Förderzeitraum 2018
Refine
Has Fulltext
- yes (127)
Is part of the Bibliography
- yes (127)
Document Type
- Journal article (127)
Language
- English (127)
Keywords
- ADHD (4)
- obesity (4)
- Positronen-Emissions-Tomografie (3)
- inflammation (3)
- physical activity (3)
- psychology (3)
- Drosophila melanogaster (2)
- Neisseria meningitidis (2)
- PET (2)
- RNA-seq (2)
- T cells (2)
- apoptosis (2)
- biokinetics (2)
- biological models (2)
- breast cancer (2)
- cardiac surgery (2)
- chemokines (2)
- classification (2)
- dosimetry (2)
- honeybee (2)
- load management (2)
- mRNA (2)
- machine learning (2)
- mouse model (2)
- muscle degeneration (2)
- optogenetics (2)
- pathogens (2)
- periprosthetic infection (2)
- stroke (2)
- two-stage exchange (2)
- 11C-HED (1)
- 11C-Hydroxyephedrine (1)
- 16S metabarcoding (1)
- 18F-LMI1195 (1)
- 3D modeling (1)
- 53BP1 (1)
- AKI (1)
- APC (1)
- Adipositas (1)
- Ahmed (1)
- Alemtuzumab (1)
- Alzheimer’s disease (1)
- American foulbrood (1)
- Apis mellifera (1)
- Aspergillus fumigatus (1)
- B cells (1)
- BRAF (1)
- Baerveldt (1)
- C5aR1 (1)
- CAGSSS (1)
- CCL4 (1)
- CD28 costimulation (1)
- CD4\(^{+}\) T helper cells (1)
- CD52 (1)
- CNG channel (1)
- CNS (1)
- COMT (1)
- Caenorhabditis elegans (1)
- Coffin-Lowry syndrome (1)
- Concealed Information Test (1)
- Copal\(^®\) spacem (1)
- DFNB68 (1)
- DFT-LDA (1)
- DNA Breaks (1)
- DNA damage (1)
- DNA transcription (1)
- DecaWave (1)
- Dmrt1bY (1)
- Drosophila melanogaster motoneuron (1)
- Drosophila model (1)
- EAE (1)
- ECG (1)
- Egypt (1)
- Epichloë (1)
- European foulbrood (1)
- F-actin (1)
- Fagus sylvatica (1)
- German healthcare system (1)
- Guinier-Preston zones (1)
- Hfq (1)
- IARS2 (1)
- IoT (1)
- KDIGO (1)
- Kirchhoff's law (1)
- Latimeria menadoensis (1)
- Lolium perenne (1)
- MIP-1β (1)
- MRI (1)
- MS (1)
- Malvaviscus arboreus (1)
- Medicago truncatula (1)
- NAFLD (1)
- NASH (1)
- NK cells (1)
- Omega-3-Fettsäuren (1)
- OncotypeDX\(^{®}\) (1)
- PABPs (1)
- PAI-1 (1)
- PALS (1)
- PEST (1)
- PKCζ, (1)
- PMMA bone cement (1)
- PRRT (1)
- Paenibacterin (1)
- ProQ (1)
- Protopterus annectens (1)
- RCT (1)
- RGB-D (1)
- RNase E (1)
- RSK2 (1)
- Ra-224 (1)
- Rhodobacter sphaeroides (1)
- S1PR2 (1)
- SLC2A3 (1)
- SNP-microarray (1)
- SWOT (1)
- Sox5 (1)
- Synovial Fluid Aspiration (1)
- T helper 1 cells (1)
- T-lymphocytes (1)
- T. brucei (1)
- TK6 cells (1)
- TRDV2 (1)
- TRGV9 (1)
- Trypanosoma (1)
- UAV (1)
- UV/Vis spectroscopy (1)
- UWB (1)
- Ureaplasma species (1)
- V800 (1)
- Vγ9Vδ2 (1)
- Xenopus laevis oocytes (1)
- ZDF rats (1)
- Zika virus (1)
- \(^{177}\)Lu-OPS201 (1)
- \(^{18}\)F-FDG (1)
- \(^{18}\)F-fluorodeoxyglucose (1)
- \(^{99m}\)Tc-MAG3 (1)
- ab initio calculations (1)
- abdominal surgery (1)
- absorbed dose (1)
- absorbed dose to the blood (1)
- action potentials (1)
- activity rhythms (1)
- activity tracker (1)
- acute kidney injury (1)
- adaptive role (1)
- adolescents (1)
- adrenal insufficiency (1)
- aerobic fitness (1)
- ageing (1)
- alcohol (1)
- alpha particles (1)
- altruism (1)
- altruistic compensation (1)
- altruistic punishment (1)
- aluminum copper alloys (1)
- amino acid analysis (1)
- anaphylatoxins (1)
- aneurysm (1)
- anger (1)
- animal behaviour (1)
- anti-microbial activit (1)
- anticoagulants (1)
- antigenic recall (1)
- antioxidants (1)
- anuria (1)
- arterial hypotension (1)
- aspergillosis (1)
- athletes (1)
- atrial fibrillation (1)
- attention bias (1)
- attention-deficit/hyperactivity disorder (1)
- atypical chemokine receptor 3 (1)
- autosomal recessive non-synstromic hearing loss (1)
- axonal degeneration (1)
- bPAC (1)
- bacteria (1)
- bacterial genomics (1)
- bacterial pathogen (1)
- bacterial transcription (1)
- bariatric surgery (1)
- bee disease (1)
- beech forests (1)
- bees (1)
- behavior (1)
- behavioral conditioning (1)
- behavioral transition (1)
- behaviour therapy (1)
- bile (1)
- bioassays (1)
- biodegradable implant (1)
- biodiversity (1)
- biodiversity estimation (1)
- biofeedback (1)
- biological dosimetry (1)
- biomedical materials (1)
- bird diversity (1)
- black woodpecker (1)
- bladder (1)
- blood (1)
- body composition (1)
- bone morphogenetic protein (1)
- brain stimulation (1)
- butyrophilin 3 (1)
- cAMP (1)
- caffeine (1)
- calcium (1)
- cancer (1)
- cancer risk (1)
- capecitabine (1)
- carabid beetles (1)
- cardiac device therapy (1)
- cardiac sympathetic nervous system (1)
- cardiopulmonary bypass (1)
- careers (1)
- carmine (1)
- cataracts (1)
- catheterization (1)
- catheters (1)
- ceftriaxone (1)
- cell membranes (1)
- cell wall synthesis (1)
- cellular stress responses (1)
- cellular waveform (1)
- ceramides (1)
- chemical ecology (1)
- chemotherapy (1)
- children/adults (1)
- chlamydomonas reinhardtii (1)
- chlamyopsin (1)
- chromatin (1)
- cicatricial pemphigoid (1)
- cirrhosis (1)
- coaptation line (1)
- coevolution (1)
- cognition (1)
- cognitive balance (1)
- cognitive dissonance (1)
- collagen-glycosaminoglycane matrix (CGM) (1)
- colon cancer (1)
- coloration (1)
- comparison (1)
- complement system (1)
- compressive strength (1)
- concealed information test (1)
- conditioned response (1)
- conjunctival defect (1)
- conjunctival hole (1)
- conjunctival repair (1)
- copy number variation (1)
- crop diversity (1)
- cross-talk (1)
- cryptochrome (1)
- crystal structure (1)
- cylic GMP (1)
- cytokine secretion (1)
- cytotoxic T cells (1)
- data mining (1)
- deception (1)
- delayed cerebral infarction (1)
- depolarization (1)
- diabetes (1)
- diabetes mellitus (1)
- diabetic cardiomyopathy (1)
- diagnosis (1)
- diet (1)
- dietary approaches to stop hypertension (1)
- differentiation (1)
- direct anterior approach (1)
- dispersal (1)
- distal radio-ulnar joint (1)
- distance measurement (1)
- dogs (1)
- dorsal instrumentation (1)
- double-stranded (1)
- drainage tube (1)
- drug regulation (1)
- drug-induced immune hemolytic anemia (1)
- dry lung syndrome (1)
- dynamic (1)
- eHealth (1)
- ecosystem services (1)
- electrical and electronic engineering (1)
- electrometer (1)
- elution (1)
- emotion regulation (1)
- endometriosis (1)
- endophytic fungi (1)
- endovascular repair (1)
- epidural block (1)
- episcleral drainage device (1)
- evaluation (1)
- evolution (1)
- exaptation (1)
- expression (1)
- extended Kalman filter (1)
- extremity trauma (1)
- eye tracking (1)
- failure (1)
- fear conditioning (1)
- feral honey bees (1)
- fibroblast growth factor (1)
- field testing (1)
- fitness (1)
- flagellate (1)
- flame test (1)
- flupyradifurone (1)
- foliar fungal community (1)
- foraging (1)
- forensic sample (1)
- fracture (1)
- fracture-associated vascular damage (1)
- free energy (1)
- functional regurgitation (1)
- functional training (1)
- fungus-plant interaction (1)
- gametogenesis (1)
- gamma rays (1)
- gender gap (1)
- gene expression (1)
- genome annotation (1)
- genotyping arrays (1)
- glaucoma drainage device (1)
- glioblastoma multiforme (1)
- glucose (1)
- glucose transporter (1)
- ground dwelling predators (1)
- groundwater (1)
- group change (1)
- growth hormone deficiency (1)
- growth pattern (1)
- guanylyl cyclase-A (1)
- gut–liver axis (1)
- haematopoietic stem cells (1)
- halothane (1)
- health promotion (1)
- healthy volunteers (1)
- heart failure (1)
- helminths (1)
- heme oxygenase-1 (1)
- hemolysis (1)
- hemorrhagic stroke (1)
- hepatitis C virus (1)
- hereditary hearing loss (1)
- high performance liquid chromatography (1)
- high-intensity interval training (1)
- hip (1)
- histones (1)
- history (1)
- hollow tree (1)
- honey bees (1)
- hub genes (1)
- human (1)
- human behaviour (1)
- human body weight (1)
- human brain microvascular endothelial cells (1)
- human learning (1)
- humans (1)
- hybrid pacemaker (1)
- hypertension (1)
- identity integration (1)
- illumina (1)
- image processing (1)
- immune cells (1)
- immune evasion (1)
- in vitro contracture test (1)
- inactivity (1)
- individualised modular treatment programme (1)
- individualized training (1)
- induced pluripotent stem cells (1)
- infection (1)
- infinium HumanOmni1-Quad (1)
- information technology (1)
- injury prevention (1)
- inmates (1)
- insect vision (1)
- insulin (1)
- insulin receptor (1)
- insulin-like growth factor 1 receptor (1)
- integrated optics (1)
- inter-rater reliability (1)
- intergroup bias (1)
- internet of things (1)
- intervention (1)
- intestine (1)
- invasive disease (1)
- inventory (1)
- inverse parameterization (1)
- ionizing radiation (1)
- ischemia-reperfusion injury (1)
- ischemic (1)
- ischemic stroke (1)
- joint aspiration (1)
- ketogenic diet (1)
- ketone bodies (1)
- kinect (1)
- knee (1)
- knee arthroplasty (1)
- laminin 332 (1)
- land use (1)
- landscape heterogeneity (1)
- laparoscopic right colectomy (1)
- leaf width (1)
- leaflet (1)
- learning (1)
- leukocytes (1)
- level of evidence: IV (1)
- levosimendan (1)
- lifetime spectroscopy (1)
- lipochitinoligosaccharides (1)
- liponeurocytoma (1)
- liver diseases (1)
- low-cost spectrometer (1)
- lying (1)
- lymph nodes (1)
- mHealth (1)
- magnesium (1)
- major depression (1)
- malignant hyperthermia (1)
- mass casualties (1)
- master sex-determining gene (1)
- medaka (1)
- medicinal plants (1)
- medicine (1)
- medicine authentication tools (1)
- medulloblastoma (1)
- melanoma (1)
- membrane potential (1)
- membrane proteins (1)
- meningitis (1)
- mental disorders (1)
- metabolic profile (1)
- metabolomics (1)
- micro-ionization chambers (1)
- microbot (1)
- microdialysis (1)
- microenvironment (1)
- micronuclei (1)
- microswimmer (1)
- minimal invasive surgery (1)
- minimally invasive (1)
- mitochondria (1)
- mitral valve (1)
- mixed hearing loss (1)
- mobile apps (1)
- module (1)
- molecular biology (1)
- molecular docking (1)
- molecular dynamics (1)
- molecular signature (1)
- mood induction (1)
- mouse (1)
- mucous membrane pemphigoid (1)
- multigene-array (1)
- multiplicity of infection (1)
- muscle (1)
- mycobacteria (1)
- myocardial sympathetic innervation imaging (1)
- nanowires (1)
- natriuretic peptides (1)
- navigation (1)
- neonatal renal failure (1)
- neural circuits (1)
- neural stem cells (1)
- neurocytoma (1)
- neuroendocrine tumor (1)
- neuroendocrine tumors (1)
- neuroinflammation (1)
- neuronal dysfunction (1)
- neuroprotection (1)
- neutral sphingomyelinase 2 (1)
- neutrophils (1)
- nine-banded armadillo (1)
- non-responder (1)
- noncoding RNA (1)
- nuclear envelope (1)
- nuclear export (1)
- nutrients (1)
- objective assessment (1)
- oesophagogastroduodenoscopy (1)
- olfaction (1)
- oligohydramnios sequence (1)
- ologen implant (1)
- omega-3 fatty acids (1)
- optimal control problem (1)
- oral anticancer drugs (1)
- ovary (1)
- parasite (1)
- pathogen vector (1)
- patient-doctor-relationship (1)
- pediatric patients (1)
- peer review (1)
- pelvic trauma (1)
- penumbra (1)
- peptide receptor radionuclide therapy (1)
- perception (1)
- periodization (1)
- peripheral nervous system (1)
- personalized treatment (1)
- pesticide (1)
- phaeochromocytoma (1)
- pharmacology (1)
- phenols (1)
- photoreceptor (1)
- phototransduction (1)
- phototrophic growth (1)
- phylogenomics (1)
- phytochemicals (1)
- pigment pattern (1)
- pigs (1)
- pilot-point-approach (1)
- placental mammals (1)
- plasmonics (1)
- polarity (1)
- policy (1)
- politics (1)
- polity (1)
- pollen (1)
- pose estimation (1)
- positron (1)
- positron annihilation lifetime spectroscopy (1)
- positron emission tomography (1)
- posttranscriptional control (1)
- potassium (1)
- potter sequence (1)
- power training (1)
- precipitates (1)
- precision medicine (1)
- prejudice (1)
- preterm (1)
- proliferation (1)
- prospective study (1)
- protein and mRNA expression (1)
- proteins (1)
- proteolipid protein (1)
- psychologists (1)
- psychometrics (1)
- pulse simulation (1)
- quality assurance (1)
- quality evaluation (1)
- quality indicators (1)
- quantitative analysis (1)
- radiation effects (1)
- radiotherapy (1)
- radium (1)
- rat hippocampal neurons (1)
- reaction time (1)
- reaction times (1)
- recategorization (1)
- rectum (1)
- recurrence (1)
- regenerative medicine (1)
- regression analysis (1)
- relative dosimetry (1)
- renal tubular dysgenesis (1)
- rescue mission (1)
- respiratory distress (1)
- revision (1)
- risk assessment (1)
- rotator cuff (1)
- sampling method (1)
- scapula (1)
- scatter radiation (1)
- scientists (1)
- seahorse (1)
- sedentary lifestyle (1)
- segmentation (1)
- senescence (1)
- sensitivity analysis (1)
- sensor fusion (1)
- sensorineural hearing loss (1)
- sensory cues (1)
- sensory neuropathy (1)
- sepsis (1)
- sex chromosomes (1)
- sex differentiation (1)
- sexual conflict (1)
- sexually antagonistic genes (1)
- signal integration (1)
- signal processing (1)
- signal transduction (1)
- simulation (1)
- skeletal dysplasia (1)
- skeletal muscle (1)
- skin conduction response (1)
- smartwatch (1)
- social bees (1)
- social identification (1)
- somatostatin receptor (1)
- spacer (1)
- species richness (1)
- spectral sensitivity (1)
- spectroscopy (1)
- spiders (1)
- spine trauma (1)
- staphylinid beetles (1)
- steady-state dendritic cells (1)
- stereotactic irradiation (1)
- storage vesicle turnover (1)
- streptozotocin (1)
- structure-activity relationship (1)
- students (1)
- subarachnoid hemorrhage (1)
- substandard and falsified medicines (1)
- supervisors (1)
- support vector machines (1)
- surgical and invasive medical procedures (1)
- surgical trauma room (1)
- sustainability (1)
- swarming (1)
- sweat osmolality (1)
- sweat secretion rate (1)
- symbiosis (1)
- sympathetic nervous system (1)
- synaptic vesicles (1)
- tDCS (1)
- taste (1)
- teleost fish (1)
- telephone-assisted self-help (1)
- tenting (1)
- teriflunomide (1)
- terror attack (1)
- testis (1)
- the microtubule-organizing center (1)
- theranostics (1)
- therapeutic approach (1)
- therapy (1)
- thermal camera (1)
- thermal stresses (1)
- thermoregulation (1)
- three-dimensional echocardiography (1)
- tikhonov regularization (1)
- tissue engineering (1)
- tolerogenic dendritic cells (1)
- total hip arthroplasty (1)
- toxicology (1)
- track and trace (1)
- training curriculum (1)
- transcriptional profiling (1)
- transcriptional rewiring (1)
- transcriptional termination (1)
- transcriptomics (1)
- transgluteal approach (1)
- translational research (1)
- tree cavity (1)
- trypanobot (1)
- trypanosoma (1)
- trypanosomes (1)
- tsetse (1)
- tumor (1)
- two-component system (1)
- type II esophageal achalasia (1)
- uPA (1)
- ulnar-shortening osteotomy (1)
- ultrasound strain elastography (1)
- urinary tract infections (1)
- vasopressin (1)
- ventromedial prefrontal cortex (1)
- virtual isocenter (1)
- virtual reality (1)
- viruses (1)
- visual pigments (1)
- vitamin D (1)
- volvox carteri (1)
- wearable (1)
- web-based apps (1)
- weighted gene co-expression network (1)
- whole exome sequencing (1)
- whole-blood model (1)
- wild honey bees (1)
- work capacity evaluation (1)
- workplace (1)
- xenobiotic metabolism (1)
- α-emitter (1)
- β-Hydroxybutyrate (1)
- β-cells (1)
- γ-H2AX (1)
Institute
- Theodor-Boveri-Institut für Biowissenschaften (29)
- Klinik und Poliklinik für Nuklearmedizin (8)
- Institut für Psychologie (7)
- Julius-von-Sachs-Institut für Biowissenschaften (6)
- Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I) (6)
- Klinik und Poliklinik für Unfall-, Hand-, Plastische und Wiederherstellungschirurgie (Chirurgische Klinik II) (6)
- Medizinische Klinik und Poliklinik II (6)
- Neurologische Klinik und Poliklinik (6)
- Institut für Sportwissenschaft (5)
- Institut für Virologie und Immunbiologie (5)
Sonstige beteiligte Institutionen
Malvaviscus arboreus Cav. is a medicinal plant belonging to family Malvaceae with both ethnomedical and culinary value; however, its phytochemical and biological profiles have been scarcely studied. Accordingly, this work was designed to explore the chemical composition and the hepatoprotective potential of M. arboreus against carbon tetrachloride (CCl\(_4\))-induced hepatotoxicity. The total extract of the aerial parts and its derived fractions (petroleum ether, dichloromethane, ethyl acetate, and aqueous) were orally administered to rats for six consecutive days, followed by injection of CCl\(_4\) (1:1 v/v, in olive oil, 1.5 ml/kg, i.p.) on the next day. Results showed that the ethyl acetate and dichloromethane fractions significantly alleviated liver injury in rats as indicated by the reduced levels of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), total bilirubin (TB), and malondialdehyde (MDA), along with enhancement of the total antioxidant capacities of their livers, with the maximum effects were recorded by the ethyl acetate fraction. Moreover, the protective actions of both fractions were comparable to those of silymarin (100 mg/kg), and have been also substantiated by histopathological evaluations. On the other hand, liquid chromatography-high resolution electrospray ionization mass spectrometry (LC‒HR‒ESI‒MS) metabolomic profiling of the crude extract of M. arboreus aerial parts showed the presence of a variety of phytochemicals, mostly phenolics, whereas the detailed chemical analysis of the most active fraction (i.e. ethyl acetate) resulted in the isolation and identification of six compounds for the first time in the genus, comprising four phenolic acids; β-resorcylic, caffeic, protocatechuic, and 4-hydroxyphenylacetic acids, in addition to two flavonoids; trifolin and astragalin. Such phenolic principles, together with their probable synergistic antioxidant and liver-protecting properties, seem to contribute to the observed hepatoprotective potential of M. arboreus.
