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Biomedical subjects

M E Wright

Publications and source records attributed to M E Wright.

At least 19 recordsLinked to original sources
PubMed2006

Direct cancer tissue proteomics: a method to identify candidate cancer biomarkers from formalin-fixed paraffin-embedded archival tissues.

Successful treatment of multiple cancer types requires early detection and identification of reliable biomarkers present in specific cancer tissues. To test the feasibility of identifying proteins from archival cancer tissues, we have developed a methodology, termed direct tissue proteomics (DTP), which can be used to identify proteins directly from formalin-fixed paraffin-embedded prostate cancer tissue samples. Using minute prostate biopsy sections, we demonstrate the identification of 428 prostate-expressed proteins using the shotgun method. Because the DTP method is not quantitative, we employed the absolute quantification method and demonstrate picogram level quantification of prostate-specific antigen. In depth bioinformatics analysis of these expressed proteins affords the categorization of metabolic pathways that may be important for distinct stages of prostate carcinogenesis. Furthermore, we validate Wnt-3 as an upregulated protein in cancerous prostate cells by immunohistochemistry. We propose that this general strategy provides a roadmap for successful identification of critical molecular targets of multiple cancer types.

Amino Acid Sequence↗
PubMed2001

Hypogonadism in patients with acromegaly: data from the multi-centre acromegaly registry pilot study.

OBJECTIVE: Because acromegaly is an uncommon disorder, epidemiological data regarding the demographics of the disease such as the prevalence of hypogonadism have been limited. In order to derive clinical and epidemiological information, including underlying hormonal factors, regarding hypogonadism in patients with acromegaly, we performed a pilot study designed to develop a multi-centre acromegaly patient registry. DESIGN AND MEASUREMENTS: Medical records of patients with acromegaly seen between 1976 and 1996 at three Institutions were reviewed, and data were entered into a database using a secure internet website. Hypogonadism was defined as amenorrhoea in women and testosterone deficiency in men. Subanalysis was performed in patients with microadenomas and women less than 50 years of age, to include women of reproductive age. RESULTS: Information was available on 363 patients, of whom 54% were women. The mean age at diagnosis was 41 +/- 13 years. In subjects less than 50 years of age, hypogonadism was present in 59%. Hyperprolactinaemia was present in 45% and 21% of hypogonadal and eugonadal patients of reproductive age, respectively (P = 0.0003). GH levels were higher in patients with hypogonadism (P = 0.03). In patients < 50 years of age with microadenomas, hypogonadism was present in nine of the 22 (41%) patients, including 55% of the women and 27% of the men (P = ns). Hyperprolactinaemia was present in three of the 10 and four of the 14 of microadenoma patients with hypogonadism and eugonadism, respectively. CONCLUSION: We developed a web-based acromegaly patient registry and used it to show that hypogonadism is a frequent consequence of acromegaly, even in patients with microadenomas, who are not at risk from hypopituitarism due to local mass effects. We also demonstrated that prolactin and GH hypersecretion contribute to the pathogenesis of hypogonadism in acromegaly, and that hypogonadism may occur in microadenoma patients even in the absence of hyperprolactinaemia.

Acromegaly↗
PubMed2001

Ongoing trials of immune-based therapies for HIV infection in adults.

Highly active antiretroviral therapy (HAART) can significantly alter the clinical course of patients infected with HIV. Unfortunately, effective lifelong HAART may not be a practical or achievable goal because of toxicities, cost, development of viral resistance and patient compliance issues. Immune-based therapies (IBTs) that target the host immune system may serve as rational additions to our current antiretroviral strategies. Investigations into IL-2 have culminated in two large Phase III clinical trials. Multiple therapeutic vaccine candidates are in various phases of investigation. In addition, gene therapy has been proposed as a potential treatment for HIV and Phase I trials are ongoing. Although IBTs are being investigated on many fronts, they remain difficult to study due to a lack of validated surrogate end points.

AIDS Vaccines↗
PubMed2000

Caspase-3 and inhibitor of apoptosis protein(s) interactions in Saccharomyces cerevisiae and mammalian cells.

Using a heterologous yeast expression assay, we show that inhibitor of apoptosis proteins (IAPs) suppress caspase-3-mediated cytotoxicity in the order of XIAP>c-IAP2>c-IAP1>survivin. The same ordering of IAP activities was demonstrated in mammalian cells expressing an auto-activating caspase-3. The relative anti-apoptotic activities of each IAP depended on the particular death stimulus. For IAP-expressing cells treated with camptothecin, survival correlated with their intrinsic anti-caspase-3 activity. However, c-IAP1-transfected cells were disproportionately resistant to tumor necrosis factor-alpha, suggesting that its anti-apoptotic activities extend beyond caspase-3 or -7 inhibition. Yeast-based caspase assays provide rapid, reliable information on specificity and activity of the IAPs and aid in identifying critical targets in mammalian apoptotic pathways.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Psychosocial factors influencing personal control in pain relief.

