Biomedical subjects

I M Modlin

Publications and source records attributed to I M Modlin.

At least 127 records · Page 7Linked to original sources

PubMed1993

Inhibition of VIP-stimulated ion transport by a novel Y-receptor phenotype in rabbit distal colon.

Neurocrine, endocrine, and paracrine regulators are critical to the control of colonic secretion. These studies have investigated the inhibition of vasoactive intestinal polypeptide (VIP)-stimulated ion transport by peptide YY (PYY) and other Y-class effectors in rabbit distal colonic mucosa mounted in Ussing chambers. PYY decreased basal short-circuit current (Isc) but did not significantly change either basal Na+ or Cl- flux. PYY inhibited VIP-stimulated increases in Isc by up to 86% and abolished VIP-induced Cl- secretion. PYY decreased VIP-generated increases in Isc by a tetrodotoxin-insensitive mechanism. PYY inhibited cholera toxin-stimulated as well as forskolin-stimulated increases in Isc but failed to alter stimulation by 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP). PYY decreased VIP-stimulated increases in tissue cAMP by 88% and forskolin-stimulated increases by 84%. PYY, neuropeptide Y (NPY), (Leu31,Pro34)-NPY, and pancreatic polypeptide (PP) all demonstrated potent inhibition of VIP-stimulated increases in Isc. PYY-(13-36) demonstrated little effect on VIP stimulation. Thus the rabbit distal colon possesses a novel Y-class receptor phenotype that demonstrates high affinity for all three PP-fold peptides, NPY, PYY, and PP.

Animals↗

PubMed1993

Partial agonism by gastrin for a cholecystokinin receptor mediating pepsinogen secretion.

Isolated gastric glands from rabbit were used to characterize the functional cholecystokinin (CCK)-like peptide receptors that mediate pepsinogen secretion. Pepsinogen secretion was stimulated by both CCK octapeptide sulfate (CCK-8) and A-71378, a selective CCK-A-type receptor agonist, with similar mean effective doses (1.0 and 0.8 nM, respectively). Compared with CCK-8, gastrin-17 (G-17-I) showed reduced potency and only partial efficacy for stimulation of pepsinogen secretion while inhibiting the maximal CCK-8-stimulated response. The nonpeptide inhibitors, asperlicin and L-364,718, inhibited pepsinogen secretion with identical pA2 values for antagonism of both CCK and gastrin, indicating that both peptides interact with the same functional receptor. Specific binding of [3H]CCK-8 to isolated chief cell membranes was displaced fully by both CCK and gastrin, indicating full receptor occupancy by both peptides. A novel synthetic peptide analogue, pseudogastrin [(Glu)5-Ala-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH2], was used to investigate the structural basis for the lower potency and efficacy of G-17-I. The potency of CCK and gastrin analogues for pepsinogen secretion was found to be dependent on both sulfation of a tyrosine residue and the position of the tyrosine residue relative to the COOH-terminal phenylalanine amide. The efficacy appears to be determined partially by the extended NH2-terminal sequence of G-17-I. The results of the present study are interpreted to show that pepsinogen secretion is mediated by a CCK-A-type receptor and gastrin acts at the same receptor as a partial agonist.

Amino Acid Sequence↗

PubMed1993

Use of radiolabeled somatostatin analogs in the identification and treatment of somatostatin receptor-bearing tumors.

Radiolabeled somatostatin analogs are potentially of considerable value in both the localization and treatment of somatostatin receptor-bearing tumors. Whole body 123I-labeled Tyr3-octreotide scintigraphy is capable of detecting and localizing primary tumors and metastatic disease that may not be detectable by other methods. Although it is possible that this technique may be applicable to a wide variety of neoplasms, 123I-Tyr3-octreotide scans appear particularly useful for imaging various gut neuroendocrine tumors, meningiomas, and paragangliomas. This primarily reflects the level of expression of somatostatin receptors by these lesions. In addition to whole body scintigraphy, intraoperative localization by receptor identification utilizing a hand-held gamma detector probe may prove to be an effective means of identifying spread and micrometastasis of somatostatin receptor-bearing tumors. Aside from identification and topographic localization of disease, the detection of an 123I-Tyr3-octreotide labeled tumor may be utilized as in vivo assay for the presence of somatostatin receptors. Such observations may prove useful in predicting the susceptibility of an individual tumor to octreotide therapy. Additionally, it may prove possible to deliver a therapeutic dose of radiation to receptor-bearing tumors by the administration of specific radiolabeled somatostatin analogs.