Although many genes have been identified using high throughput technologies in endometriosis (ES), only a small number of individual genes have been analyzed functionally. This is due to the complexity of the disease that has different stages and is affected by various genetic and environmental factors. Many genes are upregulated or downregulated at each stage of the disease, thus making it difficult to identify key genes. In addition, little is known about the differences between the different stages of the disease. We assumed that the study of the identified genes in ES at a system-level can help to better understand the molecular mechanism of the disease at different stages of the development. We used publicly available microarray data containing archived endometrial samples from women with minimal/mild endometriosis (MMES), mild/severe endometriosis (MSES) and without endometriosis. Using weighted gene co-expression analysis (WGCNA), functional modules were derived from normal endometrium (NEM) as the reference sample. Subsequently, we tested whether the topology or connectivity pattern of the modules was preserved in MMES and/or MSES. Common and specific hub genes were identified in non-preserved modules. Accordingly, hub genes were detected in the non-preserved modules at each stage. We identified sixteen co-expression modules. Of the 16 modules, nine were non-preserved in both MMES and MSES whereas five were preserved in NEM, MMES, and MSES. Importantly, two non-preserved modules were found in either MMES or MSES, highlighting differences between the two stages of the disease. Analyzing the hub genes in the non-preserved modules showed that they mostly lost or gained their centrality in NEM after developing the disease into MMES and MSES. The same scenario was observed, when the severeness of the disease switched from MMES to MSES. Interestingly, the expression analysis of the new selected gene candidates including CC2D2A, AEBP1, HOXB6, IER3, and STX18 as well as IGF-1, CYP11A1 and MMP-2 could validate such shifts between different stages. The overrepresented gene ontology (GO) terms were enriched in specific modules, such as genetic disposition, estrogen dependence, progesterone resistance and inflammation, which are known as endometriosis hallmarks. Some modules uncovered novel co-expressed gene clusters that were not previously discovered.
The number of bariatric surgeries being performed worldwide has markedly risen. While the improvement in obesity-associated comorbidities after bariatric surgery is well-established, very little is known about its impact on cancer risk. The peripheral lymphocyte micronucleus test is a widely used method for the monitoring of chromosomal damage levels in vivo, and micronucleus frequency positively correlates with cancer risk. Therefore, the aim of this study was to compare the micronucleus frequency before and after bariatric surgery in obese subjects. Peripheral blood mononuclear cells were collected from 45 obese subjects before and at two time-points after bariatric surgery (6 and 12 months) to assess spontaneous micronucleus frequency. Consistent with the increased cancer risk previously shown, bariatric surgery-induced weight loss led to a significant reduction in lymphocyte micronucleus frequency after 12 months. Interestingly, comorbidities such as type 2 diabetes mellitus and metabolic syndrome further seemed to have an impact on the lymphocyte micronucleus frequency. Our findings may indicate a successful reduction of cancer risk in patients following weight loss caused by bariatric surgery.
Background:
Ketogenic diets (KDs) or short-term fasting are popular trends amongst supportive approaches for cancer patients. Beta-hydroxybutyrate (3-OHB) is the main physiological ketone body, whose concentration can reach plasma levels of 2–6 mM during KDs or fasting. The impact of 3-OHB on the biology of tumor cells described so far is contradictory. Therefore, we investigated the effect of a physiological concentration of 3 mM 3-OHB on metabolism, proliferation, and viability of breast cancer (BC) cells in vitro.
Methods:
Seven different human BC cell lines (BT20, BT474, HBL100, MCF-7, MDA-MB 231, MDA-MB 468, and T47D) were cultured in medium with 5 mM glucose in the presence of 3 mM 3-OHB at mild hypoxia (5% oxygen) or normoxia (21% oxygen). Metabolic profiling was performed by quantification of the turnover of glucose, lactate, and 3-OHB and by Seahorse metabolic flux analysis. Expression of key enzymes of ketolysis as well as the main monocarboxylic acid transporter MCT2 and the glucose-transporter GLUT1 was analyzed by RT-qPCR and Western blotting. The effect of 3-OHB on short- and long-term cell proliferation as well as chemo- and radiosensitivity were also analyzed.
Results:
3-OHB significantly changed the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in BT20 cells resulting in a more oxidative energetic phenotype. MCF-7 and MDA-MB 468 cells had increased ECAR only in response to 3-OHB, while the other three cell types remained uninfluenced. All cells expressed MCT2 and GLUT1, thus being able to uptake the metabolites. The consumption of 3-OHB was not strongly linked to mRNA overexpression of key enzymes of ketolysis and did not correlate with lactate production and glucose consumption. Neither 3-OHB nor acetoacetate did interfere with proliferation. Further, 3-OHB incubation did not modify the response of the tested BC cell lines to chemotherapy or radiation.
Conclusions:
We found that a physiological level of 3-OHB can change the energetic profile of some BC cell lines. However, 3-OHB failed to influence different biologic processes in these cells, e.g., cell proliferation and the response to common breast cancer chemotherapy and radiotherapy. Thus, we have no evidence that 3-OHB generally influences the biology of breast cancer cells in vitro.
Obese children and adolescents are at high risk of developing cardiovascular diseases later in life. We hypothesized that cardiovascular prophylaxis with omega-3 fatty acids could benefit them. In our study, 20 children and adolescents (mean body mass index percentile: 99.1; mean age: 11.0 years) underwent two ambulatory 24 h Holter electrocardiography (ECG) recordings (before and after at least 3 months of omega-3 fatty acid supplementation). Time domain heart rate variability (HRV) and heart rate (HR) were examined for these patients. As a control, we used 24 h Holter ECG recordings of 94 nonobese children and adolescents. Time domain HRV parameters, which are indicators of vagal stimulation, were significantly lower in obese patients than in healthy controls, but HR was higher (standard deviation of the normal-to-normal [SDNN] interbeat intervals: −34.02%; root mean square of successive differences [RMSSD] between normal heartbeats: −40.66%; percentage of consecutive RR intervals [pNN50]: −60.24%; HR: +13.37%). After omega-3 fatty acid supplementation, time domain HRV parameters and HR of obese patients were similar to the values of healthy controls (SDNN interbeat intervals: −21.73%; RMSSD: −19.56%; pNN50: −25.59%; HR: +3.94%). Therefore, omega-3 fatty acid supplementation may be used for cardiovascular prophylaxis in obese children and adolescents.
Optogenetic manipulation of cells or living organisms became widely used in neuroscience following the introduction of the light-gated ion channel channelrhodopsin-2 (ChR2). ChR2 is a non-selective cation channel, ideally suited to depolarize and evoke action potentials in neurons. However, its calcium (Ca2\(^{2+}\)) permeability and single channel conductance are low and for some applications longer-lasting increases in intracellular Ca\(^{2+}\) might be desirable. Moreover, there is need for an efficient light-gated potassium (K\(^{+}\)) channel that can rapidly inhibit spiking in targeted neurons. Considering the importance of Ca\(^{2+}\) and K\(^{+}\) in cell physiology, light-activated Ca\(^{2+}\)-permeant and K\(^{+}\)-specific channels would be welcome additions to the optogenetic toolbox. Here we describe the engineering of novel light-gated Ca\(^{2+}\)-permeant and K\(^{+}\)-specific channels by fusing a bacterial photoactivated adenylyl cyclase to cyclic nucleotide-gated channels with high permeability for Ca\(^{2+}\) or for K\(^{+}\), respectively. Optimized fusion constructs showed strong light-gated conductance in Xenopus laevis oocytes and in rat hippocampal neurons. These constructs could also be used to control the motility of Drosophila melanogaster larvae, when expressed in motoneurons. Illumination led to body contraction when motoneurons expressed the light-sensitive Ca\(^{2+}\)-permeant channel, and to body extension when expressing the light-sensitive K\(^{+}\) channel, both effectively and reversibly paralyzing the larvae. Further optimization of these constructs will be required for application in adult flies since both constructs led to eclosion failure when expressed in motoneurons.
Oesophageal involvement in mucous membrane pemphigoid is considered rare, but it may be underdiagnosed. To assess the incidence of oesophageal involvement in a group of patients with newly diagnosed mucous membrane pemphigoid we retrospectively analysed the medical records of 30 consecutive patients with mucous membrane pemphigoid diagnosed between 2006 and 2016 at the Department of Dermatology, University Hospital Würzburg. Twenty-one patients (70%) reported symptoms indicative of oesophageal mucous membrane pemphigoid. Twelve patients (40%) underwent oesophagogastroduodenoscopy, and oesophageal pathology compatible with mucous membrane pemphigoid was endoscopically found in 9 cases (30%). In all patients indirect and direct immunofluorescence were performed. Patients with and without oesophageal involvement did not differ with regard to the results of indirect immunofluorescence on salt-split human skin and monkey oesophagus. Study results demonstrate the necessity of a standardized diagnostic work-up, including adequate tissue samples for direct immunofluorescence, to prevent underdiagnosis of oesophageal mucous membrane pemphigoid.
Introduction. \(^{177}\)Lu-OPS201 is a high-affinity somatostatin receptor subtype 2 antagonist for PRRT in patients with neuroendocrine tumors. The aim is to find the optimal scaling for dosimetry and to compare the biokinetics of \(^{177}\)Lu-OPS201 in animals and humans. Methods. Data on biokinetics of \(^{177}\)Lu-OPS201 were analyzed in athymic nude Foxn1\(^{nu}\) mice (28 F, weight: 26 ± 1 g), Danish Landrace pigs (3 F-1 M, weight: 28 ± 2 kg), and patients (3 F-1 M, weight: 61 ± 17 kg) with administered activities of 0.19–0.27 MBq (mice), 97–113 MBq (pigs), and 850–1086 MBq (patients). After euthanizing mice (up to 168 h), the organ-specific activity contents (including blood) were measured. Multiple planar and SPECT/CT scans were performed until 250 h (pigs) and 72 h (patients) to quantify the uptake in the kidneys and liver. Blood samples were taken up to 23 h (patients) and 300 h (pigs). In pigs and patients, kidney protection was applied. Time-dependent uptake data sets were created for each species and organ/tissue. Biexponential fits were applied to compare the biokinetics in the kidneys, liver, and blood of each species. The time-integrated activity coefficients (TIACs) were calculated by using NUKFIT. To determine the optimal scaling, several methods (relative mass scaling, time scaling, combined mass and time scaling, and allometric scaling) were compared. Results. A fast blood clearance of the compound was observed in the first phase (<56 h) for all species. In comparison with patients, pigs showed higher liver retention. Based on the direct comparison of the TIACs, an underestimation in mice (liver and kidneys) and an overestimation in pigs’ kidneys compared to the patient data (kidney TIAC: mice = 1.4 h, pigs = 7.7 h, and patients = 5.8 h; liver TIAC: mice = 0.7 h, pigs = 4.1 h, and patients = 5.3 h) were observed. Most similar TIACs were obtained by applying time scaling (mice) and combined scaling (pigs) (kidney TIAC: mice = 3.9 h, pigs = 4.8 h, and patients = 5.8 h; liver TIAC: mice = 0.9 h, pigs = 4.7 h, and patients = 5.3 h). Conclusion. If the organ mass ratios between the species are high, the combined mass and time scaling method is optimal to minimize the interspecies differences. The analysis of the fit functions and the TIACs shows that pigs are better mimicking human biokinetics.
A comparative view on sex differentiation and gametogenesis genes in lungfish and coelacanths
(2018)
Gonadal sex differentiation and reproduction are the keys to the perpetuation of favorable gene combinations and positively selected traits. In vertebrates, several gonad development features that differentiate tetrapods and fishes are likely to be, at least in part, related to the water-to-land transition. The collection of information from basal sarcopterygians, coelacanths, and lungfishes, is crucial to improve our understanding of the molecular evolution of pathways involved in reproductive functions, since these organisms are generally regarded as “living fossils” and as the direct ancestors of tetrapods. Here, we report for the first time the characterization of >50 genes related to sex differentiation and gametogenesis in Latimeria menadoensis and Protopterus annectens. Although the expression profiles of most genes is consistent with the intermediate position of basal sarcopterygians between actinopterygian fish and tetrapods, their phylogenetic placement and presence/absence patterns often reveal a closer affinity to the tetrapod orthologs. On the other hand, particular genes, for example, the male gonad factor gsdf (Gonadal Soma-Derived Factor), provide examples of ancestral traits shared with actinopterygians, which disappeared in the tetrapod lineage.
Background:
We hypothesized, that periprosthetic joint infection (PJI) accounts for the major proportion of first (primary) and repeated (secondary) Total Knee Arthroplasty revisions at our university referral arthroplasty center.
Methods:
One thousand one hundred forty-three revisions, performed between 2008 and 2016 were grouped into primary (55%) and secondary (45%) revisions. The rate of revision indications was calculated and indications were categorized by time after index operation. The odds ratios of the indications for primary versus secondary revision were calculated.
Results:
In the primary revision group PJI accounted for 22.3%, instability for 20.0%, aseptic loosening for 14.9% and retropatellar arthrosis for 14.2%. PJI (25.6%) was the most common indication up to 1 year after implantation, retropatellar arthrosis (26.8%) 1–3 years and aseptic loosening (25.6%) more than 3 years after implantation. In the secondary revision group PJI accounted for 39.7%, aseptic loosening for 16.2% and instability for 13.2%. PJI was the most common indication at any time of revision with 43.8% up to one, 35.4% 1–3 years and 39.4% more the 3 years after index operation. The odds ratios in repeated revision were 2.32 times higher (p = 0.000) for PJI. For instability and retropatellar arthrosis the odds ratios were 0.60 times (p = 0.006) and 0.22 times (p = 0.000) lower.
Conclusions:
PJI is the most common indication for secondary TKA revision and within one year after primary TKA. Aseptical failures such as instability, retropatellar arthrosis and aseptical loosening are the predominant reasons for revision more than one year after primary TKA.
Purpose. Detection of infection persistence during the two-stage exchange of the knee for periprosthetic joint infection is challenging. Synovial fluid culture (SFC) and synovial white blood cell count (SWBCC) before joint reimplantation are widespread diagnostic means for this indication. The sensitivity and specificity of SFC and of SWBCC for infection persistence before planned reimplantation were evaluated. Methods. 94 two-stage exchanges of the knee with synovial fluid aspiration performed after a drug holiday of at least 14 days and before reimplantation or spacer exchange (planned reimplantation) were retrospectively analyzed. Only cases with at least 3 intraoperative samples at planned reimplantation were included. SFC and SWBCC were compared to pathogen detection (SFC\(_{(culture)}\)/SWBCC\(_{(culture)}\) and to histopathological signs of infection persistence (SFC\(_{(histo)}\)/SWBCC\(_{(histo)}\) from intraoperative samples at planned reimplantation. For SFC, the sensitivity and specificity were calculated. For SWBCC, the optimal cut-off value with its sensitivity and specificity was calculated with the Youden-Index. Results. Sensitivity and specificity of SFC\(_{(culture)}\) were 0.0% and 98.9%. Sensitivity and specificity of SFC\(_{(histo)}\) were 3.4% and 100%. The optimal cut-off value for SWBCC\(_{(culture)}\) was 4450 cells/μl with a sensitivity of 50.0% and a specificity of 86.5%. The optimal cut-off value for SWBCC\(_{(histo)}\) was 3250 cells/μl with a sensitivity of 35.7% and a specificity of 92.9%. Conclusion. The detection of infection persistence remains challenging and a consented approach is lacking. The results do not warrant the routine performance of SFC during the two-stage exchange at the knee. SWBCC can be used to confirm infection persistence at high cut-offs, but they only occur in few patients and are therefore inappropriate for the routine use.
Purpose. Copal\(^®\) spacem is a new PMMA bone cement for fabricating spacers. This study compares elution of gentamicin, elution of vancomycin, and compressive strength of Copal\(^®\) spacem and of Palacos\(^®\) R+G at different vancomycin loadings in the powder of the cements. We hypothesized that antibiotic elution of Copal\(^®\) spacem is superior at comparable compressive strength. Methods. Compression test specimens were fabricated using Copal\(^®\) spacem manually loaded with 0.5 g gentamicin and additionally 2 g, 4 g, and 6 g of vancomycin per 40 g of cement powder (COP specimens) and using 0.5 g gentamicin premixed Palacos\(^®\) R+G manually loaded with 2 g, 4 g, and 6 g of vancomycin per 40 g of cement powder (PAL specimens). These specimens were used for determination of gentamicin and vancomycin elution (in fetal calf serum, at 22°C) and for determination of compressive strength both prior and following the elution tests. Results. Cumulative gentamicin concentrations (p < 0.005) and gentamicin concentration after 28 days (p ≤ 0.043) were significantly lower for COP specimens compared to PAL specimens. Cumulative vancomycin concentrations were significantly higher (p ≤ 0.043) for COP specimens after the second day. Vancomycin concentrations after 28 days were not significantly higher for the Copal specimens loaded with 2 g and 4 g of vancomycin. Compressive strength was not significantly different between COP specimens and PAL specimens before elution tests. Compressive strength after the elution tests was significantly lower (p = 0.005) for COP specimens loaded with 2 g of vancomycin. Conclusion. We could not demonstrate consistent superior antibiotic elution from Copal\(^®\) spacem compared to Palacos\(^®\) R+G for fabricating gentamicin and vancomycin loaded spacers. The results do not favor Copal\(^®\) spacem over Palacos\(^®\) R+G for the use as a gentamicin and vancomycin biantibiotic-loaded spacer.
