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R Moseley

Publications and source records attributed to R Moseley.

At least 19 recordsLinked to original sources
PubMed2006

A UK-based investigation of inter- and intra-observer reproducibility of Gleason grading of prostatic biopsies.

AIMS: The frequency of prostatic core biopsies to detect cancer has been increasing with more widespread prostate specific antigen (PSA) testing. Gleason score has important implications for patient management but morphological reproducibility data for British practice are limited. Using literature-based criteria nine uropathologists took part in a reproducibility study. METHODS: Each of the nine participants submitted slides from consecutive cases of biopsy-diagnosed cancer assigned to the Gleason score groups 2-4, 5-6, 7 and 8-10 in the original report. A random selection of slides was taken within each group and examined by all pathologists, who were blind to the original score. Over six circulations, new slides were mixed with previously read slides, resulting in a total of 47 of 81 slides being read more than once. RESULTS: For the first readings of the 81 slides, the agreement with the consensus score was 78% and overall interobserver agreement was kappa 0.54 for Gleason score groups 2-4, 5-6, 7, 8-10. Kappa values for each category were 0.33, 0.56, 0.44 and 0.68, respectively. For the 47 slides read more than once, intra-observer agreement was 77%, kappa 0.66. The study identified problems in core biopsy interpretation of Gleason score at levels 2-4 and 7. Patterns illustrated by Gleason as 2 tended to be categorized as 3 because of the variable acinar size and unassessable lesional margin. In slides with consensus Gleason score 7, 13% of readings were scored 6 and in slides with consensus 6, 18% of readings were scored 7. CONCLUSIONS: Recommendations include the need to increase objectivity of the Gleason criteria but limits of descriptive morphology may have to be accepted.

Biopsy↗
PubMed2006

A study of Gleason score interpretation in different groups of UK pathologists; techniques for improving reproducibility.

AIMS: To test the effectiveness of a teaching resource (a decision tree with diagnostic criteria based on published literature) in improving the proficiency of Gleason grading of prostatic cancer by general pathologists. METHODS: A decision tree with diagnostic criteria was developed by a panel of urological pathologists during a reproducibility study. Twenty-four general histopathologists tested this teaching resource. Twenty slides were selected to include a range of Gleason score groups 2-4, 5-6, 7 and 8-10. Interobserver agreement was studied before and after a presentation of the decision tree and criteria. The results were compared with those of the panel of urological pathologists. RESULTS: Before the teaching session, 83% of readings agreed within +/- 1 of the panel's consensus scores. Interobserver agreement was low (kappa = 0.33) compared with that for the panel (kappa = 0.62). After the presentation, 90% of readings agreed within +/- 1 of the panel's consensus scores and interobserver agreement amongst the pathologists increased to kappa = 0.41. Most improvement in agreement was seen for the Gleason score group 5-6. CONCLUSIONS: The lower level of agreement among general pathologists highlights the need to improve observer reproducibility. Improvement associated with a single training session is likely to be limited. Additional strategies include external quality assurance and second opinion within cancer networks.

Humans↗
PubMed2004

Genomic imbalances in 70 snap-frozen cervical squamous intraepithelial lesions: associations with lesion grade, state of the HPV16 E2 gene and clinical outcome.

Host genomic abnormalities may determine the natural history of cervical squamous intraepithelial lesions (SILs). We undertook comparative genomic hybridisation analysis of epithelium carefully microdissected from 70 cervical SILs, the largest series to date. In contrast to previous studies, we used frozen sections for optimal DNA quality and examined whether patterns of DNA copy number imbalance (CNI) are characteristic of SIL grade, human papillomavirus (HPV) status and postoperative recurrence. We identified more CNIs in cervical SIL than previously described, with more CNIs per case in high-grade squamous intraepithelial lesion (HG-SIL) than in low-grade squamous intraepithelial lesion (LG-SIL) (P=0.04). While some CNIs were seen at similar frequencies in HG-SIL and LG-SIL, others, including gain on 1q, 3q and 16q, were found frequently in HG-SIL but not in LG-SIL. There were significantly more CNIs per case in HG-SILs showing loss of the HPV16 E2 gene (a repressor of viral oncogene transcription) (P=0.026) and in HG-SILs that subsequently recurred (P=0.04). Our data are consistent with sequential acquisition of CNIs in cervical SIL progression. Higher frequency of CNI in association with E2 gene loss supports in vitro evidence that high-risk HPV integration is associated with genomic instability. Further investigation of the clinical value of specific host genomic abnormalities in cervical SIL is warranted.

