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Editorial.-- This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).

Mice deficient in the type 3 deiodinase (D3KO mice) manifest impaired clearance of thyroid hormone (TH), leading to elevated levels of TH action during development. This alteration causes reduced neonatal viability, growth retardation, and central hypothyroidism. Here we examined how these phenotypes are affected by a deficiency in the monocarboxylate transporter 8 (MCT8), which is a major contributor to the transport of the active thyroid hormone, T, into the cell. MCT8 deficiency eliminated the neonatal lethality of type 3 deiodinase (D3)-deficient mice and significantly ameliorated their growth retardation. Double-mutant newborn mice exhibited similar peripheral thyrotoxicosis and increased brain expression of T-dependent genes as mice with D3 deficiency only. Later in neonatal life and adulthood, double-mutant mice manifested central and peripheral TH status similar to mice with single MCT8 deficiency, with low serum T, elevated serum TSH and T, and decreased T-dependent gene expression in the hypothalamus. In double-mutant adult mice, both thyroid gland size and the hypothyroidism-induced rise in TSH were greater than those in mice with single D3 deficiency but less than those in mice with MCT8 deficiency alone. Our results demonstrate that the marked phenotypic abnormalities observed in the D3-deficient mouse, including perinatal mortality, growth retardation, and central hypothyroidism in adult animals, require expression of MCT8, confirming the interdependent relationship between the TH transport into cells and the deiodination processes., This work was partially supported by Grants MH083220, DK095908, and MH096050 from the National Institutes of Health; Grant CIVP16A1805 from Fundación Ramón Areces; and Grant SAF2014-54919-R from Spain’s Plan Nacional de I+D.

[Background]: Monocarboxylate transporter 8 (MCT8) is a thyroid hormone-specific cell membrane transporter. Mutations in the MCT8 gene lead to profound psychomotor retardation and abnormal thyroid hormone serum levels with low thyroxine (T4) and high triiodothyronine (T3). Currently, therapeutic options for patients are limited. Triiodothyroacetic acid (TRIAC) has potential therapeutic value. The aim of this study was to evaluate the effects and efficacy of therapeutic doses of TRIAC on Mct8-deficient mice (Mct8KO)., [Methods]: Wild-type (Wt) and Mct8KO mice were treated with 30 ng TRIAC/g BW/day, given in drinking water, from postnatal day 21 to 30. TRIAC, T4 and T3 levels in plasma, as well as T3 and TRIAC content in the cerebral cortex and striatum were measured by specific radioimmunoassays. The activities of deiodinases 1 and 2 were measured in liver and cortex. The effect of TRIAC treatment in the expression of T3-dependent genes was measured in the heart, cerebral cortex and striatum., [Results]: Plasma TRIAC concentration were the same in Wt and Mct8KO animals after treatment. TRIAC treatment greatly decreased plasma T4 in Wt and Mct8KO mice, and reduced T3 to normal levels in the Mct8KO. Deiodinase 1 activity and gene expression in the liver increased while it did not have any effect on the expression of Serca2a in the heart. TRIAC treatment did not induce the expression of T3-dependent genes in the cerebral cortex or striatum but further decreased expression of Flywch2 in the cortex and Aldh1a1 and Flywch2 in the striatum. Direct measurements of TRIAC and T3 content in the cortex and striatum revealed a decrease in T3 after treatment with no significant increase in the level of endogenous TRIAC., [Conclusions]: Therapeutic doses of TRIAC in Mct8KO mice restored plasma T3 levels but severely decreased T4 levels. TRIAC has a direct effect on deiodinase 1 in the liver and does not have an effect on gene expression in the heart. The increase in the plasma TRIAC levels after treatment is not sufficient to increase TRIAC levels in the brain and to promote the expression of T3-dependent genes in brain cells. Instead, it leads to a state of brain hypothyroidism with reduced T3 content., This work was supported by Grants from the Mehuer Foundation and the Seville's College of Pharmacists, Ramón Areces Foundation (CIVP16A1805), Spanish Ministry of Economy and Competitiveness (SAF2011-25608, SAF2014-54919-R, SAF 2012-32491) and S2010/BMD-2423 from CAM and under the frame of E‑Rare‑2 and the “Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III” under the frame of the ERA-Net for Research on Rare Diseases. S.B.-L. is recipient of a predoctoral fellowship and contract from the FPI program of the Plan Nacional de I+D+i. The cost of this publication has been paid in part by FEDER funds.

[Purpose of review]: To discuss the recent advances on thyroid hormone transport in the brain. A special attention is paid to the X-linked thyroid hormone cell transport (THCT) defect (also known as the Allan-Herndon-Dudley syndrome), caused by mutations of the specific thyroid hormone transporter MCT8 gene. [Recent findings]: MCT8 is involved in thyroid hormone transport in the brain. MRI of patients with THCT defect showed myelination delays, probably related to impaired thyroid hormone action on oligodendrocytes. MCT8 is also expressed in the thyroid and has an important role in thyroid hormone secretion. The altered circulating concentrations of thyroid hormone in the patients are partly because of impaired secretion and altered peripheral metabolism. Increased deiodinase activity is important in the pathophysiology of the syndrome. High D1 activity in liver and kidney increases T4 and rT3 deiodination, and contributes to the increased serum T3. High D2 activity in the brain contributes to compensate the deficient T3 transport by increasing local T3 production. [Summary]: Patients with suspected X-linked leukoencephalopathy should be screened for MCT8 gene mutations. Research on the brain pathophysiology of the THCT defect should focus on the specific role of Mct8 on oligodendrocytes and myelination.

Mutations of the monocarboxylate transporter 8 gene (MCT8, SLC16A2) cause the Allan-Herndon-Dudley syndrome, an X-linked syndrome of severe intellectual deficit and neurological impairment. Mct8 transports thyroid hormones (T4 and T3), and the Allan-Herndon-Dudley syndrome is likely caused by lack of T3 transport to neurons during critical periods of fetal brain development. To evaluate the role of Mct8 in thyroid hormone action in the fetal brain we administered T4 or T3 to thyroidectomized pregnant dams treated with methyl-mercapto-imidazol to produce maternal and fetal hypothyroidism. Gene expression was then measured in the fetal cerebral cortex. T4 increased Camk4, Sema3c, and Slc7a3 expression, but T3 was without effect. To investigate the cause for the lack of T3 action we analyzed the expression of organic anion transport polypeptide (Oatp14, Slco1c1), a T4 transporter, and Mct8 (Slc16a2), a T4 and T3 transporter, by confocal microscopy. Both proteins were present in the brain capillaries forming the blood-brain barrier and in the epithelial cells of the choroid plexus forming the blood-cerebrospinal fluid barrier. It is concluded that T4 from the maternal compartment influences gene expression in the fetal cerebral cortex, possibly after transport via organic anion transporter polypeptide and/or Mct8, and conversion to T3 in the astrocytes. On the other hand, T3 does not reach the target neurons despite the presence of Mct8. The data indicate that T4, through local deiodination, provides most T3 in the fetal rat brain. The role of Mct8 as a T3 transporter in the fetal rat brain is therefore uncertain. Copyright © 2011 by The Endocrine Society., This work was supported by Grants SAF2008-01168 and SAF2008-00429E from the Ministry of Science and Innovation, Spain, the European Union Integrated Project CRESCENDO (LSHM-CT-2005-018652), and by the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III. D.D. was supported by the I3P program of the Consejo Superior de Investigaciones Científicas, Spain and by a postdoctoral fellowship from The Japanese Society for the Promotion of Science.

Thyroid hormone resistance syndromes are a group of genetic conditions characterized by decreased tissue sensitivity to thyroid hormones. Three syndromes are currently recognized, in which resistance to hormone action is due respectively to mutations in the gene encoding for thyroid hormone receptor TRb, impaired T4 and T3 transport, and impaired deiodinase-mediated T4 to T3 conversion. An updated review of each of these forms of resistance is provided, and their pathogenetic mechanisms and clinical approaches are discussed.

