Application and design considerations of ROS-based nanomaterials in diabetic kidney disease.

Diabetic nephropathy (DKD) is a common chronic complication of diabetes mellitus and an important cause of cardiovascular-related death. Oxidative stress is a key mechanism leading to diabetic nephropathy. However, the current main therapeutic approach remains combination therapy and lacks specific therapies targeting oxidative stress. With the development of nanotechnology targeting ROS, therapeutic fluids regarding their treatment of diabetic nephropathy have attracted attention. In this review, we provide a brief overview of various ROS-based nanomaterials for DKD, including ROS-scavenging nanomaterials, ROS-associated nanodelivery materials, and ROS-responsive nanomaterials. In addition, we summarize and discuss key factors that should be considered when designing ROS-based nanomaterials, such as biosafety, efficacy, targeting, and detection and monitoring of ROS.

Echocardiographic Measurements in Normal Chinese Adults (EMINCA) II focusing on left ventricular and left atrial size and function by three-dimensional echocardiography.

Current guidelines encourage large studies in a diverse population to establish normal reference ranges for three-dimensional (3D) echocardiography for different ethnic groups. This study was designed to establish the normal values of 3D-left ventricular (LV) and left atrial (LA) volume and function in a nationwide, population-based cohort of healthy Han Chinese adults. A total of 1117 healthy volunteers aged 18-89 years were enrolled from 28 collaborating laboratories in China. Two sets of 3D echocardiographic instruments were used, and full-volume echocardiographic images were recorded and transmitted to a core laboratory for image analysis with a vendor-independent off-line workstation. Finally, 866 volunteers (mean age of 48.4 years, 402 men) were qualified for final analysis. Most parameters exhibited substantial differences between different sex and age groups, even after indexation by body surface area. The normal ranges of 3D-LV and 3D-LA volume and function differed from those recommended by the American Society of Echocardiography and the European Association of Cardiovascular Imaging guidelines, presented by the World Alliance Societies of Echocardiography (WASE) study, and from the 2D values in the EMINCA study. The normal reference values of 3D echocardiography-derived LV and LA volume and function were established for the first time in healthy Han Chinese adults. Normal ranges of 3D-LV and 3D-LA echocardiographic measurements stratified with sex, age, and race should be recommended for clinical applications.

Right ventricular volume and function by three-dimensional echocardiography: results of the echocardiographic measurements in normal Chinese adults (EMINCA) II.

Three-dimensional (3D) echocardiography is an emerging technique for assessing right ventricular (RV) volume and function, but 3D-RV normal values from a large Chinese population are still lacking. The aim of the present study was to establish normal values of 3D-RV volume and function in healthy Chinese volunteers. A total of 1117 Han Chinese volunteers from 28 laboratories in 20 provinces of China were enrolled, and 3D-RV images of 747 volunteers with optimal image quality were ultimately analyzed by a core laboratory. Both vendor-dependent and vendor-independent software platforms were used to analyze the 3D-RV images. We found that men had larger RV volumes than women did in the whole population, even after indexing to body surface area, and older individuals had smaller RV volumes. The normal RV volume was significantly smaller than that recommended by the American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines in both sexes. There were significant differences in 3D-RV measurements between the two vendor ultrasound systems and the different software platforms. The echocardiographic measurements in normal Chinese adults II study revealed normal 3D-RV volume and function in a large Chinese population, and there were significant differences between the sexes, ages, races, and vendor groups. Thus, normal 3D-RV values should be stratified by sex, age, race, and vendor.

Comparison of the efficacy and safety of ultrasound-guided radiofrequency ablation and microwave ablation for the treatment of unifocal papillary thyroid microcarcinoma: a retrospective study.

