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Aim: The reversal of diverting loop ileostomy (DLI) is one of surgical trainees’ first procedures. Complications of DLI reversal can cause life-threatening complications and increase patient morbidity. This study compared DLI reversals performed by surgical trainees with those by attending surgeons.
Method: This retrospective cohort study was performed at a single primary care center on 300 patients undergoing DLI reversal. The primary outcome was morbidity, according to the Clavien-Dindo classification (CDC), with special attention paid to the surgeon’s level of training. The secondary endpoint was postoperative intestinal motility dysfunction.
Results: Surgical trainees had significantly longer operation times (p < 0.001) than attending surgeons. Univariate analyses revealed no influence on the level of training for postoperative morbidity. First bowel movement later than 3 days after surgery was a significant risk factor for CDC 3 (OR, 4.348; 96% CI, 1670–11.321; p = 0.003). Independent risk factors for surgical site infections (SSIs) were an elevated BMI (OR, 1.162; 95% CI, 1.043–1.1294; p = 0.007) and a delayed bowel movement (OR, 3.973; 95% CI, 1.300–12.138; p = 0.015). For postoperative intestinal motility dysfunction, an independent risk factor was a primary malignant disease (OR, 1.980; 95% CI, 1.120–3.500; p = 0.019), and side-to-side stapled anastomosis was a protective factor (OR, 0.337; 95% CI 0.155–0.733; p = 0.006).
Conclusion: Even though surgical trainees needed significantly more time to perform the surgery, the level of surgical training was not a risk factor for increased postoperative morbidity. Instead, delayed first bowel movement was predictive of SSI.
When skeletal remains are found, professionals try to identify the deceased. Specialists, i.e. forensic osteologists, forensic pathologists and anthropologists, are trained in the identification process and answer questions of human specificity, postmortem interval, individual features such as sex, age, height and ethnic origin, as well as signs of injury. Different imaging techniques can aid in the identification process. Further, there is a widely used computer software, Fordisc®, published by Stephen Ousley and Richard Jantz that uses discriminant function analysis for the classification of unknown skeletal remains regarding sex, ancestry and body height. It uses, among others, information from the Forensic Anthropology Data Bank (FDB), which is a centralized database with contemporary skeletal data from identified forensic cases. However, the applicability of Fordisc® to other populations than North America is questionable. In the past, scientists have expressed a desire for a European equivalent of the FDB or an update with a European reference sample. In order to generate a European reference sample, cranial and postcranial measurements must be collected from identified skeletal remains. This can be done either with an analog measuring technique, formed by anthropologists, or, as research has introduced, digitally. Other studies have already investigated whether classical osteometric measurements can be reconstructed and applied from post-mortem computed tomography scans. Digital osteology could be the key to generating a European reference sample more efficiently and without legal issues.
In this study, the two different methods were used to take craniometric measurements of 25 skulls. An analog and a digital measuring technique were applied to cranial and mandibular measurements, as used by the Forensic Data Bank Forms by Fordisc®. For the digital measuring technique, the skulls were first scanned with a computed tomography scanner and underwent 3D-reconstruction. The data collected from the two independent analog and digital measurements was statistically analyzed by “Comparison of multiple methods” and visualized with Bland & Altman plots. Of all the 39 measurements, 31 measurements showed a mean difference up to ±2 mm, which is the generally accepted error in an anthropological setting. Most of the measurements, which were not within the accepted error, utilized projection points in the 3D reconstructed image to measure landmarks. The statistical analysis showed significant proportional differences in 13 measurements (p<0,05). Further, the percentage errors were determined: most of the measurements had a median percentage error of < 3%, 17 of the 39 measurements had a median of < 1,5%.
This study shows that the following measurements of the Forensic Data Bank could possibly be used to collect digital cranial osseous data with a deviation of ≥- 2 mm to ≤ 2 mm: GOL, XCB, ZYB, BPL, MAB, AUB, UFHT, WFB, UFBR, NLH, NLB, OBB left, OBH right, OBH left, EKB, DKB, FRC, PAC, FOL, FOB, ASB, ZMB, MOW, HMF right, HMF left, TMF left, TMF right, GOG, CDB, WRB right, WRB left. Taking the percentage error into consideration, it is not clear whether all the measurements with an acceptable deviation still fulfill the requirements for digital data collection. Depending on the interpretation of the median percentage error, 24 to 31 accurate measurements were identified, which can possibly be used to generate a necessary reference sample from 3D reconstructed CT images for the Forensic Data Bank. This is something researchers have been asking for, as the quality of the results, when using Fordisc®, is population dependent. Nevertheless, research should continue concerning generally accepted percentage differences or errors in a digital setting, since the meaning of an accepted 2 mm deviation in anthropology, remains unclear.
Objectives and methods: Venous thromboembolic (VTE) events are emerging as frequent complications in acute myeloid leukemia (AML); however, there is insufficient data regarding epidemiology, risk factors, and impact on outcomes. The optimal approach to balance risks of thrombosis and hemorrhage remains unclear. This retrospective single-center study in AML patients undergoing induction chemotherapy between 2007 and 2018 assessed incidence, risk factors, features, and outcomes of early-onset VTE.
Results: 423 patients (median age 59 years) were enrolled. VTE was diagnosed in 31 patients (7.3%) within 3 months of admission. The median time to VTE was 3 days. Non-central venous catheter (CVC)-related VTE occurred in 19 patients (61%). Main risk factor for VTE was leukocytosis at admission, independent of platelet counts/INR. Four patients (13%) exhibited VTE recurrence. No deaths directly related to VTE or major bleeding events associated with platelet-adjusted anticoagulation in patients with VTE were recorded. There was no clear impact of VTE on 1-year overall survival; however, non-CVC-related VTE may be associated with adverse outcomes.
Conclusions: Early-onset VTE is a common complication in newly diagnosed AML patients admitted for induction chemotherapy. Leukocytosis is an independent VTE risk factor. The potentially adverse impact of non-CVC-related VTE merits further study.
Highlights
• NPM1/NPM1c induce the autophagy-lysosome pathway by activating the master regulator TFEB
• NPM1/NPM1c bind to GABARAP proteins via an atypical module in their N-terminal regions
• The pro-autophagic activity of NPM1c depends on this GABARAP binding module
Summary
The nucleolar scaffold protein NPM1 is a multifunctional regulator of cellular homeostasis, genome integrity, and stress response. NPM1 mutations, known as NPM1c variants promoting its aberrant cytoplasmic localization, are the most frequent genetic alterations in acute myeloid leukemia (AML). A hallmark of AML cells is their dependency on elevated autophagic flux. Here, we show that NPM1 and NPM1c induce the autophagy-lysosome pathway by activating the master transcription factor TFEB, thereby coordinating the expression of lysosomal proteins and autophagy regulators. Importantly, both NPM1 and NPM1c bind to autophagy modifiers of the GABARAP subfamily through an atypical binding module preserved within its N terminus. The propensity of NPM1c to induce autophagy depends on this module, likely indicating that NPM1c exerts its pro-autophagic activity by direct engagement with GABARAPL1. Our data report a non-canonical binding mode of GABARAP family members that drives the pro-autophagic potential of NPM1c, potentially enabling therapeutic options.
Hintergrund: Ein steigendes Einsatzaufkommen lässt sich sowohl im Rettungsdienst als auch im notärztlichen System in Deutschland verzeichnen. Oft werden dabei Fehleinsätze durch leicht erkrankte/verletzte Patienten als wachsende Problematik vermutet. Die vorliegende Untersuchung überprüft die Hypothese von steigenden Einsatzzahlen mit gleichzeitiger Zunahme von gegebenenfalls nichtindizierten Einsätzen.
Material und Methoden: Es erfolgte eine retrospektive Analyse der notärztlichen Einsätze des an der Universitätsklinik Frankfurt am Main stationierten Notarzteinsatzfahrzeugs von 2014 bis 2019. Die Analyse berücksichtigt zudem Faktoren wie die notärztliche Tätigkeit, Behandlungspriorität, Alarmierungsart und das Patientenalter.
Ergebnisse: Im beobachteten Zeitraum lässt sich ein Anstieg der notärztlichen Einsatzzahlen um mehr als 20 % erkennen. Der größte Anstieg zeigt sich bei Einsätzen, bei denen keine notärztliche Tätigkeit (+80 %) notwendig war. Einsätze der niedrigsten Behandlungspriorität (+61 %) sowie der höchsten Behandlungspriorität (+61 %) nahmen ebenfalls signifikant zu.
Diskussion: Die vorliegenden Zahlen stützen die Hypothese, dass bei signifikant gesteigertem Einsatzaufkommen mehr Einsätze durch den Notarzt bewältigt werden müssen, bei denen er rückblickend nicht notwendig gewesen wäre. Trotzdem gibt es auch mehr Patienten, die einen sofortigen Arztkontakt benötigen. Die hieraus resultierende erhöhte Einsatzfrequenz kann zu einer erhöhten Belastung sowie erschwerten zeitgerechten Disposition der notärztlichen Ressource führen.
Bei polytraumatisierten Patienten hat das Thoraxtrauma einen großen Einfluss auf den weiteren Verlauf und die Prognose der schwerverletzten Patienten. In verschiedenen Untersuchungen konnte bereits gezeigt werden, dass Interleukin-6 bei Traumata oder Gewebeschäden durch geplante Operationen vermehrt auftritt und dass vor allem bei Verletzungen des Thorax im Vergleich zu anderen Organen und Geweben ein deutlich höherer IL-6-Wert messbar ist.
In der vorliegenden retrospektiven Studie wurde bei einem Patientenkollektiv mit vergleichbarer Verletzungsschwere untersucht, ob eine Korrelation zwischen der Höhe des initialen IL-6-Wertes und der Komplikationsentwicklung nach schwerem isolierten Thoraxtrauma nachzuweisen ist und dadurch ein höherer IL-6-Wert im Schockraum mit einem erhöhten Risiko für Lungenversagen assoziiert ist.
