Highlights in thyroidology: a historical vignette.

This review gives a historical overview about the development of today's understanding of benign thyroid diseases and the possibilities of their treatment.Little was known about the thyroid gland until the nineteenth century: the state of knowledge was (1) that something in food, especially in seaweed, avoided the development of goiters, (2) that goiters seemed to have something to do with cretinism, and (3) that the thyroid gland is an organ consisting of two lobes connected by an isthmus. Shortly after the detection of iodine in 1811, its impact on its ability to avoid the development and the growing of goiters has been realized. The existence of iodine within the thyroid and in human plasma was detected approximately a decade later. The clinical picture of hyperthyroidism including endocrine orbitopathy was described in detail in the middle of the nineteenth century, the etiology of the disease remaining, however, unclear until a century later. In early nineteenth century, surgical goiter exstirpation was the only available form of treatment. Vienna and Berne were the centers leading worldwide in their expertise. Subcutaneous injections of sheep thyroid extracts were developed for treatment of postoperative hypothyroidism as well as congenital myxedema. Another approach suggested by Swiss surgeons was thyroid transplantation. Radioiodine therapy of hyperthyroidism was introduced in the middle of the twentieth century. Thyrostatic drugs are available since about the same time. The different forms of thyroiditis were described at the turn of the twentieth century. The etiology of chronic autoimmune thyroiditis was, however, clarified only some 50 years later independently by two groups of scientists, one in London, UK, and the other in Buffalo, USA. Thyroxine was isolated from bovine thyroid extracts in the beginning of the twentieth century. Its synthesis and correct chemical structure were described some 10 years later. The existence of 3,5,3'-triiodothyronine (T3), the biologically most active thyroid hormone, was detected in the 1950s of the past century by a group in Paris and another in London. The extrathyroidal conversion of thyroxine to T3, as the main source of circulating T3, was suggested shortly thereafter and substantiated in 1970. Finally, the development of the radioimmunoassay method for determination of hormone serum concentrations in 1959 enabled today's exact laboratory diagnosis of thyroid diseases.

Acute cardiac disease in a young patient with Campylobacter jejuni infection: a case report.

INTRODUCTION: Infectious myocarditis is a life-threatening condition because it can lead to arrhythmia, dilated cardiomyopathy and congestive heart failure. A large number of different infectious causes have been identified as leading to myocarditis, with enteroviral infections being the most common reasons. CASE PRESENTATION: We present a rare Austrian case of bacterial-induced myocarditis in a 19-year-old immunocompetent male without any cardiac risk factors. Four days prior to the onset of severe left thoracic pain the patient developed acute gastroenteritis. The initial electrocardiogram showed sinus tachycardia, strain on the right side of the heart and signs of myocardial injury. Cardiac enzyme markers creatine kinase and troponin T were elevated to maximum values of 627 U/l and 0.52 ng/ml. Stool cultures revealed the presence of Campylobacter jejuni as the only source of infection. The clinical diagnosis of bacterial-induced myocarditis was confirmed by specific radiological findings of inflammation using cardiac magnetic resonance imaging. CONCLUSION: In recent years, instead of performing endomyocardial biopsies, the clinical diagnosis of bacterial-induced myocarditis can be confirmed by specific radiological findings in combination with positive stool cultures for Enterobacteriaceae. Due to the increasing numbers of Campylobacter infections, myocarditis should be considered as a rare but relevant extraintestinal complication also in immunocompetent patients with Campylobacter jejuni gastroenteritis.

Elevated blood markers 1 year before manifestation of malignant glioma.

We detected distinct plasma concentration profiles of S100B, neuropeptide Y, and secretagogin in 3 of 191 patients enrolled in a previous study investigating brain-tissue-related markers in the blood of patients with atrial fibrillation. Intriguingly, 2 of these 3 patients, both of whom were without neurological symptoms at the time of blood sampling, were diagnosed with malignant glioma (MG) approximately 1 year later. To our knowledge, this is the first report indicating that distinct blood biomarker profiles may be detected long before clinical manifestation of MG.

