Peripheral Nerve Endings Research Articles

Infrapatellar Fat Pad-Synovial Membrane Anatomo-Fuctional Unit: Microscopic Basis for Piezo1/2 Mechanosensors Involvement in Osteoarthritis Pain.

The Infrapatellar Fat Pad (IFP) is a fibro-adipose tissue of the knee recently reconsidered as part of a single anatomo-functional unit (AFU) together with the synovial membrane (SM). Several evidence support the role of this unit in the mechanisms that trigger and perpetuate the onset and progression of osteoarthritis (OA) disease. Additionally, the contribution of IFP-SM AFU in OA-associated pain has also been supposed, but this assumption still needs to be fully elucidated. Within this context, the recent discovery of the mechanoceptive Piezo ion channels (i.e., Piezo1 and Piezo2) in mammals and consciousness on their role in mediating both mechanoceptive and inflammatory stimuli could shed some light on knee OA pain, as well as on the process leading from acute to chronic nociceptive responses. For this purpose, the IFP-SM AFUs of both healthy donors (non-OA IFP-SM AFUs, n = 10) and OA patients (OA IFP-SM AFUs, n = 10) were processed by histology and immunohistochemistry. After the attribution of a histopathological score to IFP-SM AFUs to confirm intrinsic differences between the two groups, the specimens were investigated for the expression and localization/distribution pattern of the mechanosensors Piezo1 and Piezo2. In addition, the presence of monocytes/macrophages (CD68), peripheral nerve endings (PGP9.5) and neoangiogenesis signs (YAP1) was evaluated for a broad tissue characterization. The study results lead to a better description of the IFP-SM AFU microscopic features in both healthy and pathological conditions, highlighting peculiar differences in the study cohort. Specifically, immunopositivity towards Piezo1/2, CD68 and YAP1 markers was detected at vessels level in the OA- IFP-SM AFUs compartments, differently from the non-OA-group. A correlation with pain was also inferred, paving the way for the identification of new and effective molecules in OA management.

Role of autonomic system imbalance in neurogenic pulmonary oedema.

Neurogenic pulmonary oedema (NPE) is a life-threatening complication that develops rapidly and dramatically after an injury to the central nervous system (CNS). The autonomic system imbalance produced by severe brain damage may play an important role in the development of NPE. Activation of the sympathetic nervous system and inhibition of the vagus nerve system are essential prerequisites for autonomic system imbalance. The more severe the damage, the more pronounced the phenomenon. Sympathetic hyperactivity is associated with increased release of catecholamines from peripheral sympathetic nerve endings, which can cause dramatic changes in haemodynamics and cause pulmonary oedema. On the other hand, the abnormal inflammatory response caused by vagus nerve inhibition may also play an important role in the pathogenesis of NPE. The perspective of autonomic system imbalance seems to perfectly integrate the existing pathogenesis of NPE and can explain the entire development progression of NPE.

Modified working heart brainstem preparation for studying spike propagation through the dorsal root ganglion

The dorsal root ganglion (DRG) contains cell bodies of peripheral somatosensory nerves. These nerves generate and transmit to the CNS signals related to physical changes in the body's immediate environment or state of internal organs. DRG neurons are pseudounipolar with a short stem axon branching into peripheral and central (dorsal root; DR) aspects. Peripheral branches innervate the end organs (e.g. skin, muscle etc.), while DRs synapse in the spinal cord. On the way from peripheral nerve endings to synaptic terminals, spikes pass through branching points (t-junctions) in the ganglia.

Voltage-dependent CaV3.2 and CaV2.2 channels in nociceptive pathways.

Noxious stimuli like cold, heat, pH change, tissue damage, and inflammation depolarize a membrane of peripheral endings of specialized nociceptive neurons which eventually results in the generation of an action potential. The electrical signal is carried along a long axon of nociceptive neurons from peripheral organs to soma located in dorsal root ganglions and further to the dorsal horn of the spinal cord where it is transmitted through a chemical synapse and is carried through the spinal thalamic tract into the brain. Two subtypes of voltage-activated calcium play a major role in signal transmission: a low voltage-activated CaV3.2 channel and a high voltage-activated CaV2.2 channel. The CaV3.2 channel contributes mainly to the signal conductance along nociceptive neurons while the principal role of the CaV2.2 channel is in the synaptic transmission at the dorsal horn. Both channels contribute to the signal initiation at peripheral nerve endings. This review summarizes current knowledge about the expression and distribution of these channels in a nociceptive pathway, the regulation of their expression and gating during pain pathology, and their suitability as targets for pharmacological therapy.

