• 【评估阿尔茨海默氏病的遗传结构在记忆力下降的风险。】 复制标题 收藏 收藏
    DOI:10.3233/JAD-170834 复制DOI
    作者列表:Del-Aguila JL,Fernández MV,Schindler S,Ibanez L,Deming Y,Ma S,Saef B,Black K,Budde J,Norton J,Chasse R,Alzheimer’s Disease Neuroimaging Initiative (ADNI).,Harari O,Goate A,Xiong C,Morris JC,Cruchaga C
    BACKGROUND & AIMS: :Many genetic studies for Alzheimer's disease (AD) have been focused on the identification of common genetic variants associated with AD risk and not on other aspects of the disease, such as age at onset or rate of dementia progression. There are multiple approaches to untangling the genetic architecture of these phenotypes. We hypothesized that the genetic architecture of rate of progression is different than the risk for developing AD dementia. To test this hypothesis, we used longitudinal clinical data from ADNI and the Knight-ADRC at Washington University, and we calculated PRS (polygenic risk score) based on the IGAP study to compare the genetic architecture of AD risk and dementia progression. Dementia progression was measured by the change of Clinical Dementia Rating Sum of Boxes (CDR)-SB per year. Out of the 21 loci for AD risk, no association with the rate of dementia progression was found. The PRS rate was significantly associated with the rate of dementia progression (β= 0.146, p = 0.03). In the case of rare variants, TREM2 (β= 0.309, p = 0.02) was also associated with the rate of dementia progression. TREM2 variant carriers showed a 23% faster rate of dementia compared with non-variant carriers. In conclusion, our results indicate that the recently identified common and rare variants for AD susceptibility have a limited impact on the rate of dementia progression in AD patients.
    背景与目标: : 许多针对阿尔茨海默氏病 (AD) 的遗传学研究都集中在与AD风险相关的常见遗传变异的鉴定上,而不是该疾病的其他方面,例如发病年龄或痴呆进展速度。有多种方法可以解开这些表型的遗传结构。我们假设进展速度的遗传结构与发生AD痴呆的风险不同。为了验证这一假设,我们使用了来自ADNI和华盛顿大学Knight-ADRC的纵向临床数据,并基于IGAP研究计算了PRS (多基因风险评分),以比较AD风险和痴呆进展的遗传结构。通过每年临床痴呆评分总和 (CDR)-SB的变化来衡量痴呆的进展。在21个AD风险位点中,未发现与痴呆进展率相关。PRS率与痴呆进展率显著相关 (β =   0.146,p   =   0.03)。在罕见变异的情况下,TREM2 (β =   0.309,p   =   0.02) 也与痴呆的进展率相关。与非变异携带者相比,TREM2变异携带者的痴呆发生率23% 快。总之,我们的结果表明,最近发现的AD易感性的常见和罕见变异对AD患者痴呆进展率的影响有限。
  • 【通过非欧几里得小波的多分辨率形状特征: 在皮层厚度统计分析中的应用。】 复制标题 收藏 收藏
    DOI:10.1016/j.neuroimage.2014.02.028 复制DOI
    作者列表:Kim WH,Singh V,Chung MK,Hinrichs C,Pachauri D,Okonkwo OC,Johnson SC,Alzheimer's Disease Neuroimaging Initiative.
    BACKGROUND & AIMS: :Statistical analysis on arbitrary surface meshes such as the cortical surface is an important approach to understanding brain diseases such as Alzheimer's disease (AD). Surface analysis may be able to identify specific cortical patterns that relate to certain disease characteristics or exhibit differences between groups. Our goal in this paper is to make group analysis of signals on surfaces more sensitive. To do this, we derive multi-scale shape descriptors that characterize the signal around each mesh vertex, i.e., its local context, at varying levels of resolution. In order to define such a shape descriptor, we make use of recent results from harmonic analysis that extend traditional continuous wavelet theory from the Euclidean to a non-Euclidean setting (i.e., a graph, mesh or network). Using this descriptor, we conduct experiments on two different datasets, the Alzheimer's Disease NeuroImaging Initiative (ADNI) data and images acquired at the Wisconsin Alzheimer's Disease Research Center (W-ADRC), focusing on individuals labeled as having Alzheimer's disease (AD), mild cognitive impairment (MCI) and healthy controls. In particular, we contrast traditional univariate methods with our multi-resolution approach which show increased sensitivity and improved statistical power to detect a group-level effects. We also provide an open source implementation.
