摘要：Arrhythmogenic right ventricular cardiomyopathy(ARVC)is a progressive disease characterized by adipose and fibrous replacement of the *** elevated testosterone levels have been implicated in the pathological process of ARVC,its exact contribution to cardiac fibrosis in ARVC remains *** this study,we analyzed the potential contribution of gender-based differences on the distribution of the low-voltage area in an ARVC cohort undergoing an electrophysiological study,which was indicated by feature ***,we established engineered cardiac spheroid models in vitro using patient-specific induced pluripotent stem cell(iPSC)-derived cardiomyocytes(iPSC-CMs)and iPSC-derived cardiac fibroblasts(icFBs).We elucidated the pathogenicity of abnormal splicing in the plakophilin-2(PKP2)gene caused by an intronic ***,pathogenic validation of the desmoglein-2(DSG2)point mutation further confirms the reliability of the ***,testosterone exacerbated the DNA damage in the mutated cardiomyocytes and further activated myofibroblasts in a chain *** conclusion,we designed and constructed an in vitro three-dimensionally-engineered cardiac spheroid model of ARVC based on clinical findings and provided direct evidence of the fibrotic role of testosterone in ARVC.

摘要：Therapeutic proteins and peptides have revolutionized treatment for a number of diseases, and the expected increase in macromolecule-based therapies brings a new set of challenges for the pharmaceutics field. Due to their poor stability, large molecular weight, and poor transport properties,therapeutic proteins and peptides are predominantly limited to parenteral administration. The short serum half-lives typically require frequent injections to maintain an effective dose, and patient compliance is a growing issue as therapeutic protein treatments become more widely available. A number of studies have underscored the relationship of subcutaneous injections with patient non-adherence, estimating that over half of insulin-dependent adults intentionally skip injections. The development of oral formulations has the potential to address some issues associated with non-adherence including the interference with daily activities, embarrassment, and injection pain. Oral delivery can also help to eliminate the adverse effects and scar tissue buildup associated with repeated injections. However, there are several major challenges associated with oral delivery of proteins and peptides, such as the instability in the gastrointestinal(GI)tract, low permeability, and a narrow absorption window in the intestine. This review provides a detailed overview of the oral delivery route and associated challenges. Recent advances in formulation and drugdelivery technologies to enhance bioavailability are discussed, including the co-administration of compounds to alter conditions in the GI tract, the modification of the macromolecule physicochemical properties, and the use of improved targeted and controlled release carriers.

摘要：满足最基本需求的肺功能是早产儿存活的先决条件。早产儿肺结构和功能欠成熟,常常伴发呼吸窘迫综合征(RDS)。除结构不成熟之外,早产儿肺组织还易因出生前后各种不利状况及因素而受损,进而防碍生后肺部的正常发育,促发非成熟性慢性肺部病变,导致支气管肺发育不良(BPD)。该文将以由炎症变化而引发并与炎症变化密切相关的肺损伤为重点,全面综述用以探讨早产儿肺部炎症反应机制的各种实验模型,这其中包括用来研究绒毛膜羊膜炎发病机制的模型。人们知道,绒毛膜羊膜炎与早产密切关。从临床角度讲,胎儿宫内接触绒毛膜羊膜炎会导致胎儿肺组织发育异常,进而影响早产儿的肺功能。根据临床数据,有作者认为:暴露于绒毛膜羊膜炎的胎儿其支气管肺发育不良的风险增高,但RDS的风险反而降低。目前有实验数据表明,急性和慢性羊膜炎均可导致胎儿肺部炎症反应。一些研究人员建立了各种动物模型,他们除了借助这些模型来检测肺组织中诸如IL-1之类炎症介质的水平外,他们还用这些模型研究过炎症介质在肺发育成熟过程中的作用。在接触过宫内炎症的动物胎儿,肺组织磷脂酰胆碱的生成量及表面活性蛋白的水平增高,这表明脂酰胆碱表面活性蛋白会影响肺上皮细胞成熟,其影响程度之大小主要取决于暴露炎症因子的时间和剂量以及炎症因子的性质。使用细菌脂多糖(LPS)或解脲活性物作为炎症因子处理实验动物可以模拟人绒毛膜羊膜炎的临床表现。此外,实验数据表明,胎儿似乎具有抗衡并降低炎症反应程度的能力。目前,越来越多的证据表明抗逆内毒素是胎儿炎症调节的一个重要机制。产前用糖皮质激素(GCS)处理孕妇是早产的标准治疗方案,该处理可对胎儿肺组织和免疫细胞的成熟施以复杂的影响。有趣的是,GCS对肺形态和功能的作用与LPS诱导的宫内羊膜炎症反应雷同。然而,动物实验显示,虽然在动物炎症反应和孕妇GCS处理后肺器官在成熟过程度中其构成变化极其相似,但两者存在"质"上的不同,且涉及的分子途径也各异。比如,产前炎症可诱发胎儿肺组织的TGFβ表达增高并激活其下游信号通路,然而产前GCS处理孕妇的效果则相反。尽管这两种干预都有短期益效,但他们均可使肺泡简化,进而导致肺结构异常。在肺发育成熟过程中,即便倍他米松和LPS均能类似程度地减少肺泡壁的厚度,但孕妇产前倍他米松治疗和动物产前LPS诱导动物绒毛膜羊膜炎所激活的其他信号传导通路(比如基质金属蛋白酶MMP)也各不相同。此外,产后治疗干预可能会导致肺部炎症和损伤。包括动物实验在内的诸多研究结果使人们越来越清楚地意识到与药物治疗相关的损伤,进而也对临床治疗方案作过适当的调整。迄今,不少研究人员通过各种动物模型对围产期复苏时子宫炎症对胎儿肺功能和肺感染的作用进行过广泛的研究。比如在机械通气方面,有关呼气末正压(PEEP)对肺功能、肺表面活性剂储存以及肺部炎症介质的正面作用就有不少来自动物模型的研究报道。这些动物模型实验探讨过诸如高频振动通气(HFOV)之类的机械通气技术对肺部的损害作用,其结果支持无论有无表面活性剂替代治疗都应避免机械通气的新治疗理念。补氧可进一步损伤肺组织并引发炎症。越来越多的证据表明,活性氧与细胞生长和发育有交互影响。据此,近年来便产生了下面的假说:支气管肺发育不良是一种由氧自由基所引发的病变。动物实验数据业己揭示氧和肺损伤之间的复杂交互作用,然而其机制尚不十分清楚。产前炎症可能早已引发胎儿肺部氧化应激反应并改变抗氧化能力,这就使得氧气与肺损伤之间的复杂关系变得更为复杂。此外,有动物实验就广泛用于新生婴儿的药物如类固醇、表面活性剂、咖啡因和维生素A对肺部的炎症变化及损伤作用进行过试验。这些实验数据可作为临床试验的依据,尤其在临床数据无法解决有关治疗效果或机制的不确定性情况下更是如此。这方面的一个典型例子就是那个有关慢性肺损伤进展差异原因令人印象深刻、支持"二次打击"假说的附加解释。临床研究暗示早产婴儿生前炎症和生后机械通气可能对支气管发育不良有协同作用。然而,诸如炎症之类的围产期病变和产后不同治疗干预之间的协同效应仍有待进一步确定。精心设计的实验研究将有助于阐明肺损伤、肺部炎症、肺修复及非正常肺发育之间的复杂关系,同时也将有助于确立源于新生婴儿早期肺部发育变异与终身性呼吸功能障碍之间的联系。