Hypothyroxinemia with low levels of circulating free thyroxine and normal levels of thyrotropin, which is usually caused by iodine deficiency, may affect pregnant women even in apparently iodine-sufficient areas, and it is debated whether it increases the risk of neurodevelopmental abnormalities in children born to them. Epidemiological observations indeed indicate that this is the case. Animal models show abnormal brain cortical cytoarchitecture in pups born to mildly hypothyroxinemic dams. In regions where the availability and use of iodized salt is inadequate (where

7 páginas, 4 figuras.-- et al., Thyroid hormones influence brain development through the control of gene expression. The concentration of the active hormone T-3 in the brain depends on T-3 transport through the blood-brain barrier, mediated in part by the monocarboxylate transporter 8 (Mct8/MCT8) and the activity of type 2 deiodinase (D2) generating T-3 from T-4. The relative roles of each of these pathways in the regulation of brain gene expression is not known. To shed light on this question, we analyzed thyroid hormone-dependent gene expression in the cerebral cortex of mice with inactivated Mct8 (Slc16a2) and Dio2 genes, alone or in combination. We used 34 target genes identified to be controlled by thyroidhormone in microarray comparisons of cerebral cortex from wild-type control and hypothyroid mice on postnatal d 21. Inactivation of the Mct8 gene (Mct8KO) was without effect on the expression of 31 of these genes. Normal gene expression in the absence of the transporter was mostly due to D2 activity because the combined disruption of Mct8 and Dio2 led to similar effects as hypothyroidism on the expression of 24 genes. Dio2 disruption alone did not affect the expression of positively regulated genes, but, as in hypothyroidism, it increased that of negatively regulated genes. We conclude that gene expression in the Mct8KO cerebral cortex is compensated in part by D2-dependent mechanisms. Intriguingly, positive or negative regulation of genes by thyroid hormone is sensitive to the source of T3 because Dio2 inactivation selectively affects the expression of negatively regulated genes., This work was supported by the Center for Biomedical Research on Rare Diseases; Grants SAF2008-01168 and SAF2008-00429E from the Ministry of Science and Innovation, Spain; the European Union Integrated Project CRESCENDO (LSHM-CT-2005-018652) Grants DK15070, DK07011, and DK20595 from the National Institutes of Health; and the Sherman family. A.C. is the holder of a predoctoral fellowship from the Ministry of Science and Innovation of Spain.

Hypertrophic cardiomyopathy is a relatively common inherited cardiomyopathy that is occasionally challenging to differentiate from hypertensive heart disease and athlete hearts on the basis of morphologic or functional abnormalities alone. Echocardiography has traditionally played a preeminent role in the diagnosis, formulation of management strategies, and the prognostication of this complex disease. In this review, we briefly profile the utility and pitfalls of established echocardiographic modalities and discuss the evolving role of novel echocardiographic imaging modalities such as tissue Doppler, Doppler-based strain, 2-dimensional strain (speckle tracking imaging), and 3-dimensional imaging in the assessment of hypertrophic cardiomyopathy.

et al., Thyroid hormones have profound effects on mood and behavior, but the molecular basis of thyroid hormone action in the adult brain is relatively unknown. In particular, few thyroid hormone-dependent genes have been identified in the adult brain despite extensive work carried out on the developing brain. In this work we performed global analysis of gene expression in the adult rat striatum in search for genomic changes taking place after administration of T3 to hypothyroid rats. The hormone was administered in two different schedules: 1) a single, large dose of 25 µg per 100 g body weight (SD) or 2) 1.5 µg per 100 g body weight once daily for 5 d (RD). Twenty-four hours after the single or last of multiple doses, gene expression in the striatum was analyzed using Codelink microarrays. SD caused up-regulation of 149 genes and down-regulation of 88 genes. RD caused up-regulation of 18 genes and down-regulation of one gene. The results were confirmed by hybridization to Affymetrix microarrays and by TaqMan PCR. Among the genes identified are genes involved in circadian regulation and the regulation of signaling pathways in the striatum. These results suggest that thyroid hormone is involved in regulation of striatal physiology at multiple control points. In addition, they may explain the beneficial effects of large doses of thyroid hormone in bipolar disorders.

Iodine deficiency remains the most frequent cause worldwide, after starvation, of preventable mental retardation in children. It causes maternal hypothyroxinemia, which affects pregnant women even in apparently iodine-sufficient areas, and often goes unnoticed because L-thyroxine (T4) levels remain within the normal range, and thyroid-stimulating hormone (TSH) is not increased. Even a mild hypothyroxinemia during pregnancy increases the risk of neurodevelopmental abnormalities, and experimental data clearly demonstrate that it damages the cortical cytoarchitecture of the fetal brain. The American Thyroid Association (ATA) recommends a supplement of 150 μg iodine/day during pregnancy and lactation, in addition to the use of iodized salt. We discuss the importance of iodine supplementation to ensure adequate T4 levels in all women who are considering conception and throughout pregnancy and lactation. © 2007 Elsevier Ltd. All rights reserved., Supported by a grants of the Ministerio de Educación y Ciencia (SAF2006–14068) to PB and (BFU2005–01740) to JB.

Ras homolog enriched in striatum (Rhes) is a member of the Ras family of small GTPases detected in the thyroid. Rhes inhibits signal transduction from Galphas protein. In this study we investigated whether Rhes can interfere with stimulation of cAMP/protein kinase A (PKA) pathway of TSH, FSH and LH receptors (TSHr, FSHr, LHr) and of activated TSHr mutants. Receptors were transiently transfected in COS-7 cells with or without Rhes; cAMP was evaluated in basal conditions and after hormone stimulation. Constitutive and bovine TSH (bTSH)-stimulated activity of wild type (wt) and mutated TSHr was inhibited after Rhes co-transfection. Rhes decreased cAMP after FSH and hCG beta-subunit (betahCG) stimulation in cells expressing the cognate receptors. In binding experiments Rhes, as another membrane protein, sodium/iodide symporter (NIS), reduced membrane expression of wt TSHr (wtTSHr). In conclusion, Rhes can interfere with the functional activity of wt and mutated TSHr and with the respective hormone-stimulated cAMP production of FSHr and LHr. This interference is not specific and due to the co-expression of two membrane proteins.

El pdf del artículo es la versión de autor., Thyroid hormone influences brain maturation through interaction with nuclear receptors and regulation of gene expression. Their role on astrocyte maturation remains unclear. We have analyzed the role of thyroid hormone in rat cerebellar astrocyte maturation by comparing the sequential patterns of intermediate filament expression in normal and hypothyroid animals. During normal development astroglial cells sequentially express nestin, vimentin, and glial fibrillary acidic protein. Differentiated astrocytes appeared in the superior medullary vellum by postnatal day 2 and reached the white mater and internal granular layer by postnatal day 4. Intermediate filament marker expression was transiently lost from postnatal days 6 to 8 in anterior lobes, without an increased apoptosis. Vimentin expression was replaced by glial fibrillary acidic protein between postnatal days 10 and 32. The differentiated astrocytes were evenly distributed throughout the cerebellar slices, including the internal granular layer. Differences between normal and hypothyroid rats were observed starting from postnatal day 4, with lack of differentiated astrocytes in the internal granular layer. The transient decrease of astrocyte markers immunoreactivity in the anterior lobe did not take place in hypothyroid rats. The vimentin-glial fibrillary acidic protein transition was delayed and most differentiated astrocytes remained confined to the white matter. The results indicate that thyroid hormone deficiency induces a delay and a partial arrest of astrocyte differentiation. Astrocytes express thyroid hormone receptor α and β subtypes suggesting that astrocytes are direct target cells of thyroid hormones. © 2007 ISDN., This work was supported by grants from Ministry of Science and Technology BFU2005-01740 and the European Union Integrated Project CRESCENDO (LSHM-CT-2005-018652).

