Biomedical subjects
Publications and source records attributed to K White.
Phagocytosis is important in immune defense and development in vertebrates and invertebrates. It leads to swift ingestion of microorganisms and dying cells by phagocytes. How particles are recognized is not well understood. Studies in insects, and Drosophila in particular, argue that these are powerful model systems to dissect this process.
Exposure to irradiated Plasmodium sporozoites (gamma-spz) results in protection against malaria. Like infectious spz, gamma-spz colonize hepatocytes to undergo maturation. Disruption of liver stage development prevents the generation of protection, which appears, therefore, to depend on liver stage antigens. Although some mechanisms of protection have been identified, they do not include a role for intrahepatic mononuclear cells (IHMC). We demonstrated that P. berghei gamma-spz-immune murine IHMC adoptively transfer protection to naive recipients. Characterization of intrahepatic CD4+ T cells revealed an immediate, albeit transient, response to gamma-spz, while the response of CD8+ T cells is delayed until acquisition of protection. It is presumed that activated CD8+ T cells home to the liver to die; gamma-spz-induced CD8+CD45RB(lo)CD44(hi) T cells, however, persist in the liver, but not the spleen, during protracted protection. The association between CD8+CD45RB(lo)CD44(hi) T cells and protection has been verified using MHC class I and CD1 knockout mice and mice with disrupted liver stage parasites. Based on kinetic studies, we propose that interferon-gamma, presumably released by intrahepatic effector CD8+ T cells, mediates protection; the persistence of CD8+ T cells is, in turn, linked to Plasmodium antigen depots and cytokines released by CD4+ T cells and/or NK T cells.
The genetic tools available in Drosophila have facilitated our understanding of how apoptosis is regulated and executed in the context of the developing organism. All embryonic apoptosis is initiated by the activity of three genes, rpr, grim and hid. Each of these genes is independently regulated, allowing developmental apoptosis to be finely controlled. These initiators in turn activate the core apoptotic machinery, including the caspases. Drosophila counterparts to other conserved components of the apoptotic machinery have been recently identified, and we discuss how these may be integrated into the process of normal developmentally regulated cell death. We also outline the role that phagocytosis plays in the final stages of apoptosis and consider the molecular mechanisms guiding the elimination of apoptotic corpses.
Recently, the VMD2 gene has been identified as the causative gene in juvenile-onset vitelliform macular dystrophy (Best disease), a central retinopathy primarily characterised by an impaired function of the retinal pigment epithelium. In this study we have further characterised the spectrum of VMD2 mutations in a series of 41 unrelated Best disease patients. Furthermore we expanded our analysis to include 32 unrelated patients with adult vitelliform macular dystrophy (AVMD) and 200 patients with age-related macular degeneration (AMD). Both AVMD and AMD share some phenotypic features with Best disease such as abnormal subretinal accumulation of lipofuscin material, progressive geographic atrophy and choroidal neovascularisation, and may be the consequence of a common pathogenic mechanism. In total, we have identified 23 distinct disease-associated mutations in Best disease and four different mutations in AVMD. Two of the mutations found in the AVMD patients were also seen in Best disease suggesting a considerable overlap in the aetiology of these two disorders. There were no mutations found in the AMD group. In addition, four frequent intragenic polymorphisms did not reveal allelic association of the VMD2 locus with AMD. These data exclude a direct role of VMD2 in the predisposition to AMD.
A research project examining the support needs of families caring for a relative in palliative care was conducted in New South Wales in 1997. Data were collected from 19 families and 10 specialist palliative care nurses from eight centres throughout New South Wales using audio-taped interviews. The findings show that information was one of the most important support needs for families to enable them to effectively care for their sick relative. The information provided needed to meet the individual and varying needs of families at different stages of their palliative care journey. Often the families described not knowing what their information needs were until a crisis occurred. Lack of information on a range of areas, from practical resources to providing physical care and managing medications, was problematic. Health professionals need to take responsibility in determining if families are aware of the information available, identify the most appropriate medium for this material and provide it at the pace and time wanted by the individual family.
Nursing research in palliative care is becoming more important as cost effectiveness and evidence-based practice are becoming mandatory. Fifty-nine published and unpublished projects relating to nursing research on palliative care in Australia between 1990 and 1996 were reviewed. Findings indicated that nurses working in palliative care in Australia are interested in researching a range of topics using varied methods. The nurses' primary interests appear to be their own professional issues and management of the patient's pain. Little research on families/carers of palliative care patients was evident. There is a need for future research to focus on projects that justify the nurse's role in the palliative care team, show that nursing interventions for symptom control affect patient outcomes and prove nurses are integral to the psychosocial and spiritual wellbeing of the patient and family during the palliative care journey.
