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剩余骨高度<3mm 时联合CGF 与Bio-Oss 骨粉行液压法上颌窦内提升术并同期种植一例解孟佳1，2，周志霖1，2，张雅彤1，2，姬瑞1，2，张强2，李松南3，常财旺21.大连医科大学口腔医学院，辽宁大连116044；2.扬州大学附属医院(扬州市第一人民医院)口腔颌面外科，江苏扬州225000；3.扬州大学农业科技发展研究院(教育部农业与农产品安全国际合作联合实验室)，江苏扬州225009【摘要】上颌后牙区域牙列缺损实施种植修复所面临的问题主要是上颌窦气化和牙槽骨吸收造成的剩余骨高度(RBH)不足。
本文报告一例RBH<3mm 时上颌窦底内提升联合浓缩生长因子(CGF)与Bio-Oss 骨粉同期种植的病例，并在术后6个月和12个月的锥形束计算机断层扫描中均观察到明显的影像学变化。
【关键词】牙种植；骨增量；剩余骨高度；浓缩生长因子；上颌窦底内提升【中图分类号】R783【文献标识码】D 【文章编号】1003—6350（2023）20—3008—04One case of maxillary sinus floor elevation combined with concentrated growth factor and Bio-Oss bone powder simultaneous implantation at residual bone height<3mm.XIE Meng-jia 1,2,ZHOU Zhi-lin 1,2,ZHANG Ya-tong 1,2,JI Rui 1,2,ZHANG Qiang 2,LI Song-nan 3,CHANG Cai-wang 2.1.School of Stomatology,Dalian Medical University,Dalian 116044,Liaoning,CHINA;2.Department of Oral and Maxillofacial Surgery,Affiliated Hospital of Yangzhou University (Yangzhou First People's Hospital),Yangzhou 225000,Jiangsu,CHINA;3.Institutes of Agricultural Science and Technology Development (Joint International Research Laboratory of Agriculture and Agri-product Safety of the Ministry of Education of China),Yangzhou University,Yangzhou 225009,Jiangsu,CHINA【Abstract 】Inadequate residual bone height (RBH)caused by maxillary sinus gasification and alveolar bone re-sorption is one of the common problems in implant treatment of maxillary posterior dentition defects.This paper report-ed a case of maxillary sinus floor elevation combined with concentrated growth factor (CGF)and Bio-Oss bone powder simultaneous implantation at the RBH<3mm,and obvious imaging changes were observed in cone beam computed to-mography at 6months and 12months after operation.【Key words 】Dental implantology;Bone augmentation;Residual bone height;Concentrated growth factor;Sinus floor elevation ·个案报道·doi:10.3969/j.issn.1003-6350.2023.20.026基金项目：江苏省卫生健康委科研项目(编号：H2019035)。
2 376例地中海贫血基因筛查结果分析王云娟 1,2,3），张艳亮 1,2,3），徐秋月 1,2,3），赵 滢 1,2,3），胡赵武 4），苏 洋 1,2,3）（1）昆明医科大学第一附属医院医学检验科；2）云南省实验诊断研究所；3）云南省检验医学重点实验室，云南 昆明 650032；4）禄丰县人民医院检验科，云南 禄丰 651200）[ 摘要 ] 目的 了解于昆明医科大学第一附属医院就诊的地中海贫血（简称“地贫”）基因筛查者地贫基因阳性率和基因突变类型及分布特征。
方法 回顾性分析2017年4月1日至2018年12月31日于昆明医科大学第一附属医院就诊的地贫基因筛查者2 376例，对地贫基因进行统计分析。
结果 （1）2 376例地贫基因筛查中检出地贫基因阳性样本817例，阳性率为34.39%；其中检出α地贫基因阳性样本392例，占总阳性样本的47.98%；β地贫基因阳性样本398例，占总阳性样本的48.71%；αβ复合型地贫基因阳性27例，占总阳性样本的3.30%；（2）392例α地贫基因阳性样本中以αα/--SEA、αα/-α3.7、αα/ααCS、αα/-α4.2和-α3.7/--SEA 基因型为主，分别占α地贫的50.51%、32.91%、4.34%、3.57%和2.55%；398例β地贫基因阳性样本中以CD26、CD41-42、CD17、IVS II-654、nt28基因型为主，分别占β地贫的25.38%、23.37%、20.60%、20.60%和3.27%。
结论 云南地区地贫基因携带率仍较高，其中β地贫中CD26最多，与国内其它省市人群存在差异。
[ 关键词 ] 地中海贫血； 基因突变； 筛查[ 中图分类号 ] R556.7 [ 文献标志码 ] A [ 文章编号 ] 2095 − 610X （2021）01 − 0068 − 04Gene Screening and Result Analysis of2 376 Cases of ThalassemiaWANG Yun-juan 1,2,3），ZHANG Yan-liang 1,2,3），XU Qiu-yue 1,2,3），ZHAO Ying 1,2,3），HU Zhao-wu 4），SU Yang 1,2,3）（1） Dept. of Clinical Laboratory ，The 1st Affiliated Hospital of Kunming Medical University ;2） Yunnan Institute of Experimental Diagnosis ; 3） Yunnan Key Laboratory of Laborotory Medicine ，Kunming 650032; 4） Dept. of Clinical Laboratory ，People’s Hospital ofLufeng County ，Lufeng Yunnan 651200, China ）［Abstract ］ Objective To investigate the positive rate，gene mutation type and distribution characteristics of thalassemia gene screening patients in the First Affiliated Hospital of Kunming Medical University. Methods A retrospective analysis was made on 2 376 cases of thalassemia gene screening patients in the First Affiliated Hospital of Kunming Medical University from April 1，2017 to December 31，2018. The parameters of thalassemia gene and blood cell analysis (Hb，MCV，MCH，RDW) were statistically analyzed. Results （1） Among 2 376 cases of thalassemia gene screening，817 were positive for thalassemia gene，the positive rate was 34.39%，of which 392cases were positive for α thalassemia gene，accounting for 47.98% of the total positive samples；398 were positive samples of βthalassemia gene，accounting for 48.71% of the total positive samples；27 cases were αβcompound[收稿日期] 2020 − 07 − 23[基金项目] 云南省卫生健康委员会医学学科带头人基金资助项目（D-2018024）；昆明医科大学百名中青年学术和技术骨干基金资助项目（60117190460）[作者简介] 王云娟（1988～），女，云南嵩明人，临床检验诊断学硕士，主管检验师，主要从事临床基因检测、细菌耐药及传播机制研究工作。
第14卷 第3期2023年5月Vol. 14 No.3May 2023器官移植Organ Transplantation ·移植前沿·胰岛移植即刻经血液介导的炎症反应应对策略杨玉伟 张婷 李万里 陈继冰 高宏君【摘要】 胰岛移植作为治疗1型糖尿病和终末期2型糖尿病的有效手段，可以使患者获得较好的血糖控制能力。
即刻经血液介导的炎症反应（IBMIR ）是胰岛移植早期出现的非特异性炎症反应，发生后可迅速出现凝血级联和补体系统激活、炎症细胞聚集等，造成大量移植胰岛丢失，严重影响胰岛移植的疗效。
如何减轻IBMIR 对胰岛造成损伤是目前胰岛移植的研究热点，临床推荐的治疗胰岛移植IBMIR 的药物有肝素和肿瘤坏死因子-α抑制剂依那西普。
新近研究表明多种方法和药物可以减轻IBMIR 对胰岛的损伤，本文就这些临床研究成果和临床前研究成果进行综述，以期为胰岛移植IBMIR 的应对提供参考。
【关键词】 胰岛移植；糖尿病；即刻经血液介导的炎症反应（IBMIR ）；炎症反应；胰岛丢失；胰岛保护；胰岛封装；凝血【中图分类号】 R617，R587 【文献标志码】A 【文章编号】 1674-7445（2023）03-0005-06【Abstract 】 As an effective procedure for type 1 diabetes mellitus and end-stage type 2 diabetes mellitus, islet transplantation could enable those patients to obtain proper control of blood glucose levels. Instant blood-mediated inflammatory reaction (IBMIR) is a nonspecific inflammation during early stage after islet transplantation. After IBMIR occurs, coagulation cascade, complement system activation and inflammatory cell aggregation may be immediately provoked, leading to loss of a large quantity of transplant islets, which severely affects clinical efficacy of islet transplantation. How to alleviate the islet damage caused by IBMIR is a hot topic in islet transplantation. Heparin and etanercept, an inhibitor of tumor necrosis factor-α, are recommended as drugs for treating IBMIR following islet transplantation. Recent studies have demonstrated that multiple approaches and drugs may be adopted to mitigate the damage caused by IBMIR to the islets. In this article, the findings in clinical and preclinical researches were reviewed, aiming to provide reference for the management of IBMIR after islet transplantation.【Key words 】 Islet transplantation; Diabetes mellitus; Instant blood-mediated inflammatory reaction (IBMIR); Inflammation; Islet loss; Islet protection; Islet encapsulation; CoagulationTherapeutic strategy for instant blood-mediated inflammatory reaction after islet transplantation Yang Yuwei *, Zhang Ting, Li Wanli, Chen Jibing, Gao Hongjun.*Graduate School of Guangxi University of Chinese Medicine, Nanning 530001, China Correspondingauthor:GaoHongjun,Email:***************DOI: 10.3969/j.issn.1674-7445.2023.03.005基金项目：广西科技基地和人才专项（桂科AD22035122）；广西研究生教育创新计划项目（YCSW2022355、YCXJ2021091）作者单位：530001 南宁，广西中医药大学研究生院（杨玉伟、李万里）；广西中医药大学附属瑞康医院（张婷、陈继冰、高宏君）作者简介：杨玉伟（ORCID ：0009-0000-2017-8883），硕士研究生，住院医师，研究方向为器官移植，Email ：*****************通信作者：高宏君（ORCID ：0000-0003-1451-0725），博士，主任医师，研究方向器官移植与胰岛移植，Email ：***************对于疗效欠佳的1型糖尿病和伴有胰岛功能衰竭的2型糖尿病，胰岛移植已成为理想的治疗方法。
我国荔枝龙眼中农药最大残留限量标准现状分析与建议顾燕萍1，张树飞2，张惠云3，张湛辉4，孙海滨1，刘怀韬5，刘艳萍1，王潇楠1，常虹1，王思威1*（1.广东省农业科学院植物保护研究所，农业农村部华南果蔬绿色防控重点实验室，广东省植物保护新技术重点实验室，广东广州 510640）（2.深圳职业技术大学食品药品学院，广东深圳 518055）（3.云南省农业科学院热带亚热带经济作物研究所，云南保山 678000）（4.广州市增城区农业技术推广中心，广东广州 511300）（5.茂名市农业科技推广中心，广东茂名 525000）摘要：为了了解我国荔枝和龙眼中农药最大残留限量（Maximum Residue Limits，MRLs）标准的制定情况，保障我国荔枝龙眼产业的发展，本文以现行《食品安全国家标准食品中农药最大残留限量》（GB 2763-2021）为依据，结合我国农药在荔枝龙眼上的登记情况，分析了我国荔枝龙眼上农药MRLs标准现状，并按农药类别列出了MRLs、每日允许摄入量（Acceptable Daily Intake，ADI）和配套的检测方法标准。
统计显示，GB 2763-2021中涉及荔枝龙眼的农药MRLs有133项，涉及农药品种125个，其中推荐有配套的检测方法标准的限量有109项，在我国登记有效的限量有33项。
对比GB 2763-2019，新增限量标准53项，增长率达到66.25%。
此外，新增了方法标准3个。
但是，基于荔枝龙眼的农药监测数据，荔枝龙眼上MRLs以及检测方法标准仍需继续补充，加快荔枝龙眼上的MRLs和检测方法标准的制定。
荔枝龙眼上的MRLs和检测方法标准的制定仍需加快。
关键词：荔枝；龙眼；最大残留限量；GB 2763-2021文章编号：1673-9078(2024)03-333-341 DOI: 10.13982/j.mfst.1673-9078.2024.3.0168Current Standard Staus Analysis and Suggestion for the Maximum Residue Limits of Pesticides in Chinese Litchi and Longan GU Yanping1, ZHANG Shufei2, ZHANG Huiyun3, ZHANG Zhanhui4, SUN Haibin1, LIU Huaitao5,LIU Yanping1, WANG Xiaonan1, CHANG Hong1, WANG Siwei1*(1.Plant Protection Research Institute, Guangdong Academy of Agricultural Sciences, Key Laboratory of GreenPrevention and Control on Fruits and Vegetables in South China Ministry of Agriculture and Rural Affairs, 引文格式：顾燕萍,张树飞,张惠云,等.我国荔枝龙眼中农药最大残留限量标准现状分析与建议[J].现代食品科技,2024, 40(3):333-341.GU Yanping, ZHANG Shufei, ZHANG Huiyun, et al. Current standard staus analysis and suggestion for the maximum residue limits of pesticides in Chinese litchi and longan [J]. Modern Food Science and Technology, 2024, 40(3): 333-341.收稿日期：2023-02-17基金项目：国家荔枝龙眼产业技术体系（CARS-32）；乡村振兴战略专项资金（农业科技能力提升）（2023TS-2-5、2023TS-2-3）；广州市科技计划项目（2023A04J0805）；广东省基础和应用基础研究基金（2022A1515110473）作者简介：顾燕萍（1991-），女，硕士，实习研究员，研究方向：农药残留分析，E- m ail：；共同第一作者：张树飞（1981-），女，硕士，高级农艺师，研究方向：农药应用及分析，E -mail：；张惠云（1982-），男，硕士，副研究员，研究方向：农药应用及分析，E- m ail：；张湛辉（1980-），男，本科，农艺师，研究方向：果树栽培，E -mail：通讯作者：王思威（1984-），女，博士，副研究员，研究方向：农产品质量安全，E -mail：333荔枝（Litchi chinensis Sonn.）和龙眼（Dimocarpus longan Lour.）均是无患子目无患子科果树，在我国拥有悠久的种植历史[1] 。
热带作物学报2022, 43(1): 094 100Chinese Journal of Tropical Crops益智种质资源表型性状的遗传多样性分析李英英1，郑云柯2，晏小霞1，王清隆1，羊青1，汤欢1，王茂媛1，王祝年1*1. 中国热带农业科学院热带作物品种资源研究所，海南海口 571101；2. 中国热带农业科学院热带生物技术研究所，海南海口 571101摘要：对收集的90份益智种质资源的18个表型性状进行遗传多样性分析，以期为益智品种改良和种质创新提供依据。
