Background and Objective:Social media(SoMe)has emerged as a tool in health professions education(HPE),particularly amidst the challenges posed by the coronavirus disease 2019(COVID-19)pandemic.Despite the academia’s ...Background and Objective:Social media(SoMe)has emerged as a tool in health professions education(HPE),particularly amidst the challenges posed by the coronavirus disease 2019(COVID-19)pandemic.Despite the academia’s initial skepticism SoMe has been gaining traction in supporting learning communities,and offering opportunities for innovation in HPE.Our study aims to explore the integration of SoMe in HPE.Four key components were outlined as necessary for a successful integration,and include designing learning experiences,defining educator roles,selecting appropriate platforms,and establishing educational objectives.Methods:This article stemmed from the online Teaching Skills Series module on SoMe in education from the Ophthalmology Foundation,and drew upon evidence supporting learning theories relevant to SoMe integration and models of education.Additionally,we conducted a literature review considering Englishlanguage articles on the application of SoMe in ophthalmology from PubMed over the past decade.Key Content and Findings:Early adopters of SoMe platforms in HPE have leveraged these tools to enhance learning experiences through interaction,dialogue,content sharing,and active learning strategies.By integrating SoMe into educational programs,both online and in-person,educators can overcome time and geographical constraints,fostering more diverse and inclusive learning communities.Careful consideration is,however,necessary to address potential limitations within HPE.Conclusions:This article lays groundwork for expanding SoMe integration in HPE design,emphasizing the supportive scaffold of various learning theories,and the need of furthering robust research on examining its advantages over traditional educational formats.Our literature review underscores an ongoing multifaceted,random application of SoMe platforms in ophthalmology education.We advocate for an effective incorporation of SoMe in HPE education,with the need to comply with good educational practice.展开更多
Acquired neurological injuries initiate a pathological cascade of secondary injury processes,including inflammation,which continue for days to weeks following injury.Injury-induced neuroinflammation acts as a host def...Acquired neurological injuries initiate a pathological cascade of secondary injury processes,including inflammation,which continue for days to weeks following injury.Injury-induced neuroinflammation acts as a host defense mechanism contributing to the neutralization of the insult(removing offending factors)and restoring structure and function of the brain(establish homeostasis).The timing of these protective functions of the immune response is vital,since chronic inflammation展开更多
脑小血管病(cerebral small vessel disease,CSVD)是老年人最常见的脑血管疾病,也是引起认知功能障碍的最常见原因之一。目前对CSVD的治疗有很大的局限性。CSVD的病理机制、临床表现和影像学表现的异质性,以及对本病缺乏共识,均可影响...脑小血管病(cerebral small vessel disease,CSVD)是老年人最常见的脑血管疾病,也是引起认知功能障碍的最常见原因之一。目前对CSVD的治疗有很大的局限性。CSVD的病理机制、临床表现和影像学表现的异质性,以及对本病缺乏共识,均可影响相关药物临床试验的进展。为了给CSVD的治疗提供可靠的依据,并为今后的临床实践增加特异性药物的选择,国家神经系统疾病临床医学研究中心和中国卒中学会脑小血管病分会联合起草本共识。期望规范CSVD相关临床试验来评价药物的疗效和安全性,为CSVD的治疗提供可靠的证据支持。展开更多
第一部分 中枢神经系统肿瘤(central nerous system tumors)
一、流行病学特征(epidemiological features)
中枢神经系统原发肿瘤,从高度恶性胶质瘤和原始神经外胚层肿瘤到良性脑膜瘤、神经瘤及垂体腺瘤,可表现出不同的生物学...第一部分 中枢神经系统肿瘤(central nerous system tumors)
一、流行病学特征(epidemiological features)
中枢神经系统原发肿瘤,从高度恶性胶质瘤和原始神经外胚层肿瘤到良性脑膜瘤、神经瘤及垂体腺瘤,可表现出不同的生物学行为。根据来自美国脑肿瘤注册中心(Central Brain Tumor Registry of the United States,CBTRUS)的最新报告,每年新诊断的原发脑恶性肿瘤的人数为7.30/10万人。美国脑肿瘤注册中心2005年报告新诊断的中枢神经系统原发肿瘤患者为21690例,死亡12760例。胶质瘤占神经系统原发肿瘤的42%,占恶性肿瘤的77%。胶质瘤起源于不同的组织类型,包括少突胶质细胞瘤、星形细胞瘤、混合型少突星形细胞瘤,表现为不同的恶性程度,而且均具有向高度恶性转化的趋势,其中多形性胶质母细胞瘤(glioblasto mamultiforme,GBM)为成人中最常见的并具有浸润性的原发脑肿瘤。展开更多
Neuronal apoptosis is mediated by intrinsic and extrinsic signaling pathways such as the membrane-mediated,mitochondrial,and endoplasmic reticulum stress pathways.Few studies have examined the endoplasmic reticulum-me...Neuronal apoptosis is mediated by intrinsic and extrinsic signaling pathways such as the membrane-mediated,mitochondrial,and endoplasmic reticulum stress pathways.Few studies have examined the endoplasmic reticulum-mediated apoptosis pathway in the penumbra after traumatic brain injury,and it remains unclear whether endoplasmic reticulum stress can activate the caspase-12-dependent apoptotic pathway in the traumatic penumbra.Here,we established rat models of fluid percussion-induced traumatic brain injury and found that protein expression of caspase-12,caspase-3 and the endoplasmic reticulum stress marker 78 k Da glucose-regulated protein increased in the traumatic penumbra 6 hours after injury and peaked at 24 hours.Furthermore,numbers of terminal deoxynucleotidyl transferase-mediated d UTP nick end labeling-positive cells in the traumatic penumbra also reached peak levels 24 hours after injury.These findings suggest that caspase-12-mediated endoplasmic reticulum-related apoptosis is activated in the traumatic penumbra,and may play an important role in the pathophysiology of secondary brain injury.展开更多
