Search PubMed⌕ Search

Biomedical subjects

J Bond

Publications and source records attributed to J Bond.

At least 19 recordsLinked to original sources
PubMed1999

Telomerase repressor sequences on chromosome 3 and induction of permanent growth arrest in human breast cancer cells.

BACKGROUND: Activation of the enzyme telomerase, which has been associated with cellular immortality, may constitute a key step in the development of human cancer. Telomerase is repressed in most normal human somatic cells. This study was conducted, using a genetic complementation approach, with the aim of identifying and mapping the genes responsible for repressing telomerase and, simultaneously, to establish the effect of experimentally induced telomerase repression on human tumor cell growth. METHODS: Individual human chromosomes isolated from normal diploid cells and tagged with bacterial antibiotic resistance genes (for later selection) were introduced into cells of the human breast carcinoma cell line 21NT by means of microcell transfer. Selected hybrid clones were screened for telomerase activity by use of the polymerase chain reaction-based telomere repeat amplification protocol (TRAP) assay, and the proliferative fate of the hybrid clones was determined. Regions of the introduced chromosomes associated with telomerase repression were mapped using segregant hybrids and a deletion analysis that employed microsatellite DNA markers. RESULTS: Strong repression of telomerase was observed following transfer of human chromosome 3 into 21NT cells but not after transfer of chromosomes 8, 12, or 20. The vast majority of hybrid clones with repressed telomerase entered permanent growth arrest after 10-18 population doublings. Deletion analysis of nonrepressed segregant monochromosome 3 hybrids indicated two regions on the short arm of chromosome 3 (3p21.3-p22 and 3p12-21.1) where telomerase regulator genes may be located. CONCLUSIONS: Telomerase in human breast cancer cells is efficiently repressed by a gene or genes on normal human chromosome 3p, and this repression is associated with permanent growth arrest of the tumor cells.

Adult↗
PubMed1999

Costs of formal care for frail older people in England: the resource implications study of the MRC cognitive function and ageing study (RIS MRC CFAS).

The aim of this paper is to quantify service use and costs of supporting frail older people at home in the community, using data collected in a longitudinal multicentre stratified randomised study for 1055 mentally frail, physically frail, and mentally and physically frail subjects. Average costs per person per week were found to total 64.45 Pounds Sterling, with a small number of services accounting for a large proportion of the total costs. The level of services offered by the nonstatutory voluntary and private sectors was found to be small. To highlight issues for policy makers, the extent of cost variations between a number of different subgroups were calculated. These bivariate analyses revealed substantial variation in costs, especially according to household structure, type of frailty, whether admission to continuing care accommodation occurred and survival. Multiple regression analysis demonstrated that 26% of the variation in log average weekly costs could be explained by a number of socio-demographic and health status variables. A particularly close relationship was observed between costs and whether admission to continuing care accommodation occurred, highlighting a need for policy-makers to examine the nature and scale of provision of alternative community based care packages. The results demonstrate that descriptive cost data such as those presented can provide information useful to the planning process, enabling more informed choices to be made over the provision of services for particular groups of people.

Aged↗
PubMed1998

Estimation of a multiproduct cost function for physically frail older people.

Using the theory of multiproduct cost functions, this paper derives a cost function for physically frail older people living in private households, based on data collected between 1991 and 1995, for 472 subjects aged 65 years of age or over in four areas of England. The main characteristic of the cost function is that output categories are classified in terms of movements between different health states. These were measured by changes in activities of daily living (ADL) over 2 years, with 'low' ADL representing better functional ability than 'high' ADL. Empirical application of the approach, using four states defined in terms of worsening progression (stable low ADL; deteriorated or improved ADL; stable high ADL; deceased), indicated more favourable states were associated with lower costs. Multivariate analysis showed that the derived states were significantly related to costs which, when combined with variables indicating presence of particular chronic health conditions (diabetes or previous stroke), admission to continuing care accommodation and household structure, explained one-fifth of the variation in log average costs per week. Variables such as age, sex, carer input, social networks and level of cognitive functioning had no independent impact on costs. These findings could be used as a starting point for those interested in predicting the cost implications associated with the ageing population.