    背景与目标: : 对任意表面网格 (例如皮质表面) 进行统计分析是了解脑部疾病 (例如阿尔茨海默氏病 (AD)) 的重要方法。表面分析可能能够识别与某些疾病特征相关或表现出组间差异的特定皮质模式。本文的目标是使表面信号的组分析更加敏感。为此,我们推导了多尺度形状描述符,这些描述符以不同的分辨率水平表征每个网格顶点 (即其局部上下文) 周围的信号。为了定义这样的形状描述符,我们利用谐波分析的最新结果,将传统的连续小波理论从欧几里得扩展到非欧几里得设置 (即图,网格或网络)。使用此描述符,我们在两个不同的数据集上进行实验,即阿尔茨海默氏病神经成像计划 (ADNI) 数据和在威斯康星州阿尔茨海默氏病研究中心 (w-adrc) 获得的图像,重点是标记为患有阿尔茨海默氏病 (AD) 的个体,轻度认知障碍 (MCI) 和健康对照。特别是,我们将传统的单变量方法与我们的多分辨率方法进行了对比,后者显示出更高的灵敏度和更高的统计能力来检测组水平的影响。我们还提供了一个开源实现。
  • 【自体脂肪再生细胞的治疗性血管生成: 与骨髓单核细胞的比较。】 复制标题 收藏 收藏
    DOI:10.1152/ajpheart.00310.2014 复制DOI
    作者列表:Hao C,Shintani S,Shimizu Y,Kondo K,Ishii M,Wu H,Murohara T
    BACKGROUND & AIMS: :Transplantation of adipose-derived regenerative cell (ADRC) enhances ischemia-induced angiogenesis, but the underlying mechanism remains unknown. Here, we compared the efficacy between ADRC and bone marrow mononuclear cell (BM-MNC) transplantation in rabbits model of hindlimb ischemia and examined the possible roles of alternative phenotypic macrophages polarization in ADRC-mediated angiogenesis using mice model of hindlimb ischemia. ADRCs and BM-MNCs were isolated from New Zealand White rabbits and C57BL/6J mice. In rabbit studies, our data showed that ADRCs could incorporate into the endothelial vasculature in vitro and in vivo. Both ADRC-conditioned media (CM) and BM-MNC-CM enhanced the migratory ability and interrupted the process of apoptosis in human umbilical vein endothelial cells. Four weeks after cell transplantation, augmentation of postnatal neovascularization was observed in the ischemic muscle injected with either ADRCs or BM-MNCs. In mice studies, we presented that ADRCs polarized into the IL-10-releasing M2 macrophages through PGE2-EP2/4 axis and suppressed the expressions of TNF-α and IL-6 in the ischemic muscle. Gene expressions of several angiogenic cytokines were amplified in the macrophages cultured in ADRC-CM rather than BM-MNC-CM. Blockade of IL-10 using neutralizing MAb attenuated the ADRC-mediated angiogenesis and caused muscle apoptosis in vivo. In conclusion, ADRC transplantation harvested similar effect of neovascularization augmentation compared with BM-MNC in experimental rabbit model of hindlimb ischemia; ADRC displayed a unique immunoregulatory manner of accelerating IL-10-releasing M2 macrophages polarization through the PGE2-EP2/4 axis.
    背景与目标: 脂肪来源的再生细胞 (ADRC) 的移植增强了缺血诱导的血管生成,但其潜在机制仍然未知。在这里,我们比较了ADRC和骨髓单核细胞 (bm-mnc) 移植在兔后肢缺血模型中的功效,并使用后肢缺血小鼠模型研究了替代表型巨噬细胞极化在ADRC介导的血管生成中的可能作用。从新西兰白兔和C57BL/6J小鼠中分离出adrc和BM-mnc。在兔研究中,我们的数据表明ADRCs可以在体外和体内掺入内皮血管系统。ADRC条件培养基 (二1212) 和BM-MNC二1212均增强了人脐静脉内皮细胞的迁移能力并中断了凋亡过程。细胞移植后四周,在注射adrc或BM-mnc的缺血肌肉中观察到出生后新血管形成的增强。在小鼠研究中,我们提出ADRCs通过PGE2-EP2/4轴极化到IL-10-releasing M2巨噬细胞中,并抑制缺血肌肉中TNF-α 和IL-6的表达。在ADRC二1212而不是BM-MNC-二1212中培养的巨噬细胞中扩增了几种血管生成细胞因子的基因表达。使用中和MAb阻断IL-10会减弱ADRC介导的血管生成并在体内引起肌肉凋亡。总之,在后肢缺血的实验性兔模型中,ADRC移植获得了与bm-mnc相似的新血管形成增强作用; ADRC显示出通过PGE2-EP2/4轴加速IL-10-releasing M2巨噬细胞极化的独特免疫调节方式。
  • 【脂肪来源的再生细胞疗法治疗烧伤创面愈合: 两种递送方法的比较。】 复制标题 收藏 收藏
    DOI:10.1089/wound.2015.0672 复制DOI
    作者列表:Foubert P,Gonzalez AD,Teodosescu S,Berard F,Doyle-Eisele M,Yekkala K,Tenenhaus M,Fraser JK
    BACKGROUND & AIMS: :Objective: The use of noncultured autologous stromal vascular fraction or clinical grade adipose-derived regenerative cells (ADRCs) is a promising strategy to promote wound healing and tissue repair. Nevertheless, issues regarding the optimal mode of administration remain unclear. The purpose of this study was to compare the effects of local injection and topical spray delivery of ADRCs in a porcine model of thermal burns. Approach: Full-thickness thermal burns were created on the dorsum of 10 Gottingen minipigs. Two days following injury, wounds underwent fascial excision and were randomized to receive control vehicle or freshly isolated autologous ADRCs delivered by either multiple injections into or surrounding the wound bed, or by spray onto the wound surface (0.25 × 106 viable cells/cm2). Healing was evaluated by planimetry, histopathology, and immunohistochemistry at day 7, 12, 16, 21, and 28 posttreatment. Results:In vitro analysis demonstrated that there was no substantial loss of cell number or viability attributable to the spray procedure. Planimetric assessment revealed that delivery of ADRCs by either local injection or topical spray increased wound reepithelialization relative to control at day 14. No significant difference in wound reepithelialization was observed between both delivery approaches. In addition, on day 7 posttreatment, blood vessel density was greater in wounds receiving local or topical spray ADRCs than in the wounds treated with vehicle control. Histopathologic analysis suggests that ADRC treatment may modulate the inflammatory response by reducing neutrophil infiltration at day 7 and 12 posttreatment, irrespective of the route of administration. Conclusions: These data demonstrate that local injection and spray delivery of ADRCs modulate inflammation and improve wound angiogenesis and epithelialization. Importantly, both delivery routes exhibited similar effects on wound healing. Given the greater ease-of-use associated with topical spray delivery, these data support the use of a spray system for autologous ADRC delivery.
