PubMed Health⌕ Search

Biomedical subjects

D Führer

Publications and source records attributed to D Führer.

At least 19 recordsLinked to original sources
PubMed2006

The effects of insulin on the central nervous system--focus on appetite regulation.

Appetite and satiety are subject to complex regulation, with neuroendocrine mechanisms playing an important role. The central nervous system is attracting increasing attention as a target tissue for many hormones such as leptin, PYY3-36, ghrelin, glucagon-like-peptide 1 and many others. Among its many well-known functions, insulin is also a potent anorexigenic hormone, and insulin receptors are widely distributed throughout the central nervous system. One way to advance our understanding of central nervous regulation of hunger and satiety in humans is to develop suitable neuroimaging techniques for use in various clinical and experimental conditions. Several studies have been performed using functional magnetic resonance imaging and positron emission tomography to identify areas of the brain that are differentially activated by alteration of the feeding state. These preliminary data are taking shape as a complex neuronal network involving the hypothalamus, thalamus, limbic and paralimbic areas including the insular cortex and the anterior cingulate gyrus and the orbitofrontal cortex. Continuous efforts to understand hormonal effects on these pathways may advance our understanding of human obesity.

Animals↗
PubMed2006

Cytology and mRNA expression analysis of fine needle aspirates of thyroid nodules in an East German region with borderline iodine deficiency.

Fine needle aspiration cytology (FNAC) is widely recommended as an important tool for pre-operative identification of malignancy in patients with nodular thyroid disease. To assess the diagnostic contribution of FNAC and the potential of quantitative mRNA analysis in fine needle aspirates in daily practice, we conducted a prospective study in thyroid clinics (n=2) and endocrine practices (n=3), respectively in an East German region with borderline iodine deficiency. Two-hundred and forty-four consecutive FNACs were obtained over a period of 2 years (2002-2004) from euthyroid patients presenting for first evaluation of a solitary thyroid nodule. The mean nodule size for FNAC was 27 mm (range: 10-79 mm). In 55% of patients FNAC was performed after scintiscan detection of a cold or normal functioning thyroid nodule (CTN), while in the remainder FNAC was performed as a primary investigation. FNAC outcomes were: 57.8% benign, 22.1% indeterminate, 2.5% suspicious for malignancy, 17.6% non-diagnostic. Messenger RNA levels for a house keeping gene (beta-actin) and a thyroid specific marker (thyroglobulin, Tg) were studied as basic molecular markers using real-time PCR. Both in the IN VIVO and EX VIVO FNA series, beta-actin and Tg mRNA levels were positively correlated with the thyrocyte cell yield/respective FNA smear. However, subgroup analysis showed that FNAC with histologically confirmed follicular thyroid cancer and/or microfollicular adenoma exhibited significantly lower Tg mRNA expression despite high beta-actin levels. Sufficient mRNA quantities were obtained in >90% of FNA specimen to allow quantitative mRNA analysis of at least 5 further genes. In conclusion, quantitative mRNA analysis is feasible in FNA on a routine basis and provides a perspective for a molecular distinction of thyroid nodules, once specific marker genes have been defined for benign and malignant thyroid tumours respectively.

Actins↗
PubMed2006

The role of thiocyanate in the etiology of goiter in an industrial metropolitan area.

OBJECTIVE: Thiocyanate (SCN-) has concentration dependent antithyroid properties and a role in the etiology of goiter has been suggested in several studies. In 1991 an epidemiological survey conducted in the region of Halle/Leipzig (Saxony), an area with significant air pollution, suggested an inverse relationship between urinary iodine (I-)/SCN- excretion and goiter prevalence. 10 years later, we reinvestigated the same industrial area to clarify if the situation has changed after the elimination of most industrial waste products and moreover, if SCN- excretion levels alone or in combination with air pollution or smoking as a SCN- source are critical for thyroid function. DESIGN AND METHODS: We investigated a cohort of 708 probands for I-, SCN- and creatinine excretion in spot urine samples and determined the prevalence of goiter and thyroid nodules by high resolution ultrasonography. RESULTS: Probands with goiter (n = 79, 11%) had significantly higher urinary SCN- excretions than probands without (3.9 +/- 2.8 vs 3.1 +/- 3.4 mg SCN-/g creatinine) and significantly lower urinary I-/SCN- ratios than patients without thyroid disorders (41 +/- 38 vs 61 +/- 71 microg I-/mg SCN-/l). Mean urinary I- excretions were not different between probands with or without goiter. Smokers showed significantly elevated urinary SCN-/creatinine ratios in comparison to non-smokers (4.3 +/- 4.3 vs 2.4 +/- 2.1 mg SCN-/g creatinine). ANOVA revealed a prediction of thyroid volume through age (P < 0.001), gender (P < 0.001), body weight (P < 0.05) and smoking (P < 0.05). CONCLUSIONS: In our investigation, age, gender and smoking (raising SCN- levels by CN- inhalation) were predictive for thyroid volume and the urinary I-/SCN- ratios were able to detect probands with an increased risk of developing goiter in contrast to urinary I- excretion levels alone. These data suggest, that in an era and area of decreased cyanide pollution, SCN- may remain a cofactor in the multifactorial aetiology of goiter.

