Surrogate end-points: the case of trials on coronary atherosclerotic plaque regression

The experimental progression-regression human model offers an excellent opportunity for testing the pathophysiological hypotheses that have arisen in the study of atherosclerosis. Nevertheless, it is still necessary to demonstrate that the modifications of angiographic patterns are strictly related to changes in coronary events, and this evidence is not yet supported to date by performed trials. Ten randomized controlled trials designed with the aim of angiographically evaluating the evolution of coronary lesions in patients with coronary heart disease made over the past 13 years were reviewed to perform a meta-analysis. Quality of design and execution of the trials, and the analysis of the primary and secondary end-points chosen for each trial, as well as the methods used to measure the changes in atherosclerotic plaques were also assessed. The phenomenon of plaque regression in human beings seems to occur, but clinical, methodological and physiopathologic heterogeneity between examined trials made it unfeasible to perform a meta-analysis. Coronary events are the consequence of the interaction of known and unknown factors, and coronary arterial narrowing from a mild to moderate degree is only one of these factors. The choice of the regression of atherosclerotic plaques as the primary end-point of a trial should probably be confined to phase 2 studies, while proof of clinical efficacy should be based on harder end-points that are representative of the very objective of medical interventions: amelioration and/or prolongation of a patient's life.     

Coinfections by HIV, hepatitis B and hepatitis C in imprisoned injecting drug users

In order to know the prevalence and risk factors for coinfections by human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) among injecting drug users (IDUs), a cross-sectional study was carried out in two prisons of the province of Cantabria, northern Spain. Three hundred and sixty-two IDU inmates were recruited. All inmates were interviewed and their blood tested for HIV, HBV and HCV. Crude and multiple risk factor adjusted for (by polychotomous logistic regression) odds ratios were calculated. Prevalence of HBV-HCV coinfection (42.5%) was higher than HIV-HBV-HCV coinfection (37.3%), whereas monoinfections were very uncommon (overall: 13%). Long-term injectors and reincarceration were the foremost risk factors for both coinfections, showing a trend between the degree of association and the number of viruses infecting a patient. No significant relationship between coinfection status and sexual practices was observed. The results related to coinfections are consistent with previous studies of prevalence and risk factors for HIV, HBV and HCV, in indicating that the high rates of coinfections among IDU inmates emphasise the need to harm-reduction policy across prisons in Spain.     

Risk factors for monoinfections and coinfections with HIV,hepatitis B and hepatitis C viruses in northern Spanish prisoners.

A cross-sectional study was conducted in prisons of Cantabria (northern Spain) from June 1992 to December 1994. Inmates were asked to participate in a survey on prevalence and risk factors for monoinfections and coinfections with HIV, HBV and HCV. Crude and multiple odds ratios of risk factors were calculated (by polychotomous logistic regression). Prevalence of coinfections was higher than that of monoinfections. IDU risk factors were the main independent variables associated with monoinfections and coinfections with these agents. The strength of association increased with the degree of coinfection for IDU risk factors and penal status, e.g. duration of injecting drug use for more than 5 years yielded an adjusted OR ranging from 1.3 (95% CI: 0.4-5.1) for HBV monoinfection to 180 (95% CI: 61.0-540.0) for HIV-HBV-HCV coinfection. In comparison, sexual behaviours were less important than IDU risk factors.     

Polymorphism analysis of the VNTR locus D17S5 in Central Spain

The fragment length polymorphism YNZ22 (D17S5) was analysed for a sample of 207 unrelated individuals living in Madrid (Spanish Caucasians) using PCR-methodology and high resolution separation. Hardy-Weinberg expectations (HWE) were calculated after pooling alleles into four groups. No deviations from HWE were detectable using the conventional ²-test. The power of discrimination was estimated as 0.96 and the mean paternity exclusion chance as 0.7587. A comparison of the allele frequency distribution with those of other Caucasian groups revealed no major differences.     

蝙蝠葛中的新生物碱——蝙蝠葛新林碱

防已科植物蝙蝠葛(Menispermum daurioum DC.)的根茎,即北豆根,是一种重要的中药,具有清热解毒、消肿止痛等功效。已知含有近二十种生物碱,其中五种属双苄基四氢异喹啉类,即蝙蝠葛碱(dauricine,Ⅰ)、蝙蝠葛诺林碱(daurinoline,Ⅱ)、蝙蝠葛新诺林碱     

Identification and characterization of a T-helper peptide from carcinoembryonic antigen.

PURPOSE: The purpose of this research was to identify promiscuous T-helper cell determinants (THd) from carcinoembryonic antigen (CEA) to be used to prime T-cell help for cancer therapy. CEA was selected because this antigen is expressed in an important variety of carcinomas. EXPERIMENTAL DESIGN: Potential promiscuous THd from CEA were predicted using available computer algorithms. Predicted peptides were synthesized and tested in binding experiments to different HLA-DR molecules. Binder peptides were then used to prime T-cell responses both in vitro and in vivo. RESULTS: Twenty 15-mer peptides from CEA were predicted to bind to different HLA-DR molecules. The promiscuous character of these peptides was demonstrated in binding experiments. Fifteen of 20 peptides tested were able to bind to HLA-DR4, but only CEA (625-639) was shown to be presented after processing of recombinant CEA. CEA (625-639) was also found to be presented by HLA-DR53. Moreover, immunization of HLA-DR4 transgenic mice with CEA (625-639) in conjunction with class I epitope OVA (257-264), induced a CTL response specific of OVA (257-264). CONCLUSIONS: CEA (625-639) might be a relevant promiscuous THd peptide for cancer therapy.     

Identification of differentially expressed genes in aflatoxin B1- treated cultured primary rat hepatocytes and Fischer 344 rats

Aflatoxin B1 (AFB1), a mutagen and hepatocarcinogen in rats and humans, is a contaminant of the human food supply, particularly in parts of Africa and Asia. AFB1-induced changes in gene expression may play a part in the development of the toxic, immunosuppressive and carcinogenic properties of this fungal metabolite. An understanding of the-role of AFB1 in modulating gene regulation should provide insight regarding mechanisms of AFB1-induced carcinogenesis. We used three PCR- based subtractive techniques to identify AFB1-responsive genes in cultured primary rat hepatocyte RNA: differential display PCR (DD-PCR), representational difference analysis (RDA) and suppression subtractive hybridization (SSH). Each of the three techniques identified AFB1- responsive genes, although no individual cDNA was isolated by more than one technique. Nine cDNAs isolated using DD-PCR, RDA or SSH were found to represent eight genes that are differentially expressed as a result of AFB1 exposure. Genes whose mRNA levels were increased in cultured primary rat hepatocytes after AFB1 treatment were corticosteroid binding globulin (CBG), cytochrome P450 4F1 (CYP4F1), alpha-2 microglobulin, C4b-binding protein (C4BP), serum amyloid A-2 and glutathione S-transferase Yb2 (GST). Transferrin and a small CYP3A-like cDNA had reduced mRNA levels after AFB1 exposure. Full-length CYP3A mRNA levels were increased. When liver RNA from AFB1-treated male F344 rats was evaluated for transferrin, CBG, GST, CYP3A and CYP4F1 expression, a decrease in transferrin mRNA and an increase in CBG, GST, CYP3A and CYP4F1 mRNA levels was also seen. Analysis of the potential function of these genes in maintaining cellular homeostasis suggests that their differential expression could contribute to the toxicity associated with AFB1 exposure.