Aktuelle Herausforderungen in der Therapie des Typ-1-Diabetes beim Kind

Das 1921 entdeckte Insulin wurde 1922 erstmals als Therapie für Typ-1-Diabetes eingeführt. Hundert Jahre später wird es immer noch als einzige medikamentöse Behandlung eingesetzt. Die jüngsten Fortschritte haben zu einer erheblichen Optimierung der Stoffwechselkontrolle beigetragen. Einleitung Typ-1-Diabetes (T1D) ist eine der häufigsten chronischen Erkrankungen bei Kindern, mit einer jährlichen Inzidenzzunahme von 3% [1]. Die Ätiologie des T1D ist unbekannt, aber eine Dysregulation der Autoimmunität, dokumentiert durch die Zirkulation von Autoantikörpern, sowie eine genetische Prädisposition sind ursächlich beteiligt. Das Risiko, an T1D zu erkranken, beträgt bei Kindern 0,4%; gibt es bereits an T1D-erkrankte Familienangehörige, steigt das Risiko um das Zehnfache. Neueste Daten weisen auf einen deutlichen Anstieg der weltweiten Inzidenz während der Corona-Pandemie hin [2–5]. Ziel dieses Beitrags ist es, die neuesten Entwicklungen und aktuellen Herausforderungen bei der Behandlung des T1D bei Kindern darzustellen

No Exit? Withdrawal Rights and the Law of Corporate Reorganizations

Bankruptcy scholarship is largely a debate about the comparative merits of a mandatory regime on one hand and bankruptcy by free design on the other. By the standard account, the current law of corporate reorganization is mandatory. Various rules that cannot be avoided ensure that investors’ actions are limited and they do not exercise their rights against specialized assets in a way that destroys the value of a business as a whole. These rules solve collective action problems and reduce the risk of bargaining failure. But there are costs to a mandatory regime. In particular, investors cannot design their rights to achieve optimal monitoring as they could in a system of bankruptcy by free design. This Article suggests that the academic debate has missed a fundamental feature of the law. Bankruptcy operates on legal entities, not on firms in the economic sense. For this reason, sophisticated investors do not face a mandatory regime at all. The ability of investors to place assets in separate entities gives them the ability to create specific withdrawal rights in the event the firm encounters financial distress. There is nothing mandatory about rules like the automatic stay when assets can be partitioned off into legal entities that are beyond the reach of the bankruptcy judge. Thus, by partitioning assets of one economic enterprise into different legal entities, investors can create a tailored bankruptcy regime. In this way, legal entities serve as building blocks that can be combined to create specific and varied but transparent investor withdrawal rights. This regime of tailored bankruptcy has been unrecognized and underappreciated and may be preferable to both mandatory and free design regimes. By allowing a limited number of investors to opt out of bankruptcy in a particular, discrete, and visible way, investors as a group may be able to both limit the risk of bargaining failure and at the same time enjoy the disciplining effect that a withdrawal right brings with it

De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits:report of 25 new individuals and review of the literature

TBR1, a T-box transcription factor expressed in the cerebral cortex, regulates the expression of several candidate genes for autism spectrum disorders (ASD). Although TBR1 has been reported as a high-confidence risk gene for ASD and intellectual disability (ID) in functional and clinical reports since 2011, TBR1 has only recently been recorded as a human disease gene in the OMIM database. Currently, the neurodevelopmental disorders and structural brain anomalies associated with TBR1 variants are not well characterized. Through international data sharing, we collected data from 25 unreported individuals and compared them with data from the literature. We evaluated structural brain anomalies in seven individuals by analysis of MRI images, and compared these with anomalies observed in TBR1 mutant mice. The phenotype included ID in all individuals, associated to autistic traits in 76% of them. No recognizable facial phenotype could be identified. MRI analysis revealed a reduction of the anterior commissure and suggested new features including dysplastic hippocampus and subtle neocortical dysgenesis. This report supports the role of TBR1 in ID associated with autistic traits and suggests new structural brain malformations in humans. We hope this work will help geneticists to interpret TBR1 variants and diagnose ASD probands

West Nile virus and its emergence in the United States of America

Zoonotic West Nile virus (WNV) circulates in natural transmission cycles involving certain mosquitoes and birds, horses, humans, and a range of other vertebrates are incidental hosts. Clinical infections in humans can range in severity from uncomplicated WNV fever to fatal meningoencephalitis. Since its introduction to the Western Hemisphere in 1999, WNV had spread across North America, Central and South America and the Caribbean, although the vast majority of severe human cases have occurred in the United States of America (USA) and Canada. By 2002–2003, the WNV outbreaks have involved thousands of patients causing severe neurologic disease (meningoencephalitis and poliomyelitis-like syndrome) and hundreds of associated fatalities in USA. The purpose of this review is to present recent information on the epidemiology and pathogenicity of WNV since its emergence in North America

