Inflammatory cytokines, high-sensitivity C-reactive protein, and risk of one-year vascular events, death, and poor functional outcome after stroke and transient ischemic attack.

BACKGROUND: Inflammation driven by pro-inflammatory cytokines is a new therapeutic target in coronary disease. Few data exist on the association of key upstream cytokines and post-stroke recurrence. In a prospective cohort study, we investigated the association between pivotal cytokines, high-sensitivity C-reactive protein (hsCRP) and one-year outcomes. METHODS: BIO-STROKETIA is a multi-center prospective cohort study of non-severe ischemic stroke (modified Rankin score ≤ 3) and transient ischemic attack. Controls were patients with transient symptoms attending transient ischemic attack clinics with non-ischemic final diagnosis. Exclusion criteria were severe stroke, infection, and other pro-inflammatory disease; hsCRP and cytokines (interleukin (IL) 6, IL-1ß, IL-8, IL-10, IL-12, interferon-γ (IFN-γ), tumor-necrosis factor-α (TNF-α)) were measured. The primary outcome was one-year recurrent stroke/coronary events (fatal and non-fatal). RESULTS: In this study, 680 patients (439 stroke, 241 transient ischemic attack) and 68 controls were included. IL-6, IL-1ß, IL-8, IFN-γ, TNF-α, and hsCRP were higher in stroke/transient ischemic attack cases (p ≤ 0.01 for all). On multivariable Cox regression, IL-6, IL-8, and hsCRP independently predicted one-year recurrent vascular events (adjusted hazard ratios (aHR) per-quartile increase IL-6 1.31, confidence interval (CI) 1.02-1.68, p = 0.03; IL-8 1.47, CI 1.15-1.89, p = 0.002; hsCRP 1.28, CI 1.01-1.62, p = 0.04). IL-6 (aHR 1.98, CI 1.26-3.14, p = 0.003) and hsCRP (aHR 1.81, CI 1.20-2.74, p = 0.005) independently predicted one-year fatality. IL-6 and hsCRP (adjusted odds ratio per-unit increase 1.02, CI 1.01-1.04) predicted poor functional outcome, with a trend for IL-1ß (p = 0.054). CONCLUSION: Baseline inflammatory cytokines independently predicted late recurrence, supporting a rationale for randomized trials of anti-inflammatory agents for prevention after stroke and suggesting that targeted therapy to high-risk patients with high baseline inflammation may be beneficial.

Regression of pre-established atherosclerosis in the apoE-/- mouse by conjugated linoleic acid.

Conjugated linoleic acid (CLA) refers to a group of positional and geometric isomers of linoleic acid that has been shown to suppress the development of atherosclerosis in a rabbit model. We investigated whether CLA acts as a cyclo-oxygenase (COX) inhibitor or as an agonist of the peroxisome-proliferator-activator receptor (PPAR) gamma in the ApoE(-/-) mouse model. In vitro, a 9-cis, 11-trans isomer of CLA inhibited prostaglandin formation and oxygen consumption by both isoforms of COX, with no evidence by MS of alternative products being generated. In vivo, supplementation with CLA was found to induce resolution of atherosclerosis. The effect of CLA in vivo could not be explained by COX inhibition alone, as urinary prostaglandin levels were unchanged in animals receiving CLA supplementation, and administration of selective COX inhibitors did not induce lesion regression. There was however induction of PPAR gamma, a known response to agonists of this nuclear orphan receptor.

Cyclooxygenase-1 and -2-dependent prostacyclin formation in patients with atherosclerosis.

BACKGROUND: The formation of prostacyclin (PGI(2)), thromboxane (TX) A(2), and isoprostanes is markedly enhanced in atherosclerosis. We examined the relative contribution of cyclooxygenase (COX)-1 and -2 to the generation of these eicosanoids in patients with atherosclerosis. METHODS AND RESULTS: The study population consisted of 42 patients with atherosclerosis who were undergoing surgical revascularization. COX-2 mRNA was detected in areas of atherosclerosis but not in normal blood vessel walls, and there was evidence of COX-1 induction. The use of immunohistochemical studies localized the COX-2 to proliferating vascular smooth muscle cells and macrophages. Twenty-four patients who did not previously receive aspirin were randomized to receive either no treatment or nimesulide at 24 hours before surgery and then for 3 days. Eighteen patients who were receiving aspirin were continued on a protocol of either aspirin alone or a combination of aspirin and nimesulide. Urinary levels of 11-dehydro-TXB(2) and 2,3-dinor-6-keto-PGF(1alpha), metabolites of TXA(2) and PGI(2), respectively, were elevated in patients with atherosclerosis compared with normal subjects (3211+/-533 versus 679+/-63 pg/mg creatinine, P<0.001; 594+/-156 versus 130+/-22 pg/mg creatinine, P<0.05, respectively), as was the level of the isoprostane 8-iso-PGF(2alpha). Nimesulide reduced 2, 3-dinor-6-keto-PGF(1alpha) excretion by 46+/-5% (378.3+/-103 to 167+/-37 pg/mg creatinine, P<0.01) preoperatively and blunted the increase after surgery. Nimesulide had no significant effect on 11-dehydro-TXB(2) before (2678+/-694 to 2110+/-282 pg/mg creatinine) or after surgery. The levels of both products were lower in patients who were taking aspirin, and no further reduction was seen with the addition of nimesulide. None of the treatments influenced urinary 8-iso-PGF(2alpha) excretion. CONCLUSIONS: Both COX-1 and -2 are expressed and contribute to the increase in PGI(2) in patients with atherosclerosis, whereas TXA(2) is generated by COX-1.

Aedes togoi comes aboard.

Aedes togoi were noted as a biting nuisance on board a sailing boat anchored offshore between Vancouver Island and the Canadian mainland at the extreme north of Georgia Strait. This is the most northerly of 14 localities now known for this species in the Pacific northwest. Its distribution is mapped and briefly discussed.