Pathophysiological Features Research Articles

Guiding therapy by fractional exhaled nitric oxide & impulse oscillometry parameters in non-asthmatic individuals with chronic cough

Background & objectives Chronic airway inflammation and airway hyperresponsiveness are typical pathophysiological features of cough variant asthma. However, the characteristics of airway inflammation and airflow restriction in individuals with non-asthmatic chronic cough and their guiding value of clinical treatment remain to be determined. This study explored the characteristics and correlations between fractional exhaled nitric oxide (FeNO) and impulse oscillometry (IOS) in non-asthmatic individuals with chronic cough. It also investigated the possibility of chronic cough developing into asthma. Methods In total, 65 study participants with negative bronchial provocation test (BPT) were included in this retrospective study. Data were extracted from chronic cough patients’ electronic medical records, including the demographics, FeNO, IOS and spirometric parameters before and after BPT. Study participants were divided into high-FeNO group (FeNO≥25 ppb) and low-FeNO group (FeNO< 25 ppb) based on FeNO levels. The correlation between the markers was investigated using the Spearman rank correlation test. Results We observed that individuals with non-asthmatic chronic cough exhibited significant increases in Z5, Fres, R5 and R5-R20 after BPT compared to before BPT. In addition, the IOS values of Z5, Fres, R5, and Rc were higher in the low-FeNO group than in the high-FeNO group, but a decrease in FEV1. Correlation analysis: IOS parameters showed a negative correlation with FeNO. However, there were positive correlations of FeNO with FEV1 and PEF. Interpretation & conclusions Our findings showed that individuals with non-asthmatic chronic cough may have varying levels of small airway resistance and inflammation severity. A combined use of FeNO and IOS measurements is conducive to the early clinical treatment of individuals with non-asthmatic chronic cough.

Downstream Link of Vitamin D Pathway with Inflammation Irrespective of Plasma 25OHD3: Hints from Vitamin D-Binding Protein (DBP) and Receptor (VDR) Gene Polymorphisms

Background: Vitamin D insufficiency/deficiency is a highly prevalent condition worldwide. At the same time, chronic inflammation is a versatile pathophysiological feature and a common correlate of various disorders, including vitamin D deficiency. Methods: We investigated the possible association of inflammation with 25-hydroxyvitamin D3 (25OHD3) levels and its down-stream pathway by exploring vitamin D-binding protein (DBP) and vitamin D receptor (VDR) genes for single-nucleotide polymorphisms (SNPs), in healthy non-elderly Bahraini adults. Plasma levels of 25OHD3 were measured by chemiluminescence, and six SNPs, four in the GC gene (rs2282679AC, rs4588CA, rs7041GT, and rs2298849TC) and two in the VDR gene (rs731236TC and rs12721377AG) were genotyped by real-time PCR. The concentrations of five inflammatory biomarkers, IL6, IL8, procalcitonin (PCT), TREM1, and uPAR, were measured by ELISA. Results: The results showed no association between the 25OHD3 level and any of the inflammatory markers’ levels. However, three tested SNPs were significantly associated with the concentrations of tested biomarkers except for IL6. The TT mutant genotype of rs2298849TC was associated with lower levels of IL8 and higher levels of PCT and TREM1, the AA mutant genotype of rs2282679AC was associated with decreased levels of IL8 (p ≤ 0.001) and increased levels of TREM1 (p = 0.005), and the GG wild genotype of rs12721377AG was associated with increased levels of 25OHD3 (p = 0.026). Conclusions: Although chronic inflammation is not associated with the vitamin D system in the blood, it is downstream, as revealed by DBP and VDR genotyping. Alternatively, DBP and VDR pursue other functions beyond the vitamin D pathway.

An Easy and Quick Risk-Stratified Early Forewarning Model for Septic Shock in the Intensive Care Unit: Development, Validation, and Interpretation Study.