结果表明：供试的益智种质具有丰富的遗传多样性，质量性状中多样性指数最高的为果形（1.1507），数量性状中多样性指数最高的为株高（2.0700），变异系数最大的为结果枝数（41.32%）；提取的6个主成分累计贡献率为68.339%，第一主成分主要反映的是益智植株的叶片形态和株高，第二主成分主要反映的是益智外观形态及生长状态，第三主成分主要反映的是益智植株的分枝状况，第四主成分主要反映的是益智的产量，第五主成分主要反映的是益智的花果量，第六主成分主要反映的是益智的果产量。
通过聚类分析将供试材料划分为4大类群，其中第I类群可作为益智抗倒伏及矮化品种进行开发，第II类群可作为益智品种改良和杂交育种的材料，第III类群可作为益智育种生产材料，第IV类群可用于观赏益智材料的筛选。
本研究为益智优异种质筛选、资源合理利用、品种改良和品种选育提供参考依据。
关键词：益智；表型性状；种质资源；遗传多样性中图分类号：S326 文献标识码：AGenetic Diversity Analysis of Alpinia oxyphylla Germplasm Resourcesby Phenotypic TraitsAll Rights Reserved.LI Yingying1, ZHENG Yunke2, YAN Xiaoxia1, WANG Qinglong1, YANG Qing1, TANG Huan1,WANG Maoyuan1, WANG Zhunian1*1. Tropical Crops Genetic Resources Institute, Chinese Academy of Tripical Agricultural Sciences, Haikou, Hainan 571101, China;2. Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences, Haikou, Hainan 571101,ChinaAbstract: The genetic diversity by 18 phenotypic traits of 90 Alpinia oxyphylla germplasm resources was analyzed toprovide the basis for the improvement and germplasm innovation of Alpinia oxyphylla varieties. The genetic diversitywas rich in the germplasms. In qualitative traits, the highest Shannon-Wiener diversity index was for fruit shape(1.1507). In quantitative traits, the highest genetic diversity indexes were for plant height (2.0700), the highest coeffi-cient variation (CV) was for the branch number of fruit (41.32%). The cumulative contribution rate of the first 6 princi-pal components was 68.339%. The first principal component mainly reflected the leaf shape and plant height. The sec-ond principal component mainly reflected the appearance and growth state. The third principal component mainly re-flected the branching status. The fourth principal component mainly reflected the output. The fifth principal componentmainly reflected the amount of fruit. The sixth principal component mainly reflected the fruit yield. The experimentalmaterials were divided into four groups by cluster analysis. Group I could be developed as lodging resistant and dwarf-ing varieties. Group II could be used as the material for improvement and cross breeding. Group III could be used as theproduction material. The fourth group could be used for the screening of ornamental materials. This study would providea basis for the selection of excellent germplasm, rational utilization of resources, variety improvement and breed selection.收稿日期 2021-03-26；修回日期 2021-05-23基金项目 海南省自然科学基金项目“海南岛益智资源调查与品质评价研究”（No. 820QN344）；海南省农业农村厅农业种质资源保护项目“南药种质资源保护”（No. NYBH2021）。
苯环喹溴铵药理毒理研究进展刘红1王宝辉1王宇1张俊毅1王祥艳1孙艾楠1程颜彬1赵李宏2（1白求恩医科大学制药厂，吉林长春130012；2吉林省成大方圆医药连锁有限公司，吉林长春130041）【摘要】变应性鼻炎和慢性阻塞性肺病是当前两种发病率高、发病人群广泛、病程缠绵且危害显著的呼吸系统疾病。
作为有针对性的新一代治疗药物，苯环喹溴铵是我国自主研发的具有自主知识产权的国家一类新药，具有广阔的应用前景。
【关键词】苯环喹溴铵；药理；毒理；研究进展Research progress of pharmacological effects and toxicological informationof bencycloquidium bromideLIU Hong1 WANG Bao-hui1WANG Y u1 ZHANG Jun-yi1 W ANG Xiang-yan1 SUN Ai-nan1CHENG Y an-bin1 ZHAO Li-hong2(1 Pharmaceutical Factory Norman Bethune University of Medical Science，Jilin Changchun 130012；2 Cheng DaFang Y uan Pharmaceutical Co,Ltd of Jilin Province，Jilin Changchun 130041)【Abtract】At present, allergic rhinitis and chronic obstructive pulmonary disease are the two kinds of respiratory diseases, with the features of high incidence、widespread population incidence、long course and remarkable harm. As a new generation of targeted therapeutic drug, bencycloquidium bromide is an independent intellectual property rights and national class of drug that would get broad application prospect. 【KeyWords】bencycloquidium bromide；pharmacological effects；toxicological information；research progress变应性鼻炎（allergic rhinitis，AR）又称为过敏性鼻炎，是特应性个体接触致敏源后导致的，包含IgE介导的炎症介质释放和多种免疫活性细胞因子、细胞因子参与的鼻黏膜慢性反应性疾病。
非等位基因概述非等位基因是指同一基因座上的不同等位基因。
等位基因是指在某个给定的基因座上，可以存在多种不同的变体。
每个个体继承了一对等位基因，一对等位基因可能会导致不同的表型表达。
非等位基因的存在使得遗传学研究更加复杂，因为不同的等位基因会对个体的表型产生不同的影响。
背景在生物学中，基因座是指染色体上一个特定的位置，该位置上的基因决定了某个特征的表达方式。
每个基因座上可以有多种不同的等位基因。
等位基因是指在某个特定基因座上的不同基因变体。
每个个体都会继承一对等位基因，通过这对等位基因的不同组合，决定了个体的表型。
然而，并非所有基因座上的等位基因都具有相同的表现型。
非等位基因的影响非等位基因的存在导致不同等位基因会对个体表型产生不同的影响。
有些非等位基因会表现出显性效应，也就是说，当个体继承了一个突变的等位基因时，即使同时继承了一个正常的等位基因，但显性效应会使得突变的等位基因的表型表达得到体现。
相反，有些非等位基因会表现出隐性效应，当个体继承了两个突变的等位基因时，才会表现出突变的表型。
除了显性和隐性效应之外，非等位基因还可能发生两种其他类型的表型效应。
一种是共显效应，当个体继承了两个不同的突变等位基因时，在表型表达上会表现出一种新的特征，这个特征并不是单个突变等位基因所能导致的。
另一种是部分显性效应，当个体继承了两个不同的突变等位基因时，表型表达将介于两个单独突变等位基因的表型之间。
重组和非等位基因重组是指两个不同的染色体交换部分基因序列的过程。
在重组的过程中，非等位基因可能会发生改变，导致新的等位基因组合形成。
这一过程使得非等位基因的表型效应更加复杂，因为新的等位基因可能将不同基因座的效应组合起来。
非等位基因的重要性非等位基因对生物的适应性和多样性起着重要作用。
通过对等位基因的各种组合的研究，人们可以更好地理解基因与表型之间的关系，并揭示遗传变异对物种适应环境的重要性。
总结非等位基因是指同一基因座上的不同等位基因。
ʌ针灸研究ɔ基于 脉引筋气 思想论治经筋病❋韩㊀聪1,赵耀东1ә,金钰钧2,朱㊀玲1,赵婷婷1(1.甘肃中医药大学针灸推拿学院,兰州㊀730000;2.甘肃省中医院针灸二科,兰州㊀730000)㊀㊀摘要:经筋病是临床常见病,该病的针刺治疗多 以痛为输 ,重视局部经筋组织的实质性病变,轻视经脉气血的整体功能失调,又常失于辨证㊁辨经以及补泻手法的运用,从而影响了临床疗效㊂而杨上善 脉引筋气 思想强调经筋病的针刺治疗须首要明确其病因病机㊁病变所属经脉,在选取局部病痛穴位的基础上,循经配取远部经穴,调补肝㊁胆㊁脾㊁胃㊁阴阳跷等相关经脉,资助气血生化以濡养经筋,同时视疾病寒热虚实属性,辨证施以补泻手法,实现调理虚实㊁协调阴阳的目的㊂该思想无论是取穴特点还是补泻手法的操作应用,均体现了中医学整体观念㊁辨证论治的核心内容,掌握并灵活运用之有助于提高经筋病的治疗效果㊂㊀㊀关键词:脉引筋气;经筋病;病因病机;针刺㊀㊀中图分类号:R686.3㊀㊀文献标识码:A㊀㊀文章编号:1006-3250(2021)02-0284-04Treatment of Jingjin Disease Based on Vessel Induces Tendon Qi ThoughtsHAN Cong 1,ZHAO Yao-dong 1ә,JIN Yu-jun 2,ZHU Ling 1,ZHAO Ting-ting 11.College of Acupuncture and Tuina,Gansu University of Chinese Medicine,Lanzhou 730000,China;2.Second Department of Acupuncture and Moxibustion,Gansu Hospital of Traditional Chinese Medicine,Lanzhou 730000,China)㊀㊀Abstract :The muscle meridian disease is a common disease in the clinic.The acupuncture treatment of the disease is mostly pain-point needling ,which pays attention to the lesions of the local muscle meridian tissue ,and ignoring the overall dysfunction of the Qfi and blood.Loss of syndrome differentiation ,meridian differentiation and application of acupuncture manipulation ,which affects clinical efficacy.YANG Shang-shan s thought of "vessel induces tendon Qi"emphasizes the treatment of acupuncture through the disease.It is necessary to firstly identify the etiology and pathogenesis of the disease and the meridians of the lesions.On the basis of selecting the local acupuncture points ,select the remote acupuncture points along the meridians.Regulootong the Liver ,gallbladder ,spleen ,stomach ,Yin and Yang Qiao vessel and other related meridians help the transformation of Qi and blood to nourish the muscle meridian.At the same time ,depending on the type of nature of the disease ,and application of acupuncture manipulation achieving the purpose of regulating the reality and coordinating Yin and Yang.The characteristics of this ideological feature ,whether it is the characteristics of acupoints or the application of replenishing and purging ,embodies the core content of traditional Chinese medicine as a whole ,and the core content of syndrome differentiation and treatment.It is mastered and used flexibly to benefit the clinical improvement of the treatment effects of the muscle meridian disease.㊀㊀Key words :Vessel induces Tendon Qi ;Muscle meridian disease ;Etiology and pathogenesis ;Acupuncture❋基金项目:国家中医药管理局学术流派传承工作室建设项目(2305135901)-甘肃郑氏针法;甘肃省中医药管理局中医药科研项目(GZK-2016-16)- 温通针法 治疗寒湿型腰椎间盘突出症的临床研究作者简介:韩㊀聪(1992-),男,河南杞县人,在读硕士研究生,从事传统针刺手法的临床应用与机制研究㊂ә通讯作者:赵耀东(1972-),男,甘肃兰州人,副主任医师,副教授,硕士研究生,硕士研究生导师,从事传统针刺手法的临床㊁教学与科学研究,Tel :130****7799,E-mail :130****7799@ ㊂㊀㊀经筋以其特有的结聚散络形式循行于躯干四肢,构成了经络系统中与十二经脉密切相关的筋肉体系,其功能活动的维持依赖于经脉气血的滋养,所以筋肉体系的疾患与经脉的生理病理影响息息相关㊂经筋病多为经筋循行所过之处的筋肉㊁关节疾患,并以疼痛㊁病灶点的产生为主要病理反应[1]㊂长期以来,经筋病的治疗多崇求古训,以‘灵枢㊃经筋“所云: 以痛为输 作为优化取穴方法,倡导局部取穴的重要性㊂然杨上善 脉引筋气 思想着重强调经筋病的调治须从整体入手,明确其病因病机,调补相关经脉,选取相应经穴进行治疗,发挥经穴近治与远治的协同作用,丰富了经筋理论的内涵及临床应用,进一步提高了经筋病的治疗效果㊂本文旨在阐述笔者对 脉引筋气 思想论治经筋病的浅见,现将经筋病的病因病机㊁ 脉引筋气 思想渊源及其含义㊁思想特色与治疗分述如下㊂1㊀经筋病的病因病机简言之,经筋病就是隶属于十二经脉筋肉系统的症状群[2],风寒湿邪均为经筋致病因素㊂‘黄帝内经太素㊃五邪刺“(以下简称‘太素“)载: 正经上实下虚者,必是横络受邪,盛加大经㊂[3] 从病理角度分析,一方面风寒湿诸邪入腠袭筋之体表筋肉处,致使络阻筋伤,病态 横络 客于经脉之上,导致经脉气血运行闭阻,即 不通则痛 发为经筋痹痛;另一方面,经筋失于经脉气血的濡养,则导致经筋的进一步损伤以及经筋病灶点的出现,并围绕病灶点上下,表现为在上气血壅滞㊁在下气血虚少的病理状态㊂因此,以中医整体观为指导,全面分析经筋病的病因病机,方能指导辨证施治㊂2㊀ 脉引筋气 思想渊源及其含义脉引筋气 首见于‘太素㊃经筋“,其对‘灵枢㊃经筋“经筋其治 以痛为输 注解时云: 然邪入腠袭筋为病,不能移输,遂以病居痛处为输 依穴疗筋病者,此乃依脉引筋气也㊂[3]345-346 主张将经脉运行气血的功能与经穴转输渗灌气血的作用有机结合,保持经穴主治与经脉相关的同一性,以经穴为施术部位,以经络为通道,通过调和人体气血从而濡养经筋,最终实现调节经筋功能活动的目的㊂集中阐释了经脉气血㊁经筋㊁经穴的相互关系,从而通过对 脉引筋气 思想探赜阐微,窥知杨上善针灸学术思想精义㊂3㊀ 脉引筋气 思想特色3.1㊀欲处百病,须候经脉人体五脏六腑㊁四肢百骸㊁皮肉筋骨之所以能维持正常功能,均依赖气血的充养,而这一过程又通过经脉发挥经络系统运行气血的网络结构来完成㊂‘太素㊃经脉连环“言: 人之死生,血气先见经脉 百病所生,经脉由之,欲处分百病,须候经脉也㊂[3]159-160 人之所患经筋病由气血失常引发,并反映在经脉上的失常,亦通过经脉调理虚实,协调阴阳㊂因此,杨上善针对气血虚实的调理,倡导 人之虚实之气,欲行补泻,须通其经脉 的理念㊂即虚实之气不和,宜通之使其平;阴阳之气不和,调之使然㊂所以,无论针灸治疗脏腑病还是筋肉疾患,均应立足于经脉所属㊁所络,循行所过㊁所系的基础之上,以此为依据通过辨证分经诊察㊁循经取穴论治㊁补虚泻实于相应经穴,达到疏通经脉㊁调和气血㊁协调阴阳的目的[4]㊂3.2㊀知用针,必知形体气血溯其经旨奥义,‘太素㊃知官能“云: 用针之理,必知形气之所在㊂[3]576 杨上善用针治疗经筋病必明辨形体气血之论,从脏腑经脉㊁阴阳五行㊁营卫气血㊁针刺补泻等多角度进行阐发㊂诸如辨人之形体肥瘦㊁气之虚实,区分男女左右不同,阴阳上下各异;明三阴三阳之脉,知其血气多少,懂营卫之气运行,血气有出入汇合;察知五脏六腑,知十二经所起,须明十二经各有五输㊁五行荥输各异;审知四海(髓㊁血㊁气㊁谷)虚实,察病邪寒热;视病热,泻而去之,视寒病,留针使热;病脉坚紧,泻其邪气,诛伐恶血,明辨补泻,通利经脉,着重勿伤其经㊂可见,杨上善对经筋病形体气血之论的理解和重视,裨益于针灸临床实际应用㊂3.3㊀知补泻,首辨寒热虚实‘灵枢㊃经筋“描述经筋之病: 寒则反折筋急,热则筋弛纵不收,阴痿不用㊂阳急则反折,阴急则俯不伸㊂ 其病多以经筋功能异常导致 筋急 和 筋纵 有关,病理变化不外乎寒热虚实㊂补虚泻实㊁扶正祛邪是针刺治疗疾病最重要的原则㊂诚如‘灵枢㊃经脉“言: 盛则泻之,虚则补之,热则疾之,寒则留之,陷下则灸之,不盛不虚,以经取之 ,明确肯定了虚补实泻㊁热疾寒留的原则㊂而‘太素“对针刺补泻的认识渐臻全面[5],明确指出针刺补泻当酌别寒热,审知虚实,以施治疗,或补㊁或泻㊁或平补平泻㊁或留针深久㊁或疾出其针等㊂如从天人合一角度宏观考量刺虚实之道,以法天地而应万物,疾病征象与之有相应联系,强调因虚致病者补之须实,因实致病者泻之要虚,刺热实无热乃出针,刺寒虚留针使针下热㊂得其妙旨,倡导应寒热虚实而行补泻,以达补虚泻实㊁扶正祛邪之治㊂此外,在讨论刺禁与针刺手法方面,涉及皮㊁肉㊁筋㊁脉㊁骨的五实五虚之论㊂以此为例,若五皆虚勿近泻之,此五皆实勿远而不泻㊂针刺补泻有寒热虚实之分,要点在于针刺深浅,使之得中,得气补泻,气至机发,转瞬即逝,勿使过与不及,凸显针刺补泻不可过度或不及,时机亦不可不当的理念㊂足见其论治疾病据寒热虚实而施补泻的阐释和运用,实属针灸临床的典范㊂3.4㊀欲为针者,先须治神‘太素㊃痹论“曰: 三气以为周痹,循脉而行,至分肉之间,气聚排迫分肉,肉裂而为痛也㊂[3]891 其指出风寒湿邪充斥分肉则引发疼痛,即 神 的反应[6]㊂杨上善论及治神之理,重视 欲为针者,先须治神 ,认为此乃存生之道㊂其引经义阐其要旨,其注解神,认为 神魂魄意志,以神为主,皆名为神 ㊂将神与五脏联系而论,凸显五脏藏神要义;五脏各司其职,五神各安其脏,则神清志静㊂‘太素“称 此则针布理神之旨 ㊂所以,针刺治病的核心内涵在于治神,此处主要有两层蕴意,一是治理调节人体生命活动的物质基础 神 ,二是主宰人体一切生命活动的 神机 [7]㊂故所谓治神,必先使五神得以调理,五神自理则五脏血气安定,其论彰显了神在疾病治疗及转归中的重要意义㊂然如何治神,‘太素㊃九针要解“有云: 神气游行出入之处为节,非皮肉筋也 [3]600㊂杨上善认为腧穴并非五体等实质性结构,而是 神气 出入游行的特殊通道,亦是 神机 发挥功能活动的重要门户,故有 神在孔穴 之论㊂另言之,运针施治的实质是通过对经络腧穴的刺激,治理调节 神气 和 神机 ,从而对机体产生调节作用[8]㊂再者,其注 守刺规矩之形,故粗;守血气,中神明,故工也 [3]593,认为 神之有余气浅,故刺小络出血也 神之不足则虚,故刺而不泄也 [3]718㊂亦可看出,针灸临床上工守神是指守气血,而非粗守刺法或形体,故而持针施治也就要求医者密意专心一务,全神贯注于针下,审知虚实,施以补泻,通过调节全身气血达到 调神 的目的㊂其治神理念贯穿疾病论治始终,可窥一斑㊂3.5㊀为针之法,以调气为本身缓筋柔㊁肌肉解利是经筋的生理常态㊂杨上善论述调气之理,善审人之呼吸吐纳,认为其气平和则筋强骨健,心性调顺,倡导 为针之法,以调气为本 ,强调针刺治疗疾病的作用意在调气㊂‘太素㊃知官能“亦云: 明于调气,补泻处所,是处可补,是处可泻,不妄为之㊂[3]583 所谓调气即指通过针刺手法的实施,补不足泻有余,使人体气机升降出入有序,进而调和气机,达到治病的目的[9]㊂并且‘太素㊃九针要道“亦对补泻手法的操作详尽描述: 摇大其穴,排阳邪而出针疾 外闭其门,令卫气不得泄出㊂[3]589 其后又加以集中阐述 气若至者,依数行补泻 ,再次强调施用泻法能使邪气泄出,补法可使正气内存,应着重根据疾病虚实属性选用补泻㊂人体气机升降出入有序,是机体处于 气调 状态的前提;而气的升降出入逆乱,则是人体出现各种病理变化的基础[10]㊂通过补泻调节逆乱之气机,方能使机体恢复 气调 的状态㊂其对调气之论的多方面阐发以及在论治疾病上的实践运用都昭示楷模㊂4㊀经筋病的治疗4.1㊀治则经筋病的治疗要点在于挑拨 横络 ,解除卡压[11]㊂‘太素㊃九针要道“从 横络 形成部位㊁诊察方法㊁质感等多方面对此详尽描述: 血脉,络脉也㊂有脉横居输穴之中,视之满实,切之独坚者,是横居络脉也㊂[3]591 继而‘太素㊃五邪刺“又提出治疗原则: 病之坚紧,因适破散㊂[3]653 其从气血而论,一方面 横络 作为一种病态形征表现或病邪客于经脉其上,导致经脉气血运行不畅而壅滞;另一方面强调说明通过诊察病灶点,即血气壅盛坚紧之处,可以明确病变经筋及施术部位㊂针刺治疗应泻其邪气,除其恶血,祛邪外出,破横络去,而后疼痛自可解除,经脉得调,气血可行㊂4.2㊀整体取穴4.2.1㊀取本经经穴㊀经筋随十二经脉并行,其循行分布与十二经脉大体类似,许多经穴能治疗经筋病㊂究其原理在于‘太素㊃五脏命分“言: 十二经脉,行营血气,营于三阴三阳,濡润筋骨,利关节也㊂[3]130 有研究亦表明,经筋病灶点痛感传导路线与相对应的经穴所属经脉循行的一致性约76%[12]㊂此外,从经穴选择方面来看,经穴主治与经脉相关的同一性往往表现在肘膝以下的五输穴及络穴上,其他部位的经穴多只是主治局部病证,并未反映出与相关经脉的内在联系㊂因而经筋病的整体取穴,常取同名经脉之远端经穴通调经络㊁调和气血㊂如‘太素㊃痹论“言: 以导引瘈紧,转引令其气行 ,即是循经远取病变经筋相应经脉之荥输穴的理论依据㊂4.2.2㊀取肝胆经经穴㊀肝主筋,邪气伤筋,筋膜拘挛则为 筋急 ㊂所谓 病在筋,调之筋 ,经筋病的治疗以调筋为主㊂肝通过对全身气血的调摄,将肝之血气由足厥阴经脉输注到达同名经筋,再通过十二经脉周身流注实现对周身诸筋的充养㊂足厥阴血多气少,邪客其上,应刺之除其恶血;足少阳与足厥阴相表里,其经脉气多血少,刺之宜泄其邪气㊂因此,治疗 筋急 取足厥阴肝经原穴㊁输穴太冲,能疏调肝脏气血,通调筋气㊂同时,配合足少阳胆经合穴㊁八会穴之 筋会 阳陵泉,亦能疏利肝胆气机,柔筋利节,表里两经配穴共奏缓急止痛㊁行气活血之功㊂4.2.3㊀取阳明经㊁足太阴经穴㊀中医学认为,病发于中焦,邪在经络,搏于阳经,气行则迟,血行亦缓,以致经筋痿软无力㊁百节缓纵不收则为 筋纵 ㊂所以,治疗应补中气以生血,即所谓 治痿独取阳明 ㊂阳明经为多血多气之经,其经脉主濡润经筋,束骨而利机关,治痿首重阳明即指此而言;表里相合,足太阴为脾之经,脾主一身肌肉,脾胃气血盛实则四肢肌肉㊁筋脉得以充养㊂故临床治疗 筋纵 以取阳明经穴为主(上肢病变取手阳明大肠经腧穴为主,下肢病变取足阳明胃经腧穴为主),辅以足太阴经穴,二者相得益彰㊂因此,根据病邪寒热虚实属性以及所犯脏腑不同,配伍相应经脉之经穴,采用不同针刺手法, 补其荥而通其输,调其虚实,和其顺逆 [13],以达祛除病邪,濡养筋脉之治㊂4.2.4㊀取阴阳跷脉交会穴㊀经筋的功能活动有赖阴阳跷脉的调节,其具有交通一身阴阳之气和调节肢体肌肉运动的作用㊂阴阳跷脉脉气失调,则引发肢体内外侧经筋力学失衡㊂同时,经筋禀受卫气,始发于足太阳,足太阳经气充实则筋柔节利,舒缩自如[14]㊂申脉为足太阳膀胱经与阳跷脉交会穴;阴阳表里相合,照海为足少阴肾经与阴跷脉交会穴㊂根据杨上善形体气血之论,治疗 经筋失衡 ,先明男女左右㊁阴阳不同,男可取照海,女可取申脉,通过施行补泻以疏调跷脉㊁缓急柔筋,调节肢体肌肉运动功能㊂5㊀结语整体观是中医学的核心内容,分析经筋病的病因病机㊁病性病位㊁病理变化乃至对其辨证论治均要体现这一法则㊂从整体观角度来分析 脉引筋气 思想:经筋与经脉在生理方面,经筋功能活动的发挥与相关经脉的气血渗灌㊁濡养调节功能关系尤为密切;在病理方面,经筋病㊁经筋病灶点的产生与经脉气血失调亦有着密不可分的联系㊂故而经筋病的针刺治疗也就要求从整体调治入手,首要明确疾病病因病机,明辨病变经筋及所属经脉以确定施术部位, 以痛为输 选取局部病痛穴位或病灶点为主,配合选取远部经穴,调补肝㊁胆㊁脾㊁胃㊁阴阳跷等相关经脉,以助气血的生化运行以滋养经筋,同时酌别寒热虚实属性,明确具体证型,充分发挥针刺补泻手法,从而进一步提高经筋病的临床疗效㊂参考文献:[1]㊀刘农虞.析 以痛为输 [J].针灸临床杂志,2014,30(2):55-57.[2]㊀叶建,管遵惠.管遵惠老师经筋理论的运用经验[J].云南中医中药杂志,2005,26(3):2-3.[3]㊀杨上善.黄帝内经太素[M].北京:科学技术文献出版社,2000:655.[4]㊀梁繁荣,曹芳,唐勇.关于构建针灸临床辨证体系的思考[J].中国针灸,2008,28(8):551-553.[5]㊀钱会南.‘黄帝内经太素“设方探析[J].安徽中医药大学学报,2017,36(5):1-3.[6]㊀王子正,董宝强,林星星.从整体观角度探讨经筋与中医肝系统关系[J].辽宁中医药大学学报,2017,19(8):119-121. 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急性胰腺炎患者肠道菌群变化及益生菌的应用吕彦青，李嘉杰，刘坤禹，郭汝华，季慧范吉林大学白求恩第一医院肝胆胰内科，长春 130021通信作者：季慧范，************.cn（ORCID： 0000-0001-8816-1906）摘要：肠道菌群是人体中最复杂和最重要的微生态系统，肠道菌群失调与急性胰腺炎的发生、发展密切相关，近年来靶向调控肠道微生态辅助治疗急性胰腺炎逐步被人们重视。
本文详细叙述了急性胰腺炎患者肠道菌群变化情况及机制，总结了益生菌应用的研究现状，指出益生菌辅助治疗方案的研究方向，并提出了预测急性胰腺炎患者优势菌群的新方法，以期为急性胰腺炎的治疗带来新思路。
关键词：胰腺炎，急性坏死性；胃肠道微生物组；鼠李糖乳杆菌基金项目：吉林市人口与健康发展研究（371170143428）Changes in intestinal microbiota and application of probiotics in patients with acute pancreatitisLYU Yanqing， LI Jiajie， LIU Kunyu， GUO Ruhua， JI Huifan.（Department of Hepatobiliary and Pancreatic Medicine， The First Hospital of Jilin University， Changchun 130021， China）Corresponding author： JI Huifan，************.cn（ORCID： 0000-0001-8816-1906）Abstract：Intestinal microbiota is the most complex and important microecosystem in the human body， and gut microbiota dysbiosis is closely associated with the development and progression of acute pancreatitis. Targeted regulation of intestinal microecology in assisting the treatment of acute pancreatitis has attracted more attention in recent years. This article describes the changes in intestinal microbiota and related mechanisms in patients with acute pancreatitis，summarizes the current research status of the use of probiotics， points out the research direction of probiotics as the adjuvant treatment regime， and proposes a new method for predicting the dominant flora in patients with acute pancreatitis， in order to bring new ideas for the treatment of acute pancreatitis.Key words：Pancreatitis， Acute Necrotizing； Gastrointestinal Microbiome； Lactobacillus RhamnosusResearch funding：Research on Population and Health Development of Jilin City （371170143428）急性胰腺炎（acute pancreatitis，AP）是多种病因导致胰腺组织自身消化所致的胰腺水肿、出血及坏死等炎症性损伤，组织学上以腺泡细胞破坏为特征。
第43卷第2期生态科学43(2): 151–162 2024年3月Ecological Science Mar. 2024 廖桂堂, 林正雨, 何鹏, 等. 基于“三生用地”的四川丘陵区乡村生态系统服务价值及其供需格局评估[J]. 生态科学, 2024, 43(2): 151–162.LIAO Guitang, LIN Zhengyu, HE Peng, et al. The value and supply-demand pattern of ecosystem services based on the production-living-ecological land classification system in typical hilly areas of Sichuan[J]. Ecological Science, 2024, 43(2): 151–162.基于“三生用地”的四川丘陵区乡村生态系统服务价值及其供需格局评估廖桂堂1, 林正雨2, 何鹏2, 高雪松3, 方从刚4, 邓欧平3, 王珊5, 邓良基3, *1. 成都信息工程大学资源环境学院, 成都 6102252. 四川省农业科学院农业信息与农村经济研究所, 成都 6100663. 四川农业大学资源学院, 成都 6111304. 成都市国土资源信息中心, 成都 6100415. 内江师范学院地理与资源科学学院, 内江 641100【摘要】科学评估乡镇尺度生态系统服务价值(ESV)是乡村生态系统生产总值(GEP)定量核算以及镇域国土空间规划的重要前提。
以四川丘陵区215个典型乡镇为研究对象, 基于乡村生产—生活—生态用地(“三生用地”)分类系统和单位面积价值当量因子法, 定量评估了乡镇尺度生态系统服务价值的空间分布及供需格局特征, 并引入和弦图清晰表达了生态系统服务之间的权衡与协同关系。
研究结果表明: (1)研究区乡村ESV空间分布存在明显的空间异质性和聚集特征, 总体上南部和西南部丘陵区ESV高于北部和中部, 中部地区ESV最低同时, ESV热点主要集中于西部和南部, 冷点主要分布于中部和东北。
- 82 -31（5）：1172-1175.[6] GU H，WANG Y，DU M，et al. Effectiveness of using mean corpuscular volume and mean corpuscular hemoglobin for beta-thalassemia carrier screening in the guangdong population of China[J]. Biomedical and Environmental Sciences，2021，34（8）：667-671.[7] MANTHEI D M，HARRO D M，KEREN D F. Incorrect migration of hemoglobin after capillary electrophoresis software update complicates diagnosis of an infant with hemoglobin S/Beta+thalassemia[J]. The Journal of Applied Laboratory Medicine，2021，6（5）：1371-1375.[8]宋琪玲，郭杨柳，何勇均，等. RDW 筛查地中海贫血诊断界值的建立及其与MCV、MCH、HbA 2联合筛查的价值[J].中国实验血液学杂志，2021，29（3）：847-852.[9] MAJI S K，DOLAI T K，PRADHAN S，et al. Implications of population screening for thalassemias and hemoglobinopathies in rural areas of West Bengal, India: report of a 10-year study of 287，258 cases[J]. Hemoglobin: International Journal for Hemoglobin Research，2020，44（6）：432-437.[10]刘利，余楚壬，李珊珊，等. α地中海贫血基因携带者709例红细胞参数、血红蛋白A 2及基因检测结果分析[J].广东医学，2021，42（8）：1006-1008.[11]宋琪玲，郭杨柳，何勇均，等. RDW 筛查地中海贫血诊断界值的建立及其与MCV、MCH、HbA 2联合筛查的价值[J].中国实验血液学杂志，2021，29（3）：847-852.[12]周亚丽，李平萍，杨焜，等.临界血红蛋白A 2人群的β地中海贫血检出情况[J].广西医学，2021，43（5）：587-589.（收稿日期：2023-11-09） （本文编辑：冯乐乐）①泉州市疾病预防控制中心 福建 泉州 362000多色探针熔解曲线分析法评估结核分枝杆菌阳性患者对不同抗结核药物耐药性的诊断效能陈李晓①【摘要】 目的：分析多色探针熔解曲线分析法（MMCA）评估结核分枝杆菌阳性患者对利福平、乙胺丁醇、链霉素、异烟肼、喹诺酮耐药性的诊断效能。
安慰剂检验引用文献安慰剂检验是指在临床试验中使用安慰剂来对照治疗组进行比较，以评估新药物或治疗方法的疗效。
在医学研究中，安慰剂检验通常被用来排除患者对治疗效果的主观影响，从而更准确地评估药物的治疗效果。
关于安慰剂检验的相关文献有很多，以下是一些引用的文献：1. Hróbjartsson A, Gøtzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med. 2001;344(21):1594-1602.2. Miller FG, Colloca L. The placebo phenomenon and medical ethics: rethinking the relationship between informed consent and risk-benefit assessment. Theor Med Bioeth. 2011;32(4):229-243.3. Finniss DG, Kaptchuk TJ, Miller F, Benedetti F. Biological, clinical, and ethical advances of placebo effects. Lancet. 2010;375(9715):686-695.4. Howick J, Friedemann C, Tsakok M, Watson R, Tsakok T, Thomas J, et al. Are treatments more effective than placebos? A systematic review and meta-analysis. PLoS One. 2013;8(5):e62599.这些文献涵盖了安慰剂检验在临床试验中的应用、安慰剂效应与医学伦理学的关系、安慰剂效应的生物学、临床和伦理学方面的进展，以及安慰剂在治疗中的实际效果等方面的研究成果。
富血小板血浆在膝关节疾病治疗中的应用刘永辉赵烨王向阳郭马珑崔宏勋【摘要】富血小板血浆(platelet-rich-plasma，PRP)是利用全血各成分沉降系数不同特性离心而得到的高浓度血小板血浆，由于其富含多种促进组织修复的生长因子，且制作、使用便捷而被广泛运用到骨科领域，尤其是近几年在治疗膝关节疾病疗效方面备受关注。
本文就其治疗膝关节骨性关节炎、半月板、交叉韧带损伤及膝关节滑膜炎方面做一综述，为临床治疗膝关节常见疾病提供参考。
