Recent studies have highlighted the important role that vulnerability of nonsomatic neuronal compartments such as axons and synapses plays in the instigation and progression of neurodegenerative diseases, including Alzheimers disease, multiple sclerosis, prion disease, Huntingtons disease, and motor neuron diseases [1-4]. However, our understanding of the independent mechanisms that are required to regulate degenerative pathways in axons and synapses remains in its infancy. One powerful experimental tool that has already yielded novel insights into such pathways is the slow Wallerian degeneration (Wld s ) mutation that selectively protects axons and synapses in the central and peripheral nervous systems following a wide variety of traumatic and disease-related, degeneration-inducing stimuli [5-12].. The Wld s mutation occurred spontaneously in a breeding colony of C57Bl/6 mice, resulting in a tandem triplication of an 85 kilobase region on distal chromosome 4 [13]. The Wld s gene encodes a ...

For more than a century, scientists believed that injured axons severed from the neuron cell body passively wasted away due to a lack of nutrients. However, a mouse mutation identified in the early 1990s - called slow Wallerian degeneration (Wlds) - was able to suppress axon degeneration for weeks. This finding forced scientists to reassess Wallerian degeneration, the process through which an injured axon degenerates, as a passive process and consider the possibility that an active program of axon auto-destruction, akin to apoptotic death, was at work instead. If Wallerian degeneration was an active process, hypothesized Dr. Freeman, a Howard Hughes Medical Institute Early Career Scientist, then it should be possible through forward genetic screens in Drosophila to identify mutants exhibiting Wlds-like axon protection. Freeman and colleagues screened more than 2,000 Drosophila mutants for ones that exhibited long-term survival of severed axons. Freeman says this was a heroic effort on the part ...

P. K. Thomas, H. Sheldon; TUBULAR ARRAYS DERIVED FROM MYELIN BREAKDOWN DURING WALLERIAN DEGENERATION OF PERIPHERAL NERVE , Journal of Cell Biology, Volume 22, I

Wallerian degeneration (Fig. 2 A, left) is undoubtedly the most thoroughly investigated form of axon loss-and indeed, ongoing research is revealing the molecular pathways that result in the removal of severed axon segments. The starting point for this mechanistic deconstruction of Wallerian axon dismantling has been the serendipitous identification of a spontaneous mouse mutant with profoundly delayed Wallerian degeneration (WLDS [Wallerian degeneration slow]; Lunn et al., 1989). Molecular genetic analysis of this mutant has resulted in the surprising identification of enzymes of the NAD biosynthetic pathway as central players in axon degeneration (Coleman et al., 1998; Conforti et al., 2000), even though the details of the underlying molecular mechanisms that actually result in axon fragmentation remain to be elucidated. Importantly, the phylogenetic conservation of WLDS sensitivity has allowed identification of Wallerian-like degeneration events in screenable organisms, such as Drosophila ...

Many changes in gene expression occur in distal stumps of injured nerves but the transcriptional control of these events is poorly understood. We have examined the expression of the transcription factors ATF3 and c-Jun by non-neuronal cells during Wallerian degeneration following injury to sciatic nerves, dorsal roots and optic nerves of rats and mice, using immunohistochemistry and in situ hybridization. Following sciatic nerve injury - transection or transection and reanastomosis - ATF3 was strongly upregulated by endoneurial, but not perineurial cells, of the distal stumps of the nerves by 1 day post operation (dpo) and remained strongly expressed in the endoneurium at 30 dpo when axonal regeneration was prevented. Most ATF3+ cells were immunoreactive for the Schwann cell marker, S100. When the nerve was transected and reanastomosed, allowing regeneration of axons, most ATF3 expression had been downregulated by 30 dpo. ATF3 expression was weaker in the proximal stumps of the injured nerves than in

This study aimed to evaluate the clinical significance of diffusion tensor imaging (DTI) in the early diagnosis of pyramidal tract Wallerian degeneration (WD) and assessment of neurological recovery following cerebral infarction. This study included 23 patients with acute cerebral infarction and 10 healthy adult controls. All participants underwent both magnetic resonance imaging (MRI) and DTI scans. DTI images were analyzed using the Functional MRI of the Brain Software Library to determine the regions of interest (ROI) and obtain the mean diffusivity (MD) and fractional anisotropy (FA) value for each ROI. The correlation between FA or MD and postinfarction functional recovery of the nervous system was further analyzed to assess the feasibility of using a DTI scan in the evaluation of functional recovery of the nervous system in patients with cerebral infarction. DTI may be useful in detecting signals of early postinfarction pyramidal tract WD and is useful for the evaluation of postinfarction ...

OBJECTIVE: This study tested the hypothesis that degeneration of the corticofugal tracts (CFTs) is related to poor functional outcome in the upper limb after stroke. METHODS: . The authors used diffusion tensor imaging to determine the degree of white matter integrity of the CFT (FA(AH/UH)) in chronic stroke patients and controls. The functional integrity of the corticospinal pathway was examined using transcranial magnetic stimulation. Recruitment curves and silent period duration were measured. The relationship between FA(AH/UH) and functional outcome of the upper limb was also assessed using a battery of upper limb function tests. RESULTS: In patients, FA( AH/UH) correlated positively with the slope of recruitment curves (RC(AH/UH)) and grip strength. FA(AH/UH) also correlated negatively with the silent period duration (SP(AH/UH)). According to the FA(AH/UH), patients were also classified into groups with minimal or extensive Wallerian degeneration (WD). Patients with more extensive WD had poorer

