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.

Lebanese Plants and Plant-Derived Compounds Against Colon Cancer

Colorectal cancer (CRC) is a major health concern and demands long-term efforts in developing strategies for screening and prevention. CRC has become a preventable disease as a consequence of a better understanding of colorectal carcinogenesis. However, current therapy is unsatisfactory and necessitates the exploration of other approaches for the prevention and treatment of cancer. Plant based products have been recognized as preventive with regard to the development of colon cancer. Therefore, the potential chemopreventive use and mechanism of action of Lebanese natural product were evaluated. Towards this aim the antitumor activity of Onopordum cynarocephalum and Centaurea ainetensis has been studied using in vitro and in vivo models. In vitro, both crude extracts were non cytotoxic to normal intestinal cells and inhibited the proliferation of colon cancer cells in a dose-dependent manner. In vivo, both crude extracts reduced the number of tumors by an average of 65% at weeks 20 (adenomas stage) and 30 (adenocarcinomas stage). The activity of the C. ainetensis extract was attributed to Salograviolide A, a guaianolide-type sesquiterpene lactone, which was isolated and identified through bio-guided fractionation. The mechanism of action of thymoquinone (TQ), the active component of Nigella sativa, was established in colon cancer cells using in vitro models. By the use of N-acetyl cysteine, a radical scavenger, the direct involvement of reactive oxygen species in TQ-induced apoptotic cells was established. The analytical detection of TQ from spiked serum and its protein binding were evaluated. The average recovery of TQ from spiked serum subjected to several extraction procedures was 2.5% proving the inability of conventional methods to analyze TQ from serum. This has been explained by the extensive binding (>98%) of TQ to serum and major serum components such as bovine serum albumin (BSA) and alpha-1-acid glycoprotein (AGP). Using mass spectrometry analysis, TQ was confirmed to bind covalently to the free cysteine in position 34 and 147 of the amino acid sequence of BSA and AGP, respectively. The results of this work put at the disposal for future development new plants with anti-cancer activities and enhance the understanding of the pharmaceutical properties of TQ, a prerequisite for its future clinical development.

Matti Laurila : Jääkäriupseeri, suojeluskuntapäällikkö, rintamakomentaja

Matti Laurila (1895 1983) This is a biographical research of a Jaeger officer, a Civil Guard Chief, a Field Commander Matti Laurila. A broader practice of qualitative methods was utilized in the research. The main aim is a permanent reconstruction and reinterpretation of past events through the experiences of the study object. The life and times of Laurila are intertwined with the crucial events that led to the Finnish Declaration of Independence. Afterwards he helped to ensure that the young republic also stayed independent. As a Jaeger in the winter of 1917 Laurila witnessed an incident he would never forget. After disobeying a direct order, Sven Saarikoski from Lapua was shot dead by his commanding officer, K. A. Ståhlberg, on the ice of the river Aa. Laurila faced the horrors of war at closer quarters, for he lost his father and his brother in the battle of Länkipohja on 16th March 1918. This battle was a major turning point for Laurila and profoundly influenced the rest of his life. The relationship between Laurila and his superiors was problematic almost throughout his military career, haunted as he was by the memory of Sven Saarikoski's execution and the losses in Länkipohja The position of Laurila as an authority in South Ostrobothnia was a key factor in preventing the extreme right from rallying enough Civil Guard troops to escalate the embryonic Mäntsälä rebellion of 1932. After the rebellion Laurila routinely opposed anything he saw as a threat to the independence of the Civil Guard. He would flatly refuse to even consider the integration of the Civil Guard into the national defence force. His uncompromising stand in this matter annoyed some among the higher ranking officers. After the Winter War Laurila got himself into a dispute with Jaeger Colonel H. E. Hannuksela that would have long-lasting consequences. The conflicts between them became widely known in the attack phase of the Continuation War in 1941 at the latest. Laurila had to give up his military career at the end of 1944. In the years that followed he did what he could to ensure that the South Ostrobothnia Civil Guard patrimony remained in the province. Laurila's position as a respected authority in South Ostrobothnia remained unchanged until his death.

