Components Of Peripheral Nervous System Research Articles

Bilateral mydriasis as the first manifestation of Miller Fisher syndrome

Miller Fisher Syndrome (MFS) is a rare variant of Guillain-Barré Syndrome (GBS), characterised by a unique clinical triad of ophthalmoplegia, ataxia, and areflexia. MFS, which was first described in 1956 by Charles Miller Fisher , is frequently preceded by an infection, usually respiratory or gastrointestinal, and is believed to be triggered by an autoimmune reaction targeting peripheral nervous system components. However the MFS is further categorised into incomplete forms which can be present without the classical triad, such as acute ophthalmoparesis, acute ataxic neuropathy, acute ptosis and acute mydriasis. We report a case of a 50-year-old man presenting with dilated and unresponsive pupils, which progressed rapidly to ophthalmoplegia, ataxia, and areflexia. Given the clinical history supported by the cyto-protein dissociation in cerebrospinal fluid, the patient was diagnosed to have MFS and successfully treated with intravenous immunoglobulin. This case underscores the importance of recognising atypical features of MFS, such as primary mydriasis, and highlights the variable clinical spectrum within the syndrome. Clinicians should maintain a high index of suspicion for MFS, particularly when faced with unusual neurological presentations, to ensure timely intervention and optimal patient outcomes.

Neuroimmune cardiovascular interfaces control atherosclerosis.

Atherosclerotic plaques develop in the inner intimal layer of arteries and can cause heart attacks and strokes1. As plaques lack innervation, the effects of neuronal control on atherosclerosis remain unclear. However, the immune system responds to plaques by forming leukocyte infiltrates in the outer connective tissue coat of arteries(the adventitia)2-6. Here, because the peripheral nervous system uses the adventitia as its principal conduit to reach distant targets7-9, we postulated that the peripheral nervous system may directly interact with diseased arteries. Unexpectedly, widespread neuroimmunecardiovascular interfaces (NICIs) arose in mouse and human atherosclerosis-diseased adventitia segments showed expanded axon networks, including growth cones at axon endings near immune cells and media smooth muscle cells. Mouse NICIs established a structural artery-brain circuit (ABC): abdominal adventitia nociceptive afferents10-14 entered the central nervous system through spinal cord T6-T13 dorsal root ganglia and were traced to higher brain regions, including the parabrachial and central amygdala neurons; and sympathetic efferent neurons projected from medullary and hypothalamic neurons to the adventitia through spinal intermediolateral neurons and both coeliac and sympathetic chain ganglia. Moreover, ABC peripheral nervous system components were activated: splenic sympathetic and coeliac vagus nerve activities increased inparallel to disease progression, whereas coeliac ganglionectomy led to the disintegration of adventitial NICIs, reduced disease progression and enhanced plaque stability. Thus, the peripheral nervous system uses NICIs to assemble a structural ABC, and therapeutic intervention in the ABC attenuates atherosclerosis.

Neural crest cells and their potential therapeutic applications

Neural crest (NC) is a population of cells, formed at the intersection between non-neural ectoderm and neural tube. Neural crest progenitors are multipotent, have capacity to extensive migration and self-renewal. They can be differentiated into various cells types from craniofacial skeletal tissues to components of peripheral nervous system. Influence of signaling molecules and transcription factors, which are expressed at the different stages regulate development of NC. The regulatory network of genes determines the processes of induction, specification, migration and differentiation of neural crest cells (NCC). The purpose of this article is to compare the characteristics of NCC, obtained from tissues of the embryo, fetus and adult; experimental strategies for obtaining NCC from embryonic stem cells, induced pluripotent stem cells, skin fibroblasts; comparison of the potential of different cell types for therapeutic use in a clinical setting. Embryonic stem NCC are differentiated to the trunk, cranial, cardiac, circumpharyngeal and vagal according to the area of their initial migration. Mature stem NCC can be obtained from the dorsal root ganglia, red bone marrow, hair follicle, skin, intestines, carotid body, heart, cornea, iris, dental pulp, hard palate and oral mucosa. Genetic mutations may lead to failure of regulation of NC development, which leads to many congenital human diseases such as cardiovascular defects, craniofacial abnormalities and intestinal aganglionosis, collectively known as neurocristopathies. The identification and isolation of multipotent stem NCC derived from adult tissues, embryonic stem cells, and induced pluripotent stem cells are promising source for regenerative medicine.

