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Biomedical subjects

J D Gardner

Publications and source records attributed to J D Gardner.

At least 109 records · Page 6Linked to original sources
PubMed1989

Management of islet cell tumors in patients with multiple endocrine neoplasia: a prospective study.

As part of a study to manage islet cell tumors in patients with multiple endocrine neoplasia (MEN), patients with MEN I and Zollinger-Ellison syndrome (ZES) underwent surgery if a pancreatic islet cell tumor was identified on imaging studies. Patients with MEN I and either insulinoma or vasoactive intestinal polypeptide tumor (VIPoma) underwent surgery whether or not a tumor was identified. Each patient underwent preoperative portal venous sampling (PVS). Nine patients with MEN I and one with MEN II underwent surgery; seven had ZES, one had insulinoma, one had VIPoma, and one had both insulinoma and ZES. Eight of the nine patients with MEN I had an identifiable hormone gradient on PVS. Islet cell tumors were removed from the pancreas of each patient; two patients also had duodenal wall tumors, and three patients had malignant islet cell tumors. No patient with ZES and MEN I was cured of ZES despite the fact that islet cell tumor was removed from the region of the gastrin gradient in five of six patients. The single patient with MEN II and ZES and the three additional patients with MEN I and either insulinoma or VIPoma were cured by islet cell tumor resection. The results indicate that islet cell tumors in patients with MEN I can be both extrapancreatic and malignant. In patients with MEN I and ZES, ZES cannot be cured by tumor resection, and PVS cannot be used to select patients for curative surgery. It appears that gastrinoma in patients with MEN II, as well as either insulinoma or VIPoma in patients with MEN I, can be cured by islet cell tumor resection.

Adenoma, Islet Cell↗
PubMed1989

Recent advances in the management of gastric acid hypersecretion in patients with Zollinger-Ellison syndrome.

Several histamine H2 receptor antagonists and the H+,K(+)-ATPase inhibitor, omeprazole, have been shown to be capable of controlling gastric acid secretion safely and effectively in patients with Zollinger-Ellison syndrome. The relative merits of these agents are discussed, and their use in the acute and long-term control of acid hypersecretion and in special circumstances that require particular care are described. The surgical approaches to the control of acid secretion are described, and the current place of surgery in the management of acid hypersecretion is discussed.

Cimetidine↗
PubMed1989

Diagnosis and management of Zollinger-Ellison syndrome.

With the recent widespread availability of gastrin radioimmunoassays, the development of increasingly effective medical therapy for gastric hypersecretion, and improved methods to localize gastrinomas in patients with Zollinger-Ellison syndrome, the diagnosis, treatment of the gastric acid hypersecretion, and approach to the tumor have changed significantly. Recent advances in each of these areas and the current management of a patient with Zollinger-Ellison syndrome are reviewed.

Humans↗
PubMed1988

An analogue of substance P with broad receptor antagonist activity.

[DPro4,DTrp7,9,10]Substance P-4-11 functions as a substance P receptor antagonist in several different systems. Because some analogues of substance P can function as receptor antagonists for bombesin as well as substance P, we tested [DPro4,DTrp7,9,10]substance P-4-11 for its ability to modify the interaction of various pancreatic secretagogues with their receptors in dispersed acini from guinea pig pancreas. [DPro4,DTrp7,9,19]Substance P-4-11 did not stimulate amylase secretion and did not alter the stimulation of amylase secretion caused by secretin, vasoactive intestinal peptide, calcitonin gene-related peptide or carbachol, but did inhibit the stimulation of amylase secretion caused by substance P, bombesin or cholecystokinin. With substance P, bombesin and cholecystokinin, [DPro4,DTrp7,9,10]substance P-4-11 caused a parallel rightward shift in the dose-response curve for stimulation of amylase secretion with no change in the maximal response. Schild plots of these results gave straight lines with slopes that were not significantly different from unity. [DPro4,DTrp7,9,10]Substance P-4-11 inhibited binding of 125I-labeled substance P, 125I-[Tyr4]bombesin and 125I-cholecystokinin octapeptide over the same range of concentrations as that in which it inhibited biologic activity of each of these peptides. Half-maximal inhibition of binding of 125I-substance P occurred with 4 microM, of 125I-[Tyr4]bombesin with 17 microM and of 125I-cholecystokinin octapeptide with 5 microM. With each radiolabeled peptide the value of Ki for inhibition of binding by [DPro4,DTrp7,9,10]substance P-4-11 was not significantly different from the corresponding value of Ki calculated from the appropriate Schild plot. The present results indicate that [DPro4,DTrp7,9,10]substance P-4-11 is a competitive antagonist at receptors for substance P, for bombesin and for cholecystokinin. Thus, these receptors must share a common peptide recognition mechanism even though they interact with agonists that have no obvious structural similarity.

