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Chronic pain is a common source of morbidity in many patient populations worldwide. There are growing concerns about the potential side effects of currently prescribed medications and a continued need for effective treatment. Related to these concerns, peripheral nerve stimulation has been regaining popularity as a potential treatment modality. Peripheral nerve stimulation components include helically coiled electrical leads, which direct an applied current to afferent neurons providing sensory innervation to the painful area. In theory, the applied current to the peripheral nerve will alter the large-diameter myelinated afferent nerve fibers, which interfere with the central processing of pain signals through small-diameter afferent fibers at the level of the spinal cord. Multiple studies have shown success in the use of peripheral nerve stimulation for acute post-surgical pain for orthopedic surgery, including post total knee arthroplasty and anterior cruciate ligament surgery, and chronic knee pain. Many studies have investigated the utility of peripheral nerve stimulation for the management of chronic shoulder pain. Peripheral nerve stimulation also serves as one of the potential non-pharmacologic therapies to treat back pain along with physical therapy, application of transcutaneous electrical neurostimulation unit, radiofrequency ablation, epidural steroid injections, permanently implanted neurostimulators, and surgery. Studies regarding back pain treatment have shown that peripheral nerve stimulation led to significant improvement in all pain and quality-of-life measures and a reduction in the use of opioids. Further studies are needed as the long-term risks and benefits of peripheral nerve stimulation have not been well studied as most information available on the effectiveness of peripheral nerve stimulation is based on shorter-term improvements in chronic pain.

Graphical abstract The unremitting coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) marked a year-long phase of public health adversaries and has severely compromised healthcare globally. Early evidence of COVID-19 noted its impact on the pulmonary and cardiovascular functions, while multiple studies in recent time shed light on its substantial neurological complications, though a comprehensive understanding of the cause(s), the mechanism(s), and their neuropathological outcomes is scarce. In the present review, we conferred evidence of neurological complications in COVID-19 patients and shed light on the SARS-CoV-2 infection routes including the hematogenous, direct/neuronal, lymphatic tissue or cerebrospinal fluid, or infiltration through infected immune cells, while the underlying mechanism of SARS-CoV-2 invasion to the central nervous system (CNS) was also discussed. In an up-to-date manner, we further reviewed the impact of COVID-19 in developing diverse neurologic manifestations associated with CNS, peripheral nervous system (PNS), skeletal muscle, and also pre-existing neurological diseases, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, epilepsy, and myasthenia gravis. Furthermore, we discussed the involvement of key factors including age, sex, comorbidity, and disease severity in exacerbating the neurologic manifestations in COVID-19 patients. An outlook of present therapeutic strategies and state of existing challenges in COVID-19 management was also accessed. Conclusively, the present report provides a comprehensive review of COVID-19-related neurological complications and emphasizes the need for their early clinical management in the ongoing COVID-19 pandemic.

Fibroblast growth factors (FGFs) act as key signalling molecules in brain development, maintenance, and repair. They influence the intricate relationship between myelinating cells and axons as well as the association of astrocytic and microglial processes with neuronal perikarya and synapses. Advances in molecular genetics and imaging techniques have allowed novel insights into FGF signalling in recent years. Conditional mouse mutants have revealed the functional significance of neuronal and glial FGF receptors, not only in tissue protection, axon regeneration, and glial proliferation but also in instant behavioural changes. This review provides a summary of recent findings regarding the role of FGFs and their receptors in the nervous system and in the pathogenesis of major neurological and psychiatric disorders.

Background and aims Nonalcoholic fatty liver disease (NAFLD) is an obesity-related comorbidity, and it is characterized as a spectrum of liver abnormalities, including inflammation, steatosis, and fibrosis. The gut-liver axis is implicated in the pathogenesis and development of NAFLD. A promising drug agent targeting the gut-liver axis is expected to reverse NAFLD. Methods We utilized high-fat diet (HFD)-induced obese mice and obesity-prone Lepob mice to examine the gut-liver regulation of the natural medicine Panax Notoginseng Saponins (PNS) on NAFLD. Results PNS exhibited potent anti-lipogenesis and anti-fibrotic effects in NAFLD mice, that was associated with the TLR4-induced inflammatory signalling pathway in liver. More strikingly, PNS treatment caused a deceleration of gut-to-liver translocation of microbiota-derived short chain fatty acids (SCFAs) products. PNS-induced TLR4 inhibition and restoration of Claudin-1 and ZO-1 proteins in the gut-liver axis contributed to the reverse of leaky gut, which in turn abolished by the addition of lipopolysaccharide (LPS), an agonist of TLR4. Specifically, hepatic steatosis in HFD-treated mice was attenuated by PNS through regulating AMPKα, but restored by the replenishment of LPS. Meanwhile, the anti-fibrotic effect of PNS was abolished by LPS stimulation via the overproduction of collagen I/IV and α-SMA. Conclusion PNS exerted hepatoprotection against NAFLD in both ob/ob and HFD-induced obese mice, primarily by mediating the gut-liver axis in a TLR4-dependent manner. Graphic abstract

To facilitate analyses of purinergic signaling in peripheral nerve glia, we review recent literature and catalog purinergic receptor mRNA expression in cultured mouse Schwann cells (SCs). Purinergic signaling can decrease developmental SC proliferation, and promote SC differentiation. The purinergic receptors P2RY2 and P2RX7 are implicated in nerve development and in the ratio of Remak SCs to myelinating SCs in differentiated peripheral nerve. P2RY2, P2RX7, and other receptors are also implicated in peripheral neuropathies and SC tumors. In SC tumors lacking the tumor suppressor NF1, the SC pathway that suppresses SC growth through P2RY2‐driven β‐arrestin‐mediated AKT signaling is aberrant. SC‐released purinergic agonists acting through SC and/or neuronal purinergic receptors activate pain responses. In all these settings, purinergic receptor activation can result in calcium‐independent and calcium‐dependent release of SC ATP and UDP, growth factors, and cytokines that may contribute to disease and nerve repair. Thus, current research suggests that purinergic agonists and/or antagonists might have the potential to modulate peripheral glia function in development and in disease., MAIN POINTS SC purinergic receptors are implicated in suppressing SC proliferation, increasing SC differentiation, and elevating intracellular Ca2+ during nerve development in response to injury and/or in disease.P1R, P2XR, and P2YR receptors expressed in SCs and adjacent neurons need further study.

