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Biomedical subjects

N Firth

Publications and source records attributed to N Firth.

At least 19 recordsLinked to original sources

Oral lesions in scurvy.

Scurvy is the nutritional deficiency state associated with lowered levels of ascorbic acid (vitamin C). Lack of ascorbic acid leads to suppression of collagen synthesis and the synthesis of defective collagen among other metabolic derangements. Weakening of vascular walls results in signs and symptoms mimicking other diseases such as bleeding diatheses and deep vein thrombosis. Scurvy is rarely encountered in Western countries where there is a broad community understanding of the importance of nutritional requirements and where foods containing ascorbic acid are readily available. As a result of these factors early diagnosis may be hampered where it is not considered in the differential diagnosis, and consequently, prolonged suffering of the patient. Scurvy is easily treated with high doses of oral ascorbic acid, although recurrences may occur. Education of health care providers in recognizing the signs and symptoms of scurvy therefore cannot be over emphasized, particularly in societies in which nutritional deficiencies are considered uncommon. A case of scurvy presenting primarily with oral manifestations is reported here.

Adult↗

In vitro resistance of Staphylococcus aureus to thrombin-induced platelet microbicidal protein is associated with alterations in cytoplasmic membrane fluidity.

Platelet microbicidal proteins (PMPs) are small, cationic peptides which possess potent microbicidal activities against common bloodstream pathogens, such as Staphylococcus aureus. We previously showed that S. aureus strains exhibiting resistance to thrombin-induced PMP (tPMP-1) in vitro have an enhanced capacity to cause human and experimental endocarditis (T. Wu, M. R. Yeaman, and A. S. Bayer, Antimicrob. Agents Chemother. 38:729-732, 1994; A. S. Bayer et al., Antimicrob. Agents Chemother. 42:3169-3172, 1998; V. K. Dhawan et al., Infect. Immun. 65:3293-3299, 1997). However, the mechanisms mediating tPMP-1 resistance in S. aureus are not fully delineated. The S. aureus cell membrane appears to be a principal target for the action of tPMP-1. To gain insight into the basis of tPMP-1 resistance, we compared several parameters of membrane structure and function in three tPMP-1-resistant (tPMP-1(r)) strains and their genetically related, tPMP-1-susceptible (tPMP-1(s)) counterpart strains. The tPMP-1(r) strains were derived by three distinct methods: transposon mutagenesis, serial passage in the presence of tPMP-1 in vitro, or carriage of a naturally occurring multiresistance plasmid (pSK1). All tPMP-1(r) strains were found to possess elevated levels of longer-chain, unsaturated membrane lipids, in comparison to their tPMP-1(s) counterparts. This was reflected in corresponding differences in cell membrane fluidity in the strain pairs, with tPMP-1(r) strains exhibiting significantly higher degrees of fluidity as assessed by fluorescence polarization. These data provide further support for the concept that specific alterations in the cytoplasmic membrane of S. aureus strains are associated with tPMP-1 resistance in vitro.

Amino Acids↗

An IS257-derived hybrid promoter directs transcription of a tetA(K) tetracycline resistance gene in the Staphylococcus aureus chromosomal mec region.

Transcription of the tetA(K) tetracycline resistance determinant encoded by an IS257-flanked cointegrated copy of a pT181-like plasmid, located within the chromosomal mec region of a methicillin-resistant Staphylococcus aureus isolate, has been investigated. The results demonstrated that transcription of tetA(K) in this strain is directed by both an IS257-derived hybrid promoter, which is stronger than the native tetA(K) promoter in the autonomous form of pT181, and a complete outwardly directed promoter identified within one end of IS257. Despite lower gene dosage, the chromosomal configuration was shown to afford a higher level of resistance than that mediated by pT181 in an autonomous multicopy state. Furthermore, competition studies revealed that a strain carrying the chromosomal tetA(K) determinant exhibited a higher level of fitness in the presence of tetracycline but not in its absence. This finding suggests that tetracycline has been a selective factor in the emergence of strains carrying a cointegrated pT181-like plasmid in their chromosomes. The results highlight the potential of IS257 to influence the expression of neighboring genes, a property likely to enhance its capacity to mediate advantageous genetic rearrangements.

Anti-Bacterial Agents↗

Replication of staphylococcal multiresistance plasmids.

Based on structural and functional properties, three groups of large staphylococcal multiresistance plasmids have been recognized, viz., the pSK1 family, pSK41-like conjugative plasmids, and beta-lactamase-heavy-metal resistance plasmids. Here we describe an analysis of the replication functions of a representative of each of these plasmid groups. The replication initiation genes from the Staphylococcus aureus plasmids pSK1, pSK41, and pI9789::Tn552 were found to be related to each other and to the Staphylococcus xylosus plasmid pSX267 and are also related to rep genes of several plasmids from other gram-positive genera. Nucleotide sequence similarity between pSK1 and pI9789::Tn552 extended beyond their rep genes, encompassing upstream divergently transcribed genes, orf245 and orf256, respectively. Our analyses revealed that genes encoding proteins related to the deduced orf245 product are variously represented, in several types of organization, on plasmids possessing six seemingly evolutionarily distinct types of replication initiation genes and including both theta-mode and rolling-circle replicons. Construction of minireplicons and subsequent functional analysis demonstrated that orf245 is required for the segregational stability of the pSK1 replicon. In contrast, no gene equivalent to orf245 is evident on the conjugative plasmid pSK41, and a minireplicon encoding only the pSK41 rep gene was found to exhibit a segregational stability approaching that of the parent plasmid. Significantly, the results described establish that many of the large multiresistance plasmids that have been identified in clinical staphylococci, which were formerly presumed to be unrelated, actually utilize an evolutionarily related theta-mode replication system.

