Medical procedures are inherently invasive and carry the risk of inducing pain to the mind and body.Recently,efforts have been made to alleviate the discomfort associated with invasive medical procedures through the u...Medical procedures are inherently invasive and carry the risk of inducing pain to the mind and body.Recently,efforts have been made to alleviate the discomfort associated with invasive medical procedures through the use of virtual reality(VR)technology.VR has been demonstrated to be an effective treatment for pain associated with medical procedures,as well as for chronic pain conditions for which no effective treatment has been established.The precise mechanism by which the diversion from reality facilitated by VR contributes to the diminution of pain and anxiety has yet to be elucidated.However,the provision of positive images through VR-based visual stimulation may enhance the functionality of brain networks.The salience network is diminished,while the default mode network is enhanced.Additionally,the medial prefrontal cortex may establish a stronger connection with the default mode network,which could result in a reduction of pain and anxiety.Further research into the potential of VR technology to alleviate pain could lead to a reduction in the number of individuals who overdose on painkillers and contribute to positive change in the medical field.展开更多
Sepsis,a life-threatening condition,can lead to acute skin failure characterized by extensive skin damage.This is often due to decreased blood flow,inflammation,and increased susceptibility to infection.Acute skin fai...Sepsis,a life-threatening condition,can lead to acute skin failure characterized by extensive skin damage.This is often due to decreased blood flow,inflammation,and increased susceptibility to infection.Acute skin failure in people with sepsis is often associated with sleep disturbances,anxiety,and poor mood.Inflammatory markers and lactate levels correlate with these psychiatric symptoms,suggesting a link between skin and brain function.The skin and the central nervous system(CNS)have bidirectional communication.The CNS is also in close contact with the digestive tract.The gut,skin,and brain influence each other’s functions thr-ough nervous,hormonal,and immune pathways,forming a gut-skin-brain axis.Understanding the interaction among the gut,skin,and CNS is critical to the diag-nosis and treatment of various skin and neurological disorders.By recognizing individual variations in gut microbiota,immune responses,and neural pathways,treatments can be tailored to specific patient needs,enhancing efficacy and minimizing side effects.The gut plays a large role in mental health.Under-standing the gut skin brain axis,will lead to improved mental health outcomes.展开更多
Attention is the cornerstone of effective functioning in a complex and information-rich world.While the neural activity of attention has been extensively studied in the cortex,the brain-wide neural activity patterns a...Attention is the cornerstone of effective functioning in a complex and information-rich world.While the neural activity of attention has been extensively studied in the cortex,the brain-wide neural activity patterns are largely unknown.In this study,we conducted a comprehensive analysis of neural activity across the mouse brain during attentional processing using EEG and c-Fos staining,utilizing hierarchical clustering and c-Fos-based functional network analysis to evaluate the c-Fos activation patterns.Our findings reveal that a wide range of brain regions are activated,notably in the high-order cortex,thalamus,and brain stem regions involved in advanced cognition and arousal regulation,with the central lateral nucleus of the thalamus as a strong hub,suggesting the crucial role of the thalamus in attention control.These results provide valuable insights into the neural network mechanisms underlying attention,offering a foundation for formulating functional hypotheses and conducting circuit-level testing.展开更多
The increasing global prevalence of mild cognitive impairment(MCI)necessitates a paradigm shift in early detection strategies.Conventional neuropsychological assessment methods,predominantly paper-and-pencil tests suc...The increasing global prevalence of mild cognitive impairment(MCI)necessitates a paradigm shift in early detection strategies.Conventional neuropsychological assessment methods,predominantly paper-and-pencil tests such as the Mini-Mental State Examination and the Montreal Cognitive Assessment,exhibit inherent limitations with respect to accessibility,administration burden,and sensitivity to subtle cognitive decline,particularly among diverse populations.This commentary critically examines a recent study that champions a novel approach:The integration of gait and handwriting kinematic parameters analyzed via machine learning for MCI screening.The present study positions itself within the broader landscape of MCI detection,with a view to comparing its advantages against established neuropsychological batteries,advanced neuroimaging(e.g.,positron emission tomography,magnetic resonance imaging),and emerging fluid biomarkers(e.g.,cerebrospinal fluid,blood-based assays).While the study