BACKGROUND & AIMS: BACKGROUND:Multiple sclerosis (MS) is a leading cause of neurological disability in young adults. The most widely accepted hypothesis regarding its pathogenesis is that it is an immune-mediated disease. It has been hypothesised that intraluminal defects, compression, or hypoplasia in the internal jugular or azygos veins may be important factors in the pathogenesis of MS. This condition has been named 'chronic cerebrospinal venous insufficiency' (CCSVI). It has been suggested that these intraluminal defects restrict the normal blood flow from the brain and spinal cord, causing the deposition of iron in the brain and the eventual triggering of an auto-immune response. The proposed treatment for CCSVI is venous percutaneous transluminal angioplasty (PTA), which is claimed to improve the blood flow in the brain thereby alleviating some of the symptoms of MS. This is an update of a review first published in 2012. OBJECTIVES:To assess the benefit and safety of venous PTA in people with MS and CCSVI. SEARCH METHODS:We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group's Specialised Register up to 30 August 2018, CENTRAL (in the Cochrane Library 2018, issue 8), MEDLINE up to 30 August 2018, Embase up to 30 August 2018, metaRegister of Controlled Trials, ClinicalTrials.gov., the Australian New Zealand Clinical Trials Registry, and the World Health Organization (WHO) International Clinical Trials Registry platform. We examined the bibliographies of the included and excluded studies. SELECTION CRITERIA:We included randomised controlled trials (RCTs) in which PTA and sham interventions were compared in adults with MS and CCSVI. DATA COLLECTION AND ANALYSIS:Two authors independently assessed study eligibility and risk of bias, and extracted data. We reported results as risk ratios (RR) with 95% confidence intervals (CI). We performed statistical analyses using the random-effects model; and we assessed the certainty of the evidence using GRADE. MAIN RESULTS:We included three RCTs (238 participants) in this update. One hundred and thirty-four participants were randomised to PTA and 104 to sham treatment. We attributed low risk of bias to two (67%) studies for sequence generation and two (67%) studies for performance bias. All studies were at a low risk of detection bias, attrition bias, reporting bias and other potential sources of bias.There was moderate-quality evidence to suggest that venous PTA did not increase the proportion of patients who had operative or post-operative serious adverse events compared with the sham procedure (RR 3.33, 95% CI 0.36 to 30.44; 3 studies, 238 participants); nor did it increase the proportion of patients who improved on a functional composite measure including walking control, balance, manual dexterity, postvoid residual urine volume, and visual acuity over 12-month follow-up (RR 0.84, 95% CI 0.55 to 1.30; 1 study, 110 participants); nor did it reduce the proportion of patients who experienced new relapses at six- or 12-month follow-up (RR 0.87, 95% CI 0.51 to 1.49; 3 studies, 235 participants). There was no effect of venous PTA on disability worsening measured by the Expanded Disability Status Scale, which was reported at follow-up intervals of six months (one study), 11 months (one study) and 12 months (one study). Quality of life was reported in two studies with no difference between treatment groups. Moderate or severe pain during or post venography was reported in both PTA and sham-procedure participants in all included studies. Venous PTA was not effective in restoring blood flow assessed at one-month (one study) or 12-month follow-up (one study). AUTHORS' CONCLUSIONS:This systematic review identified moderate-quality evidence that, compared with sham procedure, venous PTA intervention did not provide benefit on patient-centred outcomes (disability, physical or cognitive functions, relapses, quality of life) in people with MS. Venous PTA has proven to be a safe technique but in view of the available evidence of its ineffectiveness, this intervention cannot be recommended in people with MS. All ongoing trials were withdrawn or terminated and hence this updated review is conclusive. No further randomised clinical studies are needed.