PURPOSE: This study aimed to compare the efficacy and safety of ultrasound-guided RFA and MWA in the treatment of unifocal PTMC. METHODS: This retrospective study included 512 patients with 512 unifocal papillary thyroid microcarcinomas (PTMCs) who underwent RFA (n = 346) and MWA (n = 166) between January 2021 and December 2021. The volumes of the ablation areas were measured during follow-up, and the volume reduction rates were evaluated. The ablation duration, volume of hydrodissection, and ablation-related complications were also compared between the groups. RESULTS: All lesions received complete ablation and no local or distant recurrences were observed in the two groups. A larger volume of isolation liquid was used for RFA than for MWA (p = 0.000). Hoarseness occurred in seven patients who underwent RFA (p = 0.102). At the 1-week follow-up, the mean volume of the areas ablated by RFA was smaller than that of the areas ablated by MWA (p = 0.049). During follow-ups at months 3, 9, 12, 15, and 18, the mean volumes of the ablated areas were larger in the RFA group than in the MWA group (all, p < 0.05). The mean volume of the ablated lesions increased slightly at the 1-week follow-up and then decreased at 1 month after ablation in both groups. The absorption curve of the ablated lesions in the RFA group was similar to that in the MWA group. CONCLUSIONS: RFA and MWA are both efficient and safe methods for treating unifocal PTMC. They may be alternative techniques for patients who are not eligible or are unwilling to undergo surgery.

Pediatric hypertension caused by congenital abdominal aortic stenosis: A case image report.

We confirm that the cause of hypertension in this pediatric patient is congenital abdominal aortic stenosis. This case serves as a reminder to be vigilant for the possibility of congenital vascular abnormalities leading to hypertension in children.

Association of FOXO3A with right ventricular myocardial fibrosis and its detection by speckle-tracking echocardiography in pulmonary hypertension.

BACKGROUND: Myocardial fibrosis can result in right ventricular (RV) dysfunction, a critical factor in poor clinical outcomes and high mortality rates among patients with pulmonary hypertension (PH). Decreased RV myocardial strain rates have been reported in PH patients. The expression of FOXO3A may play a crucial role in myocardial fibrosis; however, the relationship between myocardial fibrosis, speckle-tracking echocardiography (STE), and the transcription factor FOXO3A remains unclear. This study aimed to explore the relationship between the molecular mechanisms of myocardial fibrosis and noninvasive ultrasound evaluation indices to provide a reliable molecular foundation for the early diagnosis of right heart dysfunction in clinical settings. METHODS: A progressive right heart failure (RHF) rat model was established through subcutaneous injections of monocrotaline. Rats were divided into baseline, 2-week, 4-week, and 6-week groups based on the disease course. RV structure, function, and myocardial strain were assessed via echocardiography. Myocardial fibrosis severity was determined using PSR staining. The correlation between myocardial strain and RV myocardial fibrosis was analyzed. FOXO3A, collagen I, collagen III, and BNP expressions were tested using western blotting. RESULTS: As the disease progressed, the right ventricle significantly expanded, and the RV fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE), RV global longitudinal strain (RVLS global), and RV free wall longitudinal strain (RVLS FW) gradually declined. However, the reductions in RVLS global and RVLS FW occurred earlier than that of RVFAC, TAPSE. Significant correlations were observed between RVLS global, RVLS FW, and collagen deposition. FOXO3A expression gradually decreased with disease progression, while BNP, collagen I, and collagen III expressions gradually increased. CONCLUSIONS: Decreases in RVLS global and RVLS FW in RHF rats occurred earlier than RVFAC and were associated with RV myocardial fibrosis. Furthermore, FOXO3A may have a protective role in the process of RV myocardial fibrosis.

Pediatric restrictive cardiomyopathy: a case report.

Restrictive cardiomyopathy (RCM) is a rare childhood cardiomyopathy that is a challenging diagnostic problem for clinicians. We describe a case of an 8-year-old girl with a 2-year history of shortness of breath on exertion. Electrocardiogram and echocardiography showed biatrial enlargement, while cardiac magnetic resonance showed biatrial dilation and normal pericardial thickness. Left and right heart catheterization revealed a left ventricular (LV) end-diastolic pressure (EDP) of 20 mmHg, right ventricular (RV) EDP of 13 mmHg, and pulmonary arterial systolic pressure of 51 mmHg. LV and RV pressure traces showed that LV and RV pressures moved concordantly with respiration, and that the systolic area index was 0.98. Cardiac catheterization data were therefore supportive of RCM. Next-generation sequencing identified a heterozygous variant of the troponin I gene (TNNI3; c.574C>T). Combining these findings led to a diagnosis of RCM. The patient's parents chose conservative treatment, but at the 12-month follow-up she died of worsening heart failure and cerebral infarction. This case emphasizes the need for cardiac catheterization and genetic testing in RCM, and suggests that anticoagulants should be recommended to reduce the risk of thromboembolic events.

