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Frontiers in Immunology 2024Though 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... (Review)
Review
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.
Topics: Humans; Persian Gulf Syndrome; Cognitive Dysfunction; Phenotype; Animals
PubMed: 38919622
DOI: 10.3389/fimmu.2024.1403574 -
Pharmaceuticals (Basel, Switzerland) Apr 2024In this investigation, we explored the effects of pharmacological cholinergic stimulation on cardiac function and renal inflammation following acute myocardial...
Cholinergic Stimulation Exerts Cardioprotective Effects and Alleviates Renal Inflammatory Responses after Acute Myocardial Infarction in Spontaneous Hypertensive Rats (SHRs).
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.
PubMed: 38794117
DOI: 10.3390/ph17050547 -
The British Journal of Surgery May 2024Postoperative ileus, driven by the cholinergic anti-inflammatory pathway, is the most common complication in patients undergoing colorectal surgery. By inhibiting... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Postoperative ileus, driven by the cholinergic anti-inflammatory pathway, is the most common complication in patients undergoing colorectal surgery. By inhibiting acetylcholinesterase, pyridostigmine can potentially modulate the cholinergic anti-inflammatory pathway and accelerate gastrointestinal recovery. This study aimed to assess the efficacy of pyridostigmine in improving gastrointestinal recovery after colorectal surgery.
METHODS
This double-blinded RCT enrolled adult patients undergoing elective colorectal surgery at two hospitals in South Australia. Patients were randomized to 60 mg oral pyridostigmine or placebo twice daily starting 6 h after surgery until the first passage of stool. The primary outcome was GI-2, a validated composite measure of time to first stool and tolerance of oral diet. Secondary outcomes included incidence of postoperative ileus (defined as GI-2 greater than 4 days), duration of hospital stay, and 30-day complications, evaluated by intention-to-treat univariate analysis.
RESULTS
Of 130 patients recruited (mean(s.d.) age 58.4(16.4) years; 73 men, 56%), 65 were allocated to each arm. The median GI-2 was 1 day shorter with pyridostigmine compared with placebo (2 (i.q.r. 1-3) versus 3 (2-4) days; P = 0.015). However, there were no significant differences in postoperative ileus (17.2 versus 21.5%; P = 0.532) or duration of hospital stay (median 5 (i.q.r. 4-8.75) versus 5 (4-7.5) days; P = 0.921). Similarly, there were no significant differences in overall complications, anastomotic leak, cardiac complications, or patient-reported side effects.
CONCLUSION
Pyridostigmine resulted in a quicker return of GI-2 and was well tolerated. Larger multicentre studies are required to determine the optimal dosing and evaluate the impact of pyridostigmine in different surgical settings. Registration number: ACTRN12621000530820 (https://anzctr.org.au).
Topics: Humans; Male; Ileus; Female; Double-Blind Method; Middle Aged; Postoperative Complications; Cholinesterase Inhibitors; Pyridostigmine Bromide; Aged; Length of Stay; Adult; Treatment Outcome
PubMed: 38743864
DOI: 10.1093/bjs/znae121 -
The Clinical Neuropsychologist May 2024: Gulf War Illness (GWI) is a debilitating multisymptom condition that affects nearly a third of 1990-91 Gulf War (GW) veterans. Symptoms include pain, fatigue,...
Characterizing 1991 Gulf War women veterans from the Boston Biorepository and Integrative Network for Gulf War Illness: demographics, exposures, neuroimaging and cognitive outcomes.
: Gulf War Illness (GWI) is a debilitating multisymptom condition that affects nearly a third of 1990-91 Gulf War (GW) veterans. Symptoms include pain, fatigue, gastrointestinal issues, and cognitive decrements. Our work has shown that GWI rates and potential causes for symptoms vary between men and women veterans. Studies have documented neuropsychological and neuroimaging findings mostly in men or combined sex datasets. Data are lacking for women veterans due to lack of power and repositories of women veteran samples. : We characterized GW women veterans in terms of demographics, exposures, neuropsychological and neuroimaging outcomes from the newly collated Boston, Biorepository and Integrative Network (BBRAIN) for GWI. : BBRAIN women veterans are highly educated with an average age of 54 years. 81% met GWI criteria, 25% met criteria for current PTSD, 78% were white, and 81% served in the Army. Exposure to combined acetylcholinesterase inhibitors (AChEi) including skin pesticides, fogs/sprays and/or pyridostigmine bromide (PB) anti-nerve gas pill exposure resulted in slower processing speed on attentional tasks and a trend for executive impairment compared with non-exposed women. Brain imaging outcomes showed lower gray matter volumes and smaller caudate in exposed women. : Although subtle and limited findings were present in this group of women veterans, it suggests that continued follow-up of GW women veterans is warranted. Future research should continue to evaluate differences between men and women in GW veteran samples. The BBRAIN women sub-repository is recruiting and these data are available to the research community for studies of women veterans.
PubMed: 38692856
DOI: 10.1080/13854046.2024.2344263 -
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 -
European Journal of Pharmacology May 2024Chronic treatment with acetylcholinesterase inhibitors may be a promising therapeutic strategy for treatment of cardiovascular diseases. The aim of our study was to...
