Biomedical subjects

L Snell

Publications and source records attributed to L Snell.

At least 19 recordsLinked to original sources

PubMed2005

Somatostatin receptors in primary human breast cancer: quantitative analysis of mRNA for subtypes 1--5 and correlation with receptor protein expression and tumor pathology.

Somatostatin receptors (SSTRs) have been identified in most hormone-producing tumors as well as in breast cancer. In the present study, we determined SSTR1-5 expression in primary ductal NOS breast tumors through semi-quantitative RT-PCR and immunocytochemistry. The results from the analysis of 98 samples were correlated with several key histological markers and receptor expression. All five SSTR subtypes are variably expressed at the mRNA level in breast tumors with 91% of samples showing SSTR1, 98% SSTR2, 96% SSTR3, 76% SSTR4, and 54% SSTR5. SSTR1-5 are localized to both tumor cells and the surrounding peritumoral regions as detected by immunocytochemistry. Levels of SSTR mRNA, when corrected for beta-actin levels, were highest for SSTR3 followed by SSTR1, SSTR2, SSTR5, and SSTR4. Furthermore, there was good correlation between mRNA and protein expression with 84% for SSTR1, 79% for SSTR2, 89% for SSTR3, 68% for SSTR4, 68% for SSTR5, and 78% for all five receptors. SSTR1, 2 and 4 were correlated with ER levels whereas SSTR2 showed an additional correlation with PR levels. These correlations were independent of patient age and histological grade. Moreover, using immunocytochemistry, blood vessels exhibited receptor-specific localization for SSTR2 and SSTR5. Our results indicate significant correlations between mRNA and protein expression along with receptor-specific correlations with histological markers as well as ER and PR levels. Differential distribution of SSTR subtypes in tumors and receptor-specific expression in vascular structures may be considered as a novel diagnosis for breast tumors with receptor subtype agonists.

Adult↗

PubMed2002

Relationship of coregulator and oestrogen receptor isoform expression to de novo tamoxifen resistance in human breast cancer.

This study addresses the hypothesis that altered expression of oestrogen receptor-beta and/or altered relative expression of coactivators and corepressors of oestrogen receptors are associated with and may be mechanisms of de novo tamoxifen resistance in oestrogen receptor positive breast cancer. All cases were oestrogen receptor +, node negative, primary breast tumours from patients who later had no disease progression (tamoxifen sensitive) or whose disease progressed while on tamoxifen (tamoxifen resistant). Using an antibody to oestrogen receptor-beta that detects multiple forms of this protein (total) but not an antibody that detects only full-length oestrogen receptor-beta 1, it was found that high total oestrogen receptor beta protein expressors were more frequently observed in tamoxifen sensitive tumours than resistant tumours (Fisher's exact test, P=0.046). However, no significant differences in the relative expression of oestrogen receptor beta2, oestrogen receptor beta5 and full-length oestrogen receptor beta1 RNA in the tamoxifen sensitive and resistant groups were found. Also, when the relative expression of two known coactivators, steroid receptor RNA activator and amplified in breast cancer 1 RNA to the known corepressor, repressor of oestrogen receptor activity RNA, was examined, no significant differences between the tamoxifen sensitive and resistant groups were found. Altogether, there is little evidence for altered coregulators expression in breast tumours that are de novo tamoxifen resistant. However, our data provide preliminary evidence that the expression of oestrogen receptor beta protein isoforms may differ in primary tumours of breast cancer patients who prove to have differential sensitivity to tamoxifen therapy.

Antineoplastic Agents, Hormonal↗

PubMed2002

Immune escape mechanisms of childhood ALL and a potential countering role for DC-like leukemia cells.

