Recent advances in preclinical in vitro approaches towards quantitative prediction of hepatic clearance and drug-drug interactions involving organic anion transporting polypeptide (OATP) 1B transporters

Hepatic uptake mediated by organic anion transporting polypeptide (OATP) 1B1 and 1B3 can serve as a major elimination pathway for various anionic drugs and as a site of drug-drug interactions (DDIs). This article provides an overview of the in vitro approaches used to predict human hepatic clearance (CL_h) and the risk of DDIs involving OATP1Bs. On the basis of the so-called extended clearance concept, in vitro–in vivo extrapolation methods using human hepatocytes as in vitro systems have been used to predict the CL_h involving OATP1B-mediated hepatic uptake. CL_h can be quantitatively predicted using human donor lots possessing adequate OATP1B activities. The contribution of OATP1Bs to hepatic uptake can be estimated by the relative activity factor, the relative expression factor, or selective inhibitor approaches, which offer generally consistent outcomes. In OATP1B1 inhibition assays, substantial substrate dependency was observed. The time-dependent inhibition of OATP1B1 was also noted and may be a mechanism underlying the in vitro–in vivo differences in the inhibition constant of cyclosporine A. Although it is still challenging to quantitatively predict CL_h and DDIs involving OATP1Bs from only preclinical data, understanding the utility and limitation of the current in vitro methods will pave the way for better prediction.     

扩大经蝶入路进入海绵窦内侧腔的应用显微解剖

目的为临床开展扩大经蝶入路进入海绵窦内侧腔手术提供解剖学依据。方法用50例成人头颅标本．在显微镜下对蝶窦外侧壁、蝶鞍、海绵窦及周围结构进行解剖学观察并测量。模拟扩大经蝶入路磨除海绵窦腹侧骨质，切开海绵窦内侧壁，显露海绵窦内侧腔。结果颈内动脉（ICA）明显隆起于蝶窦侧壁的占58％，蝶窦内隆起呈管型占3％。鞍底硬膜分为2层，海绵窦内侧壁的上部南垂体硬膜构成，无骨性结构支撑；下部由骨周硬膜构成，有蝶窦侧壁骨质支撑。两侧海绵窦内侧壁的距离为（14．8±2．7）mm。海绵窦内侧腔位于C4段ICA与垂体之间，腔内为丰富的静脉丛，最宽可达7mm，但常因ICA扭曲而闭塞。无颅神经穿越海绵窦内侧腔，ICA是扩大经蝶入路探查海绵窦遇到的第一个主要结构。结论扩大经蝶入路进入海绵窦内侧腔是安全可行的。     

Compartment syndrome. Exclusively the result of increased pressure in the muscular compartment?

Summary The compartment syndrome (cs) is characterized by an increased tissue pressure in a limited space. Pathophysiologically, it is a multifactorial disease that is potentially induced by an initial trauma and develops according to the existence of cofactors. Cofactors are, for instance, the circulation of the patient and the initial treatment of the impending cs. In particular, the microcirculation is altered with endothelial destruction, development of a capillary leak, protein loss from intravasal space and the development of an interstitial and intracellular third space. An impaired drainage of the lymphatic and venous system causes a venous infarction. An arterial infarction results if the tissue pressure exceeds the arteriolar pressure. An accompanying ischemia reperfusion mechanism increases the trauma load. In disadvantageous cases, the patients are in danger of developing a multi-organ deficiency syndrome (MODS) by an uncontrolled inflammatory reaction, by intravasal volume loss and by a myonephropathic systemic reaction. Clinically, the patients suffer a disproportionate amount of pain, followed by neurological signs. Especially in noncompliant patients, tissue pressure measurement is useful. Resuscitation of the circulation as well as splitting of casts is important. In case of a manifest cs, dermatofasciotomy has to be performed as an emergency operation. Even if cs is diagnosed early and fasciotomy is carried out early, the development of sequellae cannot be avoided in every single case.      

The Role of Extended Lymphadenectomy for Adenocarcinoma of the Head of the Pancreas: Strength of the Evidence

With improvements in the safety of Whipple resection in recent decades, surgeons have continued to explore the role of more extensive lymphadenectomy in hope of improving long-term survival. A systematic literature search of level I evidence addressing the role of the extent of lymphadenectomy was undertaken. Only reports of prospective, randomized controlled trials comparing pancreaticoduodenectomy with standard lymphadenectomy to pancreaticoduodenectomy with extended lymphadenectomy where information regarding survival, morbidity, mortality, the number of resected lymph nodes in each group and detailed operative technique were included. Four prospective, randomized trials comprising some 424 patients and one meta-analysis were identified. In aggregate, these studies confirmed that the number of resected lymph nodes was significantly higher in the pancreaticoduodenectomy with extended lymphadenectomy group. Morbidity and mortality rates were comparable. Postoperative diarrhea in the early months after operation was problematic in patients undergoing extended lymphadenectomy. In none of the studies was a benefit in long-term survival demonstrated. Standard pancreaticoduodenectomy continues to be the operation of choice for adenocarcinoma of the head of the pancreas. Presented at The Society for Surgery of the Alimentary Tract Postgraduate Course “Systematic Reviews of Pancreaticobiliary Disease Customized for the Gastroenterologist and Gastrointestinal Surgeon” on May 20, 2007, Washington, D.C.     

