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Brain, Behavior, and Immunity Oct 2019Gulf War Illness (GWI), affecting 30% of veterans from the 1991 Gulf War (GW), is a multi-symptom illness with features similar to those of patients with autoimmune...
Gulf War Illness (GWI), affecting 30% of veterans from the 1991 Gulf War (GW), is a multi-symptom illness with features similar to those of patients with autoimmune diseases. The objective of the current work is to determine if exposure to GW-related pesticides, such as permethrin (PER), activates peripheral and central nervous system (CNS) adaptive immune responses. In the current study, we focused on a PER metabolite, 3-phenoxybenzoic acid (3-PBA), as this is a common metabolite previously shown to form adducts with endogenous proteins. We observed the presence of 3-PBA and 3-PBA modified lysine of protein peptides in the brain, blood and liver of pyridostigmine bromide (PB) and PER (PB+PER) exposed mice at acute and chronic post-exposure timepoints. We tested whether 3-PBA-haptenated albumin (3-PBA-albumin) can activate immune cells since it is known that chemically haptenated proteins can stimulate immune responses. We detected autoantibodies against 3-PBA-albumin in plasma from PB + PER exposed mice and veterans with GWI at chronic post-exposure timepoints. We also observed that in vitro treatment of blood with 3-PBA-albumin resulted in the activation of B- and T-helper lymphocytes and that these immune cells were also increased in blood of PB + PER exposed mice and veterans with GWI. These immune changes corresponded with elevated levels of infiltrating monocytes in the brain and blood of PB + PER exposed mice which coincided with alterations in the markers of blood-brain barrier disruption, brain macrophages and neuroinflammation. These studies suggest that pesticide exposure associated with GWI may have resulted in the activation of the peripheral and CNS adaptive immune responses, possibly contributing to an autoimmune-type phenotype in veterans with GWI.
Topics: Adaptive Immunity; Adult; Animals; Benzoates; Brain; Central Nervous System; Disease Models, Animal; Female; Gulf War; Humans; Male; Mice; Mice, Inbred C57BL; Middle Aged; Permethrin; Persian Gulf Syndrome; Pyridostigmine Bromide; Veterans
PubMed: 31325531
DOI: 10.1016/j.bbi.2019.07.015 -
Revista Da Associacao Medica Brasileira... Apr 2018As the celiac disease (CD), the non-celiac gluten sensitivity (NCGS) has also been associated with several autoimmune manifestations. It is rarely associated with... (Review)
Review
As the celiac disease (CD), the non-celiac gluten sensitivity (NCGS) has also been associated with several autoimmune manifestations. It is rarely associated with myasthenia gravis (MG). This paper shall introduce the case of a young female patient, initially presenting a peripheral neuropathy framework. During clinical and neurological follow-up, she began to present symptoms of various immune-mediated morbidities. Diseases related to gluten represent a clinical spectrum of manifestations with a trigger in common, the ingestion of gluten. CD is the most well-known and serious disease of the spectrum, also called gluten-sensitive enteropathy. The NCGS is diagnosed from clinical evidence of improvement in symptoms followed by a Gluten Free Diet (GFD) in patients without signs of enteropathy in duodenal biopsy. There are indications that, although rare, with a prevalence of 1 in 5000, myasthenia gravis (MG) may occur more often when CD is also present. Between 13 to 22% of the patients with MG have a second autoimmune disorder. However, it is often associated with dermatomyositis or polymyositis, lupus erythematosussystemic lupus erythematosus, Addison's disease, Guillain-Barré syndrome and juvenile rheumatoid arthritis. Thus, the symptoms of neuromuscular junction involvement may give a diagnostic evidence of this rare association.
Topics: Adult; Ataxia; Cerebellar Diseases; Cholinesterase Inhibitors; Female; Food Hypersensitivity; Glutens; Humans; Magnetic Resonance Imaging; Myasthenia Gravis; Neuroimmunomodulation; Pyridostigmine Bromide; Vitamin B 12 Deficiency
PubMed: 30133608
DOI: 10.1590/1806-9282.64.04.311 -
Scientific Reports Oct 2017We previously reported that cholinergic stimulation with pyridostigmine (PY) induces anti-inflammatory cell recruitment soon after myocardial infarction (MI). In this...
