Rationale: Ebstein anomaly is a common congenital heart disease that may induce severe tricuspid regurgitation and dilation of the "atrialized" portion of the right ventricle. Patients who undergo surgery to correct Ebstein anomaly are at high risk of postoperative right-sided heart failure, yet little is known about what pre-, peri-, or postoperative procedures may help reduce this risk. Patient concerns: Here, we describe 3 cases of adults with Ebstein anomaly who underwent corrective surgery and in whom right-sided heart failure occurred with severe tricuspid regurgitation detected by transesophageal echocardiography. Diagnoses: Ebstein anomaly. Intervention: Various approaches were applied to prevent right heart failure: perioperative control of atrial and ventricle arrhythmia, protection of myocardium, reduction of right-side cardiac workload after cardiopulmonary bypass, and mechanical support for right heart. Outcomes: One of the 3 patients died, another experienced kidney failure despite postoperative support on extracorporeal membrane oxygenation, and the third patient survived without complications. Lessons: Our case series suggests that surgical prognosis can be improved through aggressive preoperative treatment, vasoactive and anti-arrhythmia medications, and comprehensive measures designed to reduce myocardial injury, prevent myocardial edema, and reduce pre- and afterload on the right ventricle.
Aim: Inflammation plays a role in secondary brain injury after intracerebral hemorrhage (ICH). We aimed to determine the prognostic significance of admission white blood cell (AWC), neutrophil count (ANC), lymphocyte count, monocyte count and neutrophil to lymphocyte ratio (NLR) for 90-day outcome after ICH. Patients & methods: A total of 336 patients with spontaneous ICH were retrospectively investigated. Clinical outcome was assessed by modified Rankin Scale at 90 days. Results: Multivariate analysis showed that higher AWC, ANC, NLR were independently associated with mortality and worse outcome. Moreover, NLR showed a higher predictive ability in mortality than in poor outcome in receiver operating characteristic analysis. Linear regression analyses revealed admission Glasgow Coma Scale score and ICH volume were mostly correlated with these indices. Conclusion: Elevated levels of AWC, ANC and NLR were independently related to poor 90-day outcome after ICH. NLR may be a novel inflammatory biomarker following ICH.
Background and purposeCurrently, there are limited options for treatment of postherpetic neuralgia (PHN) patients in China. While pregabalin is an effective treatment option for PHN in several countries, there is limited information on its efficacy in Chinese patients. MethodsThis was an 8-week, double-blind, placebo-controlled trial in Chinese patients with PHN randomized (1:1) to pregabalin 300 mg/day or placebo. Primary efficacy endpoint was change from baseline in mean pain score (Daily Pain Rating Scale; 0 = no pain' to 10 = worst possible pain'). Secondary efficacy endpoints included change from baseline in overall pain intensity score, by visual analog scale (VAS; 0 = no pain' to 100 = worst possible pain') and daily sleep interference score (0 = pain does not interfere with sleep' to 10 = completely interferes'). ResultsA total of 220 patients were randomized and received treatment (111 pregabalin and 109 placebo). Improvement in mean pain score with pregabalin was significantly greater than placebo, least squares mean difference (95% CI), -0.71 (-1.08, -0.34); P = 0.0002. Improvements in VAS and sleep interference score at endpoint were significantly greater with pregabalin than placebo, least squares mean difference (95% CI), -8.18 (-11.99, -4.37); P < 0.0001, and -0.54 (-0.93, -0.14); P = 0.0079, respectively. Adverse events were consistent with current product labeling, with dizziness the most commonly reported adverse event (24.3% of pregabalin-treated patients). ConclusionPregabalin improved measures of pain and sleep, and is well tolerated in Chinese patients with PHN. These results may inform physicians treating patients with PHN in China.
