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Cirrhosis – the common end-stage of chronic liver disease – is associated with a cascade of events, of which intestinal bacterial overgrowth and dysbiosis are central. Bacterial toxins entering the portal or systemic circulation can directly cause hepatocyte death, while dysbiosis also affects gut barrier function and increases bacterial translocation, leading to infections, systemic inflammation and vasodilation, which contribute to acute decompensation and organ failure. Acute decompensation and its severe forms, pre-acute-on-chronic liver failure (ACLF) and ACLF, are characterised by sudden organ dysfunction (and failure) and high short-term mortality. Patients with pre-ACLF and ACLF present with high-grade systemic inflammation, usually precipitated by proven bacterial infection and/or severe alcoholic hepatitis. However, no precipitant is identified in 30% of these patients, in whom bacterial translocation from the gut microbiota is assumed to be responsible for systemic inflammation and decompensation. Different microbiota profiles may influence the rate of decompensation and thereby outcome in these patients. Thus, targeting the microbiota is a promising strategy for the prevention and treatment of acute decompensation, pre-ACLF and ACLF. Approaches include the use of antibiotics such as rifaximin, faecal microbial transplantation and enterosorbents (e.g. Yaq-001), which bind microbial factors without exerting a direct effect on bacterial growth kinetics. This review focuses on the role of microbiota in decompensation and strategies targeting microbiota to prevent acute decompensation.
Background: Nicolaides-Baraitser syndrome (NCBRS) is a rare disease caused by mutations in the SMRCA2 gene, which affects chromatin remodelling and leads to a wide range of symptoms including microcephaly, distinct facial features, recurrent seizures, and severe mental retardation. Until now, less than 100 cases have been reported. Case presentation: A 22-month old male infant with NCBRS underwent elective cleft palate surgery. The anaesthetists were challenged by the physiological condition of the patient: narrow face, very small mouth, mild tachypnea, slight sternal retractions, physical signs of partial monosomy 9p, and plagiocephalus, midface hypoplasia, V-shaped cleft palate, enhanced muscular hypotension, dysplastic kidneys (bilateral, estimated GFR: approx. 40 ml/m2), nocturnal oxygen demand, and combined apnea. In addition, little information was available about interaction of the NCBRS displayed by the patient and anaesthesia medications. Conclusions: The cleft palate was successfully closed using the bridge flap technique. Overall, we recommend to perform a trial video assisted laryngoscopy in the setting of spontaneous breathing with deep inhalative anaesthesia before administration of muscle relaxation to detect any airway difficulties while remaining spontaneoues breathing and protective reflexes.
Upon infection with SARS-CoV-2, a variety of changes happen inside the host cell. The virus hijacks host cell pathways for driving its own replication, while the host counteracts with response mechanisms. To gain a comprehensive understanding of COVID-19, caused by SARS-CoV-2 infection, and develop therapeutic strategies, it is crucial to observe these systematic changes in their entirety. In our recent studies, we followed the effects of SARS-CoV-2 infection on the human proteome, which led to the identification of several drugs that abolished viral proliferation in cells.
Purpose: To compare swept-source (SS) versus spectral-domain (SD) optical coherence tomography angiography (OCTA) for the detection of macular neovascularization (MNV).
Methods: In this prospective cohort study, 72 eyes of 54 patients with subretinal hyperreflective material (SHRM) and/or pigment epithelial detachment (PED) on OCT possibly corresponding to MNV in at least one eye were included. OCTA scans were acquired using two devices, the PLEX Elite 9000 SS-OCTA and the Spectralis SD-OCTA. Fluorescein angiography (FA) was used as reference. Two graders independently evaluated en face OCTA images using a preset slab as well as a manually modified slab, followed by a combination of en face and cross-sectional OCTA.
Results: Sensitivity (specificity) for the automated slabs was 51.7% (93.0%) for SS-OCTA versus 58.6% (95.3%) for SD-OCTA. Manual modification of segmentation increased sensitivity to 79.3% for SS-OCTA but not for SD-OCTA (58.6%). The combination of en face OCTA with cross-sectional OCTA reached highest sensitivity values (SS-OCTA: 82.8%, SD-OCTA: 86.2%), and lowest number of cases with discrepancies between SS-OCTA and SD-OCTA (4.2%). Fleiss kappa as measure of concordance between FA, SS-OCTA, and SD-OCTA was 0.56 for the automated slabs, 0.60 for the manual slabs, and 0.73 (good agreement) for the combination of en face OCTA with cross-sectional OCTA. Concordance to FA was moderate for the automated slabs and good for manual slabs and combination with cross-sectional OCTA of both devices.
Conclusion: Both devices reached comparable results regarding the detection of MNV on OCTA. Sensitivity for MNV detection and agreement between devices was best when evaluating a combination of en face and cross-sectional OCTA.
Hematopoietic stem cell transplantation (HSCT) is the therapeutic concept to cure the blood/immune system of patients suffering from malignancies, immunodeficiencies, red blood cell disorders, and inherited bone marrow failure syndromes. Yet, allogeneic HSCT bear considerable risks for the patient such as non-engraftment, or graft-versus host disease. Transplanting gene modified autologous HSCs is a promising approach not only for inherited blood/immune cell diseases, but also for the acquired immunodeficiency syndrome. However, there is emerging evidence for substantial heterogeneity of HSCs in situ as well as ex vivo that is also observed after HSCT. Thus, HSC gene modification concepts are suggested to consider that different blood disorders affect specific hematopoietic cell types. We will discuss the relevance of HSC heterogeneity for the development and manufacture of gene therapies and in exemplary diseases with a specific emphasis on the key target HSC types myeloid-biased, lymphoid-biased, and balanced HSCs.
Background: Various studies have been made about the most effective and safest type of treatment for vertebral compression fractures (VCFs). Long-term results are needed for qualitative evaluation.
Purpose: The purpose of the study is to evaluate the effectiveness of percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP) procedures for VCFs.
Materials and Methods: Forty-nine patients who received either PVP or PKP between 2002 and 2015 returned a specially developed questionnaire and were included in a cross-sectional outcome analysis. The questionnaire assessed pain development by use of a visual analog scale (VAS). Imaging data (CT scans) were retrospectively analyzed for identification of cement leakage.
Results: Patients’ VAS scores significantly decreased after treatment (7.0 ± 3.4 => 3.7 ± 3.4), (p < 0.001). The average pain reduction in patients treated with PVP was −3.3 ± 3.8 (p < 0.001) (median −3.5) and −4.0 ± 3.9 (p < 0.001) (median −4.5) in patients treated with PKP. Fifteen Patients (41.7%) receiving PVP and four patients (30.7%) receiving PKP experienced recurrence of pain. Cement leakage occurred in 10 patients (22.73%). Patients with cement leakage showed comparable VAS scores after treatment (6.8 ± 3.5 => 1.4 ± 1.6), (p = 0.008). Thirty-nine patients reported an increase in mobility (79.6%) and 41 patients an improvement in quality of life (83.7%).
Conclusion: Pain reduction by means of PVP or PKP in patients with VCFs was discernible over the period of observation. Percutaneous vertebroplasty and PKP contribute to the desired treatment results. However, the level of low pain may not remain constant.
Pathogens possess the ability to adapt and survive in some host species but not in others–an ecological trait known as host tropism. Transmitted through ticks and carried mainly by mammals and birds, the Lyme disease (LD) bacterium is a well-suited model to study such tropism. Three main causative agents of LD, Borrelia burgdorferi, B. afzelii, and B. garinii, vary in host ranges through mechanisms eluding characterization. By feeding ticks infected with different Borrelia species, utilizing feeding chambers and live mice and quail, we found species-level differences in bacterial transmission. These differences localize on the tick blood meal, and specifically complement, a defense in vertebrate blood, and a polymorphic bacterial protein, CspA, which inactivates complement by binding to a host complement inhibitor, Factor H (FH). CspA selectively confers bacterial transmission to vertebrates that produce FH capable of allele-specific recognition. CspA is the only member of the Pfam54 gene family to exhibit host-specific FH-binding. Phylogenetic analyses revealed convergent evolution as the driver of such uniqueness, and that FH-binding likely emerged during the last glacial maximum. Our results identify a determinant of host tropism in Lyme disease infection, thus defining an evolutionary mechanism that shapes host-pathogen associations.
Purpose: Suicidality and suicidal ideation (SI) in oncology has long been an underestimated danger. Although there are cancer-specific distress screening tools available, none of these specifically incorporates items for SI. We examined the prevalence of SI in cancer patients, investigated the relation between SI and distress, and tried to identify additional associated factors. Methods: A cross-sectional study with patients treated for cancer in a primary care hospital was conducted. Psychosocial distress and SI in 226 patients was assessed. An expert rating scale (PO-Bado-SF) and a self-assessment instrument (QSC-R23) were used to measure distress. SI was assessed with item 9 of the PHQ-9. Data was descriptively analyzed, and correlations and group comparisons between clinically distressed and non-distressed patients were calculated. Results: SI was reported by 15% of patients. Classified as clinically distressed were 24.8% (QSC-R23) to 36.7% (PO-Bado-SF). SI was correlated with externally (rτ = 0.19, p < 0.001) and self-rated distress (rτ = 0.31, p < 0.001). Symptoms sufficiently severe for at least a medium major depressive episode were recorded in 23.5% of patients (PHQ-9). Factors associated with SI were feeling bad about oneself, feeling down, depressed, and hopeless, deficits in activities of daily life, psycho-somatic afflictions, social restrictions, and restrictions in daily life. Being in a steady relationship seemed to have a protective effect. Conclusions: SI is common in cancer patients. Distress and associated factors are increased in patients with SI. A distress screening with the ability to assess SI could be an important step in prevention, but more research is necessary.
Purpose: In this study, we examined distress levels and quality of life (QoL) of patients with hematologic malignancies under treatment in an acute setting. We used external- and self-assessment instruments for distress. Additionally, we investigated the relation between distress and QoL as well as whether highly distressed patients differed from less distressed patients concerning their QoL.
Methods: A cross-sectional study with patients of the Medical Clinic II of the University Hospital Frankfurt was conducted. One hundred and nine patients were assessed with an expert rating scale and completed self-report questionnaires. Data were exploratively analyzed and group comparisons between patients who scored above the cut-off of the respective screening instruments and those who did not were conducted.
Results: Patients with hematologic malignancies experience high levels of distress and low QoL. Especially, role and social functioning are affected. Patients suffer most from fatigue, appetite loss, and insomnia. Using established cut-offs, all screening instruments were able to differentiate between patients regarding distress and QoL. Patients scoring above the cut-off were significantly more distressed and had a lower QoL. There was a medium-to-strong correlation between distress and QoL indicators.
Conclusion: Cancer-specific screening instruments seem to be able to identify treatment needs more specifically. They also allowed a better differentiation concerning QoL. The close link between distress and QoL needs to be recognized to enable a holistic approach to treatment and thereby optimize the quality of treatment.
Purpose: The coronavirus disease 2019 (COVID-19) poses major challenges to health-care systems worldwide. This pandemic demonstrates the importance of timely access to intensive care and, therefore, this study aims to explore the accessibility of intensive care beds in 14 European countries and its impact on the COVID-19 case fatality ratio (CFR).
Methods: We examined access to intensive care beds by deriving (1) a regional ratio of intensive care beds to 100,000 population capita (accessibility index, AI) and (2) the distance to the closest intensive care unit. The cross-sectional analysis was performed at a 5-by-5 km spatial resolution and results were summarized nationally for 14 European countries. The relationship between AI and CFR was analyzed at the regional level.
Results: We found national-level differences in the levels of access to intensive care beds. The AI was highest in Germany (AI = 35.3), followed by Estonia (AI = 33.5) and Austria (AI = 26.4), and lowest in Sweden (AI = 5) and Denmark (AI = 6.4). The average travel distance to the closest hospital was highest in Croatia (25.3 min by car) and lowest in Luxembourg (9.1 min). Subnational results illustrate that capacity was associated with population density and national-level inventories. The correlation analysis revealed a negative correlation of ICU accessibility and COVID-19 CFR (r = − 0.57; p < 0.001).
Conclusion: Geographical access to intensive care beds varies significantly across European countries and low ICU accessibility was associated with a higher proportion of COVID-19 deaths to cases (CFR). Important differences in access are due to the sizes of national resource inventories and the distribution of health-care facilities relative to the human population. Our findings provide a resource for officials planning public health responses beyond the current COVID-19 pandemic, such as identifying potential locations suitable for temporary facilities or establishing logistical plans for moving severely ill patients to facilities with available beds.
Improving spatial accessibility to hospitals is a major task for health care systems which can be facilitated using recent methodological improvements of spatial accessibility measures. We used the integrated floating catchment area (iFCA) method to analyze spatial accessibility of general inpatient care (internal medicine, surgery and neurology) on national level in Germany determining an accessibility index (AI) by integrating distances, hospital beds and morbidity data. The analysis of 358 million distances between hospitals and population locations revealed clusters of lower accessibility indices in areas in north east Germany. There was a correlation of urbanity and accessibility up to r = 0.31 (p < 0.001). Furthermore, 10% of the population lived in areas with significant clusters of low spatial accessibility for internal medicine and surgery (neurology: 20%). The analysis revealed the highest accessibility for heart failure (AI = 7.33) and the lowest accessibility for stroke (AI = 0.69). The method applied proofed to reveal important aspects of spatial accessibility i.e. geographic variations that need to be addressed. However, for the majority of the German population, accessibility of general inpatient care was either high or at least not significantly low, which suggests rather adequate allocation of hospital resources for most parts of Germany.
Hintergrund: Parkinson-Syndrome führen im Krankheitsverlauf zur Pflegebedürftigkeit bei den Betroffenen. Zur Prävalenz der Bewohner*innen mit einem Parkinson-Syndrom in Pflegeeinrichtungen, zu ihrer Versorgungssituation und zur vorhandenen Expertise der Pflegefachpersonen in den Einrichtungen ist wenig bekannt.
