Imperial journal of interdisciplinary research, 2017
Orofacial pain is a general term covering any pain which is felt in the face, mouth and the jaws.... more Orofacial pain is a general term covering any pain which is felt in the face, mouth and the jaws. It is estimated that over 95% of cases of orofacial pain result from dental causes and the second most common cause of orofacial pain is temporomandibular joint dysfunction. Orofacial pain has been defined as "pain localized to the region above the neck, in front of the ears and below the orbitomeatal line, also pain within the oral cavity; including pain of dental origin and temporomandibular disorders".Pain essentially involves three different levels of classification – pain mechanism, pain symptoms, and pain syndromes. Classification systems clearly need to be reliable, valid, flexible, generalizable, and comprehensive and they need to be tested using views of experts along with the available literature. There is an urgent need for a robust classification system for orofacial pain recently emphasized by the confusion arising amongst dental practitioners understanding of ch...
BackgroundSimulation training has been used in the aviation industry and surgical specialties for... more BackgroundSimulation training has been used in the aviation industry and surgical specialties for many years, but integration into neurointerventional practice is lagging behind.ObjectiveTo investigate how neurointerventionalists perceive the usefulness and limitations of simulation tools for the treatment of unruptured intracranial aneurysms (UIAs), and to identify simulation applications that were perceived to be most valuable for endovascular UIA treatment.MethodsA web-based international multidisciplinary survey was conducted among neurointerventionalists. Participants were asked for their perceptions on the usefulness of current simulation tools and the potential impact of future simulation tools in endovascular UIA treatment. They identified simulation applications that could add most value to endovascular UIA treatment and help to specifically reduce endovascular UIA treatment complications.Results233 neurointerventionalists from 38 countries completed the survey, most of who...
Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 2021
ABSTRACT:Purpose:Endovascular thrombectomy (EVT) significantly improves outcomes for acute ischem... more ABSTRACT:Purpose:Endovascular thrombectomy (EVT) significantly improves outcomes for acute ischemic stroke patients with large vessel occlusion (LVO) who present in a time sensitive manner. Prolonged EVT access times may reduce benefits for eligible patients. We evaluated the efficiency of EVT services including EVT rates, onset-to-CTA time and onset-to-groin puncture time in our province.Materials and methods:Three areas were defined: zone I- urban region, zone II-areas within 1 h drive distance from the Comprehensive Stroke Center (CSC); and zone III-areas more than 1hr drive distance from the CSC. In this retrospective cohort study, EVT rate, onset-to-groin puncture time and onset-to-CTA time were compared among the three groups using Krustal–Wallis and Wilcoxon tests.Results:The EVT rate per 100,000 inhabitants for urban zone I was 8.6 as compared to 5.1 in zone II, and 7.5 in zone III. Compared to zone I (114 min; 95% CI (96, 132); n = 128), mean onset-to-CTA time was 19 min lo...
Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 2020
ABSTRACT: Endovascular thrombectomy (EVT) has revolutionized the care of patients with acute isch... more ABSTRACT: Endovascular thrombectomy (EVT) has revolutionized the care of patients with acute ischemic stroke. The efficacy of EVT is dependent on the optimal setup of a stroke system. Extrapolating the results of clinical trials to any individual stroke center should be done with caution. This is more important for centers with suboptimal stroke systems of care. The Canadian registry has helped highlight the suboptimal outcome post EVT in Manitoba. This could potentially be optimized with the addition of an acute stroke unit in the near future. Our study will serve as a baseline for future improvement in acute stroke care.
