Pathophysiological Mechanisms Research Articles

Transcranial static magnetic stimulation for amyotrophic lateral sclerosis: a bicentric, randomised, double-blind placebo-controlled phase 2 trial

BackgroundEnhanced glutamatergic transmission leading to motor neuron death is considered the major pathophysiological mechanism of amyotrophic lateral sclerosis (ALS). Motor cortex excitability can be suppressed by transcranial static magnetic stimulation (tSMS), thus tSMS can be evaluated as a potential treatment for ALS. The aim of present study was to investigate the efficacy and safety of tSMS in ALS. MethodsIn this phase 2 trial, we randomly assigned ALS patients to receive daily tSMS or placebo stimulation over a period of 6 months. For each participant we calculated mean disease monthly progression rate (MPR) as the variation of the total ALS Functional Rating Scale-Revised (ALSRFS-R) score, before the beginning of the treatment (over a period of at least three months) and over the six-month treatment period. The primary efficacy outcome was the difference in MPR before and after the beginning of treatment. Secondary outcomes included safety and tolerability, compliance, and changes in corticospinal output. A long-term follow-up of 18 months was performed in all patients who completed the six-month treatment considering a composite endpoint event (tracheostomy or death). Trial registered at ClinicalTrials.gov, ID: NCT04393467, status: closed. FindingsForty participants were randomly assigned to real (n=21) or placebo stimulation (n=19). Thirty-two participants (18 real and 14 placebo) completed the 6-month treatment. The MPR did not show statistically significant differences between the two arms during the pre-treatment (mean ± Standard deviation; Real: 1.02 ± 0.62, Sham: 1.02 ± 0.57, p-value = 1.00) and treatment period (Real: 0.90 ± 0.55, Sham: 0.94 ± 0.55, p-value = 0.83). Results for secondary clinical endpoints showed that the treatment is feasible and safe and compliance with tSMS is high. The change in corticospinal output did not differ significantly between the two groups.At the end of the long-term follow-up of 18 months, patients of real group had a statistically significant higher tracheostomy-free survival compared with patients of placebo group (Hazard Ratio = 0.27 95% Confidence interval 0.09 to 0.80, p-value = 0.019) . InterpretationTSMS did not modify disease progression during the 6 months of treatment. However, long-term follow-up, revealed a substantial increase in tracheostomy free survival in patients treated with real stimulation supporting the evaluation of tSMS in larger and more prolonged studies. FundingThe “Fondazione 'Nicola Irti' per le opere di carità e di cultura”, Rome, Italy, supported present study.

Delirium and frailty in older adults: Clinical overlap and biological underpinnings.

Frailty and delirium are two common geriatric syndromes sharing several clinical characteristics, risk factors, and negative outcomes. Understanding their interdependency is crucial to identify shared mechanisms and implement initiatives to reduce the associated burden. This literature review summarizes scientific evidence on the complex interplay between frailty and delirium; clinical, epidemiological, and pathophysiological commonalities; and current knowledge gaps. We conducted a PubMed systematic search in June 2023, which yielded 118 eligible articles out of 991. The synthesis of the results-carried out by content experts-highlights overlapping risk factors, clinical phenotypes, and outcomes and explores the influence of one syndrome on the onset of the other. Common pathophysiological mechanisms identified include inflammation, neurodegeneration, metabolic insufficiency, and vascular burden. The review suggests that frailty is a risk factor for delirium, with some support for delirium associated with accelerated frailty. The proposed unifying framework supports the integration and measurement of both constructs in research and clinical practice, identifying the geroscience approach as a potential avenue to develop strategies for both conditions. In conclusion, we suggest that frailty and delirium might be alternative-sometimes coexisting-manifestations of accelerated biological aging. Clinically, the concepts addressed in this review can help approach older adults with either frailty or delirium from a different perspective. From a research standpoint, longitudinal studies are needed to explore the hypothesis that specific pathways within the biology of aging may underlie the clinical manifestations of frailty and delirium. Such research will pave the way for future understanding of other geriatric syndromes as well.

