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Integrative Medicine Research Jun 2022Myasthenia Gravis (MG) is a disorder of neuromuscular transmission bringing mild ocular weakness to severe generalized muscle weakness and disability. The conventional... (Review)
Review
BACKGROUND
Myasthenia Gravis (MG) is a disorder of neuromuscular transmission bringing mild ocular weakness to severe generalized muscle weakness and disability. The conventional treatments have long-term side effects, and Chinese herbal medicines (CHM) have shown possible effect and safety for MG patients, but the existing evidence was not robust enough and the results were out of date.
METHODS
Searching for randomized controlled trials (RCTs) was conducted in 7 databases and clinical trial registries until July 2021. The ROB 2 tool was used to assess the study quality and GRADE was used to assess the quality of whole evidence. Meta-analyses were conducted and the results were presented as risk ratio (RR) or mean difference (MD) with 95% confidence interval (CI).
RESULTS
Nineteen RCTs (1283 participants) testing 13 kinds of CHM with adequate randomization were included and six RCTs investigating Compound Huangqi were included in the meta-analyses. In addition to conventional treatment, nine CHMs reduced symptom scores of MG. Compound Huangqi plus conventional treatment (pyridostigmine bromide or prednisone or both) reduced the symptom scores compared with conventional treatment (MD = -3.56, 95%CI -4.86 to -2.26). Less adverse events happened in the CHM groups (3/247 in the CHM groups, 52/245 in the control groups, RR = 0.13, 95%CI 0.06 to 0.30, 9 RCTs, a total of 492 participants). The effect on quality of life was inconsistent.
CONCLUSION
Nine CHMs could probably bring benefit for MG symptom improvement. Moderate to low certainty of evidence supported Compound Huangqi added-on conventional treatment probably bring extra benefit of improving MG symptoms. Adding CHMs could be safer than giving only conventional treatment.
STUDY REGISTRATION
The protocol was registered in PROSPERO (ID: 32718).
PubMed: 35024335
DOI: 10.1016/j.imr.2021.100806 -
Health symptom trajectories and neurotoxicant exposures in Gulf War veterans: the Ft. Devens cohort.Environmental Health : a Global Access... Jan 2022Thirty years ago, Gulf War (GW) veterans returned home with numerous health symptoms that have been associated with neurotoxicant exposures experienced during...
BACKGROUND
Thirty years ago, Gulf War (GW) veterans returned home with numerous health symptoms that have been associated with neurotoxicant exposures experienced during deployment. The health effects from these exposures have been termed toxic wounds. Most GW exposure-outcome studies utilize group analyses and thus individual fluctuations in symptoms may have been masked. This study investigates health symptom trajectories in the same veterans over 25 years.
METHODS
Veterans were categorized into 5 a priori trajectory groups for each health symptom and Chronic Multisymptom Illness (CMI) clinical case status. Multinomial logistic regression models were used to investigate associations between these trajectories and neurotoxicant exposures.
RESULTS
Results indicate that more than 21 Pyridostigmine Bromide (PB) pill exposure was associated with consistent reporting of fatigue, pain, and cognitive/mood symptoms as well as the development of six additional symptoms over time. Chemical weapons exposure was associated with both consistent reporting and development of neurological symptoms over time. Reported exposure to tent heater exhaust was associated with later development of gastrointestinal and pulmonary symptoms. Veterans reporting exposure to more than 21 PB pills were more than 8 times as likely to consistently meet the criteria for CMI over time.
CONCLUSION
This study highlights the importance of the continued documentation of the health impacts experienced by GW veterans', their resulting chronic health symptoms, and the importance of exposure-outcome relationships in these veterans now 30 years post-deployment.
Topics: Chronic Disease; Cohort Studies; Gulf War; Humans; Persian Gulf Syndrome; Veterans
PubMed: 34998396
DOI: 10.1186/s12940-021-00812-0 -
Brain Sciences Nov 2021About 25-35% of United States veterans who fought in the 1990-1991 Gulf War report several moderate or severe chronic systemic symptoms, defined as Gulf War illness...
