An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for the conservative and nonpharmacological management of female pelvic floor dysfunction.

Introduction and hypothesis There has been an increasing need for the terminology on the conservative management of female pelvic floor dysfunction to be collated in a clinically based consensus report. Methods This Report combines the input of members and elected nominees of the Standardization and Terminology Committees of two International Organizations, the International Urogynecological Association (IUGA) and the International Continence Society (ICS), assisted at intervals by many external referees. An extensive process of nine rounds of internal and external review was developed to exhaustively examine each definition, with decision-making by collective opinion (consensus). Before opening up for comments on the webpages of ICS and IUGA, five experts from physiotherapy, neurology, urology, urogynecology, and nursing were invited to comment on the paper. Results A Terminology Report on the conservative management of female pelvic floor dysfunction, encompassing over 200 separate definitions, has been developed. It is clinically based, with the most common symptoms, signs, assessments, diagnoses, and treatments defined. Clarity and ease of use have been key aims to make it interpretable by practitioners and trainees in all the different specialty groups involved in female pelvic floor dysfunction. Ongoing review is not only anticipated, but will be required to keep the document updated and as widely acceptable as possible. Conclusion A consensus-based terminology report for the conservative management of female pelvic floor dysfunction has been produced, aimed at being a significant aid to clinical practice and a stimulus for research.

An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for the conservative and nonpharmacological management of female pelvic floor dysfunction.

INTRODUCTION AND HYPOTHESIS: There has been an increasing need for the terminology on the conservative management of female pelvic floor dysfunction to be collated in a clinically based consensus report. METHODS: This Report combines the input of members and elected nominees of the Standardization and Terminology Committees of two International Organizations, the International Urogynecological Association (IUGA) and the International Continence Society (ICS), assisted at intervals by many external referees. An extensive process of nine rounds of internal and external review was developed to exhaustively examine each definition, with decision-making by collective opinion (consensus). Before opening up for comments on the webpages of ICS and IUGA, five experts from physiotherapy, neurology, urology, urogynecology, and nursing were invited to comment on the paper. RESULTS: A Terminology Report on the conservative management of female pelvic floor dysfunction, encompassing over 200 separate definitions, has been developed. It is clinically based, with the most common symptoms, signs, assessments, diagnoses, and treatments defined. Clarity and ease of use have been key aims to make it interpretable by practitioners and trainees in all the different specialty groups involved in female pelvic floor dysfunction. Ongoing review is not only anticipated, but will be required to keep the document updated and as widely acceptable as possible. CONCLUSION: A consensus-based terminology report for the conservative management of female pelvic floor dysfunction has been produced, aimed at being a significant aid to clinical practice and a stimulus for research.

Incontinence: enhancing care in women's prisons.

BACKGROUND: There is no evidence on the prevalence of urinary and faecal incontinence symptoms in women prisoners. AIM: To explore the extent and management of bladder and bowel symptoms to inform prison health services and prison nursing practice. METHOD: An anonymous self-report questionnaire tailored to low levels of English literacy, and administered in one women's prison. RESULTS: Women prisons have a higher reported prevalence of urinary and faecal incontinence, constipation and nocturnal enuresis than community populations; this is an unrecognised health problem. CONCLUSION: Prison primary care nurses should consider introducing sensitive but direct questions on bladder and bowel symptoms into admission assessment processes.

MMP-2 induced vein relaxation via inhibition of [Ca2+]e-dependent mechanisms of venous smooth muscle contraction. Role of RGD peptides.

