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Biomedical subjects

S Matthews

Publications and source records attributed to S Matthews.

At least 19 recordsLinked to original sources
PubMed2001

Inhibition of T1/ST2 during respiratory syncytial virus infection prevents T helper cell type 2 (Th2)- but not Th1-driven immunopathology.

T cells secreting interleukin (IL)-4 and IL-5 (T helper cell type 2 [Th2] cells) play a detrimental role in a variety of diseases, but specific methods of regulating their activity remain elusive. T1/ST2 is a surface ligand of the IL-1 receptor family, expressed on Th2- but not on interferon (IFN)-gamma-producing Th1 cells. Prior exposure of BALB/c mice to the attachment (G) or fusion (F) protein of respiratory syncytial virus (RSV) increases illness severity during intranasal RSV challenge, due to Th2-driven lung eosinophilia and exuberant Th1-driven pulmonary infiltration, respectively. We used these polar models of viral illness to study the recruitment of T1/ST2 cells to the lung and to test the effects of anti-T1/ST2 treatment in vivo. T1/ST2 was present on a subset of CD4(+) cells from mice with eosinophilic lung disease. Monoclonal anti-T1/ST2 treatment reduced lung inflammation and the severity of illness in mice with Th2 (but not Th1) immunopathology. These results show that inhibition of T1/ST2 has a specific effect on virally induced Th2 responses and suggests that therapy targeted at this receptor might be of value in treating Th2-driven illness.

Animals↗
PubMed2001

Site-directed mutagenesis of intimin alpha modulates intimin-mediated tissue tropism and host specificity.

The hallmark of enteropathogenic (EPEC) and enterohaemorrhagic (EHEC) Escherchia coli adhesion to host cells is intimate attachment leading to the formation of distinctive 'attaching and effacing' lesions. This event is mediated, in part, by binding of the bacterial adhesion molecule intimin to a second bacterial protein, Tir, delivered by a type III secretion system into the host cell plasma membrane. The receptor-binding activity of intimin is localized to the C-terminal 280 amino acids (Int280) and at least five distinct intimin types (alpha, beta, gamma, delta and epsilon) have been identified thus far. In addition to binding to Tir, intimin can also bind to a component encoded by the host. The consequence of latter intimin-binding activity may determine tissue tropism and host specificity. In this study we selected three amino acids in intimin, which are implicated in Tir binding, for site-directed mutagenesis. We used the yeast two-hybrid system and gel overlays to study intimin-Tir protein interaction. In addition, the biological consequences of the mutagenesis was tested using a number of infection models (cultured epithelial cells, human intestinal explants and a mouse model). We report that while an I237/897A substitution (positions numbered according to Int280alpha/whole intimin alpha) in intimin alpha did not have any affect on its biological activity, a T255/914A substitution attenuated intimin activity in vivo. In contrast, the mutation V252/911A affected tissue targeting in the human intestinal explant model and attenuated the biological activity of intimin in the mouse model. This study provides the first clues of the molecular basis of how intimin mediates tissue tropism and host specificity.

Adhesins, Bacterial↗
PubMed2000

Five-year biochemical outcome and toxicity with transperineal CT-planned permanent I-125 prostate implantation for patients with localized prostate cancer.

