摘要：Peptide inhibition of the interactions of the tumor suppressor protein P53 with its negative regulators MDM2 and MDMX activates P53 in vitro and in vivo,representing a viable therapeutic strategy for cancer *** phage display techniques,we previously identified a potent peptide activator of P53,termed PMI(TSFAEYWNLLSP),with binding affinities for both MDM2 and MDMX in the low nanomolar concentration *** we report an ultrahigh affinity,dual-specificity peptide antagonist of MDM2 and MDMX obtained through systematic mutational analysis and additivitybased molecular *** assays of over 100 peptide analogs of PMI using surface plasmon resonance and fluorescence polarization techniques yielded a dodecameric peptide termed PMI-M3(LTFLEYWAQLMQ)that bound to MDM2 and MDMX with K_(d)values in the low picomolar concentration range as verified by isothermal titration ***-crystal structures of MDM2 and of MDMX in complex with PMI-M3 were solved at 1.65 and 3.0 A resolution,*** to PMI,PMI-M3 occupied the P53-binding pocket of MDM2/MDMX,which was dominated energetically by intermolecular interactions involving Phe3,Tyr6,Trp7,and Leu *** differences in binding between PMI-M3 and PMI were observed at other positions such as Leu4 and Met11 with MDM2,and Leu1 and Met11 with MDMX,collectively contributing to a significantly enhanced binding affinity of PMI-M3 for both *** adding lysine residues to both ends of PMI and PMI-M3 to improve their cellular uptake,we obtained modified peptides termed PMI-2K(KTSFAEYWNLLSPK)and M3-2K(KLTFLEYWAQLMQK).Compared with PMI-2K,M3-2K exhibited significantly improved antitumor activities in vitro and in vivo in a P53-dependent *** super-strong peptide inhibitor of the P53-MDM2/MDMX interactions may become,in its own right,a powerful lead compound for anticancer drug development,and can aid molecular design of other classes of P53 activators as well for anticancer therapy.

摘要：Background:Olmesartan,an angiotensin Ⅱ receptor blocker(ARB),is associated with gastrointestinal symptoms resembling sprue-like *** have proposed that enteropathy may be a class effect rather than *** performed a systematic review to identify literature of sprue-like enteropathy for all ***:Case reports,case series and comparative studies of ARBs were searched on PubMed and Embase databases through 21 November 2018 and then ***:A total of 82 case reports and case series as well as 5 comparative studies,including 248 cases,were selected and *** ARBs listed in the case reports were olmesartan(233 users;94.0%),telmisartan(5 users;2.0%),irbesartan(4 users;1.6%),valsartan(3 users;1.2%),losartan(2 users;0.8%)and eprosartan(1 user;0.4%).The periods between ARB initiation and onset of symptoms ranged from 2 weeks to 13 *** results were reported in 218 cases,in which 201 cases(92.2%)were villous atrophy and 131 cases(60.1%)were intraepithelial *** leucocyte antigen(HLA)testing was performed in 147 patients,among whom 105(71.4%)had HLA-DQ2 or HLA-DQ8 *** antibodies were tested in 169 patients,among whom 167(98.8%)showed negative *** exclusion from the diet failed to relieve symptoms of enteropathy in 127(97.7%)of 130 patients with *** remission of symptoms after discontinuation of ARB was reported in 233(97.4%)of the 239 patients with *** cases(2.8%)reported recurrence of symptoms after restarting olmesartan;rechallenge was not reported for the non-olmesartan *** retrospective studies conducted worldwide had inconsistent study designs(*** in periods of study and case definition)and ***:Although enteropathy is rare,clinicians should remain vigilant of this potential adverse event even years after medication initiation.

