Time-to-event clinical trial designs: Existing evidence and remaining concerns.

Well-designed placebo-controlled clinical trials are critical to the development of novel treatments for epilepsy, but their design has not changed for decades. Patients, clinicians, regulators, and innovators all have concerns that recruiting for trials is challenging, in part, due to the static design of maintaining participants for long periods on add-on placebo when there are an increasing number of options for therapy. A traditional trial maintains participants on blinded treatment for a static period (e.

The European Prevention of Alzheimer's Dementia Programme: An Innovative Medicines Initiative-funded partnership to facilitate secondary prevention of Alzheimer's disease dementia.

Introduction: Tens of millions of people worldwide will develop Alzheimer's disease (AD), and only by intervening early in the preclinical disease can we make a fundamental difference to the rates of late-stage disease where clinical symptoms and societal burden manifest. However, collectively utilizing data, samples, and knowledge amassed by large-scale projects such as the Innovative Medicines Initiative (IMI)-funded European Prevention of Alzheimer's Dementia (EPAD) program will enable the research community to learn, adapt, and implement change.

Method: In the current article, we define and discuss the substantial assets of the EPAD project for the scientific community, patient population, and industry, describe the EPAD structure with a focus on how the public and private sector interacted and collaborated within the project, reflect how IMI specifically supported the achievements of the above, and conclude with a view for future.

Development of interventions for the secondary prevention of Alzheimer's dementia: the European Prevention of Alzheimer's Dementia (EPAD) project.

Alzheimer's dementia affects more than 40 million people worldwide with substantial increases in prevalence anticipated. Interventions that either modify risk or reduce the development of early disease could delay the onset of dementia or reduce the rate of cognitive and functional decline. The European Prevention of Alzheimer's Dementia (EPAD) is a public-private consortium, funded by the Innovative Medicines Initiative, designed to increase the likelihood of successful development of new treatments for the secondary prevention of Alzheimer's dementia.

Knockdown of the type 3 iodothyronine deiodinase (D3) interacting protein peroxiredoxin 3 decreases D3-mediated deiodination in intact cells.

The type 3 iodothyronine deiodinase (D3) is the primary deiodinase that inactivates thyroid hormone. Immunoprecipitation of D3, followed by fluorescent two-dimensional difference gel electrophoresis and mass spectrometry, identified peroxiredoxin 3 (Prx3) as a D3-associated protein. This interaction was confirmed using reverse coimmunoprecipitation, in which pull-down of Prx3 resulted in D3 isolation, and by fluorescence resonance energy transfer between cyan fluorescent protein-D3 and yellow fluorescent protein-Prx3.

Type 2 iodothyronine deiodinase is essential for thyroid hormone-dependent embryonic development and pigmentation in zebrafish.

Despite the known importance of thyroid hormones (THs) in vertebrate growth and development, the role of tissue-specific TH activation in early embryogenesis remains unclear. We therefore examined the function of type 2 iodothyronine deiodinase (D2), one of the two tissue-specific enzymes catalyzing the conversion of T4 to T3, in developing zebrafish embryos (Danio rerio). Microinjection of early embryos with antisense oligonucleotides targeting either the D2 translation start site or the splice junction between the first exon and intron induced delays in development and pigmentation, as determined through the measurement of otic vesicle length, head-trunk angle, and pigmentation index at 31 h after fertilization.

The effect of 3,5,3'-triiodothyronine supplementation on zebrafish (Danio rerio) embryonic development and expression of iodothyronine deiodinases and thyroid hormone receptors.

The importance of thyroid hormones (TH) for embryonic development has long been shown in many vertebrates, but is not yet established in pre-hatch teleost models despite the presence of TH, TH receptors and iodothyronine deiodinases. Lack of data about the dynamics of TH metabolism in embryonic stages of fish does not allow to speculate about the involvement and/or role of TH in fish embryonic development. We therefore set up an experiment to examine the effect of 3,5,3'-triiodothyronine (T(3)) on zebrafish (Danio rerio) embryonic development and on the expression of some thyroid hormone-regulated genes as measured by real-time PCR.

The influence of stress on thyroid hormone production and peripheral deiodination in the Nile tilapia (Oreochromis niloticus).

The existence of an interaction between the adrenal/interrenal axis and the thyroidal axis has since long been established in vertebrates, including fish. However, in contrast to mammals, birds and amphibians, no effort was made in fish to expand these studies beyond the level of measuring plasma thyroid hormones. We therefore set out to examine the acute effects of a single dose of dexamethasone (DEX) on plasma thyroxine (T(4)) and 3,5,3'-triiodothyronine (T(3)) levels, as well as on the activity and mRNA expression of the different iodothyronine deiodinases in liver, gills, kidney and brain in Nile tilapia.

