Hepatic conversion of 1-(tetrahydro-2-furanyl)-5-fluorouracil into 5-fluorouracil in patients with hepatocellular carcinoma

The pharmacokinetics of 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT) and its conversion into 5-fluorouracil (FUra) in liver tissue were studied in ten patients with hepatocellular carcinoma (HCC). The plasma concentration of FT after its intravenous injection (dosage: 800 mg) was computerfitted to a bi-exponential function (C = Ae-alpha t + Be-beta t), indicating a two-compartment disposition. The pharmacokinetic parameters did not significantly differ between the five patients with, and the five without cirrhosis of the liver. The plasma concentrations of FUra likewise showed no significant difference between the two groups. The rates of FT degradation in the liver tissue homogenate were similar for four of the patients with cirrhosis (0.10 +/- 0.05 mumol/g liver protein/30 min) and four of those without it (0.13 +/- 0.05). The rates of cytochrome P-450-dependent FUra formation in the microsomal fraction of liver tissue from two patients (1.1 and 1.3 nmol/mg microsomal protein/30 min) were dramatically reduced to less than half of those of two control subjects (2.4 and 2.7). The estimated rates of FUra formation in the soluble fraction (105,000 X g supernatant fraction) from the two patients (0.1 and 0.13 nmol/mg protein/30 min) were almost identical to those from the controls (0.12 and 0.14), suggesting that the rate in the soluble fraction from HCC patients may not be as strongly affected as the rate in the microsomal fraction.(ABSTRACT TRUNCATED AT 250 WORDS)     

A case of Ullrich disease with distinct pathological change of muscular dystrophy

A case of Ullrich disease was presented. The patient was a 3-year-old girl with torticollis, generalized muscle weakness and acroatonia since birth. High-arched palate, protruded calcaneus, and mild contracture of proximal joints were also recognized. Intellectual development was normal. Serum level of CPK was slightly increased. In histological and histochemical examinations of quadriceps femoris muscle, proliferated connective tissue, marked variation in the muscle fiber diameter, and a lot of degenerated and regenerated fibers were recognized. Minimal injury easily causes subcutaneous hemorrhage, but no abnormality was found in the structure of collagen.     

协同学——中医药科学性的理论基础

通过深入分析我国中医药科学性研究中所存在的问题，依据协同学理论，提出了中医药科学性的理论基础是协同学的观点。基于此，阐释了中医药科学性的协同学解释，这在一定意义上为中医药科学性的研究提供了新的视角和有益的启示。     

Serine hydroxymethyltransferase isoforms are differentially inhibited by leucovorin: characterization and comparison of recombinant zebrafish serine hydroxymethyltransferases.

Serine hydroxymethyltransferase (SHMT) provides activated one-carbon units required for the biosynthesis of nucleotides, protein, and methyl group by converting serine and tetrahydrofolate to glycine and N(5),N(10)-methylenetetrahydrofolate. It is postulated that SHMT activity is associated with the development of methotrexate resistance and the in vivo activity of SHMT is regulated by the binding of N(5)-CHO-THF, the rescue agent in high-dose methotrexate chemotherapy. The aim of this study is to advance our understanding of the folate-mediated one-carbon metabolism in zebrafish by characterizing zebrafish mitochondrial SHMT. The cDNA encoding zebrafish mitochondrial SHMT was cloned, overexpressed in Escherichia coli, and purified with a three-step purification protocol. Similarities in structural, physical, and kinetic properties were revealed between the recombinant zebrafish mitochondrial SHMT and its mammalian orthologs. Surprisingly, leucovorin significantly inhibits the aldol cleavage of serine catalyzed by zebrafish cytosolic SHMT but inhibits to a lesser extent the reaction catalyzed by the mitochondrial isozyme. This is, to our knowledge, the first report on zebrafish mitochondrial folate enzyme as well as the differential inhibition of leucovorin on these two SHMT isoforms. Western blot analysis revealed tissue-specific distribution with the highest enrichment present in liver for both cytosolic and mitochondrial SHMTs. Intracellular localization was confirmed by confocal microscopy for both mitochondrial and cytosolic SHMTs. Unexpectedly, the cytosolic isoform was observed in both nucleus and cytosol. Together with the previous report on zebrafish cytosolic SHMT, we suggest that zSHMTs can be used in in vitro assays for folate-related investigation and antifolate drug discovery.     