We previously reported that cholinergic stimulation with pyridostigmine (PY) induces anti-inflammatory cell recruitment soon after myocardial infarction (MI). In this study, we evaluated the anti-inflammatory effects of PY during the proliferative phase of cardiac repair by analyzing the infiltration of macrophages, Treg lymphocytes, oxidative stress and inflammatory cytokines. Wistar rats underwent control sham surgery or ligation of the left coronary artery and were randomly allocated to remain untreated (untreated infarcted group, I) or to receive PY (30 mg·kg(-1)·day(-1)) in the supplied water (infarcted treated group, I + PY). Blood pressure and heart rate variability were registered at day 5 post-MI. The animals were euthanized 7 days after thoracotomy, when the hearts were removed and processed for immunohistochemistry (CD68, CD206, FOXP3), cytokines (IL-1β, IL-6, IL-10, TNF-α) and oxidative stress (superoxide dismutase, catalase, glutathione peroxidase, lipidic and protein peroxidation). PY treatment increased parasympathetic modulation, M2 macrophages and the anti-oxidant enzyme activity but reduced protein oxidation (carbonyls) and the concentration of IL-1β, IL-6, TNF-α and IL-10. Cholinergic stimulation induces parasympathetic neuro-immune modulation and anti-inflammatory cell enrollment as well as prevents oxidative stress and cytokine production after MI.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Cardiotonic Agents; Cholinesterase Inhibitors; Cytokines; Disease Models, Animal; Hemodynamics; Inflammation; Male; Myocardial Infarction; Oxidative Stress; Pyridostigmine Bromide; Random Allocation; Rats, Wistar
PubMed: 29057895
DOI: 10.1038/s41598-017-14021-8 -
Medicine Mar 2018Donor safety is the major concern in living donor liver transplantation, although hepatic resection may be associated with postoperative coagulopathy. Recently, the use... (Observational Study)
Observational Study
Donor safety is the major concern in living donor liver transplantation, although hepatic resection may be associated with postoperative coagulopathy. Recently, the use of sugammadex has been gradually increased, but sugammadex is known to prolong prothrombin time (PT) and activated partial thromboplastin time (aPTT). We compared the postoperative coagulation profiles and outcomes of sugammadex versus pyridostigmine group in donors receiving living donor hepatectomy.Consecutive donor hepatectomy performed between September 2013 and August 2016 was retrospectively analyzed. For reversal of rocuronium-induced neuromuscular blockade, donors received sugammadex 4 mg/kg or pyridostigmine 0.25 mg/kg. The primary end-points were laboratory findings (PT, aPTT, hemoglobin, platelet count) and clinically evaluated postoperative bleeding (relaparotomy for bleeding, cumulative volume collected in drains). Secondary outcomes were anesthesia time, postoperative hospital day.Of 992 donors, 383 treated with sugammadex and 609 treated with pyridostigmine for the reversal of neuromuscular blockade. There were no significant differences between both groups for drop in hemoglobin and platelet, prolongation in PT, aPTT, and the amount of 24-h drain volume. Bleeding events within 24 h were reported in 2 (0.3%) for pyridostigmine group and 0 (0%) for sugammadex group (P = .262). Anesthesia time was significantly longer in pyridostigmine group than that in sugammadex group (438.8 ± 71.4 vs. 421.3 ± 62.3, P < .001). Postoperative hospital stay was significantly longer in pyridostigmine group than that in sugammadex group (P = .002).Sugammadex 4 mg/kg was not associated with increased bleeding tendency, but associated with reduced anesthesia time and hospital stay. Therefore, sugammadex may be safely used and will decrease morbidity in donor undergoing living-donor hepatectomy.
Topics: Adult; Androstanols; Anesthesia Recovery Period; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Female; Hepatectomy; Humans; Liver Transplantation; Living Donors; Male; Neuromuscular Agents; Outcome and Process Assessment, Health Care; Postoperative Complications; Pyridostigmine Bromide; Retrospective Studies; Rocuronium; Sugammadex; gamma-Cyclodextrins
PubMed: 29538210
DOI: 10.1097/MD.0000000000010129 -
Medicine Nov 2023Facial-onset sensory and motor neuronopathy (FOSMN) is a greatly rare disease, so far, autopsy evidence that is associated with neurodegenerative. Myasthenia gravis (MG)...
