PET measurement of FK506 concentration in a monkey model of stroke

INTRODUCTION: The immunosuppressive agent FK506 (tacrolimus) has neuroprotective properties in an experimental model of cerebral ischemia. To improve the accuracy of clinical studies in acute stroke, a clinical dose setting should be based on the brain concentration, but not on the blood concentration of agents in humans. We have already established a measurement method using PET for FK506 concentration in the normal monkey brain, which could be applicable for human study; however, under ischemic conditions, in this study, we aimed to examine the brain concentration of FK506 in a monkey model of stroke. METHODS: Studies were performed on six male cynomolgus monkeys (Macaca fascicularis) and a middle cerebral artery (MCA) occlusion model was used. Regional cerebral blood flow (rCBF) was measured by an intravenous injection of [(15)O]H(2)O 165 min after MCA occlusion. FK506 (0.1 mg/kg) containing [(11)C]FK506 was intravenously injected into the monkeys 180 min after MCA occlusion, and dynamic PET images were acquired for 30 min after administration. FK506 concentrations in the brain were calculated in moles per liter (M) units using the specific activity of injected FK506. RESULTS: MCA occlusion produced ischemia, confirmed by rCBF measurement before the administration of [(11)C]FK506. Fifteen minutes after FK506 (0.1 mg/kg) administration, the concentrations in the contralateral and ipsilateral cortex were 22.4+/-6.4 and 19.7+/-4.0 ng/g, respectively. CONCLUSION: We successfully measured the brain concentration of FK506 in a monkey model of stroke. The difference between the contralateral and ipsilateral concentrations of FK506 was not significant. This characteristic that FK506 readily penetrates ischemic tissue as well as normal tissue might explain the neuroprotective effect of FK506 in the ischemic brain and is suitable for the treatment of stroke patients.     

First results in an MR imaging--compatible canine model of acute stroke

BACKGROUND AND PURPOSE: The purpose of this work was to develop an MR imaging-compatible animal model of reversible embolic stroke. We hypothesize that real-time MR imaging of the brain can be performed during stroke thrombolysis and can provide real-time feedback and guidance on the success of thrombolysis. METHODS: Embolic strokes were induced in 5 adult dogs by the use of autologous blood clots, with a sixth dog serving as an experimental control. Serial MR anatomic and physiologic imaging was performed to track the evolution of the stroke. The apparent diffusion coefficient (ADC) and quantitative cerebral blood flow (qCBF) were compared in the normal and stroke regions. During and after the administration of a chemical thrombolytic agent, MR imaging was performed to assess the outcome of the treatment. RESULTS: Strokes were successfully created in 5 animals. No ADC or qCBF changes were observed in the control animal. Both ADC and qCBF values were found to be significantly different in the region affected by the stroke. Restoration of flow was observed in 1 case. CONCLUSION: We have successfully implemented an MR imaging-compatible canine model of reversible embolic stroke.     

Comparing two methods for assessment of perfusion-diffusion mismatch in a rodent model of ischaemic stroke: a pilot study

This stroke experiment was designed to define the mismatch between perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) in MRI by applying early or instantly acquired PWI. Eight rats were induced with stroke through photothrombotic occlusion of the middle cerebral artery and scanned serially between 1 h and day 3 after induction using DWI and PWI with a 1.5 T MR scanner. The relative lesion volumes (rLV) on MRI and triphenyl tetrazolium chloride-stained specimens were defined as the proportion of lesion volume over brain volume. Discrepancies in the rLV between PWI- and DWI-derived apparent diffusion coefficient (ADC) maps were expressed by subtraction of the ADC from PWI, resulting in three possible patterns: (i) (PWI-ADC > 10% of PWI) denoting a mismatch; (ii) (-(10% of PWI) 相似文献   