背景与目标： 背景：多发性硬化症（MS）是年轻人神经系统残疾的主要原因。关于其发病机理的最广泛接受的假设是它是一种免疫介导的疾病。已经假设颈内静脉或合子静脉内腔内缺损，压迫或发育不全可能是MS发病机理中的重要因素。这种情况被称为“慢性脑脊髓静脉功能不全”（CCSVI）。已经提出这些管腔内缺陷限制了来自脑和脊髓的正常血流，导致铁在脑中的沉积并最终触发了自身免疫反应。提议的CCSVI治疗方法是静脉经皮腔内血管成形术（PTA），据称可改善大脑中的血流，从而减轻MS的某些症状。这是2012年首次发布的评论的更新。
目的：评估静脉PTA对MS和CCSVI患者的益处和安全性。
搜索方法：我们搜索了截至2018年8月30日的中枢神经系统小组专业注册的Cochrane多发性硬化症和罕见病，CENTRAL（位于Cochrane图书馆2018年第8期），MEDLINE截至2018年8月30日，Embase截至8月30日2018年，对照试验的metaRegister，ClinicalTrials.gov。，澳大利亚新西兰临床试验注册中心和世界卫生组织（WHO）国际临床试验注册平台。我们检查了包括和排除研究的参考书目。
选择标准：我们纳入了随机对照试验（RCT），其中比较了患有MS和CCSVI的成年人的PTA和假手术。
数据收集与分析：两位作者独立评估了研究的资格和偏倚风险，并提取了数据。我们将结果报告为具有95％置信区间（CI）的风险比（RR）。我们使用随机效应模型进行了统计分析；我们使用GRADE评估了证据的确定性。
主要结果：我们在此更新中包括了三个RCT（238名参与者）。一百三十四名参与者被随机分配到PTA，104名被随机分配到假治疗。我们将偏倚的低风险归因于两项（67％）的序列生成研究和两项（67％）的性能偏向研究。所有研究的检测偏倚，损耗偏倚，报告偏倚和其他潜在偏倚的风险均较低。有中等质量的证据表明静脉PTA不会增加手术或术后严重不良反应患者的比例与假手术相比的事件（RR 3.33，95％CI 0.36至30.44； 3个研究，238名参与者）；在12个月的随访中，使用步行控制，平衡，手部敏捷度，术后剩余尿量和视敏度等功能性综合指标改善的患者比例也没有增加（RR 0.84，95％CI 0.55至1.30； 1个研究，110个参与者）；也没有减少在6或12个月的随访中出现新复发的患者比例（RR 0.87，95％CI 0.51至1.49； 3个研究，235名参与者）。用扩展的残疾状况量表衡量，静脉PTA对残疾恶化没有影响，据报道，随访间隔为六个月（一项研究），11个月（一项研究）和12个月（一项研究）。两项研究报告了生活质量，治疗组之间无差异。在所有纳入研究中，PTA和假手术参与者均报告了静脉造影期间或之后的中度或重度疼痛。在一个月（一项研究）或12个月随访（一项研究）中评估的静脉PTA不能有效恢复血流。
作者的结论：该系统评价确定了中等质量的证据，与假手术相比，静脉PTA干预对以MS为中心的以患者为中心的结果（残疾，身体或认知功能，复发，生活质量）没有好处。静脉PTA已被证明是一种安全的技术，但鉴于现有证据表明其无效，因此不建议在MS患者中推荐这种干预措施。所有正在进行的试验都已撤回或终止，因此本次更新的审查是结论性的。无需进一步的随机临床研究。

