Autonomic Nervous Dysfunction Research Articles

Complications during Adolescence Predict Mortality in Young Adults with Childhood Onset Type 1 Diabetes

Objective. Microvascular complications increase the risk of cardiovascular disease and premature death in adults with type 1 diabetes. We examined the association between microvascular complications during adolescence, including cardiac autonomic nerve dysfunction and subsequent mortality. Research Design and Methods. We undertook data linkage with the Australian National Death Index in a cohort of 409 adolescents (diagnosed between 1973 and 1993), 48% male, median age at final complications assessment 17.4 years (interquartile range: 16.0–18.9), followed longitudinally for median 22.3 years (21.0–23.4) from diagnosis. Generalized estimating equations (GEE) were used to examine associations between mortality and adolescent complications. Mortality risk was calculated as standardized mortality ratio (SMR). Results. At final adolescent visit, 20% had CAN abnormality, 30% abnormal pupillary response, 20% albuminuria, 40% early elevation of albumin excretion rate (AER) and 45% retinopathy. Data linkage 8–13 years later showed 14 were deceased (3% of cohort), 57% male, median age 28.3 years (24.8–32.9). Acute or chronic diabetes complications accounted for 25% of deaths. In multivariable GEE, elevated AER (OR 4.54, 1.23–16.80, p=0.030), pupillary abnormality (OR 4.27, 1.20–15.22, p=0.023), systolic blood pressure SDS (OR 2.17, 1.26–3.74, p=0.005) and CAN (OR 4.65, 1.03–21.0, p=0.045) predicted mortality. HbA1c was not significant. SMR was 2.5 (1.4–4.2) and was higher in females (SMR 3.5, 1.3–7.8) but not in males (SMR 2.1, 0.9–4.0). Conclusion. Mortality in young adults with type 1 diabetes is predicted by subclinical markers of autonomic neuropathy and elevated AER during adolescence, but not glycemia. Mortality was over twice that of the background population in females but not in males.

Evaluation of peripheral and autonomic nervous systems dysfunctions in patients with Parkinson’s disease

BackgroundPeripheral neuropathy (PN) is increasingly recognized in Parkinson’s disease (PD). This study aimed to evaluate peripheral nerve and autonomic nervous system dysfunction in PD. Forty patients with PD (20 drug-naïve, 20 on treatment) and 20 controls underwent neurological examination, Toronto Clinical Neuropathy Score (TCNS), nerve conduction studies, autonomic function tests including (heart rate variability, Blood pressure changes with standing and sustained handgrip, and sudomotor pathways. The Ewing classification system scored each test to quantify autonomic failure severity). Laboratory tests (B12, homocysteine, methylmalonic acid).ResultsTreated patients with PD had higher MDS-UPDRS scores than drug-naïve (p = 0.001). TCNS indicated mild PN in some drug-naïve patients, and mild–moderate PN in treated patients. Nerve conduction studies showed significant sensory and motor neuropathy in treated versus drug-naïve PD and controls. Treated patients had lower B12, higher homocysteine/methylmalonic acid than other groups. Across autonomic tests, controls had the most normal results, followed by drug-naïve patients, with treated patients being most abnormal. Autonomic dysfunction correlated with disease duration, severity, L-dopa dose. Lower B12, higher homocysteine/methylmalonic acid levels were associated with greater neuropathy and disease severity.ConclusionPatients with PD show evidence of PN and autonomic dysfunction, which is milder in drug-naïve patients but worsens with disease progression and treatment. Peripheral nervous system assessments may help diagnose and monitor PD neuropathy and effects of interventions.

Analysis of the Relationship between Recent Small Subcortical Infarcts and Autonomic Nervous Dysfunction.

