Estimation of phase signal change in neuronal current MRI for evoke response of tactile detection with realistic somatosensory laminar network model

Magnetic field generated by neuronal activity could alter magnetic resonance imaging (MRI) signals but detection of such signal is under debate. Previous researches proposed that magnitude signal change is below current detectable level, but phase signal change (PSC) may be measurable with current MRI systems. Optimal imaging parameters like echo time, voxel size and external field direction, could increase the probability of detection of this small signal change. We simulate a voxel of cortical column to determine effect of such parameters on PSC signal. We extended a laminar network model for somatosensory cortex to find neuronal current in each segment of pyramidal neurons (PN). 60,000 PNs of simulated network were positioned randomly in a voxel. Biot–savart law applied to calculate neuronal magnetic field and additional phase. The procedure repeated for eleven neuronal arrangements in the voxel. PSC signal variation with the echo time and voxel size was assessed. The simulated results show that PSC signal increases with echo time, especially 100/80 ms after stimulus for gradient echo/spin echo sequence. It can be up to 0.1 mrad for echo time = 175 ms and voxel size = 1.48 × 1.48 × 2.18 mm³. With echo time less than 25 ms after stimulus, it was just acquired effects of physiological noise on PSC signal. The absolute value of the signal increased with decrease of voxel size, but its components had complex variation. External field orthogonal to local surface of cortex maximizes the signal. Expected PSC signal for tactile detection in the somatosensory cortex increase with echo time and have no oscillation.     

术前血清CA125、HE4和中性粒细胞与淋巴细胞比值联合检测在子宫内膜癌诊断中的作用

目的:探讨血清糖类抗原125（carbohydrate antigen 125，CA125）、人附睾蛋白4（human epididymis protein 4，HE4）、中性粒细胞与淋巴细胞比值（neutrophil-lymphocyte ratio，NLR）联合检测在子宫内膜癌诊断中的作用。方法:选取42例子宫内膜癌患者、50例子宫内膜良性疾病患者和50例健康体检人群。采用SYSMEX XN550全自动血液分析仪计数术前外周血中性粒细胞和淋巴细胞，计算NLR；采用Maglumi4000全自动化学发光仪检测术前血清CA125、HE4水平。采用ROC曲线分析CA125、HE4、NLR和三者联合指标在诊断子宫内膜癌中的作用。结果:外周血NLR在健康组、良性组和子宫内膜癌组中逐渐增高，且差异有统计学意义（P<0.05）；子宫内膜癌组HE4表达量显著高于良性组与健康组（P<0.05），而良性组与健康组之间差异无统计学意义（P>0.05）；CA125表达量在三组中差异无统计学意义（P>0.05）。CA125、HE4、NLR及三者联合标记物的AUC分别为0.530、0.733、0.795、0.823，当分别取它们的临界值时，特异性分别为70.8%、85.1%、61.7%、83.0%，敏感性分别为40.0%、63.3%、86.7%、73.3%。单项指标NLR的敏感性最高，HE4的特异性最高，联合指标的特异性和敏感性都很高。结论:术前血清CA125、HE4和NLR联合检测具有较高的特异性和敏感性，联合检测可以互为补充，提高子宫内膜癌的诊断准确率，对子宫内膜癌的诊断具有指导意义。     

Binding mode of conformations and structure-based pharmacophore development for farnesyltransferase inhibitors

