Inverse expression of prostaglandin E2-related enzymes highlights differences between diverticulitis and inflammatory bowel disease.

BACKGROUND: Prostaglandin E2 (PGE2) is the dominant prostaglandin in the colon and is associated with colonic inflammation. PGE2 levels are regulated not only by cyclooxygenases (COX-1 and COX-2) but also by 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the major PGE2-degrading enzyme. Information about the involvement of 15-PGDH in colonic inflammation is sparse. AIM: We thus aimed to determine the gene expression and immunoreactivity (IR) of COX-1, COX-2, and 15-PGDH in colonic mucosa from patients with diverse inflammatory disorders: ulcerative colitis (UC), Crohn's disease (CD), and acute diverticular disease (DD). METHODS: RNA from human colonic mucosa was extracted and assessed for gene expression by real-time PCR. Intact colon sections were processed for immunohistochemistry with immunostaining of the mucosal areas quantified using ImageJ. RESULTS: In colonic mucosa of both UC and CD, COX-2 mRNA and COX-2-IR were significantly increased, whereas 15-PGDH mRNA and 15-PGDH-IR were significantly reduced. In macroscopically undamaged acute DD mucosa, the opposite findings were seen: for both gene expression and immunoreactivity, there was a significant downregulation of COX-2 and upregulation of 15-PGDH. COX-1 mRNA and COX-1-IR remained unchanged in all diseases. CONCLUSIONS: Our study for the first time demonstrated differential expression of the PGE2-related enzymes COX-2 and 15-PGDH in colonic mucosa from UC, CD, and acute DD. The reduction of 15-PGDH in IBD provides an additional mechanism for PGE2 increase in IBD. With respect to DD, alterations of PGE2-related enzymes suggest that a low PGE2 level may precede the onset of inflammation, thus providing new insight into the pathogenesis of DD.

Hemokinin-1 stimulates prostaglandin E2 production in human colon through activation of cyclooxygenase-2 and inhibition of 15-hydroxyprostaglandin dehydrogenase.

Hemokinin-1 (HK-1) is a newly identified tachykinin, originating from the immune system rather than neurons, and may participate in the immune and inflammatory response. In colonic mucosa of patients with inflammatory bowel disease (IBD), up-regulation of the TAC4 gene encoding HK-1 and increased production of prostaglandin E2 (PGE2) occur. Our aim was to examine the mechanistic link between human HK-1 and PGE2 production in normal human colon. Exogenous HK-1 (0.1 µM) for 4 h evoked an increased PGE2 release from colonic mucosal and muscle explants by 10- and 3.5-fold, respectively, compared with unstimulated time controls. The HK-1-stimulated PGE2 release was inhibited by the tachykinin receptor antagonists (S)1-2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)piperidin-3-yl]ethyl-4-phenyl-l azonia-bicyclo[2.2.2]octane (SR140333) [neurokinin-1 (NK1)] and N-[(2S)-4-(4-acetamido-4-phenylpiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide (SR48968) [neurokinin-2 (NK2)] and was also inhibited by the cyclooxygenase (COX)-2 inhibitor N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide) (NS-398) but not by the COX-1 inhibitor 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole (SC-560). A parallel study with substance P showed similar results. Molecular studies with HK-1-treated explants demonstrated a stimulatory effect on COX-2 expression at both transcription and protein levels. It is noteworthy that this was coupled with HK-1-induced down-regulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) mRNA and protein expression. Immunoreactivity for 15-PGDH occurred on inflammatory cells, epithelial cells, platelets, and ganglia. This finding provides an additional mechanism for HK-1-evoked PGE2 increase, in which HK-1 may interfere with the downstream metabolism of PGE2 by suppressing 15-PGDH expression. In conclusion, our results uncover a novel inflammatory role for HK-1, which signals via NK1 and NK2 receptors to regulate PGE2 release from human colonic tissue, and may further explain a pathological role for HK-1 in IBD when abnormal levels of PGE2 occur.

Factor analysis identifies subgroups of constipation.

AIM: To determine whether distinct symptom groupings exist in a constipated population and whether such grouping might correlate with quantifiable pathophysiological measures of colonic dysfunction. METHODS: One hundred and ninety-one patients presenting to a Gastroenterology clinic with constipation and 32 constipated patients responding to a newspaper advertisement completed a 53-item, wide-ranging self-report questionnaire. One hundred of these patients had colonic transit measured scintigraphically. Factor analysis determined whether constipation-related symptoms grouped into distinct aspects of symptomatology. Cluster analysis was used to determine whether individual patients naturally group into distinct subtypes. RESULTS: Cluster analysis yielded a 4 cluster solution with the presence or absence of pain and laxative unresponsiveness providing the main descriptors. Amongst all clusters there was a considerable proportion of patients with demonstrable delayed colon transit, irritable bowel syndrome positive criteria and regular stool frequency. The majority of patients with these characteristics also reported regular laxative use. CONCLUSION: Factor analysis identified four constipation subgroups, based on severity and laxative unresponsiveness, in a constipated population. However, clear stratification into clinically identifiable groups remains imprecise.