Autonomic Nervous System (ANS) dysfunction may be involved in the pathogenesis of Cerebral Small Vessel Disease (CSVD). The study aimed to explore the relationship between Recent Small Subcortical Infarct (RSSI) and Blood Pressure Variability (BPV), and Heart Rate Variability (HRV). A total of 588 patients from the CSVD registration research database of Henan Province were included in this study, and were divided into two groups according to the presence of RSSI. Clinical data, including demographic characteristics, disease history, laboratory indexes, 24-hour ambulatory blood pressure and electrocardiogram indicators, and imaging markers of CSVD, were collected. Univariate and binary logistic regression analyses were used to study the relationship between RSSI and indicators of laboratory, HRV and BPV in the CSVD population. Multivariate analysis showed that higher 24-hour mean Diastolic Blood Pressure (DBP)[Odds Ratios (OR)=1.083,95% Confidence Intervals (CI)=(1.038,1.129), p < 0.001], Standard Deviation (SD) of 24-hour DBP [OR=1.059,95%CI=(1.000,1.121), p = 0.049], nocturnal mean Systolic Blood Pressure (SBP) [OR=1.020,95%CI=(1.004,1.035), p = 0.012], nocturnal mean DBP [OR=1.025,95%CI=(1.009,1.040), p = 0.002] were independent risk factors for RSSI. In contrast, the decrease of the standard deviation of N-N intervals (SDNN) [OR=0.994,95%CI=(0.989,1.000), p = 0.035] was beneficial to the occurrence of RSSI. In addition, neutrophil counts [OR=1.138,95%CI=(1.030,1.258), p = 0.011], total cholesterol (TC) [OR=1.203,95%CI=(1.008,1.437), p = 0.041] and High-Density Lipoprotein (HDL) [OR=0.391, 95%CI=(0.195,0.786), p = 0.008] were also independently associated with the occurrence of RSSI. After adjusting for confounding factors, except for TC, the other factors remained associated with the occurrence of RSSI. Increased 24-hour mean DBP, nocturnal mean SBP and DBP, SD of 24-hour DBP and decreased SDNN were independently correlated with RSSI occurrence, suggesting that sympathetic overactivity plays a role in the pathogenesis of RSSI.

Recovery of cardiac electrophysiological alterations by heart rate complexity based on multiscale entropy following liver transplantation

Autonomic nervous dysfunction is a known cardiac sequalae in patients with end-stage liver disease and is associated with a poor prognosis. Heart rate analysis using nonlinear models such as multiscale entropy (MSE) or complexity may identify marked changes in these patients where conventional heart rate variability (HRV) measurements do not. To investigate the application of heart rate complexity (HRC) based on MSE in liver transplantation settings. Thirty adult recipients of elective living donor liver transplantation were enrolled. HRV parameters using conventional HRV analysis and HRC analysis were obtained at the following time points: (1) 1 day before surgery, (2) postoperative day (POD) 7, (3) POD 14, (4) POD 90, and (5) POD 180. Preoperatively, patients with MELD score ≥ 25 had significantly lower HRC compared to patients with lower MELD scores. This difference in HRC disappeared by POD 7 following liver transplantation and subsequent analyses at POD 90 and 180 continued to show no significant difference. Our results indicated a significant negative correlation between HRC based on MSE analysis and liver disease severity preoperatively, which may be more sensitive than conventional linear HRV analysis. HRC in patients with MELD score ≧ 25 improved over time and became comparable to those with MELD < 25 as early as in 7 days.

Fulminant Myocarditis Complicated by Stiff-person Syndrome: A Case Report

This case report described a 61-year-old woman who presented with dizziness, headache, muscle ache, diplopia, and vomiting who lost consciousness. Upon hospital admission, the levels of high-sensitivity cardiac troponin I and partial pressure of carbon dioxide were increased markedly. Loss of consciousness occurred twice after removal of invasive ventilator support. Coronary angiography demonstrated no stenosis in coronary arteries. Ultrasonography revealed inactivity of respiratory muscles. Oculomotor disturbance and autonomic-nerve dysfunctions were observed. Serum antibody against glutamic acid decarboxylase was positive. The rare phenotypes of persistent stiffness of muscles in the neck, face, bilateral upper and lower limbs were observed. The patient was diagnosed with fulminant myocarditis complicated by Stiff-person syndrome. Immunomodulatory treatment (glucocorticoids and immunoglobulins) elicited satisfactory therapeutic effects. In this case report, it was found that fulminant myocarditis and Stiff-person syndrome shared a common pathogenesis: “cytokine storm”. Such patients may benefit from early treatment with immunomodulatory agents.