Metabolomic insights into idiopathic xerostomia: The central role of caffeine metabolism in salivary biochemistry

ObjectiveThis study aims to delineate the salivary metabolomic profile of patients with idiopathic xerostomia using untargeted metabolomics techniques, with the goal of addressing the lack of clear diagnostic markers and providing insights into the pathophysiological mechanisms of the condition. DesignIn this observational, cross-sectional study, saliva samples from 33 patients with idiopathic xerostomia and 34 healthy controls were analyzed using Ultra Performance Liquid Chromatography Quadrupole Time of Flight Mass Spectrometry (UPLC-QTOF MS). Metabolomic profiling was complemented by multivariate statistical analysis to differentiate between affected individuals and controls. ResultsMetabolomic analysis delineated a pronounced differentiation between patients with idiopathic xerostomia and healthy controls. A total of 195 metabolites displayed significant differential expression, each with a variable importance in projection (VIP) greater than 1 and a P-value less than 0.05. Pathway enrichment analysis, according to the Kyoto Encyclopedia of Genes and Genomes (KEGG), identified 22 metabolites that participated in 18 distinct metabolic pathways. Among these, the caffeine metabolism pathway, characterized by notable alterations in impact values (VIP, P-value, Log2-fold change, Rich factor), emerged as the most significantly disrupted, underscoring its potential role in the pathophysiology of idiopathic xerostomia (P = 0.0000395). ConclusionsThe salivary metabolomic profiling revealed distinct alterations in idiopathic xerostomia, with a significant reduction in caffeine metabolism pathways, underscoring potential neuropathic involvement. This study advances our understanding of the metabolic alterations in xerostomia, suggesting that salivary metabolomics may offer viable biomarkers for diagnosing and understanding the etiology of idiopathic xerostomia. Future research should focus on therapeutic targeting of these metabolic disturbances and evaluating their reversibility with treatment.

CircTMTC1 Mediates Nucleo-cytoplasmic Translocation of DDX3X to Regulate Osteogenic Differentiation of Human Ligamentum Flavum Cells.

This study was aimed to investigate the potential roles of circTMTC1 in the underlying pathophysiological mechanisms of ossification of the ligamentum flavum (OLF). OLF is the primary contributor to thoracic spinal stenosis, which may cause severe neurological symptoms. There is a lack of effective medical therapy for OLF available so far because the exact underlying mechanism of OLF has not been fully elucidated. CircRNAs are a special class of non-coding RNAs and have attracted a growing interest of research in various human diseases recently. Therefore, we explored the potential roles of circRNAs in the underlying pathophysiological mechanisms of OLF. We performed RNA-seq analysis to investigate the differentially expression profile of circRNAs in osteogenic differentiation of human LF cells, and identified a key circular RNA circTMTC1 functioned in OLF. Subsequently, we performed a series of experiments to investigate the exact molecular and cellular mechanisms in osteogenic differentiation of human ligamentum flavum cells. CircTMTC1 is significantly up-regulated during osteogenic differentiation of human LF cells. Mechanistically, we found that circTMTC1 could interact with the RNA binding protein DDX3X and enhance its nucleo-cytoplasmic translocation. An increased cytoplasmic level of DDX3X activated the NLRP3 inflammasome pathway and thus promoted osteogenic differentiation of human ligamentum flavum cells. Our findings suggested the circTMTC1-DDX3X-NLRP3 inflammasome signaling plays a pivotal role in osteogenic differentiation of human ligamentum flavum cells, which may provide novel diagnostic and therapeutic strategies for OLF.

