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Advanced Biology May 2023Gulf War Illness (GWI) results from chemical exposure during the Gulf War, with notable impacts on gastrointestinal motility. Due to the limited demographic impacted by...
Gulf War Illness (GWI) results from chemical exposure during the Gulf War, with notable impacts on gastrointestinal motility. Due to the limited demographic impacted by this ailment, an in-depth investigation of the GWI has yielded little regarding the underlying pathophysiological mechanisms. Here, the hypothesis that exposure to pyridostigmine bromide (PB) results in severe enteric neuro-inflammation, that cascades to disruptions in colonic motility, is tested. The analyses are performed on male C57BL/6 mice that are treated with physiologically similar doses of PB given to GW veterans. When colonic motility is assessed, GWI colons have significantly reduced forces in response to acetylcholine or electrical field stimulation. GWI is also accompanied by high levels of pro-inflammatory cytokines and chemokines, associated with increased numbers of CD40 pro-inflammatory macrophages within the myenteric plexus. Enteric neurons responsible for mediating colonic motility reside within the myenteric plexus, and PB exposure reduced their numbers. Significant smooth muscle hypertrophy is also observed due to increased inflammation. Together, the results show that PB exposure caused functional and anatomical dysfunction, promoting impaired motility within the colon. Achieving a greater understanding of the mechanisms of GWI will allow more refinement in therapeutic options that improve veterans' quality of life.
Topics: Mice; Male; Animals; Pyridostigmine Bromide; Persian Gulf Syndrome; Quality of Life; Mice, Inbred C57BL; Cholinesterase Inhibitors; Inflammation
PubMed: 36802210
DOI: 10.1002/adbi.202200254 -
Journal of Oncology Pharmacy Practice :... Jul 2023Blepharoptosis, commonly referred to as ptosis or eyelid sagging, is a condition where the upper eyelid droops over the eye. It can be congenital or acquired and is...
INTRODUCTION
Blepharoptosis, commonly referred to as ptosis or eyelid sagging, is a condition where the upper eyelid droops over the eye. It can be congenital or acquired and is caused by the weakening of the eyelid muscles.
CASE REPORT
We present a case of a 3-year-old boy with T-cell acute lymphoblastic leukemia who developed bilateral ptosis while on treatment with Berlin-Frankfurt Munster-98 protocol.
MANAGEMENT & OUTCOME
The patient was diagnosed with bilateral ptosis due to vincristine, the primary agent in the induction phase of the protocol. The addition of the neuroregenerative agents and supportive measures led to marked improvement, followed by complete resolution within 3 weeks.
DISCUSSION
Vincristine is an anticancer agent with known neurotoxicity, which has a significant role in treating hematological malignancies and sarcoma. In many studies, the addition of neuroregenerative agents such as pyridoxine and pyridostigmine has been noted to hasten recovery without any documented side effects. Similar findings were also drawn from our research due to India's higher incidence of vincristine-induced neurotoxicity. It is essential to promptly diagnose and manage symptoms at the earliest to prevent the risk of permanent nerve damage and inferior quality of life for the patient.
Topics: Male; Humans; Child, Preschool; Vincristine; Blepharoptosis; Pyridostigmine Bromide; Pyridoxine; Quality of Life; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 36734133
DOI: 10.1177/10781552231152414 -
Journal of Cellular and Molecular... Apr 2023Gulf War Illness (GWI) has been reported in 25%-35% of veterans returned from the Gulf war. Symptoms of GWI are varied and include both neurological and gastrointestinal... (Review)
Review
Gulf War Illness (GWI) has been reported in 25%-35% of veterans returned from the Gulf war. Symptoms of GWI are varied and include both neurological and gastrointestinal symptoms as well as chronic fatigue. Development of GWI has been associated with chemical exposure particularly with exposure to pyridostigmine bromide (PB) and permethrin. Recent studies have found that the pathology of GWI is connected to changes in the gut microbiota, that is the gut dysbiosis. In studies using animal models, the exposure to PB and permethrin resulted in similar changes in the gut microbiome as these found in GW veterans with GWI. Studies using animal models have also shown that phytochemicals like curcumin are beneficial in reducing the symptoms and that the extracellular vesicles (EV) released from gut bacteria and from the intestinal epithelium can both promote diseases and suppress diseases through the intercellular communication mechanisms. The intestinal epithelium cells produce EVs and these EVs of intestinal epithelium origin are found to suppress inflammatory bowel disease severity, suggesting the benefits of utilizing EV in treatments. On the contrary, EV from the plasma of septic mice enhanced the level of proinflammatory cytokines in vitro and neutrophils and macrophages in vivo, suggesting differences in the EV depending on the types of cells they were originated and/or influences of environmental changes. These studies suggest that targeting the EV that specifically have positive influences may become a new therapeutic strategy in the treatment of veterans with GWI.
