资助这项研究是由美国国家健康耳聋与沟通障碍研究院（R01 2DC007428）。

<html> 1。 IPL视频创作我们设计的视频很有趣，有吸引力，但也非自闭症儿童的厌恶，在一些方面:动画人物时，我们需要使用场景的社会/情感的动物，而不是人类具有挑战性的儿童ASD。我们使用颜色鲜艳的物体的动态场景捕获并保持关注。视频时，屏幕是空白的，一个红色闪烁灯的间距的间隔期间（ITIS）认为孩子的注意力。我们生产的语音音频，使用语音，夸张的语调和持续时间捕获并保持孩子的注意力。 图1。 （电影）一个块的名词偏差视频显示一个名词的偏置视频，测试儿童是否映射到一个新的字对象与行动。/ 4331movie1.mov"目标="_blank"&gt;点击这里观看电影。 视频刺激，通过创建商业非线性编辑程序，如FinalCut Pro或Avid的Media Composer，使用4-8秒的影片剪辑。 依次排列的第一的2个夹子，交替的左和右，搭配相同熟习音频或教学。 旁边的基准试验来，这是目前的测试激励端，但，搭配nondirecting音频。基线试验告诉我们的孩子是否有任何内在的或视觉的偏好时，无论是刺激没有语言或指导的音频。 测试试验显示，配对与测试音频，区分这两种视觉效果。 甲1kHz的音上的第二音频信道，与每个审判重合，提供视觉发病的编码器的指定，和偏移量的试验。 <ol><li>执行的父母同意过程。描述格式更详细的研究，并要求家长签署同意书。强调的是，孩子应该注意用最少的交互与父，并介绍了家长使用的MP3播放器，如果孩子坐在父母的腿上。家长听音乐的MP3播放器，一边看的IPL视频，让他/她不听IPL测试音频和潜在影响的孩子应该看哪种方式。 </li><li>设置IPL组件在指定的房间，并连接到电源，使用延长线。这是有帮助的研究助理一起带来，他们可以玩的孩子在安装过程中。设置大屏幕的背部的主要光源。将集中在屏幕背后的扬声器，两个音量调节旋钮，中途水平。三脚架将相机放置在头顶上的音频转接盒，集中在屏幕前。加载磁带插入相机和摄像头旁边的地板上的DTE。设置投影机站7-10英尺的距离从屏幕上的投影机顶部。将笔记本电脑到投影机上的立场旁边。 </li></ol><img alt="图2" fo:content-width="6in" fo:src="/files/ftp_upload/4331/4331fig2highres.jpg" src="/files/ftp_upload/4331/4331fig2.jpg" /> 图2。便携式的IPL组件和安排其安装在家里。显示的便携式IPL组件和其安装在家里的空间布局。 <a href="http://www.jove.com/files/ftp_upload/4331/4331fig2large.jpg" target="_blank">点击这里查看大图</a> 。 <ol start="3"><li>请连接的IPL组件:笔记本电脑连接，这样它的视频信号发送到投影仪。笔记本电脑还送出两个音频信号（通过分离器），与语音音频的扬声器的音音频到相机上。将相机连接，因此，它的DTE发送视频和音频信号。一旦连接，电源的所有部件。 DTE屏幕上应显示"AVI类型1"左"反"下。 </li><li>播放视频（S）的孩子:将第一个到QuickTime视频在笔记本电脑上。 <ol><li>将相机从2.5到3英尺的椅子，前面的屏幕。邀请孩子坐在椅子上，或在父母的怀里。如果父母的膝盖上，给家长的MP3播放器和耳机，告诉他/她来启动它。如果独自一人坐在孩子，家长可以坐在一起。可以鼓励儿童烦躁在视频笼统的"看电影"。 </li><li>确保孩子的脸是可见的摄像机。重新检查每当孩子四处走动。根据需要调整照明的房间。 </li><li>孩子的信息写在干擦白板（化名，性别，访问，视频，日期，出生日期，年龄）。打开摄像机，然后按记录。按记录DTE。电影日Ë白板，持续10秒。 </li><li>在笔记本电脑，玩的第一个视频，点击"查看"，然后按"Enter"全屏"。" </li><li>视频完成后，按下停止按钮上的DTE。如果孩子愿意，可能会出现另一个视频。另外，这可能是一个很好的时间休息。有些自闭症儿童的需要经常休息，但其他人可能更喜欢观看的视频在一排。 </li></ol></li><li>奖励孩子的礼物在结束访问。 </li></ol> 3。编码在实验室中<ol><li>检查孩子的眼球运动已经数字化的DTE。 <ol><li>这部电影导入到非线性编辑程序，转换的格式（AVI）使用我们自定义的编码程序，然后导出到一个安全的存储设备。 </li></ol></li><li>每个视频编码，其具体布局（ 即 ，安排熟悉/教学，基线和测试试验）。 <ol><li> Tab键通的<html> h的孩子的膜和找到1kHz的音的波形的帧中是可见的，表明正在呈现的视觉刺激儿童。 </li><li>开始编码在每个目标前试验（ 即有没有色调和中心光;应当向儿童中心或看远）间距的间隔（ITI）。标签前面一帧一帧的，记录每一个变化的凝视L（左），R（右），C（中心）或A（离开:向上，向下，最左边，最右边，背面）。 </li></ol></li></ol>输入的编码方案的产出列的数字表明每个代码的时间和类型的。因此，TSC 33499意味着，在开始的审判，3.3499秒的视频从一开始，孩子看的中心。 编码阵列的分析，通过自定义的matlab分析程序，访问的具体布局，哪一方是每次试验的每部影片的比赛。 ve_content"的分析程序，然后计算出孩子的时间和方向的寻找每个编码审判过程中，孩子的延迟匹配的刺激，先看看和次数的孩子切换注意在每个编码审判。 然后，我们比较的儿童在基线与测试试验，（B）（a）持续时间的目光投向匹配图像匹配的图像延迟，先来看看，（C）的两个图像，在整个审判的时间过程，和（d）的关注的开关的数量。 理由是理解的语言刺激，孩子会显得更长匹配的图像比他们在测试过程中试验的基准试验过程中，他们会显得更迅速（一次试验开始）比不匹配的图像匹配图像，和，他们将开关注意在测试过程中比在基准试验的试验，因为语言刺激是指导他们的期待。 ，唯一的区别之间的基线和测试试验是在语言的音频;的视觉刺激是相同的，但一个nondirecting音频（ 例如 ，"看这里！"）的基准试验，而在测试试验有一个指挥音频（ 例如 ，"在哪里的toopen ？"）因此，比较注意措施的持续时间和开关的基准试验测试试验，以告诉我们有多少导演音频引导孩子们的寻找模式。此外，如果孩子明白导演的音频，他们看起来应该更迅速地比不匹配的图像匹配的图像。