BACKGROUND & AIMS: :Does accelerated cortical atrophy in aging, especially in areas vulnerable to early Alzheimer's disease (AD), unequivocally signify neurodegenerative disease or can it be part of normal aging? We addressed this in 3 ways. First, age trajectories of cortical thickness were delineated cross-sectionally (n = 1100) and longitudinally (n = 207). Second, effects of undetected AD on the age trajectories were simulated by mixing the sample with a sample of patients with very mild to moderate AD. Third, atrophy in AD-vulnerable regions was examined in older adults with very low probability of incipient AD based on 2-year neuropsychological stability, CSF Aβ(1-42) levels, and apolipoprotein ε4 negativity. Steady decline was seen in most regions, but accelerated cortical thinning in entorhinal cortex was observed across groups. Very low-risk older adults had longitudinal entorhinal atrophy rates similar to other healthy older adults, and this atrophy was predictive of memory change. While steady decline in cortical thickness is the norm in aging, acceleration in AD-prone regions does not uniquely signify neurodegenerative illness but can be part of healthy aging. The relationship between the entorhinal changes and changes in memory performance suggests that non-AD mechanisms in AD-prone areas may still be causative for cognitive reductions.

背景与目标： ：衰老中的皮质萎缩加速，特别是在容易患早老性阿尔茨海默氏病（AD）的地区，是否明确表示神经退行性疾病或它是否可以成为正常衰老的一部分？我们通过3种方式解决了这个问题。首先，在横截面（n = 1100）和纵向（n = 207）上划定了皮质厚度的年龄轨迹。其次，通过将样本与患有轻度至中度AD的患者样本混合来模拟未检测到的AD对年龄轨迹的影响。第三，根据2年的神经心理学稳定性，脑脊液Aβ（1-42）水平和载脂蛋白ε4阴性，检查了成年人AD弱势地区的萎缩，其发生AD的可能性非常低。在大多数地区都观察到稳定的下降，但是在各组中观察到内嗅皮层的皮层加速变薄。非常低风险的老年人的纵向内脏萎缩率与其他健康的老年人相似，并且该萎缩可预测记忆力的改变。尽管皮层厚度的持续下降是衰老的常态，但AD易发地区的加速并不唯一表示神经退行性疾病，而是健康衰老的一部分。内嗅变化与记忆性能变化之间的关系表明，AD易发地区的非AD机制可能仍然是导致认知能力下降的原因。

BACKGROUND & AIMS: :We have previously demonstrated that the concentration of normal prion proteins (PrP(C)) is increased in the serum and cerebrospinal fluid (CSF) of rats deficient in vitamin B(12) (cobalamin, Cbl). In this study, we investigated whether similar increases also occur in the serum and CSF of patients deficient in Cbl (Cbl-D), and whether the increase in serum levels can be corrected by Cbl therapy. The study involved two sample populations. The first consisted of 45 patients (13 patients with pernicious anemia [PA], 19 with other forms of anemia, and 13 healthy controls); and the second, 68 patients (five with subacute combined degeneration [SCD], 18 with amyotrophic lateral sclerosis, 22 with multiple sclerosis [MS], and 23 neurological controls). Serum PrP(C) levels were measured using an enzyme-linked-immunosorbent-assay before as well as after Cbl therapy. The mean serum PrP(C) levels in patients with PA were significantly higher than those of the controls (p=0.0017) but normalized after Cbl therapy; there was no significant change in the patients with other forms of anemia. Mean CSF PrP(C) levels in the patients with SCD were significantly higher than in the neurological controls (p<0.03). The serum and CSF PrP(C) levels of patients with PA and those with SCD were correlated significantly with serum (p=0.004) and CSF (p=0.0018) Cbl levels. In patients with MS, CSF PrP(C) concentrations were significantly lower than those of the controls regardless of their CSF Cbl levels. We found a correlation between Cbl and PrP(C) levels in the serum and CSF of Cbl-D patients, which suggests that Cbl may regulate the PrP(C) levels in the serum and CSF in humans.

