Association Between Red Cell Distribution Width and Liver Injury after Cardiac and Aortic Aneurysm Surgery with Cardiopulmonary Bypass.

OBJECTIVES: This study aimed to investigate the association between preoperative red blood cell distribution width (RDW) levels and liver injury (LI) after cardiac surgery, to highlight RDW's usefulness in the early identification and intervention for patients at high risk of LI. DESIGN: A retrospective observational study. SETTING: A university-affiliated teaching hospital and tertiary referral center. PARTICIPANTS: Adult patients who underwent cardiac and aortic aneurysm surgery at Changhai Hospital in 2021. INTERVENTIONS: Postoperative LI was defined by increased liver enzyme levels and/or hyperbilirubinemia, noted from the time of surgery to discharge. Logistic regression analyses were conducted to examine the RDW-LI relationship, with stratified analyses based on age, gender, and anemia. Survival within 30 days was assessed using the Kaplan-Meier method, with survival curve differences analyzed via the log-rank test. The study included 3 sets of sensitivity analyses. MEASUREMENTS AND MAIN RESULTS: Postoperative LI was observed in 75 patients (10%). Multivariate regression analysis showed a significant association between high RDW levels and postoperative LI (adjusted odds ratio, 3.25; p = 0.033; 95% confidence intefal, 1.10-9.63), even after adjusting for all covariates. This association remained consistent across 3 sets of sensitivity analyses. Subgroup analysis showed men had a higher correlation with LI (p for interaction = 0.041). Kaplan-Meier analysis indicated a significantly lower survival rate in the LI group (76%) compared with the non-LI group (99.6%; p < 0.001). CONCLUSIONS: Preoperative RDW levels are significantly associated with postoperative LI. RDW could serve as a significant useful marker for early detection and intervention in patients at high risk of LI, thereby potentially improving patient outcomes.

Immunosuppression and phenotypic plasticity in an atlas of human hepatocholangiocarcinoma.

Background: Hepatocholangiocarcinoma (H-ChC) has the clinicopathological features of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) and is a more aggressive subtype of primary hepatic carcinoma than HCC or iCCA. Methods: We sequenced 91,112 single-cell transcriptomes from 16 human samples to elucidate the molecular mechanisms underlying the coexistence of HCC and iCCA components in H-ChC. Results: We observed two molecular subtypes of H-ChC at the whole-transcriptome level (CHP and CIP), where a metabolically active tumour cell subpopulation enriched in CHP was characterized by a cellular pre-differentiation property. To define the heterogeneity of tumours and their associated microenvironments, we observe greater tumour diversity in H-ChC than HCC and iCCA. H-ChC exhibits weaker immune cell infiltration and greater CD8+ exhausted T cell (Tex) dysfunction than HCC and iCCA. Then we defined two broad cell states of 6,852 CD8+ Tex cells: GZMK+ CD8+ Tex cells and terminal CD8+ Tex cells. GZMK+ CD8+ Tex cells exhibited higher infiltration of after treatment in H-ChC, the effector scores and expression of the immune checkpoints of them greatly increased after immunotherapy, which indicated that H-ChC might be more sensitive than HCC or iCCA to immunotherapy. Conclusions: In this paper, H-ChC was explored, hoping to contribute to the study of mixed tumours in other cancers.

The incidence, risk factors, and prognosis of acute kidney injury in patients after cardiac surgery.

Background: Acute kidney injury (AKI) represents a significant complication following cardiac surgery, associated with increased morbidity and mortality rates. Despite its clinical importance, there is a lack of universally applicable and reliable methods for the early identification and diagnosis of AKI. This study aimed to examine the incidence of AKI after cardiac surgery, identify associated risk factors, and evaluate the prognosis of patients with AKI. Method: This retrospective study included adult patients who underwent cardiac surgery at Changhai Hospital between January 7, 2021, and December 31, 2021. AKI was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Perioperative data were retrospectively obtained from electronic health records. Logistic regression analyses were used to identify independent risk factors for AKI. The 30-day survival was assessed using the Kaplan-Meier method, and differences between survival curves for different AKI severity levels were compared using the log-rank test. Results: Postoperative AKI occurred in 257 patients (29.6%), categorized as stage 1 (179 patients, 20.6%), stage 2 (39 patients, 4.5%), and stage 3 (39 patients, 4.5%). The key independent risk factors for AKI included increased mean platelet volume (MPV) and the volume of intraoperative cryoprecipitate transfusions. The 30-day mortality rate was 3.2%. Kaplan-Meier analysis showed a lower survival rate in the AKI group (89.1%) compared to the non-AKI group (100%, P < 0.001). Conclusion: AKI was notably prevalent following cardiac surgery in this study, significantly impacting survival rates. Notably, MPV and administration of cryoprecipitate may have new considerable predictive significance. Proactive identification and management of high-risk individuals are essential for reducing postoperative complications and mortality.

