Doses Of Iodide Research Articles

Transcriptomic profiling of the response to excess iodide in Keap1 hypomorphic mice reveals new gene-environment interactions in thyroid homeostasis

Iodide plays a pivotal role in thyroid homeostasis due to its crucial involvement in thyroid hormone biosynthesis. Exposure to pharmacological doses of iodide elicits in the thyroid an autoregulatory response to preserve thyroid function, as well as an antioxidant response that is mediated by the Keap1/Nrf2 signaling pathway. The objective of the present study was to investigate the transcriptional response of the thyroid to excess iodide in a background of enhanced Nrf2 signaling. Keap1 knockdown (Keap1KD) mice that have activated Nrf2 signaling were exposed or not to excess iodide in their drinking water for seven days and compared to respective wild-type mice. RNA-sequencing of individual mouse thyroids identified distinct transcriptomic patterns in response to iodide, with Keap1KD mice showing an attenuated inflammatory response, altered thyroidal autoregulation, and enhanced cell growth/proliferative signaling, as confirmed also by Western blotting for key proteins involved in antioxidant, autoregulatory and proliferative responses. These findings underscore novel gene-environment interactions between the activation status of the Keap1/Nrf2 antioxidant response system and the dietary iodide intake, which may have implications not only for the goiter phenotype of Keap1KD mice but also for humans harboring genetic variations in KEAP1 or NFE2L2 or treated with Nrf2-modulating drugs.

ODP523 Thyroid Storm in a Patient With Alemtuzumab Induced Graves’ Disease

Abstract Background Thyroid storm (TS) is a rare and life-threatening medical emergency, most commonly caused by Graves’ disease (GD). GD can beinduced by immune reconstitution therapy (IRT) such as Alemtuzumab (ALZ), a humanized monoclonal antibody against CD52, which is shown to be effective in the treatment of relapsing-remitting multiple sclerosis (RRMS). Evidence shows that ALZ induced GD may be less aggressive than conventional GD. Below we present a rare case of thyroid storm developing in a patient with ALZ induced GD. Clinical Case A 39 year-old female non-smoker, known to have RRMS, wasstarted on ALZ. Presented to our emergency room13months later with palpitation, diarrhea and oligomenorrhea. Found to have TSH of 0. 007 mIU/L (0.250-5), T4 50 pmol/L (11.5- 22.7), thyroid scan demonstrated diffusely enlarged thyroid gland with increased tracer uptake compatible withGD. Our impression was ALZ- induced GD (not in thyroid storm),she wasstarted on carbimazole and propranolol and discharged home. Neurology team gave hera second cycle of ALZas she was euthyroid on carbimazole. One month later, the patient presented to our emergency room with nausea and vomiting. On examination, she was febrile 38.2°C, tachycardic reaching 140 beats/min (regular). Her blood pressure was 138/87 mmhg. The patient was agitated, anxious, alert and oriented. She was diaphoretic with mild peripheral oedema and had pulmonary crackles. The thyroid was diffusely enlarged with no signs of graves’ ophthalmopathy, or pretibial myxedema. On the Burch-Wartofsky Point Scale for thyroid storm, she scored 60. The patient was admitted to the intensive care unit (ICU), with endocrinology and neurology consultation. Laboratory investigation revealed TSH of 0. 009 mIU/L, T3 26.5 pmol/L (3.39-5.82) T4 65 pmol/L, positive thyroid peroxidase antibody 183 units (>100 positive). Despite treatment with maximum dose of carbimazole, B-blocker, hydrocortisone, and potassium iodide her T4 was not improving, and her liver function was deteriorating. Finally, she underwent total thyroidectomy. Three days post total thyroidectomy, the patient clinically improved. Steroids were stopped and the B-blocker dose was gradually tapered. She was then maintained on Levothyroxine. Conclusion It is thought that ALZ- induced GD behaves less aggressive than the conventional GD as spontaneous and/or drug-induced remission may be more likely. However, physicians should be aware that severe thyrotoxicosis and thyroid storm can happen which required prompt recognition and aggressive therapy. Presentation: No date and time listed

