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Biomedical subjects

M McKay

Publications and source records attributed to M McKay.

At least 19 recordsLinked to original sources
PubMed2006

Heterogeneous nuclear ribonucleoprotein K is over expressed, aberrantly localised and is associated with poor prognosis in colorectal cancer.

Heterogeneous ribonucleoprotein K (hnRNP K) is a member of the hnRNP family which has several different cellular roles including transcription, mRNA shuttling, RNA editing and translation. Several reports implicate hnRNP K having a role in tumorigenesis, for instance hnRNP K increases transcription of the oncogene c-myc and hnRNP K expression is regulated by the p53/MDM 2 pathway. In this study comparing normal colon to colorectal cancer by proteomics, hnRNP K was identified as being overexpressed in this type of cancer. Immunohistochemistry with a monoclonal antibody to hnRNP K (which we developed) on colorectal cancer tissue microarray, confirmed that hnRNP K was overexpressed in colorectal cancer (P<0.001) and also showed that hnRNP K had an aberrant subcellular localisation in cancer cells. In normal colon hnRNP K was exclusively nuclear whereas in colorectal cancer the protein localised both in the cytoplasm and the nucleus. There were significant increases in both nuclear (P=0.007) and cytoplasmic (P=0.001) expression of hnRNP K in Dukes C tumours compared with early stage tumours. In Dukes C patient's good survival was associated with increased hnRNP K nuclear expression (P=0.0093). To elaborate on the recent observation that hnRNP K is regulated by p53, the expression profiles of these two proteins were also analysed. There was no correlation between hnRNP K and p53 expression, however, patients who presented tumours that were positive for hnRNP K and p53 had a poorer survival outcome (P=0.045).

Adenocarcinoma↗
PubMed2004

Clinical and cellular radiosensitivity in inherited human syndromes.

AIMS: It has been proposed that in-vitro measurements of radiosensitivity might allow individualisation of patient radiotherapy schedules, with concomitant increases in the therapeutic ratio between tumours and normal tissues. Most predictive assay research on normal tissues to date has been based on the radiosensitivity of normal lymphocytes and skin fibroblasts as determined by clonogenic cell-survival assays. Studies comparing the radiosensitivity of fibroblasts or lymphocytes with acute or late radiation damage have reported variable results. METHODS: In this study, we measured the radiosensitivity of lymphocytes from three patients displaying clinical radiation hypersensitivity who were known or suspected to carry germline mutations in genes that have been linked to increased radiosensitivity (a BRCA2 mutation carrier, a patient with Bloom's syndrome and a patient with a Fanconi anaemia-like condition), to investigate whether there is a correlation between cellular radiosensitivity and normal tissue response. RESULTS: We found no association between lymphocyte radiosensitivity and the development of adverse radiation reactions in this group of patients, as is observed in the paradigm radiosensitivity syndrome, ataxia-telangiectasia. CONCLUSIONS: Our results, and those of others, show that, at present, the evidence is not strong enough to justify routine clinical use of clonogenic cell survival assays to predict radiation response.

Adult↗
PubMed2003

Radiation-hypersensitive cancer patients do not manifest protein expression abnormalities in components of the nonhomologous end-joining (NHEJ) pathway.

Radiation therapy (RT) is utilised for the treatment of around half of all oncology patients during the course of their illness. Despite great clinical progress in the rational deployment of RT, the underlying molecular basis for its efficacy and toxicity are currently imperfectly understood. In this study, we took a biochemical approach to evaluate the potential role of key ionising radiation repair proteins in the treatment outcomes of patients with severe acute or late RT side effects. Lymphoblastoid cell lines were established from blood samples from 36 radiosensitive cases and a number of controls (the latter had had RT but did not develop significant toxicity). The expression level and migration of key proteins from the nonhomologous end-joining (NHEJ) pathway was evaluated by Western blot analysis on cases and controls. We did not observe any abnormalities in expression level or migration pattern of the following NHEJ proteins in radiosensitive cancer cases: Ku70, Ku80, XRCC4, DNA Ligase IV. These important negative results provide evidence that mutations that affect protein expression of these NHEJ components are unlikely to underlie clinical radiation sensitivity.

Cohort Studies↗
PubMed2001

Novel DNA sequence variants in the hHR21 DNA repair gene in radiosensitive cancer patients.