Pharmacology of Hydrogen Sulfide and Its Donors in Cardiometabolic Diseases.

Cardiometabolic diseases (CMDs) are major contributors to global mortality, emphasizing the critical need for novel therapeutic interventions. Hydrogen sulfide (H2S) has garnered enormous attention as a significant gasotransmitter with various physiological, pathophysiological, and pharmacological impacts within mammalian cardiometabolic systems. In addition to its roles in attenuating oxidative stress and inflammatory response, burgeoning research emphasizes the significance of H2S in regulating proteins via persulfidation, a well known modification intricately associated with the pathogenesis of CMDs. This review seeks to investigate recent updates on the physiological actions of endogenous H2S and the pharmacological roles of various H2S donors in addressing diverse aspects of CMDs across cellular, animal, and clinical studies. Of note, advanced methodologies, including multiomics, intestinal microflora analysis, organoid, and single-cell sequencing techniques, are gaining traction due to their ability to offer comprehensive insights into biomedical research. These emerging approaches hold promise in characterizing the pharmacological roles of H2S in health and diseases. We will critically assess the current literature to clarify the roles of H2S in diseases while also delineating the opportunities and challenges they present in H2S-based pharmacotherapy for CMDs. SIGNIFICANCE STATEMENT: This comprehensive review covers recent developments in H2S biology and pharmacology in cardiometabolic diseases CMDs. Endogenous H2S and its donors show great promise for the management of CMDs by regulating numerous proteins and signaling pathways. The emergence of new technologies will considerably advance the pharmacological research and clinical translation of H2S.

STING Contributes to Pulmonary Hypertension by Targeting IFN and BMPR2 Signaling through Regulating of F2RL3.

Pulmonary hypertension (PH) is an incurable disease characterized by pulmonary vascular remodeling. Endothelial injury and inflammation are the key triggers of disease initiation. Recent findings suggest that STING (stimulator of IFN genes) activation plays a critical role in endothelial dysfunction and IFN signaling. Here, we investigated the involvement of STING in the pathogenesis of PH. Patients with PH and rodent PH model samples, a Sugen 5416/hypoxia PH model, and pulmonary artery endothelial cells (PAECs) were used to evaluate the hypothesis. We found that the cyclic guanosine monophosphate-AMP synthase-STING signaling pathway was activated in lung tissues from rodent PH models and patients with PH and in TNF-α-induced PAECs in vitro. Specifically, STING expression was significantly elevated in the endothelial cells in PH disease settings. In the Sugen 5416/hypoxia mouse model, genetic knockout or pharmacological inhibition of STING prevented the progression of PH. Functionally, knockdown of STING reduced the proliferation and migration of PAECs. Mechanistically, STING transcriptionally regulates its binding partner F2RL3 (F2R-like thrombin or trypsin receptor 3) through the STING-NF-κB axis, which activated IFN signaling and repressed BMPR2 (bone morphogenetic protein receptor 2) signaling both in vitro and in vivo. Further analysis revealed that F2RL3 expression was increased in PH settings and identified negative feedback regulation of F2RL3/BMPR2 signaling. Accordingly, a positive correlation of expression amounts between STING and F2RL3/IFN-stimulated genes was observed in vivo. Our findings suggest that STING activation in PAECs plays a critical role in the pathobiology of PH. Targeting STING may be a promising therapeutic strategy for preventing the development of PH.

o8G Site-Specifically Modified tRF-1-AspGTC: A Novel Therapeutic Target and Biomarker for Pulmonary Hypertension.