Topics: Mice; Animals; Permethrin; Gastrointestinal Microbiome; Dysbiosis; Gulf War; Persian Gulf Syndrome; Pyridostigmine Bromide; Disease Models, Animal
PubMed: 36716094
DOI: 10.1111/jcmm.17631 -
European Journal of Medical Genetics Mar 2023Disease causing variants in the Ryanodine receptor 1 (RYR1) gene are a common cause for congenital myopathy and for malignant hyperthermia susceptibility. We report a 17...
Disease causing variants in the Ryanodine receptor 1 (RYR1) gene are a common cause for congenital myopathy and for malignant hyperthermia susceptibility. We report a 17 year old boy with congenital muscle weakness progressing to a myasthenia like myopathy with muscle weakness, fatigability, ptosis, and ophthalmoplegia. Muscle biopsy showed predominance and atrophy of type 1 fibers. Whole-exome trio sequencing revealed three variants in the RYR1-gene in the patient: c.6721C > T,p.(Arg2241*) and c.2122G > A,p.(Asp708Asn) in cis position, and the c.325C > T,p.(Arg109Trp) variant in trans. Treatment with pyridostigmine improved symptoms. This case supports that a myasthenia like phenotype is part of the phenotypic spectrum of RYR1 related disorders, and that treatment with pyridostigmine can be beneficial for patients with this phenotype.
Topics: Adolescent; Humans; Male; Muscle Weakness; Muscle, Skeletal; Muscular Diseases; Mutation; Phenotype; Pyridostigmine Bromide; Ryanodine Receptor Calcium Release Channel
PubMed: 36669590
DOI: 10.1016/j.ejmg.2023.104706 -
Acta Neurologica Belgica Apr 2023As new treatments are becoming available for patients with myasthenia gravis (MG), it is worth reflecting on the actual status of MG treatment to determine which... (Review)
Review
INTRODUCTION
As new treatments are becoming available for patients with myasthenia gravis (MG), it is worth reflecting on the actual status of MG treatment to determine which patients would most likely benefit from the new treatments.
METHODS
We reviewed the clinical files of all MG patients seen at the Department of Neurology of the Antwerp University Hospital during the years 2019, 2020 and 2021.
RESULTS
163 patients were included. Age at diagnosis varied from the first to the eighth decades, with a peak of incidence from 60 to 70 years for both genders, and an additional peak from 20 to 30 years in women. Diplopia and ptosis were by far the most common onset symptom. At maximum disease severity, 24% of the patients still had purely ocular symptoms and 4% needed mechanical ventilation. 97% of the patients received a treatment with pyridostigmine and 68% with corticosteroids, often in combination with immunosuppressants. More than half reported side effects. At the latest visit, 50% of the patients were symptom-free. Also, half of the symptomatic patients were fulltime at work or retired with no or mild limitations in daily living. The remaining patients were working part-time, on sick leave, or retired with severe limitations.
DISCUSSION AND CONCLUSION
The majority of MG patients are doing well with currently available treatments, but often at the cost of side effects in the short and in the long term. A significant group is in need of better treatments.
Topics: Humans; Female; Male; Belgium; Myasthenia Gravis; Pyridostigmine Bromide; Blepharoptosis; Diplopia
PubMed: 36658451
DOI: 10.1007/s13760-023-02187-0 -
Journal of Cardiothoracic Surgery Jan 2023To study the influencing factors of myasthenic crisis in non-thymoma myasthenia gravis (MG) patients during perioperative period.
OBJECTIVE
To study the influencing factors of myasthenic crisis in non-thymoma myasthenia gravis (MG) patients during perioperative period.
