What factors determine patients’ preference for tumour necrosis factor inhibitors in ankylosing spondylitis?

Tumour necrosis factor inhibitor (TNFi) therapy, either intravenous (IV) or subcutaneous (SQ), demonstrates similar efficacy in ankylosing spondylitis (AS). The objective of this study was to examine factors influencing patient preference of TNFi. Fifty-nine (79.7%) participants were male with mean age 43.9 years and disease duration of 22.0 years. Fifty-nine patients (79.7%) agreed with the statement ‘My doctor gave me a choice and I made a decision based on my personal preference’. Patients commenced first on IV TNFi most commonly cited reduced frequency of injections (96.6%), administration by a trained professional (89.7%) and use of infusion time for leisure activities (86.2%). Patients commenced on SQ TNFi cited flexibility with timing of treatment (80%), shortened administration time (73.3%) and the convenience of home therapy (73.3%). Shared clinical decision-making between clinicians and patients may be desirable for AS patients commencing TNFi therapy.     

MicroRNAs and the Regulation of Vector Tropism

Despite being small (~22 nt) microRNAs (miRNAs) profoundly influence tissue-specific gene expression by interacting with complementary target sequences in cellular messenger RNAs, impairing their translation or marking them for early destruction. Recent work has shown that tissue-specific miRNAs offer a versatile target that can be exploited to control the tropisms of gene expression vectors and of replication-competent viruses. The principle of incorporating miRNA targets into vector genomes to control their tropisms was first demonstrated for nonreplicating lentiviral and adenoviral vectors, with subsequent extension of these studies to replication-competent (oncolytic) picornaviruses, rhabdoviruses, and adenoviruses. In contrast to previous targeting approaches, miRNA targeting looks set to be applicable across the entire spectrum of viruses and gene expression vectors. Here we provide a critique of the literature relevant to this new and rapidly developing field of endeavor. We also examine the possibility of engineering viruses for expression of tropism-regulating miRNAs.     

AAV1/2-mediated CNS Gene Delivery of Dominant-negative CCL2 Mutant Suppresses Gliosis, ��-amyloidosis, and Learning Impairment of APP/PS1 Mice

Accumulation of aggregated amyloid-β (Aβ) peptide was studied as an initial step for Alzheimer''s disease (AD) pathogenesis. Following amyloid plaque formation, reactive microglia and astrocytes accumulate around plaques and cause neuroinflammation. Here brain chemokines play a major role for the glial accumulation. We have previously shown that transgenic overexpression of chemokine CCL2 in the brain results in increased microglial accumulation and diffuse amyloid plaque deposition in a transgenic mouse model of AD expressing Swedish amyloid precursor protein (APP) mutant. Here, we report that adeno-associated virus (AAV) serotype 1 and 2 hybrid efficiently deliver 7ND gene, a dominant-negative CCL2 mutant, in a dose–response manner and express >1,000-fold higher recombinant CCL2 than basal levels after a single administration. AAV1/2 hybrid virus principally infected neurons without neuroinflammation with sustained expression for 6-months. 7ND expressed in APP/presenilin-1 (APP/PS1) bigenic mice reduced astro/microgliosis, β-amyloidosis, including suppression of both fibrillar and oligomer Aβ accumulation, and improved spatial learning. Our data support the idea that the AAV1/2 system is a useful tool for CNS gene delivery, and suppression of CCL2 may be a therapeutic target for the amelioration of AD-related neuroinflammation.     

Attentional modulation of stimulus representation in human fronto-parietal cortex

Evidence from primates suggests that prefrontal and parietal regions selectively represent information that is relevant for current behavior. In humans, whilst functional imaging has shown that fronto-parietal areas are activated by a range of different cognitive demands, the actual content of representation remains unclear. The current report describes two studies designed to address this issue using fMRI adaptation. In both studies, participants completed a delayed matching task where they attended to either the color or the shape of a series of sample stimuli and indicated whether occasional test stimuli matched the preceding sample on the attended dimension. Whole brain contrasts showed that changes to the value of the currently attended dimension produced significantly greater responses in frontal and parietal areas than events where the value was repeated. In addition, prefrontal and parietal regions of interest showed strong interactions between the currently attended dimension and the type of stimulus change, reflecting an attentional modulation of responses to stimulus change. Further comparisons suggested that the differences between attended changes and stimulus repetitions carried information about specific stimulus values, and did not simply reflect a generic response to attended changes.     