A reproducible murine model of studying HIV-associated brain damage in stroke

BackgroundEmerging clinical and epidemiological data indicated that human immunodeficiency virus (HIV) is associated with an increased risk of stroke and aggravated brain damage. We aimed to develop a reproducible murine model of photothrombotic-stroke with HIV infection that mimics the clinical situation. MethodTo evaluate the impact of HIV infection on stroke, male C57BL/6 mice were infected with EcoHIV (p24 2-4 × 106/mouse; i.v.) or mock control. Four weeks post-infection, a stroke was induced by the photothrombotic method. After 72 h, a catwalk test was performed for gait impairments, and mice were euthanized for stroke outcomes. ResultsEcoHIV-infection exhibited a larger infarction, brain edema, higher IgG extravasation, hemorrhagic transformation, and gait impairments following pt-MCAO vs mock control. EcoHIV-infected mice showed higher levels of IFN-y and lower levels of IL-6, indicating immune activation without affecting IL-1β and MCP-1 in plasma and brain compared to mock pt-MCAO, suggesting unaltered inflammation. EcoHIV showed an increase oxidative stress markers (nitrotyrosine, and 4-hydroxynonenal) and thioredoxin interacting protein expression. Further, EcoHIV-infection significantly activated the microglia and astrocyte cells. ConclusionsThis animal model would be reliable and clinically relevant to future studies investigating pathophysiological mechanisms and developing new therapeutic approaches in stroke patients with HIV conditions.

Non-Alcoholic Fatty Liver Disease and Coronary Artery Disease: A Bidirectional Association Based on Endothelial Dysfunction

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is regarded as a liver manifestation of metabolic syndrome. It is linked to insulin resistance, obesity, and diabetes mellitus, all of which increase the risk of cardiovascular complications. Endothelial dysfunction (EnD) constitutes the main driver in the progression of atherosclerosis and coronary artery disease (CAD). Several pathophysiological alterations and molecular mechanisms are involved in the development of EnD in patients with NAFLD. Our aim is to examine the association of NAFLD and CAD with the parallel assessment of EnD, discussing the pathophysiological mechanisms and the genetic background that underpin this relationship. This review delves into the management of the condition, exploring potential clinical implications and available medical treatment options to facilitate the deployment of optimal treatment strategies for these patients.

Neurobiological Insights Into Cerebral Palsy: A Review of the Mechanisms and Therapeutic Strategies.

Cerebral palsy (CP) is a common neurodevelopmental disorder characterized by impaired mobility and posture caused by brain injury or abnormal development. CP relates to a variety of neurological mechanisms and pathways that impact the type and severity of motor disability, as well as comorbidities. The heterogeneity in clinical phenotype, pathogenesis, and etiology poses significant challenges for effective therapeutic intervention. The review aims to provide a comprehensive analysis of the neurobiological mechanisms underlying CP and evaluate current and prospective therapeutic strategies, highlighting the necessity for targeted interventions to address the disorder's multifaceted nature. A thorough literature review was conducted, focusing on studies published in peer-reviewed journals that explore the pathophysiological mechanisms, clinical interventions, and therapeutic strategies for CP. The pathogenesis of CP involves a complex interplay of genetic, environmental, and perinatal factors leading to brain injury. Inflammatory processes, oxidative stress, and excitotoxicity are critical in CP development. Current therapeutic approaches primarily focus on symptom management through physical and occupational therapy, as well as pharmacological interventions. Emerging therapies, including anti-inflammatory agents, antioxidants, and neuroprotective and neurotrophic agents, show potential but require further validation. Notably, although steroids provide anti-inflammatory benefits, their use in pediatric patients raises concerns regarding long-term adverse effects such as osteoporosis. Despite advances in understanding CP's neurobiological underpinnings, effective therapeutic targets remain elusive. A comprehensive approach addressing CP's heterogeneity is essential. Future research should emphasize in-depth evaluations of the efficacy and safety of therapeutic agents, particularly in pediatric populations, to develop targeted and effective treatments for CP.

Microscopical anatomy of the peripheral nervous system: An essential notion for understanding the pathophysiology of very early classic Guillain-Barré syndrome.