The role of CD8+ T-cell clones in immune thrombocytopenia.

Immune thrombocytopenia (ITP) is traditionally considered an antibody-mediated disease. However, a number of features suggest alternative mechanisms of platelet destruction. In this study, we use a multidimensional approach to explore the role of cytotoxic CD8+ T cells in ITP. We characterized patients with ITP and compared them with age-matched controls using immunophenotyping, next-generation sequencing of T-cell receptor (TCR) genes, single-cell RNA sequencing, and functional T-cell and platelet assays. We found that adults with chronic ITP have increased polyfunctional, terminally differentiated effector memory CD8+ T cells (CD45RA+CD62L-) expressing intracellular interferon gamma, tumor necrosis factor α, and granzyme B, defining them as TEMRA cells. These TEMRA cells expand when the platelet count falls and show no evidence of physiological exhaustion. Deep sequencing of the TCR showed expanded T-cell clones in patients with ITP. T-cell clones persisted over many years, were more prominent in patients with refractory disease, and expanded when the platelet count was low. Combined single-cell RNA and TCR sequencing of CD8+ T cells confirmed that the expanded clones are TEMRA cells. Using in vitro model systems, we show that CD8+ T cells from patients with ITP form aggregates with autologous platelets, release interferon gamma, and trigger platelet activation and apoptosis via the TCR-mediated release of cytotoxic granules. These findings of clonally expanded CD8+ T cells causing platelet activation and apoptosis provide an antibody-independent mechanism of platelet destruction, indicating that targeting specific T-cell clones could be a novel therapeutic approach for patients with refractory ITP.

Evaluation of left ventricular function in ischemia with non-obstructive coronary arteries: a research based on adenosine stress myocardial contrast echocardiography.

Patients with ischemia with non-obstructive coronary arteries (INOCA) have an increased risk of adverse cardiovascular events in the future, which is widespread but underdiagnosed. The purpose of this study is to explore the application value of adenosine stress myocardial contrast echocardiography (ASMCE) in INOCA disease, so that clinicians can early identify and intervene patients with left ventricular function subclinical impairment in INOCA. We enrolled 118 patients with INOCA by ASMCE and invasive coronary angiography (ICA), 97 of whom had complete data. The study population was divided into two subgroups depending on coronary flow velocity reserve (CFVR): impaired CFVR group (n = 34) and normal CFVR group (n = 63). Global longitudinal strain endocardial myocardial (GLSendo), mid-myocardial (GLSmid) and epicardial myocardial (GLSepi) increased after stress in both groups; transmural strain, wall motion scored index (WMSI) and myocardial perfusion scored index (MPSI) increased and FORCE decreased in impaired CFVR group after stress, but there was no difference in normal group before and after stress. There was no significant difference in left ventricular myocardial mechanical parameters, including ΔGLSendo, ΔGLSmid, ΔGLSepi, GLSendo-epi Reserve, Δpeak strain dispersion (PSD), PSD Reserve between the two groups, but ΔEF, strain reserve and left ventricular contractile reserve (LVCR) in the impaired CFVR group were lower than those in the normal CFVR group, while ΔWMSI and ΔMPSI were increased. CFVR can be a clinically valuable indicator in the ASMCE diagnosis of patients with microvascular angina pectoris in INOCA. In the evaluation of left ventricular function in INOCA patients, attention should be paid not only to myocardial deformation, but also to the dynamic changes of LVCR and myocardial perfusion during peak hyperemia.

Transcatheter closure for postinfarction ventricular septal defect: A meta-analysis of the current evidence.