Ultrasound of the Vagus Nerve as an indicator of autonomic nervous dysfunction in patients with diabetic neuropathy

Ultrasound of the Vagus Nerve as an indicator of autonomic nervous dysfunction in patients with diabetic neuropathy

Correlation analysis between cerebral microangiopathy and autonomic nervous dysfunction.

Our study was conducted aimed at investigating the potential correlation between cerebral microangiopathy and autonomic nervous dysfunction. We initially included 164 hospitalized patients with cerebral microangiopathy at our hospital from November 2019 to January 2021. Based on the inclusion and exclusion criteria, a final total of 162 patients with cerebral microangiopathy were selected. According to the patient's Autonomic Symptom Profile (ASP) score, patients with a score greater than 22 were categorized into a group with concomitant autonomic dysfunction (71 cases, combined group), while those with a score below 22 were categorized into a group of isolated cerebral microangiopathy (83 cases, cerebral microangiopathy group). The general data and laboratory examination results of the two groups were analyzed, and Pearson correlation analysis was performed to evaluate the correlation between cerebral microangiopathy and autonomic dysfunction, as well as the influencing factors of cerebral microangiopathy patients combined with autonomic dysfunction. There were no significant differences between the two groups in terms of sex, BMI, smoking, drinking, family dementia history, diabetes, hypothyroidism, carotid atherosclerosis, obstructive sleep apnea hypopnea syndrome, hyperuricemia, hyperlipidemia, chronic obstructive pulmonary disease, Hamilton Anxiety Scale score, Hamilton Depression Scale score, 24-h mean systolic blood pressure (SBP), 24-h mean diastolic blood pressure DBP, daytime mean systolic blood pressure (dSBP), daytime mean diastolic blood pressure, nighttime mean systolic blood pressure (nSBP), nighttime mean diastolic blood pressure, 24-h systolic blood pressure standard deviation (SBPSD), 24-h diastolic blood pressure standard deviation, daytime diastolic blood pressure standard deviation, nighttime diastolic blood pressure standard deviation (nDBPSD), nDBPSD (p>.05). However, significant differences were observed between the two groups regarding age, history of coronary heart disease, hypertension, leukoaraiosis, cognitive function, ASP score, SSR, 24-h SBPSD, daytime systolic blood pressure standard deviation (dSBPSD), nighttime systolic blood pressure standard deviation (nSBPSD), standard deviation of RR interval (SDNN), root mean square value of successive RR interval difference (RMSSD), high-frequency component (HF), and low-frequency component (LF) (p<.05). Moreover, the levels of TG, TC, HDL-C, and LDL-C did not show significant differences between the two groups (p>.05), but there were significant differences in blood uric acid and homocysteine (Hcy) levels (p<.05). Age, history of leukoaraiosis, cognitive function assessment, blood uric acid, Hcy levels, 24-h SBPSD, dSBPSD, and nSBPSD showed positive correlations with ASP scores and SSR in patients with cerebral microangiopathy (p<.001). In contrast, hypertension, SDNN, RMSSD, HF, and LF showed negative correlations with ASP scores and SSR (p<.001). Moreover, coronary heart disease was negatively correlated with ASP scores but positively correlated with SSR (p<.001). The independent variables included age, history of leukoaraiosis, cognitive function assessment, ASP score, SSR, blood uric acid, Hcy, bradykinin, coronary heart disease, hypertension, 24-h SBPSD, dSBPSD, nSBPSD, SDNN, RMSSD, HF, and LF, which were indicators with differences in general data and laboratory indicators. The dependent variable was patients with cerebral microangiopathy combined with autonomic nervous dysfunction. The analysis results showed that age, history of leukoaraiosis, ASP score, SSR, 24-h SBPSD, dSBPSD, nSBPSD, SDNN, RMSSD, HF, and LF were the influencing factors of patients with cerebral microangiopathy complicated with autonomic nervous dysfunction. We demonstrates that age, history of leukoaraiosis, cognitive function assessment, blood uric acid, Hcy level, 24-h SBPSD, dSBPSD, nSBPSD, blood pressure, SDNN, RMSSD, HF, LF, and coronary heart disease were highly associated with cerebral microangiopathy with autonomic dysfunction. Furthermore, the influencing factors of cerebral microangiopathy with autonomic dysfunction are age, history of leukoaraiosis, ASP score, SSR, blood pressure variability, and HRV.

