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Despite major improvements of the therapy, many B-cell Non-Hodgkin’s lymphoma (B-NHL) entities still have a poor prognosis. New therapeutic options are urgently needed. Therefore this study sets out to investigate oncogenic signalling pathways in the two B-NHL entities mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) in order to define new potential therapeutic targets.
MCL cells overexpress the anti-apoptotic protein BCL-2, thereby they evade apoptosis. With venetoclax, the first-in-class BCL-2 specific inhibitor was approved and achieved good response rates in MCL. However, some cases display intrinsic or acquired resistance to venetoclax. In order to improve the therapy, this study aimed to identify genes which confer sensitivity or resistance towards venetoclax upon their respective knockout. To this end, a genome-wide CRISPR/Cas9-based loss-of-function screen was conducted in the MCL cell line Maver-1. The E3 ubiquitin
ligase MARCH5 was identified as one of the top hits conferring sensitivity
towards venetoclax upon its knockout. This finding was validated in a competitive growth assay including two more MCL cell lines, Jeko-1 and Mino. MARCH5 knockout also sensitised Jeko-1 cells towards venetoclax even though this cell line was insensitive towards venetoclax in its wild-type form. Using BH3 profiling, an increased dependency on BCL-2 of MARCH5-depleted cells confirmed this finding. The sensitisation was found to be based on induction of apoptosis upon MARCH5 knockout and to an even higher extent upon additional treatment of MARCH5-depleted cells with venetoclax. As already described for epithelial cancer entities, the BCL-2 family members MCL-1 and NOXA were upregulated in MCL cell lines upon MARCH5 knockout. This led to the hypothesis that MARCH5 is a potential
regulator of intrinsic apoptosis with NOXA as a key component. A competitive growth assay with MARCH5 and NOXA co-depleted cells revealed a partial reversion of the BCL-2 sensitisation compared to MARCH5 knockout alone. Furthermore, mass spectrometry-based methods were used to gain more insight into other cellular pathways and networks which might be regulated in a MARCH5-dependent manner. In an interactome analysis, proteins which regulate mitochondrial morphology, such as Drp-1 were identified as MARCH5 interactors. Besides this expected finding, interaction between MARCH5 and several members of the BCL-2 family as well as a potential connection between MARCH5 and vesicular trafficking was discovered. As expected, an ubiquitinome analysis of MARCH5-depleted cells revealed decreased levels of MCL-1 and NOXA ubiquitination. Additionally, a potential role of MARCH5 in the ubiquitination of several members of the cell cycle regulatory
pathway was discovered. Based on the broad spectrum of cellular pathways which seem to be regulated in a MARCH5-dependent manner, it was hypothesised that MARCH5 primarily regulates BCL-2 family members which in turn regulate intrinsic apoptosis on the one hand and additionally are involved in the regulation of various other pathways on the other hand.
In summary, this study provides insight into a MARCH5-dependent MCL1-1/NOXA axis in MCL cells and potential implications into related cellular processes.
In addition to the anti-apoptotic pathways described above, B-cell receptor (BCR) signalling is known to provide a pro-survival signal to both normal and malignant B-cells. Targeting the BCR signalling pathway therefore is a promising therapeutic target for B-cell malignancies. In order to gain more insight into the differential modes of BCR signalling of ABC- and GCB-DLBCL cells, genes/proteins which displayed differential essentiality in ABC- and GCB-DLBCL cells were aimed to be defined. Consequently, data sets from a CRISPR/Cas9-based loss-of-function screen
were re-analysed. SASH3 was identified as a gene which was essential for GCB- but not for ABC-DLBCL cells. Since this protein is known to be involved in T-cell receptor (TCR)-signalling, SASH3 was assumed to play a potential role in BCR signalling as well and was therefore investigated in more detail. A competitive growth assay confirmed that SASH3 knockout was toxic exclusively for GCB-DLBCL cell lines. An interactome analysis in ABC- and GCB-DLBCL cells revealed interaction between SASH3 and many components of the proximal BCR signalling pathway as well as several downstream signalling pathways such as the PI3K or the NF-ΚB pathway.
An integration of the interactome with data from the CRISPR/Cas9-based loss-offunction screen revealed differential essentiality of the SASH3-interacting proteins in ABC- and GCB-DLBCL cells. It was hypothesised that SASH3 might regulate PI3K signalling on which GCB- but not ABC-DLBCL cells are known to dependent. Discontinuation of the regulation of PI3K signalling could therefore be exclusively toxic to GCB-DLBCL cells.
Taken together, this study describes a subtype-specific dependency of GCB-DLBCL cells on SASH3. Furthermore, the SASH3 interactome has been investigated in B-cells for the first time, thereby highlighting a potential role in proximal BCR signalling and involvement in specific BCR-related downstream signalling pathways.
Einleitung: Empathie ist ein entscheidender Faktor mit direktem Bezug auf das therapeutische Outcome in der Arzt-Patienten Beziehung. Die Ausbildung junger Mediziner:innen ist jedoch sehr fachlich orientiert, soziale Fähigkeiten werden nur in geringem Ausmaß gelehrt. Am Fachbereich Medizin der Goethe Universität Frankfurt wurden Simulationspatient:innen (SPs) bisher hauptsächlich in Prüfungen eingesetzt, nicht aber in der Lehre. Die vorliegende Arbeit beschäftigt sich mit der Fragestellung, ob der Einsatz von SPs in der curricularen Lehre im Fach Chirurgie zur Vermittlung von strukturierten chirurgischen Anamnese- und Aufklärungsgesprächen umsetzbar ist, ob dieses einen Einfluss auf das empathische Verhalten der Studierenden hat, und ob es bei der gezeigten Empathie einen Unterschied zwischen SPs und reale Patient:innen (RPs) gibt. Zusätzlich wird untersucht, ob der Einsatz von SPs einen Einfluss auf den Lernerfolg in kommunikationsbasierten Prüfungen hat.
Methoden: Studienteilnehmende waren Studierende im 3. klinischen Semester am Fachbereich Medizin der Goethe Universität, die aktuell ihr curriculares Blockpraktikum Chirurgie absolvierten. Im Rahmen des Blockpraktikums Chirurgie durchliefen die Studierenden das ‚Training Praktischer Fertigkeiten‘ und hierbei das Modul ‚Kommunikation (Anamnese und Aufklärung)‘. Das Modul dauerte insgesamt 210 Minuten und setzte sich aus theoretischen Einheiten sowie praktischen Übungen (Rollenspielen) zusammen. Die Studienteilnehmenden wurden in 3 Studiengruppen randomisiert. Alle Teilnehmenden füllten zunächst zwei Fragebögen zum selbsteingeschätzten Empathielevel aus und lernten die identischen theoretischen Inhalte des Moduls. In den Rollenspielen trainierte Gruppe 1 mit SPs und wusste auch, dass es sich um SPs handelt. Gruppe 2 übte ebenfalls mit SPs, ging aber davon aus, dass es sich um reale Patient:innen handelte (Inkognito Patient:innen = IPs), Gruppe 3 übte mit RPs und war auch darüber informiert. Im Anschluss wurden die Studierenden anhand eines 10-Items Fragebogen in Hinblick auf die gezeigte Empathie durch die (Simulations-)-Patient:innen bewertet. Der Lernerfolg wurde anhand der Ergebnisse des Chirurgie-OSCE’s, den die Teilnehmenden 5-12 Wochen nach dem Modul absolvierten, ausgewertet.
Ergebnisse: Es zeigten sich signifikante Unterschiede bei dem vom Patienten wahrgenommenen Empathielevel zwischen Gruppe 1 (SP) und 2 (IP) und 1 (SP) und 3 (RP), nicht aber zwischen Gruppe 2 (IP) und 3 (RP). In dieser Konstellation wurden Studierende, welche mit RPs übten oder zumindest davon ausgingen, signifikant weniger empathisch bewertet. Es zeigten sich signifikante Unterschiede in der Eigeneinschätzung zwischen Männern und Frauen, nicht aber in der Fremdeinschätzung. Es gab keine signifikanten Unterschiede in den Ergebnissen der kommunikationsbasierenden Stationen der Chirurgie-OSCE zwischen den einzelnen Gruppen.
Schlussfolgerung: Der Einsatz von SPs im Hinblick auf den Lernerfolg in kommunikationsbasierenden Prüfungen ist gerechtfertigt und eine gute Möglichkeit, um Studierenden das Üben von Gesprächssituationen realistisch zu ermöglichen, ohne dabei akut klinische Patient:innen rekrutieren zu müssen. Dabei muss aber beachtet werden, dass das empathische Verhalten der Studierenden ein anderes ist, wenn sie mit RPs arbeiten, beziehungsweise davon ausgehen, mit einem RP zu arbeiten. Zur Förderung der Empathie sollten RPs und Feedback durch diese früh in die studentische Lehre implementiert werden.
The postthrombotic syndrome (PTS) is beside the venous thromboembolism (VTE) recurrence and chronic thromboembolic pulmonary hypertension (CTEPH) a long-term adverse outcome and chronic complication of deep vein thrombosis (DVT) in the lower extremities and can occur in up to 20–50% of patients within 2 years after DVT. The prevalence of PTS in the adult population is expected to increase due to the growing incidence of VTE in the elderly. Although not life threatening it can impose significant morbidity and can be associated with a negative impact on quality of life associated with disease severity. From an economic point of view, PTS is an important predictor of increased health care costs after VTE.
Factors potentially related to the development of the PTS are older age, obesity, a history of previous ipsilateral DVT, iliofemoral location of the current thrombosis, failure to promptly recover from the acute symptoms and insufficient quality of oral anticoagulant therapy. Furthermore, it is known that the severity of PTS correlates with the location of the DVT, the more proximal the more severe.
PTS induces a range of symptoms and clinical signs, which can be assessed in different scales. The Villalta scale is one of the most suitable scales for defining the presence and severity of subjective symptoms and physical signs of PTS.
In the last century, various therapeutic strategies have been developed to prevent mortality due to VTE or long-term morbidity due to PTS.
