Abnormal Function Research Articles

Anti-inflammatory and glial response maintain normal colon function in trimethyltin-treated rats.

Studies on the contribution of enteric neuropathy and intestinal homeostasis to central nervous system degeneration using animal models have reported varying results. Recently, colonic myenteric plexus degeneration was observed in trimethyltin-treated rats. Further characterization of this animal model is necessary to determine its potential for investigating the relationship between the enteric nervous system and central nervous system degeneration. In this study, trimethyltin-treated rats (8mg/kg body weight, i.p.) were used to measure colonic function, structure, and possible colon abnormalities. The colonic function was assessed by measuring fecal pellet output and transit time. Hematoxylin and eosin staining and immunohistochemistry were performed to evaluate inflammatory profiles and intestinal epithelial cell homeostasis. The expression of mRNA encoding tight junction proteins was quantified with quantitative PCR to determine colon permeability. Histological examination of the colon revealed mucosal immune cell infiltration, crypt damage, and high iNOS and arginase-1 expression in the mucosal layer of trimethyltin-treated rats. At the same time, trimethyltin induced high expression of iNOS, arginase-1, and GFAP and increased cell death in the colonic myenteric plexus. The low cell proliferation and low goblet cell distribution suggested altered intestinal epithelial cell homeostasis in trimethyltin-treated rats. Trimethyltin also upregulated claudin 1 expression. However, normal colon function was preserved. In conclusion, the results show that trimethyltin induces colon inflammation and cell death in the colonic myenteric plexus, and disrupts intestinal epithelial cell homeostasis. However, the balance between anti-inflammatory and pro-inflammatory responses maintains normal colon function in trimethyltin-treated rats.

A retrospective study of an irradiation-based conditioning regimen and chidamide maintenance therapy in T-ALL/LBL.

T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/LBL) are highly malignant and aggressive hematologic tumors for which there is no standard first-line treatment. Chidamide, a novel histone deacetylase inhibitor, shows great promise. We assessed the efficacy and safety of an irradiation-containing conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) and post-transplantation chidamide maintenance in patients with T-ALL/LBL. We retrospectively analyzed the clinical data of six patients with T-ALL/LBL who underwent allo-HSCT with a radiotherapy-containing pretreatment regimen and post-transplant chidamide maintenance therapy. The endpoints were relapse, graft-versus-host disease (GVHD), transplant-related mortality (TRM), progression-free survival (PFS), overall survival (OS), and adverse events (AEs). All of the patients had uneventful post-transplant hematopoietic reconstitution, and all achieved complete molecular remission within 30 days. All six patients survived, and two relapsed with a median relapse time of 828.5 (170-1335) days. The 1-year OS rate was 100%, the 2-year PFS rate was 66.7%, and the TRM rate was 0%. After transplantation, two patients developed grade I-II acute GVHD (2/6); grade III-IV acute and chronic GVHD were not observed. The most common AEs following chidamide administration were hematological AEs, which occurred to varying degrees in all patients; liver function abnormalities occurred in two patients (grade 2), and symptoms of malaise occurred in one patient (grade 1). Chidamide maintenance therapy after T-ALL/LBL transplantation is safe, but the efficacy needs to be further investigated.

The Therapeutic Mechanisms of Shenyan Oral Liquid I Against Chronic Kidney Disease Based on Network Pharmacology and Experimental Validation.

