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Biomedical subjects

L Bardram

Publications and source records attributed to L Bardram.

At least 55 records · Page 3Linked to original sources
PubMed1990

Gastrin in non-neoplastic pancreatic tissue from patients with and without gastrinomas.

Processing-independent radioimmunoanalysis for progastrin showed that extracts of normal pancreatic tissue from normal subjects (n = 5) and from patients with adenocarcinoma of the papilla of Vater (n = 4) contain progastrin and its products. The concentrations varied from 0.1 to 5.8 pmol/g tissue, of which carboxyamidated bioactive gastrins constituted 0.03-1.9 pmol/g. In histologically normal and nonneoplastic pancreatic tissue from patients with duodenal (n = 3) and pancreatic (n = 2) gastrinomas the expression of gastrin was significantly higher-14.5 pmol/g (median), of which 28% was bioactive amidated gastrins. Gastrin-17 was the main bioactive product, but its immediate precursor, glycine-extended gastrin-17, constituted the predominant part of the preprogastrin product in pancreatic tissue. Proper gastrinoma tissue contained several precursor forms, including intact unprocessed progastrin. Progastrins were also found in high concentrations in plasma from the gastrinoma patients. The results raise the possibility that increased expression of progastrin and its products in non-neoplastic pancreatic tissue is a primary defect predisposing to neoplasia.

Adenocarcinoma↗
PubMed1989

Gastrin in human bronchogenic carcinomas: constant expression but variable processing of progastrin.

Using a library of radioimmunoassays against essential sequences of human progastrin and procholecystokinin, we have examined the occurrence of gastrin, cholecystokinin, and their precursors in bronchogenic adenocarcinomas, large-cell, small-cell, and squamous-cell carcinomas (n = 17). Progastrin and some of its bioactive (i.e., alpha-carboxyamidated) products were present in all tumors, irrespective of histological classification. The concentration of progastrin varied from 0.2 to 21.9 pmol/g tissue; glycine-extended intermediates constituted less than 0.1 to 0.5 pmol/g; and bioactive, carboxyamidated gastrin ranged from less than 0.1 to 6.1 pmol/g. Chromatography showed that the bioactive gastrins were exclusively gastrin-17 peptides, half of which were tyrosine O-sulfated. Neither procholecystokinin nor its processing products were found in the tumor extracts. Six samples of nonneoplastic human lung tissue contained traces of progastrin (range, less than 0.1-0.8 pmol/g), but neither bioactive gastrins nor any cholecystokinin. The results show that the gastrin gene is expressed in all classes of bronchogenic carcinomas. Due to incomplete posttranslational processing measurement of progastrin may be necessary to detect such expression.

Base Sequence↗
PubMed1989

Cholecystokinin, gastrin and their precursors in pheochromocytomas.

Using sequence-specific radioimmunoassays before and after cleavage with trypsin and carboxypeptidase B, we have examined the occurrence and molecular nature of cholecystokinin (CCK) and gastrin peptides in bioactive (i.e. alpha-carboxyamidated) as well as non-amidated precursor forms in extracts from 13 human pheochromocytomas. All but one tumour contained amidated CCK, but only in moderate amounts (less than or equal to 20 pmol/g tissue). In contrast to the complete sulphation in tissues which normally produce CCK (the brain and small intestine), the amidated adrenal CCK peptides were poorly sulphated (less than or equal to 17%). Four pheochromocytomas, including the one without amidated CCK, contained between 28 and 0.2 pmol amidated gastrin/g, mainly in the form of sulphated gastrin-17. In addition, all tumours contained biosynthetic precursors of both CCK and gastrin. In most extracts there was more precursor than bioactive peptide(s), the progastrin concentration ranging up to 338 pmol/g. The results show that pheochromocytomas synthesize CCK and gastrin. The posttranslational processing differs, however, markedly from that of the principal CCK and gastrin producing tissues, with respect to both proteolytic cleavages and amino acid derivatization. This emphasizes that accurate quantitation in tumours requires assays which measure the translation products irrespective of their degree of processing.