运用变性高效液相色谱对肺炎克雷伯菌产ESBL进行基因分型

目的 通过运用变性高效液相色谱（DHPLC）技术对前期研究已确认产超广谱β-内酰胺酶（ESBL）的肺炎克雷伯菌临床分离株TEM型质粒进行基因分型,试图建立一种方便快捷的用于ESBL分子诊断及其流行病学监测的新方法.方法 利用PCR技术从肺炎克雷伯菌临床分离株中扩增出TEM型质粒的编码序列,扩增产物运用DHPLC技术进行分析,分析提示,异常的样本通过测序确定其基因突变的类型,最后通过比对确定其基因型.结果 共分析了101例肺炎克雷伯菌临床分离株,全部样本均扩增出TEM型质粒的编码序列,经过DHPLC分析,52例（51.4%）样本表现为单一的洗脱峰,其形态与TEM-1标准菌株的峰型相一致,测序确定它们的碱基序列亦相一致,不存在变异,为TEM-1型;49例（48.6%）样本表现为异常的洗脱峰,它们均为双峰,形态一致,但异源双链峰的高度有差异,测序结果表明它们均存在四种相同的基因突变,在NCBI网站比对后确定为TEM-116;测序结果还提示,部分样本中TEM-1和TEM-116混合存在,其比例的不同表现为DHPLC时异源双链峰高度的差异;文献检索表明,本次确定的TEM-116为一新的基因亚型,为国内首次报道.结论 DHPLC具有简便快捷、高通量和自动化的特点,重复性好,不仅可对已知突变作出即时诊断,还可发现新的基因亚型,不失为一种较好的ESBL分子诊断方法及其流行病学监测手段.     

华南地区质粒介导超广谱β-内酰胺酶的基因分型研究

目的：了解华南地区质粒介导超广谱β－内酰胺酶（ESBLs）的发生率及基因型特征。方法：收集2001年4月－9月革兰阴性菌临床分离无重复株共1184株，采用NCCLS表型筛选和确认试验进行了ESBLs产酶的识别，E-test法检测各亚型ESBLs的MICs值，质粒接合及电转化实验，耐药质粒提取及酶切指纹分析，等电聚焦电泳，PCR通用引物扩增TEM、SHV、CTX－M、VEB、PER、SFO基因及其克隆测序进行ESBLs基因分型和质粒定位。结果：革兰阴性苗ESBLs的检出率为14．6％（173／1184）；获得产ESBLs接合子67株，电转化子11株，其中产CTX－M－14型ESBLs为33．3％（26／78）、CTX－M－3为23．1％（18／78）、CTX－M－9为14．1％（11／78）及SHV-2a为2．6％（2／78），未定型为5．1％（4／78）；29．5％（23／78）野生株伴广谱酶TEM－1或SHV－1型；各型ESBLs基因约定位在35－190kb大小的可接合性低执行者拷贝数天然质粒上；CTX－M型ESBLs以对头孢噻肟高水平高耐为特征。结论：华南地区质粒介导的ESBLs以CTX－M型衍生酶为主，其次是SHV型酶。     

Sucrose sham feeding decreases accumbens norepinephrine in the rat

Noradrenergic projections from the dorsomedial medulla reach the shell of the nucleus accumbens (NAcc), a structure implicated in both reward and feeding behavior. Despite this relationship, the effect of food reward on accumbens norepinephrine (NE) remains uninvestigated. In the course of assessing dopamine (DA) in the NAcc during sucrose ingestion [0.03, 0.1, and 0.3 M; Am. J. Physiol., Regul. Integr. Comp. Physiol., 286 (2004) R31], we also analyzed NE in the microdialysis samples from 14 ad-libitum-fed male rats. In contrast to DA, which increased with sucrose concentration (+20-47%) during sham feeding, in the same animals, NE levels were reduced (approximately -20%), regardless of sucrose concentration. These results demonstrate a novel relationship between accumbens DA and NE during orosensory stimulation with a preferred nutrient.     

