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Background Obesity is a chronic condition, affecting central and peripheral nervous system. Studies on cranial nerve conduction in obesity are scarce and unclear; therefore, we planned this study. The aim of this study was to evaluate optic and auditory nerve conductions in obesity. Methods It was a case-control study, with inclusion of 40 young males (20 obese and 20 controls) in age group of 18–30 years. We recorded pattern reversal visual evoked potential (PRVEP) and brainstem auditory evoked potential (BAEP). The PRVEP P100 latency and BAEP absolute and interpeak latencies were analyzed. Results In obese individuals, BAEP absolute latencies of wave V were significantly prolonged in both the ears and wave I in left ear. In addition, significant prolongation of interpeak latency III–V was observed in both the ears and I–V latency, in right ear among obese cases. A positive correlation was seen between body mass index and interpeak latency I–V. In PRVEP recordings, P100 latency did not show any significant difference in both the groups. Conclusion Therefore, we can conclude that obesity does not affect optic nerve conduction, but auditory nerve conduction is affected. BAEP I–V interpeak latency may be an indicator of subclinical auditory conduction defects in young obese males.

SIGNIFICANCE Reactive oxygen species (ROS) contribute to multiple aspects of peripheral nervous system (PNS) biology ranging from physiological processes (e.g. axonal outgrowth and regeneration), to pathophysiology (e.g. nerve degeneration). Although ROS are derived from multiple sources, NADPH oxidase (Nox) family members are dedicated to ROS generation. Noxs are expressed in the PNS and their overexpression is associated with detrimental effects on nerve function and contribute, at least in part, to peripheral neuropathies. Recent Advances: Of the 7 members, studies mostly focused on Nox1, Nox2, and Nox4, which are expressed in the PNS in a cell-specific manner. We have also recently identified human Nox5 in sural nerve biopsies. When maintained at homeostatic levels, Noxs regulate several aspects of peripheral nerve health, most notably neurite outgrowth and axonal regeneration following nerve lesion. While Nox2 and Nox4 dysregulation is a major source of oxidative stress in PNS disorders, including neuropathic pain and diabetic peripheral neuropathy, recent evidence also implicates Nox1 and Nox5. CRITICAL ISSUES Although there is compelling evidence for a direct role of Noxs on nerve function, little is known about their subcellular localization, intercellular regulation, and interaction. These, together with redox signaling, are considered crucial components of nerve redox status. Additionally, the lack of isoform-specific inhibitors limits conclusions about the physiological role of Noxs in the PNS and their therapeutic potential in peripheral neuropathies. FUTURE DIRECTIONS Future research using isoform-specific genetic and pharmacological approaches are therefore needed to better understand the significance of Nox enzymes in PNS (patho) physiology.

The peripheral nervous system has the remarkable ability to regenerate in response to injury. However, this is only successful over shorter nerve gaps and often provides poor outcomes for patients. Currently, the gold standard of treatment is the surgical intervention of an autograft, whereby patient tissue is harvested and transplanted to bridge the nerve gap. Despite being the gold standard, more than half of patients have dissatisfactory functional recovery after an autograft. Peripheral nerve tissue engineering aims to create biomaterials that can therapeutically surpass the autograft. Current tissue-engineered constructs are designed to deliver a combination of therapeutic benefits to the regenerating nerve, such as supportive cells, alignment, extracellular matrix, soluble factors, immunosuppressants, and other therapies. An emerging therapeutic opportunity in nerve tissue engineering is the use of electrical stimulation (ES) to modify and enhance cell function. ES has been shown to positively affect four key cell types, such as neurons, endothelial cells, macrophages, and Schwann cells, involved in peripheral nerve repair. Changes elicited include faster neurite extension, cellular alignment, and changes in cell phenotype associated with improved regeneration and functional recovery. This review considers the relevant modes of administration and cellular responses that could underpin incorporation of ES into nerve tissue engineering strategies. Impact Statement Tissue engineering is becoming increasingly complex, with multiple therapeutic modalities often included within the final tissue-engineered construct. Electrical stimulation (ES) is emerging as a viable therapeutic intervention to be included within peripheral nerve tissue engineering strategies; however, to date, there have been no review articles that collate the information regarding the effects of ES on key cell within peripheral nerve injury. This review article aims to inform the field on the different therapeutic effects that may be achieved by using ES and how they may become incorporated into existing strategies.

Publisher Summary This chapter discusses the epidemiology and classification of traumatic peripheral nerve injuries, the effects of these injuries on nerve and muscle, and how electrodiagnosis is used to help classify the injury. Traumatic injury to peripheral nerves results in considerable disability across the world. In peacetime, peripheral nerve injuries result commonly from motor vehicle accident trauma and less commonly from penetrating trauma, such as falls and industrial accidents. If plexus and root injuries are also included, the incidence is about 5%. In the upper limb, the nerve injured most commonly is the radial nerve, followed by the ulnar and median nerves. Lower limb peripheral nerve injuries are less common, and the sciatic nerve is injured most frequently, followed by the peroneal and rarely the tibial or femoral nerves. Peripheral nerve injuries may be seen in isolation, but they also often accompany central nervous system (CNS) trauma. Peripheral nerve injuries have significant impact, as they impede the recovery of function and return to work. There is also a risk of secondary disability from falls, fractures, or other injuries.

Significance. This review highlights the many intracellular processes generating reactive oxygen species (ROS) in the peripheral nervous system in the context of type 1 diabetes. The major sources ...

Neurolymphomatosis (NL) is the infiltration of cranial nerves or nerves and roots from the peripheral nervous system by lymphoma, usually by B-cell non-Hodgkin's lymphoma. It is uncommon as initial presentation of the disease and can lead to extremely heterogeneous clinical manifestations. We report the case of a 72-year old male who presented with numbness of the right hand, progressive weakness in both lower limbs and weight loss. 18F-FDG PET/CT showed bilateral hypermetabolic adrenal masses, gastric ulcer, small hypermetabolic adenopathies, multiple focal bone marrow uptake and intense uptake in both sciatic nerves and right median nerve. A node and gastric biopsy confirmed diffuse large-B-cell lymphoma, activated B cell type, with posterior resolution of peripheral nerves uptake after beginning chemotherapy.

Several neurotransmitters and neuropeptides were reported to join to or to cooperate with different cells of the immune system, bone marrow, and peripheral cells and numerous data support that neuroactive molecules might control immune system activity and hemopoiesis operating on lymphoid organs, and the primary hematopoietic unit, the hematopoietic niche. Furthermore, many compounds seem to be able to take part to the leukemogenesis and lymphomagenesis process, and in the onset of multiple myeloma. In this review, we will assess the possibility that neurotransmitters and neuropeptides may have a role in the onset of haematological neoplasms, may affect the response to treatment or may represent a useful starting point for a new therapeutic approach. More in vivo investigations are needed to evaluate neuropeptide’s role in haematological malignancies and the possible utilization as an antitumor therapeutic target. Comprehending the effect of the pharmacological administration of neuropeptide modulators on hematologic malignancies opens up new possibilities in curing clonal hematologic diseases to achieve more satisfactory outcomes.

