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M C Rees

Publications and source records attributed to M C Rees.

At least 19 recordsLinked to original sources
PubMed2006

Comparison of Bayer Advia Centaur immunoassay results obtained on samples collected in four different Becton Dickinson Vacutainer tubes.

BACKGROUND: Medicines and Healthcare products Regulatory Agency's (MHRA's) Medical Device Alert MDA/2004/048 described bias in some endocrine test results obtained on a few immunoassay platforms, particularly the Bayer Advia Centaur instrument, when using blood specimens collected into Becton Dickinson (BD) Vacutainer SSTII Advance tubes. As users of BD tubes and the Advia Centaur instrument, we addressed our concerns about the quality of the results that we had previously reported by undertaking an independent study. METHOD: We compared the results of 15 immunoassays performed on Bayer Advia Centaur using blood specimens collected into four different BD Vacutainer tubes (plain, old and newly released BD SSTII Advance, and BD PSTII). RESULTS: Compared with plain tubes, old SSTII Advance tube results showed no bias for testosterone, CA15-3, follicle-stimulating hormone and folate assays, but gave a positive bias for cortisol and a negative bias for vitamin-B12. Compared with plain tubes, BD PSTII tubes gave no significant bias for thyroid function tests, prolactin, parathyroid hormone, and CA125, but gave a negative bias for steroid assays, and a positive bias for gonadotrophins. The results obtained using new BD SSTII Advance tubes were generally comparable with those on plain tubes. CONCLUSIONS: Only for cortisol did our findings support the bias described by MHRA. Based on our results, apart from vitamin-B12 and possibly cortisol, there may have been no significant influence on clinical decisions as a result of using the old BD SSTII Advance specimen tubes. New BD SSTII Advance tubes and plain tubes give generally comparable results. BD PSTII tubes should not be used for steroid hormone measurements on the Bayer Advia Centaur instrument.

Adult↗
PubMed2001

Adrenomedullin inhibits hypoxic cell death by upregulation of Bcl-2 in endometrial cancer cells: a possible promotion mechanism for tumour growth.

Regions of hypoxia are a common feature of solid tumours. When tumour cells are exposed to hypoxic stress, transcription of a battery of genes is initiated. The angiogenic factor adrenomedullin (ADM) is a hypoxia regulated gene. ADM is thought to act through the G protein-coupled receptor calcitonin receptor-like receptor (CRLR), with specificity being conferred by the receptor associated modifying protein 2 (RAMP2). Here we report for the first time that ADM treated or stably transfected Ishikawa cells overexpressing ADM show increased resistance to hypoxia induced apoptosis. These cells also show an upregulation of the oncoprotein Bcl-2, which is protective against hypoxic cell death when transiently transfected into Ishikawa cells. Since Ishikawa cells express the putative ADM-receptor CRLR-RAMP2 the production and secretion of ADM with the consecutive upregulation of Bcl-2 could establish an autocrine/paracrine mechanism rescuing malignant cells from hypoxic cell death. These results, taken together with our previous findings that ADM is an angiogenic factor which is upregulated by the nonsteroidal antiestrogen tamoxifen (TAM) in endometrial cells, implicate this peptide as a promoter of tumour growth and a possible target for anticancer strategies.

Adrenomedullin↗
PubMed2001

Differential and cell-specific expression of calcitonin receptor-like receptor and receptor activity modifying proteins in the human uterus.

