Actin(g) toward a revised understanding of the role of cytoskeletal dynamics in neuronal bioenergetics

Neurons are energy-demanding cells.Disruptions in energy metabolism can quickly interrupt neuronal function,leading to cell death and neurodegeneration.For instance,ischemia rapidly depletes adenosine triphosphate(ATP)thereby disrupting energy-dependent cellular processes crucial for homeostasis,and axon degeneration is preceded by a collapse of axonal ATP levels.

Optical redox imaging of ANT1-de-cient muscles

Adenine nucleotide translocator(ANT)is a mitochondrial protein involved in the exchange of ADP and ATP across the mitochondrial inner membrane.It plays a crucial role in cellular energy metabolism by facilitating the transport of ATP synthesized within the mitochondria to the cytoplasm.The isoform ANT1 predominately expresses in cardiac and skeletal muscles.Mutations or dysregulation in ANT1 have been implicated in various mitochondrial disorders and neuromuscular diseases.We aimed to examine whether ANT1 deletion may affect mitochondrial redox state in our established ANT1-de-cient mice.Hearts and quadriceps resected from age-matched wild type(WT)and ANT1-de-cient mice were snap-frozen in liquid nitrogen.The Chance redox scanner was utilized to perform 3D optical redox imaging.Each sample underwent scanning across 3–5 sections.Global averaging analysis showed no signi-cant differences in the redox indices(NADH,flavin adenine dinucleotide containing-flavoproteins Fp,and the redox ratio Fp/(NADH+Fp)between WT and ANT1-de-cient groups.However,quadriceps had higher Fp than hearts in both groups(p¼0:0004 and 0.01,respectively).Furthermore,the quadriceps were also more oxidized(a higher redox ratio)than hearts in WT group(p¼0:004).NADH levels were similar in all cases.Our data suggest that under non-stressful physical condition,the ANT1-de-cient muscle cells were in the same mitochondrial state as WT ones and that the signi-cant difference in the mitochondrial redox state between quadriceps and hearts found in WT might be diminished in ANT1-de-cient ones.Redox imaging of muscles under physical stress can be conducted in future.

Challenges with non-descriptive compliance labeling of end-stage renal disease patients in accessibility for renal transplantation

Non-descriptive and convenient labels are uninformative and unfairly project blame onto patients.The language clinicians use in the Electronic Medical Record,research,and clinical settings shapes biases and subsequent behaviors of all providers involved in the enterprise of transplantation.Terminology such as noncompliant and nonadherent serve as a reason for waitlist inactivation and limit access to life-saving transplantation.These labels fail to capture all the circum-stances surrounding a patient’s inability to follow their care regimen,trivialize social determinants of health variables,and bring unsubstantiated subjectivity into decisions regarding organ allocation.Furthermore,insufficient Medicare coverage has forced patients to ration or stop taking medication,leading to allograft failure and their subsequent diagnosis of noncompliant.We argue that perpetuating non-descriptive language adds little substantive information,in-creases subjectivity to the organ allocation process,and plays a major role in reduced access to transplantation.For patients with existing barriers to care,such as racial/ethnic minorities,these effects may be even more drastic.Transplant committees must ensure thorough documentation to correctly encapsulate the entirety of a patient’s position and give voice to an already vulnerable population.

Cancer screening and management in the transgender population:Review of literature and special considerations for gender affirmation surgery

