Epidermal Nerve Fiber Research Articles

TS-HDS and FGFR3 antibodies in small fiber neuropathy and Dysautonomia.

The specificity of trisulfated heparin disaccharide/fibroblast growth factor receptor 3 (TS-HDS/FGFR3) antibodies in the diagnosis of autoimmune small fiber neuropathy (SFN) is unclear. This was a retrospective study of patients evaluated for SFN and dysautonomia in the Brigham and Women's Faulkner Hospital Autonomic Laboratory in 2019-2020. Associations were assessed between TS-HDS/FGFR3 antibodies and SFN markers, including epidermal nerve fiber density (ENFD), sweat gland nerve fiber density (SGNFD), and autonomic dysfunction assessed by Valsalva maneuver, deep breathing, sudomotor, and tilt testing. Of 322 patients; 28% had elevated anti-TS-HDS, 17% had elevated anti-FGFR3, 96% had autonomic dysfunction, 71% had abnormal ENFD, and 49% had abnormal SGNFD. TS-HDS/FGFR3 antibodies were present in patients with autonomic dysfunction irrespective of whether they had normal or abnormal skin biopsies unless ENFD/SGNFD were combined for anti-FGFR3 seropositivity. TS-HDS/FGFR3 antibodies are present in patients with evidence of autonomic dysfunction. Further studies are needed to document the clinical value of these antibodies in assessment of immune mediated dysautonomia.

Crisaborole prevents infiltration of neutrophils to suppress itch in a mouse model of atopic dermatitis

The phosphodiesterase-4 inhibitor crisaborole exerts an antipruritic effect and is effective for the treatment of mild-to-moderate atopic dermatitis. However, the mechanisms underlying the antipruritic effect of crisaborole are not completely understood. In this study, we tested whether crisaborole affects spontaneous itch-related behavior as well as neutrophil infiltration and epidermal nerve fiber density (ENFD) in the ovalbumin (OVA)-induced mouse model of atopic dermatitis. OVA treatment resulted in atopic-like skin lesions and spontaneous scratching, which was significantly inhibited by crisaborole treatment. OVA treatment significantly increased neutrophil infiltration and nonpeptidergic ENFD compared with vehicle-treated mice. Crisaborole significantly inhibited neutrophil infiltration without a significant effect on nonpeptidergic ENFD. In a cytokine array, crisaborole significantly decreased neutrophil chemokines, such as CXCL1, CXCL2, and CXCL5. Crisaborole may inhibit atopic dermatitis itch through inhibition of neutrophil infiltration and chemokine expression.

Rhinarium skin structure and epidermal innervation in selected mammals

The glabrous skin around the nostrils in mammals is called a rhinarium or planum nasale. Rhinarium skin has multiple epidermal domes that are generally assumed to form a tactile surface. The rhinarium is innervated by a branch of the trigeminal nerve which is associated with stimuli such as touch, chemical irritants and temperature. In this study, our aim was to correlate variation in rhinarium skin sensory innervation with different feeding behaviors while also covering a broad systematic spectrum. Using histological and immunohistological methods, we studied skin morphology, nerve fiber density and nerve fiber distribution in the rhinarium epidermal domes of four species: cow, ring-tailed lemur, brown bear, and dog, that all exhibit different feeding behaviors. All species share similar traits in rhinarium skin morphology, but glands were only found in cow rhinarium skin. The most substantial differences were observed in the innervation pattern. Mechanosensory skin organs were found only in the ring-tailed lemur. Dog epidermal domes possess a pronounced central dermal papilla containing a nerve bundle in its top, close to the skin surface. The abundance of free epidermal nerve fibers in epidermal domes of all species, suggest that the rhinarium skin is a sensory surface, that can be used to detect fine touch, chemical irritants or temperature. In the species where the whole epidermal dome was examined, the intraepidermal nerve fiber density is higher in the central part of the domes. The nerve distribution and the central positioning of a single gland duct in cow and the dermal papilla top organ in dog indicates that each epidermal dome can be considered a functional unit. The observed differences in innervation hint at different sensory functions of rhinaria in mammals that may be correlated to feeding behavior.