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没有利益冲突的声明。

特别需要注意的是，以确保编码器是"聋"/不知道具体的刺激，孩子正在经历一个给定的试验，让他们不知道哪一方是匹配的，不经意间的偏差及其编码。我们保证通过的1kHz音列入第二音频通道的视频，然后将其复制到孩子的眼球运动的电影。此音调的波形提供的视觉指示的发病每项试验和偏移，从而划定不知道他们的视频或音频内容的编码器的试验。 这是非常重要的，以确保分析的布局考虑的左，右的开关，当孩子的编码（ 即 ，如果匹配的场景是在左侧，而孩子是看，它会出现在正确的侧的眼动编码器，反之亦然）。 信度评估小号产量的相关性约0.98对经验丰富的编码器上随机选择的10％的数据; 3与经验不足的编码器或如果有是高转以上的编码器用于这项研究的参与者之间，我们建议每个孩子的编码的眼睛运动至少2人，并要求他们的代码（通常持续时间匹配）是在0.3秒内对方每次试验。如果他们都没有，然后是第三个，第四或第五的人应该编写孩子，直到实现可靠性。 随着孩子年龄和/或发育迟缓的儿童的参加者，这是不可避免的，有些人会不看无论是现场一定比例的每次试验中，对于一些试验，从来没有。下列约定适用于这些失误的注意事项:（一）儿童需要至少一个场景至少0.3秒计算，审判。否则，它是缺少的试验。 （b）对于一个给定的视频，孩子们需要提供一半以上的试验，以测试被包含在最终的数据集的数据。 （三）缺少试验跨在这个年龄组的儿童/条件，该项目的平均取代。 IPL是一种引用（ 例如 ，对象和操作）或命题上的水龙头儿童最早的语言形式的映射（ 即 ，单词和句子）（ 即 ，关系和事件）的含义。它可以被用来评估过程，其中不同年龄的孩子学习新单词，以及年龄，他们在了解不同类型的语法形式。只需要眼球运动的理解明显的指标（或不），IPL可用于幼儿，其行为符合普遍较低，以及一些特殊人群，如自闭症儿童的。此外，因为该技术可以被带到儿童之家，它也可能被使用很难人口以达到在传统的实验室，如儿童从低社会经济群体，在农村社区的儿童和单语非母语的父母的双语儿童。分析眼球运动的新方法，揭示学习不同类型的语言，有趣的和重要的影响和学习的话，在不同的年龄。未来的计划包括使用IPL与神经影像学检查方法，同时，使儿童的大脑活动，在语言理解，可与他们的行为指标。

