Features of liver function in pediatric patients infected with Delta variant versus Omicron variant of severe acute respiratory syndrome coronavirus 2.

Objective To summarize and analyze the features of liver function in pediatric patients infected with Delta variant versus Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS - CoV - 2). Methods In this study,an analysis was performed for the liver function test results of the locally transmitted or imported pediatric patients with SARS - CoV - 2 infection during isolation who were admitted to Guangzhou Eighth People's Hospital,Guangzhou Medical University,since May 21,2021,and the clinical data and the constituent ratio of liver injury were compared between the pediatric patients infected with Delta variant and those infected with Omicron variant. The independent samples t - test or the Mann - Whitney U test was used for comparison of continuous data between two groups,and the chi - square test or the Fisher's exact test was used for comparison of categorical data between two groups. Results A total of 85 pediatric patients infected with SARS - CoV - 2 were enrolled,among whom there were 32 (37. 6%)pediatric patients infected with Delta variant and 53 (62. 4%)pediatric patients infected with Omicron variant,and there were no significant differences between the two groups in age,sex, body height,body weight,and comorbidities (all P > 0. 05). There were no significant differences between the two groups in alanine aminotransferase (ALT),aspartate aminotransferase (AST),alkaline phosphatase (ALP),gamma - glutamyl transpeptidase,total bilirubin,albumin,and cholinesterase (all P > 0. 05),and the pediatric patients infected with Omicron variant had a significantly higher level of total bile acid (TBA)than those infected with Delta variant (Z = - 2. 336,P = 0. 020). However,the median values of TBA were within the normal range and the ratios of abnormal TBA were no significant difference between the two groups (P > 0. 05). Among the 85 pediatric patients,10 (11. 8%)had a mild increase in liver function parameters,among whom 7 had an increase in TBA,1 had an increase in ALT, 1 had increases in ALT and AST,and 1 had an increase in ALP. The analysis of liver injury in the pediatric patients infected with Delta variant or Omicron variant showed that there was no significant difference in the constituent ratio of liver injury caused by the two variants (6. 3% vs 15. 1%,chi2 = 0. 691,P = 0. 406). Conclusion Mild liver injury is observed in pediatric patients infected with Delta and Omicron variants of SARS - CoV - 2,but further studies are needed to evaluate the long - term influence of such infection on liver function.Copyright © 2022 Editorial Board of Jilin University

QSAR and DFT Studies of Some Tacrine-Hydroxamate Derivatives as Inhibitors of Cholinesterase (AChEs) in the Treatment of Alzheimer's Disease

Introduction: This work was devoted to an in silico investigation conducted on twenty-eight Tacrine-hydroxamate derivatives as a potential treatment for Alzheimer's disease using DFT and QSAR modeling techniques. Method(s): The data set was randomly partitioned into a training set (22 compounds) and a test set (6 compounds). Then, fourteen models were built and were used to compute the predicted pIC50 of compounds belonging to the test set. Result(s): Al built models were individualy validated using both internal and external validation methods, including the Y-Randomization test and Golbraikh and Tropsha's model acceptance criteria. Then, one model was selected for its higher R2, R2test, and Q2cv values (R2 = 0.768, R2adj = 0.713, MSE = 0.304, R2test=0.973, Q2cv = 0.615). From these outcomes, the activity of the studied compounds toward the main protease of Cholinesterase (AChEs) seems to be influenced by 4 descriptors, i.e., the total dipole moment of the molecule (mu), number of rotatable bonds (RB), molecular topology radius (MTR) and molecular topology polar surface area (MTPSA). The effect of these descriptors on the activity was studied, in particular, the increase in the total dipole moment and the topological radius of the molecule and the reduction of the rotatable bond and topology polar surface area increase the activity. Conclusion(s): Some newly designed compounds with higher AChEs inhibitory activity have been designed based on the best-proposed QSAR model. In addition, ADMET pharmacokinetic properties were carried out for the proposed compounds, the toxicity results indicate that 7 molecules are nontoxic.Copyright © 2023 Bentham Science Publishers.

Management of patients with cognitive impairment.