Although the functions of the peripheral nervous system in whole body homeostasis and sensation have been understood for many years, recent investigation has uncovered new roles for innervation in the musculoskeletal system. This review centers on advances regarding the function of nerves in the development and repair of two connected tissues: tendon and bone. Innervation in healthy tendons is generally confined to the tendon sheaths, and tendon-bone attachment units are typically aneural. In contrast to tendon, bone is an innervated and vascularized structure. Historically, the function of abundant peripheral nerves in bone has been limited to pain and some non-painful sensory perception in disease and injury. Indeed, much of our understanding of peripheral nerves in tendons, bones, and entheses is limited to the source and type of innervation in healthy and injured tissues. However, more recent studies have made important observations regarding the appearance, type, and innervation patterns of nerves during embryonic and postnatal development and in response to injury, which suggest a more expansive role for peripheral nerves in the formation of musculoskeletal tissues. Indeed, tendons and bones develop in a close spatiotemporal relationship in the embryonic mesoderm. Models of limb denervation have shed light on the importance of sensory innervation in bone and to a lesser extent, tendon development, and more recent work has unraveled key nerve signaling pathways. Furthermore, loss of sensory innervation also impairs healing of bone fractures and may contribute to chronic tendinopathy. However, more study is required to translate our knowledge of peripheral nerves to therapeutic strategies to combat bone and tendon diseases.

Work-related diseases of the musculoskeletal and the peripheral nervous system are classified as overload cumulative microtrauma diseases, resulting from chronic overload and/or damage of specific neuromusculoskeletal structures. Occupational activities which predispose to them are characterised by monotypy (repetition of movements during a significant part of the working shift). Authors described 4 cases of women with musculoskeletal and peripheral nervous system disorders qualified as occupational background just in the 2nd instance of medical certification. Detailed analysis of occupational exposure and medical interview with individual diagnostic approach allowed to determine the occupational etiology of diseases, regardless of non-occupational risk factors in some cases, even if the workstation was not common. Difficulties in estimating the probability of disease process induction on the background of occupational exposure are caused by frequent coexistence of non-occupational risk factors. The 2-tier system of certification provides an independent evaluation of medical history and occupational exposure. Med Pr. 2022;73(1).

Dendritic cells of the innate immune system and sensory neurons of the peripheral nervous system are embedded in barrier tissues and gather information about an organisms’ environment. While the mechanisms by which dendritic cells recognize and initiate adaptive immune responses to pathogens is well defined, how they sense allergens is poorly understood. Indeed, allergens induce dendritic cell maturation and migration in vivo, but not in vitro. How are adaptive immune responses to allergens initiated if dendritic cells do not directly sense allergens? Sensory neurons release neuropeptides within minutes of allergen exposure. Recent evidence demonstrated that while neuropeptides modify dendritic cell function during pathogen responses, they are required for dendritic cell function during allergic responses. These emerging studies suggest that sensory neurons do not just pass information along to the central nervous system, but also to dendritic cells, particularly during the initiation of adaptive immunity to allergens.

Two-pore domain potassium (K2P) channels are a diverse family of potassium channels. K2P channels generate background leak potassium currents to regulate cellular excitability and are thereby involved in a wide range of neurological disorders. K2P channels are modulated by a variety of physicochemical factors such as mechanical stretch, temperature, and pH. In the the peripheral nervous system (PNS), K2P channels are widely expressed in nociceptive neurons and play a critical roles in pain perception. In this review, we summarize the recent advances in the pharmacological properties of K2P channels, with a focus on the exogenous small-molecule activators targeting K2P channels. We emphasize the subtype-selectivity, cellular and in vivo pharmacological properties of all the reported small-molecule activators. The key underlying analgesic mechanisms mediated by K2P are also summarized based on the data in the literature from studies using small-molecule activators and genetic knock-out animals. We discuss advantages and limitations of the translational perspectives of K2P in pain medicine and provide outstanding questions for future studies in the end.

Affecting millions of people worldwide, arsenic exposure can cause several health problems, such as skin disorders and diseases of the gastrointestinal, respiratory, cardiovascular, neurological, genitourinary, endocrine, and hematopoietic systems. Arsenic is a well-known neurotoxicant that affects the central nervous system as well as the peripheral nervous system. When exposure occurs in the early developmental stages, the nervous system is more susceptible to toxic agents. Epidemiologic and animal studies have demonstrated that arsenic exposure impairs neurodevelopment, for example intellectual functions and motor functions. In this chapter, we review the presently known neurodevelopmental toxicity of arsenic in humans and animals, arsenic distribution, possible mechanisms of action, and neuroprotective effects of some agents against arsenic toxicity.

Delivery of adeno-associated viral vectors (AAVs) to cerebrospinal fluid (CSF) has emerged as a promising approach to achieve widespread transduction of the central nervous system (CNS) and peripheral nervous system (PNS), with direct applicability to the treatment of a wide range of neurological diseases, particularly lysosomal storage diseases. Although studies in small animal models have provided proof of concept and experiments in large animals demonstrated feasibility in bigger brains, there is not much information on long-term safety or durability of the effect. Here, we report a 7-year study in healthy beagle dogs after intra-CSF delivery of a single, clinically relevant dose (2 × 1013 vg/dog) of AAV9 vectors carrying the canine sulfamidase, the enzyme deficient in mucopolysaccharidosis type IIIA. Periodic monitoring of CSF and blood, clinical and neurological evaluations, and magnetic resonance and ultrasound imaging of target organs demonstrated no toxicity related to treatment. AAV9-mediated gene transfer resulted in detection of sulfamidase activity in CSF throughout the study. Analysis at tissue level showed widespread sulfamidase expression and activity in the absence of histological findings in any region of encephalon, spinal cord, or dorsal root ganglia. Altogether, these results provide proof of durability of expression and long-term safety for intra-CSF delivery of AAV-based gene transfer vectors encoding therapeutic proteins to the CNS., Graphical abstract, Seven-year follow-up of dogs after intra-CSF administration of AAV9-sulfamidase vectors results in detection of sulfamidase activity in CSF and widespread transgene expression in CNS, PNS, and liver, in the absence of any adverse events. Proof of durability and safety of this gene therapy support its clinical translation to treat CNS diseases.

Neurotropic alphaherpesviruses initiate infection in exposed mucosal tissues and, unlike most viruses, spread rapidly to sensory and autonomic nerves where life-long latency is established1. Recurrent infections arise sporadically from the peripheral nervous system throughout the life of the host, and invasion of the central nervous system may occur, with severe outcomes2. These viruses directly recruit cellular motors for transport along microtubules in nerve axons, but how the motors are manipulated to deliver the virus to neuronal nuclei is not understood. Here, using herpes simplex virus type I and pseudorabies virus as model alphaherpesviruses, we show that a cellular kinesin motor is captured by virions in epithelial cells, carried between cells, and subsequently used in neurons to traffic to nuclei. Viruses assembled in the absence of kinesin are not neuroinvasive. The findings explain a critical component of the alphaherpesvirus neuroinvasive mechanism and demonstrate that these viruses assimilate a cellular protein as an essential proviral structural component. This principle of viral assimilation may prove relevant to other virus families and offers new strategies to combat infection. Herpes simplex virus type I and pseudorabies virus assimilate kinesin from host epithelial cells and repurpose the motor to traffic to the nuclei of neurons in the peripheral nervous system.

Іпідакрин покращує роботу холінергічних синапсів і перешкоджає дегенерації нервових структур, що робить його препаратом вибору при терапії багатьох неврологічних захворювань. До унікальних властивостей іпідакрину відносять його здатність залучати декілька механізмів для досягнення лікувального ефекту (блокада потенціалзалежних К+-каналів, оборотне інгібування ацетилхолінестерази). Крім того, препарат однаково добре діє в центральних відділах і на периферії. У рамках цього огляду було висвітлено застосування парентеральних лікарських форм іпідакрину у гострій фазі ішемічного й геморагічного інсультів, при нейропатіях і радикулопатіях різного генезу.

