Background Lesion-symptom mapping(LSM)is a statistical technique to investigate the population-specific relationship between structural integrity and post-stroke clinical outcome.In clinical practice,patients are comm...Background Lesion-symptom mapping(LSM)is a statistical technique to investigate the population-specific relationship between structural integrity and post-stroke clinical outcome.In clinical practice,patients are commonly evaluated using the National Institutes of Health Stroke Scale(NIHSS),an 11-domain clinical score to quantitate neurological deficits due to stroke.So far,LSM studies have mostly used the total NIHSS score for analysis,which might not uncover subtle structure–function relationships associated with the specific sub-domains of the NIHSS evaluation.Thus,the aim of this work was to investigate the feasibility to perform LSM analyses with sub-score information to reveal category-specific structure–function relationships that a total score may not reveal.Methods Employing a multivariate technique,LSM analyses were conducted using a sample of 180 patients with NIHSS assessment at 48-hour post-stroke from the ESCAPE trial.The NIHSS domains were grouped into six categories using two schemes.LSM was conducted for each category of the two groupings and the total NIHSS score.Results Sub-score LSMs not only identify most of the brain regions that are identified as critical by the total NIHSS score but also reveal additional brain regions critical to each function category of the NIHSS assessment without requiring extensive,specialised assessments.Conclusion These findings show that widely available sub-scores of clinical outcome assessments can be used to investigate more specific structure–function relationships,which may improve predictive modelling of stroke outcomes in the context of modern clinical stroke assessments and neuroimaging.展开更多
In response to peripheral nerve injury, the inflammatory response is almost entirely comprised of infiltrating macrophages. Macrophages are a highly plastic, heterogenic immune cell, playing an indispensable role in p...In response to peripheral nerve injury, the inflammatory response is almost entirely comprised of infiltrating macrophages. Macrophages are a highly plastic, heterogenic immune cell, playing an indispensable role in peripheral nerve injury, clearing debris and regulating the microenvironment to allow for efficient regeneration. There are several cells within the microenvironment that likely interact with macrophages to support their function – most notably the Schwann cell, the glial cell of the peripheral nervous system. Schwann cells express several ligands that are known to interact with receptors expressed by macrophages, yet the effects of Schwann cells in regulating macrophage phenotype remains largely unexplored. This review discusses macrophages in peripheral nerve injury and how Schwann cells may regulate their behavior.展开更多
The brain-gut axis serves as the bidirectional connection between the gut microbiome, the intestinal barrier and the immune system that might be relevant for the pathophysiology of inflammatory demyelinating diseases....The brain-gut axis serves as the bidirectional connection between the gut microbiome, the intestinal barrier and the immune system that might be relevant for the pathophysiology of inflammatory demyelinating diseases. People with multiple sclerosis have been shown to have an altered microbiome, increased intestinal permeability and changes in bile acid metabolism. Experimental evidence suggests that these changes can lead to profound alterations of peripheral and central nervous system immune regulation. Besides being of pathophysiological interest, the brain-gut axis could also open new avenues of therapeutic targets. Modification of the microbiome, the use of probiotics, fecal microbiota transplantation, supplementation with bile acids and intestinal barrier enhancers are all promising candidates. Hopefully, pre-clinical studies and clinical trials will soon yield significant results.展开更多
Purpose:The study aimed to examine the reporting completeness of randomized controlled trials(RCTs)of non-pharmacological interventions following concussion.Methods:We searched MEDLINE,Embase,PsycInfo,CINAHL,and Web o...Purpose:The study aimed to examine the reporting completeness of randomized controlled trials(RCTs)of non-pharmacological interventions following concussion.Methods:We searched MEDLINE,Embase,PsycInfo,CINAHL,and Web of Science up to May 2022.Two reviewers independently screened studies and assessed reporting completeness using the Template for Intervention Description and Replication(TIDieR),Consensus on Exercise Reporting Template(CERT),and international Consensus on Therapeutic Exercise aNd Training(i-CONTENT)checklists.Additional information was sought my study authors where reporting was incomplete.Risk of bias(ROB)was assessed with the Cochrane ROB-2 Tool.RCTs examining non-pharmacological interventions following concussion.Results:We included 89 RCTs(n=53 high ROB)examining 11 different interventions for concussion:sub-symptom threshold aerobic exercise,cervicovestibular therapy,physical/cognitive rest,vision therapy,education,psychotherapy,hyperbaric oxygen therapy,transcranial magnetic stimulation,blue light therapy,osteopathic manipulation,and head/neck cooling.Median scores were:TIDieR 9/12(75%;interquartile range(IQR)=5;range:5-12),CERT 17/19(89%;IQR=2;range:10-19),and i-CONTENT 6/7(86%;IQR=1;range:5-7).Percentage of studies completely reporting all items was TIDieR 35%(31/89),CERT 24%(5/21),and i-CONTENT 10%(2/21).Studies were more completely reported after publication of TIDieR(t_(87)=2.08;p=0.04)and CERT(t_(19)=2.72;p=0.01).Reporting completeness was not strongly associated with journal impact factor(TIDieR:rs=0.27;p=0.01;CERT:r_(s)=-0.44;p=0.06;i-CONTENT:r_(s)=-0.17;p=0.48)or ROB(TIDieR:rs=0.11;p=0.31;CERT:rs=0.04;p=0.86;i-CONTENT:rs=0.12;p=0.60).Conclusion:RCTs of non-pharmacological interventions following concussion demonstrate moderate to good reporting completeness,but are often missing key components,particularly modifications,motivational strategies,and qualified supervisor.Reporting completeness improved after TIDieR and CERT publication,but publication in highly cited journals and low ROB 展开更多
number of different cancer chemotherapy agents such as cisplatin,oxaliplatin,and paclitaxel can lead to nerve damage,thereby giving rise to neuropathic pain states that present with mechanical and cold allodynia[1].Al...number of different cancer chemotherapy agents such as cisplatin,oxaliplatin,and paclitaxel can lead to nerve damage,thereby giving rise to neuropathic pain states that present with mechanical and cold allodynia[1].Although these pain conditions often resolve after completion of the chemotherapy,a significant portion of patients exhibit longlasting pain that can persist longer than 12 months with a negative impact on the quality of life of affected individuals[1].展开更多
