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In light of increasing division of labour in healthcare, the training and acquisition of both profession-specific and interprofessional competencies have been attributed growing significance, creating the need to test and establish specific teaching formats. Despite ever more complex and interconnected healthcare systems, an increase in patients’ active self-responsibility and innumerable pedagogical and technological innovations, educational systems have not reacted adequately to these new demands. Many authors, not lease the German Council of Science and Humanities, have therefore urged a rethinking of traditional medical education. Student-centred learning activities, such as problem-based and research-based learning, are becoming increasingly significant in view of the numbers of students achieving unsatisfactory levels of competence in critical thinking, communication and writing abilities and complex clinical decision making, for example. The Council of Science and Humanities arrived at a positive evaluation of the various model and reformed courses of study attempting to effectuate a comprehensive reorganisation of medical studies in content and structure as well as methods and didactics. The persistent pervasiveness of instructor-centred learning formats is not only to be found in medical education but in all of the health professions. Although alternative teaching and instruction formats have already been designed and their effectiveness deemed positive in empirical evaluation, the lecture remains the most practised means of transmitting knowledge. In its essence, however, learning is not a question of transmitting information but, moreover, a question of processing information. In traditional instruction units, referred to as “chalk and talk classes” by Becker and Watts, the teaching party presents material in the form of a lecture. As appropriate, questions may be permitted or short processing periods for the students may be integrated into the lecture. The knowledge-assimilating and most essential analysis of the lecture’s contents takes place in the subsequent self-instruction phase, in which the student works alone on concrete tasks. It is during the transfer of knowledge conveyed in the lectures, however, that most questions arise. Of further disadvantage in the traditional lecture is the low level of motivation among students to attend lectures as well as their often heterogeneous knowledge. The Inverted Classroom Model seems to be an eligible instrument for greater facilitation of student-centred and interprofessional learning.
Signal transducer and activator of transcription 6 (STAT6) regulates transcriptional activation in response to interleukin-4 (IL-4)-induced tyrosine phosphorylation by direct interaction with coactivators. The CREB-binding protein and the nuclear coactivator 1 (NCoA-1), a member of the p160/steroid receptor coactivator family, bind independently to specific regions of STAT6 and act as coactivators. In this study we show that an LXXLL motif in the STAT6 transactivation domain mediates the interaction with NCoA-1. Peptides representing this motif as well as antibodies generated against this motif inhibited STAT6/NCoA-1 interaction in glutathione S-transferase pulldown assays. Peptides derived from the STAT6 transactivation domain adjacent to the LXXLL motif as well as antibodies against these peptides showed no inhibitory effect. Mutagenesis of the LXXLL motif eliminated the STAT6/NCoA-1 interaction in vitro and in vivo, supporting the specific role of this motif in NCoA-1 binding. Importantly, mutagenesis of the STAT-LXXLL motif strongly diminished the IL-4-regulated activation of the endogenous STAT6 target gene eotaxin-3. Taken together, these results indicate that the STAT6-LXXLL-binding motif mediates the interaction with NCoA-1 in transcriptional activation and represents a new potential drug target for the inhibition of the STAT6 transactivation function in allergic diseases.
An ontology-based method for assessing batch effect adjustment approaches in heterogeneous datasets
(2018)
Motivation: International consortia such as the Genotype-Tissue Expression (GTEx) project, The Cancer Genome Atlas (TCGA) or the International Human Epigenetics Consortium (IHEC) have produced a wealth of genomic datasets with the goal of advancing our understanding of cell differentiation and disease mechanisms. However, utilizing all of these data effectively through integrative analysis is hampered by batch effects, large cell type heterogeneity and low replicate numbers. To study if batch effects across datasets can be observed and adjusted for, we analyze RNA-seq data of 215 samples from ENCODE, Roadmap, BLUEPRINT and DEEP as well as 1336 samples from GTEx and TCGA. While batch effects are a considerable issue, it is non-trivial to determine if batch adjustment leads to an improvement in data quality, especially in cases of low replicate numbers.
Results: We present a novel method for assessing the performance of batch effect adjustment methods on heterogeneous data. Our method borrows information from the Cell Ontology to establish if batch adjustment leads to a better agreement between observed pairwise similarity and similarity of cell types inferred from the ontology. A comparison of state-of-the art batch effect adjustment methods suggests that batch effects in heterogeneous datasets with low replicate numbers cannot be adequately adjusted. Better methods need to be developed, which can be assessed objectively in the framework presented here.
BACKGROUND: In two clinical trials, low-grade fever was observed more frequently after coadministration than after separate administration of two recommended routine pediatric vaccines. Since fever is an important issue with vaccine tolerability, we performed this open-label study on the efficacy and safety of prophylactic use of paracetamol (acetaminophen, Benuron(R)) in children administered routine 7-valent pneumococcal conjugate vaccine (PCV-7) coadministered with hexavalent vaccine (diphtheria-tetanus-acellular pertussis-hepatitis B, polio, Haemophilus influenzae type b vaccine [DTPa-HBV-IPV/Hib]) in Germany.
METHODS: Healthy infants (N = 301) who received a 3-dose infant series of PCV-7 and DTPa-HBV-IPV/Hib plus a toddler dose were randomly assigned 1:1 to prophylactic paracetamol (125 mg or 250 mg suppositories, based on body weight) at vaccination, and at 6--8 hour intervals thereafter, or a control group that received no paracetamol. Rectal temperature and local and other systemic reactions were measured for 4 days post vaccination; adverse events were collected throughout the study.
RESULTS: In the intent-to-treat population, paracetamol reduced the incidence of fever >=38[degree sign]C, but this reduction was only significant for the infant series, with computed efficacy of 43.0% (95% confidence interval [CI]: 17.4, 61.2), and not significant after the toddler dose (efficacy 15.9%; 95% CI: -19.9, 41.3); results were similar in the per protocol (PP) population. Fever >39[degree sign]C was rare during the infant series, such that there were too few cases for assessment. After the toddler dose, paracetamol effectively reduced fever >39[degree sign]C, reaching statistical significance in the PP population only (efficacy 79%; 95% CI: 3.9, 97.7). Paracetamol also reduced reactogenicity, but there were few significant differences between groups after any dose. No vaccine-related serious adverse events were reported.
CONCLUSIONS: Paracetamol effectively prevented fever and other reactions, mainly during the infant series. However, as events were generally mild and of no concern in either group our data support current recommendations to administer paracetamol to treat symptoms only and not for routine prophylaxis.Trial registration: NCT00294294.
Background: Shortening duration of peginterferon-based HCV treatment reduces associated burden for patients. Primary objectives of this study were to assess the efficacy against the minimally acceptable response rate 12 weeks post-treatment (SVR12) and safety of simeprevir plus PR in treatment-naïve HCV GT1 patients treated for 12 weeks. Additional objectives included the investigation of potential associations of rapid viral response and baseline factors with SVR12.
Methods: In this Phase III, open-label study in treatment-naïve HCV GT1 patients with F0–F2 fibrosis, patients with HCV-RNA <25 IU/mL (detectable/undetectable) at Week 2, and undetectable HCV-RNA at Weeks 4 and 8, stopped all treatment at Week 12. All other patients continued PR for a further 12 weeks. Baseline factors significantly associated with SVR12 were identified through logistic regression.
Results: Of 163 patients who participated in the study, 123 (75%) qualified for 12-week treatment; of these, 81 (66%) achieved SVR12. Baseline factors positively associated with SVR12 rates in patients receiving the 12-week regimen were: IL28B CC genotype: (94% SVR12); HCV RNA ≤800,000 IU/mL (82%); F0–F1 fibrosis (74%). Among all 163 patients, 94% experienced ≥1 adverse event (AE), 4% a serious AE, and 2.5% discontinued due to an AE. Reduced impairment in patient-reported outcomes was observed in the 12-week vs >12-week regimen.
Conclusions: Overall SVR12 rate (66%) was below the target of 80%, indicating that shortening of treatment with simeprevir plus PR to 12 weeks based on very early response is not effective. However, baseline factors associated with higher SVR12 rates were identified. Therefore, while Week 2 response alone is insufficient to predict efficacy, GT1 patients with favourable baseline factors may benefit from a shortened simeprevir plus PR regimen.
