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Biomedical subjects

J H Scholefield

Publications and source records attributed to J H Scholefield.

At least 19 recordsLinked to original sources
PubMed2005

Malignant transformation of high-grade anal intraepithelial neoplasia.

BACKGROUND: The natural history of anal intraepithelial neoplasia (AIN) is uncertain. This makes management problematic as treatment options to eradicate the condition carry morbidity. The authors report their 10-year experience with conservative management of this condition, highlighting the lessons learnt. METHODS: All patients were diagnosed with high-grade AIN (AIN III) between 1994 and 2003. Diagnosis was by full-thickness biopsy and histopathological examination. Excision of localized lesions was undertaken, and all patients underwent follow-up every 6 months. Prospective data were collected regarding recurrence, postoperative complications and progression to invasive carcinoma. RESULTS: Thirty-five patients were followed for a median of 63 (range 14-120) months. Excision of localized high-grade AIN was carried out in 28 patients with minimal morbidity. Six patients were systemically immunosuppressed at diagnosis, all of whom had multifocal perianal lesions. Three immunosuppressed patients developed invasive anal squamous carcinoma during follow-up. By contrast, no invasive carcinomas were identified among immunocompetent patients with either localized or multifocal perianal disease. CONCLUSION: AIN III appears to have a relatively low potential for malignant transformation in the immunocompetent patient. However, immunosuppressed patients are more likely to have extensive AIN III and a greater risk of malignant change.

Adult↗
PubMed2005

Comparison of the effects of nitric oxide donors and calcium channel blockers on the intrinsic myogenic tone of sheep isolated internal anal sphincter.

BACKGROUND: Chronic anal fissure is associated with considerable pain and anal hypertonia. Numerous clinical studies attest to the effectiveness of individual nitro-containing drugs and organic calcium channel blockers in this condition but there are few comparative studies. METHODS: Isolated segments of sheep internal anal sphincter were prepared for isometric tension recording. The effect of various drugs on myogenic tone was examined in the absence or presence of sodium orthovanadate (SOV), an agent used to mimic anal hypertonia by increasing myogenic tone. RESULTS: All the drugs tested produced concentration-dependent inhibition of myogenic tone, with the maximum effect ranging from 66.4 per cent (verapamil) to 100 per cent (sodium nitroprusside). Sodium nitroprusside and diltiazem were the most potent, followed by glyceryl trinitrate (GTN), nifedipine and verapamil, which had similar potency, and finally nicorandil. The potency of GTN and diltiazem was reduced threefold in the presence of 1 mmol/l SOV. The combined effect of GTN and diltiazem was greater than the effect of either agent alone, even in the presence of 3 mmol/l SOV. CONCLUSION: Nitro-containing drugs and organic calcium channel blockers are potent inhibitors of anal sphincter myogenic tone that may be used in combination to treat chronic anal fissure.

Anal Canal↗
PubMed2005

Intra-anal and rectal application of L-erythro methoxamine gel increases anal resting pressure in healthy volunteers.

BACKGROUND: This study examined the effect of a single local application of L-erythro methoxamine, an alpha(1)-adrenoceptor agonist, on mean anal resting pressure (MARP) and cardiovascular variables in healthy volunteers. METHODS: L-Erythro methoxamine gel was administered in a single-blind manner; 0.3-3 per cent gels were applied perianally (n = 12), 1-3 per cent gels intra-anally (n = 16) and 1 per cent gel rectally (n = 8). MARP, systolic blood pressure, diastolic blood pressure and pulse rate were measured before application and for up to 6 h afterwards. Blood samples were taken to estimate plasma drug levels. RESULTS: Perianal gel produced no increase in MARP. Intra-anal 1 per cent and 3 per cent gel produced a significant rapid rise in MARP for 4 and 5 h respectively after application (P = 0.012 and P = 0.017 respectively). Rectal 1 per cent gel increased MARP for 2 h after application (P = 0.036). Intra-anal gel resulted in an increase in systolic blood pressure (1 per cent gel at 2 h, P = 0.042; 3 per cent gel at 4 h, P = 0.017). One per cent intra-anal and rectal gels caused a decrease in the pulse rate for 2 h after application (P = 0.012 and P = 0.018 respectively). Six subjects complained of nausea and three of headache after gel application. CONCLUSION: Intra-anal and rectal gel produced a sustained rise in MARP with rapid onset in volunteers. This raises the possibility of a therapeutic application for L-erythro methoxamine in patients with passive incontinence and internal anal sphincter dysfunction.

