作者非常感谢来自下列来源的资金支持。发展和各种影像学分析测试是由几个赠款，最值得注意的是从健康研究加拿大学院（MOP＃13129），加拿大和老年痴呆症协会（美国），称心的老年痴呆症协会及中风基金会加拿大伙伴中风支持恢复（HSFCPSR），和LC坎贝尔基金会。 JR收到薪水的支持来自加拿大的老年痴呆症协会; SEB从森尼布鲁克研究所和医学部门在新宁和T的U，包括布里尔主席在神经学。作者还接收来自HSFCPSR工资支撑。

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作者什么都没有透露。

该LE分割和土地分割程序是专门开发的AD和正常老年人的MRI获得区域volumetrics。虽然有众多的全自动流水线适用复杂的计算算法来执行这些操作，这些工具往往缺乏个性化的准确度和精密度的LE的半自动化流水线生产。权衡与半自动流程是正确训练操作与解剖知识，需要应用这种综合管线的计算技能所需的资源。然而，个性化的成像管道的主要好处之一是获得定量volumetrics从温和到时自动流水线失败神经退行性病变的重症病例的能力。 由于LE管道先前已进行评估，并适用于各种老年人和患有痴呆症的人群1,2,13,14,19,22,23，即AR的主要问题Ë通常由训练有素的操作人员遇到了良好的记录和总结如下。 用智慧缩放器组件所需的人工检查和编辑包括TIV提取屏蔽程序，vCSF重新分配和手工清除脑干，小脑和其他幕下结构。对于脑提取，自动TIV输出一般是提供一个体面的面具，原来PD/T2图像质量都不错。然而，由于血管和神经组织内侧的相对强度值，以颞极，靠近颈动脉，这一区域通常需要一定的编辑。此外，粘液在鼻腔中往往会影响区域的强度直方图，位于前额叶区域，这往往需要自动TIVauto掩模的额外的手动编辑扭曲强度剪切销值。最后，额外的手动编辑，通常需要在最优越的地区，那里GL10:28萎缩趋于导致增加的正下方的硬膜蛛网膜下腔CSF的量。另外，与心室扩大相关联的萎缩趋向于尽量减少与vCSF调动所需的操作员干预。具有三要素配准方法的另一个优点是识别囊性流体填充梗塞近端到心室，从而可能由于脑室周围静脉血管5,24-26，它是可识别的，由于其对PD和T1相对强度（能力高信号对PD，低信号在T1）。这些低信号可以从vCSF使用实心填充操作之前，在ITK-SNAP_sb抽取的手动限制划定。因为vCSF重分配是在T1中采集空间中进行，在情况下对准偏离远离ACPC平面，可能需要第三脑室和四叠体池的限制，如果该PC是不完全可见。虽然小脑幕是一个相对容易的结构，以净胜球erentiate，几个解剖学为基础的规则协助引导手工清除脑干和幕下结构，定位大脑脚从内侧颞叶的分离特别是当的。 SABRE landmarking是标准ACPC对齐图像进行立体定位为基础的程序，允许对特定的解剖标志适度预见的本地化。例外的情况是极度萎缩和正常变化是由于神经解剖学个体差异的情况。脑萎缩导致实质的总体损失，增加CSF沿着周围大脑镰，这增加了选择合适的点放置的地标难度中线。以规则为基础的协议是必需的，查明例外的一般规则是必需的情况下。在解剖结构的正常变化，特别是在中央沟和顶枕沟的相对位置，也增加了difficulTY这些结构的人工划分的。然而，使用SABRE的图形用户界面允许表面渲染图像，在决策过程中的这些特定的标志性建筑可视化的显著帮助的实时旋转。最后，一些以规则为基础的协议已经被集成到编程软件，以防止操作人员如违反中央沟圈定被迫向后移动（线追踪防止回去到自身）。 病变赛格组件的手动检查过程需要专业知识，视觉识别相关的高信号，即暴露在扫描有不同程度的SH后只获得了视觉感知技能。假阳性最小化算法协助在初始分割去除大部分的错误。然而，扩张血管周围空间之间的差异（菲尔绍 - 罗宾空间：VRS）在豆状核和重在外部囊，屏状，极端胶囊，和subinsular区东升SH可以是困难的。这与VRS例基底节特别困难。最近的一篇文章，概述标准汇报影像学（STRIVE）血管的变化，推荐大小的标准，从腔梗区分VRS，并描述VRS更加线性和脑脊液强度对MRI检查。为了解决这些问题，与VRS标识，LE采用：a）一种解剖学为基础的规则，可防止操作员选择落在豆状核内的任何高信号，B）的尺寸标准，以排除高信号比直径5mm以内，和c）由于对PD，T2和T1 27的相对脑脊液强度的相对强度规则附加排除。此外，正常的高信号可以沿中线和大脑镰，特别是在FLAIR成像，这可能是困难的沿胼胝体相关SH区分被发现。在案件这种重叠，解剖学为基础的规则实现，其中仅上海延伸出去到脑室周围区域被接受。 总之，要理解这部分写的是为了补充在朱庇特的视频引导下，标准化的协议发布（很重要<a href="https://www.jove.com">https://www.jove.com</a> ）。而传统的静态数据有助解释一些概念，基于视频的教程更有效的沟通与参与的综合影像学的管道，如病变Explorer中的复杂方法的过程。

