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Biomedical subjects

M Bradshaw

Publications and source records attributed to M Bradshaw.

At least 19 recordsLinked to original sources
PubMed2006

Use of a prophylactic antiemetic with morphine in acute pain: randomised controlled trial.

OBJECTIVE: The aim of this study was to compare the incidence of nausea and vomiting in patients with acute pain treated with morphine along with prophylactic metoclopramide or placebo. METHOD: A randomised controlled trial was carried out on patients requiring morphine for acute pain in the emergency department (ED) setting. Children under the age of 12, patients who had been vomiting or had already received prehospital analgesia, and those unable to give consent were excluded. All patients were given either metoclopramide (10 mg) or placebo (normal saline) followed by intravenous morphine. Pain scores (measured on a visual analogue scale) before and after morphine administration, all incidents of nausea or vomiting, the dose of morphine, and the patients' demographic data were recorded. Fisher's exact test was used for comparing the two groups of patients. RESULTS: A total of 259 patients were recruited. There were 123 patients in the metoclopramide group (age range 15-94 years; median age 53) and 136 patients in the placebo group (age range 17-93 years; median age 52.5). The overall incidence of nausea and vomiting in the whole study population was 2.7%, (1.6% in the metoclopramide group and 3.7% in the placebo group). The difference between the two groups was not statistically significant (Fisher's exact test = 0.451; p = 0.3; z-test statistic = 1.02; 95% CI -6% to 2%). CONCLUSION: When intravenous morphine is administered for acute pain, the overall incidence of nausea and vomiting is low, regardless of whether these patients are given prophylactic metoclopramide or not.

Acute Disease↗
PubMed2005

Prevalence and patterns of cognitive impairment in sporadic ALS.

OBJECTIVE: To investigate the prevalence and nature of cognitive changes associated with sporadic amyotrophic lateral sclerosis (ALS) using a large scale study. METHODS: Consecutive patients with sporadic ALS (n = 279) underwent comprehensive neurologic evaluation and neuropsychological testing. Testing data from normal controls (n = 129) were used for classification and comparison purposes. RESULTS: On non-motor, non-speed-dependent tasks, 51% of patients with ALS had evidence of cognitive impairment compared to 5% of controls. Cluster analysis suggested four patient subgroups: 49% intact, 32% with mild impairment, 13% with moderate impairment, and 6% with severe impairment. Forty-one patients (15%) met criteria for frontotemporal dementia (FTD). ALS patient subgroups, excluding the intact group, performed significantly lower on tests of executive function and memory than normal controls. Patients with more severe disease also had deficits in confrontation naming. Although memory function declined with increasing severity of overall cognitive impairment, only two patients had the severe memory loss typical of Alzheimer disease. Cognitive impairment was correlated with clinical measures of word-finding, phrase length, and motor programming. Cognitive impairment was not correlated with depression scores or severity or duration of motor or bulbar symptoms. Patients with bulbar vs limb-onset ALS were not different in either level of impairment or pattern of performance. CONCLUSIONS: These data confirm the presence of cognitive impairment in 50% of patients with ALS and particularly implicate executive dysfunction and mild memory decline in the disease process. More severe impairment occurs in a subset of patients with ALS and has features consistent with FTD.

Adult↗
PubMed2005

Sequence variation within botulinum neurotoxin serotypes impacts antibody binding and neutralization.

The botulinum neurotoxins (BoNTs) are category A biothreat agents which have been the focus of intensive efforts to develop vaccines and antibody-based prophylaxis and treatment. Such approaches must take into account the extensive BoNT sequence variability; the seven BoNT serotypes differ by up to 70% at the amino acid level. Here, we have analyzed 49 complete published sequences of BoNTs and show that all toxins also exhibit variability within serotypes ranging between 2.6 and 31.6%. To determine the impact of such sequence differences on immune recognition, we studied the binding and neutralization capacity of six BoNT serotype A (BoNT/A) monoclonal antibodies (MAbs) to BoNT/A1 and BoNT/A2, which differ by 10% at the amino acid level. While all six MAbs bound BoNT/A1 with high affinity, three of the six MAbs showed a marked reduction in binding affinity of 500- to more than 1,000-fold to BoNT/A2 toxin. Binding results predicted in vivo toxin neutralization; MAbs or MAb combinations that potently neutralized A1 toxin but did not bind A2 toxin had minimal neutralizing capacity for A2 toxin. This was most striking for a combination of three binding domain MAbs which together neutralized >40,000 mouse 50% lethal doses (LD(50)s) of A1 toxin but less than 500 LD(50)s of A2 toxin. Combining three MAbs which bound both A1 and A2 toxins potently neutralized both toxins. We conclude that sequence variability exists within all toxin serotypes, and this impacts monoclonal antibody binding and neutralization. Such subtype sequence variability must be accounted for when generating and evaluating diagnostic and therapeutic antibodies.