About 25-35% of United States veterans who fought in the 1990-1991 Gulf War report several moderate or severe chronic systemic symptoms, defined as Gulf War illness (GWI). Thirty years later, there is little consensus on the causes or biological underpinnings of GWI. The Gulf War Era Cohort and Biorepository (GWECB) was designed to investigate genetic and environmental associations with GWI and consists of 1343 veterans. We investigate candidate gene-toxicant interactions that may be associated with GWI based on prior associations found in human and animal model studies, focusing on SNPs in or near , , and genes to replicate results from prior studies. was also considered as a candidate gene. CDC Severe GWI, the primary outcome, was observed in 26% of the 810 deployed veterans included in this study. The interaction between the candidate SNP rs662 and pyridostigmine bromide (PB) pills was found to be associated with CDC Severe GWI. Interactions between PB pill exposure and rs3917545, rs3917550, and rs2299255, all in high linkage disequilibrium in , were also associated with respiratory symptoms. These SNPs could point toward biological pathways through which GWI may develop, which could lead to biomarkers to detect GWI or to better treatment options for veterans with GWI.
PubMed: 34942860
DOI: 10.3390/brainsci11121558 -
Life Sciences Jan 2022To characterize neuroinflammatory and gut dysbiosis signatures that accompany exaggerated exercise fatigue and cognitive/mood deficits in a mouse model of Gulf War...
Induction of distinct neuroinflammatory markers and gut dysbiosis by differential pyridostigmine bromide dosing in a chronic mouse model of GWI showing persistent exercise fatigue and cognitive impairment.
AIMS
To characterize neuroinflammatory and gut dysbiosis signatures that accompany exaggerated exercise fatigue and cognitive/mood deficits in a mouse model of Gulf War Illness (GWI).
METHODS
Adult male C57Bl/6N mice were exposed for 28 d (5 d/wk) to pyridostigmine bromide (P.O.) at 6.5 mg/kg/d, b.i.d. (GW1) or 8.7 mg/kg/d, q.d. (GW2); topical permethrin (1.3 mg/kg), topical N,N-diethyl-meta-toluamide (33%) and restraint stress (5 min). Animals were phenotypically evaluated as described in an accompanying article [124] and sacrificed at 6.6 months post-treatment (PT) to allow measurement of brain neuroinflammation/neuropathic pain gene expression, hippocampal glial fibrillary acidic protein, brain Interleukin-6, gut dysbiosis and serum endotoxin.
KEY FINDINGS
Compared to GW1, GW2 showed a more intense neuroinflammatory transcriptional signature relative to sham stress controls. Interleukin-6 was elevated in GW2 and astrogliosis in hippocampal CA1 was seen in both GW groups. Beta-diversity PCoA using weighted Unifrac revealed that gut microbial communities changed after exposure to GW2 at PT188. Both GW1 and GW2 displayed systemic endotoxemia, suggesting a gut-brain mechanism underlies the neuropathological signatures. Using germ-free mice, probiotic supplementation with Lactobacillus reuteri produced less gut permeability than microbiota transplantation using GW2 feces.
SIGNIFICANCE
Our findings demonstrate that GW agents dose-dependently induce differential neuropathology and gut dysbiosis associated with cognitive, exercise fatigue and mood GWI phenotypes. Establishment of a comprehensive animal model that recapitulates multiple GWI symptom domains and neuroinflammation has significant implications for uncovering pathophysiology, improving diagnosis and treatment for GWI.
Topics: Animals; Biomarkers; Cholinesterase Inhibitors; Cognitive Dysfunction; Disease Models, Animal; Dose-Response Relationship, Drug; Dysbiosis; Endotoxemia; Fatigue; Gastrointestinal Microbiome; Gene Expression Profiling; Gene Expression Regulation; Gliosis; Male; Mice; Mice, Inbred C57BL; Neuralgia; Neuroinflammatory Diseases; Persian Gulf Syndrome; Physical Conditioning, Animal; Pyridostigmine Bromide
PubMed: 34801513
DOI: 10.1016/j.lfs.2021.120153 -
Scientific Reports Nov 2021We examined in a rat model of Gulf War illness (GWI), the potential of (-)-epicatechin (Epi) to reverse skeletal muscle (SkM) atrophy and dysfunction, decrease mediators...
