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Background: Correct species identification of blow flies is a crucial step for understanding their biology, which can be used not only for designing fly control programs, but also to determine the minimum time since death. Identification techniques are usually based on morphological and molecular characters. However, the use of classical morphology requires experienced entomologists for correct identification; while molecular techniques rely on a sound laboratory expertise and remain ambiguous for certain taxa. Landmark-based geometric morphometric analysis of insect wings has been extensively applied in species identification. However, few wing morphometric analyses of blow fly species have been published.
Methods: We applied a landmark-based geometric morphometric analysis of wings for species identification of 12 medically and forensically important blow fly species of Thailand. Nineteen landmarks of each right wing of 372 specimens were digitised. Variation in wing size and wing shape was analysed and evaluated for allometric effects. The latter confirmed the influence of size on the shape differences between species and sexes. Wing shape variation among genera and species were analysed using canonical variates analysis followed by a cross-validation test.
Results: Wing size was not suitable for species discrimination, whereas wing shape can be a useful tool to separate taxa on both, genus and species level depending on the analysed taxa. It appeared to be highly reliable, especially for classifying Chrysomya species, but less robust for a species discrimination in the genera Lucilia and Hemipyrellia. Allometry did not affect species separation but had an impact on sexual shape dimorphism.
Conclusions: A landmark-based geometric morphometric analysis of wings is a useful additional method for species discrimination. It is a simple, reliable and inexpensive method, but it can be time-consuming locating the landmarks for a large scale study and requires non-damaged wings for analysis.
Hintergrund: Es ist unbekannt bzw. umstritten, ob die in Deutschland eingeführten Umweltzonen (UWZ) die Feinstaubbelastung nachweisbar reduzieren.
Methode: PM10-Konzentrationen von den Messstationen innerhalb und außerhalb der UWZ in 19 deutschen Städten wurden analysiert (Augsburg, Berlin, Dortmund, Duisburg, Düsseldorf, Essen, Frankfurt a. M., Hannover, Herrenberg, Ilsfeld, Karlsruhe, Köln, Ludwigsburg, Mannheim, München, Reutlingen, Stuttgart, Tübingen, Wuppertal), um die Wirksamkeit der Fahrverbote (Stufe 1) für Fahrzeuge der Schadstoffgruppe 1 (ohne Plakette) auf die Schadstoffkonzentration zu untersuchen. Kontinuierliche Halbstundenmesswerte und gravimetrische Tagesmittelwerte wurden für den Zeitraum von ca. 2005 bis Ende 2009 übernommen. Die Analyse beruht auf vier einander paarweise zugeordneten Messwerten als gematchte Quadrupel aus zwei Index- und zwei Referenzwerten (Indexstationen liegen innerhalb, Referenzstationen messen außerhalb der UWZ). Ein Indexwert und der simultan gemessene Referenzwert wurden während der aktiven Phase der UWZ gemessen, das andere Wertepaar wurde vor Einführung der UWZ erhoben. Die Wertepaare haben eine Zeitdifferenz von 364 Tagen oder von einem Vielfachen von 364 Tagen, wodurch die Jahreszeit, der Wochentag und die Tageszeit im Quadrupel konstant gehalten werden. Differenzen der Indexwerte wurden regressionstechnisch mit den Differenzen der Referenzwerte korrigiert, wobei meteorologische Parameter (Mischungsschichthöhe, Niederschlagsmenge, Windgeschwindigkeit), Schulferienzeiten, Phase der Umweltprämie, LKW-Fahrverbotszeiten und Ausgangswerte an den Index- und Referenzstationen als Kovariablen in sog. „fixed effects“ Regressionsanalysen der Quadrupel berücksichtigt wurden (Differenzwertmethode im Zwei-Perioden-Fall). Dieser statistische Ansatz wurde vor der eigentlichen Datenanalyse an simulierten Messdaten der FU Berlin erfolgreich erprobt.
Ergebnisse: 2 110 803 Quadrupel kontinuierlicher PM10-Messungen und 15 735 gravimetrische Quadrupel wurden aus den verfügbaren Daten der Messstationen identifiziert, aus denen 61 169 Quadrupel zu Tagesmittelwerten aufgebaut wurden. Die Analysen für die erste Stufe ergaben als beste Effektschätzer (an allen Indexstationen) eine Feinstaubreduktion von ≤ 0,2 μg/m3 (bzw. relative PM10-Reduktionen ≤ 1 %). Der beste Effektschätzer an allen Verkehrsstationen (also ohne städtische Hintergrund- und Industrieindexstationen) lag unterhalb von 1 μg/m3 (bzw. weniger als 5 %).
Schlussfolgerungen: Alle Analysewerte liegen damit unter den vor Einführung von UWZ prognostizierten Feinstaubreduktionen. Diese Studie untersuchte als erste übergreifend die Wirksamkeit von UWZ der Stufe 1 in Deutschland auf die Feinstaubkonzentrationen von PM10 nach einem einheitlichen Datensammlungs- und Analyseplan und unter Berücksichtigung möglichst vieler Störeinflüsse.
Wirkung von Glia-Maturationsfaktor (GMF) und Adhäsionsfaktor (ADF) auf Kulturen leukämischer Zellen
(1987)
GMF was isolated from the glia of different brain parts of calf. Its influence on the input of 3H-TdR was tested in leukaemic and non-malignant lymphocites. GMF isolated from the diencephalon proved to be the most effective one. The used substance of reference was DBcAMP. The cAMP contents of leukaemic cells were lower than those of non-malignant cells, whereas the level of cGMP was higher in the first ones. We found both in non-malignant cultures and in cultures of leukaemic cells that the impact of GMF and AdF elevated the cAMP value and reduced cGMP. The adhesion of cAMP to the nuclei of leukaemic was reduced in comparison with non-malignant cells. The nuclei of leukaemic cells showed increased adhesive capacity after pre-incubation with GMF and AdF. The adhesive capacity of non-malignant nuclei remained unchanged. The adenylcyclase activity (AC) was diminished in leukaemic cells. It could not be stimulated by means of catecholamines. GMF and AdF produced a slight increase of the basal Ac activity in cultures of leukaemic cells only. But isoproterenol led to a distinct increase of the Ac activity in leukaemic cells when incubation with those two factors preceded it.