    背景与目标: 目的: 使用未培养的自体基质血管部分或临床级脂肪源性再生细胞 (ADRCs) 是促进伤口愈合和组织修复的一种有前途的策略。然而,关于最佳管理模式的问题仍然不清楚。这项研究的目的是比较局部注射和局部喷雾递送ADRCs在猪热烧伤模型中的效果。方法: 在10个Gottingen minipigs的背部产生了全层热烧伤。受伤后两天,伤口进行筋膜切除,并随机接受对照载体或新鲜分离的自体ADRCs,通过多次注射进入或围绕伤口床,或通过喷洒到伤口表面 (0.25  ×   106活细胞/cm2)。在治疗后第7、12、16、21和28天,通过平面测定法,组织病理学和免疫组织化学评估愈合情况。结果: 体外分析表明,喷雾过程没有造成细胞数量或活力的实质性损失。平面评估显示,与第14天的对照相比,通过局部注射或局部喷雾递送adrc会增加伤口上皮再形成。在两种递送方法之间,伤口再上皮化均未观察到显着差异。此外,在治疗后的第7天,接受局部或局部喷雾ADRCs的伤口的血管密度比接受媒介物控制的伤口要大。组织病理学分析表明,ADRC治疗可以通过减少治疗后第7天和第12天的中性粒细胞浸润来调节炎症反应,而与给药途径无关。结论: 这些数据表明ADRCs的局部注射和喷雾递送可调节炎症并改善伤口血管生成和上皮形成。重要的是,两种递送途径对伤口愈合均表现出相似的效果。鉴于与局部喷雾递送相关的更大的易用性,这些数据支持使用喷雾系统进行自体ADRC递送。
  • 【发现和合成含硫的6-取代的5,8-二甲氧基-1,4-萘醌肟衍生物作为新的和潜在的抗MDR癌症药物。】 复制标题 收藏 收藏
    DOI:10.1016/j.ejmech.2019.01.005 复制DOI
    作者列表:Huang G,Dong JY,Zhang QJ,Meng QQ,Zhao HR,Zhu BQ,Li SS
    BACKGROUND & AIMS: :Multi-drug resistance (MDR) to anticancer drugs is the primary impediment to successful treatment of cancer. Hunting for new compounds with potent anti-MDR activity is an effectual approach to conquer cancer drug resistance. In this work, 33 new sulfur-containing 1,4-naphthoquinone oxime derivatives were prepared and investigated for their cytotoxicity against a panel of tumor cell lines and fibroblast normal cell line. Cell-based assay showed that most of target compounds displayed more potent cytotoxic potency than positive controls. Meanwhile, all of compounds were non-toxic to normal cells. More importantly, the cytotoxic activity of these oxime derivatives toward drug-resistant cancer cell lines was found to be much stronger than that toward drug-susceptible cell lines (anti-drug resistance coefficient (ADRC) > 1). Of these, compound 12 m was identified as the most effective molecule with IC50 values in the range of 0.29 ± 0.01 to 1.33 ± 0.05 μM toward MDR sublines. Further mechanism studies demonstrated that 12 m could inhibit colony formation, cause G1 phase arrest and promote cell apoptosis mediated by augmenting Bax/Bcl-2 ratio of Bel7402/5-FU cells. Our findings provide promising start points for development of sulfur-containing 1,4-naphthoquinone oxime derivatives as potential anti-MDR agents.
