Vancomycin resistance factor of Lactobacillus rhamnosus GG in relation to enterococcal vancomycin resistance (van) genes

The integrins are cell surface receptors that recognize extracellular matrix adhesive proteins such as fibrinogen, fibronectin, vitronectin, and VCAM-1 (vascular cell adhesion molecule-1). Nonpeptide integrin antagonists designed after the adhesion recognition sequence RGD (Arg-Gly-Asp) not only have displayed efficacy as antithrombotic agents, but also have promise for the treatment of cancer and osteoporosis. Combinatorial organic syntheses of chemical mini-libraries have facilitated nonpeptide lead optimization of integrin antagonists with marked success. Although these accomplishments have been realized primarily for the discovery of orally active GPIIb/IIIa antagonist antithrombotics, vitronectin receptor (avb3) antagonist research has also benefited from such rapid synthesis. The purpose of this review is to report progress in combinatorial synthesis lead optimization by highlighting the drug design strategies and synthetic tactics that have led to improved integrin antagonists.     

Enterococci with acquired vancomycin resistance in pigs and chickens of different age groups

Results of isolation of glycopeptide-resistant enterococci from fecal samples of pigs and chickens were found to differ strongly depending upon the type and age of animals and isolation technique (direct selective plate or broth enrichment). Isolations were frequent in broiler chickens and in sows but rare in layer chickens.     

A closer look at vancomycin, teicoplanin, and antimicrobial resistance

The worldwide increase in the incidence of resistant Gram-positive infections has renewed interest in the glycopeptide class of antimicrobial agents. Two glycopeptides are available in many parts of the world--vancomycin and teicoplanin. These two agents appear to differ in several respects, including: potential for selecting microbial resistance, dosing convenience, safety, and efficacy in severe infection. Teicoplanin appears to have lower toxicity and greater convenience; however, its widespread acceptance has been plagued by concerns over antimicrobial resistance, efficacy, and appropriate dosing. A review of available studies suggests that teicoplanin, when dosed at 6 mg/kg/day, is better tolerated than vancomycin 15 mg/kg/q12h; however, at these doses, it appears to be somewhat less effective than vancomycin in serious Staphylococcus aureus infection, such as endocarditis. Although higher doses of teicoplanin, 12 mg/kg/day to 30 mg/kg/day, have been associated with efficacy comparable to that of vancomycin in serious S. aureus infections, such doses may eliminate some of the safety advantages conferred by lower teicoplanin doses. Teicoplanin has been associated with resistance among coagulase-negative staphylococci and the selection of resistance in S. aureus. There is some evidence that widespread use of teicoplanin might accelerate the development of S. aureus resistance to both teicoplanin and vancomycin. The selection of an appropriate glycopeptide in an individual patient should be based not only on convenience, but also on a determination of optimal efficacy, safety at an efficacious dose, and the potential for resistance.     

Observations on the risk of resistance with the extended use of vancomycin

OBJECTIVE: To document the risk of the development of vancomycin-resistant bacteria in a population of seriously burned patients during a 10-year period of common vancomycin hydrochloride use. DESIGN: Retrospective study. SETTING: The US Army Institute of Surgical Research, Burn Center, Fort Sam Houston, Tex. POPULATION AND METHODS: Microbiology, infection, and antibiotic use records collected during the hospitalization of 2266 consecutively admitted seriously burned patients were reviewed. Vancomycin was the primary therapeutic agent used for gram-positive infections and was also used as a perioperative prophylactic antibiotic during burn wound excision. This policy was established prior to this review because of a high incidence of methicillin-resistant Staphylococcus aureus colonization and an anecdotal association of increased beta-lactam resistance in endemic gram-negative pathogens associated with the use of penicillinase-resistant penicillins and cephalosporins. MAIN OUTCOME MEASURES: Isolation of vancomycin-resistant enterococci (VRE) or other gram-positive organisms resistant to vancomycin. RESULTS: Examinations of 15 125 gram-positive isolates, including 957 enterococci, for in vitro sensitivity to vancomycin yielded 3 VRE isolates in 3 patients. Vancomycin was used prior to VRE isolation in one of these patients. Resistance was found in 3 other organisms (2 Corynebacterium species, 1 Lactobacillus species). Vancomycin was used prior to these isolations in 2 of 3 patients. None of the vancomycin-resistant organisms was associated with infection and all 6 patients survived. Vancomycin-resistant enterococci or other vancomycin-resistant gram-positive organisms were not found in 663 patients treated with vancomycin for documented gram-positive infections or in 1027 patients where perioperative vancomycin was used. CONCLUSION: Use of vancomycin as the primary therapeutic agent in seriously burned patients was not associated with increased risk of VRE isolation or VRE infection.     