Septic shock (SS) is a syndrome with high mortality. Early forewarning and diagnosis of SS, which are critical in reducing mortality, are still challenging in clinical management. We propose a simple and fast risk-stratified forewarning model for SS to help physicians recognize patients in time. Moreover, further insights can be gained from the application of the model to improve our understanding of SS. A total of 5125 patients with sepsis from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database were divided into training, validation, and test sets. In addition, 2180 patients with sepsis from the eICU Collaborative Research Database (eICU) were used as an external validation set. We developed a simplified risk-stratified early forewarning model for SS based on the weight of evidence and logistic regression, which was compared with multi-feature complex models, and clinical characteristics among risk groups were evaluated. Using only vital signs and rapid arterial blood gas test features according to feature importance, we constructed the Septic Shock Risk Predictor (SORP), with an area under the curve (AUC) of 0.9458 in the test set, which is only slightly lower than that of the optimal multi-feature complex model (0.9651). A median forewarning time of 13 hours was calculated for SS patients. 4 distinct risk groups (high, medium, low, and ultralow) were identified by the SORP 6 hours before onset, and the incidence rates of SS in the 4 risk groups in the postonset interval were 88.6% (433/489), 34.5% (262/760), 2.5% (67/2707), and 0.3% (4/1301), respectively. The severity increased significantly with increasing risk in both clinical features and survival. Clustering analysis demonstrated a high similarity of pathophysiological characteristics between the high-risk patients without SS diagnosis (NS_HR) and the SS patients, while a significantly worse overall survival was shown in NS_HR patients. On further exploring the characteristics of the treatment and comorbidities of the NS_HR group, these patients demonstrated a significantly higher incidence of mean blood pressure <65 mmHg, significantly lower vasopressor use and infused volume, and more severe renal dysfunction. The above findings were further validated by multicenter eICU data. The SORP demonstrated accurate forewarning and a reliable risk stratification capability. Among patients forewarned as high risk, similar pathophysiological phenotypes and high mortality were observed in both those subsequently diagnosed as having SS and those without such a diagnosis. NS_HR patients, overlooked by the Sepsis-3 definition, may provide further insights into the pathophysiological processes of SS onset and help to complement its diagnosis and precise management. The importance of precise fluid resuscitation management in SS patients with renal dysfunction is further highlighted. For convenience, an online service for the SORP has been provided.

Intricating connections: the role of ferroptosis in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic inflammatory and autoimmune disease with multiple tissue damage. However, the pathology remains elusive, and effective treatments are lacking. Multiple types of programmed cell death (PCD) implicated in SLE progression have recently been identified. Although ferroptosis, an iron-dependent form of cell death, has numerous pathophysiological features similar to those of SLE, such as intracellular iron accumulation, mitochondrial dysfunction, lipid metabolism disorders and concentration of damage associated-molecular patterns (DAMPs), only a few reports have demonstrated that ferroptosis is involved in SLE progression and that the role of ferroptosis in SLE pathogenesis continues to be neglected. Therefore, this review elucidates the potential intricate relationship between SLE and ferroptosis to provide a reliable theoretical basis for further research on ferroptosis in the pathogenesis of SLE.

Insights from serial cardiovascular magnetic resonance imaging show early progress in diastolic dysfunction relates to impaired right ventricular deformation

Latent pulmonary vascular disease is a distinct feature already in the early pathophysiology of masked heart failure with preserved ejection fraction (HFpEF) and associated with reduced right ventricular (RV) functional reserve. We hypothesized that serial real-time cardiovascular magnetic resonance (CMR) imaging at rest and during exercise-stress may detect early progress in pathophysiological alterations in HFpEF. Patients presenting with exertional dyspnoea and signs of diastolic dysfunction (E/e’>8, left ventricular (LV) ejection fraction > 50%) were prospectively enrolled in the HFpEF Stress Trial (NCT03260621). Rest and exercise-stress echocardiography, CMR and right heart catheterisation were performed at baseline. Pulmonary capillary wedge pressure (PCWP) was used for classification of HFpEF (≥ 15/25mmHg at rest/during exercise-stress) and non-cardiac dyspnoea (NCD). Repeat rest and exercise-stress CMR was performed in median 2.94 years after recruitment during which timeframe some HFpEF patients had undergone interatrial shunt device (IASD) implantation. Cardiovascular events were assessed after 4 years.Serial CMR scans were available for NCD n = 10, HFpEF n = 10 and HFpEF with IASD implantation following baseline diagnosis n = 6. RV long axis strain at rest and during exercise-stress decreased in HFpEF (p = 0.007 for both) but neither in NCD nor HFpEF with IASD. In contrast, in NCD, an improvement in LA LAS during exercise-stress (p = 0.028) was noted. There were no functional alterations in HFpEF patients who had undergone IASD implantation. RV functional deterioration may be a pathophysiological feature during early-stage disease progress in HFpEF. In this observational study RV functional deterioration was detected in HFpEF patients only but not patients with NCD and patients with HFpEF that were treated with IASD placement. These findings should next be explored in adequately powered future research trials. Clinicaltrials.gov: NCT03260621 (First posted date 24/08/2017).

