Autonomic Nerve Fibers Research Articles

The Impact of Omega‐3 Fatty Acids on Cardiac Autonomic Nerve Fiber Innervation in High Fat‐Fed Mice

Peripheral neuropathy and cardiac autonomic neuropathy (CAN) are common and serious complications of diabetes, characterized by loss of peripheral nerves that innervate the skin and loss of parasympathetic and sympathetic nerves that innervate the heart, respectively. CAN is associated with increased risk of myocardial infarction and mortality, yet often goes undetected in patients. Both prediabetic and diabetic patients develop peripheral neuropathy and CAN, suggesting that the level of hyperglycemia at which peripheral neuropathy and CAN develop precedes the onset of diabetes. Although evidence from human and rodent studies indicate that omega-3-fatty acids prevent and/or reverse the development of peripheral neuropathy, the effects of omega-3-fatty acids on CAN has not been investigated. PURPOSE Assess the effects of omega-3-fatty acids on cardiac autonomic nerve fiber innervation in high fat diet-induced prediabetic mice. We hypothesize that omega-3 fatty acids will attenuate a reduction in cardiac autonomic nerve fiber innervation in high fat-fed mice. METHODS Male C57BL/6 mice were randomized into four diet groups (n = 12-14/group) for 14 weeks: 10% low fat fish oil (LFFO), 54% high fat-fish oil (HFFO), 10% low fat-lard (LFL), or 54% high fat-lard (HFL). The von Frey behavioral test for hindpaw mechanical sensitivity was used to characterize peripheral neuropathy at baseline then biweekly for 14 weeks. At study completion, fasting glucose and insulin values were used to calculate the homeostatic model assessment of insulin resistance (HOMA-IR). Mice were anesthetized, transcardially perfused with 1% PBS, and heart tissue was harvested and frozen in O.C.T. Heart was sectioned in three planes (anterior coronal, posterior coronal, and sagittal) and mounted on slides. Fluorescence immunohistochemistry was performed on heart cryosections using anti-choline acetyl-transferase and anti-tyrosine hydroxylase followed by Alexa Fluor secondary antibodies to visualize parasympathetic and sympathetic nerve fibers. For each mouse, nerve fibers were quantified on three slides (1 from each plane) and at least 3 areas with the highest nerve fiber density for each slide were examined. Nerve fiber density was determined using Nikon Elements and was calculated as the total length of all counted nerve fibers divided by the total area examined (µm/mm2). RESULTS Body weight, fasting insulin and glucose, and HOMA-IR were higher in HFL compared to all other groups. Fasting glucose was also higher in LFL compared to LFFO. Hindpaw withdrawal threshold was lower in HFL compared to HFFO, indicative of hindpaw hypersensitivity in HFL. CONCLUSIONS Omega-3 fatty acids prevented excess body weight, insulin resistance, elevated glucose, and hindpaw hypersensitivity in mice fed a high fat diet. Based on this data, we expect a diet rich in omega-3 fatty acids will attenuate cardiac autonomic nerve fiber denervation. Taken together, these findings would suggest that omega-3 fatty acids might hold therapeutic potential in the prevention of metabolic derangements as well as peripheral and CAN in individuals who consume a high fat, high calorie diet.

Цукровий діабет і артеріальна гіпертензія

В огляді проведений аналіз літературних джерел, присвячених сучасному стану проблеми цукрового діабету (ЦД) і артеріальної гіпертензії (АГ). За даними Всесвітньої організації охорони здоров’я, АГ та ЦД 2-го типу після ожиріння є одними з провідних чинників серцево-судинного ризику, які найбільш поширені серед населення світу. За останні 30 років поширеність АГ зменшилась до однієї четвертої частини населення світу, але захворюваність на ЦД зросла з 4,7 до 8,5%, і прогноз на майбутнє свідчить про подальший драматичний приріст. Покращення обізнаності, лікування та контролю цих захворювань є основною метою глобальної системи охорони здоров’я. Поширеність АГ у хворих на ЦД 2-го типу до трьох разів вища, ніж у пацієнтів без ЦД, а поєднання АГ і ЦД суттєво збільшує ймовірність розвитку серцево-судинних захворювань. Несприятливий взаємозв’язок цих двох станів, прискорюючи процеси атеросклерозу, може спричинити негативні патофізіологічні зміни серцево-судинної системи. Крім того, відомо, що кардіоваскулярна автономна нейропатія, яка виникає в результаті пошкодження вегетативних нервових волокон, що іннервують серце та судини, є вагомим ускладненням ЦД 2-го типу, особливо за наявності системної АГ. Зокрема, аналізуються питання, пов’язані із спільними патофізіологічними механізмами, основними системними та метаболічними чинниками, що можуть сприяти коморбідності ЦД і АГ. Наведені класифікація, особливості діагностики АГ, особливості оцінки ураження органів, опосередкованого АГ. Аналізуються питання, пов’язані з основними підходами до лікування артеріальної гіпертензії при цукровому діабеті; використанням блокаторів ренін-ангіотензинової системи, блокаторів кальцієвих каналів, тіазидних і тіазидоподібних діуретиків, блокаторів бета-адренергічних рецепторів, альфа-адреноблокаторів, антагоністів мінералокортикоїдних рецепторів; особливостями комбінованої терапії та лікування резистентної артеріальної гіпертензії.

