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Systemic arterial hypertension is accompanied by autonomic impairments that, if not contained, promotes cardiac functional and morphological damages. Pyridostigmine bromide (PYR) treatment results in positive effects on autonomic control and beneficial cardiac remodeling. These findings were also observed after aerobic physical training (APT). However, little is known about PYR effects on left ventricular contractility, mainly when it is combined with APT. We aimed to investigate the effects of chronic acetylcholinesterase inhibition on cardiac autonomic tone balance, coronary bed reactivity, and left ventricular contractility in spontaneously hypertensive rats (SHR) submitted to APT. Male SHR (18 weeks) were divided into two groups (N = 16): untrained and submitted to APT for 14 weeks (18th to 32nd week). Half of each group was treated with PYR (15 mg/kg/day) for two weeks (31st to 32nd week). The experimental protocol consisted of recording hemodynamic parameters, double autonomic blockade with atropine and propranolol, and assessment of coronary bed reactivity and ventricular contractility in isolated hearts using the Langendorff technique. PYR and APT reduced blood pressure, heart rate, and sympathetic influence on the heart. The Langendorff technique showed that APT increased coronary perfusion pressure and left ventricle contractility in response to coronary flow and ß-agonist administration. However, treatment with PYR annulled the effects of APT. In conclusion, although chronic treatment with PYR reduces cardiac sympathetic tonic influence, it does not favor coronary bed reactivity and cardiac contractility gains. PYR treatment in the trained SHR group nullified the coronary vascular reactivity and cardiac contractility gains.

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BACKGROUND: Deployment-related neurotoxicant exposures are implicated in the etiology of Gulf War illness (GWI), the multisymptom condition associated with military service in the 1990-1991 Gulf War (GW). A Q/R polymorphism at position 192 of the paraoxonase (PON)-1 enzyme produce PON1192 variants with different capacities for neutralizing specific chemicals, including certain acetylcholinesterase inhibitors. METHODS: We evaluated PON1192 status and GW exposures in 295 GWI cases and 103 GW veteran controls. Multivariable logistic regression determined independent associations of GWI with GW exposures overall and in PON1192 subgroups. Exact logistic regression explored effects of exposure combinations in PON1192 subgroups. RESULTS: Hearing chemical alarms (proxy for possible nerve agent exposure) was associated with GWI only among RR status veterans (OR = 8.60, p = 0.014). Deployment-related skin pesticide use was associated with GWI only among QQ (OR = 3.30, p = 0.010) and QR (OR = 4.22, p < 0.001) status veterans. Exploratory assessments indicated that chemical alarms were associated with GWI in the subgroup of RR status veterans who took pyridostigmine bromide (PB) (exact OR = 19.02, p = 0.009) but not RR veterans who did not take PB (exact OR = 0.97, p = 1.00). Similarly, skin pesticide use was associated with GWI among QQ status veterans who took PB (exact OR = 6.34, p = 0.001) but not QQ veterans who did not take PB (exact OR = 0.59, p = 0.782). CONCLUSION: Study results suggest a complex pattern of PON1192 exposures and exposure-exposure interactions in the development of GWI.

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DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: Elevated serum bromide levels can cause dermatological, gastrointestinal, and neurological abnormalities. As bromide and chloride are both halogens, bromide may interfere with chloride assays, causing a falsely high serum chloride concentration and a low or negative anion gap. There is a paucity of data describing bromide toxicity from high doses of pyridostigmine bromide (PB). This case report describes a patient with an elevated bromide level with neurological symptoms from a therapeutic dose of PB. SUMMARY: A 37-year-old male with myasthenia gravis secondary to type B2 thymoma status following thymectomy presented in myasthenic crisis. He required mechanical ventilation and was managed with steroids, intravenous immune globulin, plasmapheresis, and PB. On day 9, the patient experienced acute agitation. He had an anion gap of 2 mEq/L and a chloride concentration of 109 mEq/L. The plasma creatinine concentration was 0.63 to 1.15 mg/dL and urine output was 0.76 to 1.79 mL/kg/h throughout his admission. All other laboratory values were normal. The daily dose of PB was 660 mg on day 9, but the patient received 76 mg of intravenous PB over the first few days of his admission with the largest dose in 24 hours equal to 48 mg. On day 10, the patient's bromide level was 37 µg/mL. His agitation was initially managed with quetiapine, followed by PB dose reduction. To our knowledge, there are 2 cases in the literature of bromide toxicity secondary to PB. These patients experienced neurological symptoms with bromide levels of 88 to 90 µg/mL. Bromide concentrations of more than 12 µg/mL are associated with a higher risk of neuronal dysfunction demonstrated as disturbances on an electroencephalogram, and levels greater than 50 µg/mL are considered toxic. While our patient's bromide level was not as high as those previously reported, no other causes for his agitation were identified. CONCLUSION: Elevated bromide levels from therapeutic PB can occur, and monitoring of these levels should be considered.