BACKGROUND: Pre-B ALL cells generally elicit a weak immune host response, due to poor expression of co-stimulatory molecules and/or suppression of immune function. A possible way to enhance immunogenicity of pre-B ALL cells is to convert them to DC-like cells. METHODS: To study the effect of ALL cells on T-cell function, ALL cells were incubated with T adult cells activated by OKT3 MAb. Liquid culture of de novo pre-B ALL cells for 7 days, in a medium containing IL-1alpha, IL-3, IL-7, Flt 3 ligand (L) and tumor-necrosis factor alpha (TNF-alpha) produced DC-like cells. These were evaluated for morphology, viability, phenotype, as measured by flow cytometry, and function, including MLR. RESULTS: Pre-B ALL cell-lines NALM-6, BALM and de novo pre-B ALL cells failed to stimulate T cells, but suppressed stimulated T cells. The DC-like cells displayed characteristic features of DCs: filiform cytoplasmic projections, and phenotypic expression of co-stimulatory molecules CD80/86, MHC Class I and II molecules, CD83 and CD1a. Genetic monoclonality study confirmed their leukemic origin. In a 5-day MLR culture, the DC-like cells potently activated allogeneic adult and cord CD4+ and CD8+ T cells. Furthermore, both CD4+ and CD8+ T cells were primed towards a Type I. No such effect was seen with unmanipulated de novo pre-B ALL cells. DISCUSSION: DC-like cells can be generated from childhood pre-B ALL cells and are potent stimulators of adult and naïve cord CD8+ T cells via CD4+ cells. These cells may form part of an immunotherapy strategy to overcome tolerance to ALL cells.

B-Lymphocytes↗

PubMed2000

Altered expression of estrogen receptor coregulators during human breast tumorigenesis.

The hypothesis that altered expression of specific coactivators/repressors of the estrogen receptor occurs during human breast tumorigenesis in vivo is examined in this study. Using in situ hybridization and reverse transcription-PCR assays, the expression of two coactivators (SRA and AIB1) and one repressor (REA) of the estrogen receptor was compared between matched breast tumors and adjacent normal human breast tissue. The levels of SRA and AIB1 mRNA were increased in tumors compared with normal tissues (n = 19; Wilcoxon matched pairs test; P < 0.01). In contrast, the expression of REA mRNA was not different between tumors and normal tissues (n = 19; Wilcoxon; P = 0.110). The ratios of AIB1:REA and SRA:REA were higher (Wilcoxon; P < 0.05) in tumors compared with normal tissues. Furthermore, SRA:AIB1 was higher (Wilcoxon; P = 0.0058) in tumors compared with normal tissues. Although our study is small, these data are consistent with the above hypothesis and suggest that such alterations may have a role in the altered estrogen action occurring during breast tumorigenesis.

Breast↗

PubMed2000

Expression of a repressor of estrogen receptor activity in human breast tumors: relationship to some known prognostic markers.

The expression of a specific repressor of estrogen receptor activity (REA) was investigated by a semiquantitative reverse transcription-PCR assay in 40 human breast tumor biopsy samples with respect to steroid hormone receptor status and other known prognostic variables. The data showed that REA expression was positively correlated with estrogen receptor (ER) levels as defined by ligand-binding assays (Spearman r = 03231; P = 0.042) and that the median level of REA mRNA was significantly (Mann-Whitney two-tailed test, P = 0.0424) higher in ER+ tumors (median = 94.5; n = 30) compared with ER- tumors (median = 645; n = 10), with no significant differences (P = 0.4988) associated with progesterone receptor status alone. In addition, REA expression was inversely correlated with tumor grade (Spearman r = -0.4375; P = 0.0054). When the tumors were divided into two groups based on grade, REA expression was significantly (Mann-Whitney two-tailed test, P = 0.0024) higher in low-grade (median = 97; n = 16) compared with high-grade (median = 76; n = 23) tumors. These results provide preliminary data suggesting that the expression of REA varies among breast tumors and is correlated with known treatment response markers and inversely correlated with a marker of breast cancer progression. REA together with ER status may be an improved marker of endocrine therapy responsiveness in human breast cancer.

Biomarkers, Tumor↗

PubMed2000

Lumican and decorin are differentially expressed in human breast carcinoma.