Mitochondrial dysfunction is a common cause in pathophysiology of different neurodegenerative dis... more Mitochondrial dysfunction is a common cause in pathophysiology of different neurodegenerative diseases. Elimination of dysfunctional and damaged mitochondria is a key requirement for maintaining homeostasis and bioenergetics of degenerating neurons. Using global microRNA (miRNA) profiling in a systemic rotenone model of Parkinson’s disease, we have identified miR-146a as upmost-regulated miRNA, which is known as inflammation regulatory miRNA. Here, we report the role of activated nuclear factor kappa beta (NF-kβ) in miR-146a-mediated downregulation of Parkin protein, which inhibits clearance of damaged mitochondria and induces neurodegeneration. Our studies have shown that 4-week rotenone exposure (2.5 mg/kg b.wt) induced oxidative imbalance-mediated NF-kβ activation in 1-year-old rat’s brain. Activated NF-kβ binds in promoter region of miR-146a gene and induces its transcription, which downregulates levels of Parkin protein. Decreased amount of Parkin protein results in accumulatio...
BACKGROUND Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is... more BACKGROUND Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke. METHODS For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0-1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018. FINDINGS Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0-2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96-1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups. INTERPRETATION Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo. FUNDING Canadian Institutes for Health Research, Alberta Innovates, and NoNO.
Arterial recanalization to restore the blood supply and limit the brain damage is the primary goa... more Arterial recanalization to restore the blood supply and limit the brain damage is the primary goal in the management of acute ischemic stroke (AIS). Since the publication of pivotal randomized clinical trials in 2015, endovascular thrombectomy has become part of the standard of care in selected cases of AIS from large‐vessel occlusions up to 6 hours after the onset of symptoms. However, the association between endovascular reperfusion and improved functional outcome is not strictly time dependent. Rather than on rigid time windows, candidates should be selected based on vascular and physiologic information. This approach places imaging data at the center of treatment decisions. Advances in imaging‐based management of AIS provide crucial information about vessel occlusion, infarct core, ischemic penumbra, and degree of collaterals. This information is invaluable in identifying patients who are likely to benefit from reperfusion therapies and excluding those who are unlikely to benefit or are at risk of adverse effects. The approach to reperfusion therapies continues to evolve, and imaging is acquiring a greater role in the diagnostic work‐up and treatment decisions as shown in recent clinical trials with extended time window. The 2018 American Heart Association/American Stroke Association guidelines reflect a paradigm shift in the management of AIS from “Time is Brain” to “Imaging is Brain.” This review discusses the essential role of multimodal imaging developing from recent trials on therapy for AIS.
Canadian Association of Radiologists Journal, 2020
Spontaneous intracranial hypotension (SIH) is a significant cause of chronic, postural headaches.... more Spontaneous intracranial hypotension (SIH) is a significant cause of chronic, postural headaches. Spontaneous intracranial hypotension is generally believed to be associated with cerebrospinal fluid (CSF) leaks, and these leaks can be posttraumatic, iatrogenic, or idiopathic in origin. An integral part of the management of patients with this condition consists of localizing and stopping the leaks. Radiologists play a central role in the workup of this condition detecting leaks using computed tomography, magnetic resonance imaging, or nuclear imaging. In this article, we briefly review SIH and the various imaging modalities, which can be used to identify and localize a spontaneous CSF leak.
Purpose: To compare the performance of collateral- vs perfusion-based imaging paradigms in late w... more Purpose: To compare the performance of collateral- vs perfusion-based imaging paradigms in late window stroke patients. Methods: In the prospective international (PRove-IT) study, patients had baseline CT head, multi-phase CTA (mCTA) and CTP. Patients presenting 6-24 hours of onset were included. We retrospectively selected patients for EVT based on 1) Collaterals: ASPECTS ≥5, plus proximal intracranial occlusion, plus good mCTA collaterals; 2) Perfusion: using DEFUSE-3, or DAWN trial criteria. CTP was processed using RAPID software. The performance of each paradigm to predict outcomes was assessed using the area under the receiver operating characteristic curve (AUC) of logistic regression models adjusting for age, NIHSS, sex, onset to CT time, EVT treatment, and interaction of EVT and the imaging paradigm. Results: We included 83 patients; medians of age 71, NIHSS 12, ASPECTS 9, and onset/ last seen well to CT of 576 minutes. Occlusions were: ICA, M1, M2-MCA (81.9 %), distal (8.4%...