    背景与目标: 对抗癌药物的多药耐药性 (MDR) 是成功治疗癌症的主要障碍。寻找具有有效抗MDR活性的新化合物是克服癌症耐药性的有效方法。在这项工作中,制备了33种新的含硫1,4-萘醌肟衍生物,并研究了它们对一组肿瘤细胞系和成纤维细胞正常细胞系的细胞毒性。基于细胞的分析表明,大多数目标化合物显示出比阳性对照更有效的细胞毒性。同时,所有化合物均对正常细胞无毒。更重要的是,发现这些肟衍生物对耐药癌细胞系的细胞毒性比对药物敏感细胞系的细胞毒性强得多 (抗耐药系数 (ADRC) >  1)。其中,化合物12 m被鉴定为最有效的分子,其IC50值在0.29   ±   0.01至1.33   ±   0.05  μ m的范围内。进一步的机制研究表明,12 m可以通过增加Bel7402/5-FU细胞的Bax/Bcl-2比值来抑制集落形成,引起G1期阻滞,促进细胞凋亡。我们的发现为开发含硫的1,4-萘醌肟衍生物作为潜在的抗MDR剂提供了有希望的起点。
  • 【缺血性心肌病患者脂肪来源的再生细胞: 精确试验。】 复制标题 收藏 收藏
    DOI:10.1016/j.ahj.2014.03.022 复制DOI
    作者列表:Perin EC,Sanz-Ruiz R,Sánchez PL,Lasso J,Pérez-Cano R,Alonso-Farto JC,Pérez-David E,Fernández-Santos ME,Serruys PW,Duckers HJ,Kastrup J,Chamuleau S,Zheng Y,Silva GV,Willerson JT,Fernández-Avilés F
    BACKGROUND & AIMS: AIMS:Adipose-derived regenerative cells (ADRCs) can be isolated from liposuction aspirates and prepared as fresh cells for immediate administration in cell therapy. We performed the first randomized, placebo-controlled, double-blind trial to examine the safety and feasibility of the transendocardial injections of ADRCs in no-option patients with ischemic cardiomyopathy. METHODS AND RESULTS:Procedural, postoperative, and follow-up safety end points were monitored up to 36 months. After baseline measurements, efficacy was assessed by echocardiography and single-photon emission computed tomography (6, 12, and 18 months), metabolic equivalents and maximal oxygen consumption (MVO2) (6 and 18 months), and cardiac magnetic resonance imaging (6 months). We enrolled 21 ADRC-treated and 6 control patients. Liposuction was well tolerated, ADRCs were successfully prepared, and transendocardial injections were feasible in all patients. No malignant arrhythmias were seen. Adverse events were similar between groups. Metabolic equivalents and MVO2 values were preserved over time in ADRC-treated patients but declined significantly in the control group. The difference in the change in MVO2 from baseline to 6 and 18 months was significantly better in ADRC-treated patients compared with controls. The ADRC-treated patients showed significant improvements in total left ventricular mass by magnetic resonance imaging and wall motion score index. Single-photon emission computed tomography results suggested a reduction in inducible ischemia in ADRC-treated patients up to 18 months. CONCLUSION:Isolation and transendocardial injection of autologous ADRCs in no-option patients were safe and feasible. Our results suggest that ADRCs may preserve ventricular function, myocardial perfusion, and exercise capacity in these patients.
    背景与目标:
  • 【自体细胞富集脂肪移植用于隆胸。】 复制标题 收藏 收藏
    DOI:10.1007/s00266-011-9727-7 复制DOI
    作者列表:Kamakura T,Ito K
    BACKGROUND & AIMS: :Autologous fat grafting for breast augmentation has faced some historical hurdles. However, in recent years it has been gaining acceptance from the medical community. This prospective, nonrandomized open-label study of 20 Japanese women supports the use of autologous fat grafting in breast augmentation and explores enhancement of fat graft tissue with autologous adipose-derived regenerative cells (ADRCs). After adipose harvesting using syringe liposuction, the tissue is processed in the Celution 800 System(®), which washes the graft and isolates ADRCs. The average cells per gram of harvested adipose tissue was 3.42 × 10(5), and the mean cell viability measured using an automated cell counting system before graft delivery was 85.3%. All patients demonstrated improvement in circumferential breast measurement (BRM) from their baseline state, and breast measurements were stable by 3 months after surgery. The mean BRM 9 months after surgery had increased 3.3 cm from preoperative measurements. Through 9 months, overall physician satisfaction was 69% and patient satisfaction was 75%. No serious or unexpected adverse events were reported, and the procedure was safe and well tolerated in all patients. Postoperative cyst formation was seen in two patients. These prospective results demonstrate that ADRC-enriched fat grafts processed with a closed automated system maintain high cell viability and that the procedure is safe and effective, with all patients showing improvement after a single treatment.
