Prolyl hydroxylase domain 2 protein is a strong prognostic marker in human gastric cancer

Objective: According to recent research, prolyl hydroxylase domain 2 protein (PHD2) plays an important role in human carcinogenesis by inducing neovascularization and tumor growth. The aim of this study was to evaluate PHD2 expression patterns in primary gastric adenocarcinoma and to test for a potential predictive value of PHD2 expression in gastric cancer patients. Methods: In a total of 121 patients, PHD2 expression was investigated by immunohistochemistry in paraffin- embedded tissue and correlated with clinicopathological parameters and patient survival. Results: 64 of 121 gastric carcinomas (52.9%) showed PHD2 expression in tumor cell cytoplasm. In univariate analysis, PHD2- negative patients had a significantly shortened survival in compariso

The landscape of metastatic progression patterns across major human cancers

The majority of patients with solid malignancies die from metastatic burden. However, our current understanding of the mechanisms and resulting patterns of dissemination is limited. Here, we analyzed patterns of metastatic progression across 16 major cancer types in a cohort of 1008 patients with metastatic cancer autopsied between 2000 and 2013 to assess cancer specific progression patterns of disease and related risk predictions. The frequency and location of metastases were evaluated in and across 1) 16 major cancers, 2) smoking- and non-smoking-related cancers and 3) adeno- and squamous cell carcinoma. Associations between primary and secondary sites were analyzed by the fractional and the relative risk methods. We detected significantly different cancer specific patterns of metastatic progression with specific relative risk profiles for secondary site involvement. Histology and smoking etiology influenced these patterns. Backward analysis showed that metastatic patterns help to predict unknown primary sites. Solid malignancies maintain a unique and recurrent organ tropism to specific secondary sites which does not appear to be strongly influenced by advances in cancer medicine as shown by comparison with previous data sets. The delineated landscape of metastatic progression patterns is a comprehensive data resource to both clinical and basic scientists which aids fostering new hypotheses for cancer research and cancer therapies

Who Is at Risk for Diagnostic Discrepancies? Comparison of Pre- and Postmortal Diagnoses in 1800 Patients of 3 Medical Decades in East and West Berlin

<div><h3>Background</h3><p>Autopsy rates in Western countries consistently decline to an average of <5%, although clinical autopsies represent a reasonable tool for quality control in hospitals, medically and economically. Comparing pre- and postmortal diagnoses, diagnostic discrepancies as uncovered by clinical autopsies supply crucial information on how to improve clinical treatment. The study aimed at analyzing current diagnostic discrepancy rates, investigating their influencing factors and identifying risk profiles of patients that could be affected by a diagnostic discrepancy.</p> <h3>Methods and Findings</h3><p>Of all adult autopsy cases of the Charité Institute of Pathology from the years 1988, 1993, 1998, 2003 and 2008, the pre- and postmortal diagnoses and all demographic data were analyzed retrospectively. Based on power analysis, 1,800 cases were randomly selected to perform discrepancy classification (class I-VI) according to modified Goldman criteria. The rate of discrepancies in major diagnoses (class I) was 10.7% (95% CI: 7.7%–14.7%) in 2008 representing a reduction by 15.1%. Subgroup analysis revealed several influencing factors to significantly correlate with the discrepancy rate. Cardiovascular diseases had the highest frequency among class-I-discrepancies. Comparing the 1988-data of East- and West-Berlin, no significant differences were found in diagnostic discrepancies despite an autopsy rate differing by nearly 50%. A risk profile analysis visualized by intuitive heatmaps revealed a significantly high discrepancy rate in patients treated in low or intermediate care units at community hospitals. In this collective, patients with genitourinary/renal or infectious diseases were at particularly high risk.</p> <h3>Conclusions</h3><p>This is the current largest and most comprehensive study on diagnostic discrepancies worldwide. Our well-powered analysis revealed a significant rate of class-I-discrepancies indicating that autopsies are still of value. The identified risk profiles may aid both pathologists and clinicians to identify patients at increased risk for a discrepant diagnosis and possibly suboptimal treatment intra vitam.</p> </div

Identification and functional meaning of the KATP channel-related protein- complex KIR6.1/SUR2A in the regulation of tight junctions