Low-level frequency-following response

In man, the scalp-recorded 'Frequency-following response' (FFR) can be well observed only at fairly high levels of stimulation. As a consequence, it is difficult to ascertain whether the low or the high-frequency channels of the peripheral auditory system mediate this response. It is shown that the sensitivity of the recording method is considerably increased when the averaged recorded waveform is subjected to frequency analysis. Results from experiments with high-pass masking noise become unequivocal and they suggest that the low-level FFR is caused by nervous activity arising in the apical part of the cochlea and mediated by the low-frequency in the brain stem.     

Genetic organization and distribution of tetracycline resistance determinants in Clostridium perfringens

The Tet P determinant from the conjugative Clostridium perfringens R plasmid pCW3 two functional overlapping tetracycline resistance genes, tetA(P) and tetB(P). The tetA(P) gene encodes a putative 46-kDa transmembrane protein which mediates active efflux of tetracycline from the cell, while tetB(P) encodes a putative 72.6-kDa protein which has significant similarity to Tet M-like tetracycline resistance proteins (J. Sloan, L.M. McMurry, D. Lyras, S. B. Levy, and J. I. Rood, Mol. Microbiol. 11:403-415, 1994). In the present study, hybridization and PCR analysis of 81 tetracycline-resistant isolates of C. perfringens showed that they all carried the tetA(P) gene. Most of these isolates (93%) carried a second tetracycline resistance gene, with 53% carrying tetB(P) and 40% carrying a tet(M)-like gene. Despite the wide distribution of the tetB(P) and tet(M) genes, no isolate which carried both of these determinants was detected. In isolates that carried both tetA(P) and tetB(P) these genes overlapped, as in pCW3. Isolates carrying this combination of genes originated from diverse geographical locations and environmental sources. The single Clostridium paraputrificum isolate examined carried tetA(P), indicating that this gene is not confined to C.perfringens. However, neither tetA(P) nor tetB(P) was detected in the nine Clostridium difficile isolates tested. Nucleotide sequence analysis of isolates lacking tetB(P) revealed that they contained the tetA408(P) gene, which lacked the codons for the 12 carboxy-terminal amino acids of the TetA(P) protein.     

Low-level masking in the attentional blink.

If two targets (T1 and T2) are to be identified among other stimuli displayed in rapid serial visual presentation (RSVP), correct identification of T1 can produce an attentional blink (AB) lasting several hundred milliseconds, during which detection of T2 is impaired. Experiment 1 confirmed that omission of the item directly following T1 (the + 1 item) reduces the AB (J. E. Raymond, K. L. Shapiro, & K. M. Arnell, 1992). The next 3 experiments varied the spatial and temporal relationships between T1 and the + 1 item to study how masking of T1 affects the AB deficit. Perception of T1 was impaired by pattern masking arising from temporal integration or superimposition of T1 and the + 1 item; it was also impaired by metacontrast masking. We conclude that masking affects the AB indirectly by degrading T1 thereby increasing the duration of T1 processing. A 2-stage model proposed by M. M. Chun and M. C. Potter (1995) is supported. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Conjugative mobilization of a vancomycin resistance plasmid by a putative Enterococcus faecium sex pheromone response plasmid

