Myelinated Nerve Research Articles

Cellular and molecular characterization of peripheral glia in the lung and other organs.

Peripheral glia are important regulators of diverse physiologic functions yet their molecular distinctions and locations in almost all visceral organs are not well-understood. We performed a systematic analysis of peripheral glia, focusing on the lung and leveraging single cell RNA sequencing (scRNA-seq) analysis to characterize their cellular and molecular features. Using in vivo lineage studies, we characterized the anatomic, cellular, and molecular features of the Sox10+ glial lineage of the mouse lung. Using high-resolution imaging, we quantified the distribution and cellular morphologies of myelinating, non-myelinating, satellite, and terminal glial cells with their intricate extensions along peripheral nerves, including terminals at specialized neurosensory structures within the lung. Spatial analysis of selectively expressed myelinating (periaxin/Prx, claudin 19/Cldn) or non-myelinating (sodium channel/Scn7a) glial cell genes identified by scRNA-seq analysis revealed molecularly distinct populations surrounding myelinated nerve fibers in the lung. To extend this analysis to primates and other organs, we extracted rare peripheral glial cells in whole organism scRNA-seq atlases of mouse lemur and human. Our cross-species data analysis and integration of scRNA-seq data of ~700 peripheral glial cells from mouse, mouse lemur, and human glial cells identified conserved gene expression of molecularly distinct peripheral glial cell populations. This foundational knowledge facilitates subsequent functional studies targeting molecularly distinct subsets of peripheral glia and integrating them into organ-specific disorders of autonomic dysregulation. In addition, our cross-species analysis identifying conserved gene expression patterns and glial networks in extrapulmonary organs provides a valuable resource for studying the functional role of peripheral glia in multiorgan human diseases.

Harnessing polysialic acid (PSA)-embedded exudate-absorbing hydrogel for on-demand trigeminal neuralgia treatment

A key characteristic of trigeminal neuralgia (TN) is cytokine-enriched exudate and a “reactive oxygen species (ROS) storm” generated from the inflammatory cascade, resulting in demyelination of the sensory root of the trigeminal nerve, tissue swelling, and intense electric shock-like pain. The clinically approved drug carbamazepine (CBZ) is capable of inhibiting pain, reducing inflammatory factors, and alleviating oxidative stress, but its clinical application is restricted by its systemic toxicity. Herein, we developed an exudate-absorbing hydrogel incorporating polysialic acid (PSA) and CBZ (F127@PSA@CBZ) for on-demand TN treatment. Owing to the strong water absorption properties of PSA and F127, the F127@PSA@CBZ hydrogel can quickly absorb the lesion exudate and swell into a larger volume with a looser structure, thus releasing payloads sustainably, such as CBZ and PSA, for approximately 7 days in vivo. The released CBZ can scavenges the ROS storm and inhibits the levels of proinflammatory factors. More importantly, the residual PSA was found to promoted the proliferation of Schwann cells by upregulating the expression of STAT3 and Ki67, contributing to enhanced myelin sheath regeneration in a rat TN model. These findings highlight that the PSA-embedded exudate-absorbing hydrogel has great potential for facilitating the repair of the trigeminal nerve myelin sheath.

Regulation of disease-associated microglia in the optic nerve by lipoxin B4 and ocular hypertension

