Nifedipine for treatment of anal fissures.
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Administration, Topical↗
Biomedical subjects
N J Mortensen
Publications and source records attributed to N J Mortensen.
Abnormal contractile properties of rectal smooth muscle in chronic ulcerative colitis.
BACKGROUND: Patients with ulcerative colitis have abnormal rectal motility. AIM: To compare the contractile properties of rectal smooth muscle from patients with ulcerative colitis and controls. METHODS: Rectal smooth muscle strips from patients undergoing resection for ulcerative colitis or cancer (control) were mounted in an organ bath. The effects of carbachol (receptor-mediated) and potassium (causes membrane depolarization) were studied. Acetylcholinesterase histochemistry was performed and nerve counts compared. RESULTS: Ulcerative colitis (n=41) and control (n=34) strips contracted in response to potassium and carbachol. Mean (S.E. M.) maximum response to potassium in the control and ulcerative colitis groups was 1.07 (0.06) g/mg and 1.02 (0.09) g/mg tissue, respectively (P=N.S.). EC50s (concentrations required to give 50% of maximal response) were 75 (1) mM and 73 (1) mM, respectively (P=N.S. ). Although maximum responses to carbachol were similar, 2.12 (0.12) g/mg and 1.95 (0.12) g/mg tissue (P=N.S.), ulcerative colitis strips exhibited an increased sensitivity to carbachol, EC50s: 5.05 x 10-6 (0.55 x 10-6) M vs. 8.36 x 10-6 (0.88 x 10-6) M, P=0.002). There was no significant difference in nerve counts between the tissues, as assessed by staining for acetylcholinesterase. CONCLUSIONS: Ulcerative colitis tissue has an increased sensitivity to carbachol and this is not due to denervation; it may result from increased calcium release from intracellular stores since contraction due to membrane depolarization is not altered. Modulation of this pathway could potentially be used to alter rectal motility in patients with ulcerative colitis.
Acetylcholinesterase↗
Role of a defunctioning stoma in the management of large bowel Crohn's disease.
BACKGROUND: The faecal stream plays a significant role in the pathogenesis of Crohn's disease. This retrospective study aimed to assess the effect of faecal diversion on the natural history of refractory Crohn's colitis (RCC) and severe perianal disease (PAD). METHODS: All patients undergoing a defunctioning stoma without resection for RCC or PAD between 1970 and 1997 were studied. Indications for surgery, acute clinical response, subsequent outcome and stoma rates were recorded. RESULTS: Some 73 patients underwent a defunctioning stoma (55 RCC and 18 PAD). Acute remission was achieved in 63 patients (48 RCC, 15 PAD). Twenty-nine patients had subsequent closure of the defunctioning stoma (25 of 48 acute responders with RCC and four of 15 acute responders with PAD). Eleven patients with RCC and two with PAD achieved good long-term function without disease relapse (median follow-up 36 months). Overall 52 patients have undergone proctocolectomy or remain with a defunctioning stoma (37 with RCC and 15 with PAD). CONCLUSION: Faecal diversion is associated with acute clinical remission in the majority of patients with RCC and PAD, but sustained benefit occurs less often. For selected patients, diversionary surgery alone offers a realistic alternative to major bowel resection.
Adult↗
Anatomy of Denonvilliers' fascia and pelvic nerves, impotence, and implications for the colorectal surgeon.
BACKGROUND: The development and anatomy of Denonvilliers' fascia have been controversial for many years and confusion exists about its operative appearance. Better appreciation of this poorly understood anatomy, and its significance for impotence after rectal dissection, may lead to further functional improvements in pelvic surgery. METHOD: A literature review of the embryology and anatomy of Denonvilliers' fascia and impotence after pelvic rectal surgery was undertaken. RESULTS: Denonvilliers' fascia has no macroscopically discernible layers. The so-called posterior layer refers to the fascia propria of the rectum. The incidence of erectile and ejaculatory dysfunction after rectal excision is high in older patients, and when performed for rectal cancer. There is no consensus about the relationship of Denonvilliers' fascia to the plane of anterior dissection for rectal cancer. CONCLUSION: Colorectal surgeons should focus on the important anatomy between the rectum and the prostate to improve functional outcomes after rectal excision. A classification of the available anterior dissection planes is proposed. Surgeons should be encouraged to document the plane used as well as outcome in terms of sexual function.
