Development Of Metaplasia Research Articles

Loss of Function ofTrp53,but NotApc,Leads to the Development of Esophageal Adenocarcinoma in Mice with Jejunoesophageal Reflux

Introduction. APCandTP53are tumor suppressor genes known to be altered frequently in human esophageal adenocarcinoma (EAC), which arises as a complication of reflux disease. To determine the functional role of these genes in the development of EAC, we have created reflux in mice gene-targeted for eitherTrp53orApc.Methods.Wild-type (WT), p53-knockout (Trp53−/−), orApc-mutated (ApcMin/+) mice were generated in our breeding colony. Total gastrectomy with esophagojejunostomy was performed at 6 weeks of age, creating jejunoesophageal reflux. Unoperated control mice were maintained under identical conditions. Mice were sacrificed at 30 weeks of age. Histology of the esophagus and jejunal anastamosis or gastroesophageal junction was reviewed by a single pathologist blinded to the genotype of the animal.Results.The esophagus was normal in all of the unoperated mice (6ApcMin/+, 6 WT, and 6Trp53−/−). All operated mice (6ApcMin/+, 12 WT, and 4Trp53−/−) had esophagitis, with squamous hyperplasia and early focal ulceration. Barrett's metaplasia was identified in 33% of the operatedApcMin/+(2/6) and 25% of theTrp53−/−(1/4) mice, but not in the WT mice. Of 4 operatedTrp53−/−mice, all developed severe dysplasia of the squamous epithelium and 2 (50%) had EAC on histology, although no gross tumors were seen. No severe dysplasia or carcinoma was identified in any of theApcMin/+or WT mice.Conclusions.Loss of eitherTrp53orApcleads to the development of columnar metaplasia, whereas loss ofTrp53,but notApc,leads to development of cancer in mice with jejunoesophageal reflux.

Review article: exploring the link between Helicobacter pylori and gastric cancer.

Cancer of the distal stomach, both of the intestinal and diffuse type, is strongly associated with Helicobacter pylori colonization. This bacterium causes chronic active inflammation of the gastric mucosa in the majority of colonized subjects. In a considerable number of them, this will eventually lead to a loss of gastric glands, and thus the establishment of atrophic gastritis, which is associated with the development of intestinal metaplasia and dysplasia. Development of atrophy and metaplasia of the gastric mucosa are thus strongly associated with H. pylori infection, instead of a direct and inevitable consequence of ageing. Approximately 40-50% of infected subjects develop these conditions, but they are rare in non-infected subjects. The presence of these consecutive disorders leads to a 5-90-fold increased risk for cancer of the distal stomach, in particular of the intestinal type. This sequence explains the increased risk for gastric cancer in H. pylori-infected subjects, as has been shown in various cross-sectional and longitudinal studies. In a combined analysis of three longitudinal studies, a significant trend was observed towards an increased odds ratio with longer intervals between (retrospective) serological diagnosis of H. pylori infection and observation of gastric cancer, this risk being more than eight-fold increased if the interval had been at least 15 years. This is thought to reflect development of atrophic gastritis and intestinal metaplasia with loss of H. pylori colonization in the years prior to development of cancer. Atrophic gastritis and gastric cancer thus appear closely associated with the presence of H. pylori, yet not all infected subjects will eventually develop atrophy and only a small minority develop gastric cancer. Factors that influence the risks for atrophy and cancer in the presence of infection may be related to the time that infection occurred and to characteristics of the bacterial strain and the host. Evidence for the role of these factors is now increasing. Recognition of the causal role of H. pylori in the induction of gastric cancer theoretically presents tools for cancer prevention. The efficacy of screening and bacterial eradication for prevention of distal gastric cancer is being studied in a number of large-scale intervention studies in different populations. It is hoped that these studies will also provide answers to the potential preventive role of H. pylori colonization in the development of gastro-oesophageal reflux disease and associated conditions, in particular development of cancer of the proximal stomach. Infection with H. pylori plays an important role in the aetiology of atrophic gastritis and gastric cancer. Studies suggest an eight-fold increased risk for both conditions in the presence of infection. Factors that influence the risk for both conditions in the presence of infection are the age at which infection occurred and the presence of cagA as a marker for more pathogenetic H. pylori strains. The efficacy and side-effects of intervention for the prevention of distal gastric cancer has yet to be established.

Development of esophageal metaplasia and adenocarcinoma in a rat surgical model without the use of a carcinogen.

