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Biomedical subjects

M Wells

Publications and source records attributed to M Wells.

At least 19 recordsLinked to original sources

Studies of embryo transfer from cattle clinically affected by bovine spongiform encephalopathy (BSE).

Semen from 13 bulls, eight with clinical bovine spongiform encephalopathy (BSE), was used to artificially inseminate (AI) 167 cows with clinical BSE, and their resultant embryos were collected non-surgically seven days after AI. The viable and non-viable embryos with intact zonae pellucidae were washed 10 times (as recommended by the International Embryo Transfer Society) then frozen. Later, 587 of the viable embryos were transferred singly into 347 recipient heifers imported from New Zealand, and 266 live offspring were born of which 54.1 per cent had a BSE-positive sire and a BSE-positive dam. The recipients were monitored for clinical signs of BSE for seven years after the transfer, and the offspring were monitored for seven years after birth. Twenty-seven of the recipients and 20 offspring died while being monitored but none showed signs of BSE. Their brains, and the brains of the recipients and offspring killed after seven years, were examined for BSE by histopathology, PrP immunohistochemistry, and by electron microscopy for scrapie-associated fibrils. They were all negative. In addition, 1020 non-viable embryos were sonicated and injected intracerebrally into susceptible mice (20 embryos per mouse) which were monitored for up to 700 days, after which their brains were examined for spongiform lesions. They were all negative. It is concluded that embryos are unlikely to carry BSE infectivity even if they have been collected at the end-stage of the disease, when the risk of maternal transmission is believed to be highest.

Animals↗

Primary endometrioid adenocarcinoma of the large intestine arising in colorectal endometriosis.

AIMS: Three cases of endometrioid adenocarcinoma arising in colorectal endometriosis are described with discussion of their macroscopic and microscopic pathology and diagnosis, using immunohistochemistry. METHODS AND RESULTS: Three middle-aged women presented with symptoms and signs of colorectal mass effect. Two had a preceding history of gynaecological endometriosis and all three had either been on hormone replacement therapy or had functioning ovaries prior to presentation with colorectal disease. Each underwent resection of tumours of the distal large intestine. The definitive diagnosis was dependent on histological examination and immunohistochemistry, which was used to demonstrate an origin in endometriotic tissue. CONCLUSIONS: Endometrioid adenocarcinoma is a rare complication of colorectal endometriosis, this report contributing to a total of 25 cases in the literature. Definitive diagnosis, aided by immunohistochemical studies, is important to enable the identification of the optimal management for this uncommon condition.

Biomarkers, Tumor↗

The effect of phytoestrogens on the female genital tract.

Environmental oestrogens have been implicated in the pathogenesis of hormonally treated cancers (such as breast and prostate cancer), male infertility, and abnormalities of the male and female reproductive tracts. They may be derived from plants (phytoestrogens), pharmaceuticals, or other synthetic compounds not originally intended to have oestrogenic activity (including soy based infant formulas). This review will discuss the evidence from both animal studies and humans for an effect of these ubiquitous compounds on the development of the human female genital tract, in addition to prolonging the menstrual cycle, alleviating symptoms of the menopause, and protecting against the development of endometrial carcinoma.

Endometrial Neoplasms↗

The knowledge and attitudes of surgical staff towards the use of opioids in cancer pain management: can the Hospital Palliative Care Team make a difference?

The principles of cancer pain management are well established, but evidence suggests that these are not incorporated into daily practice and patients are still in pain. Deficiencies in knowledge and inappropriate attitudes towards the use of opioids may partially explain why the management of cancer pain is still such a widespread problem. This study assessed the knowledge and attitudes of 135 nursing and medical staff working in a surgical unit, before and after working with a newly established Hospital Palliative Care Team. The baseline survey highlighted the existence of a number of myths and misconceptions in relation to opioid use. Results of the follow-up survey indicated that the knowledge and attitudes of doctors and nurses had improved after working with the team, but that this probably occurred as a result of good working relationships and case discussions rather than through formal teaching. The study provided a useful method of identifying deficiencies in knowledge and attitude among staff, and helped to raise awareness of the problem of cancer pain management. Our challenge now is to work with staff to ensure that positive changes in knowledge and attitudes are translated into the everyday practice of hospital nurses and doctors caring for patients with cancer.