Previous studies have shown that lumican is expressed and increased in the stroma of breast tumours. Lumican expression has now been examined relative to other members of the small leucine-rich proteoglycan gene family in normal and neoplastic breast tissues, to begin to determine its role in breast tumour progression. Western blot study showed that lumican protein is highly abundant relative to decorin, while biglycan and fibromodulin are only detected occasionally in breast tissues (n=15 cases). Further analysis of lumican and decorin expression performed in matched normal and tumour tissues by in situ hybridization showed that both mRNAs were expressed by similar fibroblast-like cells adjacent to epithelium. However, lumican mRNA expression was significantly increased in tumours (n=34, p<0.0001), while decorin mRNA was decreased (p=0.0002) in neoplastic relative to adjacent normal stroma. This was accompanied by a significant increase in lumican protein (n=12, p=0.0122), but not decorin. Further evidence of altered lumican expression in breast cancer was manifested by discordance between lumican mRNA and protein localization in some regions of tumours but not in adjacent morphologically normal tissues. It is concluded that lumican is the most abundant of these proteoglycans in breast tumours and that lumican and decorin are inversely regulated in association with breast tumourigenesis.

Adult↗

PubMed2000

C.A.R.E.: an approach for teaching ethics in medicine.

Various societal factors have contributed to an increase in the ethical dilemmas faced by physicians, yet limited formal training in ethical decision-making is provided for those practitioners during their medical education. The pluralistic nature of contemporary medicine seems amenable to the development of common clinical and educational approaches to ethical dilemmas. The authors propose one such framework--a four question approach called C.A.R.E.--that encourages physicians at all levels of training to acknowledge individual and collective factors that enter into ethical decision-making. These questions are clearly described, and examples for use of the model in teaching settings are also provided. The authors believe that this approach can have significant utility in medical education and clinical settings, and advocate for its use and evaluation.

Attitude to Health↗

PubMed2000

A review of the evaluation of clinical teaching: new perspectives and challenges.

PURPOSE: This article discusses the importance of the process of evaluation of clinical teaching for the individual teacher and for the programme. Measurement principles, including validity, reliability, efficiency and feasibility, and methods to evaluate clinical teaching are reviewed. CONTEXT: Evaluation is usually carried out from the perspective of the learner. This article broadens the evaluation to include the perspectives of the teacher, the patient and the institutional administrators and payers in the health care system and recommends evaluation strategies. RESULTS: Each perspective provides specific feedback on factors or attributes of the clinical teacher's performance in the domains of medical expert, professional, scholar, communicator, collaborator, patient advocate and manager. Teachers should be evaluated in all domains relevant to their teaching objectives; these include knowledge, clinical competence, teaching effectiveness and professional attributes. CONCLUSIONS AND IMPLICATIONS: Using this model of evaluation, a connection can be made between teaching and learning about all the expected roles of a physician. This can form the basis for systematic investigation into the relationship between the quality of teaching and the desired outcomes, the improvement of student learning and the achievement of better health care practice. It is suggested that the extent of effort and resources devoted to evaluation should be commensurate with the value assigned to the evaluation process and its outcomes.

Education, Medical↗

PubMed2000

Strategic planning in medical education: enhancing the learning environment for students in clinical settings.

BACKGROUND: The 1999 Cambridge Conference was held in Northern Queensland, Australia, on the theme of clinical teaching and learning. It provided an opportunity for groups of academic medical educators to consider some of the challenges posed by recent changes to health care delivery and medical education across a number of countries. PURPOSE: This paper describes the issues raised by the practical challenges posed by the current environment and how they might be addressed in ways that could promote more effective learning in clinical settings. METHOD: A SWOT analysis is a tool that can help in forward planning by identifying the strengths, weaknesses, opportunities and threats presented by any situation. Our SWOT analysis was used to generate a list of items, from which we chose those most feasible and most likely to promote positive change. RESULTS: Twenty different issues were identified, with four of them chosen by consensus for further elaboration. The discussion gave rise to four main recommended strategies: ensuring that clinical teachers thoroughly understand the purpose and process of learning in clinical settings; equipping learners with 'survival skills'; making the best use of learning resources within different clinical environments and making judicious use of information technology to enhance learning efficiency. CONCLUSIONS: The four strategies were selected not only because of their inherent importance, but also because of their feasibility. Modest changes can motivate students to feel part of a clinical team and a 'community of practice' and enhance their capacity for self-regulated practice.

