W. Michael McDonnell

Induction of cytochrome P450IA genes (CYP1A) by omeprazole in the human alimentary tract

Cytochrome P450 enzymes are capable of converting procarcinogens into either active mutagens or inactive metabolites. Because the distribution of these enzymes may be important for tissue susceptibility to procarcinogens, the expression and induction of CYP1A genes in the human alimentary tract were investigated. Endoscopic biopsy specimens were obtained from buccal mucosa, esophagus, gastric body, antrum, duodenum, and colon of 6 healthy volunteers before and 1 week after taking 20 mg of omeprazole daily. Tissue specimens were analyzed for the presence of CYP1A1 and 1A2 transcripts using hybridization methods and the polymerase chain reaction. P450-dependent enzymatic activity was assessed by deethylation of ethoxyresorufin. CYP1A1 messenger RNA (mRNA) and ethoxyresorufin activity were present constitutively in the duodenum of each volunteer. Omeprazole (20 mg/day for 1 week) induced CYP1A1 mRNA and enzymatic activity in 5 of 6 volunteers. The one individual who did not initially respond had a marked increase in both mRNA and enzymatic activity after receiving 60 mg of omeprazole daily for 1 week. After treatment with omeprazole, two individuals had low levels of CYP1A1 mRNA in several other alimentary tissues as well as low levels of CYP1A2 mRNA in the duodenum. The expression and induction by a pharmaceutical agent of CYP1A genes may have implications for intestinal metabolism of ingested xenobiotics including procarcinogens.

Familial visceral neuropathy with neuronal intranuclear inclusions: diagnosis by rectal biopsy.

A family with a visceral neuropathy manifested as chronic idiopathic intestinal pseudo-obstruction is reported. Diagnoses were made histologically by simple rectal biopsy. Discrete eosinophilic intranuclear inclusions, diagnostic of a disease known as neuronal intranuclear inclusion disease, were found in the submucosal ganglion cells. Abnormalities of the autonomic nervous system were identified by pupillary examination and electroretinography. In this family, three of four siblings were affected by the disease, which is apparently transmitted from the paternal side. This pedigree was unique for several reasons: (a) diagnosis in multiple members of two generations indicates that this familial visceral neuropathy was expressed in an autosomal dominant manner, (b) central autonomic nervous system abnormalities were detected by eye examination, and (c) the definitive pathological diagnosis was established antemortem by rectal biopsy in all cases.

Identification of bilirubin UDP-GTs in the human alimentary tract in accordance with the gut as a putative metabolic organ

The initial identification of traditionally hepatic enzymes expressed in the gut has led to the hypothesis that the gut may function as a metabolic organ. The UDP glucuronosyltransferases (UDP-GTs) play an important role as phase II metabolizing enzymes. Previously members of this family have been identified in the gut by non-isoform specific immunoreactivity, and a small amount of bilirubin glucuronosyltransferase activity was detected in the colon. Recent reports of gut transplantation to reverse the metabolic defect in Gunn rats raised further interest in the expression and distribution of human bilirubin (UDP-GTs (HUG Br 1 and HUG Br 2) in the human alimentary tract. The availability of molecular genetic probes for HUG Br 1 and HUG Br 2 permits the screening of the alimentary tract for the presence of isoform specific message. RNA samples extracted from pinch biopsy specimens of buccal mucosa, esophagus, stomach body, antrum, duodenum, and colon were analyzed for expression of HUG Br 1 and HUG Br 2. HUG Br 1 hybridization was detected in duodenum > colon, whereas HUG Br2 hybridization was detected in duodenum > esophagus > colon. Immunoreactivity data confirmed the presence of HUG Br 1 protein at low levels in the duodenum, whereas the less abundant HUG Br 2 protein was below the limits of detection of isoform specific anti-peptide antibodies. Bilirubin specific reactivity was demonstrated in duodenal samples but not antrum samples, consistent with the molecular genetic data. The presence of functional bilirubin UDP-GT isoforms in human alimentary tract supports the notion that the gut may function as a metabolic organ and may have diagnostic and therapeutic implications for disorders of bilirubin metabolism.