A questionnaire was administered to 100 women (50 primigravidae, 50 multigravidae) to investigate the influence of psychosocial factors on personal control in pain relief. Personal control was measured using a 36-item scale based on the concept of 'Rule'. The women were asked to rate each rule on a 7-point Likert scale. Measures of psychosocial factors included assessment of the women's expectations of labour pain, maternal confidence, pain intensity, antenatal training and partner support. Demographic variables including parity were also recorded. The questionnaires were completed prior to and within 48 h following the women's delivery (whilst they were inpatients on the postnatal ward).Two variables, antenatal training and pain intensity, emerged as predictors of personal control in pain relief following stepwise multiple regression analysis. These findings have implications for clinical practice particularly in the area of antenatal care and planning care during labour.

Adult↗
PubMed2000

Temperature effects on embryonic development and the life cycle of Diphyllobothrium dendriticum.

Diphyllobothrium dendriticum eggs collected from hamster faeces were incubated at 10 or 20 degrees C, or maintained at 4 degrees C for 11-30 months. On day 65, 20-50% of eggs failed to hatch at 10 degrees C and 42-51% did not hatch by day 21 at 20 degrees C. Our study indicates that eggs begin to hatch in mid-August and persist until October in many lakes within the natural range of D. dendriticum. Our results demonstrate that eggs stored at 4 degrees C will hatch, suggesting they can persist in the environment for long periods and contribute to the D. dendriticum life cycle in high Arctic lakes by hatching months or years after release.

Animals↗
PubMed2000

Personal control in pain relief during labour.

Personal control is a central feature of women's involvement in their childbirth experiences. To achieve this control tacit rules and guidelines are applied to define how women and the professionals who care for them should behave. This study investigated the extent to which women exercised control in pain relief during the first stage of labour by comparing (a) the rules which they held prior to childbirth (2-3 cm cervical dilatation) with those which they afterwards felt applied to their labour and (b) the rules held by the women before and after childbirth with those held by the midwives. In a quantitative study using a repeated measures design, a questionnaire was administered to 35 midwives and to 100 women prior to and within 24 hours following their delivery. Consistency of the women's scores before and after childbirth, indicated by few statistically significant differences, tended to confirm their rules on control of pain relief. Some of the rules were held even more strongly following childbirth. A surprising finding was the even stronger agreement by midwives with some of the rules. There was a definite trend for many of the rules held by the women prior to childbirth to increase following birth towards those of the midwives. This could be the result of the experience of childbirth per se but the possibility that it was contributed to by the influence of the midwives cannot be ruled out and warrants further research. An interesting hierarchy in the rules for compliance with professional care has been highlighted.

Adaptation, Psychological↗
PubMed1999

An adipogenic cofactor bound by the differentiation domain of PPARgamma.

Ligand activation of the nuclear receptor PPARgamma induces adipogenesis and increases insulin sensitivity, while activation of other PPAR isoforms (-alpha and -delta) induces little or no fat cell differentiation. Expression and activation of chimeras formed between PPARgamma and PPARdelta in fibroblasts has allowed us to localize a major domain of PPARgamma responsible for adipogenesis to the N-terminal 138 amino acids, a region with AF-1 transcriptional activity. Using this region of PPARgamma as bait, we have used a yeast two-hybrid screen to clone a novel protein, termed PGC-2, containing a partial SCAN domain. PGC-2 binds to and increases the transcriptional activity of PPARgamma but does not interact with other PPARs or most other nuclear receptors. Ectopic expression of PGC-2 in preadipocytes containing endogenous PPARgamma causes a dramatic increase in fat cell differentiation at both the morphological and molecular levels. These results suggest that interactions between PGC-2, a receptor isoform-selective cofactor and PPARgamma contribute to the adipogenic action of this receptor.

Adipocytes↗
PubMed1999

Caspase-3 inhibits growth in Saccharomyces cerevisiae without causing cell death.

Caspase-3, a member of the caspase family of cell death proteases, cleaves cytoplasmic and nuclear substrates and promotes apoptotic cell death in mammalian cells. Although yeast homologs of apoptotic genes have not been identified, some components of apoptotic pathways retain function in yeast. Here we show that the expression of caspase-3 delays cell growth in Saccharomyces cerevesiae without causing cell death. Mutation of the caspase-3 QACRG active site abolished effects on yeast growth. Co-expression of caspase inhibitors alleviated growth inhibition in yeast as did the tripeptide caspase inhibitor ZVAD-fmk. These results suggest that substrates for caspase-3 are present in S. cerevesiae and may participate in the normal cell growth and division processes.

