BACKGROUND & AIMS: :The TIM (T cell/transmembrane, immunoglobulin and mucin) proteins are crucial regulators of Th1/Th2 immune responses and have been implicated in several diseases including HIV-1/AIDS. The TIM1 exon 4 that codes for mucin domain is highly diverse, with sequence variants associated with varying phenotypes. In this study, TIM1 exon 4 was sequenced among 227 HIV-1 seroprevalent and 288 healthy non infected individuals from North Indian population and haplotypes established. A novel but rare haplotype D1(∗) was identified among the healthy and differed from D1 by a synonymous substitution G>T at Thr208Thr. The TIM1 haplotype diversity showed no association with susceptibility to HIV-1 infection. The seroprevalent individuals carrying D3A had relatively higher median CD4+T cell counts (368/μl) than those without (313/μl; p=0.02). A comparison of CD4+T counts between D3-A individuals on ART or ART naïve did not show any significant difference plausibly due to confounding nature of ART and other factors.

背景与目标： TIM（T细胞/跨膜，免疫球蛋白和粘蛋白）蛋白是Th1 / Th2免疫反应的关键调节剂，并与包括HIV-1 / AIDS在内的多种疾病有关。编码粘蛋白结构域的TIM1外显子4高度多样化，具有与不同表型相关的序列变体。在这项研究中，TIM1外显子4在来自北印度人口的227个HIV-1血清流行和288个健康的未感染个体中进行了测序，并建立了单倍型。在健康人群中鉴定出一种新颖但罕见的单倍型D1（∗），与D1的区别在于在Thr208Thr处的同义替代G> T。 TIM1单倍型多样性表明与HIV-1感染的易感性无关。携带D3A的血清流行个体的CD4 T细胞计数中位数相对较高（不含313 /μl； p = 0.02）。由于ART和其他因素的混杂，D3-A个体或未接受过ART的D3-A个体之间CD4 T计数的比较似乎没有显示任何显着差异。

BACKGROUND & AIMS: :Reported here is the synthesis and biological evaluation of the asialoglycoprotein receptor (ASGP-R) targeted fourth generation poliamidoamine dendrimer (G(4)-PAMAM) loaded with sorafenib. The ASGP-R targeted dendrimer was obtained by conjugation of Lactobionic acid (La) to the G(4)-PAMAM dendrimer, followed by acetylation (Ac) of the free amino groups in order to reduce the non-specific interactions with the cell membrane. Moreover, by additionally grafting fluorescein (FITC), it was easy to characterize the internalization pathway and the intracellular fate of the targeted dendrimer Ac-La-G(4)-PAMAM-FITC. In vitro experiments performed on HepG-2 and HLE cell lines, allowed to study the ability of the dendrimers to affect the cell vitality. Confocal microscopy and cytofluorimetric analysis confirmed higher binding and uptake ability of the Ac-La-G(4)-PAMAM-FITC dendrimer in well differentiated and ASGP-R expressing human liver cancer cell line HepG-2 compared non-expressing HLE cells. Ac-La-G(4)-PAMAM-FITC dendrimer loaded with sorafenib was stable and showed sustained sorafenib release. As evidenced by the cytotoxicity studies, sorafenib included in the dendrimer maintained its effectiveness, and was able to produce a longer lasting effect over the time compared to molar equivalent doses of free sorafenib. This new targeted dendrimer appears to be a suitable carrier for the delivery of sorafenib to liver cancer cells expressing ASGP-R.

背景与目标： ：此处报道的是载有索拉非尼的去唾液酸糖蛋白受体（ASGP-R）靶向的第四代多巴胺胺树状聚合物（G（4）-PAMAM）的合成和生物学评估。 ASGP-R靶向树状聚合物是通过将乳酸基乳酸（La）与G（4）-PAMAM树状聚合物缀合，然后对游离氨基进行乙酰化（Ac），以减少与细胞膜的非特异性相互作用而获得的。此外，通过额外嫁接荧光素（FITC），很容易表征目标树状聚合物Ac-La-G（4）-PAMAM-FITC的内在途径和细胞内命运。在HepG-2和HLE细胞系上进行的体外实验可以研究树状聚合物影响细胞活力的能力。共聚焦显微镜和细胞荧光分析证实，Ac-La-G（4）-PAMAM-FITC树状聚合物在高分化和表达ASGP-R的人肝癌细胞系HepG-2中具有更高的结合和摄取能力，而与未表达的HLE细胞相比则更高。载有索拉非尼的Ac-La-G（4）-PAMAM-FITC树状聚合物稳定并显示索拉非尼持续释放。正如细胞毒性研究所证明的那样，与摩尔当量剂量的游离索拉非尼相比，树状大分子中包含的索拉非尼保持了其有效性，并能够在一段时间内产生更长的持久作用。这种新的靶向树状聚合物看来是将索拉非尼递送至表达ASGP-R的肝癌细胞的合适载体。