Insufficient sensitivity of joint aspiration during the two-stage exchange of the hip with spacers
(2018)
Background:
Evaluation of infection persistence during the two-stage exchange of the hip is challenging. Joint aspiration before reconstruction is supposed to rule out infection persistence. Sensitivity and specificity of synovial fluid culture and synovial leucocyte count for detecting infection persistence during the two-stage exchange of the hip were evaluated.
Methods:
Ninety-two aspirations before planned joint reconstruction during the two-stage exchange with spacers of the hip were retrospectively analyzed.
Results:
The sensitivity and specificity of synovial fluid culture was 4.6 and 94.3%. The sensitivity and specificity of synovial leucocyte count at a cut-off value of 2000 cells/μl was 25.0 and 96.9%. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) values were significantly higher before prosthesis removal and reconstruction or spacer exchange (p = 0.00; p = 0.013 and p = 0.039; p = 0.002) in the infection persistence group. Receiver operating characteristic area under the curve values before prosthesis removal and reconstruction or spacer exchange for ESR were lower (0.516 and 0.635) than for CRP (0.720 and 0.671).
Conclusions:
Synovial fluid culture and leucocyte count cannot rule out infection persistence during the two-stage exchange of the hip.
It’s a matter of design - how pitfall trap design affects trap samples and possible predictions
(2018)
Background:
Pitfall traps are commonly used to assess ground dwelling arthropod communities. The effects of different pitfall trap designs on the trapping outcome are poorly investigated however they might affect conclusions drawn from pitfall trap data greatly.
Methods:
We tested four pitfall trap types which have been used in previous studies for their effectiveness: a simple type, a faster exchangeable type with an extended plastic rim plate and two types with guidance barriers (V- and X-shaped). About 20 traps were active for 10 weeks and emptied biweekly resulting in 100 trap samples.
Results:
Pitfall traps with guidance barriers were up to five times more effective than simple pitfall traps and trap samples resulted in more similar assemblage approximations. Pitfall traps with extended plastic rim plates did not only perform poorly but also resulted in distinct carabid assemblages with less individuals of small species and a larger variation.
Discussion:
Due to the obvious trait filtering and resulting altered assemblages, we suggest not to use pitfall traps with extended plastic rim plates. In comprehensive biodiversity inventories, a smaller number of pitfall traps with guidance barriers and a larger number of spatial replicates is of advantage, while due to comparability reasons, the use of simple pitfall traps will be recommended in most other cases.
Purpose:
To quantify the contribution of penumbra in the improvement of healthy tissue sparing at reduced source‐to‐axis distance (SAD) for simple spherical target and different prescription isodoses (PI).
Method:
A TPS‐independent method was used to estimate three‐dimensional (3D) dose distribution for stereotactic treatment of spherical targets of 0.5 cm radius based on single beam two‐dimensional (2D) film dosimetry measurements. 1 cm target constitutes the worst case for the conformation with standard Multi‐Leaf Collimator (MLC) with 0.5 cm leaf width. The measured 2D transverse dose cross‐sections and the profiles in leaf and jaw directions were used to calculate radial dose distribution from isotropic beam arrangement, for both quadratic and circular beam openings, respectively. The results were compared for standard (100 cm) and reduced SAD 70 and 55 cm for different PI.
Results:
For practical reduction of SAD using quadratic openings, the improvement of healthy tissue sparing (HTS) at distances up to 3 times the PTV radius was at least 6%–12%; gradient indices (GI) were reduced by 3–39% for PI between 40% and 90%. Except for PI of 80% and 90%, quadratic apertures at SAD 70 cm improved the HTS by up to 20% compared to circular openings at 100 cm or were at least equivalent; GI were 3%–33% lower for reduced SAD in the PI range 40%–70%. For PI = 80% and 90% the results depend on the circular collimator model.
Conclusion:
Stereotactic treatments of spherical targets delivered at reduced SAD of 70 or 55 cm using MLC spare healthy tissue around the target at least as good as treatments at SAD 100 cm using circular collimators. The steeper beam penumbra at reduced SAD seems to be as important as perfect target conformity. The authors argue therefore that the beam penumbra width should be addressed in the stereotactic studies.
By promoting ceramide release at the cytosolic membrane leaflet, the neutral sphingomyelinase 2 (NSM) is capable of organizing receptor and signalosome segregation. Its role in T cell receptor (TCR) signaling remained so far unknown. We now show that TCR-driven NSM activation is dispensable for TCR clustering and initial phosphorylation, but of crucial importance for further signal amplification. In particular, at low doses of TCR stimulatory antibodies, NSM is required for Ca\(^{2+}\) mobilization and T cell proliferation. NSM-deficient T cells lack sustained CD3ζ and ZAP-70 phosphorylation and are unable to polarize and stabilize their microtubular system. We identified PKCζ as the key NSM downstream effector in this second wave of TCR signaling supporting dynamics of microtubule-organizing center (MTOC). Ceramide supplementation rescued PKCζ membrane recruitment and MTOC translocation in NSM-deficient cells. These findings identify the NSM as essential in TCR signaling when dynamic cytoskeletal reorganization promotes continued lateral and vertical supply of TCR signaling components: CD3ζ, Zap70, and PKCζ, and functional immune synapses are organized and stabilized via MTOC polarization.
Volatile anesthetic-induced preconditioning ( APC) has shown to have cardiac and cerebral protective properties in both pre-clinical models and clinical trials. Interestingly, accumulating evidences demonstrate that, except from some specific characters, the underlying molecular mechanisms of APC-induced protective effects in myocytes and neurons are very similar; they share several major intracellular signaling pathways, including mediating mitochondrial function, release of inflammatory cytokines and cell apoptosis. Among all the experimental results, cortical spreading depolarization is a relative newly discovered cellular mechanism of APC, which, however, just exists in central nervous system. Applying volatile anesthetic preconditioning to clinical practice seems to be a promising cardio- and neuroprotective strategy. In this review, we also summarized and discussed the results of recent clinical research of APC. Despite all the positive experimental evidences, large-scale, long-term, more precisely controlled clinical trials focusing on the perioperative use of volatile anesthetics for organ protection are still needed.
Background: \(^{18}\)F-N-[3-bromo-4-(3-fluoro-propoxy)-benzyl]-guanidine (\(^{18}\)F-LMI1195) is a new class of PET tracer designed for sympathetic nervous imaging of the heart. The favorable image quality with high and specific neural uptake has been previously demonstrated in animals and humans, but intracellular behavior is not yet fully understood. The aim of the present study is to verify whether it is taken up in storage vesicles and released in company with vesicle turnover.
Results: Both vesicle-rich (PC12) and vesicle-poor (SK-N-SH) norepinephrine-expressing cell lines were used for in vitro tracer uptake studies. After 2 h of \(^{18}\)F-LMI1195 preloading into both cell lines, effects of stimulants for storage vesicle turnover (high concentration KCl (100 mM) or reserpine treatment) were measured at 10, 20, and 30 min. \(^{131}\)I-meta-iodobenzylguanidine (\(^{131}\)I-MIBG) served as a reference. Both high concentration KCl and reserpine enhanced \(^{18}\)F-LMI1195 washout from PC12 cells, while tracer retention remained stable in the SK-N-SH cells. After 30 min of treatment, 18F-LMI1195 releasing index (percentage of tracer released from cells) from vesicle-rich PC12 cells achieved significant differences compared to cells without treatment condition. In contrast, such effect could not be observed using vesicle-poor SK-N-SH cell lines. Similar tracer kinetics after KCl or reserpine treatment were also observed using 131I-MIBG. In case of KCl exposure, Ca\(^{2+}\)-free buffer with the calcium chelator, ethylenediaminetetracetic acid (EDTA), could suppress the tracer washout from PC12 cells. This finding is consistent with the tracer release being mediated by Ca\(^{2+}\) influx resulting from membrane depolarization.
Conclusions: Analogous to \(^{131}\)I-MIBG, the current in vitro tracer uptake study confirmed that \(^{131}\)F-LMI1195 is also stored in vesicles in PC12 cells and released along with vesicle turnover. Understanding the basic kinetics of \(^{18}\)FLMI1195 at a subcellular level is important for the design of clinical imaging protocols and imaging interpretation.
Although posttraumatic stress disorder (PTSD; DSM-V 309.82) and anxiety disorders (DSM-V 300.xx) are widely spread mental disorders, the effectiveness of their therapy is still unsatisfying. Non-invasive brain-stimulation techniques like transcranial direct current stimulation (tDCS) might be an option to improve extinction learning, which is a main functional factor of exposure-based therapy for anxiety disorders. To examine this hypothesis, we used a fear conditioning paradigm with female faces as conditioned stimuli (CS) and a 95-dB female scream as unconditioned stimulus (UCS). We aimed to perform a tDCS of the ventromedial prefrontal cortex (vmPFC), which is mainly involved in the control of extinction-processes. Therefore, we applied two 4 × 4 cm electrodes approximately at the EEG-positions F7 and F8 and used a direct current of 1.5 mA. The 20-min stimulation was started during a 10-min break between acquisition and extinction and went on overall extinction-trials. The healthy participants were randomly assigned in two double-blinded process into two sham stimulation and two verum stimulation groups with opposite current flow directions. To measure the fear reactions, we used skin conductance responses (SCR) and subjective ratings. We performed a generalized estimating equations model for the SCR to assess the impact of tDCS and current flow direction on extinction processes for all subjects that showed a successful conditioning (N = 84). The results indicate that tDCS accelerates early extinction processes with a significantly faster loss of CS+/CS- discrimination. The discrimination loss was driven by a significant decrease in reaction toward the CS+ as well as an increase in reaction toward the CS- in the tDCS verum groups, whereas the sham groups showed no significant reaction changes during this period. Therefore, we assume that tDCS of the vmPFC can be used to enhance early extinction processes successfully. But before it should be tested in a clinical context further investigation is needed to assess the reason for the reaction increase on CS-. If this negative side effect can be avoided, tDCS may be a tool to improve exposure-based anxiety therapies.
Athletes schedule their training and recovery in periods, often utilizing a pre-defined strategy. To avoid underperformance and/or compromised health, the external load during training should take into account the individual’s physiological and perceptual responses. No single variable provides an adequate basis for planning, but continuous monitoring of a combination of several indicators of internal and external load during training, recovery and off-training as well may allow individual responsive adjustments of a training program in an effective manner. From a practical perspective, including that of coaches, monitoring of potential changes in health and performance should ideally be valid, reliable and sensitive, as well as time-efficient, easily applicable, non-fatiguing and as non-invasive as possible. Accordingly, smartphone applications, wearable sensors and point-of-care testing appear to offer a suitable monitoring framework allowing responsive adjustments to exercise prescription. Here, we outline 24-h monitoring of selected parameters by these technologies that (i) allows responsive adjustments of exercise programs, (ii) enhances performance and/or (iii) reduces the risk for overuse, injury and/or illness.
Although it is becoming increasingly popular to monitor parameters related to training, recovery, and health with wearable sensor technology (wearables), scientific evaluation of the reliability, sensitivity, and validity of such data is limited and, where available, has involved a wide variety of approaches. To improve the trustworthiness of data collected by wearables and facilitate comparisons, we have outlined recommendations for standardized evaluation. We discuss the wearable devices themselves, as well as experimental and statistical considerations. Adherence to these recommendations should be beneficial not only for the individual, but also for regulatory organizations and insurance companies.
Background:
Diagnostic guidelines recommend using a variety of methods to assess and diagnose ADHD. Applying subjective measures always incorporates risks such as informant biases or large differences between ratings obtained from diverse sources. Furthermore, it has been demonstrated that ratings and tests seem to assess somewhat different constructs. The use of objective measures might thus yield valuable information for diagnosing ADHD. This study aims at evaluating the role of objective measures when trying to distinguish between individuals with ADHD and controls. Our sample consisted of children (n = 60) and adults (n = 76) diagnosed with ADHD and matched controls who completed self- and observer ratings as well as objective tasks. Diagnosis was primarily based on clinical interviews. A popular pattern recognition approach, support vector machines, was used to predict the diagnosis.
Results:
We observed relatively high accuracy of 79% (adults) and 78% (children) applying solely objective measures. Predicting an ADHD diagnosis using both subjective and objective measures exceeded the accuracy of objective measures for both adults (89.5%) and children (86.7%), with the subjective variables proving to be the most relevant.
Conclusions:
We argue that objective measures are more robust against rater bias and errors inherent in subjective measures and may be more replicable. Considering the high accuracy of objective measures only, we found in our study, we think that they should be incorporated in diagnostic procedures for assessing ADHD.
Background:
ATF5 suppresses differentiation of neuroprogenitor cells and is overexpressed in glioblastoma (GBM). A reduction of its expression leads to apoptotic GBM cell death. Data on ATF5 expression in astrocytoma WHO grade II (low-grade astrocytoma [LGA]) are scarce and lacking on recurrent GBM.
Patients and methods:
ATF5 mRNA was extracted from frozen samples of patients’ GBM (n=79), LGA (n=40), and normal brain (NB, n=10), quantified by duplex qPCR and correlated with retrospectively collected clinical data. ATF5 protein expression was evaluated by measuring staining intensity on immunohistochemistry.
Results:
ATF5 mRNA was overexpressed in LGA (sevenfold, P<0.001) and GBM (tenfold, P<0.001) compared to NB, which was confirmed on protein level. Although ATF5 mRNA expression in GBM showed a considerable fluctuation range, groups of varying biological behavior, that is, local/multifocal growth or primary tumor/relapse and the tumor localization at diagnosis, were not significantly different. ATF5 mRNA correlated with the patients’ age (r=0.339, P=0.028) and inversely with Ki67-staining (r=-0.421, P=0.007). GBM patients were allocated to a low and a high ATF5 expression group by the median ATF5 overexpression compared to NB. Kaplan–Meier analysis and Cox regression indicated that ATF5 mRNA expression significantly correlated with short-term survival (t<12 months, median survival 18 vs 13 months, P=0.022, HR 2.827) and progression-free survival (PFS) (12 vs 6 months, P=0.024). This advantage vanished after 24 months (P=0.084).
Conclusion:
ATF5 mRNA expression could be identified as an additional, though not independent factor correlating with overall survival and PFS. Since its inhibition might lead to the selective death of glioma cells, it might serve as a potential ubiquitous therapeutic target in astrocytic tumors.
1-5% of human blood T cells are Vγ9Vδ2 T cells whose T cell receptor (TCR) contain a TRGV9/TRGJP rearrangement and a TRDV2 comprising Vδ2-chain. They respond to phosphoantigens (PAgs) like isopentenyl pyrophosphate or (E)-4-hydroxy-3-methyl-but-2-enyl-pyrophosphate (HMBPP) in a butyrophilin 3 (BTN3)-dependent manner and may contribute to the control of mycobacterial infections. These cells were thought to be restricted to primates, but we demonstrated by analysis of genomic databases that TRGV9, TRDV2, and BTN3 genes coevolved and emerged together with placental mammals. Furthermore, we identified alpaca (Vicugna pacos) as species with typical Vγ9Vδ2 TCR rearrangements and currently aim to directly identify Vγ9Vδ2 T cells and BTN3. Other candidates to study this coevolution are the bottlenose dolphin (Tursiops truncatus) and the nine-banded armadillo (Dasypus novemcinctus) with genomic sequences encoding open reading frames for TRGV9, TRDV2, and the extracellular part of BTN3. Dolphins have been shown to express Vγ9- and Vδ2-like TCR chains and possess a predicted BTN3-like gene homologous to human BTN3A3. The other candidate, the armadillo, is of medical interest since it serves as a natural reservoir for Mycobacterium leprae. In this study, we analyzed the armadillo genome and found evidence for multiple non-functional BTN3 genes including genomic context which closely resembles the organization of the human, alpaca, and dolphin BTN3A3 loci. However, no BTN3 transcript could be detected in armadillo cDNA. Additionally, attempts to identify a functional TRGV9/TRGJP rearrangement via PCR failed. In contrast, complete TRDV2 gene segments preferentially rearranged with a TRDJ4 homolog were cloned and co-expressed with a human Vγ9-chain in murine hybridoma cells. These cells could be stimulated by immobilized anti-mouse CD3 antibody but not with human RAJI-RT1Bl cells and HMBPP. So far, the lack of expression of TRGV9 rearrangements and BTN3 renders the armadillo an unlikely candidate species for PAg-reactive Vγ9Vδ2 T cells. This is in line with the postulated coevolution of the three genes, where occurrence of Vγ9Vδ2 TCRs coincides with a functional BTN3 molecule.
This review article deals with the topic of sustainability in the German healthcare system and presents an overview of how the six articles of our research relate to one another. After introducing to the context of the research, its internal principles, and the methods applied, three perspectives are presented, each also discussed in terms of the respective literature in sustainability science and political science. The review concludes by presenting a circular model and by discussing the general limitations as well as the practical implications of our research.
Loss of function mutations in the rsk2 gene cause Coffin-Lowry syndrome (CLS), which is associated with multiple symptoms including severe mental disabilities. Despite the characterization of ribosomal S6 kinase 2 (RSK2) as a protein kinase acting as a downstream effector of the well characterized ERK MAP-kinase signaling pathway, it turns out to be a challenging task to link RSK2 to specific neuronal processes dysregulated in case of mutation. Animal models such as mouse and Drosophila combine advanced genetic manipulation tools with in vivo imaging techniques, high-resolution connectome analysis and a variety of behavioral assays, thereby allowing for an in-depth analysis for gene functions in the nervous system. Although modeling mental disability in animal systems has limitations because of the complexity of phenotypes, the influence of genetic variation and species-specific characteristics at the neural circuit and behavioral level, some common aspects of RSK2 function in the nervous system have emerged, which will be presented. Only with this knowledge our understanding of the pathophysiology of CLS can be improved, which might open the door for development of potential intervention strategies.
Bacteria adapt to changing environmental conditions by rapid changes in their transcriptome. This is achieved not only by adjusting rates of transcription but also by processing and degradation of RNAs. We applied TIER-Seq (transiently inactivating an endoribonuclease followed by RNA-Seq) for the transcriptome-wide identification of RNase E cleavage sites and of 5′ RNA ends, which are enriched when RNase E activity is reduced in Rhodobacter sphaeroides. These results reveal the importance of RNase E for the maturation and turnover of mRNAs, rRNAs, and sRNAs in this guanine-cytosine-rich α-proteobacterium, some of the latter have well-described functions in the oxidative stress response. In agreement with this, a role of RNase E in the oxidative stress response is demonstrated. A remarkably strong phenotype of a mutant with reduced RNase E activity was observed regarding the formation of photosynthetic complexes and phototrophic growth, whereas there was no effect on chemotrophic growth.