Injury to the brain after intracerebral hemorrhage(ICH)results from numerous complex cellular mechanisms.At present,effective therapy for ICH is limited and a better understanding of the mechanisms of brain injury is ...Injury to the brain after intracerebral hemorrhage(ICH)results from numerous complex cellular mechanisms.At present,effective therapy for ICH is limited and a better understanding of the mechanisms of brain injury is necessary to improve prognosis.There is increasing evidence that ion channel dysregulation occurs at multiple stages in primary and secondary brain injury following ICH.Ion channels such as TWIK-related K+channel 1,sulfonylurea 1 transient receptor potential melastatin 4 and glutamate-gated channels affect ion homeostasis in ICH.They in turn participate in the formation of brain edema,disruption of the blood-brain barrier,and the generation of neurotoxicity.In this review,we summarize the interaction between ions and ion channels,the effects of ion channel dysregulation,and we discuss some therapeutics based on ion-channel modulation following ICH.展开更多
Spontaneous intracerebral haemorrhage(ICH)is a devastating type of stroke with high mortality and morbidity and for which no effective treatments are available to date.Much experimental and clinical research have been...Spontaneous intracerebral haemorrhage(ICH)is a devastating type of stroke with high mortality and morbidity and for which no effective treatments are available to date.Much experimental and clinical research have been performed to explore its mechanisms regard the subsequent inflammatory cascade and to seek the potential therapeutic strategies.The aim of this review is to discuss insights from clinical settings that have led to the development of numerous animal models of ICH.Some of the current and future challenges for clinicians to understand ICH are also surveyed.展开更多
background Inflammation-exacerbated secondary brain injury and limited tissue regeneration are barriers to favourable prognosis after intracerebral haemorrhage(ICH).As a regulator of inflammation and lipid metabolism,...background Inflammation-exacerbated secondary brain injury and limited tissue regeneration are barriers to favourable prognosis after intracerebral haemorrhage(ICH).As a regulator of inflammation and lipid metabolism,Liver X receptor(LXR)has the potential to alter microglia/macrophage(M/M)phenotype,and assist tissue repair by promoting cholesterol efflux and recycling from phagocytes.To support potential clinical translation,the benefits of enhanced LXR signalling are examined in experimental ICH.Methods Collagenase-induced ICH mice were treated with the LXR agonist GW3965 or vehicle.Behavioural tests were conducted at multiple time points.Lesion and haematoma volume,and other brain parameters were assessed using multimodal MRI with T2-weighted,diffusion tensor imaging and dynamic contrast-enhanced MRI sequences.The fixed brain cryosections were stained and confocal microscopy was applied to detect LXR downstream genes,M/M phenotype,lipid/cholesterol-laden phagocytes,oligodendrocyte lineage cells and neural stem cells.Western blot and real-time qPCR were also used.CX3CR1^(CreER):Rosa26^(iDTR) mice were employed for M/M-depletion experiments.results GW3965 treatment reduced lesion volume and white matter injury,and promoted haematoma clearance.Treated mice upregulated LXR downstream genes including ABCA1 and Apolipoprotein E,and had reduced density of M/M that apparently shifted from proinflammatory interleukin-1β+to Arginase1+CD206+regulatory phenotype.Fewer cholesterol crystal or myelin debris-laden phagocytes were observed in GW3965 mice.LXR activation increased the number of Olig2+PDGFRα+precursors and Olig2+CC1+mature oligodendrocytes in perihaematomal regions,and elevated SOX2+or nestin+neural stem cells in lesion and subventricular zone.MRI results supported better lesion recovery by GW3965,and this was corroborated by return to pre-ICH values of functional rotarod activity.The therapeutic effects of GW3965 were abrogated by M/M depletion in CX3CR1^(CreER):Rosa26^(iDTR) mice.Conclusions LXR agonism using 展开更多
The development of in vivo biomarkers of Alzheimer's disease(AD)has advanced the diagnosis of AD from a clinical syndrome to a biological construct.The preclinical stage of AD continuum is defined by the identific...The development of in vivo biomarkers of Alzheimer's disease(AD)has advanced the diagnosis of AD from a clinical syndrome to a biological construct.The preclinical stage of AD continuum is defined by the identification of AD biomarkers crossing the pathological threshold in cognitively unimpaired individuals.While neuropsychiatric symptoms(NPS)are non-cognitive symptoms that are increasingly recognized as early manifestations of AD,the associations of NPS with AD pathophysiology in preclinical AD remain unclear.Here,we review the associations between NPS and AD biomarkers amyloid-(3(Aβ),tau and neurodegeneration in preclinical AD and cognitivelyunimpaired individuals in 19 eligible English-language publications(8 cross-sectional studies,10 longitudinal,1 both cross-sectional and longitudinal).The cross-sectional studies have consistently shown that NPS,particularly depressive and anxiety symptoms,are associated with higher Aβ.The longitudinal studies have suggested that greater NPS are associated with higher Aβ and cognitive decline in cognitively unimpaired subjects over time.However,most of the studies have either cross-sectionally or longitudinally shown no association between NPS and tau pathology.For the association of NPS and neurodegeneration,two studies have shown that the cerebrospinal fluid total-tau is linked to longitudinal increase in NPS and that the NPS may predict longitudinal metabolic decline in preclinical AD,respectively.However,evidence for the association between atrophy and NPS in preclinical AD is less consistent.Therefore,future longitudinal studies with well-designed methodologies and NPS measurements are required not only to determine the relationship among AT(N)biomarkers,NPS and cognitive decline,but also to elucidate the contribution of comorbid pathology to preclinical AD.展开更多
