Prevalence, genetic and clinical characteristics in first-degree relatives of patients with familial cerebral cavernous malformations in China.

OBJECTIVE: This study aims to investigate the prevalence of familial cerebral cavernous malformations (FCCMs) in first-degree relatives (FDRs) using familial screening, to describe the distribution of initial symptoms, lesion count on cranial MRI and pathogenic gene in patients. METHODS: Patients with multiple CCMs who enrolled from the Treatments and Outcomes of Untreated Cerebral Cavernous Malformations in China database were considered as probands and FDRs were recruited. Cranial MRI was performed to screen the CCMs lesions, and whole-exome sequencing was performed to identify CCM mutations. MRI and genetic screening were combined to diagnose FCCM in FDRs, and the results were presented as prevalence and 95% CIs. The Kaplan-Meier (KM) method was used to calculate the cumulative incidence of FCCM. RESULTS: 33 (76.74%) of the 43 families (110 FDRs) were identified as FCCM (85 FDRs). Receiver operating characteristic analysis revealed three lesions on T2-weighted imaging (T2WI) were the strong indicator for distinguishing probands with FCCM (sensitivity, 87.10%; specificity, 87.50%). Of the 85 FDRs, 31 were diagnosed with FCCM, resulting in a prevalence of 36.5% (26.2%-46.7%). In families with FCCMs, the mutation rates for CCM1, CCM2 and CCM3 were 45.45%, 21.21% and 9.09%, respectively. Furthermore, 53.13% of patients were asymptomatic, 17.19% were intracranial haemorrhage and 9.38% were epilepsy. The mean age of symptom onset analysed by KM was 46.67 (40.56-52.78) years. CONCLUSION: Based on MRI and genetic analysis, the prevalence of CCMs in the FDRs of families with FCCMs in China was 36.5%. Genetic counselling and MRI screening are recommended for FDRs in patients with more than three CCM lesions on T2WI.

Pyroptosis-Related Genes as Markers for Identifying Prognosis and Microenvironment in Low-Grade Glioma.

Low-grade glioma (LGG) is one of the most common brain tumors and often develops into the worst glioblastoma (GBM). Pyroptosis is related to inflammation and immunization. It has been demonstrated to influence the progression of a variety of cancers. However, the value of pyrosis-related genes (PRGs) in LGG remains unclear. Public TCGA-LGG data are used to analyze the differential expression and genetic variation of PRGs in LGG. Subsequently, this paper identifies pyroptosis-related subtypes and constructs prognostic models. This paper analyzes the expression and function of selected CASP5 in LGG and constructs a ceRNA regulatory network. Final CASP5-related immune infiltration analysis and methylation analysis are performed. Most PRGs are differentially expressed and altered in LGG. Subtypes and prognostic models based on PRGs not only have good functions but also have a great connection with immune infiltration. Enrichment analysis of PRGs with prognostic value of LGG also shows functions correlated mainly with immunity and inflammation. CASP5 is significantly differentially expressed in different grades of gliomas and different prognoses. Despite fewer mutations, CASP5 has a clear correlation for both immune cells and immune checkpoint molecules in the LGG microenvironment. Its methylation may also have a role in the prognosis of LGG. This paper shows the association of pyrosis-related subtypes, prognostic models, and genes, with immune infiltration.

[Exploration and practice of building tele-critical care system].

OBJECTIVE: To look for the problems faced in the construction of the tele-critical care system, explore the framework of construction of the tele-critical care system, and verify the application effects of the established tele-critical care system. METHODS: Through literature review and on-site investigation and demonstration, the causes affecting the construction of the tele-critical care system were explored. Through on-site investigation of the actual situation of the critical care department in relevant hospitals, arguing and choosing intended intensive care unit (ICU) and cooperative third-party communication and equipment companies, and through the Internet of Things and 5G communication technology, a tele-critical care system with the core hospital of the group as the center and the member institutes within the group as the nodes was built. Via the established tele-critical care system, activities such as tele-monitoring, visual remote ward rounds, remote consultation, remote teaching were carried out to verify the functions of the system. RESULTS: The insufficient cognition of relevant personnel, tele-medicine practice certification requirements, information security issues and the barriers of equipment information integration were the main causes affecting the construction of tele-critical care system. There were five parts in the tele-critical care system architecture foundations, including bed unit equipment and audio and video information collection system, lossless and secure transmission of collected information, real-time display of information in the remote center, real-time staff interaction between the centre and the nodal hospitals, and information cloud storage. It has been verified that patients' diagnostic and treatment information can be transmitted safely, losslessly and in real-time by a special line through private 5G network. Through this system, real-time and stable upload of audio and video information of patients and application information of monitors, ventilators and infusion work stations can be achieved; combined with tele-conference connections to conduct two-way communication with local medical staff, real-time tele-monitoring, visual remote ward rounds, remote consultation, remote teaching and other functions can be achieved. CONCLUSIONS: The tele-critical care system we established is feasible to construct within the medical group and can safely and effectively realize the functions of real-time tele-monitoring, visual remote ward rounds, remote consultation, and remote teaching.

