Intravenous Lidocaine and Ketamine Infusions for Headache Disorders: A Retrospective Cohort Study

Introduction: The use of lidocaine (lignocaine) and ketamine infusion in the inpatient treatment of patients with headache disorders is supported by small case series. We undertook a retrospective cohort study in order to assess the efficacy, duration and safety of lidocaine and ketamine infusions. Methods: Patients admitted between 01/01/2018 and 31/07/2021 were identified by ICD code and electronic prescription. Efficacy of infusion was determined by reduction in visual analog score (VAS), and patient demographics were collected from review of the hospital electronic medical record. Results: Through the study period, 83 infusions (50 lidocaine, 33 ketamine) were initiated for a headache disorder (77 migraine, three NDPH, two SUNCT, one cluster headache). In migraine, lidocaine infusion achieved a ≥50% reduction in pain in 51.1% over a mean 6.2 days (SD 2.4). Ketamine infusion was associated with a ≥50% reduction in pain in 34.4% over a mean 5.1 days (SD 1.5). Side effects were observed in 32 and 42.4% respectively. Infusion for medication overuse headache (MOH) led to successful withdrawal of analgesia in 61.1% of lidocaine, and 41.7% of ketamine infusions. Conclusion: Lidocaine and ketamine infusions are an efficacious inpatient treatment for headache disorders, however associated with prolonged length-of-stay and possible side-effects

Structural optimization and biological evaluation of 1,5-disubstituted pyrazole-3-carboxamines as potent inhibitors of human 5-lipoxygenase

AbstractHuman 5-lipoxygenase (5-LOX) is a well-validated drug target and its inhibitors are potential drugs for treating leukotriene-related disorders. Our previous work on structural optimization of the hit compound 2 from our in-house collection identified two lead compounds, 3a and 3b, exhibiting a potent inhibitory profile against 5-LOX with IC50 values less than 1µmol/L in cell-based assays. Here, we further optimized these compounds to prepare a class of novel pyrazole derivatives by opening the fused-ring system. Several new compounds exhibited more potent inhibitory activity than the lead compounds against 5-LOX. In particular, compound 4e not only suppressed lipopolysaccharide-induced inflammation in brain inflammatory cells and protected neurons from oxidative toxicity, but also significantly decreased infarct damage in a mouse model of cerebral ischemia. Molecular docking analysis further confirmed the consistency of our theoretical results and experimental data. In conclusion, the excellent in vitro and in vivo inhibitory activities of these compounds against 5-LOX suggested that these novel chemical structures have a promising therapeutic potential to treat leukotriene-related disorders

Mechanical overloading induces GPX4-regulated chondrocyte ferroptosis in osteoarthritis via Piezo1 channel facilitated calcium influx

Introductions: Excessive mechanical stress is closely associated with cell death in various conditions. Exposure of chondrocytes to excessive mechanical loading leads to a catabolic response as well as exaggerated cell death. Ferroptosis is a recently identified form of cell death during cell aging and degeneration. However, it's potential association with mechanical stress remains to be illustrated. Objectives: To identify whether excessive mechanical stress can cause ferroptosis. To explore the role of mechanical overloading in chondrocyte ferroptosis. Methods: Chondrocytes were collected from loading and unloading zones of cartilage in patients with osteoarthritis (OA), and the ferroptosis phenotype was analyzed through transmission electron microscope and microarray. Moreover, the relationship between ferroptosis and OA was analyzed by GPX4-conditional knockout (Col2a1-CreERT: GPX4flox/flox) mice OA model and chondrocytes cultured with high strain mechanical stress. Furthermore, the role of Piezo1 ion channel in chondrocyte ferroptosis and OA development was explored by using its inhibitor (GsMTx4) and agonist (Yoda1). Additionally, chondrocyte was cultured in calcium-free medium with mechanical stress, and ferroptosis phenotype was tested. Results: Human cartilage and mouse chondrocyte experiments revealed that mechanical overloading can induce GPX4-associated ferroptosis. Conditional knockout of GPX4 in cartilage aggravated experimental OA process, while additional treatment with ferroptosis suppressor protein (FSP-1) and coenzyme Q10 (CoQ10) abated OA development in GPX4-CKO mice. In mouse OA model and chondrocyte experiments, inhibition of Piezo1 channel activity increased GPX4 expression, attenuated ferroptosis phenotype and reduced the severity of osteoarthritis. Additionally, high strain mechanical stress induced ferroptosis damage in chondrocyte was largely abolished by blocking calcium influx through calcium-free medium. Conclusions: Our findings show that mechanical overloading induces ferroptosis through Piezo1 activation and subsequent calcium influx in chondrocytes, which might provide a potential target for OA treatment

