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Simple Summary: The role of transcriptionally deregulated miRNAs (microRNAs) in classical Hodgkin lymphoma (cHL) is still not fully understood. To address this issue, we have performed global miRNA expression profiling of commonly used cHL cell lines and we present a complete cHL miRNome (microRNome). Within this group, we identify miRNAs recurrently deregulated in cHL cell lines, and compare them to non-Hodgkin lymphoma cell lines and sorted normal CD77+ germinal centre B-cells. Moreover, we show that several of the recurrently overexpressed miRNAs in cHL cell lines, and also primary microdissected HRS (Hodgkin and Reed-Sternberg) cells, target known B-cell-related transcription factors and NF-κB inhibitors. These findings provide evidence that deregulated miRNAs contribute to the loss of B-cell phenotype and NF-κB activation observed in this lymphoma.
Abstract: A hallmark of classical Hodgkin lymphoma (cHL) is the attenuation of B-cell transcription factors leading to global transcriptional reprogramming. The role of miRNAs (microRNAs) involved in this process is poorly studied. Therefore, we performed global miRNA expression profiling using RNA-seq on commonly used cHL cell lines, non-Hodgkin lymphoma cell lines and sorted normal CD77+ germinal centre B-cells as controls and characterized the cHL miRNome (microRNome). Among the 298 miRNAs expressed in cHL, 56 were significantly overexpressed and 23 downregulated (p < 0.05) compared to the controls. Moreover, we identified five miRNAs (hsa-miR-9-5p, hsa-miR-24-3p, hsa-miR-196a-5p, hsa-miR-21-5p, hsa-miR-155-5p) as especially important in the pathogenesis of this lymphoma. Target genes of the overexpressed miRNAs in cHL were significantly enriched (p < 0.05) in gene ontologies related to transcription factor activity. Therefore, we further focused on selected interactions with the SPI1 and ELF1 transcription factors attenuated in cHL and the NF-ĸB inhibitor TNFAIP3. We confirmed the interactions between hsa-miR-27a-5p:SPI1, hsa-miR-330-3p:ELF-1, hsa-miR-450b-5p:ELF-1 and hsa-miR-23a-3p:TNFAIP3, which suggest that overexpression of these miRNAs contributes to silencing of the respective genes. Moreover, by analyzing microdissected HRS cells, we demonstrated that these miRNAs are also overexpressed in primary tumor cells. Therefore, these miRNAs play a role in silencing the B-cell phenotype in cHL.
Introduction: Cancer patients tend to prefer oral instead of parenteral chemotherapy. To date, there is little evidence on the medication adherence in cancer patients. We investigated medication adherence to tyrosine kinase inhibitors in patients suffering from non-small cell lung cancer. Methods: Tyrosine kinase inhibitor adherence was measured electronically by MEMS® (medication event monitoring system) over at least six months. Adherence rates were calculated in terms of Dosing Compliance, Timing Compliance, Taking Compliance, and Drug Holidays. Patients were dichotomized as adherent when Dosing Compliance and Timing Compliance were ≥80%, Taking Compliance ranged between 90 and 110%, and <1 Drug Holiday was registered. Quality of life was assessed by two questionnaires (EORTC QLQ-C30 version 3.0, EORTC QLQ-LC13) at three time points. Adverse drug events were reported via patient diaries. Results: Out of 32 patients enrolled, data from 23 patients were evaluable. Median Dosing Compliance, Taking Compliance, and Timing Compliance adherence rates of tyrosine kinase inhibitor intake amounted to 100%, 98%, and 99%, respectively; Drug Holidays were observed in three patients. Four patients were dichotomized as non-adherent. Three of them had a twice-daily tyrosine kinase inhibitor regimen. Median quality of life scores amounted to 67 (max. 100) and remained unchanged over the study period. Fatigue and rash were the most frequently reported adverse drug events. Conclusion: Medication adherence of non-small cell lung cancer patients treated with tyrosine kinase inhibitors was extraordinarily high and is likely to support the effectiveness of tyrosine kinase inhibitor treatment and a good quality of life over a long period of time. Adherence facilitating information and education is especially relevant for patients taking tyrosine kinase inhibitors in a twice-daily regimen.
Preeclampsia (PE), a gestational hypertensive disease originating from the placenta, is characterized by an imbalance of various cellular processes. The cell cycle regulator p21Cip1/CDKN1A (p21) and its family members p27 and p57 regulate signaling pathways fundamental to placental development. The aim of the present study was to enlighten the individual roles of these cell cycle regulators in placental development and their molecular involvement in the pathogenesis of PE. The expression and localization of p21, phospho-p21 (Thr-145), p27, and p57 was immunohistochemically analyzed in placental tissues from patients with early-onset PE, early-onset PE complicated by the HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome as well as late-onset PE compared to their corresponding control tissues from well-matched women undergoing caesarean sections. The gene level was evaluated using real-time quantitative PCR. We demonstrate that the delivery mode strongly influenced placental gene expression, especially for CDKN1A (p21) and CDKN1B (p27), which were significantly upregulated in response to labor. Cell cycle regulators were highly expressed in first trimester placentas and impacted by hypoxic conditions. In support of these observations, p21 protein was abundant in trophoblast organoids and hypoxia reduced its gene expression. Microarray analysis of the trophoblastic BeWo cell line depleted of p21 revealed various interesting candidate genes and signaling pathways for the fusion process. The level of p21 was reduced in fusing cytotrophoblasts in early-onset PE placentas and depletion of p21 led to reduced expression of fusion-related genes such as syncytin-2 and human chorionic gonadotropin (β-hCG), which adversely affected the fusion capability of trophoblastic cells. These data highlight that cell cycle regulators are important for the development of the placenta. Interfering with p21 influences multiple pathways related to the pathogenesis of PE.
Although anti-cancer properties of the natural compound curcumin have been reported, low absorption and rapid metabolisation limit clinical use. The present study investigated whether irradiation with visible light may enhance the inhibitory effects of low-dosed curcumin on prostate cancer cell growth, proliferation, and metastasis in vitro. DU145 and PC3 cells were incubated with low-dosed curcumin (0.1–0.4 µg/mL) and subsequently irradiated with 1.65 J/cm2 visible light for 5 min. Controls remained untreated and/or non-irradiated. Cell growth, proliferation, apoptosis, adhesion, and chemotaxis were evaluated, as was cell cycle regulating protein expression (CDK, Cyclins), and integrins of the α- and β-family. Curcumin or light alone did not cause any significant effects on tumor growth, proliferation, or metastasis. However, curcumin combined with light irradiation significantly suppressed tumor growth, adhesion, and migration. Phosphorylation of CDK1 decreased and expression of the counter-receptors cyclin A and B was diminished. Integrin α and β subtypes were also reduced, compared to controls. Irradiation distinctly enhances the anti-tumor potential of curcumin in vitro and may hold promise in treating prostate cancer.
The aim of this study was to evaluate whether recurrent carpal tunnel syndrome (CTS) after complete and sufficient division of the transverse ligament really exists. Another goal was to analyze the underlying reasons for recurrent CTS operated on in our department. Over an observation period of eleven years, 156 patients underwent surgical intervention due to CTS. The records of each patient were analyzed with respect to baseline data (age, gender, affected hand), as were clinical signs and symptoms pre- and postoperatively. To assess long-term results, standardized telephone interviews were performed using a structured questionnaire in which the patients were questioned about persisting symptoms, if any. Of the 156 patients, 128 underwent first surgical intervention due to CTS in our department. In long-term follow-up, two-thirds of these patients had no symptoms at all; one-third of the patients described mild persisting numbness. None of the patients experienced a recurrence of CTS. The 28 patients who received their first operation outside of our department were operated on for recurrent CTS. The cause of recurrence was incomplete division of the distal part of the transverse carpal ligament in all cases. The results suggest that recurrent CTS after complete and sufficient division of the transverse ligament is very unlikely.
Background: Dentists (Ds) and dental assistants (DAs) have a high lifetime prevalence of musculoskeletal disorders (MSDs). In this context, it is assumed that they have an increased intake of substances such as pain medication. Currently, there exist no data on the use of medication among Ds and DAs with MSDs in Germany. Methods: The online questionnaire (i.e., the Nordic Questionnaire) analysed the medical therapies used by 389 Ds (240 f/149 m) and 406 DAs (401 f/5 m) to treat their MSDs. Results: Ds (28.3–11.5%) and DAs (29.4–10.3%) with MSDs took medication depending on the affected body region. A trend between the Ds and DAs in the intake of drug therapy and the frequency was found for the neck region (Ds: 21.1%, DAs: 28.7%). A single medication was taken most frequently (Ds: 60.0–33.3%, DAs: 71.4–27.3%). The frequency of use varied greatly for both occupational groups depending on the region affected. Conclusion: Ds and DAs perceived the need for medical therapies because of their MSDs. Painkillers such as ibuprofen and systemic diclofenac were the medications most frequently taken by both occupational groups. The intake of pain killers, most notably for the neck, should prevent sick leave.
Sphingosine 1 phosphate (S1P) lyase (Sgpl1) catalyses the irreversible cleavage of S1P and thereby the last step of sphingolipid degradation. Loss of Sgpl1 in humans and mice leads to accumulation of sphingolipids and multiple organ injuries. Here, we addressed the role of hepatocyte Sgpl1 for regulation of sphingolipid homoeostasis by generating mice with hepatocyte-specific deletion of Sgpl1 (Sgpl1HepKO mice). Sgpl1HepKO mice had normal body weight, liver weight, liver structure and liver enzymes both at the age of 8 weeks and 8 months. S1P, sphingosine and ceramides, but not glucosylceramides or sphingomyelin, were elevated by ~1.5–2-fold in liver, and this phenotype did not progress with age. Several ceramides were elevated in plasma, while plasma S1P was normal. Interestingly, S1P and glucosylceramides, but not ceramides, were elevated in bile of Sgpl1HepKO mice. Furthermore, liver cholesterol was elevated, while LDL cholesterol decreased in 8-month-old mice. In agreement, the LDL receptor was upregulated, suggesting enhanced uptake of LDL cholesterol. Expression of peroxisome proliferator-activated receptor-γ, liver X receptor and fatty acid synthase was unaltered. These data show that mouse hepatocytes largely compensate the loss of Sgpl1 by secretion of accumulating sphingolipids in a specific manner into blood and bile, so that they can be excreted or degraded elsewhere.
Objective: Dravet syndrome (DS) is a rare but severe drug-resistant epilepsy. Before the approval of fenfluramine (FFA) for the treatment of seizures in DS, patients in Germany could receive treatment under a compassionate use program (CUP). Methods: We conducted a multicenter, retrospective, observational study to describe the efficacy, tolerability, and retention of FFA within the CUP. Patients received add-on therapy with oral FFA gradually titrated to a target dose between .13 and .7 mg/kg/day Results: Overall, 78 patients with DS (median age = 8.0 years, range = 2.1–46.0; 53% female, median concomitant antiseizure medications [ASMs] = 3) were treated with FFA for a median duration of 255.5 days (range = 31–572). Responder rates (a ≥50% reduction; n = 78) and seizure-freedom rates at 3 months were 68% and 14% for total seizures, respectively, and 67% and 23% for generalized tonic–clonic seizures. Responder rates were consistent at 6 and 12 months (n = 66 and n = 43, respectively). Median seizure days per month significantly decreased from 10.0 (range = .5–30) to 3.0 (range = 0–30) in the 3-month period before and after FFA treatment (p < .001). Significantly fewer patients reported at least one episode of status epilepticus (28% vs. 14% patients before and after FFA initiation, p = .005). During FFA treatment, 35 (45%) patients were able to discontinue a concomitant ASM. At the last follow-up date, 66 (85%) patients remained on treatment with FFA. The most common adverse events were somnolence (36%), decreased appetite (22%), and ataxia (8%). Forty-eight (62%) patients were reported as having a meaningful global clinical improvement. Significance: In a large cohort of patients, FFA demonstrated efficacy across a range of outcomes including clinically significant reductions in convulsive seizures, and was well tolerated, providing valuable information for real-world practice.
Objective: Dravet syndrome (DS) is a rare but severe drug-resistant epilepsy. Before the approval of fenfluramine (FFA) for the treatment of seizures in DS, patients in Germany could receive treatment under a compassionate use program (CUP). Methods: We conducted a multicenter, retrospective, observational study to describe the efficacy, tolerability, and retention of FFA within the CUP. Patients received add-on therapy with oral FFA gradually titrated to a target dose between .13 and .7 mg/kg/day. Results: Overall, 78 patients with DS (median age = 8.0 years, range = 2.1–46.0; 53% female, median concomitant antiseizure medications [ASMs] = 3) were treated with FFA for a median duration of 255.5 days (range = 31–572). Responder rates (a ≥50% reduction; n = 78) and seizure-freedom rates at 3 months were 68% and 14% for total seizures, respectively, and 67% and 23% for generalized tonic–clonic seizures. Responder rates were consistent at 6 and 12 months (n = 66 and n = 43, respectively). Median seizure days per month significantly decreased from 10.0 (range = .5–30) to 3.0 (range = 0–30) in the 3-month period before and after FFA treatment (p < .001). Significantly fewer patients reported at least one episode of status epilepticus (28% vs. 14% patients before and after FFA initiation, p = .005). During FFA treatment, 35 (45%) patients were able to discontinue a concomitant ASM. At the last follow-up date, 66 (85%) patients remained on treatment with FFA. The most common adverse events were somnolence (36%), decreased appetite (22%), and ataxia (8%). Forty-eight (62%) patients were reported as having a meaningful global clinical improvement. Significance: In a large cohort of patients, FFA demonstrated efficacy across a range of outcomes including clinically significant reductions in convulsive seizures, and was well tolerated, providing valuable information for real-world practice.
Key Points: Seventy-eight patients with Dravet syndrome were treated with FFA at multiple centers within the CUP in Germany; FFA had a good retention rate over a sustained period; 85% of patients remained on treatment with FFA for a median duration of 255.5 days; FFA was associated with clinically meaningful reductions in total and convulsive seizures, seizure days per month, and episodes of status epilepticus; FFA was associated with reductions in the number or dose of concomitant antiseizure medications in 68% of patients; FFA was well tolerated, with the main adverse events being somnolence (36%), decreased appetite (22%), and ataxia (8%).
Background: To test the effect of urological primary cancers (bladder, kidney, testis, upper tract, penile, urethral) on overall mortality (OM) after secondary prostate cancer (PCa). Methods: Within the Surveillance, Epidemiology and End Results (SEER) database, patients with urological primary cancers and concomitant secondary PCa (diagnosed 2004-2016) were identified and were matched in 1:4 fashion with primary PCa controls. OM was compared between secondary and primary PCa patients and stratified according to primary urological cancer type, as well as to time interval between primary urological cancer versus secondary PCa diagnoses. Results: We identified 5,987 patients with primary urological and secondary PCa (bladder, n = 3,287; kidney, n = 2,127; testis, n = 391; upper tract, n = 125; penile, n = 47; urethral, n = 10) versus 531,732 primary PCa patients. Except for small proportions of Gleason grade group and age at diagnosis, PCa characteristics between secondary and primary PCa were comparable. Conversely, proportions of secondary PCa patients which received radical prostatectomy were smaller (29.0 vs. 33.5%), while no local treatment rates were higher (34.2 vs. 26.3%). After 1:4 matching, secondary PCa patients exhibited worse OM than primary PCa patients, except for primary testis cancer. Here, no OM differences were recorded. Finally, subgroup analyses showed that the survival disadvantage of secondary PCa patients decreased with longer time interval since primary cancer diagnosis. Conclusions: After detailed matching for PCa characteristics, secondary PCa patients exhibit worse survival, except for testis cancer patients. The survival disadvantage is attenuated, when secondary PCa diagnosis is made after longer time interval, since primary urological cancer diagnosis.
Im Bereich der Neonatologie kommen die Patient*innen oft multimorbide zu Welt oder sind für bestimmte Komplikationen gefährdet, die sich aus ihrer Unreife ergeben. Dabei spielen sowohl bei reifen kranken Neugeborenen und erst recht bei Frühgeborenen Erkrankungen der Atemwege eine Hauptrolle. Nach wie vor ist das konventionelle Röntgen in diesem Bereich der Medizin ein wichtiges Instrument. Die diagnostische Strahlenexposition bietet jedoch immer wieder Raum zur Diskussion. Die Patient*innen sind nur wenige Tage alt und besitzen somit über eine hohe Proliferationsrate und ein Maß an undifferenzierten Zellen, sie erhalten in Summe teilweise viele Aufnahmen und haben auf der anderen Seite eine hohe Lebenserwartung, wenn sie die Neugeborenenzeit ohne Komplikationen überleben. Haupteffekte ionisierender Strahlen sind für die Früh- und kranken Neugeborenen Malignome, vor allem die Leukämien. Es soll herausgefunden werden, inwieweit die Strahlenbelastung ein gesundheitliches Risiko für die Früh- und Neugeborenen darstellt.
Hintergrund: Gegenstand der wissenschaftlichen und klinischen Diskussion ist immer wieder das eventuell bestehende Risiko der einfallenden ionisierenden Röntgenstrahlung auf das Früh- oder Neugeborene, dennoch ist das Röntgen als diagnostisches Mittel notwendig. Es soll untersucht werden, wie hoch das gesundheitliche Risiko durch diagnostische Röntgenaufnahmen in der Praxis für die Früh- und Neugeborenen ist.
Material und Methoden: Alle Patient*innen des Schwerpunktes Neonatologie in der Klinik für Kinder- und Jugendmedizin aus dem Zeitraum vom 01.01.2013 bis 31.12.2018 im Universitätsklinikum Frankfurt wurden retrospektiv untersucht. Es wurden die Anzahl der Röntgenaufnahmen pro Patient*in, die zugrunde liegende Indikation, das Dosisflächenprodukt (DFP), die Effektive Dosis (ED) und das geschätzte Risiko dokumentiert, bzw. errechnet. Die ED ist eine Schätzgröße, welche mittels Konversionskoeffizienten aus den Eingangsgrößen des DFP, der Eintrittsdosis oder dem Air Kerma (Kai) berechnet wird. Im ICRP Bericht Nr. 60 finden sich Faktoren zur Risikoabschätzung von 2,8 bis 13*10-2 Sv-1. Diese Risikoeinschätzung nähert das durch Strahlung induzierte Risiko für Krebs in der ersten Lebensdekade an – vor allem für Leukämien, aber auch andere Krebsarten.
Ergebnisse: Von den insgesamt 3843 stationär in der Neonatologie behandelten Patient*innen (2013-2018) erhielten 1307 (34%) mindestens eine Röntgenaufnahme. Pro Jahr wurden in einer Abteilung für Neonatologie ca. 700 Röntgenaufnahmen angefertigt. Die mittlere Anzahl an Röntgenaufnahmen pro Patient*in betrug 3,19 Aufnahmen und korrelierte gegensinnig mit Geburtsgewicht und Gestationsalter. Am häufigsten wurden sehr kleine Frühgeborene untersucht, meistens in den ersten drei Lebenstagen. Im Laufe des Beobachtungszeitraums wurden weniger Röntgenaufnahmen angefertigt. Die häufigsten Gründe für Röntgenaufnahmen waren Kontrollen von Tubus oder ZVK-Lage. Je reifer und schwerer die Neugeborenen waren, desto seltener wurde ein pathologischer Befund erhoben. Bei niedrigem Geburtsgewicht war die Thoraxabdomenaufnahme die bevorzugte Röntgenart, bei reiferen Patient*innen die Thoraxaufnahme. Das kumulative DFP betrug im Mittel 5,95 mGy*cm² und die kumulative ED betrug im Mittel 23,7 µSv pro Aufenthalt. Damit errechnete sich ein Risiko von 3,1*10-6, das bedeutet 3,1 von 1.000.000 Patient*innen entwickeln nach dieser kumulativen Strahlendosis in der ersten Lebensdekade womöglich Krebs. Das kumulative DFP und die ED pro Aufenthalt und somit auch das Risiko, nach einer gewissen Strahlenexposition Krebs zu entwickeln, sinken mit zunehmendem Geburtsgewicht und zeigen einen Höhepunkt bei einem Geburtsgewicht von <500 g. Die maximale kumulative Strahlendosis betrug 342 µSv mit einem daraus resultierenden Risiko von 44*10-6 und ist damit selbst bei diesem Patienten nach Martin et al. als „minimal“ zu werten.
