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.
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.
Risk of dementia after stroke is a major concern for patients and carers. Reliable data for risk of dementia, particularly after transient ischaemic attack or minor stroke, are scarce. We studied the ...risks of, and risk factors for, dementia before and after transient ischaemic attack and stroke.
The Oxford Vascular Study is a prospective incidence study of all vascular events in a population of 92 728 people residing in Oxfordshire, UK. Patients with transient ischaemic attack or stroke occurring between April 1, 2002, and March 31, 2012, were ascertained with multiple methods, including assessment in a dedicated daily emergency clinic and daily review of all hospital admissions. Pre-event and post-event (incident) dementia were diagnosed at initial assessment and during 5-years' follow-up on the basis of cognitive testing supplemented by data obtained from hand searches of all hospital and primary care records. We assessed the association between post-event dementia and stroke severity (as measured with the US National Institutes of Health Stroke Scale NIHSS score), location (ie, dysphasia), previous events, markers of susceptibility or reserve (age, low education, pre-morbid dependency, leucoaraiosis), baseline cognition, and vascular risk factors with Cox regression models adjusted for age, sex, and education. We compared incidence and prevalence of dementia in our population with published UK population age-matched and sex-matched rates.
Among 2305 patients (mean age 74·4 years SD 13·0), 688 (30%) had transient ischaemic attacks and 1617 (70%) had strokes. Pre-event dementia was diagnosed in 225 patients; prevalence was highest in severe stroke (ie, NIHSS >10) and lowest in transient ischaemic attack. Of 2080 patients without pre-event dementia, 1982 (95%) were followed up to the end of study or death. Post-event dementia occurred in 432 of 2080 patients during 5 years of follow-up. The incidence of post-event dementia at 1 year was 34·4% (95% CI 29·7–41·5) in patients with severe stroke (NIHSS score >10), 8·2% (6·2–10·2) in those with minor stroke (NIHSS score <3), and 5·2% (3·4–7·0) in those with transient ischaemic attack. Compared with the UK age-matched and sex-matched population, the 1-year standardised morbidity ratio for the incidence of dementia was 47·3 (95% CI 35·9–61·2), 5·8 (4·4–7·5), and 3·5 (2·5–4·8), respectively. Consequently, prevalence of dementia in 1-year survivors was brought forward by approximately 25 years in those who had severe strokes, 4 years in those who had minor strokes, and 2 years in those who had transient ischaemic attacks. 5-year risk of dementia was associated with age, event severity, previous stroke, dysphasia, baseline cognition, low education, pre-morbid dependency, leucoaraiosis, and diabetes (p<0·0001 for all comparisons, except for previous stroke p=0·006).
The incidence of dementia in patients who have had a transient ischaemic attack or stroke varies substantially depending on clinical characteristics including lesion burden and susceptibility factors. Incidence of dementia is nearly 50 times higher in the year after a major stroke compared with that in the general population, but excess risk is substantially lower after transient ischaemic attack and minor stroke.
Wellcome Trust, Wolfson Foundation, British Heart Foundation, National Institute for Health Research, and the National Institute for Health Research Oxford Biomedical Research Centre.
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.
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.
The transient receptor potential (TRP) multigene superfamily encodes integral membrane proteins that function as ion channels. Members of this family are conserved in yeast, invertebrates and ...vertebrates. The TRP family is subdivided into seven subfamilies: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), TRPA (ankyrin) and TRPN (NOMPC-like); the latter is found only in invertebrates and fish. TRP ion channels are widely expressed in many different tissues and cell types, where they are involved in diverse physiological processes, such as sensation of different stimuli or ion homeostasis. Most TRPs are non-selective cation channels, only few are highly Ca2+ selective, some are even permeable for highly hydrated Mg2+ ions. This channel family shows a variety of gating mechanisms, with modes of activation ranging from ligand binding, voltage and changes in temperature to covalent modifications of nucleophilic residues. Activated TRP channels cause depolarization of the cellular membrane, which in turn activates voltage-dependent ion channels, resulting in a change of intracellular Ca2+ concentration; they serve as gatekeeper for transcellular transport of several cations (such as Ca2+ and Mg2+), and are required for the function of intracellular organelles (such as endosomes and lysosomes). Because of their function as intracellular Ca2+ release channels, they have an important regulatory role in cellular organelles. Mutations in several TRP genes have been implicated in diverse pathological states, including neurodegenerative disorders, skeletal dysplasia, kidney disorders and pain, and ongoing research may help find new therapies for treatments of related diseases.
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