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M Kirby

Publications and source records attributed to M Kirby.

At least 73 records · Page 4Linked to original sources
PubMed1998

Hypothalamic-pituitary-adrenal axis dysfunction in Alzheimer's disease: lack of association between longitudinal and cross-sectional findings.

OBJECTIVE: The authors examined longitudinal hypothalamic-pituitary-adrenal (HPA) axis function in Alzheimer's disease. METHOD: Cortisol levels of 30 patients with Alzheimer's disease and 17 healthy elderly subjects were measured before and after administration of dexamethasone. These measures were repeated at 9-month intervals in the patients with Alzheimer's disease. RESULTS: At baseline, cortisol levels were higher in the Alzheimer's disease group before and after dexamethasone administration. Although only two of the four patients whose cortisol levels were not suppressed by dexamethasone also had high cortisol levels before dexamethasone administration, basal and postdexamethasone cortisol levels were correlated. HPA axis dysfunction correlated with severity of dementia at baseline but was not stable longitudinally and did not increase with follow-up. CONCLUSIONS: There was no association between longitudinal and cross-sectional findings. The longitudinal data were not consistent with a role for the glucocorticoid cascade hypothesis (that hippocampal cell loss in Alzheimer's disease results in hypercortisolism, which in turn acts as a co-factor in further degeneration) in the pathophysiology of mild and moderate Alzheimer's disease.

Aged↗
PubMed1998

Telling the truth.

Explore the source record for details and available documents.

Alzheimer Disease↗
PubMed1997

Rac1 is required for cell proliferation and G2/M progression.

We have transiently expressed a dominant negative form of rac1 (N17rac1) using adenoviral-mediated gene transfer. The level of N17rac1 expression is demonstrated to be proportional to the multiplicity of infection. Expression of N17rac1 in Rat 2 fibroblasts results in cytostatic growth arrest. Cell-cycle analysis demonstrates that cells expressing N17rac1 accumulate in G2/M. These results suggest that rac1 is required for cell proliferation and provide the first demonstration in mammalian cells of a role for small GTP-binding proteins in the G2/M transition.

Adenoviridae↗
PubMed1997

Mental disorders among the community-dwelling elderly in Dublin.

BACKGROUND: The prevalence of mental disorders among the community-dwelling elderly in the catchment area of a psychiatry for the elderly service in Dublin was determined. METHOD: A sample of 1232 individuals aged 65 years and over, identified from general practitioner practice lists, was interviewed using the Geriatric Mental State-AGECAT package. RESULTS: Depression and organic disorder occurred with prevalences of 10.3 and 4.1%, respectively. Depression diagnostic cases had comorbid anxiety at case level in 17.3% and at sub-case level in a further 59.9%. Organic diagnostic cases had comorbid depressive or anxiety symptoms, at case or sub-case level, in 32%. CONCLUSIONS: Depression is the most common mental disorder among the elderly in Dublin. The frequency of anxiety symptoms in the presentation of depression may be a factor in the under-diagnosis or misdiagnosis of depression in the community-dwelling elderly. Comorbid anxiety and depression in organic disorder may represent treatable symptoms.

Aged↗
PubMed1996

Human rights and the HIV paradox.

Faced with the grave challenge to public health posed by HIV infection, governments are obliged "do something". One response, which often finds favour with the general public, is to enact laws that criminalise the activities of certain target groups. However, such laws marginalise individuals in these groups and have very little impact on containment of the epidemic. It is far better to introduce measures that protect the rights of people most at risk of infection and thereby encourage and sustain behaviour modification.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Activated neutrophils secrete stored alpha 1-antitrypsin.

