ORCID Profile
0000-0003-0896-9943
Current Organisations
University Hospital Leipzig
,
Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig
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Publications
Elevated transaminases potentiate the risk for emerging dysglycemia in children with overweight and obesity.
Publisher: Wiley
Date: 21-06-2021
DOI: 10.1111/IJPO.12822
Abstract: There is evidence that nonalcoholic fatty liver disease (NAFLD) increases the risk for dysglycemia in children in cross-sectional studies. However, the extent to which NAFLD may confer the risk for dysglycemia in longitudinal studies remains uncertain. We investigated whether elevated levels of alanine aminotransferase (ALT) as a proxy for NAFLD can serve as a predictor for future dysglycemia among children. We performed survival analysis up to 11 years of follow-up on longitudinal data of 510 children with overweight and obesity from the Leipzig Childhood Cohort. Children with overweight/obesity and elevated ALT values had a more than 2-fold increased risk (hazard ratio 2.59, 95% confidence interval 1.49 to 4.50 P < 0.01) for future dysglycemia independent of age, sex and BMI-SDS. Elevated transaminases are an early predictor for glycemic deterioration. Hence, NAFLD should further be addressed as a risk factor and therapeutic target for the early prevention of type 2 diabetes.
Short stature syndromes—potentially life-threatening diseases
Publisher: Springer Science and Business Media LLC
Date: 10-2020
DOI: 10.1007/S00112-020-01030-7
Abstract: Es gibt viele Ursachen für einen Kleinwuchs. Kleinwuchs in Kombination mit einer intrauterinen Wachstumsretardierung (IUGR), einer Entwicklungsverzögerung und/oder ungewöhnlichen Stigmata sollte immer auch an eine syndromale Ursache denken lassen. Diese Arbeit soll für Kleinwuchssyndrome sensibilisieren, deren Diagnose aufgrund der potenziell lebensbedrohlichen Folgen möglichst frühzeitig gestellt werden sollte. Die vorliegende Arbeit wurde auf Basis klinikinterner Fallberichte vor dem Hintergrund der aktuellen Literatur erstellt. Das PTEN-Hamartom-Tumor-Syndrom (PHTS), das Bloom-Syndrom (BS), der mikrozephale osteodysplastische primordiale Kleinwuchs Typ II (MOPD-II-Syndrom) sowie das Ligase-IV-Syndrom (Lig4-Syndrom) sind seltene Kleinwuchssyndrome mit potenziell letalem Ausgang. Gemeinsame Merkmale liegen in einer Abweichung des Kopfumfangs (KU) und einer Entwicklungsverzögerung. Die Verdachtsdiagnose wird molekulargenetisch gesichert. Die Behandlung erfolgt in erster Linie symptomorientiert, für das PHTS und das Ligase-IV-Syndrom existieren darüber hinaus bereits kausale Therapieansätze. Für alle Syndrome gibt es Empfehlungen im Hinblick auf gezielte Vorsorgeuntersuchungen. Bei entsprechenden Hinweisen auf einen syndromalen Kleinwuchs sollte zügig eine molekulargenetisch gestützte Diagnostik erfolgen, um rechtzeitig geeignete Therapieoptionen und Vorsorgeprogramme initiieren zu können.
Fluorescent tags influence the enzymatic activity and subcellular localization of procaspase-1
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.CLIM.2015.05.011
Abstract: Subcellular localization studies and life cell imaging approaches usually benefit from fusion-reporter proteins, such as enhanced green fluorescent protein (EGFP) and mCherry to the proteins of interest. However, such manipulations have several risks, including protein misfolding, altered protein shuttling, or functional impairment when compared to the wild-type proteins. Here, we demonstrate altered subcellular distribution and function of the pro-inflammatory enzyme procaspase-1 as a result of fusion with the reporter protein mCherry. Our observations are of central importance to further investigations of subcellular behavior and possible protein-protein interactions of naturally occurring genetic variants of human procaspase-1 which have recently been linked to autoinflammatory disorders.
