The Impact of Iodine Deficiency Eradication on Schooling: Evidence from the Introduction of Iodized Salt in Switzerland

This paper examines the impact of salt iodization in Switzerland in the 1920s and 1930s on schooling outcomes. Iodine deficiency in utero causes mental retardation, and correcting the deficiency is expected to increase the productivity of a population by increasing its cognitive ability. The exogenous increase in cognitive ability brought about by the iodization program is also useful in the context of disentangling the effects of innate ability and education in later-life outcomes. I identify the impact of iodization in three ways: first, in a differences-in-differences framework, I exploit geographic variation in iodine deficiency, as well as the fact that the nationwide campaign to decrease iodine deficiency began in 1922. Second, I use spatial and temporal variation in the introduction of iodized salt across Swiss cantons, and examine whether the level of iodized salt sales at the time of one’s birth affected one’s educational attainment. Third, I employ a fuzzy regression discontinuity design and use jumps in sales of iodized salt across Swiss cantons to identify the effect of iodization, by comparing outcomes for those born right before and right after these sudden changes in the treatment environment. These approaches indicate that the eradication of iodine deficiency in previously deficient areas increased the schooling of the population significantly. The effects are larger for females than for males, which is consistent with medical evidence showing that women are more likely to be affected by iodine deficiency disorders than men.

The Economic Effects of Micronutrient Deficiency: Evidence from Salt Iodization in the United States

Iodine deficiency is the leading cause of preventable mental retardation in the world today. Iodine deficiency was common in the developed world until the introduction of iodized salt in the 1920’s. The incidence of iodine deficiency is connected to low iodine levels in the soil and water. We examine the impact of salt iodization in the US by taking advantage of this natural geographic variation. Areas with high pre-treatment levels of iodine deficiency provide a treatment group which we can compare to a control group of low iodine deficiency areas. In the US, salt was iodized over a very short period of time around 1924. We use previously unused data collected during WWI and WWII to compare outcomes of cohorts born before and after iodization, in localities that were naturally poor and rich in iodine. We find evidence of the beneficial effects of iodization on the cognitive abilities of the cohorts exposed to it.

Sumoylated PPARalpha mediates sex-specific gene repression and protects the liver from estrogen-induced toxicity in mice.

As most metabolic studies are conducted in male animals, understanding the sex specificity of the underlying molecular pathways has been broadly neglected; for example, whether PPARs elicit sex-dependent responses has not been determined. Here we show that in mice, PPARalpha has broad female-dependent repressive actions on hepatic genes involved in steroid metabolism and immunity. In male mice, this effect was reproduced by the administration of a synthetic PPARalpha ligand. Using the steroid oxysterol 7alpha-hydroxylase cytochrome P4507b1 (Cyp7b1) gene as a model, we elucidated the molecular mechanism of this sex-specific PPARalpha-dependent repression. Initial sumoylation of the ligand-binding domain of PPARalpha triggered the interaction of PPARalpha with GA-binding protein alpha (GABPalpha) bound to the target Cyp7b1 promoter. Histone deacetylase and DNA and histone methylases were then recruited, and the adjacent Sp1-binding site and histones were methylated. These events resulted in loss of Sp1-stimulated expression and thus downregulation of Cyp7b1. Physiologically, this repression conferred on female mice protection against estrogen-induced intrahepatic cholestasis, the most common hepatic disease during pregnancy, suggesting a therapeutic target for prevention of this disease.