Neutrophil elastase (NE), a potent serine protease, is stored in primary granules of neutrophils and released following neutrophil activation. Alpha-1-antitrypsin (alpha 1-AT), the major inhibitor of NE, is synthesized by mature neutrophils. In the context of the maintenance of tissue homeostasis, we hypothesized that neutrophils may be able to store alpha 1-AT, thus having it available for release concordantly with NE. Immunofluorescence and quantitative flow-cytometric studies of neutrophils and monocytes labeled with fluorescein-conjugated alpha 1-AT-antibody demonstrated larger amounts of cytoplasmic alpha 1-AT in neutrophils than in monocytes. [35S]methionine-labeling and anti-alpha 1-AT immunoprecipitation analysis showed that although both neutrophils and monocytes synthesize alpha 1-AT, the proportion of newly synthesized intracellular alpha 1-AT was much higher in neutrophils than in monocytes. Flow-cytometric analysis showed that in the presence of surface stimulation with cytochalasin B followed by formyl-methionyleucylphenylalanine (fMLP), mean intracellular alpha 1-AT was decreased in stimulated neutrophils compared with that in resting cells, suggesting that the stored alpha 1-AT was rapidly released following surface triggering. Evaluation of surface-stimulated neutrophils by [35S]methionine labeling and anti-alpha 1-AT immunoprecipitation demonstrated increased secretion of alpha 1-AT compared with that of resting neutrophils, with some of the secreted alpha 1-AT capable of forming complexes with NE. Thus, neutrophils respond to surface stimulation not only by secreting NE but also by secreting its inhibitor, alpha 1-AT, suggesting that these cells have an inherent mechanism for damping the local effects of NE, their most powerful proteolytic enzyme.

Cytochalasin B↗
PubMed1996

A new variant translocation in acute promyelocytic leukaemia: molecular characterization and clinical correlation.

Translocation t(15;17)(q22;q21) is an acquired clonal cytogenetic change present in almost all cases of acute promelocytic leukemia (APL). The molecular genetic basis of the translocation supports its integral role in pathogenesis. We describe a patient with APL in whom the leukaemic clone was characterized by a true variant of the classical t(15;17). The patient whose disease had numerous atypical clinical features, had t(11;17)(q13;121). The chromosome 17 breakpoint was localized to intron 2 of RARA by Southern blotting, and there was no evidence at the molecular level for rearrangement at PML locus. These data, along with previous reports of rare variant translocations in APL, indicate that while dysregulation of RARA by gene fusion may be essential for the APL phenotype, the particular fusion partner may determine clinicopathological aspects, including presentation, response to treatment with all-trans retinoic acid (ATRA), and prognosis. This heterogeneity suggests that the variant fusion partners of RARA in APL encode factors with properties both common to and distinct from those of PML. Investigation of these factors promises to shed light on the complex development pathways involved in the regulation of haematopoiesis.

Bone Marrow↗
PubMed1995

Increase in suprabasilar integrin adhesion molecule expression in human epidermal neoplasms accompanies increased proliferation occurring with immortalization and tumor progression.

In a previous prospective study of 80 patients with squamous cell carcinoma of the upper aerodigestive tract, a progressive increase in expression of the integrin cell adhesion molecule alpha 6 beta 4 in suprabasilar cell layers of the tumor parenchyma was associated with an increase in early recurrence after therapy. In this study, we determined the relationship of the altered expression pattern of the integrin to changes occurring during benign, invasive, or metastatic stages of tumor development. Suprabasilar expression of integrin alpha 6 beta 4 appeared with neoplastic transformation in benign squamous papillomas, but homogeneous expression occurred more frequently in the parenchyma of primary and metastatic squamous cell carcinomas. The variation in the extent of suprabasilar integrin expression among the tumors corresponded to the variation in the population undergoing proliferation as determined by two independent markers of proliferation. Integrin expression was quantified in primary, HPV 16 DNA-immortalized, and v-ki-ras oncogene-transformed keratinocytes, and the pattern of expression was compared with cell cycle progression. Primary keratinocyte lines showed a bimodal distribution of integrin expression, with one population showing decreased integrin expression, cell size, and a block of cell cycle progression consistent with differentiation, whereas another population exhibited high integrin expression and full progression through the cell cycle, consistent with proliferation. HPV-immortalized and v-ki-ras-transformed cell lines undergoing continuous proliferation exhibited uniformly strong integrin expression, which was similar in intensity to that observed in the proliferating population of normal keratinocytes. Similar increases in expression of two additional integrins, alpha 2 beta 1 and alpha 3 beta 1, occurred along with integrin alpha 6 beta 4 in tissue specimens and cell lines derived from neoplasms. Thus, epidermal neoplasms display an increase in a population of cells exhibiting constitutive expression of a repertoire of integrins, which is similar to that found transiently in the acute phase of epidermal wound healing, a physiological response in which hyperproliferation, retention of multiple layers of proliferating cells, and migration occur. The association of a progressive increase in suprabasilar expression of these integrins with early tumor recurrence and advanced neoplasia suggests that constitutive expression and function of the same repertoire of integrins may be advantageous, rather than sufficient, for tumor progression.