demonstrates promising accuracy(74.44%area under the curve 0.74 with gait and graphic handwriting)and addresses key unmet needs in accessibility and objectivity,we highlight its cross-sectional nature,limited sample diversity,and lack of dual-task assessment as areas for future refinement.This commentary posits that kinematic biomarkers offer a distinctive,scalable,and ecologically valid approach to widespread MCI screening,thereby complementing existing methods by providing real-world functional insights.Future research should prioritize longitudinal validation,expansion to diverse cohorts,integration with multimodal data including dual-tasking,and the development of highly portable,artificial intelligence-driven solutions to achieve the democratization of early MCI detection and enable timely interventions.展开更多
Glioma incidence rates in the United States are near 20000 new cases per year, with a median survival time of 14.6 mo for high-grade gliomas due to limited therapeutic options. The origins of these tumors and their ma...Glioma incidence rates in the United States are near 20000 new cases per year, with a median survival time of 14.6 mo for high-grade gliomas due to limited therapeutic options. The origins of these tumors and their many subtypes remain a matter of investigation. Evidence from mouse models of glioma and human clinical data have provided clues about the cell types and initiating oncogenic mutations that drive gliomagenesis, a topic we review here. There has been mixed evidence as to whether or not the cells of origin are neural stem cells, progenitor cells or differentiated progeny. Many of the existing murine models target cell populations defined by lineage-specific promoters or employ lineagetracing methods to track the potential cells of origin. Our ability to target specific cell populations will likely increase concurrently with the knowledge gleaned from an understanding of neurogenesis in the adult brain. The cell of origin is one variable in tumorigenesis, as oncogenes or tumor suppressor genes may differentially transform the neuroglial cell types. Knowledge of key driver mutations and susceptible cell types will allow us to understand cancer biology from a developmental standpoint and enable early interventional strategies and biomarker discovery.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
There are various clinical treatments for traumatic brain injury,including surgery,drug therapy,and rehabilitation therapy;howeve r,the therapeutic effects are limited.Scaffolds combined with exosomes represent a prom...There are various clinical treatments for traumatic brain injury,including surgery,drug therapy,and rehabilitation therapy;howeve r,the therapeutic effects are limited.Scaffolds combined with exosomes represent a promising but challenging method for improving the repair of traumatic brain injury.In this study,we determined the ability of a novel 3D-printed collagen/chitosan scaffold loaded with exosomes derived from neural stem cells pretreated with insulin-like growth factor-1(3D-CC-INEXOS) to improve traumatic brain injury repair and functional recove ry after traumatic brain injury in rats.Composite scaffolds comprising collagen,chitosan,and exosomes derived from neural stem cells pretreated with insulin-like growth fa ctor-1(INEXOS) continuously released exosomes for 2weeks.Transplantation of 3D-CC-INExos scaffolds significantly improved motor and cognitive functions in a rat traumatic brain injury model,as assessed by the Morris water maze test and modified neurological seve rity scores.In addition,immunofluorescence staining and transmission electron microscopy showed that3D-CC-INExos implantation significantly improved the recove ry of damaged nerve tissue in the injured area.In conclusion,this study suggests that transplanted3D-CC-INExos scaffolds might provide a potential strategy for the treatment of traumatic brain injury and lay a solid foundation for clinical translation.展开更多
While brain computer interfaces(BCIs)ofer the potential of allowing those sufering from loss of muscle control to once again fully engage with their environment by bypassing the afected motor system and decoding user ...While brain computer interfaces(BCIs)ofer the potential of allowing those sufering from loss of muscle control to once again fully engage with their environment by bypassing the afected motor system and decoding user intentions directly from brain activity,they are prone to errors.One possible avenue for BCI performance improvement is to detect when the BCI user perceives the BCI to have made an unintended action and thus take corrective actions.Error-related potentials(ErrPs)are neural correlates of error awareness and as such can provide an indication of when a BCI system is not performing according to the user’s intentions.Here,we investigate the brain signals of an implanted BCI user sufering from locked-in syndrome(LIS)due to late-stage ALS that prevents her from being able to speak or move but not from using her BCI at home on a daily basis to communicate,for the presence of error-related signals.We frst establish the presence of an ErrP originating from the dorsolateral pre-frontal cortex(dLPFC)in response to errors made during a discrete feedback task that mimics the click-based spelling software she uses to communicate.Then,we show that this ErrP can also be elicited by cursor movement errors in a continuous BCI cursor control task.This work represents a frst step toward detecting ErrPs during the daily home use of a communications BCI.展开更多