Animals↗
PubMed2001

Planning oral rehabilitation: case-based computer assisted learning in clinical dentistry.

The partially edentulous adult offers a unique and problem-rich resource as a basis for a case-based learning scenario in clinical dentistry in the field of planning oral rehabilitation. However, there is little resource material available to help students negotiate the territory between diagnosis and treatment options of discrete conditions and treatment sequencing once decisions have been made. To address the educational void surrounding the teaching and learning of oral rehabilitation strategies, the authors have developed a CD-ROM 'Interactive Learning in Dentistry: Decision making in the oral rehabilitation of the partially edentulous adult'. The disc emphasises the distinction between 'doing' and 'planning to do' in the decision-making process. After using the disc the students should be able to apply a generic framework to formulate a custom oral rehabilitation plan for their own patient. The disc was evaluated by final-year students from the Faculty of Dentistry, University of Sydney. Response to the program was essentially positive and comments from students have impacted on further development.

Adult↗
PubMed2001

Clostridium botulinum and its neurotoxins: a metabolic and cellular perspective.

Clostridium botulinum comprises a diverse assemblage of clostridia that have the common property of producing a distinctive protein neurotoxin (BoNT) of similar pharmacological activity and extraordinary potency. BoNTs are produced in culture as molecular complexes consisting of BoNT, hemagglutinin (HA) and associated subcomponent proteins, nontoxic nonhemagglutinin (NTNH), and RNA. The genes encoding the protein components reside as a cluster on the chromosome, on bacteriophages, or on plasmids depending on the C. botulinum serotype. A gene BotR coding for a regulatory protein has been detected in toxin gene clusters from certain strains, as well as ORFs coding for uncharacterized components. The gene encoding TeNT is located on a large plasmid, and expression of the structural gene is controlled by the regulatory gene, TetR, located immediately upstream of the TeNT structural gene. TeNT is not known to be assembled into a protein/nucleic acid complex in culture. Cellular synthesis of BoNT and TeNT have been demonstrated to be positively regulated by the homologous proteins, BotR/A and TetR. Evidence suggests that negative regulatory factors and general control cascades such as those involved in nitrogen regulation and carbon catabolite repression also regulate synthesis of BoNTs. Neurotoxigenic clostridia have attracted considerable attention from scientists and clinicians during the past decade, and many excellent reviews are available on various aspects of these organisms and their neurotoxins. However, certain areas have not been well-studied, including metabolic regulation of toxin formation and genetic tools to study neurotoxigenic clostridia. These topics are the focus of this review.

Animals↗
PubMed2001

Subantimicrobial dose doxycycline as an adjunct to scaling and root planing: post-treatment effects.

BACKGROUND/OBJECTIVE: Subantimicrobial dose doxycycline (SDD 20 mg bid) plus scaling and root planing (SRP) significantly improved clinical attachment level (CAL) and reduced probing depth (PD) compared with placebo plus SRP in a double-blind, placebo-controlled, multicenter study of patients with adult periodontitis (AP). In a study conducted as a follow-up, the post-treatment effects of SDD were assessed in patients who completed the SRP study. METHODS: The SRP study was a 9-month, active-treatment study and the follow-up was a 3-month, no-treatment study. In the SRP study, tooth sites in qualifying quadrants were scaled and root planed and patients were randomized to receive twice daily SDD 20 mg or placebo. In the follow-up, patients received no study drug; investigators and patients remained blinded to the previous treatment group assignments. Efficacy measures included the change in CAL and PD from baseline values determined at the start of the SRP study in tooth sites stratified by baseline PD (i.e., 0-3 mm, 4-6 mm, > or =7 mm). Safety was evaluated using adverse event data and the results of clinical laboratory tests, oral pathology examinations, and microbiological assessments. RESULTS: Within each disease stratum, the incremental improvements in PD and CAL demonstrated in the SDD group over 9 months of active treatment were maintained through 3 additional months of no treatment. Treatment cessation did not result in an accelerated regression of periodontal health. No differences in the incidence of adverse events (including those related to infection) or laboratory or microbiological parameters were noted between the SDD group and the placebo group. CONCLUSIONS: The administration of SDD 20 mg bid for a period of up to 9 months is not associated with rebound effects or delayed or negative after-effects for a 3-month period after cessation of therapy.