BACKGROUND: Hypoxia and oxidative stress contribute to the development of pulmonary hypertension (PH). tRNA-derived fragments play important roles in RNA interference and cell proliferation, but their epitranscriptional roles in PH development have not been investigated. We aimed to gain insight into the mechanistic contribution of oxidative stress-induced 8-oxoguanine in pulmonary vascular remodeling. METHODS: Through small RNA modification array analysis and quantitative polymerase chain reaction, a significant upregulation of the 8-oxoguanine -modified tRF-1-AspGTC was found in the lung tissues and the serum of patients with PH. RESULTS: This modification occurs at the position 5 of the tRF-1-AspGTC (5o8G tRF). Inhibition of the 5o8G tRF reversed hypoxia-induced proliferation and apoptosis resistance in pulmonary artery smooth muscle cells. Further investigation unveiled that the 5o8G tRF retargeted mRNA of WNT5A (Wingless-type MMTV integration site family, member 5A) and CASP3 (Caspase3) and inhibited their expression. Ultimately, BMPR2 (Bone morphogenetic protein receptor 2) -reactive oxygen species/5o8G tRF/WNT5A signaling pathway exacerbated the progression of PH. CONCLUSIONS: Our study highlights the role of site-specific 8-oxoguanine-modified tRF in promoting the development of PH. Our findings present a promising therapeutic avenue for managing PH and propose 5o8G tRF as a potential innovative marker for diagnosing this disease.

Targeting NKAα1 to treat Parkinson's disease through inhibition of mitophagy-dependent ferroptosis.

Dysfunction of the Na+/K+-ATPase (NKA) has been documented in various neurodegenerative diseases, yet the specific role of NKAα1 in Parkinson's disease (PD) remains incompletely understood. In this investigation, we utilized NKAα1 haploinsufficiency (NKAα1+/-) mice to probe the influence of NKAα1 on dopaminergic (DA) neurodegeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our findings reveal that NKAα1+/- mice displayed a heightened loss of DA neurons and more pronounced motor dysfunction compared to the control group when exposed to MPTP. Intriguingly, this phenomenon coincided with the activation of ferroptosis and impaired mitophagy both in vivo and in vitro. To scrutinize the role and underlying mechanism of NKAα1 in PD, we employed DR-Ab, an antibody targeting the DR-region of the NKA α subunit. Our study demonstrates that the administration of DR-Ab effectively reinstated the membrane abundance of NKAα1, thereby mitigating MPTP-induced DA neuron loss and subsequent improvement in behavioral deficit. Mechanistically, DR-Ab heightened the formation of the surface NKAα1/SLC7A11 complex, inhibiting SLC7A11-dependent ferroptosis. Moreover, DR-Ab disrupted the cytosolic interaction between NKAα1 and Parkin, facilitating the translocation of Parkin to mitochondria and enhancing the process of mitophagy. In conclusion, this study establishes NKAα1 as a key regulator of ferroptosis and mitophagy, identifying its DR-region as a promising therapeutic target for PD.

Untargeted metabolomics reveals potential plasma biomarkers for diagnosis of primary aldosteronism using liquid chromatography-mass spectrometry.

Metabolite profiling has the potential to comprehensively bridge phenotypes and complex heterogeneous physiological and pathological states. We performed a metabolomics study using parallel liquid chromatography-mass spectrometry (LC-MS) combined with multivariate data analysis to screen for biomarkers of primary aldosteronism (PA) from a cohort of 111 PA patients and 218 primary hypertension (PH) patients. Hydrophilic interaction chromatography and reversed-phase liquid chromatography separations were employed to obtain a global plasma metabolome of endogenous metabolites. The satisfactory classification between PA and PH patients was obtained using the MVDA model. A total of 35 differential metabolites were screened out and identified. A diagnostic biomarker panel was established using the least absolute shrinkage and selection operator (LASSO) binary logistic regression model and receiver operating characteristic analysis. Joint analysis with clinical indicators, including plasma supine aldosterone level, plasma orthostatic aldosterone level, body mass index, and blood potassium, revealed that the combination of metabolite biomarker panel and plasma supine aldosterone has the best clinical diagnostic efficacy.