Thyroid hormones (TH) function in brain has been known for a very long time. In 1813, Jean-Francois Coindet, a Swiss physician, made the discovery that iodine was efficient at treating goiter and cretinism, a disease associated to mental retardation, which was endemic in his country. This started a persisting tradition of research, which first identified TH [first thyroxine (T4) and then 3,5,3′-tri-iodo-l-thyronine) (T3)] as the active iodinated compounds, which early deficiency explained cretinism. It also revealed a number of other functions for TH, not only during development but also in adult brain. It is now well established that most brain cell types need TH for a proper and timely differentiation. What makes the situation in brain different than in other organs is that the consequences of TH deficiency become quickly irreversible. After the elucidation of the corresponding signaling pathway, and the identification of the two genes, now called THRA and THRB, which encode the nuclear receptors of T3 (TRs, including TRα1, TRβ1, and TRβ2), one would expect that this research field would eventually run out of unsolved mysteries. This is far from being the case and it seems that new questions keep arising all the time. This special issue is a snapshot on some of current hot topics, which bring a stimulating overview of the current situation. One key aspect of the neurodevelopmental function of TH, bringing major complications, is that TH does not freely circulate in all brain areas and cell types, as originally postulated. TH signaling seems therefore to be heterogeneous and dynamic in brain. First of all, local metabolism by deiodinases can modulate the availability of TH. This has been exemplified in anterior cortex (1), and studied in details in inner ear (2). Second, specific transporters play a major role for the distribution of TH. Therefore, although most brain cells possess at least one of the TR, the levels of TH in serum provide little indication for the TH-signaling level in different brain areas. The physiopathological relevance of the question of TH transport in brain is best illustrated by the Allan–Herndon–Dudley syndrome, a devastating genetic disease because of a genetic mutation in MCT8, a gene encoding one of the TH transporters (3). Schroeder and Privalsky provide a clear introduction to this difficult question, which involves local metabolism of TH by deiodinases, and specific transporters required for TH to cross the blood–brain barrier or to reach the cell nucleus (4). Anticipating recent reports for the importance of non-genomic pathways for TH signaling in brain (5) they raise the hypothesis that T4 itself may be more than a prohormone, having a function different from T3 in some situations. They also explain that differential expression of coregulators may modulate TH signaling during development, a possibility that has not yet been extensively explored (6, 7). Muller and Heuer (8) provide a novel and extensive description of the main TH transporters expression patterns in mice. These new data confirm that the transporter can potentially generate a very heterogeneous distribution of TH in brain. Wirth et al. (9) provide a comprehensive overview of the growing knowledge on TH transporters in brain, in various vertebrate models. They also discuss the possibility that other iodinated compounds, which are also transported in brain, may have a neglected function, independent of the classical TR pathway. Although neurons are the primary target of T3 actions, most of the T3 present in brain is made by T4 deiodination, which takes place predominantly, if not exclusively, in glial cells: the tanycytes lining part of the third ventricle surface and in the astrocytes throughout the brain. Morte and Bernal (10) show that how the combination of primary cell cultures, genome-wide expression analysis, and mouse genetics recently revealed a dynamic evolution of this astrocytes–neurons dialog during neurodevelopment. This also led to the puzzling conclusion that the source of T3 matters: some genes, which expression is down-regulated by T3, would respond differently, depending on whether T3 crossed the brain–blood barrier, or was produced by local deiodination of T4. A general picture emerges, where TH become much more than a trophic factor, their tightly regulated distribution providing positional information to the developing neurons. The neurodevelopmental consequences of altered TH signaling have been studied in great details over the years. Cerebellum proved to be a brain area suitable for in-depth investigation in rodent models. The first advantage, compared to other brain areas, is its relatively simple neuroanatomy, which few main cell types. The other is that its maturation takes place at a late stage of brain development, within the first post-natal weeks in rodent, when the circulating level of TH is normally high. This probably explains why the histological consequences of early TH deficiency are particularly dramatic in this brain area. Faustino and Ortiga-Carvalho review the recent progresses in our understanding in the way TH coordinate cellular interactions during this process, and the limited knowledge that we have on TRα1 and TRβ1 target genes in this promising model (11). In an ambitious reflection, Berbel et al. (12) generalize these concepts to cortex development, carefully discussing the relevance of rodent models to human pathology, and placing animal studies in an evolutionary perspective. In-depth examination of T3 regulated genes reveals hidden connection between TH deficiency and major neurodevelopmental diseases: epilepsy, autism, attention deficit hyperactive disorder, and schizophrenia. This landmark review should have far reaching consequences for later investigations, as it outlines that T3 is an essential timer of brain development, and that any alteration in T3 signaling has long-term consequences on neurological and cognitive functions. Remaud et al. (13) show that TH neurodevelopmental functions in brain do not stop after maturation, but persist throughout life, as the differentiation of adult neural stem cells, present in the hippocampus and the subventricular zone, also depends on TH. This leads to the proposal that the known decline of TH levels upon aging, may partially explain several adverse effects on cognitive functions. One site in the adult brain where TH has been proved to exert a number of important functions is the hypothalamus. This is especially important because hypothalamus is a brain area, which communicates with peripheral organs and a place where many physiological processes can cross-talk. Some TH functions, which are thought to involve peripheral organs, may actually stem in the hypothalamus. One important example is that the control of energy homeostasis, originally believed to result from direct stimulation of liver, muscles, white, and brown adipose tissue. It is now demonstrated that this important function of TH also involves the hypothalamus, which secretes a number of signaling peptides and set the sympathetic tone (14). Three reviews focus on one hypothalamic function of TH, which is an area of intense investigations: the involvement of TH in the so-called seasonal clock, which allow many animal species to reproduce at a specific season. Using a fish model, Ogawa et al. present new data showing that TH can activate, directly or indirectly, the expression of Kiss2 and Gnrh genes in hypothalamus, which are important upstream effectors of the gonadotrophic axis (15). Shinomiya et al. explain how initial studies of the photoperiodic change in gene expression in hypothalamus, performed in quail by the Nagoya group, led to the discovery of a general mechanism, common to vertebrate, which allow to couple the seasonal change in day length and reproduction (16). Dardente et al. highlight several missing links in this general model, which suggest that important contributions are still ahead (17). All these contributions provide a timely update of an abundant literature, and suggest exciting avenues for new investigations. These will also be stimulated by new questions raised by the discovery of new genetic diseases altering TH signaling in brain (18) and by the concern that some environmental contaminants acting as TH disruptors might compromise normal brain development (19). Most of all, as TH act primarily on gene expression, studies of TH function in brain will continue to provide an outstanding opportunity to explore the basic genetic mechanisms, which govern neurodevelopment and adult brain functions.

The cellular influx and efflux of thyroid hormones are facilitated by transmembrane protein transporters. Of these transporters, monocarboxylate transporter 8 (MCT8) is the only one specific for the transport of thyroid hormones and some of their derivatives. Mutations in SLC16A2, the gene that encodes MCT8, lead to an X-linked syndrome with severe neurological impairment and altered concentrations of thyroid hormones. Histopathological analysis of brain tissue from patients who have impaired MCT8 function indicates that brain lesions start prenatally, and are most probably the result of cerebral hypothyroidism. A Slc16a2 knockout mouse model has revealed that Mct8 is an important mediator of thyroid hormone transport, especially T 3, through the blood-brain barrier. However, unlike humans with an MCT8 deficiency, these mice do not have neurological impairment. One explanation for this discrepancy could be differences in expression of the T 4 transporter OATP1C1 in the blood-brain barrier; OATP1C1 is more abundant in rodents than in primates and permits the passage of T 4 in the absence of T 3 transport, thus preventing full cerebral hypothyroidism. In this Review, we discuss the relevance of thyroid hormone transporters in health and disease, with a particular focus on the pathophysiology of MCT8 mutations.

Constraints on the timing of weathering processes in the northern Australian regolith have been obtained by in situ measurement of U-series disequilibria in U-rich supergene Fe-oxy/hydroxides using a laser ablation-MC-ICPMS technique. This approach has permitted the measurement of 234 U/ 238 U and 230 Th/ 238 U activity ratios in finely crystalline Fe-oxy/hydroxides from the Ranger uranium deposit with sufficient precision and spatial resolution to constrain the age of formation of these phases and to develop a geochronological framework for weathering processes. 230 Th/ 238 U systematics in the finely crystalline Fe-oxy/hydroxides yield 230 Th-ages ranging from 60 to 350 ka. The most reliable 230 Th-ages cluster between 122 and 216 ka, suggesting Fe-oxy/hydroxides formation and associated weathering, peaked during the previous 2 interglacial periods. This is supported by the 230 Th-ages and isotope composition of pisolith (Fe-oxy/hydroxide pedogenic nodules) cores which are demonstrated to behave as closed systems. The U isotopic composition of the Fe-oxy/hydroxides is consistent with an origin from groundwater in equilibrium with dissolved uraninite. Secondary overprinting is evident in some samples as a large range in 234 U/ 238 U. Our results suggest that weathering intensity varies with global climate cycles and that, together with weathering events dated by 40 Ar/ 39 Ar of Mn-oxides elsewhere in northern Australia ([Feng, Y.X. and Vasconcelos, P., 2001. Quaternary continental weathering qeochronology by laser-heating 40 Ar/ 39 Ar analysis of supergene cryptomelane. Geology, 29(7): 635–638.]), weathering rates in this region are orbitally forced.