<table border="1"><tbody><tr><td> 组件名称 </td><td> 公司 </td><td> 目录编号 </td><td> 评论（可选） </td></tr><tr><td>屏幕</td><td>德雷珀</td><td> :RoadWarrior便携式投影屏幕</td><td></td></tr><tr><td>笔记本电脑</td><td>苹果</td><td> 15英寸MacBook Pro </td><td></td></tr><tr><td>放映机</td><td> NEC </td><td> NP40投影机</td><td>数码镜头投影机</td></tr><tr><td>投影机支架</td><td> DA-LITE </td><td>项目-O站</td><td></td></tr><tr><td>扬声器</td><td> YAMAHA </td><td>监听音箱型号MS101II </td><td></td></tr><tr><td>鼎</td><td>金钟</td><td> QB-4W DF迷你的</td><td></td></tr><tr><td>摄像机</td><td>教规</td><td> VIXIA HV30 HDV </td><td>高清晰度视频</td></tr><tr><td> DTE </td><td> DTE技术</td><td> FS-H200 </td><td></td></tr><tr><td>降噪耳机</td><td>索尼</td><td> MDR-NC60 </td><td></td></tr></tbody></table>

portable intermodal preferential looking (ipl): investigating language comprehension in typically developing toddlers and young children with autism

的定义特征的自闭症光谱障碍（ASD）是语言和沟通困难。1儿童房间隔缺损的发病上讲是通常延迟，许多儿童患有ASD的一贯生产语言不太频繁和较低的词法和语法的复杂性比他们通常发展（TD）同行。6,8,12,23然而，与ASD的孩子们也表现出了显着的社会赤字，研究人员和临床医生继续讨论在社会交往帐户赤字或在何种程度上有助于语言的赤字生产。5,14,19,25 标准化的评估在自闭症儿童的语言通常包括理解组件的，然而，许多这样的理解任务评估只是一个方面，语言（ 例如 ，词汇），或有显着的电机组件（ 例如 ，指向，行为出），和/或要求孩子们刻意选择一些替代品。最后这两个被称为是具有挑战性的自闭症儿童的行为。7,12,13,16 我们提出一个方法，可以评估的青少年发育正常的儿童（9-36个月）和自闭症儿童的语言理解的。2,4,9,11,22这种方法，便携式联运优惠展望（P-IPL），项目侧端的视频图像从笔记本电脑到便携式屏幕。成对的第一视频图像与"基线"（nondirecting）音频，然后再次呈现与"测试"语言的音频相匹配的视频图像中，只有一个配对。儿童的眼​​球运动一边看视频拍摄，后来编码的。儿童理解的语言音频看起来更加迅速，并且不再在相匹配的语言的音频，视频。2,4,11,18,22,26 此范式包括多个合作mponents，最近被小型化（投影机，摄录一体机，数字化仪）在儿童之家，使便携性和易于安装。这是一个关键点，以评估幼儿ASD，经常不舒服，在新的（ 例如 ，实验室）设置。影片可以创建评估广泛的语言知识的具体组成部分，如主语 - 动词 - 对象词序，WH-问题，紧张/纵横动词后缀;视频还可以评估原则，如名词的单词学习包括文字和语音，视觉和听觉显着，耐受性良好，自闭症儿童的偏差，形状偏差和句法自举。10,14,17,21,24视频。