Background:
Despite the high persistence rate of attention-deficit/hyperactivity disorder (ADHD) throughout the lifespan, there is a considerable gap in knowledge regarding effective treatment strategies for adolescents with ADHD. This group in particular often shows substantial psychosocial impairment, low compliance and insufficient response to psychopharmacological interventions. Effective and feasible treatments should further consider the developmental shift in ADHD symptoms, comorbidity and psychosocial adversity as well as family dysfunction. Thus, individualised interventions for adolescent ADHD should comprise a multimodal treatment strategy. The randomised controlled ESCAadol study addresses the needs of this patient group and compares the outcome of short-term cognitive behavioural therapy with parent-based telephone-assisted self-help.
Methods/design:
In step 1, 160 adolescents aged 12 to 17 years with a diagnosis of ADHD will undergo a treatment as usual (TAU) observation phase of 1 month. In step 2, those still severely affected are randomised to the intervention group with an Individualised Modular Treatment Programme (IMTP) or a telephone-assisted self-help programme for parents (TASH) as an active control condition. The IMTP was specifically designed for the needs of adolescent ADHD. It comprises 10 sessions of individual cognitive behavioural therapy with the adolescents and/or the parents, for which participants choose three out of 10 available focus modules (e.g. organisational skills and planning, emotion regulation, problem solving and stress management, dysfunctional family communication). TASH combines a bibliotherapeutic component with 10 counselling sessions for the parents via telephone. Primary outcome is the change in ADHD symptoms in a clinician-rated diagnostic interview. Outcomes are assessed at inclusion into the study, after the TAU phase, after the intervention phase and after a further 12-week follow-up period. The primary statistical analysis will be by intention-to-treat, using linear regression models. Additionally, we will analyse psychometric and biological predictors and moderators of treatment response.
Discussion:
ESCAadol compares two short-term non-pharmacological interventions as cost-efficient and feasible treatment options for adolescent ADHD, addressing the specific needs and obstacles to treatment success in this group. We aim to contribute to personalised medicine for adolescent ADHD intended to be implemented in routine clinical care.
Intra- and interobserver reliability of glenoid fracture classifications by Ideberg, Euler and AO
(2018)
Background:
Representing 3%-5% of shoulder girdle injuries scapula fractures are rare. Furthermore, approximately 1% of scapula fractures are intraarticularfractures of the glenoid fossa. Because of uncertain fracture morphology and limited experience, the treatment of glenoid fossa fractures is difficult. The glenoid fracture classification by Ideberg (1984) and Euler (1996) is still commonly used in literature. In 2013 a new glenoid fracture classification was introduced by the AO. The purpose of this study was to examine the new AO classification in clinical practice in comparison with the classifications by Ideberg and Euler.
Methods:
In total CT images of 84 patients with glenoid fossa fractures from 2005 to 2018 were included. Parasagittal, paracoronary and axial reconstructions were examined according to the classifications of Ideberg, Euler and the AO by 3 investigators (orthopedic surgeon, radiologist, student of medicine) at three individual time settings. Inter- and intraobserver reliability of the three classification systems were ascertained by computing Inter- and Intraclass (ICCs) correlation coefficients using Spearman's rank correlation coefficient, 95%-confidence intervals as well as F-tests for correlation coefficients.
Results:
Inter- and intraobserver reliability for the AO classification showed a perspicuous coherence (R = 0.74 and R = 0.79). Low to moderate intraobserver reliability for Ideberg (R = 0.46) and Euler classification (R = 0.41) was found. Furthermore, data show a low Interobserver reliability for both Ideberg and Euler classification (R < 0.2). Both the Inter- and Intraclass reliability using AO is significantly higher than those using Ideberg and Euler (p < 0.05). Using the new AO classification, it was possible to find a proper class for every glenoid fossa fracture. On average, according to Euler classification 10 of 84 fractures were not classifiable whereas to Ideberg classification 21 of 84 fractures were not classifiable.
Conclusion:
The new AO classification system introduced 2013 facilitates reliable grading of glenoid fossa fractures with high inter- and intraobserver reliability in 84 patients using CT images. It should possibly be applied in order to enable a valid, reliable and consistent academic description of glenoid fossa fractures. The established classifications by Euler and Ideberg are not capable of providing a similar reliability.
Background:
Minimally invasive pedicle screw fixation has less approach-related morbidity than open screw placement and is allegedly less traumatizing on paravertebral muscles, as there is no requirement to mobilize and retract the adjacent muscle portion. The approach-related long-term effects to the morphology of the paravertebral muscles are unknown. The purpose of this study was to compare the long-term amount of fatty degeneration of the multifidus muscle in patients treated with a classical open or a minimally invasive approach.
Methods:
Fourteen Patients meeting inclusion criteria were selected. In all patients a singular fracture of the thoracolumbar spine with a two-level posterior instrumentation was treated, either using an open approach or a minimally invasive approach. All patients underwent quantitative MRI spectroscopy for quantification of the fatty degeneration in the multifidus muscle as a long-term proof for muscle loss after minimum 4-year follow-up. Clinical outcome was assessed using Oswestry Low Back Pain Disability Questionnaire, SF-36 and VA-scale for pain.
Results:
The minimally invasive approach group failed to show less muscle degeneration in comparison to the open group. Total amount of fatty degeneration was 14.22% in the MIS group and 12.60% in the open group (p = 0.64). In accordance to MRI quantitative results there was no difference in the clinical outcome after a mean follow up of 5.9 years (±1.8).
Conclusion:
As short-term advantages of minimal invasive screw placement have been widely demonstrated, no advantage of the MIS, displaying a significant difference in the amount of fatty degeneration and resulting in a better clinical outcome could be found. Besides the well-known short-term advantage of minimally invasive pedicle screw placement, a long-term advantage, such as less muscle degeneration and thus superior clinical results, compared to the open approach could not be shown.
Background:
The amount of fatty degeneration (FD) has major impact on the clinical result and cuff integrity after rotator cuff repair. A quantitative analysis with magnet resonance imaging (MRI) spectroscopy was employed to analyze possible correlation of FD with tendon retraction, tendon thickness and patients’ characteristics in full thickness supraspinatus tears.
Methods:
Forty-two patients with full-thickness supraspinatus tears underwent shoulder MRI including an experimental spectroscopic sequence allowing quantification of the fat fraction in the supraspinatus muscle belly. The amount of fatty degeneration was correlated with tendon retraction, tendon thickness, patients’ age, gender, smoker status, symptom duration and body mass index (BMI). Patients were divided in to three groups of retraction (A) 0-10 mm (n=), (B) 11-20 mm (n=) and (C) < 21 mm (n=) and the means of FD for each group were calculated.
Results:
Tendon retraction (R = 0.6) and symptom duration (R = 0.6) correlated positively, whereas tendon thickness correlated negatively (R = − 0.6) with the amount of FD. The fat fraction increased significantly with tendon retraction: Group (A) showed a mean fat mount of 3.7% (±4%), group (B) of 16.7% (±8.2%) and group (C) of 37.5% (±19%). BMI, age and smoker-status only showed weak to moderate correlation with the amount of FD in this cohort.
Conclusion:
MRI spectroscopy revealed significantly higher amount of fat with increasing grade of retraction, symptom duration and decreased tendon thickness. Thus, these parameters may indirectly be associated with the severity of tendon disease.
Background:
Vascular damage in polytrauma patients is associated with high mortality and morbidity. Therefore, specific clinical implications of vascular damage with fractures in major trauma patients are reassessed.
Methods:
This comprehensive nine-year retrospective single center cohort study analyzed demography, laboratory, treatment and outcome data from 3689 patients, 64 patients with fracture-associated vascular injuries were identified and were compared to a control group.
Results:
Vascular damage occurred in 7% of patients with upper and lower limb and pelvic fractures admitted to the trauma room. Overall survival was 80% in pelvic fracture and 97% in extremity fracture patients and comparable to non-vascular trauma patients. Additional arterial damage required substantial fluid administration and was visible as significantly anemia and disturbed coagulation tests upon admission. Open procedures were done in over 80% of peripheral extremity vascular damage. Endovascular procedures were predominant (87%) in pelvic injury.
Conclusion:
Vascular damage is associated with high mortality rates especially in combination with pelvic fractures. Initial anemia, disturbed coagulation tests and the need for extensive pre-clinical fluid substitution were observed in the cohort with vascular damage. Therefore, fast diagnosis and early interventional and surgical procedures are necessary to optimize patient-specific outcome.
Background:
Reverse oblique distal radio-ulnar joint (DRUJ) configuration is assumed to show inferior postoperative results in ulnar-shortening osteotomy due to osteoarthritis, as the joint force pressure in the DRUJ may be increased. An evaluation and comparison of the postoperative functional results with regard to clinical and radiographic signs of arthritis among different DRUJ configurations was carried out retrospectively.
Methods:
Sixty-two patients after ulnar shortening osteotomy were included. The minimum follow-up was 5 years. Preoperative x-rays were assessed for the DRUJ configuration according to the Tolat classification, whereas postoperative radiographs were evaluated with regard to signs of osteoarthritis using the Kallgren-Lawrence-Score. Functional results were evaluated using the disabilities of the arm, shoulder and hand (DASH) and Mayo Wrist Score and measuring range of motion and grip strength.
Results:
Significantly better functional results were found in patients with parallel configuration of the DRUJ (Tolat type 1 configuration) with regard to DASH score, grip strength, and supination compared with nonparallel configurations. In the Tolat type 1, configurated DRUJ mean DASH score was 9 compared with 18 in the Tolat type 2 and 3 groups. Apart from supination, no differences were observed in range of motion among groups.
Conclusion:
Although long-term postoperative range of motion failed to display statistically significant differences between DRUJ configurations except for supination, better results regarding grip strength and DASH scores were seen in a parallel-aligned DRUJ configuration. Although onset of osteoarthritis does not seem to become apparent within the observation period, nonparallel aligned configuration predisposes to inferior results.
The nuclear envelope serves as important messenger RNA (mRNA) surveillance system. In yeast and human, several control systems act in parallel to prevent nuclear export of unprocessed mRNAs. Trypanosomes lack homologues to most of the involved proteins and their nuclear mRNA metabolism is non-conventional exemplified by polycistronic transcription and mRNA processing by trans-splicing. We here visualized nuclear export in trypanosomes by intra- and intermolecular multi-colour single molecule FISH. We found that, in striking contrast to other eukaryotes, the initiation of nuclear export requires neither the completion of transcription nor splicing. Nevertheless, we show that unspliced mRNAs are mostly prevented from reaching the nucleus-distant cytoplasm and instead accumulate at the nuclear periphery in cytoplasmic nuclear periphery granules (NPGs). Further characterization of NPGs by electron microscopy and proteomics revealed that the granules are located at the cytoplasmic site of the nuclear pores and contain most cytoplasmic RNA-binding proteins but none of the major translation initiation factors, consistent with a function in preventing faulty mRNAs from reaching translation. Our data indicate that trypanosomes regulate the completion of nuclear export, rather than the initiation. Nuclear export control remains poorly understood, in any organism, and the described way of control may not be restricted to trypanosomes.
Approximately half of all melanoma patients harbour activating mutations in the serine/threonine kinase BRAF. This is the basis for one of the main treatment strategies for this tumor type, the targeted therapy with BRAF and MEK inhibitors. While the initial responsiveness to these drugs is high, resistance develops after several months, frequently at sites of the previously responding tumor. This indicates that tumor response is incomplete and that a certain tumor fraction survives even in drug-sensitive patients, e.g., in a therapy-induced senescence-like state. Here, we show in several melanoma cell lines that BRAF inhibition induces a secretome with stimulating effect on fibroblasts and naive melanoma cells. Several senescence-associated factors were found to be transcribed and secreted in response to BRAF or MEK inhibition, among them members of the fibroblast growth factor family. We identified the growth factor FGF1 as mediator of resilience towards BRAF inhibition, which limits the pro-apoptotic effects of the drug and activates fibroblasts to secrete HGF. FGF1 regulation was mediated by the PI3K pathway and by FRA1, a direct target gene of the MAPK pathway. When FGFR inhibitors were applied in parallel to BRAF inhibitors, resilience was broken, thus providing a rationale for combined therapeutical application.
Background:
Genetically caused neurological disorders of the central nervous system (CNS) are mostly characterized by poor or even fatal clinical outcome and few or no causative treatments are available. Often, these disorders are associated with low-grade, disease-promoting inflammation, another feature shared by progressive forms of multiple sclerosis (PMS). We previously generated two mouse lines carrying distinct mutations in the oligodendrocytic PLP1 gene that have initially been identified in patients diagnosed with MS. These mutations cause a loss of PLP function leading to a histopathological and clinical phenotype common to both PMS and genetic CNS disorders, like hereditary spastic paraplegias. Importantly, neuroinflammation promotes disease progression in these models, suggesting that pharmacological modulation of inflammation might ameliorate disease outcome.
Methods:
We applied teriflunomide, an approved medication for relapsing-remitting MS targeting activated T-lymphocytes, in the drinking water (10 mg/kg body weight/day). Experimental long-term treatment of PLP mutant mice was non-invasively monitored by longitudinal optical coherence tomography and by rotarod analysis. Immunomodulatory effects were subsequently analyzed by flow cytometry and immunohistochemistry and treatment effects regarding neural damage, and neurodegeneration were assessed by histology and immunohistochemistry.
Results:
Preventive treatment with teriflunomide attenuated the increase in number of CD8+ cytotoxic effector T cells and fostered the proliferation of CD8+ CD122+ PD-1+ regulatory T cells in the CNS. This led to an amelioration of axonopathic features and neuron loss in the retinotectal system, also reflected by reduced thinning of the innermost retinal composite layer in longitudinal studies and ameliorated clinical outcome upon preventive long-term treatment. Treatment of immune-incompetent PLP mutants did not provide evidence for a direct, neuroprotective effect of the medication. When treatment was terminated, no rebound of neuroinflammation occurred and histopathological improvement was preserved for at least 75 days without treatment. After disease onset, teriflunomide halted ongoing axonal perturbation and enabled a recovery of dendritic arborization by surviving ganglion cells. However, neither neuron loss nor clinical features were ameliorated, likely due to already advanced neurodegeneration before treatment onset.
Conclusions:
We identify teriflunomide as a possible medication not only for PMS but also for inflammation-related genetic diseases of the nervous system for which causal treatment options are presently lacking.
A negative mood-congruent attention bias has been consistently observed, for example, in clinical studies on major depression. This bias is assumed to be dysfunctional in that it supports maintaining a sad mood, whereas a potentially adaptive role has largely been neglected. Previous experiments involving sad mood induction techniques found a negative mood-congruent attention bias specifically for young individuals, explained by an adaptive need for information transfer in the service of mood regulation. In the present study we investigated the attentional bias in typically developing children (aged 6–12 years) when happy and sad moods were induced. Crucially, we manipulated the age (adult vs. child) of the displayed pairs of facial expressions depicting sadness, anger, fear and happiness. The results indicate that sad children indeed exhibited a mood specific attention bias toward sad facial expressions. Additionally, this bias was more pronounced for adult faces. Results are discussed in the context of an information gain which should be stronger when looking at adult faces due to their more expansive life experience. These findings bear implications for both research methods and future interventions.
Background
The role of a healthy dietary pattern in the prevention of abdominal aortic aneurysms (AAA) is unknown. We aimed to evaluate the relationship between adherence to a Dietary Approaches To Stop Hypertension‐style dietary pattern and the risk of incident AAAs.
Methods and Results
Dietary intake was assessed via a 66‐item food frequency questionnaire at baseline (1987–1989) and at visit 3 (1993–1995) in 13 496 participants enrolled in the ARIC (Atherosclerosis Risk in Communities) study without clinical AAA (mean age, 54 years). A dietary scoring index based on food times was constructed to assess self‐reported adherence to a dietary approaches to stop hypertension‐style dietary pattern. Participants were followed for incident clinical AAAs using hospital discharge diagnoses, Medicare inpatient and outpatient diagnoses, or death certificates through December 31, 2011. Cox proportional hazards models with covariate adjustment were used to estimate hazard ratios with 95% confidence intervals. During a median follow‐up of 23 years, there were 517 incident AAA cases. Individuals with a Dietary Approaches To Stop Hypertension‐style diet score in the highest quintile had a 40% lower risk of hospitalization for AAA than those in the lowest quintile (hazard ratio\(_{Q5}\) vs \(_{Q1}\): 0.60; 95% confidence intervals: 0.44, 0.83; P\(_{trend}\)=0.002). In detailed analyses, higher consumption of fruits, vegetables, whole grains, low‐fat dairy, and nuts and legumes was related to a lower risk for AAA.
Conclusions
Greater adherence to a Dietary Approaches To Stop Hypertension‐style dietary pattern was associated with lower risk for AAA. Higher consumption of fruits, vegetables, whole grains, low‐fat dairy as well as nuts and legumes may help to decrease the burden of AAAs.
Purpose:
The prescribing of oral chemotherapy agents has introduced the new challenge of ensuring patients’ adherence to therapy. Aspects of a close patient–doctor relationship are reported to be correlated with adherence to oral anticancer drugs, but data on capecitabine are scarce.
Patients and methods:
Sixty-four outpatients with a diagnosis of cancer and prescribed capecitabine were recruited from a German Comprehensive Cancer Center. We used the Patient–Doctor Relationship Questionnaire (PDRQ-9), the Medical Adherence Rating Scale (MARS), the Beliefs about Medicines Questionnaire (BMQ), and the Satisfaction with Information about Medicines Scale (SIMS) to assess patients’ perceptions and behavior. Medical data were extracted from the charts.
Results:
Non-adherence was reported by 20% of the 64 participants. The perceived quality of the patient–doctor relationship was high in general, but it did not emerge as a predictor of adherence in our survey (odds ratio [OR]=0.915, P=0.162, 95% CI=0.808–1.036). However, beliefs about medicine (OR=1.268, P<0.002; 95% CI=1.090–1.475) as well as satisfaction with information about medicine (OR=1.252, P<0.040, 95% CI=1.010–1.551) were predictors of adherence and the quality of the patient–doctor relationship was correlated with both variables (r=0.373, P=0.002 for SIMS sum score; r=0.263, P=0.036 for BMQ necessity/concern difference). Overall, adherence to capecitabine was high with a conviction that the therapy is necessary. However, concerns were expressed regarding the long-term effect of capecitabine use. Patients have unmet information needs regarding interactions of capecitabine with other medicines and the impairment of their intimate life.
Conclusions:
In order to ensure adherence to capecitabine, our results seem to encourage the default use of modern and perhaps more impersonal means of information brokerage (eg, email, internet). However, the contents of some of patients’ informational needs as well as the associations of patients’ beliefs and satisfaction about the information received suggest a benefit from a trustful patient–doctor relationship.