Chronic Kidney Disease (CKD) leads to structural and functional abnormalities of the kidneys and seriously jeopardizes human health. Shenyan Oral Liquid (SOLI), a Chinese medicinal preparation, has been reported to protect podocytes in patients with chronic kidney disease (CKD). The objective of this study is to investigate the mechanism of action of the Chinese medicinal preparation Senyan Oral Liquid (SOLI) in the treatment of CKD by protecting podocytes through network pharmacology technology and experimental validation. Compounds of SOLI and targets of CKD disease were collected and screened. The SOLI network of bioactive compounds targeting CKD and the protein-protein interaction (PPI) network were constructed using Cytoscape software and the STRING online database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the R software Cluster Profiler package. Molecular docking was performed using Autodock software to verify the binding ability of bioactive compounds and target genes. Subsequently, the potential mechanism of SOLI on CKD predicted by network pharmacological analysis was experimentally studied and verified in an adriamycin-induced nephropathy rat model. A total of 81 targets of SOLI components acting on CKD were identified. The results of the PPI analysis clarified that five key target genes (TNF, AKT1, IL6, VEGFA, and TP53) play a critical role in the treatment of CKD by SOLI. The GO analysis and KEGG enrichment analysis indicated that SOLI acts through multiple pathways, including the PI3K/AKT signaling pathway against CKD. Molecular docking showed that the main compounds of SOLI and five key genes had strong binding affinity. In a rat model of adriamycin-induced nephropathy, SOLI significantly ameliorated disease symptoms and improved renal histopathology. Mechanistic studies showed that SOLI upregulated the expression level of Nephrin, inhibited the PI3K/AKT pathway in renal tissues, and ultimately suppressed the activation of autophagy-related proteins in CKD. SOLI exerted a renoprotective effect by regulating the Nephrin-PI3K/AKT autophagy signaling pathway, and these findings provide new ideas for the development of SOLI-based therapeutic approaches for CKD.

In vivo photoreceptor base editing ameliorates rhodopsin-E150K autosomal-recessive retinitis pigmentosa in mice

Rhodopsin, the prototypical class-A G-protein coupled receptor, is a highly sensitive receptor for light that enables phototransduction in rod photoreceptors. Rhodopsin plays not only a sensory role but also a structural role as a major component of the rod outer segment disc, comprising over 90% of the protein content of the disc membrane. Mutations in RHO which lead to structural or functional abnormalities, including the autosomal recessive E150K mutation, result in rod dysfunction and death. Therefore, correction of deleterious rhodopsin mutations could rescue inherited retinal degeneration, as demonstrated for other visual genes such as RPE65 and PDE6B. In this study, we describe a CRISPR/Cas9 adenine base editing strategy to correct the E150K mutation and demonstrate precise in vivo editing in a Rho -E150K mouse model of autosomal recessive retinitis pigmentosa (RP). Using ultraviolet-visible spectroscopy, mass spectrometry, and the G-protein activation assay, we characterized wild-type rhodopsin and rhodopsin variants containing bystander base edits. Subretinal injection of dual-adeno-associated viruses delivering our base editing strategy yielded up to 44% Rho correction in homozygous Rho -E150K mice. Injection at postnatal day 15, but not later time points, restored rhodopsin expression, partially rescued retinal function, and partially preserved retinal structure. These findings demonstrate that in vivo base editing can restore the function of mutated structural and functional proteins in animal models of disease, including rhodopsin-associated RP and suggest that the timing of gene-editing is a crucial determinant of successful treatment outcomes for degenerative genetic diseases.

Deucravacitinib in Plaque Psoriasis: Laboratory Parameters Through 4 Years of Treatment in the Phase 3 POETYK PSO-1, PSO-2, and LTE Trials

Introduction: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved in multiple countries for treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy. Deucravacitinib was efficacious versus placebo and apremilast and was well tolerated in the global, 52-week, phase 3 POETYK PSO-1 (NCT03624127) and POETYK PSO-2 (NCT03611751) parent trials. At Week 52, patients could enroll in the ongoing POETYK long-term extension (LTE) (NCT04036435) trial and receive open-label deucravacitinib. Changes in blood laboratory parameters known to be associated with Janus kinase (JAK) 1,2,3 inhibitors were evaluated through 4 years of deucravacitinib treatment. Methods: Changes from baseline in lipid (cholesterol, triglycerides), chemistry (alanine aminotransferase [ALT], aspartate aminotransferase [AST], creatinine, creatine phosphokinase [CPK]), and hematology (hemoglobin, lymphocytes, neutrophils, platelets) parameters in the blood known to be affected by JAK1,2,3 inhibitors in clinical trials were evaluated through Week 208 (4 years; data cutoff, November 1, 2023). Treatment discontinuations due to laboratory abnormalities were assessed. Results: A total of 1519 patients received ≥1 deucravacitinib dose (total exposure, 4392.8 person-years); 1203 (79.2%) had ≥52 weeks and 542 (35.7%) had ≥208 weeks of continuous deucravacitinib exposure (median, 185 weeks). No trends or clinically meaningful mean changes from baseline were observed in any of the above laboratory parameters. In total, 3 patients discontinued treatment due to increased CPK, and 1 patient each discontinued due to lymphopenia, abnormal hepatic function, increased ALT, and increased AST. Discontinuations due to triglyceride elevations were not observed. Conclusion: In PSO-1/PSO-2/LTE, no trends or clinically meaningful mean changes from baseline were observed in lipid, chemistry, or hematology parameters, in contrast to signature changes (eg, increased cholesterol, creatinine, serum transaminases, CPK, cytopenias) observed with JAK1,2,3 inhibitors. Discontinuations due to laboratory abnormalities noted above were rare (n=7 events) through 4 years of deucravacitinib treatment. Results suggest deucravacitinib treatment does not warrant routine laboratory testing for all patients, in contrast with the requirements for JAK1,2,3 inhibitors, reflecting its selectivity for TYK2.

