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Biomedical subjects

D Buckley

Publications and source records attributed to D Buckley.

At least 19 recordsLinked to original sources
PubMed2006

Scan of human genome reveals no new Loci under ancient balancing selection.

There has been much speculation as to what role balancing selection has played in evolution. In an attempt to identify regions, such as HLA, at which polymorphism has been maintained in the human population for millions of years, we scanned the human genome for regions of high SNP density. We found 16 regions that, outside of HLA and ABO, are the most highly polymorphic regions yet described; however, evidence for balancing selection at these sites is notably lacking--indeed, whole-genome simulations indicate that our findings are expected under neutrality. We propose that (i) because it is rarely stable, long-term balancing selection is an evolutionary oddity, and (ii) when a balanced polymorphism is ancient in origin, the requirements for detection by means of SNP data alone will rarely be met.

ABO Blood-Group System↗
PubMed2006

Observational study of bone-anchored hearing aid infection rates using different post-operative dressings.

INTRODUCTION: Avoidance of infection at the implant site is a crucial element to the success of bone-anchored hearing aid (BAHA) implantation. However, little evidence exists to suggest the best post-operative wound dressing to use. MATERIAL AND METHODS: We report our experience with 160 consecutive BAHA patients, using four types of post-operative BAHA wound dressing (Tri-adcortyl, Mepitel, Allevyn, and Acticoat 7 with Allevyn). Patients were reviewed at week one and week two post-operatively. Infection was defined as a positive wound swab culture or evidence of cellulitis at the BAHA site. RESULTS: Post-operative BAHA infection rates were 16 per cent, 50 per cent, 10 per cent and 5 per cent, for each of the four dressings respectively, and the mean number of additional visits to wound care clinic were 1.5, 3.7, one and 0.4, respectively. DISCUSSION: Acticoat 7 with Allevyn produced the lowest infection rate and thus became the dressing of choice for our BAHA programme.

Adult↗
PubMed2006

The DNA sequence and biological annotation of human chromosome 1.

The reference sequence for each human chromosome provides the framework for understanding genome function, variation and evolution. Here we report the finished sequence and biological annotation of human chromosome 1. Chromosome 1 is gene-dense, with 3,141 genes and 991 pseudogenes, and many coding sequences overlap. Rearrangements and mutations of chromosome 1 are prevalent in cancer and many other diseases. Patterns of sequence variation reveal signals of recent selection in specific genes that may contribute to human fitness, and also in regions where no function is evident. Fine-scale recombination occurs in hotspots of varying intensity along the sequence, and is enriched near genes. These and other studies of human biology and disease encoded within chromosome 1 are made possible with the highly accurate annotated sequence, as part of the completed set of chromosome sequences that comprise the reference human genome.

Base Sequence↗
PubMed2006

Mitochondrial DNA phylogeography of Lissotriton boscai (Caudata, Salamandridae): evidence for old, multiple refugia in an Iberian endemic.

In Europe, southern peninsulas served as refugia during cold periods in the Pleistocene, acting both as centres of origin of endemisms and as sources from which formerly glaciated areas were recolonized during interglacial periods. Previous studies have revealed that within the main refugial areas, intraspecific lineages often survived in allopatric refugia. We analysed two mitochondrial markers (nad4, control region, approximately 1.4 kb) in 103 individuals representing the entire distribution of Lissotriton boscai, a newt endemic to the western Iberian Peninsula. We inferred the evolutionary history of the species through phylogenetic, phylogeographic and historical demographic analyses. The results revealed unexpected, deep levels of geographically structured genetic variability. We identified two main evolutionary lineages, each containing three well-supported clades. The first historical split involved populations from central-southwestern coastal Portugal and the ancestor of all the remaining populations around 5.8 million years ago. Both lineages were subsequently fragmented into different population groups between 2.5 and 1.2 million years ago. According to nested clade analysis, at lower hierarchical levels the patterns suggest restricted gene flow with isolation by distance, whereas at higher levels the clades exhibit signatures of contiguous range expansion. Bayesian Skyline Plots show recent bottlenecks, followed by demographic expansions in all lineages. The significant genetic structure found is consistent with long-term survival of populations in allopatric refugia, supporting the 'refugia-within-refugia' scenario for southern European peninsulas. The comparison of our results with other co-distributed species highlights the generality of this hypothesis for the Iberian herpetofauna and suggests that Mediterranean refuges had more relevance for the composition and distribution of present biodiversity patterns than currently acknowledged. We briefly discuss the taxonomic and conservation implications of our results.