Introduccion y objetivos Hay escasa informacion sobre la evolucion de los pacientes hospitalizados por dolor toracico que no presentan criterios de alto riesgo tras su evaluacion inicial, a los que se realiza una prueba de esfuerzo para su valoracion antes del alta. Nuestro objetivo fue evaluar el pronostico de este grupo de pacientes y averiguar si hay factores clinicos y derivados de la prueba de esfuerzo que permitan predecir su evolucion. Pacientes y metodo La poblacion estaba constituida por 449 pacientes hospitalizados por dolor toracico de posible origen isquemico, sin criterios de alto riesgo (sin alteraciones isquemicas en el electrocardiograma ni elevacion de la troponina), a los que se realizo una prueba de esfuerzo previa al alta, tras un periodo de observacion de al menos 12 h. La mediana de seguimiento fue 479 dias. Se consideraron acontecimientos adversos la muerte cardiaca o el reingreso por infarto agudo de miocardio (IAM) no mortal o angina inestable. Resultados De los 449 pacientes, 44 (10%) presentaron algun suceso. En el analisis de regresion de Cox se identificaron como predictores independientes de evolucion desfavorable cuatro variables clinicas (edad ≥ 65 anos, diabetes, IAM previo y caracter tipico del dolor toracico) y una prueba de esfuerzo positiva. Conclusiones Los pacientes hospitalizados por dolor toracico sin criterios de alto riesgo tras su evaluacion inicial, a los que se efectua una prueba de esfuerzo, no estan exentos de sucesos adversos tras el alta. El perfil clinico contribuye, junto con el resultado de la ergometria, a la valoracion del riesgo de estos pacientes.

Congestive heart failure (CHF) is a major public health problem that results in tremendous economic burden. Diastolic heart failure (DHF) forms an important subset with increasing incidence and prevalence. There are widely variable estimates of the prevalence, ranging from 13% to 74% of all CHF presentations, and this is predominantly a result of a lack of uniform criteria for establishing a diagnosis. New developments in management of DHF have lagged behind those for systolic heart failure (SHF), for which numerous new therapeutic and device strategies have been instituted. The renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathophysiology of both SHF as well as DHF. The beneficial role of ACE inhibitors as well as aldosterone antagonists in SHF has been well established. Because of its unique role of the RAAS in establishing fibrosis at a molecular level, RAAS blockade provides an opportunity to expand the therapeutic options for DHF. Thus far, in patients with primary DHF only the angiotensin receptor type 1 antagonist candesartan has been reported to decrease morbidity and probably mortality. Large, ongoing randomized trials including TOPCAT (Trial of Aldosterone Antagonist Therapy in Adults with Preserved Ejection Fraction Congestive Heart) and the I-PRESERVE (Irbesartan in Heart Failure with Preserved Systolic Function) are currently underway to establish the role of aldosterone antagonists in patients with DHF.

Introduction and objectives Few data are available on the outcome of patients admitted to hospital with suspected acute coronary syndrome who have no high-risk factors and who undergo exercise testing before discharge. Our objectives were to investigate outcomes in this group of patients and to determine whether clinical history-taking or exercise testing can help to predict outcome. Patients and methods The study population comprised 449 patients admitted to hospital with chest pain suggestive of acute coronary syndrome. All were judged to be at low risk of subsequent events (i.e., none had ischemic ECG changes or an elevation in troponin level). They underwent treadmill exercise testing before discharge, after an observation period of at least 12 hours. Exercise testing was performed after clinical evaluation based on an algorithm involving troponin-T level and resting ECG. The median follow-up duration was 479 days. The single combined endpoint was defined as cardiac death, or hospital admission for nonfatal acute myocardial infarction or unstable angina. Results Adverse events occurred in 44 (10%) of the 449 patients. A high event rate was associated with four clinical features (i.e., age ≥65 years, diabetes, previous acute myocardial infarction, and typical chest pain) and with a positive result on exercise testing. Conclusions Adverse events after discharge are not infrequent in patients admitted to hospital with suspected acute coronary syndrome and a low risk profile. Both the patient's clinical characteristics and exercise test results should be taken into account in accurately determining prognosis.

Supported by grants BFI2002-00489 (MCYT), BFU2004-03169 (MEC), GR/SAL/0382/2004 and GR/SAL/0773/2004 from Comunidad de Madrid and FIS, Instituto de Salud Carlos III, Red de Centros RCMN (C03/08), RCGC(C03/10), de gruposRGDM(G03/212) y PI041216 (Spain).

9 pages, 10 figures.-- et al., The development and the function of central nervous system depend on thyroid hormones. In humans, the lack of thyroid hormones causes cretinism, a syndrome of severe mental deficiency. It is assumed that thyroid hormones affect the normal development and function of the brain by activating or suppressing target gene expression because several genes expressed in the brain have been shown to be under thyroid hormone control. Among these, the Rhes gene, encoding a small GTP-binding protein, is predominantly expressed in the striatal region of the brain. To clarify the role of Rhes in vivo, we disrupted the Rhes gene by homologous recombination in embryonic stem cells and generated mice homozygous for the Rhes null mutation (Rhes(-/-)). Rhes(-/-) mice were viable but weighed less than wild-type mice. Furthermore, they showed behavioral abnormalities, displaying a gender-dependent increase in anxiety levels and a clear motor coordination deficit but no learning or memory impairment. These results suggest that Rhes disruption affects selected behavioral competencies., This work was supported in part by Telethon grant GP0208Y01, by a grant from the Associazione Italiana per la Ricerca sul Cancro (to R.D.L.), by Ministero dell'Università e della Ricerca Scientifica e Tecnologica grant “I geni dell'uomo” cluster 01, and by Italian Ministry of Health project ALZ1 (to E.A.). A.R., M.T.P., P.M., and A.A. were supported by Biogem s.c.a.r.l., Italy.

6 pages, 3 figures., Although the effects of thyroid hormones on the development of neurons and oligodendrocytes are well documented, less is known about the hormonal effects on astrocytes. Our analyses of cerebellar slices from 2-month-old T(3) receptor protein (TR)alpha1-deficient mice show that mature astrocytes, Golgi epithelial cells, and their Bergmann processes had strongly reduced glial fibrillary acidic protein (GFAP) and nestin immunoreactivity, in contrast to wild-type mice. Furthermore, the Bergmann processes exhibited an irregular GFAP staining. A similar expression of nestin and GFAP was observed in 11-d-old (P11) mutant pups. Surprisingly, however, hypothyroidism normalized the appearance of these markers in the P11 mutants, suggesting that liganded TR beta is detrimental to astroglial cell differentiation in the absence of TR alpha 1. To test this hypothesis, hypothyroid mice were treated from birth until P11 with the TR beta-selective ligand GC-1. This treatment was devastating in the TR alpha 1(-/-) mice, causing little if any nestin or GFAP immunoreactivity, whereas the wild-type mice were normal. The results thus indicate an important interplay between thyroid hormone receptor isoforms in astroglial cell maturation., This work was supported by Grant BFI2002-00489 from the Ministry of Science and Technology, FIS, Instituto de Salud Carlos III, Red de Centros RCMN (C03/08) (to J.B.), the National Institutes of Health (DK 52798) (to T.S.S.), and The Swedish Cancer Society and Karobio AB (to B.V.). B.M. is a postdoctoral fellow from the Community of Madrid, and J.M. is a predoctoral fellow from the Ministry of Science and Technology.

