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I M Modlin

Publications and source records attributed to I M Modlin.

At least 37 records · Page 2Linked to original sources
PubMed2000

Gastrin-mediated alterations in gastric epithelial apoptosis and proliferation in a mastomys rodent model of gastric neoplasia.

BACKGROUND/AIMS: Hypergastrinemia secondary to low acid secretion is associated with gastric carcinoid formation in Mastomys. We investigated the effect of gastrin on oxyntic epithelial apoptosis and proliferation in this model. METHODS: Hypergastrinemia and mucosal hyperplasia were induced by irreversible H(2) receptor blockade with loxtidine. Gastrin levels were normalised in some animals by 10 days' loxtidine withdrawal. Serum gastrin was determined by radioimmunoassay, proliferative, enterochromaffin-like cells and Bcl-2 protein family expression by immunohistochemistry, and apoptotic cells by terminal deoxyuridine nucleotide nick end labeling (TUNEL). RESULTS: Proliferating cells were increased 4-fold in loxtidine-treated animals, and returned to normal upon loxtidine withdrawal. Enterochromaffin-like cell number increased 2-fold with loxtidine, and did not decrease after withdrawal. Apoptotic epithelial cells were located at the luminal surface and increased 1.8-fold with loxtidine, returning to control levels upon withdrawal. The ratio of proliferative to apoptotic cells was lower in the control and withdrawn groups than in the loxtidine group (0.26+/-0.05 and 0.26+/-0.08 vs. 0.77+/-0.12). With hypergastrinemia, the expression of Bcl-2 and Bak was increased and Bax decreased in the middle of the gland. CONCLUSION: Hypergastrinemia is associated with alterations in both proliferation and apoptosis in Mastomys gastric mucosa. This may contribute to the pathogenesis of mucosal hyperplasia in this model.

Animals↗
PubMed2000

Helicobacter pylori lipopolysaccharide alters ECL cell DNA synthesis via a CD14 receptor and polyamine pathway in mastomys.

Chronic Helicobacter pylori infection is associated with alterations in gastric mucosal cell proliferation. Despite the recognition that bacterial lipopolysaccharide (LPS) is present in biologically active quantities in the gastric mucosa, the mechanisms by which it stimulates cells are largely unknown. We have previously established a gastric enterochromaffin-like (ECL) cell neoplasia model in the African rodent species Mastomys and identified that tumor ECL cell proliferation is associated with polyamine biosynthesis and ornithine decarboxylase (ODC) activity. In addition, we have shown that H. pylori LPS exhibits a specific mitogenic effect on naive ECL cells in vitro. The aim of this study was to evaluate whether H. pylori has a direct effect on tumor ECL cell proliferation in vitro and further to evaluate the possible molecular mechanisms for this effect. ECL cell neoplasia was generated in Mastomys by endogenous hypergastrinemia induced by H(2) blockade (loxtidine 1 g/kg/day) and tumor ECL cells prepared. The DNA synthesis in 24-hour cultured tumor cells was measured by bromodeoxyuridine uptake and ODC activity by (14)CO(2) formation from (14)C-ornithine. The putative LPS receptor, CD14, was evaluated by reverse-transcription polymerase chain reaction. Our results demonstrated: (1) H. pylori LPS (10(-12) to 10(-7) M) stimulated basal DNA synthesis (2.2-fold) with an estimated EC(50) of 10(-10) M; (2) this proliferative response correlated with an increase in ODC activity (1.4-fold, EC(50) approximately 10(-10) M) which could be inhibited by a specific ODC inhibitor, difluoromethyl ornithine, at 10(-9) M; (3) the CD14 receptor was identified in both naive and transformed ECL cells by reverse-transcription polymerase chain reaction, and (4) the effects of LPS were inhibited by blocking the CD14 receptor with its specific monoclonal antibody (1:100). Thus, H. pylori LPS appears to influence tumor ECL cell proliferation by activation of the intracellular polyamine pathway and ODC activity via a CD14 receptor on the ECL cell.

Animals↗
PubMed2000

The quincunx of surgery.

