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  • Author: Werner Waldhäusl x
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Werner K. Waldhäusl and Franz Rath

ABSTRACT

The development of antibodies against HGH (Raben) has been studied in 10 children with short stature who have been treated with HGH for from 4 months up to 5 years. Significant titres of antibody against HGH, > 1 : 3100, with a low avidity to 125I-HGH were found radioimmunologically by a simple double antibody immunoassay method in three out of 10 children. In these patients a concomitant decrease in the growth rate was observed simultaneously with the appearance of antibodies against HGH. The occurrence of clinically significant titres of antibodies against HGH in all three patients coincided with the administration of one single batch (no. 5) of HGH. However, two children who initially had shown a good response to therapeutic doses of HGH developed a rapid decrease growth rate after three years of successful treatment, without any evidence of detectable antibodies against HGH in the peripheral serum. The data obtained suggest that as well as antibodies against HGH, other factors may also account for the development of resistance to the therapeutic effect of HGH.

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Michael Roden, Peter Nowotny, Heinrich Vierhapper and Werner Waldhäusl

Abstract.

To evaluate the sensitivity of basal TSH concentrations as determined by an "ultrasensitive" IRMA-assay (RIA-gnost h-TSH-monoclonal, Behring) versus a "negative" TRH test (defined as an increment of TSH ≥0.2 mU/l 20 min after administration of 400 μg TRH iv) in the diagnosis of hyperthyroidism we examined 193 consecutive patients from our thyroid outpatient clinic: 34 patients displayed hyperthyroidism (total T4: 184.4±26.0 μmol/l, effective thyroxine index: 1.25±0.08), whereas 12 had isolated T3-hyperthyroidism (total T3: 3.47±0.48 nmol/l). Employing the producer's definition of subnormal ("suppressed") bTSH concentrations (≤0.1 mU/l), only 19 (41.3%) hyperthyroid patients would have been detected; on the other hand, one euthyroid patient would have been recognized false positively as hyperthyroid. Using the TRH test as criterion led to the correct diagnosis in 42 (sensitivity: 91.3%) hyperthyroid patients, whereas two had low bTSH concentrations (≤0.5 mU/l), but a normal TSH response to TRH (>2.0 mU/l). Raising the threshold concentration to 0.2 and, subsequently, to 0.4 mU TSH/l increased the number of correct results to 38 (sensitivity: 82.6%) and 43 (93.5%), respectively. This was associated with a concomitant decrease in specificity in the diagnosis of hyperthyroidism from 93.7 (0.1 mU/l) to 27.9% (0.4 mU/l). In conclusion, despite ultrasensitive methods for estimation of low TSH concentrations, the TRH test remains an irreplaceable tool for the correct diagnosis of hyperthyroidism.

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Paul Bratusch-Marrain, Hannes Haydl, Werner Waldhäusl, Robert Dudczak and Wolfgang Graninger

ABSTRACT

A kindred is presented in which 4 members in 3 generations showed absent or reduced serum concentrations of thyroxine-binding globulin (TBG). TBG was undetectable by radioimmunoassay in one male and decreased to varying extent in 3 female patients (4.0, 4.2 and 8.6 μg/ml; normal range 12.5–26.0 μg/ml). Total thyroxine serum concentrations in the affected subjects were well in the hypothyroid range without clinical evidence of hypothyroidism. The mode of transmission of the trait was consistent with X-chromosome linkage. A high incidence of non-toxic goitre was also present in most of the family members examined irrespective of TBG levels. The transmission of the goitre trait was compatible with autosomal dominant inheritance. Thus its association with transmission of TBG deficiency was interpreted as not causal but coincidental.

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Clemens Fürnsinn, Peter Nowotny, Michael Roden, Madeleine Rohac, Thomas Pieber, Sabina Parzer and Werner Waldhäusl

To compare the effect of short- vs long-term amylin infusion on insulin sensitivity, glucose tolerance and serum calcemia, euglycemic-hyperinsulinemic clamp (26 pmol·kg−1·min−1) and glucose tolerance tests (2.4 mmol/kg over 30 min) were performed in lean Zucker rats. Three infusion protocols were employed: control group: 24 h of iv saline; short-term amylin exposure: 22 h of iv saline followed by 2 h of iv amylin (20 μg/h); long-term amylin exposure: 24 h of iv amylin (20 μg/h). Insulin resistance was induced by short-term amylin infusion during euglycemic clamping, as shown by a 41% decrease in space-corrected glucose infusion rates (μmol·kg−1·min−1; control group, 106.0±15.0; short-term iv amylin, 62.7±15.0; p<0.00 5). After long-term amylin exposure, insulin sensitivity was identical to control values (109.9±6.7). This fading action of amylin was confirmed by data from the glucose tolerance test, demonstrating glucose intolerance after short- but not after long-term amylin exposure. Serum calcium concentration decreased during short-term (2 h) amylin infusion (from 2.52±0.15 to 2.09±0.12 mmol/l; p<0.01) and hypocalcemia of a similar extent also was present after 22 h and 24 h of amylin exposure (2.10±0.09 and 2.04±0.14 mmol/l, respectively). The data demonstrate that short-term amylin infusion induces insulin resistance and glucose intolerance, both of which vanish during long-term (>22 h) amylin exposure, being apparently independent of induced hypocalcemia.