AUTOPHAGIC MYOPATHIES / MYOFIBRILLAR MYOPATHIES / DISTAL MYOPATHIES / POMPE DISEASE: P.11 Pain characteristics and involvement of small epidermal nerve fibers in patients with late onset Pompe disease (LOPD)

In Pompe disease (glycogen storage disease type II), the lysosomal α-glucosidase deficiency leads to pathological glycogen accumulation in muscle, but also in other tissues such as the peripheral nervous system. Since chronic pain has been reported in late onset Pompe disease (LOPD), we aimed to investigate the pain characteristics and whether small fiber affection may play a role in the mediation of pain. 32 patients with LOPD under enzyme replacement therapy (56% females; age 52.8 ±13.5 years, with duration from Pompe symptom onset 15.94± 10.19 years) were enrolled.

The analysis of epidermal nerve fibre spatial distribution improves the diagnostic yield of skin biopsy.

Small fibre neuropathy (SFN) diagnosis represents a challenge for neurologists. The diagnostic gold standard is intraepidermal nerve fibre (IENF) density, but in about 10-20% of patients with symptoms/signs and abnormalities on functional tests, it remains within normal range. We propose an adjunctive parameter to improve the efficiency of skin biopsy diagnosis. We recruited 31 patients with SFN symptoms/signs, normal nerve conduction study, abnormal quantitative sensory testing and normal IENF density. We also included 31 healthy controls and 31 SFN patients with reduced IENF density as control groups. We measured the distance between consecutive IENFs in the three groups. Mean inter-fibre distances did not differ between patients with normal counts and healthy controls (66.7±14.5μm vs. 76.7±13.4μm; P=0.052), while the relative standard deviation was significantly (P<0.001) higher in patients (79.3±29.9) compared to controls (51.6±12.2). Using ROC analysis, we identified an inter-fibre distance of 350µm as the measure that better differentiated patients from controls (AUC=0.85, sensitivity: 74%, specificity: 94%). At least one such segment was also observed in all patients with reduced IENF count. Irregular spatial distribution is an SFN intrinsic feature preceding actual nerve loss. The presence of a stretch of denervated epidermis longer than 350µm is a parameter able to increase the diagnostic efficiency of skin biopsy.

255 Keratinocytes isolated from dark or light pigmented skin showed different degrees of tight junction impairment after PAR2 activation in-vitro

Protease activated receptor 2 (PAR2) is a transmembrane receptor with a tethered extracellular amino-terminus small peptide which acts as an activating ligand after cleavage. In the skin, PAR2 has extensively documented effects in promoting Th2-inflammation, skin barrier impairment and pruritus. Increased PAR2 expression was found in epidermal nerve fibers and keratinocytes in Atopic Dermatitis (AD) skin. In this study we aim to investigate the effect of PAR2 on Tight Junction (TJ) function and composition in primary human keratinocytes (PHK) isolated from dark or light pigmented foreskin. PHK were differentiated in high-Ca+2 media in the presence of the selective PAR2 agonist (SLIGKV-NH2) or reverse peptide as control. TJ integrity was assessed by trans-epithelial electrical resistance (TEER) and permeability to Na-Fluorescein. Expression of PAR2 and TJ components was evaluated at the RNA level. We confirmed greater expression of PAR2 in dark vs light-PHK. Both dark and light PHK differentiating in the context of PAR2 activation (100 μM) had a reduced TJ function resulting in reduced TEER and increased permeability to Na-Fluorescein (p≤0.05, n=5/each group). However, the degree of perturbation was greater for light-PHK as it compared to dark-PHK. Reduction in TEER after PAR2 activation was 40.8% in light-PHK vs 16.6% in dark-PHK (AUC 72-144 hours, p=0.01, n=5/each group). Also, a dose response effect was observed only in light-PHK, with significant TEER reduction after 50 μM PAR2 (p=0.03 at 120 hours). Notably, we observed a greater effect of PAR2 activation on the downregulation of CLDN1 and occludin mRNA in light-PHK. Our data highlights differences between keratinocytes of different ethnic backgrounds in TJ regulation through PAR2 activation. As we transition toward a better understating of AD phenotype, it is mandatory to keep in consideration and investigate intrinsic ethnic difference in skin barrier regulation that could be relevant to AD pathogenesis/treatment.

