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Institute
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Background: The clinical presentation of gastroesophageal reflux disease (GERD) shows a large symptom variation also in different intensities among patients. As several studies have shown, there is a large overlap in the symptomatic spectrum between proven GERD and other disorders such as dyspepsia, functional heartburn and/or somatoform disorders.
Aim: To prospectively evaluate the GERD patients with and without somatoform disorders before and after laparoscopic antireflux surgery.
Methods: In a tertiary referral center for foregut surgery over a period of 3 years patients with GERD, qualifying for the indication of laparoscopic antireflux surgery, were investigated prospectively regarding their symptomatic spectrum in order to identify GERD and associated somatoform disorders. Assessment of symptoms was performed by an instrument for the evaluation of somatoform disorders [Somatoform Symptom Index (SSI) > 17]. Quality of life was evaluated by Gastrointestinal Quality of Life Index (GIQLI).
Results: In 123 patients an indication for laparoscopic antireflux surgery was established and in 43 patients further medical therapy was suggested. The portion of somatoform tendencies in the total patient population was 20.48% (34 patients). Patients with a positive SSI had a preoperative GIQLI of 77 (32-111). Patients with a normal SSI had a GIQLI of 105 (29-140) (P < 0.0001). In patients with GERD the quality of life could be normalized from preoperative reduced values of GIQLI 102 (47-140) to postoperative values of 117 (44-144). In patients with GERD and somatoform disorders, the GIQLI was improved from preoperative GIQLI 75 (47-111) to postoperative 95 (44-122) (P < 0.0043).
Conclusion: Patients with GERD and associated somatoform disorders have significantly worse levels of quality of life. The latter patients can also benefit from laparoscopic fundoplication, however they will not reach a normal level.
Hypoxia poses a stress to cells and decreases mitochondrial respiration, in part by electron transport chain (ETC) complex reorganization. While metabolism under acute hypoxia is well characterized, alterations under chronic hypoxia largely remain unexplored. We followed oxygen consumption rates in THP-1 monocytes during acute (16 h) and chronic (72 h) hypoxia, compared to normoxia, to analyze the electron flows associated with glycolysis, glutamine, and fatty acid oxidation. Oxygen consumption under acute hypoxia predominantly demanded pyruvate, while under chronic hypoxia, fatty acid- and glutamine-oxidation dominated. Chronic hypoxia also elevated electron-transferring flavoproteins (ETF), and the knockdown of ETF–ubiquinone oxidoreductase lowered mitochondrial respiration under chronic hypoxia. Metabolomics revealed an increase in citrate under chronic hypoxia, which implied glutamine processing to α-ketoglutarate and citrate. Expression regulation of enzymes involved in this metabolic shunting corroborated this assumption. Moreover, the expression of acetyl-CoA carboxylase 1 increased, thus pointing to fatty acid synthesis under chronic hypoxia. Cells lacking complex I, which experienced a markedly impaired respiration under normoxia, also shifted their metabolism to fatty acid-dependent synthesis and usage. Taken together, we provide evidence that chronic hypoxia fuels the ETC via ETFs, increasing fatty acid production and consumption via the glutamine-citrate-fatty acid axis.
Background: Approximately every third surgical patient is anemic. The most common form, iron deficiency anemia, results from persisting iron‐deficient erythropoiesis (IDE). Zinc protoporphyrin (ZnPP) is a promising parameter for diagnosing IDE, hitherto requiring blood drawing and laboratory workup.
Study design and methods: Noninvasive ZnPP (ZnPP‐NI) measurements are compared to ZnPP reference determination of the ZnPP/heme ratio by high‐performance liquid chromatography (ZnPP‐HPLC) and the analytical performance in detecting IDE is evaluated against traditional iron status parameters (ferritin, transferrin saturation [TSAT], soluble transferrin receptor–ferritin index [sTfR‐F], soluble transferrin receptor [sTfR]), likewise measured in blood. The study was conducted at the University Hospitals of Frankfurt and Zurich.
Results: Limits of agreement between ZnPP‐NI and ZnPP‐HPLC measurements for 584 cardiac and noncardiac surgical patients equaled 19.7 μmol/mol heme (95% confidence interval, 18.0–21.3; acceptance criteria, 23.2 μmol/mol heme; absolute bias, 0 μmol/mol heme). Analytical performance for detecting IDE (inferred from area under the curve receiver operating characteristics) of parameters measured in blood was: ZnPP‐HPLC (0.95), sTfR (0.92), sTfR‐F (0.89), TSAT (0.87), and ferritin (0.67). Noninvasively measured ZnPP‐NI yielded results of 0.90.
Conclusion: ZnPP‐NI appears well suited for an initial IDE screening, informing on the state of erythropoiesis at the point of care without blood drawing and laboratory analysis. Comparison with a multiparameter IDE test revealed that ZnPP‐NI values of 40 μmol/mol heme or less allows exclusion of IDE, whereas for 65 μmol/mol heme or greater, IDE is very likely if other causes of increased values are excluded. In these cases (77% of our patients) ZnPP‐NI may suffice for a diagnosis, while values in between require analyses of additional iron status parameters.
Acne‐like skin reactions frequently occur in patients undergoing treatment with drugs inhibiting the epidermal growth factor receptor. Recently, the effects of vitamin K1 containing cream (Reconval K1) as prophylactic skin treatment in addition to doxycycline were explored in a double‐blind randomized phase II trial (EVITA) in patients with metastatic colorectal cancer receiving cetuximab. EVITA demonstrated a trend towards less severe skin rash in Reconval K1‐treated patients using the tripartite WoMo skin reaction grading score as a thorough tool for quantification of drug related skin reactions. This gender‐specific analysis of the EVITA trial evaluated the application of the WoMo score for assessment of epidermal growth factor receptor (EGFR)‐related skin toxicities according to treatment arm and gender. To show the robustness of results parametric and non‐parametric statistical analyses were conducted. All three parts of the WoMo score independently demonstrated the superiority of the treatment arm (Reconval K1) regarding a significant reduction in acneiform skin reactions in women. Men did not benefit from Reconval K1 cream at any time point in none of the WoMo score analyses. The treatment effect in women was confirmed by the use of skin rash categories based on the final WoMo overall score and mixed effect longitudinal multiple linear regression analysis. The WoMo score represents a sensitive tool for studies exploiting treatments against EGFR mediated acne‐like skin rash. Part C of the WoMo score seems to be sufficient for quantification of drug related skin toxicities in further studies. Standard WoMo skin reaction score values for future studies are provided.
Over the last years non-invasive brain stimulation techniques (NIBS) have become the ultimate tool to gain major insights about the mechanisms responsible for sensory, motor, and cognitive functions. A big issue surrounding transcranial magnetic stimulation (TMS) and transcranial electric stimulation (TES) methods is the disagreement about the aftereffects reported by studies using similar (if not the same) stimulation protocols (Robertson et al., 2003; Horvath et al., 2014). The purpose of this research topic was to collect information regarding different stimulation procedures to assess their capacity to modulate cognition including also, appropriate control and sham conditions. The first part of this report will cover contributions related to TES which were limited to transcranial direct current stimulation methods (tDCS). This will be followed by studies dedicated to real TMS and sham methodology. ...
Theory of mind (ToM), or the ability to infer and predict the intentions, thoughts and beliefs of others, involves cognitive perspective taking (cognitive ToM/cToM) and understanding emotions (affective ToM/aToM). While behavioral evidence indicates that ToM is influenced by sex and age, no study has examined the influence of these variables on the neural correlates of cToM and aToM in late childhood/adolescence. Using fMRI with 35 typically-developing youths (aged 9–18 years, 12 males), we investigated the influence of sex and age on the neural correlates of cToM and aToM. We also examined how callous-unemotional traits, indexing a lack of empathy, were related to brain responses during aToM. Across both conditions, we found convergent activity in ToM network regions, such as superior temporal sulcus/temporoparietal junction (TPJ) and precuneus across males and females, but males recruited the left TPJ significantly more than females during cToM. During aToM, age was negatively correlated with brain responses in frontal, temporal and posterior midline regions, while callous-unemotional traits were positively correlated with right anterior insula responses. These results provide the first evidence in youth that sex influences the neural correlates of cToM, while age and callous-unemotional traits are specifically related to brain responses during aToM.