A phased intervention bundle to decrease the mortality of patients with extracorporeal membrane oxygenation in intensive care unit.

Aim: To evaluate whether a phased multidimensional intervention bundle would decrease the mortality of patients with extracorporeal membrane oxygenation (ECMO) and the complication incidence. Materials and methods: We conducted a prospective observational study in comparison with a retrospective control group in six intensive care units (ICUs) in China. Patients older than 18 years supported with ECMO between March 2018 to March 2022 were included in the study. A phased intervention bundle to improve the outcome of patients with ECMO was developed and implemented. Multivariable logistic regression modeling was used to compare the mortality of patients with ECMO and the complication incidence before, during, and up to 18 months after implementation of the intervention bundle. Results: The cohort included 297 patients in 6 ICUs, mostly VA ECMO (68.7%) with a median (25th-75th percentile) duration in ECMO of 9.0 (4.0-15.0) days. The mean (SD) APECHII score was 24.1 (7.5). Overall, the mortality of ECMO decreased from 57.1% at baseline to 21.8% at 13-18 months after implementation of the study intervention (P < 0.001). In multivariable analysis, even after excluding the confounding factors, such as age, APECHII score, pre-ECMO lactate, and incidence of CRRT during ECMO, the intervention bundle still can decrease the mortality independently, which also remained true in the statistical analysis of V-V and V-A ECMO separately. Among all the ECMO-related complications, the incidence of bloodstream infection and bleeding decreased significantly at 13-18 months after implementation compared with the baseline. The CUSUM analysis revealed a typical learning curve with a point of inflection during the implementation of the bundle. Conclusion: A phased multidimensional intervention bundle resulted in a large and sustained reduction in the mortality of ECMO that was maintained throughout the 18-month study period. Clinical trial registration: [ClinicalTrials.gov], identifier [NCT05024786].

Isolevuglandins Scavenger Ameliorates Myocardial Ischemic Injury by Suppressing Oxidative Stress, Apoptosis, and Inflammation.

Augmented levels of reactive isolevuglandins (IsoLGs) are responsible for cardiovascular diseases. The role of IsoLGs in myocardial infarction (MI) remains elusive. Here we explored the effect of IsoLGs scavenger 2-hydroxybenzylamine (2-HOBA) in post-infarction cardiac repair. We observed that infarcted cardiac tissues expressed high IsoLGs in mice. Following MI injury, 2-HOBA treated mice displayed decreased infarction area and improved heart function compared with the saline-treated group. Moreover, 2-HOBA effectively attenuated MI-induced cardiac remodeling, oxidative stress, apoptosis, and inflammation. 4-hydroxybenzylamine (4-HOBA), a less reactive isomer of 2-HOBA, barely antagonized the MI-induced injury. These findings suggest that IsoLGs elimination may be helpful in MI therapy.

Comprehensive analysis of expression, prognosis and immune infiltration for TIMPs in glioblastoma.

BACKGROUND: Tissue inhibitors of metalloproteinase (TIMP) family proteins are peptidases involved in extracellular matrix (ECM) degradation. Various diseases are related to TIMPs, and the primary reason is that TIMPs can indirectly regulate remodelling of the ECM and cell signalling by regulating matrix metalloproteinase (MMP) activity. However, the link between TIMPs and glioblastoma (GBM) is unclear. OBJECTIVE: This study aimed to explore the role of TIMP expression and immune infiltration in GBM. METHODS: Oncomine, GEPIA, OSgbm, LinkedOmics, STRING, GeneMANIA, Enrichr, and TIMER were used to conduct differential expression, prognosis, and immune infiltration analyses of TIMPs in GBM. RESULTS: All members of the TIMP family had significantly higher expression levels in GBM. High TIMP3 expression correlated with better overall survival (OS) and disease-specific survival (DSS) in GBM patients. TIMP4 was associated with a long OS in GBM patients. We found a positive relationship between TIMP3 and TIMP4, identifying gene sets with similar or opposite expression directions to those in GBM patients. TIMPs and associated genes are mainly associated with extracellular matrix organization and involve proteoglycan pathways in cancer. The expression levels of TIMPs in GBM correlate with the infiltration of various immune cells, including CD4+ T cells, macrophages, neutrophils, B cells, CD8+ T cells, and dendritic cells. CONCLUSIONS: Our study inspires new ideas for the role of TIMPs in GBM and provides new directions for multiple treatment modalities, including immunotherapy, in GBM.