Neues Wissen erzeugt gleichzeitig auch Nichtwissen. Wie damit umzugehen ist, wirft in kaum einem Forschungsgebiet so viele Fragen auf wie in der Medizin. So kann die Pränataldiagnostik heute schon im ersten Schwangerschaftsdrittel bestimmte, früher nicht behandelbare Fehlbildungen erkennen. Dadurch entstehen komplexe Behandlungssituationen, die Eltern mit bisher nicht bekannten Unwägbarkeiten konfrontieren. Forschende aus Medizin und Soziologie untersuchen gemeinsam, wie Eltern während und nach der Schwangerschaft auf die schwierige Situation reagieren.
Background: Using data from the COHERE collaboration, we investigated whether primary prophylaxis for pneumocystis pneumonia (PcP) might be withheld in all patients on antiretroviral therapy (ART) with suppressed plasma human immunodeficiency virus (HIV) RNA (≤400 copies/mL), irrespective of CD4 count.
Methods: We implemented an established causal inference approach whereby observational data are used to emulate a randomized trial. Patients taking PcP prophylaxis were eligible for the emulated trial if their CD4 count was ≤200 cells/µL in line with existing recommendations. We compared the following 2 strategies for stopping prophylaxis: (1) when CD4 count was >200 cells/µL for >3 months or (2) when the patient was virologically suppressed (2 consecutive HIV RNA ≤400 copies/mL). Patients were artificially censored if they did not comply with these stopping rules. We estimated the risk of primary PcP in patients on ART, using the hazard ratio (HR) to compare the stopping strategies by fitting a pooled logistic model, including inverse probability weights to adjust for the selection bias introduced by the artificial censoring.
Results: A total of 4813 patients (10 324 person-years) complied with eligibility conditions for the emulated trial. With primary PcP diagnosis as an endpoint, the adjusted HR (aHR) indicated a slightly lower, but not statistically significant, different risk for the strategy based on viral suppression alone compared with the existing guidelines (aHR, .8; 95% confidence interval, .6–1.1; P = .2).
Conclusions: This study suggests that primary PcP prophylaxis might be safely withheld in confirmed virologically suppressed patients on ART, regardless of their CD4 count.
Reproducing the characteristics and the functional responses of the blood–brain barrier (BBB) in vitro represents an important task for the research community, and would be a critical biotechnological breakthrough. Pharmaceutical and biotechnology industries provide strong demand for inexpensive and easy-to-handle in vitro BBB models to screen novel drug candidates. Recently, it was shown that canonical Wnt signaling is responsible for the induction of the BBB properties in the neonatal brain microvasculature in vivo. In the present study, following on from earlier observations, we have developed a novel model of the BBB in vitro that may be suitable for large scale screening assays. This model is based on immortalized endothelial cell lines derived from murine and human brain, with no need for co-culture with astrocytes. To maintain the BBB endothelial cell properties, the cell lines are cultured in the presence of Wnt3a or drugs that stabilize β-catenin, or they are infected with a transcriptionally active form of β-catenin. Upon these treatments, the cell lines maintain expression of BBB-specific markers, which results in elevated transendothelial electrical resistance and reduced cell permeability. Importantly, these properties are retained for several passages in culture, and they can be reproduced and maintained in different laboratories over time. We conclude that the brain-derived endothelial cell lines that we have investigated gain their specialized characteristics upon activation of the canonical Wnt pathway. This model may be thus suitable to test the BBB permeability to chemicals or large molecular weight proteins, transmigration of inflammatory cells, treatments with cytokines, and genetic manipulation.
The blood–brain barrier (BBB) is confined to the endothelium of brain capillaries and is indispensable for fluid homeostasis and neuronal function. In this study, we show that endothelial Wnt/beta-catenin (beta-cat) signaling regulates induction and maintenance of BBB characteristics during embryonic and postnatal development. Endothelial specific stabilization of beta-cat in vivo enhances barrier maturation, whereas inactivation of beta-cat causes significant down-regulation of claudin3 (Cldn3), up-regulation of plamalemma vesicle-associated protein, and BBB breakdown. Stabilization of beta-cat in primary brain endothelial cells (ECs) in vitro by N-terminal truncation or Wnt3a treatment increases Cldn3 expression, BBB-type tight junction formation, and a BBB characteristic gene signature. Loss of beta-cat or inhibition of its signaling abrogates this effect. Furthermore, stabilization of beta-cat also increased Cldn3 and barrier properties in nonbrain-derived ECs. These findings may open new therapeutic avenues to modulate endothelial barrier function and to limit the devastating effects of BBB breakdown.
Background: Wnt signaling controls the balance between stem cell proliferation and differentiation and body patterning throughout development. Previous data demonstrated that non-canonical Wnts (Wnt5a, Wnt11) increased cardiac gene expression of circulating endothelial progenitor cells (EPC) and bone marrow-derived stem cells cultured in vitro. Since previous studies suggested a contribution of the protein kinase C (PKC) family to the Wnt5a-induced signalling, we investigated which PKC isoforms are activated by non-canonical Wnt5a in human EPC. Methodology/Principal Findings: Immunoblot experiments demonstrated that Wnt5a selectively activated the novel PKC isoform, PKC delta, as evidenced by phosphorylation and translocation. In contrast, the classical Ca2+-dependent PKC isoforms, PKC alpha and beta2, and one of the other novel PKC isoforms, PKC epsilon, were not activated by Wnt5a. The PKC delta inhibitor rottlerin significantly blocked co-culture-induced cardiac differentiation in vitro, whereas inhibitors directed against the classical Ca2+-dependent PKC isoforms or a PKC epsilon-inhibitory peptide did not block cardiac differentiation. In accordance, EPC derived from PKC delta heterozygous mice exhibited a significant reduction of Wnt5a-induced cardiac gene expression compared to wild type mice derived EPC. Conclusions/Significance: These data indicate that Wnt5a enhances cardiac gene expressions of EPC via an activation of PKC delta.