Amylases↗
PubMed1988

Probing peptide backbone function in bombesin. A reduced peptide bond analogue with potent and specific receptor antagonist activity.

Each peptide bond CONH group in the most important COOH-terminal octapeptide region of [Leu14]bombesin was replaced by a CH2NH group using recently developed rapid solid-phase methods. The resulting analogues were then examined for amylase releasing activity in guinea pig pancreatic acini and for their ability to inhibit binding of [125I-Tyr4]bombesin to acinar cells. Replacement of the Trp8-Ala9, Gly11-His12, and His12-Leu13 peptide bonds resulted in about 1000-, 200-, and 300-fold losses in both amylase releasing activity and binding affinity. The Val10-Gly11 replacement, however, retained 30% potency relative to the parent peptide. Ala9-Val10 and Leu13-Leu14 bond replacement analogues exhibited no detectable amylase releasing activity but were still able to bind to acini with Kd values of 1060 and 60 nM, respectively (compared to 15 nM for [Leu14]bombesin itself). Subsequently, both analogues were demonstrated to be competitive inhibitors of bombesin-stimulated amylase release with IC50 values of 937 and 35 nM, respectively. [Leu14-psi-CH2NH-Leu13]Bombesin exhibits a 100-fold improvement in binding affinity compared to previously reported bombesin receptor antagonists and showed no affinity for substance P receptors. It was also a potent inhibitor of bombesin-stimulated growth of murine Swiss 3T3 cells with an IC50 of 18 nM. In terms of a bombesin receptor-binding conformation, these results may aid in the delineation of intramolecular hydrogen-bonding points and the eventual design of improved, conformationally restricted analogues.

Amylases↗
PubMed1988

Medical management of patients with Zollinger-Ellison syndrome who have had previous gastric surgery: a prospective study.

We examined prospectively the criteria for medical management in 16 patients with Zollinger-Ellison syndrome who had had previous gastric surgery. Each patient received sufficient antisecretory medication to lower gastric acid output to less than 10 mEq/h during the last hour before the next dose of drug. The 7 patients with a vagotomy but no gastric resection were symptom-free and had no mucosal disease. Of 9 patients with a partial gastrectomy, 7 had mucosal disease, with or without symptoms, and 6 of the 7 patients had acid outputs of 5-10 mEq/h. In these patients, antisecretory medication was increased to reduce output to less than 5 mEq/h and symptoms and mucosal abnormalities resolved in each patient. Patients with Zollinger-Ellison syndrome and a vagotomy can be treated safely by reducing acid secretion to less than 10 mEq/h, but in patients with a partial gastrectomy, acid secretion must be reduced to less than 5 mEq/h, and adequacy of therapy must be checked further by endoscopy.

Adolescent↗
PubMed1988

Prospective study of chemotherapy in patients with metastatic gastrinoma.