Adult↗
PubMed2005

Questionnaire on management of nodular thyroid disease (Annual Meeting of the Thyroid Section of the German Society of Endocrinology 2003).

Nodular thyroid disease is highly prevalent in iodine deficient areas. In Germany it affects approximately 30 % of the adult population. Differential diagnosis of thyroid nodules is directed at exclusion of rare thyroid malignancy and assessment of the nodules' functional characteristics in order to determine the best treatment approach. In 2003 the annual meeting of the Sektion Schilddrüse, a thyroid specialist group of the German Society of Endocrinology addressed the topic of "management of benign nodular thyroid disease". To assess the current diagnostic and therapeutic approach to nodular thyroid disease by German thyroid experts we designed a questionnaire, which was sent to all members of the Thyroid Section before the meeting and was answered by 70 % of the participants. We here report the results of the questionnaire, which show a considerable national heterogeneity in the management of thyroid nodules as well as diagnostic and treatment preferences for different thyroid specialist subgroups, e.g. endocrinologists and nuclear medicine specialist. This is in agreement with results of previous questionnaires assessing state-of-the-art practise among members of the European and American Thyroid Associations and underlines the definite need for a consensus process and for carefully planned randomized trials to answer the many unresolved questions in diagnosis and therapy of nodular thyroid disease.

Biopsy, Needle↗
PubMed2005

Iodine nutrition, nodular thyroid disease, and urinary iodine excretion in a German university study population.

We determined the influence of different nutritional factors on the urinary iodine excretion in an East German university population. First, we assessed iodine excretion in spot urine samples. Second, we measured iodine content in the university canteen meals, where approximately 20% of the probands had regular meals. Third, we used a special food questionnaire to assess for other sources of nutritional iodine intake, namely iodine tablets, fish consumption, etc. Fourth, we determined the actual prevalence of goiter and thyroid nodules in our probands by high-resolution ultrasonography. The mean urinary iodine excretion in our cohort was 109 +/- 81 microg/g level indicating a borderline adequate iodine intake (100-200). The frequency of thyroid nodules was 30% and the frequency of goiter 11%. Thyroid volumes greater than 18 mL and 25 mL were considered to be enlarged in adult women and men respectively. Urinary iodine excretion was not related to the presence of goiter or thyroid nodules. In addition urinary iodine excretion did not vary with regular consumption of canteen meals, which contained approximately 50% of the daily recommended iodine intake. In contrast probands with regular supplementary intake of iodine tablets had significantly higher values of urinary iodine excretion (169 +/- 130 microg/g) compared to participants without (103 +/- 87 microg/g). No other single nutritional factor (e.g., salt, milk, or bread) had a statistically significant impact on urinary iodine excretion or was able to raise the urinary iodine excretion above the level of marginal iodine deficiency. In summary, the nutritional iodine intake in a Saxonian study population was found to be close to the margin of iodine deficiency. This shows insufficient supplementation of iodine through iodized salt/industrialized food production.

Adult↗
PubMed2005

Evaluation of peroxisome proliferator-activated receptor-gamma expression in benign and malignant thyroid pathologies.

