PubMed Health⌕ Search

Biomedical subjects

E Gardiner

Publications and source records attributed to E Gardiner.

18 recordsLinked to original sources
PubMed2003

Vascular endothelial growth factor and soluble Tie-2 receptor in colorectal cancer: associations with disease recurrence.

AIMS: A delicate balance exists between pro-angiogenic factors and anti-angiogenic factors to regulate the process of angiogenesis. To investigate the relationship of VEGF-A with other angiogenic factors and to determine their clinical usefulness. METHODS: Venous blood was obtained from 47 patients with CRC prior to curative resections. VEGF-A, sVEGFR-1, sTie-2 receptor, and TNF-alpha levels in serum were measured concurrently with quantitative ELISA. The median follow-up term for patients without cancer death was 29 months (range 20-35). RESULTS: Both serum TNF-alpha activity and sVEGFR-1 was detectable in 17% and 74% of CRC patients, respectively. Univariate analysis demonstrated that the disease free survival was significantly associated with the tumour location (P=0.031), T category (P=0.006), TNF-alpha activity (P=0.0008), sTie-2 receptor (P=0.012) and VEGF-A (P<0.00001). From the survival analysis, a higher serum VEGF-A and sTie-2 receptor level is associated with an earlier development of metastases. Using multivariate Cox's regression analysis, the only independent predictors of outcome were sTie-2 receptor (P=0.038) and VEGF-A (P=0.006). CONCLUSIONS: sTie-2 receptor and VEGF-A appear to associate independently with the development of metastases, with VEGF-A being the most powerful predictor of outcome. These data also suggest that measurement of pre-operative sTie-2 receptor and VEGF-A is superior to determining VEGF-A alone with regards to predictive value.

Aged↗
PubMed2001

Cantharimides: a new class of modified cantharidin analogues inhibiting protein phosphatases 1 and 2A.

Cantharidin and its analogues have been of considerable interest as potent inhibitors of the serine/threonine protein phosphatases 1 and 2A (PP1 and PP2A). However, limited modifications to the parent compounds is tolerated. As part of an on-going study we have developed a new series of cantharidin analogues, the cantharimides. Inhibition studies indicate that cantharimides possessing a D- or L-histidine, are more potent inhibitors of PP1 and PP2A (PP1 IC(50)=3.22+/-0.7 microM; PP2A IC(50)=0.81+/-0.1 microM and PP1 IC(50)=2.82+/-0.6 microM; PP2A IC(50)=1.35+/-0.3 microM, respectively) than norcantharidin (PP1 IC(50)=5.31+/-0.76 microM; PP2A IC(50)=2.9+/-1.04 microM) and essentially equipotent with cantharidin (PP1 IC(50)=3.6+/-0.42 microM; PP2A IC(50)=0.36+/-0.08 microM). Cantharimides with non-polar or acidic amino acid residues are only poor inhibitors of PP1 and PP2A.

Bridged Bicyclo Compounds, Heterocyclic↗
PubMed2001

The Challenging Behaviour Scale (CBS): development of a scale for staff caring for older people in residential and nursing homes.

OBJECTIVES: A review of behavioural rating scales identified the need for a measure of resident behaviours that staff in care homes for older people find difficult to manage. A 25-item, broad-based rating scale, the Challenging Behaviour Scale (CBS), was developed to meet this need and its psychometric properties were examined. DESIGN: Cross-sectional surveys. METHODS: Ratings of 484 residents, living in 16 homes across England, were used to examine four methods of collecting inter-rater reliability data. Ratings of 382 residents living in 13 homes were used to evaluate criterion validity and to establish norms. Six further homes were used to explore qualitatively the validity of the suggested norms. Ratings of 98 residents living in four further homes were used to examine concurrent validity. The predictive validity of the CBS 'challenge' score was evaluated, using time-sampled direct observation of challenging behaviour in 237 residents, living in 11 homes. RESULTS: The scale records staff reports of the incidence, frequency and 'management difficulty' of resident behaviour and it can also identify 'challenging residents' through a computed score. It has good internal consistency, good test-retest reliability and adequate validity. Inter-rater reliability is good when staff receive training or when staff groups of at least three, of mixed qualifications, complete the scale. Norms are suggested for prospective studies of the prevalence of challenging behaviour. CONCLUSIONS: The CBS is quick to complete and may have potential for the evaluation of psychosocial interventions in care settings. It is, as far as we know, the first staff observational rating scale that is based on the reports of care staff, who constitute the backbone of residential care provision. Suggestions for improvements in criterion and content validity are outlined.