176 Comparative analysis of pruritus and intraepidermal nerve fiber density in atopic dermatitis and bullous pemphigoid

Chronic pruritus significantly impacts quality of life and is a unifying symptom in patients with the inflammatory skin diseases bullous pemphigoid (BP) and atopic dermatitis (AD). Limited data are available related to neurophysiologic mechanisms underlying both pruritic conditions. Five patients with BP (n=2) or AD (n=3) were followed over a 6-month period while receiving treatment. Disease severity was calculated with the BP Disease Area Index for BP patients or the Eczema Area and Severity Index (EASI) and SCORing Atopic Dermatitis (SCORAD) for AD patients. Itch intensity was measured using the ItchyQuant self-reported pruritus severity scale. Alterations in intraepidermal nerve fiber density (IENFD) were compared between BP patients, AD patients, and healthy controls (HC) (n=7). Severity scores for patients at baseline ranged from: 11-24 (BPDAI), 0-7.4 (EASI) and 14.91-62.16 (SCORAD). Itch intensity was not altered between baseline and 6-month follow-up (mean 5.2 at both time points). Both AD and BP demonstrated a decreased IENFD compared with HC (AD 4.04 fibers/mm, BP 6.95 fibers/mm, HC 9.34 fibers/mm) at baseline. While there was no significant difference between IENFD in AD and BP at baseline, there was a significant increase in IENFD in both conditions noted at 6-month follow-up, respectively (AD 4.0 fibers/mm, BP 6.9 fibers/mm vs AD 7.4 fibers/mm, BP 11.9 fibers/mm, p=0.002). These findings suggest that neuroanatomical alterations of epidermal nerve fibers seen in chronic pruritus may be a common phenomenon in seemingly divergent inflammatory skin diseases and reversible with appropriate treatment. Future studies to elucidate mechanistic details related to changes in IENFD may inform potential novel therapeutics.

Topical Delivery of Muscarinic Receptor Antagonists Prevents and Reverses Peripheral Neuropathy in Female Diabetic Mice.

Muscarinic antagonists promote sensory neurite outgrowth in vitro and prevent and/or reverse multiple indices of peripheral neuropathy in rodent models of diabetes, chemotherapy-induced peripheral neuropathy, and HIV protein-induced neuropathy when delivered systemically. We measured plasma concentrations of the M1 receptor-selective muscarinic antagonist pirenzepine when delivered by subcutaneous injection, oral gavage, or topical application to the skin and investigated efficacy of topically delivered pirenzepine against indices of peripheral neuropathy in diabetic mice. Topical application of 2% pirenzepine to the paw resulted in plasma concentrations 6 hours postdelivery that approximated those previously shown to promote neurite outgrowth in vitro. Topical delivery of pirenzepine to the paw of mice with streptozotocin-induced diabetes dose-dependently (0.1%-10.0%) prevented tactile allodynia, thermal hypoalgesia, and loss of epidermal nerve fibers in the treated paw and attenuated large fiber motor nerve conduction slowing in the ipsilateral limb. Efficacy against some indices of neuropathy was also noted in the contralateral limb, indicating systemic effects following local treatment. Topical pirenzepine also reversed established paw heat hypoalgesia, whereas withdrawal of treatment resulted in a gradual decline in efficacy over 2-4 weeks. Efficacy of topical pirenzepine was muted when treatment was reduced from 5 to 3 or 1 day/wk. Similar local effects were noted with the nonselective muscarinic receptor antagonist atropine when applied either to the paw or to the eye. Topical delivery of muscarinic antagonists may serve as a practical therapeutic approach to treating diabetic and other peripheral neuropathies. SIGNIFICANCE STATEMENT: Muscarinic antagonist pirenzepine alleviates diabetic peripheral neuropathy when applied topically in mice.

Diagnostic Accuracy of Electrochemical Skin Conductance in the Detection of Sudomotor Fiber Loss.

