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Biomedical subjects

C E Lewis

Publications and source records attributed to C E Lewis.

At least 37 records · Page 2Linked to original sources
PubMed2002

Oral contraceptives and bone mineral density in white and black women in CARDIA. Coronary Risk Development in Young Adults.

To examine whether exposure to oral contraceptives (OCs) is associated with bone mineral density (BMD) in young women, we studied, cross-sectionally and longitudinally, 216 white and 260 black women enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Spine, hip and whole body BMDs were measured by dual-energy X-ray absorptiometry (DXA) when the women were aged 25-37 years, and whole body BMD was remeasured in 369 of the women 3 years later. A comprehensive history of OC use, including dose of ethinyl estradiol (estrogen) and duration of use, was determined from an interviewer-administered questionnaire. After adjustment for other relevant variables, we found that cumulative estrogen from OCs (mg) explained 4.0% of the variation in spine BMD ( p = 0.024) among white women, but did not explain any of the variance in BMD in black women. Cumulative OC estrogen was associated with a decreased risk for low bone density (lowest quartile) at the spine, hip and whole body in white women. The odds ratios (95% CIs) comparing women in the highest quartile of cumulative OC estrogen with those in the lowest quartile were, at the spine: 0.08 (0.02, 0.46); at the hip: 0.23 (0.06, 0.87); and at the whole body: 0.37 (0.11, 1.26). OC exposure was not related to low bone density in black women. OCs did not predict longitudinal changes in whole body BMD in either race. These results suggest that exposure to the estrogen from OCs during the premenopausal years may have a small beneficial effect on the skeleton in white women. Benefit is proportional to the cumulative estrogen exposure, suggesting that previous cross-sectional studies that considered OC use as a dichotomous variable may have lacked the power to detect an association.

Adult↗
PubMed2002

The role of cell-cell interactions in a two-phase model for avascular tumour growth.

A two-phase model is presented to describe avascular tumour growth. Conservation of mass equations, including oxygen-dependent cell growth and death terms, are coupled with equations of momentum conservation. The cellular phase behaves as a viscous liquid, while the viscosity of the extracellular water manifests itself as an interphase drag. It is assumed that the cells become mechanically stressed if they are too densely packed and that the tumour will try to increase its volume in order to relieve such stress. By contrast, the overlapping filopodia of sparsely populated cells create short-range attractive effects. Finally, oxygen is consumed by the cells as it diffuses through the tumour. The resulting system of equations are reduced to three, which describe the evolution of the tumour cell volume fraction, the cell speed and the oxygen tension. Numerical simulations indicate that the tumour either evolves to a travelling wave profile, in which it expands at a constant rate, or it settles to a steady state, in which the net rates of cell proliferation and death balance. The impact of varying key model parameters such as cellular viscosity, interphase drag, and cellular tension are discussed. For example, tumours consisting of well-differentiated (i.e. viscous) cells are shown to grow more slowly than those consisting of poorly-differentiated (i.e. less viscous) cells. Analytical results for the case of oxygen-independent growth are also presented, and the effects of varying the key parameters determined (the results are in line with the numerical simulations of the full problem). The key results and their biological implications are then summarised and future model refinements discussed.

Animals↗
PubMed2002

Macrophages in gene therapy: cellular delivery vehicles and in vivo targets.

The appearance and activation of macrophages are thought to be rapid events in the development of many pathological lesions, including malignant tumors, atherosclerotic plaques, and arthritic joints. This has prompted recent attempts to use macrophages as novel cellular vehicles for gene therapy, in which macrophages are genetically modified ex vivo and then reintroduced into the body with the hope that a proportion will then home to the diseased site. Here, we critically review the efficacy of various gene transfer methods (viral, bacterial, protozoan, and various chemical and physical methods) in transfecting macrophages in vitro, and the results obtained when transfected macrophages are used as gene delivery vehicles. Finally, we discuss the use of various viral and nonviral methods to transfer genes to macrophages in vivo. As will be seen, definitive evidence for the use of macrophages as gene transfer vehicles has yet to be provided and awaits detailed trafficking studies in vivo. Moreover, although methods for transfecting macrophages have improved considerably in efficiency in recent years, targeting of gene transfer specifically to macrophages in vivo remains a problem. However, possible solutions to this include placing transgenes under the control of macrophage-specific promoters to limit expression to macrophages or stably transfecting CD34(+) precursors of monocytes/macrophages and then differentiating these cells into monocytes/macrophages ex vivo. The latter approach could conceivably lead to the bone marrow precursor cells of patients with inherited genetic disorders being permanently fortified or even replaced with genetically modified cells.

