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Admitting Department, Hospital↗
Biomedical subjects
C Byrne
Publications and source records attributed to C Byrne.
Changing pattern of desmocollin 3 expression accompanies epidermal organisation during skin development.
The adhesive core of the desmosome is composed of cadherin-like glycoproteins of 2 families, desmocollins and desmogleins. The desmosomal cadherins show distinct patterns of expression in adult epidermis, and we have suggested that the desmocollins have a functional role in regulating the differentiation and/or morphogenesis of that epithelium (North et al. [1996] Proc. Natl. Acad. Sci. USA 93:7701-7705.). To examine this hypothesis, we cloned murine desmocollins and examined the induction patterns of desmocollins 1 and 3 during skin and skin appendage development. Desmocollins 3 and 1 were first expressed in epidermis in highly regional patterns at embryonic days 13.0 and 13.5, respectively, and both were up-regulated in general body epidermis at day 14.5. At this stage, epidermis is undifferentiated and the desmocollins showed an unexpected expression pattern. However, by day 18.5 when skin had undergone terminal differentiation, desmocollin 1 and 3 expression resembled that found in the adult. Thus, the establishment of the adult pattern of desmocollin expression corresponds to the adult pattern of epidermal stratification. We suggest that it is the ratio of desmocollin 1 to desmocollin 3 expression at different levels in the epidermis that is fundamental in establishing this pattern of differentiation.
Amino Acid Sequence↗
Regulation of gene expression in developing epidermal epithelia.
Skin is one of the most thoroughly studied epithelia and can be used as a model for transcriptional control of epithelial differentiation. In particular, the stages of epidermal development and differentiation from a simple epithelium are well characterized. Temporal gene expression during development can be used to assign roles for transcription factors in epidermal differentiation. Approaches to understanding transcriptional regulation in epidermis include extensive promoter analysis and expression studies, in some cases coupled to functional studies. This work has not produced any consensus about the importance of any particular factor or class of factors in epidermal specification. There is, as yet, nothing similar to the myo D family of tissue-specific and cell-type determining factors in epidermis. These studies, however, have revealed much about control of the differentiation process in epidermis. Most recently, there has been a suggestion that epithelial transcription can be influenced directly by the status of the adhesion complexes at the cell surface, providing a direct link between one of the distinguishing features of the epithelial state and gene transcription.
Animals↗
Background contamination by coplanar polychlorinated biphenyls (PCBs) in trace level high resolution gas chromatography/high resolution mass spectrometry (HRGC/HRMS) analytical procedures.
The addition of the "dioxin-like" polychlorinated biphenyl (PCB) congeners to the assessment of risk associated with the 2,3,7,8-chlorine substituted dioxins and furans has dramatically increased the number of laboratories worldwide that are developing analytical procedures for their detection and quantitation. Most of these procedures are based on established sample preparation and analytical techniques employing high resolution gas chromatography/high resolution mass spectrometry (HRGC/HRMS), which are used for the analyses of dioxin/furans at low parts-per-trillion (ppt) levels. A significant and widespread problem that arises when using these sample preparation procedures for the analysis of coplanar PCBs is the presence of background levels of these congeners. Industrial processes, urban incineration, leaking electrical transformers, hazardous waste accidents, and improper waste disposal practices have released appreciable quantities of PCBs into the environment. This contamination has resulted in the global distribution of these compounds via the atmosphere and their ubiquitous presence in ambient air. The background presence of these compounds in method blanks must be addressed when determining the exact concentrations of these and other congeners in environmental samples. In this study reliable procedures were developed to accurately define these background levels and assess their variability over the course of the study. The background subtraction procedures developed and employed increase the probability that the values reported accurately represent the concentrations found in the samples and were not biased due to this background contamination.
Adipose Tissue↗
Independent epidemics of heterosexual and homosexual HIV infection in South Africa--survival differences.
