Nonlinear protein binding and enzyme heterogeneity: effects on hepatic drug removal

The kinetics of substrate removal by the liver and the resulting nonlinear changes in unbound fraction along the flow path at varying input drug concentrations were examined by a model simulation study. Specifically, we varied the binding association constant, KA, and the Michaelis-Menten constants (Km and Vmax) to examine the steady state drug removal (expressed as hepatic extraction ratio E) and changes in drug binding for (i) unienzyme systems and (ii) simple, parallel metabolic pathways; zonal metabolic heterogeneity was also added as a variable. At low KA, E declined with increasing input drug concentration, due primarily to saturation of enzymes; only small differences in binding were present across the liver. At high KA, a parabolic profile for E with concentration was observed; changes in unbound fraction between the inlet and the outlet of the liver followed in parallel fashion. Protein binding was the rate-determining step at low input drug concentrations, whereas enzyme saturation was the rate-controlling factor at high input drug concentration. Heterogeneous enzymic distribution modulated changes in unbound fraction within the liver and at the outlet. Despite marked changes in unbound fraction occurring within the liver for different enzymic distributions, the overall transhepatic differences were relatively small. We then investigated the logarithmic average unbound concentration and the length averaged concentration as estimates of substrate concentration in liver in the presence of nonlinear drug binding. Fitting of simulated data, with and without assigned random error (10%), to the Michaelis-Menten equation was performed; fitting was repeated for simulated data obtained with presence of a specific inhibitor of the high-affinity, anteriorly distributed pathway. Results were similar for both concentration terms: accurate estimates were obtained for anterior, high affinity pathways; an overestimation of parameters was observed for the lower affinity posteriorly distributed pathways. Improved estimations were found for posteriorly distributed pathways upon inhibition with specific inhibitors; with added random error, however, the improvement was much decreased. We applied the method for fitting of several sets of metabolic data obtained from rat liver perfusion studies performed with salicylamide (SAM) (i) without and (ii) with the presence of 2,6-dichloro-4-nitrophenol (DCNP), a SAM sulfation inhibitor. The fitted results showed that SAM sulfation was a high-affinity high-capacity pathway; SAM glucuronidation was of lower affinity but comparable capacity as the sulfation pathway, whereas SAM hydroxylation was of lower affinity and lower capacity.     

珠江口盆地开平凹陷油气聚集条件分析

珠江口盆地自新生代以来,曾先后受到不同方向张应力的作用,造成了不同时期构造体系的交叉叠合.中中新世以来构造运动强烈,并具有东强西弱的特点,对油气的运移与聚集产生了重要影响.开平凹陷的剧烈断裂和断陷活动始于始新世,并在同期沉积了巨厚的文昌组.晚渐新世以后,由于断裂活动非常微弱,在成熟的烃源岩与其上地层之间缺乏有效的油源断层,因而自生自储、近距离运移可能是开平凹陷油气聚集的基本特征.在凹陷内部,因重力滑动和欠压实泥岩共同作用所形成的KPll-1构造带可能是该区最具有油气远景的地区.     

Genetic mapping of a major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15q

The epilepsies are a group of disorders characterised by recurrent seizures caused by episodes of abnormal neuronal hyperexcitability involving the brain. Up to 60 million people are affected worldwide and genetic factors may contribute to the aetiology in up to 40% of patients. The most common human genetic epilepsies display a complex pattern of inheritance. These are categorised as idiopathic in the absence of detectable structural or metabolic abnormalities. Juvenile myoclonic epilepsy (JME) is a distinctive and common variety of familial idiopathic generalised epilepsy (IGE) with a prevalence of 0.5-1.0 per 1000 and a ratio of sibling risk to population prevalence (lambda(s)) of 42. The molecular genetic basis of these familial idiopathic epilepsies is entirely unknown, but a mutation in the gene CHRNA4, encoding the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (nAChR), was recently identified in a rare Mendelian variety of idiopathic epilepsy. Chromosomal regions harbouring genes for nAChR subunits were therefore tested for linkage to the JME trait in 34 pedigrees. Significant evidence for linkage with heterogeneity was found to polymorphic loci encompassing the region in which the gene encoding the alpha7 subunit of nAChR (CHRNA7) maps on chromosome 15q14 (HLOD = 4.4 at alpha = 0.65; Z(all) = 2.94, P = 0.0005). This major locus contributes to genetic susceptibility to JME in a majority of the families studied.     

鲁布革水电厂计算机监控系统的更新改造

鲁布革水电厂原Ｒ３０计算机监控系统更新改造过程中，重点研究了与原西门子ＲＴＵ的数据交换，机组功率调节和线路定功率调节的实现有关问题，在对３号机组计算机监控系统改造试验的基础上，成功地实现了计算机监控系统的整体改造，改造后采用的国产ＮＡＲＩＳＳＪ－３０００计算机监控系统实用可靠，功能完善，配置灵活，具有国际，国内领先水平。     

Changes in medical stability upon admission to a rehabilitation unit

The implementation of Medicare's prospective payment system in acute care has coincided with a steady increase in medically unstable admissions to our freestanding rehabilitation facility. We investigated the consequences of these admissions by collecting medical information regarding transfers beginning in 1983. Patients requiring transfer back to the acute setting within 1 day of admission were considered medically unstable and their charts were reviewed. The number of patients requiring transfer back within 1 day increased from 1.5% of all first admissions to 3.1% in 1988 (Mantel - Haenszel chi 2 = 8.03, (df = 1), p < .01), but the increase among Medicare patients alone was not significant. This progressive increase was most pronounced in the cerebrovascular accident and spinal cord injury populations. Beginning in 1988, an intensified preadmission evaluation program was implemented, resulting in a significant decline in unstable patient transfers from hospitals where our consultants were on staff. Physiatric consultations at referral institutions decreased the number of unstable patients at admission.     

Family practice physicians' firearm safety counseling beliefs and behaviors

The purpose of this study was to identify family physicians' firearm safety counseling beliefs and behaviors. A survey was mailed to a random sample of 600 members of the American Academy of Family Physicians. A three wave mailing technique was used to maximize the response rate and yielded 271 usable surveys (55% response rate). Outcome measures included training experience in firearm safety counseling, the prevalence of firearm safety counseling by family physicians, and their perceptions regarding such counseling. The majority (78%) of family physicians lacked formal training on how to counsel patients about firearm safety and 49% believed more time should be spent in residency programs on firearm safety counseling. The majority (84%) of respondents never or rarely counseled patients on firearm safety and 50% believed firearm safety counseling should be a low priority in their delivery of primary care. The majority of respondents did not regularly counsel patients about firearm safety, did not believe firearm safety counseling should be a priority, and did not believe firearm safety counseling would be effective in reducing firearm-related trauma.     

XH－Ⅰ型岩石铵梯炸药研究

文章论述利用过期火药的一种新途径。在２号岩石铵梯炸药中加入粉碎的过期火药以代替部分梯恩梯，制成一种ＸＨ－Ⅰ型岩石铵梯炸药，适用于各种爆破工程。并具有较高的经济效益和社会效益。     

60m高度处单片露天超高混凝土悬臂墙的设计与施工

通过采用竖向预应力技术 ,解决了 60m高度处单片 8m高悬臂钢筋混凝土墙根部裂缝宽度超过规范限值的问题 ;采用将预应力钢绞线顶端锚固于墙高中段等结构和施工措施 ,控制墙体长细比不超过 3 0 ,减少了由于长细比过大对墙体承载力的不利影响