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.     

葛根素联合复方樟柳碱注射液对眼底病患者的治疗效果及对血液流变学指标的影响

目的研究葛根素联合复方樟柳碱注射液对眼底病患者的治疗效果及对血液流变学指标的影响。方法选择2013年4月至2014年4月在绵阳市第三人民医院眼科进行眼底病治疗的患者100例,并按入院顺序抽签随机分为观察组和对照组,各50例。对照组进行葛根素常规治疗(葛根素注射液0.4 g加入生理盐水250 m L中静脉滴注,每日1次,1个疗程14 d,1个疗程后停药3 d,再进行下一疗程),观察组在此基础上联合复方樟柳碱注射液进行治疗(采用复方樟柳碱2 m L在患者颞浅动脉旁行皮下注射,每日1次,1个疗程14 d,完成1个疗程后停药3 d,再换肾俞穴进行注射,1个疗程后停药3 d,再进行第一个疗程的用药)。3个疗程后,比较两组患者治疗前后血液流变学的变化、术后复发率和不良反应情况及患者的治疗效果。结果治疗后,观察组全血黏度为(4.82±0.41)m Pa·s明显低于对照组的(5.56±0.39)m Pa·s,红细胞聚集指数(3.80±0.41)明显低于对照组(4.77±0.55),纤维蛋白原(4.20±0.24)g/L明显低于对照组(5.25±0.43)g/L,差异均有统计学意义(t=9.247,9.998,15.077,P<0.01);观察组患者治疗后复发率为2.0%(1/50),不良反应的总发生率为4.0%(2/50),分别低于对照组14.0%(7/50)和18.0%(9/50)(P<0.01);观察组患者的总有效率为98.0%(49/50),显著高于对照组的82.0%(41/50)(P<0.05)。结论葛根素和复方樟柳碱注射液联合治疗眼底病患者,可改善患者血液流变学,并提高临床治疗效果。     

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.     

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.