The paper describes the basic pathogenic mechanisms of neuroendocrine disorders development in COVID-19 and post-COVID syndrome. The lesions of the central nervous system included complaints about headache, often very intensive, undue fatiguability, “intellectual fog”, periodic faintness, changes in mental state and cognitive functions. The lesions of the peripheral nervous system manifest themselves in anosmia and hypogeusia, pain in muscles and cartilages, myofascial pain, pain similar to a neurologic one, skin hyperesthesia. The impaired endocrine status manifested itself in autoimmune thyroiditis with thyroid pathology, impaired tolerance to carbohydrates and insulin-dependent diabetes mellitus (type 2), dysmenorrhea in females, and erectile dysfunction in males. The pathogenic changes of SARS-CoV-2 virus persistence cause chronic stress with hypothalamic dysfunction. Also, histological changes such as neuroglial imbalance were detected: regarding the close relationship of astrocytes and neurons, the metabolism imbalance in astrocytes results in neuron dysfunction that impacts the synaptic function of gamma-aminobutyric acid transmission. The optimization of the treatment of patients with COVID-19, post-COVID syndrome with neuroendocrine symptoms is of great relevance. Gamalate B6 is a gamma-aminobutyric acid containing medication with the best characteristics for these patients., В статье освещены основные патогенетические механизмы развития нейроэндокринных нарушений при COVID-19 и постковидном синдроме. К проявлениям поражения центральной нервной системы относятся жалобы на головную боль, часто очень сильную, повышенную утомляемость, «мозговой туман» и периодическое кратковременное головокружение, изменения психического состояния и когнитивных функций. Поражение периферической нервной системы проявляется аносмией и гипогевзией, болями в мышцах и суставах, миофасциальными болями, болями, похожими на невропатии, гиперестезией кожи. Наблюдаются нарушения эндокринного статуса в виде аутоиммунного тиреоидита с дисфункцией щитовидной железы, нарушения толерантности к углеводам или инсулиннезависимого сахарного диабета (2-го типа), дисменореи у женщин и эректильной дисфункции у мужчин. Патогенетические изменения персистенции вируса SARS-CoV-2 вызывают состояние хронического стресса с гипоталамической дисфункцией. Также выявлены гистологические изменения в виде нарушений нейроглиальных взаимодействий: с учетом тесной связи астроцитов и нейронов изменения метаболизма в астроцитах нарушают функцию нейронов, влияют на синаптическую функцию трансмиссии гамма-аминомасляной кислоты. Актуальна оптимизация терапии у пациентов с COVID-19, постковидным синдромом с нейроэндокринной симптоматикой. Гамалате В6 — препарат гамма-аминомасляной кислоты, имеющий лучшие характеристики для таких пациентов., У статті висвітлені основні патогенетичні механізми розвитку нейроендокринних порушень при COVID-19 і постковідному синдромі. До проявів ураження центральної нервової системи належать скарги на головний біль, часто дуже сильний, підвищену втомлюваність, «мозковий туман» і періодичне короткочасне запаморочення, зміни психічного стану й когнітивних функцій. Ураження периферичної нервової системи проявляється аносмією і гіпогевзією, болями в м’язах і суглобах, міофасціальними болями, болями, що схожі на невропатію, гіперестезією шкіри. Спостерігаються порушення ендокринного статусу у вигляді автоімунного тиреоїдиту з дисфункцією щитоподібної залози, порушення толерантності до вуглеводів або інсулінонезалежного цукрового діабету (2-го типу), дисменореї в жінок та еректильної дисфункції в чоловіків. Патогенетичні зміни персистенції вірусу SARS-CoV-2 викликають стан хронічного стресу з гіпоталамічною дисфункцією. Також виявлені гістологічні зміни у вигляді порушень нейрогліальної взаємодії: з огляду на тісний зв’язок астроцитів і нейронів зміни метаболізму в астроцитах порушують функцію нейронів, що впливає на синаптичну функцію трансмісії гамма-аміномасляної кислоти. Актуальною є оптимізація терапії в пацієнтів з COVID-19, постковідним синдромом з нейроендокринною симптоматикою. Гамалате В6 — препарат гамма-аміномасляної кислоти, що має найкращі характеристики для таких пацієнтів.

Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous disease affecting the peripheral nervous system that is caused by either the demyelination of Schwann cells or degeneration of the peripheral axon. Currently, there are no treatment options to improve the degeneration of peripheral nerves in CMT patients. In this research, we assessed the potency of farnesol for improving the demyelinating phenotype using an animal model of CMT type 1A. In vitro treatment with farnesol facilitated myelin gene expression and ameliorated the myelination defect caused by PMP22 overexpression, the major causative gene in CMT. In vivo administration of farnesol enhanced the peripheral neuropathic phenotype, as shown by rotarod performance in a mouse model of CMT1A. Electrophysiologically, farnesol-administered CMT1A mice exhibited increased motor nerve conduction velocity and compound muscle action potential compared with control mice. The number and diameter of myelinated axons were also increased by farnesol treatment. The expression level of myelin protein zero (MPZ) was increased, while that of the demyelination marker, neural cell adhesion molecule (NCAM), was reduced by farnesol administration. These data imply that farnesol is efficacious in ameliorating the demyelinating phenotype of CMT, and further elucidation of the underlying mechanisms of farnesol’s effect on myelination might provide a potent therapeutic strategy for the demyelinating type of CMT.

Subclinical hypothyroidism (SCH) is associated with diabetic peripheral neuropathy (DPN); however, the mechanism underlying this association remains unknown. This study is aimed at examining neurofunctional and histopathological alterations in a type 2 diabetes (T2DM) mouse model of SCH and investigating the impact of thyroid-stimulating hormone (TSH) in an in vitro DPN cell model established using RSC96 cells under high glucose (HG) and palmitic acid (PA) stimulation. Our results indicated that T2DM, in combination with SCH, aggravated abnormal glucose and lipid metabolism in T2DM and dramatically destroyed the peripheral nervous system by increasing paw withdrawal latency, decreasing motor nerve conduction velocity, and exacerbating ultrastructural deterioration of the damaged sciatic nerve caused by diabetes. Furthermore, the results of our in vitro experiments showed that TSH intensified HG/PA-induced RSC96 cell damage by inducing oxidative stress, mitochondrial dysfunction, and apoptosis. More importantly, TSHR knockout or inhibition of PA-induced TSHR palmitoylation could alleviate the apoptosis induced by TSH. Overall, in this study, the novel mechanisms by which TSH, as an independent risk factor for DPN progression, aggravating Schwann cell apoptosis and demyelination, are elucidated. These findings indicate that TSHR could be a potential target for both the prevention and treatment of DPN and, possibly, other microvascular diseases, and have implication in the clinical management of patients with DPN.

