Case Report: Resolution of high grade anal squamous intraepithelial lesion with antibiotics proposes a new role for syphilitic infection in potentiation of HPV-associated ASCC.

Introduction: Human Papillomavirus (HPV) is the primary risk factor for the development of anal intraepithelial neoplasia (AIN) and is a leading risk factor for anogenital squamous cell carcinoma (ASCC). Despite common shared risk factors for both HPV and syphilis, co-infection is not well documented, and the role of syphilitic infection in HPV-associated AIN and ASCC potentiation is not defined. Case description/methods: A 72-year-old single male presented with complaints of mild rectal pain and intermittent rectal bleeding. A flexible sigmoidoscopy was performed, and a firm 4.5cm x 3cm perianal mass was detected and superficially biopsied. Pathology findings demonstrated evidence of a high grade squamous intraepithelial lesion (HGSIL, AIN II/III/AIS) with viral cytopathic effect, consistent with HPV infection. Much of the biopsied lesion showed acanthotic squamous mucosa with intraepithelial neutrophils and abundant submucosal plasma cells, suggesting possible syphilitic involvement. Subsequent immunohistochemical staining for p16 as a surrogate marker for HPV was positive, as was an immunohistochemical stain for spirochetes, supportive of co-infection with Treponema pallidum pallidum (T. pallidum), the causative agent in venereal syphilis. The patient was referred to an infectious disease specialist for syphilitic infection and was treated with penicillin with surprisingly complete resolution of the lesion. EUAs were performed 2- and 3-months following treatment without lesion recurrence. However, one year following diagnosis, a flexible sigmoidoscopy revealed a 5 mm recurrent HPV-related low-grade AIN 1 lesion at the dentate line. Discussion: Resolution of the lesion by antibiotic treatment for syphilitic infection suggested that co-infection by T. pallidum may potentiate HPV-associated squamous cell carcinoma based on histological findings. Findings from this case, as well as a review of bacterial involvement and potentiation in various cancers, are reviewed here. Such findings offer new insight regarding the role of STI-associated bacteria and HPV co-infection in the establishment of AIN and may additionally propose new treatment modalities for ASCC.

Mesalazine granules 1.5 g once-daily maintain remission in patients with ulcerative colitis who switch from other 5-ASA formulations: a pooled analysis from two randomised controlled trials.

BACKGROUND: Mesalazine (mesalamine) granules (MG) were shown to be effective for the maintenance of remission of ulcerative colitis (UC) in two double-blind placebo-controlled trials. AIM: To evaluate the efficacy of once-daily MG for maintenance of remission in patients with UC who switched from other 5-aminosalicylic acid (5-ASA) formulations. METHODS: Data from two independent multicenter, randomised, double-blind, placebo-controlled, 6-month trials evaluating patients with UC in remission were combined for analysis of a subpopulation of patients who switched from other 5-ASA formulations to MG 1.5 g or placebo upon randomisation. The primary endpoint was the percentage of patients who remained relapse-free at Month 6 or end of treatment. Relapse was defined as a Sutherland Disease Activity Index (SDAI) rectal bleeding score ≥1 and mucosal appearance score ≥2, a UC flare or medication used to treat a UC flare. RESULTS: Of the 487 patients who received 5-ASA maintenance therapy at enrolment, 322 were in the MG group and 165 were in the placebo group. The percentage of patients who remained relapse-free (based on Sutherland Disease Activity Index scores) after 6 months was significantly higher with MG than placebo (78.3% vs. 58.8%, P < 0.001). Rectal bleeding, stool frequency and the physician's rating of disease activity remained unchanged after 6 months in a higher percentage of patients using MG compared with those on placebo (P < 0.004 for each endpoint). CONCLUSION: Mesalazine granules 1.5 g once-daily is effective for maintenance of remission in UC patients who switch from other 5-ASA formulations. ClinicalTrials.gov identifiers NCT00744016, NCT00767728.

Clinical trial: once-daily mesalamine granules for maintenance of remission of ulcerative colitis - a 6-month placebo-controlled trial.

