bluuebunny/crossref_metadata_2025 huggingface dataset:
The pathway for MHCII-mediated presentation of endogenous proteins involves peptide transport to the endo-lysosomal compartment
Authors: Dani Aadish , Chaudhry Ashutosh , Mukherjee Paushali , Rajagopal Deepa , Bhatia Sumeena , George Anna , Bal Vineeta , Rath Satyajit , Mayor Satyajit
Published: August 2004

Antigen-presenting cells (APCs) are expected to present peptides from endocytosed proteins via major histocompatibility complex (MHC) class II (MHCII) molecules to T cells. However, a large proportion of peptides purified from MHCII molecules are derived from cytosolic self-proteins making the pathway of cytosolic peptide loading onto MHCII of critical relevance in the regulation of immune self-tolerance. We show that peptides derived from cytoplasmic proteins either introduced or expressed in the cytoplasm are first detectable as MHCII-peptide complexes in LAMP-1+ lysosomes, prior to their delivery to the cell surface. These peptide-MHC complexes are formed in a variety of APCs, including peritoneal macrophages, dendritic cells, and B cells, and are able to activate T cells. This process requires invariant chain (Ii)-dependent sorting of MHCII to the lysosome and the activity of the molecular chaperone H-2M. This pathway is independent of the ER resident peptide transporter complex TAP and does not take place by cross-presentation from neighbouring cells. In conjunction with our earlier results showing that these peptides are derived by cytosolic processing via the proteasome, these observations provide evidence for a ubiquitous route for peptide transport into the lysosome for the efficient presentation of endogenous and cytoplasmic proteins to CD4 T cells.
Transient activation of FOXN1 in keratinocytes induces a transcriptional programme that promotes terminal differentiation: contrasting roles of FOXN1 and Akt
Authors: Janes Sam M. , Ofstad Tyler A. , Campbell Douglas H. , Watt Fiona M. , Prowse David M.
Published: August 2004

The forkhead transcription factor FOXN1 is required for normal cutaneous and thymic epithelial development. Mutations in FOXN1 give rise to the nude phenotype in mice, rats and man. However, the genes that are regulated by FOXN1 are unknown. To investigate FOXN1 function we expressed an inducible form of the protein, FOXN1ER, that is activated by 4-hydroxytamoxifen in primary human epidermal keratinocytes. Transient activation of FOXN1 decreased the proportion of keratinocytes that formed actively growing clones attributable to stem cell founders and increased the number of abortive clones, without inducing apoptosis. Within 24 hours the majority of cells had initiated terminal differentiation, as assessed by involucrin expression. We performed a cDNA microarray experiment to analyse changes in the transcription of approximately 6000 genes. Following FOXN1 activation we detected increases of two fold or greater in the RNA levels of over 30 genes. Genes promoting growth arrest, survival and differentiation featured prominently and markers of early events in keratinocyte differentiation were also detected. Since one of the induced genes was Akt we investigated whether Akt played a role in terminal differentiation. Activation of PI 3-kinase but not Akt was necessary for FOXN1-induced differentiation. In reconstituted epidermis FOXN1 promoted early stages of terminal differentiation whereas Akt activation was sufficient to induce late stages, including formation of the cornified layers. These results establish a role for FOXN1 in initiation of terminal differentiation and implicate Akt in subsequent events.
A member of the Fizzy-related family of APC activators is regulated by cAMP and is required at different stages of plant infection byUstilago maydis
Authors: Castillo-Lluva Sonia , García-Muse Tatiana , Pérez-Martín José
Published: August 2004

Here, we identified a new member of the Fizzy-related family of APC activators, Cru1, which is required for virulence in the corn smut fungus Ustilago maydis. We show that Cru1 promotes the degradation of B-type cyclins in U. maydis. Cells deficient in the Cru1 protein show defects in cell size, adaptation to nutritional conditions and cell separation. We propose that the phenotypes observed are a consequence of the inability of cru1Δ cells to keep under control the levels of mitotic cyclins during G1. The levels of cru1 mRNA are controlled by nutritional conditions and cAMP levels, implicating the cAMP/protein kinase A pathway in the transmission of environmental conditions to the cell cycle. Cells deficient in Cru1 function are severely impaired in their ability to infect corn plants. This low rate of plant infection is caused by several defects. First, a low level of expression of the pheromone-encoding gene, mfa1, resulted in a low frequency of dikaryotic infective filament formation. Second, proliferation of fungal cells inside the plant is also affected, resulting in the inability to induce tumors in plants. Finally, the formation and germination of teliospores is also impaired. Our results support the hypothesis that virulence and cell cycle are connected in U. maydis. We propose that along the infection process, Cru1 is required to keep the appropriate G1 length necessary for the adaptation of fungal cells to host environment through the different stages of the plant infection.
Identification of novel Prominin-1/CD133 splice variants with alternative C-termini and their expression in epididymis and testis
Authors: Fargeas Christine A. , Joester Angret , Missol-Kolka Ewa , Hellwig Andrea , Huttner Wieland B. , Corbeil Denis
Published: August 2004