Apoptosis↗
PubMed1999

Satisfaction in childbirth and perceptions of personal control in pain relief during labour.

Satisfaction in childbirth is influenced by individual and environmental factors. Of specific interest in this study is the extent to which women feel that they have been able to control what happened to them during labour. The main purpose of this study was to examine the influence of personal control on women's satisfaction with pain relief during labour. A questionnaire-based retrospective study of women's pain experiences within 48 hours of delivery was carried out on the postnatal ward of one teaching hospital in Northern Ireland. One hundred women who had had a vaginal delivery consented to take part in the study. Two main measures were used in the study; personal control in and satisfaction with pain relief during labour. The key finding of this study indicates that feelings of personal control influenced positively the women's satisfaction with pain relief during labour. Demographic and other psycho-social variables had little impact on the women's satisfaction scores. These findings have implications for clinical practice and for the management of maternity services and are discussed.

Adaptation, Psychological↗
PubMed1998

Differences in midwives' approaches to pain relief in labour.

OBJECTIVE: To examine the influence of midwives' approaches on the care given to women for pain relief during labour. DESIGN: Non-participant observation was used to collect data on midwives' behaviours during interactions with women in labour. SETTING: A large teaching hospital in Northern Ireland. PARTICIPANTS: Observations focused on interactions that were related to pain relief and involved 11 midwives caring for 15 women throughout the first stage of labour. KEY FINDINGS: Midwives' approaches to pain relief differed; at one extreme the midwife acted as 'a cold professional' whilst at the other extreme she was observed to be 'a disorganised carer'. In the middle of these two extremes was the 'warm professional'; her approach had a positive influence on the women's experience of labour pain. IMPLICATION FOR RESEARCH: Further research is needed to develop a profile of the factors that 'make' for a warm professional. The information gained could be used to teach midwives the skills of being 'a warm professional', in particular, the value of effective communication for sensitive care such as pain relief in labour.

Adult↗
PubMed1997

MRIT, a novel death-effector domain-containing protein, interacts with caspases and BclXL and initiates cell death.

Activation of the cascade of proteolytic caspases has been identified as the final common pathway of apoptosis in diverse biological systems. We have isolated a gene, termed MRIT, that possesses overall sequence homology to FLICE (MACH), a large prodomain caspase that links the aggregated complex of the death domain receptors of the tumor necrosis factor receptor family to downstream caspases. However, unlike FLICE, the C-terminal domain of MRIT lacks the caspase catalytic consensus sequence QAC(R/Q)G. Nonetheless MRIT activates caspase-dependent death. Using yeast two-hybrid assays, we demonstrate that MRIT associates with caspases possessing large and small prodomains (FLICE, and CPP32/YAMA), as well as with the adaptor molecule FADD. In addition, MRIT simultaneously and independently interacts with BclXL and FLICE in mammalian cells. Thus, MRIT is a mammalian protein that interacts simultaneously with both caspases and a Bcl-2 family member.

Adult↗
PubMed1997

Structure-activity studies of the inhibition of serine beta-lactamases by phosphonate monoesters.

A new series of phosphonyl derivatives has been prepared and tested for inhibition of serine (class A and C) beta-lactamases. Variations of the leaving group in a series of methyl phosphonates showed that leaving groups better than the previously employed p-nitrophenoxide could give more effective inhibitors. Inclusion of a negative charge in the leaving group did not, per se, lead to better inhibitors. Aryl phosphonates appeared more effective than those with electronically comparable but smaller leaving groups. The combination of a good leaving group, 2,4-dinitrophenoxide, with an amido side-chain, phenylmethylsulfonamido--the latter rather than phenylacetamido in order to increase the stability of the compound with respect to intramolecular nucleophilic catalysis of hydrolysis by the amide group--did not yield overall a better inhibitor than previously employed p-nitrophenyl phosphonates. These results give the first indication of specific interactions between a beta-lactamase and the leaving group of a phosphonate inhibitor. Only one enantiomer of a chiral thiophosphonate, presumably the Rp isomer, was an effective inhibitor. Addition of either a D- or a L-methyl group to the methylene group of a p-nitrophenyl amidomethylphosphonate did not enhance the inhibitory ability of the phosphonate. Class A beta-lactamases remain refractory to phosphonates.

Esters↗
PubMed1997

Long-term sickness absence in an NHS teaching hospital.

