.05). There was no correlation between thiopurine methyltransferase activity and 6-thioguanine nucleotide levels. The maximal 6-thioguanine nucleotide levels did not predict clinical response. When combining thiopurine methyltransferase enzyme activity and 6-thioguanine nucleotide levels, the combination of thiopurine methyltransferase low/6-thioguanine nucleotide high was associated with response in 7/7 (100%) vs. only 2/8 (25%) with the combination of thiopurine methyltransferase high/6-thioguanine nucleotide low (p=0.01). CONCLUSIONS: Thiopurine methyltransferase activity inversely correlated with clinical response to thiopurine treatment in inflammatory bowel disease. Thiopurine methyltransferase enzyme activity below 30.5 U combined with a post-treatment 6-thioguanine nucleotide level > 230 pmol/8 x 10(8) erythrocytes was the best predictor of response.

Diagnostic yield of capsule endoscopy in ulcerative colitis and inflammatory bowel disease of unclassified type (IBDU).

BACKGROUND AND STUDY AIMS: Capsule endoscopy is increasingly reported as an important diagnostic procedure in patients with known or suspected Crohn's disease, but its clinical utility in patients with ulcerative colitis or unclassified type inflammatory bowel disease (IBDU) is unclear. The aim of our study was to determine the diagnostic yield of capsule endoscopy for small-bowel disease in patients with ulcerative colitis and IBDU. PATIENTS AND METHODS: All data from patients with a history of ulcerative colitis or IBDU who underwent capsule endoscopy between October 2001 and August 2005 were analyzed for procedure indications and findings. Images were reviewed by an experienced capsule endoscopist. The finding of multiple ulcerations (three or more) on capsule endoscopy was classified as diagnostic of small-bowel Crohn's disease. RESULTS: 120 patients had undergone 122 capsule endoscopy procedures. Overall, 19 of 120 patients (15.8 %) had capsule endoscopy findings consistent with the diagnosis of Crohn's disease. The proportion of patients with small-bowel disease was significantly higher among patients with a history of colectomy (7 of 21 patients, 33 %) compared with those without colectomy (12/99, 12 %) ( P = 0.04). Among patients with positive findings on capsule endoscopy, 18 had also previously undergone a small-bowel follow-through study and only one showed findings consistent with Crohn's disease. CONCLUSIONS: Many patients with a diagnosis of ulcerative colitis and atypical features or IBDU may have small-bowel findings on capsule endoscopy that are consistent with Crohn's disease. Capsule endoscopy should be considered in ulcerative colitis patients with atypical clinical features particularly after colectomy.

CCR9-positive lymphocytes and thymus-expressed chemokine distinguish small bowel from colonic Crohn's disease.

BACKGROUND & AIMS: Thymus-expressed chemokine (TECK) or CCL25) is selectively expressed in the small bowel (SB), where lamina propria lymphocytes (LPL) and intraepithelial leukocyte expressing the cognate chemokine receptor CCR9 predominate. We characterize the role of TECK and CCR9-expresing lymphocytes in small intestinal Crohn's disease. METHODS: CCR9 expression on lymphocytes from lamina propria, mesenteric lymph node, and peripheral blood was analyzed by flow cytometry and by Northern blotting for LPL. TECK expression was analyzed in inflamed SB and colon by reverse-transcription polymerase chain reaction and immunohistochemistry. RESULTS: The fraction of CCR9(+) T cells in inflamed SB was significantly lower than in uninvolved SB mucosa. In contrast, in peripheral blood lymphocytes, CCR9(+) lymphocytes were markedly elevated in patients with small bowel Crohn's or celiac disease, but not in patients with purely colonic Crohn's. Also, TECK expression is altered in inflamed small bowel, being intensely expressed in a patchy distribution in crypt epithelial cells in proximity to lymphocytic infiltrates. TECK is not expressed in either normal or inflamed colon. CONCLUSIONS: In SB immune-mediated diseases, there is repartitioning of CCR9(+) lymphocytes between SB and blood and an altered pattern of TECK expression in SB Crohn's. The TECK/CCR9 ligand/receptor pair may play an important role in the pathogenesis of SB Crohn's disease.

Role of cytokines in the pathogenesis of inflammatory bowel disease.

