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A key challenge for stem cell therapies is the delivery of therapeutic cells to the repair site. Magnetic targeting has been proposed as a platform for defining clinical sites of delivery more effectively. In this paper, we use a combined in vitro experimental and mathematical modelling approach to explore the magnetic targeting of mesenchymal stromal cells (MSCs) labelled with magnetic nanoparticles using an external magnet. This study aims to (i) demonstrate the potential of magnetic tagging for MSC delivery, (ii) examine the effect of red blood cells (RBCs) on MSC capture efficacy and (iii) highlight how mathematical models can provide both insight into mechanics of therapy and predictions about cell targeting in vivo. In vitro MSCs are cultured with magnetic nanoparticles and circulated with RBCs over an external magnet. Cell capture efficacy is measured for varying magnetic field strengths and RBC percentages. We use a 2D continuum mathematical model to represent the flow of magnetically tagged MSCs with RBCs. Numerical simulations demonstrate qualitative agreement with experimental results showing better capture with stronger magnetic fields and lower levels of RBCs. We additionally exploit the mathematical model to make hypotheses about the role of extravasation and identify future in vitro experiments to quantify this effect.

Objectives Progress of labor has hitherto been assessed by digital vaginal examination (VE). We introduce the concept of a non-intrusive ultrasound (US)-based assessment of labor progress (the ‘sonopartogram’) and investigate its feasibility for assessing cervical dilatation and fetal head descent and rotation. Methods This was a prospective study performed in 20 women in the first stage of labor in two European maternity units. Almost simultaneous assessment of cervical dilatation and fetal head descent and rotation were made by US and digital VE. Results The total number of paired US and digital VE assessments was 52, with a median of three per woman. Overall, 5% of sonopartogram parameters were not obtained compared with 18% of conventional digital VE parameters (P

(2003). Hormone replacement therapy in climacteric and aging brain. Climacteric: Vol. 6, No. 3, pp. 188-203.

Women's health often declines in middle and old age for reasons that are avoidable. Simple measures including lifestyle change could make a significant difference. Education of women is all important. The BMS feels that the provision of a simple health check of all women at the age of 50 years would provide an excellent opportunity that would serve as a screening as well as an educational visit at which balanced information about appropriate treatments and lifestyle changes in natural and premature menopause should be given to empower women to make an informed choice.

Depression is more common in women, occurring at times of hormonal fluctuations as premenstrual depression, postnatal depression and perimenopausal depression. These are all related to changes in hormone levels and constitute the diagnosis of reproductive depression. There is a risk that severe premenstrual depression can be misdiagnosed as bipolar disorder and that women will be started on inappropriate antidepressants or mood-stabilizing therapy. The most effective treatment for severe premenstrual syndrome is by suppression of ovulation and suppression of the cyclical hormonal changes by transdermal estrogens or by GnRH analogs. Postnatal depression is more common in women with a history of premenstrual depression and also responds to transdermal estrogens. Transdermal testosterone gel can be also used in women who suffer loss of energy and loss of libido which may be due to the inappropriate prescription of antidepressants. There is also a role for the Mirena IUS and laparoscopic hysterectomy and oophorectomy in women who are progestogen-intolerant. The hormonal causation of certain common types of depression in women and the successful treatment by estrogens should be understood by psychiatrists and gynecologists.

The recent report of a two-fold increase in esophageal cancer in women taking oral bisphosphonates is yet another reason to question current relegation of hormone replacement therapy (HRT) to a minor role in the correction of many problems occurring in the younger postmenopausal woman. Women under the age of 60 years with low bone density, flushes, sweats, vaginal dryness, loss of libido and climacteric depression would be treated with estrogens by gynecologists and most general practitioners. It is regrettable that bone physicians use bisphosphonates as first-line therapy in this age group, in spite of the growing number of serious complications reported. Similarly, psychiatrists have little experience in the use of estrogens for the reproductive depression syndrome of postnatal depression, premenstrual depression and perimenopausal depression, but use antidepressants. The adverse effects reported in the 2002 Women's Health Initiative study are given as justification for not using estrogens, although serious complications did not occur in women starting HRT before the age of 60 years. But, in reality, the objection to estrogens from psychiatrists and bone physicians preceded this study by decades and was a result of their unfamiliarity with this treatment. Regrettably, PROFOX (PROzac + FOsomaX) will become an established treatment for women who really need estrogens.