Rectal sensitivity correlated with gastrointestinal-mediated glucose disposal, but not the incretin effect.

The mechanisms behind the diminished incretin effect in type 2 diabetes are uncertain, but impaired vagal transmission has been suggested. We aimed to investigate the association between the incretin effect and autonomic neuropathy, and the degree of dysglycaemia and duration of diabetes. For a cross-sectional study, we included participants with either longstanding type 2 diabetes, recent onset, untreated diabetes and controls without diabetes matched for age, sex and body mass index. Autonomic nerve function was assessed with cardiovascular reflex tests, heart rate variability and sudomotor function. Visceral afferent nerves in the gut were tested performing rapid rectal balloon distention. An oral glucose tolerance test and an intravenous isoglycaemic glucose infusion were performed to calculate the incretin effect and gastrointestinal-mediated glucose disposal (GIGD). Sixty-five participants were recruited. Participants with diabetes had rectal hyposensitivity for earliest sensation (3.7 ± 1.1 kPa in longstanding, 4.0 ± 1.3 in early), compared to controls (3.0 ± 0.9 kPa), p = .005. Rectal hyposensitivity for earliest sensation was not associated with the incretin effect (rho = -0.204, p = .106), but an association was found with GIGD (rho -0.341, p = .005). Incretin effect and GIGD were correlated with all glucose values, HbA1c and duration of diabetes. Rectal hyposensitivity was uncovered in both longstanding and early type 2 diabetes, and was not associated with the incretin effect, but with GIGD, implying a potential link between visceral neuropathy and gastrointestinal handling of glucose. Both the incretin effect and GIGD were associated with the degree of dysglycaemia and the duration of diabetes. Some of the data have previously been published and presented as a poster on the American Diabetes Association 83rd Scientific Sessions: Meling etal; 1658-P: Rectal Hyposensitivity, a Potential Marker of Enteric Autonomic Nerve Dysfunction, Is Significantly Associated with Gastrointestinally Mediated Glucose Disposal in Persons with Type 2 Diabetes. Diabetes 20 June 2023; 72 (Supplement_1): 1658-P. https://doi.org/10.2337/db23-1658-P.

Plasticity occurs in a specific phenotype of neurons in the nucleus tractus solitarius of dystrophin gene-mutated rats.

Duchenne muscular dystrophy (DMD) is a severe progressive neuromuscular disorder that causes cardiac and respiratory failure. Patients with DMD have tachycardia and autonomic nervous dysfunction at a young age, which can potentially worsen cardiorespiratory function. Therefore, we hypothesised that plasticity occurs in neurons of the cardiorespiratory brainstem nucleus (nucleus tractus solitarius [NTS]) due to DMD, thus affecting neuronal regulation because afferent information from cardiorespiratory organs changes with disease progression. Patch-clamp experiments were performed on second-order NTS neurons from Dmd-mutated (Dm) rats that showed no functional dystrophin protein expression, as confirmed by immunohistochemistry. NTS neurons are classified into two electrophysiological phenotypes: one showing a delayed onset of spiking from hyperpolarised membrane potentials, namely, delayed-onset spiking (DS)-type neurons, and the other showing a rapid onset, namely, rapid-onset spiking-type neurons. Neuroplasticity mainly occurs in DS-type neurons in Dm rats and is characterised by blunted neuronal excitability accompanied by reduced outward currents and a facilitatory effect on synaptic transmission, that is, an increased frequency of spontaneous and miniature excitatory postsynaptic currents (EPSCs) without changes in the amplitude and an increased amplitude of tractus solitarius-evoked EPSCs without changes in the paired-pulse ratio. Although we cannot rule out the possibility that the neuroplastic changes observed in Dm rats were caused by dystrophin deficiency in the neurons themselves, the plasticity could be caused by cardiorespiratory deterioration and/or adaptation in DMD patients.

Effects of autonomic nervous system disorders on male infertility.