PURPOSE: To report the 5-year prostate-specific antigen (PSA) relapse-free survival outcome and incidence of long-term morbidity for patients with localized prostate cancer treated with CT-planned permanent I-125 prostate implantation using a transperineal technique (TPI). METHODS AND MATERIALS: Between 1989-1996, 248 patients with clinically localized prostate cancer were treated with TPI. The median age was 65 years (range: 45-80 years). The clinical stage was T1c in 143 patients (58%), Stage T2a in 102 (41%), and T2b in 3 (1%). Thirty patients (12%) had Gleason scores <6, 158 patients (64%) had Gleason scores of 6, and 60 (24%) had scores >or =7. The median pretreatment PSA was 7 ng/mL (range: 1-58 ng/mL). The median prescribed implant dose was 150 Gy. Patients were characterized as having favorable risk disease if their pretreatment PSA level was < or =10.0 ng/mL and Gleason score < or = 6; those with one and two adverse prognostic features (PSA > 10 ng/mL and Gleason score >6) were classified as having intermediate and unfavorable risk disease, respectively. PSA relapse was defined according to the American Society of Therapeutic Radiation Oncology Consensus Statement, and toxicity was scored according to the Radiation Therapy Oncology Group morbidity scoring scale. The median follow-up was 48 months (range: 12-126 months). RESULTS: Thirty-eight patients (15%) developed a PSA relapse, and the overall 5-year PSA relapse-free survival (PRFS) rate was 71%. The 5-year PRFS rates for favorable-risk (n = 146), intermediate-risk (n = 85), and unfavorable-risk (n = 17) patients were 88%, 77%, and 38%, respectively (p < 0.0001). The 5-year PRFS rates among patients treated with a 2-month course of neoadjuvant androgen deprivation (NAAD) prior to TPI compared to patients treated with TPI only were 100% and 77%, respectively (p = 0.03). Multivariate analysis identified pretreatment PSA > 10 ng/mL and Gleason score >6 as independent predictors for biochemical relapse after TPI. The 5-year actuarial likelihood of late Grade 2 urinary toxicity was 41%. The 5-year likelihood of urethral stricture development was 10%, and the median time to stricture development was 18 months. One patient (0. 4%) in the early phase of this clinical experience developed a Grade 4 urethral complication. The actuarial incidence of late Grade 2 rectal bleeding was 9%. One patient (0.4%) developed a Grade 4 rectal complication. CONCLUSIONS: Especially for favorable risk disease, the 5-year biochemical outcome with this approach was excellent and appears to be comparable to other therapeutic interventions. Grade 2 urinary symptoms were common in these patients but gradually resolved in most. Improved treatment planning approaches that further constrain the urethral dose without compromising the target volume dose will likely decrease the incidence of Grade 2 and 3 urinary symptoms after TPI.

Aged↗
PubMed2000

A clinical evaluation of an Erbium:YAG laser for dental cavity preparation.

OBJECTIVE: A randomised controlled trial to determine the acceptability to dentists and patients of cavity preparation with an Erbium:YAG laser as compared with conventional handpieces. METHODS: Fifteen dentists (9 GDPs, 1 community dentist and 5 hospital dentists) treated 77 patients (age range 3.5-68 years old) who had two matched cavities, in a split mouth, randomised trial. One cavity was prepared conventionally, the other with the laser, with dentist and patient preference determined by questionnaire. RESULTS: In the majority of cases, where dentists expressed a preference, it was for conventional cavity preparation, and this was significant (P < 0.001). In more than half of the laser appointments, dentists had to use conventional handpieces to complete the cavity. Principle difficulties reported with the laser were access (25 cases) and slow speed of cutting (11 cases). Patients aged > or = 10 years who expressed a preference, preferred laser treatment, and this was significant (P < 0.001). Patients aged < 10 years, assessed using a simplified pictorial questionnaire, did not show a significant preference for either technique. CONCLUSIONS: Dentists preferred conventional handpieces for cavity preparation while patients aged > or = 10 years old preferred laser treatment. Patients < 10 years old did not express a preference.

Adolescent↗
PubMed2000

Structure of tandem RNA recognition motifs from polypyrimidine tract binding protein reveals novel features of the RRM fold.

Polypyrimidine tract binding protein (PTB), an RNA binding protein containing four RNA recognition motifs (RRMs), is involved in both pre-mRNA splicing and translation initiation directed by picornaviral internal ribosome entry sites. Sequence comparisons previously indicated that PTB is a non-canonical RRM protein. The solution structure of a PTB fragment containing RRMs 3 and 4 shows that the protein consists of two domains connected by a long, flexible linker. The two domains tumble independently in solution, having no fixed relative orientation. In addition to the betaalphabetabetaalphabeta topology, which is characteristic of RRM domains, the C-terminal extension of PTB RRM-3 incorporates an unanticipated fifth beta-strand, which extends the RNA binding surface. The long, disordered polypeptide connecting beta4 and beta5 in RRM-3 is poised above the RNA binding surface and is likely to contribute to RNA recognition. Mutational analyses show that both RRM-3 and RRM-4 contribute to RNA binding specificity and that, despite its unusual sequence, PTB binds RNA in a manner akin to that of other RRM proteins.