BACKGROUND: Ulcerative colitis (UC) is a chronic relapsing and remitting idiopathic inflammatory bowel disorder. AIM: To evaluate once-daily mesalamine (mesalazine) granules (MG) for maintenance of remission of UC. METHODS: Randomized, double-blind, placebo-controlled trial of patients (n=209 MG, n=96 placebo) with UC in remission [revised Sutherland Disease Activity Index (SDAI) rectal bleeding=0, mucosal appearance <2] who took MG 1.5 g or placebo once-daily for up to 6 months. Primary efficacy endpoint: the percentage of patients who remained relapse-free at month 6/end of treatment. Relapse was defined as SDAI rectal bleeding score ≥1 and a mucosal appearance score ≥2, a UC flare, or initiation of medication to treat a UC flare. RESULTS: The percentage of relapse-free patients at month 6/end of treatment was higher with MG than placebo (78.9% vs. 58.3%, P < 0.001) in the intent-to-treat analysis. Significant differences (P ≤ 0.025) favouring MG were observed for most secondary endpoints including improvement in rectal bleeding, physician's disease activity rating, stool frequency, the SDAI at month 6/end of treatment, patients classified as a treatment success and relapse-free duration. The incidence of adverse events was similar between groups. CONCLUSIONS: Once-daily mesalamine (mesalazine) was effective in maintaining remission of UC for 6 months.

Comparative results of endoluminal gastroplasty and laparoscopic antireflux surgery for the treatment of GERD.

BACKGROUND: Transoral endoluminal gastroplasty (EG) by the Bard Endocinch device is available for the treatment of gastroesophageal reflux disease (GERD). This study assessed the early (

Modulation of neutrophil function by novel colonic factors: possible role in the pathophysiology of ulcerative colitis.

Tissue damage in acute ulcerative colitis (UC) may be triggered by neutrophils (PMNs) and their inflammatory mediators such as reactive oxygen species (ROS). Because circulating PMNs appeared normal in subjects with UC, we hypothesized that the critical abnormality that attracts and activates PMNs in UC is a local colonic factor. Accordingly, the colonic milieu was sampled by using in vivo rectal dialysis (mol wt < or = 12 kd). Normal PMNs were exposed in vitro to rectal dialysates (RD) from control subjects (cRD) or subjects with active UC (aRD) or inactive UC (IRD). PMN-derived ROS were measured by chemiluminescence. cRD did not increase ROS production by unstimulated PMNs; aRD significantly and concentration-dependently increased ROS; IRD gave intermediate results. cRD inhibited the PMN-stimulating effects of both the bacterial peptide formyl-methionyl-leucyl-phenylalanine (fMLP) and phorbol myristate acetate (PMA). aRD and IRD blunted the effect of fMLP and PMA significantly less than did cRD. Rectal dialysates from 44% of subjects with active UC exaggerated the fMLP effect, whereas potentiation occurred for only 13% of cRDs and 18% of iRDs. cRD preconditioned with either activated or nonactivated PMNs was not significantly different than unconditioned cRD. We thus infer the existence of colonic factors in UC that (1) can trigger PMNs to produce ROS and (2) have a proinflammatory modulatory effect on bacterial peptide-induced, PMN-mediated ROS production, thereby initiating or perpetuating inflammation and eventually causing tissue damage.(ABSTRACT TRUNCATED AT 250 WORDS)

Elevated breath ethane levels in active ulcerative colitis: evidence for excessive lipid peroxidation.

OBJECTIVE: Reactive oxygen species (ROS) may be a major cause of tissue injury in ulcerative colitis (UC). One possible mechanism for ROS-mediated tissue injury is lipid peroxidation. Breath ethane and pentane excretion are noninvasive means for measuring peroxidation of omega-3 and omega-6 polyunsaturated fatty acid, respectively. Hence, we measured breath ethane in 17 subjects with active UC and correlated the results with disease severity. METHODS: Breath samples for ethane and pentane analysis were collected every 2 weeks, and rectal biopsies were obtained monthly to assess for chemiluminescence, a marker of ROS. Ethane and pentane concentrations (nmol/L) were measured by gas chromatography, and mucosal chemiluminescence was measured spectrophotometrically. Data were compared to control values (C) from healthy subjects. Disease activity was assessed both clinically and endoscopically. RESULTS: Ethane excretion was significantly elevated in patients (UC, 0.45 +/- 0.04; C, 0.33 +/- 0.06; p = 0.013). Ethane excretion was positively correlated with endoscopic score (r = 0.45; p < 0.05), symptom score (r = 0.34; p < 0.05), disease activity (r = 0.36, p < 0.05), and chemiluminescence (r = 0.65; p < 0.001). Pentane levels did not correlate with any of the clinical measurements. Chemiluminescence in the rectal tissue was positively correlated with endoscopic score (r = 0.71; p < 0.05) and disease activity (r = 0.61; p < 0.01). CONCLUSIONS: Tissue damage in UC may be ROS-induced lipid peroxidation. Disease activity can be assessed noninvasively by breath ethane excretion.