Clinical Clerkship↗

PubMed2000

Continuing educational needs in computers and informatics. McGill survey of family physicians.

OBJECTIVE: To describe family physicians' perceived educational needs in computers and informatics. DESIGN: Mailed survey. SETTING: General or family practices in Canada. PARTICIPANTS: Physicians (489 responded to a mailing sent to 2,500 physicians) who might attend sessions at the McGill Centre for CME. Two duplicate questionnaires were excluded from the analysis. METHOD: Four domains were addressed: practice profile, clinical CME needs, professional CME needs, and preferred learning formats. Data were entered on dBASE IV; analyses were performed on SPSS. MAIN FINDINGS: In the 487 questionnaires retained for analysis, "informatics and computers" was mentioned more than any other clinical diagnostic area, any other professional area, and all but three patient groups and service areas as a topic where improvement in knowledge and skills was needed in the coming year. Most physicians had no access to computer support for practice (62.6%); physicians caring for neonates, toddlers, or hospital inpatients were more likely to report some type of computer support. CONCLUSIONS: Family physicians selected knowledge and skills for computers and informatics as an area for improvement in the coming year more frequently than they selected most traditional clinical CME topics. This educational need is particularly great in small towns and in settings where some computerized hospital data are already available.

Adult↗

PubMed1999

Mammaglobin, a potential marker of breast cancer nodal metastasis.

The Mammaglobin gene, a breast-specific member of the uteroglobin gene family, has been previously identified as being overexpressed in some breast tumours, but the cellular origin and relationship to tumour progression are unknown. Using a subtractive hybridization approach, mammaglobin mRNA has also been found to be overexpressed in the in situ compared to the invasive element within an individual breast tumour. Further study by in situ hybridization performed in 13 breast tumours, selected to include normal, in situ, and invasive primary tumour elements, and in most cases axillary lymph node metastases, revealed that mammaglobin expression occurs in all elements, is restricted to epithelial cells, and is significantly increased in tumour cells compared with normal cells ( p< 0.04). Analysis of mammaglobin expression within 20 independent primary breast tumours and their corresponding axillary lymph nodes revealed that all 13 lymph nodes positive and none of the seven nodes negative for metastatic breast carcinoma by histology were mammaglobin-positive by reverse transcription-polymerase chain reaction (RT-PCR) ( p=0.0001). These results suggest that mammaglobin could be a marker of axillary lymph node breast metastases.

Adult↗

PubMed1999

Psoriasin (S100A7) expression and invasive breast cancer.

Alteration of psoriasin (S100A7) expression has previously been identified in association with the transition from preinvasive to invasive breast cancer. In this study we have examined persistence of psoriasin mRNA and protein expression in relation to prognostic factors in a cohort of 57 invasive breast tumors, comprising 34 invasive ductal carcinomas and 23 other invasive tumor types (lobular, mucinous, medullary, tubular). We first developed an IgY polyclonal chicken antibody and confirmed specificity for psoriasin by Western blot in transfected cells and tumors. The protein was localized by immunohistochemistry predominantly to epithelial cells, with both nuclear and cytoplasmic staining, as well as occasional stromal cells in psoriatic skin and breast tumors; however, in situ hybridization showed that psoriasin mRNA expression was restricted to epithelial cells. In breast tumors, higher levels of psoriasin measured by reverse transcriptase-polymerase chain reaction and Western blot (93% concordance) were significantly associated with estrogen and progesterone receptor-negative status (P < 0.0001, P = 0.0003), and with nodal metastasis in invasive ductal tumors (P = 0. 035), but not with tumor type or grade. Psoriasin expression also correlated with inflammatory infiltrates (all tumors excluding medullary, P = 0.0022). These results suggest that psoriasin may be a marker of aggressive behavior in invasive tumors and are consistent with a function as a chemotactic factor.

