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Accurate understanding of permafrost dynamics is critical for evaluating and mitigating impacts that may arise as permafrost degrades in the future; however, existing projections have large uncertainties. Studies of how permafrost responded historically during Earth's past warm periods are helpful in exploring potential future permafrost behavior and to evaluate the uncertainty of future permafrost change projections. Here, we combine a surface frost index model with outputs from the second phase of the Pliocene Model Intercomparison Project to simulate the near-surface (~3 to 4 m depth) permafrost state in the Northern Hemisphere during the mid-Pliocene warm period (mPWP, ~3.264 to 3.025 Ma). This period shares similarities with the projected future climate. Constrained by proxy-based surface air temperature records, our simulations demonstrate that near-surface permafrost was highly spatially restricted during the mPWP and was 93 ± 3% smaller than the preindustrial extent. Near-surface permafrost was present only in the eastern Siberian uplands, Canadian high Arctic Archipelago, and northernmost Greenland. The simulations are similar to near-surface permafrost changes projected for the end of this century under the SSP5-8.5 scenario and provide a perspective on the potential permafrost behavior that may be expected in a warmer world.
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The envelope (E) protein of the Japanese encephalitis virus (JEV) is a key protein for virus infection and adsorption of host cells, which determines the virulence of the virus and regulates the intensity of inflammatory response. The mutation of multiple aa residues in the E protein plays a critical role in the attenuated strain of JEV. This study demonstrated that the Asp to Gly, Ser, and His mutation of the E389 site, respectively, the replication ability of the viruses in cells was significantly reduced, and the viral neuroinvasiveness was attenuated to different degrees. Among them, the mutation at E389 site enhanced the E protein flexibility contributed to the attenuation of neuroinvasiveness. In contrast, less flexibility of E protein enhanced the neuroinvasiveness of the strain. Our results indicate that the mechanism of attenuation of E389 aa mutation attenuates neuroinvasiveness is related to increased flexibility of the E protein. In addition, the increased flexibility of E protein enhanced the viral sensitivity to heparin inhibition in vitro, which may lead to a decrease in the viral load entering brain. These results suggest that E389 residue is a potential site affecting JEV virulence, and the flexibility of the E protein of aa at this site plays an important role in the determination of neuroinvasiveness.
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Virus de la Encefalitis Japonesa (Especie) , Proteínas del Envoltorio Viral , Virus de la Encefalitis Japonesa (Especie)/genética , Virus de la Encefalitis Japonesa (Especie)/fisiología , Virus de la Encefalitis Japonesa (Especie)/efectos de los fármacos , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/metabolismo , Proteínas del Envoltorio Viral/química , Animales , Línea Celular , Virulencia , Replicación Viral , Encefalitis Japonesa/virología , Humanos , Heparina/farmacología , Sustitución de Aminoácidos , Mutación Missense , Ratones , Mutación , Factores de Virulencia/genética , Glicoproteínas de MembranaRESUMEN
AIM: Malnutrition is prevalent in hepatocellular carcinoma (HCC) patients, linked to poor outcomes, necessitating early intervention. This study aimed to investigate malnutrition in HCC patients, assess Nutrition Risk Screening 2002 (NRS-2002) and Patient-Generated Subjective Global Assessment (PG-SGA) vs. Global Leadership Initiative on Malnutrition (GLIM) criteria, and identify independent risk factors. METHOD: A cross-sectional retrospective study was conducted on 207 patients with HCC. Nutritional screening/assessment results and blood samples were collected within 72 h of admission. This study assessed the prevalence of malnutrition using the NRS-2002 and PG-SGA and retrospectively using the GLIM criteria. The performance of the screening tools was evaluated using kappa (K) values. Logistic regression analyses were performed to determine whether laboratory parameters were associated with malnutrition as identified by the GLIM criteria. RESULTS: Of the participants, 30.4% were at risk of malnutrition according to NRS-2002. The agreement between the NRS-2002 and GLIM criteria was substantial. The GLIM criteria and PG-SGA diagnosed malnutrition in 43 and 54.6% of the participants, respectively. Age, anemia, and ascites correlated with malnutrition in regression. CONCLUSION: The GLIM criteria, along with NRS-2002 and PG-SGA, aid in diagnosing malnutrition in HCC patients. Recognizing risk factors improves accuracy, enabling timely interventions for better outcomes.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Desnutrición , Humanos , Estado Nutricional , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/epidemiología , Prevalencia , Estudios Retrospectivos , Estudios Transversales , Liderazgo , Evaluación Nutricional , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/epidemiología , Desnutrición/diagnóstico , Desnutrición/epidemiología , Desnutrición/etiología , Factores de RiesgoRESUMEN
Most wild strains of Japanese encephalitis virus (JEV) produce NS1' protein, which plays an important role in viral infection and immune escape. The G66A nucleotide mutation in NS2A gene of the wild strain SA14 prevented the ribosomal frameshift that prevented the production of NS1' protein, thus reduced the virulence. In this study, the 66th nucleotide of the NS2A gene of SA14 was mutated into A, U or C, respectively. Both the G66U and G66C mutations cause the E22D mutation of the NS2A protein. Subsequently, the expression of NS1' protein, plaque size, replication ability, and virulence to mice of the three mutant strains were examined. The results showed that the three mutant viruses could not express NS1' protein, and their proliferation ability in nerve cells and virulence to mice were significantly reduced. In addition, the SA14(G66C) was less virulent than the other two mutated viruses. Our results indicate that only when G is the 66th nucleotide of NS2A, the JEV can produce NS1' protein, which affects the virulence.