背景与目标： ：我们先前已经证明，缺乏维生素B（12）（钴胺素，Cbl）的大鼠的血清和脑脊液（CSF）中正常病毒蛋白（PrP（C））的浓度会增加。在这项研究中，我们调查了Cbl缺乏症患者（Cbl-D）的血清和CSF是否也发生了类似的增加，以及是否可以通过Cbl治疗来纠正血清水平的增加。该研究涉及两个样本人群。第一名包括45例患者（13例恶性贫血[PA]，19例其他形式的贫血和13例健康对照者）；其次是68例患者（其中5例患有亚急性合并变性[SCD]，18例患有肌萎缩性侧索硬化症，22例患有多发性硬化症[MS]和23例神经系统控制）。在Cbl治疗之前和之后，使用酶联免疫吸附测定法测量血清PrP（C）水平。 PA患者的平均血清PrP（C）水平显着高于对照组（p = 0.0017），但在Cbl治疗后恢复正常；其他形式的贫血患者无明显变化。 SCD患者的平均CSF PrP（C）水平显着高于神经系统对照（p <0.03）。 PA患者和SCD患者的血清和CSF PrP（C）水平与血清​​（p = 0.004）和CSF（p = 0.0018）Cbl水平显着相关。在MS患者中，无论其CSF Cbl水平如何，CSF PrP（C）浓度均显着低于对照组。我们发现Cbl-D患者的血清和CSF中Cbl和PrP（C）水平之间存在相关性，这表明Cbl可能调节人类血清和CSF中的PrP（C）水平。

BACKGROUND & AIMS: BACKGROUND & AIMS:Previous studies have shown that hepatitis B virus (HBV) interferes with host antiviral immunity via multiple pathways. In clinical practice, interferon resistance is a serious issue for treatment of HBV infection. Now, miRNAs have been reported to be widely involved in antiviral immunity and have become a novel tool to study virus-host interaction. We question whether miRNAs play a role in HBV-induced interferon resistance in hepatocytes. METHODS:MiRNAs levels in HepG2 and HepG2.2.15 cells were compared by qRT-PCR. The effects of miR146a on HBV infection were characterized by interference miR146a level, followed by the quantification of HBV mRNA, DNA and antigens. We employed qRT-PCR and western blot to study the effects of miR146a on the IFN-α signalling pathway. The miR146a promoter activity was validated by a luciferase reporter assay. RESULTS:HBV infection impaired IFN-α signalling pathway in hepatocytes. MiR146a was upregulated in HBV+ HepG2.2.15 cells, and the transcriptional activity of miR146a in HepG2.2.15 cells was increased compared with HepG2 cells. HBV infection, especially the introduction of HBx, induced miR146a expression in vitro. Moreover, miR146a attenuated the production of type I interferon-induced antiviral factors. Low STAT1 levels were noticed in HBV+ HCC cells, and the luciferase reporter assay showed that STAT1 was post-transcriptionally downregulated by miR146a. Furthermore, the silencing of miR146a by antisense inhibitors enhanced IFN-α-mediated anti-HBV efficiency. CONCLUSIONS:Our findings demonstrate that HBV infection promotes miR146a transcription, which represses STAT1 and results in interferon resistance. These observations reveal a novel role for miR146a in HBV immunopathogenesis, and provide a potential target for the therapeutic recovery of IFN-α-induced anti-HBV effects.

背景与目标： 背景与目的：先前的研究表明，乙型肝炎病毒（HBV）通过多种途径干扰宿主的抗病毒免疫。在临床实践中，干扰素耐药性是治疗HBV感染的严重问题。现在，据报道，miRNA广泛参与抗病毒免疫，并已成为研究病毒-宿主相互作用的新工具。我们质疑miRNA是否在HBV诱导的肝细胞干扰素抗性中发挥作用。
方法：采用qRT-PCR技术比较HepG2和HepG2.2.15细胞中的miRNA水平。 miR146a对HBV感染的作用以干扰miR146a水平为特征，然后对HBV mRNA，DNA和抗原进行定量。我们采用qRT-PCR和western blot研究miR146a对IFN-α信号通路的影响。 miR146a启动子活性已通过荧光素酶报告基因分析验证。
结果：HBV感染损害了肝细胞中的IFN-α信号通路。 HBV HepG2.2.15细胞中MiR146a上调，与HepG2细胞相比，miR146a在HepG2.2.15细胞中的转录活性增加。 HBV感染（尤其是HBx的引入）在体外诱导miR146a表达。此外，miR146a减弱了I型干扰素诱导的抗病毒因子的产生。在HBV HCC细胞中发现STAT1水平较低，荧光素酶报告基因检测结果表明miR146a在转录后下调了STAT1。此外，反义抑制剂对miR146a的沉默增强了IFN-α介导的抗HBV效率。
结论：我们的研究结果表明，HBV感染可促进miR146a转录，从而抑制STAT1并导致干扰素耐药。这些发现揭示了miR146a在HBV免疫发病机制中的新作用，并为IFN-α诱导的抗HBV作用的治疗性恢复提供了潜在的靶点。