In order to establish an animal model for studying the cause and prevention of esophageal adenocarcinoma (EAC) and its frequent precursor, Barrett's esophagus (BE), factors affecting the pathogenic processes were investigated in an esophagoduodenal anastomosis model with rats. Experiments by us and others have shown that surgical treatment produced reflux esophagitis with cell hyperproliferation, but not EAC. Additional treatment with a carcinogen has been shown to be necessary for the development of EAC, squamous cell carcinomas (SCC) or EAC/SCC mixtures. We found that the surgically treated animals developed anemia due possibly to reduced iron absorption. When the operated animals were supplemented with iron, EAC occurred at a high rate (73%) after 30 weeks, and treatment with N'-nitrosonornicotine did not enhance the rate of tumorigenesis. Treatment with carcinogen, however, induced SCC in the group of rats killed after 22 weeks. The results suggest that iron overload, which is known to cause oxidative damage, is an enhancing factor for adenocarcinogenesis. The pathogenesis of EAC in the iron-supplemented, non-carcinogen treated group resembles human esophageal adenocarcinogenesis in many features. All the BE was the specialized type with goblet cells (containing sialomucin or sulfomucin) and columnar cells (containing acid or neutral mucin) as well as an incompletely developed brush border. Almost all of the BE was located at the bottom of the esophagus and was continuous with the duodenal mucosa; dysplasia became more frequent at later time points. All of the cancers were well-differentiated mucinous EAC, and most of the EAC had an adjacent area of BE with dysplasia. The results are consistent with the proposed human sequence for pathogenic events of BE progression to 'BE with dysplasia' and then to EAC. Esophagoduodenal anastomosis and iron treatment in rats produces a high rate of BE and EAC which are morphologically similar to human BE and EAC; this may be a useful animal model to study the development and prevention of EAC in humans.

Blood-group phenotypes, sulfomucins, and Helicobacter pylori in Barrett's esophagus.

Barrett's esophagus, morphologically analogous to gastric intestinal metaplasia, often precedes the development of esophageal adenocarcinoma. In the stomach, expression of sulfomucins and aberrant Lewis(a) (Le[a]) antigen is an excellent predictor of premalignant progression, and Helicobacter pylori infection is a crucial determinant for the development of atrophy, metaplasia, and adenocarcinoma. In the esophagus, the significance of sulfomucin expression is controversial, the aberrant expression of Le(a) has not been explored, and the role of H pylori in the evolution of preneoplastic conditions is unknown. We investigated in 155 patients referred for endoscopy the association of Barrett's esophagus with expression of sulfomucins, Lewis, secretor, and ABO phenotypes, and H pylori infection. We report a subtype of intestinal metaplasia, present in all patients with esophageal adenocarcinoma, similar to gastric intestinal metaplasia of colonic type (type III or incomplete), that expresses sulfomucins and aberrant Le(a) in goblet and columnar cells. Lewis(a+b-), nonsecretor and blood group A phenotypes, were all positively associated with esophageal adenocarcinoma, suggesting a genetic susceptibility. H pylori infection was detected in 75% of patients with esophageal adenocarcinoma.

Retinoids and their nuclear receptors in the development, prevention, and treatment of upper airways epithelial cancers

Retinoids and their nuclear receptors in the development, prevention, and treatment of upper airways epithelial cancers

Esophageal carcinoma: current controversies.

The incidence of esophageal adenocarcinoma and adenocarcinoma of the gastric cardia has increased so substantially in the last two decades that adenocarcinoma now accounts for approximately one half of esophageal malignancies seen in the United States and Europe. The reasons for this histological change may be related to a parallel increase in the incidence of gastroesophageal reflux disease in the Western world and the subsequent development of Barrett's metaplasia. Controversies surrounding carcinoma of the esophagus that are currently the focus of study are the relationship of Barrett's esophagus to the development of adenocarcinoma; whether adenocarcinoma of the esophagus and cardia is the same disease; the correct way to stage the disease; the treatment of disease confined to the mucosa; the extent of surgical resection to cure disease beyond the mucosa; the role of adjuvant chemotherapy in the treatment of the disease; and the methods of palliating patients with incurable disease.

