Ralph Arnold - Academia.edu (original) (raw)

Papers by Ralph Arnold

Research paper thumbnail of Biochemical and morphological investigations of 30 human insulinomas

Diabetologia, 1973

Thirty human insulinomas have been investigated histologically and their immunoreactive insulin (... more Thirty human insulinomas have been investigated histologically and their immunoreactive insulin (IRI) content estimated. In most cases immunohistological and ultrastructural studies were also performed and the percentage of proinsulin-like components (PLC) in the tumour determined. Except for 1 case the IRI concentration in the tumours was lower (0.01–89.0 U/g) than in the islet tissue. Histologically, immunohistologically and ultrastructurally a variable number of tumour cells contained few and often no beta-granules, indicating a decreased storage capacity for insulin. This defective storage capacity seems to be the major functional abnormality of insulinoma cells. Ultrastructurally four types of insulinoma can be distinguished. The ultra-structural diagnosis of an insulinoma can only be made in type I (typical beta-granules, 13 cases) and type II (typical and atypical granules, 7 cases) but not in type III (atypical granules only, 4 cases) and type IV (virtually agranular, 4 cases). The type IV tumours had the lowest IRI concentration and did not respond to diazoxide treatment. The IRI concentration of the uninvolved pancreas of 19 patients was 2.0±0.2 U/g and in the range of non-diabetic adults. — The percentage PLC in 19 insulinomas was higher (5.3–22%) than in the pancreas of human adults with and without insulinoma (1.7–4.8%). The percentage of PLC in the serum of patients with insulinoma was always higher than in their tumours (33–61%). It is suggested that the higher PLC levels found in the tumour and serum of insulinoma patients are the consequence of the reduced storage capacity of the tumour cells resulting in a rapid passage through the granular route or even a non-granular release of newly synthesized insulin.

Research paper thumbnail of Effect of Acid Inhibition on Gastric Endocrine Cells

Scandinavian Journal of Gastroenterology, 1986

There is increasing evidence that the numbers of antral G cells and of fundic argyrophil (ECL) ce... more There is increasing evidence that the numbers of antral G cells and of fundic argyrophil (ECL) cells are influenced by agents that inhibit gastric acid secretion. Antral G cells increase in states of achlorhydria in man and animals provided atrophic antral gastritis is absent. In rats, treatment with substituted benzimidazoles like omeprazole and BY 308 increase G-cell densities dose-dependently. Even high doses of histamine H-2 antagonists and antacids increase antral G-cell densities. In contrast to G cells, antral D cells decrease in these instances. Fundic ECL cells increase in all experimental conditions of complete achlorhydria provided intact antral mucosa is present, i.e. there is elevated serum gastrin. Antacid treatment is not followed by an increase of fundic ECL cells, which could be explained by the less sustained increase of serum gastrin.

Research paper thumbnail of Gastric inhibitory polypeptide (GIP), gastrin and insulin: Response to test meal in coeliac disease and after duodeno-pancreatectomy

Diabetologia, 1976

The response of serum immunoreactive gastric inhibitory polypeptide (IR-GIP), gastrin (IRG) and i... more The response of serum immunoreactive gastric inhibitory polypeptide (IR-GIP), gastrin (IRG) and insulin (IRI) to a mixed standard meal was measured in 15 controls, 6 patients with coeliac disease, 26 patients with chronic pancreatitis and 6 patients with chronic pancreatitis and partial duodenopancreatectomy (Whipple's procedure). Serum levels of IR-GIP, IRG and IRI were significantly reduced in patients with coeliac disease. The serum glucose increase was significantly smaller only during the first hour after the meal. Since small intestinal GIP- and G-cells are situated mainly in the glands of duodenal and jejunal mucosa their absolute number is not significantly reduced in coeliac disease. It is suggested that the release of IR-GIP and duodenal IRG is influenced by the rate of absorption of nutrients. In patients with chronic pancreatitis the IR-GIP release is significantly greater than in controls, the IRG release normal and the IRI response delayed. After Whipple's procedure the IR-GIP response is increased significantly while the IRG secretion is abolished. This demonstrates that the duodenum is not necessary for GIP release and that pancreatic and jejunal gastrin are without clinical significance.

Research paper thumbnail of Antral gastrin-producing G-cells and somatostatin-producing D-cells in different states of gastric acid secretion

Gut, 1982

The number of G-and D-cells per area and the ratio of G/D-cells were investigated in biopsy speci... more The number of G-and D-cells per area and the ratio of G/D-cells were investigated in biopsy specimens of the pyloric antrum from normochlorhydric subjects without peptic ulcer, from patients with duodenal ulcer, gastrinoma, pernicious anaemia, and after selective proximal vagotomy. Compared with normochlorhydric subjects antral G-cell density was significantly raised in pernicious anaemia, unchanged in duodenal ulcer, and diminished in gastrinoma patients. After vagotomy G-cell density was found to be raised if compared with patients with duodenal ulcer. D-cell density was significantly increased in gastrinoma patients, unchanged in duodenal ulcer, and diminished in pernicious anaemia and after vagotomy. The G/D-cell ratio was increased in pernicious anaemia and after vagotomy, unchanged in duodenal ulcer, and decreased in gastrinoma patients. It is concluded that the antral pH governs the ratio of G-and D-cells. Therefore, the G/D-cell ratio increases in states of reduced acid secretion and decreases in massive hyperchlorhydria. Hypergastrinaemia as such does not affect the G/D-cell ratio.