BACKGROUND & AIMS: :Accumulating evidence indicates that Toll-like receptor (TLR) signaling adapter protein interactions with Toll/Interleukin-1 Receptor (TIR) domains present in sensory neurons may modulate neuropathic pain states. Following ligand interaction with TLRs, TIR serves to both initiate intracellular signaling and facilitate recruitment of signaling adapter proteins to the intracytoplasmic domain. Although TLR TIR is central to a number of TLR signaling cascades, its role in sensory neurons is poorly understood. In this study we investigated the degree to which TLR TIR decoy peptide modified to include a TAT sequence (Trans-Activator of Transcription gene in HIV; TAT-4BB) affected LPS-induced intracellular calcium flux and excitation in sensory neurons, and behavioral changes due to TLR4 active metabolite, morphine-3-glucuronide (M3G) exposure in vivo. TAT-4BB inhibited LPS-induced calcium changes in a majority of sensory neurons and decreased LPS-dependent neuronal excitability in small diameter neurons. Acute systemic administration of the TAT-4BB reversed M3G-induced tactile allodynia in a dose-dependent manner but did not affect motor activity, anxiety or responses to noxious thermal stimulus. These data suggest that targeting TLR TIR domains may provide novel pharmacological targets to reduce or reverse TLR4-dependent pain behavior in the rodent.

背景与目标： ：越来越多的证据表明，Toll样受体（TLR）信号转接头蛋白与感觉神经元中存在的Toll / Interleukin-1受体（TIR）域相互作用可能会调节神经性疼痛状态。配体与TLR相互作用后，TIR既可以启动细胞内信号传导，也可以促进信号传导衔接子蛋白募集到胞质内域。尽管TLR TIR是许多TLR信号级联的核心，但对其在感觉神经元中的作用知之甚少。在这项研究中，我们调查了TLR TIR诱饵肽修饰为包含TAT序列（HIV转录基因的反式激活因子； TAT-4BB）在多大程度上影响LPS诱导的细胞内钙通量和感觉神经元的兴奋，以及行为改变对TLR4活性代谢产物吗啡-3-葡糖醛酸（M3G）的体内暴露。 TAT-4BB抑制了LPS诱导的大多数感觉神经元中钙的变化，并降低了小直径神经元中LPS依赖性神经元的兴奋性。 TAT-4BB的急性全身给药以剂量依赖的方式逆转了M3G诱导的触觉异常性疼痛，但并未影响运动活动，焦虑或对有害热刺激的反应。这些数据表明，靶向TLR TIR结构域可提供新的药理学靶标，以减少或逆转啮齿动物中TLR4依赖性的疼痛行为。

BACKGROUND & AIMS: :Type 2 diabetes is a strong risk factor for stroke. Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor in clinical use against type 2 diabetes. The aim of this study was to determine the potential antistroke efficacy of linagliptin in type 2 diabetic mice. To understand whether efficacy was mediated by glycemia regulation, a comparison with the sulfonylurea glimepiride was done. To determine whether linagliptin-mediated efficacy was dependent on a diabetic background, experiments in nondiabetic mice were performed. Type 2 diabetes was induced by feeding the mice a high-fat diet for 32 weeks. Mice were treated with linagliptin/glimepiride for 7 weeks. Stroke was induced at 4 weeks into the treatment by transient middle cerebral artery occlusion. Blood DPP-4 activity, glucagon-like peptide-1 (GLP-1) levels, glucose, body weight, and food intake were assessed throughout the experiments. Ischemic brain damage was measured by determining stroke volume and by stereologic quantifications of surviving neurons in the striatum/cortex. We show pronounced antistroke efficacy of linagliptin in type 2 diabetic and normal mice, whereas glimepiride proved efficacious against stroke in normal mice only. These results indicate a linagliptin-mediated neuroprotection that is glucose-independent and likely involves GLP-1. The findings may provide an impetus for the development of DPP-4 inhibitors for the prevention and treatment of stroke in diabetic patients.

背景与目标： ：2型糖尿病是中风的重要危险因素。 Linagliptin是临床上用于治疗2型糖尿病的二肽基肽酶4（DPP-4）抑制剂。这项研究的目的是确定利格列汀在2型糖尿病小鼠中的潜在抗中风功效。为了了解功效是否由血糖调节介导，与磺酰脲格列美脲进行了比较。为了确定利格列汀介导的功效是否取决于糖尿病背景，在非糖尿病小鼠中进行了实验。通过给小鼠喂高脂饮食32周来诱发2型糖尿病。用利格列汀/格列美脲治疗小鼠7周。在治疗的第4周，通过短暂性中脑动脉闭塞诱发中风。在整个实验过程中，评估了血液DPP-4活性，胰高血糖素样肽1（GLP-1）水平，葡萄糖，体重和食物摄入量。通过测定中风量和纹状体/皮层中存活的神经元的立体定量来测量缺血性脑损伤。我们在2型糖尿病和正常小鼠中显示了利格列汀的显着抗中风功效，而格列美脲仅在正常小鼠中被证明对中风有效。这些结果表明，由利格列汀介导的神经保护作用与葡萄糖无关，并且可能涉及GLP-1。这些发现可能为DPP-4抑制剂的开发提供动力，以预防和治疗糖尿病患者的中风。

BACKGROUND & AIMS: :Agents to control melanogenesis are in demand for the development of cosmetics to improve pigmentation disorders of skin and hair. In this study, we examined and evaluated the effects of flavonoids on melanogenesis in the melanogenic cells model, murine B16F10 melanoma cells. In the course of this study, we found that incubation of the cells in a medium containing 10 μM of the 4'-O-methylated flavonoids, diosmetin (4'-O-methylluteolin), acacetin (4'-O-methylapigenin) or kaempferide (4'-O-methylkaempferol), increased the melanin contents of the cells 3- to 7-fold higher than the control cells. The concentration-dependence test revealed that 20 μM acacetin showed the highest effect, up to 33-fold higher than the vehicle. On the other hand, the corresponding 4'-OH-type flavonoids, luteolin, apigenin and kaempferol, had a significantly smaller effect. Furthermore, by evaluating the melanogenic proteins, we found that the cells treated with 4'-O-methylated flavonoids showed higher tyrosinase activity, as well as upregulation of tyrosinase expression, preceded by activation of cAMP response element binding protein (CREB) and extracellular signal-regulated kinases types 1 and 2 (ERK1/2). These results indicate that the 4'-O-methyl group of flavonoids plays an important role in the induction of melanogenesis by activating its major signal transduction pathway through the upregulation of phospho-CREB in murine B16F10 melanoma cells.