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BACKGROUND: Pyridostigmine is hypothesized to improve neurogenic orthostatic hypotension (nOH) symptoms without causing or exacerbating supine hypertension. The objective of this review was to evaluate the safety and efficacy of pyridostigmine for management of nOH. METHODS: A literature search of PubMed, Embase, and CENTRAL was performed in December 2023 for prospective trials with a placebo or active comparator. RESULTS: Four randomized and two non-randomized studies were reviewed. Three studies utilizing a single dose, crossover design found significant differences of orthostatics using adjunctive pyridostigmine. Two studies assessing longer-term endpoints demonstrated conflicting efficacy of pyridostigmine with one trial finding significant improvement in orthostatics and symptoms after three months of therapy. Use of pyridostigmine did not lead to supine hypertension with most adverse effects being cholinergic. CONCLUSION: Pyridostigmine may be considered as an adjunctive medication in individuals with nOH refractory to standard treatment options as it carries a favorable safety profile with low risk for supine hypertension.

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Though it has been over 30 years since the 1990-1991 Gulf War (GW), the pathophysiology of Gulf War Illness (GWI), the complex, progressive illness affecting approximately 30% of GW Veterans, has not been fully characterized. While the symptomology of GWI is broad, many symptoms can be attributed to immune and endocrine dysfunction as these critical responses appear to be dysregulated in many GWI patients. Since such dysregulation emerges in response to immune threats or stressful situations, it is unsurprising that clinical studies suggest that GWI may present with a latent phenotype. This is most often observed in studies that include an exercise challenge during which many GWI patients experience an exacerbation of symptoms. Unfortunately, very few preclinical studies include such physiological stressors when assessing their experimental models of GWI, which creates variable results that hinder the elucidation of the mechanisms mediating GWI. Thus, the purpose of this review is to highlight the clinical and preclinical findings that investigate the inflammatory component of GWI and support the concept that GWI may be characterized as having a latent phenotype. We will mainly focus on studies assessing the progressive cognitive impairments associated with GWI and emphasize the need for physiological stressors in future work to create a more unified hypothesis that can identify potential therapeutics for this patient population.

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BACKGROUND: In this investigation, we explored the effects of pharmacological cholinergic stimulation on cardiac function and renal inflammation following acute myocardial infarction (AMI) in spontaneously hypertensive rats (SHRs). METHODS: Adult male SHRs were randomized into three experimental groups: sham-operated; AMI + Veh (infarcted, treated with vehicle); and AMI + PY (infarcted, treated with the cholinesterase inhibitor, pyridostigmine bromide (PY)-40 mg/kg, once daily for seven days). Rats were euthanized 7 or 30 days post-surgery. The clinical parameters were assessed on the day before euthanasia. Subsequent to euthanasia, blood samples were collected and renal tissues were harvested for histological and gene expression analyses aimed to evaluate inflammation and injury. RESULTS: Seven days post-surgery, the AMI + PY group demonstrated improvements in left ventricular diastolic function and autonomic regulation, and a reduction in renal macrophage infiltration compared to the AMI + Veh group. Furthermore, there was a notable downregulation in pro-inflammatory gene expression and an upregulation in anti-inflammatory gene expression. Analysis 30 days post-surgery showed that PY treatment had a sustained positive effect on renal gene expression, correlated with a decrease in biomarkers, indicative of subclinical kidney injury. CONCLUSIONS: Short-term cholinergic stimulation with PY provides both cardiac and renal protection by mitigating the inflammatory response after AMI.

