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Biomedical subjects

B O Williams

Publications and source records attributed to B O Williams.

At least 19 recordsLinked to original sources
PubMed1998

Loss of E2F-1 reduces tumorigenesis and extends the lifespan of Rb1(+/-)mice.

Mutation of the retinoblastoma tumour-suppressor gene (RB) leads to the deregulation of many proteins and transcription factors that interact with the retinoblastoma gene product (pRB), including members of the E2F transcription factor family. As pRB is known to repress E2F transcriptional activity and overexpression of E2F is sufficient for cell cycle progression, it is thought that pRB suppresses growth in part by repressing E2F-mediated transcription. Previously, we reported that loss of E2f1 in mice results in tissue-specific tumour induction and tissue atrophy, demonstrating that E2F-1 normally controls growth both positively and negatively in a tissue-specific fashion. To determine whether E2F-1 deregulation--as a result of loss of pRB--promotes proliferation in vivo, we have tested whether loss of E2f1 interferes with the pituitary and thyroid tumorigenesis that occurs in Rb1(+/-) mice. We have found that loss of E2f1 reduces the frequency of pituitary and thyroid tumours, and greatly lengthens the lifespan of Rb1(+/-); E2f1(-/-) animals, demonstrating that E2F-1 is an important downstream target of pRB during tumorigenesis. Furthermore, loss of E2f1 reduces a previously reported strain-dependent difference in Rb1(+/-) lifespan, suggesting that E2f1 or an E2F-1-regulated gene acts as a genetic modifier between the 129/Sv and C57BL/6 strains.

Animals↗
PubMed1997

Does a chest x-ray alter the management of new patients attending a geriatric day hospital?

OBJECTIVES: Studies have suggested that routine chest x-ray is never indicated but all new attenders at our day hospitals have a chest x-ray carried out. Our aim was to determine if this investigation altered the clinical management of patients and to try to select those patients in whom a chest x-ray is indicated. DESIGN: A prospective study was carried out over a 7 month period from February to September 1995. All new patients had cardiorespiratory symptoms/signs documented and a management plan made. A chest x-ray was then carried out and change in management as a result of the x-ray report noted. SETTING: Knightswood and Drumchapel Geriatric Day Hospitals, West Glasgow University NHS Trust. SUBJECTS: All new Day Hospital attenders. RESULTS: Of 207 new Day Hospital attenders, 53 had no clinical indication for a chest x-ray and although 70% had an abnormal film in no case was patient management changed as a result of this. A chest x-ray was indicated in 154 patients and of these 114 (74%) had an abnormal film with a resultant change in management in 23 patients (this comprised either a change in drug treatment or a further investigation.) Of those whose management was changed as a result of the x-ray report 61% had respiratory symptoms. CONCLUSION: We would recommend that chest x-ray should be performed in those patients who have a clear clinical indication and that the diagnostic yield is highest in the presence of respiratory symptoms or signs.

Aged↗
PubMed1996

Targeted disruption of p107: functional overlap between p107 and Rb.

To explore the physiological role of p107, a member of retinoblastoma gene (Rb) family, we disrupted the mouse gene by homologous recombination in embryonic stem cells. p107 homozygous mutant mice were viable, fertile, and displayed no obvious abnormalities. To investigate possible functional overlap between p107 and Rb, mice with mutations at both loci were generated. Rb+/-;p107-/- mice have a pronounced growth retardation and increased mortality rate during the first 3 weeks after birth. The Rb+/-;p107-/- pups that survive to adulthood did not show any altered tumor predisposition when compared with Rb+/- mice but developed multiple dysplastic lesions of the retina. Embryos homozygous for both Rb and p107 died at approximately 11.5 days of gestation, 2 days earlier than embryos homozygous for Rb alone. Histological examination revealed accelerated apoptosis in the liver and the central nervous system of Rb-/-;p107-/- embryos relative to Rb-/- embryos. These results provide the first in vivo evidence that p107 and Rb have overlapping functions in some tissues of the developing and adult mouse.

Actins↗
PubMed1996

Mechanisms of carcinogenesis and the mutant mouse.

Gene targeting in embryonic stem cells has allowed the creation of several new mouse strains carrying mutations in the murine homologs of human tumor suppressor genes. The phenotypes of these mutant strains are reviewed. In addition, recent experiments utilizing the ApcMin and p53 mutant animals to address specific mechanisms of carcinogenesis are discussed.

Adenomatous Polyposis Coli↗
PubMed1996

Efficacy of acrivastine with pseudoephedrine in treatment of allergic rhinitis due to ragweed.

