Haplotype analysis of BRCA2 8765delAG mutation carriers in French Canadian and Yemenite Jewish hereditary breast cancer families.

The BRCA2 8765delAG mutation was previously reported in hereditary breast cancer families of French Canadian and Yemenite Jewish descent. Haplotype analysis, using six microsatellite markers that span BRCA2 and two intragenic polymorphisms, was performed on 8765delAG mutation carriers to determine if there was evidence that the mutations were identical by descent. The alleles of the microsatellite markers most closely flanking BRCA2 (D13S1697 and D13S1701) were found to be identical in state in all the mutation carriers. However, the disease-associated allele of one of the intragenic markers differed between the Yemenite Jews and French Canadian families, indicating that the 8765delAG mutation has independent origins in these two geographically and ethnically distinct populations.

Do all patients in primary care who may benefit from eradication of Helicobacter pylori have access to effective care?

The purpose of this study was to identify those patients who would benefit from eradication therapy for Helicobacter pylori and to understand the scale of service changes needed to implement eradication therapy. All general practices in Bradford Health Authority were invited to take part in the study. Patients who had received more than one repeat prescription for proton pump inhibitors or H(2) receptor antagonists in the previous twelve months were identified using the repeat prescription systems in the participating practices. Their case notes were examined and the relevant data items extracted by a trained project worker. Forty-four out of 100 practices agreed to take part and they accounted for a population of 262 647 people. Of that population, 2.3% (6037) of patients were on long-term acid suppressing treatment. Seventy-nine percent (n=4784) of patients on long-term acid suppression had a diagnosis recorded in the records; 17% (n=1028) had duodenal ulcer; 5% (n=278) gastric ulcer and the rest, 58% (n=3478), consisted of patients labelled as dyspepsia, heartburn, gastritis, and non-ulcer dyspepsia. Only 131 (10%) of those patients with peptic ulcer had been prescribed eradication therapy. Endoscopy and barium meal examinations had been used to confirm the diagnosis in 2715 patients. In the remaining patients there was no information in the case notes to suggest whether the diagnosis had been confirmed by investigations.A substantial proportion of patients previously diagnosed as having peptic ulcer have not been offered eradication therapy demonstrating a delay in getting research evidence into practice. To ensure all patients within a health district who may benefit from eradication therapy, do benefit, a systematic approach including access to additional investigative facilities is required.

Expression of FHIT in primary cultures of human epithelial ovarian tumors and malignant ovarian ascites.

Abnormal FHIT gene expression has been reported in a variety of epithelial tumors shown to harbor deletions of chromosome 3p14, the chromosomal assignment of this gene. Recently, we described loss of heterozygosity of 3p in a subset of epithelial ovarian cancers. To investigate a potential role of the FHIT gene in ovarian cancer, we examined primary cell cultures derived from normal ovarian surface epithelium, ovarian tumors, and the cellular fraction of malignant ascites to determine the expression of FHIT by using reverse transcription-polymerase chain reaction. Included in this analysis were four spontaneously immortalized cell lines: three derived from malignant epithelial ovarian tumors (TOV21G, TOV112D, and TOV81D) and one from malignant ovarian ascites (OV90). OV90 was previously shown to harbor a deletion of the whole p arm of chromosome 3. The FHIT transcript was not detectable in two of 11 primary cultures derived from normal ovarian surface epithelium or in a primary culture derived from malignant ovarian ascites, whereas the remaining samples (34 malignant, eight borderline, and three benign specimens), exhibited identical expression patterns. In each case, this pattern was consistent with the co-expression of a normal FHIT transcript and a smaller transcript. DNA sequencing revealed that the abnormal-sized message lacked exons 4-7 (inclusive), which were deleted at their exact intron-exon splice sites. The aberrant-sized transcript was detectable by Northern blot analysis. There was no concordance between FHIT expression and loss of heterozygosity at the FHIT locus. Northern blot analysis also revealed that FHIT was differentially expressed, and the spontaneously immortalized cell lines TOV21G and TOV112D showed the highest level of expression. Because the same reverse transcription-polymerase chain reaction expression pattern was observed in both normal and tumor-derived primary cell cultures, these results argue against a significant role for FHIT in epithelial ovarian tumorigenesis.

