Autonomic Nerve Fibers Research Articles

Neural and Inflammatory Interactions in Wound Healing.

The skin is an intricate network of both neurons and immunocytes, where emerging evidence has indicated that the regulation of neural-inflammatory processes may play a crucial role in mediating wound healing. Disease associated abnormal immunological dysfunction and peripheral neuropathy are implicated in the pathogenesis of wound healing impairment. However, the mechanisms through which neural-inflammatory interactions modulate wound healing remain ambiguous. Understanding the underlying mechanisms may provide novel insights to develop therapeutic devices, which could manipulate neural-inflammatory crosstalk to aid wound healing. This review aims to comprehensively illustrate the neural-inflammatory interactions during different stages of the repair process. Numerous mediators including neuropeptides secreted by the sensory and autonomic nerve fibers and cytokines produced by immunocytes play an essential part during the distinct phases of wound healing.

The Crosstalk between Nerves and Cancer-A Poorly Understood Phenomenon and New Possibilities.

Crosstalk occurs between nerve and cancer cells. These interactions are important for cancer homeostasis and metabolism. Nerve cells influence the tumor microenvironment (TME) and participate in metastasis through neurogenesis, neural extension, and axonogenesis. We summarized the past and current literature on the interaction between nerves and cancer, with a special focus on pancreatic ductal adenocarcinoma (PDAC), prostate cancer (PCa), and the role of the nerve growth factor (NGF) in cancer. We reviewed PubMed and Google Scholar for the relevant literature on the relationship between nerves, neurotrophins, and cancer in general and specifically for both PCa and PDAC. The NGF helped sustain cancer cell proliferation and evade immune defense. It is a neuropeptide involved in neurogenic inflammation through the activation of several cells of the immune system by several proinflammatory cytokines. Both PCa and PDAC employ different strategies to evade immune defense. The prostate is richly innervated by both the sympathetic and parasympathetic nerves, which helps in both growth control and homeostasis. Newly formed autonomic nerve fibers grow into cancer cells and contribute to cancer initiation and progression through the activation of β-adrenergic and muscarinic cholinergic signaling. Surgical or chemical sympathectomy prevents the development of prostate cancer. Beta-blockers have a high therapeutic potential for cancer, although current clinical data have been contradictory. With a better understanding of the beta-receptors, one could identify specific receptors that could have an effect on prostate cancer development or act as therapeutic agents. The bidirectional crosstalk between the nervous system and cancer cells has emerged as a crucial regulator of cancer and its microenvironment. Denervation has been shown to be promising in vitro and in animal models. Additionally, there is a potential relationship between cancer and psychosocial biology through neurotransmitters and neurotrophins.

Understanding Samaana Vaata in relation to the physiology of digestion

Ayurveda is a way of life governed by the principle that whatever there is in the universe is there in the body also. The concept of Tridosha is one such theory which decides the well-being and the diseased condition of a human being. That is, when in equilibrium leads to health and when vitiated, leads to disease. Vaata being one of the Tridosha leads the other two Dosha, Mala, Dhatus as the wind carries the clouds in the sky. There are five types of Vaata, i.e., Prana, Udana, Samana, Vyana and Apana. Samaana, is situated near Jatharagni and moves all over the Koshta. The function of Samaana Vaata can be corelated with functions such as Grahana, Pachana, Vivechana, Munchana. The myenteric plexus, or plexus of Auerbach, is located between the longitudinal and circular smooth muscle layers of the muscularis in gastrointestinal tract. The motor neurons of these plexus mostly control GI tract motility (movement), particularly the frequency and strength of contraction of the muscularis. This can be co-related to Karma of Samana Vata like Grahana, Munchana. The submucosal plexus, also known as Meissner’s plexus, is a network of autonomic motor nerve fibres located in the submucosa of the gastrointestinal tract. The motor neurons of the submucosal plexus supply the secretory cells of the mucosal epithelium, controlling the secretions and absorption of the organs of the gastrointestinal tract. This can be co-related to Karma of Samana Vaata like Pachana, Vivechana. Hence this article is aimed at further exploration of these anatomical and physiological aspects.

Retraction Note: Genetic manipulation of autonomic nerve fiber innervation and activity and its effect on breast cancer progression.

Retraction Note: Genetic manipulation of autonomic nerve fiber innervation and activity and its effect on breast cancer progression.