End Plate Chondrocyte-Derived Exosomal miR-133a-3p Alleviates Intervertebral Disc Degeneration by Targeting the NF-κB Signaling Pathway through the miR-133a-3p/MAML1 Axis.

Chondrocyte-derived exosomes have shown efficacy in differentiating osteoarthritis-affected cartilage. Intervertebral disc degeneration (IVDD) and osteoarthritis often affect facet joints of the spine and show common epidemiological and pathophysiological characteristics. However, the potential of chondrocyte-derived exosomes for treating IVDD remains unclear. The present study aimed to confirm the effect of end plate chondrocyte-derived exosomes (EPC-Exo) on IVDD and elucidate the underlying mechanism. EPC-Exos were isolated and identified by ultracentrifugation, Western blotting, electron microscopy, and nanoparticle tracking analysis. In the in vitro, EPC-Exo uptake by nucleus pulposus (NP) cells reduced cell death by blocking the nuclear factor-κB (NF-κB) signaling pathway. In the in vivo study, EPC-Exos injected into rat intervertebral discs mitigated lipopolysaccharide-induced IVDD, as revealed by a decreased loss of disc height and improved magnetic resonance imaging findings and histological scores. Bioinformatics and sequencing analyses indicated that EPC-Exos alleviated IVDD through the miR-133a-3p/MAML1 axis. The present study suggests that EPC-Exos reduced IVDD incidence via the miR-133a-3p/MAML1 axis-mediated suppression of NF-κB signaling, which prevented the pyroptosis of NP cells.

MR Imaging Techniques for Microenvironment Mapping of the Glioma Tumors: ASystematic Review.

The tumor microenvironment (TME) is a critical regulator of cancer progression, metastasis, and treatment response. Currently, various imaging approaches exist to assess the pathophysiological features of the TME. This systematic review provides an overview of magnetic resonance imaging (MRI) methods used in clinical practice to characterize the pathophysiological features of the gliomas TME. This review involved a systematic comprehensive search of original open-access articles reporting the clinical use of MR imaging in glioma patients of all ages in the PubMed, Scopus, and Web of Science databases between January 2010 and December 2023. We restricted our research to papers published in the English language. A total of 1137 studies were preliminarily identified through electronic database searches. After duplicate studies were removed, 44 studies met the eligibility criteria. The glioma TME was accompanied by alterations in metabolism, pH, vascularity, oxygenation, and extracellular matrix components, including tumor-associated macrophages, and sodium concentration. Multiparametric MRI is capable of noninvasively assessing the pathophysiological features and tumor-supportive niches of the TME, which is in line with its application in personalized medicine.

Peripheral nerve excitability abnormalities in Neuronal Intranuclear Inclusion Disease: Assessment with histopathological analysis.

Neuronal Intranuclear Inclusion Disease (NIID) is a neurodegenerative disease affecting the central and peripheral nerves. We aimed to assess the pathophysiological features of peripheral nerve dysfunction in NIID. We observed six unrelated NIID patients through clinical records, nerve conduction studies, and multiple measures of motor nerve excitability. Additionally, we reviewed one NIID patientt who underwent a nerve biopsy. Control measures were obtained from 22 age-matched normal subjects. The NIID patients exhibited mild conduction slowing and distinct nerve excitability abnormalities, including a significant decrease in excitability through hyperpolarizing threshold electrotonus (TE) and increased overshoots in both depolarizing and hyperpolarizing conditions. Histopathology revealed thinly myelinated fibers and axonal degeneration. Mathematical modeling suggested that reduced leak conductance was the key factor contributing to the observed excitability changes. The findings indicate that NIID involves a complex interplay of axonal degeneration and myelin dysfunction, leading to unique peripheral nerve excitability changes. These results provide new insights into the pathophysiology of NIID. Nerve excitability testing offers insight into particular axonal excitability abnormalities especially combined with histopathologic studies.

Association between subtypes of diabetes and special sensations: A 2-sample Mendelian randomization study.