Single intradermal injections of nerve growth factor (NGF) evoke prolonged but temporally distinct sensitization patterns to somatosensory stimuli. Focal administration of the non-histaminergic pruritogen cowhage but not histamine resulted in elevated itch at day 21 after NGF administration. Here, we injected bovine adrenal medulla peptide 8–22 (BAM8–22), β-alanine (β-ALA) and endothelin-1 (ET-1) into NGF-treated skin of 11 healthy volunteers and investigated the corresponding itch/pain and flare reactions. β-ALA was the weakest pruritogen, while BAM8–22 and ET-1 were equally potent as histamine. NGF did not sensitize itch or flare reactions induced by any compound, but injection and evoked pain were increased at day 21 and 49. The involvement of histamine H1 receptors in itch was explored in eight subjects after oral cetirizine. ET-1-induced itch and flare were significantly reduced. BAM8–22 and β-ALA itch were not affected, but flare responses after BAM8–22 reduced by 50%. The results indicate that a single NGF injection does not sensitize for experimentally induced itch but increases pain upon pruritogen injection. In healthy humans, pruritic and algetic processing appear differentially regulated by NGF. However, in patients suffering chronic itch, prolonged elevation of NGF-levels under inflammatory conditions may contribute to elevated itch.

Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, expressed in a variety of cell types and in all tissues, control excitation and rhythm. Since their discovery in neurons and cardiac pacemaker cells, they attracted the attention of medicinal chemistry and pharmacology as novel targets to shape (patho)physiological mechanisms. To date, ivabradine represents the first-in-class drug as specific bradycardic agent in cardiac diseases; however, new applications are emerging in parallel with the demonstration of the involvement of different HCN isoforms in central and peripheral nervous system. Hence, the possibility to target specific isoforms represents an attractive development in this field; indeed, HCN1, HCN2 or HCN4 specific blockers have shown promising features in vitro and in vivo, with remarkable pharmacological differences likely depending on the diverse functional role and tissue distribution. Here, we show a recently developed compound with high potency as HCN2–HCN4 blocker; because of its unique profile, this compound may deserve further investigation.

Objective Pleckstrin homology domain-containing family G member 5 (PLEKHG5) is a nuclear factor-κ-B-activator gene that predominantly expresses in the neurons and Schwann cells of the peripheral nervous system. Variations in the PLEKHG5 have shown an intermediate form of autosomal recessive Charcot-Marie-Tooth disease and lower motor neuron disease in childhood. Materials and methods This study investigated clinically, electrophysiologically, genetically, and pathologically a young girl with lower motor neuron disease who had weakness and wasting of all limbs starting in early childhood. Results Next-generation sequencing found a novel compound heterozygous missense variation c.2038-1G>A and c.1219G>T of PLEKHG5 gene. Electromyography revealed a neurogenic pattern, and nerve conduction study indicated subclinical sensory neuropathy. Sural biopsy showed hypomyelination, hypermyelination, and infolding myelin membranes coiled into the myelinated axon. Conclusion This study identifies, pathologically, novel compound heterozygous mutations and phenotype in PLEKHG5-related lower motor neuron disease and dysmyelination in a patient with PLEKHG5 mutation.

The devastating COVID-19 pandemic is caused by the SARS-CoV-2 virus. It primarily affects the lung and induces acute respiratory distress leading to a decrease in oxygen supply to the cells. This lung insufficiency caused by SARS-CoV-2 virus contributes to hypoxia which can affect the brain and other organ systems. The heightened cytokine storm in COVID-19 patients leads to an immune reaction in the vascular endothelial cells that compromise the host defenses against the SARS-CoV-2 virus in various organs. The vascular endothelial cell membrane breach allows access for SARS-CoV-2 to infect multiple tissues and organs. The neurotropism of spike protein in SARS-CoV-2 rendered by furin site insertion may increase neuronal infections. These could result in encephalitis and encephalopathy. The COVID-19 patients suffered severe lung deficiency often showed effects in the brain and neural system. The early symptoms include headache, loss of smell, mental confusion, psychiatric disorders and strokes, and rarely encephalitis, which indicated the vulnerability of the nervous system to SARS-CoV-2. Infection of the brain and peripheral nervous system can lead to the dysfunction of other organs and result in multi-organ failure. This review focuses on discussing the vulnerability of the nervous system based on the pattern of expression of the receptors for the SARS-CoV-2 and the mechanisms of its cell invasion. The SARS-CoV-2 elicited immune response and host immune response evasion are further discussed. Then the effects on the nervous system and its consequences on neuro-sensory functions are discussed. Finally, the emerging information on the overall genetic susceptibility seen in COVID-19 patients and its implications for therapy outlook is discussed.

Neurotoxicity is a principal concern in nonclinical drug development. However, standardized and universally accepted fluid biomarkers for evaluating neurotoxicity are lacking. Increasing clinical evidence supports the potential use of neurofilament light (NfL) chain as a biomarker of several neurodegenerative diseases; therefore, we investigated changes in the cerebrospinal fluid (CSF) and serum levels of NfL in Sprague Dawley rats treated with central nervous system (CNS) toxicants (trimethyltin [TMT, 10 mg/kg po, single dose], kainic acid [KA, 12 mg/kg sc, single dose], MK-801 [1 mg/kg sc, single dose]), and a peripheral nervous system (PNS) toxicant (pyridoxine, 1200 mg/kg/day for 3 days). Animals were euthanized 1 (day 2), 3 (day 4), or 7 days after administration (day 8). Increased serum NfL was observed in TMT- and KA-treated animals, which indicated neuronal cell death in the brain on days 2, 4, and/or 8. MK-801-treated animals exhibited no changes in the serum and CSF levels of NfL and no histopathological changes in the brain at any time point. Pyridoxine-induced chromatolysis of the dorsal root ganglion on day 2 and degeneration of peripheral nerve fiber on day 4; additionally, serum NfL was increased. A strong correlation was observed between the serum and CSF levels of NfL and brain lesions caused by TMT and KA, indicating that NfL could be a useful biomarker for detecting CNS toxicity. Additionally, PNS changes were correlated with serum NfL levels. Therefore, serum NfL could serve as a useful peripheral biomarker for detecting both CNS and PNS toxicity in rats.

Purpose of review Acute central and peripheral nervous system injury may occur in association with coronavirus disease 2019 (COVID-19) caused by infection with the severe acute respiratory syndrome coronavirus 2 virus. This review will assist readers to recognize neurologic manifestations associated with COVID-19 including common and life-threatening symptoms and diagnostic testing. We will also review current recommendations for treatment of neurologic injury associated with COVID-19 infection in children. Recent findings Data from systematic reviews and prospectively collected cohorts of children with COVID-19 are beginning to characterize the breadth of neurologic manifestations associated with COVID-19 in the acute infectious and postinfectious periods. Among hospitalized children in particular, neurologic symptoms are common. Life threatening conditions including encephalitis, myelitis, stroke, and demyelinating syndromes have been reported. Within the pediatric population, age, and preexisting neurologic conditions appear to be important factors in determining likely phenotypes. Treatment at this time is based on careful neuromonitoring, supportive care, and neuromodulatory therapies as indicated. Summary Neurologic symptoms are common in children with COVID-19 and may be life threatening. The pathophysiology, therapeutic options, and long-term outcomes from COVID-19 associated neurologic injury are currently being investigated.

Background: Braak and others have proposed that Lewy-type α-synucleinopathy in Parkinson’s disease (PD) may arise from an exogenous pathogen that passes across the gastric mucosa and then is retrogradely transported up the vagus nerve to the medulla. Objective: We tested this hypothesis by immunohistochemically staining, with a method specific for p-serine 129 α-synuclein (pSyn), stomach and vagus nerve tissue from an autopsy series of 111 normal elderly subjects, 33 with incidental Lewy body disease (ILBD) and 53 with PD. Methods: Vagus nerve samples were taken adjacent to the carotid artery in the neck. Stomach samples were taken from the gastric body, midway along the greater curvature. Formalin-fixed paraffin-embedded sections were immunohistochemically stained for pSyn, shown to be highly specific and sensitive for α-synuclein pathology. Results: Median disease duration for the PD group was 13 years. In the vagus nerve none of the 111 normal subjects had pSyn in the vagus, while 12/26 ILBD (46%) and 32/36 PD (89%) subjects were pSyn-positive. In the stomach none of the 102 normal subjects had pSyn while 5/30 (17%) ILBD and 42/52 (81%) of PD subjects were pSyn-positive. Conclusion: As there was no pSyn in the vagus nerve or stomach of subjects without brain pSyn, these results support initiation of pSyn in the brain. The presence of pSyn in the vagus nerve and stomach of a subset of ILBD cases indicates that synucleinopathy within the peripheral nervous system may occur, within a subset of individuals, at preclinical stages of Lewy body disease.

