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Biomedical subjects

J Leary

Publications and source records attributed to J Leary.

At least 19 recordsLinked to original sources
PubMed2006

Evaluation of models to predict BRCA germline mutations.

The selection of candidates for BRCA germline mutation testing is an important clinical issue yet it remains a significant challenge. A number of risk prediction models have been developed to assist in pretest counselling. We have evaluated the performance and the inter-rater reliability of four of these models (BRCAPRO, Manchester, Penn and the Myriad-Frank). The four risk assessment models were applied to 380 pedigrees of families who had undergone BRCA1/2 mutation analysis. Sensitivity, specificity, positive and negative predictive values, likelihood ratios and area under the receiver operator characteristic (ROC) curve were calculated for each model. Using a greater than 10% probability threshold, the likelihood that a BRCA test result was positive in a mutation carrier compared to the likelihood that the same result would be expected in an individual without a BRCA mutation was 2.10 (95% confidence interval (CI) 1.66-2.67) for Penn, 1.74 (95% CI 1.48-2.04) for Myriad, 1.35 (95% CI 1.19-1.53) for Manchester and 1.68 (95% CI 1.39-2.03) for BRCAPRO. Application of these models, therefore, did not rule in BRCA mutation carrier status. Similar trends were observed for separate BRCA1/2 performance measures except BRCA2 assessment in the Penn model where the positive likelihood ratio was 5.93. The area under the ROC curve for each model was close to 0.75. In conclusion, the four models had very little impact on the pre-test probability of disease; there were significant clinical barriers to using some models and risk estimates varied between experts. Use of models for predicting BRCA mutation status is not currently justified for populations such as that evaluated in the current study.

Area Under Curve↗
PubMed2003

Profiling penciclovir susceptibility and prevalence of resistance of herpes simplex virus isolates across eleven clinical trials.

Asusceptibility testing program was established to determine the prevalence of resistance to penciclovir among herpes simplex virus isolates collected from patients participating in 11 world-wide clinical trials involving penciclovir (topical or intravenous formulations) or famciclovir, the oral prodrug of penciclovir. These trials represented nine randomised double blind, placebo or aciclovir-controlled studies and two open-label studies. Groups surveyed included immunocompetent or immunocompromised patients receiving 2 to 12 months chronic suppressive therapy for genital herpes, immunocompetent patients with recurrent herpes labialis treated for four days, and immunocompromised patients with mucocutaneous herpes simplex virus (HSV). Another subset of patients had been identified as non-responders to aciclovir or to valaciclovir. This program assessed the susceptibility profile for a total of 2145 herpes simplex virus isolates from 913 immunocompetent and 288 immunocompromised patients treated with penciclovir, famciclovir, aciclovir or placebo (depending on trial design). HSV isolates were tested for susceptibility to penciclovir using the plaque reduction assay (PRA) in MRC-5 cells. Resistance was defined as an IC(50)>or=2.0 microg/ml or an IC(50)> 10-fold above the wild type control virus IC(50) within that particular assay. Penciclovir-resistant HSV was isolated from 0.22% immunocompetent patients, and 2.1% of immunocompromised patients overall and therefore the frequency of penciclovir-resistant herpes simplex virus in the immunocompetent population approximates that of aciclovir-resistant herpesvirus reported previously. Penciclovir-resistant HSV isolates were more common in isolates from immunocompromised patients, consistent with aciclovir clinical experience. Treatment with penciclovir (intravenous formulation) was associated with the development of resistant HSV in only one severely immunocompromised patient (day 7 isolate IC(50) = 2.01 microg/ml), although treatment was effective and resulted in the complete clearance of the lesion by day 8. No patients receiving topical penciclovir developed treatment-associated penciclovir-resistant HSV, and a single immunocompromised patient developed resistant HSV upon treatment with oral famiciclovir.

Acyclovir↗
PubMed2001

High frequency of allelic imbalance at regions of chromosome arm 8p in ovarian carcinoma.