Adenoviridae↗
PubMed2001

Expression of hypoxia-inducible factor 1alpha by macrophages in the rheumatoid synovium: implications for targeting of therapeutic genes to the inflamed joint.

OBJECTIVE: To determine if the rheumatoid synovium is a suitable target for hypoxia-regulated gene therapy. METHODS: Sequential sections of wax-embedded synovial membrane samples were obtained from 10 patients with rheumatoid arthritis (RA), 10 with primary osteoarthritis (OA), and from 6 healthy controls. Membrane sections from each patient were immunostained for hypoxia-inducible factor 1alpha (HIF-1alpha) and CD68 (a pan-macrophage marker). RESULTS: HIF-1alpha was expressed abundantly by macrophages in most rheumatoid synovia, predominantly close to the intimal layer but also in the subintimal zone. There was markedly lower expression of HIF-1alpha in OA synovia, and it was absent from all of the healthy synovia. CONCLUSION: These observations indicate that macrophages transduced with a therapeutic gene under the control of a hypoxia-inducible promoter could be administered to RA patients systemically. Migration of these cells to synovial tissue would result in the transgene being switched on in diseased joints but not in healthy tissues.

Adult↗
PubMed2001

Estimating the selective advantage of mutant p53 tumour cells to repeated rounds of hypoxia.

The tumour suppressor gene, p53, plays an important role in tumour development. Under low levels of oxygen (hypoxia), cells expressing wild-type p53 undergo programmed cell death (apoptosis), whereas cells expressing mutations in the p53 gene may survive and express angiogenic growth factors that stimulate tumour vascularization. Given that cells expressing mutations in the p53 gene have been observed in many forms of human tumour, it is important to understand how both wild-type and mutant cells react to hypoxic conditions. In this paper a mathematical model is presented to investigate the effects of alternating periods of hypoxia and normoxia (normal oxygen levels) on a population of wild-type and mutant p53 tumour cells. The model consists of three coupled ordinary differential equations that describe the densities of the two cell types and the oxygen concentration and, as such, may describe the growth of avascular tumours in vitro and/or in vivo. Numerical and analytical techniques are used to determine how changes in the system parameters influence the time at which mutant cells become dominant within the population. A feedback mechanism, which switches off the oxygen supply when the total cell density exceeds a threshold value, is introduced into the model to investigate the impact that vessel collapse (and the associated hypoxia) has on the time at which the mutant cells become dominant within vascular tumours growing in vivo. Using the model we can predict the time it takes for a subpopulation of mutant p53 tumour cells to become the dominant population within either an avascular tumour or a localized region of a vascular tumour. Based on independent experimental results, our model suggests that the mutant population becomes dominant more quickly in vivo than in vitro (12 days vs 17 days).

Apoptosis↗
PubMed2001

Phylogenetic utility of the nuclear gene malate synthase in the palm family (Arecaceae).

There is currently a shortage of DNA regions known to be useful for phylogenetic research in palms (Arecaceae). We report the development and use of primers for amplifying and sequencing regions of the nuclear gene malate synthase. In palms the gene appears to be single-copy, with exon regions that are phylogenetically informative within the family. We constructed a phylogeny of 45 palms and five outgroup taxa using 428 bp of malate synthase exon regions. We found that some major clades within the family were recovered, but there was a lack of resolution among the genera in subfamilies Arecoideae, Ceroxyloideae, Coryphoideae, and Phytelephantoideae. In a second analysis, malate synthase exon regions totaling 1002 bp were sequenced for 16 palms and two outgroup taxa. There was increased bootstrap support for some groups and for the placement of the monotypic genus Nypa as sister to the rest of the family. A comparison with data sets from noncoding regions of the chloroplast genome indicates that malate synthase sequences are more variable and potentially contain more phylogenetic information. We found no evidence of multiple copies of the malate synthase gene in palm genomes.

Cell Nucleus↗
PubMed2001

Comparison of three in vitro human 'angiogenesis' assays with capillaries formed in vivo.