Cyclooxygenase-dependent alterations in substance P-mediated contractility and tachykinin NK1 receptor expression in the colonic circular muscle of patients with slow transit constipation.

Tachykinins are important neurotransmitters regulating intestinal motility. Slow transit constipation (STC) represents an extreme colonic dysmotility with unknown etiology that predominantly affects women. We examined whether the tachykinin system is involved in the pathogenesis of STC. Isolated sigmoid colon circular muscle from female STC and control patients was studied using functional and quantitative reverse transcriptase-polymerase chain reaction methods. A possible alteration of neurotransmission was investigated by electrical field stimulation (EFS) and ganglionic stimulation by dimethylphenylpiperazinium (DMPP). Substance P (SP)-mediated contractions in circular muscle strips were significantly diminished in STC compared with age-matched control (P < 0.001). In contrast, contractile responses to neurokinin A, the selective tachykinin NK(2) receptor agonist, [Lys(5),MeLeu(9),Nle(10)]NKA(4-10), and acetylcholine were unaltered in STC. The reduced responses to SP in STC were fully restored by indomethacin, partially reversed by tetrodotoxin (TTX), but unaffected by atropine or hexamethonium. The restoration by indomethacin was blocked by the NK(1) receptor antagonist CP99994 [(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine] and TTX. In STC colonic muscle, there was a significant increase of NK(1) receptor mRNA expression, but no difference in NK(2) mRNA level. DMPP generated biphasic responses, relaxation at lower and contraction at higher concentrations. Although the responses to DMPP were similar in STC and control, an altered contractile pattern in response to EFS was observed in STC circular muscle. In conclusion, we postulate that the diminished contractile response to SP in STC is due to an increased release of inhibitory prostaglandins through activation of up-regulated NK(1) receptors. Our results also indicate some malfunction of the enteric nervous system in STC.

Tachykinin NK2 receptor and functional mechanisms in human colon: changes with indomethacin and in diverticular disease and ulcerative colitis.

Neurokinin A (NKA) is an important spasmogen in human colon. We examined inflammatory disease-related changes in the tachykinin NK(2) receptor system in human sigmoid colon circular muscle, using functional, radioligand binding, and quantitative reverse transcription-polymerase chain reaction methods. In circular muscle strips, indomethacin enhanced contractile responses to NKA (p < 0.01) and to the NK(2) receptor-selective agonist [Lys(5),MeLeu(9),Nle(10)]-NKA(4-10) (p < 0.05) in both normal and acute diverticular disease (DD) specimens, indicating NK(2) receptor-mediated release of relaxant prostanoids. Contractile responses to both tachykinins were reduced in strips from DD (p < 0.001) and ulcerative colitis (UC) (p < 0.05) specimens. Responses to acetylcholine were no different in other strips from the same disease patients, demonstrating that the change in responsiveness to tachykinins in disease is specifically mediated by the NK(2) receptor. In membranes from UC specimens, receptor affinity for (125)I-NKA (median K(D) 0.91 nM, n = 16) was lower (p < 0.01) than that in age-matched control specimens (K(D) 0.55 nM, n = 40), whereas K(D) (0.65 nM, n = 28) in DD was no different from control. No disease-related changes in receptor number (B(max)) were found (mean, 2.0-2.5 fmol/mg of wet weight tissue), suggesting that the reduced contractile responses in disease are not due to a loss of receptor number. Different mechanisms may account for the reduced contractility in DD compared with UC. A gender-related difference in receptor density was seen in controls, with B(max) lower in females (1.77 fmol/mg, n = 15) than in males (2.60 fmol/mg, n = 25, p = 0.01). In contrast, no gender-related differences were seen in NK(2) receptor mRNA in control colonic muscle, indicating that the gender difference is a post-translational event.

Synchronous resection of colorectal primary cancer and liver metastases.