Ten consecutive patients with metastatic gastrinoma that increased in size over time were studied prospectively during treatment with monthly cycles of streptozotocin (3 g/m2), 5-fluorouracil (1.2 g/m2), and adriamycin (40 mg/m2) to determine the response rate and time-courses of changes during chemotherapy and to assess various methods of evaluating the effect of chemotherapy. Forty percent of patients demonstrated an initial objective response (greater than or equal to 25% decrease in tumor size with no new lesions) and 60% failed chemotherapy (greater than or equal to 25% increase in tumor size or appearance of new lesions). The mean dose of streptozotocin was 27 g/m2 with objective responses occurring at 3.7 +/- 0.7 mo and failures at 4.5 +/- 0.7 mo. Responses lasted 9.7 +/- 2.8 cycles and no complete responses occurred. Survival was not significantly different in responders versus nonresponders (26 +/- 11 vs. 15 +/- 4.8 mo, p greater than 0.1). Changes in serum gastrin concentration, basal acid output, or sensitivity to a given dose of histamine H2-receptor antagonist did not reflect changes in tumor size. Computed tomography and angiography were the best methods to assess changes in tumor size during chemotherapy, whereas liver-spleen scan and ultrasound were relatively insensitive. All patients developed side effects with chemotherapy: 100% had vomiting, 80% alopecia, 40% transient proteinuria, and 20% leukopenia. The present results indicate that chemotherapy with streptozotocin, 5-fluorouracil, and adriamycin is much less effective in patients with extensive metastatic gastrinoma than previously reported. Computed tomography scanning is the method of choice to assess changes in tumor size. Changes in serum gastrin concentration, acid secretion, or tumor size assessed by liver-spleen scan or ultrasound are not sensitive indicators of the tumor response during chemotherapy.

Adult↗
PubMed1988

Gastrointestinal dysfunction in systemic mastocytosis. A prospective study.

In 16 consecutive patients with systemic mastocytosis, we prospectively evaluated a variety of gastrointestinal functions and examined how they relate to the occurrence of gastrointestinal symptoms. Nine patients had either a duodenal ulcer or duodenitis. Hypersecretion of gastric acid was present in 6 patients, and in these patients the mean basal acid output was 20.7 +/- 4.1 mEq/h (range 14-39 mEq/h). Impaired small intestinal absorption occurred in 5 patients, although this was usually mild. The mean fractional emptying rate of liquids for all patients (14.7% +/- 2.3% per minute) did not differ from that for controls (10.7% +/- 0.6% per minute). Mean mouth-to-cecum transit time measured by breath hydrogen testing was the same among patients (87.7 +/- 6.7 min) and controls (86.7 +/- 8.0 min). Plasma histamine concentrations were increased in all patients (mean 1886 pg/ml, range 480-7450) and correlated with the basal acid output (r = 0.64, p less than 0.02) but not maximal acid output or the presence or absence of pain or diarrhea. Mean fasting plasma concentrations of motilin, substance P, and neurotensin from 6 patients did not differ significantly from controls, whereas gastrin and vasoactive intestinal peptide were significantly less than in controls (p less than 0.01). Gastrointestinal symptoms, consisting of abdominal pain or diarrhea, occurred in 80% of patients. Abdominal pain classified as dyspeptic was usually associated with acid-peptic disease of the duodenum and hypersecretion of gastric acid, whereas abdominal pain of a nondyspeptic character was not. Only in those cases of diarrhea consisting of greater than 200 g stool/day was gastric acid hypersecretion frequently found. Neither fecal urgency nor nondyspeptic pain could be accounted for by alterations of gastrointestinal transit. These results demonstrate that gastrointestinal symptoms, peptic disease, and mild malabsorption are much more common than described previously in patients with systemic mastocytosis. Furthermore, the results provide no evidence for the contention that altered gastrointestinal transit is involved in the pathogenesis of these symptoms.

Adult↗
PubMed1988

Intraoperative ultrasonographic localization of islet cell tumors. A prospective comparison to palpation.

The purpose of the present study was to evaluate prospectively the value of intraoperative ultrasound scanning (IOUS) in localizing islet cell tumors by comparing results of IOUS to those of palpation during 44 consecutive laparotomies for gastrinoma (36) or insulinoma (8). All patients had preoperative radiographic imaging studies and selective venous sampling for hormones, which guided the subsequent laparotomy. Any suspicious finding by palpation and/or IOUS was resected. Pathologic evidence of islet cell neoplasm served as the reference standard. Five patients were excluded from analysis because neither palpation nor IOUS had suspicious findings and no islet cell tumor was found. Seven pancreatic insulinomas were found in seven patients. IOUS was as sensitive as palpation at localizing insulinomas. Twenty-three pancreatic gastrinomas were found in 19 patients. IOUS was equal to palpation in the ability to localize gastrinomas. Gastrinomas that were successfully imaged by IOUS were significantly larger than gastrinomas that were not imaged. Twelve extrapancreatic gastrinomas were found in nine patients, and palpation was more sensitive than IOUS at localizing these small duodenal wall tumors. Five patients (11%) had their surgical management changed by IOUS. Two patients had pancreatic tumors (one gastrinoma and insulinoma) enucleated that would not have been found without IOUS, and three patients had resections of pathologically proven malignant islet cell tumors based on sonographic findings. All five patients were cured with short follow-up. The present results demonstrate that palpation and IOUS are complementary because IOUS can image tumors that are not palpable and IOUS can provide additional information concerning malignant potential not detected by palpation.