Adult↗
PubMed2000

Cloning, nucleotide sequence, and expression of the gene encoding the bacteriocin boticin B from Clostridium botulinum strain 213B.

Boticin B is a heat-stable bacteriocin produced by Clostridium botulinum strain 213B that has inhibitory activity against various strains of C. botulinum and related clostridia. The gene encoding the bacteriocin was localized to a 3.0-kb HindIII fragment of an 18. 8-kb plasmid, cloned, and sequenced. DNA sequencing revealed the boticin B structural gene, btcB, to be an open reading frame encoding 50 amino acids. A C. botulinum strain 62A transconjugant containing the HindIII fragment inserted into a clostridial shuttle vector expressed boticin B, although at much lower levels than those observed in C. botulinum 213B. To our knowledge, this is the first demonstration and characterization of a bacteriocin from toxigenic group I C. botulinum.

Amino Acid Sequence↗
PubMed2000

Treatment with subantimicrobial dose doxycycline improves the efficacy of scaling and root planing in patients with adult periodontitis.

BACKGROUND: In a previous study, subantimicrobial dose doxycycline (SDD) significantly improved clinical parameters associated with periodontal health in patients with adult periodontitis (AP) when used as an adjunct to a maintenance schedule of supragingival scaling and dental prophylaxis. In this double-blind, placebo-controlled, parallel-group, multicenter study, the efficacy and safety of SDD were evaluated in conjunction with scaling and root planing (SRP) in patients with AP. METHODS: Patients (n = 190) received SRP at the baseline visit and were randomized to receive either SDD 20 mg bid or placebo bid for 9 months. Efficacy parameters included the per-patient mean changes in clinical attachment level (CAL) and probing depth (PD) from baseline, the per-patient percentages of tooth sites with attachment loss (AL) > or = 2 mm and > or = 3 mm from baseline, and the per-patient percentage of tooth sites with bleeding on probing. Prior to analysis, tooth sites were stratified by the degree of disease severity evident at baseline RESULTS: In tooth sites with mild to moderate disease and severe disease (n = 183, intent-to-treat population), improvements in CAL and PD were significantly greater with adjunctive SDD than with adjunctive placebo at 3, 6, and 9 months (all P <0.05). In tooth sites with severe disease, the per-patient percentage of sites with AL > or = 2 mm from baseline to month 9 was significantly lower with adjunctive SDD than with adjunctive placebo (P<0.05). Improvements in clinical outcomes occurred without detrimental shifts in the normal periodontal flora or the acquisition of doxycycline resistance or multiantibiotic resistance. SDD was well tolerated, with a low incidence of discontinuations due to adverse events. CONCLUSIONS: The adjunctive use of SDD with SRP is more effective than SRP alone and may represent a new approach in the long-term management of AP.

Adult↗
PubMed2000

Long-term use of subantimicrobial dose doxycycline does not lead to changes in antimicrobial susceptibility.

BACKGROUND: Adjunctive subantimicrobial dose doxycycline (SDD) with scaling and root planing leads to improved clinical parameters of adult periodontitis, but has raised questions about potential changes in antibiotic susceptibility of the host microflora. Our four studies assessed whether long-term SDD changes antibiotic susceptibility of the oral microflora in adults with periodontitis. METHODS: In studies 1 and 2, adult patients with periodontitis were randomized to receive SDD 10 mg qd, 20 mg qd, 20 mg bid, or placebo. In study 3, patients were randomized to receive SDD 20 mg bid or placebo. No medication was administered in study 4, a follow-up to study 3. Subgingival plaque samples were collected at baseline (all studies) and at 12, 15 to 18, and 24 months (study 1); 12, 18, and 27 months (study 2); 3, 6, and 9 months (study 3); and 3 months post-study 3 (study 4). Antimicrobial susceptibility of isolated bacteria was assessed by: 1) minimum inhibitory concentration (MIC) levels (studies 1 and 2); 2) cross-resistance to non-tetracycline antibiotics (studies 2 and 3); and 3) the proportion of doxycycline-resistant isolates (studies 3 and 4). RESULTS: Organism MIC levels remained constant among all treatment groups at 18 and 24 months compared with baseline (study 1). Observed changes in susceptibility at 12 and 18 months for the 20 mg groups were attributed to the limited number of isolates tested (study 1). There were no statistically significant differences in the proportion of doxycycline-resistant isolates among treatment groups (studies 3 and 4), and no evidence of multi-antibiotic resistance (studies 3 and 4) or cross-resistance (studies 2 and 3) at any timepoint. CONCLUSION: Long-term SDD does not contribute to changes in antibiotic susceptibility.

