Hauptgeneffekt auf die Entstehung exzremer Adipositas bei Kindern und Jugendlichen durch funktionell relevante Mutationen des Melanocortin 4 Rezeptor-Gens

Adipositas stellt in unserer Gesellschaft zunehmend nicht nur ein Problem für die Gesundheit und Lebensqualität des Betroffenen, sondern auch eine sozioökonomische Belastung für die Gemeinschaft dar. Zahlreiche Studien in den letzten Jahren unterstreichen dabei neben Umwelteinflüssen die Wichtigkeit genetischer Faktoren bei der Entstehung der Adipositas. Bei Familienstudien, Mausmodellen und epidemiologischen Untersuchungen erwies sich der Melanocortin 4 Rezeptor als ein wichtiges Kandidatengen, und in Folgestudien wurden zahlreiche adipöse Träger von Mutationen und Polymorphismen in diesem Gen beschrieben. In dieser Arbeit wurde die Rolle der MC4R Mutationen bei der Entstehung der Adipositas und deren Vererbungsmechanismen präzisiert. Dazu wurden 520 extrem adipöse Kinder und Jugendliche sowie deren Eltern mit Hilfe der Polymerase-Kettenreaktion, der Einzelstrang- Koformationsanalyse und der Sequenzierung systematisch auf Veränderungen in der gesamten kodierenden Nukleotidsequenz des MC4R durchgeführt. Es wurden insgesamt 14 elterliche Mutationsträger und 11 Indexpatienten mit Mutation detektiert, wobei drei Indexprobanden und zwei Elternteile zwei Mutationen gleichzeitig aufwiesen. Unter den Mutationen fanden sich acht bis zu dem Entstehungszeitpunkt der Arbeit noch nicht beschriebene Mutationen (GA Del Codon 250, T Del Codon 320, Ser-94-Arg, Val-95-Ile, Ile-121-Thr, Ser-127-Leu, Ala-244-Glu und Ile-317-Thr). Die Transmission mutierter elterlicher Allele auf die Nachkommen konnte somit bestimmt und mit Hilfe des Transmissions Disequilibrium Tests bewertet werden. Dabei ergab sich, dass die 14 elterlichen Träger einer funktionell relevanten Mutation in 85,7 % das entsprechende Allel auf die Nachkommen transmittierten. Es zeigte sich auch, dass die elterlichen Mutationsträger einen höheren BMI als die übrigen untersuchten Eltern aufwiesen. Weiterhin war auffällig, dass von den detektierten 35 elterlichen Trägern des Val-103-Ile Polymorphismus das entsprechende Allel nur in acht Fällen auf den Indexprobanden transmittiert wurde. Dies deutet auf einen protektiven Effekt dieses Polymorphismus auf die Entstehung von Adipositas hin. Insgesamt sprechen die signifikant höhere Frequenz von funktionell relevanten Mutationen bei Adipösen im Vergleich zu nicht adipösen Kontrollen und die signifikanten TDT Ergebnisse für einen Hauptgeneffekt der MC4R Mutationen auf die Entstehung der Adipositas

Hauptgeneffekt auf die Entstehung exzremer Adipositas bei Kindern und Jugendlichen durch funktionell relevante Mutationen des Melanocortin 4 Rezeptor-Gens

Adipositas stellt in unserer Gesellschaft zunehmend nicht nur ein Problem für die Gesundheit und Lebensqualität des Betroffenen, sondern auch eine sozioökonomische Belastung für die Gemeinschaft dar. Zahlreiche Studien in den letzten Jahren unterstreichen dabei neben Umwelteinflüssen die Wichtigkeit genetischer Faktoren bei der Entstehung der Adipositas. Bei Familienstudien, Mausmodellen und epidemiologischen Untersuchungen erwies sich der Melanocortin 4 Rezeptor als ein wichtiges Kandidatengen, und in Folgestudien wurden zahlreiche adipöse Träger von Mutationen und Polymorphismen in diesem Gen beschrieben. In dieser Arbeit wurde die Rolle der MC4R Mutationen bei der Entstehung der Adipositas und deren Vererbungsmechanismen präzisiert. Dazu wurden 520 extrem adipöse Kinder und Jugendliche sowie deren Eltern mit Hilfe der Polymerase-Kettenreaktion, der Einzelstrang- Koformationsanalyse und der Sequenzierung systematisch auf Veränderungen in der gesamten kodierenden Nukleotidsequenz des MC4R durchgeführt. Es wurden insgesamt 14 elterliche Mutationsträger und 11 Indexpatienten mit Mutation detektiert, wobei drei Indexprobanden und zwei Elternteile zwei Mutationen gleichzeitig aufwiesen. Unter den Mutationen fanden sich acht bis zu dem Entstehungszeitpunkt der Arbeit noch nicht beschriebene Mutationen (GA Del Codon 250, T Del Codon 320, Ser-94-Arg, Val-95-Ile, Ile-121-Thr, Ser-127-Leu, Ala-244-Glu und Ile-317-Thr). Die Transmission mutierter elterlicher Allele auf die Nachkommen konnte somit bestimmt und mit Hilfe des Transmissions Disequilibrium Tests bewertet werden. Dabei ergab sich, dass die 14 elterlichen Träger einer funktionell relevanten Mutation in 85,7 % das entsprechende Allel auf die Nachkommen transmittierten. Es zeigte sich auch, dass die elterlichen Mutationsträger einen höheren BMI als die übrigen untersuchten Eltern aufwiesen. Weiterhin war auffällig, dass von den detektierten 35 elterlichen Trägern des Val-103-Ile Polymorphismus das entsprechende Allel nur in acht Fällen auf den Indexprobanden transmittiert wurde. Dies deutet auf einen protektiven Effekt dieses Polymorphismus auf die Entstehung von Adipositas hin. Insgesamt sprechen die signifikant höhere Frequenz von funktionell relevanten Mutationen bei Adipösen im Vergleich zu nicht adipösen Kontrollen und die signifikanten TDT Ergebnisse für einen Hauptgeneffekt der MC4R Mutationen auf die Entstehung der Adipositas

