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
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
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
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
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
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
Post-poliomyelitis syndrome (PPS) is a disorder in individuals who have had poliomyelitis, characterized by new muscle weakness and often associated with other symptoms, including cold intolerance (CI). Qigong is a Tr...Post-poliomyelitis syndrome (PPS) is a disorder in individuals who have had poliomyelitis, characterized by new muscle weakness and often associated with other symptoms, including cold intolerance (CI). Qigong is a Traditional Chinese Medicine technique to adjust energy and blood circulation. Objective: To verify the effects and late repercussions of Qigong on CI complaints in PPS patients. Methods: PPS patients (n = 22, 14 females, 8 males;ages 35 - 60) performed Qigong exercises in 40-minute sessions, three times per week, for three consecutive months. They were evaluated at baseline, the end of treatment and every three months for a year using a visual analogue scale adapted for CI (VAS-cold). Results: The systemic VAS-cold scores exhibited significant differences between the baseline, the end of treatment and throughout 12 months of follow-up. Conclusion: The CI scores were low and bearable at the end of intervention and for the following 12 months without activity.展开更多
Riboflavin transporter deficiency(RTD),previously known as Brown-Vialetto-Van Laere syndrome,is a childhoodonset neurodegenerative disorder characterized by sensory and motor neuron degeneration causing ataxia,muscle ...Riboflavin transporter deficiency(RTD),previously known as Brown-Vialetto-Van Laere syndrome,is a childhoodonset neurodegenerative disorder characterized by sensory and motor neuron degeneration causing ataxia,muscle weakness,optic atrophy,and respiratory failure.Mutations in SLC52A2 and SLC52A3,solute carrier family members that encode riboflavin(RF)transporters RFVT2 and RFVT3,are known to cause RTD types 2 and 3,respectively.展开更多
Animal experiments have confirmed that mesenchymal stem cells can inhibit motor neuron apoptosis and inflammatory factor expression and increase neurotrophic factor expression. Therefore, mesenchymal stem cells have b...Animal experiments have confirmed that mesenchymal stem cells can inhibit motor neuron apoptosis and inflammatory factor expression and increase neurotrophic factor expression. Therefore, mesenchymal stem cells have been shown to exhibit prospects in the treatment of amyotrophic lateral sclerosis. However, the safety of their clinical application needs to be validated. To investigate the safety of intrathecal injection of Wharton's jelly-derived mesenchymal stem cells in amyotrophic lateral sclerosis therapy, 43 patients(16 females and 27 males, mean age of 57.3 years) received an average dose of 0.42 × 106 cells/kg through intrathecal administration at the cervical, thoracic or lumbar region depending on the clinical symptoms. There was a 2 month interval between two injections. The adverse events occurring during a 6-month treatment period were evaluated. No adverse events occurred. Headache occurred in one case only after first injection of stem cells. This suggests that intrathecal injection of Wharton's Jelly-derived mesenchymal stem cells is well tolerated in patients with amyotrophic lateral sclerosis. This study was approved by the Bioethical Committee of School of Medicine, University of Warmia and Mazury in Olsztyn, Poland(approval No. 36/2014 and approval No. 8/2016). This study was registered with the ClinicalTrials.gov(identifier: NCT02881476)on August 29, 2016.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
BACKGROUND Plexiform neurofibromas are extremely rarely found in the region of cauda equina and can pose a significant challenge in the diagnostic and management sense.To our knowledge,only 7 cases of cauda equina neu...BACKGROUND Plexiform neurofibromas are extremely rarely found in the region of cauda equina and can pose a significant challenge in the diagnostic and management sense.To our knowledge,only 7 cases of cauda equina neurofibromatosis(CENF)have been reported up-to-date.CASE SUMMARY We describe a case of a 55-year-old man with a 10 years history of progressive lower extremities weakness and bladder dysfunction.Before presenting,patient was misdiagnosed with idiopathic polyneuropathy.Lumbar spine MRI revealed a tortuous tumorous masses in the cauda equina region,extending through the Th12-L4 vertebrae.The patient underwent Th12-L3 Laminectomy with duraplasty.During