Objective: To investigate the effects of tibolone on trabecular and cortical bone mineral density and on indices of calcium metabolism in postmenopausal women with previous fractures. Methods: In a 2-year, randomized, double-blind, placebo-controlled, bicenter study, 45 women were treated with tibolone and 43 with placebo. All subjects received 800 mg of calcium daily. Trabecular bone mineral density of lumbar spine (L1 to L4) and cortical bone mass at the femoral neck were assessed by dual energy x-ray absorptiometry at baseline and at 6-month intervals. Serum and urinary bone biochemistry variables were also assessed. Results: After 2 years, subjects in the tibolone group gained 6.9% bone mass at lumbar spine and 4.5% at femoral neck, and respective increases from baseline in the placebo group were 2.7% and 1.4%. Tibolone-treated patients gained statistically significantly more bone mass than placebo-treated patients in the spine and femur. Urinary calcium:creatinine and hydroxyproline:creatinine ratios, as well as serum alkaline phosphatase and phosphate levels, were significantly reduced with tibolone compared with placebo. Conclusion: Tibolone induced a significant increase in trabecular (lumbar spine) and cortical (femoral neck) bone mass in postmenopausal osteoporotic women compared to placebo, suggesting its potential to treat postmeno- pausal osteoporosis.

The controversy surrounding prophylactic oophorectomy is discussed. The importance of adequate hormone replacement with estradiol and particularly testosterone is discussed as is the severe limitation of considering publications which describe the unacceptable practice of hysterectomy and bilateral salpingo-oophorectomy without hormone replacement therapy. There remains a good argument for removal of ovaries at hysterectomy in women over the age of 40 with full discussion, consent and appropriate hormone replacement.

Progress of labor has hitherto been assessed by digital vaginal examination (VE). We introduce the concept of a non-intrusive ultrasound (US)-based assessment of labor progress (the 'sonopartogram') and investigate its feasibility for assessing cervical dilatation and fetal head descent and rotation.This was a prospective study performed in 20 women in the first stage of labor in two European maternity units. Almost simultaneous assessment of cervical dilatation and fetal head descent and rotation were made by US and digital VE.The total number of paired US and digital VE assessments was 52, with a median of three per woman. Overall, 5% of sonopartogram parameters were not obtained compared with 18% of conventional digital VE parameters (P 0.001). Assessment of cervical dilatation was possible in 86.5% of US examinations and 100% of digital VEs (P = 0.02), and dilatation was assessed as being greater by digital VE than by US (mean difference, 1.16 (95% limits of agreement, -0.76, 3.08) cm, r(2) = 0.68, P = 0.01). Fetal head descent was measured in all 52 cases by both methods (r(2) = 0.33, P 0.001), but correlation between the two was only moderate. Head rotation was obtainable in 98% of US examinations and 46% of digital VEs (P 0.001), with a mean difference of -3.9° (95% limits of agreement, -144.1°, 136.3°).In this proof-of-concept study, the acquisition of data regarding progress of labor was more successful for the sonopartogram than the conventional partogram. The agreement between digital VE and US was good for cervical dilatation and head rotation but less so for head descent. US assessment of the progress of labor is feasible in most cases.

(1994). Estrogen therapy in women over 60 years of age. Gynecological Endocrinology: Vol. 8, No. 3, pp. 191-196.