基于MRI DWI的影像组学模型对骨肉瘤新辅助化疗疗效的评估价值

目的 探讨基于MRI弥散加权成像（DWI）的影像组学模型对骨肉瘤新辅助化疗疗效的评估价值。 方法 回顾性分析河北医科大学第三医院2015年6月至2017年11月经术后组织病理学检查结果证实,且在接受新辅助化疗前、后均行MRI检查的41例骨肉瘤患者[男性26例、女性15例,年龄（22.0±11.0）岁,范围11~49岁]的病历及影像资料。根据术后组织病理学检查结果,将肿瘤组织坏死率≥90%者纳入疗效好组,<90%者纳入疗效差组。分别于新辅助化疗前、化疗一期结束后5 d内和完成整个化疗后测量所有患者的表观扩散系数（ADC,分别记为ADC0、ADC1、ADC2,比较疗效好组和疗效差组ADC间的差异。在化疗一期结束后的DWI（b=1000 s/mm2）和ADC图像上手动勾画病灶的感兴趣区,提取影像组学特征,用随机分组法将数据按6∶4的比例分为训练集和测试集,采用SMOTE算法对训练集上的数据进行扩充,采用方差阈值、SelectKBest、最小绝对收缩和选择算子（LASSO）法进行影像组学特征筛选,采用逻辑回归分类器构建出影像组学模型。采用独立样本t检验或Wilcoxon秩和检验进行2组间比较。采用受试者工作特征（ROC）曲线评估传统影像学（ADC）及影像组学模型对骨肉瘤新辅助化疗疗效的预测效能。 结果 疗效好组10例、疗效差组31例。2组患者ADC0的差异无统计学意义[（0.95±0.05）×10−3 mm2/s对（1.05±0.05）×10−3 mm2/s,t=1.14,P>0.05）];疗效好组的ADC1、ADC2高于疗效差组,且差异均有统计学意义[（1.44±0.10）×10−3 mm2/s对（1.10±0.06）×10−3 mm2/s,t=−2.92,P<0.05;1.68（1.55,1.85）×10−3 mm2/s对（1.33±0.06）×10−3 mm2/s,Z=−2.61,P<0.01]。ROC曲线分析结果显示,当ADC1≥1.34×10−3 mm2/s时,其对骨肉瘤新辅助化疗疗效评估的灵敏度为80%,特异度为81%,曲线下面积（AUC）为0.797（95%CI：0.629~0.965）;当ADC2≥1.51×10−3 mm2/s时,其对骨肉瘤新辅助化疗疗效评估的灵敏度为90%,特异度为71%,AUC为0.777（95%CI：0.588~0.967）。从化疗一期结束后的DWI和ADC图像中共提取出1409个影像组学特征,按6∶4的比例随机分为训练集和测试集[24（疗效好：6,疗效坏：18）∶17（疗效好：4,疗效坏：13）],将训练集数据扩充为70（疗效好：20,疗效坏：50）,经影像组学特征筛选后,最终得到5个最优影像组学特征,包括Interquartile Range、Skewness、Uniformity、Median、Maximum。采用逻辑回归分类器构建影像组学模型,训练集中该模型预测骨肉瘤新辅助化疗疗效的ROC曲线的AUC为0.881（95%CI：0.811~0.942）,灵敏度为90%,特异度为74%;测试集中AUC为0.769（95%CI：0.515~0.933）,灵敏度为75%,特异度为69%。 结论 基于MRI DWI的影像组学模型在评估骨肉瘤新辅助化疗疗效中的效能优于传统影像学（ADC）,在临床应用中潜力较大。     

CT灌注原始图像不匹配模型评价急性缺血性脑卒中缺血半暗带和梗死核心的价值

目的 评价CT灌注原始图像(CT perfusion source images,CTP-SI)不匹配模型在判断缺血半暗带和梗死核心中的价值.方法 24例急性缺血性脑卒中患者(发病时间＜9 h)行"一站式急性缺血性脑卒中CT"扫描,分析基线动脉期及静脉期CTP-SI Alberta卒中早期CT评分(Alberta Stroke Program Early CT Score,ASPECTS),并与随访影像ASPECTS进行对照.采用Wilcoxon秩和检验比较动脉期与静脉期CTP-SI ASPECTS之间的统计学差异;应用多元线性回归分析基线动脉期、静脉期CTP-SI与随访影像ASPECTS之间的线件依存关系.结果 基线动脉期、静脉期和随访影像的CTP-SI ASPECTS中位数分别为9.0分(2.0～10.0分)、9.3分(6.5～10.0分)、9.0分(7.0～10.0分).动脉期与静脉期CTP-SI ASPECTS差异有统计学意义(Z=-2.812,P=0.005),10例静脉期CTP-SI ASPECTS大于动脉期,14例静脉期CTP-SI ASPECTS等于动脉期;静脉期CTP-SIASPECTS与随访影像ASPECTS之间的线性依存关系有统计学意义,标准化回归系数(Beta)=0.715,P=0.003.结论 CT灌注原始图像不匹配模型可以预测缺血半暗带和梗死核心,为临床医师制定治疗方案时提供了更多的选择.     

An improved quantitative measurement for thyroid cancer detection based on elastography

Objective

To evaluate color thyroid elastograms quantitatively and objectively.

