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Recommendations from the ESO-Karolinska Stroke Update Conference, Stockholm 13–15 November 2016
(2017)
About the meeting: The purpose of the European Stroke Organisation (ESO)-Karolinska Stroke Update Conference is to provide updates on recent stroke therapy research and to give an opportunity for the participants to discuss how these results may be implemented into clinical routine. Several scientific sessions discussed in the meeting and each session produced consensus statements. The meeting started 20 years ago as Karolinska Stroke Update, but since 2014, it is a joint conference with ESO. Importantly, it provides a platform for discussion on the ESO guidelines process and on recommendations to the ESO guidelines committee on specific topics. By this, it adds a direct influence from stroke professionals otherwise not involved in committees and work groups on the guidelines procedure. The discussions at the conference may also inspire new guidelines when motivated. The topics raised at the meeting are selected by the scientific programme committee mainly based on recent important scientific publications. The ESO-Karolinska Stroke Update consensus statement and recommendations will be published every 2 years and it will work as implementation of ESO-guidelines
Purpose: The aim of this study was to analyze systematically the influence of the relative centrifugation force (RCF) on leukocytes, platelets and growth factor release within fluid platelet-rich fibrin matrices (PRF).
Materials and methods: Systematically using peripheral blood from six healthy volunteers, the RCF was reduced four times for each of the three experimental protocols (I–III) within the spectrum (710–44 g), while maintaining a constant centrifugation time. Flow cytometry was applied to determine the platelets and leukocyte number. The growth factor concentration was quantified 1 and 24 h after clotting using ELISA.
Results: Reducing RCF in accordance with protocol-II (177 g) led to a significantly higher platelets and leukocytes numbers compared to protocol-I (710 g). Protocol-III (44 g) showed a highly significant increase of leukocytes and platelets number in comparison to -I and -II. The growth factors’ concentration of VEGF and TGF-β1 was significantly higher in protocol-II compared to -I, whereas protocol-III exhibited significantly higher growth factor concentration compared to protocols-I and -II. These findings were observed among 1 and 24 h after clotting, as well as the accumulated growth factor concentration over 24 h.
Discussion: Based on the results, it has been demonstrated that it is possible to enrich PRF-based fluid matrices with leukocytes, platelets and growth factors by means of a single alteration of the centrifugation settings within the clinical routine.
Conclusions: We postulate that the so-called low speed centrifugation concept (LSCC) selectively enriches leukocytes, platelets and growth factors within fluid PRF-based matrices. Further studies are needed to evaluate the effect of cell and growth factor enrichment on wound healing and tissue regeneration while comparing blood concentrates gained by high and low RCF.
Einleitung: Ziel dieser Studie war es zu evaluieren, ob das Prüfungsformat einer OSPE (Objective Structured Practical Examination) durchgeführt im Fach Zahnerhaltungskunde (6. Fachsemester) den Studienerfolg im praktischen Teil des Staatsexamens (11. Fachsemester) im selben Fach prädiziert. Ferner sollte unter Berücksichtigung allgemeiner Angaben der StudienteilnehmerInnen (Abitursnote, Physikumsnote, Studiendauer, Kohorte und Geschlecht) analysiert werden, ob bezüglich der Gesamt- sowie Teilnoten der OSPE und der adäquaten Staatsexamensprüfung Zusammenhänge oder Unterschiede bestehen.
Methoden: Im Rahmen dieser longitudinalen, retrospektiven Studie wurden für einen Zeitraum von 11 Semestern prüfungsbezogene Daten von Studierenden (N=223) des Fachbereichs Zahnmedizin in Frankfurt am Main erhoben und untersucht. Für die statistische Auswertung der Daten wurden Spearman Rangkorrelationen, Partialkorrelationen, Korrelationskoeffizienten nach Pearson, und Multiple Regressionen (SPSS Statistics 21, IBM Corporation, New York) berechnet.
Ergebnisse: Die Ergebnisse zeigen, dass OSPE (Cronbachs α=.87) mit dem Erfolg im praktischen Teil des Staatsexamens im Fach Zahnerhaltungskunde korreliert (p=.01, r=.17). Als eine weitere signifikante Korrelation mit der Examensleistung erwies sich die Dauer des Studiums (p=.001, r=.23). Gemeinsam leisten diese beiden Variablen einen signifikanten Beitrag zur Vorhersage der Examensnote (p=.001, R2=.076). Das zeigte sich im größeren Umfang bei weiblichen Studierenden. Zudem wurde festgestellt, dass diese bessere Abiturnoten als männliche Studierende aufweisen (F=6.09, p=.01, η2=.027) und dass es lediglich bei männlichen Studierenden eine signifikante Korrelation zwischen der Physikumsnote (Zahnärztliche Vorprüfung) und der OSPE-Benotung gab (r=.17, p=.01).
Schlussfolgerung: In der vorliegenden Untersuchung konnte der prädiktive Effekt einer klinischen OSPE auf die Prüfungsleistung im Staatsexamen gezeigt werden. Unter Berücksichtigung der Limitation der Studie empfiehlt sich aus unserer Sicht die Durchführung eines solchen Prüfungsformats im Rahmen des klinischen Studienabschnitts im 6. Semester im Fach Zahnmedizin.
Background: The Ebola virus has been responsible for numerous outbreaks since the 1970s, with the most recent outbreak taking place between 2014 and 2016 and causing an international public health emergency. Ebola virus disease (EVD) has a high mortality rate and no approved targeted treatment exists to date. A number of established drugs are being considered as potential therapeutic agents for the treatment of EVD.
Objective: We aimed to identify potential drug repositioning candidates and to assess the scientific evidence available on their efficacy.
Methods: We conducted a systematic literature search in MEDLINE, Embase, and other relevant trial registry platforms for studies published between January 1976 and January 2017. We included drug screening, preclinical studies, and clinical studies on repurposed drugs for the treatment of EVD. The risk of bias for animal studies and nonrandomized clinical studies was assessed. The quality of reporting for case series and case reports was evaluated. Finally, we selected drugs approved by established regulatory authorities, which have positive in vitro study outcomes and at least one additional animal or clinical trial.
Results: We identified 3301 publications, of which 37 studies fulfilled our inclusion criteria. Studies were highly heterogeneous in terms of study type, methodology, and intervention. The risk of bias was high for 13 out of 14 animal studies. We selected 11 drugs with potential anti-EVD therapeutic effects and summarized their evidence.
Conclusions: Several established drugs may have therapeutic effects on EVD, but the quality and quantity of current scientific evidence is lacking. This review highlights the need for well-designed and conducted preclinical and clinical research to establish the efficacy of potential repurposed drugs against EVD.
Objective: Worldwide, the respiratory syncytial virus (RSV) represents the predominant viral agent causing bronchiolitis and pneumonia in children. To conduct research and tackle existing healthcare disparities, RSV-related research activities around the globe need to be described. Hence, we assessed the associated scientific output (represented by research articles) by geographical, chronological and socioeconomic criteria and analysed the authors publishing in the field by gender. Also, the 15 most cited articles and the most prolific journals were identified for RSV research.
Design: Retrospective, descriptive study.
Setting: The NewQIS (New Quality and Quantity Indices in Science) platform was employed to identify RSV-related articles published in the Web of Science until 2013. We performed a numerical analysis of all articles, and examined citation-based aspects (eg, citation rates); results were visualised by density equalising mapping tools.
Results: We identified 4600 RSV-related articles. The USA led the field; US-American authors published 2139 articles (46.5%% of all identified articles), which have been cited 83 000 times. When output was related to socioeconomic benchmarks such as gross domestic product or Research and Development expenditures, Guinea-Bissau, The Gambia and Chile were ranked in leading positions. A total of 614 articles on RSV (13.34% of all articles) were attributed to scientific collaborations. These were primarily established between high-income countries. The gender analysis indicated that male scientists dominated in all countries except Brazil.
Conclusions: The majority of RSV-related research articles originated from high-income countries whereas developing nations showed only minimal publication productivity and were barely part of any collaborative networks. Hence, research capacity in these nations should be increased in order to assist in addressing inequities in resource allocation and the clinical burden of RSV in these countries.
Background: This study aims at identifying orthodontic activities with the highest frequency of unfavorable/awkward and static postures held over a period of more than 4 s based on kinematic analysis. Moreover, a separate analysis of static postures for orthodontic and non-orthodontic activities serves to evaluate the duration for which these particular postures are assumed.
Methods: In total, 21 (13f/8 m) orthodontists (age: 31.5 ± 3.8 years) participated in this study. CUELA, a personal measurement system, was used to collect kinematic data for all orthodontic activities in a working day. Angle values of the head and torso were evaluated in accordance with ergonomic standards. Only those postures that were held statically for 4 s and longer were selected for further analysis. Alongside the kinematic analysis, the activities performed on-site were also subject to a detailed computerized analysis. The synchronization of data collected from both measurements arranges the patterns of posture found chronologically and in conjunction with the orthodontic activities performed ((I) "treatment" (II) "office" and (III) "other activities").
Results: For (I) we observed an anterior inclination of the head and torso area as well as a twist of the head and neck area to the right. We found anterior back inclination and lateral back torsion to the right for (II) and (III). If, furthermore, we differentiate the duration of static postures, there are primarily short to medium-term (4–30s) static postures identified for (I). Also, categories (II) and (III) predominantly demonstrate static back postures with a duration of up to 30 s. With regard to (II) we observed that the back is ventrally inclined for 10.1% of the total activity duration.
Conclusions: During treatment static strains are observed in the entire head and torso area. On the contrary, static postures prevalent in the torso area are essential for activities of the other categories, particularly office work. These findings allow for a careful selection of unfavorable and static postures for each of the activities performed and help to develop specific preventive measures.
The nervous system is a non-linear dynamical complex system with many feedback loops. A conventional wisdom is that in the brain the quantum fluctuations are self-averaging and thus functionally negligible. However, this intuition might be misleading in the case of non-linear complex systems. Because of an extreme sensitivity to initial conditions, in complex systems the microscopic fluctuations may be amplified and thereby affect the system’s behavior. In this way quantum dynamics might influence neuronal computations. Accumulating evidence in non-neuronal systems indicates that biological evolution is able to exploit quantum stochasticity. The recent rise of quantum biology as an emerging field at the border between quantum physics and the life sciences suggests that quantum events could play a non-trivial role also in neuronal cells. Direct experimental evidence for this is still missing but future research should address the possibility that quantum events contribute to an extremely high complexity, variability and computational power of neuronal dynamics.
Nutrition support is a necessary therapy for critically ill cardiac surgery patients. However, conclusive evidence for this population, consisting of well-conducted clinical trials is lacking. To clarify optimal strategies to improve outcomes, an international multidisciplinary group of 25 experts from different clinical specialties from Germany, Canada, Greece, USA and Russia discussed potential approaches to identify patients who may benefit from nutrition support, when best to initiate nutrition support, and the potential use of pharmaco-nutrition to modulate the inflammatory response to cardiopulmonary bypass. Despite conspicuous knowledge and evidence gaps, a rational nutritional support therapy is presented to benefit patients undergoing cardiac surgery.