Effect of repetitive potassium iodide on thyroid and cardiovascular functions in elderly rats

BackgroundTo date, paediatric thyroid cancer has been the most severe health consequence of the Chernobyl accident, caused by radioactive iodine (131I) aerosol's dispersion. WHO recommends a single dose of potassium iodide (KI) to reduce this risk. Following the Fukushima accident, it became obvious that repetitive doses of KI may be necessary due to multiple exposures to 131I. Knowledge about the effects of repeated ITB (Iodine Thyroid Blocking) is scarce and controversial. KI may affect the thyroid hormones synthesis; which is crucial for the cardiovascular function. Furthermore, myocardial and vascular endothelial tissues are sensitizes to subtle changes at the concentration of circulating pituitary and/or thyroid hormones. ObjectiveIn this preclinical study, we aimed to assess the effects of repeated ITB in elderly male rats. MethodsTwelve months old male Wistar rats were subjected to either KI or saline solution for eight days. Analyses were performed 24 h and 30 days after the treatment discontinuation. FindingsWe reported a significant increase (18%) in some urinary parameters related to renal function, a subtle decrease of plasma TSH level, a significant increase (379%) in renin and a significant decrease (50%) in aldosterone upon KI administration. At the molecular level, the expression of thyroid and cardiovascular genes was significantly affected by the treatment. However, in our experimental settlement, animal heart rate was not significantly affected thirty days after KI discontinuation. ECG patterns did not change after administration of KI, and arrhythmia was not observed in these conditions despite the PR-intervals decreased significantly. Cardiovascular physiology was preserved. ConclusionOur results indicate that repeated ITB in elderly rats is characterized by molecular modifications of cardiovascular key actors, particularly the Renin-angiotensin-aldosterone axis with a preserved physiological homeostasis. This new scientific evidence may be useful for the maturation of ITB guidelines especially for elderly sub-population.

The protective effect of iodide intake adjustment and 1,25(OH)2D3 supplementation in rat offspring following excess iodide intake.

Background:In this study, we aimed to investigate the effect of iodide intake adjustment, 1,25(OH)2D3 supplementation, or both, on the thyroid gland of rat offspring.Methods:The offspring of female rats administered 100 times the normal dose of iodide (100 HI; 750 μg/d) during pregnancy and lactation were divided into four different treatment groups. They were either having their iodide intake adjusted from 100 HI to normal iodide intake (7.5 μg/day) or supplemented with 25-hydroxy vitamin D3 [1,25(OH)2D3; 5 μg·kg−1·day−1], or both, for 4 weeks. Thyroid sodium pertechnetate (Na99mTcO4) uptake percentages were measured using single-photon emission computed tomography, while serum levels of free triiodothyronine (FT3), free thyroxine (FT4), thyroglobulin antibody (TgAb), thyroid peroxidase antibody (TPOAb), and vitamin D3 (VD3) were monitored using enzyme-linked immunosorbent assay. The messenger ribonucleic acid expression of interleukin (IL)-17A, interferon gamma (IFN-γ), and IL-10 in the thyroid gland was measured using quantitative real-time polymerase chain reaction, while the protein expression of thyroid-hormone-receptor α1 (TRα1) and thyroid-hormone-receptor β1 (TRβ1) in the thyroid gland was detected using Western blotting. Haematoxylin and eosin (H & E) and immunofluorescence staining were also used to assess thyroid follicular structure and lymphocytic infiltration in the thyroid glands.Results:The immunofluorescence staining showed CD4+ co-localized with TRβ1 or the vitamin D receptor in thyroid gland cells of rats that were continuously treated with 100 HI. Following iodide adjustment, 1,25(OH)2D3 supplementation, or both, an increase in serum levels of FT3, free thyroxine, and VD3, protein expression of TRα1 and TRβ1 in the thyroid gland cells, and Na99mTcO4 thyroid uptake percentages was observed. The mRNA expression levels of IL-17A and IFN-γ, decreased, while the mRNA expression levels of IL-10 increased in the thyroid cells of each treatment group, except the group with continuous 100 HI intake.Conclusion:Iodide adjustment, 1,25(OH)2D3 supplementation, or both may increase the serum levels of FT3, FT4, and VD3, as well as the protein expression levels of TRα1 and TRβ1, in thyroid cells. In addition, iodide adjustment, 1,25(OH)2D3 supplementation, or both, may potentially reverse the imbalance in pro-inflammatory and anti-inflammatory cytokines (IL-17A, IFN-γ, and IL-10) caused by 100 HI, which may be beneficial in improving Na99mTcO4 thyroid uptake percentages.