RATIONALE
Facial-onset sensory and motor neuronopathy (FOSMN) is a greatly rare disease, so far, autopsy evidence that is associated with neurodegenerative. Myasthenia gravis (MG) is an antibody-mediated and complement-involved acquired autoimmune disorder of the post-synaptic neuromuscular junction. There have been few reports about if there is related between the 2. In this study, we present the case of a man who was diagnosed as FOSMN with MG in continuity.
PATIENT CONCERNS
The patient chief complaints were right-side facial numbness and right-eyelid incomplete closure, followed by slurred speech and dysphagia, and the symptoms gradually progressed. The patient serum was positive for anti-AchR and anti-Titin antibodies.
DIAGNOSES
The patient was diagnosed FOSMN with MG.
INTERVENTIONS
The patient symptoms were relieved after pyridostigmine bromide and prednisolone treatment.
OUTCOMES
Symptoms have improved.
LESSONS
Facial-onset sensory and motor neuronopathy and MG have disparate clinical features. Therefore, we reported a rare case in which the 2 conditions concurrently existed. Immune dysfunction might be the pathogenesis of this association, while there is no definite evidence to support it, further studies are needed.
Topics: Male; Humans; Myasthenia Gravis; Pyridostigmine Bromide; Deglutition Disorders
PubMed: 37986404
DOI: 10.1097/MD.0000000000034215 -
Journal of Neurochemistry Aug 2017Gulf War Illness (GWI) is a chronic multi-symptom disorder affecting veterans of the 1991 Gulf War. Among the symptoms of GWI are those associated with sickness...
Gulf War Illness (GWI) is a chronic multi-symptom disorder affecting veterans of the 1991 Gulf War. Among the symptoms of GWI are those associated with sickness behavior, observations suggestive of underlying neuroinflammation. We have shown that exposure of mice to the stress hormone, corticosterone (CORT), and to diisopropyl fluorophosphate (DFP), as a nerve agent mimic, results in marked neuroinflammation, findings consistent with a stress/neuroimmune basis of GWI. Here, we examined the contribution of irreversible and reversible acetylcholinesterase (AChE) inhibitors to neuroinflammation in our mouse model of GWI. Male C57BL/6J mice received 4 days of CORT (400 mg/L) in the drinking water followed by a single dose of chlorpyrifos oxon (CPO; 8 mg/kg, i.p.), DFP (4 mg/kg, i.p.), pyridostigmine bromide (PB; 3 mg/kg, i.p.), or physostigmine (PHY; 0.5 mg/kg, i.p.). CPO and DFP alone caused cortical and hippocampal neuroinflammation assessed by qPCR of tumor necrosis factor-alpha, IL-6, C-C chemokine ligand 2, IL-1β, leukemia inhibitory factor and oncostatin M; CORT pretreatment markedly augmented these effects. Additionally, CORT exposure prior to DFP or CPO enhanced activation of the neuroinflammation signal transducer, signal transducer and activator of transcription 3 (STAT3). In contrast, PHY or PB alone or with CORT pretreatment did not produce neuroinflammation or STAT3 activation. While all of the CNS-acting AChE inhibitors (DFP, CPO, and PHY) decreased brain AChE activity, CORT pretreatment abrogated these effects for the irreversible inhibitors. Taken together, these findings suggest that irreversible AChE inhibitor-induced neuroinflammation and particularly its exacerbation by CORT, result from non-cholinergic effects of these compounds, pointing potentially to organophosphorylation of other neuroimmune targets.
Topics: Acetylcholinesterase; Animals; Brain; Cholinesterase Inhibitors; Corticosterone; Disease Models, Animal; Gulf War; Male; Mice, Inbred C57BL; Organophosphates; Persian Gulf Syndrome; Pyridostigmine Bromide
PubMed: 28500787
DOI: 10.1111/jnc.14071 -
Clinical Autonomic Research : Official... Jun 2015Acetylcholine (Ach) is the pre-synaptic neurotransmitter of the sympathetic nervous system. Increased pre-synaptic Ach may augment post-synaptic release of... (Clinical Trial)
Clinical Trial
INTRODUCTION
Acetylcholine (Ach) is the pre-synaptic neurotransmitter of the sympathetic nervous system. Increased pre-synaptic Ach may augment post-synaptic release of norepinephrine, thereby increasing systemic blood pressure (BP).