Conservative treatment today consists of anticoagulation - usually using direct oral anticoagulants - and compression therapy. One of the first invasive treatments with the aim of thrombus removal was surgical venous thrombectomy by Läwen in 1938. Mahorner and Fontaine improved the technique in the 1950s combining it with a course of anticoagulant treatment to prevent rethrombosis and PTS.
Mechanical thrombectomy by the use of Fogarty balloons, which started in 1963, or the creation of a transient arteriovenous fistula, performed since 1974, are now no longer recommended due to the high invasiveness, risk of fatal intraoperative embolism and a high rethrombosis rate.
In current practice, early thrombus removal mainly relies on the use of catheter-directed pharmacologic thrombolytic therapy. Another approach currently is the endovenous, device-driven thrombectomy and stenting in case of venous obstruction. There is an ongoing broad discussion as to whether these invasive therapies should be offered to patients with iliofemoral thrombosis (IFT), which remains controversial.
IFT, the major target for endovenous thrombectomy respectively pharmacologic thrombolytic therapy, is not enough represented in current literature because the used definition of proximal DVT does not necessarily include the iliac veins. In consequence, it may not be representative enough concerning questions like prevalence and severity of PTS or the effects on quality of life.
The present registry – the Iliaca-PTS registry – addresses exactly these patients and tries to answer these questions. The data of 85 patients who had suffered an IFT in the past were evaluated in the prospective registry documenting the severity of PTS, the occurrence of iliac vein compression syndrome in left-sided IFT and quality of life. A significant predictor for the development of severe PTS or venous claudication in our patient population is a high BMI.
The results of this registry show that IFT is frequently observed and only ten percent develop a moderate or severe PTS respectively venous claudication. In conclusion, the conservative treatment strategy with optimal effective anticoagulant therapy can lead to a low incidence of PTS and a high quality of life.
Background: Decedents who are repatriated to Germany from abroad are not systematically registered nationwide. In Hamburg, in addition to an epidemic hygienic examination, registration and examination of the content of the documents accompanying the corpses of German citizens has been carried out since 2007. In this way, unclear and non-natural deaths in particular are to be followed up as necessary.
Material and methods: Protocols of external and internal autopsies of German nationals who died abroad and were repatriated to Hamburg via the port or airport between 2007 and 2018 were retrospectively evaluated with respect to numbers, completeness of the autopsy abroad and correctness of manner and cause of death.
Results: Between 2007 and 2018 a total of 703 corpses were repatriated via the port or airport of Hamburg and examined by the Port Medical Service for epidemic hygiene and for anything conspicuous in the documents accompanying the corpse. Of them, 307 corpses were examined at the Institute of Legal Medicine at the University Medical Center Hamburg-Eppendorf. In total, 82.4% of the examined cases had an incorrect, unspecific or incomplete foreign death certificate. Of the deceased, 238 were subjected to a second external autopsy by a forensic pathologist and 69 deceased were autopsied again or for the first time in Hamburg. It was found that 84% of the autopsies performed abroad were not performed according to German and European standards. The most common discrepancy was incomplete preparation of the organs. In almost one quarter of the autopsies performed in Hamburg a different cause of death than abroad was determined at autopsy.
Conclusion: Since the quality of autopsies performed abroad sometimes does not meet the standards in Germany and Europe and many papers accompanying corpses are incomplete or incorrectly filled out, a systematic review procedure in the home country is recommended. Through the system established in Hamburg in 2007, at least a re-evaluation of the cases takes place.
Background: In a phase 3 clinical study, patients from Germany with moderate to severe psoriasis who were naïve to systemic treatment and received risankizumab had greater and more rapid disease improvements compared with those who received fumaric acid esters (FAEs).
Objective: To evaluate patient-reported outcomes (PROs) in patients treated with risankizumab compared with FAEs.
Methods: Adult patients were randomized 1:1 to receive either risankizumab 150 mg subcutaneous injections at weeks 0, 4 and 16 or FAEs (Fumaderm®) provided according to the prescribing label. PRO secondary endpoints assessed were Psoriasis Symptom Scale (PSS), Dermatology Life Quality Index (DLQI), 36-Item Short Form Health Survey, version 2 (SF-36v2), Patient Benefit Index (PBI), Hospital Anxiety and Depression Scale (HADS), Patient Global Assessment (PtGA) and European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L). PROs were assessed at weeks 0, 16 and 24.
Results: Sixty patients each were randomized to receive risankizumab or FAEs. A significant PSS improvement was observed with risankizumab vs. FAEs at weeks 16 and 24 for total and psoriasis-associated redness, itching and burning scores (P < 0.001). DLQI scores were significantly lower (reflecting better health-related quality of life) with risankizumab vs. FAEs, with least squares (LS) mean differences of −7.4 and −7.6 at weeks 16 and 24, respectively (both P < 0.001). Patients randomized to risankizumab also had larger improvements in SF-36 Physical and Mental Component Summary scores, HADS anxiety and depression scores, PtGA, and EQ-5D-5L index and visual analogue scale scores (all P ≤ 0.002) at weeks 16 and 24 compared with FAEs. PBI was significantly higher, indicating greater benefit, with risankizumab vs. FAEs, with an LS mean difference of 1.1 and 1.3 at weeks 16 and 24, respectively (both P < 0.001).
Conclusions: Risankizumab provides significant benefits over FAEs in improving PROs across several dimensions in patients with moderate to severe psoriasis.
Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial
(2021)
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for most children with juvenile myelomonocytic leukemia (JMML). Novel therapies controlling the disorder prior to HSCT are needed. We conducted a phase 2, multicenter, open-label study to evaluate the safety and antileukemic activity of azacitidine monotherapy prior to HSCT in newly diagnosed JMML patients. Eighteen patients enrolled from September 2015 to November 2017 were treated with azacitidine (75 mg/m2) administered IV once daily on days 1 to 7 of a 28-day cycle. The primary end point was the number of patients with clinical complete remission (cCR) or clinical partial remission (cPR) after 3 cycles of therapy. Pharmacokinetics, genome-wide DNA-methylation levels, and variant allele frequencies of leukemia-specific index mutations were also analyzed. Sixteen patients completed 3 cycles and 5 patients completed 6 cycles. After 3 cycles, 11 patients (61%) were in cPR and 7 (39%) had progressive disease. Six of 16 patients (38%) who needed platelet transfusions were transfusion-free after 3 cycles. All 7 patients with intermediate- or low-methylation signatures in genome-wide DNA-methylation studies achieved cPR. Seventeen patients received HSCT; 14 (82%) were leukemia-free at a median follow-up of 23.8 months (range, 7.0-39.3 months) after HSCT. Azacitidine was well tolerated and plasma concentration-–time profiles were similar to observed profiles in adults. In conclusion, azacitidine monotherapy is a suitable option for children with newly diagnosed JMML. Although long-term safety and efficacy remain to be fully elucidated in this population, these data demonstrate that azacitidine provides valuable clinical benefit to JMML patients prior to HSCT. This trial was registered at www.clinicaltrials.gov as #NCT02447666.
Lippen-Kiefer-Gaumenspalten sind häufige, angeborene Fehlbildungen beim Menschen und werden zumeist schon innerhalb des ersten Lebensjahres operativ korrigiert. In 5-11% der Fälle ist das Vorliegen einer solchen Anomalie mit einer schwierigen Laryngoskopie assoziiert und kann ein modifiziertes Vorgehen bei der Sicherung des Atemweges erfordern. Videolaryngoskopische Techniken kommen hierbei vermehrt zum Einsatz und können auch im Kindesalter zu einer Verbesserung der Intubationsbedingungen beitragen.
In der vorliegenden Arbeit wurden die Intubationsbedingungen zwischen der indirekten Laryngoskopie mittels Glidescope® GVL Spatel Gr. 2 und der indirekten sowie direkten Laryngoskopie mittels C-MAC® Miller-Spatel Gr. 1 bei Kindern mit Lippen-Kiefer-Gaumenspalte miteinander verglichen.
Über einen Zeitraum von acht Monaten wurden Kinder mit Lippen-Kiefer-Gaumenspalte prospektiv abwechselnd entweder indirekt mit dem Glidescope® oder direkt und indirekt mit dem C-MAC® laryngoskopiert. Die Visualisierung der Glottisebene nach der modifizierten Cormack und Lehane Klassifikation war das Hauptzielkriterium. Sekundäre Zielparameter waren unter anderem die Zeit bis zur optimalen Sicht und die Zeit bis zur Intubation.
36 Kinder, die sich einer elektiven Korrektur einer Lippen-Kiefer-Gaumenspalte unterzogen, wurden eingeschlossen und erfolgreich intubiert. Jeweils 18 Kinder wurden mit dem C-MAC® Miller-Spatel Gr. 1 und mit dem Glidescope® GVL-Spatel Gr. 2 laryngoskopiert. Im Vergleich zwischen direkter und indirekter Laryngoskopie mit dem C-MAC® zeigte sich bei vier (22%) Kindern eine deutliche Verbesserung der Visualisierung der Glottisebene von einer schlechten Visualisierung (CL2b, 3 und 4) hin zu einer guten Visualisierung (CL2a und 1) der Glottisebene. Bei Verwendung des Glidescope® lag lediglich in einem Fall eine schlechte Visualisierung der Glottisebene vor.
Der Einsatz indirekter videolaryngoskopischer Techniken kann die Visualisierung der Glottisebene verbessern und reduziert die Anzahl an schwierigen Laryngoskopien bei Kindern mit Lippen-Kiefer-Gaumenspalte.
