Innervation Of Glands Research Articles

What is the Vagal-Adrenal Axis?

Some recent publications have used the term "vagal-adrenal axis" to account for mechanisms involved in the regulation of inflammation by electroacupuncture. This concept proposes that efferent parasympathetic nerve fibers in the vagus directly innervate the adrenal glands to influence catecholamine secretion. Here, we discuss evidence for anatomical and functional links between the vagi and adrenal glands that may be relevant in the context of inflammation and its neural control by factors, including acupuncture. First, we find that evidence for any direct vagal parasympathetic efferent innervation of the adrenal glands is weak and likely artifactual. Second, we find good evidence that vagal afferent fibers directly innervate the adrenal gland, although their function is uncertain. Third, we highlight a wealth of evidence for indirect pathways, whereby vagal afferent signals act via the central nervous system to modify adrenal-dependent anti-inflammatory responses. Vagal afferents, not efferents, are thus the likely key to these phenomena.

Asymmetries of Left and Right Adrenal Glands in Neural Innervation and Glucocorticoids Production.

The adrenal gland is paired peripheral end organs of the neuroendocrine system and is responsible for producing crucial stress hormones from its two functional compartments, the adrenal cortex, and the adrenal medulla under stimuli. Left-right asymmetry in vertebrates exists from the central nervous system to peripheral paired endocrine glands. The sided difference in the cerebral cortex is extensively investigated, while the knowledge of asymmetry of paired endocrine glands is still poor. The present study aims to investigate the asymmetries of bilateral adrenal glands, which play important roles in stress adaptation and energy homeostasis via steroid hormones produced from the distinct functional zones. Left and right adrenal glands from male C57BL/6J mice were initially histologically analyzed, and high-throughput RNA sequencing was then used to detect the gene transcriptional difference between left and right adrenal glands. Subsequently, the enrichment of functional pathways and ceRNA regulatory work was validated. The results demonstrated that the left adrenal gland had higher tissue mass and levels of energy expenditure, whereas the right adrenal gland appeared to be more potent in glucocorticoid secretion. Further analysis of adrenal stem/progenitor cell markers predicted that Shh signaling might play an important role in the left-right asymmetry of adrenal glands. Of the hub miRNAs, miRNA-466i-5p was identified in the left-right differential innervation of the adrenal glands. Therefore, the present study provides evidence that there are asymmetries between the left and right adrenal glands in glucocorticoid production and neural innervation, in which Shh signaling and miRNA-466i-5p play an important role.

AURICULOTEMPORAL NERVE AND FREY'S SYNDROME

Background: The auriculotemporal nerve is one of the main branches of the mandibular nerve. It provides sensory innervation to the auricle, the scalp in the temporal region, the temporomandibular joint and part of the dura mater, the parasympathetic innervation of the parotid salivary gland, as well as the external surface of the tympanic membrane, and the sympathetic innervation of the sweat glands and of the blood vessels passing through the parotid gland. Its interruption during surgical interventions or trauma can results in its most common disease - Frey's syndrome. This article is an overview and is based on 23 foreign scientific works - articles published in refereed and renowned scientific publications and anatomy atlases by world-renowned and proven specialists in their field. Review Results: The auriculotemporal nerve is a sensory nerve which includes secretory parasympathetic vasomotor sympathetic fibers coming from the otic ganglion. It is a branch of the mandibular nerve (V3). Its five terminal nerve branches are front auricular branches, branches for the external auditory canal, branches for the temporomandibular joint, branches for the parotid gland and superficial temporal branches. Frey's syndrome occurs when the auriculotemporal nerve is cut or injured proximal to the site of separation of the branches for the parotid gland or are severed themselves. The clinical picture characteristic of Frey's syndrome includes redness, sweating, warmth and itching in the area of innervation of the nerve and less often pain. Conclusion: Knowledge of the anatomy of the auriculotemporal nerve and Frey's syndrome are essential for understanding its nature and stand on the basis of its prevention.