OBJECTIVES
The primary objective of this investigation was to determine the hemodynamic effect of pyridostigmine bromide (PYRIDO: 60 mg), an Ach inhibitor (AchI), compared to no-drug (NO-D) during head-up tilt (HUT) in individuals with spinal cord injury (SCI). Secondarily, we aimed to determine the effects of PYRIDO compared to NO-D on symptoms of orthostatic intolerance (OI) and adverse event reporting (AE).
METHODS
Ten individuals with SCI (C4-C7) were studied on two occasions: visit (1) NO-D and visit (2) PYRIDO. On each visit subjects underwent a progressive HUT maneuver to 15°, 25°, 35° for 5 min at each angle and 45 min at 45°. Supine and orthostatic heart rate (HR), systolic and diastolic BP (SBP and DBP), as well as monitored and symptoms of OI and AE were monitored and recorded.
RESULTS
Supine hemodynamics did not differ between the trials. The significant fall in SBP during the NO-D trial was diminished with PYRIDO, and five subjects had an increased DBP during HUT with PYRIDO compared to the NO-D trial. Individuals that responded to PYRIDO with an increase in orthostatic BP had significantly lower resting HR than non-responders (p < 0.01), which suggests increased levels of pre-synaptic Ach. Subjective symptoms of OI and AE reporting did not differ between the two trials.
CONCLUSIONS
These preliminary data suggest that PYRIDO is safe and may be effective at ameliorating the orthostatic fall in BP in select individuals with SCI.
Topics: Adult; Blood Pressure; Cholinesterase Inhibitors; Female; Heart Rate; Hemodynamics; Humans; Male; Middle Aged; Orthostatic Intolerance; Pyridostigmine Bromide; Quadriplegia; Spinal Cord Injuries; Supine Position; Tilt-Table Test; Young Adult
PubMed: 25916633
DOI: 10.1007/s10286-015-0272-3 -
Brain Sciences Feb 2022Veterans with difficult-to-diagnose conditions who receive care in the Department of Veterans Affairs (VA) healthcare system can be referred for evaluation at one of...
Association of Gulf War Illness-Related Symptoms with Military Exposures among 1990-1991 Gulf War Veterans Evaluated at the War-Related Illness and Injury Study Center (WRIISC).
Veterans with difficult-to-diagnose conditions who receive care in the Department of Veterans Affairs (VA) healthcare system can be referred for evaluation at one of three specialty VA War-Related Illness and Injury Study Centers (WRIISC). Veterans of the 1990−1991 Gulf War have long experienced excess rates of chronic symptoms associated with the condition known as Gulf War Illness (GWI), with hundreds evaluated at the WRIISC. Here we provide the first report from a cohort of 608 Gulf War Veterans seen at the WRIISC who completed questionnaires on chronic symptoms (>6 months) consistent with GWI as well as prominent exposures during Gulf War deployment. These included veterans’ reports of hearing chemical alarms/donning Military-Ordered Protective Posture Level 4 (MOPP4) gear, pesticide use, and use of pyridostigmine bromide (PB) pills as prophylaxis against the effects of nerve agents. Overall, veterans in the cohort were highly symptomatic and reported a high degree of exposures. In multivariable models, these exposures were significantly associated with moderate-to-severe chronic symptoms in neurocognitive/mood, fatigue/sleep, and pain domains. Specifically, exposure to pesticides was associated with problems with concentration and memory, problems sleeping, unrefreshing sleep, and joint pain. Use of MOPP4 was associated with light sensitivity and unrefreshing sleep and use of PB was associated with depression. We also evaluated the association of exposures with symptom summary scores based on veterans’ severity of symptoms in four domains and overall. In multivariable modeling, the pain symptom severity score was significantly associated with pesticide use (Odds ratio (OR): 4.13, 95% confidence intervals (CI): 1.78−9.57) and taking PB pills (OR: 2.28, 95% CI: 1.02−5.09), and overall symptom severity was significantly associated with use of PB pills (OR: 2.41, 95% CI: 1.01−5.75). Conclusion: Decades after deployment, Gulf War veterans referred to a VA tertiary evaluation center report a high burden of chronic symptoms, many of which were associated with reported neurotoxicant exposures during the war.