Fabrication of a 3D Printed PCL Nerve Guide: In Vitro and In Vivo Testing.

Nerve guides are medical devices designed to guide proximal and distal ends of injured peripheral nerves in order to assist regeneration of the damaged nerves. A 3D-printed polycaprolactone (PCL) nerve guide using an aligned gelatin-poly(3-hydroxybutyrate-co-3-hydroxyvalerate) electrospun mat, seeded with PC12 and Schwann cells (SCs) is produced. During characterization with microCT and SEM porosity (55%), pore sizes (675± 40µm), and fiber diameters (382± 25µm) are determined. Electrospun fibers have degree of alignment of 7°, indicating high potential for guidance. On Day 14, PC12 cells migrated from proximal to distal end of nerve guide when SCs are seeded on the guide. After 28 days, over 95% of PC12 are alive and aligned. PC12 cells express early differentiation marker beta-tubulin 10 times more than late marker NeuN. In a 10mm rat sciatic nerve injury, functional recovery evaluated by using static sciatic index (SSI) is observed in mat-free guides and guides containing mat and SCs. Nerve conduction velocities are also improved in these groups. Histological stainings showed tissue growth around nerve guides with highest new tissue organization being observed with mat and cell-free guides. These suggest 3D-printed PCL nerve guides have significant potential for treatment of peripheral nerve injuries.

MODERN VIEW OF DIAGNOSIS AND APPROACHES TO THE TREATMENT OF CHRONIC PAIN IN CHILDREN WITH PARALYTIC SYNDROMES (LITERATURE REVIEW)

Over the past decades, more and more attention in medical science has been paid to the diagnosis and study of pain mechanisms in the pediatric population. According to experts in the field of chronic pain in children, it occurs in 12% of all pediatric patients, which negatively affects the quality of children’s life and life of their families. Today, a particularly important problem in most countries of the world is pain in children with paralytic syndromes of III - V level according to GMFCS. About 20-35% of children with paralytic syndromes suffer from chronic pain. Although there are means and knowledge on how to treat pain, children's pain is often not recognized, ignored, or even denied. More than 50% of children with paralytic syndromes suffer from moderate to severe pain daily and in several parts of the body. The International Association for the Study of Pain (IASP) defines pain as “an unpleasant, sensual, and emotional experience associated with actual or potential tissue damage or perceived tissue damage. The inability to communicate verbally does not negate the possibility that the individual is in pain and needs appropriate analgesic treatment. Pain is always subjective ... ". Determining the type of pain helps to identify its cause, which can guide the choice of treatment. The main cause of pain in children includes acute nociceptive pain (ie pain caused by activation of peripheral nerve endings, including somatic and visceral pain), neuropathic pain (ie due to damage or dysfunction of the somatosensory system), psychosocial - spiritual - emotional pain. Chronic pain is a continuous or intermittent pain that lasts longer than the expected normal recovery period. Chronic pain can also occur and persist in the absence of a specific pathophysiology or medical condition. The expression of pain depends on a child's age, cognitive development and socio-cultural context.

Probing the multimodal fungiform papilla: complex peripheral nerve endings of chorda tympani taste and mechanosensitive fibers before and after Hedgehog pathway inhibition

The fungiform papilla (FP) is a gustatory and somatosensory structure incorporating chorda tympani (CT) nerve fibers that innervate taste buds (TB) and also contain somatosensory endings for touch and temperature. Hedgehog (HH) pathway inhibition eliminates TB, but CT innervation remains in the FP. Importantly, after HH inhibition, CT neurophysiological responses to taste stimuli are eliminated, but tactile responses remain. To examine CT fibers that respond to tactile stimuli in the absence of TB, we used Phox2b-Cre; Rosa26LSL−TdTomato reporter mice to selectively label CT fibers with TdTomato. Normally CT fibers project in a compact bundle directly into TB, but after HH pathway inhibition, CT fibers reorganize and expand just under the FP epithelium where TB were. This widened expanse of CT fibers coexpresses Synapsin-1, β-tubulin, S100, and neurofilaments. Further, GAP43 expression in these fibers suggests they are actively remodeling. Interestingly, CT fibers have complex terminals within the apical FP epithelium and in perigemmal locations in the FP apex. These extragemmal fibers remain after HH pathway inhibition. To identify tactile end organs in FP, we used a K20 antibody to label Merkel cells. In control mice, K20 was expressed in TB cells and at the base of epithelial ridges outside of FP. After HH pathway inhibition, K20 + cells remained in epithelial ridges but were eliminated in the apical FP without TB. These data suggest that the complex, extragemmal nerve endings within and disbursed under the apical FP are the mechanosensitive nerve endings of the CT that remain after HH pathway inhibition.

