可逆性胆硷酯酶抑制剂二甲氨基甲酸-5-二氢吲哚酯的合成

为了深入研究催醒宁类化合物的结构与抑酶活性的关系,设计合成了-系列1-,3-或5-位不同取代的二氢吲哚类衍生物(中间体和终产物共24个新化合物)。中间体1,3-二甲基-5-烷氧基-2-二氢吲哚酮(A)的C₃烷化。采用相转移催化方法进行;反应中还分离到三个副产物(Ⅶ～Ⅸ)。初筛结果表明:这些化合物大多有较强的抑酶活性;1,3-或5-位取代基的改变均明显影响其活性。     

Adverse events in phase one studies: a study in 430 healthy volunteers

Summary All the clinical, laboratory and electrocardiographic adverse events detected during 24 Phase I studies in the same unit over a 5 y period are reported here. 430 healthy male volunteers were involved, corresponding to 5488 days of follow-up.The overall incidence of adverse events was 13.5%, with a significant difference between active drug (15.3%) and placebo (7.4%) treatments. There were 69 distinct types of adverse events. Headache was the most frequent symptom (2%). There were severe adverse events in 20 cases (0.36%), with an incidence of 20/430 per subject (4.6%). There were no deaths or life-threatening events.Although the main objective of Phase I studies is to determine the maximum dose tolerated, cause-effect relationships with adverse events are hard to establish, because of the frequency of adverse events with placebo, and because of the limited number of subjects included such studies.     

人工心瓣膜患者微栓子信号和凝血活性的相关性研究

目的 :研究人工心瓣膜患者脑动脉微栓子信号 (MES)的数量及相对强度与凝血活性的相关性。方法 :采用双门深经颅多普勒 (TCD)检测人工心瓣膜患者脑动脉MES ,同时检测患者凝血酶原时间国际通用比值 (INR) ,观察MES数量及相对强度与INR的相关性。结果 :MES阳性发现率 83 33% (2 5 30 ) ,MES出现频率 0～ 4 0 4 (中位数 4 0 )个 h ,MES平均相对强度 11～ 38(2 3 6 3±5 13)dB。INR1 12～ 3 5 1(1 95± 0 6 9)。MES数量及相对强度与INR无相关性。结论 :人工心瓣膜患者脑动脉MES与凝血活性无关 ,提示微栓子物质不是血栓性的     

多复指数模型及其在EEG数据分析中的应用

由头皮上电极所记录下的EEG信号是大脑中各种电活动,尤其是神经元电活动,互相耦合而产生的电位变化的整体反映。有一种看法认为,表面看来随机、无规则的EEG信号,实际上它的变化只是由少量几个动力学参量控制着的非线性过程。根据这个假定,我们提出使用多复指数(MCE)模型来描述EEG信号的想法。文中首先简要地介绍了用来估计时序信号MCE模型参数的非调和Fourier展开算法(NHFE)的基本思想。然后,对一个叠加有白噪声、具有4个频率成分的模拟信号,用NHFE算法估计出其MCE模型参数,并把所得的结果与用经典的周期图谱分析方法、AR模型谱分析方法所得到的信号频谱作了比较。结果表明,在SNR高的条件下,NHFE算法所估计出的模型参数能更客观地反映信号的固有特性。基于目前的有关EEG形成的假设,应用MCE模型来描述EEG将更能反映出其特征。因此,我们对MCE模型及其参数在EEG数据分析中的几种可能应用作了初步尝试。这些应用包括:EEG信号段(或一段诱发电位,或一段事件关联电位)的特征参数的提取,这些特征参数包括优势频率值、独立的频率成分个数、幅度值、正负衰减指数的个数、频带宽度与幅度乘积(能量);EEG的频率调制特性的粗略描述等。从而看到了用通常信号分析方法所看不到的EEG信号中所反映的大脑活动的变化。由于用MCE模型及其参数来描述EEG的方法更符合目前关于大脑非线性动力学行为的假设,所以这一方法将是表示EEG信号的有效途径之一。另外,MCE模型方法在EEG信号的模拟研究与数据压缩等方面也将是有用的。文中还讨论了NHFE算法应用中的一些问题。     