Significant amounts of apoptosis take place during Drosophila development. The proapoptotic genes reaper (rpr), grim, and head involution defective (hid) are required for virtually all embryonic apoptosis. The proteins encoded by these genes share a short region of homology at their amino termini. The Drosophila IAP homolog THREAD/DIAP1 (TH/DIAP1), encoded by the thread (th) gene, negatively regulates apoptosis during development. It has been proposed that RPR, GRIM, and HID induce apoptosis by binding and inactivating TH/DIAP1. The region of homology between the three proapoptotic proteins has been proposed to bind to the conserved BIR2 domain of TH/DIAP1. Here, we present an analysis of loss-of-function and gain-of-function alleles of th, which indicates that additional domains of TH/DIAP1 are necessary for its ability to inhibit death induced by RPR, GRIM, and HID. In addition, that analysis of loss-of-function mutations demonstrates that th is necessary to block apoptosis very early in embryonic development. This may reflect a requirement to block maternally provided RPR and HID, or it may indicate another function of the TH/DIAP1 protein.
Members of the ELAV family of proteins contain three RNA recognition motifs (RRMs), which are highly conserved. ELAV, a Drosophila melanogaster member of this family, provides a vital function and exhibits a predominantly nuclear localization. To investigate if the RNA-binding property of each of the ELAV RRMs is required for ELAV's in vivo function, amino acid residues critical in RNA binding for each RRM were individually mutated. A stringent genetic complementation test revealed that when the mutant protein was the sole source of ELAV, RNA-binding ability of each RRM was essential to ELAV function. To assess the degree to which each domain was specific for ELAV function and which domains perhaps performed a function common to related ELAV proteins, we substituted an ELAV RRM with the corresponding RRM from RBP9, the D. melanogaster protein most homologous to ELAV; HuD, a human ELAV family protein; and SXL, which, although evolutionarily related, is not an ELAV family member. This analysis revealed that RRM3 replacements were fully functional, but RRM1 and RRM2 replacements were largely nonfunctional. Under less stringent conditions RRM1 and RRM2 replacements from SXL and RRM1 replacement from RBP9 were able to provide supplemental function in the presence of a mutant hypomorphic ELAV protein.
Although the Drosophila melanogaster erect wing (ewg) gene is broadly transcribed in adults, an unusual posttranscriptional regulation involving alternative and inefficient splicing generates a 116-kDa EWG protein in neurons, while protein expression elsewhere or of other isoforms is below detection at this stage. This posttranscriptional control is important, as broad expression of EWG can be lethal. In this paper, we show that ELAV, a neuron-specific RNA binding protein, is necessary to regulate EWG protein expression in ELAV-null eye imaginal disc clones and that ELAV is sufficient for EWG expression in wing disc imaginal tissue after ectopic expression. Further, analysis of EWG expression elicited from intron-containing genomic transgenes and cDNA minitransgenes in ELAV-deficient eye discs shows that this regulation is dependent on the presence of ewg introns. Analyses of the ewg splicing patterns in wild-type and ELAV-deficient eye imaginal discs and in wild-type and ectopic ELAV-expressing wing imaginal discs, show that certain neuronal splice isoforms correspond to ELAV levels. The data presented in this paper are consistent with a mechanism in which ELAV increases the splicing efficiency of ewg transcripts in alternatively spliced regions rather than with a mechanism in which stability of specific splice forms is enhanced by ELAV. Additionally, we report that ELAV promotes a neuron-enriched splice isoform of Drosophila armadillo transcript. ELAV, however, is not involved in all neuron-enriched splice events.
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We have cloned and characterized a novel gene (C11orf9) mapping to chromosome 11q12-->q13.1. The transcript was initially identified as a partial cDNA sequence in the course of constructing a transcript map of the region between markers D11S1765 and uteroglobin known to encompass the gene causing Best disease. Using a combination of EST mapping, computational exon prediction, RT-PCR, and 5'-RACE its 5. 7-kb full-length cDNA sequence was subsequently obtained. The C11orf9 gene consists of 26 exons spanning 33.1 kb of genomic DNA and is located about 4.3 kb centromeric to FEN1. Biocomputational analysis predicts that its conceptual translation product of 1,111 amino acids contains two transmembrane helices as well as two proline-rich regions. Alignment reveals significant homology to hypothetical peptides from several other species including C. elegans and D. melanogaster, indicating a high degree of conservation throughout evolution. Northern Blot and RT-PCR analyses demonstrate widespread expression of a single transcript but varying degrees of abundance among the individual tissues tested. Mutation analysis of the entire coding sequence excluded C11orf9 as the Best disease gene.