Dynamic changes of soil microorganisms in rotation farmland at the western foot of the Greater Khingan range

Crop rotation and other tillage systems can affect soil microbial communities and functions. Few studies have reported the response of soil spatial microbial communities to rotation under drought stress. Therefore, the purpose of our study was to explore the dynamic changes of the soil space microbial community under different drought stress-rotation patterns. In this study, two water treatments were set up, control W1 (mass water content 25%–28%), and drought W2 (mass water content 9%–12%). Four crop rotation patterns were set in each water content, spring wheat continuous (R1), spring wheat-potato (R2), spring wheat-potato-rape (R3) and spring wheat-rape (R4), for a total of eight treatments (W1R1, W1R2, W1R3, W1R4, W2R1, W2R2, W2R3, W2R4). Endosphere, rhizosphere and bulk soil of spring wheat in each treatment were collected, and root space microbial community data were generated. The soil microbial community changed under different treatments and their relationship with soil factors were analyzed using a co-occurrence network, mantel test, and other methods. The results revealed that the alpha diversity of microorganisms in the rhizosphere and bulk soil did not differ significantly, but it was significantly greater than in the endosphere. The bacteria community structure was more stable, fungi alpha-diversity significant changes (p < 0.05), that were more sensitive to the response of various treatments than bacteria. The co-occurrence network between fungal species was stable under rotation patterns (R2, R3, R4), while the community stability was poor under continuous cropping pattern (R1), and interactions were strengthened. Soil organic matter (SOM), microbial biomass carbon (MBC), and pH value were the most important factors dominating the bacteria community structural changed in the endosphere, rhizosphere, and bulk soil. The dominant factor that affected the fungal community structural changed in the endosphere, rhizosphere, and bulk soil was SOM. Therefore, we conclude that soil microbial community changes under the drought stress-rotation patterns are mainly influenced by soil SOM and microbial biomass content

Genome-Wide Analysis of Neuroblastomas using High-Density Single Nucleotide Polymorphism Arrays

BACKGROUND: Neuroblastomas are characterized by chromosomal alterations with biological and clinical significance. We analyzed paired blood and primary tumor samples from 22 children with high-risk neuroblastoma for loss of heterozygosity (LOH) and DNA copy number change using the Affymetrix 10K single nucleotide polymorphism (SNP) array. FINDINGS: Multiple areas of LOH and copy number gain were seen. The most commonly observed area of LOH was on chromosome arm 11q (15/22 samples; 68%). Chromosome 11q LOH was highly associated with occurrence of chromosome 3p LOH: 9 of the 15 samples with 11q LOH had concomitant 3p LOH (P = 0.016). Chromosome 1p LOH was seen in one-third of cases. LOH events on chromosomes 11q and 1p were generally accompanied by copy number loss, indicating hemizygous deletion within these regions. The one exception was on chromosome 11p, where LOH in all four cases was accompanied by normal copy number or diploidy, implying uniparental disomy. Gain of copy number was most frequently observed on chromosome arm 17q (21/22 samples; 95%) and was associated with allelic imbalance in six samples. Amplification of MYCN was also noted, and also amplification of a second gene, ALK, in a single case. CONCLUSIONS: This analysis demonstrates the power of SNP arrays for high-resolution determination of LOH and DNA copy number change in neuroblastoma, a tumor in which specific allelic changes drive clinical outcome and selection of therapy

