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This ATLAS presents in appended form the complete monographic study on the subject. The idea is to bring the results out of the "heavier" didactic format required for the scientific presentation and at the same time to systematize all the information needed for the subsequent clinical research. The present excerpt from monographic work seeks to introduce the possibility that oncological diseases become chronic (like diabetes). The theoretical basis on which we refer is the fact that cancer cells feed only on carbohydrates. In turn, there is evidence that some nitrile glycosides have anti-cancer properties. The study is divided into four parts presented in the form of goals. Proceeding from the particular to the general, the fine molecular structure and all possible biochemical reactions of Amygdalin are examined. By itself, it is highly toxic to the physiologically active animal cell. Amygdalin has NO pronounced antitumor properties. In the first goal, he examines precisely the acceptable form for admission. It is concluded that the active anticancer molecular form is a stoichiometric mixture of the amide and carboxyl derivative of the nitrile glycoside. The second goal is to study the exact action of the anti-tumor product already introduced. After an extremely precise biochemical and mathematical analysis, a series of biochemical cycles of the exact passage of the product through the digestive system, penetration into the blood, approach to cancer cells and selective passage through their cell membrane have been deduced. The third goal is to define the chemical and pharmaceutical molecular forms. 54 methodological and/or pharmaceutical models with hundreds of variables for each are reviewed and analyzed here. The fourth goal (it is this purpose that is separately brought out in this edition) presents the interpretable prediction of anticancer susceptibility of glycosidic amides. The affinities of the pharmaceutical form to each known cancer cell line are reviewed. The results surpass many times all anti-cancer drugs and with significantly reduced toxicity. In an additional part, a generalized clinical control is presented. When conducting the treatment, it is also vitally important to not divert the therapy process to irreversible pathology. Result: The cancer can become chronic and become a practically curable disease., The theoretical basis is based on - https://doi.org/10.5281/zenodo.7295357 | Full calculations are posted here*: https://doi.org/10.5281/zenodo.7550371 | *- the information is constantly updated - choose the current version at the moment, {"references":["Cadow, J., Born, J., Manica, M., Oskooei, A., & Martínez, M. R. (2020). PaccMann: a web service for interpretable anticancer compound sensitivity prediction. Nucleic Acids Research, 48(W1), W502-8. doi:10.1093/nar/gkaa327","Christopher, A. (2017). Drawing conclusions from data: descriptive statistics, inferential statistics, and hypothesis testing, In Interpreting and using statistics in psychological research. SAGE Publications Inc. doi:10.4135/9781506304144","Dimitrov, S. D., Diderich, R., Sobanski, T., Pavlov, T. S., Chankov, G., Chapkanov, A., . . . Mekenyan, O. (2016). QSAR Toolbox – workflow and major functionalities. SAR and QSAR in Environmental Research, 27(3), 203-19. doi:10.1080/1062936X.2015.1136680","Gary, W. C., Zhengyin, Y., Wensheng, L., & Masucci, A. (2012). The IC50 Concept Revisited. Current Topics in Medicinal Chemistry, 12(11). doi:10.2174/156802612800672844","Ghandi, M., Huang, F. W., & Jané-Valbuena, J. (2019). Next-generation characterization of the Cancer Cell Line Encyclopedia. Nature, 569, 503-8. doi:10.1038/s41586-019-1186-3","Hubert, M., & Vandervieren, E. (2008). An adjusted boxplot for skewed distributions. Computational Statistics & Data Analysis, 52(12), 5186-201. doi:10.1016/j.csda.2007.11.008","Marmolejo-Ramos, F., & Tian, T. (2010). he shifting boxplot. A boxplot based on essential summary statistics around the mean. International Journal of Psychological Research, 3(1), 37-45. doi:10.21500/20112084.823","Sebaugh, J. L. (2011). Guidelines for accurate EC50/IC50 estimation. Pharmaceutical Statistics, 10, 128-34. doi:10.1002/pst.426","Soares, J., Greninger, P., Yang, W., Edelman, E. J., Lightfoot, H., Forbes, S., . . . Garnett, M. (2013). Genomics of Drug Sensitivity in Cancer: a resource for therapeutic biomarker discovery in cancer cells. Nucleic Acids Research, 41(D1), D955-61. doi:10.1093/nar/gks1111","Tsanov, V., Tsanov, H., Theoretical Analysis for the Safe Form and Dosage of Amygdalin Product, Anti-Cancer Agents in Medicinal Chemistry 2020; 20(7), DOI: 10.2174/1871520620666200313163801","Tsanov, V., Tsanov, H., Theoretical Analysis of Anticancer Cellular Effects of Glycoside Amides, Anti-Cancer Agents in Medicinal Chemistry 2022; 22(6), DOI: 10.2174/1871520621666210903122831","Tsanov, V., Tsanov, H., Theoretical Study of the Process of Passage of Glycoside Amides through the Cell Membrane of Cancer Cell, Anti-Cancer Agents in Medicinal Chemistry 2021; 21(12), DOI: 10.2174/1871520620999201103201008","Tsanov, V.; Tsanov, H.,Theoretical study of anticancer activity of glycoside amides [ third supplemented edition ], pp. 857, ISBN: 978-619-91534-4-4, DOI: 10.5281/zenodo.7295357","Yordanova, D., Schultz, T., Kuseva, C., Tankova, K., Ivanova, H., Dermen, I., . . . Mekenyan, O. (2019). Automated and standardized workflows in the OECD QSAR Toolbox. Computational Toxicology, 10, 89-104. doi:10.1016/j.comtox.2019.01.006"]}

