Artesunate Combined With Metformin Ameliorate on Diabetes-Induced Xerostomia by Mitigating Superior Salivatory Nucleus and Salivary Glands Injury in Type 2 Diabetic Rats via the PI3K/AKT Pathway

Polydipsia and xerostomia are the most common complications that seriously affect oral health in patients with diabetes. However, to date, there is no effective treatment for diabetic xerostomia. Recent studies have reported that artesunate (ART) and metformin (Met) improve salivary gland (SG) hypofunction in murine Sjögren’s syndrome. Therefore, aim of this study was to investigate the effect and underlying mechanism of artesunate (ART) alone and in combination with metformin (Met) on hyposalivation in type 2 diabetes mellitus (T2DM) rats. T2DM rats were induced using a high-fat diet and streptozotocin. SPF male Sprague–Dawley rats were divided into the following five groups: normal control group, untreated diabetic group, ART-treated diabetic group (50 mg/kg), Met-treated diabetic group (150 mg/kg), and ART/Met co-treated diabetic group (50 mg/kg ART and 150 mg/kg Met). ART and Met were intragastrically administered daily for 4 weeks. The general conditions, diabetes parameters and serum lipids were evaluated after drug treatment. Furthermore, we observed changes in the central superior salivatory nucleus (SSN) and SG, and changes in the AQP5 expression, parasympathetic innervation (AChE and BDNF expression), and PI3K/AKT pathway- (p-AKT, and p-PI3K), apoptosis- (Bax, Bcl-2, and Caspase3), and autophagy- (LC3 and P62) related markers expression in T2DM rats after treatment. Our results showed that ART or Met alone and ART/Met combination attenuated a range of diabetic symptoms, including weight loss, urine volume increase, water consumption increase, hyperglycemia, insulin resistance, glucose intolerance and dyslipidemia. More importantly, we found that these three treatments, especially ART/Met combination, mitigated hyposalivation in the T2DM rats via improving the central SSN and SGs damage in hyperglycemia. Our data also indicated that ART/Met attenuated SG damage though regulating the PI3K/Akt pathway to inhibit apoptosis and autophagy of SGs in the T2DM rats. Moreover, ART/Met preserved parasympathetic innervation (AChE and BDNF expression) in SGs to alleviate diabetes-induced hyposalivation likely through rescuing central SSN damage. Taken together, these findings might provide a novel rationale and treatment strategy for future treatment of diabetes-induced xerostomia in the clinic.

Nervous system disorders in a patient with Adie syndrome (a clinical case)

Holmes-Adie syndrome, or tonic pupil syndrome, is a condition characterized by a triad of main symptoms: unilateral tonic pupil dilation, accommodative paresis without or with a significant reduction in pupillary light reflex, and decreased tendon reflexes. The disease is based on dysfunction of the parasympathetic nervous system. The syndrome results from damage to the ciliary ganglion, which carries parasympathetic innervation to the m.sphincter pupillae, cornea, and eyeball. Often the condition is accompanied by dysfunction of the spinal ganglia and, as a consequence, autonomic dysfunction in the form of sweating disorders, usually on one side of the body, rarely — by heart rhythm disorders, lability of blood pressure. A frequent sign of Adie syndrome is the absence or reduction in patellar, rarely Achilles, reflexes. The etiology of the disease is not definitively determined, bacterial or viral factors are not excluded. The diagnosis of Adie syndrome is mainly based on a clinical comparison of the symptoms of the disease, as well as on a thorough and comprehensive examination by a neuroophthalmologist with mandatory testing of pupillary responses with low doses of pilocarpine (narrowing of the pupil is characteristic). Despite the positive prognosis for the patient’s life and his ability to work, the condition belongs to the group of difficult-to-treat ones, and the management consists in symptomatic vision correction.

Participation of the Cholinergic System in the Development of Polycystic Ovary Syndrome

In rats with polycystic ovary syndrome (PCOS) induced by injection of estradiol valerate (EV), unilateral or bilateral section of the vagus nerve restores ovulatory function in 75% of animals, suggesting that the vagus nerve participates in the development of PCOS. Since the vagus nerve is a mixed nerve through which mainly cholinergic-type information passes, the objective of the present study was to analyze whether acetylcholine (ACh) is involved in the development of PCOS. Ten-day-old rats were injected with 2.0 mg EV, and at 60 days of age, they were microinjected on the day of diestrus in the bursa of the left or right ovary with 100 or 700 mg/kg of ovarian weight atropine, a blocker of muscarinic receptors, and sacrificed for histopathological examination after the surgery. Animals with PCOS microinjected with 100 mg of atropine showed a lack of ovulation, lower serum concentrations of progesterone and testosterone, and cysts. Histology of the ovaries of animals microinjected with 700 mg of atropine showed corpus luteum and follicles at different stages of development, which was accompanied by a lower concentration of progesterone and testosterone. These results allow us to suggest that in animals with PCOS, ACh, which passes through parasympathetic innervation, is an important component in the persistence and development of the pathophysiology.

