Optimal propagation of neuronal electrical impulses depends on the insulation of axons by myelin,produced in the central nervous system by oligodendrocytes.Myelin is an extension of the oligodendrocyte plasma membrane...Optimal propagation of neuronal electrical impulses depends on the insulation of axons by myelin,produced in the central nervous system by oligodendrocytes.Myelin is an extension of the oligodendrocyte plasma membrane,which wraps around an axon to form a compact multi-layered sheath.Myelin is composed of a substantially higher proportion of lipids compared to other biological membranes and enriched in a small number of specialized proteins.展开更多
Background:Liqoseal (Polyganics,B.V.) is a dural sealant patch for preventing postoperative cerebrospinal fluid (CSF) leakage.It has been extensively tested preclinically and CE (Conformite Européenne) approved f...Background:Liqoseal (Polyganics,B.V.) is a dural sealant patch for preventing postoperative cerebrospinal fluid (CSF) leakage.It has been extensively tested preclinically and CE (Conformite Européenne) approved for human use after a first cranial in-human study.However,the safety of Liqoseal for spinal application is still unknown.The aim of this study was to assess the safety of spinal Liqoseal application compared with cranial application using histology and magnetic resonance imaging characteristics.Methods:Eight female Dutch Landrace pigs underwent laminectomy,durotomy with standard suturing and Liqoseal application.Three control animals underwent the same procedure without sealant application.The histological characteristics and imaging characteristics of animals with similar survival times were compared to data from a previous cranial porcine model.Results:Similar foreign body reactions were observed in spinal and cranial dura.The foreign body reaction consisted of neutrophils and reactive fibroblasts in the first3 days,changing to a chronic granulomatous inflammatory reaction with an increasing number of macrophages and lymphocytes and the formation of a fibroblast layer on the dura by day 7.Mean Liqoseal plus dura thickness reached a maximum of 1.2mm(range 0.7-2.0mm) at day 7.Conclusion:The spinal dural histological reaction to Liqoseal during the first 7days was similar to the cranial dural reaction.Liqoseal did not swell significantly in both application areas over time.Given the current lack of a safe and effective dural sealant for spinal application,we propose that an in-human safety study of Liqoseal is the logical next step.展开更多
Background:Neuroinflammation is an essential event in Parkinson’s disease(PD).Identifying affordable and less invasive biomarkers to make an early diagnosis and monitor therapeutic strategies should be a priority amo...Background:Neuroinflammation is an essential event in Parkinson’s disease(PD).Identifying affordable and less invasive biomarkers to make an early diagnosis and monitor therapeutic strategies should be a priority among researchers.The study’s objective was to measure tear levels of cytokines in subjects with PD and their association with motor features and the presence of dry eye symptoms.Methods:A total of 16 subjects with PD and 16 age-and sex-matched controls were included.Movement Disorders Society-Unified Parkinson’s Disease Rating Scale(MDS-UPDRS),Hoehn and Yahr(HY)stage scale,Montreal Cognitive Assessment(MoCA),tear break-up time(TBUT),blink rate(BR),Dry Eye Questionnaire 5(DEQ-5)were examined,and pro-inflammatory cytokines[interleukin(IL)-1β,IL-6,IL-8,IL-10,IL-12p70 and tumor necrosis factor-alpha(TNF-α)]were quantified in tears using the BD Cytometric Bead Array Human Inflammatory Cytokine Kit.Results:Higher tear TNF-αwere quantified in PD compared to controls(2.94±3.95 vs.0.33±0.49 pg/mL,P=0.008).According to DEQ-5,50.0%(n=8)of PD subjects and 12.5%(n=2)controls had dry eye disease(DED).No differences were found in cytokines concentrations between PD patients with DED compared to those without DED.IL-8 was associated with the HY stage,TBUT,DEQ-5,and a better MoCA score.A higher BR correlated moderately with a lower HY stage(r=−0.645,P=0.007),and DED patients have lower BR in PD(12.14±2.54 vs.9.0±2.06 blinks/minute,P=0.031).Conclusions:PD patients have higher levels of TNF-αin tears than age-and sex-matched HC.IL-8 in tears may be both involved in the severity of the disease and in the development of DED in PD.In addition,our findings suggest that as HY stage increases,indicating a more advanced stage,BR decreases,indicating greater motor impairment.Conversely,the presence of DED is associated with higher levels of bradykinesia in PD patients,suggesting a potential relationship between DED and motor impairment severity.展开更多
Mature oligodendrocytes form myelin sheaths that are crucial for the insulation of axons and efficient signal transmission in the central nervous system.Recent evidence has challenged the classical view of the functio...Mature oligodendrocytes form myelin sheaths that are crucial for the insulation of axons and efficient signal transmission in the central nervous system.Recent evidence has challenged the classical view of the functionally static mature oligodendrocyte and revealed a gamut of dynamic functions such as the ability to modulate neuronal circuitry and provide metabolic support to axons.Despite the recognition of potential heterogeneity in mature oligodendrocyte function,a comprehensive summary of mature oligodendrocyte diversity is lacking.We delve into early 20th-century studies by Robertson and Río-Hortega that laid the foundation for the modern identification of regional and morphological heterogeneity in mature oligodendrocytes.Indeed,recent morphologic and functional studies call into question the long-assumed homogeneity of mature oligodendrocyte function through the identification of distinct subtypes with varying myelination preferences.Furthermore,modern molecular investigations,employing techniques such as single cell/nucleus RNA sequencing,consistently unveil at least six mature oligodendrocyte subpopulations in the human central nervous system that are highly transcriptomically diverse and vary with central nervous system region.Age and disease related mature oligodendrocyte variation denotes the impact of pathological conditions such as multiple sclerosis,Alzheimer's disease,and psychiatric disorders.Nevertheless,caution is warranted when subclassifying mature oligodendrocytes because of the simplification needed to make conclusions about cell identity from temporally confined investigations.Future studies leveraging advanced techniques like spatial transcriptomics and single-cell proteomics promise a more nuanced understanding of mature oligodendrocyte heterogeneity.Such research avenues that precisely evaluate mature oligodendrocyte heterogeneity with care to understand the mitigating influence of species,sex,central nervous system region,age,and disease,hold promise for the development of therapeutic interventions targeting varied central nervous system pathology.展开更多
Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress.Likewise,microRNAs are inv...Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress.Likewise,microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis,especially in multifactorial diseases such as Alzheimer’s disease.Therefore,our aim has been to provide partial insights into the interconnection between G9a,microRNAs,oxidative stress,and neuroinflammation.To better understand the biology of G9a,we compared the global microRNA expression between senescence-accelerated mouse-prone 8(SAMP8)control mice and SAMP8 treated with G9a inhibitor UNC0642.We found a downregulation of miR-128 after a G9a inhibition treatment,which interestingly binds to the 3′untranslated region(3′-UTR)of peroxisome-proliferator activator receptor γ(PPARG)mRNA.Accordingly,Pparg gene expression levels were higher in the SAMP8 group treated with G9a inhibitor than in the SAMP8 control group.We also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a inhibitor.To confirm these antioxidant effects,we treated primary neuron cell cultures with hydrogen peroxide as an oxidative insult.In this setting,treatment with G9a inhibitor increases both cell survival and antioxidant enzymes.Moreover,up-regulation of PPARγby G9a inhibitor could also increase the expression of genes involved in DNA damage responses and apoptosis.In addition,we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers expression.Finally,PPARγ/GADD45αpotentially contributes to enhancing synaptic plasticity and neurogenesis after G9a inhibition.Altogether,we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due,at least in part,by the modulation of PPARγ-dependent pathways by miR-128.展开更多
