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1.
Sci Total Environ ; : 175168, 2024 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-39094653

RESUMO

A large fraction of fine particulate matter (PM2.5) and ozone (O3) in the troposphere originates from secondary formation through photochemical processes, which remarkably contributes to the deterioration of regional air quality in China. The photochemical reactions initiated by hydroxyl radicals (OH) play vital roles in secondary PM2.5 and O3 formation. In contrast, the OH levels in polluted areas are underestimated by current chemical transport models (CTMs) because of the strongly unknown daytime sources of tropospheric nitric acid (HONO), which has been recognized as the dominant source of primary OH in polluted areas of China. In this study, the atmospheric HONO levels at two urban sites were found to be significantly underestimated by the WRF-Chem model based on available information on HONO sources. The HONO levels could be well reproduced by the WRF-Chem model after incorporating two new potential HONO sources from the photochemical reactions of NOx, as proposed in our previous study based on chamber experiment results. Comparing the simulations with available information of HONO sources, the simulated levels of atmospheric OH, secondary inorganic and organic aerosols (SIA and SOA), PM2.5 and daily maximum 8-h average (MDA8) O3 were evidently elevated or were closer to the observations over the North China Plain (NCP), with elevation percentages of 0.48-20.1 %, and a decrement percentage of -5.79 % for pNO3-. Additionally, the compensating errors in modeling PM2.5 and the gap in MDA8 O3 levels between observation and simulation in 2 + 26 cities became evidently smaller. The results of this study indicated that the empirical parameterization of two new potential HONO sources through photochemical reactions of NOx improved the model performance in modeling PM2.5 and O3 by narrowing the gap in daytime HONO levels between simulation and observation, although their detailed chemical mechanisms are still unknown and should be further investigated and explicitly parameterized.

2.
J Public Econ ; 2382024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39099735

RESUMO

The growth of physician vertical integration raises concerns about distorted referral patterns, higher spending, and market foreclosure. Using 100% Medicare data, we combine reduced-form analysis with a discrete choice model to estimate the effects of physician vertical integration on patients' provider choices and welfare for two common "downstream" surgical procedures. Physician-hospital integration results in an approximately 10% increase in referrals to higher-priced facilities instead of lower-priced providers. Our counterfactual analysis implies that if all primary care physicians become integrated, total Medicare spending will increase by $315 million.

3.
Front Immunol ; 15: 1428551, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39086479

RESUMO

Background: Myocardial inflammation and apoptosis induced by cirrhosis are among the primary mechanisms of cirrhotic cardiomyopathy. CD73, a common extracellular nucleotidase also known as 5'-nucleotidase, is associated with the progression of inflammation and immunity in multiple organs. However, the mechanism by which CD73 contributes to myocardial inflammation and apoptosis in cirrhosis remains unclear. Methods: In this study, a cirrhotic cardiomyopathy model in mice was established by bile duct ligation. Myocardial-specific overexpression of CD73 was achieved by tail vein injection of AAV9 (adeno-associated virus)-cTNT-NT5E-mCherry, and cardiac function in mice was assessed using echocardiography. Myocardial inflammation infiltration and apoptosis were evaluated through pathological observation and ELISA assays. The expression of CD73, A2AR, apoptotic markers, and proteins related to the NF-κB pathway in myocardial tissue were measured. Results: In the myocardial tissue of the cirrhotic cardiomyopathy mouse model, the expression of CD73 and A2AR increased. Overexpression of CD73 in the myocardium via AAV9 injection and stimulation of A2AR with CGS 21680 inhibited myocardial inflammation and cardiomyocyte apoptosis induced by cirrhosis. Additionally, overexpression of CD73 suppressed the activation of the NF-κB pathway by upregulating the expression of the adenosine receptor A2A. Conclusion: Our study reveals that the CD73/A2AR signaling axis mitigates myocardial inflammation and apoptosis induced by cirrhosis through negative feedback regulation of the NF-κB pathway.