A systems biology approach to propose a new mechanism of regulation of repetitive prophylaxis of stable iodide on sodium/iodide symporter (NIS)

Our group showed that repetitive dose of potassium iodide (KI) for eight days offers an efficient protection for exposure to repeated radioactive emissions without adverse effects on adult rats. However, differential expression of genes implicated in Wolff-Chaikoff effect was observed. To understand the Wolff-Chaikoff regulation and its molecular constituents during repetitive administration of KI, a biochemical reaction network was constructed as a “geographical” map of the thyrocyte depicting iodide and thyroid hormone synthesis. Path analysis of the network has been performed to investigate the presence of a regulatory circuit of the node iodide to the node “nis transcription”. NIS is responsible for the uptake of KI and plays an important role in the Wolff-Chaikoff effect. The map is a source for the most updated information about iodide and thyroid hormone metabolism. Based on this map, we propose a hypothesis that shows a putative mechanism behind NIS regulation and KI uptake.

Effect of repetitive potassium iodide on elderly rat’s thyroid

Background: Nuclear power plant emergencies had often been accompanied by radioactivity release into the environment, thyroid cancer is one of the major health consequences due to the effect of radioactive iodine (131I) that emits ϒ ray and β particles resulting in thyroid DNA damage and late onset thyroid cancer. Intake of a single dose of potassium iodide (KI) is recommended to reduce this risk. However in case of prolonged radioiodine release as noticed during Chernobyl and Fukushima accidents, more than one dose of KI may be basic to ensure adequate protection [1]. Whereas a single dose of KI is admitted to be safe, knowledge about the effects of repeated KI administration are scarce, few studies demonstrated the potential efficiency of repetitive KI intake in humans [2] and non-human primates [3] without hormonal variations. These studies are relevant in the field of radiation protection and give a base evidence of the possible use of repetitive KI. On the other hand, we have studies on rodents that showed an impact of chronic iodine excess on pituitary thyroid axis function [4]. Our previous work on adult male rats demonstrated the safety of repeated administration of KI over 8 days [5]. Indeed in the elderly persons KI administration in case of nuclear emergency remains a topic of debate, because of the possible impact in cardiovascular diseases. Thyroid hormones are well-known for their profound effects on cardiovascular function and metabolism; myocardial and vascular endothelial tissues have receptors for thyroid hormones and are sensitive even to subtle changes in the concentrations of circulating pituitary and/or thyroid hormones i.e. subclinical hypothyroidism and hyperthyroidism. It is well established that hyperthyroidism induces a hyper-dynamic cardiovascular state, which is associated with a faster heart rate, enhanced left ventricular systolic and diastolic function whereas hypothyroidism is characterized by the opposite changes. Atrial fibrillation is the most common cardiac arrhythmia in the elderly, the prevalence and incidence increase with advancing age [6]. Several interventional trials showed that treatment of subclinical thyroid diseases improves cardiovascular risk factors, which implies potential benefits for reducing cardiovascular events. Objective: The aim of this study is to assess the effects of repeated KI intake on the thyroid function of aged male rats. Methods: A twelve months old male rats were subjected to either KI or saline solution over 8 days. Clinical biochemistry, pituitary and thyroid hormones level, and thyroid genes expression were analyzed 30 days after the treatment discontinuation. Findings: urinary assessment shows a subtle increase of some parameters (Creatinin, Uric Acid, Urea, Glucose, Potassium, Sodium and Chlorine), plasma biochemistry reveals a subtle variation of some parameters (an increase of Creatinin, Glucose and phosphorus; and a decrease of Chlorine level). Regarding pituitary-thyroid hormones we get a significant decrease of TSH level without thyroid hormones variation. At the molecular level, we observe a significant increase of TPO (+100%), AIT (+299%) and Tg (+38%) mRNA expression. On the other hand we get a significant decrease of TSHR (-51%) mRNA expression. Conclusion and perspectives: Our first results indicate that repeated KI intake affects the clinical biochemistry and the pituitary-thyroid axis function in elderly rats. To go further we are investigating the impact of these variations on the cardiovascular function and its parameters. Cardiac output data, cardiovascular gene expression, oxidative stress and inflammatory analysis are being processed. This study will contribute to the evolution of iodine policy and the harmonization of the current KI guidelines.