Validation of the Body Scan®, a new device to detect small fiber neuropathy by assessment of the sudomotor function: agreement with the Sudoscan®.

Sudomotor dysfunction is one of the earliest manifestations of small fiber neuropathy (SFN), reflecting the alteration of sympathetic C fiber innervation of the sweat glands. Among other techniques, such innervation can be assessed by measuring electrochemical skin conductance (ESC) in microsiemens (μS). In this study, ESC was measured at the feet to detect distal SFN. For this objective, the performance of a new device, the Body Scan® (Withings, France), intended for home use, was compared with that of a reference device, the Sudoscan® (Impeto Medical, France), which requires a hospital setting. In patients with diabetes with or without neuropathy or non-diabetic patients with lower-limb neuropathy, the diagnostic performance of the Body Scan® measurement was assessed by calculating its sensitivity (Se) and specificity (Sp) to detect at least moderate SFN (Se70 and Sp70), defined by a value of feet ESC ≤ 70 μS and > 50 μS on the Sudoscan® measure, or severe SFN (Se50 and Sp50), defined by a value of feet ESC ≤ 50 μS on the Sudoscan® measure. The agreement between the two devices was assessed with the analysis of Bland-Altman plots, mean absolute error (MAE), and root mean squared error (RMSE) calculations. The repeatability of the measurements was also compared between the two devices. A total of 147 patients (52% men, mean age 59 years old, 76% diabetic) were included in the analysis. The sensitivity and specificity to detect at least moderate or severe SFN were: Se70 = 0.91 ([0.83, 0.96]), Sp70 = 0.97 ([0.88, 0.99]), Se50 = 0.91 ([0.80, 0.98]), and Sp50 = 0.99 ([0.94, 1]), respectively. The bias and 95% limits of agreement were 1.5 [-5.4, 8.4]. The MAE was 2.9 and the RMSE 3.8. The intra-sample variability was 2.0 for the Body Scan® and 2.3 for the Sudoscan®. The ESC measurements provided by the Body Scan® were in almost perfect agreement with those provided by the reference device, the Sudoscan®, which validates the accuracy of the Body Scan® for the detection of SFN. By enabling simple, rapid, and autonomous use by the patient at home, this new technique will facilitate screening and monitoring of SFN in daily practice. ClinicalTrials.gov, identifier NCT05178459.

Sweat gland nerve fiber density and association with sudomotor function, symptoms, and risk factors in adolescents with type 1 diabetes

PurposeTo quantify sweat gland nerve fiber density in adolescents with diabetes. Additionally, to investigate associations between sudomotor innervation, sweat responses, and possible risk factors for sudomotor neuropathy.MethodsCross-sectional study where 60 adolescents with type 1 diabetes (duration > 5 years) and 23 control subjects were included. Clinical data, quantitative sudomotor axon reflex test, and skin biopsies were obtained. Skin tissue was immunostained and imaged by confocal microscopy. Quantification of the sweat gland volume and three-dimensional reconstruction of the nerve fibers was performed using a design-unbiased technique.ResultsAdolescents with diabetes had a significant reduction of maximum and mean values of nerve fiber length and nerve fiber density in sweat glands compared to controls (p values < 0.05). No association between nerve fiber density and sweat responses was found (p = 0.21). In cases with reduced sweat gland nerve fiber length, nerve fiber density, and volume, the sweat response was reduced or absent. Height, systolic blood pressure, time in hypoglycemia, and total daily and basal/total insulin dose were positively correlated to sweat response, while low-density lipoprotein, and HbA1c were negatively correlated with sweat response (p values < 0.05). Other microvascular complications and high cholesterol levels increased the relative risk for reduced sweat gland nerve fiber density.ConclusionOur findings of reduced sweat gland innervation in a selected group of adolescents add new knowledge about the structural changes that occur in autonomic nerves due to diabetes. Evaluating both the sweat gland innervation and sweat gland volume was important for understanding the association with sweat responses. Further research is needed to understand its clinical relevance.

