Nutritional fads in the health and fitness world are constantly changing. Each new craze has its believers and critics. For the consumer, “what to believe” becomes a topic filled with uncertainty. This paper present...Nutritional fads in the health and fitness world are constantly changing. Each new craze has its believers and critics. For the consumer, “what to believe” becomes a topic filled with uncertainty. This paper presents a systematic approach to understanding what consumers believe about the health messaging of “raw beverages”. The paper presents both substantive results from US consumers, as well as demonstrates a general approach by which researchers can more deeply understand the consumer mind with respect to the specifics of health and wellness issues.展开更多
Autism is a heterogeneous condition with a rising prevalence and demand for specialized care.Autistic children are more likely than neurotypical peers to experience co-occurring conditions(CCs),including medical,psych...Autism is a heterogeneous condition with a rising prevalence and demand for specialized care.Autistic children are more likely than neurotypical peers to experience co-occurring conditions(CCs),including medical,psychiatric,and behavioral issues,highlighting the urgent need for autism-competent healthcare providers in general healthcare.This review aims to equip primary care providers(PCPs)with a concise summary of common CCs and strategies for effective identification.A panel of experts with extensive experience in caring for autistic children collaboratively summarized key literature,research evidence,and existing clinical trial outcomes,supplementing their clinical expertise.Autistic children consistently show higher rates of both medical and mental health issues.Despite greater healthcare utilization,many autistic individuals report unmet needs.CCs can impair behavior,functioning,and well-being,but are often treatable when recognized early.Timely identification and management of medical and psychiatric CCs are critical for improving outcomes for autistic children and their families.This evidence-based review supports PCPs in enhancing their knowledge,fostering early recognition,and delivering comprehensive,responsive care.展开更多
Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases （RIPK） associated with the tumor necrosis fact...Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases （RIPK） associated with the tumor necrosis factor-alpha （TNF-a）/death receptor. Recent evidence shows RIPK inhibitors are neuroprotective and al- leviate ischemic brain injury in a number of animal models, however, most have not yet undergone clinical trials and safety in humans remains in question. Dabrafenib, originally identified as a B-raf inhibitor that is currently used to treat melanoma, was later revealed to be a potent RIPK3 inhibitor at micromolar con- centrations. Here, we investigated whether Dabrafenib would show a similar neuroprotective effect in mice subjected to ischemic brain injury by photothrombosis. Dabrafenib administered intraperitoneally at 10 mg/ kg one hour after photothrombosis-induced focal ischemic injury significantly reduced infarct lesion size in C57BL6 mice the following day, accompanied by a markedly attenuated upregulation of TNF-u. However, subsequent lower doses （5 mg/kg/day） failed to sustain this neuroprotective effect after 4 days. Dabrafenib bl ocked lipopolysaccharides-induced activation of TNF-ct in bone marrow-derived macrophages, suggesting that Dabrafenib may attenuate TNF-ct-induced necroptotic pathway after ischemic brain injury. Since Dab- rafenib is already in clinical use for the treatment of melanoma, it might be repurposed for stroke therapy.展开更多
AIM: To examine DNA methylation profiles in a longitudinal comparison of pre-diabetes mellitus(Pre-DM) subjects who transitioned to type 2 diabetes mellitus(T2DM).METHODS: We performed DNA methylation study in bisulph...AIM: To examine DNA methylation profiles in a longitudinal comparison of pre-diabetes mellitus(Pre-DM) subjects who transitioned to type 2 diabetes mellitus(T2DM).METHODS: We performed DNA methylation study in bisulphite converted DNA from Pre-DM(n = 11) at baseline and at their transition to T2 DM using Illumina Infinium Human Methylation27 Bead Chip, that enables the query of 27578 individual cytosines at Cp G loci throughout the genome, which are focused on the promoter regions of 14495 genes.RESULTS: There were 694 Cp G sites hypomethylated and 174 Cp G sites hypermethylated in progression from Pre-DM to T2 DM, representing putative genes involved in glucose and fructose metabolism, inflammation, oxidative and mitochondrial stress, and fatty acid metabolism. These results suggest that this high throughput platform is able to identify hundreds of prospective Cp G sites associated with diverse genes that may reflect differences in Pre-DM compared with T2 DM. In addition, there were Cp G hypomethylation changes associated with a number of genes that may be associated with development of complications of diabetes, such as nephropathy. These hypomethylation changes were observed in all of the subjects.CONCLUSION: These data suggest that some epigenomic changes that may be involved in the progression of diabetes and/or the development of complications may be apparent at the Pre-DM state or during the transition to diabetes. Hypomethylation of a number of genes related to kidney function may be an early marker for developing diabetic nephropathy.展开更多
People with schizophrenia exhibit impaired social cognitive functions, particularly emotion regulation. Abnormal activations of the ventral medial prefrontal cortex （vMPFC） during emotional tasks have been demonstra...People with schizophrenia exhibit impaired social cognitive functions, particularly emotion regulation. Abnormal activations of the ventral medial prefrontal cortex （vMPFC） during emotional tasks have been demonstrated in schizophrenia, suggesting its important role in emotion processing in patients. We used the resting-state functional connectivity approach, setting a functionally relevant region, the vMPFC, as a seed region to examine the intrinsic functional interactions and communication between the vMPFC and other brain regions in schizophrenic patients. We found hypo-connectivity between the vMPFC and the medial frontal cortex, right middle temporal lobe （MTL）, right hippocampus, parahippocampal cortex （PHC） and amygdala. Further, there was a decreased strength of the negative connectivity （or anticorrelation） between the vMPFC and the bilateral dorsal lateral prefrontal cortex （DLPFC） and pre-supplementary motor areas. Among these connectivity alterations, reduced vMPFC-DLPFC connectivity was positively correlated with positive symptoms on the Positive and Negative Syndrome Scale, while vMPFC-right MTL/PHC/amygdala functional connectivity was positively correlated with the performance of emotional regulation in patients. These findings imply that communication and coordination throughout the brain networks are disrupted in schizophrenia. The emotional correlates of vMPFC connectivity suggest a role of the hypo-connectivity between these regions in the neuropathology of abnormal social cognition in chronic schizophrenia.展开更多