Ziel der Arbeit: Die vorliegende Studie untersucht die Prävalenzrate der Bewohner*innen mit einem Parkinson-Syndrom in stationären Pflegeeinrichtungen in Deutschland. Die Arbeit exploriert die Zusammenarbeit verschiedener Akteure, deren Koordination sowie Information und Wissen des Pflegepersonals. Ziel ist es, einen möglichen Bedarf an spezialisierter Pflege in Pflegeeinrichtungen aufzuzeigen.
Methode: Die schriftliche Querschnittsbefragung der Wohnbereichsleitungen von 500 zufällig ausgewählten Pflegeeinrichtungen in Deutschland erfolgte von Januar bis Juni 2020. Der eingesetzte Fragebogen wurde vorab literaturbasiert entwickelt. Die Daten wurden deskriptiv analysiert.
Ergebnisse: Aus 57 Einrichtungen wurden Fragebogen von 85 Wohnbereichen analysiert (Rücklaufquote 11,4 %). Die Prävalenzrate von Bewohner*innen mit einem Parkinson-Syndrom in der stationären Altenhilfe beträgt 13,9 %. Mehr als die Hälfte haben zusätzlich eine Demenzdiagnose (52,8 %). In 26 % der Fälle erfolgen Krankenhausaufenthalte infolge von Sturzereignissen. Eine eindeutige Koordination der Versorgung durch ärztliche oder pflegerische Spezialisten gibt es nicht.
Diskussion: Bewohner*innen mit einem Parkinson-Syndrom in der stationären Altenhilfe sind häufig, und sie zeigen komplexe motorische und nichtmotorische Symptome – auch durch die Komorbidität Demenz. Die Häufigkeit von Sturzereignissen mit Krankenhausaufenthalten und die geringe Anzahl Parkinson-Syndrom-spezifischer Hilfsmittel zeigen, dass das Wissen der Pflege vor Ort gesteigert werden kann. Eine zentrale Koordination und Unterstützung hierzu sollten in der stationären Langzeitpflege etabliert werden.
Bloodstream infections (BSI) are a frequent complication in patients with hematological and oncological diseases. However, the impact of different bacterial species causing BSI and of multiple BSI remains incompletely understood. We performed a retrospective study profiling 637 bacterial BSI episodes in hematological and oncological patients. Based on the 30-day (30d) overall survival (OS), we analyzed different types of multiple BSI and grouped BSI-associated bacteria into clusters followed by further assessment of clinical and infection-related characteristics. We discovered that polymicrobial BSI (different organisms on the first day of a BSI episode) and sequential BSI (another BSI before the respective BSI episode) were associated with a worse 30d OS. Different bacterial groups could be classified into three BSI outcome clusters based on 30d OS: favorable (FAV) including mainly common skin contaminants, Escherichia spp. and Streptococcus spp.; intermediate (INT) including mainly Enterococcus spp., vancomycin-resistant Enterococcus spp., and multidrug-resistant gram-negative bacteria (MDRGN); and adverse (ADV) including MDRGN with an additional carbapenem-resistance (MDRGN+CR). A polymicrobial or sequential BSI especially influenced the outcome in the combination of two INT cluster BSI. The presence of a polymicrobial BSI and the assignment into the BSI outcome clusters were identified as independent risk factors for 30d mortality in a Cox multivariate regression analysis. The assignment to a BSI outcome cluster and the differentiated perspective of multiple BSI open new insights into the prognosis of patients with BSI and should be further validated in other patient cohorts.
This focus issue of the European Journal of Trauma and Emergency Surgery compiles a collection of outstanding clinical research using the immense dataset of the German TraumaRegister DGU® (TR-DGU). The TR-DGU of the German Trauma Society (Deutsche Gesellschaft für Unfallchirurgie, DGU) was founded in 1993. Currently, approximately 40,000 cases from more than 600 hospitals are entered into the database every year. The selected articles of this focus on issue highlight the immense value the TR-DGU constitutes for the current, but also for the future trauma research.
Zielsetzung: Die Daten für das Jahr 2019 des Registers „Abdominelles Aortenaneurysma“ (AAA) des Deutschen Instituts für Gefäßmedizinische Gesundheitsforschung (DIGG) der Deutschen Gesellschaft für Gefäßchirurgie und Gefäßmedizin werden vorgestellt.
Methodik: Im Jahr 2019 beteiligten sich an dem Register insgesamt 109 Kliniken. Für die offene Versorgung (OR) des intakten AAA (iAAA) gaben 78 (71,6 %) Kliniken, für die endovaskuläre Versorgung (EVAR) des iAAA 102 (93,6 %) Kliniken Daten ein. Für das rupturierte AAA (rAAA) wurden von 36 Kliniken (33,0 %) (EVAR) bzw. 50 (45,9 %) Kliniken (OR) Patienten gemeldet. Ausgewertet wurden die Daten von 1967 stationär behandelten Patienten. Von den insgesamt 1793 iAAA waren 1501 infrarenal (83,7 %) und 292 (16,3 %) juxtarenal gelegen.
Ergebnisse: 1429 iAAA (79,7 %) wurden endovaskulär und 364 (20,3 %) offen versorgt. Bei den endovaskulär versorgten Patienten mit iAAA verlief der Eingriff in 86,3 % der Fälle komplikationslos. Es verstarben insgesamt 15 Patienten (1,0 %) bis zur Entlassung. Bei den offen versorgten Patienten wiesen 67,0 % der Patienten keine Komplikationen auf. Verstorben sind insgesamt 20 Patienten (5,5 %). Bei EVAR war die Klinikletalität bei Versorgung juxtarenaler AAA mit 3,7 % signifikant höher als bei Versorgung infrarenaler AAA mit 0,6 % (p = 0,002), bei OR konnten hingegen keine signifikanten Unterschiede hinsichtlich der Klinikletalität aufgezeigt werden (juxtarenal 4,8 %, infrarenal 5,8 %; p = 0,470). Von den 174 Patienten mit rAAA wurden 80 (46,0 %) endovaskulär und 94 (54,0 %) offen versorgt. Bei EVAR sind 20,0 % der Patienten während des stationären Aufenthalts verstorben, bei OR 36,2 %.
Schlussfolgerung: Die Ergebnisse des Jahres 2019 zu Klinikletalität und Morbidität bei endovaskulärer und offener Versorgung des iAAA bestätigen weitgehend die publizierten Ergebnisse für die Jahre 2013 bis 2018. Beim rAAA sind die Ergebnisse der einzelnen Jahresberichte hingegen widersprüchlich, die kleinen berichteten jährlichen Fallzahlen erlauben nur Aussagen über größere Zeiträume.
Introduction: The induced membrane technique for the treatment of large bone defects is a two-step procedure. In the first operation, a foreign body membrane is induced around a spacer, then, in the second step, several weeks or months later, the spacer is removed and the Membrane pocket is filled with autologous bone material. Induction of a functional biological membrane might be avoided by initially using a biological membrane. In this study, the effect of a human acellular dermis (hADM, Epiflex, DIZG gGmbH) was evaluated for the treatment of a large (5 mm), plate-stabilised femoral bone defect.
Material and Methods: In an established rat model, hADM was compared to the two-stage induced membrane technique and a bone defect without membrane cover. Syngeneous spongiosa from donor animals was used for defect filling in all groups. The group size in each case was n = 5, the induction time of the membrane was 3–4 weeks and the healing time after filling of the defect was 8 weeks.
Results: The ultimate loads were increased to levels comparable with native bone in both membrane groups (hADM: 63.2% ± 29.6% of the reference bone, p < 0.05 vs. no membrane, induced membrane: 52.1% ± 25.8% of the reference bone, p < 0.05 vs. no membrane) and were significantly higher than the control group without membrane (21.5%). The membrane groups were radiologically and histologically almost completely bridged by new bone formation, in contrast to the control Group where no closed osseous bridging could be observed.
Conclusion: The use of the human acellular dermis leads to equivalent healing results in comparison to the two-stage induced membrane technique. This could lead to a shortened therapy duration of large bone defects.
Aims: SARS-CoV-2 is a single-stranded RNA virus which is part of the ß-coronavirus family (like SARS 2002 and MERS 2012). The high prevalence of hospitalization and mortality, in addition to the lack of vaccines and therapeutics, forces scientists and clinicians around the world to evaluate new therapeutic options. One strategy is the repositioning of already known drugs, which were approved drugs for other indications.
Subject and method: SARS-CoV-2 entry inhibitors, RNA polymerase inhibitors, and protease inhibitors seem to be valuable targets of research. At the beginning of the pandemic, the ClinicalTrials.gov webpage listed n=479 clinical trials related to the antiviral treatment of SARS-CoV-2 (01.04.2020, “SARS-CoV-2,” “COVID-19,” “antivirals,” “therapy”), of which n=376 are still accessible online in January 2021 (10.01.2021). Taking into account further studies not listed in the CTG webpage, this narrative review appraises HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors as promising candidates for the treatment of COVID-19.
Results: Lopinavir/ritonavir, darunavir/cobicistat, remdesivir, tenofovir-disoproxilfumarate, favipriravir, and sofosbuvir are evaluated in clinical studies worldwide. Study designs show a high variability and results often are contradictory. Remdesivir is the drug, which is deployed in nearly 70% of the reviewed clinical trials, followed by lopinavir/ritonavir, favipiravir, ribavirine, and sofosbuvir.
Discussion: This review discusses the pharmacological/clinical background and questions the rationale and study design of clinical trials with already approved HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors which are repositioned during the SARS-CoV-2 pandemic worldwide. Proposals are made for future study design and drug repositioning of approved antiretroviral compounds.
Background: The prevalence of multimorbidity is increasing in recent years, and patients with multimorbidity often have a decrease in quality of life and require more health care. The aim of this study was to explore the evolution of multimorbidity taking the sequence of diseases into consideration.
Methods: We used a Belgian database collected by extracting coded parameters and more than 100 chronic conditions from the Electronic Health Records of general practitioners to study patients older than 40 years with multiple diagnoses between 1991 and 2015 (N = 65 939). We applied Markov chains to estimate the probability of developing another condition in the next state after a diagnosis. The results of Weighted Association Rule Mining (WARM) allow us to show strong associations among multiple conditions.
Results: About 66.9% of the selected patients had multimorbidity. Conditions with high prevalence, such as hypertension and depressive disorder, were likely to occur after the diagnosis of most conditions. Patterns in several disease groups were apparent based on the results of both Markov chain and WARM, such as musculoskeletal diseases and psychological diseases. Psychological diseases were frequently followed by irritable bowel syndrome.
Conclusions: Our study used Markov chains and WARM for the first time to provide a comprehensive view of the relations among 103 chronic conditions, taking sequential chronology into consideration. Some strong associations among specific conditions were detected and the results were consistent with current knowledge in literature, meaning the approaches were valid to be used on larger data sets, such as National Health care Systems or private insurers.
Das Corona-Update Frankfurt
(2022)
Seit Beginn der Coronapandemie haben die vier Arbeitsgruppen am Institut für Medizinische Virologie ihre Forschungsschwerpunkte innerhalb kürzester Zeit verlagert. Sie haben wichtige Erkenntnisse zu Teststrategien, Impfschutz und Therapieansätzen gewonnen. Dieser Weg wird durch Förderung des Landes Hessen weiter ausgebaut. Eine Bestandsaufnahme.
Aqueous solutions of a nonionic surfactant (either Tween20 or BrijL23) and an anionic surfactant (sodium dodecyl sulfate, SDS) are investigated, using small-angle neutron scattering (SANS). SANS spectra are analysed by using a core-shell model to describe the form factor of self-assembled surfactant micelles; the intermicellar interactions are modelled by using a hard-sphere Percus–Yevick (HS-PY) or a rescaled mean spherical approximation (RMSA) structure factor. Choosing these specific nonionic surfactants allows for comparison of the effect of branched (Tween20) and linear (BrijL23) surfactant headgroups, both constituted of poly-ethylene oxide (PEO) groups. The nonionic–anionic surfactant mixtures are studied at various concentrations up to highly concentrated samples (ϕ ≲ 0.45) and various mixing ratios, from pure nonionic to pure anionic surfactant solutions. The scattering data reveal the formation of mixed micelles already at concentrations below the critical micelle concentration of SDS. At higher volume fractions, excluded volume effects dominate the intermicellar structuring, even for charged micelles. In consequence, at high volume fractions, the intermicellar structuring is the same for charged and uncharged micelles. At all mixing ratios, almost spherical mixed micelles form. This offers the opportunity to create a system of colloidal particles with a variable surface charge. This excludes only roughly equimolar mixing ratios (X≈ 0.4–0.6) at which the micelles significantly increase in size and ellipticity due to specific sulfate–EO interactions.
Objective In rheumatoid arthritis (RA), chronic inflammation can enhance the development of sarcopenia with a depletion of muscle mass, strength and performance. Currently, a consensus definition for sarcopenia and solid results for the prevalence of sarcopenia in patients with RA are lacking.
Methods In this cross-sectional study, 289 patients ≥18 years with RA were recruited. Dual X-ray absorptiometry was performed to measure appendicular lean mass. Assessment of muscle function included grip strength, gait speed and chair rise time. Prevalence of sarcopenia was defined using the updated European Working Group on Sarcopenia in Older People (EWGSOP2) and the Foundation for the National Institutes of Health (FNIH) definition. In addition, the RA study population was compared with existing data of healthy controls (n=280).
