Ganglioneuroblastoma of the thymus: an adult case with the syndrome of inappropriate secretion of antidiuretic hormone.

A 61-year-old woman was admitted to the hospital because of general fatigue. Laboratory examinations showed hyponatremia, plasma hypo-osmolarity, and inappropriate increased concentration of the plasma antidiuretic hormone (ADH) in the presence of concentrated urine. Magnetic resonance imaging revealed a mass lesion in the anterior mediastinum. An extended thymectomy was performed under the diagnosis of thymoma with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Histologically the tumor was located in the thymic tissue and was diagnosed as ganglioneuroblastoma. Immunohistochemical studies showed the existence of ADH in the tumor cells. To the knowledge of the authors, this is the first case of ganglioneuroblastoma of the thymus with SIADH.

Familial pheochromocytoma associated with von Recklinghausen's disease.

We report a 19-year-old woman who presented with headache, vomiting, and elevated blood pressure; pheochromocytoma and von Recklinghausen's neurofibromatosis were diagnosed. Her mother had the same skin lesions and was also found to have pheochromocytoma. Both patients underwent surgical resection and the postoperative courses were uneventful; the daughter subsequently married and delivered a healthy child. Although both pheochromocytoma and von Recklinghausen's disease are derived from neuroectoderm and are inherited disorders, concomitant familial occurrence of these two diseases is very rare, only three families have been reported previously worldwide.

Effects of aging on plasma islet amyloid polypeptide basal level and response to oral glucose load.

To delineate the effects of aging on basal and glucose-stimulated secretion of islet amyloid polypeptide (IAPP), we compared the basal level of plasma IAPP and its response to an oral glucose load in elderly subjects with those of young subjects. Plasma IAPP level was determined by radioimmunoassay. Basal level of plasma IAPP in 20 elderly subjects (mean age 63 yr) was 5.3 +/- 0.4 pmol/l, which was not significantly different from 5.0 +/- 0.3 pmol/l in 22 young subjects (mean age 26 yr). Plasma glucose levels after an oral glucose load in elderly subjects (n = 8, mean age 67 yr) and young subjects (n = 8, mean age 29 yr) were within normal limits. However, the plasma glucose response in the aged group was significantly higher than that in the young group. The plasma insulin response to a glucose load in elderly subjects was not different from that in young subjects. The plasma IAPP level in the aged group significantly increased from 5.3 +/- 0.5 to 16.4 +/- 2.3 pmol/l 120 min after the oral glucose load. This result was quite similar to that in the young group whose plasma IAPP level increased from 4.9 +/- 0.5 to 14.1 +/- 1.5 pmol/l 120 min after the glucose load. We concluded that the basal level of plasma IAPP and its response to glucose were not affected by aging.

Plasma islet amyloid polypeptide levels in obesity, impaired glucose tolerance and non-insulin-dependent diabetes mellitus.

We examined the response of plasma islet amyloid polypeptide (IAPP) to an oral glucose load in non-obese and obese subjects with normal glucose tolerance or impaired glucose tolerance (IGT), and in non-obese patients with non-insulin-dependent diabetes mellitus (NIDDM). Plasma IAPP response to intravenous glucagon injection in NIDDM patients was also studied. Plasma IAPP concentration was determined by a sensitive and specific radioimmunoassay. Basal levels of plasma IAPP in non-obese subjects with normal glucose tolerance, IGT and NIDDM were not significantly different from each other. Non-obese subjects with IGT showed delayed and higher plasma IAPP response to oral glucose load compared to normal non-obese subjects. In NIDDM patients, IAPP response to glucose was delayed and lower when compared to normal non-obese subjects. Basal levels of plasma IAPP in normal obese subjects and obese subjects with IGT were significantly higher than those in normal non-obese subjects. Plasma IAPP response to glucose load in these obese subjects was higher than that in normal non-obese subjects. Plasma IAPP response was decreased in diabetic patients treated with diet, oral hypoglycemic agents and insulin in that order. We conclude that the secretion of IAPP is reduced with progression of NIDDM, although it appears to be rather augmented in IGT compared to normal non-obese subjects.

Use of inactive beta-D-galactosidase for elimination of interference by anti-beta-D-galactosidase antibodies in immune complex transfer enzyme immunoassay for anti-thyroglobulin IgG in serum using beta-D-galactosidase from Escherichia coli as label.

