Immunohistochemistry for CDX2 expression in non-goblet-cell Barrett's oesophagus.

Interest has increased in CDX2 gene expression in oesophageal non-goblet-cell columnar metaplasia as recent investigations indicate such metaplasia possesses neoplastic potential. This study aims to assess expression of the transcription factor CDX2 specifically in non-goblet-cell cardia and fundic oesophageal metaplastic tissue, and to compare the location of CDX2 expression in non-goblet-cell specimens to that in goblet-cell specimens. A total of 43 patient specimens (20 fundic-type metaplasia, 42 cardia-type metaplasia and 18 intestinal metaplasia goblet cell-positive) were examined in this study. These were selected over six months from a patient database using the systematised nomenclature of human and veterinary medicine coding system (SNOMED). CDX2 was detected in patient specimens with an anti-CDX2 mouse monoclonal antibody. The types of mucosa in each specimen were confirmed by haematoxylin and eosin (H&E) staining. Fundic specimens were consistently CDX2-negative (0%). CDX2 expression was distinct in 55% of cardia and 100% of intestinal cases. Nearly all cardia-positive cases displayed focal expression (95.5%) and all intestinal cases displayed diffuse distribution of expression. Almost all cardia- and intestinal-positive specimens demonstrated epithelial expression (95.5% and 100%, respectively). The percentage of cardia-positive specimens with deep tissue expression was lower than in intestinal specimens (31.8% vs. 94.4%, respectively). This study confirms CDX2 as an early marker for Barrett's oesophagus in the absence of goblet cells as expression was noted in cardia metaplasia. CDX2 appears to induce the transformation of the normal oesophageal mucosa to cardia type, which then differentiates to an intestinal type under the influence of gastro-oesophageal reflux disease.

Absorption, distribution, metabolism and excretion of an inhalation dose of [14C] 4,4'-methylenediphenyl diisocyanate in the male rat.

The received dose, tissue distribution, metabolism, routes and rates of excretion of [(14)C]-4, 4(')-methylenediphenyl diisocyanate (MDI) were investigated in the male rat following a 6-h inhalation exposure to [(14)C]-MDI at a target concentration of 2 mg m(-3). The mean dose received was equivalent to 0.078 mg MDI per animal, of this between 25 and 32% of radiolabelled material was available systemically. Radioactivity was distributed to all tissues examined with the highest proportions present in the respiratory and gastrointestinal tracts, suggesting that both oral ingestion and pulmonary absorption contributed to the systemic dose of [(14)C]-MDI derived material, with the oral ingestion and the majority of the internal dose resulting from ingestion of radiolabelled material by grooming the pelt after exposure. Radioactivity was excreted mainly via faeces (about 80% of the received dose). Excretion in bile and urine each accounted for less than 15% of the dose. MDI was extensively metabolized after uptake, with two routes of transformation evident; the proposed spontaneous formation of mixed molecular weight polyureas and the enzyme catalysed metabolism of systemically available MDI or MDI derivatives to give N-acetylated and N-acetylated hydroxylated products. No free MDA was detected in any of the biomatrices (urine, faeces, bile) investigated.

Metabolism of methyl-(E)-2-[2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate (azoxystrobin) in rat.

1. The metabolic fate of [(14)C]-methyl-(E)-2-[2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate (azoxystrobin) was determined in the male and female rat following a single oral dose of 1 and 100 mg x kg(-1) and in surgically prepared, bile duct-cannulated rats following a single oral dose of 100 mg x kg(-1). 2. Azoxystrobin was extensively metabolized with at least 15 metabolites. There was a sex difference, with females producing more metabolites than males. 3. The two principal metabolic pathways were hydrolysis of the methoxyacid followed by glucuronic acid conjugation and glutathione conjugation of the cyanophenyl ring followed by further metabolism leading to the mercapturic acid. There were also several other minor pathways.

Metabolism of 2-(4-methylsulphonyl-2-nitrobenzoyl)-1,3-cyclohexanedione (mesotrione) in rat and mouse.