Actinomyces↗
PubMed1998

Conjugative transfer of the Escherichia coli-Clostridium perfringens shuttle vector pJIR1457 to Clostridium botulinum type A strains.

An RP4-oriT shuttle vector pJIR1457 originally developed for Clostridium perfringens was successfully transferred by conjugation from Escherichia coli to Clostridium botulinum type A strains and to a nontoxigenic C. botulinum type A-transposon Tn916 mutant strain lacking the entire toxin gene cluster. The light chain (LC) of botulinum toxin was highly expressed in the toxin deletion mutant strain from a pJIR1457 construct containing the recombinant botulinal gene for LC. This shuttle vector system will be valuable for genetic analysis of C. botulinum and will enable genetic manipulation and recombinant expression studies of botulinum neurotoxins as pharmaceutical agents.

Botulinum Toxins↗
PubMed1998

An interactive multimedia solution to learning removable partial denture design.

Surveys of the dental profession and dental laboratories show that up to 60% of cases received by laboratories have little or no input from dentists into the design of their patients' removable partial dentures (RPD). Thus, there is a clear mandate for dental schools to teach RPD design in new ways that will give their students confidence and allow their graduates to approach the task readily and easily. This computer-aided learning program addresses that need. In designing it, we have exploited the unique properties of computers as a learning tool. The program uses Quicktime VR to simulate a three-dimensional perspective of diagnostic casts. It is also possible to incorporate animated diagrams to illustrate various points. Control of timed answers promotes the use of inquiry-based learning and allows the program to be interactive and completely problem-oriented. Students can practice at their own pace, on a variety of virtual cases, and thus learn the craft behind the art of designing RPDs. With this foundation, discussions with experts in the field regarding the patients they treat in senior years and as graduates can be conducted at a higher and more productive level. Student evaluation so far has been very encouraging.

Computer-Assisted Instruction↗
PubMed1996

Activation of adenosine A3 receptors on macrophages inhibits tumor necrosis factor-alpha.

Murine macrophage-derived tumor necrosis factor alpha (TNF-alpha) gene expression has been shown to be dramatically induced by bacterial lipopolysaccharide, and to be dependent upon nuclear factor-kappa B (NF-kappa B) binding sites in its promoter for the lipopolysaccharide induction. Murine J774.1 macrophage cells were found to predominantly express the adenosine A3 receptor RNA relative to adenosine A1 receptor or adenosine A2 receptor RNA. Adenosine receptor agonists, in a dose-dependent manner characteristic of the adenosine A3 receptor, blocked the endotoxin induction of the TNF-alpha gene and TNF-alpha protein expression in the J774.1 macrophage cell line. The adenosine A3 receptor antagonist BW-1433 dose-dependently reversed this adenosine inhibitory effect on TNF-alpha gene expression. Thus, the binding of adenosine receptor agonists to the adenosine A3 receptor interrupts the endotoxin CD14 receptor signal transduction pathway and blocks induction of cytokine TNF-alpha, revealing a novel cross-talk between the murine adenosine A3 receptor and the endotoxin CD14 receptor in J774.1 macrophages.

Animals↗
PubMed1995

Development of bovine microsatellite markers from a microsatellite-enriched library.

A bovine genomic library enriched for DNA fragments bearing poly(dC-dA).poly(dG-dT) sequences was prepared and screened. Twenty-four clones bearing microsatellites were subject to sequence analysis and marker development as appropriate. Three of the 24 clones had microsatellites that were not evaluated for marker development owing to presence of a satellite element in two cases and limited repeat length in the third. Of the remaining 21 clones, all but one yielded polymorphic microsatellites. All but two of the polymorphic markers could be assigned to chromosomal locations by either linkage analysis or on the basis of X-linked inheritance as determined by heterozygosity limited to females. An unexpected clustering of markers was observed as 4 of the 20 polymorphic microsatellites mapped to a region of less than approximately 30 cM on Chromosome (Chr) 19, and four markers displayed X-linked inheritance.