Angiotensin II and the Cardiac Parasympathetic Nervous System in Hypertension.

The renin–angiotensin–aldosterone system (RAAS) impacts cardiovascular homeostasis via direct actions on peripheral blood vessels and via modulation of the autonomic nervous system. To date, research has primarily focused on the actions of the RAAS on the sympathetic nervous system. Here, we review the critical role of the RAAS on parasympathetic nerve function during normal physiology and its role in cardiovascular disease, focusing on hypertension. Angiotensin (Ang) II receptors are present throughout the parasympathetic nerves and can modulate vagal activity via actions at the level of the nerve endings as well as via the circumventricular organs and as a neuromodulator acting within brain regions. There is tonic inhibition of cardiac vagal tone by endogenous Ang II. We review the actions of Ang II via peripheral nerve endings as well as via central actions on brain regions. We review the evidence that Ang II modulates arterial baroreflex function and examine the pathways via which Ang II can modulate baroreflex control of cardiac vagal drive. Although there is evidence that Ang II can modulate parasympathetic activity and has the potential to contribute to impaired baseline levels and impaired baroreflex control during hypertension, the exact central regions where Ang II acts need further investigation. The beneficial actions of angiotensin receptor blockers in hypertension may be mediated in part via actions on the parasympathetic nervous system. We highlight important unknown questions about the interaction between the RAAS and the parasympathetic nervous system and conclude that this remains an important area where future research is needed.

Investigating the Function of Adult DRG Neuron Axons Using an In Vitro Microfluidic Culture System.

A critical role of the peripheral axons of nociceptors of the dorsal root ganglion (DRG) is the conduction of all-or-nothing action potentials from peripheral nerve endings to the central nervous system for the perception of noxious stimuli. Plasticity along multiple sites along the pain axis has now been widely implicated in the maladaptive changes that occur in pathological pain states such as neuropathic and inflammatory pain. Notably, increasing evidence suggests that nociceptive axons actively participate through the local expression of ion channels, receptors, and signal transduction molecules through axonal mRNA translation machinery that is independent of the soma component. In this report, we explore the sensitization of sensory neurons through the treatment of compartmentalized axon-like structures spanning microchannels that have been treated with the cytokine IL-6 and, subsequently, capsaicin. These data demonstrate the utility of isolating DRG axon-like structures using microfluidic systems, laying the groundwork for constructing the complex in vitro models of cellular networks that are involved in pain signaling for targeted pharmacological and genetic perturbations.

Identification of a helix-turn-helix motif for high temperature dependence of vanilloid receptor TRPV2.

