"Dann gibt's zwei Sieger!"

Diese gegenständliche Arbeit befasst sich mit der Fragestellung, welche Bedeutung die Arbeit eines Therapeutischen Begleiters für die Veränderung der psychischen Strukturen eines Kindes im Kontext des Betreuungsangebots eines Instituts für Erziehungshilfe hat. Da das Konzept der Therapeutischen Begleiter ergänzend zur Psychotherapie und zur Begleitarbeit einer Sozialarbeiterin existiert, wird die durchgeführte Einzelfallstudie aus drei unterschiedlichen Perspektiven beleuchtet. Diese Diplomarbeit stellt den ersten Band dreier Bände dar, wobei in diesem die Veränderung der psychischen Strukturen eines Jungen auf die Aspekte Gier und Sättigung sowie Nähe und Distanz untersucht wurde. Zu Beginn der Diplomarbeit wird nach einer intensiven Auseinandersetzung mit dem Forschungsstand zum Konzept der Therapeutischen Begleiter auf die Forschungslücken des Projektes eingegangen und die damit verbundenen Forschungsfragen erläutert. Das zur Verfügung stehende empirische Material wurde im Zuge einer modifizierten Form der Work Discussion Methode ausgewertet, um Antworten auf die Fragestellungen geben zu können. Nachdem ein diagnostisches Persönlichkeitsprofil des Kindes zu Beginn der Betreuung erstellt wurde, zeichnete ich die Veränderungen der psychischen Strukturen des Kindes in fünf Phasen nach und erläuterte im nachstehenden Kapitel den möglichen Einfluss des Therapeutischen Begleiters auf diese. Das Zusammenspiel zwischen dem Therapeutischen Begleiter, der Psychotherapeutin und der Sozialarbeiterin im Bezug auf den Abschied wird im letzten Teil dieser Diplomarbeit vorgestellt. Diese Arbeit schließt mit einem Resümee und dem Ertrag dieser Diplomarbeit ab

Aktivitätsinduzierte Expressionsänderungen von GABA A-Rezeptor-Untereinheiten im alten Gehirn

In der vorliegenden Studie wurden die Auswirkungen eines stimulierenden Umfeldes auf die Expression der GABAA-Rezeptor-Untereinheiten alpha1, alpha2, alpha3, alpha5 und y2 im Gehirn alter Ratten an 33 Monate alten Ratten, die 3 Monate in einer reizreichen Haltung zugebracht hatten, immunhistochemisch untersucht. Bei Tieren der reizreichen Haltung zeigte sich ein signifikanter Anstieg der alpha3- und alpha5-Rezeptor-Untereinheiten, welche vor allem in den ersten postnatalen Tagen exprimiert werden. Dies könnte auf eine Rekapitulation eines juvenilen Expressionsmusters hindeuten und somit zu Veränderungen der sensomotorischen Plastizität beitragen, die bei sehr alten Ratten nach Haltung in einer reizreichen Umgebung gefunden wurde

Vitamin D receptor regulates intestinal proteins involved in cell proliferation, migration and stress response

BACKGROUND: Genome-wide association studies found low plasma levels of 25-hydroxyvitamin D and vitamin D receptor (VDR) polymorphisms associated with a higher prevalence of pathological changes in the intestine such as chronic inflammatory bowel diseases. METHODS: In this study, a proteomic approach was applied to understand the overall physiological importance of vitamin D in the small intestine, beyond its function in calcium and phosphate absorption. RESULTS: In total, 569 protein spots could be detected by two-dimensional-difference in-gel electrophoresis (2D-DIGE), and 82 proteins were considered as differentially regulated in the intestinal mucosa of VDR-deficient mice compared to that of wildtype (WT) mice. Fourteen clearly detectable proteins were identified by MS/MS and further analyzed by western blot and/or real-time RT-PCR. The differentially expressed proteins are functionally involved in cell proliferation, cell adhesion and cell migration, stress response and lipid transport. Mice lacking VDR revealed higher levels of intestinal proteins associated with proliferation and migration such as the 37/67 kDa laminin receptor, collagen type VI (alpha 1 chain), keratin-19, tropomyosin-3, adseverin and higher levels of proteins involved in protein trafficking and stress response than WT mice. In contrast, proteins that are involved in transport of bile and fatty acids were down-regulated in small intestine of mice lacking VDR compared to WT mice. However, plasma and liver concentrations of cholesterol and triglycerides were not different between the two groups of mice. CONCLUSION: Collectively, these data imply VDR as an important factor for controlling cell proliferation, migration and stress response in the small intestine

Case report: A complicated course of Collet-Sicard syndrome after internal carotid artery dissection and lenticulo-striatal artery infarction