Despite the widespread occurrence of axon and synaptic loss in the injured and diseased nervous system, the cellular and molecular mechanisms of these key degenerative processes remain incompletely understood. Wallerian degeneration (WD) is a tightly regulated form of axon loss after injury, which has been intensively studied in large myelinated fibre tracts of the spinal cord, optic nerve and peripheral nervous system (PNS). Fewer studies, however, have focused on WD in the complex neuronal circuits of the mammalian brain, and these were mainly based on conventional endpoint histological methods. Post-mortem analysis, however, cannot capture the exact sequence of events nor can it evaluate the influence of elaborated arborisation and synaptic architecture on the degeneration process, due to the non-synchronous and variable nature of WD across individual axons. To gain a comprehensive picture of the spatiotemporal dynamics and synaptic mechanisms of WD in the nervous system, we identify the factors that

Wld(S) (slow Wallerian degeneration) is a remarkable protein that can suppress Wallerian degeneration of axons and synapses, but how it exerts this effect remains unclear. Here, using Drosophila and mouse models, we identify mitochondria as a key site of action for Wld(S) neuroprotective function. Targeting the NAD(+) biosynthetic enzyme Nmnat to mitochondria was sufficient to fully phenocopy Wld(S), and Wld(S) was specifically localized to mitochondria in synaptic preparations from mouse brain. Axotomy of live wild-type axons induced a dramatic spike in axoplasmic Ca(2+) and termination of mitochondrial movement-Wld(S) potently suppressed both of these events. Surprisingly, Wld(S) also promoted increased basal mitochondrial motility in axons before injury, and genetically suppressing mitochondrial motility in vivo dramatically reduced the protective effect of Wld(S). Intriguingly, purified mitochondria from Wld(S) mice exhibited enhanced Ca(2+) buffering capacity. We propose that the enhanced ...

CD200-CD200R. CD200 is primarily expressed on the surface of neurons in both the CNS and the PNS, as well as thymocytes, recirculating B cells, activated B cells, and follicular dendritic cells (62). CD200 receptor (CD200R) initiates tyrosine phosphorylation (63) and is expressed only on cells of the microglia/macrophage lineage (63, 64). Administration of a CD200R-blocking antibody to Lewis rats exacerbated EAE (63), and CD200-deficient mice experienced earlier onset of EAE, with increased microglia/macrophage accumulation and activation in the CNS as demonstrated by increased expression of inducible NOS (iNOS) (65). We found that administration of a CD200R1 agonist attenuated disease in a chronic MS model (66). Enhanced CD200 expression was associated with reduced Wallerian degeneration in the slow Wallerian degeneration (Wlds) mouse (67), a spontaneously occurring mutant with the unique phenotype of protection against several forms of axonal injury (68-71). In vitro, Wlds neuronal cultures ...

Axons require the axonal NAD-synthesizing enzyme NMNAT2 to survive. Injury or genetically-induced depletion of NMNAT2 triggers axonal degeneration or defective axon growth. We have previously proposed that axonal NMNAT2 primarily promotes axon survival by maintaining low levels of its substrate NMN, rather than generating NAD; however, this is still debated. NMN deamidase, a bacterial enzyme, shares NMN-consuming activity with NMNAT2, but not NAD-synthesizing activity, and delays axon degeneration in primary neuronal cultures. Here, we show that NMN deamidase can also delay axon degeneration in zebrafish larvae and in transgenic mice. Like overexpressed NMNATs, NMN deamidase reduces NMN accumulation in injured mouse sciatic nerves and preserves some axons for up to 3 weeks, even when expressed at a low level. Remarkably, NMN deamidase also rescues axonal outgrowth and perinatal lethality in mice lacking NMNAT2 in a dose-dependent manner. These data further support a pro-degenerative effect of ...

A common feature of many neuropathies is axon degeneration. While the reasons for degeneration differ greatly, the process of degeneration itself is similar in most cases. Axon degeneration after axotomy is termed Wallerian degeneration, whereby injured axons rapidly fragment and disappear after a short period of latency (Waller, 1850). Wallerian degeneration was thought to be a passive process until the discovery of the Wallerian degeneration slow (Wlds) mouse mutant. In these mice, axons survive and function for weeks after nerve transection. Furthermore, when the full-length protein is inserted into mouse models of disease with an axon degeneration phenotype (such as progressive motor neuronopathy), Wlds is able to delay disease onset (for a review, see Coleman, 2005). Wlds has been cloned and was found to be a fusion event of two neighboring genes: Ube4b, which encodes an ubiquitinating enzyme, and NMNAT-1 (nicotinamide mononucleotide adenylyltransferase-1), which encodes a key factor in NAD

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition that primarily affects the motor system and shares many features with frontotemporal dementia (FTD). Evidence suggests that ALS is a dying-back disease, with peripheral denervation and axonal degeneration occurring before loss of motor neuron cell bodies. Distal to a nerve injury, a similar pattern of axonal degeneration can be seen, which is mediated by an active axon destruction mechanism called Wallerian degeneration. Sterile alpha and TIR motif-containing 1 (Sarm1) is a key gene in the Wallerian pathway and its deletion provides long-term protection against both Wallerian degeneration and Wallerian-like, non-injury induced axonopathy, a retrograde degenerative process that occurs in many neurodegenerative diseases where axonal transport is impaired. Here, we explored whether Sarm1 signalling could be a therapeutic target for ALS by deleting Sarm1 from a mouse model of ALS-FTD, a TDP-43Q331K, YFP-H double transgenic mouse.

