Search PubMed⌕ Search

Biomedical subjects

M Gottfredsson

Publications and source records attributed to M Gottfredsson.

15 recordsLinked to original sources
PubMed2001

Extracellular phospholipase activity is a virulence factor for Cryptococcus neoformans.

The human pathogenic fungus Cryptococcus neoformans secretes a phospholipase enzyme that demonstrates phospholipase B (PLB), lysophospholipase hydrolase and lysophospholipase transacylase activities. This enzyme has been postulated to be a cryptococcal virulence factor. We cloned a phospholipase-encoding gene (PLB1) from C. neoformans and constructed plb1 mutants using targeted gene disruption. All three enzyme activities were markedly reduced in the mutants compared with the wild-type parent. The plb1 strains did not have any defects in the known cryptococcal virulence phenotypes of growth at 37 degrees C, capsule formation, laccase activity and urease activity. The plb1 strains were reconstituted using the wild-type locus and this resulted in restoration of all extracellular PLB activities. In vivo testing demonstrated that the plb1 strain was significantly less virulent than the control strains in both the mouse inhalational model and the rabbit meningitis model. We also found that the plb1 strain exhibited a growth defect in a macrophage-like cell line. These data demonstrate that secretory phospholipase is a virulence factor for C. neoformans.

Acyltransferases↗
PubMed2000

Fungal meningitis.

Fungi provide many benefits to humans. However, some of these fungi have the ability to become human pathogens. All the major fungal pathogens can produce meningitis. From the common cryptococcal meningitis to the rare fungal meningitis caused by a dimorphic or filamentous fungus, medical issues are discussed in this review on a fungus-specific basis. Both primary (Cryptococcus, Blastomyces, Histoplasma, Coccidioides, and other dimorphic fungi) and secondary (Aspergillus, Candida, and a series of molds) fungal pathogens can produce life-threatening central nervous system infections. These infections require immediate and precise diagnosis and carefully selected management strategies to optimize outcomes. In this review, we examine the epidemiology, pathogenesis, clinical manifestations, and treatment for fungal meningitis in all the major fungal groups.

Aspergillus fumigatus↗
PubMed2000

Reply.

Explore the source record for details and available documents.

Journal Article↗
PubMed1999

Association of plasma levels of human immunodeficiency virus type 1 RNA and oropharyngeal Candida colonization.

The pathophysiology of oropharyngeal candidiasis in patients infected with human immunodeficiency virus (HIV) type 1 is poorly understood. Association between oropharyngeal yeast carriage and various clinical factors in HIV-1-infected patients was studied in 83 patients with no clinical evidence of thrush and no recent antifungal use. Of the clinical factors measured, the only correlate of yeast colonization was with plasma HIV-1 RNA levels (P=.001), whereas the correlation with CD4 cell count was poor (P=.36). By multivariable regression modeling, plasma HIV-1 RNA was the only parameter that correlated with the extent of colonization with Candida infection (P=.003). These data indicate that the presence and amount of asymptomatic oropharyngeal yeast carriage in persons with HIV-1 infection is more significantly correlated with plasma HIV-1 RNA levels than with CD4 cell count. Further studies on the effect of HIV-1 on oropharyngeal yeast colonization, infection, and local immunity are warranted.

AIDS-Related Opportunistic Infections↗
PubMed1998

Molecular methods for epidemiological and diagnostic studies of fungal infections.

Over the past two decades there has been a remarkable increase in the incidence of invasive fungal infections. Molecular methods, such as karyotyping, restriction analysis and polymerase chain reaction (PCR), have now been applied to improve our current understanding of the epidemiology of these fungal infections. For example, investigations on nosocomial outbreaks of fungal infections have been greatly facilitated by molecular methods. In addition, the ability to diagnose and identify deep-seated mycoses may be enhanced by the use of molecular techniques. In the near future it is possible that PCR-based methods will supplement, or perhaps even replace, traditional methods for detection of Candida albicans blood stream infections, invasive aspergillosis and Pneumocystis carinii pneumonia. This review examines the progress of molecular biology into the clinical arena of fungal epidemiology, laboratory identification and diagnosis.

DNA, Fungal↗
PubMed1998

Characteristics and dynamics of bacterial populations during postantibiotic effect determined by flow cytometry.