Animals↗
PubMed2003

Depth cue reliance in surgeons and medical students.

BACKGROUND: Depth perception is reduced in endoscopic surgery, although little is known about the effect this has on surgical performance. METHODS: To assess the role of depth cues, 45 subjects completed tests of depth cue reliance. Surgical skill was assessed using the Minimally Invasive Surgical Trainer-Virtual Reality, a previously validated laparoscopic simulator. RESULTS: We could demonstrate no difference in cue reliance for three depth cues--namely stereo, texture, and outline--between surgeons and medical students. Greater dominance on stereo for medical students was a positive finding and a negative finding for the surgeons when correlated with surgical performance. CONCLUSIONS: We suggest that surgeons learn to adapt to the nonstereo environment in MIS, and this is the first study to show evidence of this phenomenon. This difference in stereo reliance is a reflection of the experience that surgeons have with laparoscopy compared with medical students, who have none.

Adult↗
PubMed2003

Can tonic accommodation predict surgical performance?

BACKGROUND: Pilots undergo many visual tests for both selection and assessment, and we know that there are many similarities between pilots and surgeons. Hence, it would not be unreasonable to bring similar visual tests into surgery. Tonic accommodation (TA) is a stable parameter that is adopted by the eye in the absence of any stimulation. Over recent years, surgery has undergone change from traditional open surgery to minimally invasive procedures, bringing many advantages. However, not every surgeon has the ability to perform under conditions where the operative field is represented on a flat monitor. METHOD: We determined the TA values in medical students and then correlated this with their performance on a virtual reality surgical simulator. RESULTS: We found that TA values predicted the number of errors made with the dominant hand, accounting for 27% of the variance. CONCLUSION: The data suggest that TA may play a role in the individual differences that are noted when surgeons perform laparoscopic surgery. Further studies are needed to evaluate the exact role of TA in surgical performance.

Accommodation, Ocular↗
PubMed2003

Dispersal of viviparity across contact zones in Iberian populations of fire salamanders (Salamandra) inferred from discordance of genetic and morphological traits.

We used partial sequences of the cytochrome b mitochondrial DNA (mtDNA) gene, obtained from 76 individuals representing 45 populations of Iberian Salamandra salamandra plus 15 sequences of additional species of Salamandra and related genera, to investigate contact zones. These zones, identified by earlier allozymic and morphological analyses, are between populations of viviparous (S. s. bernardezi and S. s. fastuosa) and ovoviviparous (S. s. gallaica and S. s. terrestris) salamanders. The distribution of mtDNA and nuclear markers is mostly concordant at one contact zone (between S. s. gallaica and S. s. bernardezi), but at another (between S. s. fastuosa and S. s. terrestris) the markers are offset by about 250 km. The observed geographic variation fits a model of mtDNA capture. Among the potential mechanisms responsible for such discordance we favor a combination of range shifts due to climatic fluctuations and biased genetic admixture across moving contact zones. We apply our findings to the issue of possible homoplasy in the evolution of viviparity and conclude that viviparity likely arose only once within S. salamandra.

Animals↗
PubMed2001

Isolation and identification of a degradation product in a capsule formulation containing the elastase inhibitor, DMP 777.