BACKGROUND Literature focused on cancer screening and management is lacking in the transgender population.AIM To action to increase contributions to the scientific literature that drives the creation of cancer screening and management protocols for transgender and gender nonconforming(TGNC)patients.METHODS We performed a systematic search of PubMed on January 5th,2022,with the following terms:“TGNC”,OR“transgender”,OR“gender non-conforming”,OR“gender nonbinary”AND“cancer screening”,AND“breast cancer”,AND“cervical cancer”,AND“uterine cancer”,AND“ovarian cancer”,AND“prostate cancer”,AND“testicular cancer”,AND“surveillance”,AND“follow-up”,AND“management”.70 unique publications were used.The findings are discussed under“Screening”and“Management”categories.RESULTS Screening:Current cancer screening recommendations default to cis-gender protocols.However,long-term genderaffirming hormone therapy and loss to follow-up from the gender-specific specialties contribute to a higher risk for cancer development and possible delayed detection.The only known screening guidelines made specifically for this population are from the American College of Radiology for breast cancer.Management:Prior to undergoing Gender Affirmation Surgery(GAS),discussion should address cancer screening and management in the organs remaining in situ.Cancer treatment in this population requires consideration for chemotherapy,radiation,surgery and/or reconstruction.Modification of hormone therapy is decided on a case-by-case basis.The use of prophylactic vs aesthetic techniques in surgery is still debated.CONCLUSION When assessing transgender individuals for GAS,a discussion on the future oncologic risk of the sex-specific organs remaining in situ is essential.Cancer management in this population requires a multidisciplinary approach while the care should be highly individualized with considerations to social,medical,surgical and gender affirming surgery related specifications.Special considerations have to be made during planning for GAS as surgery will alter the anatomy and may render the organ difficult to sample for screening purposes.A discussion with the patient regarding the oncologic risk of remaining organs is imperative prior to GAS.Other special considerations to screening such as the conscious or unconscious will to unassociated with their remaining organs is also a key point to address.We currently lack high quality studies pertinent to the cancer topic in the gender affirmation literature.Further research is required to ensure more comprehensive and individualized care for this population.

Lin28 as a therapeutic target for central nervous system regeneration and repair

Axon disconnection in the central nervous system(CNS) usually causes signal transduction failure and severe functional deficits in patients with neurological disorders. Currently, there is no cure for patients with CNS axon injury and they usually suffer from life-long neurological defects(e.g., paralysis, loss of sensory function, and autonomic dysfunction) and life-threatening complications(e.g., autonomic dysreflexia).

Environmental cues determine the fate of astrocytes after spinal cord injury

Reactive astrogliosis occurs after central nervous system（CNS） injuries whereby resident astrocytes form rapid responses along a graded continuum. Following CNS lesions, na？ve astrocytes are converted into reactive astrocytes and eventually into scar-forming astrocytes that block axon regeneration and neural repair. It has been known for decades that scarring development and its related extracellular matrix molecules interfere with regeneration of injured axons after CNS injury, but the cellular and molecular mechanisms for controlling astrocytic scar formation and maintenance are not well known. Recent use of various genetic tools has made tremendous progress in better understanding genesis of reactive astrogliosis. Especially, the latest experiments demonstrate environment-dependent plasticity of reactive astrogliosis because reactive astrocytes isolated from injured spinal cord form scarring astrocytes when transplanted into injured spinal cord, but revert in retrograde to naive astrocytes when transplanted into naive spinal cord. The interactions between upregulated type I collagen and its receptor integrin β1 and the N-cadherin-mediated cell adhesion appear to play major roles for local astrogliosis around the lesion. This review centers on the environment-dependent plasticity of reactive astrogliosis after spinal cord injury and its potential as a therapeutic target.

Role of axon resealing in retrograde neuronal death and regeneration after spinal cord injury

Spinal cord injury leads to persistent behavioral deficits because mammalian central nervous system axons fail to regenerate. A neuron's response to axon injury results from a complex interplay of neuron-intrinsic and environmental factors. The contribution of axotomy to the death of neurons in spinal cord injury is controversial because very remote axotomy is unlikely to result in neuronal death, whereas death of neurons near an injury may reflect environmental factors such as ischemia and inflammation. In lampreys, axotomy due to spinal cord injury results in delayed apoptosis of spinal-projecting neurons in the brain, beyond the extent of these environmental factors. This retrograde apoptosis correlates with delayed resealing of the axon, and can be reversed by inducing rapid membrane resealing with polyethylene glycol. Studies in mammals also suggest that polyethylene glycol may be neuroprotective, although the mechanism(s) remain unclear. This review examines the early, mechanical, responses to axon injury in both mammals and lampreys, and the potential of polyethylene glycol to reduce injury-induced pathology. Identifying the mechanisms underlying a neuron's response to axotomy will potentially reveal new therapeutic targets to enhance regeneration and functional recovery in humans with spinal cord injury.

