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Biomedical subjects

D C Gotley

Publications and source records attributed to D C Gotley.

At least 19 recordsLinked to original sources
PubMed1998

Expression of antisense CD44 variant 6 inhibits colorectal tumor metastasis and tumor growth in a wound environment.

Up-regulation of CD44 variant isoforms has been linked to the progression of epithelial tumors and the metastatic phenotype. Here we report a functional role for CD44 variant isoforms in colorectal cancer metastasis. An antisense mRNA approach was used to down-regulate CD44 variant isoforms containing CD44 variant 6 (v6) in the metastatic colorectal tumor cell line HT29. Cell lines stably expressing antisense CD44 exon 10 (v6) showed reduced expression of alternatively spliced CD44 variant isoforms but no significant change in expression of CD44 core protein, as judged by immunohistochemical analysis using CD44 domain-specific monoclonal antibodies. Expression of antisense exon 10 (v6) had no effect on HT29 tumor cell proliferation in vitro or the ability of the cells to bind immobilized hyaluronan, but it resulted in a reduced capacity to form liver metastases in nude mice following intrasplenic injection. Metastases were not detected in nude mice inoculated with antisense CD44 exon 10 (v6)-expressing cell lines after 4 months, against a background of a 30% metastasis rate in the control HT29 parental and vector alone transfected lines. Furthermore, whereas 82% of mice intrasplenically injected with control HT29 parental and vector alone cell lines developed tumors in incisional wound sites, none of the mice injected with antisense exon 10 expressing HT29 cells developed similar tumors. This is the first demonstration that antisense RNA can be used to selectively inhibit expression of specific domains of a molecule generated through alternative mRNA splicing while allowing expression of core domains to remain unaffected. Furthermore, these results provide direct evidence for a functional role of CD44 variant isoforms in the metastasis of human colorectal tumor cells and may suggest a critical role for CD44 variants in promoting cell growth specifically in the cytokine/growth factor-enriched environment of a wound site.

Adenocarcinoma↗
PubMed1998

Captopril inhibits tumour growth in a xenograft model of human renal cell carcinoma.

The effect of captopril on tumour growth was examined in a xenograft model of human renal cell carcinoma (RCC). Inoculation of the human RCC cell line SN12K-1 (10(6) cells) under the left kidney capsule of severe combined immunodeficient (SCID) mice resulted in the growth of large tumours, with an increase in weight of the inoculated kidney of 3.69+/-1.63-fold (mean+/-s.d.) when compared with the contralateral normal kidney. In mice treated with captopril (19 mg kg(-1) day(-1) or 94 mg kg(-1) day(-1) administered in the drinking water), there was a significant dose-related reduction in tumour development; the tumour bearing kidneys weighed 1.9+/-0.42 and 1.55+/-0.42 times the normal kidneys, respectively (P< 0.05 compared with untreated animals). In vitro, captopril at clinically achievable doses (0.1-10 microM) had no significant effect on the incorporation of [3H]thymidine into SN12K-1 cells. Thus, this highly significant attenuation by captopril of in vivo tumour growth does not appear to be due to a direct effect on the proliferation of the tumour cells. Further studies are required to determine the mechanism of inhibition of tumour growth by captopril, in particular to evaluate the role of angiotensin II in this process.

Analysis of Variance↗
PubMed1998

Down-regulation of the down-regulated in adenoma (DRA) gene correlates with colon tumor progression.

The down-regulated in adenoma (DRA) gene was originally identified as a gene that was down-regulated in colon tumors. It encodes a protein with anion transporter function that is expressed predominantly in the mucosa of the lower gastrointestinal tract. In this study, expression of DRA and its cellular distribution have been investigated in a series of benign adenomatous polyps and malignant colorectal tumors and in corresponding normal colonic mucosa. We show that DRA mRNA and protein are expressed in all normal colonic tissue specimens with the protein restricted primarily to the terminally differentiated columnar epithelium and some goblet cells. Apical membrane localization was especially apparent in the columnar epithelium. The levels of DRA mRNA transcripts were down-regulated in all colon tumors examined relative to matched normal mucosa, with most specimens showing undetectable levels of DRA mRNA (77 of 104 tumors). DRA down-regulation was positively associated with colonic tumor progression according to Dukes' stage and was particularly significant in the early transition from normal mucosa to polyp to adenocarcinoma. DRA expression does not appear to be strictly associated with colonic cell differentiation; rather, its absence and down-regulation were associated with the proliferating component of the crypt epithelium and with neoplastic transformation, respectively.