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Virus de la Encefalitis Japonesa (Especie) , Encefalitis Japonesa , Animales , Ratones , Virus de la Encefalitis Japonesa (Especie)/genética , Nucleótidos/metabolismo , Virulencia/genética , Línea Celular , Proteínas no Estructurales Virales/metabolismo , Proliferación CelularRESUMEN
BACKGROUND: Acute myocardial infarction (AMI) is characterized by inflammation, oxidative stress, and atherosclerosis, contributing to increased mortality risk. High-density lipoprotein (HDL) takes a crucial part in mitigating atherosclerosis and inflammation through its diverse functionalities. Conversely, fibrinogen is implicated in the development of atherosclerotic plaques. However, the mortality risk predictive capacity of fibrinogen to HDL-cholesterol ratio (FHR) in AMI patients remains unexplored. This research aimed to evaluate the effectiveness of FHR for mortality risk prediction in relation to AMI. METHODS: A retrospective study involving 13,221 AMI patients from the Cardiorenal ImprovemeNt II cohort (NCT05050877) was conducted. Baseline FHR levels were used to categorize patients into quartiles. The assessment of survival disparities among various groups was conducted by employing KaplanâMeier diagram. Cox regression was performed for investigating the correlation between FHR and adverse clinical outcomes, while the Fine-Gray model was applied to evaluate the subdistribution hazard ratios for cardiovascular death. RESULTS: Over a median follow-up of 4.66 years, 2309 patients experienced all-cause death, with 1007 deaths attributed to cardiovascular disease (CVD). The hazard ratio (HR) and its 95% confidence interval (CI) for cardiac and all-cause death among individuals in the top quartile of FHR were 2.70 (1.99-3.65) and 1.48 (1.26-1.75), respectively, in comparison to ones in the first quartile, after covariate adjustment. Restricted cubic spline analysis revealed that FHR was linearly correlated with all-cause mortality, irrespective of whether models were adjusted or unadjusted (all P for nonlinearity > 0.05). CONCLUSION: AMI patients with increased baseline FHR values had higher all-cause and cardiovascular mortality, regardless of established CVD risk factors. FHR holds promise as a valuable tool for evaluating mortality risk in AMI patients. TRIAL REGISTRATION: The Cardiorenal ImprovemeNt II registry NCT05050877.
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Aterosclerosis , Infarto del Miocardio , Humanos , HDL-Colesterol , Estudios Retrospectivos , Fibrinógeno , Factores de Riesgo , InflamaciónRESUMEN
BACKGROUND: Transcriptional reconfiguration is central to heart failure, the most common cause of which is dilated cardiomyopathy (DCM). The effect of 3-dimensional chromatin topology on transcriptional dysregulation and pathogenesis in human DCM remains elusive. METHODS: We generated a compendium of 3-dimensional epigenome and transcriptome maps from 101 biobanked human DCM and nonfailing heart tissues through highly integrative chromatin immunoprecipitation (H3K27ac [acetylation of lysine 27 on histone H3]), in situ high-throughput chromosome conformation capture, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin using sequencing, and RNA sequencing. We used human induced pluripotent stem cell-derived cardiomyocytes and mouse models to interrogate the key transcription factor implicated in 3-dimensional chromatin organization and transcriptional regulation in DCM pathogenesis. RESULTS: We discovered that the active regulatory elements (H3K27ac peaks) and their connectome (H3K27ac loops) were extensively reprogrammed in DCM hearts and contributed to transcriptional dysregulation implicated in DCM development. For example, we identified that nontranscribing NPPA-AS1 (natriuretic peptide A antisense RNA 1) promoter functions as an enhancer and physically interacts with the NPPA (natriuretic peptide A) and NPPB (natriuretic peptide B) promoters, leading to the cotranscription of NPPA and NPPB in DCM hearts. We revealed that DCM-enriched H3K27ac loops largely resided in conserved high-order chromatin architectures (compartments, topologically associating domains) and their anchors unexpectedly had equivalent chromatin accessibility. We discovered that the DCM-enriched H3K27ac loop anchors exhibited a strong enrichment for HAND1 (heart and neural crest derivatives expressed 1), a key transcription factor involved in early cardiogenesis. In line with this, its protein expression was upregulated in human DCM and mouse failing hearts. To further validate whether HAND1 is a causal driver for the reprogramming of enhancer-promoter connectome in DCM hearts, we performed comprehensive 3-dimensional epigenome mappings in human induced pluripotent stem cell-derived cardiomyocytes. We found that forced overexpression of HAND1 in human induced pluripotent stem cell-derived cardiomyocytes induced a distinct gain of enhancer-promoter connectivity and correspondingly increased the expression of their connected genes implicated in DCM pathogenesis, thus recapitulating the transcriptional signature in human DCM hearts. Electrophysiology analysis demonstrated that forced overexpression of HAND1 in human induced pluripotent stem cell-derived cardiomyocytes induced abnormal calcium handling. Furthermore, cardiomyocyte-specific overexpression of Hand1 in the mouse hearts resulted in dilated cardiac remodeling with impaired contractility/Ca2+ handling in cardiomyocytes, increased ratio of heart weight/body weight, and compromised cardiac function, which were ascribed to recapitulation of transcriptional reprogramming in DCM. CONCLUSIONS: This study provided novel chromatin topology insights into DCM pathogenesis and illustrated a model whereby a single transcription factor (HAND1) reprograms the genome-wide enhancer-promoter connectome to drive DCM pathogenesis.
