Thyroid hormones during the perinatal period are necessary to respiratory network development of newborn rats.

Thyroid hormones (THs) are essential for foetal brain development. Because the gestating mother is the main source of THs to the foetus, maternal hypothyroidism and/or premature birth compromise neurological outcomes in the offspring. Respiratory instability and recurrent apneas due to immaturity of the respiratory control network are major causes of morbidity in infants. Inadequate TH supply may be sufficient to delay perinatal maturation of the respiratory control system; however, this hypothesis remains untested. To address this issue, maternal hypothyroidism was induced by adding methimazole (MMI; 0.02% w/v) to the drinking water of pregnant dams from conception to postpartum day 4 (P4). The effect of TH supplementation on respiratory function was tested by injecting levothyroxine (L-T4) in newborns at P1. Respiratory function was assessed by plethysmography (in vivo) and recording of phrenic output from medullary preparations (in vitro). By comparison with controls, TH deficiency increased the frequency of apneas and decreased basal ventilation in vivo and prevented the age-dependent increase in phrenic burst frequency normally observed in vitro. The effects of TH deficiency on GABAergic modulation of respiratory activity were measured by bath application of muscimol (GABAA agonist) or bicuculline (GABAA antagonist). The phrenic burst frequency responses to GABAergic agents were consistently greater in preparations from TH deficient pups. L-T4 supplementation reversed part of the respiratory anomalies related to MMI treatment in vitro. We conclude that TH deficiency during the perinatal period is sufficient to delay maturation of the respiratory control network development. Excessive GABAergic inhibition may contribute to this effect.

Thyroid Hormone Deficiency Modifies Hepatic Lipid Droplet Morphology and Molecular Properties in Lithogenic-Diet Supplemented Mice.

OBJECTIVE: Thyroid hormones have been associated with a hepatic lipid lowering effect and thyroid function has been shown to play a substantial role in development of non-alcoholic fatty liver disease. Hepatic lipid droplets differ in the number, size and molecular properties depending on metabolic state or pathological condition. However, in how far thyroid hormone deficiency affects hepatic lipid droplet morphology and molecular properties is still poorly understood. Therefore, we performed a study in mice using a lithogenic diet model of steatohepatitis and modulated the thyroid hormone status. METHODS: Male and female three months old C57BL/6 mice were divided into a euthyroid (control), a lithogenic (litho) and a lithogenic+thyroid hormone deficient (litho+hypo) group and treated for six weeks. Hepatic transmission electron microscopy and gene expression analysis of lipid-droplet associated proteins were performed. RESULTS: Increased mean diameters of hepatic lipid droplets and a shift towards raised electron-density in lipid droplets was observed under thyroid hormone deficiency. Furthermore thyroid hormone deficiency altered hepatic expression of genes involved in lipophagy and triacylglycerol mobilization. Interestingly, while the impact of thyroid hormone deficiency on lipid droplet morphology seems to be sex-independent, hepatic lipid droplet-associated gene expression differed significantly between both sexes. CONCLUSION: This study demonstrates that thyroid hormone deficiency alters hepatic lipid droplet morphology and hepatic gene expression of lipid droplet-associated proteins in a lithogenic diet mouse model of steatohepatitis.

Development of cerebral mitochondrial respiratory function is impaired by thyroid hormone deficiency before birth in a region-specific manner.