Brain natriuretic peptide correlates with the extent of atrial fibrillation-associated silent brain lesions.

OBJECTIVE: Identification of plasma markers indicative for atrial fibrillation-associated silent brain lesions. DESIGN AND METHODS: 1. Comparative determination of the plasma concentrations of secretagogin, S100B, neuropeptide Y, brain fatty acid binding protein, matrix metalloprotease 9, brain natriuretic peptide, and of D-Dimer in 222 patients with atrial fibrillation and 28 controls by immunoassays. 2. Correlation of the biochemical marker plasma concentration with the extent of silent white matter brain lesions, as determined by the Fazekas score and N-acetylaspartate-spectroscopy. RESULTS: 1. Plasma concentrations of brain natriuretic peptide, of neuropeptide Y, and of matrix metalloprotease 9 were significantly higher (all with a p<0.05) in patients suffering from atrial fibrillation than in control subjects. 2. Brain natriuretic peptide correlated significantly with the Fazekas score (R=0.41; p<0.005). 3. Brain natriuretic peptide plasma concentrations were significantly higher in patients with a pathological N-acetylaspartate magnetic resonance-spectrometry (p<0.05). CONCLUSION: Brain natriuretic peptide plasma concentrations correlate with the extent of atrial fibrillation-associated silent brain lesions.

Disturbances of thyroid function in the elderly.

Disturbances of thyroid function occur more often in the elderly than in the young. This short review gives an up-to-date overview of this topic. After discussing the difference in epidemiology of thyroid dysfunction in elderly persons in areas with different iodine nutrient status, the physiologic age-induced changes of the hypothalamic-pituitary-thyroid axis are discussed, especially with regard to their consequences on normal ranges of thyroid hormones. Although slight decreases in thyrotropin (TSH) and free triiodothyronine (T3) have been described as occurring in healthy elderly persons, it is concluded from the available data that abnormal values of thyroid hormones in serum of old people should be further investigated, since none of the described changes lead to values outside the normal range. Special emphasis is given to the fact that disturbances of thyroid function are oligosymptomatic or may even be asymptomatic in old persons. Therefore, laboratory screening for thyroid dysfunction in patients over 65 years of age seems to be justified. Lastly, differences of treatment in comparison with younger patients with hyper- or hypothyroidism are presented. The impact of subclinical disturbances of thyroid function in the elderly and their possible therapeutic consequences are also included in this discussion.

Differential expression of alphaB-crystallin and Hsp27-1 in anaplastic thyroid carcinomas because of tumor-specific alphaB-crystallin gene (CRYAB) silencing.

Expression of the small heat shock protein alphaB-crystallin in differentiated thyroid tumors has been described recently. In this study, we investigated the molecular mechanisms that affect the expression of alphaB-crystallin in benign goiters (n = 7) and highly malignant anaplastic thyroid carcinomas (ATCs) (n = 3). AlphaB-crystallin expression was compared with that of Hsp27-1. Immunoblot and quantitative real-time (RT) polymerase chain reaction revealed marked downregulation of alphaB-crystallin in all the tested ATCs and the ATC-derived cell line C-643 . In contrast, considerable expression of Hsp27-1 in benign and malignant thyroid tissue was demonstrated. Immunofluorescence analysis revealed no relevant topological differences between benign and malignant thyrocytes in the cytoplasmic staining of both proteins. Consistent and marked downregulation of TFCP2L1 was identified as one of the main mechanisms contributing to CRYAB gene silencing in ATCs. In addition, CRYAB gene promoter methylation seems to occur in distinct ATCs. In silico analysis revealed that the differential expression of alphaB-crystallin and Hsp27-1 results from differences between the alphaB-crystallin and Hsp27-1 promoter fragments (712 bp upstream from the transcriptional start site). Biological activity of the analyzed promoter element is confirmed by its heat shock inducibility. In conclusion, we demonstrate downregulation of alphaB-crystallin expression in highly dedifferentiated ATCs because of a tumor-specific transcription factor pattern. The differential expression of alphaB-crystallin and Hsp27-1 indicates functional differences between both proteins.