Progressive neurodegenerative diseases plague millions of individuals both in the United States and across the world. The current pathology of progressive neurodegenerative tauopathies, such as Alzheimer’s disease (AD), Pick’s disease, frontotemporal dementia (FTD), and progressive supranuclear palsy, primarily revolves around phosphorylation and hyperphosphorylation of the tau protein. However, more recent evidence suggests acetylation of tau protein at lysine 280 may be a critical step in molecular pathology of these neurodegenerative diseases prior to the tau hyperphosphorylation. Secondary injury cascades such as oxidative stress, endoplasmic reticulum stress, and neuroinflammation contribute to lasting damage within the brain and can be induced by a number of different risk factors. These injury cascades funnel into a common pathway of early tau acetylation, which may serve as the catalyst for progressive degeneration. The post translational modification of tau can result in production of toxic oligomers, contributing to reduced solubility as well as aggregation and formation of neurofibrillary tangles, the hallmark of AD pathology. Chronic Traumatic Encephalopathy (CTE), caused by repetitive brain trauma is also associated with a hyperphosphorylation of tau. We postulated acetylation of tau at lysine 280 in CTE disease could be present prior to the hyperphosphorylation and tested this hypothesis in CTE pathologic specimens. We also tested for ac-tau 280 in early stage Alzheimer’s disease (Braak stage 1). Histopathological examination using the ac tau 280 antibody was performed in three Alzheimer's cases and three CTE patients. Presence of ac-tau 280 was confirmed in all cases at early sites of disease manifestation. These findings suggest that tau acetylation may precede tau phosphorylation and could be the first "triggering" event leading to neuronal loss. To the best of our knowledge, this is the first study to identify acetylation of the tau protein in CTE. Prevention of tau acetylation could possibly serve as a novel target for stopping neurodegeneration before it fully begins. In this study, we highlight what is known about tau acetylation and neurodegeneration.
S1P provokes tumor lymphangiogenesis via macrophage-derived mediators such as IL-1β or lipocalin-2
(2017)
A pleiotropic signaling lipid, sphingosine-1-phosphate (S1P), has been implicated in various pathophysiological processes supporting tumor growth and metastasis. However, there are only a few descriptive studies suggesting a role of S1P in tumor lymphangiogenesis, which is critical for tumor growth and dissemination. Corroborating own data, the literature suggests that apoptotic tumor cell-derived S1P alters the phenotype of tumor-associated macrophages (TAMs) to gain protumor functions. However, mechanistically, the role of TAM-induced lymphangiogenesis has only been poorly described, mostly linked to the production of lymphangiogenic factors such as vascular endothelial growth factor C (VEGF-C) and VEGF-D, or transdifferentiation into lymphatic endothelial cells. Recent findings highlight a rather underappreciated role of S1P in tumor lymphangiogenesis, referring to the production of interleukin-1β (IL-1β) and lipocalin-2 (LCN2) by a tumor-promoting macrophage phenotype. In this review, we aim to provide to the readers with the current understanding of the molecular mechanism how apoptotic cell-derived S1P triggers TAMs to promote lymphangiogenesis.
In lebende Körper zu sehen, ohne das Messer anzusetzen, das war lange ein Traum von Wissenschaftlern und Ärzten. Was vor mehr als 120 Jahren mit Conrad Röntgens Entdeckung der X-Strahlen begann, hat sich mit Magnetenzephalographie und Magnetresonanztomographie zu gängigen Instrumenten der Hightech-Medizin entwickelt.
To assess the scope of infection control measures for multidrug-resistant bacteria in high-risk settings, a survey among university hospitals was conducted. Fourteen professionals from 8 sites participated. Reported policies varied largely with respect to the types of wards conducting screening, sample types used for screening and implementation of contact precautions. This variability among sites highlights the need for an evidence-based consensus of current infection control policies.
SDF-1/CXCR4 expression in head and neck cancer and outcome after postoperative radiochemotherapy
(2017)
Introduction: Outcome after postoperative radiochemotherapy (RT-CT) for patients with advanced head and neck squamous cell carcinomas (HNSCC) remains unsatisfactory, especially among those with HPV negative tumours. Therefore, new biomarkers are needed to further define subgroups for individualised therapeutic approaches. Preclinical and first clinical observations showed that the chemokine receptor CXCR4 and its ligand SDF-1 (CXCL12) play an important role in tumour cell proliferation, survival, cancer progression, metastasis and treatment resistance. However, the data on the prognostic value of SDF-1/CXCR4 expression for HNSCC are conflicting. The aim of our hypothesis-generating study was to retrospectively explore the prognostic potential of SDF-1/CXCR4 in a well-defined cohort of HNSCC patients collected within the multicenter biomarker study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG).
Material and methods: Patients with stage III and IVA HNSCC of the oral cavity, oropharynx and hypopharynx were treated with resection and adjuvant radiotherapy (RT) with ≥60 Gy and concurrent cisplatin-based chemotherapy (CT). Tissue micro-arrays (TMAs) from a total of 221 patients were generated from surgical specimens, 201 evaluated for the SDF-1 and CXCR4 expression by immunofluorescence and correlated with clinico-pathological and outcome data.
Results: In univariate and multivariate analyses intracellular SDF-1 expression was associated with lower loco-regional control (LRC) in the entire patient group as well as in the HPV16 DNA negative subgroup. CXCR4 expression showed a trend for lower LRC in the univariate analysis which was not confirmed in the multivariate analysis. Neither for SDF-1 nor CXCR4 expression associations with distant metastasis free or overall survival were found.
Conclusions: Our exploratory data support the hypothesis that overexpression of intracellular SDF-1 is an independent negative prognostic biomarker for LRC after postoperative RT-CT in high-risk HNSCC. Prospective validation is warranted and further exploration of SDF-1/CXCR4 as a potential therapeutic target to overcome treatment resistance in HNSCC appears promising.
Self-extracellular RNA (eRNA), released from stressed or injured cells upon various pathological situations such as ischemia-reperfusion-injury, has been shown to act as an alarmin by inducing procoagulatory and proinflammatory responses. In particular, M1-polarization of macrophages by eRNA resulted in the expression and release of a variety of cytokines, including tumor necrosis factor (TNF)-α or interleukin-6 (IL-6). The present study now investigates in which way self-eRNA may influence the response of macrophages towards various Toll-like receptor (TLR)-agonists. Isolated agonists of TLR2 (Pam2CSK4), TLR3 (PolyIC), TLR4 (LPS), or TLR7 (R848) induced the release of TNF-α in a concentration-dependent manner in murine macrophages, differentiated from bone marrow-derived stem cells by mouse colony stimulating factor. Here, the presence of eRNA shifted the dose-response curve for Pam2CSK4 (Pam) considerably to the left, indicating that eRNA synergistically enhanced the cytokine liberation from macrophages even at very low Pam-levels. The synergistic activation of TLR2 by eRNA/Pam was duplicated by other TLR2-agonists such as FSL-1 or Pam3CSK4. In contrast, for TLR4-agonists such as LPS a synergistic effect of eRNA was much weaker, and was not existent for TLR3-, or TLR7-agonists. The synergistic eRNA/Pam action was dependent on the NFκB-signaling pathway as well as on p38MAP- and MEK1/ERK-kinases and was prevented by predigestion of eRNA with RNase1 or by antibodies against TLR2. Thus, the presence of self-eRNA as alarming molecule sensitizes innate immune responses towards pathogen-associated molecular patterns (PAMPs) in a synergistic way and may thereby contribute to the differentiated outcome of inflammatory responses.
Excessive neutrophil activation accompanied by delayed apoptotic cell death in inflammatory conditions causes progressive damage of cells and tissues, leading to life-threatening multiple organ dysfunction syndrome. Previous work suggested that circulating serum factors during inflammation are critically involved in the suppression of neutrophil cell death although the identity of these antiapoptotic mediators remained elusive. In this study, we identified the acute phase protein α-1 Antitrypsin (AAT) as a potent suppressor of staurosporine (STS)-induced apoptosis in human neutrophils through a mechanism implicating caspases-independent pathways. We show here that serum levels of AAT, potentially in part released by stimulated neutrophils, are markedly elevated in major trauma patients suffering from systemic inflammatory response syndrome (SIRS). Notably, AAT depletion from serum increased sensitivity of human neutrophils for STS-induced cell death. In fact, AAT was demonstrated to confer intrinsic apoptosis resistance by preventing PKC/Akt inactivation and subsequent proteasomal degradation of antiapoptotic Mcl-1 protein in response to STS treatment. Neither MAP kinase ERK1/2 nor caspases were found to be involved in AAT-triggered antiapoptotic pathways in neutrophils. In summary, these results establish a novel pivotal role of circulating AAT in mediating survival by antagonizing the proapoptotic action of the PKC inhibitor STS and should be considered for AAT augmentation therapies in future.
Massive global spread of multidrug-resistant (MDR) Salmonella spp. expressing extended-spectrum beta-lactamase (ESBL) and additional resistance to fluoroquinolones has often been attributed to high international mobility as well as excessive use of oral antibiotics in livestock farming. However, MDR Salmonella spp. have not been mentioned as a widespread pathogen in clinical settings so far. We demonstrate the case of a 25-year-old male with primary sclerosing cholangitis who tested positive for MDR Salmonella enterica serotype Choleraesuis expressing ESBL and fluoroquinolone resistance. The pathogen was supposedly acquired during a trip to Thailand, causing severe fever, cholangitis and pancreatitis. To our knowledge, this is the first report of Salmonella enterica serotype Choleraesuis in Europe expressing such a multidrug resistance pattern. ESBL resistance of Salmonella enterica spp. should be considered in patients with obstructive biliary tract pathology and travel history in endemic countries.
Background: Malaria remains one of the most serious infections for travellers to tropical countries. Due to the lack of harmonized guidelines a large variety of treatment regimens is used in Europe to treat severe malaria.
Methods: The European Network for Tropical Medicine and Travel Health (TropNet) conducted an 8-year, multicentre, observational study to analyse epidemiology, treatment practices and outcomes of severe malaria in its member sites across Europe. Physicians at participating TropNet centres were asked to report pseudonymized retrospective data from all patients treated at their centre for microscopically confirmed severe Plasmodium falciparum malaria according to the 2006 WHO criteria.
Results: From 2006 to 2014 a total of 185 patients with severe malaria treated in 12 European countries were included. Three patients died, resulting in a 28-day survival rate of 98.4%. The majority of infections were acquired in West Africa (109/185, 59%). The proportion of patients treated with intravenous artesunate increased from 27% in 2006 to 60% in 2013. Altogether, 56 different combinations of intravenous and oral drugs were used across 28 study centres. The risk of acute renal failure (36 vs 17% p = 0.04) or cerebral malaria (54 vs 20%, p = 0.001) was significantly higher in patients ≥60 years than in younger patients. Respiratory distress with the need for mechanical ventilation was significantly associated with the risk of death in the study population (13 vs 0%, p = 0.001). Post-artemisinin delayed haemolysis was reported in 19/70 (27%) patients treated with intravenous artesunate.
