Biomedical subjects

I M Modlin

Publications and source records attributed to I M Modlin.

At least 163 records · Page 9Linked to original sources

PubMed1991

The therapeutic role of octreotide in the management of surgical disorders.

The long-acting somatostatin analogue, octreotide, has recently been made available for clinical use in the United States. This novel synthetic peptide possesses a broad spectrum of physiologic actions primarily involving the inhibition of a variety of gastrointestinal and endocrine functions. Such actions have been utilized in the management of a variety of surgical disorders. Current understanding of the indications and efficacy of this agent in the treatment of surgical disease is reviewed.

Amino Acid Sequence↗

PubMed1991

Intracellular activation of digestive zymogens in rat pancreatic acini. Stimulation by high doses of cholecystokinin.

The mechanism by which digestive zymogens become activated during acute pancreatitis remains poorly understood. Given the ability for cholecystokinin (CCK) to induce pancreatitis in vivo, the effects of high dose CCK on preparations of isolated pancreatic acini were examined. Using an immunologic technique for the detection of zymogen activation, CCK was found to stimulate the conversion of procarboxypeptidase A1 to a 35-kD form having the same net charge and electrophoretic mobility as purified recombinant carboxypeptidase A1. This enhanced conversion was proportional to the dose of CCK (maximal at 100 nM), and time dependent. CCK also produced changes in the electrophoretic mobility of procarboxypeptidase B and chymotrypsinogen 2 immunoreactivity, consistent with activation of these zymogens. These events were detectable only within acinar cell pellets and not in the incubation medium, suggesting an intracellular site of conversion. The conversion of procarboxypeptidase A1 to its active form was inhibited by pretreatment with the weak base chloroquine (40 microM) and the protonophore monensin (10 microM). This conversion was also inhibited by pretreatment with the serine protease inhibitor benzamidine (10 mM) but not the cysteine protease inhibitor E64 (100 microM). The results suggest that high dose CCK stimulates the intracellular activation of digestive zymogens within isolated pancreatic acini. This event appears to require an acidic subcellular compartment and serine protease activity.

Animals↗

PubMed1991

Distribution and immunocytochemical colocalization of peptide YY and enteroglucagon in endocrine cells of the rabbit colon.

Peptide YY (PYY) is 36 amino acid peptide hormone present in high concentrations in the colon where it is colocalized with enteroglucagon in L cells. A selective release of PYY and enteroglucagon from the rabbit colon has been described, raising the question of the exact localization of the two hormones in the rabbit colon. We have therefore examined the distribution of PYY and enteroglucagon as well as somatostatin in the rabbit colon using RIA and electron microscopic immunocytochemistry. PYY and enteroglucagon were present in high concentrations in the colorectal mucosa with peak concentrations in the left colon (PYY 544 +/- 87 pmol/g, enteroglucagon 152 +/- 10 pmol/g). Electron microscopic examination of the colonic mucosa demonstrated a large population (65%) of EC cells, a moderate population (30%) of L cells, and a small population (5%) of D cells. By immunogold labeling serotonin was localized to EC cells, PYY and enteroglucagon to L cells, and somatostatin to the D cell. Double immunogold labeling revealed PYY and enteroglucagon in all L cells examined (93 cells). A majority of the secretory granules (83%) were labeled by both PYY and glucagon antibodies, whereas a significant portion of granules (15%) was labeled by the PYY antibodies alone. The results demonstrate that L cells are the sole source of PYY and enteroglucagon in the rabbit colon and that L cells contain different populations of secretory granules. The existence of different secretory granules in L cells may explain the selective release of PYY and enteroglucagon observed in the rabbit colon.

Animals↗

PubMed1991

Short-chain fatty acid release of peptide YY in the isolated rabbit distal colon.

Short-chain fatty acids (SCFAs) form the major ionic fraction of stool, provide the major metabolic substrate for colonic epithelium, and promote mucosal ion transport. Despite this prominent role of SCFAs in metabolism of the colon, their effect on colonic endocrine cell function has not been studied. Consequently, we hypothesized that SCFAs might modulate release of peptide YY (PYY) from colonic type-L endocrine cells. The specific aims of this study were to measure release of PYY from the isolated perfused rabbit distal colon stimulated by intraluminal infusion of 0.9% saline, acetate (10 mM), acetoacetate (10 mM), n-butyrate (1, 3.3, 10, 100 mM), and pyruvate (10 mM). PYY levels were measured by radioimmunoassay in the venous effluent of the rabbit colon. All four SCFAs (10 mM) caused at least a twofold increase in integrated release of PYY from the isolated perfused rabbit colon. Graded concentrations of n-butyrate caused a stepwise release of PYY. This study suggests that SCFAs may modulate the release of colonic PYY in rabbits.