This book is a long-term study and analysis presented in a more scientifically popular form. The matter is presented in a freer way in order to explain the matter. The present monographic work seeks to introduce the possibility that oncological diseases become chronic (like diabetes). The theoretical basis on which we refer is the fact that cancer cells feed only on carbohydrates. In turn, there is evidence that some nitrile glycosides have anti-cancer properties. The study is divided into four parts presented in the form of goals. Proceeding from the particular to the general, the fine molecular structure and all possible biochemical reactions of Amygdalin are examined. By itself, it is highly toxic to the physiologically active animal cell. Amygdalin has NO pronounced antitumor properties. In the first goal, he examines precisely the acceptable form for admission. It is concluded that the active anticancer molecular form is a stoichiometric mixture of the amide and carboxyl derivative of the nitrile glycoside. The second goal is to study the exact action of the anti-tumor product already introduced. After an extremely precise biochemical and mathematical analysis, a series of biochemical cycles of the exact passage of the product through the digestive system, penetration into the blood, approach to cancer cells and selective passage through their cell membrane have been deduced. The third goal is to define the chemical and pharmaceutical molecular forms. 54 methodological and/or pharmaceutical models with hundreds of variables for each are reviewed and analyzed here. The fourth goal presents the interpretable prediction of anticancer susceptibility of glycosidic amides. The affinities of the pharmaceutical form to each known cancer cell line are reviewed. The results surpass many times all anti-cancer drugs and with significantly reduced toxicity. In an additional part, a generalized clinical control is presented. When conducting the treatment, it is also vitally important to divert the therapy process to irreversible pathology. Result: The cancer can become chronic and become a practically curable disease., ATLAS - https://doi.org/10.5281/zenodo.8009390 | Full calculations and subsequent interpretations are presented here: DOI: 10.5281/zenodo.7550371, {"references": ["ACS (Ed.). (1991). Unproven methods of cancer management: Laetrile. CA: A Cancer Journal for Clinicians, 41(3), 187-92. doi:10.3322/canjclin.41.3.187", "Ahmed, M. (2016). Ethnicity, Identity and Group Vitality: A study of Burushos of Srinagar. Journal of Ethnic and Cultural Studies, 3(1), 1-10. doi:10.29333/ejecs/51", "Airley, R. (2009). Cancer Chemotherapy: Basic Science to the Clinic. Wiley", "Allinger, N. L. (1977). Conformational analysis. 130. MM2. 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The article summarizes information about the head ganglia (the sympathetic ganglia and in the sensory cranial nerves). Gives а brief historical background on the history issue and relevance of the topic. Characterized by each node with its topography and lesion clinic. The described process of treatment, and prospects for new therapies. Raised the issue of the significance of the defeat ganglia, namely, the suffering of the sick and forced treatment costs (due to the complex differential diagnosis). In a biological sense, pain first appears in chordates and during evolution, as well as transformations of the brain and spinal cord, it acquires new types, localization and significance for the performance of a living organism. And facial pain, being a nosology with a multidisciplinary approach in diagnosis and treatment, demonstrates both its complexity and importance in human life.

The primary function of the urinary bladder is to store urine (continence) until a suitable time for voiding (micturition). These distinct processes are determined by the coordinated activation of sensory and motor components of the nervous system, which matures to enable voluntary control at the time of weaning. Our aim was to define the development and maturation of the nerve-organ interface of the mouse urinary bladder by mapping the organ and tissue distribution of major classes of autonomic (motor) and sensory axons. Innervation of the bladder was evident from E13 and progressed dorsoventrally. Increasing defasciculation of axon bundles to single axons within the muscle occurred through the prenatal period, and in several classes of axons underwent further maturation until P7. Urothelial innervation occurred more slowly than muscle innervation and showed a clear regional difference, from E18 the bladder neck having the highest density of urothelial nerves. These features of innervation were similar in males and females but varied in timing and tissue density between different axon classes. We also analysed the pelvic ganglion, the major source of motor axons that innervate the lower urinary tract and other pelvic organs. Cholinergic, nitrergic (subset of cholinergic) and noradrenergic neuronal cell bodies were present prior to visualization of these axon classes within the bladder. Examination of cholinergic structures within the pelvic ganglion indicated that connections from spinal preganglionic neurons to pelvic ganglion neurons were already present by E12, a time at which these autonomic ganglion neurons had not yet innervated the bladder. These putative preganglionic inputs increased in density prior to birth as axon terminal fields continued to expand within the bladder tissues. Our studies also revealed in numerous pelvic ganglion neurons an unexpected transient expression of calcitonin gene-related peptide, a peptide commonly used to visualise the peptidergic class of visceral sensory axons. Together, our outcomes enhance our understanding of neural regulatory elements in the lower urinary tract during development and provide a foundation for studies of plasticity and regenerative capacity in the adult system.

ObjectiveTo determine the molecular basis of a new monogenetic recessive disorder that results in familial autonomic ganglionopathy with diffuse autonomic failure.MethodsTwo adult siblings from one family (I-4 and I-5) and another participant from a second family (II-3) presented with severe neurogenic orthostatic hypotension (nOH), small nonreactive pupils, and constipation. All 3 affected members had low norepinephrine levels and diffuse panautonomic failure.ResultsWhole exome sequencing of DNA from I-4 and I-5 showed compound heterozygosity for c.907_908delCT (p.L303Dfs*115)/c.688 G>A (p.D230N) pathologic variants in the acetylcholine receptor, neuronal nicotinic, α3 subunit gene (CHRNA3). II-3 from the second family was homozygous for the same frameshift (fs) variant (p.L303Dfs*115//p.L303Dfs*115). CHRNA3 encodes a critical subunit of the nicotinic acetylcholine receptors (nAChRs) responsible for fast synaptic transmission in the autonomic ganglia. The fs variant is clearly pathogenic and the p.D230N variant is predicted to be damaging (SIFT)/probably damaging (PolyPhen2). The p.D230N variant lies on the interface between CHRNA3 and other nAChR subunits based on structural modeling and is predicted to destabilize the nAChR pentameric complex.ConclusionsWe report a novel genetic disease that affected 3 individuals from 2 unrelated families who presented with severe nOH, miosis, and constipation. These patients had rare pathologic variants in the CHRNA3 gene that cosegregate with and are predicted to be the likely cause of their diffuse panautonomic failure.