Hintergrund und Ziel der Arbeit: Aufgrund des demografischen Wandels ist mit einer Änderung des Altersspektrums bei den Obduktionen zu rechnen. Ziel der Arbeit war die Untersuchung der nichtnatürlichen Todesfälle, bei denen die Verstorbenen ein Mindestalter von 65 Jahren erreicht hatten, da dieser Populationsgruppe zukünftig eine wachsende Bedeutung zukommen wird. Material und Methoden: In dieser retrospektiven Mortalitätsstudie wurden alle nichtnatürlichen Todesfälle mit einem Sterbealter ≥ 65 Jahren analysiert, die in den Jahren 2000–2002 (Zeitraum I) und 2013–2015 (Zeitraum II) im Institut für Rechtsmedizin des Universitätsklinikums der Goethe-Universität in Frankfurt am Main obduziert wurden. Für die Analyse der suizidal Verstorbenen wurden zudem Daten nichtobduzierter Selbsttötungen (n = 100) aus Besichtigungen aufgenommen. Ergebnisse: Aus den 1206 Obduktionen resultierten 669 natürliche (55,5 %) und 404 nichtnatürliche (33,5 %) Todesfälle. Darunter ergaben sich 221 Unfälle (Zeitraum I n = 105; Zeitraum II n = 116), 82 Suizide (Zeitraum I n = 55; Zeitraum II n = 27), 41 Todesfälle im Zusammenhang mit medizinischen Interventionen (Zeitraum I n = 7; Zeitraum II n = 34) und 40 Tötungsdelikte (Zeitraum I n = 23; Zeitraum II n = 17). Verkehrsunfälle und Stürze bilden die größten Subgruppen bei den Unfällen. Erhängen und Erschießen sind die am meisten angewandten Suizidarten. Vergleicht man Zeitraum I mit II, so fällt die signifikante Zunahme von Todesfällen im Zusammenhang mit ärztlichen Maßnahmen auf. Eine signifikante Abnahme von Suizidenten ist durch die abnehmende Obduktionsrate in dieser Gruppe zu begründen. Die relative und absolute Fallzahl an Tötungsdelikten im Obduktionsgut weisen keine wesentliche Veränderung auf. Diskussion/Schlussfolgerung: Die Ergebnisse dieser Studie stimmen großteils mit der Literatur überein. Im Zeitvergleich zeigt sich eine relative Zunahme nichtnatürlicher Todesfälle im gerontologischen Obduktionsgut. Dies wird durch den Anstieg von Obduktionen nach iatrogenen Komplikationen wesentlich mitgeprägt.
Background: Tuberous sclerosis complex (TSC), a multisystem genetic disorder, affects many organs and systems, characterized by benign growths. This German multicenter study estimated the disease-specific costs and cost-driving factors associated with various organ manifestations in TSC patients. Methods: A validated, three-month, retrospective questionnaire was administered to assess the sociodemographic and clinical characteristics, organ manifestations, direct, indirect, out-of-pocket, and nursing care-level costs, completed by caregivers of patients with TSC throughout Germany. Results: The caregivers of 184 patients (mean age 9.8 ± 5.3 years, range 0.7–21.8 years) submitted questionnaires. The reported TSC disease manifestations included epilepsy (92%), skin disorders (86%), structural brain disorders (83%), heart and circulatory system disorders (67%), kidney and urinary tract disorders (53%), and psychiatric disorders (51%). Genetic variations in TSC2 were reported in 46% of patients, whereas 14% were reported in TSC1. Mean total direct health care costs were EUR 4949 [95% confidence interval (95% CI) EUR 4088–5863, median EUR 2062] per patient over three months. Medication costs represented the largest direct cost category (54% of total direct costs, mean EUR 2658), with mechanistic target of rapamycin (mTOR) inhibitors representing the largest share (47%, EUR 2309). The cost of anti-seizure drugs (ASDs) accounted for a mean of only EUR 260 (5%). Inpatient costs (21%, EUR 1027) and ancillary therapy costs (8%, EUR 407) were also important direct cost components. The mean nursing care-level costs were EUR 1163 (95% CI EUR 1027–1314, median EUR 1635) over three months. Total indirect costs totaled a mean of EUR 2813 (95% CI EUR 2221–3394, median EUR 215) for mothers and EUR 372 (95% CI EUR 193–586, median EUR 0) for fathers. Multiple regression analyses revealed polytherapy with two or more ASDs and the use of mTOR inhibitors as independent cost-driving factors of total direct costs. Disability and psychiatric disease were independent cost-driving factors for total indirect costs as well as for nursing care-level costs. Conclusions: This study revealed substantial direct (including medication), nursing care-level, and indirect costs associated with TSC over three months, highlighting the spectrum of organ manifestations and their treatment needs in the German healthcare setting.
Objectives: The aim of this study was to investigate the relationship between anamnestic, axiographic and occlusal parameters and postural control in healthy women aged between 41 and 50 years. Materials and methods: A total of 100 female participants aged between 41 and 50 (45.12 ± 2.96) years participated in the study. In addition to completing a general anamnesis questionnaire, lower jaw movements were measured axiographically, dental occlusion parameters were determined using a model analysis and postural parameters were recorded using a pressure measurement platform. The significance level was 5%. Results: An increasing weight and a rising BMI lead to a weight shifted from the rearfoot (p ≤ 0.01/0.04) to the forefoot (p ≤ 0.01/0.02). A limited laterotrusion on the right resulted in a lower forefoot load and an increased rearfoot load (p ≤ 0.01). Laterotrusion to the left (extended above the standard) showed a lower frontal sway (p ≤ 0.02) and a reduced elliptical area, height and width (p ≤ 0.01, 0.02, 0.03). Thus, the extent of deviation correlated with reduced right forefoot loading (p ≤ 0.03) and the extent of deflection correlated with increased left foot loading (p ≤ 0.01). The higher the extent of angle class II malocclusion, the larger the ellipse area (p ≤ 0.04) and the ellipse height (p ≤ 0.02) resulted. Conclusions: There is a connection between weight, BMI and laterotrusion, as well as between angle class II malocclusion and postural control in women aged between 41 and 50 years. Interdisciplinary functional examinations of mandibular movements treating possible limitations can be conducive for an improvement of postural control. Clinical relevance: Angle class II malocclusion has a negative influence on postural control.
Glioblastoma (GBM) is a cancer type with high thrombogenic potential and GBM patients are therefore at a particularly high risk for thrombotic events. To date, only limited data on anticoagulation management after pulmonary embolism (PE) in GBM is available and the sporadic use of DOACs remains off-label. A retrospective cohort analysis of patients with GBM and postoperative, thoracic CT scan confirmed PE was performed. Clinical course, follow-up at 6 and 12 months and the overall survival (OS) were evaluated using medical charts and neuroradiological data. Out of 584 GBM patients, 8% suffered from postoperative PE. Out of these, 30% received direct oral anticoagulants (DOACs) and 70% low-molecular-weight heparin (LMWH) for therapeutic anticoagulation. There was no significant difference in major intracranial hemorrhage (ICH), re-thrombosis, or re-embolism between the two cohorts. Although statistically non-significant, a tendency to reduced mRS at 6 and 12 months was observed in the LMWH cohort. Furthermore, patients receiving DOACs had a statistical benefit in OS. In our analysis, DOACs showed a satisfactory safety profile in terms of major ICH, re-thrombosis, and re-embolism compared to LMWH in GBM patients with postoperative PE. Prospective, randomized trials are urgent to evaluate DOACs for therapeutic anticoagulation in GBM patients with PE.
Objective: The aim of this study was to retrospectively review the midface and orbital floor fractures treated at our institution with regard to epidemiological aspects, surgical treatment options and postoperative complications and discuss this data with the current literature. Study design: One thousand five hundred and ninety-four patients with midface and orbital fractures treated at the Department of Oral, Cranio-Maxillofacial and Facial Plastic Surgery of the Goethe University Hospital in Frankfurt (Germany) between 2007 and 2017 were retrospectively reviewed. The patients were evaluated by age, gender, etiology, fracture pattern, defect size, surgical treatment and complications. Results: The average patient age was 46.2 (± 20.8). Most fractures (37.5%) occurred in the age between 16 and 35. Seventy-two percent of patients were male while 28% were female. The most common cause of injury was physical assault (32.0%) followed by falls (30.8%) and traffic accidents (17.0%). The average orbital wall defect size was 297.9 mm2 (± 190.8 mm2). For orbital floor reconstruction polydioxanone sheets (0.15 mm 38.3%, 0.25 mm 36.2%, 0.5 mm 2.8%) were mainly used, followed by titanium meshes (11.5%). Reconstructions with the 0.15 mm polydioxanone sheets showed the least complications (p < 0.01, r = 0.15). Eighteen percent of patients who showed persistent symptoms and post-operative complications: 12.9% suffered from persistent hypoesthesia, 4.4% suffered from post-operative diplopia and 3.9% showed intra-orbital hematoma. Conclusion: Results of the clinical outcome in our patients show that 0.15 mm resorbable polydioxanone sheets leads to significantly less post-operative complications for orbital floor defects even for defects beyond the recommended 200 mm2.
Objectives: To determine the diagnostic accuracy of dual-energy CT (DECT) virtual noncalcium (VNCa) reconstructions for assessing thoracic disk herniation compared to standard grayscale CT. Methods: In this retrospective study, 87 patients (1131 intervertebral disks; mean age, 66 years; 47 women) who underwent third-generation dual-source DECT and 3.0-T MRI within 3 weeks between November 2016 and April 2020 were included. Five blinded radiologists analyzed standard DECT and color-coded VNCa images after a time interval of 8 weeks for the presence and degree of thoracic disk herniation and spinal nerve root impingement. Consensus reading of independently evaluated MRI series served as the reference standard, assessed by two separate experienced readers. Additionally, image ratings were carried out by using 5-point Likert scales. Results: MRI revealed a total of 133 herniated thoracic disks. Color-coded VNCa images yielded higher overall sensitivity (624/665 [94%; 95% CI, 0.89–0.96] vs 485/665 [73%; 95% CI, 0.67–0.80]), specificity (4775/4990 [96%; 95% CI, 0.90–0.98] vs 4066/4990 [82%; 95% CI, 0.79–0.84]), and accuracy (5399/5655 [96%; 95% CI, 0.93–0.98] vs 4551/5655 [81%; 95% CI, 0.74–0.86]) for the assessment of thoracic disk herniation compared to standard CT (all p < .001). Interrater agreement was excellent for VNCa and fair for standard CT (ϰ = 0.82 vs 0.37; p < .001). In addition, VNCa imaging achieved higher scores regarding diagnostic confidence, image quality, and noise compared to standard CT (all p < .001). Conclusions: Color-coded VNCa imaging yielded substantially higher diagnostic accuracy and confidence for assessing thoracic disk herniation compared to standard CT.