A novel enzyme immunoassay (immune complex transfer enzyme immunoassay) for anti-thyroglobulin IgG using beta-D-galactosidase from Escherichia coli as label was reported previously. This immunoassay was highly sensitive in demonstrating anti-thyroglobulin IgG not only in all patients with Graves' disease and chronic thyroiditis but also in a large proportion of healthy subjects. However, the detection of anti-thyroglobulin IgG at low levels in some serum samples was difficult, probably due to the presence of anti-beta-D-galactosidase antibodies. In the present study, the use of inactive beta-D-galactosidase was tested for elimination of interference by anti-beta-D-galactosidase antibodies. Preincubation of serum samples with excess of inactive beta-D-galactosidase resulted in sufficiently low backgrounds to detect low levels of anti-thyroglobulin IgG with little effect on the dose-response of anti-thyroglobulin IgG. As a result, it was revealed that anti-thyroglobulin IgG was present in almost all healthy subjects as well as all patients with Graves' disease and chronic thyroiditis.

Islet amyloid polypeptide in insulinoma and in the islets of the pancreas of non-diabetic and diabetic subjects.

Amyloid deposition is a common pathological feature in insulinoma and in the islets of the pancreas in type-2 diabetic patients. The present immunohistochemical study revealed that normal B-cells, insulinoma, and amyloid deposits in insulinoma and diabetic pancreatic islets were commonly immunoreactive with antiserum to C-terminal synthetic tetradecapeptide of human islet amyloid polypeptide (IAPP) (24-37). Amyloid fibrils in insulinoma were also positive to IAPP by immunoelectron microscopy. A high level of IAPP was detected in the plasma and tissue of a insulinoma patient by radioimmunoassay suggesting that amyloid deposition in insulinoma is due to overproduction of IAPP. Amyloid deposits immunoreactive to IAPP were also seen in all diabetic pancreatic islets, but in no non-diabetic islets. There was much amyloid deposition in the islets of severe diabetics, whose B-cells demonstrated decreased immunoreactivities for IAPP and insulin. The IAPP content of the pancreas was 649.0 and 847.7 pg/mg wet weight in each of two diabetic patients, and 1034.6 and 1447.7 pg/mg wet weight in two non-diabetic patients. The present study revealed that IAPP is a bioactive peptide secreted from islet B-cells and are amyloidogenic peptide concerned in diabetogenensis and/or the progression of type-2 diabetes mellitus.

Islet amyloid polypeptide (IAPP) in the gastrointestinal tract and pancreas of man and rat.

An immunohistochemical study for islet amyloid polypeptide (IAPP) was made on the gastrointestinal (GI) tract and pancreas of man and rat, using antisera raised against a synthetic peptide of C-terminal human IAPP (24-37) and a synthetic peptide of rat IAPP (18-37). A large number of IAPP-immunoreactive cells were found in the pyloric antrum, and a small number in the body of the stomach in both man and rat. Cytoplasmic processes extended out from the bipolar peripheral region of the immunoreactive cells, rather like neuronal processes, and some appeared to make contact with other immunoreactive cells. In addition, small numbers of immunoreactive cells were also seen in the duodenum and rectum, whereas they were absent from the jejunum, ileum and large intestine. An examination was made for evidence of colocalization of IAPP-immunoreactive material with material immunoreactive for gastrin, somatostatin, vasoactive intestinal polypeptide, pancreatic polypeptide, insulin, and glucagon, but none was found. IAPP-immunoreactive cells were also found in the pancreas of non-diabetic and non-insulin-dependent diabetic patients, but they were completely absent from a patient with insulin-dependent diabetes mellitus despite the presence of IAPP in the plasma. The results of these studies suggest that the peptide may have a biological role in situ in the GI tract and, in addition to the pancreas, may be a possible source of plasma IAPP.

Gallbladder function and plasma cholecystokinin levels in diabetes mellitus.

Contractile motility of the gallbladder and plasma cholecystokinin (CCK) responses to egg yolk administration were studied in 28 diabetic patients and 12 normal subjects. The patients were divided into three groups: group A (n = 10) had no diabetic neuropathy, group B (n = 8) had diabetic neuropathy with little autonomic neuropathy, and group C (n = 10) had advanced diabetic autonomic neuropathy. In groups A and B, contraction of the gallbladder after egg yolk administration was not significantly different from that of normal subjects. However, in group C, gallbladder contraction was impaired (p less than 0.01-0.05), compared with that in normal subjects. After the administration of egg yolk, plasma CCK levels increased from 12.4 +/- 4.5 to 25.3 +/- 12.0 pg/ml in normal subjects. In group A, plasma CCK levels increased from 17.9 +/- 8.5 to 39.3 +/- 14.2 pg/ml, and in group B, from 15.2 +/- 5.1 to 38.3 +/- 9.9 pg/ml. In group C, however, plasma CCK levels increased from 33.1 +/- 13.9 to 72.4 +/- 31.9 pg/ml, and fasting CCK levels and responses to egg yolk were significantly higher than those in normal subjects and in groups A and B (p less than 0.01-0.05). In conclusion, this study showed that in a group of diabetic patients with autonomic neuropathy, gallbladder contraction was impaired despite the exaggerated CCK response to egg yolk.

