The Long COVID Symptoms and Severity Score: Development, Validation, and Application.

OBJECTIVES: The primary focus of this research is the proposition of a methodological framework for the clinical application of the long COVID symptoms and severity score (LC-SSS). This tool is not just a self-reported assessment instrument developed and validated but serves as a standardized, quantifiable means to monitor the diverse and persistent symptoms frequently observed in individuals with long COVID. METHODS: A 3-stage process was used to develop, validate, and establish scoring standards for the LC-SSS. Validation measures included correlations with other patient-reported measures, confirmatory factor analysis, Cronbach's α for internal consistency, and test-retest reliability. Scoring standards were determined using K-means clustering, with comparative assessments made against hierarchical clustering and the Gaussian Mixture Model. RESULTS: The LC-SSS showed correlations with EuroQol 5-Dimension 5-Level (rs = -0.55), EuroQol visual analog scale (rs = -0.368), Patient Health Questionnaire-9 (rs = 0.538), Beck Anxiety Inventory (rs = 0.689), and Insomnia Severity Index (rs = 0.516), confirming its construct validity. Structural validity was good with a comparative fit index of 0.969, with Cronbach's α of 0.93 indicating excellent internal consistency. Test-retest reliability was also satisfactory (intraclass correlation coefficient 0.732). K-means clustering identified 3 distinct severity categories in individuals living with long COVID, providing a basis for personalized treatment strategies. CONCLUSIONS: The LC-SSS provides a robust and valid tool for assessing long COVID. The severity categories established via K-means clustering demonstrate significant variation in symptom severity, informing personalized treatment and improving care quality for patients with long COVID.

Clinical efficacy and safety of neuroendoscopic surgery for severe thalamic hemorrhage with ventricle encroachment.

To summarize and analyze the clinical efficacy and safety of neuroendoscopic surgery (NES) in the treatment of patients for severe thalamic hemorrhage with ventricle encroachment (THVE). Eighty-three patients with severe THVE were treated in the Neurosurgery Department of Anqing Hospital Affiliated to Anhui Medical University from July 2019 to August 2021. Our study was approved by the ethics committee. The patients were randomly divided into NES group and extraventricular drainage (EVD) group. The hospital stay, Glasgow coma scale (GCS) scores on the 1st and 14th days postoperatively, the incidence of intracranial infections, and the clearance of postoperative hematomas were compared and analyzed between the two groups. The patients had follow-up evaluations 6 months postoperatively. The prognosis was evaluated based on the activity of daily living (ADL) score. A head CT or MRI was obtained to determine whether there was hydrocephalus, cerebral infarction, or other related complications. Eighty-three patients were randomly divided into 41 cases of NES group and 42 cases of EVD group. The length of postoperative hospital stay was 17.42 ± 1.53 days, the GCS scores were 6.56 ± 0.21, and 10.83 ± 0.36 on days 1 and 14, respectively; intracranial infections occurred in 3 patients (7.31%) and the hematoma clearance rate was 83.6 ± 5.18% in the NES group, all of which were significantly better than the EVD group (P < 0.05). After 6 months of follow-up, 28 patients (68.29%) had a good prognosis, 5 patients (12.19%) died, and 4 patients (9.75%) had hydrocephalus in the NES group. In the EVD group, the prognosis was good in 15 patients (35.71%), 12 patients (28.57%) died, and 17 patients (40.47%) had hydrocephalus. The prognosis, mortality rate, and incidence of hydrocephalus in the NES group were significantly better than the EVD group (P < 0.05). Compared to traditional EVD, NES for severe THVE had a higher hematoma clearance rate, and fewer intracranial infections and patients with hydrocephalus, which together improve the clinical prognosis and is thus recommended for clinical use.

Coronary Angiography Within 48 Hours Before Cardiac Surgery Increases the Risk of Postoperative Acute Kidney Injury.