PURPOSE:A phase Ⅱ study of bevacizumab(BVZ) plus irinotecan(CPT-11) was conducted in children with recurrent malignant glioma(MG) and intrinsic brainstem glioma(BSG).PATIENTS AND METHODS:Eligible patients received tw...PURPOSE:A phase Ⅱ study of bevacizumab(BVZ) plus irinotecan(CPT-11) was conducted in children with recurrent malignant glioma(MG) and intrinsic brainstem glioma(BSG).PATIENTS AND METHODS:Eligible patients received two doses of BVZ展开更多
According to clinical statistics,the mortality of patients with early brainstem hemorrhage is high.In this study,we established rat models of brainstem hemorrhage by injecting type Ⅶ collagenase into the right basote...According to clinical statistics,the mortality of patients with early brainstem hemorrhage is high.In this study,we established rat models of brainstem hemorrhage by injecting type Ⅶ collagenase into the right basotegmental pontine and investigated the pathological changes of early brainstem hemorrhage using multi-sequence magnetic resonance imaging and histopathological methods.We found that brainstem hematoma gradually formed in the injured rats over the first 3 days and then reduced after 7 days.The edema that occurred was mainly of the vasogenic type.No complete myelin sheath structure was found around the focus of the brainstem hemorrhage.The integrity and continuity of nerve fibers gradually deteriorated over the first 7 days.Neuronal degeneration was mild in the first 3 days and then obviously aggravated on the 7^(th)day.Inflammatory cytokines,interleukin-1β,and tumor necrosis factorαappeared on the 1st day after intracerebral hemorrhage,reached peak levels on the 3^(rd)day,and decreased from the 7^(th)day.Our findings show the characteristics of the progression of early brainstem hemorrhage.展开更多
Severe body stress induced by hypoxemia and hypotension may lead to total body energy state deterioration.The perfusion of the most vital organs is maintained at the expense of“less vital”organs.In the present study...Severe body stress induced by hypoxemia and hypotension may lead to total body energy state deterioration.The perfusion of the most vital organs is maintained at the expense of“less vital”organs.In the present study,we used a multi-site multiparametric(MSMP)monitoring system for real-time evaluation of tissue blood flow(TBF)and mitochondrial NADH fluorescence of the brain and the small intestine following hemorrhage.In Group 1,uncontrolled hemorrhage,mean arterial pressure(MAP)was decreased to 40mmHg within 2 minutes and shed blood was re-infused after 30minutes.In Group 2,controlled hemorrhage,during the 30minutes of hemorrhage,MAP was kept at 40mmHg.During hemorrhage,in both groups,the intestinal TBF and NADH deteriorated,while the brain remained relatively well protected.In Group 1,all parameters partly recovered within the hemorrhage phase,while in Group 2,complete recovery occurred only after resuscitation.At the end of the experiment,both models showed a decrease in intestinal viability(TBF decreased,NADH increased),while the brain metabolic state in Group 2 declined slightly.Our unique multi-parametric monitoring device demonstrated that,under hemorrhage,the small intestine responded entirely differently from the brain.This may suggest the potential usefulness of the monitoring of less vital organs,as proxy organs,in critical conditions such as massive hemorrhage.The present study also highlights the importance of mitochondrial function monitoring in similar conditions in the clinical environment.展开更多
Hyperbaric oxygenation(HBO)treatment protocols utilize low pressures up to 3ATA.Higher pressures may induce side effects such as convulsions due to brain toxicity.The optimal HBO pressure allowing for maximal therapy ...Hyperbaric oxygenation(HBO)treatment protocols utilize low pressures up to 3ATA.Higher pressures may induce side effects such as convulsions due to brain toxicity.The optimal HBO pressure allowing for maximal therapy and minimal toxicity is under controversy.However,it can be evaluated by monitoring oxygen delivery,saturation,and consumption.In this study,the monitoring system fixed on the rats’brain cortex included a time-sharing fluorometer-reflectometer for monitoring mitochondrial NADH and hemoglobin oxygenation(HbO_(2))combined with Laser Doppler Flowmetry(LDF)for blood-flow monitoring.Rats were located in a hyperbaric chamber and exposed to different pressures.The HBO pressure caused an increase in HbO_(2)and a decrease in NADH in proportion to the increase in hyperbaric pressure,up to a nearly maximum effect at 2.5ATA.At 6ATA,15 minutes before convulsions started,blood volume and NADH started to increase,while tissue O_(2)supply by hemoglobin remained stable.Oxygen pool includes oxygen dissolved in the plasma and also bounded to hemoglobin.Above 2.5ATA,hemoglobin is fully saturated and the oxygen pool nourishment derives only from the oxygen dissolved in the plasma,exceeding the physiological ability for autoregulation;hence,homeostasis is disturbed and convulsions appear.This information is vital because pressures around 2.5ATA–3ATA are standard clinically applied pressures used to treat most of the pathophysiological problems considering the potential benefit which must be balanced against the potential toxicity.This study enables,for the first time,to evaluate the oxygenation level of hemoglobin in the microcirculation.Furthermore,our study showed that additional oxygen pressure(above 2.5ATA)caused brain oxygen toxicity within a short variable period of time after the pressure elevation.展开更多