Diabetes, a chronic condition affecting millions of individuals, is divided into type 1 diabetes (T1D) and type 2 diabetes (T2D), each with unique pathophysiological characteristics. While the impact of diabetes on vision is established, its relationship with other special senses, balance, hearing, and olfaction, remains uncertain. This study utilized a 2-sample Mendelian randomization (MR) approach to investigate the associations between diabetes subtypes and specific sensory disorders. We performed MR analysis using various methods (inverse variance weighting [IVW], MR-Egger, simple mode, weighted mode, weighted median, MR-PRESSO) to assess the causal relationships between diabetes subtypes and sensory disorders (vestibular dysfunction, sensorineural hearing loss, conductive hearing loss, and olfactory dysfunction). Different diabetes genome-wide association studies datasets were utilized for validation. MR analysis revealed no significant correlations between T1D or T2D and the sensory disorders studied. Interestingly, an initial signal suggested that T1D might increase the risk of conductive hearing loss (IVW: odds ratio = 1.120, 95% CI: 1.035-1.211, P = .005), but this finding was not supported by validation studies. No evidence of horizontal pleiotropy or heterogeneity was found (P > .05). Our MR analysis and subsequent validation revealed no significant associations between diabetes subtypes and special senses. The initial suggestion of an increased risk of conductive hearing loss in T1D patients was not confirmed. Future research should further explore the intricate relationships among diabetes, sensory functions, and other factors, as well as the potential effects of diabetes management on sensory health.

Steroid-resistant nephrotic syndrome due to renal-limited thrombotic microangiopathy and membranous nephropathy after allogeneic hematopoietic stem cell transplantation successfully treated with calcineurin inhibitors.

Transplantation-associated thrombotic microangiopathy (TMA) is a severe complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with high mortality. As calcineurin inhibitors (CNIs) reportedly contribute to TMA via drug-induced endothelial injury, treatment of TMA often involves CNI discontinuation or dose reduction. However, renal-limited TMA, defined as biopsy-proven renal TMA without the classical triad (hemolytic anemia, thrombocytopenia, and organ damage), has rarely been reported after allo-HSCT, and its optimal management remains unknown. Herein, we report three cases of renal-limited TMA after allo-HSCT that presented with nephrotic syndrome, in which renal biopsy showed TMA and concurrent membranous nephropathy. All patients were refractory to glucocorticoid monotherapy and the addition of CNIs led to complete remission of nephrotic syndrome. Renal-limited TMA after allo-HSCT may present as nephrotic syndrome with distinct pathophysiological features from renal-limited TMA in non-allo-HSCT recipients. Previous reports have suggested that renal-limited TMA after allo-HSCT is associated with renal graft-versus-host disease, and thus optimizing immunosuppressive therapy, including CNI treatment, may be useful. CNI treatment may be an option even in the presence of renal-limited TMA after allo-HSCT accompanied by concurrent membranous nephropathy.

Increased expression of the small lysosomal gene SVIP in the Drosophila gut suppresses pathophysiological features associated with a high-fat diet.

Lysosomes are digestive organelles that are crucial for nutrient sensing and metabolism. Lysosome impairment is linked to a broad spectrum of metabolic disorders, underscoring their importance to human health. Thus, lysosomes are an attractive target for metabolic disease therapies. In previous work, we discovered a novel class of tubular lysosomes that are morphologically and functionally distinct from traditionally described vesicular lysosomes. Tubular lysosomes are present in multiple tissues, are broadly conserved from invertebrates to mammals, are more proficient at degrading autophagic cargo than vesicular lysosomes, and delay signs of tissue aging when induced ectopically. Thus, triggering tubular lysosome formation presents one mechanism to increase lysosome activity and, notably, overproduction of the small lysosomal protein, SVIP, is a robust genetic strategy for triggering lysosomal tubulation on demand. In this study, we examine whether SVIP overexpression in the fly gut can suppress pathophysiological phenotypes associated with an obesogenic high-fat diet. Indeed, our results indicate that increasing SVIP expression in the fly gut reduces lipid accumulation, suppresses body mass increase, and improves survival in flies fed a high-fat diet. Collectively, these data hint that increasing lysosomal activity through induction of tubular lysosomal networks, could be one strategy to combat obesity-related pathologies.

Evaluation of NAPLES Prognostic Score to Predict Long-Term Mortality in Patients with Pulmonary Embolism