Handlungsempfehlung nach der S3-Leitlinie Therapie und Prävention der Adipositas im Kindes- und Jugendalter
Publisher: Springer Science and Business Media LLC
Date: 19-05-2020
Identification of a novel leptin receptor (LEPR) variant and proof of functional relevance directing treatment decisions in patients with morbid obesity
Publisher: Elsevier BV
Date: 03-2021
DOI: 10.1016/J.METABOL.2020.154438
Abstract: Deficiency in the leptin-leptin receptor (LEPR) axis leads to severe, and potentially treatable, obesity in humans. To guide clinical decision-making, the functional relevance of variants in the LEPR gene needs to be carefully investigated. We characterized the functional impact of LEPR variants identified in two patients with severe early-onset obesity (1: compound heterozygous for the novel variant p.Tyr411del and p.Trp664Arg 2: heterozygous for p.Arg612His) by investigating leptin-mediated signaling, leptin binding, receptor expression on cell surfaces, and receptor dimerization and activation for either wild-type and/or mutant LEPR. Leptin-induced STAT3-phosphorylation was blunted the novel p.Tyr411del or the p.Trp664Arg variant and mildly reduced with the p.Arg612His variant. Computational structure prediction suggested impaired leptin binding for all three LEPR variants. Experimentally, reduced leptin binding of all mutant proteins was due to diminished LEPR expression on the cell surface, with the p.Trp664Arg mutations being the most affected. Considering the heterozygosity in our patients, we assessed the heterodimerization capacity with the wild-type LEPR, which was retained for the p.Tyr411del and p.Arg612His variants. Finally, mimicking (compound) heterozygosity, we confirmed abolished STAT3-phosphorylation for the variant combination [p.Tyr411del + p.Trp664Arg] as found in patient 1, whereas it was retained for [p.Arg612His + wilde type] as found in patient 2. The novel p.Tyr411del mutation causes complete loss of function alone (and combined with p.Trp664Arg) and is likely the cause for the early onset obesity, qualifying the patient for pharmacologic treatment. Heterozygosity for the p.Arg612His variant, however, appears unlikely to be solely responsible for the phenotype.
Aberrant expression of agouti signaling protein (ASIP) as a cause of monogenic severe childhood obesity
Publisher: Springer Science and Business Media LLC
Date: 19-12-2022
DOI: 10.1038/S42255-022-00703-9
Abstract: Here we report a heterozygous tandem duplication at the ASIP (agouti signaling protein) gene locus causing ubiquitous, ectopic ASIP expression in a female patient with extreme childhood obesity. The mutation places ASIP under control of the ubiquitously active itchy E3 ubiquitin protein ligase promoter, driving the generation of ASIP in patient-derived native and induced pluripotent stem cells for all germ layers and hypothalamic-like neurons. The patient’s phenotype of early-onset obesity, overgrowth, red hair and hyperinsulinemia is concordant with that of mutant mice ubiquitously expressing the homolog nonagouti. ASIP represses melanocyte-stimulating hormone-mediated activation as a melanocortin receptor antagonist, which might affect eating behavior, energy expenditure, adipocyte differentiation and pigmentation, as observed in the index patient. As the type of mutation escapes standard genetic screening algorithms, we rescreened the Leipzig Childhood Obesity cohort of 1,745 patients and identified four additional patients with the identical mutation, ectopic ASIP expression and a similar phenotype. Taken together, our data indicate that ubiquitous ectopic ASIP expression is likely a monogenic cause of human obesity.
Adipositas im Kindes-und Jugendalter – Kardiovaskuläre Implikationen für die Zukunft
Publisher: Georg Thieme Verlag KG
Date: 03-2021
DOI: 10.1055/A-1336-9454
Abstract: Adipositas und assoziierte kardiovaskuläre Risikofaktoren, wie arterielle Hypertonie, Dyslipidämie, Hyperinsulinämie und gestörte Glukosetoleranz, entstehen häufig bereits in der Kindheit und legen somit den Grundstein für Herz-Kreislauf-Erkrankungen im Erwachsenenalter. Gleichwohl lassen sich Folgeschäden wie endotheliale Dysfunktion, Arteriosklerose und kardiales Remodeling bereits in dieser frühen Lebensphase nachweisen. Die Risikofaktoren zeigen eine hohe Stabilität bis in das Erwachsenenalter hinein und führen in ihrer langfristigen Akkumulation zur Ausprägung kardiovaskulärer Ereignisse. Auch wenn eine Gewichtsreduktion nur in seltenen Fällen gelingt, sollte eine konsequente Therapie der Adipositas und ihrer Komorbiditäten frühzeitig versucht werden, da eine Remission während der Kindheit das Risiko für kardiovaskuläre Folgen im Erwachsenenalter auf ein Niveau senkt, welches vergleichbar mit dem der schlanken Normalbevölkerung ist.
