bluuebunny/crossref_metadata_2025 huggingface dataset:
Nutrition and osteoporosis
Authors: Nordin BE Christopher
Published: August 2004

Osteoporosis is best defined in terms of whole bone density (apparent density) and is present when this variable falls below the young normal range. Low bone density may be genetically determined or acquired. If acquired it may in principle be due to low bone formation or high resorption. It is most easily produced in experimental animals by calcium deprivation and/or ovariectomy, both of which induce high bone resorption; their effects are additive. The postmenopausal rise in bone resorption is associated with a fall in calcium absorption and a renal tubular leak of calcium which combine to increase requirement of this element but there is also an increase in the sensitivity of bone to resorbing agents. Calcium supplementation inhibits postmenopausal bone loss but not as effectively as oestrogen. Protein and sodium are nutrients which increase calcium requirement by increasing obligatory urine calcium loss. Vitamin D is a nutrient, the deficiency of which increases the risk of hip fracture and the administration of which (with calcium) has been shown to reduce the risk of this fracture in vulnerable nursing-home residents. The implications of these findings are that postmenopausal women should ingest more calcium than premenopausal women, be moderate in their consumption of protein and salt, and receive vitamin D supplementation if their 25-hydroxyvitamin D level falls below about 50 nmol/L.
The ageing process
Authors: Sayer Avan Aihie , Cooper Cyrus
Published: August 2004

Ageing may be simply defined but is yet to be well understood. Research in this area is considered a priority, with the population growing older and increasing disability, morbidity and mortality predicted. There are many theories and ageing has been described from changes at the molecular level to characteristics of ageing populations. However, distinguishing cause from effect has proved problematic largely because the underlying reasons for ageing have not been understood. Progress has now been made and the central role for repair processes is increasingly accepted. A number of approaches to modifying ageing have been explored but the only reliable method to alter the rate remains diet restriction. Instituted after weaning, diet restriction slows ageing in a number of species and has an opposite effect when started in earlier life. There is now preliminary evidence that poor early growth is associated with increased human ageing and this is an important area for future research.
Identification of women at high risk of osteoporosis in primary care
Authors: Hodson Jean , Pearson Derek
Published: August 2004

A pilot study was undertaken in 500 women to examine clinical risk factor enquiry and ultrasound densitometry as methods for identifying women at high-risk of osteoporosis in a primary care setting. As a "stand-alone" procedure for dual-energy X-ray absorptiometry (DXA) selection, ultrasound densitometry was as good as clinical risk factor enquiry. However, in combination these methods provided complementary information that increased prediction for osteoporosis. This type of service could easily be used in primary care to identify women at high-risk of osteoporosis and improve cost effectiveness of DXA selection.
Hormone replacement therapy and the eye
Authors: McKinney Karen A. , Buchanan Trevor A.S.
Published: August 2004

Over the past 20 years there has been a revolution in the management of the menopause and the use of hormone replacement therapy (HRT). As the focus on postmenopausal health changes from symptomatic relief to the protective benefits of long-term HRT both ophthalmologists and gynaecologists can expect questions to be asked by their female patients about the influence of HRT on ophthalmic disease. This paper is a review of the current best evidence of effects of HRT on the eye. As oestrogens exert significant influences on the structure and function of ocular structures, we can assume that a reduction in oestrogen levels will have a negative effect on ocular physiology and may play a role in pathological processes in the eye. There is no evidence that HRT is harmful to ocular tissues; case reports point to a beneficial effect of HRT in relation to dry-eye, cataract and macular degeneration in post menopausal women. HRT probably suppresses the formation of cataracts in postmenopausal women and may reduce the incidence of serious retinal disease.
The role of hormone replacement therapy in women with a current or past history of endometriosis
Authors: Prentice Andrew
Published: August 2004

Endometriosis is an oestrogen sensitive condition, leading to reluctance to prescribe hormone replacement therapy. Treatment of endometriosis either medically with gonadotrophin releasing hormone analogues or with surgery involving bilateral oophorectomy leads to oestrogen deficiency. While this may lead to vasomotor symptoms, the consequence which has been of most concern is a reduction in bone mass. Repeated courses of gonadotrophin releasing hormone analogues may mean that women with endometriosis enter the menopause with a below average bone density. Thus, there is a place for hormone replacement therapy both as add-back therapy in premenopausal women receiving gonadotrophin releasing hormone analogues, and in postmenopausal women with a past history of endometriosis. Addback therapy with continuous combined regimes and tibolone do not prevent disease resolution in the hypogonadal patient. The evidence regarding the use of hormone replacement therapy in patients with a history of endometriosis is poor, but suggests that we could be less conservative than we have been.
Compliance or concordance?
Authors: Brockie Janet
Published: August 2004