Administration, Rectal↗
PubMed2005

Radiation induced MMP expression from rectal cancer is short lived but contributes to in vitro invasion.

AIMS: Matrix metalloproteinase (MMP) activity is increased after radiation. The aims of this study were to assess the time course of this increase and its effects on malignant cell invasion. METHODS: Colorectal cancer (HCT 116, LoVo, C 170 HM 2, CaCO-2), fibroblast (46-BR.IGI, CCD-18 Co) and fibrosarcoma (HT1080) cell lines were irradiated at 4 gray (4 Gy) and matrix metalloproteinase gene and protein expression examined over a 96 h period by real time polymerase chain reaction and gelatin zymography. Invasion was assessed on Matrigel. Human rectal tumour MMP expression was compared before and after long course radiotherapy. RESULTS: Radiation increased MMP gene expression of tumour cell lines, and resulted in increased MMP protein activity in the HT1080 line. HT1080 and HCT 116 in monoculture and LoVo in co-culture were more invasive after radiation at 48 h in vitro, but long course radiotherapy did not result in a consistent increase in MMP expression from human rectal tumour biopsies. CONCLUSIONS: Radiation results in increased MMP expression for a limited time period. This results in an early increase in cell line invasion. Further clinical research is required to clarify if MMP inhibition given perioperatively following radiotherapy decreases local recurrence rates.

Adenocarcinoma↗
PubMed2004

Quality of life in patients with chronic anal fissure.

OBJECTIVE: Little is known about the quality of life in patients with the distressing symptoms of chronic anal fissure. This was a prospective study assessing the physical and mental health of fissure patients before and after topical treatment. PATIENTS AND METHODS: New patients attending the fissure clinic were recruited prospectively into the study over a 2-month period. On first appointment, patients were given 2 questionnaires to complete: the Short-Form 36 Health Survey (SF-36) and a general questionnaire recording patients' demographic details, previous treatment, site and duration of fissure and symptoms on a visual analogue scale (VAS). Following an 8-week course of topical treatment, patients repeated the SF-36 and symptoms were again recorded on a VAS. Healing of fissure was noted. RESULTS: Fifty-four patients entered the study, of which 39 returned for follow-up; 16 male, 23 female; mean age 38.6 years (range 17-80 years). Median duration of fissure was 6 months (3 months - 10 years). Higher VAS ratings for fissure pain were associated with worse scores for all aspects of health-related quality of life, including mental health (P < 0.001), bodily pain (P < 0.001), vitality (P < 0.006) and social functioning (P < 0.001). Compared to age and gender matched norms for the SF-36, fissure patients had more bodily pain (P < 0.001, Wilcoxon) and poorer health perceptions (P < 0.02, Wilcoxon). Gender did not affect any of the SF-36 subscales. However, females did report significantly more bleeding (P = 0.05). On follow-up, healing was complete in 27 patients (69%). Symptoms of pain, bleeding and irritation were all significantly reduced in this group. Repeating the SF-36 showed an improvement in bodily pain, role-physical functioning and vitality (P < 0.05). CONCLUSION: Successful nonsurgical treatment of chronic anal fissure leads to symptomatic improvement and beneficially affects health-related quality of life.

Adolescent↗
PubMed2003

Anal fissure: the changing management of a surgical condition.

BACKGROUND: Chronic anal fissure is a common benign disorder that causes severe, sharp anal pain during defaecation. Fissures are generally associated with raised resting anal pressures, and treatments are aimed at reduction of these pressures. Surgical sphincterotomy is very successful at healing fissures but is associated with significant morbidity. Much work has gone into the development of new pharmacological agents that can promote healing of chronic anal fissures by production of a reversible chemical sphincterotomy, with the aim of avoiding long-term problems of incontinence. METHODS: We review these recent innovations that have largely replaced surgery as first line treatment for chronic anal fissure. CONCLUSIONS: Despite there being initial success with many of these pharmacological agents in the treatment of patients with chronic anal fissures, there are still some concerns about their use. In particular, the occurrence of side effects limits their use, and, unfortunately, they are not always effective at healing fissures. However, despite these drawbacks they remain excellent first-line options in the treatment of chronic anal fissures, and surgery should be offered only to patients who fail these therapies.