Role of the c-Jun N-terminal Kinase signaling in pancreatic β-cells

L'insuline est une hormone qui diminue la concentration de sucre dans le sang et qui est produite par la cellule β du pancréas. Un défaut de production de cette hormone est une des causes principales du diabète. Cette perte de production d'insuline est la conséquence à la fois, de la réduction du nombre de cellules β et du mauvais fonctionnement des cellules β restantes. L'inflammation, en activant la voie de signalisation «c-Jun N-terminal Kinase» (JNK) contribue au déclin de ces cellules. Cette voie de signalisation est activée par des protéines telles que des kinases qui reçoivent le signal de stress. Dans ce travail de thèse nous nous sommes intéressés à étudier le rôle de «Dual leucine zipper bearing kinase» (DLK) comme protéine capable de relayer le stress inflammatoire vers l'activation de la voie JNK dans les cellules β-pancréatiques. Nous montrons que DLK est présente dans les cellules β-pancréatiques et qu'elle agit effectivement comme un activateur de la voie de signalisation de JNK. En outre, DLK joue un rôle clé dans le contrôle de l'expression de l'insuline, de la sécrétion de l'insuline en réponse au glucose et au maintien de la survie des cellules β. Si l'expression de cette protéine diminue, la cellule produit moins d'insuline et sera plus sensible à la mort en réponse au stress inflammatoire. A l'inverse si l'expression de DLK est augmentée, la cellule β produit et secrète plus d'insuline. Des variations de l'expression de DLK sont par ailleurs, associées à l'état de santé de la cellule β. Chez la ratte en gestation ou la souris obèse, dans lesquelles la cellule β produit plus d'insuline, l'expression de DLK est augmentée. En revanche dans les cellules β des patients diabétiques, l'expression de DLK est diminuée par rapport aux cellules non malades. En résumé, DLK est nécessaire pour le bon fonctionnement de la cellule β-pancréatique et son expression corrèle avec le degré de santé des cellules, faisant que cette protéine pourrait être une cible thérapeutique potentiel. Les cellules β-pancréatiques ont la capacité de réguler la sécrétion d'insuline en s'adaptant précisément au stimulus et à la glycémie. La fonction de la cellule β est cruciale dans l'homéostasie du glucose puisque sa dysfonction et sa mort mènent au développement des diabètes de type 1 et 2. De nombreuses études suggèrent que l'inflammation pourrait avoir un rôle dans la dysfonction et la destruction de ces cellules dans le diabète de type 2. L'excès chronique de cytokines proinflammatoires accélère le dysfonctionnement de la cellule β pancréatique par un mécanisme qui implique la voie de signalisation «c-Jun N-terminal Kinase» (JNK). L'activation de cette voie est organisée par des protéines d'échafaudages. Elle se fait par trois étapes successives de phosphorylation impliquant une «Mitogen Activated Protein Kinase Kinase Kinase» (MAP3K), une MAP2K et JNK. Dans ce travail de thèse nous montrons l'expression abondante et spécifique de la MAP3K «Dual Leucine Zipper Bearing Kinase» (DLK) dans les cellules β pancréatiques. Cela est la conséquence de l'absence du répresseur transcriptionnel «Repressor Element 1 Silencing Transcription». Nous montrons également que DLK régule l'activation de JNK et qu'il s'avère nécessaire pour la fonction et la survie de la cellule β pancréatique par un mécanisme impliquant le facteur de transcription PDX-1. L'invalidation de l'expression de DLK diminue l'expression de l'insuline et potentialise l'apoptose induite par des cytokines proinflammatoires. A l'inverse, la surexpression de DLK augmente l'expression et la sécrétion d'insuline induites par le glucose. Par conséquent des niveaux d'expression appropriés de DLK sont déterminants pour la fonction et la survie de la cellule β pancréatique. L'obésité et la grossesse sont caractérisées par une hyperinsulinémie qui résulte d'une augmentation de la production et de la sécrétion de l'insuline. L'expression de DLK est augmentée dans des îlots de rattes gestantes et des souris obèses comparés à leurs contrôles respectifs. A l'inverse, dans des sujets diabétiques, l'expression de DLK est diminuée. Ensemble ces résultats montrent l'importance de DLK dans l'adaptation des îlots par un mécanisme qui pourrait impliquer la voie de signalisation de JNK. Des défauts dans cette voie régulée par DLK pourraient contribuer au dysfonctionnement et la mort de la cellule β pancréatique et par conséquent au développement du diabète. L'étude détaillée du mécanisme par lequel DLK active la voie de signalisation JNK et régule la fonction de la cellule β pancréatique pourrait ouvrir la voie des nouvelles thérapies ciblant l'amélioration de la fonction de la cellule β dans le diabète. - Pancreatic β-cells are evidently plastic in their ability to regulate insulin secretion. The quantity of insulin released by these cells varies according to the stimulus, and the prevailing glucose concentration, β-cell function is pivotal in glucose homeostasis, as their dysfunction, and death can lead to development of type 1 and type 2 diabetes. There are numerous reports so far underlying the role of inflammation in dysfunction, and destruction of β-cells, in both type 1 and type 2 diabetes. Chronic excess of pro¬inflammatory cytokines promotes a β-cell decline, via induction of the c-Jun N-terminal Kinase (JNK) pathway. The activation of the JNK pathway is organized by a scaffold protein-mediated module in which, a three-step phosphorylation cascade occurs. The latter includes, Mitogen activated protein kinase kinase kinase (MAP3K), MAP2K and JNK. In this thesis, we unveil that the MAP3K Dual Leucine Zipper Bearing Kinase (DLK) is selectively, and highly expressed in pancreatic β-cells, as the result from the absence of the transcriptional repressor named, Repressor Element 1 Silencing Transcription (REST). We show that DLK regulates activation of JNK, and is required for β-cell function and survival by modulating the PDX-1 transcription factor. Silencing of DLK expression diminishes insulin expression, and potentiated cytokine-mediated apoptosis. Conversely, overexpression of DLK increased insulin expression, and glucose-induced insulin secretion. Therefore, an appropriate level of DLK is critical for β-cell function and survival. Obesity and pregnancy are characterized by hyperinsulinemia resulting from an increased production and secretion of insulin. In isolated islets of pregnant rats, and obese mice, the expression of DLK was elevated when compared to their respective controls. However, decreased expression of DLK was observed in islets of individuals with diabetes. Taken together, we highlight the importance of DLK in islet adaptation, and describe a mechanism that may involve the JNK signaling. Deficiency in the JNK pathway regulated by DLK may contribute to β-cell failure and death, and thereby development of diabetes. Unraveling the mechanism whereby DLK activates the JNK pathway, and β-cell function, may pave the way for the design of novel therapies, aiming to improve β-cell function and survival in diabetes in general.