Gastrointestinal Neoplasms↗

PubMed1993

Pancreaticobiliary juice releases motilin during phase I of the migrating motor complex in man.

The effect of duodenal perfusion with pancreaticobiliary juice on plasma motilin was investigated in eight fasting subjects. The study was undertaken with recording of gastrointestinal motility, to predict spontaneous fluctuations in plasma motilin levels. Duodenal perfusion with pancreaticobiliary juice or saline at a rate of 5 ml/min for 10 min was performed in random order after the second or third activity front. The 30-min integrated plasma motilin response was significantly greater after perfusion with pancreaticobiliary juice: 1.5 (0.7-2.3) nmol x min/l (mean and 95% confidence interval), compared with 1.0 (0.5-1.5) nmol x min/l after saline (p < 0.05). Although perfusion with pancreaticobiliary juice was followed by endogenous plasma motilin peaks after about 20 min in six of eight subjects, the mean interval to the next activity front was not significantly different. In conclusion, duodenal perfusion with pancreaticobiliary juice in phase I of the migrating motor complex releases plasma motilin without affecting the fasting motility pattern.

Adult↗

PubMed1993

Diagnosis and management of gastrointestinal neuroendocrine tumors.

Neuroendocrine tumors of the gastrointestinal tract pose substantial diagnostic and therapeutic challenges. The numerous biologically active peptides and amines produced by these lesions generate complex clinical syndromes. Unfortunately, little is known regarding the genesis of these lesions. Recent advances in understanding of the pathobiology of these lesions has facilitated characterization of the biochemistry of tumor secretions. Similarly, pharmacological blockade of tumor bioactivity using somatostatin analogs, pharmacotherapeutic probes, or specific antagonists has enhanced treatment options. Effective biochemical palliation of tumor symptoms has in turn motivated a more aggressive approach to cytoreduction of these tumors by surgery or hepatic embolization. The combination of chemical blockade and surgical therapy may permit more extended and symptom-free survival for a significant proportion of patients. We evaluate the basic principles of diagnosis and management of gastrointestinal neuroendocrine tumors.

Gastrointestinal Neoplasms↗

PubMed1993

Rapid induction of enterochromaffinlike cell tumors by histamine2-receptor blockade.

The effect of acid inhibition on gastric endocrine cells was investigated in Praomys (Mastomys) natalensis. Long-term treatment (1 to 32 weeks) with an irreversible histamine 2-receptor blocker (loxtidine) caused a sustained increase in plasma gastrin levels, which was accompanied by a gradual increase in histamine and histidine decarboxylase activity of the gastric oxyntic mucosa. The density of endocrine cells in the oxyntic mucosa increased gradually, doubled by 8 weeks, and was three times that of controls after 24 weeks of treatment. Hyperplastic changes in the endocrine cell population were evident after 2 to 8 weeks in all animals, whereas dysplastic or neoplastic lesions were observed in half the animals after 16, 24, and 32 weeks of treatment. Gross tumors in the oxyntic mucosa were observed in 1/4 of the animals treated for 24 or 32 weeks. Proliferating cells were identified as enterochromaffinlike cells because they were argyrophilic and immunopositive for chromogranin A and histamine. The results demonstrate that histamine 2-receptor blockade initiated by loxtidine promotes a rapid development of enterochromaffinlike cell tumors in Mastomys and suggest a critical role for gastrin in the formation of these tumors. However, the rate and frequency by which carcinoid tumors appeared in Mastomys after acid inhibition was much greater than that reported in other species, indicating that several factors, including hormonal and genetic factors, are important in the development of gastric endocrine tumors.

Animals↗

PubMed1993

Clinical applications of gastrointestinal hormones.

