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Biomedical subjects

G MacDonald

Publications and source records attributed to G MacDonald.

At least 19 recordsLinked to original sources
PubMed1999

Mitochondria-dependent and -independent regulation of Granzyme B-induced apoptosis.

Granzyme B (GraB) is required for the efficient activation of apoptosis by cytotoxic T lymphocytes and natural killer cells. We find that GraB and perforin induce severe mitochondrial perturbation as evidenced by the release of cytochrome c into the cytosol and suppression of transmembrane potential (Deltapsi). The earliest mitochondrial event was the release of cytochrome c, which occurred at the same time as caspase 3 processing and consistently before the activation of apoptosis. Granzyme K/perforin or perforin treatment, both of which kill target cells efficiently but are poor activators of apoptosis in short-term assays, did not induce rapid cytochrome c release. However, they suppressed Deltapsi and increased reactive oxygen species generation, indicating that mitochondrial dysfunction is also associated with this nonapoptotic cell death. Pretreatment with peptide caspase inhibitors zVAD-FMK or YVAD-CHO prevented GraB apoptosis and cytochrome c release, whereas DEVD-CHO blocked apoptosis but did not prevent cytochrome c release, indicating that caspases act both up- and downstream of mitochondria. Of additional interest, Deltapsi suppression mediated by GraK or GraB and perforin was not affected by zVAD-FMK and thus was caspase independent. Overexpression of Bcl-2 and Bcl-XL suppressed caspase activation, mitochondrial cytochrome c release, Deltapsi suppression, and apoptosis and cell death induced by GraB, GraK, or perforin. In an in vitro cell free system, GraB activates nuclear apoptosis in S-100 cytosol at high doses, however the addition of mitochondria amplified GraB activity over 15-fold. GraB- induced caspase 3 processing to p17 in S-100 cytosol was increased only threefold in the presence of mitochondria, suggesting that another caspase(s) participates in the mitochondrial amplification of GraB apoptosis. We conclude that GraB-induced apoptosis is highly amplified by mitochondria in a caspase-dependent manner but that GraB can also initiate caspase 3 processing and apoptosis in the absence of mitochondria.

Animals↗
PubMed1999

Bridging the gap.

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Adolescent↗
PubMed1998

Through the looking glass darkly? When self-doubts turn into relationship insecurities.

The authors argue that individuals regulate perceptions of their relationships in a self-protective way, finding virtue in their partners only when they feel confident that their partners also see virtues in them. In 4 experiments, the authors posed an acute threat to low and high self-esteem individuals' feelings of self-worth (e.g., guilt about a transgression, fears of being inconsiderate or intellectually inept). They then collected measures of confidence in the partner's positive regard and acceptance (i.e., reflected appraisals) and perceptions of the partner. The results revealed that low self-esteem individuals reacted to self-doubt with heightened doubts about their partners' regard, which then tarnished impressions of their partners. In contrast, high self-esteem individuals reacted to self-doubts by becoming more convinced of their partners' continued acceptance, using their relationships as a resource for self-affirmation.

Adult↗
PubMed1997

Expression of a dominant negative mutant of interleukin-1 beta converting enzyme in transgenic mice prevents neuronal cell death induced by trophic factor withdrawal and ischemic brain injury.

To explore the role of the interleukin (IL)-1 beta converting enzyme (ICE) in neuronal apoptosis, we designed a mutant ICE gene (C285G) that acts as a dominant negative ICE inhibitor. Microinjection of the mutant ICE gene into embryonal chicken dorsal root ganglial neurons inhibits trophic factor withdrawal-induced apoptosis. Transgenic mice expressing the fused mutant ICE-lacZ gene under the control of the neuron specific enolase promoter appeared neurologically normal. These mice are deficient in processing pro-IL-1 beta, indicating that mutant ICEC285G blocks ICE function. Dorsal root ganglial neurons isolated from transgenic mice were resistant to trophic factor withdrawal-induced apoptosis. In addition, the neurons isolated from newborn ICE knockout mice are similarly resistant to trophic factor withdrawal-induced apoptosis. After permanent focal ischemia by middle cerebral artery occlusion, the mutant ICEC285G transgenic mice show significantly reduced brain injury as well as less behavioral deficits when compared to the wild-type controls. Since ICE is the only enzyme with IL-1 beta convertase activity in mice, our data indicates that the mutant ICEC285G inhibits ICE, and hence mature IL-1 beta production, and through this mechanism, at least in part, inhibits apoptosis. Our data suggest that genetic manipulation using ICE family dominant negative inhibitors can ameliorate the extent of ischemia-induced brain injury and preserve neurological function.