Pruritus is a skin-specific sensation that is observed in various skin diseases, especially in inflammatory skin diseases such as atopic dermatitis, and is deeply involved in their pathogenesis. Pruritus also adversely affects patients’ sleep and mental health, placing a heavy burden on daily life. As such, pruritus control is important to the maintenance of health. The mechanism of pruritus has recently been clarified and the discovery of various pruritus mediators, the identification of specific nerves that transmit pruritus and the accumulation of knowledge on pruritus perception have led to a better understanding of all aspects of pruritus generation, transmission and recognition. In the case of pruritus caused by dermatitis, immune cells infiltrating the skin secrete inflammatory cytokines, which also act on peripheral nerves as pruritus mediators and induce an inflammatory response. Interestingly, there has been accumulating evidence that peripheral nerves are also involved in the inflammation via neuropeptides. In this article, we summarize the findings on pruritus mediators secreted by immune cells and the roles of peripheral nerves in pruritus in terms of their interactions with immunity.

Since 1916-1917, the period of the last pandemic of epidemic encephalitis, infectious diseases of the nervous system have become common and fairly frequent in medical practice. Covering in some places large groups of the population and taking away a large number of working hours from socialist construction, these diseases should be the object of serious study by practically working doctors for their rational therapy and prevention.

Introduction Juvenile-onset systemic lupus erythematosus (JSLE) is a rare autoimmune/inflammatory disease with significant morbidity and mortality. Neuropsychiatric (NP) involvement is a severe complication, encompassing a heterogeneous range of neurological and psychiatric manifestations. Methods Demographic, clinical, and laboratory features of NP-SLE were assessed in participants of the UK JSLE Cohort Study, and compared to patients in the same cohort without NP manifestations. Results A total of 428 JSLE patients were included in this study, 25% of which exhibited NP features, half of them at first visit. Most common neurological symptoms among NP-JSLE patients included headaches (78.5%), mood disorders (48.6%), cognitive impairment (42%), anxiety (23.3%), seizures (19.6%), movement disorders (17.7%), and cerebrovascular disease (14.9%). Peripheral nervous system involvement was recorded in 7% of NP-SLE patients. NP-JSLE patients more frequently exhibited thrombocytopenia (9/L) ( p = 0.04), higher C-reactive protein levels ( p = 0.01), higher global pBILAG score at first visit ( p < 0.001), and higher SLICC damage index score at first ( p = 0.02) and last ( p < 0.001) visit when compared to JSLE patients without NP involvement. Conclusions A significant proportion of JSLE patients experience NP involvement (25%). Juvenile-onset NP-SLE most commonly affects the CNS and is associated with increased overall disease activity and damage.

Wallerian degeneration is a pathological process closely related to peripheral nerve regeneration following injury, and includes the disintegration and phagocytosis of peripheral nervous system cells. Traditionally, morphological changes are observed by performing immunofluorescence staining after sectioning, which results in the loss of some histological information. The purpose of this study was to explore a new, nondestructive, and systematic method for observing axonal histological changes during Wallerian degeneration. Thirty male Thy1-YFP-16 mice (SPF grade, 6 weeks old, 20±5 g) were randomly selected and divided into clear, unobstructed brain imaging cocktails and computational analysis (CUBIC) optical clearing (n=15) and traditional method groups (n=15). Five mice in each group were sacrificed at 1st, 3rd, and 5th day following a crush operation. The histological axon changes were observed by CUBIC light optical clearing treatment, direct tissue section imaging, and HE staining. The results revealed that, compared with traditional imaging methods, there was no physical damage to the samples, which allowed for three-dimensional and deep-seated tissue imaging through CUBIC. Local image information could be nicely obtained by direct fluorescence imaging and HE staining, but it was difficult to obtain image information of the entire sample. At the same time, the image information obtained by fluorescence imaging and HE staining was partially lost. The combining of CUBIC and Thy1-YFP transgenic mice allowed for a clear and comprehensive observation of histological changes of axons in Wallerian degeneration.

Background Gait initiation is an automatized motor program that is preceded by anticipatory postural adjustments (APAs). During attentional tasks, these APAs can be modulated, producing multiple APAs. However, the role of the peripheral nervous system in the regulation of these APAs is unknown. Research question The objective of our study was to investigate whether APAs are also regulated by peripheral nervous afferents. Methods We assessed 21 patients suffering from chronic inflammatory demyelinating neuropathy and 20 healthy controls. Participants initiated gait with the right or left leg either freely (in the standard condition) or according to a visual trigger (i.e., the select condition). Kinetic and kinematic parameters of APAs and step initiation were recorded. Results The select condition was related to a higher rate of multiple APAs compared to the standard condition, and was more attention-consuming in both groups. The group with a neuropathy showed longer APAs than the control group, associated with a longer time to recover from multiple APAs. Consequently, the step execution time was delayed in patients with a peripheral neuropathy. Significance The impairment of the peripheral nervous system is therefore responsible for an alteration of the mechanisms underlying the recovery from multiple APAs during gait initiation. Our results are in favor of a role of proprioceptive afferents in the early peripheral regulation of motor errors. Further study on gait initiation in peripheral nervous disease could be helpful to better explore sensory-motor coupling in tasks requiring balance control.

Background Chronic obstructive pulmonary disease (COPD) is accompanied by substantial systemic dysregulations that comprise systemic inflammation and neurohormonal activation in addition to many neurological involvements, such as cerebrovascular diseases, polyneuropathies, motor neuron diseases, and cognitive impairment has been described in COPD patients. The aim of the current work was to detect the subclinical affection of the peripheral nervous system in patients with stable COPD. Results Forty COPD patients and 30 subjects as healthy control were enrolled. All included subjects were submitted to complete medical history, clinical evaluations, investigations in the form of; arterial blood gases, spirometry, in addition to nerve conduction study. The patients with COPD were classified according to GOLD criteria for severity in grade I in 7.5% grade II in 62.5%, grade III in 20%, and grade IV in 10%. The results show a statistically significant increase in distal latency and a statistically significant decrease of amplitude and conduction velocity in patients with COPD when compared to the examined nerves of control group. The demyelinating nerve affection was the most common. Conclusion In COPD patients the peripheral nervous system could be affected subclinically once the severity of COPD increased and the patient should be neurophysiologically observed for early recognition of peripheral nervous system affection.

