BACKGROUND & AIMS: :The advance of mitral valve repair techniques through tissue engineering is impeded by the lack of information regarding the cellular and extracellular components of the mitral valve. The present study aims to expand our understanding of the mitral valve structure by analysing the synthesis of extracellular matrix (ECM) proteins and the expression of nitric oxide synthase (NOS). Valvular endothelial cells (VECs) and valvular interstitial cells (VICs) were isolated from porcine mitral valves. Immunochemical staining of ECM components, including type I, II, III, IV and V collagen, laminin, fibronectin, elastin and chondroitin sulphate (CS), was performed on both mitral valve tissue and cell cultures. Reverse transcription polymerase chain reaction and immunochemistry were used to analyse NOS expression in native valve and in culture. Both VECs and VICs synthesised the basement membrane components, laminin and type IV collagen both in vivo and in vitro, amongst other fibrous ECM proteins. Synthesis of type I collagen and CS was absent in VEC cultures. Each cell type had a characteristic profile of NOS expression. VECs synthesised endothelial NOS both in vivo and in vitro, with a minority of VICs expressing neuronal NOS in vitro. The present study reports newly recognised aspects of the mitral valve structure and the in vitro behaviour of mitral valve cell populations based on ECM synthesis and NOS expression. The presented profiles can be used as base tools for the generation of data necessary for the selection of ideal cell sources and for the design of appropriate scaffolds for the development of effective tissue-engineered mitral valves.

背景与目标： : 缺乏有关二尖瓣细胞和细胞外成分的信息，阻碍了通过组织工程进行二尖瓣修复技术的发展。本研究旨在通过分析细胞外基质 (ECM) 蛋白的合成和一氧化氮合酶 (NOS) 的表达来扩大我们对二尖瓣结构的理解。从猪二尖瓣分离瓣膜内皮细胞 (VECs) 和瓣膜间质细胞 (VICs)。对二尖瓣组织和细胞培养物进行了ECM成分的免疫化学染色，包括I，II，III，IV和V型胶原蛋白，层粘连蛋白，纤连蛋白，弹性蛋白和硫酸软骨素 (CS)。逆转录聚合酶链反应和免疫化学用于分析天然瓣膜和培养物中NOS的表达。VECs和VICs均在体内和体外合成了基底膜成分，层粘连蛋白和IV型胶原蛋白以及其他纤维ECM蛋白。在VEC培养物中没有I型胶原蛋白和CS的合成。每种细胞类型都有NOS表达的特征。VECs在体内和体外合成了内皮NOS，少数VICs在体外表达神经元NOS。本研究报告了基于ECM合成和NOS表达的二尖瓣结构和二尖瓣细胞群体的体外行为的新认识。所呈现的配置文件可用作基础工具，用于生成选择理想细胞源所需的数据以及设计用于开发有效组织工程二尖瓣的适当支架。

BACKGROUND & AIMS: :Neurons in auditory cortex are sensitive to the probability of stimuli: responses to rare stimuli tend to be stronger than responses to common ones. Here, intra- and extracellular recordings from the auditory cortex of halothane-anesthetized rats revealed the existence of a finer sensitivity to the structure of sound sequences. Using oddball sequences in which the order of stimulus presentations is periodic, we found that tones in periodic sequences evoked smaller responses than the same tones in random sequences. Significant reduction in the responses to the common tones in periodic relative to random sequences occurred even when these tones consisted of 95% of the stimuli in the sequence. The reduction in responses paralleled the complexity of the sound sequences and could not be explained by short-term effects of clusters of deviants on succeeding standards. We conclude that neurons in auditory cortex are sensitive to the detailed structure of sound sequences over timescales of minutes.