Research progress on the pathogenesis of diabetes-related dry eye

In recent years, with the further understanding of medical circles on diabetic ocular complications, the ocular surface abnormalities of diabetes has drawn increasing concerns. Nearly 50% of diabetic patients suffer from dry eye symptoms. The main manifestations of diabetes related dry eye were abnormal lacrimal secretion, poor lacrimal stability, decreased corneal sensitivity, persistent corneal epithelial defect and even corneal ulcer, which were mainly related to the changes of structure and function of lacrimal gland, the decrease of goblet cells in conjunctiva, the abnormality of meibomian gland function and the degeneration of corneal nerve caused by diabetes. In this paper, we summarized and analyzed the recent research progress on the effect of diabetes on lacrimal film, corneal innervation and lacrimal gland innervation, and the correlation between oxidative stress, advanced glycation end products and diabetes-related dry eye, to explore the pathogenesis of diabetes-related dry eye and to provide reference for clinical diagnosis, treatment and research.

Innervation of the human minor salivary glands; immunohistochemical study for neurochemical substances

Distributions of choline acetyltransferase (ChAT), vasoactive intestinal polypeptide (VIP), dopamine β-hydroxylase (DBH), tyrosine hydroxylase (TH), neuropeptide Y (NPY) and the transient receptor potential cation channel subfamily V member 2 (TRPV2) were examined in the human minor salivary glands. ChAT-, VIP- and DBH-immunoreactive (-IR) nerve fibers were detected within nerve bundles and close to blood vessels and ducts in the salivary glands. Periacinar nerve fibers were commonly immunoreactive for ChAT in the Ebner’s gland but infrequently in other salivary glands. Periacinar VIP-IR nerve fibers were numerous in the palatal gland, moderate in the lingual gland and relatively rare in the labial and Ebner’s glands. Some TH-, NPY- and TRPV2-IR nerve fibers were also present around blood vessels and glandular acini in the palatal, lingual and Ebner’s glands. Neuronal cells in the vicinity of Ebner’s and lingual glands were immunoreactive for ChAT, VIP, TH and TRPV2. By confocal laser scanning microscopy, VIP- and ChAT-IR varicosities were located in the vicinity of myoepithelial and acinar cells in the minor salivary glands. The human minor salivary glands are probably innervated by parasympathetic and sympathetic nerves. Neurotransmitters including neuropeptides in these nerves are thought to be correlated to vasodilation and/or salivary secretion. Acetylcholine and VIP may regulate secretion of the saliva and its components in the salivary glands.

Small Fiber Pathology in CADASIL: Clinical Correlation With Cognitive Impairment.

This study investigated the cutaneous small fiber pathology of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and its clinical significance, that is, the NOTCH3 deposition in cutaneous vasculatures and CNS neurodegeneration focusing on cognitive impairment. Thirty-seven patients with CADASIL and 59 age-matched healthy controls were enrolled to evaluate cutaneous small fiber pathology by quantitative measures of intraepidermal nerve fiber density (IENFD), sweat gland innervation, and vascular innervation. Cognitive performance of patients with CADASIL was evaluated by a comprehensive neuropsychological assessment, and its association with small fiber pathology was tested using multivariable linear regression analysis adjusted for age and diabetes mellitus. We further assessed the relationships of IENFD with cutaneous vascular NOTCH3 ectodomain (NOTCH3ECD) deposition and biomarkers of neurodegeneration including structural brain MRI measures, serum neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau, and ubiquitin carboxy-terminal hydrolase L1. Patients with CADASIL showed reduced IENFD (5.22 ± 2.42 vs 7.88 ± 2.89 fibers/mm, p = 0.0001) and reduced sweat gland (p < 0.0001) and vascular (p < 0.0001) innervations compared with age-matched controls. Reduced IENFD was associated with impaired global cognition measured by Mini-Mental State Examination (B = 1.062, 95% CI = 0.370-1.753, p = 0.004), and this association remained after adjustment for age and diabetes mellitus (p = 0.043). In addition, IENFD in patients with CADASIL was associated with mean cortical thickness (Pearson r = 0.565, p = 0.0023) but not white matter hyperintensity volume, total lacune count, or total microbleed count. Reduced IENFD was associated with cutaneous vascular NOTCH3ECD deposition amount among patients harboring pathogenic variants in exon 11 (mainly p.R544C) (B = -0.092, 95% CI = -0.175 to -0.009, p = 0.031). Compared with those with normal cognition, patients with CADASIL with cognitive impairment had an elevated plasma NfL level regardless of concurrent small fiber denervation, whereas only patients with both cognitive impairment and small fiber denervation showed an elevated plasma GFAP level. Cutaneous small fiber pathology correlates with cognitive impairment and CNS neurodegeneration in patients with CADASIL, indicating a peripheral neurodegenerative process related to NOTCH3ECD aggregation.