Conclusion: The majority of patients with severe malaria in this study were tourists or migrants acquiring the infection in West Africa. Intravenous artesunate is increasingly used for treatment of severe malaria in many European treatment centres and can be given safely to European patients with severe malaria. Patients treated with intravenous artesunate should be followed up to detect and manage late haemolytic events.
Background and aims: Liver steatosis has shown to be associated with coronary artery disease (CAD). The aim of our study was to evaluate the association between the presence and severity of CAD and Non-alcoholic fatty liver disease (NAFLD) assessed by transient elastography (TE) and controlled attenuation parameter (CAP).
Methods: 576 Patients undergoing coronary angiography were enrolled in this prospective study, receiving at least 10 TE and CAP measurements using the FibroScan® M-probe. Clinically relevant CAD (CAD 3) was defined as stenosis with ≥75% reduction of the luminal diameter. NAFLD was determined by CAP ≥234 dB/m. NAFLD with advanced fibrosiswas determined by TE-values ≥7.9kPa in the presence of NAFLD and absence of congestive or right-sided heart failure. Rates and 95% confidence intervals are shown.
Results: 505 patients were available for analysis of NAFLD. However, only 392 patients were available for analysis of NAFLD with advanced fibrosis, since 24 patients had to be excluded due to non valid TE-measurements and 89 patients due to congestive or right-sided heart failure or suspected concomitant liver disease, respectively. 70.5% (66.3%-74.4%) of patients had CAD 3, 71.5% (67.3%-75.4%) were diagnosed with NAFLD, and 11.2% (8.3%-14.8%) with NAFLD with advanced fibrosis. Patients with CAD 3 had higher median CAP-values (273±61 vs. 260±66 dB/m; p = 0.038) and higher degrees of steatosis as compared to patients without CAD 3. While NAFLD was significantly more often diagnosed in patients with CAD 3 (75.0% vs. 63.1%, p = 0.0068), no significant difference was found for NAFLD with advanced fibrosis (10.7% vs. 12.5%, p = 0.60).
Conclusions: Clinically relevant CAD is frequently associated with the presence of NAFLD, but not NAFLD with advanced fibrosis.
Sex differences in the relationship between conduct disorder and cortical structure in adolescents
(2017)
Objective: Previous studies have reported reduced cortical thickness and surface area and altered gyrification in frontal and temporal regions in adolescents with conduct disorder (CD). Although there is evidence that the clinical phenotype of CD differs between males and females, no studies have examined whether such sex differences extend to cortical and subcortical structure.
Method: As part of a European multisite study (FemNAT-CD), structural magnetic resonance imaging (MRI) data were collected from 48 female and 48 male participants with CD and from 104 sex-, age-, and pubertal-status−matched controls (14–18 years of age). Data were analyzed using surface-based morphometry, testing for effects of sex, diagnosis, and sex-by-diagnosis interactions, while controlling for age, IQ, scan site, and total gray matter volume.
Results: CD was associated with cortical thinning and higher gyrification in ventromedial prefrontal cortex in both sexes. Males with CD showed lower, and females with CD showed higher, supramarginal gyrus cortical thickness compared with controls. Relative to controls, males with CD showed higher gyrification and surface area in superior frontal gyrus, whereas the opposite pattern was seen in females. There were no effects of diagnosis or sex-by-diagnosis interactions on subcortical volumes. Results are discussed with regard to attention-deficit/hyperactivity disorder, depression, and substance abuse comorbidity, medication use, handedness, and CD age of onset.
Conclusion: We found both similarities and differences between males and females in CD–cortical structure associations. This initial evidence that the pathophysiological basis of CD may be partly sex-specific highlights the need to consider sex in future neuroimaging studies and suggests that males and females may require different treatments.
Sexuelle Dysfunktionen bei Frauen mit Posttraumatischer
Belastungsstörung – ein Übersichtsartikel
(2017)
Sexual dysfunctions, clinical as well as subclinical, and other sexual complaints that accompany aversive emotions, cognitions, and sexual risk behavior are very common among women after experiences of sexual violence and are underestimated as a problem. Anyway, among victims of other kinds of traumatic experiences, a high prevalence of sexual distress is found as well. Explanatory approaches concentrate on learning theory as well as the phenomenology of Posttraumatic Stress Disorder (PTSD) itself. Sexuality is an important source of vitality, and the maintenance of sexual dysfunctions can be accompanied by a risk of impairments in quality of life and self-esteem as well as relationship problems. Aside clinical practice, there is also a lack of knowledge in clinical science regarding the association between sexual dysfunctions and traumatic experiences, especially sexual ones. In this article, the phenomenology and diagnostic instruments of female sexual dysfunctions are presented, and consequences of sexual violence on sexuality, also in the context of PTSD, are further explained. Suggestions are being made on how to include suitable interventions into therapy.
Natural killer (NK) cells are a promising tool for the use in adoptive immunotherapy, since they efficiently recognize and kill tumor cells. In this context, ex vivo cultivation is an attractive option to increase NK cells in numbers and to improve their antitumor potential prior to clinical applications. Consequently, various strategies to generate NK cells for adoptive immunotherapy have been developed. Here, we give an overview of different NK cell cultivation approaches and their impact on shaping the NK cell antitumor activity. So far, the cytokines interleukin (IL)-2, IL-12, IL-15, IL-18, and IL-21 are used to culture and expand NK cells. The selection of the respective cytokine combination is an important factor that directly affects NK cell maturation, proliferation, survival, distribution of NK cell subpopulations, activation, and function in terms of cytokine production and cytotoxic potential. Importantly, cytokines can upregulate the expression of certain activating receptors on NK cells, thereby increasing their responsiveness against tumor cells that express the corresponding ligands. Apart from using cytokines, cocultivation with autologous accessory non-NK cells or addition of growth-inactivated feeder cells are approaches for NK cell cultivation with pronounced effects on NK cell activation and expansion. Furthermore, ex vivo cultivation was reported to prime NK cells for the killing of tumor cells that were previously resistant to NK cell attack. In general, NK cells become frequently dysfunctional in cancer patients, for instance, by downregulation of NK cell activating receptors, disabling them in their antitumor response. In such scenario, ex vivo cultivation can be helpful to arm NK cells with enhanced antitumor properties to overcome immunosuppression. In this review, we summarize the current knowledge on NK cell modulation by different ex vivo cultivation strategies focused on increasing NK cytotoxicity for clinical application in malignant diseases. Moreover, we critically discuss the technical and regulatory aspects and challenges underlying NK cell based therapeutic approaches in the clinics.
G-protein-coupled receptor (GPCR) expression is extensively studied in bulk cDNA, but heterogeneity and functional patterning of GPCR expression in individual vascular cells is poorly understood. Here, we perform a microfluidic-based single-cell GPCR expression analysis in primary smooth muscle cells (SMC) and endothelial cells (EC). GPCR expression is highly heterogeneous in all cell types, which is confirmed in reporter mice, on the protein level and in human cells. Inflammatory activation in murine models of sepsis or atherosclerosis results in characteristic changes in the GPCR repertoire, and we identify functionally relevant subgroups of cells that are characterized by specific GPCR patterns. We further show that dedifferentiating SMC upregulate GPCRs such as Gpr39, Gprc5b, Gprc5c or Gpr124, and that selective targeting of Gprc5b modulates their differentiation state. Taken together, single-cell profiling identifies receptors expressed on pathologically relevant subpopulations and provides a basis for the development of new therapeutic strategies in vascular diseases.
The hallmark of classical Hodgkin lymphoma (cHL) is the presence of giant, mostly multinucleated Hodgkin-Reed-Sternberg (HRS) cells. Whereas it has recently been shown that giant HRS cells evolve from small Hodgkin cells by incomplete cytokinesis and re-fusion of tethered sister cells, it remains unsolved why this phenomenon particularly takes place in this lymphoma and what the differences between these cell types of variable sizes are. The aim of the present study was to characterize microdissected small and giant HRS cells by gene expression profiling and to assess differences of clonal growth behavior as well as susceptibility toward cytotoxic intervention between these different cell types to provide more insight into their distinct cellular potential. Applying stringent filter criteria, only two differentially expressed genes between small and giant HRS cells, SHFM1 and LDHB, were identified. With looser filter criteria, 13 genes were identified to be differentially overexpressed in small compared to giant HRS cells. These were mainly related to energy metabolism and protein synthesis, further suggesting that small Hodgkin cells resemble the proliferative compartment of cHL. SHFM1, which is known to be involved in the generation of giant cells, was downregulated in giant RS cells at the RNA level. However, reduced mRNA levels of SHFM1, LDHB and HSPA8 did not translate into decreased protein levels in giant HRS cells. In cell culture experiments it was observed that the fraction of small and big HRS cells was adjusted to the basic level several days after enrichment of these populations via cell sorting, indicating that small and big HRS cells can reconstitute the full spectrum of cells usually observed in the culture. However, assessment of clonal growth of HRS cells indicated a significantly reduced potential of big HRS cells to form single cell colonies. Taken together, our findings pinpoint to strong similarities but also some differences between small and big HRS cells.
Treatment with tyrosine kinase inhibitors is the standard of care for Philadelphia chromosome positive leukemias. However the eradication of leukemia initiating cells remains a challenge. Circumstantial evidence suggests that the cytokine microenvironment may play a role in BCR-ABL mediated leukemogenesis and in imatinib resistance. Gene expression analyses of BCR-ABL positive ALL long-term cultured cells revealed strong reduction of SOCS mRNA expression after imatinib treatment, thereby demonstrating a strong inhibition of cytokine signaling. In this study we employed SOCS1—a strong inhibitor of cytokine signaling—as a tool to terminate external cytokine signals in BCR-ABL transformed cells in vitro and in vivo. In colony formation assays with primary bone marrow cells, expression of SOCS1 decreased colony numbers under pro-proliferative cytokines, while it conferred growth resistance to anti-proliferative cytokines. Importantly, co-expression of SOCS1 with BCR-ABL led to the development of a MPD phenotype with a prolonged disease latency compared to BCR-ABL alone in a murine bone marrow transplantation model. Interestingly, SOCS1 co-expression protected 20% of mice from MPD development. In summary, we conclude that under pro-proliferative cytokine stimulation at the onset of myeloproliferative diseases SOCS1 acts as a tumor suppressor, while under anti-proliferative conditions it exerts oncogenic function. Therefore SOCS1 can promote opposing functions depending on the cytokine environment.
Necroptosis contributes to the pathophysiology of several inflammatory, infectious and degenerative disorders. TNF-induced necroptosis involves activation of the receptor-interacting protein kinases 1 and 3 (RIPK1/3) in a necrosome complex, eventually leading to the phosphorylation and relocation of mixed lineage kinase domain like protein (MLKL). Using a high-content screening of small compounds and FDA-approved drug libraries, we identified the anti-cancer drug Sorafenib tosylate as a potent inhibitor of TNF-dependent necroptosis. Interestingly, Sorafenib has a dual activity spectrum depending on its concentration. In murine and human cell lines it induces cell death, while at lower concentrations it inhibits necroptosis, without affecting NF-κB activation. Pull down experiments with biotinylated Sorafenib show that it binds independently RIPK1, RIPK3 and MLKL. Moreover, it inhibits RIPK1 and RIPK3 kinase activity. In vivo Sorafenib protects against TNF-induced systemic inflammatory response syndrome (SIRS) and renal ischemia–reperfusion injury (IRI). Altogether, we show that Sorafenib can, next to the reported Braf/Mek/Erk and VEGFR pathways, also target the necroptotic pathway and that it can protect in an acute inflammatory RIPK1/3-mediated pathology.