Alzheimer’s disease is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Recent preclinical and epidemiological studies proposed statins as a possible therapeutic drug...Alzheimer’s disease is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Recent preclinical and epidemiological studies proposed statins as a possible therapeutic drug for Alzheimer’s disease, but the exact mechanisms of action are still unknown. Biliverdin reductase-A is a pleiotropic enzyme involved in cellular stress responses. It not only transforms biliverdin-IX alpha into the antioxidant bilirubin-IX alpha but its serine/threonine/ tyrosine kinase activity is able to modulate cell signaling networks. We previously reported the beneficial effects of atorvastatin treatment on biliverdin reductase-A and heme oxygenase-1 in the brains of a well characterized pre-clinical model of Alzheimer’s disease, aged beagles, together with observed improvement in cognition. Here we extend our knowledge of the effects of atorvastatin on inducible nitric oxide synthase in parietal cortex, cerebellum and liver of the same animals. We demonstrated that atorvastatin treatment （80 mg/day for 14.5 months） to aged beagles selectively increased inducible nitric oxide synthase in the parietal cortex but not in the cerebellum. In contrast, inducible nitric oxide synthase protein levels were significantly decreased in the liver. Significant positive correlations were found between biliverdin reductase-A and inducible nitric oxide synthase as well as heme oxygenase-1 protein levels in the parietal cortex. The opposite was observed in the liver. Inducible nitric oxide synthase up-regulation in the parietal cortex was positively associated with improved biliverdin reductase-A functions, whereas the oxidative-induced impairment of biliverdin reductase-A in the liver negatively affected inducible nitric oxide synthase expression, thus suggesting a role for biliverdin reductase-A in atorvastatin-dependent inducible nitric oxide synthase changes. Interestingly, increased inducible nitric oxide synthase levels in the parietal cortex were not associated with higher oxidative/nitrosative stress levels. We hypothesize that biliverdin reductase-A-dependent inducible nitric oxide synthase regulation strongly contributes to the cognitive improvement observed following atorvastatin treatment.展开更多
Since the calcium channel blocker （CCB） has become one of the most prescribed agents for antihypertensive monotherapy in the world, this brief review will focus on the recent research and development of the dihydrop...Since the calcium channel blocker （CCB） has become one of the most prescribed agents for antihypertensive monotherapy in the world, this brief review will focus on the recent research and development of the dihydropyridine （DHP） CCB, addressing pharmacological mecha- nisms for the clinical efficacy of the third and fourth generations of the DHP CCBs, especially on their possible central mechanisms underlying lowering blood pressure.展开更多
Ischemic brain injury causes neuronal death and inflammation.Inflammation activates protein-tyrosine phosphatase 1B(PTP1B).Here,we tested the significance of PTP1B activation in glutamatergic projection neurons on fun...Ischemic brain injury causes neuronal death and inflammation.Inflammation activates protein-tyrosine phosphatase 1B(PTP1B).Here,we tested the significance of PTP1B activation in glutamatergic projection neurons on functional recovery in two models of stroke:by photothrombosis,focal ischemic lesions were induced in the sensorimotor cortex(SM stroke)or in the peri-prefrontal cortex(peri-PFC stroke).Elevated PTP1B expression was detected at 4 days and up to 6 weeks after stroke.While ablation of PTP1B in neurons of neuronal knockout(NKO)mice had no effect on the volume or resorption of ischemic lesions,markedly different effects on functional recovery were observed.SM stroke caused severe sensory and motor deficits(adhesive removal test)in wild type and NKO mice at 4 days,but NKO mice showed drastically improved sensory and motor functional recovery at 8 days.In addition,peri-PFC stroke caused anxiety-like behaviors(elevated plus maze and open field tests),and depression-like behaviors(forced swimming and tail suspension tests)in wild type mice 9 and 28 days after stroke,respectively,with minimal effect on sensory and motor function.Peri-PFC stroke-induced affective disorders were associated with fewer active(FosB+)neurons in the PFC and nucleus accumbens but more FosB+neurons in the basolateral amygdala,compared to sham-operated mice.In contrast,mice with neuronal ablation of PTP1B were protected from anxiety-like and depression-like behaviors and showed no change in FosB+neurons after peri-PFC stroke.Taken together,our study identifies neuronal PTP1B as a key component that hinders sensory and motor functional recovery and also contributes to the development of anxiety-like and depression-like behaviors after stroke.Thus,PTP1B may represent a novel therapeutic target to improve stroke recovery.All procedures for animal use were approved by the Animal Care and Use Committee of the University of Ottawa Animal Care and Veterinary Service(protocol 1806)on July 27,2018.展开更多
The activity in sensory cortices and the prefrontal cortex （PFC） throughout the delay interval of working memory （WM） tasks reflect two aspects of WM-quality and quantity, respectively. The delay activity in senso...The activity in sensory cortices and the prefrontal cortex （PFC） throughout the delay interval of working memory （WM） tasks reflect two aspects of WM-quality and quantity, respectively. The delay activity in sensory cortices is fine-tuned to sensory information and forms the neural basis of the precision of WM storage, while the delay activity in the PFC appears to represent behavioral goals and filters out irrelevant distractions, forming the neural basis of the quantity of task-relevant information in WM. The PFC and sensory cortices interact through different frequency bands of neuronal oscillation （theta, alpha, and gamma） to fulfill goal-directed behaviors.展开更多
