Thèses sur le sujet « Hypothalmic diseases »

Dysfunction of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis is a common finding in advanced dementia. In this study, the function of the LHPA axis at different levels was investigated in patients with dementia and in healthy elderly. A subtle disturbance in the feedback regulation of the LHPA axis was found in patients with early (i.e., mild to moderate) Alzheimer’s disease (AD). After 0.5 mg dexamethasone, serum cortisol levels were less suppressed in AD patients and plasma adrenocorticotropin (ACTH) levels were lower as compared with healthy elderly. After stimulation with human corticotropin-releasing hormone a blunted ACTH response was found in AD patients while relative serum cortisol, dehydroepiandrosterone, and androstenedione responses were increased. Significant correlations were found between low plasma ACTH levels and temporal lobe atrophy and between low peak plasma ACTH levels and hippocampal atrophy measured with computer tomography. Patients with advanced AD and multi-infarct dementia had lower basal levels of dehydroepiandrosterone sulphate in combination with no difference in cortisol levels, resulting in a high cortisol/DHAS ratio. The difference persisted after adjustments for age and sex in a multivariate analysis. In patients with early AD, basal serum levels of dehydroepiandrosterone and androstenedione were increased, and this increase was accentuated after stimulation with ACTH. Peripheral glucocorticoid sensitivity was examined by skin vasoconstrictor blanching tests. Patients with AD and patients treated with glucocorticoids showed skin blanching at higher clobetasol concentrations than healthy elderly. These findings justify further investigations on the role of LHPA axis dysfunction in Alzheimer’s disease and its possible importance for the pathophysiology of the disease.<br>digitalisering@umu

[Truncated abstract] G-protein coupled receptors (GPCRs) form one of the largest superfamilies of cell-surface receptors and respond to a vast range of stimuli including light, hormones and neurotransmitters. Although structurally similar, GPCRs are regulated by many diverse proteins, which allow the specific functions of each receptor to be carried out. This thesis focussed on two well-documented GPCRs, the thyrotropin releasing hormone receptor (TRHR) and gonadotrophin-releasing hormone receptor (GnRHR), which control the thyroid and reproductive endocrine pathways respectively. Although each of these anterior pituitary receptors is responsible for distinct physiological responses, both are integral to normal development and homeostasis. This thesis focused on three areas of GPCR regulation: ?-arrestin recruitment, transcription factor regulation and receptor up-regulation. The role of the cytoplasmic protein, ?-arrestin, has perhaps been previously underestimated in GPCR regulation, but it is now increasingly apparent that ?-arrestins not only inhibit further G-protein activation and assist in GPCR internalisation but also act as complex scaffolding platforms to mediate and amplify downstream signalling networks for hours after initial GPCR activation. It is therefore becoming increasingly important to be able to monitor such complexes in live cells over longer time-frames. ... Members of the E2F transcription family have been previously identified by this laboratory as potential GnRHR interacting proteins, via a yeast-2-hybrid screen and BRET. This thesis further investigated the role of E2F family members and demonstrates that a range of GPCRs are able to activate E2F transcriptional activity when stimulated by agonist. However, despite GnRHR displaying robust E2F transcriptional activation upon agonist stimulation, this did not result in any conclusive evidence for functional regulation, although it is possible E2F may modulate and assist in GnRHR trafficking. Furthermore it is apparent that E2F family members are highly redundant, as small effects in GnRHR binding and cell growth were only observed when protein levels of both E2F4 and E2F5 were altered. During the course of the investigation into the effect of E2F transcription on GPCR function, it was evident that long-term agonist stimulation of GnRHR had a profound effect on its expression. As this was explored further, it became clear that this agonist-induced up-regulation was both dose- and time-dependent. Furthermore, altering levels of intracellular calcium and receptor recycling/synthesis could modulate GnRHR up-regulation. In addition, an extremely sensitive CCD camera has been used for the first time to visualise the luciferase activity attributed to GnRHR up-regulation. Overall, this thesis demonstrates the complex nature of GPCR regulation. For the first time, long-term BRET analysis on ?-arrestin interactions with both classes of GPCRs has been examined in a variety of cellular formats. This has given valuable insights into the roles of phosphorylation and internalisation on ?-arrestin interaction. Additionally, this thesis has revealed that prolonged agonist exposure increases receptor expression levels, which has major implications for drug therapy regimes in the treatment of endocrine-related disorders and tumours.