寻找从测试使用P-IPL儿童模式的一个例子在图3中给出。 TD孩子21个月的年龄查看NounBias视频，看了看时间匹配的图像与基线试验相比，在测试过程中，这表明他们已经制定了新颖的物体上，而不是行动的话。21儿童房间隔缺损平均33个月的年龄与具有类似的举动，类似的效果的大小。21,24因此，自闭症儿童表现出相似的词TD孩子的学习偏见。查看的SVO词序视频中，孩子们在这两个群体也不再寻找到匹配的图像在基准测试过（ 即显著理解），表明认识的英文单词的顺序（ 例如 ，"女孩把男孩"是一个不同的关系"男孩把女孩"）。3,14,21发展差异的wh-疑问视频，TD儿童表现出显着的comprehens离子而显着理解自闭症儿童的年龄在54个月。在28个月的年龄，因此，自闭症儿童的延迟在学习如何正确地解释问题，如"什么苹果的命中吗？" <img alt="图3" src="/files/ftp_upload/4331/4331fig3.jpg" /> 图3。儿童的百分之寻找时间的匹配（ 即 ，对象，而不是行动），而观看的名词偏置视频。显示儿童的百分之寻找时间的匹配（ 即 ，而不是行动的对象），而观看的名词偏置视频。 图4给出了更详细的时间过程的TD的儿童观看ShapeBias视频在连续四次访问的分析，跨越20-32个月。蓝线表示的匹配（ 即 ，相同的形状对象），请注意，高度的蓝线在日E测试试验（每幅图的右侧）随着年龄的增加，越来越形状喜好。此外，随着孩子年龄的增长，蓝线上升到了比赛早在审讯中，表明他们理解的指导音频随着年龄的增长更加迅速。红色线表示望着远处的红色线条的宽度会随着年龄的增长而降低，孩子们花更少的时间望着远处的通知。粉红色的线表示希望该中心在ITI;我们使用，以确保孩子们没有偏见的审判开始之前。这些IPL的数据证实了其他方法的的形状偏差是一个日益强烈的字眼，TD孩子的学习原则。然而，重复三次没有成功地在ASD儿童表现出显着的字形状偏差。17,24 <img alt="图4" src="/files/ftp_upload/4331/4331fig4.jpg" /> 图4。 TD孩子的TIMecourse是俯视而生，而观看形状偏置视频。显示了TD儿童寻找到匹配的时间过程，非匹配，中心，并远离，而观看形状偏置视频。 <a href="http://www.jove.com/files/ftp_upload/4331/4331fig4large.jpg" target="_blank">点击此处查看大图</a> 。 图5给出了时间过程数据与ASD，当他们平均41个月的年龄相同的孩子，一边欣赏的语法的引导视频，当他们学习新的动词周围的句子帧（ 例如 ，要求，，以确定gorping在"鸭子gorping兔子"指的致病作用，而不是到一个noncausative的行动）。句法引导过程是重复在TD的孩子的许多研究的另一个词汇学习的原则。请注意，自闭症儿童的看不匹配的图像（绿线）在基线试验，但随后他们的期待是针对在匹配的图像（蓝线）在下半年的测试试验，当他们被要求找到所指的新动词（ 例如 ，"查找gorping！"）。作为一个群体，这些儿童房间隔缺损，从而能够正确地映射到致病作用的动词。交叉访问的回归分析表明，自闭症儿童的看着在比赛过程中的句法引导过程的视频有更短的延迟，在比赛时，他们观看了的语序视频，8个月前的14 <img alt="图5" src="/files/ftp_upload/4331/4331fig5.jpg" /> 图5。儿童房间隔缺损的时间过程是俯视而生，而观看视频的句法引导过程。显示儿童ASD寻找到匹配的时间过程，非匹配，中心，并远离，而观看视频的句法引导过程。

Watch this Scientific Journal Video about Portable Intermodal Preferential Looking IPL: Investigating Language Comprehension in Typically Developing Toddlers and Young Children with Autism at JoVE.com

Portable Intermodal Preferential Looking IPL: Investigating Language Comprehension in Typically Developing Toddlers and Young Children with Autism

一个可靠的以家庭为基础的方法来评估非常年轻的典型发展儿童的语言理解，以及那些患有自闭症，描述。该方法分析孩子的眼睛凝视着观看的图像，但听到的声音只匹配了一个图像。刺激的设计考虑到青少年参加。

便携式联运优惠展望（IPL）:研究语言理解在通常情况下发展幼儿和儿童自闭症

One  of the defining characteristics of autism spectrum disorder (ASD) is difficulty  with language and communication.1  Children with ASD's onset of ...

portable-intermodal-preferential-looking-ipl-investigating-language

Research

JoVE Journal

Medicine

Portable Intermodal Preferential Looking (IPL): Investigating Language Comprehension in Typically Developing Toddlers and Young Children with Autism

18.0K 次观看.  University of Connecticut. 一个可靠的以家庭为基础的方法来评估非常年轻的典型发展儿童的语言理解，以及那些患有自闭症，描述。该方法分析孩子的眼睛凝视着观看的图像，但听到的声音只匹配了一个图像。刺激的设计考虑到青少年参加。

视频: Portable Intermodal Preferential Looking IPL: Investigating Language Comprehension in Typically Developing Toddlers and Young Children with Autism

A Strategy to Identify de Novo Mutations in Common Disorders such as Autism and Schizophrenia