Axonal degeneration is an active program of self-destruction that is observed in many physiological and pathological settings. In Wallerian degeneration slow (wlds) mice, Wallerian degeneration in response to axonal injury is delayed because of a mutation that results in overexpression of a chimeric protein (Wlds) composed of the ubiquitin assembly protein Ufd2a and the nicotinamide adenine dinucleotide (NAD) biosynthetic enzyme Nmnat1. We demonstrate that increased Nmnat activity is responsible for the axon-sparing activity of the Wlds protein. Furthermore, we demonstrate that SIRT1, a mammalian ortholog of Sir2, is the downstream effector of increased Nmnat activity that leads to axonal protection. These findings suggest that novel therapeutic strategies directed at increasing the supply of NAD and/or Sir2 activation may be effective for treatment of diseases characterized by axonopathy and neurodegeneration. ...

Wallerian degenaration is a pattern of damage in nerve fibers in which the axon of a nerve breaks down because of a lesion on the...

In neurodegenerative disorders axons typically degenerate before neuronal cell death. This sequence of events, and particularly the early loss of distal axons, is known as dying back degeneration. The causes of axon degeneration include protein aggregation, inflammation, neurotoxicity and ischaemia, and many of these diverse stresses converge on a common degenerative pathway involving axonal transport impairment. Axonal transport is the bidirectional trafficking of molecules and organelles along axons for huge cellular distances. It is essential for axon survival but deficient in multiple sclerosis, glaucoma, motor neuron disease and many other disorders.. Despite the prevalence of axonal transport impairment, the specific molecular changes leading to axon degeneration are poorly understood. Cutting axons, which causes Wallerian degeneration, is a useful experimental model that can help identify the key molecular events. A mutant protein named Wallerian degeneration slow (WldS) delays ...

in Glia (2011), 59(3), 379-396. Wallerian degeneration (WD) is an inflammatory process of nerve degeneration, which occurs more rapidly in the peripheral nervous system compared with the central nervous system, resulting, respectively ... [more ▼]. Wallerian degeneration (WD) is an inflammatory process of nerve degeneration, which occurs more rapidly in the peripheral nervous system compared with the central nervous system, resulting, respectively in successful and aborted axon regeneration. In the peripheral nervous system, Schwann cells (SCs) and macrophages, under the control of a network of cytokines and chemokines, represent the main cell types involved in this process. Within this network, the role of placental growth factor (PlGF) remains totally unknown. However, properties like monocyte activation/attraction, ability to increase expression of pro-inflammatory molecules, as well as neuroprotective effects, make it a candidate likely implicated in this process. Also, nothing is ...

Intracerebral hemorrhage (ICH) often produces severe neurological deficits in survivors, which is closely related with secondary corticospinal tract (CST) injury. Rodent models of ICH have greatly promoted the understanding of histopathology underlying brain injury and were employed widely for exploring therapeutic strategies. This study investigated WD in pyramidal tract, as part of CST, after experimental ICH using diffusion tensor imaging (DTI) and T2-weighted imaging as well as with histological correlations. The results demonstrated DTI as a valuable tool for detecting WD in early phase and for longitudinal monitoring of its progress at different stages with more accuracy than T2-weighted imaging ...

We longitudinally studied the course of WD in two patients by DTI and found a pattern of progressive structural degeneration which corresponds well to findings from experimental studies of WD. From these studies we know that anisotropy of diffusion in white matter mainly results from oriented membranes, such as axonal structures and myelin.5 Disintegration of axonal structures and myelin, as occurs in WD, results in loss of anisotropy, which is detected by DTI.5 Signal changes resulting from WD after ischaemic stroke have been detected by DTI in the early subacute stage8 as well as in chronic stroke.6,7. Structural changes in WD evolve over time with progressive destruction of fibre structures followed by gliosis.1,2 We found progressive loss of anisotropy resulting from reduced first eigenvalue and increased second and third eigenvalues. We interpret these changes as a reflection of the progressive structural alterations resulting from WD. Moreover, although in the early subacute stage no clear ...

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Axon degeneration is a characteristic feature of multiple neuropathologic states and is also a mechanism of physiological neurodevelopmental pruning. The vast majority of in vivo studies looking at axon degeneration have relied on the use of classical silver degeneration stains, which have many limitations including lack of molecular specificity and incompatibility with immunolabeling methods. Because Wallerian degeneration is well known to involve cytoskeletal disassembly and because caspases are recently implicated in aspects of this process, we asked whether antibodies directed at caspase-generated neoepitopes of beta-actin and alpha-tubulin would be useful immunohistochemical markers of pathological and developmental axon degeneration. Here we demonstrate that several forms of axon degeneration involve caspase-mediated cleavage of these cytoskeletal elements and are well-visualized using this approach. We demonstrate the generation of caspase-induced neoepitopes in a) an in vitro neuronal culture

TY - JOUR. T1 - Protecting axonal degeneration by increasing nicotinamide adenine dinucleotide levels in experimental autoimmune encephalomyelitis models. AU - Kaneko, Shinjiro. AU - Wang, Jing. AU - Kaneko, Marie. AU - Yiu, Glenn C. AU - Hurrell, Joanna M.. AU - Chitnis, Tanuja. AU - Khoury, Samia J.. AU - He, Zhigang. PY - 2006/9/20. Y1 - 2006/9/20. N2 - Axonal damage is a major morphological alteration in the CNS of patients with multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the underlying mechanism for the axonal damage associated with MS/EAE and its contribution to the clinical symptoms remain unclear. The expression of a fusion protein, named Wallerian degeneration slow (Wlds), can protect axons from degeneration, likely through a β-nicotinamide adenine dinucleotide (NAD)-dependent mechanism. In this study, we find that, when induced with EAE, Wlds mice showed a modest attenuation of behavioral deficits and axon loss, suggesting ...

