Oleic acid biosynthesis in Plasmodium falciparum: characterization of the stearoyl-CoA desaturase and investigation as a potential therapeutic target.

Background: Plasmodium falciparum parasitization of erythrocytes causes a substantial increase in the levels of intracellular fatty acids, notably oleic acid. How parasites acquire this monounsaturated fatty acid has remained enigmatic. Here, we report on the biochemical and enzymatic characterization of stearoyl-CoA desaturase (SCD) in P.

An examination of IC50 and IC50-shift experiments in assessing time-dependent inhibition of CYP3A4, CYP2D6 and CYP2C9 in human liver microsomes.

The relationship between time-dependent inactivation (TDI) and IC50 is examined using a consolidated method for evaluating CYP450 inhibition during drug discovery. An IC50 fold-shift of >1.5 indicated significant TDI potency.

N-methylacetamide analog of salvinorin A: a highly potent and selective kappa-opioid receptor agonist with oral efficacy.

Several preclinical studies indicate that selective kappa-opioid receptor (KOR) antagonists have antidepressant-like effects, whereas KOR agonists have opposite effects, suggesting that each might be useful in the treatment of mood abnormalities. Salvinorin A (salvA) is a valuable KOR agonist for further study due to its high potency and receptor selectivity. However, it has short lasting effects in vivo and limited oral bioavailability, probably due to acetate metabolism.

Characterization of human embryonic stem cell lines by the International Stem Cell Initiative.

The International Stem Cell Initiative characterized 59 human embryonic stem cell lines from 17 laboratories worldwide. Despite diverse genotypes and different techniques used for derivation and maintenance, all lines exhibited similar expression patterns for several markers of human embryonic stem cells. They expressed the glycolipid antigens SSEA3 and SSEA4, the keratan sulfate antigens TRA-1-60, TRA-1-81, GCTM2 and GCT343, and the protein antigens CD9, Thy1 (also known as CD90), tissue-nonspecific alkaline phosphatase and class 1 HLA, as well as the strongly developmentally regulated genes NANOG, POU5F1 (formerly known as OCT4), TDGF1, DNMT3B, GABRB3 and GDF3.

Preference for a stimulus that follows a relatively aversive event: contrast or delay reduction?

Several types of contrast effects have been identified including incentive contrast, anticipatory contrast, and behavioral contrast. Clement, Feltus, Kaiser, and Zentall (2000) proposed a type of contrast that appears to be different from these others and called it within-trial contrast. In this form of contrast the relative value of a reinforcer depends on the events that occur immediately prior to the reinforcer.

Analysis of inhibition rate enhancement by covalent linkage of antithrombin to heparin as a potential predictor of reaction mechanism.

Antithrombin (AT) inhibition of coagulation enzymes is catalyzed by unfractionated heparin (UFH) and other heparinoids. Reaction proceeds either via conformational activation of the inhibitor or template-mediated binding of both inhibitor and protease. We investigated if the relative inhibition rates of AT + UFH and covalent AT-heparin conjugate (ATH) with coagulation factors might be indicative of the mechanism involved.

A physicians' agenda for partnering with employers and insurers: fresh ideas.

We report the results of the second phase of a multiphase qualitative investigation of the ways physicians, employers, and insurers can work together more effectively to provide better ambulatory care to employees and their dependents. This article focuses on ways physicians can develop more useful relationships among these groups. We used a grounded theory approach to conduct 71 interviews from August 12, 2004, to December 27, 2005, with 25 practicing physicians in large and small groups, urban and rural areas, private and academic settings, and primary care and specialty practices; 33 hospital administrators, medical association executives, health insurance medical officers, and health policy analysts; and 13 senior executives of large and small companies.

Protein adsorption on polyurethane catheters modified with a novel antithrombin-heparin covalent complex.

Highly anticoagulant covalent antithrombin-heparin complex (ATH) was covalently grafted onto polyurethane catheters to suppress adsorption/activation of procoagulant proteins and enhance adsorption/activation of anticoagulant proteins for blood compatibility. Consistency of catheter coating was demonstrated using immunohistochemical visualization of ATH. The ability of the resulting immobilized ATH heparin chains to bind antithrombin (AT) from plasma, as measured by binding of (125)I-radiolabeled AT, was greater than that for commercially-available heparin-coated catheters, and much greater than for uncoated catheters.

Covalent antithrombin-heparin complexes.

Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) have been utilized as primary anticoagulants for thrombosis prophylaxis and treatment. However, a number of biophysical and safety limitations have led to development of new anticoagulants. Covalent antithrombin-heparin (ATH) complexes may address many of these issues.

Structural effects of a covalent linkage between antithrombin and heparin: covalent N-terminus attachment of heparin enhances the maintenance of antithrombin's activated state.

We have produced a molecule comprising of permanently-activated covalently linked antithrombin and heparin (ATH). This study was designed to elucidate the covalent linkage point(s) for heparin on antithrombin and conformational properties of the ATH molecule. ATH was produced using Schiff base/Amadori rearrangement by incubating antithrombin with unfractionated heparin for 14 d at 40 degrees C.

Effect of substrate and fibrin polymerization inhibitor on determination of plasma thrombin generation in vitro.

Background: Thrombin generation potential, a critical haemostatic measure, can be determined by continuous detection of total thrombin or direct subsampling. However, differences between methods exist in area under the curve or peak thrombin calculated. Also, impact of anticoagulants on thrombin generation may vary depending on mode of analysis.

Chronic performance of polyurethane catheters covalently coated with ATH complex: a rabbit jugular vein model.

