Critical Role of the cGAS-STING Pathway in Doxorubicin-Induced Cardiotoxicity.

BACKGROUND: Doxorubicin is an effective chemotherapy drug for treating various types of cancer. However, lethal cardiotoxicity severely limits its clinical use. Recent evidence has indicated that aberrant activation of the cytosolic DNA-sensing cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-STING (stimulator of interferon genes) pathway plays a critical role in cardiovascular destruction. Here, we investigate the involvement of this mechanism in doxorubicin-induced cardiotoxicity (DIC). METHODS: Mice were treated with low-dose doxorubicin to induce chronic DIC. The role of the cGAS-STING pathway in DIC was evaluated in cGAS-deficiency (cGAS-/-), Sting-deficiency (Sting-/-), and interferon regulatory factor 3 (Irf3)-deficiency (Irf3-/-) mice. Endothelial cell (EC)-specific conditional Sting deficiency (Stingflox/flox/Cdh5-CreERT) mice were used to assess the importance of this pathway in ECs during DIC. We also examined the direct effects of the cGAS-STING pathway on nicotinamide adenine dinucleotide (NAD) homeostasis in vitro and in vivo. RESULTS: In the chronic DIC model, we observed significant activation of the cGAS-STING pathway in cardiac ECs. Global cGAS, Sting, and Irf3 deficiency all markedly ameliorated DIC. EC-specific Sting deficiency significantly prevented DIC and endothelial dysfunction. Mechanistically, doxorubicin activated the cardiac EC cGAS-STING pathway and its target, IRF3, which directly induced CD38 expression. In cardiac ECs, the cGAS-STING pathway caused a reduction in NAD levels and subsequent mitochondrial dysfunction via the intracellular NAD glycohydrolase (NADase) activity of CD38. Furthermore, the cardiac EC cGAS-STING pathway also regulates NAD homeostasis and mitochondrial bioenergetics in cardiomyocytes through the ecto-NADase activity of CD38. We also demonstrated that pharmacological inhibition of TANK-binding kinase 1 or CD38 effectively ameliorated DIC without compromising the anticancer effects of doxorubicin. CONCLUSIONS: Our findings indicate a critical role of the cardiac EC cGAS-STING pathway in DIC. The cGAS-STING pathway may represent a novel therapeutic target for preventing DIC.

Assessing the Role of the Generative Pretrained Transformer (GPT) in Alzheimer's Disease Management: Comparative Study of Neurologist- and Artificial Intelligence-Generated Responses.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder posing challenges to patients, caregivers, and society. Accessible and accurate information is crucial for effective AD management. OBJECTIVE: This study aimed to evaluate the accuracy, comprehensibility, clarity, and usefulness of the Generative Pretrained Transformer's (GPT) answers concerning the management and caregiving of patients with AD. METHODS: In total, 14 questions related to the prevention, treatment, and care of AD were identified and posed to GPT-3.5 and GPT-4 in Chinese and English, respectively, and 4 respondent neurologists were asked to answer them. We generated 8 sets of responses (total 112) and randomly coded them in answer sheets. Next, 5 evaluator neurologists and 5 family members of patients were asked to rate the 112 responses using separate 5-point Likert scales. We evaluated the quality of the responses using a set of 8 questions rated on a 5-point Likert scale. To gauge comprehensibility and participant satisfaction, we included 3 questions dedicated to each aspect within the same set of 8 questions. RESULTS: As of April 10, 2023, the 5 evaluator neurologists and 5 family members of patients with AD rated the 112 responses: GPT-3.5: n=28, 25%, responses; GPT-4: n=28, 25%, responses; respondent neurologists: 56 (50%) responses. The top 5 (4.5%) responses rated by evaluator neurologists had 4 (80%) GPT (GPT-3.5+GPT-4) responses and 1 (20%) respondent neurologist's response. For the top 5 (4.5%) responses rated by patients' family members, all but the third response were GPT responses. Based on the evaluation by neurologists, the neurologist-generated responses achieved a mean score of 3.9 (SD 0.7), while the GPT-generated responses scored significantly higher (mean 4.4, SD 0.6; P<.001). Language and model analyses revealed no significant differences in response quality between the GPT-3.5 and GPT-4 models (GPT-3.5: mean 4.3, SD 0.7; GPT-4: mean 4.4, SD 0.5; P=.51). However, English responses outperformed Chinese responses in terms of comprehensibility (Chinese responses: mean 4.1, SD 0.7; English responses: mean 4.6, SD 0.5; P=.005) and participant satisfaction (Chinese responses: mean 4.2, SD 0.8; English responses: mean 4.5, SD 0.5; P=.04). According to the evaluator neurologists' review, Chinese responses had a mean score of 4.4 (SD 0.6), whereas English responses had a mean score of 4.5 (SD 0.5; P=.002). As for the family members of patients with AD, no significant differences were observed between GPT and neurologists, GPT-3.5 and GPT-4, or Chinese and English responses. CONCLUSIONS: GPT can provide patient education materials on AD for patients, their families and caregivers, nurses, and neurologists. This capability can contribute to the effective health care management of patients with AD, leading to enhanced patient outcomes.