Axonal degeneration is an early feature of several neurodegenerative conditions, but the sequence of events leading to this axonal loss is still unknown. The role of calcium in this degenerative process has long been accepted, but there is no detailed understanding of the calcium source(s) and dynamics. Chelation of extracellular calcium protects against axonal degeneration triggered by axotomy (George et al., 1995), and depletion of intracellular calcium stores protects against axonal degeneration under ischemic conditions (Stys, 2005). We showed previously that a crucial event during axonal degeneration is the opening of the mPTP (Barrientos et al., 2011), which is highly dependent on calcium levels (Halestrap et al., 1986). The data that we present here establishes that the release of ER-derived calcium store is a critical step in Wallerian degeneration by activating the mPTP that leads to axonal loss.. Our results show that chelation of external calcium can protect from neurofilament ...

In the present work, we demonstrate that in peripheral nerves of P0het mice, a model for CMT1B, endogenous antibodies strongly decorate endoneurial tubes of peripheral nerves whereas nerve fibers of wt mice are only weakly labeled. These antibodies comprise IgG and IgM subtypes and are preferentially, but not exclusively, associated with nerve fiber aspects nearby nodes of Ranvier. Furthermore, in the absence of antibodies, the early demyelinating phenotype is substantially ameliorated. Reverting the neuropathy by reconstitution with murine IgG fractions identified accumulating antibodies as potentially pathogenic at this early stage of disease.. Antibody deposition as an accelerator of myelin phagocytosis has recently been demonstrated for nerve injury, inducing Wallerian degeneration [16]. After crush injury, endogenous, preexisting antibodies were strongly accumulated along endoneurial tubes of the lesioned as opposed to intact nerves, where similarly weak labeling was detected as in our wt ...

Nerve injury is injury to nervous tissue. There is no single classification system that can describe all the many variations of nerve injury. In 1941, Seddon introduced a classification of nerve injuries based on three main types of nerve fiber injury and whether there is continuity of the nerve. Usually, however, (peripheral) nerve injury is classified in five stages, based on the extent of damage to both the nerve and the surrounding connective tissue, since supporting glial cells may be involved. Unlike in the central nervous system, neuroregeneration in the peripheral nervous system is possible. The processes that occur in peripheral regeneration can be divided into the following major events: Wallerian degeneration, axon regeneration/growth, and nerve reinnervation. The events that occur in peripheral regeneration occur with respect to the axis of the nerve injury. The proximal stump refers to the end of the injured neuron that is still attached to the neuron cell body; it is the part that ...

Background Stroke is the third most common cause of death and a primary source of disability among the elderly in Taiwan. Ischemic stroke accounts for 80 to 85 percent of all strokes and occurs most frequently in the middle cerebral artery (MCA) territory. Previous studies have shown a subgroup of MCA infarct patients who developed movement disorders in the subacute period of stroke, had delayed recovery. The postinfarct movement disorders include chorea, dystonia, tremors and parkinsonism which appear to be caused by secondary trans-neuronal degeneration of the substantial nigra (SN) along with Wallerian degeneration of the corticospinal tracts. Because the occurrence of trans-synaptic neuronal degeneration is difficult to quantify, we aim to investigate quantitatively the delayed neuronal changes in SN and motor-related structures using MR inversion recovery grey matter-suppressed (GMS) technique, diffusion tensor imaging (DTI) and proton MR spectroscopy in these groups of patients in an ...

In this review we summarize the events known to occur after an injury in the peripheral nervous system. We have focused on the Schwann cells, as they are the most important cells for the repair process and facilitate axonal outgrowth. The environment created by this cell type is essential for the outcome of the repair process. The review starts with a description of the current state of knowledge about the initial events after injury, followed by Wallerian degeneration, and subsequent regeneration. The importance of surgical repair, carried out as soon as possible to increase the chances of a good outcome, is emphasized throughout the review. The review concludes by describing the target re-innervation, which today is one of the most serious problems for nerve regeneration. It is clear, compiling this data, that even though regeneration of the peripheral nervous system is possible, more research in this area is needed in order to perfect the outcome.

The most plausible explanation for the T2 signal-intensity hyperintensity along the hemispheric white matter in or around the corticospinal tract is the presence of mild brain edema, which is further supported from the results of a recent study, which, by using a coregistered MR imaging technique, demonstrated an increase in ventricular volume following medical treatment of HE.98. The T2 signal-intensity changes observed in some patients with cirrhosis are quite similar to those observed in amyotrophic lateral sclerosis, in which the pathologic bases are axonal loss, demyelination, or wallerian degeneration.99 However, none of these pathologic features have been described in association with HE. Moreover, the 1H-MR spectroscopic findings of normal N-acetylaspartate indices (a neuronal marker) and low concentrations of choline-containing compounds indicate preservation of axonal attenuation and lack of demyelinating processes (Fig 1).57 The progressive normalization of the high-signal-intensity ...

Cryoneurolysis is a minimally invasive, low side effect profile, evidence-supported intervention currently with FDA approval to produce lesions in peripheral nervous tissue, including for relief of pain associated with knee osteoarthritis. The mechanism of action on a peripheral nerve is temporary axonal signal disruption via Wallerian degeneration. While the axon and myelin sheath degenerate, the endoneurium, perineurium and epineurium are unaffected. Schwann cells and macrophages clear debris, and secrete growth factors that allow for axonal regrowth.

Background: The phenomenon of diaschisis, with wallerian degeneration, can increase the brain lesion burden in unilateral vascular ischemic lesion leading to contralateral damage. Diffusion tensor imaging (DTI) allows the visualization and measurement of white matter lesions. We tested the hypothesis that there are white matter tracts lesions in the hemisphere contralateral to the ischemic lesion.. Methods: Patients with unilateral ischemic lesions, who had performed a diagnostic MRI including DTI sequence (Philips Achieva 3T, Best, Netherlands) from August 2009 to April 2010 were selected. A neuroradiologist analyzed the images and selected the ones with unilateral ischemic lesion on middle cerebral artery territory. For comparisons, images of healthy-control subjects with similar age, from the local neuroimaging laboratory, were used. The DTI images (TR=8500, TE=61, 2mm of slice thickness, 32 directions, b-factor 1000) were analyzed using a tract based statistical study (TBSS, fMRIB software ...