The male reproductive functions are largely regulated by the autonomic nervous system. Male sexual behavior and fertility primarily depend on the normal function of the higher neural centers related to the autonomic nervous system, the hypothalamic-pituitary-gonadal axis, the autonomic nervous components within the spinal cord and spinal nerves, and certain somatic nerves in the pelvic floor. In this review article, we will summarize the role of the autonomic nervous system in regulating male reproductive capabilities and fertility, its impact on male infertility under abnormal conditions, including the role of drug-induced autonomic nervous dysfunctions on male infertility. The main purpose of this article was to provide an overview of the effects of autonomic nervous dysfunction on male reproductive function and shed light on the potential therapeutic target for male infertility.

Preservation versus resection of Denonvilliers’ fascia in total mesorectal excision for male rectal cancer: follow-up analysis of the randomized PUF-01 trial

Traditional total mesorectal excision (TME) for rectal cancer requires partial resection of Denonvilliers’ fascia (DVF), which leads to injury of pelvic autonomic nerve and postoperative urogenital dysfunction. It is still unclear whether entire preservation of DVF has better urogenital function and comparable oncological outcomes. We conducted a randomized clinical trial to investigate the superiority of DVF preservation over resection (NCT02435758). A total of 262 eligible male patients were randomized to Laparoscopic TME with DVF preservation (L-DVF-P group) or resection procedures (L-DVF-R group), 242 of which completed the study, including 122 cases of L-DVF-P and 120 cases of L-DVF-R. The initial analysis of the primary outcomes of urogenital function has previously been reported. Here, the updated analysis and secondary outcomes including 3-year survival (OS), 3-year disease-free survival (DFS), and recurrence rate between the two groups are reported for the modified intention-to-treat analysis, revealing no significant difference. In conclusion, L-DVF-P reveals better postoperative urogenital function and comparable oncological outcomes for male rectal cancer patients.

Adult patients with tetanus in Anhui Province of China from 2013 to 2022: A retrospective study.

Tetanus is a highly fatal infectious disease with an incubation period of 7 to 8 days. The aim of this study was to identify risk factors for death in tetanus patients, develop a nomogram model for predicting mortality risk. This retrospective study included tetanus patients who were admitted to the intensive care unit department between January 2013 and December 2022. The patients were divided into 2 groups based on their final outcome, namely death group and survival group. Risk factors associated with mortality were analyzed using univariate and multivariate logistic regression analysis. Finally, a nomogram model was developed using the rms package. A total of 91 patients were enrolled in this study, including 54 males and 37 females. The average age of the tetanus patients was 52.88 ± 16.56 years, with a mean incubation period of 8.51 ± 3.97 days. The foot was the most common injury site (42.86%), and metal product stabbing was the leading cause of injury (48.78%). Ventilator-associated pneumonia was the most frequent complication (21.98%). Univariate and multivariate logistic regression analyses revealed that Ablett classification (odds ratio [OR], 21.999; 95% confidence interval [CI], 4.124-117.352), white blood cell count (OR, 6.033; 95%CI, 1.275-28.552), and autonomic nervous dysfunction (OR, 22.663; 95%CI, 4.363-117.728) as independent risk factors for tetanus patients. The C-index of the nomogram model was 0.942, with an area under the curve of the receiver operating characteristic curve at 0.942 (95%CI, 0.871-0.905). Ablett classification, white blood cell count, autonomic nervous dysfunctions were associated with the prognosis of patients with tetanus. The nomogram model developed based on risk factors has high accuracy.

FGF21 prevents neuronal cell ferroptosis after spinal cord injury by activating the FGFR1/β-Klotho pathway

Spinal cord injury (SCI) is a kind of traumatic nervous system disease caused by neuronal death, causing symptoms like sensory, motor, and autonomic nerve dysfunction. The recovery of neurological function has always been a intractable problem that has greatly distressed individuals and society. Although the involvement of iron-dependent lipid peroxidation leading to nerve cell ferroptosis in SCI progression has been reported, the underlying mechanisms remain unaddressed. Thus, this study aimed to investigate the potential of recombinant human FGF21 (rhFGF21) in inhibiting ferroptosis of nerve cells and improving limb function after SCI, along with its underlying mechanisms. In vivo animal model showed that FGFR1, p-FGFR1, and β-Klotho protein gradually increased over time after injury, reaching a peak on the third day. Moreover, rhFGF21 treatment significantly reduced ACSL4, increased GPX4 expression, reduced iron deposition, and inhibited ferroptosis. Meanwhile, rhFGF21 decreased cell apoptosis following acute spinal cord damage. In contrast, FGFR1 inhibitor PD173074 partially reversed the rhFGF21-induced therapeutic effects. Overall, this work revealed that rhFGF21 activates the FGFR1/β-Klotho pathway to decrease ferroptosis of nerve cells, suggesting that FGF21 could be a new therapeutic target for SCI neurological rehabilitation.