颈动脉狭窄的筛查美国预防服务特别工作组对证据的更新

背景 在美国,脑血管病是导致死亡的第3位原因.在所有卒中病例中,由既往无症状颈动脉狭窄(carotid artery stenosis,CAS)造成的比例并不高.1996年,美国预防服务特别工作组得出结论,没有充分的证据推荐或反对通过体格检查或颈动脉超声在无症状患者中对CAS进行筛查.目的 评估采用双功能超声对无症状患者进行筛查以及应用颈动脉内膜切除术(carotid endarterectomy,CEA)对CAS进行治疗的利弊.数据来源 Medline和Cochrane数据库(检索日期为1994年1月-2007年4月)、最近的系统评价、检索文章的参考文献以及专家的建议.研究选择 选择对CAS进行筛查的英文随机对照试验(randomized controlled trial,RCT)、对CEA与药物治疗进行比较的RCT、筛查试验的系统评价以及对CEA害处的观察性研究,以回答下列问题:是否有直接证据表明使用超声筛查无症状CAS能降低卒中风险? 超声检测CAS的准确性如何? CEA治疗能否降低卒中残疾率或病死率? CAS筛查或CEA治疗是否会给患者带来伤害? 数据提取 使用预先确定的特殊工作组标准,对所有研究进行评估、提炼和质量评定.数据综合 至今尚未进行过CAS筛查的RCT.根据系统评价,超声检测CAS的敏感性约为94%,特异性约为92%.在经过选择的患者中由选定的外科医生进行手术治疗可使5年卒中风险降低约5%.在RCT中,CEA的30 d卒中和死亡发生率为2.7%～4.7%,而在观察性研究中的发生率更高(高达6.7%).局限性 证据不足以对有临床意义的CAS进行风险分层.对患者行CEA与药物治疗相比较的RCT是在经过选择的人群中由特定的外科医生实施的.结论 对无症状患者进行CAS筛查以及进行CEA治疗造成的实际卒中风险降低率尚不清楚;由于整个无症状人群中可治疗疾病的总体患病率不高且治疗会造成一定的害处,因此筛查的益处受到限制.     

Myocardial metabolic imaging: Viability and beyond

Because of the high metabolic cost of maintaining an adequate cardiac output, the heart possesses the ability to utilize a wide variety of metabolic substrates, including fatty acids, glucose, lactate, amino acids, and ketone bodies. The relative contribution of each of these substrates is regulated by multiple factors, including substrate concentration, presence of adequate blood flow and oxygen, the action of a variety of hormones, and the influences of disease states that can alter the metabolic machinery of the heart. This review summarizes the biochemical and cellular basis of myocardial substrate selection, as well as the changes in the metabolic phenotype of the heart in response to cardiac diseases. Based on this background, this review also illustrates the nuclear-based imaging techniques that can be used to assess myocardial metabolism and their current and future applications to patient care.     

Treatment of nasopharyngeal carcinoma with Epstein-Barr virus--specific T lymphocytes

Conventional treatment for nasopharyngeal carcinoma (NPC) frequently fails and is accompanied by severe long-term side effects. Since virtually all undifferentiated NPCs are associated with Epstein-Barr virus (EBV), this tumor is an attractive candidate for cellular immunotherapy targeted against tumor-associated viral antigens. We now demonstrate that EBV-specific cytotoxic T-cell (CTL) lines can readily be generated from individuals with NPC, notwithstanding the patients' prior exposure to chemotherapy/radiation. A total of 10 patients diagnosed with advanced NPC were treated with autologous CTLs. All patients tolerated the CTLs, although one developed increased swelling at the site of pre-existing disease. At 19 to 27 months after infusion, 4 patients treated in remission from locally advanced disease remain disease free. Of 6 patients with refractory disease prior to treatment, 2 had complete responses, and remain in remission over 11 to 23 months after treatment; 1 had a partial remission that persisted for 12 months; 1 has had stable disease for more than 14 months; and 2 had no response. These results demonstrate that administration of EBV-specific CTLs to patients with advanced NPC is feasible, appears to be safe, and can be associated with significant antitumor activity.