Lytic herpes simplex virus 1 (HSV-1) infection triggers disruption of transcription termination (DoTT) of most cellular genes, resulting in extensive intergenic transcription. Similarly, cellular stress responses lead to gene-specific transcription downstream of genes (DoG). In this study, we performed a detailed comparison of DoTT/DoG transcription between HSV-1 infection, salt and heat stress in primary human fibroblasts using 4sU-seq and ATAC-seq. Although DoTT at late times of HSV-1 infection was substantially more prominent than DoG transcription in salt and heat stress, poly(A) read-through due to DoTT/DoG transcription and affected genes were significantly correlated between all three conditions, in particular at earlier times of infection. We speculate that HSV-1 either directly usurps a cellular stress response or disrupts the transcription termination machinery in other ways but with similar consequences. In contrast to previous reports, we found that inhibition of Ca\(^{2+}\) signaling by BAPTA-AM did not specifically inhibit DoG transcription but globally impaired transcription. Most importantly, HSV-1-induced DoTT, but not stress-induced DoG transcription, was accompanied by a strong increase in open chromatin downstream of the affected poly(A) sites. In its extent and kinetics, downstream open chromatin essentially matched the poly(A) read-through transcription. We show that this does not cause but rather requires DoTT as well as high levels of transcription into the genomic regions downstream of genes. This raises intriguing new questions regarding the role of histone repositioning in the wake of RNA Polymerase II passage downstream of impaired poly(A) site recognition.
Sepsis caused by Neisseria meningitidis (meningococcus) is a rapidly progressing, life-threatening disease. Because its initial symptoms are rather unspecific, medical attention is often sought too late, i.e., when the systemic inflammatory response is already unleashed. This in turn limits the success of antibiotic treatment. The complement system is generally accepted as the most important innate immune determinant against invasive meningococcal disease since it protects the host through the bactericidal membrane attack complex. However, complement activation concomitantly liberates the C5a peptide, and it remains unclear whether this potent anaphylatoxin contributes to protection and/or drives the rapidly progressing immunopathogenesis associated with meningococcal disease. Here, we dissected the specific contribution of C5a receptor 1 (C5aR1), the canonical receptor for C5a, using a mouse model of meningococcal sepsis. Mice lacking C3 or C5 displayed susceptibility that was enhanced by >1,000-fold or 100-fold, respectively, consistent with the contribution of these components to protection. In clear contrast, C5ar1\(^{-/-}\) mice resisted invasive meningococcal infection and cleared N. meningitidis more rapidly than wild-type (WT) animals. This favorable outcome stemmed from an ameliorated inflammatory cytokine response to N. meningitidis in C5ar1\(^{-/-}\) mice in both in vivo and ex vivo whole-blood infections. In addition, inhibition of C5aR1 signaling without interference with the complement bactericidal activity reduced the inflammatory response also in human whole blood. Enticingly, pharmacologic C5aR1 blockade enhanced mouse survival and lowered meningococcal burden even when the treatment was administered after sepsis induction. Together, our findings demonstrate that C5aR1 drives the pathophysiology associated with meningococcal sepsis and provides a promising target for adjunctive therapy.
Importance:
The devastating consequences of N. meningitidis sepsis arise due to the rapidly arising and self-propagating inflammatory response that mobilizes antibacterial defenses but also drives the immunopathology associated with meningococcemia. The complement cascade provides innate broad-spectrum protection against infection by directly damaging the envelope of pathogenic microbes through the membrane attack complex and triggers an inflammatory response via the C5a peptide and its receptor C5aR1 aimed at mobilizing cellular effectors of immunity. Here, we consider the potential of separating the bactericidal activities of the complement cascade from its immune activating function to improve outcome of N. meningitidis sepsis. Our findings demonstrate that the specific genetic or pharmacological disruption of C5aR1 rapidly ameliorates disease by suppressing the pathogenic inflammatory response and, surprisingly, allows faster clearance of the bacterial infection. This outcome provides a clear demonstration of the therapeutic benefit of the use of C5aR1-specific inhibitors to improve the outcome of invasive meningococcal disease.
Due to intensive agriculture honeybees are threatened by various pesticides. The use of one group of them, the neonicotinoids, was recently restricted by the European Union. These chemicals bind to the nicotinic acetylcholine receptor (nAchR) in the honeybee brain. Recently, Bayer AG released a new pesticide by the name of “Sivanto” against sucking insects. It is assumed to be harmless for honeybees, although its active ingredient, flupyradifurone, binds nAchR similar to the neonicotinoids. We investigated if this pesticide affects the taste for sugar and cognitive performance in honeybee foragers. These bees are directly exposed to the pesticide while foraging for pollen or nectar. Our results demonstrate that flupyradifurone can reduce taste and appetitive learning performance in honeybees foraging for pollen and nectar, although only the highest concentration had significant effects. Most likely, honeybee foragers will not be exposed to these high concentrations. Therefore, the appropriate use of this pesticide is considered safe for honeybees, at least with respect to the behaviors studied here.
For mutagenicity testing, primary lymphocytes or mammalian cell lines are employed. However, the true target for carcinogenic action of mutagenic chemicals may be stem cells. Since hematopoietic cancers induced by chemical agents originate at the hematopoietic stem cell (HSC) stage and since one of the side effects of chemotherapeutic cancer treatment is the induction of secondary tumors, often leukemias, HSC may be a suitable cell system. We compared the sensitivity of HSC with the genotoxicity testing cell line TK6 for chromosomal mutations. HSC were less sensitive than TK6 cells for the genotoxic effects of the model genotoxins and chemotherapeutic agents doxorubicin, vinblastine, methyl methanesulfonate (MMS) and equally sensitive for mitomycin C (MMC). However, loss of viability after mitomycin C treatment was higher in HSC than in TK6 cells. Among the factors that may influence sensitivity for genomic damage, the generation or response to reactive oxygen species (ROS) and the effectiveness of DNA damage response can be discussed. Here we show that HSC can be used in a standard micronucleus test protocol for chromosomal mutations and that their sensitivity was not higher than that of a classical testing cell line.
Background:
Genetic heterogeneity and consanguineous marriages make recessive inherited hearing loss in Iran the second most common genetic disorder. Only two reported pathogenic variants (c.323G>C, p.Arg108Pro and c.419A>G, p.Tyr140Cys) in the S1PR2 gene have previously been linked to autosomal recessive hearing loss (DFNB68) in two Pakistani families. We describe a segregating novel homozygous c.323G>A, p.Arg108Gln pathogenic variant in S1PR2 that was identified in four affected individuals from a consanguineous five generation Iranian family.
Methods:
Whole exome sequencing and bioinformatics analysis of 116 hearing loss-associated genes was performed in an affected individual from a five generation Iranian family. Segregation analysis and 3D protein modeling of the p.Arg108 exchange was performed.
Results:
The two Pakistani families previously identified with S1PR2 pathogenic variants presented profound hearing loss that is also observed in the affected Iranian individuals described in the current study. Interestingly, we confirmed mixed hearing loss in one affected individual. 3D protein modeling suggests that the p.Arg108 position plays a key role in ligand receptor interaction, which is disturbed by the p.Arg108Gln change.
Conclusion:
In summary, we report the third overall mutation in S1PR2 and the first report outside the Pakistani population. Furthermore, we describe a novel variant that causes an amino acid exchange (p.Arg108Gln) in the same amino acid residue as one of the previously reported Pakistani families (p.Arg108Pro). This finding emphasizes the importance of the p.Arg108 amino acid in normal hearing and confirms and consolidates the role of S1PR2 in autosomal recessive hearing loss.
Arbuscular Mycorrhiza and Root Nodule Symbiosis are symbiotic interactions with a high benefit for plant growth and crop production. Thus, it is of great interest to understand the developmental process of these symbioses in detail. We analysed very early symbiotic responses of Medicago truncatula root hair cells, by stimulation with lipochitinoligosaccharides specific for the induction of nodules (Nod-LCOs), or the interaction with mycorrhiza (Myc-LCOs). Intracellular micro electrodes were used, in combination with Ca\(^{2+}\) sensitive reporter dyes, to study the relations between cytosolic Ca\(^{2+}\) signals and membrane potential changes. We found that sulfated Myc- as well as Nod-LCOs initiate a membrane depolarization, which depends on the chemical composition of these signaling molecules, as well as the genotype of the plants that were studied. A successive application of sulfated Myc-LCOs and Nod-LCOs resulted only in a single transient depolarization, indicating that Myc-LCOs can repress plasma membrane responses to Nod-LCOs. In contrast to current models, the Nod-LCO-induced depolarization precedes changes in the cytosolic Ca\(^{2+}\) level of root hair cells. The Nod-LCO induced membrane depolarization thus is most likely independent of cytosolic Ca\(^{2+}\) signals and nuclear Ca\(^{2+}\) spiking.
Beneficial effects of vitamin D treatment in an obese mouse model of non-alcoholic steatohepatitis
(2019)
Serum vitamin D levels negatively correlate with obesity and associated disorders such as non-alcoholic steatohepatitis (NASH). However, the mechanisms linking low vitamin D (VD) status to disease progression are not completely understood. In this study, we analyzed the effect of VD treatment on NASH in mice. C57BL6/J mice were fed a high-fat/high-sugar diet (HFSD) containing low amounts of VD for 16 weeks to induce obesity, NASH and liver fibrosis. The effects of preventive and interventional VD treatment were studied on the level of liver histology and hepatic/intestinal gene expression. Interestingly, preventive and to a lesser extent also interventional VD treatment resulted in improvements of liver histology. This included a significant decrease of steatosis, a trend towards lower non-alcoholic fatty liver disease (NAFLD) activity score and a slight non-significant decrease of fibrosis in the preventive treatment group. In line with these changes, preventive VD treatment reduced the hepatic expression of lipogenic, inflammatory and pro-fibrotic genes. Notably, these beneficial effects occurred in conjunction with a reduction of intestinal inflammation. Together, our observations suggest that timely initiation of VD supplementation (preventive vs. interventional) is a critical determinant of treatment outcome in NASH. In the applied animal model, the improvements of liver histology occurred in conjunction with reduced inflammation in the gut, suggesting a potential relevance of vitamin D as a therapeutic agent acting on the gut–liver axis.
Fibroblasts were isolated from a skin biopsy of a clinically diagnosed 51-year-old female attention-deficit/hyperactivity disorder (ADHD) patient carrying a duplication of SLC2A3, a gene encoding neuronal glucose transporter-3 (GLUT3). Patient fibroblasts were infected with Sendai virus, a single-stranded RNA virus, to generate transgene-free human induced pluripotent stem cells (iPSCs). SLC2A3-D2-iPSCs showed expression of pluripotency-associated markers, were able to differentiate into cells of the three germ layers in vitro and had a normal female karyotype. This in vitro cellular model can be used to study the role of risk genes in the pathogenesis of ADHD, in a patient-specific manner.
The cell wall synthesis pathway producing peptidoglycan is a highly coordinated and tightly regulated process. Although the major components of bacterial cell walls have been known for decades, the complex regulatory network controlling peptidoglycan synthesis and many details of the cell division machinery are not well understood. The eukaryotic-like serine/threonine kinase Stk and the cognate phosphatase Stp play an important role in cell wall biosynthesis and drug resistance in S. aureus. We show that stp deletion has a pronounced impact on cell wall synthesis. Deletion of stp leads to a thicker cell wall and decreases susceptibility to lysostaphin. Stationary phase Δstp cells accumulate peptidoglycan precursors and incorporate higher amounts of incomplete muropeptides with non-glycine, monoglycine and monoalanine interpeptide bridges into the cell wall. In line with this cell wall phenotype, we demonstrate that the lipid II:glycine glycyltransferase FemX can be phosphorylated by the Ser/Thr kinase Stk in vitro. Mass spectrometric analyses identify Thr32, Thr36 and Ser415 as phosphoacceptors. The cognate phosphatase Stp dephosphorylates these phosphorylation sites. Moreover, Stk interacts with FemA and FemB, but is unable to phosphorylate them. Our data indicate that Stk and Stp modulate cell wall synthesis and cell division at several levels.
Objective:
Halothane and caffeine are known to cause skeletal muscular contractions in vitro and have been proven to induce circumscribed metabolic reactions when injected into rat skeletal muscle. In this study 26 rats were investigated by either continuous application of calcium 160 mM or bolus injection of caffeine 160 mM or halothane 10% vol via a microdialysis probe in the tibialis anterior muscle. Tissue elasticity at the injection site was monitored by ultrasound strain elastography. Aim of this study was to detect (I) changes in local lactate concentrations and (II) whether these can be attributed to a muscular contraction detected by ultrasound elastography.
Results:
Localized metabolic reactions were verified by increasing intramuscular lactate concentrations following continuous application of calcium (0.6 [0.3;0.6] to 3.6 [3.0;4.3] mmol/l after 60 min) and bolus application of caffeine (0.2 [0.2;0.3] to 1.6 [0.9;1.9] mmol/l after 30 min) and halothane (0.3 [0.1;0.3] to 4.7 [4.3;6.3] mmol/l after 30 min). However, ultrasound elastography did not detect any differences in tissue elasticity compared to control animals. The authors identified potential limitations of the study conditions, which might be crucial to avoid for future investigations.
Synaptic vesicles (SVs) are a key component of neuronal signaling and fulfil different roles depending on their composition. In electron micrograms of neurites, two types of vesicles can be distinguished by morphological criteria, the classical “clear core” vesicles (CCV) and the typically larger “dense core” vesicles (DCV), with differences in electron density due to their diverse cargos. Compared to CCVs, the precise function of DCVs is less defined. DCVs are known to store neuropeptides, which function as neuronal messengers and modulators [1]. In C. elegans, they play a role in locomotion, dauer formation, egg-laying, and mechano- and chemosensation [2]. Another type of DCVs, also referred to as granulated vesicles, are known to transport Bassoon, Piccolo and further constituents of the presynaptic density in the center of the active zone (AZ), and therefore are important for synaptogenesis [3].
To better understand the role of different types of SVs, we present here a new automated approach to classify vesicles. We combine machine learning with an extension of our previously developed vesicle segmentation workflow, the ImageJ macro 3D ART VeSElecT. With that we reliably distinguish CCVs and DCVs in electron tomograms of C. elegans NMJs using image-based features. Analysis of the underlying ground truth data shows an increased fraction of DCVs as well as a higher mean distance between DCVs and AZs in dauer larvae compared to young adult hermaphrodites. Our machine learning based tools are adaptable and can be applied to study properties of different synaptic vesicle pools in electron tomograms of diverse model organisms.
Bee population declines are often linked to human impacts, especially habitat and biodiversity loss, but empirical evidence is lacking. To clarify the link between biodiversity loss and bee decline, we examined how floral diversity affects (reproductive) fitness and population growth of a social stingless bee. For the first time, we related available resource diversity and abundance to resource (quality and quantity) intake and colony reproduction, over more than two years. Our results reveal plant diversity as key driver of bee fitness. Social bee colonies were fitter and their populations grew faster in more florally diverse environments due to a continuous supply of food resources. Colonies responded to high plant diversity with increased resource intake and colony food stores. Our findings thus point to biodiversity loss as main reason for the observed bee decline.
Background:
In previous studies, the gram-positive firmicute genus Paenibacillus was found with significant abundances in nests of wild solitary bees. Paenibacillus larvae is well-known for beekeepers as a severe pathogen causing the fatal honey bee disease American foulbrood, and other members of the genus are either secondary invaders of European foulbrood or considered a threat to honey bees. We thus investigated whether Paenibacillus is a common bacterium associated with various wild bees and hence poses a latent threat to honey bees visiting the same flowers.
Results:
We collected 202 samples from 82 individuals or nests of 13 bee species at the same location and screened each for Paenibacillus using high-throughput sequencing-based 16S metabarcoding. We then isolated the identified strain Paenibacillus MBD-MB06 from a solitary bee nest and sequenced its genome. We did find conserved toxin genes and such encoding for chitin-binding proteins, yet none specifically related to foulbrood virulence or chitinases. Phylogenomic analysis revealed a closer relationship to strains of root-associated Paenibacillus rather than strains causing foulbrood or other accompanying diseases. We found anti-microbial evidence within the genome, confirmed by experimental bioassays with strong growth inhibition of selected fungi as well as gram-positive and gram-negative bacteria.
Conclusions:
The isolated wild bee associate Paenibacillus MBD-MB06 is a common, but irregularly occurring part of wild bee microbiomes, present on adult body surfaces and guts and within nests especially in megachilids. It was phylogenetically and functionally distinct from harmful members causing honey bee colony diseases, although it shared few conserved proteins putatively toxic to insects that might indicate ancestral predisposition for the evolution of insect pathogens within the group. By contrast, our strain showed anti-microbial capabilities and the genome further indicates abilities for chitin-binding and biofilm-forming, suggesting it is likely a useful associate to avoid fungal penetration of the bee cuticula and a beneficial inhabitant of nests to repress fungal threats in humid and nutrient-rich environments of wild bee nests.
A mathematical optimal-control tumor therapy framework consisting of radio- and anti-angiogenesis control strategies that are included in a tumor growth model is investigated. The governing system, resulting from the combination of two well established models, represents the differential constraint of a non-smooth optimal control problem that aims at reducing the volume of the tumor while keeping the radio- and anti-angiogenesis chemical dosage to a minimum. Existence of optimal solutions is proved and necessary conditions are formulated in terms of the Pontryagin maximum principle. Based on this principle, a so-called sequential quadratic Hamiltonian (SQH) method is discussed and benchmarked with an “interior point optimizer―a mathematical programming language” (IPOPT-AMPL) algorithm. Results of numerical experiments are presented that successfully validate the SQH solution scheme. Further, it is shown how to choose the optimisation weights in order to obtain treatment functions that successfully reduce the tumor volume to zero.
It is a common belief that feral honey bee colonies (Apis mellifera L.) were eradicated in Europe through the loss of habitats, domestication by man and spread of pathogens and parasites. Interestingly, no scientific data are available, neither about the past nor the present status of naturally nesting honeybee colonies. We expected near-natural beech (Fagus sylvatica L.) forests to provide enough suitable nest sites to be a home for feral honey bee colonies in Europe. Here, we made a first assessment of their occurrence and density in two German woodland areas based on two methods, the tracing of nest sites based on forager flight routes (beelining technique), and the direct inspection of potential cavity trees. Further, we established experimental swarms at forest edges and decoded dances for nest sites performed by scout bees in order to study how far swarms from beekeeper-managed hives would potentially move into a forest. We found that feral honey bee colonies regularly inhabit tree cavities in near-natural beech forests at densities of at least 0.11-0.14 colonies/km\(^{2}\). Colonies were not confined to the forest edges; they were also living deep inside the forests. We estimated a median distance of 2,600 m from the bee trees to the next apiaries, while scout bees in experimental swarms communicated nest sites in close distances (median: 470 m). We extrapolate that there are several thousand feral honey bee colonies in German woodlands. These have to be taken in account when assessing the role of forest areas in providing pollination services to the surrounding land, and their occurrence has implications for the species' perception among researchers, beekeepers and conservationists. This study provides a starting point for investigating the life-histories and the ecological interactions of honey bees in temperate European forest environments.