脑部图像分析是神经科学，需要熟练的操作与计算和神经解剖能力的程度大的新兴领域。为了从磁共振成像（MRI）获得定量信息，经过训练的操作来实现，往往需要，监控和编辑，从原材料核磁共振产生计算机生成的图像输出。虽然许多&#39;全自动&#39;成像工具都是免费的通过互联网，准确性和当一个新手操作人员缺乏知识，培训和熟悉的下载工具应用的可靠性是值得怀疑的。虽然现场培训是最可取的教学方法，视频引导下，标准化的协议的演示文稿是一个可行的选择，特别是如果伴随着图像的训练集。此外，可用于质量控制措施，如异地间信度测试图像的训练集。 该通道显影的图像处理流水线，学习老化和阿尔茨海默氏病（AD），特别是当，的allenges包括范围广泛的技术和生物的问题。虽然有些技术问题是由于个体差异和病理过程中解决与后处理校正算法3，变异引入更复杂的障碍。脑萎缩和脑室扩大可以减少注册翘曲和模板匹配的方法的可行性。与年龄相关的白质的存在改变了4和小血管疾病5,6，观察到皮质下高信号（SH）7,8，囊性充满液体的腔隙样梗塞9,10，和扩张血管周围间隙11,12，还复杂分割算法。在显著脑白质病的情况下，单一T1分割可能导致灰质（GM）13，它可以只用一个额外的本身来校正过度估计gmentation使用质子密度（PD），T2加权（T2），或液体衰减反转恢复（FLAIR）成像。鉴于这些挑战，病变总管（LE）的图像处理流水线实现了半自动三要素（T1，帕金森病，T2）的方法，利用训练有素的操作员在特定阶段时的人为干预，优选1,2。 脑提取（或颅骨剥离）通常在神经影像执行的第一操作之一。鉴于此，总的颅内储藏库（TIV）萃取过程的精度极大地影响了随后的操作进一步向下的管道。显著过度侵蚀，导致脑的损失，可能会导致过高估计的脑萎缩。另外，根据侵蚀显著，造成硬脑膜包容和其他非脑物质，可能会导致通货膨胀大脑体积的。 LE的智慧缩放器组件解决许多这些问题通过使用一个三功能（T1，T2和PD）的方法来生成一个TIV面具，这将产生比单功能的方法1骄人的业绩。此外，自动生成TIV面罩人工检查，并使用标准化的协议，该协议确定了区域易受颅骨剥离错误编辑。通用，白质（WM），或脑脊髓液（CSF）：脑提取后，分割在头骨剥离T1，其中，每个脑体素被分配给第3的标签进行的。分割是自动完成的使用应用于全球和局部强度直方图强大的曲线拟合算法;技术开发是为了解决强度不均匀性伪影和反倾销案14通用汽车和WM强度振幅的减小分离。 脑 - 缩放器组件还包括心室和清除幕下结构的手动指定程序。心室CSF（vCSF）的分割是特别重要的，因为心室大小是一种常用的BIOMARKER AD的老年痴呆症15。此外，脑室和脉络丛的划分是必要的正确识别脑室周围白质高信号（pvSH），这被认为是反映小血管病变形式特征的静脉胶原5,16,17的。使用T1仅供参考，脑脊液体素vCSF手动重新贴标签是通过分割图像上手动FLOODFILL操作。通常情况下，侧脑室更容易从脑沟CSF分化。出于这个原因，建议开始实心填充在轴向视图中，从优异的片开始和移动inferiorly。脑室系统，特别是第三脑室，内 ​​侧部件是比较困难的描绘，并给予它们在手册中概述的特殊解剖结构为基础的规则。脑分级机的最后一步包括除去脑干，小脑和其它幕下结构，利用在附加的集合O中所述手动跟踪程序f解剖学为基础的标准化协议。 半自动脑区提取（SABRE）组件是管道的土地分割程序。这个阶段需要训练有素的运营商能够识别下列解剖标志：前，后连合（AC，PC）;后路大脑边缘;中央管;正中矢状平面; preoccipital缺口;枕顶叶沟;中央沟，和;外侧裂。基于这些具有里程碑意义的坐标，塔莱拉什般的18网格自动生成和地区的土地分割是完成19。地标是很容易识别的ACPC对齐图像，这是自动生成的，之前SABRE landmarking程序手动检查。 的病变赛格组分是其中SH鉴定和定量是完成了管道的最后阶段。最初的自动S​​H分割实现复杂的算法，其中包括PD/T2-based SH segme陈述，模糊c-均值掩蔽和脑室扩大。这些操作导致被人工检查和编辑的误报和其他错误自动生成的病灶分割遮罩。由于在MRI高信号，可能导致非病理性的来源（ 如运动伪影，正常生物），需要准确的识别有关的SH适当的训练。 对LE管道的最终结果是一个包含它们parcellated到26 SABRE脑区8个不同的组织和病灶volumetrics全面的容积分布。要获得单个运营商的间信度检验异地，建议执行上提供的软件（http://sabre.brainlab.ca）训练集的完整LE管道。使用的体积的效果，类间相关系数（ICC）20统计可以计算出在每个SABRE区域的每个组织类（GM / WM / CSF）。使用segmentation幅图像，相似性指数（SI）21统计数据可以计算出评估空间一致性程度。此外，内部信度可以在同一个运营商的业绩进行评估，经过一小段时间的运营商的第一和第二分割的编辑之间已经过去了。前提是异地运营商坚持在LE手册中列出的文件命名约定，可靠性统计数据可以使用最基本的统计软件包进行计算场外。鉴于这些质量控制和视频引导标准化的协议，异地运营商可以有更大的信心，LE管道准确，可靠地应用。