Rhabdomyosarcomas are the most common pediatric soft tissue sarcoma and are a major cause of death from cancer in young patients requiring new treatment options to improve outcomes. High-risk patients include those with metastatic or relapsed disease and tumors with PAX3-FOXO1 fusion genes that encode a potent transcription factor that drives tumourigenesis through transcriptional reprogramming. Polo-Like Kinase-1 (PLK1) is a serine/threonine kinase that phosphorylates a wide range of target substrates and alters their activity. PLK1 functions as a pleiotropic master regulator of mitosis and regulates DNA replication after stress. Taken together with high levels of expression that correlate with poor outcomes in many cancers, including rhabdomyosarcomas, it is an attractive therapeutic target. This is supported in rhabdomyosarcoma models by characterization of molecular and phenotypic effects of reducing and inhibiting PLK1, including changes to the PAX3-FOXO1 fusion protein. However, as tumor re-growth has been observed, combination strategies are required. Here we review preclinical evidence and consider biological rationale for PLK1 inhibition in combination with drugs that promote apoptosis, interfere with activity of PAX3-FOXO1 and are synergistic with microtubule-destabilizing drugs such as vincristine. The preclinical effects of low doses of the PLK1 inhibitor volasertib in combination with vincristine, which is widely used in rhabdomyosarcoma treatment, show particular promise in light of recent clinical data in the pediatric setting that support achievable volasertib doses predicted to be effective. Further development of novel therapeutic strategies including PLK1 inhibition may ultimately benefit young patients with rhabdomyosarcoma and other cancers.
Introduction: The neurobiological mechanisms behind panic disorder with agoraphobia (PD/AG) are not completely explored. The functional A/T single nucleotide polymorphism (SNP) rs324981 in the neuropeptide S receptor gene (NPSR1) has repeatedly been associated with panic disorder and might partly drive function respectively dysfunction of the neural “fear network”. We aimed to investigate whether the NPSR1 T risk allele was associated with malfunctioning in a fronto-limbic network during the anticipation and perception of agoraphobia-specific stimuli.
Method: 121 patients with PD/AG and 77 healthy controls (HC) underwent functional magnetic resonance imaging (fMRI) using the disorder specific “Westphal-Paradigm”. It consists of neutral and agoraphobia-specific pictures, half of the pictures were cued to induce anticipatory anxiety.
Results: Risk allele carriers showed significantly higher amygdala activation during the perception of agoraphobia-specific stimuli than A/A homozygotes. A linear group x genotype interaction during the perception of agoraphobia-specific stimuli showed a strong trend towards significance. Patients with the one or two T alleles displayed the highest and HC with the A/A genotype the lowest activation in the inferior orbitofrontal cortex (iOFC).
Discussion: The study demonstrates an association of the NPSR1rs324981 genotype and the perception of agoraphobia-specific stimuli. These results support the assumption of a fronto-limbic dysfunction as an intermediate phenotype of PD/AG.
Background: Due to their increased precision, CAD/CAM generated bars (Computer-Aided Design/ Computer-Aided Manufacturing) are increasingly utilized in implant prosthodontics. For optimal clinical results, surface morphology should promote the integration of soft tissue while minimizing plaque and bacterial retention.
Objective: Despite their clinical use, only limited information on the biological and clinical surface quality of CAD/CAM milled bars is available. The aim of the study was therefore to characterize the surface topography of bars of different manufacturers based on the profilometric analysis and the need for manual post-processing in the laboratory.
Methods: A custom mandibular edentulous cast with four anterior implants was used as a reference cast and reproduced eight times. On each reproduction cast, corresponding scan flags were positioned and digitized. Acrylic 3D printed bar frameworks were produced and sent to the respective production center along with the digital files of the CAD bars for milling. In the course of profilometric analysis, all bars were examined in three critical Regions of Interest (ROI): Transmucosal, labial, basal. Sa and Ra values of each construction were determined. To evaluate the necessary refinishing time eight dental technicians macroscopically evaluated the bars by performing a subjective visual inspection. Kruskal-Wallis H-tests and Tukey and Kramer's post hoc tests were applied to detect differences between the samples.
Results: After profilometric examination, three specimens (Dentsply Sirona: ZDC; Straumann: ZST; CAMLOG: ZCC) demonstrated surface roughness values in the biological acceptable range (Sa 0.2-0.4 μm) in the transmucosal region and provided optimal conditions for a reliable soft tissue adaptation. The Ra measurements revealed values beyond the acceptable threshold in the transmucosal region for three bars (Straumann: ZST; Dentsply Sirona: ZDC; Amann Girrbach: LAC). Four bars (LAC: Amann Girrbach; ZBC: BEGO; Datron: LDC & LDT; Zirkonzahn: ZZC) needed undesirable extensive manual rework. The evaluation of quality and time for manual post-processing by dental technicians confirmed the measurement-based ranking of the bars.
Conclusion: It is desirable to define a clear roughness threshold for the clinical acceptance of transmucosal CAD/CAM generated surfaces. Clinical studies with profilometric data could help to further improve the surface quality of CAD/CAM milled bars and reduce the need for manual reworking time and effort.
Background: Congenital duodenal obstruction (CDO) can be complete (CCDO) or incomplete (ICDO). To date there is no outcome analysis available that compares both subtypes.
Aim: To quantify and compare the association between CCDO and ICDO with outcome parameters.
Methods: We retrospectively reviewed all patients who underwent operative repair of CCDO or ICDO in our tertiary care institution between January 2004 and January 2017. The demographics, clinical presentation, preoperative diagnostics and postoperative outcomes of 50 patients were compared between CCDO (n = 27; atresia type 1-3, annular pancreas) and ICDO (n = 23; annular pancreas, web, Ladd´s bands).
Results: In total, 50 patients who underwent CDO repair were enrolled and followed for a median of 5.2 and 3.9 years (CCDO and ICDO, resp.). CCDO was associated with a significantly higher prenatal ultrasonographic detection rate (88% versus 4%; CCDO vs ICDO, P < 0.01), lower gestational age at birth, lower age and weight at operation, higher rate of associated congenital heart disease (CHD), more extensive preoperative radiologic diagnostics, higher morbidity according to Clavien-Dindo classification and comprehensive complication index (all P ≤ 0.01). The subgroup analysis of patients without CHD and prematurity showed a longer time from operation to the initiation of enteral feeds in the CCDO group (P < 0.01).
Conclusion: CCDO and ICDO differ with regard to prenatal detection rate, gestational age, age and weight at operation, rate of associated CHD, preoperative diagnostics and morbidity. The degree of CDO in mature patients without CHD influences the postoperative initiation of enteral feeding.
Apigenin (4′,5,7-trihydroxyflavone) (Api) is an important component of the human diet, being distributed in a wide number of fruits, vegetables and herbs with the most important sources being represented by chamomile, celery, celeriac and parsley. This study was designed for a comprehensive evaluation of Api as an antiproliferative, proapoptotic, antiangiogenic and immunomodulatory phytocompound. In the set experimental conditions, Api presents antiproliferative activity against the A375 human melanoma cell line, a G2/M arrest of the cell cycle and cytotoxic events as revealed by the lactate dehydrogenase release. Caspase 3 activity was inversely proportional to the Api tested doses, namely 30 μM and 60 μM. Phenomena of early apoptosis, late apoptosis and necrosis following incubation with Api were detected by Annexin V-PI double staining. The flavone interfered with the mitochondrial respiration by modulating both glycolytic and mitochondrial pathways for ATP production. The metabolic activity of human dendritic cells (DCs) under LPS-activation was clearly attenuated by stimulation with high concentrations of Api. Il-6 and IL-10 secretion was almost completely blocked while TNF alpha secretion was reduced by about 60%. Api elicited antiangiogenic properties in a dose-dependent manner. Both concentrations of Api influenced tumour cell growth and migration, inducing a limited tumour area inside the application ring, associated with a low number of capillaries.
Objectives: There is sparse information on the safety of early primary discharge from the emergency department (ED) after rule-out of myocardial infarction in suspected acute coronary syndrome (ACS). This prospective registry aimed to confirm randomised study results in patients at low-to-intermediate risk, with a broader spectrum of symptoms, across different institutional standards and with a range of local troponin assays including high-sensitivity cTn (hs-cTn), cardiac troponin (cTn) and point-of-care troponin (POC Tn).
Design: Prospective, multicentre European registry.
Setting: 18 emergency departments in nine European countries (Germany, Austria, Switzerland, France, Spain, UK, Turkey, Lithuania and Hungary)
Participants: The final study cohort consisted of 2294 patients (57.2% males, median age 57 years) with suspected ACS.