Activities of Daily Living↗
PubMed1998

Outcomes following acute hospital care for stroke or hip fracture: how useful is an assessment of anxiety or depression for older people?

OBJECTIVE: To investigate the association between severe life events and mental health outcomes following acute hospital care for older patients with acute stroke or fractured neck of femur. DESIGN: Prospective longitudinal survey of stroke and hip fracture patients admitted to hospital from admission to 6-month follow-up. SETTING: Six district general hospitals, three in the North and three in the South of England. PARTICIPANTS: 642 patients admitted to hospital with an acute stroke (268) or hip fracture (374) resident in a private household at 6 months follow-up. MAIN OUTCOME MEASURES: Hospital Anxiety and Depression Scale, cognitive items of the Survey Psychiatric Assessment Scale, Clackmannan Disability Scale, Severe Life Events Inventory, Wenger Social Support Network Typology. RESULTS: 47% of 6-month survivors of stroke or hip fracture resident in private households had a possible psychiatric illness: dementia (13%), anxiety or depression (41%). 57% had severe or very severe disability and 48% experienced additional life events (17% two or more) after hospital admission. Severe disability was strongly associated with a higher prevalence of anxiety (p < 0.0005) or depression (p < 0.0001). Social contact was associated with a lower prevalence of anxiety (p < 0.01) or depression (p < 0.0001) and social support network type was strongly associated with depression (p < 0.001) but not anxiety (p = 0.096). Number of severe life events was associated with anxiety (p < 0.001) but not depression (p = 0.058). CONCLUSION: Disability is probably a more robust outcome measure than assessments of mental health for older people in uncontrolled studies.

Aged↗
PubMed1998

Indoor factors associated with concentrations of house dust mite allergen, Der p 1, in a random sample of houses in Norwich, UK.

BACKGROUND: Studies of house dust mite allergen concentrations suggest large variations both within and between homes. It is likely that different household characteristics influence allergen levels in different locations within the house. OBJECTIVES: To investigate household characteristics associated with higher concentrations of house dust mite allergen in a random sample of houses. METHODS: Information on indoor environment was obtained from 158 adults aged 20-44. Dust samples were collected from their living room floor, bedroom floor and mattress. Concentrations of Der p 1, the major allergen from the house dust mite Dermatophagoides pteronyssinus, were measured by monoclonal antibody immunoassay. Associations between mite allergen concentrations and household characteristics were examined using censored-normal regression models. Factors that were related to Der p 1 (P </= 0.2) in univariate analyses were included in multivariable regression models. RESULTS: Der p 1 was not detected in any location in 10 (6.3%) houses. Geometric mean concentrations of Der p 1 were 1.9 microg/g in living room floor dust, 1.7 microg/g in bedroom floor dust and 2.0 microg/g in mattress dust. Approximately 25% of living room floor and mattress, and over 30% of bedroom floor samples had Der p 1 concentrations greater than 10 microg/g. Household characteristics associated with Der p 1 concentrations in both living room and bedroom were floor level, extractor fan in the kitchen, and age of carpet. Living room Der p 1 concentrations were also associated with gas oven/hob, window condensation, open fires, vacuum cleaner type, smokers in the house and age of house. Bedroom Der p 1 concentrations were also associated with use of blankets and wash temperature of bedding. Mattress Der p 1 concentrations were associated with window condensation, concrete bedroom floor and age of mattress. CONCLUSION: Different household characteristics were associated with high Der p 1 concentrations in different parts of the house. These findings are relevant to design of allergen avoidance regimes or formulation of policy recommendations for reduction of disease associated with allergen exposure.

Adult↗
PubMed1997

Evidence for the inactivation of multiple replicative lifespan genes in immortal human squamous cell carcinoma keratinocytes.