BackgroundThe resident astrocyte-retinal ganglion cell (RGC) lipoxin circuit is impaired during retinal stress, which includes ocular hypertension-induced neuropathy. Lipoxin B4 produced by homeostatic astrocytes directly acts on RGCs to increase survival and function in ocular hypertension-induced neuropathy. RGC death in the retina and axonal degeneration in the optic nerve are driven by the complex interactions between microglia and macroglia. Whether LXB4 neuroprotective actions include regulation of other cell types in the retina and/or optic nerve is an important knowledge gap.MethodsCellular targets and signaling of LXB4 in the retina were defined by single-cell RNA sequencing. Retinal neurodegeneration was induced by injecting silicone oil into the anterior chamber of mouse eyes, which induced sustained and stable ocular hypertension. Morphological characterization of microglia populations in the retina and optic nerve was established by MorphOMICs and pseudotime trajectory analyses. The pathways and mechanisms of action of LXB4 in the optic nerve were investigated using bulk RNA sequencing. Transcriptomics data was validated by qPCR and immunohistochemistry. Differences between experimental groups were assessed by Student’s t-test and one-way ANOVA.ResultsSingle-cell transcriptomics identified microglia as a primary target for LXB4 in the healthy retina. LXB4 downregulated genes that drive microglia environmental sensing and reactivity responses. Analysis of microglial function revealed that ocular hypertension induced distinct, temporally defined, and dynamic phenotypes in the retina and, unexpectedly, in the distal myelinated optic nerve. Microglial expression of CD74, a marker of disease-associated microglia in the brain, was only induced in a unique population of optic nerve microglia, but not in the retina. Genetic deletion of lipoxin formation correlated with the presence of a CD74 optic nerve microglia population in normotensive eyes, while LXB4 treatment during ocular hypertension shifted optic nerve microglia toward a homeostatic morphology and non-reactive state and downregulated the expression of CD74. Furthermore, we identified a correlation between CD74 and phospho-phosphoinositide 3-kinases (p-PI3K) expression levels in the optic nerve, which was reduced by LXB4 treatment.ConclusionWe identified early and dynamic changes in the microglia functional phenotype, reactivity, and induction of a unique CD74 microglia population in the distal optic nerve as key features of ocular hypertension-induced neurodegeneration. Our findings establish microglia regulation as a novel LXB4 target in the retina and optic nerve. LXB4 maintenance of a homeostatic optic nerve microglia phenotype and inhibition of a disease-associated phenotype are potential neuroprotective mechanisms for the resident LXB4 pathway.

Laterality, sexual dimorphism, and human vagal projectome heterogeneity shape neuromodulation to vagus nerve stimulation

Neuromodulation by vagus nerve stimulation (VNS) provides therapeutic benefits in multiple medical conditions, including epilepsy and clinical depression, but underlying mechanisms of action are not well understood. Cervical vagus nerve biopsies were procured from transplant organ donors for high resolution light microscopy (LM) and transmission electron microscopy (TEM) to map the human fascicular and sub-fascicular organization. Cervical vagal segments show laterality with right sided dominance in fascicle numbers and cross-sectional areas as well as sexual dimorphism with female dominance in fascicle numbers. The novel and unprecedented detection of numerous small fascicles by high resolution LM and TEM expand the known fascicle size range and morphological diversity of the human vagus nerve. Ground truth TEM quantification of all myelinated and unmyelinated axons within individual nerve fascicles show marked sub-fascicular heterogeneity of nerve fiber numbers, size, and myelination. A heuristic action potential interpreter (HAPI) tool predicts VNS-evoked compound nerve action potentials (CNAPs) generated by myelinated and unmyelinated nerve fibers and validates functional dissimilarity between fascicles. Our findings of laterality, sexual dimorphism, and an expanded range of fascicle size heterogeneity provide mechanistic insights into the varied therapeutic responses and off-target effects to VNS and may guide new refinement strategies for neuromodulation.

Physical exercise halts further functional decline in an animal model for Charcot-Marie-Tooth disease 1X at an advanced disease stage.