No claim to original U.S. Government Works The Zika virus (ZIKV) epidemic is associated with fetal brain lesions and other serious birth defects classified as congenital ZIKV syndrome. Postnatal ZIKV infection in infants and children has been reported; however, data on brain anatomy, function, and behavioral outcomes following infection are absent. We show that postnatal ZIKV infection of infant rhesus macaques (RMs) results in persistent structural and functional alterations of the central nervous system compared to age-matched controls. We demonstrate ZIKV lymphoid tropism and neurotropism in infant RMs and histopathologic abnormalities in the peripheral and central nervous systems including inflammatory infiltrates, astrogliosis, and Wallerian degeneration. Structural and resting-state functional magnetic resonance imaging (MRI/rs-fMRI) show persistent enlargement of lateral ventricles, maturational changes in specific brain regions, and altered functional connectivity (FC) between brain ...

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During development of the peripheral nervous system, sensory axons extend to the periphery in excess where they compete for limiting target-derived neurotrophic support. Local neurotrophin insufficiency triggers axon degeneration, resulting in the pruning of over half of all sensory axons during development. Although axon degeneration facilitates the essential sculpting of the developing nervous system, its improper activation may underlie several neurodegenerative disorders. This process can be modeled in vitro by culturing sensory neurons from mouse dorsal root ganglia in the presence of nerve growth factor either as explant cultures or in compartmented chambers that allow independent manipulation of cell bodies and axons. The mitochondrial apoptotic pathway and the effector caspases, Caspase-3 and Caspase-6, mediate axon degeneration in both this in vitro model system and in vivo, clearly indicating a role for classical apoptotic machinery in axon degeneration. However, the full mechanism executing

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While magnetic resonance imaging has revealed progressive changes in the pyramidal tract in accordance with histopathologic stages of wallerian degeneration secondary to a supratentorial lesion, computed tomography (CT) has only demonstrated a shrinkage of the pyramidal tract in the midbrain or pons during the chronic stage. We present a patient with frontoparietal subcortical hemorrhage in whom serial CT scans clearly demonstrated wallerian degeneration along the axis of the pyramidal tract early in the acute stage.. A 63-year-old man with a history of hypertension suddenly developed a deterioration of consciousness, transcortical mixed aphasia, and dense hemiplegia on the right side. CT scans revealed a massive intracerebral hematoma in the frontoparietal subcortices of the left hemisphere. Although initial CT did not detect any hypodense areas along the left pyramidal tract below the hematoma, ill-defined areas of decreased density appeared in the posterior limb of the internal capsule, ...

TY - JOUR. T1 - Expression of genes encoding receptors for IgG (FcRIII) and for C3b/C4b (Crry) in rat sciatic nerve during development and Wallerian degeneration. AU - Vedeler, C. A.. AU - Conti, G.. AU - Bannerman, P.. AU - Pleasure, David E. PY - 1992. Y1 - 1992. N2 - Northern blots were used to examine the expression of genes encoding receptors for IgG (FcRIII) and for C3b/C4b (Crry) in rat sciatic nerve during development and Wallerian degeneration. Steady state levels of FcRIII (1.4 kb) and Crry (1.9 and 2.1 kb) mRNAs were higher in adult rat nerves than in 6 day and 21 day postnatal rat nerves, indicating that the expression of these receptors is developmentally regulated. The FcRIII and Crry cDNA probes also hybridized with total RNA from 3 day old rat Schwann cells and from adult rat peritoneal macrophages. The size of the FcRIII mRNA expressed by cultured Schwann cells (1.6 kb) differed from that expressed by peritoneal macrophages (1.4 kb); the two may be splice variants of one ...

The aim of the present study was to examine inflammatory responses during Wallerian degeneration in rat peripheral nerve when the regrowth of axons was prevented by suturing. Transected rat sciatic nerve was sutured and ligated to prevent reinnervation. The samples were collected from the left sciatic nerve distally and proximally from the point of transection. The endoneurium was separated from the surrounding epi- and perineurium to examine the expression of cytokines in both of these compartments. Macrophage invasion into endoneurium was investigated and Schwann cell proliferation was followed as well as the expression of cytokines IL-1β, IL-10, IFN-γ and TNF-α mRNA. The samples were collected from 1 day up to 5 weeks after the primary operation. At days 1 to 3 after injury in the epi-/perineurium of the proximal and distal stump, a marked expression of the pro-inflammatory cytokines TNF-α and IL-1β and of the anti-inflammatory cytokine IL-10 was observed. Concurrently, numerous macrophages

Further evidence comes from studies in Drosophila, showing that the degeneration of axons occurring during pruning requires the UPS (Watts et al., 2003). Axon pruning is an important process for the refinement of the neuronal connections in both vertebrates and invertebrates. Studying development of particular projecting neurons of the Drosophila mushroom bodies it was shown that overexpression of an ubiquitin protease or a mutant form of the Drosophila E1 ubiquitin-activating enzyme, inhibited pruning (Watts et al., 2003). Likewise, mutations in two of the subunits in the 19S regulatory particle (Fig. 1 A) also impaired pruning. This genetic evidence strongly suggests that local degeneration of protein via the UPS activity is a necessary requirement for axon pruning during development of the mushroom bodies. The relevance of these findings for Wallerian degeneration and axonal reactions in neurodegenerative diseases is not straightforward. However, there are similarities between these processes ...