The discussion over the correct term to describe effective treatment taking continues, but may prove to be a distraction from the real issue which is that uptake and continuation of hormone replacement therapy remain low. "Compliance" continues to be widely used to describe treatment problems, despite criticisms of its implied doctor/patient relationship, but has the benefit of being familiar. Compliance is also poor with other treatments, such as antihypertensives. Numerous issues affect compliance with hormone replacement therapy: lack of information, attitude and gender of the doctor, side effects, lack of symptom control, dislike of bleeding and fear of long term consequences. Nurses and pharmacists can help doctors in providing an integrated health care team. More research is required to address the process of decision making by women as to whether they take hormone replacement therapy or not.
New emerging risk factors for cardiovascular disease: their relation with menopause and hormone therapy
Authors: Smolders Raimond G.V. , Van Der Mooren Marius J.
Published: August 2004

Cardiovascular disease is the leading cause of death in women over the age of 60. Over the last decade it has become clear that many physiological mechanisms are influenced by female sex hormones. New cardiovascular risk factors and markers are being identified. The changes in cardiovascular risk factors with menopause and hormone replacement therapy are reviewed. Types and routes of hormone replacement therapy and the effect of addition of progestogens are discussed where data are available. Lipids, coagulation, inflammation, endothelin-1 and homocysteine are examined.
Pathogenesis, prevention and treatment of transplant-associated osteoporosis
Authors: Fraser William D
Published: August 2004

A reduction in bone mass is observed in a high percentage of patients following organ or marrow transplantation, with the prevalence of osteopenia or osteoporosis reported to be as high as 80%. Between 4 and 65% of transplant recipients will experience an osteoporosis-related fracture and the likelihood of such a serious outcome is dependent on pre-existing disease and immunosuppressive therapy. End-stage pulmonary disease is commonly associated with a reduction in BMD; chronic liver disease with osteomalacia and osteoporosis; and renal patients are often recognised to have osteodystrophy, osteopaenia or osteoporosis at the time of transplantation. Post-transplant glucocorticoid therapy plays a major role in the further reduction in bone mass observed in these patients. Glucocorticoids have several effects deleterious to the skeleton, transiently increasing bone resorption then subsequently inhibiting both osteoclast and osteoblast activity. They also interfere with calcium, vitamin D and PTH metabolism. The additional role of other immunosuppressant treatments in bone loss is less clear but there is some evidence to suggest that cyclosporin A (CsA) and tacrolimus (FK506) result in high bone turnover osteopenia. CsA can also result in hypogonadism when used in high doses and hypomagnesaemia which can contribute to a reduction in bone mass. Comparative studies in renal transplant patients have suggested that CsA monotherapy has less of an effect on BMD than combination therapy with glucocorticoids. Newer immunosuppressants such as rapamycin are believed to have minimal effects on bone metabolism compared to CsA or FK506. Although some variability exists in the studies reporting bone related outcomes following transplant, current evidence suggests that the cumulative dose of glucocorticoid, male gender, increasing age and development of an early menopause as a result of treatment are the factors associated with severe bone disease. Since the greatest loss of bone is observed in the first 3-6 months following transplant, coincident with glucocorticoid therapy, strategies to prevent bone loss should be directed at the peri-operative period. Reduction in the use of glucocorticoids by using steroid-sparing combination therapy has been effective and in cardiac transplant patients the use of vitamin D or its analogues in combination with calcium has also proved beneficial. Early reports of the use of intravenous pamidronate are encouraging with improved BMD and significant reductions in fractures reported.
Determinants and assessment of bone strength
Authors: Keen Richard
Published: August 2004

Osteoporosis is a systemic skeletal disease characterised by low bone mass and micro-architectual deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Bone mineral density is a major component of bone strength and is predictive of future fracture risk. It is possible to measure BMD non-invasively at various skeletal sites using dual energy absorptiometry. Techniques such as quantitative ultrasound and magnetic resonance imaging also provide additional information on other facets of skeletal strength, although at present further research is required before they are incorporated into routine clinical practice. There is currently much interest in identifying factors involved in the determination of BMD and bone strength. Based on this knowledge, it may be possible to identify subjects who will have low BMD and will therefore be at risk of future fracture. Lifestyle interventions and drug treatments could therefore be targeted to "high risk" subjects to reduce the burden of osteoporotic fractures.
The impact of hormone replacement therapy on breast cancer patients' quality of life and sexuality: a pilot study
Authors: Marsden Jo , Baum Michael , A'Hern Roger , West Andrea , Fallowfield Lesley , Whitehead Malcolm , Sacks Nigel
Published: August 2004

Objective. The effect of hormone replacement therapy (HRT) on the sexual functioning and quality of life of breast cancer patients has not received significant attention.

Study design. One hundred postmenopausal women with early stage breast cancer who were experiencing vasomotor symptoms and/or vaginal dryness participated in a randomised trial of HRT.

Main outcome measures. Women completed questionnaires at three and six months to determine changes in their quality of life, vaginal dryness and sexual activity.

Results. At baseline, 52% (49/94) of patients were sexually active. Lack of a partner was the main reason for sexual inactivity (38% (17/45)). HRT had no significant effect on the proportion of women complaining of vaginal dryness or the severity of this symptom. HRT did not increase the proportion of women who were sexually active (53%(43/81)) but was associated with non-significant trends for improvements in pleasure and reduction of discomfort during intercourse. Non-significant trends towards improvements in physical functioning, sleep disturbance and fatigue were observed with HRT. Patient numbers were too small to determine whether the concomitant use of tamoxifen influenced any of these outcomes.

