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Background
Cochlear Implants (CIs) provide near normal speech intelligibility in quiet environments to individuals suffering from sensorineural hearing loss. Perception of speech in situations with competing background noise and especially music appraisal however are still insufficient. Hence, improving speech perception in ambient noise and music intelligibility is a core challenge in CI research. Quantitatively assessing music intelligibility is a demanding task due to its inherently subjective nature. However, previous approaches have related electrophysiological measurements to speech intelligibility, a corresponding relation to music intelligibility, can be assumed. Recent studies have investigated the relation between results obtained from hearing performance tests and Spread of Excitations (SoEs) measurements. SoE functions are acquired by measuring Electrically Evoked Compound Action Potentials (ECAPs) which represent the electrical response generated in the neural structures of the auditory nerve. The parameters designed to describe SoE functions are used to estimate the dispersal of the electric field in the cochlea. The quality of spatial separation of the electrical field generated by adjacent electrodes are assumed to correlate with hearing performance measures.
Aim of study
This study investigated the relation of parameters derived by ECAP measurements and perceptive skills which aim to access the level of speech and music intelligibility in CI users. In addition, the ratings assessed in a questionnaire on self-rated music intelligibility were correlated to a test battery consisting of measures for speech reception threshold (SRT) in noise (Oldenburger Satztest (OLSA)) and music intelligibility (Adaptive Melody-Pattern-Discrimination Test (AMPDT)). We hypothesised that results from this test battery correlated to subjective ratings and measures describing SoE functions.
Methods
The patient collective covered 17 well-experienced bilateral CI listeners (8 females, 9 males) between the age of 14 and 77 years with a minimum CI experience of two years. Music enjoyment and self-rated musicality was evaluated by means of a questionnaire. The AMPDT included two psychoacoustic tests: timbre difference discrimination threshold (TDDT) and background contour discrimination threshold (BCDT). The accentuation of harmonics in a foreground melody created a background melody. Accentuation was realised by sound level increment, frequency detuning and onset asynchrony. Subjects had to detect target intervals comprising both foreground and background melody by discriminating timbre differences in a Three-Interval Three-Alternative Forced-Choice (3I3AFC) procedure. In a One-Interval Two-Alternative Forced-Choice (1I2AFC) procedure, subjects had to classify the background melody’s contour. SoE was measured via a spatial forward-masking paradigm. A basal, medial and apical recording electrode was measured. Probe electrodes were one electrode position apical to the recording. The width of normalised SoE functions was calculated at their 25 % and 50 % level (excitation distance (DIST)). Furthermore, exponential functions were calculated for SoE profiles with more than three data points for each side. The OLSA assessed SRT in noise. The noisy environment was presented through an array of four loudspeakers (MSNF). The Fastl noise-condition allows to make use of gap listening representing the temporal characteristics of speech as a fluctuating noise. The OLnoise-condition is a continuous noise resulting in a maximum portion of masking.
Results
We found that background melody contour classiffication (BCDT) is more challenging to CI users than the detection of small perceptual timbre differences (TDDT). Background melody contour classification was possible with harmonic accentuation by sound level increment whereas accentuation by onset asynchrony was more demanding. CI users failed in background melody contour classification obtained by frequency detuning. SRTs assessed in the OLSA were significantly lower in the OLnoise than in the Fastl noise masking condition. A number of N = 90 SoE functions were acquired from ECAP measurements, in which N = 48 showed a clearly present ECAP response. The DIST at the 25 % and 50 % level was narrower for the basal than for the apical and medial electrode. SoE functions showed asymmetric profiles with larger amplitudes towards the basal end of the cochlea. Correlation analysis between the AMPDT, OLSA and DISTs showed no significant correlation. Correlation analysis between the AMPDT, OLSA and the questionnaire’s results could not prove that musical activities (music listening, singing or playing instruments) improve music intelligibility. However, CI supply has restored the importance of music, self-rated musicality and musical enjoyment in this study’s subjects.
Conclusions
The present study’s results imply that CI listeners are only able to detect distinct timbre alterations throughout the course of a musical piece whereas they cannot discriminate background melodies hidden in a pattern of complex harmonic sounds. Furthermore, SoE measurements do not seem to be an adequate tool to predict neither speech nor music intelligibility in CI listeners, contrary to our initial hypothesis. This finding is consistent with a number of studies who did not find a correlation between music or speech intelligibility and channel interactions assessed by SoE measurements. It can be concluded that albeit CI supply restores musical enjoyment in patients with sensorineural hearing loss, music perception is still poor and does not significantly improve by regular musical activities such as listening to music, singing or playing instruments.
Lymphocyte function-associated antigen 1 (LFA-1) affinity and avidity changes have been assumed to mediate adhesion to intercellular adhesion molecule-1 for T-cell conjugation to dendritic cells (DC). Although the T-cell receptor (TCR) and LFA-1 can generate intracellular signals, the immune cell adaptor protein linker for the activation of T cells (LAT) couples the TCR to downstream events. Here, we show that LFA-1 can mediate both adhesion and de-adhesion, dependent on receptor clustering. Although increased affinity mediates adhesion, LFA-1 cross-linking induced the association and activation of the protein-tyrosine kinases FAK1/PYK1 that phosphorylated LAT selectively on a single Y-171 site for the binding to adaptor complex GRB-2-SKAP1. LAT-GRB2-SKAP1 complexes were distinct from canonical LAT-GADs-SLP-76 complexes. LFA-1 cross-linking increased the presence of LAT-GRB2-SKAP1 complexes relative to LAT-GADs-SLP-76 complexes. LFA-1-FAK1 decreased T-cell-dendritic cell (DC) dwell times dependent on LAT-Y171, leading to reduced DO11.10 T cell binding to DCs and proliferation to OVA peptide. Overall, our findings outline a new model for LFA-1 in which the integrin can mediate both adhesion and de-adhesion events dependent on receptor cross-linking.
Hematotoxicity is one of the major side effects of chemotherapy. The aim of this study was to examine the association between single nucleotide polymorphisms (SNPs) and hematotoxicity in breast cancer patients in a subset of patients of the SUCCESS prospective phase III chemotherapy study. All patients (n = 1678) received three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by three cycles of docetaxel or docetaxel/gemcitabine, depending on randomization. Germline DNA was genotyped for 246 SNPs selected from a previous genome-wide association study (GWAS) in a panel of lymphoblastoid cell lines, with gemcitabine toxicity as the phenotype. All SNPs were tested for their value in predicting grade 3 or 4 neutropenic or leukopenic events (NLEs). Their prognostic value in relation to overall survival and disease-free survival was also tested.
None of the SNPs was found to be predictive for NLEs during treatment with docetaxel/gemcitabine. Two SNPs in and close to the PIGB gene significantly improved the prediction of NLEs after FEC, in addition to the factors of age and body surface area. The top SNP (rs12050587) had an odds ratio of 1.38 per minor allele (95% confidence interval, 1.17 to 1.62). No associations were identified for predicting disease-free or overall survival.
Genetic variance in the PIGB gene may play a role in determining interindividual differences in relation to hematotoxicity after FEC chemotherapy.
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.
Background: Red blood cell (RBC) depletion is a standard graft manipulation technique for ABO-incompatible bone marrow (BM) transplants. The BM processing module for Spectra Optia, “BMC”, was previously introduced. We here report the largest series to date of routine quality data after performing 50 clinical-scale RBC-depletions.
Methods: Fifty successive RBC-depletions from autologous (n = 5) and allogeneic (n = 45) BM transplants were performed with the Spectra Optia BMC apheresis suite. Product quality was assessed before and after processing for volume, RBC and leukocyte content; RBC-depletion and stem cell (CD34+ cells) recovery was calculated there from. Clinical engraftment data were collected from 26/45 allogeneic recipients.