Background Long-term outcomes for Medicare beneficiaries hospitalised with transient ischaemic attack(TIA)and role of ABCD^(2) score in identifying high-risk individuals are not studied.Methods We identified 40825 Med...Background Long-term outcomes for Medicare beneficiaries hospitalised with transient ischaemic attack(TIA)and role of ABCD^(2) score in identifying high-risk individuals are not studied.Methods We identified 40825 Medicare beneficiaries hospitalised from 2011 to 2014 for a TIA to a Get With The Guidelines(GWTG)-Stroke hospital and classified them using ABCD^(2)s of mortality and rehospitalisation(all-cause,ischaemic stroke,haemorrhagic stroke,myocardial infarction,and gastrointestinal and intracranial haemorrhage)for high-risk versus low-risk groups adjusted for patient and hospital characteristics.Results Of the 40825 patients,35118(86%)were high risk(ABCD^(2)≥4)and 5707(14%)were low risk(ABCD^(2)=0-3).Overall rate of mortality during 1-year follow-up after hospital discharge for the index TIA was 11.7%,44.3% were rehospitalised for any reason and 3.6%were readmitted due to stroke.Patients with ABCD^(2) score≥4 had higher mortality at 1 year than not(adjusted HR 1.18,95%CI 1.07 to 1.30).Adjusted risks for ischaemic stroke,all-cause readmission and mortality/all-cause readmission at 1 year were also significantly higher for patients with ABCD^(2) score≥4 vs 0-3.In contrast,haemorrhagic stroke,myocardial infarction,gastrointestinal bleeding and intracranial haemorrhage risk were not significantly different by ABCD^(2) score.Conclusions This study validates the use of ABCD^(2) score for long-term risk assessment after TIA in patients aged 65 years and older.Attentive efforts for community-based follow-up care after TIA are needed for ongoing prevention in Medicare beneficiaries who were hospitalised for TIA.展开更多
Autonomous systems are an emerging AI technology functioning without human intervention underpinned by the latest advances in intelligence,cognition,computer,and systems sciences.This paper explores the intelligent an...Autonomous systems are an emerging AI technology functioning without human intervention underpinned by the latest advances in intelligence,cognition,computer,and systems sciences.This paper explores the intelligent and mathematical foundations of autonomous systems.It focuses on structural and behavioral properties that constitute the intelligent power of autonomous systems.It explains how system intelligence aggregates from reflexive,imperative,adaptive intelligence to autonomous and cognitive intelligence.A hierarchical intelligence model(HIM)is introduced to elaborate the evolution of human and system intelligence as an inductive process.The properties of system autonomy are formally analyzed towards a wide range of applications in computational intelligence and systems engineering.Emerging paradigms of autonomous systems including brain-inspired systems,cognitive robots,and autonomous knowledge learning systems are described.Advances in autonomous systems will pave a way towards highly intelligent machines for augmenting human capabilities.展开更多
Prion diseases are infectious protein misfolding disorders of the central nervous system that result from misfolding of the cellular prion protein(PrPC)into the pathologic isoform PrPSc.Pathologic hallmarks of prion d...Prion diseases are infectious protein misfolding disorders of the central nervous system that result from misfolding of the cellular prion protein(PrPC)into the pathologic isoform PrPSc.Pathologic hallmarks of prion disease are depositions of pathological prion protein PrPSc,neuronal loss,spongiform degeneration and astrogliosis in the brain.Prion diseases affect human and animals,there is no effective therapy,and they invariably remain fatal.For a long time,neuronal loss was considered the sole reason for neurodegeneration in prion pathogenesis,and the contribution of non-neuronal cells like microglia and astrocytes was considered less important.Recent evidence suggests that neurodegeneration during prion pathogenesis is a consequence of a complex interplay between neuronal and non-neuronal cells in the brain,but the exact role of these non-neuronal cells during prion pathology is still elusive.Astrocytes are non-neuronal cells that regulate brain homeostasis under physiological conditions.However,astrocytes can deposit PrPSc aggregates and propagate prions in prion-infected brains.Additionally,sub-populations of reactive astrocytes that include neurotrophic and neurotoxic species have been identified,differentially expressed in the brain during prion infection.Revealing the exact role of astrocytes in prion disease is hampered by the lack of in vitro models of prion-infected astrocytes.Recently,we established a murine astrocyte cell line persistently infected with mouse-adapted prions,and showed how such astrocytes differentially process various prion strains.Considering the complexity of the role of astrocytes in prion pathogenesis,we need more in vitro and in vivo models for exploring the contribution of sub-populations of reactive astrocytes,their differential regulation of signaling cascades,and the interaction with neurons and microglia during prion pathogenesis.This will help to establish novel in vivo models and define new therapeutic targets against prion diseases.In this review,we will discuss the comp展开更多
Background During the COVID-19 pandemic,decreased volumes of stroke admissions and mechanical thrombectomy were reported.The study’s objective was to examine whether subarachnoid haemorrhage(SAH)hospitalisations and ...Background During the COVID-19 pandemic,decreased volumes of stroke admissions and mechanical thrombectomy were reported.The study’s objective was to examine whether subarachnoid haemorrhage(SAH)hospitalisations and ruptured aneurysm coiling interventions demonstrated similar declines.Methods We conducted a cross-sectional,retrospective,observational study across 6 continents,37 countries and 140 comprehensive stroke centres.Patients with the diagnosis of SAH,aneurysmal SAH,ruptured aneurysm coiling interventions and COVID-19 were identified by prospective aneurysm databases or by International Classification of Diseases,10th Revision,codes.The 3-month cumulative volume,monthly volumes for SAH hospitalisations and ruptured aneurysm coiling procedures were compared for the period before(1 year and immediately before)and during the pandemic,defined as 1 March-31 May 2020.The prior 1-year control period(1 March-31 May 2019)was obtained to account for seasonal variation.Findings There was a significant decline in SAH hospitalisations,with 2044 admissions in the 3 months immediately before and 1585 admissions during the pandemic,representing a relative decline of 22.5%(95%CI−24.3%to−20.7%,p<0.0001).Embolisation of ruptured aneurysms declined with 1170-1035 procedures,respectively,representing an 11.5%(95%CI−13.5%to−9.8%,p=0.002)relative drop.Subgroup analysis was noted for aneurysmal SAH hospitalisation decline from 834 to 626 hospitalisations,a 24.9%relative decline(95%CI−28.0%to−22.1%,p<0.0001).A relative increase in ruptured aneurysm coiling was noted in low coiling volume hospitals of 41.1%(95%CI 32.3%to 50.6%,p=0.008)despite a decrease in SAH admissions in this tertile.Interpretation There was a relative decrease in the volume of SAH hospitalisations,aneurysmal SAH hospitalisations and ruptured aneurysm embolisations during the COVID-19 pandemic.These findings in SAH are consistent with a decrease in other emergencies,such as stroke and myocardial infarction.展开更多