Immune-Mediated Neuropathies.

The purpose of this review article is to discuss the pathogenesis of acute and chronic immune-mediated neuropathies along with the recent advances in their treatment. Since the first description of Guillain-Barre syndrome (GBS) more than a century ago, there have been numerous forms of immune-mediated neuropathies described expanding the spectrum. Understanding the role of the immune system in the pathogenesis of immune-mediated neuropathies has been an advancement towards the diagnosis and treatment. It is postulated that immune-mediated neuropathies are a group of diseases resulting from autoimmunity towards multiple components of peripheral nervous system. These have a wide range of pathologic mechanisms, defined clinical presentations, electro-diagnostic and laboratory findings which help in diagnosis and management. Although immunosuppression is the common modality of treatment for these disorders, uncovering distinct pathogenic mechanisms can allow for targeted immunomodulation.

Animal models of autoimmune neuropathy.

The peripheral nervous system (PNS) comprises the cranial nerves, the spinal nerves with their roots and rami, dorsal root ganglia neurons, the peripheral nerves, and peripheral components of the autonomic nervous system. Cell-mediated or antibody-mediated immune attack on the PNS results in distinct clinical syndromes, which are classified based on the tempo of illness, PNS component(s) involved, and the culprit antigen(s) identified. Insights into the pathogenesis of autoimmune neuropathy have been provided by ex vivo immunologic studies, biopsy materials, electrophysiologic studies, and experimental models. This review article summarizes earlier seminal observations and highlights the recent progress in our understanding of immunopathogenesis of autoimmune neuropathies based on data from animal models.

Collagen VI regulates peripheral nerve myelination and function

Collagen VI is an extracellular matrix protein with broad distribution in several tissues. Although Col6a1 is expressed by Schwann cells, the role of collagen VI in the peripheral nervous system (PNS) is yet unknown. Here we show that Schwann cells, but not axons, contribute to collagen VI deposition in peripheral nerves. By using Col6a1-null mice, in which collagen VI deposition is compromised, we demonstrate that lack of collagen VI leads to increased myelin thickness (P<0.001) along with 60-130% up-regulation in myelin-associated proteins and disorganized C fibers in the PNS. The hypermyelination of PNS in Col6a1(-/-) mice is supported by alterations of signaling pathways involved in myelination, including increase of P-FAK, P-AKT, P-ERK1, P-ERK2, and P-p38 (4.15, 1.67, 2.47, 3.34, and 2.60-fold, respectively) and reduction of vimentin (0.49-fold), P-JNK (0.74-fold), and P-c-Jun (0.50-fold). Pathologically, Col6a1(-/-) mice display an impairment of nerve conduction velocity and motor coordination (P<0.05), as well as a delayed response to acute pain stimuli (P<0.001), indicating that lack of collagen VI causes functional defects of peripheral nerves. Altogether, these results indicate that collagen VI is a critical component of PNS contributing to the structural integrity and proper function of peripheral nerves.

HESC derived neuro-epithelial rosettes recapitulate early mammalian neurulation events; an in vitro model

