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Biomedical subjects

G Royle

Publications and source records attributed to G Royle.

At least 19 recordsLinked to original sources
PubMed2006

Preliminary estimates of the calcium/phosphorus ratio at different cortical bone sites using synchrotron microCT.

The Ca/P ratio was measured in cortical bone samples from the femoral neck, front and rear tibia of female rats (1.5 years of age), using synchrotron radiation microtomography. The use of a monoenergetic x-ray beam, as provided by the synchrotron facility, generates accurate 3D maps of the linear attenuation coefficient within the sample and hence gives the ability to map different chemical components. Data sets were taken at 20 keV for each bone sample and calibration phantoms. From the 3D data sets, multiple 2D slices were reconstructed with a slice thickness of approximately 28 microm and converted to Ca/P ratios using the calibration phantom results. Mean values (M +/- SD) for cortical femoral, front and rear tibias are 2.12 +/- 0.08, 1.75 +/- 0.06 and 1.94 +/- 0.07 respectively. These values were compared with those derived from different animals. Differences between the same bone sites from different animals are not significant (0.1 < p < or = 0.9) while those between different bone sites are highly significant (p < 10(-3)) demonstrating a dependence upon life style and bone use.

Animals↗
PubMed2005

High resolution Ca/P maps of bone architecture in 3D synchrotron radiation microtomographic images.

The Ca/P ratio was measured in cortical bone samples from the femoral neck and tibia of different animal species, using synchrotron radiation microtomography. Use of a monoenergetic X-ray beam, as provided by the synchrotron facility, generates accurate 3D maps of the linear attenuation coefficient within the sample and hence gives the ability to map different chemical components. Also, by comparing normal and abnormal bones, i.e. osteoporotic (induced by inflammation), changes in the Ca/P ratio brought about by bone diseases can be detected. MicroCT data sets were collected at 20 and 28 keV for each bone sample and two calibration phantoms. From the 3D data sets, multiple 2D slices were reconstructed with a slice thickness of approximately 30 microm. Regions of interest were defined around suitable sites and were converted to Ca/P ratios using the data collected from the test phantoms. A significant difference (p<0.001) between osteoporotics and age-matched normals at both energies was detected. Differences between different bone sites from the same animal are not significant (p>0.5) while those between the same bone sites from different animals are highly significant (p<0.001). Differences between estimates made at 20 and 28 keV are not significant (p>0.5). An important aspect is the ability to map the spatial distribution of the Ca/P ratio.

Animals↗
PubMed2001

A method for defining binding sites involved in protein-protein interactions: analysis of the binding of plasminogen activator inhibitor 1 to the somatomedin domain of vitronectin.

Plasminogen activator inhibitor type-1 (PAI-1) is bound to vitronectin (VN) in plasma and in the extracellular matrix. We previously employed a domain-swapping approach to show that the high-affinity binding site for PAI-1 in VN is contained within residues 12-30 in the amino-terminal somatomedin B (SMB) domain. In this study, we attempt to further delineate the location of this site by employing a novel approach that is based on the use of monoclonal antibodies (Mabs) together with site-directed mutagenesis. Six separate Mabs were identified that bound to the SMB domain and competed with PAI-1 for binding to VN. The relative affinity of each of the Mabs, and of PAI-1 itself, for binding to individual variants of SMB (prepared by alanine scanning mutagenesis), was then determined and compared in competitive binding experiments. Three separate, partially overlapping Mab epitopes within SMB were defined by these studies, and the PAI-1 binding site was localized to the region between residues 24 and 37. When considered together with the domain swapping data, these studies suggest that the PAI-1 binding site is contained within a common seven-residue region (i.e., residues 24-30) in the SMB domain.

Alanine↗
PubMed2000

Comparison between low and high pressure suction drainage following axillary clearance.

AIM: We report the comparison of low (Exudrain) and high pressure (Redivac) drains in 69 patients following mastectomy and axillary clearance. METHODS: Volume of drainage was recorded daily for 8 days postoperatively. RESULTS: Comparison of daily drainage revealed no statistically significant difference between the two groups of patients (P>0.05). There were no complications specific to the drains and we found similar numbers of infective complications in both groups. Hospital stay was also similar in the two groups (P=0. 70). CONCLUSIONS: We conclude that the two drainage systems are equally effective in their drainage abilities although use of the low pressure may have an advantage over the high pressure system as it obviates the need for bottle changes and therefore requires less time and effort to manage.

Axilla↗
PubMed1998

D-D dimers: a poor correlate of PPIH and subsequent outcomes.