Alzheimer’s disease (AD) is the most common form of dementia in the elderly; important risk factors are old age and inheritance of the apolipoprotein E4 (APOE4) allele. Changes in amyloid precursor protein (APP) binding, trafficking, and sorting may be important AD causative factors. Secretase-mediated APP cleavage produces neurotoxic amyloid-beta (Aβ) peptides, which form lethal deposits in the brain. In vivo and in vitro studies have implicated sortilin-related receptor (SORL1) as an important factor in APP trafficking and processing. Recent in vitro evidence has associated the APOE4 allele and alterations in the SORL1 pathway with AD development and progression. Here, we analyzed SORL1 expression in neural stem cells (NSCs) from AD patients carrying null, one, or two copies of the APOE4 allele. We show reduced SORL1 expression only in NSCs of a patient carrying two copies of APOE4 allele with increased Aβ/SORL1 localization along the degenerated neurites. Interestingly, SORL1 binding to APP was largely compromised; this could be almost completely reversed by γ-secretase (but not β-secretase) inhibitor treatment. These findings may yield new insights into the complex interplay of SORL1 and AD pathology and point to NSCs as a valuable tool to address unsolved AD-related questions in vitro.
Species identification of adult African blowflies (Diptera: Calliphoridae) of forensic importance
(2017)
Necrophagous blowflies can provide an excellent source of evidence for forensic entomologists and are also relevant to problems in public health, medicine, and animal health. However, access to useful information about these blowflies is constrained by the need to correctly identify the flies, and the poor availability of reliable, accessible identification tools is a serious obstacle to the development of forensic entomology in the majority of African countries. In response to this need, a high-quality key to the adults of all species of forensically relevant blowflies of Africa has been prepared, drawing on high-quality entomological materials and modern focus-stacking photomicroscopy. This new key can be easily applied by investigators inexperienced in the taxonomy of blowflies and is made available through a highly accessible online platform. Problematic diagnostic characters used in previous keys are discussed.
Systemic sclerosis (SSc) is a rare multi-organ autoimmune disease characterized by progressive skin fibrosis. Inflammation, type 2 immunity, and fibrogenic processes are involved in disease development and may be affected by sphingolipids. However, details about early-stage pathophysiological mechanisms and implicated mediators remain elusive. The sphingolipid sphingosine-1-phosphate (S1P) is elevated in the sera of SSc patients, and its receptor S1P5 is expressed in skin tissue. Nevertheless, almost nothing is known about the dermatological contribution of S1P5 to inflammatory and pro-fibrotic processes leading to the pathological changes seen in SSc. In this study, we observed a novel effect of S1P5 on the inflammatory processes during low-dose bleomycin (BLM)-induced fibrogenesis in murine skin. By comparing 2-week-treated skin areas of wild-type (WT) and S1P5-deficient mice, we found that S1P5 is important for the transcriptional upregulation of the Th2 characteristic transcription factor GATA-3 under treatment-induced inflammatory conditions, while T-bet (Th1) and FoxP3 (Treg) mRNA expression was regulated independently of S1P5. Additionally, treatment caused a regulation of S1P receptor 1 and S1P receptor 3 mRNA as well as a regulation of long-chain ceramide profiles, which both differ significantly between the genotypes. Despite S1P5-dependent differences regarding inflammatory processes, similar macroscopic evidence of fibrosis was detected in the skin histology of WT and S1P5-deficient mice after 4 weeks of subcutaneous BLM treatment. However, at the earlier 2-week point in time, the mRNA data of pro-collagen type 1 and SMAD7 indicate a pro-fibrotic S1P5 contribution in the applied SSc mouse model. In conclusion, we propose that S1P5 plays a role as a novel modulator during the early phase of BLM-caused fibrogenesis in murine skin. An immediate relationship between dermal S1P5 expression and fibrotic processes leading to skin alterations, such as formative for SSc pathogenesis, is indicated but should be studied more profound in further investigations. Therefore, this study is an initial step in understanding the role of S1P5-mediated effects during early stages of fibrogenesis, which may encourage the ongoing search for new therapeutic options for SSc patients.
Spleen injuries are among the most frequent trauma-related injuries. At present, they are classified according to the anatomy of the injury. The optimal treatment strategy, however, should keep into consideration the hemodynamic status, the anatomic derangement, and the associated injuries. The management of splenic trauma patients aims to restore the homeostasis and the normal physiopathology especially considering the modern tools for bleeding management. Thus, the management of splenic trauma should be ultimately multidisciplinary and based on the physiology of the patient, the anatomy of the injury, and the associated lesions. Lastly, as the management of adults and children must be different, children should always be treated in dedicated pediatric trauma centers. In fact, the vast majority of pediatric patients with blunt splenic trauma can be managed non-operatively. This paper presents the World Society of Emergency Surgery (WSES) classification of splenic trauma and the management guidelines.
Sprifermin (rhFGF18) enables proliferation of chondrocytes producing a hyaline cartilage matrix
(2017)
Objective: Fibroblast growth factor (FGF) 18 has been shown to increase cartilage volume when injected intra-articularly in animal models of osteoarthritis (OA) and in patients with knee OA (during clinical development of the recombinant human FGF18, sprifermin). However, the exact nature of this effect is still unknown. In this study, we aimed to investigate the effects of sprifermin at the cellular level.
Design: A combination of different chondrocyte culture systems was used and the effects of sprifermin on proliferation, the phenotype and matrix production were evaluated. The involvement of MAPKs in sprifermin signalling was also studied.
Results: In monolayer, we observed that sprifermin promoted a round cell morphology and stimulated both cellular proliferation and Sox9 expression while strongly decreasing type I collagen expression. In 3D culture, sprifermin increased the number of matrix-producing chondrocytes, improved the type II:I collagen ratio and enabled human OA chondrocytes to produce a hyaline extracellular matrix (ECM). Furthermore, we found that sprifermin displayed a ‘hit and run’ mode of action, with intermittent exposure required for the compound to fully exert its anabolic effect. Finally, sprifermin appeared to signal through activation of ERK.
Conclusions: Our results indicate that intermittent exposure to sprifermin leads to expansion of hyaline cartilage-producing chondrocytes. These in vitro findings are consistent with the increased cartilage volume observed in the knees of OA patients after intra-articular injection with sprifermin in clinical studies.
Brain-derived neurotrophic factor (BDNF), an important neural growth factor, has gained growing interest in neuroscience, but many influencing physiological and analytical aspects still remain unclear. In this study we assessed the impact of storage time at room temperature, repeated freeze/thaw cycles, and storage at −80 °C up to 6 months on serum and ethylenediaminetetraacetic acid (EDTA)-plasma BDNF. Furthermore, we assessed correlations of serum and plasma BDNF concentrations in two independent sets of samples. Coefficients of variations (CVs) for serum BDNF concentrations were significantly lower than CVs of plasma concentrations (n = 245, p = 0.006). Mean serum and plasma concentrations at all analyzed time points remained within the acceptable change limit of the inter-assay precision as declared by the manufacturer. Serum and plasma BDNF concentrations correlated positively in both sets of samples and at all analyzed time points of the stability assessment (r = 0.455 to rs = 0.596; p < 0.004). In summary, when considering the acceptable change limit, BDNF was stable in serum and in EDTA-plasma up to 6 months. Due to a higher reliability, we suggest favoring serum over EDTA-plasma for future experiments assessing peripheral BDNF concentrations.
Patient-reported outcomes (PROs) such as quality of life and work productivity are important for measuring patient's experience. We assessed PROs during and after treatment of hepatitis C virus (HCV) patients.Data were obtained from a phase 3 open label study of sofosbuvir and ribavirin (SOF + RBV) with and without interferon (IFN). Patients completed 4 PRO assessment instruments (SF-36, Functional Assessment of Chronic Illness Therapy-Fatigue, Chronic Liver Disease Questionnaire- HCV, Work Productivity and Activity-Specific Health Problem) before, during, and after treatment.A total of 533 patients with chronic HCV were enrolled; 28.9% treatment-naïve, 23.1% cirrhotic, 219 received IFN + SOF + RBV and 314 received IFN-free SOF + RBV. At baseline, there were no differences in PROs between the IFN-free and IFN-containing treatment arms (all P > 0.05). During treatment, patients receiving IFN + SOF + RBV had a substantial impairment in their PROs (up to -24.4% by treatment week 12, up to -8.3% at week 4 post-treatment). The PRO decrements seen in the SOF + RBV arm were smaller in magnitude (up to -7.1% by treatment week 12), and all returned to baseline or improved by post-treatment week 4. By 12 weeks after treatment cessation, patients who achieved sustained viral response-12 showed some improvement of PRO scores regardless of the regimen (up to +7.1%, P < 0.0001) or previous treatment experience. In multivariate analysis, the use of IFN was independently associated with lower PROs.IFN-based regimens have a profoundly negative impact to PROs. By contrast, the impact of RBV on these PROs is relatively modest. Achieving HCV cure is associated with improvement of most of the PRO scores.
Forgetting is a common phenomenon in everyday life. Although it often has negative connotations, forgetting is an important adaptive mechanism to avoid loading the memory storage with irrelevant information. A very important aspect of forgetting is its interaction with emotion. Affective events are often granted special and priority treatment over neutral ones with regards to memory storage. As a consequence, emotional information is more resistant to extinction than neutral information. It has been suggested that intentional forgetting serves as a mechanism to cope with unwanted or disruptive emotional memories and the main goal of this study was to assess forgetting of emotional auditory material using the item-method directed forgetting (DF) paradigm using a forgetting strategy based on mindfulness as a means to enhance DF. Contrary to our prediction, the mindfulness-based strategy not only did not improve DF but reduced it for neutral material. These results suggest that an interaction between processes such as response inhibition and attention is required for intentional forgetting to succeed.