BACKGROUND Recent studies suggest that traumatic brain injury(TBI)is a risk factor for subsequent ischemic stroke,even years after the initial insult.The mechanisms of the association remain unclear.The presence of tr...BACKGROUND Recent studies suggest that traumatic brain injury(TBI)is a risk factor for subsequent ischemic stroke,even years after the initial insult.The mechanisms of the association remain unclear.The presence of traumatic subarachnoid hemorrhage(t SAH)may mediate the effect of TBI on long-term stroke risk,as it has previously been linked to short-term vasospasm and delayed cerebral ischemia.METHODS Using administrative claims data,we conducted a retrospective cohort study of acute care hospitalizations.Patients discharged with a first-recorded diagnosis of t SAH were followed for a primary diagnosis of stroke.They were matched to patients with TBI but not t SAH.Cox proportional hazards modeling was used to assess the association between t SAH and stroke while adjusting for covariates.RESULTS:We identified 40 908 patients with TBI(20 454 patients with t SAH)who were followed for a mean of 4.3+1.8 years.A total of 531 had an ischemic stroke after discharge.There was no significant difference in stroke risk between those with t SAH(1.79%;95%confidence interval[CI]1.54%-2.08%)versus without t SAH(2.12%;95%CI 1.83%-2.44%).The same pattern was found in adjusted analyses even when the group was stratified by age-group or by proxies of TBI severity.CONCLU-SIONS:Our findings do not support a role of t SAH in mediating the association between TBI and protracted stroke risk.Further study is required to elucidate the mechanisms of long-term increased stroke risk after TBI.展开更多
Alzheimer’s disease(AD)is a progressive neurodegenerative disorder associated with significant memory decline and cognitive impairment.AD is characterized by two classical neuropathological hal lmarks,namely the amyl...Alzheimer’s disease(AD)is a progressive neurodegenerative disorder associated with significant memory decline and cognitive impairment.AD is characterized by two classical neuropathological hal lmarks,namely the amyloid-beta(Aβ)plaques and neurofibril tangles.Currently,there are no disease-modifying treatments available for AD,except for a couple of the US Food and Drug Administration(FDA)-approved drugs to improve cognitive function by blocking N-methyl-D-aspartate receptors or cholinesterase activity(Panza et al.,2019).展开更多
There are roughly 282,000 individuals living with spinal cord injury in the United States alone（National Spinal Cord Injury Statistical Center,Birmingham,AL,USA）.Spinal cord injury often results in permanent functio...There are roughly 282,000 individuals living with spinal cord injury in the United States alone（National Spinal Cord Injury Statistical Center,Birmingham,AL,USA）.Spinal cord injury often results in permanent functional impairments with only a limited capacity for spontaneous recovery.For the return of motor function,such as locomotion or hand and arm dexterity,展开更多
Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebr...Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebrovascular conditions(stroke),and neurodevelopmental disorders(autism spectrum disorder).Although they affect millions of individuals around the world,only a limited number of effective treatment options are available today.Since most neurological disorders express mitochondria-related metabolic perturbations,metformin,a biguanide type II antidiabetic drug,has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy metabolism.However,controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological disorders.Given that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging,lifestyle,genetics,and environment,it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological disorders.These molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment,ultimately developing targeted therapy.In this review,we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.展开更多
Background Although previous studies have examined the effects of exercise training on other International Classification of Functioning,Disability and Health(ICF)component levels in persons with multiple sclerosis(MS...Background Although previous studies have examined the effects of exercise training on other International Classification of Functioning,Disability and Health(ICF)component levels in persons with multiple sclerosis(MS),the effects of exercise training on participation remain unclear.The objectives of this review were to:(1)characterize systematically the use of outcome measures that capture participation in exercise training studies;(2)quantify the effect of exercise training on participation in persons with MS.Methods A search of 6 electronic databases(CINAHL,SPORTDiscuss,Embase,MEDLINE,Cochrane Central,and Scopus)was conducted to identify controlled and noncontrolled trials involving exercise training and participation in persons with MS.Search strings were built from Medical Subject Headings and CINAHL headings.ICF linking rules were used to identify participation chapters and categories captured.Meta-analysis was used to quantify the effect of exercise training on participation in randomized controlled trials comparing exercise effects to no intervention/usual care.Results We included 49 articles involving controlled and noncontrolled exercise trials in the systematic review of outcome measures.We captured 16 different outcome measures that captured all 9 participation chapters and identified 89 unique participation categories.Across these 16 outcome measures,mobility was the most commonly represented participation chapter,with 108 items.A subsample of 23 randomized controlled trials was included in the meta-analysis.An overall effect of 0.60(standard error=0.12,95%confidence interval:0.36-0.84,z=4.9,p<0.001)was calculated,indicating a moderate,positive effect of exercise training on participation.Conclusion The current review provides information that can be used to guide the selection of outcome measures that capture participation in studies of exercise training in persons with MS.Exercise training has a positive effect on outcomes that capture participation,providing further evidence for the role of exercise training in promoting and maintaining engagement in everyday life.展开更多