Materials and methods

125 cases (56 malignant and 69 benign) were collected with the HITACHI Vision 900 system (Hitachi Medical System, Tokyo, Japan) and a liner-array-transducer of 6–13 MHz. Standard of reference was cytology (FNA—fine needle aspiration) or histology (core biopsy). The original color thyroid elastograms were transferred from red, green, blue (RGB) color space to hue, saturation, value (HSV) color space. Then, hard area ratio was defined. Finally, a SVM classifier was used to classify thyroid nodules into benign and malignant. The relation between the performance and hard threshold was fully investigated and studied.

Results

The classification accuracy changed with the hard threshold, and reached maximum (95.2%) at some values (from 144 to 152). It was higher than strain ratio (87.2%) and color score (83.2%). It was also higher than the one of our previous study (93.6%).

Conclusion

The hard area ratio is an important feature of elastogram, and appropriately selected hard threshold can improve classification accuracy.     

Partial-volume effect on ischemic tissue-fate delineation using quantitative perfusion and diffusion imaging on a rat stroke model.

Partial-volume effects (PVE) in stroke imaging could hinder proper delineation of normal, ischemic, and at-risk tissues. Cerebral-blood-flow (CBF) and apparent diffusion coefficient (ADC) were measured at high and low resolution (HR = 128 x 128, LR = 64 x 64) in focal ischemia in rats during the acute phase. The data were evaluated for PVE on ischemic tissue classification on a pixel-by-pixel basis and the misclassified pixels were quantified as ischemia progressed. The main drawbacks of high-resolution imaging are reduced temporal resolution and/or signal-to-noise ratio. The high- versus low-resolution scatterplots and histograms of pixels along the normal-abnormal boundaries in the ADC and CBF maps showed marked ischemia-related PVE. By comparison with the homologous regions in the contralateral normal hemisphere, the effect of increased noise and intrinsic tissue heterogeneity due to high resolution could be distinguished from ischemia-related PVE. Degrading the high-resolution (128 x 128) data to a 64 x 64 or 32 x 32 matrix increased the severity of PVE. Zero-filling of low-resolution (64 x 64) data to 128 x 128 also increased PVE. It was concluded that PVE: (1) misclassified substantial pixels along the normal-abnormal boundaries, (2) overestimated abnormal volumes at the expense of mostly "at-risk" and some "normal" tissues, (3) were more severe at the early time points postischemia, and (4) confounded the interpretation of the operationally defined ischemic penumbra.     

术前基于DWI的阿尔伯塔脑卒中早期CT评分与血管内治疗预后的相关性研究

目的：探讨基于DWI的阿尔伯塔脑卒中早期CT评分（DWI-ASPECTS）与血管内血栓切除预后的相关性,为术前评估脑卒中治疗预后提供新方法。方法：前瞻性选择76例急性缺血性脑卒中（AIS）患者。入院时采用DWI技术划定梗死核心,并记录DWI-ASPECTS（术前评估指标）。所有患者行血管内血栓切除术,记录术后24 h、出院时及出院3个月后的美国国立卫生研究院卒中量表（NIHSS）评分、改良Rankin量表评分、脑梗死溶栓量表评分、治疗延迟时间（OTID）及侧支循环量表评分（预后评估指标）。采用单因素和多因素分析术前评分与预后的相关性。结果：失访8例,有效68例。根据预后各量表评分,血管内治疗24 h后,68例中52例（76.47%）血管内治疗后24 h NIHSS（NIHSS-24）评分明显低于入院时NIHSS评分,8例（11.76%）无改善,另8例（11.76%）恶化,其中3例死亡。NIHSS-24评分与OTID呈正相关。DWI-ASPECTS与侧支循环评分呈正相关（Spearman=0.311,P=0.023）。结论：DWI-ASPECTS有助于评估AIS患者预后,提示其尽早治疗。     

Myocardial metabolism of 123I-BMIPP in a canine model with ischemia: implications of perfusion-metabolism mismatch on SPECT images in patients with ischemic heart disease.