Mood Disorders are Correlated with Autonomic Nervous Function in Chronic Insomnia Patients with OSA.

To evaluate the correlation between sleep microstructure, autonomic nervous system activity, and neuropsychological characteristics in chronic insomnia (CI) patients with obstructive sleep apnea (OSA). Forty-five CI-OSA patients, forty-six CI patients and twenty-two matched healthy control subjects (HCs) were enrolled. CI-OSA patients were then divided into two groups: mild OSA and moderate-to-severe OSA. All participants completed neuropsychological tests, which included the Hamilton Depression and Anxiety Scales (HAMD and HAMA), the Pittsburgh Sleep Quality Index (PSQI), the Insomnia Severity Index (ISI), the Epworth Sleepiness Scale (ESS), and the Mini-mental State Examination (MMSE). The autonomic nervous system activity and sleep microstructure were examined by the PSM-100A. The CI-OSA patients exhibited higher scores on the PSQI, ESS, ISI, HAMA, and HAMD than HCs and CI patients (all p < 0.01). The CI-OSA patients had a lower proportion of stable sleep, REM sleep and a higher proportion of unstable sleep ratio (all p < 0.01) than HCs and CI patients (all p < 0.01). The CI-OSA patients had higher ratios of LF and LF/HF, and lower ratios of HF and Pnn50% (all p < 0.01) than HCs and CI patients (all p < 0.01). Compared to CI-mild OSA patients, the CI-moderate-to-severe OSA patients presented with a higher ESS scores, higher ratios of LF and LF/HF, and lower ratios of HF (all p < 0.05). In CI-OSA patients, higher HAMD scores were correlated with decreased MMSE scores (r=-0.678, p < 0.01). A higher LF ratio was correlated with higher HAMD and HAMA scores (r=0.321, p=0.031, r =0.449, p =0.002), and a higher HF ratio was correlated with lower HAMD and HAMA scores (r=-0.321, P =0.031, r =-0.449, p =0.002). OSA exacerbates the abnormalities of sleep microstructure and the autonomic nervous dysfunction in CI patients. Dysfunction of the autonomic nervous system could contribute to mood deterioration in CI with OSA patients.

1658-P: Rectal Hyposensitivity, a Potential Marker of Enteric Autonomic Nerve Dysfunction, Is Significantly Associated with Gastrointestinally Mediated Glucose Disposal in Persons with Type 2 Diabetes