Autonomic Nervous System↗
DNA mismatch repair genes and colorectal cancer.
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Base Pair Mismatch↗
The role of hypermethylation of the hMLH1 promoter region in HNPCC versus MSI+ sporadic colorectal cancers.
INTRODUCTION: Hypermethylation of the promoter region of the hMLH1 gene is associated with absent expression of MLH1 protein in sporadic colorectal cancers with microsatellite instability (MSI+), and it has been proposed that methylation may be a mechanism of inactivation in Knudson's hypothesis. The incidence of hypermethylation of the hMLH1 promoter in hereditary non-polyposis colorectal cancer (HNPCC) versus MSI+ sporadic colorectal cancer was investigated and compared. METHODS: DNA was available from 10 HNPCC colorectal cancers (median age 58 years, range 39-67) with germline mutations in hMLH1 and 10 MSI+ sporadic colorectal cancers (mean age 79 years, range 41-85). MSI was determined by amplification of BAT26 and TGF-beta RII. The methylation status of the hMLH1 promoter was studied by the polymerase chain reaction (PCR) based HpaII restriction enzyme assay technique. Evidence of allelic loss at hMLH1 was searched for in the HNPCC colorectal cancers. RESULTS: All cases were confirmed to be MSI+. The promoter region of hMLH1 was hypermethylated in seven of 10 MSI+ sporadic cancers versus 0 of 10 HNPCC cancers (p<0.002). Evidence of loss of heterozygosity at hMLH1 was observed in eight of the 10 HNPCC colorectal cancers. CONCLUSION: While mutations and allelic loss are responsible for the MSI+ phenotype in HNPCC cancers, the majority of MSI+ sporadic cancers are hypermethylated in the promoter region of hMLH1. These data further support our argument that tumours from HNPCC patients, which almost always acquire a raised mutation rate, mostly follow a different pathway from MSI+ sporadic tumours.
Aged↗
Mechanisms of inactivation of mismatch repair genes in human colorectal cancer cell lines: the predominant role of hMLH1.
Fifteen to twenty-five percent of sporadic colorectal carcinomas are replication error (RER) positive. Because the frequency of mutations in the mismatch repair genes (hMLH1 and hMSH2) is low in these tumors, we have investigated the role of mutational inactivation, methylation of the promoter region, and loss of heterozygosity (LOH) as a possible explanation for the mutator phenotype of RER+ colorectal cancer cell lines. Genomic DNA was extracted from a panel of 49 human colorectal cancer cell lines. The RER status was determined by amplification of BAT-26. All exons of hMLH1 and hMSH2 were amplified with the PCR and screened by using single-strand conformational polymorphism and direct sequencing. The methylation status was ascertained by methylation-specific PCR after bisulfite modification of DNA. Western blotting for hMLH1 was performed on methylated cell lines before and after the addition of the demethylating agent 5-azacytidine. LOH was sought by GENESCAN analysis of amplified CA repeat markers and indirectly by determining the number of homozygotes in the cell lines and human random controls. Twelve cell lines from ten tumors (24%) were RER+. Hypermethylation of the hMLH1 promoter occurred in five of ten (50%) RER+ tumors, whereas three of thirty-two (6%) RER tumors showed partial methylation. None of the fully methylated cell lines expressed hMLH1, although all reexpressed hMLH1 after treatment with 5-azacytidine. There was no LOH in the RER+ tumors in either hMLH1 or hMSH2. Our results suggest that mutations of hMLH1 together with hypermethylation of the promoter region, but not LOH, are the cause of the mutator phenotype in the majority (70%) of RER+ tumors.
Adaptor Proteins, Signal Transducing↗
Mutated epithelial cadherin is associated with increased tumorigenicity and loss of adhesion and of responsiveness to the motogenic trefoil factor 2 in colon carcinoma cells.