Over 80 peptides and amines secreted by more than 20 different types of neuroendocrine cells scattered throughout the gut have been identified. The physiologic function and clinical relevance of many of these hormones await elucidation. Nevertheless, the clinical use of these agents in either diagnostic or therapeutic modalities has greatly expanded the appreciation of the relevance of many of these peptides to malignant and nonmalignant pathobiology.

Carcinoid Tumor↗

PubMed1993

A brief historical perspective and a comparison of the current systems of surgical training in Great Britain, Germany and the United States of America.

The surgical training programs of Great Britain, Germany and the United States were designed with some considerable exchange of ideas between these countries. However, although they share certain similarities, these training schemes have developed their own unique features and characteristics. Since the profession of surgery has entered a new period of transition, the education of its trainees will require judicious modifications in the near future.

Education, Medical↗

PubMed1993

Characterization of membrane and cytoskeletal compartments in cultured parietal cells: immunofluorescence and confocal microscopic examination.

Primary cultures of rabbit gastric parietal cells respond to various gastric secretagogues as evidenced by morphological alterations and [14C]aminopyrine uptake. The availability of cultures of > 95% purity has allowed us to utilize immunofluorescence and confocal microscopy to observe the direct effect of histamine upon the distribution of membrane and cytoskeletal proteins in parietal cells. Cells cultured for 3 days were incubated for 45 min with or without 10(-4) M histamine, washed, and fixed with 3% paraformaldehyde. Immunofluorescence was performed with antibodies against H+/K(+)-ATPase, Na+/K(+)-ATPase, ezrin, and beta-tubulin, as well as with Bodipy-phallacidin. Anti-H+/K(+)-ATPase antibody stained resting cells in a vesicular cytoplasmic pattern. Stimulation with histamine resulted in the development of a well-defined linear pattern, outlining the expanded secretory canaliculi. The Na+/K(+)-ATPase was restricted to predominantly the lateral surface in both the resting and stimulated cells, suggesting that the cultured parietal cells retain membrane polarity. Ezrin was visualized outlining the intracellular canaliculi in the resting state, and surrounding the large secretory canaliculi in the stimulated cell. Phallacidin labeling of F-actin localized to an area tightly surrounding the intracellular canaliculi in the resting cell, and was comparable with the staining observed with ezrin. In the stimulated cells this fluorescence pattern became more diffuse and surrounded the expanded secretory surface. In both the resting and stimulated cells, antibodies to beta-tubulin revealed a microtubular pattern located predominantly in the basal portion of the cell. These results demonstrate that the cells are capable of translocating the H+/K(+)-ATPase-containing tubulovesicles to a secretory surface, and that they exhibit organization and maintenance of basolateral and canalicular membrane domains. Furthermore, these studies demonstrate the directed movement of membrane and cytoskeletal proteins upon stimulation of the cultured parietal cells.

Actins↗

PubMed1993

Management of unresectable malignant endocrine tumors of the pancreas.

Malignant endocrine tumors of the pancreas are a heterogenous group of tumors with a multipotential secretory capacity. The lesions are generally slow growing with a relatively long life expectancy from the time of diagnosis. Death results from a combination of local and metastatic disease and the sequelae of excess hormone secretion. While potentially successful curative resections are rare, long term survival is frequently possible based on the rate of growth and the inhibition of the bioactive effects of the secretory products of the tumor. Regional control with palliative surgical debulking and transcatheter arterial embolization of hepatic metastases has an important role in terms of symptomatic relief and long term survival. These tumors respond frequently to chemotherapy. Combination chemotherapy is more effective than single agent treatment. Preliminary information suggests that leukocyte interferon is useful in treatment, but this agent still requires careful prospective evaluation. While current data do not support the use of octreotide for an antitumor effect, it is capable of producing prompt and substantial symptomatic relief with minimal side effects in a large proportion of patients with functional malignant endocrine tumors of the pancreas. Many advances have been made in the recognition, diagnosis and management of patients with malignant endocrine tumors of the pancreas. Additional basic cellular research is necessary to define the molecular and cell biologic factors of these tumor cells. Particular facets that require further understanding include their basic cytogenetic abnormality, regulation of peptide production and the role of peptides and other growth factors in endocrine, paracrine and autocrine regulatory relationships. The answers to these questions will hopefully promulgate the discovery of improved cytotoxic agents, better peptide pharmacotherapeutic agents and improve the overall management of patients with unresectable malignant endocrine tumors of the pancreas.