The calcitonin receptor-like receptor (CRLR) can function as a receptor for either calcitonin gene-related peptide (CGRP) or adrenomedullin (AM), depending upon co-expression with members of a novel family of receptor activity-modifying proteins (RAMP). RAMP1 presents the CRLR at the cell surface as a CGRP/AM receptor. RAMP2- and RAMP3-transported CRLR receptors act as AM-specific receptors. However, it is still unknown if this signalling system operates in vivo. Of particular interest is the uterus, where both peptides and their binding sites are known to be present and where both mitogenic and vasodilatory responses to AM and CGRP have been demonstrated. In this study, we examined whether CRLR and RAMP are co-expressed in the same populations of cells in human uterine tissue. Analysis by in-situ hybridization and immunocytochemistry revealed a heterogeneous and cell type-specific distribution of components of this AM/CGRP signalling system. Adrenomedullin mRNA was expressed and evenly distributed across all cell types. CRLR mRNA was predominantly found in blood vessels. RAMP1 expression was specific to myometrial myocytes and vascular smooth muscle cells in uterine arteries. RAMP2 and RAMP3 mRNA were not detectable by in-situ hybridization. The pattern of differential and cell-specific expression of CRLR and RAMP suggests the involvement of CRLR/RAMP1 in the processes of vasodilation, smooth muscle relaxation and angiogenesis in response to AM and CGRP in the human uterus, but also indicates that other receptors may be implicated.

Adrenomedullin↗
PubMed2000

Oestrogen and progestogen hormone replacement therapy for peri-menopausal and post-menopausal women: weight and body fat distribution.

BACKGROUND: Hormone replacement therapy (HRT) is commonly prescribed to treat menopausal symptoms and to prevent post-menopausal bone loss. However, many women are concerned about hormonal replacement therapy because they believe that such treatment will result in weight gain. The effect of HRT on weight and body fat distribution has not yet been examined in systematic reviews. It is an important topic since many women decline oestrogen therapy due to their concerns about resultant weight gain, and thus forego its potential therapeutic benefits. OBJECTIVES: To evaluate the effect of unopposed oestrogen or combined oestrogen and progestogen hormone replacement therapy (HRT) upon the weight and body fat distribution of perimenopausal and postmenopausal women. SEARCH STRATEGY: The search strategy of the Menstrual Disorders and Subfertility Group was used for the identification of randomised controlled trials (RCTs). Computerised searches of MEDLINE, EMBASE, Current Contents, Biological Abstracts and CINAHL were performed. Attempts were made to identify trials from citation lists of review articles and relevant papers already obtained. In most cases, first authors of each eligible trial were contacted for additional information. All those trials that had been located as at August 1998 were examined for eligibility. SELECTION CRITERIA: All randomised, placebo or no treatment controlled trials that detailed the effect of HRT on weight or body fat distribution, including studies where HRT was combined with other therapy such as diet, supplements or exercise. Studies were eligible for consideration even though the main focus of the trial may have been on another aspect of HRT. Previous HRT use should have ceased at least one month (in the case of patches, cream or gel) or three months (for oral preparations or subcutaneous pellets) before commencement of the study. DATA COLLECTION AND ANALYSIS: Twenty two RCTs were identified that fulfilled the inclusion criteria for this review. The results of one trial were not available in a form that allowed it to be included in the meta-analysis; however, it has been included in the text of the review for discussion. Twenty four RCTs are awaiting assessment pending additional information from first authors. Two reviewers extracted the data independently, and the weighted mean differences for continuous outcomes were estimated from the data. Results for unopposed oestrogen and combined oestrogen were analysed separately, and the effect of each treatment regimen on body weight, BMI, waist-hip ratio, fat mass and skinfold measurement was examined where available. The effect of differing dosage levels on these parameters was also examined. MAIN RESULTS: Outcomes were evaluated separately for unopposed oestrogen and oestrogen/progestogen regimens. Statistical analysis was performed using the weighted mean difference for continuous outcomes as recommended by the Cochrane Menstrual Disorders and Subfertility Group. No statistically significant difference was found in mean weight gain between those using unopposed oestrogen and non-HRT users (0.66 kg, 95% CI -0.62, 1.93). No significant difference was found in mean weight gain between those using oestrogen/progestogen therapy and non-HRT users (-0.47 kg, 95% CI -1.63, 0.69). Insufficient data exist to enable meta-analysis of the effect of unopposed oestrogen on BMI. The reviewers found no statistically significant difference in mean BMI increase between those using oestrogen/progestogen and non-HRT users (-0.50, 95% CI -1.06, 0.06). Insufficient data exist to enable meta-analysis of the effect of HRT on waist-hip ratio, fat mass or skinfold thickness. REVIEWER'S CONCLUSIONS: There is evidence of no effect of unopposed oestrogen or combined oestrogen on body weight, indicating that these regimens do not cause extra weight gain in addition to that normally gained at menopause. (ABSTRACT TRUNCATED)

Body Mass Index↗
PubMed2000

Adrenomedullin is an autocrine regulator of endothelial growth in human endometrium.