Nerve scarring after peripheral nerve injury can severely hamper nerve regeneration and functional recovery.Further,the anti-inflammatory cytokine,interleukin-10,can inhibit nerve scar formation.Saikosaponin a(SSa) ...Nerve scarring after peripheral nerve injury can severely hamper nerve regeneration and functional recovery.Further,the anti-inflammatory cytokine,interleukin-10,can inhibit nerve scar formation.Saikosaponin a(SSa) is a monomer molecule extracted from the Chinese medicine,Bupleurum.SSa can exert anti-inflammatory effects in spinal cord injury and traumatic brain injury.However,it has not been shown whether SSa can play a role in peripheral nerve injury.In this study,rats were randomly assigned to three groups.In the sham group,the left sciatic nerve was directly sutured after exposure.In the sciatic nerve injury(SNI) + SSa and SNI groups,the left sciatic nerve was sutured and continuously injected daily with SSa(10 mg/kg) or an equivalent volume of saline for 7 days.Enzyme linked immunosorbent assay results demonstrated that at 7 days after injury,interleukin-10 level was considerably higher in the SNI + SSa group than in the SNI group.Masson staining and western blot assay demonstrated that at 8 weeks after injury,type I and III collagen content was lower and nerve scar formation was visibly less in the SNI + SSa group compared with the SNI group.Simultaneously,sciatic functional index and nerve conduction velocity were improved in the SNI + SSa group compared with the SNI group.These results confirm that SSa can increase the expression of the anti-inflammatory factor,interleukin-10,and reduce nerve scar formation to promote functional recovery of injured sciatic nerve.展开更多
All synthetic and natural estrogen receptor agonists, in- cluding the most potent physiological molecule estrogen or estradiol (E2), work typically via activation of nuclear estrogen receptor alpha (ERα) and estr...All synthetic and natural estrogen receptor agonists, in- cluding the most potent physiological molecule estrogen or estradiol (E2), work typically via activation of nuclear estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). Both ERα and ERβ modulate the expression of a variety of genes in the cells. Neurons and glial cells express ERa and ERβ. Many studies so far from our and other laboratories have firmly established the mode of actions that ERα and ERβ agonists are very promising anti-inflammatory and neuroprotective agents in the treatment of neurodegenera- rive diseases and injuries including spinal cord injury (SCI) (Chakrabarti et al., 2014a).展开更多
Tandem internal carotid and middle cerebral artery occlusion after carotid dissection predicts poor outcome after systemic thrombolysis. Current treatments include the use of endovascular carotid stenting, which carri...Tandem internal carotid and middle cerebral artery occlusion after carotid dissection predicts poor outcome after systemic thrombolysis. Current treatments include the use of endovascular carotid stenting, which carries with it a high risk of propagating further embolic events and worsening the dissection. New strategies for avoiding the aforementioned side-effects include recanalization using cross-collaterals for delivery of intra-lesional tissue plasminogen activator(t PA). We present two cases that provide further support for this novel approach. Both patients presented with a National Institute of Health Stroke Scale of 20, received intra-arterial t PA via cross-collateralization, and made full recoveries without the need for stenting.展开更多
Oligodendrocytes are the myelinating cells of the central nervous system(CNS)that ensheath nearby axons to support action potential propagation and axon metabolism.Myelination involves the rapid production of lipid-ri...Oligodendrocytes are the myelinating cells of the central nervous system(CNS)that ensheath nearby axons to support action potential propagation and axon metabolism.Myelination involves the rapid production of lipid-rich membrane,compaction of the multilamellar myelin sheath,and the resultant restriction of cytoplasm to non-compact compartments.During myelination,septate-like junctions form between the axon and lateral cytoplasmic endings of the myelin sheath at a specialized domain called the paranode(Figure 1A).展开更多
Inflammation and coagulation are tightly interconnected in the pathophysiology of neuronal diseases.Thrombin,a pro-coagulant serine protease is associated with neurodegeneration and its indirect inhibitor,activated pr...Inflammation and coagulation are tightly interconnected in the pathophysiology of neuronal diseases.Thrombin,a pro-coagulant serine protease is associated with neurodegeneration and its indirect inhibitor,activated protein C(aPC),is considered neuroprotective.While levels of thrombin and aPC activity are readily measured in the blood,similar assays in the cerebrospinal fluid(CSF)have not been described.The aim of this study was to establish a specific and sensitive enzymatic assay to measure both thrombin and aPC activity in the CSF.CSF was collected from 14 patients with suspected normal pressure hydrocephalus served as a control group,while seven patients with central nervous system infections served as an acute neuro-inflammatory study group and one sample of CSF following traumatic lumbar puncture served as a positive control.Thrombin and aPC activities were measured by fluorescence released by specific proteolytic cleavage in the presence of endopeptidase and amino-peptidase inhibitors to ensure specificity.Specificity of the method was verified by thrombin and serine-protease inhibitors N-alpha-((2-naphthylsulfinyl)glycyl)-DL-p-amidinophenylalanylpiperidine and phenylmethanesulfonyl fluoride.Inhibition of thrombin activity by CSF samples and levels of specific thrombin inhibitors were also assessed.Thrombin and aPC activities were reliably measured and were significantly higher in the CSF of patients with central nervous system infections compared to normal pressure hydrocephalus controls,suggesting the involvement of these factors in neuro-inflammation.CSF thrombin activity levels in the presence of known thrombin concentration were high in patients with central nervous system infections,and low in normal pressure hydrocephalus patients.Quantification of endogenous thrombin inhibitors protease nexin 1,amyloid precursor protein and anti-thrombin III in CSF by western blot indicated a significant elevation of amyloid precursor protein in infectious CSF.In conclusion,this study describes a novel and sensitive assay aimed at the detection of thrombin and aPC activity in CSF.This method may be useful for measuring these factors that reflect degenerative and protective influences of coagulation on neurological disorders.The study procedure was approved by the Ethics Committee of the Chaim Sheba Medical Center(approval No.4245-17-SMC)on October 18,2018.展开更多