Results: Median RBC removal was 98.2% (range 90.8–99.1%), median CD34+ cell recovery was 93.6%, minimum recovery being 72%, total product volume was reduced to 7.5% (range 4.7–23.0%). Products engrafted with expected probability and kinetics. Performance indicators were stable over time.
Discussion: Spectra Optia BMC is a robust and efficient technology for RBC-depletion and volume reduction of BM, providing near-complete RBC removal and excellent CD34+ cell recovery.
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.
Background: Infections with the hepatitis C virus (HCV) are a global public health problem. Long-term consequences are the development of liver cirrhosis and hepatocellular carcinoma. Newly introduced direct acting antivirals, especially interferon-free regimens, have improved rates of sustained viral response above 90% in most patient groups and allow treating patients who were ineligible for treatment in the past. These new regimens have replaced former treatment and are recommended by current guidelines. However, there is an ongoing discussion on high pharmaceutical prices. Our aim was to assess the long-term cost-effectiveness of treating hepatitis C genotype 1 patients with sofosbuvir/ledipasvir (SOF/LDV) treatment in Germany.
Material and Methods: We used a Markov cohort model to simulate disease progression and assess cost-effectiveness. The model calculates lifetime costs and outcomes (quality-adjusted life years, QALYs) of SOF/LDV and other strategies. Patients were stratified by treatment status (treatment-naive and treatment-experienced) and absence/presence of cirrhosis. Different treatment strategies were compared to prior standard of care. Sensitivity analyses were performed to evaluate model robustness.
Results: Base-case analyses results show that in treatment-naive non-cirrhotic patients treatment with SOF/LDV dominates the prior standard of care (is more effective and less costly). In cirrhotic patients an incremental cost-effectiveness ratio (ICER) of 3,383 €/QALY was estimated. In treatment-experienced patients ICERs were 26,426 €/QALY and 1,397 €/QALY for treatment-naive and treatment-experienced patients, respectively. Robustness of results was confirmed in sensitivity analyses.
Conclusions: Our analysis shows that treatment with SOF/LDV is cost-effective compared to prior standard of care in all patient groups considering international costs per QALY thresholds.
Introduction: For management of complicated retinal detachments, a pars plana vitrectomy with temporary silicone oil (SO) fill is the method of choice. According to literature, the retinal redetachment rate varies between <10% and >70% with around 36% in our own group (retrospective data analysis, n = 119 eyes).
Methods: The main goal was to reduce the retinal redetachment rate. Standard operating procedures (SOPs) and evaluation protocols (EVALPs) were developed to prospectively analyse risk factors. Lab analysis of SO was performed, and the role of surgical experience was evaluated and investigated with Eyesi®.
Results: We achieved a significant reduction of the retinal redetachment rate (to 6.80%, n = 101, p = 0.002). After surgery with SO injection, neither further membrane peeling (in 16.5%) nor retinal laser coagulation (in 100%) during revision surgery had a significant effect on the reattachment rate (p = 0.167, p = 0.23), while extensive additional laser coagulation reduced visual acuity (p = 0.01). A 3-port approach had to be set up to complete SO removal. A difference in success rate depending on surgical experience was confirmed, and the performance in Eyesi correlated with that in the patients' eye.
Conclusions: A SOP- and EVALP-based management and new strategies to secure the surgical performance seem to be essential for successful surgery.
GPR116 (ADGRF5) and ELTD1 (ADGRL4) belong to different subfamilies of the adhesion G-protein-coupled receptor group but are both expressed in endothelial cells. We therefore analyzed their functions in mice lacking these receptors. While loss of GPR116 or ELTD1 alone had no obvious effect on cardiovascular or kidney function, mice lacking both, GPR116 and ELTD1, showed malformations of the aortic arch arteries and the cardiac outflow tract leading to perinatal lethality in about 50% of the mutants. In addition to cardiovascular malformations, surviving mice developed renal thrombotic microangiopathy as well as hemolysis and splenomegaly, and their lifespan was significantly reduced. Loss of GPR116 and ELTD1 specifically in endothelial cells or neural crest-derived cells did not recapitulate any of the phenotypes observed in GPR116-ELTD1 double deficient mice, indicating that loss of GPR116 and ELTD1 expressed by other cells accounts for the observed cardiovascular and renal defects.
Inhibition of the IκB kinase complex (IKK) has been implicated in the therapy of several chronic inflammatory diseases including inflammatory bowel diseases. In this study, using mice with an inactivatable IKKα kinase (IkkαAA/AA), we show that loss of IKKα function markedly impairs epithelial regeneration in a model of acute colitis. Mechanistically, this is caused by compromised secretion of cytoprotective IL-18 from IKKα-mutant intestinal epithelial cells because of elevated caspase 12 activation during an enhanced unfolded protein response (UPR). Induction of the UPR is linked to decreased ATG16L1 stabilization in IkkαAA/AA mice. We demonstrate that both TNF-R and nucleotide-binding oligomerization domain stimulation promote ATG16L1 stabilization via IKKα-dependent phosphorylation of ATG16L1 at Ser278. Thus, we propose IKKα as a central mediator sensing both cytokine and microbial stimulation to suppress endoplasmic reticulum stress, thereby assuring antiinflammatory function during acute intestinal inflammation.
Background: All European countries need to increase the number of health professionals in the near future. Most efforts have not brought the expected results so far. The current notion is that this is mainly related to the fact that female physicians will clearly outnumber their male colleagues within a few years in nearly all European countries. Still, women are underrepresented in leadership and research positions throughout Europe.
Objectives: The MedGoFem project addresses multiple perspectives with the participation of multiple stakeholders. The goal is to facilitate the implementation of Gender Equality Plans (GEP) in university hospitals; thereby, transforming the working conditions for women working as researchers and highly qualified physicians simultaneously. Our proposed innovation, a crosscutting topic in all research and clinical activities, must become an essential part of university hospital strategic concepts.
Methods: We capture the current status with gender-sensitive demographic data concerning medical staff and conduct Web-based surveys to identify cultural, country-specific, and interdisciplinary factors conducive to women’s academic success. Individual expectations of employees regarding job satisfaction and working conditions will be visualized based on “personal construct theory” through repertory grids. An expert board working out scenarios and a gender topic agenda will identify culture-, nation-, and discipline-specific aspects of gender equality. University hospitals in 7 countries will establish consensus groups, which work on related topics. Hospital management supports the consensus groups, valuates group results, and shares discussion results and suggested measures across groups. Central findings of the consensus groups will be prepared as exemplary case studies for academic teaching on research and work organization, leadership, and management.
Results: A discussion group on gender equality in academic medicine will be established on an internationally renowned open-research platform. Project results will be published in peer-reviewed journals with high-impact factors. In addition, workshops on gender dimension in research using the principles of Gendered Innovation will be held. Support and consulting services for hospitals will be introduced in order to develop a European consulting service.
Conclusions: The main impact of the project will be the implementation of innovative GEP tailored to the needs of university hospitals, which will lead to measurable institutional change in gender equality. This will impact the research at university hospitals in general, and will improve career prospects of female researchers in particular. Simultaneously, the gender dimension in medical research as an innovation factor and mandatory topic will be strengthened and integrated in each individual university hospital research activity. Research funding organizations can use the built knowledge to include mandatory topics for funding applications to enforce the use and implementation of GEP in university hospitals.
Background: PINK1 deficiency causes the autosomal recessive PARK6 variant of Parkinson’s disease. PINK1 activates ubiquitin by phosphorylation and cooperates with the downstream ubiquitin ligase PARKIN, to exert quality control and control autophagic degradation of mitochondria and of misfolded proteins in all cell types.
Methods: Global transcriptome profiling of mouse brain and neuron cultures were assessed in protein-protein interaction diagrams and by pathway enrichment algorithms. Validation by quantitative reverse transcriptase polymerase chain reaction and immunoblots was performed, including human neuroblastoma cells and patient primary skin fibroblasts.
