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Environmental Health : a Global Access... Oct 2023During deployment, veterans of the 1991 Gulf War (GW) were exposed to multiple war-related toxicants. Roughly a third of these veterans continue to exhibit neurotoxicant...
Cognitive decrements in 1991 Gulf War veterans: associations with Gulf War illness and neurotoxicant exposures in the Boston Biorepository, Recruitment, and Integrative Network (BBRAIN) cohorts.
BACKGROUND
During deployment, veterans of the 1991 Gulf War (GW) were exposed to multiple war-related toxicants. Roughly a third of these veterans continue to exhibit neurotoxicant induced symptoms of Gulf War Illness (GWI), a multi-faceted condition that includes fatigue, pain and cognitive decrements. When studied empirically, both deployed veterans with exposures and those who meet the criteria for GWI are more likely to show deficits in the area of neuropsychological functioning. Although studies have shown cognitive impairments in small sample sizes, it is necessary to revisit these findings with larger samples and newer cohorts to see if other areas of deficit emerge with more power to detect such differences. A group of researchers and clinicians with expertise in the area of GWI have identified common data elements (CDE) for use in research samples to compare data sets. At the same time, a subgroup of researchers created a new repository to share these cognitive data and biospecimens within the GWI research community.
METHODS
The present study aimed to compare cognitive measures of attention, executive functioning, and verbal memory in a large sample of GWI cases and healthy GW veteran controls using neuropsychological tests recommended in the CDEs. We additionally subdivided samples based on the specific neurotoxicant exposures related to cognitive deficits and compared exposed versus non-exposed veterans regardless of case criteria status. The total sample utilized cognitive testing outcomes from the newly collated Boston, Biorepository, Recruitment, and Integrative Network (BBRAIN) for GWI.
RESULTS
Participants included 411 GW veterans, 312 GWI (cases) and 99 healthy veterans (controls). Veterans with GWI showed significantly poorer attention, executive functioning, learning, and short-and-long term verbal memory than those without GWI. Further, GW veterans with exposures to acetylcholinesterase inhibiting pesticides and nerve gas agents, had worse performance on executive function tasks. Veterans with exposure to oil well fires had worse performance on verbal memory and those with pyridostigmine bromide anti-nerve gas pill exposures had better verbal memory and worse performance on an attention task compared to unexposed veterans.
CONCLUSIONS
This study replicates prior results regarding the utility of the currently recommended CDEs in determining impairments in cognitive functioning in veterans with GWI in a new widely-available repository cohort and provides further evidence of cognitive decrements in GW veterans related to war-related neurotoxicant exposures.
Topics: Humans; Veterans; Persian Gulf Syndrome; Gulf War; Boston; Acetylcholinesterase; Cognition
PubMed: 37794452
DOI: 10.1186/s12940-023-01018-2 -
European Neurology 2023Rituximab is a monoclonal chimeric antibody against CD20+ B cells. We aimed to assess the long-term efficacy and safety of CD20+ B cell-guided treatment with low-dose...
INTRODUCTION
Rituximab is a monoclonal chimeric antibody against CD20+ B cells. We aimed to assess the long-term efficacy and safety of CD20+ B cell-guided treatment with low-dose rituximab in refractory myasthenia gravis patients.
METHODS
Patients with refractory myasthenia gravis treated with rituximab for more than 2 years were included. Rituximab was administered when CD20+ B cells were greater than 1%. We analysed the efficacy of rituximab, treatment interval, side effects, prognosis, and treatment course.
RESULTS
A total of 22 patients were included. All patients received 2-12 doses of rituximab, and the median follow-up time was 48.5 months. The scores of the Myasthenia Gravis Activities of Daily Living and Myasthenia Gravis Composite were significantly lower than those at baseline (p < 0.05). MGFA-PIS was significantly improved in 21 (95.45%) patients and 14 (63.64%) patients have reached MGFA-PIS minimal manifestations. The average daily dose of prednisone and pyridostigmine bromide and the proportion of immunosuppressants were significantly lower (p < 0.05). Seven patients suffered from 14 worsenings. Eight patients terminated rituximab due to good efficacy. Most patients tolerated rituximab well, although 1 patient had opportunistic infection and hypogammaglobulinemia, 1 patient had an intracranial mass.