Survival with HIV infection is shorter in sub-Saharan Africa than in developed countries. The pattern of HIV transmission in our region has changed from homosexual to heterosexual, with viral subtypes similar to those in North America/Europe and Central Africa, respectively. We compared survival for the two transmission patterns after AIDS, and after the first CD4+ lymphocyte counts < 200/microliter and < 50/microliter, for adults presenting 1988-1993. Antiretroviral therapy was excluded. There were 180 homosexuals (63% White, 56% employed) and 314 heterosexuals (67% Black, 34% employed). Extrapulmonary tuberculosis was the AIDS-defining diagnosis in 36/90 heterosexuals and 5/58 homosexuals (p < 0.0001). Survival after AIDS was longer in heterosexuals (p = 0.0015), but AIDS occurred earlier as shown by their higher CD4+ count at AIDS onset (median 98/microliter vs. 40/microliter; p = 0.036). Survival was similar in the two groups after first CD4+ count < 200/microliter and < 50/microliter. Race, socioeconomic status and morbidity are markedly different in the two transmission groups. AIDS occurs with less severe immune suppression in heterosexuals, with correspondingly longer survival. Survival after defined CD4+ counts, however, is remarkably similar.
AIDS-Related Opportunistic Infections↗
Alpha-glutathione s-transferase (alpha-GST) release, an early indicator of carbon tetrachloride hepatotoxicity in the rat.
1. The use of the cytoplasmic enzyme, alpha glutathione s-transferase (alpha-GST) as an early index of carbon tetrachloride (CCl4) toxicity in the rat was investigated and compared with a standard enzyme, marker, aspartate aminotransferase (AST). The hepatotoxic effects of CCl4 in the rat were determined in a time and dose-response study. 2. Following CCl4 exposure, alpha-GST release was shown to be an earlier and more sensitive biomarker of hepatotoxicity than AST. 3. Significant increases in alpha-GST were detected 2 h after CCl4 exposure. Using the enzyme marker AST, this early hepatotoxic injury went undetected. At 6 and 16 h, alpha-GST was also a more sensitive indicator of hepatotoxicity than AST. 4. alpha-GST release was significantly increased at a dose of 5 microliters/kg, the lowest concentration of CCl4 administered and clearly responded in a dose-dependent manner with increasing doses of CCl4. In contrast, release of AST did not reach statistical significance until a dose of 25 microliters/kg. 5. Thus, these findings indicate that alpha-GST is a more sensitive and more accurate reflector of CCl4 induced hepatotoxicity than AST.
Administration, Oral↗
Risk of breast cancer associated with atypical hyperplasia of lobular and ductal types.
Epidemiological studies using the histological classification of Page for benign breast disease consistently demonstrate a positive association between atypical hyperplasia and the subsequent development of breast cancer. However, atypical hyperplasia is of either lobular or ductal types, and breast cancer risk in relation to type of atypical hyperplasia has not been studied extensively. Thus, we investigated prospectively the risk of breast cancer associated with histological subtypes of benign proliferative breast disease, including the types of atypical hyperplasia, among participants in the Nurses' Health Study who had biopsy-confirmed benign breast disease. Women who subsequently developed breast cancer were matched by year of birth and year of biopsy to participants who were free from breast cancer. Benign biopsy slides were classified according to the criteria of Page. Odds ratios (ORs) of breast cancer and 95% confidence intervals (CIs), adjusted for the matching variables and other breast cancer risk factors, were computed using unconditional logistic regression with benign nonproliferative breast disease as the referent group. Atypical ductal hyperplasia (OR = 2.4; 95% CI, 1.3-4.5) or atypical lobular hyperplasia (OR = 5.3; 95% CI, 2.7-10.4) in a prior biopsy were associated with increased breast cancer risk. Atypical lobular hyperplasia was more strongly associated with the risk of premenopausal breast cancer (OR = 9.6; 95% CI, 3.3-27.8) than with the risk of postmenopausal breast cancer (OR = 3.7; 95% CI, 1.3-10.2). The association of atypical ductal hyperplasia and breast cancer risk varied little by menopausal status. The magnitude of breast cancer risk seems to vary according to the type of atypical hyperplasia present at biopsy.