How distinct transcriptional programs are enacted to generate cellular heterogeneity and plasticity,and enable complex fate decisions are important open questions.One key regulator is the cell’s epigenome state that ...How distinct transcriptional programs are enacted to generate cellular heterogeneity and plasticity,and enable complex fate decisions are important open questions.One key regulator is the cell’s epigenome state that drives distinct transcriptional programs by regulating chromatin accessibility.Genome-wide chromatin accessibility measurements can impart insights into regulatory sequences(in)accessible to DNA-binding proteins at a single-cell resolution.This review outlines molecular methods and bioinformatic tools for capturing cell-to-cell chromatin variation using single-cell assay for transposase-accessible chromatin using sequencing(scATAC-seq)in a scalable fashion.It also covers joint profiling of chromatin with transcriptome/proteome measurements,computational strategies to integrate multi-omic measurements,and predictive bioinformatic tools to infer chromatin accessibility from single-cell transcriptomic datasets.Methodological refinements that increase power for cell discovery through robust chromatin coverage and integrate measurements from multiple modalities will further expand our understanding of gene regulation during homeostasis and disease.展开更多
BACKGROUND Patients leaving the intensive care unit(ICU)often experience gaps in care due to deficiencies in discharge communication,leaving them vulnerable to increased stress,adverse events,readmission to ICU,and de...BACKGROUND Patients leaving the intensive care unit(ICU)often experience gaps in care due to deficiencies in discharge communication,leaving them vulnerable to increased stress,adverse events,readmission to ICU,and death.To facilitate discharge communication,written summaries have been implemented to provide patients and their families with information on medications,activity and diet restrictions,follow-up appointments,symptoms to expect,and who to call if there are questions.While written discharge summaries for patients and their families are utilized frequently in surgical,rehabilitation,and pediatric settings,few have been utilized in ICU settings.AIM To develop an ICU specific patient-oriented discharge summary tool(PODS-ICU),and pilot test the tool to determine acceptability and feasibility.METHODS Patient-partners(i.e.,individuals with lived experience as an ICU patient or family member of an ICU patient),ICU clinicians(i.e.,physicians,nurses),and researchers met to discuss ICU patients’specific informational needs and design the PODS-ICU through several cycles of discussion and iterative revisions.Research team nurses piloted the PODS-ICU with patient and family participants in two ICUs in Calgary,Canada.Follow-up surveys on the PODS-ICU and its impact on discharge were administered to patients,family participants,and ICU nurses.RESULTS Most participants felt that their discharge from the ICU was good or better(n=13;87.0%),and some(n=9;60.0%)participants reported a good understanding of why the patient was in ICU.Most participants(n=12;80.0%)reported that they understood ICU events and impacts on the patient’s health.While many patients and family participants indicated the PODS-ICU was informative and useful,ICU nurses reported that the PODS-ICU was“not reasonable”in their daily clinical workflow due to“time constraint”.CONCLUSION The PODS-ICU tool provides patients and their families with essential information as they discharge from the ICU.This tool has the potential to engage and empower 展开更多
Despite intensive research,most neurodegenerative diseases cannot be cured and for some of them no treatment is available to increase survival or quality of life.Among the latter are prion diseases,fatal and transmiss...Despite intensive research,most neurodegenerative diseases cannot be cured and for some of them no treatment is available to increase survival or quality of life.Among the latter are prion diseases,fatal and transmissible neurodegenerative diseases of humans and other animals.展开更多
Neuropathic pain is a long term and common pain disorder in clinics that is refractory to treatment,however,the neural substrates and underlying mechanisms are poorly understood.Using the com bination of neuronal mapp...Neuropathic pain is a long term and common pain disorder in clinics that is refractory to treatment,however,the neural substrates and underlying mechanisms are poorly understood.Using the com bination of neuronal mapping,optogenetics,chemogenetics,eletrophysiological recording,in vivo fiber photometry and behavioral testing,we previously identified a new neural circuit of BLA-mPFC-vIPAG and its key role in encoding and modulation of the spared nerve injury(SNI)-induced neuropathic pain..Here we report that the V M-vlOFC-vIPAG circuit modulates neuropathic pain and dissects the underlying mechanisms at cellular and circuitry level.展开更多
Spinal cord injury can lead to severe motor,sensory and autonomic dysfunction.Currently,there is no effective treatment for the injured spinalcord.The transplantation of Schwann cells,neural stem cells or progenitor c...Spinal cord injury can lead to severe motor,sensory and autonomic dysfunction.Currently,there is no effective treatment for the injured spinalcord.The transplantation of Schwann cells,neural stem cells or progenitor cells,olfactory ensheathing cells,oligodendrocyte precursor cells and mesenchymal stem cells has been investigated as potential therapies for spinal cord injury.However,little is known about the mechanisms through which these individual cell types promote repair and functional improvements.The five most commonly proposed mechanisms include neuroprotection,immunomodulation,axon regeneration,neuronal relay formation and myelin regeneration.A better understanding of the mechanisms whereby these cells promote functional improvements,as well as an appreciation of the obstacles in implementing these therapies and effectively modeling spinal cord injury,will be important to make cell transplantation a viable clinical option and may lead to the development of more targeted therapies.展开更多
基金funded by the Heart and Stroke Foundation of Canada Grant in aid(G-17-0018368)the Canada Research Chairs programthe River Fund at Calgary Foundation.