Rationale: Dysregulation of dopaminergic neurotransmission, specifically altered reward processing assessed via the reward anticipation in the MID task, plays a central role in the etiopathogenesis of neuropsychiatric disorders. Objectives: We hypothesized to find a difference in the activity level of the reward system (measured by the proxy reward anticipation) under drug administration versus placebo, in that amisulpride reduces, and L-DOPA enhances, its activity. Methods: We studied the influence of dopamine agonist L-DOPA and the antagonist amisulpride on the reward system using functional magnetic resonance imaging (fMRI) during a monetary incentive delay (MID) task in n = 45 healthy volunteers in a randomized, blinded, cross-over study. Results: The MID paradigm elicits strong activation in reward-dependent structures (such as ventral striatum, putamen, caudate, anterior insula) during reward anticipation. The placebo effect demonstrated the expected significant blood oxygen level–dependent activity in reward-dependent brain regions. Neither amisulpride nor L-DOPA led to significant changes in comparison with the placebo condition. This was true for whole-brain analysis as well as analysis of a pre-defined nucleus accumbens region-of-interest mask. Conclusion: The present results cast doubt on the sensitivity of reward anticipation contrast in the MID task for assessing dopamine-specific changes in healthy volunteers by pharmaco-fMRI. While our task was not well-suited for detailed analysis of the outcome phase, we provide reasonable arguments that the lack of effect in the anticipation phase is not due to an inefficient task but points to unexpected behavior of the reward system during pharmacological challenge. Group differences of reward anticipation should therefore not be seen as simple representatives of dopaminergic states.
Der Vorstand der Deutschen Gesellschaft für Epileptologie und die Kommission „Epilepsie und Synkopen“ der Deutschen Gesellschaft für Neurologie haben die aktuelle Datenlage zur Impfung zur Vorbeugung der Corona-Virus-Krankheit 2019 (COVID-19) sowie zur Impfpriorisierung bei Menschen mit Epilepsie gesichtet, diese zusammengefasst und geben die unten genannten Empfehlungen ab.
Hintergrund: In Frankfurt am Main (~750.000 Einwohner) wird die erste Leichenschau im Auftrag der Polizei tagsüber durch einen dafür eingerichteten rechtsmedizinischen Dienst vorgenommen. Nachts und am Wochenende führen diese Tätigkeit Ärzte des ärztlichen Bereitschaftsdienstes (ÄBD) der kassenärztlichen Vereinigung durch. Material und Methoden: Für das Jahr 2019 wurden die im Rahmen dieser ersten Leichenschauen ausgestellten Leichenschauscheine hinsichtlich der attestierten Todesart ausgewertet und die Ergebnisse mit denen einer ggf. im Nachgang durchgeführten Sektion, inklusive Zusatzuntersuchungen, verglichen. Von den Ärzten des ÄBD konnten 461 Leichenschauen in die Auswertung eingeschlossen werden, davon erfolgte in 76 Fällen eine Obduktion. Im Nachgang der 364 rechtsmedizinischen Leichenschauen wurden 78 Obduktionen durchgeführt. Ergebnisse: Veränderungen in der Todesart nach Sektion ergaben sich für die Leichenschauen des ÄBD in 57, bei den rechtsmedizinischen Leichenschauen in 49 Fällen, wobei insbesondere eine bei Leichenschau attestierte ungeklärte Todesart in einen natürlichen Tod spezifiziert werden konnte. Nach der Obduktion fanden sich bei den rechtsmedizinischen Leichenschauen 8 Fälle, bei denen des ÄBD 19 Fälle eines nichtnatürlichen (statt weiterhin ungeklärten) Todes. Bei den rechtsmedizinisch beschauten Fällen änderte sich zudem nach der Sektion in einem Fall die Todesart von natürlich zu nichtnatürlich, bei denen des ÄBD kam es in einem Fall zu einer Änderung von nichtnatürlich zu natürlich. Diskussion: Die Veränderung bzw. Spezifizierung der Todesart nach der Sektion beider Kollektive verdeutlicht, wie wichtig eine Steigerung der Sektionsrate wäre, und dass auch bei professioneller Durchführung der Leichenschau das Erkennen der Todesart Probleme bereitet.
Background: About 30 million people in the EU and USA, respectively, suffer from a rare disease. Driven by European legislative requirements, national strategies for the improvement of care in rare diseases are being developed. To improve timely and correct diagnosis for patients with rare diseases, the development of a registry for undiagnosed patients was recommended by the German National Action Plan. In this paper we focus on the question on how such a registry for undiagnosed patients can be built and which information it should contain. Results: To develop a registry for undiagnosed patients, a software for data acquisition and storage, an appropriate data set and an applicable terminology/classification system for the data collected are needed. We have used the open-source software Open-Source Registry System for Rare Diseases (OSSE) to build the registry for undiagnosed patients. Our data set is based on the minimal data set for rare disease patient registries recommended by the European Rare Disease Registries Platform. We extended this Common Data Set to also include symptoms, clinical findings and other diagnoses. In order to ensure findability, comparability and statistical analysis, symptoms, clinical findings and diagnoses have to be encoded. We evaluated three medical ontologies (SNOMED CT, HPO and LOINC) for their usefulness. With exact matches of 98% of tested medical terms, a mean number of five deposited synonyms, SNOMED CT seemed to fit our needs best. HPO and LOINC provided 73% and 31% of exacts matches of clinical terms respectively. Allowing more generic codes for a defined symptom, with SNOMED CT 99%, with HPO 89% and with LOINC 39% of terms could be encoded. Conclusions: With the use of the OSSE software and a data set, which, in addition to the Common Data Set, focuses on symptoms and clinical findings, a functioning and meaningful registry for undiagnosed patients can be implemented. The next step is the implementation of the registry in centres for rare diseases. With the help of medical informatics and big data analysis, case similarity analyses could be realized and aid as a decision-support tool enabling diagnosis of some undiagnosed patients.
Nitrogen oxides (NOx), especially nitrogen dioxide (NO2), are among the most hazardous forms of air pollution. Tobacco smoke is a main indoor source of NOx, but little information is available about their concentrations in second-hand smoke (SHS), particularly in small indoors. This study presents data of NOx and its main components nitric oxide (NO) and NO2 in SHS emitted by ten different cigarette brands measured in a closed test chamber with a volume of 2.88 m3, similar to the volume of vehicle cabins. The results show substantial increases in NOx concentrations when smoking only one cigarette. The NO2 mean concentrations ranged between 105 and 293 µg/m3, the NO2 peak concentrations between 126 and 357 µg/m3. That means the one-hour mean guideline of 200 µg/m3 for NO2 of the World Health Organization was exceeded up to 47%, respectively 79%. The measured NO2 values show positive correlations with the values for tar, nicotine, and carbon monoxide stated by the cigarette manufacturers. This study provides NO2 concentrations in SHS at health hazard levels. These data give rise to the necessity of health authorities’ measures to inform about and caution against NOx exposure by smoking in indoor rooms.
Background: High sensitivity cardiac troponin T (hs-cTnT) and NT-pro-brain natriuretic peptide (NT-pro BNP) are often elevated in chronic kidney disease (CKD) and associated with both cardiovascular remodeling and outcome. Relationship between these biomarkers and quantitative imaging measures of myocardial fibrosis and edema by T1 and T2 mapping remains unknown. Methods: Consecutive patients with established CKD and estimated glomerular filtration rate (eGFR) < 59 ml/min/1.73 m2 (n = 276) were compared to age/sex matched patients with eGFR ≥ 60 ml/min/1.73 m2 (n = 242) and healthy controls (n = 38). Comprehensive cardiovascular magnetic resonance (CMR) with native T1 and T2 mapping, myocardial ischemia and scar imaging was performed with venous sampling immediately prior to CMR. Results: Patients with CKD showed significant cardiac remodeling in comparison with both healthy individuals and non-CKD patients, including a stepwise increase of native T1 and T2 (p < 0.001 between all CKD stages). Native T1 and T2 were the sole imaging markers independently associated with worsening CKD in patients [B = 0.125 (95% CI 0.022–0.235) and B = 0.272 (95% CI 0.164–0.374) with p = 0.019 and < 0.001 respectively]. At univariable analysis, both hs-cTnT and NT-pro BNP significantly correlated with native T1 and T2 in groups with eGFR 30–59 ml/min/1.73 m2 and eGFR < 29 ml/min/1.73 m2 groups, with associations being stronger at lower eGFR (NT-pro BNP (log transformed, lg10): native T1 r = 0.43 and r = 0.57, native T2 r = 0.39 and r = 0.48 respectively; log-transformed hs-cTnT(lg10): native T1 r = 0.23 and r = 0.43, native T2 r = 0.38 and r = 0.58 respectively, p < 0.001 for all, p < 0.05 for interaction). On multivariable analyses, we found independent associations of native T1 with NT-pro BNP [(B = 0.308 (95% CI 0.129–0.407), p < 0.001 and B = 0.334 (95% CI 0.154–0.660), p = 0.002 for eGFR 30–59 ml/min/1.73 m2 and eGFR < 29 ml/min/1.73 m2, respectively] and of T2 with hs-cTnT [B = 0.417 (95% CI 0.219–0.650), p < 0.001 for eGFR < 29 ml/min/1.73 m2]. Conclusions: We demonstrate independent associations between cardiac biomarkers with imaging markers of interstitial expansion, which are CKD-group specific. Our findings indicate the role of diffuse non-ischemic tissue processes, including excess of myocardial fluid in addition to diffuse fibrosis in CKD-related adverse remodeling.
Despite a high clinical need for the treatment of colorectal carcinoma (CRC) as the second leading cause of cancer-related deaths, targeted therapies are still limited. The multifunctional enzyme Transglutaminase 2 (TGM2), which harbors transamidation and GTPase activity, has been implicated in the development and progression of different types of human cancers. However, the mechanism and role of TGM2 in colorectal cancer are poorly understood. Here, we present TGM2 as a promising drug target.