Thyroid hormones regulate adult metabolism partly through actions on mitochondrial oxidative phosphorylation (OXPHOS). They also affect neurological development of the brain, but their role in cerebral OXPHOS before birth remains largely unknown, despite the increase in cerebral energy demand during the neonatal period. Thus, this study examined prepartum development of cerebral OXPHOS in hypothyroid fetal sheep. Using respirometry, Complex I (CI), Complex II (CII), and combined CI&CII OXPHOS capacity were measured in the fetal cerebellum and cortex at 128 and 142 days of gestational age (dGA) after surgical thyroidectomy or sham operation at 105 dGA (term ~145 dGA). Mitochondrial electron transfer system (ETS) complexes, mRNA transcripts related to mitochondrial biogenesis and ATP production, and mitochondrial density were quantified using molecular techniques. Cerebral morphology was assessed by immunohistochemistry and stereology. In the cortex, hypothyroidism reduced CI-linked respiration and CI abundance at 128 dGA and 142 dGA, respectively, and caused upregulation of PGC1α (regulator of mitochondrial biogenesis) and thyroid hormone receptor ß at 128 dGA and 142 dGA, respectively. In contrast, in the cerebellum, hypothyroidism reduced CI&II- and CII-linked respiration at 128 dGA, with no significant effect on the ETS complexes. In addition, cerebellar glucocorticoid hormone receptor and adenine nucleotide translocase (ANT1) were downregulated at 128 dGA and 142 dGA, respectively. These alterations in mitochondrial function were accompanied by reduced myelination. The findings demonstrate the importance of thyroid hormones in the prepartum maturation of cerebral mitochondria and have implications for the etiology and treatment of the neurodevelopmental abnormalities associated with human prematurity and congenital hypothyroidism.

Contribution of Hypothyroidism to Cognitive Impairment and Hippocampal Synaptic Plasticity Regulation in an Animal Model of Depression.

The role that thyroid hormone deficiency plays in depression and synaptic plasticity in adults has only begun to be elucidated. This paper analyzes the possible link between depression and hypothyroidism in cognitive function alterations, using Wistar-Kyoto (WKY-an animal model of depression) rats and control Wistar rats under standard and thyroid hormone deficiency conditions (propylthiouracil administration-PTU). A weakening of memory processes in the WKY rats is shown behaviorally, and in the reduction of long-term potentiation (LTP) in the dentate gyrus (DG) and CA1 hippocampal regions. PTU administration decreased LTP and increased basal excitatory transmission in the DG in Wistar rats. A decrease in short-term synaptic plasticity is shown by the paired-pulse ratio measurement, occurring during hypothyroidism in DG and CA1 in WKY rats. Differences between the strains may result from decreases in the p-CaMKII, p-AKT, and the level of acetylcholine, while in the case of the co-occurrence of depression and hypothyroidism, an increase in the p-ERK1-MAP seemed to be important. Obtained results show that thyroid hormones are less involved in the inhibition of glutamate release and/or excitability of the postsynaptic neurons in WKY rats, which may indicate a lower sensitivity of the hippocampus to the action of thyroid hormones in depression.

Hypothyroidism and isolated hypothyroxinemia in pregnancy, from physiology to the clinic.

Many changes occur in the physiology of the maternal thyroid gland to maintain an adequate level of thyroid hormones (THs) at each stage of gestation during normal pregnancy, however, some factors can produce low levels of these hormones, which can alter the onset and progression of pregnancy. Deficiency of THs can be moderate or severe, and classified as overt or clinical hypothyroidism, subclinical hypothyroidism, and isolated hypothyroxinemia. Overt hypothyroidism has been reported in 0.3-1.9% and subclinical hypothyroidism in approximately 1.5-5% of pregnancies. With respect to isolated hypothyroxinemia, the frequency has been reported in approximately 1.3% of pregnant women, however it can be as high as 25.4%. Worldwide, iodine deficiency is the most common cause of hypothyroidism, however, in iodine-sufficient countries like the United States, the most common cause is autoimmune thyroiditis or Hashimoto's thyroiditis. The diagnosis and timely treatment of deficiency of THs (before or during the first weeks of gestation) can significantly reduce some of the related adverse effects, such as recurrent pregnancy loss, preterm delivery, gestational hypertension, and alterations in the offspring. However, so far there is no consensus on the reference levels of thyroid hormones during pregnancy to establish the diagnosis and there is no consensus on universal screening of women during first trimester of pregnancy to identify thyroid dysfunction, to give treatment and to reduce adverse perinatal events, so it is necessary to carry out specific studies for each population that provide information about it.

Effects of maternal thyroid hormone deficiency on differentiation of mesenchymal stem cells in CSF-exposed neonatal Wistar rats.