文摘Background Lesion-symptom mapping(LSM)is a statistical technique to investigate the population-specific relationship between structural integrity and post-stroke clinical outcome.In clinical practice,patients are commonly evaluated using the National Institutes of Health Stroke Scale(NIHSS),an 11-domain clinical score to quantitate neurological deficits due to stroke.So far,LSM studies have mostly used the total NIHSS score for analysis,which might not uncover subtle structure–function relationships associated with the specific sub-domains of the NIHSS evaluation.Thus,the aim of this work was to investigate the feasibility to perform LSM analyses with sub-score information to reveal category-specific structure–function relationships that a total score may not reveal.Methods Employing a multivariate technique,LSM analyses were conducted using a sample of 180 patients with NIHSS assessment at 48-hour post-stroke from the ESCAPE trial.The NIHSS domains were grouped into six categories using two schemes.LSM was conducted for each category of the two groupings and the total NIHSS score.Results Sub-score LSMs not only identify most of the brain regions that are identified as critical by the total NIHSS score but also reveal additional brain regions critical to each function category of the NIHSS assessment without requiring extensive,specialised assessments.Conclusion These findings show that widely available sub-scores of clinical outcome assessments can be used to investigate more specific structure–function relationships,which may improve predictive modelling of stroke outcomes in the context of modern clinical stroke assessments and neuroimaging.
文摘In response to peripheral nerve injury, the inflammatory response is almost entirely comprised of infiltrating macrophages. Macrophages are a highly plastic, heterogenic immune cell, playing an indispensable role in peripheral nerve injury, clearing debris and regulating the microenvironment to allow for efficient regeneration. There are several cells within the microenvironment that likely interact with macrophages to support their function – most notably the Schwann cell, the glial cell of the peripheral nervous system. Schwann cells express several ligands that are known to interact with receptors expressed by macrophages, yet the effects of Schwann cells in regulating macrophage phenotype remains largely unexplored. This review discusses macrophages in peripheral nerve injury and how Schwann cells may regulate their behavior.
基金Supported by the Lejoie-Lake Fellowship(to Camara-Lemarroy CR)awarded by the Hotchkiss Brain Institute
文摘The brain-gut axis serves as the bidirectional connection between the gut microbiome, the intestinal barrier and the immune system that might be relevant for the pathophysiology of inflammatory demyelinating diseases. People with multiple sclerosis have been shown to have an altered microbiome, increased intestinal permeability and changes in bile acid metabolism. Experimental evidence suggests that these changes can lead to profound alterations of peripheral and central nervous system immune regulation. Besides being of pathophysiological interest, the brain-gut axis could also open new avenues of therapeutic targets. Modification of the microbiome, the use of probiotics, fecal microbiota transplantation, supplementation with bile acids and intestinal barrier enhancers are all promising candidates. Hopefully, pre-clinical studies and clinical trials will soon yield significant results.
文摘Purpose:The study aimed to examine the reporting completeness of randomized controlled trials(RCTs)of non-pharmacological interventions following concussion.Methods:We searched MEDLINE,Embase,PsycInfo,CINAHL,and Web of Science up to May 2022.Two reviewers independently screened studies and assessed reporting completeness using the Template for Intervention Description and Replication(TIDieR),Consensus on Exercise Reporting Template(CERT),and international Consensus on Therapeutic Exercise aNd Training(i-CONTENT)checklists.Additional information was sought my study authors where reporting was incomplete.Risk of bias(ROB)was assessed with the Cochrane ROB-2 Tool.RCTs examining non-pharmacological interventions following concussion.Results:We included 89 RCTs(n=53 high ROB)examining 11 different interventions for concussion:sub-symptom threshold aerobic exercise,cervicovestibular therapy,physical/cognitive rest,vision therapy,education,psychotherapy,hyperbaric oxygen therapy,transcranial magnetic stimulation,blue light therapy,osteopathic manipulation,and head/neck cooling.Median scores were:TIDieR 9/12(75%;interquartile range(IQR)=5;range:5-12),CERT 17/19(89%;IQR=2;range:10-19),and i-CONTENT 6/7(86%;IQR=1;range:5-7).Percentage of studies completely reporting all items was TIDieR 35%(31/89),CERT 24%(5/21),and i-CONTENT 10%(2/21).Studies were more completely reported after publication of TIDieR(t_(87)=2.08;p=0.04)and CERT(t_(19)=2.72;p=0.01).Reporting completeness was not strongly associated with journal impact factor(TIDieR:rs=0.27;p=0.01;CERT:r_(s)=-0.44;p=0.06;i-CONTENT:r_(s)=-0.17;p=0.48)or ROB(TIDieR:rs=0.11;p=0.31;CERT:rs=0.04;p=0.86;i-CONTENT:rs=0.12;p=0.60).Conclusion:RCTs of non-pharmacological interventions following concussion demonstrate moderate to good reporting completeness,but are often missing key components,particularly modifications,motivational strategies,and qualified supervisor.Reporting completeness improved after TIDieR and CERT publication,but publication in highly cited journals and low ROB
文摘number of different cancer chemotherapy agents such as cisplatin,oxaliplatin,and paclitaxel can lead to nerve damage,thereby giving rise to neuropathic pain states that present with mechanical and cold allodynia[1].Although these pain conditions often resolve after completion of the chemotherapy,a significant portion of patients exhibit longlasting pain that can persist longer than 12 months with a negative impact on the quality of life of affected individuals[1].