In primary patient material of CRC patients, we detected an increased expression and enzymatic activity of TGM2 in colon cancer tissue in comparison to matched normal colon mucosa cells. The genetic ablation of TGM2 in CRC cell lines using shRNAs or CRISPR/Cas9 inhibited cell expansion and tumorsphere formation. In vivo, tumor initiation and growth were reduced upon genetic knockdown of TGM2 in xenotransplantations. TGM2 ablation led to the induction of Caspase-3-driven apoptosis in CRC cells. Functional rescue experiments with TGM2 variants revealed that the transamidation activity is critical for the pro-survival function of TGM2. Transcriptomic and protein–protein interaction analyses applying various methods including super-resolution and time-lapse microscopy showed that TGM2 directly binds to the tumor suppressor p53, leading to its inactivation and escape of apoptosis induction.
We demonstrate here that TGM2 is an essential survival factor in CRC, highlighting the therapeutic potential of TGM2 inhibitors in CRC patients with high TGM2 expression. The inactivation of p53 by TGM2 binding indicates a general anti-apoptotic function, which may be relevant in cancers beyond CRC.
Erratum zu: Rechtsmedizin 2020. https://doi.org/10.1007/s00194-020-00447-4. Der Artikel „Aktuelle Normwerte der Organgewichte und -indizes für die rechtsmedizinische Praxis, Teil 2. Leber, Lunge, Milz und Nieren“ von C. Holländer, H. Ackermann und M. Parzeller wurde ursprünglich Online First ohne „Open Access“ auf der Internetplattform des Verlags publiziert. Nach der Veröffentlichung in Bd. 31 Heft 2 pp. 117–130 hatten sich die Autoren für eine „Open Access“-Veröffentlichung entschieden. Das Urheberrecht des Artikels wurde deshalb in © Der/die Autoren 2020 geändert. Dieser Artikel ist jetzt unter der Creative Commons Namensnennung 4.0 International Lizenz veröffentlicht, welche die Nutzung, Vervielfältigung, Bearbeitung, Verbreitung und Wiedergabe in jeglichem Medium und Format erlaubt, sofern Sie den/die ursprünglichen Autor(en) und die Quelle ordnungsgemäß nennen, einen Link zur Creative Commons Lizenz beifügen und angeben, ob Änderungen vorgenommen wurden. Die in diesem Artikel enthaltenen Bilder und sonstiges Drittmaterial unterliegen ebenfalls der genannten Creative Commons Lizenz, sofern sich aus der Abbildungslegende nichts anderes ergibt. Sofern das betreffende Material nicht unter der genannten Creative Commons Lizenz steht und die betreffende Handlung nicht nach gesetzlichen Vorschriften erlaubt ist, ist für die oben aufgeführten Weiterverwendungen des Materials die Einwilligung des jeweiligen Rechteinhabers einzuholen. Weitere Details zur Lizenz entnehmen Sie bitte der Lizenzinformation auf http://creativecommons.org/licenses/by/4.0/deed.de.
Erratum zu: Rechtsmedizin 2020. https://doi.org/10.1007/s00194-020-00447-4. Im o. g. Beitrag wurde im Abschnitt Material und Methoden auf S. 118 bei den Organindizes aufgrund eines Tippfehlers „mit p = 0,95“ statt „mit P = 0,95“ angegeben. Durch den Tippfehler könnte angenommen werden, es handle sich um eine Irrtumswahrscheinlichkeit, obwohl es sich um eine Konfidenz handelt. Zudem wurden in den Abschnitten Material und Methoden sowie Limitationen bezüglich der Erhebung von Organindizes versehentlich angeführt, es seien bei der linken und rechten Niere (♂, ♀) Ausreißer entfernt worden. Richtigerweise wurden Ausreißer bei der rechten Niere nur bei den Frauen entfernt. Die Überschrift in Tab. 6 muss richtigerweise „Tab. 6: Nichtparametrischer Toleranzbereich …“ und nicht „Tab. 6: Nichtparametrischer Normbereich …“ lauten. In Tab. 7, die sich auf den Kruskal-Wallis-Test bezieht, ist als Anmerkung „* Signifikante Korrelation“ angegeben. Aufgrund des Testverfahrens ist dies als „* Signifikanter Unterschied“ zu bezeichnen. Der Originalbeitrag wurde entsprechend korrigiert. Für diese Fehler möchten wir uns entschuldigen.
The article Therapeutic Options for Patients with Refractory Status Epilepticus in Palliative Settings or with a Limitation of Life‑Sustaining Therapies: A Systematic Review, written by Laurent M. Willems, Sebastian Bauer, Kolja Jahnke, Martin Voss, Felix Rosenow, Adam Strzelczyk, was originally published Online First without Open Access. After publication in volume 34, issue 8, pages 801–826 the author decided to opt for Open Choice and to make the article an Open Access publication. Post-publication open access was funded by Projekt DEAL. Therefore, the copyright of the article has been changed to © The Author(s) 2021 and the article is forthwith distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/. The original article has been corrected.
Beneficial acute effects of resistance exercise on cognitive functions may be modified by exercise intensity or by habitual physical activity. Twenty-six participants (9 female and 17 male; 25.5 ± 3.4 years) completed four resistance exercise interventions in a randomized order on separate days (≥48 h washout). The intensities were set at 60%, 75%, and 90% of the one repetition maximum (1RM). Three interventions had matched workloads (equal resistance*nrepetitions). One intervention applied 75% of the 1RM and a 50% reduced workload (resistance*nrepetitions = 50%). Cognitive attention (Trail Making Test A—TMTA), task switching (Trail Making Test B—TMTB), and working memory (Digit Reading Spans Backward) were assessed before and immediately after exercise. Habitual activity was assessed as MET hours per week using the International Physical Activity Questionnaire. TMTB time to completion was significantly shorter after exercise with an intensity of 60% 1RM and 75% 1RM and 100% workload. Friedman test indicated a significant effect of exercise intensity in favor of 60% 1RM. TMTA performance was significantly shorter after exercise with an intensity of 60% 1RM, 90% 1RM, and 75% 1RM (50% workload). Habitual activity with vigorous intensity correlated positively with the baseline TMTB and Digit Span Forward performance but not with pre- to post-intervention changes. Task switching, based on working memory, mental flexibility, and inhibition, was beneficially influenced by acute exercise with moderate intensity whereas attention performance was increased after exercise with moderate and vigorous intensity. The effect of regular activity had no impact on acute exercise effects.
Oral Progestins in Hormonal Contraception: Importance and Future Perspectives of a New Progestin Only-Pill Containing 4 mg Drospirenone
Thomas Römer, Johannes Bitzer, Christian Egarter et al. Geburtsh Frauenheilk. doi:10.1055/a-1471-4408
In the e-first version of this article the name of the co-author was incorrect. Correct is: Katrin Schaudig
Acinetobacter baumannii is a highly antibiotic resistant Gram-negative bacterium that causes life-threatening infections in humans with a very high mortality rate. A. baumannii is an extracellular pathogen with poorly understood virulence mechanisms. Here we report that A. baumannii employs the release of outer membrane vesicles (OMVs) containing the outer membrane protein A (OmpAAb) to promote bacterial pathogenesis and dissemination. OMVs containing OmpAAb are taken up by mammalian cells where they activate the host GTPase dynamin-related protein 1 (DRP1). OmpAAb mediated activation of DRP1 enhances its accumulation on mitochondria that causes mitochondrial fragmentation, elevation in reactive oxygen species (ROS) production and cell death. Loss of DRP1 rescues these phenotypes. Our data show that OmpAAb is sufficient to induce mitochondrial fragmentation and cytotoxicity since its expression in E. coli transfers its pathogenic properties to E. coli. A. baumannii infection in mice also induces mitochondrial damage in alveolar macrophages in an OmpAAb dependent manner. We finally show that OmpAAb is also required for systemic dissemination in the mouse lung infection model. In this study we uncover the mechanism of OmpAAb as a virulence factor in A. baumannii infections and further establish the host cell factor required for its pathogenic effects.
BCOR-rearranged sarcomas are rare and belong to the Ewing-like sarcomas (ELS). Their morphology and histopathological features make the diagnosis challenging. We present a case, initially diagnosed as an unusual extraskeletal myxoid chondrosarcoma (EMC). A 54-year-old male patient developed an asymptomatic swelling of the lower leg. Imaging showed a 9.5-cm large intramuscular soft tissue mass. Due to its morphological and immunohistochemical profile on biopsy, it was initially diagnosed as an EMC. The patient was treated by complete resection and adjuvant radiotherapy and remained free of tumor at 7 years follow-up. Using next-generation sequencing (NGS), we retrospectively identified RGAG1-BCOR gene fusion (confirmed by RT-PCR), which has not been described in somatic soft tissue tumors so far. This finding broadens the spectrum of partner genes in the BCOR-rearranged sarcomas in a tumor with a well-documented, long clinical follow-up.
Background: Radiochemotherapy (RCT) has been shown to induce changes in immune cell homeostasis which might affect antitumor immune responses. In the present study, we aimed to compare the composition and kinetics of major lymphocyte subsets in the periphery of patients with non-locoregional recurrent (n = 23) and locoregional recurrent (n = 9) squamous cell carcinoma of the head and neck (SCCHN) upon primary RCT. Methods: EDTA-blood of non-locoregional recurrent SCCHN patients was collected before (t0), after application of 20–30 Gy (t1), in the follow-up period 3 (t2) and 6 months (t3) after RCT. In patients with locoregional recurrence blood samples were taken at t0, t1, t2 and at the time of recurrence (t5). EDTA-blood of age-related, healthy volunteers (n = 22) served as a control (Ctrl). Major lymphocyte subpopulations were phenotyped by multiparameter flow cytometry. Results: Patients with non-recurrent SCCHN had significantly lower proportions of CD19+ B cells compared to healthy individuals before start of any therapy (t0) that dropped further until 3 months after RCT (t2), but reached initial levels 6 months after RCT (t3). The proportion of CD3+ T and CD3+/CD4+ T helper cells continuously decreased between t0 and t3, whereas that of CD8+ cytotoxic T cells and CD3+/CD56+ NK-like T cells (NKT) gradually increased in the same period of time in non-recurrent patients. The percentage of CD4+/CD25+/FoxP3+ regulatory T cells (Tregs) decreased directly after RCT, but increased above initial levels in the follow-up period 3 (t2) and 6 (t3) months after RCT. Patients with locoregional recurrence showed similar trends with respect to B, T cells and Tregs between t0 and t5. CD4+ T helper cells remained stably low between t0 and t5 in patients with locoregional recurrence compared to Ctrl. NKT/NK cell subsets (CD56+/CD69+, CD3−/CD56+, CD3−/CD94+, CD3−/NKG2D+, CD3−/NKp30+, CD3−/NKp46+) increased continuously up to 6 months after RCT (t0-t3) in patients without locoregional recurrence, whereas in patients with locoregional recurrence, these subsets remained stably low until time of recurrence (t5). Conclusion: Monitoring the kinetics of lymphocyte subpopulations especially activatory NK cells before and after RCT might provide a clue with respect to the development of an early locoregional recurrence in patients with SCCHN. However, studies with larger patient cohorts are needed. Trial registration: Observational Study on Biomarkers in Head and Neck Cancer (HNprädBio), NCT02059668. Registered on 11 February 2014, https://clinicaltrials.gov/ct2/show/NCT02059668.
