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41.
Rovshan M Ismailov 《World journal of cardiology》2013,5(10):394-396
The important role of atherosclerosis in pathophysiology of Alzheimer’s Disease has become evident. Mechanisms such as hyperlipidemia, inflammation, abdominal obesity and insulin resistance are important yet they may not fully explain the specific involvement of the Circle of Willis in these pathologies. The Circle of Wills is a complex geometrical structure which has several areas with different curvature as well as various branching angles of vessels composing the circle. The hemodynamics in this region should take into account the Dean number which indicates the influence of curvature on the resistance to blood flow. Thus, areas with various curvature and angles may have different hemodynamics and there are certain areas in the Circle of Willis that are more likely to develop atherosclerotic changes. Therefore, this could suggest the novel pathophysiological pathway resulting from the geometric peculiarities of the Circle of Willis. One of the directions of future research is to examine whether specific areas of the Circle of Willis are more likely to develop atherosclerotic changes compared to other ones. Selective areas of the Circle of Willis affected by atherosclerotic changes could indicate the primary role of atherosclerosis promoting Alzheimer’s disease although other pathophysiological mechanisms suggesting the opposite direction should be also examined in prospective studies. 相似文献
42.
BackgroundBreast cancer is heterogeneous at different levels: biologic subtypes, intratumoral areas, and sites of metastases. Randomized controlled trials (RCTs) classify metastatic sites as visceral or non-visceral, but this has little influence in treatment decisions, particularly in the absence of clinical urgency. Indeed, it is unclear if response to treatments differs among sites of metastases.Patients and methodsRCTs investigating 3 different anticancer strategies in metastatic breast cancer were identified: (1) new hormonal therapy, (2) new targeted therapies in hormone receptor positive tumours (everolimus or palbociclib), and (3) new anti-HER2 therapies. RCTs reporting hazard ratios (HR) for Progression Free Survival (PFS) and Overall Survival (OS) for sub-groups based on sites of metastases were weighted using generic inverse variance approach, and pooled in meta-analyses using Revman 5.3. Subgroup difference was tested with Chi2 statistics.ResultsEleven RCTs (6701 pts.) qualified. There was a significant difference in PFS between women with visceral versus non-visceral metastases when two endocrine strategies were compared, with benefits limited to women with visceral metastases [Pooled HR 0.85; 95% CI, 0.77–0.95 versus 1.02 (0.88–1.18) for non-visceral; p(difference) = 0.05]. However, combination of an endocrine therapy and a targeted therapy was associated with better PFS compared to endocrine therapy alone for both groups [HR 0.51 (0.43–0.60) versus 0.45 (0.36–0.56) for non-visceral; p(difference) = 0. 36]. Novel HER-2 targeted therapies were associated with significantly better PFS and OS only in visceral metastases [HR 0.59 (0.52–0.66) versus 0.71(0.44–1.13) for non-visceral, p(difference) = 0.45, for PFS; and 0.64 (0.56–0.73) versus 0.82 (0.57 = 1.19) for non-visceral, p(difference) = 0.20, for OS].ConclusionCombination of targeted agents and endocrine therapy results in concordant, superior PFS suggesting targetable endocrine resistance across metastatic sites. Discordant responses with endocrine strategy alone support use of targeted therapy, rather than change in endocrine agent at disease progression. HER2 targeted therapies may be less effective in areas of poor vascularization. 相似文献
43.