The functional regeneration of damaged axons and severed connections in the mature central nervous sys- tem （CNS） remains a challenging goal of neurological research. Mature CNS neurons are refractory to axon regene...The functional regeneration of damaged axons and severed connections in the mature central nervous sys- tem （CNS） remains a challenging goal of neurological research. Mature CNS neurons are refractory to axon regeneration for two major reasons, one, because the ac- tivity of cell-intrinsic mechanisms that drive axon growth during development is low- and often further suppressed after an injury - and two, because certain molecules that are part of mature extracellular matrix and myelin act as strong inhibitors of axon growth. Genetic removal of growth inhibitory molecules can increase axon sprouting, but is not sufficient to enable long-range axon growth. Since axon growth is robust during early developmental stages, it has long been hypothesized that mature injured neurons may be ＂reprogrammed＂ to the earlier growth state by re-activation of the intracellular growth signaling cascades that drive axon elongation in the developing fetus.展开更多
Glutamate is the main exc i tatory neurotransmitter in the brain and binds to two major classes of receptors,theα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid(AMPA)and the N-methyl-D-aspartate(NMDA)receptors.U...Glutamate is the main exc i tatory neurotransmitter in the brain and binds to two major classes of receptors,theα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid(AMPA)and the N-methyl-D-aspartate(NMDA)receptors.Unlike AMPA receptors that are immediately activated by glutamate release,NMDA receptors are blocked by magnesium and can only be activated by glutamate after membrane depolarization.Thus,NMDA receptors are only activated after repeated AMPA receptor activation by glutamate.NMDA receptors are,for the most part,calcium-permeable channels.Calcium influx through NMDA receptors modulates synaptic transmission in neurons based on prior history of excitation,and provides a means of scaling the strength of synapses required for Hebbian plasticity.展开更多
Therapeutic intervention for spinal cord injury is limited,with many approaches relying on strengthening the remaining substrate and driving recovery through rehabilitative training.As compared with learning novel com...Therapeutic intervention for spinal cord injury is limited,with many approaches relying on strengthening the remaining substrate and driving recovery through rehabilitative training.As compared with learning novel compensatory strategies,rehabilitation focuses on resto ring movements lost to injury.Whether rehabilitation of previously learned movements after spinal cord injury requires the molecular mechanisms of motor learning,or if it engages previously trained motor circuits without requiring novel learning remains an open question.In this study,mice we re randomly assigned to receive intrape ritoneal injection with the pan-nicotinic,non-competitive antagonist mecamylamine and the nicotinicα7 subunit selective antagonist methyllycaconitine citrate salt or vehicle(normal saline)prior to motor learning assays,then randomly reassigned after motor learning for rehabilitation study post-injury.Ce rvical spinal co rd dorsal column lesion was used as a model of in complete injury.Results of this study showed that nicotinic acetylcholine signaling was required for motor learning of the single pellet-reaching task but it was dispensable for the rehabilitation of the same task after injury.Our findings indicate that critical diffe rences exist between the molecular mechanisms supporting compensatory motor learning strategies and the restoration of behavior lost to spinal cord injury.展开更多
Gender differences are investigated from the viewpoint of cognitive neuroscience in the domain of spatial ability. Five task types of geometric problems are used for the collection of task-evoked fMRI data. Although t...Gender differences are investigated from the viewpoint of cognitive neuroscience in the domain of spatial ability. Five task types of geometric problems are used for the collection of task-evoked fMRI data. Although there was no gender-difference in task performance, we found gender differences in neural activity. Some of the important gender differences that we found are 1) that there are far more joint neuro-activations among the brain regions, co-activations or reverse-activations, in males than in females, 2) that the two types of joint activations were nearly half and half in females while it was mostly co-activations in males, 3) that males tend to have more co-activations in the left hemisphere than expected while females tend to have more between-hemisphere co-activations than expected, and 4) that the left-right pairs of BA's are more highly associated than average for males while they are far less associated than average for females.展开更多
Primate sanctuaries across Africa play a pivotal role in the rescue and rehabilitation of confiscated and rescued wild primates, many of whom have had extensive contact with humans prior to their arrival and throughou...Primate sanctuaries across Africa play a pivotal role in the rescue and rehabilitation of confiscated and rescued wild primates, many of whom have had extensive contact with humans prior to their arrival and throughout the rehabilitation process, heightening the risk of disease transmission. While tuberculosis is not naturally occurring in free-living chimpanzees, it has been extensively observed in captive primates that have been in close proximity to humans or other captive primates infected with Mycobacterium tuberculosis. This case report delves into an outbreak of extra-pulmonary tuberculosis among juvenile chimpanzees within a sanctuary, detailing the associated diagnostic challenges and treatment approaches. The five cases had close contact with a caregiver infected with tuberculosis, subsequently transmitting the infection to other in-contact chimpanzees. Prolonged treatment, employing the human protocol of quadri-therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol), followed by bi-therapy (rifampicin and isoniazid), resulted in complete resolution for all five cases. These cases underscore the critical importance of maintaining high levels of biosecurity, implementing effective quarantine measures, and adhering to strict hygiene practices when working with non-human primates.展开更多
文摘Nutritional fads in the health and fitness world are constantly changing. Each new craze has its believers and critics. For the consumer, “what to believe” becomes a topic filled with uncertainty. This paper presents a systematic approach to understanding what consumers believe about the health messaging of “raw beverages”. The paper presents both substantive results from US consumers, as well as demonstrates a general approach by which researchers can more deeply understand the consumer mind with respect to the specifics of health and wellness issues.