A putative mechanism of the Sodium/Iodide Symporter regulation during repetitive administration of stable Iodide described by a Systems Biology approach

A single dose of potassium iodide (KI) against a prolonged exposure to repeated radioactivity might not be effective enough to protect the thyroid. Our group have shown that a repetitive dose of KI for eight days offers efficient protection without adverse effects in male rats [1].

DO MULTIPLE ADMINISTRATIONS OF STABLE IODINE PROTECT POPULATION CHRONICALLY EXPOSED TO RADIOACTIVE IODINE: WHAT IS PRIODAC RESEARCH PROGRAM (2014-22) TEACHING US?

Single dose of potassium iodide (KI) is recommended to prevent the risk of thyroid cancer during nuclear accidents. However in the case of repeated/protracted radioiodine release, a unique dose of KI may not protect efficiently the thyroid against the risk of further developing a radiation-induced cancer. The new WHO guidelines for the use in planning for and responding to radiological and nuclear emergencies identify the need of more data on this subject as one of the four research priorities. The aims of the PRIODAC project are (1) to assess the associated side effects of repeated intakes of KI, (2) to better understand the molecular mechanisms regulating the metabolism of iodine, (3) to revise the regulatory French marketing authorization of 65-mg KI tablets and (4) to develop new recommendations related to the administration of KI toward a better international harmonization. A review of the literature and the preliminary data are presented here.

Iodine Prophylaxis in the Case of Nuclear Accident.

On 26th April, 1986 the greatest accident of nuclear plant in Czernobyl occured and isotopes with high percentage of release were erupted: 33-Xe, 131-I, 132-Te, 134-Cs and 137-Cs. The radioactivity of the isotopes was very high - for instance: 33-Xe 6500 PBq, 131-I 1760 PBq. Rest of the 15 isotopes represented similar radioactivity with shorter percentage of release. The most exposed group of people were 237 liquidators, and 11600 people living around had to be evacuated when the limit dose for a person (5mSv) was crossed. Ionizing radiation on the molecular level produces high energy radicals, water radiolysis and ionization of the atoms leading to damage of the enzymes activity centers and receptors, cell membranes DNA, intracellular lysosomes, and especially important for ATP synthesis - mitochondria. These destructions lead to tissue and organs damage. The aim of this article is the presentation of the protective property of iodine application in the case of nuclear accident. In Poland at that time, effective iodine prophylaxis did not exist. In the face of such exposition, a special Governement Commission was appointed. When permissioned maximal dose for children and adolescents 50mSv appeared in some areas of the country, the Commission made a decision about obligatory administration of a single pharmacological dose of potassium iodide for all children and adolescents till age 16. No relevant recent patents were available for this WHO report. In this way, the dose of 131-I to thyroid for inhabitants in high, moderated, and low contaminated regions were reduced by about 45%. However, from 1987 to 1997 increase in prevalence of the differentiated thyroid cancer in adults in Polish population especially in women over 40 years old in the southern part of Poland was observed. Actually in European countries work 185 nuclear power plants and to 2045 another 100 is planned. In 1999, WHO issued recommendations on iodine prophylaxis in the case of nuclear accident.