Assuntos
5'-Nucleotidase , Cardiomiopatias , Cirrose Hepática , NF-kappa B , Receptor A2A de Adenosina , Transdução de Sinais , Animais , 5'-Nucleotidase/metabolismo , NF-kappa B/metabolismo , Camundongos , Receptor A2A de Adenosina/metabolismo , Cardiomiopatias/metabolismo , Cardiomiopatias/etiologia , Cardiomiopatias/imunologia , Cirrose Hepática/imunologia , Cirrose Hepática/metabolismo , Masculino , Retroalimentação Fisiológica , Apoptose , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Proteínas Ligadas por GPI
4.
J Infect Dis ; 230(1): 95-102, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-39052717

RESUMO

BACKGROUND: We aimed to analyze the clinical characteristics of peripheral Epstein-Barr virus (EBV)-infected lymphocyte subtypes in children with chronic active EBV infection (CAEBV). METHODS: The levels of peripheral EBV infection of CD4+ T cells, CD8+ T cells, and CD56+ natural killer (NK) cells were determined by flow cytometry and quantitative polymerase chain reaction (qPCR) in patients with CAEBV from July 2017 to July 2022. RESULTS: In total, 112 children with CAEBV were evaluated. Of these, CD4+ type, CD8+ type, and CD56+ type were defined in 44, 21, and 47 patients, respectively. Patients with CD8+ T-cell type had a significantly higher frequency of rash, while hepatomegaly was more common in patients with CD4+ T-cell type. Generally, patients with CD8+ T-cell type had the lowest overall survival rate (P = .017). Patients treated with chemotherapy and hematopoietic stem cell transplantation (HSCT) had a better prognosis (P = .001). In multivariate analysis, rash, hemophagocytic lymphohistiocytosis, CD8+ T-cell type, and no decrease of plasma EBV-DNA after treatment were independent indicators of poor prognosis (P = .002, .024, .022, and .012, respectively). CONCLUSIONS: In children with CAEBV, rash was more frequent in patients with CD8+ T-cell type, whereas patients with CD4+ T-cell type were more likely to develop hepatomegaly. Patients with CD8+ T-cell type had a poor prognosis despite receiving chemotherapy or further HSCT.


Assuntos
Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Células Matadoras Naturais , Humanos , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Masculino , Feminino , Criança , Pré-Escolar , Herpesvirus Humano 4/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Matadoras Naturais/imunologia , Linfócitos T CD4-Positivos/imunologia , Doença Crônica , Adolescente , Subpopulações de Linfócitos/imunologia , Lactente , Prognóstico , Transplante de Células-Tronco Hematopoéticas , DNA Viral/sangue , Antígeno CD56
5.
Health Aff Sch ; 2(6): qxae081, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38915811

RESUMO

Insurer-provider integration is a new form of vertical integration, with increasing prominence in health care markets. While there are potential benefits from tighter alignment between providers and payers, risks of perverse impacts on health care markets loom large. Yet, little is known about this new wave of consolidation, which limits options for policy or regulatory responses. We focus on a dominant insurer's acquisitions of ambulatory surgery centers (ASCs) to document the growth and geographic spread of these ownership events. We found that a diverse swathe of the United States has experienced an insurer-led ASC takeover. The acquisitions are also more frequently in areas where the insurer holds a higher enrollee market share at baseline, although a linear prediction of the likelihood of ASC acquisition shows a more nuanced picture.

6.
Comput Biol Med ; 177: 108636, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38810473

RESUMO

BACKGROUND: Accurate classification of gliomas is critical to the selection of immunotherapy, and MRI contains a large number of radiomic features that may suggest some prognostic relevant signals. We aim to predict new subtypes of gliomas using radiomic features and characterize their survival, immune, genomic profiles and drug response. METHODS: We initially obtained 341 images of 36 patients from the CPTAC dataset for the development of deep learning models. Further 1812 images of 111 patients from TCGA_GBM and 152 images of 53 patients from TCGA_LGG were collected for testing and validation. A deep learning method based on Mask R-CNN was developed to identify new subtypes of glioma patients and compared the survival status, immune infiltration patterns, genomic signatures, specific drugs, and predictive models of different subtypes. RESULTS: 200 glioma patients (mean age, 33 years ± 19 [standard deviation]) were enrolled. The accuracy of the deep learning model for identifying tumor regions achieved 88.3 % (98/111) in the test set and 83 % (44/53) in the validation set. The sample was divided into two subtypes based on radiomic features showed different prognostic outcomes (hazard ratio, 2.70). According to the results of the immune infiltration analysis, the subtype with a poorer prognosis was defined as the immunosilencing radiomic (ISR) subtype (n = 43), and the other subtype was the immunoactivated radiomic (IAR) subtype (n = 53). Subtype-specific genomic signatures distinguished celllines into ISR celllines (n = 9) and control celllines (n = 13), and identified eight ISR-specific drugs, four of which were validated by the OCTAD database. Three machine learning-based classifiers showed that radiomic and genomic co-features better predicted the radiomic subtypes of gliomas. CONCLUSIONS: These findings provide insights into how radiogenomic could identify specific subtypes that predict prognosis, immune and drug sensitivity in a non-invasive manner.


