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On our initial discovery that prion protein (PrP)-derived peptides were capable of capturing the pathogenic prion protein [Prp.sup.Sc]), we have been interested in how these peptides interact with [PrP.sup.Sc]. After screening peptides from the entire human PrP sequence, we found two peptides ([PrP.sub.19-30] and [PrP.sub.100-111]) capable of binding full-length [PrP.sup.Sc] in plasma, a medium containing a complex mixture of other proteins including a vast excess of the normal prion protein ([Prp.sup.C]). The limit of detection for captured [PrP.sup.Sc] was calculated to be 8 amol from a [approximately equal to] 105-fold dilution of 10% (wt/vol) human variant Creutzfeldt-Jakob disease brain homogenate, with >3,800-fold binding specificity to [PrP.sup.Sc] over [PrP.sup.C]. Through extensive analyses, we show that positively charged amino acids play an important, but not exclusive, role in the interaction between the peptides and [PrP.sup.Sc]. Neither hydrophobic nor polar interactions appear to correlate with binding activity. The peptide-[PrP.sup.Sc] interaction was not sequence-specific, but amino acid composition affected binding. Binding occurs through a conformational domain that is only present in [PrP.sup.Sc], is species-independent, and is not affected by proteinase K digestion. These and other findings suggest a mechanism by which cationic domains of [PrP.sup.C] may play a role in the recruitment of [PrP.sup.C] to [PrP.sup.Ssc]. plasma | Creutzfeldt--Jakob disease | detection | cationic interaction | diagnostic

Abstract Background Angiogenesis is up-regulated in myocardial ischemia. However, limited data exist assessing the value of circulating angiogenic biomarkers in predicting future incidence of acute myocardial infarction (AMI). Our aim was to examine the association between circulating levels of markers of angiogenesis with risk of incident acute myocardial infarction (AMI) in men and women. Methods We performed a case-control study (nested within a large cohort of persons receiving care within Kaiser Permanente of Northern California) including 695 AMI cases and 690 controls individually matched on age, gender and race/ethnicity. Results Median [inter-quartile range] serum concentrations of vascular endothelial growth factor-A (VEGF-A; 260 [252] vs. 235 [224] pg/mL; p = 0.01) and angiopoietin-2 (Ang-2; 1.18 [0.66] vs. 1.05 [0.58] ng/mL; p < 0.0001) were significantly higher in AMI cases than in controls. By contrast, endothelium-specific receptor tyrosine kinase (Tie-2; 14.2 [3.7] vs. 14.0 [3.1] ng/mL; p = 0.07) and angiopoietin-1 levels (Ang-1; 33.1 [13.6] vs. 32.5 [12.7] ng/mL; p = 0.52) did not differ significantly by case-control status. After adjustment for educational attainment, hypertension, diabetes, smoking, alcohol consumption, body mass index, LDL-C, HDL-C, triglycerides and C-reactive protein, each increment of 1 unit of Ang-2 as a Z score was associated with 1.17-fold (95 percent confidence interval, 1.02 to 1.35) increased odds of AMI, and the upper quartile of Ang-2, relative to the lowest quartile, was associated with 1.63-fold (95 percent confidence interval, 1.09 to 2.45) increased odds of AMI. Conclusions Our data support a role of Ang-2 as a biomarker of incident AMI independent of traditional risk factors.