There are several lines of evidence supporting the role of de novo mutations as a mechanism for common disorders, such as autism and schizophrenia. First, the de novo mutation rate in humans is relatively high, so new mutations are generated at a high frequency in the population. However, de novo mutations have not been reported in most common diseases. Mutations in genes leading to severe diseases where there is a strong negative selection against the phenotype, such as lethality in embryonic stages or reduced reproductive fitness, will not be transmitted to multiple family members, and therefore will not be detected by linkage gene mapping or association studies. The observation of very high concordance in monozygotic twins and very low concordance in dizygotic twins also strongly supports the hypothesis that a significant fraction of cases may result from new mutations. Such is the case for diseases such as autism and schizophrenia. Second, despite reduced reproductive fitness1 and extremely variable environmental factors, the incidence of some diseases is maintained worldwide at a relatively high and constant rate. This is the case for autism and schizophrenia, with an incidence of approximately 1% worldwide. Mutational load can be thought of as a balance between selection for or against a deleterious mutation and its production by de novo mutation. Lower rates of reproduction constitute a negative selection factor that should reduce the number of mutant alleles in the population, ultimately leading to decreased disease prevalence. These selective pressures tend to be of different intensity in different environments. Nonetheless, these severe mental disorders have been maintained at a constant relatively high prevalence in the worldwide population across a wide range of cultures and countries despite a strong negative selection against them2. This is not what one would predict in diseases with reduced reproductive fitness, unless there was a high new mutation rate. Finally, the effects of paternal age: there is a significantly increased risk of the disease with increasing paternal age, which could result from the age related increase in paternal de novo mutations. This is the case for autism and schizophrenia3. The male-to-female ratio of mutation rate is estimated at about 4&#x2013;6:1, presumably due to a higher number of germ-cell divisions with age in males. Therefore, one would predict that de novo mutations would more frequently come from males, particularly older males4. A high rate of new mutations may in part explain why genetic studies have so far failed to identify many genes predisposing to complexes diseases genes, such as autism and schizophrenia, and why diseases have been identified for a mere 3% of genes in the human genome. Identification for de novo mutations as a cause of a disease requires a targeted molecular approach, which includes studying parents and affected subjects. The process for determining if the genetic basis of a disease may result in part from de novo mutations and the molecular approach to establish this link will be illustrated, using autism and schizophrenia as examples.

Molecular genetic strategy for finding de novo mutations causing common disorders such as autism and schizophrenia.

一项战略，以确定在常见的疾病，如自闭症和精神分裂症的新突变

There are several lines of evidence supporting the role of de novo mutations as a mechanism for common disorders, such as autism and schizophrenia. First, ...

科研

医学

Eye Tracking Young Children with Autism

The rise of accessible commercial eye-tracking systems has fueled a rapid increase in their use in psychological and psychiatric research. By providing a direct, detailed and objective measure of gaze behavior, eye-tracking has become a valuable tool for examining abnormal perceptual strategies in clinical populations and has been used to identify disorder-specific characteristics1, promote early identification2, and inform treatment3. In particular, investigators of autism spectrum disorders (ASD) have benefited from integrating eye-tracking into their research paradigms4-7. Eye-tracking has largely been used in these studies to reveal mechanisms underlying impaired task performance8 and abnormal brain functioning9, particularly during the processing of social information1,10-11. While older children and adults with ASD comprise the preponderance of research in this area, eye-tracking may be especially useful for studying young children with the disorder as it offers a non-invasive tool for assessing and quantifying early-emerging developmental abnormalities2,12-13. Implementing eye-tracking with young children with ASD, however, is associated with a number of unique challenges, including issues with compliant behavior resulting from specific task demands and disorder-related psychosocial considerations. In this protocol, we detail methodological considerations for optimizing research design, data acquisition and psychometric analysis while eye-tracking young children with ASD. The provided recommendations are also designed to be more broadly applicable for eye-tracking children with other developmental disabilities. By offering guidelines for best practices in these areas based upon lessons derived from our own work, we hope to help other investigators make sound research design and analysis choices while avoiding common pitfalls that can compromise data acquisition while eye-tracking young children with ASD or other developmental difficulties.

Eye tracking has long been used to study gaze patterns in typically-developing individuals, but recent technological advancements have made its use with clinical populations, including autism, more feasible. While eye-tracking young children with autism can offer insight into early symptom manifestations, it involves methodological challenges. Suggestions for best practices are provided.

自闭症幼儿的眼动追踪

The rise of accessible commercial eye-tracking systems has fueled a rapid increase in their use in psychological and psychiatric research. By providing a ...

Studying Pancreatic Cancer Stem Cell Characteristics for Developing New Treatment Strategies

