GABA-receptive microglia selectively sculpt developing inhibitory circuits.

Microglia, the resident immune cells of the brain, have emerged as crucial regulators of synaptic refinement and brain wiring. However, whether the remodeling of distinct synapse types during development is mediated by specialized microglia is unknown. Here, we show that GABA-receptive microglia selectively interact with inhibitory cortical synapses during a critical window of mouse postnatal development. GABA initiates a transcriptional synapse remodeling program within these specialized microglia, which in turn sculpt inhibitory connectivity without impacting excitatory synapses. Ablation of GABAB receptors within microglia impairs this process and leads to behavioral abnormalities. These findings demonstrate that brain wiring relies on the selective communication between matched neuronal and glial cell types.

Peripheral CCL2-CCR2 signalling contributes to chronic headache-related sensitization.

Migraine, especially chronic migraine, is highly debilitating and still lacks effective treatment. The persistent headache arises from activation and sensitization of primary afferent neurons in the trigeminovascular pathway, but the underlying mechanisms remain incompletely understood. Animal studies indicate that signalling through chemokine C-C motif ligand 2 (CCL2) and C-C motif chemokine receptor 2 (CCR2) mediates the development of chronic pain after tissue or nerve injury. Some migraine patients had elevated CCL2 levels in CSF or cranial periosteum. However, whether the CCL2-CCR2 signalling pathway contributes to chronic migraine is not clear. Here, we modelled chronic headache with repeated administration of nitroglycerin (NTG, a reliable migraine trigger in migraineurs) and found that both Ccl2 and Ccr2 mRNA were upregulated in dura and trigeminal ganglion (TG) tissues that are implicated in migraine pathophysiology. In Ccl2 and Ccr2 global knockout mice, repeated NTG administration did not evoke acute or persistent facial skin hypersensitivity as in wild-type mice. Intraperitoneal injection of CCL2 neutralizing antibodies inhibited chronic headache-related behaviours induced by repeated NTG administration and repetitive restraint stress, suggesting that the peripheral CCL2-CCR2 signalling mediates headache chronification. We found that CCL2 was mainly expressed in TG neurons and cells associated with dura blood vessels, whereas CCR2 was expressed in subsets of macrophages and T cells in TG and dura but not in TG neurons under both control and disease states. Deletion of Ccr2 gene in primary afferent neurons did not alter NTG-induced sensitization, but eliminating CCR2 expression in either T cells or myeloid cells abolished NTG-induced behaviours, indicating that both CCL2-CCR2 signalling in T cells and macrophages are required to establish chronic headache-related sensitization. At cellular level, repeated NTG administration increased the number of TG neurons that responded to calcitonin-gene-related peptide (CGRP) and pituitary adenylate cyclase activating polypeptide (PACAP) as well as the production of CGRP in wild-type but not Ccr2 global knockout mice. Lastly, co-administration of CCL2 and CGRP neutralizing antibodies was more effective in reversing NTG-induced behaviours than individual antibodies. Taken together, these results suggest that migraine triggers activate CCL2-CCR2 signalling in macrophages and T cells. This consequently enhances both CGRP and PACAP signalling in TG neurons, ultimately leading to persistent neuronal sensitization underlying chronic headache. Our work not only identifies the peripheral CCL2 and CCR2 as potential targets for chronic migraine therapy, but also provides proof-of-concept that inhibition of both peripheral CGRP and CCL2-CCR2 signalling is more effective than targeting either pathway alone.

Dissociation of the opioid receptor mechanisms that control mechanical and heat pain.

