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Biomedical subjects

V L Clark

Publications and source records attributed to V L Clark.

17 recordsLinked to original sources

Thrombus causing fatal left ventricular outflow tract obstruction in a heart transplant patient.

A 60 year male, orthotopic heart transplant recipient developed a fatal left ventricular outflow obstruction secondary to thrombus at 38 months post transplant. Although he had episodes of mild to moderate rejection at 2 and 16 months post transplant, subsequent biopsies were negative and annual cardiac catheterizations showed mild left ventricular hypokinesis and normal coronary arteries. This case represents a catastrophic complication of transplant rejection and illustrates the problems with identifying rejection using current diagnostic methods.

Coronary Angiography

Expression of Porphyromonas gingivalis proteolytic activity in Escherichia coli.

Porphyromonas gingivalis (formerly Bacteroides gingivalis) degrades numerous protein substrates including collagen, fibrinogen, fibronectin, gelatin, casein, immunoglobulins and complement components. In order to clone one or more of these protease genes, a genomic library was constructed with Sau3A1 restriction fragments of chromosomal DNA from P. gingivalis ATCC 33277 ligated into the temperature-regulated vector pCQV2, and expressed in Escherichia coli DH5 alpha mcr. The electro-transformants (3 x 10(4)) were screened for general protease activity on Luria broth agar containing ampicillin (50 mg/l) and sodium caseinate (2%). One casein-hydrolyzing clone was detected and subcultured, and the activity of the cell extracts was characterized. We were able to show that the protease-positive clone, (pTEM1), had broad substrate specificity. Colorimetric assays indicated the hydrolysis of azocoll, azocasein, collagen, elastin-congo red and artificial substrates. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis was used to confirm that collagen, casein, fibrinogen and fibronectin were degraded by the clone.

Amino Acid Sequence

Isolation and nucleotide sequence of the gene (aniA) encoding the major anaerobically induced outer membrane protein of Neisseria gonorrhoeae.

When grown under anaerobic conditions, Neisseria gonorrhoeae, the etiologic agent of the sexually transmitted disease gonorrhea, expresses several novel outer membrane proteins. One of these, Pan 1, has an apparent molecular mass of 54 kDa in electrophoresis and is recognized by serum samples from patients with gonococcal infection. The presence of antibodies to this protein in patient sera suggests that Pan 1 is expressed during gonococcal infection and, more importantly, that N. gonorrhoeae grows anaerobically in vivo. We have cloned the Pan 1 structural gene, aniA, by screening a gonococcal lambda gt11 expression library with monospecific, polyclonal anti-Pan 1 antiserum. Three distinct immunoreactive recombinants, containing overlapping fragments of DNA, were isolated and confirmed to be coding for Pan 1 protein sequences. Northern (RNA blot) hybridization of an insert from an aniA recombinant to total gonococcal cellular RNA revealed the presence of a 1.5-kb transcript that was specific to RNA from anaerobically grown gonococci, indicating that the aniA gene is regulated at the transcriptional level and is monocistronic. To characterize the aniA gene, we have sequenced the entire 2-kb region spanned by the overlapping recombinants. We have also performed primer extension analysis on RNA isolated from aerobically and anaerobically grown gonococci in order to define the aniA promoter region. Two putative primer extension products specific to organisms grown anaerobically were identified by homology to known Escherichia coli promoter sequences, suggesting that the regulation of aniA expression involves multiple promoter regions.

Antigens, Bacterial

The major anaerobically induced outer membrane protein of Neisseria gonorrhoeae, Pan 1, is a lipoprotein.

Pan 1 is an acidic outer membrane protein of Neisseria gonorrhoeae that is expressed only when gonococci are grown anaerobically. On silver-stained sodium dodecyl sulfate-polyacrylamide gels, Pan 1 migrates as an intense but diffuse 54-kDa protein. The deduced amino acid sequence of Pan 1 from the aniA (anaerobically induced protein) open reading frame reveals a lipoprotein consensus sequence, Ala-Leu-Ala-Ala-Cys, and a processed molecular mass of 39 kDa. Furthermore, there is strong homology at the N terminus and C terminus of Pan 1 to the termini of the gonococcal outer membrane lipoproteins Lip and Laz. [3H]palmitic acid labeling of gonococci grown under oxygen-limited conditions demonstrated specific incorporation of label into Pan 1, suggesting further that Pan 1 is a lipoprotein.