Conclusions. Lack of a significant improvement in quality of life with HRT may reflect the possibility that patient concern about HRT negated its symptomatic benefits. Failure of HRT to improve vaginal dryness may partly account for a lack of improvement in sexual functioning. There is a need for evaluation of interventions to improve sexual functioning in breast cancer patients but the use of hormonal therapy should be restricted to controlled trials.
DHEA and the menopause: a new approach to HRT?
Authors: Raven Peter W. , Hinson Joy P.
Published: August 2004

Dehydroepiandrosterone (DHEA) is the major steroid product of the adrenal cortex yet it still remains controversial as to whether it is a true hormone. The regulation of DHEA is poorly understood and no specific receptor has been characterised. Despite this, the use of DHEA as an anti-ageing treatment outside medical supervision has been increasing over recent years as people attempt to restore the levels seen in early adulthood. DHEA has also been advocated as a possible treatment for menopause, with some practitioners even suggesting it as an alternative to standard hormone replacement therapy. The proponents of DHEA replacement therapy claim positive actions on cardiovascular and immune systems, together with beneficial effects on bone metabolism and mood. In fact, there have been very few well planned randomised, placebo-controlled, double-blind clinical trials and there is very little clinical evidence to support the hope invested in this hormone. Further clinical trials are urgently needed.
Hot flushes and serotonin
Authors: Berendsen Hemmie HG
Published: August 2004

Hot flushes are experienced by the majority of menopausal women especially in the perimenopause. They are the most characteristic menopausal symptom. Hypogonadal men also suffer from hot flushes. Enough evidence exists to suggest that oestrogen withdrawal is probably the main cause of hot flushes. They are mainly experienced when circulating oestrogen levels are low and are successfully treated by replacing this steroid. However, it is clear that other non-hormonal mechanisms play an important role in the pathophysiology of hot flushes. The neurotransmitter serotonin seems to be especially involved. This review examines the involvement of serotonin in hot flushes and especially the role of the 5-HT2A receptor subtype. It is concluded that non-hormonal treatment with either 5-HT2A receptor antagonists or 5-HT2C receptor agonists may have several advantages over hormonal therapy.
Hormone replacement therapy in an anti-ageing strategy for men
Authors: Comhaire Frank
Published: August 2004

During male ageing important changes occur in the neuroendocrine environment. The most remarkable are the decreased secretion of melatonin, growth hormone, dehydroepiandrosterone, and testosterone. Hormone replacement with each one of these substances has been proposed, but few data are available on the long-term effects. Today, testosterone replacement seems to offer the most promising option. New delivery systems are under development that can restore circulating physiological testosterone levels, including circadian variability. Limited experience with a novel sustained release buccal tablet given to ageing men with subnormal testosterone concentrations suggests that optimal replacement decreases cholesterol, triglycerides, and prostate specific antigen (PSA) levels, without inducing any change in haematocrit or other vital parameters.
Androgen therapy for ageing men: the implications for arterial disease
Authors: Crook David
Published: August 2004

Steroid hormones such as oestradiol and testosterone have long been viewed as a key to long-term health. Although men do not undergo the precipitous fall in endogenous steroid hormone levels characteristic of the menopause, there is substantial interest in the therapeutic potential of low dose androgen therapies to maintain mental, skeletal and other aspects of health. Testosterone and other androgens seem to conform to the "clutch pedal" theory of hormone action. In terms of atherosclerosis, if plasma androgen levels are too low they may cause disease, but, if they are too high, atherosclerosis may also become a problem. Thus, the rationale for the use of low doses of androgens in ageing males is becoming compelling. Studies of arterial disease surrogates, such as plasma protein levels, may help optimise these therapies but the final answer on disease can only come from formal placebo-controlled trials of clinical endpoints.
Herbalism and the menopause
Authors: Ernst Edzard
Published: August 2004

Herbal medicinal products are often sold as a safe and effective alternative to HRT. Sizeable sets of trial data exist for black cohosh and soy. For other herbal medicines, only isolated trials have emerged, and their number is too low to enable one to arrive at valid conclusions. Collectively the data for black cohosh do not prove efficacy. The evidence for soy is encouraging but not compelling. Neither black cohosh nor soy is associated with major safety problems. Further research is warranted to closer define the role of herbal medicines for the menopause.
Managing women with coronary artery disease
Authors: Jackson Graham
Published: August 2004

Coronary artery disease is the greatest cause of death and disability in women. Women often have atypical chest pain which should be thoroughly evaluated. Women benefit as much as men from coronary care, thrombolysis, coronary artery bypass grafts and coronary angioplasty but are more likely to have advanced disease, and be hypertensive, diabetic and older at presentation- and thereby have increased complications and mortality. All clinical trial data published so far does not identify HRT therapy as a means of preventing or treating CAD. Since women are older at presentation they are vulnerable to age bias, which may therefore appear to be gender bias.
Management of hot flushes without oestrogen
Authors: Albertazzi Paola
Published: August 2004