Angiogenesis assays are an important tool for studying both the mechanisms of angiogenesis and the potential development of therapeutic strategies to modulate neovascularisation. In vivo angiogenesis assays are considered to be the most informative of these but are often expensive, time-consuming and require specialist training to perform. In vitro assays tend to be more rapid, less expensive and easier to interpret. In vitro angiogenesis assays operate on the principle that endothelial cells form tubule-like structures when cultured on a supportive matrix. Assays involving a matrix derived from murine tumours, Matrigel (or a growth factor reduced form of this), are now the most common in vitro tubule formation assays. However, another tubule formation assay has recently been developed in which endothelial cells are co-cultured with fibroblasts. Here, we have used quantitative image analysis to compare the morphological features of tubules formed in the Matrigel assay and this new 'Co-culture' assay, with those of capillaries formed in a microvascular bed in vivo. Tubules formed in standard and growth factor reduced Matrigel assays were short and relatively homogeneous, whereas those formed in the Co-culture assay were significantly more heterogeneous, consisting of both short and long interconnecting tubules that more closely resembled capillaries than Matrigel tubules. Moreover, cells on Matrigel, and to a lesser extent growth factor reduced (GFR) Matrigel, often clumped into large cell aggregates, a feature rarely seen in the Co-culture assay. In addition, we demonstrate that Matrigel stimulates tubule formation by various non-endothelial cell types, suggesting that tubule formation by endothelial cells may not represent true differentiation of this cell type. In summary, the morphology of tubules in the Co-culture assay appears more representative of capillary formation in vivo, than the endothelial cell changes that occur in either form of Matrigel assay.

Animals↗
PubMed2001

Fibrin fragment E stimulates the proliferation, migration and differentiation of human microvascular endothelial cells in vitro.

Various factors involved in haemostasis also regulate the development of new blood vessels by a process called angiogenesis. Enzymatic cleavage of fibrin yields a variety of fibrin degradation products, particularly in areas of intense angiogenesis such as in healing wounds and active atherosclerotic plaques. One of these, fibrin fragment E (FnE), is a potent angiogenic factor in the chick chorioallantoic membrane assay of angiogenesis. Here, we extend these studies to show that FnE stimulates the proliferation, migration and differentiation of human dermal microvascular endothelial cells (HuDMECs) in vitro, both in the absence and presence of such additional endothelial growth factors as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). We also show that these stimulatory effects occur at concentrations of the protein known to be present in angiogenic tissues in vivo. FnE enhanced the angiogenic effects of VEGF or bFGF, indicating a possible synergy between the signalling pathways used by these three angiogenic factors.

Adult↗
PubMed2001

Ten-year changes in smoking among young adults: are racial differences explained by socioeconomic factors in the CARDIA study?

OBJECTIVES: This study investigated whether socioeconomic factors explain racial/ethnic differences in regular smoking initiation and cessation. METHODS: Data were derived from the CARDIA study, a cohort of 5115 healthy adults aged 18 to 30 years at baseline (1985-1986) and recruited from the populations of 4 US cities. Respondents were followed over 10 years. RESULTS: Among 3950 respondents reexamined in 1995-1996, 20% of Whites and 33% of African Americans were smokers, as compared with 25% and 32%, respectively, in 1985-1986. On average, African Americans were of lower socioeconomic status. Ten-year regular smoking initiation rates for African American women, White women, African American men, and White men were 7.1%, 3.5%, 13.2%, and 5.1%, respectively, and the corresponding cessation rates were 25%, 35.1%, 19.2%, and 31.3%. After adjustment for socioeconomic factors, most 95% confidence intervals of the odds ratios for regular smoking initiation and cessation in African Americans vs Whites included 1. CONCLUSIONS: Less beneficial 10-year changes in smoking were observed in African Americans, but socioeconomic factors explained most of the racial disparity.

Adolescent↗
PubMed2001

Microenvironmental influence on macrophage regulation of angiogenesis in wounds and malignant tumors.

Angiogenesis is the development of blood vessels from an existing vasculature. This process is fundamental to both physiological wound healing and the growth of malignant tumors, as it restores or creates a blood supply to growing tissue. In both cases, the release of angiogenic molecules by macrophages recruited to the wound or tumor site is central to the formation of these neovessels. Reduced vascular perfusion in tissues generates tissue ischemia and a marked reduction in local levels of oxygen (hypoxia) and glucose. Cells adapt by switching to anaerobic metabolic pathways, with a concomitant increase in lactate production and reduction in extracellular pH. In tumors, these microenvironmental "stress" factors stimulate tumor cells to secrete a wide array of proangiogenic cytokines and enzymes, promoting the re-establishment of a local vascular supply. Here we review the evidence that these stress factors, in particular hypoxia and high lactate levels, stimulate macrophages to perform similar proangiogenic functions in both tumors and wounds. The resolution of wounds results in restoration of tissue integrity and perfusion, and macrophage presence is reduced to preinjury levels. However, in tumors a high number of macrophages persists and might contribute to the ongoing growth, neovascularization, and metastasis of malignant cells.