Islet amyloid polypeptide, a novel pancreatic peptide, is a circulating hormone secreted under glucose stimulation.

Islet amyloid polypeptide (IAPP) was identified in human plasma using immunoaffinity chromatography, gel filtration and reverse- phase high performance liquid chromatography coupled with radioimmunoassay specific for the peptide. IAPP[1-37], IAPP[17-37], and other two IAPP- related peptides which were putative pro-IAPPs or different processing products of IAPP, were isolated. All of these IAPPs were also found in human pancreatic extract, indicating that they were secreted from B cell secretory granules into the circulation. IAPP[1-37] is a major molecular form of IAPP in the pancreas, but it accounted for 31% of immunoreactive IAPP in the plasma. Plasma concentration of IAPP in normal individuals increased to 3.0 times the basal level in response to oral administration of 75 g glucose. This study indicated that IAPP is a circulating hormone secreted under glucose stimulation.

Islet amyloid polypeptide response to glucose, insulin, and somatostatin analogue administration.

We determined islet amyloid polypeptide (IAPP) response in plasma to oral and intravenous glucose administration and intravenous insulin injection in nondiabetic subjects. Moreover, we studied the effect of somatostatin analogue SMS 201-995 on glucose-induced IAPP secretion in nondiabetic subjects. Plasma IAPP concentration was determined by radioimmunoassay. Oral administration of 75 g glucose (n = 8) significantly increased plasma IAPP levels from 4.5 +/- 0.7 to 14.0 +/- 1.7 pM (P less than 0.01) 60 min after administration. Intravenous administration of 10 g glucose (n = 7) also caused a significant increase in plasma IAPP from 5.0 +/- 0.4 to 11.6 +/- 0.9 pM (P less than 0.01) 5 min after injection. Plasma IAPP significantly decreased from 5.1 +/- 0.4 to 2.9 +/- 0.4 pM (P less than 0.01) 60 min after intravenous insulin injection (n = 8). Pretreatment with SMS 201-995 completely abolished IAPP and insulin secretion to intravenous glucose injection. A significant correlation was found between plasma IAPP and insulin levels in oral and intravenous glucose administration and between plasma IAPP and C-peptide levels during insulin-induced hypoglycemia. These results suggest that IAPP is cosecreted with insulin in response to a glucose load and secretion of IAPP is inhibited by hypoglycemia and somatostatin. IAPP may serve as a novel pancreatic hormone to control carbohydrate metabolism.

Sensitive time-resolved fluorimetric immune-complex-transfer immunoassay for antithyroglobulin IgG in serum.

A sensitive time-resolved fluorimetric immune-complex-transfer immunoassay for antithyroglobulin IgG in serum is described. Antithyroglobulin IgG in test serum was reacted with dinitrophenyl europium ion-labeled thyroglobulin. The complex formed of antithyroglobulin IgG and dinitrophenyl europium ion-labeled thyroglobulin was trapped onto two polystyrene balls coated with affinity-purified rabbit antidinitrophenyl bovine serum albumin IgG. The polystyrene balls were washed to eliminate nonspecific IgG in the test serum, and the complex was eluted from the polystyrene balls with dinitrophenyl-L-lysine and transferred to two polystyrene balls coated with affinity-purified rabbit antihuman IgG gamma-chain IgG. Europium ion bound to the polystyrene balls was measured by time-resolved fluorimetry. Antithyroglobulin IgG was demonstrated in all patients with Graves' disease and all patients with chronic thyroiditis. This immunoassay was more sensitive than the conventional enzyme immunoassay and less time-consuming than the previously described immune-complex-transfer enzyme immunoassays, although there were larger assay variations.

Effects of atropine, proglumide, and somatostatin analogue (SMS 201-995) on bombesin-induced gallbladder contraction and CCK secretion in humans.

The effects of atropine, proglumide, and somatostatin analogue (SMS 201-995) on bombesin-induced gallbladder contraction and plasma cholecystokinin (CCK) secretion were investigated in healthy volunteers. The gallbladder size was measured by real-time ultrasonography and the plasma CCK levels by radioimmunoassay. Bombesin (5 micrograms/30 min infusion) induced gallbladder contractions that reduced the gallbladder area to 36.6 +/- 2.1% of the original area 45 min after bombesin infusion, and caused a significant increase of plasma CCK from a basal level of 10.3 +/- 1.8 pg/ml to a peak level of 42.9 +/- 8.9 pg/ml (p less than 0.01) at 20 min. Atropine (500 micrograms, im) inhibited significantly (p less than 0.01) the gallbladder contraction (maximum contractile rate, 78.7 +/- 6.4%) in response to bombesin without any change of plasma CCK secretion, whereas proglumide (800 mg/day for 3 days, per os) decreased slightly but not significantly the gallbladder contraction, and had no effect on plasma CCK secretion. On the other hand, SMS 201-995 (50 micrograms, sc) almost completely inhibited both bombesin-induced CCK secretion and gallbladder contraction (maximum contractile rate, 93.6 +/- 6.2%). These findings suggest that atropine inhibits bombesin-induced gallbladder contraction, not via suppression of CCK release, but probably by inhibiting cholinergic mechanisms, whereas somatostatin inhibits gallbladder contraction, at least in part, by the suppression of bombesin-stimulated CCK secretion.