123I-(rho-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) is a fatty acid analog for SPECT imaging. This radiopharmaceutical possesses the unique property, that is, perfusion-metabolism mismatch on SPECT images in patients with ischemic heart disease. However, the reason of this mechanism remains unclear. METHODS: Using open-chest dogs under anesthesia, we made a system to release all the blood of the great cardiac vein outside without recirculation, if necessary. Left anterior descending artery (LAD) was occluded for 30 min after reperfusion. After the injection of BMIPP into LAD, blood samplings from the cardiac vein and abdominal aorta (6 dogs) or serial biopsy specimens from the LAD region (5 dogs) were performed, and then compared with the normal control. The catabolites of BMIPP, including backdiffusion of nonmetabolized BMIPP, were evaluated with high-performance liquid chromatography (HPLC) in the efflux study. Thin-layer chromatography (TLC) technique was introduced in the tissue analytical study. RESULTS: Although the rapid extraction of BMIPP from the plasma into the myocardium and the subsequent retention were unchanged, the early washout (8 min) of radioactivity significantly increased (51% +/- 12% to 65% +/- 7%; P < 0.05) with ischemia. The metabolites from the myocardium consisted of backdiffusion of nonmetabolized BMIPP, alpha, intermediate, and full oxidation metabolites. Among these metabolites, backdiffusion of nonmetabolized BMIPP in blood significantly increased (27.9% +/- 7.7% to 42.3% +/- 8.1%; P < 0.05), especially in the early phase with ischemia. In tissue, the radioactivity was concentrated in the triglyceride pool even in the early phase, and in addition, BMIPP and alpha-oxidized metabolite significantly decreased in the early phase with ischemia (t = 1 min after BMIPP injection, 25.9% +/- 8.6% to 14.5% +/- 2.1%, P < 0.01; t = 2 min, 8.9% +/- 5.0% to 4.5% +/- 1.7%, P < 0.05). CONCLUSION: These results show that backdiffusion of nonmetabolized BMIPP from the myocardium increased and BMIPP (long-chain fatty acids) in tissue decreased with ischemia, suggesting backdiffusion of nonmetabolized BMIPP might play an important role in myocardial perfusion-metabolism mismatch on SPECT images in patients with ischemic heart disease.     

重组葡激酶动静脉溶栓治疗犬急性脑梗死的研究

目的探讨重组葡激酶（r—Sak）溶栓的安全性、有效性以及溶栓的时间窗。方法成年比格犬24条，数字表法随机等分为对照组、r—Sak 6h动脉溶栓组和3h静脉溶栓组。用介入技术建立犬急性脑梗死模型，溶栓前行脑血管造影，分别经动脉和静脉进行治疗（对照组和6h动脉溶栓组：分别在栓塞后6h经颈内动脉注入生理盐水10ml和r—Sak0．2mg／kg＋生理盐水10ml；3h静脉溶栓组：栓塞后3h经静脉注入r—Sak0．2mg／kg＋生理盐水10m1），在溶栓后30、60及120min分别行脑血管造影复查，并在溶栓前30min，溶栓后30、60及120min抽取犬静脉血检测血浆凝血酶原时间（PT）、活化的部分凝血活酶时间（APTT）和D-二聚体。栓塞后24h处死动物行病理检查。结果溶栓后6h动脉溶栓组、3h静脉溶栓组和对照组有效的血管数分别为11支（11／13）、8支（8／11）和1支（1／10），差异有统计学意义（P〈0．01）；其中完全通畅的血管分别是6支（6／13）、2支（2／11）和0支（0／10），差异有统计学意义（P〈0．05），但6h动脉溶栓组和3h静脉溶栓组间有效和完全再通的血管数比较差异均无统计学意义（P=0．630和0．211）。溶栓后PT、APTT在r-Sak溶栓组均显著延长，各组的D-二聚体在溶栓前后无明显变化（P值均〉0．05）。24h后动物均存活，6h动脉和3h静脉溶栓组临床症状较轻，病理检查未发现脑出血并发症。结论r-Sak动脉内6h溶栓治疗安全有效，早期血管再通效果较好。     

Rubidium-82 PET-CT for quantitative assessment of myocardial blood flow: validation in a canine model of coronary artery stenosis

Purpose

Absolute quantification of myocardial blood flow expands the diagnostic potential of PET for assessment of coronary artery disease. ⁸²Rb has significantly contributed to increasing utilization of PET; however, clinical studies are still mostly analysed qualitatively. The aim of this study was to reevaluate the feasibility of ⁸²Rb for flow quantification, using hybrid PET-CT in an animal model of coronary stenosis.

Methods

Nine dogs were prepared with experimental coronary artery stenosis. Dynamic PET was performed for 8 min after ⁸²Rb(1480–1850 MBq) injection during adenosine-induced vasodilation. Microspheres were injected simultaneously for reference flow measurements. CT angiography was used to determine the myocardial regions related to the stenotic vessel. Two methods for flow calculation were employed: a two-compartment model including a spill-over term, and a simplified retention index.