Results: In a first approach, we documented Pink1-deleted mice across the lifespan regarding brain mRNAs. The expression changes were always subtle, consistently affecting “intracellular membrane-bounded organelles”. Significant anomalies involved about 250 factors at age 6 weeks, 1300 at 6 months, and more than 3500 at age 18 months in the cerebellar tissue, including Srsf10, Ube3a, Mapk8, Creb3, and Nfkbia. Initially, mildly significant pathway enrichment for the spliceosome was apparent. Later, highly significant networks of ubiquitin-mediated proteolysis and endoplasmic reticulum protein processing occurred. Finally, an enrichment of neuroinflammation factors appeared, together with profiles of bacterial invasion and MAPK signaling changes—while mitophagy had minor significance. Immunohistochemistry showed pronounced cellular response of Iba1-positive microglia and GFAP-positive astrocytes; brain lipidomics observed increases of ceramides as neuroinflammatory signs at old age.
In a second approach, we assessed PINK1 deficiency in the presence of a stressor. Marked dysregulations of microbial defense factors Ifit3 and Rsad2 were consistently observed upon five analyses: (1) Pink1 −/− primary neurons in the first weeks after brain dissociation, (2) aged Pink1 −/− midbrain with transgenic A53T-alpha-synuclein overexpression, (3) human neuroblastoma cells with PINK1-knockdown and murine Pink1 −/− embryonal fibroblasts undergoing acute starvation, (4) triggering mitophagy in these cells with trifluoromethoxy carbonylcyanide phenylhydrazone (FCCP), and (5) subjecting them to pathogenic RNA-analogue poly(I:C). The stress regulation of MAVS, RSAD2, DDX58, IFIT3, IFIT1, and LRRK2 was PINK1 dependent. Dysregulation of some innate immunity genes was also found in skin fibroblast cells from PARK6 patients.
Conclusions: Thus, an individual biomarker with expression correlating to progression was not identified. Instead, more advanced disease stages involved additional pathways. Hence, our results identify PINK1 deficiency as an early modulator of innate immunity in neurons, which precedes late stages of neuroinflammation during alpha-synuclein spreading.
The Gini index is a measure of the inequality of a distribution that can be derived from Lorenz curves. While commonly used in, e.g., economic research, it suffers from ambiguity via lack of Lorenz dominance preservation. Here, investigation of large sets of empirical distributions of incomes of the World’s countries over several years indicated firstly, that the Gini indices are centered on a value of 33.33% corresponding to the Gini index of the uniform distribution and secondly, that the Lorenz curves of these distributions are consistent with Lorenz curves of log-normal distributions. This can be employed to provide a Lorenz dominance preserving equivalent of the Gini index. Therefore, a modified measure based on log-normal approximation and standardization of Lorenz curves is proposed. The so-called UGini index provides a meaningful and intuitive standardization on the uniform distribution as this characterizes societies that provide equal chances. The novel UGini index preserves Lorenz dominance. Analysis of the probability density distributions of the UGini index of the World’s counties income data indicated multimodality in two independent data sets. Applying Bayesian statistics provided a data-based classification of the World’s countries’ income distributions. The UGini index can be re-transferred into the classical index to preserve comparability with previous research.
Background: The importance of the Internet as a medium for publishing and sharing health and medical information has increased considerably during the last decade. Nonetheless, comprehensive knowledge and information are scarce and difficult to find, especially for rare diseases. Additionally, the quality of health or medical information about rare diseases is frequently difficult to assess for the patients and their family members.
Objective: The aim of this study is to assess the quality of information on the Internet about rare diseases. Additionally, the study aims to evaluate if the quality of information on rare diseases varies between different information supplier categories.
Methods: A total of 13 quality criteria for websites providing medical information about rare diseases were transferred to a self-disclosure questionnaire. Identified providers of information on the Internet about rare diseases were invited to fill out the questionnaire. The questionnaire contained questions about the information provider in general (eg, supplier category, information category, language, use of quality certificates, and target group) and about quality aspects that reflect the 13 quality criteria. Differences in subgroup analyses were performed using t tests.
Results: We identified 693 websites containing information about rare diseases. A total of 123 questionnaires (17.7%) were completely filled out by the information suppliers. For the remaining identified suppliers (570/693, 82.3%), the questionnaires were filled out by the authors based on the information available on their website. In many cases, the quality of websites was proportionally low. Furthermore, subgroup analysis showed no statistically significant differences between the quality of information provided by support group/patient organization compared to medical institution (P=.19). The quality of information by individuals (patient/relative) was significantly lower compared to information provided by support group/patient organization (P=.001), medical institution (P=.009), and other associations and sponsoring bodies (P=.001) as well.
Conclusions: Overall, the quality of information on the Internet about rare diseases is low. Quality certificates are rarely used and important quality criteria are often not fulfilled completely. Additionally, some information categories are underrepresented (eg, information about psychosocial counseling, social-legal advice, and family planning). Nevertheless, due to the high amount of information provided by support groups, this study shows that these are extremely valuable sources of information for patients suffering from a rare disease and their relatives.
Objective: The aim of this study was to report the basic cerebrospinal fluid (CSF) profile in patients with primary progressive multiple sclerosis (PPMS).
Methods: The results of CSF analysis from 254 patients with PPMS were collected at four university hospitals in Germany. Routine CSF parameters and different indices of intrathecal immunoglobulin synthesis were evaluated. We assessed possible correlations between the various CSF parameters and the expanded disability status scale (EDSS) both at the time of lumbar puncture and during the course of the disease.
Results: The median cell count and albumin concentration in the CSF did not deviate from normal values. The CSF-serum albumin-quotient (QALB) was elevated in 29.6% of the patients, while intrathecal immunoglobulin G (IgG) oligoclonal bands (OCBs) were detected in 91.1% of the patients. CSF-lactate levels as well as local IgM- and IgA-synthesis were correlated with the yearly disease progression rate, as assessed by EDSS.
Conclusion: We present the results of the hitherto largest and most detailed CSF biomarker profile in a cohort of 254 patients with PPMS. As reported previously, OCBs are the most sensitive marker for intrathecal IgG synthesis. CSF-lactate concentrations are positively correlated with the progression rate, which might suggest that mitochondrial dysfunction plays a relevant role in PPMS. The negative correlation between intrathecally produced IgM and IgA and disease progression may indicate their hitherto unexplored protective role.
Background: Treatment of patients presenting with possible acute myocardial infarction (AMI) is based on timely diagnosis and proper risk stratification aided by biomarkers. We aimed at evaluating the predictive value of GDF-15 in patients presenting with symptoms suggestive of AMI.
Methods: Consecutive patients presenting with suspected AMI were enrolled in three study centers. Cardiovascular events were assessed during a follow-up period of 6 months with a combined endpoint of death or MI.
Results: From the 1818 enrolled patients (m/f = 1208/610), 413 (22.7%) had an acute MI and 63 patients reached the combined endpoint. Patients with MI and patients with adverse outcome had higher GDF-15 levels compared with non-MI patients (967.1pg/mL vs. 692.2 pg/L, p<0.001) and with event-free patients (1660 pg/mL vs. 756.6 pg/L, p<0.001). GDF-15 levels were lower in patients with SYNTAX score ≤ 22 (797.3 pg/mL vs. 947.2 pg/L, p = 0.036). Increased GDF-15 levels on admission were associated with a hazard ratio of 2.1 for death or MI (95%CI: 1.67–2.65, p<0.001) in a model adjusted for age and sex and of 1.57 (1.13–2.19, p = 0.008) adjusted for the GRACE score variables. GDF-15 showed a relevant reclassification with regards to the GRACE score with an overall net reclassification index (NRI) of 12.5% and an integrated discrimination improvement (IDI) of 14.56% (p = 0.006).