Acute sensory inflammatory demyelinating polyneuropathy and central diabetes insipidus

Guillain-Barre syndrome (GBS) is characterized by acute, progressive monophasic course with a predominance of motor disorders in typical cases; it develops due to an aberrant immune response in some viral and bacterial infections. As ganglioside complexes are the direct cause of acute dysimmune neuropathy, it is assumed that the combined damage of peripheral nerves structure, and neurohypophysis and hypothalamus, may be based on similar immunopathogenetic mechanisms. Here we present the first case of a patient with diabetes insipidus and acute inflammatory dysimmune damage to sensory and autonomic peripheral nerve fibers due to secondary hypothalamic-pituitary system lesion. Due to the long-term persistence of arthralgias, accompanied by a low-grade fever and a single positive denatured DNA IgG antibodies test, atypical variant of GBS, hypophysitis, we differentiated the patient's condition with systemic rheumatic diseases, primary and secondary vasculitis. Those nosologies were not confirmed during the examination and observation; porphyrias and thyroid gland damage as etiological factors of nervous system damage were also excluded. This case report demonstrates the need for a prompt determination of the nature of the pathological process that causes damage to peripheral nerves' fibers and the neuroendocrine system to select an adequate treatment strategy.

Intrahepatic distribution of nerve fibers and alterations due to fibrosis in diseased liver.

Autonomic nerve fibers in the liver are distributed along the portal tract, being involved in the regulation of blood flow, bile secretion and hepatic metabolism, thus contributing to systemic homeostasis. The present study investigated changes in hepatic nerve fibers in liver biopsy specimens from patients with normal liver, viral hepatitis and non-alcoholic steatohepatitis, in relation to clinical background. The areal ratio of nerve fibers to the total portal area was automatically calculated for each sample. The nerve fiber areal ratios (NFAR) for total nerve fibers and sympathetic nerve fibers were significantly lower in liver affected by chronic hepatitis, particularly viral hepatitis, and this was also the case for advanced liver fibrosis. However, the degree of inflammatory activity did not affect NFAR for either whole nerves or sympathetic nerves. Comparison of samples obtained before and after antiviral treatment for HCV demonstrated recovery of NFAR along with improvement of liver fibrosis.

Communicating Branch of the Mental Nerve and Facial Nerve

As peripheral branches of the mandibular nerve, the mental nerve and facial nerve communicate with each other. However, investigations have not always been described in the classic anatomical texts. It remains unknown how nerve fibers of this communicating branch converge at the micro level. Thus, the objective of the present study was to observe in detail the macro and micro levels of the communicating branch of mental and facial nerves. We used five cadavers (10 samples) to conduct experiments in anatomical practice at Tokyo Dental College. A macroscopic observation was made, and the communicating branch of the mental and facial nerves was removed as a single mass. We created serial sections of this branch using the standard method and observed communicating branches of these two nerves under microscopy. As a result, the communicating branch of the mental and facial nerves was completely fused at the perineurium level. It has been reported that the mental nerve includes a small amount of autonomic nerve fiber. As for these findings, similar findings were observed for all 5 bodies and 10 sides. Thus, we believe that autonomic nerve fibers derived from the facial nerve converge with the mental nerve via this communicating branch.

Cutaneous sensory and autonomic denervation in progressive supranuclear palsy.