Research paper thumbnail of Serum Gastric Inhibitory Polypeptide (GIP) in Duodenal Ulcer Disease: Relationship to Glucose Tolerance, Insulin, and Gastrin Release

Scandinavian Journal of Gastroenterology, 1978

Serum immunoreactive gastric inhibitory polypeptide (IR-GIP), gastrin (IRG), and insulin (IRI) we... more Serum immunoreactive gastric inhibitory polypeptide (IR-GIP), gastrin (IRG), and insulin (IRI) were estimated in 41 normal weight patients with duodenal ulcer (DU) and 25 age-matched controls in response to a high calorie liquid test meal. 28 out of 41 DU patients had a hyperglycaemic glucose response during the test meal, and 15 had a pathological oral glucose tolerance test. Fasting and food-stimulated IR-GIP and IRG levels were significantly elevated in the DU patients. Serum IRI also increased to significantly higher levels in DU patients after the test meal. The degree of the greater hormone response was dependent on the glucose increase after the test meal in the case of insulin and GIP, but not in the case of gastrin. It is concluded: firstly, that a faster glucose absorption (possibly due to rapid initial gastric emptying or increased intestinal motility) is responsible for the high and short-lasting glucose peak and the increased GIP and insulin secretion; secondly, that the GIP response could well be causally related to the insulin response; thirdly, that hyposcretion of GIP is ruled out as a possible factor in the pathogenesis of gastric acid hypersecretion of duodenal ulcer patients.

Research paper thumbnail of Response of gastric inhibitory polypeptide (GIF) to test meal in chronic pancreatitis — Relationship to endocrine and exocrine insufficiency

Diabetologia, 1976

Twenty-nine patients with chronic pancreatitis had a significantly greater IR-GIP response to a t... more Twenty-nine patients with chronic pancreatitis had a significantly greater IR-GIP response to a test meal than 15 controls. This increased response was not related to the degree of steatorrhoea or glucose intolerance. It was most marked in a group of patients with moderately impaired IRI release and medium steatorrhoea. From this is concluded that the IR-GIP response to a test meal is determined by at least two factors: 1. feedback control via insulin secretion, 2. assimilation of fat. In chronic pancreatitis endocrine insufficiency may induce an exaggerated GIP response and severe exocrine insufficiency may prevent fat induced GIP release. Gastrin is not involved in the different GIP response in patients with chronic pancreatitis.

Research paper thumbnail of Gastrointestinal somatostatin: extraction and radioimmunoassay in different species

Gut, 1978

A radioimmunoassay capable of detecting 300 fg somatostatin has been developed and levels of the ... more A radioimmunoassay capable of detecting 300 fg somatostatin has been developed and levels of the polypeptide in gastrointestinal tissues from man, dog, and rat have been measured. Rapid freezing of collected samples and careful control of extraction is necessary. Concentrations in different regions of dog antrum (425 + 50 to 773 + 254 ng/g tissue) are similar to those in antrum from duodenal ulcer patients and control subjects: 614 + 125 and 465 + 104 ng/g tissue respectively. Levels in histologically normal human pancreas (253 + 43 ng/g tissue) are comparable with those in dog pancreas (333 + 66 ng/g tissue), whereas in two cases of neonatal hypoglycaemia the concentration exceeded 3000 ng/g tissue. On gel chromatography the majority of immunoreactive somatostatin elutes as the synthetic tetradecapeptide and a small fraction as a larger species. ment of somatostatin in rat and chicken tissues by 'Present address:

