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A series of 7,6- and 7,5-fused bicyclic thiazepinones and oxazepinones were generated and incorporated as conformationally restricted dipeptide surrogates in mercaptoacyl dipeptides. These compounds are potent inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) both in vitro and in vivo. Compound 1a, a 7,6-fused bicyclic thiazepinone, demonstrated excellent blood pressure lowering in a variety of animal models characterized by various levels of plasma renin activity and significantly potentiated urinary sodium, ANP, and cGMP excretion in a cynomolgus monkey assay. On the basis of its potency and duration of action, compound 1a (BMS-186716) was advanced into clinical development for the treatment of hypertension and congestive heart failure.

Summary. Background/objective: Thrombin-activatable fibrinolysis inhibitor (TAFI) is a plasma carboxypeptidase that renders a fibrin-containing thrombus less sensitive to lysis. In the present study, we describe the development of a murine model of vena cava thrombosis and its use to characterize the antithrombotic activity of potato carboxypeptidase inhibitor (PCI) of TAFIa (activated TAFI) in mice. Methods/results: Vena cava thrombosis was induced by various concentrations of FeCl 3 in C57BL/6 mice. A relatively mild stimulus (3.5% FeCl 3 ) induced thrombosis that was consistent and sensitive to reference antithrombotic agents such as clopidogrel and heparin. Dose-response studies identified a PCI dose (5 mg kg )1 bolus plus 5 mg kg, i.v.) that produced a maximum 45% decrease in vena cava thrombus mass as assessed by protein content (n ¼ 8, P < 0.01 compared to vehicle) in the 3.5% FeCl 3 -induced model without exogenous tissue plasminogen activator administration. In contrast, PCI had no effect on 3.5% FeCl 3 -induced carotid artery thrombosis in mice. In a tail transection bleeding model, the 5 mg kg )1 bolus plus 5 mg kg )1 h )1 dose of PCI increased tail-bleeding time up to 3.5 times control (n ¼ 8, P < 0.05). The ex vivo activity of antithrombotic doses of PCI was also demonstrated by the enhanced lysis of whole blood clots formed in a thrombelastograph with the addition of a sub-threshold concentration of tPA. Conclusion: These studies provide evidence for a role of TAFIa in venous thrombosis in mice, and describe an optimized vena cava injury model appropriate for the evaluation of antithrombotic drugs and the characterization of novel therapeutic targets.

Plasma kallikrein is a multifunctional serine protease involved in contact activation of coagulation. Deficiency in humans is characterised by prolonged activated partial thromboplastin time (aPTT); however, the balance between thrombosis and haemostasis is not fully understood. A study of plasma kallikrein-deficient mice revealed increased aPTT, without prolonged bleeding time. Prekallikrein antisense oligonucleotide (ASO) treatment in mice suggested potential for a positive therapeutic index. The current goal was to further define the role of plasma kallikrein in coagulation. Blood pressure and heart rate were normal in plasma kallikrein-deficient mice, and mice were completely protected from occlusion (100 ± 1.3% control flow) in 3.5% FeCl3 -induced arterial thrombosis versus heterozygotes (20 ± 11.4%) and wild-type littermates (8 ± 0%). Vessels occluded in 8/8 wild-type, 7/8 heterozygotes, and 0/8 knockouts. Anti-thrombotic protection was less pronounced in 5% FeCl3-induced arterial injury. Integrated blood flow was 8 ± 0% control in wild-type and heterozygotes, and significantly (p<0.01) improved to 43 ± 14.2% in knockouts. The number of vessels occluded was similar in all genotypes. Thrombus weight was significantly reduced in knockouts (-47%) and heterozygotes (-23%) versus wild-type in oxidative venous thrombosis. Average tail bleeding time increased modestly in knockout mice compared to wild-type. Average renal bleeding times were similar in all genotypes. These studies confirm and extend studies with prekallikrein ASO, and demonstrate that plasma kallikrein deletion prevents occlusive thrombus formation in mice with a minimal role in provoked bleeding. Additional support for the significance of the intrinsic pathway in the coagulation cascade is provided, as well as for a potential new anti-thrombotic approach.

Radiographic and physical measures of deformity do not correlate well with patients' and parents' perceptions of appearance. Patients and parents do not strongly agree on the cosmetic outcome of AIS surgery. Therefore, given that the adolescents themselves undergo the surgery, patients' assessments of their deformity, rather than radiographic measures or parents' assessments, should play a major role in the evaluation of surgical success.

A brief mock counseling session was potentially more risky but more potent than a brief videotaped counseling session as an intervention for increasing counseling self-efficacy in prepractica trainees.In the counselor training literature, much attention has been devoted to identifying specific training interventions such as role plays that improve counselor performance (e.g., Baker, Daniels, & Greeley, 1990). Although this task remains crucial to the profession, it also seems vital to examine the impact of these interventions on counseling self-efficacy, especially given the findings summarized in a recent review that link self-efficacy with coun-

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