The aim of this paper is to analyze the pathophysiological mechanisms acting in very early classic Guillain-Barré syndrome (GBS) (≤4 days of symptomatic onset). In this inaugural period, both in GBS and its animal model, experimental autoimmune neuritis, the outstanding pathological feature is inflammatory edema predominating in proximal nerve trunks, particularly spinal nerves, and possibly in preterminal nerve segments. Nerve trunks external to the subarachnoid angle possess epi- perineurium that is relatively inelastic and of low compliance. Here such edema can increase endoneurial fluid pressure that, when sufficiently critical, may stretch the perineurium and constrict transperineurial microcirculation, compromising blood flow and producing the potential for ischemic nerve injury, whose consequence is rapid partial or complete loss of nerve excitability. These histopathological features correlate well with electrophysiological and imaging findings reported in early GBS stages. Spinal nerve edema and ischemia help to understand the pattern of Wallerian-like degeneration observed in the axonal form of GBS, predominating in motor spinal roots at their exit from the dura matter (spinal nerves) with centrifugal distribution in more distant motor nerve trunks, and centripetal extension to the distal portion of intrathecal roots. The similarity of initial pathogenic mechanisms between demyelinating and axonal forms of GBS explains why an early increase of serum biomarkers of axonal damage is detected in both forms. In conclusion, knowledge of the microscopic anatomy of the peripheral nervous system is an essential step for a reliable understanding of pathophysiological mechanisms operating in the early phase of any classic GBS subtype.

Expression of thyroid antigens in the female reproductive system.

Thyroid autoimmunity (TAI) has been linked to fertility disorders and pregnancy complications, even in euthyroid women. However, the exact pathophysiological mechanism underlying this association is not fully understood. This study seeks to investigate the expression of thyroid antigens within the human female reproductive system, potentially identifying targets for thyroid antibodies. Human biopsies of endometrium and follicular granulosa cells were collected and thyroperoxidase (TPO) and thyroglobulin (TG) expression was evaluated in these tissues by immunohistochemistry. Results showed, for the first time, the expression of TG protein and confirmed the presence of thyroid TPO in human endometrium and granulosa cells. Results suggest that TPO antibodies (TPOAbs) and TG antibodies (TGAbs) could interact with TPO and TG expressed in the reproductive system in patients with positive thyroid antibodies, thereby disrupting the function of TPO and TG and generating an inflammatory response, leading to fertility disorders and pregnancy complications.

Oscillatory airflow through the hypopharyngeal and supraglottic airway

Exercise-induced laryngeal obstruction (EILO) is a known cause of exertional dyspnoea, characterised by paradoxical inward collapse of laryngeal tissues. The pathophysiological mechanisms of EILO remain to be fully established, but insufficient mechanical resistance of laryngeal tissues to air-induced loads is hypothesised. It is understood that airflow and anatomic configurations of the airway play a key role in the wall pressure distribution of the larynx. While breathing is a cyclic process with directional changes of airflow, the literature is confined to steady, unidirectional airflow. It is necessary to assess the role of oscillatory airflow on the loads on the laryngeal airway. This study investigates the effect of oscillatory airflow on the laryngeal flow fields and air-induced loads. A computational fluid dynamics model of the upper respiratory tract (URT) is developed using the Reynolds-averaged Navier-Stokes equations. Five oscillatory airflow cases through a single geometry are considered, utilising sinusoidal breathing cycles with different breathing frequencies (24, 32 and 40 breaths per minute) and peak inspiratory flow rates (96, 168 and 240 L/min). Results include the airflow velocity distribution in the URT, and the air-induced pressure and forces. It is demonstrated that inspiratory velocity distribution varies with breathing frequency and intensity. The force acting on the URT walls are in-phase with the airflow rate and therefore exhibit quasi-steady behaviour. These findings are also reflected in the force vectors acting on the aryepiglottic folds and indicate that air-induced closure of the supraglottis in EILO is influenced by the breathing intensity rather than the breathing frequency.

Liver Fibrosis Leading to Cirrhosis: Basic Mechanisms and Clinical Perspectives

Liver fibrosis is the pathological deposition of extracellular matrix rich in fibrillar collagen within the hepatocytes in response to chronic liver injury due to various causes. As the condition advances, it can progress to cirrhosis, the late stages of which are irreversible. Multiple pathophysiological mechanisms and cell types are responsible for the progression of liver fibrosis and cirrhosis. Hepatic stellate cells and myofibroblast activation represent a key event in fibrosis. Capillarization of liver sinusoidal endothelial cells further contributes to extracellular matrix deposition and an increase in portal pressure. Macrophages and neutrophils produce inflammatory cytokines and participate in activating hepatic stellate cells. Although initially believed to be irreversible, early stages of fibrosis are now found to be reversible. Furthermore, advances in noninvasive imaging and serum studies have changed and improved how cirrhosis can be evaluated and monitored. Although there are currently no specific approved therapies to reverse liver fibrosis, management of underlying diseases has been found to halt the progression, and to an extent, even reverse liver fibrosis, preventing further liver injury and cirrhosis-related complications.