Severe acute respiratory syndrome coronavirus(SARS-CoV)and SARS-CoV-2 are thought to transmit to humans via wild mammals,especially bats.However,evidence for direct bat-to-human transmission is lacking.Involvement of ...Severe acute respiratory syndrome coronavirus(SARS-CoV)and SARS-CoV-2 are thought to transmit to humans via wild mammals,especially bats.However,evidence for direct bat-to-human transmission is lacking.Involvement of intermediate hosts is considered a reason for SARS-CoV-2 transmission to humans and emergence of outbreak.Large biodiversity is found in tropical territories,such as Brazil.On the similar line,this study aimed to predict potential coronavirus hosts among Brazilian wild mammals based on angiotensin-converting enzyme 2(ACE2)sequences using evolutionary bioinformatics.Cougar,maned wolf,and bush dogs were predicted as potential hosts for coronavirus.These indigenous carnivores are philogenetically closer to the known SARS-CoV/SARS-CoV-2 hosts and presented low ACE2 divergence.A new coronavirus transmission chain was developed in which white-tailed deer,a susceptible SARS-CoV-2 host,have the central position.Cougar play an important role because of its low divergent ACE2 level in deer and humans.The discovery of these potential coronavirus hosts will be useful for epidemiological surveillance and discovery of interventions that can contribute to break the transmission chain.展开更多
Background:Liqoseal consists of a watertight layer of poly(ester)ether urethane and an adhesive layer containing polyethylene glycol-N-hydroxysuccinimide(PEG-NHS).It is designed to prevent cerebrospinal fluid(CSF)leak...Background:Liqoseal consists of a watertight layer of poly(ester)ether urethane and an adhesive layer containing polyethylene glycol-N-hydroxysuccinimide(PEG-NHS).It is designed to prevent cerebrospinal fluid(CSF)leakage after intradural surgery.This study assessed the safety and biodegradability of Liqoseal in a porcine craniotomy model.Methods:In 32 pigs a craniotomy plus durotomy was performed.In 15 pigs Liqoseal was implanted,in 11 control pigs no sealant was implanted and in 6 control pigs a control dural sealant(Duraseal or Tachosil)was implanted.The safety of Liqoseal was evaluated by clinical,MRI and histological assessment.The degradation of Liqoseal was histologically estimated.Results:Liqoseal,2 mm thick before application,did not swell and significantly was at maximum mean thickness of 2.14(±0.37)mm at one month.The foreign body reaction induced by Liqoseal,Duraseal and Tachosil were comparable.Liqoseal showed no adherence to the arachnoid layer and was completely resorbed between 6 and 12 months postoperatively.In one animal with Liqoseal,an epidural fluid collection containing CSF could not be excluded.Conclusion:Liqoseal seems to be safe for intracranial use and is biodegradable.The safety and performance in humans needs to be further assessed in clinical trials.展开更多
BACKGROUND Preterm birth(PTB)is one of the main causes of neonatal deaths globally,with approximately 15million infants are born preterm.Women from the Black,Asian,and Minority Ethnic(BAME)populations maybe at higher ...BACKGROUND Preterm birth(PTB)is one of the main causes of neonatal deaths globally,with approximately 15million infants are born preterm.Women from the Black,Asian,and Minority Ethnic(BAME)populations maybe at higher risk of PTB,therefore,the mental health impact on mothers experiencing a PTB is particularly important,within the BAME populations.AIM To determine the prevalence of mental health conditions among BAME women with PTB as well as the methods of mental health assessments used to characterise the mental health outcomes.METHODS A systematic methodology was developed and published as a protocol in PROSPERO(CRD420-20210863).Multiple databases were used to extract relevant data.I2 and Egger's tests were used to detect the heterogeneity and publication bias.A trim and fill method was used to demonstrate the influence of publication bias and the credibility of conclusions.RESULTS Thirty-nine studies met the eligibility criteria from a possible 3526.The prevalence rates of depression among PTB-BAME mothers were significantly higher than full-term mothers with a standardized mean difference of 1.5 and a 95%confidence interval(CI)29%-74%.The subgroup analysis indicated depressive symptoms to be time sensitive.Women within the very PTB category demonstrated a significantly higher prevalence of depression than those categorised as non-very PTB.The prevalence rates of anxiety and stress among PTB-BAME mothers were significantly higher than in full-term mothers(odds ratio of 88%and 60%with a CI of 42%-149%and 24%-106%,respectively).CONCLUSION BAME women with PTB suffer with mental health conditions.Many studies did not report on specific mental health outcomes for BAME populations.Therefore,the impact of PTB is not accurately represented in this population,and thus could negatively influence the quality of maternity services they receive.展开更多
Introduction: Acute tubular necrosis (ATN) is the most prevalent cause of acute renal failure (ARF). Mesenchymal stem cell transplantation has been studied as a potential treatment for renal dysfunction due to ATN. In...Introduction: Acute tubular necrosis (ATN) is the most prevalent cause of acute renal failure (ARF). Mesenchymal stem cell transplantation has been studied as a potential treatment for renal dysfunction due to ATN. Inducible nitric oxide synthase (iNOS), bone morphogenetic protein-7 (BMP-7) and B-cell lymphoma 2 (Bcl-2) are surrogate markers of renal tubular epithelial regeneration and subsequent recovery of renal function following ATN. Methods: Serum creatinine (Scr) and blood urea nitrogen (BUN), as well as expression of iNOS, BMP-7 and Bcl-2 in gentamycin-induced ATN rat kidneys was investigated after human umbilical cord-derived mesenchymal stem cell (HUC-MSC) transplantation. Immunohistochemical staining was performed in 3 groups of rats: gentamycin-induced ATN treated with HUC-MSC, gentamycin-induced ATN without HUC-MSC, and untreated rats not receiving any treatments. Results: HUC-MSC transplantation led to a reduction in Scr and BUN in the kidneys of rats with gentamycin-induced ATN. Expression of iNOS in the HUC-MSC treated group occurred later and the expression levels were much lower during gentamycin-induced ATN compared to rats with ATN that were not treated with HUC-MSC. The expression of BMP-7 and Bcl-2 in the MSC-transplanted group was significantly increased compared to both control groups of rats with injured and healthy renal tubules. Conclusions: HUC-MSCs induce renal protection in a rat model of gentamycin-induced ATN, which is associated with reduced iNOS expression and up-regulation of Bcl-2 and BMP-7.展开更多
Purpose: Rapid eye movement sleep behavior disorder (RBD) and impulse control disorders (ICDs) are common in subjects with Parkinson’s disease. The association between these two conditions has been contradictory. The...Purpose: Rapid eye movement sleep behavior disorder (RBD) and impulse control disorders (ICDs) are common in subjects with Parkinson’s disease. The association between these two conditions has been contradictory. The aim of this study is to analyze the association between these two non-motor symptoms. Methods: Consecutive subjects with Parkinson’s disease attending the Movement Disorders Outpatient Clinic were included. The presence of ICDs was assessed using the Questionnaire for Impulse Control Disorders Rating Scale. RBD was diagnosed by an overnight, single night polysomnography. Results: Fifty-five consecutive subjects with Parkinson’s disease were included. The prevalence of ICDs and related behaviors was 23.6% (ICD in 14.5% and related behaviors in 9.1%). RBD was diagnosed in 47.2% of the patients. No differences were found in the frequency of ICDs and related behaviors when comparing subjects with and without RBD (23% versus 24.1%, p = 0.926, respectively). Conclusion: No association between the presence of RBD and the frequency of ICDs in subjects with Parkinson’s disease was found.展开更多
