-
Brain, Behavior, & Immunity - Health Dec 2022Chemical overexposures and war-related stress during the 1990-1991 Gulf War (GW) are implicated in the persisting pathological symptoms that many GW veterans continue to...
Chemical overexposures and war-related stress during the 1990-1991 Gulf War (GW) are implicated in the persisting pathological symptoms that many GW veterans continue to endure. These symptoms culminate into a disease known as Gulf War Illness (GWI) and affect about a third of the GW veteran population. Currently, comprehensive effective GWI treatment options are unavailable. Here, an established GWI mouse model was utilized to explore the (1) long-term behavioral and neuroinflammatory effects of deployment-related GWI chemicals exposure and (2) ability of the immunotherapeutic lacto-N-fucopentaose III (LNFPIII) to improve deficits when given months after the end of exposure. Male C57BL6/J mice (8-9 weeks old) were administered pyridostigmine bromide (PB) and DEET for 14 days along with corticosterone (CORT; latter 7 days) to emulate wartime stress. On day 15, a single injection of the nerve agent surrogate diisopropylfluorophosphate (DFP) was given. LNFPIII treatment began 7 months post GWI chemicals exposure and continued until study completion. A battery of behavioral tests for assessment of cognition/memory, mood, and motor function in rodents was performed beginning 8 months after exposure termination and was then followed by immunohistochemcal evaluation of neuroinflammation and neurogenesis. Within tests of motor function, prior GWI chemical exposure led to hyperactivity, impaired sensorimotor function, and altered gait. LNFPIII attenuated these motor-related deficits and improved overall grip strength. GWI mice also exhibited more anxiety-like behavior that was reduced by LNFPIII; this was test-specific. Short-term, but not long-term memory, was impaired by prior GWI exposure; LNFPIII improved this measure. In the brains of GWI mice, but not in mice treated with LNFPIII, glial activation was increased. Overall, it appears that months after exposure to GWI chemicals, behavioral deficits and neuroinflammation are present. Many of these deficits were attenuated by LNFPIII when treatment began long after GWI chemical exposure termination, highlighting its therapeutic potential for veterans with GWI.
PubMed: 36405424
DOI: 10.1016/j.bbih.2022.100553 -
Computational and Structural... 2022Gulf War Illness (GWI) is a chronic illness that affects upward of 32% of deployed Veterans to the 1991 Gulf War (GW). The symptoms are medically unexplained, ranging...
Gulf War Illness (GWI) is a chronic illness that affects upward of 32% of deployed Veterans to the 1991 Gulf War (GW). The symptoms are medically unexplained, ranging across cognitive deficits, fatigue, gastrointestinal problems, and musculoskeletal pain. Research indicates that chemical warfare agents play a key role in the onset and progression of GWI. The Khamisiyah ammunition storage that housed chemical warfare agents such as sarin, an acetylcholinesterase (AChE) inhibitor, was demolished during the GW, releasing toxicants into the atmosphere affecting deployed troops. Exposure to other chemical agents such as pyridostigmine bromide, N,N-diethyl-m-toluamide, permethrin and chlorpyrifos, were also prevalent during the war. These additional chemical agents have also been shown to inhibit AChE. AChE inhibition induces an acetylcholine build-up, disrupting signals between nerves and muscles, which in high doses leads to asphyxiation. Little is known about low dose exposure. As bioactive compounds tend to interact with multiple proteins with various physiological effect, we aimed to identify other potential shared targets to understand the extent in which these chemicals could lead to GWI. We followed a reverse screening approach where each chemical is computationally docked to a library of protein targets. The programs PharmMapper and TargetNet were used for this purpose, and further analyses were conducted to mark significant changes in participants with GWI. Previously published work on DNA methylation status in GWI was reanalyzed focusing specifically on the predicted shared targets indicating significant changes in DNA methylation of the associated genes. Our findings thus suggest that exposure to GWI-related agents may converge on similar targets with roles in inflammation, neurotransmitter and lipid metabolism, and detoxification which may have impacts on neurodegenerative-like disease and oxidative stress in Veterans with GWI.
PubMed: 36420170
DOI: 10.1016/j.csbj.2022.11.006 -
Digital Journal of Ophthalmology : DJO 2024We report 2 cases of pediatric ocular myasthenia gravis. The first case was a 7-year-old girl who presented with bilateral ophthalmoplegia and ptosis that correlated...
We report 2 cases of pediatric ocular myasthenia gravis. The first case was a 7-year-old girl who presented with bilateral ophthalmoplegia and ptosis that correlated with the onset of upper respiratory symptoms. Neuroimaging and acetylcholine receptor antibody testing were unremarkable. The ice pack test was positive. Symptoms greatly improved with pyridostigmine, with full resolution of ophthalmoplegia achieved by 8-month follow-up. The second case was a 4-year-old girl who presented emergently with ptosis and bilateral ophthalmoplegia. Acetylcholine receptor antibodies testing was positive. The patient was started on pyridostigmine and intravenous immunoglobulin and is scheduled to follow-up with pediatric ophthalmology in the outpatient setting.
Topics: Female; Child; Humans; Child, Preschool; Pyridostigmine Bromide; Myasthenia Gravis; Blepharoptosis; Ophthalmoplegia; Receptors, Cholinergic; Autoantibodies
PubMed: 38601901
DOI: 10.5693/djo.02.2023.09.002 -
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 -
Muscle & Nerve Dec 2019The Myasthenia Gravis Patient Registry (MGR) is a voluntary, patient-submitted database dedicated to improve understanding of care/burden of myasthenia gravis (MG).
INTRODUCTION
The Myasthenia Gravis Patient Registry (MGR) is a voluntary, patient-submitted database dedicated to improve understanding of care/burden of myasthenia gravis (MG).
METHODS
In this study we present analyses of baseline records through July 2017 (n = 1140) containing data on the MG-Activities of Daily Living (MG-ADL) and the MG 15-item Quality of Life (MG-QOL15) instruments, two validated scales assessing quality of life in MG patients at sign-up into the MGR.
RESULTS
Most registrants reported moderate to severe impairment of health-related quality of life, with a median MG-ADL score of 6 and a median MG-QOL15 score of 21. Seventy-one percent of the patients had received pyridostigmine. Corticosteroids, mycophenolate mofetil, and azathioprine were the most common immunomodulators/immunosuppressants, with 85% of participants having ever using one of these agents. Forty-seven registrants reported receiving intravenous immunoglobulin, and 30% received plasma exchange. Twelve percent reported other treatments, and 40% were unsure whether they received less common therapies. Forty percent had undergone thymectomy.
DISCUSSION
The MGR data correlate well with other MG cohorts. Many MG patients remain negatively impacted despite treatment.
Topics: Activities of Daily Living; Adrenal Cortex Hormones; Adult; Aged; Azathioprine; Cholinesterase Inhibitors; Cross-Sectional Studies; Female; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Immunosuppressive Agents; Male; Middle Aged; Myasthenia Gravis; Mycophenolic Acid; Plasma Exchange; Pyridostigmine Bromide; Quality of Life; Registries
PubMed: 31487038
DOI: 10.1002/mus.26695 -
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 -
Journal of Occupational and... Sep 2020This analysis examined the relationship between Gulf War (GW) exposures and health symptoms reported in three time periods over 20 years in Ft. Devens Cohort veterans.
OBJECTIVE
This analysis examined the relationship between Gulf War (GW) exposures and health symptoms reported in three time periods over 20 years in Ft. Devens Cohort veterans.
METHODS
Repeated logistic regression models examined the association of exposures and health symptoms over time. Models included baseline age, active duty status, post-traumatic stress disorder status, sex, and time since deployment as covariates.
RESULTS
Exposure to tent heaters was associated with increased odds of crying easily and muscle twitching. Exposure to pyridostigmine bromide (PB) pills was associated with increased odds of depression and fatigue. Exposure to the Khamisiyah sarin plume was associated with increased odds of trouble concentrating and crying easily.
CONCLUSION
This longitudinal analysis demonstrated an association between neurotoxicant exposures and increased odds of cognitive/mood, fatigue, and neurological symptoms. In addition, most symptoms increased over time since deployment regardless of exposure.
Topics: Cohort Studies; Gulf War; Humans; Longitudinal Studies; Neurotoxins; Occupational Exposure; Persian Gulf Syndrome; Pyridostigmine Bromide; Sarin; Veterans
PubMed: 32890202
DOI: 10.1097/JOM.0000000000001910 -
Internal Medicine (Tokyo, Japan) Apr 2022We herein report two P/Q-type voltage-gated calcium channel (VGCC) antibody-positive Lambert-Eaton myasthenic syndrome (LEMS) patients who responded dramatically to...
We herein report two P/Q-type voltage-gated calcium channel (VGCC) antibody-positive Lambert-Eaton myasthenic syndrome (LEMS) patients who responded dramatically to cholinesterase inhibitors. Patient 1, a 76-year-old man, had small-cell lung cancer and developed LEMS during chemotherapy. When symptomatic treatment was started with pyridostigmine, gait disturbance was ameliorated, and his modified Rankin scale decreased from 4 points to 3 points. Patient 2, a 68-year-old man, had cancer-free LEMS. Distigmine bromide was very effective and ameliorated not only his gait disturbance but also autonomic symptoms, and his modified Rankin scale decreased from 2 points to 1 point. Cholinesterase inhibitors alone may be effective in a small portion of LEMS patients.
