CDT, GGT, and AST as markers of alcohol use: the WHO/ISBRA collaborative project

BACKGROUND: Estimates of the performance of carbohydrate deficient transferrin (CDT) and gamma glutamyltransferase (GGT) as markers of alcohol consumption have varied widely. Studies have differed in design and subject characteristics. The WHO/ISBRA Collaborative Study allows assessment and comparison of CDT, GGT, and aspartate aminotransferase (AST) as markers of drinking in a large, well-characterized, multicenter sample. METHODS: A total of 1863 subjects were recruited from five countries (Australia, Brazil, Canada, Finland, and Japan). Recruitment was stratified by alcohol use, age, and sex. Demographic characteristics, alcohol consumption, and presence of ICD-10 dependence were recorded using an interview schedule based on the AUDADIS. CDT was assayed using CDTect and GGT and AST by standard methods. Statistical techniques included receiver operating characteristic (ROC) analysis. Multiple regression was used to measure the impact of factors other than alcohol on test performance. RESULTS: CDT and GGT had comparable performance on ROC analysis, with AST performing slightly less well. CDT was a slightly but significantly better marker of high-risk consumption in men. All were more effective for detection of high-risk rather than intermediate-risk drinking. CDT and GGT levels were influenced by body mass index, sex, age, and smoking status. CONCLUSIONS: CDT was little better than GGT in detecting high- or intermediate-risk alcohol consumption in this large, multicenter, predominantly community-based sample. As the two tests are relatively independent of each other, their combination is likely to provide better performance than either test alone. Test interpretation should take account sex, age, and body mass index.     

Apolipoprotein B metabolism in normal,type IV,and type V hyperlipoproteinemic subjects

Apolipoprotein B (apoB) metabolism was investigated in four normal, three type IV, and three type V hyperlipoproteinemic subjects. Following injection of autologous radioiodinated very low density lipoprotein (VLDL) the rate of clearance of the apoprotein from this particle and its subsequent appearance in low density lipoprotein (LDL) was measured by frequent apoB specific activity determinations over an 11-day period. The resultant data were analyzed using the SAAM 27 computer program. In the normal subjects, more than 95% of the injected VLDL apoB was rapidly transferred to the LDL density range and accounted for all LDL apoB synthesis in that group. The plasma VLDL apoB concentration in the type IV group was, on average, five times the normal level. This resulted primarily from a doubling of the VLDL apoB synthetic rate associated with a defective or saturated catabolic mechanism. Only 60% of this material subsequently appeared in LDL, while the remainder was catabolized via an LDL-independent pathway. The turnover parameters of LDL apoB were normal in the type IV patients. Type V hyperlipoproteinemic subjects exhibited a 12- to 35-fold increase in plasma VLDL apoB concentration over normal. This again derived from increased VLDL apoB synthesis in the presence of defective removal of the apoprotein; the fractional catabolic rate of VLDL apoB in this group was 14% of the normal value. However, in contrast to the type IV patient data, more than 85% of the apoB in type V VLDL eventually appeared in LDL whose turnover rate was raised as a result of an increase in its catabolism; the fractional catabolic rate of LDL apoB in type V patients was four-fold above normal. The plasma LDL apoB pool size was substantially reduced in these subjects. This study shows that in hyperlipoproteinemic pheno-types IV and V there exist multiple anomalies of apoB metabolism affecting both VLDL and LDL.     

Effects of ossein-hydroxyapatite compound on ewe bone remodeling: Biochemical and histomorphometric study

Summary Ossein-hydroxyapatite compound (OHC) is a protein-mineral complex derived from bovine bone. Its effects on bone remodeling were studied in old ewes which have seasonal variations in bone remodeling. Seven animals received 200 mg OHC/kg b.w./day for 90 days from July to September. The control group consisted of 7 untreated animals followed for the same period of time. OHC was administered through a fistula into the fourth stomach. A significant decrease of bone histomorphometric parameter values was noted in controls at the end of the experiment, due to seasonal variations: the cancellous eroded perimeter decreased by 45%, the osteoblastic perimeter by 60% and the bone formation rate at the cell level by 20%. In contrast, in the treated-group, these parameters tended to increase or did not change. In conclusion, counteracting the significant seasonal reduction of bone remodeling in ewes, OHC seems able to stimulate directly or indirectly bone metabolism, especially when osteoblast activity is reduced and may partly prevent the seasonal reduction of bone turnover.     

The Discovery and Development of Boceprevir: A Novel,First-generation Inhibitor of the Hepatitis C Virus NS3/4A Serine Protease

An estimated 2–3% of the world''s population is infected with hepatitis C virus (HCV), making it a major global health problem. Consequently, over the past 15 years, there has been a concerted effort to understand the pathophysiology of HCV infection and the molecular virology of replication, and to utilize this knowledge for the development of more effective treatments. The virally encoded non-structural serine protease (NS3) is required to process the HCV polyprotein and release the individual proteins that form the viral RNA replication machinery. Given its critical role in the replication of HCV, the NS3 protease has been recognized as a potential drug target for the development of selective HCV therapies. In this review, we describe the key scientific discoveries that led to the approval of boceprevir, a first-generation, selective, small molecule inhibitor of the NS3 protease. We highlight the early studies that reported the crystal structure of the NS3 protease, its role in the processing of the HCV polyprotein, and the structural requirements critical for substrate cleavage. We also consider the novel attributes of the NS3 protease-binding pocket that challenged development of small molecule inhibitors, and the studies that ultimately yielded milligram quantities of this enzyme in a soluble, tractable form suitable for inhibitor screening programs. Finally, we describe the discovery of boceprevir, from the early chemistry studies, through the development of high-throughput assays, to the phase III clinical development program that ultimately provided the basis for approval of this drug. This latest phase in the development of boceprevir represents the culmination of a major global effort to understand the pathophysiology of HCV and develop small molecule inhibitors for the NS3 protease.     