Preoperative bowel preparation does not favor the management of colorectal anastomotic leak

BACKGROUND Controversy exists regarding the impact of preoperative bowel preparation on patients undergoing colorectal surgery. This is due to previous research studies,which fail to demonstrate protective effects of mechanical bowel preparation against postoperative complications. However, in recent studies, combination therapy with oral antibiotics(OAB) and mechanical bowel preparation seems to be beneficial for patients undergoing an elective colorectal operation.AIM To determine the association between preoperative bowel preparation and postoperative anastomotic leak management(surgical vs non-surgical).METHODS Patients with anastomotic leak after colorectal surgery were identified from the 2013 and 2014 Colectomy Targeted American College of Surgeons National Surgical Quality Improvement Program(ACS-NSQIP) database and were employed for analysis. Every patient was assigned to one of three following groups based on the type of preoperative bowel preparation: first groupmechanical bowel preparation in combination with OAB, second groupmechanical bowel preparation alone, and third group-no preparation.RESULTS A total of 652 patients had anastomotic leak after a colectomy from January 1,2013 through December 31, 2014. Baseline characteristics were assessed and found that there were no statistically significant differences between the three groups in terms of age, gender, race, American Society of Anesthesiologists score,and other preoperative characteristics. A χ~2 test of homogeneity was conducted and there was no statistically/clinically significant difference between the three categories of bowel preparation in terms of reoperation.CONCLUSION The implementation of mechanical bowel preparation and antibiotic use in patients who are going to undergo a colon resection does not influence the treatment of any possible anastomotic leakage.

Effects of purposeful soccer heading on circulating small extracellular vesicle concentration and cargo

Background:Considering the potential cumulative effects of repetitive head impact(HI)exposure,we need sensitive biomarkers to track shortand long-term effects.Circulating small extracellular vesicles(sEVs)(<200 nm)traffic biological molecules throughout the body and may have diagnostic value as biomarkers for disease.The purpose of this study was to identify the microRNA(miRNA)profile in circulating sEVs derived from human plasma following repetitive HI exposure.Methods:Healthy adult(aged 18-35 years)soccer players were randomly assigned to one of 3 groups:the HI group performed 10 standing headers,the leg impact group performed 10 soccer ball trapping maneuvers over 10 min,and the control group did not participate in any soccer drills.Plasma was collected before testing and 24 h afterward,and sEVs were isolated and characterized via nanoparticle tracking analysis.Next-generation sequencing was utilized to identify candidate miRNAs isolated from sEVs,and candidate microRNAs were analyzed via quantitative polymerase chain reaction.In silico target prediction was performed using TargetScan(Version 7.0;targetscan.org)and miRWalk(http://mirwalk.umm.uni-heidelberg.de/)programs,and target validation was performed using luciferase reporter vectors with a miR-7844-5p mimic in human embryonic kidney(HEK)293T/17 cells.Results:Plasma sEV concentration and size were not affected across time and group following repetitive HI exposure.After 24 h,the HI read count from next-generation sequencing showed a 4-fold or greater increase in miR-92b-5p,miR-423-5p,and miR-24-3p and a 3-fold or greater decrease in miR-7844-5p,miR-144-5p,miR-221-5p,and miR-22-3p.Analysis of quantitative polymerase chain reaction revealed that leg impact did not alter the candidate miRNA levels.To our knowledge,miR-7844-5p is a previously unknown miRNA.We identified 8 miR-7844-5p mRNA targets:protein phosphatase 1 regulatory inhibitor subunit 1B(PPP1R1B),LIM and senescent cell antigen-like domains 1(LIMS1),autophagy-related 12(ATG12),microtubule-associated protein 1 light chain 3 beta(MAP1LC3B),integrin subunit alpha-1(ITGA1),mitogenactivated protein kinase 1(MAPK1),glycogen synthase kinase 3b(GSK3b),and mitogen-activated protein kinase 8(MAPK8).Conclusion:Collectively,these data indicate repetitive HI exposure alters plasma sEV miRNA content,but not sEV size or number.Furthermore,for the first time we demonstrate that previously unknown miR-7844-5p targets mRNAs known to be involved in mitochondrial apoptosis,autophagy regulation,mood disorders,and neurodegenerative disease.