BACKGROUND: Cardiac surgery and coronary examination, such as invasive coronary angiography (CAG), are both possibly associated with acute kidney injury (AKI). Preoperative CAG examination and cardiac surgery within a short interval may increase the incidence of AKI. METHODS: We retrospectively reviewed 1112 patients who underwent CAG examination within 30 days prior to the cardiac operation in this study. Postoperative AKI was defined, according to Kidney Disease Improving Global Outcomes Definition and Staging (KDIGO) criteria. RESULTS: The total incidence of AKI was 40.8% and cystatin C level was 1.260 (1.028, 1.672) mg/L. For patients who received CAG, age, body mass index, cardiopulmonary time, and the time interval between preoperative CAG examination and cardiac operation within 48h was shown to be independent predictors of postoperative AKI. The incidence of AKI in patients undergoing preoperative CAG within 48h was 11.2% higher than in those more than 48h (P < 0.001). Patients undergoing valve surgery with or without coronary artery bypass grafting (CABG) exhibited a higher AKI risk than those only accepting CABG. The in-hospital stay of patients who developed AKI was 2 days longer than those without AKI. However, undergoing CAG within 48h prior to cardiac operation did not prolong ICU length of stay or hospital length of stay, nor did it increase the risk of death or renal failure after an operation. CONCLUSION: Undergoing CAG within 48 hours before cardiac surgery increases the risk of postoperative AKI.

Network Meta-Analysis on the Mechanisms Underlying Alcohol Augmentation of COVID-19 Pathologies.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is a worldwide crisis caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Many COVID-19 patients present with fever in the early phase, with some progressing to a hyperinflammatory phase. Ethanol (EtOH) exposure may lead to systemic inflammation. Network meta-analysis was conducted to examine possible relationships between EtOH consumption and COVID-19 pathologies. METHODS: Molecules affected by EtOH exposure were identified by analysis with QIAGEN Knowledge Base. Molecules affected by COVID-19 were identified from studies in MEDLINE, bioRxiv, and medRxiv reporting gene expression profiles in COVID-19 patients, QIAGEN Coronavirus Network Explorer, and analysis of the RNA-sequencing data of autopsied lungs of COVID-19 patients retrieved from the GEO database. Network meta-analysis was then conducted on these molecules using QIAGEN Ingenuity Pathway Analysis (IPA). RESULTS: Twenty-eight studies reporting significant gene expression changes in COVID-19 patients were identified. One RNA-sequencing dataset on autopsied lungs of COVID-19 patients was retrieved from GEO. Our network meta-analysis suggests that EtOH exposure may augment the effects of SARS-CoV-2 infection on hepatic fibrosis signaling pathway, cellular metabolism and homeostasis, inflammation, and neuroinflammation. EtOH may also enhance the activity of key mediators including cytokines, such as IL-1ß, IL-6, and TNF, and transcription factors, such as JUN and STAT, while inhibiting the activity of anti-inflammatory mediators including glucocorticoid receptor. Furthermore, IL-1ß, IL-6, TNF, JUN, and STAT were mapped to 10 pathways predicted to associate with SARS-CoV-2 proteins, including HMGB1, IL-1, and IL-6 signaling pathways. CONCLUSIONS: Our meta-analyses demonstrate that EtOH exposure may augment SARS-CoV-2-induced inflammation by altering the activity of key inflammatory mediators. Our findings suggest that it is important for clinicians to caution patients about the risk of alcohol consumption, which has increased during the COVID-19 pandemic. The findings also call for further investigation into how alcohol exposure affects viral infections.

Surgical Treatment of Primary Cardiac Paragangliomas: A Single-Center Experience.

BACKGROUND: Cardiac paragangliomas are rare neuroendocrine tumors that will cause significant morbidity if left undiagnosed. Because of the paucity of cohort data, their rapid diagnosis and appropriate management still pose unique challenges to cardiac surgeons. We aimed to investigate the clinical features and surgical management of primary cardiac paragangliomas in our single center. METHODS: From May 2014 to October 2020, patients diagnosed with primary cardiac paragangliomas retrospectively were reviewed. Demographic data, clinical presentation, preoperative imaging methods, surgical resection, perioperative management, histological analysis, and outcomes were recorded. Postoperative follow up also was reviewed. RESULTS: With multiple imaging methods, including echocardiography, computed tomography, positron-emission tomographic-computed tomography, and biochemical tests, there were five cases of primary cardiac paraganglioma verified by postoperative immunohistochemical staining, two of which were hormonally active. There were no metastatic cardiac paragangliomas, according to positron-emission tomographic-computed tomography, and all patients accepted surgical treatment. Preoperative adrenoceptor blockade was given to hormonally active patients, accordingly. Complete resection of the tumor was accomplished under cardiopulmonary bypass in each case. Tumor distribution included two masses on the roof of the left atrium, two masses in the right atrioventricular groove, and one between the ascending aorta and main pulmonary artery. Immunohistochemical staining for chromogranin, neuron-specific enolase, synaptophysin, and S-100 were positive, which were typical of cardiac paraganglioma. There were no operative deaths. All the patients had an uneventful recovery except one patient who underwent low cardiac output syndrome. During follow up (mean 4.2 years, range 0.6-7.0 years), all patients were well with New York Heart Association class I or II. Only one patient developed thyroid carcinoma three years after surgery but with no paraganglioma recurrence during periodic computed tomography, and this patient recovered well after thyroidectomy. CONCLUSION: Although cardiac paragangliomas are rare and may present surgical challenges for clinicians, surgical resection remains the choice of treatment with favorable outcomes through a multidisciplinary heart team. Moreover, lifelong surveillance still is recommended to detect possible recurrence or associated nonchromaffin tumors in time.