The management of patients with cognitive impairment (CI) is one of the urgent problems of modern medicine. Issues of diagnostics and therapy of patients with CI and their high mortality during the period of coronavirus infection are discussed. A wide prevalence of patients with mild CI (MCI), an important role of neuropsychological research in establishing CI, and frequent diagnosis of CI only at the stage of dementia were noted. In our country, CI is poorly diagnosed, the most common cause of CI in the elderly - Alzheimer's disease (AD) - is rarely established, patients are observed for a long time with a diagnosis of cerebrovascular disease (CVD). Some non-drug and drug methods can reduce the manifestations of CI, improve the quality of life of both the patients themselves and those around them. In severe CI, socio-psychological methods, stimulating patients to feasible household and social, physical and mental activity, and avoiding prolonged hospitalization are of primary importance. In addition to lifestyle changes, much attention in CI is given to the prevention of stroke, the treatment of arterial hypertension and diabetes mellitus. At the stage of dementia, cholinomimetic drugs (acetylcholinesterase inhibitors, donepezil, rivastigmine, galantamine) and the glutamate receptor blocker memantine are used. The use of choline alfoscerate in CI and the results of the multicenter, placebo-controlled ASCOMALVA study are discussed, in which, in patients with AD and CVD, the addition of choline alfoscerate to donepezil reduced the severity of CI, manifestations of depression, anxiety, and apathy. A new oral form of choline alfoscerate (Cerpechol) is reported that may improve patient compliance and be used in patients with swallowing disorders.Copyright © 2023 Ima-Press Publishing House. All rights reserved.

Atypical Presentation of Acetylcholinesterase Inhibitor-Induced Diarrhea in Older Adults with Cognitive Decline: An Aspect not to be Underestimated.

The rivastigmine patch is the only existing transdermal delivery system used for the treatment of Alzheimer disease. Among the most common adverse events derived from its use are gastrointestinal events, particularly diarrhea. We report a clinical case of an 81-year-old patient admitted to our hospital under long-standing treatment with rivastigmine transdermal patch who presented with atypical watery diarrhea. Anamnesis showed that the patient presented with a likely infectious gastroenteric event, the diarrheal symptoms of which persisted upon resolution of the event and resolved only upon temporary discontinuation of acetylcholinesterase inhibitors. Failure to rapidly identify the causes of profuse diarrhea in older adults can have lethal consequences. When these symptoms occur, quickly recognizing the causes and providing proper management can be lifesaving.

Management of patients with cognitive impairment.

The management of patients with cognitive impairment (CI) is one of the urgent problems of modern medicine. Issues of diagnostics and therapy of patients with CI and their high mortality during the period of coronavirus infection are discussed. A wide prevalence of patients with mild CI (MCI), an important role of neuropsychological research in establishing CI, and frequent diagnosis of CI only at the stage of dementia were noted. In our country, CI is poorly diagnosed, the most common cause of CI in the elderly - Alzheimer's disease (AD) - is rarely established, patients are observed for a long time with a diagnosis of cerebrovascular disease (CVD). Some non-drug and drug methods can reduce the manifestations of CI, improve the quality of life of both the patients themselves and those around them. In severe CI, socio-psychological methods, stimulating patients to feasible household and social, physical and mental activity, and avoiding prolonged hospitalization are of primary importance. In addition to lifestyle changes, much attention in CI is given to the prevention of stroke, the treatment of arterial hypertension and diabetes mellitus. At the stage of dementia, cholinomimetic drugs (acetylcholinesterase inhibitors, donepezil, rivastigmine, galantamine) and the glutamate receptor blocker memantine are used. The use of choline alfoscerate in CI and the results of the multicenter, placebo-controlled ASCOMALVA study are discussed, in which, in patients with AD and CVD, the addition of choline alfoscerate to donepezil reduced the severity of CI, manifestations of depression, anxiety, and apathy. A new oral form of choline alfoscerate (Cerpechol) is reported that may improve patient compliance and be used in patients with swallowing disorders.Copyright © 2023 Ima-Press Publishing House. All rights reserved.

Features of liver function in pediatric patients infected with Delta variant versus Omicron variant of severe acute respiratory syndrome Coronavirus 2