Thyrotropin or thyroid-stimulating hormone (TSH) secretion in the chicken is controlled by several hypothalamic hormones. It is stimulated by thyrotropin-releasing hormone (TRH) and corticotropin-releasing hormone (CRH), whereas somatostatin (SRIH) exerts an inhibitory effect. In order to determine the mechanism by which these hypothalamic hormones modulate chicken TSH release, we examined the cellular localization of TRH receptors (TRH-R), CRH receptors type 1 (CRH-R1) and somatostatin subtype 2 receptors (SSTR2) in the chicken pars distalis by in situ hybridization (ISH), combined with immunological staining of thyrotropes. We show that thyrotropes express TRH-Rs and SSTR2s, allowing a direct action of TRH and SRIH at the level of the thyrotropes. CRH-R1 expression is virtually confined to corticotropes, suggesting that CRH-induced adrenocorticotropin release is the result of a direct stimulation of corticotropes, whereas CRH-stimulated TSH release is not directly mediated by the known chicken CRH-R1. Possibly CRH-induced TSH secretion is mediated by a yet unknown type of CRH-R in the chicken. Alternatively, a pro-opiomelanocortin (POMC)-derived peptide, secreted by the corticotropes following CRH stimulation, could act as an activator of TSH secretion in a paracrine way.

Alien has been described as a corepressor for the thyroid hormone receptor (TR). Corepressors are coregulators that mediate gene silencing of DNA-bound transcriptional repressors. We describe here that Alien gene expression in vivo is regulated by thyroid hormone both in the rat brain and in cultured cells. In situ hybridization revealed that Alien is widely expressed in the mouse embryo and also throughout the rat brain. Hypothyroid animals exhibit lower expression of both Alien mRNAs and protein levels as compared with normal animals. Accordingly, we show that Alien gene is inducible after thyroid hormone treatment both in vivo and in cell culture. In cultured cells, the hormonal induction is mediated by either TRα or TRβ, while cells lacking detectable amounts of functional TR lack hormonal induction of Alien. We have detected two Alien-specific mRNAs by Northern experiments and two Alien-specific proteins in vivo and in cell lines by Western analysis, one of the two forms representing the CSN2 subunit of the COP9 signalosome. Interestingly, both Alien mRNAs and both detected proteins are regulated by thyroid hormone in vivo and in cell lines. Furthermore, we provide evidence for the existence of at least two Alien genes in rodents. Taken together, we conclude that Alien gene expression is under control of TR and thyroid hormone. This suggests a negative feedback mechanism between TR and its own corepressor. Thus, the reduction of corepressor levels may represent a control mechanism of TR-mediated gene silencing. © 2003 Elsevier Science (USA). All rights reserved., This work was supported by grants from the Deutscher Akademischer Austauschdienst (to A.B. and S.P.T.), the “Programa de Acciones Especiales y Acciones de Política Científica” (APC1999-0172) of the Ministerio de Educación y Cultura of Spain (to S.P.T.), the Grant SAF2001-2291 from the Ministerio de Ciencia y Tecnologia to A.M., and the SFB 397 from the Deutsche Forschungsgemeinschaft (to A.B.).

8 pages, 7 figures., The calmodulin-binding, protein kinase C substrate RC3/neurogranin is the product of a neuron-specific gene expressed in the forebrain that is under specific regional and temporal control by thyroid hormone (3,5,3'-triiodothyronine, T3). In vivo, some neuronal populations are sensitive and others are insensitive to T3. The goal of this study was to identify neuronal cell cultures that express RC3/neurogranin, to check whether they are sensitive to T3, and to examine the mechanism of regulation. We found that RC3 is induced by T3 in the hypothalamic cell line GT1-7 at the transcriptional level. The half-life of the mature mRNA was 20 h and was not affected by the hormone. Addition of T3 to the cell culture induces neurogranin mRNA after 6 h in the absence of new protein synthesis. These results suggest a direct transcriptional effect of T3 mediated through nuclear receptors. Indeed, GT1-7 cells express functional T3 receptors, as shown by northern blotting, nuclear T3-binding assays, and transactivation of reporter genes. The role of retinoic acid and glucocorticoids on RC3 expression was also evaluated, because we have previously noted the presence of consensus response elements for these hormones in the RC3 upstream promoter region. In contrast to T3, neither retinoic acid nor dexamethasone influences neurogranin expression despite the presence of respective functional receptors., This work was supported by grants from the Ministry of Health (FIS 94/0273), the Ministry of Education (PM95-00l9), and Fundacion Salud 2000. B.M. and P.I.L. are predoctoral fellows from the Communities of Madrid and the Basque Country, respectively.

Thyroid hormone (T3) is essential for brain development and most of its actions are exerted at the gene expression level after interaction with nuclear receptors. In particular, genes encoding cytoskeletal proteins are influenced by the thyroidal status. Thyroid hormone is involved in the normal downregulation of the Tα1 α-tubulin gene during postnatal growth. The action of T3 on Tα1 tubulin expression is complex and is exerted at least at two levels. In cultured cells, T3 induces a transient and fast decrease of Tα1 mRNA concentration. This effect is enhanced when transcription is blocked by actinomycin D, suggesting that T3 increases mRNA degradation. In transgenic animals T3 affects the expression of β-galactosidase under control of the Tα1 promoter in the same way as the endogenous gene, supporting an effect mediated through the Tα1 promoter. However, the Tα1 promoter is not regulated by T3 in transfected cells and, therefore, the effects of the hormone in vivo are likely to be indirect. It is concluded that regulation of Tα1 α-tubulin by thyroid hormone is the result of multiple influences including effects on mRNA half life and indirect effects at the promoter level., This work was supported by grants from the CICYT (PM98-0118) and the Community of Madrid (08.5/0044/2000 1). P. Lorenzo was supported by a fellowship from the Basque Government.

Thyroid hormone is an important regulator of mammalian brain maturation. By differential display PCR, we isolated a cDNA clone (S2) that is specifically up-regulated in the striatum of neonatal hypothyroid rats. S2 was identified as KIAA0719, the first human gene distantly homologous to the fungal Tom70, which encodes a member of the translocase mitochondrial outer membrane complex involved in the import of preproteins into the mitochondria. By northern and in situ hybridization studies, KIAA0719 was found to be up-regulated in the striatum, nucleus accumbens, and discrete cortical layers of 15-day-old hypothyroid rats. In contrast, lower expression was found in the olfactory tubercle, whereas no differences were detected in other brain regions. Significantly, treatment of hypothyroid animals with single injections of thyroxine restored the normal levels of KIAA0719 expression. Moreover, treatment of control animals with thyroxine led to a reduced expression, demonstrating a negative hormonal regulation in vivo. Thus, KIAA0719 gene expression is regulated by thyroid hormone in the neonatal rat brain in a region-specific fashion. Given the role of the homologous Tom70 gene, the alteration of KIAA0719 expression may contribute to the changes in mitochondrial morphology and physiology caused by hypothyroidism in the developing rat brain.

et al., Guideline advice of many societies on the management of subclinical hypothyroidism in pregnancy suggests treatment when TSH serum levels exceed 2.5 mU/l. Justification of this procedure is based on limited experience, mainly from studies carried out in patients with positive thyroid-specific antibodies and higher TSH levels that classically define the condition in the non-pregnant state. Taking into account a lack of clear understanding of the regulation of thyroid hormone transport through the utero-placental unit and in the absence of foetal markers to monitor the adequacy of thyroxine treatment, this review attempts to discuss currently available data and suggests a more cautious approach.