Rhabdomyosarcoma (RMS) cells have recently been reported to be sensitive to oxidative stress. Therefore, we investigated whether concomitant inhibition of the two main antioxidant defense pathways, that is, the thioredoxin (TRX) and the glutathione (GSH) systems, presents a new strategy to trigger cell death in RMS. In this study, we discover that GSH-depleting agents, i.e. γ-glutamylcysteine synthetase inhibitor, buthionine sulfoximine (BSO) or the cystine/glutamate antiporter inhibitor erastin (ERA), synergize with thioredoxin reductase (TrxR) inhibitor auranofin (AUR) to induce cell death in RMS cells. Interestingly, AUR causes accumulation of ubiquitinated proteins when combined with BSO or ERA, in line with recent reports showing that AUR inhibits the proteasome besides TrxR. Consistently, AUR/BSO or AUR/ERA cotreatment increases ubiquitination and expression of the short-lived proteins NOXA and MCL-1, accompanied by increased binding of NOXA to MCL-1. Notably, NOXA knockdown significantly rescues RMS cells from AUR/BSO- or AUR/ERA-induced cell death. In addition, AUR acts together with BSO or ERA to stimulate BAX/BAK and caspase activation. Of note, BSO or ERA abolish the AUR-stimulated increase in GSH levels, leading to reduced GSH levels upon cotreatment. Although AUR/BSO or AUR/ERA cotreatment enhances reactive oxygen species (ROS) production, only thiol-containing antioxidants (i.e., N-acetylcysteine (NAC), GSH), but not the non-thiol-containing ROS scavenger α-Tocopherol consistently suppress AUR/BSO- and AUR/ERA-stimulated cell death in both cell lines. Importantly, re-supply of GSH or its precursor NAC completely prevents AUR/ERA- and AUR/BSO-induced accumulation of ubiquitinated proteins, NOXA upregulation and cell death, indicating that GSH depletion rather than ROS production is critical for AUR/BSO- or AUR/ERA-mediated cell death. Thus, by demonstrating that GSH-depleting agents enhance the antitumor activity of AUR, we highlight new treatment options for RMS by targeting the redox homeostasis.
Recent studies have suggested increased plasticity of differentiated cells within the intestine to act both as intestinal stem cells (ISCs) and tumour-initiating cells. However, little is known of the processes that regulate this plasticity. Our previous work has shown that activating mutations of Kras or the NF-κB pathway can drive dedifferentiation of intestinal cells lacking Apc. To investigate this process further, we profiled both cells undergoing dedifferentiation in vitro and tumours generated from these cells in vivo by gene expression analysis. Remarkably, no clear differences were observed in the tumours; however, during dedifferentiation in vitro we found a marked upregulation of TGFβ signalling, a pathway commonly mutated in colorectal cancer (CRC). Genetic inactivation of TGFβ type 1 receptor (Tgfbr1/Alk5) enhanced the ability of KrasG12D/+ mutation to drive dedifferentiation and markedly accelerated tumourigenesis. Mechanistically this is associated with a marked activation of MAPK signalling. Tumourigenesis from differentiated compartments is potently inhibited by MEK inhibition. Taken together, we show that tumours arising in differentiated compartments will be exposed to different suppressive signals, for example, TGFβ and blockade of these makes tumourigenesis more efficient from this compartment.
We are pleased to introduce the sixth Journal Club. This edition is focused on several relevant studies published in the last years in the field of Strength and Conditioning, chosen by our Editorial Board members and their colleagues. We hope to stimulate your curiosity in this field and to share with you the passion for sport and exercise seen from a scientific point of view. The Editorial Board members wish you an inspiring read.
Purpose: To evaluate long-term outcome of three years and treatment patterns of patients suffering from severely drug-refractory epilepsy (SDRE).
Methods: This analysis was population-based and retrospective, with data collected from four million individuals insured by statutory German health insurance. ICD-10 codes for epilepsy (G40*) and intake of anticonvulsants were used to identify prevalent cases, which were then compared with a matched cohort drawn from the population at large. Insurance data were available from 2008 to 2013. Any patient who had been prescribed with at least four different antiepileptic drugs (AEDs) in an 18-month period was defined as an SDRE case.
Results: A total of 769 patients with SDRE were identified. Of these, 19% were children and adolescents; the overall mean age was 42.3 years, 45.4% were female and 54.6% male. An average of 2.7 AEDs per patient was prescribed during the first follow-up year. The AEDs most commonly prescribed were: levetiracetam (53.5%), lamotrigine (41.4%), valproate (41.3%), lacosamide (20.4%), and topiramate (17.8%). During 3-year follow-up, there was an annual rate of hospitalization in the range 42.7 to 55%, which was significantly higher than the 11.6–12.8% (p < 0.001) for the matched controls. Admissions to hospital because of epilepsy ranged between 1.7 and 1.9 per year, with an average duration for each epilepsy-caused hospitalization of 10–11.1 days. The number of comorbidities for SDRE patients was significantly increased compared with the matched controls: depression (28% against 10%), vascular disorders (22% against 5%), and injury rates were also higher (head 16% against 3%, trunk and limbs 16% against 8%). The 3-year mortality rate for SDRE patients was 14% against 2.1% in the matched cohort.
Conclusion: SDRE patients are treated with AED polytherapy for all of the 3-year follow-up period. They are hospitalized more frequently than the general population and show increased morbidity levels and a sevenfold increase in mortality rate over 3 years. Further examination is required of ways in which new approaches to treatment could lead to better outcomes in severely affected patients.
In 2006, the Task Force of the European Society of Cardiology published its consensus document on the use of autologous cell therapy for repair of the heart. Since then, there have been numerous clinical trials and analyses performed to establish the role of autologous cell therapy in the treatment of both acute and chronic cardiac disease. The majority of these studies have been Phase II clinical trials. Phase III clinical trials of autologous cell therapy have been launched (e.g. BAMI), which marks the successful progression of clinical investigation of autologous cell therapy in heart disease. The Task Force has reviewed its 2006 recommendations and the developments in this area of research and proposes updated recommendations for the future of autologous cell therapy in the heart. This article does not duplicate the many reviews on stem cells and the heart but gives considered recommendations based on the experience from the last 10 years.
Cellular attachment plays a vital role in the differentiation of pheochromocytoma (PC12) cells. PC12 cells are noradrenergic clonal cells isolated from the adrenal medulla of Rattus norvegicus and studied extensively as they have the ability to differentiate into sympathetic neuron-like cells. The effect of several experimental parameters including (i) the concentration of nerve growth factor (NGF); (ii) substratum coatings, such as poly-L-lysine (PLL), fibronectin (Fn), and laminin (Lam); and (iii) double coatings composed of PLL/Lam and PLL/Fn on the differentiation process of PC12 cells were studied. Cell morphology was visualised using brightfield phase contrast microscopy, cellular metabolism and proliferation were quantified using a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay, and the neurite outgrowth and axonal generation of the PC12 cells were evaluated using wide field fluorescence microscopy. It was found that double coatings of PLL/Lam and PLL/Fn supported robust adhesion and a two-fold enhanced neurite outgrowth of PC12 cells when treated with 100 ng/mL of NGF while exhibiting stable metabolic activity, leading to the accelerated generation of axons.
Background: Antidepressant medication is commonly used to treat depression. However, many patients do not respond to the first medication prescribed and improvements in symptoms are generally only detectable by clinicians 4–6 weeks after the medication has been initiated. As a result, there is often a long delay between the decision to initiate an antidepressant medication and the identification of an effective treatment regimen.
Previous work has demonstrated that antidepressant medications alter subtle measures of affective cognition in depressed patients, such as the appraisal of facial expression. Furthermore, these cognitive effects of antidepressants are apparent early in the course of treatment and can also predict later clinical response. This trial will assess whether an electronic test of affective cognition and symptoms (the Predicting Response to Depression Treatment Test; PReDicT Test) can be used to guide antidepressant treatment in depressed patients and, therefore, hasten treatment response compared to a control group of patients treated as usual.
Methods/design: The study is a randomised, two-arm, multi-centre, open-label, clinical investigation of a medical device, the PReDicT Test. It will be conducted in five European countries (UK, France, Spain, Germany and the Netherlands) in depressed patients who are commencing antidepressant medication. Patients will be randomised to treatment guided by the PReDicT Test (PReDicT arm) or to Treatment as Usual (TaU arm). Patients in the TaU arm will be treated as per current standard guidelines in their particular country. Patients in the PReDicT arm will complete the PReDicT Test after 1 (and if necessary, 2) weeks of treatment. If the test indicates non-response to the treatment, physicians will be advised to immediately alter the patient’s antidepressant therapy by dose escalation or switching to another compound. The primary outcome of the study is the proportion of patients showing a clinical response (defined as 50% or greater decrease in baseline scores of depression measured using the Quick Inventory of Depressive Symptoms – Self-Rated questionnaire) at week 8. Health economic and acceptability data will also be collected and analysed.
Discussion: This trial will test the clinical efficacy, cost-effectiveness and acceptability of using the novel PReDicT Test to guide antidepressant treatment selection in depressed patients.
Trial registration: ClinicalTrials.gov, ID: NCT02790970. Registered on 30 March 2016.
Autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD) frequently co-occur. The presence of a genetic link between ASD and ADHD symptoms is supported by twin studies, but the genetic overlap between clinically ascertained ASD and ADHD remains largely unclear. We therefore investigated how ASD and ADHD co-aggregate in individuals and in families to test for the presence of a shared genetic liability and examined potential differences between low- and high-functioning ASD in the link with ADHD. We studied 1 899 654 individuals born in Sweden between 1987 and 2006. Logistic regression was used to estimate the association between clinically ascertained ASD and ADHD in individuals and in families. Stratified estimates were obtained for ASD with (low-functioning) and without (high-functioning) intellectual disability. Individuals with ASD were at higher risk of having ADHD compared with individuals who did not have ASD (odds ratio (OR)=22.33, 95% confidence interval (CI): 21.77–22.92). The association was stronger for high-functioning than for low-functioning ASD. Relatives of individuals with ASD were at higher risk of ADHD compared with relatives of individuals without ASD. The association was stronger in monozygotic twins (OR=17.77, 95% CI: 9.80–32.22) than in dizygotic twins (OR=4.33, 95% CI: 3.21–5.85) and full siblings (OR=4.59, 95% CI: 4.39–4.80). Individuals with ASD and their relatives are at increased risk of ADHD. The pattern of association across different types of relatives supports the existence of genetic overlap between clinically ascertained ASD and ADHD, suggesting that genomic studies might have underestimated this overlap.
Background: This study sought to assess payer costs following cryoballoon or radiofrequency current (RFC) catheter ablation of paroxysmal atrial fibrillation in the randomized FIRE AND ICE trial.
Methods and Results: A trial period analysis of healthcare costs evaluated the impact of ablation modality (cryoballoon versus RFC) on differences in resource use and associated payer costs. Analyses were based on repeat interventions, rehospitalizations, and cardioversions during the trial, with unit costs based on 3 national healthcare systems (Germany [€], the United Kingdom [£], and the United States [Embedded Image]). Total payer costs were calculated by applying standard unit costs to hospital stays, using International Classification of Diseases, 10th Revision diagnoses and procedure codes that were mapped to country‐specific diagnosis‐related groups. Patients (N=750) randomized 1:1 to cryoballoon (n=374) or RFC (n=376) ablation were followed for a mean of 1.5 years. Resource use was lower in the cryoballoon than the RFC group (205 hospitalizations and/or interventions in 122 patients versus 268 events in 154 patients). The cost differences per patient in mean total payer costs during follow‐up were €640, £364, and Embedded Image925 in favor of cryoballoon ablation (P=0.012, 0.013, and 0.016, respectively). This resulted in trial period total cost savings of €245 000, £140 000, and Embedded Image355 000.