Prominin-1/CD133 is a five-membrane-span glycoprotein that is thought to act as an organizer of plasma-membrane protrusions. Here, we report the molecular and cell-biological characterization of four novel prominin-1 splice variants isolated from a mouse testis cDNA library and referred to as prominin-1.s3 to prominin-1.s6. Compared with kidney-derived prominin-1.s1, the s3, s4 and s5 variants contain a distinct cytoplasmic C-terminal domain. The s4 and s5 variants bear, in addition, two and one inframe deletion(s), respectively, in the extracellular domains. The s6 variant displays a truncated C-terminal domain caused by a premature termination resulting from intron retention. Upon their ectopic expression in Chinese hamster ovary cells, the s3 and s6 variants were found to be concentrated in plasma-membrane protrusions, whereas the s4 and s5 variants did not reach the cell surface. Biochemical analyses suggest that most of the prominin-1 in the adult male reproductive system is expressed as the s6 variant. Immunohistological and electron microscopic analyses show that prominin-1 is: (1) confined to the apical surface of the epithelium all along the epididymal duct, with the exception of the initial segment; (2) concentrated in stereocilia of the epididymal duct epithelium; and (3) found on the tail of developing spermatozoa in seminiferous tubules. Our data suggest that prominin-1 is involved in the formation and/or stabilization of epididymal stereocilia and the tail of spermatozoa, and hence might play a dual role in the biogenesis of spermatozoa.
Modifying sister chromatid cohesion for meiosis
Authors: Watanabe Yoshinori
Published: August 2004

Meiosis produces haploid gametes from diploid cells in two stages that in many ways resemble mitosis. However, the regulatory mechanisms governing kinetochore orientation and cohesion at the first meiotic division are different from those at mitosis: sister kinetochores are pulled forwards from the same spindle pole at metaphase, and centromeric cohesion is protected throughout anaphase. Consequently, homologous chromosomes, rather than sister chromatids, segregate to the opposite sides of a cell. The residual cohesion around centromeres plays an essential role at the second meiotic division, when spindle microtubules from opposite poles attach to sister chromatids. Recent studies have identified novel meiosis-specific kinetochore proteins, such as monopolin and shugoshin, and indicate that specific modifications in sister chromatid cohesion lie at the heart of the regulation of meiotic chromosome segregation.
A bouquet of chromosomes
Authors: Harper Lisa , Golubovskaya Inna , Cande W. Zacheus
Published: August 2004

During meiotic prophase, telomeres attach to the inner nuclear envelope and cluster to form the so-called meiotic bouquet. Although this has been observed in almost all organisms studied, its precise function remains elusive. The coincidence of telomere clustering and initiation of chromosome synapsis has led to the hypothesis that the bouquet facilitates homologous chromosome pairing and synapsis. However, recent mutant analysis suggests that the bouquet is not absolutely required for either homologous pairing or synapsis but that it makes both processes much faster and more efficient. The initiation of bouquet formation is independent of the initiation of recombination. However, the progression through recombination and synapsis may be required for exit from the bouquet stage. Little is known about the mechanism of telomere clustering but recent studies show that it is an active process.
Menopause health care provision: the views of women, general practitioners and practice nurses
Authors: Roberts Paula-J , Sibbald Bonnie
Published: August 2004

Objective. To investigate the views of women, general practitioners and practice nurses about current and future menopausal health care, including both health service provision and education.

Study design. Questionnaires were sent to a random sample of 1,000 women aged 40-65 and all general practitioners and practice nurses in the Wigan and Bolton area.

Main outcome measures. Responses to questions about knowledge and views about the menopause, hormone replacement therapy and health care.

Results. Completed questionnaires were returned from 59% (587/998) of women, 64% (181/281) of general practitioners and 82% (147/180) of practice nurses. Only 39% (219/555) of women, 63% (113/179) of general practitioners and 27% (39/144) of practice nurses were satisfied with their knowledge about the menopause/HRT. Ninety-four per cent (170/181) of general practitioners and 100% (143/143) of practice nurses felt the role of the practice nurse in menopause care could be developed in the future. Only 48% (66/139) of general practitioners wanted a practice based menopause/HRT clinic as opposed to 83% (109/131) of practice nurses and 82% (404/496) of women. Twenty-six per cent (41/161) of general practitioners wanted a community menopause clinic in the area as opposed to 73% (99/136) of practice nurses and 75% (351/467) of women.

