Prior randomized trials have generally shown harm or no benefit of stenting added to medical therapy for patients with symptomatic severe intracranial atherosclerotic stenosis, but it remains ...uncertain as to whether refined patient selection and more experienced surgeons might result in improved outcomes.
To compare stenting plus medical therapy vs medical therapy alone in patients with symptomatic severe intracranial atherosclerotic stenosis.
Multicenter, open-label, randomized, outcome assessor-blinded trial conducted at 8 centers in China. A total of 380 patients with transient ischemic attack or nondisabling, nonperforator (defined as nonbrainstem or non-basal ganglia end artery) territory ischemic stroke attributed to severe intracranial stenosis (70%-99%) and beyond a duration of 3 weeks from the latest ischemic symptom onset were recruited between March 5, 2014, and November 10, 2016, and followed up for 3 years (final follow-up: November 10, 2019).
Medical therapy plus stenting (n = 176) or medical therapy alone (n = 182). Medical therapy included dual-antiplatelet therapy for 90 days (single antiplatelet therapy thereafter) and stroke risk factor control.
The primary outcome was a composite of stroke or death within 30 days or stroke in the qualifying artery territory beyond 30 days through 1 year. There were 5 secondary outcomes, including stroke in the qualifying artery territory at 2 years and 3 years as well as mortality at 3 years.
Among 380 patients who were randomized, 358 were confirmed eligible (mean age, 56.3 years; 263 male 73.5%) and 343 (95.8%) completed the trial. For the stenting plus medical therapy group vs medical therapy alone, no significant difference was found for the primary outcome of risk of stroke or death (8.0% 14/176 vs 7.2% 13/181; difference, 0.4% 95% CI, -5.0% to 5.9%; hazard ratio, 1.10 95% CI, 0.52-2.35; P = .82). Of the 5 prespecified secondary end points, none showed a significant difference including stroke in the qualifying artery territory at 2 years (9.9% 17/171 vs 9.0% 16/178; difference, 0.7% 95% CI, -5.4% to 6.7%; hazard ratio, 1.10 95% CI, 0.56-2.16; P = .80) and 3 years (11.3% 19/168 vs 11.2% 19/170; difference, -0.2% 95% CI, -7.0% to 6.5%; hazard ratio, 1.00 95% CI, 0.53-1.90; P > .99). Mortality at 3 years was 4.4% (7/160) in the stenting plus medical therapy group vs 1.3% (2/159) in the medical therapy alone group (difference, 3.2% 95% CI, -0.5% to 6.9%; hazard ratio, 3.75 95% CI, 0.77-18.13; P = .08).
Among patients with transient ischemic attack or ischemic stroke due to symptomatic severe intracranial atherosclerotic stenosis, the addition of percutaneous transluminal angioplasty and stenting to medical therapy, compared with medical therapy alone, resulted in no significant difference in the risk of stroke or death within 30 days or stroke in the qualifying artery territory beyond 30 days through 1 year. The findings do not support the addition of percutaneous transluminal angioplasty and stenting to medical therapy for the treatment of patients with symptomatic severe intracranial atherosclerotic stenosis.
ClinicalTrials.gov Identifier: NCT01763320.
Background and purposeStroke is the leading cause of mortality and disability in China. Precise aetiological classification, imaging and biological markers may predict the prognosis of stroke. The ...Third China National Stroke Registry (CNSR-III), a nationwide registry of ischaemic stroke or transient ischaemic attack (TIA) in China based on aetiology, imaging and biology markers, will be considered to clarify the pathogenesis and prognostic factors of ischaemic stroke.MethodsBetween August 2015 and March 2018, the CNSR-III recruited consecutive patients with ischaemic stroke or TIA from 201 hospitals that cover 22 provinces and four municipalities in China. Clinical data were collected prospectively using an electronic data capture system by face-to-face interviews. Patients were followed for clinical outcomes at 3 months, 6 months and 1–5 year annually. Brain imaging, including brain MRI and CT, were completed at baseline. Blood samples were collected and biomarkers were tested at baseline.ResultsA total of 15 166 stroke patients were enrolled, among which 31.7% patients were women with the average age of 62.2±11.3 years. Ischaemic stroke was predominant (93.3%, n=14 146) and 1020 (6.7%) TIAs were enrolled.ConclusionsCNSR-III is a large scale nationwide registry in China. Data from this prospective registry may provide opportunity to evaluate imaging and biomarker prognostic determinants of stroke.