【关键词】富血小板血浆；膝关节骨性关节炎；半月板损伤；交叉韧带损伤；膝关节滑膜炎【Abstract】Platelet-rich-plasma is a high-concentration platelet plasma obtained by centrifugation with different characteristics of sedimentation coefficients of all components of the whole blood.It is widely used in the field of orthopedics because it is rich in a variety of growth factors to promote tissue repair and is easy to make and use，especially in the treatment of knee diseases in recent years.In this paper，the treatment of knee osteoarthritis，meniscus，cruciate ligament injury and knee synovitis are reviewed to provide reference for clinical treatment of common knee diseases.【Key words】Platelet-rich-plasma；Knee osteoarthritis；Meniscus injury；Cruciate ligament injury；Knee synovitis富血小板血浆(platelet-rich-plasma，PRP)是自体外周血离心而得到以血小板和白细胞为主的血浆，研究发现[1]，PRP中含有转化生长因子β(transforming growth factor-β，TGF-β)，成纤维细胞生长因子(fibroblast growth factor，FGF)，血小板衍化生长因子(platelet-derived growth factor，PDGF)，血管内皮生长因子(vascular endothelial growth factor，VEGF)等多种细胞因子和介质，通过PRP注射到受损组织等方式能够促进损伤组织的修复与再生[2]。
《牛类滋养层干细胞建系的研究》篇一一、引言牛类滋养层干细胞（Bull Trophoblast Stem Cells，BTSCs）是一种在生物医学研究领域具有广泛应用潜力的细胞类型。
由于其具备多向分化能力和强大的增殖能力，近年来成为畜牧业及医学研究领域的一个热门课题。
BTSCs建系研究旨在通过建立稳定的细胞系，为研究牛类胚胎发育机制、疾病模型构建以及细胞治疗等提供重要工具。
本文将就牛类滋养层干细胞的建系方法、实验过程、结果分析和未来展望等方面进行详细阐述。
二、研究背景及意义随着生物技术的不断发展，干细胞研究在畜牧业和医学领域的应用日益广泛。
BTSCs作为一类具有多向分化潜能的细胞，对于研究牛类胚胎发育、疾病模型构建以及细胞治疗具有重要意义。
通过建立稳定的BTSCs细胞系，不仅可以为牛类胚胎生物技术提供重要工具，还可以为人类干细胞研究提供借鉴。
此外，BTSCs 的建系研究还有助于推动畜牧业的发展，提高牛类养殖的经济效益。
三、实验材料与方法1. 实验材料本实验所需材料包括牛类胚胎、培养基、血清、生长因子等。
所有材料均需经过严格的质量控制，以确保实验结果的可靠性。
2. 实验方法（1）胚胎收集与处理：从牛类新鲜胚胎中获取滋养层组织，经过适当的机械和酶解处理，得到单细胞悬液。
（2）细胞培养：将单细胞悬液接种于培养皿中，加入含有生长因子和血清的培养基进行培养。
（3）干细胞筛选与鉴定：通过细胞形态观察、免疫荧光染色、分子生物学等方法，筛选出具有多向分化潜能的BTSCs并进行鉴定。
（4）细胞建系：将筛选出的BTSCs进行传代培养，建立稳定的细胞系。
四、实验过程与结果分析1. 实验过程本实验首先从新鲜牛类胚胎中获取滋养层组织，经过适当的处理得到单细胞悬液。
然后，将单细胞悬液接种于培养皿中，加入含有生长因子和血清的培养基进行培养。
在培养过程中，通过观察细胞形态、免疫荧光染色等方法筛选出具有多向分化潜能的BTSCs。
最后，将筛选出的BTSCs进行传代培养，建立稳定的细胞系。
·论著·中国当代医药2020年12月第27卷第35期新型磁分离直接化学发光方法的建立及其临床应用宋宇1刘鹏1李武2袁锦云2丛海燕1鞠毅1姚继承3王明义1▲1.威海市立医院中心实验室,山东威海264200;2.深圳市新产业生物医学工程股份有限公司,广东深圳518052;3.威海威高生物科技有限公司,山东威海264200[摘要]目的建立新型磁分离直接化学发光的方法及探讨其临床应用。
方法新型磁分离直接化学发光方法中发光标志物采用高灵敏度的异鲁米诺衍生物,分离试剂采用高特异性的羊抗异硫氰酸荧光素(FITC)多克隆抗体包被的免疫纳米磁性微珠,发光底物采用简便的NaOH 和H 2O 2。
新型磁分离直接化学发光方法的临床应用性能评估以血清促甲状腺激素(TSH)为例,选取2019年8月~2020年8月威海市立医院初诊的104例甲状腺功能亢进症患者血清作为甲亢组;121例甲状腺功能减退患者血清作为甲减组;以同期来体检的134例健康成年人血清作为对照组。
标本采用新型磁分离直接化学发光方法及ADVIA Centaur XP 同时检测,将此两种方法所得结果进行比对,评价其临床符合性。
再通过对高、中、低三种浓度标准液的重复检测,评价其灵敏度、精密度和稀释回收率。
结果实现了新型磁分离直接化学发光方法的建立,并通过了临床验证,以TSH 为例的临床应用结果显示,建立的新型磁分离直接化学发光方法的检测灵敏度为0.01μIU/mL,批内和批间变异系数(CV)均<5%,稀释回收率>80%。
本研究建立的新型磁分离直接化学发光方法与ADVIA Centaur XP 的直接化学发光法对TSH 的检测结果进行对比,相关系数为0.9874。
结论成功建立一种新型磁分离直接化学发光方法,该方法具有高灵敏度、高精密度和很好的临床相符性,具有较好的临床应用价值。
[关键词]促甲状腺激素;微量活性物质;新型磁分离直接化学发光方法;定量检测[中图分类号]R446.6[文献标识码]A[文章编号]1674-4721(2020)12(b)-0008-05Establishment of a new direct chemiluminescence method for magnetic separation and its clinical applicationSONG Yu 1LIU Peng 1LI Wu 2YUAN Jin-yun 2CONG Hai-yan 1JU Yi 1YAO Ji-cheng 3WANG Ming-yi 1▲1.Central laboratory,Weihai Municipal Hospital,Shandong Province,Weihai 264200,China;2.Shenzhen New In⁃dustry Biomedical Engineering Co.,Ltd.,Guangdong Province,Shenzhen 518052,China;3.Weihai Weigao Biotech⁃nology Co.,Ltd.,Shandong Province,Weihai 264200,China[Abstract]Objective To establish a new direct chemiluminescence method for magnetic separation and explore theclinical application.Methods A new direct chemiluminescence method for magnetic separation was developed using isoluminol derivatives with high sensitivity as luminescent markers,immunomagnetic nanoparticles coated with goat an⁃ti-fluorescein isothiocyanate (FITC)polyclonal antibody with high specificity as separation reagents,NaOH and H 2O 2as luminescent substrates.To evaluate the clinical application performance of this method,taking serum thyroid stimulat⁃ing hormone (TSH)as an example,104patients with hyperthyroidism who were newly diagnosed in Weihai Municipal Hospital from August 2019to August 2020were selected as hyperthyroidism group;121patients with hypothyroidismwere selected as hypothyroidism group;134serum samples of healthy adults at the same period were taken as control group.The samples were detected by the method established in this study and ADVIA Centaur XP at the same time.The two results were compared to evaluate the clinical compliance.The sensitivity,precision and dilution recovery were evaluated by repeated detection of high,medium and low concentrations of standard solution.Results A new direct chemiluminescence method for magnetic separation was established.The sensitivity of the method was 0.01μIU/mL.The intra and inter coefficient of variation (CV)was less than 5%,and the dilution recovery was more than 80%.The new direct chemiluminescence method for magnetic separation established in this study was compared with the directchemiluminescence method of ADVIA Centaur XP for the TSH detection results,and the correlation coefficient was0.9874.Conclusion A new magnetic separation direct chemiluminescence method has been successfully established,which has high sensitivity,high precision and good clini⁃cal compatibility,and has good clinical application value.[Key words]Thyroid stimulating hormone;Trace activesubstances;New direct chemiluminescence method formagnetic separation;Quantitative detection[基金项目]国家科技重大专项(2009ZX10004-719);国家战略性新兴产业发展专项资金计划2013年高性能医学诊疗设备专项(发改办高技[2013]2598号)▲通讯作者中国当代医药2020年12月第27卷第35期·论著·随着医疗技术水平不断提高,对微量物质的定量检测有了更高的要求,许多免疫检测方法也得到了不断的改进和完善。
Frequency Response, 1 watt/1 meter on Axis, Swept Sine-Wave Input, Half-Space Anechoic Environment (see Figure 1):52-20,000 HzLow-Frequency 3-dB-Down Point:52 HzUsable Low-Frequency Limit (10-dB-down point):47 HzHalf-Space Reference Efficiency:5.3%Long-Term Average Power-Handling Capacity per EIA Standard RS-426A (see Power-Handling Capacity section), Full Range:400 wattsLow Frequency:400 wattsHigh Frequency:250 wattsMaximum Woofer Acoustic Output:21.2 wattsSound Pressure Level at 1 Meter, 1 Watt Input, Anechoic Environment, Band-Limited Pink-Noise Signal, 200-3,000 Hz:98 dBDispersion Angle Included by 6-dB-Down Points on Polar Responses, Indicated One-Third-Octave Bands of Pink Noise, 2,000-20,000 Hz, Horizontal (see Figure 3):60° ±20°2,000-20,000 Hz, Vertical (see Figure 3): 40° +27°, –0ºDirectivity Factor Rq (Q), 500- to 16,000-Hz Median (see Figure 4):13.5 (+6.7, –10.8)Directivity Index Di , 500- to 16,000-HzMedian (see Figure 4):11.3 dB (+1.8 dB, –7.05 dB)Second Harmonic,100 Hz:1.26%1,000 Hz:1.12%10,000 Hz:13.3%Third Harmonic,100 Hz:1.2%1,000 Hz:3.5%10,000 Hz:2.8%Distortion, 0.01 Full Power Input,Second Harmonic,100 Hz:0.35%1,000 Hz:0.32%10,000 Hz:3.2%Third Harmonic,100 Hz:0.15%1,000 Hz:2.4%10,000 Hz:0.25%Transducer Complement,High Frequency:DH2010A driver; HP64M hornMid Frequency:NGM (6.5 in.)Low Frequency:DL15X high-excursion woofer (15 in.)Box Tuning Frequency:50 HzCrossover Frequencies:400 Hz, 3,000 HzCrossover Slope:12 dB per octaveNominal:8 ohmsMinimum:5.6 ohmsInput Connections:Two paralleled Neutrik Speakon®NL4MPR jacks for full-range or biampoperationEnclosure Materials and Colors:Black carpet-covered plywood Void -free fir plywoodDimensions,Height:842 mm (33.1 in.)Width:485 mm (19.1 in.)Depth:600 mm (23.6 in.)Net Weight:44 kg (97 lb)Shipping Weight:50 kg (110.3 lb)DESCRIPTIONThe Electro-Voice T351 is a 400-watt, three-way, high-efficiency stage system. It combinesprofessional-quality components, highlightedby the NGM midrange speaker which is mountedin front of the woofer. The NGM is a 6.5 inchcone midrange speaker that is driven by a 7.5inch diameter magnet structure. The speaker ismounted in its own 10 inch diameter ventedenclosure. The NGM features a high power 2.5inch diameter voice coil and a circumferentialdirectivity control device. The system may bebiamplified or used full range with the internalpassive crossover. Either way the result isclear and articulate, high-quality sound.The enclosure is constructed of void-free ply-wood. This high-strength shell is covered withdensely woven, abuse-resistant black carpet-ing and finished with metal corners, large rub-ber feet and heavy-duty recessed handles.Figure 1, Axial Frequency Response, 1 watt 1 meterT351 SPECIFICATION GRAPHICS= Horiz.