Schlussfolgerung: Die Strahlenbelastung der Früh- und Neugeborenen konnte evaluiert werden und der Zusammenhang zwischen Unreife und Strahlenbelastung konnte bestätigt werden. Die Strahlenbelastung fiel im internationalen Vergleich minimal aus und es ist nicht von einem gesundheitlichen Risiko durch diagnostische Bildgebung auszugehen. Dies lässt sich vor allem durch moderne Technik mit kurzer Belichtungszeit und hoher Aufnahmespannungen und durch die relativ niedrige Anzahl an gemachten Röntgenbildern erklären. Da bei weiterer Minimierung der eingesetzten Dosis von einem Qualitätsverlust der Bilder auszugehen ist, ist die Einsparung von Röntgenuntersuchungen und die vermehrte Nutzung von Alternativen anzuraten. Die Indikationen müssen vor allem bei Patient*innen <500 g genauestens überprüft werden. Weiterhin sollte nach Alternativen (Sonographie, Kernspintomographie) gesucht werden.
Increased intraindividual variability of reaction time is a main cognitive feature of Attention Deficit Hyperactivity Disorder. It is associated with deficits in sustained attention. While traditionally, mean and variance were used to characterize reaction time distributions, the ex-gaussian distributional model allows a more sophisticated analysis of reaction time series. Reaction time distributions are separated in a normal and an exponential component.
The present study investigates the impact of incentives on reaction time variability in a sample of adult ADHD patients. ADHD is associated with increased Tau, the output parameter of the ex-gaussian model characterizing the exponential part of the distribution. Tau is linked to “lapses of attention”, which are more frequent in ADHD patients. It is known that tau can be modulated in ADHD Patients. It was therefore postulated that tau would be higher in ADHD Patients in a paradigm where quick answers were required but could be modulated by monetary incentives. In addition, the effect of “delay discounting”, which is more distinct in ADHD patients, on reaction time variability was investigated. Eventually, the association of variability measures with strength of ADHD symptoms was tested.
To this end, reaction time distributions of 62 adult ADHD patients and 45 healthy controls from two different reaction time paradigms were analyzed. The monetary incentive delay task, by comprehending a control – and a win condition, allows an investigation of the effect of incentives on reaction times. Subjects had to react as fast as possible by keypress to a stimulus, after a cue signaled a possible monetary reward. During the Delay-Discounting-Task, subjects had to choose between sooner, but smaller, and higher delayed monetary rewards, during which they could use as much time for consideration as desired.
Results show that an increased Tau in the control condition of the monetary- incentive-delay-task could be replicated, while a distinct influence of the win condition emerged. Subjects with ADHD showed an improvement of Tau in the win condition even below the level of healthy controls. However, they showed increased variability of the “regular” responses around the mean of the normal component of the distribution, represented by sigma. Moreover, it was indicated by trend a higher reaction time variability in ADHD patients during choices of delayed rewards. Tau was associated the current symptom strength as well as with the strength of ADHD-Symptoms during childhood, assessed by questionnaire.
While the present results could have implications for etiological models of the disease, they may also contribute to the development of novel diagnostic methods. In advanced studies, neural correlates of sophisticated measures of reaction time variability should be investigated. Furthermore, they should be associated with genetic risk factors with regard to possible endophenotypes. Possible implications for clinical handling of patients should be explored.
Hintergrund: Die Verankerung der Kompetenzorientierung und die Betonung der praktisch-klinischen Ausbildung im Rahmen des Medizinstudiums sind zentrale Punkte in den Neuerungen der Ärztlichen Approbationsordnung. Mit der Entwicklung des Nationalen Kompetenzbasierten Lernzielkatalogs Medizin (NKLM) ist ein Rahmenwerk erstellt und verabschiedet worden, das die Inhalte des gesamten Medizinstudiums in Deutschland abbilden und eine Implementierung kompetenzorientierter Lernziele an den Fakultäten forcieren soll. Um diesem Ziel gerecht zu werden, müssen bereits an den Fakultäten vorhandene Lehrveranstaltungen mit dem NKLM abgeglichen und im Rahmen eines Curriculum Mappings kartiert werden. Ziel der vorliegenden Arbeit ist daher die Kartierung der im Frankfurter Blockpraktikum Chirurgie erlernten Kompetenzen im Sinne eines Curriculum Mappings in Anlehnung an die im NKLM formulierten Lernziele. Zudem wurde folgenden Fragestellungen nachgegangen: Welcher Umfang kompetenzorientierter Lernziele kann Studierenden in einem zweiwöchigen Praktikum Chirurgie vermittelt werden? Wie ist die Vermittlung der einzelnen Kapitel des NKLM im Blockpraktikum Chirurgie gewichtet? Gibt es Unterschiede der erreichten Lernziele in Abhängigkeit des Geschlechts der Studierenden, der besuchten Fachrichtung bzw. des besuchten Lehrkrankenhauses?
Material und Methoden: Im Rahmen der vorliegenden Arbeit wurden Medizinstudierende im zweiten bzw. dritten klinischen Semester unmittelbar nach Abschluss ihres Blockpraktikums Chirurgie gebeten, unter Nutzung eines Online-Fragebogens anzugeben, welche der im NKLM formulierten Lernziele sie im zweiwöchigen Blockpraktikum Chirurgie gelernt haben. Somit konnte für jedes Kapitel dargestellt werden, zu welchem prozentualen Anteil die Lernziele dieses Kapitels erreicht worden sind. Zudem wurden die soziodemographischen Daten der Studierenden, die Fachrichtung des Blockpraktikums und das Lehrkrankenhaus erfasst. Die statistische Auswertung erfolgte mit dem Wilcoxon-Mann-Whitney Test und dem Kruskal-Wallis Test.
Ergebnisse: Insgesamt nahmen 81 Studierenden (28 Männer, 53 Frauen) aus dem 2. bzw 3. klinischen Semester an der Studie teil. Insgesamt wurden im zweiwöchigen Blockpraktikum Chirurgie 8,78 ± 5,10% (Min. 1,01%; Max. 29,84%) aller Lernziele von den Studierenden erreicht. Hierbei wurden anteilig die meisten Lernziele in den Kapiteln 5-11 (Abschnitt 1 „Ärztliche Rollen“) mit 29,92 ± 15,22% (Min. 0,00%; Max. 63,10%) vermittelt. Aus Abschnitt 2 („Medizinisches Wissen, klinische Fähigkeiten und professionelle Haltungen“) wurden vor allem die Lernziele der Kapitel 14b „Klinisch-praktische Fertigkeiten“ (15,49 ± 7,78% (Min. 0,00%; Max. 41,30%) und 14c „Ärztliche Gesprächsführung“ (22,98 ± 16,47% (Min. 0,00%; Max. 70,69%) von den Studierenden erreicht. Männer geben durchschnittlich an, mehr Lernziele erreicht zu haben als Frauen (9,84% vs. 8,22%; p=0.104731). Weiterhin haben Studierende, die ihr Praktikum in einem Lehrkrankenhaus mit weniger als 100 chirurgischen Bettenplätzen (10,60 ± 6,75%; Min. 2,33%; Max. 29,84%) oder in einer Rotation (9,95 ± 6,67%; Min. 1,90%; Max. 29,84%) durch mehrere Fachrichtungen absolvierten, angegeben mehr Lernziele erreicht zu haben als andere Studierende insgesamt.
Schlussfolgerung: Das zweiwöchige Blockpraktikum Chirurgie in Frankfurt kann den Studierenden (im Hinblick auf die Gesamtdauer des Medizinstudiums) einen großen Anteil der im NKLM formulierten Lernziele vermitteln. Vor allem die Lernziele der „Ärztlichen Rollen“ und der „klinisch-praktischen Fertigkeiten“ werden erlernt. Die Vermittlung gelingt besonders umfangreich in kleineren Lehrkrankenhäusern. Trotzdem bietet das Blockpraktikum Chirurgie den Teilnehmer nur einen kleinen Einblick in den Fachbereich Chirurgie. Für die Vermittlung von spezifischen chirurgischen Fähigkeiten, Prinzipen chirurgischer Diagnostik und Therapie, sowie Aspekte der „Patientenzentrierten Gesundheitsversorgung“ sind andere Formate notwendig.
Hauptrolle für die Krankenhaushygiene : »Tag der Patientensicherheit« am Universitätsklinikum
(2015)
Ernst, aber nicht hoffnungslos : Wissenschaftler berichten über Ergebnisse aus der Demenz-Forschung
(2015)
Locomotor activity patterns of laboratory mice are widely used to analyze circadian mechanisms, but most investigations have been performed under standardized laboratory conditions. Outdoors, animals are exposed to daily changes in photoperiod and other abiotic cues that might influence their circadian system. To investigate how the locomotor activity patterns under outdoor conditions compare to controlled laboratory conditions, we placed 2 laboratory mouse strains (melatonin-deficient C57Bl and melatonin-proficient C3H) in the garden of the Dr. Senckenbergische Anatomie in Frankfurt am Main. The mice were kept singly in cages equipped with an infrared locomotion detector, a hiding box, nesting material, and with food and water ad libitum. The locomotor activity of each mouse was recorded for 1 year, together with data on ambient
temperature, light, and humidity. Chronotype, chronotype stability, total daily activity, duration of the activity period, and daily diurnality indices were determined from the actograms. C3H mice showed clear seasonal differences in the chronotype, its stability, the total daily activity, and the duration of the activity period. These pronounced seasonal differences were not observed in the C57Bl. In both strains, the onset of the main activity period was mainly determinedby the evening dusk, whereas the offset was influenced by the ambient temperature. The actograms did not reveal infra-, ultradian, or lunar rhythms or a weekday/weekend pattern. Under outdoor conditions, the 2 strains retained their nocturnal locomotor identity as observed in the laboratory. Our results indicate that the chronotype displays a seasonal plasticity that may depend on the melatoninergic system. Photoperiod and ambient temperature are the most potent abiotic entraining cues. The timing of the evening dusk mainly affects the onset of the activity period; the ambient temperature during this period influences the latter’s duration. Humidity, overall light intensities, and human activities do not affect the locomotor behavior.
Durch die sich verändernde Altersstruktur nehmen die Inzidenz und Prävalenz von Herzklappenerkrankungen wie der Mitralinsuffizienz weltweit zu, verbunden mit einem Verlust an Lebensqualität und Lebensjahren für den individuellen Patienten und hohen Kosten für das Gesundheitssystem. Die Standardtherapie, eine chirurgische Rekonstruktion oder ein Ersatz der Mitralklappe kommt aufgrund von Alter und Begleiterkrankungen (insbesondere der Herzinsuffizienz) bei bis zu 50% der Patienten nicht in Frage. Die MitraClip- Prozedur ist ein etabliertes Verfahren zur minimalinvasiven Therapie der hochgradigen Mitralklappeninsuffizienz bei Patienten mit hohem Operationsrisiko. In einigen, jedoch nicht allen Patientenkohorten konnte ein positiver Einfluss auf Rehospitalisierungen und Sterblichkeit gezeigt werden. Insbesondere Patienten mit Rechtsherzdysfunktion (RVD) scheinen weniger zu profitieren. Aufgrund des individuellen Risikos des Eingriffs und der erheblichen Kosten ist es notwendig, Patienten zu identifizieren die von dem Eingriff profitieren und solche bei denen ein ungünstiges Nutzen/ Risikoverhältnis besteht.
Im Rahmen des Frankfurter Mitralklappenregisters wurden 119 Patienten im interdisziplinären Konsens („Heart Team“) vom 07/2013 bis 02/2017 mit der MitraClip Prozedur behandelt und nach ihrem schriftlichen Einverständnis in die Analyse eingeschlossen. Der Langzeitverlauf wurde bis zum 31.12.2017 beobachtet.
Ziel der Studie war, zu erfassen, ob die Anwendung von bei Herzinsuffizienz etablierten Prognosemodellen bei diesen Patienten sinnvoll ist und ob sich das Seattle Heart Failure Model (SHFM) und der Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) Score in ihrer Genauigkeit bei diesen Patienten unterscheiden insbesondere im Kontext einer RVD.
Die Diagnose einer RVD erfolgte über den im Herzultraschall leicht zu erfassenden Parameter „Tricuspid Annular Plane Excursion“ (TAPSE), der die während der Systole zurückgelegte Strecke des Trikuspidalrings misst.
Die Genauigkeit in der Vorhersage der 1- Jahres Mortalität der beiden Scores wurde durch die Bestimmung der Area under the Receiver Operating Characteristic (AUROC) ermittelt.
Innerhalb eines Jahres nach MitraClip- Therapie verstarben 29 Patienten (28.2%) des Gesamtkollektivs. Bei Patienten mit funktioneller Mitralklappeninsuffizienz (FMR) betrug die 1- Jahres Mortalität 23,3%, bei Patienten mit degenerativer Mitralklappeninsuffizienz (DMR) 31,7%. In der Kaplan- Meier Analyse bestand eine signifikant erhöhte 1- Jahres Mortalität für Patienten mit RVD (34.8 vs 22.8%; p=0.009). Patienten mit FMR wiesen eine erhöhte Sterblichkeit auf, wenn gleichzeitig eine RVD bestand (38.1% vs 9.1% ohne RVD). Diese Assoziation bestand bei Patienten mit DMR nicht (32% mit RVD vs. 34.3%).
Die prognostische Genauigkeit beider Scores war im Gesamtkollektiv vergleichbar (SHFM: 0.704, MAGGIC: 0.692). Das gilt auch für separate Analysen nach funktioneller/ degenerativer Genese der Mitralklappeninsuffizienz (FMR: SHFM 0.696, MAGGIC 0.722; DMR: SHFM 0.727, MAGGIC 0.629). Bei Patienten ohne RVD zeigt das SHFM jedoch eine höhere diagnostische Genauigkeit als der MAGGIC Score (SHFM: 0.775; MAGGIC: 0.551, p <0.05). Bei Patienten mit Rechtsherzdysfunktion bestehen keine signifikanten Unterschiede (SHFM: 0.615; MAGGIC: 0.799, p>0.05), auch wenn ein Trend zugunsten des MAGGIC Scores bestand.
Eine bestehende RVD ist ein wichtiger prognostischer Marker für Patienten, die mit einem Mitraclip behandelt werden und sollte in der Entscheidungsfindung des „Heart Teams“ berücksichtigt werden. SHFM und MAGGIC Score besitzen eine adäquate prognostische Trennschärfe in unserer Patientenkohorte, Unterschiede bestehen bei Patienten mit/ ohne RVD. Aufgrund der Heterogenität der Erkrankung sowie der Begleiterkrankungen besteht für beide Scores nur eine moderate Trennschärfe, sie dürfen beim individuellen Patienten nicht einziges Entscheidungskriterium sein. Denkbar wäre, durch einen „machine learning“ Ansatz unter Einbeziehung klinischer, anatomischer, demographischer und laborchemischer Daten ein Score System zu entwerfen, mit dem eine höhere prognostische Genauigkeit erreicht werden könnte.
Objective: The DIRAS2 gene is associated with ADHD, but its function is largely unknown. Thus, we aimed to explore the genes and molecular pathways affected by DIRAS2. Method: Using short hairpin RNAs, we downregulated Diras2 in murine hippocampal primary cells. Gene expression was analyzed by microarray and affected pathways were identified. We used quantitative real-time polymerase chain reaction (qPCR) to confirm expression changes and analyzed enrichment of differentially expressed genes in an ADHD GWAS (genome-wide association studies) sample. Results: Diras2 knockdown altered expression of 1,612 genes, which were enriched for biological processes involved in neurodevelopment. Expression changes were confirmed for 33 out of 88 selected genes. These 33 genes showed significant enrichment in ADHD patients in a gene-set-based analysis. Conclusion: Our findings show that Diras2 affects numerous genes and thus molecular pathways that are relevant for neurodevelopmental processes. These findings may further support the hypothesis that DIRAS2 is linked to etiological processes underlying ADHD. (J. of Att. Dis. 2021; 25(4) 572-583).
The capacity of convalescent and vaccine-elicited sera and monoclonal antibodies (mAb) to neutralize SARS-CoV-2 variants is currently of high relevance to assess the protection against infections. We performed a cell culture-based neutralization assay focusing on authentic SARS-CoV-2 variants B.1.617.1 (Kappa), B.1.617.2 (Delta), B.1.427/B.1.429 (Epsilon), all harboring the spike substitution L452R. We found that authentic SARS-CoV-2 variants harboring L452R had reduced susceptibility to convalescent and vaccine-elicited sera and mAbs. Compared to B.1, Kappa and Delta showed a reduced neutralization by convalescent sera by a factor of 8.00 and 5.33, respectively, which constitutes a 2-fold greater reduction when compared to Epsilon. BNT2b2 and mRNA1273 vaccine-elicited sera were less effective against Kappa, Delta, and Epsilon compared to B.1. No difference was observed between Kappa and Delta towards vaccine-elicited sera, whereas convalescent sera were 1.51-fold less effective against Delta, respectively. Both B.1.617 variants Kappa (+E484Q) and Delta (+T478K) were less susceptible to either casirivimab or imdevimab. In conclusion, in contrast to the parallel circulating Kappa variant, the neutralization efficiency of convalescent and vaccine-elicited sera against Delta was moderately reduced. Delta was resistant to imdevimab, which, however, might be circumvented by combination therapy with casirivimab together.
Background: Inflammation is essential for the pathogenesis of multiple sclerosis (MS). While the immune system contribution to the development of neurological symptoms has been intensively studied, inflammatory biomarkers for mental symptoms such as depression are poorly understood in the context of MS. Here, we test if depression correlates with peripheral and central inflammation markers in MS patients as soon as the diagnosis is established. Methods: Forty-four patients were newly diagnosed with relapsing-remitting MS, primary progressive MS or clinically isolated syndrome. Age, gender, EDSS, C-reactive protein (CRP), albumin, white blood cells count in cerebrospinal fluid (CSF WBC), presence of gadolinium enhanced lesions (GE) on T1-weighted images and total number of typical MS lesion locations were included in linear regression models to predict Beck Depression Inventory (BDI) score and the depression dimension of the Symptoms Checklist 90-Revised (SCL90RD). Results: CRP elevation and GE predicted significantly BDI (CRP: p = 0.007; GE: p = 0.019) and SCL90RD (CRP: p = 0.004; GE: p = 0.049). The combination of both factors resulted in more pronounced depressive symptoms (p = 0.04). CSF WBC and EDSS as well as the other variables were not correlated with depressive symptoms. Conclusions: CRP elevation and GE are associated with depressive symptoms in newly diagnosed MS patients. These markers can be used to identify MS patients exhibiting a high risk for the development of depressive symptoms in early phases of the disease.
Genes encoding endocannabinoid and sphingolipid metabolism pathways were suggested to contribute to the genetic risk towards attention deficit hyperactivity disorder (ADHD). The present pilot study assessed plasma concentrations of candidate endocannabinoids, sphingolipids and ceramides in individuals with adult ADHD in comparison with healthy controls and patients with affective disorders. Targeted lipid analyses of 23 different lipid species were performed in 71 mental disorder patients and 98 healthy controls (HC). The patients were diagnosed with adult ADHD (n = 12), affective disorder (major depression, MD n = 16 or bipolar disorder, BD n = 6) or adult ADHD with comorbid affective disorders (n = 37). Canonical discriminant analysis and CHAID analyses were used to identify major components that predicted the diagnostic group. ADHD patients had increased plasma concentrations of sphingosine-1-phosphate (S1P d18:1) and sphinganine-1-phosphate (S1P d18:0). In addition, the endocannabinoids, anandamide (AEA) and arachidonoylglycerol were increased. MD/BD patients had increased long chain ceramides, most prominently Cer22:0, but low endocannabinoids in contrast to ADHD patients. Patients with ADHD and comorbid affective disorders displayed increased S1P d18:1 and increased Cer22:0, but the individual lipid levels were lower than in the non-comorbid disorders. Sphingolipid profiles differ between patients suffering from ADHD and affective disorders, with overlapping patterns in comorbid patients. The S1P d18:1 to Cer22:0 ratio may constitute a diagnostic or prognostic tool.
Pathologic data indicate that human cytomegalovirus (HCMV) infection might be associated with the pathogenesis of several human malignancies. However, no definitive evidence of a causal link between HCMV infection and cancer dissemination has been established to date. This study describes the modulation of the invasive behavior of NCAM-expressing tumor cell lines by HCMV. Neuroblastoma (NB) cells, persistently infected with the HCMV strain AD169 (UKF-NB-4AD169 and MHH-NB-11AD169), were added to endothelial cell monolayers and adhesion and penetration kinetics were measured. The 140- and 180-kDa isoforms of the adhesion receptor NCAM were evaluated by flow cytometry, Western blot, and reverse transcriptionpolymerase chain reaction (RT-PCR). The relevance of NCAM for tumor cell binding was proven by treating NB with NCAM antisense oligonucleotides or NCAM transfection. HCMV infection profoundly increased the number of adherent and penetrated NB, compared to controls. Surface expression of NCAM was significantly lower on UKF-NB-4AD169 and MHH-NB-11AD169, compared to mock-infected cells. Western-blot and RT-PCR demonstrated reduced protein and RNA levels of the 140- and 180-kDa isoform. An inverse correlation between NCAM expression and adhesion capacity of NB has been shown by antisense and transfection experiments. We conclude that HCMV infection leads to downregulation of NCAM receptors, which is associated with enhanced tumor cell invasiveness.