Interventions: Using the new dual markers strategy, 1477 patients were eligible for direct discharge, which was realised in 974 (42.5%) of patients.
Main outcome measures: The primary endpoint was all-cause mortality at 30 days.
Results: Compared with conventional workup after dual marker measurement, the median length of ED stay was 60 min shorter (228 min, 95% CI: 219 to 239 min vs 288 min, 95% CI: 279 to 300 min) in the primary dual marker strategy (DMS) discharge group. All-cause mortality was 0.1% (95% CI: 0% to 0.6%) in the primary DMS discharge group versus 1.1% (95% CI: 0.6% to 1.8%) in the conventional workup group after dual marker measurement. Conventional workup instead of discharge despite negative DMS biomarkers was observed in 503 patients (21.9%) and associated with higher prevalence of ACS (17.1% vs 0.9%, p<0.001), cardiac diagnoses (55.2% vs 23.5%, p<0.001) and risk factors (p<0.01), but with a similar all-cause mortality of 0.2% (95% CI: 0% to 1.1%) versus primary DMS discharge (p=0.64).
Conclusions: Copeptin on top of cardiac troponin supports safe discharge in patients with chest pain or other symptoms suggestive of ACS under routine conditions with the use of a broad spectrum of local standard POC, conventional and high-sensitivity troponin assays.
Trial registration number NCT02490969.
Anaplastic large cell lymphoma (ALCL) and classical Hodgkin lymphoma (cHL) are lymphomas that contain CD30-expressing tumor cells and have numerous pathological similarities. Whereas ALCL is usually diagnosed at an advanced stage, cHL more frequently presents with localized disease. The aim of the present study was to elucidate the mechanisms underlying the different clinical presentation of ALCL and cHL. Chemokine and chemokine receptor expression were similar in primary ALCL and cHL cases apart from the known overexpression of the chemokines CCL17 and CCL22 in the Hodgkin and Reed-Sternberg (HRS) cells of cHL. Consistent with the overexpression of these chemokines, primary cHL cases encountered a significantly denser T cell microenvironment than ALCL. Additionally to differences in the interaction with their microenvironment, cHL cell lines presented a lower and less efficient intrinsic cell motility than ALCL cell lines, as assessed by time-lapse microscopy in a collagen gel and transwell migration assays. We thus propose that the combination of impaired basal cell motility and differences in the interaction with the microenvironment hamper the dissemination of HRS cells in cHL when compared with the tumor cells of ALCL.
Health-related preferences of older patients with multimorbidity: the protocol for an evidence map
(2019)
Introduction: Interaction of conditions and treatments, complicated care needs and substantial treatment burden make patient–physician encounters involving multimorbid older patients highly complex. To optimally integrate patients’ preferences, define and prioritise realistic treatment goals and individualise care, a patient-centred approach is recommended. However, the preferences of older patients, who are especially vulnerable and frequently multimorbid, have not been systematically investigated with regard to their health status. The purpose of this evidence map is to explore current research addressing health-related preferences of older patients with multimorbidity, and to identify the knowledge clusters and research gaps.
Methods and analysis: To identify relevant research, we will conduct searches in the electronic databases MEDLINE, EMBASE, PsycINFO, PSYNDEX, CINAHL, Social Science Citation Index, Social Science Citation Index Expanded and the Cochrane library from their inception. We will check reference lists of relevant articles and carry out cited reference research (forward citation tracking). Two independent reviewers will screen titles and abstracts, check full texts for eligibility and extract the data. Any disagreement will be resolved and consensus reached with the help of a third reviewer. We will include both qualitative and quantitative studies, and address preferences from the patients’ perspectives in a multimorbid population of 60 years or older. There will be no restrictions on the publication language. Data extraction tables will present study and patient characteristics, aim of study, methods used to identify preferences and outcomes (ie, type of preferences). We will summarise the data using tables and figures (ie, bubble plot) to present the research landscape and to describe clusters and gaps.
Ethics and dissemination: Due to the nature of the proposed evidence map, ethics approval will not be required. Results from our research will be disseminated by means of specifically prepared materials for patients, at relevant (inter)national conferences and via publication in peer-reviewed journals.
Background: The nonmotor symptom spectrum of Parkinson’s disease (PD) includes progressive cognitive decline mainly in late stages of the disease. The aim of this study was to map the patterns of altered structural connectivity of patients with PD with different cognitive profiles ranging from cognitively unimpaired to PD-associated dementia.
Methods: Diffusion tensor imaging and neuropsychological data from the observational multicentre LANDSCAPE study were analyzed. A total of 134 patients with PD with normal cognitive function (56 PD-N), mild cognitive impairment (67 PD-MCI), and dementia (11 PD-D) as well as 72 healthy controls were subjected to whole-brain-based fractional anisotropy mapping and covariance analysis with cognitive performance measures.
Results: Structural data indicated subtle changes in the corpus callosum and thalamic radiation in PD-N, whereas severe white matter impairment was observed in both PD-MCI and PD-D patients including anterior and inferior fronto-occipital, uncinate, insular cortices, superior longitudinal fasciculi, corona radiata, and the body of the corpus callosum. These regional alterations were demonstrated for PD-MCI and were more pronounced in PD-D. The pattern of involved regions was significantly correlated with the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) total score.
Conclusions: The findings in PD-N suggest impaired cross-hemispherical white matter connectivity that can apparently be compensated for. More pronounced involvement of the corpus callosum as demonstrated for PD-MCI together with affection of fronto-parieto-temporal structural connectivity seems to lead to gradual disruption of cognition-related cortico-cortical networks and to be associated with the onset of overt cognitive deficits. The increase of regional white matter damage appears to be associated with the development of PD-associated dementia.
Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10−7), particularly in the female subsample (p = 9.8 × 10−9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10−4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.
Highlights
• The goal was to assess the intra- and inter-scanner reproducibility of qMRI data.
• Mean scan-rescan variations were not exceeding 2.14%.
• Mean inter-scanner model deviations were not exceeding 5.21%.
• Provided that identical acquisition sequences are used, discrepancies between qMRI data acquired with different scanner models are low.
Abstract
Background: Quantitative MRI (qMRI) techniques allow assessing cerebral tissue properties. However, previous studies on the accuracy of quantitative T1 and T2 mapping reported a scanner model bias of up to 10% for T1 and up to 23% for T2. Such differences would render multi-centre qMRI studies difficult and raise fundamental questions about the general precision of qMRI. A problem in previous studies was that different methods were used for qMRI parameter mapping or for measuring the transmitted radio frequency field B1 which is critical for qMRI techniques requiring corrections for B1 non-uniformities.
Aims: The goal was to assess the intra- and inter-scanner reproducibility of qMRI data at 3 T, using two different scanner models from the same vendor with exactly the same multiparametric acquisition protocol.
Methods: Proton density (PD), T1, T2* and T2 mapping was performed on healthy subjects and on a phantom, performing each measurement twice for each of two scanner models. Although the scanners had different hardware and software versions, identical imaging sequences were used for PD, T1 and T2* mapping, adapting the codes of an existing protocol on the older system line by line to match the software version of the newer scanner. For T2-mapping, the respective manufacturer’s sequence was used which depended on the software version. However, system-dependent corrections were carried out in this case. Reproducibility was assessed by average values in regions of interest.
Results: Mean scan-rescan variations were not exceeding 2.14%, with average values of 1.23% and 1.56% for the new and old system, respectively. Inter-scanner model deviations were not exceeding 5.21% with average values of about 2.2–3.8% for PD, 2.5–3.0% for T2*, 1.6–3.1% for T1 and 3.3–5.2% for T2.
Conclusions: Provided that identical acquisition sequences are used, discrepancies between qMRI data acquired with different scanner models are low. The level of systematic differences reported in this work may help to interpret multi-centre data.
Multimodal quantitative mri reveals no evidence for tissue pathology in idiopathic cervical dystonia
(2019)
Background: While in symptomatic forms of dystonia cerebral pathology is by definition present, it is unclear so far whether disease is associated with microstructural cerebral changes in idiopathic dystonia. Previous quantitative MRI (qMRI) studies assessing cerebral tissue composition in idiopathic dystonia revealed conflicting results.
Objective: Using multimodal qMRI, the presented study aimed to investigate alterations in different cerebral microstructural compartments associated with idiopathic cervical dystonia in vivo.