Pubertätsentwicklung und Adipositas
Publisher: Georg Thieme Verlag KG
Date: 02-2023
DOI: 10.1055/A-1971-8578
Abstract: Die Beurteilung der Pubertätsentwicklung sowie Übergewicht und Adipositas sind tagtäglicher Bestandteil der pädiatrischen Praxis. Dabei beeinflussen sich Pubertätsentwicklung und Adipositas wechselseitig. Während Mädchen mit Adipositas häufig eine Pubertätsakzeleration aufweisen, sind die Daten bei Jungen weniger eindeutig. Möglicherweise verursacht Übergewicht hier eine Pubertätsbeschleunigung und Adipositas eine Pubertätsverzögerung. Leicht erhöhte Androgenspiegel bei Mädchen sowie leicht erhöhte Östrogenspiegel bei Jungen und eine präpubertäre Wachstumsakzeleration bei beiden Geschlechtern sind häufige Phänomene bei Kindern mit Adipositas. Die Ursachen sind multifaktoriell. Hierbei spielt das Fettgewebe eine entscheidende Rolle, sowohl durch die zentrale Aktivierung der Hypothalamus-Hypophysen-Gonadenachse über Leptin und Kisspeptin als auch durch periphere Effekte, wie beispielweise die Umwandlung von Androgenen zu Östrogen. Syndrome, welche sowohl Störungen der Pubertätsentwicklung als auch Adipositas umfassen, dürfen bei der klinischen Einschätzung nicht übersehen werden. Zur Einschätzung der altersgerechten Pubertätsentwicklung bei Kindern und Jugendlichen mit Adipositas kann in Kenntnis der typischen Veränderungen und Warnzeichen in den meisten Fällen jedoch auf weitere Diagnostik verzichtet und der Verlauf vorerst beobachtet werden.
Stress, Stress Reduction and Obesity in Childhood and Adolescence
Publisher: S. Karger AG
Date: 09-2021
DOI: 10.1159/000519284
Abstract: b i Background: /i /b Obesity in childhood and adolescence remains a great global health challenge. Stress exposure during childhood and adolescence is associated with a higher risk for obesity, yet the linkage between stress and obesity is multidimensional, and its biological and behavioral mechanisms are still not fully understood. b i Summary: /i /b In this literature review, we identified different types of stress exposure in children and adolescents, including first studied effects of the COVID-19 pandemic as a prolonged stress exposure and their association with obesity risk. We investigated studies on the connection of altered stress biology and behavioral pathways as well as intervention programs on stress reduction in children and adolescents with obesity. b i Key Messages: /i /b There is evidence that stress exposure in childhood and adolescence promotes biological and behavioral alterations that contribute to the multifactorial pathogenesis of obesity. COVID-19 related-stress presents the most current ex le of a negative influence on weight development in children and adolescents. However, longitudinal studies on the linkage between environmental, behavioral, and biological factors across development are few, and results are partly equivocal. Intervention programs to reduce stress in children through mindfulness might be a promising adjunctive tool in the prevention and treatment of childhood and adolescent obesity that could further offer proof of concept of theoretically elaborated cause-and-effect relationships.
Holoprosenzephalie – eine Krankheit mit vielen Facetten
Publisher: Georg Thieme Verlag KG
Date: 10-2021
DOI: 10.1055/A-1560-6946
Abstract: Holoprosenzephalie (HPE) ist ein komplexes Krankheitsbild mit variabler genetischer und klinischer Ausprägung. Es existieren verschiedene Formen der HPE mit Unterschieden in der Schwere des Verlaufes. Die schwere Form der HPE stellen die lobare und alobare HPE dar, die mit Zyklopie (Vereinigung von beiden Augenanlagen in einer einzigen Orbita) einhergehen, wohingegen Minor-Formen/HPE-Spektrumerkrankungen eine Mikrozephalie und/oder Hypotelorismus oder eine Lippen-Kiefer-Gaumenspalte aufweisen. Die genetischen Mechanismen sind noch nicht abschließend geklärt. Es wurden autosomal-dominante, rezessive und digenetische Vererbungsmuster beschrieben. Wir ergänzen das Spektrum der HPE-Erkrankungen um eine Patientin mit compound heterozygoter DISP1-Mutation, die einen Panhypopituitarismus in Kombination mit Entwicklungverzögerung, Lippen-Kiefer-Gaumenspalte, persistierendem Ductus Arteriosus Botalli und Visusminderung aufweist.