Background: Small fiber neuropathy (SFN) is a common health problem. SFN is associated with loss of small fibers, either sensory, autonomic or both. Reduced autonomic sudomotor sweat gland nerve fiber density (SGNFD) and sensory epidermal nerve fiber density (ENFD) can be seen in SFN. Electrochemical skin conductance (ESC) is a non-invasive test for measurement of sudomotor function. This study evaluated the diagnostic accuracy of ESC to detect abnormal SGNFD and ENFD.Methods: This was a retrospective blinded study of participants referred for evaluation of SFN. The primary outcome measure was the specificity and sensitivity of ESC to diagnose loss of small fibers using SGNFD and ENFD as reference tests. The secondary outcome measures were the correlation between ESC and neuropathy severity, pain, and autonomic clinical scales.Results: Two hundred ten patients were enrolled in the study, age (mean ± sd) 45.5 ± 16.1 years, men/women = 52/158. ESC adjusted for weight (ESC/kg) was reduced in subjects with abnormally low SGNFD (normal/abnormal, ESC/kg = 1.19 ± 0.31/0.94 ± 0.37 μS/kg, p < 0.0001) and abnormally low ENFD (normal/abnormal ESC/kg 1.20 ± 0.37/1.04 ± 0.33 μS/kg, p < 0.0011). ESC/kg correlated with SGNFD (ρ = 0.39, p < 0.0001) and ENFD (ρ = 0.47, p < 0.0001). ESC/kg did not correlate with symptom scales. ESC/kg had 64% sensitivity and 77% specificity (ROC 0.73, p = 0.0001) to predict abnormal SGNFD and 69% sensitivity and 55% specificity (ROC 0.63, p = 0.0017) to predict abnormal ENFD. In comparison, SGNFD had 50.1% sensitivity and 85.1% specificity to predict abnormal ENFD (ROC 0.69, p = 0.0001).Conclusion: ESC/kg has modest accuracy to detect SGNFD loss. ESC may be a useful test in characterization of small fiber neuropathy.

Lack of relationship between epidermal denervation by capsaicin and incisional pain behaviours: A laser scanning confocal microscopy study in rats.

Spontaneous pain after surgical incision is a significant problem for most post-operative patients. Pain management that relies on opioids is hindered by numerous side effects, fuelling interest in non-opioid alternatives and multimodal approaches. Subcutaneous capsaicin infiltration has shown potential for reducing post-operative pain, but there are unanswered questions about safety and possible side effects. In adult rats, we characterized the analgesic effects of pre-operative capsaicin infiltration into the skin prior to plantar incision and assessed wound healing and epidermal innervation. The surgical site on the plantar surface of the rat hind paw was infiltrated with 1% capsaicin or vehicle 30min or 1week prior to surgical incision. Spontaneous and evoked pain behaviours were assessed. Digital images of incised hind paws were used to quantify the surface area of the wound after suture removal. Epidermal nerve fibre quantification was performed on peri-incisional tissue biopsies. Intraplantar administration of capsaicin 30min before surgical incision attenuated spontaneous pain behaviours, heat hyperalgesia, epidermal innervation, but it did not alter the rate of wound healing. Incisional pain hypersensitivity returned to baseline 2weeks post-incision, at a time when no recovery of epidermal innervation is observed. Subcutaneous infiltration of capsaicin prior to surgical incision attenuated incision-induced pain behaviours and reduced epidermal innervation around the incision site. The long-lasting epidermal denervation by capsaicin had no impact in the rate of wound healing and recovery from pain behaviours. Pre-operative capsaicin infiltration attenuated spontaneous pain-like behaviour and prevented the development of heat hyperalgesia following plantar skin incision. While capsaicin caused long-lasting and widespread loss of epidermal and dermal nerve fibres, there was no measurable impact on the rate of wound healing. Pre- or intra-operative infiltration of capsaicin into surgical sites could act as a safe prophylactic for post-operative pain and reduce the need for opioids during recovery.

Clinical spectrum of BICD2 mutations

Mutations in the BICD2 gene cause autosomal dominant lower extremity-predominant spinal muscular atrophy 2A (SMALED2A), a condition that is associated with a specific pattern of thigh and calf muscle involvement when studied by magnetic resonance imaging (MRI). Patients may present minor clinical sensory impairment, but objective sensory involvement has yet to be demonstrated. We collected clinical data from 11 patients from five different families carrying mutations in BICD2. Genetic diagnosis was achieved using gene panel testing and skin biopsies were taken from two patients to study the epidermal nerve fiber density. In the studied patients, three new pathogenic mutations were detected as well as the already defined pathogenic p.Ser107Leu mutation. The most frequent clinical picture was characterized by lower-limb weakness in combination with foot deformities. One patient manifested clinical and electrophysiological sensory impairment, and the epidermal nerve fiber density study of another patient revealed the existence of a small-fiber neuropathy. Muscle MRI showed a common pattern of fat deposition including selective involvement of gluteus medius and minimus at the pelvic level, the anterior compartment of the thigh and the posterior compartment of the calf, with only mild or no involvement of the intrinsic foot muscles. We report three new pathogenic mutations in the BICD2 gene. Muscle MRI confirms the existence of a selective pattern of thigh and leg muscle involvement in SMALED2A, providing additional information regarding pelvic and foot muscles. Moreover, our results raise the possibility of sensory involvement in the disease.