背景与目标： ：需要控制黑素生成的试剂来开发化妆品，以改善皮肤和头发的色素沉着障碍。在这项研究中，我们检查和评估了类黄酮对黑色素生成细胞模型鼠B16F10黑色素瘤细胞中黑色素生成的影响。在这项研究过程中，我们发现细胞在含有10μM4'-O-甲基化类黄酮，薯os皂素（4'-O-甲基木犀草素），阿沙西汀（4'-O-甲基芹菜素）或Kaempferide（4'-O-methylkaempferol）使细胞的黑色素含量比对照细胞高3至7倍。浓度依赖性试验表明，20μM醋氨蝶呤显示出最高的作用，比赋形剂高33倍。另一方面，相应的4'-OH型类黄酮，木犀草素，芹菜素和山fer酚的作用要小得多。此外，通过评估黑色素生成蛋白，我们发现用4'-O-甲基化类黄酮处理的细胞显示出更高的酪氨酸酶活性，以及​​酪氨酸酶表达的上调，然后激活cAMP反应元件结合蛋白（CREB）和细胞外信号调节的1型和2型激酶（ERK1 / 2）。这些结果表明，类黄酮的4'-O-甲基通过激活鼠B16F10黑色素瘤细胞中的磷酸-CREB激活其主要信号转导途径，从而在诱导黑色素生成中起重要作用。

BACKGROUND & AIMS: BACKGROUND:Interleukin-17 (IL-17), which is secreted by Th17 cells, is a proinflammatory cytokine that is implicated in the pathogenesis of multiple sclerosis (MS) and plays a role in nonresponse of MS patients to interferon-β (IFN-β) therapy. OBJECTIVES:The purpose of this study was to establish a correlation between nonresponders (NR) and IL-17A serum titers and binding antibodies (BAbs) to IFN-β, as well as to find a correlation between IL-17A serum levels and other features of MS patients. METHODS:Our prospective study included 72 inactive relapsing-remitting multiple sclerosis (RRMS) patients that had been treated for at least 18 months with IFN-β and 15 healthy subjects. We determined the serum levels of IL-17A and of BAbs. IL-17A levels were considered elevated (IL-17A+) if the recorded value was greater than 1.6 pg/ml. RESULTS:Twenty-seven patients (37.5%) were NR and had a significantly higher serum IL-17A level compared to the responders group. Nineteen patients (26.4%) were IL-17A+ and had had a significantly higher number of relapses in the previous year and a higher Expanded Disability Status Score. The majority of IL-17A+ patients were NR and had a shorter MS duration. CONCLUSIONS:RRMS patients with high serum IL-17A levels do not respond well to IFN-β therapy and have shorter MS duration compared to patients with low IL-17A levels. This response is not influenced by the presence of BAbs.

背景与目标： 背景：Th17细胞分泌的白细胞介素17（IL-17）是一种促炎细胞因子，与多发性硬化症（MS）的发病机制有关，并且在MS患者对干扰素-β（IFN- β）疗法。
目的：本研究的目的是建立无应答者（NR）与IL-17A血清滴度和针对IFN-β的结合抗体（BAbs）之间的相关性，以及找出IL-17A血清水平与其他特征之间的相关性MS患者。
方法：我们的前瞻性研究包括72例接受IFN-β治疗至少18个月的非活动性复发缓解型多发性硬化症（RRMS）患者和15名健康受试者。我们确定了IL-17A和BAbs的血清水平。如果记录值大于1.6 pg / ml，则认为IL-17A水平升高（IL-17A）。
结果：27名患者（37.5％）为NR，与应答者组相比，血清IL-17A水平显着更高。 19名患者（26.4％）为IL-17A，在前一年中复发率明显更高，而“扩展残疾状态评分”更高。大多数IL-17A患者为NR，MS病程较短。
结论：与低IL-17A水平的患者相比，血清IL-17A水平高的RRMS患者对IFN-β治疗的反应不佳，MS病程较短。该反应不受BAbs的存在的影响。

BACKGROUND & AIMS: :Utilizing X-ray crystal structure analysis, (3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]piperidine-3-carboxamides were designed and identified as renin inhibitors. The most potent compound 15 demonstrated favorable pharmacokinetic and pharmacodynamic profiles in rat.