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BACKGROUND & AIMS: BACKGROUND:In recent years, shared decision making (SDM) has been promoted as a model to guide interactions between persons with MS and their neurologists to reach mutually satisfying decisions about disease management - generally about deciding treatment courses of prevailing disease modifying therapies. In 2009, Dr. Paolo Zamboni introduced the world to his hypothesis of Chronic Cerebrospinal Venous Insufficiency (CCSVI) as a cause of MS and proposed venous angioplasty ('liberation therapy') as a potential therapy. This study explores the discussions that took place between persons with MS (PwMS) and their neurologists about CCSVI against the backdrop of the recent calls for the use of SDM to guide clinical conversations. METHODS:In 2012, study researchers conducted focus groups with PwMS (n = 69) in Winnipeg, Canada. Interviews with key informants were also carried out with 15 participants across Canada who were stakeholders in the MS community: advocacy organizations, MS clinicians (i.e. neurologists, nurses), clinical researchers, and government health policy makers. RESULTS:PwMS reported a variety of experiences when attempting to discuss CCSVI with their neurologist. Some found that there was little effort to engage in desired discussions or were dissatisfied with critical or cautious stances of their neurologist. This led to communication breakdowns, broken relationships, and decisions to autonomously access alternative opinions or liberation therapy. Other participants were appreciative when clinicians engaged them in discussions and were more receptive to more critical appraisals of the evidence. Key informants reported that they too had heard of neurologists who refused to discuss CCSVI with patients and that neurology as a whole had been particularly vilified for their response to the hypothesis. Clinicians indicated that they had shared information as best they could but recommended against seeking liberation therapy. They noted that being respectful of patient emotions, values, and hope were also key to maintaining good relationships. CONCLUSIONS:While CCSVI proved a challenging context to carry out patient-physician discussions and brought numerous tensions to the surface, following the approach of SDM can minimize the potential for unfortunate outcomes as much as possible because it is based on principles of respect and more two-way communication.

背景与目标： 背景：近年来，共享决策制定（SDM）已被提倡作为一种模型，以指导MS患者与其神经科医生之间的相互作用，以达成有关疾病管理的相互满意的决策-通常涉及确定流行的疾病改良疗法的治疗过程。在2009年，Paolo Zamboni博士向世界介绍了他的MS病因-慢性脑脊髓静脉功能不全（CCSVI）的假说，并提出了静脉血管成形术（“解放疗法”）作为一种潜在疗法。这项研究探索了在最近使用SDM指导临床对话的背景下，MS（PwMS）患者及其神经病学家之间关于CCSVI的讨论。
方法：2012年，研究人员在加拿大温尼伯进行了PwMS（n = 69）焦点小组研究。还与加拿大全国15位参与者进行了访谈，他们是MS社区的利益相关者：倡导组织，MS临床医生（即神经病学家，护士），临床研究人员和政府卫生政策制定者。
结果：PwMS尝试与神经科医生讨论CCSVI时报告了多种经验。一些人发现，他们很少努力进行期望的讨论，或者对神经科医生的批评或谨慎态度不满意。这导致沟通中断，关系破裂，并决定自主获取替代意见或解放疗法。当临床医生让他们参与讨论时，其他参与者会很感激，并且更愿意接受对证据进行更严格的评估。关键线人报告说，他们也听说过神经病学家拒绝与患者讨论CCSVI，并且整个神经病学因其对假说的反应而受到特别谴责。临床医生表示，他们已尽其所能地共享信息，但建议不要寻求解放疗法。他们指出，尊重患者的情感，价值观和希望也是保持良好关系的关键。
结论：尽管CCSVI证明了进行患者-医师讨论的挑战性环境，并在表面上带来了许多压力，但遵循SDM的方法可以尽可能地将不幸结果的可能性降到最低，因为它基于尊重的原则，另外两个双向通信。