Diabetic Cardiac Autonomic Neuropathy: A Review of NLRP3 Inflammasome Complicity

Debilitating and often misdiagnosed cardiac autonomic neuropathy affects people with diabetes. Damage to the biggest sympathetic trunk ganglion of autonomic nerve fibers that innervate the heart and blood vessels, the superior cervical ganglion (SCG), is the cause of aberrant heart rate and vascular dynamics in people with diabetic cardiac autonomic neuropathy (DCAN). Mediating host immunological responses to microbial infection and cellular damage, inflammasomes are a class of cytosolic protein complexes that include NLRP3. This review compiled the findings of experimental investigations on DCAN and discussed their connection to the NLRP3 inflammasome’s involvement. SCG P2X7 receptor expression can be boosted by inflammation brought on by hyperglycemia, leading to nerve injury. Unfortunately, there is a lack of research on DCAN-related inflammation in animal models, especially in inflammasome. Currently, only IncRNAUC.360+ shRNA and Schisandrin B, prove to alleviate the pathogenesis. Therefore, more research into the causes and potential remedies for DCAN is necessary.

Esophageal intramural pseudodiverticulosis.

Esophageal intramural pseudodiverticulosis (EIPD) is a disease of unknown pathogenesis characterized by usually systemic, cystic dilatation of the excretory ducts of esophageal submucosal glands. In this article, I review the epidemiology, clinical manifestations, endoscopic findings, esophagographic findings, and histopathology of EIPD. I also discuss the etiology and possible pathogenesis of EIPD based on my experiences with this disease and a review of the literature. EIPD usually presents with dysphagia in middle-aged individuals. It is often complicated with secondary infections, most commonly candidiasis. On esophagography, EIPD is delineated as small, multiple, flask-shaped outward projections within the esophageal wall. In recent years, EIPD has been mainly diagnosed by endoscopic findings of multiple, localized, small mucosal depressions. The orifices of the "pseudodiverticula" periodically open and close, and excrete mucus onto the mucosal surface. On histopathological examination, the luminal surface of dilated ducts in EIPD is covered by multilayered, hyperplastic epithelial cells, but myoepithelial cells in the glandular acini are well preserved. Treatment of EIPD is usually symptomatic therapy, and prevention of the infectious complications is important. The etiology and pathogenesis of EIPD are largely unknown, but functional abnormalities of autonomic nerve fibers innervating the esophageal glands likely play an important role, since the structures of the glands are basically preserved in this disease.

Comparison of time domain indices of heart rate variability between alcohol-dependent individuals and non-alcoholic subjects

Background: Alcohol dependence develops because of repeated alcohol intake. Alcohol damages the cardiac autonomic nerve fibers leading to autonomic imbalance, resulting in reduced heart rate variability (HRV). HRV refers to the complex beat-to-beat variation in the heart rate, produced by the interplay of sympathetic and parasympathetic neural activity at the Sino-atrial node. Our body works effectively in parasympathetic activity dominance. The time domain indices of HRV are specific markers of parasympathetic activity. A decrease in the time domain parameters indicates reduced parasympathetic activity in the heart, indicating cardiac autonomic dysfunction with vagal neuropathy. Aims and Objectives: The objectives of the study are as follows: (1) To assess the HRV in alcohol-dependent individuals using time domain indices. (2) To compare the HRV between alcoholic-dependent individuals and non-alcoholic subjects. Materials and Methods: A total of 110 individuals in the age group of 20–55 years were recruited for our study. Among them, 55 were alcohol-dependent individuals selected based on the diagnostic and statistical manual-IV, international classification of diseases-10 criteria, and 55 age and gender-matched volunteers were selected as healthy non-alcoholic controls. Short-term HRV was recorded in a supine posture, and the results were interpreted. Statistical analysis was done using the software SPSS version 21.0. Results: Our results showed a significant reduction in the time-domain parameters of HRV – SDNN, RMSSD, NN50, and pNN50 in the alcohol-dependent individuals compared to the controls, suggesting reduced parasympathetic activity in the heart indicating cardiac autonomic neuropathy. Conclusion: Alcohol affects the cardiac autonomic status leading to sudden death due to arrhythmias. HRV can be used as a non-invasive test to assess cardiac autonomic dysfunction and its biofeedback can help alcohol-dependent individuals to adopt healthy lifestyle measures.

Histology and immunohistochemistry of the human carotid sinus nerve.