Background: Refractory status epilepticus (RSE) represents a serious medical condition requiring early and targeted therapy. Given the increasing number of elderly or multimorbid patients with a limitation of life-sustaining therapy (LOT) or within a palliative care setting (PCS), guidelines-oriented therapy escalation options for RSE have to be omitted frequently. Objectives: This systematic review sought to summarize the evidence for fourth-line antiseizure drugs (ASDs) and other minimally or non-invasive therapeutic options beyond guideline recommendations in patients with RSE to elaborate on possible treatment options for patients undergoing LOT or in a PCS. Methods: A systematic review of the literature in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, focusing on fourth-line ASDs or other minimally or non-invasive therapeutic options was performed in February and June 2020 using the MEDLINE, EMBASE and Cochrane databases. The search terminology was constructed using the name of the specific ASD or therapy option and the term ‘status epilepticus’ with the use of Boolean operators, e.g. “(brivaracetam) AND (status epilepticus)”. The respective Medical Subject Headings (MeSH) and Emtree terms were used, if available. Results: There is currently no level 1, grade A evidence for the use of ASDs in RSE. The best evidence was found for the use of lacosamide and topiramate (level 3, grade C), followed by brivaracetam, perampanel (each level 4, grade D) and stiripentol, oxcarbazepine and zonisamide (each level 5, grade D). Regarding non-medicinal options, there is little evidence for the use of the ketogenic diet (level 4, grade D) and magnesium sulfate (level 5, grade D) in RSE. The broad use of immunomodulatory or immunosuppressive treatment options in the absence of a presumed autoimmune etiology cannot be recommended; however, if an autoimmune etiology is assumed, steroid pulse, intravenous immunoglobulins and plasma exchange/plasmapheresis should be considered (level 4, grade D). Even if several studies suggested that the use of neurosteroids (level 5, grade D) is beneficial in RSE, the current data situation indicates that there is formal evidence against it. Conclusions: RSE in patients undergoing LOT or in a PCS represents a challenge for modern clinicians and epileptologists. The evidence for the use of ASDs in RSE beyond that in current guidelines is low, but several effective and well-tolerated options are available that should be considered in this patient population. More so than in any other population, advance care planning, advance directives, and medical ethical aspects have to be considered carefully before and during therapy.
Gene-drive suppression of mosquito populations in large cages as a bridge between lab and field
(2021)
CRISPR-based gene-drives targeting the gene doublesex in the malaria vector Anopheles gambiae effectively suppressed the reproductive capability of mosquito populations reared in small laboratory cages. To bridge the gap between laboratory and the field, this gene-drive technology must be challenged with vector ecology. Here we report the suppressive activity of the gene-drive in age-structured An. gambiae populations in large indoor cages that permit complex feeding and reproductive behaviours. The gene-drive element spreads rapidly through the populations, fully supresses the population within one year and without selecting for resistance to the gene drive. Approximate Bayesian computation allowed retrospective inference of life-history parameters from the large cages and a more accurate prediction of gene-drive behaviour under more ecologically-relevant settings. Generating data to bridge laboratory and field studies for invasive technologies is challenging. Our study represents a paradigm for the stepwise and sound development of vector control tools based on gene-drive.
Background: There is evidence of a volume outcome relationship for liver transplantation. In Germany, there is a minimum volume threshold of 20 transplantations per year for each center. Thresholds potentially lead to centralization of the healthcare supply, generating longer travel times. Objective: This study assessed whether patients are willing to travel longer times to transplantation centers for better outcomes (lower hospital mortality and higher 3-year survival) and identified patient characteristics influencing their choices. Methods: Participants were recruited in hospitals and via random samples at registration offices. Discrete choice experiments were used to identify trade-offs in their choices between local and regional centers. Descriptive statistics and logistic regression models were used to measure patients’ preferences and quantify potentially influencing characteristics. Results: Overall, 82.22% (in-hospital mortality) and 84.44% (3-year survival) of the participants opted to accept a longer travel time in order to receive a liver transplantation with better outcomes. Conclusion: Most participants were willing to trade shorter travel times for lower mortality risks and higher 3-year survival in cases of liver transplantation.
Background: Increasingly, informal caregivers in Belgium care in group for an older patient. This study aimed to decrease the caregiver burden and to increase the well-being of caregivers and patients by supporting the needs of informal care groups of older patients (≥70 years).
Method: Through an online self-management tool, the groups were supported to make informed choices concerning the care for the older patient, taking into account the standards, values, concerns and needs of every caregiver and patient. A pre-post study was performed.
Results: Although patients and caregivers considered the self-management tool as useful and supportive, no clear evidence for decreased caregiver burden was found. There was a positive trend in group characteristics such as the distribution of tasks, communication and prevalence of conflicts. Caregivers also stated that they took more time for themselves, had less feelings of guilt and experienced less barriers to ask help.
Conclusion: Tailor-made support of informal care groups starts with facilitating and guiding a process to achieve consent within the group to optimise the care for the patient and also for the caregivers. With a shared vision and supported decisions, caregivers can enter into conversations with the professional caregiver to coordinate adjusted support regarding the care needs.
Purpose: While more advanced COVID-19 necessitates medical interventions and hospitalization, patients with mild COVID-19 do not require this. Identifying patients at risk of progressing to advanced COVID-19 might guide treatment decisions, particularly for better prioritizing patients in need for hospitalization.
Methods: We developed a machine learning-based predictor for deriving a clinical score identifying patients with asymptomatic/mild COVID-19 at risk of progressing to advanced COVID-19. Clinical data from SARS-CoV-2 positive patients from the multicenter Lean European Open Survey on SARS-CoV-2 Infected Patients (LEOSS) were used for discovery (2020-03-16 to 2020-07-14) and validation (data from 2020-07-15 to 2021-02-16).
Results: The LEOSS dataset contains 473 baseline patient parameters measured at the first patient contact. After training the predictor model on a training dataset comprising 1233 patients, 20 of the 473 parameters were selected for the predictor model. From the predictor model, we delineated a composite predictive score (SACOV-19, Score for the prediction of an Advanced stage of COVID-19) with eleven variables. In the validation cohort (n = 2264 patients), we observed good prediction performance with an area under the curve (AUC) of 0.73 ± 0.01. Besides temperature, age, body mass index and smoking habit, variables indicating pulmonary involvement (respiration rate, oxygen saturation, dyspnea), inflammation (CRP, LDH, lymphocyte counts), and acute kidney injury at diagnosis were identified. For better interpretability, the predictor was translated into a web interface.
Conclusion: We present a machine learning-based predictor model and a clinical score for identifying patients at risk of developing advanced COVID-19.
Background: We aimed to determine the association between seizure termination and side effects of isoflurane for the treatment of refractory status epilepticus (RSE) and super-refractory status epilepticus (SRSE) in neurointensive care units (neuro-ICUs).
Methods: This was a multicenter retrospective study of patients with RSE/SRSE treated with isoflurane for status epilepticus termination admitted to the neuro-ICUs of nine German university centers during 2011–2018.
Results: We identified 45 patients who received isoflurane for the treatment of RSE/SRSE. During isoflurane treatment, electroencephalograms showed no epileptiform discharges in 33 of 41 (80%) patients, and burst suppression pattern was achieved in 29 of 41 patients (71%). RSE/SRSE was finally terminated after treatment with isoflurane in 23 of 45 patients (51%) for the entire group and in 13 of 45 patients (29%) without additional therapy. Lengths of stay in the hospital and in the neuro-ICU were significantly extended in cases of ongoing status epilepticus under isoflurane treatment (p = 0.01 for length of stay in the hospital, p = 0.049 for length in the neuro-ICU). During isoflurane treatment, side effects were reported in 40 of 45 patients (89%) and mainly included hypotension (n = 40, 89%) and/or infection (n = 20, 44%). Whether side effects occurred did not affect the outcome at discharge. Of 22 patients with follow-up magnetic resonance imaging, 2 patients (9%) showed progressive magnetic resonance imaging alterations that were considered to be potentially associated with RSE/SRSE itself or with isoflurane therapy.
Conclusions; Isoflurane was associated with a good effect in stopping RSE/SRSE. Nevertheless, establishing remission remained difficult. Side effects were common but without effect on the outcome at discharge.
Mild acquired factor XIII deficiency and clinical relevance at the ICU - a retrospective analysis
(2021)
Acquired FXIII deficiency is a relevant complication in the perioperative setting; however, we still have little evidence about the incidence and management of this rarely isolated coagulopathy. This study aims to help find the right value for the substitution of patients with an acquired mild FXIII deficiency. In this retrospective single-center cohort study, we enrolled critically ill patients with mild acquired FXIII deficiency (>5% and ≤70%) and compared clinical and laboratory parameters, as well as pro-coagulatory treatments. The results of the present analysis of 104 patients support the clinical relevance of FXIII activity out of the normal range. Patients with lower FXIII levels, beginning at <60%, had lower minimum and maximum hemoglobin values, corresponding to the finding that patients with a minimum FXIII activity of <50% needed significantly more packed red blood cells. FXIII activity correlated significantly with general coagulation markers such as prothrombin time, activated partial thromboplastin time, and fibrinogen. Nevertheless, comparing the groups with a cut-off of 50%, the amount of fresh frozen plasma, thrombocytes, PPSB, AT-III, and fibrinogen given did not differ. These results indicate that a mild FXIII deficiency occurring at any point of intensive care unit stay is also probably relevant for the total need of packed red blood cells, independent of pro-coagulatory management. In alignment with the ESAIC guidelines, the measurement of FXIII in critically ill patients with the risk of bleeding and early management, with the substitution of FXIII at levels <50%-60%, could be suggested.