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Cardiomiopatía Dilatada , Células Madre Pluripotentes Inducidas , Animales , Cardiomiopatía Dilatada/metabolismo , Cromatina/genética , Cromatina/metabolismo , Histonas/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Ratones , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: Among patients with acute coronary syndrome and percutaneous coronary intervention, stress hyperglycemia ratio (SHR) is primarily associated with short-term unfavorable outcomes. However, the relationship between SHR and long-term worsen prognosis in acute myocardial infarction (AMI) patients admitted in intensive care unit (ICU) are not fully investigated, especially in those with different ethnicity. This study aimed to clarify the association of SHR with all-cause mortality in critical AMI patients from American and Chinese cohorts. METHODS: Overall 4,337 AMI patients with their first ICU admission from the American Medical Information Mart for Intensive Care (MIMIC)-IV database (n = 2,166) and Chinese multicenter registry cohort Cardiorenal ImprovemeNt II (CIN-II, n = 2,171) were included in this study. The patients were divided into 4 groups based on quantiles of SHR in both two cohorts. RESULTS: The total mortality was 23.8% (maximum follow-up time: 12.1 years) in American MIMIC-IV and 29.1% (maximum follow-up time: 14.1 years) in Chinese CIN-II. In MIMIC-IV cohort, patients with SHR of quartile 4 had higher risk of 1-year (adjusted hazard radio [aHR] = 1.87; 95% CI: 1.40-2.50) and long-term (aHR = 1.63; 95% CI: 1.27-2.09) all-cause mortality than quartile 2 (as reference). Similar results were observed in CIN-II cohort (1-year mortality: aHR = 1.44; 95%CI: 1.03-2.02; long-term mortality: aHR = 1.32; 95%CI: 1.05-1.66). In both two group, restricted cubic splines indicated a J-shaped correlation between SHR and all-cause mortality. In subgroup analysis, SHR was significantly associated with higher 1-year and long-term all-cause mortality among patients without diabetes in both MIMIC-IV and CIN-II cohort. CONCLUSION: Among critical AMI patients, elevated SHR is significantly associated with and 1-year and long-term all-cause mortality, especially in those without diabetes, and the results are consistently in both American and Chinese cohorts.
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Hiperglucemia , Infarto del Miocardio , Humanos , China/epidemiología , Pueblos del Este de Asia , Infarto del Miocardio/complicaciones , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/mortalidad , Infarto del Miocardio/terapia , Pronóstico , Estados Unidos/epidemiologíaRESUMEN
Background: Patients with secondary mitral regurgitation (sMR) often present with greater mortality and comorbidity, which may be predicted by some risk factors. This study was designed to investigate the prognostic meaning of the echocardiographically detected wall motion score index (WMSI) in coronary artery disease (CAD) patients with moderate or severe baseline sMR who underwent percutaneous coronary intervention (PCI) therapy. Methods: The present study was a multi-center and prospective cohort of consecutive CAD patients with baseline moderate or severe sMR who underwent PCI. All underwent echocardiography at baseline and at follow-up after PCI to assess sMR and WMSI. The primary endpoint was the persistence of moderate or severe sMR after the second echocardiographic measurement. Logistic and Cox proportional hazards models were constructed for the primary (persistent moderate or severe sMR) and secondary (worsening heart failure [HF]; all-cause mortality; cardiovascular-specific mortality; and major adverse cardiovascular events [MACE]) endpoints. Results: Among 920 participants, 483 had WMSI values of ≥ 1.47, and 437 were less. Of all the participants, 366 (39.8%) continued to have moderate or severe sMR after the second echocardiogram measurement. After full adjustment for confounders, elevated WMSI after PCI was independently associated with the primary endpoint during 3-12 month follow-up. Similarly, elevated WMSI was associated with increased risk of worsening HF, all-cause mortality, cardiovascular-specific mortality, and MACE. Conclusions: Persistent moderate or severe sMR is common (approximately 40%) in PCI patients. Elevated WMSI in CAD patients after PCI is a predictor of persistent moderate or severe sMR and has independent negative prognostic value. Patients with CAD and sMR should be monitored for WMSI to identify those at higher risk of mortality and comorbidity.
