Hypothesis: Is obesity an inflammatory condition?
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C-Reactive Protein↗
Biomedical subjects
M D Lee
Publications and source records attributed to M D Lee.
Drug-induced changes in P450 enzyme expression at the gene expression level: a new dimension to the analysis of drug-drug interactions.
Drug-drug interactions (DDIs) caused by direct chemical inhibition of key drug-metabolizing cytochrome P450 enzymes by a co-administered drug have been well documented and well understood. However, many other well-documented DDIs cannot be so readily explained. Recent investigations into drug and other xenobiotic-mediated expression changes of P450 genes have broadened our understanding of drug metabolism and DDI. In order to gain additional information on DDI, we have integrated existing information on drugs that are substrates, inhibitors, or inducers of important drug-metabolizing P450s with new data on drug-mediated expression changes of the same set of cytochrome P450s from a large-scale microarray gene expression database of drug-treated rat tissues. Existing information on substrates and inhibitors has been updated and reorganized into drug-cytochrome P450 matrices in order to facilitate comparative analysis of new information on inducers and suppressors. When examined at the gene expression level, a total of 119 currently marketed drugs from 265 examined were found to be cytochrome P450 inducers, and 83 were found to be suppressors. The value of this new information is illustrated with a more detailed examination of the DDI between PPARalpha agonists and HMG-CoA reductase inhibitors. This paper proposes that the well-documented, but poorly understood, increase in incidence of rhabdomyolysis when a PPARalpha agonist is co-administered with a HMG-CoA reductase inhibitor is at least in part the result of PPARalpha-induced general suppression of drug metabolism enzymes in liver. The authors believe this type of information will provide insights to other poorly understood DDI questions and stimulate further laboratory and clinical investigations on xenobiotic-mediated induction and suppression of drug metabolism.
Animals↗
Diagnosis of complete and partial posterior cruciate ligament ruptures. Stress radiography compared with KT-1000 arthrometer and posterior drawer testing.
Stress radiography was performed on 21 patients with unilateral posterior cruciate ligament tears: 10 complete and 11 partial. An 89-N posterior load was applied to the proximal tibia and a lateral radiograph was taken of each knee in 70 degrees of flexion. The relative amount of sagittal translation (involved minus noninvolved) was determined at both the medial and lateral tibial plateaus from the radiographic films. Arthrometric (KT-1000 arthrometer) and posterior drawer tests were also performed. The mean relative posterior translation averaged 12.2 +/- 3.7 mm for knees with complete tears. Arthrometer testing of the same knees showed 7.6 +/- 2.5 mm of increased translation, and posterior drawer testing showed 9.2 +/- 3.3 mm of increased dropback. Stress radiographic results were statistically similar to the electrogoniometric measurements in cadaveric knees. In knees with a partially torn posterior cruciate ligament, mean relative translation measured on stress radiographic was 5.6 +/- 1.5 mm, which was significantly different from that for knees with complete ruptures. The arthrometer and posterior drawer test data were not significantly different for knees with complete and partial tears. Stress radiography is superior to both the arthrometer and clinical posterior drawer testing for determining posterior cruciate ligament status. Eight millimeters of more of increased posterior translation on stress radiographs is indicative of complete rupture.
Adolescent↗
Temporal changes in the population genetics of Salmonella pullorum.
Salmonella pullorum is the cause of pullorum disease, which is characterized by white diarrhea and a high mortality rate in poultry. During the 1990s, the serologic "pullorum" test has occasionally failed to detect infected birds during the early stage of disease. To determine if any recent genetic changes have taken place in S. pullorum to account for poor seroconversion sometimes observed in infected flocks, S. pullorum from 1990s outbreaks and strains isolated prior to the 1980s were typed by random amplified polymorphic DNA (RAPD). Of 40 S. pullorum isolates typed by this method, eight distinct DNA patterns were identified with one of three RAPD polymerase chain reaction primers. Sixty-two percent of S. pullorum isolates shared the same RAPD DNA pattern, and a major proportion of these strains were from recent flock infections. The RAPD patterns for S. pullorum were clearly distinct from the avian Salmonella group B isolates included in this analysis. The distribution of Salmonella virulence genes among avian Salmonella isolates was also examined. Eighty-five percent of the S. pullorum isolates had both the virulence plasmid gene, spvB, and the invasion gene, invA, with the same percentage positive for the Salmonella enteriditis fimbrial gene, sef. However, significant variability was observed among S. pullorum in their ability to invade avian epithelial cells, despite the presence of the Salmonella invasion gene in these isolates.