Trial Registration: ClinicalTrials.gov NCT01846832
This is a randomized trial (ATHENA study) in de novo kidney transplant patients to compare everolimus versus mycophenolic acid (MPA) with similar tacrolimus exposure in both groups, or everolimus with concomitant tacrolimus or cyclosporine (CsA), in an unselected population. In this 12-month, multicenter, open-label study, de novo kidney transplant recipients were randomized to everolimus with tacrolimus (EVR/TAC), everolimus with CsA (EVR/CsA) or MPA with tacrolimus (MPA/TAC), with similar tacrolimus exposure in both groups. Non-inferiority of the primary end point (estimated glomerular filtration rate [eGFR] at month 12), assessed in the per-protocol population of 338 patients, was not shown for EVR/TAC or EVR/CsA versus MPA/TAC. In 123 patients with TAC levels within the protocol-specified range, eGFR outcomes were comparable between groups. The mean increase in eGFR during months 1 to 12 post-transplant, analyzed post hoc, was similar with EVR/TAC or EVR/CsA versus MPA/TAC. The incidence of treatment failure (biopsy proven acute rejection, graft loss or death) was not significant for EVR/TAC but significant for EVR/CsA versus MPA/TAC. Most biopsy-proven acute rejection events in this study were graded mild (BANFF IA). There were no differences in proteinuria between groups. Cytomegalovirus and BK virus infection were significantly more frequent with MPA/TAC. Thus, everolimus with TAC or CsA showed comparable efficacy to MPA/TAC in de novo kidney transplant patients. Non-inferiority of renal function, when pre-specified, was not shown, but the mean increase in eGFR from month 1 to 12 was comparable to MPA/TAC.
A body of research demonstrates convincingly a role for synchronization of auditory cortex to rhythmic structure in sounds including speech and music. Some studies hypothesize that an oscillator in auditory cortex could underlie important temporal processes such as segmentation and prediction. An important critique of these findings raises the plausible concern that what is measured is perhaps not an oscillator but is instead a sequence of evoked responses. The two distinct mechanisms could look very similar in the case of rhythmic input, but an oscillator might better provide the computational roles mentioned above (i.e., segmentation and prediction). We advance an approach to adjudicate between the two models: analyzing the phase lag between stimulus and neural signal across different stimulation rates. We ran numerical simulations of evoked and oscillatory computational models, showing that in the evoked case,phase lag is heavily rate-dependent, while the oscillatory model displays marked phase concentration across stimulation rates. Next, we compared these model predictions with magnetoencephalography data recorded while participants listened to music of varying note rates. Our results show that the phase concentration of the experimental data is more in line with the oscillatory model than with the evoked model. This finding supports an auditory cortical signal that (i) contains components of both bottom-up evoked responses and internal oscillatory synchronization whose strengths are weighted by their appropriateness for particular stimulus types and (ii) cannot be explained by evoked responses alone.
Background The EGF receptor has been shown to internalize via clathrin-independent endocytosis (CIE) in a ligand concentration dependent manner. From a modeling point of view, this resembles an ultrasensitive response, which is the ability of signaling networks to suppress a response for low input values and to increase to a pre-defined level for inputs exceeding a certain threshold. Several mechanisms to generate this behaviour have been described theoretically, the underlying assumptions of which, however, have not been experimentally demonstrated for the EGF receptor internalization network. Results Here, we present a mathematical model of receptor sorting into alternative pathways that explains the EGF-concentration dependent response of CIE. The described mechanism involves a saturation effect of the dominant clathrin-dependent endocytosis pathway and implies distinct steady-states into which the system is forced for low vs high EGF stimulations. The model is minimal since no experimentally unjustified reactions or parameter assumptions are imposed. We demonstrate the robustness of the sorting effect for large parameter variations and give an analytic derivation for alternative steady-states that are reached. Further, we describe extensibility of the model to more than two pathways which might play a role in contexts other than receptor internalization. Conclusions Our main result is that a scenario where different endocytosis routes consume the same form of receptor corroborates the observation of a clear-cut, stimulus dependent sorting. This is especially important since a receptor modification discriminating between the pathways has not been found. The model is not restricted to EGF receptor internalization and might account for ultrasensitivity in other cellular contexts.
In the last decade, several sophisticated and accurate imaging methods such as positron emission tomography have been developed in order to evaluate malignant potential in enlarged mediastinal lymph nodes. This case illustrates an unusual presentation of sarcoidosis that mimicked lymphatic metastases of non small cell lung carcinoma. The reported high specificity and sensitivity of positron emission tomography-Computer Tomography regarding mediastinal staging could lead in same cases of false positives to a delaying of stage adapted therapy of non small cell lung carcinoma, showing that despite the recent advances of imaging techniques, such as positron emission tomography-computer tomography, several limitations of this imaging technique are still existing.
Background: Castleman’s disease is a rare lymphoproliferative disorder. It typically presents as mediastinal masses and causes a wide range of clinical symptoms. Histologically, Castleman’s disease is classified as either a hyalinic vascular or plasma cell variant. The prognosis mainly depends on the histological type and broadly varies. We herein report our sonographic findings in a patient with Castleman’s disease, including gray-scale ultrasonography, color Doppler ultrasonography, and sonoelastography ultrasonography, which have not been previously reported in the literature. These findings allowed for a preoperative diagnosis and avoidance of overly aggressive therapy.
Case presentation: A 28-year-old European female patient with unicentric Castleman’s disease of hyalinic vascular type (HV) restricted to the axilla was referred to us because of a 4-month history of a painless, solitary mass located in the left axilla. The patient’s medical history was unremarkable.
Conclusion: Castleman’s disease is a pathologic entity of unknown etiology and pathogenesis. In this case report of unicentric HV-type CD, we demonstrate that typical sonographic findings can lead to a preoperative diagnosis of Castleman’s disease. Core needle biopsy usually allows for a final diagnosis and helps to avoid unnecessary operations and overtreatment.
Objective: The mortality associated with sepsis remains unacceptably high, despite modern high-quality intensive care. Based on the results from previous studies, anaemia and its management in patients with sepsis appear to impact outcomes; however, the transfusion policy is still being debated, and the ideal approach may be extremely specific to the individual. This study aimed to investigate the long-term impact of anaemia requiring red blood cell (RBC) transfusion on mortality and disease severity in patients with sepsis. We studied a general surgical intensive care unit (ICU) population, excluding cardiac surgery patients. 435 patients were enrolled in this observational study between 2012 and 2016.
Results: Patients who received RBC transfusion between 28 days before and 28 days after the development of sepsis (n = 302) exhibited a significantly higher 90-day mortality rate (34.1% vs 19.6%; P = 0.004, Kaplan–Meier analysis). This association remained significant after adjusting for confounders in the multivariate Cox regression analysis (hazard ratio 1.68; 95% confidence interval 1.03–2.73; P = 0.035). Patients who received transfusions also showed significantly higher morbidity scores, such as SOFA scores, and ICU lengths of stay compared to patients without transfusions (n = 133). Our results indicate that anaemia and RBC transfusion are associated with unfavourable outcomes in patients with sepsis.
Background: Nicolaides-Baraitser syndrome (NCBRS) is a rare disease caused by mutations in the SMRCA2 gene, which affects chromatin remodelling and leads to a wide range of symptoms including microcephaly, distinct facial features, recurrent seizures, and severe mental retardation. Until now, less than 100 cases have been reported. Case presentation: A 22-month old male infant with NCBRS underwent elective cleft palate surgery. The anaesthetists were challenged by the physiological condition of the patient: narrow face, very small mouth, mild tachypnea, slight sternal retractions, physical signs of partial monosomy 9p, and plagiocephalus, midface hypoplasia, V-shaped cleft palate, enhanced muscular hypotension, dysplastic kidneys (bilateral, estimated GFR: approx. 40 ml/m2), nocturnal oxygen demand, and combined apnea. In addition, little information was available about interaction of the NCBRS displayed by the patient and anaesthesia medications. Conclusions: The cleft palate was successfully closed using the bridge flap technique. Overall, we recommend to perform a trial video assisted laryngoscopy in the setting of spontaneous breathing with deep inhalative anaesthesia before administration of muscle relaxation to detect any airway difficulties while remaining spontaneoues breathing and protective reflexes.
Cerumen was found to be a promising alternative specimen for the detection of drugs. In a pilot study, drugs of abuse were identified at a higher detection rate and a longer detection window in cerumen than in urine. In this study, cerumen from subjects was analyzed after they ingested the designer stimulant 4-fluoroamphetamine (4-FA) in a controlled manner. Methods: Twelve subjects ingested placebo and 100 mg of 4-FA. Five of them were also given 150 mg of 4-FA in 150 mL Royal Club bitter lemon drink at least after 7 days. Cerumen was sampled using cotton swabs at baseline, 1 h after the ingestion of the drug and at the end of the study day (12 h). After extraction with ethyl acetate followed by solid-phase extraction, the extracts were analyzed using liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS). Results and discussion: In the cerumen of all 12 subjects, 4-FA was detected 12 h after its ingestion; in most subjects, cerumen was detected after 1 h of ingestion, ranging from 0.06 to 13.90 (median 1.52) ng per swab. The detection of 4-FA in cerumen sampled 7 days or more after the first dose suggested a long detection window of cerumen. Conclusions: Cerumen can be successfully used to detect a single drug ingestion even immediately after the ingestion when a sufficient amount of cerumen is used.