Associations of GHR, IGF-1 and IGFBP-3 expression in adipose tissue cells with obesity-related alterations in corresponding circulating levels and adipose tissue function in children
Publisher: Informa UK Limited
Date: 22-11-2022
Single Point Insulin Sensitivity Estimator (SPISE) As a Prognostic Marker for Emerging Dysglycemia in Children with Overweight or Obesity
Publisher: MDPI AG
Date: 07-01-2023
Abstract: The single point insulin sensitivity estimator (SPISE) is a recently developed fasting index for insulin sensitivity based on triglycerides, high density lipoprotein cholesterol, and body mass index. SPISE has been validated in juveniles and adults still, its role during childhood remains unclear. To evaluate the age- and sex-specific distribution of SPISE, its correlation with established fasting indexes and its application as a prognostic marker for future dysglycemia during childhood and adolescence were assessed. We performed linear modeling and correlation analyses on a cross-sectional cohort of 2107 children and adolescents (age 5 to 18.4 years) with overweight or obesity. Furthermore, survival analyses were conducted upon a longitudinal cohort of 591 children with overweight/obesity (1712 observations) with a maximum follow-up time of nearly 20 years, targeting prediabetes/dysglycemia as the end point. The SPISE index decreased significantly with age (−0.34 units per year, p 0.001) among children and adolescents with overweight and obesity. Sex did not have an influence on SPISE. There was a modest correlation between SPISE and established fasting markers of insulin resistance (R = −0.49 for HOMA-IR, R = −0.55 for QUICKI-IR). SPISE is a better prognostic marker for future dysglycemia (hazard ratio (HR) 3.47, 95% confidence interval (CI) 1.60–7.51, p 0.01) than HOMA-IR and QUICKI-IR (HR 2.44, 95% CI 1.24–4.81, p 0.05). The SPISE index is a surrogate marker for insulin resistance predicting emerging dysglycemia in children with overweight or obesity, and could, therefore, be applied to pediatric cohorts that lack direct insulin assessment.
Alters- und pubertätsspezifische Referenzwerte für die Insulinantwort auf orale Glukosebelastung bei Kindern und jungen Erwachsenen
Publisher: © Georg Thieme Verlag KG
Date: 09-2020
Chances and risks of bariatric surgery among children and adolescents - Current guidelines and their implementation at the obesity centre of the university hospital Leipzig
Publisher: Georg Thieme Verlag KG
Date: 11-2020
DOI: 10.1055/A-1267-8163
Abstract: Adipositas-chirurgische Eingriffe werden im Kindes- und Jugendalter noch immer selten durchgeführt. Erste Studien mit aussagefähigen Beobachtungszeiträumen und Fallzahlen zeigen jedoch vielversprechende Ergebnisse bei geringer operations-assoziierter Morbidität. Da die Langzeitfolgen für den sich noch entwickelnden Körper nach wie vor nicht abgeschätzt werden können, sollte die Indikationsstellung nur nach Ausschöpfen aller konservativen Maßnahmen in einem multidisziplinären Team aus Chirurg, Pädiater, Ernährungstherapeut und Psychologe als Einzelfallentscheidung erfolgen und die Operation interprofessionell begleitet werden. Besondere Bedeutung kommt hierbei der Nachsorge zu, da es neben dem Erkennen und Behandeln von operations-assoziierten Nebenwirkungen auch um die Sicherung eines langfristigen Erfolgs durch eine nachhaltige Änderung des Lebensstils unter Beachtung der psychosozialen Situation des heranwachsenden Patienten bis in das Erwachsenenalter hinein geht. Wir haben in diesem Artikel die aktuellen Empfehlungen aus nationalen Leitlinien und darüber hinaus reichenden wissenschaftlichen Veröffentlichungen anhand von Fallbeispielen aus dem Adipositas-Zentrum der Universitätsklinik Leipzig illustriert.
