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Biomedical subjects

S J Dawson

Publications and source records attributed to S J Dawson.

At least 19 recordsLinked to original sources
PubMed2006

A phase I/II trial of celecoxib with chemotherapy and radiotherapy in the treatment of patients with locally advanced oesophageal cancer.

BACKGROUND: The study's aim was to determine the maximum tolerated dose (MTD) of celecoxib combined with chemoradiotherapy (CRT) for locally advanced oesophageal cancer (OC). METHODS: CRT comprised of 5FU (1000 mg/m(2)/day, days 1-4, weeks 1 & 5), cisplatin (75 mg/m(2), days 1 & 29) and radiotherapy (50 Gy in 25 fractions or 50.4 Gy in 28 fractions). Celecoxib was given daily during CRT at one of five doses (200 mg bd to 600 mg bd). Three to six patients were assigned per dose. RESULTS: Thirteen patients were recruited before trial closure due to external safety concerns regarding celecoxib. Median follow up was 17 months (95% CI 9 - >39). The highest administered dose was 400 mg bd (n=4) with one dose-limiting toxicity at this level: grade 3 rash. Five (38%) and 8(62%) patients had grade 3 non-haematological and haematological toxicities respectively. No grade 4 toxicities occurred. Radiological response rate was 54% (n=7: all CR). Six patients had resection with one pathological CR. Median progression-free and overall survival were 8.8 (95% CI 5.1 - >24.8) and 19.6 months (95% CI 7.3 - >39) respectively. CONCLUSIONS: A MTD was not reached. The regimen was tolerable, indicating that celecoxib can be safely administered with CRT for locally advanced OC.

Adenocarcinoma↗
PubMed2006

Listeria outbreak associated with sandwich consumption from a hospital retail shop, United Kingdom.

An outbreak of listeriosis occurred in the Swindon area of the UK in autumn 2003. Five cases were detected in pregnant women. Four of these women were thought to have eaten prepacked sandwiches from a retail outlet in one particular hospital. Sampling at the supplier detected Listeria monocytogenes, which was indistinguishable on molecular testing from the patients isolates. Recent changes in UK food legislation should help diminish the risk of further outbreaks/cases such as ours occurring.

Disease Outbreaks↗
PubMed2004

Survey, characterization and susceptibility to fusidic acid of Staphylococcus aureus in the Carmarthen area.

OBJECTIVE: This retrospective study was designed to investigate the possible reasons for an apparent increase in fusidic acid resistance among Staphylococcus aureus. MATERIALS AND METHODS: The Datastore records of the Communicable Disease Surveillance Centre, Wales, UK were reviewed in conjunction with information concerning the prescribing of fusidic acid. RESULTS: During the 5 year study period (1997-2001), a rise in the incidence of fusidic acid resistance was noted, particularly among paediatric patients presenting with infected eczema and impetigo, which may be related to the observed increase in prescriptions of topical fusidic acid. Extended phenotypic and genotypic characterization of a limited number (n=31) of isolates from 2002 showed that fusidic acid-resistant strains of S. aureus were typically from patients with impetigo and isolates fell into a single clonal group. Conversely, isolates from other skin disease (eczema, dermatitis and abscesses) were usually susceptible to fusidic acid and proved a diverse group. CONCLUSION: This study provides valuable data on the prevalence of fusidic acid-resistant S. aureus, the genetic background of the strains, and their association with clinical disease in both the healthcare environment and community setting in the catchment area served by the Laboratory.

Adolescent↗
PubMed2003

The role of the infection control link nurse.

Link nurses act as a link between their own clinical area and the infection control team. Their role is to increase awareness of infection control issues in their ward and motivate staff to improve practice. It is essential that they receive training from the infection control team to ensure their competence. They have been shown to be of value to Trusts by improving clinical ward audit scores, helping infection control nurses implement policies and collecting data on hospital-acquired infections. In some hospitals, however, there are operational difficulties for link nurse schemes including high turnover of staff and insufficient time for training and monitoring their effectiveness.