Selective sympathetic and parasympathetic pathways that act on target organs represent the terminal actors in the neurobiology of homeostasis and often become compromised during a range of neurodegenerative and traumatic disorders. Here, we delineate several neurotransmitter and neuromodulator phenotypes found in diverse parasympathetic and sympathetic ganglia in humans and rodent species. The comparative approach reveals evolutionarily conserved and non-conserved phenotypic marker constellations. A developmental analysis examining the acquisition of selected neurotransmitter properties has provided a detailed, but still incomplete, understanding of the origins of a set of noradrenergic and cholinergic sympathetic neuron populations, found in the cervical and trunk region. A corresponding analysis examining cholinergic and nitrergic parasympathetic neurons in the head, and a range of pelvic neuron populations, with noradrenergic, cholinergic, nitrergic, and mixed transmitter phenotypes, remains open. Of particular interest are the molecular mechanisms and nuclear processes that are responsible for the correlated expression of the various genes required to achieve the noradrenergic phenotype, the segregation of cholinergic locus gene expression, and the regulation of genes that are necessary to generate a nitrergic phenotype. Unraveling the neuron population-specific expression of adhesion molecules, which are involved in axonal outgrowth, pathway selection, and synaptic organization, will advance the study of target-selective autonomic pathway generation.

The proposed methodological program for conservative treatment of oncological diseases does not contradict the good medical practices for chemotherapy. In order to improve the general condition of patients, chemoprevention and/or homeopathy could be applied, but not at the expense of a varied diet, incl. table salt, water, culinary acidifiers and fats. Alternative medicine should only be used to treat individual symptoms, not syndromes., This book is a long-term study and analysis presented in a more scientifically popular form. The matter is presented in a freer way in order to explain the matter. GOALS AND OBJECTIVES OF THE STUDY First goal: A study of what exactly is the reason for the long-term use of toxic amygdalin in the social group Annotation to the realization of the objective: By making a precise socio-anthropological analysis of the life of the ancient people of Botra (Hunza people, Burusho / Brusho people), we come to the hypothesis, which is confirmed by two proofs, through a number of modern quantum-mechanical, molecular-topological and bio-analytical checks. A convenient, harmless, form of amygdalin derivative is available that has the same biological and chemical activity and could be used in conservative clinical oncology. The article also presents a theoretical comparative analysis of biochemical reactivity in in vivo and in vitro media, by which we also determine the recommended dosage for patient administration. Based on a comparative analysis of the data, obtained in published clinical studies of amygdalin, is presented and summarized a scheme of the anti-tumor activity Presentation and scientific popularization of the results: some of the conducted researches are published in the format of an article - Theoretical Analysis for the Safe Form and Dosage of Amygdalin Product https://doi.org/10.2174/1871520620666200313163801. Second goal: Analysis of molecules forming activity in the environment around the cancer cell and their ability to cross the cell membrane Annotation to the realization of the objective: This scientific analysis is a continuation of the first goal (§I.1.). The hypothesis that hydrolyzed to amine/carboxylic acid cyano/nitrile glycosides are a potential anticancer drug has been proposed and theoretically confirmed there. Their biological activity remains unchanged directly from the natural compounds of this group, but their toxicity is many times lower than unmodified native molecules. After defining the chemical formula and determining the pharmaceutical form and dosage, most active groups are also identified, which directly determines their biological activity. Presentation and scientific popularization of the results some of the conducted researches are published in the format of an article - Theoretical Study of the Process of Passage of Glycoside Amides through the Cell Membrane of Cancer Cell https://doi.org/10.2174/1871520620999201103201008 . Third goal: Analysis of models for evaluation of the offered pharmaceutical forms Annotation to the realization of the objective: The pharmaceutical form allows deviation from the chemically pure substance. This is a convenient and at the same time affordable (from a financial and / or technological point of view) form of admission by patients. It is not necessary to use an "ideal" pure active substance (including a specific isomeric form). Due to the wide variety of natural glucosamide nitriles (starting material for the production of amide / carboxylic acid), modern pharmacology allows their combined use by chemical nature and concentration of the active form passing through the cell membrane. Methodology: A comparative analysis is performed based on stoichiometric calculations for the concentration of the active form and the prediction of bioactivity. For this purpose, the following methodology is used: Analysis of data on the active molecular form of anticancer cells and determination of the drug dose. Presentation and scientific popularization of the results: some of the conducted researches are published in the format of an article - Theoretical analysis of anticancer cellular effects of glycoside amides https://doi.org/10.2174/1871520621666210903122831 . AUTHOR'S NOTES With the present scientific work we have tried to present in a more generalized form our long-term theoretical research. We tried to draw every value, every dependence and every conclusion precisely, in a form that is not subject to any personal view and/or to be enslaved to a generally "accepted" opinion. Natural nitrile glycosides would not cross the tumor cell membrane. They decompose to HCN-acid, phenyl methanol and carbohydrate. They do NOT have antitumor activity due to their inability to reach the target unchanged. These compounds, in their natural form, are extremely toxic to the human body. Applying them is not a cure, even at higher concentrations they do more harm than good. Theoretically, we have derived dozens of their modified forms, but their amides and carboxylic acids are the most promising for their introduction in conservative oncology. The fact is that the tumor cell itself is trying to counteract in a way that is quite safe for it. 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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.