<table border="0" cellpadding="0" cellspacing="0" width="815">
	<tbody>
		<tr height="42">
			<td height="42" style="height:42px;width:333px;">Magnetic resonance imaging machine (1.5 Tesla)</td>
			<td style="width:91px;">General Electric</td>
			<td style="width:119px;"></td>
			<td style="width:273px;">See Table 1 for acquisition parameters</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:333px;">Magnetic resonance imaging machine (3 Tesla)</td>
			<td style="width:91px;">General Electric</td>
			<td style="width:119px;"></td>
			<td>See Table 2 for acquisition parameters</td>
		</tr>
	</tbody>
</table>

lesion explorer: a video-guided, standardized protocol for accurate and reliable mri-derived volumetrics in alzheimer's disease and normal elderly

获得在从MRI 活体人脑组织volumetrics通常是由各种技术和生物问题复杂化。这些挑战时显著脑萎缩和老年性白质的变化（ 如脑白质疏松症）的存在而更加恶化。病变资源管理器（LE）是专门为解决对阿尔茨海默氏病和正常老年人的MRI通常观察到这样的问题准确而可靠的影像学管道。这条管道是一组已在一系列内部和外部的可靠性测试1,2预先验证的半自动程序复杂。然而，LE的准确性和可靠性在很大程度上取决于适当的培训手册，操作人员来执行命令，确定不同的解剖标志，并手动编辑/验证各种计算机生成的分割输出。 LE可以分成3个主要部件，每个都需要一组命令和人工操作系统蒸发散：1）脑缩放器，2）SABRE，和3）病变赛格。脑缩放器的手动操作涉及自动颅骨剥离颅内总库（TIV）提取面具，脑室脑脊液（vCSF）称号，并去除幕下结构的编辑。该SABRE组件需要检查沿前，后连合（ACPC）平面图像比对，并确定所需的区域土地分割几个解剖标志。最后，病变赛格部分涉及皮层下高信号（SH）的假阳性错误的自动病灶分割的人工检查。 虽然现场培训的LE管道是可取的，现成的可视化教学工具，互动式训练图像是一个可行的选择。开发，以确保准确性和可靠性程度高，下面是一步一步的，视频引导下，标准化的协议为LE的手工程序。