BACKGROUND: Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of varicose veins. We have shown that MMP-2 causes relaxation of venous segments and suggested a role of venous smooth muscle (VSM) hyperpolarization; however, the downstream mechanisms are unclear. We tested whether MMP-2 induced venous relaxation involves inhibition of the Ca(2+) mobilization mechanisms of VSM contraction due to generation of Arg-Gly-Asp (RGD)-containing peptides. METHODS: Circular segments of inferior vena cava (IVC) were isolated from male Sprague-Dawley rats, suspended between two wires in a tissue bath, and isometric contraction was measured. Contraction data in mg/mg tissue were presented as means +/- SEM. RESULTS: In IVC incubated in normal Krebs (2.5 mM Ca(2+)), the alpha-adrenergic agonist phenylephrine (Phe, 10(-5) M) caused initial peak (133.2 +/- 17.5) followed by a maintained contraction (73.4 +/- 11.6), that was inhibited by MMP-2 (1 microg/mL) to 32.4 +/- 12.8 in 30 min. The inhibitory effects of MMP-2 were reversible by washing the tissue with Krebs or in the presence of the MMP inhibitors TIMP-1 (1 microg/mL), Ro 28-2653, and BB-94 (10(-6) M), and were not associated with changes in IVC structure, demonstrating specificity. Angiotensin II (AngII, 10(-6) M) caused a monophasic contraction (114.2 +/- 12.2), that was also inhibited by MMP-2 (66.0 +/- 7.4), suggesting a post-receptor effect on the downstream mechanisms of VSM contraction. To test the role of Ca(2+) release from the sarcoplasmic reticulum, IVC was incubated in Ca(2+)-free 2 mM ethylene glycol-bis(2-aminoethyl ether-N,N,N',N'-tetra-acetic acid (EGTA) Krebs with or without MMP-2. In Ca(2+)-free Krebs, caffeine did not cause contraction, suggesting a limited role of the Ca(2+)-induced Ca(2+)-release mechanism, and Phe and AngII caused a small contraction (7.2 +/- 1.7 and 14.9 +/- 2.8) that was slightly increased by MMP-2 (10.4 +/- 3.0 and 33.8 +/- 10.0), suggesting little effect on IP(3)-induced Ca(2+) release. To test the role of Ca(2+) entry through membrane channels, after eliciting a transient Phe contraction in nominally 0 Ca(2+) Krebs, increasing concentrations of CaCl(2) (0.1, 0.3, 0.6, 1, 2.5 mM) were added and the extracellular Ca(2+) concentration [Ca(2+)](e)-contraction relationship was constructed. The [Ca(2+)](e)-contraction relation was reduced in MMP-2 treated IVC, suggesting inhibition of Ca(2+) entry. In IVC treated with MMP-2, the Ca(2+) channel blocker diltiazem (10(-5)M) did not cause any further inhibition of Phe contraction, suggesting that Ca(2+) entry is already inhibited by MMP-2. To test whether MMP-2 actions involve generation of RGD and modulation of integrin receptors, experiments where repeated in IVC segments saturated with RGD (10(-5) M), or pretreated with the alpha(v)beta(3) integrin blocker cyclo(Ala-Arg-Gly-Asp-3-aminomethylbenzoyl) (cyclo-RGD). RGD-peptide caused only small relaxation of Phe contracted IVC (6.4 +/- 3.4%), and addition of MMP-2 to RGD-treated IVC caused further relaxation (69.7 +/- 3.0%). Pretreatment of IVC with cyclo-RGD did not significantly affect MMP-2 induced relaxation (55.0 +/- 5.0%). CONCLUSIONS: In rat IVC, MMP-2 attenuates [Ca(2+)](e)-dependent VSM contraction without affecting Ca(2+) release from intracellular Ca(2+) stores. MMP-2 induced VSM relaxation may not involve RGD generation or activation of alpha(v)beta(3) integrin receptor. MMP-2 induced inhibition of the Ca(2+) entry mechanism of VSM contraction may play a role in the venous dilation associated with varicose vein formation.

Incontinence in women prisoners: an exploration of the issues.

