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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
PubMed2001

Cell-autonomous and non-cell-autonomous functions of the Rb tumor suppressor in developing central nervous system.

The retinoblastoma tumor suppressor (RB) plays an important role in the regulation of cell cycle progression and terminal differentiation of many cell types. Rb(-/-) mouse embryos die at midgestation with defects in cell cycle regulation, control of apoptosis and terminal differentiation. However, chimeric mice composed of wild-type and Rb-deficient cells are viable and show minor abnormalities. To determine the role of Rb in development more precisely, we analyzed chimeric embryos and adults made with marked Rb(-/-) cells. Like their germline Rb(-/-) counterparts, brains of midgestation chimeric embryos exhibited extensive ectopic S-phase entry. In Rb-mutants, this is accompanied by widespread apoptosis. However, in chimeras, the majority of Rb-deficient cells survived and differentiated into neuronal fates. Rescue of Rb(-/-) neurons in the presence of wild-type cells occurred after induction of the p53 pathway and led to accumulation of cells with 4n DNA content. Therefore, the role of Rb during development can be divided into a cell-autonomous function in exit from the cell cycle and a non-cell-autonomous role in the suppression of apoptosis and induction of differentiation.

Animals↗
PubMed2000

A comparative evaluation of beta-catenin and plakoglobin signaling activity.

Vertebrates have two Armadillo-like proteins, beta-catenin and plakoglobin. Mutant forms of beta-catenin with oncogenic activity are found in many human tumors, but plakoglobin mutations are not commonly found. In fact, plakoglobin has been proposed to suppress tumorigenesis. To assess differences between beta-catenin and plakoglobin, we compared several of their biochemical properties. After transient transfection of 293T cells with an expression vector encoding either of the two proteins, soluble wild type beta-catenin does not significantly accumulate, whereas soluble wild type plakoglobin is readily detected. As anticipated, beta-catenin is stabilized by the oncogenic mutation S37A; however, the analogous mutation in plakoglobin (S28A) does not alter its half-life. S37A-beta-catenin activates a TCF/LEF-dependent reporter 20-fold more potently than wild type beta-catenin, and approximately 5-fold more potently than wild type or S28A plakoglobin. These differences may be attributable to an enhanced affinity of S37A beta-catenin for LEF1 and TCF4, as observed here by immunoprecipitation assays. We show that the carboxyl-terminal domain is largely responsible for the difference in signaling and that the Armadillo repeats account for the remainder of the difference. The relatively weak signaling by plakoglobin and the failure of the S28A mutation to enhance its stability, may explain why plakoglobin mutations are infrequent in malignancies.

Cell Line↗
PubMed2000

Neural crest-directed gene transfer demonstrates Wnt1 role in melanocyte expansion and differentiation during mouse development.

Wnt1 signaling has been implicated as one factor involved in neural crest-derived melanocyte (NC-M) development. Mice deficient for both Wnt1 and Wnt3a have a marked deficiency in trunk neural crest derivatives including NC-Ms. We have used cell lineage-directed gene targeting of Wnt signaling genes to examine the effects of Wnt signaling in mouse neural crest development. Gene expression was directed to cell lineages by infection with subgroup A avian leukosis virus vectors in lines of transgenic mice that express the retrovirus receptor tv-a. Transgenic mice with tva in either nestin-expressing neural precursor cells (line Ntva) or dopachrome tautomerase (DCT)-expressing melanoblasts (line DCTtva) were analyzed. We overstimulated Wnt signaling in two ways: directed gene transfer of Wnt1 to Ntva(+) cells and transfer of beta-catenin to DCTtva(+) NC-M precursor cells. In both methods, NC-M expansion and differentiation were effected. Significant increases were observed in the number of NC-Ms [melanin(+) and tyrosinase-related protein 1 (TYRP1)(+) cells], the differentiation of melanin(-) TYRP1(+) cells to melanin(+) TYRP1(+) NC-Ms, and the intensity of pigmentation per NC-M. These data are consistent with Wnt1 signaling being involved in both expansion and differentiation of migrating NC-Ms in the developing mouse embryo. The use of lineage-directed gene targeting will allow the dissection of signaling molecules involved in NC development and is adaptable to other mammalian developmental systems.

Animals↗
PubMed2000

Ageism helps to ration medical treatment.

The world's population is ageing and this will have inevitable consequences for the demands on acute and longer term health care resources. Old age is rarely characterised by positive images and older age stereotypes are often unflattering and ugly. Many older people experience social exclusion as a result of low income, poor housing, little family support, isolation, disability and illness. Ageism is a prejudice which is invoked to deny older people the things they seek and ageism in medicine probably reflects ageism in society as a whole. Old age is a criterion for rationing health care resources and it occurs at all levels in the National Health Service. Older subjects are often excluded from research trials, have their surgical operations cancelled too often and are less often accepted for cardiological investigation and intervention. Women over 65 are not routinely invited for breast cancer screening and, once they are diagnosed, they may not be offered the same treatment as younger women. Ageism in clinical practice should be combated by better education of healthcare workers and treatment decisions should only be taken on an individual basis and not on stereotypical views. 'Age, I do abhor thee, Youth, I do adore thee.' Shakespeare, The Passionate Pilgrim.

Aged↗
PubMed1999

Development of a flexible and specific gene delivery system for production of murine tumor models.