Hypersecretion and chronic phlegm are major symptoms of chronic obstructive pulmonary disease (COPD) but animal models of COPD with a defined functional hypersecretion have not been established so far. To identify an animal model of combined morphological signs of airway inflammation and functional hypersecretion, rats were continuously exposed to different levels of sulfur dioxide (SO2, 5 ppm, 10 ppm, 20 ppm, 40 ppm, 80 ppm) for 3 (short-term) or 20–25 (long-term) days. Histology revealed a dose-dependent increase in edema formation and inflammatory cell infiltration in short-term-exposed animals. The submucosal edema was replaced by fibrosis after long-term-exposure. The basal secretory activity was only significantly increased in the 20 ppm group. Also, stimulated secretion was significantly increased only after exposure to 20 ppm. BrdU-assays and AgNOR-analysis demonstrated cellular metaplasia and glandular hypertrophy rather than hyperplasia as the underlying morphological correlate of the hypersecretion.
In summary, SO2-exposure can lead to characteristic airway remodeling and changes in mucus secretion in rats. As only long-term exposure to 20 ppm leads to a combination of hypersecretion and airway inflammation, only this mode of exposure should be used to mimic human COPD. Concentrations less or higher than 20 ppm or short term exposure do not induce the respiratory symptom of hypersecretion. The present model may be used to characterize the effects of new compounds on mucus secretion in the background of experimental COPD.
Background and Objectives: Proteins of the coagulation system contribute to autoimmune inflammation in patients with multiple sclerosis (MS). On blood-brain barrier (BBB) disruption, fibrinogen enters the CNS and is rapidly converted to fibrin, unfolding pleiotropic autoimmune mechanisms. Fibrin accumulation leads to subsequent proteolytic degradation that results in D-dimer generation. The primary objective of this study was to determine intrathecal levels of D-dimer in CSF as a measure of intrathecal coagulation cascade activation and to evaluate its diagnostic utility in patients with MS in contrast to healthy subjects. Key secondary objectives included analysis of CSF D-dimer in differential diagnoses of MS and its relation to routine clinical markers of disease activity.
Methods: Patients admitted for the assessment of suspected MS were prospectively recruited from October 2017 to December 2020. Blood plasma and citrated CSF samples were analyzed using a highly sensitive luminescent oxygen channeling immunoassay. Intrathecal generation of D-dimer was analyzed by adjusting for CSF/serum albumin (Qalb) and CSF/plasma D-dimer quotients (QD-dimer), and corresponding CSF fibrinogen levels were determined. Final diagnoses after full evaluation and clinical data were recorded.
Results: Of 187 patients, 113 patients received a diagnosis of MS or clinically/radiologically isolated syndrome. We found increased intrathecal CSF D-dimer generation levels (QD-dimer/Qalb-index) for patients with relapsing-remitting MS (RRMS; n = 71, median 4.7, interquartile range [IQR] 2.5–8.0) when compared with those for disease controls (n = 22, median 2.6, IQR 2.1–4.8, p = 0.031). Absolute CSF D-dimer values correlated with CSF fibrinogen levels (r = 0.463; p < 0 .001) and CSF leukocytes (r = 0.273; p = 0.003) and were elevated in MS patients with contrast enhancement (CE) compared with MS patients without CE on MRI (n = 48, median 6 ng/mL, and IQR 3–15.25 vs n = 41, median 4 ng/mL, and IQR 2–7; p = 0.026). Exploratory subgroup analyses indicated a correlation of intrathecal inflammatory activity and CSF D-dimer levels.
Discussion: D-dimer in CSF can be reliably determined and correlates with markers of CNS inflammation and CSF fibrinogen levels. Adjusted for BBB dysfunction, CSF D-dimer may allow the identification of intrathecal coagulation cascade activation in patients with MS.
Classification of Evidence: This study provides Class I evidence that CSF D-dimer levels are elevated in patients with RRMS.
Background: Right ventricular (RV) dysfunction is frequently observed in patients with aortic stenosis (AS). Nevertheless, assessment of regional RV deformation is yet not performed. The aim of the study was to analyze the impact of moderate and severe AS on global and regional RV function by a multisegmental approach using tissue Doppler imaging (TDI).
Methods: In 50 patients (Group I – AS [n = 25] and Group II – normal controls [n = 25]), additional echocardiographic views of the RV were prospectively performed. The TDI sample volume was placed in the basal myocardial region of the anterior (RV-anterior), inferior (RV-inferior), and free RV wall (RV-free wall) to assess the following parameters: S'RV, E'RV, and A'RV waves; IVCTRV; IVRTRV; and myocardial performance index (MPIRV).
esults: In AS patients, left ventricular (LV) mass index, left atrial (LA) volume index, and LV end-diastolic pressure were significantly increased. Moreover, AS patients had higher systolic pulmonary artery pressure (sPAP) and lower values for PV AccT (P < 0.0001), but TAPSE was not different between the two groups (P = 0.062). In AS patients, IVRTRV-anterior, IVRTRV-inferior, and IVRTRV-freewall and MPIRV were statistically increased (P < 0.0001). A significant correlation between IVRTRV (evaluated at all three regions) and the parameters including sPAP, PV AccT, and ELV/e'LV ratio was observed in AS. A strong correlation was observed between IVRTRV-freewall/inferior and AS severity by evaluation of velocities, gradient, and aortic valve area (P < 0.0001).
Conclusions: The present study reports a correlation between the severity of AS and the increase of IVRTRV and MPIRV. Thus, a distinct analysis of RV performance is important for echocardiographic evaluation of patients with AS.
Background: Emergency ultrasound is gaining importance in medical education. Widespread teaching methods are frontal presentations and hands-on training. The primary goal of our study was to evaluate the impact of frontal presentations (PS) by analysis of retained knowledge rate (RKR) and learning load (LL).
Methods: Our study was conducted during four introductory courses in emergency ultrasound covering Extended Focused Assessment with Sonography for Trauma (E-FAST) and Focused Echocardiography Evaluation in Life Support (FEEL). Standardized PS (length of 10 to 50 min) were presented by experienced trainers, who were asked to provide keywords, key messages, and images and assign a score to each. Group 1 consisted of 11 medical students with no prior ultrasound experience, and group 2 consisted of 80 physicians. Each group was audience to seven to eight standard PS and requested to answer a free text questionnaire after 0 h, 2.5 h, 24 h, and 14 days.
Results: In group 1, 168/176 questionnaires were analyzed, and 161/202 were analyzed in group 2. RKR in group 1 was 32.5%, 15%, 16%, and 12% at 0 h, 2.5 h, 24 h, and 2 weeks. The physicians' RKR were 23%, 20.5%, and 22.4% after 0, 2.5, and 24 h of a respective PS. The LL was 1.6/min for students and 1.2/min for physicians. There was no difference in RKR when comparing PS with higher and lower LL for both groups; shorter or case-based PS were associated with a higher RKR (p < 0.01).
Conclusions: Our study provides evidence that only a limited amount of information can be processed at a time. Only 12% of knowledge is retained after 2 weeks. Presentations of short duration can increase the retained knowledge rate. Therefore, frontal presentations and classroom-based ultrasound training and teaching should be adapted.
Copeptin is the C-terminal end of pre-provasopressin released equimolar to vasopressin into circulation and recently discussed as promising cardiovascular biomarker amendatory to established markers such as troponins. Vasopressin is a cytokine synthesized in the hypothalamus. A direct release of copeptin from the heart into the circulation is implied by data from a rat model showing a cardiac origin in hearts put under cardiovascular wall stress. Therefore, evaluation of a potential release of copeptin from the human heart in acute myocardial infarction (AMI) has been done.
Anaphylactic shock is a severe allergic reaction involving multiple organs including the bronchial and cardiovascular system. Most anaphylactic mediators, like platelet-activating factor (PAF), histamine, and others, act through G protein – coupled receptors, which are linked to the heterotrimeric G proteins Gq /G 11 , G12/G13 , and Gi . The role of downstream signaling pathways activated by anaphylactic mediators in defi ned organs during anaphylactic reactions is largely unknown. Using genetic mouse models that allow for the conditional abrogation of G q /G 11 - and G 12 /G 13 -mediated signaling pathways by inducible Cre/loxP-mediated mutagenesis in endothelial cells (ECs), we show that Gq /G11 -mediated signaling in ECs is required for the opening of the endothelial barrier and the stimulation of nitric oxide formation by various infl ammatory mediators as well as by local anaphylaxis. The systemic effects of anaphylactic mediators like histamine and PAF, but not of bacterial lipopolysaccharide (LPS), are blunted in mice with endothelial G alpha q/G alpha 11 deficiency. Mice with endothelium-specific G alpha q /G alpha 11 deficiency, but not with G alpha 12/G alpha 13 deficiency, are protected against the fatal consequences of passive and active systemic anaphylaxis. This identifies endothelial Gq/G11 -mediated signaling as a critical mediator of fatal systemic anaphylaxis and, hence, as a potential new target to prevent or treat anaphylactic reactions.