the operation,the most enlarged electroneurographically silent nerve root was resected,anticipating inadequate decompression if nerve root was spared.The patient’s neurological condition improved post-operatively,but urinary retention became the major complaint.We provide a follow-up period of 10 years.During this time,the patient’s condition progressively worsened despite extensive decompression.The consequent MRI scans showed progressive enlargement of cauda equina roots and increasing lumbar stenosis,predominantly affecting L3-L4 segment.During the follow-up 8 years after the operation,the patient complained of worsening lower extremities sensorimotor function and neurogenic claudication.Subsequent MRI revealed lumbar spine stenosis at the level of L3-L4,requiring further decompression.The patient underwent a second surgery involving L4-L5 Laminectomy with duraplasty and L2-L5 transpedicular fixation.The post-operative period was uneventful.Latest follow-up 18 mo after the second surgery revealed substantial improvement in patient’s well-being.CONCLUSION CENF should be kept in mind during the differential diagnostic work-up for polyneuropathies.Management with an extensive decompression,duraplasty and primary spinal fixation represents a rational approach to achieve a sustained symptomatic improvement and superior overall outcome.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
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
Moyamoya disease(MMD)is a chronic occlusive cerebrovascular disease with the development of a network of abnormal vessels.Immune inflammation is associated with the occurrence and development of MMD.However,the mechan...Moyamoya disease(MMD)is a chronic occlusive cerebrovascular disease with the development of a network of abnormal vessels.Immune inflammation is associated with the occurrence and development of MMD.However,the mechanisms underlying the formation of the abnormal vascular network remain unclear.Twenty-eight patients with MMD,26 ischemic stroke patients,and 26 unrelated healthy volunteers were enrolled in this study The data showed that the levels of granulocyte-macrophage colony-stimulating factor(GM-CSF)were higher in MMD patients than in healthy controls(P<0.01),and GM-CSF was mainly from Th1 and Th17 cells in MMD.We found that increased GM-CSF drove monocytes to secrete a series of cytokines associated with angiogenesis,inflammation,and chemotaxis.In summary,our findings demonstrate for the first time the important involvement of GM-CSF in MMD and that GM-CSF is an important factor in the formation of abnormal vascular networks in MMD.展开更多
Modern day survivorship from childhood malignancies is estimated to be over 80%.However,central ner-vous system tumors remain the leading cause of cancer mortality in children and is the most common solid tumor in thi...Modern day survivorship from childhood malignancies is estimated to be over 80%.However,central ner-vous system tumors remain the leading cause of cancer mortality in children and is the most common solid tumor in this population.Improved survivorship is,in part,a result of improved multidisciplinary care,of-ten with a combination of surgery,radiation therapy,and systemic therapy.With improved survival,long term effects of treatment and quality of life impacts have been recognized and pose a challenge to maxi-mize the therapeutic ratio of treatment.It has been increasingly more apparent that precise risk stratifica-tion,such as with the inclusion of molecular classification,is instrumental in efforts to tailor radiotherapy for appropriate treatment,generally towards de-intensification for this vulnerable patient population.In ad-dition,advances in radiotherapy techniques have allowed greater conformality and accuracy of treatment for those who do require radiotherapy for tumor control.Ongoing efforts to tailor radiotherapy,including de-escalation,omission,or intensification of radiotherapy,continue to improve as increasing insight into tumor heterogeneity is recognized,coupled with advances in precision medicine employing novel molecularly-targeted therapeutics.展开更多