Conjunctival Impression Cytology in Patients Wearing Contact Lenses

Evaluation of contact lens-induced cytologic changes on the conjunctival surface. Fifty eyes of 25 patients wearing soft or rigid gas-permeable contact lenses, and 50 healthy eyes of 25 control subjects were examined with conjunctival impression cytology. Of the patients wearing contact lenses, 40% did not have any contact lens-related complaints, whereas 60% had some minor complaints related to contact lens intolerance. The material obtained by impression cytology was examined with regard to epithelial cell morphology, goblet cell density, and snake-like nuclear chromatin changes. When epithelial cell morphology was graded according to the system described by Nelson, specimens from the control group revealed 90% of the eyes to be grade 0 and 10% to be grade 1, whereas of the eyes wearing contact lenses, 8% were grade 0, 36% grade 1, 32% grade 2, and 24% grade 3. Thus statistically significant differences were observed between the control group and the contact lens group with regard to each grade (p < 0.05) as well as to the goblet cell densities (p < 0.05). Snake-like chromatin changes, on the other hand, were observed in 30 and 27% of the eyes wearing soft and rigid gas-permeable contact lenses, respectively, whereas these were not encountered in any eye in the control group. Epithelial changes were noted to be more frequent and more severe in symptomatic patients than in those without any complaints. No correlation was found between average duration of contact lens wear and the risk of contact lens intolerance or development of squamous metaplasia.

Correlation of Goblet Cell Density and Mucosal Epithelial Membrane Mucin Expression with Rose Bengal Staining in Patients with Ocular Irritation

Purpose: This study was designed to compare goblet cell densities and mucosal epithelial membrane mucin (MEM) expression in impression cytology specimens obtained from control subjects and patients with one of the following clinically defined diseases: aqueous tear deficiency (ATD) associated with Sjögren syndrome, ATD not associated with Sjögren syndrome, inflammatory Meibomian gland disease associated with rosacea, and Meibomian gland atrophy. These data were correlated with ocular surface rose Bengal staining scores, Schirmer scores, and HLA-DR antigen staining of conjunctival epithelial cells.Methods: Goblet cell density and MEM expression were studied by impression imprints with immunohistochemical staining using an anti-mucosal epithelial membrane mucin antibody in the temporal and inferior bulbar and inferior tarsal conjunctiva of study subjects.Results: Goblet cell density adjacent to the temporal limbus was significantly reduced at 3 mm posterior to the temporal limbus in both aqueous tear deficiency groups compared with the other groups and in patients with Sjögren syndrome compared with all other groups. In the inferior tarsus, goblet cell density was significantly reduced in patients with non-Sjögren syndrome ATD as compared with all other groups, except those with inflammatory Meibomian gland disease. Mucosal epithelial membrane mucin expression in the bulbar and tarsal conjunctiva was absent in a greater percentage of patients with Sjögren syndrome compared with all other groups. Total ocular surface rose Bengal staining scores were significantly higher in patients with Sjögren syndrome as compared with all other groups and in patients with non-Sjögren syndrome ATD as compared with control groups. Rose Bengal staining scores and Schirmer I test results (without anesthesia) were inversely correlated with bulbar, but not tarsal, conjunctival goblet cell densities, and with the absence of bulbar conjunctival MEM expression.Conclusions: These results suggest that reduced goblet cell density and mucosal epithelial cell mucin expression could explain increased rose Bengal staining in patients with aqueous tear deficiency. In addition, MEM may be regarded as a marker for normal differentiation of ocular surface epithelia, with its absence signifying the development of squamous metaplasia.

Inhibitory effects of retinoids on development of squamous metaplasia in rat mammary epithelial organoids cultured in Matrigel.

Squamous metaplasia (SQM) developed in cultures of rat mammary organoids in reconstituted basement membrane, Matrigel, under either a complete hormone medium (CHM) or a serum-free mammary epithelium growth medium (MEGM). Organoids cultured in CHM gave rise to fewer such SQM (approximately 5%) than those in MEGM (approximately 16%). Formation of SQM was completely suppressed when retinoids were added to CHM. However, a few SQM were still observed in cultures in MEGM with added retinoids. Addition of 5% fetal bovine serum suppressed development of SQM cultured in MEGM. Delayed addition of retinoids also inhibited further development of SQM. Development of SQM from mammary epithelial cells is not common, and regulatory molecules other than retinoids apparently are involved in their formation and prevention.

Response of rat salivary glands to mastication of pelleted vitamin A-deficient diet

Interpretation of previous studies of the effects of hypovitaminosis A on salivary glands is confounded by the atrophic effects of liquid or powdered diets. The purpose of this study was to re-evaluate the effects of vitamin A deficiency on the morphology and function of rat salivary glands using a pelleted diet that promotes physiological levels of masticatory. Profound vitamin A deficiency resulted in a marked decrease in stimulated parotid secretion. Histological evaluation demonstrated the development of squamous metaplasia in ducts of parotid, submandibular and sublingual salivary glands; however, atrophy was observed only in serous salivary glands. In the parotid gland the degree of atrophy corresponded to the decrease in stimulated secretion. Mild hypovitaminosis A (before the development of squamous metaplasia in ducts) was associated with distinctly different effects. The parotid gland was moderately enlarged. There was also a significant increase in stimulated secretion, which was not explained by changes in gland size, muscarinic receptor number or affinity, or receptor-mediated calcium signalling.