Increased production of luminol enhanced chemiluminescence by the inflamed colonic mucosa in patients with ulcerative colitis.

Reactive oxygen species have been implicated as mediators of inflammation in ulcerative colitis. Chemiluminescence is a reliable means of estimating reactive oxygen species in biological media. Increased reactive oxygen species values in the inflamed colonic mucosa in rats were seen by chemiluminescence. The aims of the study were to find out if chemiluminescence is raised in the colonic mucosa of patients with ulcerative colitis and correlates with disease activity, and to elucidate the sources of the chemiluminescence. It was found that reactive oxygen species, as measured by the chemiluminescence technique, are raised in inflamed colonic mucosa and correlates with symptom score, sigmoidoscopic score, disease activity, and activity of the neutrophil enzyme myeloperoxidase. Chemiluminescence was inhibited by a myeloperoxidase inhibitor (azide) and an H2O2 scavenger (catalase) but not by allopurinol, an inhibitor of the enzyme xanthine oxidase. Chemiluminescence was also inhibited by indomethacin, but this did not seem to be related to inhibition of cyclo-oxygenase. These findings suggest that a likely cellular source of reactive oxygen species in the inflamed colon of patients with ulcerative colitis is the neutrophil and that myeloperoxidase conversion of H2O2 to hypochlorous acid, contributes to the chemiluminescence signal and possibly, to the tissue injury. Neither cyclo-oxygenase nor lipoxygenase seem to play a part as sources for the chemiluminescence.

Mitomycin C-induced colitis in rats: a new animal model of acute colonic inflammation implicating reactive oxygen species.

The mechanism of the tissue damage induced by colonic inflammation in ulcerative colitis is not established. We therefore developed and characterized a simple new rat model of acute colonic inflammation induced by a single systemic injection of mitomycin C. After an intraperitoneal injection of mitomycin-C, colon histologic examination revealed transient (3 to 14 days) diffuse, colonic inflammation and injury that, like human ulcerative colitis, was limited to the mucosal layer. The rest of the gastrointestinal tract was spared. Gut permeability, as measured by urinary excretion of orally administered lactulose and mannitol, was unchanged 3 days after injection, when inflammation was already present; permeability was increased at 7 days, when inflammation was maximal. Mitomycin C did not produce inflammation in experimentally bypassed segments of small bowel despite the presence of colonic-type bacteria, suggesting that lack of intraluminal bacteria was not responsible for the absence of inflammation in the small intestine. Chemiluminescence, a means of estimating levels of reactive oxygen species, was greater in the intact, inflamed colon of mitomycin C-treated rats than in bypassed segments. Moreover, inflamed mucosal scrapings produced more in vitro luminol-enhanced chemiluminescence. Furthermore, the reactive oxygen species scavengers allopurinol, catalase, and WR-2721 decreased inflammation severity. We therefore conclude: (1) the mitomycin C-treated rat is a novel, easy to prepare animal model of acute inflammation of colonic mucosa, with morphologic similarities to the acute phase of ulcerative colitis in human beings; (2) increased gut permeability in mitomycin C-treated rats is the result, not the cause, of the inflammation; and (3) reactive oxygen species play an important role in colonic inflammation and tissue injury in this model, and possibly in human ulcerative colitis.

Excessive production of reactive oxygen metabolites by inflamed colon: analysis by chemiluminescence probe.