Adrenal Gland Neoplasms↗
PubMed1989

Production and evaluation of monospecific antibodies for a processing-independent sequence of human progastrin.

We have produced a series of monospecific antibodies in five rabbits by immunization with a peptide corresponding to the preprogastrin sequence 76-88. Both antibody titres (0.2 to 3.0 x 10(6)), indexes of heterogeneity (approximately 1.0), and binding affinities (Koeff approximately 0.2 to 3.7 x 10(12) 1 x mol-1) were very high. The specificity for the N-terminus of the progastrin fragment was unique because even a conservative amino acid substitution five positions from the centre of binding diminished the binding by 90% for all antibodies. We conclude that these monospecific antibodies are well suited for development of a processing-independent analysis of progastrin and its products.

Amino Acid Sequence↗
PubMed1989

Effects of omeprazole on acid secretion and acid-related symptoms in patients with Zollinger-Ellison syndrome.

In the Zollinger-Ellison syndrome, symptoms and complications are due to hypersecretion of acid, and the first therapeutic step is to suppress the acid secretion. Long-term treatment with histamine H2-receptor antagonists was compared with omeprazole treatment. A total of 30 consecutive ZES patients were treated continuously with H2-receptor antagonists. During long-term treatment, a marked tachyphylaxis was noted, more than 50% of the patients had periods of dyspepsia, recurrent ulcers were found in 10 patients and in 16 a decline in the action of the H2-receptor antagonist required a change to omeprazole after a median duration of 36 months. A total of 22 patients were treated with omeprazole. During long-term treatment, the dose could be reduced slightly. Inhibition of acid secretion was maintained in all cases, and none had dyspeptic symptoms. The median duration of treatment was 18 months, with a range of 1-120 months (H2-receptor antagonists) and 27 months with a range of 1-66 months (omeprazole). No side-effects were seen with omeprazole.

Adult↗
PubMed1989

Peptide hormone expression and precursor processing.

Insight in the mechanisms of peptide hormone expression has grown explosively by elucidation of gene, mRNA and preprohormone structures for most hormone systems during the 1980s. The preprohormones vary considerably in size and organization from poly- to mono-protein structures. According to the structural organization and sequence homology the hormones are grouped in families. The prohormones are processed to bioactive peptides by multiple enzymatic modifications during the intracellular transport from the rough endoplasmatic reticulum to the mature secretory granules. The modifications comprise different proteolytic cleavages and amino acid derivatizations. The same prohormone may be expressed in several different cell-types that process the precursor in entirely different ways. Awareness of such cell-specific processing patterns is important for the understanding of ectopic synthesis in neuroendocrine tumours.

Animals↗
PubMed1989

The unique specificity of antibodies in modern radioimmunochemistry--an essay on assays.

The gradual recognition and exploitation of the specificity of antibodies in peptide radioimmunoassays (RIA) during the last three decades are reviewed. From the old fashioned RIA techniques of the sixties through sequence-specific RIA libraries of the seventies to residue-specific immunoassays of the eighties, the RIA technique has to an increasing degree been based on the ability to select strictly monospecific antibodies in high-titered polyclonal antisera. High-avidity monospecific antibodies from polyclonal antisera provide the RIA technology of to-day with unrivalled specificity. This specificity again has increased the utility of RIA as a tool in basic as well as clinical biochemistry.

Amino Acid Sequence↗
PubMed1988

Progastrin maturation during ontogenesis. Accumulation of glycine-extended gastrins in rat antrum at weaning.

The post-translational maturation of antral progastrin was studied in the developing rat. While N-terminal proteolysis remained unchanged and tyrosine O-sulphation varied only slightly during ontogenesis, major changes were observed in the degree of alpha-carboxyamidation. In the third week of life the immediate precursor of amidated gastrin, glycine-extended gastrin, accumulated, and at weaning (day 21) the concentrations exceeded those of amidated gastrin. Our results confirm that weaning is accompanied by an increased synthesis of gastrin and imply that alpha-carboxyamidation is the rate-limiting step during the biosynthetic maturation of gastrin.