Animals↗
PubMed1997

DNA elements recognizing NF-Y and Sp1 regulate the human multidrug-resistance gene promoter.

Regulation of the human multidrug resistance gene (hMDR1) was studied by mapping DNA elements in the proximal promoter necessary for efficient transcription. Transient transfection analysis in tumor cell lines (HCT116, HepG2, and Saos2) of promoter deletions identified several regulatory domains. These cell lines expressed hMDR1 mRNA. Removal of an element between +25 and +158 reduced promoter activity by 2-3-fold, whereas deletion of sequences from approximately -5000 to -138 base pairs gave a approximately 2-fold increase. The activity of the hMDR1 promoter (-137 to +25) was comparable in activity to the SV40 early promoter and enhancer combination. Deletion of the hMDR1 promoter between -86 and -44 reduced activity by 5-10-fold, identifying an important regulatory region. This minimal region (-88 to -37) activated transcription when inserted upstream of a synthetic promoter, suggesting that it acts independently of other regulatory sequences. Two DNA elements within 85 base pairs of the transcriptional start site were required to confer efficient gene expression. A double-point mutation in the Y box (inverted CCAAT box) between -70 and -80 reduced activity of the promoter by 5-10-fold, and a single-point mutation at -52 within a GC-rich element reduced activity by 3-fold. Thus, both the Y-box and GC elements must each remain intact for optimal promoter activity. DNA-binding analyses suggest that the transcription factor NF-Y, but not YB-1 or c/EBP, is most likely responsible for controlling the activity of the Y-box element in these tumor cell lines. DNA-binding analyses also suggest that Sp1, alone or in combination with other nuclear factors, likely controls the activity of the GC element.

Base Sequence↗
PubMed1997

An innovative approach to pain management in critical care: therapeutic touch.

Nursing research suggests that pain in critically ill patients is inadequately controlled and has deleterious effects. The critical care nurse must depend on the patient's perception of pain and its expression in physiological and behavioural responses. Ventilatory support, fluctuating levels of consciousness, hemodynamic instability and severity of illness are often barriers to the expression and interpretation of pain. This article includes a review of the nursing literature pertaining to pain management in the critically ill patient. Existing practices are examined and alternative approaches explored. Therapeutic touch (TT), one innovative approach, is proposed as an adjunct to pharmacological intervention TT is a non-invasive, holistic practice that promotes comfort, relaxation, stress reduction and heating. Clinical studies suggest that TT prolongs the interval between analgesies. The authors highlight the 10-year clinical experience of a critical care nurse practising TT in a 30-bed critical care and trauma centre.

Critical Care↗
PubMed1996

Activation of an interleukin 1 converting enzyme-dependent apoptosis pathway by granzyme B.

Cytotoxic T lymphocytes (CTL) can induce apoptosis through a granzyme B-based killing mechanism. Here we show that in cells undergoing apoptosis by granzyme B, both p45 pro-interleukin 1 beta converting enzyme (ICE) and pro-CPP32 are processed. Using ICE deficient (ICE -/-) mice, embryonic fibroblasts exhibit high levels of resistance to apoptosis by granzyme B or granzyme 3, while B lymphoblasts are granzyme B-resistant, thus identifying an ICE-dependent apoptotic pathway that is activated by CTL granzymes. In contrast, an alternative ICE-independent pathway must also be activated as ICE -/- thymocytes remain susceptible to apoptosis by both granzymes. In ICE -/- B cells or HeLa cells transfected with mutant inactive ICE or Ich-1S that exhibit resistance to granzyme B, CPP32 is processed to p17 and poly(ADP-ribose) polymerase is cleaved indicating that this protease although activated was not associated with an apoptotic nuclear phenotype. Using the peptide inhibitor Ac-DEVD-CHO, apoptosis as well as p45 ICE hydrolysis are suppressed in HeLa cells, suggesting that a CPP32-like protease is upstream of ICE. In contrast, p34cdc2 kinase, which is required for granzyme B-induced apoptosis, remains inactive in ICE -/- B cells indicating it is downstream of ICE. We conclude that granzyme B activates an ICE-dependent cell death pathway in some cell types and requires a CPP32-like Ac-DEVD-CHO inhibitable protease acting upstream to initiate apoptosis.