Background:The loss of cell polarity plays a key part in retinal dystrophies such as retinitis pigmentosa(RP)and Leber congenital amaurosis(LCA),resulting in photoreceptor(PR)degeneration and vision loss.Despite not k...Background:The loss of cell polarity plays a key part in retinal dystrophies such as retinitis pigmentosa(RP)and Leber congenital amaurosis(LCA),resulting in photoreceptor(PR)degeneration and vision loss.Despite not knowing the direct genotype-to-phenotype correlation,many disease-causing mutations in the polarity determinant Crumbs(Crb1),have been identified.Indeed,the loss of Crb1 in mice was shown to cause PR death,due to the loss of adhesions between PR and Müller cells at the apical surface of the retina.Unfortunately,although the role of Crb1 in neuron polarity and survival is well established,little is known about how its intracellular trafficking is regulated.With future treatments for retinal degenerative diseases in mind,the goal of this project is to understand the mechanism by which Crb1 is regulated and how it maintains retinal integrity.Previous work in our laboratory showed that Numb,an endocytic adaptor protein,is an important regulator of protein trafficking in retinal cells.We therefore hypothesized that Numb might function as regulator of Crb1 in Müller glia.Methods:To study Numb function in Müller cells,we generated a conditional knockout(cKO)mouse line to inactivate Numb specifically in Müller cells by crossing a Glast-CreERT2 mouse line with a Numb-floxed line.At 30 days,mice were administered tamoxifen to trigger inactivation of Numb and retinas were then collected at time points varying from 2 weeks to 17 months for analysis.Firstly,we studied the retinal morphology and outer limiting membrane integrity by histology and immunohistochemistry.Using electron microscopy(EM),adhesions between Müller glia and photoreceptors were analysed and retinal function was assayed in live mice by electroretinography(ERG).To detect protein expression levels,protein extracts were prepared from cKO and control retinas for immunoblotting.To test for the presence of a biochemical interaction,Hek-293 cells were transfected with Numb and Crb1 vectors,and protein extracts were processed for co-immunoprecipitation.Results:When Numb was deleted in Müller cells,we observed a similar retinal phenotype than what was reported in the Crb1 KO.In 3-month-old animals,we found a disruption of the outer limiting membrane and an ingression of photoreceptor cells in the inner layers of the retina.In older animals(17 months),we observed a clear thinning of the photoreceptor layer and reduced ERG responses.Immunoblotting of retinal lysates revealed that Numb cKO retinas had significantly lower expression of Crb1,suggesting that Numb function in Müller cells is critical to maintain Crb1 levels and thereby outer limiting membrane integrity.Interestingly,we found that Numb can interact with Crb1 both in vitro and in vivo,suggesting that Numb might function as an adaptor protein regulating Crb1 trafficking.Conclusions:Based on these results,we suggest that,in the absence of Numb,Crb1 cannot be trafficked to the apical membrane of Müller cells,and is instead degraded.This ruptures the adhesion between Müller and photoreceptor cells,leading to photoreceptor degeneration.We anticipate that understanding the mechanisms by which Crb1 maintains the structural integrity of the retina will lead to new possibilities for target-based therapies against retinal dystrophies.展开更多
Background and Purpose: Hypertension has serious effects on cerebral blood vessels. Oxidative stress seems to be implicated in blood pressure elevation, through increased reactive oxygen species and/or decreased antio...Background and Purpose: Hypertension has serious effects on cerebral blood vessels. Oxidative stress seems to be implicated in blood pressure elevation, through increased reactive oxygen species and/or decreased antioxidant capacity. Recently blood markers indicating damage to the central nervous system were reported to be increased in hypertensive patients. However, it is unknown whether antioxidant capacity is related to these changes. This study was designed to explore if the concentration of blood markers for nervous tissue damage was associated to antioxidant capacity in hypertensive patients. Methods: Twenty hypertensive patients and 23 healthy controls were studied. They were paired by age, sex, ethnicity, or risk factors. Serum neuron specific enolase (NSE) and S100 calcium binding protein B (S100B) were measured as nervous tissue damage markers, as well as the activity of antioxidant enzymes (catalase, glutathione peroxidase, glutathione reductase and gamma-glutamyltransferase). Results: Serum neuronal specific enolase (NSE) and S100 calcium binding protein B (S100B) concentrations determined by immunoassay were significantly increased in patients vs. controls. The activities of antioxidant enzymes measured by spectrophotometry showed that plasmatic catalase and erythrocytic glutathione peroxidase were significantly increased in patients, but erythocytic catalase was decreased. Gamma-glutamyltransferase activity was significantly correlated with S100B in hypertensive patients, while erythrocytic catalase activity was decreased in subjects with higher NSE levels. Conclusion: This preliminary investigation suggested that antioxidant status might be modulated through changes in antioxidant enzymatic activity in hypertensive patients. The association of some of these changes with peripheral markers of damage to the central nervous system could indicate that the increased levels of these proteins in hypertension are partly related to oxidative stress.展开更多
Autism and Asperger’s syndrome belong to a family of neuro-developmental disorders called Pervasive Development Disorders. The aims of this study were to 1) quantify the overall functional performance and need for ca...Autism and Asperger’s syndrome belong to a family of neuro-developmental disorders called Pervasive Development Disorders. The aims of this study were to 1) quantify the overall functional performance and need for caregiver assistance in autism (A) and Asperger’s syndrome (AS), 2) compare the findings between groups and to normative data from Brazilian children. Methods: A cross-sectional study was carried out involving 52 children between three and eight years of age diagnosed with either A (n = 26) or SA (n = 26). The Brazilian version of the Pediatric Evaluation of Disability Inventory was administered. Results: The children with A and AS achieved significantly lower scores than that expected for normality. The children with AS had a significantly better social function than that the children with A had. However, those with A achieved significantly better scores than those with AS on activities related to self-care and mobility, requiring less assistance. Conclusion: While patients with AS are better at social interaction than typical autistic children, they exhibit greater deficits with regard to basic tasks, such as self-care and mobility, requiring greater assistance than children with A.展开更多
Neuromyelitis optica(NMO)refers to an antibody mediated,inflammatory disorder of the central nervous system(CNS)characterized by recurrent or monophasic attacks of optic neuritis and myelitis.Most patients with NMO po...Neuromyelitis optica(NMO)refers to an antibody mediated,inflammatory disorder of the central nervous system(CNS)characterized by recurrent or monophasic attacks of optic neuritis and myelitis.Most patients with NMO possess a specific serum immunoglobin,NMO-IgG,which can serve as a biomarker for NMO.The autoantibodies target aquaporin-4(AQP4),the main water channel protein found in the CNS including the brain,spinal cord,and optic nerve.The remaining 10-25%of patients are seronegative for NMO-IgG despite meeting the diagnostic criteria for NMO.Recent studies have shown that a subset of these patients is seropositive for antibodies against myelin oligodendrocyte glycoprotein(MOG).This paper will provide an overview of the current English scientific literature published regarding the history,epidemiology,AQP4 biomarker,MOG biomarker,diagnosis,clinical features,related diseases in NMO spectrum disorder(NMOSD),and treatments of NMO.展开更多
基金supported by on operating grant(#1038154) from the Multiple Sclerosis Society of Canada (to TEK)a Multiple Sclerosis Society of Canada Post-Doctoral Fellowship (to JDMG)。
文摘Optimal propagation of neuronal electrical impulses depends on the insulation of axons by myelin,produced in the central nervous system by oligodendrocytes.Myelin is an extension of the oligodendrocyte plasma membrane,which wraps around an axon to form a compact multi-layered sheath.Myelin is composed of a substantially higher proportion of lipids compared to other biological membranes and enriched in a small number of specialized proteins.