OBJECTIVE: Postinfarction ventricular septal defect (PIVSD) is a severe complication of acute myocardial infarction (AMI). Transcatheter closure (TCC) is an alternative option to surgical repair. This study was undertaken to examine the published literature to provide objective evidence for TCC using a meta-analysis. METHODS: We searched for significant medical and publisher databases. Two reviewers checked the quality of the studies and extracted data. Eligible studies included single-arm studies and comparative studies. Weighted means, pooled event rates, efficacy outcomes and odds ratios (ORs) for immediate shunt reduction (ISR), presence of cardiogenic shock (CS), New York Heart Association (NYHA) class IV, time from AMI to ventricular septal defect (VSD), and time to VSD closure was estimated. RESULTS: A total of 27 single-arm articles (462 patients) were included. The pooled event rate was 89.7% (95% confidence interval [CI]: 0.772-1.021) for successful device implantation, 80.9% (95% CI: 0.645-0.972) for ISR, 31.5% (95% CI: 0.149-0.482) for 30-day mortality, and 25.3% (95% CI: 0.072-0.434) for 30-day mortality of primary closure at the acute phase. CS (OR = 3.607, 95% CI: 2.301-5.653), NYHA class IV (OR = 6.491, 95% CI: 1.444-29.188) and time to VSD closure were risk predictors for TCC. There was no correlation between defect size (OR = 2.592, 95% CI: 0.380-17.661) and mortality. CONCLUSION: TCC should be a relatively safe and minimally invasive method for PIVSD, with an excellent successful device implantation rate and acceptable low 30-day mortality. The procedure appears promising, but its safety and efficacy could only be demonstrated by randomized controlled trials. Therefore, the mortality of data comparing surgery to TCC compels the need for future comparative trials.

Assessment of fetal cardiac diastolic function of gestational diabetes mellitus using dual-gate Doppler.

ABSTRACT: Gestational Diabetes Mellitus (GDM), as a common complication of pregnancy, has an increasing trend globally. GDM leads to maternal complications and fetal complications. Fetal cardiac diastolic dysfunction is strongly associated with GDM. This study aims to assess the ventricular diastolic function of fetuses exposed to GDM by looking into the diagnostic parameters using both conventional method and Dual-gate Doppler method (DD). And to investigate the potential of DD method in early detection of fetal cardiac diastolic dysfunction.56 women diagnosed with GDM and 55 non-GDM pregnant women were enrolled in their 24 to 30 weeks of gestation. Conventional method and DD method were applied to measure mitral and tricuspid inflow velocities E-waves, A-waves on pulsed-wave Doppler, and mitral and tricuspid annular velocities e'-waves, a'-waves on Tissue Doppler imaging. E/A, e'/a' and E/e' ratio was calculated. The difference between GDM and control groups was statistically tested and analysed using one-sample Kolmogorov-Smirnov test, Student t test, Mann-Whitney U test and Kruskal-Wallis test and Bland-Altman plot analysis.Intraobserver intraclass correlation coefficients of E/A, e'/a', and E/e' value of both mitral and tricuspid valve are all greater than 0.80, while interobserver intraclass correlation coefficients are between 0.71 and 0.88. Right (6.35 vs 6.79; P = .001) ventricular function showed significantly lower E/e' ratios in the GDM group compared with control fetuses by conventional method. Both left (6.16 vs 6.59; P = .036) and right (6.28 vs 6.75; P = .01) ventricular function showed significantly lower E/e' ratios in the GDM group compared with control fetuses by DD method.Exposure to high level of maternal blood glucose leads to impaired diastolic function in the fetuses. Fetal right ventricular function is a potential key point to study to enable an early detection for fetal diastolic dysfunction since the alteration and damage are more likely to happen in right ventricular. Measurement of E/e' ratio using DD method is considered as a promising method in fetal cardiac diastolic function assessment. Well or poorly control of the GDM does not have significant influence on the fetal diastolic function thus an early detection of GDM and GDM induced fetal cardiac dysfunction is necessary.

Multimodal imaging of a rare interventricular septum dissecting aneurysm: A case report.