Methods: Mapping of T1, T2, T∗2, and proton density (PD) was performed in 17 patients with idiopathic cervical dystonia and 29 matched healthy control subjects. Statistical comparisons of the parametric maps between groups were conducted for various regions of interest (ROI), including major basal ganglia nuclei, the thalamus, white matter, and the cerebellum, and voxel-wise for the whole brain.
Results: Neither whole brain voxel-wise statistics nor ROI-based analyses revealed significant group differences for any qMRI parameter under investigation.
Conclusions: The negative findings of this qMRI study argue against the presence of overt microstructural tissue change in patients with idiopathic cervical dystonia. The results seem to support a common view that idiopathic cervical dystonia might primarily resemble a functional network disease.
Background: Accurate assessment of hepatic fibrosis in patients with chronic HBeAg-negative Hepatitis B is of crucial importance not only to predict the long-term clinical course, but also to evaluate antiviral therapy indication. The aim of this study was to prospectively assess the utility of point shear wave elastography (pSWE) for longitudinal non-invasive fibrosis assessment in a large cohort of untreated patients with chronic HBeAg-negative hepatitis B virus (HBV) infection.
Methods: 407 consecutive patients with HBeAg-negative HBV infection who underwent pSWE, transient elastography (TE) as well as laboratory fibrosis markers, including fibrosis index based on four factors (FIB-4), aspartate to platelet ratio index (APRI) and FibroTest, on the same day were prospectively followed up for six years. Patients were classified into one of the three groups: inactive carriers (IC; HBV-DNA <2000 IU/mL and ALT <40 U/L); grey zone group 1 (GZ-1; HBV DNA <2000 IU/mL and ALT >40 U/L); grey zone group 2 (GZ-2; HBV-DNA >2000 IU/mL and ALT <40 U/L).
Results: pSWE results were significantly correlated with TE (r = 0.29, p < 0.001) and APRI (r = 0.17; p = 0.005). Median pSWE values did not differ between IC, GZ-1 and GZ-2 patients (p = 0.82, p = 0.17, p = 0.34). During six years of follow-up, median pSWE and TE values did not differ significantly over time (TE: p = 0.27; pSWE: p = 0.05).
Conclusion: Our data indicate that pSWE could be useful for non-invasive fibrosis assessment and follow-up in patients with HBeAg-negative chronic HBV infection.
Preclinical studies have demonstrated that the endocannabinoid system (ECS) plays an important role in the protection against intestinal inflammation and colorectal cancer (CRC); however, human data are scarce. We determined members of the ECS and related components of the ‘endocannabinoidome’ in patients with inflammatory bowel disease (IBD) and CRC, and compared them to control subjects. Anandamide (AEA) and oleoylethanolamide (OEA) were increased in plasma of ulcerative colitis (UC) and Crohn’s disease (CD) patients while 2-arachidonoylglycerol (2-AG) was elevated in patients with CD, but not UC. 2-AG, but not AEA, PEA and OEA, was elevated in CRC patients. Lysophosphatidylinositol (LPI) 18:0 showed higher levels in patients with IBD than in control subjects whereas LPI 20:4 was elevated in both CRC and IBD. Gene expression in intestinal mucosal biopsies revealed different profiles in CD and UC. CD, but not UC patients, showed increased gene expression for the 2-AG synthesizing enzyme diacylglycerol lipase alpha. Transcripts of CNR1 and GPR119 were predominantly decreased in CD. Our data show altered plasma levels of endocannabinoids and endocannabinoid-like lipids in IBD and CRC and distinct transcript profiles in UC and CD. We also report alterations for less known components in intestinal inflammation, such as GPR119, OEA and LPI.
The precise understanding of the dopaminergic (DA) system and its pharmacological modifications is crucial for diagnosis and treatment of neuropsychiatric disorders, as well as for understanding basic processes, such as motivation and reward. We probed the functional connectivity (FC) of subcortical nuclei related to the DA system according to seed regions defined according to an atlas of subcortical nuclei. We conducted a large pharmaco-fMRI study using a double-blind, placebo-controlled design, where we examined the effect of l -DOPA, a dopamine precursor, and amisulpride, a D2/D3-receptor antagonist on resting-state FC in 45 healthy young adults using a cross-over design. We examined the FC of subcortical nuclei with connection to the reward system and their reaction to opposing pharmacological probing. Amisulpride increased FC from the putamen to the precuneus and from ventral striatum to precentral gyrus. l -DOPA increased FC from the ventral tegmental area (VTA) to the insula/operculum and between ventral striatum and ventrolateral prefrontal cortex and it disrupted ventral striatal and dorsal caudate FC with the medial prefrontal cortex. In an exploratory analysis, we demonstrated that higher self-rated impulsivity goes together with a significant increase in VTA-mid-cingulate gyrus FC during l -DOPA-challenge. Therefore, our DA challenge modulated distinct large-scale subcortical connectivity networks. A dopamine-boost can increase midbrain DA nuclei connectivity to the cortex. The involvement of the VTA-cingulum connectivity in dependence of impulsivity has implications for diagnosis and therapy in disorders like ADHD.
Aim: To assess outcomes in patients with advanced adenocarcinoma non-small-cell lung cancer who received nintedanib plus docetaxel after progression on prior chemotherapy followed by immune checkpoint inhibitor (ICI) therapy. Patients & methods: VARGADO is a prospective, noninterventional study. We describe initial data from a cohort of 22 patients who received nintedanib plus docetaxel after chemotherapy and ICI therapy. Results: Median progression-free survival with nintedanib plus docetaxel was 5.5 months (95% CI: 1.9–8.7 months). The objective response rate was 7/12 (58%) and the disease control rate was 10/12 (83%). Data for overall survival rate 12 months after the start of treatment (primary end point) are not yet mature and are not reported. Of 22 patients, 73% experienced drug-related adverse events; adverse events led to treatment discontinuation in 32% of patients. Conclusion: These data highlight the potential clinical benefit of nintedanib plus docetaxel in patients who failed prior ICI therapy.
Trial registration number: NCT02392455
Systematic reviews represent the core and backbone of evidence-based medicine (EBM) strategies in all fields of medicine. In order to depict a first global sketch of the international efforts in the Cochrane database systematic reviews (CDSR), we analyzed the systematic reviews of the Cochrane database. Our global maps of systematic reviewing offer intriguing structural insights into the world of EBM strategies. They demonstrate that for the CDSR, the UK and Commonwealth countries take the lead position. Since patients, care providers and health systems all over the world benefit from systematic reviewing, institutions in other countries should increase their commitment.
Objective: Excessive inflammation in the central nervous system (CNS) and the periphery can result in neurodegeneration and parkinsonism. Recent evidence suggests that immune responses in Parkinson disease patients are dysregulated, leading to an increased inflammatory reaction to unspecific triggers. Although α‐synuclein pathology is the hallmark of Parkinson disease, it has not been investigated whether pathologic α‐synuclein is a specific trigger for excessive inflammatory responses in Parkinson disease.
Methods: We investigated the immune response of primary human monocytes and a microglial cell line to pathologic forms of α‐synuclein by assessing cytokine release upon exposure.
Results: We show that pathologic α‐synuclein (mutations, aggregation) results in a robust inflammatory activation of human monocytes and microglial BV2 cells. The activation is conformation‐ dependent, with increasing fibrillation and early onset mutations having the strongest effect on immune activation. We also found that activation of immune cells by extracellular α‐synuclein is potentiated by extracellular vesicles, possibly by facilitating the uptake of α‐synuclein. Blood extracellular vesicles from Parkinson disease patients induce a stronger activation of monocytes than blood extracellular vesicles from healthy controls. Most importantly, monocytes from Parkinson disease patients are dysregulated and hyperactive in response to stimulation with pathologic α‐synuclein. Furthermore, we demonstrate that α‐synuclein pathology in the CNS is sufficient to induce the monocyte dysregulation in the periphery of a mouse model.