文摘Background:Liqoseal (Polyganics,B.V.) is a dural sealant patch for preventing postoperative cerebrospinal fluid (CSF) leakage.It has been extensively tested preclinically and CE (Conformite Européenne) approved for human use after a first cranial in-human study.However,the safety of Liqoseal for spinal application is still unknown.The aim of this study was to assess the safety of spinal Liqoseal application compared with cranial application using histology and magnetic resonance imaging characteristics.Methods:Eight female Dutch Landrace pigs underwent laminectomy,durotomy with standard suturing and Liqoseal application.Three control animals underwent the same procedure without sealant application.The histological characteristics and imaging characteristics of animals with similar survival times were compared to data from a previous cranial porcine model.Results:Similar foreign body reactions were observed in spinal and cranial dura.The foreign body reaction consisted of neutrophils and reactive fibroblasts in the first3 days,changing to a chronic granulomatous inflammatory reaction with an increasing number of macrophages and lymphocytes and the formation of a fibroblast layer on the dura by day 7.Mean Liqoseal plus dura thickness reached a maximum of 1.2mm(range 0.7-2.0mm) at day 7.Conclusion:The spinal dural histological reaction to Liqoseal during the first 7days was similar to the cranial dural reaction.Liqoseal did not swell significantly in both application areas over time.Given the current lack of a safe and effective dural sealant for spinal application,we propose that an in-human safety study of Liqoseal is the logical next step.
基金supported by Hospital Fundacion Nuestra Senora de la Luz,Private Assistance Institution.
文摘Background:Neuroinflammation is an essential event in Parkinson’s disease(PD).Identifying affordable and less invasive biomarkers to make an early diagnosis and monitor therapeutic strategies should be a priority among researchers.The study’s objective was to measure tear levels of cytokines in subjects with PD and their association with motor features and the presence of dry eye symptoms.Methods:A total of 16 subjects with PD and 16 age-and sex-matched controls were included.Movement Disorders Society-Unified Parkinson’s Disease Rating Scale(MDS-UPDRS),Hoehn and Yahr(HY)stage scale,Montreal Cognitive Assessment(MoCA),tear break-up time(TBUT),blink rate(BR),Dry Eye Questionnaire 5(DEQ-5)were examined,and pro-inflammatory cytokines[interleukin(IL)-1β,IL-6,IL-8,IL-10,IL-12p70 and tumor necrosis factor-alpha(TNF-α)]were quantified in tears using the BD Cytometric Bead Array Human Inflammatory Cytokine Kit.Results:Higher tear TNF-αwere quantified in PD compared to controls(2.94±3.95 vs.0.33±0.49 pg/mL,P=0.008).According to DEQ-5,50.0%(n=8)of PD subjects and 12.5%(n=2)controls had dry eye disease(DED).No differences were found in cytokines concentrations between PD patients with DED compared to those without DED.IL-8 was associated with the HY stage,TBUT,DEQ-5,and a better MoCA score.A higher BR correlated moderately with a lower HY stage(r=−0.645,P=0.007),and DED patients have lower BR in PD(12.14±2.54 vs.9.0±2.06 blinks/minute,P=0.031).Conclusions:PD patients have higher levels of TNF-αin tears than age-and sex-matched HC.IL-8 in tears may be both involved in the severity of the disease and in the development of DED in PD.In addition,our findings suggest that as HY stage increases,indicating a more advanced stage,BR decreases,indicating greater motor impairment.Conversely,the presence of DED is associated with higher levels of bradykinesia in PD patients,suggesting a potential relationship between DED and motor impairment severity.
基金supported by a grant from the Progressive MS Alliance(BRAVE in MS)Le Grand Portage Fund。
文摘Mature oligodendrocytes form myelin sheaths that are crucial for the insulation of axons and efficient signal transmission in the central nervous system.Recent evidence has challenged the classical view of the functionally static mature oligodendrocyte and revealed a gamut of dynamic functions such as the ability to modulate neuronal circuitry and provide metabolic support to axons.Despite the recognition of potential heterogeneity in mature oligodendrocyte function,a comprehensive summary of mature oligodendrocyte diversity is lacking.We delve into early 20th-century studies by Robertson and Río-Hortega that laid the foundation for the modern identification of regional and morphological heterogeneity in mature oligodendrocytes.Indeed,recent morphologic and functional studies call into question the long-assumed homogeneity of mature oligodendrocyte function through the identification of distinct subtypes with varying myelination preferences.Furthermore,modern molecular investigations,employing techniques such as single cell/nucleus RNA sequencing,consistently unveil at least six mature oligodendrocyte subpopulations in the human central nervous system that are highly transcriptomically diverse and vary with central nervous system region.Age and disease related mature oligodendrocyte variation denotes the impact of pathological conditions such as multiple sclerosis,Alzheimer's disease,and psychiatric disorders.Nevertheless,caution is warranted when subclassifying mature oligodendrocytes because of the simplification needed to make conclusions about cell identity from temporally confined investigations.Future studies leveraging advanced techniques like spatial transcriptomics and single-cell proteomics promise a more nuanced understanding of mature oligodendrocyte heterogeneity.Such research avenues that precisely evaluate mature oligodendrocyte heterogeneity with care to understand the mitigating influence of species,sex,central nervous system region,age,and disease,hold promise for the development of therapeutic interventions targeting varied central nervous system pathology.
基金supported by the Ministerio de Economía,Industria y Competitividad(Agencia Estatal de Investigación,AEI,to CGF and MP)Fondo Europeo de Desarrollo Regional(MINECO-FEDER)(PID2022-139016OA-I00,PDC2022-133441-I00,to CGF and MP),Generalitat de Catalunya(2021 SGR 00357+3 种基金to CGF and MP)co-financed by Secretaria d’Universitats i Recerca del Departament d’Empresai Coneixement de la Generalitat de Catalunya 2021(Llavor 00086,to CGF)the recipient of an Alzheimer’s Association Research Fellowship(AARF-21-848511)the Agència de Gestiód’Ajuts Universitaris i de Recerca(AGAUR)for her FI-SDUR fellowship(2021FISDU 00182).