1. The metabolic fate of [14C]-2-(4-methylsulphonyl-2-nitrobenzoyl)-1,3-cyclohexanedione (mesotrione) has been determined in the male and female rat and mouse following a single oral dose of either 1 or 100 mg kg(-1), in rat given 14 consecutive oral doses of 1 mg kg(-1), and in the surgically prepared, bile duct-cannulated rat following a single oral dose of 50 mg kg(-1). The excretion of a single i.v,. dose of 1 mg kg(-1) in the male and female rat was also investigated. 2. Mesotrione was extensively absorbed and rapidly excreted via urine in both rat and mouse. The absorbed dose was not well metabolized in either species. Unabsorbed material was subject to metabolic action by the gut microflora. 3. The major metabolic pathway was hydroxylation of the aromatic ring. There was evidence for cleavage of the dione and aromatic rings followed by reduction of the nitro group in the gastrointestinal tract. 4. There were no species differences in the metabolism and excretion of mesotrione, which could explain the species differences in toxicity reported for this class of compounds.

Responsibility attitudes and interpretations are characteristic of obsessive compulsive disorder.

The cognitive-behavioural theory of Obsessive Compulsive Disorder (OCD) proposes that a key factor influencing obsessional behaviour is the way in which the intrusive cognitions are interpreted. The present paper reports an investigation of links between clinical symptoms (of anxiety, depression and obsessionality) and responsibility beliefs. These beliefs include not only measures of general responsibility attitudes (assumptions) but also more specific responsibility appraisals consequent on intrusive cognitions. The characteristics of two new questionnaires specifically designed to measure these beliefs were assessed in patients suffering from Obsessive Compulsive Disorder, in patients suffering from other anxiety disorders and in non-clinical controls. The scales measuring negative beliefs about responsibility were found to have good reliability and internal consistency. Comparisons between criterion groups indicate considerable specificity for both assumptions and appraisals with respect to OCD. There was also good evidence of specificity in the association between responsibility cognitions and obsessional symptoms across groups, and that this association was not a consequence of links with anxiety or depressive symptoms. Although the two measures were correlated, they each made unique contributions to the prediction of obsessional symptoms. Overall, the results are consistent with the hypothesis that responsibility beliefs are important in the experience of obsessional problems.

Randomised controlled trial of intensive cognitive behaviour therapy for patients with chronic schizophrenia.

OBJECTIVES: To investigate whether intensive cognitive behaviour therapy results in significant improvement in positive psychotic symptoms in patients with chronic schizophrenia. DESIGN: Patients with chronic schizophrenia were randomly allocated, stratified according to severity of symptoms and sex, to intensive cognitive behaviour therapy and routine care, supportive counselling and routine care, and routine care alone. SETTING: Adjunct treatments were carried out in outpatient clinics or in the patient's home. SUBJECTS: 87 patients with persistent positive symptoms who complied with medication; 72 completed treatment. OUTCOME MEASURES: Assessments of positive psychotic symptoms before treatment and 3 months after treatment. Number of patients who showed a 50% or more improvement in symptoms. Exacerbation of symptoms and rates of readmission to hospital. RESULTS: Significant improvements were found in the severity (F=5.42, df =2,86; P=0.006) and number (F=4.99, df=2,86; P=0.009) of positive symptoms in those treated with cognitive behaviour therapy. The supportive counselling group showed a non-significant improvement. Significantly more patients treated with cognitive behaviour therapy showed an improvement of 50% or more in their symptoms (chi2=5.18, df=1; P=0.02). Logistic regression indicated that receipt of cognitive behaviour therapy results in almost eight times greater odds (odds ratio 7.88) of showing this improvement. The group receiving routine care alone also experienced more exacerbations and days spent in hospital. CONCLUSIONS: Cognitive behaviour therapy is a potentially useful adjunct treatment in the management of patients with chronic schizophrenia.

Crohn's-like reaction in diverticular disease.

BACKGROUND: Diverticulitis and Crohn's disease affecting the colon occur at similar sites in older individuals, and in combination are said to carry a worse prognosis than either disease in isolation. It is possible that diverticulitis may initiate inflammatory changes which resemble Crohn's disease histologically, but do not carry the clinical implications of chronic inflammatory bowel disease. AIMS: To evaluate histological features and clinical outcome in individuals initially diagnosed histologically as having both Crohn's colitis and diverticulitis. PATIENTS: Eleven consecutive individuals having a colonic resection showing histological features of both Crohn's disease and diverticulitis. METHODS: Retrospective review of histological specimens, case notes, and discharge letters. RESULTS: In nine patients, the Crohn's-like reaction was confined to the segment bearing diverticula. They had no clinical evidence of Crohn's disease. CONCLUSION: A Crohn's-like inflammatory response can be a localised reaction to diverticulitis and does not necessarily indicate chronic inflammatory bowel disease.