Background: The aim of this study was to investigate the acceptance and assessment of work shadowing carried out by students and dentists in dental practices. Furthermore, the extent to which students perceive an improvement in their specialised, communication and social competencies, was to be examined.
Methods: 61 dental students in their clinical semesters at a German university participated in work shadowing placements at 27 different general dental practices. Before beginning, they received checklists of various competencies that they self-assessed using school grades (from 1 = "very good", to 6 = "failed"), which they also repeated after completion. The dentists supplemented this with their external assessments. In addition, the students were requested to fill out a 54-item questionnaire and compose a freely-structured report after the work shadowing; the dentists filled out a questionnaire containing 16 items. The statistical analysis was carried out by means of the Friedman Test, including a post-hoc test (Bonferroni-Holm correction).
Results: The analysis showed a significant overall improvement in the students’ self-assessed competencies by 0.71* ± 0.43 grades. With an average of 0.33* ± 0.36, the dentists’ external assessment proved significantly higher than the self-assessment. The greatest improvements were perceived by the students in the areas of accounting (1.17* ± 0.77), practice organisation (1.05* ± 0.61) and dentist’s discussions (0.94* ±0.80) [*p < 0.05]. The students confirmed experiencing an expansion of knowledge, an improvement in their communication skills and indicated a high degree of satisfaction in regard to the dentists (school grade 1.58 ± 0.93). A maximum amount of satisfaction towards the work shadow students was demonstrated by the dentists, and this form of teaching was assessed with a school grade of 1.69 ± 0.89.
Conclusion: Both students and dental practitioners demonstrated a high level of satisfaction in regard to the work shadowing. The students felt their knowledge had increased, viewed the dentists as motivating role models and acknowledged a significant improvement in their specialised, communication and social competencies. Work shadowing in dental teaching practices presents a sensible addition to academic teaching at a university.
Background: Only few studies deal with the workload of physical therapists and the health consequences, although this occupational group is quite important for the health care system in many industrialized countries (e.g. ca. 136 000 people are currently employed as physical therapists in Germany). Therefore, the current state of knowledge of work-related diseases and disorders of physical therapists is insufficient. The aim of the "Physical Therapist Cohort" (PTC) study is to analyze the association between work-related exposures and diseases among physical therapists in Germany. This article describes the protocol of the baseline assessment of the PTC study.
Methods/Design: A cross-sectional study will be conducted as baseline assessment and will include a representative random sample of approximately 300 physical therapists employed in Germany (exposure group), and a population-based comparison group (n = 300). The comparison group will comprise a sample of working aged (18–65 years) inhabitants of a German city. Variables of interest will be assessed using a questionnaire manual including questions regarding musculoskeletal, dermal, and infectious diseases and disorders as well as psychosocial exposures, diseases and disorders. In addition to subjective measures, a clinical examination will be used to objectify the questionnaire-based results (n = 50).
Discussion: The study, which includes extensive data collection, provides a unique opportunity to study the prospective association of work-related exposures and associated complaints of physical therapists. Baseline results will give first clues with regard to whether and how prevalent main exposures of physiotherapeutic work and typical work areas of physical therapists are associated with the development of work-related diseases. Thereby, this baseline assessment provides the basis for further investigations to examine causal relationships in accordance with a longitudinal design.
Background: Depression and anxiety are the most prevalent mental health difficulties in the workplace, costing the global economy $1 trillion each year. Evidence indicates that symptoms may be reduced by interventions in the workplace. This paper is the first to systematically review psychosocial interventions for depression, anxiety, and suicidal ideation and behaviours in small-to medium-size enterprises (SMEs).
Methods: A systematic search following PRISMA guidelines, registered in PROSPERO (CRD42020156275), was conducted for psychosocial interventions targeting depression, anxiety, and suicidal ideation/behaviour in SMEs. The PubMed, PsycINFO, Scopus, and two specific occupational health databases were searched, as well as four databases for grey literature, without time limit until 2nd December 2019.
Results: In total, 1283 records were identified, 70 were retained for full-text screening, and seven met the inclusion criteria: three randomised controlled trials (RCTs), three before and after designs and one non-randomised trial, comprising 5111 participants. Study quality was low to moderate according to the Quality Assessment Tool for Quantitative Studies. Five studies showed a reduction in depression and anxiety symptoms using techniques based on cognitive behavioural therapy (CBT), two reported no significant change.
Limitations: Low number and high heterogeneity of interventions and outcomes, high attrition and lack of rigorous RCTs.
Conclusions: Preliminary evidence indicates CBT-based interventions can be effective in targeting symptoms of depression and anxiety in SME employees. There may be unique challenges to implementing programmes in SMEs. Further research is needed in this important area.
Background: Despite the numerous associations of vitamin D with health and disease, vitamin D deficiency is still common from a global perspective. While basic research, clinical and preventive activities grow constantly in vitamin D research, there is no in-depth analysis of the related global scientific productivity available so far.
Methods: Density equalizing mapping procedures (DEMP) were combined with socioeconomic benchmarks using the NewQIS platform.
Results: A total of 25,992 vitamin D-related research articles were identified between 1900 to 2014 with a significant increase (r2 = .6541) from 1900 to 2014. Authors located in Northern America – especially in the USA – distributed the majority of global vitamin D research, followed by their Western European counterparts. DEMP-analysis illustrates that Africa and South America exhibit only minor scientific productivity. Among high-income group countries, Scandinavian nations such as Denmark or Finland (2147.9 and 1607.7 vitamin D articles per GDP in 1000 billion USD) were highly active with regard to socioeconomic figures.
