Combination antiretroviral therapy -associated lipodystrophy : insights into pathogenesis and treatment

Introduction: Combination antiretroviral therapy (cART) has decreased morbidity and mortality of individuals infected with human immunodeficiency virus type 1 (HIV-1). Its use, however, is associated with adverse effects which increase the patients risk of conditions such as diabetes and coronary heart disease. Perhaps the most stigmatizing side effect is lipodystrophy, i.e., the loss of subcutaneous adipose tissue (SAT) in the face, limbs and trunk while fat accumulates intra-abdominally and dorsocervically. The pathogenesis of cART-associated lipodystrophy is obscure. Nucleoside reverse transcriptase inhibitors (NRTI) have been implicated to cause lipoatrophy via mitochondrial toxicity. There is no known effective treatment for cART-associated lipodystrophy during unchanged antiretroviral regimen in humans, but in vitro data have shown uridine to abrogate NRTI-induced toxicity in adipocytes. Aims: To investigate whether i) cART or lipodystrophy associated with its use affect arterial stiffness; ii) lipoatrophic SAT is inflamed compared to non-lipoatrophic SAT; iii) abdominal SAT from patients with compared to those without cART-associated lipoatrophy differs with respect to mitochondrial DNA (mtDNA) content, adipose tissue inflammation and gene expression, and if NRTIs stavudine and zidovudine are associated with different degree of changes; iv) lipoatrophic abdominal SAT differs from preserved dorsocervical SAT with respect to mtDNA content, adipose tissue inflammation and gene expression in patients with cART-associated lipodystrophy and v) whether uridine can revert lipoatrophy and the associated metabolic disturbances in patients on stavudine or zidovudine based cART. Subjects and methods: 64 cART-treated patients with (n=45) and without lipodystrophy/-atrophy (n=19) were compared cross-sectionally. A marker of arterial stiffness, heart rate corrected augmentation index (AgIHR), was measured by pulse wave analysis. Body composition was measured by magnetic resonance imaging and dual-energy X-ray absorptiometry, and liver fat content by proton magnetic resonance spectroscopy. Gene expression and mtDNA content in SAT were assessed by real-time polymerase chain reaction and microarray. Adipose tissue composition and inflammation were assessed by histology and immunohistochemistry. Dorsocervical and abdominal SAT were studied. The efficacy and safety of uridine for the treatment of cART-associated lipoatrophy were evaluated in a randomized, double-blind, placebo-controlled 3-month trial in 20 lipoatrophic cART-treated patients. Results: Duration of antiretroviral treatment and cumulative exposure to NRTIs and protease inhibitors, but not the presence of cART-associated lipodystrophy, predicted AgIHR independent of age and blood pressure. Gene expression of inflammatory markers was increased in SAT of lipodystrophic as compared to non-lipodystrophic patients. Expression of genes involved in adipogenesis, triglyceride synthesis and glucose disposal was lower and of those involved in mitochondrial biogenesis, apoptosis and oxidative stress higher in SAT of patients with than without cART-associated lipoatrophy. Most changes were more pronounced in stavudine-treated than in zidovudine-treated individuals. Lipoatrophic SAT had lower mtDNA than SAT of non-lipoatrophic patients. Expression of inflammatory genes was lower in dorsocervical than in abdominal SAT. Neither depot had characteristics of brown adipose tissue. Despite being spared from lipoatrophy, dorsocervical SAT of lipodystrophic patients had lower mtDNA than the phenotypically similar corresponding depot of non-lipodystrophic patients. The greatest difference in gene expression between dorsocervical and abdominal SAT, irrespective of lipodystrophy status, was in expression of homeobox genes that regulate transcription and regionalization of organs during embryonal development. Uridine increased limb fat and its proportion of total fat, but had no effect on liver fat content and markers of insulin resistance. Conclusions: Long-term cART is associated with increased arterial stiffness and, thus, with higher cardiovascular risk. Lipoatrophic abdominal SAT is characterized by inflammation, apoptosis and mtDNA depletion. As mtDNA is depleted even in non-lipoatrophic dorsocervical SAT, lipoatrophy is unlikely to be caused directly by mtDNA depletion. Preserved dorsocervical SAT of patients with cART-associated lipodystrophy is less inflamed than their lipoatrophic abdominal SAT, and does not resemble brown adipose tissue. The greatest difference in gene expression between dorsocervical and abdominal SAT is in expression of transcriptional regulators, homeobox genes, which might explain the differential susceptibility of these adipose tissue depots to cART-induced toxicity. Uridine is able to increase peripheral SAT in lipoatrophic patients during unchanged cART.

Rhetoric and public speech in English republicanism, 1642-1681

The study analyses the ambivalent relationship republicanism, as a form of self-government free from domination, had with the ideal of participatory oratory and non-dominated speech on the one hand, and with the danger of unhindered demagogy and its possibly fatal consequences to that form of government on the other. Although previous scholarship has delved deeply into republicanism as well as into rhetoric and public speech, the interplay between those aspects has only gathered scattered interest, and there has been no systematic study considering the variety of republican approaches to rhetoric and public speech in 17th-century England. The rare attempts to do so have been studies in English literature, and they have not analysed the political philosophy of republicanism, as the focus has been on republicanism as a literary culture. This study connects the fields of political theory, political history as well as literature in order to make a multidisciplinary contribution to intellectual history. The study shows that, within the tradition of classical republicanism, individual authors could make different choices when addressing the problematic topics of public speech and rhetoric, and the variety of their conclusions often set the authors against each other, resulting in the development of their theories through internal debates within the republican tradition. The authors under study were chosen to reflect this variety and the connections between them: the similarities between James Harrington and John Streater, and between John Milton and John Hall of Durham are shown, as well the controversies between Harrington and Milton, and Streater and Hall, respectively. In addition, by analysing the writings of Marchamont Nedham the study will show that the choices were not limited to more, or less, democratic brands of republicanism. Most significantly, the study provides a thorough analysis of the political philosophies behind the various brands of republicanism, in addition to describing them. By means of this analysis, the study shows that previous attempts to assess the role of free speech and public debate, through the lenses of modern, rights-based liberal political theory have resulted in an inappropriate framework for understanding early modern English republicanism. By approaching the topics through concepts used by the republicans legitimate authority, leadership by oratory, and republican freedom and through the frames of reference available and familiar to them roles of education and institutions the study presents a thorough and systematic analysis of the role and function of rhetoric and public speech in English republicanism. The findings of this analysis have significant consequences to our current understanding of the history and development of republican political theory, and, more generally, of the connections between democratic theory and free speech.

Part-of-Speech Tagging using Parallel Weighted Finite-State Transducers

We use parallel weighted finite-state transducers to implement a part-of-speech tagger, which obtains state-of-the-art accuracy when used to tag the Europarl corpora for Finnish, Swedish and English. Our system consists of a weighted lexicon and a guesser combined with a bigram model factored into two weighted transducers. We use both lemmas and tag sequences in the bigram model, which guarantees reliable bigram estimates.