Human keratinocyte immortality is genetically recessive to the normal phenotype of limited replicative lifespan and appears to require the dysfunction of p53 and the cyclin D-Cdk inhibitor p16. In order to test for the inactivation of other candidate replicative lifespan genes in the immortal cells of human tumors, we developed a series of mortal and immortal keratinocyte cultures derived from neoplastic lesions of the head and neck which were amenable to molecular genetic analysis by the loss of heterozygosity (LOH) technique. The results indicate that keratinocyte immortalization in head and neck squamous cell carcinoma (SCC-HN) development involves the inactivation of at least two further pathways to senescence and four in all. Chromosomes 1, 4 and 7 carry genes representing immortality complementation groups C, B and D respectively and immortal keratinocytes showed LOH at either 4q32-q34 between D4S1554 and D4S171 (group B) or 7q31 (group D) but never 1q25 (group C). These results tentatively suggest that the genes responsible for the immortality complementation groups encode proteins on the same pathway to senescence. In addition, all of the immortal keratinocyte lines possessed high levels of telomerase activity and a suppressor of telomerase activity has been mapped to the short arm of chromosome 3p. Five out of eight lines showed LOH at 3p21.2-p21.3, a region which may carry a gene capable of suppressing SCC-HN telomerase. However, alternative mechanisms of telomerase reactivation were also suggested by our results. None of the above genetic alterations were seen in seven senescent neoplastic keratinocyte cultures. Other loci harbouring antiproliferative genes implicated in replicative lifespan showed few or no alterations and any alterations seen were additional to those described above.

Carcinoma, Squamous Cell↗
PubMed1997

Issues of recruitment and maintaining high response rates in a longitudinal study of older hospital patients in England--pathways through care study.

STUDY OBJECTIVES: To describe and discuss the methods used to recruit and maintain an unbiased sample of older discharged hospital patients in a study of the process and outcomes of hospital care. DESIGN: Prospective longitudinal interview study of consecutive patients admitted to hospital over a 12 month period and followed up for six months. Interviews took place in hospital five days after admission, at home 10 days after discharge, and six months after admission. SETTING: Six hospital locations: three in the north of England and three in the south. PARTICIPANTS: People aged 65 and over admitted to hospital with a new stroke or fractured neck of femur, their significant other, and nursing staff caring for them. MAIN RESULTS: Of 3105 patients referred to the study, 2111 were eligible and 1671 (79%) were recruited. Recruited stroke patients were younger than those not recruited and rates differed between locations for both stroke and fractured neck of femur. By six months after admission 25% had died. Outcome data were obtained for 85% of the surviving patients. Patients who died were older and frailer before admission. Among survivors, outcome data for stroke patients were less likely to be obtained for men, those more able initially, and those who were married. Response rates to each interview differed according to respondent types. Interviews were more likely to be obtained with significant others than patients. Patients who were not able to be interviewed were older and frailer; significant others were less likely to be interviewed if the patients were younger and more able. CONCLUSIONS: High response rates can be achieved with very frail older people if strategies are adopted to maintain their interest and if self reported data are supplemented by interviewing significant others.

Age Factors↗
PubMed1997

Early supported hospital discharge following acute stroke: pilot study results.

OBJECTIVE: To establish the feasibility and method of evaluation of an early supported hospital discharge policy for patients with acute stroke. DESIGN: A randomized controlled trial comparing an early supported discharge service to conventional care. SETTING: Three acute hospitals in Newcastle upon Tyne. SUBJECTS: Ninety-two eligible patients with acute stroke admitted between 1 February 1995 and 31 January 1996. MAIN OUTCOME MEASURES: Placement, length of stay, readmission rates, mortality, functional ability (Nottingham Extended Activities of Daily Living (ADL) Scale), handicap (Oxford Handicap Scale), global health status (Dartmouth Coop Function Charts) and carer stress (General Health Questionnaire 30 item). RESULTS: The median length of stay for patients randomized to early supported discharge was 13 days compared to 22 days in the conventional care group (p = 0.02). The median Barthel ADL index at seven days post stroke of patients randomized to early supported discharge was 15, and 13 for those randomized to conventional care (NS). At three months post stroke the median Nottingham EADL score of patients randomized to early supported discharge was 10 compared to 7 for those who received conventional care (NS). There were no statistically significant differences in the global health status of patients or carer stress. CONCLUSION: An early supported discharge service following acute stroke with individualized rehabilitation in the community is feasible and can be evaluated by a randomized controlled trial but a larger multicentre trial is needed before such a service is widely adopted.