Cerebrospinal fluid (CSF) contains growth and neurotrophic factors which regulate proliferation, differentiation, and neurogenesis. Thyroid hormones play a crucial role in the development of the nervous system and hypothyroidism during development of embryos leads to defects in the nervous system. This study aimed to survey the effects of rat neonatal CSF collected from induced hypothyroid mothers on differentiation of bone marrow mesenchymal stem cells (BM-MSCs). We hypothesized that hypothyroidism affected levels of growth factor in CSF. To induce hypothyroidism, pregnant Wistar rats received methimazole at the third day of gestation. BM-MSCs were obtained from rat femurs and tibias and cultured in medium. CSF was collected from the cisterna magna of newborn rats, and cells were subsequently exposed to CSF with concentrations of 5,7, and 10 /100 (v/v) for 72 h. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and real time polymerase chain reaction (RT-PCR) were used to quantify the cell viability and analyze the expression of neural markers, respectively. Our morphological studies showed that treatment with hypothyroidism CSF (HTH-CSF) resulted in a significant decrease in neurite growth and proliferation as compared to normal CSF (N-CSF). RT-PCR analysis also showed a significant decrease in expression of neural markers (i.e., Nestin, Neurod-1, NeuN) in cells treated with HTH-CSF as compared with the N-CSF group. The most effective concentration of CSF for BM-MSC differentiation was 5% (V/V). Our results showed a significant decrease in differentiation of BM-MSCs in the presence of neonatal CSF of hypothyroid mothers compared with neonatal CSF of healthy mothers. Thus, thyroid hormones are essential in neural development and hypothyroid defects can affect development of the neonatal brain.

Maternal Thyroid Hormone Deficiency During Gestation and Lactation Alters Metabolic and Thyroid Programming of the Offspring in the Adult Stage.

Environmental stimuli during critical developmental stages establish long-term physiological and structural patterns that "program" health during adult life. Little is known about how alterations in hormonal supply might have consequences in metabolic and thyroid programming. This work aims to prove that alterations in the supply of thyroid hormones during gestation and lactation have long-term consequences in the metabolic and thyroid programming of the offspring. Female Wistar rats were divided into euthyroid, hypothyroid, and hypothyroid with 20 µg/day of s.c. thyroxine (T4), replacement wet nurses. Rats were mating, and after birth, pups were grouped according to their wet nurses group. Milk quality of wet nurses was assessed on days 7, 14, and 21. Body mass gain and energy intake of the offspring were monitored for 28 weeks after weaning. At sacrifice, we extracted and weighed their thyroid gland and adipose reserves, and collected blood to measure its metabolic and thyroid profiles. Hypothyroid wet nurses presented a persistent low quality of milk, while both male and female hypothyroid offspring presented lower body mass gain, higher blood glucose, dyslipidemia, hyperinsulinemia, and hyperleptinemia, as well as lower total adipose reserves, but higher visceral reserve, diminished T3 and T4 concentrations, and lower weight of thyroid gland. Thyroxine replacement prevented all changes in both wet nurses and pups. We conclude that maternal thyroid hormone deficiency during congenital and lactation stages alters the metabolic and thyroid programming of the offspring, while the reestablishment of maternal thyroid status during critical periods of development can prevent these alterations.

Maternal thyroid hormone deficiency and cardiorespiratory disorder in rat pups.