Objective: To investigate the development and distribution of phosphate-activated glutaminase like immunoreactive (PAG-LI) neurons in the central pathway of trigeminal proprioception of the rat brainstem. Methods: The...Objective: To investigate the development and distribution of phosphate-activated glutaminase like immunoreactive (PAG-LI) neurons in the central pathway of trigeminal proprioception of the rat brainstem. Methods: The immunohistochemitry techniques were used. Results: (1) At embryonic day 17 (E17), PAG-LI neurons were initially observed in the mesencephalic trigeminal nucleus (Vme). All PAG-LI neurons were large round neurons with moderate immunostaining. The immunoreactivity grew intense and attained adult-like pattern at P10. (2) Not until postnatal day 10 (P10) did a few PAG-LI neurons appear in the area ven-tral to the motor trigeminal nucleus (AVM) and area dorsal to the superior olivery nucleus (ADO), and not until P12 in the dorsomedial part of the subnucleus oralis of the spinal trigeminal nucleus (Vodm) and dorso-medial part of the principal sensory trigeminal nucleus (Vpdm). As development proceeded, more and more neurons in them were immunostained, and some PAG-LI neurons were detected in the lateral reticular forma-tion adjacent to the Vodm(LRF)and the caudolateral part of the supratrigeminal nucleus (Vsup-CL) at P21. Conclusion: In the central pathway of trigeminal proprioception of the rat brainstem, PAG-LI neurons ap-peared during two stages: The first stage from E17 to P10, PAG-LI neurons appeared in the Vme and reached adult-like pattern; the second stage from P10 to P21, PAG-LI neurons appeared in the Vodm, LRF, Vpdm, Vsup-CL, ADO, AVM and gradually reached adult-like pattern. This might be relative to the estab-lishment of jaw movement patterns.展开更多
The use of anesthetics is a well-known treatment for severely injured patients.In the present study we tested the pathophysiology of several levels of injury damage in a rat model and also tested the effect of Equithe...The use of anesthetics is a well-known treatment for severely injured patients.In the present study we tested the pathophysiology of several levels of injury damage in a rat model and also tested the effect of Equithesin on brain vitality in these models.Traumatic Brain Injury(TBI)was induced using thefluid percussion injury model in four levels:mild,moderate and two levels of severe TBI.Brain real-time evaluation was performed by the multiparametric monitoring assembly(MPA)which enable cerebral bloodflow(CBF)monitoring by laser Dopplerflowmetry,mitochondrial NADH(Nicotinamide adenine dinucleotide)monitoring by thefluorometric technique,ionic homehostasis using special mini-electrodes,intracranial pressure(ICP)by the ICP camino device and needle electrodes for ECoG(Electrocorticogram)recording.Our results showed high correlation between the level of impact and the extent of changes in the physiological properties of the injury as indicated by the changes in all parameters monitored using the MPA device.Moreover,Equithesin improved CBF,ionic extracellular level and mitochondrial redox state following mild and moderate TBI while in severe TBI,Equithesin did not improve the metabolic state of the cerebral cortex,although it decreased the mortality rate from 66%to 20%,and following extra-severe TBI level,Equithesin did not improve survival rate.In conclusion it seems that Equithesin's protective effect exists under mild to moderate levels of injury and not in case of severe injuries.展开更多
Patients with brain tumors,specifically,malignant forms such as glioblastoma,medulloblastoma and ependymoma,exhibit dismal survival rates despite advances in treatment strategies.Chemotherapeutics,the primary adjuvant...Patients with brain tumors,specifically,malignant forms such as glioblastoma,medulloblastoma and ependymoma,exhibit dismal survival rates despite advances in treatment strategies.Chemotherapeutics,the primary adjuvant treatment for human brain tumors following surgery,commonly lack efficacy due to either intrinsic or acquired drug resistance.New treatments targeting epigenetic factors are being explored.Post-translational histone modification provides a critical regulatory platform for processes such as chromosome condensation and segregation,apoptosis,gene transcription,and DNA replication and repair.This work reviews how aberrant histone modifications and alterations in histone-modifying enzymes can drive the acquisition of drug resistance in brain tumors.Elucidating these mechanisms should lead to new treatments for overcoming drug resistance.展开更多