Interpretation: Taken together, our data suggest that α‐synuclein pathology and dysregulation of monocytes in Parkinson disease can act together to induce excessive inflammatory responses to α‐synuclein. ANN NEUROL 2019;86:593–606
Chordomas are rare bone tumors with few therapeutic options. Here we show, using whole-exome and genome sequencing within a precision oncology program, that advanced chordomas (n = 11) may be characterized by genomic patterns indicative of defective homologous recombination (HR) DNA repair and alterations affecting HR-related genes, including, for example, deletions and pathogenic germline variants of BRCA2, NBN, and CHEK2. A mutational signature associated with HR deficiency was significantly enriched in 72.7% of samples and co-occurred with genomic instability. The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib, which is preferentially toxic to HR-incompetent cells, led to prolonged clinical benefit in a patient with refractory chordoma, and whole-genome analysis at progression revealed a PARP1 p.T910A mutation predicted to disrupt the autoinhibitory PARP1 helical domain. These findings uncover a therapeutic opportunity in chordoma that warrants further exploration, and provide insight into the mechanisms underlying PARP inhibitor resistance.
Objective: The DIRAS2 gene is associated with ADHD, but its function is largely unknown. Thus, we aimed to explore the genes and molecular pathways affected by DIRAS2. Method: Using short hairpin RNAs, we downregulated Diras2 in murine hippocampal primary cells. Gene expression was analyzed by microarray and affected pathways were identified. We used quantitative real-time polymerase chain reaction (qPCR) to confirm expression changes and analyzed enrichment of differentially expressed genes in an ADHD GWAS (genome-wide association studies) sample. Results: Diras2 knockdown altered expression of 1,612 genes, which were enriched for biological processes involved in neurodevelopment. Expression changes were confirmed for 33 out of 88 selected genes. These 33 genes showed significant enrichment in ADHD patients in a gene-set-based analysis. Conclusion: Our findings show that Diras2 affects numerous genes and thus molecular pathways that are relevant for neurodevelopmental processes. These findings may further support the hypothesis that DIRAS2 is linked to etiological processes underlying ADHD. (J. of Att. Dis. 2021; 25(4) 572-583).
Based on accumulating evidence of a role of lipid signaling in many physiological and pathophysiological processes including psychiatric diseases, the present data driven analysis was designed to gather information needed to develop a prospective biomarker, using a targeted lipidomics approach covering different lipid mediators. Using unsupervised methods of data structure detection, implemented as hierarchal clustering, emergent self-organizing maps of neuronal networks, and principal component analysis, a cluster structure was found in the input data space comprising plasma concentrations of d = 35 different lipid-markers of various classes acquired in n = 94 subjects with the clinical diagnoses depression, bipolar disorder, ADHD, dementia, or in healthy controls. The structure separated patients with dementia from the other clinical groups, indicating that dementia is associated with a distinct lipid mediator plasma concentrations pattern possibly providing a basis for a future biomarker. This hypothesis was subsequently assessed using supervised machine-learning methods, implemented as random forests or principal component analysis followed by computed ABC analysis used for feature selection, and as random forests, k-nearest neighbors, support vector machines, multilayer perceptron, and naïve Bayesian classifiers to estimate whether the selected lipid mediators provide sufficient information that the diagnosis of dementia can be established at a higher accuracy than by guessing. This succeeded using a set of d = 7 markers comprising GluCerC16:0, Cer24:0, Cer20:0, Cer16:0, Cer24:1, C16 sphinganine, and LacCerC16:0, at an accuracy of 77%. By contrast, using random lipid markers reduced the diagnostic accuracy to values of 65% or less, whereas training the algorithms with randomly permuted data was followed by complete failure to diagnose dementia, emphasizing that the selected lipid mediators were display a particular pattern in this disease possibly qualifying as biomarkers.
Cysteinyl leukotriene receptor 1 antagonists (CysLT1RA) are frequently used as add-on medication for the treatment of asthma. Recently, these compounds have shown protective effects in cardiovascular diseases. This prompted us to investigate their influence on soluble epoxide hydrolase (sEH) and peroxisome proliferator activated receptor (PPAR) activities, two targets known to play an important role in CVD and the metabolic syndrome. Montelukast, pranlukast and zafirlukast inhibited human sEH with IC50 values of 1.9, 14.1, and 0.8 μM, respectively. In contrast, only montelukast and zafirlukast activated PPARγ in the reporter gene assay with EC50 values of 1.17 μM (21.9% max. activation) and 2.49 μM (148% max. activation), respectively. PPARα and δ were not affected by any of the compounds. The activation of PPARγ was further investigated in 3T3-L1 adipocytes. Analysis of lipid accumulation, mRNA and protein expression of target genes as well as PPARγ phosphorylation revealed that montelukast was not able to induce adipocyte differentiation. In contrast, zafirlukast triggered moderate lipid accumulation compared to rosiglitazone and upregulated PPARγ target genes. In addition, we found that montelukast and zafirlukast display antagonistic activities concerning recruitment of the PPARγ cofactor CBP upon ligand binding suggesting that both compounds act as PPARγ modulators. In addition, zafirlukast impaired the TNFα triggered phosphorylation of PPARγ2 on serine 273. Thus, zafirlukast is a novel dual sEH/PPARγ modulator representing an excellent starting point for the further development of this compound class.
Introduction: Pediatric pneumococcal pneumonia complicated by parapneumonic pleural effusion/empyema (PPE/PE) remains a major concern despite general immunization with pneumococcal conjugate vaccines (PCVs).
Methods: In a nationwide pediatric hospital surveillance study in Germany we identified 584 children <18 years of age with bacteriologically confirmed PPE/PE from October 2010 to June 2018. Streptococcus pneumoniae was identified by culture and/or PCR of blood samples and/or pleural fluid and serotyped.
Results: S. pneumoniae was identified in 256 of 584 (43.8%) children by culture (n = 122) and/or PCR (n = 207). The following pneumococcal serotypes were detected in 114 children: serotype 3 (42.1%), 1 (25.4%), 7F (12.3%), 19A (7.9%), other PCV13 serotypes (4.4%) and non-PCV13 serotypes (7.9%). Between October 2010 and June 2014 serotype 1 (38.1%) and serotype 3 (25.4%) were most prevalent, whereas between July 2014 and June 2018 serotype 3 (62.7%) and non-PCV13 serotypes (15.7%) were dominant. Compared to children with other pneumococcal serotypes, children with serotype 3 associated PPE/PE were younger (median 3.2 years [IQR 2.1–4.3 years] vs. median 5.6 years [IQR 3.8–8.2 years]; p < 0.001) and more frequently admitted to intensive care (43 [89.6%] vs. 48 [73.8%]; p = 0.04). Seventy-six of 114 (66.7%) children with pneumococcal PPE/PE had been vaccinated with pneumococcal vaccines. Thirty-nine of 76 (51.3%) had received a vaccine covering the serotype detected. Thirty of these 39 breakthrough cases were age-appropriately vaccinated with PCV13 and considered vaccine failures, including 26 children with serotype 3, three children with serotype 19A and one child with serotype 1.
Conclusion: Following the introduction of PCV13 in general childhood vaccination we observed a strong emergence of serotype 3 associated PPE/PE in the German pediatric population, including a considerable number of younger children with serotype 3 vaccine breakthrough cases and failures. Future PCVs should not only cover newly emerging serotypes, but also include a more effective component against serotype 3.
OXA-48 is the most common carbapenemase in Enterobacterales in Germany and one of the most frequent carbapenemases worldwide. Several reports have associated blaOXA–48 with a virulent host phenotype. To challenge this hypothesis, 35 OXA-48-producing clinical isolates of Escherichia coli (n = 15) and Klebsiella pneumoniae (n = 20) were studied in vitro, in vivo employing the Galleria mellonella infection model and by whole-genome sequencing. Clinical isolates belonged to 7 different sequence types (STs) in E. coli and 12 different STs in K. pneumoniae. In 26/35 isolates blaOXA–48 was located on a 63 kb IncL plasmid. Horizontal gene transfer (HGT) to E. coli J53 was high in isolates with the 63 kb IncL plasmid (transconjugation frequency: ∼103/donor) but low in isolates with non-IncL plasmids (<10–6/donor). Several clinical isolates were both highly cytotoxic against human cells and virulent in vivo. However, 63 kb IncL transconjugants generated from these highly virulent isolates were not more cytotoxic or virulent when compared to the recipient strain. Additionally, no genes associated with virulence were detected by in silico analysis of OXA-48 plasmids. The 63 kb plasmid was highly stable and did not impair growth or fitness in E. coli J53. In conclusion, OXA-48 clinical isolates in Germany are diverse but typically harbor the same 63 kb IncL plasmid which has been reported worldwide. We demonstrate that this 63 kb IncL plasmid has a low fitness burden, high plasmid stability and can be transferred by highly efficient HGT which is likely the cause of the rapid dissemination of OXA-48 rather than the expansion of a single clone or gain of virulence.