基金supported by the National Natural Science Foundation of China(82071331,81870942,and 81520108011)the National Key Research and Development Program of China(2018YFC1312200)the Canadian Institutes of Health Research(VWY).
文摘Injury to the brain after intracerebral hemorrhage(ICH)results from numerous complex cellular mechanisms.At present,effective therapy for ICH is limited and a better understanding of the mechanisms of brain injury is necessary to improve prognosis.There is increasing evidence that ion channel dysregulation occurs at multiple stages in primary and secondary brain injury following ICH.Ion channels such as TWIK-related K+channel 1,sulfonylurea 1 transient receptor potential melastatin 4 and glutamate-gated channels affect ion homeostasis in ICH.They in turn participate in the formation of brain edema,disruption of the blood-brain barrier,and the generation of neurotoxicity.In this review,we summarize the interaction between ions and ion channels,the effects of ion channel dysregulation,and we discuss some therapeutics based on ion-channel modulation following ICH.
基金The authors acknowledge operating grant support from the National Natural Science Foundation of China(grants no:81870942,81471174 and 81520108011)National Key Research and Development ProgramProgramme of China(grant no:2018YFC1312200)+1 种基金Innovation Scientists and Technicians Troop Constructions Projects of Henan Province of China(for MX)and from the Canadian Institutes of Health Sciences(VWY).
文摘Spontaneous intracerebral haemorrhage(ICH)is a devastating type of stroke with high mortality and morbidity and for which no effective treatments are available to date.Much experimental and clinical research have been performed to explore its mechanisms regard the subsequent inflammatory cascade and to seek the potential therapeutic strategies.The aim of this review is to discuss insights from clinical settings that have led to the development of numerous animal models of ICH.Some of the current and future challenges for clinicians to understand ICH are also surveyed.
基金the Canadian Institutes of Health Research(Foundation grant 1049959)(VWY)from the National Key Research and Development Program of China(grant no:2018YFC1312200)the National Natural Science Foundation of China(grants no:82071331,81870942 and 81520108011)(MX).RZ is supported by a PhD studentship from the China Scholarship Council.
文摘background Inflammation-exacerbated secondary brain injury and limited tissue regeneration are barriers to favourable prognosis after intracerebral haemorrhage(ICH).As a regulator of inflammation and lipid metabolism,Liver X receptor(LXR)has the potential to alter microglia/macrophage(M/M)phenotype,and assist tissue repair by promoting cholesterol efflux and recycling from phagocytes.To support potential clinical translation,the benefits of enhanced LXR signalling are examined in experimental ICH.Methods Collagenase-induced ICH mice were treated with the LXR agonist GW3965 or vehicle.Behavioural tests were conducted at multiple time points.Lesion and haematoma volume,and other brain parameters were assessed using multimodal MRI with T2-weighted,diffusion tensor imaging and dynamic contrast-enhanced MRI sequences.The fixed brain cryosections were stained and confocal microscopy was applied to detect LXR downstream genes,M/M phenotype,lipid/cholesterol-laden phagocytes,oligodendrocyte lineage cells and neural stem cells.Western blot and real-time qPCR were also used.CX3CR1^(CreER):Rosa26^(iDTR) mice were employed for M/M-depletion experiments.results GW3965 treatment reduced lesion volume and white matter injury,and promoted haematoma clearance.Treated mice upregulated LXR downstream genes including ABCA1 and Apolipoprotein E,and had reduced density of M/M that apparently shifted from proinflammatory interleukin-1β+to Arginase1+CD206+regulatory phenotype.Fewer cholesterol crystal or myelin debris-laden phagocytes were observed in GW3965 mice.LXR activation increased the number of Olig2+PDGFRα+precursors and Olig2+CC1+mature oligodendrocytes in perihaematomal regions,and elevated SOX2+or nestin+neural stem cells in lesion and subventricular zone.MRI results supported better lesion recovery by GW3965,and this was corroborated by return to pre-ICH values of functional rotarod activity.The therapeutic effects of GW3965 were abrogated by M/M depletion in CX3CR1^(CreER):Rosa26^(iDTR) mice.Conclusions LXR agonism using
文摘The development of in vivo biomarkers of Alzheimer's disease(AD)has advanced the diagnosis of AD from a clinical syndrome to a biological construct.The preclinical stage of AD continuum is defined by the identification of AD biomarkers crossing the pathological threshold in cognitively unimpaired individuals.While neuropsychiatric symptoms(NPS)are non-cognitive symptoms that are increasingly recognized as early manifestations of AD,the associations of NPS with AD pathophysiology in preclinical AD remain unclear.Here,we review the associations between NPS and AD biomarkers amyloid-(3(Aβ),tau and neurodegeneration in preclinical AD and cognitivelyunimpaired individuals in 19 eligible English-language publications(8 cross-sectional studies,10 longitudinal,1 both cross-sectional and longitudinal).The cross-sectional studies have consistently shown that NPS,particularly depressive and anxiety symptoms,are associated with higher Aβ.The longitudinal studies have suggested that greater NPS are associated with higher Aβ and cognitive decline in cognitively unimpaired subjects over time.However,most of the studies have either cross-sectionally or longitudinally shown no association between NPS and tau pathology.For the association of NPS and neurodegeneration,two studies have shown that the cerebrospinal fluid total-tau is linked to longitudinal increase in NPS and that the NPS may predict longitudinal metabolic decline in preclinical AD,respectively.However,evidence for the association between atrophy and NPS in preclinical AD is less consistent.Therefore,future longitudinal studies with well-designed methodologies and NPS measurements are required not only to determine the relationship among AT(N)biomarkers,NPS and cognitive decline,but also to elucidate the contribution of comorbid pathology to preclinical AD.
