Thomas R. McGinn

Attenuated familial adenomatous polyposis (AFAP) a phenotypically and genotypically distinctive variant of FAP

Background. The usual manifestation of familial adenomatous polyposis (FAP) is hundreds or thousands of colonic adenomas. The authors previously described a colon cancer‐prone syndrome characterized by fewer adenomas (1–100), most located in the proximal colon, and upper gastrointestinal lesions, particularly fundic gland polyps and duodenal adenomas. The colonic adenomas are often flat rather than polypoid, a feature emphasized in earlier reports with the term “hereditary flat adenoma syndrome.” The syndrome has an autosomal dominant pattern of inheritance and is linked to the adenomatous polyposis coli [APC] locus at 5q.

The cytotoxic effects of a novel IH636 grape seed proanthocyanidin extract on cultured human cancer cells

Grape seed proanthocyanidins are natural antioxidants which possess a broad spectrum of chemoprotective properties against free radicals and oxidative stress. In this study, we have assessed the cytotoxicity of a novel IH636 grape seed proanthocyanidin extract (GSPE) against MCF-7 human breast cancer cells, A-427 human lung cancer cells, CRL-1739 human gastric adenocarcinoma cells and K562 chronic myelogenous leukemic cells at 25 and 50 mg/lit concentrations for 0-72 h using cytomorphology and MTT cytotoxicity assay. In addition, we compared the effects on normal human gastric mucosal cells and normal J774A.1 murine macrophage cells with the effects on the cancer cell lines. Concentration- and time-dependent cytotoxic effects of GSPE were observed on the MCF-7 breast cancer, A-427 lung cancer and gastric adenocarcinoma cells. Following incubation of the MCF-7 cells with 25 mg/lit of the GSPE approximately 6.5, 30 and 43% inhibitions in cell growth were observed at 24, 48 and 72 h of incubation, respectively, while incubation of the MCF-7 cells with 50 mg/lit of the GSPE resulted in 11, 35 and 47% inhibition in cell growth at these same points, respectively. Similar results were observed in the A-427 and gastric adenocarcinoma cells. GSPE exhibited no cytotoxicity toward the neoplastic K562 myelogenous leukemic cells. However, GSPE enhanced the growth and viability of the normal human gastric mucosal cells and J774A.1 murine macrophage cells. These data demonstrate that GSPE exhibited cytotoxicity towards some cancer cells, while enhancing the growth and viability of the normal cells which were examined.

Reflux esophagitis in humans is mediated by oxygen-derived free radicals☆

BACKGROUND Oxidative stress in reflux esophagitis was investigated before and after antireflux surgery. PATIENTS AND METHODS Oxidative stress was studied in the distal and proximal esophagus of control patients (without esophagitis, but with other gastrointestinal disorders), of patients with various grades of esophagitis (including Barretts esophagus), and in patients who had a Nissen fundoplication. Oxidative stress was assessed by chemiluminescence, lipid peroxidation (LP), and by measuring superoxide dismutase (SOD). RESULTS Chemiluminescence and LP increased with the degree of esophagitis and was highest in patients with Barretts esophagus; SOD decreased with damage, except in cases of Barretts esophagus associated with mild esophagitis. Chemiluminescence and LP in reflux patients were higher in the distal than in the proximal esophagus, and SOD was lower, whereas no such difference was found in controls. Findings after Nissen fundoplication were similar to those of controls. CONCLUSIONS Reflux esophagitis is mediated by free radicals depleting SOD. Barretts esophagus is a severe form of oxidative damage; in some patients, high SOD levels may prevent severe esophagitis. Antireflux surgery prevents oxidative damage.

Helicobacter pylori-Induced Oxidative Stress and DNA Damage in a Primary Culture of Human Gastric Mucosal Cells

Helicobacter pylori has been identified in the pathogenesis of chronic active gastritis and peptic ulcer disease and is epidemiologically linked to gastric cancer and lymphoma. Our previous studies have demonstrated enhanced production of reactive oxygen species (ROS) in cultured gastric adenocarcinoma cells (ATCC CRL/1739) in association with H. pylori. Recently, we have isolated and cultured normal human gastric mucosal cells (GMC) from H. pylori-negative endoscopic biopsies. The integrity of these mucosal cells was determined by periodic acid–Schiff staining. We assessed the effects of various H. pylori strains including 60190 (a 87-kDa cytotoxin producing strain), ATCC 43504, and 60190-v1 (in which the cytotoxin gene has been disrupted) on the primary culture of human gastric mucosal cells. The induction of ROS and DNA fragmentation in the mucosal cells in association with these H. pylori strains were assessed by cytochrome c reduction (an index of superoxide anion production), hydroxyl radical production, and DNA fragmentation. Following incubation of the mucosal cells with 1:0.5 and 1:1 ratios of H. pylori strain 60190, approximately 6.2- and 9.9-fold increases were observed in cytochrome c reduction, respectively, as compared to mucosal cells in the absence of H. pylori, demonstrating the production of superoxide anion. The detection of hydroxyl radicals based on the formation of 2,3-dihydroxybenzoic acid and 2,5-dihydroxybenzoic acid was determined by using a high-performance liquid chromatograph equipped with an electrochemical detector. Approximately 3.5- and 7.7-fold increases in hydroxyl radical production were observed following incubation of the mucosal cells with 1:0.5 and 1:1 ratios of H. pylori, respectively. Approximately 3.6- and 4.5-fold increases in DNA fragmentation were observed in gastric mucosal cells following incubation with 1:0.5 and 1:1 ratios of H. pylori, respectively. The effects of culture supernatant preparations from H. pylori strains 60190 and 60190-v1 on the enhanced production of ROS and increased DNA fragmentation in mucosal cells were also investigated. Culture supernatant preparations, the prime source of the 87-kDa cytotoxin, from both H. pylori strains 60190 and 60190-v1 were extracted under identical conditions to determine the role of 87-kDa cytotoxin on the enhanced production of ROS and DNA fragmentation. The cytotoxin rich-H. pylori strain 60190 induced greater production of ROS and DNA fragmentation in mucosal cells as compared to the supernatant preparation from H. pylori strain 60190-v1, in which the cytotoxin gene has been disrupted. This study demonstrates that H. pylori induces enhanced production of ROS and DNA damage in association with human gastric mucosal cells andthat the 87-kDa cytotoxin protein plays a prime role in the induction of oxidative stress and DNA damage.