OBJECTIVE: This study aimed to explore the safety and effectiveness of selective cardiac autonomic ganglion plexus (GP) ablation on patients with bradyarrhythmia. The heart is controlled by its own intrinsic and central autonomic nerves. Increased cardiac vagal tone leads to sinus node dysfunction and atrioventricular conduction disorders, resulting in bradyarrhythmia. Pacemaker implantation can relieve the symptoms of arrhythmia caused by bradycardia, but it is not easy for patients to accept a pacemaker implantation as a form of treatment. Therefore, more and more attention has been paid to cardiac vagus nerve ablation. METHODS: In this study, 20 patients who met the inclusion criteria of GP ablation in the First Affiliated Hospital of Xinjiang Medical University from November 2019 to June 2020 were enrolled. Biochemical and other related examinations along with electrophysiological examinations were conducted before ablation, and then cardiac GP ablation was performed. The patients were followed up 3 times at 3, 6, and 12 months after the operation. RESULTS: The minimum HR and mean HR were significantly increased after treatment with cardiac autonomic GP ablation (p

PSMA-based nuclear medicine imaging impacts increasingly the clinical decision process in prostate cancer patients. A well-known PSMA pitfall is uptake into autonomic ganglia. The intensity of uptake, the shape, and the exact location of the correlating structure in CT are supposed to aid discriminating between ganglia and lymph node metastases. In this patient, we found intense uptake in a nodular shaped para-aortal soft tissue lesion suspicious of a lymph node metastases at staging as well as restaging. After secondary resection, the lesion was histologically proven an autonomic ganglion with intense PSMA expression.

Background The presence of calcitonin gene-related peptide and its receptors in multiple brain areas and peripheral tissues previously implicated in migraine initiation and its many associated symptoms raises the possibility that humanized monoclonal anti-calcitonin gene-related peptide antibodies (CGRP-mAbs) can prevent migraine by modulating neuronal behavior inside and outside the brain. Critical to our ability to conduct a fair discussion over the mechanisms of action of CGRP-mAbs in migraine prevention is data generation that determines which of the many possible peripheral and central sites are accessible to these antibodies – a question raised frequently due to their large size. Material and methods Rats with uncompromised and compromised blood-brain barrier (BBB) were injected with Alexa Fluor 594-conjugated fremanezumab (Frema594), sacrificed 4 h or 7 d later, and relevant tissues were examined for the presence of Frema594. Results In rats with uncompromised BBB, Frema594 was similarly observed at 4 h and 7 d in the dura, dural blood vessels, trigeminal ganglion, C2 dorsal root ganglion, the parasympathetic sphenopalatine ganglion and the sympathetic superior cervical ganglion but not in the spinal trigeminal nucleus, thalamus, hypothalamus or cortex. In rats with compromised BBB, Frema594 was detected in the cortex (100 µm surrounding the compromised BBB site) 4 h but not 7 d after injections. Discussion Our inability to detect fluorescent (CGRP-mAbs) in the brain supports the conclusion that CGRP-mAbs prevent the headache phase of migraine by acting mostly, if not exclusively, outside the brain as the amount of CGRP-mAbs that enters the brain (if any) is too small to be physiologically meaningful.

Japanese encephalitis (JE) is a known CNS viral infection that often involves the thalamus early. To investigate the possible role of sensory peripheral nervous system (PNS) in early neuroinvasion, we developed a left hindlimb footpad-inoculation mouse model to recapitulate human infection by a mosquito bite. A 1–5 days postinfection (dpi) study, demonstrated focal viral antigens/RNA in contralateral thalamic neurons at 3 dpi in 50% of the animals. From 4 to 5 dpi, gradual increase in viral antigens/RNA was observed in bilateral thalami, somatosensory, and piriform cortices, and then the entire CNS. Infection of neuronal bodies and adjacent nerves in dorsal root ganglia (DRGs), trigeminal ganglia, and autonomic ganglia (intestine, etc.) was also observed from 5 dpi. Infection of explant organotypic whole brain slice cultures demonstrated no viral predilection for the thalamus, while DRG and intestinal ganglia organotypic cultures confirmed sensory and autonomic ganglia susceptibility to infection, respectively. Early thalamus and sensory-associated cortex involvement suggest an important role for sensory pathways in neuroinvasion. Our results suggest that JE virus neuronotropism is much more extensive than previously known, and that the sensory PNS and autonomic system are susceptible to infection.

Objectives To evaluate: (i) the neuro-regenerative potential of chitosan membrane (CS-Me) on acutely axotomised autonomic neurones in vitro; (ii) to exclude the possibility that a pro-regenerative biomaterial could interfere with the proliferation activity of prostate cancer cell lines; (iii) to provide an in vivo proof of the biocompatibility and regeneration promoting effect of CS-Me in a standardised rat model of peripheral nerve injury and repair; (iv) finally, to evaluate the tissue reaction induced by the degrading material; as previous studies have shown promising effects of CS-Me for protection of the neurovascular bundles for potency recovery in patients that undergo nerve-sparing radical prostatectomy (RP). Materials and methods Addressing aim (i), the neuro-regenerative potential, organotypic cultures derived from primary sympathetic ganglia were cultured on CS-Me over 3 days and neurite extension and axonal sprouting were evaluated. Addressing aim (ii), effects of CS on cancer cells, different human prostate cancer cell lines (PC3, DU-145, LN-Cap) were seeded on CS-coated plates or cultured in the presence of CS-Me dissolution products. Addressing aims (iii) and (iv), functional recovery of peripheral nerve fibres and tissue reaction with the biomaterial, CS-Me and CS nerve guides were used to repair a median nerve injury in the rat. Functional recovery was evaluated during the post-recovery time by the behavioural grasping test. Results CS-Me significantly stimulated axon elongation from autonomic ganglia in comparison to control conditions in organotypic three-dimensional cultures. CS coating, as well as the dissolution products of CS-Me, led to a significantly lower proliferation rate of prostate cancer cell lines in vitro. Tissue reaction towards CS-Me and standard CS nerve guides was similar in the rat median nerve model, as was the outcome of nerve fibre regeneration and functional recovery. Conclusion The results of this study provide the first experimental evidence in support of the clinical safety of CS-Me and of their postulated effectiveness for improving functional recovery after RP. The presented results are coherent in demonstrating that acutely axotomised autonomic neurones show increased neurite outgrowth on CS-Me substrate, whilst the same substrate reduces prostate cancer cell line proliferation in vitro. Furthermore, CS-Me do not demonstrate any disadvantage for peripheral nerve repair in a standard animal model.