Myocardial deformation in children post cardiac surgery, a cross-sectional prospective study

Abstract Background Myocardial deformation by speckle tracking echocardiography provides valuable information on the left ventricular function. The study aims to assess myocardial deformation in terms of left ventricular strain as an indicator of myocardial function in children after cardiac surgery at outpatient follow-up visits. Methods The study design was a prospective observational cross-sectional study that included pediatric patients after biventricular cardiac surgery during the postoperative follow-up visits in the outpatient department. In addition to conventional echocardiographic examination, two-dimensional speckle tracking echocardiography was done to evaluate myocardial deformation in terms of left ventricular strain. Echocardiographic measurements were done offline and were compared to published reference normal values for age. Study subjects were divided according to age at follow-up into four groups (1 month–1 year, 1–2 years, 2–5 years, and 5–11 years). Results Over ten months, 100 patients (64 males and 36 females) were included in the study. The median age was 30.8 months (IQR 12.8–65.3 months), the median weight was 11.7 kg (IQR 8–17 kg) and the median duration after surgery was 7.3 months (IQR 3.2–30.8 months). Longitudinal strain values were significantly (p < 0.001) lower than reference values for different age groups. Global circumferential strain showed no significant difference from the reference values. The duration after surgery had a statistically significant effect on longitudinal strain values, with improvement of the strain values with increasing intervals after surgery. Conclusion Using myocardial deformation method to evaluate cardiac function may detect underlying cardiac function abnormalities even with normal traditional functional parameters, which could have implications for patient management and follow-up.

Differential functional change in olfactory bulb and olfactory eloquent areas in Parkinson’s disease

Abstract Olfactory dysfunction, or hyposmia, frequently occurs as a prodromal symptom and ongoing sign of Parkinson’s disease. Functional MRI is a powerful tool for studying functional changes in the olfactory brain regions in patients with Parkinson’s disease. However, existing studies show inconsistent results and no study has measured olfactory functional MRI abnormalities in the human olfactory bulb directly. This is mainly due to the well-known susceptibility artifacts in conventional functional MRI images that affect several key olfactory-eloquent brain regions, and especially the olfactory bulb. In this study, olfactory functional MRI was performed using a recently developed functional MRI approach that can minimize susceptibility artifacts and measure robust functional MRI signals in the human olfactory bulb during olfactory stimulation. Experiments were performed on high magnetic field (7T) in 24 early (< 5 years of parkinsonian symptoms) Parkinson’s disease patients and 31 matched healthy controls. Our data showed increased functional MRI signal changes (ΔS/S) in the olfactory bulb in patients with early Parkinson’s disease, which correlated with behavioral olfactory measures. Temporally, functional MRI signals in the olfactory bulb returned to the pre-stimulus state earlier after reaching peak amplitude in patients with early Parkinson’s disease, implicating a faster olfactory habituation effect. The piriform cortex showed reduced numbers of activated voxels in patients with early Parkinson’s disease, which correlated with behavioral olfactory assessment. Several secondary olfactory regions including the orbitofrontal cortex, temporal pole, and amygdala exhibited reduced numbers of activated voxels and increased functional MRI signal changes in patients with early Parkinson’s disease. Our data also showed that functional MRI results are highly dependent on voxel selection in the functional analysis. In summary, we demonstrate differential spatial and temporal characteristics of olfactory functional MRI signals between the primary and secondary olfactory regions in patients with early Parkinson’s disease. These results may assist the development of novel quantitative biomarkers (especially in the early stages of Parkinson’s disease) to track and predict disease progression, as well as potential treatment targets for early intervention.