Characterization of somatosensory neuron involvement in the SOD1G93A mouse model

SOD1G93A mice show loss of cutaneous small fibers, as in ALS patients. Our objective is to characterize the involvement of different somatosensory neuron populations and its temporal progression in the SOD1G93A mice. We aim to further define peripheral sensory involvement, analyzing at the same time points the neuronal bodies located in the dorsal root ganglia (DRG) and the distal part of their axons in the skin, in order to shed light in the mechanisms of sensory involvement in ALS. We performed immunohistochemical analysis of peptidergic (CGRP), non-peptidergic (IB4) fibers in epidermis, as well as sympathetic sudomotor fibers (VIP) in the footpads of SOD1G93A mice and wild type littermates at 4, 8, 12 and 16 weeks of age. We also immunolabeled and quantified neuronal bodies of IB4, CGRP and parvalbumin (PV) positive sensory neurons in lumbar DRG. We detected a reduction of intraepidermal nerve fiber density in the SOD1G93A mice of both peptidergic and non-peptidergic axons, compared with the WT, being the non-peptidergic the fewest. Sweat gland innervation was similarly affected in the SOD1G93A mouse at 12 weeks. Nonetheless, the number of DRG neurons from different sensory populations remained unchanged during all stages. Cutaneous sensory axons are affected in the SOD1G93A mouse, with non-peptidergic being slightly more vulnerable than peptidergic axons. Loss or lack of growth of the distal portion of sensory axons with preservation of the corresponding neuronal bodies suggest a distal axonopathy.

Nervous system and internal secretion. Collection of works of the morphological sector of the Institute for the study of the brain named after V. M. Bekhterev. P. 84. Price 3 rubles. Lenogiz, 1932

Prof. L. Ya. Pine s, whose name became known far beyond the borders of the USSR thanks to his outstanding work in the field of innervation of the endocrine glands, gives in the collection a generalization of the head. them by the sector of normal histological data on the innervation of the endocrine glands and a number of works by the employees of the sector that replenish this data. The collection contains a preface by Pines, 7 articles (L. Pines, Narovchatova, R. Maiman, I. Pis, M. Sheftel, B. Shapiro, M. Kurepin) and the minutes of the meetings of the morphology sector of the I-that of the brain for 1930/31 G.

Simultaneous Monitoring of ECG and EDA Using a Wearable Armband for Analyzing Sympathetic Nerve Activity

Simultaneous Monitoring of ECG and EDA Using a Wearable Armband for Analyzing Sympathetic Nerve Activity