Hierbei wurden insgesamt 62 Patienten mit einem AISThorax ≥ 3 und einem AIS-Wert <3 bezogen auf alle anderen Organsysteme untersucht, die zwischen dem 01.01.2015 und dem 31.12.2018 über den traumatologischen Schockraum des Universitätsklinikums Frankfurt aufgenommen wurden. Die Datenerhebung über den weiteren Verlauf wurde bis zehn Tage nach Aufnahme über die klinikinterne Dokumentation und das Traumaregister® der DGU ausgewertet. Betrachtet wurden hierbei der Verlauf der IL-6-Werte sowie präklinische und klinische Vitalparameter und klinische Parameter wie die Dauer des Intensivaufenthaltes, die Beatmungspflichtigkeit und Komplikationen wie die Entwicklung einer Pneumonie. Die Patienten wurden retrospektiv nach dem schlechtesten Horovitz-Quotienten in zwei Gruppen eingeteilt. Zehn Patienten zeigten einen Horovitz-Index < 200mmHg und wurden der Gruppe ‚Organversagen Lunge Ja‘ zugeteilt, die übrigen 52 Patienten mit einem Horovitz-Index ≥ 200mg wurden der Gruppe ‚Organversagen Lunge Nein‘ zugewiesen. In den beiden Gruppen zeigte sich vor allem bei Aufnahme in den Schockraum sowie einen Tag danach ein signifikanter Unterschied der IL-6-Werte mit einem IL-6 von 1171,2 ± 2879,7 pg/ml bei Aufnahme sowie 491,3 ± 662,0 pg/ml am ersten Tag nach Aufnahme in die Klinik in der Gruppe ‚Organversagen Lunge Ja‘. Demgegenüber wiesen die Patienten in der Gruppe ‚Organversagen Lunge Nein‘ einen signifikant geringeren IL-6-Wert mit 168,7 ± 279,3 pg/ml bei Aufnahme in den Schockraum sowie 120,0 ± 136,3 pg/ml am ersten Tag nach Aufnahme auf. Der schwerere Verlauf des Thoraxtraumas zeigte sich deutlich in der Gruppe ‚Organversagen Lunge Ja‘: Neben einer initialen Beatmungspflicht von 100 % im Gegensatz zu 36,5 % der Patienten der Gruppe ‚Organversagen Lunge Nein‘ konnte auch hier eine signifikant höhere Rate von Reintubationen, Tracheotomien und Pneumonien bei deutlich längerer Zeit der invasiven Beatmung festgestellt werden. Auch die gesamte Verweildauer auf der Intensivstation war dementsprechend in der Gruppe ‚Organversagen Lunge Ja‘ mit 16,2 ± 9,0 Tagen deutlich länger als in der Gruppe ‚Organversagen Lunge Nein‘ (6,7 ± 6,5 Tage). Insgesamt bestätigen die vorliegenden Daten, dass mit einem initial erhöhten gemessenen IL-6 ein gesteigertes Risiko einhergeht, ein Lungenversagen zu entwickeln.
Background: Percutaneous left atrial appendage occlusion (LAAO) represents an alternative stroke prevention method in patients with atrial fibrillation and an increased bleeding risk, chronic kidney disease or contraindications to oral anticoagulants. Aim of our study was to evaluate the feasibility and safety of percutaneous LAAO in high-risk, frail patients having undergone transcatheter aortic valve implantation (TAVI).
Methods: Thirty-one patients having undergone TAVI and scheduled for LAAO were prospectively included in our study.
Results:Implantation was successful in 29 of 31 cases (93.5%).There were no patients that developed a major acute cardiovascular event, stroke, or device dislocation/embolization. There was a single case of major bleeding (3.2%) and 3 cases of acute kidney injury (9.7%). At 3 months, no patients experienced a stroke, one patient had a device-related thrombus (3.4%), one patient showed a significant peri-device leak, and one patient had a persistent iatrogenic atrial septal defect.
Conclusions: Our study shows that percutaneous LAAO may represent a feasible alternative strategy for stroke prevention, that can be safely performed in high-risk, multimorbid patients with high bleeding risk or contraindications to oral anticoagulation.
Objective: To evaluate a novel healthcare programme for the treatment of patients with hip and knee osteoarthritis in southern Germany in terms of clinical and health economic outcomes. The study is based on claims data from 2014 to 2017.
Methods: We conducted a retrospective comparative cohort study of 9768 patients with hip and knee osteoarthritis, of whom 9231 were enrolled in a collaborative ambulatory orthopaedic care programme (intervention group), and 537 patients received usual orthopaedic care (control group). Key features of the programme are coordinated care, morbidity-adapted reimbursement and extended consultation times. Multivariable analysis was performed to determine effects on health utilisation outcomes. The economic analysis considered annual costs per patient from a healthcare payer perspective, stratified by healthcare service sector. Besides multivariable regression analyses, bootstrapping was used to estimate confidence intervals for predicted mean costs by group.
Results: Musculoskeletal-disease-related hospitalisation was much less likely among intervention group patients than control group patients [odds ratio (OR): 0.079; 95% CI: 0.062–0.099]. The number of physiotherapy prescriptions per patient was significantly lower in the intervention group (RR: 0.814; 95% CI: 0.721–0.919), while the likelihood of participation in exercise programmes over one year was significantly higher (OR: 3.126; 95% CI: 1.604–6.094). Enrolment in the programme was associated with significantly higher ambulatory costs (€1048 vs. €925), but costs for inpatient care, including hospital stays, were significantly lower (€1003 vs. €1497 and €928 vs. €1300 respectively). Overall annual cost-savings were €195 per patient.
Conclusions: Collaborative ambulatory orthopaedic care was associated with reduced hospitalisation in patients with hip and knee osteoarthritis. Health costs for programme participants were lower overall, despite higher costs for ambulatory care.
The thickness of a material has a significant impact on its fracture load. The aim of the study was to find and describe a mathematical relationship between the material thickness and the fracture load for dental all-ceramics. In total, 180 specimens were prepared from a leucite silicate ceramic (ESS), a lithium disilicate ceramic (EMX), and a 3Y-TZP zirconia ceramic (LP) in five thicknesses (0.4, 0.7, 1.0, 1.3, and 1.6 mm; n = 12). The fracture load of all specimens was determined using the biaxial bending test according to the DIN EN ISO 6872. The regression analyses for the linear, quadratic, and cubic curve characteristics of the materials were conducted, and the cubic regression curves showed the best correlation (coefficients of determination (R2): ESS R2 = 0.974, EMX R2 = 0.947, LP R2 = 0.969) for the fracture load values as a function of the material thickness. A cubic relationship could be described for the materials investigated. Applying the cubic function and material-specific fracture-load coefficients, the respective fracture load values can be calculated for the individual material thicknesses. These results help to improve and objectify the estimation of the fracture loads of restorations, to enable a more patient- and indication-centered situation-dependent material choice.
Ziel dieser Studie war es, zu untersuchen, ob der Ausbildungsstand des Operierenden einen Einfluss auf das Ergebnis der Ileostomarückverlagerung (ILSRV) bei den Patienten hat. Die ILSRV ist eine der ersten Operationen am Darm, die Assistenzärztinnen und Assistenzärzte durchführen. Dennoch können bei dieser Operation potenziell lebensbedrohliche Komplikationen, wie die Undichtigkeit der Naht (Anastomoseninsuffizienz), auftreten. Um eine ausreichende Patientensicherheit zu gewährleisten, sollte daher sichergestellt werden, dass die Durchführung dieser Operation durch Assistenzärztinnen und Assistenzärzte keine erhöhte postoperative Morbidität und Letalität für Patienten verursacht.
Für diese Studie wurden 300 Patienten mit einer Ileostomarückverlegung retrospektiv untersucht. Als primärer Endpunkt wurde die Morbidität, entsprechend der Clavien-Dindo-Klassifikation (CDC), mit besonderem Augenmerk auf den Ausbildungsstand der Operierenden definiert. Als sekundärer Endpunkt wurde die postoperative Darmmotilitätss
The mechanisms underlying the altered postural control and risk of falling in patients with osteoporosis are not yet fully understood. The aim of the present study was to investigate postural sway in women with osteoporosis and a control group. The postural sway of 41 women with osteoporosis (17 fallers and 24 non-fallers) and 19 healthy controls was measured in a static standing task with a force plate. The amount of sway was characterized by traditional (linear) center-of-pressure (COP) parameters. Structural (nonlinear) COP methods include spectral analysis by means of a 12-level wavelet transform and a regularity analysis via multiscale entropy (MSE) with determination of the complexity index. Patients showed increased body sway in the medial–lateral (ML) direction (standard deviation in mm: 2.63 ± 1.00 vs. 2.00 ± 0.58, p = 0.021; range of motion in mm: 15.33 ± 5.58 vs. 10.86 ± 3.14, p = 0.002) and more irregular sway in the anterior–posterior (AP) direction (complexity index: 13.75 ± 2.19 vs. 11.18 ± 4.44, p = 0.027) relative to controls. Fallers showed higher-frequency responses than non-fallers in the AP direction. Thus, postural sway is differently affected by osteoporosis in the ML and AP directions. Clinically, effective assessment and rehabilitation of balance disorders can benefit from an extended analysis of postural control with nonlinear methods, which may also contribute to the improvement of risk profiles or a screening tool for the identification of high-risk fallers, thereby prevent fractures in women with osteoporosis.
A 23-year observational follow-up clinical evaluation of direct posterior composite restorations
(2023)
The purpose of this observational follow-up clinical study was to observe the quality of posterior composite restorations more than 23 years after application. A total of 22 patients, 13 male and 9 female (mean age 66.1 years, range 50–84), with a total of 42 restorations attended the first and second follow-up examinations. The restorations were examined by one operator using modified FDI criteria. Statistical analysis was performed with the Wilcoxon Mann–Whitney U test and Wilcoxon exact matched-pairs test with a significance level of p = 0.05. Bonferroni–Holm with an adjusted significance level of alpha = 0.05 was applied. With the exception of approximal anatomical form, significantly worse scores were seen for six out of seven criteria at the second follow-up evaluation. There was no significant difference in the first and second follow-up evaluations in the grades of the restorations with regard to having been placed in the maxilla or mandible, as well as for one-surface or multiple-surface restorations. The approximal anatomical form showed significantly worse grades at the second follow-up when having been placed in molars. In conclusion, the study results show that significant differences regarding FDI criteria in posterior composite restorations occur after more than 23 years of service. Further studies with extended follow-up time and at regular and short time intervals are recommended.