The anabolic androgenic steroid fluoxymesterone inhibits 11β-hydroxysteroid dehydrogenase 2-dependent glucocorticoid inactivation.

Anabolic androgenic steroids (AAS) are testosterone derivatives used either clinically, in elite sports, or for body shaping with the goal to increase muscle size and strength. Clinically developed compounds and nonclinically tested designer steroids often marketed as food supplements are widely used. Despite the considerable evidence for various adverse effects of AAS use, the underlying molecular mechanisms are insufficiently understood. Here, we investigated whether some AAS, as a result of a lack of target selectivity, might inhibit 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2)-dependent inactivation of glucocorticoids. Using recombinant human 11β-HSD2, we observed inhibitory effects for several AAS. Whereas oxymetholone, oxymesterone, danazol, and testosterone showed medium inhibitory potential, fluoxymesterone was a potent inhibitor of human 11β-HSD2 (half-maximal inhibitory concentration [IC(50)] of 60-100nM in cell lysates; IC(50) of 160nM in intact SW-620, and 530nM in MCF-7 cells). Measurements with rat kidney microsomes and lysates of cells expressing recombinant mouse 11β-HSD2 revealed much weaker inhibition by the AAS tested, indicating that the adverse effects of AAS-dependent 11β-HSD2 inhibition cannot be investigated in rats and mice. Furthermore, we provide evidence that fluoxymesterone is metabolized to 11-oxofluoxymesterone by human 11β-HSD2. Structural modeling revealed similar binding modes for fluoxymesterone and cortisol, supporting a competitive mode of inhibition of 11β-HSD2-dependent cortisol oxidation by this AAS. No direct modulation of mineralocorticoid receptor (MR) function was observed. Thus, 11β-HSD2 inhibition by fluoxymesterone may cause cortisol-induced MR activation, thereby leading to electrolyte disturbances and contributing to the development of hypertension and cardiovascular disease.

Superfamily of steroid nuclear receptors: positive and negative regulators of gene expression.

The nuclear hormone receptor superfamily is characterized by an impressive functional diversity of its members despite a remarkable overall structural unity. A variety of ligands bind specifically to them and these receptors control gene networks that have profound effects on growth, development, and homeostasis. The ligand-receptor complexes recognize transcriptional enhancer DNA sequences, the hormone response elements, resulting in induction or repression of gene activity. The similarity between all these hormone response enhancer elements, as well as between the receptors themselves, indicates a conserved general strategy for the hormonal control of transcription by steroids. The activated receptors bind to responsive promoters and most likely mediate the assembly of stage- and tissue-specific transcription factor complexes that stimulate or inhibit gene expression.

The management of iron deficiency in inflammatory bowel disease--an online tool developed by the RAND/UCLA appropriateness method.