BACKGROUNDThere are many factors that lead to dwarfism, and the mechanism has not yet been elucidated. Next-generation sequencing may identify candidate-related gene mutations, which may clarify the molecular cause.AIMTo analyze genetic variation by using a constructed panel related to dwarfism by utilizing next-generation sequencing platform sequencing analysis to screen candidate-related gene mutations.METHODSPhysical and laboratory characteristics, including clinical examination, growth hormone drug challenge test, serum insulin-like growth factor-1 (IGF-1), IGF binding protein 3, other related tests, imaging examination, and chromosome karyotyping, were analyzed. Next-generation sequencing was performed to analyze pathogenicity variability.RESULTSIn the 39 dwarfism patients, 10 had pathogenicity variability. Gene variation was found in the OBSL1, SLC26A2, PTPN11, COL27AI, HDAC6, CUL7, FGFR3, DYNC2H1, GH1, and ATP7B genes. Of the 10 patients with pathogenicity variability, the related physical characteristics included double breast development and growth hormone deficiency, enuresis and indirect inguinal hernia on the left, two finger distance of 70.2 cm, head circumference of 49.2 cm, ischium/lower body length of 1.8 cm, weak limb muscles, and partial growth hormone deficiency. After 6 mo of growth hormone therapy, the concentrations of IGF-1 and IGF binding protein 3 increased from 215.2 ± 170.3 to 285.0 ± 166.0 and 3.9 ± 1.4 to 4.2 ± 1.1, respectively.CONCLUSIONOBSL1, SLC26A2, PTPN11, COL27AI, HDAC6, CUL7, FGFR3, DYNC2H1, GH1, and ATP7B genes may be related to the incidence of dwarfism, and more research needs to be performed to elucidate the mechanism. 相似文献
44.
《中国现代医生》2018,56(10):91-94
目的探讨依托考昔联合运动训练治疗膝骨性关节炎(KOA)的临床疗效及作用机制。方法选取2015年2月~2016年9月我院治疗的144例膝骨关节炎患者,采用统计软件SAS9.1程序产生随机分配序列,将其以1∶1∶1∶1的比例被随机分配四组,再实施盲法用A、B、C、D分别表示组别,依托考昔组(A组)、运动训练组(B组)、依托考昔联合运动训练组(C组)和健康教育组(D组)四组,各36例,所有患者均予以KOA常规治疗,A组加以依托考昔治疗,B组加以运动功能训练,C组加以运动训练联合依托考昔治疗,D组进行健康教育,四组患者均治疗12周,比较治疗前后四组患者的骨性关节炎指数评分(WOMAC)、6 min步行距离、SF-36评分及血清炎性因子表达,并记录比较四组患者临床疗效及不良反应的发生情况。结果 (1)A、B、C组治疗后WOMAC评分均低于治疗前,且C组降低更明显(P0.05);(2)A、B、C组治疗后6 min步行距离和SF-36评分均高于治疗前,且C组升高更明显(P0.05);(3)A、B、C组治疗后NF-κB、IL-1β和MMP-1水平均低于治疗前,且C组降低更明显(P0.05);(4)治疗后四组临床总有效率比较存在显著差异,且C组升高更明显(P0.05);(5)四组不良反应发生率比较差异无显著性(P0.05)。结论依托考昔联合功能训练治疗KOA临床疗效显著,可改善患者疼痛及关节运动功能,减少炎性因子表达水平,安全可靠,其机制可能通过调控NF-κB信号通路相关蛋白的表达发挥作用。 相似文献
45.
46.
《Actas dermo-sifiliográficas》2014,105(6):583-589
Although the first study on the efficacy of methotrexate in the treatment of psoriasis was reported in 1958, scientific evidence for this indication has been scant until quite recently. We now have new data on the pharmacokinetics and mechanism of action of methotrexate and new subcutaneous formulations that have improved the bioavailability, efficacy, and ease of administration of the drug. The results of recent clinical trials comparing methotrexate with several biologic agents have shown it to be the first-line therapy among the classic systemic treatments for psoriasis. Moreover, the incremental cost-effectiveness ratio for subcutaneous methotrexate has been shown to be superior to that of ciclosporin, adalimumab, and infliximab. 相似文献
47.