Im EU-Projekt „Regulatory Control Networks of Synthetic Lethality“ (SYNLET) wurden durch Vergleich der Genexpressionsprofile auf Transkriptionsebene von parentalen sensitiven Neuroblastom-Zelllinien und ihren Vincristin-resistenten Sublinien bioinformatisch 40 Kandidatengene ermittelt, die für Vincristin-Resistenz und damit Zellüberleben essentiell sein könnten. Diese Kandidatengene wurden im Rahmen dieser Dissertation einzeln in Neuroblastomzellen der Vincristin-resistenten Sublinie UKF-NB-2rVCR20 herunterreguliert durch Transfektion (Elektroporation) von small interfering RNAs (siRNAs; knock down). Anschließend wurden die Zellen ohne und mit verschiedenen Vincristin-Konzentrationen auf Zellviabilitätsveränderungen getestet. Beim Kandidatengen mit den niedrigsten Zellviabilitäten (SMARCC1) wurde ein Western Blot gemacht, um die Herunterregulierung zu bestätigen. Zu Beginn wurde das effektivste Programm zur Elektroporation der UKF-NB-2rVCR20-Zellen durch eine Transfektionsoptimierung ermittelt. Alle Kandidatengene wurden 2x transfiziert, bei unklaren oder besonders interessanten Ergebnissen auch 3x. Als positive Kontrolle wurde der ABC-Transporter MDR1 herunterreguliert, da hier die Auswirkungen auf die Resistenz gegen Vincristin bekannt sind. Bei 10 von 40 Kandidatengenen waren die Zellviabilitäten ohne Vincristin und/oder bei mindestens einer Vincristin-Konzentration extrem verändert (FOXJ1, MAP2K1, NFYB, RICS, SMARCA1, SMARCB1, SMARCC1, STK35, TOCA1 und TPM2). Das entspricht einem Prozentsatz von 25 % Kandidatengenen, bei denen die bioinformatisch vorhergesagte Wirkung in vitro bestätigt werden konnte. Allerdings sind bei diesen 10 effektiven Kandidatengenen auch 2 Gene dabei, nach deren Herunterregulierung es zu einer erhöhten Zellviabilität kam (FOXJ1 und RICS). Bei der Frage, welche Gene das Absterben der Tumorzellen beschleunigen und als ein mögliches Therapieziel in Frage kommen könnten, bleiben also 8 Kandidatengene (20 % aller Kandidatengene). Das interessanteste Kandidatengen ist SMARCC1, da die Herunterregulierung alleine (ohne Zugabe von Vincristin) zu einer massiven Abnahme der Zellviabilität führte. Damit stellt SMARCC1 ein interessantes Ziel zur Therapie in Tumorzellen dar.
Traumatische Verletzungen fordern jährlich über fünf Millionen Todesopfer. Sie sind bei unter 45-Jährigen die häufigste Ursache für Tod und körperliche Behinderung dar. Ein Polytrauma verursacht eine schwere Belastung für das Immunsystem und ist häufig von schweren Störungen der Immunregulation gekennzeichnet. Die Immunreaktion übersteigt bei schweren Traumata das für lokale Reparaturmechanismen notwendige Maß, und so kommt es je nach Ausmaß der Verletzungen innerhalb der ersten Minuten bis Stunden zu einer systemischen Hyperinflammation, dem sogenannten Systemischen Inflammatorischen Response- Syndrom (SIRS). Auch in nicht verletzten Organen verursacht SIRS Störungen in der Endothel-Funktion, wodurch die Mikrozirkulation in diesen Organgen beeinträchtigt ist. In der Folge kommt es zu interstitieller Ödembildung, zur Gewebsinfiltration durch Leukozyten und zu Zelluntergang. Diese Prozesse können zur Fehlfunktion von Organen bis hin zum Organversagen, und, da sie häufig in mehreren Organen gleichzeitig ablaufen, auch zum klinisch dann oft schwer beherrschbaren Multiorganversagen (MOV) führen. Auf der anderen Seite stoßen schwere Verletzungen antiinflammatorische Prozesse an, die zu einer ausgeprägten Immunsuppression führen können, dem Kompensatorischen Antiinflammatorischen Response-Syndrom (CARS), mit der Folge, dass polytraumatisierte Patienten erhöht anfällig für infektiöse Komplikationen sind. Die beschriebenen Funktionsstörungen des Immunsystems sind ein wichtiger Mortalitätsfaktor von polytraumatisierten Patienten. Während wir SIRS und seine Folgen über die letzten Jahre immer besser verstehen, mit signifikanten Fortschritten auch für die klinische Handhabung dieser Komplikationen des Polytraumas, ist CARS weit schlechter untersucht.
Während der post-traumatschen Immunantwort spielen nicht nur Zellen der angeborenen, sondern auch solche der erworbenen Immunabwehr eine wichtige Rolle. So sind regulatorische T-Zellen (Treg) entscheidend an der posttraumatischen Immunsuppression beteiligt. Treg beeinflussen die immunologische Homöostase Treg mit einem Arsenal immunsuppressiver Werkzeuge. Sie töten oder beeinflussen beispielsweise antigenpräsentierende Zellen oder T-Effektorzellen und verändern das Zytokinmilieu und metabolische Signalwege. Nach einem Trauma kann eine überschießende Aktivität von Treg die immunologische Balance so beeinträchtigen, dass eine posttraumatische Immunsuppression entsteht oder intensiviert wird. Die hier vorgestellte Studie Ziel dient daher dem besseren Verständnis der Dynamik von Treg nach einer stattgehabten traumatischen Verletzung. Dafür untersuchten wir die Verläufe verschiedener Subpopulationen von Treg im Blut schwer verletzter Patienten. Da der Forschung am Menschen in vivo enge ethische und methodologische Grenzen gesetzt sind, nehmen Tiermodelle in der Traumaforschung einen hohen Stellenwert ein. Daher verglichen wir die an Patienten erhobenen Daten über die posttraumatische Dynamik von Treg mit den Verläufen in einem adäquaten Tiermodell.
Aufgrund der guten anatomischen, physiologischen und genetischen Ähnlichkeit zum Menschen werden Tiermodelle am Schwein zunehmend beliebter. Ein Polytraumamodell am Schwein existiert erst seit wenigen Jahren. Über Treg wurde in diesem Rahmen bisher nicht geforscht. Die Charakterisierung ihres Immunphänotyps und ihrer Dynamik könnte die Anwendbarkeit des Schweine-Modells für Fragen der Trauma-Forschung verbessern und gleichzeitig unser Verständnis der Pathophysiologie posttraumatischer Komplikationen wir SIRS oder Sepsis erhöhen.
Bei 20 Traumapatienten (TP) mit einem Injury Severity Score (ISS) ≥ 16 wurde bei Ankunft in der Notaufnahme, nach einem und nach drei Tagen venöses Blut entnommen. Zehn gesunde Freiwillige (HV) fungierten in der Studie als Kontrollgruppe. Das Polytrauma im Großtiermodell am Schwein bestand aus einer Femurfraktur, einer Leberlazeration, einer Lungenkontusion und einem hämorrhagischen Schock, was einen ISS von 27 ergab. Auf die Traumainduktion folgte die Reanimationsphase und die chirurgische Versorgung der Femurfraktur nach dem damage-control-Prinzip. Die Blutentnahmen erfolgten bei den Versuchstieren vor und sofort nach Trauma, sowie nach 24 und 72 Stunden. Wir verglichen die Dynamik der Verläufe der Treg von TP mit denen von HV und mit Daten aus den Tierversuchen. Es herrscht noch kein wissenschaftlicher Konsens darüber, welche Kombination aus immunologischen Oberflächenmarkern die Identifikation von Treg zuverlässig gewährleisten kann. Dies liegt auch daran, dass Treg eine Gruppe verschiedener Unterpopulationen darstellen. Folglich analysierten wir verschiedene Kombinationen. Wir färbten Cluster of differentiation (CD) 4-positive und CD25-positive (CD4+CD25+), CD4+CD25+forkhead box P3 (FoxP3)+, CD4+CD25+CD127-negative (CD127−) und CD4+CD25+CD127−FoxP3+ Zellen mit Antikörpern und charakterisierten die jeweilige Gruppe mithilfe der Durchflusszytometrie. CD4+CD25+CD127− Treg sind beim Menschen bekannt. Beim Schwein werden sie in dieser Studie erstmalig beschrieben.
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Serum GFAP for stroke diagnosis in regions with limited access to brain imaging (BE FAST India)
(2021)
Introduction: Despite a high burden of stroke, access to rapid brain imaging is limited in many middle- and low-income countries. Previous studies have described the astroglial protein GFAP (glial fibrillary acidic protein) as a biomarker of intracerebral hemorrhage. The aim of this study was to test the diagnostic accuracy of GFAP for ruling out intracranial hemorrhage in a prospective cohort of Indian stroke patients. Patients and methods: This study was conducted in an Indian tertiary hospital (Christian Medical College, Ludhiana). Patients with symptoms suggestive of acute stroke admitted within 12 h of symptom onset were enrolled. Blood samples were collected at hospital admission. Single Molecule Array technology was used for determining serum GFAP concentrations. Results: A total number of 155 patients were included (70 intracranial hemorrhage, 75 ischemic stroke, 10 stroke mimics). GFAP serum concentrations were elevated in intracranial hemorrhage patients compared to ischemic stroke patients [median (interquartile range) 2.36 µg/L (0.61–7.16) vs. 0.18 µg/L (0.11–0.38), p < 0.001]. Stroke mimics patients had a median GFAP serum level of 0.14 µg/L (0.09–0.26). GFAP values below the cut-off of 0.33 µg/L (area under the curve 0.871) ruled out intracranial hemorrhage with a negative predictive value of 89.7%, (at a sensitivity for detecting intracranial hemorrhage of 90.0%). Discussion: The high negative predictive value of a GFAP test system allows ruling out patients with intracranial hemorrhage. Conclusion: In settings where immediate brain imaging is not available, this would enable to implement secondary prevention (e.g., aspirin) in suspected ischemic stroke patients as soon as possible.
Die NOD.α4-/- Maus ist eine auf hämatopoetische Zellen beschränkt α4-inkompetente Maus auf dem NOD Hintergrund. Die Maus ist vollständig gegen Diabetes gefeit, entwickelt keine Insulitis und keine Sialitis. Analysen der α- und ß-Diversität des Mikrobioms zeigen eine vergleichbare Zusammensetzung in NOD.α4-/- und NOD Kontrollmaus, während erkrankte Mäuse ein auffällig eingeschränktes Mikrobiom und atypische Spezies aufweisen. Inselzellantigen-spezifische CD8+ T-Zellen und anti-Insulin-Autoantikörper sind quantitativ stark vermindert im Vergleich zu NOD Kontrollen, jedoch sicher nachweisbar. Das 5-Linien-Differenzialblutbild ist absolut und relativ unauffällig. Die NOD.α4-/- Maus entwickelt nach adoptivem Transfer von CD3+ Zellen diabetischer NOD-Spender mit kurzer Latenz und 100%iger Penetranz Diabetes, ein isolierter Transfer diabetogener CD4+ Zellen ist hierzu nicht hinreichend. α4-kompetente CD8+ Zellen sind also unerlässlich für den adoptiven Transfer von Diabetes in die NOD.α4-/- Maus. Rekonstitution prädiabetischer wildtypischer NOD Empfänger mit NOD.α4-/- Hämatopoese schützt diese zuverlässig vor dem Progress der Insulitis zum Diabetes. Diese Arbeit unterstreicht und sichert die bisherigen α4-Antikörper Studien in der NOD Maus und korrigiert die Annahme, α4-Blockade schütze nicht vor dem Voranschreiten der Sialitis. NOD.a4-/- Lymphozyten werden regelrecht gegen Autoantigene sensibilisiert, in Ermangelung effektiver Infiltration der Zielorgane bleibt jedoch die Expansion antigenspezifischer T-zellen und das Boosten von humoralen Autoimmunantworten aus. α4-inkompetente Leukozyten migrieren auch nach Beginn einer Insulitis oder damit einhergehender Hochregulierung verschiedenster endothelialer Oberflächenproteine nicht in die entzündeten Langerhans-Inseln. Die sichere Prävention der Erkrankung durch Rekonstitution mit α4-/- Hämatopoese identifiziert die α4-Blockade als mögliche Therapie des Typ 1 Diabetes während der Phase des Prädiabetes.
Differentialdiagnostik der frühen primären Myelofibrose (präPMF) gemäß der neuen WHO-Klassifikation
(2020)
Die vorliegende Arbeit stützt sich auf die retrospektive Begutachtung von 348 Knochenmarkbiopsien, welche anhand der WHO-Klassifikation von 2016 erneut reevaluiert wurden. Insbesondere widmeten wir uns der Differentialdiagnostik der „echten ET“ und der thrombozythämisch verlaufenden Form der PMF (präPMF). Die Einteilung erfolgte anhand morphologischer Kriterien, wie sie in der WHO-Klassifikation von 2016 aufgeführt sind.
Zusammengefasst ist eine richtungsweisende diagnostische Entscheidung der Patienten mit ET und präPMF nur möglich, wenn man sowohl die molekulargenetischen und klinischen Parameter in Kombination mit histologischen Kriterien und deren charakteristischen Mustern betrachtet. Eine repräsentative Knochenmarkbiopsie und deren standardisierte Befundung ist daher von absoluter diagnostischer Wichtigkeit für die Subtypisierung der MPN. Augenmerk sollte auf das typisch dargebotene morphologische Muster gelegt werden und nicht auf einzelne Merkmale. Die vorliegende Knochenmarkbiopsie muss nicht, wie früher praktiziert, anhand vieler einzelner Merkmale detailliert betrachtet und bewertet werden. Durch eine kombinierte Betrachtung von nur wenigen morphologischen Schlüsselparametern ist bereits eine Diagnose mit hoher Reproduzierbarkeit möglich. Mit dieser Arbeit wird der Stellenwert der WHO-Klassifikation unterstrichten, da die hier vorgegebenen Kriterien absolut essentiell und trotzdem in ihrem Umfang ausreichend sind, um die Differentialdiagnostik der MPN in Zukunft zu verbessern.
In der vorliegenden Studie sollte der Einfluss eines systematischen Krafttrainings auf die ergonomische Arbeitsweise und die ergonomische Risikobeurteilung von Zahnärzten und Zahnmedizinischen Fachangestellten anhand objektiver Daten untersucht werden. Dafür wurden 22 Probanden rekrutiert. An der Studie nahmen 13 ZÄ, 7 ZFAs und 2 Studenten der Zahnmedizin teil. Als Einschlusskriterium wurden Beschwerden im Rücken- und/oder Nacken- und/oder Schulterbereich innerhalb der letzten zwölf Monaten definiert. In den Einrichtungen des Instituts für Arbeitsmedizin, Sozialmedizin und Umweltmedizin des Universitätsklinikums Frankfurt am Main (Deutschland) fanden biomechanische Prä- und Postmessungen der ergonomischen Arbeitsweise statt. Die Messungen erfolgten mit dem inertialen Messsystem MVN BIOMECH Link der Firma XSens (Enschede, Niederlande). Die Probanden arbeiteten während der Messung an einer ihnen vertrauten Behandlungseinheit und behandelten am Phantomkopf in einer ihrer Fachrichtung entsprechenden Behandlungssimulation bestehend aus praxisnahen zahnmedizinischen Aufgaben. Zwischen der Prä- und Postmessung absolvierten die Probanden eine 10- bis 12-wöchige, systematische Krafttrainingsintervention mit zwei einstündigen Trainingseinheiten pro Woche. Für das Training wurden Übungen zur Kräftigung der stabilisierenden Haltemuskulatur ausgewählt, insbesondere im Rücken, Nacken, Schultern und Rumpf, entsprechend den vorherrschenden Regionen muskuloskelettaler Beschwerden unter ZÄ und ZFAs. Das Training wurde in Kleingruppen von den Untersuchern betreut.
Die erhobenen kinematischen Daten der biomechanischen Messungen wurden im Programm Matlab (MATrix LABoratory) auf Grundlage der gemessenen Gelenkwinkel und -positionen sowie des angepassten RULA Arbeitsbogens ausgewertet. Die statistische Auswertung erfolgte mit den Programmen BiAS Version 11.12 (Epsilon Verlag, Darmstadt, Deutschland, 2020) und IBM SPSS Statistics Version 26 (IBM, New York, USA, 2019). Die erhobenen RULA Parameter wurden mit dem Wilcoxon-Matched-Pairs Test statistisch ausgewertet. Die erhobenen Gelenkwinkel wurden mithilfe des Systematic Parametric Mapping statistisch überprüft. Das Signifikanzniveau lag bei 5%.
Die vorliegende Studie konnte anhand objektiver Daten die Ergebnisse vorheriger Autoren bestätigen, dass ZÄ und ZFAs oftmals mit vorgebeugtem Nacken und Oberkörper arbeiten, während diese z.T. zusätzlich noch rotiert und/oder seitlich gebeugt sind.
Besonders der Nacken weicht bei der Arbeit stark von einer neutralen Haltung ab. Mit den oberen Extremitäten arbeiten die Behandler oftmals asymmetrisch. Der rechte Oberarm ist stärker angehoben und abduziert als der linke und weicht stärker von einer neutralen Haltung ab. Mit den Unterarmen arbeiten ZÄ und ZFAs oftmals exzentrisch über die Körpermitte hinaus bzw. außerhalb ihrer Körpermitte. Die Handgelenke sind zumeist stark angewinkelt und zeigen eine deutliche Radialdeviation. Die ergonomische Arbeitsweise von zahnmedizinischem Personal konnte anhand dieser Studie als gesundheitlich hoch risikobehaftet eingestuft werden. Besonders die Nackenregion, die Unterarme sowie die beiden Handgelenke konnten anhand der objektiven Daten als Risikobereiche ausgemacht werden. Der Einfluss des systematischen Krafttrainings wurde im Prä-Post-Vergleich anhand der kinematischen Daten überprüft. Die gemessenen Gelenkwinkel und -positionen zeigten sich nach der Trainingsintervention größtenteils unverändert oder zeigten keine Verbesserung hin zu neutralen Gelenkwinkeln. Dies suggeriert, dass ein 10-12 wöchiges systematisches Krafttraining nicht oder nur begrenzt zu einer aufrechteren, entspannten und symmetrischeren Arbeitshaltung führt wie sie für die zahnmedizinischen Berufe gefordert wird. Der Einfluss des systematischen Krafttrainings wurde ebenfalls bezüglich der ergonomische Risikobeurteilung durch RULA im Prä-Post-Vergleich überprüft. Für die Gesamtbewertung der Arbeitsweise konnte statistisch keine signifikante (p≥ 0,05) Veränderung und deskriptiv keine Verbesserung nachgewiesen werden. Auch im Vergleich der ergonomischen Risikobeurteilung der einzelnen Körperregionen zeigte nur der Nacken eine statistisch signifikante Veränderung (p ≤ 0,05). Für ihn konnte bestätigt werden, dass ein systematisches Krafttraining zu einer wenn auch geringen verbesserten objektiven Bewertung der ergonomischen Arbeitsweise und weniger Arbeitszeit in gesundheitlich riskanten ergonomischen Arbeitsweisen führt.
Mit dieser Studie konnte anhand objektiver Daten das hohe gesundheitliche Risiko zahnmedizinischer Berufe und ihrer ergonomischen Arbeitsweise bestätigt werden. Ein systematisches 10- bis 12-wöchiges Krafttraining zeigte zumeist keinen Einfluss bzw. keine Verbesserung bezüglich der ergonomischen Arbeitsweise. Die Studienergebnisse stellen in Frage, in wie fern sich die Arbeitshaltung in zahnärztlichen Berufen durch verhaltenspräventive Maßnahmen wie körperliches Training beeinflussen lassen.