Progressive genetic changes such as the inactivation of tumor suppressor genes (TSG) are thought to play an important role in the initiation and progression of ovarian cancer. Frequent nonrandom allelic imbalance (AI) at 8p11-p21 and 8p22-pter suggests the existence of TSGs that may be involved in the carcinogenesis of several human malignancies. We investigated 70 ovarian tumors with 11 highly polymorphic markers spanning 8p12-p21 and 8p22-pter to produce an AI map of 8p in epithelial ovarian cancer. Allelic imbalance was demonstrated in 54 tumors (77%), most frequently occurring at D8S136 (54%) and at D8S1992 (55%). Poorly differentiated and advanced stage cancers were more often affected by AI (G1+G2 vs. G3; 20% vs. 66%; stage I+II vs. III+IV, 36% vs. 54%, P<.001; Kruskal-Wallis test) than well differentiated and early stage tumors. There was no relationship between histological subtype and AI. Smallest regions of overlap (SRO) were delineated by analyzing 38 tumors with partial AI. This study provides compelling evidence for the involvement of TSGs on the short arm of chromosome 8, at 8p12-p21 and at 8p23 in the development and progression of epithelial ovarian cancer.

Allelic Imbalance↗
PubMed2001

Expression of cathepsins B, L, S, and D by gastric epithelial cells implicates them as antigen presenting cells in local immune responses.

Helicobacter pylori infection is linked to chronic gastritis, peptic ulcer and gastric carcinoma. During H. pylori infection, class II MHC expression by the gastric epithelium increases, as does the number of local CD4(+) T cells, which appear to be important in the associated pathogenesis. These observations suggested that the epithelium might present antigens to T cells. Thus, we sought to determine whether gastric epithelial cells process antigens to establish their function as local antigen presenting cells (APC). We examined a panel of gastric epithelial cell lines for expression of the antigen processing cathepsins B (CB), L (CL), S (CS), and D (CD). The mRNA for these enzymes were detected by RT-PCR and the enzymes in the gastric epithelial cells were identified by various independent methods. We corroborated the expression of CB and CD on gastric epithelial cells from human biopsy samples. The functions of these proteases were confirmed by assessing their ability to digest ovalbumin, a conventional dietary antigen, and proteins from H. pylori. In summary, multiple lines of evidence suggest gastric epithelial cells process antigens for presentation to CD4(+) T cells. To our knowledge, these are the first studies to document the antigen processing capacity of human gastric epithelial cells.

Antigen Presentation↗
PubMed2001

High rates of multiple antibiotic resistance in Streptococcus pneumoniae from healthy children living in isolated rural communities: association with cephalosporin use and intrafamilial transmission.

OBJECTIVE: Streptococcus pneumoniae is one of the most clinically significant pathogens with emerging antibiotic resistance. We performed a surveillance study in isolated rural populations of healthy children to estimate the prevalence of pneumococcal resistance and to contrast factors that predict pneumococcal carriage with those that specifically predict resistant pneumococcal carriage. METHODS: The study was conducted in 1998 in 2 rural communities in Utah. Families were recruited directly for participation through community canvassing. Surveillance nasopharyngeal cultures were obtained from children who were younger than 8 years. Antibiotic usage and information on other potential risk factors were obtained from questionnaires and local pharmacy records. Resistance was determined by testing isolates for susceptibility to penicillin, cefaclor, trimethoprim-sulfamethoxazole, erythromycin, ceftriaxone, and trovafloxacin. Selected resistant isolates were characterized further by serotyping, pulsed field gel electrophoresis, and Southern blot with DNA probes specific for the pneumococcal lytA gene and for antibiotic resistance genes. RESULTS: In April 1998, surveillance nasopharyngeal cultures were obtained from 368 children aged </=8 years in community A and 369 children in community B. The number of antibiotic courses per child within 1 year before culture was higher in community B than A (mean: 2.2 vs 1.7). Conversely, oral cephalosporins were more frequently used in community A than B (community A: 22% received cephalosporins within 4 months; community B: 12%). Colonization with S pneumoniae was detected in 24% of children in community A and 14% in community B; 36% of isolates from community A and 28% of isolates from community B were resistant or intermediately susceptible to at least 1 antibiotic tested. Reduced susceptibility was most common to trimethoprim-sulfamethoxazole and cefaclor (28% and 26%, respectively). Pneumococcal carriage (susceptible or resistant) was independently associated with age <5 years (odds ratio [OR]: 2.2), child care exposure (OR: 2.4), presence of a sibling with a positive culture (OR: 3.3), and residence in community A (OR: 1.7). Among carriers, age <2 years (OR: 2.6), use of cephalosporins within the preceding 4 months (OR: 2.7), and having a sibling colonized with resistant S pneumoniae (OR: 5.5) were independent predictors of reduced susceptibility or resistance. Each pair of resistant isolates from siblings was indistinguishable by pulsed field gel electrophoresis and other molecular typing techniques. Several pneumococcal isolates from these isolated rural areas had the molecular characteristics of international clones of multiple-drug-resistant pneumococci that have been associated with worldwide spread. CONCLUSIONS: Young age and intrafamilial transmission were important risk factors for carriage of both susceptible and resistant S pneumoniae. In contrast, previous cephalosporin use was linked specifically to resistant pneumococcal carriage, which suggests that modifications in antibiotic usage patterns may have salutary effects on antimicrobial resistance. These results extend previous observations in large cities regarding the penetration of multiple-drug-resistant clones of pneumococci into community populations.