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BACKGROUND: Coronary catheterization (CC) procedure inevitably exposes patients with cardiovascular disease (CVD) to radiation, while cumulative radiation exposure may lead to higher risk of cancer. METHODS: This multi-center, retrospective study was based on the CC procedure in Cardiorenal ImprovemeNt II cohort (CIN-II, NCT05050877) among five regional central tertiary teaching hospitals in China between 2007 and 2020. Patients without known cancer were stratified according to the times they received CC procedure. Baseline information from their last CC procedure was analyzed. Cox regression and Fine-Gray competing risk models were used to assess the relationship between cumulative radiation exposure from CC procedures and cancer-specific, all-cause and cardiovascular mortality. RESULTS: Of 136,495 hospitalized survivors without cancer at baseline (mean age: 62.3 ± 11.1 years, 30.9% female), 116,992 patients (85.7%) underwent CC procedure once, 15,184 patients (11.1%) on twice, and 4,319 patients (3.2%) underwent CC procedure more than three times. During the median follow-up of 4.7 years (IQR: 2.5 to 7.4), totally 18,656 patients (13.7%) died after discharge, of which 617 (0.5%) died of lung cancer. Compared with the patients who underwent CC procedure once, the risk of lung cancer mortality increased significantly with the increase of the number of CC procedure (CC 2 times vs. 1 time: HR 1.42, 95% CI 1.13 to 1.78, P < 0.001; CC ≥ 3 times vs. 1 time: HR 1.64, 95%CI 1.13 to 2.39, P < 0.05). Similar results were observed in all-cause mortality and cardiovascular mortality, but not in other cancer-specific mortality. CONCLUSIONS: Our data suggest that substantial proportion of CVD patients are exposed to multiple high levels of low-dose ionizing radiation from CC procedure, which is associated with an increased risk of cancer mortality in this population. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05050877; URL: http://www. CLINICALTRIALS: gov ; 21/09/2021.
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Enfermedades Cardiovasculares , Neoplasias Pulmonares , Exposición a la Radiación , Humanos , Femenino , Persona de Mediana Edad , Anciano , Masculino , Estudios Retrospectivos , Enfermedades Cardiovasculares/etiología , Exposición a la Radiación/efectos adversos , Cateterismo , Factores de RiesgoRESUMEN
BACKGROUND: IgG4-related autoimmune pancreatitis (AIP) is considered to be a T cell-mediated autoimmune disease. However, CD8+ T cells have only received brief mention, and have yet to be completely studied. The study aimed to investigate the expression of signaling lymphocytic activation molecule family 7 (SLAMF7) on CD8+ T cells and the features of SLAMF7+CD8+ T cells in MRL/Mp mice with AIP. METHODS: A murine model of AIP was established by intraperitoneal injection with polyinosinic:polycytidylic acid (poly I:C) for 8 weeks. Dexamethasone treatment was daily administrated for the last 2 weeks during a 6-week course of poly I:C. SLAMF7 expression on CD8+ T cells in the spleen and pancreas was detected by flow cytometry. Granzyme B (GZMB) and cytokines including IFN-γ, TNF-α, and IL-2, were monitored in an in vitro T cell activation assay. Dexamethasone suppression assays were performed to downregulate SLAMF7 expression on T cells upon T cell receptor stimulation. RESULTS: AIP in MRL/Mp mice was induced by repeated intraperitoneal administration of poly I:C and CD8+ T cells were increased in the inflamed pancreas. SLAMF7+CD8+ T cells were elevated in the spleen and pancreas of AIP mice. SLAMF7+CD8+ T subsets produced more GZMB, IFN-γ, TNF-α and IL-2 than SLAMF7-CD8+ T subsets. Dexamethasone treatment ameliorated pancreatic inflammatory and fibrosis of AIP. Dexamethasone could downregulate SLAMF7+CD8+ T cells and reduce GZMB, IFN-γ and TNF-α levels both in vitro and in vivo. CONCLUSIONS: Increased SLAMF7+CD8+ T cells exhibit enhanced cytotoxicity and cytokines secretion capacity, which may be involved in the pathogenesis of AIP.