The scope of extracorporeal membrane oxygenation (ECMO) is expanding, nevertheless, pharmacokinetics in patients receiving cardiorespiratory support are fairly unknown leading to unpredictable drug concentrations. Currently, there are no clear guidelines for antibiotic dosing during ECMO. This study aims to evaluate the pharmacokinetics (PK) of cefazolin in patients undergoing ECMO treatment. Total and unbound plasma cefazolin concentration of critically ill patients on veno-arterial ECMO were determined. Observed PK was compared to dose recommendations calculated by an online available, free dosing software. Concentration of cefazolin varied broadly despite same dosage in all patients. The mean total and unbound plasma concentration were high showing significantly (p = 5.8913 E−09) greater unbound fraction compared to a standard patient. Cefazolin clearance was significantly (p = 0.009) higher in patients with preserved renal function compared with CRRT. Based upon the calculated clearance, the use of dosing software would have led to lower but still sufficient concentrations of cefazolin in general. Our study shows that a “one size fits all” dosing regimen leads to excessive unbound cefazolin concentration in these patients. They exhibit high PK variability and decreased cefazolin clearance on ECMO appears to compensate for ECMO- and critical illness-related increases in volume of distribution.
Zielsetzung: Das Ziel dieser Arbeit war die Beurteilung der diagnostischen Leistungsfähigkeit der virtuellen Noncalcium (VNCa) Dual-Energy-Computertomographie (DECT) für den Nachweis lumbaler Bandscheibenvorfälle im Vergleich zu der konventionellen Graustufen-Computertomographie. Dabei galt die Magnetresonanztomographie (MRT) als Referenzstandard.
Material und Methodik: Für diese retrospektive Studie wurden 41 Patienten (243 Bandscheiben; Durchschnittsalter 68 Jahre; 24 Frauen [Durchschnittsal-ter, 68 Jahre] und 17 Männer [Durchschnittsalter, 68 Jahre]) zwischen März 2017 und Januar 2018 einer klinisch indizierten DECT, durchgeführt mit einem Dual-Source-Computertomographie (DSCT)-Scanner der dritten Generation (Somatom Force; Siemens Healthineers, Forchheim, Deutschland) sowie einer 3.0-Tesla MRT (Magnetom PrismaFit; Siemens Healthineers, Forchheim, Deutschland) im Abstand von maximal zwei Wochen unterzogen. Sechs Radiologen, verblindet hinsichtlich der klinischen und MRT-Informationen, untersuchten unabhängig voneinander die konventionellen Graustufen-DECT-Bildserien auf das Vorhandensein und den Grad eines Bandscheibenvorfalls sowie der Affektion der Spinalnervenwurzeln. Nach acht Wochen wurden die Bildserien von den gleichen sechs Untersuchern unter Verwendung von farbkodierten VNCa-Rekonstruktionen neu ausgewertet. Die MRT, die von zwei unabhängigen, erfahrenen und in Bezug auf klinische und DECT-Informationen verblindeten Radiologen ausgewertet wurde, diente dabei als Referenzstandard. Sensitivität und Spezifität waren die wichtigsten Kennzahlen der Diagnoseleistung.
Ergebnisse: Insgesamt wurden 112 Bandscheibenvorfälle der Lendenwirbelsäule in der MRT erfasst. VNCa zeigte insgesamt eine höhere Sensitivität (612 von 672 [91%] versus (vs.) 534 von 672 [80%]) und Spezifität (723 von 786 [92%] vs. 665 von 786 [85%]) zur Detektion eines lumbalen Bandscheibenvorfalls im Vergleich zur Standard-Computertomographie (CT) (alle Vergleiche, P < 0.001). Die Interrater-Reliabilität war „exzellent“ für VNCa und „gut“ für die Standard-CT (k = 0,82 vs. 0,67; P < 0.001). VNCa erreichte im Vergleich zum Standard-CT eine überlegene Diagnosesicherheit und Bildqualität bei niedrigerem Bildrauschen (alle Vergleiche, P < 0.001).
Schlussfolgerung: Farbkodierte Dual-Energy CT VNCa-Rekonstruktionen zeigen im Vergleich zur Standard-CT eine signifikant bessere diagnostische Genauigkeit und Sicherheit für die Detektion eines lumbalen Bandscheibenvorfalls.
Autophagy is a highly conserved catabolic process through which defective or otherwise harmful cellular components are targeted for degradation via the lysosomal route. Regulatory pathways, involving post-translational modifications such as phosphorylation, play a critical role in controlling this tightly orchestrated process. Here, we demonstrate that TBK1 regulates autophagy by phosphorylating autophagy modifiers LC3C and GABARAP-L2 on surface-exposed serine residues (LC3C S93 and S96; GABARAP-L2 S87 and S88). This phosphorylation event impedes their binding to the processing enzyme ATG4 by destabilizing the complex. Phosphorylated LC3C/GABARAP-L2 cannot be removed from liposomes by ATG4 and are thus protected from ATG4-mediated premature removal from nascent autophagosomes. This ensures a steady coat of lipidated LC3C/GABARAP-L2 throughout the early steps in autophagosome formation and aids in maintaining a unidirectional flow of the autophagosome to the lysosome. Taken together, we present a new regulatory mechanism of autophagy, which influences the conjugation and de-conjugation of LC3C and GABARAP-L2 to autophagosomes by TBK1-mediated phosphorylation.
Peri-implantitis: summary and consensus statements of group 3. The 6th EAO Consensus Conference 2021
(2021)
Objective: To evaluate the influence of implant and prosthetic components on peri-implant tissue health. A further aim was to evaluate peri-implant soft-tissue changes following surgical peri-implantitis treatment. Materials and methods: Group discussions based on two systematic reviews (SR) and one critical review (CR) addressed (i) the influence of implant material and surface characteristics on the incidence and progression of peri-implantitis, (ii) implant and restorative design elements and the associated risk for peri-implant diseases, and (iii) peri-implant soft-tissue level changes and patient-reported outcomes following peri-implantitis treatment. Consensus statements, clinical recommendations, and implications for future research were discussed within the group and approved during plenary sessions. Results: Data from preclinical in vivo studies demonstrated significantly greater radiographic bone loss and increased area of inflammatory infiltrate at modified compared to non-modified surface implants. Limited clinical data did not show differences between modified and non-modified implant surfaces in incidence or progression of peri-implantitis (SR). There is some evidence that restricted accessibility for oral hygiene and an emergence angle of >30 combined with a convex emergence profile of the abutment/prosthesis are associated with an increased risk for peri-implantitis (CR). Reconstructive therapy for peri-implantitis resulted in significantly less soft-tissue recession, when compared with access flap. Implantoplasty or the adjunctive use of a barrier membrane had no influence on the extent of peri-implant mucosal recession following peri-implantitis treatment (SR).
Background: Understanding which factors influence dietary intake, particularly in daily life, is crucial given the impact diet has on physical as well as mental health. However, a factor might influence whether but not how much an individual eats and vice versa or a factor’s importance may differ across these two facets. Distinguishing between these two facets, hence, studying dietary intake as a dual process is conceptually promising and not only allows further insights, but also solves a statistical issue. When assessing the association between a predictor (e.g. momentary affect) and subsequent dietary intake in daily life through ecological momentary assessment (EMA), the outcome variable (e.g. energy intake within a predefined time-interval) is semicontinuous. That is, one part is equal to zero (i.e. no dietary intake occurred) and the other contains right-skewed positive values (i.e. dietary intake occurred, but often only small amounts are consumed). However, linear multilevel modelling which is commonly used for EMA data to account for repeated measures within individuals cannot be applied to semicontinuous outcomes. A highly informative statistical approach for semicontinuous outcomes is multilevel two-part modelling which treats the outcome as generated by a dual process, combining a multilevel logistic/probit regression for zeros and a multilevel (generalized) linear regression for nonzero values. Methods: A multilevel two-part model combining a multilevel logistic regression to predict whether an individual eats and a multilevel gamma regression to predict how much is eaten, if an individual eats, is proposed. Its general implementation in R, a widely used and freely available statistical software, using the R-package brms is described. To illustrate its practical application, the analytical approach is applied exemplary to data from the Eat2beNICE-APPetite-study. Results: Results highlight that the proposed multilevel two-part model reveals process-specific associations which cannot be detected through traditional multilevel modelling. Conclusions: This paper is the first to introduce multilevel two-part modelling as a novel analytical approach to study dietary intake in daily life. Studying dietary intake through multilevel two-part modelling is conceptually as well as methodologically promising. Findings can be translated to tailored nutritional interventions targeting either the occurrence or the amount of dietary intake.
Das Hepatozelluläre Karzinom (HCC) steht weltweit an dritter Stelle tumorbedingter Todesursachen. Eine kurative Therapie durch Leberresektion oder Transplantation ist nur dann Erfolg versprechend, wenn der Patient in einem frühen Stadium diagnostiziert wird, in dem noch keine Fernmetastasen oder Gefäßinvasionen vorliegen. Die Ausbildung von Mikrometastasen sind mittels Bildgebung nicht detektierbar.
Mit Hilfe der „liquid biopsy“, einem Blutanalyseverfahren, das sich auf die Detektion zirkulierender Tumorzellen (CTCs) im Patientenblut fokussiert, ist es m glich, diese Tumorzellen im Anschluss an ihre Isolation auf ihre molekularen Eigenschaften hin zu untersuchen. Im Laufe des Metastasierungsprozesses kommt es zur De- und Repolarisierung der CTCs.
In der vorliegenden Promotionsarbeit wurde ein immunologisches Verfahren zur Detektion polarisierter Tumorzellen (p-CTCs) im Blut von Patienten mit HCC entwickelt. Dazu erfolgte zunächst die Isolation der CTCs mittels Dichtegradientverfahren (Oncoquick@, Fa. Greiner
bio-one) und die anschließende Immunfluoreszenzfärbung der CTCs mittels Anti-Ezrin-Alexa- Fluor 488 zum strukturellen Nachweis des zytoskelletalen Membranproteins Ezrin.
Anhand der Lokalisation des Ezrin innerhalb der CTCs war es m glich, die CTCs in polarisierte(p-CTC) und nicht-polarisierte Zellen (non-polarized CTC) zu unterteilen. Mit diesem Verfahren konnten in einem Zeitraum von Juni 2018 bis Januar 2019 Blutproben (5 ml/Patient) von 15 Patienten mit HCC und von 10 Patienten mit einer nicht malignen Lebererkrankung (NMLD) untersucht werden.
Die häufigste Grunderkrankung war mit 30,43% (n=7) C2 Abusus, gefolgt von der NASH mit 26% (n=6) und DM Typ 2 mit Leberzirrhose mit 13,04% (n=2). 10 (66,6%) HCC-Patienten hatten eine Leberzirrhose. Bei einem Patienten war die Tumorgröße <2 cm, bei 7 Patienten zwischen 2-5 cm, und 7 Patienten hatten eine Tumorgröße von > 5 cm. Die meisten Patienten hatten ein BCLC-Stadium C (n=7), gefolgt von BCLC-Stadium B (n=4), und BCLC-Stadium D (n=3) und nur ein Patient hatte ein BCLC-Stadium 0.
In 14 (93,3%) HCC-Patienten konnten CTCs 1,2 CTCs/ml (0,4-3 CTCs/ml) nachgewiesen werden. Die Falsch-Positiv-Rate lag bei 0,2 isolierte Zelle/ml (p=0,0006). P-CTC konnten in 10/14(71%) HCC-Patienten identifiziert werden. Die HCC-Gruppe wies mit 0,42 p-CTCs/ml signifikant mehr p-CTCs als die NMLD-Patienten(0 p-CTCs/ml, p=0,002).
Eine negative Korrelation fand sich zwischen der Tumorgröße, BCLC-Stadium und der Anzahl polarisierter CTCs (r=-0,029, p=ns).
Die hier vorgestellten Daten zum Nachweis der Polarisierung von CTCs in Zusammenhang mit HCC könnten zukünftig eine Rolle in der molekularen Charakterisierung von CTCs und der
Diagnose des HCC darstellen.
Background: Treatment of acute stroke is highly time-dependent and performed by a multiprofessional, interdisciplinary team. Interface problems are expectable and issues relevant to patient safety are omnipresent. The Safety Attitudes Questionnaire (SAQ) is a validated and widely used instrument to measure patient safety climate. The objective of this study was to evaluate the SAQ for the first time in the context of acute stroke care. Methods: A survey was carried out during the STREAM trial (NCT 032282) at seven university hospitals in Germany from October 2017 to October 2018. The anonymous survey included 33 questions (5-point Likert scale, 1 = disagree to 5 = agree) and addressed the entire multiprofessional stroke team. Statistical analyses were used to examine psychometric properties as well as descriptive findings. Results: 164 questionnaires were completed yielding a response rate of 66.4%. 67.7% of respondents were physicians and 25.0% were nurses. Confirmatory Factor Analysis revealed that the original 6-factor structure fits the data adequately. The SAQ for acute stroke care showed strong internal consistency (α = 0.88). Exploratory analysis revealed differences in scores on the SAQ dimensions when comparing physicians to nurses and when comparing physicians according to their duration of professional experience. Conclusion: The SAQ is a helpful and well-applicable tool to measure patient safety in acute stroke care. In comparison to other high-risk fields in medicine, patient safety climate in acute stroke care seems to be on a similar level with the potential for further improvements. Trial registration: www.ClinicalTrials.gov Identifier: NCT032282.
BH3 mimetics are novel anticancer therapeutics that induce apoptosis by targeting anti‐apoptotic BCL‐2 proteins. Highly specific inhibitors of the main anti-apoptotic proteins BCL-2, BCL‐XL and MCL‐1 promise new opportunities for the treatment of AML. However, it is currently unclear which of these anti-apoptotic BCL-2 proteins represents the most promising target in AML. Therefore, we investigated the effect of BH3 mimetics targeting either BCL-2 (ABT-199, S55746), BCL-XL (A-1331852) or MCL-1 (S63845) on eleven AML cell lines. Drug sensitivity screening revealed heterogeneous sensitivity towards the different BH3 mimetics, with the best responses observed upon targeting of MCL-1. Selected cell lines that displayed sensitivity towards the specific BH3 mimetics underwent intrinsic apoptosis, which was characterized by loss of mitochondrial membrane potential, exposure of phosphatidylserine and activation of caspases. Furthermore, S63845 turned out to displace BIMS and NOXA from MCL-1 to induce apoptotic cell death. Importantly, the translational relevance of this study was demonstrated by experiments in primary AML blasts, which displayed similar sensitivity towards BH3 mimetics as the cell lines did. Additionally, experiments with nonmalignant cells could confirm the clinical relevance of the MCL-1 inhibitor. There we could show, that S63845 does not cause cytotoxicity on HPCs at efficacious doses.
In conclusion, our findings reveal that the inhibition of BCL-2 proteins, especially MCL-1, by BH3 mimetics can be a promising strategy in AML treatment.
Hematopoietic stem cell transplantation (HSCT) is widely used in pediatric patients as a successful curative therapy for life-threatening conditions. The treatment is intensive, with risks of serious complications and lethal outcomes. This study aimed to provide insight into current data on the place and cause of death of transplanted children, the available specialized pediatric palliative care services (SPPCS), and what services HSCT professionals feel the SPPCS team should provide. First, a retrospective database analysis on the place and cause of death of transplanted pediatric HSCT patients was performed. Second, a survey was performed addressing the availability of and views on SPPCS among HSCT professionals. Database analysis included 233 patients of whom the majority died in-hospital: 38% in the pediatric intensive care unit, 20% in HSCT units, 17% in other hospitals, and 14% at home or in a hospice (11% unknown). For the survey, 98 HSCT professionals from 54 centers participated. Nearly all professionals indicated that HSCT patients should have access to SPPCS, especially for pain management, but less than half routinely referred to this service at an early stage. We, therefore, advise HSCT teams to integrate advance care planning for pediatric HSCT patients actively, ideally from diagnosis, to ensure timely SPPCS involvement and maximize end-of-life preparation.
Platelets comprise a highly interactive immune cell subset of the circulatory system traditionally known for their unique haemostatic properties. Although platelets are considered as a vault of growth factors, cytokines and chemokines with pivotal role in vascular regeneration and angiogenesis, the exact mechanisms by which they influence vascular endothelial cells (ECs) function remain underappreciated. In the present study, we examined the role of human IL-17A/IL-17RA axis in platelet-mediated pro-angiogenic responses. We reveal that IL-17A receptor (IL-17RA) mRNA is present in platelets transcriptome and a profound increase is documented on the surface of activated platelets. By quantifying the protein levels of several factors, involved in angiogenesis, we identified that IL-17A/IL17RA axis selectively induces the release of vascular endothelial growth factor, interleukin -2 and -4, as well as monocyte chemoattractant protein -1 from treated platelets. However, IL-17A exerted no effect on the release of IL-10, an anti-inflammatory factor with potentially anti-angiogenic properties, from platelets. Treatment of human endothelial cell two-dimensional tubule networks or three-dimensional spheroid and mouse aortic ring structures with IL-17A-induced platelet releasate evoked pro-angiogenic responses of ECs. Our findings suggest that IL-17A may critically affect platelet release of pro-angiogenic factors driving ECs towards a pro-angiogenic state.
Study design: Systematic review. Background and objectives: Preoperative neuromuscular function is predictive for knee function and return to sports (RTS) after reconstruction of the anterior cruciate ligament (ACL). The aim of this review was to examine the potential benefits of prehabilitation on pre-/postoperative objective, self-reported and RTS-specific outcomes. Methods: A systematic search was conducted within three databases. From the 1.071 studies screened, two randomized control trials (RCTs), two control trials (CTs) and two cohort studies (CS) met the inclusion criteria. Methodological quality rating adopted the PEDro- (RCT, CT) or Newcastle-Ottawa-Scale (CS). Results and conclusions: Methodological quality of the included studies was moderate (PEDro score: 6.5 ± 1.7; range 4 to 9). Two studies reported higher increases of the maximal quadriceps torque from baseline to pre-reconstruction: one study in the limb symmetry index (LSI), and one in both legs of the prehabilitation group compared to the controls. At 12-weeks post-reconstruction, one study (from two) indicated that the prehabilitation group had a lesser post-operative decline in the single-leg-hop for distance LSI (clinically meaningful). Similar findings were found in terms of quadriceps strength LSI (one study). At both pre-reconstruction (three studies) and two-year post-surgery (two studies), the prehabilitation groups reached significantly higher self-reported knee function (clinically meaningful) than the controls. RTS tended to be faster (one study). At two years post-surgery, RTS rates (one study) were higher in the prehabilitation groups. The results provide evidence for the relevance of prehabilitation prior to ACL-reconstruction to improve neuromuscular and self-reported knee function as well as RTS. More high quality confirmatory RCTs are warranted.
Class I and II histone deacetylases (HDAC) are considered important regulators of immunity and inflammation. Modulation of HDAC expression and activity is associated with altered inflammatory responses but reports are controversial and the specific impact of single HDACs is not clear. We examined class I and II HDACs in TLR-4 signaling pathways in murine macrophages with a focus on IκB kinase epsilon (IKKε) which has not been investigated in this context before. Therefore, we applied the pan-HDAC inhibitors (HDACi) trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) as well as HDAC-specific siRNA. Administration of HDACi reduced HDAC activity and decreased expression of IKKε although its acetylation was increased. Other pro-inflammatory genes (IL-1β, iNOS, TNFα) also decreased while COX-2 expression increased. HDAC 2, 3 and 4, respectively, might be involved in IKKε and iNOS downregulation with potential participation of NF-κB transcription factor inhibition. Suppression of HDAC 1–3, activation of NF-κB and RNA stabilization mechanisms might contribute to increased COX-2 expression. In conclusion, our results indicate that TSA and SAHA exert a number of histone- and HDAC-independent functions. Furthermore, the data show that different HDAC enzymes fulfill different functions in macrophages and might lead to both pro- and anti-inflammatory effects which have to be considered in therapeutic approaches.
Objectives: The ongoing coronavirus pandemic is challenging, especially in severely affected patients who require intubation and sedation. Although the potential benefits of sedation with volatile anesthetics in coronavirus disease 2019 patients are currently being discussed, the use of isoflurane in patients with coronavirus disease 2019–induced acute respiratory distress syndrome has not yet been reported. Design: We performed a retrospective analysis of critically ill patients with hypoxemic respiratory failure requiring mechanical ventilation. Setting: The study was conducted with patients admitted between April 4 and May 15, 2020 to our ICU. Patients: We included five patients who were previously diagnosed with severe acute respiratory syndrome coronavirus 2 infection. Intervention: Even with high doses of several IV sedatives, the targeted level of sedation could not be achieved. Therefore, the sedation regimen was switched to inhalational isoflurane. Clinical data were recorded using a patient data management system. We recorded demographical data, laboratory results, ventilation variables, sedative dosages, sedation level, prone positioning, duration of volatile sedation and outcomes. Measurements & Main Results: Mean age (four men, one women) was 53.0 (± 12.7) years. The mean duration of isoflurane sedation was 103.2 (± 66.2) hours. Our data demonstrate a substantial improvement in the oxygenation ratio when using isoflurane sedation. Deep sedation as assessed by the Richmond Agitation and Sedation Scale was rapidly and closely controlled in all patients, and the subsequent discontinuation of IV sedation was possible within the first 30 minutes. No adverse events were detected. Conclusions: Our findings demonstrate the feasibility of isoflurane sedation in five patients suffering from severe coronavirus disease 2019 infection. Volatile isoflurane was able to achieve the required deep sedation and reduced the need for IV sedation.