Coronavirus disease (COVID-19) was first identified in late December 2019. The disease began in Wuhan, Hubei province in China and since then it has spread quickly to many countries all over the world. COVID-19 is caused by a novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus was majorly seen to overwhelm the respiratory system with mild to severe acute respiratory syndrome considered pathognomic for the disease. However, with time a plethora of symptoms was observed in the patients infected with COVID-19 including strong evidence for neurological symptoms. Evidence suggests that the virus has both central and peripheral nervous system manifestations. Patients, particularly those who suffer from a severe illness, have a central nervous system (CNS) involvement and neurological manifestations. There is precise and targeted documentation of neurological symptoms with details of clinical, neurological, and electrophysiological findings. This review article thus gives an insight into the neuro-invasive potential of COVID-19 and discusses the possible pathogenesis.

In the peripheral nervous system, the vast majority of axons are accommodated within the fibre bundles that constitute the peripheral nerves. Axons within the nerves are in close contact with myelinating glia, the Schwann cells that are ideally placed to respond to, and possibly shape, axonal activity. The mechanisms of intercellular communication in the peripheral nerves may involve direct contact between the cells, as well as signalling via diffusible substances. Neurotransmitter glutamate has been proposed as a candidate extracellular molecule mediating the cross-talk between cells in the peripheral nerves. Two types of experimental findings support this idea: first, glutamate has been detected in the nerves and can be released upon electrical or chemical stimulation of the nerves; second, axons and Schwann cells in the peripheral nerves express glutamate receptors. Yet, the studies providing direct experimental evidence that intercellular glutamatergic signalling takes place in the peripheral nerves during physiological or pathological conditions are largely missing. Remarkably, in the central nervous system, axons and myelinating glia are involved in glutamatergic signalling. This signalling occurs via different mechanisms, the most intriguing of which is fast synaptic communication between axons and oligodendrocyte precursor cells. Glutamate receptors and/or synaptic axon-glia signalling are involved in regulation of proliferation, migration, and differentiation of oligodendrocyte precursor cells, survival of oligodendrocytes, and re-myelination of axons after damage. Does synaptic signalling exist between axons and Schwann cells in the peripheral nerves? What is the functional role of glutamate receptors in the peripheral nerves? Is activation of glutamate receptors in the nerves beneficial or harmful during diseases? In this review, we summarise the limited information regarding glutamate release and glutamate receptors in the peripheral nerves and speculate about possible mechanisms of glutamatergic signalling in the nerves. We highlight the necessity of further research on this topic because it should help to understand the mechanisms of peripheral nervous system development and nerve regeneration during diseases.

Pain is highly prevalent and pharmacological therapy is not always efficacious. There are a few pathophysiological reasons to believe that neuromodulation would increase the rate of success of pain management. This review article is focused on that aspect, discussing non-invasive or minimally invasive neuromodulation techniques in both the inpatient and outpatient setting. This article provides an in-depth discussion of the multiple neuromodulation techniques available over time to be suitable and effective when used as analgesic therapies for chronic pain. We reviewed the literature and discussed all available neuromodulation options that were tested in the inpatient and outpatient setting. Neuromodulation plays a very important role in treating chronic pain in both inpatient and outpatient setting.

Background Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory disorder with unclear causes. Paraneoplastic etiology may be a cause. We report a case of CLIPPERS with parotid carcinoma. Case presentation A 54-year-old man with a history of lymphoma was hospitalized with a pontocerebellar syndrome. Brain MRI revealed that the pons and cerebellum were “peppered” with punctate and curvilinear enhancement lesions that supported the diagnosis of CLIPPERS. The relapse of lymphoma was excluded by a further cerebellum biopsy revealing predominantly CD3+ T cells in white matter. The patient was relieved after pulse therapy with intravenous methylprednisolone and a large dose of corticosteroids, but he complained of a worsening gait problem when corticosteroids were tapered to a lower dose. Although the clinical symptoms gradually improved again by increasing the dosage of corticosteroids with Azathioprine, the patient still had a slight unsteady gait during follow-up. At the 7-month follow-up, a parotid mass was detected by MRI and was verified as carcinoma by biopsy. After resection of parotid carcinoma, the residual symptoms and previous MRI lesions disappeared, and no relapse occurred. Conclusions CLIPPERS may not be a distinct nosologic entity but an overlapping diagnosis with other diseases. Some cases of CLIPPERS might be a subtype of paraneoplastic neurological syndromes (PNS) due to the similar mechanism of antibody-mediated encephalitis. Tumor screening and serum paraneoplastic autoantibody tests are recommended for patients with CLIPPERS, especially for those who relapse when corticosteroids treatment is stopped or tapered.

Axon regeneration in the central nervous system is inefficient. However, the neurons in the peripheral nervous system display robust regeneration after injury, indicating that axonal regeneration is differentially controlled under various conditions. To identify those molecules regulating axon regeneration, comparative analysis from dorsal root ganglion neurons at embryonic or adult stages is utilized, which reveals that PDK1 is functions as a negative regulator of axon regeneration. PDK1 is downregulated in embryonic neurons after axotomy. In contrast, sciatic nerve axotomy upregulated PDK1 at protein levels from adult mice. The knockdown of PDK1 or the chemical inhibition of PDK1 promotes axon regeneration in vitro and in vivo. Here we present PDK1 as a new player to negatively regulate axon regeneration and as a potential target in the development of therapeutic applications.

The primary cilium plays a pivotal role during embryonic development of vertebrates. It acts as a somatic signaling hub for specific pathways, such as sonic hedgehog signaling. In humans, mutations in genes that cause dysregulation of ciliogenesis or ciliary function lead to severe developmental disorders called ciliopathies. Beyond its obvious role in early morphogenesis, growing evidence points towards an essential function of the primary cilium in neural circuit formation in the central nervous system. However, very little is known about a potential role in the formation of the peripheral nervous system. Here, we investigated the presence of the primary cilium in neural crest cells and their derivatives in the trunk of the developing chicken embryo in vivo. We found that neural crest cells, sensory neurons, and boundary cap cells all bear a primary cilium during key stages of early peripheral nervous system formation. Moreover, we described differences in the ciliation of neuronal cultures of different populations from the peripheral and central nervous system. Our results offer a framework for further in vivo and in vitro investigations on specific roles that the primary cilium might play during peripheral nervous system formation.