Curcumin is the major phenolic compound found in turmeric, a dry powder of rhizomes and roots of ... more Curcumin is the major phenolic compound found in turmeric, a dry powder of rhizomes and roots of the plant, Curcuma longa L., which is widely used as spice and food colorant around the world, and in herbal medicinal practice in Asian countries. The present study reports the leishmanicidal activity of trans-dibenzalacetone (DBA), a synthetic monoketone analog of curcumin, against Leishmania donovani parasites. We for the first time report the antiproliferative effect of a curcumin analog (DBA) on the intracellular amastigotes of L. donovani, the clinically more relevant stage of the parasite than its promastigotes stage. The leishmanicidal effect of DBA was further confirmed by scanning and transmission electron microscopies. Cell growth was arrested in G0/G1 phase with increased concentration of cytosolic calcium and dissipation of mitochondrial membrane potential. Further, the unique trypanothione/trypanothione reductase (TR) system of Leishmania cells was significantly inhibited b...
In the ESCAPE trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occl... more In the ESCAPE trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times), patients with large vessel occlusions and small infarct cores identified with computed tomography (CT)/CT angiography were randomized to endovascular therapy or standard of care. CT perfusion (CTP) was obtained in some cases but was not used to select patients. We tested the hypothesis that patients with penumbral CTP patterns have higher rates of good clinical outcome. All CTP data acquired in ESCAPE patients were analyzed centrally using a semiautomated perfusion threshold-based approach. A penumbral pattern was defined as an infarct core <70 mL, penumbral volume >15 mL, and a total hypoperfused volume:core volume ratio of >1.8. The primary outcome was good functional outcome at 90 days (modified Rankin Scale score, 0-2). CTP was acquired in 138 of 316 ESCAPE patients. Penumbral patterns were present in 116 of 128 ...
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 2018
Proteomic studies were carried out in immature (3 week), adult (18 week) and aged (48 week) rats ... more Proteomic studies were carried out in immature (3 week), adult (18 week) and aged (48 week) rats to understand the age dependent vulnerability to lindane induced neurodegeneration. 2-D and western blot analysis of protein extracts of hippocampus and substantia-nigra isolated from lindane treated rats (2.5 mg/kg; p.o. X 21 days) revealed marked dysregulation in the expression of proteins related to ubiquitin proteasome pathway, antioxidant activity, chaperones, energy metabolism, calcium homeostasis and proteins involved in neurodegeneration. These alterations were associated with marked increase in reactive oxygen species formation, lipid peroxidation, reduced glutathione content and antioxidant enzyme activities in lindane treated rats. Aged rats, in particular showed higher magnitude of alteration in these proteins when compared to immature or adult rats. Proteins involved in apoptosis and autophagy also showed marked alterations in their expression, particularly in the aged rats....
The expanded uses of zinc oxide nanoparticles (ZnO NPs) have grown rapidly in the field of nanote... more The expanded uses of zinc oxide nanoparticles (ZnO NPs) have grown rapidly in the field of nanotechnology. Thus, rising production of nanoparticles (NPs) increases the possible risks to the environment and occupationally exposed humans. Hence, it is indispensable to appraise the safety toxicity including genotoxicity for these NPs. In the present study, we have evaluated the genotoxic effect of ZnO NPs after oral administration to Swiss mice at dose levels of 300 and 2000 mg/kg body weight. These doses were administered for 2 days at 24 h apart. Chromosomal aberration (CA) and micronucleus tests were conducted following Organization for Economic Co-operation and Development guidelines. DNA damage was evaluated at 0, 24, 48, and 72 h posttreatment using a randomly amplified polymorphic DNA (RAPD) assay; additionally, semen analyses were also performed at 34.5 days post oral exposure. The reactive oxygen species (ROS), 8-oxo-2′-deoxyguanosine and CAs were increased ( p < 0.05) at t...