Amides↗
PubMed1988

Processing-independent radioimmunoanalysis: a general analytical principle applied to progastrin and its products.

Most peptide hormone assays measure only fully processed bioactive peptides. Such assays are unsuited to detect hormone gene expression by alternative or attenuated prohormone processing (tissue- or cell-specific processing). The gastrin system is expressed in several different tissues and is therefore useful for studies of tissue-specific processing. Consequently we have developed a simple processing-independent radioimmunoanalysis for progastrin. Using antisera against the NH2-terminus of a sequence, devoid of processing sites (preprogastrin76-86) after trypsination of neighboring cleavage sites, the assay quantitates the mRNA product irrespective of degree of processing. Used together with a conventional assay for the mature carboxyamidated gastrins, the processing-independent analysis shows that in different tissues only 1 to 55% of the total translation product is processed to bioactive gastrins. Thus processing-independent analysis greatly improves the detection of gastrin gene expression at the peptide level. The principle of the assay should be applicable to all protein and peptide systems.

Amino Acid Sequence↗
PubMed1988

Cell-specific processing of pro-cholecystokinin and pro-gastrin.

The present review argues that the gastrin-cholecystokinin family is a suitable model for the study of cell-specific processing of pro-hormones. First, the homologous active site of the hormones is a precisely defined tetrapeptide amide, which is well preserved during evolution. Second, the genes of both hormones are translated in a variety of cells (neurons, endocrine cells, paracrine cells, lymphocytes, etc,), but to a varying degree during ontogenesis and pathogenesis of various diseases. Third, each pro-hormone contains multiple processing sites (mono- and dibasic cleavage sites, amidation sites and consensus sequences for seryl phosphorylation and tyrosyl sulfation) leaving ample room for variations in the post-translational processing. The review discusses examples of cell-specific processing that appears to be functionally expedient.

Amino Acid Sequence↗
PubMed1988

Levels of alpha-subunits of gonadotropins can be increased in Zollinger-Ellison syndrome, both in patients with malignant tumours and with apparently benign disease.

To evaluate the value of intact hCG, the beta-subunit of hCG and the common alpha-subunit of the glycoprotein hormones as tumour markers in patients with gastrinomas, we investigated 30 patients with the Zollinger-Ellison syndrome. Fifty-seven percent of the patients with malignant disease (N = 7) and 45% of those with active and apparently benign disease (N = 20) had raised values of circulating alpha-subunit. Detectable levels of hCG or hCG-beta were found in 7 patients of whom 4 had malignant disease. Radical tumour resection in 2 patients resulted in normalisation of elevated levels of alpha-subunit, and in one patient who developed metastases, the alpha-subunit values became elevated simultaneously. By chromatographic studies we found that the alpha-subunit-like reacting substance in serum eluted as the normal free alpha-subunit in 8 patients, but in one patient with metastatic disease we found evidence for production of a larger molecular form of alpha-subunit. The results indicate that the common alpha-subunit is a valuable tumour marker in patients with gastrinomas, whereas hCG-beta is only seldomly elevated. Single estimates of any of the hormonal fragments seem not to relate with malignancy, whereas a rise in alpha-subunit concentration in some patients may be related to the development of malignancy.

Adult↗
PubMed1987

Pituitary tumors containing cholecystokinin.

We found small amounts of cholecystokinin in the normal human adenohypophysis and therefore examined pituitary tumors from 87 patients with acromegaly, Cushing's disease, Nelson's syndrome, prolactinoma, or inactive pituitary adenomas. Five adenomas associated with Nelson's syndrome contained increased amounts of cholecystokinin, the concentrations being extremely high in two: 8281 and 13,453 pmol per gram as compared with less than 30 pmol per gram in normal pituitary glands. The cholecystokinin concentrations were moderately increased in adenomas from another 12 patients, of whom 5 had Cushing's disease and 7 acromegaly with adenomas containing ACTH. The cholecystokinin peptides from the tumors were smaller and less sulfated than cholecystokinin from normal pituitary glands. We conclude that ACTH-producing pituitary cells may also produce an altered form of cholecystokinin.