The ability of mammalian CNS neurons to regrow their lesioned axons declines during late embryonic and postnatal development. Consequently, adult retinal ganglion cells of mammals respond to injuries with rapid anterograde and protracted retrograde (Wallerian) degeneration. To monitor the cascade of events initiated by neuronal injuries, and to explore whether the regressive events of this cascade can be blocked or reversed, axotomy-induced ganglion cell responses were investigated in adult rats. The aim of the experiments was to block degradation of axotomized ganglion cells with enzymes which inhibit proteolytic activities within the retina (protease inhibitors). To achieve this goal, a new fluorescence technique was employed to assess both the chronotopological pattern of degradation and the efficacy of the protease inhibitors and anti-inflammatory treatment in preventing cell death. Injection of protease inhibitors alone or combined with dexamethasone into the vitreous body of animals whose ...

Neuroregeneration refers to the regrowth or repair of nervous tissues, cells or cell products. Such mechanisms may include generation of new neurons, glia, axons, myelin, or synapses. Neuroregeneration differs between the peripheral nervous system (PNS) and the central nervous system (CNS) by the functional mechanisms and especially the extent and speed. When an axon is damaged, the distal segment undergoes Wallerian degeneration, losing its myelin sheath. The proximal segment can either die by apoptosis or undergo the chromatolytic reaction, which is an attempt at repair. In the CNS, synaptic stripping occurs as glial foot processes invade the dead synapse. Nervous system injuries affect over 90,000 people every year. It is estimated that spinal cord injuries alone affect 10,000 each year. As a result of this high incidence of neurological injuries, nerve regeneration and repair, a subfield of neural tissue engineering, is becoming a rapidly growing field dedicated to the discovery of new ways ...

1. The oxidation of the three branched-chain amino acids was regulated in parallel fashion in rat tissues studied in vitro. 2. With 0.1 mM-[1-14C]isoleucine as substrate in the presence of 5.5 mM-glucose, 14CO2 production was 0.6 mumol/2 h per g in the aorta, 0.3 in peripheral nerve, 0.2 in muscle and 0.13 in spinal cord. 3. The ratio 14C oxidized/14C incorporated into proteins with 0.1 mM-[1-14C]leucine was 1.3 in hemidiaphragms, 3.3 in sciatic nerve and 1.0 in nerves undergoing Wallerian degeneration. Leucine oxidation decreased only slightly during degeneration, but protein synthesis doubled. 4. Hemidiaphragms incubated with [1-14C]leucine or 4-methyl-2-oxo[1-14C]pentanoate increased 14CO2 production 7-9-fold as substrate concentration was increased from 0.1 to 0.5 mM; under the same conditions 14CO2 production by nerves increased only 2-3-fold. 5. 2-Oxoglutarate stimulated the oxidation of the branched-chain amino acids by muscles and peripheral nerves and the oxidation of ...

Chen P, Piao X, Bonaldo P. (2015). Role of macrophages in Wallerian degeneration and axonal regeneration after peripheral nerve injury. Acta Neuropathologica 130, 605-618. Schöneberg T, Liebscher I, Luo R, Monk KR, Piao X. (2015). Tethered agonists: a new mechanism underlying adhesion G protein-coupled receptor activation. Journal of Receptors and Signal Transduction 35, 220-223. Rao TN, Marks-Bluth J, Sullivan J, Gupta MK, Chandrakanthan V, Fitch SR, Ottersbach K, Jang YC, Piao X, Kulkarni RN, Serwold T, Pimanda JE, Wagers AJ. (2015). High-level Gpr56 expression is dispensable for the maintenance and function of hematopoietic stem and progenitor cells in mice. Stem cell research 14, 307-322. Hamann J, Aust G, Araç D, Engel FB, Formstone C, Fredriksson R, Hall RA, Harty BL, Kirchhoff C, Knapp B, Krishnan A, Liebscher I, Lin HH, Martinelli DC, Monk KR, Peeters MC, Piao X, Prömel S, Schöneberg T, Schwartz TW, Singer K, Stacey M, Ushkaryov YA, Vallon M, Wolfrum U, Wright MW, Xu L, Langenhan T, ...

It is both instructive and convenient to consider the catastrophic loss of behavioral function following spinal cord injury (SCI) as two different syndromes: the initial, or acute, phase and the subsequent chronic condition. Theoretical biological approaches to treating each are not mutually exclusive, but must take into account the distinct pathologies characteristic of each phase of the injury.. During the acute phase, a delayed, progressive and self-propagating wave of cell and tissue destruction is initiated, with the injury leading to cell death, the formation of a cicatrix and the irreversible loss of distal segments of axons through Wallerian degeneration (Griffin et al., 1995). This latter dynamic is often referred to as secondary injury (Honmou and Young, 1995), and it is the loss of white matter, which cannot be replaced, that frames the more permanent behavioral loss accompanying the long-term, or chronic, phase of the injury.. Techniques aimed at regenerating new and functional ...

Calcium influx after axonal trauma has been hypothesized to be the major activator of deleterious processes after injury (Banik et al., 1987; Young, 1992; Lopachin and Lehning, 1997). It is thought that these processes lead to a delayed disconnection of axons after traumatic axonal injury (secondary axotomy) and to Wallerian degeneration of damaged axons in the white matter (Pleasure et al., 1992; George et al., 1995; Maxwell et al., 1997; Smith and Meaney, 2000). However, increased intra-axonal Ca2+ after stretch injury has yet to be directly demonstrated. In the present study, we used an in vitro axonal stretch-injury system that allows for the continuous examination of changes in intra-axonal Ca2+ levels. Using the Ca2+-sensitive dye fluo-4, we found that there is a substantial increase in axonal Ca2+ levels after stretch injury, dependent on extracellular Ca2+. In addition, we observed that this post-traumatic rise in intra-axonal Ca2+ was completely dependent on Na+ entering through ...