PubMed: 35326276
DOI: 10.3390/brainsci12030321 -
Frontiers in Veterinary Science 2017A 6-month-old, male, intact mixed breed dog was presented for a 3-month history of progressive generalized weakness. Neurologic examination revealed non-ambulatory...
A 6-month-old, male, intact mixed breed dog was presented for a 3-month history of progressive generalized weakness. Neurologic examination revealed non-ambulatory tetraparesis, weakness of the head and neck, and decreased withdrawal reflexes in all limbs consistent with a generalized neuromuscular disorder. Electromyography and motor nerve conduction velocity were normal. Repetitive nerve stimulation showed a decremental response of the compound muscle action potential with improvement upon intravenous administration of edrophonium chloride. The serum acetylcholine receptor (AChR) antibody titer was within reference range. Cerebrospinal fluid analysis was unremarkable. A presumptive diagnosis of post-synaptic congenital myasthenic syndrome (CMS) was made. Treatment with pyridostigmine bromide was initiated with titrated increases in dosage resulting in an incomplete improvement in clinical signs. The dog was euthanized 2 months after initiation of treatment due to poor quality of life. Immunostaining for localization of antibodies against end-plate proteins in muscle biopsies was negative. Immunofluorescence staining for AChRs in external intercostal muscle biopsies showed absence of AChRs and biochemical quantitation showed a markedly decreased concentration of AChRs with no detectable AChR-bound autoantibody which confirmed the diagnosis of a CMS. Evaluation for the mutation previously identified as the causative mutation of CMS in Jack Russell Terriers was performed and was negative. This is the first reported confirmed case of CMS in a mixed breed dog and provides a review of typical clinical and diagnostic findings as well as treatment considerations.
PubMed: 29090216
DOI: 10.3389/fvets.2017.00173 -
BMC Infectious Diseases Oct 2020Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the causative agent of coronavirus disease 2019 (COVID-19), may lead to severe systemic...
A parallel-group, multicenter randomized, double-blinded, placebo-controlled, phase 2/3, clinical trial to test the efficacy of pyridostigmine bromide at low doses to reduce mortality or invasive mechanical ventilation in adults with severe SARS-CoV-2 infection: the Pyridostigmine In Severe...
BACKGROUND
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the causative agent of coronavirus disease 2019 (COVID-19), may lead to severe systemic inflammatory response, pulmonary damage, and even acute respiratory distress syndrome (ARDS). This in turn may result in respiratory failure and in death. Experimentally, acetylcholine (ACh) modulates the acute inflammatory response, a neuro-immune mechanism known as the inflammatory reflex. Recent clinical evidence suggest that electrical and chemical stimulation of the inflammatory reflex may reduce the burden of inflammation in chronic inflammatory diseases. Pyridostigmine (PDG), an ACh-esterase inhibitor (i-ACh-e), increases the half-life of endogenous ACh, therefore mimicking the inflammatory reflex. This clinical trial is aimed at evaluating if add-on of PDG leads to a decrease of invasive mechanical ventilation and death among patients with severe COVID-19.
METHODS
A parallel-group, multicenter, randomized, double-blinded, placebo-controlled, phase 2/3 clinical trial to test the efficacy of pyridostigmine bromide 60 mg/day P.O. to reduce the need for invasive mechanical ventilation and mortality in hospitalized patients with severe COVID-19.
DISCUSSION
This study will provide preliminary evidence of whether or not -by decreasing systemic inflammation- add-on PDG can improve clinical outcomes in patients with severe COVID-19.
TRIAL REGISTRATION
ClinicalTrials.gov NCT04343963 (registered on April 14, 2020).
Topics: Adult; Betacoronavirus; COVID-19; Cholinesterase Inhibitors; Coronavirus Infections; Humans; Inflammation; Lung; Pandemics; Pneumonia, Viral; Pyridostigmine Bromide; Respiration, Artificial; SARS-CoV-2
PubMed: 33066761
DOI: 10.1186/s12879-020-05485-7