    背景与目标: : 自体脂肪移植隆胸面临一些历史障碍。但是,近年来,它已获得医学界的认可。这项针对20名日本女性的前瞻性,非随机开放标签研究支持在隆胸中使用自体脂肪移植,并探索用自体脂肪来源的再生细胞 (adrc) 增强脂肪移植组织。使用注射器吸脂进行脂肪采集后,在cellution 800系统中处理组织 (®),洗涤移植物并分离ADRCs。每克收获的脂肪组织的平均细胞为3.42 × 10(5),并且85.3% 在移植物递送之前使用自动细胞计数系统测量的平均细胞活力。所有患者的周围乳房测量 (BRM) 均从基线状态改善,并且在术后3个月时乳房测量稳定。手术后9个月的平均BRM与术前测量相比3.3厘米增加。通过9个月,医生的总体满意度69%,患者满意度75%。未报告严重或意外的不良事件,所有患者均安全且耐受性良好。两名患者术后出现囊肿形成。这些前瞻性结果表明,用封闭的自动化系统处理的富含ADRC的脂肪移植物可保持较高的细胞活力,并且该过程是安全有效的,所有患者在单次治疗后均显示出改善。
  • 【痴呆患者的反复发作: 频率,发作类型和治疗结果。】 复制标题 收藏 收藏
    DOI:10.1016/j.yebeh.2008.08.012 复制DOI
    作者列表:Rao SC,Dove G,Cascino GD,Petersen RC
    BACKGROUND & AIMS: OBJECTIVE:Patients with a primary neurodegenerative disorder associated with cognitive impairment are at increased risk for epilepsy. The goal of the present study was to characterize seizure type(s), etiological diagnosis of dementia, electroencephalogram (EEG) and imaging findings, and response to antiepileptic drug (AED) therapy in these individuals. METHODS:A retrospective study was performed identifying patients in the Mayo Alzheimer Disease Patient Registry (ADPR) and Alzheimer Disease Research Center (ADRC) who were classified as having dementia and epilepsy from 1986 to 2006. Multiple clinical parameters were extracted from patient charts and evaluated to characterize the primary neurodegenerative disorder and seizure outcomes. RESULTS:Sixty-three of the 1738 ADPR and ADRC patients (3.6%) had epilepsy. Twenty-four of the 63 patients were excluded because of insufficient information regarding their epilepsy. The remaining 39 patients were analyzed. Twenty-eight of the 63 patients (72%) experienced complex partial seizures. Head MRI was performed in 35 patients (90%). Fourteen patients (36%) had MRI-identified structural lesions that included remote stroke and prior intracerebral hemorrhage. EEGs were obtained in 29 patients (74%). Fifteen patients (38%) had epileptiform discharges. Overall, it was found that 79% had an excellent response to AED therapy. Approximately one-third of the patients had dose-related side effects from an AED. CONCLUSION:The present study indicated that most individuals with the comorbidity of epilepsy and dementia have complex partial seizures that may be adequately controlled on AED therapy. The long-term effect of seizure activity on the neurodegenerative disorder is unknown.
    背景与目标:
  • 【症状性脑梗死对阿尔茨海默病患者认知能力的重要性。】 复制标题 收藏 收藏
    DOI:10.3346/jkms.2011.26.3.412 复制DOI
    作者列表:Cho SJ,Scarmeas N,Jang TW,Marder K,Tang MX,Honig LS
    BACKGROUND & AIMS: :The coexistence of cerebral infarcts and Alzheimer's disease (AD) is common, but the influence of symptomatic cerebral infarcts on cognition is uncertain in AD. We hypothesize that symptomatic cerebral infarcts may provide an additive cognitive factor contributing to dementia in the AD population. We studied 1,001 clinically probable or possible AD patients in the Alzheimer Disease Research Center (ADRC) database. Linear regression was used to evaluate for an association between symptomatic cerebral infarcts and memory, language, executive function, abstract reasoning, and visuospatial performance, separately. Models were adjusted for covariates including age, gender, education, ethnicity, hypertension, diabetes mellitus, heart disease, clinical dementia rating, the presence of silent cerebral infarcts, and multiplicity or location of infarcts. Clinical history of stroke was present in 107 patients, radiological infarcts in 308 patients, and 68 patients with both were considered to have symptomatic infarcts. Adjusting for all covariates, AD patients with symptomatic infarcts had more impairment of executive function (P < 0.05). The influence of cerebral infarcts is neither general nor diffuse, and the presence of clinical history may have a more important influence on executive performance in AD.
    背景与目标: : 脑梗死与阿尔茨海默病 (AD) 并存是常见的,但症状性脑梗死对认知的影响不确定。我们假设有症状的脑梗塞可能会提供导致AD人群痴呆的附加认知因素。我们在阿尔茨海默病研究中心 (ADRC) 数据库中研究了1,001名临床可能或可能的AD患者。线性回归用于评估症状性脑梗死与记忆,语言,执行功能,抽象推理和视觉空间表现之间的关联。对模型进行了协变量调整,包括年龄,性别,教育程度,种族,高血压,糖尿病,心脏病,临床痴呆等级,无症状性脑梗塞的存在以及梗塞的多重性或位置。107例患者有中风的临床病史,308例患者有放射性梗塞,68例患者均被认为有症状性梗塞。调整所有协变量后,有症状梗死的AD患者执行功能受损更多 (P <0.05)。脑梗死的影响既不是一般的,也不是弥漫性的,临床病史的存在可能对AD的执行绩效有更重要的影响。
  • 【脂肪来源的再生细胞的植入增强了缺血诱导的血管生成。】 复制标题 收藏 收藏
    DOI:10.1161/ATVBAHA.108.166496 复制DOI
    作者列表:Kondo K,Shintani S,Shibata R,Murakami H,Murakami R,Imaizumi M,Kitagawa Y,Murohara T
    BACKGROUND & AIMS: OBJECTIVE:Therapeutic angiogenesis using autologous stem/progenitor cells represents a novel strategy for severe ischemic diseases. Recent reports indicated that adipose tissues could supply adipose-derived regenerative cells (ADRCs). Accordingly, we examined whether implantation of ADRCs would augment ischemia-induced angiogenesis. METHOD AND RESULTS:Adipose tissue was obtained from C57BL/6J mice, and ADRCs were isolated using standard methods. ADRCs expressed stromal cell-derived factor 1 (SDF-1) mRNA and proteins. Hind limb ischemia was induced and culture-expanded ADRCs, PBS, or mature adipocytes (MAs) as control cells were injected into the ischemic muscles. At 3 weeks, the ADRC group had a greater laser Doppler blood perfusion index and a higher capillary density compared to the controls. Implantation of ADRCs increased circulating endothelial progenitor cells (EPCs). SDF-1 mRNA abundance at ischemic tissues and serum SDF-1 levels were greater in the ADRC group than in the control group. Finally, intraperitoneal injection of an anti-SDF-1 neutralizing antibody reduced the number of circulating EPCs and therapeutic efficacies of ADRCs. CONCLUSIONS:Adipose tissue would be a valuable source for cell-based therapeutic angiogenesis. Moreover, chemokine SDF-1 may play a pivotal role in the ADRCs-mediated angiogenesis at least in part by facilitating mobilization of EPCs.