文摘Background Long-term outcomes for Medicare beneficiaries hospitalised with transient ischaemic attack(TIA)and role of ABCD^(2) score in identifying high-risk individuals are not studied.Methods We identified 40825 Medicare beneficiaries hospitalised from 2011 to 2014 for a TIA to a Get With The Guidelines(GWTG)-Stroke hospital and classified them using ABCD^(2)s of mortality and rehospitalisation(all-cause,ischaemic stroke,haemorrhagic stroke,myocardial infarction,and gastrointestinal and intracranial haemorrhage)for high-risk versus low-risk groups adjusted for patient and hospital characteristics.Results Of the 40825 patients,35118(86%)were high risk(ABCD^(2)≥4)and 5707(14%)were low risk(ABCD^(2)=0-3).Overall rate of mortality during 1-year follow-up after hospital discharge for the index TIA was 11.7%,44.3% were rehospitalised for any reason and 3.6%were readmitted due to stroke.Patients with ABCD^(2) score≥4 had higher mortality at 1 year than not(adjusted HR 1.18,95%CI 1.07 to 1.30).Adjusted risks for ischaemic stroke,all-cause readmission and mortality/all-cause readmission at 1 year were also significantly higher for patients with ABCD^(2) score≥4 vs 0-3.In contrast,haemorrhagic stroke,myocardial infarction,gastrointestinal bleeding and intracranial haemorrhage risk were not significantly different by ABCD^(2) score.Conclusions This study validates the use of ABCD^(2) score for long-term risk assessment after TIA in patients aged 65 years and older.Attentive efforts for community-based follow-up care after TIA are needed for ongoing prevention in Medicare beneficiaries who were hospitalised for TIA.
基金supported in part by the Department of National Defence’s Innovation for Defence Excellence and Security(IDEa S)Program,Canadathrough the Project of Auto Defence Towards Trustworthy Technologies for Autonomous Human-Machine Systems,NSERCthe IEEE SMC Society Technical Committee on Brain-Inspired Systems(TCBCS)。
文摘Autonomous systems are an emerging AI technology functioning without human intervention underpinned by the latest advances in intelligence,cognition,computer,and systems sciences.This paper explores the intelligent and mathematical foundations of autonomous systems.It focuses on structural and behavioral properties that constitute the intelligent power of autonomous systems.It explains how system intelligence aggregates from reflexive,imperative,adaptive intelligence to autonomous and cognitive intelligence.A hierarchical intelligence model(HIM)is introduced to elaborate the evolution of human and system intelligence as an inductive process.The properties of system autonomy are formally analyzed towards a wide range of applications in computational intelligence and systems engineering.Emerging paradigms of autonomous systems including brain-inspired systems,cognitive robots,and autonomous knowledge learning systems are described.Advances in autonomous systems will pave a way towards highly intelligent machines for augmenting human capabilities.
基金supported by grants from Alberta Innovates/Alberta Prion Research Institute(APRI grants 201600010 and 201900008)(to HMS)ST had received a University of Calgary Eyes High,Killam and Alberta Innovates Health Solution(AIHS)doctoral fellowship.
文摘Prion diseases are infectious protein misfolding disorders of the central nervous system that result from misfolding of the cellular prion protein(PrPC)into the pathologic isoform PrPSc.Pathologic hallmarks of prion disease are depositions of pathological prion protein PrPSc,neuronal loss,spongiform degeneration and astrogliosis in the brain.Prion diseases affect human and animals,there is no effective therapy,and they invariably remain fatal.For a long time,neuronal loss was considered the sole reason for neurodegeneration in prion pathogenesis,and the contribution of non-neuronal cells like microglia and astrocytes was considered less important.Recent evidence suggests that neurodegeneration during prion pathogenesis is a consequence of a complex interplay between neuronal and non-neuronal cells in the brain,but the exact role of these non-neuronal cells during prion pathology is still elusive.Astrocytes are non-neuronal cells that regulate brain homeostasis under physiological conditions.However,astrocytes can deposit PrPSc aggregates and propagate prions in prion-infected brains.Additionally,sub-populations of reactive astrocytes that include neurotrophic and neurotoxic species have been identified,differentially expressed in the brain during prion infection.Revealing the exact role of astrocytes in prion disease is hampered by the lack of in vitro models of prion-infected astrocytes.Recently,we established a murine astrocyte cell line persistently infected with mouse-adapted prions,and showed how such astrocytes differentially process various prion strains.Considering the complexity of the role of astrocytes in prion pathogenesis,we need more in vitro and in vivo models for exploring the contribution of sub-populations of reactive astrocytes,their differential regulation of signaling cascades,and the interaction with neurons and microglia during prion pathogenesis.This will help to establish novel in vivo models and define new therapeutic targets against prion diseases.In this review,we will discuss the comp
文摘Background During the COVID-19 pandemic,decreased volumes of stroke admissions and mechanical thrombectomy were reported.The study’s objective was to examine whether subarachnoid haemorrhage(SAH)hospitalisations and ruptured aneurysm coiling interventions demonstrated similar declines.Methods We conducted a cross-sectional,retrospective,observational study across 6 continents,37 countries and 140 comprehensive stroke centres.Patients with the diagnosis of SAH,aneurysmal SAH,ruptured aneurysm coiling interventions and COVID-19 were identified by prospective aneurysm databases or by International Classification of Diseases,10th Revision,codes.The 3-month cumulative volume,monthly volumes for SAH hospitalisations and ruptured aneurysm coiling procedures were compared for the period before(1 year and immediately before)and during the pandemic,defined as 1 March-31 May 2020.The prior 1-year control period(1 March-31 May 2019)was obtained to account for seasonal variation.Findings There was a significant decline in SAH hospitalisations,with 2044 admissions in the 3 months immediately before and 1585 admissions during the pandemic,representing a relative decline of 22.5%(95%CI−24.3%to−20.7%,p<0.0001).Embolisation of ruptured aneurysms declined with 1170-1035 procedures,respectively,representing an 11.5%(95%CI−13.5%to−9.8%,p=0.002)relative drop.Subgroup analysis was noted for aneurysmal SAH hospitalisation decline from 834 to 626 hospitalisations,a 24.9%relative decline(95%CI−28.0%to−22.1%,p<0.0001).A relative increase in ruptured aneurysm coiling was noted in low coiling volume hospitals of 41.1%(95%CI 32.3%to 50.6%,p=0.008)despite a decrease in SAH admissions in this tertile.Interpretation There was a relative decrease in the volume of SAH hospitalisations,aneurysmal SAH hospitalisations and ruptured aneurysm embolisations during the COVID-19 pandemic.These findings in SAH are consistent with a decrease in other emergencies,such as stroke and myocardial infarction.