Conclusion: Networks dedicated to vitamin D research are present around the world. Overall, the Northern American and Western European nations occupy prominent positions. However, South American, African and Asian countries apart from Japan only play a minor role in the global research production related to vitamin D. Since vitamin D deficiency is currently increasing in the Americas, Europe and parts of the Middle East, research in these regions may need to be encouraged.
Background: A large number of idiosyncratic drug induced liver injury (iDILI) and herb induced liver injury(HILI) cases of variable quality has been published but some are a matter of concern if the cases were not evaluated for causality using a robust causality assessment method (CAM) such as RUCAM (Roussel Uclaf Causality Assessment Method) as diagnostiinjuryc algorithm. The purpose of this analysis was to evaluate the worldwide use of RUCAM in iDILI and HILI cases. Methods: The PubMed database (1993–30 June 2020) was searched for articles by using the following key terms: Roussel Uclaf Causality Assessment Method; RUCAM; Idiosyncratic drug induced liver injury; iDILI; Herb induced liver injury; HILI. Results: Considering reports published worldwide since 1993, our analysis showed the use of RUCAM for causality assessment in 95,885 cases of liver injury including 81,856 cases of idiosyncratic DILI and 14,029 cases of HILI. Among the top countries providing RUCAM based DILI cases were, in decreasing order, China, the US, Germany, Korea, and Italy, with China, Korea, Germany, India, and the US as the top countries for HILI. Conclusion: Since 1993 RUCAM is certainly the most widely used method to assess causality in IDILI and HILI. This should encourage practitioner, experts, and regulatory agencies to use it in order to reinforce their diagnosis and to take sound decisions.
In the past, the genetically diabetic-obese diabetes/diabetes (db/db) and obese/obese (ob/ob) mouse strains were used to investigate mechanisms of diabetes-impaired wound healing. Here we determined patterns of skin repair in genetically normal C57Bl/6J mice that were fed using a high fat diet (HFD) to induce a diabetes-obesity syndrome. Wound closure was markedly delayed in HFD-fed mice compared to mice which had received a standard chow diet (CD). Impaired wound tissue of HFD mice showed a marked prolongation of wound inflammation. Expression of vascular endothelial growth factor (VEGF) was delayed and associated with the disturbed formation of wound margin epithelia and an impaired angiogenesis in the reduced granulation tissue. Normal wound contraction was retarded and disordered. Wound disorders in obese C57Bl/6J mice were paralleled by a prominent degradation of the inhibitor of NFκB (IκB-α) in the absence of an Akt activation. By contrast to impaired wound conditions in ob/ob mice, late wounds of HFD mice did not develop a chronic inflammatory state and were epithelialized after 11 days of repair. Thus, only genetically obese and diabetic ob/ob mice finally developed chronic wounds and therefore represent a better suited experimental model to investigate diabetes-induced wound healing disorders.
Background: Patient information materials and decision aids are essential tools for helping patients make informed decisions and share in decision-making. The aim of this study was to investigate the quality of the written patient information materials available at general practices in Styria, Austria.
Methods: We asked general practitioners to send in all patient information materials available in their practices and to answer a short questionnaire. We evaluated the materials using the Ensuring Quality Information for Patients (EQIP-36) instrument.
Results: A total of 387 different patient information materials were available for quality assessment. These materials achieved an average score of 39 out of 100. The score was below 50 for 78% of all materials. There was a significant lack of information on the evidence base of recommendations. Only 9 % of the materials provided full disclosure of their evidence sources. We also found that, despite the poor quality of the materials, 89% of general practitioners regularly make active use of them during consultations with patients.
Conclusion: Based on international standards, the quality of patient information materials available at general practices in Styria is poor. The vast majority of the materials are not suitable as a basis for informed decisions by patients. However, most Styrian general practitioners use written patient information materials on a regular basis in their daily clinical practice. Thus, these materials not only fail to help raise the health literacy of the general population, but may actually undermine efforts to enable patients to make shared informed decisions. To increase health literacy, it is necessary to make high quality, evidence-based and easy-to-understand information material available to patients and the public. For this, it may be necessary to set up a centralized and independent clearinghouse.
Background and Aim. Spontaneous bacterial peritonitis (SBP) is one of the most common complications of liver cirrhosis. Antibiotics are the main treatment regimen of SBP. Traditional Chinese medicine Xuebijing injection has been used in such patients. Our study aimed to overview the efficacy of Xuebijing injection combined with antibiotics for the treatment of SBP.
Method. We searched the PubMed, Embase, China National Knowledge Infrastructure, VIP, and Wanfang databases. The search items included "Xuebijing", "peritonitis", "liver cirrhosis", and "random" to identify all relevant randomized controlled trials (RCTs). The Cochrane risk of bias tool was used to assess the study quality. The odd ratios (ORs) with 95% confidence intervals (CIs) were calculated by using a random-effect model. Heterogeneity was also calculated.
Results. A total of 9 RCTs were included. The study quality was unsatisfied. The overall (OR = 2.95, 95% CI = 1.97–4.42, p<0.00001) and complete (OR = 2.18, 95% CI = 1.57–3.04, p<0.00001) responses were significantly higher in the Xuebijing injection combined with antibiotics group than the antibiotics alone group. The incidence of cirrhosis related complications, including hepatic encephalopathy and hepatorenal syndrome, was lower in the Xuebijing injection combined with antibiotics group than the antibiotics alone group. No significant heterogeneity was observed among studies.
Conclusion. Additional use of Xuebijing injection may improve the efficacy of antibiotics for the treatment of SBP in liver cirrhosis. However, due to a low level of current evidence, we did not establish any recommendation regarding the use of Xuebijing injection for the treatment of SBP.
