Thyroid Hormone Mimetics: the Past, Current Status and Future Challenges.

The association between thyroid hormone status and plasma levels of low-density lipoprotein cholesterol has raised the awareness for the development of thyroid hormone mimetics as lipid-lowering agents. The discovery of the two main types of thyroid hormone receptors (α and ß) as well as the development of novel combinatorial chemistry providing organ specificity has drastically improved the selectivity of these compounds. In the past decades, several thyroid hormone mimetics have been investigated with the purpose of lowering low-density lipoprotein cholesterol levels. However, until now, none of the thyromimetics reached the stage of completing a phase III clinical trial without deleterious side effects. Here, we review the currently available literature on thyromimetics investigated for the treatment of dyslipidemia, their rise, their downfall and the challenges for the development of novel agents.

The effect of levothyroxine on expression of inflammation-related genes in healthy subjects: a controlled randomized crossover study.

An excess of thyroid hormone leads to a prothrombotic state; however, the underlying pathophysiological mechanisms remain unknown. As evidence points towards an extensive "cross-talk" between the inflammatory and coagulation cascade, inflammation has been claimed as a possible mechanism through which different risk factors trigger venous thrombus formation. We aimed to study changes in expression of inflammation-related genes of the leukocyte RNA expression profile in healthy subjects in response to supraphysiological doses of levothyroxine. In a randomized single-blinded crossover design, 12 healthy volunteers (aged 18-40 years) received levothyroxine and no medication, both for 14 days with a wash-out period of at least 28 days between the periods. Blood was sampled at baseline and day 14 of each study period. MRNA was isolated from whole blood and used for multiplex ligation-dependent probe amplification to study the expression of inflammation-related genes. Compared to the control situation no significant changes were found in the expression of proinflammatory cytokines and mediators after the intake of levothyroxine. The results of this study show that high thyroid hormone levels do not lead to an altered inflammatory profile. This provides evidence against a major role of the inflammatory system as mediator in the effect of thyroid hormone on the coagulation system. The mechanisms by which thyroid hormone may influence coagulation proteins remain to be elucidated.

The influence of thyroid function on the coagulation system and its clinical consequences.

Several studies indicate that low plasma levels of thyroid hormone shift the hemostatic system towards a hypocoagulable and hyperfibrinolytic state, whereas high levels of thyroid hormone lead to more coagulation and less fibrinolysis. Low levels of thyroid hormone thereby seem to lead to an increased bleeding risk, whereas high levels, by contrast, increase the risk of venous thromboembolism. Hypothyroidism leads to a higher incidence of acquired von Willebrand's syndrome and with increasing levels of free thyroxine, levels of fibrinogen, factor VIII and von Willebrand factor, amongst others, increase gradually, to the extent that they may lead to symptomatic venous thromboembolism in patients with hyperthyroidism. Here, we discuss the literature on the effect of thyroid hormone on the hemostatic system and the associated risk of bleeding and venous thromboembolism. Patients with hypothyroidism are at increased risk of developing bleeding complications, which could be relevant in patients undergoing invasive procedures. Furthermore, physicians should be aware of the possibility of hyperthyroidism as an underlying risk factor for venous thromboembolism, especially in unexplained cases. Clinical studies are needed to further investigate the significance for general practice of these findings. Besides the effects of hyperthyroidism on venous thromboembolism, its effects on embolism secondary to atrial fibrillation are described.

Venous thromboembolism in overt hyperthyroidism - a direct association with clinical implications?

Hyperthyroidism is associated with procoagulant changes in the haemostatic system. At present, it is uncertain whether this leads to an increased risk of venous and/or arterial thrombosis. Only a few small studies have investigated this association but due to methodological limitations it is not possible to draw any definitive conclusions at this stage. Here we report two patients with severe venous thromboembolism (VTE) and concomitant hyperthyroidism without any risk factors for VTE. Hereby, we emphasise a possible association as supported by a number of previous studies. In a planned prospective multicentre cohort study we will examine the association between hyperthyroidism and VTE and determine its clinical relevance.

Novel method for studying postoperative ileus in mice.

INTRODUCTION: Postoperative ileus (POI) is characterized by a transient inhibition of coordinated motility of the gastrointestinal (GI) tract after abdominal surgery and leads to increased morbidity and prolonged hospitalization. Currently, intestinal manipulation of the intestine is widely used as a preclinical model of POI. The technique used to manipulate the intestine is however highly variable and difficult to standardize, leading to large variations and inconsistent findings between different investigators. Therefore, we developed a device by which a fixed and adjustable pressure can be applied during intestinal manipulation. METHODS: The standardized pressure manipulation method was developed using the purpose-designed device. First, the effect of graded manipulation was examined on postoperative GI transit. Next, this new technique was compared to the conventional manipulation technique used in previous studies. GI transit was measured by evaluating the intestinal distribution of orally gavaged fluorescein isothiocyanate (FITC)-labeled dextran. Infiltration of myeloperoxidase positive cells and cytokine production (ELISA) in the muscularis externa of the intestine were assessed. RESULTS: Increasing pressures resulted in a graded reduction of intestinal transit and was associated with intestinal inflammation as demonstrated by influx of leukocytes and increased levels of IL-6, IL-1ß and MCP-1 compared to control mice. With an applied pressure of 9 grams a similar delay in intestinal transit could be obtained with a smaller standard deviation, leading to a reduced intra-individual variation. CONCLUSIONS: This method provides a reproducible model with small variation to study the pathophysiology of POI and to evaluate new anti-inflammatory strategies.

Production as a source of input for analysis: evidence from the developmental course of a word-blend.

Theoretical arguments for considering production as a source of input for analysis (the output-as-input hypothesis) are reviewed, and empirical evidence supporting this hypothesis is presented. The evidence consists of a longitudinal study of the developmental course of a self-created form, produced by one Dutch child. This form is the product of blending two words, wat and iets, to yield unitary wat-iets. In Dutch, independent wat and iets may each mean 'some' and/or 'something'. Though wat-iets is not permitted by the language, and so does not occur in environmental input, the form stays in the child's repertoire for about 10 months (between 3;8 and 4;7) and is apparently subjected to processes of generalization: first the child treats wat-iets as a two-word frame that may be regularized, later as a unitary word that may be semantically extended. After the extension of wat-iets, independent synonymous wat and iets appear for the first time in the child's speech. It is argued that the child actually analysed his own creation.