Objective: To summarize and analyze the features of liver function in pediatric patients infected with Delta variant versus Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods: In this study, an analysis was performed for the liver function test results of the locally transmitted or imported pediatric patients with SARS-CoV-2 infection during isolation who were admitted to Guangzhou Eighth People's Hospital, Guangzhou Medical University, since May 21, 2021, and the clinical data and the constituent ratio of liver injury were compared between the pediatric patients infected with Delta variant and those infected with Omicron variant. The independent samples t-test or the Mann-Whitney U test was used for comparison of continuous data between two groups, and the chi-square test or the Fisher's exact test was used for comparison of categorical data between two groups. Results: A total of 85 pediatric patients infected with SARS-CoV-2 were enrolled, among whom there were 32 (37.6%) pediatric patients infected with Delta variant and 53 (62.4%) pediatric patients infected with Omicron variant, and there were no significant differences between the two groups in age, sex, body height, body weight, and comorbidities (all P > 0.05). There were no significant differences between the two groups in elating aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase, total bilirubin, albumin, and cholinesterase (all P > 0.05), and the pediatric patients infected with Omicron variant had a significantly higher level of total bile acid (TBA) than those infected with Delta variant (Z=-2.336, P=0.020). However, the median values of TBA were within the normal range and the ratios of abnormal TBA were no significant difference between the two groups (P > 0.05). Among the 85 pediatric patients, 10 (11.8%) had a mild increase in liver function parameters, among whom 7 had an increase in TBA, 1 had an increase in ALT, 1 had increases in ALT and AST, and 1 had an increase in ALP. The analysis of liver injury in the pediatric patients infected with Delta variant or Omicron variant showed that there was no significant difference in the constituent ratio of liver injury caused by the two variants (6.3% vs 15.1%, X2=0.691, P=0.406). Conclusion: Mild liver injury is observed in pediatric patients infected with Delta and Omicron variants of SARS-CoV-2, but further studies are needed to evaluate the long-term influence of such infection on liver function.

Myasthenic Syndromes

Myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) are antibody-mediated au- toimmune diseases of the neuromuscular junction. Previous works and recently published study on European LEMS registry demonstrate that Lambert- Eaton syndrome prognosis can be influenced by symptomatic drugs and survival by the treatment of overlying cancer or other autoimmune diseases when present. It is very important to early recognise this disease and to detect and treat efficiently associated comorbidities. Autoimmune myasthénia associated with anti- RAch and Anti-MUSK antibodies is associated with fluctuating weakness in ocular muscles and in muscles of the limb and trunk. Many first-line treatments for MG, including corticosteroids, acetylcholinesterase inhibitors, and non-steroidal immunosuppressive drugs, target inhibition of acetylcholine breakdown or T-cell function. Even though they allow MG patients to maintain an acceptable level of muscle strenght, functinal ability and quality of life, these treatments are non-specific and may be associated with important side effects. Moreover, MG patients may be or become refractary to these traitements during time or develop contreindication to the treatement do to coexisting comorbidities. Over the last few years, new biological agents against complement, the FcRn receptor, or B-cell antigens have been successfully tested in clinical trials. These new therapies with a relatively rapid mode of action and few side effects extend the possibilities for targeted immunotherapies and open new venues to better manage MG. Nevertheless, several challenges may occurs concerning the choice of the drugs in different situation, the frequancy of the administration and the potential long term side effects in the recent context of COVID-19 pandemic.

Novel Agents for Treatment of Delirium: A Proposal for a Multimodal Approach

Background: Delirium, a syndrome characterized by impairment in attention and consciousness, commonly occurs in hospital setting and is associated with higher mortality and poor long-term outcomes. With precise etiology of delirium yet to be elucidated, our current understanding describes delirium as a state of multifactorial global brain dysfunction occurring in susceptible elderly and critically ill patients. (Maldonado, 2008) To treat such a multimodal disorder, we propose investigating two novel multimodal pharmacological approaches: Granulocyte-macrophage colony stimulating factor (GM-CSF) inhibitors and pro-cholinergic muscarinic-receptor agonists. Discussion: Neuroinflammation is a focus of inquiry in a number of neuropsychiatric diseases. Unlike individual cytokine (TNF, IL-6) inhibitors, GM-CSF inhibitors combat the entire inflammatory cascade implicated in delirium: blunting the cytokine response (IL-1, IL-6, TNF) to reduce inflammation, limiting chemotaxis (IL-8 inhibition), reducing cell degradation (H2O2, MMPs), and dulling the T- and B-cell response. (Patel, 2021) GC-CSF inhibitors (otilimab and TMJ2) have already been shown to be effective in and approved for the treatment of inflammatory conditions, such as Rheumatoid Arthritis, and have been effective in treatment of inflammatory processes of COVID-19. (Patel, 2021) Given the role of the neuroinflammatory cascade in delirium, we propose investigating the GM-CSF inhibitors to treat delirium. Acetylcholine dysregulation (‘anticholinergic surge’), on the other hand, has long been implicated in delirium and studies suggest some efficacy of acetylcholinesterase inhibitors in treatment of delirium. Novel schizophrenia treatment studies combine xanomeline, a M-receptor agonist, with trospium, a peripheral anticholinergic, to create a net-positive pro-cholinergic state in the brain while minimizing systemic side-effects. (Brannan, 2020) In addition to treating schizophrenia and cognitive impairment, this combination (KarXT), may be useful in reversing the anti-cholinergic state of the delirious brain. Currently in Phase III clinical trials, KarXT should be considered a viable candidate for delirium treatment, once FDA-approved. Conclusions: Pharmacological approaches to delirium have been limited to managing behavioral dysregulation and sleep-wake cycle disturbances. Presently, we are looking at two potential additional approaches to delirium treatment. One is limited to cholinergic circuitry and aims to restore AcH balance via direct M-receptor agonism. The other, based on Systems Integration Failure Hypothesis, addresses the entire inflammatory cascade via GM-CSF inhibition. As agents from both classes are either approved or are close to FDA-approval, we should consider them as candidates for delirium management. References: 1. Maldonado, J, Kapinos, G. (2008). Pathoetiological Model of Delirium, Critical care clinics. 24. 789-856, ix. 10.1016/j.ccc.2008.06.004. 2. Brannan, S, Sawchak, S, et al.(2020). Efficacy and Safety of Xanomeline, a M1/M4 Receptor Preferencing Agonist, Plus Trospium, a Peripheral Muscarinic Antagonist, in Schizophrenia. Biological Psychiatry, 87(9), S169. doi: 10.1016/j.biopsych.2020.02.446 3. Patel, S, Saxena, B., Mehta, P. (2021). Recent updates in the clinical trials of therapeutic monoclonal antibodies targeting cytokine storm for the management of COVID-19. Heliyon, 7(2), e06158. doi: 10.1016/j.heliyon.2021.e06158