Dissecting the diversity of midbrain dopamine (DA) neurons by optotagging is a promising addition to better identify their functional properties and contribution to motivated behavior. Retrograde molecular targeting of DA neurons with specific axonal projection allows further refinement of this approach. Here, we focus on adult mouse DA neurons in the substantia nigra pars compacta (SNc) projecting to dorsal striatum (DS) by demonstrating the selectivity of a floxed AAV9-based retrograde channelrhodopsin-eYFP (ChR-eYFP) labeling approach in DAT-cre mice. Furthermore, we show the utility of a sparse labeling version for anatomical single-cell reconstruction and demonstrate that ChR-eYFR expressing DA neurons retain intrinsic functional properties indistinguishable from conventionally retrogradely red-beads-labeled neurons. We systematically explore the properties of optogenetically evoked action potentials (oAPs) and their interaction with intrinsic pacemaking in this defined subpopulation of DA neurons. We found that the shape of the oAP and its first derivative, as a proxy for extracellularly recorded APs, is highly distinct from spontaneous APs (sAPs) of the same neurons and systematically varies across the pacemaker duty cycle. The timing of the oAP also affects the backbone oscillator of the intrinsic pacemaker by introducing transient “compensatory pauses”. Characterizing this systematic interplay between oAPs and sAPs in defined DA neurons will also facilitate a refinement of DA neuron optotagging in vivo.
Highlights
• Retrograde dye perfusion facilitates functional analysis of aortic valve competency.
• Retrograde dye perfusion visualizes vasa vasorum of the aorta and pulmonary artery.
• Vasa vasorum of the pulmonary artery derive from conal coronary branches in humans.
Abstract
Introduction: Multiple cardiovascular conditions can lead to unexpected fatality, which is defined as sudden cardiac death. One of these potentially underlying conditions is aortic regurgitation, which can be caused by discrete changes of the geometry of the proximal aorta. To analyze aortic valve competency and furthermore to elucidate underlying pathological alterations of the coronary arteries and the vasa vasorum a perfusion method to simulate a diastolic state was designed.
Material and methods: A postmortem approach with retrograde perfusion of the ascending aorta with methylene blue was applied to three bodies. The procedure comprised cannulation of the brachiocephalic trunk, clamping of the aortic arch between brachiocephalic trunk and left carotid artery, infusion of 250 ml of methylene blue, and optical clearing of the superficial tissue layers after perfusion. Organs were examined directly following perfusion and after optical clearing.
Results: Assessment and visualization of aortic valve competency and the vasa vasorum were possible in all three instances. Visualization of the coronary perfusion was impaired by postmortem thrombus formation. Optical clearing did not provide additional information.
Discussion: The method presented here is a time- and cost-efficient way of visualizing aortic valve competency and the vasa vasorum. The visualization of the vasa vasorum highlights the potential of this method in basic research on diseases of the great arteries and coronaries. However, for a time-efficient functional analysis of the coronaries, other methods must be applied.
Einleitung: Funde von Knochen(fragmenten) können von Interesse für Strafverfolgungs- oder Denkmalbehörden sein. Die forensisch-osteologische Begutachtung kann zur Einordnung der Bedeutung des Fundes beitragen. Ziel der Studie war, durch eine Auswertung von am Institut für Rechtsmedizin Gießen begutachteten Knochenfunden einen Überblick über Umstände und Art der Funde sowie Umfang und Ergebnisse der Begutachtungen zu erhalten.
Material und Methoden: Für den Zeitraum von 2005 bis 2019 wurden im Institut archivierte osteologische Gutachten analysiert und Daten zu Fundort, -umständen, Humanspezifität, postmortalem Intervall, Spuren von Gewalteinwirkungen und die Ergebnisse weiterführender Untersuchungen ausgewertet.
Ergebnisse: Von 172 begutachteten Knochenfunden wurden 40 % in Wald- und Wiesengebieten aufgefunden. In 58 % enthielten die Funde menschliche Knochen, davon wurde in 32 % eine forensisch relevante Liegezeit nicht ausgeschlossen. Zeichen perimortaler Gewalteinwirkung fanden sich in 6 % menschlicher Knochenfunde. Ergänzende DNA-Untersuchungen wurden in 20 % aller Funde durchgeführt; davon verlief in 62 % die Typisierung humaner STR erfolgreich, und in 41 % gelang die Zuordnung zu einem antemortalen Profil. Bei den zur Begutachtung übersandten nichtmenschlichen Knochen handelte es sich am häufigsten um Knochen von Hirsch bzw. Reh (32 %), Schwein (29 %) und Rind (14 %).
Diskussion: Die Begutachtung von Knochenfunden soll Behörden ermöglichen, die (straf-)rechtliche Relevanz eines Fundes einzuordnen. Die makroskopische Untersuchung ist dafür von großer Bedeutung. Für die Identifizierung menschlicher Knochen besitzen DNA-Vergleichsuntersuchungen einen großen Stellenwert. Sie waren für 81 % der erfolgreichen Identifizierungen der Fälle mit menschlichen Knochen verantwortlich.
Im Rahmen der Obduktion des Leichnams einer angeblich im 7. Monat Schwangeren wurde ein toter Fetus geborgen. Dieser war durch Fäulnis und Madenfraß stark verändert und wog 405 g, wobei in Anbetracht des zu Verlust gegangenen Gewebes von einem Gewicht zum Zeitpunkt des Todes über 500 g auszugehen war. Die übrigen erhobenen Maße sprachen wenigstens für ein Erreichen der 26. Schwangerschaftswoche. Dennoch wurde aufgrund des Gewichts eine Einordnung als Fehlgeburt vorgenommen. Gemäß dem später, am 01.11.2018, geänderten § 31 PStV wäre eine Klassifikation als Totgeburt möglich geworden.
Hintergrund: Nach dem Grundgesetz der Bundesrepublik Deutschland (GG) liegt die Gesetzgebungsbefugnis für Todesfeststellung und Leichenschau bei den Ländern, während das Personenstandswesen in die Bundesgesetzgebungsbefugnis fällt. Das Personenstandsrecht ist im Personenstandsgesetz (PStG) und der Personenstandsverordnung (PStV) geregelt.
Ziel der Arbeit: Untersucht werden sollten evtl. Auswirkungen der Änderung des § 31 PStV vom 01.11.2018 auf die ärztliche Leichenschau. Konkret ging es um die Abgrenzung der Tot- von der Fehlgeburt und damit der Pflicht zur ärztlichen Leichenschau unter Berücksichtigung der Bundes- und Landesgesetzgebung.
Methodik: Die „Bestattungsgesetze“ der 16 Bundesländer sowie dazugehörige Verordnungen und das PStG und die PStV wurden systematisch analysiert.
Ergebnisse: In 12 der 16 Ländergesetze wird das Totgeborene bzw. tot geborene Kind – in Abgrenzung zur Fehlgeburt (Fehlgeborenes) – über das Geburtsgewicht von mindestens 500 g definiert. In Hessen, Bremen und im Saarland wird zusätzlich als alternatives Kriterium die 24. Schwangerschaftswoche (SSW) genannt. Das Kriterium „Erreichen der 24. SSW“ kam im bremischen und saarländischen Bestattungsrecht nach der Änderung des § 31 PStV hinzu. Im hessischen Friedhofs- und Bestattungsgesetz ist alternativ „nach der 24. SSW geboren“ verwendet.
Diskussion: Unabhängig von der nicht abschließend geklärten Frage, ob es sich bei einer Totgeburt um einen personenstandsrechtlichen „Sterbefall“ handelt, lässt sich eine von den „Bestattungsgesetzen“ der Länder unabhängige Leichenschaupflicht ableiten: bei der Annahme eines Sterbefalls unmittelbar aus § 38 Nr. 4 PStV, bei Ablehnung mittelbar aus § 33 S. 3 PStV i. V. m. § 5 PStV. Für diese Leichenschaupflicht müssten bezüglich der Leichendefinition die Kriterien des Personenstandsrechts gelten. Demnach wäre in allen Bundesländern – unabhängig von den Kriterien in den jeweiligen „Bestattungsgesetzen“ – zur Differenzierung zwischen Totgeburt und Fehlgeburt das alternative Merkmal „Erreichen der 24. Schwangerschaftswoche“ zu überprüfen, falls die tote Leibesfrucht, die keine Zeichen des Gelebthabens außerhalb des Mutterleibs aufweist, unter 500 g wiegt.
Bones found by chance can be of great criminal or historical interest. The nature of their appraisal depends on the individual case, the locally effective legislation and the available resources. To assess whether a find is relevant with respect to criminal investigation, the circumstances of the find and the results of the forensic examination carried out by trained personnel must be considered. The aim of this study was to obtain an overview of the circumstances and nature of the finds as well as the results of the subsequent expert opinions by evaluating bone finds from the federal state of Hesse, Germany. For this purpose, over a 10-year period from 2011 to 2020, all bone finds examined at the Institutes of Legal Medicine in Gießen and Frankfurt am Main, Germany, were evaluated retrospectively with regard to the locations and circumstances of the finds, their nature (human or non-human), the postmortem interval, possible traces of violent impact and the results of further examinations. Of the 288 bone finds evaluated, 38.2% were found in forests, meadows and parks. In 50.7%, the finds contained human bones, of which 37.0% had a forensically relevant postmortem interval of 50 years or less. Evidence of trauma was described in 77.4% of the human bone cases: postmortem damage in 78.8%, peri-mortem injury in 9.7% and ante-mortem injury in 11.5%. DNA examinations were performed in 40.4% of the human bone finds. They yielded STR profiles in 81.3%, leading to a definite identification in 35.4%. Among the non-human bones sent in, the most common were bones from pigs (23.4%), deer (18.1%), cattle (16.4%), roe deer (11.7%) and sheep (11.7%). The macroscopic examination is the first step of the forensic-osteological evaluation and sets the course for further examinations or investigations. DNA examinations are of great importance for the reliable identification of human bones. They were responsible for 70.8% of successful identifications.