Epithelial (E)-cadherin and its associated cytoplasmic proteins (alpha-, beta-, and gamma-catenins) are important mediators of epithelial cell-cell adhesion and intracellular signaling. Much evidence exists suggesting a tumor/invasion suppressor role for E-cadherin, and loss of expression, as well as mutations, has been described in a number of epithelial cancers. To investigate whether E-cadherin gene (CDH1) mutations occur in colorectal cancer, we screened 49 human colon carcinoma cell lines from 43 patients by single-strand conformation polymorphism (SSCP) analysis and direct sequencing. In addition to silent changes, polymorphisms, and intronic variants in a number of the cell lines, we detected frameshift single-base deletions in repeat regions of exon 3 (codons 120 and 126) causing premature truncations at codon 216 in four replication-error-positive (RER+) cell lines (LS174T, HCT116, GP2d, and GP5d) derived from 3 patients. In LS174T such a mutation inevitably contributes to its lack of E-cadherin protein expression and function. Transfection of full-length E-cadherin cDNA into LS174T cells enhanced intercellular adhesion, induced differentiation, retarded proliferation, inhibited tumorigenicity, and restored responsiveness to the migratory effects induced by the motogenic trefoil factor 2 (human spasmolytic polypeptide). These results indicate that, although inactivating E-cadherin mutations occur relatively infrequently in colorectal cancer cell lines overall (3/43 = 7%), they are more common in cells with an RER+ phenotype (3/10 = 30%) and may contribute to the dysfunction of the E-cadherin-catenin-mediated adhesion/signaling system commonly seen in these tumors. These results also indicate that normal E-cadherin-mediated cell adhesion can restore the ability of colonic tumor cells to respond to trefoil factor 2.
Animals↗
"Cuffitis" and inflammatory changes in the columnar cuff, anal transitional zone, and ileal reservoir after stapled pouch-anal anastomosis.
PURPOSE: During the past eight to ten years most surgeons have adopted the double-stapled technique to accomplish the pouch-anal anastomosis in restorative proctocolectomy for ulcerative colitis. Little attention has been focused on the functional implications of retaining a segment of diseased columnar mucosa in the upper anal canal. The aim of this study was to investigate clinically significant inflammation in the columnar cuff. METHOD: In all, 113 patients were studied and 715 biopsies were performed during a 2.5-year period. Biopsy specimens were taken from two or three sites, including the columnar cuff, ileal pouch, and anal transitional zone. Acute and chronic inflammation was scored for biopsy specimens from all three sites and compared with endoscopic assessment and pouch function. RESULTS: In the columnar cuff acute histologic inflammation was found in 13 percent of patients, and in 9 percent this was symptomatic during follow-up and was accompanied by evidence of endoscopic inflammation. Most patients had mild inflammation in the cuff that persisted over time. Inflammation in the pouch, pouch frequency, and anastomotic height were not related to columnar cuff inflammation. CONCLUSIONS: Cuffitis is a cause of pouch dysfunction after a double-stapled restorative proctocolectomy. We propose a triad of diagnostic criteria, including symptoms and endoscopic and histologic inflammation.
Anal Canal↗
Effects of nifedipine on anorectal smooth muscle in vitro.
INTRODUCTION: Glyceryl trinitrate reduces anal resting pressure and aids the healing of anal fissures. However, some patients develop tachyphylaxis and the fissure fails to heal, suggesting that other agents are needed. This study assesses the effects of nifedipine (a calcium channel antagonist) in modulating resting tone and agonist-induced contractions in human internal anal sphincter (IAS) and rectal circular muscle. METHODS: Smooth muscle strips from the IAS and rectal circular muscle from ten patients undergoing surgical resection were mounted for isometric tension recording in a superfusion organ bath. The effects of noradrenaline and carbachol were assessed in the presence of various perfusates. RESULTS: LAS strips developed tone and spontaneous activity. Noradrenaline produced dose-dependent contractions. In calcium-free Krebs solution, tone and activity were abolished and no contractions were elicited in response to noradrenaline. Nifedipine also abolished tone and spontaneous activity, but contractions to noradrenaline were only slightly attenuated. In contrast, rectal smooth muscle strips developed spontaneous activity but no resting tone and contracted in response to carbachol. In calcium-free Krebs solution, the spontaneous activity and carbachol contractions were abolished. Addition of nifedipine to the perfusate abolished spontaneous activity and greatly reduced contractions. DISCUSSION: These data suggest that spontaneous activity and resting tone are dependent on extracellular calcium and flux across the cells. Agonist-induced contraction in the IAS is attributable mainly to the release of calcium from intracellular stores, whereas rectal circular smooth muscle depends principally on extracellular calcium entering the cell for contraction. The attenuation of contractions in both tissues and the abolition of resting tone in the IAS suggest that nifedipine may be useful in the management of patients with anorectal disorders.