Estrogen related receptors (ERRs), categorized as orphan nuclear receptors, are critical for ener... more Estrogen related receptors (ERRs), categorized as orphan nuclear receptors, are critical for energy homeostasis and somatic development. However, significance of ERRs in the development of reproductive organs/organelles/cells remain poorly understood, albeit their homology to estrogen receptors. In this context, here, we show that knockdown of ERR in the testes leads to improperly developed testes with mis-regulation of genes (aly, mia, bruce, bam, bgcn, fzo and eya) involved in spermatogenesis, resulting in reduced male fertility. The observed testicular deformity is consistent with the down-regulation of SOX-E group of gene (SOX100B) in Drosophila. We also show dispersion/disintegration of fusomes (microtubule based structures associated with endoplasmic reticulum derived vesicle, interconnecting spermatocytes) in ERR knockdown testes. A few ERR knockdown testes go through spermatogenesis but have significantly fewer sperm. Moreover, flagella of these sperm are defective with abno...
Canadian Association of Radiologists Journal, 2017
Diffusion-weighted imaging provides image contrast that is different from that provided by conven... more Diffusion-weighted imaging provides image contrast that is different from that provided by conventional magnetic resonance imaging techniques. It is highly sensitive for detection of cytotoxic oedema, and as such has gained favor in the detection of acute infarcts. However, diffusion-weighted imaging is underrepresented in the characterisation of many other disease processes. Our objective is to differentiate diseases that manifest with various neurological disorders, based on diffusion contrast and apparent diffusion coefficient values and review of hyper- and hypointense lesions on diffusion-weighted imaging.
Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 2016
Purpose:Computed tomography perfusion (CTP) has been performed to predict which patients with ane... more Purpose:Computed tomography perfusion (CTP) has been performed to predict which patients with aneurysmal subarachnoid hemorrhage are at risk of developing delayed cerebral ischemia (DCI). Patients with severe arterial narrowing may have significant reduction in perfusion. However, many patients have less severe arterial narrowing. There is a paucity of literature evaluating perfusion changes which occur with mild to moderate narrowing. The purpose of our study was to investigate serial whole-brain CTP/computed tomography angiography in aneurysm-related subarachnoid hemorrhage (aSAH) patients with mild to moderate angiographic narrowing.Methods:We retrospectively studied 18 aSAH patients who had baseline and follow-up whole-brain CTP/computed tomography angiography. Thirty-one regions of interest/hemisphere at six levels were grouped by vascular territory. Arterial diameters were measured at the circle of Willis. The correlation between arterial diameter and change in CTP values, cha...
Solar UV radiation is main factor of photocarcinogenesis, photoageing, and phototoxicity; thus, p... more Solar UV radiation is main factor of photocarcinogenesis, photoageing, and phototoxicity; thus, protection from UV radiation is major concern. Sunscreens containing UV filters are suggested as sun safe practices, but safety of UV filters remains in controversies. Benzophenone-1 (BP1) is commonly used in sunscreens as UV blocker. We assessed the photogenotoxicity and apoptotic parameters in human keratinocytes (HaCaT cells) by western blot, immunocytochemistry, flowcytometry, comet assay and TEM imaging. Our results exposed that BP1 photosensitized and generated intracellular ROS (2.02 folds) under sunlight/UVR. Decrease in cell viability was recorded as 80.06%, 60.98% and 56.24% under sunlight, UVA and UVB, respectively. Genotoxic potential of BP1 was confirmed through photomicronuclei and CPDs formation. BP1 enhanced lipid peroxidation and leakage of LDH enzyme (61.7%). Apoptotic cells were detected by AnnexinV/PI staining and sub G1 population of cell cycle. BP1 induced up regulation of apoptotic proteins Bax/Bcl2 ratio, Apaf-1, cytochrome c, Smac/DIABLO and cleaved caspase 3 was noticed. Down regulation of pro caspase 3 was inhibited by Z-VAD-fmk (inhibitor of caspase). Thus, study established the involvement of BP1 in photogenotoxicity and apoptosis via release of cytochrome c and Smac/DIABLO. These findings suggest sunscreen user to avoid BP1 in cosmetics preparation for its topical application.