OBJECTIVES: To ascertain the normal range of D-D dimer levels in pregnancy in our population, and whether dimer levels are of value as a correlate of proteinuric pregnancy-induced hypertension (PPIH) or a predictor of adverse outcome. METHODS: Dimer levels were measured in 44 women diagnosed with PPIH after 32 weeks' gestation and 55 controls recruited before 24 weeks' gestation. RESULTS: Mean dimer levels in the second and third trimester of normal pregnancy were 45 ng/ml (+/- 1 S.D., 15-134) and 85 ng/ml (+/- 1 S.D., 40-180), respectively (P < 0.001). Mean dimer level in PPIH was 148 ng/ml (+/- 1 S.D., 76-292), differing significantly from normal pregnancy by ELISA but not by latex particle assay. No correlation was found between dimer levels and adverse outcome, nor between dimer levels and any one particular adverse outcome. CONCLUSION: These results suggest that dimer levels are not a useful correlate of PPIH, nor do they have a useful predictive value for adverse outcome in PPIH.

Female↗
PubMed1998

The significance of involved tumour bed biopsy following wide local excision of breast cancer.

AIM: Following wide local excision of breast cancer approximately 25% of patients have residual disease in the tumour bed. The aim of this study was to determine whether positive bed biopsy correlated with either local recurrence or overall survival. METHOD: Following wide excision bed biopsies were taken at four separate sites from the tumour bed. Histopathological assessment of the bed biopsies was made and compared to features within the primary tumour. Patients were followed-up over a median period of 6.17 years and local recurrence and survival data documented. RESULTS: Two hundred and sixty-eight patients were included in the study and 63 had positive bed biopsies. In all, 85 patients had a recurrence of breast cancer and 69 died. Kaplan-Meier plots showed no evidence of a difference in survival between bed biopsy positive and negative patients. Bed biopsy positive patients were at greater risk of local recurrence. CONCLUSIONS: These findings suggest that positive bed biopsy is associated with an increase in local recurrence rates but has no effect on overall survival following wide excision of breast cancer.

Adult↗
PubMed1997

Inactivation of the Fanconi anemia group C gene augments interferon-gamma-induced apoptotic responses in hematopoietic cells.

Hematopoietic progenitor cells (HPC) from mice nullizygous at the Fanconi anemia (FA) group C locus (FAC -/-) are hypersensitive to the mitotic inhibitory effects of interferon (IFN-gamma). We tested the hypothesis that HPC from the bone marrow of Fanconi group C children are similarly hypersensitive and that the fas pathway is involved in affecting programmed cell death in response to low doses of IFN-gamma. In normal human and murine HPC, IFN-gamma primed the fas pathway and induced both fas and interferon response factor-1 (IRF-1) gene expression. These IFN-gamma-induced apoptotic responses in HPC from the marrow of a child with FA of the C group (FA-C) and in FAC -/- mice occurred at significantly lower IFN doses (by an order of magnitude) than did the apoptotic responses of normal HPC. Treatment of FA-C CD34+ cells with low doses of recombinant IFN-gamma, inhibited growth of colony forming unit granulocyte-macrophage and burst-forming unit erythroid, while treatment with blocking antibodies to fas augmented clonal growth and abrogated the clonal inhibitory effect of IFN-gamma. Transfer of the normal FAC gene into FA-C B-cell lines prevented mitomycin C-induced apoptosis, but did not suppress fas expression or inhibit the primed fas pathway. However, the kinetics of Stat1-phosphate decay in IFN-gamma-treated cells was prolonged in mutant cells and was normalized by transduction of the normal FAC gene. Therefore, the normal FAC protein serves, in part, to modulate IFN-gamma signals. HPC bearing inactivating mutations of FAC fail to normally modulate IFN-gamma signals and, as a result, undergo apoptosis executed through the fas pathway.

Anemia, Aplastic↗
PubMed1996

Germ cell defects and hematopoietic hypersensitivity to gamma-interferon in mice with a targeted disruption of the Fanconi anemia C gene.

Fanconi anemia (FA) is an autosomal recessive chromosome instability syndrome characterized by progressive bone marrow (BM) failure, skeletal defects, and increased susceptibility to malignancy. FA cells are hypersensitive to DNA cross-linking agents, oxygen and have cell cycle abnormalities. To develop an animal model of the disease we generated mice homozygous for a targeted deletion of exon 9 of the murine FA complementation group C gene (fac). Mutant mice had normal neonatal viability and gross morphology, but their cells had the expected chromosome breakage and DNA cross-linker sensitivity. Surprisingly, male and female mutant mice had reduced numbers of germ cells and females had markedly impaired fertility. No anemia was detectable in the peripheral blood during the first year of life, but the colony forming capacity of marrow progenitor cells was abnormal in vitro in mutant mice. Progenitor cells from fac knock-out mice were hypersensitive to interferon gamma. This previously unrecognized phenotype may form the basis for BM failure in human FA.

Animals↗
PubMed1996

Structural and functional analysis of the plasminogen activator inhibitor-1 binding motif in the somatomedin B domain of vitronectin.

