Triplane fracture of the proximal tibia.
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Child↗
Biomedical subjects
S Matthews
Publications and source records attributed to S Matthews.
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↗
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↗
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↗
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↗
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↗
Phenomenology of panic attacks reflects human evolutionary history of separation anxiety.
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Adult↗
Wade, G. H. (1999). Professional nurse autonomy: concept analysis and application to nursing education. Journal of Advanced Nursing, 30 (2), 310-318.
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Curriculum↗
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↗
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↗
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↗
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↗
Structure of the cell-adhesion fragment of intimin from enteropathogenic Escherichia coli.
Enteropathogenic Escherichia coli (EPEC) induce gross cytoskeletal rearrangement within epithelial cells, immediately beneath the attached bacterium. The C-terminal 280 amino acid residues of intimin (Int280; 30.1 kDa), a bacterial cell-adhesion molecule, mediate the intimate bacterial host-cell interaction. Recently, interest in this process has been stimulated by the discovery that the bacterial intimin receptor protein (Tir) is translocated into the host cell membrane, phosphorylated, and after binding intimin triggers the intimate attachment. Using multidimensional nuclear magnetic resonance (NMR) and combining perdeuteration with site-specific protonation of methyl groups, we have determined the global fold of Int280. This represents one of the largest, non-oligomeric protein structures to be determined by NMR that has not been previously resolved by X-ray crystallography. Int280 comprises three domains; two immunoglobulin-like domains and a C-type lectin-like module, which define a new family of bacterial adhesion molecules. These findings also imply that carbohydrate recognition may be important in intimin-mediated cell adhesion.
Adhesins, Bacterial↗
Binding of intimin from enteropathogenic Escherichia coli to Tir and to host cells.
Enteropathogenic Escherichia coli (EPEC) induce characteristic attaching and effacing (A/E) lesions on epithelial cells. This event is mediated, in part, by binding of the bacterial outer membrane protein, intimin, to a second EPEC protein, Tir (translocated intimin receptor), which is exported by the bacteria and integrated into the host cell plasma membrane. In this study, we have localized the intimin-binding domain of Tir to a central 107-amino-acid region, designated Tir-M. We provide evidence that both the amino- and carboxy-termini of Tir are located within the host cell. In addition, using immunogold labelling electron microscopy, we have confirmed that intimin can bind independently to host cells even in the absence of Tir. This Tir-independent interaction and the ability of EPEC to induce A/E lesions requires an intact lectin-like module residing at the carboxy-terminus of the intimin polypeptide. Using the yeast two-hybrid system and gel overlays, we show that intimin can bind both Tir and Tir-M even when the lectin-like domain is disrupted. These data provide strong evidence that intimin interacts not only with Tir but also in a lectin-like manner with a host cell intimin receptor.
Adhesins, Bacterial↗
Human herpesvirus 8: seroepidemiology among women and detection in the genital tract of seropositive women.
An indirect IFA to detect antibodies against latent nuclear antigens of human herpesvirus 8 (HHV-8) was used to determine the prevalence of HHV-8 antibodies in 169 women attending a sexually transmitted diseases clinic and a human immunodeficiency virus (HIV) clinic at a London hospital. Nested polymerase chain reaction was used to detect HHV-8 DNA in 93 blood samples and 89 cervical brush scrapes (CBS). Another 96 CBS from women attending a colposcopy clinic were also analyzed. The overall seroprevalence of HHV-8 was 18.3%. The seroprevalence was higher among women born in Africa (24.7%) than among women born elsewhere (11.5%; P=.06) and was independent of HIV serostatus. HHV-8 DNA was detected in 3 CBS and 6 peripheral blood samples from 11 HHV-8-seropositive women but not in CBS from 78 seronegative women, 96 women from the colposcopy clinic, or in blood samples from 82 seronegative women.
Africa↗
Multicenter comparison of PCR assays for detection of human herpesvirus 8 DNA in semen.