Delta and mu opioid receptors (DORs and MORs) are inhibitory G protein-coupled receptors that reportedly cooperatively regulate the transmission of pain messages by substance P and TRPV1-expressing pain fibers. Using a DOReGFP reporter mouse we now show that the DOR and MOR are, in fact, expressed by different subsets of primary afferents. The MOR is expressed in peptidergic pain fibers, the DOR in myelinated and nonpeptidergic afferents. Contrary to the prevailing view, we demonstrate that the DOR is trafficked to the cell surface under resting conditions, independently of substance P, and internalized following activation by DOR agonists. Finally, we show that the segregated DOR and MOR distribution is paralleled by a remarkably selective functional contribution of the two receptors to the control of mechanical and heat pain, respectively. These results demonstrate that behaviorally relevant pain modalities can be selectively regulated through the targeting of distinct subsets of primary afferent pain fibers.

Saponins from Chenopodium quinoa Willd. husks alleviated high-fat-diet-induced hyperlipidemia via modulating the gut microbiota and multiple metabolic pathways.

BACKGROUND: Hyperlipidemia is characterized by abnormally elevated blood lipids. Quinoa saponins (QS) have multiple pharmacological activities, including antitumor, bactericidal and immune-enhancing effects. However, the lipid-lowering effect and mechanisms of QS in vivo have been scarcely reported. METHODS: The effect of QS against hyperlipidemia induced by high-fat diet in rats was explored based on gut microbiota and serum non-targeted metabolomics. RESULTS: The study demonstrated that the supplementation of QS could reduce serum lipids, body weight, liver injury and inflammation. 16S rRNA sequencing demonstrated that QS mildly increased alpha-diversity, altered the overall structure of intestinal flora, decreased the relative richness of Firmicutes, the ratio of Firmicutes/Bacteroidetes (P < 0.05) and increased the relative richness of Actinobacteria, Bacteroidetes, Bifidobacterium, Roseburia and Coprococcus (P < 0.05). Simultaneously, metabolomics analysis showed that QS altered serum functional metabolites with respect to bile acid biosynthesis, arachidonic acid metabolism and taurine and hypotaurine metabolism, which were closely related to bile acid metabolism and fatty acid ß-oxidation. Furthermore, QS increased protein levels of farnesoid X receptor, peroxisome proliferator-activated receptor α and carnitine palmitoyltransferase 1, which were related to the screened metabolic pathways. Spearman correlation analysis showed that there was a correlation between gut microbiota and differential metabolites. CONCLUSION: QS could prevent lipid metabolism disorders in hyperlipidemic rats, which may be closely associated with the regulation of the gut microbiota and multiple metabolic pathways. This study may provide new evidence for QS as natural active substances for the prevention of hyperlipidemia. © 2023 Society of Chemical Industry.

Bringing Artificial Intelligence to the operating room: edge computing for real-time surgical phase recognition.

BACKGROUND: Automation of surgical phase recognition is a key effort toward the development of Computer Vision (CV) algorithms, for workflow optimization and video-based assessment. CV is a form of Artificial Intelligence (AI) that allows interpretation of images through a deep learning (DL)-based algorithm. The improvements in Graphic Processing Unit (GPU) computing devices allow researchers to apply these algorithms for recognition of content in videos in real-time. Edge computing, where data is collected, analyzed, and acted upon in close proximity to the collection source, is essential meet the demands of workflow optimization by providing real-time algorithm application. We implemented a real-time phase recognition workflow and demonstrated its performance on 10 Robotic Inguinal Hernia Repairs (RIHR) to obtain phase predictions during the procedure. METHODS: Our phase recognition algorithm was developed with 211 videos of RIHR originally annotated into 14 surgical phases. Using these videos, a DL model with a ResNet-50 backbone was trained and validated to automatically recognize surgical phases. The model was deployed to a GPU, the Nvidia® Jetson Xavier™ NX edge computing device. RESULTS: This model was tested on 10 inguinal hernia repairs from four surgeons in real-time. The model was improved using post-recording processing methods such as phase merging into seven final phases (peritoneal scoring, mesh placement, preperitoneal dissection, reduction of hernia, out of body, peritoneal closure, and transitionary idle) and averaging of frames. Predictions were made once per second with a processing latency of approximately 250 ms. The accuracy of the real-time predictions ranged from 59.8 to 78.2% with an average accuracy of 68.7%. CONCLUSION: A real-time phase prediction of RIHR using a CV deep learning model was successfully implemented. This real-time CV phase segmentation system can be useful for monitoring surgical progress and be integrated into software to provide hospital workflow optimization.