Weight Gain Before the Third Trimester and Risk of Hypertensive Disorders of Pregnancy: A Prospective Cohort Study.

BACKGROUND The association between excessive gestational weight gain (GWG) and the risk of hypertensive disorders of pregnancy (HDP) remains uncertain in women with increased water retention in late gestation associated with the pathophysiology of HDP. This study aimed to investigate the association between GWG before the third trimester and the risk of HDP. MATERIAL AND METHODS This was a prospective cohort study in singleton-pregnant women in Tianjin, China, from 2016. Generalized linear models were used to analyze the relationship between weight gain and the risk of HDP. RESULTS A total of 5295 singleton-pregnant women were included. Even after adjusting for relevant confounders, weight gain at approximately 28 weeks remained an independent risk factor for HDP in the normal-weight group. Compared to the reference of low weight gain (+1 SD was associated with an approximately 2.0 times greater likelihood of HDP (RR: 2.08, 95% CI: 1.06-4.08). Moreover, there was a positive relationship between weight gain in the short interval of early pregnancy and risk of HDP in overweight women. CONCLUSIONS Excessive weight gain before the third trimester was associated with a greater risk of developing HDP among women with early-pregnancy normal weight, which may provide a chance to identify subsequent hypertensive disorders. Additional research is needed to determine whether early-pregnancy weight gain is associated with HDP risk.

Subclinical Hypothyroidism Predicted Adverse Cardiovascular Events in Patients with Ejection Fraction Preserved Heart Failure.

Background: Subclinical hypothyroidism (SH) increases the risk of cardiovascular events, however the influence of SH on prognosis of ejection fraction preserved heart failure (HFpEF) is not fully understood. Methods: In this prospective observational study, patients with HFpEF were divided into euthyroidism group (n = 413) and SH group (n = 79). Patients were followed up for at least 30 months to examine the association between SH and cardiovascular events in patients with HFpEF. The primary end point was composite cardiovascular events (cardiovascular death and re-hospitalization). The patients underwent flow-mediated dilation (FMD) measurement by ultrasound in order to value endothelial function. Results: The rate of composite cardiovascular events was higher in SH group than in euthyroidism group (54.49% and 26.36%, respectively; p < 0.001). The higher risk of cardiovascular events in SH group was primarily due to a higher risk of re-hospitalization compared to euthyroidism group (45.56% and 20.58%, respectively; p < 0.001). The rate of cardiovascular death was higher in SH group than in euthyroidism group (13.92% and 5.81%, respectively; p = 0.017). Cox proportional hazards regression showed that SH (hazard ratios [HR] 1.921, 95% confidence interval [CI] 1.139-3.240), level of TSH (HR 1.025, 95% CI 1.010-1.054), age (HR 1.017, 95% CI 1.002-1.034), LVEF (HR 0.975, 95% CI 0.953-0.996), atrial fibrillation (HR 1.581, 95% CI 1.083-2.307), eGFR (HR 0.987, 95% CI 0.978-0.997), and NYHA cardiac function (HR 2.342, 95% CI 1.649-3.326) were independent predictors of cardiovascular events in patients with HFpEF (all P < 0.05). Conclusion: Subclinical hypothyroidism was associated with increased cardiovascular events and death in patients with HFpEF.

Arsenic trioxide alleviates atherosclerosis by inhibiting CD36-induced endocytosis and TLR4/NF-κB-induced inflammation in macrophage and ApoE-/- mice.