摘要：采用定组设计,以14名洛杉矶加州大学–北京大学交换学生为受试者,建立基于气相色谱–质谱联用的尿液非靶向代谢组学方法,采用包括(正交)偏最小二乘回归判别分析在内的多种统计方法识别差异物质,并基于色谱–质谱信息进行结构鉴定。通过固定站点监测数据评价研究期间两地的大气污染物暴露,采用混合效应线性模型探索污染物与指征氧化损伤的生物标志物间的关联。结果表明,两地的暴露变化与人体能量代谢、氧化损伤、肠胃菌群、蛋白质与RNA代谢(可能涉及细胞凋亡)等通路变化之间可能存在关联,受试者尿液中的尿囊素、胱氨酸和假尿嘧啶水平在北京显著上升。当以尿囊素作为指征机体急性氧化损伤的标志物时,其变化与0～96小时的PM_(2.5)、0～24小时的CO、24～48小时的NO_2、48～72小时的O_3以及24～72小时的SO_2暴露有较强的相关性。结果表明北京与洛杉矶间大气污染物暴露的差异可能导致受试者体内氧化损伤负担发生变化,同时体内可能产生抗氧化损伤的生理活动,例如通过调动能量代谢通路抵御氧化还原失衡造成的氧化损伤负担。

摘要：Objectives:This study aims to develop the Directive and Nondirective Support Scale for Patients with Type 2 Diabetes(DNSS-T2DM)to measure diabetes-specific support and patients’preference as well as evaluate the construct validity and reliability of the ***:A cross-sectional study was conducted in Tongzhou District,Beijing,China from July to September 2015.A total of 474 participants who had been diagnosed as type 2 diabetes by physicians and completed the DNSS-T2DM were *** original 11-item DNSS-T2DM contains five items on nondirective support(Items 1-5)and six items on directive support(Items 6-11).There were two parallel questions for each item with one to measure the preference for support(Preference part)and the other to measure the perception of support in reality(Reality part).The final DNSS-T2DM was determined based on the results of the exploratory factor analysis(EFA).The construct validity of the final DNSS-T2DM was evaluated by the confirmatory factor analysis(CFA).The reliability was evaluated by internal consistency with Cronbach’sα***:A final 7-item DNSS-T2DM loaded on 2 factors with four items representing nondirective support and three items representing directive support was determined based on the *** CFA indicated a satisfactory construct *** internal consistency of the 7-item DNSS-T2DM as well as the nondirective support items was satisfactory with Cronbach’sα≥***:Our study supported the validity and reliability of the 7-item *** studies on the application of the DNSS-T2DM in different settings and population are needed.

摘要：目的与常规服务相比,评估健康教练使用动机谈话(MI)的干预对改善2型糖尿病(T2DM)患者的血糖控制,以及临床、心理社会和自我保健结果的影响。设计实用性群组随机对照试验。研究地点中国北京市丰台区社区卫生服务站(CHSs)。参与者在41家随机选取的CHSs(21家干预组和20家对照组),有21家干预组CHSs(372名患者)和18家对照组(296名患者)在开始时参与试验。干预干预组患者接受电话和面对面MI健康教练服务,并同时在CHSs接受常规的服务。对照组只接受常规的服务。2组的医疗费用均得到减免。结局指标在基线、6个月和12个月进行结果评估。主要指标是糖化血红蛋白(HbAlc)。次要指标包括一组人体测量学指标、血压、空腹血糖、社会心理和自我保健。结果在12个月时,没有发现HbA1c的治疗效果差别,[调整后差别为0.02,95%可信区间(CI)-0.40~0.44,P=0.929],干预组和对照组都显示出明显的改善。不过,2个次要指标:心理忧郁(调整后差别为-2.38,95%CI-4.64~-0.12,P=0.039)和收缩压(调整后差别为-3.57,95%CI-6.08~-1.05,P=0.005)显示为明显改善的结果,与明显的治疗效果差别相一致,并得到敏感性分析的支持。有意义的是,在HbA1c之外,两组均显示出甘油三酯、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇上的明显改善。结论在当今中国初级卫生保健改革的形势下,本研究是在中国第一个在CHSs实际现场开展的、特别针对T2DM的大规模群组随机对照研究。虽然没有在HbA1c上发现治疗效果差别,但在2组的很多结果(包括HbAlc)上呈现改善,该结果支持在中国对T2DM患者进行常规和免费的临床健康检查。