Titelblatt und Inhaltsverzeichnis Einleitung Material Methoden Ergebnisse Diskussion Zusammenfassung LiteraturKATP-Kanäle gehören zur Proteinfamilie der Kaliumkanäle und kommen in zahlreichen Geweben vor. Sie zeichnen sich durch eine hohe Sensitivität gegenüber ATP aus und erfüllen gewebeabhängig unterschiedlichste Funktionen wie zum Beispiel die Regulation der Insulinfreisetzung in den β-Zellen des Pankreas oder die Protektion von Neuronen und Herzmuskelzellen während ischämischer Zustände. Unter anderem sichern KATP-Kanäle somit in Krisensituationen für bestimmte Zeit das Überleben des gesamten Organismus. Ermöglicht wird diese Funktionsvielfalt durch Kombination verschiedener Subtypen von KATP-Kanal-Untereinheiten. KATP-Kanäle sind prinzipiell aus vier porenbildenden KIR6-Untereinheiten sowie vier umgebenden, regulatorischen SUR- Untereinheiten aufgebaut. Bislang sind bei den Säugetieren zwei KIR6- (KIR6.1 und KIR6.2) und drei SUR-Untereinheiten (SUR1, SUR2A und SUR2B) identifiziert und in unterschiedlichen Kombinationen beschrieben worden. In der vorliegenden Arbeit konnte mithilfe hochspezifischer Antikörper gegen die Untereinheiten KIR6.1 und SUR2A eine bislang in der Natur nicht bekannte Kombination von KATP ¬-Kanal-Untereinheiten vorgestellt werden. Sowohl KIR6.1 als auch SUR2A zeigten in immunhistologischen Untersuchungen von gastrointestinalen und renalen Epithelien des Menschen und verschiedener anderer Säugetierspezies eine perfekte Colokalisation mit den Arealen der Tight Junctions. Interessanterweise konnte dieser neue KIR6.1/SUR2A-Komplex ausschließlich an regulierten Tight Junctions nachgewiesen werden, nicht jedoch an impermeablen Tight Junctions, wie denen des Urothels der Harnblase oder dem Epithel renaler Sammelrohre. Ausgehend von diesen Beobachtungen wurde ein neues Modellsystem am Dünndarm der Ratte entwickelt, um eine bislang nicht bekannte Funktion eines KIR6/SUR-Proteinkomplexes zu untersuchen, die Regulation der parazellulären Nährstoffaufnahme des Dünndarmepithels. Es wurden hierfür morphologisch definierte Dünndarmsegmente der Ratte entnommen und mit unterschiedlichen Inkubationslösungen befüllt. Hierbei kam ein 1987 erstmals beschriebenes Phänomen zur Anwendung, bei welchem intraluminal erhöhte Konzentrationen von D-Glucose eine Steigerung der parazellulären Permeabilität des Dünndarmepithels bewirken. Durch Zusatz der Pharmaka Tolbutamid und Diazoxid, spezifische Regulatoren von KATP-Kanälen, gelang es diese D-Glucose- induzierte Steigerung der parazellulären Permeabilität signifikant zu beeinflussen. Tolbutamid erhöhte die parazelluläre Permeabilität, Diazoxid senkte sie. Der KIR6.1/SUR2A-Komplex scheint hierbei nicht klassisch als ein K+-leitender Ionenkanal zu funktionieren, sondern interagiert vermutlich rein physikalisch mittels einer durch ATP-Hydrolyse bedingten Konformationsänderung mit weiteren Proteinen der Tight Junction. Die Daten dieser Arbeit deuten somit darauf hin, dass KIR6/SUR-Komplexe neben der bislang vornehmlich bekannten Ausbildung von ionenleitenden KATP-Kanälen auch auf andere Weise nachweisbare Funktionen ausüben können. Überraschenderweise dient die hier erstmalig beschriebene Funktion, die Regulation der parazellulären Permeabilität, ebenso wie die bekannten protektiven Mechanismen für Herz und Gehirn, dem Organismus zur Anpassung seiner