Phytoestrogens are partial estrogen agonists in the adult male mouse.

The intake, as well as serum and urinary concentrations, of phytoestrogens is high in countries where incidence of prostate cancer is low, suggesting a chemopreventive role for phytoestrogens. Their significance could be explained by the ability to antagonize the action of more potent endogenous estrogens in initiation or promotion of tumor formation. We have studied estrogenicity and antiestrogenicity of dietary soy and two phytoestrogens, coumestrol and daidzein, in our neoDES mouse model for the study or prostatic neoplasia. Soy was chosen because it is rich in phytoestrogens, is widely used in Oriental diets, and has antiestrogenic and anticarcinogenic properties in the neoDES mouse when given from fertilization onward. In short-term tests with adult animals, no evidence for estrogenicity or antiestrogenicity (capability to antagonize the action of 17 beta-estradiol) of soy was found when development of epithelial metaplasia and expression of c-fos protooncogene in prostate were used as end points of estrogen action. Estrogenic activity of coumestrol and daidzein on c-fos expression was subtle. Coumestrol, either given alone or in combination with 17 beta-estradiol, had no effect on development of epithelial metaplasia. These marginal or missing effects in adult males could be interpreted by assuming that the neonatal period is more critical for estrogenic or antiestrogenic action of soy and phytoestrogens. Once initiated, estrogen-related lesions would develop spontaneously. Alternatively, the chemopreventive action of soy is not due to antiestrogenicity of soy-derived phytoestrogens.

Pancreatic Metaplasia in Barrettʼs Esophagus An Immunohistochemical Study

While pancreatic metaplasia has been observed in gastric mucosa of patients with chronic gastritis, it has not been described in ectopic gastric mucosa. We have identified focal clusters of cells resembling pancreatic acinar cells (CPACs) in 11 of 350 biopsies of Barrett's mucosa from 120 patients with Barrett's esophagus enrolled in a clinical efficacy trial of omeprazole versus ranitidine for treatment of gastroesophageal reflux disease. Three additional cases from our surgical files were also studied. Immunoreactivity for trypsin and chymotrypsin was present in the CPACs of all 14 cases, while stains for alpha-amylase and lipase were each positive in 12 of 13. A few cells in the CPACs were also positive for chomogranins (12 of 13 cases), serotonin (seven of 13 cases), somatostatin (three of 12), gastrin (four of 11), and pancreatic polypeptide (two of 13). No staining was seen for insulin or glucagon. Ultrastructural studies performed in one case showed features of pancreatic exocrine and endocrine (PP-type) cells in cells within CPACs. These results collectively indicate that the CPACs are aggregates of true pancreatic acinar cells admixed with a few endocrine cells. This pancreatic parenchyma in Barrett's mucosa is most likely of metaplastic origin and could be derived from the transitional zone cells or from pluripotent stem cells in the esophageal mucosa or from metaplasia of mucus cells. While the development of pancreatic metaplasia in Barrett's esophagus appears to be unrelated to drug therapy, the clinical relevance of this distinctive histological finding needs further investigation.

A morphological study of the human ventricular fold: age-related changes and sex differences

A morphological study of the human ventricular fold was conducted with special reference to age-related changes and sex differences. The laryngeal specimens examined were obtained from 54 autopsy cases consisting of 27 males and 27 females ranging in age from 20 to 79 years. Each specimen was frontal-sectioned between the anterior and posterior ends of the ventricular fold to yield 8 equal portions. The surface of the entire ventricular fold was reconstructed based on examination of all of the sections, and extent of squamous metaplasia was 3-dimensionally evaluated and expressed in the form of a histological map. In the cases in which smoking history was ascertained, extent of squamous metaplasia was evaluated by the same method. In all of the cases the distribution of the different types of tissues such as glandular, adipose and connective, was examined in the midportion of the specimen (section No. 5). The following conclusions were drawn as a result. 1. The development of squamous metaplasia reached a peak in the middle-age group, particularly in males. The 3-dimensional extension of metaplasia was classified into 4 patterns, however, there were no age-specific differences in pattern, and the posterior-dominant-type and widespread-type were the most common in all age groups. The extension of metaplasia varied with smoking history, suggesting that smoking promotes the extension of squamous metaplasia. 2. Glandular tissue decreased with age, more markedly in females. The distribution of the glandular tissue was classified into 4 patterns. Atrophy of glandular tissue with age occurred in the central area of the ventricular fold, extending to the marginal portion. 3. Collagen fibers decreased slightly with age. Elastic fibers appeared frequently in the lateral portion near the laryngeal ventricle in the aged group.