Conclusions: When compared with RFC ablation, cryoballoon ablation was associated with a reduction in resource use and payer costs. In all 3 national healthcare systems analyzed, this reduction resulted in substantial trial period cost savings, primarily attributable to fewer repeat ablations and a reduction in cardiovascular rehospitalizations with cryoballoon ablation.
Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Identifier: NCT01490814.
In the article by Chun et al, "The Impact of Cryoballoon Versus Radiofrequency Ablation for Paroxysmal Atrial Fibrillation on Healthcare Utilization and Costs: An Economic Analysis From the FIRE AND ICE Trial" which published online July 27, 2017, and appeared in the August 2017 issue of the journal (J Am Heart Assoc. 2017;6:e006043. DOI: 10.1161/JAHA.117.006043.), there were errors found in Figure 1. On page 5, Figure 1, "United Kingdom" and "United States" were misspelled.
Background: In this study we evaluated the interactions of human adipose tissue-derived stem cells (ADSCs) and different human breast cancer cell lines (BRCAs) with regard to the safety of cell-assisted lipotransfers for breast reconstruction and a thereby unintended co-localization of ADSCs and BRCAs.
Methods: ADSCs were co-cultured with five different human BRCAs (MCF-7, MDA-MB-231, SK-BR-3, ZR-75-30, and EVSA-T) and primary BRCAs from one patient in a transwell system, and cell-cell-interactions were analyzed by assessing doubling time, migration and invasion, angiogenesis, quantitative real-time polymerase chain reaction (PCR) of more than 300 tumor-associated genes, and multiplex protein assays of 20 chemokines and growth factors and eight matrix metalloproteinases (MMPs). Results of co-culture were compared to those of the respective monoculture.
Results: Quantitative real-time PCR revealed remarkable changes in the expression of multiple tumor-associated genes in co-culture compared to monocultures of both ADSCs and BRCAs. Concomitantly, the concentration of several tumor-associated proteins, such as cytokines and MMPs, were strongly increased in co-culture. Furthermore, exclusively in co-culture with ADSCs, the different BRCAs were exposed to several important tumor-modulating proteins, such as CCL2, HGF, or interleukins.
Co-culture did not significantly affect cellular proliferation of either ADSCs or BRCAs (p > 0.05). The migration of MCF-7 and MDA-MB-231 BRCAs was significantly increased in co-culture with ADSCs by a mean of 11% and 23%, respectively (p = 0.04 and 0.012), as well as that of ADSCs in co-culture with MDA-MB-231, ZR-75-30, and EVSA-T (+11–15%, p = 0.035–0.045). Co-culture with MDA-MB-231, SK-BR-3, and EVSA-T BRCAs significantly increased the invasive behavior of ADSCs by a mean of 24–41% (p = 0.014–0.039). There were no significant differences in the in vitro invasive properties of BRCAs in co-culture compared to monoculture. An in vitro angiogenesis assay revealed an increased tube formation of conditioned media from co-cultured BRCAs and ADSCs compared to the respective monocultures.
Conclusion: This study further elucidates the possible interactions of primary human ADSCs with human BRCAs, pointing towards a potential increased oncological risk which should not be neglected when considering a clinical use of cell-assisted lipoaspirates in breast reconstruction.
Background: The objective of the FAVOR study was to evaluate the effect of indacaterol/glycopyrronium (IND/GLY) versus tiotropium on peak forced expiratory volume in 1 s (FEV1) and also to investigate patient satisfaction and treatment preference.
Methods: Patients with moderate-to-severe airflow limitation (FEV1/forced vital capacity ratio of <0.70), those with a COPD assessment test score of ≥10, and those who were maintained on tiotropium HandiHaler® therapy prior to enrollment were recruited for the study, and randomized (1:1) to receive either 4 weeks open-label IND/GLY (110/50 µg) once daily followed by 4 weeks of tiotropium (18 µg) once daily or vice versa. The primary endpoint was FEV1 1 h post-inhalation after 4 weeks of treatment. Other endpoints included patient’s and physician’s preference for treatment, patient’s satisfaction evaluated using a study-specific questionnaire and the abbreviated Treatment Satisfaction Questionnaire for Medication, and safety and tolerability.
Results: Eighty-seven out of 88 randomized patients completed the study and showed significantly higher FEV1 1 h post-inhalation after 4 weeks of treatment with IND/GLY versus tiotropium (treatment difference =0.081 L; p=0.0017). IND/GLY was preferred over tiotropium among the patients (69.4% versus 30.6%, p=0.0004) and the physicians (81.6% versus 18.4%, p<0.0001). A higher proportion of the patients stated they were very satisfied or satisfied with IND/GLY versus tiotropium with regard to dyspnea reduction (79.3% versus 58.0%, respectively) and reduction of dyspnea on exertion (72.4% versus 43.2%, respectively). Patients treated with IND/GLY showed significant improvement in Treatment Satisfaction Questionnaire for Medication domain scores versus tiotropium. IND/GLY demonstrated a good safety and tolerability profile.
Conclusion: This study indicated that, beyond FEV1, important patient-reported outcomes improved with the open-label dual bronchodilator IND/GLY when compared with tiotropium. This study suggests that individual patients felt the lung function benefits with IND/GLY compared with tiotropium, which, in turn, may also have contributed to the preference for IND/GLY.
Spatial attention allows us to make more accurate decisions about events in our environment. Decision confidence is thought to be intimately linked to the decision making process as confidence ratings are tightly coupled to decision accuracy. While both spatial attention and decision confidence have been subjected to extensive research, surprisingly little is known about the interaction between these two processes. Since attention increases performance it might be expected that confidence would also increase. However, two studies investigating the effects of endogenous attention on decision confidence found contradictory results. Here we investigated the effects of two distinct forms of spatial attention on decision confidence; endogenous attention and exogenous attention. We used an orientation-matching task, comparing the two attention conditions (endogenous and exogenous) to a control condition without directed attention. Participants performed better under both attention conditions than in the control condition. Higher confidence ratings than the control condition were found under endogenous attention but not under exogenous attention. This finding suggests that while attention can increase confidence ratings, it must be voluntarily deployed for this increase to take place. We discuss possible implications of this relative overconfidence found only during endogenous attention with respect to the theoretical background of decision confidence.
Aim: NADPH oxidases are important sources of reactive oxygen species (ROS). Several Nox homologues are present together in the vascular system but whether they exhibit crosstalk at the activity level is unknown. To address this, vessel function of knockout mice for the cytosolic Nox organizer proteins p47phox, NoxO1 and a p47phox-NoxO1-double knockout were studied under normal condition and during streptozotocin-induced diabetes.
Results: In the mouse aorta, mRNA expression for NoxO1 was predominant in smooth muscle and endothelial cells, whereas p47phox was markedly expressed in adventitial cells comprising leukocytes and tissue resident macrophages. Knockout of either NoxO1 or p47phox resulted in lower basal blood pressure. Deletion of any of the two subunits also prevented diabetes-induced vascular dysfunction. mRNA expression analysis by MACE (Massive Analysis of cDNA ends) identified substantial gene expression differences between the mouse lines and in response to diabetes. Deletion of p47phox induced inflammatory activation with increased markers of myeloid cells and cytokine and chemokine induction. In contrast, deletion of NoxO1 resulted in an attenuated interferon gamma signature and reduced expression of genes related to antigen presentation. This aspect was also reflected by a reduced number of circulating lymphocytes in NoxO1-/- mice.
Innovation and conclusion: ROS production stimulated by NoxO1 and p47phox limit endothelium-dependent relaxation and maintain blood pressure in mice. However, NoxO1 and p47phox cannot substitute each other despite their similar effect on vascular function. Deletion of NoxO1 induced an anti-inflammatory phenotype, whereas p47phox deletion rather elicited a hyper-inflammatory response.
Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.
Oxygenation-sensitive spin relaxation time T2′ and relaxation rate R2′ (1/T2′) are presumed to be markers of the cerebral oxygen extraction fraction (OEF) in acute ischemic stroke. In this study, we investigate the relationship of T2′/R2′ with dynamic susceptibility contrast-based relative cerebral blood flow (rCBF) in acute ischemic stroke to assess their plausibility as surrogate markers of the ischemic penumbra. Twenty-one consecutive patients with internal carotid artery and/or middle cerebral artery occlusion were studied at 3.0 T. A physiological model of the cerebral vasculature (VM) was used to process PWI raw data in addition to a conventional deconvolution technique. T2′, R2′, and rCBF values were extracted from the ischemic core and hypoperfused areas. Within hypoperfused tissue, no correlation was found between deconvolved rCBF and T2′ (r = −0.05, p = 0.788), or R2′ (r = 0.039, p = 0.836). In contrast, we found a strong positive correlation with T2′ (r = 0.444, p = 0.006) and negative correlation with R2′ (r = −0.494, p = 0.0025) for rCBFVM, indicating increasing OEF with decreasing CBF and that rCBF based on the vascular model may be more closely related to metabolic disturbances. Further research to refine and validate these techniques may enable their use as MRI-based surrogate markers of the ischemic penumbra for selecting stroke patients for interventional treatment strategies.
Introduction: The aim of this study was to ascertain whether the testing format of an OSPE (Objective Structured Practical Examination) in conservative dentistry (sixth semester) predicts the scores on the practical section of the state examination (11th semester) in the same subject. Taking general student profiles into consideration (score on the school-leaving exam [Abitur], score on the preliminary exam in dental medicine [Physikum], length of university study, cohorts, and sex), we also investigated if any correlations or differences exist in regard to the total and partial scores on the OSPE and the corresponding state examination.
Methods: Within the scope of this longitudinal retrospective study, exam-specific data spanning 11 semesters for dental students (N=223) in Frankfurt am Main were collected and analyzed. Statistical analysis was carried out by calculating Spearman rank correlations, partial correlations, Pearson’s correlation coefficients, and multiple regressions (SPSS Statistics 21, IBM Corporation, New York).
Results: The results show that the OSPE (Cronbach’s α=.87) correlates with level of success on the practical section of the state exam in conservative dentistry (p=.01, r=.17). Length of university study also emerged to correlate significantly with the state exam score (p=.001, r=.23). Together, these two variables contribute significantly to predicting the state exam score (p=.001, R2=.076). This was seen extensively among female students. It was also discovered that these female students had higher school-leaving exam scores than male students (F=6.09, p=.01, η2=.027), and that a significant correlation between scores on the Physikum (preliminary exam in dental medicine) and OSPE scores existed only for male students (r=.17, p=.01).
Conclusion: This study was able to demonstrate the predictive effect of a clinical OSPE regarding scores achieved on the state exam. Taking the limitations of this study into account, we are able to recommend using the OSPE testing format in the sixth semester during the clinical phase of dental study.