Animals↗
PubMed1995

Shared governance--a unit based concept.

Shared governance has been depicted as a way of increasing staff nurse involvement: in work, motivation, quality of worklife, organizational commitment, power to influence patient care, and professional pride. This management style is typically implemented on a corporate basis in non-unionized organizations. However, it was identified as an initiative that could enable staff growth, innovation, autonomy and professionalism on a single nursing unit within a unionized hospital. The process of implementing a Shared Governance model on a 29 bed neuroscience unit in an 850 bed acute care teaching hospital is described.

Decision Making, Organizational↗
PubMed1994

YB-1 DNA-binding protein represses interferon gamma activation of class II major histocompatibility complex genes.

Interferon gamma (IFN-gamma) is the most potent inducer of class II major histocompatibility complex (MHC) genes. This induction is uniquely mediated by three DNA elements in the promoter region of class II MHC genes. One of these DNA elements, Y, contains an inverted CCAAT box. Previously, we have screened a lambda gt11 library for Y-binding proteins and identified the YB-1 gene. Here we provide evidence that YB-1 can repress the IFN-gamma induction of class II MHC promoter as well as the Invariant chain (Ii) gene which also contains a Y element in its promoter. This was demonstrated by cotransfecting a YB-1 expression vector with promoter-reporter gene constructs. As an alternate approach, an efficient transient transfection system was developed which resulted in a > 70% transfection efficiency. Transfection of YB-1 by this procedure resulted in the near abrogation of IFN-gamma induced HLA-DR antigen and mRNA expression. These findings show the functional suppression of class II MHC gene induction by the YB-1 protein.

Animals↗
PubMed1993

Profile of transition homes/shelters for victims of family violence.

This article presents the results of the Transition Home Survey--Supplement to the Residential Care Facilities Survey (RCF) 1991/92. The RCF is an annual survey sponsored by Statistics Canada. The Transition Home Survey was the first national endeavour to gather detailed information on clients and services provided in transition homes for victims of family violence. The target universe consisted of facilities defined as 'transition homes', which include shelters, second stage housing, family resource centres, safe home networks, satellites, emergency shelters and other homes for victims of family violence. The data presented covers four topics--facilities, services, caseload and revenue and expenditures.

Adolescent↗
PubMed1992

Professional attitudes regarding the sexual abuse of children: comparing police, child welfare and community mental health.

A survey was completed involving three of the key professional groups engaged in the investigation and treatment of child sexual abuse. Police, child welfare and community mental health in a large, rural geographic area in Canada completed attitudinal items relating to professional response to child sexual abuse. An empirical scale was created which was comprised of three orthogonal factors, each with acceptable levels of internal consistency: 1) Beliefs in regard to the extensiveness and seriousness of the issue; 2) treatment versus punishment priority; and 3) view regarding identity of those who perpetrate child sexual abuse. Important gender differences were found across professional groupings in attitude toward sexual abuse. Greatest difference in attitude between service sectors was tied to emphasis placed on treatment versus punishment as a primary aspect of professional intervention. Significant differences were found between child welfare and police, the two service sectors most needing a coordinated approach during the "investigative phase" of professional intervention.

Adult↗
PubMed1991

Improvement of silent myocardial ischaemia and reduction of plasma fibrinogen during nisoldipine therapy in occult coronary arterial disease.