背景与目标： ：利用X射线晶体结构分析，设计了（3S，5R）-5- [4-（2-氯苯基）-2,2-二甲基-5-氧哌嗪-1-基]哌啶-3-甲酰胺，并将其鉴定为肾素抑制剂。最有效的化合物15在大鼠中显示出良好的药代动力学和药效学特征。

BACKGROUND & AIMS: :Antitumor agents that bind to tubulin and disrupt microtubule dynamics have attracted considerable attention in the last few years. To extend our knowledge of the thiazole ring as a suitable mimic for the cis-olefin present in combretastatin A-4, we fixed the 3,4,5-trimethoxyphenyl at the C4-position of the thiazole core. We found that the substituents at the C2- and C5-positions had a profound effect on antiproliferative activity. Comparing compounds with the same substituents at the C5-position of the thiazole ring, the moiety at the C2-position influenced antiproliferative activities, with the order of potency being NHCH(3) > Me > N(CH(3))(2). The N-methylamino substituent significantly improved antiproliferative activity on MCF-7 cells with respect to C2-amino counterparts. Increasing steric bulk at the C2-position from N-methylamino to N,N-dimethylamino caused a 1-2 log decrease in activity. The 2-N-methylamino thiazole derivatives 3b, 3d and 3e were the most active compounds as antiproliferative agents, with IC(50) values from low micromolar to single digit nanomolar, and, in addition, they are also active on multidrug-resistant cell lines over-expressing P-glycoprotein. Antiproliferative activity was probably caused by the compounds binding to the colchicines site of tubulin polymerization and disrupting microtubule dynamics. Moreover, the most active compound 3e induced apoptosis through the activation of caspase-2, -3 and -8, but 3e did not cause mitochondrial depolarization.

背景与目标： 近年来，与微管蛋白结合并破坏微管动力学的抗肿瘤剂引起了相当大的关注。为了扩展我们对噻唑环作为康美他汀A-4中存在的顺式烯烃的合适模拟物的认识，我们将3,4,5-三甲氧基苯基固定在噻唑核心的C4位。我们发现，在C2和C5位置的取代基对抗增殖活性具有深远的影响。比较噻唑环C5位上具有相同取代基的化合物，C2位上的部分影响抗增殖活性，效力顺序为NHCH（3）> Me> N（CH（3））（2） 。相对于C 2-氨基对应物，N-甲基氨基取代基显着提高了对MCF-7细胞的抗增殖活性。从N-甲基氨基到N，N-二甲基氨基的C2位增加的空间体积导致活性降低1-2 log。 2-N-甲基氨基噻唑衍生物3b，3d和3e是最有效的化合物作为抗增殖剂，其IC（50）值从低微摩尔到一位数纳摩尔，此外，它们还对耐多药细胞具有活性系过度表达P-糖蛋白。抗增殖活性可能是由于化合物与微管蛋白聚合的秋水仙碱位点结合并破坏了微管动力学而引起的。此外，活性最高的化合物3e通过激活caspase-2，-3和-8诱导细胞凋亡，但3e不会引起线粒体去极化。

BACKGROUND & AIMS: :The anti-inflammatory potential of p38 mitogen-activated protein kinase (MAPK) inhibitors was coincidentally expanded to a dual inhibition of p38α MAPK and phosphodiesterase 4 (PDE4), and the potential benefits arising from the blockage of both inflammation-related enzymes were thoroughly investigated. The most promising compound, CBS-3595 (1), was successively evaluated in in vitro experiments as well as in ex vivo and in vivo preclinical studies after administration of 1 to rodents, dogs, and monkeys. The resulting data clearly indicated a potent suppression of tumor necrosis factor alpha release. For reconfirming the findings of the animal studies when administering 1 to healthy human volunteers, a phase I clinical trial was conducted. Apart from further information regarding the pharmacokinetic and pharmacodynamic characteristics of 1, it was demonstrated that dual inhibition of p38α MAPK and PDE4 is able to synergistically attenuate the excessive anti-inflammatory response.

背景与目标： ：p38丝裂原活化蛋白激酶（MAPK）抑制剂的抗炎潜能同时扩展到了p38αMAPK和磷酸二酯酶4（PDE4）的双重抑制作用，并且两种炎症相关酶均被阻断产生了潜在的益处调查。给啮齿动物，狗和猴子施用1后，在体外实验以及离体和体内临床前研究中相继评估了最有前途的化合物CBS-3595（1）。所得数据清楚地表明有效抑制了肿瘤坏死因子α的释放。为了确认对健康的人类志愿者给药1时动物研究的结果，进行了I期临床试验。除了有关1的药代动力学和药效学特性的进一步信息外，还证明了对p38αMAPK和PDE4的双重抑制能够协同减弱过度的抗炎反应。

BACKGROUND & AIMS: :Bacterial-derived lipopolysaccharides (LPS) play an essential role in the inflammatory process of inflammatory bowel disease. A defective intestinal tight junction (TJ) barrier is an important pathogenic factor of inflammatory bowel disease and other inflammatory conditions of the gut. Despite its importance in mediating intestinal inflammation, the physiological effects of LPS on the intestinal epithelial barrier remain unclear. The major aims of this study were to determine the effects of physiologically relevant concentrations of LPS (0 to 1 ng/mL) on intestinal barrier function using an in vitro (filter-grown Caco-2 monolayers) and an in vivo (mouse intestinal perfusion) intestinal epithelial model system. LPS, at physiologically relevant concentrations (0 to 1 ng/mL), in the basolateral compartment produced a time-dependent increase in Caco-2 TJ permeability without inducing cell death. Intraperitoneal injection of LPS (0.1 mg/kg), leading to clinically relevant plasma concentrations, also caused a time-dependent increase in intestinal permeability in vivo. The LPS-induced increase in intestinal TJ permeability was mediated by an increase in enterocyte membrane TLR-4 expression and a TLR-4-dependent increase in membrane colocalization of membrane-associated protein CD14. In conclusion, these studies show for the first time that LPS causes an increase in intestinal permeability via an intracellular mechanism involving TLR-4-dependent up-regulation of CD14 membrane expression.