What Do We Know about Peripartum Cardiomyopathy? Yesterday, Today, Tomorrow

Peripartum cardiomyopathy is a disease that occurs during or after pregnancy and leads to a significant decline in cardiac function in previously healthy women. Peripartum cardiomyopathy has a varying prevalence among women depending on the part of the world where they live, but it is associated with a significant mortality and morbidity in this population. Therefore, timely diagnosis, treatment, and monitoring of this disease from its onset are of utmost importance. Although many risk factors are associated with the occurrence of peripartum cardiomyopathy, such as conditions of life, age of the woman, nutrient deficiencies, or multiple pregnancies, the exact cause of its onset remains unknown. Advances in research on the genetic associations with cardiomyopathies have provided a wealth of data indicating a possible association with peripartum cardiomyopathy, but due to numerous mutations and data inconsistencies, the exact connection remains unclear. Significant insights into the pathophysiological mechanisms underlying peripartum cardiomyopathy have been provided by the theory of an abnormal 16-kDa prolactin, which may be generated in an oxidative stress environment and lead to vascular and consequently myocardial damage. Recent studies supporting this disease mechanism also include research on the efficacy of bromocriptine (a prolactin synthesis inhibitor) in restoring cardiac function in affected patients. Despite significant progress in the research of this disease, there are still insufficient data on the safety of use of certain drugs treating heart failure during pregnancy and breastfeeding. Considering the metabolic changes that occur in different stages of pregnancy and the postpartum period, determining the correct dosing regimen of medications is of utmost importance not only for better treatment and survival of mothers but also for reducing the risk of toxic effects on the fetus.

Possibility of correction of the blood-heart barrier damage as a consequence of the impact of the SARS-CoV-2 virus on the cardiovascular system in patients with coronary artery disease in combination with COVID-19.