Evidence for atrophy and apoptosis in the ventral prostate of rats given the 5 alpha-reductase inhibitor finasteride.

Castration causes cell loss in the rat ventral prostate through a process called apoptosis. Although 5 alpha-reductase inhibition also causes prostate cell loss, the mechanisms involved have been debated. To investigate this question further, we have evaluated the histological responses of the rat ventral prostate to both castration and 5 alpha-reductase inhibition. Rats were left intact, castrated, or given the selective 5 alpha-reductase inhibitor finasteride. After 4, 9, 14, and 21 days the prostates were excised, the androgen and DNA content determined, and the tissue was subjected to histological and histomorphometric analysis. Finasteride and castration decreased prostate weight at day 21 by 65% and 93%, respectively. Castration decreased DNA content (micrograms per prostate) by a maximum of 88% at 14 days. Finasteride had no significant effect on DNA content after 4 days and decreased DNA content by a maximum of 52% at 14 days. When castrate prostate sections were stained for tissue transglutaminase, a marker of apoptotic cell death, a maximum of 23% of epithelial cells were stained by day 14 with a return to control levels by day 21. Finasteride caused a less intense increase in staining in which 16% of epithelial cells stained for tissue transglutaminase on day 9 with a return to baseline by day 14. When prostate sections were stained for DNA breaks, another marker of cell death, castration, caused a peak of staining on day 4 with 6% of epithelial cells staining and a return to near control levels by day 21. Finasteride-induced staining was less intense with peak staining at day 4 (0.7% of epithelial cells) and a return to control values by day 9. Morphometrics were used to assess the effect of castration and finasteride on prostate duct size and epithelial cell mass. After 4 days of finasteride treatment, the mean ductal mass decreased by 47%, with no significant change thereafter. The mean epithelial cell mass decreased by 15% on day 4 and 60% on day 9, with no further decrease thereafter. Castration caused a more rapid and greater decrease in both morphometric parameters with a 95% reduction in the mass of prostate ducts and a 93% decrease in epithelial cell mass by day 9. We conclude that castration induces a more profound involution of the rat ventral prostate than does 5 alpha-reductase inhibition. Cell loss occurs in both groups, but the degree of cell loss is less with finasteride.(ABSTRACT TRUNCATED AT 400 WORDS)

Aldehyde disinfectants and health in endoscopy units. British Society of Gastroenterology Endoscopy Committee.

Summary of main recommendations(1) Glutaraldehyde, used in most endoscopy units in the United Kingdom for the disinfection of flexible gastrointestinal endoscopes, is a toxic substance being an irritant and a sensitiser; symptoms associated with glutaraldehyde exposure are common among staff working in endoscopy units.(2) The Control of Substances Hazardous to Health Regulations 1988 (COSHH) obliges the employer to make a systematic assessment of risk to staff of exposure to glutaraldehyde and institute measures to deal effectively with exposure.(3) At present glutaraldehyde remains the first line agent for the disinfection of flexible gastrointestinal endoscopes. Other agents are being developed; a standard means of assessment for flexible endoscope disinfectants should be devised.(4) Equipment and accessories that are heat stable should be sterilised by autoclaving; disposable accessories should be used wherever possible.(5) Flexible gastrointestinal endoscopes should be disinfected within automated washer/disinfectors; trays, bowls or buckets for this purpose are unacceptable.(6) Local exhaust ventilation must be used to control glutaraldehyde vapour. Extracted air may be discharged direct to the atmosphere or passed over special absorbent filters and recirculated. Such control measures must be regularly tested and records retained.(7) Endoscope cleaning and disinfection should be carried out in a room dedicated to the purpose, equipped with control measures to maintain the concentration of glutaraldehyde vapour at a level certainly below the current occupational exposure standard of 0.2 ppm and preferably below the commonly used working limit of 0.1 ppm. Sites other than the endoscopy unit where endoscopy is regularly performed, such as the radiology department, should have their own fully equipped cleaning and disinfection room.(8) COSHH limits the use of personal protective equipment to those situations where other measures cannot adequately control exposure. Such equipment includes nitrile rubber gloves, apron, chemical grade eye protection, and respiratory protective equipment for organic vapours.(9) Monitoring of atmospheric levels of glutaraldehyde should be performed by a competent person such as an occupational hygienist; the currently preferred method of sampling uses a filtration technique, the commercially available meters being less reliable.(10) Health surveillance of staff is mandatory; occupational health records must be retained for 30 years.(11) Endoscopy staff must be informed of the risks of exposure to glutaraldehyde and trained in safe methods of its control. Only staff who have completed such an education and training programme should be allowed to disinfect endoscopes.(12) The unsafe use of glutaraldehyde has significant health and legal consequences; the safe use of glutaraldehyde may have revenue consequences that contribute significantly to the cost of gastrointestinal endoscopy.