METHODS
We retrospectively analyzed a total of 387 non-thymoma MG patients who underwent extended thymoma resection in the Department of Thoracic Surgery of Beijing Hospital from February 2011 to December 2021, recorded ASA score, Osserman classification, preoperative course, pyridostigmine dosage, operation method, operation time, and intraoperative blood loss, then analyzed the factors associated with postoperative myasthenic crisis by univariate and multivariate logistic regression.
RESULTS
Osserman classification IIB + III + IV (P < 0.001), history of myasthenic crisis (P = 0.013), pyridostigmine dosage greater than 240 (P < 0.001), ASA score 2 and 3 (P = 0.001) are independent risk factors for myasthenic crisis.
CONCLUSION
Patients with poor Osserman classification, history of myasthenic crisis before surgery, larger preoperative dosage of pyridostigmine, and higher ASA scores should be highly alert to the occurrence of postoperative myasthenic crisis.
Topics: Humans; Pyridostigmine Bromide; Retrospective Studies; Thymectomy; Postoperative Complications; Myasthenia Gravis; Thymoma; Thymus Neoplasms
PubMed: 36635776
DOI: 10.1186/s13019-023-02136-1 -
Neuromuscular Disorders : NMD Aug 2023
Topics: Humans; DNA-Binding Proteins; Transcription Factors; Neuromuscular Junction; Epilepsy; Pyridostigmine Bromide
PubMed: 36631330
DOI: 10.1016/j.nmd.2022.11.001 -
Human Molecular Genetics Apr 2023Congenital myasthenic syndrome (CMS) is a heterogeneous condition associated with 34 different genes, including SLC5A7, which encodes the high-affinity choline...
Congenital myasthenic syndrome (CMS) is a heterogeneous condition associated with 34 different genes, including SLC5A7, which encodes the high-affinity choline transporter 1 (CHT1). CHT1 is expressed in presynaptic neurons of the neuromuscular junction where it uses the inward sodium gradient to reuptake choline. Biallelic CHT1 mutations often lead to neonatal lethality, and less commonly to non-lethal motor weakness and developmental delays. Here, we report detailed biochemical characterization of two novel mutations in CHT1, p.I294T and p.D349N, which we identified in an 11-year-old patient with a history of neonatal respiratory distress, and subsequent hypotonia and global developmental delay. Heterologous expression of each CHT1 mutant in human embryonic kidney cells showed two different mechanisms of reduced protein function. The p.I294T CHT1 mutant transporter function was detectable, but its abundance and half-life were significantly reduced. In contrast, the p.D349N CHT1 mutant was abundantly expressed at the cell membrane, but transporter function was absent. The residual function of the p.I294T CHT1 mutant may explain the non-lethal form of CMS in this patient, and the divergent mechanisms of reduced CHT1 function that we identified may guide future functional studies of the CHT1 myasthenic syndrome. Based on these in vitro studies that provided a diagnosis, treatment with cholinesterase inhibitor together with physical and occupational therapy significantly improved the patient's strength and quality of life.
Topics: Myasthenic Syndromes, Congenital; Humans; Male; Child; HEK293 Cells; Mutant Proteins; Half-Life; Cell Membrane; Protein Transport; Staurosporine; Pyridostigmine Bromide; Quality of Life; Symporters; Mutation
PubMed: 36611016
DOI: 10.1093/hmg/ddac309 -
Thoracic Cancer Feb 2023To study the influencing factors of myasthenic crisis in patients with myasthenia gravis during perioperative period.
OBJECTIVE
To study the influencing factors of myasthenic crisis in patients with myasthenia gravis during perioperative period.
METHODS
A total of 564 myasthenia gravis (MG) patients who underwent standard expanded resection of thymoma/thymoma in the Department of Thoracic Surgery of Beijing Hospital from January 2011 to March 2022 were retrospectively included in the study. Clinical indicators such as gender, age, thymoma, American Society of Anesthesiologists (ASA) score, operation time, intraoperative blood loss, and some others were recorded.
RESULTS
Osserman-stages IIB + III + IV (odds ratio [OR] 16.091, 95% confidence interval [CI] 5.170-50.076, p value < 0.001), the dosage of pyridostigmine bromide more than 240 mg (OR 6.462, 95% CI 3.110-13.427, p value < 0.001), ASA score 2 and 3 (OR 3.203, 95% CI 1.461-7.020, p value = 0.004), low diffusion lung capacity for carbon monoxide (DLCO%) (OR 0.981, 95% CI 0.963-1.000 p value = 0.049), and blood loss greater than 1000 ml (OR 16.590, 95% CI 1.911-144.011, p value = 0.011) were independent risk factors for myasthenic crisis.