Adult↗
Determination of 2,3,7,8-chlorine-substituted dibenzo-p-dioxins and -furans at the part per trillion level in United States beef fat using high-resolution gas chromatography/high-resolution mass spectrometry.
As part of the U.S. EPA Dioxin Reassessment Program, the 2,3,7,8-chlorine-substituted dibenzo-p-dioxins and furans were measured at part per trillion (ppt) levels in beef fat collected from slaughter facilities in the United States. This is the first statistically designed national survey of these compounds in the U.S. beef supply. Analyte concentrations were determined by high-resolution gas chromatography/high-resolution mass spectrometry, using isotope dilution methodology. Method limits of detection on a whole weight basis were 0.05 ppt for TCDD and 0.10 ppt for TCDF, 0.50 ppt for the pentas (PeCDDs/PeCDFs)/hexas (HxCDDs/HxCDFs)/heptas (HpCDDs/HpCDFs), and 3.00 ppt for the octas (OCDD/OCDF). Method detection and quantitation limits were established on the basis of demonstrated performance criteria utilizing fortified samples rather than by conventional signal-to-noise or variability of response methods. The background subtraction procedures developed for this study minimized the likelihood of false positives and increased the confidence associated with reported values near the detection limits. Mean and median values for each of the 2,3,7,8-Cl-substituted dioxins and furans are reported, along with the supporting information required for their interpretation. The mean toxic equivalence values for the samples are 0.35 ppt (nondetects = 0) and 0.89 ppt (nondetects = 1/2 LOD).
Animals↗
A statistical survey of dioxin-like compounds in United States beef: a progress report.
The USEPA and the USDA have completed the first statistically designed survey of the occurrence and concentration of CDDs and CDFs in the fat of beef animals raised for human consumption in the United States. Back fat was sampled from 63 carcasses at federally inspected slaughter establishments nationwide. The sample design called for sampling beef animal classes in proportion to national annual slaughter statistics. All samples were analyzed using a modification of EPA method 1613, using isotope dilution, High Resolution GC/MS to determine the rate of occurrence of 2,3,7,8-substituted CDDs/CDFS. The whole weight method detection limits ranged from 0.05 ng kg-1 for TCDD to 3 ng kg-1 for OCDD. The results of this survey showed a mean concentration (reported as I-TEQ, lipid adjusted) in U.S. beef animals of 0.35 ng kg-1 and 0.89 ng kg-1 when either non-detects are treated as 0 value or assigned a value of 1/2 the detection limit, respectively.
Animals↗
Fast-tracking in baccalaureate nursing education: one Canadian response to students with advanced standing.
Accelerated nursing programmes for non-nursing college graduates were developed primarily to address a shortage of nurses in the USA. This article describes a unique Canadian programme which has evolved in response to demand from an increasingly older and well-qualified applicant pool for recognition of their relevant previous educational experience. In an 8-week period in the summer of 1993, 18 students completed the requirements for Year I of the 4-year baccalaureate nursing programme. When compared to their generic counterparts, these 'fast-trackers' were found to be older, more likely to be part-time and, at the end of Year 2 were academically equivalent. Students in the programme were highly enthusiastic, citing the benefits of saving a year of student costs and of entering the profession a year earlier. Faculty involved with the programme were positive about the benefits for students, although a drawback for full-time faculty was the impact of a heavy summer teaching load on other scholarly activities. Because of the programme's success, consideration is now being given to extending the fast-track option beyond Year I.
Adult↗
An 18-month follow-up on the effectiveness of a sexuality workshop: some methodological pitfalls.
Students from four health sciences programs (Medicine, Nursing, Occupational Therapy and Physiotherapy) participated in a two-day Sexuality Workshop and completed pre- and post-workshop questionnaires dealing with sexual attitudes, comfort, and knowledge. Eighteen months later, these students were asked to complete the same questionnaires. Not only had they sustained the gains made during the workshop, but they continued to show improvement in the three areas during this interval. However, of greater importance than the positive finding is the need to understand the range of methodological problems encountered in carrying out this type of follow-up educational inquiry and in seeking measures for improving the validity and generalizability of such research.