A newly identified RET proto-oncogene polymorphism is found in a high number of endocrine tumor patients.

Multiple RET proto-oncogene transcripts, due to genomic variations and alternate splicing, have been described. To investigate endocrine tumor tissue characteristic RET proto-oncogene expression, we performed quantitative RT-PCR, Northern blot and Southern blot analyses of benign and malignant endocrine-derived tissues. We newly describe RET proto-oncogene expression in carcinoid-, gastrinoma- and insulinoma-derived tissue samples. In addition, the presence of a 3'-terminally truncated RET proto-oncogene mRNA variant in benign and malignant thyroid neoplasias, as well as in a pheochromocytoma, an ovarian carcinoma and a medullary thyroid carcinoma, is demonstrated. Southern blot analysis revealed no evidence of gross RET proto-oncogene rearrangements or deletions. As the underlying cause for a bi-allelic TaqI restriction fragment length polymorphism (RFLP), a C (allele 1)/T (allele 2) transition within intron 19, was characterized. This polymorphism is close to a recently described polyadenylation site and lies within a binding site for the nucleic acid binding protein Pbx-1. Screening of healthy subjects and of patients suffering from various endocrine malignancies revealed exclusively allele 1 homozygous and allele 1/allele 2 heterozygous genotypes. Heterozygous genotypes were found in a significantly higher percentage in samples derived from endocrine tumor patients when compared with those from healthy control subjects. Homozygosity for allele 2 was found exclusively in somatic DNA derived from endocrine tumors with high malignant potential. Analysis of DNA derived from varying regions within individual anaplastic thyroid carcinomas revealed an allele 1/allele 2 switch of the RFLP banding pattern, indicating loss of heterozygosity at the RET proto-oncogene locus. In conclusion, our data demonstrate presence of a 5'-terminal RET proto-oncogene transcript in endocrine tissues and reveal a bi-allelic RET proto-oncogene polymorphism. A heterozygous genotype for this polymorphism is found in a considerable number of endocrine tumor patients.

[Thyroid dysfunction in aged persons]. / Störungen der Schilddrüsenfunktion im Alter.

This is a short review about thyroid dysfunction in the elderly. Screening investigations from the United States have shown that nearly every 4th woman above the age of 65 is affected. Therefore a state-of-the-art article about this phenomenon seems justified. Epidemiologic studies show that the pattern of thyroid dysfunction depends on the iodine-nutrient status, thyrotoxicosis being more common in countries with iodine deficiency, overt and subclinical hypothyroidism occurring very frequently in areas with sufficient iodine supplementation. After discussing the state of the art of what is known about physiologic changes induced by age in the hypothalamic-pituitary-thyroid axis, it is pointed out that abnormal values of thyroid function parameters in serum should be further investigated. Symptoms of thyroid dysfunction are very rare and often unspecific. Therefore, laboratory screening in women above the age of 65 seems to be justified. Finally, the differences of treating elderly patients with thyroid dysfunction in comparison to treating young patients is discussed. In this discussion the impact of subclinical disturbances of thyroid dysfunction is included.

Do iodine-containing contrast media induce clinically relevant changes in thyroid function parameters of euthyroid patients within the first week?