BACKGROUND: Inflammation and lipid accumulation are key events in atherosclerosis progression. Despite arsenic trioxide's (ATO) toxicity, at appropriate doses, it is a useful treatment for various diseases treatment. ATO prevents vascular restenosis; however, its effects on atherosclerotic plaque development and instability remain unclear. METHODS: ApoE-/- mice were fed high-fat diet for 4 months, and starting at the third month, ATO was intravenously administered every other day. Atherosclerotic lesion size, histological characteristics, and related protein and lipid profiles were assessed using samples from the aorta, carotid artery, and serum. The anti-inflammatory and anti-pyroptosis effects of ATO were investigated by stimulating RAW264.7 and THP-1 cell lines with oxidized low-density lipoprotein (ox-LDL) or lipopolysaccharide (LPS). RESULTS: ATO reduced atherosclerotic lesion formation and plasma lipid levels in ApoE-/- mice. In the serum and aortic plaques, ATO reduced the levels of pro-inflammatory factors, including interleukin (IL) 6 and tumor necrosis factor α, but increased IL-10 levels. Mechanistically, ATO promoted the CD36-mediated internalization of ox-LDL in a peroxisome proliferator-activated receptor γ-dependent manner. Furthermore, ATO downregulated Toll-like receptor 4 (TLR4) expression in plaques and macrophages and inhibited p65 nuclear translocation and IκBα degradation. ATO reduced macrophage pyroptosis by downregulating NLR family pyrin domain-containing 3 (NLRP3) expression and caspase 1 activation. CONCLUSION: ATO has potential atheroprotective effects, especially in macrophages. The mechanisms were inhibition of CD36-mediated foam cell formation and suppression of inflammatory responses and pyroptosis mediated by TLR4/nuclear factor κB and NLRP3 activation. Our findings provide evidence supporting the potential atheroprotective value of ATO.

Effectiveness of chest pain center accreditation on the hospital outcome of acute aortic dissection: a nationwide study in China.

BACKGROUND: The National Chest Pain Center Program (NCPCP) is a nationwide, quality enhancement program aimed at raising the standard of care for patients experiencing acute chest pain in China. The benefits of chest pain center (CPC) accreditation on acute coronary syndrome have been demonstrated. However, there is no evidence to indicate whether CPC accreditation improves outcomes for patients with acute aortic dissection (AAD). METHODS: We conducted a retrospective observational study of patients with AAD from 1671 hospitals in China, using data from the NCPCP spanning the period from January 1, 2016 to December 31, 2022. The patients were divided into 2 groups: pre-accreditation and post-accreditation admissions. The outcomes examined included in-hospital mortality, misdiagnosis, and Stanford type A AAD surgery. Multivariate logistic regression was employed to explore the relationship between CPC accreditation and in-hospital outcomes. Furthermore, we stratified the hospitals based on their geographical location (Eastern/Central/Western regions) or administrative status (provincial/non-provincial capital areas) to assess the impact of CPC accreditation on AAD patients across various regions. RESULTS: The analysis encompassed a total of 40,848 patients diagnosed with AAD. The post-accreditation group exhibited significantly lower rates of in-hospital mortality and misdiagnosis (12.1% vs. 16.3%, P < 0.001 and 2.9% vs. 5.4%, P < 0.001, respectively) as well as a notably higher rate of Stanford type A AAD surgery (61.1% vs. 42.1%, P < 0.001) compared with the pre-accreditation group. After adjusting for potential covariates, CPC accreditation was associated with substantially reduced risks of in-hospital mortality (adjusted OR 0.644, 95% CI 0.599-0.693) and misdiagnosis (adjusted OR 0.554, 95% CI 0.493-0.624), along with an increase in the proportion of patients undergoing Stanford type A AAD surgery (adjusted OR 1.973, 95% CI 1.797-2.165). Following CPC accreditation, there were significant reductions in in-hospital mortality across various regions, particularly in Western regions (from 21.5 to 14.1%). Moreover, CPC accreditation demonstrated a more pronounced impact on in-hospital mortality in non-provincial cities compared to provincial cities (adjusted OR 0.607 vs. 0.713). CONCLUSION: CPC accreditation is correlated with improved management and in-hospital outcomes for patients with AAD.

Hyperinsulinemia Impaired Coronary Collateral Circulation in Patients with Chronic Total Coronary Occlusion.

Background and Objectives: Hyperinsulinemia impaired cardiovascular system and endothelial function in the population. The purpose of this study was to explore the relationship between hyperinsulinemia and coronary collateral circulation in patients with chronic total coronary occlusion. Methods: Patients with stable angina and at least one total coronary occlusion were enrolled in this study. Collateral grade was determined according to Rentrop's classification. Patients were divided into a good coronary collateral circulation (CCC) group (grade 2 or 3 collateral vessels, n = 223) and a poor CCC group (grade 0 or 1 collateral vessels, n = 115). Fasting insulin level (FINS) and fasting glucose level (FBS) were measured. Endothelial function evaluated by flow-mediated dilation (FMD). Results: Serum FINS level was significantly increased in the poor CCC group (P < 0.01). Patients in the poor CCC group had higher levels of FBS, HbA1C, and homeostasis model assessment for insulin resistance (HOMA-IR) than patients in the good CCC group. The poor CCC group also had lower levels of FMD, lower LVEF and higher syntax scores than the good CCC group. Hyperinsulinemia (T3, FINS ≥15.22 µIU/mL) increased OR for the incidence of the poor CCC group (OR 2.419, 95% CI 1.780-3.287) in multivariate analysis. Multivariate logistic regression also revealed that diabetes, HbA1c, HOMA-IR, HDL-C and Syntax score were independent predictors of poor CCC (all P < 0.05). Conclusion: Hyperinsulinemia is a valuable predictor of poor collateral formation in patients with chronic total coronary occlusion.