Peripheral neuropathies account for the most frequent disorders seen by neurologists, and causes are manifold. The traditional diagnostic gold-standard consists of clinical neurologic examinations supplemented by nerve conduction studies. Due to well-known limitations of standard diagnostics and atypical clinical presentations, establishing the correct diagnosis can be challenging but is critical for appropriate therapies. Magnetic resonance neurography (MRN) is a relatively novel technique that was developed for the high-resolution imaging of the peripheral nervous system. In focal neuropathies, whether traumatic or due to nerve entrapment, MRN has improved the diagnostic accuracy by directly visualizing underlying nerve lesions and providing information on the exact lesion localization, extension, and spatial distribution, thereby assisting surgical planning. Notably, the differentiation between distally located, complete cross-sectional nerve lesions, and more proximally located lesions involving only certain fascicles within a nerve can hold difficulties that MRN can overcome, when basic technical requirements to achieve sufficient spatial resolution are implemented. Typical MRN-specific pitfalls are essential to understand in order to prevent overdiagnosing neuropathies. Heavily T2-weighted sequences with fat saturation are the most established sequences for MRN. Newer techniques, such as T2-relaxometry, magnetization transfer contrast imaging, and diffusion tensor imaging, allow the quantification of nerve lesions and have become increasingly important, especially when evaluating diffuse, non-focal neuropathies. Innovative studies in hereditary, metabolic or inflammatory polyneuropathies, and motor neuron diseases have contributed to a better understanding of the underlying pathomechanism. New imaging biomarkers might be used for an earlier diagnosis and monitoring of structural nerve injury under causative treatments in the future. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-021-01166-8.

Cellular metabolism is critical not only for cell survival, but also for cell fate, function, and intercellular communication. There are several different metabolic transporters expressed in the peripheral nervous system, and they each play important roles in maintaining cellular energy. The major source of energy in the peripheral nervous system is glucose, and glucose transporters 1 and 3 are expressed and allow blood glucose to be imported and utilized by peripheral nerves. There is also increasing evidence that other sources of energy, particularly monocarboxylates such as lactate that are transported primarily by monocarboxylate transporters 1 and 2 in peripheral nerves, can be efficiently utilized by peripheral nerves. Finally, emerging evidence supports an important role for connexins and possibly pannexins in the supply and regulation of metabolic energy. In this review, we will first define these critical metabolic transporter subtypes and then examine their localization in the peripheral nervous system. We will subsequently discuss the evidence, which comes both from experiments in animal models and observations from human diseases, supporting critical roles played by these metabolic transporters in the peripheral nervous system. Despite progress made in understanding the function of these transporters, many questions and some discrepancies remain, and these will also be addressed throughout this review. Peripheral nerve metabolism is fundamentally important and renewed interest in these pathways should help to answer many of these questions and potentially provide new treatments for neurologic diseases that are partly, or completely, caused by disruption of metabolism. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01150-2.

A hallmark of endometriosis – a chronic debilitating condition whose causes are poorly understood – is neuronal innervation of lesions. Recent evidence demonstrates that the peripheral nervous system plays an important role in the pathophysiology of this disease. Sensory nerves, which surround and innervate endometriotic lesions, not only drive the chronic and debilitating pain associated with endometriosis but also contribute to a pro‐growth phenotype by secreting neurotrophic factors and interacting with surrounding immune cells. The diverse array of contributions that neurons play in endometriosis indicate that it should be considered as a nerve‐centric disease. This review is focused on the emerging field of exoneural biology and how it applies to the field of endometriosis, in particular the role that peripheral nerves play in driving and maintaining endometriotic lesions. A better understanding of the mechanisms of neuronal contribution to endometriosis, as well as their interactions with accompanying stromal and immune cells, will unearth novel disease‐relevant pathways and targets, providing additional, more selective therapeutic horizons.

Symptoms of peripheral nervous system (PNS) damage are common clinical manifestations of systemic amyloidosis. Peripheral amyloid neuropathy is characterized by a progressive course, leading to the disability of patients; however, the current possibilities of pathogenetic therapy make the early diagnosis of amyloid neuropathy particularly urgent.Objective: to evaluate the informative value of laser confocal microscopy (LCM) of the cornea in diagnosing small fiber neuropathy of peripheral nerves in patients with systemic amyloidosis.Patients and methods. The study included nine patients (three men and six women) with morphologically confirmed primary amyloidosis (ALamyloidosis) and 12 patients (three men and nine women) with hereditary transthyretin amyloidosis (TTR-amyloidosis) verified by genetic and morphological methods. At baseline, the mean age of patients with AL-amyloidosis was 60.6±10.7 years, with hereditary TTR-amyloidosis – 57.1±13.1 years. According to the history of the disease in AL-amyloidosis, the mean duration of clinical symptoms was 2.7±1.4 years, with TTR-amyloidosis – 5.5±3.6 years. 20 age- and sex-adjusted healthy volunteers were included in the control group. All patients underwent a clinical neurological examination with an assessment of the severity of neuropathy according to the Neuropathy Impairment Score (NIS); 21 patients with systemic amyloidosis and all volunteers of the control group underwent LCM of the corneal nerve fibers (CNF). The coefficients of anisotropy (КΔL) and orientation symmetry (Ksym) of the CNF were calculated to assess the severity of damage to the corneal nerves.Results and discussion. Clinical neurological examination in patients with AL-amyloidosis revealed polyneuropathic syndrome (45%), tunnel syndrome (22%), their combination (22%), and autonomic dysfunction in the form of orthostatic hypotension and impaired motility of the gastrointestinal tract (GI tract; 56%). Symptoms in patients with TTR-amyloidosis were characterized by a combination of tunnel neuropathy and sensory-motor polyneuropathy (50%), distal symmetric polyneuropathy (42%). Frequent symptoms of PNS damage in systemic amyloidosis include autonomic neuropathy (56% – in AL-amyloidosis, 92% – in TTR-amyloidosis) presenting with orthostatic hypotension, impaired gastrointestinal motility, hypohidrosis, and dysuria. The mean NIS score, which characterizes the severity of somatic neuropathy, was significantly higher in patients with TTR-amyloidosis than AL-amyloidosis (pConclusion. Clinical polymorphism of peripheral somatic and autonomic nervous systems lesions is typical for patients with systemic amyloidosis. LCM of the cornea is informative in the diagnosis of small fibers neuropathy of peripheral nerves in systemic amyloidosis; however, it cannot establish the nosology of neuropathy.

MicroRNAs (miRNAs) have been implicated in nerve injury and demyelination; however, their functions in peripheral nerves remain unclear. To determine the potential functions of miRNAs, an miRNA array was carried out. Here, miRNA array analysis of neuregulin-treated Schwann cells revealed 18 upregulated (> 2-fold) and 13 downregulated (> 2-fold) miRNAs. After sciatic nerve injury, miR708-5p was highly expressed in neuregulin-treated Schwann cells, whereas it was downregulated during postnatal development. A predicted functional interaction was found between miR708-5p and transcription factor CP2‐like protein 1 (TFCP2L1) using a bioinformatics tool. This finding suggested that miR708-5p may regulate TFCP2L1. During sciatic nerve development, TFCP2L1 was upregulated on postnatal days 1 and 4, while it was downregulated after nerve axotomy and crush injury. Notably, TFCP2L1 was upregulated in cAMP-treated Schwann cells. We also found that activity of the myelin protein zero promoter was downregulated in TFCP2L1 siRNA-treated Schwann cells, whereas it was upregulated in TFCP2L1-overexpressing cells. Immunofluorescence analysis showed that TFCP2L1 was localized in Schwann cells. In addition, miR708-5p overexpression promoted migration of Schwann cells, while miR-708-5p inhibitor inhibited migration. miR708-5p inhibitor also blocked the migration of TFCP2L1 siRNA-treated Schwann cells. These findings indicate the functions of miR708-5p in TFCP2L1 regulation in the peripheral nervous system occur via regulation of Schwann cell migration.