AIM: This paper is a report of a study exploring the extent and management of bladder and bowel problems in order to inform the provision and practice of prison nursing services and health care services in women's prisons. BACKGROUND: Nurses and general practitioners provide primary care services inside prisons in the United Kingdom. While high levels of mental health and addiction problems in women prisoners are recognized, there has been less focus on physical problems. Incontinence symptoms are perceived as shameful and stigmatizing, and frequently help is not sought from healthcare professionals. Guidance for assessing prisoner health does not refer to bladder and bowel symptoms. METHODS: Women prisoners in a large, closed prison in the United Kingdom were surveyed in 2005 using an anonymous self-completed questionnaire. Women resident in the detoxification unit and the hospital unit, absent from their unit at the time of questionnaire distribution or deemed vulnerable by prison health staff were excluded. RESULTS: Questionnaires were offered to 283 women and 246 agreed to take it. Of those taken, 148 (60%) were returned. Twenty-four per cent indicated that they disclosed information about bladder and bowel problems in the survey not previously disclosed to anyone else. Forty-three per cent reported urinary symptoms. Five per cent reported nocturnal enuresis. The majority of women with symptoms reported using sanitary pads and toilet paper for containment of leakage. CONCLUSION: Prison nurses and nurse practitioners involved in reception into prison assessments should ask direct but sensitive questions about women's bladder and bowel symptoms.

Promotion of urinary continence worldwide.

Millions of individuals around the world suffer from urinary incontinence. This article discusses worldwide urinary incontinence, and the use of information and communication technology to facilitate global nursing collaboration.

RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML.

First reported in 1999, germline runt-related transcription factor 1 (RUNX1) mutations are a well-established cause of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1-mutated FPD-MM families. Genomic analyses on these families detected 2 partial gene deletions, 3 novel mutations, and 5 recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. Combining genomic data from the families reported herein with aggregated published data sets resulted in 130 germline RUNX1 families, which allowed us to investigate whether specific germline mutation characteristics (type, location) could explain the large phenotypic heterogeneity between patients with familial platelet disorder and different HMs. Comparing the somatic mutational signatures between the available familial (n = 35) and published sporadic (n = 137) RUNX1-mutated AML patients showed enrichment for somatic mutations affecting the second RUNX1 allele and GATA2. Conversely, we observed a decreased number of somatic mutations affecting NRAS, SRSF2, and DNMT3A and the collective genes associated with CHIP and epigenetic regulation. This is the largest aggregation and analysis of germline RUNX1 mutations performed to date, providing a unique opportunity to examine the factors underlying phenotypic differences and disease progression from FPD to MM.

Priority setting in research: user led mental health research.

PLAIN ENGLISH SUMMARY: Involving people in health research is increasingly recognised as being important to make sure that research is focused more on the needs of people who use health services. At present, ideas about what should be researched most often comes from researchers and/or health professionals like doctors and nurses rather than people with a lived experience of mental illness. In this study, we will talk with this group of people from across Wales to explore what they think research into their health services should focus on. The findings from this work will help to influence the work of the National Centre for Mental Health Research Partnership Group; as well as` researchers and health professionals and others who concentrate on mental health research. The Research group is a partnership between people with a lived experience of mental ill health and professionals with an interest in mental ill health. The group plan to take forward the ideas that came from this research and some of the ideas have already been used to increase funding in the area of mental health research. ABSTRACT: Background This paper is the result of continued collaboration between members of the Service User and Carer Research Partnership, based in Wales and supported by the National Centre for Mental Health, Health and Care Research Wales, and Hafal. The aim of this study was to explore the research priorities of people with experience of mental health services which include people with a lived experience of mental ill health, their carers, and professionals. Method A nominal group technique was used to gather data. A one-day workshop 'Getting Involved in Research: Priority Setting' was held to gather the ideas and suggestions for research priorities from people who have experience of mental health services. Results Twenty-five participants attended the workshop. 5 were mental health professionals, 20 had a lived experience of mental ill health, (of which 3 were also carers). 11 were male and 14 were female. 120 research ideas were generated across 6 'Ideas Generating Workstations'. Participants took part in a 3 stage vote to narrow down the ideas to 2 main research priorities. Conclusion The two main research priority areas that were identified:'Developing the knowledge of mental health issues amongst school-aged children' as a vehicle to overcome stigma and discrimination, and to support young people to manage their own mental health.'Developing education as a tool for recovery', for example by peer support. In addition, participants engaged in a notable discussion over the research priority: 'How are carers supported during the recovery of the person for whom they care?'

