Refine
Has Fulltext
- yes (19)
Is part of the Bibliography
- yes (19)
Year of publication
Document Type
- Journal article (17)
- Conference Proceeding (1)
- Doctoral Thesis (1)
Keywords
- PET (3)
- 18F-FDG (2)
- CSF (2)
- Positronen-Emissions-Tomografie (2)
- biomarker (2)
- cerebrospinal fluid (2)
- coercive measures (2)
- employee stress (2)
- forensic neuropathology (2)
- forensic neurotraumatology (2)
Institute
- Klinik und Poliklinik für Nuklearmedizin (5)
- Theodor-Boveri-Institut für Biowissenschaften (5)
- Medizinische Klinik und Poliklinik I (4)
- Institut für Rechtsmedizin (2)
- Institut für Sonderpädagogik (2)
- Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I) (2)
- Klinik und Poliklinik für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie (2)
- Medizinische Klinik und Poliklinik II (2)
- Institut für Hygiene und Mikrobiologie (1)
- Institut für Klinische Epidemiologie und Biometrie (1)
Sonstige beteiligte Institutionen
EU-Project number / Contract (GA) number
- 701983 (4)
In the last few years, quantitative analysis of metabolites in body fluids using LC/MS has become an established method in laboratory medicine and toxicology. By preparing metabolite profiles in biological specimens, we are able to understand pathophysiological mechanisms at the biochemical and thus the functional level. An innovative investigative method, which has not yet been used widely in the forensic context, is to use the clinical application of metabolomics. In a metabolomic analysis of 41 samples of postmortem cerebrospinal fluid (CSF) samples divided into cohorts of four different causes of death, namely, cardiovascular fatalities, isoIated torso trauma, traumatic brain injury, and multi-organ failure, we were able to identify relevant differences in the metabolite profile between these individual groups. According to this preliminary assessment, we assume that information on biochemical processes is not gained by differences in the concentration of individual metabolites in CSF, but by a combination of differently distributed metabolites forming the perspective of a new generation of biomarkers for diagnosing (fatal) TBI and associated neuropathological changes in the CNS using CSF samples.
The aim of this study was to investigate if the biomarkers myelin basic protein (MBP) and neurofilament-H (NF-H) yielded informative value in forensic diagnostics when examining cadaveric cerebrospinal fluid (CSF) biochemically via an enzyme-linked immunosorbent assay (ELISA) and comparing the corresponding brain tissue in fatal traumatic brain injury (TBI) autopsy cases by immunocytochemistry versus immunohistochemistry. In 21 trauma and 19 control cases, CSF was collected semi-sterile after suboccipital puncture and brain specimens after preparation. The CSF MBP (p = 0.006) and NF-H (p = 0.0002) levels after TBI were significantly higher than those in cardiovascular controls. Immunohistochemical staining against MBP and against NF-H was performed on cortical and subcortical samples from also biochemically investigated cases (5 TBI cases/5 controls). Compared to the controls, the TBI cases showed a visually reduced staining reaction against MBP or repeatedly ruptured neurofilaments against NF-H. Immunocytochemical tests showed MBP-positive phagocytizing macrophages in CSF with a survival time of > 24 h. In addition, numerous TMEM119-positive microglia could be detected with different degrees of staining intensity in the CSF of trauma cases. As a result, we were able to document that elevated levels of MBP and NF-H in the CSF should be considered as useful neuroinjury biomarkers of traumatic brain injury.
Background and Objective
This study evaluates whether Computer Tomography is an effective procedure for preoperative staging of patients with Peritoneal Carcinomatosis.
Method
A sample of 37 patients was analyzed with contrast enhanced abdominal Computer Tomography, followed by surgical staging. All Computer Tomography scans were evaluated 3 times by 2 radiologists with one radiologist reviewing 2 times. The efficacy of Computer Tomography was evaluated using the Spearman correlation coefficient. Correlations were analyzed by abdominopelvic region to assess results of the Peritoneal Carcinomatosis Index (PCI) aggregating the 13 regions. Surgical findings were compared to radiological findings.
Results
Results indicate high correlations between the surgical and radiological Peritoneal Carcinomatosis Indices. Analyses of the intra-class correlation between the first and second reading of one radiologist suggest high intra-observer reliability. Correlations by abdominopelvic region show higher values in the upper and middle regions and relatively lower values in the lower regions and the small bowel (correlation coefficients range between 0.418 and 0.726, p < 0.010; sensitivities range between 50% and 96%; and specificities range between 62% and 100%).
Conclusion
Computer Tomography represents an effective procedure in the preoperative staging of patients with PC. However, results by abdominopelvic region show lower correlation, therefore suggest lower efficacy. These results are supported by analyses of sensitivity and accuracy by lesion size. This suggests that Computer Tomography is an effective procedure for pre-operative staging but less for determining a tumor's accurate extent.