BACKGROUND: Iron deficiency is a common and undertreated problem in inflammatory bowel disease (IBD). AIM: To develop an online tool to support treatment choice at the patient-specific level. METHODS: Using the RAND/UCLA Appropriateness Method (RUAM), a European expert panel assessed the appropriateness of treatment regimens for a variety of clinical scenarios in patients with non-anaemic iron deficiency (NAID) and iron deficiency anaemia (IDA). Treatment options included adjustment of IBD medication only, oral iron supplementation, high-/low-dose intravenous (IV) regimens, IV iron plus erythropoietin-stimulating agent (ESA), and blood transfusion. The panel process consisted of two individual rating rounds (1148 treatment indications; 9-point scale) and three plenary discussion meetings. RESULTS: The panel reached agreement on 71% of treatment indications. 'No treatment' was never considered appropriate, and repeat treatment after previous failure was generally discouraged. For 98% of scenarios, at least one treatment was appropriate. Adjustment of IBD medication was deemed appropriate in all patients with active disease. Use of oral iron was mainly considered an option in NAID and mildly anaemic patients without disease activity. IV regimens were often judged appropriate, with high-dose IV iron being the preferred option in 77% of IDA scenarios. Blood transfusion and IV+ESA were indicated in exceptional cases only. CONCLUSIONS: The RUAM revealed high agreement amongst experts on the management of iron deficiency in patients with IBD. High-dose IV iron was more often considered appropriate than other options. To facilitate dissemination of the recommendations, panel outcomes were embedded in an online tool, accessible via http://ferroscope.com/.

Severe and steroid-resistant Crohn's disease.

Patients with moderate to severe disease and patients with steroid-refractory or steroid-dependent disease differ in their management, as the latter groups usually include patients with less acute situations. Systemic corticosteroids represent the mainstay of the management of moderate to severe disease and remain the first-line therapy in this setting. Infliximab is the choice alternative for patients who do not respond to steroids or in whom steroids are contraindicated. Purine analogues, methotrexate and infliximab have shown efficacy in achieving steroid-free remission in patients with steroid-refractory or -dependent disease. Other fast-acting immunosuppressors showed little benefit. Surgery may be indicated in this setting. Nataluzimab may prove useful in patients refractory to infliximab.

Human GnRH deficiency: a unique disease model to unravel the ontogeny of GnRH neurons.

Evolutionary survival of a species is largely a function of its reproductive fitness. In mammals, a sparsely populated and widely dispersed network of hypothalamic neurons, the gonadotropin-releasing hormone (GnRH) neurons, serve as the pilot light of reproduction via coordinated secretion of GnRH. Since it first description, human GnRH deficiency has been recognized both clinically and genetically as a heterogeneous disease. A spectrum of different reproductive phenotypes comprised of congenital GnRH deficiency with anosmia (Kallmann syndrome), congenital GnRH deficiency with normal olfaction (normosmic idiopathic hypogonadotropic hypogonadism), and adult-onset hypogonadotropic hypogonadism has been described. In the last two decades, several genes and pathways which govern GnRH ontogeny have been discovered by studying humans with GnRH deficiency. More importantly, detailed study of these patients has highlighted the emerging theme of oligogenicity and genotypic synergism, and also expanded the phenotypic diversity with the documentation of reversal of GnRH deficiency later in adulthood in some patients. The underlying genetic defect has also helped understand the associated nonreproductive phenotypes seen in some of these patients. These insights now provide practicing clinicians with targeted genetic diagnostic strategies and also impact on clinical management.

Reduced Prostasin (CAP1/PRSS8) Activity Eliminates HAI-1 and HAI-2 Deficiency-Associated Developmental Defects by Preventing Matriptase Activation.

Loss of either hepatocyte growth factor activator inhibitor (HAI)-1 or -2 is associated with embryonic lethality in mice, which can be rescued by the simultaneous inactivation of the membrane-anchored serine protease, matriptase, thereby demonstrating that a matriptase-dependent proteolytic pathway is a critical developmental target for both protease inhibitors. Here, we performed a genetic epistasis analysis to identify additional components of this pathway by generating mice with combined deficiency in either HAI-1 or HAI-2, along with genes encoding developmentally co-expressed candidate matriptase targets, and screening for the rescue of embryonic development. Hypomorphic mutations in Prss8, encoding the GPI-anchored serine protease, prostasin (CAP1, PRSS8), restored placentation and normal development of HAI-1-deficient embryos and prevented early embryonic lethality, mid-gestation lethality due to placental labyrinth failure, and neural tube defects in HAI-2-deficient embryos. Inactivation of genes encoding c-Met, protease-activated receptor-2 (PAR-2), or the epithelial sodium channel (ENaC) alpha subunit all failed to rescue embryonic lethality, suggesting that deregulated matriptase-prostasin activity causes developmental failure independent of aberrant c-Met and PAR-2 signaling or impaired epithelial sodium transport. Furthermore, phenotypic analysis of PAR-1 and matriptase double-deficient embryos suggests that the protease may not be critical for focal proteolytic activation of PAR-2 during neural tube closure. Paradoxically, although matriptase auto-activates and is a well-established upstream epidermal activator of prostasin, biochemical analysis of matriptase- and prostasin-deficient placental tissues revealed a requirement of prostasin for conversion of the matriptase zymogen to active matriptase, whereas prostasin zymogen activation was matriptase-independent.