Adenoma, Islet Cell↗

PubMed1993

Harvey Cushing: first guest at "The Divine Banquet of the Brayne".

Harvey Cushing will remain forever ensconced in surgical memory as the visionary who established contemporary neurosurgery. Raised in Cleveland in a middle-class family with a medical background, he gave little indication early of his later prowess. A college education at Yale University yielded a modest performance, although he showed somewhat better promise as a medical student at Harvard University. During his surgical training at the Johns Hopkins Medical School, he emerged as a bright, industrious young man with a glint of steel to his intellect. From Halsted he learned the academic basis of surgery and the meticulousness necessary for technical success. Osler became his friend and provided him with a foundation in the history of medicine and the recognition of its importance in shaping the future. The decision to spend a year in Europe visiting clinics and renowned surgeons may have laid the foundations for the subsequent configuration of his career. In Britain he saw firsthand the glorious museums and libraries of the Hunters and the legacy that their schools of surgery had endowed to the nation. In Paris and London he mixed with the surgical aristocracy of the times and learned the power of societies and the traditions of their patrons. In Berne he was exposed to the surgical purity and physiologic expertise of Kocher, supported by the estimable scientific practice of Kroneker. As an "arbeid," Kocher posed him the problem of establishing the mechanism of the regulation of cerebral perfusion. This question, which he so rapidly and successfully unraveled, probably played a large part in igniting his enthusiasm toward the study of the brain as a future career. In his travels he encountered diverse intellects and experienced a wide panoply of European medical thought. He conversed widely at both a social and professional level and integrated all information into meticulously kept diaries that served as not only a record but also a template from which later plans were derived. A final 6-week sojourn in Liverpool working on the primate cortex with Sherrington, the greatest neurophysiologist of that time, may have sealed his decision to turn his initial project with Kocher into the opus of a lifetime. The 14-month tour of Europe transformed Cushing from a relative unsophisticate into a figure of giant proportions. All that he experienced became part of his life and was integrated into his subsequent career.(ABSTRACT TRUNCATED AT 400 WORDS)

Europe↗

PubMed1992

Identification of rab2 as a tubulovesicle-membrane-associated protein in rabbit gastric parietal cells.

Rab proteins, which are ras-like low-molecular-mass GTP-binding proteins, are postulated to act as specific regulators of membrane trafficking in exocytosis and endocytosis. Previously, we reported a 23 kDa tubulovesicle-associated GTP-binding protein in rabbit gastric parietal cells [Basson, Goldenring, Tang, Lewis, Padfield, Jamieson & Modlin (1991) Biochem. J. 279, 43-48]. The major component of the 23 kDa protein is now identified as rab2. Rab2 was co-localized in tubulovesicle membranes from parietal cells. Consistent with GTP-binding activity (as documented before), upon maximal stimulation of parietal cells, rab2 immunoreactivity was redistributed from a 50,000 g to a 4000 g subcellular membrane fraction. The tubulovesicle-associated rab2 behaved as an integral membrane protein, since both 0.5 M-NaCl and 0.1 M-carbonate extraction failed to remove the protein from the tubulovesicle membrane. Utilizing a PCR the rab2 cDNA sequence from rabbit parietal cells was obtained, and it showed only one amino acid difference compared with the human sequence. The results of the present study provide strong evidence that parietal cells possess a rab2 protein which is tightly associated with tubulovesicle membranes.

Adenosine Triphosphatases↗

PubMed1992

Incidence and mortality of carcinoids of the colon. Data from the Connecticut Tumor Registry.