From the earliest days of surgery the central and unifying theme of the discipline has been the mastery of technical proficiency with the view to not only management of the diseased or damaged part but the preservation of general health and well being. This central tenet of the discipline has been supported by four critical columns of knowledge, each of which has amplified over the passage of time. Initially anatomy was the cornerstone of surgical intervention and mastery of surgery to a large part depended upon a secure grasp of the intricacies and relationships of corporeal macro structure. The second column comprised functional anatomy or physiology and the appreciation of organ activity enabled the subsequent delineation of malfunction during disease. Regardless of the level of sophistication that could be brought to bear upon the disease a requisite for most successful technical intervention was the management of pain and the prevention of sepsis. As the quincunx of surgery embraces a new century it must continue to evolve to maintain the balance of growth in the four supporting columns. Thus anatomy has been expanded into subcellular structure and the elucidation of function has amplified into the role of individual organelles. Similarly pathology has moved beyond the organ and cell into the genome and deletion may be conceived of in terms of codons and sequences rather than colons and spleens. Indeed it is feasible that antisense strategies may become more sensible than antibiotics. Manual and digital techniques will be supplanted by robotic intervention and visualization will move beyond the visible into the non-visible world of spectroscopy. Millimetric dexterity will need to become nanometric and the mantra must become molecular and intervention directed not only at adults or neonates but the fetus. In order to achieve such goals teaching and training strategies need dramatic revision to produce individuals capable of transforming from tactile to telemetric skills and from gentle technique to genomic intervention.

Adult↗
PubMed1999

Altered influence of CCK-B/gastrin receptors on HDC expression in ECL cells after neoplastic transformation.

Gastrin is one of the main factors controlling enterochromaffin-like (ECL) cell endocrine function and growth. Long-standing hypergastrinemia may give rise to ECL cell carcinoids in the gastric corpus in man and in experimental models. We have analysed the expression and function of CCK-B/gastrin receptors in normal ECL cells and in ECL cell tumours (gastric carcinoids) of the African rodent Mastomys natalensis. Hypergastrinemia induced by short-term (5 days) histamine2-receptor blockade (loxtidine) resulted in increased histidine decarboxylase (HDC) mRNA expression in the gastric oxyntic mucosa. This increase was significantly and dose-dependently reversed by selective CCK-B/gastrin receptor blockade (YM022). Long-term (12 months) hypergastrinemia, induced by histamine2-receptor blockade, gave rise to ECL cell carcinoids in the gastric oxyntic mucosa. CCK-B/gastrin receptor mRNA was only slightly elevated while HDC mRNA expression was eight-fold elevated in ECL cell carcinoids and was not influenced by CCK-B/gastrin receptor blockade. Thus CCK-B/gastrin receptor blockade of hypergastrinemic animals reduces the HDC mRNA expression in normal mucosa but not in ECL cell carcinoids. These results demonstrate that HDC mRNA expression in neoplastic ECL cells is not controlled by CCK-B/gastrin receptors.

Animals↗
PubMed1999

Biological relevance of pituitary adenylate cyclase-activating polypeptide (PACAP) in the gastrointestinal tract.

Since its initial discovery in 1989, pituitary adenylate cyclase activating peptide (PACAP) has been noted to distribute widely in the brain, the respiratory and the gastrointestinal system. It occurs in two bioactive molecules, PACAP-27 and the C-terminally extended PACAP-38, which evoke activity by binding to three distinct types of high-affinity, G-protein coupled membrane receptors. It is present throughout the entirety of the gut but is rare in certain areas such as the intestinal mucosa and islets of Langerhans. PACAP-induced biological effects are protean and include alterations of motility in the bowel and the gallbladder, stimulation of gastric acid and intestinal secretion, hormone/enzyme release from the exocrine and endocrine pancreas, and the induction as well as inhibition of proliferation in neuroendocrine cells and tumors. Its hepatic activity has to date not been elucidated in detail. One of the interesting features of PACAP is the species and organ dependent variation of its biological effects. Of particular note is its superior potency when compared with other neuropeptides identified in the gut, and the involvement of a number of different second messenger systems upon PACAP receptor activation.

Animals↗
PubMed1999

The luminati of Leiden: from Bontius to Boerhaave.