Sputum cytology: a limited role.

AIMS: To determine the cost and sensitivity of sputum cytology in routine use and to determine when sputum cytology is most appropriate. METHODS: A retrospective study, based on all sputum cytology requests received in five histopathology/cytopathology laboratories in Yorkshire from 1 January to 31 December 1993. Cytology findings were correlated with histological diagnosis or clinical outcome, and related to the speciality of the referring clinician. RESULTS: Laboratory practice and performance was similar in all five centres. The average laboratory cost of sputum cytology was 26.93. The mean absolute sensitivity was 36% and the specificity was 99.6%. The majority of specimens was submitted by general physicians or geriatricians. The largest proportion of positive specimens were submitted by chest physicians. CONCLUSIONS: Often sputum cytology is used inappropriately as a screening investigation on, or soon after, admission. In addition, it is used inappropriately before bronchoscopy. Sputum cytology should be limited to individuals in whom a histological diagnosis is desired, but in whom bronchoscopy is inappropriate or unsuccessful.

Effects of neutralizing on intrusive thoughts: an experiment investigating the etiology of obsessive-compulsive disorder.

A large sample of non-clinical subjects were screened and those who reported experiencing relatively frequent intrusive thoughts with associated neutralizing were selected. These subjects were randomly allocated to one of two conditions: both groups listened to repeated recorded presentations of one of their intrusive thoughts and were then required either to (a) neutralize it, or (b) distract themselves for a similar period. Ratings of discomfort were taken during this procedure (first phase), and during identical presentations of the same thought without neutralizing or distracting (second phase). Results showed that the group who neutralized during the first phase experienced significantly more discomfort during the second phase and significantly stronger urges to neutralize and distract. There was also evidence that engaging in neutralizing responses during the first phase made it difficult to stop neutralizing during the second phase. The results are considered in the context of the cognitive-behavioural hypothesis that obsessional disorders develop as a consequence of neutralizing normal intrusive thoughts.

Lymphocytic gastritis and associated small bowel disease: a diffuse lymphocytic gastroenteropathy?

AIM: To investigate the natural history of lymphocytic gastritis (LG) and its relation to Helicobacter pylori infection and to coeliac disease using serology, duodenal biopsy and a small intestinal permeability test. METHOD: Twenty two patients diagnosed as having LG between 1984 and 1994 were investigated by upper gastrointestinal endoscopy at which gastric and duodenal biopsy specimens were taken for histological assessment and immunohistology. Serum was collected for measurement of anti-H pylori, anti-gliadin and anti-endomysial antibodies. A lactulose/mannitol absorption test was performed within one week of endoscopy. Control groups were studied by histology, serology and permeability tests. RESULTS: Three patients had been recently diagnosed as having LG while 15 still had the condition after a mean of 13.9 (range two to 38) months. LG involved the antrum alone in three patients, antrum and body in seven, body alone in six, and gastric remnant in two. Gastroduodenal intraepithelial lymphocytes (IELs) were T cells and predominantly of T suppressor (CD8) type. Duodenal IELs were increased compared to age/sex matched controls with chronic gastritis. Four patients had duodenal villous atrophy. Four patients no longer had LG after a mean of 29.3 (10-70) months but had increased gastroduodenal IELs. H pylori was present in four (22%) of 18 patients with LG but H pylori serology was positive in 11 (61%) of 18. There was no difference in seropositivity when compared with age/sex matched controls with dyspepsia. Eleven of 20 patients with LG tested had abnormal lactulose/mannitol absorption (v none of 22 controls with chronic gastritis). Four patients with LG, all with villous atrophy, were seropositive for IgA endomysial antibody. CONCLUSIONS: The persistence of LG with time, the association with increased duodenal IELs and abnormal small intestinal permeability suggests LG may be a manifestation of a diffuse lymphocytic gastroenteropathy related to sensitivity to gluten or some other agent.

An investigation of the relationship between the hepatotoxicity and the metabolism of N-alkylformamides.