Background/Objectives: Acute pulmonary embolism (APE) is a clinical syndrome characterized by the obstruction of blood flow in the pulmonary artery, whose main pathophysiological features are respiratory and circulatory dysfunction. Acute pulmonary embolism is associated with a high mortality rate. Diagnostic and therapeutic delays can exacerbate mortality and result in prolonged hospitalization. With the increasing understanding that APE is associated with inflammation, various indices based on systemic inflammation have been shown to predict prognosis in patients with APE. The NAPLES Prognostic Score (NPS) is a new scoring system that indicates the inflammatory and nutritional status of the patient based on albumin (ALB) levels, total cholesterol (TC) levels, lymphocyte-to-monocyte ratio (LMR) and neutrophil-to-lymphocyte ratio (NLR). Our study aimed to examinate the effect of NPS on APE prognosis, so the relationship between NPS and APE prognosis was evaluated in our study. In addition, this study seeks to lay the groundwork for further investigations into this association and expand the existing body of knowledge. Methods: The clinical data of patients who applied to the Dicle University Faculty of Medicine and were diagnosed with APE between March 2014 and April 2024 were evaluated retrospectively, with 436 patients aged 18 years and over included in the study. Patients were divided into two groups according to NPS. It was statistically investigated whether there was a significant difference in long-term mortality between the two groups. Statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) version 21.0. Results: Survival was found to be statistically significantly lower in patients with NPS 3–4 (p &lt; 0.05). In the multivariate regression analyses, no statistically significant effect of NPS or other parameters except lactate on 3-month mortality was found (p &gt; 0.05). The short-term prognostic value of the NPS has been found to be equivalent to that of the sPESI score. It may be considered that APE patients with high NPS scores should be monitored more frequently. Conclusions: Increased NPS was found to be associated with poor APE prognosis in our study.

Microvascular dysfunction contributes to atrial fibrillation in hypertrophic cardiomyopathy, a multimodality study

Abstract Background Microvascular dysfunction (MVD) constitutes one of the most important pathophysiological features in hypertrophic cardiomyopathy (HCM). Chronic and recurrent myocardial ischemia potentially contributes to arrhythmic risk, namely to atrial fibrillation (AF). Purpose To analyze the impact of MVD in the occurrence of AF in HCM patients (P), assessed by coronary flow velocity reserve (CFVR) on echocardiography (echo) and ischemia on cardiovascular magnetic resonance (CMR). Methods Prospective study, which enrolled HCM P without obstructive epicardial coronary artery disease, who underwent stress echo and stress CMR. By echo, the evaluation of CFVR in the left anterior descending (LAD) artery was performed in apical three chambers view. Diastolic coronary flow velocity was measured in basal conditions and in hyperemia, induced by adenosine perfusion (0.14 mg/kg/min intravenously, during 2 minutes). CFVR was calculated as the ratio of hyperemic to basal peak diastolic flow velocities. On CMR, perfusion imaging was acquired during regadenoson-induced hyperemia. To quantify the ischemic burden, the myocardium was divided into 32 subsegments (16 AHA segments subdivided into an endocardial and epicardial layer, excluding segment 17) and the ischemic burden was calculated as the number of involved subsegments, assigning 3% of myocardium to each subsegment. Late gadolinium enhancement (LGE) was quantified used the 6 standard deviation method. Kaplan Meyer curves were performed to evaluate the impact of CFVR, ischemia, left atrial volume and LGE in the occurrence of atrial fibrillation during the follow up. Results 73P were enrolled, 47 (64%) males, mean age 54.3(14.8) years. 19 P (26%) had obstructive HCM, mean maximal wall thickness (MWT) was 20.1(4.6)mm, left ventricular (LV) mass 96.9(30.6)g/m2, LV ejection fraction 71.6(8.4)%, left atrial volume (LAV) 47.0(16.8)ml/m2, CFVR LAD 1.8(0.4), ischemic burden 22.5(17.1)% of LV. During the follow up of 54.6(7.8) months (minimum 42months, maximum 80months), P with more severe microvascular dysfunction (CFVR LAD&amp;lt;2.0 and ischemia ≥18% of LV) had significant higher incidence of atrial fibrillation (figure 1). P with CFVR LAD≥2.0 and LAV≤34ml/m2 had significantly less AF comparing to P with CFVR LAD&amp;lt;2.0 and LAV&amp;gt;34ml/m2. Interestingly, P with only one of this risk factors had similar incidence of AF, pointing toward a similar impact of microvascular dysfunction and LA dilatation. Although LGE is a well-known surrogate marker of disease severity, extension of the ischemia seemed to play a more important role in AF development, as patients with ischemia ≥ 18% of LV and LGE &amp;lt; 15% had more AF than P with ischemia &amp;lt; 18% of LV and LGE ≥ 15%. Conclusion Microvascular dysfunction and consequent ischemic burden were linked to AF, which likely reflects advanced disease, involving atrial myocardium beyond LV myocardium, contributing for atrial dysfunction and arrhythmogenicity. Figure 1

Impact of acupuncture on mortality in patients with disabilities and newly diagnosed heart failure: a nationwide cohort study