Animals↗
PubMed2000

A genome scan for renal function among hypertensives: the HyperGEN study.

Decreased renal function is often a complication of hypertension. Although it has been suggested that the response of the kidney to hypertension has an underlying genetic component, there is limited information suggesting that specific genetic regions or candidate genes contribute to the variability in creatinine clearance, a commonly used measure of kidney function. As part of the Hypertension Genetic Epidemiology Network (HyperGEN) study, creatinine clearance measurements were assessed in a large biracial sample of hypertensive siblings (466 African American subjects and 634 white subjects in 215 and 265 sibships, respectively). All participants were hypertensive before the age of 60 years, and the mean age of the siblings was 52 years among the African American subjects and 61 years among the white subjects. Two residual models were created for creatinine clearance: a minimally adjusted model (which included age and age(2)) and a fully adjusted model (which included age, age(2), lean body mass, pulse rate, pulse pressure, hormone-replacement therapy, educational status, and physical activity). Standardized residuals were calculated separately for men and women in both racial groups. The heritability of the residual creatinine clearance was 17% and 18% among the African American and white subjects, respectively. We conducted multipoint variance components linkage analysis using GENEHUNTER2 and 387 anonymous markers (Cooperative Human Linkage Center screening set 8). The best evidence for linkage in African American subjects was found on chromosome 3 (LOD = 3.61 at 214.6 cM, 3q27) with the fully adjusted model, and the best evidence in white subjects was found on chromosome 3 (LOD = 3.36 at 115.1 cM) with the minimally adjusted model. Positional candidate genes that are contained in and around the region on chromosome 3 (214.6 cM) that may contribute to renal function include enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase (EHHADH) and apolipoprotein D (ApoD). These findings suggest there may be genetic regions related to the variability of creatinine clearance among hypertensive individuals.

Black or African American↗
PubMed2000

Fibrinogen E-fragment inhibits the migration and tubule formation of human dermal microvascular endothelial cells in vitro.

Angiogenesis, the development of new blood vessels from an existing vascular bed, is essential for the growth and spread of malignant tumors. Several endogenous angiogenesis inhibitors have been discovered and shown to suppress endothelial cell function in vitro and tumor growth in vivo. Several of these are proteolytic fragments of larger, endogenous proteins. Here we show that a Mr 50,000 polypeptide derived from the plasmin cleavage of fibrinogen, fibrinogen E-fragment, inhibits endothelial cell migration and tubule formation induced by both proangiogenic growth factors, vascular endothelial growth factor and basic fibroblast growth factor, in vitro.

Adult↗
PubMed2000

Weight gain continues in the 1990s: 10-year trends in weight and overweight from the CARDIA study. Coronary Artery Risk Development in Young Adults.

The prevalence of obesity increased in the United States through the 1980s. The authors examined 10-year aging and secular (time-related) trends in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort for indications of whether these trends are continuing and for ages of peak weight gain in young adults. CARDIA is a population-based, prospective study of 5,115 African-American and White men and women aged 18-30 years at baseline. Body weight and overweight prevalence were measured at five time points from 1985-1986 to 1995-1996. Linear, mixed-model regression was used to partition weight gain into that due to secular trends and that due to aging. Prevalence of overweight (body mass index (BMI) > or = 25.0 kg/m2) increased markedly, and prevalence of severe obesity (BMI > or = 40.0 kg/m2) doubled in all race-sex groups. Each race-sex group experienced significant secular weight gains, ranging from 0.96 kg/year (95% confidence interval: 79, 1.13) in African-American women to 0.55 kg/year (95% confidence interval: 0.41, 0.69) in White women. Significant secular gains were present during each follow-up period. Each race-sex group also experienced significant weight increases related to aging during their early to midtwenties. Secular trends for weight gain are continuing in CARDIA, but the magnitude of weight gain differed among the four race-sex groups.

Adolescent↗
PubMed2000

Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer.