The central nervous system (CNS) does not recover from traumatic axonal injury, but the peripheral nervous system (PNS) does. We hypothesize that this fundamental difference in regenerative capacity may be based upon the absence of stimulatory mechanical forces in the CNS due to the protective rigidity of the vertebral column and skull. We developed a bioreactor to apply low-strain cyclic axonal stretch to adult rat dorsal root ganglia (DRG) connected to either the peripheral or central nerves in an explant model for inducing axonal growth. In response, larger diameter DRG neurons, mechanoreceptors and proprioceptors showed enhanced neurite outgrowth as well as increased Activating Transcription Factor 3 (ATF3).

Guillain-Barré syndrome (GBS) is a paralyzing autoimmune condition affecting the peripheral nervous system (PNS). Within GBS there are several variants affecting different aspects of the peripheral nerve. In general, there appears to be a role for T cells, macrophages, B cells, and complement in initiating and perpetuating attacks on gangliosides of Schwann cells and axons. Of note, GBS has an increased prevalence and severity with increasing age. In addition, there are alterations in immune cell functioning that may play a role in differences in GBS with age alongside general age-related declines in reparative processes (e.g., delayed de-differentiation of Schwann cells and decline in phagocytic ability of macrophages). The present review will explore the immune response in GBS as well as in animal models of several variants of the disorder. In addition, the potential involvement of an aging immune system in contributing to the increased prevalence and severity of GBS with age will be theorized.

BRAF (alternately referred to as v-raf murine sarcoma viral oncogene homolog B1) is a proto-oncogene involved in the mitogen-activated protein kinase (MAPK) pathway. BRAF alterations are most commonly missense mutations or aberrant fusions. These mutations are observed in numerous primary central nervous system tumors as well as metastases. This review discusses the prevalence of BRAF alteration within select notable CNS tumors, and their prognostic associations. Included are some novel entities such as diffuse leptomeningeal glioneuronal tumor (DLGNT), polymorphous low grade neuroepithelial tumor of the young (PLNTY), and multinodular and vacuolating neuronal tumor (MVNT). Knowledge of this gene’s integrity in CNS and PNS tumors can have profound diagnostic and therapeutic implications. Also reviewed are the current state of targeted therapy against aberrant BRAF as it pertains mostly to the CNS and to a lesser extent in PNS, and certain diagnostic aspects.

Cannabis is an annual plant with a long history of use as food, feed, fiber, oil, medicine, and narcotics. Despite realizing its true value, it has not yet found its true place. Cannabis has had a long history with many ups and downs, and now it is our turn to promote it. Cannabis contains approximately 600 identified and many yet unidentified potentially useful compounds. Cannabinoids, phenolic compounds, terpenoids, and alkaloids are some of the secondary metabolites present in cannabis. However, among a plethora of unique chemical compounds found in this plant, the most important ones are phytocannabinoids (PCs). Over hundreds of 21-22-carbon compounds exclusively produce in cannabis glandular hairs through either polyketide and or deoxyxylulose phosphate/methylerythritol phosphate (DOXP/MEP) pathways. Trans-Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are those that first come to mind while talking about cannabis. Nevertheless, despite the low concentration, cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabinodiol (CBND), and cannabinidiol (CBDL) may have potentially some medical effects. PCs and endocannabinoids (ECs) mediate their effects mainly through CB1 and CB2 receptors. Despite all concerns regarding cannabis, nobody can ignore the use of cannabinoids as promising tonic, analgesic, antipyretic, antiemetic, anti-inflammatory, anti-epileptic, anticancer agents, which are effective for pain relief, depression, anxiety, sleep disorders, nausea and vomiting, multiple sclerosis, cardiovascular disorders, and appetite stimulation. The scientific community and public society have now increasingly accepted cannabis specifically hemp as much more than a recreational drug. There are growing demands for cannabinoids, mainly CBD, with many diverse therapeutic and nutritional properties in veterinary or human medicine. The main objective of this review article is to historically summarize findings concerning cannabinoids, mainly THC and CBD, towards putting these valuable compounds into food, feed and health baskets and current and future trends in the consumption of products derived from cannabis.

Backround and aims After the emergence of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in the last two decades, the world is facing its new challenge in SARS-CoV-2 pandemic with unfathomable global responses. The characteristic clinical symptoms for Coronavirus (COVID-19) affected patients are high fever, dry-cough, dyspnoea, lethal pneumonia whereas some patients also show additional neurological signs such as headache, nausea, vomiting etc. The accumulative evidences suggest that SARS-CoV-2 is not only confined within the respiratory tract but may also invade the central nervous system (CNS) and peripheral nervous system (PNS) inducing some fatal neurological diseases. Here, we analyze the phylogenetic perspective of SARS-CoV-2 with other strains of β-Coronaviridae from a standpoint of neurological spectrum disorders. Methodology A Pubmed/Medline, NIH Lit Covid, Cochrane library and some open data bases (BioRxiv, MedRxiv,preprint.org and others) search were carried out by using keywords relevant to our topic of discussion. The extracted literatures are scrutinized by the authors. Results 58 literatures including original articles, case reports and case series were selected by the authors to analyze the differential distribution of neurological impairments in COVID-19 positive patients along with angiotensin-converting enzyme-2 (ACE2) expression dynamics in neuronal and non-neuronal tissue in CNS and PNS with neuroinvasive potential of SARS-CoV2. Conclusion We discuss the need for modulations in clinical approach from a neurological point of view, as a measure towards reducing disease transmission, morbidity and mortality in SARS-CoV2 positive patients., Highlights • Comparative phylogenetic analysis reveals the neuroinvasive potential of SARS-CoV2. • ACE2 expression in neuronal and neuro-glial cells augment neurotropism of SARS-CoV2. • Clinical manifestations of COVID-19 from the neurological perspective were presented.

Background Pilonidal sinus disease (PNS) is a disorder of the young population. The aim of this study is to analyze the risk factors associated with development of PNS in the secondary school students. Methods This case control study enrolled 189 participants, (Control group: 95 cases, case group: 94 cases). The inclusion criterion for the trial group was those secondary school students with PNS and age ranged between 16 and 20 years without the known risk factors of PNS. Result About 80 (42.3%) patients were male and 109 (57.7%) were female. Each group included 95 patients. There was no significant difference in both groups regarding basic features. Among the control group 36 (37.9%) participants were used to study while sitting on a hard place whereas among the case group 62 (66%) cases were used to study while sitting on a hard place, the difference was statistically significant (, Highlights • Pilonidal sinus disease is a disorder of the young population. • Several risk factors have been recognized like job, being hairy …. etc. • Studying for prolonged time has never being studied to cause PNS. • In this study, factors have been assessed to cause PNS in preparatory students.

