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Different tissue engineering techniques are used to support rapid vascularisation. A novel technique is the use of platelet-rich fibrin (PRF), an autologous source of growth factors. This study was the first to investigate the influence of PRF matrices, isolated following different centrifugation protocols, on human dermal vascular endothelial cells (ECs) in mono-culture and co-culture with human primary fibroblasts (HFs) as an in vitro model for tissue regeneration. Focus was placed on vascular structure formation and growth factor release. HFs and ECs were cultivated with PRF prepared using a high (710 ×g) or low (44 ×g) relative centrifugation force (RCF) over 14 d. Immunofluorescence staining and immunohistochemistry were used to evaluate the microvascular formation. Cell culture supernatants were collected for evaluation of growth factor release. The results showed a PRF-mediated effect on the induction of angiogenesis in ECs. Microvessel-like structure formation was promoted when ECs were combined with low-RCF PRF as compared to high-RCF PRF or control group. The percentage of vascular lumen area was significantly higher in low-RCF PRF, especially at day 7, which coincided with statistically significantly higher growth factor [vascular endothelial factor (VEGF), transforming growth factor β1 (TGF-β1) and platelet derived growth factor (PDGF)] concentration measured in low-RCF PRF as compared to high-RCF PRF or control group. In conclusion, reducing the RCF according to the low-speed centrifugation concept (LSCC) resulted in increased growth factor release and angiogenic structure formation with EC mono-culture, suggesting that PRF may be a highly beneficial therapeutic tool for tissue engineering applications.
Background: Neonatal manifestation of life-threatening hyperammonemic encephalopathy in urea cycle disorders (UCD) is often misdiagnosed as neonatal sepsis, resulting in significantly delayed start of specific treatment and poor outcome. The major aim of this study was to identify specific initial symptoms or signs to clinically distinguish hyperammonemic encephalopathy in neonates from neonatal sepsis in order to identify affected individuals with UCD and to start metabolic therapy without delay. Furthermore, we evaluated the impact of diagnostic delay, peak plasma ammonium (NH4+) concentration, mode of emergency treatment and transfer to a tertiary referral center on the outcome.
Methods: Detailed information of 17 patients (born between 1994 and 2012) with confirmed diagnosis of UCD and neonatal hyperammonemic encephalopathy were collected from the original medical records.
Results: The initially suspected diagnosis was neonatal sepsis in all patients, but was not confirmed in any of them. Unlike neonatal sepsis and not previously reported blood pressure increased above the 95th percentile in 13 (81%) of UCD patients before emergency treatment was started. Respiratory alkalosis was found in 11 (65%) of UCD patients, and in 14 (81%) plasma NH4+concentrations further increased despite initiation of metabolic therapy.
Conclusion: Detection of high blood pressure could be a valuable parameter for distinguishing neonatal sepsis from neonatal manifestation of UCD. Since high blood pressure is not typical for neonatal sepsis, other reasons such as encephalopathy and especially hyperammonemic encephalopathy (caused by e.g. UCD) should be searched for immediately. However, our result that the majority of newborns with UCD initially present with high blood pressure has to be evaluated in larger patient cohorts.
Background: The number of Mesenchymal Stem/Stromal Cells (MSCs) in the human bone marrow (BM) is small compared to other cell types. BM aspirate concentration (BMAC) may be used to increase numbers of MSCs, but the composition of MSC subpopulations and growth factors after processing are unknown. The purpose of this study was to assess the enrichment of stem/progenitor cells and growth factors in BM aspirate by two different commercial concentration devices versus standard BM aspiration.