Studies have confirmed that bone marrow-derived mesenchymal stem cells （MSCs） can be used for treatment of several nervous system diseases. However, isolation of bone marrow-derived MSCs （BMSCs） is an invasive and...Studies have confirmed that bone marrow-derived mesenchymal stem cells （MSCs） can be used for treatment of several nervous system diseases. However, isolation of bone marrow-derived MSCs （BMSCs） is an invasive and painful process and the yield is very low. Therefore, there is a need to search for other alterative stem cell sources. Adipose-derived MSCs （ADSCs） have phenotypic and gene expression profiles similar to those of BMSCs. The production of ADSCs is greater than that of BMSCs, and ADSCs proliferate faster than BMSCs. To compare the effects of venous grafts containing BMSCs or ADSCs on sciatic nerve injury, in this study, rats were randomly divided into four groups： sham （only sciatic nerve exposed）, Matrigel （MG; sciatic nerve injury ＋ intravenous transplantation of MG vehicle）, ADSCs （sciatic nerve injury ＋ intravenous MG containing ADSCs）, and BMSCs （sciatic nerve injury ＋ intravenous MG containing BMSCs） groups. Sciatic functional index was calculated to evaluate the function of injured sciatic nerve. Morphologic characteristics of nerves distal to the lesion were observed by toluidine blue staining. Spinal motor neurons labeled with Fluoro-Gold were quantitatively assessed. Compared with sham-operated rats, sciatic functional index was lower, the density of small-diameter fibers was significantly increased, and the number of motor neurons significantly decreased in rats with sciatic nerve injury. Neither ADSCs nor BMSCs significantly improved the sciatic nerve function of rats with sciatic nerve injury,increased fiber density, fiber diameters, axonal diameters, myelin sheath thickness, and G ratios （axonal diameter/fiber diameter ratios） in the sciatic nerve distal to the lesion site. There was no significant difference in the number of spinal motor neurons among ADSCs, BMSCs and MG groups. These results suggest that neither BMSCs nor ADSCs provide satisfactory results for peripheral nerve repair when using MG as the conductor for engraftment.展开更多
AIM: To examine complications associated with the use of therapeutic temperature modulation(mild hypothermia and normothermia) in patients with severe traumatic brain injury(TBI). METHODS: One hundred and fourteen cha...AIM: To examine complications associated with the use of therapeutic temperature modulation(mild hypothermia and normothermia) in patients with severe traumatic brain injury(TBI). METHODS: One hundred and fourteen charts were reviewed. Inclusion criteria were: severe TBI with Glasgow Coma Scale(GCS) < 9, intensive care unit(ICU) stay > 24 h and non-penetrating TBI. Patients were divided into two cohorts: the treatment group received therapeutic temperature modulation(TTM) with continuous surface cooling and indwelling bladder temperature probes. The control group received standard treatment with intermittent acetaminophen for fever. Information regarding complications during the time in the ICU was collected as follows: Pneumonia was identified using a combination of clinical and laboratory data. Pulmonary embolism, pneumothorax and deep venous thrombosis were identified based onimaging results. Cardiac arrhythmias and renal failure were extracted from the clinical documentation. acute respiratory distress syndrome and acute lung injury were determined based on chest imaging and arterial blood gas results. A logistic regression was conducted to predict hospital mortality and a multiple regression was used to assess number and type of clinical complications. RESULTS: One hundred and fourteen patients were included in the analysis(mean age = 41.4, SD = 19.1, 93 males), admitted to the Jackson Memorial Hospital Neuroscience ICU and Ryder Trauma Center(mean GCS = 4.67, range 3-9), were identified and included in the analysis. Method of injury included motor vehicle accident(n = 29), motor cycle crash(n = 220), blunt head trauma(n = 212), fall(n = 229), pedestrian hit by car(n = 216), and gunshot wound to the head(n = 27). Ethnicity was primarily Caucasian(n = 260), as well as Hispanic(n = 227) and African American(n = 223); four patients had unknown ethnicity. Patients received either TTM(43) or standard therapy(71). Within the TTM group eight patients were treated with normothermia after TBI and 35 patients were treated with hypothermia. A logistic regression predicting in hospital mortality with age, GCS, and TM demonstrated that GCS(Beta = 0.572, P < 0.01) and age(Beta =-0.029) but not temperature modulation(Beta = 0.797, ns) were significant predictors of in-hospital mortality [χ2(3) = 22.27, P < 0.01] A multiple regression predicting number of complications demonstrated that receiving TTM was the main contributor and was associated with a higher number of pulmonary complications(t =-3.425, P = 0.001). CONCLUSION: Exposure to TTM is associated with an increase in pulmonary complications. These findings support more attention to these complications in studies of TTM in TBI patients.展开更多
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 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 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.