Amino Acid Sequence↗

Nucleotide sequence of the F plasmid leading region.

The entire nucleotide sequence of the first DNA segment of the conjugative F plasmid to enter the recipient cell, the leading region, is described. Analysis of the sequence provides further evidence that products encoded within the 13.2-kb leading region are likely to be expressed and perform functions associated with the transferred strand in the recipient cell.

Amino Acid Sequence↗

Plasmid-mediated resistance to thrombin-induced platelet microbicidal protein in staphylococci: role of the qacA locus.

Thrombin-induced platelet microbicidal protein 1 (tPMP-1) is a small, cationic peptide released from rabbit platelets following thrombin stimulation. In vitro resistance to this peptide among strains of Staphylococcus aureus correlates with the survival advantage of such strains at sites of endothelial damage in humans as well as in experimental endovascular infections. The mechanisms involved in the phenotypic resistance of S. aureus to tPMP-1 are not fully delineated. The plasmid-encoded staphylococcal gene qacA mediates multidrug resistance to multiple organic cations via a proton motive force-dependent efflux pump. We studied whether the qacA gene might also confer resistance to cationic tPMP-1. Staphylococcal plasmids encoding qacA were found to confer resistance to tPMP-1 in an otherwise susceptible parental strain. Deletions which removed the region containing the qacA gene in the S. aureus multiresistance plasmid pSK1 abolished tPMP-1 resistance. Resistance to tPMP-1 in the qacA-bearing strains was inoculum independent but peptide concentration dependent, with the level of resistance decreasing at higher peptide concentrations for a given inoculum. There was no apparent cross-resistance in qacA-bearing strains to other endogenous cationic antimicrobial peptides which are structurally distinct from tPMP-1, including human neutrophil defensin 1, protamine, or the staphylococcal lantibiotics pep5 and nisin. These data demonstrate that the staphylococcal multidrug resistance gene qacA also mediates in vitro resistance to cationic tPMP-1.

Animals↗

Mobile elements in the evolution and spread of multiple-drug resistance in staphylococci.

Since the introduction of antimicrobial chemotherapy, staphylococci have shown a remarkable propensity to develop drug resistance. As a result, strains have evolved that are resistant to most classes of clinically useful antimicrobial agents. The emergence of these multiply-drug-resistant strains is primarily due to the capture of pre-existent resistance genes. In combination with plasmids and gene transfer mechanisms, mobile genetic elements have been central to the acquisition and dissemination of this resistance. In particular they have played a significant role in the assembly of drug-resistance gene clusters in these multiply-resistant staphylococci.

Journal Article↗

A retrospective molecular analysis of gentamicin resistance in Staphylococcus aureus strains from UK hospitals.

The composite transposon Tn4001 and a related chromosomal Tn4001-like element, encode resistance to the aminoglycosides gentamicin, tobramycin and kanamycin (GmTmKmr) in Australian strains of Staphylococcus aureus. Southern hybridisation analysis of GmTmKmr S. aureus strains isolated from various hospitals in the UK between 1975 and 1985 indicated that they predominantly encoded chromosomal copies of Tn4001 or a Tn4001-like element. However, a strain isolated in 1985 was found to carry Tn4001 on a plasmid related to pSK1, the prototypical multiresistance plasmid commonly detected in S. aureus strains from Australian hospitals.

Anti-Bacterial Agents↗

Focal epithelial hyperplasia in an HIV positive man. An illustrated case and review of the literature.

Focal epithelial hyperplasia (FEH) is a rare but distinctive entity of viral aetiology with characteristic clinical and histopathological features. It is usually seen in children and adolescents of American Indian and Eskimo background; however, it has recently been described in adults who are HIV positive. Suppression of the immune system leaves the individual vulnerable to opportunistic infections. With improved management of immunocompromised patients it is increasingly possible that the general dental practitioner will encounter secondary oral infections such as FEH and must therefore be able to recognize, diagnose and treat these lesions. The following report presents a case of FEH in an HIV-infected man, and is followed by a review of the literature.

AIDS-Related Opportunistic Infections↗

Complete nucleotide sequence of pSK41: evolution of staphylococcal conjugative multiresistance plasmids.