Results 4.5% of patients (59.4±11.3 years) and 0.4% of controls (62.9±11.9 years) were affected by sarcopenia according to the EWGSOP2 definition. Body weight (OR 0.92, 95% CI 0.86 to 0.97), body mass index (BMI) (OR 0.70, 95% CI 0.57 to 0.87), C reactive protein (CRP) (OR 1.05, 95% CI 1.01 to 1.10), disease duration (OR 1.08, 95% CI 1.02 to 1.36), current medication with glucocorticoids (OR 5.25, 95% CI 2.14 to 24.18), cumulative dose of prednisone equivalent (OR 1.04, 95% CI 1.02 to 1.05) and Health Assessment Questionnaire (HAQ) (OR 2.50, 95% CI 1.27 to 4.86) were associated with sarcopenia in patients with RA. In contrast, the prevalence was 2.8% in patients compared with 0.7% in controls when applying the FNIH definition, and body height (OR 0.75, 95% CI 0.64 to 0.88), BMI (OR 1.20, 95% CI 1.02 to 1.41), CRP (OR 1.06, 95% CI 1.01 to 1.11) and HAQ (OR 2.77, 95% CI 1.17 to 6.59) were associated with sarcopenia.
Conclusion Sarcopenia is significantly more common in patients with RA compared with controls using the EWGSOP2 criteria. The FNIH definition revealed sarcopenia in individuals with high BMI and fat mass, regardless of the presence of RA.
Trial registration number It was registered at the German Clinical Trials Registry (DRKS) as well as WHO Clinical Trials Registry (ICTRP) (DRKS00011873, registered on 16 March 2017).
Hidradenitis suppurativa/Acne inversa (HS/AI) ist eine chronisch-entzündliche Hauterkrankung, deren Behandlung sowohl konservative als auch chirurgische Behandlungsmöglichkeiten umfasst. In den Hurley-Stadien II und III ist die chirurgische Resektion irreversibel zerstörten Gewebes anzustreben. Hierzu existieren verschiedene Resektionstechniken, die sich vor allem in ihrer Invasivität und Rezidivneigung unterscheiden. Bis heute gibt es keinen allgemein akzeptierten Konsens hinsichtlich verschiedener Resektions- und Rekonstruktionstechniken sowie der Einbeziehung medikamentöser Therapien in das therapeutische Gesamtkonzept.
Omicron is the evolutionarily most distinct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant of concern (VOC) to date. We report that Omicron BA.1 breakthrough infection in BNT162b2-vaccinated individuals resulted in strong neutralizing activity against Omicron BA.1, BA.2, and previous SARS-CoV-2 VOCs but not against the Omicron sublineages BA.4 and BA.5. BA.1 breakthrough infection induced a robust recall response, primarily expanding memory B (BMEM) cells against epitopes shared broadly among variants, rather than inducing BA.1-specific B cells. The vaccination-imprinted BMEM cell pool had sufficient plasticity to be remodeled by heterologous SARS-CoV-2 spike glycoprotein exposure. Whereas selective amplification of BMEM cells recognizing shared epitopes allows for effective neutralization of most variants that evade previously established immunity, susceptibility to escape by variants that acquire alterations at hitherto conserved sites may be heightened.
Objectives: Immune checkpoint inhibitors have become the standard of care for metastatic non–small-cell lung cancer (NSCLC) progressing during or after platinum-based chemotherapy. Real-world clinical practice tends to represent more diverse patient characteristics than randomized clinical trials. We sought to evaluate overall survival (OS) outcomes in the total study population and in key subsets of patients who received nivolumab for previously treated advanced NSCLC in real-world settings in France, Germany, or Canada.
Materials and methods: Data were pooled from two prospective observational cohort studies, EVIDENS and ENLARGE, and a retrospective registry in Canada. Patients included in this analysis were aged ≥18 years, had stage IIIB/IV NSCLC, and received nivolumab after at least one prior line of systemic therapy. OS was estimated in the pooled population and in various subgroups using the Kaplan-Meier method. Timing of data collection varied across cohorts (2015–2019).
Results: Of the 2585 patients included in this analyses, 1235 (47.8 %) were treated in France, 881 (34.1 %) in Germany, and 469 (18.1 %) in Canada. Median OS for the total study population was 11.3 months (95 % CI: 10.5–12.2); this was similar across France, Germany, and Canada. The OS rate was 49 % at 1 year and 28 % at 2 years for the total study population. In univariable Cox analyses, the presence of epidermal growth factor receptor mutations in nonsquamous disease, liver, or bone metastases were associated with significantly shorter OS, whereas tumor programmed death ligand 1 expression and Eastern Cooperative Oncology Group performance status 0–1 were associated with significantly prolonged OS. Similar OS was noted across subgroups of age and prior lines of therapy.
Conclusion: OS rates in patients receiving nivolumab for previously treated advanced NSCLC in real-world clinical practice closely mirrored those in phase 3 studies, suggesting similar effectiveness of nivolumab in clinical trials and clinical practice.
Die Multiple Sklerose (MS) ist die häufigste nicht-traumatische, autoimmun-vermittelte Erkrankung des zentralen Nervensystems (ZNS), welche vor allem bei jüngeren Patienten mit Invalidisierung und anhaltenden neurologischen Defiziten einhergehen kann.
Im Rahmen eines optimalen Therapiekonzepts wurden deshalb immer neuere und potentere Medikamente eingeführt. Mit den Sphingosin-1-Phosphat-Rezeptor-1 (S1P1) -Agonisten Fingolimod und Siponimod sind seit mehreren Jahren Medikamente auf dem Markt deren Wirksamkeit bewiesen, jedoch die genauen Wirkprinzipien noch nicht vollends verstanden sind. Angenommen wurde bisher eine Lymphozytendepletion aufgrund einer Hemmung der Lymphozyteninfiltation ins ZNS über den ubiquitär exprimierten, G-protein gekoppelten S1P1-Rezeptor. Neben Wirksamkeiten im Bereich des Immunsystems spielt der S1P1-Rezeptor und sein natürliches Substrat, das S1P, in vielen essenziellen Bereichen eine entscheidende Rolle, unter anderem in der Ausbildung und Reifung des vaskulären Systems in der Embryogenese.
Die genaue Untersuchung des S1P1-Signalwegs in-vivo gestaltete sich deshalb erschwert, da S1P1-Knock-Out-Mäuse einen letalen Phänotyp ausbilden. Jedoch deuten immer mehr Untersuchungen auch auf eine direkte S1P1-Rezeptor-vermittelte Wirksamkeit von Fingolimod auf Zellen des ZNS hin, somit eine Wirkung über die bisher bekannte Lymphozytenaffektion hinaus. Eine genaue Darstellung der im ZNS-beteiligten Zellen und ihrer S1P1-Aktivität gelang bisher auf zellulärer Ebene nicht.
Mit dem in dieser Arbeit genutzten Mausmodell der genmodifizierten S1P1-Signaling-Maus sollte erstmals eine lokoregionale und zelluläre Untersuchung der am S1P1-Signalweg beteiligten Zellen im Rahmen von physiologischen und experimentellen autoimmunen Enzephalomyelitis (EAE)-Bedingungen im ZNS erfolgen. Hierbei entspricht die EAE weitgehend einem tierexperimentellen Korrelat der menschlichen MS. Bei Aktivierung eines S1P1-Rezeptors bei der S1P1-Signaling-Maus erfolgt durch eine gekoppelte Signalkaskade eine konsekutive Expression eines Histonproteins, welches an ein grün-fluoreszierendes Protein gekoppelt ist. Es resultiert eine grüne Fluoreszenz des Zellkerns der betroffenen Zelle. Bei der Kontroll-Maus findet sich keine Kopplung zwischen Rezeptor und im Zellkern befindlicher Proteine.
Hierbei konnte mit Hilfe von Immunhistochemie sowie der quantitativen Methode der Durchflusszytometrie ein S1P1-Signaling in peripheren Organen wie beispielweise der im Rahmen der MS bedeutsamen Milz nachgewiesen werden. Dadurch eröffnen sich Einblicke in Migrationsverhalten und Zusammensetzung der Lymphozyten-Subtypen und deren S1P1-Signaling im Rahmen von physiologischen Bedingungen und unter EAE-Bedingungen.
Die Darstellung des S1P1-Signalings im ZNS, als Hauptmanifestationsort der MS, gelang unter Zuhilfenahme der EAE mit dem genmodifizierten Mausmodell jedoch nicht. Da sich keine Unterschiede in der GFP-Expression zwischen der Signaling-Maus und der heterozygoten Kontroll-Maus zeigen, sind keinerlei Rückschlüsse auf ein echtes S1P1-Signaling möglich. Es zeigen sich zwar deutliche Expressionsunterschiede des GFP im Vergleich erkrankter und gesunder Versuchstiere, Rückschlüsse auf eine echte S1P1-Aktivität konnten jedoch nicht getroffen werden.
Zusammenfassend eignet sich das hier genutzte Mausmodell der genmodifizierten S1P1-Maus zur Untersuchung peripherer Organe und ihrem S1P1-Signaling, z.B. zur Untersuchung kardiovaskulärer Fragestellungen oder zur dezidierteren Veranschaulichung peripher lymphatischer Prozesse.
Zur Untersuchung ZNS-eigener Zellen sowie zur Beantwortung der Frage, ob und wie sie über den S1P1-Rezeptor agieren, bedarf es jedoch noch der Entwicklung eines geeigneteren Tiermodells.
Die bereits erprobte Möglichkeit der Biolumineszenz zeigte in vorherigen Untersuchungen zwar eine S1P1-Aktivität in-vivo, jedoch sind hier keinerlei Untersuchungen auf zellulärer Basis möglich, sodass mit dem aktuellen Stand der Forschung ein direkter Nachweis der S1P1-Aktivität auf zellulärer Ebene im ZNS nicht möglich ist.
GATA2 deficiency is a heterogeneous multi-system disorder characterized by a high risk of developing myelodysplastic syndrome (MDS) and myeloid leukemia. We analyzed the outcome of 65 patients reported to the registry of the European Working Group (EWOG) of MDS in childhood carrying a germline GATA2 mutation (GATA2mut) who had undergone hematopoietic stem cell transplantation (HSCT). At 5 years the probability of overall survival and disease-free survival (DFS) was 75% and 70%, respectively. Non-relapse mortality and relapse equally contributed to treatment failure. There was no evidence of increased incidence of graft-versus-host-disease or excessive rates of infections or organ toxicities. Advanced disease and monosomy 7 (−7) were associated with worse outcome. Patients with refractory cytopenia of childhood (RCC) and normal karyotype showed an excellent outcome (DFS 90%) compared to RCC and −7 (DFS 67%). Comparing outcome of GATA2mut with GATA2wt patients, there was no difference in DFS in patients with RCC and normal karyotype. The same was true for patients with −7 across morphological subtypes. We demonstrate that HSCT outcome is independent of GATA2 germline mutations in pediatric MDS suggesting the application of standard MDS algorithms and protocols. Our data support considering HSCT early in the course of GATA2 deficiency in young individuals.
Purpose: Colorectal cancer (CRC) is the second most common cancer in Germany. Around 60,000 people were diagnosed CRC in 2016 in Germany. Since 2019, screening colonoscopies are offered in Germany for men by the age of 50 and for women by the age of 55. It is recently discussed if women should also undergo a screening colonoscopy by the age of 50 and if there are any predictors for getting CRC.
Methods: Colonoscopies of 1553 symptomatic patients younger than 55 years were compared with colonoscopies of 1075 symptomatic patients older than 55 years. We analyzed if there are any significant differences between those two groups in the prevalence of CRC and its precursor lesions or between symptomatic men and women. We evaluated if there is a correlation between abdominal symptoms and the prevalence of CRC.
Results: In 164/1553 symptomatic patients, 194 (12.5%) polyps were detected. In total, six colorectal carcinomas (0.4%) were detected. There were no significant differences between men and women. In symptomatic patients ≥ 55 years, significantly more polyps were found (p<0.0001; 26.6% vs. 12.5%). Totally, 286 polyps (26.6%) were removed in 1075 symptomatic patients older than 55 years. Anorectal bleeding was the only abdominal symptom being a significant indicator for the prevalence of the occurrence of colon and rectum cancer in both groups (p=0.03, OR=2.73 95%-CI [1.11;6.70]), but with only low sensitivity (44%).
Conclusion: Due to no significant differences in men and women, we recommend screening colonoscopies also for women by the age of 50.
Background: This prospective randomized trial is designed to compare the performance of conventional transarterial chemoembolization (cTACE) using Lipiodol-only with additional use of degradable starch microspheres (DSM) for hepatocellular carcinoma (HCC) in BCLC-stage-B based on metric tumor response. Methods: Sixty-one patients (44 men; 17 women; range 44–85) with HCC were evaluated in this IRB-approved HIPPA compliant study. The treatment protocol included three TACE-sessions in 4-week intervals, in all cases with Mitomycin C as a chemotherapeutic agent. Multiparametric magnetic resonance imaging (MRI) was performed prior to the first and 4 weeks after the last TACE. Two treatment groups were determined using a randomization sheet: In 30 patients, TACE was performed using Lipiodol only (group 1). In 31 cases Lipiodol was combined with DSMs (group 2). Response according to tumor volume, diameter, mRECIST criteria, and the development of necrotic areas were analyzed and compared using the Mann–Whitney-U, Kruskal–Wallis-H-test, and Spearman-Rho. Survival data were analyzed using the Kaplan–Meier estimator. Results: A mean overall tumor volume reduction of 21.45% (± 62.34%) was observed with an average tumor volume reduction of 19.95% in group 1 vs. 22.95% in group 2 (p = 0.653). Mean diameter reduction was measured with 6.26% (± 34.75%), for group 1 with 11.86% vs. 4.06% in group 2 (p = 0.678). Regarding mRECIST criteria, group 1 versus group 2 showed complete response in 0 versus 3 cases, partial response in 2 versus 7 cases, stable disease in 21 versus 17 cases, and progressive disease in 3 versus 1 cases (p = 0.010). Estimated overall survival was in mean 33.4 months (95% CI 25.5–41.4) for cTACE with Lipiosol plus DSM, and 32.5 months (95% CI 26.6–38.4), for cTACE with Lipiodol-only (p = 0.844), respectively. Conclusions: The additional application of DSM during cTACE showed a significant benefit in tumor response according to mRECIST compared to cTACE with Lipiodol-only. No benefit in survival time was observed.