Activities of Daily Living↗
PubMed1997

Archaic African and Asian lineages in the genetic ancestry of modern humans.

A 3-kb region encompassing the beta-globin gene has been analyzed for allelic sequence polymorphism in nine populations from Africa, Asia, and Europe. A unique gene tree was constructed from 326 sequences of 349 in the total sample. New maximum-likelihood methods for analyzing gene trees on the basis of coalescence theory have been used. The most recent common ancestor of the beta-globin gene tree is a sequence found only in Africa and estimated to have arisen approximately 800,000 years ago. There is no evidence for an exponential expansion out of a bottlenecked founding population, and an effective population size of approximately 10,000 has been maintained. Modest differences in levels of beta-globin diversity between Africa and Asia are better explained by greater African effective population size than by greater time depth. There may have been a reduction of Asian effective population size in recent evolutionary history. Characteristically Asian ancestry is estimated to be older than 200,000 years, suggesting that the ancestral hominid population at this time was widely dispersed across Africa and Asia. Patterns of beta-globin diversity suggest extensive worldwide late Pleistocene gene flow and are not easily reconciled with a unidirectional migration out of Africa 100,000 years ago and total replacement of archaic populations in Asia.

Africa↗
PubMed1997

Psychological distress among informal supporters of frail older people at home and in institutions. The Resource Implications Study Group of the MRC Cognitive Function and Ageing Study.

OBJECTIVE: Investigate presence of psychiatric morbidity in informal carers using 30-item General Health Questionnaire (GHQ) and examine which factors best predict psychiatric morbidity. DESIGN: Two-year longitudinal, panel survey of informal supporters of frail elderly subjects, using semi-structured interview schedules. Subjects were those defined as frail after screening stratified random sample of people aged 65 or over. SETTING: Informal supporters of frail elderly subjects residing in private households or residential or nursing homes in four UK districts. RESPONDENTS: 623 informal supporters of subjects living at home, 129 regular visitors of those in long-term care. MEASURE: 30-item GHQ (cross-sectional analysis). RESULTS: Stepwise multiple regression indicated main predictors of high GHQ scores in key supporters were: subjects had at least three problems of behaviour (b = 1.56, 95% CI 1.25-1.94); supporters had to alter working hours (b = 1.70, 95% CI 1.15-2.51); supporters were female (b =1.26, 95% CI 1.06-1.50). The following variables predicted low GHQ scores: supporters able to leave subject all day (b = 0.71, 95% CI 0.64-0.80); subjects never wandered (b = 0.78, 95% CI 0.62-0.99); supporters were 'other relatives' or friends of subject (b = 0.74, 95% CI 0.59-0.91). For visitors, spouses were most likely to have high GHQ scores (b = 2.46, 95% CI 1.32-4.57). CONCLUSIONS: Results suggest the need for greater collaboration between formal and informal care. Little work has been carried out to ascertain which interventions are most effective in alleviating carer stress: a series of randomized controlled trials to determine long-term effectiveness of various interventions for different groups of carers is required.

Adult↗
PubMed1996

Evidence that transcriptional activation by p53 plays a direct role in the induction of cellular senescence.