During gestation, the mother is the main source of thyroid hormones for the foetus. Thus, hypothyroidism during pregnancy and/or preterm birth compromise thyroid hormone supply for the foetus. Maternal hypothyroidism increases risk of preterm birth and both conditions are associated with respiratory distress in infants. Since thyroid hormones are essential for normal brain development, it is plausible that maternal thyroid hormone deficiency plays a role in respiratory disorders related to neurological immaturity in the newborn; however, this hypothesis is yet to be tested. Here, we used methimazole treatment (MMI; 0.05% v/w) from the onset of pregnancy until two weeks postpartum to induce thyroid hormone deficiency in rat pups. At 14-15 days of age, we used plethysmography to measure breathing at rest and in response to hypoxia (12% O2, 20 min) in intact pups. We then used a urethane/chloralose anesthetised preparation to measure cardiorespiratory inhibition induced by laryngeal chemoreflex stimulation. In intact pups, basal breathing did not differ between groups but the breathing frequency response to hypoxia of MMI-treated pups was lower than controls. Following anesthesia, breathing frequency of MMI pups was 60% lower than controls; following laryngeal chemoreflex stimulation, the drop in O2 saturation that was 82% greater in MMI-treated pups than controls. Inactivation of GABAA receptors (bicuculline; 0.5 mg/kg) raised the frequency of anesthetised MMI pups but not control. We conclude that gestational thyroid hormone deficiency interferes with the respiratory and autonomic control systems of the offspring. Thyroid hormone supplementation could alleviate cardiorespiratory disorders in newborn, especially those born preterm.

An exonic splicing enhancer mutation in DUOX2 causes aberrant alternative splicing and severe congenital hypothyroidism in Bama pigs.

Pigs share many similarities with humans in terms of anatomy, physiology and genetics, and have long been recognized as important experimental animals in biomedical research. Using an N-ethyl-N-nitrosourea (ENU) mutagenesis screen, we previously identified a large number of pig mutants, which could be further established as human disease models. However, the identification of causative mutations in large animals with great heterogeneity remains a challenging endeavor. Here, we select one pig mutant, showing congenital nude skin and thyroid deficiency in a recessive inheritance pattern. We were able to efficiently map the causative mutation using family-based genome-wide association studies combined with whole-exome sequencing and a small sample size. A loss-of-function variant (c.1226 A>G) that resulted in a highly conserved amino acid substitution (D409G) was identified in the DUOX2 gene. This mutation, located within an exonic splicing enhancer motif, caused aberrant splicing of DUOX2 transcripts and resulted in lower H2O2 production, which might cause a severe defect in thyroid hormone production. Our findings suggest that exome sequencing is an efficient way to map causative mutations and that DUOX2D409G/D409G mutant pigs could be a potential large animal model for human congenital hypothyroidism.

Mechanisms involved in epigenetic down-regulation of Gfap under maternal hypothyroidism.

Thyroid hormones (TH) of maternal origin are crucial regulator of mammalian brain development during embryonic period. Although maternal TH deficiency during the critical periods of embryonic neo-cortical development often results in irreversible clinical outcomes, the fundamental basis of these abnormalities at a molecular level is still obscure. One of the key developmental process affected by maternal TH insufficiency is the delay in astrocyte maturation. Glial fibrillary acidic protein (Gfap) is a predominant cell marker of mature astrocyte and is regulated by TH status. Inspite, of being a TH responsive gene during neocortical development the mechanistic basis of Gfap transcriptional regulation by TH has remained elusive. In this study using rat model of maternal hypothyroidism, we provide evidence for an epigenetic silencing of Gfap under TH insufficiency and its recovery upon TH supplementation. Our results demonstrate increased DNA methylation coupled with decreased histone acetylation at the Gfap promoter leading to suppression of Gfap expression under maternal hypothyroidism. In concordance, we also observed a significant increase in histone deacetylase (HDAC) activity in neocortex of TH deficient embryos. Collectively, these results provide novel insight into the role of TH regulated epigenetic mechanisms, including DNA methylation, and histone modifications, which are critically important in mediating precise temporal neural gene regulation.

Antenatal/early postnatal hypothyroidism increases the contribution of Rho-kinase to contractile responses of mesenteric and skeletal muscle arteries in adult rats.