Container-breeding Aedes spp. (Diptera: Culicidae) mosquitoes can be surveilled at low cost using ovitraps. Hence, this method is a preferred monitoring approach of dengue vectors in low-resource settings. The ovitraps consist of a cup filled with water and an oviposition substrate for female mosquitoes. The attractiveness of the substrates for female mosquitoes can greatly differ due to differences in texture, color, and smell of the materials used. We compare four oviposition substrates, which are all low priced, easy to transport, and easy to purchase, to maximize the success of Aedes egg sampling. Sampled egg material is often reared to adulthood for further taxonomic identification and transported to (international) laboratories for specialized vector research. Here we introduce a transport technique for sampled eggs. In addition, we explored the impact of international transport by means of a bilateral hatching experiment in Nepal, the country of origin, and in Germany, in a laboratory specialized in ecophysiological research. The best low-cost oviposition substrate for the dengue vectors Aedes albopictus (Skuse) and Aedes aegypti (L.) was found to be a white cotton sheet. The introduced transport technique of sampled eggs is easy to build from laboratory and household materials and ensures good transport conditions (i.e., temperature and relative humidity). Even under good temperature (17.4–31.0 °C) and humidity conditions (58.9–94.2%), hatching success of eggs was found to be reduced after international transport to Germany when compared to the hatching success of eggs in Nepal. We postulate that air pressure during international transport may have reduced the hatching success and strongly recommend pressure-regulated transport boxes for egg transport via airplane. As the proposed operation procedure is useful in assisting the monitoring of Ae. albopictus and Ae. aegypti in low-resource settings, Aedes researchers are encouraged to follow it for the sampling and transport of Aedes eggs.
Aim: The aim of this study is to utilize the niche measurement guidelines outlined by Jordans et al. in order to establish normal values and accurate description of caesarean section scars in a normal population. After defining the normal distribution, abnormal pregestational scar characteristics will be identified for predicting adverse pregnancy outcomes. Methods: This is a prospective observational multicenter clinical study where women with a history of only one caesarean section and yet open family planning are enrolled. The uterine length, cervical length, niche length, niche depth, niche width, residual myometrial thickness, endometrial thickness, scar to internal os distance, anterior myometrial thickness superior and inferior to the scar and the posterior myometrial thickness opposite the scar, superior and inferior to it are measured in a pregestational uterus. The lower uterine segment is measured over a length of 3 cm during subsequent pregnancy and followed up until delivery. Results: Data from 500 patients will yield normal distribution curves for all predefined measurements. Establishing a correlation between deviations from the normal measures and adverse events would be instrumental for counseling women regarding subsequent pregnancy and mode of delivery.
Conclusion: This study will demonstrate the changes of the post-caesarean scar from a non-pregnant uterus until delivery and can confirm the importance of the scar characteristics in predicting pregnancy outcome.
Background: Brodalumab is a fully human monoclonal immunoglobulin IgG2 antibody that binds to the human IL-17 receptor subunit A and by that inhibits the biologic action of IL-17A, IL-17F, IL-17C and IL-17E. Therapy with fumaric acid esters (FAE) is a well established and widely used first-line systemic treatment for subjects with moderate-to-severe plaque psoriasis. Objectives: To compare brodalumab to FAE in terms of clinical efficacy, patient-reported outcomes and safety in subjects with moderate-to-severe plaque psoriasis who were naïve to systemic treatment. Methods: Eligible subjects were randomized 1 : 1 to 210 mg brodalumab injections or oral FAE according to product label in this 24-week, open-label, assessor-blinded, multi-centre, head-to-head phase 4 trial. The primary endpoints were having PASI75 and having sPGA score of 0 or 1 (sPGA 0/1). Subjects with missing values for the primary endpoints were considered non-responders. Results: A total of 210 subjects were randomized. 91/105 subjects completed brodalumab treatment and 58/105 subjects completed FAE treatment. At Week 24, significantly more subjects in the brodalumab group compared to the FAE group had PASI75 (81.0% vs. 38.1%, P < 0.001) and sPGA 0/1 (64.8% vs. 20.0%, P < 0.001). In the brodalumab group, the median time to both PASI75 and to PASI90 was significantly shorter than in the FAE group (4.1 weeks vs. 16.4 weeks, and 7.4 weeks vs. 24.4 weeks, respectively, P < 0.0001 for both). The rate of adverse events was lower in subjects treated with brodalumab compared to subjects treated with FAE (616.4 vs. 1195.8 events per 100 exposure years). No new safety signals were detected for brodalumab. Conclusions: Brodalumab was associated with rapid and significant improvements in signs and symptoms of moderate-to-severe plaque psoriasis, with a superior efficacy profile to what was observed with FAE in systemic-naïve subjects over 24 weeks.
Background: One of the lesser recognized complications of diabetes mellitus are musculoskeletal (MSK) complications of the upper and lower extremity. No prevalence studies have been conducted in general practice. Thus, the aim of this study was to investigate the prevalence of upper extremity MSK disorders in patients with type 2 diabetes (T2DM) in the Netherlands. Methods: We conducted a cross-sectional study with two different approaches, namely a representative Dutch primary care medical database study and a questionnaire study among patients with T2DM. Results: In the database study, 2669 patients with T2DM and 2669 non-diabetes patients were included. MSK disorders were observed in 16.3% of patients with T2DM compared to 11.2% of non-diabetes patients (p < 0.001, OR 1.53, 95% CI 1.31, 1.80). In the questionnaire study, 200 patients with T2DM were included who reported a lifetime prevalence of painful upper extremity body sites for at least four weeks of 67.3%. Conclusion: We found that upper extremity MSK disorders have a high prevalence in Dutch patients with T2DM presenting in general practice. The prevalence ranges from 16% based on GP registered disorders and complaints to 67% based on self-reported diagnosis and pain. Early detection and treatment of these disorders may play a role in preventing the development of chronic MSK disorders.
Biological exploration of early biomarkers for chronic kidney disease (CKD) in (pre)diabetic individuals is crucial for personalized management of diabetes. Here, we evaluated two candidate biomarkers of incident CKD (sphingomyelin (SM) C18:1 and phosphatidylcholine diacyl (PC aa) C38:0) concerning kidney function in hyperglycemic participants of the Cooperative Health Research in the Region of Augsburg (KORA) cohort, and in two biofluids and six organs of leptin receptor-deficient (db/db) mice and wild type controls. Higher serum concentrations of SM C18:1 and PC aa C38:0 in hyperglycemic individuals were found to be associated with lower estimated glomerular filtration rate (eGFR) and higher odds of CKD. In db/db mice, both metabolites had a significantly lower concentration in urine and adipose tissue, but higher in the lungs. Additionally, db/db mice had significantly higher SM C18:1 levels in plasma and liver, and PC aa C38:0 in adrenal glands. This cross-sectional human study confirms that SM C18:1 and PC aa C38:0 associate with kidney dysfunction in pre(diabetic) individuals, and the animal study suggests a potential implication of liver, lungs, adrenal glands, and visceral fat in their systemic regulation. Our results support further validation of the two phospholipids as early biomarkers of renal disease in patients with (pre)diabetes.
Electroencephalography (EEG) represents a widely established method for assessing altered and typically developing brain function. However, systematic studies on EEG data quality, its correlates, and consequences are scarce. To address this research gap, the current study focused on the percentage of artifact-free segments after standard EEG pre-processing as a data quality index. We analyzed participant-related and methodological influences, and validity by replicating landmark EEG effects. Further, effects of data quality on spectral power analyses beyond participant-related characteristics were explored. EEG data from a multicenter ADHD-cohort (age range 6 to 45 years), and a non-ADHD school-age control group were analyzed (ntotal = 305). Resting-state data during eyes open, and eyes closed conditions, and task-related data during a cued Continuous Performance Task (CPT) were collected. After pre-processing, general linear models, and stepwise regression models were fitted to the data. We found that EEG data quality was strongly related to demographic characteristics, but not to methodological factors. We were able to replicate maturational, task, and ADHD effects reported in the EEG literature, establishing a link with EEG-landmark effects. Furthermore, we showed that poor data quality significantly increases spectral power beyond effects of maturation and symptom severity. Taken together, the current results indicate that with a careful design and systematic quality control, informative large-scale multicenter trials characterizing neurophysiological mechanisms in neurodevelopmental disorders across the lifespan are feasible. Nevertheless, results are restricted to the limitations reported. Future work will clarify predictive value.
Coagulation factor XIII (FXIII) is a protransglutaminase which plays an important role in clot stabilization and composition by cross-linking the α- and γ-chains of fibrin and increasing the resistance of the clot to mechanical and proteolytic challenges. In this study, we selected six DNA aptamers specific for activated FXIII (FXIIIa) and investigated the functional characterization of FXIIIa after aptamer binding. One of these aptamers, named FA12, efficiently captures FXIIIa even in the presence of zymogenic FXIII subunits. Furthermore, this aptamer inhibits the incorporation of FXIII and α2-antiplasmin (α2AP) into fibrin(ogen) with IC50-values of 38 nM and 17 nM, respectively. In addition to FA12, also another aptamer, FA2, demonstrated significant effects in plasma-based thromboelastometry (rotational thromboelastometry analysis, ROTEM)-analysis where spiking of the aptamers into plasma decreased clot stiffness and elasticity (p < 0.0001). The structure–function correlations determined by combining modeling/docking strategies with quantitative in vitro assays revealed spatial overlap of the FA12 binding site with the binding sites of two FXIII substrates, fibrinogen and α2AP, while FA2 binding sites only overlap those of fibrinogen. Taken together, these features especially render the aptamer FA12 as an interesting candidate molecule for the development of FXIIIa-targeting therapeutic strategies and diagnostic assays.
Simple Summary: Children with acute myeloid leukemia (AML) experience high relapse rates of about 30%; still, survival rates following the first relapse are encouraging. Hence, it is critically important to examine the consequences of a second relapse; however, little is known about this subgroup of patients. This retrospective population-based analysis intends to describe response, survival and prognostic factors relevant for the survival of children with second relapse of AML. Treatment approaches include many different therapeutic regimens, including palliation and intensive treatment with curative intent (63% of the patients). Survival is poor; however, patients who respond to reinduction attempts can be rescued with subsequent hematopoietic stem cell transplantation. We deciphered risk factors, such as short time interval from first to second relapse below one year as being associated with a poor outcome. This analysis will help to improve future international treatment planning and patient care of children with advanced AML.
Abstract: Successful management of relapse is critical to improve outcomes of children with acute myeloid leukemia (AML). We evaluated response, survival and prognostic factors after a second relapse of AML. Among 1222 pediatric patients of the population-based AML-Berlin–Frankfurt–Munster (BFM) study group (2004 until 2017), 73 patients met the quality parameters for inclusion in this study. Central review of source documentation warranted the accuracy of reported data. Treatment approaches included palliation in 17 patients (23%), intensive therapy with curative intent (n = 46, 63%) and other regimens (n = 10). Twenty-five patients (35%) received hematopoietic stem cell transplantation (HSCT), 21 of whom (88%) had a prior HSCT. Survival was poor, with a five-year probability of overall survival (pOS) of 15 ± 4% and 31 ± 9% following HSCT (n = 25). Early second relapse (within one year after first relapse) was associated with dismal outcome (pOS 2 ± 2%, n = 44 vs. 33 ± 9%, n = 29; p < 0.0001). A third complete remission (CR) is required for survival: 31% (n = 14) of patients with intensive treatment achieved a third CR with a pOS of 36 ± 13%, while 28 patients (62%) were non-responders (pOS 7 ± 5%). In conclusion, survival is poor but possible, particularly after a late second relapse and an intensive chemotherapy followed by HSCT. This analysis provides a baseline for future treatment planning.
Simple Summary: The incidence of brain metastases from breast cancer is increasing and the treatment is still a major challenge. Several scores have been developed in order to estimate the prognosis of patients with brain metastases by objective criteria. Here, we validated all three published graded-prognostic-assessment (GPA)-scores in a subcohort of 882 breast cancer patients with brain metastases in the Brain Metastases in the German Breast Cancer (BMBC) registry. Although all three available GPA-scores were associated with OS, they all show limitations mainly in predicting short-term (below 3 months) survival but also in long-term (above 12 months) survival. We discuss the test performances of all scores in our work and provide evidence how physicians should use them as a tool to select patients for different treatment options.
Abstract: Several scores have been developed in order to estimate the prognosis of patients with brain metastases (BM) by objective criteria. The aim of this analysis was to validate all three published graded-prognostic-assessment (GPA)-scores in a subcohort of 882 breast cancer (BC) patients with BM in the Brain Metastases in the German Breast Cancer (BMBC) registry. The median age at diagnosis of BM was 57 years. All in all, 22.3% of patients (n = 197) had triple-negative, 33.4% (n = 295) luminal A like, 25.1% (n = 221) luminal B/HER2-enriched like and 19.2% (n = 169) HER2 positive like BC. Age ≥60 years, evidence of extracranial metastases (ECM), higher number of BM, triple-negative subtype and low Karnofsky-Performance-Status (KPS) were all associated with worse overall survival (OS) in univariate analysis (p < 0.001 each). All three GPA-scores were associated with OS. The breast-GPA showed the highest probability of classifying patients with survival above 12 months in the best prognostic group (specificity 68.7% compared with 48.1% for the updated breast-GPA and 21.8% for the original GPA). Sensitivities for predicting 3 months survival were very low for all scores. In this analysis, all GPA-scores showed only moderate diagnostic accuracy in predicting the OS of BC patients with BM.
Shikonin reduces growth of docetaxel-resistant prostate cancer cells mainly through necroptosis
(2021)
Simple Summary: Prostate carcinoma (PCa) is the most common tumor in men with an increasing age-associated risk. Several therapy strategies, one of which is docetaxel (DX) chemotherapy, have been established. However, due to the development of therapy resistance, in which chemotherapy no longer effectively combats the cancer, advanced, metastasized PCa with a poor prognosis may become manifested and therapy inevitably fails. Thus, new treatment options are urgently needed. Shikonin (SHI), from Traditional Chinese Medicine, has revealed promising antitumor activity in several tumor entities. In the current study, the impact of SHI on four therapy-sensitive and four respective DX-resistant PCa cell lines was determined. SHI induced growth inhibition mainly by necroptosis, a type of cell death, in all the tested therapy-sensitive, but more importantly, DX-resistant PCa cell lines. Corresponding molecular alterations contributing to growth inhibition after SHI exposure were found. SHI could, therefore, be a promising additive in treating advanced PCa.
Abstract: The prognosis for advanced prostate carcinoma (PCa) remains poor due to development of therapy resistance, and new treatment options are needed. Shikonin (SHI) from Traditional Chinese Medicine has induced antitumor effects in diverse tumor entities, but data related to PCa are scarce. Therefore, the parental (=sensitive) and docetaxel (DX)-resistant PCa cell lines, PC3, DU145, LNCaP, and 22Rv1 were exposed to SHI [0.1–1.5 μM], and tumor cell growth, proliferation, cell cycling, cell death (apoptosis, necrosis, and necroptosis), and metabolic activity were evaluated. Correspondingly, the expression of regulating proteins was assessed. Exposure to SHI time- and dose-dependently inhibited tumor cell growth and proliferation in parental and DX-resistant PCa cells, accompanied by cell cycle arrest in the G2/M or S phase and modulation of cell cycle regulating proteins. SHI induced apoptosis and more dominantly necroptosis in both parental and DX-resistant PCa cells. This was shown by enhanced pRIP1 and pRIP3 expression and returned growth if applying the necroptosis inhibitor necrostatin-1. No SHI-induced alteration in metabolic activity of the PCa cells was detected. The significant antitumor effects induced by SHI to parental and DX-resistant PCa cells make the addition of SHI to standard therapy a promising treatment strategy for patients with advanced PCa.
Vascular biotransformation of organic nitrates is independent of cytochrome P450 monooxygenases
(2021)
Background and Purpose: Organic nitrates such as nitroglycerin (NTG) or pentaerythritol tetranitrate (PETN) have been used for over a century in the treatment of angina or ischaemic heart disease. These compounds are prodrugs which release their nitrovasodilators upon enzymic bioactivation by aldehyde dehydrogenase (ALDH2) or cytochromes P450 (CYP). Whereas ALDH2 is known to directly activate organic nitrates in vessels, the contribution of vascular CYPs is unknown and was studied here.
Experimental Approach: As all CYPs depend on cytochrome P450 reductase (POR) as electron donor, we generated a smooth muscle cell-specific, inducible knockout mouse of POR (smcPOR−/−) to investigate the contribution of POR/CYP to vascular biotransformation of organic nitrates.
Key Results: Microsomes containing recombinant CYPs expressed in human vascular tissues released nitrite from NTG and PETN with CYP2C9 and CYP2C8 being most efficient. SFK525, a CYP suicide inhibitor, blocked this effect. smcPOR−/− mice exhibited no obvious cardiovascular phenotype (normal cardiac weight and endothelium-dependent relaxation) and plasma and vascular nitrite production was similar to control (CTL) animals. NTG- and PETN-induced relaxation of isolated endothelium-intact or endothelium-denuded vessels were identical between CTL and smcPOR−/−. Likewise, nitrite release from organic nitrates in aortic rings was not affected by deletion of POR in smooth muscle cells (SMCs). In contrast, inhibition of ALDH2 by benomyl (10 μM) inhibited NTG-induced nitrite production and relaxation. Deletion of POR did not modulate this response.
Conclusions and Implications: Our data suggest that metabolism by vascular CYPs does not contribute to the pharmacological function of organic nitrates.
Parent ratings are often used for screening during the diagnostic evaluation of anxiety disorders. Clinically, it is important to correctly differentiate between anxiety and other psychiatric disorders and to distinguish specific anxiety disorders. The present study examined the validity of the screening results obtained by the Parent Questionnaire for Anxiety and Obsessive-Compulsive Disorders (FBB-ANZ). We exam- ined whether the FBB-ANZ discriminated (1) anxiety and other psychiatric disorders and (2) specific anxiety disorders in children and adoles- cents using ROC analyses. 972 parents of 4;00–11;11-year-old children and 12;00–17;11-year-old adolescents with anxiety disorders, depres- sive episodes, or externalizing disorders completed the FBB-ANZ. Discrimination of anxiety disorders and externalizing disorders in children (AUC = .72) and adolescents (AUC = .76) as well as depressive episodes in children (AUC = .77) was moderate. Good discrimination of different anxiety disorders was found only for separation anxiety in children (AUC = .84) and adolescents (AUC = .87). The results indicate the limited di- agnostic benefit of parent ratings for discriminating different anxiety disorders in children and adolescents. Potential explanations for the re- sults are critically discussed.
Background: Transplantation of human corneal tissue is associated with the potential risk of transmittance of viral infections. In accordance with European directives and federal laws, in Germany each tissue donor has to be tested for infectious diseases such as hepatitis B and C virus (HBV and HCV) and human immunodeficiency virus (HIV) infection. However, most of the currently available CE-marked serologic and nucleic acid screening systems are only validated for antemortem blood. Methods: Twenty related and paired ante- and postmortem blood samples from cornea donors were obtained and subsequently analyzed for hepatitis B surface antigen (HBsAg), hepatitis B antibody (anti-HBc), anti-HCV, HCV RNA, anti-HIV-1/2, and HIV p24 Ag using Abbott test systems. The sera were also spiked with reference materials in concentrations giving low and high positivity for HBV, HCV, and HIV markers. Results: The spiked ante- and postmortem sera from related donors showed similar results for HBsAg, anti-HBc, anti-HCV, HCV RNA, anti-HIV, and HIV p24 Ag, indicating a high stability of viral markers in cadaveric specimens. Three cornea donors had a medical history of HBV infection and revealed anti-HBc at similar levels in the ante- and postmortem sera. In addition, there was a single postmortem sample demonstrating a weak signal of anti-HIV-1 and HIV-1 p24 Ag. False-positive or false-negative results were not detected. The results obtained with the Abbott ARCHITECT analyzer and Abbott RealTime HCV PCR showed no significant differences. Conclusion: The analyzed screening assays are suitable for the detection of infectious markers of HBV, HCV, and HIV at similar levels in spiked ante- and postmortem sera from cornea donors.