Covalent complexes of antithrombin (AT) and heparin (ATH) have superb anticoagulant activity towards thrombin and factor Xa. Stability of polyurethane central venous catheters covalently modified with radiolabeled ATH was studied using a roller pump with saline or protease P-5147. Saline wash removed loosely bound ATH molecules to decrease graft density from 26 to 12 pmol/cm2.

Selective cleavage of heparin using aqueous 2-hydroxypyridine: production of an aldose-terminating fragment with high anticoagulant activity.

Unfractionated heparin (UFH) was partially depolymerized by heating at 115 degrees C with aqueous 2-hydroxypyridine. Compared to starting UFH, no significant loss of anticoagulant (anti-Xa) activity was observed. Products consisted of polysaccharide fragments and small quantities of ammonia, sulfate, and hexuronic acid.

Tracking the prevalence of transmitted antiretroviral drug-resistant HIV-1: a decade of experience.

Transmitted resistance to antiretroviral drugs in acute and early HIV-1 infection has been well documented, although overall trends vary depending on geography and cohort characteristics. To describe the changing pattern of transmitted drug-resistant HIV-1 in a well-defined cohort in New York City, a total of 361 patients with acute or recent HIV-1 infection were prospectively studied over a decade (1995-2004) with respect to HIV-1 genotypes and longitudinal T-cell subsets and HIV-1 RNA levels. The prevalence of overall transmitted resistance changed from 13.

Biodistribution of covalent antithrombin-heparin complexes.

We have developed a covalent antithrombin-heparin (ATH) complex with advantages compared to non-covalent antithrombin:heparin (AT:H) mixtures. In addition to increased activity, ATH has a longer intravenous half-life that is partly due to reduced plasma protein binding. Given ATH's altered clearance, we investigated biodistribution of ATH in vivo.

The fibrinolytic system in newborns and children.

The fibrinolytic system comprises a series of serine proteases that interact to cleave fibrin into fibrin degradation products. Although all key components of the fibrinolytic system are present at birth, important age-dependent, quantitative and qualitative differences are present during childhood as compared to adults. These differences include decreased plasma concentrations of plasminogen, tissue-type plasminogen activator and alpha2-antiplasmin, increased plasma concentrations of plasminogen activator inhibitor-1, as well as a decrease in both plasmin generation and overall fibrinolytic activity.

The influence of age on in vitro plasmin generation in the presence of fibrin monomer.

Background And Objectives: The components of the fibrinolytic system interact to generate plasmin from its zymogen form, plasminogen. At birth, all the components of the fibrinolytic system are present but with differing plasma concentrations. The present study was undertaken to explore the effect of physiological, age-dependent factors of the fibrinolytic system during childhood on the capacity to generate plasmin.

Total hip arthroplasty as an overnight-stay procedure using an ambulatory continuous psoas compartment nerve block: a prospective feasibility study.

Objective: Total hip arthroplasty (THA) results in severe postoperative pain requiring hospitalization to provide potent analgesia. Consequently, the average duration of hospitalization after THA in the United States is 4 to 5 days. This prospective study investigated the feasibility of converting THA into an overnight-stay procedure using a continuous psoas compartment nerve block provided at home with a portable infusion pump.

Patients' perspectives on ideal physician behaviors.

We incorporated the views of patients to develop a comprehensive set of ideal physician behaviors. Telephone interviews were conducted in 2001 and 2002 with a random sample of 192 patients who were seen in 14 different medical specialties of Mayo Clinic in Scottsdale, Ariz, and Mayo Clinic in Rochester, Minn. Interviews focused on the physician-patient relationship and lasted between 20 and 50 minutes.

Valuing people: health visiting and people with learning disabilities.

People with a learning disability have spent decades being excluded from mainstream society and remain almost invisible in our communities, workplaces and in family life. As a result, the health of people with a learning disability is significantly poorer than that of the general population. Despite the many reports and policy recommendations about how to improve the situation, little has been done to address the social exclusion of this group, and their health and wellbeing continue to decline.

Total knee arthroplasty as an overnight-stay procedure using continuous femoral nerve blocks at home: a prospective feasibility study.

The average duration of hospitalization after total knee arthroplasty (TKA) in the United States is 4-5 days. In this two-phase study we investigated the feasibility of converting TKA into an overnight-stay procedure using a continuous femoral nerve block provided at home through postoperative day 4. Nine of 10 patients met discharge criteria and were discharged home the day after surgery.

Age-related differences in heparin response.

Introduction: Major physiological differences in the coagulation system throughout childhood, compared to adults, are well documented. However, the impact of this on anticoagulant drugs is unknown. This study aimed to determine whether heparin therapeutic range determination is affected by the age of plasma donors and whether age-specific therapeutic ranges for heparin therapy may need to be considered in the clinical setting.

Volutrauma activates the clotting cascade in the newborn but not adult rat.

Coagulopathy and alveolar fibrin deposition are common in sick neonates and attributed to the primary disease, as opposed to their ventilatory support. Hypothesizing that high tidal volume ventilation activates the extrinsic coagulation pathway, we air ventilated newborn and adult rats at low (10 ml/kg) or high (30 ml/kg) tidal volume and compared them with age-matched nonventilated controls. Blood was collected at the end of the experiment for measurement of clot time, tissue factor, and other coagulation factor content.

In vivo rabbit acute model tests of polyurethane catheters coated with a novel antithrombin-heparin covalent complex.

Catheter use has been associated with an increased risk of thrombotic complications. The objective was to make catheters less thrombogenic with the use of antithrombin-heparin covalent complex (ATH). The antithrombotic activity of ATH-coated catheters was compared to uncoated (control) and heparincoated catheters in an acute rabbit model of accelerated occluding clot formation.