INFLUENCE OF BUTYRYLCHOLINESTERASE ON THE COURSE OF COVID-19

Butyrylcholinesterase (BChE), a hepatic enzyme produced by the liver is affected by and influences a variety of inflammatory, infectious and metabolic dysfunction processes. Considering that COVID-19 is a multisystem disorder related to conditions influenced by BChE, the potential interrelation of the two is reviewed. BChE is altered in a variety of infectious diseases, and serves as a prognostic marker in both infections and in non-infectious diseases. Closely related to acetylcholinesterase (AChE), BChE plays a role in modulating inflammation via the cholinergic system. It forms part of the signaling pathway linking the immune system, nervous system and the endocrine system. COVID-19 progresses to a stage of unregulated inflammation in a subset of subjects. Cholinergic dysfunction could be potentially responsible for a march to cytokine storm. BChE could influence the course of COVID-19 by acting through the brain-immune-endocrine axis via cholinergic transmission, as well as affecting factors predicting adverse outcomes of COVID-19 (obesity, insulin resistance, coronary artery disease, type 2 diabetes mellitus). Interestingly, variant forms of the enzyme with impaired hydrolytic activity are reported in endogamous ethnic populations. It would be instructive to study the effect of COVID-19 in these natural human knock-out equivalents. Biomed Rev 2021;32: 37-46.

New onset myasthenia gravis and COVID-19 vaccine: a case report

Background: Myasthenia Gravis (MG) is an autoimmune disease of the neuromuscular junction characterized by fluctuating, fatigable weakness of specific muscles. Most new MG cases have no identifiable triggers, though infections have been suggested as provoking factor. In the literature have been recently described few newly diagnosed and exacerbation MG cases associated both with SARS-CoV2 infection and COVID-19 vaccine. Case presentation: A 67-year-old smoker woman presented to the Emergency Department with worsening dyspnoea and fluctuating diplopia some days apart the second dose of BNT162b2 COVID-19 vaccine. Neurological examination revealed hypophonia, diplopia, inferior limbs' weakness and fatigability, therefore MG was suspected. Computed tomography of the thorax excluded thymoma. Magnetic resonance imaging of the brain was unremarkable. The clinical suspicion of MG was confirmed by serological demonstration of MuSK antibodies and neurophysiological studies. Despite early administration of anticholinesterase inhibitors, the patient experienced a myasthenic crisis with respiratory failure requiring invasive ventilatory support. She was subsequently treated with intravenous immunoglobulin, plasma exchange and steroids resulting in clinical improvement. She was finally discharged with anticholinesterase inhibitors and long-term immunosuppression therapy. Conclusions: New onset MG following COVID-19 vaccine has rarely been described in the literature, but clinicians should be aware of this possible association to achieve earlier diagnosis and more favourable outcomes.