Pain and thermosensation rely on temperature-sensitive ion channels at peripheral nerve endings for transducing thermal cues into electrical signals. Members of the transient receptor potential (TRP) family are prominent candidates for temperature transducers in mammals. These thermal TRP channels possess an unprecedentedly steep temperature dependence, allowing them to discriminate small temperature variations. Thermodynamically, it is understood that the strong temperature sensitivity of the channel arises because opening of the channel undergoes reactions involving large enthalpy and entropy changes. However, the underlying molecular mechanisms have remained elusive. Here we investigated the molecular basis for heat activation of TRPV2, a thermal TRP channel in the vanilloid subfamily with the strongest temperature dependence among TRP channels. We unravel a minimum molecular region in the proximal N-terminus which dictates the slope temperature sensitivity of the channel. Structurally, the region comprises a helix-turn-helix motif and is positioned among the TRP helix from the C-terminus, the S2-S3 linker from the transmembrane domain and the ankyrin repeats from the distal N-terminus. Chimeric exchanges of the subregion alone sufficed to diminish the high temperature dependence in the wild-type TRPV2. Our results support a pivotal role for the structural assembly around the TRP domain in the gating of thermal TRP channels by temperature. The findings also shed insight into how the proximal N-terminal domain plays its role in the heat activation of vanilloid receptors. KEY POINTS: The vanilloid receptor subtype 2 (TRPV2) is a heat-sensitive transient receptor potential (TRP) channel with the strongest temperature dependence among thermal TRP channels. The channel also has a high temperature activation threshold above 50°C which has rendered it difficult to study by conventional patch-clamp methods. Here we utilize fast laser temperature jumps to address the challenges of technical accessibility and explore the molecular basis underlying the high temperature dependence of the channel. We unravel a short helix-turn-helix motif in the proximal N-terminus, which controls the heat activation profile of the channel. Chimeric exchanges of the subregion alone sufficed to diminish the high temperature dependence in the wild-type TRPV2. Our results provide insights on how the proximal N-terminal domain plays its role in the heat activation of vanilloid receptors.

Abstract P373: The Occurrence Of Neurovascular And Adipose Neuropathy In The Genetically Diverse Het3 Mouse With Aging

Energy homeostasis and adipose tissue metabolism are regulated in large part through peripheral sympathetic nerve innervation of metabolically important tissues and organs. This neural communication from the brain to adipose tissues results in release of the neurotransmitter norepinephrine that regulates energy expenditure through modulation of lipolysis, adipogenesis, ‘browning’ (development of brown adipocytes in white adipose depots), and non-shivering thermogenesis. Subcutaneous white adipose tissue (scWAT) is an energy storing tissue that is highly plastic, responding to metabolic need by changing mass and cellularity, as well as responding to challenges (including cold temperature, exercise, fasting) by modifying neural activity and metabolism. Within scWAT lies a dense bed of nerves and blood vessels that are integrated closely, and in large part, rely on one another to function properly. Even if not directly innervating the blood vessels themselves (as is the case with capillaries), neurites that appear to innervate single adipocytes use these blood vessels as scaffolding to traverse the tissue. We have recently demonstrated that under pathological conditions (obesity and aging), scWAT innervation decreases through a process termed ‘adipose neuropathy’. With advanced age the small fiber peripheral nerve endings in adipose die back, including reducing contact with adipose-resident blood vessels (as observed previously in the C57BL6/J mouse). This likely poses a physiological challenge for metabolism and for vascular or adipose tissue health and function. For this work, we compared C57BL6/J mice with the more genetically diverse HET3 mouse model, established for the NIA’s Intervention Testing Program to more accurately represent the variability of age-related mortality/morbidity. We investigated incidence of peripheral neuropathy with aging (skin, scWAT muscle) as well as changes to the neurovascular supply of scWAT across several ages in both males and females. We also investigated the anti-aging drug Rapamycin as a potential means to prevent or reduce adipose neuropathy. We found that HET3 mice display a reduced neuropathy phenotype compared to inbred C56BL6/J mice. Importantly, the nerve die-back around blood vessels was not observed in the HET3 model. However, male HET3 mice did reveal neuropathic phenotypes by 62wks of age, characterized by decreased mechanoreception in hind paw skin, reduced NMJ occupation, and decreased expression of the Schwann cell marker Sox10 in scWAT. Female HET3 mice appeared to have increased protection from neuropathy until advanced age (126wks) when they began to show stronger phenotypes than males (excluding Sox10 analysis.) Despite its success as a longevity treatment in mice, rapamycin had little to no effect on reducing or preventing the onset of adipose neuropathy.

Heat But Not Mechanical Hypersensitivity Depends on Voltage-Gated CaV2.2 Calcium Channel Activity in Peripheral Axon Terminals Innervating Skin.