Knockdown of lncRNA TapSAKI alleviates LPS-induced injury in HK-2 cells through the miR-205/IRF3 pathway.

Sepsis is a common and lethal syndrome. Long non-coding RNA (lncRNA) transcript predicting survival in AKI (TapSAKI) has recently been found to serve as an important regulator in sepsis. However, the underlying mechanism of TapSAKI in sepsis pathogenesis remains largely unknown. Our data demonstrated that lipopolysaccharide (LPS)-induced HK-2 cell injury by weakening cell viability and enhancing cell apoptosis and inflammation. TapSAKI was upregulated and miR-205 was downregulated in LPS-induced HK-2 cells. TapSAKI knockdown or miR-205 overexpression alleviated LPS-induced cytotoxicity in HK-2 cells. TapSAKI sequestered miR-205 via acting as a miR-205 sponge. Moreover, the mitigating effect of TapSAKI silencing on LPS-induced HK-2 cell injury was mediated by miR-205. Additionally, the interferon regulatory factor 3 (IRF3) signaling was involved in the regulation of the TapSAKI/miR-205 axis on LPS-induced HK-2 cell damage. Our current study suggested that TapSAKI silencing relieved LPS-induced injury in HK-2 cells at least in part by sponging miR-205 and regulating the IRF3 signaling pathway, highlighting a novel understanding for sepsis pathogenesis and a promising target for this disease treatment.

Association of gender and age at onset with glucocerebrosidase associated Parkinson's disease: a systematic review and meta-analysis.

Glucocerebrosidase (GBA) gene has been proved to be a risk factor for the development of Parkinson's disease (PD). However, the gender effect in the prevalence of GBA-associated PD (GBA-PD) is still controversial. And there is no conclusion whether the age at onset (AAO) of PD is different between carriers and non-carriers of GBA. To clarify the association between gender and AAO in GBA-PD, we conducted a systematic review and meta-analysis. PubMed, Web of Science, and Embase were retrieved to obtain potentially related studies. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to determine the association between gender and GBA-PD. And the weighted mean difference (WMD) with 95% CIs was employed to assess the difference of AAO between carriers and non-carriers of GBA. A total of twenty-eight studies involving 16,488 PD patients were included in this meta-analysis. The results showed the prevalence of female patients was higher in GBA-PD [OR: 1.19, (95% CI, 1.07-1.32), P = 0.001]. Meanwhile, GBA carriers had younger age at PD onset than GBA non-carriers [WMD: 2.87, (95% CI, 2.48-3.27), P < 0.001]. Results of subgroup analysis showed the prevalence of women in GBA-PD was higher than men in North American and European PD patients, while the gender difference was not significant in other areas around the world, suggesting an ethnic specificity of gender effect for GBA-PD. Our results indicate the higher female prevalence with ethnic specificity and younger AAO of GBA carriers in GBA-PD.

Corrigendum: Development and Validation of a Prognostic Nomogram to Predict Cancer-Specific Survival in Adult Patients With Pineoblastoma.

[This corrects the article DOI: 10.3389/fonc.2020.01021.].

Development and Validation of a Prognostic Nomogram to Predict Cancer-Specific Survival in Adult Patients With Pineoblastoma.