Changes in cardiovascular autonomic control induced by chronic inhibition of acetylcholinesterase during pyridostigmine or donepezil treatment of spontaneously hypertensive rats.
Chronic treatment with acetylcholinesterase inhibitors may be a promising therapeutic strategy for treatment of cardiovascular diseases. The aim of our study was to analyze the changes in blood pressure (BP) and heart rate (HR) during 14 days of treatment with two different acetylcholinesterase inhibitors - pyridostigmine (PYR) having only peripheral effects or donepezil (DON) with both peripheral and central effects. In addition, we studied their effects on the cardiovascular response to restraint stress and on sympathovagal control of HR in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). SHR were characterized by elevated BP and increased low-frequency component of systolic BP variability (LF-SBPV), but their cardiac vagal tone and HR variability (HRV) were reduced compared with WKY. Chronic treatment with either acetylcholinesterase inhibitor decreased HR and increased HRV in both strains. PYR treatment slightly decreased BP and LF-SBPV in the dark phase of the day. Neither drug significantly altered BP response to stress, but PYR attenuated HR increase during restraint stress. Regarding sympathovagal balance, acute methylatropine administration caused a greater increase of HR in WKY than in SHR. Chronic PYR or DON treatment enhanced HRV and HR response to methylatropine (vagal tone) in WKY, whereas PYR but not DON treatment potentiated HRV and vagal tone in SHR. In conclusion, vagal tone was lower in SHR compared with WKY, but was enhanced by chronic PYR treatment in both strains. Thus, chronic peripheral, but not central, acetylcholinesterase inhibition has major effects on HR and its variability in both normotensive and hypertensive rats.
Topics: Rats; Animals; Rats, Inbred SHR; Pyridostigmine Bromide; Acetylcholinesterase; Cholinesterase Inhibitors; Donepezil; Rats, Inbred WKY; Hypertension; Blood Pressure; Heart Rate; Atropine Derivatives
PubMed: 38537804
DOI: 10.1016/j.ejphar.2024.176526 -
Boletin Medico Del Hospital Infantil de... 2024This work aimed to show which treatments showed efficacy against coronavirus disease 2019 (COVID-19); therefore, the results of 37 clinical trials started in 2020 and...
This work aimed to show which treatments showed efficacy against coronavirus disease 2019 (COVID-19); therefore, the results of 37 clinical trials started in 2020 and completed in 2021 are reviewed and discussed here. These were selected from databases, excluding vaccines, computational studies, in silico, in vitro, and those with hyperimmune sera from recovered patients. We found 34 drugs, one vitamin, and one herbal remedy with pharmacological activity against symptomatic COVID-19. They reduced mortality, disease progression, or recovery time. For each treatment, the identifier and type of trial, the severity of the disease, the sponsor, the country where the trial was conducted, and the trial results are presented. The drugs were classified according to their mechanism of action. Several drugs that reduced mortality also reduced inflammation in the most severe cases. These include some that are not considered anti-inflammatory, such as Aviptadil, pyridostigmine bromide, anakinra, imatinib, baricitinib, and bevacizumab, as well as the combination of ivermectin, aspirin, dexamethasone, and enoxaparin. Nigella sativa seeds with honey have also been reported to have therapeutic activity. On the other hand, tofacitinib, novaferon with ritonavir, and lopinavir were also effective, as well as in combination with antiviral therapies such as danoprevir with ritonavir. The natural products colchicine and Vitamin D3 were only effective in patients with mild-to-moderate COVID-19, as was hydroxychloroquine. Drug repositioning has been the main tool in the search for effective therapies by expanding the pharmacological options available to patients.
Topics: Humans; COVID-19; Ritonavir; Antiviral Agents; SARS-CoV-2; Biological Products; Pandemics
PubMed: 38503318
DOI: 10.24875/BMHIM.23000016 -
Journal of Biochemical and Molecular... Mar 2024Obesity is a major cause of nonalcohol fatty liver disease (NAFLD), which is characterized by hepatic fibrosis, lipotoxicity, inflammation, and apoptosis. Previous... (Review)
Review
Obesity is a major cause of nonalcohol fatty liver disease (NAFLD), which is characterized by hepatic fibrosis, lipotoxicity, inflammation, and apoptosis. Previous studies have shown that an imbalance in the autonomic nervous system is closely related to the pathogenesis of NAFLD. In this study, we investigated the effects of pyridostigmine (PYR), a cholinesterase (AChE) inhibitor, on HFD-induced liver injury and explored the potential mechanisms involving mitochondrial damage and oxidative stress. A murine model of HFD-induced obesity was established using the C57BL/6 mice, and PYR (3 mg/kg/d) or placebo was administered for 20 weeks. PYR reduced the body weight and liver weight of the HFD-fed mice. Additionally, the serum levels of IL-6, TNF-α, cholesterol, and triglyceride were significantly lower in the PYR-treated versus the untreated mice, corresponding to a decrease in hepatic fibrosis, lipid accumulation, and apoptosis in the former. Furthermore, the mitochondrial morphology improved significantly in the PYR-treated group. Consistently, PYR upregulated ATP production and the mRNA level of the mitochondrial dynamic factors OPA1, Drp1 and Fis1, and the mitochondrial unfolded protein response (UPRmt) factors LONP1 and HSP60. Moreover, PYR treatment activated the Keap1/Nrf2 pathway and upregulated HO-1 and NQO-1, which mitigated oxidative injury as indicated by decreased 8-OHDG, MDA and H O levels, and increased SOD activity. Finally, PYR elevated acetylcholine (ACh) levels by inhibiting AChE, and upregulated the α7nAChR and M3AChR proteins in the HFD-fed mice. PYR alleviated obesity-induced hepatic injury in mice by mitigating mitochondrial damage and oxidative stress via α7nAChR and M3AChR.
