Variations in levels of apolipoprotein E have been tied to the risk and progression of Alzheimer's disease . Our group has previously compared and contrasted the promoters of the mouse and human ApoE gene promoter sequences and found notable similarities and significant differences that suggest the importance of the APOE promoter's role in the human disease. We examine here three specific single-nucleotide polymorphisms within the human APOE promoter region, specifically at -491 , -427 , and at -219 upstream from the (...) +1 transcription start site. The -219 and -491 polymorphic variations have significant association with instance of AD, and -491AA has significant risk even when stratified for the APOEepsilon4 allele. We also show significant effects on reporter gene expression in neuronal cell cultures, and, notably, these effects are modified by species origin of the cells. The -491 and -219 polymorphisms may have an interactive effect in addition to any independent activity. DNA-protein interactions differ between each polymorphic state. We propose SP1 and GATA as candidates for regulatory control of the -491 and -219 polymorphic sites. This work's significance lies in drawing connection among APOE promoter polymorphisms' associations with AD to functional promoter activity differences and specific changes in DNA-protein interactions in cell culture-based assays. Taken together, these results suggest that APOE expression levels are a risk factor for AD irrespective of APOEepsilon4 allele status. (shrink)

One of the many striking theses for which Virginia Held argues in How Terrorism Is Wrong is that terrorism is not necessarily morally wrong. In principle, she argues, terrorism can sometimes be permissible . Call this "the Non-necessity Thesis," or NNT. As so often in this deep and thought-provoking book, Held gives a powerful and illuminating argument to this thesis. The argument begins by asserting what we may call "the Violations Distribution Principle" : if we must have rights violations, then (...) a more equitable distribution of such violations is better than a less equitable . It then claims that this implies that "it is better to equalize rights violations in a transition to bring an end to rights violations than it is to subject a given group that has already suffered extensive rights violations to continued such violations" . But this in turn implies that where one group's rights are severely and systematically violated— say, by an oppression, in which their right to personal safety is systematically violated—and another group's rights are not so violated, then a transition which involves a sharing of proportionate rights violations between the oppressed and the non-oppressed is permissible, "if this and only this can be expected to lead to a situation in which rights are more adequately respected" . In those and only those circumstances, terrorism would be permissible, since it centrally violates the right to personal safety. Hence NNT. The idea, then, is that VDP implies that where there is a systematic imbalance in the distribution of severe rights violations between one group and another , and where only a transition which involves a sharing of proportionate rights violations between the oppressed and the non-oppressed can be expected to achieve a situation in which rights are more adequately respected , then terrorism aimed at the oppressors and in conformity with the Uniqueness condition is permissible. (shrink)

Originally published in 1957, this book collects together large sections of important tracts from a variety of political documents, particularly those concerned with democracy, communism, Protestantism or Catholicism. The extracts come from a wide range of authors including Bertrand Russell, Karl Marx, John Locke and Pope Pius XII. This book will be of value to anyone seeking an overview of the key political divisions in the late 20th century or who is interested in political theory generally.

It has been widely argued that words are analogous to species such that words, like species, are natural kinds. In this paper, I consider the metaphysics of word-kinds. After arguing against an essentialist approach, I argue that word-kinds are homeostatic property clusters, in line with the dominant approach to other biological and psychological kinds.

Johanna Knapstein,1 Daniel Grimm,1 Marcus A Wörns,1 Peter R Galle,1 Hauke Lang,2 Tim Zimmermann111st Department of Internal Medicine, Johannes Gutenberg-University, Mainz, Germany; 2Department of General, Visceral and Transplantation Surgery, Johannes Gutenberg-University, Mainz, GermanyIntroduction: Hepatitis C virus reinfection occurs universally after liver transplantation, with accelerated cirrhosis rates of up to 30% within 5 years after liver transplantation. Dual antiviral therapy with pegylated interferon-2a and ribavirin only reaches sustained virological response rates of ~30% after liver transplantation. With the approval of viral NS3/4A (...) protease inhibitors telaprevir, boceprevir, and simeprevir and the NS5B polymerase inhibitor sofosbuvir, combination therapy offers new therapeutic options for HCV-infected patients, resulting in considerably higher sustained virological response rates in the nontransplant setting. Case presentation: We report three cases of TVR-based triple antiviral therapy in HCV genotype 1 reinfected patients after liver transplantation, of whom a 57-year-old Caucasian female and a 43-year-old Caucasian male were therapy naïve, and a 49-year-old Caucasian male patient was pretreated ineffectively. After 4 weeks of therapy, viral load decreased one to three log10 and became negative in weeks 6 to 8 in the therapy naïve patients. The pretreated patient showed a negative viral load in week 4. TVR was administered over 12 weeks, 750 mg thrice daily. Doses of immunosuppression with cyclosporine were reduced four to six fold. Initial peg-IFN and RBV doses ranged from 135–180 µg/week and 800–1,200 mg/day, according to the patient's body weight. Doses of peg-IFN and RBV were adapted to 90–135 µg/week and 400–800 mg/day after 2 to 12 weeks of protease inhibitor therapy. Dual therapy was continued for 36 weeks with total treatment duration of 48 weeks in the therapy naïve patients leading to a sustained virological response 12 weeks after the end of therapy. In the pretreated patient a breakthrough was detected in week 24 and therapy was discontinued. Overall, antiviral therapy was well tolerated. Side effects included dysgeusia and anemia leading to erythropoietin application and blood transfusions. Conclusion: This case series emphasizes that triple therapy with TVR is an efficient treatment for therapy naïve HCV genotype 1 reinfected patients after liver transplantation. But therapeutic options for pretreated patients require improvement. Keyword: cyclosporine, interferon, ribavirin, hepatitis C, protease inhibitor. (shrink)