Changes in bacterial ultrastructure after antibiotic exposure and during the postantibiotic effect (PAE) have been demonstrated by electron microscopy (EM). However, EM is qualitative and subject to individual interpretation. In contrast, flow cytometry gives qualitative and quantitative information. The sizes and nucleic acid contents of Escherichia coli and Pseudomonas aeruginosa were studied during antimicrobial exposure as well as during the PAE period by staining the organisms with propidium iodide and analyzing them with flow cytometry and fluorescence microscopy. The effects of ampicillin, ceftriaxone, ciprofloxacin, gentamicin, and rifampin were studied for E. coli, whereas for P. aeruginosa imipenem and ciprofloxacin were investigated. After exposure of E. coli to ampicillin, ceftriaxone, and ciprofloxacin, filamentous organisms were observed by fluorescence microscopy. These changes in morphology were reflected by increased forward light scatter (FSC) and nucleic acid content as measured by flow cytometry. For the beta-lactams the extent of filamentation increased in a dose-dependent manner after drug removal, resulting in formation of distinct subpopulations of bacteria. These changes peaked at 20 to 35 min, and bacteria returned to normal after 90 min after drug removal. In contrast, the subpopulations induced by ciprofloxacin did not return to normal until > 180 min after the end of the classically defined PAE. Rifampin resulted in formation of small organisms with low FSC, whereas no distinctive characteristics were noted after gentamicin exposure. For P. aeruginosa an identifiable subpopulation of large globoid cells and increased nucleic acid content was detected after exposure to imipenem. These changes persisted past the PAE, as defined by viability counting. Swollen organisms with increased FSC were detected after ciprofloxacin exposure, even persisting during bacterial growth. In summary, for beta-lactam antibiotics and ciprofloxacin, the PAE is characterized by dynamic formation of enlarged cell populations of increased nucleic acid content, whereas rifampin induces a decrease in size and nucleic acid content in the organisms. Flow cytometry is an ideal method for future studies of bacterial phenotypic characteristics during the PAE.

Anti-Bacterial Agents↗
PubMed1997

Human immunodeficiency virus type I as a target for gene therapy.

Recent progress in our understanding of the human immunodeficiency virus type 1 (HIV-1) life cycle has lead to the identification and characterization of viral genes or gene products that have been evaluated as targets for gene therapy. Virtually every stage in the viral life cycle and every viral gene product is a potential target. Gene therapy approaches directed at several of these viral targets have been successful at inhibiting HIV-1 replication in cultured human cells, but clinical trials involving gene therapy directed at HIV-1 are still in their infancy. This manuscript begins with a brief review of the viral life cycle with an emphasis on the function of viral gene products and then summarizes the gene therapy approaches that have targeted these viral genes or gene products to inhibit HIV-1 replication.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Different patterns of bacterial DNA synthesis during postantibiotic effect.

Studies on bacterial metabolism during the postantibiotic effect (PAE) period are limited but might provide insight into the nature of the PAE. We evaluated the rate of DNA synthesis in bacteria during the PAE period after a 1-h exposure of organisms in the logarithmic growth phase to various antibiotics. Staphylococcus aureus ATCC 25923 was exposed to vancomycin, dicloxacillin, rifampin, and ciprofloxacin; Escherichia coli ATCC 25922 was exposed to gentamicin, tobramycin, rifampin, imipenem, and ciprofloxacin; and Pseudomonas aeruginosa ATCC 25783 was exposed to imipenem, tobramycin, and ciprofloxacin. DNA synthesis was determined by measuring the rate of [3H]thymidine incorporation in S. aureus and E. coli and [3H]adenine incorporation in P. aeruginosa. DNA synthesis in S. aureus was suppressed during the PAE phase with vancomycin, dicloxacillin, and rifampin, it was suppressed in E. coli with rifampin, and it was suppressed in P. aeruginosa after exposure to tobramycin. Conversely, DNA synthesis was relatively enhanced in the gram-negative bacilli after exposure to imipenem and in all three species after exposure to ciprofloxacin. However, DNA synthesis in E. coli was only minimally affected after exposure to tobramycin and gentamicin. The differences in DNA synthesis observed after exposure to various antimicrobial agents suggest multiple mechanisms for the PAE.

Anti-Bacterial Agents↗
PubMed1991

Impact of pH and cationic supplementation on in vitro postantibiotic effect.

Most studies on pharmacodynamic variables in vitro, including the postantibiotic effect (PAE), are performed at pH 7.4 in noncationic-supplemented media, a situation which may differ significantly from the true microenvironment in most infected foci. We studied the impact of five different pH levels (pH 5, 6, 7, 7.4, and 8) on the duration of the PAE, the MIC, and bactericidal activity. Acid pH was found to have in general a deleterious effect on the activity of aminoglycosides and ciprofloxacin against Escherichia coli and Pseudomonas aeruginosa, with the MIC being higher, the bactericidal rate being lower, and the PAE being shorter at pH 5 (and to a lesser extent at pH 6) than at more alkaline pH levels. Similar results were observed for imipenem against P. aeruginosa. The PAEs induced by ampicillin against E. coli and dicloxacillin against Staphylococcus aureus were not predictably dependent on the pH, whereas the PAEs induced by ciprofloxacin against S. aureus were longest at either end of the pH spectrum. The bactericidal activity of these agents was, however, pH dependent, being slower at acid pHs. The addition of 50 mg of Ca2+ and 20 mg of Mg2+ per liter of liquid medium at pH 7.4 did not affect the duration of the PAE. Since the pH in abscess cavities may be close to 5, these observations may be of importance for employment of the agents studied in closed or poorly drained infections.