Adenoma, Islet Cell↗
PubMed1988

Functionally distinct receptors for cholecystokinin and gastrin on dispersed chief cells from guinea pig stomach.

Caerulein, gastrin, and C-terminal fragments of cholecystokinin (CCK) varying in length from eight (CCK-8) to four (CCK-4) amino acids stimulate pepsinogen secretion from dispersed chief cells prepared from guinea pig stomach. C-terminal fragments of CCK containing fewer than four amino acids, even when tested at concentrations as high as 3 mM, do not stimulate pepsinogen secretion. The efficacies of gastrin and the various CCK-related peptides, coupled with the pattern of action of CCK receptor antagonists, indicate that chief cells from guinea pig stomach possess two functionally distinct classes of receptors, C-receptors and G-receptors. The C-receptors can be occupied by caerulein, CCK-8, CCK-7, des(SO3)CCK-8, or des(SO3)CCK-7, and occupation of C-receptors causes full stimulation of pepsinogen secretion. G-receptors can be occupied by gastrin I, gastrin II, CCK-6, CCK-5, or CCK-4, and occupation of G-receptors causes stimulation of pepsinogen secretion that is 60% of maximal.

Animals↗
PubMed1988

Characterization of receptors for calcitonin gene-related peptide on gastric smooth muscle cells.

Rat calcitonin gene-related peptide (rat CGRP) and related peptides did not cause contraction of gastric smooth muscle cells; however, preincubation with rat CGRP or human CGRP inhibited smooth muscle contraction caused by carbachol. Rat CGRP and human CGRP were equipotent in opposing contraction with a half-maximal effect produced by 0.1 nM, but rat calcitonin-adjacent peptide (rat CAP) and human calcitonin had no effect. Rat CGRP caused an increase in cellular adenosine 3',5'-cyclic monophosphate (cAMP) of 60%, which was augmented to 155% with 1 mM isobutyl methylxanthine (IBMX). IBMX did not influence the sensitivity of the muscle cells to rat CGRP to increase cAMP, the half maximal effect being produced by 0.4 nM in the presence or absence of IBMX. Rat CGRP and human CGRP were equipotent for stimulating cAMP, but rat CAP and human calcitonin had no effect. Binding of 125I-CGRP was temperature dependent, saturable, reversible, and specific. Rat CGRP and human CGRP were equipotent at inhibiting binding of 125I-CGRP and rat CAP, and human calcitonin did not inhibit binding. For rat CGRP and human CGRP, the dose-response curves for binding of 125I-CGRP were broad, and both peptides accelerated the rate of dissociation of bound 125I-CGRP. Computer analysis of dose-response curves demonstrated two classes of binding sites for CGRP, one with a high affinity (Kd 3 nM) and another with low affinity (Kd 3,700 nM). Our results indicate that CGRP interacts with previously undescribed receptors on gastric smooth muscle cells to increase cellular cAMP and inhibit contraction.

1-Methyl-3-isobutylxanthine↗
PubMed1988

Characterization of ability of various substance P antagonists to inhibit action of bombesin.