Die im Rahmen der Pathogenese der Erkrankung und der folgenden Chemotherapie entstehende Neutropenie prädisponiert AML-Patienten für lebensbedrohliche Infektionen. Um diese zu vermeiden, erfolgt während der Induktionschemotherapie eine antiinfektive Prophylaxe mit Antibiotika. Dabei ist zu beachten, dass Antibiotika den größten Risikofaktor für die Entwicklung einer CDI darstellen. C. difficile gilt als der häufigste nachgewiesene Erreger nosokomialer Diarrhoen. Aufgrund dessen führte das Universitätsklinikum Frankfurt eine retrospektive Studie zur Inzidenzentwicklung der CDI und zur klinischen Rolle von CDI bei AML-Patienten unter Induktionschemotherapie durch. Ein besonderer Fokus der Studie lag auf der Identifikation von Risikofaktoren für die Entstehung einer CDI.
Die Studie inkludierte 415 homogen therapierte AML-Patienten, die sich zwischen Januar 2007 und Juni 2019 einer Induktionschemotherapie am Universitätsklinikum Frankfurt am Main unterzogen. AML-Patienten, die Diarrhoen entwickelten und in deren Stuhlproben toxinproduzierende C. difficile-Bakterien nachgewiesen wurden, wurden als AML-Patienten mit CDI definiert. Es erfolgte eine detaillierte Dokumentation aller während des Aufenthalts zur Induktionschemotherapie eingesetzten Antibiotika und Antimykotika. Um die Entwicklung der Inzidenz der CDI im Verlauf zu analysieren, wurde der Beobachtungszeitraum in zwei Abschnitte unterteilt.
Im Studienzeitraum wurde bei 37 (8,9%) von 415 AML-Patienten eine CDI nachgewiesen, wobei die Inzidenz zwischen 2013 und 2019 im Vergleich zu 2007 bis 2012 um 60,9% gesunken ist. Bedingt wird dies am ehesten durch die steigende Sensibilisierung gegenüber den negativen Auswirkungen einer Antibiotikatherapie und der Implementierung des ABS-Programmes. Die Studie bestätigt die etablierten Präventionsmaßnahmen des Universitätsklinikums Frankfurt am Main und spiegelt die Entwicklung in den westlich geprägten Ländern Europas wider.
Die Studie gibt Hinweise, dass die CDI den klinischen Verlauf der AML-Patienten unter Induktionschemotherapie nur geringfügig beeinträchtigt. Zwar wiesen AMLPatienten mit CDI mehr Fiebertage auf, dies resultierte jedoch nicht in erhöhten CrP-Werten, in einer längeren Hospitalisierung oder in einer erhöhten Rate an Intensivaufenthalten. Zwischen den betrachteten Patientenkohorten ergaben sich keine Differenzen bezüglich des Erreichens einer CR und der Gesamtmortalität. AML-Patienten mit CDI wiesen weder mehr MREBesiedelungen auf, noch kam es zu häufigeren Episoden eines ANV in dieser Patientengruppe. Besonders letzteres war unter Berücksichtigung des erheblichen Risikos einer Hypovolämie durch die Diarrhoen nicht zu erwarten, da diese für ein Nierenversagen prärenaler Genese rädisponiert.
Die Analyse bestätigt die Einordnung von Antibiotikatherapien als erheblichen Risikofaktor für eine CDI. Vor allem von den Antibiotikagruppen der Glykopeptid und Carbapenem-Antibiotika ging ein erhöhtes Risiko aus. Durch die Vorgabe des bei therapierefraktären Infektionen einzusetzenden Breitspektrumantibiotikums beeinflussen hausinterne Leitlinien das individuelle Risiko eines Antibiotikums für eine CDI entscheidend. Weiterhin weist die Studie darauf hin, dass Antimykotika nicht als Risikofaktor für eine CDI eingeordnet werden können. Durch das Studiendesign und fehlende Studien zu dieser Thematik kann jedoch keine endgültige Aussage über die Rolle von Antimykotika in der Pathogenese der CDI getroffen werden.
Bezüglich der Therapie der CDI kann die Studie aufgrund der kleinen Patientenkohorte und des inzwischen geänderten Therapieregimes der CDI bei AML-Patienten keine Aussage über die Effektivität der Therapie oder der Überlegenheit eines Medikaments treffen.
Aim and Objectives: We aimed to test the impact of age on long-term urinary continence (≥12 months) in patients undergoing robotic-assisted radical prostatectomy. Methods and Materials: We relied on an institutional tertiary-care database to identify the patients who underwent robotic-assisted radical prostatectomy between January 2014 and January 2021. Patients were divided into three age groups: age group one (≤60 years), age group two (61–69 years) and age group three (≥70 years). Multivariable logistic regression models tested the differences between the age groups in the analyses addressing long-term urinary continence after robotic-assisted radical prostatectomy. Results: Of the 201 prostate cancer patients treated with robotic-assisted radical prostatectomy, 49 (24%) were assigned to age group one (≤60 years), 93 (46%) to age group two (61–69 years) and 59 (29%) to age group three (≥70 years). The three age groups differed according to long-term urinary continence: 90% vs. 84% vs. 69% for, respectively, age group one vs. two vs. three (p = 0.018). In the multivariable logistic regression, age group one (Odds Ratio (OR) 4.73, 95% CI 1.44–18.65, p = 0.015) and 2 (OR 2.94; 95% CI 1.23–7.29; p = 0.017) were independent predictors for urinary continence, compared to age group three. Conclusion: Younger age, especially ≤60 years, was associated with better urinary continence after robotic-assisted radical prostatectomy. This observation is important at the point of patient education and should be discussed in informed consent.
Endogenous time of day-dependent modulation of brain activity and visual perception in humans
(2023)
Earth’s rotation and the resulting day-night cycle of solar irradiance causes rhythmic changes in environmental conditions. The circadian system anticipates these predictable challenges and the brain integrates this information with homeostatic cues in order to time behavior accordingly. Humans highly depend on the visual system, which is most drastically affected by planetary rotation, with the most pronounced changes occurring during twilight. Yet, it is still unclear how visual perception and its underlying neural processes are modulated according to the time of day. We thus investigated human brain activity in constant dim light via the fMRI BOLD-signal during resting-state and a close-to-threshold visual detection task over 6 times of the day.
BOLD-variability decreased endogenously at times of twilight in sensory cortices during resting-state and, even more, in the visual cortex during visual perception at these times. Furthermore, the visual cortex BOLD-variability reductions were associated with improved visual detection performance. In contrast, mean BOLD-activations related to visual perception were not significantly modulated by the time of day.
In conclusion, these results imply that the visual cortex BOLD-variability reductions at times of twilight constitute a predictive mechanism facilitating visual perception to compensate for the degraded visual signal quality at these times. Individual chronotype and homeostatic sleep pressure explained part of the BOLD-variability modulation, suggesting a combined circadian and homeostatic regulation. Human activity usually extends into times of twilight, even in preindustrial societies. Therefore, anticipatory optimization of the visual system at twilight may have been crucial for survival and may still be relevant today whenever electric light is not available at these times. Moreover, the findings suggest that endogenous BOLD-variability reductions in sensory cortices constitute a novel general mechanism underlying enhanced close-to-threshold perception, further supporting the biological significance of BOLD-variability.
Objectives: Patients with open pulmonary tuberculosis (opTB) are subject to strict isolation rules. Sputum smear microscopy is used to determine infectivity, but sensitivity is lower than for culture. This study aimed to investigate the clinical relevance of this mismatch in contemporary settings.
Methods: Differential results between microscopy and culture were determined at the time of microscopic sputum conversion, from all patients with opTB between 01/2013 and 12/2017. In addition, data on HIV, multi/extensive drug-resistant TB status, time to smear- and cultural-negativity conversion were analyzed; and a Kaplan-Meier curve was developed.
Results: Of 118 patients with opTB, 58 had demographic data available for microbiological and clinical follow-up analysis; among these, 26 (44.8%) had still at least one positive culture result. Median time from opTB-treatment initiation to full microscopic sputum- or culture conversion, was 16.5 days (range 2-105), and 20 days (1-105), respectively (median difference: +3.5 days). Sixteen days after de-isolation, >90% had converted culturally. HIV- or multi/extensive drug-resistant TB status did not impact conversion time.
Conclusion: When patients with opTB were de-isolated after 3 negative sputum smear microscopy tests, a substantial part still revealed cultural growth of Mycobacterium tuberculosis complex, but it remains unclear, whether smear-negative and culturally-positive individuals on therapy are really infective. Thus, the clinical relevance of this finding warrants further investigation.
In this case report, we present a rare case of a female patient who developed pain and swelling after a total knee arthroplasty. An extensive diagnostic workup including serum and synovial testing to rule out infection was performed in addition to advanced imaging including an MRI of the knee, but it was only after an arthroscopic synovectomy that the diagnosis of secondary synovial chondromatosis was confirmed. The purpose of this case report is to highlight the occurrence of secondary synovial chondromatosis as a rare cause of pain and swelling after total knee arthroplasty, thereby assisting clinicians in providing prompt diagnosis, surgical treatment, and efficient recovery in the setting of secondary synovial chondromatosis after total knee arthroplasty.
Of mice and men: a semiquantitative analysis of Kv4.3 expression in mouse and human midbrains
(2024)
Idiopathic Parkinson syndrome is one of the most common neurodegenerative diseases and plays a major role in clinical neurological practice. However, the exact pathogenesis has not yet been fully elucidated. It is assumed that a combination of genetic and environmental factors fuels a neurodegenerative process during aging, which result in a selective loss of dopaminergic neurons in the substantia nigra. In rare instances, Parkinson disease (PD) is caused by single toxic-gain of function mutations for instance a single amino acid exchange (A53T) in the gene coding for a-synuclein (SNCA). A central event in idiopathic and mono-genetic PD is the formation of intracytoplasmic accumulation of α-synuclein in so-called Lewy bodies. On this basis, a mouse model was developed that overexpresses human α-synuclein through an A53T mutation in the SNCA gene. In previous work, this mutation was found to lead to both oxidative dysfunction and enhanced expression of Kv4.3 channels in middle-aged mice. Given the central role of aging in the pathogenesis of neurodegeneration, this study analyzed Kv4.3 protein expression in dopamine midbrain neurons using immunohistochemical methods in aged male transgenic A53T SNCA and wildtype mice.
