Cigarette smoke (CS) inhalation causes an early inflammatory response in rodent airways by stimulating capsaicin-sensitive sensory neurons that express transient receptor potential cation channel, ...subfamily V, member 1 (TRPV1) through an unknown mechanism that does not involve TRPV1. We hypothesized that 2 alpha,beta-unsaturated aldehydes present in CS, crotonaldehyde and acrolein, induce neurogenic inflammation by stimulating TRPA1, an excitatory ion channel coexpressed with TRPV1 on capsaicin-sensitive nociceptors. We found that CS aqueous extract (CSE), crotonaldehyde, and acrolein mobilized Ca2+ in cultured guinea pig jugular ganglia neurons and promoted contraction of isolated guinea pig bronchi. These responses were abolished by a TRPA1-selective antagonist and by the aldehyde scavenger glutathione but not by the TRPV1 antagonist capsazepine or by ROS scavengers. Treatment with CSE or aldehydes increased Ca2+ influx in TRPA1-transfected cells, but not in control HEK293 cells, and promoted neuropeptide release from isolated guinea pig airway tissue. Furthermore, the effect of CSE and aldehydes on Ca2+ influx in dorsal root ganglion neurons was abolished in TRPA1-deficient mice. These data identify alpha,beta-unsaturated aldehydes as the main causative agents in CS that via TRPA1 stimulation mediate airway neurogenic inflammation and suggest a role for TRPA1 in the pathogenesis of CS-induced diseases.
The voltage-frequency coupled transient stability and risk assessment issues of weak grid-connected large-scale renewable energy plants (REPs) during low voltage ride through (LVRT) have received ...little attention to date. The shape and mechanism of voltage-frequency coupled transient instability during LVRT are investigated in detail by the voltage-vector-triangle graphic (VTG) method utilized in this article, which avoids complex mathematical calculations. In addition, the margin of the transmission line's voltage angle (MTVA) is defined in this article and is then used to quantitatively assess the transient instability risk of the large-scale REPs during LVRT. Furthermore, the expressions of the MTVA are deduced under different conditions and the major influencing factors, which resulted in instability risk, are determined correspondingly. On this basis, the transient instability risk assessment standard of the large-scale REPs is built and the instability risk minimized scheduling strategy is proposed in this article, which does not change the internal control structure and parameters of the REPs during LVRT. Finally, both the correctness of the VTG method and the risk assessment standard, and the effectiveness of the scheduling strategy proposed in this article are validated by experiments and simulations.
In order to explore the impact load and instantaneous fluid pressure of transient flow on pump station system under the nonregulative operating conditions, the transient characteristics of an axial ...flow pump during start-up process are investigated experimentally and numerically. To simulate transient flow of the pump, the rational speed is set by force coupling. In order to simulate the movement of the gate with two flap doors attached, the moving mesh technique is adopted. The results of numerical simulation agree well with the experimental data. During the start-up transient process, the transient characteristics parameters, such as pump rotational speed, head, and flow rate change significantly. Transient impact head rises to a peak of 1.87 times the rated head as the rotational speed reaches the rated speed. The whole impeller passage is full of recirculation, flow separation and vortices. The pressure distribution of the impeller blade changes obviously. In the process of pump start-up, the vortex core zones gradually increase, massively appear at the leading edges of the blade and in the passage of the impeller at t=0.6 s, and then decrease. Our studies could help to avoid pump vibration and blade crack in engineering.
•The rotational speed was estimated from force coupling.•Transient impact peaks at the rated speed during the pump startup.•Recirculation and flow separation appeared in the whole impeller passage.•The vortex core zones increase at the leading edges of the blade then decrease.
Abstract
The next generation of wide-field cosmic microwave background (CMB) surveys are uniquely poised to open a new window into time-domain astronomy in the millimeter band. Here, we explore the ...discovery phase space for extragalactic transients with near-term and future CMB experiments to characterize the expected population. We use existing millimeter-band light curves of known transients (gamma-ray bursts, tidal disruption events, fast blue optical transients (FBOTs), neutron star mergers) and theoretical models, in conjunction with known and estimated volumetric rates. Using Monte Carlo simulations of various CMB survey designs (area, cadence, depth, duration) we estimate the detection rates and the resulting light-curve characteristics. We find that existing and near-term surveys will find tens to hundreds of long-duration gamma-ray bursts (LGRBs), driven primarily by detections of the reverse shock emission, and including off-axis LGRBs. Next-generation experiments (CMB-S4, CMB-HD) will find tens of FBOTs in the nearby universe and will detect a few tidal disruption events. CMB-HD will additionally detect a small number of short gamma-ray bursts, where these will be discovered within the detection volume of next-generation gravitational wave experiments like the Cosmic Explorer.