Blotting, Western↗

PubMed1999

The potential role for prolactin-inducible protein (PIP) as a marker of human breast cancer micrometastasis.

The prolactin-inducible protein (PIP/GCPD15) is believed to originate from a limited set of tissues, including breast and salivary glands, and has been applied as a clinical marker for the diagnosis of metastatic tumours of unknown origin. We have investigated the potential role of PIP mRNA as a marker of human breast cancer metastasis. Using reverse transcription polymerase chain reaction and Southern or dot blot analysis, PIP mRNA was detected in 4/6 breast cell lines, independent of oestrogen receptor (ER) status. In breast primary tumours (n = 97), analysed from histologically characterized sections, PIP mRNA was detected in most cases. Higher PIP mRNA levels correlated with ER+ (P = 0.0004), progesterone receptor positive (PR+) (P = 0.0167), low-grade (P = 0.0195) tumours, and also PIP protein levels assessed by immunohistochemistry (n = 19, P = 0.0319). PIP mRNA expression was also detectable in 11/16 (69%) of axillary node metastases. PIP mRNA expression, however, was also detected in normal breast duct epithelium, skin, salivary gland and peripheral blood leucocyte samples from normal individuals. We conclude that PIP mRNA is frequently expressed in both primary human breast tumours and nodal metastases. However, the presence of PIP expression in skin creates a potential source of contamination in venepuncture samples that should be considered in its application as a marker for breast tumour micrometastases.

Apolipoproteins↗

PubMed1998

Expression of lumican in human breast carcinoma.

Lumican mRNA has been identified as being differentially expressed between different regions of the same human breast tumor. In situ hybridization study of 26 independent breast tumors confirmed the presence of lumican mRNA in fibroblast-like cells within stroma and showed a significant increase of its expression in tumor compared to adjacent normal stroma (P < 0.001). Higher lumican expression was associated with higher tumor grade, lower estrogen receptor levels in the tumor, and younger age of the patients (P < 0.05). Reverse transcription-PCR analysis of total RNA extracted from 19 independent breast tissues exhibiting lesions that are thought to parallel tumor progression also suggests that this proteoglycan is differentially expressed during tumor progression.

Adult↗

PubMed1998

The importance of the case management approach: perceptions of multidisciplinary team members.

This article attempts to determine the importance of the case management approach as perceived by health professionals working in multidisciplinary teams. The case management approach is reported to streamline care and contain cost. The literature calls for continuing education in a multidisciplinary forum for all health professions; however, data on perceived or actual educational needs is scant. One hundred forty-one health practitioners working in clinical teams rated four case management components on 100 mm scales: assessing patient needs; educating caregivers; community agency liaison; and, cost monitoring. Statistical significance of differences was determined by Mann Whitney U and Wilcoxon rank sum testing. All scores were high, and of all variables tested, varied only by profession (p < .01). Administrators and nurses had relatively higher scores than physicians and physiotherapists. Patient needs were valued above education, education above liaison, and liaison above cost monitoring (p < .01, < .01, < .01, respectively). Continuing education providers should note that health professionals value case management and may be receptive to education. Further study is required to design educational modules for multidisciplinary use, test impact on knowledge and skills, and determine if transdisciplinary case management education can improve quality of care while containing costs.

Attitude of Health Personnel↗

PubMed1997

Use of standardized patients to assess between-physician variations in resource utilization.