文摘Medical procedures are inherently invasive and carry the risk of inducing pain to the mind and body.Recently,efforts have been made to alleviate the discomfort associated with invasive medical procedures through the use of virtual reality(VR)technology.VR has been demonstrated to be an effective treatment for pain associated with medical procedures,as well as for chronic pain conditions for which no effective treatment has been established.The precise mechanism by which the diversion from reality facilitated by VR contributes to the diminution of pain and anxiety has yet to be elucidated.However,the provision of positive images through VR-based visual stimulation may enhance the functionality of brain networks.The salience network is diminished,while the default mode network is enhanced.Additionally,the medial prefrontal cortex may establish a stronger connection with the default mode network,which could result in a reduction of pain and anxiety.Further research into the potential of VR technology to alleviate pain could lead to a reduction in the number of individuals who overdose on painkillers and contribute to positive change in the medical field.
文摘Sepsis,a life-threatening condition,can lead to acute skin failure characterized by extensive skin damage.This is often due to decreased blood flow,inflammation,and increased susceptibility to infection.Acute skin failure in people with sepsis is often associated with sleep disturbances,anxiety,and poor mood.Inflammatory markers and lactate levels correlate with these psychiatric symptoms,suggesting a link between skin and brain function.The skin and the central nervous system(CNS)have bidirectional communication.The CNS is also in close contact with the digestive tract.The gut,skin,and brain influence each other’s functions thr-ough nervous,hormonal,and immune pathways,forming a gut-skin-brain axis.Understanding the interaction among the gut,skin,and CNS is critical to the diag-nosis and treatment of various skin and neurological disorders.By recognizing individual variations in gut microbiota,immune responses,and neural pathways,treatments can be tailored to specific patient needs,enhancing efficacy and minimizing side effects.The gut plays a large role in mental health.Under-standing the gut skin brain axis,will lead to improved mental health outcomes.
文摘Attention is the cornerstone of effective functioning in a complex and information-rich world.While the neural activity of attention has been extensively studied in the cortex,the brain-wide neural activity patterns are largely unknown.In this study,we conducted a comprehensive analysis of neural activity across the mouse brain during attentional processing using EEG and c-Fos staining,utilizing hierarchical clustering and c-Fos-based functional network analysis to evaluate the c-Fos activation patterns.Our findings reveal that a wide range of brain regions are activated,notably in the high-order cortex,thalamus,and brain stem regions involved in advanced cognition and arousal regulation,with the central lateral nucleus of the thalamus as a strong hub,suggesting the crucial role of the thalamus in attention control.These results provide valuable insights into the neural network mechanisms underlying attention,offering a foundation for formulating functional hypotheses and conducting circuit-level testing.
文摘The increasing global prevalence of mild cognitive impairment(MCI)necessitates a paradigm shift in early detection strategies.Conventional neuropsychological assessment methods,predominantly paper-and-pencil tests such as the Mini-Mental State Examination and the Montreal Cognitive Assessment,exhibit inherent limitations with respect to accessibility,administration burden,and sensitivity to subtle cognitive decline,particularly among diverse populations.This commentary critically examines a recent study that champions a novel approach:The integration of gait and handwriting kinematic parameters analyzed via machine learning for MCI screening.The present study positions itself within the broader landscape of MCI detection,with a view to comparing its advantages against established neuropsychological batteries,advanced neuroimaging(e.g.,positron emission tomography,magnetic resonance imaging),and emerging fluid biomarkers(e.g.,cerebrospinal fluid,blood-based assays).While the study demonstrates promising accuracy(74.44%area under the curve 0.74 with gait and graphic handwriting)and addresses key unmet needs in accessibility and objectivity,we highlight its cross-sectional nature,limited sample diversity,and lack of dual-task assessment as areas for future refinement.This commentary posits that kinematic biomarkers offer a distinctive,scalable,and ecologically valid approach to widespread MCI screening,thereby complementing existing methods by providing real-world functional insights.Future research should prioritize longitudinal validation,expansion to diverse cohorts,integration with multimodal data including dual-tasking,and the development of highly portable,artificial intelligence-driven solutions to achieve the democratization of early MCI detection and enable timely interventions.