Changes in immune regulation in response to examination stress in atopic and healthy individuals

BACKGROUND: Stress can aggravate the allergic inflammation, but determinants of disturbed immune regulation are largely unknown. OBJECTIVE: To determine systemic immunological, local inflammatory and functional airway responses to stress in healthy and atopic individuals. METHODS: Forty-one undergraduate students, 22 with allergy of whom 16 had asthma, and 19 healthy controls, were studied in a low-stress period and in association with a large exam. Subjects completed questionnaires on stress and health behaviours, underwent lung function tests, bronchial methacholine challenge, measurements of exhaled nitric oxide and urine cortisol. Blood cells were phenotyped, and cytokines from mononuclear blood cells were analysed. RESULTS: Perceived stress and anxiety increased in both groups during the exam period while cortisol increased only in the atopy group. Cytokine production decreased broadly in response to stress in both groups, which was paralleled by an increase in the proportion of regulatory T cells (CD4(+)CD45RO(+)CD25(bright)). Interestingly, atopic individuals, but not controls, reacted with a decreased T-helper type 1/T-helper type 2 (Th1/Th2) ratio and a decrease in natural killer (NK) cell numbers in response to stress. In control subjects only, exhaled nitric oxide decreased and forced expiratory volume in one second increased during stress. CONCLUSION: Atopic and non-atopic subjects shared some immune changes in response to stress, such as a dramatic decline in cytokines and an increase in the number of regulatory T cells in peripheral blood. However, other stress-induced immune changes were unique to atopic individuals, such as a skewed Th1/Th2 ratio and reduced NK cell numbers, indicating that some pathogenic mechanisms in atopics may be more strongly affected by stress than others.     

输尿管无细胞基质移植物的制备和评价

背景：与小肠黏膜下层等材料相比，脱细胞血管具有天然管状结构，与输尿管形态结构相近，替代输尿管时仅需端端吻合即可，手术操作简单，血管外壁光滑，获取及制备方法简便等优点。 目的：拟应用同种颈动脉血管无细胞基质体外构建输尿管。 设计、时间及地点：观察性实验，于2006-09/2008-06在上海交通大学医学院附属新华医院动物实验中心完成。 材料：长风杂交白猪由上海松联实验动物公司提供。上海交通大学医学院实验动物中心提供的健康成年大鼠8只，用于血管无细胞基质的动物毒性实验。 方法：剥去猪颈动脉血管外膜，PBS冲洗若干遍，然后将血管置于pH 7.1 的PBS中4 ℃下振荡清洗，0.5%十二烷基硫酸钠振荡24 h，后使用双蒸水4 ℃下反复振荡洗涤1周，每日换双蒸水2次。对于解剖过程中肌肉残留相对稍多的血管，在双蒸水洗涤前以混合消化液37 ℃下振荡消化约2 h，再行双蒸水洗涤。制备的无细胞基质置于青、链霉素溶液中，4 ℃保存，完成脱细胞支架制备。 主要观察指标：光镜及电镜观察脱细胞后管壁无细胞基质片的主要成分。将同种异体来源内皮祖细胞培养增殖后植入血管无细胞基质，观察细胞生长情况，并进行血管无细胞基质动物毒性实验。拉力实验了解血管无细胞基质材料的收缩性能。 结果：颈动脉血管无细胞基质中已无细胞成分，无细胞基质主要由胶原成分组成。扫描电镜未见该材料表面存在细胞及细胞碎片，同时发现该无细胞基质存在孔隙样结构。体外同种异体来源的内皮祖细胞培养增殖后植入血管无细胞基质，细胞黏附于无细胞基质。血管无细胞基质按毒性分级属于无毒级。拉力实验说明该无细胞基质具有一定的韧性和牵张性。 结论：采用胰酶和十二烷基硫酸钠制备的颈动脉血管无细胞基质材料无细胞残留，具有一定的韧性和牵张性，种植于其中的种子细胞具备一定的生长能力。     

FDA’S Perspectives on Cardiovascular Devices

The Food and Drug Administration (FDA) decision process for approving or clearing medical devices is often determined by a review of robust clinical data and extensive preclinical testing of the device. The mission statement for the Center for Devices and Radiological Health (CDRH) is to review the information provided by manufacturers so that it can promote and protect the health of the public by ensuring the safety and effectiveness of medical devices deemed appropriate for human use (Food, Drug & Cosmetic Act, §903(b)(1, 2(C)), December 31, 2004; accessed December 17, 2008 ). For high-risk devices, such as ventricular assist devices (VADs), mechanical heart valves, stents, cardiac resynchronization therapy (CRT) devices, pacemakers, and defibrillators, the determination is based on FDA’s review of extensive preclinical bench and animal testing followed by use of the device in a clinical trial in humans. These clinical trials allow the manufacturer to evaluate a device in the intended use population. FDA reviews the data from the clinical trial to determine if the device performed as predicted and the clinical benefits outweigh the risks. This article reviews the regulatory framework for different marketing applications related to cardiovascular devices and describes the process of obtaining approval to study a cardiovascular device in a U.S. clinical trial.