The carotid sinus nerve (CSN) is well known as mediating baroreflexes. However, studies of its detailed histological analysis are scant in the literature. Therefore, the current anatomical study sought to better elucidate the microanatomy of the CSN. Ten fresh frozen adult cadavers underwent dissection of the CSN. Then, it was harvested and submitted for histological and immunohistochemical staining. Specimens were all shown to be nerve fibers on histology and immunohistochemistry. We identified tyrosine hydroxylase positive fibers in all CSN specimens. These fibers were always found to be within the CSN and not on its surface i.e., epineurium. Based on our findings, the majority of fibers contained in the CSN are tyrosine positive in nature. Further studies are necessary to understand the true function of this autonomic nerve fibers.

Prevalence of cardiac autonomic neuropathy in patients with type 2 diabetes mellitus.

Cardiac autonomic neuropathy (CAN) is one of the microvascular complications of diabetes mellitus, which is due to the involvement of autonomic nerve fibers innervating the heart and blood vessels. CAN was found to have a greater degree of morbidity and mortality than their non-CAN counterparts as it is underdiagnosed. Hence, this study aims to determine the prevalence and severity of CAN in type 2 diabetics in the South Indian setting. Forty-two patients with type 2 diabetes mellitus were enrolled in the study. Patients underwent tests for CAN, with the severity of CAN estimated as a CAN score, which was the sum of the scores of the four cardiovascular autonomic function tests. Out of the 42 patients, a total of 36 patients (85.7%) were diagnosed with CAN. Among those with CAN, 24 patients had early CAN (57.1%), and 12 were diagnosed with definite CAN (28.6%). Patients with any form of CAN (early and definite CAN) had higher HbA1c and mean glucose values than those without CAN. CAN was also found to be more severe among older patients with diabetes. In the present study, we found that more than 50% of the study population had early CAN and around 28.6% patients had definite CAN indicating higher prevalence of CAN in our population. Also, there was a positive correlation between the severity of CAN and the age of the patients. This study highlights the importance of understanding the importance of screening the diabetic patients for CAN to prevent adverse cardiovascular events.

Neuroproliferative dyspareunia in endometriosis and vestibulodynia.

Endometriosis is a common cause of deep dyspareunia, while provoked vestibulodynia is a common cause of superficial dyspareunia. The etiology of dyspareunia in both conditions is multifactorial and may include the role of local nerve growth (neurogenesis or neuroproliferation) that sensitizes pelvic structures and leads to pain with contact. To review the evidence for neuroproliferative dyspareunia in endometriosis and provoked vestibulodynia. Narrative review. The pelvic peritoneum and vulvar vestibule receive somatic and autonomic innervation. Various markers have been utilized for nerve subtypes, including pan-neuronal markers and those specific for sensory and autonomic nerve fibers. The nerve growth factor family includes neurotrophic factors, such as nerve growth factor and brain-derived neurotrophic factor, and their receptors. Studies of endometriosis and provoked vestibulodynia have demonstrated the presence of nerve fibers around endometriosis epithelium/stroma in the pelvic peritoneum and within the vulvar vestibule. The number of nerve fibers is higher in these pain conditions as compared with control tissue. Nerve growth factor expression by endometriosis stroma and by immune cells in the vulvar vestibule may be involved in local neuroproliferation. Local inflammation is implicated in this neuroproliferation, with potential roles of interleukin 1β and mast cells in both conditions. Several studies have shown a correlation between nerve fibers around endometriosis and dyspareunia severity, but studies are lacking in provoked vestibulodynia. There are several possible clinical ramifications of neuroproliferative dyspareunia in endometriosis and provoked vestibulodynia, in terms of history, examination, biopsy, and surgical and medical treatment. A neuroproliferative subtype of dyspareunia may be implicated in endometriosis and provoked vestibulodynia. Additional research is needed to validate this concept and to integrate it into clinical studies. Neuroproliferative pathways could serve as novel therapeutic targets for the treatment of dyspareunia in endometriosis and provoked vestibulodynia.