Voltage-gated CaV2.2 calcium channels are expressed in nociceptors at presynaptic terminals, soma, and axons. CaV2.2 channel inhibitors applied to the spinal cord relieve pain in humans and rodents, especially during pathologic pain, but a biological function of nociceptor CaV2.2 channels in processing of nociception, outside presynaptic terminals in the spinal cord, is underappreciated. Here, we demonstrate that functional CaV2.2 channels in peripheral axons innervating skin are required for capsaicin-induced heat hypersensitivity in male and female mice. We show that CaV2.2 channels in TRPV1-nociceptor endings are activated by capsaicin-induced depolarization and contribute to increased intracellular calcium. Capsaicin induces hypersensitivity of both thermal nociceptors and mechanoreceptors, but only heat hypersensitivity depends on peripheral CaV2.2 channel activity, and especially a cell-type-specific CaV2.2 splice isoform. CaV2.2 channels at peripheral nerve endings might be important therapeutic targets to mitigate certain forms of chronic pain.SIGNIFICANCE STATEMENT It is generally assumed that nociceptor termini in the spinal cord dorsal horn are the functionally significant sites of CaV2.2 channel in control of transmitter release and the transmission of sensory information from the periphery to central sites. We show that peripheral CaV2.2 channels are essential for the classic heat hypersensitivity response to develop in skin following capsaicin exposure. This function of CaV2.2 is highly selective for heat, but not mechanical hypersensitivity induced by capsaicin exposure, and is not a property of closely related CaV2.1 channels. Our findings suggest that interrupting CaV2.2-dependent calcium entry in skin might reduce heat hypersensitivity that develops after noxious heat exposure and may limit the degree of heat hypersensitivity associated with certain other forms of pain.

Repeated capsaicin patch applications in patients with localized peripheral neuropathic pain

Neuropathic pain is still a challenging problem. It is experienced by millions of people worldwide, with an approximate prevalence of 7‒10% in the general population. Despite the availability of a variety of treatment methods, a significant proportion of patients suffer from poorly controlled neuropathic pain. Capsaicin is a highly selective TRPV1 (Transient Receptor Potential Vanilloid Type 1) agonist. When applied topically, it leads to the defunctionalisation of hyperactive nociceptive receptors, temporary destruction of peripheral nerve endings, and a significant reduction or cessation of pain. Therefore 8% capsaicin patches are used to treat several peripheral, localized neuropathic pain syndromes. The study aimed to present a case series of patients suffering from peripheral, localized neuropathic pain in case the use of repeated applications of 8% capsaicin patches significantly reduced the intensity of pain. In 5 out of 6 patients we observed a gradual extension of the pain relief period until the pain disappeared, which led to the reduction or discontinuation of systemic pharmacotherapy. In summary, a therapy limited to a certain area of the body, without potential systemic adverse effects, which requires repetition at fairly long intervals, appears to be a good treatment option.

COVID-19 associated nervous system manifestations

The novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a global pandemic in the last year. Along with major respiratory distress, a myriad of neurological manifestations was also reported to be associated with COVID-19 patients. These cases indicate that SARS-CoV-2 can be considered as an opportunistic pathogen of the brain. SARS-CoV-2 enters the brain through the olfactory bulb, retrograde axonal transport from peripheral nerve endings, or via hematogenous or lymphatic routes. Notably, COVID-19 infection can cause or even present with different neurological features including encephalopathy, impaired consciousness, confusion, agitation, seizure, ataxia, headache, anosmia, ageusia, neuropathies, and neurodegenerative diseases. In this paper, we provide a brief review of observed neurological manifestations associated with COVID-19.

Pharmacological Inhibition of the Voltage-Gated Sodium Channel NaV1.7 Alleviates Chronic Visceral Pain in a Rodent Model of Irritable Bowel Syndrome.

The human nociceptor-specific voltage-gated sodium channel 1.7 (hNaV1.7) is critical for sensing various types of somatic pain, but it appears not to play a primary role in acute visceral pain. However, its role in chronic visceral pain remains to be determined. We used assay-guided fractionation to isolate a novel hNaV1.7 inhibitor, Tsp1a, from tarantula venom. Tsp1a is 28-residue peptide that potently inhibits hNaV1.7 (IC50 = 10 nM), with greater than 100-fold selectivity over hNaV1.3-hNaV1.6, 45-fold selectivity over hNaV1.1, and 24-fold selectivity over hNaV1.2. Tsp1a is a gating modifier that inhibits NaV1.7 by inducing a hyperpolarizing shift in the voltage-dependence of channel inactivation and slowing recovery from fast inactivation. NMR studies revealed that Tsp1a adopts a classical knottin fold, and like many knottin peptides, it is exceptionally stable in human serum. Remarkably, intracolonic administration of Tsp1a completely reversed chronic visceral hypersensitivity in a mouse model of irritable bowel syndrome. The ability of Tsp1a to reduce visceral hypersensitivity in a model of irritable bowel syndrome suggests that pharmacological inhibition of hNaV1.7 at peripheral sensory nerve endings might be a viable approach for eliciting analgesia in patients suffering from chronic visceral pain.

