Plasmodium falciparum Parasites Are Killed by a Transition State Analogue of Purine Nucleoside Phosphorylase in a Primate Animal Model

Plasmodium falciparum causes most of the one million annual deaths from malaria. Drug resistance is widespread and novel agents against new targets are needed to support combination-therapy approaches promoted by the World Health Organization. Plasmodium species are purine auxotrophs. Blocking purine nucleoside phosphorylase (PNP) kills cultured parasites by purine starvation. DADMe-Immucillin-G (BCX4945) is a transition state analogue of human and Plasmodium PNPs, binding with picomolar affinity. Here, we test BCX4945 in Aotus primates, an animal model for Plasmodium falciparum infections. Oral administration of BCX4945 for seven days results in parasite clearance and recrudescence in otherwise lethal infections of P. falciparum in Aotus monkeys. The molecular action of BCX4945 is demonstrated in crystal structures of human and P. falciparum PNPs. Metabolite analysis demonstrates that PNP blockade inhibits purine salvage and polyamine synthesis in the parasites. The efficacy, oral availability, chemical stability, unique mechanism of action and low toxicity of BCX4945 demonstrate potential for combination therapies with this novel antimalarial agent

Quantitative Analyses of the Left Ventricle Volume and Cardiac Function in Normal and Infarcted Yucatan Minipigs

(1) Background: The accuracy of the left ventricular volume (LVV) and contractility measurements with cardiac magnetic resonance imaging (CMRI) is decreased if the papillary muscles are abnormally enlarged, such as in hypertrophic cardiomyopathy in human patients or in pig models of human diseases. The purpose of this work was to establish the best method of LVV quantification with CMRI in pigs. (2) Methods: The LVV in 29 Yucatan minipig hearts was measured using two different techniques: the “standard method”, which uses smooth contouring along the endocardial surface and adds the papillary volume to the ventricular cavity volume, and the “detailed method”, which traces the papillary muscles and trabeculations and adds them to the ventricular mass. (3) Results: Papillary muscles add 21% to the LV mass in normal and infarcted hearts of Yucatan minipigs. The inclusion or exclusion of these from the CMRI analysis significantly affected the study results. In the normal pig hearts, the biggest differences were found in measurements of the LVV, ejection fraction (EF), LV mass and indices derived from the LV mass (p < 0.001). The EF measurement in the normal pig heart was 11% higher with the detailed method, and 19% higher in the infarcted pig hearts (p < 0.0001). The detailed method of endocardium tracing with CMRI closely represented the LV mass measured ex vivo. (4) Conclusions: The detailed method, which accounts for the large volume of the papillary muscles in the pig heart, provides better accuracy and interobserver consistency in the assessment of LV mass and ejection fraction, and might therefore be preferable for these analyses

ACR Appropriateness Criteria

In patients with chronic chest pain in the setting of high probability of coronary artery disease (CAD), imaging has major and diverse roles. First, imaging is valuable in determining and documenting the presence, extent, and severity of myocardial ischemia, hibernation, scarring, and/or the presence, site, and severity of obstructive coronary lesions. Second, imaging findings are important in determining the course of management of patients with suspected chronic myocardial ischemia and better defining those patients best suited for medical therapy, angioplasty/stenting, or surgery. Third, imaging is also necessary to determine the long-term prognosis and likely benefit from various therapeutic options by evaluating ventricular function, diastolic relaxation, and end-systolic volume. Imaging studies are also required to demonstrate other abnormalities, such as congenital/acquired coronary anomalies and severe left ventricular hypertrophy, that can produce angina in the absence of symptomatic coronary obstructive disease due to atherosclerosis. Clinical risk assessment is necessary to determine the pretest probability of CAD. Multiple methods are available to categorize patients as low, medium, or high risk for developing CAD. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment