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Neurobiology of Stress Nov 2020Gulf War illness is associated with a combination of exposure to war-related chemical agents and traumatic stress. Currently, there are no effective treatments, and the...
Gulf War illness is associated with a combination of exposure to war-related chemical agents and traumatic stress. Currently, there are no effective treatments, and the pathophysiology remains elusive. Neurological problems are among the most commonly reported symptoms. In this study, we investigated the glutamatergic system in the hippocampi of mice exposed to war-related chemical agents and stress. Mice developed Gulf War illness-like symptoms, including mood deficits, cognitive impairments, and fatigue. They exhibited the following pathological changes in hippocampi: elevated extracellular glutamate levels, impaired glutamatergic synapses, astrocyte atrophy, loss of interneurons, and decreased neurogenesis. LDN/OSU-215111 is a small-molecule that can strengthen the structure and function of both the astrocytic processes and the glutamatergic synapses that together form the tripartite synapses. We found that LDN/OSU-215111 effectively prevented the development of mood and cognitive deficits in mice when treatment was implemented immediately following the exposure. Moreover, when symptoms were already present, LDN/OSU-215111 still significantly ameliorated these deficits; impressively, benefits were sustained one month after treatment cessation, indicating disease modification. LDN/OSU-215111 effectively normalized hippocampal pathological changes. Overall, this study provides strong evidence that restoration of tripartite glutamatergic synapses by LDN/OSU-215111 is a potential therapy for Gulf War illness.
PubMed: 33344696
DOI: 10.1016/j.ynstr.2020.100240 -
BMC Neurology Dec 2020Ocular myasthenia gravis and Graves' ophthalmopathy are autoimmune diseases that are mediated by membrane receptors and share many identical clinical processes. Poland...
BACKGROUND
Ocular myasthenia gravis and Graves' ophthalmopathy are autoimmune diseases that are mediated by membrane receptors and share many identical clinical processes. Poland syndrome is a rare congenital deformity characterized by defects of the ipsilateral hand and the chest wall, and it is usually associated with hypoplasia of ipsilateral pectoral muscles and homolateral breast. However, to the best of our knowledge, the co-occurrence of these diseases has never been reported. In this study, we present a man with Poland syndrome who was diagnosed with Graves' ophthalmopathy and ocular myasthenia gravis in succession.
CASE PRESENTATION
A 43-year-old man presented with bilateral upper eyelid ptosis, bilateral eye protrusion, bilateral eye movement disorder and malformation of the right hand. Asymmetrical malformation of the chest wall and ipsilateral hand deformity were shown as Poland syndrome. He was diagnosed with ocular myasthenia gravis and Graves' ophthalmopathy on the basis of clinical manifestations and laboratory examinations, including bilateral exophthalmos and progressive asymmetrical ophthalmoparesis without pupillary dysfunction, positive autoantibody tests, repetitive nerve stimulation tests, and computed tomography scans. Treatments with pyridostigmine bromide, thymectomy, and prednisone led to partial clinical improvement. After 13 months of follow-up, the symptoms of drooping eyelids were partially improved, but the eyeball protrusion and right hand deformity remained unchanged.
CONCLUSIONS
We report the first case of co-occurrence of ocular myasthenia gravis, Graves' ophthalmopathy, and Poland syndrome. Genetic predisposition and immune dysregulation might be the pathogenesis of the association.
Topics: Adult; Graves Ophthalmopathy; Humans; Male; Myasthenia Gravis; Poland Syndrome
PubMed: 33297974
DOI: 10.1186/s12883-020-02022-6 -
International Journal of Environmental... Nov 2020Gulf War Illness (GWI) is a chronic, multi-symptom illness suffered by over one-third of American military veterans who served in the Persian Gulf War between 1990 and...
Effects of Incubation of Human Brain Microvascular Endothelial Cells and Astrocytes with Pyridostigmine Bromide, DEET, or Permethrin in the Absence or Presence of Metal Salts.