Conclusion: GDF-15 is an independent predictor of future cardiovascular events in patients presenting with suspected MI. GDF-15 levels correlate with the severity of CAD and can identify and risk-stratify patients who need coronary revascularization.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic, Th17-derived cytokine thought to critically contribute to the pathogenesis of diverse autoimmune diseases, including rheumatoid arthritis and psoriasis. Treatment with monoclonal antibodies that block GM-CSF activity is associated with favorable therapeutic effects in patients with rheumatoid arthritis. We evaluated the role of GM-CSF as a potential target for therapeutic interference in psoriasis using a combined pharmacologic and genetic approach and the mouse model of imiquimod-induced psoriasiform dermatitis (IMQPD). Neutralization of murine GM-CSF by an anti-GM-CSF antibody ameliorated IMQPD. In contrast, genetic deficiency in GM-CSF did not alter the course of IMQPD, suggesting the existence of mechanisms compensating for chronic, but not acute, absence of GM-CSF. Further investigation uncovered an alternative pathogenic pathway for IMQPD in the absence of GM-CSF characterized by an expanded plasmacytoid dendritic cell population and release of IFNα and IL-22. This pathway was not activated in wild-type mice during short-term anti-GM-CSF treatment. Our investigations support the potential value of GM-CSF as a therapeutic target in psoriatic disease. The discovery of an alternative pathogenic pathway for psoriasiform dermatitis in the permanent absence of GM-CSF, however, suggests the need for monitoring during therapeutic use of long-term GM-CSF blockade.
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.
The efficacy of cisplatin-based chemotherapy in cancer is limited by the occurrence of innate and acquired drug resistance. In order to better understand the mechanisms underlying acquired cisplatin resistance, we have compared the adenocarcinoma-derived non-small cell lung cancer (NSCLC) cell line A549 and its cisplatin-resistant sub-line A549rCDDP2000 with regard to cisplatin resistance mechanisms including cellular platinum accumulation, DNA-adduct formation, cell cycle alterations, apoptosis induction and activation of key players of DNA damage response. In A549rCDDP2000 cells, a cisplatin-induced G2/M cell cycle arrest was lacking and apoptosis was reduced compared to A549 cells, although equitoxic cisplatin concentrations resulted in comparable platinum-DNA adduct levels. These differences were accompanied by changes in the expression of proteins involved in DNA damage response. In A549 cells, cisplatin exposure led to a significantly higher expression of genes coding for proteins mediating G2/M arrest and apoptosis (mouse double minute 2 homolog (MDM2), xeroderma pigmentosum complementation group C (XPC), stress inducible protein (SIP) and p21) compared to resistant cells. This was underlined by significantly higher protein levels of phosphorylated Ataxia telangiectasia mutated (pAtm) and p53 in A549 cells compared to their respective untreated control. The results were compiled in a preliminary model of resistance-associated signaling alterations. In conclusion, these findings suggest that acquired resistance of NSCLC cells against cisplatin is the consequence of altered signaling leading to reduced G2/M cell cycle arrest and apoptosis.
Psoriasis is a frequent and often severe inflammatory skin disease, characterized by altered epidermal homeostasis. Since we found previously that Akt/mTOR signaling is hyperactivated in psoriatic skin, we aimed at elucidating the role of aberrant mTORC1 signaling in this disease. We found that under healthy conditions mTOR signaling was shut off when keratinocytes switch from proliferation to terminal differentiation. Inflammatory cytokines (IL-1β, IL-17A, TNF-α) induced aberrant mTOR activity which led to enhanced proliferation and reduced expression of differentiation markers. Conversely, regular differentiation could be restored if mTORC1 signaling was blocked. In mice, activation of mTOR through the agonist MHY1485 also led to aberrant epidermal organization and involucrin distribution. In summary, these results not only identify mTORC1 as an important signal integrator pivotal for the cells fate to either proliferate or differentiate, but emphasize the role of inflammation-dependent mTOR activation as a psoriatic pathomechanism.
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.
Mobilization of hematopoietic stem cells (HSCs) from the bone marrow to the peripheral blood is a complex mechanism that involves adhesive and chemotactic interactions of HSCs as well as their bone marrow microenvironment. In addition to a number of non-genetic factors, genetic susceptibilities also contribute to the mobilization outcome. Identification of genetic factors associated with HSC yield is important to better understand the mechanism behind HSC mobilization. In the present study, we enrolled 148 Korean participants (56 healthy donors and 92 patients) undergoing HSC mobilization for allogeneic or autologous HSC transplantation. Among a total of 53 polymorphisms in 33 candidate genes, one polymorphism (rs11264422) in relaxin/insulin-like family peptide receptor 4 (RXFP4) gene was significantly associated with a higher HSC yield after mobilization in Koreans. However, in a set of 101 Europeans, no association was found between circulating CD34+ cell counts and rs11264422 genotype. Therefore, we suggest that the ethnic differences in subjects’ genetic background may be related to HSC mobilization. In conclusion, the relaxin—relaxin receptor axis may play an important role in HSC mobilization. We believe that the results of the current study could provide new insights for therapies that use relaxin and HSC populations, as well as a better understanding of HSC regulation and mobilization at the molecular level.
Purpose: To evaluate the effect of reduced z-axis scan coverage on diagnostic performance and radiation dose of neck CT in patients with suspected cervical abscess.
Methods: Fifty-one patients with suspected cervical abscess were included and underwent contrast-enhanced neck CT on a 2nd or 3rd generation dual-source CT system. Image acquisition ranged from the aortic arch to the upper roof of the frontal sinuses (CTstd). Subsequently, series with reduced z-axis coverage (CTred) were reconstructed starting at the aortic arch up to the orbital floor. CTstd and CTred were independently assessed by two radiologists for the presence/absence of cervical abscesses and for incidental and alternative findings. In addition, diagnostic accuracy for the depiction of the cervical abscesses was calculated for both readers. Furthermore, DLP (dose-length-product), effective dose (ED) and organ doses were calculated and compared for CTred and CTstd, using a commercially available dose management platform.
Results: A total of 41 abscesses and 3 incidental/alternative findings were identified in CTstd. All abscesses and incidental/alternative findings could also be detected on CTred resulting in a sensitivity and specificity of 1.0 for both readers. DLP, ED and organ doses of the brain, the eye lenses, the red bone marrow and the salivary glands of CTred were significantly lower than for CTstd (p<0.001).
Conclusions: Reducing z-axis coverage of neck CT allows for a significant reduction of effective dose and organ doses at similar diagnostic performance as compared to CTstd.
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.
The transcription factor Meis1 drives myeloid leukemogenesis in the context of Hox gene overexpression but is currently considered undruggable. We therefore investigated whether myeloid progenitor cells transformed by Hoxa9 and Meis1 become addicted to targetable signaling pathways. A comprehensive (phospho)proteomic analysis revealed that Meis1 increased Syk protein expression and activity. Syk upregulation occurs through a Meis1-dependent feedback loop. By dissecting this loop, we show that Syk is a direct target of miR-146a, whose expression is indirectly regulated by Meis1 through the transcription factor PU.1. In the context of Hoxa9 overexpression, Syk signaling induces Meis1, recapitulating several leukemogenic features of Hoxa9/Meis1-driven leukemia. Finally, Syk inhibition disrupts the identified regulatory loop, prolonging survival of mice with Hoxa9/Meis1-driven leukemia.
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.
Background: Transient receptor potential cation channel subfamily V member 1 (TRPV1) are sensitive to heat, capsaicin, pungent chemicals and other noxious stimuli. They play important roles in the pain pathway where in concert with proinflammatory factors such as leukotrienes they mediate sensitization and hyperalgesia. TRPV1 is the target of several novel analgesics drugs under development and therefore, TRPV1 genetic variants might represent promising candidates for pharmacogenetic modulators of drug effects.