The in vitro neuralization of hESCs has been widely used to generate central and peripheral nervous system components from neural precursors (Bajpai et al., 2009; Curchoe et al., 2010), most often through an intermediate “rosette” stage. Here we confirm that hESC derived neuro-epithelial rosettes express many characteristics of the developing embryonic neural plate (Aaku-Saraste et al., 1996), characterized by expression of the tight junction proteins ZO-1 and N-Cadherin. Moreover, neuro-epithelial rosettes display a characteristic acetylated alpha tubulin cytoskeletal arrangement (similar to that observed in the developing embryonic neural plate) (Bhattacharyya et al., 1994). Demonstrated here for the first time MKLP was observed in a hESC model system. We found MKLP expression in small particles in between mitotic spindles, large particles aggregating in the lumen of neuroepithelial rosettes, and we did not observe MKLP in the nucleus of hESC derived neural precursors as previously described in the HeLa cell line. We observed MKLP + particles in aggregations in the lumen of “early” rosette structures. Furthermore, we observed that MKLP + particle aggregations can also be lost from the lumens of hESC derived neuro-epithelial rosettes, similar to a phenomenon observed in the developing neural tube in vivo (Marzesco et al., 2005). We determined that this loss of MKLP + particles occurs from “late” as opposed to “early” stage neuro-epithelial rosettes (characterized by junction type). Disrupting the apical-basal polarization of “early” stage rosettes with a 1% Matrigel overlay (Krtolica et al., 2007) nearly ablates MKLP particle aggregation in the lumen of rosettes, demonstrating that the apical-basal polarity of early NE cells is necessary for lumenal MKLP particle aggregation. We conclude that early hESC derived neuro-epithelial rosettes can model early neurulation events, such as the transition from neural plate like cells to neural tube like cells (i.e. symmetric to asymmetric NE cell division) demonstrated by polarized MKLP particle inheritance and distribution using junction type as a measure of stage.

Outcomes from building system courseware for teaching and testing in a discipline-based human structure curriculum

This study investigated the educational benefits of system-based lecture notes and interactive learning objects in a peripheral nervous system component of a traditional first-year medical school human anatomy course. The impetus for the investigation was anecdotal evidence suggesting enhanced learner satisfaction with the learning resources. Retrospective review of existing data from 2006 to 2009 was undertaken to quantify (1) the effects of Web-based system courseware on examination item performance, and (2) differences among learner opinions regarding the benefit level of the five different types of interactive learning objects as evaluated by instructional design questionnaires. Interactive patient-based case studies (IPCS) and review games (Games), simulated interactive patients (SIP), flashcards, and unit quizzes (Quizzes) developed in-house have been peer-reviewed and published in MedEdPORTAL. Statistics included one-way analysis of variance, Tukey's post hoc test, and power meta-analysis (d). Examination item analysis scores remained significantly higher (P ≤ 0.05; d = 0.3938) for learners receiving the instructional treatment incorporating system-based lecture notes and interactive learning objects than for those not receiving this treatment. Using questionnaires with a five-point Likert scale, students reported favorably on the benefit level of all learning objects. They rated the SIP and IPCS significantly higher (P ≤0.05) and games significantly lower (P ≤ 0.05) than in previous years, indicating a change in learner preferences. This study reaffirms that online system-based instructional techniques improve student examination performance and overall student satisfaction. Learners indicated stronger preferences for SIP and IPCS over exercises encouraging passive memorization of anatomical content.

Learner assessment using interactive web‐based instructional techniques enhances preclinical education

Retrospective data from 9 years of instruction involving 856 students were used to determine (1) the effect of web‐based interactive instructional techniques on written exam item performance in a web‐based peripheral nervous system component of a first‐year human anatomy course, and (2) differences between student opinions of the benefit level of the interactive learning objects used for assessment, i.e., patient case studies, review games, simulated interactive patients, flashcards, and unit quizzes. Exam item analysis scores were found to be significantly higher (p &lt; .05) for students receiving the instructional treatment incorporating web‐based interactive learning objects than for students not receiving this treatment. Questionnaires using a five‐point Likert scale were analyzed to determine student opinion ratings of the interactive learning objects. Students reported favorably on the benefit level of all learning objects. Students rated the benefit level of the simulated interactive patients highest, and this rating was significantly higher (p &lt; .05) than all other interactive learning objects. This study suggests that web‐based interactive instructional techniques improve student exam performance. Students indicated a strong acceptance of simulated interactive patient learning objects used for assessment. (Supported in part by WVU acct#:491030050, fund#:12305495.)