CONCLUSION
Long-term CD20+ B-cell-guided low-dose rituximab showed good efficacy and tolerance in patients with refractory myasthenia gravis.
Topics: Humans; Rituximab; Immunologic Factors; Activities of Daily Living; Myasthenia Gravis; Prednisone
PubMed: 37778340
DOI: 10.1159/000534336 -
Journal of the American Animal Hospital... Sep 2023Acquired myasthenia gravis (MG) in dogs can present with focal or generalized weakness and is diagnosed by the presence of circulating antibodies to the acetylcholine...
Acquired myasthenia gravis (MG) in dogs can present with focal or generalized weakness and is diagnosed by the presence of circulating antibodies to the acetylcholine receptor. Megaesophagus is the most common focal form of MG. Although exacerbation of MG has been associated with the use of fluoroquinolones in humans, it has not been previously described in dogs. The medical records of 46 dogs diagnosed with MG based on acetylcholine receptor antibody testing from 1997 to 2021 were retrospectively evaluated to identify any dogs who demonstrated exacerbation of MG after the administration of a fluoroquinolone. Exacerbation of MG, from focal to generalized, occurred in a median of 4.5 days after initiation of fluoroquinolone therapy in six dogs. In addition, one dog with generalized MG and megaesophagus developed pyridostigmine resistance subsequent to fluoroquinolone therapy. Marked improvement in generalized weakness was reported 36 hr after discontinuation of fluoroquinolone therapy alone in one dog and in combination with pyridostigmine in two dogs. Fluoroquinolone therapy was never stopped in three dogs who were euthanized because of severe weakness and one dog who died of respiratory arrest.
Topics: Humans; Dogs; Animals; Pyridostigmine Bromide; Esophageal Achalasia; Retrospective Studies; Dog Diseases; Myasthenia Gravis; Fluoroquinolones; Receptors, Cholinergic
PubMed: 37708471
DOI: 10.5326/JAAHA-MS-7353 -
Journal of Medical Case Reports Sep 2023Myasthenia gravis is an autoimmune condition affecting the neuromuscular junction and causing muscle weakness along with fatigue (myasthenia). When the clinical...
BACKGROUND
Myasthenia gravis is an autoimmune condition affecting the neuromuscular junction and causing muscle weakness along with fatigue (myasthenia). When the clinical manifestations of myasthenia gravis are isolated to the eye muscles, only causing weak eye movements, it is referred to as ocular myasthenia gravis, which can mimic a 1 and ½ syndrome.
CASE PRESENTATION
An African-American female in her fifties with past medical history of hypertension presented to our outpatient clinic with complaints of blurred vision for two weeks. Her symptoms were associated with facial discomfort and a generalized headache. On physical examination upon her initial presentation, there was demonstratable swelling of the left upper eyelid with drooping. Her extraocular movements revealed defects with the abduction and adduction of the right eye, and the left eye would not adduct, although the outward movement was normal. The left eye failed to lift/elevate completely when looking upwards, a pseudo 1 and ½ syndrome. A positive Cogan lid twitch was also noticed. Imaging of the brain and orbit ruled out central causes. Diagnosis of ocular myasthenia gravis was made in accordance with positive anti-acetylcholine receptor antibodies. With 120 mg pyridostigmine oral dose, the patient experienced improvement subjectively and objectively, and the patient was discharged on oral pyridostigmine and prednisone. Six months later, with prednisone having been tapered off, the patient developed a myasthenic crisis and was treated with plasmapheresis and intravenous immunoglobulins. After recovering from the myasthenic crisis, efgartigimod infusions were instituted, which helped our patient restore normal life.
CONCLUSION
Our patient who presented with "blurred vision" was discovered to have binocular diplopia due to significant dysconjugate eye movements. After diligently ruling out central etiologies, we concluded that her presentation was due to a peripheral etiology. Her serologies and her presentation helped confirm a diagnosis of ocular myasthenia gravis. Also, as in most cases, our patient also progressed to develop generalized myasthenia gravis while on pyridostigmine. Efgartigimod infusions instituted after our patient recovered from a myasthenic crisis have helped her restore a normal life.