Einleitung: Anastomoseninsuffizienzen sind schwerwiegende Komplikationen nach Kolonresektionen. Nur selten sind klinische oder laborchemische Zeichen Vorboten einer Insuffizienz. Material und Methoden: Wir haben unser Patientenkollektiv nach kolorektalen Resektionen retrospektiv untersucht in Hinblick auf einen Anstieg des C-rektiven Proteins (CRP) postoperativ als Zeichen einer Insuffizienz. Hierzu wurde der Unterschied vom präoperativen Messwert zum Messwert am 1. bis 7. postoperativen Tag berechnet. Bei Patienten mit Anastomoseninsuffizienz wurden die Werte nur bis zum Tag der Insuffizienz einbezogen, um einen Anstieg durch eine eventuelle Revision auszuklammern. Ergebnisse: Im Zeitraum von 8/2002 bis 8/2005 wurden bei 342 Patienten eine Kolonresektion durchgeführt. Im einzelnen waren dies 101 (29,5%) Sigmaresektionen, 89 (26,0%) Hemikolektomien rechts, 56 (16,4%) Rektumresektionen, 38 (11,1%) Ileocoecalresektionen, 24 (7,0%) Hemikolektomien links, 22 (6,4%) Segmentresektionen, 12 (3,5%) Kolektomien. Das Alter der Patienten lag bei 61,6 +/- 15,0 Jahren. Es wurden 142 (41,5%) Frauen und 200 (58,5%) Männer operiert, 301 (88%) Patienten elektiv und 41 (12%) als Notfall. Die Inzidenz von symptomatischen und asymptomatischen Anastomosen-insuffizienzen lag im Gesamtkollektiv bei 26/342 (7,6%), sie traten durchschnittlich 8,7 +/- 7,1 (1-27) Tage nach der Operation auf. Eine Analyse der CRP-Werte ergab bei den Patienten die im Verlauf eine Anastomoseninsuffizienz entwickelten signifikant höhere Anstiege von präoperativ bis zum 3. (+10,9 mg/dl versus +16,5 mg/dl, p=0,018), 5. (+4,2 mg/dl versus +13,1 mg/dl, p=0,002), 6. (+3,8 mg/dl versus +14,6 mg/dl, p=0,002), und 7. (+2,8 mg/dl versus +18,3 mg/dl, p<0,001) postoperativen Tag. Die Differenz zum 4. postoperativen Tag zeigte keinen signifikanten Unterschied (+6,5 mg/dl versus +11,2 mg/dl, p=0,3). Die absoluten Messwerte waren nicht signifikant unterschiedlich. Andere Laborparameter wie Leukozyten, Kreatinin, Albumin ergaben keinen Unterschied im Vergleich der beiden Gruppen.Die Untersuchung von Risikofaktoren für eine Anastomoseninsuffizienz konnte keinen signifikanten Unterschied zeigen für: Alter, Geschlecht, ASA, OP-Dauer, Zugang (offen oder laparoskopisch), benigne oder maligne Erkrankung, Kolon- oder Rektumresektion, elektive oder Notfalloperation. Schlussfolgerung: Der Verlauf des CRP ist ein signifikanter Marker für das Auftreten von Anastomoseninsuffizienzen nach kolorektalen Resektionen.
Background: Establishing a strong link early on between preclinical coursework and the clinical context is necessary for students to be able to recognize the practical relevance of the curriculum during their preclinical anatomical courses and to transfer knowledge more easily. Our objective was to enhance the clinical relevance of a preclinical anatomy course for second-year medical students of dentistry by implementing an interdisciplinary skills training course on "Palpation of the Head and Neck Muscles" and to measure the learning outcomes.
Methods: For the curricular development of the expanded course module, Kern’s 6-step approach was applied including subjective evaluation. We used a peer-teaching format supported by an e-learning application. A randomized control study measured effects of the two components (skills training, e-module) on learning outcomes. Four learning methods were compared: (1) lecture, (2) lecture + e-module, (3) lecture + skills training, (4) lecture + skills training + e-module. An objective structured clinical examination (OSCE) was used to measure and compare learning outcomes.
Results: The two-way variance analysis demonstrated that participation in the skills training had a statistically significant effect on the OSCE results (p = 0.0007). Students who participated in the skills training did better (φ 107.4 ± 14.4 points) than students who only attended the lecture (φ 88.8 ± 26.2 points). Students who used the e-module but did not attend the skills training earned a slightly but not significantly higher average number of points (φ 91.8 ± 31.3 points) than those who only attended the lecture. The learning outcomes of the skills training were again significantly increased when the training was combined with the e-module (φ 121.8 ± 21.8 points), thus making it the ideal method for achieving the learning objectives defined in this study.
Conclusions: The "Palpation of the Head and Neck Muscles" interdisciplinary skills training course linking basic anatomical knowledge and clinical skills led to clearly improved learning outcomes for both, anatomical knowledge and clinical skills. The additional use of an e-learning tool (e-module) improved the learning effect.
Purpose: We aim to describe the sonographic uterine anatomy after a cesarean section (CS), test the reproducibility of predefined measurements from the BSUM study, and report the distribution of these measurements. Methods: This is a descriptive observational study where 200 women with a history of only one CS were recruited 12–24 months postoperatively. A 5–13 MHz micro-convex transvaginal transducer was used for the acquisition of volumetric datasets for evaluating the CS scars. We defined 15 distinct measurements including the residual myometrial thickness (RMT). RMT ratio was calculated as a percentage of RMT to the assumed pre-cesarean anterior uterine wall thickness. A P value below 0.05 is utilized for significant statistical analysis. Results: Patients were included on average 18.5 months post-cesarean. The uterus was anteflexed in 82.5% and retroflexed in 17.5%. Myometrial defects at the site of CS manifest in two forms, either as a niche or as fibrosis. Patients are classified into four groups: those with isolated niches (45%), combined niches and fibrosis (38.5%), isolated fibrosis (11%), and lacking both (5%). The median RMT ratio for these groups was 63.09, 40.93, 59.84, and 100% with a standard deviation of 16.73, 12.95, 16.59, and 0, respectively. The interclass correlation coefficient (ICC) remained above 0.9 for all distinct measurements among these groups except for those of RMT, where ICC varied between 0.47 and 0.96. The RMT ratio shows a constant ICC at 0.94 regardless of the group. Conclusion: The post-cesarean uterus is often anteflexed, and a myometrial loss of about 50% is normally expected. The pattern of this loss is in the form of a predominantly sharp-edged and echogenic niche, fibrosis, or a combination of both. The proposed RMT ratio takes these changes into consideration and results in a reproducible quantification. We hypothesize that different adverse outcomes could be attributed to the different scar patterns.
Iron deficiency anemia (IDA) is associated with a number of pathological gastrointestinal conditions other than inflammatory bowel disease, and also with liver disorders. Different factors such as chronic bleeding, malabsorption and inflammation may contribute to IDA. Although patients with symptoms of anemia are frequently referred to gastroenterologists, the approach to diagnosis and selection of treatment as well as follow-up measures is not standardized and suboptimal. Iron deficiency, even without anemia, can substantially impact physical and cognitive function and reduce quality of life. Therefore, regular iron status assessment and awareness of the clinical consequences of impaired iron status are critical. While the range of options for treatment of IDA is increasing due to the availability of effective and well-tolerated parenteral iron preparations, a comprehensive overview of IDA and its therapy in patients with gastrointestinal conditions is currently lacking. Furthermore, definitions and assessment of iron status lack harmonization and there is a paucity of expert guidelines on this topic. This review summarizes current thinking concerning IDA as a common co-morbidity in specific gastrointestinal and liver disorders, and thus encourages a more unified treatment approach to anemia and iron deficiency, while offering gastroenterologists guidance on treatment options for IDA in everyday clinical practice.