Transient Elastography of Liver and Serum Hyaluronic Acid Levels In Adult Transfusion Dependent Thalassemia Patients

Iron overload occurs as a result of multiple blood transfusions and increased iron absorption in thalassemia patients. Iron deposition in liver results in liver stiffness and fibrosis. Non invasive methods including imaging and serum biomarkers have been introduced for assessment of liver fibrosis. We aimed to study liver stiffness using transient elastography and serum hyaluronic acid levels and correlate them with serum ferritin levels in adult transfusion dependent beta thalassemia patients. MATERIAL: 70 transfusion dependent thalassemia patients of age ≥18 years, registered at Thalassemia Day Care Centre were subjected to investigations like CBC, Liver function tests, viral markers, serum ferritin, serum hyaluronic acid levels and transient elastography. Fibrosis indices like FIB-4, AAR and APRI were also calculated. 45 patients had T2*MRI reports with them;which were also included and analysed. Spearman coefficient r was used to test correlations between TE values and serum HA levels with other variables. OBSERVATION: 70 patients (41 male and 29 female) with mean age of 24.09±5.38 years and BMI 20.51 ±3.47 kg/m², were enrolled. Median values of hemoglobin, AST, ALT, TE, serum HA and serum ferritin were, 9.15 g/dl, 42 IU/L, 47.50 IU/L, 9.1 kPa, 284 ng/dl and 1841 ng/ml, respectively . TE values had significant positive correlation with serum ferritin (r=0.5, p < 0.001), ALT (r=0.59, p < 0.001), AST (r=0.58, p< 0.001), APRI (r=0.5, p<0.001) and FIB-4 (p=0.02), respectively and significant negative correlation with T2* MRI (ms) (r= -0.5, p<0.001). No significant correlation of HA was found with any variable. CONCLUSION: Transient elastography can be used as a non expensive, easily accessible and non invasive marker of liver iron overload. Further detailed studies are required to establish the role of serum Hyaluronic acid in thalassemia patients. © Journal of the Association of Physicians of India 2011.

Long-Chain Acylcholines Link Butyrylcholinesterase to Regulation of Non-neuronal Cholinergic Signaling.

Acylcholines are comprised of an acyl chain esterified to a choline moiety; acetylcholine is the best-characterized member of this class, functioning as a neurotransmitter in the central and peripheral nervous systems as well as an inhibitor of cytokine production by macrophages and other innate immune cells. Acylcholines are metabolized by a class of cholinesterases, including acetylcholinesterase (a specific regulator of acetylcholine levels) and butyrylcholinesterase (BChE, an enigmatic enzyme whose function has not been resolved by genetic knockout models). BChE provides reserve capacity to hydrolyze acetylcholine, but its importance is arguable given acetylcholinesterase is the most catalytically efficient enzyme characterized to date. While known to be substrates of BChE in vitro, endogenous production of long-chain acylcholines is a recent discovery enabled by untargeted metabolomics. Compared to acetylcholine, long-chain acylcholines show greater stability in circulation with homeostatic levels-dictated by synthesis and clearance-suggested to impact cholinergic receptor sensitivity of acetylcholine with varying levels of antagonism. Acylcholines then provide a link between BChE and non-neuronal acetylcholine signaling, filling a gap in understanding around how imbalances between acylcholines and BChE could modulate inflammatory disease, such as the "cytokine storm" identified in severe COVID-19. Areas for further research, development, and clinical testing are outlined.

Microfabricated potentiometric sensor for personalized methacholine challenge tests during the COVID-19 pandemic.

The methacholine challenge test is considered to be the gold standard bronchoprovocation test used to diagnose asthma, and this test is always performed in pulmonary function labs or doctors' offices. Methacholine (MCH) acts by inducing airway tightening/bronchoconstriction, and more importantly, MCH is hydrolyzed by cholinesterase enzyme (ChE). Recently, the American Thoracic Society raised concerns about pulmonary function testing during the COVID-19 pandemic due to recently reported correlation between cholinesterase and COVID-19 pneumonia severity/mortality, and it was shown that cholinesterase levels are reduced in the acute phase of severe COVID-19 pneumonia. This work describes the microfabrication of potentiometric sensors using copper as the substrate and chemically polymerized graphene nanocomposites as the transducing layer for tracking the kinetics of MCH enzymatic degradation in real blood samples. The in-vitro estimation of the characteristic parameters of the MCH metabolism [Michaelis-Menten constant (Km) and reaction velocity (Vmax)] were found to be 241.041 µM and 56.8 µM/min, respectively. The proposed sensor is designed to be used as a companion diagnostic device that can (i) answer questions about patient eligibility to perform methacholine challenge tests, (ii) individualize/personalize medical dosing of methacholine, (iii) provide portable and inexpensive devices allowing automated readouts without the need for operator intervention (iv) recommend therapeutic interventions including intensive care during early stages and reflecting the disease state of COVID-19 pneumonia. We hope that this methacholine electrochemical sensor will help in assaying ChE activity in a "timely" manner and predict the severity and prognosis of COVID-19 to improve treatment outcomes and decrease mortality.