Palmitic Acid Lipotoxicity in Microglia Cells Is Ameliorated by Unsaturated Fatty Acids.

Obesity and metabolic syndrome are associated with cognitive decline and dementia. Palmitic acid (PA) is increased in the cerebrospinal fluid of obese patients with cognitive impairment. This study was therefore designed to examine fatty acid (FA) lipotoxicity in BV2 microglia cells. We found that PA induced time- and dose-dependent decrease in cell viability and increase in cell death without affecting the cell cycle profile and that PA lipotoxicity did not depend on cell surface free fatty acid receptors but rather on FA uptake. Treatment with sulfosuccinimidyl oleate (SSO), an irreversible inhibitor of fatty acid translocase CD36, significantly inhibited FA uptake in BSA- and PA-treated cells and blocked PA-induced decrease in cell viability. Inhibition of ER stress or treatment with N-acetylcysteine was not able to rescue PA lipotoxicity. Our study also showed that unsaturated fatty acids (UFAs), such as linoleic acid (LA), oleic acid (OA), α-linolenic acid (ALA), and docosahexaenoic acid (DHA), were not lipotoxic but instead protected microglia against PA-induced decrease in cell viability. Co-treatment of PA with LA, OA, and DHA significantly inhibited FA uptake in PA-treated cells. All UFAs tested induced the incorporation of FAs into and the amount of neutral lipids, while PA did not significantly affect the amount of neutral lipids compared with BSA control.

Molecular Mechanisms of Palmitic Acid Augmentation in COVID-19 Pathologies.

The coronavirus disease 2019 (COVID-19) pandemic has claimed over 2.7 million lives globally. Obesity has been associated with increased severity and mortality of COVID-19. However, the molecular mechanisms by which obesity exacerbates COVID-19 pathologies are not well-defined. The levels of free fatty acids (FFAs) are elevated in obese subjects. This study was therefore designed to examine how excess levels of different FFAs may affect the progression of COVID-19. Biological molecules associated with palmitic acid (PA) and COVID-19 were retrieved from QIAGEN Knowledge Base, and Ingenuity Pathway Analysis tools were used to analyze these datasets and explore the potential pathways affected by different FFAs. Our study found that one of the top 10 canonical pathways affected by PA was the coronavirus pathogenesis pathway, mediated by key inflammatory mediators, including PTGS2; cytokines, including IL1ß and IL6; chemokines, including CCL2 and CCL5; transcription factors, including NFκB; translation regulators, including EEF1A1; and apoptotic mediators, including BAX. In contrast, n-3 fatty acids may attenuate PA's activation of the coronavirus pathogenesis pathway by inhibiting the activity of such mediators as IL1ß, CCL2, PTGS2, and BAX. Furthermore, PA may modulate the expression of ACE2, the main cell surface receptor for the SARS-CoV-2 spike protein.

Meta-Analysis of Methamphetamine Modulation on Amyloid Precursor Protein through HMGB1 in Alzheimer's Disease.

The deposition of amyloid-beta (Aß) through the cleavage of amyloid-beta precursor protein (APP) is a biomarker of Alzheimer's disease (AD). This study used QIAGEN Ingenuity Pathway Analysis (IPA) to conduct meta-analysis on the molecular mechanisms by which methamphetamine (METH) impacts AD through modulating the expression of APP. All the molecules affected by METH and APP were collected from the QIAGEN Knowledge Base (QKB); 78 overlapping molecules were identified. Upon simulation of METH exposure using the "Molecule Activity Predictor" feature, eight molecules were found to be affected by METH and exhibited activation relationships on APP expression at a confidence of p = 0.000453 (Z-score = 3.51, two-tailed). Core Analysis of these eight molecules identified High Mobility Group Box protein 1 (HMGB1) signaling pathway among the top 5 canonical pathways with most overlap with the 8-molecule dataset. Simulated METH exposure increased APP expression through HMGB1 at a confidence of p < 0.00001 (Z-score = 7.64, two-tailed). HMGB1 is a pathogenic hallmark in AD progression. It not only increases the production of inflammatory mediators, but also mediates the disruption of the blood-brain barrier. Our analyses suggest the involvement of HMGB1 signaling pathway in METH-induced modulation of APP as a potential casual factor of AD.