damage to the blood-heart barrier (BHB) and endothelial dysfunction is a characteristic feature of congestive (cardiopulmonary) chronic heart failure (CHF), the main cause of death in elderly people with CHF caused by new coronavirus variants (SARS-CoV-2), but the mechanism of this phenomenon remains unclear. The aim of this project is to determine the mechanism of BHB damage in coronary artery disease (CAD) with COVID-19, as well as the possibility of its correction with the use of sulodexide. The endocardial endothelium (EE) is a barrier that prevents blood leakage from the endocardium to the interstitium; however, this barrier is impaired during the course of COVID-19 in patients with CAD. Previous studies have shown that one of the pathophysiological mechanisms is the activation of matrix metalloproteinases (MMPs) in CAD with CHF. MMP-9 degrades connexins, which leads to EE dysfunction. One study [Rubens P. et al. 2021] found a juxtacrine connection of EE with the myocyte and mitochondria (Mito), but how this works is still an open question. Materials and methods. We examined 65 patients with coronary artery disease diagnosed with COVID-19. Patients were divided into two groups: Group I (n=35) - patients who had been taking sulodexide at a dose of 500 LE x 2p/day for 6 months against the background of standard therapy of coronary artery disease; Group II (n=30) - patients without sulodexide. Echocardiography and laser Doppler flowmetry were performed at baseline and 6 months later. Echocardiography at the time of inclusion in the study revealed that 30 (50%) patients in group I and 14 (47%) patients in group II had reduced left ventricular ejection fraction (LV EF) values of 40 to 50%. After 6 months of treatment with sulodexide, a tendency to improve LV systolic function and decrease in left ventricular myocardial mass index (LFMMI) was noted in patients of group I. There were no differences between the groups at the time of inclusion in the study in terms of the level of the capillary flow reserve – occlusion test (CFRo) and the capillary flow reserve – nitroglycerin test (CFRn). A repeated study of CFR revealed a significant increase in CFRo and CFRn levels only in group I. In patients of group II, no significant changes in CFRo and CFRn were found. An inverse relationship between the level of CFRo and C-reactive protein (CRP) was found in patients of group I (r=0.52, p<0.05). After 6 months of treatment, plasma CRP concentrations decreased significantly: from 17.7 [1.3; 50.1] to 5.7 [1.0; 12.0] mg/L in group I (p=0.01) and from 14.2 [1.2; 27.0] to 4.2 [1.0; 11.0] mg/L in group II (p=0.01). No significant correlations between CRP level and CFRo after 6 months of treatment were found. There were correlations of CFRo and CFRn with left ventricular systolic function, as well as inverse relationships with the size of the left and right ventricles and systolic pressure in the pulmonary artery. There was a tendency to improve systolic and diastolic left ventricular function in the first group, where sulodexide was used, and no significant changes in echocardiography were noted in the second group. At the initial examination of patients, the ratio of CFRo and CFRn had no significant differences. After 6 months of treatment, a significant increase in the ratio of CFRo and CFRn was observed only in patients taking sulodexide, and no positive dynamics of this ratio was observed in group II. The results indicate that MMP-9 activation, endothelial damage, endothelial-myocyte (E-M) uncoupling, and mitochondrial-myocyte uncoupling in heart failure in patients with CAD combined with COVID-19 were detected to a significant extent; however, treatment with sulodexide successfully mitigated the destructive changes in the heart in CAD with CHF. The results obtained are directly relevant to the range of cardiac manifestations and phenotypes arising from COVID-19 complications in people with CAD. Conclusion. The obtained results confirm the improvement of microcirculation, as well as a tendency to improve systolic function and left ventricular myocardial mass index after 6 months of sulodexide treatment in patients with coronary artery disease with preserved and moderately reduced left ventricular ejection fraction (LV EF) who have undergone COVID-19. The described effects of improving endothelial function, as well as improving the state of the blood-brain barrier due to the use of sulodexide, make it possible to recommend the use of this drug in the category of patients with CAD to reduce the negative impact of COVID-19 on the cardiovascular system.

DIAGNÓSTICO E MONITORAMENTO DA ERITROBLASTOSE FETAL: UMA REVISÃO DA LITERATURA

The text addresses fetal erythroblastosis, a serious condition resulting from blood incompatibility between mother and fetus, generally due to the Rh factor. Initially, the discovery of the ABO and Rh blood systems is discussed, highlighting the importance of the latter for understanding the disease. Objective: to understand the pathophysiological mechanisms of fetal erythroblastosis, focusing on Rh incompatibility, thereby analyzing the impacts of fetal erythroblastosis on health of the fetus and newborn.Methods: The work is a bibliographical review where topics such as pathophysiology, diagnosis and prevention of the disease studied were researched.Conclusion: Diagnosis is essential, being done through prenatal exams, such as the Coombs test, which detects the presence of maternal antibodies against fetal antigens. Treatment includes administration of anti-Rh immunoglobulin to prevent the mother’s sensitization to the baby’s Rh factor. Prevention also involves the administration of this immunoglobulin during pregnancy and after birth, if necessary, to avoid future complications and ensure the baby’s safety.