Progressive Supranuclear Palsy (PSP) is a progressive neurodegenerative tauopathy characterised by motor, behavioural and cognitive dysfunction. While in the last decade, sensory and autonomic disturbances as well as peripheral nerve involvement are well-recognised in Parkinson's Disease (PD), little is known in this regard for PSP. Herein, we aim to assess peripheral sensory and autonomic nerve involvement in PSP and to characterise possible differences in morpho-functional pattern compared to PD patients. We studied 27 PSP and 33 PD patients without electrophysiological signs of neuropathy, and 33 healthy controls (HC). In addition to motor impairment, evaluated by means of UPDRS-III and the PSP rating scale, all patients underwent clinical, functional and morphological assessment of sensory-autonomic nerves through dedicated questionnaires, sympathetic skin response, dynamic sweat test and skin biopsies. The analysis of cutaneous sensory and autonomic innervation was performed using indirect immunofluorescence and confocal microscopy. PSP patients displayed a length-dependent loss of sensory and autonomic nerve fibres associated with functional impairment compared to HC and, overall, a more severe picture than in PD patients. The disease severity correlated with the loss of intraepidermal nerve fibre density in the leg of PSP patients (p<0.05). We demonstrated a length-dependent small fibre pathology in PSP, more severe compared to PD, and paralleling disease severity. Our findings suggest the morphological and functional study of cutaneous nerves as possible biomarkers to monitor disease progression and response to new treatments.

Neuromuscular amyloidosis: Unmasking the master of disguise.

Amyloidosis refers to an etiologically heterogeneous group of protein misfolding diseases, pathologically characterized by extracellular amyloid fibrils producing congophillic amorphous deposits in organs and tissues, which may lead to severe organ dysfunction and mortality. Clinical presentations vary and are often nonspecific, depending on what organs or tissues are affected. In systemic amyloidosis, the peripheral nervous system is commonly affected, whereas the skeletal muscles are only rarely involved. Immunoglobulin light chain (AL) amyloidosis and hereditary transthyretin (ATTRv) amyloidosis are the most frequent types of systemic amyloidosis involving the neuromuscular system. Localized amyloidosis can occur in skeletal muscle, so-called isolated amyloid myopathy. Amyloid neuropathy typically involves small myelinated and unmyelinated sensory and autonomic nerve fibers early in the course of the disease, followed by large myelinated fiber sensory and motor deficits. The relentlessly progressive nature with motor, painful sensory and severe autonomic dysfunction, profound weight loss, and systemic features are distinct characteristics of amyloid neuropathy. Amyloid myopathy presentation differs between systemic amyloidosis and isolated amyloid myopathy. Long-standing symptoms, distal predominant myopathy, markedly elevated creatine kinase level, and lack of peripheral neuropathy or systemic features are highly suggestive of isolated amyloid myopathy. In ATTR and AL amyloidosis, early treatment correlates with favorable outcomes. Therefore, awareness of these disorders and active screening for amyloidosis in patients with neuropathy or myopathy are crucial in detecting these patients in the everyday practice of neuromuscular medicine. Herein, we review the clinical manifestations of neuromuscular amyloidosis and provide a diagnostic approach to this disorder.

Ультраструктурні зміни слизової оболонки ясен пацієнтів із хронічним генералізованим пародонтитом та ішемічною хворобою серця

Abstract. Coronary artery disease (CAD), which is based on atherosclerotic lesions of vessels and systemic hemodynamic disorders, can cause profound metabolic and functional disorders in periodontal tissues, including the hemomicrocirculatory bed. The purpose. With the use of electron microscopy method of study to complement the scientific data on the structure of the gingival mucous membrane , in particular the epithelial layer, cells and cellular elements, stromal structures and hemocapillaries of the connective tissue of the gums in patients with CGP and CAD. Materials and methods. Electron microscopy study was performed in 10 patients (mean age 54.2±5.3 years) with CGP initial-I, II degree and CAD. The material for the study were gingival biopsy samples fixed in the 2 % solution of osmium tetroxide in 0.1 M phosphate buffer. Ultrathin slices were obtained with the ultramicrotome УМТП-3М and studied using the electronic microscope УЭМВ-100К. Results. Study of the ultrathin slices of the gingival mucous membrane in patients with CGP and CAD revealed changes which are typical for tissue hypoxia. Disorders of local blood circulation are primarily associated with narrowing of the hemocapillaries or their dilation. It was observed the violation of the blood rheological properties in these microvessels, which were manifested by the erythrocyte hyperaggregation in the lumens of hemocapillaries and plasma hypercoagulation. It was revealed the changes in the epithelial layer of the connective tissue of the gums, in particular, an increase in the area of penetration of the basement membrane into the main substance of connective tissue, changes in the shape and intracellular structures of cells of the spinous and granular layers, disintegration of intercellular desmosomes. The presence of disorganized unmyelinated nerve fibers indicates the local dysfunction of the autonomic nerve fibers of the gingival mucous membrane. Conclusions. Electron microscopy study revealed ultrastructural changes in the gingival mucous membrane in patients with CGP and CAD, which are the result of hypoxia in periodontal tissues. Key words: ultrastructure, gingiva, hemocapillaries, hypoxia, generalized periodontitis, coronary artery disease.