Methods: 120 mL of BM was aspirated from the iliac crest of 10 male donors. Each sample was processed simultaneously by either Emcyte GenesisCS® (Emcyte) or Harvest SmartPReP2 BMAC (Harvest) devices and compared to untreated BM aspirate. Samples were analyzed with multicolor flow cytometry for cellular viability and expression of stem/progenitor cells markers. Stem/progenitor cell content was verified by quantification of colony forming unit-fibroblasts (CFU-F). Platelet, red blood cell and total nucleated cell (TNC) content were determined using an automated hematology analyzer. Growth factors contents were analyzed with protein quantification assays. Statistical analyses were performed by ANOVA analysis of variance followed by Tukey’s multiple comparison test or Wilcoxon matched-pairs signed rank test with p < 0.05 for significance.
Results: Cell viability after processing was approximately 90% in all groups. Compared to control, both devices significantly enriched TNCs and platelets, as well as the CD45−CD73+ and CD45−CD73+CD90+ cell populations. Further, Harvest significantly concentrated CD45−CD10+, CD45−CD29+, CD45−CD90+, CD45−CD105+, CD45−CD119+ cells, and CD45dimCD90+CD271+ MSCs, whereas Emcyte significantly enriched CD45dimCD44+CD271+ MSCs. BM concentration also increased the numbers of CFU-F, platelet-derived growth factor, vascular endothelial growth factor, macrophage colony-stimulating factor, interleukin-1b, VCAM-1 and total protein. Neither system concentrated red blood cells, hematopoietic stem cells or bone morphogenetic proteins.
Conclusion: This data could contribute to the development of BMAC quality control assays as both BMAC systems concentrated platelets, growth factors and non-hematopoietic stem cell subpopulations with distinct phenotypes without loss of cell viability when compared to unprocessed BM.
Objective: To determine whether the performance of multiple sclerosis (MS) patients in the sound-induced flash illusion (SiFi), a multisensory perceptual illusion, would reflect their cognitive impairment.
Methods: We performed the SiFi task as well as an extensive neuropsychological testing in 95 subjects [39 patients with relapse-remitting MS (RRMS), 16 subjects with progressive multiple sclerosis (PMS) and 40 healthy control subjects (HC)].
Results: MS patients reported more frequently the multisensory SiFi than HC. In contrast, there were no group differences in the control conditions. Essentially, patients with progressive type of MS continued to perceive the illusion at stimulus onset asynchronies (SOA) that were more than three times longer than the SOA at which the illusion was already disrupted for healthy controls. Furthermore, MS patients' degree of cognitive impairment measured with a broad neuropsychological battery encompassing tests for memory, attention, executive functions, and fluency was predicted by their performance in the SiFi task for the longest SOA of 500 ms.
Conclusions: These findings support the notion that MS patients exhibit an altered multisensory perception in the SiFi task and that their susceptibility to the perceptual illusion is negatively correlated with their neuropsychological test performance. Since MS lesions affect white matter tracts and cortical regions which seem to be involved in the transfer and processing of both crossmodal and cognitive information, this might be one possible explanation for our findings. SiFi might be considered as a brief, non-expensive, language- and education-independent screening test for cognitive deficits in MS patients.
Anaerobic ammonium oxidation (anammox) is a major process in the biogeochemical nitrogen cycle in which nitrite and ammonium are converted to dinitrogen gas and water through the highly reactive intermediate hydrazine. So far, it is unknown how anammox organisms convert the toxic hydrazine into nitrogen and harvest the extremely low potential electrons (−750 mV) released in this process. We report the crystal structure and cryo electron microscopy structures of the responsible enzyme, hydrazine dehydrogenase, which is a 1.7 MDa multiprotein complex containing an extended electron transfer network of 192 heme groups spanning the entire complex. This unique molecular arrangement suggests a way in which the protein stores and releases the electrons obtained from hydrazine conversion, the final step in the globally important anammox process.
