Current trends in the study of potassium channel openers

Some eight years ago it was found that certain smooth muscle relaxants exert their effect by opening a specific K⁺ channel resulting in cell membrane hyperpolarization. The use of K⁺channel openers (cromakalim, pinacidil and RP-52891) and compounds which antagonize their actions (glibenclamide, phentolamine and alinidine) has enabled a great deal of research to be performed into the role of this K⁺ channel, not only in smooth muscle, but also in cardiac and skeletal muscle as well as neural and endocrine organ function. Much of the attention has centred on the smooth muscle relaxant actions of the K⁺ channel openers, since they have potential therapeutic use in disorders involving smooth muscle over-reactivity such as hypertension and asthma. More recently the cardiac actions of the K⁺ channel openers have become the focus of interest. Although there appear to be good theoretical reasons why K⁺ channel openers may be of use in some arrhythmias and in ischaemic heart disease there are major hurdles to overcome. In particular, given that the effect of these compounds on vascular smooth muscle occurs at a concentration 20- to 100-fold lower than that required to produce cardiac effects, it is likely their therapeutic usefulness will be limited until a breakthrough in cardiac/vascular selectivity is made. There is also growing interest in endogenous K⁺ channel openers and the physiological role of the K⁺ channel which they open. Opening of K⁺ channels, either spontaneously or by endogenous regulators, could possibly be an important hypotensive mechanism both under normal conditions and in a number of pathological conditions. Research into these areas will need to continue if the true therapeutic potential of K⁺ channel openers and their antagonists are to be realized.     

半乳糖凝集素-3与慢性心力衰竭的相关性研究

目的：研究血浆半乳糖凝集素3水平在慢性心脏衰竭(CHF)中的临床价值。方法：选取(纽约心脏协会心功能分级II-IV级)慢性心力衰竭患者120例及对照组40例。酶联免疫吸附法测定血浆Gal-3和NT-proBNP水平。超声心动图检查测定舒张期左房内径(LAD),左室舒张末期内径(LVEDD),左室射血分数(LVEF)。受试者工作特征(ROC)曲线分析Gal-3或NT-proBNP水平在CHF的诊断价值。结果：心衰组Gal-3水平显著高于对照组(P<0.05),且随心功能分级的增加而升高。同时血浆Gal-3水平与LAD呈正相关(r=0.280,P<0.05),与左室舒张末期内径成正相关(r=0.496,P <0.05),与LVEF呈负相关(r=-0.634,P<0.01)。血浆Gal-3水平与NT-proBNP呈正相关(r=0.766,P<0.01)。Gal-3对诊断心衰同样有较高诊断价值。结论：血浆Gal-3水平与CHF具有一定相关性,血浆Gal-3水平与左室结构和功能变化相关,表明Gal-3参与了CHF左室重构过程,Gal-3对慢性心衰的诊断价值也很高。     

Cerebrospinal fluid beta2-microglobulin: a study in controls and patients with metastatic and non-metastatic neurological diseases

We studied cerebrospinal fluid Beta₂-microglobulin (CSF B₂-m) in 197 patients with a variety of neurological diseases to evaluate the usefulness of B₂-m in the detection of meningeal dissemination of malignancy. In the control group we found a relationship between CSF log B₂-m and age (P < 10⁻⁴). Age standardized reference values were established as 0.65–2.2 mg/l. The results show that CSF B₂-m was elevated in leptomeningeal metastases from solid and haematological tumors. We observed slight elevations of CSF B₂-m in epidural and parenchym metastases from solid tumors. Our study shows that B₂-m in CSF is a sensitive marker for meningeal metastases especially from hemopoietic tumors.     

FMR1基因突变与女性生殖能力和妊娠结局

近年来原发性卵巢功能不全（primary ovarian insufficiency,POI）、不明原因的早期自然流产、复发性流产、胚胎停育等生育能力低下和反复生育失败的疾病越来越多,女性生殖健康也日益受到关注。脆性X智力低下1（fragile X mental retardation 1,FMR1）基因参与胚胎发育的基因调控过程,该基因的突变可引起多种女性生殖健康疾病,且与绝经年龄相关。因此FMR1基因的筛查对协助诊疗女性生殖健康疾病有重要的临床价值,也为疾病的早期预防、诊断和治疗提供了新思路。     

Clinical evaluation of human papillomavirus 16/18 oncoprotein test for cervical cancer screening and HPV positive women triage

The prognostic role of tumor‐infiltrating tryptase⁺ mast cells in human solid tumors remains controversial. Herein, we conducted a meta‐analysis including 28 published studies with 4224 patients identified from PubMed and EBSCO to assess the prognostic impact of tumor‐infiltrating tryptase⁺ mast cells in human solid tumors. We found that tryptase⁺ mast cell infiltration significantly decreased overall survival (OS) and disease‐free survival (DFS) in all types of solid tumors. In stratified analyses, tryptase⁺ mast cell infiltration was significantly associated with worse OS in non‐small cell lung cancer, hepatocellular carcinoma and 5‐year survival in colorectal cancer. And these cells were inversely associated with DFS in hepatocellular and colorectal cancer. In addition, high density of intratumoral tryptase⁺ mast cells significantly correlated with lymph node metastasis of solid tumor. In conclusion, Tryptase⁺ mast cell infiltration leads to an unfavorable clinical outcome in solid tumors, implicating that it is a valuable biomarker for prognostic prediction for human solid malignances and targeting it may have a potential for effective treatment.     