DNA-Binding Proteins↗
PubMed2004

Fluoride-induced changes to proteoglycan structure synthesised within the dentine-pulp complex in vitro.

Fluoride is known to influence mineralisation patterns within dentine, where alterations in the post-translational modification of proteoglycans (PG) have been proposed as an implicating factor. In light of recent studies elucidating changing PG profiles in the transition of predentine to mineralised dentine, this study investigates the influence of fluoride on the major PG populations (decorin, biglycan and versican) within the pulp, predentine and dentine. Tooth sections from rat incisors were cultured for 14 days in the presence 0, 1 and 6 mM sodium fluoride and the PG extracted from the pulp, predentine and dentine matrices. PG species and corresponding metabolites were identified by their immuno-reactivity to antibodies against decorin, biglycan and versican. Component glycosaminoglycan chains were characterised with respect to their nature, chain length and disaccharide composition. Levels of PG extracted from pulp and predentine were reduced, particularly for biglycan. Fluoride did not influence levels of decorin or versican within predentine or dentine, although the processing of these macromolecules within pulp and predentine was affected, particularly at higher fluoride concentrations. Levels of dermatan sulfate were reduced within pulp and predentine, although the effect was less pronounced for predentine. Fluoride reduced sulfation of glycosaminoglycan chains within pulp and predentine tissues, with a notable reduction in Deltadi6S evident. In all three tissues, glycosaminoglycan chain length was reduced. Considering the various roles for PG in the dentine-pulp complex, either directly or indirectly in the mineralisation process, changes in the synthesis, structure and processing of the different PG species within the pulp, predentine and dentine matrices provides a further molecular explanation for the altered mineralisation patterns witnessed during fluorosis.

Amino Acid Sequence↗
PubMed2004

Extracellular matrix metabolites as potential biomarkers of disease activity in wound fluid: lessons learned from other inflammatory diseases?

The new era of pharmacogenetics has identified a potential for individuals to receive customized treatments for a variety of disease states. For such individualized treatments to fulfil their potential, it will be essential for clinicians to be able to monitor disease activity, ideally in a rapid, noninvasive fashion. The accessibility of the skin offers much potential to develop noninvasive tests of metabolic and disease activity for clinical use. Impaired human wound healing in the skin is a chronic inflammatory disorder in which the development of such tests has considerable potential, aiding clinical decision making and monitoring responses to treatment. This review article discusses how studies in other human diseases have highlighted potential biochemical markers (biomarkers) of disease activity in secreted biofluids, as aids to determining disease and metabolic activity within tissues. Using, as examples, lessons learned in the study of disease activity and prognosis of other chronic inflammatory conditions, such as osteoarthritis and periodontal disease, this review highlights the potential of dermal extracellular matrix (ECM) components (collagens, proteoglycans, hyaluronan and glycoproteins) for such uses. The limitations of currently utilized techniques and the concept that analysis of ECM components in wound fluid may represent useful biomarkers of disease activity are also discussed.

Biomarkers↗
PubMed2003

The influence of fluoride exposure on dentin mineralization using an in vitro organ culture model.

This study aimed to characterize fluoride-induced alterations in dentin mineralization within a dentin-pulp organ culture system. Tooth sections derived from male Wistar rat incisors were cultured in Trowel-type culture for 14 days, in the presence of 0 mM, 1 mM, 3 mM and 6 mM sodium fluoride. Tooth sections were processed and analyzed for uptake of fluoride, its subsequent effect on dentin mineralization by tetracycline hydrochloride incorporation and mineral composition, expressed as calcium/phosphorous (Ca/P) ratios. Tetracycline hydrochloride incorporation was demonstrated to decrease with increased fluoride exposure, accompanied by significant increases in both Ca/P ratios and fluoride incorporation. These findings provide further evidence that the established alterations in dentin formation during fluorosis are a consequence of disruption to the mineralization process, and provide a model system with which to investigate further the potential role the extracellular matrix plays in inducing the apparent changes in mineral composition.