Toxicology of Repeated Iodine Thyroid Blocking in Adult Rat

Radioactive iodines emitted following nuclear accidents are responsible for the dramatic increase of the late-onset thyroid cancer. Until the Fukushima disaster, a single dose of potassium iodide (KI) has been considered as an efficient countermeasure. Indeed, recently it has been suggested that repeated administration of KI may be necessary to ensure adequate protection in case of protracted exposure. Whereas, the effect of a single dose of KI has largely been studied ensuring its safety, studies regarding adverse effects of repeated iodine thyroid blocking (ITB) administration are scarce. Our objective was to assess the long term overall impact of KI in adult rats after repeated intake. Adult Wistar rats were subjected to either KI or saline solution over eight days. Biochemical homeostasis, hormones level, autoimmunity status, thyroid morphology and thyroid transcriptome profile were analyzed thirty days after the discontinuation of KI administration. Biochemical parameters, plasma levels of TSH; thyroid hormones; anti-TPO and anti-Tg did not differ between treated and control rats, the thyroid histology was not affected by the treatment and no long term transcriptome signature attributable to the treatment was noticed. Based on these data, we conclude the safety of repeated KI intake in adult rats; these data are prominent and may contribute to the ongoing development of KI guidelines and marketing authorization.

Effects of repeated potassium iodide administration on genes involved in synthesis and secretion of thyroid hormone in adult male rat.

A single dose of potassium iodide (KI) is recommended to reduce the risk of thyroid cancer during nuclear accidents. However in case of prolonged radioiodine exposure, more than one dose of KI may be necessary. This work aims to evaluate the potential toxic effect of repeated administration of KI. Adult Wistar rats received an optimal dose of KI 1 mg/kg over a period of 1, 4 or 8 days. hormonal status (TSH, FT4) of treated rats was unaffected. Contrariwise, a sequential Wolff-Chaikoff effect was observed, resulting in a prompt decrease of NIS and MCT8 mRNA expression (-58% and-26% respectively), followed by a delayed decrease of TPO mRNA expression (-33%) in conjunction with a stimulation of PDS mRNA expression (+62%). we show for the first time that repeated administration of KI at 1 mg/kg/24h doesn't cause modification of thyroid hormones level, but leads to a reversible modification of the expression of genes involved in the synthesis and secretion of thyroid hormones.

Optimal KI Prophylactic Dose Determination for Thyroid Radiation Protection After a Single Administration in Adult Rats.

A dose–response study was performed in adult rats to select an optimal stable potassium iodide (KI) dose which could be implemented in repeated prophylaxis, in case of prolonged exposure to radioactive iodine. Increasing doses of KI were given orally to rats 1 hour before internal exposure simulated by I-125 injection. I-125 incorporation in the thyroid was measured by γ-spectrometry, and KI protection effect was modeled by pharmacological functions. The measurement method by inductively coupled plasma mass spectrometry previously developed for the quantification of stable iodine in urine was adapted to correlate KI effect with its distribution in the thyroid. More than 75% blockade of iodine I-125 incorporation in the thyroid was achieved for KI single doses above 0.5 to 0.7 mg/kg. Stable iodine content in the thyroid 24 hours after KI administration displayed a biphasic response, with a maximum level for a dose around 1 mg/kg. Besides, the urinary excretion of stable iodine is described by a sigmoid function. The change in the rate of iodine excretion for doses above 1 mg/kg KI suggests a body overload in iodine and corroborates a possible saturation of the thyroid. The results show that 1 mg/kg KI could be regarded as an optimal dose for thyroid protection.