    背景与目标:
  • 【脂肪来源的再生细胞和脂肪移植物治疗乳腺癌相关淋巴水肿的可行性和安全性研究.】 复制标题 收藏 收藏
    DOI:10.1002/sctm.17-0037 复制DOI
    作者列表:Toyserkani NM,Jensen CH,Andersen DC,Sheikh SP,Sørensen JA
    BACKGROUND & AIMS: :Breast cancer-related lymphedema (BCRL) is a debilitating late complication with a lack of treatment opportunities. Recent studies have suggested that mesenchymal stromal cells can alleviate lymphedema. Herein, we report the results from the first human pilot study with freshly isolated adipose-derived regenerative cells (ADRC) for treating lymphedema with 6 months follow-up. Ten BCRL patients were included. ADRC was injected directly into the axillary region, which was combined with a scar-releasing fat graft procedure. Primary endpoints were change in arm volume. Secondary endpoints were change in patient reported outcome and safety. The study is registered with ClinicalTrials.gov (NCT02592213). During follow-up, a small volume reduction was noted but was not significant. Five patients reduced their use of conservative management. Patient-reported outcomes improved significantly over time. ADRCs were well tolerated and only minor transient adverse events related to liposuction were noted. In this pilot study, a single injection of ADRC improved lymphedema based on patient-reported outcome measures, and there were no serious adverse events in the 6 months follow-up period. In addition, half of the patients reduced their use of conservative management. ADRC therapy is a promising interventional therapy for alleviating lymphedema, but results need to be confirmed in randomized clinical trials. Stem Cells Translational Medicine 2017;6:1666-1672.
    背景与目标: 乳腺癌相关淋巴水肿 (BCRL) 是一种衰弱的晚期并发症,缺乏治疗机会。最近的研究表明,间充质基质细胞可以减轻淋巴水肿。在此,我们报告了首次人类试验研究的结果,该研究使用新鲜分离的脂肪来源的再生细胞 (ADRC) 治疗淋巴水肿,并进行了6个月的随访。包括10名BCRL患者。将ADRC直接注射到腋窝区域,并与释放疤痕的脂肪移植手术相结合。主要终点是手臂体积的变化。次要终点是患者报告的结局和安全性的变化。该研究已在临床医生.Gov (NCT02592213) 注册。在随访期间,注意到少量体积减少,但不明显。五名患者减少了保守治疗的使用。患者报告的结果随着时间的推移显著改善。ADRCs耐受性良好,仅注意到与吸脂相关的轻微短暂不良事件。在这项初步研究中,根据患者报告的结局指标,单次注射ADRC可改善淋巴水肿,并且在6个月的随访期内没有严重的不良事件。此外,一半的患者减少了保守治疗的使用。ADRC治疗是缓解淋巴水肿的一种有前途的介入治疗方法,但结果需要在随机临床试验中得到证实。干细胞转化医学2017;6:1666-1672。
  • 【脂肪来源的再生细胞补充脂肪移植物可改善移植物的长期保留。】 复制标题 收藏 收藏
    DOI:10.1097/SAP.0b013e31819ae05c 复制DOI
    作者列表:Zhu M,Zhou Z,Chen Y,Schreiber R,Ransom JT,Fraser JK,Hedrick MH,Pinkernell K,Kuo HC
    BACKGROUND & AIMS: :Current practice of autologous fat transfer for soft tissue augmentation is limited by poor long-term graft retention. Adipose-derived regenerative cells (ADRCs) contain several types of stem and regenerative cells, which may help improve graft retention through multiple mechanisms. Using a murine fat transplantation model, ADRCs were added to transplanted fat to test whether ADRCs could improve the long-term retention of the grafts. This study showed, at both 6 and 9 months after transplantation, ADRCs not only increased graft retention by 2-fold but also improved the quality of the grafts. ADRC-supplemented grafts had a higher capillary density, indicating ADRCs could promote neovascularization. Further cell tracking and gene expression studies suggest ADRCs may promote angiogenesis and adipocyte differentiation and prevent apoptosis through the expression of various growth factors, including VEGFA and IGF-1. Taken together, these results suggest a potential clinical utility of ADRCs in facilitating autologous fat transfer for soft tissue augmentation.