Charcot-Marie-Tooth (CMT) type 1 neuropathies are the most common inherited diseases of the peripheral nervous system. Although more than 100 causative genes have been identified so far, therapeutic options are still missing. We could previously identify that early-onset physical exercise (voluntary wheel running, VWR) dampens peripheral nerve inflammation, improves neuropathological alterations, and clinical outcome in Cx32def mice, a model for CMT1X. We here investigate the clinical and histopathological effect of late-onset exercise in Cx32def mice at an advanced disease stage. Nine-month-old Cx32def mice were allowed to run for 4 days/week on a commercially available running wheel for 3 months, with timely limited access to running wheels, representing a running distance of ~2000 m. Control mutants had no access to running wheels. Afterward, mice were investigated by distinct functional tests and by immunohistochemical and electron microscopical techniques. We found that late-onset physical exercise (late VWRlim) prevented the robust functional decline in 12-month-old Cx32def mice. This was accompanied by improved neuromuscular innervation of distal muscles and axonal preservation in femoral quadriceps nerves. In contrast to a "pre-symptomatic" start of physical exercise in Cx32def mice, late-onset VWR did not alter nerve inflammation and myelin thickness at 12 months of age. We conclude that VWR has robust beneficial effects on nerve function in Cx32def mice, even when applied at a progressed disease stage. These results have important translational implications, suggesting that physical exercise might be an effective treatment option for CMT1 patients, even when disease symptoms have already progressed.

Ultrathin visible-light OCT endomicroscopy for in vivo ultrahigh-resolution neuroimaging in deep brain

Deep-brain neuroimaging, a task that demands high-resolution imaging techniques for visualizing intricate brain structures, assessing deep-seated disease histopathology, and offering real-time intervention guidance, is challenged by the resolution-depth trade-off of current methods. We propose an optical coherence tomography (OCT) endomicroscopy device for high-resolution in vivo imaging of deep brain microstructures and histopathology. A unique liquid shaping technique enables the direct fabrication of a microlens on the fiber tip of the imaging probe, optimizing imaging performance parameters, such as longitudinal focal shift, focused spot size, and working distance. In addition, a broadband visible-light source enhances axial resolution and OCT imaging contrast. As a result, the first monolithic visible-light OCT (vis-OCT) endomicroscope, with a submillimeter outer diameter (∼0.4 mm), is presented, achieving an ultrahigh resolution of 1.4 μm axial × 4.5 μm transverse in air. This compact probe allows minimally invasive in vivo deep-brain imaging in mice at a depth of 7.2 mm. Key regions in the mouse deep brain, such as the isocortex, corpus callosum, and caudate putamen, were successfully identified using our vis-OCT endomicroscope. In addition, we examined the myeloarchitectures and cytoarchitectures in the isocortex. Our findings demonstrate that the vis-OCT endomicroscope offers enhanced visualization of myelinated axon fibers and nerve fiber bundles compared to its 800 nm counterpart. This vis-OCT endomicroscope, overcoming resolution and imaging depth limitations of conventional methods, offers a novel tool for minimally invasive, ultrahigh-resolution in vivo deep brain neuroimaging.

Retinal Vascular Changes in a Case of Straatsma Syndrome.

A 34-year-old asymptomatic woman with a history of amblyopia in her right eye presented for a routine examination. Fundus examination revealed broad myelinated nerve fibers along with telangiectatic vessels. Wide-field fluorescein angiography revealed no evidence of ischemia or active retinal neovascularization. However, myelinated nerve fibers can infrequently exhibit cooccurring retinal vascular anomalies, harboring the potential for sight-threatening complications. Patients should be carefully monitored for the development of neovascularization and secondary complications. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Regulation of Diseases-Associated Microglia in the Optic Nerve by Lipoxin B4 and Ocular Hypertension.