基金Supported by The Medical Scientist Training Program at NYU School of Medicine to Modrek ASNYSTEM Institutional training grant#CO26880 to Bayin NS+1 种基金NIH/NINDS(1 R21 NS087241-01)the NYU Cancer Institute Developmental Projects Program and the NYU Clinical and Translational Science Institute(NYU CTSA grant#UL1TR000038 from the National Center for the Advancement of Translational Science NCATS,NIH)to Placantonakis DG
文摘Glioma incidence rates in the United States are near 20000 new cases per year, with a median survival time of 14.6 mo for high-grade gliomas due to limited therapeutic options. The origins of these tumors and their many subtypes remain a matter of investigation. Evidence from mouse models of glioma and human clinical data have provided clues about the cell types and initiating oncogenic mutations that drive gliomagenesis, a topic we review here. There has been mixed evidence as to whether or not the cells of origin are neural stem cells, progenitor cells or differentiated progeny. Many of the existing murine models target cell populations defined by lineage-specific promoters or employ lineagetracing methods to track the potential cells of origin. Our ability to target specific cell populations will likely increase concurrently with the knowledge gleaned from an understanding of neurogenesis in the adult brain. The cell of origin is one variable in tumorigenesis, as oncogenes or tumor suppressor genes may differentially transform the neuroglial cell types. Knowledge of key driver mutations and susceptible cell types will allow us to understand cancer biology from a developmental standpoint and enable early interventional strategies and biomarker discovery.
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.
基金supported by the National Major Scientific and Technological Special Project for Significant New Drugs Development,No.2019ZX09301-147 (to LXZ)。
文摘There are various clinical treatments for traumatic brain injury,including surgery,drug therapy,and rehabilitation therapy;howeve r,the therapeutic effects are limited.Scaffolds combined with exosomes represent a promising but challenging method for improving the repair of traumatic brain injury.In this study,we determined the ability of a novel 3D-printed collagen/chitosan scaffold loaded with exosomes derived from neural stem cells pretreated with insulin-like growth factor-1(3D-CC-INEXOS) to improve traumatic brain injury repair and functional recove ry after traumatic brain injury in rats.Composite scaffolds comprising collagen,chitosan,and exosomes derived from neural stem cells pretreated with insulin-like growth fa ctor-1(INEXOS) continuously released exosomes for 2weeks.Transplantation of 3D-CC-INExos scaffolds significantly improved motor and cognitive functions in a rat traumatic brain injury model,as assessed by the Morris water maze test and modified neurological seve rity scores.In addition,immunofluorescence staining and transmission electron microscopy showed that3D-CC-INExos implantation significantly improved the recove ry of damaged nerve tissue in the injured area.In conclusion,this study suggests that transplanted3D-CC-INExos scaffolds might provide a potential strategy for the treatment of traumatic brain injury and lay a solid foundation for clinical translation.
文摘While brain computer interfaces(BCIs)ofer the potential of allowing those sufering from loss of muscle control to once again fully engage with their environment by bypassing the afected motor system and decoding user intentions directly from brain activity,they are prone to errors.One possible avenue for BCI performance improvement is to detect when the BCI user perceives the BCI to have made an unintended action and thus take corrective actions.Error-related potentials(ErrPs)are neural correlates of error awareness and as such can provide an indication of when a BCI system is not performing according to the user’s intentions.Here,we investigate the brain signals of an implanted BCI user sufering from locked-in syndrome(LIS)due to late-stage ALS that prevents her from being able to speak or move but not from using her BCI at home on a daily basis to communicate,for the presence of error-related signals.We frst establish the presence of an ErrP originating from the dorsolateral pre-frontal cortex(dLPFC)in response to errors made during a discrete feedback task that mimics the click-based spelling software she uses to communicate.Then,we show that this ErrP can also be elicited by cursor movement errors in a continuous BCI cursor control task.This work represents a frst step toward detecting ErrPs during the daily home use of a communications BCI.