The novel coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is believed to have emerged from an animal source and has been spreading rapidly among humans. Recent evidence shows that SARS-CoV-2 exhibits neurotropic properties and causes neurological diseases. Here we review the literature on neurological involvement in SARS-CoV-2 infections and the possible mechanisms of invasion of the nervous system by this virus, to provide a summary and critical analysis of the early reporting of neurological involvement in COVID-19. An exhaustive search of scientific articles on neurological involvement in COVID-19 was performed in the Web of Science, Scopus, Medline/PubMed, and several other databases. Nineteen relevant articles that had been published or were in preprint were carefully selected according to the inclusion and exclusion criteria. Based on our research, we found that patients with COVID-19 can present with neurological symptoms that can be broadly divided into central nervous system involvement, such as headache, dizziness, altered mental state, and disorientation, and peripheral nervous system involvement, such as anosmia and hypogeusia. Most of these patients are in the older age group and exhibit comorbidities, especially hypertension, and severe infection. In extreme presentations of COVID-19, some patients exhibit seizures, stroke, flaccid paraparesis, corticospinal weakness, and even coma. Moreover, the neurological manifestations can occur independently of the respiratory system. In conclusion, SARS-CoV-2 infection can cause multiple neurological syndromes in a more complex presentation. Therefore, this review elucidated the involvement of the nervous system in SARS-CoV-2 infection and will hopefully help improve the management of COVID-19.

An injury to peripheral nerves leads to skin denervation, which often is followed by increased pain sensitivity of the denervated areas and the development of neuropathic pain. Changes in innervation patterns during the reinnervation process of the denervated skin could contribute to the development of neuropathic pain. Here, we examined the changes in the innervation pattern during reinnervation and correlated them with the symptoms of neuropathic pain. Using a multispectral labeling technique&mdash, PainBow, which we developed, we characterized dorsal root ganglion (DRG) neurons innervating distinct areas of the rats&rsquo, paw. We then used spared nerve injury, causing partial denervation of the paw, and examined the changes in innervation patterns of the denervated areas during the development of allodynia and hyperalgesia. We found that, differently from normal conditions, during the development of neuropathic pain, these areas were mainly innervated by large, non-nociceptive neurons. Moreover, we found that the development of neuropathic pain is correlated with an overall decrease in the number of DRG neurons innervating these areas. Importantly, treatment with ouabain facilitated reinnervation and alleviated neuropathic pain. Our results suggest that local changes in peripheral innervation following denervation contribute to neuropathic pain development. The reversal of these changes decreases neuropathic pain.

HIV-associated neurocognitive disorders (HAND) are characterized by synaptic damage and neuronal loss in the brain, ultimately leading to progressive decline of cognitive abilities and memory. Chemokine CC motif ligand 2 (CCL2) is elevated in cerebrospinal fluid (CSF), and has been believed to contribute to HAND. Previous studies by our research team have shown that CCL2 enhances N-Methyl-D-aspartate receptor (NMDAR)-mediated excitatory postsynaptic currents (EPSCs) and causes nerve cell damage. However, there are few drugs currently available to treat nerve damage that is caused by CCL2. Panax notoginseng saponins (PNS) are isolated from Panax notoginseng and benefit the human body in various ways, including the neuroprotective effect. However, the protective effect of PNS on CCL2-induced neurotoxicity remains unknown. In this study, we found that PNS improved CCL2-induced learning and memory impairment, and inhibited CCL2-induced cell death. These effects may be due to inhibiting over-activation of NMDA receptors by alleviating the dysfunction of glutamate metabolism. Furthermore, PNS-modulated CCL2-inducd intracellular oxidative stress was found to attenuate cell inflammation. Additionally, PNS pretreatment evidently inhibited apoptotic pathways by reducing the Bax/BCL-2 ratio and caspase-3, 8, 9 expressions. In conclusion, this study demonstrates that PNS provides substantial neuroprotection against CCL2-induced neurotoxicity, and may be a novel therapeutic agent in CCL2-induced HAND or other neurodegenerative diseases.

Background: Myelin is an essential component of the peripheral and central nervous system, enabling fast axonal conduction and supporting axonal integrity, limited tools exist for analysis of myelin composition in-vivo. Objective: To demonstrate that the photophysical properties of myelin-incorporated solvatochromic dyes can be exploited to probe the biochemical composition of living peripheral nerve myelin at high spatial resolution. Methods: Using the myelin-incorporated fluorescent dye Nile Red we sequentially analyzed the spectral characteristics of remyelinating myelin membranes both in-vitro and in-vivo, including in living rats. Results: We demonstrated a consistent bi-phasic evolution of emission spectra during early remyelination, and visually report the reliable biochemical flux of myelin membrane composition in-vitro and in-vivo. Conclusions: Solvatochromic spectroscopy enables the analysis of myelin membrane maturity during remyelination, and can be performed in-vivo. As the formation of myelin during early-to-late remyelination likely incorporates fluctuating fractions of lipophilic components and changes in lateral membrane mobility, we propose that our spectrochemical data reflects the observation of these biochemical processes.

Peripheral nerve stimulators serve as an alternative modality to treat chronic pain conditions; however, long-term complications, specifically lead migration, may occur., Introduction: Peripheral nerve stimulators have emerged as a new generation of advanced modalities to treat chronic pain and avoid opioids. They transmit electrical stimulation through implanted leads and wireless, wearable, external generators. Common complications include infection, nerve damage, and migration of stimulating leads. This article describes 2 cases of complications from lead migration. Methods: Case 1 describes a 61-year-old man with chronic groin pain who underwent an uncomplicated ultrasound-guided ilioinguinal peripheral nerve lead implantation. Case 2 describes a 54-year-old woman with left shoulder pain who underwent an uncomplicated ultrasound-guided percutaneous lead placement near the axillary nerve through a deltoid approach. Both peripheral nerve stimulators were confirmed with fluoroscopy, and each patient was followed up every 2 months for the following 2 years. Results: Both patients experienced lead migration to the skin resulting in erythema and need for lead removal. Initial unsuccessful removal by traction resulted in retained fragments and need for open surgical removal. Discussion: Neurologic complications of peripheral nerve stimulator implantation are rare, but device-associated complications, specifically lead migration, remain a source of long-term problems that can result in decreased coverage of the intended neural target. Conclusion: Thorough patient education, early postimplantation assessment, and extended routine follow-up are necessary to decrease lead-associated complications. If migration does occur, the potential impact of scar tissue on removal should be considered.