In the present study the ability of two classes of substance P (SP) antagonists to affect SP- and bombesin (Bn)-stimulated amylase release, as well as binding of 125I-Bolton-Hunter (BH)-SP and 125I-[Tyr4]Bn, was studied to determine their mechanism of action and the relationship between inhibition of the action of SP and the action of Bn. Four SP analogues ([D-Pro2,D-Phe7,D-Trp9]SP, [D-Pro2,D-Trp7,9]SP, [D-Arg1,D-Pro2,D-Trp7,9,Leu11]SP, and [D-Arg1,D-Trp7,9,Leu11]SP) and two SP-(4-11) analogues ([D-Pro4,D-Trp7,9]SP-(4-11) and [D-Pro4,D-Trp7,9,10]SP-(4-11)] did not stimulate amylase release when present alone but inhibited SP- and Bn-stimulated amylase release. For each SP analogue, inhibition was specific for peptides that stimulate release by interacting with SP or Bn receptors, whereas both SP-(4-11) analogues also inhibited cholecystokinin-stimulated amylase release. Each SP analogue's inhibition of Bn-stimulated amylase release was reversible. Each analogue inhibited binding of 125I-BH-SP with the same potency as it inhibited SP-stimulated amylase release and 125I-[Tyr4]Bn binding with the same potency as it inhibited Bn-stimulated amylase. In contrast, SP itself or SP-(4-11) itself did not inhibit Bn-stimulated amylase release or binding of 125I-[Tyr4]Bn. The relative affinities of the analogues for interacting with Bn and SP receptors differed. None of the analogues increased the dissociation of bound 125I-BH-SP or 125I-[Tyr4]Bn.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1988

Kinetics of binding of cholecystokinin to pancreatic acini.

In the present study we examined the kinetics of binding of iodinated COOH-terminal octapeptide of cholecystokinin (125I-CCK-8) to its receptors on dispersed acini prepared from guinea pig pancreas. At 37 degrees C, binding of 125I-CCK-8 reached a steady state after 60 min of incubation. Dissociation of bound 125I-CCK-8 was biphasic, indicating that the labeled peptide binds in two distinct states: a rapidly dissociating state and a slowly dissociating state. Binding of 125I-CCK-8 in the rapidly dissociating state was maximal within 3 min of incubation, did not depend on incubation temperature or cellular energy metabolism, could be stripped by 0.5 M potassium thiocyanate, and showed accelerated dissociation with CCK-8 or dibutyrylguanosine 3',5'-cyclic monophosphate (Bt2cGMP). Binding of 125I-CCK-8 in the slowly dissociating state was maximal after 60 min of incubation, was decreased by reducing the incubation temperature or inhibiting cellular energy metabolism, was not stripped by 0.5 M potassium thiocyanate, and did not show accelerated dissociation with CCK-8 or Bt2cGMP. Increasing the concentration of 125I-CCK-8 increased the fraction of radioactivity bound in the rapidly dissociating state. When binding of 125I-CCK-8 reached a steady state, nearly all of the bound radioactivity was in the slowly dissociating state. Computer analysis of the inhibition of 125I-CCK-8 by CCK-8 under experimental conditions where the rapidly dissociating state predominates demonstrated a complete loss of high-affinity binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Cholecystokinin receptors on gallbladder muscle and pancreatic acinar cells: a comparative study.

To compare receptors for cholecystokinin (CCK) in pancreas and gallbladder, we measured binding of 125I-Bolton-Hunter-labeled CCK-8 (125I-BH-CCK-8) to tissue sections from guinea pig gallbladder and pancreas under identical conditions. In both tissues, binding had similar time-, temperature-, and pH dependence, was reversible, saturable and inhibited only by CCK related peptides or CCK receptor antagonists. Autoradiography localized 125I-BH-CCK-8 binding to the smooth muscle layer in the gallbladder. Binding of 125I-BH-CCK-8 to gallbladder sections was inhibited by various agonists with the following potencies (IC50):CCK-8 (0.4 nM) greater than des(SO3)CCK-8 (0.07 microM) greater than gastrin-17-I (1.7 +/- 0.3 microM) and by various receptor antagonists with the following potencies: L364,718 (1.5 nM) greater than CR 1409 (0.19 microM) greater than asperlicin = CBZ-CCK-(27-32)-NH2 (1 microM) greater than Bt2cGMP (120 microM). Similar potencies were found for the agonists and antagonists for pancreas sections. Inhibition of binding of 125I-BH-CCK-8 by 11 different analogues of proglumide gave similar potencies for both pancreas and gallbladder. The potencies of agonists in stimulating and antagonists in inhibiting CCK-stimulated contraction or amylase release correlated closely with their abilities to inhibit 125I-BH-CCK-8 binding to gallbladder or pancreas sections or acini, respectively. The present results demonstrate and characterize a method that can be used to compare the CCK receptors in guinea pig gallbladder and pancreas under identical conditions. Moreover, this study demonstrates that gallbladder and pancreatic CCK receptors have similar affinities for the various agonists and antagonists tested and, therefore, provides no evidence that they represent different subtypes of CCK receptors that can be distinguished pharmacologically.