BACKGROUND: Maternal thyroid deficiency can increase Rho-kinase procontractile influence in arteries of 2-week-old progeny. Here we hypothesized that augmented role of Rho-kinase persists in arteries from adult progeny of hypothyroid rats. METHODS: Dams were treated with 6-propyl-2-thiouracil (PTU) in drinking water (0.0007%) during pregnancy and 2 weeks postpartum; control (CON) females received PTU-free water. At the age of 10-12-weeks, serum T3/T4 levels did not differ between PTU and CON male offspring. Cutaneous (saphenous), mesenteric, and skeletal muscle (sural) arteries were studied by wire myography, qPCR, and Western blotting. RESULTS: Saphenous arteries of PTU and CON groups showed similar responses to α1-adrenoceptor agonist methoxamine and were equally suppressed by Rho-kinase inhibitor Y27632. Responses of mesenteric arteries also did not differ between PTU and CON, but the effects of Y27632 were more prominent in the PTU group. Sural arteries of PTU rats compared to CON demonstrated augmented responses to methoxamine, increased RhoA mRNA contents and higher levels of MYPT1 phosphorylation at Thr855. Intergroup differences in contractile responses and phospho-MYPT1-Thr855 were eliminated by Y27632. CONCLUSION: Rho-kinase contribution to contractile responses of mesenteric and especially sural arteries is augmented in adult PTU rats. Therefore, maternal thyroid deficiency may have long-term detrimental consequences for vasculature in adult offspring.

Developmental Thyroid Hormone Insufficiency Induces a Cortical Brain Malformation and Learning Impairments: A Cross-Fostering Study.

Thyroid hormones (THs) are essential for brain development, but few rodent models exist that link TH inefficiency to apical neurodevelopmental endpoints. We have previously described a structural anomaly, a heterotopia, in the brains of rats treated in utero with propylthiouracil (PTU). However, how the timing of an exposure relates to this birth defect is unknown. This study seeks to understand how various temporal treatments of the mother relates to TH insufficiency and adverse neurodevelopment of the offspring. Pregnant rats were exposed to PTU (0 or 3 ppm) through the drinking water from gestational day 6 until postnatal day (PN) 14. On PN2 a subset of pups was cross-fostered to a dam of the opposite treatment, to create 4 conditions: pups exposed to PTU prenatally, postnatally, during both periods, or not at all (control). Both PTU and TH concentrations were characterized in the mother and offspring over time, to capture the dynamics of a developmental xenobiotic exposure. Brains of offspring were examined for heterotopia presence and severity, and adult littermates were assessed for memory impairments. Heterotopia were observed under conditions of prenatal exposure, and its severity increased in animals in the most prolonged exposure group. This malformation was also permanent, but not sex biased. In contrast, behavioral impairments were limited to males, and only in animals exposed to PTU during both the gestational and postnatal periods. This suggests a distinct TH-dependent etiology for both phenotypes, and illustrates how timing of hypothyroxinemia can induce abnormal brain structure and function.

Prevalence of malnutrition-inflammation complex syndrome and its correlation with thyroid hormones in chronic haemodialysis patients. / Prevalencia del síndrome complejo de malnutrición e inflamación y su correlación con las hormonas tiroideas en pacientes en hemodiálisis crónica.

INTRODUCTION: Low levels of thyroid hormones, total triiodothyronine (T3) and free triiodothyronine (FT3) in haemodialysis patients is a marker of malnutrition and inflammation and are predictors of mortality. The aim of this study was to determine the prevalence of malnutrition-inflammation complex syndrome in haemodialysis and its relationship with the thyroid hormones thyrotropin, T3, FT3 and free thyroxine (FT4), as well as to evaluate the prevalence of low FT3 syndrome and its correlation with nutritional and inflammatory markers. MATERIALS AND METHODS: Cross-sectional, analytical and comparative study that enrolled 128 haemodialysis patients: 50.8% females; mean age 45.05±17.01 years; mean time on haemodialysis 45.4±38.8 months; 29.7% diabetics; 79.7% with hypertension. Serum thyroid hormones thyrotropin, T3, FT3 and FT4 concentrations were measured and Malnutritition-Inflammation Score (MIS) was applie to diagnostic. RESULTS: Mean thyroid hormone values were: thyroid hormones thyrotropin 2.48±1.8 mIU/ml (range: 0.015-9.5), T3 1.18±0.39 ng/ml (range 0.67-2.64), FT3 5.21±0.96pmol/l (range: 3.47-9.75); FT4 1.35±0.4 ng/ml (range: 0.52-2.57). Malnutrition-inflammation complex syndrome prevalence was 53.9%; 11.7% presented low FT3 levels. Serum T3 and FT3 concentrations inversely correlated with Malnutritition-Inflammation Score (MIS), while FT4 correlated positively with Malnutrition-Inflammation Score. In the linear regression analysis, low FT3 was associated with IL-6 (ß= 0.265, p=.031), C-reactive protein (CRP) (ß= -0.313, p=.018) and albumin (ß= 0.276, p=.002). CONCLUSION: Low T3 and FT3 levels are correlated with malnutrition and inflammation parameters. Malnutrition-inflammation complex syndrome can affect serum concentrations of thyroid hormones.