背景与目标： : 听觉皮层中的神经元对刺激的可能性敏感: 对罕见刺激的反应往往比对普通刺激的反应更强。在这里，来自氟烷麻醉大鼠的听觉皮层的细胞内和细胞外记录表明，对声音序列结构的敏感性更高。使用刺激呈现顺序是周期性的奇数球序列，我们发现周期性序列中的音调比随机序列中的相同音调引起的响应较小。即使当这些音调由序列中的95% 刺激组成时，相对于随机序列，周期性的对共同音调的响应也会显着降低。响应的减少与声音序列的复杂性平行，不能用异常簇对后续标准的短期影响来解释。我们得出的结论是，听觉皮层中的神经元在几分钟的时间范围内对声音序列的详细结构敏感。

BACKGROUND & AIMS: :Accurate muscle geometry (muscle length and moment arm) is required to estimate muscle function when using musculoskeletal modelling. In shoulder, muscles are often modelled as a collection of independent line segments, leading to non-physiological muscles trajectory, especially for the rotator cuff muscles. To prevent this, a surface mesh model was developed and validated against 7 MRI positions in one participant. Mean moment arm errors was 11.4% for the line vs. 8.8% for the mesh model. While the model with independent lines led to some non-physiological trajectories, the mesh model gave lower misestimations of muscle lengths and moment arms.

背景与目标： : 使用肌肉骨骼模型时，需要准确的肌肉几何形状 (肌肉长度和力矩臂) 来估计肌肉功能。在肩部，肌肉通常被建模为独立线段的集合，从而导致非生理肌肉轨迹，尤其是对于肩袖肌肉。为了防止这种情况，开发了一个表面网格模型，并针对一名参与者的7个MRI位置进行了验证。11.4% 直线的平均力矩臂误差与网格模型的8.8%。虽然具有独立线条的模型导致了一些非生理轨迹，但网格模型对肌肉长度和力矩臂的误判较低。

BACKGROUND & AIMS: :The records of 100 patients (116 hips) with Legg-Calvé-Perthes' (LCP) disease, with a minimum follow-up of 4 years and treated at the University Hospital, Pellenberg, were reviewed. Sex, Salter's, and Catterall's classifications and lateral subluxation were found to be important prognostic indices. Older children tended to do worse than younger children, but statistical significance could not be established. "Head at risk" factors other than lateral subluxation were found to be unimportant as prognostic indices. Salter's classification was found to be simple, accurate, and significant, and could be made quite early. In the future, this should be an important consideration when making decisions on the management of LCP.

背景与目标： : 回顾了100例Legg-Calvé-perthes (LCP) 病患者 (116髋) 的记录，至少随访4年，并在佩伦贝格大学医院接受治疗。性别，Salter和Catterall的分类以及外侧半脱位被发现是重要的预后指标。年龄较大的孩子往往比年龄较小的孩子做得更差，但无法确定统计学意义。发现除外侧半脱位以外的 “处于危险中的头部” 因素作为预后指标并不重要。Salter的分类被发现简单，准确且重要，并且可以很早就进行。将来，在制定LCP管理决策时，这应该是一个重要的考虑因素。

BACKGROUND & AIMS: :In this editorial, we propose that the association between depression and cardiovascular disease may be conceptualised as a continuous, bidirectional process that originates in youth. The paper byÅberg and colleagues in this issue adds to this literature showing that low cardiovascular fitness at adolescence increases the risk of future depression.

背景与目标： : 在这篇社论中，我们建议抑郁症与心血管疾病之间的关联可以概念化为一个持续的，双向的过程，起源于青年。这期的论文by å berg及其同事补充了这些文献，表明青春期心血管健康水平低会增加未来抑郁症的风险。

BACKGROUND & AIMS: :This study examined the validity of commonly used regression equations for the Actigraph and Actical accelerometers in predicting energy expenditure (EE) in children and adolescents. Sixty healthy (8-16 yrs) participants completed four treadmill (TM) and five self-paced activities of daily living (ADL). Four Actigraph (AG) and three Actical (AC) regression equations were used to estimate EE. Bias (± 95% CI) and root mean squared errors were used to assess the validity of the regression equations compared with indirect calorimetry. For children, the Freedson (AG) model accurately predicted EE for all activities combined and the Treuth (AG) model accurately predicted EE for TM activities. For adolescents, the Freedson model accurately predicted EE for TM activities and the Treuth model accurately predicted EE for all activities and for TM activities. No other equation accurately estimated EE. The percent agreement for the AG and AC equations were better for light and vigorous compared with moderate intensity activities. The Trost (AG) equation most accurately classified all activity intensity categories. Overall, equations yield inconsistent point estimates of EE.