PURPOSE: Radiation therapy is an important treatment modality for oncology patients. DNA sequence variants have so far been identified in only a few genes in radiosensitive cancer patients. Patients known to be clinically radiosensitive were tested for mutation of a gene involved in DNA double-strand break repair and sister chromatid cohesion--hHR21. METHODS AND MATERIALS: Clinically radiation-sensitive patients were accrued to the study after giving informed consent. Blood samples were obtained and lymphoblastoid cell lines established. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to amplify the hHR21 gene, and the DNA product was sequenced to identify any genetic abnormalities. Northern blot analysis, cell survival, and growth assays were performed on control cells and cells with hHR21 variants, and a restriction digest assay was developed to screen for carriers of a detected gene variant. RESULTS: The DNA sequence of the hHR21 gene was determined in 19 radiation-sensitive cancer patients. In 6 of the 19 patients, a thymidine (T) to cytosine (C) transition was detected at position 1440 of the hHR21 open reading frame (T1440C). This variant did not alter the amino acid sequence and was likely to be a polymorphism. One patient with a particularly severe radiation reaction had a second sequence variant immediately adjacent to the first. This was a guanine (G) to adenine (A) transition (G1441A), resulting in a change of the amino acid sequence (glycine --> arginine) in a portion of the protein conserved in evolution. This suggests that this DNA alteration may be biologically significant. Restriction digest with the HpaII enzyme confirmed the presence of both sequence variants on the same allele. CONCLUSIONS: We describe the first two DNA sequence variants ever found in the hHR21 gene, in patients with clinical radiation hypersensitivity. Although no direct evidence for the involvement of hHR21 alterations in the radiosensitivity of the cancer patients examined has been demonstrated, the possibility exists that homozygous mutations or other mutations of this gene could contribute to radiosensitivity. A simple test is described that could be applied to screening for these variants in relevant populations.

Amino Acid Sequence↗
PubMed2001

Boys starting school disadvantaged: implications from teachers' ratings of behaviour and achievement in the first two years.

BACKGROUND: Consistent evidence indicates that low socio-economic status (SES) acts as an important stressor and vulnerability factor for children's school learning. However, specific mechanism(s) of this process are still not well understood. AIM: This study was a follow-up of the classroom learning behaviour and perceived achievement of low and middle income children after two years at school, who had previously been rated soon after starting school. It examined whether teachers' ratings displayed predictive stability over that period, and whether significant differences evident at age 5 in SES and gender were still operative at age 7. SAMPLE: Two samples, of low income (N = 85) and middle income (N = 63) children, were rated following school entry (mean age 5 years 3 months) and rated again after two years at school. METHOD: The children were rated at both points by their regular classroom teachers using the Learning Behaviours Scale (Stott et al., 1998) with subscales of Distractible, Apprehensive and Uncooperative, together with ratings of academic achievement and their personal perception of each child. RESULTS: SES was found to be a very limited predictor for the learning behaviour subscale ratings and for teachers' personal perceptions at both ages 5 and 7. SES did significantly predict expected Academic Achievement at age 5, but this effect disappeared completely by age 7. Conversely, within the two defined groups, Low Income boys were found to display significantly poorer learning behaviours at age 5, especially in terms of distractible behaviour, compared with Middle Income boys and with girls generally. This pattern was maintained over the next two years of their schooling. The effect of SES was thus demonstrated more powerfully in between-group differences than by means of regression. The findings emphasised the persistence of teachers' initial negative impressions about distractible 'hard to manage' boys from low SES families. CONCLUSION: The outcomes of this study suggest that low SES boys commenced school significantly disadvantaged by a pattern of perceived distractible behaviour in particular, and that this perception continued to operate over the next two years of their schooling. Such a pattern implied that these boys were perceived by their teachers, from early in their school careers, as being demanding and difficult to teach. Once teachers gave certain boys a label it appeared to 'stick'. SES per se was thus not the main risk factor. It was primarily the effect of boys' greater activity level, distractibility, and initial inability to 'settle' to classroom routines, which seemed to be particularly associated with certain lower SES child-rearing practices. These behaviours had a serious negative impact on the children's teachers and the way they responded to them.

Achievement↗
PubMed2001

Enhancement of rural community committee capacity for heart health promotion in Manitoba.

The province of Manitoba is 'rural' by nature, although 70% of its one million people reside within two large urban centres. The Manitoba Heart Health Project (MHHP) province-wide survey (1989) showed that cardiovascular disease (CVD) risk factors were highest and heart health-related knowledge was lowest in the rural population. Working with rural communities, the MHHP Demonstration Project (1992-95) carried out rural heart health promotion using a rural community committee-driven approach with appropriate training, limited resources and at low cost.

Community Participation↗
PubMed2001

Children in crashes: mechanisms of injury and restraint systems.