Adenoma↗
PubMed1997

Evidence that "myofibroblast-like" cells are the cellular source of capsular collagen in hepatocellular carcinoma.

BACKGROUND/AIMS: The prognosis for patients with hepatocellular carcinoma is poor although tumour encapsulation has been associated with improved survival and disease-free rates. While the source of the tumour capsule is unclear, the major role that activated hepatic stellate cells play in the deposition of liver matrix in normal and diseased states suggests the possible involvement of these cells in tumour encapsulation. METHODS: Twenty-four liver tumours (seven encapsulated HCC, seven non-encapsulated HCC, 10 colorectal metastases) were studied. Activated hepatic stellate cells were identified by immunohistochemistry for alpha-smooth muscle actin (alpha-SMA) and in situ hybridization for pro-collagen alpha1 (I) mRNA. Collagen deposition was localized using Masson's trichrome stain. RESULTS: Pro-collagen alpha1 (I) mRNA co-localized to alpha-SMA positive hepatic stellate cells within the region of increased collagen deposition in (i) the tumour capsule of encapsulated HCC, and (ii) the tumour junction of non-encapsulated HCC and colorectal metastasis. In addition, there was marked peritumour expression of alpha-SMA and procollagen alpha1 (I) mRNA, which diminished with distance away from the tumour in all tumour groups. The degree of expression was greatest with encapsulated HCC, less with non-encapsulated HCC and least with colorectal metastasis. This contrasted with the absence of alpha-SMA expression in normal liver from the same patients. Within the tumours, colorectal metastases differed from HCC by demonstrating marked alpha-SMA expression and collagen deposition in the septa. CONCLUSIONS: Our findings demonstrate that activated hepatic stellate cells (i) are responsible for increased peritumour collagen production in non-encapsulated HCC and colorectal metastasis, and (ii) may be implicated in tumour capsule formation in HCC and metastasis stroma development. Thus, stellate cells may influence the local hepatic invasion by these tumours.

Adult↗
PubMed1997

Diffuse oesophageal spasm: diagnosis by ambulatory 24 hour manometry.

BACKGROUND: Diffuse oesophageal spasm (DOS) is a potential cause of intermittent chest pain and/or dysphagia. In the past, the diagnosis of DOS has relied on criteria obtained from standard oesophageal manometry (more than one simultaneous contraction in a series of 10 wet swallows with the rest being peristaltic). As symptoms are intermittent, however, 24 hour manometry may well be more suited to its investigation. AIMS: To determine the ability of 24 hour manometry to detect the symptomatic contractions of DOS and to compare standard, laboratory based manometry with 24 hour manometry in its diagnosis. PATIENTS: Three hundred and ninety consecutive patients referred with suspected oesophageal disorders. METHODS: Standard laboratory based manometry and 24 hour outpatient manometry. RESULTS: Sixteen patients were classified by 24 hour manometry as having DOS on the basis of painful contractions (spasms) of excessive duration and increased amplitude. Laboratory based manometry failed to detect the majority of these patients with DOS (14/16), and 53/55 were incorrectly labelled as having DOS on the basis of asymptomatic manometric findings. CONCLUSION: The detection of symptomatic DOS requires 24 hour manometry.

Adult↗
PubMed1996

The deleted in colon cancer (DCC) gene is consistently expressed in colorectal cancers and metastases.

The DCC (deleted in colorectal cancer) gene was originally identified as a candidate tumour suppressor gene in colon carcinogenesis on the basis of allelic losses in chromosome 18q.21 in 70% of colon cancers. Reverse transcriptase polymerase chain reaction (RT-PCR) of DCC mRNA suggests that DCC expression may also be reduced in colon cancers. We have used monoclonal antibodies generated against the DCC immunoglobulin-like domain to investigate DCC isoforms and DCC protein expression during colon cancer progression. Normal mucosa and colonic tumour specimens representative of the range of colonic tumour progression from benign adenomatous polyps to metastases were compared by Western blot analyses. We show that while M(r) 194 000 DCC is present in normal colonic mucosa and adenomatous polyps, it is also similarly expressed in colorectal carcinomas and colonic metastases in the liver. The presence of DCC protein is consistent with the presence of DCC mRNA transcripts in the same tissue specimens. Notably DCC was not completely lost in any colonic tumour specimens examined, even those that had progressed to metastatic cancers. Quantitation of DCC protein expression in tissue specimens by densitometry demonstrated that both normal and malignant specimens exhibit a wide range of DCC protein levels and there was no significant correlation between diminished DCC protein expression and colon cancer progression. These results demonstrate the pattern of expression of the DCC gene product in colonic tumour progression and show that absence of DCC expression is not associated with colonic tumour progression.