Perchlorate versus other environmental sodium/iodide symporter inhibitors: potential thyroid-related health effects.

Objective: Perchlorate is a known competitive inhibitor of the sodium/iodide symporter (NIS). Possible thyroid-related effects of environmental perchlorate have created great health concerns, especially in the US, resulting in a debated reference dose (RfD) of 0.0007 mg/kg per day in drinking water recommended by the National Academy of Sciences (NAS).

Characterization of recombinant Xenopus laevis type I iodothyronine deiodinase: substitution of a proline residue in the catalytic center by serine (Pro132Ser) restores sensitivity to 6-propyl-2-thiouracil.

In frogs such as Rana and Xenopus, metamorphosis does not occur in the absence of a functional thyroid gland. Previous studies indicated that coordinated development in frogs requires tissue and stage-dependent type II and type III iodothyronine deiodinase expression patterns to obtain requisite levels of intracellular T(3) in tissues at the appropriate stages of metamorphosis. No type I iodothyronine deiodinase (D1), defined as T(4) or reverse T(3) (rT3) outer-ring deiodinase (ORD) activity with Michaelis constant (K(m)) values in the micromolar range and sensitivity to 6-propyl-2-thiouracil (6-PTU), could be detected in tadpoles so far.

Thyroid hormone deiodination in birds.

Because the avian thyroid gland secretes almost exclusively thyroxine (T4), the availability of receptor-active 3,3',5-triiodothyronine (T3) has to be regulated in the extrathyroidal tissues, essentially by deiodination. Like mammals and most other vertebrates, birds possess three types of iodothyronine deiodinases (D1, D2, and D3) that closely resemble their mammalian counterparts, as shown by biochemical characterization studies in several avian species and by cDNA cloning of the three enzymes in chicken. The tissue distribution of these deiodinases has been studied in detail in chicken at the level of activity and mRNA expression.

Role of corticotropin-releasing hormone as a thyrotropin-releasing factor in non-mammalian vertebrates.

The finding that thyrotropin-releasing hormone does not always act as a thyrotropin (TSH)-releasing factor in non-mammalian vertebrates has led researchers to believe that another hypothalamic factor may exhibit this function. In representatives of all non-mammalian vertebrate classes, corticotropin-releasing hormone (CRH) appears to be a potent stimulator of hypophyseal TSH secretion, and might therefore function as a common regulator of both the thyroidal and adrenal/interrenal axes. CRH exerts its dual hypophysiotropic action through two different types of CRH receptors.

Tissue thyroid hormone levels in critical illness.

Context: Pronounced alterations in serum thyroid hormone levels occur during critical illness. T3 decreases and rT3 increases, the magnitudes of which are related to the severity of disease. It is unclear whether these changes are associated with decreased tissue T3 concentrations and, thus, reduced thyroid hormone bioactivity.

Characterization of an iodothyronine 5'-deiodinase in gilthead seabream (Sparus auratus) that is inhibited by dithiothreitol.

Iodothyronine deiodinases catalyze the conversion of the thyroid prohormone T(4) to T(3) by outer ring deiodination (ORD) of the iodothyronine molecule. The catalytic cycle of deiodinases is considered to be critically dependent on a reducing thiol cosubstrate that regenerates the selenoenzyme to its native state. The endogenous cosubstrate has still not been firmly identified; in studies in vitro the sulfhydryl reagent dithiothreitol (DTT) is commonly used to activate ORD.

Cloning and hypothalamic distribution of the chicken thyrotropin-releasing hormone precursor cDNA.

In this paper we report the cloning of the chicken preprothyrotropin-releasing hormone (TRH) cDNA and the study of its hypothalamic distribution. Chicken pre-proTRH contains five exact copies of the TRH progenitor sequence (Glu-His-Pro-Gly) of which only four are flanked by pairs of basic amino acids. In addition, the amino acid sequence contains three sequences that resemble the TRH progenitor sequence but seem to have lost their TRH-coding function during vertebrate evolution.

Peripheral ghrelin reduces food intake and respiratory quotient in chicken.

Ghrelin injection, either centrally or peripherally strongly stimulates feeding in human and rodents. In contrast, centrally injected ghrelin inhibits food intake in neonatal chickens. No information is available about the mechanism and its relationship with energy homeostasis in chicken.