Teleost fish provide some of the most intriguing examples of sexually dimorphic coloration, which is often advantageous for only one of the sexes. Mapping studies demonstrated that the genetic loci underlying such color patterns are frequently in tight linkage to the sex-determining locus of a species, ensuring sex-specific expression of the corresponding trait. Several genes affecting color synthesis and pigment cell development have been previously described, but the color loci on the sex chromosomes have mostly remained elusive as yet. Here, we summarize the current knowledge about the genetics of such color loci in teleosts, mainly from studies on poeciliids and cichlids. Further studies on these color loci will certainly provide important insights into the evolution of sex chromosomes.
In tissue engineering, the generation and functional maintenance of dense voluminous tissues is mainly restricted due to insufficient nutrient supply. Larger three-dimensional constructs, which exceed the nutrient diffusion limit become necrotic and/or apoptotic in long-term culture if not provided with an appropriate vascularization. Here, we established protocols for the generation of a pre-vascularized biological scaffold with intact arterio-venous capillary loops from rat intestine, which is decellularized under preservation of the feeding and draining vascular tree. Vessel integrity was proven by marker expression, media/blood reflow and endothelial LDL uptake. In vitro maintenance persisted up to 7 weeks in a bioreactor system allowing a stepwise reconstruction of fully vascularized human tissues and successful in vivo implantation for up to 4 weeks, although with time-dependent decrease of cell viability. The vascularization of the construct lead to a 1.5× increase in cellular drug release compared to a conventional static culture in vitro. For the first time, we performed proof-of-concept studies demonstrating that 3D tissues can be maintained within a miniaturized vascularized scaffold in vitro and successfully implanted after re-anastomosis to the intrinsic blood circulation in vivo. We hypothesize that this technology could serve as a powerful platform technology in tissue engineering and regenerative medicine.
Although questionable research practices (QRPs) and p-hacking have received attention in recent years, little research has focused on their prevalence and acceptance in students. Students are the researchers of the future and will represent the field in the future. Therefore, they should not be learning to use and accept QRPs, which would reduce their ability to produce and evaluate meaningful research. 207 psychology students and fresh graduates provided self-report data on the prevalence and predictors of QRPs. Attitudes towards QRPs, belief that significant results constitute better science or lead to better grades, motivation, and stress levels were predictors. Furthermore, we assessed perceived supervisor attitudes towards QRPs as an important predictive factor. The results were in line with estimates of QRP prevalence from academia. The best predictor of QRP use was students’ QRP attitudes. Perceived supervisor attitudes exerted both a direct and indirect effect via student attitudes. Motivation to write a good thesis was a protective factor, whereas stress had no effect. Students in this sample did not subscribe to beliefs that significant results were better for science or their grades. Such beliefs further did not impact QRP attitudes or use in this sample. Finally, students engaged in more QRPs pertaining to reporting and analysis than those pertaining to study design. We conclude that supervisors have an important function in shaping students’ attitudes towards QRPs and can improve their research practices by motivating them well. Furthermore, this research provides some impetus towards identifying predictors of QRP use in academia.
The honeybee olfactory pathway comprises an intriguing pattern of convergence and divergence: ~60.000 olfactory sensory neurons (OSN) convey olfactory information on ~900 projection neurons (PN) in the antennal lobe (AL). To transmit this information reliably, PNs employ relatively high spiking frequencies with complex patterns. PNs project via a dual olfactory pathway to the mushroom bodies (MB). This pathway comprises the medial (m-ALT) and the lateral antennal lobe tract (l-ALT). PNs from both tracts transmit information from a wide range of similar odors, but with distinct differences in coding properties. In the MBs, PNs form synapses with many Kenyon cells (KC) that encode odors in a spatially and temporally sparse way. The transformation from complex information coding to sparse coding is a well-known phenomenon in insect olfactory coding. Intrinsic neuronal properties as well as GABAergic inhibition are thought to contribute to this change in odor representation. In the present study, we identified intrinsic neuronal properties promoting coding differences between PNs and KCs using in-situ patch-clamp recordings in the intact brain. We found very prominent K+ currents in KCs clearly differing from the PN currents. This suggests that odor coding differences between PNs and KCs may be caused by differences in their specific ion channel properties. Comparison of ionic currents of m- and l-ALT PNs did not reveal any differences at a qualitative level.
The human body is constantly attacked by pathogens. Various lines of defence have evolved, among which the immune system is principal. In contrast to most pathogens, the African trypanosomes thrive freely in the blood circulation, where they escape immune destruction by antigenic variation and incessant motility. These unicellular parasites are flagellate microswimmers that also withstand the harsh mechanical forces prevailing in the bloodstream. They undergo complex developmental cycles in the bloodstream and organs of the mammalian host, as well as the disease-transmitting tsetse fly. Each life cycle stage has been shaped by evolution for manoeuvring in distinct microenvironments. Here, we introduce trypanosomes as blueprints for nature-inspired design of trypanobots, micromachines that, in the future, could explore the human body without affecting its physiology. We review cell biological and biophysical aspects of trypanosome motion. While this could provide a basis for the engineering of microbots, their actuation and control still appear more like fiction than science. Here, we discuss potentials and challenges of trypanosome-inspired microswimmer robots.
Background:
To analyze whether magnesium has a neuroprotective effect during episodes that indicate a critical brain perfusion after aneurysmal subarachnoid hemorrhage (SAH).
Methods:
107 patients with aSAH were randomized to continuously receive intravenous magnesium sulfate with target serum levels of 2.0 – 2.5 mmol/l (n = 54) or isotonic saline (n = 53). Neurological examination and transcranial Doppler sonography (TCD) were performed daily, Perfusion-CT (PCT) was acquired in 3-day intervals, angiography in case of suspected vasospasm. The primary endpoint was the development of secondary infarction following episodes of delayed ischemic neurological deficit (DIND), elevated mean flow velocity (MFV) in TCD or pathological findings in PCT.
Results:
In the magnesium group, 9 episodes of DIND were registered, none was followed by secondary infarction. In the control group, 23 episodes of DIND were registered, 9 were followed by secondary infarction (p < 0.05). In the magnesium group, 114 TCD-measurements showed an elevated MFV(> 140 cm/s). 7 were followed by new infarction. In control patients, 135 measurements showed elevated MFV, 32 were followed by new infarction (p < 0.05). 10 of 117 abnormal PCT-findings were followed by new infarction, compared to 30 of 122 in the control-group (p < 0.05).
Conclusion:
DIND, elevated MFV in TCD and abnormal PCT are findings which are associated with an increased risk to develop delayed secondary infarction. The results of this analysis suggest that magnesium-treatment may reduce the risk to develop infarction in a state of critical brain perfusion.
Epichloë endophytes associated with cool-season grass species can protect their hosts from herbivory and can suppress mycorrhizal colonization of the hosts’ roots. However, little is known about whether or not Epichloë endophyte infection can also change the foliar fungal assemblages of the host. We tested 52 grassland study sites along a land-use intensity gradient in three study regions over two seasons (spring vs. summer) to determine whether Epichloë infection of the host grass Lolium perenne changes the fungal community structure in leaves. Foliar fungal communities were assessed by Next Generation Sequencing of the ITS rRNA gene region. Fungal community structure was strongly affected by study region and season in our study, while land-use intensity and infection with Epichloë endophytes had no significant effects. We conclude that effects on non-systemic endophytes resulting from land use practices and Epichloë infection reported in other studies were masked by local and seasonal variability in this study’s grassland sites.
Compared to naive T cells, differentiated T cells are thought to be less dependent on CD28 costimulation for full activation. To revisit the role of CD28 costimulation in mouse T cell recall responses, we adoptively transferred in vitro generated OT-II T helper (Th) 1 cells into C57BL/6 mice (Thy1.2\(^{+}\)) and then either blocked CD28–ligand interactions with Fab fragments of the anti-CD28 monoclonal antibody (mAb) E18 or deleted CD28 expression using inducible CD28 knock-out OT-II mice as T cell donors. After injection of ovalbumin protein in adjuvant into the recipient mice we observed that systemic interferon (IFN)γ release strongly depended on CD28 costimulation of the Th1 cells, while secondary clonal expansion was not reduced in the absence of CD28 costimulation. For human memory CD4\(^{+}\) T cell responses we also noted that cytokine release was reduced upon inhibition of CD28 costimulation. Together, our data highlight the so far underestimated role of CD28 costimulation for the reactivation of fully differentiated CD4\(^{+}\) T cells.
Background:
Drug induced immune hemolytic anemia (DIIHA) is a rare complication and often underdiagnosed. DIIHA is frequently associated with a bad outcome, including organ failure and even death. For the last decades, ceftriaxone has been one of the most common drugs causing DIIHA, and ceftriaxone-induced immune hemolytic anemia (IHA) has especially been reported to cause severe complications and fatal outcomes.
Case Presentation:
A 76-year-old male patient was treated with ceftriaxone for cholangitis. Short time after antibiotic exposure the patient was referred to intensive care unit due to cardiopulmonary instability. Hemolysis was observed on laboratory testing and the patient developed severe renal failure with a need for hemodialysis for 2 weeks. Medical history revealed that the patient had been previously exposed to ceftriaxone less than 3 weeks before with subsequent hemolytic reaction. Further causes for hemolytic anemia were excluded and drug-induced immune hemolytic (DIIHA) anemia to ceftriaxone could be confirmed.
Conclusions:
The case demonstrates the severity of ceftriaxone-induced immune hemolytic anemia, a rare, but immediately life-threatening condition of a frequently used antibiotic in clinical practice. Early and correct diagnosis of DIIHA is crucial, as immediate withdrawal of the causative drug is essential for the patient prognosis. Thus, awareness for this complication must be raised among treating physicians.
Background:
The compound eyes of insects allow them to catch photons and convert the energy into electric signals. All compound eyes consist of numerous ommatidia, each comprising a fixed number of photoreceptors. Different ommatidial types are characterized by a specific set of photoreceptors differing in spectral sensitivity. In honey bees, males and females possess different ommatidial types forming distinct retinal mosaics. However, data are lacking on retinal ontogeny and the mechanisms by which the eyes are patterned. In this study, we investigated the intrinsic temporal and circadian expression patterns of the opsins that give rise to the ultraviolet, blue and green sensitive photoreceptors, as well as the morphological maturation of the retina during pupal development of honey bees.
Results:
qPCR and histological labeling revealed that temporal opsin mRNA expression differs between sexes and correlates with rhabdom elongation during photoreceptor development. In the first half of the pupal stage, when the rhabdoms of the photoreceptors are still short, worker and (dorsal) drone retinae exhibit similar expression patterns with relatively high levels of UV (UVop) and only marginal levels of blue (BLop) and green (Lop1) opsin mRNA. In the second half of pupation, when photoreceptors and rhabdoms elongate, opsin expression in workers becomes dominated by Lop1 mRNA. In contrast, the dorsal drone eye shows high expression levels of UVop and BLop mRNA, whereas Lop1 mRNA level decreases. Interestingly, opsin expression levels increase up to 22-fold during early adult life. We also found evidence that opsin expression in adult bees is under the control of the endogenous clock.
Conclusions:
Our data indicate that the formation of the sex-specific retinal composition of photoreceptors takes place during the second half of the pupal development, and that opsin mRNA expression levels continue to increase in young bees, which stands in contrast to Drosophila, where the highest expression levels are found during the late pupal stage and remain constant in adults. From an evolutionary perspective, we hypothesize that the delayed retinal maturation during the early adult phase is linked to the delayed transition from indoor to outdoor activities in bees, when vision becomes important.
Background:
Cerebellar liponeurocytoma is an extremely rare tumour entity of the central nervous system. It is histologically characterised by prominent neuronal/neurocytic differentiation with focal lipidisation and corresponding histologically to WHO grade II. It typically develops in adults, and usually shows a low proliferative potential. Recurrences have been reported in almost 50% of cases, and in some cases the recurrent tumour may display increased mitotic activity and proliferation index, vascular proliferations and necrosis. Thus pathological diagnosis of liponeurocytoma is challenging. This case presentation highlights the main clinical, radiographic and pathological features of a cerebellar liponeurocytoma.
Case presentation:
A 59-year-old, right-handed woman presented at our department with a short history of persistent headache, vertigo and gait disturbances. Examination at presentation revealed that the patient was awake, alert and fully oriented. The cranial nerve status was normal. Uncertainties were noted in the bilateral finger-to-nose testing with bradydiadochokinesis on both sides. Strength was full and no pronator drift was observed. Sensation was intact. No signs of pyramidal tract dysfunction were detected. Her gait appeared insecure. The patient underwent surgical resection. Afterward no further disturbances could be detected.
Conclusions:
To date >40 cases of liponeurocytoma have been reported, including cases with supratentorial location. A review of the 5 published cases of recurrent cerebellar. Liponeurocytoma revealed that the median interval between the first and second relapse was rather short, indicating uncertain malignant potential. The most recent WHO classification of brain tumours (2016) classifies the cerebellar liponeurocytoma as a separate entity and assigns the tumour to WHO grade II. Medulloblastoma is the most important differential diagnosis commonly seen in children and young adults. In contrast, cerebellar liponeurocytoma is typically diagnosed in adults. The importance of accurate diagnosis should not be underestimated especially in the view of possible further therapeutic interventions and for the determination of the patient's prognosis.
Highly invasive animal based test procedures for risk assessment such as the Draize eye test are under increasing criticism due to poor transferability for the human organism and animal-welfare concerns. However, besides all efforts, the Draize eye test is still not completely replaced by alternative animal-free methods. To develop an in vitro test to identify all categories of eye irritation, we combined organotypic cornea models based on primary human cells with an electrical readout system that measures the impedance of the test models. First, we showed that employing a primary human cornea epithelial cell based model is advantageous in native marker expression to the primary human epidermal keratinocytes derived models. Secondly, by employing a non-destructive measuring system based on impedance spectroscopy, we could increase the sensitivity of the test system. Thereby, all globally harmonized systems categories of eye irritation could be identified by repeated measurements over a period of 7 days. Based on a novel prediction model we achieved an accuracy of 78% with a reproducibility of 88.9% to determine all three categories of eye irritation in one single test. This could pave the way according to the 3R principle to replace the Draize eye test.
Background:
Acute kidney injury (AKI) is a serious complication after cardiac surgery that is associated with increased mortality and morbidity. Heme oxygenase-1 (HO-1) is an enzyme synthesized in renal tubular cells as one of the most intense responses to oxidant stress linked with protective, anti-inflammatory properties. Yet, it is unknown if serum HO-1 induction following cardiac surgical procedure involving cardiopulmonary bypass (CPB) is associated with incidence and severity of AKI.
Patients and methods:
In the present study, we used data from a prospective cohort study of 150 adult cardiac surgical patients. HO-1 measurements were performed before, immediately after and 24 hours post-CPB. In univariate and multivariate analyses, the association between HO-1 and AKI was investigated.
Results:
AKI with an incidence of 23.3% (35 patients) was not associated with an early elevation of HO-1 after CPB in all patients (P=0.88), whereas patients suffering from AKI developed a second burst of HO-1 24 hours after CBP. In patients without AKI, the HO-1 concentrations dropped to baseline values (P=0.031). Furthermore, early HO-1 induction was associated with CPB time (P=0.046), while the ones 24 hours later lost this association (P=0.219).
Conclusion:
The association of the second HO-1 burst 24 hours after CBP might help to distinguish between the causality of AKI in patients undergoing CBP, thus helping to adapt patient stratification and management.
Background
The impact of risk factors on poor outcome after ischemic stroke is well known, but estimating the amount of poor outcome attributable to single factors is challenging in presence of multimorbidity. We aim to compare population attributable risk estimates obtained from different statistical approaches regarding their consistency. We use a real-life data set from the PROSCIS study to identify predictors for mortality and functional impairment one year after first-ever ischemic stroke and quantify their contribution to poor outcome using population attributable risks.
Methods
The PROSpective Cohort with Incident Stroke (PROSCIS) is a prospective observational hospital-based cohort study of patients after first-ever stroke conducted independently in Berlin (PROSCIS-B) and Munich (PROSCIS-M). The association of baseline factors with poor outcome one year after stroke in PROSCIS-B was analysed using multiple logistic regression analysis and population attributable risks were calculated, which were estimated using sequential population attributable risk based on a multiple generalized additive regression model, doubly robust estimation, as well as using average sequential population attributable risk. Findings were reproduced in an independent validation sample from PROSCIS-M.
Results
Out of 507 patients with available outcome information after 12 months in PROSCIS-B, 20.5% suffered from poor outcome. Factors associated with poor outcome were age, pre-stroke physical disability, stroke severity (NIHSS), education, and diabetes mellitus. The order of risk factors ranked by magnitudes of population attributable risk was almost similar for all methods, but population attributable risk estimates varied markedly between the methods. In PROSCIS-M, incidence of poor outcome and distribution of baseline parameters were comparable. The multiple logistic regression model could be reproduced for all predictors, except pre-stroke physical disability. Similar to PROSCIS-B, the order of risk factors ranked by magnitudes of population attributable risk was almost similar for all methods, but magnitudes of population attributable risk differed markedly between the methods.
Conclusions
Ranking of risk factors by population impact is not affected by the different statistical approaches. Thus, for a rational decision on which risk factor to target in disease interventions, population attributable risk is a supportive tool. However, population attributable risk estimates are difficult to interpret and are not comparable when they origin from studies applying different methodology. The predictors for poor outcome identified in PROSCIS-B have a relevant impact on mortality and functional impairment one year after first-ever ischemic stroke.
Background:
The saprophytic fungus Aspergillus fumigatus reproduces by generation of conidia, which are spread by airflow throughout nature. Since humans are inhaling certain amounts of spores every day, the (innate) immune system is constantly challenged. Even though macrophages and neutrophils carry the main burden, also NK cells are regarded to contribute to the antifungal immune response. While NK cells reveal a low frequency, expression and release of immunomodulatory molecules seem to be a natural way of their involvement.
Results:
In this study we show, that NK cells secrete chemokines such as CCL3/MIP-1α, CCL4/MIP-1β and CCL5/RANTES early on after stimulation with Aspergillus fumigatus and, in addition, adjust the concentration of chemokines released to the multiplicity of infection of Aspergillus fumigatus.
Conclusions:
These results further corroborate the relevance of NK cells within the antifungal immune response, which is regarded to be more and more important in the development and outcome of invasive aspergillosis in immunocompromised patients after hematopoietic stem cell transplantation. Additionally, the correlation between the multiplicity of infection and the expression and release of chemokines shown here may be useful in further studies for the quantification and/or surveillance of the NK cell involvement in antifungal immune responses.