Runx1 Deficiency Promotes M2 Macrophage Polarization Through Enhancing STAT6 Phosphorylation.

Our previous study had demonstrated that Runx1 promoted LPS-induced macrophage inflammatory response, however, the role of Runx1 in M2 macrophage polarization still remains largely unknown. This study was conducted to investigate the role of Runx1 in IL-4/IL-13-induced M2 macrophage polarization and its potential regulatory mechanism. We found that exposure of macrophages to IL-4/IL-13 induced a remarkable increasement in Runx1 expression level. Specifically, we established genetically modified mice lacking Runx1 in myeloid cells, including macrophages. RNA-Seq was performed to identify differentially expressed genes (DEGs) between Runx1 knockout and WT control bone marrow-derived macrophages (BMDMs). We identified 686 DEGs, including many genes which were highly expressed in M2 macrophage. In addition, bioinformatics analysis indicated that these DEGs were significantly enriched in extracellular matrix-related processes. Moreover, RT-qPCR analysis showed that there was an obvious upregulation in the relative expression levels of M2 marker genes, including Arg1, Ym1, Fizz1, CD71, Mmp9, and Tgm2, in Runx1 knockout macrophages, as compared to WT controls. Consistently, similar results were obtained in the protein and enzymatic activity levels of Arg1. Finally, we found that the STAT6 phosphorylation level was significantly enhanced in Runx1 knockout macrophages, and the STAT6 inhibitor AS1517499 partly reduced the upregulated effect of Runx1 deficiency on the M2 macrophage polarization. Taken together, Runx1 deficiency facilitates IL-4/IL-13-induced M2 macrophage polarization through enhancing STAT6 phosphorylation.

IRGM/Irgm1 deficiency inhibits neutrophil-platelet interactions and thrombosis in experimental atherosclerosis and arterial injury.

BACKGROUND: Neutrophil extracellular traps (NETs) closely link inflammation and thrombosis. The immune-related GTPase family M protein (IRGM) and its ortholog of mouse IRGM1 are positively correlated with plaque rupture during atherosclerosis process. However, whether and how IRGM/IRGM1 affects NETs formation and atherosclerotic thrombosis remains unknown, which will further promote the development of antithrombotic treatment tools. METHODS: The thrombi images, platelet activation makers and NETs makers were detected in the serum of STEMI patients and controls. To futher investigate IRGM/IRGM1 affects NETs formation and atherothrombosis in vivo, ApoE-/-Irgm1+/- and ApoE-/- mice received diets rich in fat and 2.5% FeCl3 was then used to induce experimental arterial thrombosis in an atherosclerosis background. In vitro, PMA and thrombin were used to stimulate neutrophils and platelets, respectively, and the expression of IRGM/IRGM1 were modified. To reveal the molecular mechanisms, MAPK-cPLA2 signals inhibitors were used. RESULTS: Serum IRGM was positively correlated with PF4 and neutrophil elastase. Subsequently, Irgm1 deficient mice have a longer occlusion time and lower growth rate. In vitro, as expected, IRGM/Irgm1 deficiency inhibits platelet activation and platelet-neutrophil interaction. More importantly, IRGM promoted NETs production through activating MAPK-cPLA2 signals in PMA stimulated neuropils, whereas inhibiting the production of NETs eliminated the difference in platelet activation and thrombosis caused by IRGM/Irgm1 modification in vivo and vitro. Similarly, inhibition of platelet activation also eliminated the influence of IRGM/Irgm1 modification on NETs production. CONCLUSIONS: Overall, our data indicate that IRGM/Irgm1 deficiency in neuropils inhibits the intense interaction between neutrophils and platelets, and ultimately inhibits thrombosis.

An ischemic area-targeting, peroxynitrite-responsive, biomimetic carbon monoxide nanogenerator for preventing myocardial ischemia-reperfusion injury.