et al., [Context]: Mutations in the MCT8 (SLC16A2) gene, encoding a specific thyroid hormone transporter, cause an X-linked disease with profound psychomotor retardation, neurological impairment, and abnormal serumt hyroid hormone levels. The nature of the central nervous system damage is unknown., [Objective]: The objective of the study was to define the neuropathology of the syndrome by analyzing brain tissue sections from MCT8-deficient subjects., [Design]: We analyzed brain sections from a 30th gestational week male fetus and an 11-year-old boy and as controls, brain tissue from a 30th and 28th gestational week male and female fetuses, respectively, and a 10-year-old girl and a 12-year-old boy., [Methods]: Staining with hematoxylin-eosin and immunostaining for myelin basic protein, 70-kDa neurofilament, parvalbumin, calbindin-D28k, and synaptophysin were performed. Thyroid hormone determinations and quantitative PCR for deiodinases were also performed., [Results]: The MCT8-deficient fetus showed a delay in cortical and cerebellar development and myelination, loss of parvalbumin expression, abnormal calbindin-D28k content, impaired axonal maturation, and diminished biochemical differentiation of Purkinje cells. The 11-year-old boy showed altered cerebellar structure, deficient myelination, deficient synaptophysin and parvalbumin expression, and abnormal calbindin-D28k expression. The MCT8-deficient fetal cerebral cortex showed50%reduction of thyroid hormones and increased type 2 deiodinase and decreased type 3 deiodinase mRNAs., [Conclusions]: The following conclusions were reached: 1) brain damage in MCT8 deficiency is diffuse, without evidence of focal lesions,andpresent from fetal stages despite apparent normality at birth; 2) deficient hypomyelination persists up to 11 years of age; and 3) the findings are compatible with the deficient action of thyroid hormones in the developing brain caused by impaired transport to the target neural cells., This study was supported by Grant SAF2011-25608 from the Plan Nacional de IDi and the Center for Research on Rare Diseases (Centro de Investigación Biomédica en Red Enfermedades Raras), Instituto de Salud Carlos III, Madrid, Spain; Grant DK15070 from the National Institutes of Health, Bethesda, Maryland; and a grant from the Sherman Family. D.L.-E. is recipient of a fellowship from the “Fellowship Training Program for Advanced Human Capital, Becas Chile” from the National Commission for Scientific and Technological Research, Gobierno de Chile.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY)., Thyroid hormone (TH) action is exerted mainly through regulation of gene expression by binding of T3 to the nuclear receptors. T4 plays an important role as a source of intracellular T3 in the central nervous system via the action of the type 2 deiodinase (D2), expressed in the astrocytes. A model of T3 availability to neural cells has been proposed and validated. The model contemplates that brain T3 has a double origin: a fraction is available directly from the circulation, and another is produced locally from T4 in the astrocytes by D2. The fetal brain depends almost entirely on the T3 generated locally. The contribution of systemic T3 increases subsequently during development to account for approximately 50% of total brain T3 in the late postnatal and adult stages. In this article, we review the experimental data in support of this model, and how the factors affecting T3 availability in the brain, such as deiodinases and transporters, play a decisive role in modulating local TH action during development.

Commentary.-- et al., This work was supported in part by Grants R37DK15070 and UL1TR000430 from the National Institutes of Health.

El objetivo del trabajo fue el de determinar la tasa de parasitismo en huevos de Oebalus insularis en diferentes variedades (CONAGRO-2, ESTRELLA-92, IDIAP-5405) de arroz. La tasa de parasitismo de los huevos de O. insularis se determino en condiciones controladas de temperatura (25±1 °C), humedad relativa (85±3%) y fotofase (12 horas). Se identificaron los parasitoides Telenomus podisi y Trissolcus basalis. La tasa de parasitismo promedio del complejo de parasitoides fue superior al 90% y la especie mas abundante fue T. podisi, con 81,8% de parasitismo.

This is an open-access article distributed under the terms of the Creative Commons Attribution License., The effects of thyroid hormone on brain development and function are largely mediated by the binding of 3,5,3′-triiodo-L-thyronine (T3) to its nuclear receptors (TR) to regulate positively or negatively gene expression. We have analyzed by quantitative polymerase chain reaction the effect of T3 on primary cultured cells from the embryonic mouse cerebral cortex, on the expression of Hr, Klf9, Shh, Dio3, Aldh1a1, and Aldh1a3. In particular we focused on T3 receptor specificity, and on the crosstalk between T3, retinoic acid and dexamethasone. To check for receptor subtype specificity we used cerebrocortical cells derived from wild type mice and from mice deficient in thyroid hormone receptor subtypes. Receptor subtype specificity was found for Dio3 and Aldh1a1, which were induced by T3 only in cells expressing the T3 receptor alpha 1 subtype. Interactions of T3 with retinoic acid signaling through the control of retinoic acid metabolism are likely to be important during development. T3 had opposing influences on retinoic acid synthesizing enzymes, increasing the expression of Aldh1a1, and decreasing Aldh1a3, while increasing the retinoic acid degrading enzyme Cyp26b1. Dexamethasone increased Klf9 and Aldh1a1 expression. The effects of T3 and dexamethasone on Aldh1a1 were highly synergistic, with mRNA increments of up to 20 fold. The results provide new data on thyroid hormone regulation of gene expression and underscore the importance of thyroid hormone interactions with retinoic acid and glucocorticoids during neural development. © 2014 Gil-Ibáñez et al., Supported with grants from Plan Nacional de I+D SAF2011-25608, the Ramon Areces Foundation, and the Center for Biomedical Research on Rare Diseases (CIBERER), Instituto Carlos III, Spain. PG-I is recipient of a Junta de Ampliación de Estudios (JAE) predoctoral contract from the Consejo Superior de Investigaciones Científicas (CSIC).

et al., Maternal thyroid hormones (THs) are essential for normal offspring's neurodevelopment even after onset of fetal thyroid function. This is particularly relevant for preterm children who are deprived of maternal THs following birth, are at risk of suffering hypothyroxinemia, and develop attention-deficit/hyperactivity disorder. Expression of neocortical Ca2+/calmodulin kinase IV (Camk4), a genomic target of thyroid hormone, and nuclear receptor-related 1 protein (Nurr1), a postnatal marker of cortical subplate (SP) cells, was studied in euthyroid fetuses and in pups born to dams thyroidectomized in late gestation (LMH group, a model of prematurity), and compared with control and developmentally hypothyroid pups (C and MMI groups, respectively). In LMH pups, the extinction of heavy Camk4 expression in an SP was 1–2 days delayed postnatally compared with C pups. The heavy Camk4 and Nurr1 expression in the SP was prolonged in MMI pups, whereas heavy Camk4 and Nurr1 expression in layer VIb remains at P60. The abnormal expression of Camk4 in the cortical SP and in layer VIb might cause altered cortical connectivity affecting neocortical function., This work was supported by the Spanish Ministerio de Ciencia e Innovación (SAF2009-10689 to P.B. and SAF2011-25608 to J.B.).

The financial structure of megaprojects, known in the literature as project finance, is characterized by the creation of a legally independent project company financed with a concentrated equity ownership and a high level of non-recourse debt. Research in this field may yield new ideas and theories about the existing theoretical framework on capital structure, stakeholder management and risk management. A case-study is analyzed in this paper: the financial performance of the first metro line in Seville (Spain). In spite of previous cost overruns in the construction stage, the present operation stage is considered successful from the point of view of social and financial profitability, whereby the risks have been theoretically transferred to stakeholders, as defined by Value for Money considerations. The objective of this study involves: first to determine whether this megaproject meets the expectations for which it was created in terms of hope of return of the shareholders, and the expectations of the economic and financial feasibility under a change of subsidy policies; and secondly to determine whether the conditions remain for not including the investment as public debt. This issue is crucial in a budgetary constraint context for the planning of future metro lines. By taking this first experience into account, this article also provides information for potential participants in the projects of the new metro lines, which are currently in the planning stage.

Las hormonas tiroideas intervienen de forma critica en el desarrollo del sistema nervioso central. El hipotiroidismo fetal y/o neonatal ocasiona defectos de mielinizacion, asi como de migracion y diferenciacion neuronales, que dan lugar a retraso mental y sintomas neurologicos. La mayoria de las acciones de las hormonas tiroideas son debidas a la interaccion de la forma activa, T3, con receptores nucleares que estan ya presentes en el cerebro fetal de rata el dia 14 despues de la concepcion, y en el feto humano en la decima semana de gestacion. Las hormonas tiroideas presentes en el feto pueden ser de procedencia materna o fetal. La T4 de origen materno contribuye mas del 50% de la T4 fetal a termino. La concentracion de T3 en el sistema nervioso central esta estrechamente regulada por las desyodasas tipos II y III. La desyodasa tipo II, que se expresa en tanicitos y en astrocitos, genera localmente, a partir de T4, la mayor parte de T3 presente en el sistema nervioso. La desyodasa tipo III, en neuronas, degrada T4 y T3 a metabolitos inactivos. La hormona tiroidea regula la expresion de una serie de genes que codifican proteinas de diversa funcion fisiologica: proteinas de mielina, proteinas implicadas en la adhesion y migracion celulares, proteinas de senalizacion, componentes del citosqueleto, proteinas mitocondriales, factores de transcripcion, etc. El papel de la hormona tiroidea es el de ajustar los niveles de expresion, a la alta o a la baja, durante un periodo corto del desarrollo. Solo una pequena fraccion de los genes identificados son regulados en sistema nervioso central adulto. En la mayoria de los casos, el papel de la hormona tiroidea consiste en acelerar los cambios de expresion que ocurren durante el desarrollo, sin influir en la concentracion final del producto genico que, aunque con retraso, llega a alcanzar un valor normal en animales hipotiroideos, aun en ausencia de tratamiento. Desde el punto de vista clinico, aparte de los sindromes por deficiencia profunda de yodo, o hipotiroidismo congenito, se esta prestando especial atencion a los estados de hipotiroxinemia materna.