Attitude of Health Personnel↗
PubMed2001

The human CD8 coreceptor effects cytotoxic T cell activation and antigen sensitivity primarily by mediating complete phosphorylation of the T cell receptor zeta chain.

Recognition of antigen by cytotoxic T lymphocytes (CTL) is determined by interaction of both the T cell receptor and its CD8 coreceptor with peptide-major histocompatibility complex (pMHC) class I molecules. We examine the relative roles of these receptors in the activation of human CTL using mutations in MHC class I designed to diminish or abrogate the CD8/pMHC interaction. We use surface plasmon resonance to determine that point mutation of the alpha3 loop of HLA A2 abrogates the CD8/pMHC interaction without affecting the affinity of the T cell receptor/pMHC interaction. Antigen-presenting cells expressing HLA A2 which does not bind to CD8 fail to activate CTL at any peptide concentration. Comparison of CTL activation by targets expressing HLA A2 with normal, abrogated, or diminished CD8/pMHC interaction show that the CD8/pMHC interaction enhances sensitivity to antigen. We determine that the biochemical basis for coreceptor dependence is the activation of the 23-kDa phosphoform of the CD3zeta chain. In addition, we produce mutant MHC class I multimers that specifically stain but do not activate CTL. These reagents may prove useful in circumventing undesirable activation-related perturbation of intracellular processes when pMHC multimers are used to phenotype antigen-specific CD8+ lymphocytes.

Amino Acid Sequence↗
PubMed2001

Variable fate of virus-specific CD4(+) T cells during primary HIV-1 infection.

Impairment of CD4(+) T lymphocyte responses to human immunodeficiency virus (HIV)-derived antigens is the classic immunological defect observed during the chronic phase of HIV-1 infection. Early intervention with potent antiretroviral therapy (ART) can preserve HIV-specific CD4(+) T lymphocyte reactivity, providing indirect evidence that such responses are mounted during primary infection and subsequently lost in the majority of infected individuals. Here, we demonstrate early and dramatic expansions of functional HIV-specific CD4(+) T lymphocyte frequencies directly ex vivo. These responses are initially of broad specificity, and can disappear rapidly during the natural course of primary infection. This process of loss is variable, such that the rapidity and extent of functional compromise differs between individuals. Institution of ART during these early phases of HIV-1 infection preserves patterns of functional reactivity within the HIV-specific CD4(+) T lymphocyte population. However, there was no evidence for the restoration of deleted responses. These findings indicate that, in some individuals at least, ART must be administered within a narrow window of opportunity during primary HIV-1 infection to effect substantial immune preservation.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Case control study of epidural catheter infections in a district general hospital.

Ten infections associated with the use of epidural catheters for post-operative pain relief were identified in patients of a district general hospital in 1997 and 1998. A case control study showed that the infections were commoner in the summer months and associated with analgesia infused by syringes rather than pumps. Infection rates and risk factors can be analysed regularly if pain teams maintain a database of epidural catheters inserted, which includes information about infections.

Analgesia, Epidural↗
PubMed1999

Meningococcal disease in siblings caused by rifampicin sensitive and rifampicin resistant strains.

Two brothers presented with meningococcal infection in a five day period, the first with a rifampicin sensitive strain and the second, who had received rifampicin chemoprophylaxis, with a resistant strain. Secondary cases of meningococcal disease can occur despite chemoprophylaxis, and may be rifampicin resistant. Close contacts should be informed of the early symptoms of meningococcal disease and of the need to seek medical advice urgently if they occur.

Antibiotic Prophylaxis↗
PubMed1998

Activation of the iNOS gene promoter by Brn-3 POU family transcription factors is dependent upon the octamer motif in the promoter.