Autonomic Small-Fiber Pathology in Patients With Fibromyalgia

In this clinical and skin biopsy study, we aimed to investigate whether fibromyalgia-associated small-fiber pathology (SFP), consisting of an intraepidermal nerve fiber loss, implies damage of dermal autonomic nerve fibers and how this damage is associated with autonomic symptoms that patients with fibromyalgia syndrome experience. Using skin biopsy, we investigated intraepidermal nerve fiber density, piloerector muscle, and sweat gland nerve fiber density (SGNFD) in 138 participants, that is, 58 patients with fibromyalgia syndrome, 48 healthy subjects, and 32 patients with small-fiber neuropathy. In patients with fibromyalgia-associated SFP, we also investigated how the different skin biopsy variables correlated with autonomic symptoms, as assessed with the Composite Autonomic Symptom Score 31 questionnaire. We found that in patients with fibromyalgia-associated SFP, the piloerector muscle and SGNFD were lower than that in healthy subjects. However, the autonomic small-fiber damage had no correlation with autonomic symptoms severity. In patients with SFP, the intraepidermal, piloerector muscle, and SGNFD were higher than that in patients with small-fiber neuropathy. Our clinical and skin biopsy study shows that patients with fibromyalgia have a reduction of dermal autonomic small fibers paralleling the intraepidermal nerve fiber loss, thus indicating that SFP also implies autonomic small nerve fiber damage. However, the autonomic small-fiber damage we found had no correlation with the severity of autonomic symptoms, and thus its clinical impact is still undetermined. PerspectiveIn patients with fibromyalgia, SFP also affects autonomic fibers. These novel data provide additional insights into the pathophysiology of fibromyalgia syndrome, highlighting the complex role of small-fiber damage in the clinical picture of fibromyalgia.

Nociceptin/Orphanin FQ Opioid Peptide-Receptor Expression in the Endometriosis-Associated Nerve Fibers-Possible Treatment Option?

Endometriosis (EM) is a chronic inflammatory disease affecting millions of women worldwide. Chronic pelvic pain is one of the main problems of this condition, leading to quality-of-life impairment. Currently, available treatment options are not able to treat these women accurately. A better understanding of the pain mechanisms would be beneficial to integrate additional therapeutic management strategies, especially specific analgesic options. To understand pain in more detail, nociceptin/orphanin FQ peptide (NOP) receptor expression was analyzed in EM-associated nerve fibers (NFs) for the first time. Laparoscopically excised peritoneal samples from 94 symptomatic women (73 with EM and 21 controls) were immunohistochemically stained for NOP, protein gene product 9.5 (PGP9.5), substance P (SP), calcitonin gene-related peptide (CGRP), tyrosine hydroxylase (TH), and vasoactive intestinal peptide (VIP). Peritoneal NFs of EM patients and healthy controls were positive for NOP and often colocalized with SP-, CGRP-, TH-, and VIP-positive nerve fibers, suggesting that NOP is expressed in sensory and autonomic nerve fibers. In addition, NOP expression was increased in EM associate NF. Our findings highlight the potential of NOP agonists, particularly in chronic EM-associated pain syndromes and deserve further study, as the efficacy of NOP-selective agonists in clinical trials.

Characterizing the innervation of the vulvar vestibule and the immunohistochemical features of neuroproliferative vestibulodynia.

Provoked vestibulodynia (PVD) is a chronic pain condition characterized by allodynia localized to the vulvar vestibule. The finding of increased densities of nerve fibers in the vestibular mucosa of patients with PVD has led to the identification of a neuroproliferative subtype. The etiology of PVD, including neuroproliferative vestibulodynia (NPV), is not fully understood. The gross and microscopic innervation of the vulvar vestibule remains incompletely described, despite the preliminary data supporting the role of peripheral innervation in PVD. To characterize the gross anatomic and microscopic innervation of the vulvar vestibule through cadaveric dissection and immunohistochemistry. The pudendal nerve and inferior hypogastric plexus (IHP) were dissected using 6 cadaveric donors. Histology and immunohistochemistry were used to confirm patterns of innervation identified gross anatomically. Immunohistochemistry was performed on vestibulectomy specimens obtained from 6 patients diagnosed with NPV and compared with cadaveric vestibular tissues. Outcomes included (1) dissection of pelvic innervation and (2) immunohistochemical localization of markers for the following: general innervation protein gene product 9.5 (PGP9.5), sensory innervation (calcitonin gene-related peptide), autonomic innervation (vasoactive intestinal polypeptide, tyrosine hydroxylase), neuroproliferation (nerve growth factor [NGF]), and immune activation (C-kit). Perineal (pudendal) nerve branches were traced to the external wall of the vulvar vestibule. Some anatomic heterogeneity was observed in perineal nerve-branching patterns. Fibers from the IHP were identified in close proximity to the vulvar vestibule. Autonomic and sensory nerve fibers were identified in both patient and cadaveric vulvar vestibule samples. Patient samples were characterized by the proliferation of PGP9.5-positive nerve fibers and C-kit-positive mast cells, which were in proximity to neve bundles and showed coexpression with putative NGF-positive cells. NGF expression was localized to a subset of nerves, including those that demonstrated co-expression of sensory and autonomic nerve markers. Increased densities of autonomic fibers positive for vasoactive intestinal polypeptide and tyrosine hydroxylase were observed in 1 patient sample. Heterogeneity in gross and microscopic patterns of innervation could explain variability in clinical response to treatment and should be used to inform future therapeutic interventions. This study used a combination of approaches to elucidate the innervation of the vulvar vestibule, including in NPV. The small sample size is a limitation. The vulvar vestibule contains both sensory and autonomic innervation, which may originate from the pudendal nerve and IHP. Our results support the existence of a neuroproliferative subtype that is characterized by the proliferation of sensory and autonomic nerve fibers and neuroimmune interactions.