Glutamate (Glu) is the predominant excitatory neurotransmitter in the central nervous system (CNS). Glutamatergic transmission is critical for controlling neuronal activity. In presynaptic neurons, Glu is stored in synaptic vesicles and released by stimulation. The homeostasis of glutamatergic system is maintained by a set of transporters in the membrane of synaptic vesicles. The family of vesicular Glu transporters in mammals is comprised of three highly homologous proteins: VGLUT1-3. Among them, VGLUT1 accounts for the largest proportion. However, most of the Glu is transported into the synaptic vesicles via the type 1 vesicle Glu transporter (VGLUT1). So, the expression of particular VGLUT1 is largely complementary with limited overlap and so far it is most specific markers for neurons that use Glu as neurotransmitter. Controlling the activity of VGLUT1 could potentially modulate the efficiency of excitatory neuro-transmission and change the filling level of synaptic vesicles. This review summarizes the recent knowledge concerning molecular and functional characteristic of VGLUT1, their development, contribution to a series of central nervous system and peripheral nervous system diseases such as learning and memory disorders, Alzheimer’s disease, Parkinson’s disease and sensitized nociception or pain pathology et al.

Cigarette consumption is a worldwide epidemic and its reduction is one of the major public health concerns. In Brazil, although there is a wide literature on smoking cessation it is restricted to experimental studies. Based on data from the 2013 National Health Survey (PNS), this study uses the survival methodology and use population data and consumer’s profile to investigate which characteristics will affect smoking cessation hazard. The results showed that the people who are less likely to quit smoking are older, single men, with low income and fewer education years. They also do not practice physical exercise. The findings of cigarette cessation hazard to Brazilian population are similar of experimental studies with smokers and ex-smokers in country. Therefore, in order to decrease public health spending, Brazilian health policies regarding tobacco cessation could focus on those groups who will likely smoke for a long time. Resumo O consumo de cigarro é uma epidemia mundial e sua redução é uma das principais preocupações de saúde pública. No Brasil, embora exista uma ampla literatura sobre a cessação do tabagismo, ela se restringe a estudos experimentais. Com base nos dados da Pesquisa Nacional de Saúde de 2013 (PNS), este estudo usa a metodologia de sobrevivência e usa dados da população e os perfis dos consumidores para investigar quais características afetarão as chances de cessação do tabagismo. Os resultados mostraram que as pessoas com menor probabilidade de parar de fumar são homens mais velhos e solteiros, com baixa renda e menos anos de estudo, que não praticam exercícios físicos. Os achados do risco de cessação do cigarro para a população brasileira são semelhantes a estudos experimentais com fumantes e ex-fumantes no país. Portanto, para diminuir os gastos em saúde pública, as políticas de saúde brasileiras em relação à cessação do tabaco poderiam se concentrar nos grupos que fumarão por mais tempo.

Neurons and glial cells coordinate with each other in many different aspects of nervous system development. Both types of cells are receiving multiple guidance cues to guide the neurons and glial cells to their proper final position. The lateral chordotonal organs (lch5) of the Drosophila peripheral nervous system (PNS) are composed of five sensory neurons surrounded by four different glial cells, scolopale cells, cap cells, attachment cells and ligament cells. During embryogenesis, the lch5 neurons go through a rotation and ventral migration to reach their final position in the lateral region of the abdomen. We show here that the extracellular ligandsliis required for the proper ventral migration and morphology of the lch5 neurons. We further show that mutations in the Sli receptors Robo and Robo2 also display similar defects as loss ofsli, suggesting a role for Slit-Robo signaling in lch5 migration and positioning. Additionally, we demonstrate that the scolopale, cap and attachment cells follow the mis-migrated lch5 neurons inslimutants, while the ventral stretching of the ligament cells seems to be independent of the lch5 neurons. This study sheds light on the role of Slit-Robo signaling in sensory neuron development.

To describe and analyze the clinical features and prognosis of patients with anti-Hu associated paraneoplastic neurological syndromes (PNS). The symptoms, MRI findings, cerebrospinal fluid (CSF) changes, electroencephalogram (EEG) characteristics and prognoses of 9 well-diagnosed anti-Hu associated PNS patients were analyzed. The study enrolled 6 female and 3 male patients. Three patients presented with vertigo and 6 patients exhibited a depressed mood, numbness of the lower limbs, generalized pains, seizures, mental disturbances, and a temporary unilateral hand tremor on initial presentation. Three patients presented with MRI abnormalities localized in the mesial temporal lobe and the thalamus. Abnormal interictal EEG readings were observed in all 5 patients who underwent EEG study. Four patients were found lung cancer (3 during hospitalization, 1 during follow-up). Seven patients were treated with immunotherapy and improved in symptoms. Three patients died during follow-up (2 with lung cancer). The clinical manifestation of anti-Hu associated PNS is diverse and multifocal. EEG may be more sensitive than MRI for early diagnosis of PNS. Long-term follow-up for patients with CT-negative anti-Hu associated PNS is necessary.