Adult↗

Precursor lesions of ovarian epithelial malignancy.

Most ovarian carcinomas arise from the mesothelial surface lining of the ovaries, or from invaginations of this lining into the superficial ovarian cortex to form cortical inclusion cysts. The native ovarian surface mesothelium is of an 'uncommitted' phenotype, and has potential to modulate to epithelial or mesenchymal phenotypes in response to signals such as those associated with ovulation. The exposure of the mesothelial lining of an inclusion cyst to the ovarian stromal microenvironment may be responsible for the phenotypic change to Müllerian epithelium so commonly seen in these cysts. Müllerian metaplasia is usually to a serous phenotype, and it is possible that undefined molecular events occurring in an inclusion cyst that has undergone Müllerian metaplasia may initiate neoplastic change in these cysts. This may be the developmental pathway of most invasive serous carcinomas. Occasional rare cases of ovarian intraepithelial neoplasia, manifested by epithelial atypia in an inclusion cyst or on the surface epithelium without invasive carcinoma, are identified histologically. Serous borderline tumours represent a separate category and in most cases probably do not progress to frank carcinoma. Mucinous carcinomas may in some cases have arisen from pre-existing benign and borderline mucinous tumours. Endometriosis of the ovary is associated with genetic abnormalities and is frequently found in association with clear cell and endometrioid carcinomas, suggesting that in many cases these latter two types of carcinoma may have arisen directly from endometriotic deposits. Ovaries removed prophylactically from women with a family history of ovarian carcinoma or with a mutation in one of the genes predisposing to ovarian carcinoma should be processed in their entirety, and examined closely not just for obviously neoplastic lesions, but also for more subtle morphological abnormalities of the surface epithelium or the epithelium lining cortical inclusion cysts.

Carcinoma↗

Over-diagnosis of hydatidiform mole in early tubal ectopic pregnancy.

AIMS: Tubal ectopic hydatidiform moles are rare lesions, and only 40 cases have been reported in the world literature. We investigated the apparently high incidence of tubal ectopic hydatidiform moles in women referred for treatment to a Supraregional Trophoblastic Tumour Screening and Treatment Centre between 1986 and 1996. METHODS AND RESULTS: Of 4261 women referred during the study period, 25 (0.6%) had a suspected tubal ectopic hydatidiform mole and paraffin-embedded tissue was available in 20 (80%) of these. Each case was reviewed by two pathologists and DNA flow cytometric analysis was undertaken when the histological diagnosis was initially deemed equivocal or suggestive of hydatidiform mole. On review, 17 cases (85%) showed no evidence of hydatidiform mole (circumferential trophoblastic proliferation, hydrops, scalloped villi, and stromal karyorrhexis). Of these, 11 cases (65%) showed features of early placentation and six (35%) showed hydropic abortion. DNA flow cytometry was performed in 14 (82%) of these cases and revealed a diploid population in each case. Three cases of molar pregnancy (15%) were identified. Each of these cases had the histological features of an early complete hydatidiform mole. Sufficient tissue was available for DNA flow cytometric analysis in two of these cases and confirmed the presence of diploidy in each. CONCLUSION: Our results show that tubal ectopic hydatidiform mole is a rare entity and demonstrate that it is over-diagnosed. Polar trophoblastic proliferation and hydropic villi are features of early placentation and of hydropic abortion. Sheets of extravillous trophoblast may be particularly prominent in tubal ectopic gestation. In the absence of circumferential trophoblastic proliferation combined with hydropic change a diagnosis of gestational trophoblastic disease should be avoided.

Abortion, Spontaneous↗

Hormone replacement therapy and the endometrium.