Host Rock Classification (HRC) system for nuclear waste disposal in crystalline bedrock

A new rock mass classification scheme, the Host Rock Classification system (HRC-system) has been developed for evaluating the suitability of volumes of rock mass for the disposal of high-level nuclear waste in Precambrian crystalline bedrock. To support the development of the system, the requirements of host rock to be used for disposal have been studied in detail and the significance of the various rock mass properties have been examined. The HRC-system considers both the long-term safety of the repository and the constructability in the rock mass. The system is specific to the KBS-3V disposal concept and can be used only at sites that have been evaluated to be suitable at the site scale. By using the HRC-system, it is possible to identify potentially suitable volumes within the site at several different scales (repository, tunnel and canister scales). The selection of the classification parameters to be included in the HRC-system is based on an extensive study on the rock mass properties and their various influences on the long-term safety, the constructability and the layout and location of the repository. The parameters proposed for the classification at the repository scale include fracture zones, strength/stress ratio, hydraulic conductivity and the Groundwater Chemistry Index. The parameters proposed for the classification at the tunnel scale include hydraulic conductivity, Q´ and fracture zones and the parameters proposed for the classification at the canister scale include hydraulic conductivity, Q´, fracture zones, fracture width (aperture + filling) and fracture trace length. The parameter values will be used to determine the suitability classes for the volumes of rock to be classified. The HRC-system includes four suitability classes at the repository and tunnel scales and three suitability classes at the canister scale and the classification process is linked to several important decisions regarding the location and acceptability of many components of the repository at all three scales. The HRC-system is, thereby, one possible design tool that aids in locating the different repository components into volumes of host rock that are more suitable than others and that are considered to fulfil the fundamental requirements set for the repository host rock. The generic HRC-system, which is the main result of this work, is also adjusted to the site-specific properties of the Olkiluoto site in Finland and the classification procedure is demonstrated by a test classification using data from Olkiluoto. Keywords: host rock, classification, HRC-system, nuclear waste disposal, long-term safety, constructability, KBS-3V, crystalline bedrock, Olkiluoto

Local Politicizations : A Comparison of Finns and French Practicing Democracy

This study examines how do the processes of politicization differ in the Finnish and the French local contexts, and what kinds of consequences do these processes have on the local civic practices, the definitions and redefinitions of democracy and citizenship, the dynamics of power and resistance, and the ways of solving controversies in the public sphere. By means of comparative anthropology of the state , focusing on how democracy actually is practiced in different contexts, politicizations the processes of opening political arenas and recognizing controversy are analyzed. The focus of the study is on local activists engaged in different struggles on various levels of the local public spheres, and local politicians and civil servants participating in these struggles from their respective positions, in two middle-size European cities, Helsinki and Lyon. The empirical analyses of the book compare different political actors and levels of practicing democracy simultaneously. The study is empirically based on four different bodies of material: Ethnographic notes taken during a fieldwork among the activities of several local activist groups; 47 interviews of local activists and politicians; images representing different levels of public portrayals from activist websites (Helsinki N=274, Lyon N=232) and from city information magazines (Helsinki-info N=208, Lyon Citoyen N= 357); and finally, newspaper articles concerning local conflict issues, and reporting on the encounters between local citizens and representatives of the cities (January-June in 2005; Helsingin Sanomat N=96 and Le Progrès N= 102). The study makes three distinctive contributions to the study of current democratic societies: (1) a conceptual one by bringing politicization at the center of a comparison of political cultures, and by considering in parallel the ethnographic group styles theory by Nina Eliasoph and Paul Lichterman, the theory on counter-democracy by Pierre Rosanvallon and the pragmatist justification theory by Luc Boltanski and Laurent Thévenot; (2) an empirical one through the triangulation of ethnographic, thematic interview, visual, and newspaper data through which the different aspects of democratic practices are examined; and (3) a methodological one by developing new ways of analyzing comparative cases an application of Frame Analysis to visual material and the creation of Public Justification Analysis for analyzing morally loaded claims in newspaper reports thus building bridges between cultural, political, and pragmatic sociology. The results of the study indicate that the cultural tools the Finnish civic actors had at their disposal were prone to hinder more than support politicization, whereas the tools the French actors mainly relied on were frequently apt for making politicization possible. This crystallization is defined and detailed in many ways in the analyses of the book. Its consequences to the understanding and future research on the current developments of democracy are multiple, as politicization, while not assuring good results as such, is central to a functioning and vibrant democracy in which injustices can be fixed and new directions and solutions sought collectively.