We examined in a rat model of Gulf War illness (GWI), the potential of (-)-epicatechin (Epi) to reverse skeletal muscle (SkM) atrophy and dysfunction, decrease mediators of inflammation and normalize metabolic perturbations. Male Wistar rats (n = 15) were provided orally with pyridostigmine bromide (PB) 1.3 mg/kg/day, permethrin (PM) 0.13 mg/kg/day (skin), DEET 40 mg/kg/day (skin) and were physically restrained for 5 min/day for 3 weeks. A one-week period ensued to fully develop the GWI-like profile followed by 2 weeks of either Epi treatment at 1 mg/kg/day by gavage (n = 8) or water (n = 7) for controls. A normal, control group (n = 15) was given vehicle and not restrained. At 6 weeks, animals were subjected to treadmill and limb strength testing followed by euthanasia. SkM and blood sampling was used for histological, biochemical and plasma pro-inflammatory cytokine and metabolomics assessments. GWI animals developed an intoxication profile characterized SkM atrophy and loss of function accompanied by increases in modulators of muscle atrophy, degradation markers and plasma pro-inflammatory cytokine levels. Treatment of GWI animals with Epi yielded either a significant partial or full normalization of the above stated indicators relative to normal controls. Plasma metabolomics revealed that metabolites linked to inflammation and SkM waste pathways were dysregulated in the GWI group whereas Epi, attenuated such changes. In conclusion, in a rat model of GWI, Epi partially reverses detrimental changes in SkM structure including modulators of atrophy, inflammation and select plasma metabolites yielding improved function.
Topics: Animals; Catechin; Dietary Supplements; Disease Models, Animal; Fatigue; Humans; Male; Metabolome; Muscle Development; Muscle, Skeletal; Muscular Atrophy; Persian Gulf Syndrome; Rats; Rats, Wistar
PubMed: 34750405
DOI: 10.1038/s41598-021-01093-w -
PloS One 2021Serum Paraoxonase 2 (PON2) level is a potential biomarker owing to its association with a number of pathophysiological conditions such as atherosclerosis and...
Serum Paraoxonase 2 (PON2) level is a potential biomarker owing to its association with a number of pathophysiological conditions such as atherosclerosis and cardiovascular disease. Since cholinergic deficiency is closely linked with Alzheimer's disease (AD) progression, acetylcholinesterase inhibitors (AChEIs) are the treatment of choice for patients with AD. However, there is a heterogenous response to these drugs and mostly the subjects do not respond to the treatment. Gene polymorphism, the simultaneous occurrence of two or more discontinuous alleles in a population, could be one of the important factors for this. Hence, we hypothesized that PON2 and its polymorphic forms may be hydrolyzing the AChEIs differently, and thus, different patients respond differently. To investigate this, two AChEIs, donepezil hydrochloride (DHC) and pyridostigmine bromide (PB), were selected. Human PON2 wildtype gene and four mutants, two catalytic sites, and two polymorphic sites were cloned, recombinantly expressed, and purified for in vitro analysis. Enzyme activity and AChE activity were measured to quantitate the amount of DHC and PB hydrolyzed by the wildtype and the mutant proteins. Herein, PON2 esterase activity and AChE inhibitor efficiency were found to be inversely related. A significant difference in enzyme activity of the catalytic site mutants was observed as compared to the wildtype, and subsequent AChE activity showed that esterase activity of PON2 is responsible for the hydrolysis of DHC and PB. Interestingly, PON2 polymorphic site mutants showed increased esterase activity; therefore, this could be the reason for the ineffectiveness of the drugs. Thus, our data suggested that the esterase activity of PON2 was mainly responsible for the hydrolysis of AChEI, DHC, and PB, and that might be responsible for the variation in individual response to AChEI therapy.
Topics: Alzheimer Disease; Aryldialkylphosphatase; Cholinesterase Inhibitors; Donepezil; Humans; Mutation; Protein Binding; Pyridostigmine Bromide
PubMed: 34714861
DOI: 10.1371/journal.pone.0258879 -
Life Sciences Jan 2022To characterize exercise fatigue, metabolic phenotype and cognitive and mood deficits correlated with brain neuroinflammatory and gut microbiome changes in a chronic...
AIMS
To characterize exercise fatigue, metabolic phenotype and cognitive and mood deficits correlated with brain neuroinflammatory and gut microbiome changes in a chronic Gulf War Illness (GWI) mouse model. The latter have been described in an accompanying paper [1].
MAIN METHODS
Adult male C57Bl/6N mice were exposed for 28 days (5 days/week) to pyridostigmine bromide: 6.5 mg/kg, b.i.d., P.O. (GW1) or 8.7 mg/kg, q.d., P.O. (GW2); topical permethrin (1.3 mg/kg in 100% DMSO) and N,N-diethyl-meta-toluamide (DEET 33% in 70% EtOH) and restraint stress (5 min). Exercise, metabolic and behavioral endpoints were compared to sham stress control (CON/S).
KEY FINDINGS
Relative to CON/S, GW2 presented persistent exercise intolerance (through post-treatment (PT) day 161), deficient associative learning/memory, and transient insulin insensitivity. In contrast to GW2, GW1 showed deficient long-term object recognition memory, milder associative learning/memory deficit, and behavioral despair.