Modern hormone replacement therapy (HRT) regimens contain oestrogen and progestogen, given either in a cyclical or continuous combined manner. Most endometrial biopsies from women on sequential HRT show weak secretory features. Approximately 15% show proliferative activity, although this figure may be less if more than nine days of progestogen is given in each cycle. A small proportion will show an inactive or atrophic endometrium. Up to 50% of biopsies from women on continuous combined HRT contain minimal endometrial tissue for histopathological analysis: this correlates well with an atrophic endometrium with no appreciable pathology. Of the 50% with more substantial material, approximately one half will show endometrial atrophy, and one half will show weak secretory features. Proliferative, menstrual, and pseudodecidual changes are rare. Approximately 20% of women given unopposed oestrogen for one year develop endometrial hyperplasia. The relative risk of endometrial carcinoma is two to three. This is dramatically reduced by the addition of progestogen to the regimen, but cyclical progestogen as part of a sequential HRT regimen does not completely eliminate the risk of carcinoma. The prevalence of endometrial hyperplasia associated with sequential HRT is 5.4%, and that of atypical hyperplasia (endometrial intraepithelial neoplasia) is 0.7%. Continuous combined HRT is not associated with the development of hyperplasia or carcinoma, and may normalise the endometrium of women who have developed complex hyperplasia on sequential HRT. The probability of a histopathologist finding clinically relevant pathology in an endometrial biopsy specimen of a patient on HRT is low and is more likely to be a manifestation of pre-existing disease.

Biopsy↗

Critters in the cube farm: perceived psychological and organizational effects of pets in the workplace.

This article reports the findings of an exploratory study examining the perceived functions and psychological and organizational effects of pets in the workplace. Participants were 193 employees from 31 companies allowing pets in the workplace who completed anonymous questionnaires. Results indicated that participants perceived pets in the workplace to reduce stress and to positively affect employee health and the organization. Participants who brought their pets to work perceived greater benefits than participants who did not bring their pets to work and participants who did not own pets.

Analysis of Variance↗

Preincubation with endothelial cell monolayers increases gene transfer efficiency into human bone marrow CD34(+)CD38(-) progenitor cells.

Retroviral gene transfer studies targeting bone marrow CD34(+)CD38(-) stem cells have been disappointing because of the rarity of these cells, their G(0) cell cycle status, and their low or absent expression of surface retroviral receptors. In this study, we examined whether preincubation of bone marrow CD34(+)CD38(-) stem cells with a hematopoietically supportive porcine microvascular endothelial cell line (PMVECs) could impact the cell cycle status and expression of retroviral receptors in pluripotent CD34+CD38- cells and the efficiency of gene transfer into these primitive target cells. PMVEC coculture supplemented with GM-CSF + IL-3 + IL-6 + SCF + Flt-3 ligand induced >93% of the CD34(+)CD38(-) population to enter the G(1) or G(2)/S/M phase while increasing this population from 1.4% on day 0 to 6.5% of the total population by day 5. Liquid cultures supplemented with the identical cytokines induced 73% of the CD34(+)CD38(-) population into cell cycle but did not maintain cells with the CD34(+)CD38(-) phenotype over time. We found no significant increase in the levels of AmphoR or GaLVR mRNA in PMVEC-expanded CD34(+)CD38(-) cells after coculture. Despite this, the efficiency of gene transfer using either amphotropic vector (PA317) or GaLV vector (PG13) was significantly greater in PMVEC-expanded CD34(+)CD38(-) cells (11.4 +/- 5.6 and 10.9 +/- 5.2%, respectively) than in either steady state bone marrow CD34(+)CD38(-) cells (0.6 +/- 1.7 and 0.2 +/- 0.6%, respectively; p < 0.01 and p < 0.01) or liquid culture-expanded CD34(+)CD38(-) cells (1.4 +/- 3.5 and 0.0%, respectively; p < 0.01 and p < 0.01). Since PMVEC coculture induces a high level of cell cycling in human bone marrow CD34(+)CD38(-) cells and expands hematopoietic cells capable of in vivo repopulation, this system offers potential advantages for application in clinical gene therapy protocols.