Progress in application of medical absorbable haemostatic materials for haemostasis in orthopaedic surgery

The application progress of medical absorbable haemostatic material (MAHM) in hemostasis during orthoapedic surgery was reviewed, in order to provide reference for clinical hemostasis program. The domestic and foreign literature on the application of MAHM for hemostasis in orthopedic surgery was extensively reviewed and summarized. According to biocompatibility, MAHM can be divided into oxidized cellulose/oxidized regenerated cellulose materials, chitosan and its derivatives materials, starch materials, collagen and gelatin materials, and fibrin glue materials, etc., which can effectively reduce blood loss when used in orthopedic surgery for hemostasis. Each hemostatic material has different coagulation mechanism and suitable population. Oxidized cellulose/oxidized regenerated cellulose, chitosan and its derivatives, starch hemostatic material mainly stops bleeding by stimulating blood vessel contraction and gathering blood cells, which is suitable for people with abnormal coagulation function. Collagen, gelatin and fibrin glue hemostatic materials mainly affect the physiological coagulation mechanism of the human body to stop bleeding, suitable for people with normal coagulation function. Reasonable selection of MAHM can effectively reduce perioperative blood loss and reduce the risk of postoperative complications, but at present, single hemostatic material can not meet clinical needs, and a new composite hemostatic material with higher hemostatic efficiency needs to be developed.

Assessment of Immunological, Skeletal, and Thyroid Function Abnormalities in Paediatric Morphoea

Abstract Background: Morphoea is a sclerosing disorder of skin and subcutaneous tissue. Paediatric morphoea shows increased prevalence of various auto-immune diseases, bone deformities, and systemic abnormalities. There is paucity of studies on various immunological, skeletal, and thyroid function abnormalities in paediatric morphoea. Aims and Objectives: To describe immunological, skeletal, and thyroid function abnormalities present in paediatric morphoea patients. Materials and Methods: This cross-sectional study was conducted from January 2021 to March 2023 in the Dermatology outpatient department in a tertiary care hospital. All paediatric morphoea patients were included in this study. All were subjected to detailed history, clinical examination, and investigations including complete blood count, serum IgE, anti-nuclear antibody, thyroid function tests, anti-thyroid peroxidase antibodies, and radiological investigations. Results: A total of 42 children were recruited, out of which 61.90% were females and 38.09% were males. The majority were in the age group of 4–8 years. The most common type of morphoea was encoup de sabre. Anaemia was present in 14.28% patients. Serum IgE levels were raised in 33.33% patients. Thyroid stimulating hormone was raised in 11.9% patients. 33.33% had raised anti-thyroid peroxidase levels. Anti-nuclear antibody titres and rheumatoid factor were raised in 7.14% and 4.76% patients, respectively. Magnetic resonance imaging brain revealed abnormalities in three patients as hyper-intensities in subcortical white matter. Conclusion: Morphoea in children can be associated with varied immunological, osteoarticular, and neurological abnormalities. This study highlights the multi-system involvement in morphoea and the need for larger data and well-designed therapeutic trials for generating evidence-based treatment of this potentially disfiguring disease.

Exploring the Nephrotoxicity and Molecular Mechanisms of Di-2-ethylhexyl phthalate: A Comprehensive Review.

Di-2-ethylhexyl phthalate (DEHP), a widely applied plasticizer in various products, can be absorbed into the human body through several channels and accumulate in the lungs, liver, testes, and kidneys, potentially impairing the function of these organs. Recently, the nephrotoxicity of DEHP has received heightened attention. Numerous epidemiologic findings have demonstrated that DEHP exposure may contribute to renal damage, leading to structural and functional abnormalities and exacerbating the progression of kidney disease. Recent research has discovered the mechanisms behind DEHP-induced nephrotoxicity may involve a variety of pathways, including apoptosis, autophagy, ferroptosis, oxidative stress, inflammation, DNA damage, and lipid metabolism disorders. This review discusses the impact of DEHP on kidney function and delves into the molecular mechanisms of nephrotoxicity mediated by DEHP in recent years. In addition, the review examines evidence for the antioxidant and anti-inflammatory capacities of lycopene, green tea polyphenols, and quercetin in ameliorating DEHP-induced renal injury is reviewed, providing a basis for further research.