    背景与目标: : 目前自体脂肪转移用于软组织增强的实践受到长期移植物保留不良的限制。脂肪来源的再生细胞 (adrc) 包含几种类型的干细胞和再生细胞,这可能有助于通过多种机制改善移植物的保留。使用鼠脂肪移植模型,将ADRCs添加到移植脂肪中,以测试ADRCs是否可以改善移植物的长期保留。这项研究表明,在移植后的6个月和9个月,ADRCs不仅将移植物的保留率提高了2倍,而且还提高了移植物的质量。补充ADRC的移植物具有较高的毛细血管密度,表明ADRC可以促进新生血管形成。进一步的细胞跟踪和基因表达研究表明,ADRCs可能通过表达各种生长因子 (包括VEGFA和IGF-1) 来促进血管生成和脂肪细胞分化并防止凋亡。总之,这些结果表明adrc在促进自体脂肪转移以增强软组织方面具有潜在的临床应用价值。
  • 【富含细胞的自体脂肪移植到毛囊生态位可改善早期雄激素性脱发的头发再生。】 复制标题 收藏 收藏
    DOI:10.1093/asj/sjaa037 复制DOI
    作者列表:Kuka G,Epstein J,Aronowitz J,Glasgold MJ,Rogal JG,Brown W,Geronemus RG,Daniels EJ,Washenik K
    BACKGROUND & AIMS: BACKGROUND:Adipose and adipose derived regenerative cells (ADRCs) play an increasing role in androgenetic alopecia. OBJECTIVES:The authors sought to evaluate the safety and feasibility of fat grafts enriched with ADRCs in early androgenetic alopecia. METHODS:Seventy-one patients were treated: 16 with Puregraft fat and 1.0 × 106 ADRCs/cm2 scalp; 22 with Puregraft fat and 0.5 × 106 ADRCs/cm2 scalp, 24 with Puregraft fat alone, and 9 with saline control. Treatments were delivered into the skin and subcutaneous layer of the scalp. A total of 40 cm2 of scalp was treated and macrophotography and global photography were obtained at baseline and at 6, 24, and 52 weeks. RESULTS:A total of 71 patients tolerated the procedures well. No unanticipated associated adverse events were reported. When evaluating all patients at 24 weeks, there were no statistical differences between any of the treatment groups with respect to nonvellus (terminal) hair counts or width. There were increases (mean change from baseline) in terminal hair count for the low-dose ADRC group in the Norwood Hamilton 3 subgroup at week 6 (13.90 ± 16.68), week 12 (11.75 ± 19.42), week 24 (16.56 ± 14.68), and week 52 (2.78 ± 16.15). For this subgroup, the difference in hair count between the low-dose ADRC group and no-fat saline control was statistically significant (P = 0.0318) at week 24. CONCLUSIONS:Puregraft fat and ADRCs are safe and well tolerated. In early male hair loss, this therapy demonstrated a statistically significant increase in terminal hair counts relative to the control population at 24 weeks and represents a promising approach for early androgenetic alopecia. LEVEL OF EVIDENCE: 2:
    背景与目标:
  • 【阿尔茨海默病与精神病症状的全基因组关联研究。】 复制标题 收藏 收藏
    DOI:10.1038/mp.2011.125 复制DOI
    作者列表:
    BACKGROUND & AIMS: :Psychotic symptoms occur in ~40% of subjects with Alzheimer's disease (AD) and are associated with more rapid cognitive decline and increased functional deficits. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. We undertook a combined analysis of three genome-wide association studies (GWASs) to identify loci that (1) increase susceptibility to an AD and subsequent psychotic symptoms; or (2) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. In all, 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD-P) and 5659 controls were drawn from Genetic and Environmental Risk in AD Consortium 1 (GERAD1), the National Institute on Aging Late-Onset Alzheimer's Disease (NIA-LOAD) family study and the University of Pittsburgh Alzheimer Disease Research Center (ADRC) GWASs. Unobserved genotypes were imputed to provide data on >1.8 million single-nucleotide polymorphisms (SNPs). Analyses in each data set were completed comparing (1) AD+P to AD-P cases, and (2) AD+P cases with controls (GERAD1, ADRC only). Aside from the apolipoprotein E (APOE) locus, the strongest evidence for association was observed in an intergenic region on chromosome 4 (rs753129; 'AD+PvAD-P' P=2.85 × 10(-7); 'AD+PvControls' P=1.11 × 10(-4)). SNPs upstream of SLC2A9 (rs6834555, P=3.0 × 10(-7)) and within VSNL1 (rs4038131, P=5.9 × 10(-7)) showed strongest evidence for association with AD+P when compared with controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterized.
