Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Salmonella Typhimurium Type III Secretion Effectors Stimulate Innate Immune Responses in Cultured Epithelial Cells

Recognition of conserved bacterial products by innate immune receptors leads to inflammatory responses that control pathogen spread but that can also result in pathology. Intestinal epithelial cells are exposed to bacterial products and therefore must prevent signaling through innate immune receptors to avoid pathology. However, enteric pathogens are able to stimulate intestinal inflammation. We show here that the enteric pathogen Salmonella Typhimurium can stimulate innate immune responses in cultured epithelial cells by mechanisms that do not involve receptors of the innate immune system. Instead, S. Typhimurium stimulates these responses by delivering through its type III secretion system the bacterial effector proteins SopE, SopE2, and SopB, which in a redundant fashion stimulate Rho-family GTPases leading to the activation of mitogen-activated protein (MAP) kinase and NF-κB signaling. These observations have implications for the understanding of the mechanisms by which Salmonella Typhimurium induces intestinal inflammation as well as other intestinal inflammatory pathologies

Characterisation of Innate Fungal Recognition in the Lung

The innate recognition of fungi by leukocytes is mediated by pattern recognition receptors (PRR), such as Dectin-1, and is thought to occur at the cell surface triggering intracellular signalling cascades which lead to the induction of protective host responses. In the lung, this recognition is aided by surfactant which also serves to maintain the balance between inflammation and pulmonary function, although the underlying mechanisms are unknown. Here we have explored pulmonary innate recognition of a variety of fungal particles, including zymosan, Candida albicans and Aspergillus fumigatus, and demonstrate that opsonisation with surfactant components can limit inflammation by reducing host-cell fungal interactions. However, we found that this opsonisation does not contribute directly to innate fungal recognition and that this process is mediated through non-opsonic PRRs, including Dectin-1. Moreover, we found that pulmonary inflammatory responses to resting Aspergillus conidia were initiated by these PRRs in acidified phagolysosomes, following the uptake of fungal particles by leukocytes. Our data therefore provides crucial new insights into the mechanisms by which surfactant can maintain pulmonary function in the face of microbial challenge, and defines the phagolysosome as a novel intracellular compartment involved in the innate sensing of extracellular pathogens in the lung

Discovery and paleoenvironmental implications of a Zoophycos-group trace fossil (?Echinospira) from the Middle Pennsylvanian Sydney Mines Formation of Nova Scotia

The discovery of a Zoophycos-group trace fossil questionably attributed to Echinospira is reported from the Middle Pennsylvanian Sydney Mines Formation of Nova Scotia. Zoophycos-group trace fossils are composed of a central axis from which helicoidally arranged sheets of spreite emanate, giving the appearance of stacked cones. Such traces are commonly reported from marine paleoenvironments throughout the Phanerozoic. This occurrence, the first of its kind in the Maritimes Basin, provides further evidence for marine influence during the deposition of these dominantly terrestrial coal-bearing successions. RÉSUMÉ On signale la découverte d’un ichnofossile du groupe Zoophycos rattaché de façon douteuse à Échinospira dans la formation du Pennsylvanien moyen de Sydney Mines, en Nouvelle-Écosse. Les ichnofossiles du groupe Zoophycos sont constitués d’un axe central duquel émanent des feuilles de spréite disposées de façon héliocoïdale leur conférant l’aspect de cônes étagés. Ces ichnofossiles sont communément signalés dans les paléoenvironnements marins du Phanérozoïque. La présence de cet ichnofossile particulier, premier du genre dans le bassin des Maritimes, fournit une autre preuve de l’influence marine pendant la sédimentation de ces successions carbonifères en prédominance terrestres. [Traduit par la rédaction

Fire-prone plant communities and palaeoclimate of a Late Cretaceous fluvial to estuarine environment, Pecinov quarry, Czech Republic

The botanical identity and facies distribution of fossil charcoal is described from Middle to Late Cenomanian (90–94 Ma) fluvial to estuarine units at Pecínov quarry, near Prague, Czech Republic. Braided alluvial facies associations contain charred conifer woods (family Pinaceae) possibly derived from upland forest fires, and abundant charred angiosperm woods, flowers and inflorescences (families Lauraceae and ?Platanaceae) derived from riparian gallery forest fires (Unit 2). Retrogradational coastal salt marsh facies associations contain abundant charred conifer wood (families Cheirolepidiaceae and Cupressaceae/Taxodiaceae) derived from fires in halophytic backswamp forest, and rare pinaceous charred cones and lauraceous angiosperm wood washed downstream from fires further inland (Units 3–4). Progradational coastal facies associations within an estuary mouth setting contain abundant charred conifer wood (family Cupressaceae/Taxodiaceae), common taxodiaceous conifer and angiosperm leaves, fern rachises, and lycopsid stems derived from fires in mesic backswamp taxodiaceous forests and supra-tidal fern-lycopsid thickets (Unit 5). Growth rings in angiosperm and conifer woods, leaf physiognomy and computer models indicate that climate was equable, warm and humid, but that there was a short annual dry season; most fires probably occurred during these annual drought periods. The abundance of charcoal and the diversity of taxa preserved in this state indicate that nearly all plant communities were fire-prone. Physiognomically, the Pecínov flora resembles present-day seasonally-dry subtropical forests where fires are a common occurrence