Novel pathogenic variants in an Indian cohort with epidermolysis bullosa: Expanding the genotypic spectrum

BackgroundEpidermolysis bullosa (EB) is a genodermatosis characterized by skin fragility and blisters with variable severity. Patients with Dystrophic EB (DEB) or Junctional EB (JEB) mainly present to clinic due to greater functional impairment. Pathogenic sequence variations in COL7A1 are implicated in DEB.ObjectiveWe have tried to decipher the molecular spectrum and genotype phenotype correlation of 21 Indian patients with EB.MethodsNext generation sequencing (NGS) was performed to determine the pathogenic variants. Sanger sequencing was also done for validation of the variants in eleven individuals.ResultsPathogenic variants were detected in 20 individuals (diagnostic yield of 95%). Majority of them (90%) had sequence variation in COL7A1 while two had pathogenic variants in ITGB4 and KRT14 respectively. Out of the 18 patients confirmed to have DEB, 3 had Dominant DEB (DDEB) whereas 15 patients had Recessive DEB (RDEB). Amongst 23 sequence variations identified, 12 were found to be novel (3 were missense, 5 were premature termination codon variants while 4 were splice-site changes).ConclusionGenotype phenotype correlation was noted with milder manifestations in those with dominant inheritance types. Exact molecular diagnosis can be ascertained by NGS in majority of cases.     

人格特质对二胎返岗护士产适应水平的影响

目的 了解二胎返岗护士适应水平现状,并探讨人格特质对其返岗适应水平的影响。方法 2018年1-12月,采用便利抽样法选取山东省3所三级甲等医院360名护士为研究对象,采用一般资料调查表、艾森克人格问卷、护士产后返岗适应问卷对其进行调查。结果 护士产二胎后返岗适应水平均分为(2.16±0.51)分;外向型人格特征与返岗适应水平呈正相关(r=0.540,P<0.001),精神质、神经质人格特征与返岗适应水平均呈负相关(r=-0.410,P<0.001;r=-0.350,P<0.001)。多元线性回归分析结果显示,年龄、返岗时间、工作负荷、返岗培训、内-外倾向、精神质、神经质是护士产二胎后返岗适应的独立影响因素。结论 护士产二胎后返岗适应处于中等偏下水平,人格特质、生育年龄、返岗时间、工作负荷、返岗培训为其影响因素,护理管理者可结合人格特质等特点采取管理策略,提高护士产二胎后返岗适应的水平。     

Differences in Evidentiary Requirements Between European Medicines Agency and European Health Technology Assessment of Oncology Drugs—Can Alignment Be Enhanced?

ObjectivesNational health technology assessments (HTAs) across Europe show differences in evidentiary requirements from assessments by the European Medicines Agency (EMA), affecting time to patient access for drugs after marketing authorization. This article analyzes the differences between EMA and HTA bodies’ evidentiary requirements for oncology drugs and provides recommendations on potential further alignment to minimize and optimally manage the remaining differences.MethodsInterviews were performed with representatives and drug assessment experts from EMA and HTA bodies to identify evidentiary requirements for several subdomains and collect recommendations for potentially more efficiently addressing differences. A comparative analysis of acceptability of the evidence by EMA and the HTA bodies and for potential further alignment between both authorities was conducted.ResultsAcceptability of available evidence was higher for EMA than HTA bodies. HTA bodies and EMA were aligned on evidentiary requirements in most cases. The subdomains showing notable differences concerned the acceptance of limitation of the target population and extrapolation of target populations, progression-free survival and (other) surrogate endpoints as outcomes, cross-over designs, short trial duration, and clinical relevance of the effect size. Recommendations for reducing or optimally managing differences included joint early dialogues, joint relative effectiveness assessments, and the use of managed entry agreements.ConclusionsDifferences between assessments of EMA and HTA bodies were identified in important areas of evidentiary requirements. Increased alignment between EMA and HTA bodies is suggested and recommendations for realization are discussed.     