Severe Vestibular Dysfunction Following Unilateral Cochlear Implant: A Case Report and Management Approach

Abstract Cochlear implantation (CI) is a highly effective treatment for severe-to-profound hearing loss, but it can result in postoperative vestibular dysfunction, including vertigo and imbalance. This case report describes a 22-year-old female who developed severe vertigo and imbalance following right ear CI surgery. Audiological assessment confirmed normal hearing in the left ear and profound sensorineural hearing loss in the right ear. Vestibular tests revealed significant dysfunction, including left-beating spontaneous nystagmus, vestibular hypofunction, and abnormal saccular function in the implanted ear. This case underscores the prevalence of vestibular complications post-CI, reported in up to 75% of recipients. Comprehensive preoperative vestibular assessment is essential for identifying potential risks and guiding surgical decisions, such as choosing between unilateral and bilateral implantation. Early identification and management of vestibular issues can improve outcomes and quality of life for CI patients.

Rapid Disease Progression of Myelodysplastic Syndrome is Reflected in Transcriptomic and Functional Abnormalities of Bone Marrow MSCs.

Bone marrow (BM) mesenchymal stromal cells (MSCs) are important regulators of hematopoietic stem and progenitor cells (HSPCs). When transformed to a dysplastic phenotype, MSCs contribute to hematopoietic diseases such as myelodysplastic syndromes (MDS), but it remains unclear if there are specific properties in MDS-MSCs that contribute to the disease course. To understand this, we investigated MDS-MSCs from fast (MDSfast) vs slow (MDSslow) progressing disease groups and discovered differences between these groups. MDSfast-MSCs secrete more inflammatory factors, support myeloid-skewed differentiation of HSPCs, and importantly, show poorer response to hypomethylation as a key differentiator in GSEA analysis. When exposed to long-term in vivo stimulation with primary MDSfast-MSCs-based scaffolds, healthy donor (HD) HSPCs show elevated NF-κB expression, similar to leukemic HSPCs in MDS. Those "MDSfast-MSCs-primed" HD-HSPCs continue to show enhanced engraftment rates in secondary MDS-MSC-based scaffolds, providing evidence for the microenvironmental selection pressures in MDS towards leukemic HSPCs. Together, our data point towards a degree of co-development between MSCs and HSPCs during the progression of MDS, where changes in MDS-MSCs take place mainly at the transcriptomic and functional levels. These unique differences in MDS-MSCs can be utilized to improve disease prognostication and implement targeted therapy for unmet clinical needs.

Association between nutritional status, injury severity, and physiological responses in trauma patients

PurposeTo evaluate the predictive value of the Controlling Nutritional Status (CONUT) score and Injury Severity Score (ISS) in assessing physiological abnormalities and outcomes in trauma patients.MethodsA retrospective analysis was conducted on 354 trauma patients. Physiological parameters were assessed, including cardiovascular function, inflammatory response, liver and kidney function, and nutritional status. The CONUT score and ISS were calculated for each patient. Binary logistic regression was used to identify independent predictors of trauma severity. Receiver operating characteristic (ROC) curve analysis evaluated the predictive accuracy of the CONUT and ISS scores for adverse outcomes.ResultsSeverely injured patients exhibited more significant abnormalities in cardiovascular function, inflammatory response, liver and kidney function, and nutritional status compared to those with minor injuries. These patients had significantly higher CONUT scores. Logistic regression analysis identified white blood cell count, hemoglobin, and CONUT score as independent predictors of trauma severity. ROC analysis showed that both CONUT and ISS scores effectively predicted adverse outcomes, with ISS demonstrating better specificity.ConclusionThe CONUT and ISS scores are effective tools for predicting physiological abnormalities and adverse outcomes in trauma patients. Incorporating these scores into clinical practice may enhance prognostic assessments and improve management strategies for trauma patients.