The effectiveness and safety of rescue treatments in 108 patients with steroid-refractory ulcerative colitis with sequential rescue therapies in a subgroup of patients.

BACKGROUND: Among patients with steroid-refractory ulcerative colitis (UC) in whom a first rescue therapy has failed, a second line salvage treatment can be considered to avoid colectomy. AIM: To evaluate the efficacy and safety of second or third line rescue therapy over a one-year period. METHODS: Response to single or sequential rescue treatments with infliximab (5mg/kg intravenously (iv) at week 0, 2, 6 and then every 8weeks), ciclosporin (iv 2mg/kg/daily and then oral 5mg/kg/daily) or tacrolimus (0.05mg/kg divided in 2 doses) in steroid-refractory moderate to severe UC patients from 7 Swiss and 1 Serbian tertiary IBD centers was retrospectively studied. The primary endpoint was the one year colectomy rate. RESULTS: 60% of patients responded to the first rescue therapy, 10% went to colectomy and 30% non-responders were switched to a 2(nd) line rescue treatment. 66% of patients responded to the 2(nd) line treatment whereas 34% failed, of which 15% went to colectomy and 19% received a 3(rd) line rescue treatment. Among those, 50% patients went to colectomy. Overall colectomy rate of the whole cohort was 18%. Steroid-free remission rate was 39%. The adverse event rates were 33%, 37.5% and 30% for the first, second and third line treatment respectively. CONCLUSION: Our data show that medical intervention even with 2(nd) and 3(rd) rescue treatments decreased colectomy frequency within one year of follow up. A longer follow-up will be necessary to investigate whether sequential therapy will only postpone colectomy and what percentage of patients will remain in long-term remission.

De CATMARC a MARC 21: actuacions del Consorci de Biblioteques Universitàries de Catalunya

Aquesta comunicació descriu el procés de preparació dels registres bibliogràfics del Catàleg Col·lectiu de les Universitats de Catalunya (CCUC) i dels catàlegs locals que el conformen, per al canvi del format CATMARC al format MARC 21.

Endogenous steroid profiling in the athlete biological passport.

The Athlete Biological Passport (ABP) is an individual electronic document that collects data regarding a specific athlete that is useful in differentiating between natural physiologic variations of selected biomarkers and deviations caused by artificial manipulations. A subsidiary of the endocrine module of the ABP, that which here is called Athlete Steroidal Passport (ASP), collects data on markers of an altered metabolism of endogenous steroidal hormones measured in urine samples. The ASP aims to identify not only doping with anabolic-androgenic steroids, but also most indirect steroid doping strategies such as doping with estrogen receptor antagonists and aromatase inhibitors. Development of specific markers of steroid doping, use of the athlete's previous measurements to define individual limits, with the athlete becoming his or her own reference, the inclusion of heterogeneous factors such as the UDPglucuronosyltransferase B17 genotype of the athlete, the knowledge of potentially confounding effects such as heavy alcohol consumption, the development of an external quality control system to control analytical uncertainty, and finally the use of Bayesian inferential methods to evaluate the value of indirect evidence have made the ASP a valuable alternative to deter steroid doping in elite sports. The ASP can be used to target athletes for gas chromatography/combustion/ isotope ratio mass spectrometry (GC/C/IRMS) testing, to withdraw temporarily the athlete from competing when an abnormality has been detected, and ultimately to lead to an antidoping infraction if that abnormality cannot be explained by a medical condition. Although the ASP has been developed primarily to ensure fairness in elite sports, its application in endocrinology for clinical purposes is straightforward in an evidence-based medicine paradigm.