    背景与目标: : 精神病症状发生在约40% 的阿尔茨海默氏病 (AD) 受试者中,并与更快的认知能力下降和功能障碍增加有关。它们显示出高达61% 的遗传力,并且已被提议作为适合于基因定位工作的疾病亚型的标记。我们对三个全基因组关联研究 (GWASs) 进行了联合分析,以确定以下位点 :( 1) 增加对AD和随后的精神病症状的敏感性; 或 (2) 在存在由AD引起的神经变性的情况下改变精神病症状的风险。共有1299例患有精神病的AD病例 (AD + P),735例没有精神病的AD病例 (AD-P) 和5659对照来自AD联盟1 (GERAD1) 的遗传和环境风险,美国国家老年迟发性阿尔茨海默病研究所 (NIA-LOAD) 家庭研究和匹兹堡大学阿尔茨海默病研究中心 (ADRC) GWASs。输入未观察到的基因型以提供关于> 180万单核苷酸多态性 (snp) 的数据。完成了每个数据集中的分析,比较了 (1) AD P与AD-P病例,以及 (2) AD P病例与对照组 (仅GERAD1,ADRC)。除了载脂蛋白E (APOE) 基因座外,在4号染色体的基因间区域中观察到最强的关联证据 (rs753129; 'AD pvad-p' P = 2.85 × 10(-7); 'AD PvControls' P = 1.11 × 10(-4))。与对照组相比,SLC2A9上游 (rs6834555,P = 3.0 × 10(-7)) 和VSNL1内 (rs4038131,P = 5.9 × 10(-7)) 的snp显示出与AD + P相关的最强证据。这些发现值得在较大的,适当功率的样本中进行进一步的研究,在这些样本中,已经很好地表征了AD中精神病症状的存在。
  • 【X射线管性能对血管造影系统成像效率影响的研究】 复制标题 收藏 收藏
    DOI:10.1088/1361-6560/abbb7a 复制DOI
    作者列表:Dehairs M,Bosmans H,Marshall NW
    BACKGROUND & AIMS: :This work compared the impact of x-ray tube performance and automatic dose rate control (ADRC) parameter selection on system imaging efficiency of two Siemens angiography systems: a Siemens Megalix x-ray tube installed on an Artis Zee system (denoted 'MEGALIX') and a newer generation Gigalix x-ray tube installed on an Artis Q (denoted 'GIGALIX'). A method was used that accounted for two potential sources of bias in this comparison: differences in radiation output between the x-ray tubes and differences between the x-ray detectors on the two systems. First, ADRC x-ray factors (tube voltage, tube current, pulse length, focus size, spectral prefilter) and radiation output were recorded as a function of poly(methyl) methacrylate (PMMA) thickness on the MEGALIX unit. These factors were then applied manually on the GIGALIX system and incident air kerma rate (IAKR) and signal difference to noise ratio (SDNR) were measured. Second, the ADRC on the GIGALIX system was used to give the x-ray factors and both IAKR and SDNR relevant to the GIGALIX based system directly. This method enabled the SDNR to be measured from images acquired on the same x-ray detector. SDNR and IAKR were measured on both systems using a PMMA phantom covering thicknesses from 6 cm to 40 cm. A small 0.3 mm iron insert was used to measure SDNR, which was then multiplied by modulation transfer function based weighting factors for focal spot blurring and motion blurring. These factors were evaluated for an object motion of 25 mm s-1 and at a spatial frequency of 1.4 mm-1 in the object plane, relevant to interventional cardiology, giving a spatial frequency dependent SDNR(u). In the second phase of the study, a technical figure of merit (FOM) was used to express imaging performance of both systems, calculated as SDNR2(u)/IAKR. Averaged over all phantom thicknesses, the FOM of the GIGALIX-based system was 42% and 73% higher compared to that of the MEGALIX based system, for fluoroscopy and acquisition mode respectively. The results indicate that increased x-ray tube power and smaller foci can improve overall system efficiency and reduce doses.
    背景与目标: : 这项工作比较了两个西门子血管造影系统的x射线管性能和自动剂量率控制 (ADRC) 参数选择对系统成像效率的影响: 安装在Artis Zee系统上的Siemens Megalix x射线管 (表示为 “Megalix”) 和安装在Artis Q上的新一代Gigalix x射线管 (表示为 “Gigalix”)。在此比较中,使用了一种方法来解释两个潜在的偏差源: x射线管之间的辐射输出差异和两个系统上的x射线检测器之间的差异。首先,将ADRC x射线因子 (管电压,管电流,脉冲长度,焦点大小,光谱预滤波器) 和辐射输出记录为MEGALIX单元上的聚甲基丙烯酸甲酯 (PMMA) 厚度的函数。然后将这些因素手动应用于GIGALIX系统,并测量了入射空气比 (IAKR) 和信噪比 (SDNR)。其次,使用GIGALIX系统上的ADRC直接给出与基于GIGALIX的系统相关的x射线因子以及IAKR和SDNR。此方法使SDNR可以从在同一x射线检测器上获取的图像中测量。SDNR和IAKR在两个系统上使用覆盖厚度从6厘米到40厘米的PMMA体模测量。使用小的0.3毫米铁插入物来测量SDNR,然后将其乘以基于调制传递函数的加权因子以用于焦点模糊和运动模糊。评估这些因素的对象运动为25毫米s-1,并且在对象平面中的空间频率为1.4毫米-1,与介入心脏病学相关,给出了空间频率依赖性SDNR(u)。在研究的第二阶段,使用技术品质因数 (FOM) 表示两个系统的成像性能,计算为SDNR2(u)/IAKR。对于荧光透视和采集模式,与基于MEGALIX的系统相比,基于GIGALIX的系统的FOM在所有体模厚度上平均为42% 和73%。结果表明,增加x射线管功率和较小的病灶可以提高系统的整体效率并减少剂量。

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