The study was undertaken to determine the effect of advice to discontinue hormone replacement therapy (HRT) on 100 women who were well established on treatment without side-effects.The study was retrospective from November 2003 to April 2004, in a single gynecological practice in London, UK. One hundred consecutive long-term estrogen and testosterone hormone implant users were assessed as to their knowledge of recent studies regarding risks of long-term HRT and whether they wished to discontinue hormones.All women receiving estrogen and testosterone implants, for a mean duration of 17.65 years (range 10-28 years), felt well informed concerning the Women's Health Initiative Study and the Million Women Study but only three women were happy to discontinue. The reasons given for the continuation of therapy were that they felt well and their quality of life had greatly improved. The mean estradiol and testosterone levels were 921 pmol/l and 1.91 nmol/l, respectively.The high rate of continuation of hormone treatment indicates that, despite the recent adverse publicity, these women feel well informed and were not willing to discontinue with their hormone therapy if they felt well. A regular discussion of the risks and benefits of HRT remains mandatory.

Nine women with primary ovarian failure, who were having their artificial menstrual cycles manipulated with physiological levels of estrogen and high doses of progesterone, were entered into the study. They filled in urinary symptom questionnaires and had urodynamic investigations in the two phases of treatment: estrogen and progesterone, and estrogen alone. The number of voids per 24 hours was significantly greater in the progesterone phase, as was the end filling pressure on cystometry. This is the first report in the literature of the effects of high-dose progesterone on the lower urinary tract.

It is well recognized that estrogen (E(2)) prevents postmenopausal bone loss by suppressing bone resorption. Despite evidence that E(2) may also stimulate bone formation in animals, an anabolic effect in humans is still controversial. To investigate this, we studied 22 older postmenopausal females, with a mean age of 65.4 yr and mean interval of 16.9 yr since menopause and low bone mineral density. Transcortical iliac bone biopsies were performed before and 6 yr after E(2) replacement therapy (ERT) [75 mg percutaneous E(2) replaced 6-monthly plus oral medroxy progesterone acetate (5 mg daily) for 10 days each calendar month]. The mean serum E(2) level after 6 yr of treatment was 1077 (range, 180-2568) pmol/L. Bone mineral density improved in every patient, with a median increase of 31.4% at the lumbar spine and 15.1% at the proximal femur. Bone histomorphometry showed an increase in cancellous bone volume from 10.75% to 17.31% (P0.001). The wall thickness after 6 yr of E(2) treatment was 38.30 micrometer compared with 31.20 micrometer before commencement of ERT (P0.0005), indicating net bone gain. This is the first report showing histological evidence for an increase in cancellous bone volume, together with an increase in wall thickness, in a longitudinal follow-up study of ERT in older postmenopausal women. Our results show that E(2) is capable of exerting an anabolic effect in women with osteoporosis, even when started well into the menopause.

The usefulness of the gonadotrophin-releasing hormone (GnRH) agonists in treating benign chronic gynaecological disorders, such as endometriosis and uterine fibroids, or pre-menstrual syndrome (PMS), is limited by their hypo-oestrogenic side effects, including bone demineralisation and vasomotor symptoms. Studies in patients receiving GnRH agonists and hormone replacement therapy (HRT) show that whilst the efficacy of GnRH agonist monotherapy in treating endometriosis and fibroids is maintained, the concomitant add-back HRT can prevent the bone loss and reduce the incidence and severity of vasomotor symptoms. However, in a study of add-back HRT (an oestrogenic plus a progestogenic agent) in severe PMS, although the efficacy of Zoladex (goserelin acetate) against oestrogen-responsive symptoms, such as mood, was still evident, progestogenic side effects still occurred. It is likely that add-back HRT may need to be tailored to individual indications.

Hormone replacement therapy (HRT) is perhaps the most important development in preventive medicine in the Western world for half a century, yet long-term compliance is notoriously poor. Up to 75% of women who start on HRT are reported to drop out within the first 6 months. Poor compliance may arise from a lack of awareness of the benefits of HRT, or from a number of common misconceptions, particularly the idea that HRT is ¿unnatural', and will cause weight gain, cancer, or unpleasant side effects. While side effects (usually progestogenic) may of course occur on HRT, they can usually be managed by a change in the regimen. Studies of the efficacy and safety of Menorest, an adhesive matrix transdermal system, used in combination with dydrogesterone for 12 days in each cycle, show it to be effective in relieving menopausal symptoms and increasing lumbar and spinal bone mass. Menorest was as effective and well-tolerated as a reference oral treatment (conjugated estrogens), and its twice weekly application may be considered to promote compliance.