Highlights • Neuropathic pain is a chronic condition that represents a major health problem. • There is a need for new medications with greater efficacy and less adverse effects. • TRP channels are ...emerging targets for neuropathic pain therapeutics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Transient receptor potential (TRP) channels are nonselective cation channels and participate in various physiological roles. Thus, changes in TRP channel function or expression have been linked to ...several disorders. Among the many TRP channel subtypes, the TRP ankyrin type 1 (TRPA1), TRP melastatin type 8 (TRPM8), and TRP vanilloid type 1 (TRPV1) channels are temperature-sensitive and recognized as thermo-TRPs, which are expressed in the primary afferent nerve. Thermal stimuli are converted into neuronal activity. Several studies have described the expression of TRPA1, TRPM8, and TRPV1 in the cardiovascular system, where these channels can modulate physiological and pathological conditions, including hypertension. This review provides a complete understanding of the functional role of the opposing thermo-receptors TRPA1/TRPM8/TRPV1 in hypertension and a more comprehensive appreciation of TRPA1/TRPM8/TRPV1-dependent mechanisms involved in hypertension. These channels varied activation and inactivation have revealed a signaling pathway that may lead to innovative future treatment options for hypertension and correlated vascular diseases.
Real-time prediction of transient stability after a fault can potentially prevent occurrence of grid blackouts. In this paper, the measurement data obtained from phasor measurement unit (PMU) located ...at generator buses are used to compute the transient stability margin after a fault has occurred. For evaluating various control actions to be taken to stabilize severely disturbed and unstable generators, the stability margin is estimated using the transient energy function (TEF) technique. A look-up table of various modes of disturbance (MOD) is built offline for different fault locations and post fault topology. Following an actual fault, the most probable MODs are ranked by matching the "normalized" kinetic energy with the look-up table. The correct MOD is then chosen based on the lowest normalized potential energy margin and the Controlling Unstable Equilibrium Point (CUEP) is calculated. This technique overcomes previously reported difficulties in finding the CUEP in real-time applications. With knowledge of prefault operating condition obtained from SCADA and the information of the tripped line by analyzing the PMU data, the first swing transient stability margin is computed. The amount of control action needed is subsequently calculated. The proposed method has been tested on the IEEE 39 Bus Test System.