The purpose of this study was to develop a model of gastrointestinal carcinogenesis using C57BL/6 mice. Treatment regimens consisted of one control group and 2 groups which received N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in drinking water: 50 micrograms/ml x 52 weeks and 100 micrograms/ml x 27 weeks. In addition, 2 protocols using adjuvant agents intended to increase tumor formation were used: MNNG (100 micrograms/ml) x 27 weeks + 0.2% taurocholic acid added to the diet from weeks 13-52, and MNNG (50 micrograms/ml) x 33 weeks+caerulein (10 micrograms/kg) subcutaneously 3 times/week from weeks 21-52. High-grade dysplasia was observed in the duodenum of 1/13 mice treated with MNNG (50 micrograms/ml). The combination of the latter and caerulein did not augment tumorigenesis. Mice treated with MNNG (100 micrograms/ml) frequently developed neoplasia in the duodenum and upper jejunum. Foci of low-grade and high-grade dysplasia alone were found in 3/12 (25%) mice; and intramucosal and invasive adenocarcinoma were found in 7/12 (58.3%) mice. The addition of taurocholic acid significantly increased the number and histological stages of the tumors (adenocarcinoma occurred in 100%, P = 0.03) and decreased the time for tumor formation.     

Low-level resistance to camptothecin in a human small-cell lung cancer cell line without reduction in DNA topoisomerase I or drug-induced cleavable complex formation

To study the evolution of camptothecin (CPT) resistance, we have established two small-cell lung cancer cell lines with low (3.2-fold, NYH/CAM15) and high (18-fold, NYH/CAM50) resistance to CPT by stepwise drug exposure. NYH/CAM50 cells had reduced topoisomerase I (topo I) content and activity, and consequently CPT-induced DNA single strand breaks (SSBs) were reduced, as measured by alkaline elution. In contrast, NYH/CAM15 cells had identical topo I content and activity as compared with wild-type (wt) cells. CPT-mediated SSBs and the rate of their reversal after drug removal were also equal in wt and NYH/CAM15 cells, as were doubling time, the fraction of cells in S-phase and DNA synthesis rate in response to CPT. As the conversion of DNA SSBs to DNA double strand breaks (DSBs) is thought to represent a critical event leading to cell death, we measured DNA DSBs by neutral elution. In contrast to DNA SSBs, CPT induced fewer DNA DSBs in NYH/CAM15 than in wt cells. DNA flow cytometry showed that, in CPT-treated cells, the G1 phase was emptied as cells accumulated in late S- and G2M phase. A Spearman rank correlation showed that depletion of G1 and accumulation in late S and G2M correlated to CPT sensitivity in these three cell lines. In conclusion, acquired resistance to CPT can occur without a reduction in either topo I enzyme or CPT-induced cleavable complex formation, while a decrease in the level of CPT-induced DNA DSBs may be of major importance in the early stages of CPT resistance.     

Low-level laser therapy in osteoarticular diseases in geriatric patients]

The formation of the antibody variable domain binding unit (Fv) is the net result of three competing assembly reactions. The affinities of concurrent homologous interactions of heavy and light chain variable domains limits the heterologous interaction leading to productive formation of the Fv. To address the possible role of light chain dimerization in this phenomenon, the Gln38 residue at the dimer interface of an immunoglobulin light chain variable domain (VL) was replaced by charged amino acids. The effects of these mutations on VL homodimer formation were monitored by small-zone size exclusion HPLC and the affinities of interaction were determined by computer simulation. Reduced VL homodimerization was observed in three of the four mutants, Q38R, Q38D and Q38K. The association constants for the Q38R and Q38D homodimers were 1.2 x 10(4) and 3.2 x 10(3) M(-1), respectively. This corresponded to a 20-75-fold reduction in the homodimer association constant relative to the wild-type VL, which had an association constant of 2.4 x 10(5) M(-1). Surprisingly, the fourth charge mutant, Q38E, had a higher association constant than the wild-type VL. The potential for charged residues to facilitate heterodimeric assembly of immunoglobulin domains was also tested. Heterodimerization was observed between the Q38D and Q38R V(L)s, but with an association constant of 4.7 x 10(4) M(-1), approximately fivefold lower than that obtained for homodimerization of the native V(L). In addition, replacement of the neutral, solvent-accessible Gln38 residue with either Asp or Arg was found to be significantly destabilizing. These results suggest that charged residues could be introduced at immunoglobulin domain interfaces to guide heterodimer formation and to minimize unfavorable competing homologous associations. Nonetheless, these apparently simple modifications may also result in unintended consequences that are likely to depend upon structural features of particular variable domains.     