copyright 2000 American Phytopathology Society Journals Datos y artículo incluido por Lisela Moreira Carmona, responsable de depósitos de publicaciones del área de Patógenos y Plagas del CIBCM Chayote mosaic virus (ChMV) is a putative tymovirus isolated from chayote crops in Costa Rica. ChMV was characterized at the host range, serological, and molecular levels. ChMV was transmitted mechanically and induced disease symptoms mainly in Cucurbitaceae hosts. Asymptomatic infections were detected in other host families. Serologically, ChMV is related to the Andean potato latent virus (APLV) and the Eggplant mosaic virus (EMV), both members of the genus Tymovirus infecting solanaceous hosts in the Caribbean Basin and South America. The sequence of the genomic RNA of ChMV was determined and its genetic organization was typical of tymoviruses. Comparisons with other tymoviral sequences showed that ChMV was a new member of the genus Tymovirus. The phylogenetic analyses of the coat protein gene were consistent with serological comparisons and positioned ChMV within a cluster of tymoviruses infecting mainly cucurbit or solanaceous hosts, including APLV and EMV. Phylogenetic analyses of the replicase protein gene confirmed the close relationship of ChMV and EMV. Our results suggest that ChMV is related to two tymoviruses (APLV and EMV) of proximal geographical provenance but with different natural host ranges. ChMV is the first cucurbit-infecting tymovirus to be fully characterized at the genomic level. Universidad de Costa Rica/[801-95-581]/UCR7Costa Rica UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Biología Celular y Molecular (CIBCM)

Introduccion y objetivos La prueba de esfuerzo debajo riesgo se relaciona con un buen pronostico en los pacientescon cardiopatia isquemica cronica. Sin embargo,apenas existen estudios que hayan evaluado prospectivamenteel pronostico de los pacientes con angina inestablecontrolada con tratamiento medico y que realizan unaprueba de esfuerzo de bajo riesgo. Nuestro objetivo fuedeterminar el pronostico de esta poblacion especifica y siexisten variables clinicas o derivadas de la ergometriapredictoras de eventos. Metodos Se diseno un protocolo de estudio prospectivo,segun el cual se evaluaron 175 pacientes con diagnosticode angina inestable, a los que se realizo unaprueba de esfuerzo para la valoracion pronostica antesdel alta hospitalaria durante un periodo de dos anos. Lapoblacion de estudio estaba constituida por los 93 pacientes(un 82% de varones; edad: 60 ± 9 anos) que nopresentaron criterios de alto riesgo previamente definidosen la prueba de esfuerzo y fueron dados de alta con tratamientofarmacologico. Resultados Tras un periodo de seguimiento medio de13 ± 6 meses, 30 pacientes (32%) padecieron algun evento:2 muertes (2%); 6 infarto agudo de miocardio no mortal (6%);18 angina inestable (19%) y 4 revascularizacion (4%). En elanalisis multivariado, solo la angina durante la prueba de esfuerzofue un predictor independiente de eventos (odds ratio:2,35; intervalo de confianza del 95%: 1,22-4,50; p = 0,01). Conclusiones Los pacientes con angina inestable querealizan una ergometria de bajo riesgo y son dados dealta con tratamiento medico tienen una incidencia deeventos relativamente elevada durante el primer ano. Enesta poblacion especifica, la presencia de angina durantela ergometria se asocia a una evolucion desfavorable.

We have characterized an apparently full-length cDNA corresponding to a rat mRNA, SE6C, previously identified by subtractive hybridization as being expressed predominantly in the striatal region of the brain. The SE6C mRNA encodes a 266 amino acid protein with significant similarity to members of the Ras-like GTP-binding protein family; thus, we have chosen the name Rhes, for Ras homolog enriched in striatum. The human homolog was found in a genomic sequence from human chromosome 22q13.1 and shares 95% identity with rat Rhes. Among the family of small G-proteins, Rhes shares 62% identity with Dexras1, a mouse dexamethasone-inducible Ras-like protein. Both Rhes and Dexras1 have substantially longer C-termini than other members of the Ras-like small G-protein family. Divergence between the C-terminal sequences of Rhes and Dexras1 suggests that, although their functions are probably similar, they have unique properties. Bacterially expressed Rhes binds GTP, suggesting that the protein indeed has GTPase functionality. Although Rhes was not induced by dexamethasone, its full expression is dependent upon thyroid hormone availability. Its accumulation is postnatal, consistent with the dependence upon thyroid hormone. It is noteworthy that most striatum-“specific” mRNAs characterized to date encode components of signal transduction cascades. J. Neurosci. Res. 57:782–788, 1999. © 1999 Wiley-Liss, Inc.

The relative occurrence in Spain of two whitefly transmitted closteroviruses causing similar yellowing diseases in melon and cucumber greenhouse crops was studied. Based on a RT-PCR assay, a 1994‐1997 survey of Spanish greenhouses showed that the recently described Bemisia tabaci-transmitted cucurbit yellow stunting disorder virus (CYSDV) has displaced the Trialeurodes vaporariorum -transmitted beet pseudo-yellows virus (BPYV), a virus that was present in the area since the late 1970s. The CYSDV transmission rates by each of the two biotypes of B. tabaci present in Spain were compared. The results showed that the ubiquitous ‘B’ biotype and the resident ‘Q’ biotype (found in Spain and Portugal) were able to transmit CYSDV with similar efficiency. The out-of-season cultivation of cucurbits in plastic greenhouses has major economic importance in many Mediterranean countries. Only in Spain the cultivation of melon (Cucumis melo L.) and cucumber (Cucumis sativus L.) amounts for 16,000 ha of plastic greenhouses along the southeastern (SE) coast. Since the late 1970s these two crops have been seriously affected by yellowing diseases transmitted by whiteflies. Two viruses have been associated with these diseases in Spain. First, a virus transmitted by the greenhouse whitefly ( Trialeurodes vaporariorum Westwood) was reported to occur in greenhouse-grown cucurbits in several countries including Spain (Jord ´ a

NRGN is the human homolog of the neuron-specific rat RC3/neurogranin gene. This gene encodes a postsynaptic 78-amino acid protein kinase substrate that binds calmodulin in the absence of calcium, and that has been implicated in dendritic spine formation and synaptic plasticity. In the rat brain RC3 is under thyroid hormone control in specific neuronal subsets in both developing and adult animals. To evaluate whether the human gene is also a target of thyroid hormone we have searched for T3-responsive elements in NRGN cloned genomic fragments spanning the whole gene. Labeled DNA fragments were incubated with T3 receptors (T3R) and 9-cis-retinoic acid receptors and immunoprecipitated using an anti T3R antibody. A receptor-binding site was localized in the first intron, 3000 bp downstream from the origin of transcription. Footprinting analysis revealed the sequence GGATTAAATGAGGTAA, closely related to the consensus T3-responsive element of the direct repeat (DR4) type. This sequence binds the T3R-9-cis-retin...

The development of the brain is critically dependent on an adequate supply of iodine. Iodine is an integral part of thyroid hormone, which acts on brain development by regulating the expression of target genes. The active thyroid hormone, T3, is generated in part in the thyroid gland, but about 80% of T3 in brain is formed locally from T4 deiodination mainly by the action of a specific iodothyronine deiodinase. This enzyme is highly expressed in astrocytes, which take up T4 from the blood and deliver T3 for neuronal use. In the target cells T3 binds to nuclear receptors which are transcription factors. The T3 receptors are expressed in the brain before fetal thyroid gland function and may be activated by maternal thyroid hormone during midgestation. Although a group of thyroid hormone target genes has been identified in recent years, many basic questions of thyroid hormone action in the brain remain to be elucidated.