Pancreatic ductal adenocarcinoma (PDAC) contains a subset of exclusively tumorigenic cancer stem cells (CSCs) which have been shown to drive tumor initiation, metastasis and resistance to radio- and chemotherapy. Here we describe a specific methodology for culturing primary human pancreatic CSCs as tumor spheres in anchorage-independent conditions. Cells are grown in serum-free, non-adherent conditions in order to enrich for CSCs while their more differentiated progenies do not survive and proliferate during the initial phase following seeding of single cells. This assay can be used to estimate the percentage of CSCs present in a population of tumor cells. Both size (which can range from 35 to 250 micrometers) and number of tumor spheres formed represents CSC activity harbored in either bulk populations of cultured cancer cells or freshly harvested and digested tumors 1,2. Using this assay, we recently found that metformin selectively ablates pancreatic CSCs; a finding that was subsequently further corroborated by demonstrating diminished expression of pluripotency-associated genes/surface markers and reduced in vivo tumorigenicity of metformin-treated cells. As the final step for preclinical development we treated mice bearing established tumors with metformin and found significantly prolonged survival. Clinical studies testing the use of metformin in patients with PDAC are currently underway (e.g., NCT01210911, NCT01167738, and NCT01488552). Mechanistically, we found that metformin induces a fatal energy crisis in CSCs by enhancing reactive oxygen species (ROS) production and reducing mitochondrial transmembrane potential. In contrast, non-CSCs were not eliminated by metformin treatment, but rather underwent reversible cell cycle arrest. Therefore, our study serves as a successful example for the potential of in vitro sphere formation as a screening tool to identify compounds that potentially target CSCs, but this technique will require further in vitro and in vivo validation to eliminate false discoveries.

Pancreatic cancer stem cells (CSCs) can be expanded in vitro using the anchorage-independent sphere culture technique, which represents a powerful tool to study CSC biology and can serve as the first step to develop novel CSC-targeting therapies. Here the methodology for expanding, analyzing and targeting of pancreatic CSCs is provided.

研究胰腺癌干细胞特性开发新的治疗策略

Pancreatic ductal adenocarcinoma (PDAC) contains a subset of exclusively tumorigenic cancer stem cells (CSCs) which have been shown to drive tumor ...

Measuring Cardiac Autonomic Nervous System (ANS) Activity in Toddlers - Resting and Developmental Challenges

The autonomic nervous system (ANS) consists of two branches, the parasympathetic and sympathetic nervous systems, and controls the function of internal organs (e.g., heart rate, respiration, digestion) and responds to everyday and adverse experiences 1. ANS measures in children have been found to be related to behavior problems, emotion regulation, and health 2-7. Therefore, understanding the factors that affect ANS development during early childhood is important. Both branches of the ANS affect young children&#8217;s cardiovascular responses to stimuli and have been measured noninvasively, via external monitoring equipment, using valid and reliable measures of physiological change 8-11. However, there are few studies of very young children with simultaneous measures of the parasympathetic and sympathetic nervous systems, which limits understanding of the integrated functioning of the two systems. In addition, the majority of existing studies of young children report on infants&#8217; resting ANS measures or their reactivity to commonly used mother-child interaction paradigms, and less is known about ANS reactivity to other challenging conditions. We present a study design and standardized protocol for a non-invasive and rapid assessment of cardiac autonomic control in 18 month old children. We describe methods for continuous monitoring of the parasympathetic and sympathetic branches of the ANS under resting and challenge conditions during a home or laboratory visit and provide descriptive findings from our sample of 140 ethnically diverse toddlers using validated equipment and scoring software. Results revealed that this protocol can produce a range of&#160;physiological responses to both resting and developmentally challenging conditions, as indicated by changes in heart rate and indices of parasympathetic and sympathetic activity. Individuals demonstrated&#160;variability in resting levels, responses to challenges, and challenge reactivity, which provides additional evidence that this protocol is useful for the examination of ANS individual differences for toddlers.

Measuring Cardiac Autonomic Nervous System ANS Activity in Toddlers - Resting and Developmental Challenges

We describe the methods for continuous monitoring of the autonomic nervous system under resting and challenge conditions with 18 month old children. Results revealed that this protocol can produce meaningful physiological responses in both branches of the autonomic nervous system and elicit significant individual variability in patterns of responses.

测量心脏自主神经系统（ANS）活性的幼儿 - 安静和发展挑战

The autonomic nervous system (ANS) consists of two branches, the parasympathetic and sympathetic nervous systems, and controls the function of internal ...

Induction and Assessment of Exertional Skeletal Muscle Damage in Humans

Contraction-induced muscle damage via voluntary eccentric (lengthening) contractions offers an excellent model for studying muscle adaptation and recovery in humans. Herein we discuss the design of an eccentric exercise protocol to induce damage in the quadriceps muscles, marked by changes in strength, soreness, and plasma creatine kinase levels. This method is simple, ethical, and widely applicable since it is performed in human participants and eliminates the interspecies translation of the results. Subjects perform 300 maximal eccentric contractions of the knee extensor muscles at a speed of 120&#176;/sec on an isokinetic dynamometer. The extent of the damage is measurable using relatively non-invasive isokinetic and isometric measures of strength loss, soreness, and plasma creatine kinase levels over several days following the exercise. Therefore, its application can be directed to specific populations in an attempt to identify mechanisms for muscle adaptation and regeneration.

This article describes a safe and reliable method to induce and quantify exertional skeletal muscle damage in human subjects.