Imperial journal of interdisciplinary research, 2017
Orofacial pain is a general term covering any pain which is felt in the face, mouth and the jaws.... more Orofacial pain is a general term covering any pain which is felt in the face, mouth and the jaws. It is estimated that over 95% of cases of orofacial pain result from dental causes and the second most common cause of orofacial pain is temporomandibular joint dysfunction. Orofacial pain has been defined as "pain localized to the region above the neck, in front of the ears and below the orbitomeatal line, also pain within the oral cavity; including pain of dental origin and temporomandibular disorders".Pain essentially involves three different levels of classification – pain mechanism, pain symptoms, and pain syndromes. Classification systems clearly need to be reliable, valid, flexible, generalizable, and comprehensive and they need to be tested using views of experts along with the available literature. There is an urgent need for a robust classification system for orofacial pain recently emphasized by the confusion arising amongst dental practitioners understanding of ch...
BackgroundSimulation training has been used in the aviation industry and surgical specialties for... more BackgroundSimulation training has been used in the aviation industry and surgical specialties for many years, but integration into neurointerventional practice is lagging behind.ObjectiveTo investigate how neurointerventionalists perceive the usefulness and limitations of simulation tools for the treatment of unruptured intracranial aneurysms (UIAs), and to identify simulation applications that were perceived to be most valuable for endovascular UIA treatment.MethodsA web-based international multidisciplinary survey was conducted among neurointerventionalists. Participants were asked for their perceptions on the usefulness of current simulation tools and the potential impact of future simulation tools in endovascular UIA treatment. They identified simulation applications that could add most value to endovascular UIA treatment and help to specifically reduce endovascular UIA treatment complications.Results233 neurointerventionalists from 38 countries completed the survey, most of who...
Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 2021
ABSTRACT:Purpose:Endovascular thrombectomy (EVT) significantly improves outcomes for acute ischem... more ABSTRACT:Purpose:Endovascular thrombectomy (EVT) significantly improves outcomes for acute ischemic stroke patients with large vessel occlusion (LVO) who present in a time sensitive manner. Prolonged EVT access times may reduce benefits for eligible patients. We evaluated the efficiency of EVT services including EVT rates, onset-to-CTA time and onset-to-groin puncture time in our province.Materials and methods:Three areas were defined: zone I- urban region, zone II-areas within 1 h drive distance from the Comprehensive Stroke Center (CSC); and zone III-areas more than 1hr drive distance from the CSC. In this retrospective cohort study, EVT rate, onset-to-groin puncture time and onset-to-CTA time were compared among the three groups using Krustal–Wallis and Wilcoxon tests.Results:The EVT rate per 100,000 inhabitants for urban zone I was 8.6 as compared to 5.1 in zone II, and 7.5 in zone III. Compared to zone I (114 min; 95% CI (96, 132); n = 128), mean onset-to-CTA time was 19 min lo...
Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 2020
ABSTRACT: Endovascular thrombectomy (EVT) has revolutionized the care of patients with acute isch... more ABSTRACT: Endovascular thrombectomy (EVT) has revolutionized the care of patients with acute ischemic stroke. The efficacy of EVT is dependent on the optimal setup of a stroke system. Extrapolating the results of clinical trials to any individual stroke center should be done with caution. This is more important for centers with suboptimal stroke systems of care. The Canadian registry has helped highlight the suboptimal outcome post EVT in Manitoba. This could potentially be optimized with the addition of an acute stroke unit in the near future. Our study will serve as a baseline for future improvement in acute stroke care.