Depression is associated with an increased risk of cardiovascular disease (CVD). One possible mechanism of this effect is dysregulation of the biological stress systems, the autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis. The current thesis aimed to better understand the relationship between depression and these two systems. In the first study, the effect of major depression on heart rate recovery following exercise, a marker of ANS tone, was examined in cardiac patients. Depression was associated with poor early heart rate recovery, suggesting reduced post-exercise parasympathetic activation. The second study, which included healthy participants, examined the effect of cognitive and somatic depressive symptoms in relation to recovery of heart rate and heart rate variability, two markers of ANS tone, in response to interpersonal laboratory stressors. Both types of symptoms were found to predict post-stress recovery. The third study aimed to examine the relationship between major depression both ANS and HPA axis activity in response to a stressful diagnostic test. Furthermore, it aimed to determine whether antidepressant medication is effective in restoring a normal stress response in depressed individuals. Depressed cardiac patients exhibited elevated cortisol levels in response to the test but this effect was not seen among depressed individuals taking antidepressant medication. However, neither depression nor antidepressant use was associated with heart rate variability. As a whole, these studies suggest a modest and inconsistent relationship between depression and prolonged post-stress ANS activation. On the other hand, the relationship between depression and exaggerated HPA axis activity appears to be relatively strong. Finally, antidepressant medication may be effective in reversing the excessive HPA axis activation observed in depressed individuals.<br>La dépression est associée à un risque élevé de maladie cardiaque. Un mécanisme qui pourrait expliquer cette association est la dysfonction du système nerveux autonome (SNA) et l'axe hypothalamo-hypophyso-surrénalien (HHS), qui sont les deux systèmes impliqués dans la réaction physiologique au stress. Cette thèse avait comme but de mieux comprendre la relation entre la dépression et ces deux systèmes. Dans la première étude, l'effet de la dépression majeure sur le rétablissement de la fréquence cardiaque après l'exercice, un marqueur de la balance autonome, a été examiné chez des patients cardiaques. La dépression était associée à un pauvre rétablissement cardiaque immédiatement après l'exercice, ce qui suggère un délai dans l'activation du système parasympathique. Dans la deuxième étude, qui incluait des participants en santé, on examinait l'effet des symptômes dépressifs cognitifs et somatiques en relation avec le rétablissement de la fréquence cardiaque et la variabilité de la fréquence cardiaque, deux marqueurs de l'activation du SNA, en réaction à des stress interpersonnels de laboratoire. Les deux types de symptômes étaient associés avec un moins bon rétablissement cardiaque après les stress. Finalement, la troisième étude examinait la relation entre la dépression majeure et l'activité du SNA et de l'axe HHS en réaction à un test diagnostique stressant. De plus, l'étude a eu comme but de déterminer si les antidépresseurs sont efficaces dans le rétablissement d'une réponse normale au stress chez les dépressifs. Les patients cardiaques dépressifs avaient un niveau de cortisol plus élevé tout au long du test, ce qui indique une activation plus forte de l'axe HHS. Cet effet n'a pas été observé chez les dépressifs qui prenaient des antidépresseurs; par contre, ni la dépression ni l'utilisation des antidépresseurs étaient associées à la variabilité de la fréquence cardiaque. Ces études suggèrent une relation modeste et inconsistante entre la dépression et une activation altérée du SNA. Par contre, la relation entre la dépression et la suractivation de l'axe HHS apparait relativement forte. Finalement, les antidépresseurs semblent être efficaces en annulant la suractivation de l'axe HHS chez les dépressifs.

