Antibiotic sensitization using biphenyl tetrazoles as potent inhibitors of Bacteroides fragilis metallo-beta-lactamase

BACKGROUND: High level resistance to carbapenem antibiotics in gram negative bacteria such as Bacteroides fragilis is caused, in part, by expression of a wide-spectrum metallo-beta-lactamase that hydrolyzes the drug to an inactive form. Co-administration of metallo-beta-lactamase inhibitors to resistant bacteria is expected to restore the antibacterial activity of carbapenems. RESULTS: Biphenyl tetrazoles (BPTs) are a structural class of potent competitive inhibitors of metallo-beta-lactamase identified through screening and predicted using molecular modeling of the enzyme structure. The X-ray crystal structure of the enzyme bound to the BPT L-159,061 shows that the tetrazole moiety of the inhibitor interacts directly with one of the two zinc atoms in the active site, replacing a metal-bound water molecule. Inhibition of metallo-beta-lactamase by BPTs in vitro correlates well with antibiotic sensitization of resistant B. fragilis. CONCLUSIONS: BPT inhibitors can sensitize a resistant B. fragilis clinical isolate expressing metallo-beta-lactamase to the antibiotics imipenem or penicillin G but not to rifampicin.     

Gastrointestinal absorption of metals

Estimating gastrointestinal absorption remains a significant challenge in the risk assessment of metals. This presentation reviews our current understanding of the gastrointestinal absorption of lead (Pb) to illustrate physiological mechanisms involved in metal absorption, new approaches that are being applied to the problem of estimating metal absorption in humans, and issues related to integrating this information into risk assessment. Absorption of metals can be highly variable in human populations because it is influenced by a variety of factors that include the chemical form of the metal, environmental matrix in which the ingested metal is contained, gastrointestinal tract contents, diet, nutritional status, age, and, in some cases, genotype. Thus, in risk assessment models, gastrointestinal absorption is best described as a variable whose distribution is determined in part by the above multiple influences. Although we cannot expect to evaluate empirically each of the above factors in human populations, we can expect to achieve a sufficiently detailed understanding of absorption mechanisms to develop conceptual and, eventually, quantitative models of absorption that account for some aspects of individual variability. A conceptual model is presented of the physiological processes involved in the transfer of ingested metals from the lumen of the gastrointestinal tract to the blood circulation. Components of the model include delivery to the site(s) of absorption; distribution among intracellular and extracellular ligands and transcellular and paracellular pathways of transfer across the gastrointestinal tract epithelium. The gastrointestinal absorption of Pb is discussed in the context of this model.     

Use of laboratory animals in the teaching of emergency procedures

The Division of Emergency Medicine, University of Chicago Hospitals and Clinics uses animal laboratory sessions to train emergency medicine residents in manipulative skills. Certain animals realistically represent the human for these purposes and are delineated for various procedures. On the other hand, animal tissue characteristics and anatomical landmarks generally differ from those of humans. How procedures such as cricothyreotomy; tracheostomy, tube thoracostomy, thoractomy, cardiac repair, aortic cross clamping, venous cutdown, peritoneal lavage, abdominal stab wound exploration and laparotomy can be performed and must be modified is discussed. A rational procedural sequence is required to maintain the animal's vitality through the end of the session.     

Intravenous aminophylline in patients with cystic fibrosis. Pharmacokinetics and effect on pulmonary function

Intravenous aminophylline was administered to ten patients with cystic fibrosis (CF) to determine if the medication would improve pulmonary function and to study theophylline pharmacokinetics. Intravenous normal saline was given on another day as a control. Thoracic gas volume and airway resistance, measured in a volume displacement body plethysmograph, and maximal expiratory flow-volume curves were performed before and after each infusion. No significant improvement was noted in pulmonary function after normal saline infusion. Following aminophylline infusion. Following aminophylline infusion, significant improvement in thoracic gas volume, residual volume, specific airway conductance, and maximal expiratory flow at 60% of total lung capacity was noted. The pharmacokinetic analysis revealed a mean half-life of 4.7 hours, a total clearance of 91 mL/hr/kg, and a volume of distribution of 574 mL/kg. Intravenous aminophylline can acutely decrease airway obstruction in children with CF.     

Aspects of the anodic behaviour of duplex stainless steels aged for long periods at low temperatures

Duplex stainless steel samples were aged at low temperatures (300 and 400 °C) for 1000 and 2000 h. Their anodic behaviour was studied in a 0.1 N concentration of sulphuric acid, which revealed that the polarisation curves were dependent on the aging temperature and time. Complex anodic current peaks occurred at low and high potentials due to the dual austenite and ferrite microstructure. The aging treatment promoted silicon enrichment of the passivated film, probably over the austenite phase, as indicated by X-ray photoelectron spectroscopy measurements. G phase precipitation and spinodal decomposition was identified by transmission electron microscopy.     

Attentional bias in anxiety: Selective search or defective filtering?

Two experimental tasks were used to investigate the nature of a previously documented bias in attention associated with anxiety. Results from the first task failed to reveal any differences between anxious and nonanxious subjects, either in attention focusing or selective search for letters. The second task, with words as targets and distractors, suggested that selective search was less efficient in anxious subjects when distractors were present. Currently anxious subjects were slower than controls when required to search for the target among distractors of any type, whereas both currently anxious and recovered subjects were slower when the distractors were threatening words. It was therefore suggested that a bias favoring threat cues during perceptual search is an enduring feature of individuals vulnerable to anxiety, rather than a transient consequence of current mood state alone. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Vaccinia virus induces Ca2+-independent cell-matrix adhesion during the motile phase of infection

Vaccinia virus (VV) induces two forms of cell motility: cell migration, which is dependent on the expression of early genes, and the formation of cellular projections, which requires the expression of late genes. The need for viral gene expression prior to cell motility suggests that VV proteins may affect how infected cells interact with the extracellular matrix. To address this, we have analyzed changes in cell-matrix adhesion after infection of BS-C-1 cells with VV. Whereas uninfected cells round up and detach from the culture flask in the presence of EGTA, infected cells remain attached to the culture flask with a stellate morphology. Ca2+-independent cell-matrix adhesion was evident by 10 h postinfection, after the onset of cell motility but before the formation of virus-induced cellular projections. Progression to Ca2+-independent adhesion required the expression of late viral genes but not the formation of intracellular enveloped virus particles or intracellular actin tails. Analyses of specific matrix proteins identified vitronectin and fibronectin as optimal ligands for Ca2+-independent adhesion and the formation of cellular projections. Adhesion to fibronectin was mediated via RGD motifs alone and was not inhibited by 500 micrograms of heparin/ml. Kistrin, a disintegrin which binds preferentially to the alphav beta3 (vitronectin/fibronectin) receptor inhibited the formation of cellular projections without disrupting preformed matrix interactions. Finally, we show that Ca2+-independent cell-matrix adhesion is a dynamic process which mediates changes in the morphology of VV-infected cells and uninfected cells which exhibit a transformed phenotype.