OBJECTIVES: To explore the levels of protection offered to children involved in motor vehicle collisions. DESIGN: A joint study by the Children's Hospital of Eastern Ontario (CHEO) and Transport Canada, Ottawa, conducted in 2 phases: retrospective from 1990 to 1997 and prospective from 1998 to 2000. SETTING: CHEO, a university affiliated tertiary care centre. PATIENTS: Children admitted to CHEO between 1990 and 2000 with spinal trauma due to motor vehical crashes (MVCs). Phase I of the study involved analysis, in a series of 45 children after MVAs, by location of spinal injury versus belt type. Phase 2 was a prospective study of 22 children injured in 15 MVAs. INTERVENTIONS: A biomechanical assessment of the vehicle and its influence on the injuries sustained. MAIN OUTCOME MEASURES: The nature and extent of the injuries sustained, and the vehicle dynamics and associated occupant kinematics. RESULTS: The odds ratio of sustaining a spinal injury while wearing a 2-point belt versus a 3-point belt was 24 (95% confidence interval 2.0-2.45, p < 0.1), indicating a much higher incidence with a lap belt than a shoulder strap. CONCLUSIONS: Proper seat-belt restraint reduces the morbidity in children involved in MVCs. Children under the age of 12 years should not be front-seat passengers until the sensitivity of air bags has been improved. Three-point pediatric seat belts should be available for family automobiles to reduce childhood trauma in MVCs.

Accidents, Traffic↗
PubMed2000

Mutation analysis of BRCA1 and BRCA2 cancer predisposition genes in radiation hypersensitive cancer patients.

PURPOSE: The dose intensity of radiotherapy (RT) used in cancer treatment is limited in rare individuals who display severe normal tissue reactions after standard RT treatments. Novel predictive assays are required to identify these individuals prior to treatment. The mechanisms responsible for such reactions are unknown, but may involve dysfunction of genes involved in the sensing and response of cells to DNA damage. The breast cancer susceptibility genes BRCA1 and BRCA2 are implicated in DNA damage repair and the control of genome stability. The purpose of this study was to determine if clinical radiation hypersensitivity is related to mutations of the BRCA1 and BRCA2 genes. Such information is of potential use in the clinical management of BRCA mutation carriers and their families. METHODS AND MATERIALS: Twenty-two cancer patients who developed severe normal tissue reactions after RT were screened for mutations of BRCA1 and BRCA2, using various methods including protein truncation testing, direct DNA sequencing, and a PCR-based BRCA1 exon 13 duplication test. RESULTS: No mutations were detected in the 22 patients tested, despite screening for the majority of commonly described types of mutations of BRCA1 and BRCA2. CONCLUSION: These early results suggest that genes other than BRCA1 and BRCA2 probably account for most cases of clinical radiation hypersensitivity, and that screening for mutations of BRCA1 and BRCA2 is unlikely to be useful in predicting response to radiotherapy. However, it has not been excluded that some BRCA1 or BRCA2 heterozygotes might experience unexpected RT toxicity; further BRCA mutation screening on radiation sensitive individuals is warranted.

BRCA2 Protein↗
PubMed2000

The Huntingdon Day Hospital Trial: secondary outcome measures.

OBJECTIVE: To compare day hospital to day centre rehabilitation using scales to measure mobility, activities of daily living and quality of life. DESIGN: Single blind randomized controlled trial with home assessments at baseline (twice), six weeks and three months. SETTING: Mainly rural health district. Day hospital and social services day centres in market towns. INTERVENTIONS: Day hospital treatment or day centre rehabilitation by a physiotherapist and two health support workers. MAIN OUTCOME MEASURES: World Health Organization mobility scale scored with and without aid, Nottingham Extended Activities of Daily Living Scale and Nottingham Health Profile. SUBJECTS: One hundred and five physically disabled older patients living at home referred for day hospital rehabilitation or maintenance before discharge from hospital (66) or referred as outpatients (39). RESULTS: At three months there were no statistically significant differences between rehabilitation at day hospital and day centre for any of the outcome measurements. However, there were significant improvements between baseline and three months for the following subscales [mean change per six-week period (95% confidence interval) ]: WHO mobility subscale (with aid) -0.67 (-0.99,-0.35); Nottingham Health Profile mobility subscale -10 (-15.5,-4.5) Nottingham extended ADL mobility subscale +3.08 (1.78,4.37); Nottingham extended ADL leisure subscale +1.66 (0.96,2.36). CONCLUSION: There were no differences between day hospital and day centre in the outcomes measured. Day rehabilitation appeared to improve functional ability and mobility and scales reflecting these domains deserve further evaluation as outcome measures in this patient group. However, no improvement in quality of life was observed.