Background: The aim of this study was to assess the knowledge and attitudes towards pregnancy-related issues of Zika virus (ZIKV) infection among general practitioners (GPs), a frontline healthcare worker group, in Indonesia.
Methods: A cross-sectional, online survey assessing knowledge and attitudes towards ZIKV infection on multiple-item scales was sent to GPs in the Sumatra and Java islands of Indonesia. The associations between independent factors and either knowledge or attitude were assessed with logistic regressions. The correlation and association between knowledge and attitude were estimated.
Results: We included 457 (53.7%) out of 850 responses in the analysis. Among these, 304 (66.5%) and 111 (24.2%) respondents had a good knowledge and attitude, respectively. No demographic, workplace, professional development, or experiential characteristics related to ZIKV infection were associated with knowledge. In the multivariate analysis, only contact experience was associated with attitude. There was a significant, positive correlation between knowledge and attitude scores.
Conclusions: Although knowledge of pregnancy-related complications of ZIKV infection is relatively high among GPs in Indonesia, more than 75% of them had a poor attitude towards pregnancy-related issues of Zika. Strategies for enhancing the capacity of GPs to develop positive attitudes and respond to ZIKV infection are needed.
"Medizin bringt einem den Menschen nahe", sagt Dietmar Schranz. Schon als junger Arzt bereiste er die Welt. Er behandelte Leprakranke in Pakistan und war mit "Cap Anamur – Deutsche Not-Ärzte" in Asien. Dass er schließlich Kinderkardiologe wurde, verdankt er vier geistigen Vätern. Heute ist er selbst für viele Kardiologen weltweit zu einer prägenden Figur geworden.
In der Prävention und Behandlung des frühen Mammakarzinoms sind über die Jahre immer wieder kleine, aber bedeutsame Fortschritte gemacht worden. In der Prävention gewinnen die sogenannten Panel-Gen-Analysen immer mehr an Bedeutung, da das durch die getesteten Gene bedingte Risiko immer besser verstanden wird und somit Konzepte für die Integration in die Krankenversorgung erarbeitet werden können. In der adjuvanten Situation konnte die erste Studie in der sogenannten postneoadjuvanten Situation bei fehlender pathologischer Komplettremission nach Trastuzumab oder Pertuzumab + Trastuzumab eine deutliche Verbesserung der Prognose zeigen. Weitere Studien mit diesem postneoadjuvanten Therapiekonzept werden zurzeit noch durchgeführt. Die CDK4/6-Inhibitoren, die in der metastasierten Situation eine deutliche Verbesserung des progressionsfreien Überlebens gezeigt hatten, werden zurzeit in der adjuvanten Situation in großen Therapiestudien getestet. Diese und weitere neue Daten zur Behandlung oder Prävention des primären Mammakarzinoms werden in dieser Übersichtsarbeit vor dem Hintergrund aktueller Studien vorgestellt.
For many years, small but significant advancements have been made time and again in the prevention and treatment of early breast cancer. The so-called panel gene analyses are becoming more and more important in prevention, since the risk due to the tested genes is better understood and as a result, concepts for integration in health care can be developed. In the adjuvant situation, the first study in the so-called post-neoadjuvant situation was able to demonstrate a clear improvement in the prognosis with an absent pathological complete remission following trastuzumab or pertuzumab + trastuzumab. Additional studies with this post-neoadjuvant therapeutic concept are still being conducted at present. The CDK4/6 inhibitors which had shown a significant improvement in progression-free survival in a metastatic situation are currently being tested in the adjuvant situation in large therapeutic studies. These and other new data for the treatment or prevention of primary breast cancer are presented in this review against the backdrop of current studies.
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) can present with different histopathological growth patterns. The impact of these histopathological growth patterns on relapse characteristics is unknown. We therefore analyzed paired biopsies obtained at initial diagnosis and relapse from 33 NLPHL patients who had received first‐line treatment within German Hodgkin Study Group (GHSG) trial protocols, and from a second cohort of 41 relapsed NLPHL patients who had been treated outside GHSG studies. Among the 33 GHSG patients, 21 patients presented with a typical growth pattern at initial diagnosis, whereas 12 patients had a variant histology. The histopathological growth patterns at initial diagnosis and at relapse were consistent in 67% of cases. A variant histology at initial diagnosis was associated with a shorter median time to lymphoma recurrence (2.8 vs 5.2 years; P = .0219). A similar tendency towards a shorter median time to lymphoma recurrence was observed for patients presenting with a variant histology at relapse, irrespective of the growth pattern at initial diagnosis. Results obtained from the 41 NLPHL patients who had been treated outside GHSG studies were comparable (median time to lymphoma recurrence for variant histology vs typical growth pattern at initial diagnosis: 1.5 vs 7.0 years). In conclusion, the histopathological growth pattern remains consistent at relapse in the majority of NLPHL cases, and has major impact on the time of relapse.
Background: Malaria is an increasing concern in Indonesia. Socio-demographic factors were found to strongly influence malaria prevalence. This research aimed to explore the associations between socio-demographic factors and malaria prevalence in Indonesia.
Methods: The study used a cross-sectional design and analysed relationships among the explanatory variables of malaria prevalence in five endemic provinces using multivariable logistic regression.
Results: The analysis of baseline socio-demographic data revealed the following independent risk variables related to malaria prevalence: gender, age, occupation, knowledge of the availability of healthcare services, measures taken to protect from mosquito bites, and housing condition of study participants. Multivariable analysis showed that participants who were unaware of the availability of health facilities were 4.2 times more likely to have malaria than those who were aware of the health facilities (adjusted odds ratio = 4.18; 95% CI 1.52–11.45; P = 0.005).
Conclusions: Factors that can be managed and would favour malaria elimination include a range of prevention behaviours at the individual level and using the networks at the community level of primary healthcare centres. This study suggests that improving the availability of a variety of health facilities in endemic areas, information about their services, and access to these is essential.
Background and Aims: Vitamin D has an inhibitory role in the inflammatory signaling pathways and supports the integrity of the intestinal barrier. Due to its immunomodulatory effect, vitamin D plays a role in chronic inflammatory bowel disease (IBD) and a deficiency is associated with an increased risk for a flare. We aimed to investigate to what extent the 25-hydroxyvitamin D (25(OH)D3) level correlates with disease activity and whether a cut-off value can be defined that discriminates between active disease and remission. Methods: Patients with IBD, treated at the University Hospital Frankfurt were analyzed retrospectively. The 25(OH)D3 levels were correlated with clinical activity indices and laboratory chemical activity parameters. A deficiency was defined as 25(OH)D3 levels <30 ng/mL. Results: A total of 470 (257 female) patients with IBD were included, 272 (57.9%) with Crohn’s disease (CD), 198 (42.1%) with ulcerative colitis (UC). The median age of the patients was 41 (18–84). In 283 patients (60.2%), a vitamin D deficiency was detected. 245 (53.6%) patients received oral vitamin D supplementation, and supplemented patients had significantly higher vitamin D levels (p < 0.0001). Remission, vitamin D substitution, and male gender were independently associated with the 25(OH)D3 serum concentration in our cohort in regression analysis. A 25(OH)D3 serum concentration of 27.5 ng/mL was the optimal cut-off value. Conclusion: Vitamin D deficiency is common in IBD patients and appears to be associated with increased disease activity. In our study, vitamin D levels were inversely associated with disease activity. Thus, close monitoring should be established, and optimized supplementation should take place.
Background: Patients with head and neck cancer (HNC) are at high risk for malnutrition because of tumour localisation and therapy. Prophylactic percutaneous endoscopic gastrostomy (PEG) tube placement is common practice to prevent malnutrition.
Objective: To investigate the benefits of prophylactic PEG tube placement for HNC patients in terms of the influence on patients’ nutritional status, utilisation rate, complications and to identify the predictors of PEG tube utilisation.
Methods: All consecutive HNC patients who underwent prophylactic PEG tube insertion between 1 January 2011 and 31 December 2012 prior to therapy were enrolled. The PEG tube utilisation rate, complications, the patients’ nutritional status and tumour therapy were evaluated with the help of electronic patient charts and telephone interviews.
