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Biomedical subjects

M Murphy

Publications and source records attributed to M Murphy.

At least 163 records · Page 9Linked to original sources
PubMed1998

The role of MAP4 expression in the sensitivity to paclitaxel and resistance to vinca alkaloids in p53 mutant cells.

Mutations in p53 change the sensitivity to cancer chemotherapeutic drugs. Whereas many drugs, including the vinca alkaloids, often become less effective when p53 is transcriptionally inactivated, several, most notably paclitaxel, may become more effective. In studying the underlying mechanism(s), we found that increased MAP4 expression, which occurs with transcriptionally silent p53, is associated with increased sensitivity to paclitaxel and decreased sensitivity to vinca alkaloids. Using murine fibroblasts transfected with MAP4, we directly demonstrated that the changes in drug sensitivity were associated with parallel alterations in drug-induced apoptosis and cell-cycle arrest. Immunofluorescent staining of the microtubule network revealed that cells with increased MAP4 expression displayed an increase in polymerized microtubules and an increased binding of fluorsceinated paclitaxel. Since MAP4 stabilizes polymerized microtubules, overexpression of this gene provides a plausible mechanism to explain the altered sensitivity to microtubule-active drugs in the presence of mutant p53.

3T3 Cells↗
PubMed1998

Neural precursor differentiation into astrocytes requires signaling through the leukemia inhibitory factor receptor.

The differentiation of precursor cells into neurons or astrocytes in the developing brain has been thought to be regulated in part by growth factors. We show here that neural precursors isolated from the developing forebrain of mice that are deficient in the gene for the low-affinity leukemia inhibitory factor receptor (LIFR-/-) fail to generate astrocytes expressing glial fibrillary acidic protein (GFAP) when cultured in vitro. Precursors from mice heterozygous for the null allele show normal levels of GFAP expression. These findings support the in vivo findings that show extremely low levels of GFAP mRNA in brains of embryonic day 19 LIFR-/- mice. In addition, monolayers of neural cells from LIFR-/- mice are far less able to support the neuronal differentiation of normal neural precursors than are monolayers from heterozygous or wild-type animals, indicating that endogenous signaling through the LIFR is required for the expression of both functional and phenotypic markers of astrocyte differentiation. LIFR-/- precursors are not irreversibly blocked from differentiating into astrocytes: they express GFAP after long-term passaging or stimulation with bone morphogenetic protein-2. These findings strongly implicate the LIF family of cytokines in the regulation of astrocyte differentiation and indeed the LIF-deficient animals show a significant reduction in the number of GFAP cells in the hippocampus. However, because this reduction is only partial it suggests that LIF may not be the predominant endogenous ligand signaling through the LIFR.

Animals↗
PubMed1998

Psychosocial factors associated with the use/non-use of mental health services by primary carers of individuals with dementia.

The study investigated psychosocial factors associated with the use/non-use of services by primary carers of people with dementia (caring for relative/friend with dementia). The factors considered were individual differences, health, stress, family/social support, years of caring, age of carers/person with dementia, gender and level of behavioural disturbance presented by the person with dementia. The participants were referred to the study by health services, social services representatives and GPs. The carers (N = 50) were divided into two groups (service user/non-user). The findings indicated that primary carers in the non-user service group scored significantly higher on a measure (sense of coherence; SOC) estimating an individual's ability to deal with stressful situations. The individual's ability to deal with caring responsibilities was associated with a reduction in the level of diagnosable psychiatric disorder or 'caseness' and the non-use of services. None of the other factors considered were found to be significantly different between the two career groups. However, a significant inverse association between health, stress and individual ability to deal with stressful situations was found when the two career groups were combined.

Adaptation, Psychological↗
PubMed1998

p21(cip1) rescues human mesenchymal stem cells from apoptosis induced by low-density culture.

Mammalian cells are programmed to undergo programmed cell death in response to a variety of conditions. We demonstrate that human mesenchymal stem cells (hMSCs) undergo programmed cell death upon seeding at low density. Under these conditions, we observed an increased proportion of cells in S-phase and a decreased proportion of cells in G1-phase. This indicated that a change in control of G1-S-phase transition in response to low-density seeding had occurred and, therefore, we measured the level of cyclin-dependent kinase inhibitory proteins governing this transition. Human MSCs cultured at low density exhibited lowered levels of both the p21 and p27 cyclin-dependent kinase inhibitors, and these protein levels appear to be regulated at a post-transcriptional level. Conversely, overexpression of the p21 cell cycle-dependent kinase inhibitor but not that of p27 protected hMSCs from programmed cell death upon culture at low density. Furthermore, p21 and p27 are expressed differentially during endochondrial bone development. The loss of p21 in hypertrophic chondrocytes correlates with the onset of apoptosis during endochondrial ossification. We suggest that p21 and p27 play a central role in skeletal development.