Background:
Mitral regurgitation in ischemic heart disease (IMR) is a strong predictor of outcome but until now, pathophysiology is not sufficiently understood and treatment is not satisfying. We aimed to systematically evaluate structural and functional mitral valve leaflet and annular characteristics in patients with IMR to determine the differences in geometric and dynamic changes of the MV between significant and mild IMR.
Methods:
Thirty-seven patients with IMR (18 mild (m)MR, 19 significant (moderate+severe) (s)MR) and 33 controls underwent TEE. 3D volumes were analyzed using 3D feature-tracking software.
Results:
All IMR patients showed a loss of mitral annular motility and non-planarity, whereas mitral annulus dilation and leaflet enlargement occurred in sMR only. Active-posterior-leaflet-area decreased in early systole in all three groups accompanied by an increase in active-anterior-leaflet-area in early systole in controls and mMR but only in late systole in sMR.
Conclusions:
In addition to a significant enlargement and loss in motility of the MV annulus, patients with significant IMR showed a spatio-temporal alteration of the mitral valve coaptation line due to a delayed increase in active-anterior-leaflet-area. This abnormality is likely to contribute to IMR severity and is worth the evaluation of becoming a parameter for clinical decision-making. Further, addressing the leaflets aiming to increase the active leaflet-area is a promising therapeutic approach for significant IMR. Additional studies with a larger sample size and post-operative assessment are warranted to further validate our findings and help understand the dynamics of the mitral valve.
Background:
The Catechol-O-methyltransferase (COMT) represents the key enzyme in catecholamine degradation. Recent studies suggest that the COMT rs4680 polymorphism is associated with the response to endogenous and exogenous catecholamines. There are, however, conflicting data regarding the COMT Met/Met phenotype being associated with an increased risk of acute kidney injury (AKI) after cardiac surgery. The aim of the current study is to prospectively investigate the impact of the COMT rs4680 polymorphism on the incidence of AKI in patients undergoing cardiac surgery.
Methods:
In this prospective single center cohort study consecutive patients hospitalized for elective cardiac surgery including cardiopulmonary-bypass (CPB) were screened for participation. Demographic clinical data, blood, urine and tissue samples were collected at predefined time points throughout the clinical stay. AKI was defined according to recent recommendations of the Kidney Disease Improving Global Outcome (KDIGO) group. Genetic analysis was performed after patient enrolment was completed.
Results:
Between April and December 2014, 150 patients were recruited. The COMT genotypes were distributed as follows: Val/Met 48.7%, Met/Met 29.3%, Val/Val 21.3%. No significant differences were found for demography, comorbidities, or operative strategy according to the underlying COMT genotype. AKI occurred in 35 patients (23.5%) of the total cohort, and no differences were evident between the COMT genotypes (20.5% Met/Met, 24.7% Val/Met, 25.0% Val/Val, p = 0.66). There were also no differences in the post-operative period, including ICU or in-hospital stay.
Conclusions:
We did not find statistically significant variations in the risk for postoperative AKI, length of ICU or in-hospital stay according to the underlying COMT genotype.
The modulation of an animal’s behavior through external sensory stimuli, previous experience and its internal state is crucial to survive in a constantly changing environment. In most insects, octopamine (OA) and its precursor tyramine (TA) modulate a variety of physiological processes and behaviors by shifting the organism from a relaxed or dormant condition to a responsive, excited and alerted state. Even though OA/TA neurons of the central brain are described on single cell level in Drosophila melanogaster, the periphery was largely omitted from anatomical studies. Given that OA/TA is involved in behaviors like feeding, flying and locomotion, which highly depend on a variety of peripheral organs, it is necessary to study the peripheral connections of these neurons to get a complete picture of the OA/TA circuitry. We here describe the anatomy of this aminergic system in relation to peripheral tissues of the entire fly. OA/TA neurons arborize onto skeletal muscles all over the body and innervate reproductive organs, the heart, the corpora allata, and sensory organs in the antennae, legs, wings and halteres underlining their relevance in modulating complex behaviors.
Background:
The treatment strategies for colorectal cancer located in the right side of the colon have changed dramatically during the last decade. Due to the introduction of complete mesocolic excision (CME) with central ligation of the vessels and systematic lymph node dissection, the long-term survival of affected patients has increased significantly. It has also been proposed that right-sided colon resection can be performed laparoscopically with the same extent of resection and equal long-term results.
Methods:
A retrospective evaluation of a prospectively expanded database on right-sided colorectal cancer or adenoma treated at the University Hospital of Wuerzburg between 2009 and 2016 was performed. All patients underwent CME. This data was analyzed alone and in comparison to the published data describing laparoscopic right-sided colon resection for colon cancer.
Results:
The database contains 279 patients, who underwent right-sided colon resection due to colorectal cancer or colorectal adenoma (255 open; 24 laparoscopic). Operation data (time, length of stay, time on ICU) was equal or superior to laparoscopy, which is comparable to the published results. Surprisingly, the surrogate parameter for correct CME (the number of removed lymph nodes) was significantly higher in the open group. In a subgroup analysis only including patients who were feasible for laparoscopic resection and had been operated with an open procedure by an experienced surgeon, operation time was significantly shorter and the number of removed lymph nodes is significantly higher in the open group.
Conclusion:
So far, several studies demonstrate that laparoscopic right-sided colon resection is comparable to open resection. Our data suggests that a consequent CME during an open operation leads to significantly more removed lymph nodes than in laparoscopically resected patients and in several so far published data of open control groups from Europe. Further prospective randomized trials comparing the long-term outcome are urgently needed before laparoscopy for right-sided colon resection can be recommended ubiquitously.
Positron annihilation lifetime spectroscopy (PALS) provides a powerful technique for non-destructive microstructure investigations in a broad field of material classes such as metals, semiconductors, polymers or porous glasses. Even though this method is well established for more than five decades, no proper standardization for the used setup configuration and subsequent data processing exists. Eventually, this could lead to an insufficiency of data reproducibility and avoidable deviations.
Here we present experimentally obtained and simulated data of positron lifetime spectra at various statistics measured on pure tin (4N-Sn) by using a semi-analog/digital setup, where the digital section consists of the DRS4 evaluation board, “Design and performance of the 6 GHz waveform digitizing chip DRS4” [1]. The analog section consists of nuclear instrument modules (NIM), which externally trigger the DRS4 evaluation board to reduce the digitization and, thus, increase the acquisition efficiency. For the experimentally obtained lifetime spectra, 22Na sealed in Kapton foil served as a positron source, whereas 60Co was used for the acquisition of the prompt spectrum, i.e. the quasi instrument response function. Both types of measurements were carried out under the same conditions.
All necessary data and information regarding the data acquisition and data reduction are provided to allow reproducibility by other research groups.
DLTPulseGenerator: a library for the simulation of lifetime spectra based on detector-output pulses
(2018)
The quantitative analysis of lifetime spectra relevant in both life and materials sciences presents one of the ill-posed inverse problems and, hence, leads to most stringent requirements on the hardware specifications and the analysis algorithms. Here we present DLTPulseGenerator, a library written in native C++ 11, which provides a simulation of lifetime spectra according to the measurement setup. The simulation is based on pairs of non-TTL detector output-pulses. Those pulses require the Constant Fraction Principle (CFD) for the determination of the exact timing signal and, thus, the calculation of the time difference i.e. the lifetime. To verify the functionality, simulation results were compared to experimentally obtained data using Positron Annihilation Lifetime Spectroscopy (PALS) on pure tin.
This paper describes the estimation of the body weight of a person in front of an RGB-D camera. A survey of different methods for body weight estimation based on depth sensors is given. First, an estimation of people standing in front of a camera is presented. Second, an approach based on a stream of depth images is used to obtain the body weight of a person walking towards a sensor. The algorithm first extracts features from a point cloud and forwards them to an artificial neural network (ANN) to obtain an estimation of body weight. Besides the algorithm for the estimation, this paper further presents an open-access dataset based on measurements from a trauma room in a hospital as well as data from visitors of a public event. In total, the dataset contains 439 measurements. The article illustrates the efficiency of the approach with experiments with persons lying down in a hospital, standing persons, and walking persons. Applicable scenarios for the presented algorithm are body weight-related dosing of emergency patients.
Substandard and falsified (SF) medicines have emerged as a global public health issue within the last two decades especially in low- and middle-income countries (LMICs). Serious consequences of this problem include a loss of trust and increased financial costs due to less disease control and more frequent complications during therapy. Of note, antimicrobial resistance is an additional long-term implication of poor-quality antimicrobials. This review covers information technology tools including medicines authentication tools (MAT) as mobile apps and messaging service, 2D barcoding approaches with drug safety alert systems, web based drug safety alerts, radiofrequency identification tags, databases to support visual inspection, digital aids to enhance the performance of quality evaluation kits, reference libraries for identification of falsified and substandard medicines, and quality evaluation kits based on machine learning for field testing. While being easy to access and simple to use, these initiatives are gaining acceptance in LMICs. Implementing 2D barcoding based on end-to-end verification and "Track and Trace" systems has emerged as a step toward global security in the supply chain. A breakthrough in web-based drug safety alert systems and data bases was the establishment of the Global Surveillance and Monitoring System by the World Health Organization in 2013. Future applications include concepts including "lab on a chip" and "paper analytical devices" and are claimed to be convenient and simple to use as well as affordable. The principles discussed herein are making profound impact in the fight against substandard and falsified medicines, offering cheap and accessible solutions.
Background & aims
Serum interferon-gamma-inducible protein-10 (IP-10) is elevated in cholestatic liver diseases and predicts response to antiviral therapy in patients with chronic hepatitis C virus (HCV) infection. Dipeptidylpeptidase 4 (DPPIV) cleaves active IP-10 into an inactive form, which inhibits recruitment of CXCR3+ T cells to the liver. In this study the link between IP-10 levels, DPPIV activity in serum and CXCR3+ T cells is analysed in cholestatic and non-cholestatic liver patients.
Methods
In serum DPPIV activity (by enzymatic assay), IP-10 (by ELISA) and bile acids (BA) (by enzymatic assay) were analysed in 229 naive HCV genotype (GT) 1 patients and in 16 patients with cholestatic liver disease. In a prospective follow-up (FU) cohort of 27 HCV GT 1 patients peripheral CD3+CXCR3+, CD4+CXCR3+ and CD8+CXCR3+ cells were measured by FACS.
Results
In 229 HCV patients serum IP-10 levels correlated positively to DPPIV serum activity. Higher IP-10 levels and DPPIV activity were detected in cholestatic and in cirrhotic HCV patients. Increased IP-10 serum levels were associated with therapeutic non-response to antiviral treatment with pegylated-interferon and ribavirin. In the HCV FU cohort elevated IP-10 serum levels and increased BA were associated with higher frequencies of peripheral CD3+CXCR3+, CD4+CXCR3+ and CD8+CXCR3+ T cells. Positive correlation between serum IP-10 levels and DPPIV activity was likewise validated in patients with cholestatic liver diseases.
Conclusions
A strong correlation between elevated serum levels of IP-10 and DPPIV activity was seen in different cholestatic patient groups. Furthermore, in cholestatic HCV patients a functional link to increased numbers of peripheral CXCR3+ immune cells could be observed. The source of DPPIV release in cholestatic patients remains open.
The validity of Kirchhoff’s laws in plasmonic nanocircuitry is investigated by studying a junction of plasmonic two-wire transmission lines. We find that Kirchhoff’s laws are valid for sufficiently small values of a phenomenological parameter κ relating the geometrical parameters of the transmission line with the effective wavelength of the guided mode. Beyond such regime, for large values of the phenomenological parameter, increasing deviations occur and the equivalent impedance description (Kirchhoff’s laws) can only provide rough, but nevertheless useful, guidelines for the design of more complex plasmonic circuitry. As an example we investigate a system composed of a two-wire transmission line and a nanoantenna as the load. By addition of a parallel stub designed according to Kirchhoff’s laws we achieve maximum signal transfer to the nanoantenna.
Crop diversification has been proposed as farm management tool that could mitigate the externalities of conventional farming while reducing productivity-biodiversity trade-offs. Yet evidence for the acclaimed biodiversity benefits of landscape-level crop diversity is ambiguous. Effects may strongly depend on spatial scale and the level of landscape heterogeneity (e.g. overall habitat diversity). At the same time, contrasting within-taxon responses obscure benefits to specific functional groups (i.e. species with shared characteristics or requirements) if studied at the community level. The objectives of this study were to 1) disentangle the relative effects of crop diversity and landscape heterogeneity on avian species richness across five spatial scales ranging from 250 to 3000 m radii around focal winter wheat fields; and 2) assess whether functional groups (feeding guild, conservation status, habitat preference, nesting behaviour) determine the strength and direction of responses to crop diversity and landscape heterogeneity. In central Germany, 14 landscapes were selected along independent gradients of crop diversity (annual arable crops) and landscape heterogeneity. Bird species richness in each landscape was estimated using four point counts throughout the breeding season. We found no effects of landscape-level crop diversity on bird richness and functional groups. Instead, landscape heterogeneity was strongly associated with increased total bird richness across all spatial scales. In particular, insect-feeding and non-farmland birds were favoured in heterogeneous landscapes, as were species not classified as endangered or vulnerable on the regional Red List. Crop-nesting farmland birds, however, were less species-rich in these landscapes. Accordingly, crop diversification may be less suitable for conserving avian diversity and associated ecosystem services (e.g. biological pest control), although confounding interactions with management intensity need yet to be confirmed. In contrast, enhancement of landscape heterogeneity by increasing perennial habitat diversity, reducing field sizes and the amount of cropland has the potential to benefit overall bird richness. Specialist farmland birds, however, may require more targeted management approaches.
Background:
The presented prospective randomized controlled single-centre study compares the clinical outcome up to 12 months after total hip arthroplasty using a minimally invasive single-incision direct anterior (DAA) and a direct transgluteal lateral approach.
Methods:
A total of 123 arthroplasties were evaluated utilizing the Harris Hip Score (HHS), the extra short musculoskeletal functional assessment questionnaire (XSFMA), the Short Form 36 (SF-36) health survey, a Stepwatch™ Activity Monitor (SAM), and a timed 25 m foot walk (T25-FW). Postoperative x-ray images after THA were reviewed to determine inclination and stem positioning.
Results:
At final follow-up, the XSFMA functional index scores were 10.3 (anterior) and 15.08 (lateral) while the bother index summed up to a score of 15.8 (anterior) and 21.66 (lateral) respectively, thus only differing significantly for the functional index (p = 0.040 and p = 0.056). The SF-36 physical component score (PCS) was 47.49 (anterior) and 42.91 (lateral) while the mental component score (MCS) summed up to 55.0 (anterior) and 56.23 (lateral) with a significant difference evident for the PCS (p = 0.017; p = 0.714). Patients undergoing THA through a DAA undertook a mean of 6402 cycles per day while those who had undergone THA through a transgluteal approach undertook a mean of 5340 cycles per day (p = 0.012). Furthermore, the obtained outcome for the T25-FW with 18.4 s (anterior) and 19.75 s (lateral) and the maximum walking distance (5932 m and 5125 m) differed significantly (p = 0.046 and p = 0.045). The average HHS showed no significant difference equaling 92.4 points in the anterior group and 91.43 in the lateral group (p = 0.477). The radiographic analysis revealed an average cup inclination of 38.6° (anterior) and 40.28° (lateral) without signs of migration.
Conclusion:
In summary, our outcomes show that after 1 year THA through the direct anterior approach results in a higher patient activity compared to THA utilizing a transgluteal lateral approach while no differences regarding hip function are evident.
Altruistic punishment is connected to trait anger, not trait altruism, if compensation is available
(2018)
Altruistic punishment and altruistic compensation are important concepts that are used to investigate altruism. However, altruistic punishment has been found to be correlated with anger. We were interested whether altruistic punishment and altruistic compensation are both driven by trait altruism and trait anger or whether the influence of those two traits is more specific to one of the behavioral options. We found that if the participants were able to apply altruistic compensation and altruistic punishment together in one paradigm, trait anger only predicts altruistic punishment and trait altruism only predicts altruistic compensation. Interestingly, these relations are disguised in classical altruistic punishment and altruistic compensation paradigms where participants can either only punish or compensate. Hence altruistic punishment and altruistic compensation paradigms should be merged together if one is interested in trait altruism without the confounding influence of trait anger.
Background:
To report the results of the repair of conjunctival erosions resulting from glaucoma drainage device surgery using collagen-glycosaminoglycane matrices (CGM).
Methods:
Case series of 8 patients who underwent revision surgery due to conjunctival defects with exposed tubes through necrosis of the overlying scleral flap and conjunctiva after Baerveldt drainage device surgery. The defects were repaired by lateral displacement of the tube towards the sclera, with a slice of a CGM as a patch, covered by adjacent conjunctiva.
Result:
Successful, lasting closure (follow-up of 12 to 42 months) of the conjunctival defects was achieved without any side-effects or complications in all eight cases.
Conclusions:
Erosion of the drainage tube, creating buttonholes in the conjunctiva after implantation of glaucoma drainage devices, is a potentially serious problem. It can be managed successfully using a biodegradable CGM as a patch.
The present article introduces a model based on cognitive consistency principles to predict how new identities become integrated into the self-concept, with consequences for intergroup attitudes. The model specifies four concepts (self-concept, stereotypes, identification, and group compatibility) as associative connections. The model builds on two cognitive principles, balance-congruity and imbalance-dissonance, to predict identification with social groups that people currently belong to, belonged to in the past, or newly belong to. More precisely, the model suggests that the relative strength of self-group associations (i.e., identification) depends in part on the (in)compatibility of the different social groups. Combining insights into cognitive representation of knowledge, intergroup bias, and explicit/implicit attitude change, we further derive predictions for intergroup attitudes. We suggest that intergroup attitudes alter depending on the relative associative strength between the social groups and the self, which in turn is determined by the (in)compatibility between social groups. This model unifies existing models on the integration of social identities into the self-concept by suggesting that basic cognitive mechanisms play an important role in facilitating or hindering identity integration and thus contribute to reducing or increasing intergroup bias.
Bees receive nectar and pollen as reward for pollinating plants. Pollen of different plant species varies widely in nutritional composition. In order to select pollen of appropriate nutritional quality, bees would benefit if they could distinguish different pollen types. Whether they rely on visual, olfactory and/or chemotactile cues to distinguish between different pollen types, has however been little studied. In this study, we examined whether and how Apis mellifera workers differentiate between almond and apple pollen. We used differential proboscis extension response conditioning with olfactory and chemotactile stimulation, in light and darkness, and in summer and winter bees. We found that honeybees were only able to differentiate between different pollen types, when they could use both chemotactile and olfactory cues. Visual cues further improved learning performance. Summer bees learned faster than winter bees. Our results thus highlight the importance of multisensory information for pollen discrimination.