Myocardial ischemia-reperfusion (MI/R) injury is common in patients who undergo revascularization therapy for myocardial infarction, often leading to cardiac dysfunction. Carbon monoxide (CO) has emerged as a therapeutic molecule due to its beneficial properties such as anti-inflammatory, anti-apoptotic, and mitochondrial biogenesis-promoting properties. However, its clinical application is limited due to uncontrolled release, potential toxicity, and poor targeting efficiency. To address these limitations, a peroxynitrite (ONOO-)-triggered CO donor (PCOD585) is utilized to generate a poly (lactic-co-glycolic acid) (PLGA)-based, biomimetic CO nanogenerator (M/PCOD@PLGA) that is coated with the macrophage membrane, which could target to the ischemic area and neutralize proinflammatory cytokines. In the ischemic area, local produced ONOO- triggers the continuous release of CO from M/PCOD@PLGA, which efficiently ameliorates MI/R injury by clearing harmful ONOO-, attenuating the inflammatory response, inhibiting cardiomyocyte apoptosis, and promoting mitochondrial biogenesis. This study provides a novel insight into the safe therapeutic use of CO for MI/R injury by utilizing a novel CO donor combined with biomimetic technology. The M/PCOD@PLGA nanogenerator offers targeted delivery of CO to the ischemic area, minimizing potential toxicity and enhancing therapeutic efficacy.

The relationship between high-normal blood pressure in the first half of pregnancy and the risk of hypertensive disease of pregnancy.

Early warning of hypertensive disorder in pregnancy (HDP) can improve maternal and infant outcomes. However, few studies had evaluated the warning value of high-normal blood pressure (BP) before the onset of HDP. This was a prospective cohort study to investigate the relationship between high-normal BP in the first half of pregnancy and the risk of HDP. According to the maximum BP measured before 20+6  weeks of gestation, the cohort was divided into three groups: optimal BP (SBP < 120 mmHg and DBP < 80 mmHg), normal BP (120 mmHg ≤ SBP < 130 mmHg or 80 mmHg ≤ DBP < 85 mmHg), and high-normal BP (130 mmHg ≤ SBP < 140 mmHg or 85 mmHg ≤ DBP < 90 mmHg). The relationship between different BP levels in the first half of pregnancy and HDP risk was assessed by general linear models. Ten thousand one hundred and ninety-three normotensive pregnant women with complete information were finally included for data analysis. Among them, 532 pregnant women were diagnosed with HDP, with a total HDP incidence of 5.2%. The incidences in the optimal, normal, and high-normal BP groups were 2.4%, 6.0%, and 21.8%, respectively. Compared to women with optimal BP in the first half of pregnancy, women with high-normal BP had a 445% increased risk of HDP (aRR: 5.45, 95% CI: 4.24-7.00), and even women with normal BP had a 107% increased risk of HDP (aRR: 2.07, 95% CI: 1.68-2.56). This study demonstrated that among low-risk healthy women, women with high-normal BP in the first half of pregnancy had a significantly higher risk of HDP.

Arsenic trioxide induces macrophage autophagy and atheroprotection by regulating ROS-dependent TFEB nuclear translocation and AKT/mTOR pathway.

Inducing autophagy and inhibiting apoptosis may provide a therapeutic treatment for atherosclerosis (AS). For the treatment of progressive AS, arsenic trioxide (ATO) has been used to coat vascular stents. However, the effect of ATO on autophagy of macrophages is still unknown. Therefore, the aims of this study were to characterize the effects and the mechanism of actions of ATO on autophagy in macrophages. Our results showed that ATO-induced activation of autophagy was an earlier event than ATO-induced inhibition of the expression of apoptosis markers in macrophages and foam cells. Nuclear transcription factor EB (TFEB) prevents atherosclerosis by activating macrophage autophagy and promoting lysosomal biogenesis. Here, we report that ATO triggered the nuclear translocation of TFEB, which in turn promoted autophagy and autophagosome-lysosome fusion. Both the latter events were prevented by TFEB knockdown. Moreover, ATO decreased the p-AKT and p-mTOR in the PI3K/AKT/mTOR signaling pathway, thus inducing autophagy. Correspondingly, treatment with the autophagy inhibitor 3-methyladenine (3-MA) abolished the autophagy-inducing effects of ATO. Meanwhile, PI3K inhibitor (LY294002) and mTOR inhibitor (rapamycin) cooperated with ATO to induce autophagy. Furthermore, reactive oxygen species (ROS) were generated in macrophages after treatment with ATO. The ROS scavenger N-acetyl-1-cysteine (NAC) abolished ATO-induced nuclear translocation of TFEB, as well as changes in key molecules of the AKT/mTOR signaling pathway and downstream autophagy. More importantly, ATO promoted autophagy in the aorta of ApoE-/- mice and reduced atherosclerotic lesions in early AS, which were reversed by 3-MA treatment. In summary, our data indicated that ATO promoted ROS induction, which resulted in nuclear translocation of TFEB and inhibition of the PI3K/AKT/mTOR pathway. These actions ultimately promoted macrophage autophagy and reduced atherosclerotic lesions at early stages. These findings may provide a new perspective for the clinical treatment of early-stage atherosclerosis and should be further studied.