Lower leg fractures in children and adolescents - comparison of conservative vs. ECMES treatment
(2021)
Background: Lower leg fractures are one of the most common fractures in pediatric age. In general, treatment of lower leg fractures is predominantly non-operative, requiring clinical and radiological controls. Nevertheless, it can be observed that in recent years tibial shaft fractures have increasingly been treated surgically. The aim of the present study is to investigate treatment strategies in the context of different fracture types of the lower leg Methods: In this retrospective chart review, we analyzed 168 children with a diaphyseal fracture of the lower leg admitted to a trauma center between 2005 and 2017. The fractures were classified according to the AO Pediatric Comprehensive Classification of Long Bone Fractures (AO-PCCF). Results: The frequency of fractures based on the AO-PCCF classification was as follows: Simple oblique fracture of the tibia (43.5%, n = 73), hereof 32 toddler's fractures, multifragmentary oblique fracture of the tibia in 14.3% (n = 24) and simple oblique fracture of both, tibia and fibula in 18 patients (10.7%). Most pediatric fractures were treated conservatively by cast (n = 125). Thirty-seven patients received an ECMES, whereas 3 patients were treated with an external fixator and also 3 fractures were stabilized by plate osteosynthesis. Conservatively treated patients were significantly younger (mean age 6.0) compared to patients treated with ECMES (mean age 10.2) or plate osteosynthesis (PO)/external fixator (EF) (mean age 11.3), even if toddler's fractures (mean age 2.0) are excluded (mean age 7.4). There was no difference in time to full weight-bearing, hospitalization of patients treated with ECMES compared to conservative therapy although ECMES-treated fractures show more instability. The consolidation time was significantly higher in ECMES treated patients compared to conservative therapy. Conclusion: Pediatric patients (≤4 years) with lower leg fractures most often showed simple oblique fractures of the tibia, half of them toddler's fractures, which were treated predominantly by conservative therapy. All in all, the consolidation time was longer in intramedullary nailing (ECMES) than in conservative therapy. Nevertheless, time to full weight bearing and duration of cast was the same in both groups, even though ECMES treated fractures show more instability.
Background: The alpha7 nicotinic acetylcholine receptor (Chrna7) plays an essential anti-inflammatory role in immune homeostasis and was recently found on mast cells (MC). Psychosocial stress can trigger MC hyperactivation and increases pro-inflammatory cytokines in target tissues such as the skin. If the cholinergic system (CS) and Chrna7 ligands play a role in these cascades is largely unknown. Objective: To elucidate the role of the CS in the response to psychosocial stress using a mouse-model for stress-triggered cutaneous inflammatory circuits. Methods: Key CS markers (ACh, Ch, SLURP-1, SLURP-2, Lynx1, Chrm3, Chrna7, Chrna9, ChAT, VAChT, Oct3, AChE, and BChE) in skin and its MC (sMC), MC activation, immune parameters (TNFα, IL1β, IL10, TGFβ, HIF1α, and STAT3) and oxidative stress were analyzed in skin from 24 h noise-stressed mice and in cultured MC (cMC) from C57BL/6 or Chrna7-Knockout mice. Results: First, Chrna7 and SLURP-1 mRNA were exclusively upregulated in stressed skin. Second, histomorphometry located Chrna7 and SLURP-1 in nerves and sMC and demonstrated upregulated contacts and increased Chrna7+ sMC in stressed skin, while 5 ng/mL SLURP-1 degranulated cMC. Third, IL1β+ sMC were high in stressed skin, and while SLURP-1 alone had no significant effect on cMC cytokines, it upregulated IL1β in cMC from Chrna7-KO and in IL1β-treated wildtype cMC. In addition, HIF1α+ sMC were high in stressed skin and Chrna7-agonist AR-R 17779 induced ROS in cMC while SLURP-1 upregulated TNFα and IL1β in cMC when HIF1α was blocked. Conclusions: These data infer that the CS plays a role in the regulation of stress-sensitive inflammatory responses but may have a surprising pro-inflammatory effect in healthy skin, driving IL1β expression if SLURP-1 is involved.
Complement has been considered as an important factor impacting the host–pathogen association of spirochetes belonging to the Borrelia burgdorferi sensu lato complex, and may play a role in the spirochete’s ecology. Birds are known to be important hosts for ticks and in the maintenance of borreliae. Recent field surveys and laboratory transmission studies indicated that certain avian species act as reservoir hosts for different Borrelia species. Nevertheless, our current understanding of the molecular mechanisms determining host tropism of Borrelia is still in its fledgling stage. Concerning the role of complement in avian-host tropism, only a few bird species and Borrelia species have been analysed so far. Here, we performed in vitro serum bactericidal assays with serum samples collected from four bird species including the European robin Erithacus rubecula, the great tit Parus major, the Eurasian blackbird Turdus merula, and the racing pigeon Columba livia, as well as four Borrelia species (B. afzelii, B. garinii, B. valaisiana, and B. burgdorferi sensu stricto). From July to September 2019, juvenile wild birds were caught using mist nets in Portugal. Racing pigeons were sampled in a loft in October 2019. Independent of the bird species analysed, all Borrelia species displayed an intermediate serum-resistant or serum-resistant phenotype except for B. afzelii challenged with serum from blackbirds. This genospecies was efficiently killed by avian complement, suggesting that blackbirds served as dead-end hosts for B. afzelii. In summary, these findings suggest that complement contributes in the avian–spirochete–tick infection cycle and in Borrelia-host tropism.
Background: To investigate patients’ perspectives on polypharmacy and the use of a digital decision support system to assist general practitioners (GPs) in performing medication reviews. Methods: Qualitative interviews with patients or informal caregivers recruited from participants in a cluster-randomized controlled clinical trial (cRCT). The interviews were transcribed verbatim and analyzed using thematic analysis. Results: We conducted 13 interviews and identified the following seven themes: the patients successfully integrated medication use in their everyday lives, used medication plans, had both good and bad personal experiences with their drugs, regarded their healthcare providers as the main source of medication-related information, discussed medication changes with their GPs, had trusting relationships with them, and viewed the use of digital decision support tools for medication reviews positively. No unwanted adverse effects were reported. Conclusions: Despite drug-related problems, patients appeared to cope well with their medications. They also trusted their GPs, despite acknowledging polypharmacy to be a complex field for them. The use of a digital support system was appreciated and linked to the hope that reasons for selecting specific medication regimens would become more comprehensible. Further research with a more diverse sampling might add more patient perspectives.
Background: To assess the potential of radiomic features to quantify components of blood in intraaortic vessels to non-invasively predict moderate-to-severe anemia in non-contrast enhanced CT scans. Methods: One hundred patients (median age, 69 years; range, 19–94 years) who received CT scans of the thoracolumbar spine and blood-testing for hemoglobin and hematocrit levels ± 24 h between 08/2018 and 11/2019 were retrospectively included. Intraaortic blood was segmented using a spherical volume of interest of 1 cm diameter with consecutive radiomic analysis applying PyRadiomics software. Feature selection was performed applying analysis of correlation and collinearity. The final feature set was obtained to differentiate moderate-to-severe anemia. Random forest machine learning was applied and predictive performance was assessed. A decision-tree was obtained to propose a cut-off value of CT Hounsfield units (HU). Results: High correlation with hemoglobin and hematocrit levels was shown for first-order radiomic features (p < 0.001 to p = 0.032). The top 3 features showed high correlation to hemoglobin values (p) and minimal collinearity (r) to the top ranked feature Median (p < 0.001), Energy (p = 0.002, r = 0.387), Minimum (p = 0.032, r = 0.437). Median (p < 0.001) and Minimum (p = 0.003) differed in moderate-to-severe anemia compared to non-anemic state. Median yielded superiority to the combination of Median and Minimum (p(AUC) = 0.015, p(precision) = 0.017, p(accuracy) = 0.612) in the predictive performance employing random forest analysis. A Median HU value ≤ 36.5 indicated moderate-to-severe anemia (accuracy = 0.90, precision = 0.80). Conclusions: First-order radiomic features correlate with hemoglobin levels and may be feasible for the prediction of moderate-to-severe anemia. High dimensional radiomic features did not aid augmenting the data in our exemplary use case of intraluminal blood component assessment.
Die Sonografie wird als primäre Untersuchungsmethode zur Abklärung vielfältiger Krankheitsbilder eingesetzt und hat sich auch in Leitlinien etabliert. Die Rolle der Sonografie in der Geriatrie ist weniger bekannt und nicht systematisch untersucht.
Ziel der Studie war die Evaluierung der Sonografie als routinemäßig eingesetztes Verfahren und erweiterte körperliche Untersuchung bei geriatrischen Patienten in der medizinischen Akutversorgung. Alle sogenannten geriatrischen Assessments und auch die Sonografie als Screening-Untersuchung erfolgten unabhängig von der Symptomatik des geriatrischen Patienten. Die Befunde wurden mit einem hand-held ultrasound device (HHUSD) und einem high-end ultrasound (HEUS) erhoben und dann verglichen. Die HEUS-Ergebnisse wurden als Goldstandard angesehen. Die Untersuchungen mit HEUS erfolgten meist zu einem späteren Zeitpunkt als mit HHUSD; in der Regel in einem Zeitraum von bis zu sieben Tagen.
Es handelt sich um eine prospektive Studie, die 86 Patienten in einem Zeitraum von 10 Monaten eingeschlossen hat. Die Untersucherin und Doktorandin stellte Folgendes dar: Das Abdomen und die basalen Abschnitte des Thorax sowie die Schilddrüse. Zusätzlich erfolgte eine elastografische Untersuchung der Leber mittels FibroScan.
Die Ultraschalluntersuchung war bei 22/86 (25,6 %) Patienten aufgrund der Symptomatik indiziert und erfolgte bei 64/86 (74,4 %) Patienten als Screening, also ohne klinische Fragestellung. Die Indikationen der Untersuchungen waren: Tumorsuche (8/86 (9,3 %)), Anämie (5/86 (5,8 %)), Leberwert-Erhöhung (5/86 (5,8 %)), Dyspnoe (5/86 (5,8 %)), Frage nach Milzpathologien (2/86 (2,3 %)), Gewichtsverlust (1/86 (1,2 %)), Infektfokussuche (1/86 (1,2 %)), Durchfall (1/86 (1,2 %)), Frage nach intraabdominalem Hämatom (1/86 (1,2 %)) und Kontrolle bei bekanntem Bauchaortenaneurysma (1/86 (1,2 %)). Bei einigen Patienten kamen mehrere Fragestellungen vor.
Die Befunde, die am häufigsten gefunden wurden, waren: Cholezystolithiasis (28/86 (32,6 %); mit HHUSD 5 falsch negative Ergebnisse), rechtsseitiger Pleuraerguss (27/86 (31,4 %); 5 falsch positive Ergebnisse mit HHUSD), Schilddrüsenknoten (26/86 (30,2 %); 2 falsch negative und 1 falsch positiver Befunde mit HHUSD), Nierenzysten (24/86 (27,9 %); 6 falsch negative Ergebnisse mit HHUSD) und Fettleber (23/86 (26,7 %); 3 falsch negative Befunde mit HHUSD). Von 64/86 (74,4 %) untersuchten Patienten ergab sich bei 8/86 (9,3 %) eine therapeutische Konsequenz. Die wichtigsten Befunde, die mit HHUSD übersehen wurden waren: 2 zystische Formationen im Pankreas (2/86 (2,3 %); mit HEUS insgesamt (6/86 (7,0 %)), eine Lebezirrhose (mit HEUS 2/86 (2,3 %)), eine Choledocholithiasis (1/86 (1,2 %); mit HEUS 2/86 (2,3 %)) und ein Lungeninfiltrat (1/86 (1,2 %); mit HEUS 2/86 (2,3 %)). Alle übersehenen Befunde hatten keine dringende therapeutische Konsequenz, so dass die point of care Sonografie (POCUS) hier ausreichend war, um die „ja/nein“-Fragen zu klären.
Bei 65/86 (75,6 %) Patienten war eine Messung der Lebersteifigkeit mittels FibroScan erfolgreich.
Es gab keine Interobserver-Variabilität. Die Untersucherin war eine Fachärztin für Innere Medizin aber keine DEGUM-ausgebildete Ultraschallerin.
Insgesamt zeigte sich eine ausreichende bis gute Übereinstimmung der erhobenen Befunde zwischen HHUSD und HEUS. Die POCUS-Untersuchung lieferte in den meisten Fällen eine Antwort auf die häufigsten Fragestellungen in der Geriatrie (wie Hydratationsstatus, Harnverhalt). Weiterhin konnte die Behandlung bei zufällig gescreenten Patienten optimiert werden. Zur Bestimmung der Organgröße konnte ebenfalls eine gute Korrelation der beiden Geräte festgestellt werden, so dass sich die alleinige Untersuchung mit HHUSD in diesen Fällen ausreichend gezeigt hätte. Ein routinemäßiger Einsatz der Sonografie in der Geriatrie muss in weiteren Studien untersucht werden. Da es sich bei geriatrischen Patienten um multimorbide Patienten mit entsprechend angepassten therapeutischen Zielen handelt, hatten mehrere der erhobenen Befunde in dieser Studie zum Zeitpunkt der geriatrischen Behandlung keine therapeutische Konsequenz.
Mycophenolate-Mofetil (MMF) clinically used as CellCept is inserted as immunosuppressive xenobiotic drug for preventing transplantate rejection. It is well known that MMF works selectively through inhibiting the IMPDH which is an essential enzyme in the de novo pathway for biosynthesis of guanosine Nukleotides.
In this study, we investigated the effects of MMF on the astrocytes, because astrocytes are important glial cells of the CNS with various functions in the healthy tissue, such as being involved in the neuronal differentiation, axonal growth and regulation of the environmental composition. They also build up the scared tissue during acute CNS lesions by releasing neurotoxic substances such as NO and different inflammatory Zytokines, e.g. IL-1ß and TNF-a, which even influence the microglial cell proliferation, migration and activity. Therefore, astrocytes are impressingly involved in the extent of the neuronal damage.
Our observations revealed an influence of astrocytic proliferation dependent on the concentration of the serum (10%, 5%, 2%, 1% and serum free medium) used for the in vitro cultivation: the more the serum part in the medium the more the extent of the cell proliferation. The proliferation of astrocytes cultured in serum free medium can be increased by Corticotropin Releasing Factor (CRF) 10µM and Guanosine application. Dose-dependent MMF led to a suppression of the astrocytic proliferation which is antagonisable with Guanosine only.
The number of the isolated proliferating astrocytes labeled by BrdU was significantly reduced after simultaneous treatment with serum (10% or 1%) and dose-dependent MMF (10µg/ ml, 1µg/ ml and 0,1µg/ ml) application, whereas LPS showed no effect on the proliferating rate. But, as measured by ELISA, with LPS conditioned medium contained relevant amounts of TNF-a and NO, but surprisingly not of IL-1ß. There were a significant reduction of cytokine and NO amounts determined in the astrocytic conditioned medium treated only with MMF dependent of the concentration (10µg/ml, 1µg/ml and 0,1µg/ml). Even the simultaneous treatment with LPS and MMF revealed compared to the LPS stimulated astrocytic group a measurable significant decrease of TNF-a. The treatment of the astrocytic cultures with guanosine lifted up the effects of MMF on TNF-a secretion. Therefore, we conclude, that the immunosuppressive drug MMF might have a neuroprotective and scar formation modulating effect through the antiproliferative potency on astrocytic cells and modulating character of the microenvironment by influencing the TNF-a secretion. Moreover, these regulatory effect on microglial cells are described as suppression (Hailer NP,Wirjatijana F,Roser N,Hirschebeth GT,Korf HW,Dehghani F,2001).
Background: Gait kinematics after total hip replacement only partly explain the differences in the joint moments in the frontal plane between hip osteoarthritis patients after hip replacement and healthy controls. The goal of this study was to determine if total hip replacement surgery affects radiological leg alignment (Hip-Knee-Shaft-Angle, femoral offset, Neck-Shaft-Angle and varus/valgus alignment) and which of these parameters can explain the joint moments, additionally to the gait kinematics.
Methods: 22 unilateral hip osteoarthritis patients who were scheduled for total hip replacement were included in the study. Preoperatively and 1 year postoperatively all patients had biplanar radiographic examinations and 3D gait analysis.
Results: The operated leg showed significantly (P < 0.05) more varus (1.1°) as well as a larger femoral offset (+ 8 mm) and a larger Hip-Knee-Shaft-Angle (+ 1.3°) after total hip replacement; however no significant differences in the joint moments in the frontal plane compared to healthy controls were found. The hip moment (first half of stance) and the knee moments (first and second half of stance) were mostly determined by the varus/valgus alignment (29% and respectively 36% and 35%). The combination with a kinematic parameter (knee range of motion, foot progression angle) increased the predictive value for the knee moments.
Conclusion: In our patient group the joint moments after total hip replacement did not differ from healthy controls, whereas radiological leg alignment parameters changed significantly after the total hip replacement. A combination of these radiological leg parameters, especially the varus alignment, and the deviating kinematics explain the joint moments in the frontal plane during gait after total hip replacement surgery. For surgeons it is important not to create too much of a structural varus alignment by implanting the new hip joint as varus alignment can increase the knee adduction moment and the risk for osteoarthritis of the medial knee compartment.
Trial registration: This study was retrospectively registered with DRKS (German Clinical Trials Register) under the number DRKS00015053. Registered 1st of August 2018.
Zielstellung: Es sollte im Rahmen dieser Arbeit geprüft werden ob (1) ein Zusammenhang zwischen einer radiologischen Beinlängendifferenz und einer veränderten Hüft- bzw. Kniegelenksbelastung bei Coxarthrosepatienten besteht. Des Weiteren galt es zu prüfen (2) ob die radiologisch-anatomische Beinachse bei Coxarthrosepatienten einen Einfluss auf die Gelenksbelastung von Hüfte und Knie habe und (3) ob sich in diesem Zusammenhang Unterschiede zwischen unilateral und bilateral betroffenem Patientenkollektiv darstellen ließe.
Hintergründe: Es konnte bereits gezeigt werden, dass Coxarthrosepatienten ein verändertes Gangbild aufweisen. Diese Veränderungen sind mitverantwortlich für eine veränderete Gelenkbelastung sowohl in Knie als auch Hüfte, sowohl im Vergleich zwischen betroffener und nicht betroffener Seite als auch im Vergleich zu hüftgesunden Normprobanden. Insbesondere bezüglich der Kniegelenksbelastung konnte bei den Betroffenen ein reduziertes Knieadduktionsmoment (KAM) während der Standphase nachgewiesen werden. Dies steht im Einklang mit der Beobachtung, dass Coxarthrosepatienten vermehrt eine laterale Kniearthrose auf der ipsilateralen Seite entwickeln. Coxarthrosepatienten zeigten darüber hinaus eine veränderte Beinachse, mit einer Tendenz hin zu einer Valgusfehlstellung. In wieweit insbesondere die proximale Beinachse einen Einfluss auf die alterierten Gelenkmomente hat, bleibt bislang jedoch offen. Zu bilateralen Patienten sind darüber hinaus nur wenige Daten vorliegend.
Methoden: Um die oben genannten Hypothesen zu prüfen wurden bei insgesamt 29 Patienten, bei welchen die Indikation für eine Hüfttotalendoprothese aufgrund einer fortgeschrittenen Coxarthrose gestellt wurde, eine instrumentelle Bewegungsanalyse sowie eine biplanare EOSRöntgenaufnahme, welche in diesem Zusammenhang die konventionelle präoperative Planungsaufnahme ersetzte, durchgeführt. Anschließend wurden die Daten, die aus der 3D EOS Rekonstruktion über die Beinachse gewonnen wurden, sowie die Ergebnisse der Bewegungsanalyse mit bereits zuvor erhobenen Normdaten sowie untereinander verglichen und statistisch analysiert.
Ergebnisse: Es zeigte sich, dass die Patienten eine bis auf MFA nicht von der Norm abweichende Beinachse hatten. Die bilateralen zeigten eine signifikant größere Beinlängendifferenz als die Norm, die unilateralen Patienten jedoch diesbezüglich keine Abweichung. Insgesamt zeigten die Patienten ein verändertes Gangbild, welches weitgehend den bereits in der Literatur beschriebenen Veränderungen entsprach.