Anti-Bacterial Agents↗
PubMed2000

Hierarchical mutation screening protocol for the BRCA1 gene.

The identification of mutations in the BRCA1 gene poses difficulties in achieving a screening outcome that satisfies the twin needs of speed and accuracy. These needs must also take into account the patient's family history and the statistical evaluation of the probability of detecting a mutation. Given the above, we present here a hierarchical mutation screening strategy that comprises two tiers: first, multiplex heteroduplex and exon 13 duplication analysis; second, exon amplification and direct sequencing using a 96-well tray format. The advantages of this strategy are two-fold: first, the division of analytical tools in order to achieve low and high-resolution mutation screening, respectively; second, a streamlined sequencing approach that leads to a sensitive and rapid assay that reduces labor costs and handling errors. The success of this approach is shown by the identification of a novel deletion mutation in exon 14 of the BRCA1 gene, which was not detected by the more conventional protein truncation assay due to the small size of the predicted truncated protein.

Adult↗
PubMed1998

Occupational stress and community mental health nursing: what CPNs really said.

The Claybury Nursing Stress Study assessed the levels of occupational stress experienced by both ward-based and community nurses. This paper presents the results obtained from a qualitative analysis of statements made by community psychiatric nurses during a questionnaire based interview. Key areas identified by CPNs as relevant to stress and coping are reported and suggestions for further, qualitative research in this area are made.

Adaptation, Psychological↗
PubMed1998

Transvaginal sonographic diagnosis of short-rib polydactyly dysplasia at 13 weeks' gestation.

Short-rib polydactyly dysplasia (SRP) is an autosomal recessive, lethal skeletal dysplasia. Sonographic assessment of subsequent pregnancies is, therefore, recommended. This case indicates that this diagnosis can be made in the latter part of the first trimester. A 30-year-old multigravid woman presented at 13 weeks' gestation for an ultrasound examination. She had had a termination of pregnancy for a fetus with pathologically confirmed short-rib polydactyly dysplasia, type I (Saldino-Noonan). On transvaginal sonography, a narrow chest, symmetrical micromelia, polydactyly and anasarca were present. An autopsy confirmed recurrent SRP. Short-rib polydactyly dysplasia may be diagnosed with transvaginal sonography in the first trimester.

Adult↗
PubMed1996

Sonographic visualization of the ovaries throughout pregnancy.