Glucose intolerance is associated with resting heart rate among individuals without diabetes

Elevated resting heart rate is associated with cardiovascular diseases and all-cause mortality. Unmanaged diabetes is associated with high blood pressure and high resting heart rate. Persistent high blood glucose levels in diabetes is known to contribute to the dysfunction of the autonomic nervous system including cardiovascular autonomic nerve fibers leading to higher resting heart rate, heart failure and stroke. In a population without diabetes, however, there is limited knowledge about the relationship between glucose tolerance and indicators of cardiovascular health, therefore, the purpose of the study was to determine how glucose intolerance is associated with resting heart rate and blood pressure in individuals without diabetes. We hypothesized that glucose intolerance will be associated with resting heart rate and blood pressure in a healthy population without diabetes. Eighty five (32 males, 53 females) individuals without diabetes from the border region of El Paso participated in this study (age 26.69±9.45years; BMI 27.85±6.45kg/m2; fasting blood glucose 95.38±10.09mg/dL; resting heart rate 66.15±10.54 bpm; systolic blood pressure 109.2±11.74 mmHg and diastolic blood pressure 71.24±9.03 mmHg). Following an overnight fast of at least 8 hours, resting heart rate systolic blood pressure and diastolic blood pressure were measured with a sphygmomanometer. Fasting blood glucose was measured and a 3-hour oral glucose tolerance test (OGTT) was performed by consuming 75 grams of glucose drink and measuring blood glucose at 15, 30, 90, 120, 150 and 180 minutes after the glucose consumption via a handheld glucometer. Glucose tolerance was assessed by calculating glucose area under the curve (AUC) during OGTT. Spearman’s correlations were performed at 0.05 alpha to determine the associations. Glucose area under the curve, AUC positively correlated with resting heart rate (r=0.39, p=0.0005) whereas fasting blood glucose did not (r=0.02, p=0.9). Blood glucose concentrations at 15 minutes (r=0.10, p=0.4), 30 minutes (r=0.07, p=0.6), and 60 minutes (r=0.2, p=0.1) did not correlate with resting heart rate while blood glucose concentrations at 90 minutes (r=0.3, p=0.02), 120 minutes (r=0.35, p=0.002), 150 minutes (r=0.33, p=0.003), and 180 minutes (r=0.29, p=0.01) during OGTT positively correlated with resting heart rate. Glucose area under the curve was not associated with neither systolic (r=-0.02, p=0.9) nor diastolic (r=0.2, p=0.2) blood pressures. Fasting blood glucose was not associated with neither systolic (r=0.2, p=0.2) nor diastolic (r=0.1, p=0.4) blood pressure. Glucose intolerance rather than fasting blood glucose is reflective of elevated resting heart rate among a healthy population without diabetes. Dodson Grant This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

COVID-19 Induced Postural Orthostatic Tachycardia Syndrome (POTS): A Review.