Corticotropin-releasing hormone-mediated metamorphosis in the neotenic axolotl Ambystoma mexicanum: synergistic involvement of thyroxine and corticoids on brain type II deiodinase.

In the present study, morphological changes leading to complete metamorphosis have been induced in the neotenic axolotl Ambystoma mexicanum using a submetamorphic dose of T(4) together with an injection of corticotropin-releasing hormone (CRH). An injection of CRH alone is ineffective in this regard presumably due to a lack of thyrotropic stimulation. Using this low hormone profile for induction of metamorphosis, the deiodinating enzymes D2 and D3 known to be present in amphibians were measured in liver and brain 24h following an intraperitoneal injection.

Corticosterone-induced negative feedback mechanisms within the hypothalamo-pituitary-adrenal axis of the chicken.

This paper reports the results of in vivo and in vitro experiments on the feedback effects of corticosterone on the hypothalamo-pituitary-adrenal axis in embryos at day 18 of incubation and in 9-day-old chickens. In vivo, a significant negative feedback was detected on the levels of corticotropin-releasing factor (CRF) precursor (proCRF) mRNA and on the plasma concentration of corticosterone, two hours after a single intravenous injection with 40 microg corticosterone. In contrast, the levels of CRF peptide in the hypothalamic area, the CRF receptor type 1 (CRF-R1) mRNA and pro-opiomelanocortin (POMC) mRNA levels in the pituitary were not affected by the in vivo administration of corticosterone.

The release of growth hormone (GH): relation to the thyrotropic- and corticotropic axis in the chicken.

In the chicken and other avian species, the secretion of GH is under a dual stimulatory and inhibitory control of hypothalamic hypophysiotropic factors. Additionally, the thyrotropin-releasing hormone (TRH), contrary to the mammalian situation, is also somatotropic and equally important in releasing GH in chick embryos and juvenile chicks compared to the (mammalian) growth hormone-releasing hormone (GHRH) itself. Consequently, the negative feedback loop for GH release not only involves the insulin-like growth factor IGF-I but also thyroid hormones.

Regulation of thyroid hormone availability by iodothyronine deiodinases at the blood-brain barrier in birds.

It is accepted that type II iodothyronine deiodinase (D2) is predominantly found in brain, where it maintains homeostasis of thyroid hormone (TH) levels. The current study describes the production of a polyclonal D2 antiserum and its use in the comparison of D2 protein distribution with that of type I (D1) and type III (D3) deiodinase protein in the chicken choroid plexus (CP). Immunocytochemistry showed high D2 protein expression in the epithelial cells of the CP, whereas the D1 and D3 proteins were absent.

Neurotoxicity of polychlorinated biphenyls (PCBs) by disturbance of thyroid hormone-regulated genes.

PCBs are known as neurotoxic compounds. Part of this neurotoxicity could be due to an alteration of the expression of TH-regulated genes in brain. To identify such genes, brain protein extracts of hypo- and hyperthyroid as well as PCB-treated embryos were compared by fluorescent 2D-DIGE.

Thyroid hormone availability and activity in avian species: a review.

The intracellular thyroid hormone (TH) availability is influenced by different metabolic pathways. Some of the changes in intracellular TH availability can be linked to changes in local deiodination and sulfation capacities. The secretion of the chicken thyroid consists predominantly of thyroxine (T4).

Developmentally defined regulation of thyroid hormone metabolism by glucocorticoids in the rat.

Glucocorticoids are known regulators of thyroid function in vertebrates. In birds they have clear tissue-specific and age-dependent effects on thyroid hormone metabolism. In mammals, however, few studies exist addressing these aspects using an in vivo model system.

Iodothyronine deiodinases and the control of plasma and tissue thyroid hormone levels in hyperthyroid tilapia (Oreochromis niloticus).

Thyroid status is one of the most potent regulators of peripheral thyroid hormone metabolism in vertebrates. Despite this, the few papers that have been published concerning the role of thyroid hormones in the regulation of thyroid function in fish often offer conflicting data. We therefore set out to investigate the effects of tetraiodothyronine (thyroxine) (T4) or tri-iodothyronine (T3) supplementation (48 p.

Regulation of thyroid hormone availability in liver and brain by glucocorticoids.

Glucocorticoids as well as thyroid hormones are essential for normal brain development. Exogenous glucocorticoids stimulate 3,3',5-triiodothyronine (T(3)) availability in circulation of birds and similar effects have been observed in sheep. Chicken data indicate that glucocorticoid administration also stimulates thyroid hormone metabolism in brain but the effects on local thyroid hormone concentrations are not known.