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

Further clinical and molecular characterization of an XLID syndrome associated with BRWD3 variants, a gene implicated in the leukemia-related JAK-STAT pathway

Background: Since the first description of a BRWD3-associated nonsydromic intellectual disability (ID) disorder in 2007, 21 additional families have been reported in the literature.Methods: Using exome sequencing (ES) and international data sharing, we identified 14 additional unrelated individuals with pathogenic BRWD3 variants (12 males and 2 females, including one with skewed X -inactiva-tion). We reviewed the 31 previously published cases in the literature with clinical data available, and describe the collective phenotypes of 43 males and 2 females, with 33 different BRWD3 variants.Results: The most common features in males (excluding one patient with a mosaic variant) included ID (39/39 males), speech delay (24/25 males), postnatal macrocephaly (28/35 males) with prominent forehead (18/25 males) and large ears (14/26 males), and obesity (12/27 males). Both females presented with macrocephaly, speech delay, and epilepsy, while epilepsy was only observed in 4/41 males. Among the 28 variants with available segregation reported, 19 were inherited from unaffected mothers and 9 were de novo.Conclusion: This study demonstrates that the BRWD3-related phenotypes are largely non-specific, leading to difficulty in clinical recognition of this disorder. A genotype-first approach, however, allows for the more effi-cient diagnosis of the BRWD3-related nonsyndromic ID. The refined clinical features presented here may provide additional diagnostic assistance for reverse phenotyping efforts.Genetics of disease, diagnosis and treatmen

A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants

Bi-allelic disruptive variants (nonsense, frameshift, and splicing variants) in KDM5B have been identified as causative for autosomal recessive intellectual developmental disorder type 65. In contrast, dominant variants, usually disruptive as well, have been more difficult to implicate in a specific phenotype, since some of them have been found in unaffected controls or relatives. Here, we describe individuals with likely pathogenic variants in KDM5B, including eight individuals with dominant missense variants. This study is a retrospective case series of 21 individuals with variants in KDM5B. We performed deep phenotyping and collected the clinical information and molecular data of these individuals’ family members. We compared the phenotypes according to variant type and to those previously described in the literature. The most common features were developmental delay, impaired intellectual development, behavioral problems, autistic behaviors, sleep disorders, facial dysmorphism, and overgrowth. DD, ASD behaviors, and sleep disorders were more common in individuals with dominant disruptive KDM5B variants, while individuals with dominant missense variants presented more frequently with renal and skin anomalies. This study extends our understanding of the KDM5B-related neurodevelopmental disorder and suggests the pathogenicity of certain dominant KDM5B missense variants

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

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

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