Left ventricular myocardial deformation in patients on maintenance haemodialysis

Background Patients with chronic kidney disease (CKD) undergoing maintenance haemodialysis (MHD) develop several abnormalities of left ventricular (LV) structure and function. Speckle-tracking echocardiography permits compressive assessment of LV myocardial deformation. Previous studies involving CKD patients have shown a significant reduction in LV global longitudinal strain (GLS) with strong prognostic implications. However, the other components of LV deformation have not been fully elucidated. Methods A total of 90 CKD patients undergoing MHD (mean age 41.3 ± 12.5 years, 80% men) were compared with 45 apparently healthy age- and gender-matched controls. Results The CKD patients had a high prevalence (77.8% patients) of LV hypertrophy. They also had a significantly elevated ratio of early diastolic mitral inflow velocity to annular velocity (12.1 ± 4.6 vs. 7.1 ± 1.5, p < .001) indicating a high prevalence of LV diastolic dysfunction. LV ejection fraction (LVEF) was the same between the two groups, but the CKD patients had significantly impaired LVGLS (−17.8 ± 3.9 vs. −20.8 ± 2.6, p < .001), global circumferential strain (−14.0 ± 3.5 vs. −16.1 ± 3.4, p = .001), LV apical rotation (6.6 ± 4.7° vs. 8.8 ± 4.0°, p = .008) and LV twist (12.8 ± 6.1° vs. 15.0 ± 6.0°, p = .037). There was no difference in the global radial strain between the two groups. Conclusions The present study shows that CKD patients on MHD have significantly impaired LV longitudinal and circumferential mechanics despite preserved LVEF. The prognostic implications of reduced LVGLS have already been demonstrated previously. Future studies are needed to assess the prognostic implications of abnormal LV circumferential mechanics as well as their reversibility following renal transplant.

Abstract 4136863: Diffuse Functional and Structural Abnormalities in Fibrosis: Potential Structural Basis for Sustaining Atrial Fibrillation

Background: Structural remodeling is associated with atrial fibrillation (AF), but detailed structural and functional characteristics is not well defined. Goal: Using a novel transgenic goat model with cardiac-specific overexpression of TGF-β1 leading to increased cardiac fibrosis, we evaluated detailed structural and functional differences between fibrotic and healthy regions of the atria. Methods: Ex-vivo MRI and histology were used to evaluate fibrosis, fiber disarray, and structural anisotropy. Ex-vivo MRI intensity values were scaled to standard deviations around the mean. The functional analysis examined conduction speeds and direction heterogeneity. Conduction anisotropy was measured along the fiber direction obtained with diffusion tensor imaging. Results: The transgenic goats (n=12) had, on average, 21% of the left atria labeled as fibrotic determined from ex-vivo MRI. The histology samples taken from the labeled fibrotic regions had an increase in fibrosis percentage compared to labeled healthy regions (7.78±3.76% vs 2.80±1.86%, p&lt;0.01). The structural anisotropy was lower in fibrotic regions (0.196±0.002 vs 0.244±0.002, p&lt;0.01). Fiber disarray was greater in the fibrotic regions (20.3±0.2° vs 19.2±0.1°, p&lt;0.01). The fibrotic regions had slower conduction speeds (0.78±0.02 m/s vs 1.12±0.02 m/s, p&lt;0.01) and more aligned conduction directions (30.5±0.2° vs 31.6±0.1°, p&lt;0.01), potentially developing unidirectional conduction block. Conduction anisotropy, measured on the fiber directions, was found to be lower in the fibrotic regions (1.86±0.05 vs 2.10±0.02, p=0.04). As scaled MRI intensity increased, the conduction speed, heterogeneity, and anisotropy all decreased. Conclusions: Functional and structural differences exist between fibrotic and healthy regions of the atria. Though statistically significant, the changes are not discrete. The correlation showed gradual functional abnormalities with MRI intensities. Fibrotic regions tended to have increased fiber disarray, slower conduction, and more unidirectional propagation with lower conduction and structural anisotropy. Diffuse functional and structural abnormalities may allow fibrotic regions to serve as a substrate to sustain AF.