Differential effect of 5 alpha-reductase inhibition and castration on androgen-regulated gene expression in rat prostate.

Castration reduces prostate size and causes intraprostatic testosterone (T) and dihydrotestosterone (DHT) to fall to very low levels. 5 alpha-Reductase inhibition also reduces prostate size, but results in a marked increase in intraprostatic T levels. To compare the effects of 5 alpha-reductase inhibition and castration on prostate physiology, male Sprague-Dawley rats were left intact, castrated, or given the selective 5 alpha-reductase inhibitor finasteride for up to 9 days. To be sure that finasteride itself did not directly affect gene expression, an additional group of rats was castrated and given finasteride for 4 days. The prostates were weighed, intraprostatic RNA, DNA, and androgen levels were measured, and mRNAs for two androgen-regulated genes, prostate steroid-binding protein (PSBP; an androgen-induced gene) and testosterone-repressed prostate message (TRPM-2), were quantitated by Northern and slot blot analyses. Finasteride caused a 95% reduction in intraprostatic DHT levels and a 10-fold increase in intraprostatic T levels. Finasteride, as expected, caused a pronounced decrease in prostate weight (45% on day 4). DNA content fell correspondingly (48% on day 4). Intraprostatic DNA (micrograms of DNA per gland) on day 4 was 328 +/- 53 in control rats, 171 +/- 10 in finasteride-treated rats (P less than 0.001 compared to controls), 115 +/- 2 in castrated rats (P less than 0.05 compared to finasteride), and 107 +/- 43 in finasteride-treated plus castrated rats (P = NS compared to castration alone). There were no significant differences in DNA levels among the groups when expressed per mg prostate tissue, indicating that mean prostate cell size was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral bowel lavage preparation for colonoscopy.

Colonoscopy is a commonly performed diagnostic and therapeutic procedure in most general hospitals, which requires effective bowel preparation to be worthwhile. We report the effect of replacing a diet, laxative and bowel washout preparation with oral bowel lavage using a balanced electrolyte formulation, in our unit. The preparation was acceptable to patients, medical and nursing staff, generally preferred to previous preparations by those who had experienced them, allowed a more complete colonoscopy with an excellent quality of view, and was less expensive in nursing time. We regard oral bowel lavage as currently the method of choice for bowel preparation prior to colonoscopy in the majority of patients.

Iopamidol as contrast medium in endoscopic retrograde pancreatography: a prospective randomised comparison with diatrizoate.

In a prospective double-blind comparison of contrast media for retrograde pancreatography, 85 consecutive patients undergoing endoscopic retrograde cholangio-pancreatography (ERCP) were randomised to receive either the non-ionic medium, iopamidol (Niopam) or the ionic medium, meglumine diatrizoate (Urografin). The quality of pancreatograms obtained was assessed "blindly" using a specially devised scoring system, and patients were observed for clinical and biochemical evidence of acute pancreatitis following ERCP. Pancreatogram scores were similar in the "Niopam" and "Urografin" groups. No patients developed clinical evidence of acute pancreatitis. Eighteen hours after ERCP median increments in serum amylase and lipase in the "Niopam" group were significantly lower and hyperamylasemia and hyperlipasemia significantly less frequent than in the "Urografin" group. Niopam may be a safer contrast medium than Urografin for retrograde pancreatography, particularly in patients in whom the risk of acute pancreatitis is high. However, in view of its relatively high cost, further direct clinical evidence of reduced toxicity is required before Niopam can be recommended for routine use at ERCP.