Research paper thumbnail of Immunohistologic investigations of human insulinomas

Diabetologia, 1972

14 insulinomas were examined immunohistologically using the peroxidase labelled antibody method. ... more 14 insulinomas were examined immunohistologically using the peroxidase labelled antibody method. 8 tumours were investigated immediately after extirpation. 7 of these reacted with insulin and porcine-C-peptide antisera but not with glucagon antiserum. Only a B-cell carcinoma with an unusually low insulin concentration was negative. One year after embedding in paraffin the immunohistologic reaction with insulin antiserum had markedly decreased in the tumours; however, not in the islet of the adjacent pancreas. From 6 patients 1 to 4 years old paraffin-embedded material of the tumour and the normal pancreas was available. In this group 4 tumours with an elevated insulin concentration reacted immunohistologically only weakly with an insulin antiserum and two tumours (one with high and one with low insulin concentration were immunohistologically negative, while the islets of the adjacent panceas of all six cases showed a strong reaction. Thus the immunohistilogic reaction of insulin in B-cell tumours but not in normal islets depends on the time elapsed between the paraffin embedding and the examination. Only tumours fixed in Bouin's fluid but not in Karnovsky's solution gave a positive immunohistologie reaction, while the islets of the adjacent pancreas reacted positively also after fixation in Karnovsky's solution. These findings suggest differences between the normal and the tumour insulin. A correlation between aldehyde-thionin stain and immunohistology indicates the superiority of immunohistology in identifying insulin producing tumour cells. 14 insulinomes ont été soumis à un examen immunohistologique à l'aide de la méthode de l'anticorps marqué à la peroxydase. 8 tumeurs ont été étudiées immédiatement après leur extirpation. 7 d'entre elles réagissaient avec les sérums anti-insuline et anti-porcine-C-peptide, mais non avec le sérum anti-glucagon. Un seul carcinome à cellules B avec un contenu en insuline inhabituellement bas, a été négatif. Un an après l'inclusion dans la paraffine, la réaction immunohistologique avec le sérum anti-insuline avait nettement diminué dans les tumeurs, mais non dans les îlots du pancréas adjacent. Chez 6 patients, on disposait de fragments de la tumeur et du pancréas normal inclus dans la paraffine depuis 1 à 4 ans. Dans ce groupe, 4 tumeurs avec un contenu élevé en insuline, n'avaient qu'une faible réaction immunohistologique avec un sérum antiinsuline, et deux tumeurs (l'une avec un contenu élevé en insuline, l'autre avec un contenu faible) ont eu une réaction immunohistologique négative, tandis que les îlots du pancréas adjacent réagissaient fortement dans les six cas. Donc, la réaction immunohistologique de l'insuline dans les tumeurs à cellules B, mais non dans les îlots normaux, dépend du temps écoulé entre l'inclusion dans la paraffine et le moment où elles sont examinées. Seules les tumeurs fixées dans du liquide de Bouin, mais non dans la solution de Karnovsky, ont eu une réaction immunohistologique positive, tandis que les îlots du pancréas adjacent réagissaient positivement après fixation dans la solution de Karnovsky. Ces résultats suggèrent qu'il existe des différences entre l'insuline du pancréas normal et l'insuline des tumeurs. Une comparaison entre la coloration à l'aldéhyde-thionine et l'immunohistologie indique la supériorité de l'immunohistologie dans l'identification des cellules tumorales produisant de l'insuline. 14 insulinproduzierende Tumoren wurden mittels Peroxydase-markierter Antikörper immunhistologisch untersucht. 8 Tumoren gelangten unmittelbar postoperativ zur Untersuchung. Hiervon ließen sich 7 mit einem Antiserum gegen Insulin und Schweine-C-Peptid, nicht aber mit einem Antiserum gegen Glucagon anfärben. Dagegen reagierte ein B-Zellcarcinom mit einer sehr niedrigen Insulinkonzentration mit keinem dieser Seren. Bereits ein Jahr nach der Einbettung in Paraffin ließ die Anfärbbarkeit dieser Tumoren mit einem Antiinsulinserum deutlich nach, während die Inseln des umgebenden normalen Pankreas mit dem gleichen Serum unverändert stark reagierten. — Von 6 weiteren Inseladenomen standen außerdem 1– 4 Jahre altes paraffineingebettetes Tumor- und Pankreasgewebe zur Verfügung. 4 dieser Tumoren hatten eine erhöhte Insulinkonzentration, reagierten immunhistologisch jedoch mit einem Antiinsulinserum nur schwach. Die beiden restlichen Tumoren — einer mit einer hohen, der andere mit einer niedrigen Insulinkonzentration — verhielten sich immunhistologisch negativ. Im Gegensatz zu den Tumoren ließen sich die Inseln des umgebenden Pankreas sämtlicher 6 Fälle mit einem Insulinantiserum gut anfärben. Somit scheint der erfolgreiche immunhistologische Nachweis von Insulin in insulinproduzierenden Tumoren von der Dauer der Einbettung des Tumormaterials in Paraffin abzuhängen. Das Insulin in den Pankreasinseln unterliegt dagegen diesem „Alterungseffekt“ nicht. — TumorInsulin läßt sich nur in Bouin-fixiertem, nicht aber in Karnovsky-fixiertem Gewebe immunhistologisch nachweisen, während das Insulin des normalen Pankreas auch nach Karnovsky-Fixation immunhistologisch nachweisbar ist. Die Befunde sprechen für Unterschiede zwischen normalem pankreatischen und Tumor-Insulin. — Die Färbung der B-Zellen von Tumoren mit Aldehyd-Thionin gelingt seltener als der immunhistologische Nachweis von Insulin in diesen Zellen. Die immunhistologische Untersuchung ist daher zur Identifizierung von B-Zelltumoren den üblichen spezifischen Färbungen überlegen.

Research paper thumbnail of The antrat gastrin-producing G-cell: Biochemical and ultrastructural responses to feeding

Cell and Tissue Research, 1978

The effect of feeding on serum and antral immunoreactive gastrin (IRG) concentrations and on the ... more The effect of feeding on serum and antral immunoreactive gastrin (IRG) concentrations and on the ultrastructural appearance of antral G-cell granules has been examined. Serum and tissue IRG concentrations were dependent upon the length of time (12 or 48 h) the rats had been fasted before receiving food; IRG release was biphasic; the first peak was more pronounced in rats fasted 12h. Antral tissue IRG content increased significantly postprandially. An initial depletion of antral IRG was seen in rats fasted 48 h. Examination of the subcellular distribution of antral IRG revealed more of the 5–15 min postprandal total IRG in the cytoplasm and less in the secretory granules. Ultrastructurally, G-cells from fasting rats contained mainly electron-dense granules. Five minutes postprandially numerous electron-lucent granules were observed. More electron dense granules were apparent 60 and 120 min postprandially. Fasting rats had the highest G-cell granule density index; a significantly lower index was observed 5 min postprandially. Indices at 60 and 120 min postprandially increased but were still lower than the fasting index. These studies indicate that gastrin biosynthesis is necessary for food stimulated gastrin release and that the electron density of the G-cells' granules is not an accurate reflection of the G-cell gastrin content.