Background:
Recurrent airway infections are common in patients with Down's syndrome (DS). Hence, ruling out Cystic Fibrosis (CF) in these patients is often required. In the past, the value of sweat testing the gold standard to diagnose CF -has been questioned in DS as false positive results have been reported. However, these reports are based on measurements of sweat osmolality or sodium concentrations, not chloride concentrations. This study analyses sweat secretion rate and chloride concentration in sweat samples of patients with DS in comparison to healthy controls.
Methods:
We assessed sweat samples in 16 patients with DS and 16 healthy controls regarding sweat secretion rate (SSR) and sweat chloride concentration.
Results:
All measured chloride concentrations were within the normal range. The chloride concentrations were slightly, but not significantly lower in patients with DS (15,54 mmol/l (±4,47)) compared to healthy controls (18,31 mmol/l (±10,12)). While no gender gap in chloride concentration could be found, chloride concentration increased with age in both groups.
Insufficient sweat was collected in 2 females with DS (12.5% of the study group) but not in an individual of the control group. A significant lower sweat secretion rate was found in the DS group (27,6 μl/30 min (± 12,18)) compared to the control group (42,7 μl/30 min (± 21,22)). In a sub-analysis, female patients produced significantly less sweat (20,8 ± 10,6 μl/30 min) than male patients with DS (36,4 ± 7,8 μl/30 min), which accounts for the difference between patients and controls. Furthermore, while the sweating secretion rate increased with age in the control group, it did not do so in the DS group. Once again this was due to female patients with DS, who did not show a significant increase of sweat secretion rate with age.
Conclusions:
Sweat chloride concentrations were within the normal range in patients with DS and therefore seem to be a reliable tool for testing for CF in these patients. Interestingly, we found a reduced sweat secretion rate in the DS group. Whether the last one has a functional and clinical counterpart, possibly due to a disturbed thermoregulation in DS patients, requires further investigation.
Background:
Oligohydramnios sequence can be caused by renal tubular dysgenesis (RTD), a rare condition resulting in pulmonary and renal morbidity. Besides typical features of Potter-sequence, the infants present with severe arterial hypotension and anuria as main symptoms. Establishing an adequate arterial blood pressure and sufficient renal perfusion is crucial for the survival of these infants.
Case presentation:
We describe a male preterm infant of 34 + 0 weeks of gestation. Prenatally oligohydramnios of unknown cause was detected. After uneventful delivery and good adaptation the infant developed respiratory distress due to a spontaneous right-sided pneumothorax and required thoracocentesis and placement of a chest tube; he showed no major respiratory concerns thereafter and needed only minimal ventilatory support. Echocardiography revealed no abnormalities, especially no pulmonary hypertension. However, he suffered from severe arterial hypotension and anuria refractory to catecholamine therapy (dobutamine, epinephrine and noradrenaline). After 36 h of life, vasopressin therapy was initiated resulting in an almost immediate stabilization of arterial blood pressure and subsequent onset of diuresis. Therapy with vasopressin was necessary for three weeks to maintain adequate arterial blood pressure levels and diuresis. Sepsis and adrenal insufficiency were ruled out as inflammation markers, microbiological tests and cortisol level were normal. At two weeks of age, our patient developed electrolyte disturbances which were successfully treated with fludrocortisone. He did not need renal replacement therapy. Genetic analyses revealed a novel compound hyterozygous mutation of RTD. Now 17 months of age, the patient is in clinically stable condition with treatment of fludrocortisone and sodium bicarbonate. He suffers from stage 2 chronic kidney disease; blood pressure, motor and cognitive development are normal.
Conclusions:
RTD is a rare cause of oligohydramnios sequence. Next to pulmonary hypoplasia, severe arterial hypotension is responsible for poor survival. We present the only second surviving infant with RTD, who did not require renal replacement therapy during the neonatal period. It can be speculated whether the use of vasopressin prevents renal replacement therapy as vasopressin increases urinary output by improving renal blood flow.
After a large outbreak in Brazil, novel drugs against Zika virus became extremely necessary. Evaluation of virus-based pharmacological strategies concerning essential host factors brought us to the idea that targeting the Axl receptor by blocking its dimerization function could be critical for virus entry. Starting from experimentally validated compounds, such as RU-301, RU-302, warfarin, and R428, we identified a novel compound 2′ (R428 derivative) to be the most potent for this task amongst a number of alternative compounds and leads. The improved affinity of compound 2′ was confirmed by molecular docking as well as molecular dynamics simulation techniques using implicit solvation models. The current study summarizes a new possibility for inhibition of the Axl function as a potential target for future antiviral therapies.
To understand basic principles about the interaction of electromagnetic radiation with matter is often a challenge in chemical education due to the difficult theoretical background of this topic. The present contribution therefore offers an experimental based introduction into the basic principles of UV/Vis spectroscopy following a three-step strategy. The starting point is to construct a simple self-built spectrometer working within the visible range of light. Learners can explore the most important components of such a device and understand their functions without previous knowledge. In a second step, emission spectra of different common light sources are investigated and compared. Finally, spectroscopic experiments are suggested for chemical education such as the qualitative detection of cations and the quantitative analysis of the dye carmine in food. This context-based introduction links chemical applications with the everyday life. It can be presumed that this way, learners are provided an easier access to radiation-matter interaction.
Background:
Sex determination relies on a hierarchically structured network of genes, and is one of the most plastic processes in evolution. The evolution of sex-determining genes within a network, by neo- or sub-functionalization, also requires the regulatory landscape to be rewired to accommodate these novel gene functions. We previously showed that in medaka fish, the regulatory landscape of the master male-determining gene dmrt1bY underwent a profound rearrangement, concomitantly with acquiring a dominant position within the sex-determining network. This rewiring was brought about by the exaptation of a transposable element (TE) called Izanagi, which is co-opted to act as a silencer to turn off the dmrt1bY gene after it performed its function in sex determination.
Results:
We now show that a second TE, Rex1, has been incorporated into Izanagi. The insertion of Rex1 brought in a preformed regulatory element for the transcription factor Sox5, which here functions in establishing the temporal and cell-type-specific expression pattern of dmrt1bY. Mutant analysis demonstrates the importance of Sox5 in the gonadal development of medaka, and possibly in mice, in a dmrt1bY-independent manner. Moreover, Sox5 medaka mutants have complete female-to-male sex reversal.
Conclusions:
Our work reveals an unexpected complexity in TE-mediated transcriptional rewiring, with the exaptation of a second TE into a network already rewired by a TE. We also show a dual role for Sox5 during sex determination: first, as an evolutionarily conserved regulator of germ-cell number in medaka, and second, by de novo regulation of dmrt1 transcriptional activity during primary sex determination due to exaptation of the Rex1 transposable element.
Cryptochromes (CRYs) are a class of flavoproteins that sense blue light. In animals, CRYs are expressed in the eyes and in the clock neurons that control sleep/wake cycles and are implied in the generation and/or entrainment of circadian rhythmicity. Moreover, CRYs are sensing magnetic fields in insects as well as in humans. Here, we show that in the fruit fly Drosophila melanogaster CRY plays a light-independent role as “assembling” protein in the rhabdomeres of the compound eyes. CRY interacts with actin and appears to increase light sensitivity of the eyes by keeping the “signalplex” of the phototransduction cascade close to the membrane. By this way, CRY also enhances light-responses of the circadian clock.
Unraveling the connection between fibroblast growth factor and bone morphogenetic protein signaling
(2018)
Ontogeny of higher organisms as well the regulation of tissue homeostasis in adult individuals requires a fine-balanced interplay of regulating factors that individually trigger the fate of particular cells to either stay undifferentiated or to differentiate towards distinct tissue specific lineages. In some cases, these factors act synergistically to promote certain cellular responses, whereas in other tissues the same factors antagonize each other. However, the molecular basis of this obvious dual signaling activity is still only poorly understood. Bone morphogenetic proteins (BMPs) and fibroblast growth factors (FGFs) are two major signal protein families that have a lot in common: They are both highly preserved between different species, involved in essential cellular functions, and their ligands vastly outnumber their receptors, making extensive signal regulation necessary. In this review we discuss where and how BMP and FGF signaling cross paths. The compiled data reflect that both factors synchronously act in many tissues, and that antagonism and synergism both exist in a context-dependent manner. Therefore, by challenging a generalization of the connection between these two pathways a new chapter in BMP FGF signaling research will be introduced.
Background:
Irradiation with α-particles creates densely packed damage tracks along particle trajectories in exposed cells, including complex DNA damage and closely spaced double-strand breaks (DSBs) in hit nuclei. Here, we investigated the correlation of the absorbed dose to the blood and the number of α-induced DNA damage tracks elicited in human blood leukocytes after ex-vivo in-solution exposure with Ra-224. The aim was to compare the data to previously published data on Ra-223 and to investigate differences in DNA damage induction between the two radium isotopes.
Results:
Blood samples from three healthy volunteers were exposed ex-vivo to six different concentrations of Ra-224 dichloride. Absorbed doses to the blood were calculated assuming local energy deposition of all α- and β-particles of the Ra-224 decay chain, ranging from 0 to 127 mGy. γ-H2AX + 53BP1 DNA damage co-staining and analysis was performed on ethanol-fixed leukocytes isolated from the irradiated blood samples. For damage quantification, α-induced DNA damage tracks and small γ-H2AX + 53BP1 DSB foci were enumerated in the exposed leukocytes. This revealed a linear relationship between the frequency of α-induced γ-H2AX damage tracks and the absorbed dose to the blood, while the frequency of small γ-H2AX + 53BP1 DSB foci indicative of β-irradiation was similar to baseline values.
Conclusions:
Our data provide a first estimation of the DNA damage induced by Ra-224 in peripheral blood mononuclear cells. A comparison with our previously published Ra-223 data suggests that there is no difference in the induction of radiation-induced DNA damage between the two radium isotopes due to their similar decay properties.
DNA damage in leukocytes after internal ex-vivo irradiation of blood with the α-emitter Ra-223
(2018)
Irradiation with high linear energy transfer α-emitters, like the clinically used Ra-223 dichloride, severely damages cells and induces complex DNA damage including closely spaced double-strand breaks (DSBs). As the hematopoietic system is an organ-at-risk for the treatment, knowledge about Ra-223-induced DNA damage in blood leukocytes is highly desirable. Therefore, 36 blood samples from six healthy volunteers were exposed ex-vivo (in solution) to different concentrations of Ra-223. Absorbed doses to the blood were calculated assuming local energy deposition of all α- and β-particles of the decay, ranging from 0 to 142 mGy. γ-H2AX + 53BP1 co-staining and analysis was performed in leukocytes isolated from the irradiated blood samples. For DNA damage quantification, leukocyte samples were screened for occurrence of α-induced DNA damage tracks and small γ-H2AX + 53BP1 DSB foci. This revealed a linear relationship between the frequency of α-induced γ-H2AX damage tracks and the absorbed dose to the blood, while the frequency of small γ-H2AX + 53BP1 DSB foci indicative of β-irradiation was similar to baseline values, being in agreement with a negligible β-contribution (3.7%) to the total absorbed dose to the blood. Our calibration curve will contribute to the biodosimetry of Ra-223-treated patients and early after incorporation of α-emitters.
Background:
The calcium sensitizer levosimendan is increasingly used to improve hemodynamics in patients with acutely decompensated heart failure. By binding to cardiac troponin C the conformation of the calcium-troponin C complex is stabilized, which leads to acceleration of actin-myosin crossbrigde formation and increased force generating capacity of muscle fibers. Besides indications in cardiac failure, beneficial effects of levosimendan in skeletal muscle disorders are currently evaluated. The aim of this study was to investigate differential effects of levosimendan on skeletal muscle of pigs with and without susceptibility to malignant hyperthermia (MH) in order to identify possible risks of this emerging drug for patients with predisposition to MH.
Methods:
Muscle bundles of 17 pigs (9 MH susceptible (MHS); 8 MH non-susceptible (MHN)) were excised under general anesthesia and examined in the tissue bath with increasing concentrations of levosimendan (0.065; 0.125; 0.5; 1.0; 10 and 50 μg/ml). Baseline tension and twitch force were monitored continuously. Data are presented as median and interquartile range. Statistical evaluation was performed using D’Agostino & Pearson test for normal distribution and student’s t test and 2-way ANOVA for differences between the groups. P < 0.05 was considered significant.
Results:
There were no differences between the groups concerning length, weight, initial twitch force and pre-drug resting tension of the investigated muscle strips. After an initial decrease in both groups, twitch amplitude was significantly higher in MHN (− 3.0 [− 5.2–0.2] mN) compared to MHS (− 7.5 [− 10.8- -4.5] mN) (p = 0.0034) muscle at an applied levosimendan concentration of 50 μg/ml. A marked increase in resting tension was detected following levosimendan incubation with 50 μg/ml in MHS muscle bundles (3.3 [0.9–6.1] mN) compared to MHN (− 0.7 [− 1.3–0.0] mN) (p < 0.0001).
Conclusions:
This in vitro investigation revealed the development of significant contractures in muscle bundles of MHS pigs after incubation with levosimendan. However, the effect appeared only at supra-therapeutic concentrations and further research is needed to determine the impact of levosimendan on MHS individuals in vivo.
Sodium-glucose transporters (SGLT) belong to the solute carrier 5 family, which is characterized by sodium dependent transport of sugars and other solutes. In contrast, the human SGLT3 (hSGLT3) isoform, encoded by SLC5A4, acts as a glucose sensor that does not transport sugar but induces membrane depolarization by Na\(^{+}\) currents upon ligand binding. Whole-exome sequencing (WES) of several extended pedigrees with high density of attention-deficit/hyperactivity disorder (ADHD) identified a triplet ATG deletion in SLC5A4 leading to a single amino acid loss (ΔM500) in the hSGLT3 protein imperfectly co-segregating with the clinical phenotype of ADHD. Since mutations in homologous domains of hSGLT1 and hSGLT2 were found to affect intestinal and renal function, respectively, we analyzed the functional properties of hSGLT3[wt] and [ΔM500] by voltage clamp and current clamp recordings from cRNA-injected Xenopus laevis oocytes.
The cation conductance of hSGLT3[wt] was activated by application of glucose or the specific agonist 1-desoxynojirimycin (DNJ) as revealed by inward currents in the voltage clamp configuration and cell depolarization in the current clamp mode. Almost no currents and changes in membrane potential were observed when glucose or DNJ were applied to hSGLT3[ΔM500]-injected oocytes, demonstrating a loss of function by this amino acid deletion in hSGLT3. To monitor membrane targeting of wt and mutant hSGLT3, fusion constructs with YFP were generated, heterologously expressed in Xenopus laevis oocytes and analyzed for membrane fluorescence by confocal microscopy. In comparison to hSGLT3[wt] the fluorescent signal of mutant [ΔM500] was reduced by 43% indicating that the mutant phenotype might mainly result from inaccurate membrane targeting. As revealed by homology modeling, residue M500 is located in TM11 suggesting that in addition to the core structure (TM1-TM10) of the transporter, the surrounding TMs are equally crucial for transport/sensor function.
In conclusion, our findings indicate that the deletion [ΔM500] in hSGLT3 inhibits membrane targeting and thus largely disrupts glucose-induced sodium conductance, which may, in interaction with other ADHD risk-related gene variants, influence the risk for ADHD in deletion carriers.
Background:
Atypical chemokine receptor 3 (ACKR3, synonym CXCR7) is increasingly considered relevant in neuroinflammatory conditions, in which its upregulation contributes to compromised endothelial barrier function and may ultimately allow inflammatory brain injury. While an impact of ACKR3 has been recognized in several neurological autoimmune diseases, neuroinflammation may also result from infectious agents, including Ureaplasma species (spp.). Although commonly regarded as commensals of the adult urogenital tract, Ureaplasma spp. may cause invasive infections in immunocompromised adults as well as in neonates and appear to be relevant pathogens in neonatal meningitis. Nonetheless, clinical and in vitro data on Ureaplasma-induced inflammation are scarce.
Methods:
We established a cell culture model of Ureaplasma meningitis, aiming to analyze ACKR3 variances as a possible pathomechanism in Ureaplasma-associated neuroinflammation. Non-immortalized human brain microvascular endothelial cells (HBMEC) were exposed to bacterial lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α), and native as well as LPS-primed HBMEC were cultured with Ureaplasma urealyticum serovar 8 (Uu8) and U. parvum serovar 3 (Up3). ACKR3 responses were assessed via qRT-PCR, RNA sequencing, flow cytometry, and immunocytochemistry.
Results:
LPS, TNF-α, and Ureaplasma spp. influenced ACKR3 expression in HBMEC. LPS and TNF-α significantly induced ACKR3 mRNA expression (p < 0.001, vs. control), whereas Ureaplasma spp. enhanced ACKR3 protein expression in HBMEC (p < 0.01, vs. broth control). Co-stimulation with LPS and either Ureaplasma isolate intensified ACKR3 responses (p < 0.05, vs. LPS). Furthermore, stimulation wielded a differential influence on the receptor’s ligands.
Conclusions:
We introduce an in vitro model of Ureaplasma meningitis. We are able to demonstrate a pro-inflammatory capacity of Ureaplasma spp. in native and, even more so, in LPS-primed HBMEC, underlining their clinical relevance particularly in a setting of co-infection. Furthermore, our data may indicate a novel role for ACKR3, with an impact not limited to auto-inflammatory diseases, but extending to infection-related neuroinflammation as well. AKCR3-induced blood-brain barrier breakdown might constitute a potential common pathomechanism.
Background:
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) for which several new treatment options were recently introduced. Among them is the monoclonal anti-CD52 antibody alemtuzumab that depletes mainly B cells and T cells in the immune periphery. Considering the ongoing controversy about the involvement of B cells and in particular the formation of B cell aggregates in the brains of progressive MS patients, an in-depth understanding of the effects of anti-CD52 antibody treatment on the B cell compartment in the CNS itself is desirable.
Methods:
We used myelin basic protein (MBP)-proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 (B6) mice as B cell-dependent model of MS. Mice were treated intraperitoneally either at the peak of EAE or at 60 days after onset with 200 μg murine anti-CD52 vs. IgG2a isotype control antibody for five consecutive days. Disease was subsequently monitored for 10 days. The antigen-specific B cell/antibody response was measured by ELISPOT and ELISA. Effects on CNS infiltration and B cell aggregation were determined by immunohistochemistry. Neurodegeneration was evaluated by Luxol Fast Blue, SMI-32, and Olig2/APC staining as well as by electron microscopy and phosphorylated heavy neurofilament serum ELISA.
Results:
Treatment with anti-CD52 antibody attenuated EAE only when administered at the peak of disease. While there was no effect on the production of MP4-specific IgG, the treatment almost completely depleted CNS infiltrates and B cell aggregates even when given as late as 60 days after onset. On the ultrastructural level, we observed significantly less axonal damage in the spinal cord and cerebellum in chronic EAE after anti-CD52 treatment.
Conclusion:
Anti-CD52 treatment abrogated B cell infiltration and disrupted existing B cell aggregates in the CNS.