= Vert.Figure 2, BeamwidthFigure 3, PolarsFigure 5,Distortion Response (40 w)1 10% Rated Power (on axis at 1 meter from system)Figure 4, Directivity2nd Harmonic3rd HarmonicVertical HorizontalThe high-frequency section of the T351 utilizes a 60° x 40° rotatable, constant-directivity horn driven by a wide-bandwidth, titanium-diaphragm driver. This driver uses a unique convex-drive Time Path TM phasing plug structure (U.S. Patent #4,525,604) for smooth and extended high-frequency performance. The voice coil is coupled to the diaphragm with EV’s exclusive Resonant Drive TM technology. This increases and smooths the high-frequency response and reduces the amount of internal equalization required for flat frequency response.EV’s self-resetting PRO TM circuit is built into the crossover network to guard the compression driver from damage. If input power to the driver exceeds the nominal rating, the PRO TM circuit is activated, reducing the power delivered to the driver by 6 dB. The system will remain in this mode of operation until input power is reduced to a safe level.The optimally vented bass section of the T351is designed using Thiele-Small parameters for efficient performance to below 52 Hz. The DL15X high-excursion 15-inch woofer is used for its outstanding performance. It features beryllium copper lead wires with a low-mass,extended-length, edge-wound voice coil and high-temperature materials. EV’s unique Thermo Inductive Ring (TIR TM ) is placed on top of the pole piece, where the extended-length voice coil would normally be exposed, placing metal in close proximity to the coil and provid-ing a major heat-transfer path that helps keep the voice coil cool. Also, the part of the mag-netic structure adjacent to the coil is insulated from any rubbing contact induced by high power inputs, using EV’s exclusive PROTEF TM coating (U.S. Patent #4,547,632). The coil is driven by a massive, 16-lb magnetic structure.FREQUENCY RESPONSEThe combination of DL15X 15-inch woofer,NGM 6.5-inch midrange, DH2010A wide-band-width high-frequency driver and equalized crossover results in the wide and smooth over-all response shown in Figure 1. The T351’s axial frequency response was measured in Electro-Voice’s large anechoic chamber at a distance of 10 feet with a swept sine-wave input of 4 volts. Figure 1 has been averaged and corrected for 1 watt/1 meter.DIRECTIVITYThe polar response of the T351 speaker sys-tem at selected one-third-octave bandwidths is shown in Figure 2. These polar responses were measured in an anechoic environment at 10feet using one-third-octave pink-noise inputs.The frequencies selected are fully representa-tive of the polar response of the system.Beamwidth of the system utilizing the complete one-third-octave polar data is shown in Figure 3. R q and directivity index (D i ) are plotted in Figure 4.BIAMPED OPERATIONThe T351 is shipped from the factory in "full-range mode" with its passive crossover uti-lized. If biamp operation is desired, this is easily achieved. The input panel/crossover assembly (on the back of the system) must first be removed using a #2 Phillips screwdriver. After removing the input panel/crossover, refer to the instruction label in the side of the panel.There are three automotive fuses on the printed circuit board. These fuses are not functioning as fuses, but rather are functioning together asa three-pole switch. To convert the T351 to biamp operation, move each fuse over one position. The fuses should, once again, all be in one column. Replace the input panel/cross-over assembly in the enclosure and carefully replace the screws–being careful not to strip the holes. To return the system to full-range operation, repeat the steps in a similar manner.Remember, ALL FUSES MUST BE AR-RANGED IN ONE VERTICAL COLUMN FOR SAFE, PROPER OPERATION. The crossover frequency should be 500 Hz with slopes of 12-dB-per-octave or greater. If 500 Hz. is not an available frequency, then 800 Hz should be used.CONNECTIONSThe T351 is equipped with Neutrik Speakon®NL4MPR connectors. Two connectors are in-stalled in parallel allowing additional T351’s to be connected in parallel. One mating Speakon®NL4FC connector is supplied with each sys-tem. These connectors are locking, self-polar-izing and capable of 30 amps rms continu-ously. Additional connectors and cables can be purchased from your dealer.Full-range pin arrangements are:1– = IN, FULL RANGE(–)1+ = IN, FULL RANGE(+)2– = Not used 2+ = Not usedBiamp pin arrangements are:1– = IN, LOW FREQUENCY (–)1+ = IN, LOW FREQUENCY (+)2– = IN, MID AND HIGH FREQUENCY (–)2+ = IN, MID AND HIGH FREQUENCY (+)If you experience any difficulty in obtaining cables, connectors or wiring accessories, the following companies can be contacted:Neutrik USA, Inc.1600 Malone Street Millville, NJ 08332Pro Co Sound, Inc.135 E. Kalamazoo Avenue Kalamazoo, MI 49007Whirlwind Music Distributors, Inc.P.O. Box 1075Rochester, NY 14603POWER-HANDLING TESTElectro-Voice components and systems are manufactured to exacting standards, ensuring they will hold up, not only through the most rigorous of power tests, but also through con-tinued use in arduous, real-life conditions. The EIA Loudspeaker Power Rating Full Range (ANSI/EIA RS-426-A 1980) used a noise spec-trum which mimics typical music and tests the thermal and mechanical capabilities of the com-ponents. Electro-Voice will support relevant additional standards as and when they become available. Extreme, in-house power tests, which push the performance boundaries of the woof-ers, are also performed and passed to ensure years of trouble-free service.Specifically, the T351 passes ANSI/EIA RS-426-A 1980 with the following values:R SR = 6.9 ohms (1.15 x R E )P E(MAX) = 400 wattsTest Voltage = 52.5 volts RMS,105 volts peakThe "peak" power-handling capacity of a woofer is determined by the peak test voltage amount.For the T351, a 105-volt peak test voltage translates into 1,600 watts short-term peak power-handling capacity. This is the equivalent of four times the "average" power-handling capacity and is a peak that can be sustained for only a few milliseconds. However, this sort of short-duration peak is very typical in speech and music. Provided the amplifier can reporduce the signal accurately, without clipping, the woofer will also perform accurately and reli-ably, even at these levels.ARCHITECTS' AND ENGINEERS' SPECIFI-CATIONSThe loudspeaker system shall be a three-way, full-range design consisting of a 38.1-cm (15-inch) woofer in a vented enclosure,an NGM (6.5-inch) midrange speaker, a high-frequency compression driver mounted on a 60° x 40° constant-directivity horn, and a passive crossover/equalizer network, of which the lower frequency may be bypassed for use with an external low-level active dividing net-work with a corner frequency of 600 Hz. The loudspeaker shall meet the following perfor-mance criteria: frequency response of 52-20,000 Hz, –3 dB; full-range power handling of 400 watts long term and 1,600 watts short term with a shaped random-noise input per EIA Standard RS-426A; low-frequency power handling below 500 Hz in the biamp mode of 400 watts long term and 1,600 watts short term with a shaped random-noise input per EIA Standard RS-426A; high-frequency power handling above 500 Hz in the biamp mode of 250 watts long term and 1,000 watts short term with a shaped random-noise input per EIA Standard RS-426A; sensitivity of 100 dB SPL at 1 meter with a 1-watt, 300- to 2,000-Hz pink-noise input; 6-dB-down hori-zontal coverage angle of 60° ±20° in the 2,000- to 20,000-Hz range; 6-dB-down verti-cal coverage angle of 40° +27°, –0º in the 2,000- to 20,000-Hz range; crossover fre-quencies of 400 and 3,000 Hz; nominal impedance of 8 ohms; and minimum imped-ance of 5.6ohms. Input connections shall be two paralleled Neutrik Speakon ® NL4MPR jacks for full-range and biamp operation. The enclo-sure shall be constructed of plywood, covered in black carpet and fitted with a black steel grille,metal corner protectors, rubber feet and two recessed carrying handles. Dimensions shall be 842 mm (33.1 in.) high x 485 mm (19.1 in.)wide x 600 mm (23.6 in.) deep. Net weight shall be 44 kg (97 lb).The loudspeaker system shall be the Electro-Voice T351.WARRANTY (LIMITED)Electro-Voice products are guaranteed against malfunction due to defects in materials or work-manship for a specified period, as noted in the individual product-line statement(s) below, or in the individual product data sheet or owner’s manual, beginning with the date of original purchase. If such malfunction occurs during the specified period, the product will be re-paired or replaced (at our option) without charge.The product will be returned to the customer prepaid. Exclusions and Limitations: The Limited Warranty does not apply to: (a) exterior finish or appearance; (b) certain specific items described in the individual product-line statement(s) below, or in the individual productdata sheet or owner’s manual; (c) malfunction resulting from use or operation of the product other than as specified in the product data sheet or owner’s manual; (d) malfunction re-sulting from misuse or abuse of the product; or (e) malfunction occurring at any time after repairs have been made to the product by anyone other than Electro-Voice or any of its authorized service representatives. Obtaining Warranty Service: To obtain warranty service, a customer must deliver the product, prepaid, to Electro-Voice or any of its authorized service representatives together with proof of purchase of the product in the form of a bill of sale or receipted invoice. A list of authorized service representatives is available from Electro-Voice at 600 Cecil Street, Buchanan, MI 49107 (616/ 695-6831 or 800/234-6831). Incidental and。