摘要：目的:研究包含传统泰式按摩、草药以及物理疗法的康复治疗方案是否能够改善脑卒中患者的日常活动能力、情绪、睡眠质量以及疼痛程度。方法:本研究的设计为前瞻性队列研究,研究周期为3个月。患者来自泰国北部一家有42张床位的康复中心,该中心主要针对脑卒中、头部创伤和脊柱病患者进行康复治疗。结果:本研究共纳入脑卒中患者62人,55%为男性。患者平均年龄59岁,其中63%为已婚,首次卒中时间平均为15个月。在基线水平,巴氏量表平均指数为50.7,情绪、疼痛及睡眠平均指数分别为2.6、3.1、3.2。在进行年龄、性别和首次卒中时间的纵向模型评估1个月后,巴氏量表指数、情绪、疼痛和睡眠指数均显著提高,分别上升了6.1、0.7、0.5、0.5分(均P<0.01);3个月后,各指数分别提高了14.2、0.9、0.5、0.6分(均P<0.01)。结论:该康复治疗方案能明显改善患者的日常生活、情绪、睡眠质量以及疼痛程度。我们还需要进一步比较接受该康复治疗方案和接受常规康复治疗方案的患者来支持这一结论。

摘要：The present study aimed at determining whether short-term exposure to art in shared common areas in congregate housing units could affect health and health determinants among the residents. Ten residents (mean age 80.4 years) at one block were exposed to visual art environmental enrichment in common areas over a period of three months. Thirteen persons (mean age 86.6 years) living in another block played in-house boule. Cornell’s test, Mini-Mental tests (MMT), and face recognition test were performed to assess depression, cognition, and episodic memory, respectively before and after the intervention. The results show that visual art environmental enrichment in common areas and lack of stimulating and guiding dialogues show a change in depression scores in the intervention group (p = 0.018) and the control group (p = 0.009). MMT scores improved only in the control group (p = 0.003). No changes in episodic memory in any of the groups were observed. It could be concluded that in order to obtain a positive result of short term visual art environmental enrichment, guiding art dialogues conducted by nurses, as described in previous research, should be added to visual art environmental enrichment in healthcare settings.

摘要：一般情况下,每年冬季是季节性流感高发季节,但在当前2019冠状病毒病(COVID-19)大流行期间,全球季节性流感活动呈“断崖式”下降。为应对即将到来的流感季节,亟需弄清这种前所未有的流感低水平流行的原因。本文中,我们探索了一种国家特异性推理模型,利用该模型估计中国、英国和美国这三个国家中佩戴口罩、人员流动变化(国际和国内)以及严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)干扰的影响。结果发现,在这些地区增加一周佩戴口罩的干预措施,流感活动可减少11.3%~35.2%。实施一周的限制人员流动措施对国际(1.7%~6.5%)和国内社区(1.6%~2.8%)的影响较小。2020年至2021年,仅佩戴口罩这一项干预措施就可使阳性率下降13.3%至19.8%。仅人员流动变化可使阳性率降低5.2%至14.0%,其中79.8%~98.2%归因于国际旅行限制。SARS-CoV-2干扰仅在2019年至2020年具有统计学显著效应。中国北方地区及英国的阳性百分比分别降低7.6%(2.4~14.4)和10.2%(7.2~13.6)。探索所得出的结果对了解非药物干预措施和其他呼吸系统疾病背景下的流感演变有一定意义,有助于制定卫生政策,并可为公共卫生措施的个性化设计提供信息。