Differential Diagnosis Of Shoulder Pain Followed By Progressive Weakness: A Case Report

Upper extremity weakness can be the result of a myriad of conditions ranging from contractile tissue injury, joint injury, or injury to central or peripheral nervous system components. Accurate diagnosis is important in establishing an optimal treatment regimen and sound prognosis. This report provides an overview of the diagnosis and treatment of Parsonage-Turner Syndrome, a relatively rare cause of upper extremity weakness and dysfunction.

Ablation of least shrew central neurokinin NK₁ receptors reduces GR73632-induced vomiting.

The neurocircuitry mediating the emetic reflex is still incompletely understood, and a key question is the degree to which central and/or peripheral components contribute to the overall vomiting mechanism. Having previously found a significant peripheral component in neurokinin NK-receptor mediated emesis, the authors undertook this study to examine the putative central component. Adult least shrews were injected intracerebroventricularly (icv) with saline or the blood-brain barrier impermeable toxin, stable substance P-saporin (SSP-SAP), which ablates cells expressing NK receptors. After 3 days, shrews were challenged intraperitoneally with the emetogenic NK agonist GR73632 at different doses, and vomiting and scratching behaviors were quantified. Ablation of NK1-bearing cells was verified immunohistochemically. Although SSP-SAP injection reduced emesis at GR73632 doses of 2.5 and 5 mg/kg, no injections completely eliminated emesis. These data demonstrate that there is both a major central nervous system component and a minor peripheral nervous system component to tachykinin-mediated vomiting. Side effects of the current generation of antiemetics could potentially be reduced by improving bioavailability of the drugs in the more potent central nervous system compartment while reducing bioavailability in the less potent peripheral compartment.

Effects of interactive instructional techniques in a web-based peripheral nervous system component for human anatomy

Background: This study investigated the effects of interactive instructional techniques in a web-based peripheral nervous system (PNS) component of a first year medical school human anatomy course.Method: Existing data from 9 years of instruction involving 856 students were used to determine (1) the effect of web-based interactive instructional techniques on written exam item performance and (2) differences between student opinions of the benefit level of five different types of interactive learning objects used. The interactive learning objects included Patient Case studies, review Games, Simulated Interactive Patients (SIP), Flashcards, and unit Quizzes.Results: Exam item analysis scores were found to be significantly higher (p < 0.05) for students receiving the instructional treatment incorporating the web-based interactive learning objects than for students not receiving this treatment. Questionnaires using a five-point Likert scale were analysed to determine student opinion ratings of the interactive learning objects. Students reported favorably on the benefit level of all learning objects. Students rated the benefit level of the Simulated Interactive Patients (SIP) highest, and this rating was significantly higher (p < 0.05) than all other learning objects.Conclusion: This study suggests that web-based interactive instructional techniques improve student exam performance. Students indicated a strong acceptance of Simulated Interactive Patient learning objects.

Glycosyltransferase encoding gene EXTL3 is differentially expressed in the developing and adult mouse cerebral cortex

Exostosin tumor-like 3 (EXTL3) is a glycosyltransferase involved in heparan sulfate (HS) biosynthesis. HS proteoglycans are critically involved in different steps during brain development. The present in situ hybridization in mice revealed wide EXTL3 expression at different grades in the central and peripheral nervous system components including the neural retina and neural crest-derived structures at embryonic days (E) 11.5, E12.5, E14.5, and E16.5. In the neopallial cortex, an intense EXTL3 expression was observed in the neuroepithelial cells lining the ventricular zone at E11.5 and E12.5. The signal decreased at E14.5 and was further downregulated at E16.5 in the ventricular zone. The pioneer neurons of the preplate at E12.5 differentially expressed the gene. Heavily stained among weakly or negatively stained neurons were observed. At E14.5, the cortical plate cells were moderately and homogeneously stained. In contrast, at E16.5, an upregulated and differential expression pattern was detected. The labeling pattern at E16.5 subdivided the cortical plate cells into a large number of heavily, a moderate number of less intensely, and some negatively stained cell populations. Interestingly, the distinct expression pattern displayed by the three main cell types of the adult cerebral cortex was similar to that of the late corticogenesis stage (E16.5). In the adult, the strongest expression was observed in the pyramidal neurons. The granule-type neurons showed less intense staining while the glia cells were devoid of signals. Our data revealed that EXTL3 expression is developmentally regulated in the mouse nervous system and suggested that it differentially contributes to brain development and corticogenesis.