CONCLUSIONS
Patients with poor Osserman stages, higher preoperative dosage of pyridostigmine bromide, higher ASA score, poor pulmonary function (low DLCO%), and more intraoperative bleeding should be highly vigilant for the occurrence of postoperative myasthenic crisis.
Topics: Humans; Thymoma; Pyridostigmine Bromide; Retrospective Studies; Thymectomy; Postoperative Complications; Myasthenia Gravis; Thymus Neoplasms
PubMed: 36594520
DOI: 10.1111/1759-7714.14774 -
Photodiagnosis and Photodynamic Therapy Mar 2023Although the mechanism is not clear, the inability of the orbicularis oculi muscle, especially the deeper segment (Horner muscle), is thought to be responsible in...
BACKGROUND
Although the mechanism is not clear, the inability of the orbicularis oculi muscle, especially the deeper segment (Horner muscle), is thought to be responsible in epiphora. This study evaluates the effect of the anticholinergic drug pyridostigmine (Mestinon) in patients with patent but dysfunctional lacrimal drainage system.
MATERIAL AND METHODS
Twenty patients with bilateral epiphora (mean age:60.78 ± 6.49 yrs) were included in this study. Patients with a patent lacrimal irrigation test based on persistent and symptomatic epiphora, wiping >10 times daily or continuous tearing and grade 4-5 epiphora according to Munk scale, showing neuropathic involvement in the orbicularis oculi muscle by the quantitative motor unit potential (MUP) analysis method were evaluated prospectively. Fluorescein dye disappearance test (a semi-quantitative assessment of delayed tear outflow) together with a Schirmer test reading were performed in order to detect dry eye. The patients were evaluated for tear meniscus measurements by anterior segment optical coherence topography (OCT) and non-invasive tear break-up time (NI-BUT) was measured by Oculus Keratograph 5 M. Those with a NI-BUT value above 10 s, without eyelid laxity, previous ocular surgery or ocular surface disease, or nasolacrimal duct obstruction, and who agreed to use the drug were included in the study. Each subject underwent OCT measurements of the lower tear meniscus of both eyes before and 15 mins after taking Mestinon (1 × 60 mg tablet). Upon measurement of the positive effect of the drug on tear meniscus height (TMH), the patients were asked to continue this regime daily for 1 month and then evaluated for relief in their epiphora complaints and any systemic drug side effects.
RESULTS
A total of 20 patients (40 eyes) with bilateral epiphora were included in the study. All eyes had grade 4 Munk-score epiphora, Schirmer's test was within the normal range in all eyes (mean, 14 ± 4 mm), and patent lacrimal irrigation test. The lower mean TMH reductions 15 min after Mestinon in the right and left eyes were 135.41 ± 85.47 and 55.44 ± 61.56 mm, respectively, a statistically significant decrease in both eyes (p = 0.001, p < 0.01). The mean tear meniscus area (TMA) in the right and left eyes was 131.83 ± 68.27 mm and 62.72 ± 50.57 mm, respectively; 15 mins after administration of Mestinon, the mean TMA in the right and left eyes was 77.27 ± 48.34 and 59.18 ± 44.74 mm, respectively (p = 0.001, p < 0.01). The mean decreases of 54.56 ± 39.34 mm in the right eye area and 3.53 ± 42.32 mm in the left eye area were statistically significant (p = 0.041, p < 0.05).
CONCLUSION
Symptomatic relief for epiphora cannot be achieved with known treatment options due to lacrimal pump dysfunction. We found that pyridostigmine (Mestinon) provided relief in patients' complaints of epiphora consistent with a significant reduction in TMH levels.
Topics: Humans; Middle Aged; Aged; Pyridostigmine Bromide; Lacrimal Duct Obstruction; Nasolacrimal Duct; Tomography, Optical Coherence; Photochemotherapy; Photosensitizing Agents
PubMed: 36592783
DOI: 10.1016/j.pdpdt.2022.103240