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Enfermedades Autoinmunes , Pancreatitis Autoinmune , Ratones , Animales , Linfocitos T CD8-positivos , Interleucina-2/efectos adversos , Factor de Necrosis Tumoral alfa , Enfermedades Autoinmunes/patología , Poli I-C/efectos adversos , Dexametasona/efectos adversos , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismoRESUMEN
OBJECTIVE: Preeclampsia is a common disease during pregnancy that leads to fetal and maternal adverse events. Few head-to-head clinical trials are currently comparing the effectiveness of prophylactic strategies for preeclampsia. In this network meta-analysis, we aimed to compare the efficacy of prophylactic strategies for preventing preeclampsia in pregnant women at risk. DATA SOURCES: Articles published in or before September 2021 from PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov, references of key articles, and previous meta-analyses were manually searched. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials comparing prophylactic strategies preventing preeclampsia with each other or with negative controls were included. METHODS: Two reviewers independently extracted data, assessed the risk of bias, and assessed evidence certainty. The efficacy of prophylactic strategies was estimated by frequentist and Bayesian network meta-analysis models. The primary composite outcome was preeclampsia/ pregnancy-induced hypertension. RESULTS: In total, 130 trials with a total of 112,916 patients were included to assess 13 prophylactic strategies. Low-molecular-weight heparin (0.60; 95% confidence interval, 0.42-0.87), vitamin D supplementation (0.65; 95% confidence interval, 0.45-0.95), and exercise (0.68; 95% confidence interval, 0.50-0.92) were as efficacious as calcium supplementation (0.71; 95% confidence interval, 0.62-0.82) and aspirin (0.79; 95% confidence interval, 0.72-0.86) in preventing preeclampsia/pregnancy-induced hypertension, with a P score ranking of 85%, 79%, 76%, 74%, and 61%, respectively. In the head-to-head comparison, no differences were found between these effective prophylactic strategies for preventing preeclampsia and pregnancy-induced hypertension, except with regard to exercise, which tended to be superior to aspirin and calcium supplementation in preventing pregnancy-induced hypertension. Furthermore, the prophylactic effects of aspirin and calcium supplementation were robust across subgroups. However, the prophylactic effects of low-molecular-weight heparin, exercise, and vitamin D supplementation on preeclampsia and pregnancy-induced hypertension varied with different risk populations, dosages, areas, etc. The certainty of the evidence was moderate to very low. CONCLUSION: Low-molecular-weight heparin, vitamin D supplementation, exercise, calcium supplementation, and aspirin reduce the risk of preeclampsia/pregnancy-induced hypertension. No significant differences between effective prophylactic strategies were found in preventing preeclampsia. These findings raise the necessity to reevaluate the prophylactic effects of low-molecular-weight heparin, vitamin D supplementation, and exercise on preeclampsia.
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Hipertensión Inducida en el Embarazo , Preeclampsia , Embarazo , Humanos , Femenino , Preeclampsia/prevención & control , Preeclampsia/tratamiento farmacológico , Hipertensión Inducida en el Embarazo/tratamiento farmacológico , Calcio , Metaanálisis en Red , Teorema de Bayes , Ensayos Clínicos Controlados Aleatorios como Asunto , Aspirina/uso terapéutico , Heparina de Bajo-Peso-Molecular/uso terapéutico , Vitamina D/uso terapéuticoRESUMEN
Colorectal cancer (CRC) is an exceptionally deadly disease, whereas effective therapeutic drugs for CRC have declined over the past few decades. Natural products have become a reliable source of anticancer drugs. Previously we isolated an alkaloid named (-)-N-hydroxyapiosporamide (NHAP), which exerts potent antitumor effects, but its effect and mechanism in CRC remain unclear. This study aimed to reveal the antitumor target of NHAP and identify NHAP as a promising lead compound for CRC. Various biochemical methods and animal models were used to investigate the antitumor effect and molecular mechanism for NHAP. These results showed that NHAP exhibited potent cytotoxicity, induced both apoptosis and autophagic cell death of CRC cells, and inhibited the NF-κB signaling pathway by blocking the interaction of the TAK1-TRAF6 complex. NHAP also markedly inhibited CRC tumor growth in vivo without obvious toxicities and possessed good pharmacokinetic characteristics. These findings identify, for the first time, that NHAP is an NF-κB inhibitor with potent antitumor activity in vitro and in vivo. This study clarifies the antitumor target of NHAP against CRC, which will contribute to the future development of NHAP as a novel therapeutic lead compound for CRC.