文摘Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress.Likewise,microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis,especially in multifactorial diseases such as Alzheimer’s disease.Therefore,our aim has been to provide partial insights into the interconnection between G9a,microRNAs,oxidative stress,and neuroinflammation.To better understand the biology of G9a,we compared the global microRNA expression between senescence-accelerated mouse-prone 8(SAMP8)control mice and SAMP8 treated with G9a inhibitor UNC0642.We found a downregulation of miR-128 after a G9a inhibition treatment,which interestingly binds to the 3′untranslated region(3′-UTR)of peroxisome-proliferator activator receptor γ(PPARG)mRNA.Accordingly,Pparg gene expression levels were higher in the SAMP8 group treated with G9a inhibitor than in the SAMP8 control group.We also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a inhibitor.To confirm these antioxidant effects,we treated primary neuron cell cultures with hydrogen peroxide as an oxidative insult.In this setting,treatment with G9a inhibitor increases both cell survival and antioxidant enzymes.Moreover,up-regulation of PPARγby G9a inhibitor could also increase the expression of genes involved in DNA damage responses and apoptosis.In addition,we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers expression.Finally,PPARγ/GADD45αpotentially contributes to enhancing synaptic plasticity and neurogenesis after G9a inhibition.Altogether,we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due,at least in part,by the modulation of PPARγ-dependent pathways by miR-128.
基金financially supported by the National Natural Science Foundation of China,No.11672332,11102235,8167050417the National Key Research and Development Plan of China,No.2016YFC1101500+1 种基金the Key Science and Technology Support Foundation of Tianjin City of China,No.17YFZCSY00620the Natural Science Foundation of Tianjin City of China,No.15JCYBJC28600,17JCZDJC35400
文摘Nerve scarring after peripheral nerve injury can severely hamper nerve regeneration and functional recovery.Further,the anti-inflammatory cytokine,interleukin-10,can inhibit nerve scar formation.Saikosaponin a(SSa) is a monomer molecule extracted from the Chinese medicine,Bupleurum.SSa can exert anti-inflammatory effects in spinal cord injury and traumatic brain injury.However,it has not been shown whether SSa can play a role in peripheral nerve injury.In this study,rats were randomly assigned to three groups.In the sham group,the left sciatic nerve was directly sutured after exposure.In the sciatic nerve injury(SNI) + SSa and SNI groups,the left sciatic nerve was sutured and continuously injected daily with SSa(10 mg/kg) or an equivalent volume of saline for 7 days.Enzyme linked immunosorbent assay results demonstrated that at 7 days after injury,interleukin-10 level was considerably higher in the SNI + SSa group than in the SNI group.Masson staining and western blot assay demonstrated that at 8 weeks after injury,type I and III collagen content was lower and nerve scar formation was visibly less in the SNI + SSa group compared with the SNI group.Simultaneously,sciatic functional index and nerve conduction velocity were improved in the SNI + SSa group compared with the SNI group.These results confirm that SSa can increase the expression of the anti-inflammatory factor,interleukin-10,and reduce nerve scar formation to promote functional recovery of injured sciatic nerve.
基金supported in part by the grants from the South Carolina Spinal Cord Injury Research Fund(SC SCIRF-2015-I-01,Columbia,SC,USA)the United Soybean Board(USB,Chesterfield,MO,USA)to SKR
文摘All synthetic and natural estrogen receptor agonists, in- cluding the most potent physiological molecule estrogen or estradiol (E2), work typically via activation of nuclear estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). Both ERα and ERβ modulate the expression of a variety of genes in the cells. Neurons and glial cells express ERa and ERβ. Many studies so far from our and other laboratories have firmly established the mode of actions that ERα and ERβ agonists are very promising anti-inflammatory and neuroprotective agents in the treatment of neurodegenera- rive diseases and injuries including spinal cord injury (SCI) (Chakrabarti et al., 2014a).
文摘Tandem internal carotid and middle cerebral artery occlusion after carotid dissection predicts poor outcome after systemic thrombolysis. Current treatments include the use of endovascular carotid stenting, which carries with it a high risk of propagating further embolic events and worsening the dissection. New strategies for avoiding the aforementioned side-effects include recanalization using cross-collaterals for delivery of intra-lesional tissue plasminogen activator(t PA). We present two cases that provide further support for this novel approach. Both patients presented with a National Institute of Health Stroke Scale of 20, received intra-arterial t PA via cross-collateralization, and made full recoveries without the need for stenting.
基金This work was supported by grants from the Multiple Sclerosis Society of Canada(No.3009 to TEK and No.2407 to DSN).
文摘Oligodendrocytes are the myelinating cells of the central nervous system(CNS)that ensheath nearby axons to support action potential propagation and axon metabolism.Myelination involves the rapid production of lipid-rich membrane,compaction of the multilamellar myelin sheath,and the resultant restriction of cytoplasm to non-compact compartments.During myelination,septate-like junctions form between the axon and lateral cytoplasmic endings of the myelin sheath at a specialized domain called the paranode(Figure 1A).
文摘Inflammation and coagulation are tightly interconnected in the pathophysiology of neuronal diseases.Thrombin,a pro-coagulant serine protease is associated with neurodegeneration and its indirect inhibitor,activated protein C(aPC),is considered neuroprotective.While levels of thrombin and aPC activity are readily measured in the blood,similar assays in the cerebrospinal fluid(CSF)have not been described.The aim of this study was to establish a specific and sensitive enzymatic assay to measure both thrombin and aPC activity in the CSF.CSF was collected from 14 patients with suspected normal pressure hydrocephalus served as a control group,while seven patients with central nervous system infections served as an acute neuro-inflammatory study group and one sample of CSF following traumatic lumbar puncture served as a positive control.Thrombin and aPC activities were measured by fluorescence released by specific proteolytic cleavage in the presence of endopeptidase and amino-peptidase inhibitors to ensure specificity.Specificity of the method was verified by thrombin and serine-protease inhibitors N-alpha-((2-naphthylsulfinyl)glycyl)-DL-p-amidinophenylalanylpiperidine and phenylmethanesulfonyl fluoride.Inhibition of thrombin activity by CSF samples and levels of specific thrombin inhibitors were also assessed.Thrombin and aPC activities were reliably measured and were significantly higher in the CSF of patients with central nervous system infections compared to normal pressure hydrocephalus controls,suggesting the involvement of these factors in neuro-inflammation.CSF thrombin activity levels in the presence of known thrombin concentration were high in patients with central nervous system infections,and low in normal pressure hydrocephalus patients.Quantification of endogenous thrombin inhibitors protease nexin 1,amyloid precursor protein and anti-thrombin III in CSF by western blot indicated a significant elevation of amyloid precursor protein in infectious CSF.In conclusion,this study describes a novel and sensitive assay aimed at the detection of thrombin and aPC activity in CSF.This method may be useful for measuring these factors that reflect degenerative and protective influences of coagulation on neurological disorders.The study procedure was approved by the Ethics Committee of the Chaim Sheba Medical Center(approval No.4245-17-SMC)on October 18,2018.