Methods: A next-generation sequencing (NGS) panel was created for the human TRPV1 gene and in addition, for the leukotriene receptors BLT1 and BLT2 recently described to modulate TRPV1 mediated sensitisation processes rendering the coding genes LTB4R and LTB4R2 important co-players in pharmacogenetic approaches involving TRPV1. The NGS workflow was based on a custom AmpliSeq™ panel and designed for sequencing of human genes on an Ion PGM™ Sequencer. A cohort of 80 healthy subjects of Western European descent was screened to evaluate and validate the detection of exomic sequences of the coding genes with 25 base pair exon padding.
Results: The amplicons covered approximately 97% of the target sequence. A median of 2.81 x 10 6 reads per run was obtained. This identified approximately 140 chromosome loci where nucleotides deviated from the reference sequence GRCh37 hg19 comprising the three genes TRPV1, LTB4R and LTB4R2. Correspondence between NGS and Sanger derived nucleotide sequences was 100%.
Conclusions: Results suggested that the NGS approach based on AmpliSeq™ libraries and Ion Personal Genome Machine (PGM) sequencing is a highly efficient mutation detection method. It is suitable for large-scale sequencing of TRPV1 and functionally related genes. The method adds a large amount of genetic information as a basis for complete analysis of TRPV1 ion channel genetics and its functional consequences.
Epilepsy is a complex neurological disorder which can severely affect neuronal function. Some patients may experience status epilepticus, a life-threatening state of ongoing seizure activity associated with postictal cognitive dysfunction. However, the molecular mechanisms by which status epilepticus influences brain function beyond seizure activity remain not well understood. Here, we addressed the question of whether pilocarpine-induced status epilepticus affects synaptopodin (SP), an actin-binding protein, which regulates the ability of neurons to express synaptic plasticity. This makes SP an interesting marker for epilepsy-associated alterations in synaptic function. Indeed, single dose intraperitoneal pilocarpine injection (250 mg/kg) in three-month-old male C57BL/6J mice leads to a rapid reduction in hippocampal SP-cluster sizes and numbers (in CA1 stratum radiatum of the dorsal hippocampus; 90 min after injection). In line with this observation (and previous work using SP-deficient mice), a defect in the ability to induce long-term potentiation (LTP) of Schaffer collateral-CA1 synapses is observed. Based on these findings we propose that status epilepticus could exert its aftereffects on cognition at least in part by perturbing SP-dependent mechanisms of synaptic plasticity.
IFN-lambda (IFNλ) is a member of the type III IFN family and is reported to possess anti-pathogen, anti-cancer, and immunomodulatory properties; however, there are limited data regarding its impact on host immune responses in vivo. We performed longitudinal and comprehensive immunosurveillance to assess the ability of pegylated (peg)-IFNλ to augment antiviral host immunity as part of a clinical trial assessing the efficacy of peg-IFNλ in chronic hepatitis B (CHB) patients. These patients were pretreated with directly acting antiviral therapy (entecavir) for 12 weeks with subsequent addition of peg-IFNλ for up to 32 weeks. In a subgroup of patients, the addition of peg-IFNλ provoked high serum levels of antiviral cytokine IL-18. We also observed the enhancement of natural killer cell polyfunctionality and the recovery of a pan-genotypic HBV-specific CD4+ T cells producing IFN-γ with maintenance of HBV-specific CD8+ T cell antiviral and cytotoxic activities. It was only in these patients that we observed strong virological control with reductions in both viral replication and HBV antigen levels. Here, we show for the first time that in vivo peg-IFNλ displays significant immunostimulatory properties with improvements in the main effectors mediating anti-HBV immunity. Interestingly, the maintenance in HBV-specific CD8+ T cells in the presence of peg-IFNλ is in contrast to previous studies showing that peg-IFNα treatment for CHB results in a detrimental effect on the functionality of this important antiviral T cell compartment.
Young children are at greatest risk of exposure to lead and its effects. Although lead is one of the most widely used elements with known health hazard, there is little data on the blood lead level (BLL) of children in the Kathmandu Valley. Thus, this study aimed to assess factors associated with high BLL in children who were 6–36 months of age and resided in the Kathmandu Valley. In this hospital-based cross-sectional study 6–36 month-old children visiting the Paediatrics Outpatient Department of Tribhuvan University Teaching Hospital, Patan Hospital, and Siddhi Memorial Hospital were enrolled. All three hospitals are located in different areas inside the Kathmandu Valley. Written informed consent was obtained from the parents, and exposure data were collected using a structured questionnaire. Portable Anodic Stripping Voltammetry (ASV) was used to determine BLLs in children. Data were analyzed using SPSS version 16. Of 312 children enrolled in the study, 64.4% had BLLs ≥5μg/dl. A significant association was found between BLL and exposure to enamel paints in the household in the form of painting materials used in different parts of the house like walls, windows and doors (p = 0.001). Furthermore, multivariate analyses showed that BLLs were 4.5 times higher in children playing with dirt and dust (p = 0.006) and that children belonging to the community of lower caste/ethnicity groups had significantly higher BLLs compared to those from the upper caste groups (p = 0.02). Our study demonstrated that children living in households that have used enamel paints, children belonging to lower caste/ethnic groups, and children frequently playing with dirt and dust had significantly higher BLLs. The results of this study highlight the importance of policy decisions to limit environmental lead contamination, and to roll out awareness building measures designed to limit lead exposure and break the poverty cycle associated with chronic lead poisoning.
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.
Background: Electrical stimulation (ES) has been successfully used to treat bone defects clinically. Recently, both cellular and molecular approaches have demonstrated that ES can change cell behavior such as migration, proliferation and differentiation.
Methods: In the present study we exposed rat bone marrow- (BM-) and adipose tissue- (AT-) derived mesenchymal stem cells (MSCs) to direct current electrical stimulation (DC ES) and assessed temporal changes in osteogenic differentiation. We applied 100 mV/mm of DC ES for 1 h per day for three, seven and 14 days to cells cultivated in osteogenic differentiation medium and assessed viability and calcium deposition at the different time points. In addition, expression of osteogenic genes, Runx2, Osteopontin, and Col1A2 was assessed in BM- and AT-derived MSCs at the different time points.
Results: Results showed that ES changed osteogenic gene expression patterns in both BM- and AT-MSCs, and these changes differed between the two groups. In BM-MSCs, ES caused a significant increase in mRNA levels of Runx2, Osteopontin and Col1A2 at day 7, while in AT-MSCs, the increase in Runx2 and Osteopontin expression were observed after 14 days of ES.
Discussion: This study shows that rat bone marrow- and adipose tissue-derived stem cells react differently to electrical stimuli, an observation that could be important for application of electrical stimulation in tissue engineering.
Background/objectives: Obesity is independently associated with left ventricular (LV) diastolic dysfunction and altered cardiac morphology. Morbidity and mortality in patients with diastolic dysfunction are similar to values observed in patients with systolic heart failure. We hypothesized that dysfunctional cardiac responses in people with obesity are reversible after weight loss. Thus, we studied the effect of dietary weight reduction on LV diastolic function as well as on cardiac structure using transthoracic echocardiography and tissue Doppler imaging (TDI).
Subjects/methods: Thirty-two subjects with obesity underwent a 12-week low-calorie fasting phase of a formula diet. Echocardiographic tissue Doppler indices of diastolic function and measurements of cardiac size were obtained prior to and after the fasting phase.
Results: A 12-week diet significantly reduced body mass index from 40.3 ± 6.6 kg/m 2 to 33.2 ± 6.1 kg/m 2 ( p < 0.01). Weight loss was associated with a significant reduction in blood pressure and heart rate. Echocardiography revealed diastolic dysfunction in subjects with obesity, which was improved by dieting. After weight loss, trans-mitral Doppler echocardiography showed a significant reduction in A-wave velocity, from 65.8 ± 19.2 cm/s to 57.0 ± 16.8 cm/s, and an increase in E/A ratio from 1.2 ± 0.4 to 1.4 ± 0.5 ( p < 0.01). TDI displayed a significantly lower a'-wave velocity (10.3 ± 2.3 cm/s and 8.9 ± 1.7 cm/s; p < 0.01). Left atrial and LV dimensions were normal and remained unchanged after weight loss.