Assuntos
Neoplasias Encefálicas , Aprendizado Profundo , Glioma , Humanos , Glioma/genética , Glioma/diagnóstico por imagem , Glioma/imunologia , Feminino , Masculino , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/imunologia , Pessoa de Meia-Idade , Imageamento por Ressonância Magnética , Prognóstico , Radiômica
7.
Environ Sci Technol ; 58(21): 9227-9235, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38751196

RESUMO

Severe ozone (O3) pollution has been a major air quality issue and affects environmental sustainability in China. Conventional mitigation strategies focusing on reducing volatile organic compounds and nitrogen oxides (NOx) remain complex and challenging. Here, through field flux measurements and laboratory simulations, we observe substantial nitrous acid (HONO) emissions (FHONO) enhanced by nitrogen fertilizer application at an agricultural site. The observed FHONO significantly improves model performance in predicting atmospheric HONO and leads to regional O3 increases by 37%. We also demonstrate the significant potential of nitrification inhibitors in reducing emissions of reactive nitrogen, including HONO and NOx, by as much as 90%, as well as greenhouse gases like nitrous oxide by up to 60%. Our findings introduce a feasible concept for mitigating O3 pollution: reducing soil HONO emissions. Hence, this study has important implications for policy decisions related to the control of O3 pollution and climate change.


Assuntos
Ácido Nitroso , Ozônio , Solo , Ácido Nitroso/química , Solo/química , Poluição do Ar/prevenção & controle , Poluentes Atmosféricos , China , Mudança Climática , Óxido Nitroso
8.
Brain Sci ; 14(5)2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38790483

RESUMO

Electrocardiogram (ECG) abnormalities are the most common cardiac complications after acute ischemic stroke (AIS) and predict poor outcomes. The arterial baroreflex is an essential determinant of cardiovascular autonomic regulation, with receptors mainly residing in carotid sinuses and aortic arch. The atherosclerosis of these baroreceptor-resident arteries (BRA) is very common in AIS patients and might impair baroreflex function. However, the associations between the atherosclerosis of BRA and ECG abnormalities after AIS are still unknown. In total, 228 AIS patients within 7 days after onset without a pre-existing heart disease were prospectively recruited. With computed tomography angiography, atherosclerosis conditions in 10 segments of the carotid sinuses and aortic arch were scored and summed as the Total Atherosclerosis Burden of BRA (TAB-BRA), and asymptomatic coronary artery stenosis (ACAS) ≥50% was simultaneously assessed. We performed 12-lead ECG to dynamically detect abnormal repolarization, and 24 h Holter ECG to monitor arrhythmias and heart rate variability (HRV) parameters, which are reliable indicators to assess cardiac autonomic function. We found that TAB-BRA was positively associated with abnormal repolarization (OR 1.09; CI% 1.03-1.16; p = 0.003) and serious cardiac arrhythmias (OR 1.08; CI% 1.01-1.15; p = 0.021). In addition, TAB-BRA was an important predictor of abnormal repolarization, persisting over 3 days (OR 1.17; CI% 1.05-1.30; p = 0.003). However, ACAS ≥ 50% did not relate to these ECG abnormalities. TAB-BRA was negatively correlated with parasympathetic-related HRV parameters. Our results indicated that AIS patients with a high TAB-BRA are more likely to have ECG abnormalities and delayed normalization, which may relate to the decreased cardiac parasympathetic activity, but not the accompanied ACAS ≥ 50%.

9.
Sci Rep ; 14(1): 11773, 2024 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-38783071

RESUMO

Patients with ischemic cerebrovascular disease (ICVD) frequently develop concomitant peripheral artery disease (PAD) or renal artery stenosis (RAS), and multiterritorial atherosclerotic patients usually have a worse prognosis. We aimed to evaluate the status of peripheral atherosclerosis (AS) and cervicocephalic AS (CAS) in ICVD patients with AS, their correlation, and related risk factors contributing to coexisting cervicocephalic-peripheral AS (CPAS). Based on the severity and extent of AS evaluated by computed tomography angiography and ultrasound, the degree of AS was triple categorized to assess the correlation between CAS and PAD/RAS. CAS and PAD/RAS were defined as the most severe stenosis being ≥ 50% luminal diameter in cervicocephalic or lower limb arteries, and a peak systolic velocity at the turbulent site being ≥ 180 cm/s in the renal artery. Among 403 patients with symptom onset within 30 days, CAS, PAD, and RAS occurrence rates were 68.7%, 25.3%, and 9.9%, respectively. PAD was independently associated with the degree of extracranial and intracranial CAS (p = 0.042, OR = 1.428, 95% CI 1.014-2.012; p = 0.002, OR = 1.680, 95% CI 1.206-2.339), while RAS was independently associated with the degree of extracranial CAS (p = 0.001, OR = 2.880, 95% CI 1.556-5.329). Independent CPAS risk factors included an ischemic stroke history (p = 0.033), increased age (p < 0.01), as well as elevated fibrinogen (p = 0.021) and D-dimer levels (p = 0.019). In conclusion, the occurrence rates of RAS and PAD in ICVD patients with AS is relatively high, and with the severity of RAS or PAD increase, the severity of CAS also increase. Strengthening the evaluation of peripheral AS and controlling elevated fibrinogen might be crucial for preventing and delaying the progression of multiterritorial AS in ICVD patients with AS, thereby improving risk stratification and promoting more effective prevention and treatment strategies.