The aims of the present study were to describe, in male rats, the anatomical organization of the major and accessory pelvic ganglia (MPG, AG; respectively), the interrelationship of the pelvic plexus components, and the morphometry of the pelvic postganglionic neurons. Anatomical, histochemical and histological studies were performed in anesthetized adult Wistar male rats. We found that the pelvic plexus consists of intricate neural circuits composed of two MPG, and three pairs of AG (AGI, AGII, AGIII) anatomically interrelated through ipsilateral and contralateral commissural nerves. Around 30 nerves emerge from each MPG and 17 from AGI and AGII. The MPG efferent nerves spread out preganglionic information to several pelvic organs controlling urinary, bowel, reproductive and sexual functions, while AG innervation is more regional, and it is confined to reproductive organs located in the rostral region of the urogenital tract. Both MPG and AG contain nerve fascicles, blood vessels, small intensely fluorescent cells, satellite cells and oval neuronal somata with one to three nucleoli. The soma area of AG neurons is larger than those of MPG neurons (p 0.005). The MPG contains about 75% of the total pelvic postganglionic neurons. Our findings corroborated previous reports about MPG inputs, and add new information regarding pelvic ganglia efferent branches, AG neurons (number and morphometry), and neural interrelationship between the pelvic plexus components. This information will be useful in designing future studies about the role of pelvic innervation in the physiology and pathophysiology of pelvic functions.

Small fiber polyneuropathy is a well-recognized syndrome mitigated by somatic sensory afferent and autonomic efferent nerve fibers that respectively mediate pain, heat and cold temperature afferent and autonomic efferent function in the skin. A patient with low serum titers of neuronal acetylcholine receptor ganglionic antibodies and autonomic failure had symptomatic small fiber polyneuropathy late in life in the setting of autoimmune dementia and encephalopathy and prostate cancer. Large and small fiber polyneuropathy and dysautonomia were detected in routine electrodiagnostic and autonomic laboratory studies, and epidermal nerve fiber analysis of the calf and thigh. Clinical improvement for one year concomitant with intravenous immune globulin therapy preceded a clinical decline in neurocognitive function and death. Postmortem examination showed typical features of Alzheimer disease with neuropathic neuropathological changes in the peripheral nervous system, and viable autonomic ganglia consistent with a channelopathy mechanism involving postsynaptic neuronal nAChRs.

Neuronal aggregates of misfolded alpha-synuclein protein are found in the brain and periphery of patients with Parkinson’s disease. Braak and colleagues have hypothesized that the initial formation of misfolded alpha-synuclein may start in the gut, and then spread to the brain via peripheral autonomic nerves hereby affecting several organs, including the heart and intestine. Age is considered the greatest risk factor for Parkinson’s disease, but the effect of age on the formation of pathology and its propagation has not been studied in detail. We aimed to investigate whether propagation of alpha-synuclein pathology from the gut to the brain is more efficient in old versus young wild-type rats, upon gastrointestinal injection of aggregated alpha-synuclein. Our results demonstrate a robust age-dependent gut-to-brain and brain-to-gut spread of alpha-synuclein pathology along the sympathetic and parasympathetic nerves, resulting in age-dependent dysfunction of the heart and stomach, as observed in patients with Parkinson’s disease. Moreover, alpha-synuclein pathology is more densely packed and resistant to enzymatic digestion in old rats, indicating an age-dependent maturation of alpha-synuclein aggregates. Our study is the first to provide a detailed investigation of alpha-synuclein pathology in several organs within one animal model, including the brain, skin, heart, intestine, spinal cord and autonomic ganglia. Taken together, our findings suggest that age is a crucial factor for alpha-synuclein aggregation and complete propagation to heart, stomach and skin, similar to patients. Given that age is the greatest risk factor for human Parkinson’s disease, it seems likely that older experimental animals will yield the most relevant and reliable findings. These results have important implications for future research to optimize diagnostics and therapeutics in Parkinson’s disease and other age-associated synucleinopathies. Increased emphasis should be placed on using aged animals in preclinical studies and to elucidate the nature of age-dependent interactions., Van DB et al. show that ageing facilitates the propagation of alpha-synuclein pathology from gut to brain in rats. In aged rats, alpha-synuclein pathology is also more resistant to enzymatic digestion, suggesting that older animals may provide superior models of neurodegenerative diseases such as Parkinson's disease.

BACKGROUND In mice, Schwann cell (SC) progenitors give rise to autonomic ganglion cells and migrate into the gut to become enteric neurons. It is unknown whether SC progenitors have a similar fate in humans. In search of evidence for human SC-derived neurogenesis in the gastrointestinal (GI) tract, we studied the rectums from cadaveric controls and children with anorectal malformations (ARM). METHODS We analyzed distal rectal tissue taken at autopsy from 10 children with normal GI tracts and resected rectal specimens in 48 cases of ARM. Of these specimens, 6 had neurons within the extrinsic rectal innervation. These were further investigated with immunohistochemistry for neuronal and SC/glial markers. KEY RESULTS Perirectal tissue from control and ARM contained GLUT1-positive extrinsic nerves, many containing neurons. SC/glial markers (SOX10, CDH19, and PLP1) were expressed by glia in the enteric nervous system and perirectal nerves, while MPZ predominated only in glia of perirectal nerves, in both control and ARM. Neurons in perirectal nerves were 61% larger in ARM samples and co-expressed SOX10 (81%), PLP1 (73%), and CDH19 (56%). In ARM, cytoplasmic SOX10 was co-expressed with neuronal antigens in ~57% of submucosal and myenteric neurons, vs. ~3% in control. Furthermore, intrinsic gut neurons in ARM specimens co-expressed PLP1 (18%) and CDH19 (18%); however, neuronal co-expression of PLP1 and CDH19 was rarely (

Ganglioneuromas (GNs) are benign, differentiated tumors that are derived from neural crest sympathogonia. They can be found anywhere in the body along autonomic ganglia. These tumors are seen most often in individuals over 10 years of age and are usually asymptomatic. However, GNs can grow large and cause symptoms due to mass effect. GNs are rarely located within the suprarenal gland and are benign tumors that are often diagnosed late in their course due to mass effect or found incidentally on imaging studies. We describe a case of a 22-year-old female who presented to clinic with vague abdominal pain. She underwent an extensive workup which ultimately revealed a rare presentation of a left suprarenal GN that required surgical removal. She underwent an extensive workup which ultimately revealed a left suprarenal GN that required surgical removal. The patient underwent laparotomy and surgical excision of the mass and made a full recovery.