OBJECTIVE: To determine the frequency with which one or both normal ovaries can be visualized during a routine obstetric ultrasound examination. METHODS: The population consisted of 5617 pregnant women at 5.0-39.9 weeks' gestation, studied cross-sectionally. The sonographic visualization rate for one or both normal ovaries, as well as their position above or below the level of the umbilicus, was recorded for one examination in each patient. RESULTS: The study population was divided into three groups according to gestational age: first trimester, 5.0-12.9 weeks; second trimester, 13.0-26.9 weeks; and third trimester, 27.0-39.9 weeks. There were 829, 3195, and 1593 women in the first, second, and third trimesters, respectively. Most women were examined transvaginally in the first trimester; transabdominal sonography was used in the second and third trimesters. The ability to visualize one or both ovaries declined significantly (P < .05) from the first trimester to the second, as well as from the second trimester to the third (P < .001). The percentage of ovaries that were visualized above the umbilicus increased from 2.4% in the first trimester to 10.1% in the second trimester (P < .001), and to 21.7% in the third trimester (P < .001). CONCLUSION: As gestational age advances, there is a significant reduction in the ultrasound visualization rate of normal ovaries. This investigation provides normative data for ovarian visualization throughout pregnancy that may be helpful in establishing ultrasound laboratory standards.

Female↗
PubMed1996

Stress, coping and burnout in mental health nurses: findings from three research studies.

In this paper we present data from three research studies on stress, coping and burnout in mental health nurses. All three studies used a range of self report questionnaires. Measures included a demographic checklist, the General Health Questionnaire (GHQ-28), the Maslach Burnout Inventory, the DCL Stress Scale and the Cooper Coping Skills Scale. In all, 648 ward based mental health nurses were surveyed. There were no significant differences between levels of psychological distress on GHQ Total Score, but there were differences in caseness rates. In Study 3, some 38% of nurses were found to score at or above the criterion for caseness. The main stressors for ward staff were to do with staff shortages, health service changes, poor morale and not being notified of changes before they occurred. Differences in coping skills were found across studies. The study group with the highest stress scores also had the lowest coping skills scores. This was also associated with significantly higher alcohol consumption and greater self reported sickness absence. Scores on the Maslach Burnout Inventory showed higher levels of burnout amongst nurses in Study 3. These three studies have confirmed that stress is a problem for ward based mental health nurses. Two main implications arise from this work. Firstly we need models of the stress process that are empirically based, and which help us identify the moderating variables that reduce the impact of stressors on nurses. Secondly, we need to utilise this knowledge to deliver stress management interventions for staff. We end by outlining a model which may help us both understand the process of stress causation, and move towards our goal of stress reduction.

Adaptation, Psychological↗
PubMed1995

The Claybury Community Psychiatric Nurse Stress Study: is it more stressful to work in hospital or the community?

The Claybury community psychiatric nurse (CPN) stress study collected data on stress levels in 250 CPNs and 323 ward-based psychiatric nurses (WBPN) in the North East Thames region. Four out of 10 CPNs were found to be experiencing high levels of psychological distress on GHQ scores. Whilst both CPNs and WBPNs scored highly on scores of occupational burnout, especially on emotional exhaustion scores, WBPNs scored worse on emotional detachment from their patients and were achieving less personal fulfilment from their work. Both groups of nurses were more satisfied with direct patient clinical work than with their employment conditions, particularly their working environments and, for CPNs, their relationships with their managers. The different patterns of coping skills are explored and discussed for both groups of nurses, especially the use of social support, time management and organization of tasks. The study concludes that whilst major changes are occurring in the psychiatric arena for both groups of nurses, stress is reaping its toll on mental health nurses, in terms of higher absence rates, lower self-esteem and personal unfulfilment. This could not only affect the quality of patient care but also future career prospects for nurses. The study invites serious consideration of introducing stress-reducing measures in the work-place as well as further research into specific stressors for different groups of nurses.

Adaptation, Psychological↗
PubMed1995

Stress and coping strategies in community psychiatric nurses: a Q-methodological study.

With the development of the concept of community care there has been a significant expansion of the community psychiatric nurse (CPN) profession. The present study attempts to examine which aspects of their work CPNs currently find stressful. The study also examines the various strategies which CPNs feel to be useful in attempting to cope with such occupational stress. Forty-four CPNs in four health districts participated in this Q-methodological study which provided the opportunity for CPNs to construct their own concepts of stressors and coping strategies. The results obtained indicated that CPNs identified nine distinct areas of stress within their work, along with 12 distinct coping strategies which they considered useful in attempting to deal with such stress. The implications of these findings are discussed.