间信度可以用几个指标进行评估。使用网上提供的（训练集<a href="http://sabre.brainlab.ca">http://sabre.brainlab.ca</a> ），建议采取以下步骤LE完成后，评估间信度为每个处理阶段。 脑缩放器： 为了评估的脑提取程序间信度，产生volumetrics每个TIV-E口罩，&lt;NAME&gt; _TIVedit，使用&lt;img_count&gt;命令。输入这些volumetrics成一个统计软件包（ 如 SPSS），同时还规定了每个训练集的TIVedit volumetrics（在线看提供的Excel / csv文件），并计算出评判间相关系数（ICC）。全脑volumetrics用于内部培训的评定者获得报告的ICC = 0.99，P &lt;0.0001 1,2。此外，空间一致性的TIV掩蔽的评估可使用评估SI 21。 MATLAB代码是在网上提供计算两个评分者之间的SI值。 为了评估心室的重新分配，使用&lt;img_count&gt;命令为每个再分配的vCSF体素， 即分割文件的生成vCSF卷。 &lt;NAME&gt; _ seg_vcsf。该vCSF量排&#39;7卷“，”标题栏下“旁边的值。使用相同的程序，以评估TIV间信度，计算ICC和SI的vCSF。 切除脑干，小脑和幕下结构同样可以通过在&lt;NAME&gt; _seg_vcsf_st运行&lt;img_count&gt;命令进行评估。用于这种分割遮罩的卷显示在标题为“非零体素总数：&#39;倒数第二排在&#39;量&#39;（右边的最后一列）。使用相同的程序，以评估TIV和vCSF，计算ICC和SI这个屏蔽procedu重新使用所提供的excel文件的volumetrics和&lt;NAME&gt; _seg_vcsf_st文件。 SABRE： 而智慧缩放器的手动程序可以很容易地使用标准的指标进行评估，ACPC对准稍微有点难度。出于这个原因，提供了矩阵文件直观地比较非现场培训操作人员。 ACPC对准完成​​后，打开一个新的ITK-SNAP_sb窗口，载入T1图像，然后加载矩阵提供的培训的情况下上网，&lt;NAME&gt; _T1_IHCpre_toACPC.mat，并直观地比较俯仰，滚转，偏航和ACPC片两个图像之间。 为了评估SABRE landmarking程序，对parcellated面膜运行&lt;img_count&gt;，&lt;NAME&gt; _SABREparcel_inACPC对于每个训练案例。输入volumetrics每个区域（​​3-28）。 SABRE区域代码是在网上提供。使用相同的程序，以评估TIV和vCSF，ICC计算每个SABRE大脑区域。SABRE parcellated区域volumetrics用于内部培训的评定者获得报告的平均的ICC = 0.98，P &lt;0.01，与ICC值介于0.91-0.99 1,2。 病变段： 因为这部分是对LE管道的最后阶段，可靠性和精度将取决于之前的阶段。 SH分割间信度是使用SH卷的区域ICC和SH口罩的空间协议的方式完成。评价地区上海卷，运行&lt;SH_volumetrics&gt;，进入无论是在T1采集空间lobmask文件，&lt;NAME&gt; _SABREparcel和最终编辑病灶分割文件，&lt;NAME&gt; _LEedit。使用相同的程序，以评估SABRE volumetrics，ICC计算每个SABRE大脑区域内的病变体积。使用相同的程序来评价TIV掩蔽过程的空间一致性，计算SI为最后编辑病变口罩，&lt;NAME&gt; _LEedit（或FLEXedit）。同样的可靠性测试上都可以PD/T2-based分割和FLAIR序列为基础的分割进行。 <table border="0" cellpadding="0" cellspacing="0"><tbody><tr><td></td><td> 3D T1 </td><td> PD/T2 </td></tr><tr><td> 成像参数 </td><td>轴向体积SAT（S 1）SPGR </td><td>轴向自旋回波FC VEMP VB（交织） </td></tr><tr><td> 脉冲时序 </td><td></td><td></td></tr><tr><td> TE（毫秒） </td><td> 5 </td><td> 30/80 </td></tr><tr><td> TR（毫秒） </td><td> 35 </td><td> 3,000 </td></tr><tr><td>翻转角（°） </td><td> 35 </td><td> 90 </td></tr><tr><td>德州仪器（毫秒） </td><td> N / A </td><td> N / A </td></tr><tr><td> 扫描范围 </td><td></td><td></td></tr><tr><td> FOV（厘米） </td><td> 22 </td><td> 20 </td></tr><tr><td>切片厚度（mm） </td><td> 1.2 / 0 </td><td> 3/0 </td></tr><tr><td>片号</td><td> 124 </td><td> 62 </td></tr><tr><td> 获得 </td><td></td><td></td></tr><tr><td>矩阵大小</td><td> 256×192 </td><td> 256×192 </td></tr><tr><td>体素尺寸（mm） </td><td> 0.86 x 0.86×1.4 </td><td> 0.78×0.78×3 </td></tr><tr><td> NEX </td><td> 1 </td><td> 0.5 </td></tr><tr><td> 总时间（min） </td><td> 11:00 </td><td> 12:00 </td></tr></tbody></table> 表1通用电气1.5T核磁共振结构采集参数。 <table border="0" cellpadding="0" cellspacing="0"><tbody><tr><td></td><td> 3D T1 </td><td> PD/T2 </td><td> FLAIR </td></tr><tr><td> 成像参数 </td><td>轴向3D FSPGR EDR红外线准备</td><td>轴向2D FSE-XL，EDR，快速，脂肪坐</td> &lt;TD&gt;轴向T2Flair，EDR，快速</td></tr><tr><td> 脉冲时序 </td><td></td><td></td><td></td></tr><tr><td><h2> TE（毫秒） </h2></td><td> 3.2 </td><td> 11.1 / 90 </td><td> 140 </td></tr><tr><td> TR（毫秒） </td><td> 8.1 </td><td> 2,500 </td><td> 9,700 </td></tr><tr><td>翻转角（°） </td><td> 8° </td><td> 90° </td><td> 90° </td></tr><tr><td>德州仪器（毫秒） </td><td> 650 </td><td> N / A </td><td> 2,200 </td></tr><tr><td> 扫描范围 </td><td></td><td></td><td></td></tr><tr><td> FOV（厘米） </td><td> 22 </td><td> 22 </td><td> 22 </td></tr><tr><td>切片厚度（mm） </td><td> 1 </td><td> 3 </td><td> 3 </td></tr><tr><td>片号</td><td> 186 </td><td> 48 </td><td> 48 </td></tr><tr><td> 获得 </td><td></td><td></td><td></td></tr><tr><td>矩阵大小</t开发&gt; <td> 256×192 </td><td> 256×192 </td><td> 256×192 </td></tr><tr><td>体素尺寸（mm） </td><td> 0.86 x 0.86×1 </td><td> 0.86 x 0.86×3 </td><td> 0.86 x 0.86×3 </td></tr><tr><td> NEX </td><td> 1 </td><td> 1 </td><td> 1 </td></tr><tr><td> 总时间（min） </td><td> 7:20 </td><td> 6:10 </td><td> 7:20 </td></tr></tbody></table> 表2。通用电气3T磁共振结构采集参数。 <img alt="图1" fo:content-width="5in" src="/files/ftp_upload/50887/50887fig1highres.jpg" width="500" /> 图1。轴向T1与未经编辑的颅内总库（TIV）面膜叠加（绿色），这是利用ITK-SNAP_sb封闭多边形工具，以消除非脑组织作为智慧的手工编辑程序的一部分的一个例子筛的TIV提取过程。 <p类=“jove_content”FO：保持together.within页=“总是”&gt; <img alt="图2" fo:content-width="5in" src="/files/ftp_upload/50887/50887fig2highres.jpg" width="500" /> 轴向T1与组织分割叠加图2。请注意，标签颜色是任意的，并且可以使用标注工具进行修改。左边的图像显示默认颜色。中间的图像显示了脑脊液（5 =紫色）被重新分配到vCSF（7 =洋红色）。右侧图像显示了WM的颜色可以在不改变组织类的标签， 即进行修改。标签3 = WM仍然存在，但颜色可修改成蓝色。 <img alt="图3" fo:content-width="5in" src="/files/ftp_upload/50887/50887fig3highres.jpg" width="500" /> 图3。轴向T1与组织分割叠加（左图，GM =黄色，WM =橙，脑脊液=紫色）（左）。描绘的是使用了封闭polygoÑ工具在ITK- 手工清除幕下结构的一个例子SNAP_sb（中）和删除（右）后的最终组织分割。如在图2中，右侧图像显示了WM的颜色可以在不改变组织类的标签， 即进行修改。标签3 = WM仍然存在，但颜色可修改成蓝色。 <img alt="图4" fo:content-width="5in" src="/files/ftp_upload/50887/50887fig4highres.jpg" width="500" /> 图4。轴向T1中采集空间之前（左）和后（右）的AC-PC对准被执行。 <img alt="图5" fo:content-width="5in" src="/files/ftp_upload/50887/50887fig5highres.jpg" width="500" /> 交流（黄色） 图5。两个例子说明的SABRE landmarking程序。轴向AC-PC对齐T1，PC（蓝色）和后缘（粉红色）标志性存款（左）。三维表面渲染T1（右）与外侧裂（紫色）和分RAL沟（粉红色）的划分。 <img alt="图6" fo:content-width="5in" src="/files/ftp_upload/50887/50887fig6highres.jpg" width="500" /> 图6。轴向帕金森病（左）与自动生成的病灶覆盖（中心），并手动编辑病变（红色）覆盖（右）。 <img alt="图7" fo:content-width="5in" src="/files/ftp_upload/50887/50887fig7highres.jpg" width="500" /> 图7。轴向FLAIR（左），与自动生成的病灶覆盖（中心），并手动编辑病变（红色）覆盖（右）。