The objectives of this thesis were: (1) to evaluate the downregulation of the stallion hypothalamic-pituitary-gonadal (HPG) axis by a GnRH antagonist (acyline) based upon endocrine, seminal, testicular and behavioral effects, and (2) to assess recovery after treatment. Stallions were treated for 50 days (n=4; 330µg/kg acyline q 5d) and controls (n=4) received vehicle alone. Stallions were assessed pre-treatment and for 72 days after last treatment. Treatment induced declines (p<0.05) in FSH, LH, testosterone (to castrate levels) and estrone sulfate. Gonadotropins and testosterone returned to control values within nine days and estrone sulfate by 14 days after treatment discontinuation. Acyline-treated stallions failed to respond with FSH, LH and testosterone increase after exogenous GnRH stimulation (25µg gonadorelin, IV) compared to pre-treatment and control stimulation. Total sperm numbers and motility were reduced in acyline-treated stallions, as well as total seminal plasma protein and testicular volume (p<0.05). Time to ejaculation was increased in acyline group (p<0.5). Testicular, sexual behavior and most seminal parameters regained normal levels within 72 days after treatment ceased. Sperm output of acyline-treated stallions was regained within seven months after ending treatment. Acyline reversibly suppressed the stallion HPG axis, thus has potential for treating the androgen-dependent Equine-Arteritis-Virus carrier state and as behavior modulator.

As doenças inflamatórias intestinais (DII) são causadas por desequilíbrio entre as respostas imunes efetoras e reguladoras na mucosa intestinal e podem ser moduladas pelo eixo hipotálamo-hipófise-adrenal (HPA) por meio de interações neuroimunoendócrinas e secreção de cortisol. Embora os glicocorticóides (GC) sejam utilizados para tratar a DII, o cortisol produzido pelas glândulas supra-renais também está envolvido na resposta ao estresse, que pode levar a doenças inflamatórias descontroladas. Portanto, o objetivo deste trabalho é avaliar a participação do eixo HPA na modulação da resposta imune de mucosa intestinal. Para tal, camundongos C57BL/6 foram submetidos à remoção das glândulas adrenais seguida por indução de colite pela administração de água contendo 3% de dextran sulfato de sódio (DSS). Os resultados demonstraram que a ausência das adrenais levou à maior suscetibilidade à doença e mortalidade precoce, fenômeno que não foi prevenido pela reposição de GC. Os animais adrenalectomizados com colite apresentaram níveis significativamente menores de LPS, concomitantemente ao aumento de IL-6 no soro quando comparados aos camundongos não adrenalectomizados. Além disso, os animais adrenalectomizados apresentaram menor celularidade na lâmina própria (LP), menos áreas de erosão e menor escore histopatológico associado ao aumento de IFN-? e FasL, no intestino, sem produção local compensatória de corticosterona. Houve aumento na atividade das enzimas mieloperoxidase (MPO), N- acetilglicosaminidase (NAG) e eosinófilo-peroxidase (EPO) no intestino dos animais expostos ao DSS quando comparados ao grupo de camundongos controles saudáveis, independentemente da presença do eixo HPA intacto e o tratamento com GC nos animais adrenalectomizados levou à redução significativa da atividade de MPO. Também foi observado na LP dos camundongos adrenalectomizados aumento significativo na frequência de células dendríticas tolerogênicas CD11b+CD11c+CD103+, T auxiliares (CD3+CD4+), T citolíticas (CD3+CD8+) e NKT (CD3+CD49b+), além de redução significativa da população de células dendríticas pró-inflamatórias CD11b+CD11c+CD103-, leucócitos CD11b+ e linfócitos intra-epiteliais, de maneira dependente de GC. A ausência do eixo HPA intacto levou à diminuição de leucócitos totais no baço quando comparados ao grupo com colite, relacionada principalmente à redução significativa na frequência de células NKT (CD3+CD49b+), as quais foram restauradas nos camundongos tratados com GC exógenos. Durante a exposição ao DSS houve aumento de células Th2 e Th1 no baço dos camundongos não adrenalectomizados, enquanto que a remoção das adrenais levou a notável redução na população de células T CD4 produtoras de IL-4, IL-10, IFN-? ou IL-17, com aumento de células Th17 e diminuição significativa de células Th1 no baço dos camundongos adrenalectomizados e tratados com GC. De forma interessante, houve menor acúmulo de células T