Results

The two-compartment model data were in good agreement with microsphere flow (y?=?0.84x + 0.20; r?=?0.92, p<0.0001), although there was variability in the physiological flow range <3 ml/g per minute (y?=?0.54x + 0.53; r =?0.53, p?=?0.042). Results from the retention index also correlated well with microsphere flow (y?=?0.47x + 0.52; r?=?0.75, p?=?0.0004). Error increased with higher flow, but the correlation was good in the physiological range (y?=?0.62x + 0.29; r?=?0.84, p?=?0.0001).

Conclusion

Using current state-of-the-art PET-CT systems, quantification of myocardial blood flow is feasible with ⁸²Rb. A simplified approach based on tracer retention is practicable in the physiological flow range. These results encourage further testing of the robustness and usefulness in the clinical context of cardiac hybrid imaging.     

Mechanics of the healed meniscus in a canine model

The mechanical behavior of the intact canine stifle joint was studied, using a surgical model of meniscal injury and repair. Thirty-eight animals were divided into five study groups: Group S received only a sham arthrotomy (without a meniscal incision), Groups P13 and P26 received peripheral medial meniscal incisions, and Groups R13 and R26 received radial medial meniscus incisions. All meniscal incisions were repaired anatomically with absorbable suture. Groups P13 and R13 were sacrificed at 13 weeks following surgery and Groups P26 and R26 at 26 weeks. Following sacrifice, the joints were subjected to gross and histologic examination, and structural and material properties testing. All meniscal repairs healed, and the peripheral repairs were virtually invisible, with no articular damage. The radial repairs healed with 3 to 5 mm wide fibrovascular scars, and several joints demonstrated articular erosions. The radial repair tissue contained unorganized collagen bundles and ground substance deficient in mucopolysaccharides. Groups S, P13 and P26 demonstrated no statistically significant differences between test and control limbs in compressive force-displacement behavior, input energy (EI), and ratio of dissipated to input energy (ED/EI). There were significant test-control differences in the load-displacement characteristics of Groups R13 (P less than 0.05) and R26 (P less than 0.05), with the repaired joint stiffer than the control. EI decreased 26% in Group R13 (not significant) and 34% in Group R26 (P less than 0.05), while the ratio ED/EI increased from 27% to 44% in Group R13 (not significant) and from 31% to 38% in Group R26 (P less than 0.05). Medial compartment contact area did not change significantly in either peripheral repair group, but decreased by 25% in Group R13 (P less than 0.05) and by 13% in Group R26 (P less than 0.05). Yield stress, maximum stress, and Young's modulus decreased significantly (P less than 0.05) relative to the controls in tensile tests of the radial repair tissue. There were no significant changes in these properties from 13 to 26 weeks. We concluded that in this animal model, the mechanical function of the meniscus is restored following repair of peripheral longitudinal lesions; however, it appears that in the radial repairs, progressive spreading at the repair site (filled by a fibrovascular scar) altered normal meniscal geometry and structure, adversely influencing mechanical function. Future studies may document whether protective measures (immobilization, limited weightbearing, etc.) can preserve normal mechanical function following repair of radial lesions.     

Renal bleeding: scintigraphic detection in a canine model

The authors evaluated a method of detecting urinary tract bleeding using Tc-99m sulfur colloid in a canine model.     

Temporal evolution of the signal intensity of hyper-acute ischemic lesions in a canine stroke model: influence of hyperintense acute reperfusion marker

Background

To assess the influence of the hyperintense acute reperfusion marker (HARM) on the relative signal intensity (rSI) and apparent diffusion coefficient (ADC) of hyper-acute ischemic lesions in a canine stroke model.

Methods

Middle cerebral artery occlusion models were established using autologous clot embolization. Diffusion-weighted (DW) and fluid-attenuated inversion recovery (FLAIR) imaging was performed at 1, 2, 3, 4.5 and 6 h after embolization. HARM was defined as the delayed enhancement of cerebrospinal fluid on the subsequent FLAIR images after contrast media used.

Results

Twenty-four stroke models were successfully established and divided into the HARM (n = 16) and No-HARM group (n = 8). No significant differences were found in the rSI on DWI (b0 and b1000 map) and relative ADC between the two groups at each time point after embolization (all P > 0.05). There were no significant differences in the rSI on FLAIR at 1 and 2 h after embolization between the two groups (P > 0.05), while the HARM group showed significantly higher rSI on FLAIR than the No-HARM group at 3, 4.5 and 6 h after embolization (P = 0.044, 0.036 and 0.001, respectively).

Conclusions

HARM should be noted during the quantitative analysis of FLAIR images in future clinical practice.