Fascial tissues form a ubiquitous network throughout the whole body, which is usually regarded as a passive contributor to biomechanical behavior. We aimed to answer the question, whether fascia may possess the capacity for cellular contraction which, in turn, could play an active role in musculoskeletal mechanics. Human and rat fascial specimens from different body sites were investigated for the presence of myofibroblasts using immunohistochemical staining for α-smooth muscle actin (n = 31 donors, n = 20 animals). In addition, mechanographic force registrations were performed on isolated rat fascial tissues (n = 8 to n = 18), which had been exposed to pharmacological stimulants. The density of myofibroblasts was increased in the human lumbar fascia in comparison to fasciae from the two other regions examined in this study: fascia lata and plantar fascia [H(2) = 14.0, p < 0.01]. Mechanographic force measurements revealed contractions in response to stimulation by fetal bovine serum, the thromboxane A2 analog U46619, TGF-β1, and mepyramine, while challenge by botulinum toxin type C3–used as a Rho kinase inhibitor– provoked relaxation (p < 0.05). In contrast, fascial tissues were insensitive to angiotensin II and caffeine (p < 0.05). A positive correlation between myofibroblast density and contractile response was found (rs = 0.83, p < 0.001). The hypothetical application of the registered forces to human lumbar tissues predicts a potential impact below the threshold for mechanical spinal stability but strong enough to possibly alter motoneuronal coordination in the lumbar region. It is concluded that tension of myofascial tissue is actively regulated by myofibroblasts with the potential to impact active musculoskeletal dynamics.
Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders with significant and often lifelong effects on social, emotional, and cognitive functioning. Influential neurocognitive models of ADHD link behavioral symptoms to altered connections between and within functional brain networks. Here, we investigate whether network-based theories of ADHD can be generalized to understanding variations in ADHD-related behaviors within the normal (i.e., clinically unaffected) adult population. In a large and representative sample, self-rated presence of ADHD symptoms varied widely; only eight out of 291 participants scored in the clinical range. Subject-specific brain-network graphs were modeled from functional MRI resting-state data and revealed significant associations between (non-clinical) ADHD symptoms and region-specific profiles of between-module and within-module connectivity. Effects were located in brain regions associated with multiple neuronal systems including the default-mode network, the salience network, and the central executive system. Our results are consistent with network perspectives of ADHD and provide further evidence for the relevance of an appropriate information transfer between task-negative (default-mode) and task-positive brain regions. More generally, our findings support a dimensional conceptualization of ADHD and contribute to a growing understanding of cognition as an emerging property of functional brain networks.
GOeTHEO : Ausgabe 20
(2019)
Chordomas are rare bone tumors with few therapeutic options. Here we show, using whole-exome and genome sequencing within a precision oncology program, that advanced chordomas (n = 11) may be characterized by genomic patterns indicative of defective homologous recombination (HR) DNA repair and alterations affecting HR-related genes, including, for example, deletions and pathogenic germline variants of BRCA2, NBN, and CHEK2. A mutational signature associated with HR deficiency was significantly enriched in 72.7% of samples and co-occurred with genomic instability. The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib, which is preferentially toxic to HR-incompetent cells, led to prolonged clinical benefit in a patient with refractory chordoma, and whole-genome analysis at progression revealed a PARP1 p.T910A mutation predicted to disrupt the autoinhibitory PARP1 helical domain. These findings uncover a therapeutic opportunity in chordoma that warrants further exploration, and provide insight into the mechanisms underlying PARP inhibitor resistance.
Background: To evaluate the current indications, resection strategies and short-term outcomes of surgery for benign goitre in a country with endemic goitre. Methods: Data of patients who underwent surgery for benign goitre were retrieved from the prospective StuDoQ/Thyroid registry and retrospectively analysed regarding the patient’s demographics, indications for surgery, surgical procedures, histology, and perioperative outcomes. Results: In a 15-month period, 12,888 patients from 83 departments underwent thyroid resections for benign conditions. Main indications for surgery were exclusion of malignancy (68%), compression symptoms (20.7%) and hyperthyroidism (9.7%). Preoperative fine needle aspiration cytology was performed in only 12.2% of patients with the indication "exclusion of malignancy". Thyroidectomy (49.8%) or hemithyroidectomy (36.9%) were performed in 86.7% of patients. Minimally invasive or alternative surgical techniques were applied in only 2.2%. Intraoperative neuromonitoring was used in 98.4% of procedures, in 97.5% of patients at least one parathyroid gland was visualized, and in 15.3% of patients parathyroid tissue was autografted, respectively. The rates of unilateral and bilateral transient recurrent nerve palsy were 3.6% and 0.07% of nerves at risk, the rate of transitory hypoparathyroidism was 15.3%. The rates of postoperative bleeding and wound infections requiring reoperation were 1.4% and 0.07%, respectively. Conclusions: The indication "exclusion of malignancy" is made too liberally, and there is a strong attitude to perform complete thyroid resections. Postoperative hypoparathyroidism is the major complication after surgery for benign thyroid disease, thus requiring more awareness.