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The present study focuses on the development of a simple, rapid, specific, and stability-indicating HPLC method for the simultaneous analysis of pyridostigmine bromide (PGB) and sodium benzoate (SBN) in oral liquid dosage forms. Analytical techniques should enhance sensitivity and specificity for the estimation of pharmaceutical drug products. Stress studies were conducted under various International Conference on Harmonization (ICH) conditions for evaluation. The further optimized HPLC method was validated in accordance with the current ICH guidelines. Chromatographic separation was accomplished using a mobile phase consisting of a 950:50 v/v ratio of perchloric acid buffer and acetonitrile as mobile phase-A, and 100% acetonitrile as mobile phase-B. The flow rate is 1.0 mL/min, and the injection volume is 20 µL. Detection of components was carried out at 220 nm for PGB and 228 nm for SBN. The validated HPLC method demonstrated high specificity, with linearity ranging between 24 and 72 µg/mL for PGB and 5.2-15.6 µg/mL for SBN. The correlation coefficient for both drugs exceeded 0.999. The method demonstrated high accuracy, exceeding 97%. In stress studies, PGB was found to be sensitive to alkaline stress conditions. The results reveal the successful applicability of the current method for the estimation of PGB and SBN in its marketed formulation, which can be reasonably inferred to assess other formulation systems.

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INTRODUCTION: Exposure to nerve agents, pyridostigmine bromide (PB), pesticides, and oil-well fires during the 1991 Gulf War (GW) are major contributors to the etiology of Gulf War Illness (GWI). Since the apolipoprotein E (APOE) ε4 allele is associated with the risk of cognitive decline with age, particularly in the presence of environmental exposures, and cognitive impairment is one of the most common symptoms experienced by veterans with GWI, we examined whether the ε4 allele was associated with GWI. METHODS: Using a case-control design, we obtained data on APOE genotypes, demographics, and self-reported GW exposures and symptoms that were deposited in the Boston Biorepository and Integrative Network (BBRAIN) for veterans diagnosed with GWI (n = 220) and healthy GW control veterans (n = 131). Diagnosis of GWI was performed using the Kansas and/or Center for Disease Control (CDC) criteria. RESULTS: Age- and sex-adjusted analyses showed a significantly higher odds ratio for meeting the GWI case criteria in the presence of the ε4 allele (Odds ratio [OR] = 1.84, 95% confidence interval [CI = 1.07-3.15], p ≤ 0.05) and with two copies of the ε4 allele (OR = 1.99, 95% CI [1.23-3.21], p ≤ 0.01). Combined exposure to pesticides and PB pills (OR = 4.10 [2.12-7.91], p ≤ 0.05) as well as chemical alarms and PB pills (OR = 3.30 [1.56-6.97] p ≤ 0.05) during the war were also associated with a higher odds ratio for meeting GWI case criteria. There was also an interaction between the ε4 allele and exposure to oil well fires (OR = 2.46, 95% CI [1.07-5.62], p ≤ 0.05) among those who met the GWI case criteria. CONCLUSION: These findings suggest that the presence of the ε4 allele was associated with meeting the GWI case criteria. Gulf War veterans who reported exposure to oil well fires and have an ε4 allele were more likely to meet GWI case criteria. Long-term surveillance of veterans with GWI, particularly those with oil well fire exposure, is required to better assess the future risk of cognitive decline among this vulnerable population.

