In rural West China, the risk of premature death is nearly 5 times higher in people with convulsive epilepsy than in the general Chinese population and especially high among young people. Accidental death, including drowning, and probable SUDEP are the leading putative causes of death in people with convulsive epilepsy in rural West China.

Cryptochromes function in animal circadian regulation. Zebrafish are known to have six cryptochrome (cry) genes but their evolutionary relationships are not yet fully resolved. Here, comparative genomic analyses revealed that a local duplication of ancestral chordate Cry occurred likely before the first round of vertebrate genome duplication (VGD); following two successive rounds of VGD and subsequent gene losses, coelacanths retained cry1a, cry1b, cry2 and cry3; and following the third-round teleost genome duplication (TGD) and subsequent gene losses, zebrafish retained six cry genes, renamed as cry1aa (zcry1a in the old nomenclature), cry1ab (zcry1b), cry1ba (zcry2a), cry1bb (zcry2b), cry2 (zcry3) and cry3 (zcry4). Molecular evolutionary analyses suggested that zebrafish cry genes have evolved divergent functions, which is further supported by their distinct and rhythmic expression patterns as shown by both in situ hybridization and quantitative real-time PCR. Systematic cell transfection assays divided six Cry proteins into repressive Cry1aa, Cry1ab, Cry1ba and Cry1bb, and non-repressive Cry2 and Cry3. Cry2 is non-repressive because it lacks an effective protein-protein interaction domain although it does possess a nuclear localization signal (NLS) motif, whilst Cry3 lacks both an NLS motif and a protein-protein interaction domain. These findings provide a better understanding of evolution of zebrafish cry genes.

In this study, we reported millepachine (MIL), a novel chalcone compound for the first time isolated from Millettia pachycarpa Benth (Leguminosae), induced cell cycle arrest and apoptosis in human hepatocarcinoma cells in vitro and in vivo. In in vitro screening experiments, MIL showed strong antiproliferation activity in several human cancer cell lines, especially in HepG2 cells with an IC50 of 1.51 µM. Therefore, we chose HepG2 and SK-HEP-1 cells to study MIL's antitumor mechanism. Flow cytometry showed that MIL induced a G2/M arrest and apoptosis in a dose-dependent manner. Western blot demonstrated that MIL-induced G2/M arrest was correlated with the inhibition of cyclin-dependent kinase 1 activity, including a remarkable decrease in cell division cycle (cdc) 2 synthesis, the accumulation of phosphorylated-Thr14 and decrease of phosphorylation at Thr161 of cdc2. This effect was associated with the downregulation of cdc25C and upmodulation of checkpoint kinase 2 in response to DNA damage. MIL also activated caspase 9 and caspase 3, and significantly increased the ratio of Bax/Bcl-2 and stimulated the release of cytochrome c into cytosol, suggesting MIL induced apoptosis via mitochondrial apoptotic pathway. Associated with those effects, MIL also induced the generation of reactive oxygen species. In HepG2 tumor-bearing mice models, MIL remarkably and dose dependently inhibited tumor growth. Treatment of mice with MIL (20mg/kg intravenous [i.v.]) caused more than 65% tumor inhibition without cardiac damage compared with 47.57% tumor reduction by 5mg/kg i.v. doxorubicin with significant cardiac damage. These effects suggested that MIL and its easily modified structural derivative might be a potential lead compound for antitumor drug.

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Post-stroke depression (PSD) is the most prevalent psychiatric complication of acute ischemic stroke. The neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) are indicators of inflammation and are associated with stroke and depression. Therefore, the purpose of the present study was to examine the relationship between NLR/PLR and PSD. Retrospective analysis was carried out in 376 patients with first-ever acute ischemic stroke in the First Affiliated Yijishan Hospital of Wannan Medical College between March 2015 and September 2017. Patients were divided into PSD (n=104; 27.7%) and non-PSD (n=272; 72.3%) groups according to the Diagnostic and Statistical Manual of Mental Disorders-IV criteria at 6 months after stroke. Clinical data were collected retrospectively. NLR and PLR were acquired retrospectively from the routine blood tests performed at admission. A total of 120 healthy volunteers from the physical examination center in the First Affiliated Yijishan Hospital of Wannan Medical College were recruited as controls. Using logistic regression analysis, NLR (≥4.02) and PLR (≥203.74) were independently associated with PSD. NLR, odds ratio (OR) 3.926, 95% confidence intervals (CI, 2.365-7.947), P<0.001; PLR, OR 3.853, 95% CI (2.214-6.632), P=0.002. The ability of the combined index [area under the receiver operating characteristic curve, 0.701; 95% CI (0.622-0.780); P<0.001] to diagnose PSD was greater than that of either ratio alone. Higher NLRs and PLRs (≥4th quartile) were associated with PSD with a 5.79-fold (P<0.001) increase compared with lower levels of both. Higher NLRs and PLRs were found to be associated with depression 6 months after stroke, and the combined index was more meaningful than either alone in the early clinical detection of PSD.