Plasminogen activator inhibitor 1 (PAI-1) binds to the somatomedin B (SMB) domain of vitronectin (VN), a domain present in at least seven other proteins. In this study, we investigate the PAI-1 binding activity of these SMB homologs and attempt to more specifically localize the PAI-1 binding site within this domain. SMBVN and several of its homologs were expressed in Escherichia coli, purified, and tested for PAI-1 binding activity in a competitive ligand binding assay. Although recombinant SMBVN was fully active in this assay, none of the homologs bound to PAI-1 or competed with VN for PAI-1 binding. These inactive homologs are structurally related to SMBVN, having 33-45% sequence identity and containing all 8 cysteines at conserved positions. Thus, homolog-scanning experiments were conducted by exchanging progressively larger portions of the NH2- or COOH-terminal regions of active SMBVN with the corresponding regions of the inactive homologs. These experiments revealed that the minimum PAI-1-binding sequence was present in the central region (residues 12-30) of SMBVN. Alanine scanning mutagenesis further demonstrated that each of the 8 cysteines as well as Gly12, Asp22, Leu24, Try27, Tyr28, and Asp34 were critical for PAI-1 binding and were required to stabilize PAI-1 activity. These results indicate that the PAI-1 binding motif is localized to residues 12-30 of SMBVN and suggest that this motif is anchored in the active conformation by disulfide bonds.

Amino Acid Sequence↗
PubMed1994

Genetic epidemiology of early onset breast cancer.

Risks for breast cancer when there is a family history of the disease are usually calculated using data from segregation analyses which favour a single dominant gene with high penetrance. There are, however, at least three loci known to be associated with familial breast cancer (p53, BRCA1, and an as yet unpublished locus) and the frequencies and penetrances of these genes are not likely to be the same. We have attempted to address the problem of which genetic parameters should be used to calculate risks for different patterns of familial breast cancer. Data from 384 nuclear families ascertained through a proband selected for early onset breast cancer were subjected to complex segregation analysis, correcting for ascertainment bias resulting from selection for severe phenotype. Age of onset of breast cancer, incorporated as severity, provides additional information to the segregation model over and above that given by assigning liability classes on the basis of age at observation. The use of this additional parameter in the analysis is described. There is fair agreement between estimates from this sample and previous predictions from consecutive probands and consultands. The differences suggest more than one rare dominant gene for susceptibility to breast cancer, with different penetrances. Although refinements of segregation analysis will help to delineate these different genes, perfect resolution will require identification of the mutant alleles. Methods to estimate genetic parameters under genotype specific mortality need to be developed. Meanwhile, we suggest that high and low estimates of penetrance be used in risk estimation for genetic counselling, and as a guide to candidates for entry into clinical trials of screening and chemoprevention in breast cancer.

Adult↗
PubMed1993

Management of screen-detected breast cancer: audit of the first 100 cases in the Southampton and Salisbury breast screening programme.

With the natural history and optimal treatment of a high proportion of screen-detected breast cancers yet to be determined, treatment poses the management team with a number of therapeutic dilemmas. This study surveys the management policy and treatment of a consecutive series of 100 screen-detected cancers treated in a single breast unit. The problems encountered are discussed. There were 87 women with stage Tis or T1 tumours, including 26 women with in situ cancers, four with invasive cancers less than 5 mm in size, and seven with tubular cancers. Sixty-six women were managed with breast-conserving surgery and 36 women underwent localisation biopsy as the sole surgical treatment of the breast. With selection bias for high-grade and lateral tumours, only 2/13 cancers up to 10 mm in size were lymph node positive on axillary clearance. All lymph node positive women received adjuvant therapy. No adjuvant therapy was given in 43 cases, including those with in situ cancer. Thirty-six had extensive intraductal component (EIC). Patient and surgeon choice tends to be a major factor both in type of surgery and adjuvant therapy for screen-detected breast cancer. The optimal treatment for tumours detected by breast cancer screening is debatable and randomised trials on their management need to be expedited.

Breast Neoplasms↗
PubMed1992

Myelodysplastic syndrome and trisomy 14q.

Trisomy 14 as a sole karyotypic abnormality in neoplasia is extremely rare. In hematologic disorders, 18 cases have been reported so far, 17 of which involved disorders of the myeloid lineage. Five were cases of myelodysplastic syndrome (MDS), and a further four involved Philadelphia-negative atypical chronic myeloid leukemia. The case presented here is the second case of trisomy 14q in MDS involving the chronic myelomonocytic leukemia subtype. There were certain features in common with some of the previously reported cases. We raise the possibility that this represents a specific entity.

Aged↗
PubMed1992

Recent changes in the surgical management of T1/2 breast cancer in England.

Following the results of a study undertaken in 1985, a second survey was undertaken to examine whether there had been any changes in England in the surgical management of patients with a T1/2/NOMO breast cancer. The major findings were that: (i) there was a significant increase in the number of surgeons who would undertake breast conservation surgery; (ii) there was a significant increase in the number of surgeons who would discuss breast reconstruction where mastectomy was the preferred form of treatment; (iii) that significantly more surgeons would offer the patient a choice of surgery when there was more than one surgical option; and (iv) that significantly more surgeons had access to a breast specialist nurse and/or a cancer counsellor. These changes are consistent with the recommendations of the 1986 King's Fund Consensus' Conference for breast cancer treatment.

Adult↗