基金a Cancer Research Society award(Scholarships for the New Generation of Scientists).NJB was supported by Multiple Myeloma Research Foundation.ATS was supported by the National Institutes of Health(NIHGrant No.K08CA230188)+2 种基金the Parker Institute for Cancer Immunotherapy,a Cancer Research Institute Technology Impact Award,a Career Award for Medical Scientists from the Burroughs Wellcome Fund,and the Human Vaccines Project Michelson Prize.HJ and WZ were supported by the National Human Genome Research Institute of NIH(Grant Nos.R01HG009518 and R01HG010889)JAS was supported by an Alberta Children’s Hospital Research Institute Postdoctoral Fellowship.AJ was supported by an Alberta Innovates Summer Studentship.JB was supported by Canadian Institutes of Health Research(PJT-401394)Calgary Firefighters Burn Treatment Society.
文摘How distinct transcriptional programs are enacted to generate cellular heterogeneity and plasticity,and enable complex fate decisions are important open questions.One key regulator is the cell’s epigenome state that drives distinct transcriptional programs by regulating chromatin accessibility.Genome-wide chromatin accessibility measurements can impart insights into regulatory sequences(in)accessible to DNA-binding proteins at a single-cell resolution.This review outlines molecular methods and bioinformatic tools for capturing cell-to-cell chromatin variation using single-cell assay for transposase-accessible chromatin using sequencing(scATAC-seq)in a scalable fashion.It also covers joint profiling of chromatin with transcriptome/proteome measurements,computational strategies to integrate multi-omic measurements,and predictive bioinformatic tools to infer chromatin accessibility from single-cell transcriptomic datasets.Methodological refinements that increase power for cell discovery through robust chromatin coverage and integrate measurements from multiple modalities will further expand our understanding of gene regulation during homeostasis and disease.
文摘BACKGROUND Patients leaving the intensive care unit(ICU)often experience gaps in care due to deficiencies in discharge communication,leaving them vulnerable to increased stress,adverse events,readmission to ICU,and death.To facilitate discharge communication,written summaries have been implemented to provide patients and their families with information on medications,activity and diet restrictions,follow-up appointments,symptoms to expect,and who to call if there are questions.While written discharge summaries for patients and their families are utilized frequently in surgical,rehabilitation,and pediatric settings,few have been utilized in ICU settings.AIM To develop an ICU specific patient-oriented discharge summary tool(PODS-ICU),and pilot test the tool to determine acceptability and feasibility.METHODS Patient-partners(i.e.,individuals with lived experience as an ICU patient or family member of an ICU patient),ICU clinicians(i.e.,physicians,nurses),and researchers met to discuss ICU patients’specific informational needs and design the PODS-ICU through several cycles of discussion and iterative revisions.Research team nurses piloted the PODS-ICU with patient and family participants in two ICUs in Calgary,Canada.Follow-up surveys on the PODS-ICU and its impact on discharge were administered to patients,family participants,and ICU nurses.RESULTS Most participants felt that their discharge from the ICU was good or better(n=13;87.0%),and some(n=9;60.0%)participants reported a good understanding of why the patient was in ICU.Most participants(n=12;80.0%)reported that they understood ICU events and impacts on the patient’s health.While many patients and family participants indicated the PODS-ICU was informative and useful,ICU nurses reported that the PODS-ICU was“not reasonable”in their daily clinical workflow due to“time constraint”.CONCLUSION The PODS-ICU tool provides patients and their families with essential information as they discharge from the ICU.This tool has the potential to engage and empower
基金funded by grants from the Alberta Prion Research Institutethe Alzheimer Society of Alberta and Northwest Territories+2 种基金the Natural Sciences and Engineering Research Council(NSERC)of Canadasupported by the Canada Research Chair programa postdoctoral fellowship from the German Research Foundation(DFG)
文摘Despite intensive research,most neurodegenerative diseases cannot be cured and for some of them no treatment is available to increase survival or quality of life.Among the latter are prion diseases,fatal and transmissible neurodegenerative diseases of humans and other animals.
文摘Neuropathic pain is a long term and common pain disorder in clinics that is refractory to treatment,however,the neural substrates and underlying mechanisms are poorly understood.Using the com bination of neuronal mapping,optogenetics,chemogenetics,eletrophysiological recording,in vivo fiber photometry and behavioral testing,we previously identified a new neural circuit of BLA-mPFC-vIPAG and its key role in encoding and modulation of the spared nerve injury(SNI)-induced neuropathic pain..Here we report that the V M-vlOFC-vIPAG circuit modulates neuropathic pain and dissects the underlying mechanisms at cellular and circuitry level.
文摘Spinal cord injury can lead to severe motor,sensory and autonomic dysfunction.Currently,there is no effective treatment for the injured spinalcord.The transplantation of Schwann cells,neural stem cells or progenitor cells,olfactory ensheathing cells,oligodendrocyte precursor cells and mesenchymal stem cells has been investigated as potential therapies for spinal cord injury.However,little is known about the mechanisms through which these individual cell types promote repair and functional improvements.The five most commonly proposed mechanisms include neuroprotection,immunomodulation,axon regeneration,neuronal relay formation and myelin regeneration.A better understanding of the mechanisms whereby these cells promote functional improvements,as well as an appreciation of the obstacles in implementing these therapies and effectively modeling spinal cord injury,will be important to make cell transplantation a viable clinical option and may lead to the development of more targeted therapies.