Watch this Scientific Journal Video about Lesion Explorer: A Video-guided, Standardized Protocol for Accurate and Reliable MRI-derived Volumetrics in Alzheimer's Disease and Normal Elderly at JoVE.com

Lesion Explorer: A Video-guided, Standardized Protocol for Accurate and Reliable MRI-derived Volumetrics in Alzheimer&#039;s Disease and Normal Elderly

病变资源管理器（LE）为开发以获得区域的脑组织及皮层下高信号病灶volumetrics从阿尔茨海默氏病和正常老年人的结构MRI半自动，图像处理管道。为确保精度和可靠性高的水平，下面是一个视频指导，标准化的协议为LE的手工程序。

病变资源管理器：一个视频引导，标准化为老年痴呆症准确，可靠的MRI衍生Volumetrics和正常老年人协议

Obtaining in vivo human brain tissue volumetrics from MRI is often complicated by various technical and biological issues. These challenges are ...

lesion-explorer-video-guided-standardized-protocol-for-accurate

Research

JoVE Journal

Medicine

Lesion Explorer: A Video-guided, Standardized Protocol for Accurate and Reliable MRI-derived Volumetrics in Alzheimer's Disease and Normal Elderly

39.5K 次观看.  Sunnybrook Health Sciences Centre. 病变资源管理器（LE）为开发以获得区域的脑组织及皮层下高信号病灶volumetrics从阿尔茨海默氏病和正常老年人的结构MRI半自动，图像处理管道。为确保精度和可靠性高的水平，下面是一个视频指导，标准化的协议为LE的手工程序。 

视频: Lesion Explorer: A Video-guided, Standardized Protocol for Accurate and Reliable MRI-derived Volumetrics in Alzheimer's Disease and Normal Elderly

Accurate and Simple Measurement of the Pro-inflammatory Cytokine IL-1&beta; using a Whole Blood Stimulation Assay

Inflammatory processes resulting from the secretion of soluble mediators by immune cells, lead to various manifestations in skin, joints and other tissues as well as altered cytokine homeostasis. The innate immune system plays a crucial role in recognizing pathogens and other endogenous danger stimuli. One of the major cytokines released by innate immune cells is Interleukin (IL)-1. Therefore, we utilize a whole blood stimulation assay in order to measure the secretion of inflammatory cytokines and specifically of the pro-inflammatory cytokine IL-1&beta; 1, 2, 3.
Patients with genetic dysfunctions of the innate immune system causing autoinflammatory syndromes show an exaggerated release of mature IL-1&beta; upon stimulation with LPS alone. In order to evaluate the innate immune component of patients who present with inflammatory-associated pathologies, we use a specific immunoassay to detect cellular immune responses to pathogen-associated molecular patterns (PAMPs), such as the gram-negative bacterial endotoxin, lipopolysaccharide (LPS). These PAMPs are recognized by pathogen recognition receptors (PRRs), which are found on the cells of the innate immune system 4, 5, 6, 7. A primary signal, LPS, in conjunction with a secondary signal, ATP, is necessary for the activation of the inflammasome, a multiprotein complex that processes pro-IL-1&beta; to its mature, bioactive form 4, 5, 6, 8, 9, 10.
The whole blood assay requires minimal sample manipulation to assess cytokine production when compared to other methods that require labor intensive isolation and culturing of specific cell populations. This method differs from other whole blood stimulation assays; rather than diluting samples with a ratio of RPMI media, we perform a white blood cell count directly from diluted whole blood and therefore, stimulate a known number of white blood cells in culture 2. The results of this particular whole blood assay demonstrate a novel technique useful in elucidating patient cohorts presenting with autoinflammatory pathophysiologies.

Accurate and Simple Measurement of the Pro-inflammatory Cytokine IL-1&amp;#946; using a Whole Blood Stimulation Assay

We describe a simple immunoassay to measure the production of pro-inflammatory cytokines, such as IL-1 beta production, in patients presenting with autoinflammatory phenotypes. By activating cells in whole blood cultures with pathogen-associated molecular patterns, specifically with lipopolysaccharide, cytokine secretion can be conveniently evaluated in whole blood supernatants.

使用全血刺激试验的促炎性细胞因子IL -1β的精确和简单的测量

Inflammatory processes resulting from the secretion of soluble mediators by immune cells, lead to various manifestations in skin, joints and other tissues ...