贫化电炉低空污染的治理

介绍江铜集团贵溪冶炼厂熔炼车间贫化电炉系统的工作原理及工艺流程,贫化电炉生产过程中产生的有害气体的种类及危害,有害气体给周边环境造成了一定的低空污染,为治理低空污染经摸索与研究发现了贫化电炉存在的问题,针对贫化电炉存在的问题进行了一系列的整改措施.     

The kinetic profile of vancomycin in neonates

The pharmacokinetic parameters of vancomycin in a neonatal population have been characterized to enable development of optimum dosage guidelines for neonatal intensive-care units and to examine the relationship between these pharmacokinetic parameters and various demographic, developmental and clinical factors which might be associated with changes in the kinetic profile of vancomycin. Forty-four infants (twenty-five males and nineteen females) with suspected or proven Gram-positive infection and who received intravenous vancomycin between October 1993 and December 1996 were included in this retrospective analysis. Gestational age ranged from 25 to 40 weeks and postconceptional age at the time of the study ranged from 28 to 45 weeks. Sixty case-studies were obtained from the forty-four patients, with one period of study corresponding to one week or one cycle of therapy. Vancomycin pharmacokinetic parameters were determined by use of a one-compartment model. By regression analysis the current weight (g) was shown to be the stronger covariate, and both vancomycin clearance (L h(-1)) and volume of distribution (L) had to be normalized. The vancomycin volume of distribution depended on the postconceptional age with a cut-off at 32 weeks, whereas vancomycin clearance depended on the presence or absence of concomitant treatment with indomethacin or of mechanical ventilation, or both. On the basis of the pharmacokinetic parameters obtained we suggest initial dosage guidelines for vancomycin ranging from 10 mg kg(-1) every 8 h to 10 mg kg(-1) every 12 h, depending on the demographic and clinical characteristics of the patients. The results obtained enabled application of better a priori and a posteriori dosage schedules to infants in neonatal intensive-care units by use of the Bayesian approach, although further prospective study is recommended before direct extrapolation to patients in other settings.     

Low-level relationship aggression and couple therapy outcomes.

Increasing evidence supports the efficacy of conjoint therapies that focus on intimate partner violence for couples who engage in mild to moderate physical aggression but want to preserve the relationship and end the aggression. However, there has been no examination of how this population responds to couple therapy that does not have a specific focus on aggression. This lacuna in the research literature is of concern because couples with a history of low-level aggression often seek couple therapy, but couple therapy without a focus on violence is thought to potentially exacerbate aggression. In the current study, the authors examined the efficacy of non-aggression-focused behavioral couple therapy for couples with and without a history of mild physical aggression. One hundred thirty-four couples, 45% of whom had experienced low-level aggression in the year prior to therapy, completed up to 26 sessions of couple therapy and 2 years of follow-up assessments. Results demonstrated no significant differences in relationship and individual outcomes by history of aggression. In addition, couples maintained very low levels of physical aggression during and after treatment and showed reductions in psychological aggression when relationship and individual functioning improved. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Simulated dipeptide recognition by vancomycin

The antimicrobial activity of vancomycin and related glycopeptide antibiotics is due to stereospecific recognition of polypeptide components in bacterial cell walls. To better understand how these antibiotics recognize polypeptide determinants, we have developed dynamic models of the complexes formed by the vancomycin aglycon and two different dipeptide ligands, Ac-D-ala-D-ala and Ac-D-ala-gly. Molecular dynamics simulations of the two complexes, initially conditioned with distance constraints derived from two-dimensional nuclear magnetic resonance (NMR) studies, are conformationally stable and propagate in a manner consistent with the NMR-derived constraints after the constraints are removed. Free energy calculations accurately predict the relative binding affinity of these two complexes and help validate the simulation models for detailed structural analysis. Although the two ligands adopt similar conformations when bound to the antibiotic, there are clear differences in the configuration of intermolecular hydrogen bonds, the overall shape of the antibiotic, and other structural features of the two complexes. This analysis illustrates how complex structural and dynamic factors interrelate and contribute to differences in binding affinity.     