The effect of the long-acting calcium channel blocking agent, nisoldipine, on silent myocardial ischaemia due to occult atherosclerotic coronary arterial disease has been evaluated in 12 asymptomatic patients (seven diabetics and five claudicants), none of whom had any history suggestive of ischaemic chest pain or previous myocardial infarction. All patients had normal resting electrocardiograms but positive exercise testing using 16-lead electrocardiographic mapping of the chest wall. They also had silent episodes of ST-segment depression during 24-hour ambulatory (Holter) monitoring. The study was of double-blind, cross-over design with four weeks randomised nisoldipine 10 mg twice daily versus placebo twice daily. Both the exercise test and Holter monitoring were carried out before entry to the trial and at the end of each randomised active and placebo phase. Plasma fibrinogen was also estimated at entry to the trial and at the end of each randomised phase. There were significant reductions in the magnitude (P less than 0.001) and duration (P less than 0.001) of depression of the ST segment on exercise testing and in the number of episodes (P less than 0.01), magnitude (P less than 0.001) and duration (P less than 0.02) of ST-segment depression on Holter monitoring at the end of the nisoldipine phase as compared to the randomised placebo phase. A significant reduction in plasma fibrinogen was also noted at the end of the nisoldipine phase (P less than 0.001). This study demonstrates the efficacy and usefulness of nisoldipine in treating myocardial ischaemia due to occult coronary arterial disease in asymptomatic subjects presenting with diabetes mellitus or intermittent claudication. Its use was associated with reduction in plasma fibrinogen.

Adult↗
PubMed1991

Fine structure physical mapping of the region of mouse chromosome 10 homologous to human chromosome 21.

Comparative mapping of human and mouse DNA for regions of genetic homology between human Chromosome 21 and the mouse genome is of interest because of the possibility of developing mouse models of human trisomy 21 (Down syndrome), understanding chromosome evolution, and isolating novel sequences conserved between the two species. At least two mouse chromosomes are known to carry sequences homologous to those on human Chromosome 21: mouse Chromosome 16 (D21S16h, D21S13h, D21S52h, App, Sod-1, Mx-1, Ets-2, Prgs,Ifnar) and mouse Chromosome 17 (D21S56h, Crya-1, and Cbs). Recently, five additional genes have been mapped within region 21q22 of human Chromosome 21:PFKL, CD18, COL6A1, COL6A2, and S100B. To assign these sequences to specific mouse chromosomes, we used human cDNA probes for COL6A1, COL6A2, CD18, and PFKL and a rat brain cDNA probe for S100B in conjunction with a panel of seven Chinese hamster-mouse somatic cell hybrids segregating mouse chromosomes. The specific chromosome complements of the hybrid cell lines and the presence or absence of hybridizing mouse sequences in their DNAs allow us to assign all five sequences to mouse Chromosome 10, with the assignment of Pfkl reported here for the first time. Analysis of genomic mouse DNA fragments produced by digestion with rare-cutting restriction enzymes and separated using pulsed-field gel electrophoresis allows us to construct a fine-structure physical map of two segments of the region of Chromosome 10 containing these five markers. The five loci span at least 1900 kb of mouse DNA and are consistent with the human order: Pfkl-Cd-18-Col6a-1-Col6a-2-S100b.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Complacency, risk perception and the problem of HIV education.

Many public surveys on the issue of HIV and AIDS have concentrated on the relationship between attitudes and knowledge. Often this relationship has been found wanting or at most tenuous. A recent survey of 1,002 people in Wales has supported these earlier findings, but found additionally that discriminatory and complacent attitudes on AIDS or towards people with the 'AIDS virus' are held by a significant proportion of the population. The survey also discovered that people correctly perceive the risk of HIV infection as being minimal. Depending on the question 17%-65% of the sample expressed discriminatory attitudes towards people that have the 'AIDS virus'. There was also no marked change over previous surveys in the degree of complacency surrounding AIDS. Younger people (aged (15-34) considered themselves to be more at risk of infection with the 'AIDS virus' but overall the perceived risk of infection was low. A sustained low key education programme in a variety of settings and independent of perceived risk is necessary to combat prejudice and complacency.

Adolescent↗