PubMed Health⌕ Search

Biomedical subjects

B O Williams

Publications and source records attributed to B O Williams.

At least 37 records · Page 2Linked to original sources
PubMed1995

A subset of p53-deficient embryos exhibit exencephaly.

Defects in neural tube formation are among the most common malformations leading to infant mortality. Although numerous genetic loci appear to contribute to the defects observed in humans and in animal model systems, few of the genes involved have been characterized at the molecular level. Mice lacking the p53 tumour suppressor gene are predisposed to tumours, but the viability of these animals indicates that p53 function is not essential for embryonic development. Here, we demonstrate that a fraction of p53-deficient embryos in fact do not develop normally. These animals display defects in neural tube closure resulting in an overgrowth of neural tissue in the region of the mid-brain, a condition known as exencephaly.

Animals↗
PubMed1994

Extensive contribution of Rb-deficient cells to adult chimeric mice with limited histopathological consequences.

Homozygosity for a mutation in the Rb tumor suppressor gene causes mid-gestation embryonic lethality in the mouse. Using a two-step targeting protocol, we have constructed Rb homozygous mutant mouse embryonic stem cells and used them to create chimeric animals partially composed of Rb-deficient cells. Analysis of these chimeras demonstrates widespread contribution of the mutant cells to adult tissues, including the retina and mature erythrocytes. Despite the presence of large numbers of Rb-deficient cells in most tissues of these mice, they are remarkably normal but do exhibit certain histological defects including cataracts, hyperplasia of the adrenal medulla, and enlarged cells in the cerebellum and the liver. Like animals heterozygous for the Rb mutation, the chimeras develop tumors of the intermediate lobe of the pituitary, and the rate of pituitary tumorigenesis is greatly accelerated.

Adrenal Glands↗
PubMed1994

p53-dependent apoptosis produced by Rb-deficiency in the developing mouse lens.

The retinoblastoma tumour-suppressor gene (RB) has been implicated in negative growth regulation, induction of differentiation, and inhibition of cellular transformation. Homozygous inactivation of the Rb gene in the mouse leads to mid-gestational lethality with defects in erythropoiesis and neurogenesis. Here we describe the effects of the Rb-deficient state on the development of the ocular lens. The regional compartmentalization of growth, differentiation and apoptosis in the developing lens provides an ideal system to examine more closely the relationships of these processes in vivo. We demonstrate that loss of Rb function is associated with unchecked proliferation, impaired expression of differentiation markers, and inappropriate apoptosis in lens fibre cells. In addition, we show that ectopic apoptosis in Rb-deficient lenses is dependent on p53, because embryos doubly null for Rb and p53 show a nearly complete suppression of this effect. This developmental system provides a framework for understanding the consequences of the frequent mutation of both RB and p53 in human cancer.

Animals↗
PubMed1994

p53-dependent G1 arrest involves pRB-related proteins and is disrupted by the human papillomavirus 16 E7 oncoprotein.

The cell cycle regulatory tumor suppressor proteins p53 and pRB are targeted for inactivation by several tumor viruses, including the high-risk types of human papillomaviruses (HPVs) via interactions of the HPV E6 and E7 oncoproteins with p53 and pRB, respectively. p53 plays a central role in a signal transduction pathway that mediates G1 arrest after DNA damage, though the mechanism by which G1 arrest occurs has not been elucidated. The cyclin-associated protein p21waf1/cip1 has recently been shown to be induced by p53 and to inhibit cyclin complex-mediated phosphorylation of pRB in vitro. Thus, we investigated a possible role for pRB in the p53-mediated DNA damage response. After gamma-irradiation, cells expressing wild-type p53 arrested in G1, contained increased levels of WAF1/CIP1 mRNA, and demonstrated accumulation of hypophosphorylated pRB. In contrast, cell lines with abnormal p53 genes or with p53 functionally inactivated by the E6 oncoprotein of HPV16 (a high-risk HPV) failed to arrest in G1, did not elevate WAF1/CIP1 mRNA, and did not accumulate hypophosphorylated pRB. Despite apparently normal elevation of p53 protein and WAF1/CIP1 mRNA after irradiation, cells expressing HPV16 E7 also failed to arrest in G1 and did not accumulate hypophosphorylated pRB. Disruption of RB genes alone did not totally abrogate this G1 arrest. Our results suggest that p53 indirectly regulates phosphorylation of pRB and that pRB and/or other pRB-like molecules that bind to HPV16 E7 participate in the DNA damage-mediated G1 arrest signal. In the process of HPV infection, the HPV E6 and E7 oncoproteins may undermine this cell cycle checkpoint, contributing to the accumulation of genetic alterations during tumorigenesis.

Cell Cycle↗
PubMed1994

Tumor spectrum analysis in p53-mutant mice.