文摘Severe acute respiratory syndrome coronavirus(SARS-CoV)and SARS-CoV-2 are thought to transmit to humans via wild mammals,especially bats.However,evidence for direct bat-to-human transmission is lacking.Involvement of intermediate hosts is considered a reason for SARS-CoV-2 transmission to humans and emergence of outbreak.Large biodiversity is found in tropical territories,such as Brazil.On the similar line,this study aimed to predict potential coronavirus hosts among Brazilian wild mammals based on angiotensin-converting enzyme 2(ACE2)sequences using evolutionary bioinformatics.Cougar,maned wolf,and bush dogs were predicted as potential hosts for coronavirus.These indigenous carnivores are philogenetically closer to the known SARS-CoV/SARS-CoV-2 hosts and presented low ACE2 divergence.A new coronavirus transmission chain was developed in which white-tailed deer,a susceptible SARS-CoV-2 host,have the central position.Cougar play an important role because of its low divergent ACE2 level in deer and humans.The discovery of these potential coronavirus hosts will be useful for epidemiological surveillance and discovery of interventions that can contribute to break the transmission chain.
文摘Background:Liqoseal consists of a watertight layer of poly(ester)ether urethane and an adhesive layer containing polyethylene glycol-N-hydroxysuccinimide(PEG-NHS).It is designed to prevent cerebrospinal fluid(CSF)leakage after intradural surgery.This study assessed the safety and biodegradability of Liqoseal in a porcine craniotomy model.Methods:In 32 pigs a craniotomy plus durotomy was performed.In 15 pigs Liqoseal was implanted,in 11 control pigs no sealant was implanted and in 6 control pigs a control dural sealant(Duraseal or Tachosil)was implanted.The safety of Liqoseal was evaluated by clinical,MRI and histological assessment.The degradation of Liqoseal was histologically estimated.Results:Liqoseal,2 mm thick before application,did not swell and significantly was at maximum mean thickness of 2.14(±0.37)mm at one month.The foreign body reaction induced by Liqoseal,Duraseal and Tachosil were comparable.Liqoseal showed no adherence to the arachnoid layer and was completely resorbed between 6 and 12 months postoperatively.In one animal with Liqoseal,an epidural fluid collection containing CSF could not be excluded.Conclusion:Liqoseal seems to be safe for intracranial use and is biodegradable.The safety and performance in humans needs to be further assessed in clinical trials.
基金support from Southern Health NHS Foundation Trust,University College London and Liverpool Women’s hospital.part of the multifaceted ELEMI project that is sponsored by Southern Health NHS Foundation Trust and in collaboration with the University of Liverpool,Liverpool Women’s Hospital,University College London,University College London NHS Foundation Trust,University of Southampton,Robinson Institute-University of Adelaide,Ramaiah Memorial Hospital(India),University of Geneva and Manchester University NHS Foundation Trust。
文摘BACKGROUND Preterm birth(PTB)is one of the main causes of neonatal deaths globally,with approximately 15million infants are born preterm.Women from the Black,Asian,and Minority Ethnic(BAME)populations maybe at higher risk of PTB,therefore,the mental health impact on mothers experiencing a PTB is particularly important,within the BAME populations.AIM To determine the prevalence of mental health conditions among BAME women with PTB as well as the methods of mental health assessments used to characterise the mental health outcomes.METHODS A systematic methodology was developed and published as a protocol in PROSPERO(CRD420-20210863).Multiple databases were used to extract relevant data.I2 and Egger's tests were used to detect the heterogeneity and publication bias.A trim and fill method was used to demonstrate the influence of publication bias and the credibility of conclusions.RESULTS Thirty-nine studies met the eligibility criteria from a possible 3526.The prevalence rates of depression among PTB-BAME mothers were significantly higher than full-term mothers with a standardized mean difference of 1.5 and a 95%confidence interval(CI)29%-74%.The subgroup analysis indicated depressive symptoms to be time sensitive.Women within the very PTB category demonstrated a significantly higher prevalence of depression than those categorised as non-very PTB.The prevalence rates of anxiety and stress among PTB-BAME mothers were significantly higher than in full-term mothers(odds ratio of 88%and 60%with a CI of 42%-149%and 24%-106%,respectively).CONCLUSION BAME women with PTB suffer with mental health conditions.Many studies did not report on specific mental health outcomes for BAME populations.Therefore,the impact of PTB is not accurately represented in this population,and thus could negatively influence the quality of maternity services they receive.
文摘Introduction: Acute tubular necrosis (ATN) is the most prevalent cause of acute renal failure (ARF). Mesenchymal stem cell transplantation has been studied as a potential treatment for renal dysfunction due to ATN. Inducible nitric oxide synthase (iNOS), bone morphogenetic protein-7 (BMP-7) and B-cell lymphoma 2 (Bcl-2) are surrogate markers of renal tubular epithelial regeneration and subsequent recovery of renal function following ATN. Methods: Serum creatinine (Scr) and blood urea nitrogen (BUN), as well as expression of iNOS, BMP-7 and Bcl-2 in gentamycin-induced ATN rat kidneys was investigated after human umbilical cord-derived mesenchymal stem cell (HUC-MSC) transplantation. Immunohistochemical staining was performed in 3 groups of rats: gentamycin-induced ATN treated with HUC-MSC, gentamycin-induced ATN without HUC-MSC, and untreated rats not receiving any treatments. Results: HUC-MSC transplantation led to a reduction in Scr and BUN in the kidneys of rats with gentamycin-induced ATN. Expression of iNOS in the HUC-MSC treated group occurred later and the expression levels were much lower during gentamycin-induced ATN compared to rats with ATN that were not treated with HUC-MSC. The expression of BMP-7 and Bcl-2 in the MSC-transplanted group was significantly increased compared to both control groups of rats with injured and healthy renal tubules. Conclusions: HUC-MSCs induce renal protection in a rat model of gentamycin-induced ATN, which is associated with reduced iNOS expression and up-regulation of Bcl-2 and BMP-7.