The promoter of the gene encoding the inducible nitric oxide synthase (iNOS) contains an octamer motif which is of importance for its activation by specific stimuli. We show that in contrast to the promoter of the neuronal nitric oxide synthase gene (nNOS) which is strongly activated by the Oct-2 octamer-binding POU family transcription factor, the iNOS gene is only weakly activated by Oct-2 via its octamer motif. Unlike the nNOS promoter, however, the iNOS promoter is strongly activated by the POU family transcription factors Brn-3a and Brn-3b. This activation is dependent upon the octamer motif in the iNOS promoter and requires the activation domain located within the POU domain of Brn-3a or Brn-3b but not the N-terminal activation domain of Brn-3a. Thus different but related POU proteins play important roles in the regulation of the genes encoding different forms of nitric oxide synthase.

Animals↗
PubMed1998

The N-terminal domain unique to the long form of the Brn-3a transcription factor is essential to protect neuronal cells from apoptosis and for the activation of Bbcl-2 gene expression.

The ability of the POU family transcription factor Brn-3a to stimulate neurite outgrowth and the expression of the genes encoding neuronal proteins such as the neurofilaments and SNAP-25 has previously been shown to be dependent upon the C-terminal POU domain which can mediate both DNA binding and transcriptional activation. We show here, however, that the ability of Brn-3a to activate Bcl-2 expression and protect neuronal cells from apoptosis (programmed cell death) requires a distinct N-terminal activation domain. Bcl-2 gene activation and protection from apoptosis are thus produced only by the long form of Brn-3a which contains this domain and not by a naturally occurring short form lacking this domain or by the isolated POU domain, although all these forms of Brn-3a can stimulate neurite outgrowth. Hence Brn-3a is a multi-functional transcription factor with different regions of the factor mediating its different effects and two distinct forms with different properties being generated by alternative splicing.

Animals↗
PubMed1998

Functional role of position 22 in the homeodomain of Brn-3 transcription factors.

The Brn-3a POU family transcription factor activates a number of neuronal promoters which are repressed by the closely related Brn-3b factor. Although transcriptional activation by mutant forms of Brn-3a/Brn-3b can occur with a number of different amino acids at position 22 of the POU homeodomain, an isoleucine at this position is of critical importance for transcriptional repression. In addition, this isoleucine residue can mediate an interaction with the herpes simplex virus Vmw65 regulatory protein whereas the valine found in Brn-3a cannot do so. Thus, position 22 in the homeodomain plays a critical role in the function of neuronally expressed POU factors by controlling their interaction with viral and cellular co-activator/co-repressor proteins.

Animals↗
PubMed1998

Adjacent proline residues in the inhibitory domain of the Oct-2 transcription factor play distinct functional roles.

A 40 amino acid region of Oct-2 from amino acids 142 to 181 functions as an active repressor domain capable of inhibiting both basal activity and activation of promoters containing a TATA box, but not of those that contain an initiator element. Based on our observation that the equivalent region of the closely related Oct-1 factor does not act as an inhibitory domain, we have mutated specific residues in the Oct-2 domain in an attempt to probe their importance in repressor domain function. Although mutations of several residues have no or minimal effect, mutation of proline 175 to arginine abolishes the ability to inhibit both basal and activated transcription. In contrast, mutation of proline 174 to arginine confers upon the domain the ability to repress activation of an initiator-containing promoter by acidic activation domains, and also suppresses the effect of the proline 175 mutation. Hence, adjacent proline residues play key roles in the functioning of the inhibitory domain and in limiting its specificity to TATA-box-containing promoters.

Amino Acid Sequence↗
PubMed1997

The different inhibitory domains of the Oct-2 transcription factor have distinct functional activities.

The Oct-2 POU family transcription factor contains three distinct regions whose deletion reduces its ability to inhibit transcription via its octamer binding site. Here we show that only one of these inhibitory domains is capable of also inhibiting the activity of activating molecules bound at adjacent sites upstream of a TATA box-containing promoter whereas the other two regions are inactive in this assay. None of the three regions is able to achieve this effect when located upstream of the same promoter containing an initiator motif. The mechanisms of action of these domains and their role in the functioning of the Oct-2 factor are discussed.

Animals↗