背景与目标： 细菌脂多糖（LPS）在炎症性肠病的炎症过程中起着至关重要的作用。肠紧密连接（TJ）屏障缺陷是炎症性肠病和肠道其他炎症性状的重要致病因素。尽管其在介导肠炎症中的重要性，但是LPS对肠上皮屏障的生理作用仍不清楚。这项研究的主要目的是使用体外（滤器生长的Caco-2单层）和体内（小鼠肠灌注）确定生理相关浓度的LPS（0至1 ng / mL）对肠屏障功能的影响）肠上皮模型系统。在生理相关浓度（0到1 ng / mL）下，基底外侧隔室中的LPS导致Caco-2 TJ通透性随时间的增加，而不会引起细胞死亡。腹膜内注射LPS（0.1 mg / kg）会导致临床上相关的血浆浓度，还会引起体内肠道通透性的时间依赖性增加。 LPS诱导的肠道TJ通透性增加是由肠上皮细胞膜TLR-4表达的增加和与膜相关的蛋白质CD14的膜共定位中TLR-4依赖性的增加介导的。总之，这些研究首次显示LPS通过涉及TLR-4依赖性CD14膜表达上调的细胞内机制引起肠道通透性增加。

BACKGROUND & AIMS: :The effects of bread consumption change over time on anthropometric measures have been scarcely studied. We analysed 2213 participants at high risk for CVD from the PREvención con DIeta MEDiterránea (PREDIMED) trial to assess the association between changes in the consumption of bread and weight and waist circumference gain over time. Dietary habits were assessed with validated FFQ at baseline and repeatedly every year during 4 years of follow-up. Using multivariate models to adjust for covariates, long-term weight and waist circumference changes according to quartiles of change in energy-adjusted white and whole-grain bread consumption were calculated. The present results showed that over 4 years, participants in the highest quartile of change in white bread intake gained 0·76 kg more than those in the lowest quartile (P for trend = 0·003) and 1·28 cm more than those in the lowest quartile (P for trend < 0·001). No significant dose-response relationships were observed for change in whole-bread consumption and anthropometric measures. Gaining weight (>2 kg) and gaining waist circumference (>2 cm) during follow-up was not associated with increase in bread consumption, but participants in the highest quartile of changes in white bread intake had a reduction of 33 % in the odds of losing weight (>2 kg) and a reduction of 36 % in the odds of losing waist circumference (>2 cm). The present results suggest that reducing white bread, but not whole-grain bread consumption, within a Mediterranean-style food pattern setting is associated with lower gains in weight and abdominal fat.

背景与目标： ：很少研究面包消耗量随时间变化对人体测量学的影响。我们从PREVENCIónCON DIetaMEDiterránea（PREDIMED）试验中分析了2213名有CVD高风险的参与者，以评估面包消耗量和体重变化与腰围增加之间的关系。饮食习惯在基线时通过有效的FFQ进行评估，并在随访的4年中每年重复进行。使用多元模型对协变量进行调整，根据能量调整后的白面包和全麦面包消耗量的变化的四分位数，计算了长期体重和腰围的变化。目前的结果表明，在过去4年中，白面包摄入量变化最高四分位数的参与者比最低四分位数的参与者增加了0·76 kg（趋势P = 0·003），比最低四分位数的参与者增加了1·28 cm。最低四分位数（趋势<0·001的P）。没有观察到明显的剂量反应关系，即全面包消费和人体测量学的变化。随访期间体重增加（> 2 kg）和腰围增加（> 2 cm）与面包消耗量增加无关，但是参加白面包摄入量变化最高四分位数的参与者的机率降低了33％减轻体重（> 2 kg），减少腰围（> 2 cm）的几率降低36％。目前的结果表明，在地中海式饮食模式下减少白面包食用而不是全麦面包食用与体重增加和腹部脂肪减少有关。

BACKGROUND & AIMS: :IL-23 and IL-17 are pro-inflammatory cytokines. IL-23 is secreted by activated macrophages and dendritic cells, while IL-17 by Th17 cells. Serum IL-23 and IL-17 are known to be elevated in numerous inflammatory diseases including neurodegenerative diseases. The role of serum IL-23 and IL-17 in aneurysmal subarachnoid hemorrhage (aSAH) has still not been investigated. The present work investigates the serum IL-23 and IL-17 levels and their association with post hemorrhagic complications and clinical outcome in patients with aSAH. METHODS:In this study, 80 patients with aSAH (Hunt and Hess grade I-V) were prospectively recruited. We enrolled 24 control patients with lumbar spinal stenosis. Peripheral venous blood was withdrawn from controls and from aSAH patients at day 1 and day 7, allowed to clot and centrifuged to obtain serum. Enzyme linked immunoassay kits were employed to quantify the serum levels of IL-23 and IL-17 by applying 50µL of serum samples. Post hemorrhagic complications and clinical outcome were documented prospectively from patient's hospital record. RESULTS:Serum IL-23 and IL-17 levels were significantly elevated in aSAH patients at day 1 and day 7 (n=80) as compared to control patients (n=24). Further analysis after dichotomy of patients who suffered from post hemorrhagic complications including cerebral vasospasm, chronic hydrocephalus, seizures, cerebral ischemia, delayed neurological deficits showed differential correlations with different post hemorrhagic complications (Table 1). Serum IL-23 and IL-17 levels did not correlate with clinical outcome. CONCLUSION:Serum IL-23 and IL-17 levels were elevated in patients with aSAH showing upregulation of IL-23/IL-17 inflammatory axis after aSAH. Serum IL-23 and IL-17 showed differential correlations with post hemorrhagic complications and no correlation with clinical outcome.