Imaging pediatric acute head trauma using 100-kVp low dose CT with adaptive statistical iterative reconstruction (ASIR-V) in single rotation on a 16 cm wide-detector CT.

OBJECTIVE: To demonstrate the ability of achieving low dose and high-quality head CT images for children with acute head trauma using 100 kVp and adaptive statistical iterative reconstruction (ASIR-V) algorithm in single rotation on a 16 cm wide-detector system. MATERIALS AND METHODS: We retrospectively analyzed the CT dose index (CTDI) and image quality of 104 children aged 0-6 years with acute head trauma (1 hour -3 days) in two groups: Group 1(n = 50) on a 256-row CT with single rotation at a reduced-dose of 100 kVp/240 mA and reconstructed using ASIR-V at 70%level; Group 2(n = 54) on a 64-row CT with multiple rotations at a standard dose of 120 kVp/ 180mA and reconstructed using a conventional filtered back-projection (FBP). Both groups used the 0.5 s/r axial scan mode. CT dose index (CTDI) and quantitative image quality measurements were compared using the Student t test; qualitative image quality comparison was carried out using Mann-Whitney rank test and the inter-reviewer agreement was evaluated using Kappa test. RESULTS: The exposure time was 0.5 s for Group 1 and 3.27±0.29 s for Group 2. The CTDI in Group 1 was 9.74±0.86mGy, 36.38%lower than the 15.31mGy in Group 2 (p < 0.001). Group 1 and Group 2 had similar artifact index (2.06±1.06 vs. 2.37±1.18) in the cerebellar hemispheres, and similar contrast-to-noise ratio (2.32±0.83 vs. 1.69±0.68), (1.47±0.72 vs. 1.10±0.43) respectively for cerebellum and thalamus (p > 0.05). Image quality was acceptable for diagnosis, and motion artifacts were reduced in Group 1 (p < 0.001). CONCLUSION: Single rotation CT with 100 kVp and 70%ASIR-V on 16 cm wide-detector CT reduces radiation dose and motion artifacts for children with acute head trauma without compromising diagnostic quality as compared with standard dose protocol. Thus, it provides a novel imaging method in management of pediatric acute head trauma.

Evolution of CT findings in patients with mild COVID-19 pneumonia.

OBJECTIVES: To delineate the evolution of CT findings in patients with mild COVID-19 pneumonia. METHODS: CT images and medical records of 88 patients with confirmed mild COVID-19 pneumonia, a baseline CT, and at least one follow-up CT were retrospectively reviewed. CT features including lobar distribution and presence of ground glass opacities (GGO), consolidation, and linear opacities were analyzed on per-patient basis during each of five time intervals spanning the 3 weeks after disease onset. Total severity scores were calculated. RESULTS: Of patients, 85.2% had travel history to Wuhan or known contact with infected individuals. The most common symptoms were fever (84.1%) and cough (56.8%). The baseline CT was obtained on average 5 days from symptom onset. Four patients (4.5%) had negative initial CT. Significant differences were found among the time intervals in the proportion of pulmonary lesions that are (1) pure GGO, (2) mixed attenuation, (3) mixed attenuation with linear opacities, (4) consolidation with linear opacities, and (5) pure consolidation. The majority of patients had involvement of ≥ 3 lobes. Bilateral involvement was more prevalent than unilateral involvement. The proportions of patients observed to have pure GGO or GGO and consolidation decreased over time while the proportion of patients with GGO and linear opacities increased. Total severity score showed an increasing trend in the first 2 weeks. CONCLUSIONS: While bilateral GGO are predominant features, CT findings changed during different time intervals in the 3 weeks after symptom onset in patients with COVID-19. KEY POINTS: • Four of 88 (4.5%) patients with COVID-19 had negative initial CT. • Majority of COVID-19 patients had abnormal CT findings in ≥ 3 lobes. • A proportion of patients with pure ground glass opacities decreased over the 3 weeks after symptom onset.