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Gulf War Illness (GWI) collectively describes the multitude of central and peripheral disturbances affecting soldiers who served in the 1990-1991 Gulf War. While the mechanisms responsible for GWI remain elusive, the prophylactic use of the reversible acetylcholinesterase inhibitor, pyridostigmine bromide (PB), and war-related stress have been identified as chief factors in GWI pathology. Post-deployment stress is a common challenge faced by veterans, and aberrant cholinergic and/or immune responses to these psychological stressors may play an important role in GWI pathology, especially the cognitive impairments experienced by many GWI patients. Therefore, the current study investigated if an immobilization stress challenge would produce abnormal responses in PB-treated rats three months later. Results indicate that hippocampal cholinergic responses to an immobilization stress challenge are impaired three months after PB administration. We also assessed if an immune or stress challenge reveals deficits in PB-treated animals during hippocampal-dependent learning and memory tasks at this delayed timepoint. Novel object recognition (NOR) testing paired with either acute saline or lipopolysaccharide (LPS, 30 µg/kg, i.p.), as well as Morris water maze (MWM) testing was conducted approximately three months after PB administration and/or repeated restraint stress. Rats with a history of PB treatment exhibited 24-hour hippocampal-dependent memory deficits when challenged with LPS, but not saline, in the NOR task. Similarly, in the same cohort, PB-treated rats showed 24-hour memory deficits in the MWM task. Ultimately, these studies highlight the long-term effects of PB treatment on hippocampal function and provide insight into the progressive cognitive deficits observed in veterans with GWI.

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BACKGROUND: Myasthenia gravis is a chronic, autoimmune disease with muscle weakness. Acetylcholinesterase inhibitors are used in the symptomatic treatment of the disease. Allergic reaction to pyridostigmine bromide is rare. In the literature, no allergic reaction to pyridostigmine bromide has been reported in the pediatric population. CASE: A 12-year-old female patient diagnosed with myasthenia gravis consulted our clinic with the complaint of urticaria due to pyridostigmine bromide. The oral challenge test performed with pyridostigmine bromide was positive. As the patient was required to be continue pyridostigmine bromide with no suitable alternatives, it was decided that the patient had to be desensitized to pyridostigmine. During and after the desensitization protocol, no reaction was observed. CONCLUSIONS: In this report, a successful desensitization protocol for pyridostigmine bromide in a child with myasthenia gravis is discussed.

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To examine associations between the pyridostigmine bromide (PB) pill and/or pesticide exposure during the 1990-1991 Gulf War (GW) and eye findings years after deployment. A cross-sectional study of South Florida veterans who were deployed on active duty during the GW Era (GWE). Information on GW exposures and ocular surface symptoms were collected via standardized questionnaires and an ocular surface examination was performed. Participants underwent spectral domain-ocular coherence tomography (SD-OCT) imaging that included retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), and macular maps. We examined for differences in eye findings between individuals exposed versus not exposed to PB pills or pesticides during service. A total of 40.7% (n = 44) of individuals reported exposure to PB pills and 41.7% (n = 45) to pesticides; additionally, 24 reported exposure to both in the GW arena. Demographics were comparable across groups. Individuals exposed to PB pills reported higher dry eye (DE) symptoms scores (the 5-Item Dry Eye Questionnaire, DEQ-5: 9.3 ± 5.3 vs. 7.3 ± 4.7, p = 0.04) and more intense ocular pain (average over the last week: 2.4 ± 2.6 vs. 1.5 ± 1.8, p = 0.03; Neuropathic Pain Symptom Inventory modified for the Eye (NPSI-E): 18.2 ± 20.0 vs. 10.8 ± 13.8, p = 0.03) compared to their non-exposed counterparts. DE signs were comparable between the groups. Individuals exposed to PB pills also had thicker OCT measurements, with the largest difference in the outer temporal segment of the macula (268.5 ± 22.2 µm vs. 260.6 ± 14.5 µm, p = 0.03) compared to non-exposed individuals. These differences remained significant when examined in multivariable models that included demographics and deployment history. Individuals exposed to pesticides had higher neuropathic ocular pain scores (NPSI-E: 17.1 ± 21.1 vs. 11.6 ± 12.9, p = 0.049), but this difference did not remain significant in a multivariable model. Individuals exposed to PB pills during the GWE reported more severe ocular surface symptoms and had thicker OCT measures years after deployment compared to their non-exposed counterparts.