BACKGROUND: The incidence of non-Hodgkin's lymphoma (NHL) has been increasing in Canada. This study assessed the effect of occupational exposure to specific chemicals on the risk of NHL. PATIENTS AND METHODS: Mailed questionnaires were used to obtain data on 1469 newly diagnosed, histologically confirmed NHL cases and 5073 population controls between 1994 and 1997 in eight Canadian provinces. Data was collected on socioeconomic status, life-style, diet, occupation, and years of exposure to any of 17 chemicals. Odds ratios (OR) and 95% confidence intervals (95% CI) were derived by logistic regression. RESULTS: The study found an increased risk of NHL among males exposed to benzidine, mineral, cutting, or lubricating oil, pesticides, and herbicides. Compared with non-exposure to each specific chemical, the adjusted ORs were 1.9 (95% CI: 1.1-3.4) for benzidine, 1.3 (95% CI: 1.0-1.5) for mineral, cutting, or lubricating oil, 1.3 (95% CI: 1.0-1.6) for herbicides, and 1.3 (95% CI: 1.0-1.6) for pesticides. Excess risk of NHL among females was associated with exposure to pesticides and wood dust. ORs increased with increasing exposure in years to benzidine and herbicides for males and with increasing exposure years to wood dust for females. These trends were statistically significant (P < 0.05). CONCLUSIONS: The findings in this study suggest that occupational exposure to specific chemicals plays an important role in the development of NHL in Canada.
As part of a multicenter study supported by the German Mildred Scheel foundation we have established an interdisciplinary counseling setting for members of breast and/or ovarian cancer families. We offer simultaneous counseling by a team consisting of a geneticist, a gynecologist and a psycho-oncologist. Here we describe our counseling protocol and our first short-term experience with this interdisciplinary approach. Preliminary data on patient perceptions and behaviors in the context of DNA testing are reported. Overall, our counseling approach was perceived as beneficial both by the counselors and the consultants. A marked overestimation of the risk to develop breast and/or ovarian cancer was noted in the group of unaffected individuals from medium to low risk breast cancer families in contrast to an appropriate risk perception in members from high risk families. All participants shared many of the same expectations about genetic testing and counseling and appeared to base their decision-making about testing on the risk classification given by the genetic counselor. The reported participation in gynecological cancer prevention programs was high in all families at risk, but was less sufficient in unaffected as compared to affected persons. Although current data on BRCA1/BRCA2 mutation analyses render testing in medium to low risk individuals questionable, our findings emphasize the importance of genetic counseling and education in all risk categories of breast and/or ovarian cancer families.
OBJECTIVE: To determine the concurrent validity and responsiveness of the 6 minute walk test (6-MWT) as a measure of cardiorespiratory fitness in people with fibromyalgia. METHODS: Subjects completed the 6-MWT, a Fibromyalgia Impact Questionnaire (FIQ), and a peak oxygen consumption (pVO2) exercise test before (n = 28) and after (n = 20) a 12 week exercise program. RESULTS: The correlations between 6-MWT distance and pVO2 before (r = 0.328) and after (r = 0.420) the exercise program were not significant. Significant correlations were obtained between 6-MWT distance and FIQ total (r = -0.494, p < 0.01) and physical impairment (r = -0.403, p < 0.05) scores. Fifteen of 28 subjects completed the exercise program, with significant (p < 0.05) changes in 6-MWT distance (+78 m), pVO2 (+1.8 ml/kg/min), and FIQ total score (-9.9). The change in 6-MWT distance was correlated significantly (p < 0.05) with change in FIQ total score but no change in pVO2. CONCLUSION: The 6-MWT was not a valid predictor of cardiorespiratory fitness. However, it was sensitive to change and was also significantly related to FIQ total score.
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In situ bioremediation is an innovative technique for the remediation of contaminated aquifers that involves the use of microorganisms to remediate soils and groundwaters polluted by hazardous substances. During its application, this process may require the addition of nutrients and/or electron acceptors to stimulate appropriate biological activity. Hydrogen peroxide has been commonly used as an oxygen source because of the limited concentrations of oxygen that can be transferred into the groundwater using above-ground aeration followed by reinjection of the oxygenated groundwater into the aquifer or subsurface air sparging of the aquifer. Because of several potential interactions of H2O2 with various aquifer material constituents, its decomposition may be too rapid, making effective introduction of the H2O2 into targeted treatment zones extremely difficult and costly. Therefore, a bench-scale study was conducted to determine the fate of H2O2 within subsurface aquifer environments. The purpose of this investigation was to identify those aquifer constituents, both biotic and abiotic, that are most active in controlling the fate of H2O2. The decomposition rates of H2O2 were determined using both equilibrated water samples and soil slurries. Results showed H2O2 decomposition to be effected by several commonly found inorganic soil components; however, biologically mediated catalytic reactions were determined to be the most substantial.
Investigations were performed on the strength of dental porcelain depending on whether it was exposed to saliva before or after the final firing. Forty porcelain specimens were fabricated and subjected to different treatments. A three-point flexural test was performed. In a second study investigations were performed to compare how the cervical shape of the preparation influenced the fracture strength of fixed partial dentures made of glass-infiltrated aluminium oxide. It was concluded that short-term exposure to saliva could have a negative effect on the strength of porcelain and that all-ceramic bridges luted with non-adhesive luting techniques should be supported by abutments with shoulder preparations.
Patients found support in the clinical friendship of nurses. The nurses instilled a sense of normality into their activities, creating a supportive atmosphere. Patients expressed a need for reciprocity in their relationship with the nurses. This relationship should be balanced and sustainable.