Amino Acid Motifs↗
PubMed2000

Structural basis for recognition of the translocated intimin receptor (Tir) by intimin from enteropathogenic Escherichia coli.

Intimin is a bacterial adhesion molecule involved in intimate attachment of enteropathogenic and enterohaemorrhagic Escherichia coli to mammalian host cells. Intimin targets the translocated intimin receptor (Tir), which is exported by the bacteria and integrated into the host cell plasma membrane. In this study we localized the Tir-binding region of intimin to the C-terminal 190 amino acids (Int190). We have also determined the region's high-resolution solution structure, which comprises an immunoglobulin domain that is intimately coupled to a novel C-type lectin domain. This fragment, which is necessary and sufficient for Tir interaction, defines a new super domain in intimin that exhibits striking structural similarity to the integrin-binding domain of the Yersinia invasin and C-type lectin families. The extracellular portion of intimin comprises an articulated rod of immunoglobulin domains extending from the bacterium surface, conveying a highly accessible 'adhesive tip' to the target cell. The interpretation of NMR-titration and mutagenesis data has enabled us to identify, for the first time, the binding site for Tir, which is located at the extremity of the Int190 moiety.

Adhesins, Bacterial↗
PubMed2000

A phase I-II study of 9-cis retinoic acid and interferon-alpha2b in patients with advanced renal-cell carcinoma: an NCIC Clinical Trials Group study.

Although advanced renal-cell carcinoma (RCC) responds poorly to standard therapies, phase I-II trials have shown activity for combinations of interferon-alpha2b (IFN) with a retinoid. Alitretinoin (9-cis RA) is an endogenous retinoid with high binding affinity for both RAR and RXR receptor families. This phase I-II study enrolled 38 patients with RCC in a dose-escalation study of tolerability, pharmacokinetics (PK), and efficacy of twice daily oral 9-cis RA with subcutaneous IFN. In contrast to studies with similar doses of daily 9-cis RA, PK studies found a consistent reduction in 9-cis RA concentrations of about 50% after multiple b.i.d. doses of 30 or 50 mg/m2, independent of cotreatment with IFN. In the phase I portion, toxicities included systemic symptoms typical of IFN and biochemical abnormalities previously associated with retinoids. Two patients experienced dose-limiting toxicity at 50 mg/m2 b.i.d. of 9-cis RA, thus the recommended phase II dose was 30 mg/m2 b.i.d. One of twenty-six evaluable patients achieved a durable objective partial remission, and repeated dosing with this regimen was poorly tolerated. This combination of retinoid and interferon is not recommended for further study in RCC.

Adult↗
PubMed2000

Diaries of evidence-based tutors: beyond 'numbers needed to teach'...

Interprofessional evidence-based health care courses have been held throughout the UK over the last few years, modelled on the approach used in McMaster University of using problem-based facilitated small-group formats to achieve the stated goals. Both delegates and tutors have been aware of the tensions which are inherent within these courses between: (a) the variation in learning cultures which is exhibited by the delegates and the effect this has on processes (i.e. the tension between the reductionist approach of bioscience and the more qualitative leanings of the applied and 'caring' disciplines); and (b) the conflict which arises between the goal of 'learning' applied healthcare biostatistics and the ability to leave the course with the skills to teach others. This qualitative study uses tutor-kept diaries to understand some of the tensions apparent to the teaching faculty during a week-long course in Wales, UK.

Evidence-Based Medicine↗
PubMed2000

National audit of the management and outcome of carcinoma of the cervix treated with radiotherapy in 1993.