Using semi-quantitative analysis of confocal images of fluorescent Kv4.3 immunosignals, I found significantly reduced Kv4.3 protein expression in old A53T SNCA animals compared to those in age-matched WT mice.
To improve comparison between mouse models and human brain tissue, I also developed a protocol for identical histological processing of human and murine brain sections and Kv4.3 immunohistochemistry. This protocol will be useful to study Kv4.3 expression in DA neurons of human control brains and in various stages of PD.
Highlights
• Pediatric patients with RASopathies exhibit an increased heart mass.
• Cardiomyocyte size and volume are reduced in pediatric patients with RASopathies.
• Cardiomyocyte numbers per heart are increased in pediatric RASopathy patients.
• Cardiomyocytes in juvenile RASopathy have an immature state.
• Elevated LV mass in RASopathy patients is mainly due to cardiomyocyte hyperplasia.
Abstract
Aims: RASopathies are caused by mutations in genes that alter the MAP kinase pathway and are marked by several malformations with cardiovascular disorders as the predominant cause of mortality. Mechanistic insights in the underlying pathogenesis in affected cardiac tissue are rare. The aim of the study was to assess the impact of RASopathy causing mutations on the human heart.
Methods and results: Using single cell approaches and histopathology we analyzed cardiac tissue from children with different RASopathy-associated mutations compared to age-matched dilated cardiomyopathy (DCM) and control hearts. The volume of cardiomyocytes was reduced in RASopathy conditions compared to controls and DCM patients, and the estimated number of cardiomyocytes per heart was ∼4–10 times higher. Single nuclei RNA sequencing of a 13-year-old RASopathy patient (carrying a PTPN11 c.1528C > G mutation) revealed that myocardial cell composition and transcriptional patterns were similar to <1 year old DCM hearts. Additionally, immaturity of cardiomyocytes is shown by an increased MYH6/MYH7 expression ratio and reduced expression of genes associated with fatty acid metabolism. In the patient with the PTPN11 mutation activation of the MAP kinase pathway was not evident in cardiomyocytes, whereas increased phosphorylation of PDK1 and its downstream kinase Akt was detected.
Conclusion: In conclusion, an immature cardiomyocyte differentiation status appears to be preserved in juvenile RASopathy patients. The increased mass of the heart in such patients is due to an increase in cardiomyocyte number (hyperplasia) but not an enlargement of individual cardiomyocytes (hypertrophy).
Objective: This study presents data from the admission trial to show the feasibility, safety and effectiveness of the Nit-Occlud® Lê VSD in the treatment of perimembranous ventricular septal defects with an aneurysmal configuration and a diameter up to 8 mm.
Background: The majority of ventricular septal defects (VSD) are still closed surgically, while a less invasive transcatheter treatment by closure devices is available. Device-based closure is reported to be associated with the risk of complete atrio-ventricular block, especially with double-disc devices in perimembranous defects.
Methods: In six tertiary centers in Germany and Israel, an interventional closure of a periembranous VSD was attempted in 88 patients using the Nit-Occlud® Lê VSD.
Results: The interventional VSD closure was performed in 85 patients. Patients had a median age of 8.0 (2–65) years and a median body weight of 26.7 (10–109) kg. A complete closure of the defects was achieved in 85.4% 2 weeks after device implantation, in 88.9% after three months and in 98.6% at the 5-year follow-up. There was no incidence of death during the study nor did any patient suffer of permanent atrio-ventricular block of higher degree. Serious adverse events, by definition, are potentially life-threatening or require surgery to correct, while major serious events require medical or transcatheter intervention to correct. The study results exhibit a serious adverse event rate of 3.5% (3/85 patients) and a major adverse event rate of 5.9% (5/85 patients).
Conclusion: The Nit-Occlud® Lê VSD coil offers the possibility of an effective and safe approach in patients with aneurysmal perimembranous ventricular septal defects.
Background: Newborns with hypoplastic left heart (HLH) are usually palliated with the Norwood procedure or a hybrid stage I procedure. Hybrid is our preferred approach. Given the critical relationship between stage I, interstage, and comprehensive stage II or advanced biventricular repair, we hypothesized that appropriate drug treatment is a significant therapeutic cornerstone, especially for the management of the high-risk interstage.
Methods: We report a single-center observational study addressing the cardiovascular effects of, in particular, oral β-blockers and the additional use of angiotensin-converting enzyme (ACE) and mineralocorticoid inhibitors.
Results: In total, 51 newborns—30 with HLH syndrome (HLHS) and 21 with HLH complex (HLHC)—with a median bodyweight of 3.0 kg (range 1.9–4.4; nine with bodyweight ≤ 2500 g) underwent an uneventful “Giessen hybrid approach” using a newly approved duct stent. All patients were discharged home with a single, double or triple therapy consisting of ß-blockers, ACE and mineralocorticoid inhibitors; 90% of the patients received bisoprolol, 10% received propranolol, 72% received lisinopril, and 78% received spironolactone. Resting heart rate decreased from 138 bpm (range 112–172; n = 51) at admission to 123 bpm (range 99–139; n = 51) at discharge and 110 bpm before stage II/biventricular repair/heart transplantation (range 90–140; n = 37) accompanied by favorable bodyweight gain. No side effects were evident.
Conclusion: In view of drug risk/benefit profiles, as well as the variable morphology and hemodynamics, the highly selective β1-adrenoceptor blocker bisoprolol is our preferred drug for treatment of HLHS/HLHC in the interstage. We avoid using ACE inhibitor monotherapy and exclude potential risks for coronary and cerebral perfusion pressure beforehand.
Arterial duct stenting, pioneered in the early 1990s for newborns with a duct-dependent pulmonary and systemic circulation, has evolved significantly over the past decades. This progressive technique has led to the development of novel therapeutic strategies, including the Hybrid approach introduced three decades ago, and more recently, a complete transcatheter approach for treating newborns with hypoplastic left heart syndrome (HLHS). Subsequently, the transcatheter method has been extended to bi-ventricular lesions and patients with pulmonary hypertension, establishing a reverse Potts-shunt pathophysiology. Considering current experiences, this review aims to assess the strengths, weaknesses, and complications associated with ductal stenting, which represents a critical component of these complex treatment strategies. Despite advancements, the mortality rate of Norwood and Hybrid stage-1 procedures has plateaued, underscoring the importance of enhancing the quality of life of affected patients as the primary therapeutic goal. The prerequisite is a gentle, almost atraumatic medicine, particularly during the newborn period. It is essential to recognize that both the Hybrid and total transcatheter approaches demand comparable experience to Norwood surgery. Successful outcomes hinge on much more than merely inserting a stent into the duct; they require meticulous attention to detail and comprehensive management strategies.
Given the heterogenous etiology of pediatric heart failure (pHF), evidence-based studies improving pHF are unlikely. A paradigm shift towards updated medicine-based evidence is therefore necessary. In view of the life expectancy of children, cardiac regeneration strategies are required. Therefore, age- and disease-related differences in myocardial (receptor) physiology require individualized precision medicine. First-line diuretic therapy, adopted from the treatment of adults with HF with no chance for recovery, should be questioned in the treatment of pHF with potential for recovery. Inadequate use of diuretics is a common reason for additional stimulation of the neurohumoral axis. Consecutive intravascular volume depletion led to an inadequate treatment with β-blocker and renin–angiotensin–aldosterone antagonists. Given the age-related catecholamine-driven cardiovascular (patho-) physiology, highly selective β1-blockers (bisoprolol) protect against β1-(noradrenaline)-related myocytic apoptosis and necrosis, but allow β2-receptor-mediated myocardial regeneration. Based on its high safety–efficacy profile with rarely seen adverse effects but easily monitorable efficacy by the surrogate of heart rate (reduction), bisoprolol is our first-line drug in infancy. Reduced heart rate economizes the heart and full body oxygen consumption and extends the diastolic filling and coronary perfusion time. Based on our many years of institutional experience, physicians should be encouraged to use β1-selected blockers in infants with dilated cardiomyopathy and hypoplastic left heart syndrome after stage-1 procedure, but also to treat ventricular septal defects with a significant left-to-right shunt. In summary, individualized pHF therapy is the prerequisite for a causal treatment to improve HF symptoms, but above all for the most functional regeneration possible.
The hypoplasia of left-sided heart structures shows great variability and complexity. What the many variants have in common is that their heart structures are neither fully developed before nor after birth. Fetuses and newborns require an individual therapy depending on anatomy and function of the heart. Fetal interventions focus on improving left heart structures by catheter-based interventions and maternal hyperoxygenation which promotes growth as the left ventricular preload and blood flow within the cavity increase. Stage-I management of newborns with single ventricle physiology is usually based on the Norwood/Sano surgery or the Hybrid approach. Two more steps are required to ultimately achieve a Fontan circulation. Some centers also use the Hybrid approach for subsequent Norwood operation beyond the neonatal period. After the Hybrid approach, a comprehensive stage-II or corrective surgery is performed, the latter if a bi-ventricular circulation is possible. With progressively improved catheter-based interventions, particularly ductal stenting and manipulations of the atrial septum, the next advance is to develop a bespoke flow restrictor that can be easily inserted into the branches of the pulmonary artery. The main goal is to avoid complex heart operations under general anesthesia, followed by substantial intensive care in the neonatal period, especially for patients with complex heart defects. Based on the current state of the art of surgical treatment of hypoplastic left heart syndrome and variants with the Norwood surgery or the Hybrid approach, our main focus is on an alternative percutaneous transcatheter technique in the sense of a completely non-surgical stage-I approach.