肺腺癌对一代EGFR-TKIs原发耐药的危险因素分析

目的:分析对一代表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitors,EGFR-TKIs)原发耐药的EGFR突变肺腺癌患者的临床特征,为预测肺腺癌患者是否对一代EGFR-TKIs原发耐药提供依据。方法:收集2014年01月至2019年04月于本院住院,一线使用一代EGFR-TKIs且随访时间超过6个月的EGFR敏感突变(19Del/21L858R)肺腺癌患者,根据疗效纳入原发性耐药组(NR=40)和敏感组(NS=237),比较两组患者的临床、影像特征及实验室指标之间的差异,分析对一代EGFR-TKIs原发耐药的危险因素。结果:EGFR敏感突变患者的原发性耐药发生率为14.4%。原发性耐药组与敏感组患者相比,二者在吸烟指数(P=0.004)及淋巴结转移(P=0.03)的差异有统计学意义。血清神经元特异性烯醇化酶(neuron specific enolase,NSE)≥10.725 ng/mL、肿瘤直径≥3.55 cm的患者更易对一代EGFR-TKIs耐药(P<0.05),各因素AUC值分别为0.615、0.716。联合NSE+肿瘤直径两项指标时AUC为0.735(95%CI:0.665~0.804),联合NSE+肿瘤直径+吸烟指数三项指标时AUC为0.751(95%CI:0.679~0.822),均优于单项指标。多因素Logistics回归分析证实,血清NSE浓度、肿瘤直径及吸烟指数是预测EGFR敏感突变患者对一代EGFR-TKI原发耐药的独立影响因素(P<0.05)。结论:吸烟指数≥400、病灶直径≥3.55 cm、血清NSE浓度≥10.725 ng/mL的患者更易对一代EGFR-TKIs原发耐药。单因素对预测EGFR突变患者是否对一代EGFR-TKIs原发耐药准确性较低,综合上述三项指标预测效果更好。     

Use of neuroendocrine effects in discrimination between CNS-active drugs in the rat

Different psychotropic drugs were investigated in order to determine their effect on the release of prolactin and corticosterone and their influence on the tuberoinfundibular dopamine (TIDA) neuron activity. The results were used in a principal component analysis, which grouped the psychotropic drugs into different clusters. In the plot showing these clusters the anxiolytic drugs were found to be grouped together and differ from the antidepressant drugs by their potent ability to increase plasma corticosterone. The antipsychotic drugs formed a separate group being clustered together. Typical neuroleptic and atypical antipsychotic drugs could be separated within the cluster by their different effects on plasma prolactin and corticosterone and on TIDA neuron activity. The results indicate that the neuroendocrine profiles of antidepressant and anxiolytic drugs are different from those of antipsychotic drugs and that the neuroendocrine measurements could be a useful tool in the early classification of psychotropic drugs. © 1993 Wiley-Liss, Inc.     

Serotonin-induced increase in cAMP in ganglia isolated from the myenteric plexus of the guinea pig small intestine: Mediation by a novel 5-HT receptor