Algorithms↗
PubMed2003

L-arginine-induced relaxation of the internal anal sphincter is not mediated by nitric oxide.

BACKGROUND: Topical application of L-arginine, the precursor of nitric oxide, reduces resting anal pressure without significant side-effects and may therefore be of benefit in the treatment of anal fissure. This in vitro study investigated the effect of L-arginine on sheep and human isolated internal anal sphincter (IAS) to ascertain the role played by nitric oxide and guanosine 3',5'-cyclic monophosphate. METHODS: Strips of sheep and human IAS were mounted in isolated organ baths. The effects on myogenic tone of increasing concentrations of L-arginine, D-arginine and other amino acids were evaluated. RESULTS: L-Arginine, D-arginine and other basic amino acids (L-lysine and L-ornithine) all caused a concentration-dependent reduction in myogenic tone. L-Arginine was the most effective and produced a mean(s.e.m.) maximal reduction in myogenic tone of 78.2(7.1) and 40.2(9.3) per cent in sheep and human tissue respectively. These responses were not affected by N(G)-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, or 1H-[1,2,4]oxadiazolo[4,3-a]-quinoxalin-1-one, an inhibitor of soluble guanylyl cyclase. Changes in pH per se were unable to explain the relaxation fully, but an equiosmolar sodium chloride solution produced a concentration-response relationship similar to that of L-arginine. CONCLUSION: The ability of L-arginine to reduce myogenic tone is independent of nitric oxide. This effect may be partially pH dependent but the osmolality of the solution appears to be a major factor. Hyperosmolar solutions might be worthy of further investigation as agents that affect anal tone.

Anal Canal↗
PubMed2003

Origin of symptoms in diverticular disease.

BACKGROUND: A significant number of patients with colonic diverticula experience unexplained, recurrent, short-lived but often debilitating abdominal pain and alteration in bowel habit. Such patients account for many medical consultations every year but, as our understanding of the cause of their symptoms remains imperfect, treatment options are limited. This article reviews the possible mechanisms that may be responsible for the symptoms of diverticular disease. METHODS: Medline and Science Citation Index searches were performed to locate English language articles relating to colonic diverticula and symptoms published between January 1966 and July 2002. Manual cross-referencing was also performed and some historical articles were included. RESULTS AND CONCLUSION: Several theories now exist about the mechanisms underlying the symptoms of diverticular disease. Initial studies suggested that they may be due to alterations in the intracolonic pressure, extrapolating earlier thoughts on the likely pathogenesis of diverticula. It seems more likely, however, that several inter-related processes, such as muscular dysfunction, visceral hypersensitivity and inflammation, are involved in symptom generation.

Abdominal Pain↗
PubMed2003

Colorectal cancer, screening and survival: the influence of socio-economic deprivation.

OBJECTIVES: To determine the extent to which socio-economic deprivation explains colorectal cancer prevalence, subject participation in screening, and postoperative survival and life expectancy. METHODS: Regression analyses of clinical data from a large randomized controlled trial, augmented by geographical-based indices of deprivation. RESULTS: Deprivation appears to exert no significant impact on colorectal cancer prevalence but is a major factor explaining subject participation in screening. Cancer detection at later stages reduces life expectancy at time of treatment. Females from more-deprived areas have poorer post-treatment life expectancies and survival prospects, independently of their screening behaviour. CONCLUSIONS: Screening increases the chances of having a cancer treated at an earlier stage, and treatment at an earlier stage is associated with longer subsequent life expectancy. However, those from more-deprived areas are less likely to accept an invitation to be screened.

Aged↗
PubMed2003

A dose finding study with 0.1%, 0.2%, and 0.4% glyceryl trinitrate ointment in patients with chronic anal fissures.