Adult↗
Differences in contractile properties of anorectal smooth muscle and the effects of calcium channel blockade.
BACKGROUND: Pharmacological manipulation of the anal sphincter is hampered by a lack of specificity. This study aimed to determine differences in the role of intracellular and extracellular calcium in the development of tone and agonist-induced contractions between internal anal sphincter (IAS) and rectal circular muscle which might allow targeted manipulation. METHODS: Smooth muscle strips from the IAS and rectal circular muscle of 24 Large White pigs were mounted for isometric tension recording in a superfusion organ bath in the presence of different perfusates. RESULTS: IAS developed tone and spontaneous activity that were abolished by nifedipine, which also reduced contractions to noradrenaline to 72 per cent of control values. Rectal smooth muscle developed spontaneous activity but no tone. Nifedipine abolished the activity and reduced contractions to carbachol to 17 per cent of control. Contractile activity was abolished in both tissues in calcium-free solution. Transient exposure to a high calcium concentration reloaded the stores, and the ability of agonists to release stored calcium was tested after 3 min in calcium-free solution. In IAS, noradrenaline contraction was 76 per cent of control and in rectal circular muscle carbachol contraction was 57 per cent of control. Store loading was prevented by nifedipine in rectal smooth muscle but not IAS. Cyclopiazonic acid reduced store filling in both tissues. CONCLUSION: Agonist-induced contraction of IAS is largely due to release of stored calcium and L-type calcium channels are not needed for store filling. Rectal circular smooth muscle depends more on extracellular calcium and uses L-type calcium channels for agonist-induced contraction and store filling. These differences suggest that targeted manipulation may be possible in patients with anorectal disorders.
Adrenergic alpha-Antagonists↗
Preoperative radiotherapy for rectal cancer: implications for surgeons, pathologists and radiologists.
BACKGROUND: Over 10,000 new cases of rectal cancer are reported in the UK each year and adjuvant treatments, such as preoperative radiotherapy, are now being used almost routinely. METHODS: A literature review was performed on the Medline database for English language publications on preoperative radiotherapy and rectal cancer. The radioresponsiveness of rectal cancer, tumour downstaging, radiological staging of irradiated rectal cancer, effects of radiotherapy on anastomotic integrity, anorectal and genitourinary function, the role of preoperative radiotherapy in local excision of rectal cancer, and the histological changes peculiar to radiotherapy were evaluated. RESULTS AND CONCLUSION: Following preoperative radiotherapy, rectal cancer may be downstaged or, occasionally, eradicated histologically. Rectal cancer can now be staged accurately before operation, but this is significantly less reliable following irradiation. The pathological specimen must be examined thoroughly before a tumour can be reported to have been eradicated, especially as unique histological changes are produced by radiotherapy. There is no evidence to suggest that preoperative radiotherapy adversely affects anastomotic integrity. It appears that preoperative radiotherapy has some adverse affects on long-term anorectal dysfunction, but this must not distract from its main objectives in rectal cancer, namely reduced local recurrence rates and improved overall survival.
Colorectal Neoplasms↗
MRI scanning in perianal Crohn's disease: an important diagnostic adjunct.
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Crohn Disease↗
The incidence and Dukes' staging of colorectal cancer over 3 decades.