Conclusions. Women, general practitioners and practice nurses want better menopause care provision. There is a need for further education of both women and health professionals and a great deal of support for extending the role of the practice nurse. General practitioners' views on clinic based care are discussed.
The discovery of oestrogenic hormones
Authors: Sneader Walter
Published: August 2004

The small amounts of oestrogen present in the ovary and initial inability to assay oestrogenic activity were major impediments to the isolation of these hormones. The development of a simple assay and the discovery of high levels of the hormones in urine during pregnancy led to both their isolation and commercial extraction. A variety of synthetic compounds were also found to exhibit oestrogenic activity. This review examines the discovery of both the natural and synthetic oestrogens.
Hormone replacement therapy and epilepsy
Authors: Duncan Susan
Published: August 2004

Since ancient times the menstrual cycle has been thought to influence the occurrence and frequency of seizures. The phenomenon of catamenial epilepsy seizures, which either occur at or around the time of menstruation, or become more frequent at this time, has been the subject of much research, although the literature is beset by methodological problems. In contrast, epilepsy at the menopause has not attracted the same attention and in the last 15 years only three studies have been published. None of them has produced conclusive results on the effect of the menopause on the course of epilepsy or the effects, if any, of hormone replacement therapy on seizure control.
The economics and management of cardiovascular disease in postmenopausal women
Authors: Lynch Mauricea
Published: August 2004

Cardiovascular disease (CVD) in the UK is an important public health problem and a significant burden to the National Health Service and Social Services. In 1998 ischaemic heart disease and cerebrovascular disease were the underlying causes of 32.4% of all deaths among women aged 50 years and over in England and Wales (personal communication from the Office for National Statistics). This review discusses the economics of interventions in the management of CVD in postmenopausal women. The evidence of net health effects of hormone replacement therapy (HRT) indicates that, at least in the case of primary interventions, healthcare professionals should consider alternatives to prescribing HRT to healthy postmenopausal women. A targeted programme of multiple interventions covering drug treatment for reducing blood pressure and lowering cholesterol in the high-risk groups combined with health education should play an important role in the prevention of CVD in this population. Given the multi-factorial aspects of the use of HRT, the effectiveness of alternative preventive treatments for other conditions, apart from CVD, such as osteoporosis and climacteric symptoms, should be investigated, preferably in randomised control trials.
Menopause research and audit
Authors: McMillan John
Published: August 2004

This review begins by outlining some of the history behind the World Medical Association's Declaration of Helsinki. The Helsinki distinction between therapeutic and non-therapeutic research will be described and how this relates to a hypothetical HRT trial is considered. Then the ethical significance of research when it is combined with professional care is discussed.

The concept of clinical equipoise is one relevant to menopause research when it involves randomising treatments to participants. Other important considerations mentioned include minimal risk and scientific merit. The final section of the review suggests that the distinction between clinical audit and research is one likely to become increasingly important and that many of the more significant issues associated with audit will relate to confidentiality.
Premature ovarian failure: a practical approach
Authors: Seeley Tony , Ashton Sharon
Published: August 2004

Premature ovarian failure (POF) could be more appropriately called "premature ovarian dysfunction", as spontaneous return of activity may occur. By definition POF occurs in women under 40, at an incidence of 1% of the population, the usual presenting symptom being amenorrhoea. It is associated with increased mortality which can be prevented by hormone replacement therapy. Affected women should be kept under regular review as related conditions such as hypothyroidism, diabetes and osteoporosis commonly occur. The infertility treatment of choice is in vitro fertilisation using donor eggs, although sporadic and unpredictable return of ovarian function may lead to spontaneous pregnancies.
The Annual Meeting of The British Menopause Society Exeter, July 2000
Authors: Rees Margaret
Published: August 2004

This year, as in 1999, a supplement is being devoted to the annual meeting of the British Menopause Society. The supplement contains the Solvay lecture, the other invited lectures, the oral free communications and posters. The abstracts of the other invited lectures are in the programme sections. The Poster Presentations are in alphabetical order according to the first author. Only the abstracts of those oral free communications and posters which were presented at the designated session of the meeting and whose authors submitted texts are included. The recipients of the prizes for best oral free communication and Poster Presentations are indicated.
The past, the present and the future o oestrogen and progestogen therapy for cardiovascular disease in postmenopausal women
Authors: Archer David F
Published: August 2004

The overwhelming body of evidence indicating that oestrogen or hormone replacement therapy may be beneficial as primary prevention in cardiovascular disease in women leads one to continue to actively counsel women who have or do not have cardiovascular risk factors that oestrogen will be indeed cardioprotective. A lack of significant data other than the HERS trial, which is the only prospective randomised trial of secondary intervention, leads one to be reluctant to intervene with oestrogen plus progestin in women who have had a cardiac event. Can oestrogen be used more than one year after the acute event is a question that can only be answered by future research. The data from the HERS trial would suggest that, if oestrogen is used, its effect on preventing subsequent cardiovascular events is low. The reason for this is that other agents used to prevent recurrent cardiovascular events such as statins have a greater efficacy. The use of other agents, most notably statins initially, with a later addition of oestrogen, should be considered. It should be remembered that oestrogen can have other positive effects on the skeleton and the central nervous system.

Markers of cardiovascular risk such as C-reactive protein, homocysteine, and lipids, can be useful in counselling women who are at increased risk for coronary heart disease. The measurement of C-reactive protein, homocysteine, and a lipid profile in postmenopausal women now appears to be useful and should be incorporated into the physician's evaluation. These results should be factored into a treatment plan.