Acetates↗

PubMed1991

Enterochromaffin-like cells and gastric argyrophil carcinoidosis.

The relevance of enterochromaffin-like (ECL) cells in gastric pathobiology has generated considerable interest particularly since the recent description of a pathological state characterized as gastric argyrophilic carcinoidosis. The morphological and biofunctional properties of these cells are distinct from other gastric endocrine cells. It is probable that ECL cells have a major role in the regulation of parietal cell function. Other possible functions may include a trophic regulatory influence. Of particular interest is the recent observation that agents which result in profound and sustained acid inhibition may cause ECL cell hyperplasia. This phenomenon has also been noted in human disease states in which a significant decrease in acid section is evident (pernicious anemia/atrophic gastritis). In patients with gastrinomas of the multiple endocrine neoplasia type I group, therapeutically induced acid inhibition may result in gastric ECL hyperplasia and even neoplasia (gastric carcinoid or ECLoma). Similarly, in the rodent species mastomys, which is genetically predisposed to the formation of gastric carcinoids, exposure to acid inhibitory agents results in rapid (90-120 days) development of gastric carcinoids. The pathobiological relevance of ECL cells and the mechanisms of their inducible hyperplasia and neoplasia may be of considerable significance in understanding the regulatory role of gastric endocrine cells.

Animals↗

PubMed1991

Sustained suppression of gastric secretion and the risk of neoplasia in the gastric mucosa.

Long-term risks of medications that cause profound and sustained suppression of acid secretion are an increasing source of concern. Because of concerns over a potentially increased incidence of gastric malignancies in patients with pernicious anemia, clinicians have become increasingly aware of changes in gastric flora, and levels of carcinogen, as well as changes in hormonal milieu, which can accompany profound suppression of acid secretion. The risks of gastric epithelial and endocrine cell neoplasia in patients receiving powerful antisecretory agents are not yet known, but cannot be dismissed until long-term follow-up studies are available. The relationship between proliferation of epithelial and endocrine elements and sustained suppression of acid secretion may provide new insight into processes that regulate replication and growth of cells in the gastric mucosa.

Achlorhydria↗

PubMed1990

Increasing incidence of cecal and sigmoid carcinoma. Data from the Connecticut Tumor Registry.

We have studied both the distribution and incidence of colorectal cancer using The Connecticut Tumor Registry, the oldest tumor registry in the United States. During the time period 1973 to 1985, left-sided colon cancers accounted for 63% of the cancers, right-sided cancers 33%, and cancers with unspecified sites 4%. Indeed, this pattern of distribution has remained constant for 25 years. For the period 1935 to 1985, we calculated the sex-specific, age-adjusted (normalized to the 1970 U.S. Census) incidence. Age-adjusted incidence of rectal cancer has remained stable for 50 years: for men, 22.8 cases/100,000/year, and for women, 13.9 cases/100,000/year. During these 50 years, the age-adjusted incidence of cecal carcinoma for men has increased from 3.6 to 16.7 cases/100,000/year, while for women, it has increased from 4.9 to 14.2 cases/100,000/year. Sigmoid carcinoma for men has increased from 8.8 to 18.7 cases/100,000/year, and for women, it has increased from 7.7 to 12.8 cases/100,000/year. The incidence of colon cancer at each site has been and continues to be increasing at a constant rate. Age-adjusted incidence for all colorectal cancers has increased from 35.2 to 70.2 cases/100,000/year for men and from 32.1 to 49.2 cases/100,000/year for women. Thus, distribution of colorectal cancers by site in Connecticut has remained stable for 25 years. More importantly, however, the age-adjusted incidence of colon cancer has continued to increase for 50 years, whereas that of rectal cancer has remained relatively stable.

Cecal Neoplasms↗

PubMed1990

Significance of gastric endocrine tumor and age-related gut peptide alterations in Mastomys.