In the glittering canopy of the history of great medical centers of Europe, none was more viviscent than Leiden. Although wealthy nations nurtured great medical establishments in Padua, Salerno, Montpellier, and Paris, it was from a diminutive market town in The Netherlands that a group of medical cognoscenti arose whose intellectual prowess blazed across the intellectual firmament of seventeenth and eighteenth century Europe. The tradition of medical excellence established by Bontius was amplified by the surgeon Peter Paaw, whose stewardship of the Anatomical Theater guided it to heights comparable to those achieved at Padua. At the same time, Clusius established a botanical garden that would have no rival for two centuries. The multitalented Sylvius educated some of the greatest minds of the generation, accepted the Harveian theories of circulation, and succeeded in fostering an intellectual environment characterized by novel ideas and tolerance of thought. van Horne defined and chartered the existence of lymphatic circulation, and Bartholin destroyed the myth of the liver as a source of blood. Exalting in the freedom of thought, the cabal of Ruysch, Steensen, de Graaf, and Swammerdam banded together under Sylvius and van Horne and made significant advances in pancreatic, lymphatic, reproductive, and respiratory physiology. There is little doubt, however, that of all the great names linked with Leiden, it is Boerhaave's that is universally held to be synonymous with that of the city. As a clinician, scientist, and teacher, the aura of his knowledge and fame spread to the farthest corners of Europe. Without doubt, the great medical schools of Edinburgh, Vienna, and Gottingen owe their subsequent potency to him. Thus the legacy of Leiden provides the richest of all earthly concepts-an appreciation of the unique spiritual power and intellectual wealth that devolves from the pursuit of the life of the mind.

General Surgery↗
PubMed1999

Pituitary adenylate cyclase-activating polypeptide modulates gastric enterochromaffin-like cell proliferation in rats.

BACKGROUND & AIMS: Gastric carcinoids (types I and II) involve the transformation of naive enterochromaffin-like (ECL) cells to the neoplastic state and are associated primarily with hypergastrinemia. In this study, we evaluated the effects of two related neuropeptides, pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP), on ECL cell proliferation and characterized the receptor subtype(s) and signal transduction pathways that mediate this effect. METHODS: Purified rat ECL cells were analyzed in culture for DNA synthesis as measured by 24-hour 5-bromo-2-deoxyuridine (BrdU) uptake. Reverse-transcription polymerase chain reaction (RT-PCR) with gene-specific oligonucleotide primers was performed to characterize the PACAP/VIP receptor subtype(s). RESULTS: PACAP/VIP neuropeptide-stimulated BrdU uptake was significantly greater (3.4-3.8-fold greater than control) than that at the maximal dose of gastrin (2.2-fold greater than control). PACAP-stimulated ECL cell proliferation (EC50, approximately 3 x 10(-)14 mol/L) was approximately 100-fold more potent than VIP (EC50, approximately 3x 10(-)12 mol/L). The stimulated BrdU uptake by both PACAP and VIP was competitively inhibited by PACAP-receptor antagonist (IC50, 10(-)9 mol/L, 3 x 10(-)9 mol/L, respectively) and VIP-receptor antagonist (IC50, 3 x 10(-)7 mol/L, 5 x 10(-)7 mol/L, respectively). RT-PCR identified the presence of the PACAP-specific but not PACAP/VIP receptor subtypes. The PACAP-stimulated BrdU uptake was inhibited (70%-80%) by inhibitors of adenosine 3',5'-cyclic monophosphate, phosphatidylinositol 3 kinase, and protein tyrosine kinase as well as mitogen-activated protein kinase. CONCLUSIONS: PACAP/VIP-related peptides are more potent modulators of ECL cell proliferation than gastrin, and their effect is mediated by a PACAP-specific receptor whose activation is transduced by multiple intracellular messenger systems.

Androstadienes↗
PubMed1999

Review article: current status of gastrointestinal carcinoids.

Carcinoid tumours are enigmatic, slow growing malignancies which occur most frequently (74%) in the gastrointestinal tract. In recent years, it has become apparent that the term 'carcinoid' represents a wide spectrum of different neoplasms originating from a variety of different neuroendocrine cell types. Carcinoid lesions are usually identified histologically by their affinity for silver salts, by general neuroendocrine markers, or more specifically by immunocytochemistry using antibodies against their specific cellular products. Within the gut, the most frequent sites are the small bowel (29%), the appendix (19%) and rectum (13%). Clinical manifestations are often vague or absent. Nevertheless, in approximately 10% of patients the tumours secrete bioactive mediators which may engender various elements of characteristic carcinoid syndrome. In many instances the neoplasms are detected incidentally at the time of surgery for other gastrointestinal disorders. The tendency for metastatic spread correlates with tumour size, and is substantially higher in lesions larger than 2.0 cm. An association with noncarcinoid neoplasms is ascribed in 8-17% of lesions. Treatment consists of radical surgical excision of the tumour, although gastric (type I and II) and rectal carcinoids may be managed with local excision. Overall 5-year survival is excellent for carcinoids of the appendix (86%) and rectum (72%), whereas small intestinal (55%), gastric (49%) and colonic carcinoids (42%) exhibit a far worse prognosis.