Impairment of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) function through a dominant negative PAX-8/PPAR-gamma fusion gene or other events resulting in wild-type PPAR-gamma downregulation has been implicated in malignant thyroid cell transformation. The aim of our study was to perform a systematic evaluation of PPAR-gamma mRNA and protein expression in normal thyroid tissue as opposed to benign thyroid pathologies of different functional status and thyroid malignancy, to gain further insights into a putative physiological role of PPAR-gamma in the thyroid and to define whether PPAR-gamma could serve as a marker of thyroid cell differentiation. Ten cold benign (CTN) and 10 toxic (TTN) thyroid nodules and corresponding normal thyroid tissues, 10 follicular thyroid cancers (FTC), 10 papillary thyroid cancers (PTC) and 8 Graves' disease (GD) thyroids were studied by real-time polymerase chain reaction (PCR), immunohistochemistry and reverse transcriptase (RT)-PCR (PAX-8/PPAR-gamma fusion gene). PPAR-gamma mRNA expression was demonstrated in all samples. When comparing benign nodular and normal thyroid tissue of the same patient no significant difference in PPAR-gamma mRNA expression was observed. PPAR-gamma mRNA levels were similar in CTN and FTC. In contrast, PPAR-gamma mRNA expression was downregulated in 9 of 10 PTC and all GD samples, whereby at least 4 fold downregulation (compared with normal and benign nodular thyroid tissues) was observed in the latter. Immunohistochemistry showed an increased, patchy PPAR-gamma nuclear staining in CTNs and TTNs and only faint staining in the corresponding normal thyroid tissues. A diffuse and weak PPAR-gamma staining pattern was observed in all GD samples. No PAX-8/PPAR-gamma rearrangements were detected in any of the 68 thyroid tissue samples. In conclusion PPAR-gamma mRNA and protein expression levels are not concordant in benign thyroid nodular disease. Furthermore there is no clear-cut association of PPAR-gamma mRNA expression with follicular thyroid tumorigenesis. Absence of a PAX-8/PPAR-gamma fusion gene in the series of 68 thyroid samples is in agreement with the suggestion of PAX-8/PPAR-gamma rearrangement being restricted to a subset of follicular thyroid cancers. The marked downregulation of PPAR-gamma in GD warrants further investigation and could be linked, for example, with changes in apoptosis.

Adenoma↗
PubMed2004

Quantitative proteome analysis in benign thyroid nodular disease using the fluorescent ruthenium II tris(bathophenanthroline disulfonate) stain.

Thyroid tumorigenesis involves qualitative and quantitative changes in protein expression, which can be comprehensively studied by proteome analysis. However, one of the technical bottlenecks of proteomics remains a reliable, sensitive and inexpensive method for quantification of differentially expressed proteins. This is due to the limited linear range of most available protein stains, i.e. silver and Coomassie blue, and high costs of commercially available fluorescent stains. In this paper we describe our experience with a lab-made ruthenium based fluorescent stain (ruthenium II tris(bathophenanthroline disulfonate) (RuBPs)) to perform proteome analysis of nodular thyroid disease. We first compared the properties of RuBPs with two highly sensitive protein stains: (1) silver staining and (2) the commercially available fluorescent dye Sypro Ruby. We show that in addition to its highly sensitive staining capabilities similar to Sypro Ruby and silver (2 ng), RuBPs offers several advantages such as a broad dynamic range (similar to Sypro Ruby and 500 times broader than the dynamic range of silver stain), low costs ( 0.03 per gel) and excellent compatibility with mass spectrometry. We then applied the inexpensive RuBPs stain to 2D gels (pH 4-7) of four benign thyroid nodules and normal thyroid tissue. We were able to detect approximately 1800 protein spots/gel in our thyroid samples. Quantitative changes in protein expression levels of at least 20-42 proteins were noted in the benign nodules compared with the normal thyroid tissue of the same patient. Differentially expressed spots were further characterised by nano-LC-FTICR and MALDI-TOF mass spectrometry. In summary we demonstrate, that the novel fluorescent ruthenium II tris(bathophenanthroline disulfonate) stain is a highly sensitive, reliable and inexpensive tool for quantitative proteome analysis in thyroid nodular disease.

Dextrans↗
PubMed2004

Does tumor heterogeneity limit the use of the Weiss criteria in the evaluation of adrenocortical tumors?