摘要：Background Most incidental gastric polyps identified during upper endoscopy are considered ***,current guidelines recommend sampling all gastric polyps for histopathologic *** aimed to devise a simple narrow-band imaging(NBI)classification to reduce the need for routine biopsies of low-risk gastric *** Pairs of NBI and white-light images were collected from 73 gastric polyps for which concurrent histopathologic diagnosis was available.A diagnostic accuracy cohort study was *** blinded endoscopists independently analysed NBI features of each polyp for color,vessel pattern,surface pattern,and any combinations thereof to develop a classification scheme to differentiate low-risk polyps(fundic-gland or hyperplastic)from high-risk polyps(adenomatous or adenocarcinoma)and fundic-gland polyps(FGPs)from *** An isolated lacy vessel pattern and a homogenous absence of surface pattern successfully differentiated low-risk from high-risk gastric *** both descriptors into a single algorithm resulted in a negative predictive value(NPV)of 100%[95%confidence interval(CI):100%–100%],positive predictive value(PPV)of 13.7%(95%CI:2.6–24.8),sensitivity of 100%(95%CI:100%–100%),and specificity of 53.7%(95%CI:45.3%–62.0%)for high-risk *** would reduce the number of polyps requiring biopsy by 50%,while still capturing all high-risk *** FGPs,using a rule not to biopsy polyps with isolated lacy vessels resulted in a 94.9%NPV(95%CI:89.2%–100%),63.2%PPV(95%CI:47.2%–79.2%),94.8%sensitivity(95%CI:89.5%–100%),and 63.6%specificity(95%CI:51.3%–76.0%)for *** In this derivation cohort study,NBI is helpful for differentiating between high-risk and low-risk gastric polyps,thereby reducing the need for routine sampling of low-risk *** results need to be validated in a separate test population.

摘要：Every year there are more than 11000 hospitalizations related to heart failure in children resulting in significant morbidity and *** the last two decades,our understanding,diagnosis and management of pediatric heart failure is evolving but our ability to prognosticate outcomes in pediatric heart acute heart failure is extremely limited due to lack of *** adult heart failure patients,the role of cardiac biomarkers has exponentially increased over the last two *** guidelines for management of heart failure emphasize the role of cardiac biomarkers in diagnosis,management and prognostication of heart *** is also noteworthy that these biomarkers reflect important biological processes that also open up the possibility of therapeutic *** is however,a significant gap present in the pediatric population with regards to biomarkers in pediatric heart ***,we seek to review available data regarding cardiac biomarkers in the pediatric population and also explore some of the emerging biomarkers from adult literature that may be pertinent to pediatric heart failure.