Inhibition of central axon regeneration: perspective from chondroitin sulfate proteoglycans in lamprey spinal cord injury

Background:Failure of axon regeneration after spinal cord injury(SCI)underlies the paralysis that so profoundly affects patients’quality of life.Many factors are involved in the regeneration failure.Chondroitin sulfate proteoglycans(CSPGs),normal constituents of the perineuronal nets in central nervous system(CNS),are secreted at the injury site and initially were thought to act as a purely physical barrier.In the past decade,the receptor-like protein tyrosine phosphatases,protein tyrosine phosphatase sigma(PTPσ),and leukocyte common antigen-related phosphatase(LAR),have been identified as transmembrane receptors for CSPGs.The two receptors for myelin-associated growth inhibitors,Nogo receptors 1 and 3(NgR1 and NgR3)also have been found to bind with CSPGs(Sharma et al.,2012).These findings suggest that CSPGs inhibit regeneration by interacting with these receptors,initiating downstream inhibitory signaling(Figure 1).

Combination of mesenchymal stem cells and three-dimensional collagen scaffold preserves ventricular remodeling in rat myocardial infarction model

BACKGROUND Cardiovascular diseases are the major cause of mortality worldwide.Regeneration of the damaged myocardium remains a challenge due to mechanical constraints and limited healing ability of the adult heart tissue.Cardiac tissue engineering using biomaterial scaffolds combined with stem cells and bioactive molecules could be a highly promising approach for cardiac repair.Use of biomaterials can provide suitable microenvironment to the cells and can solve cell engraftment problems associated with cell transplantation alone.Mesenchymal stem cells(MSCs)are potential candidates in cardiac tissue engineering because of their multilineage differentiation potential and ease of isolation.Use of DNA methyl transferase inhibitor,such as zebularine,in combination with three-dimensional(3D)scaffold can promote efficient MSC differentiation into cardiac lineage,as epigenetic modifications play a fundamental role in determining cell fate and lineage specific gene expression.AIM To investigate the role of collagen scaffold and zebularine in the differentiation of rat bone marrow(BM)-MSCs and their subsequent in vivo effects.METHODS MSCs were isolated from rat BM and characterized morphologically,immunophenotypically and by multilineage differentiation potential.MSCs were seeded in collagen scaffold and treated with 3μmol/L zebularine in three different ways.Cytotoxicity analysis was done and cardiac differentiation was analyzed at the gene and protein levels.Treated and untreated MSC-seeded scaffolds were transplanted in the rat myocardial infarction(MI)model and cardiac function was assessed by echocardiography.Cell tracking was performed by DiI dye labeling,while regeneration and neovascularization were evaluated by histological and immunohistochemical analysis,respectively.RESULTS MSCs were successfully isolated and seeded in collagen scaffold.Cytotoxicity analysis revealed that zebularine was not cytotoxic in any of the treatment groups.Cardiac differentiation analysis showed more pronounced results in the type 3 treatment group which was subsequently chosen for the transplantation in the in vivo MI model.Significant improvement in cardiac function was observed in the zebularine treated MSC-seeded scaffold group as compared to the MI control.Histological analysis also showed reduction in fibrotic scar,improvement in left ventricular wall thickness and preservation of ventricular remodeling in the zebularine treated MSC-seeded scaffold group.Immunohistochemical analysis revealed significant expression of cardiac proteins in DiI labeled transplanted cells and a significant increase in the number of blood vessels in the zebularine treated MSC-seeded collagen scaffold transplanted group.CONCLUSION Combination of 3D collagen scaffold and zebularine treatment enhances cardiac differentiation potential of MSCs,improves cell engraftment at the infarcted region,reduces infarct size and improves cardiac function.

Heterogeneity in the regenerative abilities of central nervous system axons within species: why do some neurons regenerate better than others?

Some neurons,especially in mammalian peripheral nervous system or in lower vertebrate or in vertebrate central nervous system(CNS)regenerate after axotomy,while most mammalian CNS neurons fail to regenerate.There is an emerging consensus that neurons have different intrinsic regenerative capabilities,which theoretically could be manipulated therapeutically to improve regeneration.Population-based comparisons between"good regenerating"and"bad regenerating"neurons in the CNS and peripheral nervous system of most vertebrates yield results that are inconclusive or difficult to interpret.At least in part,this reflects the great diversity of cells in the mammalian CNS.Using mammalian nervous system imposes several methodical limitations.First,the small sizes and large numbers of neurons in the CNS make it very difficult to distinguish regenerating neurons from non-regenerating ones.Second,the lack of identifiable neurons makes it impossible to correlate biochemical changes in a neuron with axonal damage of the same neuron,and therefore,to dissect the molecular mechanisms of regeneration on the level of single neurons.This review will survey the reported responses to axon injury and the determinants of axon regeneration,emphasizing non-mammalian model organisms,which are often under-utilized,but in which the data are especially easy to interpret.