Education↗
A comparison of food habit and food frequency data as predictors of breast cancer in the NHANES I/NHEFS cohort.
We compared two methods of assessing dietary fat and breast cancer incidence in the first complete follow-up of the National Health Epidemiologic Follow-up Study (NHEFS) cohort. Between 1982 and 1984, 6156 women aged 32-86 y completed the NHEFS survey, which included a 93-item food frequency questionnaire (FFQ). In addition, women answered questions regarding food habits, such as choice of salad dressing, trimming fat from meat, and eating skin on poultry. In the 4 y of follow-up, these women contributed a total of 23,949 person years, during which 53 women reported a breast cancer diagnosis. The rate ratio (RR) and 95% confidence interval (CI) for each quartile of percentage of energy from fat were 1.0, 0.96 (0.5-2.1), 1.0 (0.5-2.2) and 0.98 (0.5-2.1). Thus the breast cancer rates for women in the upper three quartiles, who reported a diet with higher than 30% of energy from fat, were not different from those of women in the lowest quartile of intake (< or = 29.4% energy from fat). In contrast, the "high-fat" response to three of the four food habit questions identified women at increased risk of developing breast cancer: women who used salad dressings other than low fat had a RR and 95% CI of 1.3 (0.7-2.3), women who reported eating the skin on poultry had a RR and 95% CI of 1.7 (0.9-2.9), and women who did not use lean or extra lean ground beef had a RR and 95% CI of 2.2 (1.2-4.0). These food habit questions may be less subject to misclassification than dietary information of fat intake derived from the FFQ. Further investigation is needed to evaluate what is measured by the food habit questions.
Adult↗
The relationship between AIDS dementia complex and the presence of macrophage tropic and non-syncytium inducing isolates of human immunodeficiency virus type 1 in the cerebrospinal fluid.
We sought to determine the clinical significance of macrophage tropic and non-syncytium inducing isolates of human immunodeficiency virus type 1 (HIV-1) in the cerebrospinal fluid (CSF) of patients with and without AIDS dementia complex (ADC). HIV-1 was isolated from the CSF of 31 patients with and without ADC. The isolates were then characterised as to the degree of macrophage tropism by quantitation of p24 production and the presence of syncytium inducing (SI) or non-syncytium inducing (NSI) isolates by MT2 assay and SupT1 coculture. The degree of macrophage tropism varied according to the donor macrophage that was used except in strongly macrophage tropic isolates. Moderate and severe ADC (stage > or = 2) was associated with the presence of highly macrophage tropic isolates in the CSF (P = 0.01). The sensitivity and specificity values of a highly macrophage tropic isolate in the CSF for ADC stage > or = 2 were 82% and 66% respectively while the predictive value was 64%. Three of four asymptomatic patients with such highly macrophage tropic isolates in the CSF subsequently developed ADC after an average of 4 months. Twenty-eight isolates from the CSF and 23 from the blood were NSI regardless of the presence or absence of ADC. The predictive value of an SI isolate in the blood reflecting an SI isolate in the CSF was 37.5% while the predictive value of an NSI isolate in the blood reflecting an NSI in the CSF was 100%. These data suggest that host factors are essential in determining the degree of macrophage tropism in HIV-1 and that such tropism is important for the presence and possibly subsequent development of ADC. The CSF usually has NSI isolates regardless of the presence of ADC and irrespective of the presence of such isolates in the blood thereby suggesting that the CSF is behaving virologically as a separate compartment to the blood.
AIDS Dementia Complex↗
PCR amplification of short tandem repeat sequences allows serial studies of chimaerism/engraftment following BMT in rodents.