BACKGROUND: The p53 tumor suppressor gene is mutated in a large percentage of human malignancies, including tumors of the colon, breast, lung and brain. Individuals who inherit one mutant allele of p53 are susceptible to a wide range of tumor types. The gene encodes a transcriptional regulator that may function in the cellular response to DNA damage. The construction of mouse strains carrying germline mutations of p53 facilitates analysis of the function of p53 in normal cells and tumorigenesis. RESULTS: In order to study the effects of p53 mutation in vivo, we have constructed a mouse strain carrying a germline disruption of the gene. This mutation removes approximately 40% of the coding capacity of p53 and completely eliminates synthesis of p53 protein. As observed previously for a different germline mutation of p53, animals homozygous for this p53 deletion mutation are viable but highly predisposed to malignancy. Heterozygous animals also have an increased cancer risk, although the distribution of tumor types in these animals differs from that in homozygous mutants. In most cases, tumorigenesis in heterozygous animals is accompanied by loss of the wild-type p53 allele. CONCLUSION: We reaffirm that p53 function is not required for normal mouse development and conclude that p53 status can strongly influence tumor latency and tissue distribution.

Alleles↗
PubMed1994

Cooperative tumorigenic effects of germline mutations in Rb and p53.

The tumour suppressor genes Rb and p53 are mutated in several types of human cancer, and many tumour types carry mutations in both genes. To study how these genes normally function, we and others have created mouse strains with Rb and p53 mutations. Here we describe the phenotypic effects of combined germline mutations in these two tumour suppressor genes. Mice mutant for both genes have reduced viability and exhibit novel pathology including pinealoblastomas, islet cell tumours, bronchial epithelial hyperplasia and retinal dysplasia. These data indicate that mutations in Rb and p53 can cooperate in the transformation of certain cell types in the mouse.

Adenoma, Islet Cell↗
PubMed1994

Antithrombotic therapy prescribed for patients with non-rheumatic atrial fibrillation.

Patients with non-rheumatic atrial fibrillation have a fivefold increased risk of stroke. Warfarin reduces this risk by approximately two thirds, but evidence for benefit from aspirin is less compelling. We assessed whether our current practice reflects the message of the trials. In a retrospective case record study we reviewed notes of 131 patients with atrial fibrillation (AF), mean age 79 (range 53-95) years, admitted to a medical unit (72) or geriatric assessment unit (59). Thirty-two patients had paroxysmal AF. Of 115 patients with nonrheumatic AF, 36 (31%) had one or more recorded contraindication to anti-coagulation. Although 79 patients (69%) had no recorded contraindication to warfarin, only 2 took warfarin and 15 aspirin prior to admission. Ten patients commenced warfarin and 8 aspirin before discharge. Thirty-nine patients (53%) without contraindication, were discharged without antithrombotic therapy. Despite evidence to support anticoagulating patients with non-rheumatic AF, this rarely occurs.

Aged↗
PubMed1993

Do stroke units save lives?

Management of stroke patients in specialist stroke units hastens recovery but is not believed to influence mortality. We did a statistical overview of randomised controlled trials reported between 1962 and 1993 in which the management of stroke patients in a specialist unit was compared with that in general wards. We identified 10 trials, 8 of which used a strict randomisation procedure. 1586 stroke patients were included; 766 were allocated to a stroke unit and 820 to general wards. The odds ratio (stroke unit vs general wards) for mortality within the first 4 months (median follow-up 3 months) after the stroke was 0.72 (95% CI 0.56-0.92), consistent with a reduction in mortality of 28% (2p < 0.01). This reduction persisted (odds ratio 0.79, 95% CI 0.63-0.99, 2p < 0.05) when calculated for mortality during the first 12 months. The findings were not significantly altered if the analysis was limited to studies that used a formal randomisation procedure. We conclude that management of stroke patients in a stroke unit is associated with a sustained reduction in mortality.

Aged↗
PubMed1991

Hemodynamic effects of a single moderate dose of alcohol in elderly subjects.

The effects of 0.5 g ethanol/kg body weight and of an iso-volumic control drink were compared in eight normotensive subjects aged 70-96 years. Blood alcohol concentration reached a mean (+/- SEM) maximum of 44.4 +/- 5.0 mg/dl at 50 minutes after the start of drinking. Compared to control, alcohol increased mean sitting and standing heart rates by 3.4 +/- 1.3 (p = .08) and 5.4 +/- 1.9 (p less than .05) beats/minute, respectively; mean venous haematocrit rose by 3.9 +/- 1.3% (p less than .05). There were no significant changes in sitting or standing systolic or diastolic blood pressures after alcohol compared to the control drink. A single moderate dose of alcohol has only minor haemodynamic effects in normotensive elderly subjects. The rise in heart rate after alcohol may be a reflex response that helps to maintain blood pressure in the face of reduced circulating plasma volume due to alcohol-induced diuresis.