Three‐dimensional neuroanatomy of the intraepidermal nervous system

Intra-epidermal nerve fibers (IENFs) are presumed to comprise mainly of itch-transmitting nerve fibers, and variations in their density have been studied in itch disorders; epidermal nerve fiber density is also a criterion in diagnosing small fiber neuropathy in clinical neurological practice. IENFs are typically identified with 2-dimensional (2D) histological slides, but 2D sections do not accurately represent nerves, which branch out in three-dimensions (3D).

Hyaluronic Acid-Povidone-Iodine Compound Facilitates Diabetic Wound Healing in a Streptozotocin-Induced Diabetes Rodent Model

Sir: We read with great interest the article entitled “Hyaluronic Acid-Povidone-Iodine Compound Facilitates Diabetic Wound Healing in a Streptozotocin-Induced Diabetes Rodent Model” by Dr. Chen et al.,1 published in the May 2019 issue of Plastic and Reconstructive Surgery. The authors found that higher-molecular-weight hyaluronic acid plus povidone-iodine complex dressing could facilitate diabetic wound healing, which provided a new idea for treating diabetic foot ulcer in clinical practice. Inspired by the authors, we would like to express our opinions on the research of diabetic wound healing. The diabetic foot ulcer represents a prevalent complication of diabetes mellitus and it is more common in people with type 2 diabetes.2 Streptozotocin can selectively damage pancreatic β cells and has been reported to induce both insulin-dependent diabetes mellitus (type 1) and non–insulin-dependent diabetes mellitus (type 2). Type 1 was believed to be induced by a single streptozotocin injection, whereas type 2 has to be induced by a low-dose streptozotocin injection following high-fat diet feeding.3 However, in this article, we noticed that the authors used the diabetic animal model induced by a single injection of streptozotocin, which should be interpreted as type 1. Although the blood glucose level was higher than normal, it cannot reflect the characteristics of type 2 diabetes mellitus with insulin resistance and relative insulin deficiency. Thus, the results of this study may need to be further validated on a specific type 2 diabetic animal model. On the other hand, the authors tested some immunohistochemical indices, such as Ki67, CD45, and vascular endothelial growth factor, to explain the effect of higher-molecular-weight hyaluronic acid plus povidone-iodine compound treatment on cellular proliferation, inflammatory response, and angiogenesis. The early sign of diabetic foot ulcer is peripheral sensory neuropathy caused by the damage of tiny blood vessels in the legs. Thus, it would be better to further test indicators such as substance P and nerve growth factor for epidermal and dermal nerve fibers and clarify whether the therapy has some positive effect on modulating nerve fibers in diabetic wounds. All in all, we appreciate that the authors suggest a new method for the treatment of diabetic foot ulcer. The results of this method used in diabetic patients are worth expecting. DISCLOSURE The authors declare that they have no conflicts of interest. No funding was received for this communication. Sisi Luan, M.D.Department of EndocrinologyShandong Provincial Hospital affiliated to Shandong UniverstiySchool of MedicineShandong UniversityJinan, Shandong, China Chenglong Wang, M.D.Department of Aesthetic and Reconstructive Breast SurgeryPlastic Surgery HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing, China

Interacting cluster point process model for epidermal nerve fibers

We propose an interacting cluster model for the spatial distribution of epidermal nerve fibers (ENF). The model consists of a spatial process of parent points modeling the base points of nerve fiber bundles. To each base point there is an offspring point process of fibers end points associated. The parent process is, possibly, inhibited by fiber endings that belong to different base bundles. The fibers themselves have random length and spatial orientation. We consider a non-orphan process where we can connect each offspring to a parent. We examine the processes that can be described with our model, how coefficient estimation can be performed under the Bayesian paradigm via Markov chain Monte Carlo methods, and detail approaches for the implementation of efficient MCMC sampling schemes. We study the performance of the estimation procedure through a simulation study. An application to data from skin blister biopsy images of ENFs is presented.