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Mutations of the monocarboxylate transporter 8 (MCT8) cause a severe X-linked intellectual deficit and neurological impairment. MCT8 is a specific thyroid hormone (T4 and T3) transporter and the patients also present unusual abnormalities in the serum profile of thyroid hormone concentrations due to altered secretion and metabolism of T4 and T3. Given the role of thyroid hormones in brain development, it is thought that the neurological impairment is due to restricted transport of thyroid hormones to the target neurons. In this work we have investigated cerebral metabolism in mice with Mct8 deficiency. Adult male mice were infused for 30 minutes with (1-13C) glucose and brain extracts prepared and analyzed by 13C nuclear magnetic resonance spectroscopy. Genetic inactivation of Mct8 resulted in increased oxidative metabolism as reflected by increased glutamate C4 enrichment, and of glutamatergic and GABAergic neurotransmissions as observed by the increases in glutamine C4 and GABA C2 enrichments, respectively. These changes were distinct to those produced by hypothyroidism or hyperthyroidism. Similar increments in glutamate C4 enrichment and GABAergic neurotransmission were observed in the combined inactivation of Mct8 and D2, indicating that the increased neurotransmission and metabolic activity were not due to increased production of cerebral T3 by the D2-encoded type 2 deiodinase. In conclusion, Mct8 deficiency has important metabolic consequences in the brain that could not be correlated with deficiency or excess of thyroid hormone supply to the brain during adulthood. © 2013 Rodrigues et al., Supported with grants from Plan Nacional de I+D SAF2008-01168 and SAF2011-25608 (BM and JB) and SAF2011-23622 (SC), the Ramon Areces Foundation (BM and JB), the Center for Biomedical Research on Rare Diseases (CIBERER), Instituto Carlos III, Spain (BM and JB), S2010/BMD-2349 from the Community of Madrid (SC), grant DK15070 (SR) from the National Institutes of Health, USA, an Intra-European Marie Curie (FP7-PEOPLE-2009-IEF, Imaging Lymphoma) and a Long-term EMBO (EMBO-ALT-1145-2009) fellowships (TBR).

MCT8 is a specific transporter for the T4 and T3 thyroid hormones that allows their entry in the brain and other organs. Mutations in MCT8 (Allan-Herndon-Dudley syndrome) lead to a severe form of X-linked psychomotor retardation, which is characterised by elevated plasma T3 and low T4.We describe the first case diagnosed in Spain with this syndrome and review the published literature about this topic. We both review the various clinical presentations, genetic advances, differential diagnosis and therapeutic perspectives of this syndrome and propose a diagnostic algorithm for it.A 5 year-old boy, with a clinical picture compatible with Pelizaeus-Merzbacher disease. PLP1 gene sequencing showed no abnormalities. All the genetic and metabolic studies conducted were normal. Finally, a complete study of thyroid profile revealed abnormalities that were consistent with MCT8 transporter deficiency. The sequencing of the SLC16A2 gene (MCT8) showed a mutation in exon 3 and the study made at a cellular level, has confirmed that this mutation changes the properties of the protein.In the last five years, there have been many publications about this syndrome, with the identification of more than 50 families worldwide. It is important to both know and suspect this syndrome, because the diagnosis is easy, cheap and accessible (thyroid profile) and, although it has no specific treatment, early diagnosis prevents unnecessary testing and allows to offer genetic counseling to the families affected by it.Deficiencia del transportador celular de hormona tiroidea MCT8: caso clinico y revision de la bibliografia.Introduccion. El MCT8 es un transportador especifico para las hormonas tiroideas T4 y T3, que permite su entrada en el cerebro y otros organos. La deficiencia de MCT8, o sindrome de Allan-Herndon-Dudley, es un trastorno ligado a X que, generalmente, se presenta como un cuadro neurologico grave de inicio precoz, con un perfil tiroideo caracteristico (aumento de T3 y disminucion de T4 y rT3). Objetivo. Se presenta el primer caso diagnosticado en España con este sindrome y se revisa la bibliografia publicada, las distintas formas de presentacion clinica, los avances geneticos, el diagnostico diferencial y las perspectivas terapeuticas, y se propone un algoritmo diagnostico. Caso clinico. Varon de 5 años con un cuadro clinico compatible con una enfermedad de Pelizaeus-Merzbacher. La secuenciacion del gen PLP1 no mostro alteraciones. Todos los estudios metabolicos y geneticos realizados fueron normales. Finalmente, un estudio completo del perfil tiroideo revelo alteraciones compatibles con una deficiencia del transportador MCT8. La secuenciacion del gen SLC16A2 (MCT8) mostro una mutacion en el exon 3 y el estudio celular confirmo que esta mutacion cambia las propiedades de la proteina. Conclusiones. En los ultimos años se han multiplicado las publicaciones sobre este sindrome, con la identificacion de mas de 50 familias en el mundo. Es importante conocer este sindrome y sospecharlo, porque el diagnostico es facil, economico y accesible (perfil tiroideo), y, aunque no tiene tratamiento especifico, el diagnostico precoz evita pruebas innecesarias y permite ofrecer consejo genetico a las familias afectadas.

The effects of thyroid hormones (THs) on brain development and function are largely mediated by the control of gene expression. This is achieved by the binding of the genomically active T3 to transcriptionally active nuclear TH receptors (TRs). T3 and the TRs can either induce or repress transcription. In hypothyroidism, the reduction of T3 lowers the expression of a set of genes, the positively regulated genes, and increases the expression of negatively regulated genes. Two mechanisms may account for the effect of hypothyroidism on genes regulated directly by T3: first, the loss of T3 signaling and TR transactivation, and second, an intrinsic activity of the unliganded TRs directly responsible for repression of positive genes and enhancement of negative genes. To analyze the contribution of the TR subtypes α and β, we have measured by RT-PCR the expression of a set of positive and negative genes in the cerebral cortex and the striatum of TR-knockout male and female mice. The results indicate that TRα1 exerts a predominant but not exclusive role in the regulation of positive and negative genes. However, a fraction of the genes analyzed are not or only mildly affected by the total absence of TRs. Furthermore, hypothyroidism has a mild effect on these genes in the absence of TRα1, in agreement with a role of unliganded TRα1 in the effects of hypothyroidism., This work was supported by Grants SAF2011-25608 from the Plan Nacional de IDi, the Ramón Areces Foundation, and the Center for Research on Rare Diseases (Ciberer), Instituto de Salud Carlos III, Madrid, Spain. P.G.-I. is recipient of a Junta de Ampliación de Estudios predoctoral fellowship from the Consejo Superior de Investigaciones Científicas.

et al., Patients with the monocarboxylate transporter 8 (MCT8) deficiency syndrome present with a severe psychomotor retardation and abnormal serum thyroid hormone (TH) levels, consisting of high T3 and low T4 and rT 3. Mice deficient in Mct8 replicate the thyroid phenotype of patients with the MCT8 gene mutations. We analyzed the serum TH levels and action in the cerebral cortex and in the liver during the perinatal period of mice deficient in Mct8 to assess how the thyroid abnormalities of Mct8 deficiency develop and to study the thyroidal status of specific tissues. During perinatal life, the thyroid phenotype of Mct8-deficient mice is different from that of adult mice. They manifest hyperthyroxinemia at embryonic day 18 and postnatal day 0. This perinatal hyperthyroxinemia is accompanied by manifestations of TH excess as evidenced by a relative increase in the expression of genes positively regulated by T3 in both the cerebral cortex and liver. A nincreased tissue accumulation of T4 and T3 and the expression of TH alternative transporters, including Lat1, Lat2, Oatp1c1, and Oatp3a1 in the cortex and Lat2 and Oatp1b2 in the liver, suggested that Mct8 deficiency either directly interferes with tissue efflux ofTHor indirectly activates other transporters to increase TH uptake. This report is the first to identify that the ontogenesis of TH abnormalities in Mct8-deficient mice manifests with TH excess in the perinatal period. Copyright © 2013 by The Endocrine Society., This work was supported in part by Grant DK15070 from the National Institute of Diabetes and Digestive and Kidney Diseases (to S.R.), Grant SAF2011-25608 from the Sherman family, and Centro de Investigación Biomédica en Red Enfermedades Raras Instituto de Salud Carlos III (Madrid, Spain). A.M.D. was supported by National Institutes of Health Grant F32 DK91016, and P.G.-I. was a recipient of a Junta de Ampliación de Estudio fellowship (Consejo Superior de Investigaciones Científicas, Spain).