The on-surface synthesis of bisheptahelicene by Ullmann coupling of 9-bromoheptahelicene on Au(111) and its temperature-induced dehydrogenation is studied using temperature-programmed reaction spectroscopy and time-of-flight secondary ion mass spectrometry. Specific dehydrogenation products of bisheptahelicene after loss of 6, 8 and 10 hydrogen atoms are identified, corresponding to molecules having undergone Diels–Alder transformations and intramolecular C–C coupling reactions. By combining with atomic hydrogen produced by dehydrogenation, the Ullmann coupling side-product bromine desorbs as HBr. H2 desorption emerges only after all Br has desorbed. Such characteristic behavior is explained by a kinetic model which explicitly considers the coverage of transient atomic H on the surface. Heating experiments performed with saturated layers of different Br-containing molecules reveal that the onset of HBr desorption depends strictly on the dehydrogenation step and therefore on the structure of the molecules.
Apigenin (4′,5,7-trihydroxyflavone) (Api) is an important component of the human diet, being distributed in a wide number of fruits, vegetables and herbs with the most important sources being represented by chamomile, celery, celeriac and parsley. This study was designed for a comprehensive evaluation of Api as an antiproliferative, proapoptotic, antiangiogenic and immunomodulatory phytocompound. In the set experimental conditions, Api presents antiproliferative activity against the A375 human melanoma cell line, a G2/M arrest of the cell cycle and cytotoxic events as revealed by the lactate dehydrogenase release. Caspase 3 activity was inversely proportional to the Api tested doses, namely 30 μM and 60 μM. Phenomena of early apoptosis, late apoptosis and necrosis following incubation with Api were detected by Annexin V-PI double staining. The flavone interfered with the mitochondrial respiration by modulating both glycolytic and mitochondrial pathways for ATP production. The metabolic activity of human dendritic cells (DCs) under LPS-activation was clearly attenuated by stimulation with high concentrations of Api. Il-6 and IL-10 secretion was almost completely blocked while TNF alpha secretion was reduced by about 60%. Api elicited antiangiogenic properties in a dose-dependent manner. Both concentrations of Api influenced tumour cell growth and migration, inducing a limited tumour area inside the application ring, associated with a low number of capillaries.
Latent tuberculosis infection (LTBI) is established in over 90% of persons infected with Mycobacterium tuberculosis (Mtb), from whom new active TB cases will arise. Understanding the spatio-temporal dynamics of host immune responses in LTBI granulomas is essential to designing effective post-exposure therapies that inhibit progression to TB. Information arising from cancer studies and other modalities – where local chronic inflammation leads to immunopathology – can help provide insights into the biological pathways at play in LTBI granulomas. Translational studies using patient material as well as LTBI+ donor-derived tissue samples are instrumental in understanding the various components of granuloma dynamics, immunological landscapes therein and how this could help to identify therapeutic targets. Deep sequencing technologies may aid to decipher the genetic changes in lung granuloma and blood samples from LTBI+ individuals associated with progression to active TB disease. This may lead to advancement of development of targeted Host-Directed Therapies (HDTs) and their evaluation as adjunct TB therapies for improving treatment outcomes for LTBI and pulmonary TB.