An Interview Study of College Students' Health Emergency Literacy in the Context of COVID-19 Normalized Prevention and Control.

Objective: To explore the changes in college students' awareness of health protection under the normalization of COVID-19, and to seek its connection with the epidemic management in colleges and universities, so as to provide reference information for continuous health education activities and the cultivation of college students' health emergency literacy in colleges and universities. Methods: Qualitative interviews were used to understand the extent of health emergency literacy among college students enrolled in the context of a normalized epidemic and the factors associated with it that cause changes around a question outline. Results: The interviewees generally had a lax mentality in the late stage of the interview, the importance they attached to epidemic prevention and control decreased significantly, and the way to know about epidemic protection measures and other knowledge was mainly through the mass news media. All respondents affirm the importance of social software for outbreak prevention and control. All 17 interviewees were able to mention basic outbreak protection methods, but 15 of them showed inconsistent behavior in words and actions later. Conclusion: The vast majority of respondents' health emergency literacy appears to weaken in the late stages of epidemic normalization, and the effect of traditional approaches used by universities to improve college students' health emergency literacy is weak.

Safety evaluation of rare ginsenosides of stems and leaves from American ginseng: 90-day exposure toxicity study combined with intestinal flora analysis and metabonomics in rats.

Rare ginsenosides have already been widely applied in many fields, including health food and bio-medicine. The human being can expose to rare ginsenosides directly or indirectly increasingly. However, there are few studies on the safety assessment of rare ginsenoside mixtures. In the present study, the sub-chronic toxicity of rare ginsenosides for 90 days on SD rats was performed by combining the intestinal flora analysis and urine metabonomics aiming to illustrate the safety of long-term consumption of rare ginsenosides and the potential damage for liver and intestinal. 48 adult rats were divided into four groups: control (0 mg/kg), low-dose (60 mg/kg), medium-dose (200 mg/kg), and high-dose (600 mg/kg). Rats in the high-dose group showed inflammatory changes in their livers and intestines. The strong bactericidal effect of rare ginsenosides caused intestinal flora disorder and changed the structure of intestinal flora in rats, thus inducing intestinal damage in rats. In the high-dose group, levels of alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and alkaline phosphatase (AKP) increased significantly. As a result of the high-dose treatment, certain metabolic pathways were altered, such as vitamin B6 metabolism, methionine metabolism, glutathione metabolism, and others. These results indicated that high doses of rare ginsenosides induced liver injury by affecting the above metabolic pathways. Rare ginsenosides with no observed adverse effect level (NOAEL) were below 200 mg/kg/day in vivo. Thus, this present study provides insight into the rational use of rare ginsenosides.

Oxidative damage induced by combined exposure of titanium dioxide nanoparticles and cypermethrin in rats for 90 days.

Titanium dioxide nanoparticles (TiO2NPs) and cypermethrin (CPM) are widely used in various fields, and they can enter the environment in different ways. Combined exposure of TiO2NPs and CPM may increase the accumulation of pollutants in organisms and affect human health. This study was undertaken to evaluate the oxidative and inflammatory parameters associated with the combined exposure of TiO2NPs and CPM in rats. Twenty-four healthy male adult SD rats were randomly divided into four groups. The first group served as the control, while groups 2, 3, and 4 were treated with TiO2NPs (450 mg/m3); CPM (6.67 mg/m3) or combined exposure of TiO2NPs and CPM by inhalation for 90 days. We investigated the oxidative damage induced through combined exposure of TiO2NPs and CPM in rats by evaluating hematology of the rats and determining the blood biochemical index. Our results demonstrated that inhalation of TiO2NPs and CPM increased the levels of oxidative stress markers such as malondialdehyde and alkaline phosphatase in the serum of rats. These were accompanied by a decreased glutathione peroxidase and total superoxide dismutase levels. Furthermore, the level of glutathione peroxidase was further decreased while malondialdehyde was increased in the combined exposure of TiO2NPs and CPM. Interestingly, pathological sections showed that different degrees of tissue injury could be seen in the liver and lung tissues of each exposure group. In summary, the combined exposure of TiO2NPs and CPM can cause increased oxidative damage in rats and damage the tissue structure of the liver and lung.