Lymphocyte propionyl-CoA carboxylase and its activation by biotin are sensitive indicators of marginal biotin deficiency in humans.

BACKGROUND: Marginal biotin deficiency may be a human teratogen. A biotin status indicator that is not dependent on renal function may be useful in studies of biotin status during pregnancy. A previous study of experimental biotin deficiency suggested that propionyl-coenzyme A carboxylase (PCC) activity in peripheral blood lymphocytes (PBLs) is a sensitive indicator of biotin status. OBJECTIVE: We examined the utility of measuring PCC activity and the activation of PCC by biotin in detecting marginal biotin deficiency. DESIGN: Marginal biotin deficiency was induced in 7 adults (3 women) by egg-white feeding for 28 d. Blood and urine were obtained on days 0, 14, and 28 (depletion phase) and 44 and 65 (repletion phase). PBLs were incubated with (activated) or without (control) biotin before PCC assay. The activation coefficient of PCC is the ratio of PCC activity in activated PBLs to that in control PBLs. The significance of differences for all measurements was tested by repeated-measures analysis of variance with Fisher's post hoc test and Bonferroni correction. RESULTS: Changes in the urinary excretion of biotin and of 3-hydroxyisovaleric acid confirmed that marginal biotin deficiency was successfully induced. By day 14, PCC activity had decreased (P < 0.0001) to below the lower limit of normal in all subjects. By day 28, the activation coefficient of PCC had increased significantly (P = 0.003) and was above the upper limit of normal in 6 of 7 subjects. CONCLUSION: PCC activity is the most sensitive indicator of biotin status tested to date. In future pregnancy studies, the use of lymphocyte PCC activity data should prove valuable in the assessment of biotin status.

Beef and soy-based food supplements differentially affect serum lipoprotein-lipid profiles because of changes in carbohydrate intake and novel nutrient intake ratios in older men who resistive-train.

OBJECTIVE: We examined if the predominant source of dietary protein influenced the lipoprotein-lipid profile in older men who performed resistive exercise training (RT). DESIGN: This is a 14-week, randomized, repeated-measures study with a 12-week period of RT with supplementation of different sources of dietary protein (beef and soy). SETTING: Nutrition, Metabolism, and Exercise Laboratory, Central Arkansas Veteran's Healthcare System, North Little Rock, Ark. Subjects Twenty-six healthy men were recruited, and 21 men (age 65 +/- 5 years, body mass index 28.2 +/- 2.6 kg/m 2 ) completed the study. Interventions For 14 weeks, all men were counseled to self-select a lacto-ovo-vegetarian diet. For 2 weeks (baseline), all men also consumed 0.6 g-protein/kg per day from portioned quantities of soy-based texturized vegetable protein foods. For the next 12 weeks, 11 men were randomized to continue with texturized vegetable protein foods (VEG group), whereas 10 men were randomized to receive 0.6 g-protein/kg per day from portioned quantities of beef (BEEF group) and continue their otherwise lacto-ovo-vegetarian diet. All men participated in RT 3 d/wk during this 12-week period. Assessments of upper and lower body muscle strength and power, serum lipoprotein-lipid profile, and dietary nutrient intakes were made at baseline and week 12 of RT (POST). RESULTS: The BEEF and VEG groups increased ( P < .05) overall muscle strength and muscle power with RT, with no differences between groups. From baseline to POST, the BEEF group had increased concentrations of high-density lipoprotein cholesterol ( P = .025; HDL-C), low-density lipoprotein cholesterol ( P = .027; LDL-C), and total cholesterol ( P = .015: CHOL), with no changes ( P > .05) in triacylglycerol (TG), the CHOL/HDL-C ratio, or the TG/HDL-C ratio. The VEG group did not experience within-group changes ( P > .05) in any lipoprotein-lipid parameter. At POST, the concentrations of HDL-C, LDL-C, and CHOL were greater in the BEEF group compared with the VEG group. There were significant interaction effects for HDL-C ( P = .004) and the TG/HDL-C ratio ( P = .022). Multiple regression analysis determined that, regardless of intervention, change in the saturated fat/fiber ratio (SF/fiber) predicted CHOL (adjusted R 2 = 0.34); the SF/fiber ratio predicted LDL-C (adjusted R 2 = 0.36); the cholesterol/fiber intake ratio predicted HDL-C (adjusted R 2 = 0.26), and the change in carbohydrate intake predicted the CHOL/HDL-C ratio (adjusted R 2 = 0.37) and TG (adjusted R 2 = 0.44). CONCLUSIONS: These results suggest that the lipoprotein-lipid profile in these older men was differentially affected by supplementation with beef versus soy-based foods during RT. Regardless of group, the lipoprotein-lipid changes were predicted by differences in the SF/fiber ratio and cholesterol/fiber ratio and increases in carbohydrate intake over time.