SIGNIFICANCE
Our findings demonstrate that GW chemicals dose-dependently determine the presentation of exercise fatigue and severity/type of cognitive/mood-deficient phenotypes that show persistence. Our comprehensive mouse model of GWI recapitulates the major multiple symptom domains characterizing GWI, including fatigue and cognitive impairment that can be used to more efficiently develop diagnostic tests and curative treatments for ill Gulf War veterans.
Topics: Animals; Disease Models, Animal; Fatigue; Glucose; Humans; Learning Disabilities; Male; Mice; Persian Gulf Syndrome; Pyridostigmine Bromide
PubMed: 34710444
DOI: 10.1016/j.lfs.2021.120094 -
Journal of Medical Case Reports Oct 2021Autoimmune diseases refers to a class of diseases involving abnormal immune response of human body and tissue damage caused by the dysregulation of autoimmune balance or...
BACKGROUND
Autoimmune diseases refers to a class of diseases involving abnormal immune response of human body and tissue damage caused by the dysregulation of autoimmune balance or destruction of immune tolerance. Recent research has revealed that the occurrence of autoimmune diseases is influenced by genetic, hormonal, immunological, and environmental factors. As sex hormone levels change obviously during pregnancy and postpartum, the morbidity and recurrence rate of autoimmune diseases increase during this period.
CASE PRESENTATION
A 31-year-old Asian woman was admitted to our hospital for myasthenia gravis and treated with methylprednisolone and pyridostigmine bromide 3 months postpartum. Physical examination and laboratory inspection after admission suggested that the patient had primary biliary cirrhosis. Subsequently, azathioprine was added to the treatment, and the symptoms of both diseases were successfully controlled.
CONCLUSIONS
This case exhibits a rare condition of myasthenia gravis combined with primary biliary cirrhosis postpartum. Given the fluctuation of the immune status during the postpartum period, combined autoimmune diseases need to be taken into account when patients develop clinical symptoms of an autoimmune disease. Therefore, detailed physical and laboratory examination can help to prevent the missed diagnosis of these diseases.
Topics: Adult; Female; Humans; Liver Cirrhosis, Biliary; Myasthenia Gravis; Neoplasm Recurrence, Local; Postpartum Period; Pregnancy; Pyridostigmine Bromide
PubMed: 34627357
DOI: 10.1186/s13256-021-03092-x -
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 -
Journal of Biochemical and Molecular... Dec 2021Gulf War Illness (GWI) is defined by the Centers for Disease Control and Prevention (CDC) as a multi-symptom illness having at least one symptom from two of three...
Gulf War Illness (GWI) is defined by the Centers for Disease Control and Prevention (CDC) as a multi-symptom illness having at least one symptom from two of three factors, which include: fatigue, mood-cognition problems, and musculoskeletal disorders. The cluster of long-term symptoms is unique to military personnel from coalition countries including United States, Australia, and the United Kingdom that served in Operation Desert Storm from 1990 to 1991. Reporting of these symptoms is much lower among soldiers deployed in other parts of the world like Bosnia during the same time period. The exact cause of GWI is unknown, but combined exposure to N,N-diethyl-m-toluamide (DEET), organophosphates like chlorpyrifos (CPF), and pyridostigmine bromide (PB), has been hypothesized as a potential mechanism. Mitochondrial dysfunction is known to occur in most neurodegenerative diseases that share symptoms with GWI and has therefore been implicated in GWI. Although exposure to these and other toxicants continues to be investigated as potential causes of GWI, their combined impact on mitochondrial physiology remains unknown. In this study, the effects of combined GWI toxicant exposure on mitochondrial function were determined in a commonly used and readily available immortalized cell line (N2a), whose higher rate of oxygen consumption resembles that of highly metabolic neurons in vivo. We report that combined exposure containing pesticide CPF 71 μM, insect repellants DEET 78 μM, and antitoxins PB 19 μM, causes profound mitochondrial dysfunction after a 4-h incubation resulting in decreased mitochondrial respiratory states in the absence of proapoptotic signaling, proton leak, or significant increase in reactive oxygen species production.
Topics: Adenosine Triphosphate; Animals; Apoptosis; Cell Line, Tumor; Chlorpyrifos; DEET; Humans; Mice; Mitochondria; Neuroblastoma; Oxygen Consumption; Persian Gulf Syndrome; Protein Kinases; Pyridostigmine Bromide; Signal Transduction; War Exposure
PubMed: 34528356
DOI: 10.1002/jbt.22913