Retrospective evaluation of stuttering cases with and without PANDAS comorbidity

Purpose: The aim of this study is to evaluate the clinical, demographic, and autoimmune characteristics of stuttering cases with and without Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) comorbidity. Materials and Methods: The study included 271 children and adolescents aged 2-17 years who were brought to our outpatient clinic between 2012 and 2022 and diagnosed with stuttering. The demographic information and medical characteristics of the patients and their families, such as infections, allergies, rheumatic diseases, and tonsillectomy or penicillin prophylaxis, were evaluated retrospectively. Their routine laboratory test results were also documented. Results: In total, 55 girls (20.3%) and 216 (79.7%) boys at a mean age of 7.6±3.6 years were included. Forty-eight cases (17%) were in the PANDAS group, and 223 (82.3%) were in the non-PANDAS group. The comparison of the PANDAS and non-PANDAS groups showed that the PANDAS group had significantly higher rates of history of tonsillectomy, history of adenoidectomy, and history of frequent infections. The rates of psychiatric, autoimmune, and allergic diseases in the families of the cases in the PANDAS group were significantly higher. The PANDAS group had a significantly greater frequency of comorbid conditions such as obsessive-compulsive disorder, tics, attention-deficit/hyperactivity disorder, and anxiety, as well as a greater mean number of comorbid conditions with at least one diagnosis. Additionally, the age at onset of psychiatric symptoms and the mean age of cases were higher in the PANDAS group. The mean initial anti-streptolysin O level of the PANDAS group was 326.5±335.3 IU/mL, while the mean level in the non-PANDAS group was 155.6±215.1 IU/mL. Conclusion: Both the individuals in the PANDAS group and their families had high rates of comorbidities and inflammatory and autoimmune disorders. In cases of stuttering, there is a need to evaluate these conditions, determine the required methodologies, and explain the relevant pathophysiological mechanisms.

Neurological Mechanisms of Long COVID

Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection, refers to a condition where individuals continue to experience a range of symptoms weeks to months after the acute phase of COVID-19 has resolved. While respiratory symptoms are commonly associated with COVID-19, emerging evidence suggests that neurological manifestations play a significant role in the long-term effects of the disease. This article explores the neurological basis of long COVID, delving into the various symptoms, pathophysiological mechanisms, impact on cognitive function, neuroimaging findings, current treatment approaches, long-term prognosis, and future research directions in understanding and managing the neurological sequelae of long COVID.

Terlipressin-induced skin necrosis in cirrhotic patients-A case report and comprehensive literature review.

The occurrence of terlipressin-induced skin necrosis in cirrhotic patients is a rare but serious adverse event that warrants further investigation. Clinicians should be aware of this potential complication in cirrhotic patients receiving terlipressin therapy and closely monitor for any signs of skin necrosis. Early recognition and prompt intervention are crucial in preventing further complications and improving patient outcomes. Further research is needed to better understand the risk factors associated with terlipressin-induced skin necrosis and to develop effective preventive strategies. Overall, healthcare providers should exercise caution when prescribing terlipressin to cirrhotic patients, weighing the potential benefits against the risks of this rare but significant adverse event. Terlipressin is commonly used to manage conditions related to portal hypertension, such as hepatorenal syndrome and esophageal variceal bleeding. Despite its therapeutic benefits, terlipressin can rarely lead to severe ischemic complications involving the skin vasculature, known as terlipressin-induced skin necrosis. We present a 50-year-old male with cirrhosis and acute variceal bleeding who developed skin necrosis following terlipressin administration. We performed a comprehensive review of the literature by analyzing 18 case reports/case series comprising 22 cirrhotic patients with terlipressin-induced skin necrosis. Among these individuals, we found a mean age of 51 years with a male predominance (78%). Further analysis showed that the onset of skin necrosis ranged from 2 to 5 days post-terlipressin initiation, with bolus administration being predominant (85.7%). The underlying pathophysiological mechanisms of terlipressin-induced skin ischemia are still elusive but primarily attributed to the vasoconstrictive and thrombogenic effects. Management involves terlipressin discontinuation and supportive care. Physicians should be aware of this potential complication in patients receiving terlipressin and closely observe for any signs of skin rash.

Sodium Butyrate Ameliorates Postoperative Delirium by Regulating Gut Microbiota Dysbiosis to Inhibit Astrocyte Activation in Aged Mice.