诱导和人类劳力骨骼肌损伤评估

Contraction-induced muscle damage via voluntary eccentric (lengthening) contractions offers an excellent model for studying muscle adaptation and recovery ...

Nerve-sparing Mid-urethral Obstruction (NeMO) in Female Small Rodents

Partial bladder outlet obstruction (pBOO) has a high prevalence, causes significant patient burden, and immense health care costs. The most common animal model to investigate bladder remodeling in pBOO are female rodents undergoing partial obstruction at the proximal urethra. Variability in the degree of obstruction and animal mortality are major concerns with proximal obstruction. Furthermore, dissecting around the proximal urethra and bladder neck jeopardizes bladder innervation.
We developed a nerve-sparing mid-urethral obstruction (NeMO) model for pBOO avoiding the disadvantages of the traditional model. We approached the urethra just inferior to the pubic symphysis, which obviated the need for laparotomy as well as for dissection in this area; also, the striated urethral sphincter remained untouched. We performed NeMO in female Sprague-Dawley rats (12 obstructions, 6 sham animals) as well as in female C57/bl6 mice (20 obstructions, 18 sham animals). After two weeks, we evaluated bladder function, bladder mass, and body mass.
We had no mortalities among obstructed- or sham-operated female rats; as described for the traditional proximal pBOO-method, we tied the suture around the proximal urethra and a temporarily placed 0.9 mm metal rod. NeMO induced an 85% increase in bladder mass after two weeks, average residual urine volume was 0.4 mL in partially obstructed rats while only 0.03 mL in sham animals. In mice, we tested 3 sizes of cannulas that we placed along the urethra when tying the suture. We found that using a 27-gauge cannula resulted in over 50% animal mortality; placing the 25-gauge cannula did not yield the desired response in increasing bladder mass; utilizing a 26-gauge cannula yielded favorable results with minimal animal mortality (1/8) yet a significant 2-fold increase in bladder mass.

Nerve-sparing Mid-urethral Obstruction NeMO in Female Small Rodents

Traditional modeling of partial bladder outlet obstruction in rodents is fraught with animal mortality. A denervation injury from dissection around the proximal urethra and bladder neck is also of major concern. We developed and evaluated a safe and reliable mid-urethral obstruction model, avoiding the shortcomings of the traditional model.

在女小鼠害保留神经的中期尿道梗阻（NEMO）

Partial bladder outlet obstruction (pBOO) has a high prevalence, causes significant patient burden, and immense health care costs. The most common animal ...

Oral Biofilm Sampling for Microbiome Analysis in Healthy Children

Oral biofilm and its molecular analysis provide a basis for investigating various dental research and clinical questions. Knowledge of biofilm composition leads to a better understanding of cariogenic and periopathogenic mechanisms. Microbial changes taking place in the oral cavity during childhood are of interest for several reasons. The evolution of the child oral microbiota and shifts in its composition need to be analyzed further to understand and possibly prevent the onset of disease. At the same time, advanced knowledge of the natural composition of oral biofilm is needed. Early stages of caries-free permanent dentition with healthy gums provide a widely unaffected subgingival habitat that can serve as an in situ baseline for studying features of oral health and disease. Analysis of children's oral biofilm during different stages in life is thus an important theme in the field. Modern molecular analysis methods can provide comprehensive information about the bacterial diversity of such biofilms. To enable microbiota data comparison, it is important to standardize each step in the procedure for molecular data generation. This procedure spans from clinical sampling, Next Generation Sequencing (NGS), bioinformatic data processing, to taxonomic interpretation. One of the most critical factors here is biofilm sampling. Sampling in children is even more challenging in particular due to limited space in subgingival areas. We thus focus on the use of paper points for subgingival sampling. This article provides a detailed protocol for oral biofilm sampling of the subgingival sulcus, the mucosa, and saliva in children.

Changes in the oral microbiome throughout childhood are of growing interest. Comparison of different microbiome studies reveals a lack of standardized sampling protocols. Limited space makes sampling the sound subgingival sulcus of children challenging. Paper point sampling is presented here in detail as the method of choice for this area.

口腔生物膜取样在健康儿童中的微生物分析

Oral biofilm and its molecular analysis provide a basis for investigating various dental research and clinical questions. Knowledge of biofilm composition ...