Hot flushes are probably the most common symptom resulting in medical consultation in relation to the menopause. The association between the two is so strong that the connection is often invoked even when hot flushes occur in a regularly menstruating woman. Oestrogen significantly reduces hot flushes but is not used by all women—either because of contraindications or a reluctance to take oestrogen-based therapy. In addition, hot flushes may persist in spite of adequate oestrogen replacement, and physicians are often faced with the dilemma of finding something instead of, or in addition to, oestrogen for symptom relief. The available alternatives for the management of hot flushes are reviewed.
No increased risk of endometrial hyperplasia with fixed long-cycle hormone replacement therapy after two years
Authors: Erkkola Risto , Kumento Ulpu , Lehmuskoski Sirpa , Mattila Leena , Mustonen Mika
Published: August 2004

The appropriate dose of progestogen during long-cycle hormone replacement is still under debate. We present preliminary two-year results from an open five-year clinical trial of 132 postmenopausal women. All subjects had long-cycle HRT consisting of 70 days 2 mg oestradiol valerate (E2V), followed by 14 days 2 mg E2V plus 20 mg medroxyprogesterone acetate, and a seven-day hormone-free period. No endometrial samples with hyperplasia or indicative of malignancy were found at 24 months.
Symptom reporting at menopause: a review of cross-cultural findings
Authors: Lock Margaret
Published: August 2004

Extensive cross-cultural and comparative research reveals that the majority of women do not find the menopausal transition a difficult time. This research also shows considerable variation in symptom reporting at the end of menstruation. It is argued that socio/cultural variables, including language usage and expectations about the menopausal experience, do not fully account for these differences, and that biological variation must also be taken into account. In those societies where subjective reporting of symptoms, including vasomotor symptoms, is low, such findings should not be dismissed as the result of learned cultural expectations that mask reality.
Changes in body composition at menopause—age, lifestyle or hormone deficiency?
Authors: Sørensen Morten B
Published: August 2004

One of the major concerns of perimenopausal women is obesity—and for a good reason. Both general and abdominal obesity as well as loss of skeletal muscle (sarcopenia) are accelerated through the menopausal transition and lifestyle changes as well as sex hormone deficiency play important roles. Most well conducted clinical trials have demonstrated hormone replacement therapy induced reversal or at least impairment of menopausal changes in body composition and the common worry that it causes weight gain is unsubstantiated. Coaching of weight loss in obese individuals is often a frustrating task but is nevertheless of immense importance because of the health hazards of obesity. Through the climacteric period, short-term hormone replacement therapy, with or without androgens for preservation of muscle mass, might inhibit obesity and this is likely to boost motivation for introduction of more comprehensive and long-lasting initiatives linked to persistent weight loss and long-term health benefit.
Women's health in midlife: findings from a British birth cohort study
Authors: Kuh Diana , Hardy Rebecca
Published: August 2004

The Medical Research Council's National Survey of Health and Development (MRCNSHD) is a prospective cohort study of 2547 women and 2815 men, a sample of all the births that took place in England, Scotland and Wales between 3-9 March 1946. It is one of the longest running large-scale studies of human development in the world, aiming to identify lifetime biological, social and psychological pathways to health and disease, from early life to ageing. A special study of women's health in midlife and the menopausal transition in this cohort was undertaken by sending to women study members eight annual postal questionnaires from when they were 47 to when they were 54 years old. The findings from the women's health study so far have highlighted associations between multiple risk factors at each life stage, and women's health and disease in later life. The authors suggest that a life course approach may provide a better understanding of women's health during the middle years of life than an approach which restricts itself to contemporary social or hormonal experiences. Of particular interest are their results linking ovarian ageing to developmental factors. Replication of these findings in other life course cohorts is being sought.
Hormone replacement therapy and epithelial ovarian cancer: is there and association?
Authors: Riman Tomas
Published: August 2004

Recently it was estimated that about one-third of postmenopausal British women aged 50-64 years currently uses hormone replacement therapy (HRT) for treatment of climacteric symptoms and for other medical reasons. To reduce an excess risk of endometrial cancer induced by oestrogens, modern HRT regimens contain either sequential or continuous progestogens. The protective effect of parity and oral contraceptive use observed in the majority of epidemiological studies on epithelial ovarian cancer (EOC) suggest that hormonal factors are likely to operate in ovarian carcinogenesis. However, the studies where HRT was examined in relation to the risk of EOC have reported conflicting results. The objective of this epidemiological review is to evaluate the risk of EOC in relation to the use of HRT, with particular focus on the few studies where oestrogens and progestogens in HRT were assessed separately. Further, the findings regarding HRT and EOC risk will be discussed in the context of available aetiological hypotheses. Finally, any clinical implications are commented upon.
Understanding the implications of population ageing for mid-life women
Authors: Harper Sarah
Published: August 2004