Background: The brain cancer stem cell (CSC) model describes a small subset of glioma cells as being responsible for tumor initiation, conferring therapy resistance and tumor recurrence. In brain CSC, the PI3-K/AKT and the RAS/mitogen activated protein kinase (MAPK) pathways are found to be activated. In consequence, the human transcription factor YB-1, knowing to be responsible for the emergence of drug resistance and driving adenoviral replication, is phosphorylated and activated. With this knowledge, YB-1 was established in the past as a biomarker for disease progression and prognosis. This study determines the expression of YB-1 in glioblastoma (GBM) specimen in vivo and in brain CSC lines. In addition, the capacity of Ad-Delo3-RGD, an YB-1 dependent oncolytic adenovirus, to eradicate CSC was evaluated both in vitro and in vivo.
Methods: YB-1 expression was investigated by immunoblot and immuno-histochemistry. In vitro, viral replication as well as the capacity of Ad-Delo3-RGD to replicate in and, in consequence, to kill CSC was determined by real-time PCR and clonogenic dilution assays. In vivo, Ad-Delo3-RGD-mediated tumor growth inhibition was evaluated in an orthotopic mouse GBM model. Safety and specificity of Ad-Delo3-RGD were investigated in immortalized human astrocytes and by siRNA-mediated downregulation of YB-1.
Results: YB-1 is highly expressed in brain CSC lines and in GBM specimen. Efficient viral replication in and virus-mediated lysis of CSC was observed in vitro. Experiments addressing safety aspects of Ad-Delo3-RGD showed that (i) virus production in human astrocytes was significantly reduced compared to wild type adenovirus (Ad-WT) and (ii) knockdown of YB-1 significantly reduced virus replication. Mice harboring othotopic GBM developed from a temozolomide (TMZ)-resistant GBM derived CSC line which was intratumorally injected with Ad-Delo3-RGD survived significantly longer than mice receiving PBS-injections or TMZ treatment.
Conclusion: The results of this study supported YB-1 based virotherapy as an attractive therapeutic strategy for GBM treatment which will be exploited further in multimodal treatment concepts.
Progranulin deficiency in humans is associated with neurodegeneration. Its mechanisms are not yet fully understood. We performed a Yeast-2-Hybrid screen using human full-length progranulin as bait to assess the interactions of progranulin. Progranulin was screened against human fetal brain and human bone marrow libraries using the standard Matchmaker technology (Clontech). This article contains the full Y2H data table, including blast results and sequences, a sorted table according to selection criteria for likely positive, putatively positive, likely false and false preys, and tables showing the gene ontology terms associated with the likely and putative preys of the brain and bone marrow libraries. The interactions with autophagy proteins were confirmed and functionally analyzed in "Progranulin overexpression in sensory neurons attenuates neuropathic pain in mice: Role of autophagy" (C. Altmann, S. Hardt, C. Fischer, J. Heidler, H.Y. Lim, A. Haussler, B. Albuquerque, B. Zimmer, C. Moser, C. Behrends, F. Koentgen, I. Wittig, M.H. Schmidt, A.M. Clement, T. Deller, I. Tegeder, 2016).
Background: A number of scientific papers on yellow fever have been published but no broad scientometric analysis on the published research of yellow fever has been reported. The aim of the article based study was to provide an in-depth evaluation of the yellow fever field using large-scale data analysis and employment of bibliometric indicators of production and quantity.
Methods: Data were retrieved from the Web of Science database (WoS) and analyzed as part of the NewQis platform. Then data were extracted from each file, transferred to databases and visualized as diagrams. Partially by means of density-equalizing mapping makes the findings clear and emphasizes the output of the analysis.
Results: In the study period from 1900 to 2012 a total of 5,053 yellow fever-associated items were published by 79 countries. The United States (USA) having the highest publication rate at 42% (n = 751) followed by far from Brazil (n = 203), France (n = 149) and the United Kingdom (n = 113). The most productive journals are the "Public Health Reports", the "American Journal of Tropical Medicine and Hygiene" and the "Journal of Virology". The gender analysis showed an overall steady increase of female authorship from 1950 to 2011. Brazil is the only country of the five most productive countries with a higher proportion of female scientists.
Conclusions: The present data shows an increase in research productivity over the entire study period, in particular an increase of female scientists. Brazil shows a majority of female authors, a fact that is confirmed by other studies.
Yellow fever virus (YFV) represents a re-emerging zoonotic pathogen, transmitted by mosquito vectors to humans from primate reservoirs. Sporadic outbreaks of YFV occur in endemic tropical regions, causing a viral hemorrhagic fever (VHF) associated with high mortality rates. Despite a highly effective vaccine, no antiviral treatments currently exist. Therefore, YFV represents a neglected tropical disease and is chronically understudied, with many aspects of YFV biology incompletely defined including host range, host–virus interactions and correlates of host immunity and pathogenicity. In this article, we review the current state of YFV research, focusing on the viral lifecycle, host responses to infection, species tropism and the success and associated limitations of the YFV-17D vaccine. In addition, we highlight the current lack of available treatments and use publicly available sequence and structural data to assess global patterns of YFV sequence diversity and identify potential drug targets. Finally, we discuss how technological advances, including real-time epidemiological monitoring of outbreaks using next-generation sequencing and CRISPR/Cas9 modification of vector species, could be utilized in future battles against this re-emerging pathogen which continues to cause devastating disease.