Assuntos
Doença Arterial Periférica , Humanos , Feminino , Masculino , Fatores de Risco , Idoso , Pessoa de Meia-Idade , Doença Arterial Periférica/etiologia , Doença Arterial Periférica/complicações , Aterosclerose/complicações , Isquemia Encefálica/etiologia , Angiografia por Tomografia Computadorizada , Transtornos Cerebrovasculares/etiologia , Obstrução da Artéria Renal/complicações , Obstrução da Artéria Renal/etiologia , Obstrução da Artéria Renal/epidemiologia
10.
Arch Pathol Lab Med ; 2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38749502

RESUMO

CONTEXT.­: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm that predominantly affects young children. OBJECTIVE.­: To investigate genetic alterations and their correlation with clinical characteristics and prognosis in pediatric LCH. DESIGN.­: We performed targeted sequencing to detect mutations in LCH lesions from pediatric patients. RESULTS.­: A total of 30 genomic alterations in 5 genes of the MAPK pathway were identified in 187 of 223 patients (83.9%). BRAF V600E (B-Raf proto-oncogene, serine/threonine kinase) was the most common mutation (51.6%), followed by MAP2K1 (mitogen-activated protein kinase kinase 1) alterations (17.0%) and other BRAF mutations (13.0%). ARAF (A-Raf proto-oncogene, serine/threonine kinase) and KRAS (KRAS proto-oncogene, GTPase) mutations were relatively rare (2.2% and 0.9%, respectively). Additionally, FNBP1 (formin-binding protein 1)::BRAF fusion and MAP3K10 (mitogen-activated protein kinase kinase 10) mutations A17T and R823C were identified in 1 case each, with possible constitutive activation of ERK1/2 phosphorylation. BRAF V600E was more frequent in patients with risk organ involvement, while MAP2K1 mutation was more prevalent in patients with single-system LCH (P = .001). BRAF V600E was associated with craniofacial bone, skin, liver, spleen, and ear involvement (all P < .05). Patients with other BRAF mutations had a higher proportion of spinal column involvement (P = .006). Univariate analysis showed a significant difference in progression-free survival among the 4 molecular subgroups for patients treated with first-line therapy (P = .02). According to multivariate analysis, risk organ involvement was the strongest independent adverse prognostic factor (hazard ratio, 8.854; P < .001); BRAF or MAP2K1 mutation was not an independent prognostic factor. CONCLUSIONS.­: Most pediatric patients with LCH carry somatic mutations involving the MAPK pathway, correlating with clinical characteristics and outcomes for first-line chemotherapy.

11.
Sci Total Environ ; 927: 172396, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38608903

RESUMO

Size-segregated aerosols collected in Beijing from 2021 to 2022 were used to investigate the contribution of organic aerosols to the aerosol liquid water content (ALWC), the influencing factors of ALWC, and the concentrations and size distribution characteristics of water-soluble organic carbon (WSOC) after clean air actions. The results showed that the concentration of WSOC in particulate matter (PM)1.8 was 3.52 ± 2.43 µg/m3 during the sampling period. Obvious changes were observed in the size distribution of WSOC after clean air actions, which may be attributed to the enhancement of atmospheric oxidation capacity and the decrease in PM concentration. The contribution of organic aerosols to the ALWC in fine PM was 18.1 % during the sampling period, which was more significant at lower particles concentration and smaller particle size ranges. The ambient relative humidity (RH) and the ratio of NO3-/SO42- had an apparent influence on ALWC. The continuous increase in the nitrate proportion significantly reduced the deliquescence point of the aerosols, making them prone to hygroscopic growth at lower RH. Analysis of the relation among nitrogen oxidation ratio (sulfur oxidation ratio), ALWC and PM1.8 mass concentrations suggests that organic matter has a significant effect on the formation of secondary inorganic aerosols in the initial phase of pollution formation and plays a crucial role in aerosol pollution formation in Beijing. These results are conducive to understanding the formation mechanism of aerosols and provide scientific data and theoretical support for the formulation of more effective emission-reduction measures.