The use of statins for prevention and active treatment after cardiovascular events in women is changing the prescribing habits of obstetricians and gynaecologists in the USA. Physicians treating and counselling older women now should be comfortable with including lipid altering agents in their armamentarium. The information on the selective oestrogen receptor modulator raloxifene and alternative therapies such as soy protein and isoflavones are limited and, at the present time, do not lend themselves to making definitive statements as to their efficacy in long-term cardiovascular prevention and/or treatment as secondary interventions.
Age, gender, oestrogen therapy and dentition replacement
Authors: Walls Angus WG , Pack Angela RC
Published: August 2004

An increasing number of older people are retaining their teeth in the UK. Edentulism is gradually declining and will increasingly become a feature of social deprivation. This review covers the processes of ageing in teeth, the peridontium, the oral mucosa, muscles of mastication, salivary glands and taste. Diseases of the oral mucosa, in particular cancer, are examined. Tooth decay and peridontal disease are discussed. The relationship between systemic health and oral health status are becoming increasingly important. The effect of diet and tobacco smoking are explored. Finally, the association between peridontal disease and osteoporosis, atherosclerosis, venous thromboembolism are discussed.
Management of the menopause in women with migraine
Authors: MacGregor E Anne
Published: August 2004

Migraine is more common in women than in men, with a prevalence ratio of 3:1 respectively during the early 40s. The years leading up to the menopause mark a time of exacerbation of migraine for many women.1 Menstruation becomes a more prominent trigger and attacks often increase in frequency, as periods become increasingly irregular. Unpredictable attacks, coupled with menopausal symptoms, can make it hard for many women to cope. Unfortunately, women are often told that hormone replacement therapy (HRT) will make migraine worse and they do not receive effective treatment.
Colorectal cancer and hormone replacement therapy: a review of epidemiological studies
Authors: Fernandez Esteve , Franceschi Silvia , La Vecchia Carlo
Published: August 2004

Mortality rates for colorectal cancer in many developed countries have declined in women more than in men. Possible explanations of the sex differentials in colorectal cancer mainly, but not only, refer to different exposure to exogenous hormones. This paper aims to review the available epidemiological evidence on this issue. Seven cohort studies reported information on HRT use and colorectal cancer risk, with relative risks (RRs) around or below unity, and significant inverse association was found in two of them. Of 12 case-control studies, five reported significant risk reductions among ever-users of HRT, while two investigations showed moderate, non-significant inverse associations and none showed a significant increased risk. Two recent meta-analysis showed a 20% reduction in the risk of colon cancer among current users. Overall, the studies reviewed support the existence of an inverse association between colorectal cancer and HRT. Although these epidemiological observations are consistent, surveillance bias may account for part of the association.
Hormone replacement therapy and benign breast disease
Authors: Hyett Anthony R , Sacks Nigel PM
Published: August 2004

The exact incidence of new breast symptoms with hormone replacement therapy (HRT) and its trophic effects on benign breast disorders is not well quantified and remains relatively understudied. This is a rapidly growing clinical issue as the rate of HRT use is increasing. Significant mastalgia with breast tenderness, mammographic changes and benign and premalignant breast proliferative epithelial diseases with and without atypia are common with HRT. Mammographic sensitivity and specificity are decreased by the increased focal and diffuse mammographic density caused by oestrogen and/or progestogen. There is a widely perceived but incorrect belief that progestogens are beneficial for the breast in terms of symptoms and breast cancer risk; however, the opposite now appears to be the case. The small but significant risk of the diagnosis of invasive breast cancer with HRT has diverted attention in the medical literature away from the actual increase in the incidence of benign breast disease. This is well and truly counter-balanced by the many proven important health benefits of therapy in postmenopausal women including prevention of osteoporosis and improved quality of life.
Antioestrogens and breast cancer
Authors: Santhanam S , O'Byrne KJ
Published: August 2004

Antioestrogens are among the most widely used agents in the treatment of breast cancer. There has been a recent surge of interest in these compounds because of their potential breast cancer chemopreventive properties. The newer generation of antioestrogens, with increased selectivity and better toxicity profiles, have the potential to increase the effectiveness of hormonal treatment of breast cancer. The selective oestrogen receptor modulators (SERMs) hold the promise of revolutionising the care of healthy postmenopausal women with their beneficial effects on bone and lipids in addition to the chemoprevention of breast cancer.
The treatment of hyperlipidaemia in postmenopausal women
Authors: Seed Mary , Mandeno R , Le Roux C
Published: August 2004

This review summarises current evidence for therapeutic options for hyperlipidaemia in post menopausal women. The two situations in which treatment is recommended are:

1. Primary prevention, which requires assessment of total risk factors for coronary heart disease.

a) Statins. AFCAPS/TEXCAPS is the only randomised controlled trial (RCT) to include women. Fewer coronary heart disease (CHD) events, but no difference in mortality was found.

b) Hormone replacement therapy (HRT). While there are numerous reports of positive observational epidemiological studies for HRT, there are no completed RCTs. There is little evidence for statin use in women except for familial hypercholesterolaemia. HRT is therefore not only appropriate for its multiple effects on lipoproteins, vascular function and insulin sensitivity but also for prevention of osteoporosis.