Ataxia telangiectasia is a monogenetic disorder caused by mutations in the ATM gene. Its encoded protein kinase ATM plays a fundamental role in DNA repair of double strand breaks (DSBs). Impaired function of this kinase leads to a multisystemic disorder including immunodeficiency, progressive cerebellar degeneration, radiation sensitivity, dilated blood vessels, premature aging and a predisposition to cancer. Since allogenic hematopoietic stem cell (HSC) transplantation improved disease outcome, gene therapy based on autologous HSCs is an alternative promising concept. However, due to the large cDNA of ATM (9.2 kb), efficient packaging of retroviral particles and sufficient transduction of HSCs remains challenging.
We generated lentiviral, gammaretroviral and foamy viral vectors with a GFP.F2A.Atm fusion or a GFP transgene and systematically compared transduction efficiencies. Vector titers dropped with increasing transgene size, but despite their described limited packaging capacity, we were able to produce lentiviral and gammaretroviral particles. The reduction in titers could not be explained by impaired packaging of the viral genomes, but the main differences occurred after transduction. Finally, after transduction of Atm-deficient (ATM-KO) murine fibroblasts with the lentiviral vector expressing Atm, we could show the expression of ATM protein which phosphorylated its downstream substrates (pKap1 and p-p53).
Purpose: Soft tissue infections can be severe and life-threatening. Their treatment consists currently in radical surgical wound debridement and combined systemic antimicrobial therapy. Different side effects are possible. Local antibiotic therapy represents a new approach to reduce side effects and improve healing. The aim of this study is to assess the effectiveness of the local sprayed use of antibiotics with fibrin sealing compared with negative pressure wound therapy as an established treatment of soft-tissue infections.
Methods: In this retrospective study, patients with soft tissue infections who underwent surgical treatment were analysed. One group consists of patients, who received local fibrin-antibiotic spray (FAS) (n = 62). Patients treated by vacuum-assisted wound therapy (VAWT) as the established treatment were the control group (n = 57). Main outcomes were differences in the success of healing, the duration until healing and the number of needed operations.
Results: Clinical healing could be achieved for 55 patients (98.21%) in the FAS group vs. 47 patients (92.16%) in the VAWT group (p = 0.19). Time to require this was 10.65 ± 10.38 days in the FAS group and 22.85 ± 14.02 days in the VAWT group (p < 0.001). In the FAS group, patients underwent an average of 1.44 ± 0.72 vs.3.46 ± 1.66 operations in the VAWT group (p < 0.001).
Conclusion: Compared to vacuum-assisted wound therapy in soft tissue infections, local fibrin-antibiotic spray shows faster clinical healing and less needed operations. Leading to shorter hospital stays and more satisfied patients. The combination of sprayed fibrin and antibiotics can be seen as a promising and effective method.
Um die muskarinische Modulation der GABAergen Übertragung zu untersuchen, wurden mit Hilfe der Patch- Clamp- Technik an akut isolierten IC Schnitten der Ratte (P4-P14) inhibitorische postsynaptische Ströme aufgezeichnet (IPSCs). Die Aufnahmen erfolgten bei einem Haltepotential von -60mV. In allen Experimenten konnte unter der Anwesenheit von Strychnin (0,5μM, Glycinrezeptor- Antagonist) und Kynurensäure (1mM; Glutamatrezeptoren- Antagonist) spontane GABAerge IPSCs in allen untersuchten IC-Neuronen aufgezeichnet werden. Die Anwesenheit von Kynurenat blockierte auch Ströme, die möglicherweise durch nAChRen mit der Untereinheit α7 vermittelt wurden.
Die Muskarin (1μM) Applikation zeigte, eine deutliche Erhöhung der IPSCs- Frequenz (618% der Kontrolle), was uns beweist, dass die Aktivierung von mAChRen im IC zu einer Steigerung der GABAergen Übertragung führt.
Die durch Muskarin induzierten IPSCs konnten komplett durch den GABAA- Rezeptor- Antagonisten Bicucullin (10μM und 50μM) blockiert werden. Dies zeigte, dass die IPSCS durch GABAA- Rezeptoren vermittelt wurden.
4-DAMP (50nM; M3-Rezeptor Antagonist) blockierte den durch Muskarin ausgelösten Anstieg der IPSC-Frequenz. Die Muscarin-Antagonisten Telenzepin (50nM; M1-präferierend), Methoctramin (10μM; bevorzugt M2) und Himbazin (10μM; bevorzugt M4) sowie der Nikotinrezeptor-Antagonist Mecamylamin (10μM) beeinflussten die Muskarinwirkung nicht signifikant.
Diese Ergebnisse deuten darauf hin, dass die muskarinische Modulation der GABAergen Übertragung hauptsächlich durch den M3-Rezeptor vermittelt wird, während M1-, M2- und M4- sowie Nikotinrezeptoren nicht wesentlich beteiligt sind.
In Gegenwart von Tetrodotoxin (0,5μM) konnte Muscarin die IPSC-Frequenz nicht erhöhen. Dies lässt auf eine über spannungsabhängige Natriumkanäle vermittelte erhöhte Transmitterausschüttung schließen. Zudem spricht dies für eine präterminale Modulation der GABAergen Transmission durch mAChRen.
Muskarin erhöhte die Häufigkeit der GABAergen IPSCs, ohne ihre Amplituden und Zerfallskinetik zu beeinflussen, was auf einen präsynaptischen Mechanismus hindeutet.
Muskarin veränderte den Membranruhestrom und die Leitfähigkeit in den untersuchten IC-Neuronen nicht.
Der Mechanismus der durch Muscarin induzierten Verstärkung der GABAergen Übertragung im IC muss noch abgeklärt werden.
Die Behandlung von akuten und chronischen Knocheninfektionen mit begleitender Weichteilinfektion besteht derzeit in einem radikalen chirurgischen Wunddebridement. Gute Ergebnisse konnten mit der kombinierten Unterdruck-Wundtherapie (NPWT) oder dem vakuumunterstützten Verschluss (VAC) erzielt werden. Zur Behandlung und Vorbeugung von Infektionen in der Chirurgie ist eine Kombination mit einer systemischen antimikrobiellen Behandlung erforderlich, die jedoch zahlreiche Nebenwirkungen mit sich bringt. Die lokale Antibiotikatherapie stellt einen neuen Ansatz zur Verringerung der Nebenwirkungen und zur Verbesserung der Heilung dar. Ziel dieser Studie ist es, die Wirksamkeit der kombinierten Verwendung von Fibrin mit Antibiotika im Vergleich zur Unterdruck-Wundtherapie als etablierte Behandlung von Weichteilinfektionen zu bewerten.
In dieser retrospektiven Studie wurden Patienten mit Weichteilinfektionen mit oder ohne Knochenbeteiligung, die sich einer chirurgischen Behandlung unterzogen, analysiert. Eine Gruppe bestand aus Patienten, die die neuartige Fibrin-Antibiotika-Sprühung (FAS) erhielten (n=62). Die Kontrollgruppe bestand aus Patienten, die mit der etablierten vakuumunterstützten Wundtherapie (VAWT) behandelt wurden (n=57). Hauptergebnisse waren Unterschiede im Heilungserfolg, in der Dauer bis zur Heilung und in der Anzahl der notwendigen Operationen.
In der FAS-Gruppe waren 55 Patienten (98,21%) nach der letzten Operation nicht mehr infiziert, in der VAWT-Gruppe war dies bei 47 Patienten (92,16%) der Fall (p = 0,19). Die Dauer bis zur klinischen Heilung ab der ersten Operation betrug in der FAS-Gruppe 10,65 +/- 10,38 Tage und in der VAWT-Gruppe 22,85 +/- 14,02 Tage (p < 0,001). In der FAS-Gruppe benötigten 41 Patienten eine Operation (66,13%) und 17 Patienten zwei Operationen (27,42%). Die Patienten der VAWT-Gruppe benötigen mindestens zwei (n=19; 33,34%), drei (n=19; 33,34%) oder mehr Operationen.
Im Vergleich zur vakuumunterstützten Wundtherapie bei Weichteilinfektionen zeigt Fibrin-Antibiotika-Spray bessere Ergebnisse. Die Heilung setzt schneller ein und es sind weniger Operationen erforderlich, was zu einer Verkürzung des Krankenhausaufenthalts, einem geringeren Narkoserisiko und einer höheren Patientenzufriedenheit führt. Die Kombination von Fibrin und Antibiotika kann als eine vielversprechende und wirksame Methode angesehen werden.
The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3,4,5,6,7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
Introduction: Multimorbidity is the simultaneous occurrence of several (chronic) diseases. Persons living with multimorbidity not only have complex care needs, but the burden of care often has a negative impact on their family lives, leisure time and professional activities. The aim of this project is to systematically review the literature to assess how multimorbidity affects the everyday lives of middle-aged persons, and to find out what abilities and resources help in the development of coping strategies to overcome the challenges of living with it.
Methods and analysis: We will systematically search for studies reporting on the everyday life experiences of middle-aged persons (30–60 years) with multimorbidity (≥2 chronic conditions) in MEDLINE, CINAHL, PsycINFO, Social Sciences Citation Index, Social Sciences Citation Index Expanded, PSYNDEX and The Cochrane Library from inception. We will include all primary studies that use quantitative, qualitative and mixed methodologies, irrespective of publication date/study setting.
Two independent reviewers will screen titles/abstracts/full texts, extract data from the selected studies and present evidence in terms of study/population characteristics, data collection method and the phenomenon of interest, that is, everyday life experiences of middle-aged persons with multimorbidity. Risk of bias will be independently assessed by two reviewers using the Mixed Methods Appraisal Tool. We will use a convergent integrated approach on qualitative/quantitative studies, whereby information will be synthesised narratively and, if possible, quantitatively.
Ethics and dissemination: Ethical approval is not required due to the nature of the proposed systematic review. Results from this research will be disseminated at relevant (inter)national conferences and via publication in peer-reviewed journals.