The available literature provides relatively little information on the morphology of the autonomic head ganglia in rodents including their neurochemical codding. The present study was thus designed to investigate the morphology and neurochemical properties of the otic ganglion in the chinchilla. The results will contribute to our knowledge of the organization of the autonomic nerve system in mammals.Morphological investigations of the otic ganglion were performed using the modified acetylcholinesterase method. The cellular structure was investigated with histological techniques and neurochemical properties were studied with double-labelling immunofluorescence methodMacromorphological investigations allowed the otic ganglion to be identified as a compact, oval agglomeration of neurons and nerve fibers located inside the skull on the medial surface of the mandibular nerve, just above the oval foramen. Multidimensional cross-sections revealed densely arranged neuronal perikarya and two populations of nerve cells differing in size were distinguished. The large cells (40–50 μm) accounted for about 80% of the neurons in the otic ganglion cross-sections. Moreover, a small number of intraganglionic nerve fibers was observed. Immunohistochemical staining revealed that over 85% of the neuronal cell bodies in the otic ganglion contained immunoreactivity to VAChT or ChAT. VIP-immunoreactive perikarya comprised approximately 10% of the ganglionic cells. Double staining revealed the presence of VAChT and NOS-positive neurons which amounted to about 45% of the nerve cells in the otic ganglion. NOS-positive only perikarya comprised approx. 15% of all the neurons. Immunoreactivity to enkephalin, substance P, somatostatin and galanin was expressed in single nerve cell bodies and nerve fibres except numerous SP-positive intraganglionic nerve fibres. Some of them stained also for CGRP. Single neurons stained for TH.The present results, compared with previous findings, suggest the existence interspecies differences in the morphology, cellular structure and immunohistochemical properties of the head autonomic ganglia in mammals.

One of the major roles of the intracardiac nervous system (ICNS) is to act as the final site of signal integration for efferent information destined for the myocardium to enable local control of heart rate and rhythm. Multiple subtypes of neurons exist in the ICNS where they are organized into clusters termed ganglionated plexi (GP). The majority of cells in the ICNS are actually glial cells; however, despite this, ICNS glial cells have received little attention to date. In the central nervous system, where glial cell function has been widely studied, glia are no longer viewed simply as supportive cells but rather have been shown to play an active role in modulating neuronal excitability and synaptic plasticity. Pioneering studies have demonstrated that in addition to glia within the brain stem, glial cells within multiple autonomic ganglia in the peripheral nervous system, including the ICNS, can also act to modulate cardiovascular function. Clinically, patients with atrial fibrillation (AF) undergoing catheter ablation show high plasma levels of S100B, a protein produced by cardiac glial cells, correlated with decreased AF recurrence. Interestingly, S100B also alters GP neuron excitability and neurite outgrowth in the ICNS. These studies highlight the importance of understanding how glial cells can affect the heart by modulating GP neuron activity or synaptic inputs. Here, we review studies investigating glia both in the central and peripheral nervous systems to discuss the potential role of glia in controlling cardiac function in health and disease, paying particular attention to the glial cells of the ICNS.

The pelvic ganglia are unusual autonomic ganglia in that they receive innervation from both the lumbar and sacral spinal cord, i.e. they are "mixed" sympathetic and parasympathetic ganglia. The hypogastric and pelvic nerves carry preganglionic inputs from the lumbar and sacral spinal cord, respectively. Studies in other autonomic ganglia have shown that when a proportion of preganglionic inputs are removed (partial decentralisation), reorganisation occurs within the ganglia where remaining preganglionic axons grow collaterals that reinnervate neurons that have lost spinal inputs. These new fibres successfully form viable synapses. Although fewer studies have examined collateral axon growth from ganglion cells after decentralisation, a small number of reports indicate that this occurs. Previous animal studies have suggested that after either lumbar or sacral nerve injury, some functional connections are restored between preganglionic and postganglionic neurons. It has been proposed that intact preganglionic axons grow sprouts and supply denervated ganglion cells as demonstrated in partial decentralisation experiments in purely sympathetic and parasympathetic ganglia. However, this type of sprout growth has never been demonstrated in the pelvic ganglia. Since sprout growth from ganglion cells has been reported after decentralisation the aims of this thesis are therefore to determine if sprouting from pelvic ganglion neurons could contribute to reorganisation seen in these animal studies, and whether nerve growth factor plays a role in some of this sprout growth.In order to understand changes after injury, the normal characteristics of pelvic ganglion neurons must be established. At the time of commencing this project the innervation of most pelvic ganglion projections in the rat had been characterised. The only exception was the autonomic innervation of the seminal vesicles. Retrograde tracing from the seminal vesicles and immunohistochemical analysis of labelled neurons identified pelvic ganglion neurons projecting to this organ. Neuropeptide Y was found to be the most abundant marker followed by tyrosine hydroxylase and vasoactive intestinal peptide. The hypogastric or pelvic nerves were then cut and remaining spinal inputs were visualised. The majority of the neurons innervating the seminal vesicles receive inputs from the lumbar spinal cord (i.e. sympathetic) and a small proportion of these were of a cholinergic phenotype. Furthermore, after cutting the hypogastric, pelvic or both nerves, the three markers used to immunolabel these neurons were examined to determine if their expression was changing substantially after decentralisation. The number of neurons containing tyrosine hydroxylase and neuropeptide Y did not alter after any type of injury, whereas there was a very small reduction in the number of VIP neurons whenever the pelvic nerve was transected.The next section of the thesis investigated whether ganglion cells themselves contribute to sprout growth and restoration of peripheral circuitry. The growth of sprouts from ganglion cells was monitored after partial decentralisation (hypogastric or pelvic nerve transection) or total decentralisation (dual nerve cut), and visualised by immunolabelling the three markers mentioned above. The proportion of pelvic neurons closely associated with newly formed varicose, immunostained fibres was then assessed.