2. Secondary prevention, to achieve target total and low density lipoprotein (LDL) cholesterol.

a) Statins. The major measurable effect of these drugs is to reduce total and LDL cholesterol. In the RCTs 4S, CARE and LIPID, where 20% of subjects were female, CHD events, but neither CHD mortality nor total mortality were significantly reduced in women.

b) HRT. Data available from two RCTs using conjugated equine oestrogens and medroxyprogesterone acetate show no benefit. Other studies of HRT have been observational and positive. The effects of treatment on lipoproteins with statins, HRT and the combination have been investigated. In secondary prevention for hyperlipidaemic women to achieve cholesterol <5 and LDL<3 mmol/L statins will be first choice, with HRT a possible addition for its other benefits on cardiovascular risk factors.

Choice of HRT medication. The route of administration will affect specific risk factors, eg, oral oestrogen reduces Lp(a) and LDL, increases HDL, while the transdermal route is less effective at reducing Lp(a) and LDL but does not increase triglyceride. Both routes reduce fibrinogen, factor VII and adhesion molecules and improve blood flow. The choice of progestogen will also affect cardiovascular risk factors. The most important lipid risk factors in women are HDL, triglyceride and Lp(a). The risk associated with raised triglyceride and LDL is offset by high HDL. Thus, in women with risk factors in primary prevention, theoretically oral HRT with a non-androgenic progestogen is likely to be of most benefit. However, since long-term adherence to therapy is important in reducing cardiovascular risk, the individual's choice of route and type of HRT is paramount.
Prevention of cardiovascular disease in women: evidence for the use of hormone replacement therapy
Authors: Shibata Marcelo , Lees Belinda , Collins Peter , Stevenson John , Mister Rebecca , Flather Marcus
Published: August 2004

Coronary artery disease (CAD) is the number one cause of death and disability in the Western world. Its incidence increases with age and women present with symptomatic CAD on average about ten years later than men. Rationale for using hormone replacement therapy (HRT) is based on its effects on vasoreactivity, progression of atherosclerosis, lipids and lipoproteins, effects on the haemostatic system and impaired glucose tolerance. However, unopposed oestrogen might be related to an increased risk of endometrial cancer. The overall beneficial effect of HRT on cardiovascular diseases is derived from prospective cohort studies. The Heart and Estrogen/progestin Replacement Study showed no beneficial effect of HRT on cardiovascular morbidity and mortality. However, there are uncertainties about the duration and optimal type of HRT regimen. Ongoing trials addressing similar questions are not expected to be published within the next five years. The Women's Hormone Intervention Secondary Prevention (WHISP) pilot study addresses the effect of a novel HRT regimen on lipid and haemostatic risk markers of heart disease and may pave the way for a large trial evaluating the effect of HRT on morbidity and mortality.
Clinical use of bisphosphonates in the UK
Authors: Francis RM
Published: August 2004

Bisphosphonates are synthetic analogues of naturally occurring pyrophosphate, but contain a P-C-P bond in the middle of the molecule instead of a P-O-P bond. The addition of different side chains allows many structural variations, producing bisphosphonates with a range of potencies and properties. Bisphosphonates are poorly absorbed from the bowel, but once absorbed they localise to the skeleton, where they inhibit the recruitment and function of osteoclasts. This provides a rationale for their use in the management of patients with bone diseases. Osteoporosis is characterised by a reduction in bone density, associated with skeletal fragility and an increased risk of fracture after minimal trauma. Bisphosphonates decrease bone resorption and formation, but because of the transient uncoupling of these processes, there is an increase in bone density of 5-10%. Cyclical etidronate, alendronate and risedronate decrease the incidence of further vertebral fractures, but only alendronate and risedronate have been shown to reduce the risk of hip and other non-vertebral fractures. Paget's disease is a focal disorder of bone remodelling, associated with bone pain, skeletal deformity and increased risk of fracture. Specific treatment is directed at suppressing the overactivity of osteoclasts, thereby decreasing bone turnover. Tiludronate, risedronate and iv pamidronate reduce the activity of Paget's more effectively than etidronate. Although bisphosphonates decrease bone pain and reduce the activity of Paget's disease, there is currently no evidence that any treatment will prevent skeletal deformity, fractures or other complications of the condition. The choice of bisphosphonate for the treatment of osteoporosis and Paget's disease will depend on the potential advantages and disadvantages in the individual patient.
Environmental and dietary endocrine disruptors and women's health
Authors: Holmes Philip , Harrison Paul TC
Published: August 2004

Endocrine disruptors are substances which can potentially modify the normal hormonal functions of the body, and include both naturally occurring compounds (such as plant phytoestogens) and anthropogenically derived environmental contaminants. This article reviews the evidence for possible links between exposure to anthropogenic chemicals and a number of common conditions in women, including breast cancer, cardiovascular disease and atherosclerosis, osteoporosis, endometrial disease, autoimmunity and menopausal symptoms. The question whether phytoestrogens might exert some beneficial effects during the postmenopausal period is also addressed. In addition, the possible consequences of early life exposure to potential endocrine disruptors or phytoestrogens are discussed.
Memory and the perimenopausal woman: clinical implications of recent research findings
Authors: Hurrell Eleanor , Slade Pauline
Published: August 2004