Adaptation, Psychological↗
PubMed1995

Stress and the community mental health nurse: the development of a measure.

The issue of stress amongst health care professionals is currently a major concern within the British National Health Service. It is important for researchers to develop both reliable and valid psychometric measures to assess occupational stress. This paper outlines the development and piloting of a measure of professional stress for community mental health nurses, the CPN Stress Questionnaire (Revised). Data on the reliability and validity of this new measure are presented. It is concluded that this measure has good psychometric properties. A range of possible research applications is outlined.

Burnout, Professional↗
PubMed1994

Homozygous deletions on the short arm of chromosome 9 in ovarian adenocarcinoma cell lines and loss of heterozygosity in sporadic tumors.

Rat ovarian surface epithelial cells transformed spontaneously in vitro have been found to have homozygous deletions of the interferon alpha (IFNA) gene. This suggests that inactivation of a tumor-suppressor gene in this region may be crucial for the development of ovarian cancer. We therefore used microsatellite markers and Southern analysis to examine the homologous region in humans--the short arm of chromosome 9--for deletions in sporadic ovarian adenocarcinomas and ovarian tumor cell lines. Loss of heterozygosity occurred in 34 (37%) of 91 informative sporadic tumors, including some benign, low-malignant-potential and early-stage tumors, suggesting that it is an early event in the development of ovarian adenocarcinoma. Furthermore, homozygous deletions on 9p were found in 2 of 10 independent cell lines. Deletion mapping of the tumors and lines indicates that the candidate suppressor gene inactivated as a consequence lies between D9S171 and the IFNA locus, a region that is also deleted in several other tumors and that contains the melanoma predisposition gene, MLM.

Adenocarcinoma↗
PubMed1992

A function-associated molecule on rat natural killer cells identified by anti-idiotypic monoclonal antibodies.

Monoclonal antibodies were generated against idiotopes on an NK target antigen-specific IgM monoclonal antibody (mab). This mab (18C2) was originally produced against (NC-37) human EBV-transformed B cells. The 18C2 mab inhibits natural killer cell lysis of NC-37 and other target cells by preventing conjugate formation. Anti-18C2(id) mabs were tested for binding to effector cells and screened by ELISA, flow cytometry, and by inhibition of NK cytotoxicity. Two of the anti-18C2(id) (anti-id) mabs (12H1.C5 and 6D9.B11) were chosen for further study. The idiotypic specificity of these anti-id mabs was confirmed by testing their binding to 18C2 hybridoma cells in the presence of homologous and heterologous "cold" inhibitor mabs. Experiments were also conducted to determine the functional properties of these mabs. Anti-18C2(id) mab 12H1.C5 inhibited the cytotoxic activity of rat splenic NK (nylon wool nonadherent cells, NWNA) and rat ALAK cells. Flow cytometric (FCM) analysis of the binding of the anti-18C2(id) mabs demonstrated that mab 12H1.C5 bound 75.43% rat NWNA spleen cells, 43.74% rat ALAK cells, and 74.33% rat CRC- cells. Anti-id mab 6D9.B11 bound 45.20% NWNA cells, 70.45% rat ALAK cells, and 55.86% CRC- cells. Two-color FCM analysis demonstrated that the anti-id mabs not only bound to the same molecule on NK cells, but also these mabs bound to the same molecule as 5C6, an anti-NK cell mab. Biochemical analysis of the antigen recognized by mab 12H1.C5 was determined by Western blotting. The determinant on NWNA cells recognized by mab 12H1.C5 had an M(r) of 40 kDa and appeared to be identical to that recognized by mab 5C6. The same experiment using a transformed rat RNK-16 (CRC-) cell extract and Western blot analysis, demonstrated an M(r) of 42 and 48 kDa in the presence of mabs 5C6 and 12H1.C5. Monoclonal antibody 5C6 was previously shown to recognize a vimentin-like function-associated molecule on NK cell membranes. The anti-id mabs were also shown to have cross-reactivity with the intermediate filament vimentin as determined by Western blot analysis.

Animals↗