Disorders of sex development – biologic, genetic, cultural, societal, and psychologic diversity of the human nature
Publisher: Walter de Gruyter GmbH
Date: 09-12-2022
Referenzwerte für Nüchternindices des Glukose-Insulin-Stoffwechsels – Einflussfaktoren, Altersverlauf und Vergleich zu herkömmlichen Diabetes Typ 2 Diagnosekriterien
Publisher: © Georg Thieme Verlag KG
Date: 09-2020
Beyond genetic screening—functionality-based precision medicine in monogenic obesity
Publisher: Elsevier BV
Date: 03-2023
Immune modulating effects of receptor interacting protein 2 (RIP2) in autoinflammation and immunity.
Publisher: Elsevier BV
Date: 02-2020
Enzymatically Inactive Procaspase 1 stabilizes the ASC Pyroptosome and Supports Pyroptosome Spreading during Cell Division
Publisher: Elsevier BV
Date: 08-2016
Mental health in children and adolescents with overweight or obesity.
Publisher: Springer Science and Business Media LLC
Date: 19-01-2023
DOI: 10.1186/S12889-023-15032-Z
Abstract: Overweight and obesity represent huge concerns for children's physical and mental well-being. This study examined the relationship between body mass index (BMI) and health-related quality of life (HRQoL), somatoform complaints, and behavioral problems in children and adolescents. Additionally, the influence of sex, age, and socioeconomic status (SES) on these associations was considered. In total, we studied 2350 participants between the ages of 4 and 18 years (1213 4- to 10-years-old (child s le) and 1137 11-to 18-year-olds (adolescent s le)). To assess HRQoL, somatoform complaints, and behavioral difficulties, we applied the KIDSCREEN-27, a short form of the Giessen Complaints Questionnaire, and the Strengths and Difficulties Questionnaire (SDQ). The BMI was transformed to BMI standard deviation scores (BMI-SDS), according to German gender- and age-specific reference data. Associations were investigated using linear regression analyses. Each association was checked for interaction with sex, age, and SES. Regarding HRQoL, we found worsening scores in physical well-being and psychological well-being with increasing BMI-SDS. Somatoform complaints were not significantly associated with BMI-SDS. Conduct problems, peer relationship problems, and emotional problems (the latter only in the adolescent s le) were positively associated with BMI-SDS. While we did not observe any significant interactions with sex, we found some significant interactions with age and/or SES. Our findings highlight the importance of mental difficulties in children and adolescents with higher BMI and, consequently, underline the relevance of including psychological interventions in the treatment of overweight or obesity.
CASP1 variants influence subcellular caspase-1 localization, pyroptosome formation, pro-inflammatory cell death and macrophage deformability
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.CLIM.2019.06.008
Abstract: CASP1 variants result in reduced enzymatic activity of procaspase-1 and impaired IL-1β release. Despite this, affected in iduals can develop systemic autoinflammatory disease. These seemingly contradictory observations have only partially been explained by increased NF-κB activation through prolonged interaction of variant procaspase-1 with RIP2. To identify further disease underlying pathomechanisms, we established an in vitro model using shRNA-directed knock-down of procaspase-1 followed by viral transduction of human monocytes (THP-1) with plasmids encoding for wild-type procaspase-1, disease-associated CASP1 variants (p.L265S, p.R240Q) or a missense mutation in the active center of procaspase-1 (p.C285A). THP1-derived macrophages carrying CASP1 variants exhibited mutation-specific molecular alterations. We here provide in vitro evidence for abnormal pyroptosome formation (p.C285A, p.240Q, p.L265S), impaired nuclear (pro)caspase-1 localization (p.L265S), reduced pro-inflammatory cell death (p.C285A) and changes in macrophage deformability that may contribute to disease pathophysiology of patients with CASP1 variants. This offers previously unknown molecular pathomechanisms in patients with systemic autoinflammatory disease.
Related Organisations
Helmholtz Institute For Metabolic, Obesity And Vascular Research (HI-MAG) Of The Helmholtz Zentrum München At The University Of Leipzig And University Hospital Leipzig
Location: Germany
Related Funding Activities
No related grants have been discovered for Robert Stein.