A compendium of genetic regulatory effects across pig tissues

The Farm Animal Genotype-Tissue Expression (FarmGTEx) project has been established to develop a public resource of genetic regulatory variants in livestock, which is essential for linking genetic polymorphisms to variation in phenotypes, helping fundamental biological discovery and exploitation in animal breeding and human biomedicine. Here we show results from the pilot phase of PigGTEx by processing 5,457 RNA-sequencing and 1,602 whole-genome sequencing samples passing quality control from pigs. We build a pig genotype imputation panel and associate millions of genetic variants with five types of transcriptomic phenotypes in 34 tissues. We evaluate tissue specificity of regulatory effects and elucidate molecular mechanisms of their action using multi-omics data. Leveraging this resource, we decipher regulatory mechanisms underlying 207 pig complex phenotypes and demonstrate the similarity of pigs to humans in gene expression and the genetic regulation behind complex phenotypes, supporting the importance of pigs as a human biomedical model.</p

Investigation of Solar Flares Impact on GPS/BDS/GALILEO Broadcast Ionospheric Models

The ionosphere is significant to solar-terrestrial space environment, and the ionospheric delay is considered as one main error source in Global Navigation Satellite System (GNSS). For GNSS single-frequency users, broadcast ionospheric models (BIMs) play an important role in mitigating the ionospheric delay. Solar activity induces ionospheric disturbances, which can reduce the performance of GNSS. In this study, solar flares impact on Global Positioning System/BeiDou satellite navigation System/Galileo (GPS/BDS/GALILEO) BIMs was investigated in the Asia-Pacific region. Twelve X-class and M-class large solar flares were selected for this study. Total electron content (TEC) derived from selected International GNSS Service and Crustal Movement Observation Network of China (CMONOC) were used to analyze the TEC anomalies and the adaptability of the GPS/BDS/GALILEO BIMs during sample solar flare events. It is verified that very noticeable sudden increase in TEC clearly took place during solar flares. The temporal variation of rate of TEC is more pronounced and rapid with respect to that of TEC. Especially, solar flares impact on the correction accuracy of the GPS/BDS/GALILEO BIMs is significant, as illustrated by a noticeable decrease in relative difference between the observed and modeled TEC values of the GPS/BDS/GALILEO BIMs occurred during the events. Through our investigation, we found that the adaptability of BDS BIM is better than GPS and GALILEO BIMs under solar flare conditions because its coefficients were updated more frequently, while the accuracy of the GALILEO BIM is the highest among current GPS/BDS/GALILEO BIMs in general

Multi-Scale Ionospheric Anomalies Monitoring and Spatio-Temporal Analysis during Intense Storm

The ionosphere is a significant component of the geospace environment. Storm-induced ionospheric anomalies severely affect the performance of Global Navigation Satellite System (GNSS) Positioning, Navigation, and Timing (PNT) and human space activities, e.g., the Earth observation, deep space exploration, and space weather monitoring and prediction. In this study, we present and discuss the multi-scale ionospheric anomalies monitoring over China using the GNSS observations from the Crustal Movement Observation Network of China (CMONOC) during the 2015 St. Patrick’s Day storm. Total Electron Content (TEC), Ionospheric Electron Density (IED), and the ionospheric disturbance index are used to monitor the storm-induced ionospheric anomalies. This study finally reveals the occurrence of the large-scale ionospheric storms and small-scale ionospheric scintillation during the storm. The results show that this magnetic storm was accompanied by a positive phase and a negative phase ionospheric storm. At the beginning of the main phase of the magnetic storm, both TEC and IED were significantly enhanced. There was long-duration depletion in the topside ionospheric TEC during the recovery phase of the storm. This study also reveals the response and variations in regional ionosphere scintillation. The Rate of the TEC Index (ROTI) was exploited to investigate the ionospheric scintillation and compared with the temporal dynamics of vertical TEC. The analysis of the ROTI proved these storm-induced TEC depletions, which suppressed the occurrence of the ionospheric scintillation. To improve the spatial resolution for ionospheric anomalies monitoring, the regional Three-Dimensional (3D) ionospheric model is reconstructed by the Computerized Ionospheric Tomography (CIT) technique. The spatial-temporal dynamics of ionospheric anomalies during the severe geomagnetic storm was reflected in detail. The IED varied with latitude and altitude dramatically; the maximum IED decreased, and the area where IEDs were maximum moved southward