文摘PURPOSE:A phase Ⅱ study of bevacizumab(BVZ) plus irinotecan(CPT-11) was conducted in children with recurrent malignant glioma(MG) and intrinsic brainstem glioma(BSG).PATIENTS AND METHODS:Eligible patients received two doses of BVZ
基金supported by the Natural Science Foundation of Xinjiang Uygur Autonomous Region, No. 2020D01A13 (to CWW)Chengdu Science and Technology Bureau, No. 2019-YF05-00511-SN (to MT)1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University, Nos. ZY2016102 (to MT), and ZY2016203 (to CY)
文摘According to clinical statistics,the mortality of patients with early brainstem hemorrhage is high.In this study,we established rat models of brainstem hemorrhage by injecting type Ⅶ collagenase into the right basotegmental pontine and investigated the pathological changes of early brainstem hemorrhage using multi-sequence magnetic resonance imaging and histopathological methods.We found that brainstem hematoma gradually formed in the injured rats over the first 3 days and then reduced after 7 days.The edema that occurred was mainly of the vasogenic type.No complete myelin sheath structure was found around the focus of the brainstem hemorrhage.The integrity and continuity of nerve fibers gradually deteriorated over the first 7 days.Neuronal degeneration was mild in the first 3 days and then obviously aggravated on the 7^(th)day.Inflammatory cytokines,interleukin-1β,and tumor necrosis factorαappeared on the 1st day after intracerebral hemorrhage,reached peak levels on the 3^(rd)day,and decreased from the 7^(th)day.Our findings show the characteristics of the progression of early brainstem hemorrhage.
基金supported by grant 358/04-3 of“The Israeli Science Foundation”.
文摘Severe body stress induced by hypoxemia and hypotension may lead to total body energy state deterioration.The perfusion of the most vital organs is maintained at the expense of“less vital”organs.In the present study,we used a multi-site multiparametric(MSMP)monitoring system for real-time evaluation of tissue blood flow(TBF)and mitochondrial NADH fluorescence of the brain and the small intestine following hemorrhage.In Group 1,uncontrolled hemorrhage,mean arterial pressure(MAP)was decreased to 40mmHg within 2 minutes and shed blood was re-infused after 30minutes.In Group 2,controlled hemorrhage,during the 30minutes of hemorrhage,MAP was kept at 40mmHg.During hemorrhage,in both groups,the intestinal TBF and NADH deteriorated,while the brain remained relatively well protected.In Group 1,all parameters partly recovered within the hemorrhage phase,while in Group 2,complete recovery occurred only after resuscitation.At the end of the experiment,both models showed a decrease in intestinal viability(TBF decreased,NADH increased),while the brain metabolic state in Group 2 declined slightly.Our unique multi-parametric monitoring device demonstrated that,under hemorrhage,the small intestine responded entirely differently from the brain.This may suggest the potential usefulness of the monitoring of less vital organs,as proxy organs,in critical conditions such as massive hemorrhage.The present study also highlights the importance of mitochondrial function monitoring in similar conditions in the clinical environment.
文摘Hyperbaric oxygenation(HBO)treatment protocols utilize low pressures up to 3ATA.Higher pressures may induce side effects such as convulsions due to brain toxicity.The optimal HBO pressure allowing for maximal therapy and minimal toxicity is under controversy.However,it can be evaluated by monitoring oxygen delivery,saturation,and consumption.In this study,the monitoring system fixed on the rats’brain cortex included a time-sharing fluorometer-reflectometer for monitoring mitochondrial NADH and hemoglobin oxygenation(HbO_(2))combined with Laser Doppler Flowmetry(LDF)for blood-flow monitoring.Rats were located in a hyperbaric chamber and exposed to different pressures.The HBO pressure caused an increase in HbO_(2)and a decrease in NADH in proportion to the increase in hyperbaric pressure,up to a nearly maximum effect at 2.5ATA.At 6ATA,15 minutes before convulsions started,blood volume and NADH started to increase,while tissue O_(2)supply by hemoglobin remained stable.Oxygen pool includes oxygen dissolved in the plasma and also bounded to hemoglobin.Above 2.5ATA,hemoglobin is fully saturated and the oxygen pool nourishment derives only from the oxygen dissolved in the plasma,exceeding the physiological ability for autoregulation;hence,homeostasis is disturbed and convulsions appear.This information is vital because pressures around 2.5ATA–3ATA are standard clinically applied pressures used to treat most of the pathophysiological problems considering the potential benefit which must be balanced against the potential toxicity.This study enables,for the first time,to evaluate the oxygenation level of hemoglobin in the microcirculation.Furthermore,our study showed that additional oxygen pressure(above 2.5ATA)caused brain oxygen toxicity within a short variable period of time after the pressure elevation.