The pharmacology of TRP channels Holzer, Peter; Izzo, Angelo A
British journal of pharmacology,
20/May , Letnik:
171, Številka:
10
Journal Article
Recenzirano
Odprti dostop
This themed issue of the British Journal of Pharmacology contains review and research articles on recent advances in transient receptor potential (TRP) channel pharmacology. The review articles, ...written by a panel of distinguished experts, address the rapid progress in TRP channel research in fields as diverse as oncology, urology, dermatology, migraine, inflammation and pain. These reviews are complemented by original research reports focusing, among others, on the emerging roles of TRPV1 in osteoporosis and cystitis and on evodiamine as a lead structure for the development of potent TRPV1 agonists/desensitizers. Other papers highlight the differences in TRPV3 pharmacology between recombinant and native systems, the mechanisms of TRPM3 activation/inhibition and TRPP2 as a target of naringenin, a dietary flavonoid with anticancer actions. New therapeutic opportunities in pain may arise from the strategy to combine TRP channel and cell membrane impermeant sodium channel blockers to inhibit sensory nerve activity.
Linked Articles
This article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue‐10
The association of genetic polymorphisms and clopidogrel efficacy in patients with ischemic stroke or transient ischemic attack (TIA) remains controversial. We performed a systematic review and ...meta-analysis to assess the association between genetic polymorphisms, especially CYP2C19 genotype, and clopidogrel efficacy for ischemic stroke or TIA.
We conducted a comprehensive search of PubMed and EMBASE from their inceptions to June 24, 2016. Studies that reported clopidogrel-treated patients with stroke or TIA and with information on genetic polymorphisms were included. The end points were stroke, composite vascular events, and any bleeding.
Among 15 studies of 4762 patients with stroke or TIA treated with clopidogrel, carriers of CYP2C19 loss-of-function alleles (*2, *3, and *8) were at increased risk of stroke in comparison with noncarriers (12.0% versus 5.8%; risk ratio, 1.92, 95% confidence interval, 1.57-2.35; P<0.001). Composite vascular events were also more frequent in carriers of CYP2C19 loss-of-function alleles than in noncarriers (13.7% versus 9.4%; risk ratio, 1.51, 95% confidence interval, 1.10-2.06; P=0.01), whereas bleeding rates were similar (2.4% versus 3.1%; risk ratio, 0.89, 95% confidence interval, 0.58-1.35; P=0.59). There was no evidence of statistical heterogeneity among the included studies for stroke, but there was for composite vascular events. Genetic variants other than CYP2C19 were not associated with clinical outcomes, with the exception that significant associations of PON1, P2Y12, and COX-1 with outcomes were observed in 1 study.
Carriers of CYP2C19 loss-of-function alleles are at greater risk of stroke and composite vascular events than noncarriers among patients with ischemic stroke or TIA treated with clopidogrel.
Atrial fibrillation is a leading preventable cause of recurrent stroke for which early detection and treatment are critical. However, paroxysmal atrial fibrillation is often asymptomatic and likely ...to go undetected and untreated in the routine care of patients with ischemic stroke or transient ischemic attack (TIA).
We randomly assigned 572 patients 55 years of age or older, without known atrial fibrillation, who had had a cryptogenic ischemic stroke or TIA within the previous 6 months (cause undetermined after standard tests, including 24-hour electrocardiography ECG), to undergo additional noninvasive ambulatory ECG monitoring with either a 30-day event-triggered recorder (intervention group) or a conventional 24-hour monitor (control group). The primary outcome was newly detected atrial fibrillation lasting 30 seconds or longer within 90 days after randomization. Secondary outcomes included episodes of atrial fibrillation lasting 2.5 minutes or longer and anticoagulation status at 90 days.
Atrial fibrillation lasting 30 seconds or longer was detected in 45 of 280 patients (16.1%) in the intervention group, as compared with 9 of 277 (3.2%) in the control group (absolute difference, 12.9 percentage points; 95% confidence interval CI, 8.0 to 17.6; P<0.001; number needed to screen, 8). Atrial fibrillation lasting 2.5 minutes or longer was present in 28 of 284 patients (9.9%) in the intervention group, as compared with 7 of 277 (2.5%) in the control group (absolute difference, 7.4 percentage points; 95% CI, 3.4 to 11.3; P<0.001). By 90 days, oral anticoagulant therapy had been prescribed for more patients in the intervention group than in the control group (52 of 280 patients 18.6% vs. 31 of 279 11.1%; absolute difference, 7.5 percentage points; 95% CI, 1.6 to 13.3; P=0.01).