Despite extensive research, there is still no treatment that would lead to remission in all patients with rheumatoid arthritis as our understanding of the affected site, the synovium, is still incomplete. Recently, single-cell technologies helped to decipher the cellular heterogeneity of the synovium; however, certain synovial cell populations, such as endothelial cells or peripheral neurons, remain to be profiled on a single-cell level. Furthermore, associations between certain cellular states and inflammation were found; whether these cells cause the inflammation remains to be answered. Similarly, cellular zonation and interactions between individual effectors in the synovium are yet to be fully determined. A deeper understanding of cell signalling and interactions in the synovium is crucial for a better design of therapeutics with the goal of complete remission in all patients.

Axons in the adult mammalian central nervous system fail to regenerate after injury. By contrast, spontaneous axon regeneration occurs in the peripheral nervous system (PNS) due to a supportive PNS environment and an increase in the intrinsic growth potential induced by injury via cooperative activation of multifaceted biological pathways. This study compared axon regeneration and injury responses in C57BL/6 male and female mice after sciatic nerve crush (SNC) injury. The extent of axon regeneration in vivo was indistinguishable in male and female mice when observed at 3 days after SNC injury, and primary dorsal root ganglion (DRG) neurons from injured, male and female mice extended axons to a similar length. Moreover, the induction of selected regeneration-associated genes (RAGs), such as Atf3, Sprr1a, Gap43, Sox11, Jun, Gadd45a, and Smad1 were comparable in male and female DRGs when assessed by quantitative real-time reverse transcription polymerase chain reaction. Furthermore, the RNA-seq analysis of male and female DRGs revealed that differentially expressed genes (DEGs) in SNC groups compared to sham-operated groups included many common genes associated with neurite outgrowth. However, we also found that a large number of genes in the DEGs were sex dependent, implicating the involvement of distinct gene regulatory network in the two sexes following peripheral nerve injury. In conclusion, we found that male and female mice mounted a comparable axon regeneration response and many RAGs were commonly induced in response to SNC. However, given that many DEGs were sex-dependently expressed, future studies are needed to investigate whether they contribute to peripheral axon regeneration, and if so, to what extent.

Peripheral nerve injuries (PNIs) are some of the most common types of traumatic lesions affecting the nervous system. Although the peripheral nervous system has a higher regenerative ability than the central nervous system, delayed treatment is associated with disturbances in both distal sensory and functional abilities. Over the past decades, adult stem cell-based therapies for peripheral nerve injuries have drawn attention from researchers. This is because various stem cells can promote regeneration after peripheral nerve injuries by differentiating into neural-line cells, secreting various neurotrophic factors, and regulating the activity of in situ Schwann cells (SCs). This article reviewed research from the past 10 years on the role of stem cells in the repair of PNIs. We concluded that adult stem cell-based therapies promote the regeneration of PNI in various ways.

Antiphospholipid syndrome (APS) is an autoimmune process that increases the risk of arterial and venous thrombosis. The mechanism of damage to the central nervous system (CNS) can be not only due to thrombosis, but also antiphospholipid antibodies (APA) circulating in the peripheral blood. The latter can damage the cerebral vascular endothelium, alter the resistance of the blood-brain barrier and penetrate into the central nervous system, exerting a damaging effect on astroglia and neurons, as evidenced by the release of neurospecific proteins into the peripheral bloodstream. The role of APS in developing cerebral ischemia, migraine, epilepsy, chorea, transverse myelitis, multiple sclerosis, cognitive impairment and mental disorders, as well as the peripheral nervous system is described. It should also be noted about a role of APS for emerging neurological disorders in COVID-19, enabled apart from thrombogenesis due to APA via 2 potential mechanisms - molecular mimicry and neoepitope formation. Further study of the APS pathogenesis and interdisciplinary interaction are necessary to develop effective methods for patient management.

Introduction: COVID 19 often presents with flu-like symptoms. Elderly patients with systemic comorbidities are more likely to have severe COVID 19 infections and deaths. Severe neurological complications are frequently reported in severely and critically ill patients. In COVID-19, both central and peripheral nervous systems can be affected. The study aims to overview the spectrum, characteristics, and outcomes of neurologic manifestations associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods: A total of 1000 confirmed CoVID-19 patients were enrolled for the study. Demographic features and initial clinical manifestations were noted, and patients were followed during the hospital stay to develop any new neurological signs and symptoms. For analytical purposes, neurological presentations were grouped into the central nervous system, peripheral nervous system, and musculoskeletal system manifestations. Appropriate laboratory testing was employed as required on a case-to-case basis. Results: The mean age was 44.6 ± 14.3 years. 625 (62.5%) patients were male, while 375 (37.5%) were female. The neurological illness was a primary manifestation in 119 (11.9%) cases. These included encephalopathy (n=78), ischemic stroke (n=28), Guillain- Barre syndrome, (n=3), facial nerve palsy (n=4), and encephalitis (n=6). The most common neurological symptoms were headache 313 (31.3%) and hyposmia 52 (5.2%), followed by encephalopathy 78 (7.8%). More serious complications like seizures 18 (1.8%) and stroke 28 (2.8%) were also seen. Conclusion: CoVID-19 can present with a neurological illness, and we should remain vigilant to the possibility of neurological presentation of COVID-19 that can be thrombo-embolic, inflammatory, or immune-mediated. Bangladesh Journal of Medical Science Vol.20(5) 2021 p.155-161

The review presents the pathogenetic mechanisms of central and peripheral nervous system pathology in primary hypothyroidism. Lack of thyroid hormones leads to changes in the organization of the central nervous system, decrease in the energy supply of neurons, changes in the synthesis of some specific proteins of the nervous system that cause the development of cretinism in children. The role of hypothyroidism in the development of cognitive impairment in adults, such as decreased cognitive function, memory and attention, has been proved. The impairment of logical thinking is found already in patients with subclinical hypothyroidism. Disorders in mediation exchange lead to the development of depression. Neuromuscular disorders (hypothyroid myopathy and myotonic phenomenon) and affection to the peripheral nerves are best studied in hypothyroidism. Primary hypothyroidism may be masked by tunnel neuropathy, polyneuropathy and atactic syndrome. Despite the existing papers on the problem of hypothyroidism and its neurological complications, some issues of pathogenesis, diagnosis, course and treatment of neurological pathology in primary hypothyroidism require further research.

The article presents the pathogenesis of polyneuropathy symptoms in patients with hypothyroidism, whereby the approaches to the pathogenetic therapy are substantiated. The article represents the most important aspects of hypothyroid polyneuropathy treatment according to the latest international guidelines and perspective scientific approaches to optimize the medical care for patients with this pathology.

The formation of the glutamatergic system of the spinal cord is intensively studied, however, there are hardly any studies devoted to the investigation of the dynamics of the formation of glutamine synthetase-containing structures that protect the nerve cells of the embryonic spinal cord from the toxic effects of glutamate. In this paper, the localization, distribution, and morphological features of rat spinal cord (SC) cells expressing glutamine synthetase (GS) in the embryonic and early postnatal period were studied using immunohistochemical methods. It was found that the first GS-containing cells are identified in the ventral part of the ependymal layer of the formed SC during the beginning of gliogenesis, on the 15th day of embryonic development. After 1 day, cells expressing this enzyme are also present in the mantle layer of the SC. In this study, it was shown for the first time that a part of the boundary cap cells located in the transition zone between the SC and the peripheral nervous system synthesizes glutamine synthetase. The present study allowed us to determine the dynamics of the formation of GS-containing glial cells of the embryonic spinal cord and to assume the functional significance of such cells in embryogenesis.