摘要：Background Most interventions for conditions with a small cohort size,such as transplantation,are unlikely to be part of a clinical *** condition-specific evidence is lacking,expert consensus can offer more precise guidance to improve *** of cardiovascular risk in liver-transplant recipients is one example for which clinicians have,to date,adapted evidence-based guidelines from studies in the general ***,even when consensus is achieved,implementation of practice guidance is often inadequate and *** report on a novel mixed-methods approach,the Northwestern MethodVC,for the development of clinical-practice guidance when condition-specific evidence is *** illustrate the method through the development of practice guidance for managing cardiovascular risk in liver-transplant *** The Northwestern MethodVC consists of(i)adaptation of relevant,existing,evidence-based clinical-practice guidelines for the target population;(ii)consensus by experts of the proposed practice guidance;(iii)identification of barriers to guidance adherence in current practice;and(iv)recommendation for implementation and dissemination of the practice *** method is based on an iterative,user-centered approach in which the needs,wants,and limitations of all end users,including patients,are attended to at each stage of the design and development *** The Northwestern MethodVC for clinical-practice-guidance development uses a mixed-methods approach to bring together broad representation from multiple disciplines and practice settings to develop consensus considering the unique needs and preferences of patients,caregivers,and practitioners who are directly impacted by clinical-practice-guidance *** hypothesize that a priori involvement of end users in the guidance-development process will lead to sustainable implementation of guidance statements into clinical practice.

摘要：BACKGROUND: As per the "Disaster Management Act, 2005" of India, it is mandatory for government hospitals in India to prepare a disaster plan. This study aimed to prepare a disaster manual of a 1 900 bed tertiary care hospital, in consultation and involvement of all concerned ***: A committee of members from hospital administration, clinical, diagnostic and supportive departments worked on an initial document prepared according to the Act and gave their inputs to frame a final disaster ***: The prepared departmental standard operating procedures involved 116 people(doctors and paramedical staff), and were then synchronized, in 12 committee meetings, to produce the final hospital disaster ***: The present disaster manual is one of the few comprehensive plans prepared by the stakeholders of a government hospital in India, who themselves form a part of the disaster response team. It also helped in co-ordinated conduction of mock drills.

摘要：The development of new proton-pump inhibitors (PPIs) with less adverse effects by lowering the pKa values of nitrogen atoms in pyrimidine rings has been previously suggested by our group. In this work, we proposed that new PPIs should have the following features:(1) number of ring II = number of ring I+ 1;(2) preferably five, six, or seven-membered heteroatomic ring for stability;and (3) 1<pKa1<4. Six molecular scaffolds based on the aforementioned criteria were constructed, and R groups were extracted from compounds in extensive data sources. A virtual molecule dataset was established, and the pKa values of specific atoms on the molecules in the dataset were calculated to select the molecules with required pKa values. Drug-likeness screening was further conducted to obtain the candidates that significantly reduced the adverse effects of long-term PPI use. This study provided insights and tools for designing targeted molecules in silico that are suitable for practical applications.

摘要：Objective: To screen a triple helix-forming oligodeoxyribonucleotide (TFO) that can bind HBV core promoter at target site with high affinity and specificity, and to observe the ability of manganese porphyrin modified TFO to combine and cleave HBV DNA. Methods: Similar homopurine domain (1 734 - 1 754) in HBV core promoter was selected as target sequence. Several corresponding TFOs were synthesized. The affinities and specificities of TFOs binding target sequence were tested with electrophoretic mobility shift and DNase I footprinting assays. The selected best TFO was modified with manganese porphyrin and acridine. The ability of the TFO derivative to cleave HBV DNA was observed with cleavage experiment. Results: Under the condition of 371 and pH 7. 4, the TFO consisting of cytidylate and thymidylate (CT-TFO) and the parallel TFO consisting of guanylate and thymidylate (GT-TFOp) bound the target sequence weakly with Kd values much more than 10 -6 mol/L. The affinities of anti-parallel GT-TFO ( GT-TFOap) and short TFO consisting of adenine nucleotide and guanylate (AG-TFOsh) binding the target sequence were higher than those of the formers, with Kd values of 5 μ 10-7 mol/L and 2. 5 μ 10-8 mol/L respectively. Long AG-TFO (AG-TF01) had the highest binding affinity with a Kd value of 3 μ 10 -9 mol/L among all the TFOs studied for sequence specificity. In the presence of potassium monopersulfate, KHSO5, TFO modified with manganese porphyrin and acridine cleaved the target sequence where the triplex DNA formed. Conclusion: TFO containing AG or GT binds homopurine in HBV core promoter in adverse parallel direction to form triple helix. AG-TFO1 has the highest binding affinity among all the TFOs studied. After modified with manganese porphyrin, AG-TFO1 completely binds and cleaves the target HBV DNA sequence where triplex DNA is formed.

摘要：写出优秀的论文很重要，但更重要的是首先要有好数据。然而，调查研究若没有计划或者开展好，便不会有好的数据。所以写出好文章的关键是在研究前进行详尽完备的研究设计。因此．本文着重讲述合理的设计实验并写出优秀的论文。