Background: While systemic inflammation is recognized as playing a central role in the pathogenesis of organ failures in patients with liver cirrhosis, less is known about its relevance in the development of classical hepatic decompensation. Aim: To characterize the relationship between systemic inflammation, hemodynamics, and anemia with decompensation of liver cirrhosis. Methods: This is a post-hoc analysis of a cohort study of outpatients with advanced liver fibrosis or cirrhosis. Results: Analysis included 338 patients of whom 51 patients (15%) were hospitalized due to decompensation of liver cirrhosis during a median follow-up time of six months. In univariate analysis, active alcoholism (p = 0.002), model of end-stage liver disease (MELD) score (p = 0.00002), serum IL-6 concentration (p = 0.006), heart rate (p = 0.03), low arterial blood pressure (p < 0.05), maximal portal venous flow (p = 0.008), and low hemoglobin concentration (p < 0.00001) were associated with hospitalization during follow-up. Multivariate analysis revealed an independent association of low hemoglobin (OR = 0.62, 95% CI = 0.51–0.78, p = 0.001) and serum IL-6 concentration (OR = 1.02, 95% CI = 1.01–1.04, p = 0.03)—but not of hemodynamic parameters—with hepatic decompensation. An inverse correlation between hemoglobin concentration and portal venous flow (R = −0.362, p < 0.0001) was detected for the non-hospitalized patients. Accuracy of baseline hemoglobin levels for predicting hospitalization (AUC = 0.84, p < 0.000001) was high. Conclusion: Anemia and systemic inflammation, rather than arterial circulatory dysfunction, are strong and independent predictors of hepatic decompensation in outpatients with liver cirrhosis.
In der internationalen Norm DIN EN ISO 15189 (kurz ISO 15189) sind für medizinische Laboratorien besondere Anforderungen an die Qualität und Kompetenz festgelegt. Die ISO 15189 gilt für alle medizinischen Laboratorien. Sie wurde für den Bereich der Virologie durch eine gemeinsame Arbeitsgruppe der Gesellschaft für Virologie (GfV) und der Deutschen Vereinigung zur Bekämpfung der Viruskrankheiten (DVV) in Form von fachspezifischen Checklisten konkretisiert.
Viele medizinische Laboratorien lassen sich im Rahmen einer Akkreditierung bestätigen, dass sie die Anforderungen der ISO 15189 erfüllen. Wesentlicher Bestandteil der Akkreditierung ist eine Begutachtung in den Laboratorien. Die Begutachtungen in der Virologie werden von Experten durchgeführt, die von der GfV benannt werden.
Gründe der Laboratorien für eine Akkreditierung können sehr unterschiedlich sein. Sie reichen von der Verbesserung der internen Abläufe und Ermittlung sicherer/richtiger Untersuchungsergebnisse bis zu einer besseren Positionierung am Markt.
Der Artikel stellt die Anforderungen und Probleme virusdiagnostisch tätiger Laboratorien, basierend auf der ISO 15189, als Erfahrungsbericht vor. Dabei wird auf die Infektionsserologie, die molekularbiologische Diagnostik und die Virusisolierung auf Zellkulturen eingegangen.
ANGIOGENES : knowledge database for protein-coding and noncoding RNA genes in endothelial cells
(2016)
Increasing evidence indicates the presence of long noncoding RNAs (lncRNAs) is specific to various cell types. Although lncRNAs are speculated to be more numerous than protein-coding genes, the annotations of lncRNAs remain primitive due to the lack of well-structured schemes for their identification and description. Here, we introduce a new knowledge database “ANGIOGENES” (http://angiogenes.uni-frankfurt.de) to allow for in silico screening of protein-coding genes and lncRNAs expressed in various types of endothelial cells, which are present in all tissues. Using the latest annotations of protein-coding genes and lncRNAs, publicly-available RNA-seq data was analyzed to identify transcripts that are expressed in endothelial cells of human, mouse and zebrafish. The analyzed data were incorporated into ANGIOGENES to provide a one-stop-shop for transcriptomics data to facilitate further biological validation. ANGIOGENES is an intuitive and easy-to-use database to allow in silico screening of expressed, enriched and/or specific endothelial transcripts under various conditions. We anticipate that ANGIOGENES serves as a starting point for functional studies to elucidate the roles of protein-coding genes and lncRNAs in angiogenesis.
Since the introduction of radiological examination techniques, such as an angiographic computed tomography (ACT) and a computed tomographic angiography (CTA), the diagnosis and treatment planning for cerebral aneurysms became quicker and safer. Unfortunately, the state of development of these techniques, and their possible indications and benefits are still today restricted to specialized centers. The objective of this update was to analyze the current scientific evidence about their actual interventional and diagnostic use and identify the individual advantages of each through a literature review and personal experience-based data.
Die Bestimmung von ACE im Serum oder Heparinplasma stellt einen wesentlichen Bestandteil der Diagnostik, Verlaufskontrolle und Therapieüberwachung von benignen Lungenerkrankungen dar. ACE ist ein Marker, der bei Sarkoidose wertvolle Aussagen zur Diagnosefindung ermöglicht. Hier zeichnet er sich durch hohe Sensitivität und Spezifität aus.
Proline-rich tyrosine kinase 2 (PYK2) can be activated by angiotensin II (Ang II) and reactive oxygen species. We report that in endothelial cells, Ang II enhances the tyrosine phosphorylation of endothelial NO synthase (eNOS) in an AT1-, H2O2-, and PYK2-dependent manner. Low concentrations (1–100 µmol/liter) of H2O2 stimulated the phosphorylation of eNOS Tyr657 without affecting that of Ser1177, and attenuated basal and agonist-induced NO production. In isolated mouse aortae, 30 µmol/liter H2O2 induced phosphorylation of eNOS on Tyr657 and impaired acetylcholine-induced relaxation. Endothelial overexpression of a dominant-negative PYK2 mutant protected against H2O2-induced endothelial dysfunction. Correspondingly, carotid arteries from eNOS–/– mice overexpressing the nonphosphorylatable eNOS Y657F mutant were also protected against H2O2. In vivo, 3 wk of treatment with Ang II considerably increased levels of Tyr657-phosphorylated eNOS in the aortae of wild-type but not Nox2y/– mice, and this was again associated with a clear impairment in endothelium-dependent vasodilatation in the wild-type but not in the Nox2y/– mice. Collectively, endothelial PYK2 activation by Ang II and H2O2 causes the phosphorylation of eNOS on Tyr657, attenuating NO production and endothelium-dependent vasodilatation. This mechanism may contribute to the endothelial dysfunction observed in cardiovascular diseases associated with increased activity of the renin–angiotensin system and elevated redox stress.
Aims: Patients with cardiovascular comorbidities have a significantly increased risk for a critical course of COVID-19. As the SARS-CoV2 virus enters cells via the angiotensin-converting enzyme receptor II (ACE2), drugs which interact with the renin angiotensin aldosterone system (RAAS) were suspected to influence disease severity.
Methods and results: We analyzed 1946 consecutive patients with cardiovascular comorbidities or hypertension enrolled in one of the largest European COVID-19 registries, the Lean European Open Survey on SARS-CoV-2 (LEOSS) registry. Here, we show that angiotensin II receptor blocker intake is associated with decreased mortality in patients with COVID-19 [OR 0.75 (95% CI 0,59–0.96; p = 0.013)]. This effect was mainly driven by patients, who presented in an early phase of COVID-19 at baseline [OR 0,64 (95% CI 0,43–0,96; p = 0.029)]. Kaplan-Meier analysis revealed a significantly lower incidence of death in patients on an angiotensin receptor blocker (ARB) (n = 33/318;10,4%) compared to patients using an angiotensin-converting enzyme inhibitor (ACEi) (n = 60/348;17,2%) or patients who received neither an ACE-inhibitor nor an ARB at baseline in the uncomplicated phase (n = 90/466; 19,3%; p<0.034). Patients taking an ARB were significantly less frequently reaching the mortality predicting threshold for leukocytes (p<0.001), neutrophils (p = 0.002) and the inflammatory markers CRP (p = 0.021), procalcitonin (p = 0.001) and IL-6 (p = 0.049). ACE2 expression levels in human lung samples were not altered in patients taking RAAS modulators.
Conclusion: These data suggest a beneficial effect of ARBs on disease severity in patients with cardiovascular comorbidities and COVID-19, which is linked to dampened systemic inflammatory activity.
It is now accepted that heart failure (HF) is a complex multifunctional disease rather than simply a hemodynamic dysfunction. Despite its complexity, stressed cardiomyocytes often follow conserved patterns of structural remodelling in order to adapt, survive, and regenerate. When cardiac adaptations cannot cope with mechanical, ischemic, and metabolic loads efficiently or become chronically activated, as, for example, after infection, then the ongoing structural remodelling and dedifferentiation often lead to compromised pump function and patient death. It is, therefore, of major importance to understand key events in the progression from a compensatory left ventricular (LV) systolic dysfunction to a decompensatory LV systolic dysfunction and HF. To achieve this, various animal models in combination with an “omics” toolbox can be used. These approaches will ultimately lead to the identification of an arsenal of biomarkers and therapeutic targets which have the potential to shape the medicine of the future.