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Heinrich Vierhapper, Anton Laggner, Werner Waldhäusl, Beatrix Grubeck-Loebenstein and Gunther Kleinberger

Abstract.

Thyroid and pituitary function was studied in 10 male and 6 patients female during critical non-endocrine disease. Low concentrations of TT3 were observed in each case. Seven patients out of whom 3 survived, presented with low levels of TT4 due to deficiency in TBG in the presence of normal values of FTI and FT4, whereas a 'low T4-syndrome', characterized by low concentrations of both TT4 and FT4 was seen in 9 patients, 8 of whom died 1 to 16 days after evaluation of pituitary function. A diminished response of TSH to iv TRH (400 μg), as observed in 4 patients with normal FT4 and in all patients with 'low T4-syndrome', was not accompanied by a concomitant lack in stimulated release of LH, FSH and Prl in the majority of cases. However, the secretory maximum of LH and FSH following stimulation by LRH (100 μg iv) was delayed in 10 and in 9 patients, respectively, including patients both with normal and subnormal concentrations of FT4. From the above it appears that low stimulated concentrations of TSH in the presence of subnormal concentrations of FT4 indicate an extremely poor prognosis in critically ill patients. The abnormal behaviour of TSH in this group of patients cannot be explained by generalized pituitary insufficiency or by an increase in FT4.

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Clemens Fürnsinn, Martin Komjati, Ole D Madsen, Barbara Schneider and Werner Waldhäusl

Genetically obese Zucker rats (fa/fa) on a diabetogenic diet rich in lard and sucrose develop chronic hyperglycemia accompanied by severe hyperinsulinemia. Non-enzymatically glycated protein content was increased in tendon (p<0.0001) and aorta (p<0.04), but not nerve, from hyperglycemic rats as compared to normoglycemic lean litter-mates on a conventional chow diet (mmol furosine/mol tyrosine in tissue hydrolysate from 61-week-old rats: tendon, 29.8±1.8 vs 25.9±1.3; aorta, 12.0±1.0 vs 11.0±1.1). In pancreatic islets, non-enzymatically glycated protein was neither found in lean rats of any age nor in the obese up to an age of 36 weeks. At an age of 61 weeks, non-enzymatically glycated protein accumulated in islets of obese animals, resulting in levels of 17.02–44.65 mmol furosine/mol tyrosine. This rise in islet glycated protein content was not accompanied by a comparable increase in plasma glycemia, but simultaneous histological examination of pancreatic tissue revealed fibrosis of islets. Fibers were probably of collagenic quality without islet amyloid polypeptide immunoreactivity. Because collagen is known to be highly susceptible to non-enzymatic glycation, we suspect that collagenic fibers but not endocrine cells are the main source of glycated protein accumulation in these islets. Hence, our data do not give evidence that non-enzymatic protein glycation plays a role in the islet degeneration occurring in hyperglycemia. Furthermore, immunohistochemical staining for various endocrine peptides did not suggest loss of any hormone-producing cell type or defective pancreatic hormone production in hyperglycemic old, obese Zucker rats. The more soluble nature of rat vs human islet amyloid polypeptide may explain the fact that hyperglycemia-induced fibrosis in rat islets does not include amyloidosis, which may contribute to late beta cell failure in human type II diabetes.

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Sabina Baumgartner-Parzer, Oswald Wagner, Peter Nowotny, Heinrich Vierhapper and Werner Waldhäusl

Baumgartner-Parzer S, Wagner 0, Nowotny P, Vierhapper H, Waldhäusl W. Stimulation of endothelin-1 production by thrombin, but lack of interference by high ambient glucose in vitro. Eur J Endocrinol 1994;130:271–5. ISSN 0804–4643

Diabetic vascular disease is associated with a state of hypercoagulability and altered endothelial properties, leading to elevated plasma levels of endothelium-derived peptides and proteins, e.g. endothelin-1. von Willebrand factor or fibronectin. This study determined dynamic immunoreactive endothelin-1 secretion by human umbilical vein endothelial cells exposed to thrombin (5 × 106 mU/l) in the presence (40 mmol/l) and absence (5.5 mmol/l) of excessive glucose in the cell culture medium. Exposure to high glucose and thrombin concentrations was initiated after cell confluency and applied for 24 h for measurements of endothelin-1 and for 2 and 5 h for the determination of preproendothelin-1, von Willebrand factor and fibronectin messenger ribonucleic acid. Comparisons were made versus cells incubated with normal glucose concentrations or with high mannose or NaCl concentrations as osmotic control. Neither preproendothelin-1, fibronectin and von Willebrand factor messenger ribonucleic acid expression nor endothelin-1 release was affected by high concentrations of glucose, mannose or sodium chloride.

Sabina Baumgartner-Parzer, Department of Medicine III, Division of Endocrinology and Metabolism, Währinger Gürtel 18-20, 1090 Vienna, Austria