Schwann cell c-Jun is implicated in adaptive and maladaptive functions in peripheral nerves. In injured nerves, this transcription factor promotes the repair Schwann cell phenotype and regeneration and promotes Schwann-cell-mediated neurotrophic support in models of peripheral neuropathies. However, c-Jun is associated with tumor formation in some systems, potentially suppresses myelin genes, and has been implicated in demyelinating neuropathies. To clarify these issues and to determine how c-Jun levels determine its function, we have generated c-Jun OE/+ and c-Jun OE/OE mice with graded expression of c-Jun in Schwann cells and examined these lines during development, in adulthood, and after injury using RNA sequencing analysis, quantitative electron microscopic morphometry, Western blotting, and functional tests. Schwann cells are remarkably tolerant of elevated c-Jun because the nerves of c-Jun OE/+ mice, in which c-Jun is elevated ∼6-fold, are normal with the exception of modestly reduced myelin thickness. The stronger elevation of c-Jun in c-Jun OE/OE mice is, however, sufficient to induce significant hypomyelination pathology, implicating c-Jun as a potential player in demyelinating neuropathies. The tumor suppressor P19ARF is strongly activated in the nerves of these mice and, even in aged c-Jun OE/OE mice, there is no evidence of tumors. This is consistent with the fact that tumors do not form in injured nerves, although they contain proliferating Schwann cells with strikingly elevated c-Jun. Furthermore, in crushed nerves of c-Jun OE/+ mice, where c-Jun levels are overexpressed sufficiently to accelerate axonal regeneration, myelination and function are restored after injury. SIGNIFICANCE STATEMENT In injured and diseased nerves, the transcription factor c-Jun in Schwann cells is elevated and variously implicated in controlling beneficial or adverse functions, including trophic Schwann cell support for neurons, promotion of regeneration, tumorigenesis, and suppression of myelination. To analyze the functions of c-Jun, we have used transgenic mice with graded elevation of Schwann cell c-Jun. We show that high c-Jun elevation is a potential pathogenic mechanism because it inhibits myelination. Conversely, we did not find a link between c-Jun elevation and tumorigenesis. Modest c-Jun elevation, which is beneficial for regeneration, is well tolerated during Schwann cell development and in the adult and is compatible with restoration of myelination and nerve function after injury.

Coronary artery disease (CAD) is a major public health problem and the chief cause of morbidity and mortality worldwide. Panax notoginseng, a valuable herb in traditional Chinese medicine (TCM) with obvious efficacy and favorable safety, shows a great promise as a novel option for CAD and is increasingly recognized clinically. Firstly, this review introduced recent clinical trials on treatment with PNS either alone or in combination with conventional drugs as novel treatment strategies. Then we discussed the mechanisms of P. notoginseng and Panax notoginseng saponins (PNS), which can regulate signaling pathways associated with inflammation, lipid metabolism, the coagulation system, apoptosis, angiogenesis, atherosclerosis, and myocardial ischaemia.

Reconstitution of the PMP22 protein into lipid bilayers results in membrane assemblies that share common features with myelin., Peripheral myelin protein 22 (PMP22) is highly expressed in myelinating Schwann cells of the peripheral nervous system. PMP22 genetic alterations cause the most common forms of Charcot-Marie-Tooth disease (CMTD), which is characterized by severe dysmyelination in the peripheral nerves. However, the functions of PMP22 in Schwann cell membranes remain unclear. We demonstrate that reconstitution of purified PMP22 into lipid vesicles results in the formation of compressed and cylindrically wrapped protein-lipid vesicles that share common organizational traits with compact myelin of peripheral nerves in vivo. The formation of these myelin-like assemblies depends on the lipid-to-PMP22 ratio, as well as on the PMP22 extracellular loops. Formation of the myelin-like assemblies is disrupted by a CMTD-causing mutation. This study provides both a biochemical assay for PMP22 function and evidence that PMP22 directly contributes to membrane organization in compact myelin.

Injuries to peripheral nerves cause loss of motor and sensory function, greatly affecting life quality. Successful repair of the lesioned nerve requires efficient cell debris removal, followed by axon regeneration and reinnervation of target organs. Such process is orchestrated by several cellular and molecular events in which glial and immune cells actively participate. It is known that tissue clearance is largely improved by macrophages, which activation is potentiated by cells and molecules of the acquired immune system, such as T helper lymphocytes and antibodies, respectively. In the present work, we evaluated the contribution of lymphocytes in the regenerative process of crushed sciatic nerves of immunocompetent (wild-type, WT) and T and B-deficient (RAG-KO) mice. In Knockout animals, we found increased amount of macrophages under basal conditions and during the initial phase of the regenerative process, that was evaluated at 2, 4, and 8 weeks after lesion (wal). That parallels with faster axonal regeneration evidenced by the quantification of neurofilament and a growth associated protein immunolabeling. The motor function, evaluated by the sciatic function index, was fully recovered in both mouse strains within 4 wal, either in a progressive fashion, as observed for RAG-KO mice, or presenting a subtle regression, as seen in WT mice between 2 and 3 wal. Interestingly, boosting the immune response by early adoptive transference of activated WT lymphocytes at 3 days after lesion improved motor recovery in WT and RAG-KO mice, which was not ameliorated when cells were transferred at 2 wal. When monitoring lymphocytes by in vivo imaging, in both mouse strains, cells migrated to the lesion site shortly after transference, remaining in the injured limb up to its complete motor recovery. Moreover, a first peak of hyperalgesia, determined by von-Frey test, was coincident with increased lymphocyte infiltration in the damaged paw. Overall, the present results suggest that a wave of immune cell infiltration takes place during subacute phase of axonal regeneration, resulting in transient set back of motor recovery following peripheral axonal injury. Moreover, modulation of the immune response can be an efficient approach to speed up nerve regeneration.

Recent advances in MRI technology are presented, with emphasis on how this new technology impacts clinical operations (better image quality, faster exam times, and improved throughput). In addition, implications for patient safety are discussed with emphasis on the risk of patient injury due to either high local specific absorption rate (SAR) or large cumulative energy doses delivered during long exam times. Patient comfort issues are examined as well.

The purpose of this article was to provide a literature review of occupational neurological disorders and related research in Korea, focusing on chemical hazards. We reviewed occupational neurological disorders investigated by the Occupational Safety and Health Research Institute of Korean Occupational Safety and Health Agency between 1992 and 2009, categorizing them as neurological disorders of the central nervous system (CNS), of the peripheral nervous system (PNS) or as neurodegenerative disorders. We also examined peer-reviewed journal articles related to neurotoxicology, published from 1984 to 2009. Outbreaks of occupational neurological disorder of the CNS due to inorganic mercury and carbon disulfide poisoning had helped prompt the development of the occupational safety and health system of Korea. Other major neurological disorders of the CNS included methyl bromide intoxication and chronic toxic encephalopathy. Most of the PNS disorders were n-hexane-induced peripheral neuritis, reported from the electronics industry. Reports of manganese-induced Parkinsonism resulted in the introduction of neuroimaging techniques to occupational medicine. Since the late 1990s, the direction of research has been moving toward degenerative disorder and early effect of neurotoxicity. To understand the early effects of neurotoxic chemicals in the preclinical stage, more follow-up studies of a longer duration are necessary.