背景与目标： : 这项研究检验了Actigraph和Actical加速度计常用回归方程在预测儿童和青少年能量消耗 (EE) 中的有效性。60名健康 (8-16岁) 的参与者完成了四项跑步机 (TM) 和五项日常生活的自定进度活动 (ADL)。使用四个Actigraph (AG) 和三个Actical (AC) 回归方程来估计EE。与间接量热法相比，使用偏差 (± 95% CI) 和均方根误差来评估回归方程的有效性。对于儿童，Freedson (AG) 模型准确地预测了所有组合活动的EE，而Treuth (AG) 模型准确地预测了TM活动的EE。对于青少年，Freedson模型准确地预测了TM活动的EE，而Treuth模型准确地预测了所有活动和TM活动的EE。没有其他方程准确估计EE。与中等强度的活动相比，AG和AC方程的百分比一致性对于光和活力更好。Trost (AG) 方程最准确地对所有活动强度类别进行了分类。总的来说，方程产生不一致的EE点估计。

BACKGROUND & AIMS: OBJECTIVE:This pilot study was a comparison of dimensional models assessing personality traits and personality pathology in a clinical sample of adults diagnosed with ADHD and adults diagnosed with borderline personality disorder (BPD), and a nonclinical control sample of healthy adults. METHOD:Personality traits were assessed using the NEO-Personality Inventory-Revised (NEO-PI-R) and dimensional personality pathology with the Dimensional Assessment of Personality Pathology-Basic Questionnaire (DAPP-BQ). RESULTS:Adults with ADHD and BPD produced higher Emotional Dysregulation/Neuroticism and Dissocial Behavior scores than controls. For the Extraversion/Inhibitedness scale, adults with BPD produced significantly lower scores than adults with ADHD and controls. On the Conscientiousness/Compulsivity domains, Conscientiousness scores were lower for both disorders, whereas low Compulsivity values were specific to adult ADHD. CONCLUSION:Our results suggest that patients with adult ADHD and BPD have distinguishable profiles of personality traits and personality pathology.

背景与目标：

BACKGROUND & AIMS: :By regulatory authorities the rat is considered to be a suitable animal model to predict the percutaneous absorption of hazardous substances in humans. In our study, the percutaneous penetration of 2-butoxyethanol (BE) and toluene was compared in different rat models. Intradermal microdialysis and static diffusion cells were used in in vivo and in vitro experiments with haired Wistar and hairless Lewis rats. Microdialysis experiments showed a steady-state penetration for BE and a penetration maximum for toluene in both rat strains at approximately 60 min after beginning of exposure. However, in diffusion cell experiments the penetration of the test compounds in both rat strains increased until the end of exposure (4 h). Additionally, in microdialysis experiments BE penetrated in hairless rats in a higher amount than in haired rats (factor: 1.4; P < 0.01), for toluene it was just the opposite (factor: 1.9; P < 0.001). In diffusion cell experiments, the penetrated amounts of both compounds were higher in hairless rats compared to haired rats. The fluxes for BE were in diffusion cell experiments at a factor of 14.5 (haired rat) and 18.1 (hairless rat) higher than in microdialysis experiments, the difference factor for toluene was 2.6 (haired rat) and 12.9 (hairless rat). The lag times indicate a significantly faster penetration in microdialysis experiments compared with diffusion cell experiments (P < 0.001). There are great differences in percutaneous penetration behaviour between the techniques and the rat strains. The diffusion cell method has difficulties to describe the percutaneous penetration kinetics, whereas microdialysis describes it more reliable. Due to these differences the reliability of a conversion factor for the transfer of percutaneous absorption data from rat to human skin, as proposed in the literature, is questionable.

背景与目标： : 监管机构认为该大鼠是预测人体内有害物质经皮吸收的合适动物模型。在我们的研究中，比较了2-丁氧基乙醇 (BE) 和甲苯在不同大鼠模型中的经皮渗透。皮内微透析和静态扩散细胞用于有毛Wistar和无毛Lewis大鼠的体内和体外实验。微透析实验显示，在暴露开始后约60分钟，两种大鼠菌株中BE的稳态渗透和甲苯的最大渗透。然而，在扩散细胞实验中，测试化合物在两种大鼠品系中的渗透增加，直到暴露结束 (4小时)。此外，在微透析实验中，无毛大鼠的渗透量高于毛发大鼠 (因子: 1.4; P <0.01)，对于甲苯则相反 (因子: 1.9; P <0.001)。在扩散细胞实验中，与无毛大鼠相比，无毛大鼠中两种化合物的渗透量更高。在扩散池实验中，BE的通量为14.5 (毛大鼠) 和18.1 (无毛大鼠) 高于微透析实验中的系数，甲苯的差异系数为2.6 (毛大鼠) 和12.9 (无毛大鼠)。滞后时间表明与扩散池实验相比，微透析实验中的渗透明显更快 (P <0.001)。该技术与大鼠品系之间的经皮穿透行为存在很大差异。扩散池方法难以描述经皮渗透动力学，而微透析则描述其更可靠。由于这些差异，如文献中所述，将经皮吸收数据从大鼠转移到人皮肤的转换因子的可靠性值得怀疑。