Survivin is a drug target and its suppressant YM155 a drug candidate mainly investigated for high-risk neuroblastoma. Findings from one YM155-adapted subline of the neuroblastoma cell line UKF-NB-3 had suggested that increased ABCB1 (mediates YM155 efflux) levels, decreased SLC35F2 (mediates YM155 uptake) levels, decreased survivin levels, and TP53 mutations indicate YM155 resistance. Here, the investigation of 10 additional YM155-adapted UKF-NB-3 sublines only confirmed the roles of ABCB1 and SLC35F2. However, cellular ABCB1 and SLC35F2 levels did not indicate YM155 sensitivity in YM155-naïve cells, as indicated by drug response data derived from the Cancer Therapeutics Response Portal (CTRP) and the Genomics of Drug Sensitivity in Cancer (GDSC) databases. Moreover, the resistant sublines were characterized by a remarkable heterogeneity. Only seven sublines developed on-target resistance as indicated by resistance to RNAi-mediated survivin depletion. The sublines also varied in their response to other anti-cancer drugs. In conclusion, cancer cell populations of limited intrinsic heterogeneity can develop various resistance phenotypes in response to treatment. Therefore, individualized therapies will require monitoring of cancer cell evolution in response to treatment. Moreover, biomarkers can indicate resistance formation in the acquired resistance setting, even when they are not predictive in the intrinsic resistance setting.
You are what you eat!
(2019)
Nowadays almost everyone is aware of the link between high blood cholesterol levels and cardiovascular disease. There are effective treatments that target blood cholesterol. his overview highlights some well known and some new mediators implicated in cardiovascular disease with the common theme that all of them can be influenced by the diet.
Mutations in the Von Hippel–Lindau (VHL) gene are the driving force in many forms of clear cell renal cell carcinoma (ccRCC) and promote hypoxia-inducible factor (HIF)-dependent tumor proliferation, metastasis and angiogenesis. Despite the progress that has already been made, ccRCC generally remain resistant to conventional therapies and ccRCC patients suffer from metastasis and acquired resistance, highlighting the need for novel therapeutic options. Cysteinyl leukotriene receptor 1 (CysLTR1) antagonists, like zafirlukast, are administered in bronchial asthma to control eicosanoid signaling. Intriguingly, long-term use of zafirlukast decreases cancer risk and leukotriene receptor antagonists inhibit tumor growth, but the mechanisms still remain unexplored. Therefore, we aim to understand the mechanisms of zafirlukast-mediated cell death in ccRCC cells. We show that zafirlukast induces VHL-dependent and TNFα-independent non-apoptotic and non-necroptotic cell death in ccRCC cells. Cell death triggered by zafirlukast could be rescued with antioxidants and the PARP-1 inhibitor Olaparib, and additionally relies on HIF-2α. Finally, MG-132-mediated proteasome inhibition sensitized VHL wild-type cells to zafirlukast-induced cell death and inhibition of HIF-2α rescued zafirlukast- and MG-132-triggered cell death. Together, these results highlight the importance of VHL, HIF and proteasomal degradation in zafirlukast-induced oxidative cell death with potentially novel therapeutic implications for ccRCC.
Cysteinyl leukotriene receptor 1 antagonists (CysLT1RA) are frequently used as add-on medication for the treatment of asthma. Recently, these compounds have shown protective effects in cardiovascular diseases. This prompted us to investigate their influence on soluble epoxide hydrolase (sEH) and peroxisome proliferator activated receptor (PPAR) activities, two targets known to play an important role in CVD and the metabolic syndrome. Montelukast, pranlukast and zafirlukast inhibited human sEH with IC50 values of 1.9, 14.1, and 0.8 μM, respectively. In contrast, only montelukast and zafirlukast activated PPARγ in the reporter gene assay with EC50 values of 1.17 μM (21.9% max. activation) and 2.49 μM (148% max. activation), respectively. PPARα and δ were not affected by any of the compounds. The activation of PPARγ was further investigated in 3T3-L1 adipocytes. Analysis of lipid accumulation, mRNA and protein expression of target genes as well as PPARγ phosphorylation revealed that montelukast was not able to induce adipocyte differentiation. In contrast, zafirlukast triggered moderate lipid accumulation compared to rosiglitazone and upregulated PPARγ target genes. In addition, we found that montelukast and zafirlukast display antagonistic activities concerning recruitment of the PPARγ cofactor CBP upon ligand binding suggesting that both compounds act as PPARγ modulators. In addition, zafirlukast impaired the TNFα triggered phosphorylation of PPARγ2 on serine 273. Thus, zafirlukast is a novel dual sEH/PPARγ modulator representing an excellent starting point for the further development of this compound class.
Um eine gezielte Prophylaxe und Therapie der Urolithiasis zu ermöglichen und um die Rezidivrate zu senken, ist die genaue Kenntnis der Steinzusammensetzung erforderlich. Wegen des hohen Beschaffungspreises sind Röntgendiffraktion und Infrarotspektroskopie nur wenigen Laboratorien vorbehalten, andererseits sollten unspezifisch-chemische Steinanalysenmethoden wegen deren geringeren Sensitivität und Spezifität heute nicht mehr angewendet werden.
In dieser Arbeit wird eine unter dem Mikroskop durchführbare Harnsteinkomponentenanalysenmethode (Harzalith) beschrieben. Es handelt sich um eine mikroskopisch-mikrochemische Harnsteinanalysenmethode. Sie basiert auf der Auswertung mikroskopisch typischer, leicht einprägsamer Farbmuster, die sich je nach Steinzusammensetzung in charakteristischer Weise nach Zugabe des Steinmaterials zum Reagenz innerhalb von Sekunden entwickeln.
Eine Bewertung der mikroskopisch-mikrochemischen Harnsteinkomponentenanalyse gegenüber Röntgendiffraktion, Infrarotspektroskopie und unspezifisch-chemischen Methoden erfolgt anhand von Ergebnissen aus über 10jähriger eigener Anwendungserfahrung.
Folgende Vorteile werden kurz dargestellt:
1. Es werden Steinkomponenten und nicht nur Ionen erfaßt.
2. Es können geringste Steinprobenmengen analysiert werden.
3. Die Ergebnisse der Methode hinsichtlich Richtigkeit, Sensitivität und Spezifität sind in gleicher Größenordnung wie die von Infrarotspektroskopie und Röntgendiffraktion.
