Staphylococcus aureus strains that express serotype 5 or serotype 8 capsular polysaccharides differ in virulence.

Most isolates of Staphylococcus aureus produce a serotype 5 (CP5) or 8 (CP8) capsular polysaccharide. To investigate whether CP5 and CP8 differ in their biological properties, we created isogenic mutants of S. aureus Reynolds that expressed CP5, CP8, or no capsule.

Method validation and measurement of biomarkers in nonclinical and clinical samples in drug development: a conference report.

Biomarkers are increasingly used in drug development to aid scientific and clinical decisions regarding the progress of candidate and marketed therapeutics. Biomarkers can improve the understanding of diseases as well as therapeutic and off-target effects of drugs. Early implementation of biomarker strategies thus promises to reduce costs and time-to-market as drugs proceed through increasingly costly and complex clinical development programs.

T cell cross-reactivity and conformational changes during TCR engagement.

All thymically selected T cells are inherently cross-reactive, yet many data indicate a fine specificity in antigen recognition, which enables virus escape from immune control by mutation in infections such as the human immunodeficiency virus (HIV). To address this paradox, we analyzed the fine specificity of T cells recognizing a human histocompatibility leukocyte antigen (HLA)-A2-restricted, strongly immunodominant, HIV gag epitope (SLFNTVATL). The majority of 171 variant peptides tested bound HLA-A2, but only one third were recognized.

Complementary and alternative medicine education in the United States, China, and Taiwan.

As public demand for complementary and alternative medicine increases,it is important for physical medicine and rehabilitation physicians to have some basic understanding of complementary and alternative medicine or at least to appreciate some of the approved indications so that appropriate referrals can be made. Because the concept of evidence-based medicine is essential for a successful physical medicine and rehabilitation practice in either academic or private facilities, well-developed research projects, such as randomized, controlled trials of large sample size, are needed to investigate the efficacy and safety of complementary and alternative medicine therapy.

Differentiation of extrahepatic bile duct cholangiocarcinoma from benign stricture: findings at MRCP versus ERCP.

Purpose: To retrospectively evaluate criteria for differentiating extrahepatic bile duct cholangiocarcinoma from benign cause of stricture at magnetic resonance cholangiopancreatography (MRCP) and to compare diagnostic accuracy with this modality versus endoscopic retrograde cholangiopancreatography (ERCP).

Materials And Methods: MRCP and ERCP images in 50 patients (27 with cholangiocarcinoma [18 men, nine women; mean age, 58 years] and 23 with benign cause of stricture [13 men, 10 women; mean age, 60 years]) were retrospectively reviewed to assess the appearance of bile duct strictures. Final diagnosis was based on surgical or biopsy findings.

Analysis of genetic polymorphisms in CCR5, CCR2, stromal cell-derived factor-1, RANTES, and dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin in seronegative individuals repeatedly exposed to HIV-1.

To determine the influence of host genetics on human immunodeficiency virus (HIV) type 1 infection, we examined 94 repeatedly exposed seronegative (ES) individuals for polymorphisms in multiple genes and compared the results with those for 316 HIV-1-seropositive and 425 HIV-1-seronegative individuals. The frequency of homozygous C-C chemokine receptor (CCR) 5- Delta 32 was higher in ES (3.2%) than in HIV-1-seropositive individuals (0.

Reduction of tissue hyperplasia with a rhenium-188 mercaptoacetyltriglycine-3-filled balloon: preliminary study in a canine urethral model.

Purpose: To evaluate the efficacy of beta-radiation therapy with rhenium-188 mercaptoacetyltriglycine-3 (MAG(3))-filled balloons to reduce tissue hyperplasia secondary to stent placement in 18 canine urethras.

Materials And Methods: Eight dogs were treated with 188-Re MAG(3)-filled balloon dilation immediately after stent placement and were killed 4 weeks later (group I, n = 4) or 8 weeks later (group II, n = 4). Five dogs were treated with 188-Re MAG(3)-filled balloon dilation 2 weeks after stent placement and were killed 4 weeks after stent placement (group III).

Mechanism of action of NB2001 and NB2030, novel antibacterial agents activated by beta-lactamases.

Two potent antibacterial agents designed to undergo enzyme-catalyzed therapeutic activation were evaluated for their mechanisms of action. The compounds, NB2001 and NB2030, contain a cephalosporin with a thienyl (NB2001) or a tetrazole (NB2030) ring at the C-7 position and are linked to the antibacterial triclosan at the C-3 position. The compounds exploit beta-lactamases to release triclosan through hydrolysis of the beta-lactam ring.

Staphylococcus aureus capsular polysaccharides.

Serotype 5 and 8 capsular polysaccharides predominate among clinical isolates of Staphylococcus aureus. The results of experiments in animal models of infection have revealed that staphylococcal capsules are important in the pathogenesis of S. aureus infections.

Biomarkers, validation and pharmacokinetic-pharmacodynamic modelling.

Four elements are crucial to successful pharmacokinetic-pharmacodynamic (PK/PD) modelling and simulation for efficient and effective rational drug development: (i) mechanism-based biomarker selection and correlation to clinical endpoints; (ii) quantification of drug and/or metabolites in biological fluids under good laboratory practices (GLP); (iii) GLP-like biomarker method validation and measurements and; (iv) mechanism-based PK/PD modelling and validation. Biomarkers can provide great predictive value in early drug development if they reflect the mechanism of action for the intervention even if they do not become surrogate endpoints. PK/PD modelling and simulation can play a critical role in this process.

A multicenter, prospective, randomized, comparative evaluation of dual- versus triple-lumen catheters for hemodialysis and apheresis in 485 patients.