Bezüglich der Gelenkmomente zeigte sich ein im Vergleich zur Norm erniedrigtes KAM 2, die übrigen Gelenkmomente zeigten keine Abweichungen von der Norm.
Es zeigten sich weder für die Beinachse noch für die Gelenkmomente signifikante Unterschiede zwischen unilateralem und bilateralem Patientenkollektiv.
Die unilateralen Patienten als gesamtes zeigten keine Korrelationen mit der absoluten Beinlängendifferenz. In einer unilateralen Subgruppe, in der die betroffene Seite länger war, konnte eine inverse Korrelation mit HAM 1 und HAM 2 gefunden werden.
KAM 1 und KAM 2 korrelierten signifikant mit allen Beinachsenparametern. In einer schrittweisen Regressionsanalyse mit HKA, FO und MFA konnten damit 68% der KAM 1 Alterationen und 57,5 % der Veränderungen von KAM 2 erklärt werden. HAM 1 und HAM 2 zeigten jeweils eine signifikante Korrelation mit MFA.
Schlussfolgerung: Die vorliegenden Ergebnisse zeigen, dass die Beinachse, insbesondere das Offset, einen Teil der Veränderungen der Kniegelenksbelastung erklären. Eine intraoperative Vergrößerung des Offsets und damit eine Varisierung der Beinachse könnte möglicherweise so zu einer Normalisierung der Kniegelenksbelastung führen.
Exploring mechanisms of drug resistance to targeted small molecule drugs is critical for an extended clinical benefit in the treatment of non-small cell lung cancer (NSCLC) patients carrying activating epidermal growth factor receptor (EGFR) mutations. Here, we identified constitutive cell proliferation regulating inhibitor of protein phosphatase 2A (CIP2A) in the HCC4006rErlo0.5 NSCLC cell line adapted to erlotinib as a model of acquired drug resistance. Constitutive CIP2A resulted in a constitutive activation of Akt signaling. The proteasome inhibitor bortezomib was able to reduce CIP2A levels, which resulted in an activation of protein phosphatase 2A and deactivation of Akt. Combination experiments with erlotinib and bortezomib revealed a lack of interaction between the two drugs. However, the effect size of bortezomib was higher in HCC4006rErlo0.5, compared to the erlotinib-sensitive HCC4006 cells, as indicated by an increase in Emax (0.911 (95%CI 0.867–0.954) vs. 0.585 (95%CI 0.568–0.622), respectively) and decrease in EC50 (52.4 µM (95%CI 46.1–58.8 µM) vs. 73.0 µM (95%CI 60.4–111 µM), respectively) in the concentration–effect model, an earlier onset of cell death induction, and a reduced colony surviving fraction (0.38 ± 0.18 vs. 0.95 ± 0.25, respectively, n = 3, p < 0.05). Therefore, modulation of CIP2A with bortezomib could be an interesting approach to overcome drug resistance to erlotinib treatment in NSCLC.
Background: Non-clear cell renal cell cancers (nccRCC) are rare entities, and the optimal therapy in metastatic disease has still to be defined. Methods: In this small prospectively randomized phase IIa multicenter trial, we investigated temsirolimus (TEM) versus sunitinib (SUN) as first-line therapy in patients with metastatic nccRCC. The patients were randomized 1:1 to either TEM in a dose of 25 mg i.v. once a week or SUN with 50 mg p.o. daily for 4 weeks on and 2 weeks off. Primary endpoint was progression-free survival (PFS). In total, 22 patients were included with predominantly papillary RCC (16/22) followed by chromophobe RCC and others. Results: The male to female ratio was 16:6. The tumor control rate (CR + PR + SD) was 58% for TEM and 90% for SUN-treated patients. There was also a trend for improved PFS with 9.3 versus 13.2 months (HR 1.64; 95% CI 0.65–4.18) in favor of SUN. There was no trend for overall survival. Conclusions: Despite this trial had to be terminated earlier due to low recruitment, the results match the other studies published so far with the mTOR inhibitor everolimus and SUN, which show a trend in favor of SUN for ORR and PFS.
Background: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB. Methods: A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, n = 55) versus those with both liver and extra-hepatic metastasis (cohort B, n = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan–Meier method. Log-rank tests, χ2 tests, and t-tests were performed to detect significant differences between both cohorts. Results: The median OS of the overall population was 16 months (95% CI 13.4–23.7) and the median PFS, 2.8 months (95% CI 2.5–3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months; p = 0.071). The best objective response rate to dual ICB was 13.8% and to anti-PD-1 monotherapy 8.9% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7% vs. cohort B 16.7%; p = 0.45). Adverse events (AE) occurred in 41.6%. Severe AE were observed in 26.3% and evenly distributed between both cohorts. Conclusion: The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only.
Treatment options of locoregional recurrent head and neck squamous cell cancer (HNSCC) include both local strategies as surgery or re-radiotherapy and systemic therapy. In this prospective, multi-center, non-interventional study, patients were treated either with platinum-based chemotherapy and cetuximab (CT + Cet) or re-radiotherapy and cetuximab (RT + Cet). In the current analysis, progression-free survival (PFS) and overall survival (OS) were compared in patients with locoregional recurrence. Four hundred seventy patients were registered in 97 German centers. After exclusion of patients with distant metastases, a cohort of 192 patients was analyzed (129 CT + Cet, 63 RT + Cet). Radiotherapy was delivered as re-irradiation to 70% of the patients. The mean radiation dose was 51.8 Gy, whereas a radiation dose of ≥60 Gy was delivered in 33% of the patients. Chemotherapy mainly consisted of cisplatin/5-flurouracil (40%) or carboplatin/5-flurouracil (29%). The median PFS was 9.2 months in the RT + Cet group versus 5.1 months in the CT + Cet group (hazard ratio for disease progression or death, 0.40, 95% CI, 0.27–0.57, p < 0.0001). Median OS was 12.8 months in the RT + Cet group versus 7.9 months in the CT + Cet group (hazard ratio for death, 0.50, 95% CI, 0.33–0.75, p = 0.0008). In conclusion, radiotherapy combined with cetuximab improved survival compared to chemotherapy combined with cetuximab in locally recurrent HNSCC.
Medulloblastoma is a rare brain malignancy. Patients after puberty are rare and bear an intermediate prognosis. Standard treatment consists of maximal resection plus radio-chemotherapy. Treatment toxicity is high and produces disabling long-term side effects. The sonic hedgehog (SHH) subgroup is highly overrepresented in the post-pubertal and adult population and can be targeted by smoothened (SMO) inhibitors. No practice-changing prospective randomized data have been generated in adults. The EORTC 1634-BTG/NOA-23 trial will randomize patients between standard-dose vs. reduced-dosed craniospinal radiotherapy and SHH-subgroup patients between the SMO inhibitor sonidegib (OdomzoTM, Sun Pharmaceuticals Industries, Inc., New York, USA) in addition to standard radio-chemotherapy vs. standard radio-chemotherapy alone to improve outcomes in view of decreased radiotherapy-related toxicity and increased efficacy. We will further investigate tumor tissue, blood, and cerebrospinal fluid as well as magnetic resonance imaging and radiotherapy plans to generate information that helps to further improve treatment outcomes. Given that treatment side effects typically occur late, long-term follow-up will monitor classic side effects of therapy, but also health-related quality of life, cognition, social and professional outcome, and reproduction and fertility. In summary, we will generate unprecedented data that will be translated into treatment changes in post-pubertal patients with medulloblastoma and will help to design future clinical trials.
Background: A major disadvantage of current spacers for two-stage revision total knee arthroplasty (R-TKA) is the risk of (sub-) luxation during mobilization in the prosthesis-free interval, limiting their clinical success with detrimental consequences for the patient. The present study introduces a novel inverse spacer, which prevents major complications, such as spacer (sub-) luxations and/or fractures of spacer or bone. Methods: The hand-made inverse spacer consisted of convex tibial and concave femoral components of polymethylmethacrylate bone cement and was intra-operatively molded under maximum longitudinal tension in 5° flexion and 5° valgus position. Both components were equipped with a stem for rotational stability. This spacer was implanted during an R-TKA in 110 knees with diagnosed or suspected periprosthetic infection. Postoperative therapy included a straight leg brace and physiotherapist-guided, crutch-supported mobilization with full sole contact. X-rays were taken before and after prosthesis removal and re-implantation. Results: None of the patients experienced (sub-) luxations/fractures of the spacer, periprosthetic fractures, or soft tissue compromise requiring reoperation. All patients were successfully re-implanted after a prosthesis-free interval of 8 weeks, except for three patients requiring an early exchange of the spacer due to persisting infection. In these cases, the prosthetic-free interval was prolonged for one week. Conclusion: The inverse spacer in conjunction with our routine procedure is a safe and cost-effective alternative to other articulating or static spacers, and allows crutch-supported sole contact mobilization without major post-operative complications. Maximum longitudinal intra-operative tension in 5° flexion and 5° valgus position appears crucial for the success of surgery.
Background: Clinical practice guidelines for patients with primary biliary cholangitis (PBC) have been recently revised and implemented for well-established response criteria to standard first-line ursodeoxycholic acid (UDCA) therapy at 12 months after treatment initiation for the early identification of high-risk patients with inadequate treatment responses who may require treatment modification. However, there are only very limited data concerning the real-world clinical management of patients with PBC in Germany. Objective: The aim of this retrospective multicenter study was to evaluate response rates to standard first-line UDCA therapy and subsequent Second-line treatment regimens in a large cohort of well-characterized patients with PBC from 10 independent hepatological referral centers in Germany prior to the introduction of obeticholic acid as a licensed second-line treatment option. Methods: Diagnostic confirmation of PBC, standard first-line UDCA treatment regimens and response rates at 12 months according to Paris-I, Paris-II, and Barcelona criteria, the follow-up cut-off alkaline phosphatase (ALP) ≤ 1.67 × upper limit of normal (ULN) and the normalization of bilirubin (bilirubin ≤ 1 × ULN) were retrospectively examined between June 1986 and March 2017. The management and hitherto applied second-line treatment regimens in patients with an inadequate response to UDCA and subsequent response rates at 12 months were also evaluated. Results: Overall, 480 PBC patients were included in this study. The median UDCA dosage was 13.2 mg UDCA/kg bodyweight (BW)/d. Adequate UDCA treatment response rates according to Paris-I, Paris-II, and Barcelona criteria were observed in 91, 71.3, and 61.3% of patients, respectively. In 83.8% of patients, ALP ≤ 1.67 × ULN were achieved. A total of 116 patients (24.2%) showed an inadequate response to UDCA according to at least one criterion. The diverse second-line treatment regimens applied led to significantly higher response rates according to Paris-II (35 vs. 60%, p = 0.005), Barcelona (13 vs. 34%, p = 0.0005), ALP ≤ 1.67 × ULN and bilirubin ≤ 1 × ULN (52.1 vs. 75%, p = 0.002). The addition of bezafibrates appeared to induce the strongest beneficial effect in this cohort (Paris II: 24 vs. 74%, p = 0.004; Barcelona: 50 vs. 84%, p = 0.046; ALP < 1.67 × ULN and bilirubin ≤ 1 × ULN: 33 vs. 86%, p = 0.001). Conclusion: Our large retrospective multicenter study confirms high response rates following UDCA first-line standard treatment in patients with PBC and highlights the need for close monitoring and early treatment modification in high-risk patients with an insufficient response to UDCA since early treatment modification significantly increases subsequent response rates of these patients.
Bloodstream infections (BSI) are a severe complication of antineoplastic chemotherapy or hematopoietic stem cell transplantation (HSCT), especially in the presence of antibiotic resistance (AR). A multinational, multicenter retrospective study in patients aged ≤ 18 years, treated with chemotherapy or HSCT from 2015 to 2017 was implemented to analyze AR among non-common skin commensals BSI. Risk factors associated with AR, intensive care unit (ICU) admission and mortality were analyzed by multilevel mixed effects or standard logistic regressions. A total of 1291 BSIs with 1379 strains were reported in 1031 patients. Among Gram-negatives more than 20% were resistant to ceftazidime, cefepime, piperacillin-tazobactam and ciprofloxacin while 9% was resistant to meropenem. Methicillin-resistance was observed in 17% of S. aureus and vancomycin resistance in 40% of E. faecium. Previous exposure to antibiotics, especially to carbapenems, was significantly associated with resistant Gram-negative BSI while previous colonization with methicillin-resistant S. aureus was associated with BSI due to this pathogen. Hematological malignancies, neutropenia and Gram-negatives resistant to >3 antibiotics were significantly associated with higher risk of ICU admission. Underlying disease in relapse/progression, previous exposure to antibiotics, and need of ICU admission were significantly associated with mortality. Center-level variation showed a greater impact on AR, while patient-level variation had more effect on ICU admission and mortality. Previous exposure to antibiotics or colonization by resistant pathogens can be the cause of AR BSI. Resistant Gram-negatives are significantly associated with ICU admission and mortality, with a significant role for the treating center too. The significant evidence of center-level variations on AR, ICU admission and mortality, stress the need for careful local antibiotic stewardship and infection control programs.
Simple Summary: Tooth roots are increasingly applied for bone reconstruction before implant placement. Growth factors stored in the dentin are assumed to enhance bone regeneration, however, the evidence is low. To this aim, collagen membranes were coated with dentin lysates obtained from extracted porcine teeth or remain untreated. The collagen membranes were tested for their capacity to stimulate bone formation in rat calvarial bone defects. After four weeks of healing, micro-computed tomography and histological analyses revealed that dentin lysates coating had no significant impact on the rather strong bone regeneration reaching a nearly complete defect closure even in untreated defects. It can thus be concluded that dentin lysates do not hinder bone regeneration. Conclusions concerning a possible stimulation of bone regeneration by dentin lysates should not be drawn.
Abstract: Autogenous tooth roots are increasingly applied as a grafting material in alveolar bone augmentation. Since tooth roots undergo creeping substitution similar to bone grafts, it can be hypothesized that osteoclasts release the growth factors stored in the dentin thereby influencing bone formation. To test this hypothesis, collagen membranes were either soaked in acid dentin lysates (ADL) from extracted porcine teeth or serum–free medium followed by lyophilization. Thereafter, these membranes covered standardized 5-mm-diameter critical-size defects in calvarial bone on rats. After four weeks of healing, micro-computed tomography and histological analyses using undecalcified thin ground sections were performed. Micro-computed tomography of the inner 4.5 mm calvaria defects revealed a median bone defect coverage of 91% (CI: 87–95) in the ADL group and 94% (CI: 65–100) in the control group, without significant differences between the groups (intergroup p > 0.05). Furthermore, bone volume (BV) was similar between ADL group (5.7 mm3, CI: 3.4–7.1) and control group (5.7 mm3, CI: 2.9–9.7). Histomorphometry of the defect area confirmed these findings with bone area values amounting to 2.1 mm2 (CI: 1.2–2.6) in the ADL group and 2.0 mm2 (CI: 1.1–3.0) in the control group. Together, these data suggest that acid dentin lysate lyophilized onto collagen membranes failed to modulate the robust bone formation when placed onto calvarial defects.
The rapid detection of pathogens in infected wounds can significantly improve the clinical outcome. Wound exudate, which can be collected in a non-invasive way, offers an attractive sample material for the detection of pathogens at the point-of-care (POC). Here, we report the development of a nucleic acid lateral flow immunoassay for direct detection of isothermally amplified DNA combined with fast sample preparation. The streamlined protocol was evaluated using human wound exudate spiked with the opportunistic pathogen Pseudomonas aeruginosa that cause severe health issues upon wound colonization. A detection limit of 2.1 × 105 CFU per mL of wound fluid was achieved, and no cross-reaction with other pathogens was observed. Furthermore, we integrated an internal amplification control that excludes false negative results and, in combination with the flow control, ensures the validity of the test result. The paper-based approach with only three simple hands-on steps has a turn-around time of less than 30 min and covers the complete analytical process chain from sample to answer. This newly developed workflow for wound fluid diagnostics has tremendous potential for reliable pathogen POC testing and subsequent target-oriented therapy.
Causality assessment in liver injury induced by drugs and herbs remains a debated issue, requiring innovation and thorough understanding based on detailed information. Artificial intelligence (AI) principles recommend the use of algorithms for solving complex processes and are included in the diagnostic algorithm of Roussel Uclaf Causality Assessment Method (RUCAM) to help assess causality in suspected cases of idiosyncratic drug-induced liver injury (DILI) and herb-induced liver injury (HILI). From 1993 until the middle of 2020, a total of 95,865 DILI and HILI cases were assessed by RUCAM, outperforming by case numbers any other causality assessment method. The success of RUCAM can be traced back to its quantitative features with specific data elements that are individually scored leading to a final causality grading. RUCAM is objective, user friendly, transparent, and liver injury specific, with an updated version that should be used in future DILI and HILI cases. Support of RUCAM was also provided by scientists from China, not affiliated to any network, in the results of a scientometric evaluation of the global knowledge base of DILI. They highlighted the original RUCAM of 1993 and their authors as a publication quoted the greatest number of times and ranked first in the category of the top 10 references related to DILI. In conclusion, for stakeholders involved in DILI and HILI, RUCAM seems to be an effective diagnostic algorithm in line with AI principles.
The aim of this study was to evaluate the clinical and microbiological effects of subgingival instrumentation (SI) alone or combined with either local drug delivery (LDD) or photodynamic therapy (PDT) in persistent/recurrent pockets in patients enrolled in supportive periodontal therapy (SPT). A total of 105 patients enrolled in SPT were randomly treated as follows: group A (n = 35): SI +PDT and 7 days later 2nd PDT; group B (n = 35): SI+LDD; group C (n = 35): SI (control). Prior intervention, at 3 and 6 months after therapy, probing pocket depths, clinical attachment level, number of treated sites with bleeding on probing (n BOP), full mouth plaque and bleeding scores (gingival bleeding index, %BOP) were recorded. At the same time points, 8 periodontopathogens were quantitatively determined. All three treatments resulted in statistically significant improvements (p < 0.05) of all clinical parameters without statistically significant intergroup differences (p > 0.05). Several bacterial species were reduced in both test groups, with statistically significantly higher reductions for LDD compared to PDT and the control group. In conclusion, the present data indicate that: (a) In periodontal patients enrolled in SPT, treatment of persistent/recurrent pockets with SI alone or combined with either PDT or LDD may lead to comparable clinical improvements and (b) the adjunctive use of LDD appears to provide better microbiological improvements for some periodontal pathogens than SI alone or combined with PDT.
Simple Summary: Renal insufficiency is frequently seen in newly diagnosed multiple myeloma and can be due to the disease itself but also caused by medical interventions or infections. Patients with severe renal insufficiency are known to have an adverse prognosis, but recently, it was shown that even moderately impaired kidney function can have long-term sequelae. Achieving quick disease control by effective antimyeloma therapy can lead to the recovery of renal function. We investigated the kidney-specific variables in a large cohort of 770 myeloma patients receiving three different three-drug regimens for initial myeloma treatment to learn more about the differential effects on kidney function in an early disease phase. All regimens had a positive impact on kidney function without a difference in the proportion of patients who reached normal renal function after three cycles. Interestingly, patients who received bortezomib, lenalidomide, and dexamethasone tended to have higher risk for a worse renal function following induction when compared to the initial values.
Abstract: Background: Preservation of kidney function in newly diagnosed (ND) multiple myeloma (MM) helps to prevent excess toxicity. Patients (pts) from two prospective trials were analyzed, provided postinduction (PInd) restaging was performed. Pts received three cycles with bortezomib (btz), cyclophosphamide, and dexamethasone (dex; VCD) or btz, lenalidomide (len), and dex (VRd) or len, adriamycin, and dex (RAD). The minimum required estimated glomerular filtration rate (eGFR) was >30 mL/min. We analyzed the percent change of the renal function using the International Myeloma Working Group (IMWG) criteria and Kidney Disease: Improving Global Outcomes (KDIGO)-defined categories. Results: Seven hundred and seventy-two patients were eligible. Three hundred and fifty-six received VCD, 214 VRd, and 202 RAD. VCD patients had the best baseline eGFR. The proportion of pts with eGFR <45 mL/min decreased from 7.3% at baseline to 1.9% PInd (p < 0.0001). Thirty-seven point one percent of VCD versus 49% of VRd patients had a decrease of GFR (p = 0.0872). IMWG-defined “renal complete response (CRrenal)” was achieved in 17/25 (68%) pts after VCD, 12/19 (63%) after RAD, and 14/27 (52%) after VRd (p = 0.4747). Conclusions: Analyzing a large and representative newly diagnosed myeloma (NDMM) group, we found no difference in CRrenal that occurred independently from the myeloma response across the three regimens. A trend towards deterioration of the renal function with VRd versus VCD may be explained by a better pretreatment “renal fitness” in the latter group.