背景与目标： ：IL-23和IL-17是促炎性细胞因子。 IL-23由活化的巨噬细胞和树突状细胞分泌，而IL-17由Th17细胞分泌。已知血清IL-23和IL-17在包括神经退行性疾病在内的许多炎性疾病中均升高。血清IL-23和IL-17在动脉瘤性蛛网膜下腔出血（aSAH）中的作用尚未进行研究。本工作调查了aSAH患者的血清IL-23和IL-17水平及其与出血后并发症和临床结局的关系。
方法：在这项研究中，前瞻性招募了80例aSAH患者（Hunt和Hess I-V级）。我们招募了24名腰椎管狭窄的对照患者。在第1天和第7天从对照和aSAH患者中抽取外周静脉血，使其凝结并离心以获得血清。采用酶联免疫分析试剂盒，通过施加50µL血清样品定量IL-23和IL-17的血清水平。从患者的住院记录中前瞻性地记录了出血后并发症和临床结局。
结果：与对照组患者（n = 24）相比，aSAH患者在第1天和第7天的血清IL-23和IL-17水平显着升高（n = 80）。二分法对患有出血后并发症（包括脑血管痉挛，慢性脑积水，癫痫发作，脑缺血，迟发性神经功能缺损）的患者进行二分法手术后的进一步分析显示，不同出血后并发症的相关性不同（表1）。血清IL-23和IL-17水平与临床结果无关。
结论：aSAH患者血清IL-23和IL-17水平升高，显示aSAH后IL-23 / IL-17炎症轴上调。血清IL-23和IL-17与出血后并发症呈差异相关，与临床结局无相关性。

BACKGROUND & AIMS: :Traumatic brain injury (TBI) remains the leading cause of injury-related death and disability. Brain edema, one of the most major complications of TBI, contributes to elevated intracranial pressure, and poor prognosis following TBI. Nerve growth factor (NGF) appears to be a viable strategy to treat brain edema and TBI. Unfortunately, due to its poor blood-brain barrier (BBB) permeability, the clinical application of NGF has been greatly limited. We previously demonstrated that intranasal NGF could bypass the BBB and distribute throughout the brain. Here we further studied whether intranasal NGF could attenuate TBI-induced brain edema and its putative mechanisms. TBI was produced by a modified weight-drop model. We found that intranasal administration of NGF (5μg/d) attenuated the brain edema, as assayed by hemisphere water content, at 12h, 24h and 72h after TBI induction. This attenuation was associated with a prominent decrease of the content of aquaporin-4, which plays a pivotal role in the formation of brain edema. By the use of RT-PCR and ELISA, we showed that intranasal NGF markedly inhibited the transcription and expression of pro-inflammatory cytokines including IL-1β and TNF-α. An electrophoretic mobility shift assay (EMSA) displayed a significant activation of nuclear factor-κB following TBI, which was, however, much lowered in the NGF-treated rats. Furthermore, upon intranasal NGF supplementation, mitochondria-mediated apoptosis following TBI was minimized, as indicated by upregulation of Bcl-2 and downregulation of caspase-3. Collectively, our findings suggested that intranasal NGF may be a promising strategy to treat brain edema and TBI.

背景与目标： ：脑外伤（TBI）仍然是与伤害相关的死亡和残疾的主要原因。脑水肿是TBI最主要的并发症之一，导致颅内压升高，TBI后预后较差。神经生长因子（NGF）似乎是治疗脑水肿和TBI的可行策略。不幸的是，由于其不良的血脑屏障（BBB）通透性，NGF的临床应用受到了极大的限制。我们先前证明了鼻内NGF可以绕过BBB并分布在整个大脑中。在这里，我们进一步研究了鼻内NGF是否可以减轻TBI诱导的脑水肿及其可能的机制。 TBI是通过修改后的体重减轻模型产生的。我们发现鼻内施用NGF（5μg/ d）可以减轻脑水肿，通过​​TBI诱导后12h，24h和72h的半球水含量进行分析。这种衰减与aquaporin-4含量的显着下降有关，aquaporin-4的含量在脑水肿的形成中起着关键作用。通过使用RT-PCR和ELISA，我们显示鼻内NGF明显抑制促炎细胞因子包括IL-1β和TNF-α的转录和表达。电泳迁移率迁移分析（EMSA）显示TBI后核因子-κB的显着激活，但是在NGF治疗的大鼠中其活性大大降低。此外，鼻内补充NGF后，TBI后线粒体介导的凋亡得以最小化，如Bcl-2的上调和caspase-3的下调所示。总体而言，我们的研究结果表明，鼻内NGF可能是治疗脑水肿和TBI的一种有前途的策略。

