Erythrocyte G Protein as a Novel Target for Malarial Chemotherapy

BACKGROUND: Malaria remains a serious health problem because resistance develops to all currently used drugs when their parasite targets mutate. Novel antimalarial drug targets are urgently needed to reduce global morbidity and mortality. Our prior results suggested that inhibiting erythrocyte G(s) signaling blocked invasion by the human malaria parasite Plasmodium falciparum. METHODS AND FINDINGS: We investigated the erythrocyte guanine nucleotide regulatory protein G(s) as a novel antimalarial target. Erythrocyte “ghosts” loaded with a G(s) peptide designed to block G(s) interaction with its receptors, were blocked in β-adrenergic agonist-induced signaling. This finding directly demonstrates that erythrocyte G(s) is functional and that propranolol, an antagonist of G protein–coupled β-adrenergic receptors, dampens G(s) activity in erythrocytes. We subsequently used the ghost system to directly link inhibition of host G(s) to parasite entry. In addition, we discovered that ghosts loaded with the peptide were inhibited in intracellular parasite maturation. Propranolol also inhibited blood-stage parasite growth, as did other β(2)-antagonists. β-blocker growth inhibition appeared to be due to delay in the terminal schizont stage. When used in combination with existing antimalarials in cell culture, propranolol reduced the 50% and 90% inhibitory concentrations for existing drugs against P. falciparum by 5- to 10-fold and was also effective in reducing drug dose in animal models of infection. CONCLUSIONS: Together these data establish that, in addition to invasion, erythrocyte G protein signaling is needed for intracellular parasite proliferation and thus may present a novel antimalarial target. The results provide proof of the concept that erythrocyte G(s) antagonism offers a novel strategy to fight infection and that it has potential to be used to develop combination therapies with existing antimalarials

The impact of statins on health services utilization and mortality in older adults discharged from hospital with ischemic heart disease: a cohort study

<p>Abstract</p> <p>Background</p> <p>Cardiovascular disease (CVD) carries a high burden of morbidity and mortality and is associated with significant utilization of health care resources, especially in the elderly. Numerous randomized trials have established the efficacy of cholesterol reduction with statin medications in decreasing mortality in high-risk populations. However, it is not known what the effect of the utilization of these medications in complex older adults has had on mortality and on the utilization of health services, such as physician visits, hospitalizations or cardiovascular procedures.</p> <p>Methods</p> <p>This project linked clinical and hospital data from the Improving Cardiovascular Outcomes in Nova Scotia (ICONS) database with administrative data from the Population Health Research Unit to identify all older adults hospitalized with ischemic heart disease between October 15, 1997 and March 31, 2001. All patients were followed for at least one year or until death. Multiple regression techniques, including Cox proportional hazards models and generalized linear models were employed to compare health services utilization and mortality for statin users and non-statin users.</p> <p>Results</p> <p>Of 4232 older adults discharged alive from the hospital, 1629 (38%) received a statin after discharge. In multivariate models after adjustment for demographic and clinical characteristics, and propensity score, statins were associated with a 26% reduction in all- cause mortality (hazard ratio (HR) 0.74, 95% confidence interval (CI) 0.63-0.88). However, statin use was not associated with subsequent reductions in health service utilization, including re-hospitalizations (HR, 0.98, 95% CI 0.91-1.06), physician visits (relative risk (RR) 0.97, 95% CI 0.92-1.02) or coronary revascularization procedures (HR 1.15, 95% CI 0.97-1.36).</p> <p>Conclusion</p> <p>As the utilization of statins continues to grow, their impact on the health care system will continue to be important. Future studies are needed to continue to ensure that those who would realize significant benefit from the medication receive it.</p

From Craft to Nature: The Emergence of Natural Teleology

A teleological explanation is an explanation in terms of an end or a purpose. So saying that ‘X came about for the sake of Y’ is a teleological account of X. It is a striking feature of ancient Greek philosophy that many thinkers accepted that the world should be explained in this way. However, before Aristotle, teleological explanations of the cosmos were generally based on the idea that it had been created by a divine intelligence. If an intelligent power made the world, then it makes sense that it did so with a purpose in mind, so grasping this purpose will help us understand the world. This is the pattern of teleological explanation that we find in the Presocratics and in Plato. However, with Aristotle teleology underwent a change: instead of thinking that the ends were explanatory because a mind had sought to bring them about, Aristotle took the ends to operate in natural beings independently of the efforts of any creative intelligence. Indeed, he thought that his predecessors had failed to understand what was distinctive of nature, namely, that its ends work from the inside of natural beings themselves

Aristotle on the Matter for Birth, Life, and the Elements

This essay considers three case studies of Aristotle’s use of matter, drawn from three different scientific contexts: menstrual fluid as the matter of animal generation in the Generation of Animals, the living body as matter of an organism in Aristotle’s On the Soul (De Anima), and the matter of elemental transformation in Generation and Corruption. I argue that Aristotle conceives of matter differently in these treatises (1) because of the different sorts of changes under consideration, and (2) because sometimes he is considering the matter for one specific change, and sometimes the matter for all of a thing’s natural changes. My account allows me to explain some of the strange features that Aristotle ascribes to the matter for elemental transformation in Generation and Corruption II. These features were interpreted by later commentators as general features of all matter. I argue that they are a result of the specific way that Aristotle thinks about the transmutation of the elements