Background: A reliable distinction between ischemic stroke (IS) and intracerebral hemorrhage (ICH) is required for diagnosis-specific treatment and effective secondary prevention in patients with stroke. However, in resource-limited settings brain imaging, which is the current diagnostic gold standard for this purpose, is not always available in time. Hence, an easily accessible and broadly applicable blood biomarker-based diagnostic test differing stroke subtypes would be desirable. Using an explorative proteomics approach, this pilot study aimed to identify novel blood biomarker candidates for distinguishing IS from ICH.
Material and Methods: Plasma samples from patients with IS and ICH were drawn during hospitalization and were analyzed by using liquid chromatography/mass spectrometry. Proteins were identified using the human reference proteome database UniProtKB, and label-free quantification (LFQ) data were further analyzed using bioinformatic tools.
Results: Plasma specimens of three patients with IS and four patients with ICH with a median National Institute of Health Stroke Scale (NIHSS) of 12 [interquartile range (IQR) 10.5–18.5] as well as serum samples from two healthy volunteers were analyzed. Among 495 identified protein groups, a total of 368 protein groups exhibited enough data points to be entered into quantitative analysis. Of the remaining 22 top-listed proteins, a significant difference between IS and ICH was found for Carboxypeptidase N subunit 2 (CPN2), Coagulation factor XII (FXII), Plasminogen, Mannan-binding lectin serine protease 1, Serum amyloid P-component, Paraoxonase 1, Carbonic anhydrase 1, Fibulin-1, and Granulins.
Discussion: In this exploratory proteomics-based pilot study, nine candidate biomarkers for differentiation of IS and ICH were identified. The proteins belong to the immune system, the coagulation cascade, and the apoptosis system, respectively. Further investigations in larger cohorts of patients with stroke using additional biochemical analysis methods, such as ELISA or Western Blotting are now necessary to validate these markers, and to characterize diagnostic accuracy with regard to the development of a point-of-care-system for use in resource-limited areas.
KRAS is one of the most commonly mutated oncogenes in cancer, enabling tumor proliferation and maintenance. After various approaches to target KRAS have failed over the past decades, the first specific inhibitor of the p.G12C mutation of KRAS was recently approved by the FDA after showing promising results in adenocarcinomas of the lung and other solid tumors. Lung cancer, the most common cancer worldwide, is a promising use case for these new therapies, as adenocarcinomas in particular frequently harbor KRAS mutations. However, in squamous cell carcinoma (SCC) of the lung, KRAS mutations are rare and their impact on clinical outcome is poorly understood. In this review, we discuss the current knowledge on the prevalence and prognostic and predictive significance of KRAS mutations in the context of SCC.
The neuroanatomy of autism spectrum disorder (ASD) shows highly heterogeneous developmental trajectories across individuals. Mapping atypical brain development onto clinical phenotypes, and establishing their molecular underpinnings, is therefore crucial for patient stratification and subtyping. In this longitudinal study we examined intra- and inter-individual differences in the developmental trajectory of cortical thickness (CT) in childhood and adolescence, and their genomic underpinnings, in 33 individuals with ASD and 37 typically developing controls (aged 11–18 years). Moreover, we aimed to link regional atypical CT development to intra-individual variations in restricted and repetitive behavior (RRB) over a two-year time period. Individuals with ASD showed significantly reduced cortical thinning in several of the brain regions functionally related to wider autism symptoms and traits (e.g., fronto-temporal and cingulate cortices). The spatial patterns of the neuroanatomical differences in CT were enriched for genes known to be associated with ASD at a genetic and transcriptomic level. Further, intra-individual differences in CT correlated with within-subject variability in the severity of RRBs. Our findings represent an important step towards characterizing the neuroanatomical underpinnings of ASD across development based upon measures of CT. Moreover, our findings provide important novel insights into the link between microscopic and macroscopic pathology in ASD, as well as their relationship with different clinical ASD phenotypes.
Einleitung: Der Abgrenzung zwischen Totgeburt und Fehlgeburt kommt eine erhebliche Bedeutung für die ärztliche Praxis zu: Nur die Totgeburt gilt als Leiche und benötigt demzufolge eine ärztliche Leichenschau. Die Pflicht zur ärztlichen Leichenschau vor der Bestattung eines Verstorbenen ist in Deutschland in den jeweiligen „Bestattungsgesetzen“ der 16 Bundesländer und ggf. ergänzenden Verordnungen geregelt. Nach dem Grundgesetz der Bundesrepublik Deutschland (GG) liegt die Gesetzgebungsbefugnis für Todesfeststellung und Leichenschau bei den Ländern, während das Personenstandswesen in die Legitimation der Bundesgesetzgebung fällt. Die vorliegende Arbeit sollte dazu beitragen, vor dem Hintergrund der komplizierten Gefüge von Landes- und Bundesgesetzgebung sowie der Änderung des § 31 PStV vom 01.11.2018 Rechtssicherheit in der Abgrenzung von Totgeburt und Fehlgeburt für Ärztinnen und Ärzte im Rahmen der Leichenschau sowie bei der Obduktion von verstorbenen Schwangeren und Feten zu schaffen.
Material und Methoden: Alle relevanten Landesgesetze und Bundesgesetze sowie einschlägige juristische Kommentare wurden analysiert. Abfragen bezüglich der Erfordernisse bei der Meldung einer Totgeburt wurden bei Standesämtern durchgeführt, die diese Informationen online zur Verfügung gestellt hatten. Abschließend wurden die auf der aktuellen Gesetzeslage basierenden Erkenntnisse auf einen Fall vor dem Jahr 2018 hypothetisch angewandt.
Ergebnisse: In 12 der 16 Ländergesetze wird das Totgeborene – in Abgrenzung zur Fehlgeburt – nur über das Geburtsgewicht von mindestens 500 g definiert. In Hessen, Bremen und im Saarland wird zusätzlich als alternatives Kriterium die 24. Schwangerschaftswoche (SSW) genannt.
Es wurden 15 Standesämter in vier Bundesländern ermittelt. Davon forderten 10 bei Meldung einer Totgeburt die Vorlage einer ärztlichen Todesbescheinigung, dagegen 4 nicht. 14 Standesämter werteten die Totgeburt als Geburtsfall, eines gab keine Informationen dazu. 5 Standesämter werteten eine Totgeburt nicht als Sterbefall, 6 hingegen schon, und 4 stellten keine Informationen dazu zur Verfügung. 7 Standesämter gaben die aktuelle Definition einer Totgeburt an, wohingegen 5 lediglich die veraltete Definition zugrunde legten, und 3 keine Informationen diesbezüglich bereitstellten.
Diskussion: Nach den vorliegenden Ergebnissen lässt sich eine von den „Bestattungsgesetzen“ der Länder unabhängige Leichenschaupflicht für tote Leibesfrüchte ableiten, für die bezüglich der Leichendefinition die Kriterien des Personenstandsrechts gelten müssten. Demnach wäre in allen Bundesländern, unabhängig von den Kriterien in den jeweiligen „Bestattungsgesetzen“, zur Differenzierung zwischen Totgeburt und Fehlgeburt das alternative Merkmal „Erreichen der 24. SSW“ zu überprüfen, falls die tote Leibesfrucht, die keine Zeichen des Gelebthabens außerhalb des Mutterleibs aufweist, unter 500 g wiegt.
Obwohl die Abfrage bei den Standesämtern nicht als repräsentativ zu bezeichnen ist, waren dennoch die verschiedenen Vorgehensweisen unter den 15 ausgewerteten Standesämtern keine Einzelphänomene. Demzufolge erscheint zumindest die Feststellung der erheblichen Heterogenität von Standesämtern im Umgang mit Totgeburten gerechtfertigt.
Die Ausgangsfrage bei dem Fallbericht war, ob es sich bei einer aus dem Leichnam der Mutter im Rahmen einer Obduktion geborgenen toten Leibesfrucht um einen Leichnam handelt oder nicht. Es wurde damals entschieden, gemäß den gültigen Fassungen des § 31 PStV und des hessischen Friedhofs- und Bestattungsgesetzes (FBG HE), aufgrund des Unterschreitens der Gewichtsgrenze von 500 g von einer Fehlgeburt auszugehen, mit allen rechtlichen Konsequenzen. Nach der aktuellen Version des § 31 PStV wäre das Alternativkriterium „Erreichen der 24. SSW“ anwendbar gewesen.
Patienten/Innen (Pat.) mit Periventrikulärer Nodulärer Heterotopie (PNH) leiden häufig an pharmakoresistenter Epilepsie. Zur Identifizierung epileptogener Strukturen werden in der Forschung verschiedene Parameter als Marker für Epiletogenität untersucht. Der mittels Magnetenzephalographie (MEG) ermittelte Delta-Power-Wert ist nach der Literatur mit ischämischen und strukturellen Hirnläsionen, sowie mit wiederkehrenden epileptischen Anfällen assoziiert. Diese Studie untersuchte die Aussagekraft von durch Sensordatenanalyse ermittelte Delta-Power-Werte bei PNH Pat.. Dazu wurde eine Kohorte von 16 PNH Pat. und 16 nach Alter und Geschlecht gematchten Kontrollen mittels MEG, Magnetresonanztomographie (MRT) und neuropsychologischer Testung untersucht. Es wurden mögliche Unterschiede der Delta-Power-Werte zwischen an PNH erkrankten Epilepsiepatienten/innen und gesunden Kontrollen untersucht. Zudem wurde der Zusammenhang der Delta-Power-Werte einerseits mit Lokalisation und Volumen der Heterotopien und andererseits mit den neuropsychologischen Fähigkeiten (visuomotorischen Verarbeitungsgeschwindigkeit und exekutiven Funktion) untersucht.
Die Untersuchungen zeigten, dass das die Delta-Power-Werte sowohl global als auch lokal keine Aussagekraft über Lokalisation, Volumen oder Epileptogenität der PNHs hatten. Die exekutive Funktion und visuomotorische Verarbeitungsgeschwindigkeit waren bei den PNH Pat. signifikant schlechter als bei den gematchten Kontrollen. Zusammenfassend deuten diese Untersuchungen daraufhin, dass weder Delta-Power-Werte an sich oder Delta-Power-Werte im Sensorraum einen diagnostischen Wert bei PNH Pat. hatten. Die neuropsychologischen Tests hingegen zeigen Unterschiede der Gruppen auf und könnten daher als diagnostisches Kriterium betrachtet werden. Um feststellen zu können, ob Delta-Power-Werte an sich, oder aber Sensordaten nicht aussagekräftig in der Diagnostik von PNHs sind, müssten die MEG-Daten erneut mit veränderter Untersuchungsmethode (Quelldatenanalyse statt Sensordatenanlayse) untersucht werden.