Abnormal venous atrial (VA) connections present a congenital heart disease (CHD) challenge for pediatric cardiologists. Fully anatomical evaluation is very difficult in prenatal and perinatal follow-up, but it has a profound impact on surgical correction and outcome. The echocardiogram is first-line imaging and represents the gold standard tool for simple abnormal VA connection. CT and MRI are mandatory for more complex heart disease and “nightmare cases”. 3D post-processing of volumetric CT and MRI acquisition helps to clarify anatomical relationships and allows for the creation of 3D printing models that can become crucial in customizing surgical strategy.
Introduction: This study reports about antenatal characteristics of Roma minority population. The study was designed to investigate data about health behaviours known to be associated with reproductive outcomes of Roma women that have very good living conditions and relatively high resource availability.
Methods: A retrospective study included 204 Roma and 408 non-Roma hospitalised singleton births that occurred in the Maternity Ward of the General Hospital Virovitica in the period from 1991 to 2010. Data about women’s age, marital status, smoking, reproductive health (abortions, delivery), antenatal care, perinatal complications and gestational age were taken from hospital records and analysed.
Results: Roma women were averagely more than three years younger than non-Roma women, only 10.8% were married. Smoking was more frequent. The average number of births of Roma and non-Roma women was similar, averagely two children per woman. The rate of induced abortions in the Roma women was higher, while the frequency of spontaneous abortions was equal. Inadequate antenatal care of Roma women was associated with two times higher incidence of perinatal complications. A higher frequency of deliveries at home without professional assistance in Roma pregnancy resulted in lower perinatal outcomes. It was confirmed that Roma mothers give birth earlier (38+6 vs. 39+4 weeks) and have a higher incidence of premature births (9.3% vs. 2.2%).
Conclusions: In the comparison of antenatal parameters between the two researched groups, poorer prenatal outcomes in the Roma population were found, despite full integration and considerable improvement in living standards of this ethnic Roma population.
Anti-angiogenesis in hepatocellular carcinoma treatment : current evidence and future perspectives
(2011)
Hepatocellular carcinoma (HCC) is among the most common cancer diseases worldwide. Arterial hypervascularisation is an essential step for HCC tumorigenesis and can be targeted by transarterial chemoembolization (TACE). This interventional method is the standard treatment for patients with intermediate stage HCC, but is also applied as “bridging” therapy for patients awaiting liver transplantation in many centers worldwide. Usually the devascularization effect induced by TACE is transient, consequently resulting in repeated cycles of TACE every 4-8 wk. Despite documented survival benefits, TACE can also induce the up-regulation of proangiogenic and growth factors, which might contribute to accelerated progression in patients with incomplete response. In 2007, sorafenib, a multi-tyrosine kinase and angiogenesis inhibitor, was approved as the first systemic treatment for advanced stage HCC. Other active targeted compounds, either inhibitors of angiogenesis and/or growth factors, are currently being investigated in numerous clinical trials. To overcome revascularisation or tumor progression under TACE treatment it seems therefore attractive to combine TACE with systemic targeted agents, which might theoretically block the effects of proangiogenic and growth factors. Over the last 12 mo, several retrospecretrospective or prospective cohort studies combining TACE and sorafenib have been published. Nevertheless, robust results of the efficacy and tolerability of such combination strategies as proven by randomized, controlled trials are awaited in the next two years.
Objective: ACPAs are associated with bone destruction in RA. The aim of this study was to evaluate the association between ACPA and bone destruction in patients with a distinct inflammatory disorder, PsA.
Methods: We used baseline data from a large observational study of PsA patients preparing to initiate treatment with adalimumab to analyse demographic and disease characteristics by ACPA status. To ensure a homogeneous PsA study population, only patients with active psoriatic skin manifestations who met Classification of Psoriatic Arthritis criteria for PsA were included in the analyses, thereby minimizing the risk of including misdiagnosed RA patients. Multiple logistic regression analyses were used to explore potential associations between ACPA seropositivity and bone destruction.
Results: Of 1996 PsA patients who met the strict inclusion criteria, 105 (5.3%) were positive for ACPA. ACPA-positive patients had significantly higher swollen joint counts and 28-joint DAS values than ACPA-negative patients and significantly higher rates of erosive changes and dactylitis. Multiple logistic regression analysis confirmed the association of ACPA seropositivity with a 2.8-fold increase in the risk of erosive disease.
Conclusion: As has been previously shown for RA, ACPA is associated with bone destruction in PsA, suggesting that the osteocatabolic effect of ACPA is not confined to RA but is also detectable in the different pathogenetic context of a distinct disease entity.
Trial registration: ClinicalTrials.gov, NCT01111240.
Background and Aims: In patients with Rat sarcoma proto-oncogene (RAS) wild-type metastatic colorectal cancer (mCRC), anti-epidermal growth factor receptor (EGFR) antibodies have been established in first- and further therapy lines. Due to limited treatment options upon disease progression, anti-EGFR re-exposure is increasingly employed in real-world oncology. The aim of this study was to assess clinical implementation and utility of anti-EGFR retreatment strategies in real-world mCRC patients. Methods: In this monocentric retrospective study, we included 524 patients with CRC and identified patients who received an anti-EGFR-based treatment as well as anti-EGFR rechallenge (progression on first-line anti-EGFR therapy) or reintroduction (discontinuation due to intolerance/toxicity/other). Results: In total, 143 patients received an anti-EGFR-based first- or second-line treatment, showing a similar overall survival (OS) compared to the non-anti-EGFR treatment group (38.3 vs. 39.6 months, p = 0.88). Thirty-three patients met the inclusion criteria for anti-EGFR re-exposure and were either assigned to rechallenge (n = 21) or reintroduction (n = 12) subgroups. The median FU after re-exposure was 45.8 months. Cetuximab and Panitumumab were used in 21 and 12 patients, respectively, and the main chemotherapy at re-exposure was FOLFIRI in 39.4%. Anti-EGFR re-exposure was associated with a distinct trend towards a better outcome (median OS 56.0 vs. 35.4 months, p = 0.06). In a subgroup comparison, reintroduction was associated with a higher OS and PFS in trend compared to the rechallenge (mOS 66 vs. 52.4, n.s., mPFS 7.33 vs. 3.68 months, n.s.). Conclusions: This retrospective study provides real-world evidence underscoring that anti-EGFR re-exposure strategies might benefit patients independently of the reason for prior discontinuation.
Background: Hepatitis delta frequently leads to liver cirrhosis and hepatic decompensation. As treatment options are limited, there is a need for biomarkers to determine disease activity and to predict the risk of disease progression. We hypothesized that anti-HDV IgM could represent such a marker.
Methods: Samples of 120 HDV-infected patients recruited in an international multicenter treatment trial (HIDIT-2) were studied. Anti-HDV IgM testing was performed using ETI-DELTA-IGMK-2-assay (DiaSorin). In addition, fifty cytokines, chemokines and angiogenetic factors were measured using multiplex technology (Bio-Plex System). A second independent cohort of 78 patients was studied for the development of liver-related clinical endpoints (decompensation, HCC, liver transplantation or death; median follow up of 3.0 years, range 0.6–12).
Results: Anti-HDV IgM serum levels were negative in 18 (15%), low (OD<0.5) in 76 (63%), and high in 26 (22%) patients of the HIDIT-2 cohort. Anti-HDV IgM were significantly associated with histological inflammatory (p<0.01) and biochemical disease activity (ALT, AST p<0.01). HDV replication was independent from anti-HDV IgM, however, low HBV-DNA levels were observed in groups with higher anti-HDV IgM levels (p<0.01). While high IP-10 (CXCL10) levels were seen in greater groups of anti-HDV IgM levels, various other antiviral cytokines were negatively associated with anti-HDV IgM. Associations between anti-HDV IgM and ALT, AST, HBV-DNA were confirmed in the independent cohort. Clinical endpoints occurred in 26 anti-HDV IgM positive patients (39%) but in only one anti-HDV IgM negative individual (9%; p = 0.05).
Conclusions: Serum anti-HDV IgM is a robust, easy-to-apply and relatively cheap marker to determine disease activity in hepatitis delta which has prognostic implications. High anti-HDV IgM levels may indicate an activated interferon system but exhausted antiviral immunity.