Ultrastructural identification of peripheral myelin proteins by a pre-embedding immunogold labeling method.

Ultrastructural immunolabeling of peripheral nervous system components is an important tool to study the relation between structure and function. Owing to the scarcity of certain antigens and the dense structure of the peripheral nerve, a pre-embedding technique is likely appropriate. After several investigations on procedures for pre-embedding immunolabeling, we propose a method that offers a good compromise between detection of antigenic sites and preservation of morphology at the ultrastructural level, and that is easy to use and suitable for investigations on peripheral nerve biopsies from humans. Pre-fixation by immersion in paraformaldehyde/glutaraldehyde is necessary to stabilize the ultrastructure. Then, ultrasmall gold particles with silver enhancement are advised. Antibodies against myelin protein zero and myelin basic protein were chosen for demonstration. The same technique was applied to localize a 35 kDa myelin protein.

Mediators of the female sexual response: pharmacotherapeutic implications.

A basic understanding of the mediators and related mechanisms involved in the genital physiology of the female sexual response, and, in particular, the physiology of arousal, is paramount for the clinical practitioner whose medical knowledge and practice pertain to female sexual dysfunction. Familiarity with established and evolving scientific principles relating to female genital physiology offers insight into functional aspects as well as disturbances of function relating to the female sexual response. Improved knowledge with regard to the central and peripheral nervous system components of female genital responses, chemical mediators, including endocrine factors determining the female sexual response, and other cellular and subcellular mechanisms should advance pharmacologic management for female sexual arousal disorder.

Signalling between the hindbrain and paraxial tissues dictates neural crest migration pathways.

Cranial neural crest cells are a pluripotent population of cells derived from the neural tube that migrate into the branchial arches to generate the distinctive bone, connective tissue and peripheral nervous system components characteristic of the vertebrate head. The highly conserved segmental organisation of the vertebrate hindbrain plays an important role in patterning the pathways of neural crest cell migration and in generating the distinct or separate streams of crest cells that form unique structures in each arch. We have used focal injections of DiI into the developing mouse hindbrain in combination with in vitro whole embryo culture to map the patterns of cranial neural crest cell migration into the developing branchial arches. Our results show that mouse hindbrain-derived neural crest cells migrate in three segregated streams adjacent to the even-numbered rhombomeres into the branchial arches, and each stream contains contributions of cells from three rhombomeres in a pattern very similar to that observed in the chick embryo. There are clear neural crest-free zones adjacent to r3 and r5. Furthermore, using grafting and lineage-tracing techniques in cultured mouse embryos to investigate the differential ability of odd and even-numbered segments to generate neural crest cells, we find that odd and even segments have an intrinsic ability to produce equivalent numbers of neural crest cells. This implies that inter-rhombomeric signalling is less important than combinatorial interactions between the hindbrain and the adjacent arch environment in specific regions, in the process of restricting the generation and migration of neural crest cells. This creates crest-free territories and suggests that tissue interactions established during development and patterning of the branchial arches may set up signals that the neural plate is primed to interpret during the progressive events leading to the delamination and migration of neural crest cells. Using interspecies grafting experiments between mouse and chick embryos, we have shown that this process forms part of a conserved mechanism for generating neural crest-free zones and contributing to the separation of migrating crest populations with distinct Hox expression during vertebrate head development.

Tyrosine phosphorylation of myelin protein PO.