Purpose Currently available local anesthetics have not demonstrated sufficient analgesia beyond 12-24 h postoperatively. The purpose of the study was to assess the safety and efficacy of HTX-011 (bupivacaine and meloxicam in Biochronomer ® polymer technology), a long-acting investigational anesthetic, in reducing both postoperative pain over 72 h and postoperative opioid use compared to bupivacaine hydrochloride (HCl). Methods A phase 3, randomized, double-blind, active-controlled multi-center study (EPOCH 2; NCT03237481) in subjects undergoing unilateral open inguinal herniorrhaphy with mesh placement was performed. Subjects randomly received a single intraoperative dose of HTX-011, immediate-release bupivacaine HCl, or saline placebo prior to closure. Results The study evaluated 418 subjects, and the primary and all key secondary efficacy endpoints were in favor of HTX-011. HTX-011 reduced mean pain intensity by 23% versus placebo (primary endpoint; p < 0.001) and by 21% versus bupivacaine HCl (p < 0.001) with significant reductions in the number of patients experiencing severe pain. Opioid consumption over 72 h was reduced by 38% versus placebo (p < 0.001) and 25% versus bupivacaine HCl (p = 0.024). Overall, 51% of HTX-011 subjects were opioid-free through 72 h (versus 22% for placebo [p < 0.001] and 40% for bupivacaine HCl [p = 0.049]). HTX-011 was generally well-tolerated with fewer opioid-related adverse events reported compared to the bupivacaine HCl and placebo and no evidence of local anesthetic systemic toxicity. Conclusions HTX-011 demonstrated significant improvement in postoperative pain control and a clinically meaningful reduction in opioid consumption when compared to the most widely used local anesthetic, bupivacaine HCl.

Background— Coronary artery vein graft failure, resulting from thrombosis, intimal thickening, and atherosclerosis, is a significant clinical problem, with approximately 50% of vein grafts failing within 10 years. Intimal thickening is caused by migration of vascular smooth muscle cells from the media to the intima, where they proliferate. Interventions using gene transfer to inhibit vascular smooth muscle cells proliferation and migration are attractive because ex vivo access to the graft is possible. The involvement of matrix-degrading metalloproteinases in intimal thickening is well established, and we previously showed that adenoviral-delivered overexpression of an endogenous inhibitor, the tissue inhibitor of metalloproteinases-3 (TIMP-3), significantly retarded intimal thickening in short-term autologous porcine arteriovenous interposition grafts (28 days). However, it is essential to determine whether this approach will provide longer-term benefits. Methods and Results— We assessed whether a recombinant adenovirus that overexpresses TIMP-3 (RAdTIMP-3) affects vein graft intimal thickening in the longer term (at 3 months). Porcine saphenous veins were subjected to luminal infection with 2.5×10 10 pfu/mL RAdTIMP-3 or RAd60 (control virus) or vehicle control, for 30 minutes before implantation into the carotid artery. Analysis of grafts harvested 3 months after delivery revealed that RAdTIMP-3–infected grafts had significantly reduced intimal areas compared with both controls (3.2±0.4 mm 2 versus 5.6±0.7 mm 2 and 5.9±0.5 mm 2 , RAdTIMP-3, RAd60, and vehicle, respectively). Medial areas were also significantly decreased by TIMP-3 (3.8±0.3 mm 2 versus 6.7±1.0 mm 2 and 5.2±0.4 mm 2 , RAdTIMP-3, RAd60, and vehicle, respectively). Conclusions— Overexpression of TIMP-3 provides a sustained retardation of vein graft intimal thickening and highlights the translational potential for ex vivo TIMP-3 gene therapy.