Neuroendocrine neoplasms of the lung account for approximately 20% of all primary lung tumors. The most frequent entity within this group, as well as the most lethal, is small cell lung cancer (SCLC) occurring in around 15% of the cases. For this particular entity, though there have been several breakthroughs in recent years, overall understanding remains insufficient, especially when it comes to new, personalized therapeutic options. The lack of fresh tissue samples is most certainly one of the limiting factors for research. The goal of this study was to utilize archival formalin-fixed paraffin-embedded (FFPE) samples of SCLC and, more precisely, to establish and implement an efficient technique for single-cell isolation of substantial quantity and quality for translational cancer research. To establish this technique representative artificial samples and real-life samples have been carefully chosen. To generate single-cell suspensions, two different methods were suggested by current literature based on mechanical disruption (incellPREP by CellSee) and a combination of enzymatic and mechanical disruption (Miltenyi). The feasibility of these two methods was pre-evaluated by subsequent analytics such us Cytospin-PAP staining and flow cytometry to refine the protocol and apply a final selection of samples for 3′ MACE (massive analysis of cDNA ends) RNA-sequencing (GenXPro). By this, pre-analytical quality and secondary analytical output could be evaluated and implemented as a first standard guideline within the Dr. Senckenberg Institute of Pathology for ongoing projects when using archival FFPE samples. To summarize, FFPE samples are an underestimated and rarely used material for single-cell sequencing studies. Therefore, their utilization opens a possibility to apply this technique to different tumor types, especially when fresh or fresh frozen tissue samples are not available. Conducting the proper analysis of data could lead to a deeper understanding of cancer biology and to find new therapeutic vulnerabilities.
Objective: To evaluate the efficacy and safety of an oral selective tyrosine kinase 2 (TYK2) inhibitor, deucravacitinib, in patients with active psoriatic arthritis (PsA).
Methods: In this double-blind, phase II trial, 203 patients with PsA were randomised 1:1:1 to placebo, deucravacitinib 6 mg once a day or 12 mg once a day. The primary endpoint was American College of Rheumatology-20 (ACR-20) response at week 16.
Results: ACR-20 response was significantly higher with deucravacitinib 6 mg once a day (52.9%, p=0.0134) and 12 mg once a day (62.7%, p=0.0004) versus placebo (31.8%) at week 16. Both deucravacitinib doses resulted in significant improvements versus placebo (p≤0.05) in the multiplicity-controlled secondary endpoints of change from baseline in Health Assessment Questionnaire-Disability Index and Short Form-36 Physical Component Summary score and in Psoriasis Area and Severity Index-75 response. Improvements were also seen in multiple exploratory endpoints with deucravacitinib treatment. The most common adverse events (AEs) (≥5%) in deucravacitinib-treated patients were nasopharyngitis, upper respiratory tract infection, sinusitis, bronchitis, rash, headache and diarrhoea. There were no serious AEs and no occurrence of herpes zoster, opportunistic infections and major adverse cardiovascular events, or differences versus placebo in mean changes in laboratory parameters with deucravacitinib treatment.
Conclusions: Treatment with the selective TYK2 inhibitor deucravacitinib was well tolerated and resulted in greater improvements than placebo in ACR-20, multiplicity-controlled secondary endpoints and other exploratory efficacy measures in patients with PsA. Larger trials over longer periods of time with deucravacitinib are warranted to confirm its safety profile and benefits in PsA.
Aufgrund der vielfältigen Vorteile von Biomarkern stehen diese seit einiger Zeit im Fokus der Forschung bei Multipler Sklerose (MS). Bisher existieren vorwiegend Daten zu Markern, die eine Verschlechterung der Krankheit anzeigen – Kenntnisse zu Markern für eine Verbesserung sind begrenzt. Mit dieser Studie sollte der Frage nachgegangen werden, ob veränderte Konzentrationen von Neurofilament Light Chain (NfL) und Brain-Derived Neurotrophic Factor (BDNF) im Serum (sNfL/sBDNF) und Liquor (cNfL/cBDNF) einer neurologischen und kognitiven Veränderung bei MS vorausgehen. Es wurde vermutet, dass NfL eine Verschlechterung und BDNF eine Verbesserung der Funktionen prognostiziert. Im Rahmen einer monozentrischen prospektiven Kohortenstudie wurden bei insgesamt 50 Patienten mit MS-Phänotyp (klinisch isoliertes Syndrom, schubförmigremittierende MS und primär progrediente MS) zu Studienbeginn (Messzeitpunkt T1) Serum- und Liquorproben abgenommen sowie eine neurologische und kognitive Testung durchgeführt. Nach zwölf Monaten (Messzeitpunkt T2) wurden die neurologische (n = 36) und die kognitive (n = 34) Testung wiederholt. Anhand der Dynamik ihrer Expanded Disability Status Scale (EDSS)- und globalen z-Werte wurden die Patienten vier Gruppenpaaren zugeordnet: Keine neurologische Verschlechterung versus Neurologische Verschlechterung (Anstieg EDSS ≥ 0.5), Keine kognitive Verschlechterung versus Kognitive Verschlechterung (Abfall globales z ≥ 0.5), Keine neurologische Verbesserung versus Neurologische Verbesserung (Abfall EDSS ≥ 0.5) und Keine kognitive Verbesserung versus Kognitive Verbesserung (Anstieg globales z ≥ 0.5). Die NfL- und BDNF-Konzentrationen der Patienten aus den jeweiligen Gruppen wurden anhand von Kovarianzanalysen unter Berücksichtigung von Kovariaten verglichen. Hinsichtlich der Prognose einer Verschlechterung präsentierten sich keine signifikanten Ergebnisse. Zur Prognose einer Verbesserung ergab sich Folgendes: Patienten mit einer neurologischen Verbesserung wiesen einen höheren sBDNF-Spiegel bei Studienbeginn auf im Vergleich zu Probanden mit keiner neurologischen Verbesserung (q = 0.04). Patienten mit einer kognitiven Verbesserung hatten zu Beginn höhere cBDNF-Konzentrationen als Patienten ohne kognitive Verbesserung (q = 0.004). In post-hoc durchgeführten Korrelationsanalysen stellten sich signifikante
Korrelationen zwischen sBDNF und EDSS-Wert-Veränderung (q = 0.036), cBDNF und globaler z-Wert-Veränderung (q = 0.04) und cBDNF und Anzahl an kognitiven Tests mit Verbesserung (q = 0.04) dar. Diese Ergebnisse deuten auf eine mögliche Rolle von BDNF als Biomarker zur Prognose von neurologischen und kognitiven Verbesserungen bei MS hin. Es bedarf jedoch weiterer Studien mit einer größeren Stichprobe und methodischen Anpassungen, um diese Schlussfolgerung zu untermauern.
Tubulogenesis is essential for the formation and function of internal organs. One such organ is the trachea, which allows gas exchange between the external environment and the lungs. However, the cellular and molecular mechanisms underlying tracheal tube development remain poorly understood. Here, we show that the potassium channel KCNJ13 is a critical modulator of tracheal tubulogenesis. We identify Kcnj13 in an ethylnitrosourea forward genetic screen for regulators of mouse respiratory organ development. Kcnj13 mutants exhibit a shorter trachea as well as defective smooth muscle (SM) cell alignment and polarity. KCNJ13 is essential to maintain ion homeostasis in tracheal SM cells, which is required for actin polymerization. This process appears to be mediated, at least in part, through activation of the actin regulator AKT, as pharmacological increase of AKT phosphorylation ameliorates the Kcnj13 mutant trachea phenotypes. These results provide insights into the role of ion homeostasis in cytoskeletal organization during tubulogenesis.
Regulatory T cells (Tregs) are important mediators of immunological self-tolerance and homeostasis. Being cluster of differentiation 4+Forkhead box protein3+ (CD4+FOXP3+), these cells are a subset of CD4+ T lymphocytes and can originate from the thymus (tTregs) or from the periphery (pTregs). The malfunction of CD4+ Tregs is associated with autoimmune responses such as rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes (T1D), inflammatory bowel diseases (IBD), psoriasis, systemic lupus erythematosus (SLE), and transplant rejection. Recent evidence supports an opposed role in sepsis. Therefore, maintaining functional Tregs is considered as a therapy regimen to prevent autoimmunity and allograft rejection, whereas blocking Treg differentiation might be favorable in sepsis patients. It has been shown that Tregs can be generated from conventional naïve T cells, called iTregs, due to their induced differentiation. Moreover, Tregs can be effectively expanded in vitro based on blood-derived tTregs. Taking into consideration that the suppressive role of Tregs has been mainly attributed to the expression and function of the transcription factor Foxp3, modulating its expression and binding to the promoter regions of target genes by altering the chromatin histone acetylation state may turn out beneficial. Hence, we discuss the role of histone deacetylation inhibitors as epigenetic modulators of Tregs in this review in detail.
Several studies suggested that transcription factor (TF) binding to DNA may be impaired or enhanced by DNA methylation. We present MeDeMo, a toolbox for TF motif analysis that combines information about DNA methylation with models capturing intra-motif dependencies. In a large-scale study using ChIP-seq data for 335 TFs, we identify novel TFs that show a binding behaviour associated with DNA methylation. Overall, we find that the presence of CpG methylation decreases the likelihood of binding for the majority of methylation-associated TFs. For a considerable subset of TFs, we show that intra-motif dependencies are pivotal for accurately modelling the impact of DNA methylation on TF binding. We illustrate that the novel methylation-aware TF binding models allow to predict differential ChIP-seq peaks and improve the genome-wide analysis of TF binding. Our work indicates that simplistic models that neglect the effect of DNA methylation on DNA binding may lead to systematic underperformance for methylation-associated TFs.