Measurements of Motor Function and Other Clinical Outcome Parameters in Ambulant Children with Duchenne Muscular Dystrophy

While the number of new treatment options tested in patients with Duchenne muscular dystrophy (DMD) is increasing, there is still no defining of the most reliable assessments regarding therapeutic efficacy. We present clinical and radiological outcome measures used in ambulatory patients participating in our trial &#34;Treatment with L-citrulline and metformin in Duchenne muscular dystrophy&#34;. The motor function measure is a validated test in patients with neuromuscular disorders that consists of 32 items and assesses all three dimensions of motor performance including standing and transfer (D1 subscore), axial and proximal motor function (D2 subscore), and distal motor function (D3 subscore). The test shows high intra- and inter-rater variability but only when strictly following guidelines of the materials, examination steps, and calculation of scores. The 6-minute walk test, timed 10-meter walk/run test, and supine-up time are commonly used timed functional tests that also sufficiently monitor changes in muscle function; however, they strongly depend on patient collaboration. Quantitative MRI is an objective and sensitive biomarker to detect subclinical changes, though the examination costs may be a reason for its limited use. In this study, a high correlation between all clinical assessments and quantitative MRI scans was found. The combinational use of these methods provides a better understanding about disease progression; however, longitudinal studies are needed to validate their reliability.

The aim of this study is to present the most reliable clinical outcome measures and their correlations with quantitative muscle MRI in ambulant patients with Duchenne muscular dystrophy.

治疗杜氏肌营养不良患儿运动功能及其他临床结果参数的测量

While the number of new treatment options tested in patients with Duchenne muscular dystrophy (DMD) is increasing, there is still no defining of the most ...

Investigating Intestinal Barrier Breakdown in Living Organoids

Organoids and three-dimensional (3D) cell cultures allow the investigation of complex biological mechanisms and regulations in vitro, which previously was not possible in classical cell culture monolayers. Moreover, monolayer cell cultures are good in vitro model systems but do not represent the complex cellular differentiation processes and functions that rely on 3D structure. This has so far only been possible in animal experiments, which are laborious, time consuming, and hard to assess by optical techniques. Here we describe an assay to quantitatively determine the barrier integrity over time in living small intestinal mouse organoids. To validate our model, we applied interferon gamma (IFN-&#947;) as a positive control for barrier destruction and organoids derived from IFN-&#947; receptor 2 knock out mice as a negative control. The assay allowed us to determine the impact of IFN-&#947; on the intestinal barrier integrity and the IFN-&#947; induced degradation of the tight junction proteins claudin-2, -7, and -15. This assay could also be used to investigate the impact of chemical compounds, proteins, toxins, bacteria, or patient-derived probes on the intestinal barrier integrity.

Here we describe a technique to quantify the barrier integrity of small intestinal organoids. The fact that the method is based on living organoids enables the sequential investigation of different barrier integrity modulating substances or combinations thereof in a time-resolved manner.

研究活体器官的肠道屏障分解

Organoids and three-dimensional (3D) cell cultures allow the investigation of complex biological mechanisms and regulations in vitro, which previously was ...

Involving Individuals with Developmental Language Disorder and Their Parents/Carers in Research Priority Setting

A protocol for involving individuals presenting with developmental language disorder (DLD) (iDLD) and their parents/carers (iDLDPC) in a research priority setting exercise is presented.
iDLD have difficulties with communication skills, such as understanding language, word-finding and discourse. Such difficulties mean existing research priority setting protocols are difficult for iDLD to access, since they require sophisticated communication skills. Thus, a novel protocol for involving iDLD in these exercises is warranted. The same protocol is recommended for use with iDLDPC, to ensure accessibility.
The protocol is presented in 4 steps. Step 1 describes a program of activities delivered by trained, specialist DLD speech and language therapists (SLTs) that prepares iDLD/iDLDPC for involvement. Step 2 outlines an approach to elicit iDLD/iDLDPC&#8217;s opinions on research priorities. Steps 3 and 4 describe methods to analyze and integrate this data at multiple stages of the research priority setting process.
9 trained specialist DLD SLTs delivered steps 1 and 2. 17 iDLDs and 25 iDLDPCs consented to involvement. Opinions from all participants were elicited, and this data was used to influence the process and output of the exercise.
An advantage of this protocol is its accommodation of the heterogeneity in support needs of iDLD/iDLDPC, through a menu of options, whilst also providing a structured framework. Due to the novelty of the protocol, the methods for data integration were developed by the research group. These are potential limitations of the protocol, and may bring the reliability and validity under scrutiny, which are yet to be tested.
This protocol enables meaningful involvement of iDLD/iDLDPC in&#160;research priority setting and could be utilized for people with other kinds of speech, language or communication needs. Further research should evaluate the effectiveness of the protocol and whether it can be adapted for involvement of such populations in other research studies.

A protocol to enable individuals with developmental language disorder (DLD) and their parents/carers to meaningfully participate in a research priority setting exercise is established. The protocol includes a defined program of activities for data collection, and methods to incorporate this data into the broader research priority setting process.

让发育性语言障碍患者及其父母/照顾者参与研究重点设定

A protocol for involving individuals presenting with developmental language disorder (DLD) (iDLD) and their parents/carers (iDLDPC) in a research priority ...