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.
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.
The role and timing of radiotherapy (RT) in prostate cancer (PCa) patients treated with radical prostatectomy (RP) remains controversial. While recent trials support the oncological safety of early salvage RT (SRT) compared to adjuvant RT (ART) in selected patients, previous randomized studies demonstrated that ART might improve recurrence-free survival in patients at high risk for local recurrence based on adverse pathology. Although ART might improve survival, this approach is characterized by a risk of overtreatment in up to 40% of cases. SRT is defined as the administration of RT to the prostatic bed and to the surrounding tissues in the patient with PSA recurrence after surgery but no evidence of distant metastatic disease. The delivery of salvage therapies exclusively in men who experience biochemical recurrence (BCR) has the potential advantage of reducing the risk of side effects without theoretically compromising outcomes. However, how to select patients at risk of progression who are more likely to benefit from a more aggressive treatment after RP, the exact timing of RT after RP, and the use of hormone therapy and its duration at the time of RT are still open issues. Moreover, what the role of novel imaging techniques and genomic classifiers are in identifying the most optimal post-operative management of PCa patients treated with RP is yet to be clarified. This narrative review summarizes most relevant published data to guide a multidisciplinary team in selecting appropriate candidates for post-prostatectomy radiation therapy.
Focal therapy is a modern alternative to selectively treat a specific part of the prostate harboring clinically significant disease while preserving the rest of the gland. The aim of this therapeutic approach is to retain the oncological benefit of active treatment and to minimize the side-effects of common radical treatments. The oncological effectiveness of focal therapy is yet to be proven in long-term robust trials. In contrast, the toxicity profile is well-established in randomized controlled trials and multiple robust prospective cohort studies. This narrative review summarizes the relevant evidence on complications and their management after focal therapy. When compared to whole gland treatments, focal therapy provides a substantial benefit in terms of adverse events reduction and preservation of genito-urinary function. The most common complications occur in the peri-operative period. Urinary tract infection and acute urinary retention can occur in up to 17% of patients, while dysuria and haematuria are more common. Urinary incontinence following focal therapy is very rare (0–5%), and the vast majority of patients recover in few weeks. Erectile dysfunction can occur after focal therapy in 0–46%: the baseline function and the ablation template are the most important factors predicting post-operative erectile dysfunction. Focal therapy in the salvage setting after external beam radiotherapy has a significantly higher rate of complications. Up to one man in 10 will present a severe complication.
Systemic lupus erythematosus (SLE) is a severe autoimmune disease of unknown etiology. The major histocompatibility complex (MHC) class I-related chain A (MICA) and B (MICB) are stress-inducible cell surface molecules. MICA and MICB label malfunctioning cells for their recognition by cytotoxic lymphocytes such as natural killer (NK) cells. Alterations in this recognition have been found in SLE. MICA/MICB can be shed from the cell surface, subsequently acting either as a soluble decoy receptor (sMICA/sMICB) or in CD4+ T-cell expansion. Conversely, NK cells are frequently defective in SLE and lower NK cell numbers have been reported in patients with active SLE. However, these cells are also thought to exert regulatory functions and to prevent autoimmunity. We therefore investigated whether, and how, plasma membrane and soluble MICA/B are modulated in SLE and whether they influence NK cell activity, in order to better understand how MICA/B may participate in disease development. We report significantly elevated concentrations of circulating sMICA/B in SLE patients compared with healthy individuals or a control patient group. In SLE patients, sMICA concentrations were significantly higher in patients positive for anti-SSB and anti-RNP autoantibodies. In order to study the mechanism and the potential source of sMICA, we analyzed circulating sMICA concentration in Behcet patients before and after interferon (IFN)-α therapy: no modulation was observed, suggesting that IFN-α is not intrinsically crucial for sMICA release in vivo. We also show that monocytes and neutrophils stimulated in vitro with cytokines or extracellular chromatin up-regulate plasma membrane MICA expression, without releasing sMICA. Importantly, in peripheral blood mononuclear cells from healthy individuals stimulated in vitro by cell-free chromatin, NK cells up-regulate CD69 and CD107 in a monocyte-dependent manner and at least partly via MICA-NKG2D interaction, whereas NK cells were exhausted in SLE patients. In conclusion, sMICA concentrations are elevated in SLE patients, whereas plasma membrane MICA is up-regulated in response to some lupus stimuli and triggers NK cell activation. Those results suggest the requirement for a tight control in vivo and highlight the complex role of the MICA/sMICA system in SLE.
[Nachruf] Helmut Siefert
(2012)
Wolfgang Schlote : 80 Jahre
(2012)
Das Institut für Medizinische Virologie, untergebracht in dem 100 Jahre alten Gebäude des ehemaligen Frankfurter Gesundheitsamtes direkt neben dem Georg-Speyer-Haus, ist eine wunderbare Kombination von Funktionalität und Schönheit. Von der geschwungenen Holztreppe des historischen Treppenhauses geht der Blick immer wieder in hochmoderne biomedizinische Laboratorien, gesichert hinter dicken Glastüren – ein Blick in eine futuristisch anmutende Welt.
Hausherr ist hier seit April 2012 der mehrfach ausgezeichnete HIV/AIDS-Experte Professor Oliver T. Keppler. Unter seiner Leitung ist das Institut umgehend mit Wirkung zum 1. Oktober 2012 vom Präsidenten des Robert-Koch-Instituts zum „Nationalen Referenzzentrum für Retroviren“ berufen worden. Mit Retroviren sind zu 95 Prozent HI-Viren (Humanes Immundefizienz-Virus) gemeint – die restlichen fünf Prozent umfassen die HTL-Viren (Humanes T-lymphotropes-Virus), mit denen weltweit etwa 20 Millionen Menschen infiziert sind, das jedoch kaum in Deutschland vorkommt. Das Institut ist damit das deutsche Referenzlabor für die Routine- und Spezialdiagnostik von Retroviren, Schwerpunkt HIV-Infektionen, sowie für Stellungnahmen zu Fragen der Krankheitsentstehung und Behandlung.
Objective: We aimed to estimate the incidence of cerebral sinus and venous thrombosis (CVT) within 1 month from first dose administration and the frequency of vaccine-induced immune thrombotic thrombocytopenia (VITT) as the underlying mechanism after vaccination with BNT162b2, ChAdOx1, and mRNA-1273, in Germany. Methods: A web-based questionnaire was e-mailed to all departments of neurology. We requested a report of cases of CVT occurring within 1 month of a COVID-19 vaccination. Other cerebral events could also be reported. Incidence rates of CVT were calculated by using official statistics of 9 German states. Results: A total of 45 CVT cases were reported. In addition, 9 primary ischemic strokes, 4 primary intracerebral hemorrhages, and 4 other neurological events were recorded. Of the CVT patients, 35 (77.8%) were female, and 36 (80.0%) were younger than 60 years. Fifty-three events were observed after vaccination with ChAdOx1 (85.5%), 9 after BNT162b2 (14.5%) vaccination, and none after mRNA-1273 vaccination. After 7,126,434 first vaccine doses, the incidence rate of CVT within 1 month from first dose administration was 0.55 (95% confidence interval [CI] = 0.38–0.78) per 100,000 person-months (which corresponds to a risk of CVT within the first 31 days of 0.55 per 100,000 individuals) for all vaccines and 1.52 (95% CI = 1.00–2.21) for ChAdOx1 (after 2,320,535 ChAdOx1 first doses). The adjusted incidence rate ratio was 9.68 (95% CI = 3.46–34.98) for ChAdOx1 compared to mRNA-based vaccines and 3.14 (95% CI = 1.22–10.65) for females compared to non-females. In 26 of 45 patients with CVT (57.8%), VITT was graded highly probable. Interpretation: Given an incidence of 0.02 to 0.15 per 100,000 person-months for CVT in the general population, these findings point toward a higher risk for CVT after ChAdOx1 vaccination, especially for women.
Under natural conditions, the visual system often sees a given input repeatedly. This provides an opportunity to optimize processing of the repeated stimuli. Stimulus repetition has been shown to strongly modulate neuronal-gamma band synchronization, yet crucial questions remained open. Here we used magnetoencephalography in 30 human subjects and find that gamma decreases across ≈10 repetitions and then increases across further repetitions, revealing plastic changes of the activated neuronal circuits. Crucially, increases induced by one stimulus did not affect responses to other stimuli, demonstrating stimulus specificity. Changes partially persisted when the inducing stimulus was repeated after 25 minutes of intervening stimuli. They were strongest in early visual cortex and increased interareal feedforward influences. Our results suggest that early visual cortex gamma synchronization enables adaptive neuronal processing of recurring stimuli. These and previously reported changes might be due to an interaction of oscillatory dynamics with established synaptic plasticity mechanisms.
Background: In the emerging era of digitalization and electronic health, various health-related apps have been launched, including apps for sexually transmitted diseases. Until now, little has been known about how patients perceive the value of such apps.
Objective: To investigate patient’s attitudes and awareness toward sexually transmitted disease–related apps in an outpatient sexually transmitted disease clinic setting.
Methods: A cross-sectional study was conducted at a dermatovenereological outpatient unit between April and July 2019. Patients completed a self-administered questionnaire on their perceptions of the popularity and usefulness of sexually transmitted disease–related apps. Descriptive analysis was performed with expression of categorical variables as frequencies and percentages. For continuous variables, the median, range, and interquartile range were indicated. Contingency tables and chi-square tests were used to investigate associations between sociodemographic data and items of the questionnaire.
Results: A total of 226 patients were surveyed (heterosexual: 137/193, 71.0%; homosexual: 44/193, 22.8%; bisexual: 12/193, 6.2%); 11.9% (27/225) had previously used health-related apps. Nearly half of the patients (97/214, 45.3%) specifically considered sexually transmitted disease–related apps useful, 47.8% (100/209) voted that they could supplement or support the consultation of a physician. Interestingly, only 35.1% (74/211) preferred a printed patient brochure on sexually transmitted diseases over downloading and using an app, but 64.0% (134/209) would download a sexually transmitted disease–related app recommended by their physician. General information regarding sexually transmitted diseases (93/167, 55.7%), evaluation of skin diseases based on photos or videos (78/167, 53.3%), information on the prevention of sexually transmitted diseases (76/167, 45.5%), mediation of nearby contact points or test sites (74/167, 44.3%), anonymous medical advice (69/167, 41.3%), and calculation of the risk of having a sexually transmitted disease (63/167, 37.3%) were rated as the most important features. Men were more likely than women to find sexually transmitted disease–related apps useful in general (P=.04; χ2=6.28) and to pay for such apps (P=.01; χ2=9.19). Patients aged <40 years would rather download an app recommended by their physician (P=.03; χ2=7.23), whereas patients aged >40 years preferred reading a patient brochure on sexually transmitted diseases (P=.02; χ2=8.14).
Conclusions: This study demonstrated high general interest in the use of sexually transmitted disease–related apps in this sample of dermatovenereological outpatients. In particular, young age and male sex were significantly associated with a positive perception, underlining the high potential of apps in the prevention and early recognition of sexually transmitted diseases in this group. Future studies are warranted to validate these findings in other populations.
Hintergrund: Die Atheroskleroseexpression unterscheidet sich nicht nur in unterschiedlichen Gefässbetten (koronar, zerebrovaskulär, peripher), sondern auch innerhalb des peripheren Gefässbettes. Der zugrundeliegende Mechanismus für unterschiedliche Atherosklerose-Phänotypen mit proximalem (iliakale Arterien) oder distalem (infragenikuläre Arterien) Atheroskleroseverteilungsmuster ist bis jetzt noch nicht abschliessend geklärt.
Zielsetzung: Das Ziel dieser monozentrischen retrospektiven Kohortenstudie ist es, den Zusammenhang zwischen kardiovaskulären Risikofaktoren und dem Atheroskleroseverteilungs-muster bei Patienten mit PAVK zu untersuchen. Dafür werden symptomatische Patienten mit extremen Atherosklerosephänotypen (proximale vs. distale Atherosklerose) genauer untersucht.
Methodik: Für diese Querschnittsstudie wurden Daten von 15’000 Patienten, welche sich im Zeitraum von 2000-2018 aufgrund einer symptomatischen PAVK einer primären endovaskulären Rekanalisation an den unteren Extremitäten unterziehen liessen, ausgewertet. Dabei wurden die Patienten herausgefiltert, welche angiographisch ein proximales (iliakal) oder distales (krural) Atheroskleroseexpressionsmuster aufwiesen. Von diesen Personen wurden in der Datenbank personen- und gesundheitsbezogene klinischen Angaben extrahiert. In einer multiplen logistischen Regressionsanalyse mit Rückwärtselimination der unabhängigen Variablen wurde der Einfluss verschiedener kardiovaskulärer Risikofaktoren mit proximaler oder distaler Atherosklerosexpression ermittelt.