Acute-onset and severe sensory and autonomic deficits with no motor dysfunction, typically preceded by a febrile illness, with poor recovery, and often fatal outcome are the hallmark features of acute sensory and autonomic neuronopathy (ASANN). Pathologically and electrophysiologically, ASANN is characterized by an extensive ganglionopathy affecting sensory and autonomic ganglia with preservation of motor neurons. Consequently, patients, usually children or young adult, develop acute-onset profound widespread loss of all sensory modalities resulting in automutilations, as well as autonomic failure causing neurogenic orthostatic hypotension, neurogenic underactive bladder, and gastroparesis and constipation. The diagnosis is clinical with support of nerve conduction studies and autonomic testing, as well as spinal cord magnetic resonance imaging showing characteristic posterior cord hyperintensities. Although the presumed etiology is immune-mediated, further studies are required to clarify the physiopathology of the disease. We here performed a systematic review of the epidemiology, pathophysiology, diagnosis, and management of ASANN, with three representative cases that recently presented at our clinic. All three patients had the typical clinical manifestations of ASANN but in different combinations, illustrating the variable phenotype of the disorder. Immunosuppression is seldom effective. Management options are limited to supportive and symptomatic care with the goal of minimizing complications and preventing death.

Renaissance England witnessed a series of brief epidemics of a rapid and often fatal illness, the predominant feature of which was a disturbance of the autonomic nervous system. Profuse sweating was both an emblematic and ominous sign of this Sudor Anglicus. Its story is medically fascinating as well as historically noteworthy. Possible sites of pathological involvement include the hypothalamus, serotonergic neurons in the brainstem or spinal cord, autonomic ganglia, peripheral sympathetic nerves, neuroeffector junctions, or eccrine glands. Of candidate etiologic agents, a virus is most likely, given the seasonal variation, geographic clustering, and pattern of spread of the epidemics. Hantaviruses, enteroviruses, influenza, and others provide clinical comparisons, but a definitive match with known viruses has remained elusive.

The pelvic splanchnic nerves are essential for pelvic organ function and have been proposed as targets for neuromodulation. We have focused on the rodent homologue of these nerves, the pelvic nerves. Our goal was to define within the pelvic nerve the projections of organ‐specific sensory axons labelled by microinjection of neural tracer (cholera toxin, subunit B) into the bladder, urethra or rectum. We also examined the location of peptidergic sensory axons within the pelvic nerves to determine whether they aggregated separately from sacral preganglionic and paravertebral sympathetic postganglionic axons travelling in the same nerve. To address these aims, microscopy was performed on the major pelvic ganglion (MPG) with attached pelvic nerves, microdissected from young adult male Sprague–Dawley rats (6–8 weeks old) and processed as whole mounts for fluorescence immunohistochemistry. The pelvic nerves were typically composed of five discrete fascicles. Each fascicle contained peptidergic sensory, cholinergic preganglionic and noradrenergic postganglionic axons. Sensory axons innervating the lower urinary tract (LUT) consistently projected in specific fascicles within the pelvic nerves, whereas sensory axons innervating the rectum projected in a complementary group of fascicles. These discrete aggregations of organ‐specific sensory projections could be followed along the full length of the pelvic nerves. From the junction of the pelvic nerve with the MPG, sensory axons immunoreactive for calcitonin gene‐related peptide (CGRP) showed several distinct patterns of projection: some projected directly to the cavernous nerve, others projected directly across the surface of the MPG to the accessory nerves and a third class entered the MPG, encircling specific cholinergic neurons projecting to the LUT. A subpopulation of preganglionic inputs to noradrenergic MPG neurons also showed CGRP immunoreactivity. Together, these studies reveal new molecular and structural features of the pelvic nerves and suggest functional targets of sensory nerves in the MPG. These anatomical data will facilitate the design of experimental bioengineering strategies to specifically modulate each axon class., The pelvic nerve is a mixed sensory‐motor nerve and a potential target of neuromodulation for pelvic organ dysfunction. We have visualised neural components within its individual fascicles and identified segregation of sensory pathways innervating the lower bowel and urinary tracts. We have also defined new features of sensory connectivity in the pelvic ganglia. These anatomical data will facilitate the design of experimental bioengineering strategies to specifically modulate each axon class.

International audience; The bilateral major pelvic ganglia (MPG; synonym, pelvic ganglia) are the primary source of postganglionic sympathetic and parasympathetic neurons innervating pelvic organs of rodents; the functionally equivalent structure in humans is the inferior hypogastric plexus. The major pelvic ganglia also provide the route by which lumbar and sacral sensory axons reach the pelvic organs. These complex, mixed ganglia can prove challenging to identify and dissect for further experimental study of normal autonomic mechanisms or to establish preclinical models of disease, injury or visceral pain. Here we describe a protocol to access and visualize these ganglia and their associated nerve tracts. We provide this protocol with schematics for both male and female rats, as the ganglion size and landmarks for identification differ between sexes. The protocol describes removal of the ganglion for in vitro studies, but this method can be integrated into a surgical recovery protocol for experimental interventions (e.g., nerve crush, nerve resection) or for mapping neuronal circuits (e.g., by microinjection of neural tracers). We also demonstrate the primary structures of the ganglion and its associated nerves immediately following dissection and following immunohistochemical staining.

