Mechanisms to safely eliminate amyloids and preamyloid oligomers associated with many devastating diseases are urgently needed. Biophysical principles dictate that small molecules are unlikely to perturb large intermolecular protein-protein interfaces, let alone extraordinarily stable amyloid interfaces. Yet 4,5-dianilinophthalimide (DAPH-1) reverses A␤42 amyloidogenesis and neurotoxicity, which is associated with Alzheimer's disease. Here, we show that DAPH-1 and select derivatives are ineffective against several amyloidogenic proteins, including tau, ␣-synuclein, Ure2, and PrP, but antagonize the yeast prion protein, Sup35, in vitro and in vivo. This allowed us to exploit several powerful new tools created for studying the conformational transitions of Sup35 and decipher the mechanisms by which DAPH-1 and related compounds antagonize the prion state. During fibrillization, inhibitory DAPHs alter the folding of Sup35's amyloidogenic core, preventing amyloidogenic oligomerization and specific recognition events that nucleate prion assembly. Select DAPHs also are capable of attacking preformed amyloids. They remodel Sup35 prion-specific intermolecular interfaces to create morphologically altered aggregates with diminished infectivity and self-templating activity. Our studies provide mechanistic insights and reinvigorate hopes for small-molecule therapies that specifically disrupt intermolecular amyloid contacts.

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The in vitro and in vivo corrosion characteristics of two alloys, cast Co-Cr-Mo (ASTM F75) and wrought Ni-Cr-Mo, were evaluated using electro-chemical corrosion analysis. Two in vitro electrolytic solutions were utilized, an isotonic saline solution consisting of 0.9 w/o NaCl in distilled water and an isotonic saline solution with 10 v/o sterile calf serum. The in vivo environment was created by implanting cylindrically shaped specimens of each alloy into the back muscles of New Zealand white rabbits. Cyclic anodic and cathodic polarization curves were generated for the three test conditions and subsequently were compared. Anodic curves conducted using the isotonic saline and isotonic saline plus serum electrolyte solutions were very similar to the anodic curves generated for the implanted alloy specimens for both alloys. The corrosion rates predicted from the in vitro and in vivo cathodic polarization curves were not statistically different for the three test conditions. Overall, the corrosion data generated using the in vitro environmental conditions adequately predicted the in vivo corrosion behavior of the cast Co-Cr-Mo and wrought Ni-Cr-Mo alloys.

1427 Introduction: Thrombotic thrombocytopenic purpura (TTP) is a syndrome characterized by thrombocytopenia and microangiopathic hemolytic anemia (MAHA) without an alternative explanation, caused by systemic platelet thrombi. Although TTP may be secondary to underlying diseases or drugs, it is often idiopathic. The latter is associated with severe deficiency (defined as ≤10% activity) of the plasma protease ADAMTS13. Low ADAMTS13 is caused by autoantibodies and allows for the accumulation of unusually large multimers of von Willebrand factor in the circulation, which causes spontaneous platelet aggregates and microvascular thrombosis. Therapeutic plasma exchange (TPE) decreases TTP mortality from 90% to 10%. Unfortunately, approximately 30% of treated patients will experience a relapse and require TPE again. The University of Alabama at Birmingham (UAB) Hospital is a referral center for TTP patients from throughout the state. The Oklahoma TTP-Hemolytic Uremic Syndrome (HUS) Registry is a population-based inception cohort of all consecutive patients treated for TTP in central-western Oklahoma since 1989. The aim of this collaboration between the two centers was to characterize the first symptoms experienced by patients with idiopathic TTP preceding their first episode and the timing of these symptoms in relation to the diagnosis (defined as the day TPE was started). Methods: We conducted a retrospective chart review of patients seen at the two centers from January 1, 2007 to June 30, 2010. Using apheresis and electronic medical records, we completed a data collection form with demographic information, clinical presentation, pre-existing risk factors, and clinical course. Results: At UAB, 31 patients were treated for idiopathic TTP; 26 had their first episode during the study window and were included in the analysis. At Oklahoma, 28 patients were identified and 23 fulfilled criteria for inclusion. Of the combined 49 patients, 35 (71%) were female and 14 (29%) were male (gender distribution almost identical between the two centers). The average age of the group was 46 years old (median: 44). At UAB, most patients were African-Americans (77%), followed by Caucasians (19%) and Asians (4%). In Oklahoma, 74% of patients were Caucasian, 18% were African-Americans, and 4% each were American-Indian or Other. These 49 patients reported 27 different first symptoms, with the most common in order of frequency being: abdominal pain (n = 9; 18%), nausea (n = 5; 10%), headache (n = 4; 8%), vomiting (n = 4; 8%), severe neurologic symptoms such as coma, seizures, aphasia (n = 3; 6%), and weakness (n = 3; 6%). Overall, 20 patients (41%) initially noted neurologic symptoms, 13 patients (26.5%) localized their symptoms to the gastrointestinal tract, and 5 patients (10%) reported hematologic symptoms such as mucocutaneous bleeding or signs of hemolysis. The median time to treatment from the onset of symptoms was 5 days (range: 0–132 days), while 82% of patients reported symptoms for 10 days or less. Of 45 patients in whom ADAMTS13 activity was measured, the median result was 4% (range: 4–100%), and 34 of them (75.5%) had an activity of ≤10%, which defines severe deficiency. Two patients (4%) died and the other 47 had resolution of their hematologic abnormalities. Conclusions: Our data confirm the heterogeneity of presentation and nonspecific nature of signs and symptoms of TTP. Thus, physician education and vigilance is necessary to suspect TTP and refer patients for TPE. While many patients were likely to have TTP for several days prior to the diagnosis, TPE must begin promptly once the findings of thrombocytopenia and microangiopathic hemolytic anemia without an alternative diagnosis are noted, in order to avoid a fatal outcome. Disclosures: No relevant conflicts of interest to declare.