Abstract 4123637: Prevalence of Invasively Diagnosed Coronary Endothelial Dysfunction in Patients with Chest Pain and Normal Coronary Flow Reserve: The Systematically Missed Diagnosis on Non-invasive Testing

Background: Invasive coronary reactivity testing (CRT) is the gold standard for comprehensive assessment of coronary endothelial and microvascular dysfunction in patients with angina and non-obstructive CAD (ANOCA). Non-invasive imaging modalities (PET and CMR) have emerged as potential alternatives. However, due to the inability to systemically administer acetylcholine, patients with normal coronary flow reserve (CFR) but abnormal endothelial function on invasive Ach testing are systemically missed on non-invasive testing. We aimed to assess the prevalence of coronary endothelial dysfunction in ANOCA patients with normal CFR. Methods: Consecutive patients undergoing CRT at our institution were included. Those with normal adenosine-based CFR (&gt;2.5), were further stratified as having normal coronary endothelial function (NEF, &lt;20% epicardial coronary diameter constriction and &gt;50% increase in coronary blood flow in response to ACh) vs abnormal endothelial function (AEF, &gt;20% epicardial coronary diameter constriction and/or &lt;50% increase in coronary blood flow in response to Ach). We then assessed the proportion of AEF patients who would have been otherwise diagnosed with normal coronary physiology based on CFR alone on non-invasive testing. Results: 37 patients underwent CRT. Mean age was 55 years ± 25, 68% were females. 25 out of 37 patients (68%) had normal CFR. Of those patients, 17 (68%) patients had AEF. Distribution of coronary epicardial vs microvascular endothelial dysfunction is represented in Fig. 1. Conclusion: 68% of ANOCA patients with normal CFR had coronary epicardial and/or microvascular endothelial dysfunction and would have otherwise been labeled as ‘normal coronary physiology’ by non-invasive microvascular function testing. Our findings re-enforce the need for comprehensive invasive CRT for accurate comprehensive diagnosis of patients with ANOCA.

Abstract 4127513: Cardiopulmonary long-term effects 6, 18 and 30 months after severe covid-19 infection

Background: SARS-CoV-2 infection affects the cardiopulmonary system in both the acute and long-term phase. This study aimed to comprehensively assess symptoms and potential long-term impairments 6, 18 and 30 months in patients previously hospitalized for severe Covid-19 infection. Methods: This prospective registry included patients hospitalized for PCR-confirmed Covid-19 infection. Approximately 6 months post-discharge, follow-up examination included patient history, clinical examination, echocardiography, electrocardiogram, cardiac magnetic resonance imaging (cMRI), chest computed tomography (CT) scan, pulmonary function test (PFT), six-minute walk test (6MWT) and a comprehensive laboratory panel. Patients with pathologic findings during the first visit underwent a second (at 18 months) and third (at 30 months) follow-up examination. Those without pathologic findings or who refused further medical examinations were contacted via phone to inquire about symptoms. Results: Between July 2020 and April 2022, 200 patients (91% general ward, 9% intensive care unit) were recruited. Due to dropouts, the second visit was conducted in 170 patients, and the third visit in 139 (74 in person, 65 via telephone). Long Covid criteria were fulfilled by 73% at 6 months, 52% at 18 months and 49% at 30 months post-discharge, with fatigue being the most common symptom (Figure 1). Echocardiography at 6 months showed impaired left ventricular function in 15 patients, with normalization in 80% at 18 months and further 66% at 30 months (Figure 2). cMRI revealed pericardial effusions in 28 patients at 6 months, which resolved in 47% at 18 months and in further 60% at 30 months. Signs of peri- or myocarditis were present in 7 patients at 6 months and were resolved in all 4 patients who attended control studies at 18 months. Chest CT scans at 6 months identified post-infectious residues in 41 patients, with full recovery in 20% at 18 months without further normalization after 30 months. The length of in-hospital stay was identified as a significant predictor for persisting Long Covid 6 months after discharge (95% CI: 1.005 - 1.12, p=0.03). Conclusion: While the prevalence of Long Covid decreased over time, a significant symptom burden persisted at 6, 18 and even 30 months after severe Covid-19 infection. Structural and functional abnormalities were less frequent compared to reported symptoms, posing a challenge in substantiating the causes of these symptoms.