文摘Autism is a heterogeneous condition with a rising prevalence and demand for specialized care.Autistic children are more likely than neurotypical peers to experience co-occurring conditions(CCs),including medical,psychiatric,and behavioral issues,highlighting the urgent need for autism-competent healthcare providers in general healthcare.This review aims to equip primary care providers(PCPs)with a concise summary of common CCs and strategies for effective identification.A panel of experts with extensive experience in caring for autistic children collaboratively summarized key literature,research evidence,and existing clinical trial outcomes,supplementing their clinical expertise.Autistic children consistently show higher rates of both medical and mental health issues.Despite greater healthcare utilization,many autistic individuals report unmet needs.CCs can impair behavior,functioning,and well-being,but are often treatable when recognized early.Timely identification and management of medical and psychiatric CCs are critical for improving outcomes for autistic children and their families.This evidence-based review supports PCPs in enhancing their knowledge,fostering early recognition,and delivering comprehensive,responsive care.
基金supported by grants from the Heart and Stroke Foundation of Canada(HHC,AFRS)the Canadian Institutes of Health Research(to HHC and AFRS)supported by a Mid-Career Investigator Award from the Heart and Stroke Foundation of Ontario
文摘Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases （RIPK） associated with the tumor necrosis factor-alpha （TNF-a）/death receptor. Recent evidence shows RIPK inhibitors are neuroprotective and al- leviate ischemic brain injury in a number of animal models, however, most have not yet undergone clinical trials and safety in humans remains in question. Dabrafenib, originally identified as a B-raf inhibitor that is currently used to treat melanoma, was later revealed to be a potent RIPK3 inhibitor at micromolar con- centrations. Here, we investigated whether Dabrafenib would show a similar neuroprotective effect in mice subjected to ischemic brain injury by photothrombosis. Dabrafenib administered intraperitoneally at 10 mg/ kg one hour after photothrombosis-induced focal ischemic injury significantly reduced infarct lesion size in C57BL6 mice the following day, accompanied by a markedly attenuated upregulation of TNF-u. However, subsequent lower doses （5 mg/kg/day） failed to sustain this neuroprotective effect after 4 days. Dabrafenib bl ocked lipopolysaccharides-induced activation of TNF-ct in bone marrow-derived macrophages, suggesting that Dabrafenib may attenuate TNF-ct-induced necroptotic pathway after ischemic brain injury. Since Dab- rafenib is already in clinical use for the treatment of melanoma, it might be repurposed for stroke therapy.
基金Supported by The grants from the National Center for Research Resources,No.5P20RR016480-12The National Institute of General Medical Sciences of the NIH,No.8P20GM103451-12+2 种基金the partial support from the National Center for Advancing Translational Sciences of the National Institutes of Health,No.8UL1TR000041the University of New Mexico Clinical and Translational Science Centerthe cost for clinical phenotyping and payments to participants was supported under a UNM Health Sciences Center-based Cardiovascular and Metabolic Diseases Signature Program
文摘AIM: To examine DNA methylation profiles in a longitudinal comparison of pre-diabetes mellitus(Pre-DM) subjects who transitioned to type 2 diabetes mellitus(T2DM).METHODS: We performed DNA methylation study in bisulphite converted DNA from Pre-DM(n = 11) at baseline and at their transition to T2 DM using Illumina Infinium Human Methylation27 Bead Chip, that enables the query of 27578 individual cytosines at Cp G loci throughout the genome, which are focused on the promoter regions of 14495 genes.RESULTS: There were 694 Cp G sites hypomethylated and 174 Cp G sites hypermethylated in progression from Pre-DM to T2 DM, representing putative genes involved in glucose and fructose metabolism, inflammation, oxidative and mitochondrial stress, and fatty acid metabolism. These results suggest that this high throughput platform is able to identify hundreds of prospective Cp G sites associated with diverse genes that may reflect differences in Pre-DM compared with T2 DM. In addition, there were Cp G hypomethylation changes associated with a number of genes that may be associated with development of complications of diabetes, such as nephropathy. These hypomethylation changes were observed in all of the subjects.CONCLUSION: These data suggest that some epigenomic changes that may be involved in the progression of diabetes and/or the development of complications may be apparent at the Pre-DM state or during the transition to diabetes. Hypomethylation of a number of genes related to kidney function may be an early marker for developing diabetic nephropathy.
基金supported by grants from the Beijing Municipal Science & Technology Commission(D0906001040191,D101107047810005,D101100050010051)the Beijing Natural Science Foundation(7102086)+3 种基金the Fund for Capital Medical Development and Research(2007-3059)the National Natural Science Foundation of China(81171409)Startup Foundation for Distinguished Research Professors of the Institute for Psychology(Y0CX492S03)Fund for Outstanding Talents in Beijing(2012D003034000003)
文摘People with schizophrenia exhibit impaired social cognitive functions, particularly emotion regulation. Abnormal activations of the ventral medial prefrontal cortex （vMPFC） during emotional tasks have been demonstrated in schizophrenia, suggesting its important role in emotion processing in patients. We used the resting-state functional connectivity approach, setting a functionally relevant region, the vMPFC, as a seed region to examine the intrinsic functional interactions and communication between the vMPFC and other brain regions in schizophrenic patients. We found hypo-connectivity between the vMPFC and the medial frontal cortex, right middle temporal lobe （MTL）, right hippocampus, parahippocampal cortex （PHC） and amygdala. Further, there was a decreased strength of the negative connectivity （or anticorrelation） between the vMPFC and the bilateral dorsal lateral prefrontal cortex （DLPFC） and pre-supplementary motor areas. Among these connectivity alterations, reduced vMPFC-DLPFC connectivity was positively correlated with positive symptoms on the Positive and Negative Syndrome Scale, while vMPFC-right MTL/PHC/amygdala functional connectivity was positively correlated with the performance of emotional regulation in patients. These findings imply that communication and coordination throughout the brain networks are disrupted in schizophrenia. The emotional correlates of vMPFC connectivity suggest a role of the hypo-connectivity between these regions in the neuropathology of abnormal social cognition in chronic schizophrenia.