Evaluation of dynamic lung changes during coronavirus disease 2019 (COVID-19) by quantitative computed tomography.

OBJECTIVES: This study aims to trace the dynamic lung changes of coronavirus disease 2019 (COVID-19) using computed tomography (CT) images by a quantitative method. METHODS: In this retrospective study, 28 confirmed COVID-19 cases with 145 CT scans are collected. The lesions are detected automatically and the parameters including lesion volume (LeV/mL), lesion percentage to lung volume (LeV%), mean lesion density (MLeD/HU), low attenuation area lower than - 400HU (LAA-400%), and lesion weight (LM/mL*HU) are computed for quantification. The dynamic changes of lungs are traced from the day of initial symptoms to the day of discharge. The lesion distribution among the five lobes and the dynamic changes in each lobe are also analyzed. RESULTS: LeV%, MLeD, and LM reach peaks on days 9, 6 and 8, followed by a decrease trend in the next two weeks. LAA-400% (mostly the ground glass opacity) declines to the lowest on days 4-5, and then increases. The lesion is mostly seen in the bilateral lower lobes, followed by the left upper lobe, right upper lobe and right middle lobe (p < 0.05). The right middle lobe is the earliest one (on days 6-7), while the right lower lobe is the latest one (on days 9-10) that reaches to peak among the five lobes. CONCLUSIONS: Severity of COVID-19 increases from the day of initial symptoms, reaches to the peak around on day 8, and then decreases. Lesion is more commonly seen in the bilateral lower lobes.

Imaging the Infant Chest without Sedation: Feasibility of Using Single Axial Rotation with 16-cm Wide-Detector CT.

Purpose To compare image quality, patient preparation time, and radiation dose using a single axial rotation with 16-cm wide-detector computed tomography (CT) in imaging the infant chest without sedation with those in infants examined by using a 64-row CT and sedation. Materials and Methods Thirty-two infants (group 1) were prospectively enrolled to undergo nonenhanced chest CT without sedation using a single axial rotation on a 16-cm wide-detector CT scanner. Patients were imaged with automatic tube current modulation and tube voltages of 80 kVp for patients weighing 5 kg or less and 100 kVp for patients weighing more than 5 kg. Patient preparation time, CT dose index (CTDI), dose-length product (DLP), and image quality were compared with those in a historical control group consisting of 30 infants (group 2) who underwent conventional helical scanning with sedation performed by using a 64-row volume CT scanner. The Student t test for independent samples was used to assess continuous variables. The Mann-Whitney rank test and the κ test were used to evaluate image quality. Results There was no statistically significant difference in body weight, age, mean CT attenuation value, image noise, and subjective image quality score between the two groups. However, compared with the group scanned by using a 64-row volume CT scanner (group 2), group 1 experienced significantly reduced scan time by 83% (0.35 second vs 2.01 seconds ± 0.21 [standard deviation]), preparation time by 57% (41.25 minutes ± 103.78 vs 96.5 minutes ± 151.77), CTDI by 42% (2.03 mGy ± 0.4 vs 3.52 mGy ± 0.03), and DLP by 52% (27.07 mGy·cm ± 6.97 vs 55.84 mGy·cm ± 6.46) (P < .05 for all). Conclusion Compared with conventional 64-row helical CT with sedation, use of a single axial rotation with 16-cm wide-detector CT in imaging the infant chest without sedation can reduce radiation dose, preparation time, and total scan time, while providing comparable image quality. © RSNA, 2017.

Endoscopic therapy and curative effect in pituitary adenoma patients complicated by acromegalic cardiomyopathy.