Po (M(r) 30 kDa), the major protein component of peripheral nervous system (PNS) myelin, is known to be phosphorylated by protein kinase C on serine residues at multiple sites. This study was conducted to assess whether other amino acids might be phosphorylated in the protein. Segments of rat sciatic nerve were incubated with 32P in either the presence or absence of phorbol ester. Labeled Po was isolated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and subjected to partial acid hydrolysis. Upon separation of the hydrolysis products by either thin-layer electrophoresis or thin-layer chromatography, a radioactive spot was detected which comigrated with authentic phosphotyrosine. In other experiments, nerves were incubated with the tyrosine phosphatase inhibitors vanadate or vanadyl hydroperoxide (pervanadate). When the nerve homogenate proteins were separated on gels and probed with a monoclonal antibody to phosphotyrosine on Western blots, a positive immune reaction was obtained for a protein species which migrated with the same mobility as PO on Coomassie Blue-stained gels. In the absence of 2-mercaptoethanol, this immunoreactive band displayed increased mobility on gels which is characteristic of the migration pattern of Po. The same immunostaining results were obtained using a purified peripheral myelin fraction prepared from nerve homogenates. Furthermore, the positions of immunoreactive bands produced by anti-Po and antiphosphotyrosine antibodies coincided on the same immunoblot of myelin proteins and purified Po. These data indicate that one or more tyrosyl residues in Po can be phosphorylated in intact sciatic nerve.

Experimental autoimmune peripheral neuritis induced in BALB/c mice by myelin basic protein-specific T cell clones.

In vivo adoptive transfer of CD4+ T helper cell type 1 clones reactive with autologous myelin basic protein (MBP) may initiate an inflammatory demyelinating disease of the central nervous system called experimental autoimmune encephalomyelitis. Although MBP is also a component of peripheral nervous system (PNS) myelin, previous studies have failed to demonstrate inflammation in the PNS induced by MBP-reactive T cells. Here, we report on two MBP-specific T cell clones that preferentially initiate inflammatory and demyelinating peripheral neuritis when adoptively transferred to syngeneic recipients. The MBP epitope recognized by these clones spans the junction of exons 6 and 7 and, therefore, is present in the 21- and 18.5-kD but not the 14- and 17-kD MBP isoforms, in which exon 5 is spliced to exon 7. The data suggest that MBP may be processed and presented differently in the central nervous system and PNS, and they provide evidence for MBP as a potential target for autoimmune reactions in the PNS.

Implantation of PNS Graft Inhibits the Induction of Neuronal Nitric Oxide Synthase and Enhances the Survival of Spinal Motoneurons Following Root Avulsion

In a spinal root injury model, our previous studies have shown that induction of nitric oxide synthase (NOS) appears only in spinal motoneurons of the root-avulsed segment in which significant motoneuron loss occurs but not in those of the distal root-axotomized segment (root axotomy 5-10 mm from the spinal cord) in which most motoneurons survive the injury. One hypothesis for the different response of motoneurons to root avulsion and distal root axotomy is that neurotrophic factors produced by the remaining peripheral nervous system (PNS) component are available for the distally axotomized motoneurons but are not available following avulsion. This hypothesis is tested in the present study by implantation of a PNS graft following the root avulsion. Results of the present study show that implantation of a PNS graft significantly enhances the survival of motoneurons following avulsion. Expression of NOS due to avulsion injury is completely inhibited in all motoneurons that regrow into the PNS graft. These results indicate that induction of NOS in avulsed motoneurons may result from the deprivation of neurotrophic factors produced by the PNS component, and the survival promoting effects of neurotrophic factors may be achieved by modifying certain cellular molecules such as NOS.

Postexercise depression of motor evoked potentials: a measure of central nervous system fatigue.

Fatigue of voluntary muscular effort is a complex and multifaceted phenomenon. Fatigue of peripheral nervous system components, including the contractile apparatus and the neuromuscular junction, has been well studied. Central nervous system components also fatigue, but studies have lagged for want of objective methods. Transcranial magnetic stimulation is a relatively new technique that can be used to assess central nervous system excitability from the motor cortex to the alpha-motoneuron. In six normal volunteers, including four of the investigators, the amplitudes of motor evoked potentials elicited by transcranial magnetic stimulation were transiently decreased after exercise, indicating fatigue of motor pathways in the central nervous system. The decrease in amplitude was associated with a feeling of fatigue. The mechanism of this phenomenon is apparently decreased efficiency in the generation of the motor command in the motor cortex.