Resultate: Von insgesamt 637 indentifizierten Patienten (29% Frauen) mit einer primären endovaskulären Rekanalisation hatten 351 (55%) ein proximales und 286 (45%) ein distales Atheroskleroseverteilungsmuster. Weibliches Geschlecht (OR 0.33, (95%CI 0.20-0.54), p=0.011), aktiver Nikotinkonsum (OR 0.16, (95%CI 0.09-0.28), p<0.001), vormaliger Nikotinkonsum (OR 0.33, (95%CI 0.20-0.57), p<0.001), Hypertriglyzeridämie (OR 0.76, (95%CI 0.60-0.96), p=0.021) waren assoziiert mit einem proximalen Befall. Diabetes mellitus (OR 3.25, (95%CI 1.93-5.46), p<0.001), chronische Niereninsuffizienz (OR 1.18, (95%CI 1.08-1.28), p<0.001) und höheres Alter (OR 1.31, (95%CI 1.06-1.61), p=0.011) waren hin-gegen mit einem distalen Befall assoziiert. Andere Faktoren wie Body Mass Index, arterielle Hypertonie, HDL-, LDL-Cholesterin zeigten keine Assoziation mit den untersuchten atherosklerotischen Prädilektionsstellen. Die Resultate der primären Analysen konnten mit den Subgruppenanalysen (Geschlecht, Nikotinkonsum, Diabetes) bestätigt werden.
Schlussfolgerung: Für distale (krurale) Atherosklerose wurden als Hauptrisikofaktoren Diabetes mellitus und chronische Niereninsuffizienz ermittelt. Obwohl kardiovaskuläre Risikofaktoren auf das gesamte Gefässbett wirken, lassen sich aus den Daten in Bezug auf das Atheroskleroseverteilungsmuster eine geschlechtspezifische und eine individuelle Suszeptibilität für kardiovaskuläre Risikofaktoren vermuten. Ausserdem deuten die Daten darauf hin, dass die PAVK mindestens zwei verschiedene atherosklerotische Phänotypen aufweist.
Niemann-Pick type C (NPC) disease, a lysosomal storage disorder caused by defective NPC1/NPC2 function, results in the accumulation of cholesterol and glycosphingolipids in lysosomes of affected organs, such as liver and brain. Moreover, increase of mitochondrial cholesterol (mchol) content and impaired mitochondrial function and GSH depletion contribute to NPC disease. However, the underlying mechanism of mchol accumulation in NPC disease remains unknown. As STARD1 is crucial in intramitochondrial cholesterol trafficking and acid ceramidase (ACDase) has been shown to regulate STARD1, we explored the functional relationship between ACDase and STARD1 in NPC disease. Liver and brain of Npc1−/− mice presented a significant increase in mchol levels and STARD1 expression. U18666A, an amphiphilic sterol that inhibits lysosomal cholesterol efflux, increased mchol levels in hepatocytes from Stard1f/f mice but not Stard1ΔHep mice. We dissociate the induction of STARD1 expression from endoplasmic reticulum stress, and establish an inverse relationship between ACDase and STARD1 expression and LRH-1 levels. Hepatocytes from Npc1+/+ mice treated with U18666A exhibited increased mchol accumulation, STARD1 upregulation and decreased ACDase expression, effects that were reversed by cholesterol extraction with 2-hydroxypropyl-β-cyclodextrin. Moreover, transfection of fibroblasts from NPC patients with ACDase, decreased STARD1 expression and mchol accumulation, resulting in increased mitochondrial GSH levels, improved mitochondrial functional performance, decreased oxidative stress and protected NPC fibroblasts against oxidative stress-mediated cell death. Our results demonstrate a cholesterol-dependent inverse relationship between ACDase and STARD1 and provide a novel approach to target the accumulation of cholesterol in mitochondria in NPC disease.
Purpose: Amblyopia with eccentric fixation, especially when not diagnosed early, is a therapeutic challenge, as visual outcome is known to be poorer than in amblyopia with central fixation. Consequently, treatment after late diagnosis is often denied. Electronic monitoring of occlusion provides us the chance to gain first focussed insight into age-dependent dose response and treatment efficiency, as well as the shift of fixation in this rare group of paediatric patients. Methods: In our prospective pilot study, we examined amblyopes with eccentric fixation during 12 months of occlusion treatment. We evaluated their visual acuity, recorded patching duration using a TheraMon®-microsensor, and determined their fixation with a direct ophthalmoscope. Dose-response relationship and treatment efficiency were calculated. Results: The study included 12 participants with strabismic and combined amblyopia aged 2.9–12.4 years (mean 6.5). Median prescription of occlusion was 7.7 h/day (range 6.6–9.9) and median daily received occlusion was 5.2 h/day (range 0.7–9.7). At study end, median acuity gain was 0.6 log units (range 0–1.6) and residual interocular visual acuity difference (IOVAD) 0.3 log units (range 0–1.8). There was neither significant acuity gain nor reduction in IOVAD after the 6th month of treatment. Children younger than 4 years showed best response with lowest residual IOVAD at study end. Efficiency calculation showed an acuity gain of approximately one line from 100 h of patching in the first 2 months and half a line after 6 months. There was a significant decline of treatment efficiency with age (p = 0.01). Foveolar fixation was achieved after median 3 months (range 1–6). Three patients (> 6 years) did not gain central fixation. Conclusion: Eccentric fixation is a challenge to therapy success. Based on electronic monitoring, our study quantified for the first time the reduction of treatment efficiency with increasing age in amblyopes with eccentric fixation. Despite some improvement in patients up to 8 years, older patients showed significantly lower treatment efficiency. In younger patients with good adherence, despite poor initial acuity, central fixation and low residual IOVAD could be attained after median 3 months. Hence, the necessity of early diagnosis and intensive occlusion should be emphasized.
Introduction: Deep brain stimulation (DBS) has become a well-established treatment modality for a variety of conditions over the last decades. Multiple surgeries are an essential part in the postoperative course of DBS patients if nonrechargeable implanted pulse generators (IPGs) are applied. So far, the rate of subclinical infections in this field is unknown. In this prospective cohort study, we used sonication to evaluate possible microbial colonization of IPGs from replacement surgery. Methods: All consecutive patients undergoing IPG replacement between May 1, 2019 and November 15, 2020 were evaluated. The removed hardware was investigated using sonication to detect biofilm-associated bacteria. Demographic and clinical data were analyzed. Results: A total of 71 patients with a mean (±SD) of 64.5 ± 15.3 years were evaluated. In 23 of these (i.e., 32.4%) patients, a positive sonication culture was found. In total, 25 microorganisms were detected. The most common isolated microorganisms were Cutibacterium acnes (formerly known as Propionibacterium acnes) (68%) and coagulase-negative Staphylococci (28%). Within the follow-up period (5.2 ± 4.3 months), none of the patients developed a clinical manifest infection. Discussions/Conclusions: Bacterial colonization of IPGs without clinical signs of infection is common but does not lead to manifest infection. Further larger studies are warranted to clarify the impact of low-virulent pathogens in clinically asymptomatic patients.
Inflammatory diseases including psoriasis are associated with metabolic and cardiovascular comorbidities, including obesity and metabolic syndrome. Obesity is associated with greater psoriasis disease severity and reduced response to treatment. Therefore, targeting metabolic comorbidities could improve patients’ health status and psoriasis-specific outcomes. METABOLyx is a randomized controlled trial evaluating the combination of a lifestyle intervention program with secukinumab treatment in psoriasis. Here, the rationale, methodology and baseline patient characteristics of METABOLyx are presented. A total of 768 patients with concomitant moderate to severe plaque psoriasis and metabolic syndrome were randomized to secukinumab 300 mg, or secukinumab 300 mg plus a tailored lifestyle intervention program, over 24 weeks. A substudy of immunologic and metabolic biomarkers is ongoing. The primary endpoint of METABOLyx is PASI90 response at week 24. Other endpoints include patient-reported outcomes and safety. METABOLyx represents the first large scale clinical trial of an immunomodulatory biologic in combination with a standardized lifestyle intervention.
Human babesiosis in Europe
(2021)
Babesiosis is attracting increasing attention as a worldwide emerging zoonosis. The first case of human babesiosis in Europe was described in the late 1950s and since then more than 60 cases have been reported in Europe. While the disease is relatively rare in Europe, it is significant because the majority of cases present as life-threatening fulminant infections, mainly in immunocompromised patients. Although appearing clinically similar to human babesiosis elsewhere, particularly in the USA, most European forms of the disease are distinct entities, especially concerning epidemiology, human susceptibility to infection and clinical management. This paper describes the history of the disease and reviews all published cases that have occurred in Europe with regard to the identity and genetic characteristics of the etiological agents, pathogenesis, aspects of epidemiology including the eco-epidemiology of the vectors, the clinical courses of infection, diagnostic tools and clinical management and treatment.
In der Akuten Lymphatischen Leukämie (ALL) im Erwachsenenalter beträgt die 5–Jahres-Überlebensrate trotz verbesserter Therapien unter 40%. Die Prognose wird durch das Auftreten von Rezidiven signifikant verschlechtert. ALL entsteht durch genetische Veränderungen lymphatischer Vorläuferzellen im Knochenmark, welche zu einem Differenzierungsblock und zu starker Zunahme der Vorläufer-zellen führen. Eine mögliche Erklärung für das bestehende hohe Rezidiv-Risiko wird in der unvollständigen Elimination von Leukämie-induzierenden Zellen (LIZ) durch die Primärtherapie gesehen. Die Identifizierung und Charakterisierung von LIZ in der ALL anhand spezifischer Oberflächenmarker war bisher nicht möglich, daher ist die molekulare und funktionelle Charakterisierung von LIZ für die Entwicklung moderner Therapieansätze unabdingbar. Metabolische Analysen primärer ALL-Langzeitkulturen (LZK) in Vorarbeiten zeigten eine deutliche Abweichung des Kohlenhydratstoffwechsels vom physiologischen metabolischen Profil einer Knochenmarkszelle hin zur Nutzung der Glykolyse mit zunehmendem leukämogenen Potential der etablierten LZK. Folglich ist in dieser Dissertation der Zusammenhang zwischen höherer Glukoseaffinität, schnellerer Glukoseaufnahme und dem Vorliegen eines höheren leukämogenen Potentials der Zellen und damit einer Definition der LIZ anhand ihres Energiestoffwechsels untersucht worden.
Hierfür wurden Tests im Mausmodell in vivo und in vitro mit drei ALL-LZK CR, PH und BV durchgeführt. Wir etablierten unter Verwendung des fluoreszenzmarkierten Glukoseanalogons 2–NBDG sowie eines gegen den GLUT–1 gerichteten Antikör-pers jeweils ein durchflusszytometrisches Verfahren zur quantitativen Messung der Glukoseaufnahme. Anhand dieser Parameter erfolgte die FACS-Anreicherung unterschiedlicher Zellpopulationen der LZK und die Xenotransplantation zur Evaluation potentieller Unterschiede des leukämogenen Potentials.
Durch durchflusszytometrische Messungen konnten in den drei LZK jeweils drei Subpopulationen von Zellen anhand ihrer Glukoseaffinität unterschieden werden (2–NBDG negativ, 2–NBDG positiv und 2–NBDG hochaffin). Auch zeigten sich Unterschiede in der Kinetik der Glukoseaufnahme der drei getesteten LZK, wobei CR Zellen mit Abstand am schnellsten 2–NBDG aufnahmen, gefolgt von PH. Die schnellere Glukoseaufnahme der LZK CR und PH wurde durch eine vermehrte Expression des GLUT-1 Rezeptors und einen höheren Anteil an GLUT–1 positiver Zellen hervorgerufen. Interessanterweise bestand auch eine Korrelation zwischen höherem leukämogenem Potential mit schnellerer Glukoseaufnahme und stärkerer GLUT–1 Expression. Hierbei zeigte sich, dass die HIF-1α Stabilisierung unter Normoxie in einer vermehrten GLUT–1 Expression und daraufhin vermehrter Glukoseaufnahme resultierte. Die prospektive Anreicherung von distinkten Zellsubpopulationen der LZK CR und PH aufgrund ihrer Glukoseaufnahme (gemessen durch 2–NBDG) und Transplantation der sortierten Zellpopulationen in NSG Empfängermäuse zeigte keine kohärente Beziehung zwischen der Glukoseaffinität der Zellen und der Entwicklung der Leukämie. Während es bei CR Zellen initial zu einer beschleunigten Expansion der 2–NBDG-positiv sortierten Leukämiezellen kommt, was sich aber nicht signifikant auf das Gesamtüberleben der Empfängermäuse auswirkt, zeigte die serielle Transplantation von 2–NBDG negativen Zellen ein schnelleres Ableben der Tiere. Bei der LZK PH expandierten 2–NBDG-negative Zellen schneller in primären Empfängermäusen als positive Zellen. Dabei konnten zelltoxische Effekte durch die Verwendung von 2–NBDG ausgeschlossen werden. Auch die Transplantation von GLUT-1 positiven bzw. negativen CR Zellen zeigte, dass GLUT-1 negative Zellen schneller in den Mäusen expandierten, eine aggressivere Leukämie verursachten und zu einem früheren Ableben der Mäuse führte.
Diese Ergebnisse zeigen keine unmittelbare Korrelation von Glukoseaufnahme oder GLUT-1 Expression und der Leukämogenität der untersuchten ALL Zellen. Daher können diese Eigenschaften nicht dazu verwendet werden LIZ in ALL prospektiv anzureichern. Im Rahmen dieser Dissertation zeigte sich aber auch, dass sich die LZK in ihrer jeweiligen Gesamtpopulation bezüglich ihres Glukoseaufnahmeverhaltens und ihrem Anteil GLUT-1-positiver Zellen unterschieden. Weiterführende Untersuchungen sind nötig, um den Grund der differentiellen Expression von GLUT-1 und der damit zusammenhängenden gesteigerten Glukoseaufnahme einzelner Zellen in der ALL zu ermitteln.
Stereotaktische Biospien gehören seit vielen Jahren zu den Standardoperationen zahlreicher neurochirurgischer Kliniken. Hierbei werden Proben von Hirnläsionen entnommen, um diese histopathologisch zu untersuchen.