Validation and Comparison of Two Calibration Methods for the Measurement of Stable Iodine in the Urinary Matrix by ICP-MS: Standard Addition vs. External Calibration

Background: In the context of a nuclear reactor accident, thyroid is the main target organ of radioactive iodines. To avoid as much as possible thyroid disorders or even cancer development, it is recommended to administer a single dose of potassium iodide to people at risk of exposure. Nevertheless, the Fukushima Dai-ichi disaster has pointed out many questions about the conditions of stable iodine prophylaxis implementation highlighting the need for reflection further revision of the actual “iodine doctrine”. Therefore, providing useful data is required notably through the implementation of animal experiments to strengthen current knowledge and to edit new recommendations. Methods: Urinary iodine constitutes a very good indicator to investigate the function of thyroid, its interpretation demands reliable analyses. Prior to perform animal experiments, two calibration methods were designed by our lab and compared together (standard addition and external calibration) to assess the urinary concentration of stable iodine in urine by ICP-MS. They were validated based on several key parameters especially linearity, accuracy and limits of detection (LOD) and quantification (LOQ). Results: The results were nicely satisfying. Indeed, both calibration methods have indicated very good coefficients of correlations, accuracies with low expanded relative uncertainties were obtained. The estimated LOD in the sample for standard addition method and external calibration were fully acceptable, 0.39 μg·L-1 and 0.35 μg·L-1, respectively. All performance criteria have been thus fulfilled successfully. The established methods were proven to be accurate, robust and sensitive. Once validated, both calibration methods were applied to rat urine samples and the results of z-score and Wilcoxon W test concluded that there were no statistically significant differences between both methods.

Flow cytometry reliability analysis and variations in sugarcane DNA content.

The aim of this study was to evaluate the reliability of flow cytometry analysis and the use of this technique to differentiate species and varieties of sugarcane (Saccharum spp) according to their relative DNA content. We analyzed 16 varieties and three species belonging to this genus. To determine a reliable protocol, we evaluated three extraction buffers (LB01, Marie, and Tris·MgCl2), the presence and absence of RNase, six doses of propidium iodide (10, 15, 20, 25, and 30 μg), four periods of exposure to propidium iodide (0, 5, 10, and 20 min), and seven external reference standards (peas, beans, corn, radish, rye, soybean, and tomato) with reference to the coefficient of variation and the DNA content. For statistical analyses, we used the programs Sisvar(®) and Xlstat(®). We recommend using the Marie extraction buffer and at least 15 μg propidium iodide. The samples should not be analyzed immediately after the addition of propidium iodide. The use of RNase is optional, and tomato should be used as an external reference standard. The results show that sugarcane has a variable genome size (8.42 to 12.12 pg/2C) and the individuals analyzed could be separated into four groups according to their DNA content with relative equality in the genome sizes of the commercial varieties.

Значение йода в прегравидарном периоде жизни женщины

Iodine is an essential trace element, which is essential for the formation and development of a complete organism. Attempts to eliminate iodine deficiency are reduced to mass prevention by iodination of certain foods, but it is not possible to prevent iodine deficiency in groups with an increased need for this groups. This demonstrates the need for drug use potassium iodide into the population groups for which iodine deficiency is the most dangerous - for pregnant, lactating women and children. Iodine deficiency can cause mental retardation, which creates health and social threat to many countries of the world, therefore the world conducts research on the basis on the dose of potassium iodide to prevent iodine deficiency in different populations.