Leucorrhoea and the autonomic nervous system Каlоtli (Arch. f. G., Bd. 125)

Kalotli (Arch. F. G., Bd. 125) thinks that the primary leucorrhoea occurs when irritation touches organs with parasympathetic innervation. This fluor is the result of increased secretion of the cervical glands, and not extravasation of the vaginal wall. Neither the nature of the vaginal flora, nor the glycogen content, nor the degree of acidity are the primary causes of such leucorrhoea.

Location of Parasympathetic Innervation Regions From Electrograms to Guide Atrial Fibrillation Ablation Therapy: An in silico Modeling Study

The autonomic nervous system (ANS) plays an essential role in the generation and maintenance of cardiac arrhythmias. The cardiac ANS can be divided into its extrinsic and intrinsic components, with the latter being organized in an epicardial neural network of interconnecting axons and clusters of autonomic ganglia called ganglionated plexi (GPs). GP ablation has been associated with a decreased risk of atrial fibrillation (AF) recurrence, but the accurate location of GPs is required for ablation to be effective. Although GP stimulation triggers both sympathetic and parasympathetic ANS branches, a predominance of parasympathetic activity has been shown. This study aims was to develop a method to locate atrial parasympathetic innervation sites based on measurements from a grid of electrograms (EGMs). Electrophysiological models representative of non-AF, paroxysmal AF (PxAF), and persistent AF (PsAF) tissues were developed. Parasympathetic effects were modeled by increasing the concentration of the neurotransmitter acetylcholine (ACh) in randomly distributed circles across the tissue. Different circle sizes of ACh and fibrosis geometries were considered, accounting for both uniform diffuse and non-uniform diffuse fibrosis. Computational simulations were performed, from which unipolar EGMs were computed in a 16 × 1 6 electrode mesh. Different distances of the electrodes to the tissue (0.5, 1, and 2 mm) and noise levels with signal-to-noise ratio (SNR) values of 0, 5, 10, 15, and 20 dB were tested. The amplitude of the atrial EGM repolarization wave was found to be representative of the presence or absence of ACh release sites, with larger positive amplitudes indicating that the electrode was placed over an ACh region. Statistical analysis was performed to identify the optimal thresholds for the identification of ACh sites. In all non-AF, PxAF, and PsAF tissues, the repolarization amplitude rendered successful identification. The algorithm performed better in the absence of fibrosis or when fibrosis was uniformly diffuse, with a mean accuracy of 0.94 in contrast with a mean accuracy of 0.89 for non-uniform diffuse fibrotic cases. The algorithm was robust against noise and worked for the tested ranges of electrode-to-tissue distance. In conclusion, the results from this study support the feasibility to locate atrial parasympathetic innervation sites from the amplitude of repolarization wave.

Effects of pulse field and radiofrequency pulmonary vein isolation on parasympathetic cardiac innervation

Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): IKEM Background Pulmonary vein isolation (PVI) is an established treatment modality for patients with atrial fibrillation (AF). PVI performed by radiofrequency (RF) energy results in parasympathetic denervation of the heart by collateral ganglionic plexi ablation. Pulse field (PF) is a novel nonthermal energy source for PVI that selectively ablates atrial myocardium while preserving cardiac autonomic nerves, which may affect the outcome after PVI. Purpose The study compared the effect of PVI between RF and PF ablation on cardiac autonomic function and a short-term AF recurrence rate. The resting heart rate (HR) was evaluated as a simple index of sinus nodal parasympathetic innervation. Methods We investigated 45 patients (aged 64 ± 7 years, 4 women) who underwent PVI by novel three-dimensional electroanatomical mapping/ablation system (lattice electrode ablation system). PVI was performed by either high-energy RF (n = 21) or PF (n = 24) energy using the identical ablation catheter. Resting HR assessed by standard ECG was recorded the day before the procedure and at the 3-month visit. Arrhythmia recurrences were analysed by 24-Holter at the 3-month visit. Results All PVs were acutely isolated in all patients. The HR data are shown in the Table. The baseline HR did not differ between both groups. A significant increase in HR was observed only in the RF ablation subgroup. The between-group difference remained significant even after adjustment for age, gender, and baseline HR. There was no difference in arrhythmia recurrences at the 3-month visit between study groups. Conclusions Parasympathetic denervation effects on HR after the PF ablation are virtually absent. Comparable AF recurrence rate at 3-month visit after RF and PF ablation suggests that preservation of autonomic innervation has no impact on AF recurrence during short-term follow-up. Table RF PVI (n = 21) PF PVI (n = 24) P Baseline HR (bpm) 60.0 ± 7.1 63.8 ± 9.4 n.s. HR change - 3-month visit (bpm) 14.4 ± 6.9 0.3 ± 8.6 P <0.001 Arrhythmia recurrences 3/21 (14%) 2/24 (8%) n.s.