Adrenal incidentalomas are detected more frequently with high-resolution imaging modalities. It is difficult to distinguish between benign and malignant lesions despite the so-called histologic Weiss criteria, imaging features, and molecular studies. We here present a 52 yr-old man who was found to have an adrenal incidentaloma during an annual check-up at his urologist. An 8 cm large adrenal lesion was detected on ultrasound, computed tomography, and magnetic resonance imaging with imaging features suggestive of malignancy. The lesion was hormonally inactive. A left-sided adrenalectomy was performed and histologic grading revealed a Weiss score of 2, suggesting a benign tumor. However, on further follow-up, the patient developed a local recurrence and pulmonary metastases diagnosed 6 yr after initial presentation. After repeat surgery in the left adrenal bed adrenocortical tumor tissue had a Weiss score of 8, clearly suggesting histologic malignancy. The patient received adjuvant mitotane therapy. Under this therapy, he developed a right-sided adrenal mass (contralateral from the primary tumor) of 2 cm size which disappeared during the following 9 months, whereas the pulmonary metastases remained unchanged, suggesting tumor clones with a variable response to treatment or spontaneous apoptosis. This case suggests that adrenal incidentalomas larger than 6 cm with imaging features such as intratumoral necrosis suggestive of malignancy, should be managed as potential cancers independent of the so-called Weiss criteria. In such patients, close follow-up examinations including high-resolution imaging (preferably 3 monthly) are needed and should be carried out by a physician familiar/specialized in endocrine oncology.

Adrenal Cortex↗
PubMed2003

Two somatic TSH receptor mutations in a patient with toxic metastasising follicular thyroid carcinoma and non-functional lung metastases.

In a 59-year-old patient, thyroid follicular cancer was diagnosed in two right-sided toxic thyroid nodules, which had presented clinically as unilateral thyroid autonomy. In addition, the patient had histologically proven lung metastases of thyroid cancer; however, these failed to exhibit iodine uptake and were resistant to radioiodine treatment. The functional activity of the thyroid nodules prompted us to screen for TSH receptor (TSHR) mutations, and the histological diagnosis of follicular carcinoma led us to search for the PAX8-PPARgamma1 rearrangement and mutations in the ras genes. Each thyroid nodule harboured a different TSHR mutation (large nodule, Asp633Tyr; small nodule, Phe631Ile). Presence of both mutations in one sample suggestive of local invasion of a thyroid carcinoma could not be demonstrated, although several specimens from different nodule locations were screened. Only the wild-type TSHR sequence was identified in the histologically normal left thyroid lobe, and no genetic alterations were found in the other investigated genes. No TSHR mutations were detected in the pulmonary metastases. This is the first case report of a patient with toxic follicular thyroid carcinoma harbouring two different TSHR mutations and presenting with non-functional lung metastases.

Adenocarcinoma, Follicular↗
PubMed2001

Detection of thyroid-stimulating hormone receptor and Gsalpha mutations: in 75 toxic thyroid nodules by denaturing gradient gel electrophoresis.

The actual frequency of constitutively activating thyrotropin receptor or Gsalpha mutations in toxic thyroid nodules (TTNs) remains controversial as considerable variation in the prevalence of these mutations has been reported. We studied a series of 75 consecutive TTNs and performed mutation screening by the more sensitive method of denaturing gradient gel electrophoresis (DGGE) in addition to direct sequencing. Furthermore, the likelihood of somatic mutations occurring in genes other than that for the thyroid-stimulating hormone receptor (TSHR) and exons 7-9 of the Gsalpha protein gene was determined by clonality analysis of TTNs, which did not harbor mutations in the investigated genes. In 43 of 75 TTNs (57%) constitutively active TSHR mutations were identified. Six TSHR mutations were detected only by DGGE, underlining the importance of a sensitive screening method. Novel, constitutively activating mutations were identified at positions 425 (Ser-->Leu) and 512 (Leu-->Glu/Arg). Furthermore, a new base substitution was detected at position Pro639Ala (CCA-->GCA). Ten of 20 TSHR or Gsalpha mutation negative cases (50%) showed nonrandom X-chromosome inactivation, indicating clonal origin. In conclusion, somatic, constitutively activating TSHR mutations appear to be a major cause of TTNs (57%), while mutations in Gsalpha play a minor role (3%). The mutation negative but clonal cases indicate a probable involvement of somatic mutations other than in the TSH receptor or Gsalpha genes as the molecular cause of these hot nodules.