The resident astrocyte-retinal ganglion cell (RGC) lipoxin circuit is impaired during retinal stress, which includes ocular hypertension-induced neuropathy. Lipoxin B4 produced by homeostatic astrocytes directly acts on RGCs to increase survival and function in ocular hypertension-induced neuropathy. RGC death in the retina and axonal degeneration in the optic nerve are driven by the complex interactions between microglia and macroglia. Whether LXB4 neuroprotective actions include regulation of other cell types in the retina and/or optic nerve is an important knowledge gap. Cellular targets and signaling of LXB4 in the retina were defined by single-cell RNA sequencing. Retinal neurodegeneration was induced by injecting silicone oil into the anterior chamber of the mouse eyes, which induced sustained and stable ocular hypertension. Morphological characterization of microglia populations in the retina and optic nerve was established by MorphOMICs and pseudotime trajectory analyses. The pathways and mechanisms of action of LXB4 in the optic nerve were investigated using bulk RNA sequencing. Transcriptomics data was validated by qPCR and immunohistochemistry. Differences between experimental groups were assessed by Student's t-test and one-way ANOVA. Single-cell transcriptomics identified microglia as a primary target for LXB4 in the healthy retina. LXB4 downregulated genes that drive microglia environmental sensing and reactivity responses. Analysis of microglial function revealed that ocular hypertension induced distinct, temporally defined, and dynamic phenotypes in the retina and, unexpectedly, in the distal myelinated optic nerve. Microglial expression of CD74, a marker of disease-associated microglia in the brain, was only induced in a unique population of optic nerve microglia, but not in the retina. Genetic deletion of lipoxin formation correlated with the presence of a CD74 optic nerve microglia population in normotensive eyes, while LXB4 treatment during ocular hypertension shifted optic nerve microglia toward a homeostatic morphology and non-reactive state and downregulated the expression of CD74. Furthermore, we identified a correlation between CD74 and phospho-phosphoinositide 3-kinases (p-PI3K) expression levels in the optic nerve, which was reduced by LXB4 treatment. We identified early and dynamic changes in the microglia functional phenotype, reactivity, and induction of a unique CD74 microglia population in the distal optic nerve as key features of ocular hypertension-induced neurodegeneration. Our findings establish microglia regulation as a novel LXB4 target in the retina and optic nerve. LXB4 maintenance of a homeostatic optic nerve microglia phenotype and inhibition of a disease-associated phenotype are potential neuroprotective mechanisms for the resident LXB4 pathway.

Camillo Golgi's contributions to the anatomic basis of sensitivity in tendons.

Between 1878 and 1880 Camillo Golgi, professor of Histology and General Pathology at the University of Pavia, studied the termination of the nerves inside the tendons, near their muscular insertion. He defined two fundamental categories of corpuscles. The first type, which he called muscle-tendon terminal organs, was morphologically characterized by spindle structures which at one end seemed to relate to the muscle fibers while at the other end they gradually merged with the tendon bundles. Golgi discovered that these structures received from one to four myelinated nerve fibers, which lost their myelin sheath as they entered the bundle, within which they divided dichotically, ending in a large number of terminal arborizations that had the appearance of reticular intertwines. In the superficial thickness of the tendon, near the muscle, Golgi also noticed a second category of corpuscles, which he described as claviform bodies or formations similar to Pacinian bodies. In 1890 Vittorio Mazzoni precisely defined their morphological characteristics. These corpuscles were later called Golgi muscle-tendon organs and Golgi-Mazzoni corpuscles. On the basis of their position and histological appearance, Golgi also correctly hypothesized their physiological role: to be receptors of muscular tension for the muscle-tendon organs and transducers of sensitivity to touch and pressure for the Golgi-Mazzoni corpuscles.

Hypertension is associated with the reduction in epidermal small fibres independently of sural nerve inflammation in type 2 diabetic subjects.