基金the National Nature Science Foundation of China (No. 39870262) by Foundation for University Key Teacher by the Ministry of Education of China
文摘Objective: To investigate the development and distribution of phosphate-activated glutaminase like immunoreactive (PAG-LI) neurons in the central pathway of trigeminal proprioception of the rat brainstem. Methods: The immunohistochemitry techniques were used. Results: (1) At embryonic day 17 (E17), PAG-LI neurons were initially observed in the mesencephalic trigeminal nucleus (Vme). All PAG-LI neurons were large round neurons with moderate immunostaining. The immunoreactivity grew intense and attained adult-like pattern at P10. (2) Not until postnatal day 10 (P10) did a few PAG-LI neurons appear in the area ven-tral to the motor trigeminal nucleus (AVM) and area dorsal to the superior olivery nucleus (ADO), and not until P12 in the dorsomedial part of the subnucleus oralis of the spinal trigeminal nucleus (Vodm) and dorso-medial part of the principal sensory trigeminal nucleus (Vpdm). As development proceeded, more and more neurons in them were immunostained, and some PAG-LI neurons were detected in the lateral reticular forma-tion adjacent to the Vodm(LRF)and the caudolateral part of the supratrigeminal nucleus (Vsup-CL) at P21. Conclusion: In the central pathway of trigeminal proprioception of the rat brainstem, PAG-LI neurons ap-peared during two stages: The first stage from E17 to P10, PAG-LI neurons appeared in the Vme and reached adult-like pattern; the second stage from P10 to P21, PAG-LI neurons appeared in the Vodm, LRF, Vpdm, Vsup-CL, ADO, AVM and gradually reached adult-like pattern. This might be relative to the estab-lishment of jaw movement patterns.
基金This work was supported by the Mina and Everard Goodman Faculty of Life Sciences,and the Leslie and Susan Gonda Multidisciplinary Brain Research Center,Bar-Ilan University,Ramat-Gan,Israel.
文摘The use of anesthetics is a well-known treatment for severely injured patients.In the present study we tested the pathophysiology of several levels of injury damage in a rat model and also tested the effect of Equithesin on brain vitality in these models.Traumatic Brain Injury(TBI)was induced using thefluid percussion injury model in four levels:mild,moderate and two levels of severe TBI.Brain real-time evaluation was performed by the multiparametric monitoring assembly(MPA)which enable cerebral bloodflow(CBF)monitoring by laser Dopplerflowmetry,mitochondrial NADH(Nicotinamide adenine dinucleotide)monitoring by thefluorometric technique,ionic homehostasis using special mini-electrodes,intracranial pressure(ICP)by the ICP camino device and needle electrodes for ECoG(Electrocorticogram)recording.Our results showed high correlation between the level of impact and the extent of changes in the physiological properties of the injury as indicated by the changes in all parameters monitored using the MPA device.Moreover,Equithesin improved CBF,ionic extracellular level and mitochondrial redox state following mild and moderate TBI while in severe TBI,Equithesin did not improve the metabolic state of the cerebral cortex,although it decreased the mortality rate from 66%to 20%,and following extra-severe TBI level,Equithesin did not improve survival rate.In conclusion it seems that Equithesin's protective effect exists under mild to moderate levels of injury and not in case of severe injuries.
基金Supported by the Rory David Deutsch Foundationthe Surgical Neuro-oncology Research Fund of Ann&Robert H Lurie Children’s Hospital(A&RLCH) of Chicagothe Dr.Ralph and Marian C.Falk Medical Research Trust
文摘Patients with brain tumors,specifically,malignant forms such as glioblastoma,medulloblastoma and ependymoma,exhibit dismal survival rates despite advances in treatment strategies.Chemotherapeutics,the primary adjuvant treatment for human brain tumors following surgery,commonly lack efficacy due to either intrinsic or acquired drug resistance.New treatments targeting epigenetic factors are being explored.Post-translational histone modification provides a critical regulatory platform for processes such as chromosome condensation and segregation,apoptosis,gene transcription,and DNA replication and repair.This work reviews how aberrant histone modifications and alterations in histone-modifying enzymes can drive the acquisition of drug resistance in brain tumors.Elucidating these mechanisms should lead to new treatments for overcoming drug resistance.