Die histopathologische Diagnose unklarer Hirnläsionen ist zwingend erforderlich, um eine adäquate Therapie durchzuführen. Eine weitere Therapie kann aus Bestrahlung, Chemotherapie, Kombination beider oder Resektion bestehen. In wenigen Fällen wird eine zweite oder dritte Biopsie benötigt, um eine endgültige Diagnose zu erhalten. Das Ziel dieser Studie war es, jene Patienten genauer zu untersuchen, bei denen die erste Biopsie kein definitives Ergebnis erbracht hatte. Die meisten dieser Patienten mussten sich einer zweiten Biopsie unterziehen. Wir haben eine umfassende Recherche der letzten 10 Jahre durchgeführt und eine Datenbank mit den Patienten erstellt, bei denen die erste Biopsie kein Ergebnis erbracht hatte.
Hierbei wurden klinische Parameter, welche einen Einfluss auf die nicht zielführenden Biopsie haben können, erhoben, beschrieben und diskutiert. Die Parameter umfassten die entnommene Probenanzahl, Kontrastmittelaufnahme der Läsion, Lokalisation der Läsion, Erfahrung des Operateurs, neuroradiologische Verdachtsdiagnose und Vorbehandlung.
Wir haben in dieser retrospektiven Arbeit unser Augenmerk auf die klinischen Aspekte der einzelnen Patienten, bei denen die erste Biopsie kein definitives Ergebnis erbrachte, gelegt.
Hier zeigten sich keinerlei Auffälligkeiten, welche positiv mit einer nichtzielführenden Biopsie einhergehen könnten.
Wir folgern, dass in den meisten Fällen eine definitive Diagnose zu erwarten ist. Unklar bleibt, bei welchen Patienten keine zielführende Biopsie erfolgen wird, so dass sie einer erneuten Biopsie unterzogen werden müssen.
Beim Auffinden menschlicher Überreste stellt sich neben der Beurteilung des postmortalen Intervalls auch konsequent die Frage nach der Möglichkeit des Vorliegens eines Tötungsdelikts. Da Weichgewebe nur in begrenztem Ausmaß Verwesung, Fäulnis oder Umwelteinflüssen standhält, ist dieses nur bedingt geeignet, auch langfristig Spuren von Gewalteinwirkung zu konservieren. Knochengewebe hingegen kann Läsionen noch nach langen Zeiträumen nahezu unverändert abbilden und stellt somit einen forensisch bedeutenden Spurenträger dar.
Im Rahmen dieser retrospektiven Studie sollte geklärt werden, inwieweit und in welchem Ausmaß bei Tötungsdelikten knöcherne Verletzungen entstehen. Ob bei definierten Formen letaler Gewalteinwirkung unterschiedliche Häufigkeiten des Auftretens knöcherner Verletzungen zu beobachten und zudem bevorzugte Körperregionen zu identifizieren sind, stellte eine weitere wesentliche Fragestellung der Arbeit dar.
Nach Auswertung der Sektionsprotokolle von insgesamt 897 im Institut für Rechtsmedizin in Frankfurt am Main obduzierten, im In- und Ausland begangenen Tötungsdelikten im Zeitraum 01.01.1994 bis 31.12.2014 zeigte sich, dass unabhängig von der Art der tödlichen Gewalteinwirkung 70,9% der Opfer mindestens eine knöcherne Verletzung aufwiesen und darüber hinaus bei insgesamt 45,5% der Opfer mehrfache knöcherne Verletzungen nachgewiesen werden konnten.
Zudem zeigte sich, dass unterschiedliche, definierte letale Gewalteinwirkungen entsprechend charakteristische Häufigkeiten und Verteilungen knöcherner Verletzungen zur Folge haben. So sind mit 92,6 % die häufigsten knöchernen Läsionen bei Schussopfern festzustellen. Nach stumpfer und scharfer Gewalt mit je 80 % und 66,3 % ließ sich auch nach tödlicher Gewalteinwirkung gegen den Hals in 53,3 % der Fälle mindestens eine knöcherne Läsion nachweisen.
Das Fehlen knöcherner Verletzungen in insgesamt 29% der im Auswertungszeitraum untersuchten 897 Tötungsdelikte zeigt auch, dass selbst bei knöchern unversehrten, vollständigen Skelettfunden ein Homizid keineswegs ausgeschlossen werden kann. Neben der gerichtlichen Leichenöffnung sind stets ergänzende forensische Aufarbeitungen der menschlichen Überreste zu fordern. Hierbei sind einerseits physikalische und chemische Methoden in Betracht zu ziehen, vor allem jedoch auch radiologische Untersuchungen. Weitere Untersuchungen der gewonnenen Ergebnisse im Rahmen einer weiteren Studie sollen klären, welcher Stellenwert der postmortalen Computertomographie zugesprochen werden kann.
Aims: Inadequate treatment is one of the factors interfering with a successful social and working life. Among students, it can impair their health and learning progress. In the field of medicine the problem of inadequate treatment seems widespread. This study examines wether inadequate treatment in internships differs between medicine and other academic disciplines.
Method: Using a questionnaire, the frequency, forms and severity of inadequate treatment among students were compared between the disciplines of medicine, civil engineering and teaching.
Results: 69,3% of medical students reported inadequate treatment during their internships, about twice as many as students of other disciplines. The ratios of verbal, non-verbal and organisational inadequate treatment were similar between the different academic disciplines. However, medical students executed tasks without receiving sufficient safety precautions or training significantly more often (sevenfold) than students of other disciplines. In total however, the experienced incidents of inadequate treatment were seen as similarly severe across the different academic fields.
Conclusion: Inadequate treatment of students during internships is a larger problem in medicine than in civil engineering or teaching, particularly concerning the performance of unsafe tasks. With regard to the health of students and patients, inadequate treatment in the medical education should be tackled. Previous studies suggest that this goal can be achieved only through longtime extensive measures on the level of students, lecturers, faculty and teaching hospitals.
Hämophilie A (HA) ist eine X-chromosomal-rezessiv vererbte Blutgerinnungsstörung mit einem vollständigen Fehlen oder einem funktionellen Defizit des Gerinnungsfaktors VIII (FVIII). Trotz der Therapiefortschritte innerhalb der letzten Jahre, zeigen HA-Patienten auch unter der regelmäßigen FVIII-Substitutionstherapie weiterhin multiple Komplikationen, einschließlich Gelenkschäden, Entstehung einer Immunantwort (Hemmkörper) und reduzierter Lebensqualität. Im Gegensatz zu den bisherigen Therapieoptionen stellt die Gentherapie (GT) die vielversprechende Möglichkeit einer dauerhaften Anhebung des FVIII-Spiegels bis hin zur Heilung der HA in Aussicht.
In der vorliegenden Arbeit konnte ein geeignetes HA-Zellmodell auf Basis der primären humanen hepatischen sinusoidalen Endothelzellen (HHSEC) etabliert werden, um die zukünftige Erforschung einer SaCas-CRISPR-basierten HA-GT in vitro zu evaluieren, sowie wichtige Erkenntnisse für weiterführende Arbeiten gewonnen werden.
Mittels stabiler Integration des Doxycyclin-induzierbaren large T-Onkogens konnte eine gut charakterisierte, immortale HHSEC_LT-Zelllinie hergestellt werden, welche funktionalen FVIII exprimiert. Weiterhin konnte gezeigt werden, dass die Immortalisierung in Abhängigkeit von Doxycyclin für weiterführende Experimente in der Zellkultur essenziell ist, um Stressreaktionen der HHSEC, aufgrund ra-scher Seneszenz und Apoptose, zu umgehen.
Im weiteren Verlauf des GT-Projektes sollten verschiedene HHSEC-F8-Mutations-Zelllinien hergestellt werden. Neben der Gensequenzierung wurden in der vorliegenden Arbeit mehrere in Betracht kommende FVIII-Detektionsverfahren getestet, um den Erfolg einer eingeführten F8-Genmutation in HHSEC sowie ihrer anschließenden Reparatur im weiteren Verlauf des GT-Projektes auch auf Proteinebene zu demonstrieren. Hierbei konnte gezeigt wer-den, dass für die vorliegende Fragestellung sich insbesondere die Immunfluoreszenz- (IF-) Mikroskopie und die Quantifizierung der FVIII-Aktivität (FVIII:C) mittels aPTT-basierter Messung zur spezifischen Detektion von FVIII in HHSEC bewähren.
In Anlehnung an patientenspezifische F8-Genmutationen mit einem Frameshift-Effekt wurden fünf verschiedene sgRNA/SaCas9-CRISPR-Expressionsvektoren konstruiert und mittels lentiviralem Gentransfer in die immortalisierten HHSEC stabil transduziert. Nach PCR-Amplifikation der betreffenden genomischen Loci dieser fünf verschiedenen stabil transduzierten HHSEC-F8-Mutations-Zelllinien zeigte die anschließende Sequenzierung, dass vier der fünf hergestellten Konstrukte Genveränderungen mit potenziellen Frameshift-Effekten in HHSEC generieren konnten, wovon zwei sehr gute Ergebnisse erzielten. Korrelierend zu den Sequenzierergebnissen konnten ebenfalls Verminderungen der FVIII-Fluoreszenzintensität mittels mikroskopischer IF-Aufnahmen sowie der FVIII:C mittels aPTT-basierter Messung dargestellt werden.
Weiterhin konnte bei der Beurteilung des morphologischen Erscheinungsbildes der stabil transduzierten HHSECs eine optisch veränderte Zellmorphologie sowie ein Wachstumsnachteil innerhalb der beiden Zellpools mit den höchst erreichten Indel-Raten und der niedrigsten FVIII:C beobachtet werden. Diese Beobachtungen erlaubten die Formulierungen neuartiger, vielversprechender Hypothesen in Bezug auf das Grundverständnis der HA-Erkrankung.
Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.
Introduction: Dravet syndrome (DS), a prototypic developmental and genetic epileptic encephalopathy (DEE), is characterized by an early onset of treatment-refractory seizures, together with impairments in motor control, behavior, and cognition. Even with multiple conventional anti-epileptic drugs, seizures remain poorly controlled, and there has been a considerable unmet need for effective and tolerable treatments. Areas covered: This targeted literature review aims to highlight recent changes to the therapeutic landscape for DS by summarizing the most up-to-date, evidence-based research, including pivotal data from the clinical development of stiripentol, cannabidiol, and fenfluramine, which are important milestones for DS treatment, together with the latest findings of other pharmacotherapies in development. In phase III, double-blind, placebo-controlled randomized controlled trials stiripentol, cannabidiol, and fenfluramine have shown clinically relevant reductions in convulsive seizure frequency, and are generally well tolerated. Stiripentol was associated with responder rates (greater than 50% reduction in convulsive seizure frequency) of 67%-71%, when added to valproic acid and clobazam; cannabidiol was associated with responder rates of 43%-49% (48%-63% in conjunction with clobazam), and fenfluramine of 54%-68% across studies. Therapies in development include soticlestat, ataluren, verapamil, and clemizole, with strategies to treat the underlying cause of DS, including gene therapy and antisense oligonucleotides beginning to emerge from preclinical studies. Expert opinion: Despite the challenges of drug development in rare diseases, this is an exciting time for the treatment of DS, with the promise of new efficacious and well-tolerated therapies, which may pave the way for treatment advances in other DEEs.
Introduction: Prognosis of survivors from cardiac arrest is generally poor. Acute kidney injury (AKI) is a common finding in these patients. In general, AKI is well characterized as a marker of adverse outcome. In-hospital cardiac arrest (IHCA) represents a special subset of cardiac arrest scenarios with differential predisposing factors and courses after the event, compared to out-of-hospital resuscitations. Data about AKI in survivors after in-hospital cardiac arrest are scarce. Methods: In this study, we retrospectively analyzed patients after IHCA for incidence and risk factors of AKI and its prognostic impact on mortality. For inclusion in the analysis, patients had to survive at least 48 h after IHCA. Results: A total of 238 IHCA events with successful resuscitation and survival beyond 48 h after the initial event were recorded. Of those, 89.9% were patients of internal medicine, and 10.1% of patients from surgery, neurology or other departments. In 120/238 patients (50.4%), AKI was diagnosed. In 28 patients (23.3%), transient or permanent renal replacement therapy had to be initiated. Male gender, preexisting chronic kidney disease and a non-shockable first ECG rhythm during resuscitation were significantly associated with a higher incidence of AKI in IHCA-survivors. In-hospital mortality in survivors from IHCA without AKI was 29.7%, and 60.8% in patients after IHCA who developed AKI (p < 0.01 between groups). By multivariate analysis, AKI after IHCA persisted as an independent predictor of in-hospital mortality (HR 3.7 (95% CI 2.14–6.33, p ≤ 0.01)). Conclusion: In this cohort of survivors from IHCA, AKI is a frequent finding, with adverse impact on outcome. Therefore, therapeutic strategies to prevent AKI in post-IHCA patients are warranted.
Tuberous sclerosis complex (TSC) is a rare genetic disorder caused by mutations in the TSC1 or TSC2 genes, which encode proteins that antagonise the mammalian isoform of the target of rapamycin complex 1 (mTORC1) – a key mediator of cell growth and metabolism. TSC is characterised by the development of benign tumours in multiple organs, together with neurological manifestations including epilepsy and TSC-associated neuropsychiatric disorders (TAND). Epilepsy occurs frequently and is associated with significant morbidity and mortality; however, the management is challenging due to the intractable nature of the seizures. Preventative epilepsy treatment is a key aim, especially as patients with epilepsy may be at a higher risk of developing severe cognitive and behavioural impairment. Vigabatrin given preventatively reduces the risk and severity of epilepsy although the benefits for TAND are inconclusive. These promising results could pave the way for evaluating other treatments in a preventative capacity, especially those that may address the underlying pathophysiology of TSC, including everolimus, cannabidiol and the ketogenic diet (KD). Everolimus is an mTOR inhibitor approved for the adjunctive treatment of refractory TSC-associated seizures that has demonstrated significant reductions in seizure frequency compared with placebo, improvements that were sustained after 2 years of treatment. Highly purified cannabidiol, recently approved in the US as Epidiolex® for TSC-associated seizures in patients ⩾1 years of age, and the KD, may also participate in the regulation of the mTOR pathway. This review focusses on the pivotal clinical evidence surrounding these potential targeted therapies that may form the foundation of precision medicine for TSC-associated epilepsy, as well as other current treatments including anti-seizure drugs, vagus nerve stimulation and surgery. New future therapies are also discussed, together with the potential for preventative treatment with targeted therapies. Due to advances in understanding the molecular genetics and pathophysiology, TSC represents a prototypic clinical syndrome for studying epileptogenesis and the impact of precision medicine.