Aged↗
PubMed2001

The inhibition of protein phosphatases 1 and 2A: a new target for rational anti-cancer drug design?

Recent investigations in our laboratories have highlighted that the inhibition of the serine/threonine protein phosphatases 1 and 2A (PP1 and PP2A) is an excellent target for the development of novel anti-cancer agents. Using a combination of the known crystal structure of PP1 and the modelled structure of PP2A, we have rationally designed a new class of protein phosphatase inhibitors, cantharimides, which exhibit broad-spectrum anti-cancer activity. Synthetic modifications of the simplest known PP1 and PP2A inhibitor, norcantharidin, has led to the development of potent PP1 and PP2A inhibitors.

Antineoplastic Agents↗
PubMed2000

Plugging the intramedullary canal of the femur in total knee arthroplasty: reduction in postoperative blood loss.

A prospective, randomized trial comparing postoperative drainage was carried out in 120 consecutive knees undergoing total knee arthroplasties divided into 2 groups. In one (55 knees), the entry point for the femoral intramedullary rod was left open. In the other (65 knees), the entry point was closed by an autologous bone plug. The mean drainage after 24 hours and the total drainage were lower when the femoral canal was plugged (800 vs 960 mL and 925 vs 1,165 mL). The bone plug always united, and no loose bodies were seen 6 months after operation. We conclude that the femoral intramedullary guide hole should be plugged with autologous bone because this technique results in a small but significant reduction in early blood loss without countervailing disadvantages.

Adult↗
PubMed2000

Pre-operative serum vascular endothelial growth factor can select patients for adjuvant treatment after curative resection in colorectal cancer.

We aim to determine the clinical usefulness of pre-operative serum vascular endothelial growth factor (VEGF) as a predictor of outcome in patients undergoing curative resection for colorectal cancer. Serum VEGF was assayed by quantitative ELISA in 81 patients prior to curative resection for node-negative (n = 53) and node-positive (n = 28) disease. Median follow-up for patients without cancer death was 27 months (range 21-37). Pre-operative serum VEGF was significantly higher in patients who went on to develop metastases than those who did not (median, 713 pg ml-1 vs. 314 pg ml-1, P < 0.0001). Using multivariate Cox regression analysis, pre-operative serum VEGF was the most important prognostic factor independent of nodal status and adjuvant chemotherapy, and was superior to nodal status in predicting outcome (P < 0.00001). At 575 pg ml-1, pre-operative serum VEGF was 64% sensitive and 89% specific in predicting the development of metastases in curative resections, with a positive predictive value of 73% and a negative predictive value of 85%. Pre-operative serum VEGF is a powerful predictor of outcome following curative surgery for colorectal cancer. These data support the measurement of pre-operative serum VEGF as a method for selecting patients who require adjuvant therapy.

Aged↗
PubMed1999

Do the rich really die young? Alcohol-related mortality and social class in Great Britain, 1988-94.