Pineoblastoma (PB) is a rare neoplasm of the central nervous system. This analysis aimed to identify factors and establish a predictive model for the prognosis of adult patients with PB. Data for 213 adult patients with PB (Surveillance, Epidemiology, and End Results database) were randomly divided into primary and validation cohorts. A predictive model was established and optimized based on the Akaike Information Criterion and visualized by a nomogram. Its predictive performance (concordance index and receiver operating characteristic curve) and clinical utility (decision curve analyses) were evaluated. We internally and externally validated the model using calibration curves. Multivariate Cox regression analysis identified age, year of diagnosis, therapy, tumor size, and tumor extension as independent predictors of PB. The model exhibited great discriminative ability (concordance index of the nomogram: 0.802; 95% confidence interval: 0.78-0.83; area under the receiver operating characteristic curve: ranging from 0.7 to 0.8). Calibration plots (probability of survival) showed good consistency between the actual observation and the nomogram prediction in both cohorts, and the decision curve analyses demonstrated great clinical utility of the nomogram. The nomogram is a useful and practical tool for evaluating prognosis and determining appropriate therapy strategies.

[Effect of pushing manipulation on Qiaogong acupoint on hemodynamics in cynomolgus monkeys with mild carotid atherosclerotic plaques].

OBJECTIVE: To explore the hemodynamic changes in cynomolgus monkeys with mild carotid atherosclerotic (CAS) plaques after therapy with pushing manipulation on Qiaogong acupoint (MPQ). METHODS: Nine cynomolgus monkeys were equally randomized into MPQ group, mild CAS model group and blank control group. Mild CAS models were established in the monkeys in MPQ and model groups, and the monkeys in MPQ group received treatment with MPQ intervention after the modeling. The conditions of the carotid artery and the hemodynamic changes in the 3 groups were evaluated after the treatment. RESULTS: Formation of CAS plaques was detected in monkeys in both MPQ and model groups. The vascular cross?sectional area, plaque cross?sectional area and stenosis rate of the plaques in the two groups all differed significantly from those in the blank control group (P<0.05), but these parameters were similar between MPQ group and the model group (P>0.05). Compared with those in the blank control group, the hemodynamic parameters showed significant changes in MPQ and the model groups (P<0.05) but remained similar between the latter two groups (P>0.05). CONCLUSION: CAS plaques can cause changes in hemodynamic parameters. Short?term therapy with MPQ does not affect the stability of the plaques or cause adverse effects on hemodynamics in cynomolgus monkeys with mild CAS plaques.

In vivo kinetics of the uremic toxin p-cresyl sulfate in mice with variable renal function.

Uremic toxins such as p-cresyl sulfate (PCS) are associated with increased mortality for chronic kidney disease (CKD) patients, but in vivo PCS toxicity studies are limited due to the lack of a standard animal model. To establish such a model, we measured the pharmacokinetics of PCS in mice with variable renal function. Male Balb/c mice subjected to 5/6 nephrectomy (CRF), unilateral nephrectomy (UNX), or no surgery (controls) were given PCS (po, 50 mg/kg). Blood samples were collected over time and plasma PCS concentrations were measured. Over 4 h, PCS was significantly higher in the plasma of CRF mice (63.28 ± 2.76 mg/L), compared to UNX mice (3.11 ± 0.64 mg/L) and controls (0.39 ± 0.12 mg/L). The PCS half-life was greatest in CRF mice (12.07 ± 0.12 h), compared to 0.79 ± 0.04 h in UNX mice and 0.48 ± 0.02 h in control mice. However, the potential presence of additional uremic toxins along with PCS in CRF mice and rapid PCS clearance in control mice suggest that the UNX mouse would be a better PCS model to study toxicity.

P-cresol, but not p-cresylsulphate, disrupts endothelial progenitor cell function in vitro.

BACKGROUND: Patients afflicted with chronic kidney disease (CKD) typically suffer from cardiovascular disease (CVD) which is a leading cause of patient mortality. It has been demonstrated that two distinct physiological events contribute to this disease state. These include the abundance of abnormally high levels of protein-bound uraemic toxins as well as functionally aberrant endothelial progenitor cells (EPCs). Specifically, it has been demonstrated that the uraemic toxin p-cresol (pC; 4-methylphenol) inhibits EPC proliferation and tube formation in previous in vitro studies. More recently, however, it has been demonstrated that circulating pC is actually conjugated and that p-cresylsulphate (pCS) is its main metabolite. Therefore, within the context of this study, we examined the in vitro effects of pC and pCS treatment on cultured human EPCs. METHODS: Late-outgrowth EPCs were treated with physiological concentrations of pC or pCS (10, 40, 80, and 160 or 10, 40, 80, 160 and 320 µg/mL for up to 72 h, respectively) in the presence of 4% human serum albumin (HSA). Cell proliferation was determined using WST-1 assay, while migration and tube formation assays were used to evaluate EPC function in vitro. Cell cycle analyses were also performed to determine the effects of pC and pCS on cell cycle status. RESULTS: With regard to EPC proliferation, data demonstrate that pC in the presence or absence of HSA had an IC50 of 80.1 and 100.8 µg/mL 72 h post-treatment, respectively, while pCS-treated groups did not impair EPC proliferation. Similarly, pC-treated groups showed limited vessel formation and migration compared with controls and no detrimental effects were seen with pCS treatment. Lastly, pC treatment of EPCs caused cells to accumulate in the G2/M phase of the cell cycle with accompanied down-regulation of cyclin B1 and phosphorylated CDK1. pCS had no effect on cell cycle parameters. CONCLUSIONS: Our data demonstrate that pC and pCS have different effects on EPC function. Since there is a dearth of data that have focused on the toxicity of pCS, further research should be performed to determine the exact biological toxicity of pCS on the cardiovascular system.