The aim of the study was to investigate the UK prevalence of late, severe side-effects associated with radical radiotherapy for cancer of the cervix and try to identify associated factors. All patients treated for cancer of the cervix with radical radiotherapy in 1993 were identified and retrospective case notes studied to determine mortality and severe complications occurring following treatment. Of the 55 radiotherapy departments in the UK that were treating gynaecological malignancy in 1993, 53 participated in the study. There were 1558 patients with carcinoma of the cervix receiving radical radiotherapy as part of their treatment regimen in 1993, whose patterns of treatment were assessed. The main outcome measures were the development of late severe complications as defined by the Franco-Italian Glossary and mortality. Of the patients receiving surgery and radiotherapy, 58.5% underwent Wertheim's procedure. The crude rate of late severe complications in all patients with cervical cancer treated with radical radiotherapy in 1993 was 6.1% (actuarial rate 8%) at 5 years, and only four of the 91 patients who developed complications died as a result of their morbidity. There was no significant correlation of stage, centre size, surgery or radiotherapeutic approach with late morbidity in univariate analysis. The overall survival at 5 years was 47% and was lower than that of the European data from FIGO's 1990-92 cohort, for all stages. Increasing FIGO stage was the only factor significantly associated with mortality. The absence of variables that were significantly associated with late complications may well be related to the relatively low event rate compared to the sample size. Differences in surgical treatment prior to radiotherapy and radiation technique may be confounding the comparison of outcomes. The relatively poor survival for locally advanced disease and the difficulty with which these data were collated indicates that national prospective data collection is urgently required to monitor performance and hence derive best practice.

Adult↗
PubMed2000

Dichotomous or categorical response? Analysing self-rated health and lifetime social class.

BACKGROUND: Self-rated health is a commonly used measure of health status, usually having three to five categories. The measure is often collapsed into a dichotomous variable of good versus less than good health. This categorization has not yet been justified. METHODS: Using data from the 1958 British birth cohort, we examined the relationship between socioeconomic conditions, indicated by occupational class at four ages, and self-rated health. Results obtained for a dichotomous variable using logistic regression were compared with alternative methods for ordered categorical variables including polytomous regression, cumulative odds, continuation ratio and adjacent categories models. RESULTS AND CONCLUSIONS: Findings concerning the relationship between socioeconomic position and self-rated health yielded by a logistic regression model were confirmed by alternative statistical methods which incorporate the ordered nature of self-rated health. Similarity of results was found regarding size and significance of main effects, type of association and interactive effects.

Adult↗
PubMed2000

Fetal hypothalamic-pituitary adrenal (HPA) development and activation as a determinant of the timing of birth, and of postnatal disease.

Birth in most animal species is triggered by the fetus through activation of the fetal hypothalamic-pituitary-adrenal (HPA) axis. Preterm birth, may be associated with precocious activation of fetal HPA function, reflecting the fetal response to an adverse intrauterine environment. There is a progressive and concurrent increase of ACTH1-39 and cortisol (F) in the circulation of fetal sheep during the last 15-20 days of pregnancy (term, day 145-150) associated with increased expression of hypothalamic CRH pituitary POMC and adrenal ACTH receptor and steroidogenic enzymes, particularly P450 C17. Similar changes occur with fetal hypoxemia. Negative feedback is ameliorated by decreased pituitary and hypothalamic glucocorticoid receptor, increased CBG, and altered fetal pituitary 11B-hydroxysteroid dehydrogenase type 1. Repeated fetal hypoxemia, diminishes the fetal-pituitary ACTH response, but increases fetal adrenal responsiveness. Fetuses exposed to maternal glucocorticoid in late gestation are growth restricted with altered postnatal HPA responsiveness and glycemic responses that reproduce the insulin resistance of type 2 diabetes. We conclude that the level of fetal HPA activity is crucial not only for determining gestation length, but also predicts pathophysiologic adjustment in later life.

Animal Diseases↗
PubMed1999

Dynamic re-distribution of protein kinase D (PKD) as revealed by a GFP-PKD fusion protein: dissociation from PKD activation.