Effect of protein source on resistive-training-induced changes in body composition and muscle size in older men.

BACKGROUND: Aging is associated with reductions in muscle mass and strength, but nutrition and exercise interventions can delay this progression and enhance the quality of life. OBJECTIVE: We examined whether the predominant source of protein consumed by older men influenced measures of muscle size and strength, body composition, resting energy expenditure, and skeletal muscle creatine concentrations in response to 12 wk of resistive training. DESIGN: After consuming a lactoovovegetarian (LOV) diet for 2 wk, 21 men aged 65 +/- 5 y were randomly assigned to either consume a beef-containing (BC) diet (n = 10) or to continue the LOV diet (n = 11) throughout resistive training. The BC diet included 0.6 g protein. kg(-1). d(-1) from beef and the LOV diet included 0.6 g protein. kg(-1). d(-1) from textured vegetable protein (soy) sources. The remaining protein in the diets came from self-selected LOV sources. RESULTS: The mean total protein intake for both groups ranged from 1.03 to 1.17 g. kg(-1). d(-1) during the intervention. Men in both groups had improvements (14-38%) in maximal dynamic strength of all the muscle groups trained with no significant difference between groups. With resistive training, cross-sectional muscle area of the vastus lateralis increased in both groups (4.2 +/- 3.0% and 6.0 +/- 2.6% for the LOV and BC groups, respectively) with no significant difference between groups. Body composition, resting energy expenditure, and concentrations of muscle creatine, phosphocreatine, and total creatine did not differ significantly between groups or change over time. CONCLUSIONS: These data suggest that increases in muscle strength and size were not influenced by the predominant source of protein consumed by older men with adequate total protein intake.

Comparisons of vegetarian and beef-containing diets on hematological indexes and iron stores during a period of resistive training in older men.

OBJECTIVE: To test the hypothesis that older men who consumed a vegetarian (lacto-ovo) diet would develop a lower iron status compared with older men who consumed a beef-containing diet during a period of resistive training (RT). DESIGN: Experimental, repeated measures study. SUBJECTS: Twenty-one healthy men aged 59 to 78 years, with a BMI range of 24 to 33 kg/m(2), completed the study. INTERVENTION: All men consumed a vegetarian diet for 2 weeks (baseline). After this, the men were randomly assigned to one of two dietary groups. Eleven men consumed a beef-containing diet, and 10 men continued to consume a vegetarian diet for 12 weeks. During this time all subjects participated in RT three days per week, designated as RT1 to RT12. MAIN OUTCOME MEASURES: Serum ferritin and serum iron concentrations, transferrin saturation, transferrin receptor, total iron binding capacity, and selected hematological variables, as well as selected nutrient intakes and estimated iron bioavailability from three-day diet records, were determined at baseline, RT5, and RT12. STATISTICAL ANALYSES: A general linear model repeated-measures ANOVA was used to examine the effects of group, time, and group x time interactions for iron status and dietary data. RESULTS: Total iron intake was not different between the two groups; however, the beef group had a three to four times greater intake of bioavailable iron (P<.01) than the vegetarian group. Serum iron, total iron binding capacity, transferrin saturation, and transferrin receptor were not significantly different between the beef and vegetarian groups, or changed over time with RT. Serum ferritin decreased over time in both the beef and vegetarian groups during RT (P<.01). Re-introduction of beef into the diets of the beef group increased hemoglobin concentration and hematocrit compared with the vegetarian group during the 12 weeks of RT (group x time, P<.05). These changes were within clinically normal limits. APPLICATIONS/CONCLUSIONS: Older men who consume a beef-containing, higher-bioavailable-iron diet, compared with a vegetarian, lower-bioavailable-iron diet, have an increased hematological profile during a 12-week period of RT. Older men who consume either a beef-containing or a vegetarian diet maintain a hematological profile within clinically normal limits during 12 weeks of RT.

