Protein phosphatase 1 associates with the integrin alphaIIb subunit and regulates signaling.

Regulation of integrin activation occurs by specific interactions among cytoplasmic proteins and integrin alpha and beta cytoplasmic tails. We report that the catalytic subunit of protein phosphatase 1 (PP1c) constitutively associates with the prototypic integrin alphaIIbbeta3 in platelets and in cell lines overexpressing the integrin. PP1c binds directly to the cytoplasmic domain of integrin alphaIIb subunit containing a conserved PP1c binding motif 989KVGF992.

Characterization of the choline carrier of Plasmodium falciparum: a route for the selective delivery of novel antimalarial drugs.

New drugs are urgently needed to combat the growing problem of drug resistance in Plasmodium falciparum malaria. The infected erythrocyte is a multicompartmental system, and its transporters are of interest as drug targets in their own right and as potential routes for the delivery of antimalarial drugs. Choline is an important nutrient that penetrates infected erythrocyte membranes through the endogenous carrier and through parasite-induced permeability pathways, but nothing is known about its transport into the intracellular parasite.

Antimalarial and antitumor evaluation of novel C-10 non-acetal dimers of 10beta-(2-hydroxyethyl)deoxoartemisinin.

Four series of C-10 non-acetal dimers were prepared from key trioxane alcohol 10beta-(2-hydroxyethyl)deoxoartemisinin (9b). All of the dimers prepared displayed potent low nanomolar antimalarial activity versus the K1 and HB3 strains of Plasmodium falciparum. The most potent compound assayed was phosphate dimer 14a, which was greater than 50 times more potent than the parent drug artemisinin and about 15 times more potent than the clinically used acetal artemether.

Survival of microvascular physeal allograft transplants following withdrawal of short-term postoperative immunosuppression.

Background: Physeal necrosis following vascularized allograft transplantation occurs because of vascular rejection. The effect of immunosuppression withdrawal on physeal viability after bone-healing to the recipient site was investigated with use of a validated model for heterotopic microvascular transplantation of rabbit tibial physeal allografts. Our hypothesis was that an allograft survives after withdrawal of immunosuppression only if bone-healing, and therefore epiphyseal and metaphyseal vascular continuity, occurs between the transplanted physis and the recipient bone.

Genetic variation responsible for mouse strain differences in integrin alpha 2 expression is associated with altered platelet responses to collagen.

As mouse models have become commonplace for studying hemostasis and thrombosis, we considered whether the mouse system had utility for assessing genetic alterations in platelet receptors. Platelets from 5 mouse strains (C57BL/6 [C57], FVB/N [FVB], BALB/c, C3H/He, and 129Sv) showed only minor differences in the expression of integrin alpha(IIb), integrin beta(3), glycoprotein (GP) Ib alpha, or GPVI across strains. However, FVB platelets expressed approximately 50% the level of integrin alpha(2) as platelets from other strains (P <.

Scalp ulceration from a circumferential head dressing after craniotomy: Case report of an uncommon complication due to human error.

The present paper describes a previously unpublished complication of the application of a circumferential head dressing after cranial neuro-surgery. A 34-year-old woman developed a large area of skin necrosis on her forehead from a circumferential head dressing applied after the surgical removal of a colloid cyst. Neurological recovery was excellent but plastic surgical repair of her iatrogenic cosmetic injury was required.

Platelets of female mice are intrinsically more sensitive to agonists than are platelets of males.

Objective: It has been reported that women fare worse after ischemic coronary events, but the mechanisms remain unclear. Because platelets play a central role in the formation of occlusive thrombi at sites of ruptured atherosclerotic plaques, we studied male/female paired mouse littermates for sex differences in platelet function.

Methods And Results: We compared platelet reactivity in male/female mouse littermates by monitoring agonist-induced fibrinogen (FGN) binding and platelet aggregation.

Platelet hyperreactivity in women from families with premature atherosclerosis.

Objectives: This study was designed to determine whether sex differences in platelet function exist in families with premature atherosclerosis. Compared with men, women have a greater risk of death and recurrent events following myocardial infarction and coronary artery bypass graft surgery. The reasons for this sex discrepancy are unknown.

Isoquine and related amodiaquine analogues: a new generation of improved 4-aminoquinoline antimalarials.

Amodiaquine (AQ) (2) is a 4-aminoquinoline antimalarial that can cause adverse side effects including agranulocytosis and liver damage. The observed drug toxicity is believed to involve the formation of an electrophilic metabolite, amodiaquine quinoneimine (AQQI), which can bind to cellular macromolecules and initiate hypersensitivity reactions. We proposed that interchange of the 3' hydroxyl and the 4' Mannich side-chain function of amodiaquine would provide a new series of analogues that cannot form toxic quinoneimine metabolites via cytochrome P450-mediated metabolism.

Duration of exposure to high fluid shear stress is critical in shear-induced platelet activation-aggregation.

Platelet functions are increasingly measured under flow conditions to account for blood hydrodynamic effects. Typically, these studies involve exposing platelets to high shear stress for periods significantly longer than would occur in vivo. In the current study, we demonstrate that the platelet response to high shear depends on the duration of shear exposure.

Effects of rotation on the sleep state-dependent midlatency auditory evoked P50 potential in the human.