12.
Pharmacol Biochem Behav ; 237: 173726, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38360104

RESUMO

BACKGROUND: Some studies have highlighted the crucial role of aversion in addiction treatment. The pathway from the anterior paraventricular thalamus (PVT) to the shell of the nucleus accumbens (NAc) has been reported as an essential regulatory pathway for processing aversion and is also closely associated with substance addiction. However, its impact on alcohol addiction has been relatively underexplored. Therefore, this study focused on the role of the PVT-NAc pathway in the formation and relapse of alcohol addiction-like behaviour, offering a new perspective on the mechanisms of alcohol addiction. RESULTS: The chemogenetic inhibition of the PVT-NAc pathway in male mice resulted in a notable decrease in the establishment of ethanol-induced conditioned place aversion (CPA), and NAc-projecting PVT neurons were recruited due to aversive effects. Conversely, activation of the PVT-NAc pathway considerably impeded the formation of ethanol-induced conditioned place preference (CPP). Furthermore, during the memory reconsolidation phase, activation of this pathway effectively disrupted the animals' preference for alcohol-associated contexts. Whether it was administered urgently 24 h later or after a long-term withdrawal of 10 days, a low dose of alcohol could still not induce the reinstatement of ethanol-induced CPP. CONCLUSIONS: Our results demonstrated PVT-NAc circuit processing aversion, which may be one of the neurobiological mechanisms underlying aversive counterconditioning, and highlighted potential targets for inhibiting the development of alcohol addiction-like behaviour and relapse after long-term withdrawal.


Assuntos
Alcoolismo , Núcleo Accumbens , Camundongos , Masculino , Animais , Núcleo Accumbens/metabolismo , Alcoolismo/metabolismo , Tálamo , Etanol/farmacologia , Etanol/metabolismo , Recidiva
13.
BMC Pregnancy Childbirth ; 24(1): 2, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38166713

RESUMO

BACKGROUND: This study aimed to assess whether maternal telomere length is a more accurate predictor of trisomy 21 than maternal age while also exploring the factors influencing maternal and fetal telomere length. METHODS: Forty mothers with fetuses carrying extra maternal copies of chromosome 21 were defined as trisomy 21 cases, and 18 mothers with normal karyotype fetuses were defined as controls. Telomere lengths of maternal blood lymphocytes and amniotic fluid cells were determined using real-time polymerase chain reaction. Fetal and maternal telomere lengths were compared between the two groups. Moreover, we analyzed the factors influencing maternal and fetal telomere length in the trisomy 21 pedigree. A logistic regression model was used to analyze the correlation between maternal telomere length and trisomy 21 risk. In addition, receiver operating characteristic (ROC) curve analysis was used to determine the accuracy of using maternal telomere length as an indicator of trisomy 21 risk. RESULTS: The study revealed that both maternal and fetal telomere lengths were significantly shorter in trisomy 21 cases than in the controls. In the trisomy 21 group, the maternal age, occupation, and nationality showed no significant correlation with their telomere length; fetal telomere length exhibited a positive correlation with maternal telomere length. Furthermore, maternal telomere length shortening is associated with trisomy 21 (OR = 0.311; 95% CI, 0.109-0.885, P < 0.05). The results of ROC curve analysis indicated that a combined assessment of maternal age and maternal telomere length predicted fetal chromosome trisomy more effectively than a single assessment (area under the curve 0.808, 95% CI, 0.674-0.941, P < 0.001). CONCLUSION: Maternal age combined with maternal telomere length proved to be a superior predictor of trisomy risk. Additionally, maternal telomere length was found to influence fetal telomere length.