Topics: Female; Humans; Diplopia; Pyridostigmine Bromide; Prednisone; Vision Disorders; Myasthenia Gravis; Muscle Weakness
PubMed: 37679826
DOI: 10.1186/s13256-023-04089-4 -
Clinical Neurophysiology : Official... Oct 2023To investigate the electrophysiological basis of pyridostigmine enhancement of endurance performance documented earlier in patients with spinal muscular atrophy (SMA). (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To investigate the electrophysiological basis of pyridostigmine enhancement of endurance performance documented earlier in patients with spinal muscular atrophy (SMA).
METHODS
We recorded surface electromyography (sEMG) in four upper extremity muscles of 31 patients with SMA types 2 and 3 performing endurance shuttle tests (EST) and maximal voluntary contraction (MVC) measurements during a randomized, double blind, cross-over, phase II trial. Linear mixed effect models (LMM) were used to assess the effect of pyridostigmine on (i) time courses of median frequencies and of root mean square (RMS) amplitudes of sEMG signals and (ii) maximal RMS amplitudes during MVC measurements. These sEMG changes over time indicate levels of peripheral muscle fatigue and recruitment of new motor units, respectively.
RESULTS
In comparison to a placebo, patients with SMA using pyridostigmine had fourfold smaller decreases in frequency and twofold smaller increases in amplitudes of sEMG signals in some muscles, recorded during ESTs (p < 0.05). We found no effect of pyridostigmine on MVC RMS amplitudes.
CONCLUSIONS
sEMG parameters indicate enhanced low-threshold (LT) motor unit (MU) function in upper-extremity muscles of patients with SMA treated with pyridostigmine. This may underlie their improved endurance.
SIGNIFICANCE
Our results suggest that enhancing LT MU function may constitute a therapeutic strategy to reduce fatigability in patients with SMA.
Topics: Humans; Pyridostigmine Bromide; Muscular Atrophy, Spinal; Electromyography; Muscles; Muscle Fatigue; Muscle, Skeletal
PubMed: 37595479
DOI: 10.1016/j.clinph.2023.06.024 -
Toxicology Mechanisms and Methods Nov 2023The carbamate pyridostigmine bromide (PB) is the only fielded pharmacological prophylaxis for military use against nerve agents. Previous studies have shown differences...
The carbamate pyridostigmine bromide (PB) is the only fielded pharmacological prophylaxis for military use against nerve agents. Previous studies have shown differences in the PB-pretreatment efficacy for various nerve agents and in the influence of post-exposure treatment with common antidotes. In the present study, the aim was to evaluate the possibility of using an rat precision-cut lung slice model to determine the impact of PB pretreatment on VX-induced bronchoconstriction. In addition, the efficacy of post-exposure treatment with atropine sulfate following PB-prophylaxis was investigated.Bronchoconstriction was induced by electric-field stimulation and was significantly aggravated by 10 µM PB. Airway recovery was decreased by both 1 and 10 µM PB. Evaluation of acetylcholineesterese inhibition by PB showed that the lower concentration met the clinical criteria of residual enzyme activity while the higher concentration completely inhibited the activity. Exposure to VX with or without pretreatment demonstrated similar contractions. However, VX-incubation following pretreatment caused decreased airway relaxation compared to pretreatment alone. Atropine treatment following PB- and VX-exposure significantly decreased the maximum airway contraction and increased the relaxation.In conclusion, no beneficial effect of PB-prophylaxis on VX-induced contractions was observed. The atropine efficacy to relax airways was significant demonstrating the importance of efficient post-exposure therapeutics to protect against the life-threatening respiratory contractions.
Topics: Rats; Animals; Pyridostigmine Bromide; Nerve Agents; Atropine; Lung; Cholinesterase Inhibitors
PubMed: 37537757
DOI: 10.1080/15376516.2023.2238060 -
Current Gastroenterology Reports Sep 2023Acute Colonic Pseudo-obstruction (ACPO) is a cause of large intestinal dilation and obstruction without any physical transition point. It remains difficult to diagnose... (Review)
Review
PURPOSE OF REVIEW
Acute Colonic Pseudo-obstruction (ACPO) is a cause of large intestinal dilation and obstruction without any physical transition point. It remains difficult to diagnose and treat. We review the recent updates on diagnosis and management of ACPO.