The incretin effect in type 2 diabetes is reduced, but the mechanisms behind are uncertain. We hypothesized that the incretin effect associates with degree of enteric autonomic nerve dysfunction and evaluated gastrointestinally mediated glucose disposal (GIGD), as a proxy for the incretin effect, and rectal sensitivity to mechanical distension representing afferent gut signalling. Sixty-six participants with either 1) longstanding type 2 diabetes, 2) newly onset (&amp;lt;1 year), medically untreated diabetes, or 3) healthy controls, underwent a 75 g oral glucose tolerance test (OGTT) and an intravenous isoglycemic glucose infusion to determine GIGD. Earliest sensation to rectal rapid balloon distention was determined as a proxy for autonomic neuropathy. Compared to controls (59.3±14.4%), GIGD was reduced in both early (36.4±14.7%) and longstanding diabetes (17.4±22.3%), with significant difference between all three groups (P&amp;lt;0.01). Both groups of diabetes needed higher pressure during rapid rectal balloon distention (3.7±1.1 kPa for longstanding diabetes, 4.0±1.3 for early diabetes), compared to controls (3.0±0.9 kPa, P&amp;lt;0.01), with no significant difference between the two diabetes groups. GIGD was inversely correlated with pressure at earliest sensation (rho 0.341, P&amp;lt;0.01). For those needing a pressure between 1 and 3 kPa and between 4 and 7 kPa, respectively, GIGD was 46.2%±24.9 and 34.4±23.9% (P=0.05). GIGD was inversely and significantly correlated with glucose values during OGTT, with strongest correlation to the 90-minute value (rho 0.873, P&amp;lt;0.01), and HbA1c (rho 0.653, P&amp;lt;0.01). We show that the degree of rectal hyposensitivity correlates with reduced GIGD and confirm that GIGD correlates with the degree of dysglycemia. These results warrant further studies on the potential role of gut autonomic dysfunction in the reduced incretin effect characterizing type 2 diabetes. Disclosure S.Meling: Consultant; Novo Nordisk, Lilly, AstraZeneca, Boehringer-Ingelheim, Sanofi. E.Tjora: None. N.Ejskjaer: None. S.Carlsen: None. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. P.Njølstad: None. C.Brock: Research Support; Abbott, ElectroCore. R.B.Nedergaard: Other Relationship; Grünenthal Group. E.Søfteland: None. Funding Helse Vest, Norway (F-11637/4800002072); Johan Selmer Kvanes Legat (Legacy)

Monitoring of the regulatory ability and regulatory state of the autonomic nervous system and its application to the management of hypertensive patients: a study protocol for randomised controlled trials

IntroductionMany causes lead to sympathetic-vagus imbalance, which promotes the development of hypertension and accelerates the process of target organ damage. Many studies have shown that exercise training and heart rate...

Involvement of Abnormal p-α-syn Accumulation and TLR2-Mediated Inflammation of Schwann Cells in Enteric Autonomic Nerve Dysfunction of Parkinson's Disease: an Animal Model Study.

The study was designed to investigate the pathogenesis of gastrointestinal (GI) impairment in Parkinson's disease (PD). We utilized 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 20mg/kg) and probenecid (250mg/kg) to prepare a PD mice model. MPTP modeling was first confirmed. GI motility was measured using stool collection test and enteric plexus loss was also detected. Intestinal phosphorylated α-synuclein (p-α-syn), inflammation, and S100 were assessed using western blotting. Association between Toll-like receptor 2(TLR2) and GI function was validated by Pearson's correlations. Immunofluorescence was applied to show co-localizations of intestinal p-α-syn, inflammation, and Schwann cells (SCs). CU-CPT22 (3mg/kg, a TLR1/TLR2 inhibitor) was adopted then. Success in modeling, damaged GI neuron and function, and activated intestinal p-α-syn, inflammation, and SCs responses were observed in MPTP group, with TLR2 related to GI damage. Increased p-α-syn and inflammatory factors were shown in SCs of myenteron for MPTP mice. Recovered fecal water content and depression of inflammation, p-α-syn deposition, and SCs activity were noticed after TLR2 suppression. The study investigates a novel mechanism of PD GI autonomic dysfunction, demonstrating that p-α-syn accumulation and TLR2 signaling of SCs were involved in disrupted gut homeostasis and treatments targeting TLR2-mediated pathway might be a possible therapy for PD.

Immune system perturbations in patients with severe long COVID

Abstract SARS-CoV-2 infections have different outcomes ranging from mild to severe acute infection as well as post-infectious multi-system inflammatory syndromes (MIS-C/A). Post-acute sequelae of COVID-19 (PASC) or long COVID is another outcome, which is poorly understood and range from mild to very severe persistent organ dysfunction and damages. To maximize our chances of identifying underlying mechanisms of long COVID we focus on the most severe cases with objective measures of disease such as lung damages, microvascular and autonomic nerve dysfunction. We are testing the following hypotheses that I) long COVID is a super-antigen mediated disease, II) an autoimmune condition driven by pathogenic autoantibodies, and/or III) a disease caused by viral persistence. A cohort of over 100 long COVID patients, 24 recovered long COVID patients as well as 9 COVID convalescent controls have been recruited thus far and blood samples analyzed for plasma proteome (Olink assays), immune cell composition and phenotypes (mass cytometry), T-cell repertoire (scTCR-seq), innate cell activation (circulating nucleosomes), and auto-antibody analyses (Luminex arrays) in order to understand immune perturbations in severe long COVID patients. Unlike children with hyperinflammatory MIS-C, we have not found any evidence of superantigen-mediated T-cell activation in long COVID, but instead substantial clonal expansion of memory T cell clones with effector memory states and shared clonality across patients. Additionally, cytokine perturbations such as elevated levels of IL8 and elevated levels of circulating nucleosomes indicate persistent activation of neutrophils in severe long COVID.

