Efficacy of clarithromycin against Streptococcus pneumoniae expressing mef(A)-mediated resistance.

As a result of macrolide resistance rates of 25% for pneumococci in the US, the clinical use of this class as empirical therapy has been questioned. However, macrolides continue to be used with clinical success. Using an immunocompromised murine pneumonia model, this study evaluated in vivo efficacy of human simulated exposures of clarithromycin for 62 isolates of Streptococcus pneumoniae considered resistant by current methods of breakpoint determinations.

Monosodium urate monohydrate crystals induce the release of the proinflammatory protein S100A8/A9 from neutrophils.

The neutrophil cytoplasmic protein S100A8/A9 (along with S100A8 and S100A9) is chemotactic and stimulates neutrophil adhesion by activating the beta2-integrin CD11b/CD18. It is also essential to neutrophil migration in vivo in response to monosodium urate monohydrate (MSUM) crystals, the principal etiologic agent of gout. S100A8/A9 is present in the synovial fluid of patients with gout and arthritis and is secreted by activated monocytes; however, its mechanism of release by neutrophils remains unknown.

Determination of the pharmacodynamic profile of daptomycin against Streptococcus pneumoniae isolates with varying susceptibility to penicillin in a murine thigh infection model.

Background: Daptomycin has demonstrated in vitro activity against gram-positive organisms, including Streptococcus pneumoniae. However, the pharmacodynamic (PD) profile of daptomycin is needed to relate the activity of the drug to biologically achievable concentrations.

Methods: The PD profile of daptomycin against four S.

Direct measurement of protein osmotic second virial cross coefficients by cross-interaction chromatography.

The importance of weak protein interactions, such as protein self-association, is widely recognized in a variety of biological and technological processes. Although protein self-association has been studied extensively, much less attention has been devoted to weak protein cross-association, mainly due to the difficulties in measuring weak interactions between different proteins in solution. Here a framework is presented for quantifying the osmotic second virial cross coefficient directly using a modified form of self-interaction chromatography called cross-interaction chromatography.

Pharmacodynamics of moxifloxacin and levofloxacin at simulated epithelial lining fluid drug concentrations against Streptococcus pneumoniae.

Recent clinical failures associated with levofloxacin treatment for Streptococcus pneumoniae infections and growing evidence of frequent mutations in the isolate population have led to increased concerns regarding fluoroquinolone resistance. Our objective was to characterize the efficacies of levofloxacin and moxifloxacin against various genotypes of S. pneumoniae after simulated bronchopulmonary exposures.

Hemozoin-inducible proinflammatory events in vivo: potential role in malaria infection.

During malaria infection, high levels of proinflammatory molecules (e.g., cytokines, chemokines) correlate with disease severity.

Measurements of protein self-association as a guide to crystallization.

The challenge of crystallizing proteins has led to a significant amount of research in understanding protein self-association and assembly. Arguably the most influential finding in this field in the past decade has been that weakly attractive protein interactions, characterized in terms of the osmotic second virial coefficient, correlate with solution conditions that are conducive to crystallization. Recent work in this area has focused on the development of more efficient techniques for measuring the second virial coefficient, as traditional characterization methods suffer from poor efficiency in terms of time and protein consumption.

Blockade of S100A8 and S100A9 suppresses neutrophil migration in response to lipopolysaccharide.

Recently, proinflammatory activities had been described for S100A8 and S100A9, two proteins found at inflammatory sites and within the neutrophil cytoplasm. In this study, we investigated the role of these proteins in neutrophil migration in vivo in response to LPS. LPS was injected into the murine air pouch, which led to the release of S100A8, S100A9, and S100A8/A9 in the pouch exudates that preceded accumulation of neutrophils.

Pharmacodynamic profile of daptomycin against Enterococcus species and methicillin-resistant Staphylococcus aureus in a murine thigh infection model.