Health risk cause of water around landfill in hilly area and prevention and control countermeasures.

Evaluating the health risks of the groundwater and surface water in landfill areas is of great significance to the health and safety of local residents. The current practice of health risk assessment is based only on the analysis results of groundwater and surface water samples, which reflect the current situation of water security in landfill areas. However, due to the neglect of risk causes analysis, thus a health risk assessment is insufficient to provide rigorous scientific countermeasures for risk prevention and control. The health risks caused by groundwater and surface water is mainly controlled by the water quality, which is comprehensively controlled by the conditions of its formation and evolution. When a landfill site is located in a hilly area, the environmental characteristics, causes, main controlling factors, and evolution processes of the surface water and groundwater in different parts of the catchment are significantly different. This study used a municipal solid waste landfill area in a hilly area as an example and defined the causes and main controlling factors of regional health risks caused by water based on an analysis of the characteristics of natural and anthropogenic factors affecting the groundwater and surface water. Then, prevention and control countermeasures were proposed for health risks caused by water in different parts of the landfill area. This study provides a method for the causes analysis and prevention and control countermeasures of health risks caused by water in municipal solid waste landfills in hilly areas.

The human health risk assessment and countermeasures study of groundwater quality.

Due to various geological, hydrogeological conditions and human activities, groundwater of different regions has distinct hydrochemical characteristics. The harmful chemical components of groundwater affect human health, and thus, the groundwater quality health risk assessment (GQHR) is important to local residents. It is vital to select GQHR factors combined with hydrochemical features, and to explore their formation, concentration characteristics and the prominent controlling role of influencing risk distribution from natural and human reasons. The factors of NO3-, NO2-, NH4+ and F- were extracted as assessment factors to evaluate the GQHR. The factors NO3-, NO2- and NH4+ are derived by human activities and F- stems from irrigation of geogenic high-fluoride groundwater and fertilizer use. The results of GQHR showed the risk order as children > adult females > adult males. The low- and medium-risk regions correspond to high groundwater levels, which are mainly controlled by natural factors. The high-risk regions located in eastern part of the study area, which were affected by both natural and human reasons. The targeted measures to prevent the increase of groundwater health risk caused by different dominant controlling effects were put forward. The research provides a scientific basis for the safety of groundwater supply and environmental exposure in this area. The research ideas and methods can be a reference for similar studies.

PPARγ modulates refractive development and form deprivation myopia in Guinea pigs.

Form deprivation myopia (FDM) is characterized by loss of choroidal thickness (ChT), reduced choroidal blood perfusion (ChBP), and consequently scleral hypoxia. In some tissues, changes in levels of peroxisome proliferator-activated receptor γ (PPARγ) expression modulate hypoxia-induced pathological responses. We determined if PPARγ modulates FDM through changes in ChT, ChBP, scleral hypoxia-inducible transcription factor (HIF-1α) that in turn regulate scleral collagen type 1 (COL1) expression levels in guinea pigs. Myopia was induced by occluding one eye, while the fellow eye served as control. They received daily peribulbar injections of either the PPARγ antagonist GW9662, or the GW1929 agonist, with or without ocular occlusion for 4 weeks. Ocular refraction and biometric parameters were estimated at baseline, 2 and 4 weeks post-treatment. ChT and ChBP were measured at the 2- and 4-week time points. Western blot analysis determined the expression levels of scleral HIF-1α and COL1. GW9662 induced a myopic shift in unoccluded eyes. Conversely, GW1929 inhibited FDM progression without affecting the refraction in unoccluded eyes. GW9662 reduced both ChT and ChBP in unoccluded eyes, while GW1929 inhibited their declines in occluded eyes. Scleral HIF-1α expression rose in GW9662-treated unoccluded eyes whereas GW1929 reduced HIF-1α upregulation in occluded eyes. GW9662 downregulated scleral COL1 expression in unoccluded eyes, while GW1929 reduced their decreases in occluded eyes. Therefore, PPARγ modulates collagen expression levels and FDM through an inverse relationship between changes in PPARγ and HIF-1α expression levels.