ObjectivePeople with disabilities have high rates of cardiovascular diseases and mortality, and heart failure can worsen their condition. Therefore, preventing and managing cardiovascular diseases is particularly important for this population. Although acupuncture has been used for heart failure, research on its impact on mortality is limited. Given the unique pathophysiological characteristics of people with disabilities, this study aimed to evaluate the effect of acupuncture on mortality in those newly diagnosed with heart failure.MethodsThis retrospective cohort study used data from the Korean National Health Insurance Service, focusing on people with disabilities diagnosed with heart failure between 2014 and 2016. Acupuncture exposure within 1 year of diagnosis was assessed by dividing the participants into acupuncture-exposed and non-exposed groups. Propensity score matching (PSM) was used to adjust for group differences, and all-cause mortality was tracked for 3 years. Cox proportional hazard models were employed to calculate hazard ratios (HRs) and confidence intervals (CIs). Dose-response relationships were also analyzed by dividing acupuncture frequency into quartiles.ResultsAfter PSM, 21,001 individuals were included in both groups. The acupuncture-exposed group had a 20% lower risk of all-cause mortality (adjusted HR 0.80, 95% CI 0.76–0.84) than those in the non-exposed group. Higher acupuncture doses were associated with a greater reduction in mortality, with the highest dose group showing a 36% lower risk (adjusted HR 0.64, 95% CI 0.58–0.69) than those in the non-exposed group. The subgroup analysis showed a consistent reduction in mortality across most groups, particularly in women, older adults, higher-income individuals, and those with severe disabilities.ConclusionThis study suggests that acupuncture exposure is associated with reduced mortality in people with disabilities who are newly diagnosed with heart failure. While several limitations exist, we highlight the potential role of acupuncture in managing cardiovascular diseases in this population and encourage further research to support healthcare policies.

Modeling Heart Failure With Preserved Ejection Fraction Using Human Induced Pluripotent Stem Cell-Derived Cardiac Organoids.

The therapeutic armamentarium for heart failure with preserved ejection fraction (HFpEF) remains notably constrained. A factor contributing to this problem could be the scarcity of in vitro models for HFpEF, which hinders progress in developing new therapeutic strategies. Here, we aimed at developing a novel, comorbidity-inspired, human, in vitro model for HFpEF. Human induced pluripotent stem cells-derived cardiomyocytes were used to produce cardiac organoids. The generated organoids were then subjected to HFpEF-associated, comorbidity-inspired conditions, such as hypertension, diabetes, and obesity-related inflammation. To assess the development of HFpEF pathophysiological features, organoids were thoroughly evaluated for their structural, functional, electrophysiological, and metabolic properties. Exposure to the combination of all comorbidity-mimicking conditions resulted in the largest cellular volume of 1692±52 versus 1346±84 µm3 in RPMI (Roswell Park Memorial Institute medium) control group (P=0.003), while lower in obesity, hypertension, and diabetes groups: 1059±40 µm3 (P=0.014), 1276±35 µm3 (P=0.940), and 1575±70 µm3 (P=0.146), respectively. Similarly, ultrastructural fibrosis was most significantly observed after exposure to the combination of all HFpEF-inducing conditions 14.6±1.2% compared with single condition exposure 5.2±1.3% (obesity), 6.7±3.5% (hypertension), and 9.0±1.1% (diabetes; P<0.001). Moreover, HFpEF-related conditions led to an increase in passive force compared with control (7.52±1.08 versus 2.33±0.46 mN/mm, P<0.001), whereas no significant alterations were noted in active contractile forces. Relaxation constant τ was significantly prolonged after exposure to HFpEF conditions showing a prolongation of 95.9 ms (36.4-106.4; P=0.028) compared with a shortening of 35.6 ms (43.3-67.3; P=0.80) in the control. Finally, organoid exposure to HFpEF conditions led to a significant increase in oxidative stress levels and a significant decline in oxygen consumption rate. We established a novel, human, in vitro model for HFpEF, based on comorbidity-inspired conditions. The model faithfully recapitulated the structural, functional, and mechanistic features of HFpEF. This model holds the potential to provide mechanistic insights and facilitate the identification of novel therapeutic targets.