Gastric metaplasia and Helicobacter pylori infection.

Duodenal and antral mucosal biopsy specimens were obtained from 139 patients with dyspeptic complaints to study the prevalence and extent of gastric metaplasia in the duodenal bulb in relation to Helicobacter pylori (H pylori) infection and duodenal ulcer disease. On logistic regression, the presence and extent of gastric metaplasia was not significantly associated with H pylori infection. The prevalence of gastric metaplasia, however, was found to be higher in patients with current or past evidence of duodenal ulcer disease in comparison with subjects with functional dyspepsia (p = 0.01). A follow up study on 22 patients before and at least one year after eradication of H pylori showed that the mean extent of gastric metaplasia did not change significantly after eradication and did not differ when compared with 21 patients with persisting infection. It is concluded that the unchanged gastric acid output after eradication of H pylori is a more important factor in the development of gastric metaplasia than the H pylori related inflammatory process.

Experimental study of the therapeutic effects of folate, vitamin A, and vitamin B12 on squamous metaplasia of the bronchial epithelium.

Vitamin deficiency may be related to carcinogenesis. Cytologic examinations of sputum have already found that the administration of folate and vitamin B12 suppressed the development of squamous metaplasia and atypia in smokers' airways. The authors investigated the effect of folic acid, vitamin B12, and vitamin A on the formation of metaplasia and hyperplasia in methylcholanthrene (MCA)-treated rats. The SD strain of rats received 10 mg of MCA intratracheally and was divided into six groups as follows: (1) vitamin A; (2) folic acid; (3) vitamin B12; (4) vitamin B12 with folic acid; (5) a combination of vitamin A, folic acid, and vitamin B12; and (6) no vitamins. The Lower respiratory tract epithelia of the rats were examined histologically 20, 32, and 36 weeks after MCA administration and at the end of the experiment. A clear difference was detected between the group receiving folic acid and that receiving vitamin A. In the former group, metaplasia was found in only one rat, atypia was not found, and hyperplasia with marked changes was present in less than 50% of other groups. In the latter group, atypia was found in all of the metaplastic foci. It was suggested that the epithelial hyperplasia and metaplasia of respiratory tract induced by MCA can be suppressed by the administration of folic acid.

Implication of RARB in Epidermoid (Squamous) Lung Cancer

We report a higher frequency of loss of heterozygosity at loci on the short arm of chromosome 3 in human epidermoid lung tumors than in other non-small cell lung tumors. This observation together with the already known involvement of the retinoids in the development of epidermoid metaplasia and neoplasia, especially in lung tissue, prompted us to investigate by RNAase protection assays the status of expression of a gene that maps on chromosome band 3p24 and codes for the B receptor for retinoic acid (RARB). We show that expression of RARB is detectable in normal lung tissue and in most of the cell lines derived from lung tumors, including the five non-small cell lines that clearly had a non-epidermoid phenotype. Strikingly, however, only one of the five epidermoid-tumor-derived cell lines studied showed detectable expression of RARB. Of two lines derived from adenosquamous tumors, one had a clear epidermoid differentiation, and this line also did not express RARB. Taken together, our results strongly implicate RARB in the evolution of epidermoid lung tumors.

Effect of the Addition of Estrogen to Medical Castration on Prostatic Size, Symptoms, Histology and Serum Prostate Specific Antigen in 4 Men with Benign Prostatic Hypertrophy

A total of 4 men with benign prostatic hypertrophy who underwent medical castration therapy with a long-acting gonadotropin-releasing hormone agonist (leuprolide) for more than 6 months elected to add an estrogen transdermal patch (0.05mg. to the skin biweekly) to the leuprolide regimen. The average prostatic size (transrectal ultrasound), serum prostate specific antigen (PSA) levels and symptoms of prostatism were dramatically decreased with leuprolide alone. The addition of estrogen for 6 months did not result in any change in prostate size, symptoms or serum PSA levels over that seen with leuprolide alone. The development of squamous metaplasia was noted in 1 man with leuprolide alone and in 1 man after the addition of estrogen. Immunohistochemical staining with anticytokeratin 903 antibodies reveals that squamous metaplasia appears to arise from prostatic basal cells. We postulate that the target cell for estrogen action in the prostate is the prostatic basal cell. In the absence of androgen the only direct effect of estrogens is the induction of squamous metaplasia.