Effects of cerebellar transcranial alternating current stimulation in cerebellar ataxia: study protocol for a randomised controlled trial.

Cerebellar ataxia (CA) is a movement disorder that can affect balance and gait, limb movement, oculomotor control, and cognition. Multiple system atrophy-cerebellar type (MSA-C) and spinocerebellar ataxia type 3 (SCA3) are the most common forms of CA, for which no effective treatment is currently available. Transcranial alternating current stimulation (tACS) is a non-invasive method of brain stimulation supposed to alter cortical excitability and brain electrical activity, modulating functional connectivity within the brain. The cerebellar tACS can modulate the cerebellar outflow and cerebellum-linked behavior and it is a proven safe technique for humans. Therefore, the aim of this study is to 1) examine whether cerebellar tACS improves ataxia severity and various non-motor symptoms in a homogeneous cohort of CA patients consisting of MSA-C and SCA3, 2) explore the time course of these effects, and 3) assess the safety and tolerance of cerebellar tACS in all participants. This is a 2-week, triple-blind, randomised, sham-controlled study. 164 patients (MSA-C: 84, SCA3: 80) will be recruited and randomly assigned to either active cerebellar tACS or sham cerebellar tACS, in a 1:1 ratio. Patients, investigators, and outcome assessors are unaware of treatment allocation. Cerebellar tACS (40 min, 2 mA, ramp-up and down periods of 10s each) will be delivered over 10 sessions, distributed in two groups of five consecutive days with a two-day break in between. Outcomes are assessed after the tenth stimulation (T1), and after 1 month (T2) and 3 months (T3). The primary outcome measure is the difference between the active and sham groups in the proportion of patients with an improvement of 1.5 points in the Scale for the Assessment and Rating of Ataxia (SARA) score after 2 weeks of treatment. In addition, effects on a variety of non-motor symptoms, quality of life, and autonomic nerve dysfunctions are assessed via relative scales. Gait imbalance, dysarthria, and finger dexterity are objectively valued via relative tools. Finally, functional magnetic resonance imaging is performed to explore the possible mechanism of treatment effects. The results of this study will inform whether repeated sessions of active cerebellar tACS benefit CA patients and whether this form of non-invasive stimulation might be a novel therapeutic approach to consider in a neuro-rehabilitation setting.Clinical Trial Registration: ClinicalTrials.gov, identifier NCT05557786; https://www.clinicaltrials.gov/ct2/show/NCT05557786.

The mechanism of sudden unexpected death in epilepsy: A mini review.

Sudden unexpected death in epilepsy (SUDEP) is defined as a sudden, unexpected, non-traumatic, non-drowning death in a person with epilepsy. SUDEP is generally considered to result from seizure-related cardiac dysfunction, respiratory depression, autonomic nervous dysfunction, or brain dysfunction. Frequency of generalized tonic clonic seizures (GTCS), prone posture, and refractory epilepsy are considered risk factors. SUDEP has also been associated with inherited cardiac ion channel disease and severe obstructive sleep apnea. Most previous studies of SUDEP mechanisms have focused on cardiac and respiratory dysfunction and imbalance of the neural regulatory system. Cardiac-related mechanisms include reduction in heart rate variability and prolongation of QT interval, which can lead to arrhythmias. Laryngospasm and amygdala activation may cause obstructive and central apnea, respectively. Neural mechanisms include impairment of 5-HT and adenosine neuromodulation. The research to date regarding molecular mechanisms of SUDEP is relatively limited. Most studies have focused on p-glycoprotein, catecholamines, potassium channels, and the renin-angiotensin system, all of which affect cardiac and respiratory function.