The influence of mood on the effort in trying to shift one's attention from a mind wandering phase to focusing on ongoing activities in a laboratory and in daily life.

This research investigated the effect of mood on self-reported effort in trying to focus back from mind wandering to ongoing things. We conducted three studies (one correlational and two experimental studies). Study 1 served as a correlational demonstration (questionnaires) of the negative relations between focus back effort and negative mood and between mind wandering and focus back effort at the trait level. Furthermore, a self-reported measure of focus back effort was developed to examine the effect of mood inductions on the ratings of focus back effort in the laboratory (Study 2) and daily life (Study 3). The findings of Studies 2 and 3 revealed that both in the laboratory and in daily life, participants in a negative mood reported lower levels of focus back effort rating than those in a positive mood. Thus, moods modulated mind wandering and an individual's effort in trying to focus back to some extent. Future work should account for the role of moods in mind wandering or focus back episodes.

In Situ Self-Polymerization to Form Hollow Graphitized Carbon Nanocages with Embedded Cobalt Nanoparticles for High-Performance Lithium-Sulfur Batteries.

Lithium-sulfur batteries, owing to the multi-electron participation in the redox reaction, possess enormous energy density, which has aroused much attention. Nevertheless, the detrimental shuttle effect, volume expansion, and electrical insulation of sulfur, have hindered their application. To improve the cyclability, a functional host, consisting of Co nanoparticles and N-doped hollow graphitized carbon (Co-NHGC) material, is elaborated, which has the advantages of: 1) the graphitized carbon material working as an electronic matrix to improve the utilization rate of sulfur; 2) the hollow structure relieving the stress change caused by volume expansion; 3) the rich active sites catalyze the electrochemical reaction of sulfur and entrap polysulfides. These advantages significantly improve the performance of the lithium-sulfur batteries. Accordingly, the S@Co-NHGC cathode exhibits excellent initial specific capacity, high coulombic efficiency, and excellent rate performance. This work utilizes a novel method of dopamine in situ etching of a metal-organic framework to synthetize the Co-NHGC host of sulfur, which will hopefully provide inspiration for other energy materials.

Ultrasound-guided percutaneous microwave ablation for hepatocellular carcinoma adjacent to large vessels: a propensity score matching analysis.

PURPOSE: This study aimed to compare the efficacy and safety of ultrasound-guided percutaneous microwave ablation (MWA) for hepatocellular carcinoma (HCC) adjacent to large vessels with those far from large vessels. METHODS: The clinical data of patients who underwent ultrasound-guided percutaneous MWA for HCC were retrospectively analyzed between January 2011 and December 2018 in Shengjing Hospital. Patients with HCC adjacent to large vessels were included in the Vessel group, the remaining patients were included in the Control group. Propensity score matching analysis was used to reduce confounding bias. The rates of complete ablation, local recurrence, recurrence-free survival (RFS), overall survival (OS) and complications were compared between the two groups. RESULTS: A total of 134 patients with 157 nodules (size range, 0.6-3.8 cm) were enrolled in this study, 23 in the Vessel group and 111 in the Control group. A total of 21 patients in the Vessel group (91.3%) and 105 patients in the Control group (94.6%) achieved complete ablation (p = .902). Following 1:2 propensity score matching, 22 patients were included in the Vessel group and 40 patients were enrolled in the Control group. Local recurrence was observed in 2 (9.1%) patients in the Vessel group and 5 (12.5%) in the Control group (p = .86). No significant difference in local recurrence rate, RFS and OS were observed between the two groups. CONCLUSIONS: Ultrasound-guided percutaneous MWA appears to be a safe procedure and can achieve comparable oncological efficacy for HCC abutting large vessels.