Protein kinase D (PKD)/protein kinase Cmicro (PKCmicro, a serine/threonine protein kinase with distinct structural and enzymological properties, is rapidly activated in intact cells via PKC. The amino-terminal region of PKD contains a cysteine-rich domain (CRD) that directly binds phorbol esters with a high affinity. Here, we show that treatment of transfected RBL 2H3 cells with phorbol 12,13-dibutyrate (PDB) induces a striking CRD-dependent translocation of PKD from the cytosol to the plasma membrane, as shown by real time visualization of a functional green fluorescent protein (GFP)-PKD fusion protein. A single amino acid substitution in the second cysteine-rich motif of PKD (P287G) prevented PDB-induced membrane translocation but did not affect PKD activation. Our results indicate that PKD translocation and activation are distinct processes that operate in parallel to regulate the activity and localization of this enzyme in intact cells.

Amino Acid Substitution↗
PubMed1999

RNA polymerase subunit H features a beta-ribbon motif within a novel fold that is present in archaea and eukaryotes.

The archaeal H and eukaryotic RPB5 RNA polymerase subunits are highly homologous and are likely to play a fundamental role in transcription that extends from archaea to humans. We report the structure of subunit H, in solution, from the archaeon Methanococcus jannaschii using multidimensional nuclear magnetic resonance. The structure reveals a novel fold containing a four-stranded mixed beta sheet that is flanked on one side by three short helices. The dominant feature is beta-ribbon motif, which presents a hydrophobic, basic surface, and defines a general RNA polymerase architectural scaffold.

Amino Acid Sequence↗
PubMed1999

Social inequalities in health: are there gender differences?

Some studies suggest that socio-economic status (SES) inequalities in health are smaller in women than men, but the evidence is inconsistent as to whether this applies across various health measures and life stages. The first aim of this paper was to establish whether the magnitude of social inequality in health differs for men and women during early adulthood, specifically in respect to self rated health, limiting long-standing illness, psychological distress, respiratory symptoms, asthma/wheezing, height and obesity; second, to determine whether explanations for socioeconomic inequality in poor self rated health differ for men and women. Analyses are based on longitudinal data from the British 1958 birth cohort study using information from birth to age 33. When gender differences in inequalities were examined using social class, no significant differences emerged across the seven health measures examined at ages 23 and 33. SES inequalities based on education, however, showed greater inequality among men at age 33 for limiting long-standing illness and respiratory symptoms, but greater inequality among women for poor rated health at age 23 and psychological distress at age 33. Hence, gender differences in the magnitude of health inequality were inconsistent across age and health measures. An analysis of the contribution of explanatory factors to social class differences in self-rated health suggested that causes of inequality were similar for men and women. However, some discrepancies emerged, notably in the greater contribution of job insecurity to class differences for men and in the greater contribution of age at first child for women. The magnitude and explanations for gender differences in SES health inequalities are likely to vary according to life stage and health measure.

Adult↗
PubMed1999

Social support at age 33: the influence of gender, employment status and social class.

This paper investigates the conceptualisation and operationalisation of social support and it's relationship to gender, employment status and social class. Clarification of these relationships is sought in order to better understand associations between social support and health. We used data from the 33-year survey of the 1958 British birth cohort study. Individual items and subscales of practical and emotional support were examined. In general, men had lower support than women and social classes IV and V had lower support than classes I and II. Emotional support, either from personal (for example, from friends or family), or combined with organisational sources of support (such as from a church or a financial institution), showed consistent gender and social class patterns. This suggests that emotional support is a robust concept across socio-demographic groups. Less consistent trends were found for practical support, in that socio-demographic trends depended on how practical support was measured. In particular, it depended on whether both personal and organisational sources of support were examined. Gender differences in social support were large and might therefore be expected to contribute to gender differences in health, whereas social class differences in social support were modest, suggesting a minor explanatory role for this factor in accounting for inequalities in health.

Adult↗