Aged↗
PubMed1990

Functional capacity and mental status of elderly people in long-term care in west Glasgow.

Functional capacity and mental status were assessed in 821 patients in long-term care in West Glasgow. In geriatric medical long-term care only five (1.3%) out of 387 patients were independent in activities of daily living (walking, transfers from bed and chair, dressing, toileting, urinary and faecal continence) and were not severely mentally impaired (AMT score greater than 6/10); in psychogeriatric care n = 6/143 (4.2%) in private nursing homes n = 6/66 (9.1%) and in residential care n = 100/235 (42.6%). Patients in geriatric medical care had a greater prevalence of immobility and urinary incontinence but less mental impairment than those in psychogeriatric care. Nearly all patients placed in geriatric medical or psychogeriatric care had major functional disability or mental impairment. The level of disability was less in private nursing than in geriatric medical care. Although 57% of those in residential care required some assistance or supervision in activities of daily living or had severe mental impairment, 86% were independent in walking and 83% were continent of urine. The implications of these findings for the provision of care for physically and mentally frail elderly are discussed.

Activities of Daily Living↗
PubMed1989

A comparison of acquired immunodeficiency syndrome and Kaposi's sarcoma incidence rates, Atlanta, 1983-86.

Recent temporal trends in incidence rates for acquired immunodeficiency syndrome (AIDS) and Kaposi's sarcoma were compared in metropolitan Atlanta, Georgia. From 1983 through 1986 the age-adjusted incidence rate of Kaposi's sarcoma among White males ages 25-49 increased 11-fold (2.2-24.4/100,000 person years). The annual incidence rate of AIDS increased ten-fold (11.3-113.3/100,000). These findings do not support earlier reports that the proportion of AIDS patients with Kaposi's sarcoma has decreased over time.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Prospective randomised study of an orthopaedic geriatric inpatient service.

A randomised controlled trial of two management regimens was carried out in women patients over 65 years of age with hip fractures. Ninety seven patients were admitted to a designated orthopaedic geriatric unit and 125 to orthopaedic wards. No difference was observed in mortality, length of stay, or placement of patients between the two groups. More medical conditions were recognised and treated in patients in the orthopaedic geriatric unit group. It is concluded that designated orthopaedic geriatric units can provide medical care to these patients and should be administered without additional cost.

Activities of Daily Living↗
PubMed1988

Undergraduate teaching of geriatric medicine in the United Kingdom: changes in the years 1981-1986.

A follow-up survey of undergraduate teaching of geriatric medicine was carried out in 1986. All 27 clinical medical schools responded. Geriatric medicine is taught to all medical students in 25 and to only a proportion of students in two. Fifty-nine per cent of schools have academic departments teaching for a mean of 89 hours compared with 33 hours in non-academic departments--an overall mean of 68 hours. The subject is taught by various methods with 70% of teaching time spent on bedside clinical instruction. Other aspects of institutional and community care are often covered. The subject is examined in 18 schools. New academic departments are planned at four schools, and an increase in teaching time planned in five. To meet the needs of the population of the next century, reconsideration of curricula in some of the medical schools is recommended.

Curriculum↗
PubMed1987

Prospective study of drug reporting by general practitioners for an elderly population referred to a geriatric service.

A prospective study was carried out in which the drug history of patients which was provided by general practitioners was compared with the drugs found by geriatricians in patients' homes in 700 referrals to geriatricians. Drug compliance was not assessed. The drug history appeared to be accurate in one third of referrals. Underreporting of medication was common and increased as the number of prescribed drugs increased. Roughly one fifth of patients had at least one potential drug interaction. Keeping careful prescription records, regular review, and accurate reporting of medication should reduce drug associated morbidity in elderly patients.

Aged↗
PubMed1985

Haemodynamic response to postural stress in the elderly with and without postural hypotension.

The haemodynamic response to postural stress (60 degrees foot-down tilt) was measured by impedance cardiography in six elderly cardiovascular-normal patients and 39 with symptomatic postural hypotension (systolic blood pressure drop greater than or equal to 20 mmHg or more). In the normal elderly the mean increase in heart rate, fall in blood pressure and cardiac output, and rise in peripheral resistance was less than that described in younger subjects. The changes were at their maximum in 1 min, and there was little further change over the next 5 min. In those with postural hypotension, orthostatic reduction (or failure to rise) of the peripheral resistance was the mechanism in 83% of cases, whatever the cause, and the time course of the haemodynamic changes was the same in the majority as in the normals. Serial tests in patients whose postural hypotension was controlled (by cessation of causal drugs, often multiple, by fludrocortisone, or by dihydroergotamine) showed return to normal.

Aged↗