Diabetic polyneuropathy (DPN) is a multifactorial disease associated not only with hyperglycaemia but also with circulatory disturbances such as hypertension. A close interaction between the immune system and hypertension is known. It remains unclear whether the inflammatory response is associated with hypertension in the pathology of human DPN. Autopsied patients were evaluated: 7 non-diabetic patients (nDM), 11 non-diabetic patients with hypertension (nDMHT), 6 patients with diabetes (DM) and 9 patients with hypertension and diabetes (DMHT). Intraepidermal nerve fibre density (IENFD) was examined by immunofluorescent staining. Dissected sural nerve (SNs) were morphometrically quantified. Dermal and endoneurial macrophage infiltration was evaluated by double immunostaining using anti-CD68 and anti-CD206 antibodies. IENFD was significantly decreased in DM compared to nDM (p < 0.05) and was further decreased in DMHT (p < 0.05). Myelinated nerve fibre density (MNFD) in the SN was significantly decreased in DM compared with nDM (p < 0.05) and further decreased in DMHT (p < 0.01 vs. DM). The infiltration of CD206-/CD68+ proinflammatory macrophages in the SN was significantly increased in DM compared to nDM (p < 0.05), whilst the number of CD206+/CD68+ anti-inflammatory macrophages was decreased in DM (p < 0.05). Hypertension had no impact on macrophage infiltration. The ratio of CD206- and CD206+ macrophage was negatively correlated with MNFD (r = 0.42, p < 0.05) but not IENFD (r = 0.30, p = 0.09). Dermal CD206+ macrophage infiltration was similar amongst all groups. Diabetes complicated by hypertension significantly increased the total diffusion barrier thickness (p < 0.01 vs. DM). Total diffusion barrier thickness was inversely correlated with both IENFD (r = -0.59, p < 0.01) and MNFD (r =-0.62, p < 0.01). Our results suggest that vascular factors and inflammation might be synergistically involved in pathological changes in human diabetic patients through different mechanisms.

Gynostemma pentaphyllum (Thunb.) Makino Affects Autophagy and Improves Diabetic Peripheral Neuropathy Through TXNIP-Mediated PI3K/AKT/mTOR Signaling Pathway.

TXNIP is closely associated with diabetic peripheral neuropathy (DPN). Gynostemma pentaphyllum (Thunb.) Makino (GP), a perennial herb with five leaves, is considered to have medicinal values. However, it is unknown whether GP alleviates DPN by modulating TXNIP-mediated autophagy. The aim of this study was to evaluate the effect of GP on Schwann cell injury during DPN and to investigate the mechanism of GP in DPN for the first time. High-fat diet-fed GK rats and high-glucose-cultured RSC96 cells were used to establish DPN models. The effects of GP on DPN were investigated by blood glucose assay, neurological function assay, pathology assay, and immunohistochemistry. To investigate the effect of GP on autophagy and upstream PI3K/AKT/mTOR signaling pathway in Schwann cells, Western blot and immunofluorescence assay were performed on RSC96 cells to detect the expression of beclin-1 and LC3. Western blot method was used to detect the expression of PI3K, p-Akt/Akt, p-mTOR/mTOR, and RT-qPCR method and was used to detect the expression of PI3K. Apoptosis was detected by flow cytometry. The effects of TXNIP on the above indicators were also detected in RSC96 cells. Finally, the mechanism of GP regulation of autophagy and apoptosis in RSC96 cells was verified. GP reduced blood glucose level, attenuated peripheral nerve myelin damage, and improved nerve function in DPN rats. In addition, GP enhanced autophagy activity and reduced apoptosis in RSC96 cells. GP promoted autophagy by regulating TXNIP-mediated PI3K/AKT/mTOR signaling pathway, and GP reduced apoptosis in RSC96 cells by promoting cellular autophagy. GP attenuates DPN myelin damage in RSC96 cells by enhancing autophagy, and its mechanism may be related to the inhibition of PI3K/AKT/mTOR signaling pathway by up-regulating the expression of TXNIP.

Pharmacologically increasing cGMP improves proteostasis and reduces neuropathy in mouse models of CMT1