Research paper thumbnail of Pathomorphologic, biochemical, and diagnostic aspects of gastrinomas (Zollinger-Ellison syndrome

Human Pathology, 1975

The clinical symptomatolog y of the Zollinger-Ellison syndrome and the pathologic anatomy of gast... more The clinical symptomatolog y of the Zollinger-Ellison syndrome and the pathologic anatomy of gastrinomas are reviewed. Experience with 17 patients with the Zollinger-Ellison syndrome is presented with special reference to stimulation tests (secretin, glucagon, calcium infnsion, test meal) and to localization and immunohistologic, tdtrastructural, and biochemical findings in gastrinomas. Muhiple hormone production by the tumors is frequent. The ultrastructure and the Sephadex G-50 gel filtration patterns of imnaunol'eactive gastrin in sera and tumors are not uniform and are not related to localization of the tumors in the pancreas or duodenum or to the gastrin concentration. Hyperplasia of the pancreatic islets is a frequent finding in gastrinorna patients, suggesting that hypergastrinemia may stimnlate islet growth.

Research paper thumbnail of Gastrin and G-Cells in the Antral Mucosa of Patients with Pernicious Anaemia, Acromegaly and Hyperparathyroidism and in a Zollinger-Ellison Tumour of the Pancreas

European Journal of Clinical Investigation, 1971

Abstract. In extracts of human gastric biopsies gastrin has been estimated with an immunochemical... more Abstract. In extracts of human gastric biopsies gastrin has been estimated with an immunochemical method. In the same biopsies G-cells have been localized with an immunohistological method using peroxidase-labelled antibodies and the endocrine cells investigated electron-microscopically. Gastrin and G-cells could be found regularly in the antral mucosa and only in insignificant amounts or not at all in the fundic mucosa of six normal persons. With the same methods gastrin and G-cells could be demonstrated in the antral mucosa of rats and guinea-pigs. The gastrin content of the antral mucosa of six patients with pernicious anaemia and achlorhydria with elevated serum gastrin levels was more than 20 times higher than in the controls and the G-cells were significantly more numerous. Besides hyperplasia of the G-cells, increased secretory activity was found electron-microscopically. The gastrin release from the G-cells seems to take place mainly via intracellular dissolution of the granule content within the membranous sacs. Although the number of other endocrine cells was increased in pernicious anaemia the ultrastructural identity of the G-cells could be established by comparison with the cells of a Zollinger-Ellison tumour. This tumour contained gastrin and gave a positive immunohistological reaction for this hormone. Also, the fundic mucosa of patients with pernicious anaemia contained gastrin and G-cells, but considerably less than the antral mucosa. Hyperplasia of G-cells was found in six cases of acromegaly, four of which also had a significantly increased gastrin content of the antral mucosa. This finding suggests a trophic function of the hypophysis, especially growth hormone, on the G-cells. Hyperplasia of the G-cells in the antral mucosa of three patients with primary hyperparathyroidism and increased gastrin content in two of the three cases also suggest a trophic function of the serum calcium level on the G-cells.

Research paper thumbnail of Mucosal gastrin concentration, molecular forms of gastrin, number and ultrastructure of G-cells in patients with duodenal ulcer

Gut, 1976

The mean antral immunoreactive gastrin (IRG) concentration of 38 duodenal ulcer (DU) patients was... more The mean antral immunoreactive gastrin (IRG) concentration of 38 duodenal ulcer (DU) patients was significantly higher (35.9 ± 5 2 jg/g) than that of 21 controls (15.9 + 2-6 jg/g). Also the mean IRG concentration in the proximal duodenal mucosa of 15 DU patients (3.2 ± 0O8 jg/g) was higher (but not significantly) than that of 10 controls (1-8 0S5 jg/g). The number of G-cells in the antral mucosa of 58 DU patients and in the duodenal mucosa of 29 DU patients was not larger than that of controls. The distribution of immunoreactivity in gastrin components has been investigated in the antral and duodenal mucosa of six DU patients and six controls. In the antral mucosa the mean percentage of G-17 was 93 3 % in DU patients and 920 0% in controls. G-34 amounted to 4-0°% in DU patients and to 5-0% in controls. The G-34 percentage in the duodenal mucosa was higher (however not significantly) in the DU patients than in the controls (50 1 % versus 35 8 %). Ultrastructurally, the antral G-cells of DU patients had a significantly lower density index of their secretory granules suggesting higher functional activity. It is concluded that the exaggerated serum IRG response of DU patients to different stimuli is not a consequence of an increased G-cell mass.

Research paper thumbnail of Measurement of 223 Ra and 224 Ra in coastal waters using a delayed coincidence counter

We describe a nuclear detector system for measuring low activities of 223 Ra and 224 Ra in natura... more We describe a nuclear detector system for measuring low activities of 223 Ra and 224 Ra in natural waters based on an original design of . Samples are obtained by adsorbing 223 Ra and 224 Ra onto a column of Mn0 2 coated fiber (Mn fiber). The short-lived Rn daughters of 223 Ra and 224 Ra which recoil from the Mn fiber are swept into a scintillation detector where alpha decays of Rn and Po occur. Signals from the detector are sent to a delayed coincidence circuit which discriminates decays of the 224 Ra daughters, 220 Rn and 216 Po, from decays of the 223 Ra daughters, 219 Rn and 215 Po. The system is calibrated using 232 Th and 227 Ac standards with daughters in equilibrium adsorbed on Mn fiber. Results of samples from Tampa Bay, Florida, and the Atchafalaya and Mississippi Rivers mixing zones are reported. The method is extendible to measurements of 227 Ac , 231 Pa, 228 Th, and 228 Ra.