A rapid, sensitive, and robust reversed-phase liquid chromatography with tandem mass spectrometry method was developed and validated for the determination of total and unbound ceritinib, a secondgeneration ALK inhibit...A rapid, sensitive, and robust reversed-phase liquid chromatography with tandem mass spectrometry method was developed and validated for the determination of total and unbound ceritinib, a secondgeneration ALK inhibitor, in patient plasma and brain tumor tissue samples. Sample preparation involved simple protein precipitation with acetonitrile. Chromatographic separation was achieved on a Waters ACQUITY UPLC BEH C_(18) column using a 4-min gradient elution consisting of mobile phase A(0.1% formic acid in water) and mobile phase B(0.1% formic acid in acetonitrile), at a flow rate of 0.4 m L/min. Ceritinib and the internal standard([^(13)C_6]ceritinib) were monitored using multiple reaction monitoring mode under positive electrospray ionization. The lower limit of quantitation(LLOQ) was 1 n M of ceritinib in plasma. The calibration curve was linear over ceritinib concentration range of 1–2000 n M in plasma. The intra-and interday precision and accuracy were within the generally accepted criteria for bioanalytical method( o15%).The method was successfully applied to assess ceritinib brain tumor penetration, as assessed by the unbound drug brain concentration to unbound drug plasma concentration ratio, in patients with brain tumors.展开更多
A sensitive and rapid liquid chromatography tandem mass spectrometry(LC-MS/MS)method was established for the quantification of total and unbound concentrations of LY3214996,an extracellular signal-regulated kinase inh...A sensitive and rapid liquid chromatography tandem mass spectrometry(LC-MS/MS)method was established for the quantification of total and unbound concentrations of LY3214996,an extracellular signal-regulated kinase inhibitor;abemaciclib,a cyclin-dependent kinase 4/6 inhibitor;and abemaciclib active metabolites,M2 and M20,in human plasma,brain tumor,and cerebrospinal fluid samples.The method was validated over a concentration range of 0.2e500 nM within a total run time of 3.8 min using isocratic elution on a Kinetex^(TM) F_(5) column.Detection was performed on a Sciex QTRAP 6500t mass spectrometer employing multiple reaction monitoring mode under positive electrospray ionization.The intra-and inter-batch accuracy as well as the precision of the method for all matrices was within ±20% and ≤20% at the lower limit of quantification,and within ±15% and ≤15% for other quality control levels for all analytes.The unbound fractions of drugs and metabolites in spiked and patient samples were determined using an optimized equilibrium dialysis.The validated method was successfully applied in a phase 0/2 clinical trial to assess the central nervous system penetration of LY3214996 and abemaciclib.展开更多
We report the first case of a neonate with concurrent Chiari II malformation and achondroplasia. Although rare, both these conditions contribute to several deleterious anatomical changes at the cervicomedullary juncti...We report the first case of a neonate with concurrent Chiari II malformation and achondroplasia. Although rare, both these conditions contribute to several deleterious anatomical changes at the cervicomedullary junction and thus predispose to acute hydrocephalus. Although our patient was initially asymptomatic, hydrocephalus ensued several weeks after birth and required cerebral spinal fluid diversion. We discuss the potential links between the two conditions, the pathophysiology, and the important clinical implications for the management of the increased risk of hydrocephalus.展开更多
Glaucoma is a multifactorial optic neuropathy characterized by the damage and death of the retinal ganglion cells.This disease results in vision loss and blindness.Any vision loss resulting from the disease cannot be ...Glaucoma is a multifactorial optic neuropathy characterized by the damage and death of the retinal ganglion cells.This disease results in vision loss and blindness.Any vision loss resulting from the disease cannot be restored and nowadays there is no available cure for glaucoma; however an early detection and treatment,could offer neuronal protection and avoid later serious damages to the visual function.A full understanding of the etiology of the disease will still require the contribution of many scientific efforts.Glial activation has been observed in glaucoma,being microglial proliferation a hallmark in this neurodegenerative disease.A typical project studying these cellular changes involved in glaucoma often needs thousands of images- from several animals- covering different layers and regions of the retina.The gold standard to evaluate them is the manual count.This method requires a large amount of time from specialized personnel.It is a tedious process and prone to human error.We present here a new method to count microglial cells by using a computer algorithm.It counts in one hour the same number of images that a researcher counts in four weeks,with no loss of reliability.展开更多