To develop models of human cancer we have expressed the avian retroviral receptor, TVA, under a variety of mammalian promoters in transgenic mice, thus rendering mice susceptible to infection with avian leukosis virus-derived gene vectors. TVA-based retroviral gene transfer offers advantages over current murine models of human cancer. A single transgenic mouse line can be used to evaluate multiple genetic lesions, individually and in combination. Furthermore, mutant genes are introduced somatically into animals, as occurs in the majority of naturally occurring tumors. Because the avian viral vectors replicate only in avian cells, the viral receptor in infected transgenic mouse cells remains available for multiple rounds of infection with different ASLV vectors. We discuss the theoretical and practical aspects of using recombinant avian retroviruses with TVA transgenic mice to generate cancer models.

Alpharetrovirus↗
PubMed1999

Regulation of Wnt signaling by Sox proteins: XSox17 alpha/beta and XSox3 physically interact with beta-catenin.

Using a functional screen in Xenopus embryos, we identified a novel function for the HMG box protein XSox17 beta. Ectopic expression of XSox17 beta ventralizes embryos by inhibiting the Wnt pathway downstream of beta-catenin but upstream of the Wnt-responsive gene Siamois. XSox17 beta also represses transactivation of a TCF/LEF-dependent reporter construct by Wnt and beta-catenin. In animal cap experiments, it both activates transcription of endodermal genes and represses beta-catenin-stimulated expression of dorsal genes. The inhibition activity of XSox17 beta maps to a region C-terminal to the HMG box; this region of XSox17 beta physically interacts with the Armadillo repeats of beta-catenin. Two additional Sox proteins, XSox17 alpha and XSox3, likewise bind to beta-catenin and inhibit its TCF-mediated signaling activity. These results reveal an unexpected mechanism by which Sox proteins can modulate Wnt signaling pathways.

Animals↗
PubMed1999

A double-blind, placebo-controlled study of the efficacy and safety of non-prescription ranitidine 75 mg in the prevention of meal-induced heartburn.

BACKGROUND: Ranitidine 75 mg (Zantac 75) has been shown to be effective for the treatment of pre-existing heartburn symptoms. AIM: To compare the efficacy of dosing ranitidine 75 mg or placebo 30 min prior to a proven heartburn-provoking meal in completely preventing or reducing subsequent heartburn symptoms. METHODS: A randomized, double-blind, parallel methodology was used at nine investigative centres. Following a screening visit, patients ate a standard test meal consisting of chili, chips and a soft drink on two occasions. On the first occasion, patients received single-blind placebo 30 min before the meal. This meal was used to qualify patients and to ensure the onset of a minimum level of heartburn. Patients who qualified were randomized (n = 284) to receive double-blind ranitidine 75 mg or placebo 30 min before a second test meal administered 4-14 days later at the treatment visit. Patients recorded whether heartburn was present and rated heartburn severity by completing visual analogue scales at 15-min intervals over the 4. 5 h meal evaluation periods. RESULTS: Statistically significant differences favouring ranitidine 75 mg were determined for complete prevention of heartburn (P < 0.006), heartburn severity area under the curve (P < 0.001), a clinical success end-point (P < 0.001), and all other end-points (P < 0.001). CONCLUSIONS: These data clearly demonstrate that ranitidine 75 mg is effective in completely preventing or decreasing heartburn when administered 30 min prior to a provocative meal.

Adult↗
PubMed1999

Membrane-anchored plakoglobins have multiple mechanisms of action in Wnt signaling.

In Wnt signaling, beta-catenin and plakoglobin transduce signals to the nucleus through interactions with TCF-type transcription factors. However, when plakoglobin is artificially engineered to restrict it to the cytoplasm by fusion with the transmembrane domain of connexin (cnxPg), it efficiently induces a Wnt-like axis duplication phenotype in Xenopus. In Xenopus embryos, maternal XTCF3 normally represses ventral expression of the dorsalizing gene Siamois. Two models have been proposed to explain the Wnt-like activity of cnxPg: 1) that cnxPg inhibits the machinery involved in the turnover of cytosolic beta-catenin, which then accumulates and inhibits maternal XTCF3, and 2) that cnxPg directly acts to inhibit XTCF3 activity. To distinguish between these models, we created a series of N-terminal deletion mutations of cnxPg and examined their ability to induce an ectopic axis in Xenopus, activate a TCF-responsive reporter (OT), stabilize beta-catenin, and colocalize with components of the Wnt signaling pathway. cnxPg does not colocalize with the Wnt pathway component Dishevelled, but it does lead to the redistribution of APC and Axin, two proteins involved in the regulation of beta-catenin turnover. Expression of cnxPg increases levels of cytosolic beta-catenin; however, this effect does not completely explain its signaling activity. Although cnxPg and Wnt-1 stabilize beta-catenin to similar extents, cnxPg activates OT to 10- to 20-fold higher levels than Wnt-1. Moreover, although LEF1 and TCF4 synergize with beta-catenin and plakoglobin to activate OT, both suppress the signaling activity of cnxPg. In contrast, XTCF3 suppresses the signaling activity of both beta-catenin and cnxPg. Both exogenous XLEF1 and XTCF3 are sequestered in the cytoplasm of Xenopus cells by cnxPg. Based on these data, we conclude that, in addition to its effects on beta-catenin, cnxPg interacts with other components of the Wnt pathway, perhaps TCFs, and that these interactions contribute to its signaling activity.

Animals↗
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↗
PubMed1998

Team work and skillmix. Do they improve care for older patients?

The Jansson Memorial Lectures were instituted by the Council of the Royal College of Speech and Language Therapists in September 1960 as a result of a bequest left to the College in her will by Miss Gladys Astrild Jansson. Miss Jansson had died at the age of 74 years after having spent a life of unselfish devotion to the practice of speech therapy in the Bath area.

Aged↗
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↗