Animal models of bone marrow transplantation (BMT) allow evaluation of new experimental treatment strategies. One potential strategy involves the treatment of donor marrow with ultra-violet B light to allow transplantation across histocompatibility boundaries without an increase in graft rejection or graft-versus-host disease. A major requirement for a new experimental protocol, particularly if it involves manipulation of the donor marrow, is that the manipulated marrow gives rise to long-term multilineage engraftment. DNA based methodologies are now routinely used by many centres to evaluate engraftment and degree of chimaerism post-BMT in humans. We report the adaptation of this methodology to the serial study of engraftment in rodents. Conditions have been defined which allow analysis of serial tail vein samples using PCR of short tandem repeat sequences (STR-PCR). These markers have been used to evaluate the contribution of ultraviolet B treated marrow to engraftment following BMT in rodents without compromising the health of the animals under study. Chimaerism data from sequential tail vein samples and bone marrow from selected sacrificed animals showed excellent correlation, thus confirming the validity of this approach in analysing haemopoietic tissue. Thus the use of this assay may facilitate experimental studies in animal BMT.
Animals↗
Proportion of breast cancer cases in the United States explained by well-established risk factors.
BACKGROUND: Few estimates of the fraction of cases of breast cancer attributable to recognized risk factors have been published. All estimates are based on selected groups, making their generalizability to the U.S. population uncertain. PURPOSE: Our goal was to estimate the fraction of breast cancer cases in the United States attributable to well-established risk factors (i.e., later age at first birth, nulliparity, higher family income, and first-degree family history of breast cancer), using data from the first National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Follow-up Study (NHEFS), the survey and follow-up of a probability sample of the U.S. population. METHODS: From a cohort of 7508 female participants surveyed in the early 1970s, and followed up between 1982 and 1984 and again in 1987, 193 breast cancer cases were accrued for study. We calculated incidence rates, relative risks (RRs), and population attributable risks (PARs) for breast cancer risk factors and extended our results to the U.S. female population by using sample weights from the NHANES I survey. RESULTS: Our PAR estimates suggest that later age at first birth and nulliparity accounted for a large fraction of U.S. breast cancer cases, 29.5% (95% confidence interval [CI] = 5.6%-53.3%); higher income contributed 18.9% (95% CI = -4.3% to 42.1%), and family history of breast cancer accounted for 9.1% (95% CI = 3.0%-15.2%). Taken together, these well-established risk factors accounted for approximately 47% (95% CI = 17%-77%) of breast cancer cases in the NHEFS cohort and about 41% (95% CI = 2%-80%) in the U.S. population. CONCLUSIONS: The RRs for most of these risk factors were modest, but their prevalence as a group was high, leading to estimates that suggest that a substantial proportion of breast cancer cases in the United States are explained by well-established risk factors. IMPLICATIONS: Elucidation of the determinants underlying recognized factors and study of other factors that may confer risk or protection are needed in efforts to advance understanding of breast cancer etiology and to aid in devising strategies for prevention.
Adult↗
Mammographic features and breast cancer risk: effects with time, age, and menopause status.
BACKGROUND: Mammographic images from women with a high proportion of epithelial and stromal breast tissues are described as showing high-density parenchymal patterns. Most past studies that noted an increase in breast cancer risk associated with mammographic parenchymal patterns showing high density either 1) lacked information on other breast cancer risk factors, 2) were too small, or 3) included insufficient follow-up time to adequately resolve persisting doubts whether mammographic features are "independent" measures of breast cancer risk and not a detection artifact. PURPOSE: The purpose of this study was twofold: 1) to evaluate the associations between mammographic features and other breast cancer risk factors and 2) to assess effects of mammographic features on breast cancer risk by time, age, and menopause status. METHODS: To address these questions, we analyzed detailed information from a large, nested case-control study with 16 years of follow-up. This study used information from both screening and follow-up phases of the Breast Cancer Detection Demonstration Project, a nationwide program that offered annual breast cancer screening for more than 280,000 women from 1973 to 1980. Mammographic features were assessed from the base-line screening mammographic examination for 1880 incident case subjects and 2152 control subjects. Control subjects were randomly selected from women of the same age and race as each case subject. Control subjects attended the same screening center as the case subject and were free of breast cancer at the case subject's date of diagnosis. Odds ratios (ORs) with 95% confidence intervals (CIs) provided estimates of the relative risk of breast cancer. RESULTS: Mammographic features were associated with known breast cancer risk factors. However, the high-density parenchymal pattern effects were independent of family history, age at first birth, alcohol consumption, and benign breast disease. The increase risk for women with Wolfe's two high-density parenchymal patterns, P2 (OR = 3.2; 95% CI = 2.5-4.0) and Dy (OR = 2.9; 95% CI = 2.2-3.9), was explained primarily by measured percent of the breast with dense mammographic appearance. Compared with women with no visible breast density, women who had a breast density of 75% or greater had an almost fivefold increased risk of breast cancer (95% CI = 3.6-7.1). These effects persisted for 10 or more years and were noted for both premenopausal and postmenopausal women of all ages. CONCLUSIONS: Of the breast cancer risk factors assessed in the participants, high-density mammographic parenchymal patterns, as measured by the proportion of breast area composed of epithelial and stromal tissue, had the greatest impact on breast cancer risk. Of the breast cancers in this study, 28% were attributable to having 50% or greater breast density.