Reported prevalences of human herpesvirus 8 (HHV-8) (Kaposi's sarcoma-associated herpesvirus) in semen have ranged widely. This is possibly due to differences in assay sensitivity, geographic or population-based differences in the true presence of the virus in semen, and PCR contamination. This study assessed interlaboratory sensitivity and reproducibility in the analysis of blinded experimental panels, each consisting of 48 specimens and being composed of semen specimens from different healthy artificial-insemination donors (n = 30) and human immunodeficiency virus (HIV)-infected patients (n = 7) plus positive (n = 4) and negative (n = 7) controls. The experimental panels analyzed in each laboratory were identical except for being independently coded. Of 10 experiments done in five laboratories, 5 experiments from three laboratories had evidence of PCR contamination; all instances of contamination were in the context of nested PCR procedures. In the experiments with no false-positive results, HHV-8 DNA was detected in three (8%) of the 37 semen specimens (two from artificial-insemination donors and one from an HIV-positive patient) but in only 3 (1.6%) of the 184 PCRs in which these specimens were analyzed. This suggests that HHV-8 DNA is present in semen at concentrations that can be too low to allow its consistent detection. This study emphasizes the importance of performing blinded, multi-institution experiments to provide a coherent basis for comparing results and to motivate standardization of methods.
DNA, Viral↗
The duration and timing of exposure: effects of socioeconomic environment on adult health.
OBJECTIVES: This study investigated timing and duration effects of socioeconomic status (SES) on self-rated health at 33 years of age and established whether health risks are modified by changing SES and whether cumulative SES operates through education. METHODS: Data were from the 1958 British birth cohort. Occupational class at birth and at 16, 23, and 33 years of age was used to generate a lifetime SES score. RESULTS: At 33 years of age, 12% of men and women reported poor health. SES at birth and at 16, 23, and 33 years of age was significantly associated with poor health: all ages except 16 years in men made an additional contribution to the prediction of poor health. No large differences in effect sizes emerged, suggesting that timing was not a major factor. Odds of poor health increased by 15% (men) and 18% (women) with a 1-unit increase in the lifetime SES score. Strong effects of lifetime SES persisted after adjustment for education level. CONCLUSIONS: SES from birth to 33 years of age had a cumulative effect on poor health in early adulthood. This highlights the importance of duration of exposure to socioeconomic conditions for adult health.
Adult↗
Host genetic determinants of vaccine-induced eosinophilia during respiratory syncytial virus infection.
In BALB/c mice, sensitization with the attachment protein (G) of respiratory syncytial virus (RSV) leads to CD4+ T cell-mediated lung eosinophilia during subsequent challenge with RSV. To determine the host genetic influences on this model of lung eosinophilia, we tested 15 different inbred mouse strains. Eosinophilia developed in all H-2d (BALB/c, DBA/2n, and B10.D2), but not in H-2k (CBA/Ca, CBA/J, C3H, BALB.K, or B10.BR) mouse strains. Among H-2b mice, 129 and BALB.B developed eosinophilia, whereas C57BL/6 and C57BL/10 did not. Testing first generation crosses between sensitive and resistant strains showed that eosinophilia developed in all H-2dxk (n = 5), irrespective of background genes, but not in H-2dxb (n = 2) mice. In vivo depletion of CD8+ T cells or IFN-gamma rendered C57BL/6, but not BALB.K mice, susceptible to eosinophilia. Analysis of B10 recombinant mice showed that the Dd allele (in B10.A(5R) mice) prevented CD8+ T cell accumulation in the lung, resulting in intense lung eosinophilia. However, the Db allele (in B10.A(2R) and B10.A(4R) mice) supported CD8+ T cell expansion and prevented eosinophilia. Intracellular cytokine staining showed that lung eosinophilia correlated with reduced IFN-gamma and increased IL-10 expression in lung T cells. These results are compatible with the unifying model that Th2 cells mediate the disease but can be inhibited by CD8+ T cells secreting IFN-gamma. Our findings have important implications for the development of protective, nonpathogenic vaccines for RSV disease.
Animals↗