文摘Purpose: Rapid eye movement sleep behavior disorder (RBD) and impulse control disorders (ICDs) are common in subjects with Parkinson’s disease. The association between these two conditions has been contradictory. The aim of this study is to analyze the association between these two non-motor symptoms. Methods: Consecutive subjects with Parkinson’s disease attending the Movement Disorders Outpatient Clinic were included. The presence of ICDs was assessed using the Questionnaire for Impulse Control Disorders Rating Scale. RBD was diagnosed by an overnight, single night polysomnography. Results: Fifty-five consecutive subjects with Parkinson’s disease were included. The prevalence of ICDs and related behaviors was 23.6% (ICD in 14.5% and related behaviors in 9.1%). RBD was diagnosed in 47.2% of the patients. No differences were found in the frequency of ICDs and related behaviors when comparing subjects with and without RBD (23% versus 24.1%, p = 0.926, respectively). Conclusion: No association between the presence of RBD and the frequency of ICDs in subjects with Parkinson’s disease was found.
文摘Background:The loss of cell polarity plays a key part in retinal dystrophies such as retinitis pigmentosa(RP)and Leber congenital amaurosis(LCA),resulting in photoreceptor(PR)degeneration and vision loss.Despite not knowing the direct genotype-to-phenotype correlation,many disease-causing mutations in the polarity determinant Crumbs(Crb1),have been identified.Indeed,the loss of Crb1 in mice was shown to cause PR death,due to the loss of adhesions between PR and Müller cells at the apical surface of the retina.Unfortunately,although the role of Crb1 in neuron polarity and survival is well established,little is known about how its intracellular trafficking is regulated.With future treatments for retinal degenerative diseases in mind,the goal of this project is to understand the mechanism by which Crb1 is regulated and how it maintains retinal integrity.Previous work in our laboratory showed that Numb,an endocytic adaptor protein,is an important regulator of protein trafficking in retinal cells.We therefore hypothesized that Numb might function as regulator of Crb1 in Müller glia.Methods:To study Numb function in Müller cells,we generated a conditional knockout(cKO)mouse line to inactivate Numb specifically in Müller cells by crossing a Glast-CreERT2 mouse line with a Numb-floxed line.At 30 days,mice were administered tamoxifen to trigger inactivation of Numb and retinas were then collected at time points varying from 2 weeks to 17 months for analysis.Firstly,we studied the retinal morphology and outer limiting membrane integrity by histology and immunohistochemistry.Using electron microscopy(EM),adhesions between Müller glia and photoreceptors were analysed and retinal function was assayed in live mice by electroretinography(ERG).To detect protein expression levels,protein extracts were prepared from cKO and control retinas for immunoblotting.To test for the presence of a biochemical interaction,Hek-293 cells were transfected with Numb and Crb1 vectors,and protein extracts were processed for co-immunoprecipitation.Results:When Numb was deleted in Müller cells,we observed a similar retinal phenotype than what was reported in the Crb1 KO.In 3-month-old animals,we found a disruption of the outer limiting membrane and an ingression of photoreceptor cells in the inner layers of the retina.In older animals(17 months),we observed a clear thinning of the photoreceptor layer and reduced ERG responses.Immunoblotting of retinal lysates revealed that Numb cKO retinas had significantly lower expression of Crb1,suggesting that Numb function in Müller cells is critical to maintain Crb1 levels and thereby outer limiting membrane integrity.Interestingly,we found that Numb can interact with Crb1 both in vitro and in vivo,suggesting that Numb might function as an adaptor protein regulating Crb1 trafficking.Conclusions:Based on these results,we suggest that,in the absence of Numb,Crb1 cannot be trafficked to the apical membrane of Müller cells,and is instead degraded.This ruptures the adhesion between Müller and photoreceptor cells,leading to photoreceptor degeneration.We anticipate that understanding the mechanisms by which Crb1 maintains the structural integrity of the retina will lead to new possibilities for target-based therapies against retinal dystrophies.
文摘Background and Purpose: Hypertension has serious effects on cerebral blood vessels. Oxidative stress seems to be implicated in blood pressure elevation, through increased reactive oxygen species and/or decreased antioxidant capacity. Recently blood markers indicating damage to the central nervous system were reported to be increased in hypertensive patients. However, it is unknown whether antioxidant capacity is related to these changes. This study was designed to explore if the concentration of blood markers for nervous tissue damage was associated to antioxidant capacity in hypertensive patients. Methods: Twenty hypertensive patients and 23 healthy controls were studied. They were paired by age, sex, ethnicity, or risk factors. Serum neuron specific enolase (NSE) and S100 calcium binding protein B (S100B) were measured as nervous tissue damage markers, as well as the activity of antioxidant enzymes (catalase, glutathione peroxidase, glutathione reductase and gamma-glutamyltransferase). Results: Serum neuronal specific enolase (NSE) and S100 calcium binding protein B (S100B) concentrations determined by immunoassay were significantly increased in patients vs. controls. The activities of antioxidant enzymes measured by spectrophotometry showed that plasmatic catalase and erythrocytic glutathione peroxidase were significantly increased in patients, but erythocytic catalase was decreased. Gamma-glutamyltransferase activity was significantly correlated with S100B in hypertensive patients, while erythrocytic catalase activity was decreased in subjects with higher NSE levels. Conclusion: This preliminary investigation suggested that antioxidant status might be modulated through changes in antioxidant enzymatic activity in hypertensive patients. The association of some of these changes with peripheral markers of damage to the central nervous system could indicate that the increased levels of these proteins in hypertension are partly related to oxidative stress.
基金supported by the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo(FAPESP)—Proc.2011/14116-5.
文摘Autism and Asperger’s syndrome belong to a family of neuro-developmental disorders called Pervasive Development Disorders. The aims of this study were to 1) quantify the overall functional performance and need for caregiver assistance in autism (A) and Asperger’s syndrome (AS), 2) compare the findings between groups and to normative data from Brazilian children. Methods: A cross-sectional study was carried out involving 52 children between three and eight years of age diagnosed with either A (n = 26) or SA (n = 26). The Brazilian version of the Pediatric Evaluation of Disability Inventory was administered. Results: The children with A and AS achieved significantly lower scores than that expected for normality. The children with AS had a significantly better social function than that the children with A had. However, those with A achieved significantly better scores than those with AS on activities related to self-care and mobility, requiring less assistance. Conclusion: While patients with AS are better at social interaction than typical autistic children, they exhibit greater deficits with regard to basic tasks, such as self-care and mobility, requiring greater assistance than children with A.
文摘Neuromyelitis optica(NMO)refers to an antibody mediated,inflammatory disorder of the central nervous system(CNS)characterized by recurrent or monophasic attacks of optic neuritis and myelitis.Most patients with NMO possess a specific serum immunoglobin,NMO-IgG,which can serve as a biomarker for NMO.The autoantibodies target aquaporin-4(AQP4),the main water channel protein found in the CNS including the brain,spinal cord,and optic nerve.The remaining 10-25%of patients are seronegative for NMO-IgG despite meeting the diagnostic criteria for NMO.Recent studies have shown that a subset of these patients is seropositive for antibodies against myelin oligodendrocyte glycoprotein(MOG).This paper will provide an overview of the current English scientific literature published regarding the history,epidemiology,AQP4 biomarker,MOG biomarker,diagnosis,clinical features,related diseases in NMO spectrum disorder(NMOSD),and treatments of NMO.