Effects of opioid-free anaesthesia compared with balanced general anaesthesia on nausea and vomiting after video-assisted thoracoscopic surgery: a single-centre randomised controlled trial.

OBJECTIVES: Opioid-free anaesthesia (OFA) has emerged as a promising approach for mitigating the adverse effects associated with opioids. The objective of this study was to evaluate the impact of OFA on postoperative nausea and vomiting (PONV) following video-assisted thoracic surgery. DESIGN: Single-centre randomised controlled trial. SETTING: Tertiary hospital in Shanghai, China. PARTICIPANTS: Patients undergoing video-assisted thoracic surgery were recruited from September 2021 to June 2022. INTERVENTION: Patients were randomly allocated to OFA or traditional general anaesthesia with a 1:1 allocation ratio. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was the incidence of PONV within 48 hours post-surgery, and the secondary outcomes included PONV severity, postoperative pain, haemodynamic changes during anaesthesia, and length of stay (LOS) in the recovery ward and hospital. RESULTS: A total of 86 and 88 patients were included in the OFA and control groups, respectively. Two patients were excluded because of severe adverse events including extreme bradycardia and epilepsy-like convulsion. The incidence and severity of PONV did not significantly differ between the two groups (29 patients (33.0%) in the control group and 22 patients (25.6%) in the OFA group; relative risk 0.78, 95% CI 0.49 to 1.23; p=0.285). Notably, the OFA approach used was associated with an increase in heart rate (89±17 vs 77±15 beats/min, t-test: p<0.001; U test: p<0.001) and diastolic blood pressure (87±17 vs 80±13 mm Hg, t-test: p=0.003; U test: p=0.004) after trachea intubation. Conversely, the control group exhibited more median hypotensive events per patient (mean 0.5±0.8 vs 1.0±2.0, t-test: p=0.02; median 0 (0-4) vs 0 (0-15), U test: p=0.02) during surgery. Postoperative pain scores, and LOS in the recovery ward and hospital did not significantly differ between the two groups. CONCLUSIONS: Our study findings suggest that the implementation of OFA does not effectively reduce the incidence of PONV following thoracic surgery when compared with traditional total intravenous anaesthesia. The opioid-free strategy used in our study may be associated with severe adverse cardiovascular events. TRIAL REGISTRATION NUMBER: ChiCTR2100050738.

Study on the correlation between controlling nutritional status score and clinical biochemical indicators in patients with colorectal cancer.

Purpose: The controlling nutritional status (CONUT) score is an important tool for predicting the prognosis of colorectal cancer (CRC); however, its effectiveness is relatively insufficient. This study aimed to screen for more effective clinical indicators as supplements to the CONUT scoring system and improve the predictive value of CRC prognosis. Patients and methods: Between 2014 and 2020, the clinical information of all CRC patients in our unit was retrospectively collected, and the CONUT scores were calculated based on the levels of serum albumin (ALB), lymphocytes (LC), and total cholesterol. The included patients were divided into the following three groups: normal nutrition (0-1), mild malnutrition (2-4), and moderate-to-severe malnutrition (5-12). The correlations between the CONUT score and baseline characteristics and clinical indicators were evaluated. Results: This study ultimately included 5014 CRC patients. The nutritional status of patients with colon cancer (CC) was worse than that of rectal cancer (RC). The nutritional status was worse in men than in women. The older the patient, the poorer the nutritional status, and the poorer the nutritional status, the longer the hospital stay. In addition, poor nutritional status in patients is indicated by higher values of neutrophils (NE), monocytes (MC), eosinophils (EOS), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), carcinoembryogenic antigen (CEA), and lower values of white blood cells (WBC), basophils (BAS), haemoglobin (HB), total protein (TP), triglycerides (TG), low density lipoprotein (LDL), aspartate transaminase (AST), and blood urea nitrogen (BUN), which was statistically significant (P < 0.05). Indicators that significantly correlated with the CONUT score reflected the immune nutritional status, including WBC (odds ratio [OR] = 0.036, P < 0.001), NE (OR = 30.815, P < 0.001), MC (OR = 41.388, P < 0.001), EOS (OR = 27.577, P < 0.001), BAS (OR = 0.006, P = 0.046), and LDL (OR = 0.319, P < 0.001). Conclusion: Additional variables such as WBC, NE, MC, EOS, BAS, and LDL may be used as supplementary indicators in the CONUT scoring system to more effectively predict the clinical prognosis of CRC patients.