Human endometrium is a mucosa served by a microvascular blood supply that involves benign angiogenesis under the control of ovarian steroids throughout reproductive life. Adrenomedullin is a multifunctional 52-amino acid peptide involved in numerous physiological and pathological processes, including angiogenesis, growth regulation, differentiation, vasodilation and smooth muscle relaxation. We have previously shown that adrenomedullin is present in the human uterus. To investigate further the role of adrenomedullin in human endometrial angiogenesis, a method for the isolation and culture of non-pregnant endometrial endothelium was developed. Enzymatic dispersion and 'Percoll' gradient centrifugation, followed by positive selection using Ulex europaeus agglutinin-coated immunomagnetic beads, yielded pure isolates of endothelium. The cells formed a typical 'cobblestone' monolayer within 5-7 days and expressed the classic endothelial markers, CD31 and von Willebrand factor. The presence of adrenomedullin immunoreactivity in endometrial endothelial cells was shown by immunohistochemistry both in vitro and in vivo. Adrenomedullin promotes growth of endothelial cells as measured by [methyl-(3)H] thymidine uptake. Adrenomedullin also induced cyclic AMP in endometrial endothelial cells. These results demonstrate, for the first time, that adrenomedullin is an autocrine growth factor for human endometrial endothelial cells and is thus involved in endometrial angiogenesis.

Adrenomedullin↗
PubMed2000

Steroids and the endometrium.

Steroids are commonly employed in current clinical practice. The benefits of steroids in hormone replacement therapy, contraception and prevention or treatment of breast cancer are limited by their side effects arising from disorders in endometrial function. These side effects are complex and enclose bleeding problems and endometrial proliferation during hormone replacement therapy and antioestrogen treatment or menstrual disturbances during oral contraception. Numerous reports have identified gene targets influenced by steroids and have implicated these products as contributors to endometrial physiology or pathology. The expression of estrogen and progesterone receptors is regulated by steroids. The new estrogen receptor (ER) subtype ERbeta with different functional characteristics from ERalpha was recently described in endometrium. In addition, there is now increasing evidence that the functionally distinct progesterone receptor (PR) isoforms A and B are differentially expressed in this tissue. The relative proportions of these steroid receptors and their interaction determine the expression of specific genes upon steroidal stimulation. Steroids induce endometrial expression of various growth and angiogenic factors. Dysregulations of this steroid modulated expression is believed to be involved in the pathogenesis of many endometrial diseases. Irregular bleeding induced by steroidal contraception, for example, is thought to involve aberrant endometrial vascular development and expression of angiogenic growth factors. The antioestrogen tamoxifen induces growth factors like vascular endothelial growth factor and adrenomedullin which may be key mediators of endometrial neoplastic effects. This review describes recent advances regarding the mechanism of action of steroids on endometrium. The expression of oestrogen and progesterone receptors as well as steroid hormone dependent growth factors and angiogenic modulators are going to be discussed.

Animals↗
PubMed2000

Expression of the hypoxically regulated angiogenic factor adrenomedullin correlates with uterine leiomyoma vascular density.