Assessment of sudomotor function in hypertensive with/without type-2 diabetes patients using SUDOSCAN: An electrophysiological study

ObjectiveElectrochemical skin conductance (ESC) test is a simple and non-invasive screening test can detect dysfunction of the peripheral sudomotor, and indirectly estimates the function of cardiac autonomic nerves. This study aimed to assess the ESC values in hypertensive patients with/without type-2 diabetes by using SUDOSCAN technology. Moreover, this study evaluated the role of cardiometabolic risk factors on the results of ESC test. MethodsThis cross-sectional study was carried on three groups of participants, includinghealthy subjects (Group I, n = 49), hypertensive without type-2 diabetes (Group II, n = 75) patients, and hypertensive with type-2 diabetes (Group III, n = 76) patients. Body mass index (BMI), blood pressure (systolic, diastolic and pulse pressure index), fasting serum glucose, and lipid profile were determined. ESC test as a measurement sudomotor function was determined by applying a small direct current at low voltage to hands and feet sensor plates through SUDOSCAN device. ResultsESC values of the peripheral sudomotor nerves in the Group II and III patients were significantly lower than the corresponding values of Group I. SUDOSCAN results of Group II and III. Significant discriminators of cardiac autonomic neuropathy (≥30 score) that determined by the area under the curve (AUC) with 95% confidence interval (95% C.I.) were, duration of the disease, BMI, and mean blood pressure in Group II, while the duration of the disease and the BMI were significant discriminators in Group III. ConclusionsSUDOSCAN is a simple, useful device, which can detect the impairment of peripheral autonomic small nerve fibers and the risk of cardiac autonomic neuropathy in hypertension. Moreover, the duration of the disease and the associated cardiometabolic risk factors are important predictors of significant SUDOSCAN findings. SignificanceESC test is useful in detecting subclinical neuropathy in hypertensive patients as well as in type 2 diabetes.

Histologic Investigation of the Female Vesicourethral Junction and Adjacent Tissues for Nerve-sparing Radical Cystectomy

ObjectiveTo understand the structures around the vesicourethral junction and to improve functional outcomes after nerve-sparing radical cystectomy with orthotopic urinary diversion for female patients, we histologically elucidated the fibromuscular construction and nerve distribution around the vesicourethral junction. MethodsPelvic specimens containing all the pelvic viscera were obtained from 33 donated female cadavers. Macroslices that included the urethra, the anterior wall of the vagina, and the inferomedial edge of the levator ani muscle were made and performed elastica Masson and immunohistochemical staining. The intraoperative findings were collected in 3 female patients undergoing nerve-sparing radical cystectomy. ResultsIn 18 out of the 33 cadavers, smooth muscle mass occupied a space between the urethra and the inferomedial edge of the levator ani muscle and covered the inferior margin of the bladder detrusor. We termed this mass the hiatal smooth muscle. The detrusor nerves entered the bladder, and the cavernous and sphincter nerves ran between the hiatal smooth muscle and vesicourethral junction. The boundary between hiatal smooth muscle and urethral smooth muscle was easily distinguished intraoperatively during dissection of the vesicourethral junction. ConclusionWe found that more than half of elderly women have hiatal smooth muscle between the urethra and inferior edge of the levator ani. Autonomic nerve fibers innervating the urethral sphincter, run between the hiatal smooth muscle and vesicourethral junction in female cadavers with hiatal smooth muscle. When performing female radical cystectomy before neobladder reconstruction, nerve sparing can be reliably performed using the hiatal smooth muscle as a landmark.