Screening by colonoscopy for colonic epithelial dysplasia in inflammatory bowel disease.

We report the results of a prospective study of screening for colorectal epithelial dysplasia by regular colonoscopy in patients with longstanding, extensive colitis (DET group: 112 patients, 366 colonoscopies) together with the findings in all other patients with colitis who have undergone colonoscopy in our unit (non-DET group: 77 patients, 196 colonoscopies). Thirty six DET patients had dysplasia on at least one examination: two patients with high grade dysplasia (HGD) were colonoscoped on suspicion of carcinoma, one asymptomatic patient had HGD at first colonoscopy and one patient had HGD on his sixth colonoscopy, all having carcinomas resected at surgery; the remainder had low grade dysplasia (LGD). Of the DET patients, 100 constituted an ongoing surveillance group (354 colonoscopies) in which LGD was common, being seen on at least one occasion in 33% of patients (16.4% of examinations), but HGD was noted only once with a Dukes A cancer found at surgery. Six non-DET patients had dysplasia diagnosed, this being LGD in all. Even in a carefully selected group of colitics the incidence of HGD is low, but its detection may enable the removal of a colorectal carcinoma at an early and curable stage.

Adverse reactions to sulphasalazine and 5-amino salicylic acid in the same patient.

We report a patient who developed sulphasalazine-related hepatitis with a subsequent adverse reaction to rectal 5-amino salicylic acid, in the form of pain and fever without associated liver dysfunction, suggesting reactions to both components of sulphasalazine. Included is a review of the literature. Caution should be observed when prescribing 5-amino salicylic acid to sulphasalazine-intolerant patients.

Endoscopic retrograde cholangio-pancreatography in pancreatitis with persistent or recurrent pain.

We have reviewed the endoscopic retrograde cholangiopancreatograms (ERCPs) of 115 patients already known to have pancreatitis, who were referred because of persistent or recurrent pain, in order to determine the prevalence of those lesions that have been regarded as amenable to conservative surgery. Such lesions were seen on the pancreatograms of 35 patients and on the cholangiograms of 29 patients. In all, 53 patients (46.1%) had 'treatable' lesions demonstrated at ERCP. Preoperative ERCP is helpful in demonstrating operable features in both pancreatic and biliary systems, and should be part of any prospective long-term study of pain relief in pancreatitis.

Analysis of patients referred to the gastroenterology service of a VA medical center.

We recorded clinical information over a 12-month period on consecutive consultations to the gastroenterology service of the Durham VA Medical Center. Of 902 consultations, 789 were prospectively collected. Eighty-five percent of the patients were between 40 and 70 years old. Seventy-five percent of the referrals were from the internal medicine service. The most frequent reasons for consultation were abdominal pain (19%), GI bleeding (active, 16%; occult, 9%), abnormal results of liver tests (18%), and request for a procedure (11%). Diseases of the liver (32%) and "peptic diseases" (30%) were the most common diagnoses. One or more procedures were done in 71% of consultations. When these data are compared with those of a practicing gastroenterologist, using an identical instrument, it is apparent that trainees' experience with structurally identifiable gastroenterologic disease and with a variety of procedures was similar in scope. There were, however, differences in that the physicians at the VA saw substantially fewer patients with so-called "functional" illness. If these data are applicable to other VA Medical Centers, then the training of physicians in gastroenterology at a VA Medical Center should probably be broadened.

Analysis of patients referred to a gastroenterologist practicing in a community hospital.