Optimally Phasing Long Genomic Regionsusing Local Haplotype PredictionsEleazar Eskin Eran Halperin Roded SharanAbstractIn this study we propose a novel approach for phasing genotypes over long regions,which is based on combining information from local predictions on short,overlapping regions.The phasing is done in a way which maximizes a natural maximum likelihood criterion.Among other things,this criterion takes into ac-count the physical length between neighboring SNPs.We further give a confidence score to each position of the prediction,and use correlation information from the entire population to correct low confidence predic-tions.We evaluated our algorithm on two real datasets using two different measures.Our results demonstrate the effectiveness of the approach.In all our tests we significantly outperformed the PHASE[20]method. Our method is publicly available via a webserver at /compbio/hap/.1IntroductionSingle nucleotide polymorphisms(SNPs)are differences,across the population,in a single base,within an otherwise conserved genomic sequence.Approximately10million common SNPs[15,7],each with a frequency of10%to50%,account for the majority of the variation between DNA sequences of different people[17].Variation in the allelic content of SNPs are often associated with medical condition.Thus, efficient and accurate methods for SNP typing are of great clinical,scientific and commercial value.The sequence of alleles in contiguous SNP positions along a chromosomal region is called a haplotype. For diploid organisms,two haplotypes make up a genotype,which is the list of allele-pairs along the chro-mosomal segment.The genotype contains information solely on the combination of alleles in a given site and not on the association of each allele with one of the two chromosomes,also called its phase.Current technology,suitable for large scale polymorphism screening,obtains the genotype information at each SNP, but not its phase.The latter information can be obtained at a considerably higher cost[17].It is therefore desirable to develop efficient methods for inferring haplotypes from genotype information.Numerous approaches have been suggested in the literature to resolve haplotypes from genotype data. These methods include the seminal approach of Clark[1],parsimony approaches[8,9,12],maximum likelihood methods[4,5,11,14],statistical methods such as PHASE[20]and HAPLOTYPER[16],and perfect phylogeny-based approaches[10,3].All these methods perform very well across short genomic regions with limited diversity(see Figure1),but few extend to large regions with high diversity.Consider for example the entire SNPs in the KB region examined in[2].Out of the haplotypes in the population,the most common haplotype only occurs in individuals and haplotypes occur only in oneindividual.Indeed,the switch distance of the state-of-the-art PHASE[20]over this long region is about 11%(See Section5).As the effort to characterize human variation will be a tremendous undertaking[15], methods for haplotyping long genomic regions will be essential for analyzing data from large-scale genotype studies.In this paper,we propose a novel method,HAP-TILE,for phasing long genomic regions.Our method is based on using accurate phase predictions over short overlapping regions,obtained by any extant method,to recover haplotypes over long regions.We present an efficient dynamic programming algorithm for optimally combining the overlapping local predictions with respect to a natural maximum likelihood criterion.The maximum likelihood criterion takes into account an estimate of the accuracy of the prediction based on the physical length of the region and the entropy of the distribution of the haplotypes therein.To the best of our knowledge,the physical distance between neighboring SNPs,which is an extremely valuable information for phase reconstruction,was never used in previous haplotyping algorithms.To illustrate its importance, consider for example the data of Daly et al.[2].The distance between SNPs98and99is133KB,while the distance between SNPs6and7is only38bases.Clearly,the a-priori correlation between SNPs and is higher than the a-priori correlation between SNPs and.At each point of our tiled prediction,we assign a confidence score,based on the consistency of the local haplotype predictions with the global one at that point.The confidence scores reflect an estimation of the correctness of the prediction in each position.These scores significantly improve the usability of the system since in many cases,haplotype resolution is inherently ambiguous.For instance,such a case occurs when two heterozygous positions are separated by a very long stretch of homozygous positions.In these cases the confidence scores allow a user to determine which part of the prediction is reliable.After performing the tiling and computing the confidence scores,we are typically left with phased genotypes consisting of high confidence regions separated by low confidence regions.We rephase the low confidence regions by using correlation information from the entire population,enhancing the accuracy of our predictions.Our method follows similar intuitions to the HAPLOTYPER method[16],which was used subsequently in PL-EM[18].In the partition-ligation(PL)method,a long region is partitioned into a set of short regions; each of the regions is phased;and neighboring regions are then phased together recursively until a complete haplotype is reconstructed.One deficiency with the PL method is that the short regions are chosen arbitrarily, and due to the nature of the ligation step,the method is not guaranteed to produce a global optimum. In contrast,our method considers predictions over all possible short region segments,and uses a tiling technique that is guaranteed tofind a solution with maximum likelihood.We applied our method to two real datasets.We compared the performance of HAP-TILE to that of the popular PHASE method[20].Throughout our tests,HAP-TILE produced significantly more accurate results according to twofigures of merit.HAP-TILE is publicly available via a webserver at/compbio/hap/.The rest of the paper is organized as follows:Section2presents our probabilistic model for local hap-lotype predictions over a given region,and the computational problem of computing a maximum likelihood solution to the haplotyping problem under this model.Section3studies the complexity of the latter problem and gives a dynamic programming solution for it.Section4details the steps of our practical haplotyping algorithm.Finally,Section5presents our results on real datasets.2The Generative Probabilistic ModelIn this section we define a probabilistic model for the generation of local predictions of phasing algorithms given a set of genotypes over some genomic region.We focus on binary SNPs(having only two alleles). We use the following notation:A haplotype is a binary string.A genotype is a string over the alphabet050100150200250300350400450500050100150200250E n t r o p yLength in KBDaly et al. 2001 Haplotype Diversity vs Region LengthFigure 1:Haplotype diversity as a function of region length for the data of Daly et al.[2].Each point corresponds to a region.The x-axis shows the length of the region in kilobases and the y-axis shows the entropy of the haplotype distribution.For shorter regions,the entropy of the distribution is smaller,and the haplotypes are less diverse..We say that a genotype is compatible with the haplotypes ,if for every the following two conditions hold:(1)If or ,i.e.,is a homozygous position,then ;and (2)if ,i.e.,is an heterozygous position,then .If are compatible with we say that is a phase of .Let be the input genotypes,where the (true)phase of is .We considerwindows,,each of length ,where window contains positions .For every genotype ,and every window ,the model generates two haplotypes ,which we call the local predictions of window .At first,and ,that is,and are simply the copies of the two haplotypes in those positions.We then swap the values of and with probability ,is a copyof(in the corresponding positions)and is a copy of ,and with probability for everyposition .Suppose now thatare local predictions for the genotypes,generated as described above,where and .Let be a suggested phasing of the genotypes.Then the log likelihood of this solution according to our model is:finding a pair of haplotypes,for which is minimized.This gives rise to the following problem:Problem1(Minimum Conflict Phasing(MCP)).Given an unphased genotype and a set of local pre-diction for it,each of which is compatible with,find two haplotypes that are compatible with and minimize the number of disagreements with the local predictions.3The Minimum Conflict Phasing ProblemIn this section we study the Minimum Conflict Phasing problem.First,we prove that the problem is NP-hard.We then provide a linear time algorithm for it when the length of a local prediction isfixed. Theorem3.1.Minimum Conflict Phasing is NP-hard.Proof.We give a reduction from MAX-CUT.Let be an instance of MAX-CUT. Define an instance of MCP as follows:We set the window length to,and the length of the genotype to.Thus,the total number of windows is.We letbe the set of positions shared by all windows,which we call vertex positions.For convenience,we refer to position,corresponding to vertex,as.We define the genotype as having missing entries over all vertex positions,and being homozygous with a value of 1elsewhere.With every edge we associate two arbitrary windows.If,the local predictions for the