Animals↗
PubMed2003

The influence of fluoride on the cellular morphology and synthetic activity of the rat dentine-pulp complex in vitro.

Exposure to high fluoride concentrations in the immediate environment of the tissue is recognized to result in the post-translational modification of non-collagenous dentine extracellular matrix (ECM) components, potentially altering dentine mineralization. However, less is known about the effects of fluoride exposure on the morphology or metabolism of the cells associated with the dentine-pulp complex. This study examined the effects of fluoride exposure at defined concentrations on the cellular morphology and ECM synthetic activities of odontoblasts and pulpal fibroblasts by the culture of tooth sections from male Wistar rat incisors in Trowel-type cultures for up to 14 days, in the presence and absence of 6mM sodium fluoride. Histomorphometric analysis of the dentine-pulp complex of sodium fluoride-exposed tooth sections demonstrated no obvious gross morphological differences with respect to the odontoblasts and pulpal fibroblasts throughout the 14-day culture period, in comparison with unexposed tooth sections. No significant differences in odontoblast and pulpal fibroblast cell numbers were determined in the absence and presence of fluoride. Image analysis examination of odontoblast cytoplasmic:nuclear (C/N) ratios also showed no significant differences in fluoride-exposed and unexposed tooth sections, although reductions in the C/N ratios of pulpal fibroblasts were evident in fluoride-exposed sections at days 10 and 14. No significant differences in predentine width were observed in fluoride-exposed and unexposed tooth sections over the 14-day culture period. Autoradiography following [3H]proline incorporation into the dentine-pulp complex demonstrated inhibition of collagen synthesis, particularly by the odontoblasts in tooth sections exposed to 6mM sodium fluoride. These findings, in association with those from previous studies, imply that dentine ECM alterations may contribute to the altered mineralization of dentine during fluorosis, rather than secretory-related changes in odontoblast morphology.

Animals↗
PubMed2003

Comparison of the antioxidant properties of wound dressing materials--carboxymethylcellulose, hyaluronan benzyl ester and hyaluronan, towards polymorphonuclear leukocyte-derived reactive oxygen species.

In chronic wounds, factors are released which perpetuate inflammatory processes, including polymorphonuclear leukocyte (PMN)-derived reactive oxygen species (ROS), such as superoxide radical (O(2)*-) and hydroxyl radical (*OH) species. The glycosaminoglycan, hyaluronan, has established antioxidant properties towards ROS, although the antioxidant potential of wound dressing biomaterials, such as 75% benzyl esterified hyaluronan (BEHA) and carboxymethylcellulose (CMCH), are less characterised. This study compared the antioxidant properties of high and low molecular weight hyaluronan (HMWT HA and LMWT HA), BEHA and CMCH towards ROS, generated by stimulated PMN in vitro. The antioxidant capacities of each biomaterial were assessed by their inhibition of O(2)*- -induced cytochrome C reduction, generated via PMN stimulation by phorbol myristyl acetate (PMA); and their inhibition of *OH-induced 2-deoxy-D-ribose degradation, generated by PMA stimulated PMN in the presence of a ferric chloride-EDTA chelate. All biomaterials, except LMWT HA, possessed dose-dependent antioxidant properties against O(2)*-, BEHA having greatest antioxidant potential, followed by HMWT HA and CMCH. HMWT HA exhibited the highest dose-dependent antioxidant properties towards *OH, followed by BEHA and CMCH. LMWT HA demonstrated no antioxidant properties towards *OH. These antioxidant activities, particularly towards O(2)*-, may be beneficial in removing the initial source of ROS necessary for the secondary formation of *OH, implicated as a causal factor for the extensive metabolic alterations observed in chronic wounds.