Increasing cyclic GMP activates 26S proteasomes via phosphorylation by Protein Kinase G and stimulates the intracellular degradation of misfolded proteins. Therefore, agents that raise cGMP may be useful therapeutics against neurodegenerative diseases and other diseases in which protein degradation is reduced and misfolded proteins accumulate, including Charcot Marie Tooth 1A and 1B peripheral neuropathies, for which there are no treatments. Here we increased cGMP in the S63del mouse model of CMT1B by treating for three weeks with either the phosphodiesterase 5 inhibitor tadalafil, or the brain-penetrant soluble guanylyl cyclase stimulator CYR119. Both molecules activated proteasomes in the affected peripheral nerves, reduced polyubiquitinated proteins, and improved myelin thickness and nerve conduction. CYR119 increased cGMP more than tadalafil in the peripheral nerves of S63del mice and elicited greater biochemical and functional improvements. To determine whether raising cGMP could be beneficial in other neuropathies, we first showed that polyubiquitinated proteins and the disease-causing protein accumulate in the sciatic nerves of the C3 mouse model of CMT1A. Treatment of these mice with CYR119 reduced the levels of polyubiquitinated proteins and the disease-causing protein, presumably by increasing their degradation, and improved myelination, nerve conduction, and motor coordination. Thus, pharmacological agents that increase cGMP are promising treatments for CMT1 neuropathies and may be useful against other proteotoxic and neurodegenerative diseases.

The concept of the Schwann cell by Louis Ranvier and his school: The ‘interannular segment’ as a cell unit

ABSTRACT The hundredth anniversary of the death of French histologist Louis Ranvier (1835‒1922) is an opportunity to reexamine his elaboration of the first concept of the Schwann cell. A loyal supporter of Theodor Schwann and his discoveries, and an attentive reader of the work of Albert von Kölliker, Ranvier studied the anatomic details of the myelinated nerve fiber with picrocarminate staining. The diffusion of the dye into the nerve fiber at the cut ends and at the sites of the annular constrictions (Ranvier’s nodes) set him on the path to defining a new cellular entity surrounding the axon, the “interannular segment,” comprising a Schwann nucleus, myelin, and cytoplasm. Ramón y Cajal recognized in 1913 that this concept of the Schwann cell according to Ranvier and his pupil William Vignal had been a brilliant intuition, but it was widely rejected until it was rediscovered using electron microscopy in the 1950s. The article reconstructs the steps of Ranvier and Vignal in building this Schwann cell concept, as well as establishing bridges with the discoveries of the 1950s.

Progressive maculopathy in a child resulting from vitreopapillary traction on a congenitally anomalous nerve.

To present a case of worsening maculopathy and vision loss due to vitreopapillary traction associated with an anomalous optic nerve head in a pediatric patient successfully managed with pars plana vitrectomy. Retrospective case report. A 13-year-old boy presented with unilateral maculopathy that slowly progressed over a four-year period. As his visual acuity declined, he became increasingly symptomatic. The macular pathology occurred in the setting of vitreopapillary traction overlying multiple congenital optic nerve abnormalities, including a myelinated nerve fiber layer and a Bergmeister papilla. Following pars plana vitrectomy to alleviate the traction, the patient's macular appearance improved, and his vision slowly recovered to baseline. There are limited reports of congenital optic nerve anomalies associated with vitreopapillary traction and maculopathy among any age group. This report illustrates a pediatric case in which removal of traction on the nerve head by pars plana vitrectomy was the key therapeutic intervention to alleviate the maculopathy.

Clinical and biochemical characterization of asymptomatic carriers and symptomatic patients with hereditary transthyretin amyloidosis caused by TTR V30L mutation.

Hereditary transthyretin amyloidosis (ATTR) is an autosomal dominant disease characterized by amyloid fibril deposition. The TTR c.148G > T mutation (V30L) in ATTR is rarely reported, and its biochemical properties are unknown. Seven patients and two asymptomatic carriers from two unrelated families diagnosed with V30L variant of ATTR were included. Data on clinical manifestations, laboratory examination, electrophysiology, ophthalmological corneal confocal microscopy (CCM), pathology and molecular biological experiments was collected and analyzed. Most patients initially experienced paresthesia, with varying degrees of peripheral neuropathy, autonomic dysfunction, and cardiac involvement. Nerve conduction studies showed extensive motor and sensory nerve involvement in upper and lower limbs. CCM revealed reduced corneal nerve density and fiber length. Sural nerve biopsies indicated loss of myelinated nerve fibers, with neurogenic patterns in gastrocnemius muscle biopsies. Asymptomatic carriers had nearly normal electrophysiology but mild reductions in corneal nerve fiber density and length. Sural nerve biopsies in carriers showed mild reductions in small myelinated nerve fibers. V30L mutation impaired thermodynamic and kinetic stability of the mutant protein. Plasma TTR tetramer concentration was lower in ATTR V30L patients compared to healthy donors. Small molecule stabilizers failed to exhibit satisfactory inhibition on fibril formation of V30L mutation in vitro. This study highlights the multisystem involvement in ATTR V30L patients, including neuropathy and cardiac issues. Both patients and carriers showed abnormalities in nerve conduction, corneal microscopy, and pathology. The V30L mutation impaired protein stability and reduced plasma TTR tetramer levels. Small molecule stabilizers were ineffective, indicating a need for alternative treatments.