An unexpected degradation product, greater than 0.10%, was observed in a DMP 777 capsule formulation stored at 40 degrees C/75% r.h. for 3 months and 25 degrees C/60% r.h. for 2 years. The degradant of interest was prepared in quantity by refluxing the drug substance in dilute acid. A preparative HPLC method was developed to separate the various degradants and to collect each as a separate fraction. Each fraction was analyzed by the analytical HPLC gradient test method to assure positive identification of each peak and to correlate each peak to the original capsule sample. Key isolated degradation products were used for structure elucidation with mass spectrometry and NMR. The major degradant of interest in the capsule formulation was found to be a carboxylic acid resulting from the acid hydrolysis of an amide bond.

Acids↗
PubMed2000

A cell viability assay based on monitoring respiration by optical oxygen sensing.

A cell viability assay based on monitoring of the metabolic activity of living cells via their consumption of dissolved oxygen has been developed. It uses a microwell plate format and disposable phosphorescent sensor inserts incorporated into each sample. The wells are subsequently sealed from ambient oxygen using a layer of mineral oil, and periodically scanned from underneath with a simple fiber-optic phosphorescent phase detector. Thus, dissolved oxygen levels and time profiles of cell respiration can be determined noninvasively and compared to each other. The system was tested by monitoring the viability of the fission yeast Schizosaccharomyces pombe. In comparison with the conventional cell densitometry assay, the optical oxygen sensor method could reliably monitor lower numbers of cells (10(4)-10(5) vs 10(6)-10(7) cells/ml for densitometry), and accurately determine culture viability within 1 h. The assay was then applied to determine the viability of samples treated with toxic agents such as azide and in response to expression of a physiological inducer of cell death, the Bcl-2 family member Bak. The results obtained confirm that measurement of cell respiration by this assay can serve as a predictable, reliable, and fast method for high-throughput determination of cell viability and growth.

Biological Assay↗
PubMed2000

Determinants of object recognition.

We demonstrate that performance on an object recognition task can be explained in terms of observer-specific perceptual profiles. These profiles are derived from a battery of tests, including the effects of stereo, texture, outline (occluding contour), and motion cues on amplitude judgements of curved surfaces. Using a task in which observers learned to recognise 'amoeboid' objects, a multivariate regression analysis revealed that three psychometric variables derived from the test battery account for 74% of the variance in learning rate. These variables are choice reaction time, and the relative dependence of amplitude judgements on motion and outline cues. The implications of these findings for the existence of observer-specific perceptual profiles, and their relation to the fundamental psychophysical competences associated with object recognition are discussed.

Adult↗
PubMed2000

Exploring sequential stereopsis for co-planarity tasks.

We used the sequential stereopsis paradigm and apparatus described by Enright (Vision Research, 36, (1996) 307-312). The observer's task was to set targets to equidistance in Experiments 1-3, and to make them co-planar in Experiment 4. However, it is argued that in all experiments observers exploited a co-planarity setting strategy. Sequential stereopsis produced good performance throughout in terms of low disparity thresholds when head position was varied by rotations around three axes: vertical (azimuth condition); horizontal (elevation); and midline (tilt). It also produced good performance when the targets were shifted in position so that they both lay on one side of the median plane of the head. These results cannot be accounted for by Enright's isovergence hypothesis unless it is extended to incorporate other information about eye positions. Performance was better but not greatly so in control simultaneous stereopsis conditions, nor did it deteriorate much when the observer's view was restricted solely to the targets by removing visibility of the room in which the apparatus was located. Target settings were typically located on a concave arc centred on the median plane. This effect was quantitatively modelled using disparity correction for a relief task of co-planarity (Gârding, Porrill, Mayhew, & Frisby. Vision Research, 35 (1995) 703-722). This modelling indicated over-estimations of c.10-20 cm in fixation distance for target distances in the range 71.5-112.5 cm.

Adolescent↗
PubMed2000

Magnetic resonance imaging screening in women at genetic risk of breast cancer: imaging and analysis protocol for the UK multicentre study. UK MRI Breast Screening Study Advisory Group.