The Mastomys (Praomys natalensis) species are a unique natural model in which the bioactivity of gastric carcinoids may be studied. Several investigators have previously demonstrated that these tumors contain large amounts of histamine. In this study we investigated the presence of peptides associated with the neoplasm. The levels and location of gastrin, gastric inhibitory peptide (GIP), neurotensin, peptide YY (PYY), pancreatic polypeptide (PP), glucagon, bombesin, vasoactive intestinal peptide (VIP) and somatostatin (SRIF) were investigated by radioimmunoassay and immunocytochemistry. In addition the distribution of these peptides were evaluated in the gastrointestinal tract of young and old animals to investigate possible age-related changes. PYY and enteroglucagon (EG) were significantly (P less than 0.001) elevated in both tumor tissue (676 +/- 152, 551 +/- 164 pmol/g) and plasma (620 +/- 160, 500 +/- 147 pmol/l) of tumor-bearing animals. Immunocytochemistry revealed PYY- and EG-like immunoreactivity in 20-30% of tumor cells. A significant decrease (P less than 0.05) in bombesin was noted in older animals, but no changes in gastric tissue content of PYY or EG could be detected between young and old animals. Gastrin was not detected in tumors and there were no significant changes in tissue or plasma levels with age. Small bowel concentrations of VIP and PYY were higher in the older mastomys (P less than 0.05). In contrast, colonic levels of bombesin, VIP, somatostatin and PYY were significantly lower (P less than 0.05) in older mastomys compared with young. The age-related changes in several peptides may reflect an adaptive response to acid hypersecretion. The multi-hormonal character of these neoplasms suggests that these tumors develop from a pluripotential stem cell.

Age Factors↗

PubMed1990

Amelioration of cholinergic-induced pancreatitis with a selective cholecystokinin receptor antagonist.

Acute edematous pancreatitis follows excessive cholinergic stimulation in patients exposed to anticholinesterase-containing insecticides. We describe the role of cholecystokinin and the benefits of cholecystokinin receptor blockade in this form of pancreatitis. A cholinergic mimetic (carbachol) was administered to rats weighing 300 to 350 g and produced a form of edematous pancreatitis that mimics that seen in humans. Animals received carbachol intraperitoneally, either alone (250 micrograms/kg of body weight) or with cholecystokinin-receptor antagonist devazepide (3 mg/kg of body weight) and were killed 4 hours later. Carbachol administration resulted in a 19% increase in pancreatic weight, a fourfold increase in serum amylase levels, and a 14-fold increase in serum lipase levels. Plasma cholecystokinin levels, however, were not altered. Devazepide administered prior to cholinergic hyperstimulation blocked pancreatic weight increase and reduced elevations in serum amylase levels twofold and lipase levels fourfold. Although cholecystokinin levels are not elevated in this model of pancreatitis, blockade of even low, background concentrations of this regulatory peptide is beneficial.

Acute Disease↗

PubMed1990

Neuropeptide Y inhibition of vasoactive intestinal polypeptide-stimulated ion transport in the rabbit distal colon.

We have studied the effect of neuropeptide Y on basal and vasoactive intestinal polypeptide-stimulated changes in the short-circuit current of strips of colonic mucosa from New Zealand white rabbits mounted in Ussing chambers. When administered to the basolateral surface, neuropeptide Y is found to decrease basal short-circuit current. Neuropeptide Y inhibits vasoactive intestinal peptide-stimulated increases in short-circuit current in a concentration-dependent fashion by a tetrodotoxin-insensitive mechanism. Also, neuropeptide Y inhibited increases in short-circuit current produced by direct stimulation of adenylate cyclase with forskolin. Furthermore, neuropeptide Y prevents vasoactive intestinal peptide-stimulated increases in tissue cyclic adenosine monophosphate levels. These results indicate that neuropeptide Y administered to the basolateral membrane inhibits vasoactive intestinal peptide-stimulated short-circuit current changes by a tetrodotoxin-insensitive mechanism that decreases tissue levels of cyclic adenosine 3',5'-monophosphate.

Animals↗

PubMed1990

Intra-ocular transplantation of carcinoid tumours from mastomys and humans.