The capsaicin receptor TRPV1 is the first line defense protecting from acute non damaging heat: a translational approach

BackgroundPain is the vital sense preventing tissue damage by harmful noxious stimuli. The capsaicin receptor TRPV1 is activated by noxious temperatures, however, acute heat pain is only marginally affected in mice after TRPV1 knockout but completely eliminated in mice lacking TRPV1 positive fibers. Exploring contribution of candidate signal transduction mechanisms to heat pain in humans needs translational models.MethodsWe used focused, non-damaging, short near-infrared laser heat stimuli (wavelength 1470/1475 nm) to study the involvement of TRPV1-expressing nerve fibers in the encoding of heat pain intensity. Human psychophysics (both sexes) were compared to calcium transients in native rat DRG neurons and heterologously expressing HEK293 cells.ResultsHeating of dermal and epidermal nerve fibers in humans with laser stimuli of ≥ 2.5 mJ (≥ 25 ms, 100 mW) induced pain that increased linearly as a function of stimulus intensity in double logarithmic space across two orders of magnitude and was completely abolished by desensitization using topical capsaicin. In DRG neurons and TRPV1-expressing HEK cells, heat sensitivity was restricted to capsaicin sensitive cells. Strength duration curves (2–10 ms range) and thresholds (DRGs 0.56 mJ, HEK cells 0.52 mJ) were nearly identical. Tachyphylaxis upon repetitive stimulation occurred in HEK cells (54%), DRGs (59%), and humans (25%).ConclusionTRPV1-expressing nociceptors encode transient non-damaging heat pain in humans, thermal gating of TRPV1 is similar in HEK cells and DRG neurons, and TRPV1 tachyphylaxis is an important modulator of heat pain sensitivity. These findings suggest that TRPV1 expressed in dermal and epidermal populations of nociceptors serves as first line defense against heat injury.

Exosomes Derived From Schwann Cells Ameliorate Peripheral Neuropathy in Type 2 Diabetic Mice.

Schwann cell-derived exosomes communicate with dorsal root ganglia (DRG) neurons. The current study investigated the therapeutic effect of exosomes derived from healthy Schwann cells (SC-Exos) on diabetic peripheral neuropathy (DPN). We found that intravenous administration of SC-Exos to type 2 diabetic db/db mice with peripheral neuropathy remarkably ameliorated DPN by improving sciatic nerve conduction velocity and increasing thermal and mechanical sensitivity. These functional improvements were associated with the augmentation of epidermal nerve fibers and remyelination of sciatic nerves. Quantitative RT-PCR and Western blot analysis of sciatic nerve tissues showed that SC-Exo treatment reversed diabetes-reduced mature form of miRNA (miR)-21, -27a, and -146a and diabetes-increased semaphorin 6A (SEMA6A); Ras homolog gene family, member A (RhoA); phosphatase and tensin homolog (PTEN); and nuclear factor-κB (NF-κB). In vitro data showed that SC-Exos promoted neurite outgrowth of diabetic DRG neurons and migration of Schwann cells challenged by high glucose. Collectively, these novel data provide evidence that SC-Exos have a therapeutic effect on DPN in mice and suggest that SC-Exo modulation of miRs contributes to this therapy.

Diagnostic utility of small fiber analysis in skin biopsies from children with chronic pain.

Small fiber neuropathies (SFN) are associated with a reduction in quality of life. In adults, epidermal nerve fiber density (END) analysis is recommended for the diagnosis of SFN. In children, END assessment is not often performed. We analyzed small nerve fiber innervation to elucidate the potential diagnostic role of skin biopsies in young patients with pain. Epidermal nerve fiber density and sudomotor neurite density (SND) were assessed in skin biopsies from 26 patients aged 7 to 20 years (15 female patients) with unexplained chronic pain. The results were compared with clinical data. Epidermal nerve fiber density was abnormal in 50% and borderline in 35% of patients. An underlying medical condition was found in 42% of patients, including metabolic, autoimmune, and genetic disorders. Reduction of epidermal nerve fibers can be associated with treatable conditions. Therefore, the analysis of END in children with pain may help to uncover a possible cause and guide potential treatment options.