Results: A total of 181 patients (48 female, median 67.5 years) were included. The PEG utilisation rate in the entire cohort was 91.7%. One hundred and forty‐nine patients (82.3%) used the PEG tube for total enteral nutrition, 17 patients (9.4%) for supplemental nutrition and 15 patients (8.3%) made no use of the PEG tube. Peristomal wound infections were the most common complications (40.3%) in this study. A high Nutritional Risk Screening (NRS) score prior to tube insertion was found to be independently associated with PEG utilisation. No significant weight changes were observed across the three patient subgroups.
Conclusions: The overall PEG tube utilisation rate was high in this study. However, given the high rate of infections, diligent patient selection is crucial in order to determine which patients benefit most from prophylactic PEG tube insertion.
Lysine-specific demethylase 1 (LSD1), a histone lysine demethylase with the main specificity for H3K4me2, has been shown to be overexpressed in rhabdomyosarcoma (RMS) tumor samples. However, its role in RMS biology is not yet well understood. Here, we identified a new role of LSD1 in regulating adhesion of RMS cells. Genetic knockdown of LSD1 profoundly suppressed clonogenic growth in a panel of RMS cell lines, whereas LSD1 proved to be largely dispensable for regulating cell death and short-term survival. Combined RNA and ChIP-sequencing performed to analyze RNA expression and histone methylation at promoter regions revealed a gene set enrichment for adhesion-associated terms upon LSD1 knockdown. Consistently, LSD1 knockdown significantly reduced adhesion to untreated surfaces. Importantly, precoating of the plates with the adhesives collagen I or fibronectin rescued this reduced adhesion of LSD1 knockdown cells back to levels of control cells. Using KEGG pathway analysis, we identified 17 differentially expressed genes (DEGs) in LSD1 knockdown cells related to adhesion processes, which were validated by qRT-PCR. Combining RNA and ChIP-sequencing results revealed that, within this set of genes, SPP1, C3AR1, ITGA10 and SERPINE1 also exhibited increased H3K4me2 levels at their promoter regions in LSD1 knockdown compared to control cells. Indeed, LSD1 ChIP experiments confirmed enrichment of LSD1 at their promoter regions, suggesting a direct transcriptional regulation by LSD1. By identifying a new role of LSD1 in the modulation of cell adhesion and clonogenic growth of RMS cells, these findings highlight the importance of LSD1 in RMS.
Background: Hepatitis C virus (HCV) is currently classified into 8 genotypes and 86 subtypes. The objective of this study was to characterize novel HCV subtypes and to investigate the impact of subtypes on treatment outcome.
Methods: Full-genome sequencing was performed on HCV plasma samples with <85% sequence homology of NS3, NS5A, and/or NS5B to HCV genotype (GT) 1–8 reference strains.
Results: A total of 14 653 patients with GT1–6 HCV infection were enrolled in clinical studies of sofosbuvir-based regimens. For the majority of the patients, a specific subtype could be assigned based on a close genetic relationship to previously described subtypes. However, for 19 patients, novel subtypes were identified with <85% homology compared with previously described subtypes. These novel subtypes had the following genotypes: 9 in GT2, 5 in GT4, 2 in GT6, and 1 each in GT1, GT3, and GT5. Despite the presence of polymorphisms at resistance-associated substitution positions, 18 of the 19 patients treated with sofosbuvir-containing therapy achieved SVR12.
Conclusions: Nineteen novel HCV subtypes were identified, suggesting an even greater genetic diversity of HCV subtypes than previously recognized.
The ‘European Alliance Against Depression’ community-based intervention approach simultaneously targets depression and suicidal behaviour by a multifaceted community based intervention and has been implemented in more than 115 regions worldwide. The two main aims of the European Union funded project “Optimizing Suicide Prevention Programmes and Their Implementation in Europe” were to optimise this approach and to evaluate its implementation and impact. This paper reports on the primary outcome of the intervention (the number of completed and attempted suicides combined as ‘suicidal acts’) and on results concerning process evaluation analysis. Interventions were implemented in four European cities in Germany, Hungary, Portugal and Ireland, with matched control sites. The intervention comprised activities with predefined minimal intensity at four levels: training of primary care providers, a public awareness campaign, training of community facilitators, support for patients and their relatives. Changes in frequency of suicidal acts with respect to a one-year baseline in the four intervention regions were compared to those in the four control regions (chi-square tests). The decrease in suicidal acts compared to baseline in the intervention regions (-58 cases, -3.26%) did not differ significantly (χ2 = 0.13; p = 0.72) from the decrease in the control regions (-18 cases, -1.40%). However, intervention effects differed between countries (χ2 = 8.59; p = 0.04), with significant effects on suicidal acts in Portugal (χ2 = 4.82; p = 0.03). The interviews and observations explored local circumstances in each site throughout the study. Hypothesised mechanisms of action for successful implementation were observed and drivers for ‘added-value’ were identified: local partnership working and ‘in-kind’ contributions; an approach which valued existing partnership strengths; and synergies operating across intervention levels. It can be assumed that significant events during the implementation phase had a certain impact on the observed outcomes. However, this impact was, of course, not proven.
Objectives: Novel formulations (gastro-resistant tablet and intravenous solution) of posaconazole (POS) have been approved in prophylaxis and therapy of invasive fungal diseases (IFDs). Study aim was to analyze treatment strategies and clinical effectiveness.
Methods: We set up a web-based registry on www.ClinicalSurveys.net for documentation of comprehensive data of patients who received novel POS formulations. Data analysis was split into two groups of patients who received novel POS formulations for antifungal prophylaxis (posaconazole prophylaxis group) and antifungal therapy (posaconazole therapy group), respectively.
Results: Overall, 180 patients (151 in the posaconazole prophylaxis group and 29 in the posaconazole therapy group) from six German tertiary care centers and hospitalized between 05/2014 – 03/2016 were observed. Median age was 58 years (range: 19 – 77 years) and the most common risk factor for IFD was chemotherapy (n = 136; 76%). In the posaconazole prophylaxis group and posaconazole therapy group, median POS serum levels at steady-state were 1,068 μg/L (IQR 573–1,498 μg/L) and 904 μg/L (IQR 728–1,550 μg/L), respectively (P = 0.776). During antifungal prophylaxis with POS, nine (6%) probable/proven fungal breakthroughs were reported and overall survival rate of hospitalization was 86%. The median overall duration of POS therapy was 18 days (IQR: 7 – 23 days). Fourteen patients (48%) had progressive IFD under POS therapy, of these five patients (36%) died related to or likely related to IFD.
Conclusions: Our study demonstrates clinical effectiveness of antifungal prophylaxis with novel POS formulations. In patients treated for possible/probable/proven IFD, we observed considerable mortality in patients receiving salvage treatment and with infections due to rare fungal species.
Neuroblastoma (NB) is the most common solid extracranial tumor in childhood. Despite therapeutic progress, prognosis in high-risk NB is poor and innovative therapies are urgently needed. Therefore, we addressed the potential cytotoxic capacity of interleukin (IL)-activated natural killer (NK) cells compared to cytokine-induced killer (CIK) cells for the treatment of NB. NK cells were isolated from peripheral blood mononuclear cells (PBMCs) by indirect CD56-enrichment or CD3/CD19-depletion and expanded with different cytokine combinations, such as IL-2, IL-15, and/or IL-21 under feeder-cell free conditions. CIK cells were generated from PBMCs by ex vivo stimulation with interferon-γ, IL-2, OKT-3, and IL-15. Comparative analysis of expansion rate, purity, phenotype and cytotoxicity was performed. CD56-enriched NK cells showed a median expansion rate of 4.3-fold with up to 99% NK cell content. The cell product after CD3/CD19-depletion consisted of a median 43.5% NK cells that expanded significantly faster reaching also 99% of NK cell purity. After 10–12 days of expansion, both NK cell preparations showed a significantly higher median cytotoxic capacity against NB cells relative to CIK cells. Remarkably, these NK cells were also capable of efficiently killing NB spheroidal 3D culture in long-term cytotoxicity assays. Further optimization using a novel NK cell culture medium and a prolonged culturing procedure after CD3/CD19-depletion for up to 15 days enhanced the expansion rate up to 24.4-fold by maintaining the cytotoxic potential. Addition of an IL-21 boost prior to harvesting significantly increased the cytotoxicity. The final cell product consisted for the major part of CD16−, NCR-expressing, poly-functional NK cells with regard to cytokine production, CD107a degranulation and antitumor capacity. In summary, our study revealed that NK cells have a significantly higher cytotoxic potential to combat NB than CIK cell products, especially following the synergistic use of IL-15 and IL-21 for NK cell activation. Therefore, the use of IL-15+IL-21 expanded NK cells generated from CD3/CD19-depleted apheresis products seems to be highly promising as an immunotherapy in combination with haploidentical stem cell transplantation (SCT) for high-risk NB patients.