IRGM/Irgm1 facilitates macrophage apoptosis through ROS generation and MAPK signal transduction: Irgm1+/- mice display increases atherosclerotic plaque stability.

Rationale: Atherosclerosis plaque rupture (PR) is the pathological basis and chief culprit of most acute cardiovascular events and death. Given the complex and important role of macrophage apoptosis and autophagy in affecting plaque stability, an important unanswered question include is whether, and how, immunity-related GTPase family M protein (IRGM) and its mouse orthologue IRGM1 affect macrophage survival and atherosclerotic plaque stability. Methods: To investigate whether serum IRGM of ST-segment elevation myocardial infarction (STEMI) patients is related to plaque morphology, we divided 85 STEMI patients into those with and without plaque rupture (PR and non-PR, respectively) based on OCT image analysis, and quantified the patients' serum IRGM levels. Next, we engineered Irgm1 deficient mice (Irgm1+/-) and chimera mice with Irgm1 deficiency in the bone marrow on an ApoE-/- background, which were then fed a high-fat diet for 16 weeks. Pathological staining was used to detect necrotic plaque cores, ratios of neutral lipids and cholesterol crystal, as well as collagen fiber contents in these mice to characterize plaque stability. In addition, immunofluorescence, immunohistochemical staining and western blot were used to detect the apoptosis of macrophages in the plaques. In vitro, THP-1 and RAW264.7 cells were stimulated with ox-LDL to mimic the in vivo environment, and IRGM/IRGM1 expression were modified by specific siRNA (knockdown) or IRGM plasmid (knocked-in). The effect of IRGM/Irgm1 on autophagy and apoptosis of macrophages induced by ox-LDL was then evaluated. In addition, we introduced inhibitors of the JNK/p38/ERK signaling pathway to verify the specific mechanism by which Irgm1 regulates RAW264.7 cell apoptosis. Results: The serum IRGM levels of PR patients is significantly higher than that of non-PR patients and healthy volunteers, which may be an effective predictor of PR. On a high-fat diet, Irgm1-deficient mice exhibit reduced necrotic plaque cores, as well as neutral lipid and cholesterol crystal ratios, with increased collagen fiber content. Additionally, macrophage apoptosis is inhibited in the plaques of Irgm1-deficient mice. In vitro, IRGM/Irgm1 deficiency rapidly inhibits ox-LDL-induced macrophage autophagy while inhibiting ox-LDL-induced macrophage apoptosis in late stages. Additionally, IRGM/Irgm1 deficiency suppresses reactive oxygen species (ROS) production in macrophages, while removal of ROS effectively inhibits macrophage apoptosis induced by IRGM overexpression. We further show that Irgm1 can affect macrophage apoptosis by regulating JNK/p38/ERK phosphorylation in the MAPK signaling pathway. Conclusions: Serum IRGM may be related to the process of PR in STEMI patients, and IRGM/Irgm1 deficiency increases plaque stability. In addition, IRGM/Irgm1 deficiency suppresses macrophage apoptosis by inhibiting ROS generation and MAPK signaling transduction. Cumulatively, these results suggest that targeting IRGM may represent a new treatment strategy for the prevention and treatment of acute cardiovascular deaths caused by PR.

Predictors of drug-resistance in epilepsy with auditory features.

OBJECTIVE: To investigate predictors of drug-resistance in epilepsy with auditory features (EAF). METHODS: Drug-resistant epilepsy (DRE) was defined according to International League Against Epilepsy guidelines. For univariate analysis, the chi-squared, Fisher's exact, and Mann-Whitney test were used. Odds ratios (OR) and 95% confidence intervals (CIs) of predictors were estimated by logistic regression analyses. RESULTS: A total of 107 patients (52 male) between the ages of 13.0 and 78.8 years were included in this cohort. In univariate analysis, ten variables, including age at seizure onset < or = 10 years, febrile seizures, psychiatric disorders, seizures during sleep, multiple first ictal symptoms, electroencephalogram epileptiform discharges during waking, non-specific abnormalities in electroencephalogram, oxcarbazepine as the first drug, oxcarbazepine in the first two drugs and valproic acid in the first two drugs, showed possibilities as prognostic factors of EAF (p < 0.10). After logistic regression analyses, two positive predictors of drug-resistance, including age at seizures onset < or = 10 (OR = 6.37, 95% CI = 1.08-37.7, p = 0.041) and seizures during sleep (OR = 4.42, 95% CI = 1.45-13.48, p = 0.009) were found. Oxcarbazepine as the first AED is a negative predictive factor of drug-resistance (OR = 0.22, 95% CI = 0.06-0.84, p = 0.027). CONCLUSIONS: Three predictors may help early diagnosis of DRE in EAF. Early use of oxcarbazepine is a negative predictor of drug-resistance, which may provide an intervention point to minimize the risk of drug-resistance.