GARCIA-JUAREZ, Jaime et al. Evaluation of the Effect of Treatment with Lipoic Acid Administered to the Wistar Rat Intoxicated with the Fruit of Karwinskia humboldtiana. Int. J. Morphol. [online]. 2012, vol.30, n.2, pp.572-578. ISSN 0717-9502. http://dx.doi.org/10.4067/S0717-95022012000200035.. The accidental ingestion of Karwinskia humboldtiana causes a flaccid, symmetrical, progressive and ascending paralysis, similar to Guillain-Barre syndrome. It evolves over the course of 3 to 12 months until full recovery, but severe cases end in death due to respiratory failure. There is no specific treatment. The histopathological lesions described in peripheral nerve of patients and in experimental animals, corresponds to segmental demyelination accompanied by Wallerian degeneration. One of the toxins extracted from the seed, T-514, causes an increase of free radicals in vitro. Free radicals have been associated to demyelination that occurs in other types of neuropathy such as diabetic neuropathy. Since ...

Chung, R. S., Staal, J. A., McCormack, G. H., Dickson, T. C., Cozens, M. A., Chuckowree, J. A., Quilty, M. C., Vickers, J. C., 2005. Mild axonal stretch injury in vitro induces a progressive series of neurofilament alterations ultimately leading to delayed axotomy, Journal of neurotrauma, 22(10), 1081-91, which has now been formally published in final form at Journal of neurotrauma at https://doi.org/ 10.1089/neu.2005.22.1081. The original submission version of the article may be used for non-commercial purposes in accordance with the Mary Ann Liebert, Inc., publishers self-archiving terms and conditions.. Chapter 4 appears to be, in part, the equivalent of the peer reviewed version of the following article: Staal, J., Dickson, T., Chung, R., Vickers, J., 2007. Cyclosporin‐A treatment attenuates delayed cytoskeletal alterations and secondary axotomy following mild axonal stretch injury, Developmental deurobiology, 67(14), 1831-1842, which has been published in final form at ...

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2.0 ppm: N-Acetyl Aspartate (NAA) is regarded as a marker of neuronal integrity and will be reduced if neurons are being destroyed by a disease process.. • 3.0 ppm: Creatine (Cr) is the total peak from phosphocreatine and creatine and is often taken as a reference level, as it is relatively constant throughout the brain and it tends not to change significantly in disease process. However, there is evidence that it can change particularly in malignant tumours.. • 3.2 ppm: Choline (Cho) is considered to be an indicator of membrane activity since phosphocholines are released during myelin breakdown and it is often elevated if malignant processes are present.. • 3.6 ppm: myo-Inositol (mI) is a sugar alcohol which is thought to be a product of myelin breakdown and its peak is often higher in conditions such as Alzheimers disease and malignant tumours.. Lactate (Lac) at 1.3 ppm (on in vivo spectra its often hard to distinguish lipid from lactate) and Glutamine & Glutamate complex (Glx) at ...

The Trinity research group, led by Smurfit Professor of Medical Genetics, Professor Seamus Martin, has just published its findings in the internationally renowned, peer-reviewed Cell Press journal, Cell Reports.. Although mutation of Parkin has been known to lead to an early onset form of Parkinsons for many years, understanding what it actually did within cells has been difficult to solve. Now, Professor Martin and colleagues have discovered that in response to specific types of cell damage, Parkin can trigger the self-destruction of injured nerve cells by switching on a controlled process of cellular suicide called apoptosis.. Using cutting-edge research techniques, the Martin laboratory, funded by Science Foundation Ireland, found that damage to mitochondria (which function as cellular battery packs) activates the Parkin protein, which results in one of two different outcomes - either self-destruction or a repair mode. Which outcome was chosen depended on the degree of damage suffered ...

Importantly, the Trinity team also discovered that members of the Bcl-2 gene family could override this process, switching off the self-eating process and leading to survival of cancerous cells. This suggests that drugs targeting Bcl-2 might reactivate the natural self-destruction pathway and help to shrink tumours. The fact that mutant Ras triggers self-destruction of cells carrying this gene also helps to explain why the emergence of fully cancerous cells is relatively rare when we consider that the average human makes hundreds of billions of cells over the course of their lifetime. Commenting on the findings, Professor Martin stated: This discovery is an important step forward in our understanding of how cells in the early stages of cancer hit the autodestruct button and suggests new ways in which we may be able to re-activate this process in cancers that do manage to establish. This breakthrough has led directly from investment in research made by the Irish state over the past 10 years ...

For two decades, Silverstein provided frontman Shane Told with a nomadic and destructive lifestyle that kept adulthood at bay, paired with enough noise to help drown out his very real inner struggles. Now its time for reflection, growing up and the pursuit of health and happiness…

Why should the Center Party worry about EKRE? Yes, they have temporarily become the second most popular party, with their vertigo now obvious. But their statements will culminate in a painful hangover. The Center Party will not allow them to spin lies of a police state, coercive treatment and the dangers of the European Union, Jaanus Karilaid writes.

In a Special Comment, Countdowns Keith Olbermann argues that President Barack Obama shouldnt accept a resignation from Gen. Stanley McChrystal.