Quantitative Analysis of Mouse Dural Afferent Neurons Expressing TRPM8, VGLUT3, and NF200.

OBJECTIVE: To quantify the abundance of dural afferent neurons expressing transient receptor potential channel melastatin 8 (TRPM8), vesicular glutamate transporter 3 (VGLUT3), and neurofilament 200 (NF200) in adult mice. BACKGROUND: With the increasing use of mice as a model system to study headache mechanisms, it is important to understand the composition of dural afferent neurons in mice. In a previous study, we have measured the abundance of mouse dural afferent neurons that express neuropeptide calcitonin gene-related peptide as well as two TRP channels TRPV1 and TRPA1, respectively. Here, we conducted quantitative analysis of three other dural afferent subpopulations in adult mice. METHODS: We used the fluorescent tracer Fluoro-Gold to retrogradely label dural afferent neurons in adult mice expressing enhanced green fluorescent protein in discrete subpopulations of trigeminal ganglion (TG) neurons. Mechanoreceptors with myelinated fibers were identified by NF200 immunoreactivity. We also conducted Ca2+ -imaging experiments to test the overlap between TRPM8 and VGLUT3 expression in mouse primary afferent neurons (PANs). RESULTS: The abundance of TRPM8-expressing neurons in dural afferent neurons was significantly lower than that in total TG neurons. The percentages of dural afferent neurons expressing VGLUT3 and NF200 were comparable to those of total TG neurons, respectively. TRPM8 agonist menthol evoked Ca2+ influx in less than 7% VGLUT3-expressing PANs in adult mice. CONCLUSIONS: TG neurons expressing TRPM8, VGLUT3, and NF200 all innervate adult mouse dura. TRPM8 and VGLUT3 are expressed in distinct subpopulations of PANs in adult mice. These results provide an anatomical basis to investigate headache mechanisms in mouse models.

Determination of Vancomycin in Human Serum by Cyclodextrin-Micellar Electrokinetic Capillary Chromatography (CD-MEKC) and Application for PDAP Patients.

A simple and sensitive cyclodextrin-micellar electrokinetic capillary chromatography (CD-MEKC) method with UV detection was developed and validated for the determination of vancomycin (VCM) in serum. The separation was achieved in 14 min at 25 °C with a fused-silica capillary column of 40.2 cm × 50 mm i.d. (effective length 30.2 cm) and a run buffer containing 25 mM borate buffer with 50 mM sodium dodecylsulfonate (SDS) (pH 9.5) and 2% sulfobutyl-ß-cyclodextrin (sulfobutyl-ß-CD). Under optimal conditions for biological samples, good separations with high efficiency and short analysis time were achieved. Several parameters affecting the drug separation from biological matrices were studied, including buffer types, concentrations, and pHs. The methods were validated over the range of 0.9998-99.98 µg/mL. Calibration curves of VCM also showed good linearity (r² > 0.999). Intra- and interday precisions (relative standard deviation, RSD) were less than 5.80% and 7.38%, and lower limit of quantification (LLOQ) were lower than 1.0 µg/mL. The mean recoveries ranged between 84.03% and 91.69%. The method was successfully applied for monitoring VCM concentrations in serum of patients with peritoneal dialysis-associated peritonitis (PDAP). The assay should be applicable to pharmacokinetic studies and routine therapeutic drug monitoring of this drug in serum.

Radical Pair-Driven Luminescence of Quantum Dots for Specific Detection of Peroxynitrite in Living Cells.