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.
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.
基金Scholarship from CAPES Foundation,Ministry of Education of Brazil,Brasilia—DF 70040-020,Brazil.In process.11/06/2332
文摘Post-poliomyelitis syndrome (PPS) is a disorder in individuals who have had poliomyelitis, characterized by new muscle weakness and often associated with other symptoms, including cold intolerance (CI). Qigong is a Traditional Chinese Medicine technique to adjust energy and blood circulation. Objective: To verify the effects and late repercussions of Qigong on CI complaints in PPS patients. Methods: PPS patients (n = 22, 14 females, 8 males;ages 35 - 60) performed Qigong exercises in 40-minute sessions, three times per week, for three consecutive months. They were evaluated at baseline, the end of treatment and every three months for a year using a visual analogue scale adapted for CI (VAS-cold). Results: The systemic VAS-cold scores exhibited significant differences between the baseline, the end of treatment and throughout 12 months of follow-up. Conclusion: The CI scores were low and bearable at the end of intervention and for the following 12 months without activity.
基金support was provided by the Cure RTD Foundation and Australian Medical Research Future Fund(MRFF)Genomics Health Futures Mission Grant(No.2007681)funded by the NIH Office of the Research Infrastructure programs(P400D010440).
文摘Riboflavin transporter deficiency(RTD),previously known as Brown-Vialetto-Van Laere syndrome,is a childhoodonset neurodegenerative disorder characterized by sensory and motor neuron degeneration causing ataxia,muscle weakness,optic atrophy,and respiratory failure.Mutations in SLC52A2 and SLC52A3,solute carrier family members that encode riboflavin(RF)transporters RFVT2 and RFVT3,are known to cause RTD types 2 and 3,respectively.
基金supported by Instytut Terapii Komórkowych w Olsztynie(Cell Therapies Institute,FamiCord Group)in Olsztyn(to MB,SM,and TS)
文摘Animal experiments have confirmed that mesenchymal stem cells can inhibit motor neuron apoptosis and inflammatory factor expression and increase neurotrophic factor expression. Therefore, mesenchymal stem cells have been shown to exhibit prospects in the treatment of amyotrophic lateral sclerosis. However, the safety of their clinical application needs to be validated. To investigate the safety of intrathecal injection of Wharton's jelly-derived mesenchymal stem cells in amyotrophic lateral sclerosis therapy, 43 patients(16 females and 27 males, mean age of 57.3 years) received an average dose of 0.42 × 106 cells/kg through intrathecal administration at the cervical, thoracic or lumbar region depending on the clinical symptoms. There was a 2 month interval between two injections. The adverse events occurring during a 6-month treatment period were evaluated. No adverse events occurred. Headache occurred in one case only after first injection of stem cells. This suggests that intrathecal injection of Wharton's Jelly-derived mesenchymal stem cells is well tolerated in patients with amyotrophic lateral sclerosis. This study was approved by the Bioethical Committee of School of Medicine, University of Warmia and Mazury in Olsztyn, Poland(approval No. 36/2014 and approval No. 8/2016). This study was registered with the ClinicalTrials.gov(identifier: NCT02881476)on August 29, 2016.