Background: The purpose of this study is to compare a new temporary triple-lumen catheter (TLC) for dialysis that has a third lumen devoted to fluid and medication administration or blood sampling with a marketed dual-lumen catheter (DLC).

Methods: Four hundred eighty-five patients referred for acute hemodialysis or apheresis were randomly assigned to either a TLC or DLC in a multicenter, prospective, randomized trial.

Results: Analysis of blood flow rates was completed on 464 patients (228 patients, DLC; 236 patients, TLC) with a total of 1,681 hemodialysis (808 treatments, DLC; 873 treatments, TLC) and 82 apheresis treatments (37 treatments, DLC; 45 treatments, TLC).

Primary sequence characterization of catestatin intermediates and peptides defines proteolytic cleavage sites utilized for converting chromogranin a into active catestatin secreted from neuroendocrine chromaffin cells.

Catestatin is an active 21-residue peptide derived from the chromogranin A (CgA) precursor, and catestatin is secreted from neuroendocrine chromaffin cells as an autocrine regulator of nicotine-stimulated catecholamine release. The goal of this study was to characterize the primary sequences of high molecular mass catestatin intermediates and peptides to define the proteolytic cleavage sites within CgA that are utilized in the biosynthesis of catestatin. Catestatin-containing polypeptides, demonstrated by anti-catestatin western blots, of 54-56, 50, 32, and 17 kDa contained NH(2)-terminal peptide sequences that indicated proteolytic cleavages of the CgA precursor at KK downward arrow, KR downward arrow, R downward arrow, and KR downward arrow basic residue sites, respectively.

Persistence of extraordinarily low levels of genetically homogeneous human immunodeficiency virus type 1 in exposed seronegative individuals.

Some individuals remain inexplicably seronegative and lack evidence for human immunodeficiency virus type 1 (HIV-1) infection by conventional serologic or virologic testing despite repeated high-risk virus exposures. Here, we examined 10 exposed seronegative (ES) individuals exhibiting HIV-1-specific cytotoxicity for the presence of HIV-1. We discovered HIV-1 DNA in resting CD4(+) T cells (mean, 0.

Three highly conserved proteins catalyze the conversion of UDP-N-acetyl-D-glucosamine to precursors for the biosynthesis of O antigen in Pseudomonas aeruginosa O11 and capsule in Staphylococcus aureus type 5. Implications for the UDP-N-acetyl-L-fucosamine biosynthetic pathway.

N-Acetyl-l-fucosamine is a constituent of surface polysaccharide structures of Pseudomonas aeruginosa and Staphylococcus aureus. The three P. aeruginosa enzymes WbjB, WbjC, and WbjD, as well as the S.

NB2001, a novel antibacterial agent with broad-spectrum activity and enhanced potency against beta-lactamase-producing strains.

Enzyme-catalyzed therapeutic activation (ECTA) is a novel prodrug strategy to overcome drug resistance resulting from enzyme overexpression. beta-Lactamase overexpression is a common mechanism of bacterial resistance to beta-lactam antibiotics. We present here the results for one of the beta-lactamase ECTA compounds, NB2001, which consists of the antibacterial agent triclosan in a prodrug form with a cephalosporin scaffold.

Plasma protein binding of amphotericin B and pharmacokinetics of bound versus unbound amphotericin B after administration of intravenous liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate.

Unilamellar liposomal amphotericin B (AmBisome) (liposomal AMB) reduces the toxicity of this antifungal drug. The unique composition of liposomal AMB stabilizes the liposomes, producing higher sustained drug levels in plasma and reducing renal and hepatic excretion. When liposomes release their drug payload, unbound, protein-bound, and liposomal drug pools may exist simultaneously in the body.

Pharmacokinetics, excretion, and mass balance of liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate in humans.

The pharmacokinetics, excretion, and mass balance of liposomal amphotericin B (AmBisome) (liposomal AMB) and the conventional formulation, AMB deoxycholate (AMB-DOC), were compared in a phase IV, open-label, parallel study in healthy volunteers. After a single 2-h infusion of 2 mg of liposomal AMB/kg of body weight or 0.6 mg of AMB-DOC/kg, plasma, urine, and feces were collected for 168 h.

Regulation of Staphylococcus aureus capsular polysaccharide expression by agr and sarA.

This study addresses the regulation of Staphylococcus aureus type 8 capsular polysaccharide (CP8) expression by the global regulators agr and sarA. We analyzed CP8 production, cap8-specific mRNA synthesis, and blaZ reporter gene activities of the transcriptional and translational fusions in strain Becker and its agr, sarA, and agr-sarA isogenic mutants during different phases of bacterial growth. In the wild-type strain, cap8 mRNA was undetectable until the mid-logarithmic phase of growth, whereas CP8 production was undetectable until 2 h later, at the onset of stationary phase.

Development of Antistaphylococcal Vaccines.

Staphylococcus aureus is frequently isolated from both hospital-acquired and community-acquired infections, and the emergence of antibiotic resistance among clinical isolates has made treatment of staphylococcal infections difficult. This scenario has sparked renewed interest in the development of a vaccine for individuals at high risk for staphylococcal infections. As part of the effort to develop a multicomponent vaccine against S.

The Staphylococcus aureus allelic genetic loci for serotype 5 and 8 capsule expression contain the type-specific genes flanked by common genes.

The nucleotide sequences of two gene clusters, cap5 and cap8, involved in the synthesis of Staphylococcus aureus type 5 and type 8 capsular polysaccharides (CPs), respectively were determined. Each gene cluster contained 16 ORFs, which were named cap5A through cap5P for type 5 CP and cap8A through cap8P for type 8 CP. The cap5 and cap8 loci were allelic and were mapped to the SmaI-G fragment in the standard SmaI map of Staph.