- 作者列表："De Meo E","Storelli L","Moiola L","Ghezzi A","Veggiotti P","Filippi M","Rocca MA
:The thalamus represents one of the first structures affected by neurodegenerative processes in multiple sclerosis. A greater thalamic volume reduction over time, on its CSF side, has been described in paediatric multiple sclerosis patients. However, its determinants and the underlying pathological changes, likely occurring before this phenomenon becomes measurable, have never been explored. Using a multiparametric magnetic resonance approach, we quantified, in vivo, the different processes that can involve the thalamus in terms of focal lesions, microstructural damage and atrophy in paediatric multiple sclerosis patients and their distribution according to the distance from CSF/thalamus interface and thalamus/white matter interface. In 70 paediatric multiple sclerosis patients and 26 age- and sex-matched healthy controls, we tested for differences in thalamic volume and quantitative MRI metrics-including fractional anisotropy, mean diffusivity and T1/T2-weighted ratio-in the whole thalamus and in thalamic white matter, globally and within concentric bands originating from CSF/thalamus interface. In paediatric multiple sclerosis patients, the relationship of thalamic abnormalities with cortical thickness and white matter lesions was also investigated. Compared to healthy controls, patients had significantly increased fractional anisotropy in whole thalamus (f2 = 0.145; P = 0.03), reduced fractional anisotropy (f2 = 0.219; P = 0.006) and increased mean diffusivity (f2 = 0.178; P = 0.009) in thalamic white matter and a trend towards a reduced thalamic volume (f2 = 0.027; P = 0.058). By segmenting the whole thalamus and thalamic white matter into concentric bands, in paediatric multiple sclerosis we detected significant fractional anisotropy abnormalities in bands nearest to CSF (f2 = 0.208; P = 0.002) and in those closest to white matter (f2 range = 0.183-0.369; P range = 0.010-0.046), while we found significant mean diffusivity (f2 range = 0.101-0.369; P range = 0.018-0.042) and T1/T2-weighted ratio (f2 = 0.773; P = 0.001) abnormalities in thalamic bands closest to CSF. The increase in fractional anisotropy and decrease in mean diffusivity detected at the CSF/thalamus interface correlated with cortical thickness reduction (r range = -0.27-0.34; P range = 0.004-0.028), whereas the increase in fractional anisotropy detected at the thalamus/white matter interface correlated with white matter lesion volumes (r range = 0.24-0.27; P range = 0.006-0.050). Globally, our results support the hypothesis of heterogeneous pathological processes, including retrograde degeneration from white matter lesions and CSF-mediated damage, leading to thalamic microstructural abnormalities, likely preceding macroscopic tissue loss. Assessing thalamic microstructural changes using a multiparametric magnetic resonance approach may represent a target to monitor the efficacy of neuroprotective strategies early in the disease course.
: 丘脑代表了在多发性硬化中受神经变性过程影响的第一个结构之一。在儿童多发性硬化症患者中已经描述了在其CSF侧上随着时间的推移更大的丘脑体积减少。然而，它的决定因素和潜在的病理变化，可能发生在这种现象变得可测量之前，从未被探索过。使用多参数磁共振方法，我们在体内定量了儿童多发性硬化症患者中可能涉及丘脑的局灶性病变、微结构损伤和萎缩的不同过程，以及它们根据与CSF/丘脑界面和丘脑/白质界面的距离的分布。在70名儿童多发性硬化症患者和26名年龄和性别匹配的健康对照中，我们测试了整个丘脑和丘脑白质中丘脑体积和定量MRI指标的差异，包括部分各向异性、平均扩散率和T1/T2-weighted比值，全局和起源于CSF/丘脑界面的同心带内。在儿童多发性硬化患者中，还研究了丘脑异常与皮质厚度和白质病变的关系。与健康对照组相比，患者整个丘脑的各向异性分数显著增加 (f2 = 0.145; P = 0.03)，各向异性分数降低 (f2 = 0.219; P = 0.006)，平均扩散率增加 (f2 = 0.178; P = 0.009) 丘脑白质和丘脑体积减小的趋势 (f2 = 0.027; P = 0.058)。通过将整个丘脑和丘脑白质分割成同心条带，在儿童多发性硬化症中，我们在最接近CSF的条带 (f2 = 0.208; P = 0.002) 和最接近白质的条带 (f2范围 = 0.183-0.369) 中检测到显著的部分各向异性异常; P范围 = 0.010-0.046)，而我们发现显著的平均扩散率(f2范围 = 0.101-0.369; P范围 = 0.018-0.042) 和T1/T2-weighted比值 (f2 = 0.773; P = 0.001) 最接近CSF的丘脑带异常。在CSF/丘脑界面检测到的部分各向异性的增加和平均扩散率的降低与皮质厚度减少相关 (r范围 = -0.27-0.34; P范围 = 0.004-0.028)，而在丘脑/白质界面检测到的各向异性分数增加与白质病变体积相关 (r范围 = 0.24-0.27; P范围 = 0.006-0.050)。在全球范围内，我们的结果支持异质性病理过程的假设，包括脑白质病变的逆行变性和CSF介导的损伤，导致丘脑微结构异常，可能在宏观组织丢失之前。使用多参数磁共振方法评估丘脑微结构变化可能是在病程早期监测神经保护策略功效的目标。