AIMS: Two previous studies (1966-1971 and 1979-1983) of patients with colorectal cancer (CRC) have been reported from our hospital. A large increase in the incidence of CRC was noted, and an improvement in Dukes' staging of tumours at treatment. We report a series of patients admitted with newly diagnosed CRC to evaluate this trend further. METHODS: A prospective study was made of all patients with newly diagnosed CRC admitted to the John Radcliffe Hospital, Oxford in 1995. Means of diagnosis and Dukes' staging were recorded. RESULTS: In 1 year 177 patients were admitted with newly diagnosed CRC. Previous studies had shown an increase from 52.8 to 103.4 patients per year. The number of patients diagnosed by colonoscopy doubled from 19.4% in 1979-1983 to 41% in 1995. No significant change in the proportion of patients with Dukes' A or B tumours was found. CONCLUSION: The number of patients treated annually with CRC in a stable population has more than trebled in the last 3 decades. A real increase in the incidence of CRC is likely as this rise cannot be explained solely by changing referral patterns or an ageing community. There are no significant changes in presentation patterns despite the availability of colonoscopy since 1975.
Aged↗
Early colorectal cancer: recognition, classification and treatment.
BACKGROUND: With the introduction of colorectal cancer screening and improvements in endoscopic technology, the recognition and management of early colorectal cancer assumes increasing importance. METHODS: A literature review was undertaken using Medline (National Library of Medicine, Washington DC, USA) searches of the headings early colonic, colorectal and rectal cancer, carcinoma and adenocarcinoma up to and including 1997. All relevant references were examined. RESULTS AND CONCLUSION: The diagnosis, classification and treatment options are described. Accurate diagnosis, preoperative and histopathological staging is crucial in the management of early colorectal cancer.
Colorectal Neoplasms↗
Management of faecal incontinence following obstetric injury.
BACKGROUND: Faecal incontinence is common in women and the major aetiological factor is childbirth. Increasing numbers of women with faecal incontinence are presenting to surgical clinics. METHODS: A literature review was performed on Medline database for English language publications an obstetric injury. The incidence, presentation, assessment and treatment of faecal incontinence following obstetric injury were evaluated. RESULTS AND CONCLUSIONS: Third-degree tear occurs in association with less than 1 per cent of vaginal deliveries, but occult sphincter injury occurs at one-third of deliveries and may be significant in later life. Incontinence may result from sphincter damage or nerve injury, or both. Risk factors for these injuries can be identified. Clinical evaluation, anorectal physiology and endoanal ultrasonography allow accurate planning of subsequent surgery. Overlapping anterior anal sphincter repair provides symptomatic control of continence in 80 per cent of patients. Repair of an acute anal sphincter injury after a third-degree tear is controversial and a defined policy should be agreed between obstetric and colorectal teams.
Anal Canal↗
What patients think of day-surgery proctology.
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Adolescent↗
A new look at the anal transitional zone with reference to restorative proctocolectomy and the columnar cuff.
BACKGROUND: The anal transitional zone (ATZ) is of interest in relation to anorectal function and its fate during the operation of restorative proctocolectomy. There are only a few studies describing the anatomy of this structure. This study applied new techniques to quantify the ATZ in normal and inflammatory bowel disease states. METHODS: The epithelial linings of 28 anal canals were analysed by two techniques: whole-mount Alcian blue staining and a new method of creating a computer map of the histological findings based on longitudinal sections taken every 3 mm. The Alcian blue pictures and the histology maps were measured and compared using image analysis software. RESULTS: The ATZ usually commences just above the dentate line, which is situated a median of 1.05 cm above the lower border of the internal sphincter. The median length of the ATZ measured from computer maps of the histology was 0.45 cm. This was significantly smaller than the 0.73 cm obtained by the Alcian blue technique, which overestimates the length of the ATZ. The amount of columnar epithelium in the ATZ is very small. The median lowest point of columnar epithelium in the anal canal was 1.1 cm above the lower border of the internal sphincter. CONCLUSION: The ATZ is only half the length described previously. After double-stapled restorative proctocolectomy there is a 1.5-2.0-cm cuff of diseased columnar epithelium remaining in the upper anal canal above the ATZ. This is suitably termed the 'columnar cuff' and is an important consideration in long-term follow-up.
Anal Canal↗