Amino Acid Substitution↗
PubMed2000

Functional characterization of five constitutively activating thyrotrophin receptor mutations.

OBJECTIVE: Gain of function mutations of the thyrotrophin receptor (TSHR) affect several functional characteristics, such as cAMP and inositol phosphate (IP) accumulation, cell surface expression and TSH affinity. In this study we compared five constitutively activating TSHR mutations, four receptors with a point mutation (S505N, L629F, I630L, V656F) and a nine amino acid (aa) deletion mutant (aa positions 613-621) for these functional parameters in parallel transfection experiments. METHODS: The wild-type TSHR (wt) and TSHRs containing the mutations S505N, L629F, I630L, V656F and the deletion 613-621 (all cloned in the expression vector pSVL) were transiently expressed in COS-7 cells in parallel experiments. Forty-eight hours after transfection the basal and stimulated cAMP and inositol phosphate accumulation as well as the cell surface expression (by FACS and ELISA), KD-values and TSHR down regulation by different stimuli were determined. RESULTS: In contrast to the very different values for specific constitutive activity (sca) (ranging from 7.5 to 100.3-fold wt) and very different levels of receptor cell surface expression (11-94% wt level) the basal cAMP accumulation determined in transfected COS-7 cells was surprisingly uniform (6.5-8.0 over wt basal). None of the point mutated receptors constitutively activates the phospholipase C cascade. In contrast the deletion 613-621 mutant showed constitutive activity for the IP pathway with a twofold increase in basal IP accumulation compared to the wild type TSHR. All investigated TSHR-mutants showed a TSH-stimulated receptor down-regulation, which seems to be independent of the phospholipase C pathway. CONCLUSIONS: The uniform basal cAMP values in spite of the large variation in specific constitutive activity values suggest that the COS-7 cell overexpression system used for the in vitro characterization is partly regulated. This regulation is most likely due to receptor down regulation. The TSHR deletion mutant (613-621) showed a constitutive activity for both the Galphas and the Galphaq/11 pathways. The TSH-mediated IP-stimulation by this mutant contrasts with its unresponsiveness to TSH for cAMP accumulation and therefore supports the model of different active conformations of the TSHR.

Animals↗
PubMed1999

Variable phenotype associated with Ser505Asn-activating thyrotropin-receptor germline mutation.

Constitutively activating thyrotropin-receptor (TSHR) germline mutations have been identified as a molecular cause of hereditary nonautoimmune hyperthyroidism. To date, seven cases of familial and six cases of sporadic nonautoimmune hyperthyroidism have been described associated with 13 different TSHR germline mutations, with a variable clinical course. We report the case of a 12.3-year-old girl with a history of thyrotoxicosis since the age of 11 months who developed diffuse thyroid hyperplasia at the age of 4.5 years. The patient has required continuous moderate-dose antithyroid medication, to maintain euthyroidism. There were no clinical signs of autoimmune thyroid disease and autoantibodies were negative. An activating germline mutation in the TSHR gene was suspected and was found in TSHR exon 10 (Ser505Asn) but was absent in the girl's mother. This same mutation, was first reported in a patient with severe intrauterine hyperthyroidism with early and progressive goiter development. Our patient had a significantly less severe clinical course with later onset compared to the original patient with the same TSHR germline mutation.

Child↗
PubMed1998

Autosomal dominant nonautoimmune hyperthyroidism. Clinical features-diagnosis-therapy.

Autosomal dominant nonautoimmune hyperthyroidism is a hereditary form of hyperthyroidism caused by constitutively activating germline mutations in the TSH-receptor gene. Clinical features comprise familial prevalence of thyroid autonomy in more than 2 generations and conditions of persisting neonatal hyperthyroidism or nonautoimmune hyperthyroidism of childhood onset with frequent relapses of hyperthyroidism under thyrostatic therapy and after thyroid surgery. Once clinically suspected the diagnosis can be confirmed by mutation analysis of genomic DNA extracted from a routinely obtainable EDTA blood sample. In patients with hereditary nonautoimmune hyperthyroidism a near total thyroidectomy is recommended as the first line treatment to avoid relapses from residual thyroid tissue with the activating TSHR mutation. Furthermore, genetic counselling of the affected patients is advised.

Adult↗