The aims of this study were to calculate the true incidence of colonic carcinoids in Connecticut from 1976 to 1986 and to determine the outcome of patients with these lesions. Fifty-four patients with carcinoids of the colon were identified (23 male and 31 female patients). Their average age was 64.1 +/- 2.1 years, with a range of 12 to 83 years. The age-adjusted incidence was 0.31 cases/100,000 population/year. Forty-eight percent of the carcinoids were located in the cecum; 16%, ascending colon; 6%, transverse colon; 11%, descending colon; 13%, sigmoid colon; and 6%, not assigned. Follow-up information was available in all cases. The crude 2-year survival rate was 63%, whereas the 5-year survival rate was 37%. Only one of six (16.6%) lesions that were 2 cm or smaller metastasized, whereas 23 of 31 lesions larger than 2 cm metastasized (74%). Six patients have survived an average of 43.5 months after local excision of their carcinoids. Fourteen patients died of their carcinoids. Metachronous gastrointestinal malignant neoplasms developed in six patients. These results suggest that, when found at an early stage, carcinoids of the colon (2 cm or smaller) can be treated by local excision. The vast majority of colonic carcinoids, however, are discovered at an advanced stage and should be treated aggressively with standard colonic resection. In addition, surveillance of the entire gastrointestinal tract should be initiated in these patients because of a high rate of other gastrointestinal malignant neoplasms.

Adolescent↗

PubMed1992

Gastrin and colorectal cancer. Evidence against an association.

Plasma gastrin has been reported to be elevated among patients with colorectal cancer. The objectives of the present study were to confirm this observation and, if confirmed, to shed light on the reason for the elevation. Presurgical and postsurgical fasting plasma gastrin levels were compared between 24 patients hospitalized for colorectal adenocarcinoma resection and 25 control patients hospitalized for other surgery. Elevated presurgical gastrin levels in the case group that fell after surgery would be consistent with production of gastrin by the tumor. High presurgical gastrin levels in the case group that did not change following surgery would be consistent with excess gastrin production by G cells. The mean presurgical gastrin levels were 21.9 +/- 3.7 pM (cases) and 45.1 +/- 18.0 pM (controls). The mean postsurgical gastrin levels were 20.5 +/- 3.9 pM (cases) and 43.4 +/- 14.6 pM (controls). These results do not provide support for the hypotheses that gastrin is elevated in colorectal cancer patients or that gastrin is secreted by colorectal tumors in sufficient quantities to be measurable in the plasma.

Adenocarcinoma↗

PubMed1992

Implications of sustained suppression of gastric acid secretion.

The implications of profound and sustained suppression of acid secretion are of increasing concern. Short-term inhibition of acid secretion by H2-receptor blockade or proton pump inhibition alters the gastric luminal flora and increases the risk of nosocomial pneumonia in critically ill patients who are receiving prophylaxis for stress gastritis. Long-term suppression alters gut flora, carcinogen levels in the gastric lumen, and the hormonal milieu, leading to proliferative changes in the fundic mucosa. Previous reports have noted a significant incidence of gastric malignancies in the achlorhydric environment of atrophic gastritis and pernicious anemia. Concern has also been expressed regarding the possibility of gastric neoplasia that arises after vagotomy and distal gastrectomy. The exact risk of gastric epithelial and endocrine hyperplasia or neoplasia in patients receiving potent antisecretory agents is not yet known, but such risks cannot be dismissed until long-term follow-up studies are available. The relationship between sustained suppression of acid secretion and the proliferation of epithelial and endocrine elements may provide insight into processes that regulate replication and growth of cells in the gastric mucosa.

Gastric Acid↗

PubMed1992

Possible role of transforming growth factor alpha in the pathogenesis of Ménétrier's disease: supportive evidence form humans and transgenic mice.