Base Sequence↗
PubMed1996

Alternatively spliced variants of the cell adhesion molecule CD44 and tumour progression in colorectal cancer.

Increased expression of alternatively spliced variants of the CD44 family of cell adhesion molecules has been associated with tumour metastasis. In the present study, expression of alternatively spliced variants of CD44 and their cellular distribution have been investigated in human colonic tumours and in the corresponding normal mucosa, in addition to benign adenomatous polyps. The expression of CD44 alternatively spliced variants has been correlated with tumour progression according to Dukes' histological stage. CD44 variant expression was determined by immunohistochemisty using monoclonal antibodies directed against specific CD44 variant domains together with RT-PCR analysis of CD44 variant mRNA expression in the same tissue specimens. We demonstrate that as well as being expressed in colonic tumour cells, the full range of CD44 variants, CD44v2-v10, are widely expressed in normal colonic crypt epithelium, predominantly in the crypt base. CD44v6, the epitope which is most commonly associated with tumour progression and metastasis, was not only expressed by many benign colonic tumours, but was expressed as frequently in normal basal crypt epithelium as in malignant colonic tumour cells, and surprisingly, was even absent from some metastatic colorectal tumours. Expression of none of the CD44 variant epitopes was found to be positively correlated with tumour progression or with colorectal tumour metastasis to the liver, results which are inconsistent with a role for CD44 variants as indicators of colonic cancer progression.

Alternative Splicing↗
PubMed1996

Laparoscopic Nissen fundoplication--200 consecutive cases.

PATIENTS: Laparoscopic Nissen fundoplication was undertaken in 200 patients between 1991 and 1994. METHODS: Pre-operative assessment included symptom score, endoscopy, manometry, and 24 hour pH monitoring of the oesophagus. Patients were evaluated at three and 12 months after surgery with symptom scoring and 96 patients also underwent 24 hour pH studies at three to six months postoperatively. RESULTS: In the first 100 patients median duration of operation was 155 minutes (range: 70-330), conversion rate to laparotomy was 7%, median hospital stay was three days (range: 2-57), and total morbidity was 16%. This compared with a median operation time of 120 minutes (60-240) (p = 0.0003, 95% CI 10, 40), a conversion rate of 2% (p = 0.2), a hospital stay of three days (1-18) (p = 0.0016, 95% CI 0, 1), and total morbidity of 7% (p = 0.15) in the second 100 patients. Median total symptom scores fell from 5/9 to 0/9 after fundoplication (< 0.0001) while median 24 hour oesophageal acid exposure in 96 patients was reduced from 10% to 1% (p < 0.001). CONCLUSIONS: Laparoscopic Nissen fundoplication is a safe and effective procedure for gastro-oesophageal reflux disease. With experience, the duration of operation falls and the hospital stay is shorter. Shortterm symptomatic and pH results are consistently improved by surgery.

Adolescent↗
PubMed1996

Laparoscopic Nissen fundoplication and postoperative dysphagia-can it be predicted?

Temporary swallowing difficulty has been reported in up to 100% of patients after laparoscopic Nissen fundoplication for gastro-oesophageal reflux, but the long-term prevalence of dysphagia is not known. If reliable predictors of persistent postoperative dysphagia exist, their identification may permit tailoring of the fundoplication for specific cases at risk. Of 475 consecutive cases of laparoscopic fundoplication, 202 have undergone detailed symptom scoring at 1 year postoperatively. In each case, a short, 360 degrees loose wrap was constructed over an intra-oesophageal bougie, and short gastric vessels were divided when insufficient fundal mobility was encountered. At one year postoperatively, 24% complained of grade 1 dysphagia (intermittent sensation of food sticking), 9% of grade 2 (food sticking requiring liquids to clear) and 1 patient had regular dysphagia for solids (grade 3). Gender, preoperative complaint of dysphagia, endoscopic grade of oesophagitis, oesophageal motility, lower oesophageal sphincter pressure, and division of short gastric vessels were reviewed in relation to dysphagia. Dysphagia is common after laparoscopic Nissen fundoplication, but is less prevalent than before operation. It is usually mild, intermittent and improves with time. Those with division of short gastric vessels had a reduced risk of postoperative dysphagia.

Adolescent↗
PubMed1995

Oesophageal acid clearance in patients with severe reflux oesophagitis.