BACKGROUND & AIMS: :An effective immune response to antigen requires professional antigen-presenting cell (APC), which not only present antigen, but also provide costimulation and cytokines (eg, IL-12) that drive T cell differentiation down the appropriate effector pathway (Tc1/TH1). For T cell-based immunotherapy protocols, the availability of large numbers of autologous professional APC is a major limitation because professional APC do not proliferate in vitro. T cells themselves can proliferate exponentially in vitro and have the ability to present antigen. They can also express costimulatory molecules after activation. Therefore, we hypothesized that if activated T cells were genetically modified to express proinflammatory cytokines required to polarize T cells toward a Tc1 response, they could fulfill the requirements for an abundant, autologous APC. To test this potential, T cells were activated by CD3/CD28 antibodies and pulsed with model HLA-A2+ peptides derived from CMVpp65, MAGE-3, and MART-1. Activated T-APC readily reactivated CD8 pp65 memory T cells from healthy CMV seropositive donors; however, the activation of MAGE-3 and MART-1-specific CD8 T cells required both IL-7 and IL-12, which could be provided either exogenously or by genetic modification of the T-APC. Responder T cells could be expanded to large numbers with subsequent stimulations using activated, peptide-pulsed T-APC and IL-2. Tumor antigen-specific T cell lines killed both peptide-pulsed target cells and tumor cell lines. Thus, T cells provide a platform for the generation of autologous APC that can be customized to express both antigens and therapeutic molecules for the induction of antigen-specific T cell immunity.

背景与目标： ：对抗原的有效免疫反应需要专业的抗原呈递细胞（APC），它不仅呈递抗原，而且还提供共刺激和细胞因子（例如IL-12），以驱动T细胞向适当的效应子途径（Tc1 / TH1）分化）。对于基于T细胞的免疫疗法方案，大量的自体专业APC的可用性是一个主要限制，因为专业APC不会在体外增殖。 T细胞本身可以在体外成倍增殖，并具有呈递抗原的能力。它们还可以在激活后表达共刺激分子。因此，我们假设，如果对活化的T细胞进行基因修饰以表达使T细胞朝Tc1反应极化所需的促炎细胞因子，那么它们就可以满足丰富的自体APC的要求。为了测试这种潜力，T细胞被CD3 / CD28抗体激活，并用衍生自CMVpp65，MAGE-3和MART-1的模型HLA-A2肽脉冲。激活的T-APC可以很容易地激活来自健康CMV血清反应阳性供体的CD8 pp65记忆T细胞。然而，MAGE-3和MART-1特异性CD8 T细胞的激活需要IL-7和IL-12，这可以通过外源或通过T-APC的遗传修饰来提供。可以使用激活的，肽脉冲的T-APC和IL-2在随后的刺激下将应答剂T细胞扩增为大量。肿瘤抗原特异性T细胞系杀死了肽脉冲的靶细胞和肿瘤细胞系。因此，T细胞提供了用于产生自体APC的平台，该平台可以被定制以表达抗原和治疗性分子以诱导抗原特异性T细胞免疫。

BACKGROUND & AIMS: BACKGROUND CONTEXT:Although autogenous bone is still considered to be the gold standard graft material for promoting spinal fusion, other bone graft substitutes have been developed in an attempt to improve arthrodesis rates and avoid the complications associated with the procurement of autograft. The bone morphogenetic proteins (BMPs) represent a family of osteoinductive growth factors that are known to stimulate the osteoblastic differentiation of stem cells. Osteogenic protein-1 (OP-1) Putty is a commercially available BMP preparation that is already approved for use in humans. Previous clinical studies involving patients with degenerative spondylolisthesis have reported that the efficacy and safety of OP-1 Putty is comparable to that of autograft at both 1- and 2-year follow-up. PURPOSE:The purpose of this study was to evaluate the intermediate-term efficacy and safety of OP-1 Putty as an alternative to autogenous bone by comparing the 4-year radiographic, clinical, and safety data of these same patients who underwent decompression and uninstrumented fusion with either OP-1 Putty or iliac crest autograft. STUDY DESIGN/SETTING:A prospective, randomized, controlled, multicenter clinical pilot study. PATIENT SAMPLE:Thirty-six patients undergoing decompressive laminectomy and single-level uninstrumented fusion for degenerative spondylolisthesis and symptomatic spinal stenosis were randomized in a 2:1 fashion to receive either OP-1 Putty (24 patients) or autogenous iliac crest bone graft (12 patients). OUTCOME MEASURES:Patient-reported outcome measures consisting of Oswestry Disability Index and Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) scores were used to evaluate clinical efficacy. Perioperative data including operative time, estimated blood loss, and duration of hospital stay were also recorded for each surgery. Postoperatively, a neurological examination and an assessment of donor-site pain (if applicable) were performed at every follow-up visit. Radiographic fusion success was defined as the presence of continuous bridging bone formation between the transverse processes at the level of the spondylolisthesis with minimal motion evident on dynamic lateral x-ray films. The primary efficacy endpoint was the overall success rate, a composite measure derived from both radiographic and clinical parameters. The safety of OP-1 Putty was confirmed by comparing the nature and frequency of all adverse events and complications that were prospectively observed in either of the groups. METHODS:Thirty-six patients with degenerative spondylolisthesis and symptoms of neurogenic claudication underwent decompressive laminectomy and single-level uninstrumented fusion with either OP-1 Putty or autograft. All patients were evaluated at 6 weeks and 3, 6, 9, 12, and 24 months, after which time they were instructed to return on a yearly basis. Multiple neuroradiologists blinded to the assigned treatment reviewed static and dynamic X-ray films with digital calipers to assess fusion status according to the presence of continuous bridging bone across the transverse processes as well as the amount of residual motion evident at the level of interest. Oswestry Disability Index surveys and SF-36 questionnaires were used to assess clinical outcomes. RESULTS:At the 48-month time point, complete radiographic and clinical data were available for 22 of 36 patients (16 OP-1 Putty and 6 autograft) and 25 of 36 patients (18 OP-1 Putty and 7 autograft), respectively. Radiographic evidence of a solid arthrodesis was present in 11 of 16 OP-1 Putty patients (68.8%) and 3 of 6 autograft patients (50%). Clinically successful outcomes defined as at least a 20% improvement in preoperative Oswestry scores were experienced by 14 of 19 OP-1 Putty patients (73.7%) and 4 of 7 autograft patients (57.1%); these clinical findings were corroborated by similar increases in SF-36 scores. The respective overall success rates of the OP-1 Putty and autograft group were 62.5% and 33.3%. In this study, there were no incidents of local or systemic toxicity, ectopic bone production, or other adverse events directly related to the use of OP-1 Putty. CONCLUSION:Despite the challenges associated with obtaining a solid uninstrumented fusion in patients with degenerative spondylolisthesis, the rates of radiographic fusion, clinical improvement, and overall success associated with the use of OP-1 Putty were at least comparable to that of the autograft controls for at least 48 months after surgery. These results appear to validate the short-term results previously reported for OP-1 Putty and suggest that this material may potentially represent a viable bone graft substitute for certain fusion applications.