Background: Approximately 10% of children, adolescents and young adults with an intellectual and developmental disability (IDD) in Bavaria live in residential institutions. 2015 saw media reports raising suspicions about excessive use of coercive measures (cM) in those institutions. Until a law reform at the end of 2017 made permission from family courts mandatory for cM, their use was governed by parental consent. The REDUGIA project conducted a representative survey comparing cM and their relation to challenging behaviour (cB) and employee stress in Bavaria pre and post reform.
Methods: We sent questionnaires to 65 residential institutions for children, adolescents and young adults with IDD in 2017 (pre reform, T1) and 2019 (post reform, T2). To assess changes, we analysed data from all available questionnaire pairs (T1 and T2, N = 43). We calculated paired t-test and correlative analyses concerning the relationship between cB, cM, and employee stress.
Results: The number of residents overall (T1: N = 1,661; T2: N = 1,673) and per institution (T1: m = 38.6 ± 32.0; T2: m = 38.9 ± 34.5, p = 0.920) remained stable. We did not see any changes in the Index cB (p = 0.508) or the proportion of residents per institution displaying various types of challenging behaviour (all ps>0.220). There was no change in the Index cM (p = 0.089) or any indicator of employee stress, all ps > 0.323. At follow-up, the Index cB correlated positively with the Index cM (r = 0.519 p < 0.001). Regarding employee stress, the Index cB correlated positively with the frequency of sick leave (r = 0.322, p = 0.037) and physical attacks on employees (r = 0.552, p < 0.001). The Index cM also correlated positively with the frequency of sick leave (r = 0.340, p = 0.028) and physical attacks on employees (r = 0.492, p = 0.001).
Discussion: Coercive measures are not a general phenomenon, but are focused on specialised institutions. The law reform did not lead to changes in the number of children, adolescents and young adults with IDD affected by coercive measures in residential institutions in Bavaria. There were still large discrepancies between institutions in the prevalence of challenging behaviour and coercive measures. Coercive measures were associated with challenging behaviour and employee stress. Taken together, findings from REDUGIA emphasise the need to prevent challenging behaviour and thus coercive measures.
Fragestellung: In Bayern leben etwa 10 % aller jungen Menschen mit Intelligenzminderung in Heimeinrichtungen. 2016 wurde in Presseberichten der Vorwurf unzulässiger freiheitsentziehender Maßnahmen formuliert. Im Rahmen des Projekts REDUGIA wurde in bayerischen Heimeinrichtungen eine repräsentative Erhebung zu freiheitsentziehenden Maßnahmen (FeM), herausforderndem Verhalten (hfV) und der Mitarbeiterbelastung (MaB) durchgeführt. Methodik: 65 Einrichtungen für junge Menschen mit Intelligenzminderung in Bayern wurde ein Fragebogen zu strukturellen Gegebenheiten sowie MaB, hfV und FeM zugesendet. Neben deskriptiven Auswertungen wurden korrelative Analysen bzw. Regressionsanalysen zum Zusammenhang zwischen hfV, FeM und MaB durchgeführt. Ergebnisse: Es wurden Daten zu 1839 Personen in 61 Einrichtungen erhoben. 84.3 % der Einrichtungen berichteten geringe Raten an hfV und FeM, während 15.7 % ein gehäuftes Vorkommen von hfV und FeM angaben. Auf n = 1809 Vollzeitäquivalente kam es innerhalb von 14 Tagen zu 639 körperlichen Angriffen durch Bewohner_innen. In 12 Monaten wurden problemverhaltensassoziiert 85 Krankmeldungen sowie 33 Versetzungsanträge/Kündigungen berichtet. Es zeigte sich ein signifikant positiver Zusammenhang zwischen hfV und FeM (R² = .307, F = 21.719, p < .001). Die Mitarbeiterbelastung korrelierte positiv mit hfV (r = .507, p < .001). Schlussfolgerungen: Die Studienbefunde weisen darauf hin, dass hfV sowie FeM bei jungen Menschen mit Intelligenzminderung kein flächendeckendes Phänomen darstellen, sondern sich auf wenige spezialisierte Einrichtungen fokussieren. Mögliche Maßnahmen zur Prävention von Problemverhalten und Freiheitsentzug werden diskutiert.
Biodiversity loss can affect the viability of ecosystems by decreasing the ability of communities to respond to environmental change and disturbances. Agricultural intensification is a major driver of biodiversity loss and has multiple components operating at different spatial scales: from in-field management intensity to landscape-scale simplification. Here we show that landscape-level effects dominate functional community composition and can even buffer the effects of in-field management intensification on functional homogenization, and that animal communities in real-world managed landscapes show a unified response (across orders and guilds) to both landscape-scale simplification and in-field intensification. Adults and larvae with specialized feeding habits, species with shorter activity periods and relatively small body sizes are selected against in simplified landscapes with intense in-field management. Our results demonstrate that the diversity of land cover types at the landscape scale is critical for maintaining communities, which are functionally diverse, even in landscapes where in-field management intensity is high.