Activities of Daily Living↗
PubMed1999

A randomized controlled trial of day hospital and day centre therapy.

OBJECTIVE: To compare the outcome of day hospital to day centre rehabilitation. DESIGN: Single blind randomized controlled trial with home assessments at baseline (twice), six weeks and three months. SETTING: Mainly rural health district. Day hospital and social services day centres in market towns. SUBJECTS: One hundred and five physically disabled older patients living at home referred for day hospital rehabilitation or maintenance before discharge from hospital (66) or referred as outpatients (39). INTERVENTIONS: Day hospital treatment or day centre rehabilitation by a physiotherapist and two health support workers. MAIN OUTCOME MEASURES: Barthel Index, Philadelphia Geriatric Morale Scale and Caregiver Strain Index. RESULTS: More day centre (23/55) than day hospital patients (6/50) (p <0.001) withdrew from allocated treatment by choice or because of operational difficulties. Both groups improved significantly in functional ability and reduction of care-giver strain by three months but there was no significant difference between groups. The mean improvement in Barthel Index (standard error) for day hospital = +1.5 (0.41) (n = 34) and day centres = +1.5 (0.48) (n = 38). The mean difference (95% confidence interval) between day hospital and day centre was 0 (-1.28, +1.28). Likewise the mean Philadelphia Geriatric Morale Scale improvement for day hospital +1.8 (0.66) (n = 35) and day centres was +0.9 (0.63) (n = 38). The mean difference was -0.88 (-2.7, +0.95). The mean reduction in Caregiver Strain for day hospital was -1.45 (0.5) (n = 23) and day centre was -1.59 (0.47) (n = 27). The difference was -0.14 (1.52, +1.24). (These analyses are all on an intention-to-treat basis.) CONCLUSION: Whilst the improvement in functional ability and care-giver strain was similar in both groups, day centre rehabilitation was less popular and had practical difficulties. If these difficulties can be overcome the model should be tested elsewhere.

Aged↗
PubMed1998

Implementation of an on-line Emergency Unit nursing system.

We designed and implemented an Emergency Unit nursing system which has been in practice since March of 1995. The system has been very successful and is used on 97% of all Emergency Unit visits. The system is designed for rapid entry and retrieval of information. We have found that the time spent by nurses documenting patient care in this system is minimal. On average, over a six day study period only five minutes per patient visit, and about 30 minutes per nurse per shift was spent actually entering information into the system. We plan to continue to evaluate the use of the system and expand it to include use by other disciplines in the near future.

Emergency Service, Hospital↗
PubMed1997

Anaesthetic potency of inhalation agents is independent of membrane microviscosity.

The decrease in membrane microviscosity of erythrocyte ghosts in the presence of clinically relevant concentrations of seven inhalation anaesthetic agents was studied using fluorescence polarization anisotropy of the membrane incorporated fluorescent probes 1,6-diphenyl-1,3,5-hexatriene and 1-[4-trimethylammoniumphenyl]-6-phenyl-1,3,5-hexatriene. All anaesthetic agents produced a dose-dependent decrease in anisotropy of both probes, indicating decreased membrane microviscosity. The reduction in anisotropy measured at the minimum alveolar concentration (ED50) for anaesthesia was related inversely to the anaesthetic potency of the agent and was directly proportional to the hypothetical concentration of agent in the membrane calculated from lipid-water partition coefficients. These findings do not support the hypothesis that volatile anaesthetic agents act by increasing membrane microviscosity of the bulk lipid bilayer to produce anaesthesia.

Anesthetics, Inhalation↗
PubMed1997

Childhood needlestick injuries in the Dublin metropolitan area.

Childhood needlestick injuries and other risk exposures outside of hospital are becoming increasingly common. A retrospective review of casenotes to ascertain the incidence, epidemiology and adequacy of management and follow-up of exposures in the Dublin metropolitan area revealed 52 cases between July 1995 and October 1996. Median age of children was 7.4 years. Most occurred in inner city areas with a recognised high prevalence of i.v. drug use. Only 2 high-risk exposures were identified. On presentation all cases received Hepatitis B vaccination and 56% received Hepatitis B immunoglobulin. Following Hepatitis B virus, Hepatitis C virus and Human immunodeficiency virus testing, no seroconversions have been identified to date in 9 children with completed tests. General follow-up and Hepatitis B immunisation when initiated were not always complete. Standardised management protocols and wider availability of counselling are recommended.

Adolescent↗