Conclusion: Obesity is associated with diastolic dysfunction. A 12-week low-calorie diet with successful weight loss can reduce blood pressure and heart rate and partially normalize diastolic dysfunction.
Broad AOX expression in a genetically tractable mouse model does not disturb normal physiology
(2017)
Plants and many lower organisms, but not mammals, express alternative oxidases (AOXs) that branch the mitochondrial respiratory chain, transferring electrons directly from ubiquinol to oxygen without proton pumping. Thus, they maintain electron flow under conditions when the classical respiratory chain is impaired, limiting excess production of oxygen radicals and supporting redox and metabolic homeostasis. AOX from Ciona intestinalis has been used to study and mitigate mitochondrial impairments in mammalian cell lines, Drosophila disease models and, most recently, in the mouse, where multiple lentivector-AOX transgenes conferred substantial expression in specific tissues. Here, we describe a genetically tractable mouse model in which Ciona AOX has been targeted to the Rosa26 locus for ubiquitous expression. The AOXRosa26 mouse exhibited only subtle phenotypic effects on respiratory complex formation, oxygen consumption or the global metabolome, and showed an essentially normal physiology. AOX conferred robust resistance to inhibitors of the respiratory chain in organello; moreover, animals exposed to a systemically applied LD50 dose of cyanide did not succumb. The AOXRosa26 mouse is a useful tool to investigate respiratory control mechanisms and to decipher mitochondrial disease aetiology in vivo.
The disruption of coupling between brain areas has been suggested as the mechanism underlying loss of consciousness in anesthesia. This hypothesis has been tested previously by measuring the information transfer between brain areas, and by taking reduced information transfer as a proxy for decoupling. Yet, information transfer is a function of the amount of information available in the information source—such that transfer decreases even for unchanged coupling when less source information is available. Therefore, we reconsidered past interpretations of reduced information transfer as a sign of decoupling, and asked whether impaired local information processing leads to a loss of information transfer. An important prediction of this alternative hypothesis is that changes in locally available information (signal entropy) should be at least as pronounced as changes in information transfer. We tested this prediction by recording local field potentials in two ferrets after administration of isoflurane in concentrations of 0.0%, 0.5%, and 1.0%. We found strong decreases in the source entropy under isoflurane in area V1 and the prefrontal cortex (PFC)—as predicted by our alternative hypothesis. The decrease in source entropy was stronger in PFC compared to V1. Information transfer between V1 and PFC was reduced bidirectionally, but with a stronger decrease from PFC to V1. This links the stronger decrease in information transfer to the stronger decrease in source entropy—suggesting reduced source entropy reduces information transfer. This conclusion fits the observation that the synaptic targets of isoflurane are located in local cortical circuits rather than on the synapses formed by interareal axonal projections. Thus, changes in information transfer under isoflurane seem to be a consequence of changes in local processing more than of decoupling between brain areas. We suggest that source entropy changes must be considered whenever interpreting changes in information transfer as decoupling.
Purpose: Prisoners are at a particularly high risk of suicide. In contrast to other psychosocial risk factors it remains unclear to what degree the risk of suicide differs between prisoners with local citizenship and foreigners. In order to provide more detailed information for suicide prevention in prisons, this study aims to compare suicide rates (SR) between these populations in German criminal custody.
Methods: Based on a German national database of completed suicide in custody, suicides by prisoners were analysed and compared with epidemiological data of the prison population and the general population, stratified for German and foreign citizenship. Data analysis was adjusted for differences in the age distribution of both populations by calculating standard mortality ratios (SMR) for suicide.
Results: SR were higher in prisoners with German citizenship than those with foreign citizenship (SR = 76.5 vs. SR = 42.8, P<0.01). This association was not specific to the prison population, as the higher SR in citizens compared to non-citizens (SR = 19.3 vs. SR = 9.0, P<0.01) were also found in the general population. The association between prison suicide and citizenship was comparable in juvenile and adult prisoners, indicating its relevance to both the juvenile and adult detention systems.
Conclusion: Imprisonment is associated with a substantially increased risk of suicide in both German and non-German citizens, a finding which needs to be taken into consideration by the justice system. The lower suicide risk in non-German citizens is independent of whether or not they are in custody.
Local treatment of unresectable colorectal liver metastases : results of a randomized phase II trial
(2017)
Background: Tumor ablation is often employed for unresectable colorectal liver metastases. However, no survival benefit has ever been demonstrated in prospective randomized studies. Here, we investigate the long-term benefits of such an aggressive approach.
Methods: In this randomized phase II trial, 119 patients with unresectable colorectal liver metastases (n < 10 and no extrahepatic disease) received systemic treatment alone or systemic treatment plus aggressive local treatment by radiofrequency ablation ± resection. Previously, we reported that the primary end point (30-month overall survival [OS] > 38%) was met. We now report on long-term OS results. All statistical tests were two-sided. The analyses were according to intention to treat.
Results: At a median follow up of 9.7 years, 92 of 119 (77.3%) patients had died: 39 of 60 (65.0%) in the combined modality arm and 53 of 59 (89.8%) in the systemic treatment arm. Almost all patients died of progressive disease (35 patients in the combined modality arm, 49 patients in the systemic treatment arm). There was a statistically significant difference in OS in favor of the combined modality arm (hazard ratio [HR] = 0.58, 95% confidence interval [CI] = 0.38 to 0.88, P = .01). Three-, five-, and eight-year OS were 56.9% (95% CI = 43.3% to 68.5%), 43.1% (95% CI = 30.3% to 55.3%), 35.9% (95% CI = 23.8% to 48.2%), respectively, in the combined modality arm and 55.2% (95% CI = 41.6% to 66.9%), 30.3% (95% CI = 19.0% to 42.4%), 8.9% (95% CI = 3.3% to 18.1%), respectively, in the systemic treatment arm. Median OS was 45.6 months (95% CI = 30.3 to 67.8 months) in the combined modality arm vs 40.5 months (95% CI = 27.5 to 47.7 months) in the systemic treatment arm.
Conclusions: This phase II trial is the first randomized study demonstrating that aggressive local treatment can prolong OS in patients with unresectable colorectal liver metastases.
Genetic mutations underlying neurodegenerative disorders impair ribosomal DNA (rDNA) transcription suggesting that nucleolar dysfunction could be a novel pathomechanism in polyglutamine diseases and in certain forms of amyotrophic lateral sclerosis/frontotemporal dementia. Here, we investigated nucleolar activity in pre-symptomatic digenic models of Parkinson's disease (PD) that model the multifactorial aetiology of this disease. To this end, we analysed a novel mouse model mildly overexpressing mutant human α-synuclein (hA53T-SNCA) in a PTEN-induced kinase 1 (PINK1/PARK6) knockout background and mutant mice lacking both DJ-1 (also known as PARK7) and PINK1. We showed that overexpressed hA53T-SNCA localizes to the nucleolus. Moreover, these mutants show a progressive reduction of rDNA transcription linked to a reduced mouse lifespan. By contrast, rDNA transcription is preserved in DJ-1/PINK1 double knockout (DKO) mice. mRNA levels of the nucleolar transcription initiation factor 1A (TIF-IA, also known as RRN3) decrease in the substantia nigra of individuals with PD. Because loss of TIF-IA, as a tool to mimic nucleolar stress, increases oxidative stress and because DJ-1 and PINK1 mutations result in higher vulnerability to oxidative stress, we further explored the synergism between these PD-associated genes and impaired nucleolar function. By the conditional ablation of TIF-IA, we blocked ribosomal RNA (rRNA) synthesis in adult dopaminergic neurons in a DJ-1/PINK1 DKO background. However, the early phenotype of these triple knockout mice was similar to those mice exclusively lacking TIF-IA. These data sustain a model in which loss of DJ-1 and PINK1 does not impair nucleolar activity in a pre-symptomatic stage. This is the first study to analyse nucleolar function in digenic PD models. We can conclude that, at least in these models, the nucleolus is not as severely disrupted as previously shown in DA neurons from PD patients and neurotoxin-based PD mouse models. The results also show that the early increase in rDNA transcription and nucleolar integrity may represent specific homeostatic responses in these digenic pre-symptomatic PD models.