This study was carried out to investigate the incidence and causes of long-term sickness absence in an NHS teaching hospital and to explore the role of the Occupational Health Service (OHS) in the management of long-term absence. Examination of attendance records of non-medical staff revealed an annual loss of 20,772 days due to spells of absence lasting 30 calendar days or more, (incidence 0.0528/WTE employees/year, prevalence 5.53 days long-term absence/WTE employee/year). A self-administered questionnaire was sent to 190 staff who had taken long-term absence during the previous 12 months. The response rate was 75%. Musculoskeletal problems and back pain in particular were the main reasons for absence, accounting for 30% of total days lost. Work-related illness made an important contribution with a third of those with musculoskeletal and a quarter of those with mental illness attributing the reason for their absence to work. Many staff reported non-medical factors such as delays in waiting for treatment and anxiety about return to work which prevented them from returning to work sooner. Only a minority of staff had attended OHS and referral was often delayed. OHS may have an important role to play in both prevention and management of long-term absence by early assessment and intervention such as expediting treatment or arranging rehabilitation programmes. However in order to be effective, a clear policy to encourage early and consistent referral is required.

Absenteeism↗
PubMed1995

A case-control study of maternal nutrition and neural tube defects in Northern Ireland.

OBJECTIVE: to compare dietary intake and biochemical indices of nutritional status in women following birth of a baby/termination of a pregnancy affected by neural tube defect (NTD) and women with a normal baby. DESIGN: quantitative, using case control methods. SETTING: dietary records were completed by women in their own home, blood samples were taken in the local health centres. PARTICIPANTS: 15 women referred to the study following an affected pregnancy (subjects), matched with 15 women whose pregnancy outcome was normal (controls). MEASUREMENTS AND FINDINGS: 7-day weighed dietary records indicated no statistically significant differences in nutrient intake but a tendency for lower fruit and vegetable consumption in subjects than in controls. Biochemical analysis of nutritional status showed that levels of serum vitamin B12 were significantly lower in subjects, and activities of two of the nucleotide salvage pathway enzymes were significantly higher. KEY CONCLUSIONS: the findings are consistent with the findings of other research on NTD and the metabolism of folate and vitamin B12. IMPLICATIONS FOR PRACTICE: this study, and other research in this area, has implications for health professionals, including midwives with their particular involvement in prenatal care, and also highlights the need for a clearer focus on nutrition in nursing and midwifery education.

Adult↗
PubMed1993

Sequence of the ompH gene from the deep-sea bacterium Photobacterium SS9.

In contrast to studies of many other extremophiles, the molecular characterization of the barophilic or high-pressure-adapted bacteria of the deep ocean is virtually nonexistent. One exception is the discovery that the moderate barophile Photobacterium SS9 preferentially synthesizes a 37-kDa outer membrane protein, designated OmpH, in response to elevated hydrostatic pressure. We report here on the molecular characterization of the ompH gene. The deduced amino acid sequence of mature OmpH is similar to a number of porin proteins, including significant similarity to porin protein P2 from Haemophilus influenzae. It appears likely that OmpH is a unique porin whose synthesis is responsive to changes in the pressure regime of the deep-sea bacterium.

Adaptation, Physiological↗
PubMed1993

Identification of genes encoding components of the swarmer cell flagellar motor and propeller and a sigma factor controlling differentiation of Vibrio parahaemolyticus.

Vibrio parahaemolyticus possesses two distinct motility systems, the polar system used for swimming in liquid environments and the lateral system used for swarming over surfaces. Growth on surfaces induces swarmer cell differentiation and expression of the lateral motility system. Mutants, created by transposon mutagenesis of a clone expressing lateral flagellin and gene disruption in V. parahaemolyticus, were unable to swarm and failed to make lateral flagellin; therefore, unlike the case for the polar system, there is one gene (lafA) encoding lateral flagellin. In addition to lafA, other genes required for swarming but not for swimming were identified by gene replacement mutagenesis. The nucleotide sequence of the clone determined open reading frames (ORFs) and deduced amino acid sequences showed similarities to flagellar components of other bacteria: flagellin, hook-associated protein (HAP2), motor components, and flagellar sigma factor (sigma 28). Many sigma 28 factors have been shown to recognize cognate promoters; however, expression of lafA in Escherichia coli required LafS, and E. coli sigma 28 did not substitute. Also, there were no sequences preceding genes encoding flagellin or HAP2 resembling the sigma 28 consensus promoter. The product of the sigma-like gene seems to be a unique member of the sigma 28 cluster. It appears the result of requiring expression for immunodetection of flagellin clones was that the sigma locus was fortuitously cloned, since the sigma and lafA loci were not contiguous in the chromosome. This work initiates identification and placement of genes in a scheme of control for swarmer cell differentiation; three levels have been identified in the transcriptional hierarchy.

Amino Acid Sequence↗