METHODS::The ATP binding-cassette superfamily corresponds the mostly transmembrane transporters family found in humans. These proteins actively transport endogenous and exogenous substrates through biological membranes in body tissues, so they have an important role in the regulation of many physiological functions necessary for human homeostasis, as well as in response regulation to several pharmacological substrates. The development of multidrug resistance has become one of the main troubles in conventional chemotherapy in different illnesses including cancer, being the increased efflux of antineoplastic drugs the main reason for this multidrug resistance, with a key role of the ABC superfamily. Likely, the interindividual variability in the pharmacological response among patients is well known, and may be due to intrinsically factors of the disease, genetic and environmental ones. Thus, the understanding of this variability, especially the genetic variability associated with the efficacy and toxicity of drugs, can provide a safer and more effective pharmacological treatment, so ABC genes are considered as important regulators due to their relationship with the reduction in pharmacological response. In this review, updated information about transporters belonging to this superfamily was collected, the possible role of these transporters in cancer, the role of genetic variability in their genes, as well as some therapeutic tools that have been tried to raise against main transporters associated with chemoresistance in cancer.
METHODS:BACKGROUND:Cholinergic neurotransmission regulates neuroinflammation in Parkinson disease (PD). RESEARCH DESIGN AND METHODS:The authors conducted a delayed-start study of donepezil for cognitive decline in non-demented PD patients. The study consisted of a 96-week randomized placebo-controlled double-blind phase 1, followed by a 24-week donepezil extension phase 2. The primary outcome measure was a change in the Mini-Mental State Examination (MMSE) at week 120. RESULTS:A total of 98 patients were randomly allocated to the early-start (donepezil-to-donepezil) and delayed-start (placebo-to-donepezil) groups. Mean (SD) of the baseline MMSE was 27.6 (2.0) and 28.0 (2.1), respectively. MMSE change at week 120 was better in the early-start group than in the delayed-start group, but the difference was not significant. The MMSE declined in apolipoprotein ε4 carriers, but not in non-carriers, and the factor interaction (intervention × ε4 genotype) was highly significant (P < 0.001). Analyzed with the interaction, the difference was significant (group difference 1.95 [0.33 to 3.57], P = 0.018). The MMSE decline slope in phase 1 was significantly better in the early-start group than in the delayed-start group (P = 0.048). CONCLUSIONS:Cognitive function deteriorated in ε4 carriers, but not in non-carriers, and early-start donepezil may postpone cognitive decline in the former.
METHODS::Since the discovery of dental pulp stem cells, a lot of teams have expressed an interest in dental pulp regeneration. Many approaches, experimental models and biological explorations have been developed, each including the use of stem cells and scaffolds with the final goal being clinical application in humans. In this review, the authors' objective was to compare the experimental models and strategies used for the development of biomaterials for tissue engineering of dental pulp with stem cells. Electronic queries were conducted on PubMed using the following terms: pulp regeneration, scaffold, stem cells, tissue engineering and biomaterial. The extracted data included the following information: the strategy envisaged, the type of stem cells, the experimental models, the exploration or analysis methods, the cytotoxicity or viability or proliferation cellular tests, the tests of scaffold antibacterial properties and take into account the vascularization of the regenerated dental pulp. From the 71 selected articles, 59% focused on the "cell-transplantation" strategy, 82% used in vitro experimentation, 58% in vivo animal models and only one described an in vivo in situ human clinical study. 87% used dental pulp stem cells. A majority of the studies reported histology (75%) and immunohistochemistry explorations (66%). 73% mentioned the use of cytotoxicity, proliferation or viability tests. 48% took vascularization into account but only 6% studied the antibacterial properties of the scaffolds. This article gives an overview of the methods used to regenerate dental pulp from stem cells and should help researchers create the best development strategies for research in this field.