Population ageing now affects every region of the world, with all societies beginning to adopt a mature demographic profile. Falling fertility and increased longevity impact upon women's transitions as workers, carers, mothers and grandmothers, and also on the social structures within which these individual roles and responsibilities occur. Shifts from a high-mortality/high-fertility society to a low-mortality/low-fertility society and the ageing of family transitions have significant implications for both family relationships and kinship roles. Low-mortality/low-fertility results in an increase in the number of living generations, and a decrease in the number of living relatives within these generations. Women in mid-life will thus face increasing care demands as children of frail parents and mothers of adult working children with children. In addition, they will increasingly face mid and late life divorce, and the new demands of reconstituted or step families. This will occur within the framework of reduced extended kin to call upon for practical and psychological support.
Managing postmenopausal health
Authors: Rees Margaret CP
Published: August 2004

summary

The ageing and expanding of the female population led to the design of the Women's Health Initiative (WHI) to examine strategies for the prevention and control of some of the most common causes of morbidity and mortality among postmenopausal women. The diseases of old age are cardiovascular disease, cancer, osteoporosis and dementia. This review reassesses current strategies to manage postmenopausal health in terms of their risks and benefits. Some commonly used pharmacological and non-pharmacological interventions are discussed, including hormone replacement, bisphosphonates, raloxifene, calcium and vitamin D supplementation, and hip protectors. It is essential to evaluate critically the findings of all studies and decide whether they are relevant to particular individuals, rather than apply findings generically. Women are now turning to dietary supplements and alternative and complementary therapies, but caution has to be exercised in view of current paucity of evidence.
Long-term adherence to continuous combined HRT: Seven-year update on the Heikkinen study
Authors: Van De Weijer Peter Hm
Published: August 2004

The Heikkinen study is a randomised double-blinded study of the effects of six different continuous combined HRT regimens (Indivina, estradiol valerate and medroxyprogesterone acetate, Orion Pharma Finland). Four-hundred-and-nineteen healthy postmenopausal women received 1 or 2 mg oestradiol valerate (E2V) with either 2.5 or 5 mg medroxyprogesterone acetate (MPA).

In two groups, the dose of E2V was increased from 1 to 2 mg after six months of treatment. Women recorded their symptoms and were reviewed by clinic staff at regular intervals. After two years, all treatment arms experienced significant improvements in bleeding patterns and climacteric symptoms. After seven years of therapy, adherence continues to be good, with nearly 78% of the women in the 1 mg E2 V groups and almost 60% of the women in the 2 mg E2 V groups remaining in the study. The majority of the women who discontinued therapy were taking the 2 mg E2 V + 2.5 mg MPA dose combination. Improvements in lipid profile and bone mineral density have been maintained and endometrial protection has been safeguarded. A total of 97 subjects (23.2%) presented with a serious adverse event over the course of the study period. In 60 subjects (14.6%) adverse events were possibly related to treatment. There were fewer treatment-related adverse effects in women in the lowest-dose group compared to the higher-dose E2 V groups (p<0.001). Quality of life in the study population was rated as better than that of an age- and sex-matched sample of the general population (p<0.05).
Management of endocrine resistant breast cancer
Authors: Sundar Santhanam , Decatris Marios P , O'Byrne Kenneth J
Published: August 2004

Metastatic breast cancer (MBC) may present de novo but more commonly develops in women initially presenting with early breast cancer despite the widespread use of adjuvant hormonal and cytotoxic chemotherapy. MBC is incurable. Hormone sensitive MBC eventually becomes resistant to endocrine therapy in most women. Anthracyclines are the agents of choice in the treatment of endocrine resistant MBC. With the widespread use of anthracyclines in the adjuvant setting, taxanes have become the agents of choice for many patients. Recently capecitabine has become established as a standard of care for patients pretreated with anthracyclines and taxanes. However, a range of agents have activity as third line treatment. These include gemcitabine, vinorelbine and platinum analogues. The sequential use of non-cross resistant single agents rather than combination therapy is preferable in most women with MBC. Even though combination therapy can improve response rates and increase progression free interval, there is no robust evidence to indicate an advantage in terms of overall survival. Moreover, combination therapy is associated with a higher toxicity rate and poor quality of life. There is no role for dose-intense therapy, high dose therapy or maintenance chemotherapy outside the context of a clinical trial. The introduction of trastuzumab, monoclonal antibody targeting growth factor receptors, has improved the therapeutic options for women with tumours overexpressing HER2/neu. DNA micro-array profiles of tumours can potentially help to individualise therapy in future. Molecular targeted therapy has the potential to revolutionise the management of MBC.
Red Clover Isoflavones in Practice: A Clinician's View
Authors: Pitkin Joan
Published: August 2004

The subject of phytoestrogen use must be seen against the background of increasing controversy surrounding the role of hormone replacement therapy. Phytoestrogens such as those derived from red clover may help with hot flushes, which are a common menopausal complaint. Red clover isoflavones have more evidence base than most herbal medicinal products, although the literature is beset by difference in methodologies making direct comparison between studies difficult. There certainly does not appear to be any increased risk for women with breast cancer, who often suffer severely from sweats and flushes. There is currently insufficient evidence to recommend its use for bone protection in a group of women who are at high risk.
Toxic metals and the menopause
Authors: Vahter Marie , Berglund Marika , Åkesson Agneta
Published: August 2004