Acromegaly↗
PubMed1987

Gastrin in pituitary tumours.

Twelve of 87 pituitary adenomas from patients with acromegaly, Cushing's syndrome. Nelson's syndrome, hyperprolactinaemia and without symptoms of hormone hypersecretion contained gastrin in concentrations from 0.5 to 166 pmol/g. Only ACTH-producing tumours contained gastrin, which occurred in forms smaller than those present in the normal adenohypophysis. The results indicate that corticotropic tumours may synthesize gastrin in moderate amounts.

Adenoma↗
PubMed1986

Gastric endocrine cells in omeprazole-treated and untreated patients with the Zollinger-Ellison syndrome.

We have investigated the gastric endocrine cells in 19 patients with the Zollinger-Ellison syndrome. Six received a long-term treatment with omeprazole, 5 one with H2 receptor antagonists and 8 had no medical treatment. Fifteen patients (79%) had hyperplasia of the endocrine cells in the oxyntic mucosa independent of treatment. The hyperplasia involved both enterochromaffin-like (ECL) and D1 cells and was positively related to the duration of disease (p less than 0.05). The duration of hypergastrinaemia was longer in the omeprazole-treated patients, but the hyperplasia was not significantly more pronounced in these patients. Gastric carcinoid tumours consisting mainly of ECL cells are rare in man and are most often seen in states of hypergastrinaemia such as chronic atrophic gastritis. It has seldomly been reported in Zollinger-Ellison patients; but now, when potent antisecretory drugs make it possible to avoid total gastrectomy, a raised incidence might result, and an increased attention to this aspect seems appropriate.

Female↗
PubMed1986

The requirement for gastrin measurements.

In order to evaluate the clinical requirement for gastrin measurements, we examined all gastrin measurements requested over 1.5 years in a homogeneous population of 5.1 million inhabitants. Gastrin was quantitated with a radioimmunoassay that measured bioactive gastrins with equimolar potency. We received 1392 serum samples from 931 patients. In 394 samples from 121 patients the gastrin concentration was above the limit of the reference interval (50 pmol/l). Of the 121 patients, 19 were known Zollinger-Ellison patients followed for control of the therapy. In 11 previously unknown patients the gastrin analysis suggested presence of gastrin-producing tumours. Of these, four had classical Zollinger-Ellison syndromes, three had mixed endocrine tumours without peptic ulcer, and four were awaiting final confirmation of gastrinomas. Two vitiligo patients were hypergastrinaemic suggesting latent pernicious anaemia. Upon second measurement the plasma gastrin concentrations were within the reference interval in 14 previously hypergastrinaemic ulcer patients. In the remaining 75 patients the hypergastrinaemia was secondary to other gastrointestinal diseases. The results indicate that diagnosis, localization, and therapeutic control of gastrinomas require 200 gastrin measurements per million inhabitants per year. We suggest that this number be used in planning gastrin-assay services.

Blood Specimen Collection↗
PubMed1986

Omeprazole in the Zollinger-Ellison syndrome.

Treatment with omeprazole was evaluated in nine patients with the Zollinger-Ellison syndrome, in whom the effect of H2-receptor antagonists had become inadequate. Treatment with 20-80 mg omeprazole daily reduced basal acid secretion by 77-100%. The effect persisted during a continuous treatment of up to 2 years. In five patients the initial dose could be reduced after some time of treatment. In eight patients the treatment promptly relieved all symptoms, and in the last patient, who had disseminated metastatic disease and large anastomotic ulcers, the symptoms disappeared gradually over a period of 10 weeks. No adverse events were seen. We conclude that omeprazole is an effective inhibitor of the acid hypersecretion in Zollinger-Ellison patients, also when H2-receptor antagonists have failed.

Adult↗