POTS (Postural Orthostatic Tachycardia Syndrome) is a multisystem disorder characterized by the abnormal autonomic response to an upright posture, causing orthostatic intolerance and excessive tachycardia without hypotension. Recent reports suggest that a significant percentage of COVID-19 survivors develop POTS within 6 to 8 months of infection. Prominent symptoms of POTS include fatigue, orthostatic intolerance, tachycardia, and cognitive impairment. The exact mechanisms of post-COVID-19 POTS are unclear. Still, different hypotheses have been given, including autoantibody production against autonomic nerve fibers, direct toxic effects of SARS-CoV-2, or sympathetic nervous system stimulation secondary to infection. Physicians should have a high suspicion of POTS in COVID-19 survival when presented with symptoms of autonomic dysfunction and should conduct diagnostic tests like the Tilt table and others to confirm it. The management of COVID-19-related POTS requires a comprehensive approach. Most patients respond to initial non-pharmacological options, but when the symptoms become more severe and they do not respond to the non-pharmacological approach, pharmacological options are considered. We have limited understanding and knowledge of post-COVID-19 POTS, and further research is warranted to improve our understanding and formulate a better management plan.

Effect of Ramipril on Cardiac Autonomic Neuropathy in Patients With Type II Diabetes Mellitus.

Background Cardiovascular autonomic neuropathy (CAN), an important form of DAN is caused by the impairment of the autonomic nerve fibers that innervate the heart and blood vessels and leads to abnormalities in cardiovascular dynamics. The earliest finding of CAN, even at the subclinical stage, is a decrease in heart rate variability (HRV). Objective The objective is to assess the effect of ramipril 2.5mg once daily on cardiac autonomic neuropathyin type II DM patients as an add-on to a standard antidiabetic regimen for a duration of 12 months. Materials and methods A prospective, open-label,randomized, parallel-group study was conducted on type II DM with autonomic dysfunction. Patients in Group A received tablet ramipril 2.5mg daily along with the standard antidiabetic regimen which consist of Tab Metformin 500mg twice a day and Tab Vildagliptin 50mg twice a day and group B received only the standard antidiabetic regimen for 12 months. Results Among 26 patients with CAN, 18 patients completed the study. After one year in group A, Delta HR value increases from 9.77±1.71 to 21.44±8.44 and the E:I ratio (ratio of the longest R-R interval during expiration and shortest R-R intervalduring inspiration) improved from 1.23±0.35 to 1.29±0.23 signifying significant improvement in parasympathetic tone. Results of the postural test showed significant improvement in SBP.Analysis of HRV by time domain method showed that the standard deviation of RR (SDRR) interval and Standard deviation of differences between adjacent RR interval (SDSD)value increased significantly in group A.Analysis of HRV frequency domain indices showed that LFP:HFP ratio improved after treatment in ramipril group indicating improvement in sympatho-vagal balance. Conclusion Ramipril improves parasympathetic component more as compared to sympathetic component of DCAN in type II DM. Ramipril could be a promising option having favorable long-term outcomes in diabetic patients especially when treatment begins at subclinical stage.

Pancreas and islet morphology in cystic fibrosis: clues to the etiology of cystic fibrosis-related diabetes.

Cystic fibrosis (CF) is a multi-organ disease caused by loss-of-function mutations in CFTR (which encodes the CF transmembrane conductance regulator ion channel). Cystic fibrosis related diabetes (CFRD) occurs in 40-50% of adults with CF and is associated with significantly increased morbidity and mortality. CFRD arises from insufficient insulin release from β cells in the pancreatic islet, but the mechanisms underlying the loss of β cell function remain understudied. Widespread pathological changes in the CF pancreas provide clues to these mechanisms. The exocrine pancreas is the epicenter of pancreas pathology in CF, with ductal pathology being the initiating event. Loss of CFTR function results in ductal plugging and subsequent obliteration. This in turn leads to destruction of acinar cells, fibrosis and fatty replacement. Despite this adverse environment, islets remain relatively well preserved. However, islet composition and arrangement are abnormal, including a modest decrease in β cells and an increase in α, δ and γ cell abundance. The small amount of available data suggest that substantial loss of pancreatic/islet microvasculature, autonomic nerve fibers and intra-islet macrophages occur. Conversely, T-cell infiltration is increased and, in CFRD, islet amyloid deposition is a frequent occurrence. Together, these pathological changes clearly demonstrate that CF is a disease of the pancreas/islet microenvironment. Any or all of these changes are likely to have a dramatic effect on the β cell, which relies on positive signals from all of these neighboring cell types for its normal function and survival. A thorough characterization of the CF pancreas microenvironment is needed to develop better therapies to treat, and ultimately prevent CFRD.