The study aimed to retrospectively analyze the clinical characteristics of patients with pituitary adenomas complicated by acromegalic cardiomyopathy and to evaluate the effect of endoscopic surgery. Eighty-six pituitary adenoma patients complicated by acromegalic cardiomyopathy who were treated with endoscopic surgery in the First Affiliated Hospital of Soochow University from January 2010 to December 2016 were enrolled. We noted patient clinical characteristics and explored the relationships with surgical treatment. Before and after surgery, all patients underwent an examination of pituitary endocrinology, brain magnetic resonance (MR), and echocardiography. The serum levels of growth hormone (GH), left ventricular end-diastolic diameter (LVIDd), interventricular septal thickness (IVST), left ventricular posterior wall thickness (LVPWT), left ventricular ejection fraction (EF), and mitral valve (E/A ratio) were examined with non-invasive methods, and the results were compared. Of the 86 patients, there were 23 with microadenomas, 27 with large adenomas, and 36 with giant adenomas. There were 28 patients with invasive adenomas and 58 with non-invasive adenomas. The pre-operative mean GH level was 71.23 ± 3.29 µg/L, which was positively correlated with tumor volume (r = 0.751, P < 0.01). Via trans-sphenoidal endoscopic pituitary adenoma resection, 51 patients underwent total tumor resections, 25 underwent subtotal resections, 8 underwent major part resections, and 2 underwent partial resections. After surgery, the GH mean level was 3.81 ± 1.03 µg/L, which was significantly different (t = 3.72, P < 0.01) from the pre-operative level. Cardiac function indices, including LVIDd, IVST, LVPWT, E/A, and EF, were significantly improved. The long-term curative rate was 39.17% and the remission rate was 77.29%. For pituitary adenoma patients complicated by acromegalic cardiomyopathy, endoscopic surgery resulted in a good curative effect and the growth hormone levels were maintained, which can significantly improve cardiac structure and function.

A bubble-template approach for assembling Ni-Co oxide hollow microspheres with an enhanced electrochemical performance as an anode for lithium ion batteries.

Although significant advancements in the preparation of metal oxide hollow structures have been achieved, most synthesis routes have some complicated aspects such as requiring a hard-template, multistep procedures or other special reagents. This paper proposes a green and facile bubble-template approach to synthesize and organize Ni-Co hollow microspheres. The entire formation mechanism for the hollow spherical structures, including integration for nucleation, morphological tailoring and an Ostwald ripening process, has been elucidated based on time-dependent observations. The Ni-Co hollow microspheres revealed an excellent cycling stability (730 mA h g(-1) even after 140 cycles at 300 mA g(-1)) and good rate capability when evaluated as an anode material for lithium ion batteries (LIBs). The excellent electrochemical performance can be attributed to the rational design and organization of the hollow structures, which offer a large void space for accommodating volume changes, shorten the diffusion path for Li ions and electron transfer, as well as increase the contact area between the electrodes and electrolyte. Moreover, the synergistic effects of the nickel and cobalt ions with different lithiation potentials allowed the volume change to occur in a stepwise manner. The bubble-template strategy was convenient and very effective for constructing the hollow structures, and if well engineered, it could be extended to the synthesis of other advanced metal oxide anode materials for high energy storage devices and many other applications.

Activation of pyruvate dehydrogenase by dichloroacetate has the potential to induce epigenetic remodeling in the heart.

Dichloroacetate (DCA) promotes pyruvate entry into the Krebs cycle by inhibiting pyruvate dehydrogenase (PDH) kinase and thereby maintaining PDH in the active dephosphorylated state. DCA has recently gained attention as a potential metabolic-targeting therapy for heart failure but the molecular basis of the therapeutic effect of DCA in the heart remains a mystery. Once-daily oral administration of DCA alleviates pressure overload-induced left ventricular remodeling. We examined changes in the metabolic fate of pyruvate carbon (derived from glucose) entering the Krebs cycle by metabolic interventions of DCA. (13)C6-glucose pathway tracing analysis revealed that instead of being completely oxidized in the mitochondria for ATP production, DCA-mediated PDH dephosphorylation results in an increased acetyl-CoA pool both in control and pressure-overloaded hearts. DCA induces hyperacetylation of histone H3K9 and H4 in a dose-dependent manner in parallel to the dephosphorylation of PDH in cultured cardiomyocytes. DCA administration increases histone H3K9 acetylation in in vivo mouse heart. Interestingly, DCA-dependent histone acetylation was associated with an up-regulation of 2.3% of genes (545 out of 23,474 examined). Gene ontology analysis revealed that these genes are highly enriched in transcription-related categories. This evidence suggests that sustained activation of PDH by DCA results in an overproduction of acetyl-CoA, which exceeds oxidation in the Krebs cycle and results in histone acetylation. We propose that DCA-mediated PDH activation has the potential to induce epigenetic remodeling in the heart, which, at least in part, forms the molecular basis for the therapeutic effect of DCA in the heart.

Pyroptosis-Related Genes as Diagnostic Markers in Chronic Obstructive Pulmonary Disease and Its Correlation with Immune Infiltration.