Amino Acid Sequence

Arterial catheterization.

Arterial catheterization is used frequently in the management of critically ill patients, both for continuous blood pressure monitoring and access to the arterial circulation to obtain frequent blood gas measurements. The procedure is usually easily accomplished at the bedside using percutaneous methods such as the Seldinger technique to cannulate the radial, brachial, axillary, femoral, or dorsalis pedis artery. Meticulous attention to aseptic technique is necessary during insertion and catheter maintenance to minimize the risk of catheter-related infection. Other potential complications include hemorrhage, ischemia, arteriovenous fistula, and pseudoaneurysm formation.

Aftercare

Enhancement of the invasive ability of Neisseria gonorrhoeae by contact with HecIB, an adenocarcinoma endometrial cell line.

Since Neisseria gonorrhoeae is an obligate pathogen, there is no animal model for identification of virulence factors for this bacterium. An alternative model for assessment of gonococcal virulence is invasion of the adenocarcinoma endometrial cell line, HecIB. Preincubation of gonococci with glutaraldehyde-fixed HecIB cells eliminated the six- to eight-hour lag in entry of bacteria into a fresh HeIIB monolayer seen with unpreincubated gonococci or gonococci preincubated in tissue-culture medium alone. Gonococci tightly bound to fixed HecIB cells were more invasive than cells free in the tissue-culture medium, suggesting that actual contact with HecIB cells was required for the enhancement of invasive ability. Chloramphenicol addition during the preincubation prevented the enhanced invasion. Preincubated gonococci were not more adherent to HecIB cells, suggesting that a stage in invasion after binding of gonococci to HecIB cells was enhanced. The enhanced invasion occurred only when gonococci were preincubated with HecIB cells and not with HEp-2, HeLa, Chang or CHO cells. This eukaryotic cell specificity for induction of enhanced invasion may indicate a role for invasion in gonococcal infection of the endometrium.

Bacterial Adhesion

Distribution of gonococcal lipopolysaccharide biosynthesis genes among strains of Neisseria gonorrhoeae and other neisserial species.

A plasmid, pTME6, containing Neisseria gonorrhoeae lipopolysaccharide biosynthesis genes was used as a probe to analyze DNA from strains of N. gonorrhoeae, N. meningitidis and various commensal Neisseria by Southern blotting. Chromosomal DNA from 26 gonococcal strains probed with 32P-labeled pTME6 produced five different hybridization patterns. No correlation between hybridization pattern and auxotype, serotype, serum sensitivity or SDS-urea-PAGE migration of LPS was observed. DNA from strains of N. meningitidis, N. lactamica and N. cinerea, but not other commensal Neisseria species, hybridized strongly to pTME6.

DNA, Bacterial

Distribution of a protein antigenically related to the major anaerobically induced gonococcal outer membrane protein among other Neisseria species.

The Pan 1 protein of Neisseria gonorrhoeae is a novel 54-kDa outer membrane protein expressed only when gonococci are grown in the absence of oxygen. It is a major antigen recognized by sera from patients with gonococcal infection. We raised mouse monospecific polyclonal antiserum to gel-purified Pan 1 from gonococcal strain F62. The antiserum was broadly cross-reactive among gonococcal strains; all strains tested reacted in immunoblot analysis proportionate to the amount of Pan 1 visible in silver-stained sodium dodecyl sulfate (SDS)-polyacrylamide gels. In immunoblot experiments, N. lactamica and N. cinerea reacted very strongly to the anti-Pan 1 antiserum, whereas N. sicca, N. flava, and N. mucosa did not react at all. The other commensals tested, N. subflava and N. perflava, exhibited only a minor reaction. These results correlated with the apparent amount of Pan 1 seen on SDS-polyacrylamide gels of outer membranes. SDS-polyacrylamide gel analysis of six meningococcal strains revealed no visible anaerobically induced outer membrane proteins, and the subsequent immunoblots showed only slight or no reaction to the anti-Pan 1 antibody. In the four meningococcal strains that did react slightly with the antiserum, a Pan 1-like protein was seen only in anaerobically grown cells. Thus, meningococci did not express Pan 1 at levels comparable to that found in gonococci; however, when Pan 1 was expressed in meningococcal strains, it was oxygen regulated. This is the first example of a protein found in the gonococcal outer membrane that, under identical growth conditions, is not expressed at similar levels in the meningococcus.