Space-filling neurons extensively sample their receptive fields with fine dendritic branches. In this study we show that a member of the conserved Robo receptor family, Robo, and its ligand Slit regulate the dendritic differentiation of space-filling neurons. Loss of Robo or Slit function leads to faster elongating and less branched dendrites of the complex and space-filling class IV multi-dendritic dendrite-arborization (md-da) neurons in the Drosophila embryonic peripheral nervous system, but not of the simpler class I neurons. The total dendrite length of Class IV neurons is not modified in robo or slit mutant embryos. Robo mediates this process cell-autonomously. Upon Robo over-expression in md-da neurons the dendritic tree is simplified and time-lapse analysis during larval stages indicates that this is due to reduction in the number of newly formed branches. We propose that Slit, through Robo, provides an extrinsic signal to coordinate the growth rate and the branching level of space-filling neurons, thus allowing them to appropriately cover their target field.

The cell adhesion molecule neurofascin (NF) has a major neuronal isoform (NF186) containing a mucin-like domain followed by a fifth fibronectin type III repeat while these domains are absent from glial NF155. Neuronal NF isoforms lacking one or both of these domains are expressed transiently in embryonic dorsal root ganglia (DRG). These two domains are co-expressed in mature NF186, which peaks in expression prior to birth and then persists almost exclusively at nodes of Ranvier on myelinated axons. In contrast, glial NF155 is only detected postnatally with the onset of myelination. All these forms of NF bound homophilically and to Schwann cells but only the mature NF186 isoform inhibits cell adhesion, and this activity may be important in formation of the node of Ranvier. Schwann cells deficient in NF155 myelinated DRG axons in a delayed manner and they showed significantly decreased clustering of both NF and Caspr in regions where paranodes normally form. The combined results suggest that NF186 is expressed prenatally on DRG neurons and it may modulate their adhesive interactions with Schwann cells, which express NF155 postnatally and require it for development of axon–glial paranodal junctions.

Repair of the injured spinal cord is a major challenge in medicine. The limited intrinsic regenerative response mounted by adult central nervous system (CNS) neurons is further hampered by astrogliosis, myelin debris and scar tissue that characterize the damaged CNS. Improved axon regeneration and recovery can be elicited by targeting extrinsic factors as well as by boosting neuron-intrinsic growth regulators. Our knowledge of the molecular basis of intrinsic and extrinsic regulators of regeneration has expanded rapidly, resulting in promising new targets to promote repair. Intriguingly certain neuron-intrinsic growth regulators are emerging as promising targets to both stimulate growth and relieve extrinsic inhibition of regeneration. This crossroads between the intrinsic and extrinsic aspects of spinal cord injury is a promising target for effective therapies for this unmet need.

The Ig cell adhesion molecules (CAM) neurofascin (NF) and Nr-CAM are localized at developing nodes of Ranvier in peripheral myelinated axons prior to clustering of Na + channels. Different isoforms of NF are expressed on neurons and glia, and NF binding on both cells has been suggested to play roles in node and paranode formation. To clarify the role of NF further, we analyzed effects of NF-Fc fusion proteins in Schwann cell–DRG neuron myelinating cocultures. NF-Fc significantly inhibited nodal clustering of Na + channels, ankyrin G , and βIV spectrin, and modestly reduced Caspr clustering at paranodal junctions; it did not significantly affect lengths or numbers of myelin-positive segments, axon initial segments, or accumulations of phosphorylated-ERM proteins in Schwann cell nodal microvilli. NF-Fc binds to Schwann cells but little or no binding to DRG neurons was detected. The results suggest a critical early role for axonal NF in clustering of Na + channels at nodes of Ranvier via interactions with receptors on Schwann cells.

The Pox neuro (Poxn) gene of Drosophila plays a crucial role in the development of poly-innervated external sensory (p-es) organs. However, how Poxn exerts this role has remained elusive. In this study, we have analyzed the cell lineages of all larval p-es organs, namely of the kölbchen, papilla 6, and hair 3. Surprisingly, these lineages are distinct from any previously reported cell lineages of sensory organs. Unlike the well-established lineage of mono-innervated external sensory (m-es) organs and a previously proposed model of the p-es lineage, we demonstrate that all wild-type p-es lineages exhibit the following features: the secondary precursor, pIIa, gives rise to all three support cells—socket, shaft, and sheath, whereas the other secondary precursor, pIIb, is neuronal and gives rise to all neurons. We further show that in one of the p-es lineages, that of papilla 6, one cell undergoes apoptosis. By contrast in Poxn null mutants, all p-es lineages have a reduced number of cells and their pattern of cell divisions is changed to that of an m-es organ, with the exception of a lineage in a minority of mutant kölbchen that retains a second bipolar neuron. Indeed, the role of Poxn in p-es lineages is consistent with the specification of the developmental potential of secondary precursors and the regulation of cell division but not apoptosis.

Progesterone is synthesized and actively metabolized in the central and peripheral nervous system, into neuroactive steroid metabolites, such as dihydroprogesterone, allopregnanolone and isopregnanolone. Progesterone and/or its metabolites exert a variety of effects acting as physiological regulators of neuronal and glial development and plasticity, controlling reproduction, neuroendocrine events, mood and affection. In addition, these neuroactive steroids maintain neural homeostasis and exert neuroprotective actions. In agreement, metabolic pathways of progesterone are affected by modifications in the level of gonadal hormones and by pathology or injury with a regional specificity and in a sex-dimorphic way. Therefore, observations here summarized may provide a background to design sex-specific therapies based on progesterone metabolites. On this point of view, considering that one of the major limits of a therapy based on neuroactive steroids could be modifications in their plasma levels and their consequent peripheral effects, pharmacological treatments aimed to increase their levels in the nervous system could provide an interesting therapeutic option. © 2013 Elsevier Ltd.