Sopite syndrome, characterized by loss of initiative, sensitivity to normally innocuous sensory stimuli, and impaired concentration amounting to a sensory gating deficit, is commonly associated with Space Motion Sickness (SMS). The amplitude of the P50 potential is a measure of level of arousal, and a paired-stimulus paradigm can be used to measure sensory gating. We used the rotary chair to elicit the sensory mismatch that occurs with SMS by overstimulating the vestibular apparatus.

Iatrogenic vertebral arteriovenous fistula treated with a hemobahn stent-graft.

Purpose: To illustrate the utility of color flow duplex ultrasound (CFDU) in the diagnosis and stent-graft treatment of a rare arteriovenous fistula (AVF) involving the vertebral artery and vein.

Case Report: An iatrogenic AVF involving the right vertebral artery and vein was diagnosed in a 45-year-old man using CFDU. Treatment was recommended due to the large volume of blood shunted through the fistula and the associated loud bruit.

Percutaneous treatment of long superficial femoral artery occlusive disease: efficacy of the Hemobahn stent-graft.

Purpose: To assess the efficacy of the Hemobahn stent-graft in the percutaneous treatment of long occlusive lesions of the superficial femoral artery (SFA).

Methods: Fifty-nine limbs in 54 patients (42 men; mean age 73.3+/-8.

Artemisinins target the SERCA of Plasmodium falciparum.

Artemisinins are extracted from sweet wormwood (Artemisia annua) and are the most potent antimalarials available, rapidly killing all asexual stages of Plasmodium falciparum. Artemisinins are sesquiterpene lactones widely used to treat multidrug-resistant malaria, a disease that annually claims 1 million lives. Despite extensive clinical and laboratory experience their molecular target is not yet identified.

Heme binding contributes to antimalarial activity of bis-quaternary ammoniums.

Quaternary ammonium compounds have received recent attention due to their potent in vivo antimalarial activity based on their ability to inhibit de novo phosphatidylcholine synthesis. Here we show that in addition to this, heme binding significantly contributes to the antimalarial activity of these compounds. For the study, we used a recently synthesized bis-quaternary ammonium compound, T16 (1,12-dodecanemethylene bis[4-methyl-5-ethylthiazolium] diodide), which exhibits potent antimalarial activity (50% inhibitory concentration, approximately 25 nM).

Platelet FcgammaRIIA His131Arg polymorphism and platelet function: antibodies to platelet-bound fibrinogen induce platelet activation.

The His131Arg polymorphism of platelet FcgammaRIIA affects the binding affinity of certain IgG subclasses. The Arg131 allele has been associated with (auto)immune thrombocytopenia and heparin-induced thrombocytopenia in some studies. Because FcgammaRIIA can transmit platelet activation signals, we studied platelet responsiveness from 73 healthy donors to determine if this polymorphism modulated platelet function.

Chemosensitization of Plasmodium falciparum by probenecid in vitro.

Resistance to drugs can result from changes in drug transport, and this resistance can sometimes be overcome by a second drug that modifies the transport mechanisms of the cell. This strategy has been exploited to partly reverse resistance to chloroquine in Plasmodium falciparum. Studies with human tumor cells have shown that probenecid can reverse resistance to the antifolate methotrexate, but the potential for reversal of antifolate resistance has not been studied in P.

Pentamidine uptake and resistance in pathogenic protozoa: past, present and future.

Diamidines, and pentamidine in particular, have a long history as valuable chemotherapeutic agents against infectious disease. Their selectivity is due mostly to selective accumulation by the pathogen, rather than the host cell; and acquired resistance is frequently the result of changes in transmembrane transport of the drug. Here, recent progress in elucidating the mechanisms of diamidine transport in three important protozoan pathogens, Trypanosoma brucei, Leishmania and Plasmodium falciparum, is reviewed, and the implications for drug resistance are discussed.

Variations of the human glucocorticoid receptor gene (NR3C1): pathological and in vitro mutations and polymorphisms.

Glucocorticoid (GC) resistance can occur in a number of diseases. It can be either generalized (i.e.

Development and validation of new model for microvascular transplantation of epiphyseal plate allografts with minimal adjoining epiphyseal and metaphyseal bone.

A model for the free allograft microvascular transplantation of rabbit proximal tibial epiphyseal plate allografts was developed, validated, and tested in an in vivo animal model. Transplants contained the minimum amount of adjacent epiphyseal and metaphyseal bone compatible with preservation of the epiphyseal-plate vascular supply, as determined by corrosion casting. Perfusion to this graft was evaluated quantitatively using radioactive microspheres, and qualitatively using India-ink injection.

The digestive food vacuole of the malaria parasite is a dynamic intracellular Ca2+ store.

The acidic food vacuole of Plasmodium falciparum has been the subject of intense scientific investigation in the 40 years since its role in the digestion of host hemoglobin was first suggested. This proposed role has important implications for the complex host-parasite inter-relationship and also for the mode of action of several of the most effective antimalarial drugs. In addition, adaptive changes in the physiology of this organelle are implicated in drug resistance.

Relative value to surgical patients and anesthesia providers of selected anesthesia related outcomes.

Background: Anesthesia side effects are almost inevitable in most situations. In order to optimize the anesthetic experience from the patient's viewpoint, it makes intuitive sense to attempt to avoid the side effects that the patient fears the most.

Methods: We obtained rankings and quantitative estimates of the relative importance of nine experiences that commonly occur after anesthesia and surgery from 109 patients prior to their surgery and from 30 anesthesiologists.