Diabetic cardiovascular autonomic neuropathy in children

Abstract Diabetic cardiovascular autonomic neuropathy (CAN) encompasses damage to the autonomic nerve fibers innervating the heart and blood vessels, resulting in abnormalities in heart rate control and vascular dynamics. Clinical symptoms associated with CAN include resting tachycardia, postural hypotension, dizziness, syncope, exercise intolerance, silent myocardial infarction. The earliest finding of CAN, even at the subclinical stage, is a decrease in heart rate variability (HRV) Purpose To study CAN prevalence and understand the diagnostic capabilities of HRV - tests of diabetic cardiovascular autonomic neuropathy in children with type 1 diabetes. Methods 100 children with type 1 diabetes were assessed for CAN (age 15.2 yrs [9.0–17.8], duration 6.5 yrs [4.0–10.6], HbA1c 8.1% 6.3–9.7]). The degree of compensation of diabetes was estimated according to criteria ISPAD Consensus Guidelines, 2018. Optimal level (HbA1c &amp;lt;7.0%) of compensation was revealed in 62% of children (group I) and nonoptimal in 38% of children (group II). For evaluation of the CAN we used HRV - tests: RR 30:15 ratio, ΔRR quiet breath, ΔRR deep breath, BP response to standing. Results Diabetic cardiovascular autonomic neuropathy was diagnosed in 41 children: in group I – in 6 (29%) and in group II – 35 (71%) children (p=0.00001). The prevalence of DCN correlated with HbA1c level in children and adolescents (groups I and II): ΔRR quiet breath r=−0.47 &amp; r=−0.9; ΔRR deep breath r=−0.65 &amp; r=−0.85; RR30:15 r=−0.77 &amp; r=−0.88 respectively. Prevalence of CAN increased parallel to type 1 diabetes duration (p&amp;lt;0.01). Conclusions Diabetic cardiovascular autonomic neuropathy in children with type 1 diabetes was diagnosed in 41%. Prevalence of diabetic cardiovascular autonomic neuropathy increases parallel to type 1 diabetes duration (p&amp;lt;0.01). In this study we found an association between HRV indexes and HbA1c level. This provides support for HRV - testing to assess diabetic cardiovascular autonomic neuropathy in children. Funding Acknowledgement Type of funding source: None

Expression of Microtubule Associated Protein Tau in Mouse Pancreatic Islets Is Restricted to Autonomic Nerve Fibers.

Evidence from clinical studies and basic research has shown a strong correlation between Alzheimer's disease (AD) and type 2 diabetes. Tau, a neuronal microtubule-associated protein, is hyperphosphorylated and aggregated into neurofibrillary tangles in the AD brain. However, the expression of tau in pancreas is under debate. We determined the expression of tau in mouse pancreas. We used western blots, immunoprecipitation, and immunohistochemical staining to analyze pancreatic expression of tau in mice. We found that neither total tau nor phosphorylated tau was detectable in the mouse pancreas by western blots. Immunostaining with pan tau antibodies R134d and Tau-5 revealed bright and dense varicosities in the pancreatic islets and the exocrine pancreas. These varicosities were immunoreactive to synapsin 1, a presynaptic marker which can outline autonomic nerve profiles in pancreas, exhibiting complete colocalization with tau. Importantly, endocrine cells in islets did not exhibit specific immunoreactivity to any of pan tau antibodies tested, nor did the exocrine cells. In the mouse pancreas, we found that tau is exclusively expressed in autonomic nerve fibers, but there is no detectable expression in endocrine cells in the islet.

Paraspinal structures of thermoregulation

A detailed analysis of the literature on the structure and functions of the paraspinal structures of human thermoregulation involved in maintaining temperature homeostasis is presented. It is shown that in the process of evolution, a peculiar paraspinal morphofunctional complex is formed around the spinal center of thermoregulation, including thermal- generating structures (adipose and muscle tissue); venous thermal distribution rings formed by paraspinal venous plexuses and thermoregulatory nervous apparatus (meningeal and posterior branches of the spinal nerves and their nerve endings). It was found that the heat-generating structures are represented by adipose tissue of the epidural space, adipose tissue of the bone marrow, paravertebral and interscapular adipose tissue, back muscles and intercostal muscles). Bone marrow fatty tissue plays an important role not only in thermoregulation, but also in bone remodeling. Fatty tissue mainly includes components of white and a small amount of brown adipose tissue. Heat from muscles through the venous system of the spinal column affects the functioning of the spinal center of thermoregulation by contractile thermogenesis. It has been shown that around the center of thermoregulation of the spinal cord, venous vessels form four thermal distribution rings. The first of them is the venous bed of the soft membrane of the spinal cord and cerebrospinal fluid of the subarachnoid space; the second is the internal vertebral venous plexus; the third - intraosseous (intraorgan) venous plexuses of the vertebrae; the fourth is the anterior and posterior external vertebral venous plexuses. All four thermal distribution venous rings anastomose among themselves, forming a single thermal distribution system around the spinal center of thermoregulation. The innervation of thermal generating structures and thermal distribution of venous rings is carried out by somatic and autonomic nerve fibers.