Assuntos
Síndrome de Down , Trissomia , Feminino , Humanos , Trissomia/diagnóstico , Trissomia/genética , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Encurtamento do Telômero , Aneuploidia , Feto , Sangue Fetal
14.
Diabetes Metab Syndr Obes ; 17: 247-257, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38269338

RESUMO

Purpose: The aim of this study was to investigate the effects and mechanisms of SGLT2 inhibitor empagliflozin on diabetic coronary function. Methods: A rat diabetic model was established by injection of streptozotocin. Rats in the treated group were administered empagliflozin by gavage and rat coronary vascular tensions were measured after eight weeks. Large conductance calcium activated K+ channel currents were recorded using a patch clamp technique, while human coronary artery smooth muscle cells were used to explore the underlying mechanisms. Results: After incubation with empagliflozin (10, 30, 100, 300, 1000 µmol/L), the Δ relaxation % of rat coronary arteries were 2.459 ± 1.304, 3.251 ± 1.119, 6.946 ± 3.407, 28.36 ± 11.47, 86.90 ± 3.868, respectively. Without and with empagliflozin in the bath solution, BK channel opening probabilities at a membrane potential of +60 mV were 0.0458 ± 0.0517 and 0.3413 ± 0.2047, respectively (p < 0.05, n = 4 cells). After incubation with iberiotoxin, the Δ tensions of rat coronary arteries in the control (Ctrl), untreated (DM), low empagliflozin (10 mg/kg/d)-treated (DM+L-EMPA) and high empagliflozin (30mg/kg/d)-treated (DM+H-EMPA) group were 103.20 ± 5.85, 40.37 ± 22.12, 99.47 ± 28.51, 78.06 ± 40.98, respectively (p < 0.01 vs Ctrl, n = 3-7; p < 0.001 vs DM+L-EMPA, n = 5-7). Empagliflozin restored high glucose-induced downregulation of Sirt1, Nrf2, and BK-ß1, while the effect of empagliflozin disappeared in the presence of EX-527, a Sirt1 selective inhibitor. Conclusion: Empagliflozin has a vasodilation effect on the coronary arteries in a concentration-dependent manner and can activate BK channels via the Sirt1-Nrf2 mechanism.

15.
Ann Hematol ; 103(1): 17-28, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37851074

RESUMO

To analyze the genetic variation and prognosis of primary hemophagocytic lymphohistiocytosis (pHLH) in children and the clinical features of isolated central nervous system HLH (CNS-HLH). We retrospectively analyzed the clinical and genetic data of 480 HLH children admitted to our hospital from September 2017 to September 2022. There were 66 patients (13.75%) with pHLH, and the median age was 3.21 years (0.17-12.92 years). Variants in UNC13D (22/66, 33.33%), PRF1 (20/66, 30.30%) and XIAP (11/66, 16.67%) were the most common. More CNS involvement was observed in pHLH patients than in secondary hemophagocytic lymphohistiocytosis (sHLH) patients (50% vs. 25.3%, P = 0.001). Eight pHLH patients had isolated CNS-HLH at onset, which progressed to systemic HLH within 10-30 days to several years. Among them, five patients who underwent hematopoietic stem cell transplantation (HSCT) survived without CNS sequelae, and the three patients who did not undergo HSCT died of disease progression or recurrence. Determination of natural killer (NK) cell cytotoxicity and CD107a levels had low sensitivity and specificity in the diagnosis of pHLH, especially in patients with PRF1 and XIAP mutations. The 3-year overall survival (OS) was significantly lower in pHLH patients than in sHLH patients (74.5% ± 14.7% vs. 89.2% ± 3.53%, P = 0.021) and in patients with CNS involvement than in those without (53.8% ± 26.07% vs. 94.4% ± 10.58%, P = 0.012). There was a significant difference in OS among pHLH patients with different gene variants (P = 0.032); patients with PRF1 variants had poor 3-year OS, and patients with XIAP variants had good 3-year OS (50% ± 28.22% and 100%, respectively). pHLH patients with distinct variants have different prognoses. Isolated CNS-HLH patients are easily misdiagnosed, and HSCT may be beneficial for these patients. Determination of NK cell cytotoxicity and CD107a levels cannot precisely distinguish pHLH from sHLH.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfo-Histiocitose Hemofagocítica , Criança , Humanos , Pré-Escolar , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/terapia , Estudos Retrospectivos , Prognóstico , Mutação , Proteínas de Membrana/genética
16.
J Pediatr Hematol Oncol ; 46(1): e71-e82, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38018972