Disruption of the blood-air barrier, which is formed by lung microvascular endothelial and alveolar epithelial cells, is a hallmark of acute lung injury. It was shown that alveolar epithelial cells release an unidentified soluble factor that enhances the barrier function of lung microvascular endothelial cells. In this study we reveal that primarily prostaglandin (PG) E2 accounts for this endothelial barrier-promoting activity. Conditioned media from alveolar epithelial cells (primary ATI-like cells) collected from BALB/c mice and A549 cells increased the electrical resistance of pulmonary human microvascular endothelial cells, respectively. This effect was reversed by pretreating alveolar epithelial cells with a cyclooxygenase-2 inhibitor or by blockade of EP4 receptors on endothelial cells, and in A549 cells also by blocking the sphingosine-1-phosphate1 receptor. Cyclooxygenase-2 was constitutively expressed in A549 cells and in primary ATI-like cells, and was upregulated by lipopolysaccharide treatment. This was accompanied by enhanced PGE2 secretion into conditioned media. Therefore, we conclude that epithelium-derived PGE2 is a key regulator of endothelial barrier integrity via EP4 receptors under physiologic and inflammatory conditions. Given that pharmacologic treatment options are still unavailable for diseases with compromised air-blood barrier, like acute lung injury, our data thus support the therapeutic potential of selective EP4 receptor agonists.
The role of endogenous melatonin for the control of the circadian system under entrained conditions and for the determination of the chronotype is still poorly understood. Mice with deletions in the melatoninergic system (melatonin deficiency or the lack of melatonin receptors, respectively) do not display any obvious defects in either their spontaneous (circadian) or entrained (diurnal) rhythmic behavior. However, there are effects that can be detected by analyzing the periodicity of the locomotor behaviors in some detail. We found that melatonin-deficient mice (C57Bl), as well as melatonin-proficient C3H mice that lack the melatonin receptors (MT) 1 and 2 (C3H MT1,2 KO), reproduce their diurnal locomotor rhythms with significantly less accuracy than mice with an intact melatoninergic system. However, their respective chronotypes remained unaltered. These results show that one function of the endogenous melatoninergic system might be to stabilize internal rhythms under conditions of a steady entrainment, while it has no effects on the chronotype.
Rhabdomyosarcoma (RMS), the most common cancer of connective tissues in pediatrics, is often resistant to conventional therapies. One underlying mechanism of this resistance is the overexpression of Inhibitor of Apoptosis (IAP) proteins, leading to a dysfunctional cell death program within tumor cells. Smac mimetics (SM) are small molecules that can reactivate the cell death program by antagonizing IAP proteins and thereby compensating their overexpression. Here, we report that SM sensitize two RMS cell lines (RD and RH30) toward natural killer (NK) cell-mediated killing on the one hand, and increase the cytotoxic potential of NK cells on the other. The SM-induced sensitization of RH30 cells toward NK cell-mediated killing is significantly reduced through blocking tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on NK cells prior to coculture. In addition, the presence of zVAD.fmk, a pancaspase inhibitor, rescues tumor cells from the increase in killing, indicating an apoptosis-dependent cell death. On the NK cell side, the presence of SM in addition to IL-2 during the ex vivo expansion leads to an increase in their cytotoxic activity against RH30 cells. This effect is mainly TNFα-dependent and partially mediated by NK cell activation, which is associated with transcriptional upregulation of NF-κB target genes such as IκBα and RelB. Taken together, our findings implicate that SM represent a novel double-hit strategy, sensitizing tumor and activating NK cells with one single drug.
Neuroblastoma is a biologically and clinically heterogeneous pediatric malignancy that includes a high-risk subset for which new therapeutic agents are urgently required. As well as MYCN amplification, activating point mutations of ALK and NRAS are associated with high-risk and relapsing neuroblastoma. As both ALK and RAS signal through the MEK/ERK pathway, we sought to evaluate two previously reported inhibitors of ETS-related transcription factors, which are transcriptional mediators of the Ras-MEK/ERK pathway in other cancers. Here we show that YK-4-279 suppressed growth and triggered apoptosis in nine neuroblastoma cell lines, while BRD32048, another ETV1 inhibitor, was ineffective. These results suggest that YK-4-279 acts independently of ETS-related transcription factors. Further analysis reveals that YK-4-279 induces mitotic arrest in prometaphase, resulting in subsequent cell death. Mechanistically, we show that YK-4-279 inhibits the formation of kinetochore microtubules, with treated cells showing a broad range of abnormalities including multipolar, fragmented and unseparated spindles, together leading to disrupted progression through mitosis. Notably, YK-4-279 does not affect microtubule acetylation, unlike the conventional mitotic poisons paclitaxel and vincristine. Consistent with this, we demonstrate that YK-4-279 overcomes vincristine-induced resistance in two neuroblastoma cell-line models. Furthermore, combinations of YK-4-279 with vincristine, paclitaxel or the Aurora kinase A inhibitor MLN8237/Alisertib show strong synergy, particularly at low doses. Thus, YK-4-279 could potentially be used as a single-agent or in combination therapies for the treatment of high-risk and relapsing neuroblastoma, as well as other cancers.
Neurogenesis of hippocampal granule cells (GCs) persists throughout mammalian life and is important for learning and memory. How newborn GCs differentiate and mature into an existing circuit during this time period is not yet fully understood. We established a method to visualize postnatally generated GCs in organotypic entorhino-hippocampal slice cultures (OTCs) using retroviral (RV) GFP-labeling and performed time-lapse imaging to study their morphological development in vitro. Using anterograde tracing we could, furthermore, demonstrate that the postnatally generated GCs in OTCs, similar to adult born GCs, grow into an existing entorhino-dentate circuitry. RV-labeled GCs were identified and individual cells were followed for up to four weeks post injection. Postnatally born GCs exhibited highly dynamic structural changes, including dendritic growth spurts but also retraction of dendrites and phases of dendritic stabilization. In contrast, older, presumably prenatally born GCs labeled with an adeno-associated virus (AAV), were far less dynamic. We propose that the high degree of structural flexibility seen in our preparations is necessary for the integration of newborn granule cells into an already existing neuronal circuit of the dentate gyrus in which they have to compete for entorhinal input with cells generated and integrated earlier.
Sustainable Development Goals (SDGs) comprise of 17 goals and 169 targets. All SDGs are interlinked to produce synergetic eff ects and emphasize health in all policies. Among the 17 Goals, Goal 3 has a central focus on health, which is underpinned by 13 targets. Th e other 16 goals are also directly or indirectly related to health and will contribute to achieving the associated targets for Goal 3. Th e ambitious SDG agenda and their progress can be tracked by measuring numerous goals, targets, and indicators. The main objective of this paper is to provide an overview about how health- related SDGs and their targets and indicators are being tracked in the national context of Nepal. Adequate investment in research for knowledge generation, capacity building and innovation, and continous research communication among policy makers, researchers and external development partners will contribute to tracking the progress of SDGs in Nepal.
Objectives: It is known that transition, as a shift of care, marks a vulnerable phase in the adolescents’ lives with an increased risk for non-adherence and allograft failure. Still, the transition process of adolescents and young adults living with a kidney transplant in Germany is not well defined. The present research aims to assess transition-relevant structures for this group of young people. Special attention is paid to the timing of the process.
Setting: In an observational study, we visited 21 departments of paediatric nephrology in Germany. Participants were doctors (n=19), nurses (n=14) and psychosocial staff (n=16) who were responsible for transition in the relevant centres. Structural elements were surveyed using a short questionnaire. The experiential viewpoint was collected by interviews which were transcribedverbatim before thematic analysis was performed.
Results: This study highlights that professionals working within paediatric nephrology in Germany are well aware of the importance of successful transition. Key elements of transitional care are well understood and mutually agreed on. Nonetheless, implementation within daily routine seems challenging, and the absence of written, structured procedures may hamper successful transition.
Conclusions: While professionals aim for an individual timing of transfer based on medical, social, emotional and structural aspects, rigid regulations on transfer age as given by the relevant health authorities add on to the challenge.
Trial registration: number ISRCTN Registry no 22988897; results (phase I) and pre-results (phase II).
A high proportion of patients with breast cancer develop bone metastases, yet data on routine treatment with bone-targeted agents (BTA) are rare. We report real-life outcome data of patients with breast cancer metastasised to the bone treated by office-based oncologists in Germany.
The ongoing, prospective, multicentre, population-based cohort study Tumour Registry Breast Cancer (TMK) was started in 2007 in 140 centres across Germany.
This interim analysis of 1094 patients with bone metastases revealed differences among the tumour subtypes: at start of first-line therapy, 36% of the patients with hormone receptor (HR)-positive and only 20% of the patients with HR-negative tumours presented with bone-only metastasis. The majority of patients with bone metastases (89%, n = 976) received BTA therapy. In 2014–2015, 37% of the patients received the bisphosphonate zoledronic acid and 36% the antibody denosumab. Median duration of BTA therapy was 20 months (interquartile range 31.5 months), starting a median of 3 weeks after diagnosis of bone metastases, and ending a median of 7 weeks before death. The median overall survival (OS) also varied among the types of metastasis at start of first-line therapy ranging from 54 months (95% confidence interval [CI] 37.6–70.8), 38 months (95% CI 29.4–44.2) to 28 months (95% CI 24.2–31.0) for patients with bone-only metastases, non-visceral with or without bone metastases and visceral with or without bone metastases respectively.
We show that choice and duration of BTA therapies are in conformity with guidelines applicable in Germany. To our knowledge, this is the first presentation of data on incidence, metastatic pattern, treatment and survival of patients with bone metastases in routine practice.
Treatment of refractory ascites with an automated low-flow ascites pump in patients with cirrhosis
(2017)
Background: Refractory ascites (RA) is a frequent complication of cirrhosis, requiring large volume paracentesis or placement of a transjugular intrahepatic portosystemic shunt (TIPSS). The automated low-flow ascites pump (alfapump, Sequana Medical AG, Zurich, Switzerland) is an innovative treatment option for patients with RA.
Aim: To assess safety and efficacy of this treatment in patients with a contraindication to TIPSS.
Methods: Fifty-six patients (43 males; mean age 62 years) from centres in Germany, Switzerland, UK and Spain were included and followed for up to 24 months. Complications, device deficiencies, paracentesis frequency and patient survival were recorded.
Results: At the time of this analysis, 3 patients completed the 24-month observation period, monitoring of 3 was ongoing, 9 underwent liver transplantation, 17 patients were withdrawn due to serious adverse events and 23 patients died. Most frequently observed technical complication was blocking of the peritoneal catheter. Twenty-three pump-related reinterventions (17 patients) and 12 pump exchanges (11 patients) were required during follow-up. The pump system was explanted in 48% of patients (in 17 patients due to serious adverse events, in 9 at the time of liver transplantation and in 1 due to recovery from RA). Median frequency of paracentesis dropped from 2.17 to 0.17 per month.
Conclusions: The alfapump can expand therapeutic options for cirrhotic patients with RA. Continuous drainage of ascites in a closed loop automated system led to significant reduction in paracentesis frequency. Technical and procedural improvements are required to reduce the rate of adverse events and reinterventions.
BACKGROUND: The analysis of microarray time series promises a deeper insight into the dynamics of the cellular response following stimulation. A common observation in this type of data is that some genes respond with quick, transient dynamics, while other genes change their expression slowly over time. The existing methods for detecting significant expression dynamics often fail when the expression dynamics show a large heterogeneity. Moreover, these methods often cannot cope with irregular and sparse measurements.