Uterine leiomyomas are the most prevalent benign tumor type in women of reproductive age and are one of the most common indications for hysterectomy. The expression of five angiogenic factors, adrenomedullin (ADM), vascular endothelial growth factor (VEGF), acidic fibroblast growth factor, basic fibroblast growth factor, and platelet-derived endothelial cell growth factor/thymidine phosphorylase, were examined in 91 uteri collected throughout the menstrual cycle; 52 of which contained leiomyomata, and the remainder were normal controls. The microvascular density and endothelial proliferative indices were then determined for each of the uterine sections. ADM and VEGF were the most widely expressed angiogenic factors in the leiomyomas. Furthermore, the expression of ADM and VEGF in the endometrium and myometrium was up-regulated in leiomyoma-bearing uteri compared with controls. Although acidic fibroblast growth factor and basic fibroblast growth factor were expressed in leiomyomas and endometrium in all of the uterine samples examined, they were only expressed in the myometrium of leiomyomata-bearing uteri. Endothelial proliferation in leiomyomas was statistically greater than that of the myometrium and endometrium, both within and between uteri (P < 0.05). The vascular density in the myometrium but not the endometrium was significantly increased in leiomyoma-containing uteri (P < 0.05). Expression of ADM alone correlated directly with vascular density and endothelial cell proliferation index in leiomyomas and myometrium and may account for the high vascularity found in leiomyomas and the myometrium of leiomyoma-bearing uteri. As such, ADM is identified as a novel target for antiangiogenic therapy of these benign, clinically problematic uterine tumors.

Adrenomedullin↗
PubMed1998

PCR display identifies tamoxifen induction of the novel angiogenic factor adrenomedullin by a non estrogenic mechanism in the human endometrium.

Tamoxifen is currently the most widely used drug for the treatment of breast cancer, but there now exists considerable evidence that tamoxifen can also induce endometrial hyperplasia in pre menopausal women. We have used PCR differential display on primary human endometrial isolates in an attempt to identify genes induced by tamoxifen but not estrogen. Eight such differentially expressed bands were cloned and sequenced, one of which was found to be the peptide adrenomedullin. We have shown that adrenomedullin is a novel growth factor for endothelial cells and is angiogenic in vivo in the chick chorioallantoic membrane assay. Immunohistochemical analysis of endometrial sections have shown that while macrophages in the endometrium express adrenomedullin at a low level, endometrial macrophages of women receiving tamoxifen strongly express adrenomedullin (P=0.008). We postulate that endometrial induction of the angiogenic factor adrenomedullin by tamoxifen is part of the mechanism by which tamoxifen results in endometrial hyperplasia.

Adrenomedullin↗
PubMed1998

Validation of anti-vascular endothelial growth factor (anti-VEGF) antibodies for immunohistochemical localization of VEGF in tissue sections: expression of VEGF in the human endometrium.

Transient transfection of COS-1 cells followed by fixation, embedding in paraffin, and immunohistochemistry has identified anti-vascular endothelial growth factor (anti-VEGF) mouse monoclonal antibodies that efficiently immunostain VEGF in paraffin-embedded tissue sections. Immunohistochemical localization of VEGF in 34 specimens of normal human endometrium that had been collected at different stages of the menstrual cycle was then performed. VEGF was present at all stages of the cycle, but both the pattern and the intensity of staining varied. Thus, VEGF expression occurred predominantly in the endometrial epithelium and while weak in the proliferative phase, was strong in the secretory phase. VEGF expression in the stroma was weaker than in the proliferative phase glands and did not change throughout the cycle. These findings are in agreement with reports of VEGF mRNA expression in the endometrium, but disagree with previous immunohistochemical studies that employed an immunohistochemically unvalidated antiserum. This study has shown that the commercially available anti-VEGF monoclonal antibody M293 is excellent for the immunohistochemical localization of VEGF in paraffin sections.

Adenocarcinoma↗
PubMed1998

Angiogenesis in the endometrium.

Human endometrial vasculature has the unique property of undergoing benign angiogenesis during each menstrual cycle under the influence of the ovarian steroids estradiol and progesterone. However, neither has intrinsic angiogenic activity and endometrial angiogenesis involves stimulation by ovarian steroids of angiogenic factor release by the epithelium and stroma which then act on the endothelium. In vitro models using cultures of isolated endometrial epithelium, stroma and endothelium now allow mechanistic questions to be addressed. Vascular endothelial growth factor and platelet-derived endothelial cell growth factor/thymidine phosphorylase at present appear to be key players in endometrial angiogenesis.

Journal Article↗
PubMed1997

Expression and hormone regulation of Wnt2, 3, 4, 5a, 7a, 7b and 10b in normal human endometrium and endometrial carcinoma.