Echinococcus granulosus: protoscolicidal effect of high intensity focused ultrasound.

High intensity focused ultrasound (HIFU) is a new non-invasive technique which can cause cell death and tissue necrosis by focusing high-energy ultrasonic waves on a single location. The aim of our work is to investigate the damaging effect of HIFU on Echinococcus granulosus protoscolices, as well as its inhibitory effect on growth of hydatid cysts derived from protoscolices. The damaging effect of HIFU on protoscolices was investigated by following parasite mortality after irradiation, while the inhibitory effect was investigated by infection experiments in vivo. The results demonstrated that HIFU was able to damage protoscolices and the protoscolicidal effect was dose-dependent and showed late-onset. The growth of protoscolices that survived the exposure to HIFU was obviously suppressed in vitro, and the mean weight of hydatid cysts resulting from such protoscolices in the experimental group was less than that in controls. Evidences including the protoscolicidal effect, fragmentized protoscolices and low post exposure temperatures, suggest that cavitation may contribute to the protoscolicidal effect of HIFU. In addition, the structure of the germinal membrane in cysts developing from the irradiated protoscolices was not as normal or intact as that from non-irradiated ones, and morphological changes related to degeneration were observed, suggesting that HIFU could prevent protoscolices from developing normal germinal membrane and consequently stop the proliferation of secondary hydatid cysts. HIFU demonstrated damaging effect on protoscolices, inhibited the growth of protoscolices in vitro and in vivo, and could be a possible therapeutic option for cystic echinococcosis.

Factors predicting uncontrolled seizures in epilepsy with auditory features.

PURPOSE: To analyse the factors predicting uncontrolled seizures in epilepsy with auditory features (EAF). METHODS: We analysed individual data from EAF patients who were previously reported. Two authors independently reviewed the titles and abstracts identified and extracted data from each eligible study using a standardized form. The outcome measure was uncontrolled seizures. The odds ratio (OR) and 95% confidence interval (CI) were used. RESULTS: A total of 27 studies including 181 patients with familial and sporadic EAF met our inclusion criteria. None of the clinical factors appeared to affect seizure outcomes significantly except that treatment with carbamazepine was a protective factor against uncontrolled seizures (OR = 0.399, 95% CI: 0.195-0.820, p = 0.012), and polytherapy was associated with uncontrolled seizures. Treatment with carbamazepine was also a protective factor against uncontrolled seizures for families with LGI1 mutations (OR = 0.248, 95% CI: 0.085-0.724, p = 0.011). Carbamazepine might have a better efficacy in patients with frequent seizures (p = 0.041). Low-dose carbamazepine might completely control seizures in some EAF patients, although other effective doses of antiepileptic drugs might not. Patients without carbamazepine treatment were more likely to use new antiepileptic drugs, which might be due to the higher rate of uncontrolled seizures. CONCLUSIONS: Carbamazepine treatment is a protective factor against uncontrolled seizures for EAF. However, this evidence is not strong enough to state that carbamazepine is the first choice drug for EAF.

Treatment of the bone marrow stromal stem cell supernatant by nasal administration-a new approach to EAE therapy.

INTRODUCTION: Multiple sclerosis (MS) is one of the most common autoimmune diseases of the central nervous system (CNS). CNS has its own unique structural and functional features, while the lack of precision regulatory element with high specificity as therapeutic targets makes the development of disease treatment in the bottleneck. Recently, the immunomodulation and neuroprotection capabilities of bone marrow stromal stem cells (BMSCs) were shown in experimental autoimmune encephalomyelitis (EAE). However, the administration route and the safety evaluation limit the application of BMSC. In this study, we investigated the therapeutic effect of BMSC supernatant by nasal administration. METHODS: In the basis of the establishment of the EAE model, the BMSC supernatant were treated by nasal administration. The clinical score and weight were used to determine the therapeutic effect. The demyelination of the spinal cord was detected by LFB staining. ELISA was used to detect the expression of inflammatory factors in serum of peripheral blood. Flow cytometry was performed to detect pro-inflammatory cells in the spleen and draining lymph nodes. RESULTS: BMSC supernatant by nasal administration can alleviate B cell-mediated clinical symptoms of EAE, decrease the degree of demyelination, and reduce the inflammatory cells infiltrated into the central nervous system; lessen the antibody titer in peripheral bloods; and significantly lower the expression of inflammatory factors. As a new, non-invasive treatment, there are no differences in the therapeutic effects between BMSC supernatant treated by nasal route and the conventional applications, i.e. intraperitoneal or intravenous injection. CONCLUSIONS: BMSC supernatant administered via the nasal cavity provide new sights and new ways for the EAE therapy.