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Alcaloides , Antineoplásicos , Neoplasias Colorrectales , Animales , Alcaloides/farmacología , Alcaloides/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , FN-kappa B/metabolismo , Factor 6 Asociado a Receptor de TNF/metabolismo , Factor 6 Asociado a Receptor de TNF/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
INTRODUCTION: Nonischemic dilated cardiomyopathy (NIDCM) is a heterogeneous disease, and patients still have high risk of sudden cardiac death even after receiving treatment. The Selvester QRS score and the ESTIMATED score reported as predictors contain many variables and are complex to calculate. There is a need for a simple predictive score to accurately assess prognosis in clinical practice. METHODS: A total of 953 elderly patients (age ≥60 years) diagnosed with NIDCM were enrolled from January 2010 to December 2019. In-hospital and long-term outcomes were studied. RESULTS: Univariate logistic regression analysis showed that the AGEF score was associated with in-hospital mortality (OR: 1.828; 95% CI: 1.559-2.144; p < 0.001). Receiver operator characteristic curve analysis showed that the AGEF score was excellent at predicting clinical outcomes. The optimal cutoff value of the AGEF score for predicting long-term mortality was 2.50 (AUC = 0.743; 95% CI: 0.710-0.776; p < 0.001). Kaplan-Meier survival analysis showed that patients with an AGEF score >2.50 had a worse prognosis than those with an AGEF score ≤2.50 (log-rank χ2 103.69, p < 0.001). Moreover, multivariate Cox proportional hazard analysis showed that an AGEF score ≤2.50 was associated with a lower risk of long-term mortality in elderly patients with NIDCM (HR: 0.405; 95% CI: 0.310-0.529; p < 0.001). CONCLUSIONS: The AGEF score could be considered as a simple and useful tool for risk stratification in elderly patients with NIDCM.
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Cardiomiopatía Dilatada , Humanos , Anciano , Cardiomiopatía Dilatada/diagnóstico , Cardiomiopatía Dilatada/complicaciones , Volumen Sistólico , PronósticoRESUMEN
BACKGROUND: International guidelines recommend natriuretic peptide biomarker-based screening for patients at high heart failure (HF) risk to allow early detection. There have been few reports about the incorporation of screening procedure to existing clinical practice. OBJECTIVE: To implement screening of left ventricular dysfunction in patients with type 2 diabetes mellitus (DM). METHOD: A prospective screening study at the DM complication screening centre was performed. RESULTS: Between 2018 and 2019, 1043 patients (age: 63.7±12.4 years; male: 56.3%) with mean glycated haemoglobin of 7.25%±1.34% were recruited. 81.8% patients had concomitant hypertension, 31.1% had coronary artery disease, 8.0% had previous stroke, 5.5% had peripheral artery disease and 30.7% had chronic kidney disease (CKD) stages 3-5. 43 patients (4.1%) had an elevated N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentration above the age-specific diagnostic thresholds for HF, and 43 patients (4.1%) had newly detected atrial fibrillation (AF). The prevalence of elevated NT-proBNP increased with age from 0.85% in patients aged <50 years to 7.14% in those aged 70-79 years and worsening kidney function from 0.43% in patients with CKD stage 1 to 42.86% in CKD stage 5. In multivariate logistic regression, male gender (OR: 3.67 (1.47-9.16), p = 0.005*), prior stroke (OR: 3.26 (1.38-7.69), p = 0.007*), CKD (p<0.001*) and newly detected AF (OR: 7.02 (2.65-18.57), p<0.001*) were significantly associated with elevated NT-proBNP. Among patients with elevated NT-proBNP, their mean left ventricular ejection fraction (LVEF) was 51.4%±14.7%, and 45% patients had an LVEF <50%. CONCLUSION: NT-proBNP and ECG screening could be implemented with relative ease to facilitate early detection of cardiovascular complication and improve long-term outcomes.
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Fibrilación Atrial , Diabetes Mellitus Tipo 2 , Insuficiencia Cardíaca , Insuficiencia Renal Crónica , Accidente Cerebrovascular , Disfunción Ventricular Izquierda , Humanos , Masculino , Persona de Mediana Edad , Anciano , Volumen Sistólico , Función Ventricular Izquierda , Estudios Prospectivos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/etiología , Biomarcadores , Accidente Cerebrovascular/etiología , Péptido Natriurético Encefálico , Fragmentos de Péptidos , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/diagnósticoRESUMEN
BACKGROUND: Lipids are critical in bone metabolism, and several studies have highlighted their importance. This study aimed to investigate the relationship between apolipoprotein B (apo B) and bone mineral density (BMD) at different skeletal sites (lumbar spine, femoral neck, and total femur) and to compare the influence of apo B with other traditional lipid markers. METHODS: The study included participants from the National Health and Nutrition Examination Survey (NHANES) between 2011 and 2016 who had complete data for apo B and BMD at the three skeletal sites. We used weighted multivariate regression analysis, subgroup analysis, and interaction tests to examine associations. Restricted cubic spline (RCS) was used to examine the non-linear relationship. RESULTS: A total of 4,258 adults were included in the study. Multivariate linear regression analysis showed that the relationship between apo B and BMD varied by skeletal site: a negative association was found with lumbar spine BMD [ß = -0.054, 95%CI: (-0.073, -0.035)]. In contrast, a positive association was found with femoral neck BMD [ß = 0.031, 95%CI: (0.011, 0.051)] and no significant association between apo B and total femur BMD. CONCLUSIONS: Our findings suggest that apo B is associated with BMD in a site-specific manner.