Antigens, Surface↗
PubMed1995

Long-term in vivo expression of the human glucocerebrosidase gene in nonhuman primates after CD34+ hematopoietic cell transduction with cell-free retroviral vector preparations.

Successful gene transfer into stem cells would provide a potentially useful therapeutic modality for treatment of inherited and acquired disorders affecting hematopoietic tissues. Coculture of primate bone marrow cells with retroviral producer cells, autologous stroma, or an engineered stromal cell line expressing human stem cell factor has resulted in a low efficiency of gene transfer as reflected by the presence of 0.1-5% of genetically modified cells in the blood of reconstituted animals. Our experiments in a nonhuman primate model were designed to explore various transduction protocols that did not involve coculture in an effort to define clinically useful conditions and to enhance transduction efficiency of repopulating cells. We report the presence of genetically modified cells at levels ranging from 0.1% (granulocytes) to 14% (B lymphocytes) more than 1 year following reconstitution of myeloablated animals with CD34+ immunoselected cells transduced in suspension culture with cytokines for 4 days with a retrovirus containing the glucocerebrosidase gene. A period of prestimulation for 7 days in the presence of autologous stroma separated from the CD34+ cells by a porous membrane did not appear to enhance transduction efficiency. Infusion of transduced CD34+ cells into animals without myeloablation resulted in only transient appearance of genetically modified cells in peripheral blood. Our results document that retroviral transduction of primate repopulating cells can be achieved without coculture with stroma or producer cells and that the proportion of genetically modified cells may be highest in the B-lymphoid lineage under the given transduction conditions.

Animals↗
PubMed1995

Use of a Gammarus pulex bioassay to measure the effects of transient carbofuran runoff from farmland.

There is now much information on the presence of pesticides in surface waters, but very little about their actual effects on aquatic life. This paper reports on the transient concentrations of a carbamate insecticide carbofuran, which were observed in a head-water stream draining treated farmland, and describes the resulting effects on a bioassay organism. One month after an application of 3 kg carbofuran/ha as broadcast granules to an oilseed rape crop, carbofuran concentrations of up to 26 micrograms/liter were measured in a nearby headwater stream after heavy rainfall. The majority of the carbofuran was translocated via field drains (where concentrations up to 264 micrograms/liter were detected), although the possibility of some surface runoff cannot be ruled out. Peak carbofuran concentrations only persisted for about 24 hr after the rainfall event, although measurable levels could be detected for at least 4 days. An in situ bioassay of streamwater which monitored the feeding rate of the gammarid amphipod crustacean Gammarus pulex showed that feeding stopped completely during the rainfall event, and was rapidly followed by death of all the caged organisms. Subsequent laboratory studies of toxicity showed that the peak concentrations of carbofuran had exceeded the G. pulex 24-hr LC50 of 21 micrograms/liter, and that concentrations as low as 4 micrograms/liter could reduce feeding rate. These findings are discussed with reference to regulatory risk evaluation procedures.

Agrochemicals↗
PubMed1995

Patients' rights--why the Australian courts have rejected 'Bolam'.

This point of view compares the issue of informed patient consent primarily as it operates in Australia and the United Kingdom. It affords an overview, also, of the applicable law in the United States and Canada. It particularly focuses on the legal test to be applied to patient consent as established in the Bolam case in the United Kingdom. The case, following its approval by the House of Lords, holds that the negligent standard in patient consent situations is to be determined, in cases of dispute, in accordance with standards as viewed by a proper body of competent medical practitioners. By contrast, the law in the United States is premised on the notion of the fundamental right of patients to determine what should or should not be done with their own bodies. In Australia the Bolam test has been rejected by the High Court of Australia following earlier decisions in the State Supreme Courts. The Australian courts did not accept that the setting of standards by the medical profession was an acceptable way of determining the entitlements of a patient who has suffered harm. The author places this discussion in the context of greater community awareness of medical procedures, the heightened accountability of professionals and the increasing practice of having a substantial patient input into medical decisions. He also suggests that the differing social and professional attitudes to authority and fundamental rights to be found between Australia and the United Kingdom have influenced the outcome of the cases in the higher courts of both countries. He suggests that the Bolam test is an illustration of the tendency of authority in the United Kingdom to believe that 'Nanny know best'.

Australia↗