BACKGROUND & AIMS: :Bilateral synchronous epileptiform discharges registered in patients with partial epilepsies may be generated by different pathophysiological mechanisms. Differentiation between underlying mechanisms is often crucial for correct diagnosis and adequate treatment in clinical epileptology. The aim of this study was to model in rats two possible mechanisms--secondary bilateral sychrony and interaction between multiple epilepic foci. Furthermore, to describe in detail semiology, laterality and differences in motor phenomena. Secondary bilateral synchrony was modeled by unilateral topical application of bicuculline methiodide (BMI) over the sensorimotor cortex. Bilateral symmetric application of BMI was used as a model of multiple epileptic foci. Electrographic and behavioural phenomena were recorded for 1h following the application of BMI. Electroencephalogram in both groups was characterized by presence of bilateral synchronous discharges. Myoclonic and clonic seizures involving forelimb and head muscles represented the most common motor seizure pattern in both groups. Significant differences were found in the laterality of motor phenomena. Motor seizures in unilateral foci always started in the contralateral limbs whereas symmetrical foci exhibited bilateral independent onset of convulsions. Similar lateralization was observed in interictal motor phenomena (myoclonic jerks). An important influence of posture on epileptic motor phenomena was demonstrated. Active or passive changes in animal posture (verticalization to bipedal posture) caused conversion from unilateral myoclonic jerks or clonic seizures to bilaterally synchronous (generalized) motor phenomena in both groups.

背景与目标： : 部分性癫痫患者的双侧同步癫痫样放电可能是由不同的病理生理机制产生的。潜在机制之间的区分对于临床表皮病的正确诊断和适当治疗通常至关重要。这项研究的目的是在大鼠中建立两种可能的机制-继发性双侧粘连和多个表位灶之间的相互作用。此外，要详细描述符号学，偏侧性和运动现象的差异。次级双侧同步性是通过在感觉运动皮层上单方面局部应用双苏氨酸甲碘化物 (BMI) 来模拟的。双侧对称应用BMI被用作多个癫痫灶的模型。应用BMI后1小时记录了电学和行为现象。两组的脑电图均以双侧同步放电为特征。涉及前肢和头部肌肉的肌阵挛和阵挛性癫痫发作是两组中最常见的运动癫痫发作模式。在运动现象的偏侧性方面发现了显着差异。单侧病灶的运动性癫痫发作总是在对侧肢体开始，而对称性病灶表现出双侧独立的抽搐发作。在发作间运动现象 (肌阵挛抽搐) 中观察到类似的偏侧化。证明了姿势对癫痫运动现象的重要影响。动物姿势的主动或被动变化 (垂直化为两足姿势) 导致两组患者从单侧肌阵挛抽搐或阵挛性癫痫发作转变为双侧同步 (广义) 运动现象。

BACKGROUND & AIMS: :It is becoming increasingly clear that the genetic background of mice and rats, even in inbred strains, can have a profound influence on measures of seizure susceptibility and epilepsy. These differences can be capitalized upon through genetic mapping studies to reveal genes important for seizures and epilepsy. However, strain background and particularly mixed genetic backgrounds of transgenic animals need careful consideration in both the selection of strains and in the interpretation of results and conclusions. For instance, mice with targeted deletions of genes involved in epilepsy can have profoundly disparate phenotypes depending on the background strain. In this review, we discuss findings related to how this genetic heterogeneity has and can be utilized in the epilepsy field to reveal novel insights into seizures and epilepsy. Moreover, we discuss how caution is needed in regards to rodent strain or even animal vendor choice, and how this can significantly influence seizure and epilepsy parameters in unexpected ways. This is particularly critical in decisions regarding the strain of choice used in generating mice with targeted deletions of genes. Finally, we discuss the role of environment (at vendor and/or laboratory) and epigenetic factors for inter- and intrastrain differences and how such differences can affect the expression of seizures and the animals' performance in behavioral tests that often accompany acute and chronic seizure testing.