科研

医学

Isolation of Soluble and Insoluble PrP Oligomers in the Normal Human Brain

The central event in the pathogenesis of prion diseases involves a conversion of the host-encoded cellular prion protein PrPC into its pathogenic isoform PrPSc 1. PrPC is detergent-soluble and sensitive to proteinase K (PK)-digestion, whereas PrPSc forms detergent-insoluble aggregates and is partially resistant to PK2-6. The conversion of PrPC to PrPSc is known to involve a conformational transition of &alpha;-helical to &beta;-sheet structures of the protein. However, the in vivo pathway is still poorly understood. A tentative endogenous PrPSc, intermediate PrP* or "silent prion", has yet to be identified in the uninfected brain7.
Using a combination of biophysical and biochemical approaches, we identified insoluble PrPC aggregates (designated iPrPC) from uninfected mammalian brains and cultured neuronal cells8, 9. Here, we describe detailed procedures of these methods, including ultracentrifugation in detergent buffer, sucrose step gradient sedimentation, size exclusion chromatography, iPrP enrichment by gene 5 protein (g5p) that specifically bind to structurally altered PrP forms10, and PK-treatment. The combination of these approaches isolates not only insoluble PrPSc and PrPC aggregates but also soluble PrPC oligomers from the normal human brain. Since the protocols described here have been used to isolate both PrPSc from infected brains and iPrPC from uninfected brains, they provide us with an opportunity to compare differences in physicochemical features, neurotoxicity, and infectivity between the two isoforms. Such a study will greatly improve our understanding of the infectious proteinaceous pathogens. The physiology and pathophysiology of iPrPC are unclear at present. Notably, in a newly-identified human prion disease termed variably protease-sensitive prionopathy, we found a new PrPSc that shares the immunoreactive behavior and fragmentation with iPrPC 11, 12. Moreover, we recently demonstrated that iPrPC is the main species that interacts with amyloid-&beta; protein in Alzheimer disease13. In the same study, these methods were used to isolate Abeta aggregates and oligomers in Alzheimer's disease13, suggesting their application to non-prion protein aggregates involved in other neurodegenerative disorders.

A new species of cellular prion protein (PrPC) has recently been identified in uninfected human brains using the methods described here. These methods can be used to isolate various PrP species, while some of them are also useful in isolating other misfolded protein aggregates from human brains.

在正常人脑分离的可溶性和不溶性朊蛋白低聚物

The central event in the pathogenesis of prion diseases involves a conversion of the host-encoded cellular prion protein PrPC into its pathogenic isoform ...

Parabiosis in Mice: A Detailed Protocol

Parabiosis is a surgical union of two organisms allowing sharing of the blood circulation. Attaching the skin of two animals promotes formation of microvasculature at the site of inflammation. Parabiotic partners share their circulating antigens and thus are free of adverse immune reaction. First described by Paul Bert in 18641, the parabiosis surgery was refined by Bunster and Meyer in 1933 to improve animal survival2. In the current protocol, two mice are surgically joined following a modification of the Bunster and Meyer technique. Animals are connected through the elbow and knee joints followed by attachment of the skin allowing firm support that prevents strain on the sutured skin. Herein, we describe in detail the parabiotic joining of a ubiquitous GFP expressing mouse to a wild type (WT) mouse. Two weeks after the procedure, the pair is separated and GFP positive cells can be detected by flow cytometric analysis in the blood circulation of the WT mouse. The blood chimerism allows one to examine the contribution of the circulating cells from one animal in the other.

Parabiotic joining of two organisms leads to the development of a shared circulatory system. In this protocol, we describe the surgical steps to form a parabiotic connection between a wild-type mouse and a constitutive GFP-expressing mouse.

联体小鼠：一个详细的协议

Parabiosis is a surgical union of two organisms allowing sharing of the blood circulation. Attaching the skin of two animals promotes formation of ...

Fast and Accurate Exhaled Breath Ammonia Measurement

This exhaled breath ammonia method uses a fast and highly sensitive spectroscopic method known as quartz enhanced photoacoustic spectroscopy (QEPAS) that uses a quantum cascade based laser. The monitor is coupled to a sampler that measures mouth pressure and carbon dioxide. The system is temperature controlled and specifically designed to address the reactivity of this compound. The sampler provides immediate feedback to the subject and the technician on the quality of the breath effort. Together with the quick response time of the monitor, this system is capable of accurately measuring exhaled breath ammonia representative of deep lung systemic levels. 
Because the system is easy to use and produces real time results, it has enabled experiments to identify factors that influence measurements. For example, mouth rinse and oral pH reproducibly and significantly affect results and therefore must be controlled. Temperature and mode of breathing are other examples. As our understanding of these factors evolves, error is reduced, and clinical studies become more meaningful. This system is very reliable and individual measurements are inexpensive. 
The sampler is relatively inexpensive and quite portable, but the monitor is neither. This limits options for some clinical studies and provides rational for future innovations.

Ammonia is an important physiologic metabolite relevant to various disease and wellness states. It is also a difficult molecule to measure in breath, which demands particular precautions be taken to obtain accurate results. Not all factors influencing ammonia are known, but progress can be difficult without accounting for these factors.

快速，准确的呼出气测量氨

This exhaled breath ammonia method uses a fast and highly sensitive spectroscopic method known as quartz enhanced photoacoustic spectroscopy (QEPAS) that ...