Animals↗
DNA fingerprinting of plasmid-containing serotype A: 3,4 Pasteurella multocida isolated from cases of fowl cholera in chickens and turkeys.
The live, attenuated vaccine strains of Pasteurella multocida have been hypothesized to be responsible for homologous serotype outbreaks of fowl cholera on farms that use the commercial vaccines. We have further hypothesized that the naturally occurring Clemson University (CU) vaccine strain may be transformed to virulence by the acquisition of plasmid DNA. To test this hypothesis, we obtained seven homologous serotype (A:3,4) P. multocida isolates, all plasmid bearing, that were cultured from fowl cholera cases in vaccinated flocks and compared the isolates with the CU reference vaccine by molecular methods. Restriction fragment length polymorphisms (RFLPs) were detected by DNA/DNA hybridization with labeled probes specific for the cya, aroA, and rrn genes of P. multocida. The RFLPs obtained from BglII-digested genomic DNA probed with cya demonstrated no differences among the isolates. Although three isolates probed with aroA showed a RFLP identical to the vaccine strain, five isolates were distinctly different. Isolates probed with rrn grouped into three different restriction patterns that were dissimilar from that of the vaccine strain. Therefore, we have shown that these fowl cholera isolates are different from the CU vaccine strain and that these outbreaks were not vaccine related.
Animals↗
Comparison of a quantitative microtiter method, a quantitative automated method, and the plate-count method for determining microbial complement resistance.
A quantitative microtiter method for determining the degree of complement resistance or sensitivity of microorganisms is described. The microtiter method is compared with a quantitative automated system and the standard plate-count technique. Data were accumulated from 30 avian Escherichia coli isolates incubated at 35 C with either chicken plasma or heat-inactivated chicken plasma. Analysis of data generated by the automated system and plate-count techniques resulted in a classification of the microorganisms into three groups: those sensitive to the action of complement; those of intermediate sensitivity to the action of complement; and those resistant to the action of complement. Although the three methods studied did not agree absolutely, there were statistically significant correlations among them.
Animals↗
Characterization of Pasteurella multocida mutants of low virulence.
Ten temperature-sensitive mutants of the Clemson University (CU) vaccine strain of Pasteurella multocida have been developed and were characterized by phenotypic attributes such as carbohydrate fermentation, antibiotic resistance, and membrane protein profiles. Some mutants were found to have lost the ability to utilize some substrates, notably xylose and gluconate, whereas others were able to ferment additional carbohydrates such as arabinose and rhamnose. CU was found to be resistant to sulfisoxazole, of intermediate resistance to bacitracin, and sensitive to rifampin; the sensitivity to these three antibiotics varied among the mutant strains, but 60% were resistant to rifampin. Membrane protein profiles demonstrated some changes in major bands, and there was variation in 50% of the mutants in proteins in the 31 kilodalton range. All strains were assayed for the presence of several virulence factors, and many were found to produce siderophore and to exhibit some degree of complement resistance.
Animals↗
Comparison of Pasteurella multocida serotype 3,4 isolates from turkeys with fowl cholera.
Nine isolates of Pasteurella multocida serotype 3,4 were isolated from turkeys that had been vaccinated against fowl cholera but that subsequently experienced outbreaks of fowl cholera. These isolates were compared with the CU vaccine strain. Characteristics examined were antimicrobial susceptibility profiles; carbohydrate fermentation; production of bacteriocin, siderophore, and hemolysin; resistance to serum complement; membrane proteins; enzyme activities; presence of plasmids; transferability of R-plasmids; and pathogenicity. Differences were observed between the CU strain and virulent isolates of P. multocida serotype 3,4 for resistance to serum complement, presence of plasmids, hemolysis, membrane proteins, and pathogenicity. Other parameters compared did not differ significantly between the two groups. The presence of plasmids and resistance to the lytic action of complement of the isolates of P. multocida serotype 3,4 correlated with the mortality rates caused by these bacteria.
Animals↗
The relationship of pathogenicity to the growth of Pasteurella multocida serotype 3,4 isolates in normal turkey plasma.
The percent mortality (M%) caused by various isolates of Pasteurella multocida serotypes 3,4 in turkeys challenged with these organisms was significantly associated with the growth curve when these organisms were grown in normal turkey plasma. The organisms that lysed the most caused the least mortality. In turn, the longer it took for an organism to reach the lowest point on its growth curve, the lower the M%. The highest point on the growth curve and the time that it took to reach that point were analyzed in normal and heat-treated plasma (HTP). The isolates with the maximum growth had the highest M%. The isolates that reached their maximum growth faster also had the greatest M%.