背景与目标： : 越来越清楚的是，即使在近交品系中，小鼠和大鼠的遗传背景也可能对癫痫发作易感性和癫痫的测量产生深远的影响。这些差异可以通过基因图谱研究来利用，以揭示对癫痫发作和癫痫重要的基因。然而，在菌株的选择以及结果和结论的解释中，需要仔细考虑菌株的背景，尤其是转基因动物的混合遗传背景。例如，根据背景菌株，具有与癫痫有关的基因靶向缺失的小鼠可能具有截然不同的表型。在这篇综述中，我们讨论了与这种遗传异质性如何具有并可以在癫痫领域中使用的发现，以揭示对癫痫发作和癫痫的新见解。此外，我们讨论了在啮齿动物菌株甚至动物供应商的选择方面如何谨慎，以及这如何以意想不到的方式显着影响癫痫发作和癫痫参数。这在决定用于产生具有靶向基因缺失的小鼠的选择菌株方面尤为重要。最后，我们讨论环境 (在供应商和/或实验室) 和表观遗传因素对菌株间和内差异的作用，以及这些差异如何影响癫痫发作的表达和动物在行为测试中的表现，通常伴随急性和慢性癫痫发作测试。

BACKGROUND & AIMS: :Why dopamine-containing neurons of the brain's substantia nigra pars compacta die in Parkinson's disease has been an enduring mystery. Our studies suggest that the unusual reliance of these neurons on L-type Ca(v)1.3 Ca2+ channels to drive their maintained, rhythmic pacemaking renders them vulnerable to stressors thought to contribute to disease progression. The reliance on these channels increases with age, as juvenile dopamine-containing neurons in the substantia nigra pars compacta use pacemaking mechanisms common to neurons not affected in Parkinson's disease. These mechanisms remain latent in adulthood, and blocking Ca(v)1.3 Ca2+ channels in adult neurons induces a reversion to the juvenile form of pacemaking. Such blocking ('rejuvenation') protects these neurons in both in vitro and in vivo models of Parkinson's disease, pointing to a new strategy that could slow or stop the progression of the disease.

背景与目标： : 为什么大脑黑质的含多巴胺神经元在帕金森氏病中死亡一直是一个持久的谜。我们的研究表明，这些神经元对L型Ca(v)1.3 Ca2通道的异常依赖，以驱动其维持的节律性起搏，使其容易受到被认为有助于疾病进展的应激源的影响。对这些通道的依赖随着年龄的增长而增加，因为黑质致密部中含有多巴胺的少年神经元使用了帕金森氏病未受影响的神经元常见的起搏机制。这些机制在成年期仍然是潜在的，并且在成年神经元中阻断Ca(v)1.3 Ca2通道会导致恢复到幼年的起搏形式。这种阻断 (“恢复活力”) 在帕金森氏病的体外和体内模型中保护这些神经元，这表明了一种可以减缓或阻止疾病进展的新策略。

BACKGROUND & AIMS: :Water plays an active role in many fundamental phenomena in cellular systems such as molecular recognition, folding and conformational equilibria, reaction kinetics and phase partitioning. Hence, our ability to account for the energetics of these processes is highly dependent on the models we use for calculating solvation effects. For example, theoretical prediction of protein-ligand binding modes (i.e., docking) and binding affinities (i.e., scoring) requires an accurate description of the change in hydration that accompanies solute binding. In this review, we discuss the challenges of constructing solvation models that capture these effects, with an emphasis on continuum models and on more recent developments in the field. In our discussion of methods, relatively greater attention will be given to boundary element solutions to the Poisson equation and to nonpolar solvation models, two areas that have become increasingly important but are likely to be less familiar to many readers. The other focus will be upon the trending efforts for evaluating solvation models in order to uncover limitations, biases, and potentially attractive directions for their improvement and applicability. The prospective and retrospective performance of a variety of solvation models in the SAMPL blind challenges will be discussed in detail. After just a few years, these benchmarking exercises have already had a tangible effect in guiding the improvement of solvation models.