Botulinum toxin usefulness in the treatment of drooling in childhood

Sialorrhea is defined as the involuntary excess of saliva in the mouth that exceeds the lip margin. This is not due to excessive saliva production but also to an alteration in the process of oral secretions that occurs mostly in people with neurological damage. Among the pathologies that can be treated with sialorrhea are Parkinson's disease, cerebral palsy, stroke, amyotrophic lateral sclerosis or facial paralysis, among others. It is a disabling symptom which, although sometimes is unnoticed and not always recorded, can lead to significant medical problems. Complications include the appearance of cavities, persistent cough, difficulty in eating, dermatitis, skin infections due to Candida Albicans or Staphylococcus Aureus cause d by persistent humidity, and even recurrent pneumonia and aspiration. Furthermore, it has been proved that it harms the patient social life, causing alterations in speech and diminishing their quality of life, sometimes even leading to social isolation. For the therapeutic management of sialorrhoea, there are currently different treatment alternatives. Oral motor training is postulated as a type of conservative therapy that, although it does not completely stop sialorrhoea, can reduce its clinical severity. Functional management is considered to be beneficial especially when is performed concomitantly with other types of treatment. However, these techniques has limited evidence and requires a capacity for understanding and patient participation that is not possible in all cases Pharmacological treatments, such as anticholinergics (glycopyrrolate or atropine), are the most widely used drugs, due to their mechanism of action: they block the parasympathetic innervation of the salivary glands. However, the reduction of side effects such as tachycardia, confusion, or urinary retention after taking this medication is not negligible. Other invasive techniques include radiotherapy of the salivary glands or surgery to remove the glands, ligation of the duct, or neurotomy of the tympanic nerve. This type of treatment, as it obtains irreversible results, is usually carried out when all other therapies fail. Currently, botulinum toxin is one of the most commonly used therapeutic procedures for the treatment of sialorrhea. Although its aesthetic use has historically been the best known, in recent years its therapeutic use has been consolidated by being introduced in numerous pathologies such as focal spasticity, dystonia or facial paralysis. It is a powerful neurotoxin, produced by the bacterium Clostridium, Botulinum, which reduces sialorrhoea by inhibiting the release of acetylcholine in the cholinergic neurosecretory junction of the salivary glands. The main objective of our study was to evaluate the efficacy of the treatment with botulinum toxin type A infiltrations under ultrasound control in children with sialorrhea treated at our Rehabilitation Unit between 2009 and 2019 and to analyse the factors associated with better results of the technique.

A Case of Mistaken Identity: Doubled Superior Cervical Ganglia

The sympathetic chain serves as a major hub for distribution of both sensory and motor innervation of smooth muscle, cardiac muscle and glands throughout the entire body. The sympathetic chain, along its course from the base of the skull to the tip of the coccyx, includes numerous ganglia that house cell bodies of postsynaptic neurons. The cervical portion of the sympathetic chain includes superior, middle, inferior/stellate and vertebral ganglia. As a group, these ganglia are subject to significant anatomical variation in their location and even presence. While the superior cervical ganglion appears to be the most consistent of these ganglia, there remains a discrepancy in the literature. Specifically, the superior cervical ganglion has been reported to be doubled but this appears to have been perpetuated without clear documentation. This discrepancy was brought to our attention during a detailed dissection of the retropharyngeal region that exposed the superior cervical ganglion and structures at the skull base, including what appeared to be a ganglion anterior to the carotid sheath. This dissection matched exactly the earliest report of a doubled superior cervical ganglion. However, histological examination revealed the mass anterior to the carotid sheath to be a retropharyngeal lymph node. Based on this finding, consistent with large-scale studies of the cervical sympathetic chain, we posit the original observation was of a lymph node and not a doubled superior cervical ganglion.