Percutaneous estradiol (E2) implants effectively preserve bone density in postmenopausal women. However, these implants are often given with testosterone, which may itself have an anabolic effect on bone. To determine whether testosterone confers any additional bone-sparing effect, we studied 50 postmenopausal women randomly allocated to receive E2 (75 mg) alone or with testosterone (100 mg) every 6 months for 1 year. Women with an intact uterus received cyclic norethindrone (5 mg) for 10 days of each calendar month. Twenty-five untreated women were recruited to act as a reference group. Bone density was measured at the lumbar spine and proximal femur by dual x-ray densitometry. By 1 year, bone density at the lumbar spine had fallen by 1.8% in the reference group. In the women treated with E2 alone, it increased significantly by 7.8% (P less than .0001) and in those receiving E2 with testosterone, it increased by 6.3% (P less than .0001). At the femoral neck, bone density decreased by 3% in the controls and increased by approximately 4% in both treated groups (P less than .0001). The increase in bone density at these sites was unrelated to the woman's chronological age, menopausal age, or initial bone density. However, it correlated significantly with the serum E2 levels attained after 1 year of therapy. In no treated patients did bone density decrease significantly. These data show that testosterone confers no additional bone-sparing effect in postmenopausal women.

The effect of hormone implants on the bone density of postmenopausal women was studied in 110 patients (mean age 54.7 years; mean menopausal age 8.6 years, range 2-30) who had received hormone replacement in the form of estradiol (50-75 mg) and testosterone (100 mg) pellets at 6-month intervals for 2-24 years (mean 5.2). They were compared with 254 untreated women (mean age 55.0 years; mean menopausal age 6.8 years, range 1-37). The bone density at the spine, measured by quantitative digital radiography, was 1.123 grams hydroxyapatite (gHa)/cm2 in the treated group and 0.951 gHa/cm2 in the controls (P less than .0001). The total bone density at the proximal femur was 1.002 gHa/cm2 in the treated group, compared with 0.914 gHa/cm2 in the controls (P less than .0001). There were significant differences in the density of the trochanteric, intertrochanteric, and neck areas of the proximal femur as well as the Ward triangle (all P less than .0001). These differences became significant from the age of 55 at the neck of the femur, Ward triangle, and lumbar spine, and from age 60 for all other values. Subcutaneous estradiol and testosterone prevent postmenopausal osteoporosis and maintain normal bone density for as long as treatment is continued.

One hundred and fifty new patients attending the Menopause Clinic at Dulwich Hospital were questioned on their attitudes and fears about hormone replacement therapy and the perceived attitudes of their general practitioner. The majority of patients attending the clinic had initiated referral themselves and many had travelled from outside the health authority area in order to be seen. The waiting list for an appointment was often unacceptable. We conclude that specialist menopause clinics in teaching hospitals are unable to cope with the demand for information about the menopause and hormone replacement from post-menopausal women and suggest alternative means for providing this service.

The nineteenth-century medical attitude to normal female sexuality was cruel, with gynaecologists and psychiatrists leading the way designing operations for the cure of the serious contemporary disorders of masturbation and nymphomania. The gynaecologist, Isaac Baker Brown (1811-1873), and the distinguished endocrinologist, Charles Brown-Sequard (1817-1894) advocated clitoridectomy to prevent the progression to masturbatory melancholia, paralysis, blindness and even death. Even after the public disgrace of Baker Brown in 1866-7, the operation remained respectable and widely used in other parts of Europe. This medical contempt for normal female sexual development was reflected in public and literary attitudes. Or perhaps it led and encouraged public opinion. There is virtually no novel or opera in the last half of the 19th century where the heroine with “a past” survives to the end. H G Well's Ann Veronica and Richard Strauss's Der Rosenkavalier, both of which appeared in 1909, break the mould and are important milestones. In the last 50 years new research into the sociology, psychology and physiology of sexuality has provided an understanding of decreased libido and inadequate sexual response in the form of Female Sexual Disorder (FSD) or Hypoactive Sexual Desire Disorder (HSDD). This is now regarded as a disorder worthy of treatment, either by various forms of counseling or by the use of hormones, particularly estrogens and testosterone.