Experimental and Imaging Techniques for Examining Fibrin Clot Structures in Normal and Diseased States

Fibrin is an extracellular matrix protein that is responsible for maintaining the structural integrity of blood clots. Much research has been done on fibrin in the past years to include the investigation of synthesis, structure-function, and lysis of clots. However, there is still much unknown about the morphological and structural features of clots that ensue from patients with disease. In this research study, experimental techniques are presented that allow for the examination of morphological differences of abnormal clot structures due to diseased states such as diabetes and sickle cell anemia. Our study focuses on the preparation and evaluation of fibrin clots in order to assess morphological differences using various experimental assays and confocal microscopy. In addition, a method is also described that allows for continuous, real-time calculation of lysis rates in fibrin clots. The techniques described herein are important for researchers and clinicians seeking to elucidate comorbid thrombotic pathologies such as myocardial infarctions, ischemic heart disease, and strokes in patients with diabetes or sickle cell disease.

In this manuscript, experimental techniques, including blood preparation, confocal microscopy, and lysis rate analysis, to examine the morphological differences between normal and abnormal clot structures due to diseased states are presented.

对于检查纤维蛋白凝块结构在正常和疾病状态的实验和成像技术

Fibrin is an extracellular matrix protein that is responsible for maintaining the structural integrity of blood clots. Much research has been done on ...

Establishment and Characterization of UTI and CAUTI in a Mouse Model

Urinary tract infections (UTI) are highly prevalent, a significant cause of morbidity and are increasingly resistant to treatment with antibiotics. Females are disproportionately afflicted by UTI: 50% of all women will have a UTI in their lifetime. Additionally, 20-40% of these women who have an initial UTI will suffer a recurrence with some suffering frequent recurrences with serious deterioration in the quality of life, pain and discomfort, disruption of daily activities, increased healthcare costs, and few treatment options other than long-term antibiotic prophylaxis. Uropathogenic Escherichia coli (UPEC) is the primary causative agent of community acquired UTI. Catheter-associated UTI (CAUTI) is the most common hospital acquired infection accounting for a million occurrences in the US annually and dramatic healthcare costs. While UPEC is also the primary cause of CAUTI, other causative agents are of increased significance including Enterococcus faecalis. Here we utilize two well-established mouse models that recapitulate many of the clinical characteristics of these human diseases. For UTI, a C3H/HeN model recapitulates many of the features of UPEC virulence observed in humans including host responses, IBC formation and filamentation. For CAUTI, a model using C57BL/6 mice, which retain catheter bladder implants, has been shown to be susceptible to E. faecalis bladder infection. These representative models are being used to gain striking new insights into the pathogenesis of UTI disease, which is leading to the development of novel therapeutics and management or prevention strategies.

The ability to model urinary tract infections (UTI) is crucial in order to be able to understand bacterial pathogenesis and spawn the development of novel therapeutics. This work&#8217;s goal is to demonstrate mouse models of experimental UTI and catheter associated UTI that recapitulate and predict findings seen in humans.

建立和UTI和CAUTI表征在小鼠模型

Urinary tract infections (UTI) are highly prevalent, a significant cause of morbidity and are increasingly resistant to treatment with antibiotics. ...

Motor and Hippocampal Dependent Spatial Learning and Reference Memory Assessment in a Transgenic Rat Model of Alzheimer's Disease with Stroke

Alzheimer&#39;s disease (AD) is a debilitating neurodegenerative disease that results in neurodegeneration and memory loss. While age is a major risk factor for AD, stroke has also been implicated as a risk factor and an exacerbating factor. The co-morbidity of stroke and AD results in worsened stroke-related motor control and AD-related cognitive deficits when compared to each condition alone. To model the combined condition of stroke and AD, a novel transgenic rat model of AD, with a mutated form of amyloid precursor protein (a key protein involved in the development of AD) incorporated into its DNA, is given a small unilateral striatal stroke.
For a model with the combination of both stroke and AD, behavioral tests that assess stroke-related motor control, locomotion and AD-related cognitive function must be implemented. The cylinder task involves a cost-efficient, multipurpose apparatus that assesses spontaneous forelimb motor use. In this task, a rat is placed in a cylindrical apparatus, where the rat will spontaneously rear and contact the wall of the cylinder with its forelimbs. These contacts are considered forelimb motor use and quantified during video analysis after testing. Another cost-efficient motor task implemented is the beam-walk task, which assesses forelimb control, hindlimb control and locomotion. This task involves a rat walking across a wooden beam allowing for the assessment of limb motor control through analysis of forelimb slips, hindlimb slips and falls. Assessment of learning and memory is completed with Morris water maze for this behavioral paradigm. The protocol starts with spatial learning, whereby the rat locates a stationary hidden platform. After spatial learning, the platform is removed and both short-term and long-term spatial reference memory is assessed. All three of these tasks are sensitive to behavioral differences and completed within 28 days for this model, making this paradigm time-efficient and cost-efficient.

Motor and Hippocampal Dependent Spatial Learning and Reference Memory Assessment in a Transgenic Rat Model of Alzheimer&#039;s Disease with Stroke

To investigate the co-morbid Alzheimer&#39;s disease (AD) and stroke condition in a novel model, three behavior tasks are described that assess both motor control and cognitive behaviors. These tasks include the beam-walk task, cylinder task and Morris water maze.

汽车和海马依赖空间学习和记忆参考评估与中风阿尔茨海默氏病的转基因大鼠模型

Alzheimer&#39;s disease (AD) is a debilitating neurodegenerative disease that results in neurodegeneration and memory loss. While age is a major risk ...