[Pharmacological approaches for correction of thyroid dysfunctions in diabetes mellitus]. / Farmakologicheskie podkhody dlia korrektsii disfunktsii shchitovidnoi zhelezy v usloviiakh sakharnogo diabeta.

Thyroid diseases are closely associated with the development of types 1 and 2 diabetes mellitus (DM), and as a consequence, the development of effective approaches for their treatment is one of the urgent problems of endocrinology. Traditionally, thyroid hormones (TH) are used to correct functions of the thyroid system. However, they are characterized by many side effects, such as their negative effect on the cardiovascular system as well as the ability of TH to enhance insulin resistance and to disturb insulin-producing function of pancreas, exacerbating thereby diabetic pathology. Therefore, the analogues of TH, selective for certain types of TH receptors, that do not have these side effects, are being developed. The peptide and low-molecular weight regulators of thyroid-stimulating hormone receptor, which regulate the activity of the thyroid axis at the stage of TH synthesis and secretion in thyrocytes, are being created. Systemic and intranasal administration of insulin, metformin therapy and drugs with antioxidant activity are effective for the treatment of thyroid pathology in types 1 and 2 DM. In the review, the literature data and the results of own investigations on pharmacological approaches for the treatment and prevention of thyroid diseases in patients with types 1 and 2 DM are summarized and analyzed.

Receipt of thyroid hormone deficiency treatment and risk of herpes zoster.

OBJECTIVE: Thyroid hormone (TH) has been suggested to control herpes virus gene expression and replication in neurons via epigenetics through its nuclear receptors. It has previously been shown that patients with hypothyroidism are predisposed to herpes zoster (HZ), suggesting that the TH deficiency may be a risk factor for varicella zoster virus (VZV) reactivation. The aim of this study was to test the hypothesis that TH treatment will ameliorate the complication of HZ. METHODS: This study investigated the hypothesis by enquiring into a comprehensive medical database at Kaiser Permanente Southern California (KPSC) to verify whether patients taking TH medication experience a reduction in HZ occurrence. RESULTS: It was shown by Kaplan-Meier analysis that hypothyroidism patients taking TH medicines had a lower risk of HZ. The fully adjusted analysis indicated that patients receiving medication for the treatment of TH deficiency exhibited a reduced risk of HZ (hazard ratio 0.60, 95% confidence interval 0.51-0.71). This lower risk of HZ was significant in all age groups except the 18-39 years cohort. In addition, female patients taking TH treatment exhibited a lower risk than their male counterparts. CONCLUSIONS: Together these findings support the hypothesis that a constant level of TH will provide a degree of protection from contracting HZ. More studies are underway to evaluate the laboratory data for an analysis of hormonal effects on individuals.

Residual pyruvate kinase activity in PKLR-deficient erythroid precursors of a patient suffering from severe haemolytic anaemia.