The autonomic innervation in the anterior chamber (AC) structures might play an efferent role in neural intraocular pressure (IOP) regulation, the center of which is thought to be located in the hypothalamus. In this study, we identified the efferent pathway from the hypothalamus to the autonomic innervation in the AC structures. Retrograde trans-multisynaptic pseudorabies virus (PRV) expressing green or red fluorescent protein, PRV531 and PRV724, was injected into the right and left AC of five rats, respectively; PRV531 was injected into the right AC of another five rats, and a non-trans-synaptic tracer, FAST Dil, was injected into the right AC of five rats as a control. Fluorescence signals in autonomic ganglia,the spinal cord and the central nervous system (CNS) were observed. Seven days after FAST Dil right AC injection, FAST Dil-labeled neurons were observed in the ipsilateral autonomic ganglia, including the superior cervical ganglion, pterygopalatine ganglion, and ciliary ganglion, but not in the CNS. Four and a half days after PRV531 injection into the right AC, PRV531-labeled neurons could be observed in the ipsilateral autonomic ganglia and bilateral hypothalamus nuclei, especially in the suprachiasmatic nucleus, paraventricular nucleus, dorsomedial hypothalamus, perifornical hypothalamus and ventral mammillary nucleus. Fluorescence signals of PRV531 mainly located in the ipsilateral autonomic preganglionic nuclei (Edinger-Westphal nucleus, superior salivatory nucleus and intermediolateral nucleus), but not in sensory trigeminal nuclei. Four and a half days after PRV531 right AC injection and PRV724 left AC injection, PRV531-labeled, PRV724-labeled, and double-labeled neurons could be observed in the above mentioned bilateral hypothalamus nuclei; but few contralateral infection-involving neurons (including double-labeled neurons) could be detected in the autonomic preganglionic nuclei. Our results indicate that there exist a both crossed and uncrossed hypothalamo-pre-parasympathetic and -pre-sympathetic tracts in the efferent pathways between the bilateral hypothalamic nuclei and the autonomic innervation of the bilateral AC.

Data on the role of the autonomic nervous system in the mechanism of transmission of cardioprotective signals associated with remote ischemic preconditioning (RIPre) are contradictory. Most investigators refer to the important role of the autonomic nervous system in transmitting the defensive signal from the ischemic organ to the heart. Thus, blockade of autonomic ganglia or impairments to the integrity of the conducting nerves have been found to prevent the development of the infarct-limiting effect of RIPre. At the same time, the authors of other studies have not seen a role for the autonomic nervous system in the mechanism of the cardioprotective effect of RIPre, assigning the major role to humoral factors. Some studies have demonstrated a contribution to the cardioprotective effect of RIPre via both humoral factors and the autonomic nervous system. Analysis of these data showed that there is still no clear answer to the question of why in some cases the autonomic nervous system plays an important role in remote preconditioning while in others it does not.

Background Ganglioneuroma (GN) is a slow-growing tumor originating from the neural crest–derived cells, which form the sympathetic nervous system. These tumors can affect anywhere along the peripheral autonomic ganglion sites and are most commonly found in the mediastinum and retroperitoneum. Spinal GNs are extremely rare and, so far, only 1 case arising from a lumbar nerve root has been reported in the English literature. GNs are often asymptomatic, and the majority of them are found incidentally in healthy subjects. Because of their slow growth, symptoms may result from the compressive effect of the tumor. Case Description A 40-year-old man presented with a right sciatica episode accompanied by global muscle weakness and tingling pain. Findings of the neurologic examination displayed positive Lasegue test and sensory deficit over L5–S1 dermatomes. Magnetic resonance imaging of the lumbar spine without contrast showed a well-circumscribed longitudinal lesion arising from L5–S1 disc space, moving us toward a diagnosis of lumbar disc herniation. During surgery, we observed a mass well-encapsulated and oval-shaped inside S1 right root. The patient underwent subtotal resection. Histopathologic examination showed clusters of ganglion mature cells with neuromatous stroma, consistent with a ganglioneuroma. Conclusions We report a case that illustrates the clinical, radiologic, and histopathologic features of a ganglioneuroma mimicking a lumbosciatica syndrome and review related literature and similar cases.

Peripheral nervous system (PNS) toxicity is surveyed inconsistently in nonclinical general toxicity studies. These Society of Toxicologic Pathology “best practice” recommendations are designed to ensure consistent, efficient, and effective sampling, processing, and evaluation of PNS tissues for four different situations encountered during nonclinical general toxicity (screening) and dedicated neurotoxicity studies. For toxicity studies where neurotoxicity is unknown or not anticipated (situation 1), PNS evaluation may be limited to one sensorimotor spinal nerve. If somatic PNS neurotoxicity is suspected (situation 2), analysis minimally should include three spinal nerves, multiple dorsal root ganglia, and a trigeminal ganglion. If autonomic PNS neuropathy is suspected (situation 3), parasympathetic and sympathetic ganglia should be assessed. For dedicated neurotoxicity studies where a neurotoxic effect is expected (situation 4), PNS sampling follows the strategy for situations 2 and/or 3, as dictated by functional or other compound/target-specific data. For all situations, bilateral sampling with unilateral processing is acceptable. For situations 1–3, PNS is processed conventionally (immersion in buffered formalin, paraffin embedding, and hematoxylin and eosin staining). For situation 4 (and situations 2 and 3 if resources and timing permit), perfusion fixation with methanol-free fixative is recommended. Where PNS neurotoxicity is suspected or likely, at least one (situations 2 and 3) or two (situation 4) nerve cross sections should be postfixed with glutaraldehyde and osmium before hard plastic resin embedding; soft plastic embedding is not a suitable substitute for hard plastic. Special methods may be used if warranted to further characterize PNS findings. Initial PNS analysis should be informed, not masked (“blinded”). Institutions may adapt these recommendations to fit their specific programmatic requirements but may need to explain in project documentation the rationale for their chosen PNS sampling, processing, and evaluation strategy.