Objective: To describe the pharmacodynamic profile of daptomycin against methicillin-resistant Staphylococcus aureus (MRSA) and Enterococci species based on bacterial density in an immunocompromised mouse thigh infection model.

Materials And Methods: The pharmacodynamic (PD) profile of daptomycin was determined against two MRSA, one vancomycin-resistant Enterococcus faecium, and one vancomycin-susceptible Enterococcus faecalis using the immunocompromised murine thigh model. Efficacy was assessed by the change in log10 cfu in thighs after 24 h of drug treatment.

(Z)-tamoxifen and tetrasubstituted alkenes and dienes via a regio- and stereospecific three-component magnesium carbometalation palladium(0) cross-coupling strategy.

[reaction: see text] The synthesis of various tetrasubstituted alkenes and dienes in a regio- and stereocontrolled manner is described. This three-component coupling strategy involves the addition of Grignard reagents to propargyl alcohols followed by palladium(0)-mediated cross-coupling with aryl or vinyl halides. This protocol has been applied to the synthesis of (Z)-Tamoxifen and related mimics.

Role of S100A8 and S100A9 in neutrophil recruitment in response to monosodium urate monohydrate crystals in the air-pouch model of acute gouty arthritis.

Objective: To examine the role of chemokines, S100A8, and S100A9 in neutrophil accumulation induced by the causative agent of gout, monosodium urate monohydrate (MSU) crystals.

Methods: MSU crystal-induced neutrophil migration was studied in the murine air-pouch model. Release of chemokines, S100A8, S100A9, and S100A8/A9 in response to MSU crystals was quantified by enzyme-linked immunosorbent assays.

The calcium-binding protein S100A12 induces neutrophil adhesion, migration, and release from bone marrow in mouse at concentrations similar to those found in human inflammatory arthritis.

We investigated the proinflammatory activities of S100A12 in the context of synovial inflammation. S100A12 levels were increased in the synovial fluids and plasma of patients with gout, rheumatoid arthritis, psoriatic arthritis, and undetectable in osteoarthritis, a noninflammatory disorder. S100A12 proved to induce neutrophil adhesion to fibrinogen via Mac-1 at concentrations similar to those found in the synovial fluids.

Proinflammatory activities of S100: proteins S100A8, S100A9, and S100A8/A9 induce neutrophil chemotaxis and adhesion.

S100A8 and S100A9 are small calcium-binding proteins that are highly expressed in neutrophil and monocyte cytosol and are found at high levels in the extracellular milieu during inflammatory conditions. Although reports have proposed a proinflammatory role for these proteins, their extracellular activity remains controversial. In this study, we report that S100A8, S100A9, and S100A8/A9 caused neutrophil chemotaxis at concentrations of 10(-12)-10(-9) M.

Predictive crystallization of ribonuclease A via rapid screening of osmotic second virial coefficients.

Important progress has been made in recent years toward developing a molecular-level understanding of protein phase behavior in terms of the osmotic second virial coefficient, a thermodynamic parameter that characterizes pairwise protein interactions. Yet there has been little practical application of this knowledge to the field of protein crystallization, largely because of the difficult and time-consuming nature of traditional techniques for characterizing protein interactions. Self-interaction chromatography has recently been proposed as a highly efficient method for measuring the osmotic second virial coefficient.

Switching outpatients with schizophrenia and related disorders on long-acting injectable antipsychotics to olanzapine: an open-label naturalistic pilot study.

Little is known about the feasibility of switching patients with schizophrenia from long-acting injectable antipsychotics to oral olanzapine. We completed an open-label 14-week study to assess such a transition. This study included 25 stable outpatients (DSM-IV diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder) who were receiving long-acting injectable antipsychotics.

Self-interaction chromatography: a novel screening method for rational protein crystallization.