The Cost of Unfractionated and Low-Molecular Weight Heparin Therapy in the Management of Unstable Coronary Syndromes

ABSTRACTObjectives: To determine the direct costs involved in the administration of intravenous (IV) unfractionated heparin (UFH) compared with the projected costs of subcutaneous (SC) low molecular weight heparin (LMWH), dalteparin, in the management of acute coronary syndromes (unstable angina or acute myocardial infarction) from a hospital perspective.Methods: A 9-week prospective time-motion study was conducted in a 9-bed coronary care unit (CCU) of a Canadian university-affiliated hospital. Direct costs (expressed in 1998 Canadian dollars) including all drug, labour, supply and equipment costs associated with the preparation, administration, and monitoring of IV UFH were calculated. Throughout the duration of therapy, the number and types of heparin-related activities and the time spent completing these activities were self-recorded by 25 CCU nurses for 116 consecutive patients with acute coronary syndromes requiring IV UFH. The final labour cost was determined by multiplying the mean hourly nursing wage by the mean times recorded during the time-motion study. The projected costs from use of SC dalteparin for this indication were also estimated.Results: IV UFH was associated with a drug cost of $4.19 per day plus nursing time ($7.28 ± 0.32), supplies ($4.13) and laboratory monitoring ($10.09 ± 0.49) for a total daily cost of $25.68 ± 0.81. The projected cost of dalteparin SC was quite similar at$28.82 ± 0.47 per day consisting mainly of drug acquisition ($26.56 ± 0.47) with a small component for administration ($2.26).Conclusions: The administration of IV UFH for the management of acute coronary syndromes involves a number of activities and consumption of resources beyond the price of drugs alone, and overall the daily costs are similar to using a SC LMWH regimen. The decision to use a LMWH for acute coronarv syndromes therefore should be based on the further consideration of clinical outcomes rather than focusing on drug acquisition cost. RÉSUMÉObjectifs : Déterminer les coût directs engages dans l’administration intraveineuse (I.V.) d’héparine non fractionnée (HNF) comparativement à ceux projetés dans l’administration sous-cutanée (S.-C.) d’héparine de faible poids moléculaire (HFPM), la daltéparine, dans le traitement des syndromes coronariens instables (angine instable ou infarctus du myocarde aigu) d’un point de vue hospitalier.Méthode : Une étude prospective temps-mouvements de neuf semaines a été menée dans une unité de soins coronariens (USC) de neuf lits d’un centre hospitalier canadien affilié à une université. Les coûts directs (exprimés en dollars canadiens de 1998) comprenant ceux de tous les médicaments, de la main d’oeuvre, des fournitures et des équipements associés à la préparation, à l’administration, et au suivi de l’administration IV HNF ont été calculés. Pendant toute la durée du traitement, le nombre et les types d’activités liées à l’administration d’héparine et le temps passé à accomplir ces activités ont été inscrits par 25 infirmières de l’USC pour 116 patients consécutifs présentant des syndromes coronariens instables nécessitant l’administration IV HNF. Le coût final de la main d’ouevre a été détermine en multipliant le salaire horaire moyen d’une infirmière par les temps moyens d’une infirmière par les temps moyens inscrits au cours de cette étude temps-mouvements. Les coûts projetés de l’utilisation de la daltéparine sous-cutanée dans ces cas ont aussi été évalués.Résultats : L’administration IV HNF a été associée à un coût de 4,19 $par jour pour le médicament, plus la main d’oeuvre du personnel infirmier (7,28 ± 0,32$), les fournitures (4,13 $) et le suivi du laboratoire (10,09 ± 0,49$), pour un total quatidien de 25,68 ± 0,81 $. Le coût projeté de l’administration de la daltéparine S.-C. était très semblable, soit 28,82 ± 0,47$ par jour, et consistait principalement en coût d’acquisition du médicament (26,56 ± 0,47 $) avec une faible partie pour l’administration (2,26$).Conclusions: L’administration IV HNF dans le traitement des syndromes coronariens instables implique un certain nombre d’activités et la consommation de ressources en-deça du prix du médicament seul, et les coûts globaux quotidiens sont semblables à ceux de l’utilisation du traitement S.-C. HFPM. La décision d’utiliser une HFPM pour les syndromes coronariens instables devrait par conséquent être fondée sur une évaluation plus poussée des résultats cliniques plutôt que sur le coût d’acquisition du médicament

A national survey of antimicrobial prophylaxis in adult cardiac surgery across Canada

OBJECTIVE: To characterize national and regional patterns of antimicrobial prophylaxis in adult cardiac surgery across Canada