B Trultzsch, T Nebel and R Paschke
H Gharib, E Papini and R Paschke
In 2006, two major society-sponsored guidelines and one major consensus statement for thyroid diagnosis and management were published by: the American Association of Clinical Endocrinologists/Associazione Medici Endocrinologi (AACE/AME); the American Thyroid Association (ATA); and the European Thyroid Association (ETA). A careful review of these guidelines reveals that despite many similarities, significant differences are also present, likely reflecting differences in practice patterns, interpretation of existing data, and availability of resources in different regions. The methodology of the guidelines is similar, but a few differences in the rating scale make a rapid comparison of the strength of both evidence and recommendations difficult for the use in current clinical practice. Some recommendations are based mostly on experts' opinion. Thus, a same recommendation may be based on a different evidence; on the other hand, sometimes the same evidence may induce a different recommendation. Therefore, efforts are needed to produce a few high-quality clinical studies to close the evidence gaps in the still controversial fields of thyroid disease and to create a joint task force of the most authoritative societies in the field of thyroid disease in order to reach a common document for clinical practice recommendations.
J. TEUBER, R. PASCHKE, R. SCHMEIDL, J. CHRISTOPHEL and U. SCHWEDES
U. SCHWEDES, J. TEUBER, R. PASCHKE and K. H. USADEL
R. PASCHKE, J. TEUBER, U. SCHWEDES and K. H. USADEL
R. Paschke, J. Teuber, U. Schwedes and K. H. Usadel
In several autoimmune diseases there is evidence for a possible role of antiidiotypic antibodies in the regulation of disease remission (Wasserman et al. 1982). In Graves' disease a significant increase in the incidence of circulating immune complexes in patients with negative TSI could be observed (Van der Heide et al. 1980). This finding has led to the suggestion that antiidiotypic antibodies may regulate the maintenance and re-establishment of a natural tolerance for the TSH-receptor.
Subsequently the production, biologic action and possible therapeutic implications of antiidiotypic antibodies in autoimmune thyroid disease could be demonstrated in two animal models (Zanetti et al. 1981; Islam et al. 1983). Recently antiidiotypic antibodies could be demonstrated in the sera of Graves' disease patients (Raines et al. 1985). Their presence correlated inversely with the presence of TSH receptor antibodies. To further elucidate the possible role of antiidiotypic antibodies for the regulation of remission in Graves' disease
S Miedlich, T Lohmann, U Schneyer, P Lamesch and R Paschke
OBJECTIVE: Familial isolated primary hyperparathyroidism (FIHP) is defined as hereditary primary hyperparathyroidism without the association of other diseases or tumors. Linkage analyses suggest that different genotypes can lead to the same phenotype of primary hyperparathyroidism. Hereditary syndromes associated with primary hyperparathyroidism are multiple endocrine neoplasia type 1 and type 2 (MEN 1 and MEN 2). In MEN 1, multiple parathyroid adenomas occur in more than 90% of the patients. Therefore, it has been suggested that FIHP could represent a variant or partial expression of MEN 1. DESIGN: We report on a large FIHP kindred with a MEN1 gene mutation. Nineteen family members (aged 10 to 87 years) were screened. Furthermore, statistical comparison by Fisher's exact tests of FIHP families with MEN1 gene mutations and MEN 1 families with two or more endocrinopathies was carried out to investigate genotype-phenotype correlations. METHODS: Mutational analysis of leucocyte DNA was carried out by direct sequencing of the complete coding region of the MEN1 gene. Screening of MEN 1 manifestations was carried out by determination of serum calcium, phosphate, parathyroid hormone, prolactin, ACTH, cortisol, IGF-I, gastrin, glucose, insulin, glucagon, serum potassium, aldosterone, plasma renin and urinary hydroxyindoleacetic acid. RESULTS: We detected an in-frame deletion mutation in exon 8 of the MEN1 gene resulting in the deletion of one glutamine acid residue at position 363. It was found in eight individuals. Two of these family members (aged 42 and 60 years) were operated for primary hyperparathyroidism, and three (aged 13 to 40 years) showed mild hypercalcemia and parathyroid hormone levels within the upper normal range or slightly elevated, without any clinical symptoms. Two individuals (aged 12 and 19 years) were normocalcemic. One could not be tested. None of them had clinical evidence of other MEN 1 manifestations. Statistical comparison of the mutation types in families with FIHP and families with two or more MEN 1-associated endocrinopathies reported in other studies reveals a significant difference. In families with FIHP, missense/in-frame mutations have been found in 87.5% of cases whereas in families with tumors in various endocrine glands these mutation types occur much less frequently (21-34%, P<0.05). CONCLUSIONS: These studies indicate that FIHP can represent a partial MEN 1 variant and is often caused by missense/in-frame mutations.