Prevention of Acute Lung Allograft Rejection in Rat by CTLA4Ig

CTLA4 immunoglobulin (CTLA4Ig), which binds with a high affinity to B7-1 and B7-2, interrupts T-cell activation by inhibiting costimulatory signal. CTLA4Ig has been used in hopes of achieving antigen-specific tolerance induction in several solid organ transplants. In lung allograft rejection, however, its use has been controversial in terms of its effect on prevention of rejection. In the present study, the effect of murine CTLA4Ig on rat-lung allograft rejection was investigated. Rat left-lung transplantation was performed in an RT1 incompatible donor (Brown Norway; BN)-recipient (F344) combination. All allografts (n = 12) without any treatment were rejected within 7 days after transplantation. A single injection of murine form CTLA41g at a dose of 100 microg intraperitoneally (ip) or intravenously (iv) on day 1 post-transplantation achieved long-term graft survival (>90days) in 2/5 (40%) and 3/8 (38%), respectively. Moreover, 6/7 (86%) allografts in rats that received iv injection of 500 microg CTLA4Ig survived more than 90days. Allograft survival in the CTLA4Ig 500 microg iv recipient group was significantly longer than that in the no-treatment control or control immunoglobulin group (p <0.01). Four out of seven recipients bearing functional allografts for more than 90 days with the CTLA4Ig treatment accepted donor-specific skin grafts, whereas all third-party skin grafts (n=3) were rejected. Prevention of rat-lung allograft rejection could be achieved by intravenous administration of CTLA4Ig, resulting in long-term allograft survival with acceptance of donor-specific skin grafts.     

Multistep phase difference phase contrast imaging

A new technique for multistep phase-contrast image processing is presented. The N-step method consists of simply forming the linear average of the N — 1 adjacent phase-difference signals. It has similar noise reduction properties as other multistep techniques, but the simplicity of the noise variance of the N-step technique allows intuitive insight into phase-difference phase-contrast processing and noise reduction, which can aid in the design of efficient and improved phase-contrast imaging sequences. As well, the computational simplicity of the N-step phase-difference technique compared with any other known multistep technique is advantageous. Like other multistep techniques, it has far more efficient noise reduction properties than simple two-step, multiple average phase-contrast imaging, even when normalized for total scan time. A three-step phase-difference velocity image has 50% less variance than an image acquired with two steps and two scans averaged but is obtained in 25% less scan time. Given its advantages, it should now be the chosen technique for increasing velocity-to-noise and contrast-to-noise ratios in all phase-difference phase-contrast clinical applications.     

Phase-derivative analysis in MR angiography: Reduced Venc dependency and improved vessel wall detection in laminar and disturbed flow

A problem of current MRA techniques is the inability to accurately depict the vascular anatomy, particularly in areas of disturbed flow. Various reasons, such as intravoxel phase dispersion, saturation, temporal variations, and maximum intensity projection (MIP) nonlinearity, cause a wrong delineation of vessel boundaries. A phase contrast (PC)-based postprocessing operation, the phase derivative (PhD), is introduced to detect phase fluctuations indicating flow. Two-dimensional and three-dimensional angiographic reconstruction algorithms are presented. Mathematical formulas are derived to predict the effect of sampling to flow profiles and the effect on the PhD of these profiles. Numerical, phantom, and preliminary in vivo experiments demonstrate that PhD images do not suffer from phase wraps and allow a velocity dynamic range extension only limited by a differential phase change. It is also shown that PhD MIPs produce higher signal-to-noise ratios than conventional PC angiograms and give a better impression of the anatomy of (stenotic) vessels and of their diameters for both laminar and disturbed flow.     

Velocity and flow quantitation in the superior sagittal sinus with ungated and cine (gated) phase-contrast MR imaging

Normal blood flow and velocity in the superior sagittal sinus were measured in 30 patients. A fast two-dimensional ungated phase-contrast (PC) pulse sequence was compared with a peripherally gated cine PC technique for velocity and flow quantitation. The same imaging parameters were used for both methods. Measured values for mean velocity and flow obtained with the two methods were compared by using regression analysis and t testing. For blood flow, the correlation coefficient was 0.976. For velocity measurements, r was 0.950. Mean flow was 285 mL/min ± 19 with the ungated PC method and 281 mL/min ± 19 with the cine PC method. The mean velocities measured with the two methods were 12.94 cm/sec ± 1.1 and 13.59 cm/sec ± 1.1, respectively. There was no significant difference (paired t test) between the methods for mean flow or velocity data. This was true even though flow in the superior sagittal sinus is moderately pulsatile, as shown with the cine PC technique. The ungated PC method provided these data in 13 seconds versus 3.5 minutes for the cine PC method.     

In vivo comparison of two through-plane MR velocity mapping methods: Fast fourier encoding and phase mapping

Magnetic resonance imaging maps of velocity were acquired with a 1.5-T system in 10 subjects in a plane perpendicular to the main pulmonary artery. Velocity images were successively acquired with a method developed from Fourier-encoding velocity imaging (FEVI) principles with eight gradient steps and one excitation, and with two-point phase-subtraction mapping. Reconstruction in FEVI was implemented by zero-filling interpolation around the eight gradient steps and then around the four central steps. The methods were compared by using estimates of noise in velocity measurements based on the difference between the experimental map and a smooth fitted map. For the same acquisition time, FEVI with four encoding steps was more precise in velocity measurements than phase mapping. Precision was further increased by the use of eight encoding steps, but acquisition time was doubled.