Antioxidants↗
PubMed2002

Comparison of the antioxidant properties of HYAFF-11p75, AQUACEL and hyaluronan towards reactive oxygen species in vitro.

In chronic wounds, a number of host factors are released which perpetuate the inflammatory process, including polymorphonuclear leukocyte (PMN)-derived reactive oxygen species (ROS), such as superoxide radical (O2*-) and hydroxyl radical (*OH) species. The glycosaminoglycan. hyaluronan, has been shown to act as an antioxidant towards ROS, although the potential for biomaterials, such as HYAFF -11p75 (the 75% benzyl ester of hyaluronan) and AQUACEL (carboxymethylcellulose), to act in this manner has yet to be elucidated. This study compared the antioxidant properties of high and low molecular weight hyaluronan (HMWT HA and LMWT HA), HYAFF -11p75, AQUACEL and an AQUACEL /hyaluronan composite (AQUACEL /HA) against O2*- and *OH. The antioxidant capacities of each material were assessed by their ability to inhibit cytochrome C reduction by O2*- fluxes, generated via the oxidation of hypoxanthine by xanthine oxidase, and their inhibition of 2-deoxy-D-ribose degradation by *OH fluxes, generated by the reaction of hydrogen peroxide (H2O2) and iron (Fe2+). All materials studied possessed dose dependent antioxidant properties towards O2*-, with HYAFF 11p75 having the greatest antioxidant potential towards these species, followed by AQUACEL, HMWT HA, AQUACEL /HA and LMWT HA. Only HMWT HA exhibited dose dependent antioxidant properties towards *OH at the fluxes examined. Gas chromatography/mass spectrometry analysis implied that ester bonds between the hyaluronan backbone and benzyl groups of HYAFF -11p75 are highly susceptible to O2*- hydrolysis, with the de-esterified benzyl alcohol being rapidly degraded in the presence of *OH. This data supports the hypothesis that HYAFF -11p75 has greater antioxidant capacity towards O2*-, due to the esterified benzyl groups providing alternative sites for O2*- attack other than the hyaluronan backbone of HYAFF -11p75 itself and explains the inability of HYAFF -11p75 to scavenge *OH, due to benzyl alcohol degradation by *OH. The antioxidant activities of these biomaterials, particularly HYAFF -11p75 and AQUACEL, towards O2*- could be beneficial, as the scavenging of PMN-derived O2*- may remove initial sources of O2*- and further prevent the secondary formation of *OH. These ROS are thought to be a primary causal factor for the extensive degradation and metabolic alterations observed in chronic wounds.

Antioxidants↗
PubMed2002

TGF-beta latency-associated peptides (LAPs) in human dentin matrix and pulp.

Transforming growth factor (TGF)-beta s in dentin matrix provide a pool of bioactive molecules, but association with latency-associated peptides (LAPs) may influence their activity. We investigated TGF-beta 1, -beta 2, and -beta 3 LAP expression in sound and carious human teeth. Teeth were fixed and processed immediately following extraction prior to staining with rabbit polyclonal antibodies to the TGF-beta LAPs. A soluble dentin matrix fraction was prepared from dissected human dentin and sequential extraction of pulpal ECM was performed prior to purification. Fractions were Western blotted and probed with the LAP antibodies. All three LAPs were present in odontoblasts, cells of the pulp, and predentin; however, no staining of mineralized dentin matrix was seen. Similar patterns of expression were seen in carious tissue. Expression of TGF-beta LAPs in cells and pulpal matrix of healthy and carious teeth will be important in regulation of TGF-beta activity and may modulate the tissue response to injury.

Dental Caries↗
PubMed2000

A randomized, controlled trial to assess a novel colorectal cancer screening strategy: the conversion strategy--a comparison of sequential sigmoidoscopy and colonoscopy with immediate conversion from sigmoidoscopy to colonoscopy in patients with an abnormal screening sigmoidoscopy.