Acetylcorynoline alleviates acute liver injury via inhibiting TLR4/JNK/NF-ĸB pathway Based on RNA-seq and molecular docking in vivo and in vitro

Acute liver injury is characterized by massive inflammatory cell infiltration, destruction of liver structure and abnormalities in liver function. Acetylcorynoline (AC) is one of the main chemical components of Corydalis bungeana Turcz. which has been shown to have a protective effect against acute liver injury. However, Whether AC is protective against acute liver injury remains unclear. This study aimed to explore the protective mechanism of AC against acute liver injury from in vivo as well as experiments in vitro. In experimental in vivo studies, AC pretreatment reduced the serum levels of ALT and AST and inhibited the expression of inflammatory factors in the liver of LPS/D-GalN-induced mice and alcohol liver disease mice. RNA-sequencing and molecular docking were used to predict that AC exerts its anti-inflammatory effects through the Toll-like receptor signaling pathway. Using RT-qPCR and Western blotting to detect expression levels of key genes and nodal proteins of the Toll-like receptor signaling pathway, AC was found to inhibit the phosphorylation of nuclear factor-kappaB (NF-ĸB) and c-Jun amino-terminal kinase (JNK). This finding was validated in cellular experiments. In conclusion, AC exerts its anti-hepatic injury effect by suppressing inflammation through inhibition of the TLR4/JNK/NF-ĸB pathway.

From immune response to mental health: neutrophils in schizophrenia

Schizophrenia is a multifaceted psychiatric disorder with a complex etiology that includes genetic, environmental, and immunological factors. Emerging research has increasingly focused on the role of the immune system, particularly neutrophils, in the pathogenesis of schizophrenia. Neutrophils, the most abundant type of white blood cells, are crucial in the body’s defense mechanisms against infections and in the regulation of inflammation. This review explores the evolving evidence that implicates neutrophils in schizophrenia, highlighting their potential contribution to the disorder’s onset and progression through mechanisms such as neuroinflammation and oxidative stress. Recent studies have demonstrated elevated neutrophil counts and neutrophil-to-lymphocyte ratios (NLR) in individuals with schizophrenia, correlating with the severity of psychotic symptoms and cognitive impairments. Furthermore, genetic and molecular analyses have revealed abnormalities in neutrophil function and immune-related gene expression in schizophrenia patients. These findings suggest that neutrophil dysfunction and the resulting chronic inflammation could play a significant role in the disorder’s pathophysiology, affecting neuronal function and contributing to the clinical manifestations of schizophrenia. Neutrophil-related biomarkers, such as NLR, could aid in the diagnosis and monitoring of disease progression. Additionally, targeting neutrophil activity and associated inflammatory pathways presents a promising avenue for developing new therapeutic interventions. This review underscores the need for further research to elucidate the precise mechanisms by which neutrophils influence schizophrenia and to explore potential treatments that could improve outcomes for patients.

Abstract 4134655: Clinical Outcomes of Patients with Alcoholic Cirrhosis and Acute STEMI Undergoing PCI

Original research: Background: The objective is to evaluate the outcomes of percutaneous coronary intervention (PCI) in patients with alcoholic cirrhosis presenting with ST-segment elevation myocardial infarction (STEMI). Methods: We analyzed data from the National Inpatient Sample (NIS) for the years 2016-2020. Our cohort included patients admitted with STEMI and a secondary diagnosis of alcoholic cirrhosis, excluding those under 18 or those not receiving PCI. Propensity score matching using a kernel method was applied to adjust for 22 variables, including patient demographics, hospital characteristics, and comorbid conditions. Results: Among 119,799 patients, 98 had alcoholic cirrhosis. These patients exhibited higher mortality (18% vs. 5%) and longer hospital stays (5.4 days vs. 3.6 days). They also had increased risks of acute blood loss anemia (13% vs. 3.5%) and gastrointestinal bleeding (18% vs. 2%). Additionally, acute kidney injury was more prevalent in the cirrhosis group (25.5% vs. 14%). Although heart failure exacerbation and cardiac arrhythmias were more common, these were not statistically significant (Table 1). Conclusion: Our study indicates a significantly higher mortality rate among patients with alcoholic cirrhosis undergoing PCI for STEMI. These patients are also at increased risk of postoperative bleeding due to compromised liver function and hemostatic abnormalities, as reflected by higher incidences of acute blood loss anemia and gastrointestinal bleeding. Additionally, there is an elevated risk of acute kidney injury post-PCI, highlighting the need for renal-protective strategies. These findings stress the necessity for specialized care, vigilant monitoring, and tailored protocols to address the unique challenges faced by this population, aiming to reduce morbidity and mortality.