Toxicity of chemicals and environmental pollutants may be expressed differently in women than in men. Until recently, most research involved men. With the initiation of studies on the effects of environmental pollutants in women, there is increasing evidence of effects at specific periods in a woman's life; however, accrual of data is slow. This review focuses on the kinetics and effects of the toxic metals lead and cadmium related to menopause. Data on other metals are extremely limited. One of the few well described examples of menopausal-related effects of metals is the very painful disease called Itai-itai, which is a combination of osteoporosis, osteomalacia and renal damage caused by consumption of cadmium-polluted rice. Recent data demonstrate mild effects of cadmium on both kidney and bone with present environmental exposure levels. Women may be at greater risk than men, because of increased gastrointestinal uptake of cadmium at low iron stores, which is common in women of childbearing age. Thus, improvement of iron status, which often occurs at menopause, has a positive effect on cadmium exposure in the sense that its absorption decreases. Cadmium accumulates in the kidney with a half-life of 10-30 years. The health effects appear around menopause, concurrent with the peak in renal cadmium concentrations. About 90% of body lead is localised to bone. There is a significant release of bone lead after the menopause, in association with the acceleration of bone resorption. Thus, postmenopausal women may be at increased risk of adverse effects of lead.
The use of testosterone after menopause
Authors: Davis Susan R.
Published: August 2004

There is now substantial evidence from randomised controlled trials that testosterone therapy will improve sexual satisfaction and mood in surgically menopausal women treated with concurrent oestrogen, with less data in naturally menopausal women and premenopausal women. However, long-term safety data for combined-oestrogen testosterone therapy are lacking, and the effects of testosterone-only therapy in postmenopausal women are unknown. Although there appears to be considerable potential for testosterone to improve the quality of life for selected women, inappropriate and/or excessive use of testosterone carries the risk of masculinisation and possibly more serious side effects. All women treated with testosterone need to be carefully monitored both biochemically and clinically and should have long term follow up for adverse sequelae.
QSAR study of β‐lactam antibiotic efflux by the bacterial multidrug resistance pump AcrB
Authors: Ferreira Márcia M. C. , Kiralj R.
Published: August 2004

AcrAB‐TolC is the most important efflux pump system of Gram‐negative bacteria, responsible for their resistance to lipophilic and amphilic drugs. In this work, HCA–PCA studies were performed to investigate the relationship between efflux activities (negative logarithm of minial inhibitor concentration, pMIC) of three strains of S. thypimurium with respect to β‐lactams, and to analyze the relationship between lipophilicity parameters calculated by different methods. The analyses demonstrate that pMICs strongly depend on properties of both bacterial strains and drug molecules, and that lipophilicity parameters do not necessarily contain the same information about the drugs. QSAR studies have shown that the calculated lipophilicities, in some cases, are non linearly related to the pMICs originated by active AcrAB‐TolC bacterial pumps, due to the existence of β‐lactams with nitrogen‐ and sulfur‐rich substituents. Among the most important β‐lactam molecular properties quantitatively related to pMICs are lipophilicity and electronic and hydrogen–bonding properties. Parameters describing these properties were included in the QSAR study to obtain parsimonius regression models for MICs. β‐Lactams were classified as good, moderately good and poor AcrAB‐TolC substrates. Their stereoelectronic molecular properties, especially the Y‐component of the molecular dipole moment and hydrogen binding properties, reflected this classification. Copyright © 2004 John Wiley & Sons, Ltd.
Marginal zone B cell enrichment and strong follicular B cell reduction correlate with a delayed IgG response in a light chain diversity restricted mouse model
Authors: Amrani Yacine M. , Voegtlé Danielle , Barbier Eliane , Six Adrien , Cazenave Pierre‐André
Published: August 2004

Recently developed B6.κ–λSEG mice (by crossing κ– and C57BL/6 mice congenic for the wild Mus spretus SEG strain λ locus lacking genes coding for λ1 and λ3) have a very reduced light chain diversity. B6.κ–λSEG mice produce only λ2 and λx light chains. Regardless of their Igh haplotype, B6.κ–λSEG mice show a restricted B cell distribution by light chain subtype with λx dominance in all peripheral compartments except peritoneal cavity where λ2 is dominant. This distribution suggests that selection mechanisms act differently in different B cell compartments on λ2 and λx bearing B cells. Sequence analysis before or following immunization did not reveal unusual mechanisms of diversification. B6.κ–λSEG mice still respond to various challenging antigens using new Ab patterns. In particular, regardless of Igha or Ighb haplotypes, the anti‐2,4‐dinitrophenyl response is characterized by a restricted diversity for both heavy and light chains and a delayed IgG response when compared to B6 and B6.κ– mice. We suggest that the delayed IgG response is due to the expansion of marginal zone B cells whereas follicular B cells are strongly reduced.
Molecular and functional characterization of a CS1 (CRACC) splice variant expressed in human NK cells that does not contain immunoreceptor tyrosine‐based switch motifs
Authors: Lee Jae Kyung , Boles Kent S. , Mathew Porunelloor A.
Published: August 2004