A questionnaire was designed to provide information on consecutive patient referrals over a 12-mo period to a consultant in gastroenterology practicing in a community hospital serving approximately 100,000 people. Data were entered into a computer for ease of storage and analysis. One thousand two hundred seventy-six consultations were seen in 1188 patients. Ages ranged from 1 to 97 yr; most were in the 5th to 7th decade. The majority of consultations were from 11 general internists (66.2%); fewer consultations were from 7 general surgeons (16.0%), 8 general practitioners (10.3%), and 6 pediatricians (2.7%). The most frequent reasons for patient referral were abdominal pain (27.8%), consideration of a procedure (23.7%), and an x-ray abnormality (16.6%). The gastroenterologist performed 1217 procedures as part of 1026 consultations; the most frequently performed was upper gastrointestinal endoscopy (60.1%). The gastroenterologist made 1604 diagnoses in his subspecialty; diagnoses relating to the esophagus were made at 276 consultations, the stomach at 317, the duodenum at 204, the small bowel at 26, the colon-rectum at 321, the liver/biliary tree at 184, and the pancreas at 66. The major objective of this investigation was realized by the prospective collection of the experience of a practicing gastroenterologist. This data collection was accomplished without apparent omissions or encumbrance on the practice routine. These data provide a perspective on the role of a practicing consultant gastroenterologist and appear relevant to considerations of the training of gastroenterologists.

Towards positive diagnosis of the irritable bowel.

A questionnaire to establish the presence of 15 symptoms thought to be typical of the irritable bowel syndrome (IBS) was given to 109 unselected patients referred to gastroenterology or surgery clinics with abdominal pain or a change in bowel habit or both. Review of case records 17--26 months later established a definite diagnosis of IBS in 32 patients and of organic disease in 33. Four symptoms were significantly more common among patients with IBS--namely, distension, relief of pain with bowel movement, and looser and more frequent bowel movements with the onset of pain. Mucus and a sensation of incomplete evacuation were also common in these patients. The more of these symptoms that were present the more likely was it that the patient's pain or altered bowel habit, or both, was due to IBS. We conclude that a careful history can increase diagnostic confidence and reduce the amount of investigation in many patients with chronic abdominal pain.

Colonscopy for investigation of unexplained rectal bleeding.

215 colonsocopic examinations were performed on patients with rectal bleeding whose cause had not been determined by barium enema. The probable or definite source of the bleeding was diagnosed in 41% of cases. 13% had a carcinoma, 14% had one or more colonic polyps, 7% had previously unrecognised inflammatory bowel disease. The remainder had various other colonic conditions. The source of bleeding was twice as likely to be found by colonoscopy in patients presenting with frank rectal blood-loss as in those with occult blood. A carcinoma was found twice as often in those patients with diverticular disease as in those without this condition. A lesion was discovered in the majority of patients who had had two or more negative barium enemas. These results emphasise the importance of rectal bleeding as a symptom of colonic abnormality and the value of colonscopy in its investigation in patients where the results of radiology are negative.

Variability of colonic function in healthy subjects.

Twenty healthy subjects eating normal diets made repeated five-day stool collections, the 10 females making their collections in four to six successive weeks. In most subjects there were striking variations in transit time, measured by Hinton's method. The variability of average faecal wet and dry weight, faecal volume, and the frequency of defaecation was equally great, suggesting that the transit time variations were genuine. The size of individual stools varied even more, often tenfold or more. Faecal water content was relatively constant. There were no significant differences between males and females, and in the females there were no obvious changes related to the phases of the menstrual cycle. The normal variability of colonic function should be taken into account in planning experiments and in interpreting existing data.

Wheat fibre and irritable bowel syndrome. A controlled trial.

Twenty-six patients with irritable bowel syndrome entered a controlled trial of diets with a high or low wheat-fibre content. After 6 weeks on the high-wheat fibre regimen there was significant improvement in symptoms and an objective change in colonic motor activity. No such improvement occurred on the low-fibre regimen. Patients with irritable bowel syndrome should be encouraged to increase their daily intake of wheat fibre.

Preparation of the large bowel for endoscopy.

After the use of a number of varied purgation regimens for precolonoscopy preparation of the bowel and use of X-Prep liquid for the purgation phase in 500 patients with a very high success rate and low side-effects, we have found that this preparation provides the best results, both for the patient and the endoscopist.