Postoperative delirium (POD) is a common complication in elderly surgical patients, with limited targeted interventions due to incomplete understanding of its pathophysiological mechanisms. Central nervous system (CNS) inflammation, involving glial cell activation, particularly astrocytes, is considered crucial in POD development. Butyrate, a four-carbon fatty acid, has shown protective effects in CNS diseases, but its potential in mitigating POD remains unclear. This study aimed to investigate the impact of sodium butyrate on POD in aged mice. Behavioral tests, including open field, Y maze, and food burying tests, demonstrated that sodium butyrate preconditioning ameliorated laparotomy-induced delirium in aged mice. Pre-treatment with sodium butyrate inhibited astrocyte activation in the hippocampus, reduced interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) expression levels, and protected hippocampal neurons. Furthermore, the study revealed a connection between gut microbiota regulation and central neuroprotective effects mediated by astrocyte activation inhibition. Sodium butyrate improved the intestinal morphological barrier by rebalancing gut microbiota, inhibiting Proteobacteria and Actinobacteria, reducing Allobaculum and Bacteroides abundance, and increasing Oscillospira abundance. This regulation decreased gut permeability, limiting the entry of toxic substances into the bloodstream, thereby reducing inflammation spread and astrocyte overactivation, leading to central anti-inflammatory effects. In conclusion, sodium butyrate may ameliorate POD by inhibiting astrocyte-mediated neuroinflammation through gut microbiota rebalancing.

Association of corticosteroid therapy with reduced acute kidney injury and lower NET markers in severe COVID-19: an observational study

BackgroundAcute kidney injury (AKI) is common in critical cases of coronavirus disease 2019 (COVID-19) and associated with worse outcome. Dysregulated neutrophil extracellular trap (NET) formation is one of several suggested pathophysiological mechanisms involved in the development of COVID-19 associated AKI. The corticosteroid dexamethasone was implemented as a standard treatment for severe COVID-19 as of June 2020. A sub-analysis of a prospective observational single center study was performed to evaluate the effect of corticosteroid treatment on AKI development and NET markers in critical cases of COVID-19.ResultsTwo hundred and ten adult patients admitted to intensive care at a tertiary level hospital due to respiratory failure or shock secondary to SARS-CoV-2-infection between March 13th 2020 and January 14th 2021 were included in the study. Ninety-seven of those did not receive corticosteroids. One hundred and thirteen patients were treated with corticosteroids [dexamethasone (n = 98) or equivalent treatment (n = 15)], but the incidence of AKI was assessed only in patients that received corticosteroids before any registered renal dysfunction (n = 63). Corticosteroids were associated with a lower incidence of AKI (19% vs 55.8%, p < 0.001). Fewer patients demonstrated detectable concentrations of extracellular histones in plasma when treated with corticosteroids (8.7% vs 43.1%; p < 0.001). Extracellular histones and in particular non-proteolyzed histones were observed more frequently with increasing AKI severity (p < 0.001). MPO-DNA was found in lower concentrations in patients that received corticosteroids before established renal dysfunction (p = 0.03) and was found in higher concentrations in patients with AKI stage 3 (p = 0.03). Corticosteroids did not ameliorate established AKI during the first week of treatment.ConclusionCorticosteroid treatment in severe COVID-19 is associated with a lower incidence of AKI and reduced concentrations of NET markers in plasma.

Research progress on the pathogenesis of AKI complicated by ECMO.

Extracorporeal membrane oxygenation (ECMO) stands as a pivotal intervention for patients grappling with cardiopulmonary insufficiency. However, alongside its therapeutic benefits, ECMO carries the risk of complications, with acute kidney injury (AKI) emerging as a significant concern. The precise pathophysiological underpinnings of AKI in the context of ECMO remain incompletely elucidated. A comprehensive literature review was conducted to explore the epidemiology and pathophysiological mechanisms underlying the utilization of ECMO in the management of AKI. ECMO initiates a multifaceted cascade of inflammatory reactions, encompassing complement activation, endothelial dysfunction, white blood cell activation, and cytokine release. Furthermore, factors such as renal hypoperfusion, ischemia-reperfusion injury, hemolysis, and fluid overload exacerbate AKI. Specifically, veno-arterial ECMO (VA-ECMO) may directly induce renal hypoperfusion, whereas veno-venous ECMO (VV-ECMO) predominantly impacts pulmonary function, indirectly influencing renal function. While ECMO offers significant therapeutic advantages, AKI persists as a potentially fatal complication. A thorough comprehension of the pathogenesis underlying ECMO-associated AKI is imperative for effective prevention and management strategies. Moreover, additional research is warranted to delineate the incidence of AKI secondary to ECMO and to refine clinical approaches accordingly.