Mitochondrial dysfunction is a common cause in pathophysiology of different neurodegenerative dis... more Mitochondrial dysfunction is a common cause in pathophysiology of different neurodegenerative diseases. Elimination of dysfunctional and damaged mitochondria is a key requirement for maintaining homeostasis and bioenergetics of degenerating neurons. Using global microRNA (miRNA) profiling in a systemic rotenone model of Parkinson’s disease, we have identified miR-146a as upmost-regulated miRNA, which is known as inflammation regulatory miRNA. Here, we report the role of activated nuclear factor kappa beta (NF-kβ) in miR-146a-mediated downregulation of Parkin protein, which inhibits clearance of damaged mitochondria and induces neurodegeneration. Our studies have shown that 4-week rotenone exposure (2.5 mg/kg b.wt) induced oxidative imbalance-mediated NF-kβ activation in 1-year-old rat’s brain. Activated NF-kβ binds in promoter region of miR-146a gene and induces its transcription, which downregulates levels of Parkin protein. Decreased amount of Parkin protein results in accumulatio...
BACKGROUND Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is... more BACKGROUND Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke. METHODS For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0-1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018. FINDINGS Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0-2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96-1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups. INTERPRETATION Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo. FUNDING Canadian Institutes for Health Research, Alberta Innovates, and NoNO.
Arterial recanalization to restore the blood supply and limit the brain damage is the primary goa... more Arterial recanalization to restore the blood supply and limit the brain damage is the primary goal in the management of acute ischemic stroke (AIS). Since the publication of pivotal randomized clinical trials in 2015, endovascular thrombectomy has become part of the standard of care in selected cases of AIS from large‐vessel occlusions up to 6 hours after the onset of symptoms. However, the association between endovascular reperfusion and improved functional outcome is not strictly time dependent. Rather than on rigid time windows, candidates should be selected based on vascular and physiologic information. This approach places imaging data at the center of treatment decisions. Advances in imaging‐based management of AIS provide crucial information about vessel occlusion, infarct core, ischemic penumbra, and degree of collaterals. This information is invaluable in identifying patients who are likely to benefit from reperfusion therapies and excluding those who are unlikely to benefit or are at risk of adverse effects. The approach to reperfusion therapies continues to evolve, and imaging is acquiring a greater role in the diagnostic work‐up and treatment decisions as shown in recent clinical trials with extended time window. The 2018 American Heart Association/American Stroke Association guidelines reflect a paradigm shift in the management of AIS from “Time is Brain” to “Imaging is Brain.” This review discusses the essential role of multimodal imaging developing from recent trials on therapy for AIS.
Canadian Association of Radiologists Journal, 2020
Spontaneous intracranial hypotension (SIH) is a significant cause of chronic, postural headaches.... more Spontaneous intracranial hypotension (SIH) is a significant cause of chronic, postural headaches. Spontaneous intracranial hypotension is generally believed to be associated with cerebrospinal fluid (CSF) leaks, and these leaks can be posttraumatic, iatrogenic, or idiopathic in origin. An integral part of the management of patients with this condition consists of localizing and stopping the leaks. Radiologists play a central role in the workup of this condition detecting leaks using computed tomography, magnetic resonance imaging, or nuclear imaging. In this article, we briefly review SIH and the various imaging modalities, which can be used to identify and localize a spontaneous CSF leak.
Purpose: To compare the performance of collateral- vs perfusion-based imaging paradigms in late w... more Purpose: To compare the performance of collateral- vs perfusion-based imaging paradigms in late window stroke patients. Methods: In the prospective international (PRove-IT) study, patients had baseline CT head, multi-phase CTA (mCTA) and CTP. Patients presenting 6-24 hours of onset were included. We retrospectively selected patients for EVT based on 1) Collaterals: ASPECTS ≥5, plus proximal intracranial occlusion, plus good mCTA collaterals; 2) Perfusion: using DEFUSE-3, or DAWN trial criteria. CTP was processed using RAPID software. The performance of each paradigm to predict outcomes was assessed using the area under the receiver operating characteristic curve (AUC) of logistic regression models adjusting for age, NIHSS, sex, onset to CT time, EVT treatment, and interaction of EVT and the imaging paradigm. Results: We included 83 patients; medians of age 71, NIHSS 12, ASPECTS 9, and onset/ last seen well to CT of 576 minutes. Occlusions were: ICA, M1, M2-MCA (81.9 %), distal (8.4%...