Animals↗
PubMed1988

A prospective study of perioperative and postoperative control of acid hypersecretion in patients with Zollinger-Ellison syndrome undergoing gastrinoma resection.

Fifty-five consecutive patients with Zollinger-Ellison syndrome who underwent exploratory laparotomies for gastrinoma resection were evaluated prospectively to determine the effect of gastrinoma resection on acid secretion and to establish criteria for safe and effective perioperative management of gastric acid hypersecretion. In 15 patients (27%) no tumor was found and postoperative serum gastrin, basal acid output (BAO), and maximal acid output (MAO) were unchanged. Twenty-one patients (38%) had gastrinomas resected and were biochemically cured. Median fasting gastrin, median delta secretin, mean BAO, and mean MAO decreased 89%, 94%, 80%, and 43%, respectively, at 3-month follow-up in these patients. In 19 patients gastrinomas were resected, but patients were not cured, and median fasting gastrin, median delta secretin, mean BAO, and mean MAO decreased 47%, 10%, 26%, and 25%, respectively. Forty percent of patients with gastrinoma resected and cured and 81% of patients with gastrinoma resected but not cured continued to hypersecrete acid (BAO greater than 10 mEq/hr) at 3- to 6-month follow-up. Acid control was managed perioperatively during gastrinoma resection by continuous intravenous infusion of H2 receptor antagonists at a dose established by preoperative titration to decrease acid output to less than 10 mEq/hr. Thirty patients were treated with cimetidine at a mean dose of 3.2 mg/kg/hr for a mean of 13.8 days. Twenty-one patients were treated with ranitidine at a mean dose of 1.1 mg/kg/hr for a mean of 8 days. No patients suffered any complications related to acid hypersecretion or side effects of the H2 antagonists. Patients undergoing gastrinoma resection can be managed safely by continuous infusion of H2 antagonists. Successful gastrinoma resection can reduce acid output, but even 40% of biochemically cured patients will continue to hypersecrete acid at short-term follow-up and will require continuation of antisecretory medication.

Adult↗
PubMed1987

Cholecystokinin-induced residual stimulation of enzyme secretion from mouse pancreatic acini.

When dispersed acini from mouse pancreas are first incubated with cholecystokinin octapeptide, washed and then reincubated with no additions there is significant stimulation of amylase secretion during the second incubation (residual stimulation of enzyme secretion). Cholecystokinin-induced residual stimulation of enzyme secretion is modified, but not abolished, by reducing the temperature of the first incubation from 37 degrees C to 4 degrees C. Measurement of binding of 125I-labeled cholecystokinin octapeptide indicated that maximal cholecystokinin induced residual stimulation of enzyme secretion occurs when 12-20% of cholecystokinin receptors are occupied by cholecystokinin octapeptide. Moreover, maximal cholecystokinin-induced residual stimulation of amylase secretion is 25% greater than maximal cholecystokinin-induced direct stimulation of amylase secretion. Cholecystokinin tetrapeptide, which causes the same maximal direct stimulation of amylase secretion as does cholecystokinin octapeptide, causes a maximal residual stimulation of enzyme secretion that is only 30% of that caused by a maximally effective concentration of cholecystokinin octapeptide. Adding dibutyryl cyclic GMP to the second incubation can reverse the residual stimulation caused by adding cholecystokinin to the first incubation. The pattern and extent of the dibutyryl cyclic GMP-induced reversal of residual stimulation varies, depending on the temperature and concentration of cholecystokinin octapeptide in the first incubation. The present results are compatible with the hypothesis that mouse pancreatic acini possess two classes of cholecystokinin receptors. One class has a relatively high affinity for cholecystokinin and produces stimulation of enzyme secretion; the other class has a relatively low affinity for cholecystokinin and produces inhibition of enzyme secretion.

Amylases↗