Which Method for Diagnosing Small Fiber Neuropathy?

Introduction: Small fiber neuropathies (SFN) induce pain and/or autonomic symptoms. The diagnosis of SFN poses a challenge because the role of skin biopsy as a reference method and of each neurophysiological test remain to be discussed. This study compares six methods evaluating small sensory and autonomic nerve fibers: skin biopsy, Quantitative Sensory Testing (QST), quantitative sweat measurement system (Q-Sweat), Laser Evoked Potentials (LEP), Electrochemical Skin Conductance (ESC) measurement and Autonomic CardioVascular Tests (ACVT).Methods: This is a single center, retrospective study including patients tested for symptoms compatible with SFN between 2013 and 2016 using the afore-mentioned tests. Patients were ultimately classified according to the results and clinical features as “definite SFN,” “possible SFN” or “no SFN.” The sensitivity (Se) and specificity (Sp) of each test were calculated based on the final diagnosis and the best diagnostic strategy was then evaluated.Results: Two hundred and forty-five patients were enrolled (164 females (66.9%), age: 50.4 ± 15 years). The results are as follows: skin biopsy: Se = 58%, Sp = 91%; QST: Se = 72%, Sp = 39%; Q-Sweat: Se = 53%, Sp = 69%; LEP: Se = 66%, Sp = 89%; ESC: Se = 60%, Sp = 89%; Cardiovascular tests: Se = 15%, Sp = 99%. The combination of skin biopsy, LEP, QST and ESC has a Se of 90% and a Sp of 87%.Conclusion: Our study outlines the benefits of combining skin biopsy, ESC, LEP and QST in the diagnosis of SFN.

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.

Involvement of small nerve fibres and autonomic nervous system in AL amyloidosis: comprehensive characteristics and clinical implications

Peripheral nerve involvement in immunoglobulin light chain (AL) amyloidosis is common, characterised by severe progressive mixed neuropathy with autonomic dysfunction but there is limited data on the implications and the characteristics of small nerve fibres dysfunction (SNFD). The aim of our prospective study was to evaluate SNFD and its clinical implications in newly diagnosed AL patients. Twenty-three consecutive patients (10 male, mean age 61.78 years) and 21 age- and gender-matched healthy controls (8 male, mean age 61.28 years) underwent clinical evaluation and standard nerve conduction studies (NCS), baroreflex sensitivity (BRS) test, quantitative sensory testing (QST) and skin biopsy at the lower leg for measuring the density of the nerve fibres innervating the epidermis (IENFD). Axonal degeneration of the large nerve fibres was revealed in 15 out of 23 patients while SNFD was indicated by QST and skin biopsy in 56% and 61% of the patients respectively. BRS index significantly correlated with the IENFD and the QST results while low IENFD was associated with significantly poorer survival. Our study provides new insights and also an initial evaluation of new tools for assessment of the involvement of autonomic and small nerve fibres in AL amyloidosis. These findings also appear to have prognostic implications.

The evaluation of QTc prolongation and QT dispersion in type 2 diabetes mellitus as an indicator of cardiac autonomic neuropathy