A Step by Step Protocol for Subretinal Surgery in Rabbits

Age related macular degeneration (AMD), retinitis pigmentosa, and other RPE related diseases are the most common causes for irreversible loss of vision in adults in industrially developed countries. RPE transplantation appears to be a promising therapy, as it may replace dysfunctional RPE, restore its function, and thereby vision.
Here we describe a method for transplanting a cultured RPE monolayer on a scaffold into the subretinal space (SRS) of rabbits. After vitrectomy xenotransplants were delivered into the SRS using a custom made shooter consisting of a 20-gauge metallic nozzle with a polytetrafluoroethylene (PTFE) coated plunger. The current technique evolved in over 150 rabbit surgeries over 6 years. Post-operative follow-up can be obtained using non-invasive and repetitive in vivo imaging such as spectral domain optical coherence tomography (SD-OCT) followed by perfusion-fixed histology.
The method has well-defined steps for easy learning and high success rate. Rabbits are considered a large eye animal model useful in preclinical studies for clinical translation. In this context rabbits are a cost-efficient and perhaps convenient alternative to other large eye animal models.

Retinal pigment epithelium (RPE) replacement strategies and gene-based therapy are considered for several retinal degenerative conditions. For clinical translation, large eye animal models are required to study surgical techniques applicable in patients. Here we present a rabbit model for subretinal surgery geared towards RPE transplantation, which is versatile and cost-efficient.

一种用于兔视网膜下手术分步协议

Age related macular degeneration (AMD), retinitis pigmentosa, and other RPE related diseases are the most common causes for irreversible loss of vision in ...

An Intramedullary Locking Nail for Standardized Fixation of Femur Osteotomies to Analyze Normal and Defective Bone Healing in Mice

Bone healing models are essential to the development of new therapeutic strategies for clinical fracture treatment. Furthermore, mouse models are becoming more commonly used in trauma research. They offer a large number of mutant strains and antibodies for the analysis of the molecular mechanisms behind the highly differentiated process of bone healing. To control the biomechanical environment, standardized and well-characterized osteosynthesis techniques are mandatory in mice. Here, we report on the design and use of an intramedullary nail to stabilize open femur osteotomies in mice. The nail, made of medical-grade stainless steel, provides high axial and rotational stiffness. The implant further allows the creation of defined, constant osteotomy gap sizes from 0.00 mm to 2.00 mm. Intramedullary locking nail stabilization of femur osteotomies with gap sizes of 0.00 mm and 0.25 mm result in adequate bone healing through endochondral and intramembranous ossification. Stabilization of femur osteotomies with a gap size of 2.00 mm results in atrophic non-union. Thus, the intramedullary locking nail can be used in healing and non-healing models. A further advantage of the use of the nail compared to other open bone healing models is the possibility to adequately fix bone substitutes and scaffolds in order to study the process of osseous integration. A disadvantage of the use of the intramedullary nail is the more invasive surgical procedure, inherent to all open procedures compared to closed models. A further disadvantage may be the induction of some damage to the intramedullary cavity, inherent to all intramedullary stabilization techniques compared to extramedullary stabilization procedures.

This protocol describes an osteosynthesis technique using an intramedullary locking nail for standardized fixation of femur osteotomies, which can be used to analyze normal and defective bone healing in mice.

髓内锁钉股骨截骨标准化固定用于分析正常和有缺陷的骨愈合小鼠

Bone healing models are essential to the development of new therapeutic strategies for clinical fracture treatment. Furthermore, mouse models are becoming ...

Application of Granger Causality Analysis of the Directed Functional Connection in Alzheimer's Disease and Mild Cognitive Impairment

Impaired functional connectivity in the Default Mode Network (DMN) may be involved in the progression of Alzheimer&#39;s Disease (AD). The Posterior Cingulate Cortex (PCC) is a potential imaging marker for monitoring the progression of AD. Previous studies did not focus on the functional connectivity between the PCC and nodes in regions outside the DMN, but our study is an effort to explore these overlooked functional connections. For collecting data, we used functional Magnetic Resonance Imaging (fMRI) and Granger Causality Analysis (GCA). fMRI provides a non-invasive method for studying the dynamic interactions between the different brain regions. GCA is a statistical hypothesis test for determining whether one-time series is useful in forecasting another. In simple terms, it is judged by comparing the &#34;Known all the information on the last moment, the distribution of the probability of X at this time&#34; and the &#34;Known all the information on the last moment except Y, the distribution of the probability of X at this time&#34;, to determine whether there is a causal relationship between Y and X. This definition is based on the complete information source and stationary chronological sequence. The main step of this analysis is to use X and Y to establish the regression equation and draw a causal relationship by a hypothetical test. Since GCA can measure causal effects, we used it to investigate the anisotropy of the functional connectivity and explore the hub function of the PCC. Here, we screened 116 participants for MRI scanning, and after preprocessing the data obtained from neuroimaging, we used GCA to derive the causal relationship of each node. Finally, we concluded that the directed connection is significantly different between the Mild Cognitive Impairment (MCI) and AD groups, both from the PCC to the whole brain and from the whole brain to the PCC.

Application of Granger Causality Analysis of the Directed Functional Connection in Alzheimer&#039;s Disease and Mild Cognitive Impairment

Based on resting-state functional magnetic resonance imaging with Granger causality analysis, we investigated the alterations in the directed functional connectivity between the posterior cingulate cortex and whole brain in patients with Alzheimer&#39;s Disease (AD), patients with Mild Cognitive Impairment (MCI), and healthy controls.

在阿尔茨海默病和轻度认知功能损害的定向功能连接格兰杰因果关系分析中的应用

Impaired functional connectivity in the Default Mode Network (DMN) may be involved in the progression of Alzheimer&#39;s Disease (AD). The Posterior ...