Evidence-based medicine(EBM) is a common concept among medical practitioners, yet unique challenges arise when EBM is applied to spinal surgery. Due to the relative rarity of certain spinal disorders, and a lack of ma...Evidence-based medicine(EBM) is a common concept among medical practitioners, yet unique challenges arise when EBM is applied to spinal surgery. Due to the relative rarity of certain spinal disorders, and a lack of management equipoise, randomized controlled trials may be difficult to execute. Despite this, responsibility rests with spinal surgeons to design high quality studies in order to justify certain treatment modalities. The authors therefore review the tenets of implementing evidencebased research, through the lens of spinal disorders. The process of EBM begins with asking the correct question.An appropriate study is then designed based on the research question. Understanding study designs allows the spinal surgeon to assess the level of evidence provided.Validated outcome measurements allow clinicians to communicate the success of treatment strategies, and will increase the quality of a given study design. Importantly,one must recognize that the randomized controlled trial is not always the optimal study design for a given research question. Rather, prospective observational cohort studies may be more appropriate in certain circumstances, and would provide superior generalizability. Despite the challenges involved with EBM, it is the future of medicine. These issues surrounding EBM are important for spinal surgeons, as well as health policy makers and editorial boards, to have familiarity.展开更多
Traumatic brain injury(TBI) is a leading cause of death and disability worldwide,with estimates indicating that -50% of the world's population will acquire a head injury at some point in their lifetime(Maas et al....Traumatic brain injury(TBI) is a leading cause of death and disability worldwide,with estimates indicating that -50% of the world's population will acquire a head injury at some point in their lifetime(Maas et al.,2017).Mild TBIs account for -80% of all reported cases,with up to 43% of all TBI patients reporting symptoms beyond 2 weeks postinjury.As of 2016,only 7% of preclinical TBI experiments included both male and female sexes,and fewer studies analyzed the data using sex as a biological variable(Spani et al.,2018).展开更多
Background: Magnetic resonance imaging (MRI) studies have shown diffuse cereb ral atrophy following traumatic brain injury. In the past, quantitative volumetr ic analysis of these changes was carried out by manually t...Background: Magnetic resonance imaging (MRI) studies have shown diffuse cereb ral atrophy following traumatic brain injury. In the past, quantitative volumetr ic analysis of these changes was carried out by manually tracing specific region s of interest. In contrast, voxel based morphometry (VBM) is a fully automated t echnique that allows examination of the whole brain on a voxel by voxel basis. O bjective: To use VBM to evaluate changes in grey matter concentration following traumatic brain injury. Methods: Nine patients with a history or traumatic brain injury (ranging from mild to severe) about one year previously were compared wi th nine age and sex matched healthy volunteers. T1 weighted three dimensional MR I images were acquired and then analysed with statistical parametric mapping sof tware (SPM2). The patients with traumatic brain injury also completed cognitive testing to determine whether regional grey matter concentration correlated with a measure of attention and initial injury severity. Results: Compared with contr ols, the brain injured patients had decreased grey matter concentration in multi ple brain regions including frontal and temporal cortices, cingulate gyrus, subc ortical grey matter, and the cerebellum. Decreased grey matter concentration cor related with lower scores on tests of attention and lower Glasgow coma scale sco res. Conclusions: Using VBM, regions of decreased grey matter concentration were observed in subjects with traumatic brain injury compared with well matched con trols. In the brain injured patients, there was a relation between grey matter c oncentration and attentional ability.展开更多
Alcohol use disorder(AUD)is a serious public health problem that affects approximately 17 million Americans and results in tremendous social,legal and medical costs to the society.Unlike other addictive drugs(e.g.,mor...Alcohol use disorder(AUD)is a serious public health problem that affects approximately 17 million Americans and results in tremendous social,legal and medical costs to the society.Unlike other addictive drugs(e.g.,morphine,cocaine or nicotine)that have specific molecular targets,ethanol(EtOH)has no specific target.In most previous studies,EtOH concentrations used for investigation were too high(e.g.,>50 mmol·L-1)compared to the EtOH concentrations in human brain after alcohol drinking,and the high dose EtOH may produce nonspecific modulations of a variety of receptors,ion channels,intracellular signaling cascades,and gene expression in the brain.Therefore,it is important to understand low dose(e.g.,<10 mmol·L-1)EtOH effects in the brain.Unfortunately,the molecular and cellular targets that mediate the sensitivity to low dose EtOH remain to be defined.nAChRs containingα6 subunits(α6*-nAChRs)shows a highly restricted distribution in midbrain dopaminergic neurons that are associated with drug dependence and addiction.Here,we report that low dose EtOH(0.1~5 mmol·L-1)significantly potentiatesα6*-nAChR function using patch-clamp whole-cell recordings.Since EtOH modulatesα6*-nAChR-mediated function depending on both EtOH and nicotine concentrations,representing a positive allosteric modulation.In conclusion,our results demonstrate a functionalα6*-nAChR transfected in human SH-EP1 cells that can be used as an excellent cell model to investigateα6*-nAChR function and pharmacology.Under patch-clamp recording condition,low dose EtOH modulatesα6*-nAChR function as a positive allosteric modulator.Through this mechanism,brainα6*-nAChRs may play a critical role in mediating low dose alcohol’effects on alcohol reward and dependence.展开更多
