Systemic Inflammation and the Breakdown of Intestinal Homeostasis Are Key Events in Chronic Spinal Cord Injury Patients

Our aim was to investigate the subset distribution and function of circulating monocytes, proinflammatory cytokine levels, gut barrier damage, and bacterial translocation in chronic spinal cord injury (SCI) patients. Thus, 56 SCI patients and 28 healthy donors were studied. The levels of circulating CD14^+highCD16⁻, CD14^+highCD16⁺, and CD14^+lowCD16⁺ monocytes, membrane TLR2, TLR4, and TLR9, phagocytic activity, ROS generation, and intracytoplasmic TNF-α, IL-1, IL-6, and IL-10 after lipopolysaccharide (LPS) stimulation were analyzed by polychromatic flow cytometry. Serum TNF-α, IL-1, IL-6 and IL-10 levels were measured by Luminex and LPS-binding protein (LBP), intestinal fatty acid-binding protein (I-FABP) and zonulin by ELISA. SCI patients had normal monocyte counts and subset distribution. CD14^+highCD16⁻ and CD14^+highCD16⁺ monocytes exhibited decreased TLR4, normal TLR2 and increased TLR9 expression. CD14^+highCD16⁻ monocytes had increased LPS-induced TNF-α but normal IL-1, IL-6, and IL-10 production. Monocytes exhibited defective phagocytosis but normal ROS production. Patients had enhanced serum TNF-α and IL-6 levels, normal IL-1 and IL-10 levels, and increased circulating LBP, I-FABP, and zonulin levels. Chronic SCI patients displayed impaired circulating monocyte function. These patients exhibited a systemic proinflammatory state characterized by enhanced serum TNF-α and IL-6 levels. These patients also had increased bacterial translocation and gut barrier damage.     

Spinal Excitatory Dynorphinergic Interneurons Contribute to Burn Injury-Induced Nociception Mediated by Phosphorylated Histone 3 at Serine 10 in Rodents

The phosphorylation of serine 10 in histone 3 (p-S10H3) has recently been demonstrated to participate in spinal nociceptive processing. However, superficial dorsal horn (SDH) neurons involved in p-S10H3-mediated nociception have not been fully characterized. In the present work, we combined immunohistochemistry, in situ hybridization with the retrograde labeling of projection neurons to reveal the subset of dorsal horn neurons presenting an elevated level of p-S10H3 in response to noxious heat (60 °C), causing burn injury. Projection neurons only represented a small percentage (5%) of p-S10H3-positive cells, while the greater part of them belonged to excitatory SDH interneurons. The combined immunolabeling of p-S10H3 with markers of already established interneuronal classes of the SDH revealed that the largest subset of neurons with burn injury-induced p-S10H3 expression was dynorphin immunopositive in mice. Furthermore, the majority of p-S10H3-expressing dynorphinergic neurons proved to be excitatory, as they lacked Pax-2 and showed Lmx1b-immunopositivity. Thus, we showed that neurochemically heterogeneous SDH neurons exhibit the upregulation of p-S10H3 shortly after noxious heat-induced burn injury and consequential tissue damage, and that a dedicated subset of excitatory dynorphinergic neurons is likely a key player in the development of central sensitization via the p-S10H3 mediated pathway.     

Botulinum Toxin: From Poison to Possible Treatment for Spasticity in Spinal Cord Injury

Botulism has been known for about three centuries, and since its discovery, botulinum toxin has been considered one of the most powerful toxins. However, throughout the 20th century, several medical applications have been discovered, among which the treatment of spasticity stands out. Botulinum toxin is the only pharmacological treatment recommended for spasticity of strokes and cerebral palsy. Although its use as an adjuvant treatment against spasticity in spinal cord injuries is not even approved, botulinum toxin is being used against such injuries. This article describes the advances that have been made throughout history leading to the therapeutic use of botulinum toxin and, in particular, its application to the treatment of spasticity in spinal cord injury.     

Incidence and costs of bicycle-related traumatic brain injuries in the Netherlands