Carcinoid tumours from man and Mastomys (Praomys) natalensis produce a variety of peptide hormones. The study of these peptide-secreting tumours has been difficult because of the small amount of tissue available and because of limitations with present cell culture systems. The aim of this study was to establish an experimental model where carcinoid tumours could be maintained and their hormone secretion studied. The intra-ocular transplantation technique was chosen for its simplicity and high rate of success. Gastric carcinoid tumours from mastomys (n = 4) and human carcinoids (n = 2) (one bronchial and one ileal) were transplanted to the anterior eye chamber of Sprague-Dawley rats. Pieces of fresh tumour tissue were injected into the anterior eye chamber of rats and allowed to grow for 4-8 weeks. Rats transplanted with human tissue were immunosuppressed by daily injections with cyclosporin A (20 mg/kg). Eye chambers were inspected regularly and plasma from transplanted rats was collected for assay of peptide YY (PYY) and glucagon. Vascularization of transplants occurred within 1-2 days after transplantation in 70-80 per cent of all experiments. Microscopic analysis of transplants demonstrated a rich supply of blood vessels to tumour cells which contained characteristic neurosecretory granules. Transplanted rats had significantly (P less than 0.05) elevated levels of PYY (44-165 pmol/l) and glucagon (67-162 pmol/l) in plasma as compared with sham-operated rats (PYY 28-40 pmol/l, glucagon 33-40 pmol/l), indicating that hormone secretion by tumour cells in oculo was maintained.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Colorectal disease in spinal cord patients. An occult diagnosis.

Undiagnosed abdominal emergencies account for 10 percent of all fatalities among patients with spinal cord injuries. A large number of these emergencies involve the lower gastrointestinal tract. The purpose of this study is to bring attention to the occult nature of colorectal disease in spinal cord patients and to highlight the subtle, but characteristic, symptoms and signs that develop in these patients. The authors identified 13 spinal cord patients in whom a lesion developed in either the appendix, colon, rectum, or anus. The average age of all patients was 36.2 years. Trauma and multiple sclerosis were the most common etiology of spinal cord injury. The most common presenting symptoms were abdominal distention, vomiting, and constipation. The average delay in diagnosis of the colorectal disease was 35.8 hours. An 84% morbidity and 22% mortality were observed. This study indicates that any deviation from the normal lifestyle of the spinal cord patient should alert one to the possibility of visceral inflammation. Furthermore, close attention to the signs of autonomic dysreflexia or changes in spasticity, along with a thorough evaluation of the ill-appearing spinal cord patient, may uncover occult colonic or rectal disease.

Adolescent↗

PubMed1990

Effect of cholecystokinin receptor blockade on human lymphocyte proliferation.

Cholecystokinin is a peptide produced by neuroendocrine cells in gut and neurons in brain and gut. Proliferating human peripheral blood mononuclear cells (H-PBMC) also make small amounts of cholecystokinin. Cholecystokinin increases intracellular calcium (Ca2+) in H-PBMC. This can be blocked with L 364, 718, a non-toxic specific cholecystokinin antagonist. Cholecystokinin is a comitogen for H-PBMC and activates H-PBMC in a cyclosporine-resistant fashion. If cholecystokinin is a critical lymphokine, then L 364, 718 should block H-PBMC mitogenesis. H-PBMC from healthy donors were stimulated in vitro with either phytohemagglutinin or anti-CD3 monoclonal antibody. L 364, 718 was not toxic for H-PBMC, yet inhibited mitogenesis at 10(-7), 10(-6), and 10(-5) M. The small amount of cholecystokinin made by H-PBMC may play a critical role in H-PBMC mitogenesis.

Antibodies, Monoclonal↗

PubMed1990

Experimental models of acute pancreatitis.

Acute pancreatitis remains a disease of uncertain pathogenesis and nonspecific therapy. Because of the practical problems plaguing investigation of pancreatitis in man, investigators have developed various experimental animal models of pancreatitis in order to develop rationale concepts regarding pathogenesis and therapy. Despite numerous investigations over the past century, the events involved in the initiation and progression of pancreatitis remain obscure. Indeed, identification of the cellular mechanisms responsible for the initiation of this disease may allow for significant advances in therapy. Previous studies have largely focused on the mechanism of pancreatitis at the organ level. It is now apparent that the early initiating events in acute pancreatitis probably occur at a membrane or intracellular level. The resolution of the cellular events which underlie the development of pancreatitis in combination with the introduction of new therapeutic agents may enable a rational and safe protocol to be developed for the support of patients with pancreatitis. In this review different experimental models of acute pancreatitis are discussed. Emphasis is placed on the relevance of various models to clinical pancreatitis.