Research paper thumbnail of Biochemical and morphological investigations of 30 human insulinomas

Diabetologia, 1973

Thirty human insulinomas have been investigated histologically and their immunoreactive insulin (... more Thirty human insulinomas have been investigated histologically and their immunoreactive insulin (IRI) content estimated. In most cases immunohistological and ultrastructural studies were also performed and the percentage of proinsulin-like components (PLC) in the tumour determined. Except for 1 case the IRI concentration in the tumours was lower (0.01–89.0 U/g) than in the islet tissue. Histologically, immunohistologically and ultrastructurally a variable number of tumour cells contained few and often no beta-granules, indicating a decreased storage capacity for insulin. This defective storage capacity seems to be the major functional abnormality of insulinoma cells. Ultrastructurally four types of insulinoma can be distinguished. The ultra-structural diagnosis of an insulinoma can only be made in type I (typical beta-granules, 13 cases) and type II (typical and atypical granules, 7 cases) but not in type III (atypical granules only, 4 cases) and type IV (virtually agranular, 4 cases). The type IV tumours had the lowest IRI concentration and did not respond to diazoxide treatment. The IRI concentration of the uninvolved pancreas of 19 patients was 2.0±0.2 U/g and in the range of non-diabetic adults. — The percentage PLC in 19 insulinomas was higher (5.3–22%) than in the pancreas of human adults with and without insulinoma (1.7–4.8%). The percentage of PLC in the serum of patients with insulinoma was always higher than in their tumours (33–61%). It is suggested that the higher PLC levels found in the tumour and serum of insulinoma patients are the consequence of the reduced storage capacity of the tumour cells resulting in a rapid passage through the granular route or even a non-granular release of newly synthesized insulin.

Research paper thumbnail of Effect of Acid Inhibition on Gastric Endocrine Cells

Scandinavian Journal of Gastroenterology, 1986

There is increasing evidence that the numbers of antral G cells and of fundic argyrophil (ECL) ce... more There is increasing evidence that the numbers of antral G cells and of fundic argyrophil (ECL) cells are influenced by agents that inhibit gastric acid secretion. Antral G cells increase in states of achlorhydria in man and animals provided atrophic antral gastritis is absent. In rats, treatment with substituted benzimidazoles like omeprazole and BY 308 increase G-cell densities dose-dependently. Even high doses of histamine H-2 antagonists and antacids increase antral G-cell densities. In contrast to G cells, antral D cells decrease in these instances. Fundic ECL cells increase in all experimental conditions of complete achlorhydria provided intact antral mucosa is present, i.e. there is elevated serum gastrin. Antacid treatment is not followed by an increase of fundic ECL cells, which could be explained by the less sustained increase of serum gastrin.

Research paper thumbnail of Gastric inhibitory polypeptide (GIP), gastrin and insulin: Response to test meal in coeliac disease and after duodeno-pancreatectomy

Diabetologia, 1976

The response of serum immunoreactive gastric inhibitory polypeptide (IR-GIP), gastrin (IRG) and i... more The response of serum immunoreactive gastric inhibitory polypeptide (IR-GIP), gastrin (IRG) and insulin (IRI) to a mixed standard meal was measured in 15 controls, 6 patients with coeliac disease, 26 patients with chronic pancreatitis and 6 patients with chronic pancreatitis and partial duodenopancreatectomy (Whipple's procedure). Serum levels of IR-GIP, IRG and IRI were significantly reduced in patients with coeliac disease. The serum glucose increase was significantly smaller only during the first hour after the meal. Since small intestinal GIP- and G-cells are situated mainly in the glands of duodenal and jejunal mucosa their absolute number is not significantly reduced in coeliac disease. It is suggested that the release of IR-GIP and duodenal IRG is influenced by the rate of absorption of nutrients. In patients with chronic pancreatitis the IR-GIP release is significantly greater than in controls, the IRG release normal and the IRI response delayed. After Whipple's procedure the IR-GIP response is increased significantly while the IRG secretion is abolished. This demonstrates that the duodenum is not necessary for GIP release and that pancreatic and jejunal gastrin are without clinical significance.

Research paper thumbnail of Antral gastrin-producing G-cells and somatostatin-producing D-cells in different states of gastric acid secretion

Gut, 1982

The number of G-and D-cells per area and the ratio of G/D-cells were investigated in biopsy speci... more The number of G-and D-cells per area and the ratio of G/D-cells were investigated in biopsy specimens of the pyloric antrum from normochlorhydric subjects without peptic ulcer, from patients with duodenal ulcer, gastrinoma, pernicious anaemia, and after selective proximal vagotomy. Compared with normochlorhydric subjects antral G-cell density was significantly raised in pernicious anaemia, unchanged in duodenal ulcer, and diminished in gastrinoma patients. After vagotomy G-cell density was found to be raised if compared with patients with duodenal ulcer. D-cell density was significantly increased in gastrinoma patients, unchanged in duodenal ulcer, and diminished in pernicious anaemia and after vagotomy. The G/D-cell ratio was increased in pernicious anaemia and after vagotomy, unchanged in duodenal ulcer, and decreased in gastrinoma patients. It is concluded that the antral pH governs the ratio of G-and D-cells. Therefore, the G/D-cell ratio increases in states of reduced acid secretion and decreases in massive hyperchlorhydria. Hypergastrinaemia as such does not affect the G/D-cell ratio.