AIMS: To determine whether social class is a major influence on alcohol-related mortality in the general, economically active population of Great Britain. DESIGN AND PARTICIPANTS: Poisson regression of rates of mortality known to be directly caused by alcohol consumption by age, sex and social class in England, Wales and Scotland. MEASUREMENTS: The measure of alcohol-related mortality is total deaths from ICD-9 categories 291; 303; 357.5; 425.5; 535.3; 305; 790.3; and 571.0-571.3 over the 7-year period 1988-94. (It excludes deaths for which alcohol-attributable fractions would need to be calculated.) The measure of social class is the British Registrar General's six-fold occupational classification, used to code census and death certification data. FINDINGS: Alcohol-related mortality rates are higher for men in the manual occupations than in the non-manual occupations, but the relative magnitude depends on age. Men aged 25-39 in the unskilled manual class are 10-20 times more likely to die from alcohol-related causes than those in the professional class, whereas men aged between 55 and 64 in the unskilled manual class are only about 2.5-4 times more likely to die. For women in paid employment there is no consistent class gradient; younger women in the manual classes are more likely to die from alcohol-related causes, but for older women it is those in the professional class who suffer elevated mortality. CONCLUSIONS: Social class is a risk factor for alcohol-related mortality in Britain, although it is mediated by age and sex. Alcohol appears to be similar to other psychoactive substances, therefore, in that problem use is linked to social structural factors such as poverty, disadvantage and social class. This suggests that social interventions aimed at reducing poverty and inequality have the potential to reduce current levels of alcohol-related harm among the poorest groups in the community.

Adolescent↗
PubMed1998

Tissue specific and vitamin D responsive gene expression in bone.

Studies of gene expression in bone have adopted a number of molecular approaches that seek to determine those cis and trans-acting factors responsible for the development and physiological regulation of this unique tissue. The majority of studies have been performed in vitro, focussing on the expression of genes such as osteocalcin, bone sialoprotein and type I collagen which demonstrate restricted or altered expression patterns in osteoblasts. These studies have demonstrated a large number of cis and trans acting factors that modulate the tissue specific and vitamin D responsive expression of these genes. These include the response elements and regions mediating basal and vitamin D dependent transcription of these genes as well as some of the transcription factors that bind to these regions and the nucleosomal organisation of these genes within a nuclear framework. In vivo studies, including the introduction of transgenes into transgenic mice, extend these in vitro observations within a physiological context. However, in part due to limitations in each approach, these in vitro and in vivo studies are yet to accurately define all the necessary cis and trans-acting factors required for tissue specific and vitamin D responsive gene expression. Advances have been made in identifying many cis-acting regions within the flanking regions of these genes that are responsible for their restricted expression patterns, but a vector incorporating all the necessary cis-acting regions capable of directing gene expression independent of integration site has not yet been described. Similarly, trans-acting factors that determine the developmental destiny of osteoblast progenitors and the restricted expression of these genes remain elusive and, despite advances in the understanding of protein-DNA interactions at vitamin D response elements contained within these genes, further intermediary factors that interact with the transcriptional machinery to modulate vitamin D responsiveness need to be identified.

Animals↗
PubMed1998

A comparison of T2 and gadolinium enhanced MRI with CT myelography in cervical radiculopathy.

Two MRI strategies which have been reported to be effective in assessing cervical exit foramina, were prospectively compared with CT myelography in 20 patients with cervical radiculopathy. The first strategy utilized 3D T2* images, the second gadolinium enhanced 2D T1 images. Gadolinium (dimeglumine gadopentetate, Schering Ltd) enhanced images did not confer any benefit in the investigation of this condition, probably due to enhancement of herniated disc material and osteophytes adjacent to the neurocentral joint. Three-dimensional (3D) T2* white cerebrospinal fluid images had an accuracy approaching 90% for the diagnosis of foraminal encroachment, compared with a gold standard. MRI including a 3D T2* sequence is thus an acceptable primary investigation for cervical radiculopathy, but when the findings are incompatible with clinical symptomatology, CT myelography is still indicated.

Adult↗
PubMed1997

The inter-rate reliability of a generic measure of severity of illness.

BACKGROUND: There has been increasing interest in the development of measures to quantify baseline severity of illness and thus provide a more meaningful interpretation of health outcomes. OBJECTIVE: We aimed to assess the inter-rater reliability of a generic measure of illness severity, the Duke University Severity of Illness (DUSOI) checklist. METHODS: Selected general practices and hospital outpatient departments across Tyneside and Humberside in the UK were used as the setting. Thirty-three clinicians were posted copies of the same set of 14 patient records and asked to rate the severity of illness of each patient using the DUSOI. The subjects were 27 GPs, three consultant chest physicians and three diabetologists. The main outcome measures were: (i) intraclass correlation coefficients used to express clinician agreement upon severity scores; and (ii) a 'gold standard', constructed in order to assess clinician agreement upon the health problems identified in the patient record to be considered as constituents of overall severity. RESULTS: It was found that the degree of inter-rater reliability of severity scoring was satisfactory, with an intraclass correlation coefficient of 0.43. In terms of identification of problems to be rated, there was considerable agreement between raters and a specially compiled 'gold standard' of health problems. CONCLUSION: The DUSOI has potential use in routine clinical practice, but strategies should be developed in order to maximize the reliability of rating illness severity on such a generic measure.