Expression and regulation of cytochrome P-450I genes (CYP1A1 and CYP1A2) in the rat alimentary tract

Cytochrome P-450 (P450) enzymes in the mucosa of the alimentary tract may be involved in the activation and/or inactivation of ingested xenobiotics and procarcinogens. Since the multiple P450 enzymes have overlapping substrate specificities and, in some cases, similar antigenic determinants, definitive identification of P450 genes that are expressed in various tissues requires molecular analysis. In this study, a sensitive and specific polymerase chain reaction assay along with hybridization analysis was used to examine the expression of the CYP1A gene family in the rat alimentary tract. CYP1A1 mRNA was expressed throughout the alimentary tract in untreated rats, as determined by the polymerase chain reaction. However, Northern blot analysis detected CYP1A1 mRNA and enzymatic activity only in small intestine and liver, with greater amounts in intestine. After treatment with beta-naphthoflavone, CYP1A1 mRNA and enzymatic activity was markedly induced in each alimentary tissue including esophagus, fore-stomach, glandular stomach, small intestine and colon. A single dose of inducer resulted in a rapid rise in CYP1A1 mRNA which was shown by nuclear run-on assays to be primarily due to an increase in transcription of the CYP1A1 gene. CYP1A2 mRNA was detected in significant amounts only in glandular stomach following induction although the polymerase chain reaction assay identified low levels of CYP1A2 mRNA in several other tissues. The definitive identification of the CYP1A genes that are expressed in alimentary tissue will allow the design of experiments to investigate the importance of these enzymes in the metabolism of carcinogens, and ultimately carcinogenesis, in the gastrointestinal tract. In addition, these data suggest that the aromatic hydrocarbon receptor, which mediates transcriptional induction of multiple genes by xenobiotics, is expressed through the alimentary tract.

Effect of iron on the guaiac reaction

Most studies show that oral ingestion of iron does not cause a positive stool guaiac reaction. However, all in vitro studies show that iron does cause a positive guaiac reaction and some in vivo studies have shown a positive stool guaiac reaction in response to oral iron. This study examines this unresolved question. Twenty-five normal volunteers were given 900 mg of ferrous sulfate a day. Two Hemoccult II and two HemoQuant tests were obtained before and during iron therapy. All Hemoccult II tests were negative before and after oral iron. Four HemoQuant tests were slightly elevated before oral iron and one was slightly elevated after oral iron. Ferrous sulfate, 300 mg, was dissolved in 1 L of water. The solution was acidic (pH = 3.9) and produced a positive Hemoccult II test. When the solution was titrated with sodium hydroxide to a pH of greater than or equal to 6.0, iron precipitated out and the mixture no longer produced a positive Hemoccult II reaction. Our data show that ferric iron (Fe3+) in solution will give a positive guaiac reaction directly and ferrous iron (Fe2+) will give a positive guaiac reaction after hydrogen peroxide is added because it oxidizes Fe2+ to Fe3+. Iron solutions are acidic and when titrated toward a neutral pH, the iron is precipitated out and the solution is then guaiac-negative. Thus, our in vivo data confirm most previous in vivo studies; furthermore, the discrepancy between in vivo and in vitro studies can be explained as a pH-dependent phenomenon of in vitro iron solutions. Oral iron should not cause a positive guaiac reaction, and the HemoQuant results show no increase in occult blood loss in subjects on oral iron therapy.

Effects of Smoking on Interdigestive Gastrointestinal Motility

The effect of smoking on interdigestive gastrointestinal motility is little studied but may play a role in gastrointestinal morbidity. We studied gastroduodenal motility in 10 volunteers (five smokers and five nonsmokers) using a water-perfused pressure catheter. A pH probe was placed in the duodenal bulb. Baseline motility was recorded until phase III of the migrating motor complex had occurred in the stomach three times in order to record two complete cycles of MMC activity. Subjects then began smoking until phase III activity occurred again (mean duration of smoking 117 min). During the control period, all subjects had normal MMC cycles and there were no differences between smokers and nonsmokers. While smoking, no gastric phase III was observed in any subject and gastric motility was markedly reduced. In seven of 10 subjects, smoking did not prevent the occurrence of normal duodenal phase III activity. Three subjects had no duodenal phase III activity during smoking. The duodenal pH profile did not change during smoking and motilin levels continued to fluctuate in conjunction with phase III activity. In conclusion, smoking abolished phase III activity in the stomach without affecting the plasma motilin cyclic fluctuations or duodenal bulb pH. In contrast, smoking has little effect on duodenal motility.