Farnesyltransferase (FTase) is one of the prenyltransferase family enzymes that catalyse the transfer of 15-membered isoprenoid (farnesyl) moiety to the cysteine of CAAX motif-containing proteins including Rho and Ras family of G proteins. Inhibitors of FTase act as drugs for cancer, malaria, progeria and other diseases. In the present investigation, we have developed two structure-based pharmacophore models from protein–ligand complex (3E33 and 3E37) obtained from the protein data bank. Molecular dynamics (MD) simulations were performed on the complexes, and different conformers of the same complex were generated. These conformers were undergone protein–ligand interaction fingerprint (PLIF) analysis, and the fingerprint bits have been used for structure-based pharmacophore model development. The PLIF results showed that Lys164, Tyr166, TrpB106 and TyrB361 are the major interacting residues in both the complexes. The RMSD and RMSF analyses on the MD-simulated systems showed that the absence of FPP in the complex 3E37 has significant effect in the conformational changes of the ligands. During this conformational change, some interactions between the protein and the ligands are lost, but regained after some simulations (after 2 ns). The structure-based pharmacophore models showed that the hydrophobic and acceptor contours are predominantly present in the models. The pharmacophore models were validated using reference compounds, which significantly identified as HITs with smaller RMSD values. The developed structure-based pharmacophore models are significant, and the methodology used in this study is novel from the existing methods (the original X-ray crystallographic coordination of the ligands is used for the model building). In our study, along with the original coordination of the ligand, different conformers of the same complex (protein–ligand) are used. It concluded that the developed methodology is significant for the virtual screening of novel molecules on different targets.     

Dying is the Most Grown-Up Thing We Ever Do: But Do Health Care Professionals Prevent Us from Taking It Seriously?

This paper takes a somewhat slant perspective on flourishing and care in the context of suffering, death and dying, arguing that care in this context consists principally of ‘acts of work and courage that enable flourishing’. Starting with the perception that individuals, society and health care professionals have become dulled to death and the process of dying in Western advanced health systems, it suggests that for flourishing to occur, both of these aspects of life need to be faced more directly. The last days of life need to be ‘undulled’. Reflections upon the experiences of the author as carer and daughter in the face of her mother’s experience of death are used as basis for making suggestions about how care systems and professionals might better assist people in dealing with ‘the most grown up thing’ humans ever do, which is to die.     

扶正消瘤颗粒对原发性肝癌血清中VEGF、HIF-1α表达的影响及临床意义＊

目的 探讨扶正消瘤颗粒对原发性肝癌血清中血管内皮生长因子（Vascular endothelial growth factor，VEGF）和缺氧诱导因子-1α（Hypoxia inducible factor-1α，HIF-1α）表达的影响及临床意义。方法 选择符合纳入标准的原发性肝癌患者66例，按1∶1随机分试验组和对照组。观察治疗过程中两组VEGF、HIF-1α水平的变化及对患者临床疗效指标的影响。结果 （1）在性别、年龄、合并乙型肝炎、Child-Pugh分级、AFP值、临床分期方面，试验组和对照组差异无统计学意义（P > 0.05）。（2）肝癌患者在治疗各时间节点的VEGF和HIF-1α表达水平呈线性正相关（r = 0.829，P < 0.001）。（3）VEGF浓度在经导管动脉化疗栓塞术（Transcatheter arterial chemoembolization，TACE）后3月降至术前水平（P > 0.05），HIF-1α在TACE后3月仍高于术前（P < 0.05）。（4）扶正消瘤颗粒可降低HIF-1α水平，下调VEGF的表达。（5）扶正消瘤颗粒可减少TACE序贯RFA治疗后的不良反应，提高患者的生活质量（P < 0.05）。（6）血清中VEGF水平与生活质量无明显相关性（P > 0.05，r = 0.251），HIF-1α水平与生活质量存在正相关性（P < 0.05，r = 0.450）。结论 扶正消瘤颗粒可明显改善TACE序贯RFA治疗后患者生活质量，降低HIF-1α水平，下调VEGF的表达，抑制肿瘤血管生成。     

Nanomedicines: From Bench to Bedside and Beyond

Advancing nanomedicines from concept to clinic requires integration of new science with traditional pharmaceutical development. The medical and commercial success of nanomedicines is greatly facilitated when those charged with developing nanomedicines are cognizant of the unique opportunities and technical challenges that these products present. These individuals must also be knowledgeable about the processes of clinical and product development, including regulatory considerations, to maximize the odds for successful product registration. This article outlines these topics with a goal to accelerate the combination of academic innovation with collaborative industrial scientists who understand pharmaceutical development and regulatory approval requirements—only together can they realize the full potential of nanomedicines for patients.