Apoptosis↗
PubMed1998

Down-regulation of p27 is associated with development of colorectal adenocarcinoma metastases.

The cyclin-dependent kinase inhibitor p27 is a negative regulator of the cell cycle and a potential tumor suppressor gene. Because we had previously demonstrated that loss of p27 protein is associated with aggressive behavior in colorectal adenocarcinomas, we used immunohistochemistry and in situ hybridization to evaluate the potential role of alterations in p27 expression in primary and metastatic colorectal adenocarcinomas. Parallel immunostaining was performed for Ki-67 and p53. We evaluated 13 cases of metachronous and 23 cases of synchronous primary and metastatic colorectal tumor pairs. In the synchronous subgroup (Stage IV tumors), 57% of the primary tumor and metastases pairs did not express p27 protein and the remainder were low expressors. In the metachronous subgroup, 54% of the primary tumors were low expressors and the remainder high expressors of p27 protein. There was a significant reduction in the expression of p27 in the metachronous metastases (mean positive cells: 14.5%) when compared to the corresponding primary tumors (mean positive cells: 41.8%), P = 0.0023. All the primary and metastatic tumors in the metachronous subgroup showed high levels of p27 mRNA expression. There was no association between loss of p27 and either Ki-67 count or p53 expression. Because p27 is known to be up-regulated when epithelial cells are grown in suspension, the down-regulation of p27 in circulating tumor cells may confer the ability to grow in an environment of altered extracellular matrix or intercellular adhesion properties, two situations which may facilitate metastases.

Adenocarcinoma↗
PubMed1998

Fibroblasts cultured from distal lower extremities in patients with venous reflux display cellular characteristics of senescence.

PURPOSE: Venous reflux precedes the development of venous ulcers. Our earlier work showed that the fibroblasts that are cultured from these wounds display more characteristics of senescence. We evaluated fibroblast senescence in patients with venous reflux but without ulcers to further investigate the role of venous reflux in the predisposition to venous ulcers. METHODS: Fibroblasts that were isolated from skin biopsy specimens of the "gaiter" area (distal) and of the ipsilateral thigh of the same patient (proximal) were compared. Twelve patients with venous reflux (9 patients in clinical, etiologic, anatomic, and pathologic classification 4; 3 patients in classification 5) with an average venous filling index of 5.45 mL/s and 4 patients without venous reflux were enrolled in the study. The growth rates, the response to basic fibroblast growth factor (b-FGF), and the senescence markers (beta-galactosidase activity at a pH level of 6, unstimulated fibroblasts fibronectin protein, and messenger RNA levels) were determined for each cell population. RESULTS: The number of senescence-associated beta-galactosidase positive cells (8.3% +/- 1.9% vs 2.2% +/- 0.8%; P =.008) and the level of cellular fibronectin protein (455.7 +/- 80 vs 210 +/- 51; P =.04) and messenger RNA (16.8 +/- 6.8 vs 13.5 +/- 5.7; P =.042) were significantly higher in the distal fibroblasts as compared with the proximal fibroblast cultures. The growth rates of the distal fibroblasts were lower when compared with the proximal fibroblasts (15,746 +/- 4287 cells/day vs 29,550 +/- 5035 cells/day; P <.002) but were not different in the presence of b-FGF (41,717 +/- 9542 cells/day vs 47,030 +/- 6133 cells/day; P =.53). In the patients without venous reflux, no site differences were noted in the growth rates or the senescence markers between the proximal and distal fibroblasts. CONCLUSION: Distal fibroblasts that are isolated from patients with venous reflux display more senescence characteristics than do proximal fibroblasts and have significantly lower growth rates. Despite senescence, b-FGF restored the distal-fibroblasts growth rate to that of the stimulated proximal fibroblasts, which proposes a therapeutic role for b-FGF. These changes precede ulcer formation and suggest a mechanism that is focal and intrinsically related to venous reflux.

Adult↗
PubMed1998

LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator.

Herpes simplex virus (HSV) 1 and 2 infect activated T lymphocytes by attachment of the HSV envelope glycoprotein D (gD) to the cellular herpesvirus entry mediator (HVEM), an orphan member of the tumor necrosis factor receptor superfamily. Here, we demonstrate that HVEM binds two cellular ligands, secreted lymphotoxin alpha (LTalpha) and LIGHT, a new member of the TNF superfamily. LIGHT is a 29 kDa type II transmembrane protein produced by activated T cells that also engages the receptor for the LTalphabeta heterotrimer but does not form complexes with either LTalpha or LTbeta. HSV1 gD inhibits the interaction of HVEM with LIGHT, and LIGHT and gD interfere with HVEM-dependent cell entry by HSV1. This characterizes herpesvirus gD as a membrane-bound viokine and establishes LIGHT-HVEM as integral components of the lymphotoxin cytokine-receptor system.