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Recently, the main interest of analytical chemistry researchers has been the development of green analytical methods to minimize harmful effects on the environment and natural life. Therefore, an RP-HPLC method was developed and assessed regarding its greenness criteria using three greenness assessment tools: an analytical eco-scale, an analytical greenness metric approach and a green analytical procedure index. This method aims to separate and quantitatively determine three co-administered drugs, namely pyridostigmine bromide (PYR), 6-mercaptopurine (MRC) and prednisolone (PRD), in their tertiary mixture and spiked human plasma. These drugs are co-administered to manage myasthenia gravis autoimmune disease. The separation was done using a C18 column and a gradient elution of a mixture of 0.1% H3 PO4 aqueous solution (pH 2.3) and methanol. The flow rate was adjusted to 1 ml/min and detection was done at 254 (for PYR and PRD) and at 330 nm (for MRC). The lower limits of quantitation were 15, 2, and 5 µg/ml for PYR, MER and PRD, respectively. Linear correlations were obtained and found to be near 1. In addition, the proposed method was validated according to the US Food and Drug Administration's instructions, and the results proved its success to determine the three studied drugs in their tertiary mixture and spiked human plasma.

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@#Myasthenia gravis is an autoimmune disease，which is usually mediated by antibodies to acetylcholine receptors at the neuromuscular junction. It is commonly treated with cholinesterase inhibitors such as pyridostigmine bromide. Although cardiovascular events with the drug are rare，it is very important to early recognize disease changes and be alert to potential cardiovascular events in patients with myasthenia gravis. Therefore，we report a case of an elderly female patient with myasthenia gravis developing acute myocardial infarction and then sudden cardiac death following anticholinesterase therapy，and discuss the possible causes of adverse cardiovascular events based on this case.

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INTRODUCTION: This review highlights the potential mechanisms of neuromuscular manifestation of COVID-19, especially myasthenia gravis (MG). METHODS: An extensive literature search was conducted by two independent investigators using PubMed/MEDLINE and Google Scholar from its inception to December 2020. RESULTS: Exacerbations of clinical symptoms in patients of MG who were treated with some commonly used COVID-19 drugs has been reported, with updated recommendations of management of symptoms of neuromuscular disorders. Severe acute respiratory syndrome coronavirus 2 can induce the immune response to trigger autoimmune neurological disorders. CONCLUSIONS: Further clinical studies are warranted to indicate and rather confirm if MG in the setting of COVID-19 can pre-existent subclinically or develop as a new-onset disease.

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Gulf War Illness (GWI) is a multi-symptom illness that continues to affect over 250,000 American Gulf War veterans. The causes of GWI remain equivocal; however, prophylactic use of the acetylcholinesterase inhibitor pyridostigmine bromide (PB), and the stress of combat have been identified as two potential causative factors. Both PB and stress alter acetylcholine (ACh), which mediates both cognition and anti-inflammatory responses. As inflammation has been proposed to contribute to the cognitive deficits and immune dysregulation in GWI, the goal of this study was to determine the long-term effects of PB and stress on the cholinergic anti-inflammatory pathway in the central nervous system and periphery. We used our previously established rat model of GWI and in vivo microdialysis to assess cholinergic neurochemistry in the prefrontal cortex (PFC) and hippocampus following a mild immune challenge (lipopolysaccharide; LPS). We then examined LPS-induced changes in inflammatory markers in PFC and hippocampal homogenates. We found that PB treatment produces a long-lasting potentiation of the cholinergic response to LPS in both the PFC and hippocampus. Interestingly, this prolonged effect of PB treatment enhancing cholinergic responses to LPS was accompanied by paradoxical increases in the release of pro-inflammatory cytokines in these brain regions. Collectively, these findings provide evidence that neuroinflammation resulting from dysregulation of the cholinergic anti-inflammatory pathway is a mechanistic mediator in the progression of the neurochemical and neurocognitive deficits in GWI and more broadly suggest that dysregulation of this pathway may contribute to neuroinflammatory processes in stress-related neurological disorders.