two windows are set in the following way:Let and be the two pairs of haplotypes corresponding to the two windows.For positions we set, ,and.For every other vertex position we set and.In every non-vertex position all windows are homozygous with value.We now claim that has a maximum cut with size at least iff the MCP instance has a solution with at most disagreements.Suppose there is phase of with at most disagreements. In particular,consider a phase that induces a minimum number of disagreements.W.l.o.g.,for every vertex position we have.Consider the cut induced by the setof vertices,whose corresponding positions were assigned1in.Let denote the number of edges crossing the cut.For every edge,if then the number of conflicts with the windows in positions and is zero.If,then the number of disagreements is four.For every other vertex position,the number of conflicts with is exactly two,and for every non-vertex position the number of conflicts with is zero.Therefore,the total number of conflicts isConversely,given a cut of size at least,we define to have value1in non-vertex positions.For a vertex position we define iff,and iff.It is easy to verify that the number of disagreements induced by this solution is at most.3.1A Dynamic Programming SolutionWe now provide a linear time dynamic programming solution to MCP when the size of the window isfixed. We assume that we are given a genotype of length,and local predictions for. In what follows,we describe the construction of one of the haplotypes.The other haplotype can be derived from and in a straightforward manner.Denote by the best haplotype assignment for thefirst positions in,where the last bits are.For every assignment to at positions,denote bythe total number of disagreements between and and between and,where is the implied assignment to at these positions.Let.Then the following recurrence formula gives:where for all.It is easy to compute for every possible and in time .Using the recurrence formula we canfind for all.By tracing the solution that leads to a minimal value to(over all values of),we can reconstruct the haplotypes that attain the maximum likelihood.4The Practical AlgorithmWe devised a four-step method,called HAP-TILE,for phasing genotype data,which is based on the dy-namic programming algorithm presented in Section3.1.HAP-TILE starts by computing local predictions for all possible short segments of the genotyped region(up to length12).It then uses the dynamic program-ming algorithm to tile the local predictions into complete haplotype predictions.The third step computes confidence scores for each position in the prediction.Finally,HAP-TILE uses information from the entire population to correct low confidence predictions.Each of the steps is detailed below.4.1Computing Local Haplotype PredictionsWe scan the genotypes with a sliding window and compute local predictions in each window.In practice,we do not use afixed-size window,but rather use all possible window sizes from2to(where).This is needed since the density of heterozygous SNPs may vary considerably along the typed region.Hence,at every SNP,we have local predictions starting at this SNP.With each local prediction we associate a confidence level,which reflects the probability that a local prediction of length that starts at SNP is correct.The estimation of these confidence levels assumes that the less diverse the haplotypes in a region are, the more accurate their prediction is.We compute a confidence level as the product of twofigures.The first is an a-priori estimate of the probability of having strong correlation in a certain region based on its physical length.We use an exponential distribution for this estimate,as commonly used for modeling the occurrence of recombinations.This allows us to take into account the distance between SNPs in our predictions.Returning to our example on the data of[2],local predictions that span SNPs98and99will have lower confidence than predictions that span SNPs6and7.The secondfigure is an estimate of the probability to have such a phase prediction given that the data is generated by random mating of individuals from the population,whose sample we observe.This estimate is computed as in[3].This in turn,can be shown to be equivalent to the entropy of the haplotype distribution.In order to combine the estimated confidence levels into the dynamic programming algorithm,we rede-fine as follows:Using the notation of Section3.1,let be the total number of disagreements for a prediction of length.We define.4.2Computing Global Prediction Confidence ScoresNext,we assign two confidence scores to our global predictions based on the their consistency with the local predictions.Thefirst is a site confidence,which measures the confidence in the prediction of a specific site in an individual.The second is a phase confidence which measures the confidence in the predicted phase relation between two consecutive SNPs.These two types of confidence scores correspond to different potential sources of error.Site confidence corresponds to an error where within a local region,a single SNP is phased incorrectly with respect to its neighboring SNPs.Phase confidence corresponds to a more global error,where local regions are incorrectly phased with respect to each other.The site confidence for position in a given haplotype is computed as follows:Let denote the number of predictions,weighted by their confidence levels,that are consistent with a value of or in position,respectively.Then the site confidence is defined as the probability of observing a value ofor more,assuming a null model in which each local prediction at position is0with probability0.5and1 with probability0.5.If for all values of and,then the site confidence is simply the tail of a binomial distribution with parameter0.5.Otherwise,it is the average probability over all possible local predictions at position,weighted by their likelihoods.For the next step of the algorithm we also compute the probability to have1in the-th position of the haplotype:1341MF13GGTTTGTGATGCGGTCCTGCTGCTCTCCCTTTTGCCGCCTCA1341MF13GAGTTCTGGGTTGGTCAGGCCACTTTTGCTTCTGCAGCCTCAConf1-||--|--|7||9---||--||--|-||---|---|------Conf2-34--1--60939---99--99--9-99---9---9------Conf X-xxxx444655333337555533333411112222-------1341MM14AGGTTCCGATTTGGTCAGGCCACTTTTGTTTTTGCCGCTTCA1341MM14AGTTTCTCATTTAGTCAGGCCACTTTTCCTCTTGCCGCCTCAConf1--|---||----|--------------||-|-------|---Conf2--4---99----9--------------99-9-------6---Conf X--5555855555xxxxxxxxxxxxxxx777xxxxxxxx----Figure2:A sample output of confidence scores for two individuals from region53a in the Gabriel et al.[6]data.Thefirst two lines show the predicted haplotypes.The next two lines give the site confidences and the last line gives the phase confidence.A pair of dashes in lines3and4(site confidences)represents a homozygous site.A single vertical line in the third line represents a heterozygous site,with the site confidence for the two predictions in the fourth line.A pair of numbers represents the site confidences for missing genotypes.The format was designed so that a user can easily observe which sites are homozygous, heterozygous or missing.The phase confidence is represented by a number,or“x”for zero confidence.All confidences values are linearly scaled from0to9(in order tofit into a single position in the output). where homozygous sites are ignored in the computation.We switch the phasing in position iff .This step is executed in parallel on all individuals and positions.5Experimental ResultsWe applied our algorithm to two real datasets,and compared its performance to that of PHASE[20].Thefirst dataset contains the genotypes of129mother,father and child trios from a European-derived population[2, 19].The data was collected over a500KB region of chromosome5q31,containing SNPs,in an attempt to identify a genetic risk factor for Crohn’s disease.A significant portion of the genotype data()ismissing.For evaluation purpose,we focused on the children genotypes,and used the pedigree information on the trios to partially infer their true haplotypes,as in[3].Our second dataset consists of populations and from the data of Gabriel et al.[6].Each population contains approximately SNPs,partitioned into62regions.Population consists of individuals from multi-generational pedigrees of European ancestry and population consists of individuals from trios from Yoruba.Again,we used the available pedigree information to partially infer the true haplotypes. In some cases for population,there are Mendelian conflicts in the resolution of the multi-generational pedigrees.For these cases,we throw out the entire pedigree and only report results of predictions over the non-conflicting pedigrees.Note that in our experiments on this data we used all available individuals,due to the small number of independent ones.We evaluated the quality of our predictions using the switch distance measure[13],which is well suited for measuring errors over long regions.The switch distance measures the number of phase switches thatseparate the predicted from the correct haplotypes.Consider a set of SNPs where the correct haplotypes are and.A prediction of and would have a switch distance of,while a prediction of and would have a switch distance of.Since the number of heterozygous genotypes vary per individual,for evaluation,we report the total switch distance among all individuals divided by twice the number of heterozygous sites in the data.We compared the accuracy of our predictions to that of the popular PHASE method[20].The average switch distances obtained by the algorithms on each of the datasets are summarized in Table5(A).A more detailed comparison on the data of Gabriel et al.