Reactive oxygen metabolites (ROMs) are involved in inflammatory diseases and are postulated to contribute to tissue injury in colitis. To determine whether excessive ROMs are generated by inflamed colonic mucosa and to identify possible sources and type of ROMs, mucosal ROMs were estimated in rats and humans using a chemiluminescence probe. Colitis was induced in rats by intracolonic injection of acetic acid or intraperitoneal injection of mitomycin C. Intact, inflamed colon in rats produced more ultraweak chemiluminescence than normal colon. Inflamed mucosal scrapings from both rat models produced significantly more luminol-enhanced chemiluminescence. Addition of catalase, an H2O2 scavenger, or azide, a myeloperoxidase inhibitor, into the media significantly decreased chemiluminescence from inflamed mucosal scrapings. Indomethacin, an antioxidant cyclo-oxygenase inhibitor, also decreased chemiluminescence, but MK-866, a 5-lipoxygenase inhibitor, had no effect. Colonic biopsy specimens obtained during colonoscopy from patients with ulcerative colitis also produced more catalase-inhibitable chemiluminescence than normal colonic mucosa. These data indicate that excessive ROMs are produced by inflamed colonic mucosa in both humans and rats, which may contribute to tissue injury.

Effect of acute ethanol on esophageal motility in cat.

In man, acute ethanol administration decreases lower esophageal sphincter pressure (LESP), prolongs the duration, and lowers the amplitude of esophageal contractions. These changes may contribute to gastroesophageal reflux and esophagitis. To evaluate the underlying mechanisms of these changes an animal model is needed. Hence, we studied the effect of various doses of ethanol on esophageal motility in cats, an animal with an esophagus similar to man's. Similar to man, intravenous administration of ethanol significantly decreased LESP and amplitude of lower (smooth muscle portion) esophageal contractions. It also prolonged the duration of lower esophageal contractions, even through it had no effect on contraction velocity. The effect of ethanol on upper (striated muscle portion) esophagus was different. Ethanol had no effect on the amplitude of contractions, whereas it prolonged their duration and decreased their velocity. The effect of acute ethanol on LESP in four withdrawing alcoholic cats was similar to controls. However, the acute effect of ethanol on the esophageal contractions was less marked in alcoholics. Bilateral cervical vagotomy and intravenous injection of the neurotoxin tetrodotoxin before the administration of ethanol did not prevent the effect of ethanol on LESP. This data suggests that cat esophagus is a good model for studying the underlying mechanisms of the effects of acute ethanol because its response is similar to the esophagus of man, and the acute effect of ethanol on LESP is not neurally mediated but is the result of its direct effect on muscle.

Role of reactive oxygen metabolites in experimental colitis.

Reactive oxygen metabolites are potent inflammatory mediators that may be involved in tissue injury in inflammatory bowel disease. To evaluate their role in inflammatory bowel disease, we investigated the effects of lowering the activities of reactive oxygen metabolites in experimental colitis induced by intracolonic administration of acetic acid in rats. Intracolonic administration of 5% acetic acid caused severe inflammation (mean (SEM) inflammatory score was 24.3 (0.7) of a maximum score of 32). Acetic acid at 2.5% produced moderate inflammation (score = 17 (1.4) v 4.0 (0.5) in control rats). This lower dose was used for subsequent experiments. Specific superoxide anion scavenger methoxypolyethylene glycol:superoxide dismutase, and reactive oxygen metabolites scavenger, sulfasalazine, significantly decreased the severity of inflammation (scores: 8 (4.4) and 9.8 (2.2) respectively). The xanthine oxidase inhibitors, tungsten and pterin aldehyde, failed to improve inflammation but another xanthine oxidase inhibitor, allopurinol, a compound with known superoxide anion scavenging effect, did limit the inflammation (10(2)). Inhibition of hydroxyl radical production by deferoxamine or lowering hydroxyl radical values by a scavenger, dimethyl sulfoxide, did not affect the severity of inflammation. These data suggest: (1) that reactive oxygen metabolites play an important role in experimental colitis, (2) that the xanthine oxidase pathway is not a major source of reactive oxygen metabolites in colitis, and (3) that tissue injury in experimental colitis is not caused by generation of hydroxyl radicals.