4. Die Methode ist einfach zu erlernen, schnell, genau und von leichter Handhabung. Sie ist damit eine echte Alternative gegenüber den anderen apparativ-aufwendigen Harnsteinanalysenverfahren.
Krankhafte Erweiterungen der Bauchschlagader (Aorten-Aneurysmen), sind wie tickende Zeitbomben: Wenn sie platzen, stirbt der Betroffene oft noch bevor er ein Krankenhaus erreicht an inneren Blutungen. Niemand kann mit Bestimmtheit vorhersagen, wann dies eintritt, aber gemeinsam mit Ingenieuren finden Gefäßchirurgen jetzt neue Anhaltspunkte dafür, wann eine Operation ratsam ist.
Iron deficiency (ID) is a common manifestation of inflammatory bowel disease (IBD), arising primarily due to chronic inflammation and/or blood loss. There is no gold standard for ID diagnosis, which is often complicated by concomitant inflammation. Zinc protoporphyrin (ZnPP) correlates with parameters of iron homeostasis and has been identified as a promising marker for ID, irrespective of inflammation. We investigated the diagnostic performance of ZnPP in ID, iron deficiency anemia, anemia of chronic disease and mixed anemia in a cross-sectional study in 130 patients with IBD. Different parameters were compared by receiver operator characteristic (ROC) analysis as detectors of iron-restricted erythropoiesis (IRE). IRE was detected in 91 patients (70.0%); fifty-nine (64.8%) had absolute ID and 23 (25.4%) functional ID. When inflammation was present, ZnPP was a more reliable sole biomarker of IRE than MCV, transferrin saturation (TSAT) or ferritin (AUC; 0.855 vs. 0.763, 0.834% and 0.772, respectively). The specificity of TSAT was significantly lower than ZnPP when inflammation was present (38% vs. 71%, respectively). We conclude that ZnPP is a reliable biomarker of functional ID in patients with IBD and more dependable than ferritin or TSAT, which are influenced by chronic inflammation. We propose that ZnPP may also have utility in patients with other chronic diseases.
Zinc finger proteins (ZNF) are a large group of transcription factors with diverse functions. We recently discovered that endothelial cells harbour a specific mechanism to limit the action of ZNF354C, whose function in endothelial cells is unknown. Given that ZNF354C has so far only been studied in bone and tumour, its function was determined in endothelial cells. ZNF354C is expressed in vascular cells and localises to the nucleus and cytoplasm. Overexpression of ZNF354C in human endothelial cells results in a marked inhibition of endothelial sprouting. RNA-sequencing of human microvascular endothelial cells with and without overexpression of ZNF354C revealed that the protein is a potent transcriptional repressor. ZNF354C contains an active KRAB domain which mediates this suppression as shown by mutagenesis analysis. ZNF354C interacts with dsDNA, TRIM28 and histones, as observed by proximity ligation and immunoprecipitation. Moreover, chromatin immunoprecipitation revealed that the ZNF binds to specific endothelial-relevant target-gene promoters. ZNF354C suppresses these genes as shown by CRISPR/Cas knockout and RNAi. Inhibition of endothelial sprouting by ZNF354C is dependent on the amino acids DV and MLE of the KRAB domain. These results demonstrate that ZNF354C is a repressive transcription factor which acts through a KRAB domain to inhibit endothelial angiogenic sprouting.
Die Labordiagnose einer Infektionskrankheit beruht auf dem Nachweis des Infektionserregers oder der spezifischen Immunreaktion unter Berücksichtigung der klinischen Plausibilität. Biologische Testverfahren wie der Zellkulturversuch erbringen nur näherungsweise ein quantitatives Ergebnis und sind mit einer relativ großen Streuung behaftet. Das gilt auch für Antikörperassays, soweit sie über ein biologisches Testsignal abgelesen werden (CPE, Agglutination, Komplementverbrauch). Moderne serologische und molekularbiologische Untersuchungsmethoden der Virologie werden i. d. R. über ein physikochemisches Testssignal abgelesen und quantitativ ausgewertet. Dadurch gelingt die nationale und internationale Standardisierung, die sich in Ringversuchen gut überprüfen lässt. Aus biologischen Gründen ist meist eine log. Ergebnisberechnung angezeigt, was für „ signifikante “ Unterschiede in Verlaufsuntersuchungen zu berücksichtigen ist: Da sowohl Infektion als auch Immunreaktion dynamische Prozesse darstellen, können Normalwerte in der virologischen Labordiagnostik nur restriktiv definiert werden. Ihre Ergebnisse sind mehr oder minder individuell interpretationsbedürftig.
Wir erprobten die Verwendung von Primärgefäßen in einem voll selektiven, patientenorientiert arbeitenden Analysensystem. Unter Routinebedingungen wurden die Veränderungen von 18 Blutbestandteilen (Enzyme, Substrate, Elektrolyte) in Serumproben untersucht, die im Probennahmegefäß nach Zentrifugation längere Zeit über dem Blutkuchen aufbewahrt wurden. Innerhalb von 5 Std. waren nur geringfügige und kaum klinisch relevante Differenzen zu beobachten. Um auch im Einzelfall hämolyse- bzw. diffusionsbedingte Veränderungen von Serumbestandteilen auszuschließen, bemühten wir uns um die Entwicklung eines Ventilfilters, der hinsichtlich seiner Handhabung und Funktionalität Routine-Anforderungen genügt und die Geometrie 'des Primärgefäßes nicht verändert.
1. Electron micrographs of ultra-thin sections of Staphylococcus aureus and Micrococcus lysodeikticus in Vestopal as embedding medium disclose a multiplicity of DNA containing threads with varying interparticular distances.
2. The diameter of these threads is about one tenth of the average optimal section thickness.
3. This section thickness inevitably is implicated in the visualization of the internal distances between the threads as well as in some common trends in the DNA pool, a fact that has to be accounted for in the analysis of the macromolecules.