Aims: The purpose of this study was to analyze the prevalence of depression, anxiety, adjustment disorders, and somatoform disorders in patients diagnosed with age-related macular degeneration (AMD) in Germany.
Methods: This study included 7,580 patients between the ages of 40 and 90 diagnosed with AMD between January 2011 and December 2014 in 1,072 primary care practices (index date). The last follow-up was in July 2016. We also included 7,580 controls without AMD, which were matched (1:1) to the AMD cases by age, sex, type of health insurance (private or statutory), physician, and Charlson comorbidity score as a generic marker of comorbidity. The outcome of the study was the prevalence of depression, anxiety, adjustment disorders, and somatoform disorders recorded in the database between the index date and the end of follow-up.
Results: The mean age among subjects was 75.7 years (SD=10.1 years), 34.0% were men, and 7.8% had private health insurance coverage. The Charlson comorbidity index was 2.0 (SD=1.8). Depression was the most frequent disease (33.7% in AMD patients versus 27.3% in controls), followed by somatoform disorders (19.6% and 16.7%), adjustment disorders (14.8% and 10.5%), and anxiety disorders (11.7% and 8.2%). Depression (OR=1.37, 95% CI: 1.27–1.47), anxiety (OR=1.50, 95% CI: 1.35–1.67), adjustment disorders (OR=1.50, 95% CI: 1.36–1.65), and somatoform disorders (OR=1.22, 95% CI: 1.12–1.32) were all positively associated with AMD.
Conclusion: Overall, a significant association was found between AMD and depression, anxiety, adjustment disorders, and somatoform disorders.
Green tea (GT) and green tea extracts (GTE) have been postulated to decrease cancer incidence. In vitro results indicate a possible effect; however, epidemiological data do not support cancer chemoprevention. We have performed a PubMED literature search for green tea consumption and the correlation to the common tumor types lung, colorectal, breast, prostate, esophageal and gastric cancer, with cohorts from both Western and Asian countries. We additionally included selected mechanistical studies for a possible mode of action. The comparability between studies was limited due to major differences in study outlines; a meta analysis was thus not possible and studies were evaluated individually. Only for breast cancer could a possible small protective effect be seen in Asian and Western cohorts, whereas for esophagus and stomach cancer, green tea increased the cancer incidence, possibly due to heat stress. No effect was found for colonic/colorectal and prostatic cancer in any country, for lung cancer Chinese studies found a protective effect, but not studies from outside China. Epidemiological studies thus do not support a cancer protective effect. GT as an indicator of as yet undefined parameters in lifestyle, environment and/or ethnicity may explain some of the observed differences between China and other countries.
Objective: The glucose stimulation of insulin secretion (GSIS) by pancreatic β-cells critically depends on increased production of metabolic coupling factors, including NADPH. Nicotinamide nucleotide transhydrogenase (NNT) typically produces NADPH at the expense of NADH and ΔpH in energized mitochondria. Its spontaneous inactivation in C57BL/6J mice was previously shown to alter ATP production, Ca2+ influx, and GSIS, thereby leading to glucose intolerance. Here, we tested the role of NNT in the glucose regulation of mitochondrial NADPH and glutathione redox state and reinvestigated its role in GSIS coupling events in mouse pancreatic islets.
Methods: Islets were isolated from female C57BL/6J mice (J-islets), which lack functional NNT, and genetically close C57BL/6N mice (N-islets). Wild-type mouse NNT was expressed in J-islets by adenoviral infection. Mitochondrial and cytosolic glutathione oxidation was measured with glutaredoxin 1-fused roGFP2 probes targeted or not to the mitochondrial matrix. NADPH and NADH redox state was measured biochemically. Insulin secretion and upstream coupling events were measured under dynamic or static conditions by standard procedures.
Results: NNT is largely responsible for the acute glucose-induced rise in islet NADPH/NADP+ ratio and decrease in mitochondrial glutathione oxidation, with a small impact on cytosolic glutathione. However, contrary to current views on NNT in β-cells, these effects resulted from a glucose-dependent reduction in NADPH consumption by NNT reverse mode of operation, rather than from a stimulation of its forward mode of operation. Accordingly, the lack of NNT in J-islets decreased their sensitivity to exogenous H2O2 at non-stimulating glucose. Surprisingly, the lack of NNT did not alter the glucose-stimulation of Ca2+ influx and upstream mitochondrial events, but it markedly reduced both phases of GSIS by altering Ca2+-induced exocytosis and its metabolic amplification.
Conclusion: These results drastically modify current views on NNT operation and mitochondrial function in pancreatic β-cells.
Photodynamic treatment of oral squamous cell carcinoma cells with low curcumin concentrations
(2017)
Objective: Curcumin is known for its anti-oxidative, anti-inflammatory and anti-tumorigenic qualities at concentrations ranging from 3.7µg/ml to 55µg/ml. Therefore it is pre-destined for tumour therapy. Due to high oral doses that have to be administered and the low bioavailability of curcumin new therapy concepts have to be developed. One of these therapy concepts is the combination of low curcumin concentrations and UVA or visible light. Aim of our study was to investigate the influence of this treatment regime on oral squamous cell carcinoma cells.
Materials and Methods: A human oral squamous cell carcinoma cell line (HN) was pre-incubated with low curcumin concentrations (0.01µg/ml to 1µg/ml). Thereafter cell cultures were either left un-irradiated or were irradiated either with 1J/cm2 UVA or for 5min with visible light. Quantitative analysis of proliferation, membrane integrity, oxidative potential and DNA fragmentation were done.
Results: It could be shown that low curcumin concentrations neither influenced proliferation, nor cell morphology, nor cell integrity nor apoptosis. When combining these curcumin concentrations with UVA or visible light irradiation cell proliferation as well as development of reactive oxygen species was reduced whereas DNA fragmentation was increased. Concentration as well as light entity specific effects could be observed.
Conclusions: The present findings substantiate the potential of the combination of low curcumin concentrations and light as a new therapeutic concept to increase the efficacy of curcumin in the treatment of cancer of the oral mucosa.
Bevacizumab for patients with recurrent gliomas presenting with a gliomatosis cerebri growth pattern
(2017)
Bevacizumab has been shown to improve progression-free survival and neurologic function, but failed to improve overall survival in newly diagnosed glioblastoma and at first recurrence. Nonetheless, bevacizumab is widely used in patients with recurrent glioma. However, its use in patients with gliomas showing a gliomatosis cerebri growth pattern is contentious. Due to the marked diffuse and infiltrative growth with less angiogenic tumor growth, it may appear questionable whether bevacizumab can have a therapeutic effect in those patients. However, the development of nodular, necrotic, and/or contrast-enhancing lesions in patients with a gliomatosis cerebri growth pattern is not uncommon and may indicate focal neo-angiogenesis. Therefore, control of growth of these lesions as well as control of edema and reduction of steroid use may be regarded as rationales for the use of bevacizumab in these patients. In this retrospective patient series, we report on 17 patients with primary brain tumors displaying a gliomatosis cerebri growth pattern (including seven glioblastomas, two anaplastic astrocytomas, one anaplastic oligodendroglioma, and seven diffuse astrocytomas). Patients have been treated with bevacizumab alone or in combination with lomustine or irinotecan. Seventeen matched patients treated with bevacizumab for gliomas with a classical growth pattern served as a control cohort. Response rate, progression-free survival, and overall survival were similar in both groups. Based on these results, anti-angiogenic therapy with bevacizumab should also be considered in patients suffering from gliomas with a mainly infiltrative phenotype.