ADP-ribosyl Cyclase↗

The role of the nurse in urinary incontinence.

Specialist nursing is dynamic and needs to be sensitive, flexible and responsive to changes in care delivery. Clinical, educational, managerial, audit and research activities are all integral to the role of the specialist continence nurse. Nurse specialists need to be careful that they do not de-skill the role of more generalist nurses, but rather enhance their contribution to continence care. They also need to work collaboratively with their Specialist Continence Physiotherapist colleagues. There is evidence that care in the community setting and on ward areas is sub-optimal. Recent audit activities have shown that nurses feel comfortable about assessing the person with continence problems but less certain about treatment. One way to address this imbalance is through the use of care pathways, examples of which are illustrated.

Community Health Nursing↗

Inverse relationship between the expression of the human papillomavirus type 16 transcription factor E2 and virus DNA copy number during the progression of cervical intraepithelial neoplasia.

The human papillomavirus type 16 (HPV-16) status of 43 cervical biopsies, which had been characterized histologically as normal, various grades of cervical intraepithelial neoplasia (CIN) and invasive squamous cell carcinoma, was examined by using (i) a novel antibody against the HPV-16 E2 protein, (ii) sensitive HPV-16 DNA in situ hybridization and (iii) microdissection/PCR for the E2 ORF. The data indicate that E2 protein expression is highest in koilocytes in lower-grade CIN (I), but decreases with increasing grade, whereas the detection of HPV DNA is delayed until CIN I/II, rising to the highest levels in carcinoma cells. Co-localization of E2 with HPV-16 DNA-positive cells was most commonly observed in koilocytes in CIN II lesions. PCR analyses of microdissected epithelium from the same or serial sections indicated that E2 ORFs were retained in an intact form in a number of higher-grade CIN lesions and invasive carcinomas.

Carcinoma, Squamous Cell↗

The endometrial response to sequential and continuous combined oestrogen-progestogen replacement therapy.

OBJECTIVES: 1. To determine the prevalence of endometrial hyperplasia in postmenopausal women taking standard proprietary regimens of sequential oestrogen/progestogen; 2. to determine the effects of nine months treatment with an oral continuous combined regimen of 2 mg 17beta-oestradiol and 1 mg norethisterone acetate (Kliofem [Kliogest outside the UK]; Novo Nordisk, Denmark) on endometrial histology in postmenopausal women. DESIGN: An open, prospective study in postmenopausal women. SETTING: Fifty-four menopause clinics in the UK. PARTICIPANTS: 2028 postmenopausal women: 1312 (Group A) taking sequential oestrogen-progestogen hormone replacement therapy (HRT), and 716 (Group B) not taking HRT, were recruited. In Group A, 388 women took preparations containing 10 days of progestogen, 921 had 12 days, and 3 had 13 days per cycle. METHODS: Endometrial aspiration biopsies were taken towards the end of a three-month run-in period (Group A) or at study entry (Group B), before administration of the continuous combined HRT regimen. Biopsies were repeated at the end of the nine month treatment period. MAIN OUTCOME MEASURE: Endometrial histology. RESULTS: Initial endometrial biopsy data were available for 1106 women in Group A, who by the time of endometrial investigation had been taking HRT for a median duration of 2.56 years (5th to 95th centiles: 0.77 to 8.49 years). Data were available for 661 untreated women, who had no bleeding and had not taken HRT within the last year (Group B). Complex hyperplasia was found in 59 women (5.3%), and atypical hyperplasia in a further eight (0.7%) in Group A. In Group B there were no cases with complex hyperplasia, but one woman showed atypical hyperplasia (0.2%). At the end of the nine months of continuous combined therapy there was no case of hyperplasia among 1196 biopsies (upper 95% confidence limit of risk 0.31%) in women completing the study. Within this Group all of the women with complex hyperplasia arising during previous sequential HRT and who completed the study (n = 38) reverted to normal endometrial patterns. There was no case of endometrial carcinoma during the study. CONCLUSIONS: Despite taking standard regimens of sequential HRT containing at least 10 days of progestogen, there was a 5.3% prevalence of complex endometrial hyperplasia, and a 0.7% prevalence of atypical hyperplasia. However, continuous combined HRT (Kliofem) containing daily progestogen is not associated with an increased risk of hyperplasia and will convert the endometrium to normal in those with complex hyperplasia arising during previous sequential HRT.

