No abstract

Skin and soft-tissue abscesses, a common problem among injection drug users (IDUs), result in serious morbidity for the patient and costly hospitalizations for incision and drainage; however, there has been little etiologic or preventive epidemiologic research on this problem. We performed a case-control study that enrolled 151 IDUs who had been given a new diagnosis of abscess requiring incision and drainage (cases) and 267 IDUs who did not have abscess or other bacterial infection during the previous year and who were stratum-matched to cases according to age, sex, and race (controls). Subcutaneous or intramuscular, instead of intravenous, injection is a major risk factor for abscess among IDUs. The injection of a cocaine and heroin mixture, or "speedball," may predispose patients to develop abscess by inducing soft-tissue ischemia. Cleaning the skin with alcohol before injection was found to have a protective effect. Neither human immunodeficiency virus nor human T-lymphotropic virus type II seropositivity was significantly associated with abscess.

Ischemic tolerance can be induced by numerous preconditioning stimuli, including various Toll-like receptor (TLR) ligands. We have shown previously that systemic administration of the TLR4 ligand, lipopolysaccharide (LPS) or the TLR9 ligand, unmethylated CpG ODNs prior to transient brain ischemia in mice confers substantial protection against ischemic damage. To elucidate the molecular mechanisms of preconditioning, we compared brain genomic profiles in response to preconditioning with these TLR ligands and to preconditioning via exposure to brief ischemia. We found that exposure to the TLR ligands and brief ischemia induced genomic changes in the brain characteristic of a TLR pathway mediated response. Interestingly, all three preconditioning stimuli resulted in a reprogrammed response to stroke injury that converged on a shared subset of 13 genes not evident in the genomic profile from brains that were subjected to stroke without prior preconditioning. Analysis of the promoter region of these shared genes showed sequences required for interferon regulatory factor (IRF) mediated transcription. The importance of this IRF gene network was tested using mice deficient in IRF3 or IRF7. Our data show that both transcription factors are required for TLR mediated preconditioning and neuroprotection. These studies are the first to discover a convergent mechanism of neuroprotection induced by preconditioning—one that potentially results in reprogramming of the TLR-mediated response to stroke and requires the presence of IRF3 and IRF7.

• Factor XII can contribute to thrombus formation in human and nonhuman primate blood.• An antibody that blocks factor XII activation (15H8) produces an antithrombotic effect in a primate thrombosis model.The plasma zymogens factor XII (fXII) and factor XI (fXI) contribute to thrombosis in a variety of mouse models. These proteins serve a limited role in hemostasis, suggesting that antithrombotic therapies targeting them may be associated with low bleeding risks.Although there is substantial epidemiologic evidence supporting a role for fXI in human thrombosis, the situation is not as clear for fXII. We generated monoclonal antibodies (9A2 and 15H8) against the human fXII heavy chain that interfere with fXII conversion to the protease factor XIIa (fXIIa). The anti-fXII antibodies were tested in models in which anti-fXI antibodies are known to have antithrombotic effects. Both anti-fXII antibodies reduced fibrin formation in human blood perfused through collagen-coated tubes. fXII-deficient mice are resistant to ferric chloride-induced arterial thrombosis, and this resistance can be reversed by infusion of human fXII. 9A2 partially blocks, and 15H8 completely blocks, the prothrombotic effect of fXII in this model. 15H8 prolonged the activated partial thromboplastin time of baboon and human plasmas. 15H8 reduced fibrin formation in collagen-coated vascular grafts inserted into arteriovenous shunts in baboons, and reduced fibrin and platelet accumulation downstream of the graft. These findings support a role for fXII in