Coronavirus disease-2019(COVID‐19)has become a global pandemic.COVID-19 runs its course in two phases,the initial incubation phase and later clinical symptomatic phase.Patients in the initial incubation phase often h...Coronavirus disease-2019(COVID‐19)has become a global pandemic.COVID-19 runs its course in two phases,the initial incubation phase and later clinical symptomatic phase.Patients in the initial incubation phase often have insidious clinical symptoms,but they are still highly contagious.At the later clinical symptomatic phase,the immune system is fully activated and the disease may enter the severe infection stage in this phase.Although many patients are known for their respiratory symptoms,they had neurological symptoms in their first 1-2 days of clinical symptomatic phase,and ischaemic stroke occurred 2 weeks after the onset of the clinical symptomatic phase.The key is to prevent a patient from progressing to this severe infection from mild infection.We are sharing our experience on prevention and management of COVID-19.展开更多
Background and purpose The therapeutic potential of different stem cells for ischaemic stroke treatment is intriguing and somewhat controversial.Recent results from our laboratory have demonstrated the potential benef...Background and purpose The therapeutic potential of different stem cells for ischaemic stroke treatment is intriguing and somewhat controversial.Recent results from our laboratory have demonstrated the potential benefits of human umbilical cord blood-derived mesenchymal stem cells(MSC)in a rodent stroke model.We hypothesised that MSC treatment would effectively promote the recovery of sensory and motor function in both males and females,despite any apparent sex differences in post stroke brain injury.Methods Transient focal cerebral ischaemia was induced in adult Sprague-Dawley rats by occlusion of the middle cerebral artery.Following the procedure,male and female rats of the untreated group were euthanised 1 day after reperfusion and their brains were used to estimate the resulting infarct volume and tissue swelling.Additional groups of stroke-induced male and female rats were treated with MSC or vehicle and were subsequently subjected to a battery of standard neurological/neurobehavioral tests(Modified Neurological Severity Score assessment,adhesive tape removal,beam walk and rotarod).The tests were administered at regular intervals(at days 1,3,5,7 and 14)after reperfusion to determine the time course of neurological and functional recovery after stroke.Results The infarct volume and extent of swelling of the ischaemic brain were similar in males and females.Despite similar pathological stroke lesions,the clinical manifestations of stroke were more pronounced in males than females,as indicated by the neurological scores and other tests.MSC treatment significantly improved the recovery of sensory and motor function in both sexes,and it demonstrated efficacy in both moderate stroke(females)and severe stroke(males).Conclusions Despite sex differences in the severity of post stroke outcomes,MSC treatment promoted the recovery of sensory and motor function in male and female rats,suggesting that it may be a promising treatment for stroke.展开更多
Background China is one of the countries with the highest burden of stroke.Implementing multidimensional management guidelines will help clinicians practise evidence-based care,improve patient outcomes and alleviate s...Background China is one of the countries with the highest burden of stroke.Implementing multidimensional management guidelines will help clinicians practise evidence-based care,improve patient outcomes and alleviate societal burdens.This update of the 2019 edition will provide the latest comprehensive recommendations for the diagnosis and treatment of ischaemic cerebrovascular diseases.Methods We conducted a comprehensive search on MEDLINE(via PubMed)up to 31 August 2023.The writing team established the recommendations through multiple rounds of online and offline discussions.Each recommendation was graded using the evidence grading algorithm developed by the Chinese Stroke Association(CSA).The draft was reviewed and finalised by the CSA Stroke Guidelines Writing Committee.Results This update included revisions of 15 existing recommendations and 136 new recommendations in the following areas of stroke care:emergency assessment and diagnosis of ischaemic cerebrovascular disease,acute-phase reperfusion therapy,evaluation of underlying mechanisms,antithrombotic therapy,prevention and treatment of complications,and risk factor management.Conclusions This guideline updated the recommendations for the clinical management of ischaemic cerebrovascular disease from 2019.展开更多