Substantial evidence shows that physical activity and fitness play a protective role in the development of stress related disorders. However, the beneficial effects of fitness for resilience to modern life stress are not fully understood. Potentially protective effects may be attributed to enhanced resilience via underlying psychosocial mechanisms such as self-efficacy expectations. This study investigated whether physical activity and fitness contribute to prospectively measured resilience and examined the mediating effect of general self-efficacy. 431 initially healthy adults participated in fitness assessments as part of a longitudinal-prospective study, designed to identify mechanisms of resilience. Self-efficacy and habitual activity were assessed in parallel to cardiorespiratory and muscular fitness, which were determined by a submaximal step-test, hand strength and standing long jump test. Resilience was indexed by stressor reactivity: mental health problems in relation to reported life events and daily hassles, monitored quarterly for nine months. Hierarchical linear regression models and bootstrapped mediation analyses were applied. We could show that muscular and self-perceived fitness were positively associated with stress resilience. Extending this finding, the muscular fitness–resilience relationship was partly mediated by self-efficacy expectations. In this context, self-efficacy expectations may act as one underlying psychological mechanism, with complementary benefits for the promotion of mental health. While physical activity and cardiorespiratory fitness did not predict resilience prospectively, we found muscular and self-perceived fitness to be significant prognostic parameters for stress resilience. Although there is still more need to identify specific fitness parameters in light of stress resilience, our study underscores the general relevance of fitness for stress-related disorders prevention.
Purpose: Amblyopia with eccentric fixation, especially when not diagnosed early, is a therapeutic challenge, as visual outcome is known to be poorer than in amblyopia with central fixation. Consequently, treatment after late diagnosis is often denied. Electronic monitoring of occlusion provides us the chance to gain first focussed insight into age-dependent dose response and treatment efficiency, as well as the shift of fixation in this rare group of paediatric patients. Methods: In our prospective pilot study, we examined amblyopes with eccentric fixation during 12 months of occlusion treatment. We evaluated their visual acuity, recorded patching duration using a TheraMon®-microsensor, and determined their fixation with a direct ophthalmoscope. Dose-response relationship and treatment efficiency were calculated. Results: The study included 12 participants with strabismic and combined amblyopia aged 2.9–12.4 years (mean 6.5). Median prescription of occlusion was 7.7 h/day (range 6.6–9.9) and median daily received occlusion was 5.2 h/day (range 0.7–9.7). At study end, median acuity gain was 0.6 log units (range 0–1.6) and residual interocular visual acuity difference (IOVAD) 0.3 log units (range 0–1.8). There was neither significant acuity gain nor reduction in IOVAD after the 6th month of treatment. Children younger than 4 years showed best response with lowest residual IOVAD at study end. Efficiency calculation showed an acuity gain of approximately one line from 100 h of patching in the first 2 months and half a line after 6 months. There was a significant decline of treatment efficiency with age (p = 0.01). Foveolar fixation was achieved after median 3 months (range 1–6). Three patients (> 6 years) did not gain central fixation. Conclusion: Eccentric fixation is a challenge to therapy success. Based on electronic monitoring, our study quantified for the first time the reduction of treatment efficiency with increasing age in amblyopes with eccentric fixation. Despite some improvement in patients up to 8 years, older patients showed significantly lower treatment efficiency. In younger patients with good adherence, despite poor initial acuity, central fixation and low residual IOVAD could be attained after median 3 months. Hence, the necessity of early diagnosis and intensive occlusion should be emphasized.
Pancreatic cancer (PC) still remains a major cause of cancer-related death worldwide and alternative treatments are urgently required. A common problem of PC is the development of resistance against apoptosis that limits therapeutic success. Here we demonstrate that the prototypical Smac mimetic BV6 cooperates with the stimulator of interferon (IFN) genes (STING) ligand 2′,3′-cyclic guanosine monophosphate–adenosine monophosphate (2′3′-cGAMP) to trigger necroptosis in apoptosis-deficient PC cells. Pharmacological inhibition of key components of necroptosis signaling, such as receptor-interacting protein 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL), significantly rescues PC cells from 2′3′-cGAMP/BV6/zVAD.fmk-mediated cell death, suggesting the induction of necroptosis. Consistently, 2′3′-cGAMP/BV6 co-treatment promotes phosphorylation of MLKL. Furthermore, we show that 2′3′-cGAMP stimulates the production of type I IFNs, which cooperate with BV6 to trigger necroptosis in apoptosis-deficient settings. STING silencing via siRNA or CRISPR/Cas9-mediated gene knockout protects PC cells from 2′3′-cGAMP/BV6/zVAD.fmk-mediated cell death. Interestingly, we demonstrate that nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNFα), and IFN-regulatory factor 1 (IRF1) signaling are involved in triggering 2′3′-cGAMP/BV6/zVAD.fmk-induced necroptosis. In conclusion, we show that activated STING and BV6 act together to exert antitumor effects on PC cells with important implications for the design of new PC treatment concepts.
Doping ist ein Thema, das den modernen Leistungssport – und nicht nur diesen – seit jeher begleitet. Immer wieder werden Sportler – oft noch nach Jahren – überführt, illegale Substanzen zur Leistungssteigerung eingenommen zu haben. Der Landessportbund Hessen e. V. hat im Sommer 2013 Professor Dr. Dr. Gerd Geißlinger zum Anti-Doping-Beauftragten berufen. Für den UniReport hat Dr. Beate Meichsner mit dem Direktor des Instituts für Klinische Pharmakologie am Klinikum der Goethe-Universität über die damit verbundenen Aufgaben, Ziele und
Möglichkeiten gesprochen.
Bei seiner Einschulung hatte Wolfgang Niedecken ein besonderes Erlebnis, als er im Alter von 6 Jahren bemerkte, dass es höchste Zeit war, ordentlich sprechen zu lernen. Im Elternhaus war ausschließlich Kölsch gesprochen worden. Hochdeutsch war seine erste Fremdsprache, die sie in letzter Konsequenz auch immer geblieben ist. Denken, empfinden und träumen tut Niedecken nach wie vor auf Kölsch, wie er selbst beteuert.
Im Sommer 1976 schreibt Wolfgang Niedecken seinen ersten Song auf Kölsch: "Helfe kann dir keiner". 1979 erscheint sein erstes Album mit dem Titel: "Wolfgang Niedecken’s BAP rockt andere kölsche Leeder".
Nie hat sich BAP auf seinen Tourneen vor den „Karren politischer Machthaber“ spannen lassen. Zu Zeiten zweier deutscher Staaten sorgten die offenen Worte von „Deshalv spill`mer he“ für einen Eklat. Das Lied sprach sich unmissverständlich nicht nur für die westdeutsche Friedensbewegung, sondern ebenfalls für die ostdeutschen Friedens- und Menschenrechtsinitiativen aus. Als die DDR-Kulturbehörden BAP verboten, den Song zu spielen, platzt am Vorabend des ersten Konzertes im Berliner Palast der Republik die über 14 Stationen geplante und längst ausverkaufte DDR-Tournee.
Am 9. November 1992 findet das „Arsch huh“-Konzert gegen Ausländerfeindlichkeit und Rassismus auf dem Kölner Chlodwigplatz vor über 100.000 Menschen statt. Danach ähnliche Konzerte in Frankfurt „Heute die, morgen Du“ und in Leipzig „Gewalt ätzt“ vor ähnlich großer Kulisse. Für sein gesellschaftspolitisches Engagement bekommt Niedecken 1998 das Bundesverdienstkreuz von Bundespräsident Roman Herzog überreicht. In der Laudatio heißt es: „Kölsch-Rock, BAP und Kölner Dialekt sind untrennbar mit ihm verbunden. Er ist einer der profiliertesten Rockmusiker Deutschlands. Als engagierter Künstler hat er sich nachhaltig für Frieden, Toleranz, Demokratie und gegen Fremdenfeindlichkeit eingesetzt.“
Zu Niedeckens 60. Geburtstag, den er am 30. März 2011 mit etwa 500 Gästen auf einem Rheinschiff feiert, sendet der WDR die „Niedecken-Nacht“. Zu seinem Geburtstag erscheint im Verlag Hoffmann und Campe auch das Buch „Für 'ne Moment. Autobiographie“. Auf über 500 Seiten erzählt der Musiker von seiner Familie, einer behüteten frühen Kindheit und der schwierigen Zeit als Heranwachsender im katholischen Internat, von seinem Kunststudium und Aufenthalten in der New Yorker Kunstszene, der ehe zufälligen Gründung von BAP, die zur erfolgreichsten Mundartgruppe Deutschlands wurde.
Und dann das: Am 2. November gegen 13 Uhr bemerkt Wolfgang Niedecken beim Lesen, „dass ich nichts mehr kapierte. Ich musste die Seiten immer wieder neu lesen. Dann wurde es nebelig vor den Augen, alles sah merkwürdig aus, mein ganzes Umfeld hatte amorphe Formen. Und dann begegnete ich Gott sei Dank meinem Schutzengel.“ Wolfgang Niedecken hatte einen Schlaganfall erlitten, obwohl er eigentlich kein typischer Schlaganfallpatient war. Es kann also jeden treffen! Dank des schnellen Reagierens seiner Frau Tina konnte das Schlimmste verhindert werden.
Gentechnik im Klassenzimmer
(2010)
Gerlach zum zweiten Mal in den Rat der Gesundheitsweisen berufen Foto: Institut für Allgemeinmedizin
(2010)
Purpose: Scientific and clinical achievements in radiation, medical, and surgical oncology are changing the landscape of interdisciplinary oncology. The German Society for Radiation Oncology (DEGRO) working group of young clinicians and scientists (yDEGRO) and the DEGRO representation of associate and full professors (AKRO) are aware of the essential role of radiation oncology in multidisciplinary treatment approaches. Together, yDEGRO and AKRO endorsed developing a German radiotherapy & radiation oncology vision 2030 to address future challenges in patient care, research, and education. The vision 2030 aims to identify priorities and goals for the next decade in the field of radiation oncology. Methods: The vision development comprised three phases. During the first phase, areas of interest, objectives, and the process of vision development were defined jointly by the yDEGRO, AKRO, and the DEGRO board. In the second phase, a one-day strategy retreat was held to develop AKRO and yDEGRO representatives’ final vision from medicine, biology, and physics. The third phase was dedicated to vision interpretation and program development by yDEGRO representatives. Results: The strategy retreat’s development process resulted in conception of the final vision “Innovative radiation oncology Together – Precise, Personalized, Human.” The first term “Innovative radiation oncology” comprises the promotion of preclinical research and clinical trials and highlights the development of a national committee for strategic development in radiation oncology research. The term “together” underpins collaborations within radiation oncology departments as well as with other partners in the clinical and scientific setting. “Precise” mainly covers technological precision in radiotherapy as well as targeted oncologic therapeutics. “Personalized” emphasizes biology-directed individualization of radiation treatment. Finally, “Human” underlines the patient-centered approach and points towards the need for individual longer-term career curricula for clinicians and researchers in the field. Conclusion: The vision 2030 balances the ambition of physical, technological, and biological innovation as well as a comprehensive, patient-centered, and collaborative approach towards radiotherapy & radiation oncology in Germany.
Patients with neuroendocrine tumors (NET) often go through a long phase between onset of symptoms and initial diagnosis. Assessment of time to diagnosis and pre-clinical pathway in patients with gastroenteropancreatic NET (GEP-NET) with regard to metastases and symptoms. Retrospective analysis of patients with GEP-NET at a tertiary referral center from 1984 to 2019; inclusion criteria: Patients ≥18 years, diagnosis of GEP-NET; statistical analysis using non-parametrical methods. Four hundred eighty-six patients with 488 tumors were identified; median age at first diagnosis (478/486, 8 unknown) was 59 years; 52.9% male patients. Pancreatic NET: 143/488 tumors; 29.3%; small intestinal NET: 145/488 tumors, 29.7%. 128/303 patients (42.2%) showed NET specific and 122/486 (25%) patients other tumor-specific symptoms. 222/279 patients had distant metastases at initial diagnosis (187/222 liver metastases). 154/488 (31.6%) of GEP-NET were incidental findings. Median time from tumor manifestation (e.g., symptoms related to NET) to initial diagnosis across all entities was 19.5 (95% CI: 12–28) days. No significant difference in patients with or without distant metastases (median 73 vs 105 days, P = .42). A large proportion of GEP-NET are incidental findings and only about half of all patients are symptomatic at the time of diagnosis. We did not find a significant influence of the presence of metastases on time to diagnosis, which shows a large variability with a median of <30 days.