Topics: Activities of Daily Living; Aged; Cholinesterase Inhibitors; Humans; Lambert-Eaton Myasthenic Syndrome; Lung Neoplasms; Male; Small Cell Lung Carcinoma
PubMed: 34544947
DOI: 10.2169/internalmedicine.7902-21 -
Neuromuscular Disorders : NMD Sep 2019The distribution of muscle weakness in myasthenia gravis (MG) patients with acetylcholine receptor (AChR) antibodies is highly variable. As muscle groups respond...
The distribution of muscle weakness in myasthenia gravis (MG) patients with acetylcholine receptor (AChR) antibodies is highly variable. As muscle groups respond differently to therapeutic interventions, it is important to acknowledge this variability. We analysed the distribution of muscle weakness in 225 AChR MG patients over time. On the basis of combinations of muscle weakness, seven phenotypes were defined: 'ocular' (O), 'bulbar' (B), 'neck/limbs/respiratory' (NLR), or a combination (O+B, O+NLR, B+NLR and O+B+NLR). MG remained restricted to ocular weakness in 5%, whereas 7% never had ocular weakness. At last follow-up, ocular or bulbar weakness had resolved more frequently than NLR weakness (40%, 38% and 25%; p = 0.003, respectively). Patients with O, B or OB phenotype at baseline had a higher age at onset and were more frequently male than patients with NLR, ONLR, BNLR or OBNLR phenotype (52.7 ± 17.5 vs. 44.0 ± 18.9; p = 0.007 and 64% vs. 37%; p = 0.002, respectively). MG patients have heterogeneous distributions of muscle weakness and frequently shift between phenotypes. The phenotypic variations found in AChR MG suggest that also other factors aside from the AChR antibody mediated immune response are of importance in determining the disease expression in MG.
Topics: Adult; Age of Onset; Aged; Blepharoptosis; Cholinesterase Inhibitors; Cohort Studies; Deglutition Disorders; Diplopia; Disease Progression; Dysarthria; Extremities; Facial Muscles; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Mastication; Masticatory Muscles; Middle Aged; Muscle Weakness; Muscle, Skeletal; Myasthenia Gravis; Neck Muscles; Oculomotor Muscles; Pharyngeal Muscles; Phenotype; Prednisone; Prospective Studies; Pyridostigmine Bromide; Respiratory Muscles
PubMed: 31488385
DOI: 10.1016/j.nmd.2019.07.006 -
The Journal of Pharmacology and... Oct 2020Earlier reports suggested that galantamine, a drug approved to treat mild-to-moderate Alzheimer's disease (AD), and other centrally acting reversible...
Earlier reports suggested that galantamine, a drug approved to treat mild-to-moderate Alzheimer's disease (AD), and other centrally acting reversible acetylcholinesterase (AChE) inhibitors can serve as adjunct pretreatments against poisoning by organophosphorus compounds, including the nerve agent soman. The present study was designed to determine whether pretreatment with a clinically relevant oral dose of galantamine HBr mitigates the acute toxicity of 4.0×LD soman (15.08 µg/kg) in posttreated intramuscularly with the conventional antidotes atropine (0.4 mg/kg), 2-pyridine aldoxime methyl chloride (30 mg/kg), and midazolam (0.32 mg/kg). The pharmacokinetic profile and maximal degree of blood AChE inhibition (∼25%-40%) revealed that the oral doses of 1.5 and 3.0 mg/kg galantamine HBr in these nonhuman primates (NHPs) translate to human-equivalent doses that are within the range used for AD treatment. Subsequent experiments demonstrated that 100% of NHPs pretreated with either dose of galantamine, challenged with soman, and posttreated with conventional antidotes survived 24 hours. By contrast, given the same posttreatments, 0% and 40% of the NHPs pretreated, respectively, with vehicle and pyridostigmine bromide (1.2 mg/kg, oral), a peripherally acting reversible AChE inhibitor approved as pretreatment for military personnel at risk of exposure to soman, survived 24 hours after the challenge. In addition, soman caused extensive neurodegeneration in the hippocampi of saline- or pyridostigmine-pretreated NHPs, but not in the hippocampi of galantamine-pretreated animals. To our knowledge, this is the first study to demonstrate the effectiveness of clinically relevant oral doses of galantamine to prevent the acute toxicity of supralethal doses of soman in NHPs. SIGNIFICANCE STATEMENT: This is the first study to demonstrate that a clinically relevant oral dose of galantamine effectively prevents lethality and neuropathology induced by a supralethal dose of the nerve agent soman in Cynomolgus monkeys posttreated with conventional antidotes. These findings are of major significance for the continued development of galantamine as an adjunct pretreatment against nerve agent poisoning.
Topics: Acetylcholinesterase; Administration, Oral; Animals; Antidotes; Area Under Curve; Chemical Warfare Agents; Galantamine; Hippocampus; Lethal Dose 50; Macaca fascicularis; Male; Organophosphate Poisoning; Soman
PubMed: 32759369
DOI: 10.1124/jpet.120.265843