Anti-Bacterial Agents↗
PubMed1991

Quantitation of postantibiotic effect by measuring CO2 generation of bacteria with the BACTEC blood culture system.

The duration of the postantibiotic effect (PAE) determined by bacterial CO2 production measured by using the BACTEC NR 730 blood culture system was compared with PAEs determined by standard viability counting. PAEs for Staphylococcus aureus after exposure to dicloxacillin, vancomycin, rifampin, gentamicin, and ciprofloxacin and for Escherichia coli after exposure to ampicillin, gentamicin, and ciprofloxacin were quantitated by the two methods, and an excellent correlation (r = 0.93) was demonstrated. The difference in the PAE durations determined by the two methods was 0.1 +/- 0.4 (mean +/- standard deviation) h. Thus, the BACTEC CO2 generation method provides a simple, alternate way of determining the PAE in vitro.

Anti-Bacterial Agents↗
PubMed1990

Metabolic and ultrastructural effects induced by ciprofloxacin in Staphylococcus aureus during the postantibiotic effect (PAE) phase.

The new quinolone antibacterial agents have been found to produce a postantibiotic effect (PAE) of 1-4 h in bacteria but the underlying mechanism is still unknown. After exposure to ciprofloxacin in concentrations of 1-16 x MIC for 1 hr the DNA synthesis in S. aureus ATCC 25923 was investigated during the PAE. Ultrastructure was also investigated by electron microscopy after exposure to a concentration of 2 x MIC. The rate of DNA synthesis per organism (measured as CPM/cfu/ml) increased progressively up to a maximum value at 1 1/2 h after drug removal. The maximal 3H-thymidine incorporation per organism at this moment correlated directly with the duration of the PAE. Bacterial swelling with scarcity and vacuole-formation of the cytoplasm characterized the majority of the staphylococci during the PAE. The physiological importance of the increased DNA synthesis is unknown, but the increased metabolic activity, coincident with increased duration of the PAE, suggests a possible common mechanism.

Ciprofloxacin↗
PubMed1990

The postantibiotic effect induced by antimicrobial combinations.

Antimicrobial combinations are frequently needed for the successful treatment of serious infections. Generally, the same dosing schedules are employed irrespective of whether the drugs are used singly or in combination. A postantibiotic effect (PAE) has been described for all antibiotics used singly against Gram-positive cocci, but only for non-beta-lactams against Gram-negative bacilli with the exception of carbapenems against Pseudomonas aeruginosa. The major clinical relevance of the PAE pertains to its impact on antimicrobial dosing, where agents inducing a long PAE may be administered with longer dosing intervals than currently employed, without loss of efficacy. The purpose of this study was to examine whether PAEs induced by drug combinations differed from the PAEs induced by the drugs alone, and whether a pattern of synergism, addition or antagonism could be defined in this regard. The study organisms, 7 strains of Staphylococcus aureus, 4 strains of Escherichia coli, 4 strains of Klebsiella pneumoniae and 6 strains of Ps. aeruginosa, were exposed to several beta-lactams, aminoglycosides, rifampin and ciprofloxacin singly and in combination. The antimicrobial combinations used against S. aureus affected the PAE in either an additive or an indifferent manner when compared to the PAEs induced by the drugs as single agents. Enhancement of PAEs against Gram-negative bacilli was primarily dependent on the ability of each individual drug to induce a PAE. Thus, for a combination of drugs where both agents induced a PAE individually, the final PAE was a rough mathematical sum of the individual PAEs (addition). When only one of the agents induced a PAE, the final result was similar to the PAE of that particular drug (indifference). Ciprofloxacin seemed to be an exception to this rule, since it did not increase the PAE of a PAE producing drug, despite exhibiting a PAE itself. Rifampin was unique in that it prolonged the PAE in a marked synergistic fashion, when employed with one or more other PAE-producing agents. Further studies in vivo are clearly needed to confirm these observations, but they could have significant impact on the design of dosing regimens for antimicrobial combinations.

Anti-Bacterial Agents↗
PubMedDate not supplied

Ultrastructural alterations of bacteria during the postantibiotic effect.

Ultrastructural alterations of Staphylococcus aureus and Pseudomonas aeruginosa were examined during the postantibiotic effect (PAE) with transmission electron microscopy. After exposure to dicloxacillin the staphylococci were characterized by an increase in the number of crosswalls, rifampin produced thickening of the cell wall, but only minimal changes were induced by gentamicin. Intracellular electrondense aggregates were observed in P. aeruginosa after exposure to imipenem, tobramycin and ciprofloxacin, and imipenem caused globoid cell formations. These alterations were not uniform in every organism, but they correlated well with the duration of the PAE determined by viable counts.

Anti-Bacterial Agents↗