Measurement of anti-thyroglobulin IgG in serum by novel and sensitive immune complex transfer enzyme immunoassay.

Anti-thyroglobulin IgG in human serum was measured by a novel and sensitive immune complex transfer enzyme immunoassay. Anti-thyroglobulin IgG in human serum was reacted with dinitrophenyl thyroglobulin, and the complex formed between human anti-thyroglobulin IgG and dinitrophenyl thyroglobulin was trapped onto an affinity-purified rabbit (anti-dinitrophenyl bovine serum albumin) IgG-coated polystyrene ball. The polystyrene ball was washed to eliminate most nonspecific IgG in test serum, and the complex was eluted from the polystyrene ball, to which nonspecific IgG had been adsorbed, with dinitrophenyl-L-lysine and transferred to a clean polystyrene ball coated with rabbit anti-thyroglobulin IgG. The amount of human anti-thyroglobulin IgG in the complex on the rabbit anti-thyroglobulin IgG-coated polystyrene ball was estimated using rabbit (anti-human IgG gamma-chain) Fab'-horseradish peroxidase conjugate. The present enzyme immunoassay was 1,000 to 3,000-fold more sensitive than the conventional enzyme immunoassay, in which a human thyroglobulin-coated polystyrene ball was incubated with serum containing human anti-thyroglobulin IgG and, after washing, with rabbit (anti-human IgG gamma-chain) Fab'-horseradish peroxidase conjugate. By the present enzyme immunoassay, anti-thyroglobulin IgG was demonstrated in about 10% of healthy subjects and in all patients with Graves' disease and chronic thyroiditis. The principle of the present method may make it possible to sensitively measure other autoantibodies including anti-thyroid peroxidase and anti-thyrotropin receptor antibodies to aid diagnosis of thyroid diseases.

More sensitive and simpler immune complex transfer enzyme immunoassay for antithyroglobulin IgG in serum.

A more sensitive and simpler immune complex transfer enzyme immunoassay for antithyroglobulin IgG in serum and its use for the measurement of antithyroglobulin IgG in healthy subjects and patients with thyroid diseases are described. Antithyroglobulin IgG in test serum was reacted simultaneously with dinitrophenylthyroglobulin and thyroglobulin-beta-D-galactosidase conjugate. The complex formed of antithyroglobulin IgG, dinitrophenyl thyroglobulin, and thyroglobulin-beta-D-galactosidase conjugate was trapped onto two polystyrene balls coated with affinity-purified rabbit (antidinitrophenyl bovine serum albumin) IgG. The polystyrene balls were washed to eliminate nonspecific IgG in the test serum, and the complex was eluted from the polystyrene balls with dinitrophenyl-L-lysine and transferred to two polystyrene balls coated with affinity-purified rabbit (anti-human IgG gamma-chain) IgG. beta-D-Galactosidase activity bound to the polystyrene balls was assayed by fluorimetry using 4-methylumbelliferyl-beta-D-galactoside as substrate. As compared with the previous immune complex transfer enzyme immunoassay, the procedure was simplified by reducing one incubation step and one washing step, and the detection limit of antithyroglobulin IgG in serum (0.1 microgram/liter) was lowered 100-fold. More careful and extensive examination than in a previous study revealed the presence of antithyroglobulin IgG in a large proportion of healthy subjects and in all patients with Graves' disease and chronic thyroiditis.

Sensory and autonomic polyneuropathy associated with hypergammaglobulinemia.

Sensory and autonomic polyneuropathy is a rare disease characterized by a sensory nerve disorder and postganglionic autonomic dysfunction. The etiology of this disease is unknown. We described a 51-year-old woman who had a chronic sensory dominant polyneuropathy and dysautonomia associated with hypergammaglobulinemia. In the previous reports of sensory and autonomic polyneuropathy, not much attention was given to coexisting hypergammaglobulinemia. By reviewing the literatures, hypergammaglobulinemia was frequently present in these case reports. This fact leads us to consider that an immunological mechanism may be playing a role in the pathogenesis of this disorder.