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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Fluvastatin therapy could not decrease progression of paroxysmal atrial fibrillation in non-valvular disease patients.

OBJECTIVE: This study aimed to evaluate whether fluvastatin therapy could decrease the probability of atrial fibrillation (AF) progression from paroxysmal AF to permanent AF and decrease the recurrence frequency of AF. METHODS: Analyses were performed using two-tailed Student's t test or Mann-Whitney U tests. Categorical variables were compared with the χ2 statistics or Fisher's exact test. Patients with paroxysmal AF were randomized case-control, prospective into either the fluvastatin group (n=61) or control group (n=57). Patients were followed up for 24 months. The primary endpoint event was paroxysmal AF that progressed to permanent AF. Secondary endpoints were AF recurrence, cardiac dysfunction, stroke, or death. RESULTS: There were no differences in AF progression (fluvastatin group, 8.19% vs. control group, 12.51%; p>0.05) and stroke (fluvastatin group. 6.55% vs. CONTROL GROUP: 8.77%; p>0.05). Patients in the fluvastatin group had a lower rate of AF recurrence (fluvastatin group, 24.59% vs. control group, 49.12%; p<0.05) and a lower rate of cardiac dysfunction (fluvastatin group, 6.55% vs. control group, 19.29%; p<0.05). Death did not occur in both the groups. After 1 week of fluvastatin therapy, C-reactive protein (CRP) and homocysteine (HCY) levels were lower in the fluvastatin group than in the control group. At 24 months of follow-up, CRP and HCY levels remained lower in the fluvastatin group than in the control group. The number of endothelial progenitor cells (EPCs) increased in the fluvastatin group compared with that in the control group (fluvastatin group, 72.27±12.49 counts/105 vs. control group, 57.45±8.24 counts/105, p=0.001). CONCLUSION: Fluvastatin therapy could not decrease AF progression. However, it could decrease the recurrence frequency of paroxysmal AF and cardiac dysfunction. This may occur because of depressing inflammation and improving circulating EPCs.

Permanent atrial fibrillation impairs the function of circulating endothelial progenitor cells.

OBJECTIVE: to determine whether functions of endothelial progenitor cells (EPCs) were impaired in patients with permanent atrial fibrillation (AF). METHODS: 35 patients with permanent AF (AF group) and 35 age and sex matched controls (control group) were collected. The numbers of circulating CD34+/KDR+ cells were determined with flow cytometry in the two groups. Cell proliferation, tube formation, nitric oxygen (NO) and vascular endothelial growth factor (VEGF) were assayed. RESULTS: the numbers of CD34+/KDR+ cells were lower in the AF group than the control group (20.01 ± 12.66 /105 vs 77.93 ± 58.93 /105，p = 0.022). Colony formation unit (CFU) of EPCs were decreased in AF group compared to the control group（1.76 ± 0.59 CFU vs 3.45 ± 0.82 CFU, p = 0.0000). The AF group had lower cell proliferation ability than control group（0.401 ± 0.113 A vs 0.558 ± 0.130 A, p = 0.004). Tube formation ability was decreased in AF patients compared to controls（434.30 ± 96.22µm/mm2 vs 568.09 ± 196.17µm/mm2，p = 0.041). AF patients had lower VEGF secretion than controls (27.35 ± 9.93 ng/L vs 41.86 ± 7.31 ng/L，p = 0.001），they also had lower NO secretion than controls（16.55 ± 6.92µmol/l vs 23.65 ± 5.48，p = 0.012). CONCLUSIONS: proliferation, tube formation and paracrine of EPCs were reduced in patients with permanent AF.

Reproductive and metabolic abnormalities in women taking valproate for bipolar disorder: a meta-analysis.

OBJECTIVE: We aimed to evaluate the relationship between valproate (VPA) and reproductive endocrine abnormalities in women with bipolar disorder. METHODS: We searched studies in electronic databases of China Biology Medicine disc, PubMed, and Embase. Two authors collected articles and extracted data independently. Meta-analysis was performed for polycystic ovary syndrome (PCOS) and its components. The mean difference (MD) and 95% confidence interval (CI) were used to compare continuous variables. The Mantel-Haenszel formula was used to calculate the odds ratio (OR). RESULTS: There were statistically significant differences between the VPA treated and non-VPA treated groups in PCOS (OR 6.74; 95% CI 1.66-27.32; P=0.00), menstrual disorder (OR 1.81; 95% CI 1.02-3.23; P=0.04), and hyperandrogenism (HA) (OR 2.02; 95% CI 1.11-3.65; P=0.02). There was no statistically significant difference between the VPA treated and non-VPA treated groups in PCO (OR 1.37; 95% CI 0.71-2.66; P=0.35). The overall risk of menstrual disorders, PCO, and HA in the VPA treated group was higher than in the non-VPA treated group (OR 1.75; 95% CI 1.23-2.47; P=0.00). The levels of total and free testosterone in the VPA treated group were higher than in the non-VPA treated group (MD 0.12; 95% CI 0.05-0.19; P=0.00; MD 0.14, 95% CI 0.07-0.21; P=0.00, respectively). CONCLUSIONS: VPA was associated with the elevated levels of testosterone and HA in women with BD.

Levetiracetam vs. brivaracetam for adults with refractory focal seizures: A meta-analysis and indirect comparison.

PURPOSE: The study aimed to compare the efficacy and tolerability of levetiracetam (LEV) and brivaracetam (BRV) in adults with refractory focal seizures. METHOD: We systematically queried Medline, Embase, and the Cochrane Library. We looked for additional studies in the references of all identified publications and ClinicalTrials.gov. The cutoff day was November 6, 2015. Randomized, double-blind, placebo-controlled trials were included. The indirect comparison for 50% responder rate, seizure-free rate, and adverse effects were conducted. RESULTS: Thirteen trials enrolling 1765 patients in the LEV group and 1919 patients in the BRV group were included. No statistically significant differences were found in efficacy between LEV and BRV at various dose levels. However, most risk ratios (RRs) at three dose levels and the overall RR were >1 for 50% response proportions. The majority of statistically significant differences for adverse events and withdrawal of LEV and BRV were found at high- and middle-dose levels. The indirect comparison of adverse effects (AEs) showed statistically statistical differences in dizziness. CONCLUSION: Our results suggested that LEV might have a slightly higher efficacy with a lower probability of dizziness compared with BRV for patients with refractory focal seizures.