The main cause of death and serious disability in bicycle accidents is traumatic brain injury (TBI). The aim of this population-based study was to assess the incidence and costs of bicycle-related TBI across various age groups, and in comparison to all bicycle-related injuries, to identify main risk groups for the development of preventive strategies.Data from the National Injury Surveillance System and National Medical Registration were used for all patients with bicycle-related injuries and TBI who visited a Dutch emergency department (ED) between 1998 and 2012. Demographics and national, weighted estimates of injury mechanism, injury severity and costs were analysed per age group. Direct healthcare costs and indirect costs were determined using the incidence-based Dutch Burden of Injury Model.Between 1998 and 2012, the incidence of ED treatments due to bicycle-related TBI strongly increased with 54%, to 43 per 100,000 persons in 2012. However, the incidence of all bicycle-related injuries remained stable, from 444 in 1998 to 456/100,000 in 2012. Incidence of hospital admission increased in both TBI (92%) and all injuries from cycling (71%). Highest increase in incidence of both ED treatments and hospital admissions was seen in adults aged 55+. The injury rate of TBI per kilometre travelled increased (44%) except in children, but decreased (−4%) for all injuries, showing a strong decrease in children (−36%) but an increase in men aged 25+, and women aged 15+. Total costs of bicycle-related TBI were €74.5 million annually. Although bicycle-related TBI accounted for 9% of the incidence of all ED treatments due to cycling, it accounted for 18% of the total costs due to all bicycle-related injuries (€410.7 million). Children and adolescents (aged 0–24) had highest incidence of ED treatments due to bicycle-related injuries. Men in the working population (aged 15–64) had highest indirect costs following injuries from cycling, including TBI. Older cyclists (aged 55+) were identified as main risk group for TBI, as they had highest ED attendance, injury rate, injury severity, admission to hospital or intensive care unit, and costs.Incidence of ED treatments due to cycling are high and often involve TBI, imposing a high burden on individuals and society. Older cyclists aged 55+ were identified as main risk group for TBI to be targeted in preventive strategies, due to their high risk for (serious) injuries and ever-increasing share of ED visits and hospital admissions.     

In Silico Analysis and Experimental Validation of Active Compounds from Cichorium intybus L. Ameliorating Liver Injury

This study aimed at investigating the possible mechanisms of hepatic protective activity of Cichorium intybus L. (chicory) in acute liver injury. Pathological observation, reactive oxygen species (ROS) detection and measurements of biochemical indexes on mouse models proved hepatic protective effect of Cichorium intybus L. Identification of active compounds in Cichorium intybus L. was executed through several methods including ultra performance liquid chromatography/time of flight mass spectrometry (UPLC-TOF-MS). Similarity ensemble approach (SEA) docking, molecular modeling, molecular docking, and molecular dynamics (MD) simulation were applied in this study to explore possible mechanisms of the hepato-protective potential of Cichorium intybus L. We then analyzed the chemical composition of Cichorium intybus L., and found their key targets. Furthermore, in vitro cytological examination and western blot were used for validating the efficacy of the selected compounds. In silico analysis and western blot together demonstrated that selected compound 10 in Cichorium intybus L. targeted Akt-1 in hepatocytes. Besides, compound 13 targeted both caspase-1 and Akt-1. These small compounds may ameliorate liver injury by acting on their targets, which are related to apoptosis or autophagy. The conclusions above may shed light on the complex molecular mechanisms of Cichorium intybus L. acting on hepatocytes and ameliorating liver injury.     

Failed Neuroprotection of Combined Inhibition of L-Type and ASIC1a Calcium Channels with Nimodipine and Amiloride

Effective pharmacological neuroprotection is one of the most desired aims in modern medicine. We postulated that a combination of two clinically used drugs—nimodipine (L-Type voltage-gated calcium channel blocker) and amiloride (acid-sensing ion channel inhibitor)—might act synergistically in an experimental model of ischaemia, targeting the intracellular rise in calcium as a pathway in neuronal cell death. We used organotypic hippocampal slices of mice pups and a well-established regimen of oxygen-glucose deprivation (OGD) to assess a possible neuroprotective effect. Neither nimodipine (at 10 or 20 µM) alone or in combination with amiloride (at 100 µM) showed any amelioration. Dissolved at 2.0 Vol.% dimethyl-sulfoxide (DMSO), the combination of both components even increased cell damage (p = 0.0001), an effect not observed with amiloride alone. We conclude that neither amiloride nor nimodipine do offer neuroprotection in an in vitro ischaemia model. On a technical note, the use of DMSO should be carefully evaluated in neuroprotective experiments, since it possibly alters cell damage.     

Quantitative Proteomic Approach Reveals Altered Metabolic Pathways in Response to the Inhibition of Lysine Deacetylases in A549 Cells under Normoxia and Hypoxia

Growing evidence is showing that acetylation plays an essential role in cancer, but studies on the impact of KDAC inhibition (KDACi) on the metabolic profile are still in their infancy. Here, we analyzed, by using an iTRAQ-based quantitative proteomics approach, the changes in the proteome of KRAS-mutated non-small cell lung cancer (NSCLC) A549 cells in response to trichostatin-A (TSA) and nicotinamide (NAM) under normoxia and hypoxia. Part of this response was further validated by molecular and biochemical analyses and correlated with the proliferation rates, apoptotic cell death, and activation of ROS scavenging mechanisms in opposition to the ROS production. Despite the differences among the KDAC inhibitors, up-regulation of glycolysis, TCA cycle, oxidative phosphorylation and fatty acid synthesis emerged as a common metabolic response underlying KDACi. We also observed that some of the KDACi effects at metabolic levels are enhanced under hypoxia. Furthermore, we used a drug repositioning machine learning approach to list candidate metabolic therapeutic agents for KRAS mutated NSCLC. Together, these results allow us to better understand the metabolic regulations underlying KDACi in NSCLC, taking into account the microenvironment of tumors related to hypoxia, and bring new insights for the future rational design of new therapies.     