We report the case of a patient who presented with chest pain and palpitation, and in whom multimodality imaging, including transthoracic echocardiography, computer tomography angiogram, and coronary angiogram led to the diagnosis of interventricular septum dissecting aneurysm resulting from the rupture of a sinus of Valsalva aneurysm and paravalvular aortic root pseudoaneurysm. The patient underwent the modified Cabrol procedure in the cardiac surgery department. His ruptured sinus of Valsalva aneurysm was repaired and its communication with the pseudoaneurysm was closed. This case report highlights the role of multimodality cardiac imaging.

Prevalence of Congenital Heart Disease Amongst Schoolchildren in Southwest China.

OBJECTIVE: To investigate the prevalence and risk factors of congenital heart disease in Yunnan, China which has diverse ethnic groups. METHODS: This cross-sectional study enrolled 244,023 children from 2010 to 2015. To diagnose CHD, a conventional physical examination was used to screen suspicious cases, which were further confirmed by echocardiography. RESULTS: A total of 1695 children were diagnosed with CHD. The estimated prevalence was 6.94%. Atrial septal defects were the most common cardiac abnormalities. A higher prevalence of CHD was observed with preterm birth, low birth weight, maternal age ≥35 years, and high-altitude regions. The prevalence also showed differences between diverse ethnic groups. CONCLUSIONS: The prevalence of CHD in China may have ethnic differences.

Incidence of chromosomal anomalies in fetuses with isolated right aortic arch: A meta-analysis.

OBJECTIVE: Right aortic arch (RAA) can be associated with chromosomal anomalies. However, the incidence of chromosomal anomalies when RAA is isolated (iRAA), ie, not associated with intracardiac anomalies, varies between different studies (0%-28.5%). We have performed a meta-analysis to allow a more accurate prenatal counselling. METHODS: We searched PubMed, Embase, and Web of Science for articles related to chromosomal anomalies among iRAA fetuses until April 2019. A total of 22 relevant studies, including 670 fetuses, were selected in the final meta-analysis. RESULTS: The results revealed that the overall rates of chromosomal anomalies and 22q11.2 deletion in iRAA fetuses were 7.5% (95% confidence interval [CI], 4.7%-10.8%) and 4.3% (95% CI, 2.6%-6.4%), respectively, while the rates were lower in iRAA without extracardiac anomalies, 4.7% (95% CI, 1.1%-10.8%) and 2.4% (95% CI, 0.5%-5.7%). The rate of chromosomal or copy number variants including 22q11.2 deletion identified by chromosomal microarray analysis (CMA) in iRAA fetuses was 8.2% (95% CI, 5.0%-12.1%) and 3.7% (95% CI, 1.7%-6.6%), respectively, compared with 5.1% (95% CI, 2.5%-8.4%) and 2.4% (95% CI, 0.7%-5.1%) identified by traditional karyotyping. CONCLUSIONS: A considerable proportion of iRAA cases have associated chromosomal anomalies and prevalence of associated 22q11.2 deletion, and CMA is recommended if invasive prenatal testing is performed.

Metformin mitigates autoimmune insulitis by inhibiting Th1 and Th17 responses while promoting Treg production.

Type 1 diabetes mellitus (T1DM) is still one of the major threats on global public health. This autoimmune condition is mainly caused by the imbalance of auto-reactive inflammatory effector T cells (Teffs) and protective regulatory T cells (Tregs). Therefore, inhibiting the development of Teffs and/or promoting Tregs provides a therapeutic strategy for preventing the development of T1DM. Pathways of energy metabolism have been shown to play a pivotal role in dictating the activation, differentiation and immune function of T cells. Studies have shown that inhibition of glycolysis suppresses the development of Th1 and Th17 cells, but promotes Treg production. AMP-activated protein kinase (AMPK) is a master sensor and regulator of cellular energy metabolism in mammals, which has also been demonstrated to interfere with T cell differentiation and effector function through inhibiting mammalian target of rapamycin (mTOR) and subsequent inhibition of glycolysis, and enhancement of lipid oxidation. In this study, we found that AMPK activator metformin suppresses T cell proliferation and inhibits the differentiation of Th1 and Th17 cells while promoting the development of Tregs in vitro in a dose-dependent manner. Treatment of NOD mice with metformin significantly mitigated autoimmune insulitis and substantially decreased the number of pro-inflammatory IFN-γ+ as well as IL17+ CD4 T cells in the spleens of NOD mice. However, a significantly increased percentage of regulatory IL-10+ and Foxp3+ CD4 T cells were seen. We provided a novel potential therapeutic method--by regulating T cell metabolism through targeting AMPK, to reduce the severity of autoimmune insulitis.