Gulf War Illness (GWI) is a chronic, multi-symptom illness suffered by over one-third of American military veterans who served in the Persian Gulf War between 1990 and 1991. No current single-exposure scenario accounts for all the symptoms observed in GWI, and instead may be due to a multi-exposure scenario. As a larger effort to understand how one category of multi-exposure scenarios of organic compounds such as nerve gas prophylactic pyridostigmine bromide, or insecticides/pesticides such as N,N-diethyl--toluamide (DEET) and permethrin, plus heavy metals found in inhaled dust particles (Al, Fe, Ni, Sr, DU, Co, Cu, Mn, and Zn) might play a role in neural aspects of GWI, we begin this initial study to examine the toxicity and oxidative damage markers of human brain endothelial cell and human astrocyte cell cultures in response to these compounds. A battery of cytotoxicity assessments, including the MTT assay, Neutral Red uptake, and direct microscopic observation, was used to determine a non-toxic dose of the test compounds. After testing a wide range of doses of each compound, we chose a sub-toxic dose of 10 µM for the three organic compounds and 1 µM for the nine metals of interest for co-exposure experiments on cell cultures and examined an array of oxidative stress-response markers including nitric oxide production, formation of protein carbonyls, production of thiobarbituric acid-reactive substances, and expression of proteins involved in oxidative stress and cell damage. Many markers were not significantly altered, but we report a significant increase in nitric oxide after exposure to any of the three compounds in conjunction with depleted uranium.
Topics: Astrocytes; Brain; Cells, Cultured; DEET; Endothelial Cells; Humans; Metals, Heavy; Permethrin; Persian Gulf Syndrome; Pyridostigmine Bromide; Salts
PubMed: 33187257
DOI: 10.3390/ijerph17228336 -
PloS One 2020Gulf War (GW) Illness (GWI) is a debilitating condition with a complex constellation of immune, endocrine and neurological symptoms, including cognitive impairment,...
The peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone, ameliorates neurofunctional and neuroinflammatory abnormalities in a rat model of Gulf War Illness.
BACKGROUND
Gulf War (GW) Illness (GWI) is a debilitating condition with a complex constellation of immune, endocrine and neurological symptoms, including cognitive impairment, anxiety and depression. We studied a novel model of GWI based on 3 known common GW exposures (GWE): (i) intranasal lipopolysaccharide, to which personnel were exposed during desert sand storms; (ii) pyridostigmine bromide, used as prophylaxis against chemical warfare; and (iii) chronic unpredictable stress, an inescapable element of war. We used this model to evaluate prophylactic treatment with the PPARγ agonist, rosiglitazone (ROSI).
METHODS
Rats were subjected to the three GWE for 33 days. In series 1 and 2, male and female GWE-rats were compared to naïve rats. In series 3, male rats with GWE were randomly assigned to prophylactic treatment with ROSI (GWE-ROSI) or vehicle. After the 33-day exposures, three neurofunctional domains were evaluated: cognition (novel object recognition), anxiety-like behaviors (elevated plus maze, open field) and depression-like behaviors (coat state, sucrose preference, splash test, tail suspension and forced swim). Brains were analyzed for astrocytic and microglial activation and neuroinflammation (GFAP, Iba1, tumor necrosis factor and translocator protein). Neurofunctional data from rats with similar exposures were pooled into 3 groups: naïve, GWE and GWE-ROSI.
RESULTS
Compared to naïve rats, GWE-rats showed significant abnormalities in the three neurofunctional domains, along with significant neuroinflammation in amygdala and hippocampus. There were no differences between males and females with GWE. GWE-ROSI rats showed significant attenuation of neuroinflammation and of some of the neurofunctional abnormalities.
CONCLUSION
This novel GWI model recapitulates critical neurofunctional abnormalities reported by Veterans with GWI. Concurrent prophylactic treatment with ROSI was beneficial in this model.
Topics: Animals; Anxiety; Astrocytes; Brain; Cognition; Disease Models, Animal; Female; Hippocampus; Lipopolysaccharides; Male; PPAR gamma; Persian Gulf Syndrome; Pyridostigmine Bromide; Rats; Rats, Wistar; Rosiglitazone; Stress, Psychological
PubMed: 33186383
DOI: 10.1371/journal.pone.0242427 -
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 -
Scientific Reports Oct 2020Organophosphorus (OP) compounds represent a serious health hazard worldwide. The dominant mechanism of their action results from covalent inhibition of...