4. By spreading lysozyme protoplasts of M. lysodeikticus on a water-air interface in a Langmuir trough and by transferring this surface layer to carbon supported Formvar films, two-dimensional systems can be demonstrated which as a thread of constant width comprise the total DNA content of one microorganism each.
5. Such a macromolecular system shows equally shaped, coiled loops in a peripheral zone and many crossings towards the center. Branching of threads never has been observed so far.
From this evidence we conlude:
a) Intracellular DNA in these bacteria seems to exist in one pool as a “woolen ball” which is centered in the cytoplasm as a more or less dense object.
b) This “woolen ball“ embodies the total amount of DNA most probably as one single threadlike unit.
6. Partial destruction of the thread system of protoplasts will result upon changing optimal spreading conditions.
7. The same kind of destruction is shown upon isolation of the DNA from protoplasts, the length of the threads being an inverse function of the number of precipitation steps showing purification.
α-ketoglutarate dehydrogenase inhibition counteracts breast cancer-associated lung metastasis
(2018)
Metastasis formation requires active energy production and is regulated at multiple levels by mitochondrial metabolism. The hyperactive metabolism of cancer cells supports their extreme adaptability and plasticity and facilitates resistance to common anticancer therapies. In spite the potential relevance of a metastasis metabolic control therapy, so far, limited experience is available in this direction. Here, we evaluated the effect of the recently described α-ketoglutarate dehydrogenase (KGDH) inhibitor, (S)-2-[(2,6-dichlorobenzoyl) amino] succinic acid (AA6), in an orthotopic mouse model of breast cancer 4T1 and in other human breast cancer cell lines. In all conditions, AA6 altered Krebs cycle causing intracellular α-ketoglutarate (α-KG) accumulation. Consequently, the activity of the α-KG-dependent epigenetic enzymes, including the DNA demethylation ten-eleven translocation translocation hydroxylases (TETs), was increased. In mice, AA6 injection reduced metastasis formation and increased 5hmC levels in primary tumours. Moreover, in vitro and in vivo treatment with AA6 determined an α-KG accumulation paralleled by an enhanced production of nitric oxide (NO). This epigenetically remodelled metabolic environment efficiently counteracted the initiating steps of tumour invasion inhibiting the epithelial-to-mesenchymal transition (EMT). Mechanistically, AA6 treatment could be linked to upregulation of the NO-sensitive anti-metastatic miRNA 200 family and down-modulation of EMT-associated transcription factor Zeb1 and its CtBP1 cofactor. This scenario led to a decrease of the matrix metalloproteinase 3 (MMP3) and to an impairment of 4T1 aggressiveness. Overall, our data suggest that AA6 determines an α-KG-dependent epigenetic regulation of the TET–miR200–Zeb1/CtBP1–MMP3 axis providing an anti-metastatic effect in a mouse model of breast cancer-associated metastasis.
Purpose: Recent studies demonstrated a contribution of adrenoceptors (ARs) to osteoarthritis (OA) pathogenesis. Several AR subtypes are expressed in joint tissues and the β2-AR subtype seems to play a major role during OA progression. However, the importance of β2-AR has not yet been investigated in knee OA. Therefore, we examined the development of knee OA in β2-AR-deficient (Adrb2-/-) mice after surgical OA induction.
Methods: OA was induced by destabilization of the medial meniscus (DMM) in male wildtype (WT) and Adrb2-/- mice. Cartilage degeneration and synovial inflammation were evaluated by histological scoring. Subchondral bone remodeling was analyzed using micro-CT. Osteoblast (alkaline phosphatase - ALP) and osteoclast (cathepsin K - CatK) activity were analyzed by immunostainings. To evaluate β2-AR deficiency-associated effects, body weight, sympathetic tone (splenic norepinephrine (NE) via HPLC) and serum leptin levels (ELISA) were determined. Expression of the second major AR, the α2-AR, was analyzed in joint tissues by immunostaining.
Results: WT and Adrb2-/- DMM mice developed comparable changes in cartilage degeneration and synovial inflammation. Adrb2-/- DMM mice displayed elevated calcified cartilage and subchondral bone plate thickness as well as increased epiphyseal BV/TV compared to WTs, while there were no significant differences in Sham animals. In the subchondral bone of Adrb2-/- mice, osteoblasts activity increased and osteoclast activity deceased. Adrb2-/- mice had significantly higher body weight and fat mass compared to WT mice. Serum leptin levels increased in Adrb2-/- DMM compared to WT DMM without any difference between the respective Shams. There was no difference in the development of meniscal ossicles and osteophytes or in the subarticular trabecular microstructure between Adrb2-/- and WT DMM as well as Adrb2-/- and WT Sham mice. Number of α2-AR-positive cells was lower in Adrb2-/- than in WT mice in all analyzed tissues and decreased in both Adrb2-/- and WT over time.
Conclusion: We propose that the increased bone mass in Adrb2-/- DMM mice was not only due to β2-AR deficiency but to a synergistic effect of OA and elevated leptin concentrations. Taken together, β2-AR plays a major role in OA-related subchondral bone remodeling and is thus an attractive target for the exploration of novel therapeutic avenues.
Although, during the past decades, substantial advances emerged in identifying major local and systemic factors contributing to initiation and progression of osteoarthritis (OA), some neuroendocrine mechanisms are still not understood or even neglected when thinking about novel therapeutic options. One of which is the sympathetic nervous system that exhibits various OA-promoting effects in different tissues of the joint. Interestingly, the β2-adrenoceptor (AR) mediates the majority of these effects as demonstrated by several in vitro, in vivo as well as in clinical studies. This review article does not only summarize studies of the past two decades demonstrating that the β2-AR plays an OA-promoting role in different tissues of the joint but also aims to encourage the reader to think about next-level research to discover novel and innovative preventive and/or therapeutic strategies targeting the β2-AR in OA.
„Ein Griff ins Rohr!“
(2022)