The nerve supply of the mammary gland

Proper development and functioning of the mammary gland depends not only on hormones, but also on the nervous system. The aim of this paper was to summarize the existing knowledge on the innervation of the mammary gland in various mammalian species, including domestic animals. In general, the pattern of innervation of this gland is similar in all studied species, i.e. large farm animals, rodents, dogs and beavers, as well as humans. Using the pan-neuronal marker of neural structures PGP-9.5, it was found that the mammary gland is well supplied with nerve fibres. Very rich innervation was discovered in the nipple, and less numerous nerve endings were found in the parenchyma. Nerve fibres supply the skin, especially the nipple, and many nerve terminals are associated with blood vessels and smooth muscles throughout the organ. Immunohistochemical investigations have made it possible to distinguish two major subpopulations of nerve fibres supplying the mammary gland. One of them consists of putative sensory fibres expressing CGRP, SP, GAL and/or PACAP, and the other is presumably composed of adrenergic axons containing TH, DBH, SOM and/or VIP. Studies on the sources of innervation of the mammary gland have confirmed assumptions about the nature of the nerve fibres and have revealed that they derive from the spinal ganglia (DRG) and sympathetic trunk ganglia (SChG). In the rat, mammary gland-projecting (MGP) neurons were also found in the nodose ganglion. So far, the rat and the pig have been tested most comprehensively for the sources of the mammary gland innervation. The MGP sensory neurons were observed ipsilaterally in several consecutive DRG, suggesting that the same neurons supply several successive glands. In the case of the SChG, it was found that MGP neurons are located, among others, in the L1-L4 ganglia, which constitute a specific „mammary gland nerve centre”. Previous studies on the sources of nerve supply to female reproductive organs have revealed that the SChG L1-L4 ganglia also contain nerve cells that project to the ovary, fallopian tube and uterus. Some clinical implications of the mammary gland innervation are also discussed.

Characterization of the innervation of the meibomian glands in humans, rats and mice

Aim of the present study was to identify the nerve structures of meibomian glands in humans, rats and mice into sympathetic, parasympathetic and sensory parts as well as their topographical relation with regard to the gland architecture.The upper and lower eyelids of humans, rats and mice were examined by means of immunohistochemistry and indirect immunofluorescence. Specimen were investigated with antibodies against vesicular acetylcholine transporter (VAChT), tyrosine hydroxylase (TH), nitric oxide synthase (NOS), and calcitonin gene-related peptide (CGRP). For overview and general identification of the nervous structures, protein gene product 9.5 (PGP 9.5) was used.PGP-immunoreactive nerve fibers were detectable in the interstitium of the meibomian glands, especially in the neighborhood to the basement membrane of the acini. The axons were positive for CGRP, VAChT, TH and NOS. In addition, the fluorescence labeling also revealed isolated nerve endings surrounding the duct system of the glands, especially along the main duct and in adjacent blood vessels.The density of the innervation of the meibomian glands and the detection of various neuropeptides suggest an influence of the nervous system on the function of the glands. To what extent these may play a role in the modulation of glandular function and the pathogenesis of dry eye disease, or perhaps even represent a possible therapeutic approach, needs further investigation.

Lacrimal Gland Postganglionic Innervation: Unveiling the Role of Parasympathetic and Sympathetic Nerves in Stimulating Tear Secretion

This commentary highlights the article by Jin etal that studied the regulation of lacrimal gland innervation by sympathetic and parasympathetic components.

Innovations in Electrodermal Activity Data Collection and Signal Processing: A Systematic Review.

The electrodermal activity (EDA) signal is an electrical manifestation of the sympathetic innervation of the sweat glands. EDA has a history in psychophysiological (including emotional or cognitive stress) research since 1879, but it was not until recent years that researchers began using EDA for pathophysiological applications like the assessment of fatigue, pain, sleepiness, exercise recovery, diagnosis of epilepsy, neuropathies, depression, and so forth. The advent of new devices and applications for EDA has increased the development of novel signal processing techniques, creating a growing pool of measures derived mathematically from the EDA. For many years, simply computing the mean of EDA values over a period was used to assess arousal. Much later, researchers found that EDA contains information not only in the slow changes (tonic component) that the mean value represents, but also in the rapid or phasic changes of the signal. The techniques that have ensued have intended to provide a more sophisticated analysis of EDA, beyond the traditional tonic/phasic decomposition of the signal. With many researchers from the social sciences, engineering, medicine, and other areas recently working with EDA, it is timely to summarize and review the recent developments and provide an updated and synthesized framework for all researchers interested in incorporating EDA into their research.