Organophosphorus (OP) compounds represent a serious health hazard worldwide. The dominant mechanism of their action results from covalent inhibition of acetylcholinesterase (AChE). Standard therapy of acute OP poisoning is partially effective. However, prophylactic administration of reversible or pseudo-irreversible AChE inhibitors before OP exposure increases the efficiency of standard therapy. The purpose of the study was to test the duration of the protective effect of a slow-binding reversible AChE inhibitor (C547) in a mouse model against acute exposure to paraoxon (POX). It was shown that the rate of inhibition of AChE by POX in vitro after pre-inhibition with C547 was several times lower than without C547. Ex vivo pre-incubation of mouse diaphragm with C547 significantly prevented the POX-induced muscle weakness. Then it was shown that pre-treatment of mice with C547 at the dose of 0.01 mg/kg significantly increased survival after poisoning by 2xLD POX. The duration of the pre-treatment was effective up to 96 h, whereas currently used drug for pre-exposure treatment, pyridostigmine at a dose of 0.15 mg/kg was effective less than 24 h. Thus, long-lasting slow-binding reversible AChE inhibitors can be considered as new potential drugs to increase the duration of pre-exposure treatment of OP poisoning.
Topics: Animals; Benzylammonium Compounds; Bromides; Cholinesterase Inhibitors; Delayed-Action Preparations; Disease Models, Animal; Mice; Organophosphate Poisoning; Organophosphorus Compounds; Paraoxon; Pyridostigmine Bromide; Time Factors
PubMed: 33024231
DOI: 10.1038/s41598-020-73822-6 -
Journal of Cardiothoracic Surgery Sep 2020Despite the burgeoning literature describing preoperative and postoperative risks of a myasthenic crisis after thymectomy (MCAT) in patients with myasthenia gravis,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Despite the burgeoning literature describing preoperative and postoperative risks of a myasthenic crisis after thymectomy (MCAT) in patients with myasthenia gravis, substantial differences exist in the risk factors identified by previous studies. We conducted a meta-analysis to assess the reported risk factors and MCAT risk.
METHODS
We collected relevant studies on the risk factors for MCAT by searching the PubMed, Embase, The Cochrane Library, China Biology Medicine (CBM), WanFang Data, VIP and CNKI databases. The search period ranged from the establishment of the database to November 2019.
RESULTS
Twenty-five of the 458 identified studies were eligible for the meta-analysis. Seven retrospective cohort studies and 18 case-control studies were included, and 14 risk factors for MCAT were extracted. Meta-analyses of the association between MCAT and risk factors related to the patient's preoperative condition included a preoperative history of MC, preoperative bulbar symptoms, IIa + IIb + III + VI, IIb + III + VI, VI + V, dosage of pyridostigmine bromide prior to the operation, a preoperative AchR-Ab level > 100 (nm/L), preoperative pulmonary function, preoperative complications, and preoperative disease course. Meta-analyses of the association between MCAT and surgery-related risk factors included intraoperative blood loss > 1000 mL and the mode of operation. Meta-analyses of the association between MCAT and postoperative risk factors included postoperative lung infection, thymoma and the WHO classification. The operation time was not an independent risk factor for MCAT.
CONCLUSIONS
The independent risk factors for MCAT were a preoperative history of MC, preoperative bulbar symptoms, preoperative MG Osserman stage, preoperative dosage of pyridostigmine bromide, preoperative serum AchR-Ab level, lung function, major postoperative complications, disease duration before thymectomy, blood loss, thoracotomy, postoperative lung infection, thymoma, and WHO classification.
Topics: Blood Loss, Surgical; Databases, Factual; Female; Humans; Male; Myasthenia Gravis; Operative Time; Postoperative Complications; Risk Factors; Thymectomy
PubMed: 32993739
DOI: 10.1186/s13019-020-01320-x -
International Journal of Environmental... Sep 2020The microbiota's influence on host (patho) physiology has gained interest in the context of Gulf War Illness (GWI), a chronic disorder featuring dysregulation of the...
The microbiota's influence on host (patho) physiology has gained interest in the context of Gulf War Illness (GWI), a chronic disorder featuring dysregulation of the gut-brain-immune axis. This study examined short- and long-term effects of GWI-related chemicals on gut health and fecal microbiota and the potential benefits of Lacto-N-fucopentaose-III (LNFPIII) treatment in a GWI model. Male C57BL/6J mice were administered pyridostigmine bromide (PB; 0.7 mg/kg) and permethrin (PM; 200 mg/kg) for 10 days with concurrent LNFPIII treatment (35 μg/mouse) in a short-term study (12 days total) and delayed LNFPIII treatment (2×/week) beginning 4 months after 10 days of PB/PM exposure in a long-term study (9 months total). Fecal 16S rRNA sequencing was performed on all samples post-LNFPIII treatment to assess microbiota effects of GWI chemicals and acute/delayed LNFPIII administration. Although PB/PM did not affect species composition on a global scale, it affected specific taxa in both short- and long-term settings. PB/PM elicited more prominent long-term effects, notably, on the abundances of bacteria belonging to and families and the genus . LNFPIII improved a marker of gut health (i.e., decreased lipocalin-2) independent of GWI and, importantly, increased butyrate producers (e.g., , ) in PB/PM-treated mice, indicating a positive selection pressure for these bacteria. Multiple operational taxonomic units correlated with aberrant behavior and lipocalin-2 in PB/PM samples; LNFPIII was modulatory. Overall, significant and lasting GWI effects occurred on specific microbiota and LNFPIII treatment was beneficial.