RESUMO

BACKGROUND: Accurate histologic and molecular genetic diagnosis is critical for the pathogenesis study of pediatric patients with lymphoblastic lymphoma (LBL). Optical genome mapping (OGM) as all-in-one process allows the detection of most major genomic risk markers, which addresses some of the limitations associated with conventional cytogenomic testing, such as low resolution and throughput, difficulty in ascertaining genomic localization, and orientation of segments in duplication, inversions, and insertions. Here, for the first time, we examined the cytogenetics of 5 children with LBL using OGM. METHODS: OGM was used to analyze 5 samples of pediatric LBL patients treated according to the modified NHL-BFM95 backbone regimen. Whole-exon Sequencing (WES) was used to confirm the existence of structural variants (SVs) identified by OGM with potentially clinical significance on MGI Tech (DNBSEQ-T7) platform. According to the fusion exon sequences revealed by WES, the HBS1L :: AHI1 fusion mRNA in case 4 was amplified by cDNA-based PCR. RESULTS: In total, OGM identified 251 rare variants (67 insertions, 129 deletions, 3 inversion, 25 duplications, 15 intrachromosomal translocations, and 12 interchromosomal translocations) and 229 copy number variants calls (203 gains and 26 losses). Besides all of the reproducible and pathologically significant genomic SVs detected by conventional cytogenetic techniques, OGM identified more SVs with definite or potential pathologic significance that were not detected by traditional methods, including 2 new fusion genes, HBS1L :: AHI1 and GRIK1::NSDHL , which were confirmed by WES and/or Reverse Transcription-Polymerase Chain Reaction. CONCLUSIONS: Our results demonstrate the feasibility of OGM to detect genomic aberrations, which may play an important role in the occurrence and development of lymphomagenesis as an important driving factor.


Assuntos
Linfoma não Hodgkin , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Criança , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Variações do Número de Cópias de DNA , Éxons , Mapeamento Cromossômico
17.
Am J Drug Alcohol Abuse ; 49(6): 746-755, 2023 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-38059570

RESUMO

Background: Overwhelming evidence suggests that increasing alcohol taxes is an effective strategy for curbing alcohol consumption. However, research on the effects of such strategies in low- and middle-income nations is limited.Objective: The aim is to explore the temporal effect of alcohol tax policy in China.Methods: We employ interrupted time series analysis to investigate the temporal effects of tax policy changes on alcohol consumption and related consequences in Mainland China from 1961 to 2019. The study population, the total population of mainland region of China, aged more than 15 years.Results: The results show that the volume tax policy, which was announced in 2000 and implemented in 2001, led to an immediate reduction in the alcohol consumption (coefficient = -0.429, p < .001). Following the implementation of higher alcohol taxes in 1998 and 2001, the prevalence of alcohol use disorders (AUDs) and related years lived with disability (YLDs) gradually decreased. The relaxation of tax policy in 2006 led to a significant increase in alcohol consumption, both immediately (coefficient = 0.406, p < .001) and in the middle term (coefficient = 0.495, p < .001), as well as contribute to an immediate or medium term significant increase in the prevalence of AUDs (coefficient = 0.038, p = .010; coefficient = 0.032, p < .001) and YLDs (coefficient = 4.363, p = .001; coefficient = 4.226, p < .001).Conclusion: This study demonstrates that changes in alcohol consumption and related consequences (increase or decrease) have followed corresponding changes in alcohol tax policies (easing or tightening), indicating that increasing alcohol taxes can be an effective strategy in China for controlling alcohol consumption and related harms.


Assuntos
Alcoolismo , Humanos , Alcoolismo/epidemiologia , Alcoolismo/prevenção & controle , Análise de Séries Temporais Interrompida , Consumo de Bebidas Alcoólicas/epidemiologia , Política Pública , Impostos , China/epidemiologia , Bebidas Alcoólicas
18.
Eur J Pharmacol ; 961: 176167, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-37939994

RESUMO

BACKGROUND: Recent evidence revealed that glucose fluctuation might be more likely to cause arrhythmia than persistent hyperglycemia, whereas its mechanisms were elusive. We aimed to investigate the effect of glucose fluctuation on the occurrence of ventricular arrhythmia and its mechanism. METHODS: Streptozotocin (STZ) induced diabetic rats were randomized to five groups: the controlled blood glucose (C-STZ) group, uncontrolled blood glucose (U-STZ) group, fluctuated blood glucose (GF-STZ) group, and GF-STZ rats with 100 mg/kg Tempol (GF-STZ + Tempol) group or with 5 mg/kg KN93 (GF-STZ + KN93) group. Six weeks later, the susceptibility of ventricular arrhythmias and the electrophysiological dysfunctions of ventricular myocytes were evaluated using electrocardiogram and patch-clamp technique, respectively. The levels of reactive oxygen species (ROS) and oxidized CaMKII (ox-CaMKII) were determined by fluorescence assay and Western blot, respectively. Neonatal rat cardiomyocytes and H9C2 cells in vitro were used to explore the underlying mechanisms. RESULTS: The induction rate of ventricular arrhythmias was 10%, 55%, and 90% in C-STZ group, U-STZ group, and GF-STZ group, respectively (P < 0.05). The electrophysiological dysfunctions of ventricular myocytes, including action potential duration at repolarization of 90% (APD90), APD90 short-term variability (APD90-STV), late sodium current (INa-L), early after depolarization (EAD) and delayed after depolarizations (DAD), as well as the levels of ROS and ox-CaMKII, were significantly increased in GF-STZ group. In vivo and ex vivo, inhibition of ROS or ox-CaMKII reversed these effects. Inhibition of INa-L also significantly alleviated the electrophysiological dysfunctions. In vitro, inhibition of ROS increase could significantly decrease the ox-CaMKII activation induced by glucose fluctuations. CONCLUSIONS: Glucose fluctuations aggravated the INa-L induced ventricular arrhythmias though the activation of ROS/CaMKII pathway.