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BACKGROUND Plexiform neurofibromas are extremely rarely found in the region of cauda equina and can pose a significant challenge in the diagnostic and management sense.To our knowledge,only 7 cases of cauda equina neurofibromatosis(CENF)have been reported up-to-date.CASE SUMMARY We describe a case of a 55-year-old man with a 10 years history of progressive lower extremities weakness and bladder dysfunction.Before presenting,patient was misdiagnosed with idiopathic polyneuropathy.Lumbar spine MRI revealed a tortuous tumorous masses in the cauda equina region,extending through the Th12-L4 vertebrae.The patient underwent Th12-L3 Laminectomy with duraplasty.During the operation,the most enlarged electroneurographically silent nerve root was resected,anticipating inadequate decompression if nerve root was spared.The patient’s neurological condition improved post-operatively,but urinary retention became the major complaint.We provide a follow-up period of 10 years.During this time,the patient’s condition progressively worsened despite extensive decompression.The consequent MRI scans showed progressive enlargement of cauda equina roots and increasing lumbar stenosis,predominantly affecting L3-L4 segment.During the follow-up 8 years after the operation,the patient complained of worsening lower extremities sensorimotor function and neurogenic claudication.Subsequent MRI revealed lumbar spine stenosis at the level of L3-L4,requiring further decompression.The patient underwent a second surgery involving L4-L5 Laminectomy with duraplasty and L2-L5 transpedicular fixation.The post-operative period was uneventful.Latest follow-up 18 mo after the second surgery revealed substantial improvement in patient’s well-being.CONCLUSION CENF should be kept in mind during the differential diagnostic work-up for polyneuropathies.Management with an extensive decompression,duraplasty and primary spinal fixation represents a rational approach to achieve a sustained symptomatic improvement and superior overall outcome.
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.
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.
基金supported by the National Natural Science Foundation of China(82271334,82130036,81920108017,82171310)the National Science and Technology Innovation 2030--Major Program of"Brain Science and Brain-Like Research"(2022ZD0211800)+1 种基金Jiangsu Provincial‘333’High-level Talent Training Project Funding,the Key Research and Development Program of Jiangsu Province of China(BE2020620)Jiangsu Province Key Medical Discipline(ZDXK202216).
文摘Moyamoya disease(MMD)is a chronic occlusive cerebrovascular disease with the development of a network of abnormal vessels.Immune inflammation is associated with the occurrence and development of MMD.However,the mechanisms underlying the formation of the abnormal vascular network remain unclear.Twenty-eight patients with MMD,26 ischemic stroke patients,and 26 unrelated healthy volunteers were enrolled in this study The data showed that the levels of granulocyte-macrophage colony-stimulating factor(GM-CSF)were higher in MMD patients than in healthy controls(P<0.01),and GM-CSF was mainly from Th1 and Th17 cells in MMD.We found that increased GM-CSF drove monocytes to secrete a series of cytokines associated with angiogenesis,inflammation,and chemotaxis.In summary,our findings demonstrate for the first time the important involvement of GM-CSF in MMD and that GM-CSF is an important factor in the formation of abnormal vascular networks in MMD.
文摘Modern day survivorship from childhood malignancies is estimated to be over 80%.However,central ner-vous system tumors remain the leading cause of cancer mortality in children and is the most common solid tumor in this population.Improved survivorship is,in part,a result of improved multidisciplinary care,of-ten with a combination of surgery,radiation therapy,and systemic therapy.With improved survival,long term effects of treatment and quality of life impacts have been recognized and pose a challenge to maxi-mize the therapeutic ratio of treatment.It has been increasingly more apparent that precise risk stratifica-tion,such as with the inclusion of molecular classification,is instrumental in efforts to tailor radiotherapy for appropriate treatment,generally towards de-intensification for this vulnerable patient population.In ad-dition,advances in radiotherapy techniques have allowed greater conformality and accuracy of treatment for those who do require radiotherapy for tumor control.Ongoing efforts to tailor radiotherapy,including de-escalation,omission,or intensification of radiotherapy,continue to improve as increasing insight into tumor heterogeneity is recognized,coupled with advances in precision medicine employing novel molecularly-targeted therapeutics.