BACKGROUND: Anal fissure is a common painful condition affecting the anal canal. The majority of acute fissures heal spontaneously. However, some of these acute fissures do not resolve but become chronic. Chronic anal fissures were traditionally treated by anal dilation or by lateral sphincterotomy. However, both of these surgical treatments may cause a degree of incontinence in up to 30% of patients. Several recent trials have shown that nitric oxide donors such as glyceryl trinitrate (GTN) can reduce sphincter pressure and heal up to 70% of chronic fissures. AIM: This study addressed the dose-response to three different concentrations of GTN ointment compared with placebo in a double blind randomised controlled trial. METHOD: A double blind, multicentre, randomised controlled trial was set up to compare placebo ointment against three active treatment arms (0.1%, 0.2%, and 0.4% GTN ointment applied at a dose of 220 mg twice daily) in chronic anal fissures. The primary end point was complete healing of the fissure. RESULTS: Two hundred patients were recruited over an eight month period from 18 centres. After eight weeks of treatment the healing rate in the placebo group was 37.5% compared with 46.9% for 0.1%, 40.4% for 0.2%, and 54.1% for 0.4% GTN. None was significantly better than the placebo response. A secondary analysis excluded fissures without secondary criteria for chronicity. Healing rates were then found to be 24% in the placebo group compared with 50% in the 0.1% GTN group, 36% in the 0.2% group, and 57% in the 0.4% GTN group. These values were statistically significantly different for the placebo group compared with 0.1% GTN, 0.4% GTN, and for the GTN treated group as a whole. CONCLUSIONS: The results of this study have demonstrated the significant benefit of topical GTN when applied to patients suffering from chronic anal fissures but acute fissures showed a tendency to resolve spontaneously. The high proportion of fissures which healed in the placebo group suggests that the definition of "chronicity" needs to be reassessed. Further studies are required to confirm the optimal therapeutic strategy.

Adult↗
PubMed2003

Finding the best from the rest: evaluation of the quality of patient information on the Internet.

INTRODUCTION: Information is of utmost importance for patients at risk of developing cancer who require regular screening. Quality assessment is vital to ensure correct information is published on the Internet. METHOD: A postal questionnaire was sent to patients under follow-up for Barrett's oesophagus and colonic polyps. Questions related to computer/Internet access, where patients had previously sought information, whether web-sites would be of use, and what information they would like displayed. A review of on-line patient literature for Barrett's oesophagus and colorectal adenomas was performed. RESULTS: Of the 200 questionnaires sent, 161 patients responded (80.1%). The majority of patients (88%, n = 141) wanted more information on their condition, with 45% (73) having home Internet access and a further 32% (52) having web access from other sources. Only 8% (12) had used the Internet as a source of information; however, the majority of patients (57%) would access a recommended web-site. The Barrett's search resulted in 10/200 sites with full information (i.e. score > 8/10 points). For colorectal polyps there were 12/200 sites. CONCLUSIONS: Accessing quality Internet health information is very time consuming. Recommended web-sites that provide the best information would help patients avoid being overwhelmed with irrelevant and confusing literature.

Barrett Esophagus↗
PubMed2002

Topical L-arginine gel lowers resting anal pressure: possible treatment for anal fissure.

PURPOSE: Exogenous nitric oxide donors, such as glyceryl trinitrate, have been used as treatment for anal fissures; however, headaches develop in 60 percent of patients. Nitric oxide produced from the cellular metabolism of L-arginine mediates relaxation of the internal anal sphincter. This study investigated whether topical L-arginine gel reduces maximum anal resting pressure in volunteers. METHOD: In a two-center study, volunteers received a single topical dose of L-arginine or placebo (Aquagel ). Anal manometry was performed for two hours after application of 400 mg of L-arginine gel or placebo gel to the anal verge in 25 volunteers. Side effects were recorded after single application and also after repeated dosing for three days. RESULTS: L-Arginine reduced maximum anal resting pressure by 46 percent from a median of 65 cm of water to a minimal value of 35 cm of water ( P< 0.001, Wilcoxon's signed-rank test). The difference between L-arginine and placebo using repeated-measures testing was significant at P< 0.005. No side effects occurred with either gel; in particular, no episodes of headache were recorded. CONCLUSION: Topical L-arginine gel significantly lowers maximum anal resting pressure; its onset of action is rapid, and duration is at least two hours ( P< 0.01). L-arginine may have therapeutic potential, but further evaluation is needed before it can be used as a possible alternative treatment for chronic anal fissure.