The imaging and analysis protocol of the UK multicentre study of magnetic resonance imaging (MRI) as a method of screening for breast cancer in women at genetic risk is described. The study will compare the sensitivity and specificity of contrast-enhanced MRI with two-view x-ray mammography. Approximately 500 women below the age of 50 at high genetic risk of breast cancer will be recruited per year for three years, with annual MRI and x-ray mammography continuing for up to 5 years. A symptomatic cohort will be measured in the first year to ensure consistent reporting between centres. The MRI examination comprises a high-sensitivity three-dimensional contrast-enhanced assessment, followed by a high-specificity contrast-enhanced study in equivocal cases. Multiparametric analysis will encompass morphological assessment, the kinetics of contrast agent uptake and determination of quantitative pharmacokinetic parameters. Retrospective analysis will identify the most specific indicators of malignancy. Sensitivity and specificity, together with diagnostic performance, diagnostic impact and therapeutic impact will be assessed with reference to pathology, follow-up and changes in diagnostic certainty and therapeutic decisions. Mammography, lesion localisation, pathology and cytology will be performed in accordance with the UK NHS Breast Screening Programme quality assurance standards. Similar standards of quality assurance will be applied for MR measurements and evaluation.

Adult↗
PubMed2000

Factors associated with reintegration to normal living after subarachnoid hemorrhage.

OBJECTIVE: Recent reports have suggested improvement in the last decade in global outcome measures after subarachnoid hemorrhage (SAH), particularly in patients presenting in good initial neurological status. We used a standardized self-report instrument, the Reintegration to Normal Living (RNL) Index, to assess a patient-based quality of life measure and a self-report of work status. We tested the hypothesis that several patient-based factors were related to these outcomes, including depressive symptoms, physical disability, age, and initial Hunt and Hess grade. Using these data, we report the total management morbidity and mortality at 1 to 5 years after SAH for patients initially presenting in good neurological condition. METHODS: The study population consisted of 246 consecutive patients admitted to our tertiary care center with aneurysmal SAH in good neurological condition (Hunt and Hess Grades I-III). Patients underwent either surgical (92%), endovascular (7%), or medical (1 %) management of aneurysmal SAH. Eighty-three percent of surviving patients completed a written or telephone questionnaire incorporating the Barthel Index, the Zung Self-rating Depression Scale, the RNL Index, and a work status assessment. RESULTS: An aneurysm-related mortality rate of 6% was observed in the patient population. Fifty-five percent of patients reported a complete reintegration into their normal living situation, as measured by the RNL Index. Sixty-seven percent of previously full-time workers returned to a full-time status. Thirty-six percent of patients reported depressive symptoms, and 23% of patients reported physical disability. In a multivariate model, the two factors that contributed most to an impairment of reintegration were depression and physical disability, whereas a failure to return to work was related to older age and a higher-grade initial neurological status. CONCLUSION: In this series of patients undergoing multimodality management of lower-grade SAH, more than one-half of patients subsequently reported a normal reintegration into their social situation, as assessed by the RNL Index. Standardized assessments of cofactors associated with impaired reintegration revealed that depressive symptoms and physical disability played a strong role in overall reintegration. Standardized assessments, such as the RNL Index, offer the potential for improved comparison of different treatment regimens and specific therapeutic targeting of factors, such as depression, which contribute to decreased quality of life.

Activities of Daily Living↗
PubMed2000

A neoadjuvant clinical trial in colorectal cancer patients of the human anti-idiotypic antibody 105AD7, which mimics CD55.