Serotonin (5-HT) is a mediator (through 5-HT_1P receptors) of slow EPSPs in myenteric ganglia of the small intestine. The effect of 5-HT can be mimicked by elevating cAMP; therefore, we tested the hypothesis that the slow EPSP-like response to 5-HT is cAMP-mediated. Guinea pig gut was enzymatically dissociated; myenteric ganglia remained intact and were collected by filtration. Neurons in the isolated ganglia retained their ability to manifest the slow EPSP-like response to 5-HT. Exposure to 5-HT raised the ganglionic level of cAMP (ED₅₀ 0.3 μM). This effect was not antagonized by the 5-HT_1P antagonist, N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan amide (100.0 μM), or mimicked by the 5-HT_1P agonist, 5-hydroxyindalpine (10.0 μM). Increases in cAMP were also evoked by the 5-HT₁ agonist, 5-carboxyamidotryptamine (10.0 μM), the 5-HT₂ agonist, (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 1.0–10.0 μM), and by the 5-HT₄ agonists, renzapride (1.0–10.0 μM) and 5-methoxytryptamine (1.0–10.0 μM); however, neither the 5-HT₁/5-HT₂ antagonists, spiperone, methysergide, and methiothepin, nor the 5-HT₄ antagonist, tropisetron (ICS 205–930; 10.0 μM), were able to inhibit the rise in cAMP evoked by these compounds or by 5-HT (0.1–10.0 μM). The 5-HT-evoked elevation of cAMP was antagonized by ketanserin (10.0 μM), which also blocked the effects of 5-methoxytryptamine and DOI, but not those of renzapride. The effective concentration of DOI, however, was higher than that needed for activation of 5-HT₂ receptors, and Northern analysis using a cDNA probe encoding the rat 5-HT₂ receptor failed to reveal the presence of 5-HT₂ mRNA in myenteric ganglia, although it hybridizes with mRNA of the right size in the guinea pig brain. Compounds that failed to change levels of cAMP or to antagonize the action of 5-HT included 8-hydroxy-di-n-propylamino tetralin, R58639, R88226, and sumatriptan. It is concluded that the receptor responsible for the 5-HT-induced rise in cAMP in ganglia isolated from the guinea pig myenteric plexus is not a known subtype of 5-HT receptor. Since the pharmacology of this novel receptor is different from that of the slow EPSP-like response to 5-HT, the receptor probably does not mediate the slow EPSP. © 1993 Wiley-Liss, Inc.     

胃癌雌激素受体表达及新一代抗受体药物在胃癌治疗中的探讨

目的　探讨胃癌雌激素受体 (ER)实际表达率 ,为临床使用新一代抗ER药物 (toremifene ,TOR)治疗胃癌提供临床病理依据。方法　用免疫组化法对 349例胃癌标本进行ER的检测 ,其中 2 99例用ABC(avidinbiotinperoxidasecomplex)法 ,5 0例用葡聚糖聚合物技术二步法进行检测。在检测ER的同时也检测 p5 3及PCNA的表达。结果　两种检测方法的ER阳性率分别为 2 .3% (7/ 2 99)及 0 % (0 / 5 0 ) ,p5 3阳性率 37.1% (111/ 2 99)及 4 6 %(2 3/ 5 0 ) ,PCNA 94 .3% (2 82 / 2 99)及 96 % (48/ 5 0 )。结论　胃癌细胞可表达ER但实际表达率很低 ,而且存在质和量的变化。tamoxifen (TAM )及TOR的抗胃癌效应需要进一步研究     

Tracking the status of language development in language-minority kindergartners

As our world becomes increasingly multicultural in nature, multilingual skills constitute an everyday phenomenon in schools. Since most of the second-language research has focused on school-age students, more research had to be conducted with language-minority students at the kindergarten level in order for psychologists and educators to develop effective and efficient systems for evaluating and tracking the developmental status of young language-minority children. The purpose of this study was to investigate the potential usefulness of a standardized continuous progress measure, the Picture Naming Individual Growth and Development Indicator, to longitudinally assess language development in 23 language-minority children, as well as in 13 native English-speaking children. Results indicated that we could use the Picture Naming Individual Growth and Development Indicator to detect differences in first-language and second-language development in language-minority children, as well as to detect differences between the two groups of children in their expressive English-language skills.     

掌背动脉逆行岛状筋膜瓣修复手部皮肤缺损

目的:介绍掌背动脉逆行筋膜瓣修复手部皮肤缺损的临床应用。方法:采用第二、第三掌背动脉逆行岛状筋膜瓣分别修复手部皮肤缺损10例。皮肤缺损面积2.0cm×3.0cm-3.0cm×5.0cm。结果:10例筋膜瓣移位均成活,效果满意。结论:应用第二、三掌背动脉逆行岛状筋膜瓣移植是治疗手部皮肤缺损一种简单有效的手术方法。