The allosteric regulation triggering the protein's functional activity via conformational changes is an intrinsic function of protein under many physiological and pathological conditions, including cancer. Identification of the biological effects of specific somatic variants on allosteric proteins and the phenotypes that they alter during tumor initiation and progression is a central challenge for cancer genomes in the post-genomic era. Here, we mapped more than 47,000 somatic missense mutations observed in approximately 7,000 tumor-normal matched samples across 33 cancer types into protein allosteric sites to prioritize the mutated allosteric proteins and we tested our prediction in cancer cell lines. We found that the deleterious mutations identified in cancer genomes were more significantly enriched at protein allosteric sites than tolerated mutations, suggesting a critical role for protein allosteric variants in cancer. Next, we developed a statistical approach, namely AlloDriver, and further identified 15 potential mutated allosteric proteins during pan-cancer and individual cancer-type analyses. More importantly, we experimentally confirmed that p.Pro360Ala on PDE10A played a potential oncogenic role in mediating tumorigenesis in non-small cell lung cancer (NSCLC). In summary, these findings shed light on the role of allosteric regulation during tumorigenesis and provide a useful tool for the timely development of targeted cancer therapies.
ObjectiveTo systematically review the diagnostic value of neuron specific enolase (NSE) for malignant pleural effusion. MethodsWe comprehensively searched databases including The Cochrane Library (Issue 1, 2012), EMbase, MEDLINE, CBM, CNKI, WanFang Data and VIP from inception to January 2012 to collect studies about the diagnostic value of NSE for malignant pleural effusion. Literature screening according to the inclusion and exclusion criteria, data extraction and methodological quality assessment were completed by two reviewers independently. Then Meta-DiSc software (version 1.4) was used for pooling analysis. ResultsA total of 12 studies were finally included. The results of meta-analysis showed that the value of pooled specificity, sensitivity, positive likelihood radio, negative likelihood radio and diagnostic odds ratio (DOR) were 0.79 (0.76 to 0.84), 0.55 (0.51 to 0.59), 3.2 (1.94 to 5.29), 0.58 (0.45 to 0.74), 7.56 (3.74 to 15.30), respectively; and the area under SROC curve (AUC) was 0.813 1. ConclusionUsing NSE as a maker to diagnose malignant pleural effusion is of certain clinical value, which is used to differentiate benign and malignant pleural effusion.
Background: Necrotizing enterocolitis (NEC) is the leading cause of neonatal gastrointestinal mortality; effective interventions are lacking with limited understanding of the pathogenesis of NEC. The importance of Toll-like receptor 4 (TLR4) signaling in NEC is well documented; however, the potential mechanisms that regulate enterocyte inflammation and apoptosis remain unclear. The aim of this study was to characterize the role of TLR4-mediated inflammation and apoptosis in the development of NEC and to determine the major apoptotic pathways and regulators in the process. Methods: TLR4-deficient C57BL/10ScNJ mice and lentivirus-mediated stable TLR4-silent cell line (IEC-6) were used. NEC was induced by formula gavage, cold, hypoxia, combined with lipopolysaccharide in vivo or lipopolysaccharide stimulation in vitro. Enterocyte apoptosis was evaluated by TUNEL or Annexin analysis. The expression of TLR4, caspase3, caspase8, caspase9, Bip, Bax, Bcl-2, and RIP was detected by Western blot and immunofluorescence. Inflammatory factors such as tumor necrosis factor-a and interleukin-2 were examined by Luminex. Results: Defect of TLR4 led to suppressed enterocytes apoptosis both in vitro and in vivo; the expression of caspase3, caspase8, Bip, and Bax was decreased; and caspase9 and Bcl-2 were increased. NEC severity was attenuated in TLR4-deficient mice compared with wild-type counterparts, and enterocytes apoptosis was correlated with NEC severity. RIP and cytokine level of tumor necrosis factor-a and interleukin-2 were also decreased. Conclusions: TLR4-induced inflammation and apoptosis play a critical role in the pathogenesis of NEC. TLR4 inhibition, combined with extrinsic (caspase8) and/or endoplasmic reticulum stress (Bip) apoptosis signaling blockade could serve as a potential effective treating strategy for NEC.