Ménétrier's disease is an uncommon disorder of unknown etiology characterized by enlarged gastric folds with foveolar hyperplasia and cystic dilatation of gastric glands. Biochemical features that are seen frequently include hypoproteinemia, hypochlorhydria, and increased gastric mucus. Because transforming growth factor alpha (TGF alpha) is an epithelial cell mitogen that inhibits gastric acid secretion and increases gastric mucin content, we hypothesized that its altered expression might be involved in the pathogenesis of this disease. Therefore, we characterized TGF alpha immunoreactivity in the gastric mucosa of 4 patients with Ménétrier's disease. In contrast to the normal pattern of TGF alpha immunostaining in which TGF alpha appears most concentrated in parietal cells, there was intense staining in the majority of mucous cells in the gastric mucosa of patients with Ménétrier's disease. In one patient from whom sufficient fresh tissue was obtained to isolate RNA, expression of TGF alpha and the epidermal growth factor receptor was higher in the gastric mucosa relative to a normal control. In addition, metallothionein-TGF alpha transgenic mice, which overexpress TGF alpha in gastric mucosa, show a number of features characteristic of Ménétrier's disease. These include foveolar hyperplasia and glandular cystic dilatation, increased gastric neutral mucin staining, and reduced basal and histamine-stimulated rates of acid production. Taken together, observations derived from the human material and correlation with data from a transgenic mouse model support an important role for TGF alpha in the pathogenesis of Ménétrier's disease.

Animals↗

PubMed1992

Erythromycin stimulates ileal motility by activation of dihydropyridine-sensitive calcium channels.

Erythromycin, a macrolide antibiotic, is a potent stimulant of small bowel motor activity (MA) which may motility either via the peptide motilin receptor or neural mechanisms. We hypothesized that erythromycin stimulates directly stimulates smooth muscle cells by a calcium-mediated event. Thus, we evaluated the effect of neuronal blockade with tetrodotoxin, muscarinic blockade with atropine, and opiate blockade with naloxone on erythromycin-stimulated MA in isolated perfused segments of rabbit terminal ileum. We also tested the effect of nonspecific calcium channel blockade (verapamil and cadmiun) and specific blockade (dihydroxypyridine and nichol) on erythromycin-stimulated MA. MA was measured with a multichannel continuous perfusion manometry catheter. Erythromycin caused a concentration-dependent increase in MA (ED100 5 x 10(-4) M). Tetrodotoxin, atropine, and naloxone did not effect erythromycin-stimulated MA (P greater than 0.05). Both verapamil (10(-7) M) and cadmium (10(-2)-10(-4) M) inhibited erythromycin-stimulated MA. Selective blockade of "l" type calcium channels using dihydropyridine (10(-6) M) and "t" channels with nickel (10(-2)-10(-4) M) both reversed erythromycin-stimulated MA. Since the isolated segments of terminal ileum were free of exogenous humoral and neural effects, these studies indicated that erythromycin directly stimulated MA in the terminal ileum. Furthermore, since tetrodotoxin, atropine, and naloxone did not inhibit this increase in MA, erythromycin acted by a mechanism which was independent of the intrinsic nervous and opiate systems. In conclusion, these data are consistent with the model that erythromycin stimulates ileal motility by a mechanism involving activation of dihydroxypyridine and nickel-sensitive calcium channels.

Animals↗

PubMed1992

Multiple glomus tumors of the stomach with intravascular spread.

Gastric glomus tumors are characteristically benign solitary lesions. We present a case of multiple glomus tumors involving the stomach wall and perigastric adipose tissue. Histologically, the major portion of each tumor was composed of "typical" glomus cells arranged in a predominantly solid pattern. Cavernous hemangiomalike areas were present toward the periphery. The tumor cells were immunoreactive for alpha-smooth muscle actin, vimentin, laminin, and type IV collagen, but did not express desmin. There were several focal areas where the tumor cells had a signet-ring cell-like appearance, intermingled with cells having clear cytoplasm and hyperchromatic nuclei. Rare mitoses were noted. A striking feature was the presence of widespread but subtle extension of the glomocytes along venous channels subendothelially, with formation of intravascular nodules focally. The multiple separate tumor nodules found in perigastric fat are interpreted as having arisen in this manner. This entity is distinct from previously described typical and atypical solitary glomus tumors, glomangiosarcoma, and the syndrome of multiple glomus tumors of subcutaneous tissues. It may represent an early stage of development of the large, multilobulated glomus tumors that have rarely been reported to involve stomach and adjacent viscera.

Aged↗