Unusual pathophysiological mechanisms of ptyalism in two horses

SummaryThis report outlines two cases of ptyalism that were not associated with oral conditions or primary dysphagia. The first, a 9‐year‐old Thoroughbred gelding, was associated with left‐sided peripheral vestibular disease and bone modelling around the left tympanic bulla. The second, a 7‐year‐old Dutch Warmblood mare, was associated with progressive bilateral laryngeal paralysis and a mediastinal T‐cell lymphoma. In Case 1, a neurological pathophysiology was proposed involving altered autonomic innervation of the salivary glands; whilst in Case 2, the mechanism remains unclear but may have involved mechanical compression of the intrathoracic oesophagus or stimulation of afferents within the vagus nerve. This case series highlights rare causes of ptyalism that have not been previously reported in the literature.

Ultrastructural mapping of salivary gland innervation in the tick Ixodes ricinus

The salivary gland of hard ticks is a highly innervated tissue where multiple intertwined axonal projections enter each individual acini. In the present study, we investigated the ultrastructural architecture of axonal projections within granular salivary gland type II and III acini of Ixodes ricinus female. Using immunogold labeling, we specifically examined the associations of SIFamide neuropeptide, SIFamide receptor (SIFa_R), neuropeptide pigment dispersing factor (PDF), and the invertebrate-specific D1-like dopamine receptor (InvD1L), with acinar cells. In both acini types, SIFamide-positive axons were found to be in direct contact with either basal epithelial cells or a single adlumenal myoepithelial cell in close proximity to the either the acinar duct or its valve, respectively. Accordingly, SIFa_R staining correlated with SIFamide-positive axons in both basal epithelial and myoepithelial cells. Immunoreactivity for both InvD1L and PDF (type II acini exclusively) revealed positive axons radiating along the acinar lumen. These axons were primarily enclosed by the adlumenal myoepithelial cell plasma membrane and interstitial projections of ablumenal epithelial cells. Our study has revealed the detailed ultrastructure of I. ricinus salivary glands, and provides a solid baseline for a comprehensive understanding of the cell-axon interactions and their functions in this essential tick organ.

Skin nerve pathology: Biomarkers of premanifest and manifest amyloid neuropathy.

Small-fiber sensory and autonomic symptoms are early presentations of familial amyloid polyneuropathy (FAP) with transthyretin (TTR) mutations. This study aimed to explore the potential of skin nerve pathologies as early and disease-progression biomarkers and their relationship with skin amyloid deposits. Skin biopsies were performed in patients and carriers to measure intraepidermal nerve fiber (IENF) density, sweat gland innervation index of structural protein gene product 9.5 (SGII[PGP9.5]) and peptidergic vasoactive intestinal peptide (SGII[VIP]), and cutaneous amyloid index. These skin pathologies were analyzed with clinical disability assessed by FAP stage score (stage 0-4) and compared to neurophysiological and psychophysical tests. There were 70 TTR-mutant subjects (22 carriers and 48 patients), and 66 cases were TTR-A97S. Skin nerve pathologies were distinct according to stage. In carriers, both skin denervation and peptidergic sudomotor denervation were evident: (1) IENF density was gradually reduced from stage 0 through 4, and (2) SGII(VIP) was markedly reduced from stage 1 to 2. In contrast, SGII(PGP9.5) was similar between carriers and controls, but it declined in patients from stage 2. Skin amyloids were absent in carriers and became detectable from stage 1. Cutaneous amyloid index was correlated with SGII(PGP9.5) and stage in a multivariate mixed-effect model. When all tests were compared, only IENF density, SGII(PGP9.5), and cutaneous amyloid index were correlated with stage, and IENF density had the highest abnormal rate in carriers. Biomarkers of sensory and sudomotor innervation exhibited a stage-dependent progression pattern, with sensory nerve degeneration as the early skin nerve pathology. Ann Neurol 2019;85:560-573.