Adipose-derived stem cell transplantation enhances spinal cord regeneration by upregulating PGRN expression.

This study aims to investigate the effect of adipose-derived stem cells (ADSCs) transplantation on progranulin (PGRN) expression and functional recovery in rats with spinal cord injury (SCI). ADSCs were isolated from the inguinal adipose tissue of rats. A SCI model was created, and ADSCs were injected into the injured area. Various techniques were used to assess the effects of ADSCs transplantation, including hematoxylin-eosin staining, Masson staining, immunofluorescence staining, electron microscopy, MRI, and motor function assessment. The potential mechanisms of ADSC transplantation were investigated using gene expression analysis and protein analysis. Finally, the safety of this therapy was evaluated through hematoxylin-eosin staining and indicators of liver and kidney damage in serum. PGRN expression increased in the injured spinal cord, and ADSCs transplantation further enhanced PGRN levels. The group that received ADSCs transplantation showed reduced inflammation, decreased scar formation, increased nerve regeneration, and faster recovery of bladder function. Importantly, motor function significantly improved in the ADSC transplantation group. ADSCs transplantation enhances functional regeneration in SCI by upregulating PGRN expression, reducing inflammation and scar formation, and promoting nerve regeneration and myelin repair. These findings suggest that ADSC transplantation is a potential therapy for SCI.

Beyond pain: Using Unsupervised Machine Learning to Identify Phenotypic Clusters of Small Fiber Neuropathy.

Small fiber neuropathy (SFN) is characterized by dysfunction and loss of peripheral unmyelinated and thinly myelinated nerve fibers, resulting in a phenotype that includes varying combinations of somatosensory and dysautonomia symptoms, which can be profoundly disabling and lead to decreased quality of life. Treatment aimed mainly at pain reduction, which may not target the underlying pathophysiology, is frequently ineffective. Another impediment to the effective management of SFN may be the significant between-patient heterogeneity. Accordingly, we launched this study to gain insights into the symptomatic variability of SFN and determine if SFN patients can be sub-grouped based on clinical characteristics. To characterize the phenotype and investigate how patients with SFN differ from those with large fiber involvement, 105 patients with skin-biopsy proven SFN and 45 with mixed fiber neuropathy (MFN) were recruited. Using unsupervised machine learning, SFN patients were clustered based upon symptom concurrence and severity. Demographics, clinical data, symptoms, and skin biopsy- and laboratory findings were compared between the groups. MFN- as compared to SFN patients, were more likely to be male, older, had a lower intraepidermal nerve fiber density at the ankle and more frequent abnormal immunofixation. Beyond these differences, symptom prevalence and intensities were similar in the two cohorts. SFN patients comprised three distinct phenotypic clusters, which differed significantly in symptom severity, co-occurrence, localization, and skin biopsy findings. Only one subgroup, constituting about 20% of the patient population, was characterized by intense neuropathic pain, which was always associated with several other SFN symptoms of similarly high intensities. A pauci-symptomatic cluster comprised patients who experienced few SFN symptoms, generally of low to moderate intensity. The largest cluster was characterized by intense fatigue, myalgias and subjective weakness, but lower intensities of burning pain and paresthesia. This data-driven study introduces a new approach to subgrouping patients with SFN. Considering both neuropathic pain and pernicious symptoms beyond pain, we identified three clusters, which may be related to distinct pathophysiological mechanisms. Although additional validation will be required, our findings represent a step towards stratified treatment approaches and, ultimately, personalized treatment.