OBJECTIVE: Here, we present a 7-year-old patient suffering from severe haemolytic anaemia. The most common cause of chronic hereditary non-spherocytic haemolytic anaemia is red blood cell pyruvate kinase (PK-R) deficiency. Because red blood cells rely solely on glycolysis to generate ATP, PK-R deficiency can severely impact energy supply and cause reduction in red blood cell lifespan. We determined the underlying cause of the anaemia and investigated how erythroid precursors in the patient survive. METHODS: PK activity assays, Western blot and Sanger sequencing were employed to determine the underlying cause of the anaemia. Patient erythroblasts were cultured and reticulocytes were isolated to determine PK-R and PKM2 contribution to glycolytic activity during erythrocyte development. RESULTS: We found a novel homozygous mutation (c.583G>A) in the PK-R coding gene (PKLR). Although this mutation did not influence PKLR mRNA production, no PK-R protein could be detected in the red blood cells nor in its precursors. In spite of the absence of PK-R, the reticulocytes of the patient exhibited 20% PK activity compared with control. Western blotting revealed that patient erythroid precursors, like controls, express residual PKM2. CONCLUSIONS: We conclude that PKM2 rescues glycolysis in PK-R-deficient erythroid precursors.

High Prevalence of Diastolic Dysfunction in Incident Patients on Peritoneal Dialysis: Association with Low Thyroid Hormones.

BACKGROUND/AIMS: Diastolic dysfunction (DD) and low levels of thyroid hormones (TH) are frequent found in chronic kidney disease; both are associated with all-cause and cardiovascular mortality. However, a link between them has not yet been established. The aim of this study was to analyze DD as a surrogate marker of fibrosis and its association with TH in incident patients on peritoneal dialysis (PD). METHODS: A cross-sectional study with 183 incident patients on PD with preserved ejection fraction was performed. Clinical and demographic data were registered. Serum total and free (t/f) triiodothyronine (T3), thyroxin (T4), and thyroid stimulating hormone levels were determined by RIA kits, albumin and high-sensitivity C-reactive protein by conventional assays. Transthoracic 2D echocardiogram was performed for evaluation of left ventricular (LV) mass and ejection fraction. DD was evaluated using pulsed-wave tissue Doppler imaging. RESULTS: Patients were 43 ± 12, 42% with diabetes mellitus (DM). Some degree of DD was found in 62% of patients; 18% had grade I DD, 8% grade II DD and 36% grade III DD. Patients with grade III DD were more likely to have diabetes, older, high LV mass and low serum albumin, t/fT3 and tT4 levels. In logistic multivariate regression analysis, it was found that diabetes (B = -0.86, 95% CI 0.182-0.992, p < 0.05), hypertension (B = -0.95, 95% CI 0.184-0.817, p = 0.01) and tT3 (B = -1.94, 95% CI 0.023-0.876, p < 0.05) were associated with grade III DD. CONCLUSIONS: High prevalence of grade III DD was found in incident patients on PD. In addition to DM and hypertension, tT3 was found to be an independent risk factor for grade III DD and more studies are needed to understand the reasons as to why this association is present.

Influence of maternal thyroid hormones during gestation on fetal brain development.

Thyroid hormones (THs) play an obligatory role in many fundamental processes underlying brain development and maturation. The developing embryo/fetus is dependent on maternal supply of TH. The fetal thyroid gland does not commence TH synthesis until mid gestation, and the adverse consequences of severe maternal TH deficiency on offspring neurodevelopment are well established. Recent evidence suggests that even more moderate forms of maternal thyroid dysfunction, particularly during early gestation, may have a long-lasting influence on child cognitive development and risk of neurodevelopmental disorders. Moreover, these observed alterations appear to be largely irreversible after birth. It is, therefore, important to gain a better understanding of the role of maternal thyroid dysfunction on offspring neurodevelopment in terms of the nature, magnitude, time-specificity, and context-specificity of its effects. With respect to the issue of context specificity, it is possible that maternal stress and stress-related biological processes during pregnancy may modulate maternal thyroid function. The possibility of an interaction between the thyroid and stress systems in the context of fetal brain development has, however, not been addressed to date. We begin this review with a brief overview of TH biology during pregnancy and a summary of the literature on its effect on the developing brain. Next, we consider and discuss whether and how processes related to maternal stress and stress biology may interact with and modify the effects of maternal thyroid function on offspring brain development. We synthesize several research areas and identify important knowledge gaps that may warrant further study. The scientific and public health relevance of this review relates to achieving a better understanding of the timing, mechanisms and contexts of thyroid programing of brain development, with implications for early identification of risk, primary prevention and intervention.