Melanocortin-4 receptor gene: case-control study and transmission disequilibrium test confirm that functionally relevant mutations are compatible with a major gene effect for extreme obesity

We initially performed a mutation screen of the coding region of the MC4R in 808 extremely obese children and adolescents and 327 underweight or normal-weight controls allowing for a case-control study. A total of 16 different missense, nonsense, and frameshift mutations were found in the obese study group; five of these have not been observed previously. In vitro assays revealed that nine [the haplotype (Y35X; D37V) was counted as one mutation] of the 16 mutations led to impaired cAMP responses, compared with wild-type receptor constructs. In contrast, only one novel missense mutation was detected in the controls, which did not alter receptor function. The association test based on functionally relevant mutations was positive (P = 0.006, Fisher's exact test, one-sided). We proceeded by screening a total of 1040 parents of 520 of the aforementioned obese young index patients to perform transmission disequilibrium tests. The 11 parental carriers of functionally relevant mutations transmitted the mutation in 81.8% (P = 0.033; exact one-sided McNemar test). These results support the hypothesis that these MC4R mutations represent major gene effects for obesity

One Step at a Time: How Model Time Step Significantly Affects Convection‐Permitting Simulations

We show that there is a strong sensitivity of cloud microphysics to model time step in idealized convection-permitting simulations using the COnsortium for Small-scale MOdeling model. Specifically, we found a 53% reduction in precipitation when the time step is increased from 1 to 15 s, changes to the location of precipitation and hail reaching the surface, and changes to the vertical distribution of hydrometeors. The effect of cloud condensation nuclei perturbations on precipitation also changes both magnitude and sign with the changing model time step. The sensitivity arises because of the numerical implementation of processes in the model, specifically the so-called “splitting” of the dynamics (e.g., advection and diffusion) and the parameterized physics (e.g., microphysics scheme). Calculating one step at a time (sequential-update splitting) gives a significant time step dependence because large supersaturation with respect to liquid is generated in updraft regions, which strongly affect parameterized microphysical process rates—in particular, ice nucleation. In comparison, calculating both dynamics and microphysics using the same inputs of temperature and water vapor (hybrid parallel splitting) or adding an additional saturation adjustment within the dynamics reduces the time step sensitivity of surface precipitation by limiting the supersaturation seen by the microphysics, although sensitivity to time step remains for some processes

The trial of an ex-child soldier - a closer look at the case of Dominik Ongwen

The Lords Resistance Army is one of the most brutal rebel groups in Africa and which is mainly active in northern Uganda. It is famous for abducting children in order to use them as child soldiers. One of the abductees has gained prominence his name is Dominic Ongwen. He was abducted at the age of ten while walking home from school, and has then risen through the ranks of the Lords Resistance Army to become one of its senior commanders. Over the years, he has committed multiple war crimes and crimes against humanity, and is now standing trial before the International Criminal Court. His offences range from murder, slavery, rape and destruction of property amongst other crimes. Not only did he commit these crimes, but he also is a victim of some of them, like the use of children under the age of 15 as child soldiers. Dominic Ongwen is the first former child soldier to stand trial before the International Criminal Court. His special situation gives rise to criticism, especially because he was forced into a position where he was forced to commit atrocities due to the childhood indoctrination by the rebel group affecting his decisions as well as his own victim status. This thesis asks the question whether some of his crimes can be justified with duress. In order to answer this question, some background information on the situation in Uganda and the rise of the Lords Resistance Army will be given in the first part of this paper. Also, the life story of Dominic Ongwen will be outlined to explain how he became a defendant before the International Criminal Court. The second part comprises the reasons why he is standing trial and his charges will be explained. The indoctrination Dominic Ongwen went through as a child and the circumstances he grew up in, constituted an ongoing threat to his life and his family. However, whether the requirements for duress are fulfilled in his case, is discussed in the third part of this thesis.submitted by Constanze VogelUniversität Linz, Diplomarbeit, 2018(VLID)316170