Animals↗
PubMed1995

Polymerase chain reaction based genotyping for characterization of SLA-DQB and SLA-DRB alleles in domestic pigs.

Molecular genotyping of swine major histocompatibility complex SLA-DQB and SLA-DRB genes using polymerase chain reaction (PCR)-based amplification is described. Locus-specific oligonucleotide primers were designed for the analysis of expressed SLA genes by reverse transcription-polymerase chain reaction (RT-PCR). RT-PCR products were sequenced, and the information gained was used to design primers for PCR genotyping of the exon 2 (beta 1) region from genomic DNA templates. A single segregating amplification product was detected for both DQB and DRB in all animals. PCR products were digested with restriction enzymes. Seven SLA-DQB PCR-restriction fragment length polymorphism (RFLP) pattern types were observed for both HaeIII and RsaI that defined 14 SLA-DQB alleles. A total of seven SLA-DRB PCR-RFLP pattern types were defined using MspI (3 RFLP pattern types) and RsaI (6 RFLP pattern types). In order to demonstrate their universal utility, the primers were tested on genomic DNA samples from 10 different swine breeds. No breed-specific alleles were observed. These results show that locus-specific oligonucleotide primers and RFLP analysis provide a simple and rapid method for genotyping expressed SLA-DQB and SLA-DRB from genomic DNA.

Alleles↗
PubMed1995

Specific transcriptional inhibition of bone marrow-derived macrophage tumor necrosis factor-alpha gene expression and protein production using novel enantiomeric carbocyclic nucleoside analogues.

Tumor necrosis factor-alpha (TNF-alpha) is a powerful macrophage-derived proinflammatory cytokine, via both direct effects on host tissues as well as indirectly through the induction of other proinflammatory mediators, including interleukin- (IL) 1 beta and IL-6. Activation of murine bone marrow-derived macrophages (BMDM phi) with lipopolysaccharide (LPS) causes rapid expression of TNF-alpha, which as an autocrine factor enhances BMDM phi function through IL-1 beta and IL-6 production. In this study, we have examined the specific transcriptional inhibition of BMDM phi TNF-alpha using novel enantiomeric carbocyclic nucleoside analogues. BMDM phi were derived in vitro from murine bone marrow progenitors using colony stimulating factor-1 and treated with combinations of LPS (1-100 nG/ml) and the enantiomeric carbocyclic nucleoside (10-100 microM) analogues MDL 201, 112 (9-[(1S,3R)-cis-cyclopentan-3-ol]adenine); MDL 201,451 (9-[1R,3S)-cis-cyclopentan-3-ol]adenine); MDL 201,449 (9-[(1R,3R)-trans-cyclopentan-3-ol]adenine) and MDL 201,484 (9-[(1S,3S)-trans-cyclopentan-3-ol]adenine). Northern blot analysis showed that MDL 201,449 was the most effective agent in vitro at selectively inhibiting TNF-alpha. MDL 201,449 reduced TNF-alpha mRNA levels by nearly 50% for up to 4 hr after the simultaneous addition of LPS and the synthetic agent. In contrast, mRNA and secreted protein levels for IL-1 beta (measured by the D10.S bioassay) and mRNA for TNF-alpha receptor p60 and TNF-alpha receptor p80 were not significantly affected. Carbocyclic nucleoside analogues were effective when added to BMDM phi up-to 2 hr after LPS treatment and at concentrations as low as 10 microM. Regulation of BMDM phi IL-6 by carbocyclic nucleoside analogues in response to LPS appears to be both concentration and time dependent, because IL-6 mRNA and secreted protein levels were inhibited at only high drug concentrations (100 microM) and effective only at longer exposure times (+4 hr of incubation) to LPS. These data support the concept that M phi-derived proinflammatory cytokine gene expression is differentially, rather than coordinately, regulated by selective signal transduction and/or molecular pathways. Enantiomeric carbocyclic nucleoside analogues that specifically inhibit TNF-alpha may have therapeutic potential in inflammatory diseases, such as systemic inflammatory response syndrome, where TNF-alpha has been shown to have an important role in initiating the early stages of disease.

Adenine↗