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BACKGROUND & AIMS: OBJECTIVES:To analyze all the arguments against chronic cerebrospinal venous insufficiency (CCSVI) as a medical entity, and its association with multiple sclerosis (MS) and to revise all the findings suggesting a possible connection between these two entities. METHODS:We revised the methodology and results of all fourteen published studies on prevalence of CCSVI in MS patients. Furthermore, we take into consideration other work dealing with possible causes and explanations of venous, as well as vascular dysfunctions linked with MS. RESULTS:Studies of prevalence show a great variability in prevalence of CCSVI in MS patients. However, a recent meta-analysis assessed an over 13 times increased prevalence in MS. Global hypoperfusion of the brain, and reduced cerebral spinal fluid dynamics in MS was shown to be related to CCSVI. Post-mortem studies show a higher prevalence of intraluminal defects in the main extracranial vein in MS patients in respect to controls. DISCUSSION:Taking into account the current epidemiological data, the autoptic findings, and the relationship between CCSVI and both hypoperfusion and cerebrospinal fluid flow, CCSVI can be inserted in the list of multiple factors involved in MS pathogenesis. Our careful data analysis may conclude that great variability in prevalence of CCSVI in MS patients can be a result of different methodologies used in venous ultrasound assessment. Finally, it has been proven that CCSVI share the three main risk factors with MS. On the other hand, smoking is the most important risk factor for endothelial cell damage, vitamin D has a protective role and Epstein-Barr virus passes the blood-brain barrier by invading the endothelial cells, therefore, epidemiologically, linking the imbalance of these three factors to MS through autoimmunity.

背景与目标： 目的：分析所有反对慢性脑脊髓静脉功能不全（CCSVI）作为医学实体的论点，及其与多发性硬化症（MS）的关联，并修订所有发现，暗示这两个实体之间可能存在联系。
方法：我们修订了所有十四项有关MS患者CCSVI患病率的已发表研究的方法和结果。此外，我们考虑了其他有关可能的原因和解释，以及与MS相关的血管功能障碍的解释的工作。
结果：患病率研究显示，MS患者的CCSVI患病率存在​​很大差异。但是，最近的一项荟萃​​分析估计，MS患病率增加了13倍以上。研究表明，脑部整体灌注不足和MS中脑脊髓液动力学的降低与CCSVI有关。验尸研究表明，与对照组相比，MS患者颅内主要静脉腔内缺陷的患病率更高。
讨论：考虑到当前的流行病学数据，尸检结果以及CCSVI与灌注不足和脑脊髓液流量的关系，可以将CCSVI插入与MS发病机制有关的多种因素中。我们仔细的数据分析可能会得出结论，MS患者CCSVI患病率的巨大差异可能是静脉超声评估中使用不同方法的结果。最后，已证明CCSVI与MS共同承担了三个主要风险因素。另一方面，吸烟是内皮细胞受损的最重要危险因素，维生素D具有保护作用，爱泼斯坦-巴尔病毒通过侵入内皮细胞而通过血脑屏障，因此在流行病学上将这三个因素的失衡联系在一起自身免疫是影响MS的因素。