The osmotic second virial coefficient, B(22), has become the quantity most widely used in developing a rational understanding of protein crystallization. In this work a novel method of measuring B22 using self-interaction chromatography (SIC) is presented that is at least an order of magnitude more efficient than traditional characterization methods, such as static light scattering. It is shown that SIC measurements of second virial coefficients for BSA are in quantitative agreement with static light scattering results.

Bactericidal effect and pharmacodynamics of cethromycin (ABT-773) in a murine pneumococcal pneumonia model.

Cethromycin (ABT-773), a new ketolide, possesses potent in vitro activity against Streptococcus pneumoniae. The objective of this study was to investigate the in vivo bactericidal activity of cethromycin against macrolide-susceptible and -resistant S. pneumoniae in a murine pneumonia model and to describe the pharmacodynamic (PD) profile of cethromycin.

HIV-1 transcription and virus production are both accentuated by the proinflammatory myeloid-related proteins in human CD4+ T lymphocytes.

S100A8, S100A9, and S100A12, collectively known as myeloid-related proteins (MRPs), are highly expressed by the myeloid cell lineage and are found in the extracellular milieu during infections and inflammatory conditions. Recent data showed high levels of MRPs in the serum of HIV type 1 (HIV-1)-infected patients which correlated with disease progression and low CD4(+) counts. Therefore, we set out to investigate the effect of MRPs on HIV-1 replication.

Pharmacodynamic assessment of clarithromycin in a murine model of pneumococcal pneumonia.

The pharmacodynamic profile of clarithromycin (CLR) was evaluated with a murine model of pneumonia. Eight Streptococcus pneumoniae isolates, including three macrolide-sensitive and five macrolide-resistant strains, were inoculated intratracheally into immunocompromised ICR mice as 10(8)-CFU bacterial suspensions. Orally administered CLR daily doses ranging from 5 to 600 mg/kg of body weight were given over 5 days, during which animal survival was monitored.

Special report: lengthening the nose: thoughts on correction with a reexamination of some basic principles.

Background And Objectives: Providing thin, well-vascularized lining flaps is still the most elusive achievement in corrective nasal surgery. The purpose of this article is to reexamine some of the principles of correction.

Methods And Materials: To demonstrate the importance of releasing or sectioning nasal lining, the authors review the principles of lengthening the nose, illustrated with seven clinical cases from their surgical experience and a detailed 12-drawing presentation of the surgical approach by Tessier--the senior surgeon.

Rapid measurement of protein osmotic second virial coefficients by self-interaction chromatography.

Weak protein interactions are often characterized in terms of the osmotic second virial coefficient (B(22)), which has been shown to correlate with protein phase behavior, such as crystallization. Traditional methods for measuring B(22), such as static light scattering, are too expensive in terms of both time and protein to allow extensive exploration of the effects of solution conditions on B(22). In this work we have measured protein interactions using self-interaction chromatography, in which protein is immobilized on chromatographic particles and the retention of the same protein is measured in isocratic elution.

The S100 family heterodimer, MRP-8/14, binds with high affinity to heparin and heparan sulfate glycosaminoglycans on endothelial cells.

The S100 family proteins MRP-8 (S100A8) and MRP-14 (S100A9) form a heterodimer that is abundantly expressed in neutrophils, monocytes, and some secretory epithelia. In inflamed tissues, the MRP-8/14 complex is deposited onto the endothelium of venules associated with extravasating leukocytes. To explore the receptor interactions of MRP-8/14, we use a model system in which the purified MRP-8/14 complex binds to the cell surface of an endothelial cell line, HMEC-1.

Activation of human neutrophils in vitro and dieldrin-induced neutrophilic inflammation in vivo.

Many chemicals of environmental concern are known to alter the immune system and are considered toxic molecules because they affect immune cell functions. Inflammation related to environmental chemical exposure, however, is poorly documented, except that from air pollutants. In this study, we found that the organochlorine insecticide dieldrin could not alter the ability of human neutrophils to phagocytose opsonized sheep red blood cells at nonnecrotic concentrations (0.