Transition to Kindergarten: Negative Associations between the Emotional Availability in Mother–Child Relationships and Elevated Cortisol Levels in Children with an Immigrant Background

Background: The transition to child care is a challenging time in a child’s life and leads to elevated levels of cortisol. These elevations may be influenced by the quality of the mother–child relationship. However, remarkably little is known about cortisol production in response to the beginning of child care among children-at-risk such as children with an immigrant background. However, attending kindergarten or any other child day-care institution can for example have a compensating effect on potential language deficits thus improving the educational opportunities of these children.Method: Data of a subsample of N = 24 “hard-to-reach” mother–child dyads was collected in the context of the psychoanalytic early prevention project FIRST STEPS. The project focuses on the earliest integration of children with an immigrant background by supporting parenting capacities in the critical phase of migration and early parenthood. Children’s hair cortisol concentration (HCC) was assessed 1 week before (mean age = 38.77 months) and 3 months after kindergarten entry (mean age = 42.26 months). Hair analysis was conducted for both times of measurement, reflecting the first 3 months after kindergarten entry and 3 months prior. Furthermore, the emotional quality of the mother–child relationship was assessed with the help of the Emotional Availability Scales (EAS; Biringen, 2008) shortly before kindergarten entry when the children were about 3 years old (mean age = 37.2).Results and Conclusion: Children’s mean cumulated HCC was higher after kindergarten entry than before. The increase correlated negatively with several dimensions of the EAS. Repeated measures ANCOVA revealed that particularly responsive children and children who had experienced less intrusive mother–child relationships demonstrated lower elevations in HCC after kindergarten entry. Furthermore, a decreased EA score was found in all EA dimensions, besides the dimension “mother’s non-hostility,” indicating problematic EA within the mother–child relationships of the sample. The results suggest that children with an immigrant background who experience more emotional available mother–child relationships seem to regulate stress induced by kindergarten entry more effectively, indicated by lower cortisol elevations after entry. This implicates that supporting early mother–child relationships by intervention may have a positive effect on the children’s ability to regulate stress induced by kindergarten entry thus promoting child development

Cultural Sensitivity in Preventive Infant Mental Health Care: An Example From the Developmental Guidance Project FIRST STEPS in Belgium

Gefördert durch den Publikationsfonds der Universität Kasse

Profile and Outcome of Supraclavicular Metastases in Patients with Metastatic Breast Cancer: Discordance of Receptor Status Between Primary and Metastatic Site

Background: Breast cancer is a heterogenous and complex disease. A rare site of metastatic breast cancer disease is the neck. Data about supraclavicular metastases in patients with metastatic breast cancer are still lacking. Hence, our study aimed to analyze histological subtypes of supraclavicular metastases compared to the primary site. Materials and Methods: This was a retrospective hospital-based cohort study of patients with breast cancer who developed supraclavicular metastases. Diagnosis of supraclavicular metastases was confirmed by biopsy or diagnostic lymph node extirpation. Histological subtypes were analyzed and Kaplan-Meier estimates were calculated for overall survival. Results: A total of 20 patients were included in the analysis. The majority of the patients (12/20) had hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative supraclavicular metastases, disease in 3/20 patients was HR-positive/HER2-positive, HRnegative/HER2-positive in 1/20 patients and basal-like in 4/20 patients. Total discordance rates for estrogen receptor, progesterone receptor and HER2 between primary and metastatic tumors were 20.0%, 36.8% and 29.4%, respectively. The 5-year overall survival was 80%, whereas the 5-year survival after the onset of neck metastasis was 45%. Conclusion: As a rare site of metastatic breast cancer, supraclavicular metastases are associated with a worse median overall survival from their onset. The high rate of discordance of histological subtype stresses the necessity for biopsies in patients with supraclavicular metastasis

The Role of Previous Therapies and Sites of Metastasis as Influencing Factors on Discordance of ER, PR and HER2 Status Between Primary and Metastasized Breast Cancer

Background/Aim: The aim of the present study was to analyze metastasized breast cancer (BC) patients with regard to the discordance of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). We especially aimed to analyze the association between the change of tumor biology and previous treatment or metastatic sites. Patients and Methods: Patients with metastasized BC who were treated at the Department of Gynecology/Breast Center of the University Hospital of Cologne were analyzed. Results: Loss of HER2 occurred more frequently in lymph node metastases that were not in the axillary region (p=0.026). Letrozole showed a significant correlation with loss of ER and/or PR (p=0.041). Improved overall survival and post-metastasis survival were noticed with a gain of HER2 (p=0.044 and p=0.009, respectively) and concordant positive ER and PR status (p=0.002 and p=0.001, respectively). Conclusion: The discordance of receptors and the dependence of BC on therapies as well as metastatic sites stresses the necessity of early sample taking to offer patients suitable therapy options