Defining minor stroke can be complicated.A minor stroke can be called a mini or small stroke.It is often defined by the severity of neurological deficit,size of ischaemic lesion(s)on neuroimaging,and level of disabili...Defining minor stroke can be complicated.A minor stroke can be called a mini or small stroke.It is often defined by the severity of neurological deficit,size of ischaemic lesion(s)on neuroimaging,and level of disability.The definition of minor stroke is often tangled with that of transient ischaemic attack(TIA).展开更多
文摘Background and Objective:Social media(SoMe)has emerged as a tool in health professions education(HPE),particularly amidst the challenges posed by the coronavirus disease 2019(COVID-19)pandemic.Despite the academia’s initial skepticism SoMe has been gaining traction in supporting learning communities,and offering opportunities for innovation in HPE.Our study aims to explore the integration of SoMe in HPE.Four key components were outlined as necessary for a successful integration,and include designing learning experiences,defining educator roles,selecting appropriate platforms,and establishing educational objectives.Methods:This article stemmed from the online Teaching Skills Series module on SoMe in education from the Ophthalmology Foundation,and drew upon evidence supporting learning theories relevant to SoMe integration and models of education.Additionally,we conducted a literature review considering Englishlanguage articles on the application of SoMe in ophthalmology from PubMed over the past decade.Key Content and Findings:Early adopters of SoMe platforms in HPE have leveraged these tools to enhance learning experiences through interaction,dialogue,content sharing,and active learning strategies.By integrating SoMe into educational programs,both online and in-person,educators can overcome time and geographical constraints,fostering more diverse and inclusive learning communities.Careful consideration is,however,necessary to address potential limitations within HPE.Conclusions:This article lays groundwork for expanding SoMe integration in HPE design,emphasizing the supportive scaffold of various learning theories,and the need of furthering robust research on examining its advantages over traditional educational formats.Our literature review underscores an ongoing multifaceted,random application of SoMe platforms in ophthalmology education.We advocate for an effective incorporation of SoMe in HPE education,with the need to comply with good educational practice.
文摘Acquired neurological injuries initiate a pathological cascade of secondary injury processes,including inflammation,which continue for days to weeks following injury.Injury-induced neuroinflammation acts as a host defense mechanism contributing to the neutralization of the insult(removing offending factors)and restoring structure and function of the brain(establish homeostasis).The timing of these protective functions of the immune response is vital,since chronic inflammation
文摘脑小血管病(cerebral small vessel disease,CSVD)是老年人最常见的脑血管疾病,也是引起认知功能障碍的最常见原因之一。目前对CSVD的治疗有很大的局限性。CSVD的病理机制、临床表现和影像学表现的异质性,以及对本病缺乏共识,均可影响相关药物临床试验的进展。为了给CSVD的治疗提供可靠的依据,并为今后的临床实践增加特异性药物的选择,国家神经系统疾病临床医学研究中心和中国卒中学会脑小血管病分会联合起草本共识。期望规范CSVD相关临床试验来评价药物的疗效和安全性,为CSVD的治疗提供可靠的证据支持。
文摘第一部分 中枢神经系统肿瘤(central nerous system tumors)
一、流行病学特征(epidemiological features)
中枢神经系统原发肿瘤,从高度恶性胶质瘤和原始神经外胚层肿瘤到良性脑膜瘤、神经瘤及垂体腺瘤,可表现出不同的生物学行为。根据来自美国脑肿瘤注册中心(Central Brain Tumor Registry of the United States,CBTRUS)的最新报告,每年新诊断的原发脑恶性肿瘤的人数为7.30/10万人。美国脑肿瘤注册中心2005年报告新诊断的中枢神经系统原发肿瘤患者为21690例,死亡12760例。胶质瘤占神经系统原发肿瘤的42%,占恶性肿瘤的77%。胶质瘤起源于不同的组织类型,包括少突胶质细胞瘤、星形细胞瘤、混合型少突星形细胞瘤,表现为不同的恶性程度,而且均具有向高度恶性转化的趋势,其中多形性胶质母细胞瘤(glioblasto mamultiforme,GBM)为成人中最常见的并具有浸润性的原发脑肿瘤。
基金supported by the Natural Science Foundation of Hebei Province of China,No.H2014206383Foundation for High-Level Personnel Projects in Hebei Province of China,No.A201401041
文摘Neuronal apoptosis is mediated by intrinsic and extrinsic signaling pathways such as the membrane-mediated,mitochondrial,and endoplasmic reticulum stress pathways.Few studies have examined the endoplasmic reticulum-mediated apoptosis pathway in the penumbra after traumatic brain injury,and it remains unclear whether endoplasmic reticulum stress can activate the caspase-12-dependent apoptotic pathway in the traumatic penumbra.Here,we established rat models of fluid percussion-induced traumatic brain injury and found that protein expression of caspase-12,caspase-3 and the endoplasmic reticulum stress marker 78 k Da glucose-regulated protein increased in the traumatic penumbra 6 hours after injury and peaked at 24 hours.Furthermore,numbers of terminal deoxynucleotidyl transferase-mediated d UTP nick end labeling-positive cells in the traumatic penumbra also reached peak levels 24 hours after injury.These findings suggest that caspase-12-mediated endoplasmic reticulum-related apoptosis is activated in the traumatic penumbra,and may play an important role in the pathophysiology of secondary brain injury.