Background and purpose: The ENIGMA-EEG working group was established to enable large-scale international collaborations among cohorts that investigate the genetics of brain function measured with electroencephalography (EEG). In this perspective, we will discuss why analyzing the genetics of functional brain activity may be crucial for understanding how neurological and psychiatric liability genes affect the brain. Methods: We summarize how we have performed our currently largest genome-wide association study of oscillatory brain activity in EEG recordings by meta-analyzing the results across five participating cohorts, resulting in the first genome-wide significant hits for oscillatory brain function located in/near genes that were previously associated with psychiatric disorders. We describe how we have tackled methodological issues surrounding genetic meta-analysis of EEG features. We discuss the importance of harmonizing EEG signal processing, cleaning, and feature extraction. Finally, we explain our selection of EEG features currently being investigated, including the temporal dynamics of oscillations and the connectivity network based on synchronization of oscillations. Results: We present data that show how to perform systematic quality control and evaluate how choices in reference electrode and montage affect individual differences in EEG parameters. Conclusion: The long list of potential challenges to our large-scale meta-analytic approach requires extensive effort and organization between participating cohorts; however, our perspective shows that these challenges are surmountable. Our perspective argues that elucidating the genetic of EEG oscillatory activity is a worthwhile effort in order to elucidate the pathway from gene to disease liability.
Einleitung: Die Obduktion nimmt einen wichtigen Stellenwert in der Medizin ein, da sie nicht nur der Klärung der Todesart und -ursache eines Verstorbenen dient, sondern auch zum Verständnis der Pathophysiologie von Erkrankungen beiträgt. In diesem zweiten Teil der Studie wurden aktuelle Normwerte für das Gewicht für die folgenden adulten Organe entwickelt: Leber, Lunge, Milz, Nieren. Zudem wurden Zusammenhänge zwischen Organgewichten und der Todesart untersucht. Material und Methoden: Die im Dreijahreszeitraum von 2011 bis 2013 im Institut für Rechtsmedizin in Frankfurt am Main durchgeführten Obduktionen wurden retrospektiv ausgewertet. Die statistischen Berechnungen erfolgten mithilfe des Programmes „BiAS. für Windows“ (epsilon-Verlag GbR, Hochheim-Darmstadt, Deutschland). Ergebnisse: Folgende Normwerte bzw. -bereiche wurden an der Studienpopulation erhoben: Leber 1047,0–2740,0 g (♂, n = 191) bzw. 749,0–2182,0 g (♀, n = 115), linke Lunge 230,0–840,0 g (♂, n = 119) bzw. 186,8–891,3 g (♀, n = 97), rechte Lunge 249,3–1005,8 g (♂, n = 116) bzw. 215,3–907,5 g (♀, n = 100), Milz 55,0–373,2 g (♂, n = 306) bzw. 50,0–355,0 g (♀, n = 204), linke Niere 110,0–255,0 g (♂, n = 258) bzw. 71,8–215,0 g (♀, n = 137), rechte Niere 100,0–270,0 g (♂, n = 266) bzw. 75,0–212,1 g (♀, n = 140). Für die am stärksten mit Organgewichten korrelierenden Körpermaße, nämlich Body-Mass-Index (BMI), Körperoberfläche („body surface area“, BSA) und Körpergewicht, wurden nach Subgruppen getrennte Normwerte ermittelt. Ein signifikanter Unterschied des Organgewichtes je nach Todesart lag bei Männern bei der Milz und bei den Nieren vor. Bei Frauen war bei keinem der Organe ein von der Todesart abhängiger signifikanter Gewichtsunterschied feststellbar. Außerdem wurden Organindizes entwickelt, mittels derer der Anwender berechnen kann, ob ein Organgewicht, Körpermaßen bzw. Alter entsprechend, im Normbereich liegt. Diskussion: Organgewichte unterliegen wie Körpermaße einem säkularen Trend, welcher jedoch nicht linear und für jedes Organ individuell verläuft. Für die Auswertung von Organgewichten im Rahmen der Obduktion werden deshalb aktuelle, an einer vergleichbaren Population erhobene Normtabellen benötigt. Bei deren Erstellung können sowohl Fälle mit natürlichem als auch mit nichtnatürlichem Tod unter weitestgehendem Ausschluss pathologisch veränderter Organe herangezogen werden.
Portal hypertension, defined as increased pressure in the portal vein, develops as a consequence of increased intrahepatic vascular resistance due to the dysregulation of liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs), frequently arising from chronic liver diseases. Extrahepatic haemodynamic changes contribute to the aggravation of portal hypertension. The pathogenic complexity of portal hypertension and the unsuccessful translation of preclinical studies have impeded the development of effective therapeutics for patients with cirrhosis, while counteracting hepatic and extrahepatic mechanisms also pose a major obstacle to effective treatment. In this review article, we will discuss the following topics: i) cellular and molecular mechanisms of portal hypertension, focusing on dysregulation of LSECs, HSCs and hepatic microvascular thrombosis, as well as changes in the extrahepatic vasculature, since these are the major contributors to portal hypertension; ii) translational/clinical advances in our knowledge of portal hypertension; and iii) future directions.
22q11.2 Deletion Syndrome (22q11.2DS) is the most common microdeletion in humans, with a heterogenous clinical presentation including medical, behavioural and psychiatric conditions. Previous neuroimaging studies examining the neuroanatomical underpinnings of 22q11.2DS show alterations in cortical volume (CV), cortical thickness (CT) and surface area (SA). The aim of this study was to identify (1) the spatially distributed networks of differences in CT and SA in 22q11.2DS compared to controls, (2) their unique and spatial overlap, as well as (3) their relative contribution to observed differences in CV. Structural MRI scans were obtained from 62 individuals with 22q11.2DS and 57 age-and-gender-matched controls (aged 6–31). Using FreeSurfer, we examined differences in vertex-wise estimates of CV, CT and SA at each vertex, and compared the frequencies of vertices with a unique or overlapping difference for each morphometric feature. Our findings indicate that CT and SA make both common and unique contributions to volumetric differences in 22q11.2DS, and in some areas, their strong opposite effects mask differences in CV. By identifying the neuroanatomic variability in 22q11.2DS, and the separate contributions of CT and SA, we can start exploring the shared and distinct mechanisms that mediate neuropsychiatric symptoms across disorders, e.g. 22q11.2DS-related ASD and/or psychosis/schizophrenia.
Purpose: Despite the high number of patients with phalangeal fractures, evidence-based recommendations for the treatment of specific phalangeal fractures could not be concluded from the literature. The purpose of the present study was to assess current epidemiological data, classification of the fracture type, and mode of treatment.
Methods: This study presents a retrospective review of 261 patients with 283 phalangeal fractures ≥ 18 years of age who were treated in our level I trauma centre between 2017 and 2018. The data were obtained by the analysis of the institution’s database, and radiological examinations.
Results: The average age of the patients was 40.4 years (range 18–98). The ratio of male to female patients was 2.7:1. The two most typical injury mechanisms were crush injuries (33%) and falls (23%). Most phalangeal fractures occurred in the distal phalanx (P3 43%). The 4th ray (D4 29%) was most frequently affected. The P3 tuft fractures, and the middle phalanx (P2) base fractures each accounted for 25% of fracture types. A total of 74% of fractures were treated conservatively, and 26% required surgery, with Kirschner wire(s) (37%) as the preferred surgical treatment. The decision for surgical treatment correlated with the degree of angular and/or rotational deformity, intraarticular step, and sub-/luxation of specific phalangeal fractures, but not with age and gender.
Conclusions: Our findings demonstrated the popularity of conservative treatment of phalangeal fractures, while surgery was only required in properly selected cases. The correct definition of precise fracture pattern in addition to topography is essential to facilitate treatment decision-making.
Introduction: Quinolone prophylaxis is recommended for patients with advanced cirrhosis at high risk of spontaneous bacterial peritonitis (SBP) or with prior SBP. Yet, the impact of long-term antibiotic prophylaxis on the microbiome of these patients is poorly characterized.
Methods: Patients with liver cirrhosis receiving long-term quinolone prophylaxis to prevent SBP were prospectively included and sputum and stool samples were obtained at baseline, 1, 4 and 12 weeks thereafter. Both bacterial DNA and RNA were assessed with 16S rRNA sequencing. Relative abundance, alpha and beta diversity were calculated and correlated with clinical outcome.
Results: Overall, 35 stool and 19 sputum samples were obtained from 11 patients. Two patients died (day 9 and 12) all others were followed for 180 days. Reduction of Shannon diversity and bacterial richness was insignificant after initiation of quinolone prophylaxis (p > 0.05). Gut microbiota were significantly different between patients (p < 0.001) but non-significantly altered between the different time points before and after initiation of antibiotic prophylaxis (p > 0.05). A high relative abundance of Enterobacteriaceae > 20% during quinolone prophylaxis was found in three patients. Specific clinical scenarios (development of secondary infections during antibiotic prophylaxis or the detection of multidrug-resistant Enterobacteriaceae) characterized these patients. Sputum microbiota were not significantly altered in individuals during prophylaxis.
Conclusion: The present exploratory study with small sample size showed that inter-individual differences in diversity of gut microbiota were high at baseline, yet quinolone prophylaxis had only a moderate impact. High relative abundances of Enterobacteriaceae during follow-up might indicate failure of or non-adherence to quinolone prophylaxis. However, our results may not be clinically significant given the limitations of the study and therefore future studies are needed to further investigate this phenomenon.