Angiogenesis is esential for tumour growth and metastasis. Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and is an important component of the angiogenic stimulus in a range of human neoplasias. In addition to its mitogenic activities, VEGF has also been found to stimulate migration in macrophages via the flt-1 VEGF receptor. It has previously been shown that increased focal tumour macrophage infiltration is associated with increased angiogenesis and worsened relapse-free and overall survival in breast cancer. Macrophages are able to stimulate angiogenesis by their production of a range of factors including VEGF, tumour necrosis factor-alpha (TNF-alpha), and thymidine phosphorylase (TP). Thus, in breast cancer, VEGF could have a dual role in the regulation of angiogenesis, by direct mitogenic stimulation of endothelial cells, and also indirectly by attracting macrophages into avascular tumours. The purpose of this study was to localize VEGF protein in a series of 96 consecutive primary breast carcinomas and to determine its relationship to focal macrophage infiltration (macrophage index). These two variables were also compared with the pathological features of the tumours, as well as oestrogen receptor (ER), epidermal growth factor receptor (EGFR), microvessel density, macrophage index, and survival. An inverse relationship (p=0.0006) was noted between VEGF and EGFR, with high VEGF expression correlating with low EGFR levels. In the EGFR-negative group of cases (n=56), positive associations were observed between VEGF expression and macrophage index (p=0.005), ER (p=0.05), p53 (p=0. 006), tumour grade (p=0.02), and tumour necrosis (p=0.03). Macrophage counts were higher in EGFR-positive tumours (p=0.0006) and no associations were found between VEGF expression and increased microvessel density. These results show that in breast cancers there are two types of macrophage infiltrates, one associated with the presence of EGFR and low VEGF expression in tumours and the other with high VEGF expression in EGFR-negative tumours. VEGF expression may be an important factor in the recruitment of tumour-associated macrophages into breast carcinomas and may thus have an additional, indirect, pathway of angiogenic stimulation in this type of tumour.

Adult↗
PubMed2000

Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas.

Angiogenesis is essential to the growth and metastasis of solid tumours. Vascular endothelial growth factor (VEGF) is a potent pro-angiogenic cytokine that is overexpressed in malignant tumours such as invasive carcinoma of the breast. The low oxygen tensions (hypoxia) present in these tumours are known to up-regulate the expression of VEGF by tumour cells. Human macrophages also respond to hypoxia by increasing their release of VEGF in vitro, although the effect of hypoxia on VEGF expression by macrophages in vivo has yet to be demonstrated. The present study compared the expression of VEGF by macrophages in areas of low and high vascularity in 24 invasive breast carcinomas (12 lobular, 12 ductal). The cellular distributions of VEGF protein, CD31 (vessels), and CD68 (macrophages) were compared in sequential sections for each tumour. In ten tumours, both tumour cells and macrophages were immunoreactive for VEGF protein. Use of non-isotopic in situ hybridization to localize VEGF mRNA showed that these cell types also expressed VEGF mRNA. No significant differences in the cellular distribution of VEGF protein were found between lobular and ductal carcinomas. In all tumours, macrophages accumulated in higher numbers in poorly vascularized than in highly vascularized areas. In VEGF-positive tumours, macrophages were immunoreactive for VEGF only in avascular areas where tumour cells also expressed VEGF. This suggests that VEGF expression by these two cell types may be regulated by the same microenvironmental stimuli in breast carcinomas. In addition, significantly more macrophages were present in poorly vascularized areas of VEGF-positive than VEGF-negative tumours. This suggests that VEGF may exert a chemotactic action on macrophages in vivo and guide their migration into avascular tumour sites.

Adult↗
PubMed2000

Overview of women's decision making regarding elective hysterectomy, oophorectomy, and hormone replacement therapy.

Over 600,000 hysterectomies are performed each year in the United States, the majority of which are to improve quality of life for perimenopausal women. Hysterectomy rates for common conditions differ between African American and white women, and African American women undergo surgery at a younger age for most diagnoses. Many hysterectomies are accompanied by elective oophorectomy, and hormone replacement therapy (HRT) is commonly used, especially among women experiencing surgical menopause, despite questions about its long-term benefits and risks. Despite the high rates of hysterectomy in the United States, little is known about how women make decisions regarding this surgery and, in particular, how ethnic and cultural factors may influence these decisions. This article provides a review of what is currently known about the epidemiology of hysterectomy, oophorectomy, and HRT use and identifies gaps in knowledge about women's decision making, with a special focus on ethnic variations and cultural influences, issues addressed by the Ethnicity, Needs, and Decisions of Women (ENDOW) project.

Cultural Characteristics↗