Assuntos
Diabetes Mellitus Experimental , Glucose , Animais , Ratos , Potenciais de Ação , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/metabolismo , Glicemia/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Diabetes Mellitus Experimental/metabolismo , Glucose/metabolismo , Miócitos Cardíacos , Espécies Reativas de Oxigênio/metabolismo , Sódio/metabolismo
19.
J Infect Dis ; 2023 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-37787605

RESUMO

PURPOSE: To analyze the clinical characteristics of peripheral Epstein-Barr virus(EBV)-infected lymphocyte subtypes in children with chronic active EBV infection(CAEBV). METHODS: The levels of peripheral EBV infection of CD4 + T cells, CD8 + T cells, and CD56 + NK cells were determined by flow cytometry and qPCR in patients with CAEBV from July 2017 to July 2022. RESULTS: A total of 112 children with CAEBV were evaluated in the study. Of them, CD4 + type, CD8 + type, and CD56 + type were defined in 44, 21, and 47 patients, respectively. Patients with CD8 + T-cell type had a significantly higher frequency of rash, while hepatomegaly was more common in patients with CD4 + T-cell type. Generally, patients with CD8 + T-cell type had the lowest overall survival(OS) rate(P = 0.017). As for treatment, patients treated with chemotherapy and hematopoietic stem cell transplantation had a better prognosis(P = 0.001). In multivariate analysis, rash, HLH, CD8 + T-cell type, and no decrease of plasma EBV-DNA after treatment were indicated as independent factors of poor prognosis(P = 0.002, 0.024, 0.022, and 0.012, respectively). CONCLUSION: In children with CAEBV, the rash was more frequent in patients with CD8 + T-cell type, whereas patients with CD4 + T-cell type were more likely to develop hepatomegaly. Patients with CD8 + T-cell type had a poor prognosis despite receiving chemotherapy or further HSCT.

20.
Diabetol Metab Syndr ; 15(1): 217, 2023 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-37891701

RESUMO

BACKGROUND: Glucose fluctuations (GF) are a risk factor for cardiovascular complications associated with type 2 diabetes. However, there is a lack of adequate research on the effect of GF on myocardial fibrosis and the underlying mechanisms in type 2 diabetes. This study aimed to investigate the impact of glucose fluctuations on myocardial fibrosis and explore the potential mechanisms in type 2 diabetes. METHODS: Sprague Dawley (SD) rats were randomly divided into three groups: the control (Con) group, the type 2 diabetic (DM) group and the glucose fluctuations (GF) group. The type 2 diabetic rat model was established using a high-fat diet combined with low-dose streptozotocin injection and the GF model was induced by using staggered glucose and insulin injections daily. After eight weeks, echocardiography was used to assess the cardiac function of the three groups. Hematoxylin-eosin and Masson staining were utilized to evaluate the degree of pathological damage and fibrosis. Meanwhile, a neonatal rat cardiac fibroblast model with GF was established. Western and immunofluorescence were used to find the specific mechanism of myocardial fibrosis caused by GF. RESULTS: Compared with rats in the Con and the DM group, cardiac function in the GF group showed significant impairments. Additionally, the results showed that GF aggravated myocardial fibrosis in vitro and in vivo. Moreover, Ca2+/calmodulin­dependent protein kinase II (CaMKII) was activated by phosphorylation, prompting an increase in phosphorylation of signal transducer and activator of transcription 3 (Stat3) and induced nuclear translocation. Pretreatment with KN-93 (a CaMKII inhibitor) blocked GF-induced Stat3 activation and significantly suppressed myocardial fibrosis. CONCLUSIONS: Glucose fluctuations exacerbate myocardial fibrosis by triggering the CaMKII/Stat3 pathway in type 2 diabetes.

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