Research paper thumbnail of Serum Gastric Inhibitory Polypeptide (GIP) in Duodenal Ulcer Disease: Relationship to Glucose Tolerance, Insulin, and Gastrin Release

Scandinavian Journal of Gastroenterology, 1978

Serum immunoreactive gastric inhibitory polypeptide (IR-GIP), gastrin (IRG), and insulin (IRI) we... more Serum immunoreactive gastric inhibitory polypeptide (IR-GIP), gastrin (IRG), and insulin (IRI) were estimated in 41 normal weight patients with duodenal ulcer (DU) and 25 age-matched controls in response to a high calorie liquid test meal. 28 out of 41 DU patients had a hyperglycaemic glucose response during the test meal, and 15 had a pathological oral glucose tolerance test. Fasting and food-stimulated IR-GIP and IRG levels were significantly elevated in the DU patients. Serum IRI also increased to significantly higher levels in DU patients after the test meal. The degree of the greater hormone response was dependent on the glucose increase after the test meal in the case of insulin and GIP, but not in the case of gastrin. It is concluded: firstly, that a faster glucose absorption (possibly due to rapid initial gastric emptying or increased intestinal motility) is responsible for the high and short-lasting glucose peak and the increased GIP and insulin secretion; secondly, that the GIP response could well be causally related to the insulin response; thirdly, that hyposcretion of GIP is ruled out as a possible factor in the pathogenesis of gastric acid hypersecretion of duodenal ulcer patients.

Research paper thumbnail of Response of gastric inhibitory polypeptide (GIF) to test meal in chronic pancreatitis — Relationship to endocrine and exocrine insufficiency

Diabetologia, 1976

Twenty-nine patients with chronic pancreatitis had a significantly greater IR-GIP response to a t... more Twenty-nine patients with chronic pancreatitis had a significantly greater IR-GIP response to a test meal than 15 controls. This increased response was not related to the degree of steatorrhoea or glucose intolerance. It was most marked in a group of patients with moderately impaired IRI release and medium steatorrhoea. From this is concluded that the IR-GIP response to a test meal is determined by at least two factors: 1. feedback control via insulin secretion, 2. assimilation of fat. In chronic pancreatitis endocrine insufficiency may induce an exaggerated GIP response and severe exocrine insufficiency may prevent fat induced GIP release. Gastrin is not involved in the different GIP response in patients with chronic pancreatitis.

Research paper thumbnail of Gastrointestinal somatostatin: extraction and radioimmunoassay in different species

Gut, 1978

A radioimmunoassay capable of detecting 300 fg somatostatin has been developed and levels of the ... more A radioimmunoassay capable of detecting 300 fg somatostatin has been developed and levels of the polypeptide in gastrointestinal tissues from man, dog, and rat have been measured. Rapid freezing of collected samples and careful control of extraction is necessary. Concentrations in different regions of dog antrum (425 + 50 to 773 + 254 ng/g tissue) are similar to those in antrum from duodenal ulcer patients and control subjects: 614 + 125 and 465 + 104 ng/g tissue respectively. Levels in histologically normal human pancreas (253 + 43 ng/g tissue) are comparable with those in dog pancreas (333 + 66 ng/g tissue), whereas in two cases of neonatal hypoglycaemia the concentration exceeded 3000 ng/g tissue. On gel chromatography the majority of immunoreactive somatostatin elutes as the synthetic tetradecapeptide and a small fraction as a larger species. ment of somatostatin in rat and chicken tissues by 'Present address:

Research paper thumbnail of Immunohistologic investigations of human insulinomas

Diabetologia, 1972

14 insulinomas were examined immunohistologically using the peroxidase labelled antibody method. ... more 14 insulinomas were examined immunohistologically using the peroxidase labelled antibody method. 8 tumours were investigated immediately after extirpation. 7 of these reacted with insulin and porcine-C-peptide antisera but not with glucagon antiserum. Only a B-cell carcinoma with an unusually low insulin concentration was negative. One year after embedding in paraffin the immunohistologic reaction with insulin antiserum had markedly decreased in the tumours; however, not in the islet of the adjacent pancreas. From 6 patients 1 to 4 years old paraffin-embedded material of the tumour and the normal pancreas was available. In this group 4 tumours with an elevated insulin concentration reacted immunohistologically only weakly with an insulin antiserum and two tumours (one with high and one with low insulin concentration were immunohistologically negative, while the islets of the adjacent panceas of all six cases showed a strong reaction. Thus the immunohistilogic reaction of insulin in B-cell tumours but not in normal islets depends on the time elapsed between the paraffin embedding and the examination. Only tumours fixed in Bouin's fluid but not in Karnovsky's solution gave a positive immunohistologie reaction, while the islets of the adjacent pancreas reacted positively also after fixation in Karnovsky's solution. These findings suggest differences between the normal and the tumour insulin. A correlation between aldehyde-thionin stain and immunohistology indicates the superiority of immunohistology in identifying insulin producing tumour cells. 14 insulinomes ont été soumis à un examen immunohistologique à l'aide de la méthode de l'anticorps marqué à la peroxydase. 8 tumeurs ont été étudiées immédiatement après leur extirpation. 7 d'entre elles réagissaient avec les sérums anti-insuline et anti-porcine-C-peptide, mais non avec le sérum anti-glucagon. Un seul carcinome à cellules B avec un contenu en insuline inhabituellement bas, a été négatif. Un an après l'inclusion dans la paraffine, la réaction immunohistologique avec le sérum anti-insuline avait nettement diminué dans les tumeurs, mais non dans les îlots du pancréas adjacent. Chez 6 patients, on disposait de fragments de la tumeur et du pancréas normal inclus dans la paraffine depuis 1 à 4 ans. Dans ce groupe, 4 tumeurs avec un contenu élevé en insuline, n'avaient qu'une faible réaction immunohistologique avec un sérum antiinsuline, et deux tumeurs (l'une avec un contenu élevé en insuline, l'autre avec un contenu faible) ont eu une réaction immunohistologique négative, tandis que les îlots du pancréas adjacent réagissaient fortement dans les six cas. Donc, la réaction immunohistologique de l'insuline dans les tumeurs à cellules B, mais non dans les îlots normaux, dépend du temps écoulé entre l'inclusion dans la paraffine et le moment où elles sont examinées. Seules les tumeurs fixées dans du liquide de Bouin, mais non dans la solution de Karnovsky, ont eu une réaction immunohistologique positive, tandis que les îlots du pancréas adjacent réagissaient positivement après fixation dans la solution de Karnovsky. Ces résultats suggèrent qu'il existe des différences entre l'insuline du pancréas normal et l'insuline des tumeurs. Une comparaison entre la coloration à l'aldéhyde-thionine et l'immunohistologie indique la supériorité de l'immunohistologie dans l'identification des cellules tumorales produisant de l'insuline. 14 insulinproduzierende Tumoren wurden mittels Peroxydase-markierter Antikörper immunhistologisch untersucht. 8 Tumoren gelangten unmittelbar postoperativ zur Untersuchung. Hiervon ließen sich 7 mit einem Antiserum gegen Insulin und Schweine-C-Peptid, nicht aber mit einem Antiserum gegen Glucagon anfärben. Dagegen reagierte ein B-Zellcarcinom mit einer sehr niedrigen Insulinkonzentration mit keinem dieser Seren. Bereits ein Jahr nach der Einbettung in Paraffin ließ die Anfärbbarkeit dieser Tumoren mit einem Antiinsulinserum deutlich nach, während die Inseln des umgebenden normalen Pankreas mit dem gleichen Serum unverändert stark reagierten. — Von 6 weiteren Inseladenomen standen außerdem 1– 4 Jahre altes paraffineingebettetes Tumor- und Pankreasgewebe zur Verfügung. 4 dieser Tumoren hatten eine erhöhte Insulinkonzentration, reagierten immunhistologisch jedoch mit einem Antiinsulinserum nur schwach. Die beiden restlichen Tumoren — einer mit einer hohen, der andere mit einer niedrigen Insulinkonzentration — verhielten sich immunhistologisch negativ. Im Gegensatz zu den Tumoren ließen sich die Inseln des umgebenden Pankreas sämtlicher 6 Fälle mit einem Insulinantiserum gut anfärben. Somit scheint der erfolgreiche immunhistologische Nachweis von Insulin in insulinproduzierenden Tumoren von der Dauer der Einbettung des Tumormaterials in Paraffin abzuhängen. Das Insulin in den Pankreasinseln unterliegt dagegen diesem „Alterungseffekt“ nicht. — TumorInsulin läßt sich nur in Bouin-fixiertem, nicht aber in Karnovsky-fixiertem Gewebe immunhistologisch nachweisen, während das Insulin des normalen Pankreas auch nach Karnovsky-Fixation immunhistologisch nachweisbar ist. Die Befunde sprechen für Unterschiede zwischen normalem pankreatischen und Tumor-Insulin. — Die Färbung der B-Zellen von Tumoren mit Aldehyd-Thionin gelingt seltener als der immunhistologische Nachweis von Insulin in diesen Zellen. Die immunhistologische Untersuchung ist daher zur Identifizierung von B-Zelltumoren den üblichen spezifischen Färbungen überlegen.

Research paper thumbnail of The antrat gastrin-producing G-cell: Biochemical and ultrastructural responses to feeding

Cell and Tissue Research, 1978

The effect of feeding on serum and antral immunoreactive gastrin (IRG) concentrations and on the ... more The effect of feeding on serum and antral immunoreactive gastrin (IRG) concentrations and on the ultrastructural appearance of antral G-cell granules has been examined. Serum and tissue IRG concentrations were dependent upon the length of time (12 or 48 h) the rats had been fasted before receiving food; IRG release was biphasic; the first peak was more pronounced in rats fasted 12h. Antral tissue IRG content increased significantly postprandially. An initial depletion of antral IRG was seen in rats fasted 48 h. Examination of the subcellular distribution of antral IRG revealed more of the 5–15 min postprandal total IRG in the cytoplasm and less in the secretory granules. Ultrastructurally, G-cells from fasting rats contained mainly electron-dense granules. Five minutes postprandially numerous electron-lucent granules were observed. More electron dense granules were apparent 60 and 120 min postprandially. Fasting rats had the highest G-cell granule density index; a significantly lower index was observed 5 min postprandially. Indices at 60 and 120 min postprandially increased but were still lower than the fasting index. These studies indicate that gastrin biosynthesis is necessary for food stimulated gastrin release and that the electron density of the G-cells' granules is not an accurate reflection of the G-cell gastrin content.