Carcinoid Tumor↗
PubMed1999

Cell and tumour biology of the gastric enterochromaffin-like cell.

The recent recognition of the nature of gastric carcinoids and the elucidation of the biological events associated with enterochromaffin-like cell transformation has provided an opportunity to advance the understanding of this particular type of neuroendocrine tumour. The relationship between hypergastrinaemia present in low acid disease states and the development of gastric carcinoids has led to an appreciation of the role of gastrin as a growth mediator in the evolution of this type of neoplasia. In addition, evidence exists to support a genetic predisposition to this tumour type in individuals with Multiple Endocrine Neoplasia type 1 syndrome, and in an experimental model--the African rodent species, Mastomys. The recent development of an isolated pure enterochromaffin-like cell preparation has facilitated the elucidation of the molecular physiology of the naive enterochromaffin-like cell and, in addition, allowed the evaluation of the cellular events associated with enterochromaffin-like cell transformation from the naive state to the neoplastic phenotype. This synopsis seeks to present information relevant to both the animal model and the human disease state. The aim is to facilitate an appreciation of the regulatory mechanisms of the enterochromaffin-like cell and delineate the changes consequent to the development of the neoplastic phenotype.

Animals↗
PubMed1999

[Influence of Helicobacter pylori lipopolysaccharide on the function of enterochromaffin-like cells in vitro].

OBJECTIVE: To investigate the relationship between Helicobacter pylori (Hp) infection and pathophysiology of abnormal gastric acid secretion and mucosal proliferation by studying the effect of Hp lipopolysaccharide (LPS) on the function of enterochromaffin-like (ECL) cells in vitro. METHODS: Pure isolated ECL cell preparation with a purity of +/- 95% was developed by proteinase digestion, elutriation and density gradient centrifugation with viability of > 95% as determined by trypan blue exclusion. After a short duration of culture basal and stimulated histamine secretion and DNA synthesis of ECL cells were measured by enzyme immunoassay and bromodeoxyuridine (BrdU) uptake, respectively. RESULTS: Hp LPS stimulated basal and gastrin-stimulated histamine secretion (EC(50)4 x 10(-11) mol/L and EC(50) 10(-10) mol/L respectively). These effects were completely inhibited by somatostatin (10(-10) mol/L) but not by gastrin receptor antagonist L(365 260). Hp LPS did not stimulate basal DNA synthesis but significantly increased gastrin stimulated BrdU uptake with EC(50) of 10(-10) mol/L. Escherichia coil LPS had no significant effect on both histamine secretion and DNA synthesis. CONCLUSION: Hp stimulates both ECL cell proliferation and secretion in vitro. An interaction between Hp LPS and ECL cells may contribute to the reported abnormalities in acid secretion and gastric pathophysiology noted in Hp infection.

Animals↗
PubMed1998

Surgical triumvirate of Theodor Kocher, Harvey Cushing, and William Halsted.

It is difficult to evaluate precisely the effects of one individual on an entire discipline such as surgery. Indeed, it is impossible to do so when such a discipline spans so vast a country as the United States of America. Nevertheless, as a mountain peak can be seen from afar, so may one perceive the influence of man of Kocher's stature. His connection with Halsted and especially Cushing provided a direct link between the grandeur of Kocher's achievements and their lineal translation to a generation of evolving American surgeons. Both individuals, by personal example and professional endeavor, transmitted the precepts of Kocher to the nascent surgical fellowship of America. Thus the icon of Swiss surgery, recognized by a Nobel laureate and esteemed by his European colleagues, became a profound influence on American surgery. The triumvirate of Kocher, Cushing, and Halsted may thus be acknowledged as of vital consequence to the establishment of American surgery during the twentieth century.