Little is known about the reaction of normal thyroid glands to the iodine load given by x-ray dyes. We have therefore investigated the short-term effects of high doses of iodine on thyroid parameters in euthyroid patients. We measured free triiodothyronine (FT3), free thyroxine (FT4), and thyrotropin (TSH) serum concentrations before and daily for 1 week after parenteral application of x-ray dyes (coronary angiography: n = 16; computed tomography [CT] of either thorax or abdomen: n = 6; iodine dose range from 300-1221 mg of iodine per kilogram). Inclusion criteria were as follows: normal FT4, normal TSH, negative thyroid antibodies, urinary iodine excretion below 30 microg/dL, no palpable goiter and no euthyroid sick syndrome. All but one patient reacted with a TSH increase. Mean TSH values increased significantly 3-5 days after the iodine load within the normal range. Four patients (18%) had a TSH increase above normal, the maximal observed value being 6.4 microU/mL. Basal TSH values of these four patients were above 2 microU/mL. The day peak TSH concentrations were reached varied from day 1 to day 7, the majority (32%) having the peak on day 3. Peak TSH was significantly correlated with basal TSH values (r = 0.794, p < 0.0001). FT4 and FT3 remained unchanged and there was no significant correlation between the dose of iodine and the TSH reaction. In conclusion, iodine-containing contrast media can induce transiently subclinical hypothyroidism even in euthyroid patients. The TSH reaction seems to depend on the preexisting state of thyroid function.

How you slice it: smarter segmentation for your sales force.

Three years ago, 70-year-old Hill-Rom Incorporated was in a position familiar to many mature businesses: The company was strong but needed to be stronger. It was a top producer of hospital beds and specialty mattresses, its core product lines. It also had competitive complementary lines of stretchers, furniture, and architectural equipment. It had an extensive customer base, a respected sales force, and solid profit margins. But by the time Ernest Waaser took over as chief executive in early 2001, revenue growth had been slowing, and competition was on the rise. To secure Hill-Rom's place in the market, Waaser decided to focus first on the sales organization--partly because the cost of sales had risen gradually over the past five years and partly because acquisitions and other initiatives had made the sales organization more complex. The CEO took several steps to restructure the sales force. First, the company changed its customer segments to better reflect customers' demands and financial status, ultimately targeting two main groups: key and prime customers. It then changed the overall structure of the sales organization so it could tailor its approach to these two segments; key customers received more specialized service than prime customers. Finally, Hill-Rom adjusted the sales force after the company took an in-depth look at historical data on products and services and sales completed. Reasons for staffing changes were carefully communicated to the sales force. Because of Hill-Rom's initiatives, the cost of sales is down, short-term revenue growth is up, the outlook for long-term revenue growth looks bright, sales and profit margins are up, and customer satisfaction has increased. Best practice, indeed.

The ATP-dependent helicase RUVBL1/TIP49a associates with tubulin during mitosis.

RUVBL1/TIP49a/Pontin52 is a recently identified multi-functional protein with 2 ATP binding (WALKER) sites, which is essential for cell proliferation. We recovered and identified RUVBL1/TIP49a as a tubulin-binding protein from Triton X-100 lysates of U937 promonocytic cells by protein affinity chromatography and tryptic peptide microsequencing. Performing co-immunoprecipitation using newly generated RUVBL1/TIP49a-specific antibodies (mAb and rabbit polyclonal Ab) and RUVBL1/TIP49a-GST fusion protein-pull down assays we demonstrate co-precipitation of alpha- and gamma tubulin with RUVBL1/TIP49a. Confocal immunoflourescence microscopy reveals that RUVBL1/TIP49a was present not only in the nucleus, as expected, but was also concentrated at the centrosome and at the mitotic spindle in colocalization with tubulin. The topology of RUVBL1/TIP49a at the mitotic spindle varied, depending on the mitotic stage. The protein was localized at the centrosome and at the polar and astral microtubules in metaphase, and was detectable at the zone of polar tubule interdigitation in anaphase B and telophase. During cytokinesis the protein reappeared at the area of decondensing chromosomes. Whereas preincubation of U937 cells with colcemid resulted in inhibition of mitotic spindle formation with subsequent loss of RUVBL1/TIP49a mitotic spindle staining, no relevant influence of colcemid on RUVBL1/TIP49a-tubulin binding was observed. An agonistic effect of RUVBL1/TIP49a on in vitro tubulin assembly is demonstrated. Our results reveal a new functional aspect of RUVBL1/TIP49a.