Metabolic reprogramming of glial cells as a new target for central nervous system axon regeneration

After central nervous system(CNS)injury,severed axons fail to regenerate and their disconnections to the original targets result in permanent functional deficits in patients(Mahar and Cavalli,2018).Both the diminished intrinsic regenerative capacity of mature neurons and the inhibitory CNS milieu contribute to the regenerative failure following CNS injury.

Vasoactive-Ventilation-Renal Score Predicts Cardiac Care Unit Length of Stay in Patients Undergoing Re-Entry Sternotomy: A Derivation Study

Background: The vasoactive-ventilation-renal (VVR) score includes pulmonary and renal dysfunctions not previously addressed by the vasoactive inotrope score (VIS) and may be a better predictor of cardiac care unit (CCU) length of stay (LOS) in patients undergoing re-entry sternotomy (defined as no earlier than 30 days after previous sternotomy) for congenital heart disease (CHD). Methods: Patients undergoing re-entry sternotomy for CHD from August 1, 2009 to June 30, 2016 were studied retrospectively. A total of 96 patients undergoing 133 re-entry procedures were identified. VVR scores were calculated on CCU admission post-procedure (at 0 hour), 24-hour, and 48-hour after admission to the CCU. The response variable was CCU LOS.? Recursive partition analysis identified variables predicting LOS. Results: 133 re-entry sternotomies in 96 patients made up the samples of the database;11 samples were removed due to incomplete data or placement on ECMO. Of the initial 25 features, 5 were removed for near zero variance and 3 categorical features were removed for non-information. Covariance analysis did not demonstrate any significant correlation amongst the remaining features. Initial recursive tree regression using ANOVA, cross validation and conditional predictive p-value (cp) = 0.01 produced 3 trees. The tree with lowest cross validation error was selected. The resulting 2 split trees with ventilator days less than 20 days and VVR score at 48 hours greater than 23 identified three CCU LOS groups with mean CCU LOS of 77.6, 55.1, and 9.5 days. Conclusions: Recursive partition analysis identified ventilator days greater than 20 days and the sub-population VVR at 48 hours as predictive of CCU LOS in patients undergoing re-entry sternotomy for CHD.

RhoA as a target to promote neuronal survival and axon regeneration

Paralysis following spinal cord injury （SCI） is due to failure of axonal regeneration. It is believed that the capacities of neurons to regrow their axons are due partly to their intrinsic characteristics, which in turn are greatly influenced by several types of inhibitory molecules that are present, or even increased in the extracellular environment of the injured spinal cord. Many of these inhibitory molecules have been studied extensively in recent years. It has been suggested that the small GTPase RhoA is an intracellular convergence point for signaling by these extracellular inhibitory molecules, but due to the complexity of the central nervous system （CNS） in mammals, and the limitation of pharmacological tools, the specific roles of RhoA are unclear. By exploiting the anatomical and technical advantages of the lamprey CNS, we recently demonstrated that RhoA knockdown promotes true axon regeneration through the lesion site after SCI. In addition, we found that RhoA knockdown protects the large, identified reticulospinal neurons from apoptosis after their axons were axotomized in spinal cord. Therefore, manipulation of the RhoA signaling pathway may be an important approach in the development of treatments that are both neuroprotective and axon regeneration-promoting, to enhance functional recovery after SCI.