Oestrogen is thought to have a role in cognitive function, specifically verbal memory. Despite the growing evidence that memory function may be preserved in older women and surgically menopausal women through the administration of oestrogen replacement therapy, the implications for perimenopausal women remain unclear. This paper overviews the literature in this area and suggests that there are insufficient grounds at present to conclude that memory is impaired during the menopausal transition. However, given the lack of information about cognitive function in the climacteric, a number of issues are presented which may be helpful to consider in assessing women during this period who may be experiencing memory difficulties. Some directions for future research are also considered.
The pathophysiology and management of postmenopausal urogenital oestrogen deficiency
Authors: Robinson Dudley , Cardozo Linda
Published: August 2004

Increasing life expectancy has led to an increasingly elderly population and it is now common for women to spend a third of their lives in the oestrogen-deficient postmenopausal state. Oestrogen is known to have an important physiological impact on the female lower urinary tract and the loss of endogenous oestrogen is associated with the development of urogenital atrophy and lower urinary tract dysfunction, offering a rationale for prevention and treatment. Whilst the role of systemic hormone replacement therapy and the use of topical oestrogens in the management of urogenital atrophy has been firmly established, the use of oestrogens in urinary incontinence remains more controversial. Oestrogen therapy alone has been shown to have little effect in management of genuine stress incontinence, although it may have a synergistic role when used with an α-adrenergic agonist. When considering the irritative urinary symptoms associated with urinary urgency and urge incontinence, oestrogen may be beneficialalthough this may simply reflect a reversal of urogenital atrophy rather than a direct effect on the lower urinary tract. Finally, oestrogens would appear to be efficacious in the management of recurrent lower urinary tract infections, with the most convincing evidence being in support of local vaginal administration.
Cancer prevention in postmenopausal women
Authors: La Vecchia Carlo , Altieri Andrea , Brinton Louise A. , McTiernan Anne , Tavani Alessandra
Published: August 2004

The risk of breast cancer is moderately elevated in current and recent hormone replacement therapy users, with an approximate 2.3% excess risk per year of use. Some excess risk has also been reported for ovarian cancer in long-term users. Unopposed oestrogens are strongly related to endometrial cancer risk, but cyclic progestogen addition appears to reduce this side effect, possibly further increasing the risk of breast cancer. There is a moderate inverse association between colorectal cancer and hormone replacement therapy. Most potential favourable and adverse effects of hormone replacement therapy on cancer risk are restricted to current users. Selective oestrogen receptor modulators may offer advantages in reducing breast cancer risk. Regular aspirin use and high levels of physical activity induce a moderate reduction of risk for colorectal, and possibly for breast, ovarian and endometrial cancer. Overweight and obesity are strongly related to gallbladder, endometrial and breast cancer, and appear to be also related to colorectal, renal, pancreatic and ovarian cancer.
Premenopausal risk factors for osteoporosis
Authors: Walker-Bone Karen , Pearson Gill , Cooper Cyrus
Published: August 2004

Osteoporosis is a major public health problem because of its association with fractures. Prevention of osteoporosis is of utmost importance in reducing the health and human costs related to the disease. Bone mass in adult life is determined partly by the peak bone mass accrued as a young adult, and partly by the subsequent rate of bone loss. Understanding the determinants of premenopausal bone mineral status is important in order to develop a prevention strategy. Non-modifiable risk factors are heredity and race/ethnicity. Potentially modifiable are non-genetic host factors such as intrauterine programming, body build, reproductive factors, diseases and drugs, and environmental factors such as diet, exercise and smoking and alcohol.
The respiratory system and the menopause
Authors: Ojoo Josephine C. , Kastelik Jack A. , Mori Alyn H.
Published: August 2004

There is a decline in respiratory function with age that is independent of sex. However, women present with respiratory illness twice as commonly as men. This review will examine the effects of ovarian steroids on normal and abnormal respiratory function. The effects of age, menopausal status and hormone replacement therapy on specific symptoms such as dyspnoea, cough, airway hyper-responsiveness and snoring will be examined. Studies examining the effects of menopausal status and hormone replacement on the respiratory system are limited. While hormone replacement therapy may predispose to asthma, its use in women with the disease does not have an adverse effect.
Why do women have a menopause?
Authors: Finn Colin A
Published: August 2004