Ambulatory Care↗
PubMed1997

Ethnic differences in substance use and alcohol-use-related mortality among first generation migrants to England and Wales.

Epidemiological studies among migrant ethnic groups are potentially important as a way to provide insight into the relative importance of genetic, cultural, and socioeconomic factors in the etiology of substance use disorders. This paper summarizes prior United Kingdom studies of the prevalence of substance-use-associated problems in different ethnic groups before analyzing trends in recent mortality data by country of birth. On this evidence, rates of alcohol-related mortality may be marginally higher for those born in the Caribbean than for the native British, but are substantially raised for those born in Ireland and the Indian subcontinent. There is some indication that rates for the Caribbean and possibly the Irish groups have risen more rapidly than for the national population over a 12-year period. These differences in mortality rates seem to have arisen for complex reasons.

Adolescent↗
PubMed1996

Accuracy and reliability of assessment of severity of illness before and after an educational intervention.

Severity-of-illness measurement is considered to be an important factor in the risk adjustment of medical outcomes. However, for those measures that involve a high level of clinical judgment, strategies have to be developed to maximize the consistency of rating severity that can be implemented, especially when rating is based upon medical record review. A group of 25 clinicians were sent the same set of 14 patient records, and requested to use the Duke University Severity of Illness (DUSOI) checklist to rate the severity of patients' illness. Written instructions for the use of this instrument were provided. A short educational intervention was than made by the research team, and the clinicians were sent the same set of records to be rated again. Any improvement in the accuracy and reliability of severity assessment over the two ratings was then studied. The educational intervention resulted in identification of fewer irrelevant health problems. However, it had little impact upon the reliability of severity scoring itself, as measured by the intraclass correlation coefficient. Measuring severity of illness is a conceptually complex procedure. However, given its role in outcome interpretation, it may be worth pursuing strategies aimed at maximizing consistency of clinician rating. There are a number of options, including improved written instructions and more intensive training, that could be implemented.

Clinical Competence↗
PubMed1995

Identification and characterisation of a novel human RNA-binding protein.

The processing of heterogeneous nuclear RNA (hnRNA) into a mature message occurs within a number of different nuclear ribonucleoprotein (RNP) complexes which bind to the hnRNA and provide the machinery for these modifying events. Although some components of the nuclear RNP complexes have been isolated, many remain to be elucidated. We report here the isolation of a novel human nucleic-acid-binding protein isolated by screening a lambda gt11 expression library with an oligodeoxyribonucleotide probe. The complete cDNA clone (E5.1) is homologous to a recently published murine sequence. The human gene encodes a ubiquitously expressed mRNA sequence with a putative open reading frame of 305 amino acids and contains a number of domains found in well characterised RNA-binding proteins. The E5.1-derived RNA recognition motif (RRM) is phylogenetically most related to the hnRNP C protein, a component of heterogeneous nuclear RNP particles which participates in mRNA splicing in vitro. E5.1 may, therefore, represent a novel gene, encoding a protein involved in processing of precursor RNAs into mature mRNA.

Amino Acid Sequence↗
PubMed1995

G/C element contributes to the cell line-specific expression of the proximal osteocalcin promoter.