Exogenous adenosine and its metabolite inosine exert anti-inflammatory effects in synoviocytes of osteoarthritis (OA) and rheumatoid arthritis (RA) patients. We analyzed whether these cells are able to synthesize adenosine/inosine and which adenosine receptors (ARs) contribute to anti-inflammatory effects. The functionality of synthesizing enzymes and ARs was tested using agonists/antagonists. Both OA and RA cells expressed CD39 (converts ATP to AMP), CD73 (converts AMP to adenosine), ADA (converts adenosine to inosine), ENT1/2 (adenosine transporters), all AR subtypes (A1, A2A, A2B and A3) and synthesized predominantly adenosine. The CD73 inhibitor AMPCP significantly increased IL-6 and decreased IL-10 in both cell types, while TNF only increased in RA cells. The ADA inhibitor DAA significantly reduced IL-6 and induced IL-10 in both OA and RA cells. The A2AAR agonist CGS 21680 significantly inhibited IL-6 and induced TNF and IL-10 only in RA, while the A2BAR agonist BAY 60-6583 had the same effect in both OA and RA. Taken together, OA and RA synoviocytes express the complete enzymatic machinery to synthesize adenosine/inosine; however, mainly adenosine is responsible for the anti- (IL-6 and IL-10) or pro-inflammatory (TNF) effects mediated by A2A- and A2BAR. Stimulating CD39/CD73 with simultaneous ADA blockage in addition to TNF inhibition might represent a promising therapeutic strategy.
Combined diabetes-obesity syndromes severely impair regeneration of acute skin wounds in mouse models. This study assessed the contribution of subcutaneous adipose tissue to exacerbated wound inflammatory conditions. Genetically obese (ob/ob) mice showed an increased expression of positive transcriptional effectors of adipocyte differentiation such as Krüppel-like factor (KLF)-5 and peroxisome proliferator-activated receptor (PPAR)-γ and an associated expression of leptin and fatty acid-binding protein (FABP)-4, but also CXCL2 in isolated subcutaneous fat. This observation in obese mice is in keeping with differentially elevated levels of KLF-5, PPAR-γ, leptin, FABP-4 and CXCL2 in in vitro-differentiated 3T3-L1 adipocytes. Notably, CXCL2 expression restrictively appeared upon cytokine (IL-1β/TNF-α) stimulation only in mature, but not immature 3T3-L1 adipocytes. Of importance, the critical regulator of adipocyte maturation, PPAR-γ, was merely expressed in the final phase of in-vitro induced adipocyte differentiation from 3T3-L1 pre-adipocytes. Consistently, the PPAR-γ agonist rosiglitazone suppressed cytokine-induced CXCL2 release from mature adipocytes, but not from early 3T3-L1 adipocyte stages. The inhibitory effect of PPAR-γ activation on CXCL2 release appeared to be a general anti-inflammatory effect in mature adipocytes, as cytokine-induced cyclooxygenase (Cox)-2 was simultaneously repressed by rosiglitazone. In accordance with these findings, oral administration of rosiglitazone to wounded obese mice significantly changed subcutaneous adipocyte morphology, reduced wound CXCL2 and Cox-2 expression and improved tissue regeneration. Thus, our data suggest that PPAR-γ might provide a target to suppress inflammatory signals from mature adipocytes, which add to the prolonged wound inflammation observed in diabetes-obesity conditions.
Anti-inflammatory response of Vitamin D on extracranial vessels after subarachnoid hemorrhage
(2023)
Oral e-Poster Presentations - Booth 1: Vascular A (Aneurysms), September 25, 2023, 1:00 PM - 2:30 PM
Background: Vitamin D has been promoted to vascular regeneration in non-cerebral arteries because of its anti-inflammatory properties. Systematic inflammatory reaction as a multifactorial complication after subarachnoid hemorrhage (SAH), correlated with higher mortality and poor outcome, is the result of a multifactorial mechanism with vasoactive inflammation on extracranial vessels. We therefore hypothesized that vitamin D attenuates the systemic vascular inflammatory reaction.
Methods: We investigated the effect of vitamin D pretreatment (100 ng/kg/d; 5 days) in a blood injection SAH model in adult male C57BL6 mice. Vasomotor function (via wire myograph) of carotid and femoral artery and neurological deficits were measured. Different inflammatory factors such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM), were also tested.
Results: A significantly enhanced vasorelaxation was identified in Vitamin D pretreated mice (SAH-VitD versus SAH-control: p<0,001; n=10). Missing a relevant difference in vasocontraction of carotid and femoral artery comparing SAH mice with and without vitamin D treatment, there was a significantly higher endothelial related vasorelaxing effect in treated SAH mice (p<0,01, n=5). Neurological deficits in vitamin D pre-treated SAH mice were significantly decreased (p<0,05; n=10). All tested inflammatory factors were down-regulated in vitamin D pre-treated mice (SAH-VitD versus SAH-control: p<0,0001; n=10).
Conclusions: Extracranial vascular Inflammation after SAH, as one of the influencing components in the follow-up after SAH onset, was significantly attenuated by Vitamin D pretreatment. Furthermore, anti-inflammatory effect of vitamin D resulted in a decrease of extracranial vasoconstriction and neurological deficits. Further research should be focused on vitamin D to optimize therapeutic strategies for SAH patients in critical care units.
Diabetic retinopathy (DR) is an important cause of vision loss around the world, being the leading cause in the population between 20 and 60 years old. Among patients with DR, diabetic macular edema (DME) is the most frequent cause of vision impairment and represents a significant public health issue. Macular photocoagulation has been the standard treatment for this condition reducing the risk of moderate visual loss by approximately 50%. The role of vascular endothelial growth factor (VEGF) in DR and DME pathogenesis has been demonstrated in recent studies. This review addresses and summarizes data from the clinical trials that investigated anti-VEGF for the management of DME and evaluates their impact on clinical practice. The literature searches were conducted between August and October 2013 in PubMed and Cochrane Library with no date restrictions and went through the most relevant studies on pegaptanib, ranibizumab, bevacizumab, and aflibercept for the management of DME. The efficacy and safety of intravitreal anti-VEGF as therapy for DME have recently been proved by various clinical trials providing significantly positive visual and anatomical results. Regarding clinical practice, those outcomes have placed intravitreal injection of anti-VEGF as an option that must be considered for the treatment of DME.
Antiaging ist en vogue. Viele Menschen nutzen diesen Begriff, verstehen darunter jedoch ganz unterschiedliche Dinge. Das Spektrum reicht von Gymnastik für ältere Menschen bis hin zu Maßnahmen der plastischen Chirurgie im Sinne einer »Schönheitschirurgie «, von sinnvollen und richtigen Angeboten bis hin zu Dingen, deren Nähe zur Scharlatanerie aus Sicht der Schulmedizin nicht zu verkennen ist. Dieser Artikel soll einen Überblick geben über die Aspekte des Antiaging, die einer Betrachtung aus Sicht der wissenschaftlich orientierten Medizin zugänglich sind.
Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors predominate as first-line therapy options for renal cell carcinoma. When first-line TKI therapy fails due to resistance development, an optimal second-line therapy has not yet been established. The present investigation is directed towards comparing the anti-angiogenic properties of the TKIs, sorafenib and axitinib on human endothelial cells (HUVECs) with acquired resistance towards the TKI sunitinib. HUVECs were driven to resistance by continuously exposing them to sunitinib for six weeks. They were then switched to a 24 h or further six weeks treatment with sorafenib or axitinib. HUVEC growth, as well as angiogenesis (tube formation and scratch wound assay), were evaluated. Cell cycle proteins of the CDK-cyclin axis (CDK1 and 2, total and phosphorylated, cyclin A and B) and the mTOR pathway (AKT, total and phosphorylated) were also assessed. Axitinib (but not sorafenib) significantly suppressed growth of sunitinib-resistant HUVECs when they were exposed for six weeks. This axinitib-associated growth reduction was accompanied by a cell cycle block at the G0/G1-phase. Both axitinib and sorafenib reduced HUVEC tube length and prevented wound closure (sorafenib > axitinib) when applied to sunitinib-resistant HUVECs for six weeks. Protein analysis revealed diminished phosphorylation of CDK1, CDK2 and pAKT, accompanied by a suppression of cyclin A and B. Both drugs modulated CDK-cyclin and AKT-dependent signaling, associated either with both HUVEC growth and angiogenesis (axitinib) or angiogenesis alone (sorafenib). Axitinib and sorafenib may be equally applicable as second line treatment options, following sunitinib resistance.
Mobile genetic elements (MGEs), especially multidrug-resistance plasmids, are major vehicles for the dissemination of antimicrobial resistance determinants. Herein, we analyse the MGEs in three extensively drug-resistant (XDR) Klebsiella pneumoniae isolates from Germany. Whole genome sequencing (WGS) is performed using Illumina and MinION platforms followed by core-genome multi-locus sequence typing (MLST). The plasmid content is analysed by conjugation, S1-pulsed-field gel electrophoresis (S1-PFGE) and Southern blot experiments. The K. pneumoniae isolates belong to the international high-risk clone ST147 and form a cluster of closely related isolates. They harbour the blaOXA-181 carbapenemase on a ColKP3 plasmid, and 12 antibiotic resistance determinants on an multidrug-resistant (MDR) IncR plasmid with a recombinogenic nature and encoding a large number of insertion elements. The IncR plasmids within the three isolates share a high degree of homology, but present also genetic variations, such as inversion or deletion of genetic regions in close proximity to MGEs. In addition, six plasmids not harbouring any antibiotic resistance determinants are present in each isolate. Our study indicates that genetic variations can be observed within a cluster of closely related isolates, due to the dynamic nature of MGEs. The mobilome of the K. pneumoniae isolates combined with the emergence of the XDR ST147 high-risk clone have the potential to become a major challenge for global healthcare.