Lei Gao,1,2,&ast; Jian-Feng Zhang,3,&ast; John P Williams,4 Yi-Ning Yan,1 Xi-Lai Xiao,1 Wan-Rui Shi,5 Xiao-Yan Qian,1 Jian-Xiong An1– 3,6 1Department of Anesthesiology, Pain and Sleep Medicine, Aviation General Hospital of China Medical University and Beijing Institute of Translational Medicine, Chinese Academy of Sciences, Beijing, People’s Republic of China; 2School of Anesthesiology, Weifang Medical University, Weifang, Shangdong, People’s Republic of China; 3Savaid Medical School, University of Chinese Academy of Sciences, Beijing, People’s Republic of China; 4Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 5Department of Anesthesiology, Peking University Third Hospital, Beijing, People’s Republic of China; 6School of Medical Science & Engineering, Beijing Advanced Innovation Center for Biomedical Engineering, Beihang University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jian-Xiong AnDepartment of Anesthesiology, Pain and Sleep Medicine, Aviation General Hospital of China Medical University, Beiyuan Road 3#, Beijing, 100012, People’s Republic of ChinaTel +86 13801281750Fax +86 59520233Email anjianxiong@yeah.netPurpose: It is unclear whether neuropathological structural changes in the peripheral nervous system and central nervous system can occur in the spared nerve injury model. In this study, we investigated the pathological changes in the nervous system in a model of neuropathic pain as well as the effects of electroacupuncture (EA) and pregabalin (PGB) administration as regards pain relief and tissue repair.Patients and Methods: Forty adult male SD rats were equally and randomly divided into 4 groups: spared nerve injury group (SNI, n = 10), SNI with electroacupuncture group (EA, n = 10), SNI with pregabalin group (PGB, n =10) and sham-operated group (Sham, n=10). EA and PGB were given from postoperative day (POD) 14 to 36. EA (2 Hz and 100 Hz alternating frequencies, intensities ranging from 1– 1.5– 2 mA) was applied to the left “zusanli” (ST36) and “Yanglingquan” (GB34) acupoints for 30 minutes. The mechanical withdrawal thresholds (MWTs) were tested with von Frey filaments. Moreover, the organizational and structural alterations of the bilateral prefrontal cortex, hippocampus, sciatic nerves and the thoracic, lumbar spinal cords and dorsal root ganglions (DRGs) were examined via light and electron microscopy.Results: MWTs of left hind paw demonstrated a remarkable decrease in the SNI model (P < 0.05). In the SNI model, ultrastructural changes including demyelination and damaged neurons were observed at all levels of the peripheral nervous system (PNS) and central nervous system (CNS). In addition, EA improved MWTs and restored the normal structure of neurons. However, the effect was not found in the PGB treatment group.Conclusion: Chronic pain can induce extensive damage to the central and peripheral nervous systems. Meanwhile, EA and PGB can both alleviate chronic pain syndromes in rats, but EA also restores the normal cellular structures, while PGB is associated with no improvement.Keywords: neuropathic pain, structural changes, electroacupuncture, pregabalin

Background: \ud Hereditary sensory and autonomic neuropathies (HSANs) are a group of genetic disorders affecting the peripheral nervous system. Two different associated variants have been identified in dogs: 1 in Border Collies and 1 in Spaniels and Pointers.\ud \ud Objectives: \ud Clinically and genetically characterize HSAN in a family of mixed breed dogs.\ud \ud Animals: \ud Five 7-month-old mixed breed dogs from 2 related litters were presented for evaluation of a 2-month history of acral mutilation and progressive pelvic limb gait abnormalities.\ud \ud Methods: \ud Complete physical, neurological, electrodiagnostic, and histopathological evaluations were performed. Whole genome sequencing of 2 affected dogs (1 from each litter) was used to identify variants that were homozygous or heterozygous in both cases, but wild type in 217 control genomes of 100 breeds. Immunohistochemistry was used to assess protein expression.\ud \ud Results: \ud Complete physical, neurological, electrodiagnostic, and histopathological evaluations confirmed a disorder affecting sensory and autonomic nerves. Whole genome sequencing identified a missense variant in the RETREG1 (reticulophagy regulator 1) gene (c.656C > T, p.P219L). All affected dogs were homozygous for the variant, which was not detected in 1193 dogs from different breeds. Immunohistochemistry showed no expression of RETREG1 in the cerebellum of affected dogs. One of the affected dogs lived for 5 years and showed gradual progression of the clinical signs.\ud \ud Conclusions and Clinical Importance: \ud We confirmed the diagnosis of HSAN in a family of mixed breed dogs and identified a novel and possibly pathogenic RETREG1 variant. Affected dogs experienced gradual deterioration over several years.

Summary Polyarteritis nodosa is a necrotizing systemic vasculitis of medium caliber arteries whose cause, most often unknown, may be hepatitis B virus. It is a serious condition diagnosed on the basis of well-defined criteria. Clinically, it is manifested by signs of kidney, skin, digestive, cardiac, joint or even vascular damage. The neurological manifestations of polyarteritis nodosa are frequent and make the disease serious. Peripheral neuropathy is the most frequent and earliest symptom. Central nervous system manifestations are less frequent and usually occur at a late stage. The objective of this review article is to describe the clinical manifestations of polyarteritis nodosa with a focus on damage to the central and peripheral nervous system.

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive inflammatory vasculopathy characterized by systemic vasculitis, early-onset stroke and livedo racemosa. We report a family cohort of 3 patients with ADA2 compound heterozygous mutation p.[Thr360Ala] and [Gly383Ser]. Two of them had progressive involvement of the peripheral nervous system in the fourth decade, both after stroke. In one patient, clinical and neurophysiological studies showed progression of mononeuritis multiplex to chronic axonal sensorimotor polyneuropathy, nerve biopsy had features of small vessel vasculitic neuropathy, and muscle biopsy disclosed neurogenic atrophy with reinnervation. The second patient presented with progressive sensory symptoms of the lower limbs and chronic axonal sensorimotor polyneuropathy in nerve conduction studies. These two patients had absent plasma ADA2 activity. The third patient had no neurological affection despite low, but not absent, plasma ADA2 activity. Patients were started on a tumor necrosis factor (TNF) inhibitor, which has presumed benefits for the vasculitic phenotype of DADA2.

Peripheral nerve injuries (PNIs) are common and debilitating, cause significant health care costs for society, and rely predominately on autografts, which necessitate grafting a nerve section non-locally to repair the nerve injury. One possible approach to improving treatment is bolstering endogenous regenerative mechanisms or bioengineering new nervous tissue in the peripheral nervous system. In this review, we discuss critical-sized nerve gaps and nerve regeneration in rats, and summarize the roles of adipose-derived stem cells (ADSCs) in the treatment of PNIs. Several regenerative treatment modalities for PNI are described: ADSCs differentiating into Schwann cells (SCs), ADSCs secreting growth factors to promote peripheral nerve growth, ADSCs promoting myelination growth, and ADSCs treatments with scaffolds. ADSCs' roles in regenerative treatment and features are compared to mesenchymal stem cells, and the administration routes, cell dosages, and cell fates are discussed. ADSCs secrete neurotrophic factors and exosomes and can differentiate into Schwann cell-like cells (SCLCs) that share features with naturally occurring SCs, including the ability to promote nerve regeneration in the PNS. Future clinical applications are also discussed.