Performance of aldosterone-to-renin ratio before washout of antihypertensive drugs in screening of primary aldosteronism.

OBJECTIVE: The aim of this study is to evaluate performance of aldosterone-to-renin ratio (ARR) before washout of antihypertensive drugs as a screening test for primary aldosteronism (PA). METHODS: This retrospective analysis included consecutive patients suspected of having secondary hypertension during a period from January 2017 to May 2022 at authors' institute. For inclusion in the final analysis, ARR must be available prior to as well as after discontinuation of antihypertensives. Patients with ARR ≥2.4(ng/dL)/(µIU/mL) after washout proceeded to confirmatory tests. Diagnosis of PA was established based on positive result of the confirmatory test. Diagnostic accuracy of ARR prior to the washout in predicting PA are shown as sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). RESULTS: The analysis included a total of 1306 patients [median age of 50.2 (41.0-59.0) years, 64.0% male]. Confirmatory tests showed PA in 215(16.5%) patients and essential hypertension (EH) in the remaining 1091(83.5%) patients. In comparison to the second screening test, the first screening test (before washout of antihypertensives) yielded lower plasma aldosterone and higher renin, and consequently lower ARR in both the PA and EH groups. At a cutoff of 0.7(ng/dL)/(µIU/ml), ARR before washout had 96.3% sensitivity, 61.2% specificity, 0.33 PPV and 0.99 NPV. At a lower cutoff of 0.5(ng/dL)/(µIU/ml), the sensitivity, specificity, PPV and NPV are 97.7%, 52.0%, 0.29 and 0.99. CONCLUSIONS: ARR prior to washout of antihypertensives is a sensitive screening test for PA. Washout of antihypertensives could be omitted and further investigation for PA is not warranted if ARR was ≤ 0.7(ng/dL)/(µIU/ml) before washout.

Disruption of the Na+/K+-ATPase-purinergic P2X7 receptor complex in microglia promotes stress-induced anxiety.

Na+/K+-ATPase (NKA) plays an important role in the central nervous system. However, little is known about its function in the microglia. Here, we found that NKAα1 forms a complex with the purinergic P2X7 receptor (P2X7R), an adenosine 5'-triphosphate (ATP)-gated ion channel, under physiological conditions. Chronic stress or treatment with lipopolysaccharide plus ATP decreased the membrane expression of NKAα1 in microglia, facilitated P2X7R function, and promoted microglia inflammatory activation via activation of the NLRP3 inflammasome. Accordingly, global deletion or conditional deletion of NKAα1 in microglia under chronic stress-induced aggravated anxiety-like behavior and neuronal hyperexcitability. DR5-12D, a monoclonal antibody that stabilizes membrane NKAα1, improved stress-induced anxiety-like behavior and ameliorated neuronal hyperexcitability and neurogenesis deficits in the ventral hippocampus of mice. Our results reveal that NKAα1 limits microglia inflammation and may provide a target for the treatment of stress-related neuroinflammation and diseases.