Cell-specific alterations in glycoconjugates in the development of squamous metaplasia induced by benzo[ a]pyrene in hamster tracheal explants

Squamous metaplasia of tracheal mucosa, putative preneoplastic lesions, involves replacement of normal mucociliary epithelium with epidermoid lesions. Alterations in cell differentiation and neoplasia accompany changes in glycoconjugates at the plasma membrane. Lectins which bind to specific cell surface glycoconjugates are used to elucidate such alterations. We have used peanut agglutinin (PNA) and concanavalin A (Con A) as specific molecular probes to elucidate cell specific alterations in the development and progression of squamous metaplasia in the hamster tracheal explants induced by benzo[ a]pyrene (BP), a component of cigarette smoke. The tracheal explants were cultured in serum-free chemically defined medium and treated with BP (7.5 μg/ml) for up to 15 days. At this time, 80–90% of the carcinogen treated explants exhibited epidermoid lesions at various stages of development. The untreated control explants maintained normal pseudostratified epithelium. In these explants, PNA and Con A exhibited moderate reaction in the cytoplasm of luminal mucociliary cells; the basal cells showed no reaction. In early metaplastic lesions PNA and Con A stained only the cytoplasm of luminal cells; the metaplastic cells along the basal lamina were negative. In well-developed lesions, in which the luminal mucociliary layer was still intact overlying the lesions, the metaplastic epithelium remained unreactive with the lectins. In highly advanced lesions exhibiting cornification, and in which the mucociliary layer was sloughed, the metaplastic lesions showed strong reaction with both the lectins. The reaction was limited mainly to the plasma membrane of the metaplastic cells. These results show that induction and progression of the BP induced lesions accompany dynamic cell specific alterations in glycoconjugates. The epidermoid lesions acquire glycoconjugates rich in β- d-galactose and d-mannose. These results are also consistent with the basal cell origin of the metaplastic lesions.

Occurrence of sister-chromatid exchange and chromosomal aberration during vitamin A-induced cell differentiation in vitro

Prompted by the recent growth in interest in the mechanisms of vitamin A (VA) action, we studied the effects of VA on the frequency of sister-chromatid exchange (SCE) and chromosome aberration (CA) in a culture system using a fetal Syrian hamster (female) pulmonary epithelial cell line (M3E3/C3). When manipulated by specific culture conditions, the cells in this system could be rendered competent for activation of polycyclic aromatic hydrocarbons. Cells induced to such a state were exposed to 0, 2, 8 and 24 μg/ml of VA for 4 days. The average frequency of SCE per metaphase increased from 1.64 at 0 μg/ml to 3.44 at 24 μg/ml with a moderate degree of dose dependence. In addition, the q-terminal area of X-chromosomes appears to be one of the most specifically vulnerable sites for SCE due to VA. The frequency of CA encompassing triradial, quadriradial, quiqueradial, ring and dicentric chromosomes also increased in a rather sigmoid fashion from 3.6% at 0 μg/ml to 14.8% at 24 μg/ml. Apart from the frequently demonstrated protective roles or otherwise less often encountered promotional effects of VA in the development of squamous metaplasia, neoplasia, neoplastic transformation or mutation, an alternative interpretation for the current results implies a possible relationship between SCE and CA caused by VA and cell differentiation and/or drug resistance mechanisms.

Helicobacter Pylori

Helicobacter pylori is a unique pathogen and the leading cause of chronic gastric inflammation. For many individuals the organism is of low virulence, causing only mild inflammation and generating few, if any, dyspeptic symptoms. For those with more severe inflammation, H. pylori infection may be causal in the generation of dyspeptic symptoms. H. pylori infection appears to be the dominant factor in peptic ulcer disease. Events considered to be of importance are a disturbed gastrin homeostasis and the development of gastric metaplasia in the bulb. The most important argument in support of the dominant role of H. pylori in duodenal ulcer disease is the markedly reduced ulcer relapse after successful eradication. Eradication proves to be difficult, presumably because of the peculiar habitat of the organism. Currently the best pharmacologic approach is triple therapy, combining a bismuth salt, metronidazole, and amoxycillin or tetracycline.