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Densidad Ósea , Cuello Femoral , Adulto , Humanos , Absorciometría de Fotón , Apolipoproteínas B , Cuello Femoral/diagnóstico por imagen , Vértebras Lumbares/diagnóstico por imagen , Encuestas NutricionalesRESUMEN
Warm periods in Earth's history offer opportunities to understand the dynamics of the Earth system under conditions that are similar to those expected in the near future. The Middle Pliocene warm period (MPWP), from 3.3 to 3.0 My B.P, is the most recent time when atmospheric CO2 levels were as high as today. However, climate model simulations of the Pliocene underestimate high-latitude warming that has been reconstructed from fossil pollen samples and other geological archives. One possible reason for this is that enhanced non-CO2 trace gas radiative forcing during the Pliocene, including from methane (CH4), has not been included in modeling. We use a suite of terrestrial biogeochemistry models forced with MPWP climate model simulations from four different climate models to produce a comprehensive reconstruction of the MPWP CH4 cycle, including uncertainty. We simulate an atmospheric CH4 mixing ratio of 1,000 to 1,200 ppbv, which in combination with estimates of radiative forcing from N2O and O3, contributes a non-CO2 radiative forcing of 0.9 [Formula: see text] (range 0.6 to 1.1), which is 43% (range 36 to 56%) of the CO2 radiative forcing used in MPWP climate simulations. This additional forcing would cause a global surface temperature increase of 0.6 to 1.0 °C, with amplified changes at high latitudes, improving agreement with geological evidence of Middle Pliocene climate. We conclude that natural trace gas feedbacks are critical for interpreting climate warmth during the Pliocene and potentially many other warm phases of the Cenezoic. These results also imply that using Pliocene CO2 and temperature reconstructions alone may lead to overestimates of the fast or Charney climate sensitivity.
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The existing treatment modalities for skin injuries mainly include dressings, negative-pressure wound treatment, autologous skin grafting, and high-pressure wound treatment. All of these therapies have limitations such as high time cost, the inability to remove inactivated tissue in a timely manner, surgical debridement, and oxygen toxicity. Mesenchymal stem cells have a unique self-renewal ability and wide differentiation potential, and they are one of the most promising stem cell types in cell therapy and have great application prospects in the field of regenerative medicine. Collagen exerts structural roles by promoting the molecular structure, shape, and mechanical properties of cells, and adding it to cell cultures can also promote cell proliferation and shorten the cell doubling time. The effects of collagen on MSCs were examined using Giemsa staining, EdU staining, and growth curves. Mice were subjected to allogeneic experiments and autologous experiments to reduce individual differences; all animals were separated into four groups. Neonatal skin sections were detected by HE staining, Masson staining, immunohistochemical staining, and immunofluorescence staining. We found that the MSCs pretreated with collagen accelerated the healing of skin wounds in mice and canines by promoting epidermal layer repair, collagen deposition, hair follicle angiogenesis, and an inflammatory response. Collagen promotes the secretion of the chemokines and growth factors associated with skin healing by MSCs, which positively influences skin healing. This study supports the treatment of skin injuries with MSCs cultured in medium with collagen added.