biologischen Aktivität an das Angebot verfügbarer Ressourcen. Diese Beobachtungen deuten somit auf ein übergeordnetes Prinzip der Funktionsweise von KIR/SUR-Komplexen, welches sich im Verlaufe der Evolution dieser Proteinfamilie herausgebildet hat.KATP channels belong to the protein family of potassium channels and occur in numerous tissues. They are characterised by a high sensitivity against ATP and fulfil different functions, for example, the regulation of insulin liberation in the β-cells of the pancreas or the protection of neurons and heart muscle cells during ischemic states. Thus, amongst other things KATP channels ensure the survival of the whole organism for a certain time. This diversity of functions is enabled by the combination of different subtypes of KATP channel subunits. Principally, KATP channels are composed of four pore-forming KIR6 subunits and four surrounding regulatory SUR subunits. So far, two KIR6 (KIR6.1 and KIR6.2) and three SUR subunits (SUR1, SUR2A and SUR2B) have been identified in mammals and described in different combinations. By using highly specific antibodies against the subunits KIR6.1 and SUR2A, a combination of KATP channel subunits so far not known in nature conditions is introduced in the present work. Both KIR6.1 and SUR2A revealed a perfect colocalisation with the areas of tight junctions in immune histological investigations of gastrointestinal and renal epithelia of man and other mammals. Interestingly, this new KIR6.1/SUR2A complex was detectable only at regulated tight junctions and not at impermeable tight junctions like those in the urothelium of the urinary bladder or in the epithelium of renal collecting ducts. Based on these observations a new model system with rat small intestine was developed to investigate a so far unknown function of a KIR6/SUR protein complex, the regulation of paracellular nutrient absorption of the small intestinal epithelium. Therefore, morphological well-defined segments of rat small intestine were excised and filled with different incubation buffers. Here, it was used a phenomenon first described in 1987 where intralumenal increased concentrations of D-glucose caused an increase in paracellular permeability of the small intestinal epithelium. By addition of the pharmaceuticals tolbutamide and diazoxide, specific regulators of KATP channels, it was possible to influence significally this increase in paracellular permeability induced by D-glucose. Tolbutamide increased the paracellular permeability, whereas diazoxide decreased it. In this process the KIR6.1/SUR2A complex does not seem to work as a classical K+ conducting channel for ions but it presumably interacts purely physically with other tight junction proteins by an ATP hydrolysis-caused change of conformation. Thus, the data of this work suggest that KIR6/SUR complexes also execute detectable functions in other ways apart from just forming ion gating KATP channels. Surprisingly, the here new described function of the regulation of paracellular permeability provides the organism an adaptation of its biological activity to the supply of available resources as well as the known protective mechanisms in heart and brain. Those observations suggest a superior principle of the purpose of KIR6/SUR complexes which has been developed during the evolution of that protein family