BACKGROUND: Semprex-D capsules contain acrivastine 8 mg (a second generation H1-antagonist) plus pseudoephedrine HCl 60 mg and were developed to satisfy the needs of allergy suffers who prefer combination products designed to provide broader symptom relief. Approval of combination products by the US Food and Drug Administration requires demonstration that each component contributes to the overall effectiveness. OBJECTIVE: The objective of the study was to demonstrate that both acrivastine and pseudoephedrine share in the efficacy of the combination in relieving allergy symptoms in patients sensitive to ragweed pollen. METHODS: This was a double-blind, randomized, placebo-controlled, parallel groups, balanced design, multicenter (13 sites) study. Patients 12 years of age or older with skin test reactivity to ragweed were recruited. Patients who qualified for the study were dispensed either (1) acrivastine + pseudoephedrine, (2) acrivastine, (3) pseudoephedrine, or (4) placebo with instructions to take one capsule 4 times daily and to record allergy symptom scores in a symptom diary 3 times daily for 14 days. Assessments of health, global allergy symptoms, protocol compliance, adverse events, and vital signs were also documented. RESULTS: A total of 702 patients were enrolled in this study. Over the 2-week period, the combination of acrivastine + pseudophedrine was significantly more effective than acrivastine, pseudoephedrine, and placebo for relief of all symptoms (P range .01 to .001); pseudoephedrine for treating symptoms responsive to antihistamines (P = .003); and acrivastine for treating symptoms responsive to nasal decongestants (P < .001). Relatively small increases in adverse experience rates were observed for the combination relative to the placebo. CONCLUSIONS: These findings in a large clinical trial demonstrate that each component of the combination of acrivastine 8 mg plus pseudoephedrine HCl 60 mg contributes to the overall efficacy, thereby supporting the conclusion that the combination is rational, safe, and effective for the treatment of allergic rhinitis.

Adolescent↗
PubMed1996

Efficacy of acrivastine plus pseudoephedrine for symptomatic relief of seasonal allergic rhinitis due to mountain cedar.

BACKGROUND: Acrivastine is a second-generation H1-antagonist chemically related to triprolidine, but more polar and with less central nervous system penetration than triprolidine. OBJECTIVE: The efficacy of the antihistamine-decongestant combination product (Semprex-D capsules) containing acrivastine 8 mg plus pseudoephedrine HCl 60 mg was evaluated for the treatment of seasonal allergic rhinitis symptoms. METHODS: A total of 676 patients sensitive to mountain cedar pollen was enrolled into a 6-center, randomized, double-blind, placebo-controlled, parallel, 4-group study designed to compare acrivastine + pseudoephedrine, acrivastine, pseudoephedrine, and placebo. Patients with demonstrable diary symptom scores at baseline took study medication (4 doses/day) and recorded symptom scores twice daily for 2 weeks. The effectiveness of the acrivastine + pseudoephedrine combination was examined relative to the individual components and placebo in terms of changes in diary symptom scores. RESULTS: Over the 2-week period, the combination of acrivastine plus pseudoephedrine was significantly more effective than (1) acrivastine, pseudoephedrine, and placebo (P < .001) for relief of all symptoms; (2) pseudoephedrine (P < .001) for relieving allergy symptoms, ie, running nose, sneezing, itchy nose/throat and tearing; and (3) acrivastine (P < .001) for reducing nasal congestion. Relative to placebo, small increases in adverse experience rates were observed with acrivastine + pseudoephedrine for dry mouth, insomnia, somnolence, and headache. CONCLUSION: These findings in a large clinical trial demonstrate (1) the efficacy of acrivastine and (2) that each component of the combination of acrivastine 8 mg plus pseudoephedrine HCl 60 mg contributes to the overall efficacy, thereby supporting the conclusion that the combination is rational, safe, and effective for the treatment of allergic rhinitis.

Adolescent↗
PubMed1996

Altered cell cycle kinetics, gene expression, and G1 restriction point regulation in Rb-deficient fibroblasts.

Fibroblasts prepared from retinoblastoma (Rb) gene-negative mouse embryos exhibit a shorter G1 phase of the growth cycle and smaller size than wild-type cells. In addition, the mutant cells are no longer inhibited by low levels of cycloheximide at any point in G1 but do remain sensitive to serum withdrawal until late in G1. Certain cell cycle-regulated genes showed no temporal or quantitative differences in expression. In contrast, cyclin E expression in Rb-deficient cells is deregulated in two ways. Cyclin E mRNA is generally derepressed in mutant cells and reaches peak levels about 6 h earlier in G1 than in wild-type cells. Moreover, cyclin E protein levels are higher in the Rb-/- cells than would be predicted from the levels of its mRNA. Thus, the selective growth advantage conferred by Rb gene deletion during tumorigenesis may be explained in part by changes in the regulation of cyclin E. In addition, the mechanisms defining the restriction point of late G1 may consist of at least two molecular events, one cycloheximide sensitive and pRb dependent and the other serum sensitive and pRb independent.

Animals↗
PubMed1996

Clinical trials in the elderly. Should we do more?

Much of the information on which treatment decisions are based in elderly patients is derived from studies involving younger adults. The benefit to risk ratio of any given intervention may be quite different in frail older patients with significant comorbidities, and the applicability of such study findings to routine geriatric medical practice is therefore limited. The recruitment of significant numbers of elderly patients into trials is necessary to enable clinicians to make informed and rational therapeutic decisions in this expanding population.

Aged↗
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↗