In murine models, the expression of inducible nitric oxide synthase (iNOS) in myocardial infarction (MI) has been reported to be the result of tissue injury and inflammation. In the present study, mRNA expression of iNOS, hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF) was investigated in postmortem human infarction hearts. Since HIF-1α is the inducible subunit of the transcription factor HIF-1, which regulates transcription of iNOS and VEGF, the interrelation between the three genes was observed, to examine the molecular processes during the emergence of MI. iNOS and VEGF mRNAs were found to be significantly upregulated in the affected regions of MI hearts in comparison to healthy controls. Upregulation of HIF-1α was also present but not significant. Correlation analysis of the three genes indicated a stronger and significant correlation between HIF-1α and iNOS mRNAs than between HIF-1α and VEGF. The results of the study revealed differences in the expression patterns of HIF-1 downstream targets. The stronger transcription of iNOS by HIF-1 in the affected regions of MI hearts may represent a pathological process, since no correlation of iNOS and HIF-1α mRNA was found in non-affected areas of MI hearts. Oxidative stress is considered to cause molecular changes in MI, leading to increased iNOS expression. Therefore, it may also represent a forensic marker for detection of early changes in heart tissue.
Zielsetzung: Die Daten für das Jahr 2018 des Registers „Abdominelles Aortenaneurysma“ (AAA) des Deutschen Instituts für Gefäßmedizinische Gesundheitsforschung (DIGG) der Deutschen Gesellschaft für Gefäßchirurgie und Gefäßmedizin werden vorgestellt.
Methodik: Im Jahr 2018 beteiligten sich an dem Register insgesamt 135 Kliniken. Für die offene Versorgung (OR) des intakten AAA (iAAA) gaben 118 (87,4 %) Kliniken, für die endovaskuläre Versorgung (EVAR) des iAAA 133 (98,5 %) Kliniken Daten ein. Für das rupturierte AAA (rAAA) wurden von 80 Kliniken (59,3 %) (EVAR) bzw. 65 (48,1 %) Kliniken (OR) Patienten gemeldet. Ausgewertet wurden die Daten von 4051 stationär behandelten Patienten.
Ergebnisse: 2800 iAAA (75,8 %) wurden endovaskulär und 895 (24,2 %) offen versorgt. Bei den endovaskulär versorgten Patienten mit iAAA verlief der Eingriff in 86,4 % der Fälle komplikationslos. Es verstarben insgesamt 32 Patienten (1,1 %) bis zur Entlassung. Bei den offen versorgten Patienten wiesen 73,4 % der Patienten keine Komplikationen auf. Verstorben sind insgesamt 42 Patienten (4,7 %). Von den 356 Patienten mit rAAA wurden 192 (53,9 %) endovaskulär und 164 (46,1 %) offen versorgt. Nur 11,0 % der mit OR versorgten Patienten, aber 23,4 % bei EVAR wiesen freies Blut in der Bauchhöhle auf. Bei EVAR sind 30,7 % der Patienten während des stationären Aufenthalts verstorben, bei OR 20,1 %.
Schlussfolgerung: Die Ergebnisse des Jahres 2018 zu Klinikletalität und Morbidität bei endovaskulärer und offener Versorgung des iAAA bestätigen weitestgehend die publizierten Ergebnisse für die Jahre 2013 bis 2017. Beim rAAA wurde 2018 erstmals über mehr endovaskuläre als offene Versorgungen berichtet – mit Ergebnissen, die denen der Vorjahre diametral entgegengesetzt waren. Patienten mit EVAR wiesen die höhere Komorbidität als Patienten mit OR auf und die Klinikletalität war höher. Es bleiben die Ergebnisse der Folgejahre abzuwarten, um diesen Trend genauer bewerten zu können.
Onkologische Erkrankungen im Kindesalter und jungen Erwachsenenalter haben nicht selten eine gute Prognose. Entsprechend wird für Betroffene früher oder später die Frage relevant, inwieweit nach einer onkologischen Behandlung die Fertilität beeinträchtigt ist. Nicht nur der Zeitraum der Fertilität, sondern auch die Wahrscheinlichkeit eines vorzeitigen Ovarialversagens mit allen Risiken eines längerfristigen Östrogenmangels ist für die Lebensplanung der Frauen wichtig. Mittlerweile können vor Behandlung fertilitätserhaltende Maßnahmen angeboten werden. Sie bieten manchmal die einzige Chance, auf ovarielle Reserven nach Behandlung zurückgreifen zu können, sind aber nicht immer nötig und von späterem Nutzen. Das Anti-Müller-Hormon (AMH) hat sich als validester Marker für die Beurteilung der ovariellen Reserve herausgestellt. Mithilfe dessen sind Prognosen über die Ovarreserve vor und nach der onkologischen Therapie möglich. Dies erleichtert die Entscheidung für die Indikation für fertilitätserhaltende Maßnahmen und kann wegweisend in der Lebensplanung der Frauen und Familien sein.
Objective: To assess the influence of biphasic calcium phosphate materials with different surface topographies on bone formation and osseointegration of titanium implants in standardized alveolar ridge defects.
Materials and methods: Standardized alveolar ridge defects (6 × 6 mm) were created in the mandible of 8 minipigs and filled with three biphasic calcium phosphate materials (BCP1–3, 90% tricalcium phosphate/10% hydroxyapatite) with different surface properties (micro- and macroporosities) as well as a bovine-derived natural bone mineral (NBM) as a control. At 12 weeks, implants were placed into the augmented defects. After further 8 weeks of healing, dissected blocks were processed for histological analysis (e.g., mineralized (MT), residual bone graft material (BS), bone-to-implant contact (BIC)).
Results: All four biomaterials showed well-integrated graft particles and new bone formation within the defect area. MT values were comparable in all groups. BS values were highest in the NBM group (21.25 ± 13.52%) and markedly reduced in the different BCP groups, reaching statistical significance at BCP1-treated sites (9.2 ± 3.28%). All test and control groups investigated revealed comparable and statistically not significant different BIC values, ranging from 73.38 ± 20.5% (BCP2) to 84.11 ± 7.84% (BCP1), respectively.
Conclusion* All bone graft materials facilitated new bone formation and osseointegration after 12 + 8 weeks of healing.
Endocannabinoids are important lipid-signaling mediators. Both protective and deleterious effects of endocannabinoids in the cardiovascular system have been reported but the mechanistic basis for these contradicting observations is unclear. We set out to identify anti-inflammatory mechanisms of endocannabinoids in the murine aorta and in human vascular smooth muscle cells (hVSMC). In response to combined stimulation with cytokines, IL-1β and TNFα, the murine aorta released several endocannabinoids, with anandamide (AEA) levels being the most significantly increased. AEA pretreatment had profound effects on cytokine-induced gene expression in hVSMC and murine aorta. As revealed by RNA-Seq analysis, the induction of a subset of 21 inflammatory target genes, including the important cytokine CCL2 was blocked by AEA. This effect was not mediated through AEA-dependent interference of the AP-1 or NF-κB pathways but rather through an epigenetic mechanism. In the presence of AEA, ATAC-Seq analysis and chromatin-immunoprecipitations revealed that CCL2 induction was blocked due to increased levels of H3K27me3 and a decrease of H3K27ac leading to compacted chromatin structure in the CCL2 promoter. These effects were mediated by recruitment of HDAC4 and the nuclear corepressor NCoR1 to the CCL2 promoter. This study therefore establishes a novel anti-inflammatory mechanism for the endogenous endocannabinoid AEA in vascular smooth muscle cells. Furthermore, this work provides a link between endogenous endocannabinoid signaling and epigenetic regulation.
Background: The importance of Silver diamine fluoride (SDF) as a minimally invasive and nonaerosolizing management during COVID-19 pandemic has highly increased. SDF is a caries-arresting agent that causes staining of tooth structure. Managing this discoloration will increase its acceptance in treating primary teeth. The main aim of this study was to quantify the color change associated with the application of SDF on extracted carious primary molars, the potential masking of this color change by potassium iodide (KI), composite (CMP) and glass ionomer cement (GI) and the effect of aging on this color masking effect.
Methods: An in-vitro study in which 52 carious primary molars were collected, prepared, and distributed randomly into four groups equally as follows: Group A: SDF 38%; Group B: SDF 38% + KI; Group C: SDF 38% + CMP; Group D: SDF 38% + GI. Color changes were recorded for each sample at baseline, and after application of the tested materials. Moreover, all samples had undergone Suntest aging followed by a third color reading. CIELAB values L*, a*, b*, ΔL, Δa, and Δb were measured, ΔE was calculated, and data were analyzed using multivariate analysis of variance (MANOVA) and post-Hoc Scheffé test (p < 0.05).
Results: MANOVA revealed the significant influence of the factor ‘material’. SDF caused an obvious color change compared to the color of carious dentin. Regarding ΔL, the color change of groups C and D was not significant directly after application of the tested materials. After aging, it was significant among all groups, including groups C and D. In Δa there was a difference between SDF and groups B and C after application of the tested materials, and aging produced the same results. The color shifts of Δb of all tested groups varied significantly from one another. After aging, there was no difference between group D and either group A or B.
Conclusions: Treatment with SDF caused obvious discoloration of carious dentin. Directly after SDF application, all tested materials could effectively mask the color change associated with the application of SDF. CMP was the only material whose color masking effect was not completely reversed by aging.
Blood-pressure-lowering drugs are proposed to foster SARS-CoV-2 infection by pharmacological upregulation of angiotensin-converting enzyme 2 (ACE2), the binding partner of the virus spike (S) protein, located on the surface of the host cells. Conversely, it is postulated that angiotensin–renin system antagonists may prevent lung damage caused by SARS-CoV-2 infection, by reducing angiotensin II levels, which can induce permeability of lung endothelial barrier via its interaction with the AT1 receptor (AT1R). Methods: We have investigated the influence of the ACE inhibitors (lisinopril, captopril) and the AT1 antagonists (telmisartan, olmesartan) on the level of ACE2 mRNA and protein expression as well as their influence on the cytopathic effect of SARS-CoV-2 and on the cell barrier integrity in a Caco-2 cell model. Results: The drugs revealed no effect on ACE2 mRNA and protein expression. ACE inhibitors and AT1R antagonist olmesartan did not influence the infection rate of SARS-CoV-2 and were unable to prevent the SARS-CoV-2-induced cell barrier disturbance. A concentration of 25 µg/mL telmisartan significantly reduced the virus replication rate. Conclusion: ACE inhibitors and AT1R antagonist showed neither beneficial nor detrimental effects on SARS-CoV-2-infection and cell barrier integrity in vitro at pharmacologically relevant concentrations.