Thyroid disorders and nitric oxide in cardiovascular adaptation to hypovolemia.

This study aimed to investigate whether nitric oxide participates in the cardiovascular function and haemodynamic adaptation to acute haemorrhage in animals with thyroid disorders. Sprague-Dawley rats aged 2months old treated with T3 (hyper, 20µg/100g body weight) or 0.02% methimazole (hypo, w/v) during 28days were pre-treated with N(G) nitro-l-arginine methyl ester (L-NAME) and submitted to 20% blood loss. Heart function was evaluated by echocardiography. Measurements of arterial blood pressure, heart rate, nitric oxide synthase activity and protein levels were performed. We found that hypo decreased fractional shortening and ejection fraction and increased left ventricle internal diameter. Hyper decreased ventricle diameter and no changes in cardiac contractility. Haemorrhage elicited a hypotension of similar magnitude within 10min. Then, this parameter was stabilized at about 30-40min and maintained until finalized, 120min. L-NAME rats showed that the immediate hypotension would be independent of nitric oxide. Nitric oxide synthase inhibition blunted the changes of heart rate induced by blood loss. Hyper and hypo had lower atrial enzyme activity associated with a decreased enzyme isoform in hypo. In ventricle, hyper and hypo had a higher enzyme activity, which was not correlated with changes in protein levels. Haemorrhage induced an increased heart nitric oxide production. We concluded that thyroid disorders were associated with hypertrophic remodelling which impacted differently on cardiac function and its adaptation to a hypovolemia. Hypovolemia triggered a nitric oxide synthase activation modulating the heart function to maintain haemodynamic homeostasis. This involvement depends on a specific enzyme isoform, cardiac chamber and thyroid state.

Thyroid hormone-dependent formation of a subcortical band heterotopia (SBH) in the neonatal brain is not exacerbated under conditions of low dietary iron (FeD).

Thyroid hormones (TH) are critical for brain development and insufficiencies can lead to structural abnormalities in specific brain regions. Administration of the goitrogen propylthiouracil (PTU) reduces TH production by inhibiting thyroperoxidase (TPO), an enzyme that oxidizes iodide for the synthesis of TH. TPO activity is iron (Fe)-dependent and dietary iron deficiency (FeD) also reduces circulating levels of TH. We have previously shown that modest degrees of TH insufficiency induced in pregnant rat dams alters the expression of TH-responsive genes in the cortex and hippocampus of the neonate, and results in the formation of a subcortical band heterotopia (SBH) in the corpus callosum (Royland et al., 2008, Bastian et al., 2014, Gilbert et al., 2014). The present experiment investigated if FeD alone was sufficient to induce a SBH or if FeD would augment SBH formation at lower doses of PTU. One set of pregnant rats was administered 0, 1, 3, or 10ppm of PTU via drinking water starting on gestational day (GD) 6. FeD was induced in a 2nd set of dams beginning on GD2. A third set of dams received the FeD diet from GD2 paired with either 1ppm or 3ppm PTU beginning on GD6. All treatments continued until the time of sacrifice. On PN18, one female pup from each litter was sacrificed and the brain examined for SBH. We observed lower maternal, PN2 and PN18 pup serum T4 in response to PTU. FeD reduced serum T4 in pups on PN16, but did not affect serum T4 in dams or PN2 pups. Neither did FeD in combination with PTU alter T4 levels in dams on PN18 or pups on PN2 compared to PTU treatment alone. By PN16, however more severe T4 reductions were observed in pups when FeD was combined with PTU. SBH increased with increasing dosage of PTU, but counter to our hypothesis, no SBH was detected in the offspring of FeD dams. As such, T4 levels in dams and newborn pups rather than older neonates appear to be a better predictor SBH associated with TH insufficiency. These data indirectly support previous work indicating prenatal TH insufficiency but not postnatal TH insufficiency in offspring is required for SBH formation.