Simple Summary: Forensic entomologists are most often tasked with determining when arthropods colonized living or deceased vertebrates. In most cases, this estimation involves humans; however, pets, livestock, and other domesticated animals can also be illegally killed or victims of neglect. Globally, there is no standard format for the case report, and much of the content is based on the personal preferences of the analyst or standards set within a country. The article below proposes a general overview of sections to be considered when drafting a case report.
Abstract: Forensic practitioners analyzing entomological evidence are faced with numerous challenges when presenting their findings to law practitioners, particularly in terms of terminology used to describe insect age, what this means for colonization time of remains, and the limitations to estimates made. Due to varying legal requirements in different countries, there is no standard format for the entomological case report prepared, nor any guidelines as to the sections that are required, optional or unnecessary in a case report. The authors herein propose sections that should be considered when drafting an entomological case report. The criteria under which entomological evidence is analyzed are discussed, as well as the limitations for each criterion. The concept of a global, standardized entomological case report is impossible to achieve due to national legislative differences, but the authors here propose a basic template which can be adapted and changed according to the needs of the practitioner. Furthermore, while the discussion is fairly detailed, capturing all differences between nations could not be accomplished, and those initiating casework for the first time are encouraged to engage other practicing forensic entomologists or professional associations within their own nation or region, to ensure a complete report is generated that meets lab or national requirements, prior to generating a finalized report.
Tumor antigen-specific redirection of cytotoxic T cells (CTLs) or natural killer (NK) cells including chimeric antigen receptor (CAR-) and T cell receptor (TCR-) cell therapy is currently being evaluated in different tumor entities including melanoma. Expression of melanoma-specific antigen recognized by the respective CAR or TCR directly or presented by HLA molecules is an indispensable prerequisite for this innovative therapy. In this study, we investigated in 168 FFPE tumor specimens of patients with stage I-IV melanoma the protein expression of HER2, TRP2, ABCB5, gp100, p53, and GD2 by immunohistochemistry (IHC). These results were correlated with clinical parameters. Membrane expression of HER2 and GD2 was also investigated in ten melanoma cell lines by flow cytometry for which corresponding tumors were analyzed by IHC. Our results demonstrated that gp100 was the most frequently overexpressed protein (61%), followed by TRP2 (50%), GD2 (38%), p53 (37%), ABCB5 (17%), and HER2 (3%). TRP2 expression was higher in primary tumors compared to metastases (p = 0.005). Accordingly, TRP2 and ABCB5 expression was significantly associated with lower tumor thickness of the primary (p = 0.013 and p = 0.025). There was no association between protein expression levels and survival in advanced melanoma patients. Flow cytometric analysis revealed abundant surface expression of GD2 and HER2 in all melanoma cell lines. The discordant HER2 expression in situ and in vitro suggests a tissue culture associated induction. In summary, our data support the use of gp100 and GD2 as a potential target for developing engineered TCR- or CAR-cell therapies, respectively, against melanoma.
Simple Summary: Currently, it is unclear which kind of axillary staging surgery breast cancer patients with lymph node metastasis should receive after neoadjuvant chemotherapy. For decades, these patients have been treated with a full axillary lymph node dissection, even if they converted to clinical node negativity. However, the removal of a large number of lymph nodes during the procedure can increase arm morbidity and impact quality of life. Therefore, several studies investigated less radical surgical strategies in this setting, such as sentinel lymph node biopsy or targeted axillary dissection, i.e., removal of a previously marked node combined with sentinel node removal. In this review, we summarize current evidence on the different surgical techniques and compare national and international recommendations. We show that many questions regarding oncological safety of different surgery types and the optimal marking technique remain unanswered and present the multinational prospective cohort study AXSANA that will address these open issues.
Abstract: In the last two decades, surgical methods for axillary staging in breast cancer patients have become less extensive, and full axillary lymph node dissection (ALND) is confined to selected patients. In initially node-positive patients undergoing neoadjuvant chemotherapy, however, the optimal management remains unclear. Current guidelines vary widely, endorsing different strategies. We performed a literature review on axillary staging strategies and their place in international recommendations. This overview defines knowledge gaps associated with specific procedures, summarizes currently ongoing clinical trials that address these unsolved issues, and provides the rationale for further research. While some guidelines have already implemented surgical de-escalation, replacing ALND with, e.g., sentinel lymph node biopsy (SLNB) or targeted axillary dissection (TAD) in cN+ patients converting to clinical node negativity, others recommend ALND. Numerous techniques are in use for tagging lymph node metastasis, but many questions regarding the marking technique, i.e., the optimal time for marker placement and the number of marked nodes, remain unanswered. The optimal number of SLNs to be excised also remains a matter of debate. Data on oncological safety and quality of life following different staging procedures are lacking. These results provide the rationale for the multinational prospective cohort study AXSANA initiated by EUBREAST, which started enrollment in June 2020 and aims at recruiting 3000 patients in 20 countries (NCT04373655; Funded by AGO-B, Claudia von Schilling Foundation for Breast Cancer Research, AWOgyn, EndoMag, Mammotome, and MeritMedical).
The pathophysiological role of neural autoantibodies in acute psychotic disorders is receiving increased attention. However, there is still an ongoing debate, whether predominantly psychotic manifestations of autoimmune encephalitides exist that may remain undetected and, thus, untreated. Furthermore, it is discussed if such conditions can be diagnosed based on serum antibody results or if a reliable diagnosis requires additional cerebrospinal fluids (CSF) results. In this study, we screened pairs of serum and CSF samples from antipsychotic-naïve individuals with first-episode schizophrenic psychosis (FEP, n = 103), clinical high risk for psychosis (CHR, n = 47), and healthy volunteers (HV, n = 40) for eight different antibodies against various antigens that have been shown to be associated with autoimmune encephalitides: N-methyl-D-aspartate receptor (NMDAR, NR1 subunits only), glutamic acid decarboxylase (GAD65), leucine-rich glioma inactivated protein 1 (LGI1), contactin-associated protein-like 2 protein (CASPR2), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit 1, AMPAR subunit 2, γ-aminobutyric acid-B receptors (GABABR), and glycine receptors. All patients were within the norm with regards to a careful neurological examination, a magnetic resonance imaging (MRI) of the brain, an electroencephalogram (EEG), and routine blood pathology. All CSF samples were autoantibody-negative. In three serum samples of individuals with FEP, we detected low-titer CASPR2 immunoglobulin (Ig) G antibodies (≤1:160, n = 2) and non-IgG antibodies against NMDAR (n = 1) (overall serum-autoantibody prevalence in FEP: 2.91%). However, the IgG titers were below the laboratory cut-off defined for positivity, and non-IgG antibodies are of no clinical relevance. This suggests that there were no cases of autoimmune encephalitis in our cohort. Our results highlight the importance and the high specificity of CSF analysis to reliably detect autoantibodies. They confirm the hypothesis that pure psychotic manifestations of antibody-associated autoimmune encephalitides without any additional neuropsychiatric findings are very rare. However, special attention must be paid to those presenting with atypical mental illnesses with additional neurological symptoms, evidence of clinically-significant cognitive involvement, profound sleep-wake perturbations, seizures, electroencephalographic, or magnetic resonance imaging pathologies to be able to identify cases with autoimmune-mediated psychiatric syndromes.
Background: Treatment of first-time shoulder dislocation (FSD) is a topic of debate. After high rates of recurrent instability after nonoperative management were reported in the literature, primary repair of FSD significantly increased. At the same time, new concepts were proposed that had promising results for immobilization in external rotation (ER) and abduction (ABD). Purpose: The aim of this study was to evaluate the recurrence rates (primary outcome) and clinical outcomes (secondary outcome parameters) of immobilization in ER+ABD versus arthroscopic primary stabilization after FSD. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: In a multicenter randomized controlled trial, patients with FSD were randomized to either treatment with immobilization in 60° of ER plus 30° of ABD (group 1) or surgical treatment with arthroscopic Bankart repair (group 2). Clinical evaluation was performed 1, 3, and 6 weeks as well as 6, 12, and 24 months postoperatively or after reduction, including range of motion, instability testing, subjective shoulder value, Constant-Murley score, Rowe score, and Western Ontario Shoulder Instability Index. Recurrent instability events were prospectively recorded. Results: Between 2011 and 2017, a total of 112 patients were included in this study. Of these, 60 patients were allocated to group 1 and 52 to group 2. At the 24-month follow-up, 91 patients (81.3%) were available for clinical examination. The recurrence rate was 19.1% in group 1 and 2.3% in group 2 (P = .016). No significant differences were found between groups regarding clinical shoulder scores (P > .05). Due to noncompliance with the immobilization treatment protocol, 4 patients (6.7%) were excluded. Conclusion: Immobilization in ER+ABD versus primary arthroscopic shoulder stabilization for the treatment of FSD showed no differences in clinical shoulder scores. However, recurrent instability was significantly higher after nonoperative treatment.
Background: Gan–Dou–Fu–Mu decoction (GDFMD) improves liver fibrosis in experimental and clinical studies including those on toxic mouse model of Wilson disease (Model). However, the mechanisms underlying the effect of GDFMD have not been characterized. Herein, we deciphered the potential therapeutic targets of GDFMD using transcriptome analysis.
Methods: We constructed a tx-j Wilson disease (WD) mouse model, and assessed the effect of GDFMD on the liver of model mice by hematoxylin and eosin, Masson, and immunohistochemical staining. Subsequently, we identified differentially expressed genes (DEGs) that were upregulated in the Model (Model vs. control) and those that were downregulated upon GDFMD treatment (compared to the Model) using RNA-sequencing (RNA-Seq). Biological functions and signaling pathways in which the DEGs were involved were determined by gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway analyses. A protein–protein interaction (PPI) network was constructed using the STRING database, and the modules were identified using MCODE plugin with the Cytoscape software. Several genes identified in the RNA-Seq analysis were validated by real-time quantitative PCR. Results: Total of 2124 DEGs were screened through the Model vs. control and Model vs. GDFMD comparisons, and dozens of GO and KEGG pathway terms modulated by GDFMD were identified. Dozens of pathways involved in metabolism (including metabolic processes for organic acids, carboxylic acids, monocarboxylic acids, lipids, fatty acids, cellular lipids, steroids, alcohols, eicosanoids, long-chain fatty acids), immune and inflammatory response (such as complement and coagulation cascades, cytokine–cytokine receptor interaction, inflammatory mediator regulation of TRP channels, antigen processing and presentation, T-cell receptor signaling pathway), liver fibrosis (such as ECM-receptor interactions), and cell death (PI3K-Akt signaling pathway, apoptosis, TGF-beta signaling pathway, etc.) were identified as potential targets of GDFMD in the Model. Some hub genes and four modules were identified in the PPI network. The results of real-time quantitative PCR analysis were consistent with those of RNA-Seq analysis. Conclusions: We performed gene expression profiling of GDFMD-treated WD model mice using RNA-Seq analysis and found the genes, pathways, and processes effected by the treatment. Our study provides a theoretical basis to prevent liver fibrosis resulting from WD using GDFMD.
Simple Summary: Mutations in RAS-family genes frequently cause different types of human cancers. Inhibitors of the MEK (mitogen-activated protein kinase) and ERK (extracellular signal-regulated kinase) protein kinases that function downstream of RAS proteins have shown some clinical benefits when used for the treatment of these cancers, but drug resistance frequently emerges. Here we show that combined treatment with MEK and ERK inhibitors blocks the emergence of resistance to either drug alone. However, if cancer cells have already developed resistance to MEK inhibitors or to ERK inhibitors, the combined therapy is frequently ineffective. These findings imply that these inhibitors should be used together for cancer therapy. We also show that drug resistance involves complex patterns of rewiring of cellular kinase signaling networks that do not overlap between each different cancer cell line. Nonetheless, we show that MAP4K4 is required for efficient cell proliferation in several different MEK/ERK inhibitor resistant cancer cell lines, uncovering a potential new therapeutic target.
Abstract: Oncogenic mutations in RAS family genes arise frequently in metastatic human cancers. Here we developed new mouse and cellular models of oncogenic HrasG12V-driven undifferentiated pleomorphic sarcoma metastasis and of KrasG12D-driven pancreatic ductal adenocarcinoma metastasis. Through analyses of these cells and of human oncogenic KRAS-, NRAS- and BRAF-driven cancer cell lines we identified that resistance to single MEK inhibitor and ERK inhibitor treatments arise rapidly but combination therapy completely blocks the emergence of resistance. The prior evolution of resistance to either single agent frequently leads to resistance to dual treatment. Dual MEK inhibitor plus ERK inhibitor therapy shows anti-tumor efficacy in an HrasG12V-driven autochthonous sarcoma model but features of drug resistance in vivo were also evident. Array-based kinome activity profiling revealed an absence of common patterns of signaling rewiring in single or double MEK and ERK inhibitor resistant cells, showing that the development of resistance to downstream signaling inhibition in oncogenic RAS-driven tumors represents a heterogeneous process. Nonetheless, in some single and double MEK and ERK inhibitor resistant cell lines we identified newly acquired drug sensitivities. These may represent additional therapeutic targets in oncogenic RAS-driven tumors and provide general proof-of-principle that therapeutic vulnerabilities of drug resistant cells can be identified.
Neurogenic/neuropathic bowel dysfunction (NBD) is common in children who are affected by congenital and acquired neurological disease, and negatively impacts quality of life. In the past, NBD received less attention than neurogenic bladder, generally being considered only in spina bifida (the most common cause of pediatric NBD). Many methods of conservative and medical management of NBD are reported, including relatively recently Transanal Irrigation (TAI). Based on the literature and personal experience, an expert group (pediatric urologists/surgeons/gastroenterologists with specific experience in NBD) focused on NBD in children and adolescents. A statement document was created using a modified Delphi method. The range of causes of pediatric NBD are discussed in this paper. The various therapeutic approaches are presented to improve clinical management. The population of children and adolescents with NBD is increasing, due both to the higher survival rate and better diagnosis. While NBD is relatively predictable in producing either constipation or fecal incontinence, or both, its various effects on each patient will depend on a wide range of underlying causes and accompanying comorbidities. For this reason, management of NBD should be tailored individually with a combined multidisciplinary therapy appropriate for the status of the affected child and caregivers.
Postoperative Psychosen
(1916)
Background: Myocardial efficiency should be maintained stable under light-to-moderate stress conditions, but ischemia puts the myocardium at risk for impaired functionality. Additionally, the measurement of such efficiency typically requires invasive heart catheterization and exposure to ionizing radiation. In this work, we aimed to non-invasively assess myocardial power and the resulting efficiency during pharmacological stress testing and ischemia induction. Methods: In a cohort of n = 10 healthy Landrace pigs, dobutamine stress testing was performed, followed by verapamil-induced ischemia alongside cardiac magnetic resonance (CMR) imaging. External myocardial power, internal myocardial power, and myocardial efficiency were assessed non-invasively using geometrical and functional parameters from CMR volumetric as well as blood flow and pressure measurements. Results: External myocardial power significantly increased under dobutamine stress [2.3 (1.6–3.1) W/m2 vs. 1.3 (1.1–1.6) W/m2, p = 0.005] and significantly decreased under verapamil-induced ischemia [0.8 (0.5–0.9) W/m2, p = 0.005]. Internal myocardial power [baseline: 5.9 (4.6–8.5) W/m2] was not affected by dobutamine [7.5 (6.9–9.0) W/m2, p = 0.241] nor verapamil [5.8 (4.7–8.8) W/m2, p = 0.878]. Myocardial efficiency did not change from baseline to dobutamine [21% (15–27) vs. 31% (20–44), p = 0.059] but decreased significantly during verapamil-induced ischemia [10% (8–13), p = 0.005]. Conclusion: In healthy Landrace pigs, dobutamine stress increased external myocardial power, whereas myocardial efficiency was maintained stable. On the contrary, verapamil-induced ischemia substantially decreased external myocardial power and myocardial efficiency. Non-invasive CMR was able to quantify these efficiency losses and might be useful for future clinical studies evaluating the effects of therapeutic interventions on myocardial energetics.
The effects of exercise interventions on unspecific chronic low back pain (CLBP) have been investigated in many studies, but the results are inconclusive regarding exercise types, efficiency, and sustainability. This may be because the influence of psychosocial factors on exercise induced adaptation regarding CLBP is neglected. Therefore, this study assessed psychosocial characteristics, which moderate and mediate the effects of sensorimotor exercise on LBP. A single-blind 3-arm multicenter randomized controlled trial was conducted for 12-weeks. Three exercise groups, sensorimotor exercise (SMT), sensorimotor and behavioral training (SMT-BT), and regular routines (CG) were randomly assigned to 662 volunteers. Primary outcomes (pain intensity and disability) and psychosocial characteristics were assessed at baseline (M1) and follow-up (3/6/12/24 weeks, M2-M5). Multiple regression models were used to analyze whether psychosocial characteristics are moderators of the relationship between exercise and pain, meaning that psychosocial factors and exercise interact. Causal mediation analysis were conducted to analyze, whether psychosocial characteristics mediate the exercise effect on pain. A total of 453 participants with intermittent pain (mean age = 39.5 ± 12.2 years, f = 62%) completed the training. It was shown, that depressive symptomatology (at M4, M5), vital exhaustion (at M4), and perceived social support (at M5) are significant moderators of the relationship between exercise and the reduction of pain intensity. Further depressive mood (at M4), social-satisfaction (at M4), and anxiety (at M5 SMT) significantly moderate the exercise effect on pain disability. The amount of moderation was of clinical relevance. In contrast, there were no psychosocial variables which mediated exercise effects on pain. In conclusion it was shown, that psychosocial variables can be moderators in the relationship between sensorimotor exercise induced adaptation on CLBP which may explain conflicting results in the past regarding the merit of exercise interventions in CLBP. Results suggest further an early identification of psychosocial risk factors by diagnostic tools, which may essential support the planning of personalized exercise therapy.
Specific protocols define eligibility, conditioning, donor selection, graft composition and prophylaxis of graft vs. host disease for children and young adults undergoing hematopoietic stem cell transplant (HSCT). However, international protocols rarely, if ever, detail supportive care, including pharmaceutical infection prophylaxis, physical protection with face masks and cohort isolation or food restrictions. Supportive care suffers from a lack of scientific evidence and implementation of practices in the transplant centers brings extensive restrictions to the child's and family's daily life after HSCT. Therefore, the Board of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) held a series of dedicated workshops since 2017 with the aim of initiating the production of a set of minimal recommendations. The present paper describes the consensus reached within the field of infection prophylaxis.
The bile acid pool with its individual bile acids (BA) is modulated in the enterohepatic circulation by the liver as the primary site of synthesis, the motility of the gallbladder and of the intestinal tract, as well as by bacterial enzymes in the intestine. The nuclear receptor farnesoid X receptor (FXR) and Gpbar1 (TGR5) are important set screws in this process. Bile acids have a vasodilatory effect, at least according to in vitro studies. The present review examines the question of the extent to which the increase in bile acids in plasma could be responsible for the hyperdynamic circulatory disturbance of liver cirrhosis and whether modulation of the bile acid pool, for example, via administration of ursodeoxycholic acid (UDCA) or via modulation of the dysbiosis present in liver cirrhosis could influence the hemodynamic disorder of liver cirrhosis. According to our analysis, the evidence for this is limited. Long-term studies on this question are lacking.
Optimal distribution-preserving downsampling of large biomedical data sets (opdisDownsampling)
(2021)
Motivation: The size of today’s biomedical data sets pushes computer equipment to its limits, even for seemingly standard analysis tasks such as data projection or clustering. Reducing large biomedical data by downsampling is therefore a common early step in data processing, often performed as random uniform class-proportional downsampling. In this report, we hypothesized that this can be optimized to obtain samples that better reflect the entire data set than those obtained using the current standard method. Results: By repeating the random sampling and comparing the distribution of the drawn sample with the distribution of the original data, it was possible to establish a method for obtaining subsets of data that better reflect the entire data set than taking only the first randomly selected subsample, as is the current standard. Experiments on artificial and real biomedical data sets showed that the reconstruction of the remaining data from the original data set from the downsampled data improved significantly. This was observed with both principal component analysis and autoencoding neural networks. The fidelity was dependent on both the number of cases drawn from the original and the number of samples drawn. Conclusions: Optimal distribution-preserving class-proportional downsampling yields data subsets that reflect the structure of the entire data better than those obtained with the standard method. By using distributional similarity as the only selection criterion, the proposed method does not in any way affect the results of a later planned analysis.