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Gulf War illness (GWI) is a chronic, multi-symptom disorder that has impacted approximately one third of Gulf War veterans. GWI and its symptoms have been linked to the exposure to neurological chemicals, including the anti-nerve gas drug pyridostigmine bromide (PB) and the insecticide permethrin (PER), among others. Mouse models utilizing these chemicals have reported symptomology analogous to human GWI. These changes include behavioral and cognitive impairment, neuroinflammation and hippocampal pathogenesis. Disease modifying interventions that target these pathological components are desperately needed. Vagus nerve stimulation (VNS) is FDA approved for drug-resistant epilepsy and depression. VNS has also been used off-label to target a myriad of symptoms, some of which are encompassed within the Kansas and CDC definitions of clinical GWI symptomology. A GWI animal model in which mice are exposed to a daily injection of PB and PER for 10 consecutive days has been shown to exhibit cognitive impairment and hippocampal pathology. The purpose of this study was to determine if 2-4 weeks of continuous vagus nerve stimulation initiated at 32 weeks after exposure to PB and PER would improve cognitive performance and hippocampal pathology. The results of the study revealed that exposure to PB and PER produces long-term cognitive deficits and reduced hippocampal neurogenesis. The results also showed that the VNS treatment was anxiolytic, improved some aspects of pattern separation deficits, and mitigated the reduced hippocampal neurogenesis. Thus, VNS improves outcomes in a mouse model of GWI and should be examined as a potential therapeutic strategy for mitigating some symptomology associated with GWI.

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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.

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Background: Swallowing is one of the most complex functions of the central nervous system (CNS), which is controlled by different parts of the brain. Oropharyngeal dysphagia (OD) is one of the most common complications after stroke. Despite a variety of behavioral, compensatory, and rehabilitative methods, many stroke patients still suffer from swallowing disorders that adversely affect their quality of life (QOL). The aim of this study was to evaluate the effect of pyridostigmine on patients with post-stroke dysphagia. Methods: A randomized, double-blind, placebo-controlled clinical trial was carried out on 40 patients suffering from post-stroke dysphagia. Patients were assigned randomly into two groups: intervention and control groups (20 in each group). The intervention group was treated with pyridostigmine (60 mg, three times a day, 30 minutes before each meal for three weeks), and the control group received placebo treatment in the same way. All patients (intervention and control) were evaluated according to National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), and Functional Communication Measures (FCM)/American Speech-Language-Hearing Association (ASHA) criteria at baseline and after three weeks of intervention. Values of P < 0.05 were considered statistically significant. Results: In the intervention group, the mean values of NIHSS, mRS, and ASHA/FCM were significantly reduced following three weeks of treatment with pyridostigmine (P = 0.002, P = 0.003, and P < 0.001, respectively), but no significant differences were found in the mean NIHSS, mRS, and ASHA/FCM in the placebo group. Conclusion: Although pyridogestamine is somewhat effective in post-stroke dysphagia, it has not been shown to be more important in preventing aspiration pneumonia and length of hospital stay.

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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 ACHE, BCHE, and PON1 genes to replicate results from prior studies. SOD1 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 PON1, 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.

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Gulf War Illness (GWI) is estimated to have affected about one third of the Veterans who participated in the first Persian Gulf War. The symptoms of GWI include chronic neurologic impairments, chronic fatigue syndrome, as well as fibromyalgia and immune system disorders, collectively referred to as chronic multi-symptom illness. Thirty years after the war, we still do not have an effective treatment for GWI. It is necessary to understand the molecular basis of the symptoms of GWI in order to develop appropriate therapeutic strategies. Cellular energetics are critical to the maintenance of cellular homeostasis, a process that is highly dependent on intact mitochondrial function and there is significant evidence from both human studies and animal models that mitochondrial impairments may lead to GWI symptoms. The available clinical and pre-clinical data suggest that agents that improve mitochondrial function have the potential to restore cellular energetics and treat GWI. To date, the experiments conducted in animal models of GWI have mainly focused on neurobehavioral aspects of the illness. Additional studies to address the fundamental biological processes that trigger the dysregulation of cellular energetics in GWI are warranted to better understand the underlying pathology and to develop new treatment methods. This review highlights studies related to mitochondrial dysfunction observed in both GW veterans and in animal models of GWI.

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