The effects of low-dose nepsilon-(carboxymethyl)lysine (CML) and nepsilon-(carboxyethyl)lysine (CEL), two main glycation free adducts considered as potential uremic toxins, on endothelial progenitor cell function.

BACKGROUND: Patients with chronic kidney disease (CKD) are at high risk of cardiovascular disease (CVD). Endothelial progenitor cell (EPCs) dysfunction plays a key role in this pathogenesis. Uremic retention toxins have been reported to be in associated with EPC dysfunction. Advanced glycation end-products (AGEs) free adducts, including nepsilon-(carboxymethyl)lysine (CML) and nepsilon-(carboxyethyl)lysine (CEL), are formed by physiological proteolysis of AGEs and released into plasma for urinary excretion. They are retained in CKD patients and are considered to be potential uremic toxins. Though AGEs have been demonstrated to impair EPC function in various ways, the effect of AGE free adducts on EPC function has not been studied. Thus, we examined the role of CML and CEL in the regulation of growth-factor-dependent function in cultured human EPCs and the mechanisms by which they may affect EPC function. METHODS: Late outgrowth EPCs were incubated with different concentrations of CML or CEL for up to 72 hours. Cell proliferation was determined using WST-1 and BrdU assays. Cell apoptosis was tested with annexin V staining. Migration and tube formation assays were used to evaluate EPC function. RESULTS: Though CML and CEL were determined to have anti-proliferative effects on EPCs, cells treated with concentrations of CML and CEL in the range found in CKD patients had no observable impairment on migration or tube formation. CML and CEL did not induce EPC apoptosis. The reduced growth response was accompanied by significantly less phosphorylation of mitogen-activated protein kinases (MAPKs). CONCLUSIONS: Our study revealed that CML and CEL at uremic concentrations have low biological toxicity when separately tested. The biologic effects of AGE free adducts on the cardiovascular system merit further study.

Hemocompatibility of drug-eluting coronary stents coated with sulfonated poly (styrene-block-isobutylene-block-styrene).

The presence of polymer coating on a coronary stent is a major mediator of coronary inflammation reaction thereby affects re-endothelialization. Poly(styrene-block-isobutylene-block-styrene) (SIBS) is one of the most attractive alternatives to serve as stent coating, but has shown less than optimal biocompatibility. Increasing the sulfonic acid content in the polymer can result in increased strength and hydrophilicity. The present study was undertaken to determine the mechanism of action and in vivo efficacy of sulfonated SIBS (S-SIBS) designed specifically as a stent polymer with reduced inflammatory potential and greater endothelialization preservation potential. The blood compatibility of S-SIBS in vitro and its ability to support the attachment of human umbilical vein endothelial cells (HUVECs) were first assessed to get some insight into its potential use in vivo. Baer metal stent (BMS), S-SIBS-coated stent without drug (BMS Plus S-SIBS), standard drug-eluting stent (DES) and S-SIBS-coated drug-eluting stent (DES Plus S-SIBS) were then implanted in the coronary arteries of a porcine model. Neointimal hyperplasia was evaluated at 28 and 180 days, and re-endothelialization was evaluated at 7 and 28 days post stents implantation. The results showed that DES Plus S-SIBS exhibited similar ability to reduce neointimal hyperplasia but preserved endothelialization compared with standard DES. These results suggest potentially promising performance of S-SIBS-coated stent in human clinical applications of coronary stenting.