基金supported by Brazilian grants from Fundacao de Amparo à Pesquisa do Estado de Sao Paulo(FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq)CAPES
文摘Studies have confirmed that bone marrow-derived mesenchymal stem cells （MSCs） can be used for treatment of several nervous system diseases. However, isolation of bone marrow-derived MSCs （BMSCs） is an invasive and painful process and the yield is very low. Therefore, there is a need to search for other alterative stem cell sources. Adipose-derived MSCs （ADSCs） have phenotypic and gene expression profiles similar to those of BMSCs. The production of ADSCs is greater than that of BMSCs, and ADSCs proliferate faster than BMSCs. To compare the effects of venous grafts containing BMSCs or ADSCs on sciatic nerve injury, in this study, rats were randomly divided into four groups： sham （only sciatic nerve exposed）, Matrigel （MG; sciatic nerve injury ＋ intravenous transplantation of MG vehicle）, ADSCs （sciatic nerve injury ＋ intravenous MG containing ADSCs）, and BMSCs （sciatic nerve injury ＋ intravenous MG containing BMSCs） groups. Sciatic functional index was calculated to evaluate the function of injured sciatic nerve. Morphologic characteristics of nerves distal to the lesion were observed by toluidine blue staining. Spinal motor neurons labeled with Fluoro-Gold were quantitatively assessed. Compared with sham-operated rats, sciatic functional index was lower, the density of small-diameter fibers was significantly increased, and the number of motor neurons significantly decreased in rats with sciatic nerve injury. Neither ADSCs nor BMSCs significantly improved the sciatic nerve function of rats with sciatic nerve injury,increased fiber density, fiber diameters, axonal diameters, myelin sheath thickness, and G ratios （axonal diameter/fiber diameter ratios） in the sciatic nerve distal to the lesion site. There was no significant difference in the number of spinal motor neurons among ADSCs, BMSCs and MG groups. These results suggest that neither BMSCs nor ADSCs provide satisfactory results for peripheral nerve repair when using MG as the conductor for engraftment.
文摘AIM: To examine complications associated with the use of therapeutic temperature modulation(mild hypothermia and normothermia) in patients with severe traumatic brain injury(TBI). METHODS: One hundred and fourteen charts were reviewed. Inclusion criteria were: severe TBI with Glasgow Coma Scale(GCS) < 9, intensive care unit(ICU) stay > 24 h and non-penetrating TBI. Patients were divided into two cohorts: the treatment group received therapeutic temperature modulation(TTM) with continuous surface cooling and indwelling bladder temperature probes. The control group received standard treatment with intermittent acetaminophen for fever. Information regarding complications during the time in the ICU was collected as follows: Pneumonia was identified using a combination of clinical and laboratory data. Pulmonary embolism, pneumothorax and deep venous thrombosis were identified based onimaging results. Cardiac arrhythmias and renal failure were extracted from the clinical documentation. acute respiratory distress syndrome and acute lung injury were determined based on chest imaging and arterial blood gas results. A logistic regression was conducted to predict hospital mortality and a multiple regression was used to assess number and type of clinical complications. RESULTS: One hundred and fourteen patients were included in the analysis(mean age = 41.4, SD = 19.1, 93 males), admitted to the Jackson Memorial Hospital Neuroscience ICU and Ryder Trauma Center(mean GCS = 4.67, range 3-9), were identified and included in the analysis. Method of injury included motor vehicle accident(n = 29), motor cycle crash(n = 220), blunt head trauma(n = 212), fall(n = 229), pedestrian hit by car(n = 216), and gunshot wound to the head(n = 27). Ethnicity was primarily Caucasian(n = 260), as well as Hispanic(n = 227) and African American(n = 223); four patients had unknown ethnicity. Patients received either TTM(43) or standard therapy(71). Within the TTM group eight patients were treated with normothermia after TBI and 35 patients were treated with hypothermia. A logistic regression predicting in hospital mortality with age, GCS, and TM demonstrated that GCS(Beta = 0.572, P < 0.01) and age(Beta =-0.029) but not temperature modulation(Beta = 0.797, ns) were significant predictors of in-hospital mortality [χ2(3) = 22.27, P < 0.01] A multiple regression predicting number of complications demonstrated that receiving TTM was the main contributor and was associated with a higher number of pulmonary complications(t =-3.425, P = 0.001). CONCLUSION: Exposure to TTM is associated with an increase in pulmonary complications. These findings support more attention to these complications in studies of TTM in TBI patients.