背景与目标： : 水在细胞系统中的许多基本现象中起着积极作用，例如分子识别，折叠和构象平衡，反应动力学和相分配。因此，我们解释这些过程的能量学的能力在很大程度上取决于我们用于计算溶剂化效应的模型。例如，蛋白质-配体结合模式 (即对接) 和结合亲和力 (即评分) 的理论预测需要准确描述伴随溶质结合的水合变化。在这篇综述中，我们讨论了构建捕获这些影响的溶剂化模型的挑战，重点是连续模型和该领域的最新发展。在我们对方法的讨论中，将相对更多地关注泊松方程的边界元解和非极性溶剂化模型，这两个领域已变得越来越重要，但许多读者可能不太熟悉。另一个重点将放在评估溶剂化模型的趋势上，以发现局限性，偏见以及其改进和适用性的潜在吸引力方向。将详细讨论SAMPL盲挑战中各种溶剂化模型的前瞻性和回顾性表现。短短几年后，这些基准测试工作已经在指导溶剂化模型的改进方面产生了切实的效果。

BACKGROUND & AIMS: :Twenty first century systems toxicology approaches enable the discovery of biological pathways affected in response to active substances. Here, we briefly summarize current network approaches that facilitate the detailed mechanistic understanding of the impact of a given stimulus on a biological system. We also introduce our network-based method with two use cases and show how causal biological network models combined with computational methods provide quantitative mechanistic insights. Our approach provides a robust comparison of the transcriptional responses in different experimental systems and enables the identification of network-based biomarkers modulated in response to exposure. These advances can also be applied to pharmacology, where the understanding of disease mechanisms and adverse drug effects is imperative for the development of efficient and safe treatment options.

背景与目标： : 二十一世纪系统毒理学方法能够发现对活性物质有反应的生物途径。在这里，我们简要总结了当前的网络方法，这些方法有助于对给定刺激对生物系统的影响进行详细的机械理解。我们还通过两个用例介绍了基于网络的方法，并展示了因果生物网络模型与计算方法的结合如何提供定量的机械见解。我们的方法提供了不同实验系统中转录反应的可靠比较，并能够识别响应于暴露而调制的基于网络的生物标志物。这些进展也可以应用于药理学，在药理学中，了解疾病机制和药物不良反应对于开发有效和安全的治疗选择至关重要。

BACKGROUND & AIMS: :Application of functional imaging techniques to animal models is vital to understand pain mechanisms, but is often confounded by the need to limit movement artefacts with anaesthesia, and a focus on evoked responses rather than clinically relevant spontaneous pain and related hyperalgesia. The aim of the present study was to investigate the potential of manganese-enhanced magnetic resonance imaging (MEMRI) to measure neural responses during on-going pain that underpins hyperalgesia in pre-clinical models of nociception. As a proof of concept that MEMRI is sensitive to the neural activity of spontaneous, intermittent behaviour, we studied a separate positive control group undergoing a voluntary running wheel experiment. In the pain models, pain behaviour (weight bearing asymmetry and hindpaw withdrawal thresholds (PWTs)) was measured at baseline and following either intra-articular injection of nerve growth factor (NGF, 10µg/50µl; acute pain model, n=4 rats per group), or the chondrocyte toxin monosodium iodoacetate (MIA, 1mg/50µl; chronic model, n=8 rats per group), or control injection. Separate groups of rats underwent a voluntary wheel running protocol (n=8 rats per group). Rats were administered with paramagnetic ion Mn2+ as soluble MnCl2 over seven days (subcutaneous osmotic pump) to allow cumulative activity-dependent neural accumulation in the models of pain, or over a period of running. T1-weighted MR imaging at 7T was performed under isoflurane anaesthesia using a receive-only rat head coil in combination with a 72mm volume coil for excitation. The pain models resulted in weight bearing asymmetry (NGF: 20.0 ± 5.2%, MIA: 15 ± 3%), and a reduction in PWT in the MIA model (8.3 ± 1.5g) on the final day of assessment before undergoing MR imaging. Voxel-wise and region-based analysis of MEMRI data did not identify group differences in T1 signal. However, MnCl2 accumulation in the VTA, right Ce amygdala, and left cingulate was negatively correlated with pain responses (greater differences in weight bearing), similarly MnCl2 accumulation was reduced in the VTA in line with hyperalgesia (lower PWTs), which suggests reduced regional activation as a result of the intensity and duration of pain experienced during the 7 days of MnCl2 exposure. Motor cortex T1-weighted signal increase was associated with the distance ran in the wheel running study, while no between group difference was seen. Our data suggest that on-going pain related signal changes identified using MEMRI offers a new window to study the neural underpinnings of spontaneous pain in rats.