Topics: Mice; Animals; Non-alcoholic Fatty Liver Disease; Pyridostigmine Bromide; alpha7 Nicotinic Acetylcholine Receptor; Kelch-Like ECH-Associated Protein 1; Chemical and Drug Induced Liver Injury, Chronic; Mice, Inbred C57BL; NF-E2-Related Factor 2; Liver; Oxidative Stress; Liver Cirrhosis; Obesity; Diet; Diet, High-Fat
PubMed: 38454809
DOI: 10.1002/jbt.23671 -
Frontiers in Neuroscience 2024Gulf War Illness (GWI) is a multi-symptom disorder that manifests with fatigue, sleep disturbances, mood-cognition pathologies, and musculoskeletal symptoms. GWI affects...
Gulf War Illness (GWI) is a multi-symptom disorder that manifests with fatigue, sleep disturbances, mood-cognition pathologies, and musculoskeletal symptoms. GWI affects at least 25% of the military personnel that served in Operations Desert Shield and Desert Storm from 1990 to 1991. We modeled Gulf War toxicant exposure in C57BL/6J mice by combined exposure to pyridostigmine bromide (an anti-sarin drug), chlorpyrifos (an organophosphate insecticide), and DEET (an insect repellent) for 10 days followed by oral treatment with root extract for 21 days beginning at 12 weeks post-exposure. , commonly referred to as ashwagandha, has been used in traditional Ayurvedic medicine for centuries to improve memory and reduce inflammation, and its roots contain bioactive molecules which share functional groups with modern pain, cancer, and anti-inflammatory drugs. Previously, we observed that GWI mice displayed chronic reductions in dendritic arbor and loss of spines in granule cells of the dentate gyrus of the hippocampus at 14 weeks post-exposure. Here, we examined the effects of treatment with root extract on chronic dendrite and spine morphology in dentate granule cells of the mouse hippocampus following Gulf War toxicant exposure. GWI mice showed approximately 25% decreases in dendritic length ( < 0.0001) and overall dendritic spine density with significant reductions in thin and mushroom spines. GWI mice treated with the Ayurvedic extract exhibited dendritic lengths and spine densities near normal levels. These findings demonstrate the efficacy of the Ayurvedic treatment for neuroprotection following these toxic exposures. We hope that the extract and the neuronal processes influenced will open new avenues of research regarding treatment of Gulf War Illness and neurodegenerative disorders.
PubMed: 38449731
DOI: 10.3389/fnins.2024.1368667 -
Pediatric Neurology Apr 2024Currently, there is no universally accepted standard treatment for ocular myasthenia gravis (OMG) in children. We aimed to investigate the possible proper regimens and...
BACKGROUND
Currently, there is no universally accepted standard treatment for ocular myasthenia gravis (OMG) in children. We aimed to investigate the possible proper regimens and timing of treatment for pediatric OMG cases based on the clinical manifestations: OMG with ptosis only and OMG with other features.
METHODS
One hundred and forty two OMG cases attended at the Department of Pediatrics, Xiangya Hospital, Central South University, from 2010 to 2019 were included, and information from medical records was reviewed and recorded. Comparisons of clinical characteristics between patients with OMG with ptosis only and patients with OMG with other features as well as between patients treated with glucocorticoid (GC) within or after six months from disease onset were performed.
RESULTS
OMG with other features constituted about 54.9% of the cases, and 66.2% of the patients achieved optimal outcome. Patients with OMG with ptosis only responded to pyridostigmine alone more than patients with OMG with other features who required several therapies (P < 0.001). Patients with OMG with ptosis only had a larger proportion of optimal outcome than the patients with OMG with other features (P = 0.002), and the difference remained significant even when the individual outcome groups were compared (P < 0.001). Patients who received GC within six months had a greater proportion of optimal outcome than those who received it after six months (P < 0.001).
CONCLUSIONS
Although OMG with other features is a more common subtype of OMG, it is also more severe than OMG with ptosis only. An earlier addition of GC leads to optimal outcome.
Topics: Humans; Child; Myasthenia Gravis; Blepharoptosis; Pyridostigmine Bromide; Glucocorticoids; Retrospective Studies
PubMed: 38382246
DOI: 10.1016/j.pediatrneurol.2024.01.014