目的：了解大鼠脑出血后血肿周围组织细胞凋亡与神经元特异性烯醇化酶（NSE）的表达及大鼠神经功能缺损程度的关系。方法：用胶原酶注入到大鼠尾状核的方法制作脑出血模型。将大鼠分为脑出血、假手术组、正常组3组。采用苏木素伊红(HE) 染色、NSE免疫组织化学染色及TUNEL分别观察各组在脑出血后第6 h、12 h、24 h、48 h、72 h、5 d、7 d时血肿周围NSE及TUNEL的表达。用Longa评分法评价大鼠神经功能缺损程度。结果：大鼠在胶原酶注入6 h后形成稳定的血肿，在造模24～48 h神经功能缺损程度最重；6 h即见到TUNEL阳性细胞的表达，在48 h最明显；NSE从神经元中漏出弥散到细胞间隙也在48 h达高峰。结论：脑出血血肿周围凋亡与神经功能缺损及NSE的变化有关，凋亡可能在脑出血的神经损伤中起重要的作用。
The plasminogen activator inhibitor-1 (PAI-1) is a candidate gene for stroke based on PAI-1's crucial role in fibrinolytic system. However, association studies have yielded conflicting results regarding the association between PAI-1 polymorphisms and stroke susceptibility. To further elucidate the putative association, we performed a systematic review and meta-analysis to provide a complete picture of the loci investigated for association of PAI-1 polymorphism with stroke risk and to derive a precise estimation. PubMed, Embase, and China National Knowledge Infrastructure (CNKI) databases were searched until June 2015 to identify eligible studies. Forty data sets from 39 studies with a total of 8336 cases and 14,403 controls were included. The most commonly investigated polymorphism was -675 4G/5G, followed by -844 G/A, 11053 T > G, HindIII C/G, and (CA)n. Overall, our meta-analysis provided evidence for the significant association of PAI-1 4G/5G polymorphism with an increased risk of adult but not pediatric ischemic stroke (adult: 4G/4G vs. 4G/5G + 5G/5G, OR = 1.21, 95 % CI = 1.04-1.42). In the subgroup analysis, significant association was detected in Asians (4G/4G vs. 4G/5G + 5G/5G, OR = 1.45, 95 % CI = 1.14-1.85) but not Caucasians. Moreover, we found that -844 G/A but not 11053 T > G polymorphism was associated with an increased risk of ischemic stroke (-844G/A: A/A vs. G/G: OR = 1.32, 95 % CI = 1.01-1.73). A tendency of PAI-1 4G/5G polymorphism towards a decreased risk of hemorrhagic stroke was observed (4G/4G + 4G/5G vs. 5G/5G, OR = 0.77, 95 % CI = 0.59-1.02, P = 0.066). Future well-designed studies in large well-characterized sample size and presenting results stratified by gender, age, and stroke subtype are warranted.
Recombinant adeno-associated virus (rAAV) is an attractive tool for basic science and translational medicine including gene therapy, due to the versatility in its cell and organ transduction. Previous work indicates that rAAV transduction patterns are highly dependent on route of administration. Based on this relationship, we hypothesized that intraperitoneal (IP) administration of rAAV produces unique patterns of tissue tropism. To test this hypothesis, we investigated the transduction efficiency of 12 rAAV serotypes carrying an enhanced green fluorescent protein (EGFP) reporter gene in a panel of 12 organs after IP injection. Our data suggest that IP administration emphasizes transduction patterns that are different from previously reported intravascular delivery methods. Using this approach, rAAV efficiently transduces the liver, pancreas, skeletal muscle, heart and diaphragm without causing significant histopathological changes. Of note, rAAVrh.10 showed excellent muscle transduction following IP administration, highlighting its potential as a new muscle-targeting vector.