Anaerobiosis

The RNA polymerases of Porphyromonas gingivalis and Fusobacterium nucleatum are unrelated to the RNA polymerase of Escherichia coli.

Western blot analysis that used antisera to the E. coli core enzyme and sigma factors was used for examination of the RNA polymerase of Actinobacillus actinomycetemcomitans, Streptococcus mutans, Fusobacterium nucleatum, and Porphyromonas gingivalis. Both antisera reacted with proteins in A. actinomycetemcomitans and S. mutans whole-cell extracts. Reactions were seen with some F. nucleatum proteins when the anti-core RNA polymerase antisera were used, but the cross-reacting proteins were not of an expected molecular weight for beta or beta'. No reaction with F. nucleatum proteins was seen when extracts were reacted with antisera to E. coli sigma factor. There were no cross-reacting proteins detected in P. gingivalis extracts with either antisera. These results suggest that E. coli RNA polymerase may not be sufficiently similar to P. gingivalis and F. nucleatum RNA polymerase for E. coli RNA polymerase to recognize P. gingivalis or F. nucleatum promoters. Partially purified P. gingivalis and F. nucleatum RNA polymerase exhibited a specificity for a P. gingivalis DNA template, while having a decreased activity from an E. coli DNA template. The antibiotic sensitivity profile of P. gingivalis and F. nucleatum RNA polymerase activity was shown to differ from that of E. coli, with these activities not being affected by rifampicin, streptovaricin, or streptolydigin. We conclude that the efficient cloning and expression of P. gingivalis and F. nucleatum genes in E. coli will require the use of promoter-containing expression vectors.

Bacteroides

Sinus of Valsalva aneurysm presenting with complete heart block.

An elderly woman presented with sudden unresponsiveness and complete heart block and subsequently expired. Postmortem examination revealed an aneurysm of the right sinus of Valsalva impinging on the cardiac conducting tissue. Only a few cases associated with complete heart block have been previously reported.

Aged

Identification of subunits of gonococcal RNA polymerase by immunoblot analysis: evidence for multiple sigma factors.

Heparin-agarose and single-stranded DNA-cellulose chromatography were used to purify RNA polymerase 25-fold from Neisseria gonorrhoeae, and the activity of the polymerase was characterized in altered assay systems. The core subunits (beta, beta', and alpha) were tentatively identified as major proteins copurifying with polymerase activity. The identification of the core subunits was confirmed by Western (immunoblot) analysis with polyclonal antisera to Escherichia coli core RNA polymerase. Gonococcal sigma factor heterogeneity was examined by Western blot analysis with polyclonal antiserum to the major E. coli sigma factor, sigma 70, to the E. coli heat shock sigma factor, sigma 32, and with a monoclonal antiserum to Salmonella typhimurium NtrA (sigma 54). Purified RNA polymerase and whole-cell extracts from type 1, type 4, heat-shocked, and anaerobically grown gonococci were examined. Four putative gonococcal sigma factors were detected in purified RNA polymerase preparations and in whole-cell extracts from all cell types. Two of these bands appeared as a doublet, which had an estimated Mr of 80,000. A single lower-Mr band, estimated to be 40,000, was also present. All three of these bands reacted with antisera to E. coli sigma 70 and to E. coli sigma 32. A fourth gonococcal protein reacted solely with a highly specific monoclonal antibody to sigma 54 and had an Mr of 90,000. We conclude that N. gonorrhoeae may contain multiple sigma factors, which it may use to regulate gene expression.

Animals

Isolation and characterization of an endogenous inhibitor of protein synthesis in Escherichia coli K-12.

A low-molecular-weight factor was isolated from cell extracts of Escherichia coli K-12. The concentration of the factor in cells was dependent upon nutritional conditions, the concentration being higher in faster growing cells. Treatment of cells with colicin K caused an increase in concentration of the factor. The factor inhibited protein synthesis in E. coli. This inhibition was reversible, apparently because of metabolism of the factor. The inhibition of synthesis of beta-galactosidase lasted longer than the inhibition of protein synthesis; cyclic AMP eliminated this difference. The factor inhibited the synthesis of beta-galactosidase from preformed lac mRNA, indicating an inhibition of translation. Kinetic studies of the onset of inhibition of beta-galactosidase synthesis by the factor suggested that the factor may inhibit protein synthesis at the initiation of translation.