The long MS disease process which can essentially last a lifetime starts with low level inflammation, progresses to greatly increased inflammation and associated nerve axon degeneration and ends with continual nerve axon degeneration. Most of the accumulated disability is due to the degeneration component of the disease process. To avoid reaching the phase of steady degeneration and experiencing a downward spiral into serious disability, one must shut off the inflammatory process as early as possible. The ideal would be for susceptible persons to use a few nutritional strategies such as adequate vitamin D in childhood. However few do this because most believe that MS will never affect them. More rigorous nutritional strategies and perhaps even one of the MS drugs are needed once MS is diagnosed. The sooner they are instituted the better the chance to short circuit the disease process and the appearance of long-term disability. Because many people do not experience serious symptoms in the early ...

It would be retrogression to attach oneself today to the ossified formulas of the Enlightenment. Social dogmatism leaves us completely helpless in front of the trials of our times. Even if we are spared destruction by war, our lives will have to change if we want to save life from self-destruction. We cannot avoid revising the fundamental definitions of human life and human society. Is it true that man is above everything? Is there no Superior Spirit above him? Is it right that mans life and societys activities have to be determined by material expansion in the first place? Is it permissible to promote such expansion to the detriment of our spiritual integrity? If the world has not come to its end, it has approached a major turn in history, equal in importance to the turn from the Middle Ages to the Renaissance. It will exact from us a spiritual upsurge, we shall have to rise to a new height of vision, to a new level of life where our physical nature will not be cursed as in the Middle Ages, ...

It would be retrogression to attach oneself today to the ossified formulas of the Enlightenment. Social dogmatism leaves us completely helpless in front of the trials of our times. Even if we are spared destruction by war, our lives will have to change if we want to save life from self-destruction. We cannot avoid revising the fundamental definitions of human life and human society. Is it true that man is above everything? Is there no Superior Spirit above him? Is it right that mans life and societys activities have to be determined by material expansion in the first place? Is it permissible to promote such expansion to the detriment of our spiritual integrity? If the world has not come to its end, it has approached a major turn in history, equal in importance to the turn from the Middle Ages to the Renaissance. It will exact from us a spiritual upsurge, we shall have to rise to a new height of vision, to a new level of life where our physical nature will not be cursed as in the Middle Ages, ...

Here is an interesting short blog post by our friend and evolutionary biologists, Josh Mitteldorf which he titles Aging is a Military Coup. In it he suggests two things, which I paraphrase thusly: Aging is not the passive process we used to think it was. Instead, aging is programmed into the body, and it is often a result of the body actively attacking itself in one way or another - commonly a result of the immune system response to inflammation. From a multi-level natural selection perspective, this self-destruction by individuals may be the way a community/society clears out its weaker members to make way for a new generation, and thereby promote the flourishing of the group. I dont think anyone can argue with #1 - aging, at least in the manifest forms Josh enumerates, does appear to be a very active, programmed response. But Im much more skeptical about #2. It seems plausible, but far from proven. Here is how Josh describes it: If evolution found it necessary to regulate the individuals ...

Sequential waves of stickers bearing a Jim Joness photo have been flooding many squares and streets in downtown Rome. Reverend Jim Jones was the founder, and the terminal angel of death, of the Peoples Temple, a Californian sect-church which committed suicide with a cyanide-laced soft drink on November 18, 1978. The ritual of self-destruction took [...]. ...

Must we keep fighting like this? You cannot get rid of me, Man. You derived from me, Daemon! Dont confuse me with a demon. The two are not the same thing. I am the unrest that exists in you, which forces you into the unknown, leading you to self-discovery or self-destruction, whichever you choose. Im…

The following provings were conducted under the Constantine Hering Foundation at the Hahnemann Hospital of Philadelphia and upon students at that institution.. The students took the 3rd potency of the remedy every two hours, and in all the proving was carried along approximately about seven weeks or more.. Mention will be made in a brief fashion only of those outstanding characteristics strongly indicative of the main sphere of action of the drug.. All the symptoms about to be summarized are strongly characteristic and were persistently provided in such a manner that they might be denominated truly enough, the Red String Keynotes calling for the employment of this useful medicine in the cure of the disease.. 1. Great fearfulness and a pronounced disposition to worry over all sorts of inconsequential trifles. Thoughts of an impulsive nature brooding about self-destruction.. 2. Tremendous formation of gas in the whole belly - much belching of gas - a great deal of gas is passed at the call to ...

Colias Eurydice ©Jo Whaley. Like moths attracted to the light of a flame only to perish in that flight, I wonder if we, too, are tied to self-destruction through a drive toward greater ...

Two posts from the ded fwed which I didnt realise was ded (thanks Grigory) - btw the new threads are almost always invisible to me - using latest Firefox - until some hours later:. Gerard Depardieu is a remarkable chap. Ugly, huge and ungainly, he is nevertheless capable of being anything on screen - lover, villain, hero, fool. His Asterix movies are magnificent - but so are others where he has played hard-bitten cops and lovestruck idiots.. A while back, he was accused of behaving badly on a plane, and it went all over the world. They wouldnt let him go to the toilet, so he allegedly peed in the aisle. Here was his response:. http://www.youtube.com/watch?v=DIMvCA2mSag. Its only a couple of minutes long, and well worth a look.. Losing Gerard should be a serious warning to the French government that they are on the path to self-destruction.. and. Tim Blair could have a bit of fun with ...

Help practice social distancing with these Social Distancing Stock Graphic Wall Decals! These durable decals are designed to adhere to a variety of smooth, flat surfaces but can easily be removed, if needed. Price includes pre-printed Please Practice Social Distancing stock graphics in Medium Blue, NO LOGO, on white vinyl with removable adhesive ...

NMNAT2小鼠单克隆抗体(ab56980)可与小鼠, 人样本反应并经WB, IHC, Flow Cyt, ICC/IF实验严格验证，被2篇文献引用并得到1个独立的用户反馈。