Animals↗
Invasion of epithelial cell monolayers by turkey strains of Pasteurella multocida.
Two serotype 3,4:A strains of Pasteurella multocida that differ in virulence in turkeys were examined for their ability to invade epithelial cell monolayers grown in tissue culture. Both organisms were comparably adherent to cells of turkey kidney origin. However, the virulent strain (86-1913) penetrated primary turkey kidney epithelial cell monolayers at 10 times the level of the low-virulence vaccine strain. The virulent strain was also able to invade porcine epithelial cells (PK15) and feline epithelial cells (CRFK) in cell culture. Neither organism invaded rabbit epithelial cells (RK13). Invasion of turkey cells was prevented by inhibition of bacterial protein or RNA synthesis but not by pretreatment of the monolayers with periodate, trypsin, or neuraminidase. Invasion might be a mechanism of pathogenicity for this organism, contributing to colonization or virulence.
Animals↗
The effect of plasmid acquisition on potential virulence attributes of Pasteurella multocida.
Several plasmids that were isolated from complement-resistant Pasteurella multocida or Escherichia coli were evaluated for phenotypic markers. Plasmid p2267, isolated from a tetracycline-resistant, complement-resistant fowl cholera field isolate of P. multocida (PM2267), was used to transform a K-12 E. coli (C600); this resulted in increased complement resistance, which was eliminated by curing. Either of two plasmids (p1870 or p70-1, isolated from P. multocida and E. coli, respectively) conferred an increase in complement resistance and invasiveness to turkey epithelial cells when expressed in the Clemson University (CU) vaccine strain of P. multocida. Additionally, the CU strain containing p1870 was more virulent in turkey challenge, and the plasmid appeared amplified in vivo. No detectable differences in major outer-membrane proteins, capsule, or carbohydrate fermentation were found to be associated with the acquisition of these plasmids.
Animals↗
The effect of bacterial surface structures on the pathogenesis of Salmonella typhimurium infection in chickens.
Mutants of Salmonella typhimurium strain SR11 containing Tn10 insertions in genes encoding for the motility and fimbriation phenotypes were evaluated for adhesion, invasion, and virulence in avian models. Mutations abolishing mannose-sensitive or mannose-resistant hemagglutination did not influence adherence or invasion in epithelial cells in vitro. A double hemagglutinin-deficient mutant, lacking both mannose-sensitive and mannose-resistant hemagglutinins, was diminished in ability to adhere to chick kidney epithelial cells in vitro, but invasion in vitro was not significantly affected. Compared with the wild-type parent, mutations that decreased motility reduced invasion levels in vitro and increased the peroral LD50 in one-day-old chicks. A mutant deficient in both motility and mannose-sensitive hemagglutination was greatly reduced in its ability to invade epithelial cells in vitro and persist in the liver and spleen of orally challenged chicks. Results of this study indicate that loss of motility in S. typhimurium attenuates peroral virulence in chicks.
Animals↗
Molecular typing of avian Escherichia coli isolates by random amplification of polymorphic DNA.
Escherichia coli is a common inhabitant of the gastrointestinal tract of most animals. Like most pathogenic E. coli, avian isolates cannot be distinguished biochemically from the normal commensals inhabiting the gastrointestinal tract of birds. Using a molecular approach, we were able to identify genetic differences among avian E. coli isolates by restriction fragment length polymorphism (RFLP) and random amplification of polymorphic DNA (RAPD) by the polymerase chain reaction (PCR). Several different RFLPs were observed among avian E. coli isolates using DNA probes for 16S ribosomal RNA genes (rrn) and insertion sequence elements (IS2). We were also able to observe differences in DNA banding patterns generated by RAPD analysis. Similarities and differences among avian E. coli were discernible using RFLPs and RAPD analysis, whereas conventional bacteriological methods failed to differentiate these isolates. Based on RAPD patterns, avian E. coli appear to be genetically diverse. Of 16 different RAPD types (RT) encountered, 84% of E. coli fell into seven major RTs. One RT was present in clinical isolates but absent from the commensals isolated in this study. Many of these different E. coli RTs were not geographically restricted to northern Georgia but were also observed in other southern states in the United States. Resistance to various antibiotics was randomly associated with different E. coli RTs. Sarafloxacin resistance was present among different E. coli RTs, suggesting that antibiotic usage is not selecting for a clonal population in avian E. coli. RAPD provides a rapid and powerful tool to study the epidemiology of avian E. coli.
Animals↗