Decision-making in patient s with epilepsy: A systematic review and meta-analysis.

OBJECTIVE: Decision-making (DM) is an essential ability in everyday life. Some studies have reported DM deficits in patients with epilepsy. However, the reliability of the conclusions was limited by small sample sizes and inconsistent results. This review evaluated the current evidence concerning DM ability in epilepsy to provide a more detailed understanding and reliable conclusions. METHODS: Seven databases were searched to collect studies about DM ability in epilepsy. The weighted mean difference (WMD), standardised mean difference (SMD) and 95% confidence interval (CI) were used to compare continuous variables. RESULTS: A total of 13 studies, including 395 patients with epilepsy, met our inclusion criteria. The overall size of DM deficits was moderate (SMD = -0.372, 95% CI = -0.529 - -0.215, p < 0.001). The performance of the Iowa Gambling Task were impaired (WMD = -11.961, 95% CI = -20.543 - -3.380, p = 0.006; SMD = -0.694, 95% CI = -0.856 - -0.532, <0.001). The performance of other DM tests was not significantly less in either WMD or SMD. Patients with right TLE and with left TLE had no statistically significant difference in DM ability. An amygdala or (and) hippocampus resection might be related to more severe DM deficits. Various cognitive domains were related to decision-making capacity, although these correlations were not consistent across studies. CONCLUSION: Patients with epilepsy had poorer scores in avoid making risky decisions under ambiguity. Other types of DM ability might not be impaired; however, insufficient studies, with small samples, limited reliability of the results.

Association between HLA alleles and lamotrigine-induced cutaneous adverse drug reactions in Asian populations: A meta-analysis.

PURPOSE: The aim of this study was to assess the association between human leukocyte antigen (HLA) variants and lamotrigine (LTG)-induced cutaneous adverse drug reactions (cARDs). METHODS: A comprehensive literature search was conducted on the relationship of HLA alleles with LTG-induced cADRs in Asian populations, through PubMed, Embase, and Cochrane Library. The last search was in February 2018. The pooled odds ratio (OR) with 95% confidence interval (95% CI) was used to access the strength of the association between an HLA allele and LTG-induced cADRs. RESULTS: A total of 11 studies met the inclusion criteria and were enrolled in our meta- analysis, which were based on Chinese, Korean, and Thai populations. Among these populations, we observed that HLA-B*1502 is a risk allele for LTG-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in Chinese populations (pooled OR 2.4, 95% CI: 1.20-4.78, P = 0.01), HLA-A*2402 was found to be a significant risk allele for both SJS/TEN (pooled OR 3.50, 95% CI: 1.61-7.59, P = 0.002) and maculopapular eruption (MPE) (pooled OR 2.14, 95% CI: 1.10-4.16, P = 0.03), and HLA-B*3303 was considered to be a protective marker for MPE in Chinese and Korean populations (pooled OR 0.2, 95% CI 0.06-0.64, P = 0.007). CONCLUSIONS: In Asian populations, HLA-B*1502 is a risk factor for LTG-induced bullous lesions such as SJS/TEN in Chinese populations, and HLA-A*2402 is associated with the susceptibility to either SJS/TEN or MPE. HLA-A*3303 is a protective allele against LTG-induced MPE in Chinese and Korean populations.

[Pathological change in hydatid cysts of Echinococcus granulosus treated with high intensity focused ultrasound].

OBJECTIVE: To investigate the pathological change in Echinococcus granulosus hydatid cysts treated with high intensity focus ultrasound (HIFU). METHODS: Thirty cysts with thinner wall and proper elasticity, taken from livers of infected sheep, were randomly divided into three groups. By cyclical multilayer radiation around the cyst wall, two experiment groups were treated with HIFU under 150 W and 250 W sound power respectively. The control group was treated by ordinary ultrasound for 2 min. RESULTS: The inner cyst wall of hydatid treated with HIFU became curved, thicker, stiffer, white and less transparent. The germinal layer was detached mostly from the laminated layers of hydatid in the experiment groups. Images from the transmission electron microscopy showed that in the experiment groups fabric texture of hydatid changed significantly and germinal cells were broken. CONCLUSION: HIFU in a model of cyclical multilayer radiation causes pathological damage of the E. granulosus hydatid.