Wild-type p53 is necessary for the growth arrest of human diploid fibroblasts (HDF) (and many other cell types) at the end of their proliferative lifespan. Although p53 may actively mediate senescence, possibly in response to telomere erosion, it is however equally possible that it is merely a permissive factor required for response to some other inducer. To address this question, we have generated stable transfectants of early passage HDF, represented here by clone LacZ21, in which expression of a beta-galactosidase reporter construct reflects p53 transactivation activity. During continuous passage, the proportion of beta-gal positive LacZ21 cells remained below 2% for 25 population doublings (pd), first became significantly increased after 29 pd, and thereafter increased rapidly, reaching a maximum of 88% in fully-senescent cells (32 pd), which exceeded the response observed following an optimum dose (20 J/m2) of u.v. radiation. Correspondingly, the proportion of cells incorporating bromodeoxyuridine (BrdU) (initially 45-50%) began to fall at 29 pd and thereafter dropped rapidly to below 1% by pd 32. There was therefore a near-perfect reciprocal relationship between reporter construct expression and DNA synthesis as cells approached senescence. Furthermore, a dominant-negative p53 mutant (introduced by retroviral transduction) rescued LacZ21 cells from senescence and generated colonies with extended lifespan in which beta-gal expression was totally abolished. These data, although not excluding the need for other p53 functions, strongly suggest that p53-mediated transactivation of growth regulatory genes is a direct trigger, rather than a permissive factor, for cellular senescence.

Cell Line↗
PubMed1996

Liquefaction of cortical tissue in diabetic and galactosemic rat lenses defined by confocal laser scanning microscopy.

PURPOSE: To investigate whether a histologic link exists between osmotic fiber cell swelling and cortical tissue liquefaction in experimentally induced diabetic and galactosemic cataractogenesis of the rat lens. METHODS: Confocal laser scanning microscopy, in conjunction with specific membrane labels and correlative transmission electron microscopy, was used to image large cortical areas with precise definition of the individual cells. RESULTS: In both cataract models, tissue liquefaction--defined as the disintegration of tissue and the appearance of large fluid-filled spaces--typically was limited to a discrete zone in the lens cortex. The borders of the liquefaction zone were characterized by transitions between normal-appearing cells and swollen cells, which gained in size as plasma membranes ruptured and cytoplasmic contents fused and ultimately burst, thereby contributing to the formation of large fluid-filled spaces. During cataractogenesis, before tissue liquefaction became evident, selected fiber cells appeared swollen and accumulated specifically in the zone destined for tissue liquefaction. With increasing duration of diabetes or galactosemia, swollen fiber cells in this zone became more frequent and enlarged, resulting first in tissue disorder and then in tissue disintegration and the formation of large fluid-filled spaces. CONCLUSIONS: New imaging protocols strongly support a direct involvement of lens fiber cell swelling in the liquefaction of cortical tissue. The appearance of swollen fiber cells in the lens cortex, therefore, can be used as an early indicator of the histopathology of sugar cataractogenesis.

Animals↗
PubMed1995

Calcium supplementation and rectal mucosal proliferation: a randomized controlled trial.