基金Funding for the canine atorvastatin study was through the Alzheimer's Association IIRG-03-5673 to Elizabeth Head
文摘Alzheimer’s disease is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Recent preclinical and epidemiological studies proposed statins as a possible therapeutic drug for Alzheimer’s disease, but the exact mechanisms of action are still unknown. Biliverdin reductase-A is a pleiotropic enzyme involved in cellular stress responses. It not only transforms biliverdin-IX alpha into the antioxidant bilirubin-IX alpha but its serine/threonine/ tyrosine kinase activity is able to modulate cell signaling networks. We previously reported the beneficial effects of atorvastatin treatment on biliverdin reductase-A and heme oxygenase-1 in the brains of a well characterized pre-clinical model of Alzheimer’s disease, aged beagles, together with observed improvement in cognition. Here we extend our knowledge of the effects of atorvastatin on inducible nitric oxide synthase in parietal cortex, cerebellum and liver of the same animals. We demonstrated that atorvastatin treatment （80 mg/day for 14.5 months） to aged beagles selectively increased inducible nitric oxide synthase in the parietal cortex but not in the cerebellum. In contrast, inducible nitric oxide synthase protein levels were significantly decreased in the liver. Significant positive correlations were found between biliverdin reductase-A and inducible nitric oxide synthase as well as heme oxygenase-1 protein levels in the parietal cortex. The opposite was observed in the liver. Inducible nitric oxide synthase up-regulation in the parietal cortex was positively associated with improved biliverdin reductase-A functions, whereas the oxidative-induced impairment of biliverdin reductase-A in the liver negatively affected inducible nitric oxide synthase expression, thus suggesting a role for biliverdin reductase-A in atorvastatin-dependent inducible nitric oxide synthase changes. Interestingly, increased inducible nitric oxide synthase levels in the parietal cortex were not associated with higher oxidative/nitrosative stress levels. We hypothesize that biliverdin reductase-A-dependent inducible nitric oxide synthase regulation strongly contributes to the cognitive improvement observed following atorvastatin treatment.
文摘Since the calcium channel blocker （CCB） has become one of the most prescribed agents for antihypertensive monotherapy in the world, this brief review will focus on the recent research and development of the dihydropyridine （DHP） CCB, addressing pharmacological mecha- nisms for the clinical efficacy of the third and fourth generations of the DHP CCBs, especially on their possible central mechanisms underlying lowering blood pressure.
基金This work was supported by grants from the Heart and Stroke Foundation of Canada(Nos.G-13-0002596&G-18-0022157,to HHCNo.G-16-00014085,to AFRS)+2 种基金the Natural Science and Engineering Research Council of Canada(No.RGPIN/06212-2014,to HHC,No.RGPIN/2016-04985,to AFRS)the Canadian Institutes of Health Research(No.201610PJT,to HHC)HHC is also supported by a Mid-Career Investigator Award(No.7506)from the Heart and Stroke Foundation of Ontario.How to cite this article:Cruz SA。
文摘Ischemic brain injury causes neuronal death and inflammation.Inflammation activates protein-tyrosine phosphatase 1B(PTP1B).Here,we tested the significance of PTP1B activation in glutamatergic projection neurons on functional recovery in two models of stroke:by photothrombosis,focal ischemic lesions were induced in the sensorimotor cortex(SM stroke)or in the peri-prefrontal cortex(peri-PFC stroke).Elevated PTP1B expression was detected at 4 days and up to 6 weeks after stroke.While ablation of PTP1B in neurons of neuronal knockout(NKO)mice had no effect on the volume or resorption of ischemic lesions,markedly different effects on functional recovery were observed.SM stroke caused severe sensory and motor deficits(adhesive removal test)in wild type and NKO mice at 4 days,but NKO mice showed drastically improved sensory and motor functional recovery at 8 days.In addition,peri-PFC stroke caused anxiety-like behaviors(elevated plus maze and open field tests),and depression-like behaviors(forced swimming and tail suspension tests)in wild type mice 9 and 28 days after stroke,respectively,with minimal effect on sensory and motor function.Peri-PFC stroke-induced affective disorders were associated with fewer active(FosB+)neurons in the PFC and nucleus accumbens but more FosB+neurons in the basolateral amygdala,compared to sham-operated mice.In contrast,mice with neuronal ablation of PTP1B were protected from anxiety-like and depression-like behaviors and showed no change in FosB+neurons after peri-PFC stroke.Taken together,our study identifies neuronal PTP1B as a key component that hinders sensory and motor functional recovery and also contributes to the development of anxiety-like and depression-like behaviors after stroke.Thus,PTP1B may represent a novel therapeutic target to improve stroke recovery.All procedures for animal use were approved by the Animal Care and Use Committee of the University of Ottawa Animal Care and Veterinary Service(protocol 1806)on July 27,2018.