Venoocclusive disease of the liver following renal transplantation

Hepatic venoocclusive disease (VOD) is a nonthrombotic, and often progressive , oblite ration of the central and sublobular ve ins without obstruction of the hepatic vein. Originally described as a result of ingestion of pyrrolizidine alkaloids (1), hepatic VOD is now more commonly encounte red as a complication of antineoplastic chemotherapy, particularly in the setting of bone marrow transplantation (2± 4). Hepatic VOD has also been described in renal transplant recipients (5± 11) . In this clinical setting, hepatic VOD has been linke d to azathioprine in standard immunosuppressive doses, although a causal association remains unclear. We describe the progre ssion of histopathologic features and the distinctive computed tomographic (CT) ® ndings in a renal transplant patient with progressive live r failure due to VOD. This case report is of particular inte rest because CT ® ndings were interpreted to be most consistent with an infectious or metastatic process, resulting in temporary reconsideration of the patient’ s candidacy for combined live r/ kidne y transplantation.

Massive secretory diarrhea and pseudo-obstruction as the initial presentation of Crohn's disease

We report large-volume secretory diarrhea and intestinal pseudo-obstruction in a man whom ultimately proved to have Crohns disease that responded to sulfasalazine and steroids with resolution of all his symptoms. Although this is an unusual presentation, Crohns disease should be included in the differential diagnosis in patients whose initial symptoms are intestinal pseudo-obstruction and secretory diarrhea.

Hemophilus influenzae type B cellulitis in adults

Cellulitis due to Hemophilus influenzae type B is a rare but treatable event in adults. Herein is described a 67-year-old woman with anterior neck cellulitis caused by H. influenzae type B, documented by positive blood culture results. Six additional cases reported in the literature are reviewed. The following clinical syndrome emerges: the patient is usually older than 50 years of age, and pharyngitis develops first, followed by the onset of high fever and rapidly progressive anterior neck swelling, tenderness, and erythema associated with dysphagia. Because the causative organism may be resistant to ampicillin, the early use of chloramphenicol is recommended along with a beta-lactamase-resistant penicillin or cephalosporin (to cover other potential pathogens), or an appropriate third-generation cephalosporin that would also adequately cover all possible pathogens.

A randomized, controlled trial to assess a novel colorectal cancer screening strategy: the conversion strategy

OBJECTIVE:Our study was a randomized, controlled trial to assess a novel strategy that provides comprehensive colorectal cancer screening in a single visit versus traditional sigmoidoscopy and, where appropriate, colonoscopy on a subsequent day.METHODS:Consecutive patients referred for screening were randomized to control or so-called “conversion” groups. Patients in the control group were prepared for sigmoidoscopy with oral phospho-soda. Those with an abnormal sigmoidoscopy were scheduled for colonoscopy on a future day after oral polyethylene glycol preparation. In the conversion group, patients were prepared with oral phospho-soda. Patients with a polyp >5 mm or multiple diminutive polyps were converted from sigmoidoscopy to colonoscopy, allowing comprehensive screening in a single visit. Clinical outcomes were assessed by postprocedure physician and patient questionnaires.RESULTS:Two hundred thirty-five patients were randomized (control = 121, conversion = 114). In the control group, 28% had an indication for colonoscopy. Three of 33 (9%) with an abnormal sigmoidoscopy did not return for colonoscopy. At colonoscopy, 27% had a proximal adenoma. In the conversion group, 28% had an abnormal sigmoidoscopy and underwent conversion to colonoscopy. Forty-one percent undergoing colonoscopy in the conversion group had a proximal adenoma. Physicians reported no differences in preparation or procedure difficulty, whereas patients reported no differences in the level of comfort or overall satisfaction between groups. When queried regarding preferences for future screening, 96% chose the conversion strategy.CONCLUSIONS:The conversion strategy led to similar outcomes compared to traditional screening while improving compliance with colonoscopy in patients with an abnormal sigmoidoscopy.