In all multicellular animals the female germ cells are dependent on somatic organs for successful propagation, and it is the ageing of these organs, especially the uterus in viviparous animals, which limits reproductive output. Studies on laboratory rodents have shown that females cease producing litters well before the end of life, due to failure of the uterus to carry offspring to term. At this time and at death the ovary still has a store of oocytes. The major exception to this is women, in whom the ovary is depleted of oocytes during middle age; this gives rise to the menopause. It appears that the menopause is a non-adaptive consequence of two evolutionary developments. The first, which is common to all mammals and birds, is the entry of all female gametogonia into meiosis before birth, giving a finite store of oocytes in the ovary. The second, which is common to both male and female humans, is their very greatly increased longevity compared to other mammals of equivalent size. This results in the ovary using up its store of oocytes whilst ageing processes in somatic organs are at an early stage. In view of the dual origin of the human menopause and the fact that other mammals have an equivalent period of reproductive quiescence, it is unlikely that the menopause would have evolved in response to adaptive pressure.
Treatment of postmenopausal osteoporosis: which agent at what age
Authors: Peel Nicola
Published: August 2004

A number of agents are now available which are effective in the prevention and treatment of postmenopausal osteoporosis. The management strategy of this condition will be influenced by factors including the age, clinical presentation, bone mineral density and treatment preferences of the individual woman. Assessment of fracture risk and intervention thresholds will be discussed. The available therapeutic agents and how to target treatment appropriately at different ages will be examined.
The genetics of Alzheimer's disease
Authors: Holmes Clive
Published: August 2004

A number of studies have determined a major role for genetic factors in the development of early onset familial Alzheimer's Disease (AD). These include the findings of rare, largely highly penetrant, autosomal dominant mutations in the genes coding for amyloid precursor protein, presenilin-1 and presenilin-2. In contrast, late onset AD, defined as age of onset at or after 65 years, is a complex disorder with a multi-factorial aetiology of variable genetic penetrance. To date, although a number of other candidates have been proposed, the clearest genetic risk factor associated with late onset AD remains the common ε4 polymorphism of apolipoprotein E (ApoE). The identification of new genetic risk factors for late onset AD is likely to depend upon a combination of both linkage and association studies.
The genetics of breast cancer
Authors: Mitchell Gillian , Eeles Rosalind A
Published: August 2004

Only a small proportion of all female breast cancer can be accounted for by the inheritance of a germline mutation in a cancer predisposition gene. However, for the individuals affected the risk of developing cancer can be very high. It is likely that the development of cancer may be modulated by other factors such as endogenous or exogenous hormonal exposure and research is continuing in this area to try to find preventative agents. Testing for mutations in these genes is possible, although currently a live affected family member is necessary for the identification of the specific familial mutation before predictive testing of unaffected family members is possible. Specialist genetic counselling of these families is necessary to provide information about cancer risks, advice about screening and cancer prevention and the implications for other family members.
Hot flushes in men: prevalence and possible mechanisms
Authors: Spetz Anna-Clara E , Hammar Mats L
Published: August 2004

In men treated with castration because of prostatic carcinoma hot flushes are as common as in women after menopause. Flushes also occur in normal ageing men, but the prevalence is unknown. Hot flushes are probably caused by an instability in the thermoregulatory centre, because of decreased sex hormone concentrations. Calcitonin gene-related peptide (CGRP) is involved in menopausal hot flushes in women and possibly in men with castrational therapy. Serotonin may also be implicated. Alternative treatments for hot flushes are needed, since men with prostatic carcinoma may not be treated with testosterone, and oestrogen therapy in men has many draw-backs. Therefore, development of a CGRP-antagonist may be useful. In conclusion vasomotor symptoms are common in men with castrational therapy and also exist in normal, ageing men. Since CGRP, serotonin and a decrease in sex steroids seem to be involved in hot flushes, the mechanisms behind hot flushes in men and women may be similar.
Urinary incontinence in men over 50
Authors: Edlund Christer , Peeker Ralph , Fall Magnus
Published: August 2004

Although urinary incontinence (UI) in men is an increasing problem, it has not been investigated to the same degree as that in women. In an urbanised environment, with diverse demands on health professionals, incontinence remains a problem difficult to solve not only for the individual patient but also in terms of a public health strategy, since costs related to urinary incontinence are impressive.

The prevalence of UI is increasing since this complaint is much more common in the elderly - and this section of the population is increasing in Western societies. Greater public awareness and education are further increasing demands for effective therapy for the male population.
Genetic risk factors for familial ovarian cancer
Authors: Stickeler Elmar , Runnebaum Ingo B
Published: August 2004

In Europe ovarian cancer represents the third most common cancer of the female genital tract, with 30,000 newly diagnosed patients per year. Family history is the most significant risk factor. Lifetime risk for ovarian cancer increases from 1.4% for women with a negative family history to 14.6-32.2% in women from affected families. About 5-10% of ovarian cancers are hereditary and supposed to occur in three different forms: hereditary breast and ovarian cancer syndrome (HBOC), site-specific hereditary ovarian cancer (HOC) and hereditary nonpolyposis colorectal cancer syndrome (HNPCC). HBOC and HOC account for 80-90% of the cases and are associated with inactivating germline mutations of the BRCA1 and BRCA2 genes. For BRCA1 and BRCA2 mutation carriers the cumulative risk by age 70 of developing ovarian cancer is 45-60% and 25-30%, respectively. Approximately 10-15% of familial ovarian cancers are related to the HNPCC syndrome with a cumulative ovarian cancer risk of 9% by age 70. Germline polymorphisms may further modify ovarian cancer risk. Bilateral prophylactic oophorectomy reduces the risk of developing ovarian cancer in HBOC and HOC families by 50%. Tubal ligation also significantly reduces the risk in BRCA1 mutation carriers (odds ratio 0.39). Knowledge of the genetic background provides an objective basis for individual risk assessment and prevention.
Can antioxidant nutraceuticals benefit the menopause?
Authors: Valencia Erick , Marin Angela , Hardy Gil
Published: August 2004