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Células Madre Mesenquimatosas , Cicatrización de Heridas , Ratones , Animales , Perros , Cicatrización de Heridas/fisiología , Piel/lesiones , Colágeno , Proliferación CelularRESUMEN
BACKGROUND: The triglyceride glucose (TyG) index is an alternative to insulin resistance (IR) as an early indicator of worsening heart failure (HF). Patients with secondary mitral regurgitation (sMR) often experience progressive deterioration of cardiac function. This study aimed to investigate the relationship between the TyG index and worsening of HF in significant sMR (grade ≥ 2) following percutaneous coronary intervention (PCI). METHODS: This study enrolled participants with significant sMR following PCI from a multicenter cohort study. The patients were divided into the following 3 groups according to tertiles of TyG index: T1, TyG ≤ 8.51; T2, TyG > 8.51 to ≤ 8.98; and T3, TyG > 8.98. The main clinical outcome was worsening HF including unplanned rehospitalization or unscheduled physician office/emergency department visit due to HF and unplanned mitral valve surgery. RESULTS: A total of 922 patients (mean ± SD age, 64.1 ± 11.0 years; 79.6% male) were enrolled. The incidence of worsening HF was 15.5% in T1, 15.7% in T2, and 26.4% in T3. In the multivariable model, the highest TyG tertile (T3 group) was more strongly correlated with worsening HF than the lowest tertile (T1 group) after adjusting for confounders (adjusted hazard ratio, 2.44; 95% confidence interval, 1.59-3.72; P < 0.001). The addition of TyG to risk factors such as N-terminal pro brain natriuretic peptide and clinical models improved the predictive ability of TyG for worsening HF. CONCLUSIONS: Elevated preprocedural TyG index is a significant and independent risk factor for worsening HF in sMR following PCI that can be used for risk stratification.
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Insuficiencia Cardíaca , Insuficiencia de la Válvula Mitral , Intervención Coronaria Percutánea , Humanos , Masculino , Persona de Mediana Edad , Anciano , Femenino , Insuficiencia de la Válvula Mitral/diagnóstico por imagen , Insuficiencia de la Válvula Mitral/cirugía , Intervención Coronaria Percutánea/efectos adversos , Triglicéridos , Glucosa , Estudios de Cohortes , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/terapiaRESUMEN
Background: Peripheral arterial disease (PAD) can severely compromise limb vitality and function. Angiogenesis plays an important role in healing of ischemic lesions. Radiolabeled RGD (Arg-Gly-Asp) peptides specifically targeting α v ß 3 integrin are promising tracers for imaging angiogenesis. In this study, we investigated the application of a one-step labeled RGD in evaluation of angiogenesis and therapy response in a mouse model of hindlimb ischemia (HI) by positron emission tomography (PET). Methods: HI was induced by ablation of the femoral artery in mice. PET imaging using 18F-AlF-NOTA-PRGD2 (18F-PRGD2) tracer was performed at day 0 (pre-surgery) and days 3, 7, 14, and 21 after surgery to evaluate hindlimb angiogenesis longitudinally and noninvasively. The control peptide RAD (Arg-Ala-Asp) labeled with a similar procedure and a block agent were used to confirm the specific binding of 18F-PRGD2 to α v ß 3 integrin. Ex vivo CD31 staining was performed to detect angiogenesis. In addition, the angiogenic therapy response was monitored with 18F-PRGD2 tracer and immunofluorescence staining to confirm the imaging data. Results: The successful establishment of HI model was confirmed by ultrasound imaging and laser doppler perfusion imaging (LDPI). Specific binding of 18F-PRGD2 to α v ß 3 integrin was validated by minimal tracer uptake of the control peptide RAD and significant decrease of tracer accumulation when a block agent was added. Local accumulation of 18F-RRGD2 in ischemic hindlimb was detected as early as 3 days and reached a peak at 7 days after surgery. The temporal change of focal tracer uptake was positively correlated with the pattern of vascular density. Moreover, vascular endothelial growth factor (VEGF) treatment increased the tracer uptake and enhanced angiogenesis, which is consistent with integrin ß 3 expression. Conclusions: PET imaging of a one-step labeled tracer 18F-PRGD2 targeted to α v ß 3 integrin allows longitudinal monitoring of ischemia-induced angiogenesis and noninvasive assessment of VEGF treatment response in a mouse model of hindlimb ischemia. The simple synthesis procedure and in vivo performance of this PET tracer enables the feasibility of future clinical translation in ischemic cardiovascular diseases.
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Two highly oxygenated pentacyclic polyketides with two new carbon skeletons, trichopsistide A (1) and trichopsistide B (2), were isolated from the plant endophyte Trichoderma koningiopsis WZ-196 derived from the leaf of Rubia podantha Diels. The structures of these polyketides with full configurations were determined by comprehensive spectroscopic analysis, computer-assisted structure elucidation software, computational calculation, and X-ray crystal diffraction. Among them, 1 represented the first example of an unprecedented 5/6/6/6/5 pentacyclic ketal-containing polyketide pyridine alkaloid, and 2 possessed a novel 6/6/6/6/5 pentacyclic ketal-containing polyketide scaffold fused with an α-pyrone. The plausible biosynthetic route for 1 and 2 was also proposed. Moreover, biological activity assays showed that 1 and 2 possessed inhibitory effects on the NF-κB signaling pathway with IC50 values of 14.77 and 8.58 µM, respectively. Furthermore, 1 and 2 could also inhibit the expression of IκBα and p65 phosphorylation, decrease the expression of MCP-1, E-selectin, and IL-8 at the mRNA level, and inhibit the TNF-α-induced nuclear translocation of p65.