Mesenchymal stem cells in combination with low-dose rapamycin significantly prolong islet allograft survival through induction of regulatory T cells.

We previously demonstrated the protective effect of MSCs in an adaptive transfer mouse model. However, their therapeutic potential in an allogeneic immunocompetent setting mimicking clinical context of islet transplantation remained unknown. The aim of this study was to determine whether MSCs therapy, either by itself, or combined with Rapamycin could benefit the allograft survival of fully MHC-mismatched mouse islet transplant. Combination therapy of MSCs and low-dose Rapamycin significantly prolonged the survival of islet allografts, whereas treatment of MSCs, or Rapamycin alone, had no impact. Interestingly, this protective effect was associated with an induced expansion of regulatory T cells in islet grafts and draining lymph nodes, a skewed T-cell differentiation toward immunotolerance, and a profound suppression of alloreactivity against donor antigen. Our study suggests that a combination therapy of MSCs and low-dose Rapamycin can prolong the survival and preserve the function of islet allograft in the MHC-mismatched mouse model of islet transplantation.

Protease nexin 1 induces apoptosis of prostate tumor cells through inhibition of X-chromosome-linked inhibitor of apoptosis protein.

Protease nexin 1 (PN1) is an endogenous serine protease inhibitor (SERPIN), expressed at high levels in the prostate, and capable of inhibiting the proliferation of prostate cancer cells. We previously showed that PN1-uPA complexes inhibited Sonic Hedgehog (SHH) signalling through engagement of the LRP receptor. Here, we describe an alternative anti-proliferative mechanism through which PN1 expression leads to apoptosis. In prostate cancer cells, increased expression of PN1 led to substantial reduction of XIAP levels and apoptosis mediated through the uPAR, but not the LRP receptor. The alterations in XIAP were effected in two ways 1) via alteration in the NF-κB pathway, a pathway known to signal XIAP transcription and 2) by promoting XIAP instability. The AKT pathway is known to phosphorylate XIAP at serine 87 leading to protein stability and PN1 expression is shown to interfere with this process. As a result of both mechanisms, programmed cell death is substantially increased. Consistent with these observations, reduced PN1 protein correlated with elevated p65/XIAP expression and with higher Gleason scores in human prostate tissue arrays. Thus, PN1 expression appears to differentially down-regulate distinct oncogenic pathways depending upon the cell surface receptor engaged by its complexes and demonstrates a novel molecular mechanism by which the protein can promote tumor cell apoptosis.

Adiponectin receptor signaling on dendritic cells blunts antitumor immunity.

Immune escape is a fundamental trait of cancer. Dendritic cells (DC) that interact with T cells represent a crucial site for the development of tolerance to tumor antigens, but there remains incomplete knowledge about how DC-tolerizing signals evolve during tumorigenesis. In this study, we show that DCs isolated from patients with metastatic or locally advanced breast cancer express high levels of the adiponectin receptors AdipoR1 and AdipoR2, which are sufficient to blunt antitumor immunity. Mechanistic investigations of ligand-receptor interactions on DCs revealed novel signaling pathways for each receptor. AdipoR1 stimulated IL10 production by activating the AMPK and MAPKp38 pathways, whereas AdipoR2 modified inflammatory processes by activating the COX-2 and PPARγ pathways. Stimulation of these pathways was sufficient to block activation of NF-κB in DC, thereby attenuating their ability to stimulate antigen-specific T-cell responses. Together, our findings reveal novel insights into how DC-tolerizing signals evolve in cancer to promote immune escape. Furthermore, by defining a critical role for adiponectin signaling in this process, our work suggests new and broadly applicable strategies for immunometabolic therapy in patients with cancer.