CONTEXT: As medical costs are increasingly being scrutinized, there is heightened interest in defining variations in physician behavior in clinical settings. OBJECTIVE: To evaluate if standardized patient (SP) technology is a reliable and feasible method of studying interphysician variations in test ordering, referral requests, prescribing behavior, and visit costs. DESIGN: The study was conducted with blinded SP visits to family medicine and internal medicine residents, university-affiliated family physicians, and community-based family physicians. Resource utilization and visit costs were assessed using test requisitions, consult requests, and prescriptions that were collected by the SPs. SETTING: Physicians' offices in ambulatory care, hospital-based clinics and in the community. PARTICIPANTS: Four persons (aged 57-77 years) trained to simulate having osteoarthritis of the hip. In one simulation, the patient had gastropathy due to nonsteroidal anti-inflammatory drug use, and in the other, the patient sought therapy for hip discomfort. MAIN OUTCOME MEASURES: Reliability of cost estimates of physician services, tests, consultations, prescriptions, and total visits and test-ordering behavior for nonsteroidal anti-inflammatory gastropathy. RESULTS: Overall, 112 (63%) of the physicians who were sent invitations to the study agreed to participate. Of 312 total SP visits conducted over a 1-year period, unblinding due to SP detection occurred on 36 occasions (11.5%). Reliable cost estimates of physician services, tests, and consultations, and moderately reliable estimates of total visit costs, were obtained with 4 visits per practicing physician and with 2 visits per resident. There were extreme variations in total visit costs generated by the study physicians. A small number of physicians had a major impact on this variability. CONCLUSION: Standardized patient technology provides a reliable, feasible method to assess variations in resource utilization between physicians.

Diagnosis-Related Groups↗

PubMed1997

Unnecessary prescribing of NSAIDs and the management of NSAID-related gastropathy in medical practice.

BACKGROUND: Use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk for hospitalization and death from gastrointestinal bleeding and perforation. OBJECTIVES: To 1) estimate the extent to which NSAIDs are prescribed unnecessarily and NSAID-related side effects are inaccurately diagnosed and inappropriately managed and 2) identify the physician and visit characteristics associated with suboptimal use of NSAIDs. DESIGN: Prospective cohort study. SETTING: Montreal, Canada. PARTICIPANTS: 112 physicians representing academically affilliated general practitioners, community-based general practitioners, and residents in family medicine and internal medicine. INTERVENTIONS: Blinded, office-based assessment of the management of two clinical cases (chronic hip pain due to early osteoarthritis and NSAID-related gastropathy) using elderly standardized patients. MEASUREMENTS: Quality of drug management and potential predictors of suboptimal drug management. RESULTS: Unnecessary prescriptions for NSAIDs or other drugs were written during 41.7% of visits. Gastropathy related to NSAID use was correctly diagnosed in 93.4% of visits and was acceptably managed in 77.4% of visits. The risk for an unnecessary NSAID prescription was greater when the contraindications to NSAID therapy were incompletely assessed (odds ratio, 2.3 [95% CI, 1.0 to 5.2]) and when the case was managed by residents in internal medicine (odds ratio, 4.1 [CI, 1.2 to 14.7]). The risk for suboptimal management of NSAID-related side effects was increased by incorrect diagnosis (odds ratio, 16.6 [CI, 3.6 to 76.5]) and shorter visits. CONCLUSIONS: Unnecessary NSAID prescribing and suboptimal management of NSAID-related side effects were sufficiently common to raise questions about the appropriateness of NSAID use in the general population. If these results reflect current practice, prescribing patterns may contribute to avoidable gastrointestinal morbidity in elderly persons.

Aged↗

PubMed1997

Leukaemia presenting as marrow hypoplasia: molecular detection of the leukaemic clone at the time of initial presentation.

Occasional cases of transient marrow hypoplasia in childhood evolve into acute leukaemia. We studied two children who presented with marrow hypoplasia following infection and who developed acute lymphoblastic leukaemia 2-3 months later. A simple polymerase-chain-reaction (PCR) test for monoclonality showed that immunoglobulin heavy-chain gene rearrangements of the same size were present at the times of both hypoplasia and leukaemia, and DNA sequencing confirmed identity of these rearrangements. PCR-based quantification, using patient-specific primers, showed in both patients that the leukaemic clone made up 20-25% of the marrow cells during hypoplasia. In contrast, four patients with typical aplastic anaemia showed only polyclonal B-cell populations in the marrow. We conclude that the leukaemic clone was already present at the time of hypoplasia in the two index patients and that in future a simple PCR test for monoclonality could be used to screen patients with marrow aplasia or hypoplasia for the presence of a monoclonal B-cell population. Patients with monoclonal populations could then be monitored carefully for subsequent development of leukaemia.

Anemia, Aplastic↗