Background: Specific cell targeting is an important, yet unsolved problem in bacteria-based therapeutic applications, like tumor or gene therapy. Here, we describe the construction of a novel, internalin A and B (InlAB)-deficient Listeria monocytogenes strain (Lm-spa+), which expresses protein A of Staphylococcus aureus (SPA) and anchors SPA in the correct orientation on the bacterial cell surface. Results: This listerial strain efficiently binds antibodies allowing specific interaction of the bacterium with the target recognized by the antibody. Binding of Trastuzumab (Herceptin®) or Cetuximab (Erbitux®) to Lm-spa+, two clinically approved monoclonal antibodies directed against HER2/neu and EGFR/HER1, respectively, triggers InlABindependent internalization into non-phagocytic cancer cell lines overexpressing the respective receptors. Internalization, subsequent escape into the host cell cytosol and intracellular replication of these bacteria are as efficient as of the corresponding InlAB-positive, SPA-negative parental strain. This specific antibody/receptormediated internalization of Lm-spa+ is shown in the murine 4T1 tumor cell line, the isogenic 4T1-HER2 cell line as well as the human cancer cell lines SK-BR-3 and SK-OV-3. Importantly, this targeting approach is applicable in a xenograft mouse tumor model after crosslinking the antibody to SPA on the listerial cell surface. Conclusions: Binding of receptor-specific antibodies to SPA-expressing L. monocytogenes may represent a promising approach to target L. monocytogenes to host cells expressing specific receptors triggering internalization.
Targeting the intrinsic metabolism of immune or tumor cells is a therapeutic strategy in autoimmunity, chronic inflammation or cancer. Metabolite repair enzymes may represent an alternative target class for selective metabolic inhibition, but pharmacological tools to test this concept are needed. Here, we demonstrate that phosphoglycolate phosphatase (PGP), a prototypical metabolite repair enzyme in glycolysis, is a pharmacologically actionable target. Using a combination of small molecule screening, protein crystallography, molecular dynamics simulations and NMR metabolomics, we discover and analyze a compound (CP1) that inhibits PGP with high selectivity and submicromolar potency. CP1 locks the phosphatase in a catalytically inactive conformation, dampens glycolytic flux, and phenocopies effects of cellular PGP-deficiency. This study provides key insights into effective and precise PGP targeting, at the same time validating an allosteric approach to control glycolysis that could advance discoveries of innovative therapeutic candidates.
Purpose
A successful focused surgical approach in primary hyperparathyroidism (pHPT) relies on accurate preoperative localization of the parathyroid adenoma (PA). Most often, ultrasound is followed by [\(^{99m}\)Tc]-sestamibi scintigraphy, but the value of this approach is disputed. Here, we evaluated the diagnostic approach in patients with surgically treated pHPT in our center with the aim to further refine preoperative diagnostic procedures.
Methods
A single-center retrospective analysis of patients with pHPT from 01/2005 to 08/2021 was carried out followed by evaluation of the preoperative imaging modalities to localize PA. The localization of the PA had to be confirmed intraoperatively by the fresh frozen section and significant dropping of the intraoperative parathyroid hormone (PTH) levels.
Results
From 658 patients diagnosed with pHPT, 30 patients were excluded from the analysis because of surgery for recurrent or persistent disease. Median age of patients was 58.0 (13–93) years and 71% were female. Neck ultrasound was carried out in 91.7% and localized a PA in 76.6%. In 23.4% (135/576) of the patients, preoperative neck ultrasound did not detect a PA. In this group, [\(^{99m}\)Tc]-sestamibi correctly identified PA in only 25.4% of patients. In contrast, in the same cohort, the use of [\(^{11}\)C]-methionine or [\(^{11}\)C]-choline PET resulted in the correct identification of PA in 79.4% of patients (OR 13.23; 95% CI 5.24–33.56).
Conclusion
[\(^{11}\)C]-Methionine or [\(^{11}\)C]-choline PET/CT are superior second-line imaging methods to select patients for a focused surgical approach when previous ultrasound failed to identify PA.
Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARF-BP1, MULE) associates with both MYC and the MYC-associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models. Using high-throughput screening, we identify small molecule inhibitors of HUWE1, which inhibit MYC-dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE1 stabilizes MIZ1. MIZ1 globally accumulates on MYC target genes and contributes to repression of MYC-activated target genes upon HUWE1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ1 and identify a novel principle that allows for inhibition of MYC function in tumor cells.