Wnt genes are transforming to mouse breast epithelium and are hormonally regulated in vivo. To assess their role in another endocrine-responsive human cancer, the expression of seven Wnt genes (Wnt 2, 3, 4, 5a, 7a, 7b and 10b) in normal human endometrium and endometrial cells, and endometrial carcinoma tissues and cell lines was investigated by ribonuclease protection analysis. Wnt2, 3, 4 and 5a mRNAs but not Wnt7a, 7b or 10b mRNAs were expressed in primary culture of normal endometrial epithelial (NEE) and stromal (NES) cells. In contrast, in four endometrial carcinoma cell lines (RL95-2, HEC-1-A, AN3 CA and Ishikawa), Wnt2 and Wnt3 mRNAs were absent. Wnt4 was expressed in only one out of four cell lines (RL95-2), and Wnt5a was much lower. Wnt7a and Wnt7b mRNAs were expressed in three out of four cell lines (RL95-2, HEC-1-A and Ishikawa). Wnt10b mRNA was expressed in RL95-2 and AN3 CA. In fresh tissues, all Wnt genes apart from Wnt10b were expressed in normal endometrium and endometrial carcinoma. Similar to the cell lines, the level of Wnt4 mRNA expression was significantly higher in the normal endometrium than endometrial carcinoma. Wnt2, 3 and 5a mRNAs were also lower in endometrial carcinoma compared with normal endometrium. There was no difference in the level of Wnt2, 3, 4 and 5a mRNA expression between proliferative phase and secretory phase of the menstrual cycle, or between either menstrual phase and the first trimester of pregnancy. In vitro, progesterone and/or 17beta-oestradiol had no effect on Wnt2, 3, 4, 5a and 7b mRNA expression in NES and all endometrial carcinoma cell lines. The data indicate that all Wnt genes were expressed in vitro, six out of seven Wnt genes (Wnt 2, 3, 4, 5a, 7a and 7b) were expressed endogenously in the human endometrium, their mRNA expression was hormonally independent and Wnt4 gene down-regulation as well as down-regulation of Wnt 2, 3 and 5a may be associated with endometrial carcinoma.

Down-Regulation↗
PubMed1997

Regulation of the expression of the angiogenic enzyme platelet-derived endothelial cell growth factor/thymidine phosphorylase in endometrial isolates by ovarian steroids and cytokines.

The angiogenic enzyme platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) was strongly expressed in the endometrial glands in the luteal and menstrual, but not the proliferative, phases of the cycle. The converse was seen in the stroma, where expression was strong in the proliferative, but not the luteal or menstrual, phases. Inflammatory cytokines induced PD-ECGF/TP expression in primary cultures of human normal endometrial epithelial (NEE) and normal endometrial stromal cells. The profile of cytokine induction of PD-ECGF/TP was cell dependent. Thus, in NEE cells, PD-ECGF/TP expression was strongly induced by the combination tumor necrosis factor-a and interferon-gamma. In contrast, in normal endometrial stromal cells, interferon-gamma gave, by far, the strongest induction of PD-ECGF/TP. Expression of the enzyme was not regulated by ovarian hormones alone. Although treatment of NEE cells with a physiological concentration of progesterone (5 X 10[-8] M) or transforming growth factor-beta1 (10 ng/ml) alone had no effect on PD-ECGF/TP expression, when delivered together at the same dose they induced a 48-fold increase in expression. This expression correlates with cyclic changes in progesterone and transforming growth factor-beta1 levels in the uterus.

Adenocarcinoma↗
PubMed1996

The uterus and the menopause.

The endometrial effects of HRT are of prime importance in compliance with long-term use, and safety with therapy. Different regimens have to be advocated according to menopausal status, to produce acceptable bleeding patterns.

Biopsy↗
PubMed1995

Treating menorrhagia in primary care. An overview of drug trials and a survey of prescribing practice.