After the hypocrisy and tyranny directed at female sexuality in the 19th Century the change of attitude occurred slowly. Literature became more permissive with authors like D. H. Laurence, Henry Miller and Anais Nin being influential. Theatre and cinema remain conservative. In the real world Marie Stopes’Married Love was greatly influential, listed by Bragg as one of “the 12 books that changed the world”, stressed the emotional importance of sexual intercourse within marriage. She did not discuss contraception, masturbation or sex outside of marriage in the earlier editions. Kinsey and colleagues in 1953 broke the scientific silence by publishing details of the sexual behaviour in the human female. Seymour Fisher devoted a whole book to the female orgasm and Shere Hite in her extensive use of questionnaires from women described six basic types of masturbation in women. Masters and Johnson's work on the physiology was a landmark in understanding normal sexual response. Greenblatt pioneered the use of testosterone for loss of libido and subsequently the female androgen deficiency syndrome (FADS) has been recognised. There are now good control studies indicating the value of testosterone implants, tablets and patches by Davis and her colleagues to improve the problems of hypoactive sexual desire disorder (HSDD).

The usefulness of the gonadotrophin-releasing hormone (GnRH) agonists in treating benign chronic gynaecological disorders, such as endometriosis and uterine fibroids, or pre-menstrual syndrome (PMS), is limited by their hypo-oestrogenic side effects, including bone demineralisation and vasomotor symptoms. Studies in patients receiving GnRH agonists and hormone replacement therapy (HRT) show that whilst the efficacy of GnRH agonist monotherapy in treating endometriosis and fibroids is maintained, the concomitant add-back HRT can prevent the bone loss and reduce the incidence and severity of vasomotor symptoms. However, in a study of add-back HRT (an oestrogenic plus a progestogenic agent) in severe PMS, although the efficacy of Zoladex (goserelin acetate) against oestrogen-responsive symptoms, such as mood, was still evident, progestogenic side effects still occurred. It is likely that add-back HRT may need to be tailored to individual indications.

The labour stencil representing the expected cervimetric progress of normal labour was used in 741 consecutive spontaneous labours to identify high-risk labours which needed oxytocic stimulation. Uterine contractions were stimulated if progress extended two hours past the nomogram, which resulted in shorter labours, fewer instrumental deliveries and caesarean sections, and babies with higher Apgar scores than in those dysfunctional labours which were not stimulated. According to the protocol used 36% of primigravid and 13% of multigravid labours needed acceleration. The remaining patients did not need any oxytocic interference during the first stage. This selection of patients is important to prevent a major obstetric advance being abused and discredited at a time when the profession and public are questioning the safety of active labour.

Relative protein clearance measurements have gone a long way toward characterizing the nature of pregnancy proteinuria but have failed to distinguish between preeclampsia and primary renal disease. The prognostic significance of different degrees of selectivity has been a source of disagreement in past studies. The polymer clearance studies reported here, using tracer doses of labeled PVP, have demonstrated two forms of proteinuria: a benign form due to a vasoconstrictor effect where fetal outlook is good ("vasoactive"), and a form associated with intravascular coagulation which indicates worse fetal prognosis ("membranous"). Underlying chronic renal damage of minor degree is identifiable with PVP clearance. Concurrent measurements of protein clearance, using smaller-sized proteins than is customary, gave hope for future development of meaningful clinical tests.

Gamete intrafallopian transfer (GIFT) is a new technique of assisted conception appropriate for women with normal fallopian tubes. As 60% of infertile patients have normal and patent tubes (idiopathic infertility, immune causes, male infertility and endometriosis) they can be treated with this technique which is both simpler and more successful than in vitro fertilization.