Potassium iodide (KI) to block the thyroid from exposure to I-131: current questions and answers to be discussed

Thyroid cancer in children and adolescents has to be considered as the most severe health consequence of a nuclear reactor emergency with release of radioiodine into the atmosphere. High doses of potassium iodide are effective to block radioiodine thyroid uptake and to prevent development of thyroid cancer years later. However, there are controversies concerning thyroid cancer risk induced by radioiodine exposure in adults. Further, the interaction of nutritional supply of potassium iodide and radioiodine uptake as well as the interaction of radioiodine with certain drugs has not been addressed properly in existing guidelines and recommendations. How to proceed in case of repeated release of radioiodine is an open, very important question which came up again recently during the Fukushima accident. Lastly, the side effects of iodine thyroid blocking and alternatives of this procedure have not been addressed systematically up to now in guidelines and recommendations. These questions can be answered as follows: in adults, the risk to develop thyroid cancer is negligible. In countries, where nutritional iodine deficiency is still an issue, the risk to develop thyroid cancer after a nuclear reactor emergency has to be considered higher because the thyroid takes up more radioiodine as in the replete condition. Similarly, in patients suffering from thyrotoxicosis, hypothyroidism or endemic goitre not being adequately treated radioiodine uptake is higher than in healthy people. In case of repeated or continued radioiodine release, more than one dose of potassium iodide may be necessary and be taken up to 1 week. Repeated iodine thyroid blocking obviously is not harmful. Side effects of iodine thyroid blocking should not be overestimated; there is little evidence for adverse effects in adults. Newborns and babies, however, may be more sensitive to side effects. In the rare case of iodine hypersensitivity, potassium perchlorate may be applied as an alternative to iodine for thyroid blocking.

A practical solution to ‘Continuing Care Site’ issues in neonatal clinical trials – a pragmatic approach to regulatory and research governance review

I2S2 is a randomised controlled trial of iodine supplementation in preterm infants examining whether iodine supplementation can improve neurodevelopmental outcome at two years of age. 20 Neonatal Units in the UK will recruit around 1400 infants <31 weeks of gestation into the trial; infants will receive a daily dose of sodium iodide or sodium chloride placebo until 34 week’s corrected age. Due to the nature of neonatal care, approximately 50% of infants participating in I2S2 are likely to be transferred from the ‘Recruiting Site’ to another hospital for continuation of their clinical care. Hospitals which are not the primary research site may receive infants with little warning and be required to continue treatment under the trial protocol. Hospitals which are research active but have a reduced level of involvement have been defined as ‘Continuing Care Sites’ and ‘Data Collection Sites’; such sites require Research Management and Governance review proportionate to their level of involvement in the clinical trial. This three-tiered approach was negotiated between the NPEU Clinical Trials Unit, RD both documents negate the need for site agreements with the sponsor. NHS permissions are granted for each Neonatal Unit across the UK; those sites without identified Principal Investigators issue provisional NHS Trust approval with confirmation of Principal Investigator on point of transfer. Appropriate trial specific training materials are provided to all sites including training in the reporting of SAE’s and SUSAR’s. This approach allows NHS permissions to be issued in advance of any transfer and ensures infants recruited to I2S2 can continue trial procedures at different sites. Withdrawing an infant from the trial because regulatory and research governance paperwork is not in place, seems a wasted effort for all individuals involved, and more importantly unethical to parents. This streamlined, pragmatic approach to governance review has proved a successful strategy from which many can learn. Trial registry [http://www.clinicaltrials.gov]; Identifier: NCT00638092. Funded by UK Medical Research Council.

Regulation of Thyroid Oxidative State by Thioredoxin Reductase Has a Crucial Role in Thyroid Responses to Iodide Excess