CS1 (CRACC, novel Ly9) is a novel member of the CD2 family expressed on natural killer (NK), T and stimulated B cells. Although the cytoplasmic domain of CS1 contains immunoreceptor tyrosine‐based switch motifs (ITSM), which enables to recruite signaling lymphocyte activation molecule (SLAM)‐associated protein (SAP/SH2D1A), it activates NK cells in the absence of a functional SAP. CS1 is a self ligand and homophilic interaction of CS1 regulates NK cell cytolytic activity. Here we have identified a novel splice variant of CS1 (CS1‐S), which lacks ITSM. Human NK cells express mRNA for both wild‐type CS1 (CS1‐L) and CS1‐S and their expression level remained steady upon various stimulations. To determine the function of each isoform, cDNA for CS1‐L and CS1‐S were transfected into the rat NK cell line RNK‐16 and functionally tested using redirected cytotoxicity assays and calcium flux experiments. CS1‐L was able to mediate redirected cytotoxicity of P815 target cells in the presence of monoclonal antibody against CS1 and a rise in intracellular calcium within RNK‐16 cells, suggesting that CS1‐L is an activating receptor, whereas CS1‐S showed no effects. Interestingly, SAP associated with unstimulated CS1‐L and dissociated upon pervanadate stimulation. These results indicate that CS1‐L and CS1‐S may differentially regulate human NK cell functions.
Cdk2 activation acts upstream of the mitochondrion during glucocorticoid induced thymocyte apoptosis
Authors: Granés Francesc , Roig Maurici B. , Brady Hugh J. M. , Gil‐Gómez Gabriel
Published: August 2004

Thymocytes undergo apoptosis during negative selection in vivo and following treatment with glucocorticoids or DNA‐damaging drugs in vitro. The post‐mitochondrial biochemical steps leading to apoptosis induced by these stimuli are well characterized, however, much less is known about the pathways connecting receptor triggering, apical caspase activation and induction of mitochondrial dysfunction. These stimuli specifically activate the kinase Cdk2 and this step is obligatory for these forms of thymocyte apoptosis. We report here that Cdk2 activation is a very early step during thymocyte apoptosis preceding apical caspase activation and phosphatidylserine exposure. Furthermore, Cdk2 activation is required for mitochondrial permeability disruption, cytochrome c release and, as a consequence, activation of the downstream caspases 9 and 3. Our data allow an integrated linear pathway regulating DNA damage and glucocorticoid‐induced thymocyte apoptosis to be proposed.
Frontline: IL‐7 does not prevent pro‐B/pre‐B cell maturation to the immature/sIgM+ stage
Authors: Milne Craig D. , Fleming Heather E. , Paige Christopher J.
Published: August 2004

IL‐7 plays many fundamental roles during murine B lineage development. One reported function is to maintain progenitors in a developmentally immature state by preventing differentiation to the surface IgM (sIgM)+ stage. Withdrawal of IL‐7 from cultures has been shown to lead to increases in mature traits such as RAG expression, IgL rearrangements and expression of sIgM. These observations have been interpreted as an inductive event promoting the differentiation of progenitor cells. In contrast to this, we reproducibly observe sIgM+ cells that have differentiated in cultures containing IL‐7. We find that sIgM+ cells arise as a normal consequence when B lineage cells are cultured in the presence of IL‐7. However, these cells are short‐lived and are quickly replaced by newly emerging sIgM+ cells that differentiate from sIgM– progenitors. Withdrawal of IL‐7 from these cultures only prevents the survival and proliferation of CD2–sIgM– pro‐B cells but does not change the number of cells that differentiate to the sIgM+ stage. This changes the ratio of sIgM–:sIgM+ cells and results only in an apparent maturation of the culture as a whole. Therefore withdrawal of IL‐7 from these cultures acts as a selection event, not an induction event, for populations that are normally present.

See accompanying commentary http://dx.doi.org/10.1002/eji.200425532
Frontline: Self‐peptides that bind with low affinity to the diabetes‐associated I‐Ag7 molecule readily induce T cell tolerance in non‐obese diabetic mice
Authors: Ferlin Walter G. , Mougneau Evelyne , Hugues Stéphanie , Appel Heiner , Jang Mei‐Huei , Cazareth Julie , Beaudoin Lucie , Schricke Corinne , Lehuen Agnès , Wucherpfennig Kai W. , Glaichenhaus Nicolas
Published: August 2004

Although non‐obese diabetic (NOD) mice spontaneously develop T cell autoimmunity, it is not clear whether this phenomenon results from a defect in tolerance to self‐Ag. Furthermore, as autoimmunity has been postulated to result from T cell responses directed toward self‐peptides that bind with low affinity to NOD I‐Ag7 MHC class II molecules, it is important to determine whether the expression of such peptides induces tolerance. We have constructed NOD transgenic (Tg) mice expressing the Leishmania antigen receptor for C kinase (LACK) Ag in either the thymus or pancreatic β cells. We identified LACK peptides that were the targets of T cells in LACK‐immunized NOD mice while binding to I‐Ag7 with low affinity. While CD4+ T cells from NOD mice secreted IFN‐γ, IL‐4, IL‐5 and IL‐10 in response to LACK, those from LACK‐expressing Tg mice secreted reduced levels of cytokines. Experiments using peptide/MHC multimers showed that LACK‐expressing Tg mice exhibited self‐reactive CD4+ T cells with impaired proliferation capabilities. Hence, even self‐peptides that bind to I‐Ag7 with low affinity can induce tolerance in NOD mice. This result is important in light of the commonly held hypothesis that T cells reacting to peptides that bind to MHC with low affinity escape tolerance induction and cause autoimmunity.
Mini‐review: Overcoming tumor‐intrinsic resistance to immune effector function
Authors: Ganss Ruth , Arnold Bernd , Hämmerling Günter J.
Published: August 2004