Thirty-five patients received 105AD7 human anti-idiotype vaccination prior to surgery for colorectal carcinoma. Patients were immunized before and also received one to two immunizations after surgical resection of their colorectal cancer. The vaccine was well tolerated with no associated toxicity. Lymphocytic infiltration within the resected tumors was quantified by immunohistochemistry and image analysis. Enhanced infiltration of helper T cells (CD4) and natural killer (NK) cells (CD56) were observed in the tumors from immunized patients when compared with tumors from stage, grade, site, age, and sex matched unimmunized patients. NK activity was increased in the blood, peaking 7-10 days post immunization and then dropping rapidly and correlating with NK extravasation within the tumor. Comparison of the amino acid sequences of 105AD7 anti-idiotype and the antigen it mimics, CD55, has predicted that patients with HLA-DR1, HLA-DR3, and HLA-DR7 haplotypes should show helper T cell responses following 105AD7 vaccination. Eighty-three percent of patients expressing these haplotypes responded to 105AD7, whereas 88% of patients who failed to express these haplotypes were nonresponders. With a median follow-up of 4 years (range, 2.5-6 years) 65% of patients remained disease free. This trial shows that 105AD7 stimulates antitumor inflammatory responses allowing extravasation within tumor deposits of both helper T cells and NK cells. This represents a way of evaluating immune responses in patients both within the blood and at the tumor site. The study confirms that immunization with a human anti-idiotypic antibody results in immune responses in 83% of patients with a permissive haplotype.

Antibodies, Anti-Idiotypic↗
PubMed2000

Segmental phenolic ablation for ingrown toenails in general practice.

Ingrown toenails cause a great deal of discomfort and may result in missed time from school, work and sports. Traditionally, this problem was quickly dealt with by a simple nail avulsion or wedge avulsion in general practice, Accident and Emergency departments or O.P.D.s. However, this treatment has a high relapse rate (73%). In this survey ingrown toenails were treated by wedge resection and ablation of the nail bed with 80% fresh phenol under ring block anaesthesia and a bloodless field. The aim of this prospective study was to assess the feasibility, cure rate and complications of Segmental Phenolic Ablation for ingrown toenails in general practice. A prospective analysis of 201 consecutive Wedge Resections and Phenol Ablations for ingrown toenails in 111 patients by one General Practitioner over a five and a half year period. All patients were followed up for at least six months post-operatively. There was a relapse rate of 4.5%. Two-thirds of the recurrences occurred in patients who had relapsed after previous surgery before entering this study. All recurrences were successfully treated by repeat phenol cauterisation. The relapse rate for cases who had never been previously operated on (137 edges) was 2.2% (3 edges). There were no major peri-operative or post-operative complications. No patient had to be referred to hospital for treatment of their ingrown toenails. Wedge Resection and Phenol Ablation for ingrown toenails can be carried out safely and successfully in general practice and is recommended as the surgical treatment of choice.

Adult↗
PubMed1999

Structural insights into the mechanism of intramolecular proteolysis.

A variety of proteins, including glycosylasparaginase, have recently been found to activate functions by self-catalyzed peptide bond rearrangements from single-chain precursors. Here we present the 1.9 A crystal structures of glycosylasparaginase precursors that are able to autoproteolyze via an N --> O acyl shift. Several conserved residues are aligned around the scissile peptide bond that is in a highly strained trans peptide bond configuration. The structure illustrates how a nucleophilic side chain may attack the scissile peptide bond at the immediate upstream backbone carbonyl and provides an understanding of the structural basis for peptide bond cleavage via an N --> O or N --> S acyl shift that is used by various groups of intramolecular autoprocessing proteins.

Aspartylglucosylaminase↗
PubMed1999

Robust and optimal use of information in stereo vision.

Differences between the left and right eye's views of the world carry information about three-dimensional scene structure and about the position of the eyes in the head. The contemporary Bayesian approach to perception implies that human performance in using this source of eye-position information can be analysed most usefully by comparison with the performance of a statistically optimal observer. Here we argue that the comparison observer should also be statistically robust, and we find that this requirement leads to qualitatively new behaviours. For example, when presented with a class of stereoscopic stimuli containing inconsistent information about eccentricity of gaze, estimates of this gaze parameter recorded from one robust ideal observer bifurcate at a critical value of stimulus inconsistency. We report an experiment in which human observers also show this phenomenon and we use the experimentally determined critical value to estimate the vertical acuity of the visual system. The Bayesian analysis also provides a highly reliable and biologically plausible algorithm that can recover eye positions even before the classic stereo-correspondence problem is solved, that is, before deciding which features in the left and right images are to be matched.

Algorithms↗