BACKGROUND: Patients with synchronous colorectal liver metastases are thought to have a less favorable prognosis than those with colorectal cancer alone. Surgical treatment options are controversial, be it synchronous resection or staged resection. This study compared the clinical, perioperative, disease-free survival (DFS), and overall survival (OS) results of patients undergoing synchronous resection versus staged resection. METHODS: An observational cohort study of 103 patients with synchronous colorectal liver metastases was performed. All data were collected prospectively. Clinical, perioperative, DFS, and OS results of patients undergoing synchronous resection (group I, n = 73) and staged resection (group II, n = 30) were compared. RESULTS: More patients in group I had poorly differentiated colorectal cancer, bilobar liver metastases, more than three liver metastases, < or =4 cm liver metastases, and shorter hospital stays than patients in group II. There were no significant statistically differences in DFS and OS between the two groups. The median DFS of groups I and II were 28 and 26 months, respectively (p = 0.585). The median OS of groups I and II were 37 and 36 months, respectively (p = 0.900). CONCLUSIONS: Synchronous resection achieved DFSs and OSs similar to those seen after staged resection while avoiding a second major operation.

Bowel, bladder and sexual function in women undergoing laparoscopic posterior compartment repair in the presence of apical or anterior compartment dysfunction.

OBJECTIVE: The aim of the study was to analyse the functional outcome of women undergoing a laparoscopic posterior compartment repair in the presence of anterior or apical compartment dysfunction. DESIGN: Prospective cohort study. METHODS: Forty women, median age 65 years (41-78), with symptoms of genital prolapse 31 (78%), urinary dysfunction 32 (80%) and bowel dysfunction 40 (100%), underwent laparoscopic posterior compartment repair in conjunction with an anterior compartment repair. Pre-operative and postoperative bowel and bladder function was prospectively assessed with a Wexner continence score, Vienna constipation score and a urinary dysfunction score. Twenty-eight (70%) and 24 patients (60%) had pre-operative urodynamics and anorectal manometry. Post-operatively all women were also assessed with a Watt's sexual dysfunction score and a linear analogue patient satisfaction score. Twelve women (30%) had postoperative anal manometry. RESULTS: At 20 months median follow-up, 30 (97%), 20 (62%) and 12 (31%) women reported improvement in their prolapse, urinary and bowel symptoms, respectively. Post-operatively, one woman reported denovo faecal incontinence, four worsening obstructive defecation and three denovo urinary dysfunction. Nine women (35%) reported denovo dyspareunia. The mean time to clinical deterioration following surgery was 11 months. Bowel function improvement was the only factor to significantly correlate with postoperative patient satisfaction. CONCLUSION: The functional outcome of laparoscopic posterior compartment repair in the presence of anterior compartment dysfunction is disappointing. Preoperative counselling is important to ensure that patients have reasonable and realistic expectations from repair surgery, and an understanding that anatomical improvement might not be followed by long-term functional improvement.

Abnormal predefecatory colonic motor patterns define constipation in obstructed defecation.

BACKGROUND & AIMS: The pathophysiology of constipation in the syndrome of obstructed defecation is unknown. Using 24-hour pancolonic manometric recordings of the unprepared colon to record basal pressures and spontaneous defecation episodes, we tested the hypothesis that the frequency, timing, or spatial distribution of propagating colonic pressure waves is abnormal in patients with obstructed defecation. METHODS: In 11 patients with obstructed defecation and 16 healthy controls, pressures were recorded using a nasocolonic catheter that was positioned such that 16 recording sites spanned the unprepared colon at 7.5-cm intervals. RESULTS: The overall frequency of propagating sequences (PS) in the colon did not differ between patients and controls. When compared with controls, patients had a significant increase in the frequency of retrograde and antegrade PS (P < 0.05) in the left colon and a significant reduction in the amplitude of propagating pressure waves throughout the entire colon (P < 0.03). Defecation occurred in 6 of 11 patients and 9 of 16 controls. In the 15 minutes before defecation, controls showed a highly significant increase in frequency (P = 0.001) and amplitude (P = 0.01) of PS. In contrast, patients did not demonstrate this or the typical spatiotemporal organization of PS normally observed before expulsion of stool. CONCLUSIONS: Patients with obstructed defecation lack the normal predefecatory augmentation in frequency and amplitude of propagating pressure waves and lack the normal stereotypic spatiotemporal patterning of colonic pressure waves that would normally culminate in effective expulsion of stool.

Use of endoscopic titanium stapler in rectal anastomotic stricture.

A quick and effective technique is described here for the treatment of rectal anastomotic stricture. It consisted of cutting the stricture using the Ethicon 35-mm Endoscopic Titanium Stapler. A patient was treated here as a day-surgery case. Good functional and anatomic results were achieved on follow-up.