The phenomenon that supraphysiological doses of iodide (I(-)) temporarily inhibit thyroid hormone synthesis is known as thyroid iodide autoregulation. Recovery of thyroid function has been attributed to sodium-iodide symporter (NIS) inhibition, but the diversity of available data makes it difficult to reach definitive conclusions. Iodide excess induces reactive oxygen species production and cell toxicity. However, the roles of the oxidative state of the cell and antioxidant selenoproteins in I(-) autoregulation have never been explored. Here we analyze the effects of high I(-) doses in rat thyroids and in PCCl3 cells in the period comprising I(-) autoregulation (i.e. 0-72 h after I(-) administration), focusing on NIS expression, redox state, and the expression and activity of selenoproteins. Our results show that NIS mRNA inhibition by I(-) does not occur at the transcriptional level, because neither NIS promoter activity nor Pax8 expression or its binding to DNA was modulated. Because I(-) uptake was inhibited much earlier than NIS protein, and no effect was observed on its subcellular localization, we suggest that I(-) is inhibiting NIS in the plasma membrane. The increased reactive oxygen species production leads to an increase in thioredoxin reductase mRNA levels and enzyme activity, which reduces the oxidative stress. Inhibition of thioredoxin reductase at either gene expression or activity levels prevented NIS recovery, thus illustrating a new role played by this selenoprotein in the regulation of cell homeostasis and consequently in I(-) autoregulation.

Facing the Nuclear Threat: Thyroid Blocking Revisited

People being exposed to potentially harmful amounts of radioactive iodine need prophylaxis to prevent high radiation-absorbed doses to the thyroid. Parameters determining the individual protective effect of a pharmacological intervention were investigated. Biokinetics of (123)I was evaluated in 27 healthy volunteers (aged 22-46 yr, median 25 yr, in total 48 assessments) twice in a baseline measurement of the undisturbed kinetics and in an intervention assessment 48 h later. Seven regimens using single doses of potassium iodide (KI) or sodium perchlorate (SP) at different times relative to exposure were compared: 100 mg KI (-24, 2, 8, 24 h), 100 mg SP (2 h), or 1 g SP (2, 8 h). Different drugs and dosages and the influence of individual parameters of iodine kinetics should be tested. Mean dose reductions for interventions at -24, 2, 8, and 24 h relative to the activity incorporation were 88.7, 59.7, 25.4, and 2.8%, respectively. One gram SP was equally effective as 100 mg KI; residual uptake was observed after 100 mg SP. The individual dose reduction decreased exponentially with the effective half-life of the activity in the blood. Kinetics in subjects older than 40 yr was as assumed in official guidelines for the prophylaxis after nuclear accidents but was faster in younger participants. Data on the efficacy of thyroid blocking used in the guidelines are adequate for older people but not for young individuals with their typically faster kinetics. SP may be used for thyroid blocking as alternative for individuals with iodine hypersensitivity.

Vulvar pythiosis in two captive camels (Camelus dromedarius)

Two camels (Camelus dromedarius), 3- and 4-years-old, respectively, from an eastern Tennessee wildlife farm presented with persistent weight loss and large vulvar masses. An initial biopsy of the vulvar mass of one of the camels performed by a local veterinarian showed eosinophilic dermatitis. An allergic or parasitic dermatitis was suspected. The two camels were treated with one dose of sodium iodide (66 mg/kg, in 1.0 L of normosolR, IV) and ivermectin 1% (200 ug/kg PO). Upon presentation at the Veterinary Teaching Hospital, University of Tennessee, additional biopsies of the masses again revealed eosinophilic dermatitis. Microscopic examination of a Gomori methenamine silver (GMS)-stained section prepared from the biopsy of one of the camels revealed the presence of fungal-like hyphae of a mold which was suspected to be Pythium insidiosum. The vulvar masses were surgically debulked in both animals and sodium iodide and Pythium-immunotherapy prescribed. Pythium insidiosum was isolated in culture and hyphae elements were detected in histological sections confirming the diagnosis of pythiosis in both animals. Despite signs of progressive healing of the vulvar surgical areas, postoperative persistent weight lost in one of the camels suggested the possibility of gastro intestinal (GI) tract pythiosis. This camel died 5 months after the first onset of clinical signs and unfortunately a necropsy was not performed. The other camel responded well to the combination of surgery, iodides, and immunotherapy and has currently rejoined the other members of the herd.