The 46.4-kb nucleotide sequence of pSK41, a prototypical multiresistance plasmid from Staphylococcus aureus, has been determined, representing the first completely sequenced conjugative plasmid from a gram-positive organism. Analysis of the sequence has enabled the identification of the probable replication, maintenance, and transfer functions of the plasmid and has provided insights into the evolution of a clinically significant group of plasmids. The basis of deletions commonly associated with pSK41 family plasmids has been investigated, as has the observed insertion site specificity of Tn552-like beta-lactamase transposons within them. Several of the resistance determinants carried by pSK41-like plasmids were found to be located on up to four smaller cointegrated plasmids. pSK41 and related plasmids appear to represent a consolidation of antimicrobial resistance functions, collected by a preexisting conjugative plasmid via transposon insertion and IS257-mediated cointegrative capture of other plasmids.

Amino Acid Sequence↗

Molecular evolution of multiply-antibiotic-resistant staphylococci.

Methicillin-resistant Staphylococcus aureus (MRSA) is an intractable nosocomial pathogen. The chemotherapeutic intransigence of this organism stems from its predilection to antimicrobial resistance as a consequential response to selective pressures prevailing in the clinical environment. MRSA isolates are frequently resistant to all practicable antimicrobials except the glycopeptide, vancomycin. Although antimicrobial resistance sometimes arises via chromosomal mutation, the emergence of multiply-antibiotic-resistant staphylococci is primarily due to the acquisition of pre-existent resistance genes; such determinants can be encoded chromosomally or by plasmids and are often associated with transposons or insertion sequences. Clinical staphylococci commonly carry one or more plasmids, ranging from small replicons that are phenotypically cryptic or contain only a single resistance gene, to larger episomes that possess several such determinants and sometimes additionally encode systems that mediate their own conjugative transmission and the mobilization of other plasmids. The detection of closely related plasmids, elements and/or genes in other hosts, including coagulase-negative staphylococci and enterococci, attests to interspecific and intergeneric genetic exchange facilitated by mobile genetic elements and DNA transfer mechanisms. The extended genetic reservoir accessible to staphylococci afforded by such horizontal gene flux is fundamental to the acquisition, maintenance and dissemination of staphylococcal antimicrobial resistance in general, and multiresistance in particular.

Drug Resistance, Microbial↗

Molecular analysis of a mobilizable theta-mode trimethoprim resistance plasmid from coagulase-negative staphylococci.

The Staphylococcus epidermidis plasmid pSK639 is the prototype of a newly described family of small plasmids identified in clinical staphylococcal isolates. pSK639 is 8 kb in length and possesses a composite structure consisting of an IS257-flanked segment mediating trimethoprim resistance (Tpr), and regions responsible for replication and mobilization of the plasmid. Comparative sequence analysis suggests that a pSK639-like plasmid may represent a progenitor of previously identified staphylococcal Tpr determinants related to the transposon-like structure, Tn4003. In contrast to the small staphylococcal plasmids characterized to date that all utilize a rolling circle mode of replication, the replication region of pSK639 was found to contain features typical of an iteron-controlled theta-mode replicon. pSK639 is the first small plasmid of this type to be identified in the staphylococci.

Amino Acid Sequence↗

IS257-mediated cointegration in the evolution of a family of staphylococcal trimethoprim resistance plasmids.

Analyses of the Staphylococcus epidermidis multiresistance plasmids pSK697 and pSK818 have revealed them to be closely related to the trimethoprim resistance plasmid pSK639, also isolated from S. epidermidis. pSK697 and pSK818 were found to contain a cointegrated copy of a second plasmid related to the S. epidermidis multidrug antiseptic and disinfectant resistance plasmid pSK108 and the S. aureus tetracycline resistance plasmid pT181, respectively. In contrast to pSK639, both plasmids were found to contain a third copy of IS257, such that the integrated plasmids in both cases are flanked by a copy of this element. This organization and the presence of duplicated sequences at the extremities of the integrated plasmids implicate IS257 in the formation of these cointegrate plasmids. Sequence analysis of the IS257 elements from these plasmids has provided insights into the probable mechanism of cointegration, viz., nonresolved replicative transposition of IS257.

Amino Acid Sequence↗

Multidrug resistance plasmid pSK108 from coagulase-negative staphylococci; relationships to Staphylococcus aureus qacC plasmids.

The 2.4-kb Staphylococcus epidermidis plasmid, pSK108, encodes a qacC multidrug resistance determinant. Sequence analysis has revealed that pSK108 is a member of the pC194 family of rolling circle replicating plasmids and suggests that the DNA segment containing qacC, which is bounded by the replication nick site and the minus origin palA, represents a resistance gene cassette that has undergone horizontal genetic exchange.

Amino Acid Sequence↗

Mucopolysaccharidosis: MPS VI and associated delayed tooth eruption.

Eight cases of mucopolysaccharidosis Type VI (Maroteaux-Lamy syndrome) are reviewed and two cases are presented in detail. Developmental dental anomalies including unerupted and impacted permanent teeth and associated hyperplastic tooth follicles are seen frequently in MPS patients. The surgical implications and management are discussed. All patients reviewed had significant cardiovalvular disease. It is essential for the primary medical provider to establish early basic dental care and evaluation for delayed eruption of primary and permanent dentition. This will probably minimize the possibility of infective endocarditis and allow for early treatment of impacted teeth.

Child↗