M Fasshauer, J Klein, U Lossner and R Paschke
OBJECTIVE: Galectin-12 has recently been shown to be a predominantly adipocyte-expressed protein which is stimulated by insulin-sensitizing thiazolidinediones and possesses apoptosis-inducing activity. METHODS: To further clarify galectin-12 regulation and its potential involvement in the development of insulin resistance, 3T3-L1 adipocytes were chronically treated with various hormones known to impair insulin sensitivity, and galectin-12 mRNA was measured by quantitative real-time reverse transcription-polymerase chain reaction. RESULTS: Treatment of 3T3-L1 cells for 16 h with 10 micromol/l isoproterenol, 100 nmol/l insulin, 0.6 nmol/l tumor necrosis factor alpha (TNFalpha), and 100 nmol/l dexamethasone reduced galectin-12 gene expression between 47% and 85%. These negative effects were dose-dependent with significant inhibition detectable at concentrations as low as 10 nmol/l isoproterenol, 0.06 nmol/l TNFalpha, and 1 nmol/l dexamethasone. Furthermore, the inhibitory effect of isoproterenol could be almost completely reversed by pretreatment with the beta-adrenergic antagonist propranolol and mimicked by stimulation of G(S)-proteins with cholera toxin or by activation of adenylyl cyclase with forskolin and dibutyryl-cAMP. CONCLUSIONS: Our results suggest that galectin-12 is an adipocyte-expressed protein which is downregulated by various insulin resistance-inducing hormones. These findings imply a role for galectin-12 in the pathogenesis of insulin resistance.
M Eszlinger, HP Holzapfel, C Voigt, C Arkenau and R Paschke
OBJECTIVE: A new family of guanosine triphosphatase-activating proteins known as regulators of G protein signaling (RGS) has been found to regulate the desensitization of several G protein-coupled ligand-induced processes. The expression of nine RGS mRNAs was found in human thyroid tissue (RGS 2, 3, 5, 6, 9, 10, 12, 14 and 16). At present, little is known as to whether any of the RGS proteins play a role in TSH signaling. DESIGN AND METHODS: To explore the involvement of RGS proteins in the regulation of TSH receptor (TSHR) signal transduction, mRNA expression levels of the RGS proteins were analyzed after TSH stimulation of human thyroid primary cultures by real-time RT-PCR. Furthermore, the effects of RGS 2 expression on TSHR signaling (cAMP-, inositol-3-phosphate accumulation, TSHR cell surface expression) were studied in COS-7 cells. RESULTS: Only RGS 2 mRNA was found to be regulated by TSH in thyroid primary cultures. Co-expression of RGS 2 and TSHR in COS-7 cells reduced the TSHR signaling via inositol-3-phosphate but not via cAMP after stimulation with TSH. CONCLUSION: TSH-dependent RGS 2 mRNA expression and the suppression of TSH-G(q)alpha signaling by the overexpression of RGS 2 imply that RGS 2 is involved in TSHR-induced G(q) signal transduction.
M Eszlinger, S Neumann, L Otto and R Paschke
BACKGROUND: The detection of serum thyroglobulin (Tg) by immunoassay is widely used to detect residual, recurring or metastatic thyroid carcinoma tIssue in patients with differentiated thyroid cancer (DTC) after total thyroidectomy and radioiodine therapy. However, this method requires thyroid hormone withdrawal to increase sensitivity and is limited by the interference of anti-Tg antibodies. To solve these problems, the detection of Tg mRNA from circulating thyroid cells by reverse transcription (RT)-PCR has been suggested as an alternative method. However, different previous reports show discrepant conclusions as to the clinical usefulness of Tg mRNA quantification. METHODS: We compared three methods of blood collection and RNA extraction, and quantified Tg mRNA (by real time RT-PCR) in the peripheral blood of a) probands without thyroid disease (n=42), patients with b) thyroid autonomy (n=15), c) Graves' disease (n=22), d) euthyroid goiter (n=6), and in DTC-patients after thyroidectomy and radioiodine therapy e) with (n=16) and f) without (n=37) metastasis. As the use of citrate blood in combination with a subsequent separation of mononuclear cells showed a significantly better RNA yield than the extraction of RNA from EDTA or citrate blood without the separation of mononuclear cells, this was the method used. Total RNA was reverse transcribed with random hexamer primers and Tg mRNA was amplified by real time RT-PCR using specific primers and hybridization probes. The Tg mRNA concentrations were normalized to beta-actin mRNA concentrations. RESULTS: Mean circulating Tg mRNA for each group detailed above, expressed as the ratio of Tg to beta-actin concentrations x 1000, were: a) 2.3 (range 0.03-70.89), b) 0.25 (range 0.02-0.55), c) 0.31 (range 0.05-1.36), d) 0.18 (range 0.08-0.35), e) 0.57 (range 0.03-3.03) and f) 0.17 (range 0.02-0.60). Furthermore, we found no correlation between serum Tg and Tg mRNA. CONCLUSIONS: In summary, our data do not show significant differences in Tg mRNA expression between the investigated groups. Therefore, the detection and quantification of Tg mRNA in peripheral blood is unlikely to be suitable for the follow-up of DTC.