Among patients with a recent cryptogenic stroke or TIA who were 55 years of age or older, paroxysmal atrial fibrillation was common. Noninvasive ambulatory ECG monitoring for a target of 30 days significantly improved the detection of atrial fibrillation by a factor of more than five and nearly doubled the rate of anticoagulant treatment, as compared with the standard practice of short-duration ECG monitoring. (Funded by the Canadian Stroke Network and others; EMBRACE ClinicalTrials.gov number, NCT00846924.).
Comparisons between ticagrelor and clopidogrel for the secondary prevention of stroke in
loss-of-function carriers have not been extensively performed.
We conducted a randomized, double-blind, ...placebo-controlled trial at 202 centers in China involving patients with a minor ischemic stroke or transient ischemic attack (TIA) who carried
loss-of-function alleles. Patients were assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive ticagrelor (180 mg on day 1 followed by 90 mg twice daily on days 2 through 90) and placebo clopidogrel or to receive clopidogrel (300 mg on day 1 followed by 75 mg once daily on days 2 through 90) and placebo ticagrelor; both groups received aspirin for 21 days. The primary efficacy outcome was new stroke, and the primary safety outcome was severe or moderate bleeding, both within 90 days.
A total of 11,255 patients were screened and 6412 patients were enrolled, with 3205 assigned to the ticagrelor group and 3207 to the clopidogrel group. The median age of the patients was 64.8 years, and 33.8% were women; 98.0% belonged to the Han Chinese ethnic group. Stroke occurred within 90 days in 191 patients (6.0%) in the ticagrelor group and 243 patients (7.6%) in the clopidogrel group (hazard ratio, 0.77; 95% confidence interval, 0.64 to 0.94; P = 0.008). Secondary outcomes were generally in the same direction as the primary outcome. Severe or moderate bleeding occurred in 9 patients (0.3%) in the ticagrelor group and in 11 patients (0.3%) in the clopidogrel group; any bleeding occurred in 170 patients (5.3%) and 80 patients (2.5%), respectively.
Among Chinese patients with minor ischemic stroke or TIA who were carriers of
loss-of-function alleles, the risk of stroke at 90 days was modestly lower with ticagrelor than with clopidogrel. The risk of severe or moderate bleeding did not differ between the two treatment groups, but ticagrelor was associated with more total bleeding events than clopidogrel. (Funded by the Ministry of Science and Technology of the People's Republic of China and others; CHANCE-2 ClinicalTrials.gov number, NCT04078737.).
At least 240 000 individuals experience a transient ischemic attack each year in the United States. Transient ischemic attack is a strong predictor of subsequent stroke. The 90-day stroke risk after ...transient ischemic attack can be as high as 17.8%, with almost half occurring within 2 days of the index event. Diagnosing transient ischemic attack can also be challenging given the transitory nature of symptoms, often reassuring neurological examination at the time of evaluation, and lack of confirmatory testing. Limited resources, such as imaging availability and access to specialists, can further exacerbate this challenge. This scientific statement focuses on the correct clinical diagnosis, risk assessment, and management decisions of patients with suspected transient ischemic attack. Identification of high-risk patients can be achieved through use of comprehensive protocols incorporating acute phase imaging of both the brain and cerebral vasculature, thoughtful use of risk stratification scales, and ancillary testing with the ultimate goal of determining who can be safely discharged home from the emergency department versus admitted to the hospital. We discuss various methods for rapid yet comprehensive evaluations, keeping resource-limited sites in mind. In addition, we discuss strategies for secondary prevention of future cerebrovascular events using maximal medical therapy and patient education.
The grid-forming (GFM) converter has excellent active support capabilities, but it will face problems of transient instability and transient overcurrent during grid faults, which brings challenges to ...its large-scale application. Aiming at this problem, in this article, we analyze the transient instability mechanism and the transient overcurrent causes of the GFM converter. The analysis results show that active power imbalance is the essential reason that drives the power angle to increase and even causes transient instability, and the increase in power angle and the approximately constant internal potential cause the converter to generate transient overcurrent. Based on the above analysis, an active power and voltage cooperative control strategy is proposed to improve the fault ride-through capability of the GFM converter. This strategy consists of transient active power control and transient voltage control, which can eliminate the active power imbalance and flexibly regulate the internal potential according to the fault current, thus ensuring the transient stable operation of the converter while suppressing transient overcurrent. More importantly, the proposed control strategy is not affected by the fault degree and fault duration. Simulation and experimental results verify the effectiveness of the proposed strategy.
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