[6]is given in Table2.Notably,HAP-TILE outperforms PHASE consistently,over all our experiments,and its switch distance was on average smaller by about than that of PHASE.Dataset PHASE0.05990.05250.0798HAP-TILEDaly et al.[2]0.0522 Gabriel et al.[6](A)0.0593 Gabriel et al.[6](D)0.1059A BTable1:Comparison between HAP-TILE and PHASE[20]on different datasets.For each dataset,shown are the average switch distance(A)and the average missing distance(B).The smaller distance appears in bold-face.We also evaluated the accuracy of the algorithms in predicting missing data.To this end we devised a missing distance measure,which follows the same intuitions of switch distance.For each site with missing data,it computes the number of errors in the predicted haplotype,byfirst correcting its phase using switches up to site(including it),and counting the number of errors induced on site.These counts are then averages over all missing sites.For example,consider as above a set of SNPs where the correct haplotypes are and.If the third position is a missing site and the remaining positions are heterozygous,the number of errors for the predictions and would be ,while the number of errors for the prediction and would be since if we correct the heterozygous sites up to the second position(by performing a switch in the second position),the missing data would be predicted correctly.The results of comparing the performance of HAP-TILE and PHASE in predicting missing data are shown in Table5(B).Detailed results on the data of Gabriel et al.[6]are given in Table3.Again,our algorithm consistently outperforms PHASE over all datasets.Finally,we examined the relation between the confidence that is assigned to a position and the correct-ness of the prediction at that position.To this end we computed the switch distance of the predictions for different confidence thresholds,where predictions with phase confidence below the threshold were omit-ted.Figure3depicts this relation.As thefigure shows,most of the errors are made on low confidence predictions.AcknowledgmentsThis research was supported in part by NSF ITR Grant CCR-0121555.References[1]A.G.Clark.Inference of haplotypes from PCR-amplified samples of diploid populations.Journal of MolecularBiology and Evolution,7(2):111–122,1990.00.010.020.030.040.050.0600.20.40.60.81S w i t c h D i s t a n c e Percentage of Omitted PredictionsGabriel et al. 2001 Region 41a Confidence Rated PredictionsFigure 3:Performance of confidence rated predictions for region 41a of Gabriel et al.[6].Each point measures the performance under a different confidence threshold.The y-axis shows the switch distance and the x-axis shows the percent of predictions with phase confidence below the threshold.[2]M.J.Daly,J.D.Rioux,S.F.Schaffner,T.J.Hudson,and nder.High-resolution haplotype structure in the human genome.Nature Genetics ,29(2):229–32,2001.[3]E.Eskin,E.Halperin,and R.M.Karp.Efficient reconstruction of haplotype structure via perfect phylogeny.Journal of Bioinformatics and Computational Biology ,1(1):1–20,2003.[4]L.Excoffier and M.Slatkin.Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population.Molecular Biology and Evolution ,12(5):921–7,1995.[5]D.Fallin and N.J.Schork.Accuracy of haplotype frequency estimation for biallelic loci,via the expectation-maximization algorithm for unphased diploid genotype data.American Journal of Human Genetics ,67(4):947–959,2000.[6]G.B.Gabriel,S.F.Schaffner,H.Nguyen,et al.The structure of haplotype blocks in the human genome.Science ,296:2225–2229,2002.[7]The International SNP Map Working Group.A map of human genome sequence variation containing 1.42million single nucleotide polymorphisms.Nature ,409(6822):928–33,2001.[8]D.Gusfield.A practical algorithm for optimal inference of haplotypes from diploid populations.In Proceedings of the Eighth International Conference on Intelligent Systems for Molecular Biology ,pages 183–189,2000.[9]D.Gusfield.Inference of haplotypes from samples of diploid populations:complexity and algorithms.Journal of Computational Biology ,8(3):305–23,2001.[10]D.Gusfield.Haplotyping as perfect phylogeny:Conceptual framework and efficient solutions.In Proceedingsof the 6th International Conference on Computational Molecular Biology (RECOMB’02),pages 166–175,2002.[11]M.E.Hawley and K.K.Kidd.Haplo:a program using the EM algorithm to estimate the frequencies of multi-sitehaplotypes.Journal of Heredity ,86(5):409–11,1995.[12]ncia,V .Bafna,S.Istrail,R.Lippert,and R.Schwartz.SNPs problems,algorithms and complexity,europeansymposium on algorithms.In Springer-Verlag,editor,Proceedings of the European Symposium on Algorithms (ESA’01),Lecture Notes in Computer Science ,volume 2161,pages 182–193,2001.[13]S.Lin,D.Cutler,M.Zwick,and A.Chakravarti.Haplotype inference in random population samples.Am.J.Hum.Genet.,71:1129–1137,2002.[14]J.C.Long,R.C.Williams,and M.Urbanek.An EM algorithm and testing strategy for multiple-locus haplotypes.American Journal of Human Genetics,56(3):799–810,1995.[15]rge-scale genotyping for the haplotype map of the human genome.RFA:HG-02-005,2002.[16]T.Niu,S.Qin,X.Xu,and J.Liu.Bayesian haplotype inference for multiple linked single nucleotide polymor-phisms.Am.J.Hum.Genet.,70:157–169,2002.[17]N.Patil,A.J.Berno,D.A.Hinds,et al.Blocks of limited haplotype diversity revealed by high-resolution scanningof human chromosome21.Science,294(5547):1719–23,2001.[18]Z.Qin,T.Nu,and J.Liu.Partitioning-ligation-expectation-maximization algorithm for haplotype inference withsingle-nucleotide polymorphisms.American Journal of Human Genetics,71:1242–1247,2002.[19]J.D.Rioux,M.J.Daly,M.S.Silverberg,et al.Genetic variation in the5q31cytokine gene cluster conferssusceptibility to crohn disease.Nature Genetics,29(2):223–8,2001.[20]M.Stephens,N.Smith,and P.Donnelly.A new statistical method for haplotype reconstruction from populationdata.American Journal of Human Genetics,68:978–989,2001.Region HAP-TILEof SwitchDistance1a0.0489130.0139 2a0.0448140.0417 3a0.0407900.0590 7a0.0620120.0460 8a0.0717370.0655 10a0.0186370.0415 12b0.0588210.0606 14a0.0652370.0714 16a0.0355530.0687 17a0.0333730.0536 19a0.0366740.0227 21a0.140480.0882 22a0.0241720.1016 24a0.0276140.0360 25b0.0280570.0669 27a0.0314770.0581 29a0.0244690.0396 31a0.0244430.0168 32a0.0618560.0645 33b0.0952820.0736 35a0.0506500.0147 37a0.0393740.0425 39a0.032990.0000 40a0.04211240.1296 42a0.0723440.0534 44a0.0325490.0627 45a0.0980770.0411 47a0.1426580.0780 49a0.1000710.0974 51a0.0477520.1175 53a0.1191620.074132770.0621Region HAPof SwitchDistance1a0.1019160.0689 2a0.0705130.1088 3a0.0602840.0930 7a0.0513130.0336 8a0.1092630.0950 10a0.0441400.1167 12b0.0309490.1062 14a0.0813420.1068 16a0.0883520.0876 17a0.0837530.1136 19a0.0647430.0802 21a0.081060.0417 22a0.0466710.1209 24a0.0649140.0710 25b0.0399620.0841 27a0.0613840.1219 29a0.0679300.0983 31a0.0455350.0704 32a0.0855340.0972 33b0.0000460.0579 35a0.0419520.1083 37a0.0834730.1126 39a0.054990.0519 40a0.08441140.1327 42a0.1266480.0950 44a0.1015480.1060 45a0.0849640.0606 47a0.1466610.1156 49a0.1274600.1343 51a0.0895340.1088 53a0.1263560.117030610.1027Region HAP-TILEof MissingDistance1a0.0450130.0126 2a0.0460140.0420 3a0.0478900.0597 7a0.0796120.0509 8a0.0782370.0510 10a0.0257370.0364 12b0.0556210.0494 14a0.0623370.0585 16a0.0523530.0627 17a0.0390730.0540 19a0.0446740.0245 21a0.134880.0811 22a0.0308720.0998 24a0.0289140.0323 25b0.0545570.0616 27a0.0338770.0533 29a0.0268690.0412 31a0.0206430.0162 32a0.0676560.0604 33b0.0980820.0653 35a0.0504500.0129 37a0.0447740.0415 39a0.041390.0000 40a0.04491240.1185 42a0.0675440.0427 44a0.0374490.0556 45a0.1053770.0410 47a0.1336580.0728 49a0.1304710.0931 51a0.0546520.0966 53a0.1188620.063832770.0593Region HAPof MissingDistance1a0.1054160.0683 2a0.0706130.0951 3a0.0657840.1052 7a0.0597130.0300 8a0.1095630.1047 10a0.0507400.1189 12b0.0383490.1053 14a0.0893420.1058 16a0.1099520.0953 17a0.0905530.1177 19a0.0765430.0839 21a0.103060.0238 22a0.0529710.1206 24a0.0682140.0793 25b0.0435620.0841 27a0.0657840.1288 29a0.0685300.1080 31a0.0499350.0675 32a0.0905340.0956 33b0.0000460.0697 35a0.0460520.1083 37a0.0856730.1168 39a0.059090.0500 40a0.08341140.1234 42a0.1328480.0941 44a0.1030480.1154 45a0.0886640.0636 47a0.1422610.1183 49a0.0935600.1363 51a0.0899340.1172 53a0.1319560.116530610.1059。
