The Toxic Effects of Cigarette Additives. Philip Morris' Project Mix Reconsidered: An Analysis of Documents Released through Litigation

Stanton Glantz and colleagues analyzed previously secret tobacco industry documents and peer-reviewed published results of Philip Morris' Project MIX about research on cigarette additives, and show that this research on the use of cigarette additives cannot be taken at face value

The Immune System in Stroke

Stroke represents an unresolved challenge for both developed and developing countries and has a huge socio-economic impact. Although considerable effort has been made to limit stroke incidence and improve outcome, strategies aimed at protecting injured neurons in the brain have all failed. This failure is likely to be due to both the incompleteness of modelling the disease and its causes in experimental research, and also the lack of understanding of how systemic mechanisms lead to an acute cerebrovascular event or contribute to outcome. Inflammation has been implicated in all forms of brain injury and it is now clear that immune mechanisms profoundly influence (and are responsible for the development of) risk and causation of stroke, and the outcome following the onset of cerebral ischemia. Until very recently, systemic inflammatory mechanisms, with respect to common comorbidities in stroke, have largely been ignored in experimental studies. The main aim is therefore to understand interactions between the immune system and brain injury in order to develop novel therapeutic approaches. Recent data from clinical and experimental research clearly show that systemic inflammatory diseases -such as atherosclerosis, obesity, diabetes or infection - similar to stress and advanced age, are associated with dysregulated immune responses which can profoundly contribute to cerebrovascular inflammation and injury in the central nervous system. In this review, we summarize recent advances in the field of inflammation and stroke, focusing on the challenges of translation between pre-clinical and clinical studies, and potential anti-inflammatory/immunomodulatory therapeutic approaches

Langevin diffusion of heavy quarks in non-conformal holographic backgrounds

73 pages, 13 figuresInternational audienceThe Langevin diffusion process of a relativistic heavy quark in a non-conformal holographic setup is discussed. The bulk geometry is a general, five-dimensional asymptotically AdS black hole. The heavy quark is described by a trailing string attached to a flavor brane, moving at constant velocity. From the equations describing linearized fluctuations of the string world-sheet, the correlation functions defining a generalized Langevin process are constructed via the AdS/CFT prescription. In the local limit, analytic expressions for the Langevin diffusion and friction coefficients are obtained in terms of the bulk string metric. Modified Einstein relations between these quantities are also derived. The spectral densities associated to the Langevin correlators are analyzed, and simple analytic expressions are obtained in the small and large frequency limits. Finally, a numerical analysis of the jet-quenching parameter, and a comparison to RHIC phenomenology are performed in the case of Improved Holographic QCD

Assessing in vitro combinations of antifungal drugs against yeasts and filamentous fungi: comparison of different drug interaction models.

Contains fulltext : 48405.pdf (publisher's version ) (Closed access)Non-parametric and parametric approaches of two competing zero-interaction theories--the Loewe additivity and the Bliss independence - were evaluated for analyzing the in vitro interactions of various antifungal drugs. Fifty-one data sets, derived from three drug combinations, tested in triplicate against 17 clinical yeast and mold isolates with a two-dimensional checkerboard microdilution technique, were selected to span from strong synergy to strong antagonism. These were analyzed with the standard FIC index model and modern concentration-effect response surface models: the fully parametric model developed by Greco et al. and the 3-D analysis developed by Prichard et al. The FIC index model is subjective, sensitive to experimental errors and resulted in approximated results and variable conclusions depending on the MIC endpoints determined and interpretation endpoints used. By using the MIC-2 endpoint (lowest drug concentration showing 50% of growth) for calculating the FIC indices, problems due to trailing phenomena were reduced and weak interactions could be detected; higher levels of reproducibility and agreement with the other models were achieved using the MIC-0 and MIC-1 (lowest drug concentration showing 10 and 25% of growth, respectively). High reproducibility was achieved in interpreting the FIC indices when the cutoffs of 0.25 and 4 (for single experiments) and the cutoff of 1 (for replicates) were used for defining the limits of additivity/indifference. Although the fully parametric Greco model did not describe precisely the entire response surface of all antifungal drug interactions, it was able to differentiate synergistic from non-synergistic interactions with a non-unit, reproducible, concentration-independent interaction parameter, including its uncertainty, without requiring replication. The Bliss independence based models resulted in mosaics of synergistic and antagonistic combinations, raising questions about the concentration-dependent nature of antifungal drug interaction. The sum of all statistically significant interactions were used as a summary interaction parameter for the entire response surface, concluding synergy or antagonism when it was positive or negative, respectively. The cutoffs of 100% and 200% were used to distinguish weak and moderate interactions, respectively in 12-16 x 8-12 checkerboard formats. Semi-parametric approaches need particular care as experimental errors are not eliminated from the entire response surface

Glucosidase II and N-glycan mannose content regulate the half-lives of monoglucosylated species in vivo

A decrease in N-glycan mannose content significantly diminishes in vivo glucosidase II–mediated deglucosylation rates but does not affect in vivo UDP-glucose:glycoprotein glucosyltransferase–mediated glucosylation, thus increasing the possibility of displaying monoglucosylated structures able to interact with calnexin/calreticulin for longer time periods