Investigations of the functional role of connexin36 in sensory and sympathetic systems in adult mice

Electrical synapses formed by gap junctions composed of connexin36 (Cx36) occur between neurons in widespread areas of the mammalian central nervous system and enable neuron-to-neuron electrical coupling. We previously reported that dorsal root ganglia (DRG) sensory neurons containing transient receptor potential (TRP) channels, including TRPV1 and TRPM8, and those containing substance P in nociceptive DRG neurons express high levels of Cx36. It has also been reported that Cx36 is expressed in sympathetic preganglionic neurons (SPNs). Here we examined the functional roles of electrical synapses in primary afferent and SPN neural networks by using mice with global knockout (ko) of the Cx36 gene (Cx36 ko mice) and their wildtype (Wt) counterparts. Based on previous evidence showing that spinal neurons in Cx36 ko mice have attenuated responses to nociceptive stimulation when examined ex vivo; our hypothesis was that responses to nociceptive stimulation would be attenuated in vivo in intact Cx36 ko mice compared to Wt. To examine the role of coupling between DRG neurons, in vivo imaging was used to measure the fluorescence signal of Evans blue dye extravasation in skin of live animals after nociceptor activation. The extravasation levels relative to baseline fluorescence were 61.7±4% in Wt mice and 33.2±7% Cx36 ko mice (n=5 matched pairs, all males) after hind paw pinprick. Xylene applied topically on one of the ears induced more extravasation in the wt (255.4 ±3%) than in the Cx36 ko mice (204.6 ±1%). Using a fibre optic blood pressure monitoring system, we found that topical xylene application under isoflurane anesthesia changes the blood pressure, the heart rate, and the respiratory rate additionally to evoking the plasma extravasation. The attenuated extravasation response in the Cx36 ko mice suggests that electrical synapses known to occur between peripheral unmyelinated sensory fibers impact signal transmission from peripheral nerve endings and release other mediators that cause this response. To examine functional roles of coupling between SPNs, we compared physiological responses to colorectal distension (CRD) in Wt and Cx36 ko) mice in mice under isoflurane anesthesia. Mean arterial blood pressure during CRD increased to 108 ± 8% of baseline in Wt mice (n = 7), while this parameter did not change significantly in Cx36 ko mice (n = 12), but did show a tendency to decrease (to 97 ± 2%). Heart rate did not show significant changes, but we found that respiratory rate changes also occurred as part of the systemic response to CRD in both lines of mice. These data show differential regulation of sympathetic activity associated with electrical coupling between SPNs in Wt vs. Cx36 ko mice. In Wt mice with mid-thoracic complete spinal transection (n = 2), CRD also increased blood pressure when tested at 6-8 days after injury. The results taken together, point to the possibility that Cx36 in DRG and SPNs of adult mice has a significant functional role and warrant further research to understand how the presence of Cx36 in DRG and SPNs influences pain processing and associated autonomic responses.

Fibromyalgia vs small fiber neuropathy: diverse keratinocyte transcriptome signature.

Damage to thinly myelinated and unmyelinated nerve fibers causes small fiber pathology, which is increasingly found in pain syndromes such as small fiber neuropathy (SFN) and fibromyalgia syndrome (FMS). The peripheral nerve endings of the small nerve fibers terminate within the epidermis, where they are surrounded by keratinocytes that may act as primary nociceptive transducers. We performed RNA sequencing of keratinocytes obtained from patients with SFN, FMS, and healthy controls. We found 141 deregulated protein coding genes between SFN patients and healthy controls and no differentially expressed genes between patients with FMS and healthy controls. When comparing patients with SFN with patients with FMS, we detected 167 differentially expressed protein coding genes (129 upregulated and 38 downregulated). Further analysis revealed enriched inflammatory pathways. Validation of selected candidates in an independent cohort confirmed higher expression of the proinflammatory mediators interleukin-8, C-X-C motif chemokine 3, endothelin receptor type A, and the voltage-gated sodium channel 1.7 in SFN compared with patients with FMS. We provide a diverse keratinocyte transcriptome signature between patients with SFN and patients with FMS, which may hint toward distinct pathomechanisms of small fiber sensitization in both entities and lay the basis for advanced diagnostics.

