Inherited Variants in SCARB1 Cause Severe Early-Onset Coronary Artery Disease.

[Figure: see text].

Expression profiling of winged- and wingless-destined pea aphid embryos implicates insulin/insulin growth factor signaling in morph differences.

Developmental plasticity allows the matching of adult phenotypes to different environments. Although considerable effort has gone into understanding the evolution and ecology of plasticity, less is known about its developmental genetic basis. We focused on the pea aphid wing polyphenism, in which high- or low-density environments cause viviparous aphid mothers to produce winged or wingless offspring, respectively. Maternally provided ecdysone signals to embryos to be winged or wingless, but it is unknown how embryos respond to that signal. We used transcriptional profiling to investigate the gene expression state of winged-destined (WD) and wingless-destined (WLD) embryos at two developmental stages. We found that embryos differed in a small number of genes, and that gene sets were enriched for the insulin-signaling portion of the FoxO pathway. To look for a global signature of insulin signaling, we examined the size and stage of WD and WLD embryos but found no differences. These data suggest the hypothesis that FoxO signaling is important for morph development in a tissue-specific manner. We posit that maternally supplied ecdysone affects embryonic FoxO signaling, which ultimately plays a role in alternative morph development. Our study is one of an increasing number that implicate insulin signaling in the generation of alternative environmentally induced morphologies.

Mechanisms and Alterations of Cardiac Ion Channels Leading to Disease: Role of Ankyrin-B in Cardiac Function.

Ankyrin-B (encoded by ANK2), originally identified as a key cytoskeletal-associated protein in the brain, is highly expressed in the heart and plays critical roles in cardiac physiology and cell biology. In the heart, ankyrin-B plays key roles in the targeting and localization of key ion channels and transporters, structural proteins, and signaling molecules. The role of ankyrin-B in normal cardiac function is illustrated in animal models lacking ankyrin-B expression, which display significant electrical and structural phenotypes and life-threatening arrhythmias. Further, ankyrin-B dysfunction has been associated with cardiac phenotypes in humans (now referred to as "ankyrin-B syndrome") including sinus node dysfunction, heart rate variability, atrial fibrillation, conduction block, arrhythmogenic cardiomyopathy, structural remodeling, and sudden cardiac death. Here, we review the diverse roles of ankyrin-B in the vertebrate heart with a significant focus on ankyrin-B-linked cell- and molecular-pathways and disease.

The ageing female reproductive axis I.

The female reproductive axis includes the hypothalamo-pituitary unit, the ovaries and the uterus. While changes in the brain may contribute to reproductive ageing, the major focus of current research is on the ovary, where the progressive loss of follicles ultimately leads to absent follicular function and consequent permanent cessation of menstruation, the menopause. The pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone, stimulate ovarian secretion of oestradiol and the inhibins from follicular granulosa cells, and androgens from interstitial cells, including the theca. A primary event in the ageing of the reproductive axis appears to be a decline in the secretion of inhibin B as follicle numbers fall. This leads to a slow rise in FSH in women who continue to cycle regularly, particularly in the last decade of reproductive life. As the menopause approaches, decreasing concentrations of both oestradiol and inhibin B lead to more marked increases in the gonadotropins, which reach their postmenopausal peak 2-3 years after final menses. In contrast, total testosterone concentrations are maintained across the menopausal transition, with a fall in sex hormone binding globulin (SHBG) and hence a rise in free testosterone.

Hormones, mood, sexuality, and the menopausal transition.

OBJECTIVE: To determine the extent of changes in women's sexual functioning and well-being during the menopausal transition and the relationship to hormonal changes. DESIGN: Prospective observational study. SETTING: Population-based sample assessed at home. PATIENT(S): 438 Australian-born women 45-55 of years who were still menstruating at baseline. Of these, 226 were studied for effects of hormones on sexual functioning. MAIN OUTCOME MEASURE(S): Short Personal Experiences Questionnaire (SPEQ) and Affectometer 2 scores and annual blood sampling. RESULT(S): From the early to late menopausal transition, the percentage of women with SPEQ scores indicating sexual dysfunction increased from 42% to 88%. Mood scores did not change significantly. In the early menopausal transition, women with low total SPEQ scores had lower estradiol level but similar androgen levels to those with higher scores. Decreasing SPEQ scores correlated with decreasing estradiol level but not with androgen levels. Hormone levels were not related to mood scores. CONCLUSION(S): Female sexual functioning declines with the natural menopausal transition. This decline relates more to decreasing estradiol levels than to androgen levels.