reguladoras juntamente à redução na intensidade média de fluorescência (MFI) de FOXP3 em células T CD4+CD25+ do baço dos camundongos adrenalectomizados expostos ao DSS, de maneira geral dependente de GC. Por fim, esta diminuição de mecanismos reguladores foi acompanhada de menor índice de proliferação e aumento de IL-10 no sobrenadante de cultura de esplenócitos de camundongos com o eixo HPA não ii funcional, indicando que a ausência de GC endógenos pode alterar significativamente a homeostase do sistema imunológico. Juntos, nossos resultados demonstram que o eixo HPA é importante na modulação da resposta imunológica durante a colite induzida experimentalmente<br>Inflammatory bowel diseases (IBD) are caused by imbalance between regulatory and effector immune responses in the intestinal mucosa and can be modulated by the hypothalamic-pituitary-adrenal (HPA) axis via neuroimmune endocrine interactions and secretion of cortisol. Although glucocorticoids (GC) are used to treat IBD, cortisol produced by the adrenals glands is also involved in the stress response, which can lead to uncontrolled inflammatory diseases. Therefore, the aim of this study was to evaluate the HPA axis in the modulation of the immune response of intestinal mucosa. C57BL/6 mice were subjected to removal of the adrenal glands followed by induction of colitis by administration of water containing 3% dextran sulfate sodium (DSS). The results showed that the absence of adrenals led to increased susceptibility to disease and early mortality, a phenomenon that was not prevented by GC replacement. Adrenalectomized animals exposed to DSS had significantly lower levels of LPS, concomitantly to increased IL-6 in the serum when compared to non-adrenalectomized mice. In addition, adrenalectomized animals had lower cellularity in the lamina propria (LP), less erosion areas and less histopathologic score associated with increased IFN-? and FasL in the intestine, without compensatory local production of corticosterone. There was an increase in the activity of the myeloperoxidase (MPO) enzyme, N- acetilglicosaminidase (NAG) and eosinophil-peroxidase (EPO) in the intestines of DSS-exposed animals when compared to the healthy control group of mice, regardless of the presence of intact HPA axis, while treatment with GC led to significantly reduced MPO activity. It was also observed in the LP of adrenalectomized mice significant increase in the frequency of tolerogenic dendritic cells CD11b+CD11c+CD103+, helper T (CD3+ CD4+), cytolytic T (CD3+ CD8+) and NKT (CD3+ CD49b+) besides significant reduction in the population of pro-inflammatory dendritic cells CD11c+ CD11b+ CD103-, leukocyte CD11b+ and intraepithelial lymphocytes, GC-dependent manner. The absence HPA intact carried decrease in total leukocytes in spleen when compared to the group with colitis, related mainly to significant reduction in the frequency of NKT cells (CD3+CD49b+), which were restored in the GC treated mice. During exposure to DSS there was increased Th2 and Th1 cells in the spleen of non-adrenalectomized mice, while the removal of the adrenals was associated to a marked reduction in the population of CD4 T cells producing IL-4, IL-10, IFN-? or IL-17 with increased Th17 cells and significant decrease in Th1 cells in the spleen of adrenalectomized mice treated with GC. Interestingly there was less accumulation of regulatory T cells together to a reduction in mean fluorescence intensity (MFI) of FOXP3 in CD4+CD25+ T cells in the spleen of mice exposed to DSS after adrenalectomy, most dependent on GC. Finally, the decline of regulatory mechanisms was accompanied by lower rates of proliferation and increased IL-10 in the supernatant culture of splenocytes of mice with disrupted HPA axis, indicating that the absence of endogenous GC altered significantly the homeostasis of the immune system. Together, our results demonstrate that the HPA axis is important in modulating the immune response during experimentally induced colitis