Administration, Topical↗
PubMed2002

Effect of preoperative radiotherapy on matrilysin gene expression in rectal cancer.

Matrilysin, a member of matrix metalloproteinase family, is believed to play a significant role in the growth and proliferation of colon cancer cells. Overexpression of the matrilysin gene has been shown to correlate with Dukes' stage and increased metastatic potential in colorectal cancer. The aim of this study was to evaluate the effect of preoperative high-dose radiotherapy (25 Gy in five fractions over 5 days) on matrilysin (MMP-7) gene expression, in patients with resectable rectal cancer, by a quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Biopsy samples of tumour (n=30) and distant normal mucosa (n=12) from 15 patients were obtained pre- and post-radiotherapy. Messenger (m)RNA was extracted from all of the tissue samples and reverse transcribed to double-stranded cDNA. Quantitative RT-PCR was performed to study the effect of preoperative radiotherapy on matrilysin gene expression in both the tumour and normal mucosal specimens. Matrilysin mRNA values were expressed relative to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) for each sample. In 14 out of 15 cases, matrilysin mRNA was detected in the cancerous tissue. Although all six normal mucosal specimens expressed matrilysin mRNA, the levels were approximately 10-fold lower compared with those seen in the paired tumour samples. Preoperative radiotherapy led to a significant 6- to 7-fold increase (P=0.001) in the expression of matrilysin mRNA in rectal cancer tissue. In contrast, there was no significant change in the matrilysin mRNA expression of normal mucosal specimens post-radiotherapy. Preoperative high-dose radiotherapy upregulates matrilysin gene expression in rectal cancer. Matrilysin inhibition may be a useful preventive or therapeutic adjunct to radiotherapy in rectal cancer.

Adenocarcinoma↗
PubMed2002

Pathogenesis of colonic diverticula.

BACKGROUND: Diverticula are herniations through the colonic wall and are therefore likely to be due to a weakness within the wall, an alteration in intracolonic pressures or a combination of these factors. This article reviews these aspects in relation to the pathogenesis of colonic diverticula. METHODS: Medline and Science Citation Index searches were performed to locate English language articles relating to the pathogenesis of colonic diverticulosis published since 1960. Manual cross-referencing was also performed and some historical articles were included. RESULTS AND CONCLUSION: Several theories now exist about the development of colonic diverticula. The majority of the evidence suggests that the morphological changes are the response to a lifelong consumption of a low-residue diet. However, there are complex relations between colonic structure, motility and dietary factors, and it is likely that all of these (and possibly genetic influences) play a role in the pathogenesis to a greater or lesser degree.

Age Factors↗
PubMed2002

The role of topical diltiazem in the treatment of chronic anal fissures that have failed glyceryl trinitrate therapy.

OBJECTIVE: The treatment of anal fissures has evolved over the last 5 years with the development of topical treatments aimed at reducing sphincter hypertonia. This is thought to improve anal mucosal blood flow and promote healing of the fissure. This study reports the use of topical diltiazem in patients with chronic anal fissures that have failed previous treatment with topical 0.2% glyceryl trinitrate (GTN). PATIENTS AND METHODS: Forty-seven patients with chronic anal fissure who had previously failed at least one course of topical GTN were recruited prospectively from a single centre. Patients were instructed to apply 2 cm (approximately 0.7 g) of 2% diltiazem cream to the anal verge twice daily for eight weeks. Symptoms of pain, bleeding and itching were recorded on a linear analogue score prior to starting the cream and then repeated at 2 weekly intervals. Patients were asked to report side-effects throughout the study period. Healing of the fissure was assessed after 8 weeks of treatment. RESULTS: Forty-six patients completed treatment; of these, 22 had healed fissures (48%). Ten of the 24 patients with persistent fissures were symptomatically improved and wished no further treatment. Of the 14 patients who remained symptomatic, one was given a repeat course of 0.2% glyceryl trinitrate with subsequent healing of the fissure, 10 were recruited into an ongoing study involving injections of botulinum toxin into the internal anal sphincter and three were referred for surgery. CONCLUSION: This study shows that topical 2% diltiazem is an effective and safe treatment for chronic anal fissure in patients who have failed topical 0.2% GTN. The need for sphincterotomy can be avoided in up to 70% of cases.

Journal Article↗