Background: Diabetes mellitus refers to group of metabolic disorders characterized by hyperglycemia due to an absolute or relative deficit in insulin production or action. Diabetes mellitus produces pathological changes in most organs of the body including heart, blood vessels, kidneys, nerves and eyes. Cardiovascular autonomic neuropathy (CAN) is a severely debilitating yet underdiagnosed complication of diabetes. Diabetes-associated cardiovascular autonomic neuropathy damages autonomic nerve fibers that innervate the heart and blood vessels causing abnormalities in heart rate and vascular dynamics.Methods: Total 80 cases of diabetes mellitus were selected. Cardiac autonomic neuropathy in them was diagnosed by a series of tests recommended by Ewing et al, which include - Valsalva ratio, Deep Breath Test, Heart rate response to standing, Postural Hypotension, SHGT Increase in diastolic BP on sustained hand grip. They were divided into 2 groups A and B depending on presence or absence of cardiac autonomic neuropathy. ECG was done to calculate QTc and QTd.Results: In group A mean QTc was 0.344 sec and in group B in patients with mild CAN mean QTc was 0.432, moderate CAN mean QTc was 0.444, and in patients of severe CAN mean QTc was 0.481. p value was 0.001 that it is highly significant. Means more was degree of CAN more was prolongation of QT and similarly more the degree of CAN more was QTd.Conclusions: Diagnosis of cardiac autonomic neuropathy by battery of cardiac autonomic function tests is a comlex procedure. The prolongation of QTc interval and more specifically QTd interval on ECG is a marker in diagnosis of cardiac autonomic neuropathy which can be easily evaluated.

The Contribution of the Left Phrenic Nerve to Innervation of the Esophagogastric Junction.

The contribution of the left phrenic nerve to innervation of the esophagogastric junction. The esophagogastric junction is part of the barrier preventing gastroesophageal reflux. We have investigated the contribution of the phrenic nerves to innervation of the esophagogastric junction in humans and piglets by dissecting 30 embalmed human specimens and 14 piglets. Samples were microdissected and nerves were stained and examined by light and electron microscopy. In 76.6% of the human specimens, the left phrenic nerve participated in the innervation of the esophagogastric junction by forming a neural network together with the celiac plexus (46.6%) or by sending off a distinct phrenic branch, which joined the anterior vagal trunk (20%). Distinct left phrenic branches were always accompanied by small branches of the left inferior phrenic artery. In 10% there were indirect connections with a distinct phrenic nerve branch joining the celiac ganglion, from which celiac plexus branches to the esophagogastric junction emerged. Morphological examination of phrenic branches revealed strong similarities to autonomic celiac plexus branches. There was no contribution of the left phrenic nerve or accompanying arteries from the caudal phrenic artery in any of the piglets. The right phrenic nerve made no contribution in any of the human or piglet samples. We conclude that the left phrenic nerve in humans contributes to the innervation of the esophagogastric junction by providing ancillary autonomic nerve fibers. Experimental studies of the innervation in pigs should consider that neither of the phrenic nerves was found to contribute. Clin. Anat. 33:265–274, 2020. © 2019 Wiley Periodicals, Inc.

Autonomic nerve dysfunction and impaired diabetic wound healing: The role of neuropeptides.

Lower extremity ulcerations represent a major complication in diabetes mellitus and involve multiple physiological factors that lead to impairment of wound healing. Neuropeptides are neuromodulators implicated in various processes including diabetic wound healing. Diabetes causes autonomic and small sensory nerve fibers neuropathy as well as inflammatory dysregulation, which manifest with decreased neuropeptide expression and a disproportion in pro- and anti- inflammatory cytokine response. Therefore to fully understand the contribution of autonomic nerve dysfunction in diabetic wound healing it is crucial to explore the implication of neuropeptides. Here, we will discuss recent studies elucidating the role of specific neuropeptides in wound healing.

Architecture of the Cutaneous Autonomic Nervous System.

The human skin is a highly specialized organ for receiving sensory information but also to preserve the body's homeostasis. These functions are mediated by cutaneous small nerve fibers which display a complex anatomical architecture and are commonly classified into cutaneous A-beta, A-delta and C-fibers based on their diameter, myelinization, and velocity of conduction of action potentials. Knowledge on structure and function of these nerve fibers is relevant as they are selectively targeted by various autonomic neuropathies such as diabetic neuropathy or Parkinson's disease. Functional integrity of autonomic skin nerve fibers can be assessed by quantitative analysis of cutaneous responses to local pharmacological induction of axon reflex responses which result in dilation of cutaneous vessels, sweating, or piloerection depending on the agent used to stimulate this neurogenic response. Sensory fibers can be assessed using quantitative sensory test. Complementing these functional assessments, immunohistochemical staining of superficial skin biopsies allow analysis of structural integrity of cutaneous nerve fibers, a technique which has gained attention due to its capacity of detecting pathogenic depositions of alpha-synuclein in patients with Parkinson's disease. Here, we reviewed the current literature on the anatomy and functional pathways of the cutaneous autonomic nervous system as well as diagnostic techniques to assess its functional and structural integrity.