Amino Acid Sequence↗
PubMed1998

Autism, affective and other psychiatric disorders: patterns of familial aggregation.

BACKGROUND: The liability to autism confers a risk for a range of more subtle autistic-like impairments, but it remains unclear whether it also confers a risk for other psychiatric disturbances. METHODS: To investigate this, we studied the pattern of familial aggregation of psychiatric disorders in relatives of 99 autistic and 36 Down's probands, using family history and direct interview measures. RESULTS: Family history data showed that motor tics, obsessive-compulsive (OCD) and affective disorders were significantly more common in relatives of autistic probands and that individuals with OCD were more likely to exhibit autistic-like social and communication impairments. Direct interview data confirmed the increased rate of affective disorders (especially major depressive disorder) in the first-degree relatives. There was no evidence to indicate significant co-morbidity between affective disorders and the broadly defined phenotype of autism. Moreover, the characteristics of the probands' and the relatives' that were associated with the liability to familiarity of the broader phenotype of autism differed from those that predicted the liability to the familiarity of affective disorders. Examination of the onset of affective disorders suggested that the increased risk was not confined to the period following the birth of the child with autism. CONCLUSIONS: Overall, the results indicated that OCD, but not affective disorders, may index an underlying liability to autism. They also indicated that the increased risk of affective disorders was not solely the consequence of the stress of raising a child with autism and that further research will be required to clarify the mechanisms involved.

Adolescent↗
PubMed1998

Expression of the lymphotoxin beta receptor on follicular stromal cells in human lymphoid tissues.

The lymphotoxin beta receptor (LTbetaR), and its ligand, LTalpha1beta2, have been proposed to play a key role in the development and organization of lymphoid tissues. The LTbetaR is expressed on a variety of human primary and transformed cells, but strikingly absent on T or B lymphocytes and primary monocytes or peripheral dendritic cells, although LTbetaR is detected on some myeloid leukemic lines. In the developing thymus LTbetaR is prominent along the trabeculae and into the medulla upto corticomedullary junction. In the spleen, LTbetaR is prominently expressed by cells in the red pulp and along the borders of red and white pulp which colocalizes with reticular stromal cells. The LTbetaR is expressed on a human follicular dendritic cell line, FDC-1, and signals expression of CD54 when ligated with the LTalpha1beta2 complex. These results support the concept that directional interactions between LTalpha1beta2 bearing lymphocytes and LTbetaR bearing stromal cells are involved in the organization of lymphoid tissue.

Cell Line↗
PubMed1998

'Back to sleep': the position in Oxfordshire and Northampton.

We examined hospital and domestic infant care practices in Oxfordshire and Northampton Health Districts to measure changes in prevalence of sudden infant death syndrome (SIDS) risk factors, and to evaluate a specific educational intervention restricted to Oxfordshire. We sent a postal questionnaire to 2781 parents of babies newly born in January 1992, July 1992 and January 1993 and achieved an 88% response rate. Overall, in hospital a relatively constant proportion (81%) slept on their sides and few prone, whereas at home 52% (but increasing) slept supine and 8% prone part or all of the time. Significant differences existed by district, both in hospital and at home, with more sleeping supine in Oxfordshire and more side-sleeping/propping in Northampton. First-time parents were more receptive to safety guidelines about sleeping position and several other risk factors also. We detected no modifying effect of the Oxfordshire advice. Professional practice can influence parental behaviour but general media coverage may produce the biggest effects.

Bedding and Linens↗
PubMed1998

Regulation of neural stem cell differentiation in the forebrain.

In the developing forebrain, mounting evidence suggests that neural stem cell proliferation and differentiation is regulated by growth factors. In vitro in the presence of serum, stem cell proliferation is predominantly mediated by fibroblast growth factor-2 (FGF-2) whereas neuronal differentiation can be triggered by FGF-1 in association with a specific heparan sulphate proteoglycan. On the other hand, astrocyte differentiation in vivo and in vitro appears to be dependent on signalling through the leukaemia inhibitory factor receptor (LIFR). The evidence suggests that in the absence of LIFR signalling, the stem cell population is present at approximately the same frequency and can generate neurons but is blocked from producing astrocytes that express glial fibrillary acidic protein (GFAP) or have trophic functions. The block can be overcome by other growth factors such as BMP-2/4 or interferon-gamma, providing further evidence that the inhibition to astrocyte development does not result from loss of a precursor population. Signalling through the LIFR, in addition to stimulating astrocyte differentiation, may also inhibit neuronal differentiation, which may explain why this receptor is expressed at the earliest stages of neurogenesis. Another signalling system which also exerts its influence on neurogenesis through active inhibition is Delta-Notch. We show in vitro that at high cell densities which impede neuronal production by FGF-1, lowering the levels of expression of the receptor Notch by antisense oligonucleotide results in a significant increase in neuronal production. Thus, stem cell differentiation appears to be dependent on the outcome of interactions between a number of signalling pathways, some which promote specific lineages and some which inhibit.