Relevance of Lipoprotein Composition in Endothelial Dysfunction and the Development of Hypertension

Endothelial dysfunction and chronic inflammation are determining factors in the development and progression of chronic degenerative diseases, such as hypertension and atherosclerosis. Among the shared pathophysiological characteristics of these two diseases is a metabolic disorder of lipids and lipoproteins. Therefore, the contents and quality of the lipids and proteins of lipoproteins become the targets of therapeutic objective. One of the stages of lipoprotein formation occurs through the incorporation of dietary lipids by enterocytes into the chylomicrons. Consequently, the composition, structure, and especially the properties of lipoproteins could be modified through the intake of bioactive compounds. The objective of this review is to describe the roles of the different lipid and protein components of lipoproteins and their receptors in endothelial dysfunction and the development of hypertension. In addition, we review the use of some non-pharmacological treatments that could improve endothelial function and/or prevent endothelial damage. The reviewed information contributes to the understanding of lipoproteins as vehicles of regulatory factors involved in the modulation of inflammatory and hemostatic processes, the attenuation of oxidative stress, and the neutralization of toxins, rather than only cholesterol and phospholipid transporters. For this review, a bibliographic search was carried out in different online metabases.

A surgical orthotopic xenograft approach with immune response for colorectal cancer research.

The high morbidity and mortality of colorectal cancer (CRC) is a major challenge in clinical practice. Although a series of alternative research models of CRC have been developed, appropriate orthotopic animal models that reproduce the specific clinical response as well as pathophysiological immune features of CRC are still lacking. In the current study, we constructed a CRC orthotopic xenograft model by implanting the tumor tubes at the colorectum of mice and monitored the model development using bioluminescence imaging. This model successfully recapitulates the clinical chemotherapy efficacy, including reduced total flux, tumor weight, and the expression of Ki67 after treatment of the first-line chemotherapy regime of CRC (FOLFOX: oxaliplatin and 5-fluorouracil/calcium folinate). The model also reproduced the immunosuppressive effect of FOLFOX, indicated by decreased infiltration of macrophages and increased Treg cells in tumor. Additionally, the orthotopic xenograft approach may be applied in immunodeficient NCG/NSG mice for constructing patient-derived xenografts, and being used in clinical precision medicine and drug evaluation. We believe the current model is a successful surgical orthotopic xenograft approach for cancer research and deserves to be popularized, which will provide a convenient and efficient platform for in-depth mechanism exploration of CRC and preclinical drug evaluation.

Dynamic pathophysiological features of early primary blast lung injury: a novel functional incapacity pig model

IntroductionWhile there is evidence supporting the use of ultrasound for real-time monitoring of primary blast lung injury (PBLI), uncertainties remain regarding the timely detection of early PBLI and the limited data correlating it with commonly used clinical parameters. Our objective is to develop a functional incapacity model for PBLI that better addresses practical needs and to verify the early diagnostic effectiveness of lung ultrasound in identifying PBLI.MethodsWe selected six healthy male pigs to develop an animal model using a bio-shock tube (BST-I). The injuries were induced at a pressure of 4.8 MPa. We monitored the animals before and after the injury using various methods to detect changes in vital signs, lung function, and hemodynamics.ResultsThe experimental peak overpressure was measured at 405.89 ± 4.14KPa, with the duration of the first positive peak pressure being 50.01ms. The mortality rate six hours after injury was 50%. The average Military Combat Injury Scale was higher than 3. Significant increases were observed in heart rate (HR), shock index (SI), alveolar-arterial oxygen gradient (AaDO2), lung ultrasound scores(LUS), and pulmonary vascular permeability index (PVPI) at 0.5 h, 3 h, and 6 h after-injury (p < 0.05). Conversely, there were notable decreases in average arterial pressure(MAP), oxygenation index (OI), stroke volume per heartbeat(SV), cardiac output power index(CPI), global end-diastolic index (GEDI), and intrathoracic blood volume index (ITBI) during the same time periods (p < 0.05). Meanwhile, the extrapulmonary water index (ELWI) showed a significant increase at 0.5 h and 6 h after injury (p < 0.05). At 6 h after injury, pulmonary ultrasound scores were positively correlated with HR (R = 0.731, p < 0.001), AaDO2 (R = 0.612, p = 0.012), SI (R = 0.661, p = 0.004), ELWI (R = 0.811, p < 0.001), PVPI (R = 0.705, p = 0.002). In contrast, these scores were negatively correlated with SpO2 (R = -0.583, p = 0.007),OI (R = -0.772, p < 0.001), ITBI (R = -0.637, p = 0.006).ConclusionWe have successfully developed a novel, and highly reproducible animal model for assessing serious PBLI functional incapacity. This model displays immediate symptoms of hypoxia, decreased cardiac output, decreased blood volume, and abnormal lung ultrasound findings within 0.5 h of injury, with syptoms lasting for up to 6 h. Lung ultrasound evaluation is crucial for the early assessment of injuries, and is comparable to commonly used clinical parameters.