Curcumin is the major phenolic compound found in turmeric, a dry powder of rhizomes and roots of ... more Curcumin is the major phenolic compound found in turmeric, a dry powder of rhizomes and roots of the plant, Curcuma longa L., which is widely used as spice and food colorant around the world, and in herbal medicinal practice in Asian countries. The present study reports the leishmanicidal activity of trans-dibenzalacetone (DBA), a synthetic monoketone analog of curcumin, against Leishmania donovani parasites. We for the first time report the antiproliferative effect of a curcumin analog (DBA) on the intracellular amastigotes of L. donovani, the clinically more relevant stage of the parasite than its promastigotes stage. The leishmanicidal effect of DBA was further confirmed by scanning and transmission electron microscopies. Cell growth was arrested in G0/G1 phase with increased concentration of cytosolic calcium and dissipation of mitochondrial membrane potential. Further, the unique trypanothione/trypanothione reductase (TR) system of Leishmania cells was significantly inhibited b...
In the ESCAPE trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occl... more In the ESCAPE trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times), patients with large vessel occlusions and small infarct cores identified with computed tomography (CT)/CT angiography were randomized to endovascular therapy or standard of care. CT perfusion (CTP) was obtained in some cases but was not used to select patients. We tested the hypothesis that patients with penumbral CTP patterns have higher rates of good clinical outcome. All CTP data acquired in ESCAPE patients were analyzed centrally using a semiautomated perfusion threshold-based approach. A penumbral pattern was defined as an infarct core <70 mL, penumbral volume >15 mL, and a total hypoperfused volume:core volume ratio of >1.8. The primary outcome was good functional outcome at 90 days (modified Rankin Scale score, 0-2). CTP was acquired in 138 of 316 ESCAPE patients. Penumbral patterns were present in 116 of 128 ...
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 2018
Proteomic studies were carried out in immature (3 week), adult (18 week) and aged (48 week) rats ... more Proteomic studies were carried out in immature (3 week), adult (18 week) and aged (48 week) rats to understand the age dependent vulnerability to lindane induced neurodegeneration. 2-D and western blot analysis of protein extracts of hippocampus and substantia-nigra isolated from lindane treated rats (2.5 mg/kg; p.o. X 21 days) revealed marked dysregulation in the expression of proteins related to ubiquitin proteasome pathway, antioxidant activity, chaperones, energy metabolism, calcium homeostasis and proteins involved in neurodegeneration. These alterations were associated with marked increase in reactive oxygen species formation, lipid peroxidation, reduced glutathione content and antioxidant enzyme activities in lindane treated rats. Aged rats, in particular showed higher magnitude of alteration in these proteins when compared to immature or adult rats. Proteins involved in apoptosis and autophagy also showed marked alterations in their expression, particularly in the aged rats....
The expanded uses of zinc oxide nanoparticles (ZnO NPs) have grown rapidly in the field of nanote... more The expanded uses of zinc oxide nanoparticles (ZnO NPs) have grown rapidly in the field of nanotechnology. Thus, rising production of nanoparticles (NPs) increases the possible risks to the environment and occupationally exposed humans. Hence, it is indispensable to appraise the safety toxicity including genotoxicity for these NPs. In the present study, we have evaluated the genotoxic effect of ZnO NPs after oral administration to Swiss mice at dose levels of 300 and 2000 mg/kg body weight. These doses were administered for 2 days at 24 h apart. Chromosomal aberration (CA) and micronucleus tests were conducted following Organization for Economic Co-operation and Development guidelines. DNA damage was evaluated at 0, 24, 48, and 72 h posttreatment using a randomly amplified polymorphic DNA (RAPD) assay; additionally, semen analyses were also performed at 34.5 days post oral exposure. The reactive oxygen species (ROS), 8-oxo-2′-deoxyguanosine and CAs were increased ( p < 0.05) at t...