Animals↗
PubMed1998

Use of videophones and low-cost standard telephone lines to provide a social presence in telepsychiatry.

Research findings suggest that the value added by the video channel of currently available video conferencing technology is limited to the creation of a social presence of the other party. Almost all clinical information exchange takes place on the audio channel, while the interpersonal interactions (nods, blinks, facial expressions, and body language), which are so important in a face-to-face meeting, may not be adequately captured by the video. Several of our case studies are presented which suggest that, consistent with the social presence role for video, low-cost videophones may be effectively substituted for expensive ISDN-based systems in many mental health applications.

Aged↗
PubMed1998

What if socioeconomics made no difference?: access to a cadaver kidney transplant as an example.

OBJECTIVES: Several studies have noted the impact of socioeconomic factors on access to expensive medical care, but none of those studies controlled for self-reported health and functional status or attitudes about treatment alternatives when analyses were completed. Because these factors may be correlated with socioeconomic status, the failure to control for them may have led to bias in other studies. The authors merged data from secondary sources with telephone survey data from a national sample of 456 end-stage renal disease patients to show how estimates of the effects of socioeconomic factors change when self-reported health and functional status and attitudes about treatment are incorporated into statistical models. The authors also showed how kidney transplant rates would change if socioeconomic factors no longer influences organ allocation decisions. METHODS: Weibull proportional hazard analyses were used to show relationships between socioeconomic measures and waiting list entry and kidney transplant rates, before versus after accounting for self-reported health and functional status, attitudes about treatment, and other variables. Simulation analyses were used to estimate the number of waiting list spots and transplant operations that would move from economically advantaged to disadvantaged persons if socioeconomics no longer influenced organ allocation decisions. RESULTS: Incorporating information about health and functional status, attitudes about treatment, and other factors into the hazard models often reduced the estimated impact of socioeconomic measures on the odds of (1) being on a waiting list for a cadaver kidney transplant and (2) receiving a transplant. Simulations showed that 30 to 65 waiting list spots or transplant operations per 1,000 patients would shift from economically advantaged to disadvantaged persons if socioeconomics no longer influenced organ allocation decisions. CONCLUSIONS: Successful efforts to level the playing field would result in substantial redistributions of kidney transplants from economically advantaged to disadvantaged persons.

Adolescent↗
PubMed1998

Breast cancer in reduction mammoplasty: case reports and a survey of plastic surgeons.

A discussion of occult breast carcinomas in breast reduction surgery has not occurred in the last 25 years. My recent experience in discovering two occult breast carcinomas in breast reduction specimens led to the creation of a survey of local plastic surgeons and a review of the literature with the goal being precise recommendations for such occurrences. Our survey of breast reductions performed on 2576 patients shows a 0.16 percent incidence of occult breast carcinoma, significantly lower than the 0.38 percent incidence seen in the Snyderman and Lizardo study of 1959. This decrease in the rate of occult breast carcinomas could be explained by many advances in early detection, improvements in patient education, and more thorough pathologic examination of the surgical specimens. The results of this survey and review suggest that we as plastic surgeons performing breast reduction surgery be well versed in all aspects of breast cancer detection, evaluation, and treatment.

Adult↗
PubMed1998

Protein kinases C: potential targets for intervention in diabetic nephropathy.

Protein kinases C are a family of serine threonine protein kinases that play key roles in extracellular signal transduction. Inappropriate activation of protein kinase C has been implicated in the pathophysiology of many diseases, including diabetes mellitus. Indeed, protein kinase C activation may contribute not only to the pathogenesis of diabetic complications such as nephropathy and retinopathy, but also to insulin resistance. Growing awareness that protein kinase C isoforms subserve specific subcellular functions has led to the development of isoform-specific inhibitors, which may be useful investigational tools and therapeutic agents for attenuating the effects of inappropriate protein kinase C activity. Here we review the role played by protein kinases C in diabetic nephropathy and the recent progress that has been made to modulate its activity using specific inhibitors.

Animals↗