Administration, Oral↗

Peroxisome proliferator-activated receptor gamma as a novel target in cancer therapy: binding and activation by an aromatic fatty acid with clinical antitumor activity.

Aromatic fatty acids, of which phenylacetate is a prototype, constitute a class of low toxicity drugs with demonstrated antitumor activity in experimental models and in humans. Using in vitro models, we show here a tight correlation between tumor growth arrest by phenylacetate and activation of peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear receptor superfamily. In support are the following observations: (a) the efficacy of phenylacetate as a cytostatic agent was correlated with pre-treatment levels of PPARgamma, as documented using established tumor lines and forced expression models; (b) in responsive tumor cells, PPARgamma expression was up-regulated within 2-9 h of treatment preceding increases in p21waf1, a marker of cell cycle arrest; (c) inhibition of mitogen-activated protein kinase, a negative regulator of PPARgamma, enhanced drug activity; and (d) phenylacetate interacted directly with the ligand-binding site of PPARgamma and activated its transcriptional function. The ability to bind and activate PPARgamma was common to biologically active analogues of phenylacetate and corresponded to their potency as antitumor agents (phenylacetate < phenylbutyrate < p-chloro-phenylacetate < p-iodo-phenylbutyrate), whereas an inactive derivative, phenylacetylglutamine, had no effect on PPARgamma. These findings point to PPARgamma as a novel target in cancer therapy and provide the first identification of ligands that have selective antitumor activity in patients.

Animals↗

Overexpression of H-Ryk in epithelial ovarian cancer: prognostic significance of receptor expression.

H-Ryk is an atypical receptor tyrosine kinase that is expressed in a differentiation-specific manner in epithelial tissues. We have previously shown by in situ hybridization and immunohistochemistry that H-Ryk is overexpressed in malignant ovarian tumors. In addition, we have demonstrated that overexpression of H-Ryk is transforming in vitro and in vivo. To evaluate whether expression of H-Ryk is a prognostic factor in epithelial ovarian cancer, we carried out a retrospective study of 88 primary malignant ovarian tumors (28 serous tumors, 11 mucinous tumors, 29 endometrioid tumors, 13 clear cell tumors, 3 malignant mixed Mullerian tumors, 1 mixed epithelial tumor, 1 primary peritoneal tumor, 1 undifferentiated tumor, and 1 transitional carcinoma) diagnosed between 1990 and 1993 using immunohistochemistry. On univariate analysis, overall survival decreased significantly with age (P = 0.01); in patients with International Federation of Gynecology and Obstetrics (FIGO) stage II (P = 0.008), FIGO stage III (P < 0.001), and FIGO stage IV (P < 0.001) disease; and in patients with residual disease (residual disease < or = 2 cm, P = 0.007; residual disease > 2 cm, P < 0.001) after surgery. In addition, overexpression of the H-Ryk receptor in malignant epithelium (P = 0.04) and blood vessel (P = 0.01) was associated with a significantly decreased overall survival. H-Ryk blood vessel overexpression (P = 0.03), residual disease > 2 cm (P = 0.006), and residual disease < or = 2 cm (P = 0.01) conferred a significantly shorter progression-free survival. No correlation was found between H-Ryk overexpression and age, histological subtype, degree of differentiation, FIGO stage, or residual disease. Overall, after adjustment for all of the prognostic factors by multivariate analysis (Cox proportional hazards model), residual disease was the most powerful prognostic indicator for overall survival (P < 0.001) and progression-free survival (P = 0.01) in this patient subset. This implies that H-Ryk acts cooperatively with other biological factors in the pathogenesis of ovarian cancer.

Adult↗