The α-Synuclein Origin and Connectome Model (SOC Model) of Parkinson’s Disease: Explaining Motor Asymmetry, Non-Motor Phenotypes, and Cognitive Decline

A new model of Parkinson’s disease (PD) pathogenesis is proposed, the α-Synuclein Origin site and Connectome (SOC) model, incorporating two aspects of α-synuclein pathobiology that impact the disease course for each patient: the anatomical location of the initial α-synuclein inclusion, and α-synuclein propagation dependent on the ipsilateral connections that dominate connectivity of the human brain. In some patients, initial α-synuclein pathology occurs within the CNS, leading to a brain-first subtype of PD. In others, pathology begins in the peripheral autonomic nervous system, leading to a body-first subtype. In brain-first cases, it is proposed that the first pathology appears unilaterally, often in the amygdala. If α-synuclein propagation depends on connection strength, a unilateral focus of pathology will disseminate more to the ipsilateral hemisphere. Thus, α-synuclein spreads mainly to ipsilateral structures including the substantia nigra. The asymmetric distribution of pathology leads to asymmetric dopaminergic degeneration and motor asymmetry. In body-first cases, the α-synuclein pathology ascends via the vagus to both the left and right dorsal motor nuclei of the vagus owing to the overlapping parasympathetic innervation of the gut. Consequently, the initial α-synuclein pathology inside the CNS is more symmetric, which promotes more symmetric propagation in the brainstem, leading to more symmetric dopaminergic degeneration and less motor asymmetry. At diagnosis, body-first patients already have a larger, more symmetric burden of α-synuclein pathology, which in turn promotes faster disease progression and accelerated cognitive decline. The SOC model is supported by a considerable body of existing evidence and may have improved explanatory power.

Anatomical Variants of Post-ganglionic Fibers within the Pterygopalatine Fossa: Implications for Endonasal Skull Base Surgery

Objectives The vidian nerve provides parasympathetic innervation to the nasal cavity and the lacrimal gland. Previous anatomic studies have primarily focused on preservation or severance of the vidian nerve proximal to the pterygopalatine ganglion (PPG). This study aimed to assess its neural fibers within the pterygopalatine fossa after synapsing at the PPG, and to explore potential clinical implications for endoscopic endonasal skull base surgery. Methods An endonasal transpterygoid approach was performed on eight cadaveric specimens (16 sides). The PPG and maxillary nerve within the pterygopalatine fossa were divided. The vidian nerve was traced retrograde into the foramen lacerum, and postganglionic fibers distal to the PPG were dissected following the zygomatic nerve into the orbit. Potential communicating branches between the ophthalmic nerve (V1) and the PPG were also explored. Results All sides showed a plexus of neural communications between the PPG and the maxillary nerve. The zygomatic nerve exits the maxillary nerve close to the foramen rotundum, piercing the orbitalis muscle to enter the orbit in all sides. The zygomatic nerve was identified running beneath the inferior rectus muscle toward a lateral direction. In 7/16 sides (43.75%), a connecting branch between V1 and the pterygopalatine ganglion was observed. Conclusion Neural communications between the PPG and the maxillary nerve were present in all specimens. A neural branch from V1 to the PPG potentially contributes additional postganglionic parasympathetic function to the lacrimal gland.

Regions of Highly Recurrent Electrogram Morphology at Sites of Low Cycle Length Accurately Reflect Arrhythmogenic Substrate for Atrial Fibrillation – Implications For a New, Mechanism Guided Therapeutic Approach for Atrial Fibrillation

ABSTRACTBackgroundAlthough atrial electrograms (EGMs) are thought to reflect pathophysiological substrate for atrial fibrillation (AF), it is not known which electrograms are suitable targets during AF ablation. We hypothesized that electrogram morphology recurrence (EMR) better reflects arrhythmogenic AF substrate than traditional frequency and complexity measures of AF. In a canine rapid atrial pacing (RAP) model of AF, we assessed the relationship between EMR and traditional AF electrogram measures, rotational activity in the atria, fibrosis, myofiber orientation and parasympathetic innervation.MethodsPersistent AF was induced in 13 dogs by RAP for 6-8 weeks. High-density epicardial mapping (117 electrodes) was performed in six atrial sub-regions. EMR measures Recurrence percentage (Rec%) and cycle length of the most frequent electrogram morphology (CLR), Fractionated Interval (FI), Organization Index (OI), Dominant Frequency (DF) and Shannon’s Entropy (ShEn) were analyzed before and after atropine administration. Myocyte fiber orientation, amount of fibrosis and spatial distribution of parasympathetic nerve fibers were quantified.ResultsRec% was greatest in the appendages, and CLR was lowest in the posterior left atrium. Rec%/CLR correlated with FI, OI and the complexity measure ShEn, but not with DF. All electrogram measures were poorly correlated with fibrosis and myofiber anisotropy. Rec% correlated closely with stability of rotational activity. Unlike other measures, Rec% correlated closely with spatial heterogeneity of parasympathetic nerve fibers; this was reflected in CLR response to atropine.ConclusionEMR correlates closely with stability of rotational activity and with the pattern of atrial parasympathetic innervation. CLR may therefore be a viable therapeutic target in persistent AF.