The hepatotoxicity and metabolism of the following close analogs of the hepatotoxic antitumor agent N-methylformamide (NMF) were investigated in CBA/CA mice: N-ethylformamide (NEF), dimethylformamide (DMF), formamide and N-methylacetamide (NMA). Apart from NMF only NEF was potently hepatotoxic as measured by the elevation of plasma activities of the enzymes sorbitol dehydrogenase and alanine and aspartate aminotransferases 24 hr after drug administration. In freeze-dried urine samples of mice which had received NEF or NMF, but not in the case of DMF, formamide or NMA, thioesters were detected by thin-layer chromatography. Evidence based on high-pressure liquid chromatography analysis and 400 MHz 1H-NMR and mass spectrometry suggests that the thioester metabolite of NEF is S-(N-ethylcarbamoyl)-N-acetylcysteine. It has been shown previously that NMF is metabolized to S-(N-methylcarbamoyl)-N-acetylcysteine. NEF also underwent extensive metabolism to ethylamine; similarly NMF was biotransformed to methylamine. In contrast, the urine of mice which had received DMF contained only very small amounts of dimethylamine and methylamine could not be detected as a metabolite of NMA. Instead, the major metabolite of NMA was identified by 400 MHz 1H-NMR spectrometry as N-(hydroxymethyl)acetamide. DMF is known to undergo extensive metabolism to its N-hydroxymethyl derivative. The results suggest that two metabolic pathways of N-alkylformamides can be distinguished: Hydroxylation at the alpha-carbon of the N-alkyl group and oxidation of the formyl moiety. The former pathway presumably constitutes a detoxification route, and the latter may well be associated with hepatotoxicity, and affords a glutathione conjugate, excreted in the urine as a mercapturate.

Necrotizing sarcoid granulomatosis.

We report a patient with necrotizing sarcoid granulomatosis (NSG) and point out that while the latter may have certain histological and radiological features distinct from sarcoidosis, sophisticated immunological tests show that the two disorders have essentially similar underlying immune mechanisms. We also stress that although the clinical course of NSG has been repeatedly described as benign and responsive to steroid therapy, the young patient may initially be critically ill with symptoms suggestive of an infective process rather than a granulomatous cause.

Variation in the argyrophil cell population of the rectum in ulcerative colitis and adenocarcinoma.

Longstanding ulcerative colitis predisposes to carcinoma of the colon. Argyrophil cell hyperplasia has been observed in association with dysplasia and neoplasia in ulcerative colitis. As the argyrophil cell population includes those cells producing enterglucagon, a hormone thought to stimulate mucosal proliferation, this study was designed to determine whether there was any consistent variation in the argyrophil cell population in longstanding ulcerative colitis. Argyrophil cells were demonstrated by the Grimelius method of silver impregnation in sections of non-tumour bearing mucosa from the rectosigmoid colon of normal bowel, ulcerative colitis with and without tumour, and mucosa adjacent to, and distant from, carcinoma arising in otherwise normal bowel. Cell numbers were expressed as ratios of argyrophil cells per crypt, per mm of epithelium, and per mm of underlying muscularis mucosae. There was marked individual variation within all groups in all parameters. Between groups, the only significant difference was an increase in argyrophil cells per crypt in ulcerative colitis. The significance of this finding is discussed.

Enteroendocrine cell hyperplasia, carcinoid tumours and adenocarcinoma in long-standing ulcerative colitis.

Chronic ulcerative colitis may be accompanied by a variety of epithelial changes, including loss of goblet cells, Paneth cell metaplasia, villous metaplasia, and dysplasia. Total colitis is also accompanied by an increased incidence of adenocarcinoma. All these changes are assumed to be secondary to repeated mucosal damage, but how they develop is unknown. Little attention has been paid to the enteroendocrine cell population, despite the postulated role of these cells as producers of trophic hormones. We describe two patients with long-standing ulcerative colitis who developed both adenocarcinoma and carcinoid tumours. In both, there were increased numbers of enteroendocrine cells in the uninvolved colonic mucosa. We suggest that an increased enteroendocrine cell mass may be part of a non-specific reaction to chronic mucosal injury, and by producing an elevated level of trophic hormones may act as a promoter in the development of neoplasia.

Juvenile xanthogranuloma of the testis.

A 7-month-old boy presented with numerous xanthomatous skin lesions and a hard irregular swelling of the right testis. Clinically, the testicular lesion was impossible to distinguish from a malignant neoplasm. Histological examination of a skin biopsy and of the testis following orchiectomy showed lesions typical of juvenile xanthogranuloma.

Ectopic prostatic tissue.

A case is described in which a nodule of ectopic prostatic tissue was found in the pericolic fat, a previously undescribed site. A possible explanation for such a site is discussed with reference to the normal embryology of the region.