基金supported by the United States Public Health Service Cancer Center Support Grant P30 CA022453Novartis for providing the study drug and isotope-labeled internal standard and providing financial support for the clinical study
文摘A rapid, sensitive, and robust reversed-phase liquid chromatography with tandem mass spectrometry method was developed and validated for the determination of total and unbound ceritinib, a secondgeneration ALK inhibitor, in patient plasma and brain tumor tissue samples. Sample preparation involved simple protein precipitation with acetonitrile. Chromatographic separation was achieved on a Waters ACQUITY UPLC BEH C_(18) column using a 4-min gradient elution consisting of mobile phase A(0.1% formic acid in water) and mobile phase B(0.1% formic acid in acetonitrile), at a flow rate of 0.4 m L/min. Ceritinib and the internal standard([^(13)C_6]ceritinib) were monitored using multiple reaction monitoring mode under positive electrospray ionization. The lower limit of quantitation(LLOQ) was 1 n M of ceritinib in plasma. The calibration curve was linear over ceritinib concentration range of 1–2000 n M in plasma. The intra-and interday precision and accuracy were within the generally accepted criteria for bioanalytical method( o15%).The method was successfully applied to assess ceritinib brain tumor penetration, as assessed by the unbound drug brain concentration to unbound drug plasma concentration ratio, in patients with brain tumors.
基金funding provided by the Ben and Catherine Ivy Foundation.
文摘A sensitive and rapid liquid chromatography tandem mass spectrometry(LC-MS/MS)method was established for the quantification of total and unbound concentrations of LY3214996,an extracellular signal-regulated kinase inhibitor;abemaciclib,a cyclin-dependent kinase 4/6 inhibitor;and abemaciclib active metabolites,M2 and M20,in human plasma,brain tumor,and cerebrospinal fluid samples.The method was validated over a concentration range of 0.2e500 nM within a total run time of 3.8 min using isocratic elution on a Kinetex^(TM) F_(5) column.Detection was performed on a Sciex QTRAP 6500t mass spectrometer employing multiple reaction monitoring mode under positive electrospray ionization.The intra-and inter-batch accuracy as well as the precision of the method for all matrices was within ±20% and ≤20% at the lower limit of quantification,and within ±15% and ≤15% for other quality control levels for all analytes.The unbound fractions of drugs and metabolites in spiked and patient samples were determined using an optimized equilibrium dialysis.The validated method was successfully applied in a phase 0/2 clinical trial to assess the central nervous system penetration of LY3214996 and abemaciclib.
文摘We report the first case of a neonate with concurrent Chiari II malformation and achondroplasia. Although rare, both these conditions contribute to several deleterious anatomical changes at the cervicomedullary junction and thus predispose to acute hydrocephalus. Although our patient was initially asymptomatic, hydrocephalus ensued several weeks after birth and required cerebral spinal fluid diversion. We discuss the potential links between the two conditions, the pathophysiology, and the important clinical implications for the management of the increased risk of hydrocephalus.