Previous studies examining oesophageal acid clearance have employed a variety of techniques to induce or simulate acid reflux. Clearance abnormalities have been deduced from abnormal standard motility studies, barium radiology or from 24-h pH recordings. In this study a 24-h pH and oesophageal motility recording system was used to study naturally occurring acid reflux episodes in control subjects and in two groups of patients with severe acid reflux disease (erosive oesophagitis and oesophageal stricture). Acid clearance was compared between the subject groups. Patients with oesophageal stricture were found to have poor oesophageal peristaltic ability and particularly poor oesophageal acid clearance. Those with erosive oesophagitis had normal peristaltic swallowing but abnormal acid clearance. This study has characterized, for the first time, the abnormalities in acid clearance during naturally occurring acid reflux episodes in patients with severe reflux disease. A more complete understanding of these clearance abnormalities could influence future medical and surgical strategies in the management of severe gastro-oesophageal reflux disease.

Adult↗
PubMed1995

Precipitating causes of acid reflux episodes in ambulant patients with gastro-oesophageal reflux disease.

Previous studies of the mechanisms that precipitate acid reflux episodes have used short term hospital based measurements. A 24 hour pH and motility recording system, incorporating a sphincter monitoring device, has been developed to study naturally occurring acid reflux episodes in control subjects and patient groups with different grades of oesophagitis. Lower oesophageal sphincter relaxations related to episodes of acid reflux were common in control subjects (67% of episodes) but became more difficult to detect as the grade of oesophagitis increased (grade 0/1 - 67%, grade 2/3 - 35%, grade 4 - 13%). A variety of events that produced recognisable transdiaphragmatic pressure patterns were associated with acid reflux episodes. In control subjects 74% of acid reflux episodes were precipitated by belching but this mechanism became less evident as the grade of oesophagitis increased (grade 0/1 - 43%, grade 2/3 - 40%, grade 4 - 29%). Activities that produced a pressure gradient across the diaphragm became increasingly important as events precipitating acid reflux as oesophagitis became more severe (controls--2%, grade 0/1 - 15%, grade 2/3 - 11%, grade 4 - 22%). This study has shown the pressure events surrounding acid reflux in fully ambulant patients with gastro-oesophageal reflux disease.

Adult↗
PubMed1993

Pressure events surrounding oesophageal acid reflux episodes and acid clearance in ambulant healthy volunteers.

Previous studies of the mechanisms that precipitate acid reflux episodes and acid clearance have used unphysiological, short term hospital based data. A new 24 hour pH and motility recording system combined with computerised data analysis have been used to study naturally occurring acid reflux episodes in healthy ambulant volunteers. A variety of events that produced recognisable transdiaphragmatic pressure patterns were associated with acid reflux episodes (particularly belching). Peristaltic waves were the predominant contractions leading to oesophageal acid clearance and were the commonest contraction type during reflux episodes. Peristaltic wave parameters (amplitude, velocity, frequency, and percentage proportion) varied during different periods of the 24 hour recording. This study has produced new information about 24 hour oesophageal function and naturally occurring acid reflux which will provide a basis for comparison with patients with gastro-oesophageal reflux disease.

Adolescent↗
PubMed1992

Ambulatory measurement of oesophageal function: clinical use of a new pH and motility recording system.

Conventional oesophageal manometric studies are open to criticism in that they take place on fasted immobile subjects in the artificial setting of a motility laboratory. A new 24-h pH and motility recording system combined with computerized data analysis was used to study patients with gastro-oesophageal reflux disease and oesophageal motor abnormalities under ambulant conditions. Acid reflux episodes were found to be precipitated by a variety of events with recognizable pressure patterns. Acid clearance abnormalities were demonstrated in patients with erosive oesophagitis but were confined to those with abnormal oesophageal motor function. Improved diagnostic accuracy was demonstrated in the recognition of oesophageal motor disorders.

Circadian Rhythm↗
PubMed1992

Bile acids and trypsin are unimportant in alkaline esophageal reflux.