Estrogen related receptors (ERRs), categorized as orphan nuclear receptors, are critical for ener... more Estrogen related receptors (ERRs), categorized as orphan nuclear receptors, are critical for energy homeostasis and somatic development. However, significance of ERRs in the development of reproductive organs/organelles/cells remain poorly understood, albeit their homology to estrogen receptors. In this context, here, we show that knockdown of ERR in the testes leads to improperly developed testes with mis-regulation of genes (aly, mia, bruce, bam, bgcn, fzo and eya) involved in spermatogenesis, resulting in reduced male fertility. The observed testicular deformity is consistent with the down-regulation of SOX-E group of gene (SOX100B) in Drosophila. We also show dispersion/disintegration of fusomes (microtubule based structures associated with endoplasmic reticulum derived vesicle, interconnecting spermatocytes) in ERR knockdown testes. A few ERR knockdown testes go through spermatogenesis but have significantly fewer sperm. Moreover, flagella of these sperm are defective with abno...
Canadian Association of Radiologists Journal, 2017
Diffusion-weighted imaging provides image contrast that is different from that provided by conven... more Diffusion-weighted imaging provides image contrast that is different from that provided by conventional magnetic resonance imaging techniques. It is highly sensitive for detection of cytotoxic oedema, and as such has gained favor in the detection of acute infarcts. However, diffusion-weighted imaging is underrepresented in the characterisation of many other disease processes. Our objective is to differentiate diseases that manifest with various neurological disorders, based on diffusion contrast and apparent diffusion coefficient values and review of hyper- and hypointense lesions on diffusion-weighted imaging.
Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 2016
Purpose:Computed tomography perfusion (CTP) has been performed to predict which patients with ane... more Purpose:Computed tomography perfusion (CTP) has been performed to predict which patients with aneurysmal subarachnoid hemorrhage are at risk of developing delayed cerebral ischemia (DCI). Patients with severe arterial narrowing may have significant reduction in perfusion. However, many patients have less severe arterial narrowing. There is a paucity of literature evaluating perfusion changes which occur with mild to moderate narrowing. The purpose of our study was to investigate serial whole-brain CTP/computed tomography angiography in aneurysm-related subarachnoid hemorrhage (aSAH) patients with mild to moderate angiographic narrowing.Methods:We retrospectively studied 18 aSAH patients who had baseline and follow-up whole-brain CTP/computed tomography angiography. Thirty-one regions of interest/hemisphere at six levels were grouped by vascular territory. Arterial diameters were measured at the circle of Willis. The correlation between arterial diameter and change in CTP values, cha...
Solar UV radiation is main factor of photocarcinogenesis, photoageing, and phototoxicity; thus, p... more Solar UV radiation is main factor of photocarcinogenesis, photoageing, and phototoxicity; thus, protection from UV radiation is major concern. Sunscreens containing UV filters are suggested as sun safe practices, but safety of UV filters remains in controversies. Benzophenone-1 (BP1) is commonly used in sunscreens as UV blocker. We assessed the photogenotoxicity and apoptotic parameters in human keratinocytes (HaCaT cells) by western blot, immunocytochemistry, flowcytometry, comet assay and TEM imaging. Our results exposed that BP1 photosensitized and generated intracellular ROS (2.02 folds) under sunlight/UVR. Decrease in cell viability was recorded as 80.06%, 60.98% and 56.24% under sunlight, UVA and UVB, respectively. Genotoxic potential of BP1 was confirmed through photomicronuclei and CPDs formation. BP1 enhanced lipid peroxidation and leakage of LDH enzyme (61.7%). Apoptotic cells were detected by AnnexinV/PI staining and sub G1 population of cell cycle. BP1 induced up regulation of apoptotic proteins Bax/Bcl2 ratio, Apaf-1, cytochrome c, Smac/DIABLO and cleaved caspase 3 was noticed. Down regulation of pro caspase 3 was inhibited by Z-VAD-fmk (inhibitor of caspase). Thus, study established the involvement of BP1 in photogenotoxicity and apoptosis via release of cytochrome c and Smac/DIABLO. These findings suggest sunscreen user to avoid BP1 in cosmetics preparation for its topical application.
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Papers by jai shankar