ErbB3 Governs Endothelial Dysfunction in Hypoxia-Induced Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension, characterized by vascular remodeling, currently lacks curative therapeutic options. The dysfunction of pulmonary artery endothelial cells plays a pivotal role in the initiation and progression of pulmonary hypertension (PH). ErbB3 (human epidermal growth factor receptor 3), also recognized as HER3, is a member of the ErbB family of receptor tyrosine kinases. METHODS: Microarray, immunofluorescence, and Western blotting analyses were conducted to investigate the pathological role of ErbB3. Blood samples were collected for biomarker examination from healthy donors or patients with hypoxic PH. The pathological functions of ErbB3 were further validated in rodents subjected to chronic hypoxia- and Sugen-induced PH, with or without adeno-associated virus-mediated ErbB3 overexpression, systemic deletion, or endothelial cell-specific ErbB3 knockdown. Primary human pulmonary artery endothelial cells and pulmonary artery smooth muscle cells were used to elucidate the underlying mechanisms. RESULTS: ErbB3 exhibited significant upregulation in the serum, lungs, distal pulmonary arteries, and pulmonary artery endothelial cells isolated from patients with PH compared with those from healthy donors. ErbB3 overexpression stimulated hypoxia-induced endothelial cell proliferation, exacerbated pulmonary artery remodeling, elevated systolic pressure in the right ventricle, and promoted right ventricular hypertrophy in murine models of PH. Conversely, systemic deletion or endothelial cell-specific knockout of ErbB3 yielded opposite effects. Coimmunoprecipitation and proteomic analysis identified YB-1 (Y-box binding protein 1) as a downstream target of ErbB3. ErbB3 induced nuclear translocation of YB-1 and subsequently promoted hypoxia-inducible factor 1/2α transcription. A positive loop involving ErbB3-periostin-hypoxia-inducible factor 1/2α was identified to mediate the progressive development of this disease. MM-121, a human anti-ErbB3 monoclonal antibody, exhibited both preventive and therapeutic effects against hypoxia-induced PH. CONCLUSIONS: Our study reveals, for the first time, that ErbB3 serves as a novel biomarker and a promising target for the treatment of PH.

ADAR1 regulates vascular remodeling in hypoxic pulmonary hypertension through N1-methyladenosine modification of circCDK17.

Pulmonary hypertension (PH) is an extremely malignant pulmonary vascular disease of unknown etiology. ADAR1 is an RNA editing enzyme that converts adenosine in RNA to inosine, thereby affecting RNA expression. However, the role of ADAR1 in PH development remains unclear. In the present study, we investigated the biological role and molecular mechanism of ADAR1 in PH pulmonary vascular remodeling. Overexpression of ADAR1 aggravated PH progression and promoted the proliferation of pulmonary artery smooth muscle cells (PASMCs). Conversely, inhibition of ADAR1 produced opposite effects. High-throughput whole transcriptome sequencing showed that ADAR1 was an important regulator of circRNAs in PH. CircCDK17 level was significantly lowered in the serum of PH patients. The effects of ADAR1 on cell cycle progression and proliferation were mediated by circCDK17. ADAR1 affects the stability of circCDK17 by mediating A-to-I modification at the A5 and A293 sites of circCDK17 to prevent it from m1A modification. We demonstrate for the first time that ADAR1 contributes to the PH development, at least partially, through m1A modification of circCDK17 and the subsequent PASMCs proliferation. Our study provides a novel therapeutic strategy for treatment of PH and the evidence for circCDK17 as a potential novel marker for the diagnosis of this disease.

[Source Analysis of Ozone and Its Precursors in Zibo Based on 3-D Air Quality Model].

Based on the ISAM module in the WRF-CMAQ model, this study analyzed the source contribution(both regional and sectoral) of O3 and its precursors(NO2 and VOCs) in Zibo in June 2021. Days with a maximum daily 8-h average(MDA8) O3 higher(lower) than 160 µg·m-3 were defined as polluted(clean) days. Differences in the source contribution between clean days and polluted days were compared, and a typical pollution period was selected for further process analysis. The results showed that NO2 in Zibo mainly came from local emissions in summer, with a relative contribution of 45.1%. Vehicle emissions(33.8%) and natural sources(20.7%) were the primary NO2 sources. VOC contributions from natural sources, solvent usage, and the petrochemical industry were significant, with a total contribution of 78.5%. The MDA8 contribution from local sources was 21.4%, whereas the impact of regional transport(32%) and surrounding cities(26.8%) was also substantial. Among local emission sources, vehicle emissions, the power industry, and the building materials industry contributed 10.9%-18.8% to local MDA8. On O3 pollution days, the MDA8 contribution from local emissions and surrounding cities increased. However, the relative contributions from local sources were similar under different pollution conditions.

Nursing Management of a Patient With Fulminant Myocarditis and Electrical Storm Receiving ECMO: A Case Report.