The immunologic dominance of an epitope within a rationally designed poly-epitope vaccine is influenced by multiple factors

IntroductionCD4⁺ T cells are essential for inducing optimal CD8⁺ T cell and antibody-producing B cell responses and maintaining their long-term immunological memory. Therefore, CD4⁺ T cells are a critical component in HIV vaccine development. Due to enormous viral gene variation and significant human host genetic diversity, HIV vaccines may need to be custom-made for different countries.MethodsPreviously, we designed a CD4⁺ T cell vaccine based on Chinese HIV isolates and HLA-DR alleles using bioinformatics tools and predicted that 20 epitopes could cover 98.1% of the Chinese population. In vivo testing of the poly-epitope antigen in mice only activated specific T cells for some epitopes. To elucidate the mechanism of the observed differential immunogenicity, we examined poly-epitope antigen processing and presentation using in vitro and in vivo analytical methods.ResultsEnzymatic digestion indicated that all 20 epitopes comprising the poly-epitope antigen could be liberated, but MHC II binding assays showed that neither binding affinity nor dissociation rate was associated with the magnitude of T cell immune responses elicited by each peptide epitope in vaccinated mice. Mass spectrometry analysis of MHC II-bound peptides suggested that the abundance of endogenously processed peptides bound to MHC II molecules was significantly associated with the relative immunodominance of these epitopes.ConclusionThese results provide a new rationale for improving the design and testing of poly-epitope vaccines for HIV and other diseases.     

非接触式眼压计与回弹式眼压计在眼压测量中的准确度分析

目的：分析非接触式眼压计(non contact tonometer,NCT)、ICare回弹式眼压计(ICare rebound tonometer,RBT)在青光眼患者中眼压测量结果的准确性。

方法：回顾性病例对照研究。选取青光眼患者113例185眼。用RBT、NCT和Goldmann眼压计(GAT)分别于9：00、16：00两次进行眼压测量并记录为两组数据,分别用秩和检验、国际标准8621指南评估其准确性,Bland-Altman一致性分析两组测量结果的一致性,并以GAT测量值作为标准将数据分为异常眼压组(<10mmHg或>21mmHg)和正常眼压组(10～21mmHg),在不同组间分析其一致性。应用Spearman相关分析眼压计间的相关性。

结果：GAT、NCT和RBT三组测量值间存在差异(P<0.01); GAT获得的眼压测量值与RBT和NCT测量值间存在相关性(r_s=0.71、0.77,P<0.001)。NCT与GAT测量值接近(P=0.92),而RBT与GAT相比,眼压测量值较高(P<0.05)。然而NCT、RBT同GAT相比一致性界限范围均较宽,分别为-6.2～6.0、-5.2～7.6mmHg,在正常眼压组一致性界限范围分别为-5.9～5.9、-4.3～7.5mmHg,在非正常眼压组分别为-7.3～6.4、-7.5～5.6mmHg。根据ISO 8612指南进行评价,NCT和RBT在三组中超过95%的一致性限制的异常值分别为3.9%、11.3%、12.2%和26.3%、11.3%、12.2%。

结论：NCT和RBT均不能简单代替GAT用于青光眼患者眼压的测量。在青光眼患者中,随着测量值偏离正常眼压范围,NCT和RBT的测量误差也有所增大。     

Integrated microRNA/mRNA expression profiling of the skin of psoriasis patients

BackgroundPsoriasis is a chronic inflammatory disease characterized by demarcated, raised, and scaling skin lesions. It often serves as a model for immune-mediated disorders. Gene expression profiling of affected skin has allowed insights into psoriasis pathogenesis. However, the mechanisms leading to specific mRNA expression alterations in psoriasis are barely understood.ObjectivesTo perform integrated microRNA-mRNA expression studies of non-lesional, peri-lesional, and lesional skin from psoriasis patients.MethodsCutaneous microRNA and mRNA expression profiles of 14 patients using Nanostring nCounter-technology and RNA sequencing as well as in vitro keratinocyte stimulation and qPCR studies.ResultsOnly 3.5 % of microRNAs manifested a robust gradual expression trend from non-lesional to paired lesional skin, with 61 % being upregulated and 39 % being downregulated. Relevance of these microRNA regulations was supported by their inverse association with 57 % of the mRNA species found to be regulated during psoriatic lesion development. Many of the involved mRNAs were downregulated and functionally related to keratinocyte metabolism, barrier function, and neuronal signaling, and were already regulated in peri-lesional skin. An integrated correlation analysis revealed a robust interaction for 134 microRNAs/mRNAs pairs. In vitro keratinocyte studies of selected microRNAs/mRNAs revealed regulations of all analyzed microRNAs in a psoriasis-like manner by IL-17A/TNF-α (e.g. hsa-miR-23a-3p), IFN-γ (e.g. hsa-miR-106a-5p/miR-17-5p), or IL-24 (e.g. hsa-miR-203a-3p). Moreover, most of their predicted target mRNAs (e.g. ID4, EPHB2) were respectively altered by the same cytokines.ConclusionOur study suggests that, during development of psoriatic lesions, defined aspects of psoriasis pathogenesis are regulated by the action of microRNAs.     

介入治疗在原发性肝癌中的应用

原发性肝癌在我国属于高发病率、高死亡率的恶性肿瘤,由于其早期症状不突出且无特异性,因此一旦发病,预后很差。原发性肝癌具有特殊的血供方式,1978年日本Yamada教授首次提出了经导管动脉化疗栓塞治疗肝脏肿瘤的设想并实践成功,至此介入治疗成为原发性肝癌的又一种治疗方法。随着新思想、新技术、新材料的不断涌现,介入治疗的优势越来越明显,逐渐成为治疗原发性肝癌的主要方法,甚至是常规方法之一。