(-)-Epigallocatechin-3-gallate enhances poly I:C-induced interferon-λ1 production and inhibits hepatitis C virus replication in hepatocytes

AIM To investigate the effect of(-)-epigallocatechin-3-gallate(EGCG) on polyinosinic-polycytidylic acid(poly I:C)-triggered intracellular innate immunity against hepatitis C virus(HCV) in hepatocytes. METHODS A cell culture model of HCV infection was generated by infecting a hepatoma cell line, Huh7, with HCV JFH-1 strain(JFH-1-Huh7). Poly I:C with a high molecular weight and EGCG were used to stimulate the JFH-1-Huh7 cells. Real-time reverse transcription-polymerase chain reaction was used to detect the expression levels of intracellular m RNAs and of intracellular and extracellular HCV RNA. Enzyme-linked immunosorbent assay was used to evaluate the interferon(IFN)-λ1 protein level in the cell culture supernatant. Immunostaining was used to examine HCV core protein expression in Huh7 cells.RESULTS Our recent study showed that HCV replication could impair poly I:C-triggered intracellular innate immune responses in hepatocytes. In the current study, we showed that EGCG treatment significantly increased the poly I:C-induced expression of Toll-like receptor 3(TLR3), retinoic acid-inducible gene I, and IFN-λ1 in JFH-1-Huh7 cells. In addition, supplementation with EGCG increased the poly I:C-mediated antiviral activity in JFH-1-Huh7 cells at the intracellular and extracellular HCV RNA and protein levels. Further investigation of the mechanisms showed that EGCG treatment significantly enhanced the poly I:C-induced expression of IFN-regulatory factor 9 and several antiviral IFNstimulated genes, including ISG15, ISG56, myxovirus resistance A, and 2'-5'-oligoadenylate synthetase 1, which encode the key antiviral elements in the IFN signaling pathway. CONCLUSION Our observations provide experimental evidence that EGCG has the ability to enhance poly I:C-induced intracellular antiviral innate immunity against HCV replication in hepatocytes.

Oligodendrocyte pathology in fetal alcohol spectrum disorders

The pathology of fetal alcohol syndrome and the less severe fetal alcohol spectrum disorders includes brain dysmyelination.Recent studies have shed light on the molecular mechanisms underlying these white matter abnormalities.Rodent models of fetal alcohol syndrome and human studies have shown suppressed oligodendrocyte differentiation and apoptosis of oligodendrocyte precursor cells.Ethanol exposure led to reduced expression of myelin basic protein and delayed myelin basic protein expression in rat and mouse models of fetal alcohol syndrome and in human histopathological specimens.Several studies have reported increased expression of many chemokines in dysmyelinating disorders in central nervous system,including multiple sclerosis and fetal alcohol syndrome.Acute ethanol exposure reduced levels of the neuroprotective insulin-like growth factor-1 in fetal and maternal sheep and in human fetal brain tissues,while ethanol increased the expression of tumor necrosis factor α in mouse and human neurons.White matter lesions have been induced in the developing sheep brain by alcohol exposure in early gestation.Rat fetal alcohol syndrome models have shown reduced axon diameters,with thinner myelin sheaths,as well as reduced numbers of oligodendrocytes,which were also morphologically aberrant oligodendrocytes.Expressions of markers for mature myelination,including myelin basic protein,also were reduced.The accumulating knowledge concerning the mechanisms of ethanol-induced dysmyelination could lead to the development of strategies to prevent dysmyelination in children exposed to ethanol during fetal development.Future studies using fetal oligodendrocyte-and oligodendrocyte precursor cell-derived exosomes isolated from the mother's blood may identify biomarkers for fetal alcohol syndrome and even implicate epigenetic changes in early development that affect oligodendrocyte precursor cell and oligodendrocyte function in adulthood.By combining various imaging modalities with molecular studies,it may be possible to determine which fetuses are at risk and to intervene therapeutically early in the pregnancy.

Regional anesthesia for orthopedic procedures:What orthopedic surgeons need to know