Background: Chronic obstructive pulmonary disease (COPD) stands as a predominant cause of global morbidity and mortality. This study aims to elucidate the relationship between pyroptosis-related genes (PRGs) and COPD diagnosis in the context of immune infiltration, ultimately proposing a PRG-based diagnostic model for predicting COPD outcomes. Methods: Clinical data and PRGs of COPD patients were sourced from the GEO database. The "ConsensusClusterPlus" package was employed to generate molecular subtypes derived from PRGs that were identified through differential expression analysis and LASSO Cox analysis. A diagnostic signature including eight genes (CASP4, CASP5, ELANE, GPX4, NLRP1, GSDME, NOD1and IL18) was also constructed. Immune cell infiltration calculated by the ESTIMATE score, Stroma scores and Immune scores were also compared on the basis of pyroptosis-related molecular subtypes and the risk signature. We finally used qRT - PCR to detect the expression levels of eight genes in COPD patient and normal. Results: The diagnostic model, anchored on eight PRGs, underwent validation with an independent experimental cohort. The area under the receiver operating characteristic (ROC) curves (AUC) for the diagnostic model showcased values of 0.809, 0.765, and 0.956 for the GSE76925, GSE8545, and GSE5058 datasets, respectively. Distinct expression patterns and clinical attributes of PRGs were observed between the comparative groups, with functional analysis underscoring a disparity in immune-related functions between them. Conclusion: In this study, we developed a potential as diagnostic biomarkers for COPD and have a significant role in modulating the immune response. Such insights pave the way for novel diagnostic and therapeutic strategies for COPD.

Acute hyperglycaemia enhances oxidative stress and aggravates myocardial ischaemia/reperfusion injury: role of thioredoxin-interacting protein.

Hyperglycaemia during acute myocardial infarction is common and associated with increased mortality. Thioredoxin-interacting protein (Txnip) is a modulator of cellular redox state and contributes to cell apoptosis. This study aimed to investigate whether or not hyperglycaemia enhances Txnip expression in myocardial ischaemia/reperfusion (MI/R) and consequently exacerbates MI/R injury. Rats were subjected to 30 min. of left coronary artery ligation followed by 4 hrs of reperfusion and treated with saline or high glucose (HG, 500 g/l, 4 ml/kg/h intravenously). In vitro study was performed on cultured rat cardiomyocytes subjected to simulated ischaemia/reperfusion (SI/R) and incubated with HG (25 mM) or normal glucose (5.6 mM) medium. In vivo HG infusion during MI/R significantly impaired cardiac function, aggravated myocardial injury and increased cardiac oxidative stress. Meanwhile, Txnip expression was enhanced whereas thioredoxin activity was inhibited following HG treatment in ischaemia/reperfusion (I/R) hearts. In addition, HG activated p38 MAPK and inhibited Akt in I/R hearts. In cultured cardiomyocytes subjected to SI/R, HG incubation stimulated Txnip expression and reduced thioredoxin activity. Overexpression of Txnip enhanced HG-induced superoxide generation and aggravated cardiomyocyte apoptosis, whereas Txnip RNAi significantly blunted the deleterious effects of HG. Moreover, inhibition of p38 MAPK or activation of Akt markedly blocked HG-induced Txnip expression in I/R cardiomyocytes. Most importantly, intramyocardial injection of Txnip siRNA markedly decreased Txnip expression and alleviated MI/R injury in HG-treated rats. Hyperglycaemia enhances myocardial Txnip expression, possibly through reciprocally modulating p38 MAPK and Akt activation, leading to aggravated oxidative stress and subsequently, amplification of cardiac injury following MI/R.

Catalpol decreases peroxynitrite formation and consequently exerts cardioprotective effects against ischemia/reperfusion insult.