Objective: We performed more than 350 peripheral nerve stimulation procedures since 1991. We mostly treated patients with Causalgia (CRPS II). Incomplete or complete lesion of the stimulated peripheral nerves was determined in all patients. Surgical treatment failed or wouldn't be indicated in [for full text, please go to the a.m. URL], 63. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Japanischen Gesellschaft für Neurochirurgie (JNS)

International audience; The analysis of the molecular mechanisms involved in the initial interaction between neurons and Schwann cells is a key issue in understanding the myelination process. We recently identified Cthrc1 (Collagen triple helix repeat containing 1) as a gene upregulated in Schwann cells upon interaction with the axon. Cthrc1 encodes a secreted protein previously shown to be involved in migration and proliferation in different cell types. We performed a functional analysis of Cthrc1 in Schwann cells by loss- and gain-of-function approaches, using RNA interference knock-down in cell culture and a transgenic mouse line that overexpresses the gene. This work establishes that Cthrc1 enhances Schwann cell proliferation, but prevents myelination. In particular, time-course analysis of myelin formation in transgenic animals reveals that overexpression of Cthrc1 in Schwann cells leads to a delay in myelin formation, with cells maintaining a proliferative state. Our data therefore demonstrate that Cthrc1 plays a negative regulatory role, fine-tuning the onset of peripheral myelination.

Myelin sheath thickness is precisely adjusted to axon caliber, and in the peripheral nervous system, neuregulin 1 (NRG1) type III is a key regulator of this process. It has been proposed that the protease BACE1 activates NRG1 dependent myelination. Here, we characterize the predicted product of BACE1-mediated NRG1 type III processing in transgenic mice. Neuronal overexpression of a NRG1 type III-variant, designed to mimic prior cleavage in the juxtamembrane stalk region, induces hypermyelination in vivo and is sufficient to restore myelination of NRG1 type III-deficient neurons. This observation implies that the NRG1 cytoplasmic domain is dispensable and that processed NRG1 type III is sufficient for all steps of myelination. Surprisingly, transgenic neuronal overexpression of full-length NRG1 type III promotes hypermyelination also in BACE1 null mutant mice. Moreover, NRG1 processing is impaired but not abolished in BACE1 null mutants. Thus, BACE1 is not essential for the activation of NRG1 type III to promote myelination. Taken together, these findings suggest that multiple neuronal proteases collectively regulate NRG1 processing. © 2011 Wiley Periodicals, Inc.

Objective: Peripheral nerve stimulation (PNS) is known to deliver targeted relief of neuropathic pain. Little is known about optimal stimulation strategies to ensure lasting and stabile effects. Some specific effects of PNS are based on sustained excitability of the stimulated axons. Since tonic stimulation[for full text, please go to the a.m. URL], 63. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Japanischen Gesellschaft für Neurochirurgie (JNS)

Peripheral neuropathic pain is a severe chronic pain condition which may result from trauma to sensory nerves in the peripheral nervous system. The spared nerve injury (SNI) model induces symptoms of neuropathic pain such as mechanical allodynia i.e. pain due to tactile stimuli that do not normally provoke a painful response [1]. The SNI mouse model involves ligation of two of the three branches of the sciatic nerve (the tibial nerve and the common peroneal nerve), while the sural nerve is left intact [2]. The lesion results in marked hypersensitivity in the lateral area of the paw, which is innervated by the spared sural nerve. The non-operated side of the mouse can be used as a control. The advantages of the SNI model are the robustness of the response and that it doesn’t require expert microsurgical skills. The threshold for mechanical pain response is determined by testing with von Frey filaments of increasing bending force, which are repetitively pressed against the lateral area of the paw [3], [4]. A positive pain reaction is defined as sudden paw withdrawal, flinching and/or paw licking induced by the filament. A positive response in three out of five repetitive stimuli is defined as the pain threshold. As demonstrated in the video protocol, C57BL/6 mice experience profound allodynia as early as the day following surgery and maintain this for several weeks.

Duchenne muscular dystrophy is caused by mutations in the dystrophin gene and is characterized by progressive muscle wasting. A number of Duchenne patients also present with mental retardation. The dystrophin protein is part of the highly conserved dystrophin-associated glycoprotein complex (DGC) which accumulates at the neuromuscular junction (NMJ) and at a variety of synapses in the peripheral and central nervous systems. Many years of research into the roles of the DGC in muscle have revealed its structural function in stabilizing the sarcolemma. In addition, the DGC also acts as a scaffold for various signaling pathways. Here, we discuss recent advances in understanding DGC roles in the nervous system, gained from studies in both vertebrate and invertebrate model systems. From these studies, it has become clear that the DGC is important for the maturation of neurotransmitter receptor complexes and for the regulation of neurotransmitter release at the NMJ and central synapses. Furthermore, roles for the DGC have been established in consolidation of long-term spatial and recognition memory. The challenges ahead include the integration of the behavioral and mechanistic studies and the use of this information to identify therapeutic targets.

Proper sampling of sensory inputs critically depends upon neuron morphogenesis and expression of sensory channels. The highly stereotyped organisation of the Drosophila peripheral nervous system (PNS) provides a model to study neuronal determination and morphogenesis. Here, we report that Collier/Knot (Col/Kn), the Drosophila member of the COE family of transcription factors, is transiently expressed in the subset of multidendritic arborisation (da) sensory neurons that display an highly branched dendritic arborisation, class IV neurons. When lacking Col activity, class IV da neurons are formed but display a reduced dendrite arborisation. Col control on dendrite branching is distinct from that exerted by Cut, another transcription factor expressed in class IV neurons and necessary for proper dendrite morphogenesis. Col is also required for the class IV da-specific expression of pickpocket (ppk), which encodes a degenerin/epithelial sodium channel subunit required for larval locomotion. Characterisation of the col upstream region identified a 9-kb cis-regulatory region driving col expression in all class IV md neurons, even though these originate from two types of sensory precursor cells. Altogether, these findings indicate that col is required in at least two distinct programs that control the morphological and sensory specificity of Drosophila md neurons.

The X-linked form of Charcot-Marie-Tooth disease (CMTX) is caused by mutations in connexin32 (Cx32), a gap junction protein expressed by Schwann cells where it forms reflexive channels that allow the passage of ions and signaling molecules across the myelin sheath. Although most mutations result in loss of function, several studies have reported that some retain the ability to form homotypic intercellular channels. To gain insight into the molecular defect of three functional CMTX variants, S26L, Delta111-116 and R220stop, we have used several fluorescent tracers of different size and ionic charge to compare their permeation properties to those of wild-type Cx32. Although all mutations allowed the passage of the dye with the smallest molecular mass, they exhibited a clear reduction in the permeability of either one or all of the probes with respect to wild-type channels, as assessed by the percentage of injections showing dye coupling. These data reveal that a lower size cutoff distinguishes these functional CMTX variants from wild-type channels and suggest that this defect may be of pathophysiological relevance.