Age Factors↗
Lymphoid enhancer factor 1 directs hair follicle patterning and epithelial cell fate.
T cell-specific transcription factor (TCF-1) and lymphoid enhancer factor 1 (LEF-1) have been implicated exclusively in the regulation of T cell-specific genes. The only adult tissue other than thymus known to express these factors is spleen and lymph node, which contain low levels of LEF-1 and no TCF-1. We noticed that genes involved in hair-specific gene expression possess LEF-1/TCF-1 consensus motifs located in similar positions relative to their TATA box. We show that of the two factors only LEF-1 is expressed in hair follicles; it can be cloned in both splice forms from human skin keratinocytes and it can bind to these sites in the hair promoters. We show that LEF-1 mRNA is present in pluripotent ectoderm, and it is up-regulated in a highly restricted pattern just before the formation of underlying mesenchymal condensates and commitment of overlying ectodermal cells to invaginate and become hair follicles. New waves of ectodermal LEF-1 spots appear concomitant with new waves of follicle morphogenesis. To test whether LEF-1 patterning might be functionally important for hair patterning and morphogenesis, we used transgenic technology to alter the patterning and timing of LEF-1 over the surface ectoderm. Striking abnormalities arose in the positioning and orientation of hair follicles, leaving a marked disruption of this normally uniform patterning. This provides the first direct evidence that ectodermal cues are critical in establishing these developmental processes, which at later stages are known to be influenced by underlying mesenchyme. Remarkably, elevated LEF-1 in the lip furrow epithelium of developing transgenic animals triggered these cells to invaginate, sometimes leading to the inappropriate adoption of hair follicle and tooth cell fates. Collectively, our findings demonstrate that ectodermal expression of LEF-1 plays a central role in gene expression, pattern formation, and other developmental processes involving epithelial-mesenchymal associations.
Alternative Splicing↗
More effective and less expensive: lessons from five studies examining community approaches to care.
Does the nature of community health services used by chronically ill clients and their caregivers have an impact on utilization of services, expenditure and well-being outcomes? A series of five studies, (four historic cohort and one randomized trial) examined clients suffering from a variety of chronic conditions in a number of community settings in different regions of Southern Ontario. Study sample composition and size varied. Each study was designed to quantify the well-being outcomes, and expenditure associated with different community approaches is covered under a nation-wide system of health insurance plans. As a collective, these studies represent increasing methodological rigor. Multiple-perspective client well-being outcome measures were used. Caregiver burden was also analyzed. A common approach to quantification and evaluation of expenditure for service consumption was applied across all five studies. The nature of community health services (proactive versus reactive approaches to care) was found to have direct and measurable impact on total expenditure for health service utilization and client well-being outcomes. A recurring pattern of lower expenditure for community health service utilization and equal or better client outcomes was associated with well-integrated proactive services when compared with individual fragmented, reactive approaches to care. The main lesson emerging from examining the five studies on approaches to community care is that it is as, or more, effective and less expensive to offer complete proactive health care services to chronically ill people in the early stages of their illness than to provide services on demand in a piecemeal manner.
Caregivers↗