Predictors of declining self-rated health during the transition to menopause.

OBJECTIVE: To determine factors associated with declining self-rated health as measured annually for 8 years in a prospective population-based cohort of middle-aged Australian-born women. In particular, to investigate the potential role of the menopausal transition in changing self-rated health. METHODS: A total of 262 women from the Melbourne Women's Midlife Health Project were asked to rate their present health compared with other women about the same age as worse than, the same as or better than most. RESULTS: Women reporting their health to be "better than most" decreased from 51.2% at Year 1 to 41.3% at Year 8. In the year prior to the late menopausal transition, women reporting their health to be 'better than most' declined by 5%. Comparing women who experienced the menopausal transition with women whose menopausal status did not change, there was no significant difference in changes in self-rated health. Change in body mass index (OR = 1.53; 95% CI = 1.13 to 2.06) and change in feelings for partner (OR = 0.38; 95% CI = 0.17 to 0.86) predicted a change in self-rated health from a baseline status of 'better than most.' Having an operation or procedure in the last year (OR = 8.63; 95% CI = 1.84 to 40.4) and an increase in the number of symptoms (OR = 1.32; 95% CI = 1.01 to 1.72) predicted a decline in self-rated health from baseline status of 'same as others.' CONCLUSION: This prospective study found a small decline in self-rated health with age but no significant effect of the menopausal transition. Different factors relate to differing self-rated health groupings. Further studies involving other ethnic groups and larger sample sizes are needed.

Evaluation of a short scale to assess female sexual functioning.

This article provides information on the external and concurrent validity, test-retest reliability, and sensitivity to change of a short form of the Personal Experiences Questionnaire, which was adapted from the McCoy Female Sexuality Questionnaire. We drew participants from convenience samples of women attending three different clinic settings: family planning clinics, psychiatrists, and sex therapists. We chose the psychiatry and sex therapy clinics as samples likely to show poor sexual functioning in order to assist with external validity assessment and to establish a cut-off score indicating sexual dysfunction. Satisfactory external criterion validity, concurrent validity, reliability on re-test, and validation of the composite score were demonstrated. A cut-off score of 7 or below distinguishes with 79% specificity and sensitivity those with sexual dysfunction.

Hormonal changes in the menopause transition.

The menopause is the permanent cessation of menstruation resulting from the loss of ovarian follicular activity. It is heralded by the menopausal transition, a period when the endocrine, biological, and clinical features of approaching menopause begin. A common initial marker is the onset of menstrual irregularity. The biology underlying the transition to menopause includes central neuroendocrine changes as well as changes within the ovary, the most striking of which is a profound decline in follicle numbers. Follicle-stimulating hormone (FSH) is an established indirect marker of follicular activity. In studies of groups of women, its concentration, particularly in the early follicular phase of the menstrual cycle, begins to increase some years before there are any clinical indications of approaching menopause. The rise in FSH is the result of declining levels of inhibin B (INH-B), a dimeric protein that reflects the fall in ovarian follicle numbers, with or without any change in the ability of the lining granulosa cells to secrete INH-B. Estradiol levels remain relatively unchanged or tend to rise with age until the onset of the transition and are usually well preserved until the late perimenopause, presumably in response to the elevated FSH levels. During the transition, hormone levels frequently vary markedly - hence, measures of FSH and estradiol are unreliable guides to menopausal status. Concentrations of testosterone have been reported to fall by about 50% during reproductive life, between the ages of 20 and 40. They change little during the transition and, after menopause, may even rise. Dehydroepiandrosterone (DHEA) and DHEAS, its sulphate, on the other hand, decline with age, without any specific influence of the menopause. Symptoms of the menopause can be interpreted as resulting primarily from the profound fall in estradiol, occurring over a 3- to 4-year period around final menses, a fall that presumably contributes importantly to the beginning, in the late perimenopause, of loss of bone mineral density.