A 40-year-old Caucasian man presented with sudden onset of left-sided hemiparesis associated with dysphonia, dysphagia, and right-sided weakness on shoulder elevation and head rotation. The clinical examination revealed deviation of the tongue to the right, absence of right-sided gag reflex, right-sided palatal and vocal cord paresis, and weakness of the right trapezius and sternocleidomastoid muscles; all were in addition to left-sided brachiocephalic-accentuated hemiparesis. The diagnostic examination revealed dissection of the right carotid artery with occlusion of the middle cerebral artery and infarction in the lenticular-striatal artery territory. Mechanical thrombectomy with stent angioplasty of the right internal carotid artery was performed. The paresis of the left side of the body completely regressed within a week after symptom onset, but the dysphonia, weakness of the right trapezius and sternocleidomastoid muscles, and especially dysphagia persisted and regressed slowly but gradually. The patient required percutaneous gastric tube feeding for the next 12 weeks, possibly because of involvement of subcortical white matter tracts. The constellation of symptoms and clinical findings were consistent with Collet-Sicard syndrome, an extremely rare disorder caused by direct compression of the caudal cranial nerves at the base of the skull

In Vitro Systematic Drug Testing Reveals Carboplatin, Paclitaxel, and Alpelisib as a Potential Novel Combination Treatment for Adult Granulosa Cell Tumors

Simple Summary: Granulosa cell tumor treatment is challenging as there are few effective options besides surgery. In this study, we obtained tumor tissue from patients at surgery and cultured tumor cells in the laboratory. After sufficient expansion, we tested the effects of current treatments, such as chemotherapy and anti-hormonal treatment, and novel anti-cancer treatment options on cell survival. Results were generated within three weeks after tissue collection. We found that all drugs were ineffective when used as single treatments; however, some combinations were very effective. The PI3K protein inhibitor alpelisib was effective in combination with chemotherapy and achieved 50% cell death at assumed tolerable patient plasma concentrations. In conclusion, this study shows an approach to rapidly establish patient-derived cell lines for drug screens. The effectiveness of combined treatment with alpelisib and chemotherapy in granulosa cell tumors should be further investigated and may be a promising novel treatment option in patients with a granulosa cell tumor. Adult granulosa cell tumors (AGCTs) arise from the estrogen-producing granulosa cells. Treatment of recurrence remains a clinical challenge, as systemic anti-hormonal treatment or chemotherapy is only effective in selected patients. We established a method to rapidly screen for drug responses in vitro using direct patient-derived cell lines in order to optimize treatment selection. The response to 11 monotherapies and 12 combination therapies, including chemotherapeutic, anti-hormonal, and targeted agents, were tested in 12 AGCT-patient-derived cell lines and an AGCT cell line (KGN). Drug screens were performed within 3 weeks after tissue collection by measurement of cell viability 72 h after drug application. The potential synergy of drug combinations was assessed. The human maximum drug plasma concentration (Cmax) and steady state (Css) thresholds obtained from available phase I/II clinical trials were used to predict potential toxicity in patients. Patient-derived AGCT cell lines demonstrated resistance to all monotherapies. All cell lines showed synergistic growth inhibition by combination treatment with carboplatin, paclitaxel, and alpelisib at a concentration needed to obtain 50% cell death (IC50) that are below the maximum achievable concentration in patients (IC50 <Cmax). We show that AGCT cell lines can be rapidly established and used for patient-specific in vitro drug testing, which may guide treatment decisions. Combination treatment with carboplatin, paclitaxel, and alpelisib was consistently effective in AGCT cell lines and should be further studied as a potential effective combination for AGCT treatment in patients

A systematic analysis of oncogenic gene fusions in primary colon cancer

Genomic rearrangements that give rise to oncogenic gene fusions can offer actionable targets for cancer therapy. Here we present a systematic analysis of oncogenic gene fusions among a clinically well-characterized, prospectively collected set of 278 primary colon cancers spanning diverse tumor stages and clinical outcomes. Gene fusions and somatic genetic variations were identified in fresh frozen clinical specimens by Illumina RNA-sequencing, the STAR fusion gene detection pipeline, and GATK RNA-seq variant calling. We considered gene fusions to be pathogenically relevant when recurrent, producing divergent gene expression (outlier analysis), or as functionally important (e.g., kinase fusions). Overall, 2.5% of all specimens were defined as harboring a relevant gene fusion (kinase fusions 1.8%). Novel configurations of BRAF, NTRK3, and RET gene fusions resulting from chromosomal translocations were identified. An R-spondin fusion was found in only one tumor (0.35%), much less than an earlier reported frequency of 10% in colorectal cancers. We also found a novel fusion involving USP9X-ERAS formed by chromothripsis and leading to high expression of ERAS, a constitutively active RAS protein normally expressed only in embryonic stem cells. This USP9X–ERAS fusion appeared highly oncogenic on the basis of its ability to activate AKT signaling. Oncogenic fusions were identified only in lymph node–negative tumors that lacked BRAF or KRAS mutations. In summary, we identified several novel oncogenic gene fusions in colorectal cancer that may drive malignant development and offer new targets for personalized therapy