摘要：目的比较四药联用(四联)和三药联用(三联)的抗逆转录病毒疗法作为HIV感染者一线治疗的疗效和安全性,并探讨现有的临床试验对临床实践及未来研究的启示。研究设计随机对照试验的系统综述和meta分析。数据来源系统检索了PubMed、EMBASE、CENTRAL、Web of Science及Allied health Literature数据库2001年3月至2016年12月期间发表的研究(其中PubMed和EMBASE的检索更新至2018年6月),以及合格研究和相关综述的参考文献。入选标准比较四联与三联抗逆转录病毒疗法作为HIV感染者一线治疗的作用,并评价了至少一种疗效或安全性结局的随机对照试验。分析方法对检测不到的HIV-1 RNA、CD4 T细胞计数、病毒学失败、新发艾滋病事件、死亡和严重不良反应等结局的资料采用随机效应模型进行meta分析。结果共找到12项合格研究,包括4251例HIV感染者。四联和三联抗逆转录病毒疗法对各个疗效和安全性结局的影响均类似,且没有一个总体效应估计值的点值落在支持四联疗法的一侧。与三联疗法相比,四联疗法组出现不同结局的相对危险度及其95%可信区间如下:检测不到的HIV-1 RNA,0.99(0.93~1.05);病毒学失败,1.00(0.90~1.11);新发艾滋病事件,1.17(0.84~1.63);死亡,1.23(0.74~2.05);严重不良反应,1.09(0.89~1.33)。两组CD4 T细胞计数增加的平均差值为-19.55个细胞/μl(-43.02~3.92)。无论联合抗逆转录病毒疗法的具体方案如何,上述2组比较的结果大体不变,且在所有亚组和敏感性分析中均变化不大。结论在HIV感染者的一线治疗中,四联抗逆转录病毒疗法的效果并不优于三联疗法。这一发现为当前推荐三联疗法作为一线治疗的指南提供了支持。除非对现有证据的系统综述显示确有必要,否则不应该再开展新的临床试验去比较四联与三联疗法。当然,本系统综述并不排除当有新的抗逆转录病毒药物种类出现时包含该类药物的四联疗法比三联疗法更好的可能性。

摘要：背景：妇女应用雌孕激素联合替代治疗(combined estrogen and progestine hormone replacement therapy，CHRT)会增加乳腺癌的危险；然而，目前仍缺乏长期使用和不同治疗方案所致危险性的资料。目的：通过组织病理学类型及激素受体状况，评估CHRT应用时间及方式与乳腺癌的关系。设计：人群病例．对照研究。地点：华盛顿州西部三个县。参试者：自1997年4月1日至1999年5月31日，975例65～79岁诊断为侵袭性乳腺癌的妇女(组织学：196例小叶癌，656例导管癌，114例其他组织类型以及9例非特异组织学类型；雌激素受体(ER)／孕激素受体(PR)状况：646例ER+／PR+，147例ER+／PR-，101例ER-／PR-[6例ER-／PR+和75例ER／PR状况不明者未包括于本研究中]，1007例正常人作为对照。主要观察指标：发生侵袭性乳腺小叶癌、乳腺导管癌以及ER+／PR+、ER+／PR-和ER-／PR-乳腺癌的危险。结果：应用非对抗性雌激素替代治疗(estrogen replacement therapy，ERT)的妇女(仅用ERT者)，即使应用25年以上，乳腺癌发病危险无明显增加(尽管其相关优势比与可能存在微弱影响并非不一致)。曾经应用CHRT者(包括也使用过ERT的CHRT使用者)乳腺癌危险性增加1．7倍(95％可信区间[CI]，1．3～2．2)，其中包括侵袭性小叶癌危险性增加2．7倍(95％CI，1．7～4．3)，侵袭性导管癌增加1．5倍(95％CI，1．1～2．0)，ER+／PR+乳腺癌危险性增加2．0倍(95％CI，1．5～2．7)。危险性增加在较长期使用CHRT的妇女最为明显，应用CHRT在5～14．9年和≥15年者，侵袭性导管癌的危险性分别增加1．5倍(95％CI，1．0～2．3)和1．6倍(95％CI，1．0～2．6)，侵袭性小叶癌的危险性则分别增加了3．7倍(95％CI，2．0～6．6)和2．6倍(95％CI，1．3～5．3)。在按期使用和连续使用CHRT的妇女，相关程度大致相似。任何使用方式均不增加ER+／PR-和ER-／PR-肿瘤的危险性；然而，由于这些肿瘤患者的数量少，限制了我们发现可能联系的把握度。结论：研究资料提示，CHRT的使用，无论是按期或者持续使用孕激素，均与乳腺癌特别是侵袭性小叶癌危险性增加相关。