Menorrhagia can be treated by drug therapy or surgery. General practitioners (GPs) can prescribe drugs to reduce menstrual blood loss as first-line treatment, referring patients for surgical treatment if drug therapy fails. This study examined the efficacy of drugs used to treat menorrhagia and surveyed British GPs to discover the extent to which they prescribed the most effective drugs for this condition. The results suggest that treatment of this condition in primary care falls short of desirable standards. A meta-analysis of randomized trials of drug therapy revealed wide differences in efficacy and side effects. The most effective drug (tranexamic acid) is little used by British GPs, whereas the least effective drug (norethisterone) is the most frequently prescribed.

Adult↗
PubMed1995

The isolation, characterization and culture of human decidual endothelium.

A novel method has been developed for the isolation of microvascular endothelium from first trimester decidua. Enzymatic dispersion and Percoll gradient centrifugation, followed by positive selection using Ulex europaeus coated immunomagnetic beads, yields pure isolates of endothelium. Typical 'cobblestone' monolayers form within 3-5 days; cells express the classical endothelial markers CD31 and Von Willebrand factor and the inducible cell adhesion molecules endothelial-leukocyte adhesion molecule and vascular cell adhesion molecule. Cell growth is dependent on both high concentrations of magnesium ions and human serum. Of the endothelial growth factors examined, only vascular endothelial growth factor stimulated growth, suggesting an important role for this factor in uterine angiogenesis.

Cell Division↗
PubMed1995

The isolation and long-term culture of normal human endometrial epithelium and stroma. Expression of mRNAs for angiogenic polypeptides basally and on oestrogen and progesterone challenges.

A highly reproducible and technically straightforward technique for the isolation and long-term culture of normal human endometrial epithelial cells is described. The essential conditions for long-term culture are that the cells be seeded onto a gelatin matrix and that 'endothelial cell growth supplement' be present in the culture medium. Normal endometrial epithelial cells express cytokeratins and oestrogen receptors. They may be passaged five to six times without change in properties. Growth of normal endometrial epithelial cells was stimulated by 17-beta-oestradiol and epidermal growth factor. Expression of the mRNA coding for seven polypeptide angiogenic factors, by normal endometrial epithelial, stromal and three endometrial carcinoma lines, was examined. The endometrial epithelial and stromal cells express mRNA for the polypeptide angiogenic factors, basic fibroblast growth factor, vascular endothelial cell growth factor, transforming growth factor-beta 1 and pleiotrophin, as well as the cytokine midkine. Expression of the mRNA for both vascular endothelial growth factor and midkine by normal endometrial epithelial cells showed a 2-fold increase on treatment with a physiological dose of 17-beta-oestradiol (10(-10) M) while, in contrast, the mRNA of transforming growth factor-beta 1 decreased 4-fold on treatment with 17-beta-oestradiol (10(-10) M) and was abolished by exposure to progesterone (5 x 10(-9) M). Expression of the mRNAs for angiogenic polypeptides by the endometrial carcinoma lines was more restricted.

Adenocarcinoma↗
PubMed1993

Immunohistochemical properties of the endothelial cells in the human uterus during the menstrual cycle.

Expression of vascular cell adhesion molecule (VCAM) and endothelial leukocyte adhesion molecule (ELAM)-1 on human uterine endothelium was examined by immunohistochemistry. Endomyometrial blocks were obtained from 26 hysterectomy specimens (n = 6, menstrual; n = 6, follicular; n = 14, luteal). VCAM and ELAM-1 expression was compared to that of the classic endothelial markers Factor VIIIRA, CD31, CD34 and CD36, which were found to be present in samples taken from all stages of the cycle. Factor VIIIRA, CD31 and CD34 were expressed on most endothelium whereas CD36 was expressed primarily on that of small vessels. CD36 was also found to be strongly expressed on endometrial epithelium and no changes were apparent during the menstrual cycle. ELAM-1 expression was not detected in any of the tissues examined. VCAM expression varied during the cycle, appearing on endometrial endothelium in the mid- and late luteal phases, stages at which large granular lymphocytes migrate into endometrium. VCAM or a VCAM-like molecule may be involved in migration of large granular lymphocytes into endometrium.

Adult↗