Small Fibre Neuropathy in Parkinson's Disease: Comparison of Skin Biopsies from the More Affected and Less Affected Sides.

We assessed small nerve fibre degeneration and regeneration in more and less affected sides in Parkinson’s disease (PD). Bilateral skin biopsies from 23 PD patients were immunostained for PGP9.5 for Intraepidermal Nerve Fibre Density (IENFD) and GAP-43 for mean axonal length (MAL), total epidermal (TNFL) and subepidermal nerve fibre length (SKTNFL). IENFD (p < 0.001) and SKTNFL (p < 0.001) were lower, whilst MAL (p < 0.001) and TNFL (p < 0.05) were higher in more affected versus less affected side. These results suggest increased small nerve fibre degeneration accompanied by enhanced nerve regeneration on the side more affected by PD and GAP-43 usefulness in skin biopsy assessment.

Effectively treating painful peripheral neuropathy: A study of six cases

Patients need an effective treatment to combat the harm painful peripheral neuropathy (PPN) inflicts on them. Experts describe our current treatments as “inadequate,” “frustrating and maybe even appalling” while claiming that “nerves in patients with neuropathy are irreversibly damaged.” Thus, Regenerating nerves, Reducing pain, and Restoring function without side effects defines a truly effective treatment. Odell and Sorgnard brilliantly developed CET (Combined Electrochemical Treatment) to effectively treat neuropathy. A retrospective outpatient study using CET on six patients with PPN did not require Institutional Review Board approval, but did receive consent from each of the treated patients. Epidermal Nerve Fiber Density (ENFD) biopsies were done before and after treatment. The highest pain scores and functioning indexes were recorded during the treatment, at the end of treatment and when last seen. Changes in medication use and side effects were recorded. Five of six patients were followed for an average of 26 months after ending treatment and one lost to follow-up. On average, five of six (83%) had a 91% increase in their nerve fibers. The average patient reduced their pain 75% at the end of treatment and 81% when last seen, while improving their function by 60% at the end of treatment and 65% when last seen. Four of five patients on medication for PPN stopped one or more of these. None had side effects. These results prove that CET, which can easily be used in any office that treats neuropathy, meets the definition of an effective treatment for PPN.

Therapeutic Effect of Y-27632 on Tumorigenesis and Cisplatin-Induced Peripheral Sensory Loss through RhoA-NF-κB.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of cancer therapy that frequently requires a reduction or cessation of treatments and negatively impacts the patient's quality of life. There is currently no effective means to prevent or treat CIPN. In this study, we developed and applied CIPN in an immunocompetent, syngeneic murine Lewis Lung Carcinoma (LLCab) model that enabled the elucidation of both tumor and host responses to cisplatin and treatments of Y-27632, a selective inhibitor of Rho kinase/p160ROCK. Y-27632 not only preserved cisplatin's efficacy toward tumor suppression but also the combination treatment inhibited tumor cell proliferation and increased cellular apoptosis. By alleviating the cisplatin-induced loss of epidermal nerve fibers (ENFs), Y-27632 protected tumor-bearing mice from cisplatin-induced reduction of touch sensation. Furthermore, quantitative proteomic analysis revealed the striking cisplatin-induced dysregulation in cellular stress (inflammation, mitochondrial deficiency, DNA repair, etc.)-associated proteins. Y-27632 was able to reverse the changes of these proteins that are associated with Rho GTPase and NF-κB signaling network, and also decreased cisplatin-induced NF-κB hyperactivation in both footpad tissues and tumor. Therefore, Y-27632 is an effective adjuvant in tumor suppression and peripheral neuroprotection. These studies highlight the potential of targeting the RhoA-NF-κB axis as a combination therapy to treat CIPN. IMPLICATIONS: This study, for the first time, demonstrated the dual antineoplastic and neuroprotective effects of Rho kinase/p160ROCK inhibition in a syngeneic immunocompetent tumor-bearing mouse model, opening the door for further clinical adjuvant development of RhoA-NF-κB axis to improve chemotherapeutic outcomes.