The changing molecular epidemiology and establishment of endemicity of vancomycin resistance in enterococci at one hospital over a 6-year period

The contributions of clonal spread, transfer of genetic elements, and introduction of new strains to the establishment of endemicity of vancomycin-resistant enterococci (VRE) were determined. The study took place at one hospital between 1990, when VRE were first detected, and 1996, when endemicity had become established. Isolates from 183 patients were categorized into 24 strain types by pulsed-field gel electrophoresis; the resistance genotype was determined by polymerase chain reaction. Between 1990 and 1993, 69% of patients were infected with the same vanB Enterococcus faecium strain. VanA resistance was not detected until 1993, but in 1996, the ratio of vanA to vanB was 2.2:1. Over time, 8 vanA strains were detected; a 35- or 40-kb conjugative vanA plasmid was found in 4 of the 8 strains. Clonal spread was a major factor in the establishment of endemicity. Transfer of genetic elements and introduction of new strain types were detected less often. However, these events may have been equally important evolutionarily.     

Toxicity of vancomycin on corneal endothelium in rabbits

PURPOSE: To evaluate the toxic effect of vancomycin on the corneal endothelium related to concentrations of vancomycin. METHODS: The toxic effect is assessed with a weighing method that gives a measure of endothelial function. Thirty-three rabbit corneas were divided into four groups. Three groups of seven corneas each were exposed to concentrations of 1.0 mg/ml, 3.0 mg/ml and 5.0 mg/ml vancomycin, respectively. The fourth group of twelve corneas served as a control group. RESULTS: The corneas exposed to 1.0 mg/ml vancomycin showed no significant weight increase, while the corneas exposed to 3.0 mg/ml and 5.0 mg/ml showed a significant weight increase as compared to the control corneas. The weight increase was significantly larger in the group of corneas exposed to 5.0 mg/ml as compared to 3.0 mg/ml. CONCLUSIONS: In the interval of tested concentrations there is a dose response relationship between vancomycin concentrations and endothelial toxicity. This experiment shows that vancomycin in the concentration of 1.0 mg/ml is non-toxic to the endothelium, while 3.0 mg/ml and 5.0 mg/ml increasingly impair endothelial function.     

Population pharmacokinetics of vancomycin in Japanese adult patients

MICA is a new polymorphic gene in the HLA region expressed in epithelial cell lines and gastrointestinal epithelium. Little is yet known about the MICA protein, and the pattern of its expression by freshly isolated cells has not been established. In the present experiments, we used antibodies raised in rabbits against alpha1 and alpha2 domain-peptides to study the expression of MICA. By western blot and immunoprecipitation, we detected a band of 62 000 Mr in various cell lines (THP-1, U937, HeLa, A431, Raji, MOLT-4, and HUV-EC-C) and in freshly isolated keratinocytes, endothelial cells, and monocytes but not in CD4+ and CD8+ T cells, and CD19+ cells (B lymphocytes). It was not possible to up-regulate the expression of MICA in different cells by stimulation with gamma-interferon, but the expression of MICA was induced in phytohemagglutinin-stimulated T cells. We confirmed that MICA is expressed at the cell surface by flow cytometry. Results of immunoprecipitation studies of beta2-microglobulin (beta2m)- or MICA-depleted, metabolically labeled HeLa cells indicated that MICA was not associated with beta2m. Although the function of MICA is still unknown, its restricted pattern of tissue expression, the fact that it is expressed on the cell surface, and its polymorphic nature suggest that this new molecule, encoded close to HLA class I, may play a role in the interaction between epithelial cells and cells of the immune system.