CONTEXT: Peroxynitrite (ONOO(-)) formation triggers oxidative/nitrative stress and contributes to exacerbated myocardial ischemia/reperfusion (MI/R) injury. Catalpol, an iridoid glycoside, abundantly found in the roots of Rehmannia glutinosa L. that is included in the family Phrymaceae in the order Lamiales, endemic to China, was found to have neuroprotective effects. However, the effect of catalpol on MI/R injury has not been identified. OBJECTIVE: This study investigated whether catalpol attenuates oxidative/nitrative stress in acute MI/R. MATERIALS AND METHODS: Adult male rats were subjected to 30 min of myocardial ischemia and 3 h of reperfusion and were treated with saline, catalpol (5 mg/kg, i.p., 5 min before reperfusion) or catalpol plus wortmannin (15 µg/kg intraperitoneally injected 15 min before reperfusion). RESULTS: Pretreatment with catalpol significantly improved cardiac functions, reduced myocardial infarction, apoptosis and necrosis of cardiomyocytes after MI/R (all p < 0.05). Meanwhile, ONOO(-) formation was markedly reduced after catalpol treatment (3.01 ± 0.22 vs. 4.66 ± 0.53 pmol/mg protein in vehicle, p < 0.05). In addition, catalpol increased Akt and endothelial nitric oxide synthase phosphorylation, nitric oxide (NO) production, anti-oxidant capacity and reduced MI/R-induced inducible nitric oxide synthase expression and superoxide anion (·O(2)(-)) production in I/R hearts. PI3K inhibitor wortmannin not only blocked catalpol-induced Akt activation, but also attenuated all the beneficial effects of catalpol. Suppression of ONOO(-) formation by either catalpol or an ONOO(-) scavenger uric acid (5 mg/kg) reduced myocardial infarct size in MI/R rats. DISCUSSION AND CONCLUSION: In conclusion, catalpol affords cardioprotection against MI/R insult by attenuating ONOO(-) formation, which is attributable to increased physiological NO and decreased ·O(2)(-) production.

Elevated branched-chain amino acid promotes atherosclerosis progression by enhancing mitochondrial-to-nuclear H2O2-disulfide HMGB1 in macrophages.

As the essential amino acids, branched-chain amino acid (BCAA) from diets is indispensable for health. BCAA supplementation is often recommended for patients with consumptive diseases or healthy people who exercise regularly. Latest studies and ours reported that elevated BCAA level was positively correlated with metabolic syndrome, diabetes, thrombosis and heart failure. However, the adverse effect of BCAA in atherosclerosis (AS) and its underlying mechanism remain unknown. Here, we found elevated plasma BCAA level was an independent risk factor for CHD patients by a human cohort study. By employing the HCD-fed ApoE-/- mice of AS model, ingestion of BCAA significantly increased plaque volume, instability and inflammation in AS. Elevated BCAA due to high dietary BCAA intake or BCAA catabolic defects promoted AS progression. Furthermore, BCAA catabolic defects were found in the monocytes of patients with CHD and abdominal macrophages in AS mice. Improvement of BCAA catabolism in macrophages alleviated AS burden in mice. The protein screening assay revealed HMGB1 as a potential molecular target of BCAA in activating proinflammatory macrophages. Excessive BCAA induced the formation and secretion of disulfide HMGB1 as well as subsequent inflammatory cascade of macrophages in a mitochondrial-nuclear H2O2 dependent manner. Scavenging nuclear H2O2 by overexpression of nucleus-targeting catalase (nCAT) effectively inhibited BCAA-induced inflammation in macrophages. All of the results above illustrate that elevated BCAA promotes AS progression by inducing redox-regulated HMGB1 translocation and further proinflammatory macrophage activation. Our findings provide novel insights into the role of animo acids as the daily dietary nutrients in AS development, and also suggest that restricting excessive dietary BCAA consuming and promoting BCAA catabolism may serve as promising strategies to alleviate and prevent AS and its subsequent CHD.

Accuracy assessment of pharmacogenetic algorithms for warfarin dose prediction in Chinese patients.

A few warfarin pharmacogenetic dosing algorithms have been proposed,based on multiethnic or homogeneous populations, to estimate warfarin therapeutic doses. However, it remains to be proven that which algorithm is accurate in predicting warfarin dose in Chinese people. We selected eight warfarin dose predictive pharmacogenetic algorithms and retrospectively assessed the predictive accuracy of each algorithm in a total of 368 eligible outpatients by comparing the actual stable therapeutic dose to the dose predicted by the algorithm. Our results showed that a high level of performance was demonstrated by three algorithms,Gage et al., Anderson et al., and Wu et al., having a similar performance in coefficient of determination (R2) and percentage of patients predicted dose within 20% of actual dose. The Gage et al. algorithm had the lowest mean absolute error (MAE). These results indicated that the algorithm by Gage et al. provided a more accurate prediction than did the others,which suggests that this pharmacogenetic algorithm might be used in clinical practice to guide rational administration of warfarin.