Baseline liver fibrosis-4 score correlates to the progression of anxiety and cognitive impairment in patients with Parkinson’s disease

BackgroundNon-alcoholic fatty liver disease (NAFLD) or liver fibrosis may share similar pathophysiological features with Parkinson’s disease (PD), yet their correlation was unclear. This study aimed to explore their correlation between PD and liver fibrosis using the fibrosis-4 score (FIB-4) as a surrogate marker.MethodsWe analyzed Parkinson’s Progression Markers Initiative (PPMI) data and enrolled PD patients with comprehensive baseline and 5-year follow-up time-point clinical data. Participants were categorized based on FIB-4 levels to assess the association between FIB-4 scores and various clinical scales, controlling for potential confounders. Differences in the progression of clinical scales over five years were compared using generalized linear mixed models (GLMM).ResultsBaseline FIB-4 levels positively correlated to scores of baseline section III of the Unified-Parkinson Disease Rating Scale (UPDRS III) (r = 0.145, p = 0.017), Epworth Sleepiness Scale (EPSS) (r = 0.140, P = 0.022), Hopkins Verbal Learning Test (HVLT)-delayed recall (r = 0.128, P = 0.036) and HVLT-retention (r = 0.128, p = 0.036). GLMM analysis revealed an independent correlation between FIB-4 subgroup*time and several clinical scales including the State-trait Anxiety Inventory (STAI), Symbol Digit Modalities Test (SDMT), Semantic Fluency Test (SF), HVLT-total recall, and HVLT-delayed recall, with the high FIB-4 subgroup exhibiting a greater decline in these scores compared to the low FIB-4 subgroup (all p&amp;lt;0.05).ConclusionElevated baseline FIB-4 correlated to more severe baseline daytime sleepiness, motor symptoms, and memory function in PD patients, along with a more rapid decline in cognitive functions such as executive function, information processing ability, and memory. Additionally, a high FIB-4 might confer a protective effect against anxiety.

P0054 Human colonoid-derived monolayers and Caco-2: comparative analysis of inflammatory responses

Abstract Background Given the increasing incidence of inflammatory bowel diseases, there is a growing need for reliable preclinical models that replicate the inflamed intestinal epithelium. Immortalized Caco-2 cells are widely considered the standard in vitro model for intestinal studies, but human-derived colonoid monolayers (CDMs) could be proposed as a powerful alternative to more accurately mimic the pathophysiological features of intestinal inflammation. The present study aims to compare the functional and morphological responses induced by inflammatory cytokines TNFα and IFNγ on CDMs and Caco-2. Methods Human colonic crypts from biopsies of 5 healthy volunteers were embedded in Matrigel® and cultured for 5-7 days. IntestiCult™ OGM was used to expand cystic-like colonoids, and single cells were seeded onto coated 24-well inserts. Upon reaching confluence, the medium was switched to IntestiCult™ ODM. Caco-2 cells were cultured for 21 days on 24-well inserts. Differentiated CDMs and Caco-2 monolayers were exposed to 25 ng/mL TNFα-IFNγ for 24 hours. Cell differentiation was assessed by immunocytochemistry (ICC), and barrier integrity was evaluated by transepithelial electrical resistance (TEER) measurement. Cytotoxicity was assessed through the LDH assay. IL-8 and CCL20 release were quantified. Results Both models showed increasing TEER over the growth period, indicating the gradual development of epithelial barriers, up to 484±58 Ω*cm2 for CDMs and 700±184 Ω*cm2 for Caco-2. ICC staining for epithelial markers villin and MUC2 confirmed polarization and differentiation under basal conditions in both models, cytokines reduced the expression of epithelial markers. Inflammation reduced the barrier integrity of the monolayers (approximately 18%), although more uniformly in Caco-2 than in CDMs. IL-8 and CCL20 release was augmented by cytokines in both models, (for IL-8 of about 20 times in CDM and 2 times in Caco-2). As regards cell viability, CDMs (40% cytotoxicity) showed higher sensitivity to cytokines than Caco-2 (22% cytotoxicity). Conclusion Exposure to an inflammatory environment altered cell morphology and impaired epithelial barrier integrity in both CDMs and Caco-2 monolayers. These findings highlight the potential of CDMs as an advanced model for studying personalized responses in intestinal inflammation.