RESULTS: The method proposed here is specifically designed for the analysis of perturbation responses. It combines different scores to capture fast and transient dynamics as well as slow expression changes, and performs well in the presence of low replicate numbers and irregular sampling times. The results are given in the form of tables including links to figures showing the expression dynamics of the respective transcript. These allow to quickly recognise the relevance of detection, to identify possible false positives and to discriminate early and late changes in gene expression. An extension of the method allows the analysis of the expression dynamics of functional groups of genes, providing a quick overview of the cellular response. The performance of this package was tested on microarray data derived from lung cancer cells stimulated with epidermal growth factor (EGF).
CONCLUSION: Here we describe a new, efficient method for the analysis of sparse and heterogeneous time course data with high detection sensitivity and transparency. It is implemented as R package TTCA (transcript time course analysis) and can be installed from the Comprehensive R Archive Network, CRAN. The source code is provided with the Additional file 1.
Tumor-associated macrophages, angiogenesis, and tumor cell migration in oral squamous cell carcinoma
(2017)
Objective: To investigate the relationship between tumor-associated macrophages (TAMs), neovascularization, and tumor cell migration in oral squamous cell carcinoma (OSCC) of an African subpopulation.
Materials and Methods: Twenty OSCC paraffin blocks underwent immunohistochemistry to TAM1 (CCR7), TAM2 (CD206), Twist, E-cadherin, N-cadherin, and CD34. The relative percentage of CCR7 + and CD206 + cells to overall immune cell population was calculated for three high power fields and an average was taken. TAM-related microvessel density (MVD) was determined as the mean of the three recorded values. Cases that had no CD34 + vessels adjacent to the TAMs region were regarded as having an MVD score of 0.
Results: Ten cases (50%) expressed greater CCR7 activity than CD206, seven cases (35%) expressed approximately equal activity of CCR7 and CD206, while three cases (15%) expressed greater activity of CD206 than CCR7. Twist expression was strong in some cases with strong N-cadherin and weak E-cadherin, but the expression of Twist was not consistently high in all cases that expressed strong N-cadherin and weak E-cadherin.
Conclusions: TAMs distribution suggested antitumor activity and the potential for tumor metastasis was only partly due to Twist-mediated epithelial–mesenchymal transition.
Cytokine regulation of high-output nitric oxide (NO) derived from inducible NO synthase (iNOS) is critically involved in inflammation biology and host defense. Herein, we set out to characterize the role of type I interferon (IFN) as potential regulator of hepatic iNOS in vitro and in vivo. In this regard, we identified in murine Hepa1-6 hepatoma cells a potent synergism between pro-inflammatory interleukin-β/tumor necrosis factor-α and immunoregulatory IFNβ as detected by analysis of iNOS expression and nitrite release. Upregulation of iNOS by IFNβ coincided with enhanced binding of signal transducer and activator of transcription-1 to a regulatory region at the murine iNOS promoter known to support target gene expression in response to this signaling pathway. Synergistic iNOS induction under the influence of IFNβ was confirmed in alternate murine Hepa56.1D hepatoma cells and primary hepatocytes. To assess iNOS regulation by type I IFN in vivo, murine acetaminophen (APAP)-induced sterile liver inflammation was investigated. In this model of acute liver injury, excessive necroinflammation drives iNOS expression in diverse liver cell types, among others hepatocytes. Herein, we demonstrate impaired iNOS expression in type I IFN receptor-deficient mice which associated with diminished APAP-induced liver damage. Data presented indicate a vital role of type I IFN within the inflamed liver for fine-tuning pathological processes such as overt iNOS expression.
Dendrites form predominantly binary trees that are exquisitely embedded in the networks of the brain. While neuronal computation is known to depend on the morphology of dendrites, their underlying topological blueprint remains unknown. Here, we used a centripetal branch ordering scheme originally developed to describe river networks—the Horton-Strahler order (SO)–to examine hierarchical relationships of branching statistics in reconstructed and model dendritic trees. We report on a number of universal topological relationships with SO that are true for all binary trees and distinguish those from SO-sorted metric measures that appear to be cell type-specific. The latter are therefore potential new candidates for categorising dendritic tree structures. Interestingly, we find a faithful correlation of branch diameters with centripetal branch orders, indicating a possible functional importance of SO for dendritic morphology and growth. Also, simulated local voltage responses to synaptic inputs are strongly correlated with SO. In summary, our study identifies important SO-dependent measures in dendritic morphology that are relevant for neural function while at the same time it describes other relationships that are universal for all dendrites.
Background: In oldest-old patients (>80), few trials showed efficacy of treating hypertension and they included mostly the healthiest elderly. The resulting lack of knowledge has led to inconsistent guidelines, mainly based on systolic blood pressure (SBP), cardiovascular disease (CVD) but not on frailty despite the high prevalence in oldest-old. This may lead to variation how General Practitioners (GPs) treat hypertension. Our aim was to investigate treatment variation of GPs in oldest-olds across countries and to identify the role of frailty in that decision.
Methods: Using a survey, we compared treatment decisions in cases of oldest-old varying in SBP, CVD, and frailty. GPs were asked if they would start antihypertensive treatment in each case. In 2016, we invited GPs in Europe, Brazil, Israel, and New Zealand. We compared the percentage of cases that would be treated per countries. A logistic mixed-effects model was used to derive odds ratio (OR) for frailty with 95% confidence intervals (CI), adjusted for SBP, CVD, and GP characteristics (sex, location and prevalence of oldest-old per GP office, and years of experience). The mixed-effects model was used to account for the multiple assessments per GP.
Results: The 29 countries yielded 2543 participating GPs: 52% were female, 51% located in a city, 71% reported a high prevalence of oldest-old in their offices, 38% and had >20 years of experience. Across countries, considerable variation was found in the decision to start antihypertensive treatment in the oldest-old ranging from 34 to 88%. In 24/29 (83%) countries, frailty was associated with GPs’ decision not to start treatment even after adjustment for SBP, CVD, and GP characteristics (OR 0.53, 95%CI 0.48–0.59; ORs per country 0.11–1.78).
Conclusions: Across countries, we found considerable variation in starting antihypertensive medication in oldest-old. The frail oldest-old had an odds ratio of 0.53 of receiving antihypertensive treatment. Future hypertension trials should also include frail patients to acquire evidence on the efficacy of antihypertensive treatment in oldest-old patients with frailty, with the aim to get evidence-based data for clinical decision-making.
Sphingolipids are characterized by a broad range of bioactive properties. Particularly, the development of insulin resistance, a major pathophysiological hallmark of Type 2 Diabetes mellitus (T2D), has been linked to ceramide signaling. Since vitamin D supplementation may slow down T2D progression by improving glucose concentrations and insulin sensitivity, we investigated whether vitamin D supplementation impacts on plasma sphingolipid levels in T2D patients. Thus, plasma samples of 59 patients with non-insulin-requiring T2D from a placebo-controlled, randomized, and double-blind study were retrospectively analyzed. Once per week, patients received either 20 drops of Vigantol oil, corresponding to a daily dose of 1904 IU/d vitamin D (verum: n = 31), or a placebo oil consisting of medium chain triglycerides (placebo: n = 28). Blood samples were taken from all of the participants at three different time points: 1) at the beginning of the study (baseline), 2) after 6 months supplementation, and 3) after an additional 6 months of follow-up. Plasma sphingolipids were measured by high-performance liquid chromatography tandem mass spectrometry. At baseline and 6 months follow-up, no significant differences in plasma sphingolipid species were detected between the placebo and verum groups. After 6 months, vitamin D supplementation significantly enhanced plasma C18dihydroceramide (dhCer; N-stearoyl-sphinganine (d18:0/18:0)) and C18ceramide (Cer; N-stearoyl-sphingosine (d18:1/18:0)) levels were observed in the verum group compared to the placebo group. This was accompanied by significantly higher 25-hydroxyvitamin D3 (25(OH)D3) blood levels in patients receiving vitamin D compared to the placebo group. Taken together, vitamin D supplementation induced changes of the C18 chain-length-specific dhCer and Cer plasma levels in patients with T2D. The regulation of sphingolipid signaling by vitamin D may thus unravel a novel mechanism by which vitamin D can influence glucose utilization and insulin action. Whether this acts favorably or unfavorably for the progression of T2D needs to be clarified.
Background: Treatment of asthma does not always comply with asthma guidelines (AG). This may be rooted in direct or indirect resistance on the doctors’ and/or patients’ side or be caused by the healthcare system. To assess whether patients’ concepts and attitudes are really an implementation barrier for AG, we analysed the patients’ perspective of a “good asthma therapy” and contrasted their wishes with current recommendations.
Methods: Using a qualitative exploratory design, topic centred focus group (FG) discussions were performed until theoretical saturation was reached. Inclusion criteria were an asthma diagnosis and age above 18. FG sessions were recorded audio-visually and analysed via a mapping technique and content analysis performed according to Mayring (supported by MAXQDA®). Participants’ speech times and the proportion of time devoted to different themes were calculated using the Videograph System® and related to the content analysis.
Results: Thirteen men and 24 women aged between 20 and 77 from rural and urban areas attended five FG. Some patients had been recently diagnosed with asthma, others years previously or in childhood. The following topics were addressed: (a) concern about or rejection of therapy components, particularly corticosteroids, which sometimes resulted in autonomous uncommunicated medication changes, (b) lack of time or money for optimal treatment, (c) insufficient involvement in therapy choices and (d) a desire for greater empowerment, (e) suboptimal communication between healthcare professionals and (f) difficulties with recommendations conflicting with daily life. Primarily, (g) participants wanted more time with doctors to discuss difficulties and (h) all aspects of living with an impairing condition.
Conclusions: We identified some important patient driven barriers to implementing AG recommendations. In order to advance AG implementation and improve asthma treatment, the patients’ perspective needs to be considered before drafting new versions of AG. These issues should be addressed at the planning stage.
Trial registration: DRKS00000562 (German Clinical Trials Registry).
Current theories of schizophrenia (ScZ) posit that the symptoms and cognitive dysfunctions arise from a dysconnection syndrome. However, studies that have examined this hypothesis with physiological data at realistic time scales are so far scarce. The current study employed a state-of-the-art approach using Magnetoencephalography (MEG) to test alterations in large-scale phase synchronization in a sample of n = 16 chronic ScZ patients, 10 males and n = 19 healthy participants, 10 males, during a perceptual closure task. We identified large-scale networks from source reconstructed MEG data using data-driven analyses of neuronal synchronization. Oscillation amplitudes and interareal phase-synchronization in the 3–120 Hz frequency range were estimated for 400 cortical parcels and correlated with clinical symptoms and neuropsychological scores. ScZ patients were characterized by a reduction in γ-band (30–120 Hz) oscillation amplitudes that was accompanied by a pronounced deficit in large-scale synchronization at γ-band frequencies. Synchronization was reduced within visual regions as well as between visual and frontal cortex and the reduction of synchronization correlated with elevated clinical disorganization. Accordingly, these data highlight that ScZ is associated with a profound disruption of transient synchronization, providing critical support for the notion that core aspect of the pathophysiology arises from an impairment in coordination of distributed neural activity.
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.