Nurul Haiza Sapiee Ashvin Thambyah Peter A. Robertson Neil D. Broom 《The spine journal》2019,19(3):532-544
BACKGROUND CONTEXT
The cartilaginous and bony material that can be present in herniated tissue suggests that failure can involve both cartilaginous and vertebral-endplates. How structural integration is achieved across the junction between these two distinct tissue regions via its fibril and mineral components is clearly relevant to the modes of endplate failure that occur.PURPOSE
To understand how structural integration is achieved across the cartilaginous-vertebral endplate junction.STUDY DESIGN
A micro- and fibril-level structural analysis of the cartilage-vertebral endplate region was carried out using healthy, mature ovine motion segments.METHODS
Oblique vertebra-annulus-vertebra samples were prepared such that alternate layers of lamellar fibers extended from vertebra to vertebra. The endplate region of each sample was then decalcified in a targeted manner before being loaded in tension along the fiber direction to achieve incomplete rupture within the region of the endplate. The failure regions were then analyzed with differential interference contrast microscopy and scanning electron microscopy.RESULTS
Microstructural analysis revealed that failure within the endplate region was not confined to the cement line. Instead, rupture continued into the underlying vertebral endplate with bony material still attached to the now unanchored annular bundles. Ultrastructural analysis of the partially ruptured regions of the cement line revealed clear evidence of blending/interweaving relationships between the fibrils of the annular bundles, the calcified cartilage and the bone with no one pattern of association appearing dominant. These findings suggest that fibril-based structural cohesion exists across the cement line at the site of annular insertion, with strengthening via a mechanism somewhat analogous to steel-reinforced concrete. The fibrils are brought into a close intermingling association with interfibril forces mediated via the mineral component.CONCLUSIONS
This study provides clear evidence of structural connectivity across the cartilaginous-vertebral endplate junction by the intermingling of their fibrillar components and mediated by the mineral phase. This is consistent with the clinical observation that in some disc herniations bony material can be still attached to the extruded soft tissue. 相似文献48.
《药学学报(英文版)》2020,10(2):327-343
Our recent studies demonstrated that the natural product nobiletin (NOB) served as a promising multidrug resistance (MDR) reversal agent and improved the effectiveness of cancer chemotherapy in vitro. However, low aqueous solubility and difficulty in total synthesis limited its application as a therapeutic agent. To tackle these challenges, NOB was synthesized in a high yield by a concise route of six steps and fourteen derivatives were synthesized with remarkable solubility and efficacy. All the compounds showed improved sensitivity to paclitaxel (PTX) in P-glycoprotein (P-gp) overexpressing MDR cancer cells. Among them, compound 29d exhibited water solubility 280-fold higher than NOB. A drug-resistance A549/T xenograft model showed that 29d, at a dose of 50 mg/kg co-administered with PTX (15 mg/kg), inhibited tumor growth more effective than NOB and remarkably increased PTX concentration in the tumors via P-gp inhibition. Moreover, Western blot experiments revealed that 29d inhibited expression of NRF2, phosphorylated ERK and AKT in MDR cancer cells, thus implying 29d of multiple mechanisms to reverse MDR in lung cancer. 相似文献
49.
目的 采用网络药理学及实验验证的方法,探索皮类中药石榴皮治疗痤疮的作用机制。方法 利用网络药理学技术筛选石榴皮治疗痤疮的活性成分和作用靶点,采用String数据库对活性成分靶点与痤疮疾病靶点进行蛋白互作网络分析,并通过David数据库对其结果进行KEGG通路富集分析。基于以上结果,采用Cytoscape3.6.1软件构建石榴皮治疗痤疮的“成分-靶点-通路”网络关系图。通过动物实验,观察石榴皮多酚乳膏对金黄地鼠皮脂腺斑面积及PI3K蛋白表达情况的影响。结果 本研究共获得药效成分31个,药物靶点193个,痤疮靶点1371个,药效成分与疾病的交集靶点79个。石榴皮治疗痤疮的主要成分为槲皮素、山奈酚、木犀草素等;核心靶点为Akt1、IL-6、VEGFA和PTSG2;关键信号通路可能包括PI3K-Akt信号通路、TNF信号通路、T细胞受体信号通路、FoxO信号通路等。体内实验证实,石榴皮能够降低金黄地鼠皮脂腺斑PI3K蛋白表达水平,抗皮脂腺斑增生。结论 本研究预测了石榴皮治疗痤疮可能的作用机制,为“以皮治皮”理论在中医皮肤科的应用提供现代理论依据。 相似文献
50.