We recorded esophageal alkaline exposure time (AET) in 52 patients with gastroesophageal reflux and in 20 control subjects to determine whether esophageal pH monitoring can measure reflux of bile acids and trypsin from the duodenum. Patients underwent a further 16-h study (divided into 2-h periods) in which AET was correlated with bile acid and trypsin concentrations in esophageal aspirates. Patients had greater nocturnal AET than controls (22.7 versus 0.9%, p = 0.005). Patients with a stricture had a greater AET than patients with erosive esophagitis (25.2 versus 13%, p less than 0.05). There was no relationship between esophageal bile acid concentrations and AET, and total bile acid concentrations were similar regardless of whether a 2-h period contained alkaline episodes. Esophageal bile acid concentrations were no different, in patients with a normal esophagus, esophagitis, stricture, or Barrett's esophagus. Trypsin was found in only 5% of aspirates, and could not be predicted by AET. We conclude that measurement of AET is not useful in the clinical evaluation of duodeno-esophageal bile reflux, and bile acids and trypsin are not important in the pathogenesis of reflux esophagitis.

Adult↗
PubMed1992

Bile acids do not modify the effects of pepsin on the fine structure of human oesophageal epithelium.

Oesophageal mucosal specimens (n = 250) were taken from 25 normal subjects (14 females, 11 males; median age 52 years; range 19-63 years) and incubated in physiological saline, pepsin and bile acid solutions to determine whether conjugated bile acids modify the epithelial cytotoxic action of pepsin. Short (5 min) and long (22 min) incubations were carried out and the results were assessed by transmission electron microscopy. Six different parameters of epithelial damage were scored (0-4) by a single 'blinded' pathologist for each of four epithelial layers. The scores after incubation in saline (pH 7 and titrated to pH 2 with HCl) were not different from those of the controls (P = 0.35). Both pepsin and bile acids (pH 2) caused more damage than saline at pH 2 (P less than 0.001) which was similar for the two substances (P = 0.136). Conjugated bile acids in combination with pepsin (pH 2) did not alter the overall extent or pattern of damage caused by pepsin alone (pH 2); P = 0.142). Conjugated bile acids, in concentrations commonly encountered during gastro-oesophageal reflux, did not appear to modify the cytopathic effects of pepsin on oesophageal mucosal cells in vitro. Conjugated bile acids may not be important in the pathogenesis of oesophagitis in patients with acid/peptic gastro-oesophageal reflux.

Adult↗
PubMed1992

Evaluation and surgical correction of esophagitis after partial gastrectomy.

Among 51 patients with refractory symptomatic reflux esophagitis seen during an 18-month period, 8 (16%) had undergone previous partial gastrectomy. Either Billroth II (n = 6) or Billroth I (n = 2) resection had been carried out for peptic ulceration 18 months to 30 years beforehand. Each patients was evaluated by symptom scoring, endoscopy, and 24-hour pH monitoring plus a 16-hour esophageal aspiration study, in which 2-hourly aliquots were measured for acid, pepsin, conjugated and unconjugated bile acids, and trypsin. After conversion to a 45 cm Roux-en-Y gastroenterostomy, symptom scoring and endoscopy were repeated at 6 to 12 months in all eight patients. Pepsin, acid, and unconjugated bile acids were seldom present in esophageal aspirates. Conjugated bile acids in concentrations up to 30 mmol/L and trypsin up to 428 micrograms/ml were found in cases of severe esophagitis, mostly during nocturnal rest. Esophagitis, heartburn, regurgitation, and bilious vomiting were eradicated by Roux-en-Y conversion, but other postgastrectomy symptoms (early satiety, dumping, epigastric pain, and diarrhea) were largely unchanged. Postgastrectomy esophagitis resistant to medical therapy seems likely to be caused by nocturnal exposure to trypsin and conjugated bile acids; it is well controlled by a 45 cm Roux-en-Y conversion.

Aged↗
PubMed1991

The sphinctometer: a new device for measurement of lower oesophageal sphincter function.

Current evidence suggests that lower oesophageal sphincter (LOS) competence depends upon both pressure and length. Existing devices can measure length and pressure, but not simultaneously. This methodological problem is a fundamental drawback to understanding LOS function and its role in oesophageal disease. A 'sphinctometer' has been developed, consisting of an oil-filled 3-mm diameter Silastic chamber, 6 cm in length, incorporating a pressure microtransducer designed to provide an integrated pressure reading as a function of length. Its performance has been tested in vitro using human cadaver oesophagus in a specially constructed chamber in which sphincter length and pressure can be varied independently. Comparisons were made with a conventional pull-through technique. Sphinctometer response was linear throughout the LOS pressure range of 0 to 50 mmHg at a fixed LOS length (RS = 0.99; P less than 0.001). Sphinctometer response was also linear at fixed LOS pressure for sphincter lengths from 1 to 6 cm (RS = 0.99; P less than 0.001). This device thus appeared suitable for monitoring function of the human LOS, and has subsequently been successfully incorporated into an ambulatory system for patient use.

Biometry↗