International Journal of Molecular Sciences / Methylmercury Uptake into BeWo Cells Depends on LAT2-4F2hc, a System L Amino Acid Transporter

The organic mercury compound methylmercury (MeHg) is able to target the fetal brain. However, the uptake of the toxicant into placental cells is incompletely understood. MeHg strongly binds to thiol-S containing molecules such as cysteine. This MeHg-l-cysteine exhibits some structural similarity to methionine. System L plays a crucial role in placental transport of essential amino acids such as leucine and methionine and thus has been assumed to also transport MeHg-l-cysteine across the placenta. The uptake of methylmercury and tritiated leucine and methionine into the choriocarcinoma cell line BeWo was examined using transwell assay and small interfering (si)RNA mediated gene knockdown. Upon the downregulation of large neutral amino acids transporter (LAT)2 and 4F2 cell-surface antigen heavy chain (4F2hc), respectively, the levels of [H]leucine in BeWo cells are significantly reduced compared to controls treated with non-targeting siRNA (p < 0.05). The uptake of [H]methionine was reduced upon LAT2 down-regulation as well as methylmercury uptake after 4F2hc silencing (p < 0.05, respectively). These findings suggest an important role of system L in the placental uptake of the metal. Comparing the cellular accumulation of mercury, leucine, and methionine, it can be assumed that (1) MeHg is transported through system L amino acid transporters and (2) system L is responsible for the uptake of amino acids and MeHg primarily at the apical membrane of the trophoblast. The findings together can explain why mercury in contrast to other heavy metals such as lead or cadmium is efficiently transported to fetal blood.(VLID)486719

Markers Indicating Body Vitamin D Stores and Responses of Liver and Adipose Tissues to Changes in Vitamin D Intake in Male Mice

Circulating 25-hydroxyvitamin D (25(OH)D) is regarded as the most reliable biomarker of vitamin D status. However, limited data exist concerning the suitability of 25(OH)D as an indicator of body vitamin D stores and the ability of adipose tissue to mobilize vitamin D. In the first study, in which male mice received different vitamin D3 doses for three weeks, we found strong linear response relationships between vitamin D3 intake and levels of vitamin D3 in the plasma (p &lt; 0.001), liver (p &lt; 0.001) and adipose tissues (p &lt; 0.001), and strong positive correlations between plasma and tissue stores of vitamin D3 (p &lt; 0.001). Plasma levels of 25(OH)D3 and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) showed weak or no correlations with tissue vitamin D3 stores. Data from a second study demonstrate a strong and rapid response of plasma 25(OH)D3 in vitamin D3-treated mice with a low vitamin D status. Additionally, mice fed a vitamin D-free diet showed a strong and rapid decline in vitamin D3 in the liver, whereas the decline in different adipose tissues was distinctly lower than that in the liver. To conclude, tissue stores of vitamin D3 were best reflected by plasma vitamin D3. In contrast to the liver, adipose tissues responded less sensitively to an absence of vitamin D intake

Towards the Circular Soil Concept: Optimization of Engineered Soils for Green Infrastructure Application

At conventional construction sites, the removal of soil and other excavated materials causes enormous mass movement, with a significant climate impact and contribution to global CO2 release. This study aimed to generate a Circular Soil concept for reusing excavated materials by creating engineered soils for landscape construction at large building sites. Engineered soils act as a substitute for natural soils and fulfill vital technical and soil functions when installing an urban green infrastructure (GI). In a field study, the vegetation performance on engineered soils was evaluated to establish a methodological approach, to assess the applicability of the Circular Soil concept. First, the technical specifications (grain-size distribution) were modeled for intensive green roof and turfgrass applications. Then, the soil components were optimized, mixed, installed and tested for greenery purposes, focusing on plant growth performance indicators (vitality, projective cover ratio and grass-herb ratio) to assess the vegetation performance. The results showed that the engineered soils match the performance of the reference soil alternatives. In conclusion, the Circular Soil concept has a high potential to contribute considerably to sustainable on-site soil management and the circular economy. It can be applied on a larger scale for urban GI development and sustainable resources management in the landscaping and construction sector