Mitochondrial Bioenergetic,Photobiomodulation and Trigeminal Branches Nerve Damage,What’s the Connection? A Review

Background: Injury of the trigeminal nerve in oral and maxillofacial surgery can occur. Schwann cell mitochondria are regulators in the development, maintenance and regeneration of peripheral nerve axons. Evidence shows that after the nerve injury, mitochondrial bioenergetic dysfunction occurs and is associated with pain, neuropathy and nerve regeneration deficit. A challenge for research is to individuate new therapies able to normalise mitochondrial and energetic metabolism to aid nerve recovery after damage. Photobiomodulation therapy can be an interesting candidate, because it is a technique involving cell manipulation through the photonic energy of a non-ionising light source (visible and NIR light), which produces a nonthermal therapeutic effect on the stressed tissue. Methods: The review was based on the following questions: (1) Can photo-biomodulation by red and NIR light affect mitochondrial bioenergetics? (2) Can photobiomodulation support damage to the trigeminal nerve branches? (preclinical and clinical studies), and, if yes, (3) What is the best photobiomodulatory therapy for the recovery of the trigeminal nerve branches? The papers were searched using the PubMed, Scopus and Cochrane databases. This review followed the ARRIVE-2.0, PRISMA and Cochrane RoB-2 guidelines. Results and conclusions: The reliability of photobiomodulatory event strongly bases on biological and physical-chemical evidence. Its principal player is the mitochondrion, whether its cytochromes are directly involved as a photoacceptor or indirectly through a vibrational and energetic variation of bound water: water as the photoacceptor. The 808-nm and 100 J/cm² (0.07 W; 2.5 W/cm²; pulsed 50 Hz; 27 J per point; 80 s) on rats and 800-nm and 0.2 W/cm² (0.2 W; 12 J/cm²; 12 J per point; 60 s, CW) on humans resulted as trustworthy therapies, which could be supported by extensive studies.     

减少手术创伤始终是妇科肿瘤手术快速康复的决定性因素

减少手术创伤始终是快速康复的决定性因素,这一点在目前的加速康复外科研究尤其是复杂手术,如妇科肿瘤手术中尚未得到充分重视。尊重学习曲线、全面规划手术方案、总结失利经验、开展前瞻性研究是解决此问题的主要方案。本文着重讨论妇科肿瘤手术创伤对术后加速康复的影响及可能的改进措施。     

Superior foetal electrocardiogram signal elicitation using a novel artificial intelligent Bayesian methodology

Innumerable casualties due to intrauterine hypoxia are a major worry during prenatal phase besides advanced patient monitoring with latest science and technology. Hence, the analysis of foetal electrocardiogram (fECG) signals is very vital in order to evaluate the foetal heart status for timely recognition of cardiac abnormalities. Regrettably, the latest technology in the cutting edge field of biomedical signal processing does not seem to yield the desired quality of fECG signals required by physicians, which is the major cause for the pathetic condition. The focus of this work is to extort non-invasive fECG signal with highest possible quality with a motive to support physicians in utilizing the methodology for the latest intrapartum monitoring technique called STAN (ST analysis) for forecasting intrapartum foetal hypoxia. However, the critical quandary is that the non-invasive fECG signals recorded from the maternal abdomen are affected by several interferences like power line interference, baseline drift interference, electrode motion interference, muscle movement interference and the maternal electrocardiogram (mECG) being the dominant interference. A novel hybrid methodology called BANFIS (Bayesian adaptive neuro fuzzy inference system) is proposed. The BANFIS includes a Bayesian filter and an adaptive neuro fuzzy filter for mECG elimination and non-linear artefacts removal to yield high quality fECG signal. Kalman filtering frame work has been utilized to estimate the nonlinear transformed mECG component in the abdominal electrocardiogram (aECG). The adaptive neuro fuzzy filter is employed to discover the nonlinearity of the nonlinear transformed version of mECG and to align the estimated mECG signal with the maternal component in the aECG signal for annulment. The outcomes of the investigation by the proposed BANFIS system proved valuable for STAN system for efficient prediction of foetal hypoxia.