Strategies to modulate the pancreatic beta-cell mass to prevent type 1 diabetes

Type 1 diabetes (T1DM) results from the autoimmune destruction of most insulin-producing pancreatic beta-cells. For affected patients, diagnosis of T1DM represents the beginning of a life-long treatment with insulin. Insulin permits survival but mean life expectancy of diabetic patients remains shorter than in controls and the treatment has a significant impact on the patients' quality of life. There is urgent need for strategies aiming at preventing the destruction of the pancreatic beta-cells or even at restoring a functional beta-cell mass after diagnosis of the disease. The aim of this thesis is to review the current knowledge about the risk factors for T1DM, as well as about the molecular pathways leading to the destruction of the insulin-producing beta-cells. Four articles are presented. They focus on the identification of mechanisms permitting either the modulation of the beta-cell mass or the modulation of the beta-cell sensitivity to cytokines such as interleukin 1β (IL-1β), tumor necrosis factor α (TNFα) and interferon γ (IFNγ), all of which being implicated in the beta-cell destruction in a context of T1DM. The work underlying this thesis opens the basis for further studies aiming at dissecting the mechanisms by which pharmacological agonists may modulate the resistance of pancreatic beta-cells against auto-immune attacks. Moreover, since beta-cell apoptosis in a context of type 2 diabetes (T2DM) shares common pathways with cell death observed in T1DM, it would be important to determine whether the protective mechanisms identified in this thesis may also apply to glucotoxicity, lipotoxicity and low grade inflammation, as seen in T2DM

Différencier les effets des connexines et de l'hormone de croissance sur la croissance des cellules bêta pancréatiques

Les diabètes de type 1 et de type 2 résultent d'une diminution de la masse cellulaire bêta fonctionnelle. Dans cette thèse, nous avons mis en évidence le fait que la masse cellulaire bêta pouvait être modifiée en modulant le niveau d'expression de certaines protéines exprimée dans ces cellules. En effet, des souris transgéniques sur-exprimant la connexion 36 (Cx36) en combinaison avec l'hormone de croissance humaine (hGH) présentaient une masse cellulaire bêta, ainsi qu'une taille d'îlots augmentées. A l'inverse, des souris n'exprimant que l'hGH ou ne sur-exprimant que la Cx36 ne montraient pas d'augmentation de la masse cellulaire, indiquant une synergie entre la Cx36 et l'hGH. Le mécanisme aboutissant à une modification, soit de la production, soit de la mort des cellules bêta n'est pas encore identifé. Cette thèse ouvre des perspectives excitantes quant au traitement ou à la prévention des diabètes de type 1 ou 2

Association Between Lactates, Blood Glucose, and Systemic Oxygen Delivery in Children After Cardiopulmonary Bypass

Objective: Lactate is often used as a surrogate marker of inappropriate oxygen delivery. It has been shown that hyperlactatemia is associated with worse clinical outcome in children after cardiac surgery. The purpose of this study is to evaluate the association of hyperlactatemia, low systemic oxygen delivery, and hyperglycemia, in children admitted to the pediatric critical care unit after cardiopulmonary bypass. Design: Secondary analysis of an observational cohort study. Setting: Tertiary pediatric critical care unit (PICU). Patients: Ninety-three patients, aged 6 months to 16 years, undergoing cardiac surgery with cardiopulmonary bypass. Interventions: None. Measurements and Main Results: Metabolic tests (blood glucose, lactate, lactate/pyruvate ratio, and ketones) and oxygen extraction (SaO2-SvO2) were performed before anesthesia, at the end of cardiopulmonary bypass, at PICU admission, and at 4 and 12 h after PICU admission. Four hours after PICU admission, 62% of the patients had hyperlactatemia (>2 mmol/L), of whom 55% had normal oxygen extraction (SaO2-SvO2 < 30%). There was no correlation between lactate and oxygen extraction (R = -0.09, p = 0.41) but there was a moderate correlation between lactate and blood glucose (R = 0.55, p < 0.001). Using a logistic regression model, hyperlactatemia at 4 h after PICU admission was independently associated with hyperglycemia (p = 0.007) and lactate/pyruvate ratio (p = 0.007) at the same timepoint, as well as with lactate at PICU admission (p = 0.002), but not with weight (p = 0.45), severity of the cardiac lesion (p = 0.85), duration of bypass (p = 0.16), or oxygen extraction, as evaluated by SaO2-SvO2 (p = 0.54). At 12 h after PICU admission, there was a very week correlation between lactate and blood glucose (R = 0.27, p = 0.007), but none between lactate and oxygen extraction (R = 0.13, p = 0.20). Conclusion: In children after cardiopulmonary bypass, lactates are not correlated with higher oxygen extraction, but are correlated with hyperglycemia, at both 4 and 12 h after PICU admission. Future research is warranted to better define this relationship

Modeling intrauterine growth retardation in rodents: Impact on pancreas development and glucose homeostasis

Fetal adverse environment, such as insufficient maternal nutrition, placental insufficiency and stress, alters organ development and leads to poor fetal growth, also called intrauterine growth retardation (IUGR). IUGR is associated with an increased risk of perinatal mortality and morbidity as well as late-onset metabolic diseases, such as obesity, diabetes and hypertension in adulthood. In the rodent model, IUGR can be induced by fetal caloric restriction, fetal protein restriction, by exposure to high levels of glucocorticoids or by restricted placental blood supply. Such experimental IUGR models show a decreased beta cell mass and lower pancreatic insulin content. Recent research has provided an insight into the mechanisms responsible for the loss of beta cells. Here we review models that give further details about the molecular determinants of fetal and postnatal pancreatic islet development that are required to understand the consequences of fetal insults

Diabetic Striatopathy in Childhood: A Case Report

Diabetic striatopathy is a well-known complication of diabetes in adults. To our knowledge, only 2 cases have been reported in children. We here report the case of a teenager in whom diabetic striatopathy was revealed by the subacute appearance of hemichorea-hemiballism in the context of weight loss, polyuria, and polydipsia. Glycemia control allowed rapid clinical recovery despite established striatal lesions documented on MRI. We also discuss current hypotheses about pathophysiological processes underlying this entity