Bacterial Proteins

D-alanine incorporation into macromolecules and effects of D-alanine deprivation on active transport in Bacillus subtilis.

An auxotroph of Bacillus subtilis 168 unable to synthesize D-alanine loses the ability to support endogenously energized transport when deprived of D-alanine. Revertants of the mutant retain transport activity. The loss of transport is specific for substrates taken up by active transport; substrates taken up by group translocation are transported at normal rates. The loss of transport can be retarded by pretreatment of the cells with inhibitors of protein synthesis. Since the loss of transport could be due to an alteration in a D-alanine-containing polymer, we investigated the incorporation of D-[14C]alanine into macromolecules. The major D-alanine-containing polymers in B. subtilis are peptidoglycan and teichoic acid, with 4 to 6% of the D-[14C]alanine label found in trypsin-soluble material. Whereas the peptidoglycan and teichoic acid undergo turnover, the trypsin-soluble material does not. Treatment of the trypsin-soluble material with Pronase releases free D-alanine. Analysis of acid-hydrolyzed trypsin-soluble material indicated that approximately 75% of the radioactivity is present as D-alanine, with the remainder present as L-alanine. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of partially purified D-[14C]alanine-labeled membranes indicated the presence of two peaks of radioactivity (molecular weights, 230,000 and 80,000) that could be digested by trypsin. The results suggest that D-alanine may be covalently bound to cellular proteins.

Alanine

Inducible resistance to D-cycloserine in Bacillus subtilis 168.

Resistance to d-cycloserine could be induced in Bacillus subtilis 168 by sublethal concentrations of d-cycloserine. Sensitivity to the antibiotic could be regained by growth in the absence of d-cycloserine. The bactericidal activity of d-cycloserine apparently was not altered by resistant cells, and peptidoglycan synthesis was still inhibited by d-cycloserine in resistant cells. The d-cycloserine resistance apparently resulted from a decreased uptake of the antibiotic. The decrease in d-cycloserine transport could be prevented by simultaneous treatment of the cells with rifampin and d-cycloserine. d-Cycloserine was transported by the same system as glycine in B. subtilis. d-Cycloserine was able to exchange for intracellular glycine in both sensitive and resistant cells, suggesting that d-cycloserine is not excluded from the cell in resistant cultures.

Bacillus subtilis

D-Cycloserine-induced alterations in the transport of D-alanine and glycine in Bacillus subtilis 168.

d-Alanine, l-alanine, and glycine transport was investigated in Bacillus subtilis 168 cells that were phenotypically resistant to d-cycloserine. These cells showed enhanced rates of uptake as compared with that observed in sensitive cells. The usual enhancement in d-alanine and glycine transport resulting from treatment of the cells with d-cycloserine could be prevented by the addition of rifampin. Kinetic analyses of the initial rate of glycine transport indicated an increase in the V(max) for transport in resistant cells, with no alteration in the K(m) for glycine. Investigations of the net transport of glycine revealed that resistant cells maintained a higher gradient of glycine than did sensitive cells. Kinetic analyses of the net transport of glycine suggested that a new system for the accumulation of glycine was present in d-cycloserine-resistant cells.

Alanine

The heat shock response of type 1 and type 4 gonococci.

A heat shock response, characterized by the elevated expression of certain proteins in response to a shift to a higher temperature, has been observed in both eukaryotic and prokaryotic organisms. We have characterized the heat shock response of the pathogenic organism N. gonorrhoeae, colony types 1 and 4. Following a shift up in temperature from 37 C to 43 C, two-dimensional gel electrophoretic analysis was used to identify 19 heat shock proteins in Type 1 and 37 heat shock proteins in Type 4 gonococci. One heat shock protein was found only in Type 1, 19 were common to both Type 1 and Type 4, and 19 were found only in Type 4 gonococci. Most heat shock proteins were found in the cytoplasm, some in the cytoplasmic membrane, and none could be detected in the outer membrane. Pulse-chase experiments revealed that heat shock proteins were very stable.

Autoradiography