BACKGROUND: Data from studies using rodents suggest that dietary calcium inhibits bile acid-induced mucosal damage and experimental carcinogenesis in the large bowel. However, in humans, the effect of dietary calcium and calcium supplementation on proliferation and carcinogenesis in the large bowel has been unclear. PURPOSE: To assess the effect of calcium supplementation on rectal mucosal proliferation in humans, we conducted a multicenter, randomized, placebo-controlled, double-blinded trial. METHODS: Participants were part of a larger multicenter chemoprevention trial; all were at high risk for large-bowel neoplasia, with at least one large-bowel adenoma removed endoscopically within the 3 months before study entry but with no known polyps remaining. Subjects were randomly assigned to receive daily either 3000 mg of calcium carbonate (providing 1200 mg elemental calcium) or an identical-appearing placebo tablet. During a scheduled endoscopy 6-9 months after random assignment (approximately 1 year after the qualifying endoscopy), rectal mucosal samples were obtained from 333 patients (173 assigned to calcium and 160 assigned to placebo). Proliferating cell nuclear antigen (PCNA) labeling indices (LIs) were computed as the measure of proliferation in specimens from 146 patients receiving calcium and 129 patients receiving placebo. Bromodeoxyuridine (BrdU) labeling was used to measure proliferation in a smaller number of specimens (27 calcium-receiving and 31 placebo-receiving participants). For each scorable crypt having at least one labeled cell (or surrounded by crypts with at least one labeled cell), a crypt LI was calculated as the number of labeled cells divided by the total number of crypt cells. Crypt LIs were averaged to produce a participant's average LI. RESULTS: The overall unadjusted mean PCNA LIs (+/- SE) were similar in the calcium and placebo groups (3.85% +/- 0.08% versus 3.92% +/- 0.08%, respectively, P = .30). The overall unadjusted mean BrdU LIs (+/- SE) were 3.88% +/- 0.30% in the calcium group and 3.54% +/- 0.21% in the placebo group (P = .54). PCNA labeling indices in the most luminal 40% of the crypt were small but, if anything, were higher in the calcium group. There was no patient subgroup within which calcium had an antiproliferative effect; the overall findings persisted among patients with high and low calcium intake, high and low fat intake, and high and low fiber intake. CONCLUSIONS: Calcium supplementation does not decrease rectal mucosal proliferation, as measured by PCNA (and BrdU) immunohistochemistry, in patients with previous large-bowel adenomas. This study, therefore, does not provide evidence for an anticarcinogenic effect of calcium.

Adenoma↗
PubMed1995

Ocular lens gap junctions: protein expression, assembly, and structure-function analysis.

Recent advances in understanding lens fiber gap junction formation are reviewed. These include studies of junctional protein expression in the embryonic lens, and of age related changes affecting gap junction structure and composition in the adult lens. An in vitro assembly system based on detergent solubilized pore complexes and endogenous lipids has been developed to provide information on the molecular interactions involved in gap junction formation and to provide material for structure analysis. Important information on the electrical properties of lens gap junction channels is obtained using electrophysiological techniques including planar lipid bilayer analysis and patch clamping.

Animals↗
PubMed1994

Administering amphotericin B--a practical approach.

Despite the introduction in recent years of novel antifungal agents, the potency and broad spectrum of activity of amphotericin B have ensured that it remains the treatment of choice for most deep-seated mycoses. However, this agent is not without significant toxicity, particularly in patients who are already seriously ill and/or who are receiving other potentially nephrotoxic drugs. We review the various routes by which amphotericin B can be administered, focusing mainly on the intravenous route. The use of more rapid infusion rates, lipid-complexed preparations, sodium supplementation in salt-depleted patients and strategies to reduce the incidence of infusion-related reactions and nephrotoxicity are also considered. Finally, detailed recommendations for the administration of amphotericin B are provided.

Amphotericin B↗
PubMed1994

Studies on the effects of growth hormone administration in vivo on the rates of glucose transport and utilization in rat skeletal muscle.

The effects of growth hormone (GH) administration to rats in vivo on the sensitivity of the rate of glucose utilization to insulin were studied in soleus muscles isolated from these rats. A single injection of GH did not increase the rate of glucose transport within 1-2 h. However, 12 h after, the rate of glucose transport was increased at 10 mU insulin l-1 and was accompanied by a similar increase in the rate of lactate formation but no change in the rate of glycogen synthesis. Prolonged treatment with GH decreased the rate of glucose transport and glycogen synthesis and increased the content of glucose 6-phosphate at physiological levels of insulin but did not affect the rate of lactate formation. These results suggest that: (a) GH does not increase the rate of glucose transport acutely; however, after several hours, the sensitivity of glucose transport and glycolysis to insulin are increased; (b) prolonged elevations of the level of GH in plasma decrease the sensitivity of the rate of glucose transport and glycogen synthesis to insulin. However, redirection of glucose residues away from the pathway of glycogen synthesis towards that of glycolysis and a possible increase in the rate of glycogenolysis maintain a normal rate of lactate formation, although the rate of glucose transport is decreased.

Animals↗