Update on the differential diagnosis, surveillance and management of hereditary non-polyposis colorectal cancer

Hereditary non-polyposis colorectal cancer (HNPCC) is the most common hereditary form of colorectal cancer (CRC), accounting for approximately 10% of the total CRC burden. HNPCC lacks premonitory physical stigmata, thereby making the family history crucial for diagnosis. Advances in molecular genetics during the past 2 years have led to the cloning of four HNPCC genes (MHS2, MLH1, PMS1 and PMS2). It is now possible to provide presymptomatic DNA testing followed by genetic counselling for gene carriers. Some studies have shown that adenomas in HNPCC are larger, more villous, and have more high grade dysplasia than sporadic cases, suggesting an accelerated adenoma-carcinoma sequence. Given the early age of onset and proximal predominance of CRC, we initiate colonoscopy at age 20-25 years and we recommend that it be performed every 1-2 years. The wealth of clinical and molecular genetic knowledge currently available to physicians about HNPCC can be used effectively for cancer control.

The hypertensive lower esophageal sphincter

BACKGROUND This study defines the entity of the hypertensive lower esophageal sphincter (HLES) and its treatment, including surgical implications. METHODS Esophageal manometry was performed on 1,300 patients. Of these, 53 (4%) had HLES with resting pressure > 26.5 mm Hg, defined as the upper limit of normal resting LES pressure. Thirty-two of these patients had 24-hour esophageal pH studies. The response to treatment was assessed. RESULTS Fourteen patients (26%) with HLES had achalasia. Of the remaining 39 (74%), 25 had an isolated HLES with normal esophageal body motility, 5 had a nonspecific esophageal motility disorders (NEMD), 4 were post-Nissen fundoplication, 3 had a nutcracker esophagus, and 2 had diffuse esophageal spasm (DES). Nineteen percent of HLES patients had gastroesophageal reflux on pH studies. Eighty-two percent of HLES patients responded well to symptom-directed medical therapy. Two patients with esophageal body dysmotility responded well to an esophageal myotomy with a partial fundoplication. CONCLUSIONS Patients with the HLES form a heterogeneous group. Gastroesophageal reflux in HLES patients is not uncommon. Patients with HLES respond well to medical therapy. Carefully selected patients require surgery.

Mechanism of gastroprotection by bismuth subsalicylate against chemically induced oxidative stress in cultured human gastric mucosal cells.

Reactive oxygen species (ROS) are implicated inthe pathogenesis of chemically induced gastric mucosalinjury. We have investigated the effects of ethanol,hydrochloric acid (HCl), and sodium hydroxide (NaOH) on: (1) enhanced production of ROSincluding superoxide anion and hydroxyl radicals, (2)modulation of intracellular oxidized states by laserscanning confocal microscopy, and (3) DNA fragmentation, indices of oxidative tissue, and DNA damage ina primary culture of normal human gastric mucosal cells(GC), which were isolated and cultured from Helicobacterpylori-negative endoscopic biopsies from human subjects. The induction of ROS and DNAdamage in these cells following exposure to ethanol(15%), HCl (150 mM) and NaOH (150 mM) were assessed bycytochrome c reduction (superoxide anion production), HPLC detection for enhanced production ofhydroxyl radicals, changes in intracellular oxidizedstates by laser scanning confocal microscopy, and DNAdamage by quantitating DNA fragmentation. Furthermore, the protective ability of bismuth subsalicylate(BSS) was assessed at concentrations of 25, 50, and 100mg/liter. Incubation of GC with ethanol, HCl, and NaOHincreased superoxide anion production by approximately 8.0-, 6.1- and 7.1-fold and increased hydroxylradical production by 13.3-, 9.6-, and 8.9-fold,respectively, compared to the untreated gastric cells.Incubation of GC with ethanol, HCl, and NaOH increased DNA fragmentation by approximately 6.7-, 4.3-,and 4.8-fold, respectively. Approximately 20.3-, 17.5-,and 13.1-fold increases in fluorescence intensities wereobserved following incubation of gastric cells with ethanol, HCl, and NaOH, respectively,demonstrating dramatic changes in the intracellularoxidized states of GC following exposure to thesenecrotizing agents. Preincubation of GC with 25, 50, and 100 mg/liter of BSS decreased ethanol-inducedincreases in intracellular oxidized states in thesecells by 36%, 56%, and 66%, respectively, demonstratinga concentration-dependent protective ability by BSS. Similar results were observed withrespect to BSS in terms of superoxide anion and hydroxylradical production, and DNA damage. The present studydemonstrates that ethanol, HCl, and NaOH induce oxidative stress and DNA damage in GC and thatBSS can significantly attenuate gastric injury byscavenging these ROS.