Bloodstream infections (BSI) are a severe complication of antineoplastic chemotherapy or hematopoietic stem cell transplantation (HSCT), especially in the presence of antibiotic resistance (AR). A multinational, multicenter retrospective study in patients aged ≤ 18 years, treated with chemotherapy or HSCT from 2015 to 2017 was implemented to analyze AR among non-common skin commensals BSI. Risk factors associated with AR, intensive care unit (ICU) admission and mortality were analyzed by multilevel mixed effects or standard logistic regressions. A total of 1291 BSIs with 1379 strains were reported in 1031 patients. Among Gram-negatives more than 20% were resistant to ceftazidime, cefepime, piperacillin-tazobactam and ciprofloxacin while 9% was resistant to meropenem. Methicillin-resistance was observed in 17% of S. aureus and vancomycin resistance in 40% of E. faecium. Previous exposure to antibiotics, especially to carbapenems, was significantly associated with resistant Gram-negative BSI while previous colonization with methicillin-resistant S. aureus was associated with BSI due to this pathogen. Hematological malignancies, neutropenia and Gram-negatives resistant to >3 antibiotics were significantly associated with higher risk of ICU admission. Underlying disease in relapse/progression, previous exposure to antibiotics, and need of ICU admission were significantly associated with mortality. Center-level variation showed a greater impact on AR, while patient-level variation had more effect on ICU admission and mortality. Previous exposure to antibiotics or colonization by resistant pathogens can be the cause of AR BSI. Resistant Gram-negatives are significantly associated with ICU admission and mortality, with a significant role for the treating center too. The significant evidence of center-level variations on AR, ICU admission and mortality, stress the need for careful local antibiotic stewardship and infection control programs.
Background: Antibody detection of SARS-CoV-2 requires an understanding of its variation, course, and duration.
Methods: Antibody response to SARS-CoV-2 was evaluated over 5–430 days on 828 samples across COVID-19 severity levels, for total antibody (TAb), IgG, IgA, IgM, neutralizing antibody (NAb), antibody avidity, and for receptor-binding-domain (RBD), spike (S), or nucleoprotein (N). Specificity was determined on 676 pre-pandemic samples.
Results: Sensitivity at 30–60 days post symptom onset (pso) for TAb-S/RBD, TAb-N, IgG-S, IgG-N, IgA-S, IgM-RBD, and NAb was 96.6%, 99.5%, 89.7%, 94.3%, 80.9%, 76.9% and 92.8%, respectively. Follow-up 430 days pso revealed: TAb-S/RBD increased slightly (100.0%); TAb-N decreased slightly (97.1%); IgG-S and IgA-S decreased moderately (81.4%, 65.7%); NAb remained positive (94.3%), slightly decreasing in activity after 300 days; there was correlation with IgG-S (Rs = 0.88) and IgA-S (Rs = 0.71); IgG-N decreased significantly from day 120 (15.7%); IgM-RBD dropped after 30–60 days (22.9%). High antibody avidity developed against S/RBD steadily with time in 94.3% of patients after 430 days. This correlated with persistent antibody detection depending on antibody-binding efficiency of the test design. Severe COVID-19 correlated with earlier and higher antibody response, mild COVID-19 was heterogeneous with a wide range of antibody reactivities. Specificity of the tests was ≥99%, except for IgA (96%).
Conclusion: Sensitivity of anti-SARS-CoV-2 assays was determined by test design, target antigen, antibody avidity, and COVID-19 severity. Sustained antibody detection was mainly determined by avidity progression for RBD and S. Testing by TAb and for S/RBD provided the highest sensitivity and longest detection duration of 14 months so far.
The capacity of convalescent and vaccine-elicited sera and monoclonal antibodies (mAb) to neutralize SARS-CoV-2 variants is currently of high relevance to assess the protection against infections. We performed a cell culture-based neutralization assay focusing on authentic SARS-CoV-2 variants B.1.617.1 (Kappa), B.1.617.2 (Delta), B.1.427/B.1.429 (Epsilon), all harboring the spike substitution L452R. We found that authentic SARS-CoV-2 variants harboring L452R had reduced susceptibility to convalescent and vaccine-elicited sera and mAbs. Compared to B.1, Kappa and Delta showed a reduced neutralization by convalescent sera by a factor of 8.00 and 5.33, respectively, which constitutes a 2-fold greater reduction when compared to Epsilon. BNT2b2 and mRNA1273 vaccine-elicited sera were less effective against Kappa, Delta, and Epsilon compared to B.1. No difference was observed between Kappa and Delta towards vaccine-elicited sera, whereas convalescent sera were 1.51-fold less effective against Delta, respectively. Both B.1.617 variants Kappa (+E484Q) and Delta (+T478K) were less susceptible to either casirivimab or imdevimab. In conclusion, in contrast to the parallel circulating Kappa variant, the neutralization efficiency of convalescent and vaccine-elicited sera against Delta was moderately reduced. Delta was resistant to imdevimab, which, however, might be circumvented by combination therapy with casirivimab together.
The human immunodeficiency virus (HIV) protease inhibitor saquinavir shows anticancer activity. Although its nitric oxide-modified derivative saquinavir-NO (saq-NO) was less toxic to normal cells, it exerted stronger inhibition of B16 melanoma growth in syngeneic C57BL/6 mice than saquinavir did. Saq-NO has been shown to block proliferation, upregulate p53 expression, and promote differentiation of C6 glioma and B16 cells. The anticancer activity of substances is frequently hampered by cancer cell chemoresistance mechanisms. Therefore, we here investigated the roles of p53 and the ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein 1 (BCRP1) in cancer cell sensitivity to saq-NO to get more information about the potential of saq-NO as anticancer drug. Saq-NO exerted anticancer effects in lower concentrations than saquinavir in a panel of human cancer cell lines. Neither p53 mutation or depletion nor expression of P-gp, MRP1, or BCRP1 affected anticancer activity of saq-NO or saquinavir. Moreover, saq-NO sensitized P-gp-, MRP1-, or BCRP1-expressing cancer cells to chemotherapy. Saq-NO induced enhanced sensitization of P-gp- or MRP1-expressing cancer cells to chemotherapy compared with saquinavir, whereas both substances similarly sensitized BCRP1-expressing cells. Washout kinetics and ABC transporter ATPase activities demonstrated that saq-NO is a substrate of P-gp as well as of MRP1. These data support the further investigation of saq-NO as an anticancer drug, especially in multidrug-resistant tumors.
Objectives The aims of our study were to examine the anticholinergic drug use and to assess the association between anticholinergic burden and cognitive function in the multimorbid elderly patients of the MultiCare cohort.
Setting MultiCare was conducted as a longitudinal cohort study in primary care, located in eight different study centres in Germany.
Participants 3189 patients (59.3% female).
Primary and secondary outcome measures Baseline data were used for the following analyses. Drugs were classified according to the well-established anticholinergic drug scale (ADS) and the recently published German anticholinergic burden (German ACB). Cognitive function was measured using a letter digit substitution test (LDST) and a mixed-effect multivariate linear regression was performed to calculate the influence of anticholinergic burden on the cognitive function.
Results Patients used 1764 anticholinergic drugs according to ADS and 2750 anticholinergics according to the German ACB score (prevalence 38.4% and 53.7%, respectively). The mean ADS score was 0.8 (±1.3), and the mean German ACB score was 1.2 (±1.6) per patient. The most common ADS anticholinergic was furosemide (5.8%) and the most common ACB anticholinergic was metformin (13.7%). The majority of the identified anticholinergics were drugs with low anticholinergic potential: 80.2% (ADS) and 73.4% (ACB), respectively. An increasing ADS and German ACB score was associated with reduced cognitive function according to the LDST (−0.26; p=0.008 and −0.24; p=0.003, respectively).
Conclusion Multimorbid elderly patients are in a high risk for using anticholinergic drugs according to ADS and German ACB score. We especially need to gain greater awareness for the contribution of drugs with low anticholinergic potential from the cardiovascular system. As anticholinergic drug use is associated with reduced cognitive function in multimorbid elderly patients, the importance of rational prescribing and also deprescribing needs to be further evaluated.
Trial registration number ISRCTN89818205.