INTRODUCTION: Fulminant myocarditis is a devastating disease with significant mortality and complications. The care of patients with fulminant myocarditis is rarely reported. CLINICAL FINDINGS: A 17-year-old female patient was admitted to the emergency department with dizziness, amaurosis fugax, and chest tightness. Initial assessment revealed elevated levels of troponin T (4.753 ng/mL), troponin I (49.540 ng/mL), creatine kinase (1306 U/L), creatine kinase-MB isoenzymes (75.71 ng/mL), lactate dehydrogenase (509 U/L), and N-terminal pro-B-type natriuretic peptide (6345 pg/mL). The patient had recurrent ventricular tachycardia and failed to maintain a sinus rhythm after multiple electrical cardioversions. DIAGNOSIS: Echocardiography revealed a left ventricular ejection fraction of 34%. Magnetic resonance imaging results confirmed the diagnosis of myocarditis. INTERVENTIONS: The patient received extracorporeal membrane oxygenation for 6 days, intra-aortic balloon pump support for 7 days, and mechanical ventilation for 5 days. Norepinephrine and dopamine were used to keep circulation stable, lidocaine and amiodarone were used to control heart rate, and glucocorticoids and immunoglobulins were used to modulate immunity. OUTCOMES: The patient was discharged after 23 days. A month after discharge, echocardiography showed that the ejection fraction was 60%. The patient reported complete resolution of signs and symptoms of fulminant myocarditis at follow-up assessment. CONCLUSION: This case report presents the activities of bedside nurses in caring for a patient with fulminant myocarditis and broadens the literature describing nursing interventions for patients with fulminant myocarditis.

Captopril challenge test in the diagnosis of primary aldosteronism: consistency between 1- and 2- h sampling.

Objective: To examine the consistency of plasma aldosterone concentration at 1 and 2 h in the captopril challenge test (CCT) and to explore the possibility of replacing 2-h aldosterone concentration with 1-h aldosterone concentration for diagnosis of primary aldosteronism (PA). Methods: This retrospective analysis included a total of 204 hypertensive patients suspected of having PA. Subjects received oral captopril challenge at 50 mg (25 mg if the systolic blood pressure was <120 mmHg), and plasma aldosterone concentration and direct renin concentration were measured at 1 and 2 h afterward (chemiluminescence immunoassay Liaison® DiaSorin, Italy). Sensitivity and specificity were used to reflect the diagnostic performance of 1-h aldosterone concentration using 2-h aldosterone concentration (11 ng/dl as the cutoff) as the reference. A receiver operating characteristic curve analysis was also conducted. Results: Among the 204 included patients [median age of 57.0 (48.0-61.0) years, 54.4% men], a diagnosis of PA was established in 94 patients. Aldosterone concentration in the patients with essential hypertension was 8.40 (interquartile range 7.05-11.00) ng/dl at 1 h and 7.65 (5.98-9.30) ng/dl at 2 h (P < 0.001). In patients with PA, aldosterone concentration was 16.80 (12.58-20.50) ng/dl at 1 h and 15.55 (12.60-20.85) ng/dl at 2 h (P > 0.999). At a cutoff of 11 ng/dl, the sensitivity and specificity of using 1-h aldosterone concentration to diagnose PA were 87.2% and 78.2%, respectively. A higher cutoff of 12.5 ng/ml increased specificity to 90.0% but decreased sensitivity to 75.5%. A lower cutoff of 9.3 ng/ml increased sensitivity to 97.9% but decreased specificity to 65.4%. Conclusions: When diagnosing PA with CCT, 1-h aldosterone concentration could not be used to replace 2-h aldosterone concentration.

DR region of NKAα1 is a target to ameliorate hepatic lipid metabolism disturbance in obese mice.