Sequential activation of cell type-specific genes occurs during osteoblast development. The promoter of one such gene, osteocalcin, has been widely studied, but the DNA sequences that govern osteoblast-specific expression have not been defined. The proximal osteocalcin promoter linked to pTKCAT directs strong promoter activity in osteoblast-like ROS17/2.8 cells and comparatively weak promoter activity in nonosteoblastic NIH3T3 cells. To identify sequences important in conferring cell-specific expression of the osteocalcin gene, a deletion series of the human proximal promoter was constructed and the activities assessed in ROS17/2.8 and NIH3T3 cells. These studies identified a 30 bp sequence within the proximal promoter (osteocalcin repressor element-1 [ORE-1]) which is responsible for repressing the transcriptional activity in NIH3T3 cells. In electrophoretic mobility shift assays from both NIH3T3 and ROS17/2.8 cells, a protein complex bound to the ORE-1 that was related to a complex which binds the G/C-rich repressor element in the collagen type I (alpha 1) promoter. In addition, there was a second complex from NIH3T3 cells but not ROS17/2.8 cells that bound the ORE-1 fragment. The presence of this additional factor in NIH3T3 cells parallels the observation that constructs carrying the ORE-1 sequence have repressed promoter activity relative to the analogous constructs lacking the ORE-1 when transfected into NIH3T3 and suggests that the NIH3T3-specific factor is a repressor. These data indicate that the G/C element in the ORE-1 contributes to the repression of osteocalcin gene transcription in a nonosteoblast cell line. The high homology between the ORE-1 sequence and a related sequence in the collagen type I (alpha 2) proximal promoter suggests that homologous regions in other osteoblast-expressed genes may function similarly.

3T3 Cells↗
PubMed1995

The osteocalcin and collagen type I (alpha 1) promoters share common basal regulatory units.

Sequential activation of osteoblast-specific genes occurs during cell development. Regulation of these genes is through the cooperation between basal, hormone-responsive, and growth factor-responsive transcriptional control elements. The active hormone, 1,25-dihydroxyvitamin D3 plays an important role in the regulation of osteocalcin and other osteoblast-expressed genes. As well as containing a vitamin D response element, the upstream region of the osteocalcin promoter also has potent basal activity in the osteoblast-like ROS17/2.8 cell line. The present study identifies a short DNA sequence that contributes to basal promoter activity. This osteocalcin cis-acting response element (OSCARE-1) has two basal regulatory elements: a G/C-rich element and an adjacent reverse CCAAT element. Homologous sequences have been characterized as negative and positive basal regulatory elements, respectively, in the promoter of the collagen type I (alpha 1) gene. In electrophoretic mobility-shift assays, this collagen regulatory unit and OSCARE-1 produce similar banding patterns and bind common ROS17/2.8 nuclear proteins. Mutations of the G/C element in the collagen promoter showed that it functions as an inhibitory element in NIH-3T3 cells. Introduction of the same mutations into the G/C element of the OSCARE-1 unit exposed a similar repressive activity in NIH-3T3 cells, which correlated with an altered electrophoretic mobility-shift assay banding pattern. We have shown a similarity between a basal regulatory unit in the distal osteocalcin promoter and a unit in the proximal collagen type I (alpha 1) promoter. The fact that similar units are present in other osteoblast-specific promoters suggests that OSCARE-1-like units may be a common regulator of osteoblast-expressed genes.

3T3 Cells↗
PubMed1981

Deficiency of malic enzyme: a possible marker for malignancy in lymphoid cells.

Soluble malic enzyme (MEs) has been examined in long-term human lymphoid cell lines cultured from 101 individuals. In 65 out of 66 lines derived from people without lymphoreticular malignancy the enzyme was very active. Lines established from 35 individuals with various forms of lymphoreticular malignancy were also examined, including in some cases more than 1 line derived from the same patient. In all cases where the cell line was thought to be derived from normal cells MEs was active, but in 27 out of 29 lines thought to be derived from malignant cells (from 25 patients) MEs was not detected. In the case of two patients with chronic lymphatic leukaemia 'normal' lines active for malic enzyme, and 'leukaemic' lines lacking malic enzyme, had been cultured from the same individual. Preliminary investigations of the lack of malic enzyme in somatic cell hybrids derived from lymphoma and leukaemia cell lines are compatible with an alteration at the level of the structural locus MEs on chromosome 6. However, the restoration of MEs activity in one line by fusion with mouse teratocarcinoma cells suggests that the alteration may be of a regulatory nature.

Animals↗