The antioxidants glutathione, selenium and vitamins C and E meet the criteria for nutraceuticals and their in vivo concentrations can undoubtedly influence and improve many disease processes. In an attempt to quantify and correlate their individual roles as nutritional supplements with their therapeutic potential to improve symptoms and lifestyle during the menopause, we conducted a literature search covering the 15 years up to 2001. Few publications were found dealing specifically with menopausal women. Approximately 90% reported research with vitamins and/or selenium and only one paper investigated a possible correlation between glutathione and breast cancer. This relatively low level of research interest in nutritional or antioxidant aspects of the menopause may just reflect a preoccupation with the more general chronic diseases of an ageing population, without necessarily acknowledging the important physiological changes that occur in women. The little encouraging data in the literature should stimulate more research into the prognostic value, mechanisms and efficacy of nutraceutical supplementation that specifically relate to menopausal women.
Premenopausal risk factors for coronary artery disease
Authors: Lloyd Guy W , Jackson Graham
Published: August 2004

The premenopausal period is a time when the risk of coronary events for women is low. It is, however, a key period during which the atherosclerotic process, the leading cause of death in women, becomes established. The role of female sex hormones in protecting premenopausal women from overt atherosclerosis is widely accepted. Proof of a direct oestrogen, atheroprotective effect, however, continues to prove elusive. The specific risk factors are diabetes, hypertension, lipid abnormalities, smoking, body habitus, inflammatory disease and prothrombotic tendencies. Reproductive factors do not appear to play a major role in defining cardiac risk and the absolute risk posed by the oral contraceptive is low; concerns about cardiac risk should not be exaggerated.
Sexual function after 60
Authors: May Kathryn , Riley Alan
Published: August 2004

Ageing need not herald the end of a satisfying sex life. Research shows that men and women over the age of 60 can enjoy sexual activity, and it appears to be factors arising from the male that, most frequently, influence whether or not sexual activity will continue. With improved treatments now available to treat male sexual dysfunction and an ongoing search for greater understanding of the aetiology and management of female sexual dysfunction, in addition to improved general health, it is anticipated that the proportion of sexually active older people will increase. It is the responsibility of healthcare professionals to ensure that elderly people feel comfortable seeking help for sexual difficulties and that help is made available to all, irrespective of age and sex.
Statins and menopausal health
Authors: Mueck Alfred O , Seeger Harald
Published: August 2004

Cardiovascular disease is associated with high morbidity and mortality. Cholesterol-lowering statins can reduce health risks both in men and women. While this benefit has thus far been attributed to the lipid-lowering effects of these drugs, the importance of their direct actions on vascular tissue is gaining more recognition. Furthermore, recent studies suggest that statins might also be effective in preventing osteoporosis and Alzheimer's disease. Equally interesting are experimental results showing that statins may inhibit growth of certain malignancies such as the breast.

When statins are combined with hormone replacement therapy (HRT), even greater beneficial effects on the lipid profile can be obtained. To our knowledge we have investigated for the first time direct vascular effects by combining statins with HRT. We were able to identify significant beneficial effects on endothelial function and vascular smooth muscle proliferation. In the context of current discussions on the benefits and risks of HRT in treating patients with pre-existing cardiovascular disease, it appears particularly important that interventional studies should be conducted to evaluate the therapeutic relevance of statin/HRT combinations. At present, this is the most important conclusion drawn from the data collected thus far on the combination of these two drug types. There is some evidence suggesting drug-specific effects, particularly adverse reactions and statin interactions, which should be considered when using this combination therapy.
Homeopathy and the menopause
Authors: Thompson Elizabeth A
Published: August 2004

Significant numbers of patients in developed countries use complementary, alternative, or unconventional medicine. Homoeopathy is one of the most widespread and controversial of these therapies and has been used for over 150 years. There are two main theoretical tenets: the principle of "similars" and the use of dilutions called "potencies". The principle of "similars" states that patients with particular signs and symptoms can be cured if given a drug that produces the same signs and symptoms in a healthy individual. The second principle is that remedies retain biological activity if they are repeatedly diluted and agitated or shaken between each dilution. Data from case histories, observational studies and uncontrolled trials suggest that the homeopathic approach can offer a clinically relevant choice for women with menopausal symptoms and those with breast cancer whether they are taking tamoxifen or not. Randomised controlled trials are being conducted to investigate this potential benefit.