OBJECTIVE: Our study was a randomized, controlled trial to assess a novel strategy that provides comprehensive colorectal cancer screening in a single visit versus traditional sigmoidoscopy and, where appropriate, colonoscopy on a subsequent day. METHODS: Consecutive patients referred for screening were randomized to control or so-called "conversion" groups. Patients in the control group were prepared for sigmoidoscopy with oral phospho-soda. Those with an abnormal sigmoidoscopy were scheduled for colonoscopy on a future day after oral polyethylene glycol preparation. In the conversion group, patients were prepared with oral phosphosoda. Patients with a polyp >5 mm or multiple diminutive polyps were converted from sigmoidoscopy to colonoscopy, allowing comprehensive screening in a single visit. Clinical outcomes were assessed by postprocedure physician and patient questionnaires. RESULTS: Two hundred thirty-five patients were randomized (control = 121, conversion = 114). In the control group, 28% had an indication for colonoscopy. Three of 33 (9%) with an abnormal sigmoidoscopy did not return for colonoscopy. At colonoscopy, 27% had a proximal adenoma. In the conversion group, 28% had an abnormal sigmoidoscopy and underwent conversion to colonoscopy. Forty-one percent undergoing colonoscopy in the conversion group had a proximal adenoma. Physicians reported no differences in preparation or procedure difficulty, whereas patients reported no differences in the level of comfort or overall satisfaction between groups. When queried regarding preferences for future screening, 96% chose the conversion strategy. CONCLUSIONS: The conversion strategy led to similar outcomes compared to traditional screening while improving compliance with colonoscopy in patients with an abnormal sigmoidoscopy.

Adenoma↗
PubMed2000

Reactive oxygen species: a potential role in the pathogenesis of periodontal diseases.

The pathological events leading to the destruction of the periodontium during inflammatory periodontal diseases are likely to represent complex interactions involving an imbalance in enzymic and non-enzymic degradative mechanisms. This paper aims to review the increasing body of evidence implicating reactive oxygen species (ROS), derived from many metabolic sources, in the pathogenesis of periodontal tissue destruction. ROS are generated predominantly by polymorphonuclear leukocytes (PMN) during an inflammatory response and are regarded as being highly destructive in nature. The detection of ROS oxidation products, the elevation of iron and copper ions, which catalyse the production of the most reactive radical species, and the identification of an imbalance in the oxidant/antioxidant activity within periodontal pockets, suggests a significant role for ROS in periodontal tissue destruction. In vitro studies have shown that ROS are capable of degrading a number of extracellular matrix components including proteoglycans, resulting in the modification of amino acid functional groups, leading to fragmentation of the core protein, whilst the constituent glycosaminoglycan chains undergo limited depolymerisation. The identification and characterisation of connective tissue metabolites in gingival crevicular fluid (GCF) resulting from the degradation of periodontal tissues, notably alveolar bone, provides further evidence for a role for ROS in tissue destruction associated with inflammatory periodontal diseases.

Antioxidants↗
PubMed1998

The modification of alveolar bone proteoglycans by reactive oxygen species in vitro.

Reactive oxygen species (ROS) are being increasingly implicated in the connective tissue degradation associated with chronic inflammatory conditions, such as periodontal disease. The present study investigated the effects of ROS on the proteoglycans (PG) of alveolar bone which are important structural components within the periodontium. PG were isolated from ovine alveolar bone and exposed to increasing concentrations of hydrogen peroxide (H2O2) or to a hydroxyl radical (.OH) flux for 1 h or 24 h, and the degradation products examined for depolymerisation and chemical modification of the PG structure. ROS were demonstrated to be capable of degrading alveolar bone PG in vitro, the .OH species resulting in greater modification than H2O2. The degradative effects observed included cleavage of the protein core and depolymerisation of the GAG chains. The core proteins were more susceptible to degradation than the GAG chains in the presence of H2O2 alone, although both the core proteins and the GAG chains were extensively degraded in the presence of a .OH flux for both 1 h and 24 h. Exposure of the PG to .OH for 24 h resulted in significant modification to the amino acid composition with decreases in the proportion of leucine and the complete loss of proline, tyrosine and phenylalanine evident. The results highlight the potential role of ROS as an important mechanism in considering the pathology of periodontal tissue destruction.

Alveolar Bone Loss↗