The adaptor protein Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) plays a crucial role in T cell activation by linking antigen receptor (T cell receptor, TCR) signals to downstream pathways. At its N terminus, SLP-76 has three key tyrosines (Tyr-113, Tyr-128, and Tyr-145, “3Y”) as well as a sterile α motif (SAM) domain whose function is unclear. We showed previously that the SAM domain has two binding regions that mediate dimer and oligomer formation. In this study, we have identified SAM domain-carrying non-receptor tyrosine kinase, activated Cdc42-associated tyrosine kinase 1 (ACK1; also known as Tnk2, tyrosine kinase non-receptor 2) as a novel binding partner of SLP-76. Co-precipitation, laser-scanning confocal microscopy, and in situ proximity analysis confirmed the binding of ACK1 to SLP-76. Further, the interaction was induced in response to the anti-TCR ligation and abrogated by the deletion of SLP-76 SAM domain (ΔSAM) or mutation of Tyr-113, Tyr-128, and Tyr-145 to phenylalanine (3Y3F). ACK1 induced phosphorylation of the SLP-76 N-terminal tyrosines (3Y) dependent on the SAM domain. Further, ACK1 promoted calcium flux and NFAT-AP1 promoter activity and decreased the motility of murine CD4+ primary T cells on ICAM-1-coated plates, an event reversed by a small molecule inhibitor of ACK1 (AIM-100). These findings identify ACK1 as a novel SLP-76-associated protein-tyrosine kinase that modulates early activation events in T cells.
Stroke patients with proximal occlusions of the main stems of cerebral arteries are no optimal candidates for i. v. thrombolysis. For many years interventional stroke treatment could not be established as alternative. This changed with the introduction of stent retrievers and flexible large lumen aspiration catheters. Randomized trials now proved a significant benefit from intervention for a wide spectrum of severely compromised stroke patients in time windows of up to 8 hrs. However, the randomized trials leave open questions concerning proper patient selection. The benefit for patients with larger infarcts with an ASPECTS between 3 and 5 or patients in time windows above 8 hrs is still uncertain. Especially for critical candidates imaging for reliable detection of the ischemic core and surrounding salvageable brain tissue plays an important role. Technically equivalence between new aspiration techniques as alternative to the use of stent-retrievers is not finally proven. Recanalization of tandem occlusions with the necessity of acute stenting demands better materials for plaque coverage and thrombus withhold. Management of cases with occlusions due to intracranial atherosclerosis is also debatable. The positive trial results provide especially new challenges to establish countrywide neurointerventional services. Even in developed countries recruitment and training of interventional radiologists as well as priority transportation of stroke patients is challenging to organize.
This is an abstract presented in the 33rd Iranian congress of radiology (ICR) and the 15th congress of Iranian radiographic science association (IRSA).
Background: Currently, there is inadequate evidence on which to base clinical management of neurotoxic snakebite envenoming, especially in the choice of initial antivenom dosage. This randomised controlled trial compared the effectiveness and safety of high versus low initial antivenom dosage in victims of neurotoxic envenoming.
Methodology/ Principal findings: This was a balanced, randomised, double-blind trial that was conducted in three health care centers located in the Terai plains of Nepal. Participants received either low (two vials) or high (10 vials) initial dosage of Indian polyvalent antivenom. The primary composite outcome consisted of death, the need for assisted ventilation and worsening/recurrence of neurotoxicity. Hourly evaluations followed antivenom treatment. Between April 2011 and October 2012, 157 snakebite victims were enrolled, of which 154 were analysed (76 in the low and 78 in the high initial dose group). Sixty-seven (43·5%) participants met the primary outcome definition. The proportions were similar in the low (37 or 48.7%) vs. high (30 or 38.5%) initial dose group (difference = 10·2%, 95%CI [-6·7 to 27·1], p = 0·264). The mean number of vials used was similar between treatment groups. Overall, patients bitten by kraits did worse than those bitten by cobras. The occurrence of treatment-related adverse events did not differ among treatment groups. A total of 19 serious adverse events occurred, including seven attributed to antivenom.
Conclusions: This first robust trial investigating antivenom dosage for neurotoxic snakebite envenoming shows that the antivenom currently used in Nepal performs poorly. Although the high initial dose regimen is not more effective than the low initial dose, it offers the practical advantage of being a single dose, while not incurring higher consumption or enhanced risk of adverse reaction. The development of new and more effective antivenoms that better target the species responsible for bites in the region will help improve future patients’ outcomes.
Trial registration: The study was registered on clinicaltrials.gov (NCT01284855) (GJ 5/1)
Hematopoietic differentiation is controlled by key transcription factors, which regulate stem cell functions and differentiation. TAL1 is a central transcription factor for hematopoietic stem cell development in the embryo and for gene regulation during erythroid/megakaryocytic differentiation. Knowledge of the target genes controlled by a given transcription factor is important to understand its contribution to normal development and disease. To uncover direct target genes of TAL1 we used high affinity streptavidin/biotin-based chromatin precipitation (Strep-CP) followed by Strep-CP on ChIP analysis using ChIP promoter arrays. We identified 451 TAL1 target genes in K562 cells. Furthermore, we analysed the regulation of one of these genes, the catalytic subunit beta of protein kinase A (PRKACB), during megakaryopoiesis of K562 and primary human CD34+ stem cell/progenitor cells. We found that TAL1 together with hematopoietic transcription factors RUNX1 and GATA1 binds to the promoter of the isoform 3 of PRKACB (Cβ3). During megakaryocytic differentiation a coactivator complex on the Cβ3 promoter, which includes WDR5 and p300, is replaced with a corepressor complex. In this manner, activating chromatin modifications are removed and expression of the PRKACB-Cβ3 isoform during megakaryocytic differentiation is reduced. Our data uncover a role of the TAL1 complex in controlling differential isoform expression of PRKACB. These results reveal a novel function of TAL1, RUNX1 and GATA1 in the transcriptional control of protein kinase A activity, with implications for cellular signalling control during differentiation and disease.
A recent report showed PINK1 transcript levels to be up- or down-regulated by the gain or loss of Ataxin-2 function, respectively, in human blood, in a human neural cell line and in mouse tissues. These observations may have profound implications for the regulation of cell growth and may be medically exploited for the treatment of cancer and neural atrophy...
Background: Women’s participation in medicine and the need for gender equality in healthcare are increasingly recognised, yet little attention is paid to leadership and management positions in large publicly funded academic health centres. This study illustrates such a need, taking the case of four large European centres: Charité – Universitätsmedizin Berlin (Germany), Karolinska Institutet (Sweden), Medizinische Universität Wien (Austria), and Oxford Academic Health Science Centre (United Kingdom).
Case:The percentage of female medical students and doctors in all four countries is now well within the 40–60% gender balance zone. Women are less well represented among specialists and remain significantly under-represented among senior doctors and full professors. All four centres have made progress in closing the gender leadership gap on boards and other top-level decision-making bodies, but a gender leadership gap remains relevant. The level of achieved gender balance varies significantly between the centres and largely mirrors country-specific welfare state models, with more equal gender relations in Sweden than in the other countries. Notably, there are also similar trends across countries and centres: gender inequality is stronger within academic enterprises than within hospital enterprises and stronger in middle management than at the top level. These novel findings reveal fissures in the ‘glass ceiling’ effects at top-level management, while the barriers for women shift to middle-level management and remain strong in academic positions. The uneven shifts in the leadership gap are highly relevant and have policy implications.
Conclusion: Setting gender balance objectives exclusively for top-level decision-making bodies may not effectively promote a wider goal of gender equality. Academic health centres should pay greater attention to gender equality as an issue of organisational performance and good leadership at all levels of management, with particular attention to academic enterprises and newly created management structures. Developing comprehensive gender-sensitive health workforce monitoring systems and comparing progress across academic health centres in Europe could help to identify the gender leadership gap and utilise health human resources more effectively.
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.