基金supported by the National Basic Research Development Program (973 Program) of China (2013CB329501)a Scientific Project of the Science and Technology Commission of Shanghai Municipality, China (11140900600)+2 种基金the Shanghai Committee of Science and Technology (15ZR1410600)the National Natural Science Foundation of China (31100742)funds from the MIND Research Institute, Irvine, CA, USA
文摘The activity in sensory cortices and the prefrontal cortex （PFC） throughout the delay interval of working memory （WM） tasks reflect two aspects of WM-quality and quantity, respectively. The delay activity in sensory cortices is fine-tuned to sensory information and forms the neural basis of the precision of WM storage, while the delay activity in the PFC appears to represent behavioral goals and filters out irrelevant distractions, forming the neural basis of the quantity of task-relevant information in WM. The PFC and sensory cortices interact through different frequency bands of neuronal oscillation （theta, alpha, and gamma） to fulfill goal-directed behaviors.
文摘BACKGROUND Recent studies suggest that traumatic brain injury(TBI)is a risk factor for subsequent ischemic stroke,even years after the initial insult.The mechanisms of the association remain unclear.The presence of traumatic subarachnoid hemorrhage(t SAH)may mediate the effect of TBI on long-term stroke risk,as it has previously been linked to short-term vasospasm and delayed cerebral ischemia.METHODS Using administrative claims data,we conducted a retrospective cohort study of acute care hospitalizations.Patients discharged with a first-recorded diagnosis of t SAH were followed for a primary diagnosis of stroke.They were matched to patients with TBI but not t SAH.Cox proportional hazards modeling was used to assess the association between t SAH and stroke while adjusting for covariates.RESULTS:We identified 40 908 patients with TBI(20 454 patients with t SAH)who were followed for a mean of 4.3+1.8 years.A total of 531 had an ischemic stroke after discharge.There was no significant difference in stroke risk between those with t SAH(1.79%;95%confidence interval[CI]1.54%-2.08%)versus without t SAH(2.12%;95%CI 1.83%-2.44%).The same pattern was found in adjusted analyses even when the group was stratified by age-group or by proxies of TBI severity.CONCLU-SIONS:Our findings do not support a role of t SAH in mediating the association between TBI and protracted stroke risk.Further study is required to elucidate the mechanisms of long-term increased stroke risk after TBI.
基金This work was supported by Ottawa Hospital Foundation,Scottish Rite Charitable Foundation research grant,NSERC and CIHR project grant(to JW).
文摘Alzheimer’s disease(AD)is a progressive neurodegenerative disorder associated with significant memory decline and cognitive impairment.AD is characterized by two classical neuropathological hal lmarks,namely the amyloid-beta(Aβ)plaques and neurofibril tangles.Currently,there are no disease-modifying treatments available for AD,except for a couple of the US Food and Drug Administration(FDA)-approved drugs to improve cognitive function by blocking N-methyl-D-aspartate receptors or cholinesterase activity(Panza et al.,2019).
基金supported by funding to Edmund R.Hollis II(The Winifred Masterson Burke Foundation)
文摘There are roughly 282,000 individuals living with spinal cord injury in the United States alone（National Spinal Cord Injury Statistical Center,Birmingham,AL,USA）.Spinal cord injury often results in permanent functional impairments with only a limited capacity for spontaneous recovery.For the return of motor function,such as locomotion or hand and arm dexterity,
文摘Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebrovascular conditions(stroke),and neurodevelopmental disorders(autism spectrum disorder).Although they affect millions of individuals around the world,only a limited number of effective treatment options are available today.Since most neurological disorders express mitochondria-related metabolic perturbations,metformin,a biguanide type II antidiabetic drug,has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy metabolism.However,controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological disorders.Given that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging,lifestyle,genetics,and environment,it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological disorders.These molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment,ultimately developing targeted therapy.In this review,we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.
基金provided by the Canadian Institutes of Health Research Canada Graduate Scholarshipsthe Michael Smith Foreign Study Supplement program (Funding number:162728)
文摘Background Although previous studies have examined the effects of exercise training on other International Classification of Functioning,Disability and Health(ICF)component levels in persons with multiple sclerosis(MS),the effects of exercise training on participation remain unclear.The objectives of this review were to:(1)characterize systematically the use of outcome measures that capture participation in exercise training studies;(2)quantify the effect of exercise training on participation in persons with MS.Methods A search of 6 electronic databases(CINAHL,SPORTDiscuss,Embase,MEDLINE,Cochrane Central,and Scopus)was conducted to identify controlled and noncontrolled trials involving exercise training and participation in persons with MS.Search strings were built from Medical Subject Headings and CINAHL headings.ICF linking rules were used to identify participation chapters and categories captured.Meta-analysis was used to quantify the effect of exercise training on participation in randomized controlled trials comparing exercise effects to no intervention/usual care.Results We included 49 articles involving controlled and noncontrolled exercise trials in the systematic review of outcome measures.We captured 16 different outcome measures that captured all 9 participation chapters and identified 89 unique participation categories.Across these 16 outcome measures,mobility was the most commonly represented participation chapter,with 108 items.A subsample of 23 randomized controlled trials was included in the meta-analysis.An overall effect of 0.60(standard error=0.12,95%confidence interval:0.36-0.84,z=4.9,p<0.001)was calculated,indicating a moderate,positive effect of exercise training on participation.Conclusion The current review provides information that can be used to guide the selection of outcome measures that capture participation in studies of exercise training in persons with MS.Exercise training has a positive effect on outcomes that capture participation,providing further evidence for the role of exercise training in promoting and maintaining engagement in everyday life.