The TRPA1 ion channel (also known as the wasabi receptor) is a detector of noxious chemical agents encountered in our environment or produced endogenously during tissue injury or drug metabolism. ...These include a broad class of electrophiles that activate the channel through covalent protein modification. TRPA1 antagonists hold potential for treating neurogenic inflammatory conditions provoked or exacerbated by irritant exposure. Despite compelling reasons to understand TRPA1 function, structural mechanisms underlying channel regulation remain obscure. Here we use single-particle electron cryo- microscopy to determine the structure of full-length human TRPA1 to ∼4 Å resolution in the presence of pharmacophores, including a potent antagonist. Several unexpected features are revealed, including an extensive coiled-coil assembly domain stabilized by polyphosphate co-factors and a highly integrated nexus that converges on an unpredicted transient receptor potential (TRP)-like allosteric domain. These findings provide new insights into the mechanisms of TRPA1 regulation, and establish a blueprint for structure-based design of analgesic and anti-inflammatory agents.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The Transient Receptor Potential Ankyrin 1 channel (TRPA1), is a member of the large TRP family of ion channels, and functions as a Ca
2+
permeable non-selective cation channel in many different cell ...processes, ranging from sensory to homeostatic tasks. TRPA1 is highly conserved across the animal kingdom. The only mammalian TRPA subfamily member, TRPA1, is widely expressed in neuronal (e.g. sensory dorsal root and trigeminal ganglia neurons)- and in non-neuronal cells (e.g. epithelial cells, hair cells). It exhibits 14–19 amino-(
N
-)terminal ankyrin repeats, an unusual structural feature. The TRPA1 channel is activated by noxious cold (<17 °C) as well as by a plethora of chemical compounds that includes not only electrophilic compounds and oxidants that can modify, in an alkylative or oxidative fashion, nucleophilic cysteine residues in the channel’s
N
-terminus, but also compounds that do not covalently bind to the channel proteins (e.g. menthol, nifedipin). Based on localization and functional properties, TRPA1 is considered a key player in acute and chronic (neuropathic) pain and inflammation. Moreover, its role in the (patho)physiology of nearly all organ systems is anticipated, and will be discussed along with the potential of TRPA1 as a drug target for the management of various pathological conditions.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
9.
TRP modulation by natural compounds Meotti, Flavia Carla; Lemos de Andrade, Edinéia; Calixto, João B
Handbook of experimental pharmacology,
2014, Volume:
223
Journal Article
Peer reviewed
The use of medicinal plants or other naturally derived products to relieve illness can be traced back over several millennia, and these natural products are still extensively used nowadays. Studies ...on natural products have, over the years, enormously contributed to the development of therapeutic drugs used in modern medicine. By means of the use of these substances as selective agonists, antagonists, enzyme inhibitors or activators, it has been possible to understand the complex function of many relevant targets. For instance, in an attempt to understand how pepper species evoke hot and painful actions, the pungent and active constituent capsaicin (from Capsicum sp.) was isolated in 1846 and the receptor for the biological actions of capsaicin was cloned in 1997, which is now known as TRPV1 (transient receptor potential vanilloid 1). Thus, TRPV1 agonists and antagonists have currently been tested in order to find new drug classes to treat different disorders. Indeed, the transient receptor potential (TRP) proteins are targets for several natural compounds, and antagonists of TRPs have been synthesised based on the knowledge of naturally derived products. In this context, this chapter focuses on naturally derived compounds (from plants and animals) that are reported to be able to modulate TRP channels. To clarify and make the understanding of the modulatory effects of natural compounds on TRPs easier, this chapter is divided into groups according to TRP subfamilies: TRPV (TRP vanilloid), TRPA (TRP ankyrin), TRPM (TRP melastatin), TRPC (TRP canonical) and TRPP (TRP polycystin). A general overview on the naturally derived compounds that modulate TRPs is depicted in Table 1.
The transient responses and stability followed by grid faults of the modern power systems experience diverse changes and have created concerns, especially for those dominated by doubly fed induction ...generator (DFIG) based wind turbines (WTs), since the transient characteristics of the DFIG-based WT are totally different from those of a synchronous generator (SG). To physically understand the transient response and theoretically analyze the transient stability of DFIG-based WT, this paper proposes a magnitude/phase dynamical model with synthetical consideration on the controllers in the rotor speed control timescale (around seconds). The proposed model physically explains the relationship between the imbalanced active power as well as the output active/reactive powers themselves and the DFIG-based WT's internal voltage vector, whose form is similar to that of the SG. By comparing with the SG, the distinctive transient phase characteristics of the DFIG-based WT are illustrated. An additional phase limitation is found, exceeding which the operation point does not exist. Based on the proposed model, the transient stability of a simple DFIG-based WT-dominated system is theoretically analyzed, and a new instability phenomenon different from that in an SG-dominated system is identified. Furthermore, some key factors influencing the transient stability are discussed.
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