In immunological cancer therapy, the current treatment emphasis is on the generation of effector cells that are specific for tumor antigens. However, there is a distressing lack of correlation between the induction of specific immunity in cancer patients and measurable clinical benefit. By studying mouse models of de novo tumorigenesis we are beginning to understand that the tumor itself, in particular the manifestation of a distinct tumor environment, impairs immune effector function; this concept is yet to be applied in human malignancy.
A Bayesian approach to compare observed rainfall data to deterministic simulations
Authors: Sansó Bruno , Guenni Lelys
Published: August 2004

We compare ground rainfall with purely deterministic Regional Climate Model (RCM) simulations within a Bayesian framework. A truncated normal model is fitted to the observed ground data to represent spatial variability. The predictive posterior distribution of the spatially aggregated rainfall is obtained by using a Markov chain Monte Carlo method and compared to the RCM simulations. Also, the predictive posterior distribution of the RCM output is downscaled using the truncated normal model and obtaining pointwise rainfall estimates from aerial observations which are compared to the ground observations. These two procedures allow us to determine if the differences between the two sources of information are compatible with the variability predicted by the spatial model. Also, point rainfall estimates at locations without rainfall measurements conditioned on RCM observations can be obtained. We considered a set of data from an area in Nebraska for which time is considered fixed and rainfall is accumulated monthly. Copyright © 2004 John Wiley & Sons, Ltd.
Simulating the growth of tafoni
Authors: Huinink H. P. , Pel L. , Kopinga K.
Published: August 2004

Throughout the world, large caves in rocks (tafoni) are found, which originate from salt weathering. The mechanisms that control their development are poorly understood. The growth of tafoni has been studied with a model that describes how a rock surface, containing a small pit, disintegrates by salt crystallization during wetting/drying cycles. In the model the rock is mapped on a grid. The migration and crystallization of salts are simulated explicitly in the drying phase of a cycle. At the end of each wetting/drying cycle the amount of salt deposited at the grid nodes is evaluated and the shape of the rock surface is adjusted by removing nodes. The length of the drying period in a single cycle proved to be the key parameter. For short drying periods the amount of crystallized salt at the surface is proportional to the drying rate. Therefore, for short drying periods most salts are deposited at the more exterior parts of the rock surface. As a result, most damage will develop at these parts of the surface, which results in smooth surfaces. Due to the characteristics of the drying process for long drying periods, most salts accumulate at regions with low evaporation rates, which are the sheltered parts of the rock surface. These parts are not exposed to the wind or the sun. As a result, the pit grows and a tafone develops. Copyright © 2004 John Wiley & Sons, Ltd.
The geomorphic dynamics and environmental history of an upper deltaic floodplain tract in the Sacramento–San Joaquin Delta, California, USA
Authors: Brown K. J. , Pasternack G. B.
Published: August 2004

A multi‐proxy approach was used to examine the geomorphic dynamics and environmental history of an upper deltaic ﬂoodplain tract in the Sacramento–San Joaquin Delta, California. Three long cores were collected from the McCormack–Williamson Tract (MWT) and these cores were analyzed for bulk density, loss‐on‐ignition, ﬁne (clay and silt) content, Al concentration, magnetic susceptibility, pollen, and charcoal. Radiocarbon dates obtained for the cores were converted into calendar years and an age–depth model was constructed. Long‐term vertical accretion and sedimentation rates were estimated from the age–depth model. Cross‐core relations show that coarse sediment generally accumulates more rapidly and has greater magnetic susceptibility compared to ﬁne sediment. Percentage ﬁne and LOI data show a strong linear relationship that indicates ﬂooding is the primary mechanism for the deposition of particular organic matter on the ﬂoodplain and that landscape wash load has contributed a highly consistent fraction of persistent organic matter averaging 5·5 per cent to the site. Down‐core grain size proﬁles show two hydrological domains in the cores, namely millennial ﬁne–coarse ﬂuctuations superimposed on general up‐core ﬁning. Coarse sediment is viewed as channel or near‐channel overbank deposits, whereas ﬁne deposits are considered to be distal overbank ﬂood deposits. The coarse–ﬁne ﬂuctuations are indicative of changing depositional settings as channels migrated laterally across MWT, whereas the upward ﬁning trend reﬂects a combination of self‐limiting overbank deposition as ﬂoodplain elevation increased and decreasing competence as sea‐level rise reduced ﬂood‐pulse energy slopes. MWT has been cross‐cut and incised numerous times in the past, only to have the channels abandoned and subsequently ﬁlled by ﬁne sediment. The channels around MWT attained their modern conﬁguration about 4000 years ago. MWT likely came under tidal inﬂuence at about 2500 cal BP. Wetlands have recently developed on MWT, but they are inorganic sediment dominated. Copyright © 2004 John Wiley & Sons, Ltd.