Recent advances in the drug treatment of inflammatory bowel disease (IBD) have paralleled our understanding of the pathophysiology of ulcerative colitis and Crohn's disease. Several proinflammatory and immune-regulatory cytokines are upregulated in the mucosa of patients with IBD, and differences and similarities in the cytokine profiles of ulcerative colitis and Crohn's disease have been elucidated. Several clinical trials involving a chimeric anti-TNF-alpha (tumor necrosis factor-alpha) antibody have shown marked clinical benefit in the majority of patients with Crohn's disease, verifying the importance of TNF-alpha in the pathogenesis of Crohn's disease. In preliminary studies, treatment with recombinant human interleukin-10 has been beneficial in Crohn's disease but not in ulcerative colitis. Future treatment of IBD may include combination or sequential cytokine and anticytokine administration in defined groups of patients based on their mucosal cytokine profiles.

The clinical spectrum of stenotrophomonas (xanthomonas) maltophilia respiratory infection.

During a 15-month retrospective clinical study in an academic referral-based cancer center, 26 patients with S. maltophilia respiratory tract infections were identified (which were associated with bacteremia in 13 patients). Five of these 26 patients had previously undescribed sinopulmonary involvement. The infections were typically nosocomial. Nine patients with solid tumors had malignant involvement of the respiratory tract (five with obstruction). In two patients, the infection co-existed with pulmonary aspergillosis. Fifteen patients (58%) died of the infection. The factors that correlated with a poor outcome included bacteremic pneumonia, persistent neutropenia, presence of obstruction, development of septic shock or multiple organ dysfunction, and delay in institution of appropriate antibiotic therapy. In multivariate analysis, only septic shock and delayed therapy remained significant. Trimethoprim-sulfamethoxazole and/or ticarcillin-clavulanate were most commonly associated with a favorable outcome.

An open-label pilot study of low-dose thalidomide in chronically active, steroid-dependent Crohn's disease.

BACKGROUND & AIMS: Thalidomide decreases production of tumor necrosis factor alpha, a proinflammatory cytokine associated with Crohn's disease (CD). In this study the safety, tolerance, and efficacy of low-dose thalidomide were evaluated for treatment of moderate-to-severe, steroid-dependent CD. METHODS: Twelve adult male patients with Crohn's Disease Activity Index (CDAI) scores of > or = 250 and < or = 500 despite > or = 20 mg prednisone/day were enrolled. The first 6 patients received 50 mg thalidomide every night, the next 6 received 100 mg every night. Steroid doses were stable during the first 4 weeks of treatment, then tapered during weeks 5-12. CDAI was used to assess response. RESULTS: (1) Disease activity improved consistently in all patients during weeks 1-4: 58% response, 17% remission. (2) Clinical improvement was generally maintained despite steroid taper during weeks 5-12. All patients were able to reduce steroids by >/=50%. Forty-four percent discontinued steroids entirely. In weeks 5-12, 70% of patients responded and 20% achieved remission. (3) Side effects were mild and mostly transient, with the most common being drowsiness, peripheral neuropathy, edema, and dermatitis. CONCLUSIONS: Low-dose thalidomide appears to be well tolerated and effective over a 12-week period. Results of this pilot study support the need for controlled multicenter trials of thalidomide for treatment of CD.

Stenotrophomonas maltophilia meningitis. Report of two cases and review of the literature.

The authors report two cases of meningitis caused by Stenotrophomonas maltophilia in cancer patients following placement of an Ommaya reservoir for treatment of meningeal carcinomatosis. In addition, they review eight other cases of S. maltophilia that have been reported to date. Stenotrophomonas maltophilia meningitis is often associated with neurosurgical procedures; however, spontaneous infection may also occur, mainly in neonates. The disease's clinical presentation is similar to that of other forms of meningitis caused by Gram-negative bacilli. The overall mortality rate of this disease is 20% and is limited to neonates with spontaneous meningitis in whom effective antibiotic therapy is delayed. Meningitis caused by S. maltophilia in the modern era should be considered in immunocompromised hosts with significant central nervous system disease who have undergone neurosurgical procedures and who do not readily respond to broad-spectrum antimicrobial coverage.

Stenotrophomonas (Xanthomonas) maltophilia urinary tract infection. A disease that is usually severe and complicated.