Purpose: Early detection of adenocarcinomas in the esophagus is crucial for achieving curative endoscopic therapy. Targeted biopsies of suspicious lesions, as well as four-quadrant biopsies, represent the current diagnostic standard. However, this procedure is time-consuming, cost-intensive, and examiner-dependent. The aim of this study was to test whether impedance spectroscopy is capable of distinguishing between healthy, premalignant, and malignant lesions. An ex vivo measurement method was developed to examine esophageal lesions using impedance spectroscopy immediately after endoscopic resection. Methods: After endoscopic resection of suspicious lesions in the esophagus, impedance measurements were performed on resected cork-covered tissue using a measuring head that was developed, with eight gold electrodes, over 10 different measurement settings and with frequencies from 100 Hz to 1 MHz. Results: A total of 105 measurements were performed in 60 patients. A dataset of 400 per investigation and a total of more than 42,000 impedance measurements were therefore collected. Electrical impedance spectroscopy (EIS) was able to detect dysplastic esophageal mucosa with a sensitivity of 81% in Barrett’s esophagus. Conclusion: In summary, EIS was able to distinguish different tissue characteristics in the different esophageal tissues. EIS thus holds potential for further development of targeted biopsies during surveillance endoscopy.
Purpose: To investigate short-term (3 months follow-up) changes in visual quality following Descemet membrane endothelial keratoplasty (DMEK) for Fuchs endothelial dystrophy (FED). Methods: In this prospective institutional case series, 51 patients that underwent DMEK for FED were included. Assessment included the Quality of Vision (QoV) questionnaire preoperatively, at 1 month, and 3 months after surgery. Secondary outcome measures were anterior segment parameters acquired by Scheimpflug imaging, corrected distance visual acuity (CDVA), and endothelial cell density (ECD). Results: Glare, hazy vision, blurred vision, and daily fluctuation in vision were the symptoms mostly reported preoperatively. All symptoms demonstrated a significant reduction of item scores for severity, frequency, and bothersome in the course after DMEK (P < 0.01). Glare and fluctuation in vision remained to some extent during the follow-up period (median score = 1). Preoperatively, corneal densitometry correlated moderately to weakly with severity of hazy vision (rs = 0.39; P = 0.03) and frequency (rs = 0.26; P = 0.02) as well as severity (rs = 0.27; P = 0.03) of blurry vision. CDVA and central corneal thickness (CCT) did not correlate with visual complains. Conclusions: Following DMEK for FED, patient-reported visual symptoms assessed by the QoV questionnaire represent a useful tool providing valuable information on the impact of DMEK on visual quality that cannot be directly estimated by morphological parameters and visual acuity only.
Cancer stem cells (CSCs) are nowadays one of the major focuses in tumor research since this subpopulation was revealed to be a great obstacle for successful treatment. The identification of CSCs in pediatric solid tumors harbors major challenges because of the immature character of these tumors. Here, we present CD34, CD90, OV-6 and cell-surface vimentin (csVimentin) as reliable markers to identify CSCs in hepatoblastoma cell lines. We were able to identify CSC characteristics for the subset of CD34+CD90+OV-6+csVimentin+-co-expressing cells, such as pluripotency, self-renewal, increased expression of EMT markers and migration. Treatment with Cisplatin as the standard chemotherapeutic drug in hepatoblastoma therapy further revealed the chemo-resistance of this subset, which is a main characteristic of CSCs. When we treated the cells with the Hsp90 inhibitor 17-AAG, we observed a significant reduction in the CSC subset. With our study, we identified CSCs of hepatoblastoma using CD34, CD90, OV-6 and csVimentin. This set of markers could be helpful to estimate the success of novel therapeutic approaches, as resistant CSCs are responsible for tumor relapses.
A high incidence of thromboembolic events associated with high mortality has been reported in severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infections with respiratory failure. The present study characterized post-transcriptional gene regulation by global microRNA (miRNA) expression in relation to activated coagulation and inflammation in 21 critically ill SARS-CoV-2 patients. The cohort consisted of patients with moderate respiratory failure (n = 11) and severe respiratory failure (n = 10) at an acute stage (day 0–3) and in the later course of the disease (>7 days). All patients needed supplemental oxygen and severe patients were defined by the requirement of positive pressure ventilation (intubation). Levels of D-dimers, activated partial thromboplastin time (aPTT), C-reactive protein (CRP), and interleukin (IL)-6 were significantly higher in patients with severe compared with moderate respiratory failure. Concurrently, next generation sequencing (NGS) analysis demonstrated increased dysregulation of miRNA expression with progression of disease severity connected to extreme downregulation of miR-320a, miR-320b and miR-320c. Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed involvement in the Hippo signaling pathway, the transforming growth factor (TGF)-β signaling pathway and in the regulation of adherens junctions. The expression of all miR-320 family members was significantly correlated with CRP, IL-6, and D-dimer levels. In conclusion, our analysis underlines the importance of thromboembolic processes in patients with respiratory failure and emphasizes miRNA-320s as potential biomarkers for severe progressive SARS-CoV-2 infection.
Objective: To evaluate the prognostic impact of gastrointestinal involvement on the survival of children with Langerhans cell histiocytosis (GI-LCH) registered with the international clinical trials of the Histiocyte Society. Study design: This was a retrospective analysis of 2414 pediatric patients registered onto the consecutive trials DAL-HX 83, DAL-HX 90, LCH-I, LCH-II, and LCH-III. Results: Among the 1289 patients with single-system LCH, there was no single case confined to the GI tract; 114 of 1125 (10%) patients with multisystem LCH (MS-LCH) had GI-LCH at initial presentation. GI-LCH was significantly more common in children aged <2 years at diagnosis (13% vs 6% in those aged >2 years; P < .001) and in those with risk organ involvement (15% vs 6% in those without risk organ involvement; P < .001). The 5-year overall survival (OS) in patients without risk organ involvement was excellent irrespective of GI disease (98% vs 97% in patients with GI-LCH; P = .789). In patients with risk organ involvement, the 5-year OS was 51% in 70 patients with GI-LCH vs 72% in 394 patients without GI-LCH (P < .001). Conclusions: GI-LCH has an additive unfavorable prognostic impact in children with MS-LCH and risk organ involvement. The emerding need for more intensive or alternative treatments mandates prospective evaluation.
Selfish genetic elements that act as post-segregation distorters cause lethality in non-carrier individuals after fertilization. Two post-segregation distorters have been previously identified in Caenorhabditis elegans, the peel-1/zeel-1 and the sup-35/pha-1 elements. These elements seem to act as modification-rescue systems, also called toxin/antidote pairs. Here we show that the maternal-effect toxin/zygotic antidote pair sup-35/pha-1 is required for proper expression of apical junction (AJ) components in epithelia and that sup-35 toxicity increases when pathways that establish and maintain basal epithelial characteristics, die-1, elt-1, lin-26, and vab-10, are compromised. We demonstrate that pha-1(e2123) embryos, which lack the antidote, are defective in epidermal morphogenesis and frequently fail to elongate. Moreover, seam cells are frequently misshaped and mispositioned and cell bond tension is reduced in pha-1(e2123) embryos, suggesting altered tissue material properties in the epidermis. Several aspects of this phenotype can also be induced in wild-type embryos by exerting mechanical stress through uniaxial loading. Seam cell shape, tissue mechanics, and elongation can be restored in pha-1(e2123) embryos if expression of the AJ molecule DLG-1/Discs large is reduced. Thus, our experiments suggest that maternal-effect toxicity disrupts proper development of the epidermis which involves distinct transcriptional regulators and AJ components.
Background: This study aims to test the effect of the 10 most common nonurological primary cancers (skin, rectal, colon, lymphoma, leukemia, pancreas, stomach, esophagus, liver, lung) on overall mortality (OM) after secondary prostate cancer (PCa). Material and Methods: Within the Surveillance, Epidemiology, and End Results (SEER) database, patients with 10 most common primary cancers and concomitant secondary PCa (diagnosed 2004–2016) were identified and were matched in 1:4 fashion (age, year at diagnosis, race/ethnicity, treatment type, TNM stage) with primary PCa controls. OM was compared between secondary and primary PCa patients and was stratified according to primary cancer type, as well as according to time interval between primary cancer vs. secondary PCa diagnoses. Results: We identified 24,848 secondary PCa patients (skin, n = 3,871; rectal, n = 798; colon, n = 3,665; lymphoma, n = 2,583; leukemia, n = 1,102; pancreatic, n = 118; stomach, n = 361; esophagus, n = 219; liver, n = 160; lung, n = 1,328) vs. 531,732 primary PCa patients. Secondary PCa characteristics were less favorable than those of primary PCa patients (PSA and grade), and smaller proportions of secondary PCa patients received active treatment. After 1:4 matching, all secondary PCa exhibited worse OM than primary PCa patients. Finally, subgroup analyses showed that the survival disadvantage of secondary PCa patients decreased with longer time interval since primary cancer diagnosis and subsequent secondary PCa. Conclusion: Patients with secondary PCa are diagnosed with less favorable PSA and grade. Even after matching for PCa characteristics, secondary PCa patients still exhibit worse survival. However, the survival disadvantage is attenuated, when secondary PCa diagnosis is made after longer time interval, since primary cancer diagnosis.
Eines der übergeordneten Ziele neurowissenschaftlicher Grundlagenforschung ist es, die Pathomechanismen neuropsychiatrischer Erkrankungsbilder besser zu verstehen. Als Erklärungsmodell für einige dieser Erkrankungen dient unter anderem ein gestörtes Verhältnis zwischen Exzitation und Inhibition im Gehirn. Synaptische Strukturproteine sind wichtige Modulatoren dieses Verhältnisses. Für eine unbeeinträchtigte inhibitorische synaptische Transmission spielt das postsynaptische Zelladhäsionsprotein Neuroligin 2 eine maßgebliche Rolle, um das Gleichgewicht zwischen Exzitation und Inhibition aufrechtzuerhalten. Neuroligin 2 ist an der inhibitorischen Synapse lokalisiert und beeinflusst die Entwicklung, Reifung und Funktion dieser Synapse. Die klinische Relevanz von Neuroligin 2 wurde bereits bei zahlreichen Erkrankungsbildern wie Schizophrenie, Depression oder Epilepsie im Rahmen von Studien nachgewiesen. Um das Verhältnis zwischen Exzitation und Inhibition in vivo sowie Mechanismen der synaptischen Übertragung und Plastizität zu untersuchen, hat sich die Ableitung von Feldpotentialen im Gyrus Dentatus des Hippocampus etabliert. Im Neuroligin 2 Knockout Mausmodell konnte bereits gezeigt werden, dass eine pränatale Deletion dieses Proteins eine stark erhöhte Erregbarkeit der Körnerzellen und eine verminderte GABAerge Netzwerkinhibition im Gyrus Dentatus in vivo zur Folge hat.
Unklar blieb bisher, ob diese durch den konventionellen Neuroligin 2 Knockout (pränatal) hervorgerufenen Netzwerkveränderungen alleine auf das Fehlen dieses Proteins zurückzuführen sind oder durch eine zusätzliche Beeinträchtigung der Hirnentwicklung hervorgerufen werden. Ziel dieser Dissertation ist es deshalb, die Rolle von Neuroligin 2 im Gyrus Dentatus durch einen induzierten Knockout in adulten Mäusen (postnatal) unabhängig von einem möglichen Entwicklungseffekt zu klären.
Dazu wurde im ersten methodischen Schritt dieser Dissertation durch orale Tamoxifen-Gabe eine zeitspezifische konditionale Eliminierung von Neuroligin 2 in genetisch modifizierten, adulten Mäusen erzielt. Im Anschluss an diese konditionale Eliminierung wurde die synaptische Transmission, Plastizität sowie neuronale Erregbarkeit von Körnerzellen im Gyrus Dentatus mittels elektrophysiologischer Experimente untersucht. Hierzu wurde zunächst der Tractus Perforans und die Körnerzellschicht durch stereotaktische Chirurgie in anästhesierten Mäusen lokalisiert. Anschließend wurde eine Stimulation des Tractus Perforans sowie eine Ableitung von Feldpotentialen im Gyrus Dentatus durchgeführt. Um die Erregbarkeit der Körnerzellen, die synaptische Transmission, Kurz- und Langzeitplastizität sowie Netzwerkinhibition im Gyrus Dentatus zu analysieren, wurden unterschiedliche Stimulationsprotokolle verwendet. Im Anschluss an die elektrophysiologischen Experimente wurden die Hippocampi beidseitig entnommen, konserviert und später einer Proteinquantifizierung von Neuroligin 2 mittels Western-Blotting unterzogen.
Die Ergebnisse zeigten ein signifikant verringertes Proteinlevel von Neuroligin 2 auf 41,07% im Hippocampus von konditionalen Neuroligin 2 Knockout Mäusen. Unter dieser Reduktion von Neuroligin 2 in adulten Mäusen war die in vivo Erregbarkeit der Körnerzellen des Gyrus Dentatus sowie GABAerge Netzwerkinhibition weitgehend unbeeinträchtigt und die signifikanten Beobachtungen des konventionellen Knockout Modells ließen sich nicht reproduzieren. Aufgrund der unvollständigen Proteinreduktion lässt sich jedoch nicht abschließend beurteilen, ob die Restmenge den elektrophysiologischen Effekt kompensiert oder ob die im konventionellen Neuroligin 2 Knockout Modell beobachteten Effekte auf eine ausschließliche Rolle von Neuroligin 2 in der Hirnentwicklungsperiode zurückzuführen sind. Kürzlich veröffentlichte Daten zeigten allerdings, dass die postnatale Deletion von Neuroligin 2 in anderen Hirnregionen zu einer verminderten Netzwerkinhibition führt.
Neben der hier verwendeten in vivo Methodik ist eine Ergänzung von Untersuchungen in nicht-anästhesierten Tieren sowie Messungen einzelner Zellen durch whole-cell patch-clamp Untersuchungen in vitro oder in vivo zu erwägen. Es sollte dabei auf eine konditionale Proteineliminierung geachtet werden, damit mögliche Kompensationsmechanismen weitgehend ausgeschlossen werden können. Eine weiterführende immunhistochemische Bildgebung der Hippocampuspräparate, wie sie im konventionellen Knockout durchgeführt wurde, könnte sich hierbei ebenso als aufschlussreich für die Funktion von Neuroligin 2 im Hippocampus des adulten Tieres erweisen.