Regional anesthesia is an integral component of successful orthopedic surgery.Neuraxial anesthesia is commonly used for surgical anesthesia while peripheral nerve blocks are often used for postoperative analgesia.Patient evaluation for regional anesthesia should include neurological,pulmonary,cardiovascular,and hematological assessments.Neuraxial blocks include spinal,epidural,and combined spinal epidural.Upper extremity peripheral nerve blocks include interscalene,supraclavicular,infraclavicular,and axillary.Lower extremity peripheral nerve blocks include femoral nerve block,saphenous nerve block,sciatic nerve block,iPACK block,ankle block and lumbar plexus block.The choice of regional anesthesia is a unanimous decision made by the surgeon,the anesthesiologist,and the patient based on a risk-benefit assessment.The choice of the regional block depends on patient cooperation,patient positing,operative structures,operative manipulation,tourniquet use and the impact of postoperative motor blockade on initiation of physical therapy.Regional anesthesia is safe but has an inherent risk of failure and a relatively low incidence of complications such as local anesthetic systemic toxicity(LAST),nerve injury,falls,hematoma,infection and allergic reactions.Ultrasound should be used for regional anesthesia procedures to improve the efficacy and minimize complications.LAST treatment guidelines and rescue medications(intralipid)should be readily available during the regional anesthesia administration.

Aging is associated with cardiac autonomic nerve fiber depletion and reduced cardiac and circulating BDNF levels

Background Aging is a multifactorial process associated with an impairment of autonomic nervous system(ANS)function.Progressive ANS remodeling includes upregulation of expression of circulating catecholamines and depletion of cardiac autonomic nerve fibers,and it is responsible,in part,for the increased susceptibility to cardiac diseases observed in elderly subjects.Neurotrophic factors,such as brain-derived neurotrophic factor(BDNF)and nerve growth factor(NGF),are involved in synaptogenesis and neurite outgrowth processes,supporting neuronal cell differentiation and maturation.However,whether and how these factors and their downstream signaling are involved in cardiac aging remains unclear.Here,we tested whether,in the aged heart,the overall extent of autonomic fibers is reduced,owing to lower production of trophic factors such as BDNF and NGF.Methods In vivo,we used young(age:3 months;n=10)and old(age:24 months;n=11)male Fisher rats,whereas,we used human neuroblastoma(SH-SY5 Y)cells in vitro.Results Compared to the young rats,old rats displayed a marked reduction in the overall ANS fiber density,affecting both sympathetic and cholinergic compartments,as indicated by dopamineβ-hydroxylase(dβh)and vesicular acetylcholine transporter(Va Ch T)immunohistochemical staining.In addition,a marked downregulation of GAP-43 and BDNF protein was observed in the left ventricular lysates of old rats compared to those of young rats.Interestingly,we did not find any significant difference in cardiac NGF levels between the young and old groups.To further explore the impact of aging on ANS fibers,we treated SH-SY5 Y cells in vitro with serum obtained from young and old rats.Sera from both groups induced a remarkable increase in neuronal sprouting,as evidenced by a crystal violet assay.However,this effect was blunted in cells cultured with old rat serum and was accompanied by a marked reduction in GAP-43 and BDNF protein levels.Conclusions Our data indicate that physiological aging is associated with an impairment of ANS structure and function and that reduced BDNF levels are responsible,at least in part,for these phenomena.

Reactive astrocyte scar and axon regeneration:suppressor or facilitator?

Several major factors are known to contribute to CNS axon regenerative failure after injury, including reduced intrinsic growth capacity of developed neurons and extrinsic factors mediating axon outgrowth. For the latter, a non-permissive environment around the lesion and the lack of sufficient neurotrophic support within the adult CNS play important roles （Silver et al., 2015）. In addition to generation of various inhibitory substrates by oligodendrocytes, fibrotic tissues, inflammatory cells and other cell types, reactive astrocytes surrounding lesions are thought to highly suppress regeneration of injured CNS axons （Silver and Miller, 2004; Ohtake and Li, 2014）. A great number of studies suggest that reactive astrocytic scars form one of the major barriers preventing axon regeneration after CNS iniuries, including spinal cord injury （SCI）. However, reactive astrocytes were reported to provide a beneficial role by reducing infiltrating immunoreactive cells into adjacent domains, protecting bordering neural tissue from damage and generating numerous supportive extracellular matrix （ECM） components to promote cell survival and growth （Bush et al., 1999）. Previ- ous data showed that ablation of reactive astrocytes increased inflammation and secondary tissue damage, prevented blood- brain barrier formation and increased local neurite growth. Interestingly, a recent study by Anderson et al （2016） provides evidence that reactive astrocytes around the lesioned spinal cord support axon regeneration after SCI, rather than block regrowth （Anderson et al., 2016）.