The morphological and microscopical characteristics of posterior layer of human thoracolumbar fascia; A potential source of low back pain

Posterior layer of thoracolumbar fascia (PTLF) is the deep fascia of back of the trunk, which connects the trunk, upper limb and lower limb muscles. Very few cadaveric studies of posterior layer of thoracolumbar fascia (PTLF) are found in the literature, which mention the presence of nerve receptors in it but, quantification of the nerve receptors where not found. Providing the morphological and morphometrical data of PTLF may help the exercise physiologists, sports physicians, occupational health assistants and, physiotherapists to modify or invent new protocol of treatment to help the society. In this study, twenty formalin embalmed human cadavers were used and we have documented the orientation of the PTLF and quantified the number of peripheral nerve endings at the different vertebral levels. Mean distance of PTLF from vertebral spines to the musculofascial junction was at thoracic region 3.38cm and 3.34cm; at lumbar region, it was 7.4cm and 7.36cm and at sacral region it was 2.98cm and 2.96cm on right and left side, respectively. The angulation of PTLF varies from 18-110 degrees at different vertebral levels. The microscopic data shows the thickness of PTLF and number of nerve endings in the sacral level is increased compared to that of thoracic vertebral levels. We have contributed the novel morphological and microscopical details to the limited existing data on PTLF. We also have provided the quantitative data of nerve fibers, which are possible nociceptors of PTLF.

Pathophysiological Clues to How the Emergent SARS-CoV-2 Can Potentially Increase the Susceptibility to Neurodegeneration.

Along with emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in late 2019, a myriad of neurologic symptoms, associated with structural brain changes, were reported. In this paper, we provide evidence to critically discuss the claim that the survived patients could possibly be at increased risk for neurodegenerative diseases via various mechanisms. This virus can directly invade the brain through olfactory bulb, retrograde axonal transport from peripheral nerve endings, or via hematogenous or lymphatic routes. Infection of the neurons along with peripheral leukocytes activation results in pro-inflammatory cytokine increment, rendering the brain to neurodegenerative changes. Also, occupation of the angiotensin-converting enzyme 2 (ACE-2) with the virus may lead to a decline in ACE-2 activity, which acts as a neuroprotective factor. Furthermore, acute respiratory distress syndrome (ARDS) and septicemia induce hypoxemia and hypoperfusion, which are locally exacerbated due to the hypercoagulable state and micro-thrombosis in brain vessels, leading to oxidative stress and neurodegeneration. Common risk factors for COVID-19 and neurodegenerative diseases, such as metabolic risk factors, genetic predispositions, and even gut microbiota dysbiosis, can contribute to higher occurrence of neurodegenerative diseases in COVID-19 survivors. However, it should be considered that severity of the infection, the extent of neurologic symptoms, and the persistence of viral infection consequences are major determinants of this association. Importantly, whether this pandemic will increase the overall incidence of neurodegeneration is not clear, as a high percentage of patients with severe form of COVID-19 might probably not survive enough to develop neurodegenerative diseases.

Neurological complications of COVID-19: from pathophysiology to rehabilitation. An overview.

Objective:To evaluate how the SARS-COV2 is able to affect the nervous system, the main neurological manifestation, and the treatment used, including neurorehabilitation.Methods:Studies performed during the current year that fulfilled inclusion criteria were selected from PubMed, Scopus, Cochrane, and Web of Sciences databases. The search combined the terms “Covid 19,” “rehabilitation/treatment,” and “neurological complications.”Results:The exact route by which SARS-CoV-2 can penetrate the CNS is still unknown, although a possible retrograde transynaptic pathway from peripheral nerve endings, and/or through the olfactory bulb, have been suggested. An early management of COVID-19 by a multiprofessional team is fundamental to avoid long term sequaele. Rehabilitation is recommended to improve respiratory and cardiac function, as well as to avoid long term neurological complications.Conclusions:As no specific conclusions in term of prognosis and treatment could be done, research and consensus paper are needed to provide NeuroCovid patients with the best treatment options, including neurorehabilitation. (www.actabiomedica.it)