A safe procedure? The unusual case of a fatal airway obstruction by silicone during the production process of a tracheostomal epithesis in a 13-year-old boy

A tracheostomal epithesis is a plastic prosthesis that serves for sealing a tracheostoma and ensuring the position of the tracheostomy tube. The production of a tracheostomal epithesis requires an impression of the tracheostoma. To this end, silicone impression material is applied by an anaplastologist in and around the tracheostomal region, including the trachea. The blocked cuff of the tracheostomy tube serves to prevent aspiration of the material. We report on a 13-year-old boy who died during this procedure because the lower airways were obstructed with cured silicone. Forensic autopsy confirmed asphyctic suffocation as cause of death. Forensic physical investigation of the tracheostomy tube and its cuff revealed no structural or functional defects. Yet, the investigation results prove that the viscous silicone must have passed the cuff. To conclude, this case report demonstrates that the production of an impression of a tracheostoma is a procedure with a potentially lethal outcome. Hence, professional guidelines, including clear safety precautions, are urgently needed

Heiße Spuren

&lt;jats:title&gt;Zusammenfassung&lt;/jats:title&gt;&lt;jats:p&gt;Die Differenzialdiagnostik von Hautläsionen bei Lebenden gehört zum wesentlichen Aufgabenspektrum der „klinischen Rechtsmedizin“. Im vorliegenden Fall eines 10 Monate alten Jungen mit nichtjuckenden, jedoch geformt wirkenden Hautläsionen bat die behandelnde Kinderarztpraxis um rechtsmedizinische Mitbeurteilung wegen des Verdachts einer Misshandlung von Schutzbefohlenen mittels glühender Zigarettenspitzen. Auf Fotografien vom Tag der Erstvorstellung in der Kinderarztpraxis sowie von der Wiedervorstellung einen Tag später waren im linken oberen Rückenbereich mehrere rundliche Hautläsionen zu erkennen. Bei der nachfolgenden rechtsmedizinischen Untersuchung erschienen diese Läsionen nun mit goldgelb-braunen Krustenbildungen. Die Kenntnis der Läsionsentwicklung sowie der charakteristische Endbefund ermöglichten die sichere Diagnose einer Impetigo contagiosa. Der Fall verdeutlicht die Notwendigkeit der engen Kooperation zwischen Klinik und Rechtsmedizin bei Sachlagen und Befunden mit initial möglich erscheinender strafrechtlicher Relevanz.&lt;/jats:p&gt

Violence against children by means of shaken baby syndrome: Criminal-sociological studies on the socio-economic state of suspects who made a confession

The shaken baby syndrome (SBS) is a common variant of the abusive head trauma in infants and toddlers, and it represents a particularly severe form of child abuse. Little is known about the socio-economic background of confessed perpetrators of SBS.The basis of the case collective, which was composed by using a multi-center approach including three institutes of legal medicine, were 72 expert reports in closed SBS cases on living infants and toddlers between 2006 and 2015. The actual study cohort comprises 16 suspects (4 women and 12 men), who had previously been identified during a comprehensive analysis of case-associated court files and who had confessed during the criminal proceeding.In the present study, a confession was predominantly made by suspects with a low state of education, with a low level of the working status, and with a low income. A low state of these three parameters basically corresponds to a low socio-economic state. Thus, only those people were willing to make a confession. It was striking that persons with a higher socio-economic state could not be found in the present study sample and, accordingly, those people did not make a confession.Therefore, the present data support the hypothesis that the willingness of making a confession to child abuse could be relatively small in higher social classes compared with persons having a lower socio-economic state. The aspects of the >> selective visibility of perpetrators << should be taken into account in preventive concepts

Two fatal tiger attacks in zoos

Two captive tiger attacks are presented that took place in Cologne and Munster zoos. Both attacks occurred when the handlers, intent on cleaning the enclosures, entered whilst the tigers accidently retained access to the location, and thus defended their territory against the perceived intruders. Both victims suffered fatal neck injuries from the bites. At Munster, colleagues managed to lure the tiger away from its victim to enable treatment, whilst the Cologne zoo tiger had to be shot in order to allow access to be gained. Whilst it was judged that human error led to the deaths of the experienced zookeepers, the investigation in Munster was closed as no third party was found to be at fault, whereas the Cologne zoo director was initially charged with being negligent. These charges were subsequently dismissed as safety regulations were found to be up to date

Magnetic resonance imaging of the proximal tibial epiphysis is suitable for statements as to the question of majority: a validation study in forensic age diagnostics

Determining majority plays a key role for forensic age diagnostics in living individuals. Recent data suggest that magnetic resonance imaging (MRI) of the proximal tibial epiphysis (PTE) may be a suitable alternative or at least an additional tool to clarify whether an individual has reached majority. However, the reference data situation is still sparse. Hence, the present dual center study retrospectively analyzed routine MRI of the knee in 413 cases (214 males and 199 females) of a Western Caucasian population aged between 12 and 25 years. MRI was performed at 1.5 and 3.0 T clinical scanners using T1- and T2-weighted sequences. The classification system by Vieth et al. (Eur Radiol 2018; 28:3255-3262) was applied for determining the ossification stages of the PTE. Intra-observer agreement was 'very good' (κ = 0.931), and inter-observer agreement was 'good' (κ = 0.798). Minimum ages above the age of 18 years were observed with the final stage (stage 6) in either sex (20.27 years in males and 18.55 years in females). The results are not in contradiction with the previous data and can be considered a strong and valuable support of the so far existing database. Therefore, the investigation of the PTE using routine MRI (either at 1.5 or 3.0 T) could be taken into consideration for application in forensic age estimation practice in near future