Research paper thumbnail of Pathomorphologic, biochemical, and diagnostic aspects of gastrinomas (Zollinger-Ellison syndrome

Human Pathology, 1975

The clinical symptomatolog y of the Zollinger-Ellison syndrome and the pathologic anatomy of gast... more The clinical symptomatolog y of the Zollinger-Ellison syndrome and the pathologic anatomy of gastrinomas are reviewed. Experience with 17 patients with the Zollinger-Ellison syndrome is presented with special reference to stimulation tests (secretin, glucagon, calcium infnsion, test meal) and to localization and immunohistologic, tdtrastructural, and biochemical findings in gastrinomas. Muhiple hormone production by the tumors is frequent. The ultrastructure and the Sephadex G-50 gel filtration patterns of imnaunol'eactive gastrin in sera and tumors are not uniform and are not related to localization of the tumors in the pancreas or duodenum or to the gastrin concentration. Hyperplasia of the pancreatic islets is a frequent finding in gastrinorna patients, suggesting that hypergastrinemia may stimnlate islet growth.

Research paper thumbnail of Gastrin and G-Cells in the Antral Mucosa of Patients with Pernicious Anaemia, Acromegaly and Hyperparathyroidism and in a Zollinger-Ellison Tumour of the Pancreas

European Journal of Clinical Investigation, 1971

Abstract. In extracts of human gastric biopsies gastrin has been estimated with an immunochemical... more Abstract. In extracts of human gastric biopsies gastrin has been estimated with an immunochemical method. In the same biopsies G-cells have been localized with an immunohistological method using peroxidase-labelled antibodies and the endocrine cells investigated electron-microscopically. Gastrin and G-cells could be found regularly in the antral mucosa and only in insignificant amounts or not at all in the fundic mucosa of six normal persons. With the same methods gastrin and G-cells could be demonstrated in the antral mucosa of rats and guinea-pigs. The gastrin content of the antral mucosa of six patients with pernicious anaemia and achlorhydria with elevated serum gastrin levels was more than 20 times higher than in the controls and the G-cells were significantly more numerous. Besides hyperplasia of the G-cells, increased secretory activity was found electron-microscopically. The gastrin release from the G-cells seems to take place mainly via intracellular dissolution of the granule content within the membranous sacs. Although the number of other endocrine cells was increased in pernicious anaemia the ultrastructural identity of the G-cells could be established by comparison with the cells of a Zollinger-Ellison tumour. This tumour contained gastrin and gave a positive immunohistological reaction for this hormone. Also, the fundic mucosa of patients with pernicious anaemia contained gastrin and G-cells, but considerably less than the antral mucosa. Hyperplasia of G-cells was found in six cases of acromegaly, four of which also had a significantly increased gastrin content of the antral mucosa. This finding suggests a trophic function of the hypophysis, especially growth hormone, on the G-cells. Hyperplasia of the G-cells in the antral mucosa of three patients with primary hyperparathyroidism and increased gastrin content in two of the three cases also suggest a trophic function of the serum calcium level on the G-cells.

Research paper thumbnail of Mucosal gastrin concentration, molecular forms of gastrin, number and ultrastructure of G-cells in patients with duodenal ulcer

Gut, 1976

The mean antral immunoreactive gastrin (IRG) concentration of 38 duodenal ulcer (DU) patients was... more The mean antral immunoreactive gastrin (IRG) concentration of 38 duodenal ulcer (DU) patients was significantly higher (35.9 ± 5 2 jg/g) than that of 21 controls (15.9 + 2-6 jg/g). Also the mean IRG concentration in the proximal duodenal mucosa of 15 DU patients (3.2 ± 0O8 jg/g) was higher (but not significantly) than that of 10 controls (1-8 0S5 jg/g). The number of G-cells in the antral mucosa of 58 DU patients and in the duodenal mucosa of 29 DU patients was not larger than that of controls. The distribution of immunoreactivity in gastrin components has been investigated in the antral and duodenal mucosa of six DU patients and six controls. In the antral mucosa the mean percentage of G-17 was 93 3 % in DU patients and 920 0% in controls. G-34 amounted to 4-0°% in DU patients and to 5-0% in controls. The G-34 percentage in the duodenal mucosa was higher (however not significantly) in the DU patients than in the controls (50 1 % versus 35 8 %). Ultrastructurally, the antral G-cells of DU patients had a significantly lower density index of their secretory granules suggesting higher functional activity. It is concluded that the exaggerated serum IRG response of DU patients to different stimuli is not a consequence of an increased G-cell mass.

Research paper thumbnail of Measurement of 223 Ra and 224 Ra in coastal waters using a delayed coincidence counter

We describe a nuclear detector system for measuring low activities of 223 Ra and 224 Ra in natura... more We describe a nuclear detector system for measuring low activities of 223 Ra and 224 Ra in natural waters based on an original design of . Samples are obtained by adsorbing 223 Ra and 224 Ra onto a column of Mn0 2 coated fiber (Mn fiber). The short-lived Rn daughters of 223 Ra and 224 Ra which recoil from the Mn fiber are swept into a scintillation detector where alpha decays of Rn and Po occur. Signals from the detector are sent to a delayed coincidence circuit which discriminates decays of the 224 Ra daughters, 220 Rn and 216 Po, from decays of the 223 Ra daughters, 219 Rn and 215 Po. The system is calibrated using 232 Th and 227 Ac standards with daughters in equilibrium adsorbed on Mn fiber. Results of samples from Tampa Bay, Florida, and the Atchafalaya and Mississippi Rivers mixing zones are reported. The method is extendible to measurements of 227 Ac , 231 Pa, 228 Th, and 228 Ra.