病毒性脑膜炎、脑炎患儿的病原分析及部分生化指标变化的临床意义

目的：探讨病毒性脑膜炎、脑炎的病原及与部分生化指标改变的关系。方法：采用ELISA法进行血清抗体检测，终点法及速率法进行生化分析。结果：病毒性脑膜炎、脑炎患儿的病原分析：Ⅰ型副流感病毒（PIV）占24．5％，腺病毒（ADV）18．0％。柯萨奇B组病毒（CVB）占11．0％，呼吸道合胞病毒（RSV）占11．0％，乙脑病毒占9．0％，甲型流感病毒（IVA）占4．5％。小儿病毒性脑膜炎、脑炎的脑脊液（Cerebrospinal fluid，CSF）中，胆碱酯酶（CHE）的活性、总蛋白与磷（phosphor，P）的含量有显著改变（P＜0．05），且CHE的活性与总蛋白、P的含量有相关性，钙（Ca）及镁（Mg）含量无显著改变（P＞0．05）。结论：（1）在已知的几种致病病毒中，小儿病毒性脑膜炎、脑炎主要由PIV引起，其次是ADV、CVB、RSV。（2）小儿病毒性脑膜炎、脑炎的脑脊液中CHE的活性明显增高，提示小儿病毒性脑膜炎、脑炎将会影响胆碱能神经元的功能。（3）不同病毒对脑脊液CHE的活性影响不同，在已知的几种病毒中CVB对CHE的活性影响最大。     

磁处理水对培养液中某些生化指标的影响

为探讨不同磁场处理水对淋巴细胞转化率的影响,采用交变磁场和静磁场处理水配制细胞培养液,与蒸馏水配制的细胞培养液进行比较。各种培养液均在相同条件下培养72h后离心并分离淋巴细胞,结果2种磁处理水能显著增强淋巴细胞转化率和提高细胞培养液中K~+、Na~+、Ca~（2+）、Cl~-、MMS、BUN、葡萄糖的含量（P<0.01）,同时也能显著增强培养液中ALT、LDH的活性（P<0.01）。实验表明,磁处理水具有增强机体免疫功能和促进细胞物质能量代谢的作用。     

Glutathione peroxidase activity in rat lens and other tissues in relation to dietary selenium intake

Glutathione peroxidase (E.C. 1.11.1.9: glutathione: H₂O₂ oxidoreductase) activity and selenium concentration were measured in lenses of female rats and their offspring after long-term feeding of either a selenium-supplemented ($\text{0·1 parts}\text{10}{}^6$) or selenium-deficient ($\text{<}\text{0·02 parts}\text{10}{}^6$) diet. Long-term selenium deficiency decreased lens glutathione peroxidase activity in parent rats and their offspring to 15 and 14% respectively of supplemented controls. For comparison to lens, glutathione peroxidase was also measured in liver, heart, lung, erythrocytes, kidney, adrenal, testis, and brain of the offspring. Selenium deficiency caused the enzyme to decrease most dramatically in liver (to 0) and least in brain (to 62% of selenium supplemented controls). Although glutathione peroxidase in lens was lower than that in the other organs assayed, it was among the organs more sensitive to depletion caused by selenium deficiency. A short-term selenium deficiency of 8 weeks in newborn lambs had no effect on lens glutathione peroxidase, but the enzyme in organs such as liver was dramatically decreased. Therefore, an extensive period of selenium deficiency appears necessary to affect lens glutathione peroxidase activity, which probably relates to the relatively slow turnover and slow growth of the lens. The possible role of the seleno-enzyme, glutathione peroxidase, in the prevention of cataracts and the relationship of selenium to vitamin E and sulfur-containing amino acids in this regard are discussed.     

Sex hormones and metabolism of glycosaminoglycans. I. Effect of orchidectomy and administration of testosterone in rabbits

The effect of orchidectomy in male rabbits and administration of testosterone to orchidectomized animals on the metabolism of glycosaminoglycans (GAG) has been studied. The response of the different GAG fractions in the aorta varies with the nature of the GAG, and in some cases is different in different segments of the aorta. Orchidectomy produced an increase in hyaluronic acid fraction, decrease in heparin sulphate fraction, and no response in the chondroitin sulphate A fraction in the aortic arch, thoracic aorta, and abdominal aorta. Chondroitin sulphate C and chondroitin sulphate B fractions decreased only in the abdominal aorta and were not significantly altered in the other two segments, while heparin fraction decreased only in the thoracic aorta and was not affected in the other segments. Administration of testosterone to the orchidectomized animals counteracted these changes in the aortic GAG fractions. The enzymes concerned with the synthesis of precursors of GAG—L-glutamine: D-fructose-6-phosphate aminotransferase, UDPG dehydrogenase, and UDPG pyrophosphorylase—all decreased in the orchidectomized animals; testosterone administration increased their activity in the orchidectomized animals. Enzymes concerned with degradation of GAG—β-glucuronidase, β-hexosaminidase, aryl sulphatase, cathepsin, and hyaluronidase—increased in the orchidectomized animals and decreased on administration of testosterone. Concentration of PAPS and activity of sulphate-activating system and sulphotransferase also decreased in the orchidectomized animals, and testosterone administration tended to restore this decrease to normal levels.