Acute Disease↗

PubMed1990

Hypothermia and acidosis worsen coagulopathy in the patient requiring massive transfusion.

Massive transfusion may cause abnormalities of electrolytes, clotting factors, pH, and temperature and may occur in a scenario of refractory coagulopathy and irreversible shock. Identification of correctable variables to improve survival is complicated by the interplay of this pathophysiology. Temperature may be an under-appreciated problem in the genesis of coagulopathy. In vitro studies have demonstrated that platelet function and vascular response are critically temperature-dependent. We reviewed the records of 45 trauma patients without head injury or co-morbid medical illness who required massive transfusions. The mean Injury Severity Score was 55 +/- 6, a mean of 22.5 +/- 5 units of blood was transfused, and mortality was 33%. Nonsurvivors were more likely to have had penetrating injury (88% versus 55%), received more transfusions (26.5 +/- 9 versus 18.6 +/- 1, p less than 0.05), had lower pH (pH 7.04 +/- 0.06 versus 7.18 +/- 0.02, p less than 0.05), had lower core temperature (31 +/- 1 degree C versus 34 +/- 1 degree C, p less than 0.01), and had a higher incidence of clinical coagulopathy (73% versus 23%). Severe hypothermia (temperature less than 34 degrees C) occurred in 80% of the nonsurvivors and in 36% of survivors. Patients who were hypothermic and acidotic developed clinically significant bleeding despite adequate blood, plasma, and platelet replacement. Avoidance or correction of hypothermia may be critical in preventing or correcting coagulopathy in the patient receiving massive transfusion.

Acidosis↗

PubMed1990

The increasing prevalence of acalculous cholecystitis in outpatients. Results of a 7-year study.

Acute acalculous cholecystitis (AAC) is a disease that causes high rates of morbidity such as those traditionally observed in the critically ill. Recently we noted an increase in the de novo presentation of outpatients with this disease. Our aim was to characterize this disease in outpatients, identify risk factors, and assess clinical outcome. Therefore a 7-year review of the Yale experience with AAC was undertaken. Forty-seven patients were identified. Seventy-seven per cent (36 of 47 patients) developed AAC at home without evidence of acute illness or trauma, while 23% (11 of 47 patients) developed the disease while hospitalized. Significant vascular disease was observed in 72% of outpatients. A 38% morbidity rate and 6% mortality rate were observed. We conclude that AAC occurs commonly in elderly male outpatients with vascular disease and that these patients incur significant morbidity in association with this condition. AAC should be suspected and prompt surgical management instituted when these patients present with an acute right upper quadrant inflammatory process.

Acute Disease↗

PubMed1990

Acute pancreatitis at its centenary. The contribution of Reginald Fitz.

1989 represents the 100th anniversary of Reginald Fitz's initial characterization of acute pancreatitis. Our current understanding of this disease has advanced little beyond Fitz's early description. While survival from pancreatitis has improved largely through advancements in critical care techniques, no medical or surgical therapy exists that can limit pancreatic autodigestion and inflammation. Recent investigations have suggested that pancreatitis may result from a disruption of normal stimulus-secretion coupling within the acinar cell. Future research based on these observations may ultimately result in successful therapy for this disease.

Acute Disease↗

PubMed1990

Effects of epidermal growth factor on signal transduction in rabbit parietal cells.

The aim of this study was to elucidate the cellular mechanisms of action of epidermal growth factor (EGF) inhibition of parietal cell secretion. EGF effects on histamine- and carbachol-stimulated [14C]aminopyrine (AP) uptake and intrinsic factor (IF) secretion were evaluated in isolated rabbit parietal cells. EGF inhibited histamine-stimulated [14C]AP uptake and IF secretion through a reduction in stimulated adenosine 3',5'-cyclic monophosphate (cAMP) levels. EGF decreased the phosphorylation of a cytosolic 30-kDa, histamine-stimulated, cAMP-dependent protein kinase substrate. These effects on histamine-stimulated activation were reversed by pertussis toxin preincubation. EGF inhibited carbachol-stimulated [14C]AP uptake and IF secretion, but did not alter the carbachol-stimulated Ca2+ transient. These results indicate that EGF inhibits histamine-stimulated secretion through the inhibitory Gi guanosine 5'-triphosphate-binding protein and carbachol-stimulated secretion through a mechanism independent of the activation of an increase in intracellular Ca2+.

Aminopyrine↗