Glioblastomas (GBs) frequently display activation of the epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR). mTOR exists as part of two multiprotein complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2). In GBs, mTORC1 inhibitors such as rapamycin have performed poorly in clinical trials, and in vitro protect GB cells from nutrient and oxygen deprivation. Next generation ATP-competitive mTOR inhibitors with affinity for both mTOR complexes have been developed, but data exploring their effects on GB metabolism are scarce. In this study, we compared the ATP-competitive mTORC1/2 inhibitors torin2, INK-128 and NVP-Bez235 to the allosteric mTORC1 inhibitor rapamycin under conditions that mimic the glioma microenvironment. In addition to inhibiting mTORC2 signaling, INK-128 and NVP-Bez235 more effectively blocked mTORC1 signaling and prompted a stronger cell growth inhibition, partly by inducing cell cycle arrest. However, under hypoxic and nutrient-poor conditions mTORC1/2 inhibitors displayed even stronger cytoprotective effects than rapamycin by reducing oxygen and glucose consumption. Thus, therapies that arrest proliferation and inhibit anabolic metabolism must be expected to improve energy homeostasis of tumor cells. These results mandate caution when treating physiologically or therapeutically induced hypoxic GBs with mTOR inhibitors.
The family of NADPH oxidases represents an important source of reactive oxygen species (ROS) within the cell. Nox4 is a special member of this family as it constitutively produces H2O2 and its loss promotes inflammation. A major cellular component of inflammation is the macrophage population, which can be divided into several subpopulations depending on their phenotype, with proinflammatory M(LPS+IFNγ) and wound-healing M(IL4+IL13) macrophages being extremes of the functional spectrum. Whether Nox4 is expressed in macrophages is discussed controversially. Here, we show that macrophages besides a high level of Nox2 indeed express Nox4. As Nox4 contributes to differentiation of many cells, we hypothesize that Nox4 plays a role in determining the polarization and the phenotype of macrophages. In bone marrow-derived monocytes, ex vivo treatment with LPS/IFNγ or IL4/IL13 results in polarization of the cells into M(LPS+IFNγ) or M(IL4+IL13) macrophages, respectively. In this ex vivo setting, Nox4 deficiency reduces M(IL4+IL13) polarization and forces M(LPS+IFNγ). Nox4-/- M(LPS+IFNγ)-polarized macrophages express more Nox2 and produce more superoxide anions than wild type M(LPS+IFNγ)-polarized macrophages. Mechanistically, Nox4 deficiency reduces STAT6 activation and promotes NFκB activity, with the latter being responsible for the higher level of Nox2 in Nox4-deficient M(LPS+IFNγ)-polarized macrophages. According to those findings, in vivo, in a murine inflammation-driven fibrosarcoma model, Nox4 deficiency forces the expression of proinflammatory genes and cytokines, accompanied by an increase in the number of proinflammatory Ly6C+ macrophages in the tumors. Collectively, the data obtained in this study suggest an anti-inflammatory role for Nox4 in macrophages. Nox4 deficiency results in less M(IL4+IL13) polarization and suppression of NFκB activity in monocytes.
Sleep impairments are a hallmark of acute bipolar disorder (BD) episodes and are present even in the euthymic state. Studying healthy subjects who are vulnerable to BD can improve our understanding of whether sleep impairment is a predisposing factor. Therefore, we investigated whether vulnerability to BD, dimensionally assessed by the hypomanic personality scale (HPS), is associated with sleep disturbances in healthy subjects. We analyzed participants from a population-based cohort who had completed the HPS and had either a 7-day actigraphy recording or a Pittsburgh sleep quality index (PSQI) assessment. In addition, subjects had to be free of confounding diseases or medications. This resulted in 771 subjects for actigraphy and 1766 for PSQI analyses. We found strong evidence that higher HPS scores are associated with greater intraindividual sleep variability, more disturbed sleep and more daytime sleepiness. In addition, factor analyses revealed that core hypomanic features were especially associated with self-reported sleep impairments. Results support the assumption of disturbed sleep as a possibly predisposing factor for BD and suggest sleep improvement as a potential early prevention target.
Background: Uveal melanoma (UM) is highly refractory to treatment with dismal prognosis in advanced stages. The value of the combined checkpoint blockade with CTLA-4 and PD-1 inhibition in metastatic UM is currently unclear.
Methods: Patients with metastatic or unresectable UM treated with ipilimumab in combination with a PD-1 inhibitor were collected from 16 German skin cancer centers. Patient records of 64 cases were analyzed for response, progression-free survival (PFS), overall survival (OS), and safety. Clinical parameters and serum biomarkers associated with OS and treatment response were determined with Cox regression modelling and logistic regression.
Results: The best overall response rate to combined checkpoint blockade was 15.6% with 3.1 and 12.5% complete and partial response, respectively. The median duration of response was 25.5 months (range 9.0–65.0). Stable disease was achieved in 21.9%, resulting in a disease control rate of 37.5% with a median duration of the clinical benefit of 28.0 months (range 7.0–65.0). The median PFS was 3.0 months (95% CI 2.4–3.6). The median OS was estimated to 16.1 months (95% CI 12.9–19.3). Regarding safety, 39.1% of treated patients experienced a severe, treatment-related adverse event according to the CTCAE criteria (grade 3: 37.5%; grade 4: 1.6%). The most common toxicities were colitis (20.3%), hepatitis (20.3%), thyreoiditis (15.6%), and hypophysitis (7.8%). A poor ECOG performance status was an independent risk factor for decreased OS (p = 0.007).
Conclusions: The tolerability of the combined checkpoint blockade in UM may possibly be better than in trials on cutaneous melanoma. This study implies that combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic UM available outside of clinical trials.
Selection and prioritization of patients with HCC for LT are based on pretransplant imaging diagnostic, taking the risk of incorrect diagnosis. According to the German waitlist guidelines, imaging has to be reported to the allocation organization (Eurotransplant) and pathology reports have to be submitted thereafter. In order to assess current procedures we performed a retrospective multicenter analysis in all German transplant centers with focus on accuracy of imaging diagnostic and tumor classification. 1168 primary LT for HCC were conducted between 2007 and 2013 in Germany. Patients inside the Milan, UCSF, and up-to-seven criteria were misclassified with definitive histologic results in 18%, 15%, and 11%, respectively. Patients pretransplant outside the Milan, UCSF, and up-to-seven criteria were otherwise misclassified in 34%, 43%, and 41%. Recurrence-free survival correlated with classification by posttransplant histological report, but not pretransplant imaging diagnostic. Univariate analysis revealed tumor size, vascular invasion, and grading as significant parameters for outcome, while tumor grading was the only parameter persisting by multivariate testing. Conclusion. There was a relevant percentage (15-40%) of patients misclassified by imaging diagnosis at a time prior to LI-RADS and guidelines to improve imaging of HCC. Outcome analysis showed a good correlation to histological, in contrast poor correlation to imaging diagnosis, suggesting an adjustment of the LT selection and prioritization criteria.
Autophagy is a highly conserved catabolic process through which defective or otherwise harmful cellular components are targeted for degradation via the lysosomal route. Regulatory pathways, involving post-translational modifications such as phosphorylation, play a critical role in controlling this tightly orchestrated process. Here, we demonstrate that TBK1 regulates autophagy by phosphorylating autophagy modifiers LC3C and GABARAP-L2 on surface-exposed serine residues (LC3C S93 and S96; GABARAP-L2 S87 and S88). This phosphorylation event impedes their binding to the processing enzyme ATG4 by destabilizing the complex. Phosphorylated LC3C/GABARAP-L2 cannot be removed from liposomes by ATG4 and are thus protected from ATG4-mediated premature removal from nascent autophagosomes. This ensures a steady coat of lipidated LC3C/GABARAP-L2 throughout the early steps in autophagosome formation and aids in maintaining a unidirectional flow of the autophagosome to the lysosome. Taken together, we present a new regulatory mechanism of autophagy, which influences the conjugation and de-conjugation of LC3C and GABARAP-L2 to autophagosomes by TBK1-mediated phosphorylation.