Multivariate Genetic Analysis of Brain Structure in an Extended Twin Design

The hunt for genes influencing behavior may be aided by the study of intermediate phenotypes for several reasons. First, intermediate phenotypes may be influenced by only a few genes, which facilitates their detection. Second, many intermediate phenotypes can be measured on a continuous quantitative scale and thus can be assessed in affected and unaffected individuals. Continuous measures increase the statistical power to detect genetic effects (Neale et al., 1994), and allow studies to be designed to collect data from informative subjects such as extreme concordant or discordant pairs. Intermediate phenotypes for discrete traits, such as psychiatric disorders, can be neurotransmitter levels, brain function, or structure. In this paper we conduct a multivariate analysis of data from 111 twin pairs and 34 additional siblings on cerebellar volume, intracranial space, and body height. The analysis is carried out on the raw data and specifies a model for the mean and the covariance structure. Results suggest that cerebellar volume and intracranial space vary with age and sex. Brain volumes tend to decrease slightly with age, and males generally have a larger brain volume than females. The remaining phenotypic variance of cerebellar volume is largely genetic (88%). These genetic factors partly overlap with the genetic factors that explain variance in intracranial space and body height. The applied method is presented as a general approach for the analysis of intermediate phenotypes in which the effects of correlated variables on the observed scores are modeled through multivariate analysis.     

Multiviszerale Resektion des fortgeschrittenen kolorektalen Karzinoms Multivisceral resection in advanced colorectal carcinoma

Zusammenfassung Berichtet wird über die operative Behandlung von 1232 Patienten mit einem kolorektalen Karzinom aus dem Zeitraum 1.09.1984 bis 1.01.1990. Entsprechend einer Resektionsquote von 90,3 % wurden 1112 Patienten (kurativ: n = 917, palliativ: n = 195) reseziert. Bei 82 Patienten war wegen Organüberschreitung des Tumors eine multiviszerale Resektion von einem oder mehreren benachbarten Organen (69mal kurativ, 13mal palliativ) notwendig. Komplikationsraten (26,7% zu 27,5 %) und die 30-Tageletalität (3,4% zu 2,9 %) waren in beiden Gruppen der kurativ and kurativ erweitert resezierten Patienten gleich. Die Berechnung der Fünfjahresüberlebensrate ergab für die kurativ resezierten Patienten ohne Erweiterung einen Wert von 58% gegenüber 55 mit Erweiterung. Auch die Subgruppenanalyse ergab keinen Unterschied in den einzelnen Stadien. Die Ergebnisse lassen den Schlul zu, da bei gleicher Komplikations-und Letalitätsrate die kurativ erweiterte Resektion von pT3- and pT4-Tumoren gleiche Spdtergebnisse wie die entsprechende Behandlung von nicht erweitert resezierten pT3-Tumoren erwarten lät. Die Daten zeigen, da eine Infiltration von Nachbarorganen durch ein kolorektales Karzinom nicht als Inoperabilitätskriterium gelten darf.

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From 1 September to 1 January 1990, a total of 1232 patients underwent surgery for colorectal cancer. Resection was performed on 1112 (90.3%) patients. It was curative in 917 cases and palliative in 195. Multivisceral resection was necessary 82 times because of tumour infiltration of adjacent organs (curative: 69 cases; palliative: 13 cases). The complication rate (26.7% vs 27.5%) and mortality rate (3.4% vs 2.9%) were similar to those for curative resections without multivisceral extension. The 5-year survival rate was also similar in the two groups (58% vs 55%). These results show that curative multivisceral resections can lead to the same long-term results as conventional curative resections. These data are encouraging, and tumour infiltration of neighbouring organs should not be taken to demonstrate inoperability.

     

Improved accuracy and extended flow range for a Fleisch pneumotachograph

A large linear flow range and a small instrumental dead space volume are incompatible properties for a pneumotachometer (PTM). The linearity of a Fleisch number 2 PTM is studied for flows up to 6 litre s-1 (nominal range 0-2 litre s-1) with various up- and downstream geometries. It is hypothesised that using an array of calibration factors (conductance; flow/pressure), instead of a single calibration factor over the entire flow range, could improve accuracy and also extend the applicable flow range. The conductance against pressure characteristics are calculated with a previously described weighted averaging technique based on multiple strokes from a precision syringe. A single conductance value gives stroke volume errors in the range of -5 to 3% (0-2 litre s-1) and -6 to 11% (0-6 litre s-1) for validation using the same geometry as for calibration. The pressure dependent conductance improves accuracy to within -3% and 1% independent of flow range. However, for validation using a different geometry than for calibration, errors range from -5% to +8%. The degree of non-linearity varies between the geometries (range 3-15%) and is highest when using a one-directional valve upstream of the PTM and a Y-shaped connector. In conclusion, a pressure-dependent conductance improves accuracy and can also be used to extend the applicable flow range up to at least three times the nominal flow range.