背景与目标： 背景技术：尽管自体骨仍被认为是促进脊柱融合的金标准移植材料，但已开发出其他骨移植替代品以试图提高关节固定率并避免与自体移植相关的并发症。骨形态发生蛋白（BMP）代表一类骨诱导生长因子，已知这些因子可刺激干细胞的成骨细胞分化。成骨蛋白1（OP-1）腻子是一种可商购的BMP制剂，已被批准用于人类。先前涉及退行性脊椎滑脱患者的临床研究报告，在1年和2年的随访中，OP-1腻子的功效和安全性与自体移植相当。
目的：本研究的目的是通过比较这些接受减压和非器械治疗的患者的4年放射学，临床和安全性数据，评估OP-1油灰替代自体骨的中期疗效和安全性与OP-1油灰或骨自体融合。
研究设计/设置：一项前瞻性，随机，对照，多中心临床试验研究。
患者样本：36例行减压椎板切除术和单级非器械融合治疗退行性腰椎滑脱和症状性椎管狭窄的患者以2：1方式随机接受OP-1腻子（24例）或自体骨植骨（12例）耐心）。
结局指标：采用Oswestry残疾指数和医学结局研究36项简表健康调查（SF-36）评分组成的患者报告结局指标，用于评估临床疗效。每次手术还记录了围手术期数据，包括手术时间，估计的失血量和住院时间。术后，每次随访均进行神经系统检查和对供体部位疼痛的评估（如果适用）。影像学上的融合成功定义为在横向滑突之间在脊椎滑脱水平处连续桥接骨形成，而在动态侧向X射线胶片上可见的运动极小。主要功效终点是总体成功率，这是一项从放射学和临床参数中得出的综合指标。 OP-1腻子的安全性通过比较两组中预期观察到的所有不良事件和并发症的性质和频率来确定。
方法：36例退行性腰椎滑脱和神经源性lau行症状的患者接受减压椎板切除术和单层非器械融合OP-1腻子或自体移植。在第6周和第3、6、9、12和24个月对所有患者进行评估，然后指示他们每年返回一次。多位神经放射科医生对指定的治疗方法视而不见，并用数字卡尺检查了静态和动态X射线胶片，以根据横断过程中连续桥接骨的存在以及感兴趣水平上明显的残余运动量来评估融合状态。 Oswestry残疾指数调查和SF-36问卷用于评估临床结局。
结果：在48个月的时间点，分别可获得36例患者中的22例（16例OP-1腻子和6例自体移植）和36例患者中的25例（18例OP-1腻子和7例自体移植）的完整影像学和临床资料。 16例OP-1腻子患者中有11例（68.8％）和6例自体移植患者中有3例（50％）出现了牢固的关节固定的影像学证据。 19例OP-1腻子患者中的14例（73.7％）和7例自体移植患者中的4例（57.1％）经历了临床上成功的结果，定义为术前Oswestry评分至少提高了20％。这些临床发现被SF-36分数的类似提高所证实。 OP-1腻子和自体移植组的总体总体成功率分别为62.5％和33.3％。在这项研究中，没有发生局部或全身毒性，异位骨生成或与使用OP-1腻子直接相关的其他不良事件的事件。
结论：尽管在退行性脊椎滑脱患者中获得牢固的非器械融合具有挑战性，但与使用OP-1腻子相关的放射成像融合率，临床改善率和总体成功率至少可与自体植骨对照用于手术后至少48个月。这些结果似乎证实了先前报道的OP-1油灰的短期结果，并表明该材料可能是某些融合应用中可行的骨移植替代品。