Effects of whey and fortified collagen hydrolysate protein supplements on nitrogen balance and body composition in older women.

Many elderly people have a low intake of dietary protein, yet their protein requirement may be higher than the current Recommended Dietary Allowance. High-quality protein supplements may be useful to enhance nitrogen retention and increase the availability of essential amino acids in elderly people. We compared the nitrogen balance of two protein supplements (Resource Beneprotein Instant Protein Powder, Nestlé HealthCare Nutrition, Minnetonka, MN, a whey protein concentrate; or Pro-Stat 101, Medical Nutrition USA, Englewood, NJ, a concentrated, fortified, collagen protein hydrolysate) varying in type but not amount of protein content using a crossover study design. The study consisted of two 15-day diet trials separated by a > or = 1-week washout period. Nine healthy elderly women (age 71+/-1 years) were provided a eucaloric diet containing approximately the protein Recommended Dietary Allowance of 0.8 g/kg body weight/day. The supplements constituted about half of the total protein provided to each subject. Nitrogen balance responses were assessed over days 6 to 10 and days 11 to 14 of each trial. Measured nitrogen content of the foods indicated that subjects consumed 0.81+/-0.02 g protein/kg/day and 0.85+/-0.05 g/kg/day for the whey and fortified collagen protein trials, respectively. Body weight decreased (P=0.02) after consumption of the whey supplement, with no significant changes in body weight or composition resulting from the consumption of the collagen supplement. Nitrogen excretion was higher during the whey supplement trial than during the collagen trial (P=0.047). Therefore, a concentrated, fortified, hydrolyzed collagen protein supplement maintained nitrogen balance and preserved lean body mass during 15 days of consumption of a relatively low-protein diet.

Research into Specific Modulators of Vascular Sex Hormone Receptors in the Management of Postmenopausal Cardiovascular Disease.

Cardiovascular disease (CVD) is more common in men and postmenopausal women than premenopausal women, suggesting vascular benefits of female sex hormones. Studies on the vasculature have identified estrogen receptors ERα, ERß and a novel estrogen binding membrane protein GPR30, that mediate genomic and/or non-genomic effects. Estrogen promotes endothelium-dependent relaxation by inducing the production/activity of nitric oxide, prostacyclin, and hyperpolarizing factor, and inhibits the mechanisms of vascular smooth muscle contraction including [Ca(2+)](i), protein kinase C, Rho kinase and mitogen-activated protein kinase. Additional effects of estrogen on the cytoskeleton, matrix metalloproteinases and inflammatory factors contribute to vascular remodeling. However, the experimental evidence did not translate into vascular benefits of menopausal hormone therapy (MHT), and the HERS, HERS-II and WHI clinical trials demonstrated adverse cardiovascular events. The discrepancy has been partly related to delayed MHT and potential changes in the vascular ER amount, integrity, affinity, and downstream signaling pathways due to the subjects' age and preexisting CVD. The adverse vascular effects of MHT also highlighted the need of specific modulators of vascular sex hormone receptors. The effectiveness of MHT can be improved by delineating the differences in phramcokinetics and pharmacodynamics of natural, synthetic, and conjugated equine estrogens. Estriol, "hormone bioidenticals" and phytoestrogens are potential estradiol substitutes. The benefits of low dose MHT, and transdermal or vaginal estrogens over oral preparations are being evaluated. Specific ER modulators (SERMs) and ER agonists are being developed to maximize the effects on vascular ERs. Also, the effects of estrogen are being examined in the context of the whole body hormonal environment and the levels of progesterone and androgens. Thus, the experimental vascular benefits of estrogen can be translated to the outcome of MHT in postmenopausal CVD, as more specific modulators of sex hormone receptors become available and are used at the right dose, route of administration and timing, depending on the subject's age and preexisting cardiovascular condition.