General Surgery↗
PubMed1998

The cost-effectiveness of octreotide acetate in the treatment of carcinoid syndrome and VIPoma.

Markov modeling was used to evaluate the cost-effectiveness of octreotide in treating carcinoid syndrome and VIPoma. For each condition, using octreotide was associated with doubled survival time. Octreotide was cost-effective for treating carcinoid tumor ($752 per additional year of life, two additional years on average), and cost saving for VIPoma.

Antineoplastic Agents, Hormonal↗
PubMed1998

Gastrin-regulated expression of p53 in transformed enterochromaffin-like cells in the African rodent mastomys.

The tumor suppressor p53 functions at the G1/S-phase checkpoint of the cell cycle to direct cells that have accumulated somatic mutations toward apoptosis and away from mitosis. The p53 gene is commonly mutated in human cancers, but the molecular mechanisms regulating this event are not clear. The African rodent mastomys exhibits a genetic predisposition to develop gastric carcinoids derived from enterochromaffin-like (ECL) cells. The ECL cell transformation can be accelerated by acid inhibition-induced hypergastrinemia. This study evaluates the alteration of p53 during the rapid ECL cell transformation. Hypergastrinemia was generated by the irreversible histamine-2 receptor antagonist loxtidine for 8 weeks (hyperplasia) and 16 weeks (neoplasia). p53 expression was evaluated in fundic mucosa from different stages of transformation by Western blot analysis and immunohistochemistry using monoclonal antibodies against wild-type p53. RT-PCR and molecular sequence analysis of p53 were undertaken with mRNA isolated from purified ECL cells. Overproduction of the wild type of p53 was evident in ECL cells during hypergastrinemia, and the molecular characteristics of p53 were determined in naive and transformed ECL cells. p53 was mutated at the C-terminus in ECLoma induced by hypergastrinemia. Therefore, p53 is altered from overproduction to mutation during the development of hypergastrinemia-induced ECLoma and it may therefore play a role in the cell transformation.

Amino Acid Sequence↗
PubMed1998

Helicobacter pylori--more light, less heat.

Several areas of broad agreement exist concerning the management of specific patient groups with clear-cut complications of H. pylori-colonization. Other aspects of this infection remain less well defined. These include the mode of transmission and pathogenesis of H. pylori, the clinical management of patients who do not have ulcer disease, and the approach to populations at risk of the clinical consequences of this bacterium. This review focuses on the unresolved issues of H. pylori infection that are of concern to the clinical gastroenterologist.

Disease Models, Animal↗
PubMed1998

A retrospective analysis of 1570 appendiceal carcinoids.

OBJECTIVE: Information about the management and outcome of appendiceal carcinoids is sparse, because few series comprise more than 100 cases. In this study we have analyzed the epidemiology of 1570 appendiceal carcinoids, to compare outcome with other gastrointestinal carcinoid tumors. METHODS: We evaluated 1570 appendiceal carcinoids in a series of 8305 carcinoid tumors from the SEER, the End Results Group, and the Third National Cancer Survey programs of the National Cancer Institute over the time period 1950-1991. RESULTS: Appendiceal carcinoids comprised 18.9% of all carcinoid tumors and exhibited a marked female predominance (M/F ratio: 0.47). Age-adjusted incidence rates were 1.7-fold higher in women compared to men. Appendiceal carcinoids present earlier (average age: 42.2 yr) than other gastrointestinal carcinoids (62.9 yr) or noncarcinoid appendiceal tumors (61.9 yr). At the time of diagnosis 35.4% were nonlocalized. The overall 5-yr survival for localized lesions was 94%, for regional invasion 84.6%, and for distant metastases 33.7%. The 5-yr survival of appendiceal carcinoids (85.9%) was the highest among all types of carcinoid tumors. In 14.6% noncarcinoid tumors at other sites were also evident. CONCLUSION: The high relative incidence of carcinoid tumors in the appendix is still poorly understood. The good overall 5-yr survival rates of appendiceal carcinoids as opposed to other carcinoids represents either a different biological behavior, earlier diagnosis, or expeditious management (appendectomy). However, the increased likelihood of coexisting neoplasms and the not uncommon presentation of metastatic disease should warrant careful evaluation and postoperative follow-up of such lesions.

Adult↗