基金funding from the National Eye Institute (R01EY022409)the Craig H. Neilsen Foundation (296098)+2 种基金the Wings for Life Foundation (WFL-US-028/14)the New York State Spinal Cord Injury Research Trust Fundthe Burke Foundation
文摘The functional regeneration of damaged axons and severed connections in the mature central nervous sys- tem （CNS） remains a challenging goal of neurological research. Mature CNS neurons are refractory to axon regeneration for two major reasons, one, because the ac- tivity of cell-intrinsic mechanisms that drive axon growth during development is low- and often further suppressed after an injury - and two, because certain molecules that are part of mature extracellular matrix and myelin act as strong inhibitors of axon growth. Genetic removal of growth inhibitory molecules can increase axon sprouting, but is not sufficient to enable long-range axon growth. Since axon growth is robust during early developmental stages, it has long been hypothesized that mature injured neurons may be ＂reprogrammed＂ to the earlier growth state by re-activation of the intracellular growth signaling cascades that drive axon elongation in the developing fetus.
基金supported by grants from the Heart and Stroke Foundation of Canada(G-13-0002596&G-18-0022157,to HHCG-16-00014085,to AFRS)+4 种基金Ontario Mental Health Foundation(to HHC),the Canadian Institutes of Health Research(201610PJT#376403,to HHC201610PJT#376503,to AFRS)the Natural Science and Engineering Research Council of Canada(RGPIN/06212-2014,to HHCRGPIN/2016-04985,to AFRS)supported by a Mid-Career Investigator Award(grant#7506)from the Heart and Stroke Foundation of Ontario.
文摘Glutamate is the main exc i tatory neurotransmitter in the brain and binds to two major classes of receptors,theα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid(AMPA)and the N-methyl-D-aspartate(NMDA)receptors.Unlike AMPA receptors that are immediately activated by glutamate release,NMDA receptors are blocked by magnesium and can only be activated by glutamate after membrane depolarization.Thus,NMDA receptors are only activated after repeated AMPA receptor activation by glutamate.NMDA receptors are,for the most part,calcium-permeable channels.Calcium influx through NMDA receptors modulates synaptic transmission in neurons based on prior history of excitation,and provides a means of scaling the strength of synapses required for Hebbian plasticity.
基金supported by the Burke Foundation and the National Institutes of Health Common Fund,No.DP2 NS106663(to ERH)the New York State Department of Health Spinal Cord Injury Research Board Postdoctoral Fellowship,No.C32633GG(to YL)。
文摘Therapeutic intervention for spinal cord injury is limited,with many approaches relying on strengthening the remaining substrate and driving recovery through rehabilitative training.As compared with learning novel compensatory strategies,rehabilitation focuses on resto ring movements lost to injury.Whether rehabilitation of previously learned movements after spinal cord injury requires the molecular mechanisms of motor learning,or if it engages previously trained motor circuits without requiring novel learning remains an open question.In this study,mice we re randomly assigned to receive intrape ritoneal injection with the pan-nicotinic,non-competitive antagonist mecamylamine and the nicotinicα7 subunit selective antagonist methyllycaconitine citrate salt or vehicle(normal saline)prior to motor learning assays,then randomly reassigned after motor learning for rehabilitation study post-injury.Ce rvical spinal co rd dorsal column lesion was used as a model of in complete injury.Results of this study showed that nicotinic acetylcholine signaling was required for motor learning of the single pellet-reaching task but it was dispensable for the rehabilitation of the same task after injury.Our findings indicate that critical diffe rences exist between the molecular mechanisms supporting compensatory motor learning strategies and the restoration of behavior lost to spinal cord injury.
文摘Gender differences are investigated from the viewpoint of cognitive neuroscience in the domain of spatial ability. Five task types of geometric problems are used for the collection of task-evoked fMRI data. Although there was no gender-difference in task performance, we found gender differences in neural activity. Some of the important gender differences that we found are 1) that there are far more joint neuro-activations among the brain regions, co-activations or reverse-activations, in males than in females, 2) that the two types of joint activations were nearly half and half in females while it was mostly co-activations in males, 3) that males tend to have more co-activations in the left hemisphere than expected while females tend to have more between-hemisphere co-activations than expected, and 4) that the left-right pairs of BA's are more highly associated than average for males while they are far less associated than average for females.
文摘Primate sanctuaries across Africa play a pivotal role in the rescue and rehabilitation of confiscated and rescued wild primates, many of whom have had extensive contact with humans prior to their arrival and throughout the rehabilitation process, heightening the risk of disease transmission. While tuberculosis is not naturally occurring in free-living chimpanzees, it has been extensively observed in captive primates that have been in close proximity to humans or other captive primates infected with Mycobacterium tuberculosis. This case report delves into an outbreak of extra-pulmonary tuberculosis among juvenile chimpanzees within a sanctuary, detailing the associated diagnostic challenges and treatment approaches. The five cases had close contact with a caregiver infected with tuberculosis, subsequently transmitting the infection to other in-contact chimpanzees. Prolonged treatment, employing the human protocol of quadri-therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol), followed by bi-therapy (rifampicin and isoniazid), resulted in complete resolution for all five cases. These cases underscore the critical importance of maintaining high levels of biosecurity, implementing effective quarantine measures, and adhering to strict hygiene practices when working with non-human primates.