背景与目标： : 将功能成像技术应用于动物模型对于了解疼痛机制至关重要，但通常由于需要限制麻醉的运动伪影，并且关注诱发反应而不是临床相关的自发性疼痛和相关的痛觉过敏而感到困惑。本研究的目的是研究锰增强磁共振成像 (MEMRI) 在持续疼痛期间测量神经反应的潜力，这种疼痛是伤害感受的临床前模型中痛觉过敏的基础。为了证明MEMRI对自发的间歇性行为的神经活动敏感，我们研究了一个单独的阳性对照组，并进行了自愿的跑步轮实验。在疼痛模型中，在基线和关节内注射神经生长因子 (NGF，10 µ g/50 µ l; 急性疼痛模型，每组n = 4只大鼠) 后测量疼痛行为 (负重不对称和后爪戒断阈值 (PWTs))，或软骨细胞毒素碘乙酸单钠 (MIA，1mg/50 µ l; 慢性模型，每组n = 8只大鼠) 或对照注射。不同组的大鼠接受了自愿轮跑方案 (每组n = 8只大鼠)。在7天内 (皮下渗透泵) 给大鼠以顺磁性离子Mn2作为可溶性MnCl2，以允许在疼痛模型中或在一段时间内累积活动依赖性神经积累。在异氟醚麻醉下，使用仅接收的大鼠头线圈和72毫米体积线圈进行激发，在7t下进行T1-weighted MR成像。疼痛模型导致负重不对称 (NGF: 20.0 ± 5.2%，MIA: 15 ± 3%)，并且在进行MR成像之前的评估的最后一天，MIA模型中的PWT降低 (8.3 ± 1.5g)。对MEMRI数据进行的体素分析和基于区域的分析未识别T1信号的组差异。然而，VTA，右Ce杏仁核和左扣带回中的MnCl2积累与疼痛反应呈负相关 (负重差异更大)，类似地，VTA中的MnCl2积累与痛觉过敏 (较低的PWTs) 相一致，这表明由于MnCl2暴露7天期间经历的疼痛强度和持续时间导致区域激活减少。在车轮运行研究中，运动皮层T1-weighted信号的增加与行驶距离有关，而组之间没有差异。我们的数据表明，使用MEMRI识别出的与疼痛相关的持续信号变化为研究大鼠自发性疼痛的神经基础提供了新的窗口。

BACKGROUND & AIMS: :Drug concentrations in one-compartment systems are frequently modeled using a single exponential function. Two methods of estimation are commonly used for determining the parameters of such a model. In the first method, non-linear least-squares regression is used to calculate the parameters. In the second method, the data are first transformed by a logarithmic function, and then the log-concentration data are fit using linear least-squares regression. The assumptions for fitting these models are discussed with special emphasis on which data points are most influential in determining parameter values. The similarities between fitting a linear regression model to the log-concentration data and fitting a weighted regression model to the original data are noted. An example is presented that illustrates the differences in fitting a model to the log-transformed data versus fitting unweighted and weighted models to the original-scale data.

背景与目标： : 单室系统中的药物浓度通常使用单个指数函数进行建模。通常使用两种估计方法来确定此类模型的参数。在第一种方法中，使用非线性最小二乘回归来计算参数。在第二种方法中，首先通过对数函数对数据进行变换，然后使用线性最小二乘回归对对数浓度数据进行拟合。讨论了拟合这些模型的假设，并特别强调了哪些数据点对确定参数值最有影响。注意将线性回归模型拟合到对数浓度数据与将加权回归模型拟合到原始数据之间的相似性。给出了一个示例，该示例说明了将模型拟合到对数转换数据与将未加权和加权模型拟合到原始比例数据的差异。