BACKGROUND: Stenotrophomonas (Xanthomonas) maltophilia has emerged as a causative agent of serious nosocomial infections. However, well-documented cases of urinary tract infection with this organism have rarely been reported. METHODS: review of the medical records of patients admitted to a large cancer center with cultures yielding S maltophilia from urinary sources during a 15-month period. RESULTS: All urinary tract infections were serious: 13 were complicated and two were acute uncomplicated pyelonephritis. The urinary tracts of 13 other patients were colonized with S maltophilia. Most of the colonized and infected patients were hospitalized with genitourinary malignancy, underwent urinary catheterization, and were receiving antibiotics inactive against S maltophilia. Neutropenia and urinary structural abnormalities were significantly associated with infection. The clinical course of infection was usually severe: fever (100%), sepsis disorder (47%), neutrophilia (70% of patients without neutropenia), bacteremia (13%) and death (7%). Still, response to treatment was prompt. CONCLUSIONS: Stenotrophomonas maltophilia urinary tract infection is usually associated with a severe clinical course. Risk factors for urinary colonization by this organism include hospitalization, urinary catheterization, and administration of inactive antibiotics. Risk factors for urinary tract infection include neutropenia and urinary structural abnormalities. In the presence of these risk factors, treatment of S maltophilia should be considered in patients with urinary colonization by the organism or in those with nosocomial urinary tract infection caused by an unknown pathogen and that is unresponsive to therapy with the antibiotics that are used to treat the common uropathogens.

Stenotrophomonas maltophilia: an unusual cause of biliary sepsis.

We report three cases of cholangitis caused by Stenotrophomonas maltophilia and review two other cases reported in the literature. All five episodes occurred in patients with hepatobiliary malignancy complicated by biliary tract obstruction. All five episodes occurred in patients with hepatobiliary malignancy complicated by biliary tract obstruction. All patients had undergone biliary tract instrumentation. Before infection developed, four of the five patients had received therapy with antibiotics that do not have in vitro activity against this organism. Four patients responded to appropriate antibiotic therapy and biliary tract decompression, whereas the fifth patient, who had persistent biliary obstruction, did not respond to appropriate antibiotic therapy.

Mucocutaneous and soft tissue infections caused by Xanthomonas maltophilia. A new spectrum.

OBJECTIVE: To describe the mucocutaneous and soft tissue infections caused by Xanthomonas maltophilia in patients with cancer. DESIGN: A retrospective 15-month clinical study. SETTING: Academic, referral-based cancer center. PATIENTS: Of 237 patients with X. maltophilia isolated from all sites during the 15-month study period, 114 patients were judged to have true X. maltophilia infections. Only patients with mucocutaneous and soft tissue infections were included in the study. RESULTS: 17 (15%) of the 114 patients with X. maltophilia infection had mucocutaneous and soft tissue infections: Six patients had metastatic cellulitis, 5 had primary cellulitis usually associated with catheter use, and 6 had infected mucocutaneous ulcers. The metastatic cellulitis consisted of previously undescribed multiple, hard, tender nodules with surrounding and distant cellulitis (5 patients) or ecthyma gangrenosum (1 patient). Four of these patients died of the infection. Metastatic cellulitis and mucocutaneous infections occurred in hospitalized, neutropenic patients who received broad-spectrum antibiotics (beta-lactams, quinolones), often with in vitro activity against the infecting organisms. Response usually correlated with recovery from myelosuppression and administration of trimethoprim-sulfamethoxazole with or without ticarcillin-clavulanate. Catheter removal contributed to response in the treatment of primary cellulitis. CONCLUSIONS: Mucocutaneous and soft tissue infections caused by X. maltophilia are not uncommon, and X. maltophilia can cause metastatic nodular skin lesions that mimic disseminated fungal infections. It also causes serious morbidity and high mortality in patients with metastatic skin nodules and can cause superinfections in patients receiving broad-spectrum beta-lactam or quinolone antibiotics to which the organisms are susceptible when the infections develop. Catheter removal contributes to a favorable outcome in patients with catheter-associated cellulitis without bacteremia. Xanthomonas maltophilia infection should be added to the differential diagnosis of mucocutaneous or soft tissue infection in patients with cancer. Trimethoprim-sulfamethoxazole with or without ticarcillin-clavulanate is the current treatment of choice for culture-proven infections, but early empiric therapy may improve outcome.