RECENT FINDINGS
Recent guidelines have posited that conservative management can be tried in most cases of ACPO, but that early decompression and surgery should be considered. Use of neostigmine is still a viable option but there is also promising data on pyridostigmine as well as prucalopride. Resolution of ACPO should be followed by daily use of polyethylene glycol (PEG) to help prevent recurrence. ACPO warrants early and accurate diagnosis with exclusion of alternate causes of large bowel dilation. Conservative management can be attempted for 48-72 h in those with cecal diameters < 12 cm and without signs of peritonitis and perforation. Early escalation of management should be attempted with neostigmine followed by endoscopy and/or surgery as needed, given that longer periods of dilation are associated with worse outcomes. There is promising new evidence for use of pyridostigmine and prucalopride, but further trials are needed prior to incorporating them into regular use. Finally, studies are lacking regarding prevention of ACPO after initial resolution.
Topics: Humans; Acute Disease; Colonic Pseudo-Obstruction; Endoscopy, Gastrointestinal; Neostigmine; Polyethylene Glycols; Pyridostigmine Bromide; Cholinesterase Inhibitors; Parasympathomimetics; Treatment Outcome
PubMed: 37486594
DOI: 10.1007/s11894-023-00881-w -
Brain, Behavior, and Immunity Oct 2023Gulf War Illness (GWI) collectively describes the multitude of central and peripheral disturbances affecting soldiers who served in the 1990-1991 Gulf War. While the...
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.
Topics: Rats; Animals; Persian Gulf Syndrome; Gulf War; Lipopolysaccharides; Acetylcholinesterase; Cholinesterase Inhibitors; Pyridostigmine Bromide; Cognitive Dysfunction; Memory Disorders; Disease Models, Animal
PubMed: 37437820
DOI: 10.1016/j.bbi.2023.07.003 -
Environmental Health : a Global Access... Jul 2023Exposure 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...
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.
Topics: Persian Gulf Syndrome; Humans; Apolipoproteins E; Veterans; Pyridostigmine Bromide; Pesticides; Hazardous Substances; Male; Female; Middle Aged; Smoke
PubMed: 37415220
DOI: 10.1186/s12940-023-01002-w -
Scandinavian Journal of Rheumatology Nov 2023Rheumatoid arthritis (RA) is a chronic inflammatory disorder. Pyridostigmine (PYR), an acetylcholinesterase (AChE) inhibitor, has been shown to reduce inflammation and...
OBJECTIVE
Rheumatoid arthritis (RA) is a chronic inflammatory disorder. Pyridostigmine (PYR), an acetylcholinesterase (AChE) inhibitor, has been shown to reduce inflammation and oxidative stress in several animal models for inflammation-associated conditions. The present study aimed to investigate the effects of PYR on pristane-induced (PIA) in Dark Agouti (DA) rats.
METHOD
DA rats were intradermally infused with pristane to establish the PIA model, which was treated with PYR (10 mg/kg/day) for 27 days. The effects of PYR on synovial inflammation, oxidative stress, and gut microbiota were evaluated by determining arthritis scores, H&E staining, quantitative polymerase chain reaction, and biochemical assays, as well as 16S rDNA sequencing.
RESULTS
Pristane induced arthritis, with swollen paws and body weight loss, increased arthritis scores, synovium hyperplasia, and bone or cartilage erosion. The expression of pro-inflammatory cytokines in synovium was higher in the PIA group than in the control group. PIA rats also displayed elevated levels of malondialdehyde, nitric oxide, superoxide dismutase, and catalase in plasma. Moreover, sequencing results showed that the richness, diversity, and composition of the gut microbiota dramatically changed in PIA rats. PYR abolished pristane-induced inflammation and oxidative stress, and corrected the gut microbiota dysbiosis.
CONCLUSION
The results of this study support the protective role of PYR in PIA in DA rats, associated with the attenuation of inflammation and correction of gut microbiota dysbiosis. These findings open new perspectives for pharmacological interventions in animal models of RA.
Topics: Rats; Humans; Animals; Arthritis, Experimental; Pyridostigmine Bromide; Acetylcholinesterase; Dysbiosis; Arthritis, Rheumatoid; Inflammation; Terpenes
PubMed: 37339380
DOI: 10.1080/03009742.2023.2196783