Morphometrical analysis of myelinated nerve fibers: is there a room for improvement?

Despite advancements in automatic approaches for histomorphometry analysis of peripheral nerves, manual and semi-automated methods are widely utilized. Standard software functions are often unsuitable for analysis due to their irregular shapes, especially in pathological conditions. This study aims to assess the reproducibility of nerves morphometric analysis and compare results obtained using both default and new alternative algorithms. Sciatic nerves from Wistar rats (untreated and after administration of intraperitoneal hydrargyrum chloride), previously embedded in resin, were used. Morphometric analysis (diameters, myelin thickness, g-ratio, and circularity) was conducted using ImageJ on semithin sections, with axon and myelin boundaries manually outlined. Default diameters were calculated as the mean of Feret diameters, with subsequent calculations for myelin thickness and g-ratio. The alternative approach estimated diameters based on the geometric center of axons, iterating through selected coordinates; myelin thickness was obtained using line equations. In the control group, inter-rater agreement was higher or within expected reliability (0.8 ± 0.05). However, in the experimental group, myelin thickness, g-ratio, and axon circularity showed lower agreement (0.66, 0.58, and 0.68, respectively) without visible patterns on Bland-Altman plots. The alternative approach did not reveal significant differences between approaches, except for g-ratio in the control group and fiber diameter in the experimental group (p < 0.05), with effect sizes of 0.29-0.30 and 0.19-0.20, respectively. This study highlights reduced agreement among investigators analyzing nerve fibers under pathological conditions, raising concerns about the current standard measurement methods. The proposed approach, based on a single geometric center, provides more natural estimations for irregular fibers, and can be implemented in automated nerve fibers acquisition systems.

IgG subclass shifts occurring at acute exacerbations in autoimmune nodopathies.

Autoimmune nodopathy associated with anti-contactin1 (CNTN1) IgG4 antibodies frequently manifests as acute axonal degeneration in addition to detachment of the paranodal myelin loops. The acute destruction of myelinated nerve fibers does not match the function of IgG4, which cannot activate the complement pathway. IgG subclass switching from IgG1 or IgG3 to IgG4 has been observed in some patients with autoimmune diseases associated with IgG4 throughout their disease course. Serial changes in IgG subclasses, clinico-neurophysiological features, and nerve and renal pathology were reviewed in three patients with anti-CNTN1-associated autoimmune nodopathy and one patient with anti-contactin-associated protein1 (Caspr1) autoimmune nodopathy. All four patients had predominantly IgG4 autoantibodies, whereas they showed evidence of acute axonal degeneration. The IgG1 subclass was present in all patients at their progressing stage but then disappeared at follow-up. Nerve pathology in the patients with anti-CNTN1 and anti-Caspr1 autoimmune nodopathies showed both structural changes in the paranodes and evidence of acute axonal degeneration. Renal biopsy specimens from two patients with membranous glomerulonephritis and anti-CNTN1 autoimmune nodopathy showed deposition of IgG1 and complement on the glomerular basement membrane, as well as IgG4. In patients with autoimmune nodopathies associated with anti-CNTN1 and anti-Caspr1 IgG4 antibodies, IgG1 subclass autoantibodies were present at their acute exacerbations and might have contributed to the axonal degeneration and glomerular injury. IgG1 disappeared with the cessation of disease progression, which indicates that the IgG1 subclass is a possible biomarker of disease activity.

First Application of Whole Genome Sequencing in Myelinated Retinal Nerve Fibers (MRNF)

First Application of Whole Genome Sequencing in Myelinated Retinal Nerve Fibers (MRNF)