There is currently great interest in developing chemiluminescence (CL) probes that can selectively detect peroxynitrite (ONOO(-)) in living cells. In comparison with other reactive oxygen species (ROS), ONOO(-) can spontaneously decompose into a series of radicals. Notably, the interaction of quantum dots (QDs) with oxidizing/reducing ROS radicals can generate a strong CL emission by electron-transfer annihilation. Herein, we report a novel CL probe that affords the ability to distinguish ONOO(-) from other ROS in living cells. ONOO(-) can activate luminescence of QDs in the absence of excitation source, effectively avoiding background noise and scattering of light from biological matrixes produced by in situ excitation; however, there is no response to other ROS including (1)O2, H2O2, (•)OH, O2(•-), and ClO(-). The outstanding selectivity of the present CL probe leads us to detect the exogenous release of ONOO(-) from 3-morpholinosydnonimine (SIN-1) in living cells. These results suggest that this present probe-based CL provides a promising platform for highly selective and sensitive detection of ONOO(-) in biological systems.

TRPM8 and Migraine.

Migraine is among the most common diseases on earth and one of the most disabling, the latter due in large part to poor treatment efficacy. Development of new therapeutics is dependent on the identification of mechanisms contributing to migraine and discovery of targets for new drugs. Numerous genome-wide association studies (GWAS) have implicated the transient receptor-potential M8 (TRPM8) channel in migraine. This channel is predominantly expressed on peripheral sensory neurons and is known as the sensor for cold temperature in cutaneous tissue but is also expressed on deep visceral afferents where cold is not likely a stimulus. Consequently, a number of alternative endogenous agonists have been proposed. Apart from its role in cold sensation, TRPM8 also contributes to cold allodynia after nerve injury or inflammation, and it is necessary for cooling/menthol-based analgesia. How it might contribute to migraine is less clear. The purpose of this review is to discuss the anatomical and physiological mechanisms by which meningeal TRPM8 may play a role in migraine as well as the potential of TRPM8 as a therapeutic target. TRPM8 is expressed on sensory afferents innervating the meninges, and these neurons are subject to developmental changes that may influence their contribution to migraine. As in viscera, meningeal TRPM8 channels are unlikely to be activated by temperature fluctuations and their endogenous ligands remain unknown. Preclinical migraine studies show that activation of meningeal TRPM8 by exogenous agonists can both cause and alleviate headache behaviors, depending on whether other meningeal afferents concurrently receive noxious stimuli. This is reminiscent of the fact that cold can trigger migraine in humans but menthol can also alleviate headache. We propose that both TRPM8 agonists and antagonists may be potential therapeutics, depending on how migraine is triggered in individual patients. In this regard, TRPM8 may be a novel target for personalized medicine in migraine treatment.

On-Line Organic Solvent Field Enhanced Sample Injection in Capillary Zone Electrophoresis for Analysis of Quetiapine in Beagle Dog Plasma.

A rapid and sensitive capillary zone electrophoresis (CZE) method with field enhanced sample injection (FESI) was developed and validated for the determination of quetiapine fumarate in beagle dog plasma, with a sample pretreatment by LLE in 96-well deep format plate. The optimum separation was carried out in an uncoated 31.2 cm × 75 µm fused-silica capillary with an applied voltage of 13 kV. The electrophoretic analysis was performed by 50 mM phosphate at pH 2.5. The detection wavelength was 210 nm. Under these optimized conditions, FESI with acetonitrile enhanced the sensitivity of quetiapine about 40-50 folds in total. The method was suitably validated with respect to stability, specificity, linearity, lower limit of quantitation, accuracy, precision and extraction recovery. Using mirtazapine as an internal standard (100 ng/mL), the response of quetiapine was linear over the range of 1-1000 ng/mL. The lower limit of quantification was 1 ng/mL. The intra- and inter-day precisions for the assay were within 4.8% and 12.7%, respectively. The method represents the first application of FESI-CZE to the analysis of quetiapine fumarate in beagle dog plasma after oral administration.