基金supported by the Science Foundation of Arizona through the Bisgrove Program to PdG,Grant Number:BSP 0529-13the Ophthalmological Network OFTARED(RD12-0034/0002)+5 种基金the Institute of Health Carlos IIIthe PN I+D+i 2008–2011the ISCIII-Subdireccion General de Redes y Centros de Investigación Cooperativathe European Programme FEDERthe project SAF2014-53779-Rthe project:“The role of encapsulated NSAIDs in PLGA microparticles as a neuroprotective treatment” funded by the Spanish Ministry of Economy and Competitiveness
文摘Glaucoma is a multifactorial optic neuropathy characterized by the damage and death of the retinal ganglion cells.This disease results in vision loss and blindness.Any vision loss resulting from the disease cannot be restored and nowadays there is no available cure for glaucoma; however an early detection and treatment,could offer neuronal protection and avoid later serious damages to the visual function.A full understanding of the etiology of the disease will still require the contribution of many scientific efforts.Glial activation has been observed in glaucoma,being microglial proliferation a hallmark in this neurodegenerative disease.A typical project studying these cellular changes involved in glaucoma often needs thousands of images- from several animals- covering different layers and regions of the retina.The gold standard to evaluate them is the manual count.This method requires a large amount of time from specialized personnel.It is a tedious process and prone to human error.We present here a new method to count microglial cells by using a computer algorithm.It counts in one hour the same number of images that a researcher counts in four weeks,with no loss of reliability.
文摘Evidence-based medicine(EBM) is a common concept among medical practitioners, yet unique challenges arise when EBM is applied to spinal surgery. Due to the relative rarity of certain spinal disorders, and a lack of management equipoise, randomized controlled trials may be difficult to execute. Despite this, responsibility rests with spinal surgeons to design high quality studies in order to justify certain treatment modalities. The authors therefore review the tenets of implementing evidencebased research, through the lens of spinal disorders. The process of EBM begins with asking the correct question.An appropriate study is then designed based on the research question. Understanding study designs allows the spinal surgeon to assess the level of evidence provided.Validated outcome measurements allow clinicians to communicate the success of treatment strategies, and will increase the quality of a given study design. Importantly,one must recognize that the randomized controlled trial is not always the optimal study design for a given research question. Rather, prospective observational cohort studies may be more appropriate in certain circumstances, and would provide superior generalizability. Despite the challenges involved with EBM, it is the future of medicine. These issues surrounding EBM are important for spinal surgeons, as well as health policy makers and editorial boards, to have familiarity.
基金supported by the National Institutes of Health (R01NS100793)Phoenix Children's Hospital Mission Support。
文摘Traumatic brain injury(TBI) is a leading cause of death and disability worldwide,with estimates indicating that -50% of the world's population will acquire a head injury at some point in their lifetime(Maas et al.,2017).Mild TBIs account for -80% of all reported cases,with up to 43% of all TBI patients reporting symptoms beyond 2 weeks postinjury.As of 2016,only 7% of preclinical TBI experiments included both male and female sexes,and fewer studies analyzed the data using sex as a biological variable(Spani et al.,2018).
文摘Background: Magnetic resonance imaging (MRI) studies have shown diffuse cereb ral atrophy following traumatic brain injury. In the past, quantitative volumetr ic analysis of these changes was carried out by manually tracing specific region s of interest. In contrast, voxel based morphometry (VBM) is a fully automated t echnique that allows examination of the whole brain on a voxel by voxel basis. O bjective: To use VBM to evaluate changes in grey matter concentration following traumatic brain injury. Methods: Nine patients with a history or traumatic brain injury (ranging from mild to severe) about one year previously were compared wi th nine age and sex matched healthy volunteers. T1 weighted three dimensional MR I images were acquired and then analysed with statistical parametric mapping sof tware (SPM2). The patients with traumatic brain injury also completed cognitive testing to determine whether regional grey matter concentration correlated with a measure of attention and initial injury severity. Results: Compared with contr ols, the brain injured patients had decreased grey matter concentration in multi ple brain regions including frontal and temporal cortices, cingulate gyrus, subc ortical grey matter, and the cerebellum. Decreased grey matter concentration cor related with lower scores on tests of attention and lower Glasgow coma scale sco res. Conclusions: Using VBM, regions of decreased grey matter concentration were observed in subjects with traumatic brain injury compared with well matched con trols. In the brain injured patients, there was a relation between grey matter c oncentration and attentional ability.
文摘Alcohol use disorder(AUD)is a serious public health problem that affects approximately 17 million Americans and results in tremendous social,legal and medical costs to the society.Unlike other addictive drugs(e.g.,morphine,cocaine or nicotine)that have specific molecular targets,ethanol(EtOH)has no specific target.In most previous studies,EtOH concentrations used for investigation were too high(e.g.,>50 mmol·L-1)compared to the EtOH concentrations in human brain after alcohol drinking,and the high dose EtOH may produce nonspecific modulations of a variety of receptors,ion channels,intracellular signaling cascades,and gene expression in the brain.Therefore,it is important to understand low dose(e.g.,<10 mmol·L-1)EtOH effects in the brain.Unfortunately,the molecular and cellular targets that mediate the sensitivity to low dose EtOH remain to be defined.nAChRs containingα6 subunits(α6*-nAChRs)shows a highly restricted distribution in midbrain dopaminergic neurons that are associated with drug dependence and addiction.Here,we report that low dose EtOH(0.1~5 mmol·L-1)significantly potentiatesα6*-nAChR function using patch-clamp whole-cell recordings.Since EtOH modulatesα6*-nAChR-mediated function depending on both EtOH and nicotine concentrations,representing a positive allosteric modulation.In conclusion,our results demonstrate a functionalα6*-nAChR transfected in human SH-EP1 cells that can be used as an excellent cell model to investigateα6*-nAChR function and pharmacology.Under patch-clamp recording condition,low dose EtOH modulatesα6*-nAChR function as a positive allosteric modulator.Through this mechanism,brainα6*-nAChRs may play a critical role in mediating low dose alcohol’effects on alcohol reward and dependence.