Central Sensitization and Small-fiber Neuropathy Are Associated in Patients With Fibromyalgia

To study the prevalence of small-fiber neuropathy (SFN) in a large cohort of patients with fibromyalgia (FM) and to better characterize the subset of patients with both FM and SFN. This 1-year, retrospective, observational cohort study included 265 patients with FM. They all performed electrochemical skin conductance (ESC) using the Sudoscan device, 1 of the simplest and most reliable technique to assess the distal autonomic nerve fibers. They completed 4 self-assessment questionnaires: (1) the Central Sensitization Inventory (CSI), (2) the Neuropathic Pain Symptom Inventory (NPSI), and (3) the Hospital Anxiety and Depression Scale (HADS), the Fibromyalgia Impact Questionnaire (FIQ). Fifty-three patients (20%) had reduced ESC values. These patients had higher CSI and HADS scores, and a larger intake of analgesic drugs compared with patients with no ESC abnormalities. Central sensitization, which was extreme in 69% of the patients (CSI score ≥60), was 1 of the main determinants of ESC abnormalities and was associated with a higher NPSI score, even though these 2 factors were not correlated. Over the past 10 years, studies have shown that a significant proportion of patients with FM have signs of small nerve fiber impairment. The possible involvement of SFN, in the occurrence and presentation of clinical symptoms in FM patients, remains however unclear. This is the first study that showed an association between central sensitization and both small nerve fiber impairment and neuropathic pain features in FM patients, rather than a direct association between SFN and neuropathic pain.

Neural Component of the Tumor Microenvironment in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive primary malignancy of the pancreas, with a dismal prognosis and limited treatment options. It possesses a unique tumor microenvironment (TME), generating dense stroma with complex elements cross-talking with each other to promote tumor growth and progression. Diversified neural components makes for not having a full understanding of their influence on its aggressive behavior. The aim of the study was to summarize and integrate the role of nerves in the pancreatic tumor microenvironment. The role of autonomic nerve fibers on PDAC development has been recently studied, which resulted in considering the targeting of sympathetic and parasympathetic pathways as a novel treatment opportunity. Perineural invasion (PNI) is commonly found in PDAC. As the severity of the PNI correlates with a poorer prognosis, new quantification of this phenomenon, distinguishing between perineural and endoneural invasion, could feature in routine pathological examination. The concepts of cancer-related neurogenesis and axonogenesis in PDAC are understudied; so, further research in this field may be warranted. A better understanding of the interdependence between the neural component and cancer cells in the PDAC microenvironment could bring new nerve-oriented treatment options into clinical practice and improve outcomes in patients with pancreatic cancer. In this review, we aim to summarize and integrate the current state of knowledge and future challenges concerning nerve-cancer interactions in PDAC.

Autonomic Nerve Fibers Aberrantly Reinnervate Denervated Facial Muscles and Alter Muscle Fiber Population.

The surgical redirection of efferent neural input to a denervated muscle via a nerve transfer can reestablish neuromuscular control after nerve injuries. The role of autonomic nerve fibers during the process of muscular reinnervation remains largely unknown. Here, we investigated the neurobiological mechanisms behind the spontaneous functional recovery of denervated facial muscles in male rodents. Recovered facial muscles demonstrated an abundance of cholinergic axonal endings establishing functional neuromuscular junctions. The parasympathetic source of the neuronal input was confirmed to be in the pterygopalatine ganglion. Furthermore, the autonomically reinnervated facial muscles underwent a muscle fiber change to a purely intermediate muscle fiber population myosin heavy chain type IIa. Finally, electrophysiological tests revealed that the postganglionic parasympathetic fibers travel to the facial muscles via the sensory infraorbital nerve. Our findings demonstrated expanded neuromuscular plasticity of denervated striated muscles enabling functional recovery via alien autonomic fibers. These findings may further explain the underlying mechanisms of sensory protection implemented to prevent atrophy of a denervated muscle.SIGNIFICANCE STATEMENT Nerve injuries represent significant morbidity and disability for patients. Rewiring motor nerve fibers to other target muscles has shown to be a successful approach in the restoration of motor function. This demonstrates the remarkable capacity of the CNS to adapt to the needs of the neuromuscular system. Yet, the capability of skeletal muscles being reinnervated by nonmotor axons remains largely unknown. Here, we show that under deprivation of original efferent input, the neuromuscular system can undergo functional and morphologic remodeling via autonomic nerve fibers. This may explain neurobiological mechanisms of the sensory protection phenomenon, which is because of parasympathetic reinnervation.