Modulators of vascular sex hormone receptors and their effects in estrogen-deficiency states associated with menopause.

Cardiovascular disease (CVD) is more prevalent in postmenopausal than premenopausal women, suggesting vascular protective effects of estrogen. Also, experimental studies have demonstrated beneficial effects of estrogen in improving vascular function and reducing vascular injury. However, clinical trials including HERS I, HERS II, WHI and WISDOM have demonstrated minimal beneficial vascular effects of menopausal hormone therapy (MHT) in postmenopausal women with CVD. The discrepancies between the experimental findings and clinical data may be related to the vascular estrogen receptors (ER), the type, route of administration, or dosage of MHT, and subject's age. Vascular ERs mediate both genomic and non-genomic effects of estrogen on the endothelium, vascular smooth muscle (VSM), and extracellular matrix (ECM). Postmenopausal changes in vascular ER structure, polymorphisms, amount, subcellular location, affinity or signaling could modify their responsiveness to estrogen and thereby the outcome of MHT. Recent investigations and patents have been centered on developing new ER modulators and alternatives for the traditional natural and synthetic forms of MHT which carry the risk of invasive breast cancer and venous thromoboembolism. Phytoestrogens may have similar effects as traditional MHT and have not demonstrated harmful side effects. Specific estrogen receptor modulators (SERMs) such as raloxifene and tamoxifen have also been tested. ER agonists that selectively target ERalpha, ERbeta and perhaps GPR30 may modify specific vascular signaling pathways. Also, the dose, route of administration, and timing of MHT are integral to optimizing the beneficial effects and minimizing the side effects of MHT. Progesterone, testosterone and modulators of their specific receptors may also affect the overall vascular effects of MHT in estrogen-deficiency states associated with menopause.

Biotin deficiency reduces expression of SLC19A3, a potential biotin transporter, in leukocytes from human blood.

In evaluating potential indicators of biotin status, we quantitated the expression of biotin-related genes in leukocytes from human blood of normal subjects before and after inducing marginal biotin deficiency. Biotin deficiency was induced experimentally by feeding an egg-white diet for 28 d. Gene expression was quantitated for the following biotin-related proteins: methylcrotonyl-CoA carboxylase chains A (MCCA) and B (MCCB); propionyl-CoA carboxylase chains A (PCCA) and B (PCCB); pyruvate carboxylase (PC); acetyl-CoA carboxylase isoforms A (ACCA) and B (ACCB); holocarboxylase synthetase (HCS); biotinidase; and 2 potential biotin transporters: sodium-dependent multivitamin transporter (SMVT) and solute carrier family 19 member 3 (SLC19A3). For 7 subjects who successfully completed the study, the abundance of the specific mRNAs was determined by quantitative real-time RT-PCR at d 0 and 28. At d 28, SLC19A3 expression had decreased to 33% of d 0 (P < 0.02 by two-tailed, paired t test). Expression of MCCA, PCCA, PC, ACCA, ACCB, HCS, biotinidase, and SMVT decreased to approximately 80% of d 0 (P < 0.05). Expression of the MCCB and PCCB chains that do not carry the biotin-binding motif did not change significantly; we speculate that expression of the biotin-binding chains of biotin-dependent carboxylases is more responsive to biotin status changes. These data provide evidence that expression of SLC19A3 is a relatively sensitive indicator of marginal biotin deficiency.