基金supported by the National Key Research and Development Program of China(No.2018YFC1312200 to BH)the National Natural Science Foundation of China(No.81820108010 to BH).
文摘Coronavirus disease-2019(COVID‐19)has become a global pandemic.COVID-19 runs its course in two phases,the initial incubation phase and later clinical symptomatic phase.Patients in the initial incubation phase often have insidious clinical symptoms,but they are still highly contagious.At the later clinical symptomatic phase,the immune system is fully activated and the disease may enter the severe infection stage in this phase.Although many patients are known for their respiratory symptoms,they had neurological symptoms in their first 1-2 days of clinical symptomatic phase,and ischaemic stroke occurred 2 weeks after the onset of the clinical symptomatic phase.The key is to prevent a patient from progressing to this severe infection from mild infection.We are sharing our experience on prevention and management of COVID-19.
基金This work was supported by research grants from the William E.McElroy Charitable Foundation,the OSF HealthCare Illinois Neurological Institute and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health(award number R01NS102573)to KKV.
文摘Background and purpose The therapeutic potential of different stem cells for ischaemic stroke treatment is intriguing and somewhat controversial.Recent results from our laboratory have demonstrated the potential benefits of human umbilical cord blood-derived mesenchymal stem cells(MSC)in a rodent stroke model.We hypothesised that MSC treatment would effectively promote the recovery of sensory and motor function in both males and females,despite any apparent sex differences in post stroke brain injury.Methods Transient focal cerebral ischaemia was induced in adult Sprague-Dawley rats by occlusion of the middle cerebral artery.Following the procedure,male and female rats of the untreated group were euthanised 1 day after reperfusion and their brains were used to estimate the resulting infarct volume and tissue swelling.Additional groups of stroke-induced male and female rats were treated with MSC or vehicle and were subsequently subjected to a battery of standard neurological/neurobehavioral tests(Modified Neurological Severity Score assessment,adhesive tape removal,beam walk and rotarod).The tests were administered at regular intervals(at days 1,3,5,7 and 14)after reperfusion to determine the time course of neurological and functional recovery after stroke.Results The infarct volume and extent of swelling of the ischaemic brain were similar in males and females.Despite similar pathological stroke lesions,the clinical manifestations of stroke were more pronounced in males than females,as indicated by the neurological scores and other tests.MSC treatment significantly improved the recovery of sensory and motor function in both sexes,and it demonstrated efficacy in both moderate stroke(females)and severe stroke(males).Conclusions Despite sex differences in the severity of post stroke outcomes,MSC treatment promoted the recovery of sensory and motor function in male and female rats,suggesting that it may be a promising treatment for stroke.
基金This research received specific funding from the Chinese Stroke Association.
文摘Background China is one of the countries with the highest burden of stroke.Implementing multidimensional management guidelines will help clinicians practise evidence-based care,improve patient outcomes and alleviate societal burdens.This update of the 2019 edition will provide the latest comprehensive recommendations for the diagnosis and treatment of ischaemic cerebrovascular diseases.Methods We conducted a comprehensive search on MEDLINE(via PubMed)up to 31 August 2023.The writing team established the recommendations through multiple rounds of online and offline discussions.Each recommendation was graded using the evidence grading algorithm developed by the Chinese Stroke Association(CSA).The draft was reviewed and finalised by the CSA Stroke Guidelines Writing Committee.Results This update included revisions of 15 existing recommendations and 136 new recommendations in the following areas of stroke care:emergency assessment and diagnosis of ischaemic cerebrovascular disease,acute-phase reperfusion therapy,evaluation of underlying mechanisms,antithrombotic therapy,prevention and treatment of complications,and risk factor management.Conclusions This guideline updated the recommendations for the clinical management of ischaemic cerebrovascular disease from 2019.
文摘Defining minor stroke can be complicated.A minor stroke can be called a mini or small stroke.It is often defined by the severity of neurological deficit,size of ischaemic lesion(s)on neuroimaging,and level of disability.The definition of minor stroke is often tangled with that of transient ischaemic attack(TIA).