BACKGROUND: Na+/K+-ATPase (NKA), an ion pumping enzyme ubiquitously expressed in various cells, is critically involved in cellular ion homeostasis and signal transduction. However, the role of NKA in hepatic lipid homeostasis has yet to be fully characterized. METHODS: The activity of NKA and NKAα1 expression were determined in steatotic cells, mice and patients. The roles of NKAα1 in hepatosteatosis were detected using hepatocyte knockout or specific overexpression of NKAα1 in mice. RESULTS: Herein, we demonstrated that the expression and activity of α1 subunit of NKA (NKAα1) were lowered in the livers of nonalcoholic fatty liver disease (NAFLD) patients, high-fat diet (HFD)-induced obese mice, and genetically obese (ob/ob, db/db) mice, as well as oleic acid-induced hepatocytes. Hepatic deficiency of NKAα1 exacerbated, while adeno-associated virus-mediated liver specific overexpression of NKAα1 alleviated hepatic steatosis through regulation of fatty acid oxidation (FAO) and lipogenesis. Mechanistically, we revealed that NKAα1 upregulated sirtuin 1 (SIRT1) via interacting with ubiquitin specific peptidase 22 (USP22), a deubiquitinating enzyme for the stabilization and deubiquitination of SIRT1, thus activating the downstream autophagy signaling. Blockade of the SIRT1/autophagy signaling pathway eliminated the protective effects of NKAα1 against lipid deposition in hepatocytes. Importantly, we found that an antibody against the DR region (897DVEDSYGQQWTYEQR911) of NKAα1 subunit (DR-Ab) ameliorated hepatic steatosis through maintaining the membrane density of NKAα1 and inducing its activation. CONCLUSIONS: Collectively, this study renews the functions of NKAα1 in liver lipid metabolism and provides a new clue for gene therapy or antibody treatment of hepatic lipid metabolism disturbance by targeting NKAα1.

Targeting the Na+/K+ ATPase DR-region with DR-Ab improves doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX) is a potent chemotherapeutic drug for various cancers. Yet, the cardiotoxic side effects limit its application in clinical uses, in which ferroptosis serves as a crucial pathological mechanism in DOX-induced cardiotoxicity (DIC). A reduction of Na+/K + ATPase (NKA) activity is closely associated with DIC progression. However, whether abnormal NKA function was involved in DOX-induced cardiotoxicity and ferroptosis remains unknown. Here, we aim to decipher the cellular and molecular mechanisms of dysfunctional NKA in DOX-induced ferroptosis and investigate NKA as a potential therapeutic target for DIC. A decrease activity of NKA further aggravated DOX-triggered cardiac dysfunction and ferroptosis in NKAα1 haploinsufficiency mice. In contrast, antibodies against the DR-region of NKAα-subunit (DR-Ab) attenuated the cardiac dysfunction and ferroptosis induced by DOX. Mechanistically, NKAα1 interacted with SLC7A11 to form a novel protein complex, which was directly implicated in the disease progression of DIC. Furthermore, the therapeutic effect of DR-Ab on DIC was mediated by reducing ferroptosis by promoting the association of NKAα1/SLC7A11 complex and maintaining the stability of SLC7A11 on the cell surface. These results indicate that antibodies targeting the DR-region of NKA may serve as a novel therapeutic strategy to alleviate DOX-induced cardiotoxicity.

PD-L1 promotes GSDMD-mediated NET release by maintaining the transcriptional activity of Stat3 in sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE), as shown as acute and long-term cognitive impairment, is associated with increased mortality of sepsis. The causative factors of SAE are diverse and the underlying pathological mechanisms of SAE remain to be fully elucidated. Multiple studies have demonstrated a crucial role of microglia in the development of SAE, but the role of neutrophils and neutrophil extracellular traps (NETs) in SAE is still unclear. Here, we firstly show that in murine sepsis model, neutrophils and NETs promote blood-brain barrier (BBB) disruption, neuronal apoptosis and microglia activation in hippocampus and induce hippocampus-dependent memory impairment. Anti-Gr-1 antibody or DNase I treatment attenuates these sepsis-induced changes. Then, we find that genetic deletion of neutrophil GSDMD or PD-L1 reduces NET release and improves SAE in murine sepsis model. Finally, in human septic neutrophils, p-Y705-Stat3 binds to PD-L1, promotes PD-L1 nuclear translocation and enhances transcription of the gasdermin D (GSDMD) gene. In summary, our findings firstly identify a novel function of PD-L1 in maintaining transcriptional activity of p-Y705-Stat3 to promote GSDMD-dependent NET release in septic neutrophils, which plays a critical role in the development of SAE.