Topics: Amino Sugars; Animals; Gastrointestinal Microbiome; Gulf War; Male; Mice; Mice, Inbred C57BL; Persian Gulf Syndrome; Polysaccharides; RNA, Ribosomal, 16S
PubMed: 32992640
DOI: 10.3390/ijerph17197081 -
Journal of Investigative Medicine High... 2020Supine orthostatic hypertension with orthostatic hypotension is an autonomic dysfunction where the patients present with hypertension when supine and with decrease in...
Supine orthostatic hypertension with orthostatic hypotension is an autonomic dysfunction where the patients present with hypertension when supine and with decrease in blood pressure while bearing an upright posture. We report on a 74-year-old male who was admitted with dizziness and was found to have profound orthostatic hypotension with supine hypertension. The patient also developed orthostatic paroxysmal premature ventricular beats as well as nonsustained ventricular tachycardia. In this report, we attempt to present the possible mechanism of orthostatic ventricular tachycardia in our patient and the overview of the treatment strategies used in management of patients with supine hypertension and orthostatic hypotension.
Topics: Aged; Blood Pressure; Coronary Angiography; Coronary Artery Disease; Electrocardiography; Humans; Hypotension, Orthostatic; Male; Percutaneous Coronary Intervention; Posture; Pyridostigmine Bromide; Tachycardia, Ventricular; Treatment Outcome
PubMed: 32911993
DOI: 10.1177/2324709620958303 -
Neurology Nov 2020To find determinants of the occurrence of repetitive compound muscle action potential (R-CMAP) and to assess the efficacy of channel blocker therapy in slow-channel...
OBJECTIVE
To find determinants of the occurrence of repetitive compound muscle action potential (R-CMAP) and to assess the efficacy of channel blocker therapy in slow-channel congenital myasthenic syndrome (SCCMS).
METHODS
Neurologic examination, EMG study, laboratory test, muscle biopsy, and next-generation and Sanger sequencing; literature review of reported patients with SCCMS, including EMG, kinetics of mutant acetylcholine receptors (AChRs), and response to therapy; and simulation of the decay phase of endplate potential (EPP) were performed.
RESULTS
Three newly characterized and 57 reported patients with SCCMS with mutations of AChR subunits were included. In patients with R-CMAP, the length of channel opening bursts of mutant AChR was increased 8.68 ± 2.82 (mean ± SD)-fold compared to wild-type; in patients without R-CMAP, the length was increased 3.84 ± 0.65-fold (95% confidence interval 3.18-6.50, = 0.000014). The EPP amplitude after refractory period of action potential in muscle fiber is above the threshold in patients with R-CMAP but below the threshold in patients without R-CMAP. In patients with good results from channel blocker therapy, treatment was initiated 11.60 ± 5.17 years after onset of symptoms; in patients with no to moderate benefit from channel blocker therapy, treatment was initiated 30.70 ± 12.72 years after onset (95% confidence interval -28.57 to -9.63, = 0.00089).
CONCLUSIONS
In SCCMS, the R-CMAP occurrence is related to the extent of prolongation of the opening episodes of mutant AChR channel. Channel blocker treatment is more effective the sooner it is started after the onset of symptoms.
CLASSIFICATION OF EVIDENCE
This study provides Class IV evidence that channel blocker therapy in patients with SCCMS improves symptoms.
Topics: Adult; Cholinesterase Inhibitors; Electromyography; Female; Humans; Membrane Transport Modulators; Middle Aged; Muscle, Skeletal; Myasthenic Syndromes, Congenital; Pedigree; Pyridostigmine Bromide; Receptors, Cholinergic; Young Adult
PubMed: 32907971
DOI: 10.1212/WNL.0000000000010734