Low birth weight is associated with an increased risk of impaired glucose tolerance and type 2 diabetes and with signs of increased hypothalamic pituitary adrenal axis activity in later life (1, 2). Low birth usually weight reflects a reduction in fetal growth, which largely depends on an adequate supply of nutrients and oxygen. Variations in supply modify the metabolic and neuroendocrine characteristics of the fetus, which in turn modulate the pattern of functional development as well as growth (3). An adverse fetal environment, evident as low birth weight, is therefore proposed to alter functional development with long term effects for the function and risk of disease in the individual later in life (4, 5). Increased HPAA impairs metabolic homeostasis and could therefore mediate effect of prenatal challenge on later metabolic control (6). It was therefore hypothesised that restriction of fetal growth, increases circulating cortisol and/or alters sensitivity to cortisol, which increases fasting blood glucose, and impairs glucose tolerance in the young adult. Large litter size in the guinea pig is characterised by reduced placental and fetal growth, reduced size at birth and insulin resistance in offspring in later life, providing a suitable model to test this hypothesis. Spontaneous restriction of fetal growth in the guinea pig, evident as small size at birth, was associated with increased salivary cortisol, in both sexes but at different stages of postnatal life. In males, salivary cortisol was increased with small size at birth in early and adult life, but reduced later with ageing. In females however, salivary cortisol was increased in juveniles and in aged adults, possibly reflecting the impact of the oestrus cycle on cortisol production in mature cycling females. Altered activity of the HPGA, which can influence that of the HPAA, has also been reported to be programmed by prenatal restriction. In the guinea pig, salivary testosterone in males increased with age and small size at birth in juveniles, young and aged adults. In females, salivary progesterone increased with age up to 300 days, and decreased with size at birth in the young guinea pig. Although testosterone inhibits HPAA activity, in males, mean salivary cortisol correlated positively with mean salivary testosterone at 100 and 300 days of age. In contrast, progesterone may enhance HPAA activity, and consistent with this, in females, mean salivary progesterone correlated with mean salivary cortisol at 400 days of age. Therefore, salivary testosterone in the male and salivary progesterone in the female guinea pig changes with maturation and has previously reported in this or other species, but small size at birth increases salivary testosterone in males with modest effects in early life in females. This together with the unexpected positive associations of salivary cortisol with testosterone in males, suggests that programming of the HPAA makes little contribution to that of the HPAA as indicated by salivary cortisol. Here we show that low birth weight is associated with increased fasting blood glucose and impaired glucose tolerance in both male and female young adult guinea pigs aged 100 days. Fasting and mean (during IVGTT) plasma cortisol was reduced in low birth weight female adult guinea pigs, and is not vary with size at birth at this age in males. This suggests that circulating cortisol does not contribute to the impaired glycaemia associated with small size at birth in the guinea pig. Glucose tolerance was increasingly impaired in males but not females, as mean plasma cortisol increased. This is consistent with cortisol impairing glycaemia in the guinea pig as in other species, in males at least. To assess the role of cortisol in prentally programmed impairment of glycaemia directly, metyrapone or vehicle containing 24% ethanol was administered to young adult guinea pigs for 3 days. Treatment with the latter impaired fasting blood glucose and glucose tolerance in females and the latter in males compared to a previous IVGTT and this was exacerbated in low birth weight females. Metyrapone prevented this impairment of fasting glycaemia and glucose tolerance in the low birth weight adult female guinea pig and in the male guinea pig regardless of birth weight class. Neither vehicle or metyrapone altered plasma cortisol, before or during a second IVGTT. Limited numbers of animals, particularly females, limited this study however and additional investigation is required. Nevertheless this shows for the first time that inhibition of glucocorticoid synthesis in the guinea pig improves glucose control. Furthermore this suggests that the low birth weight guinea pig may be more sensitive to cortisol, have increased cortisol synthesis or reduced inactivation of cortisol in peripheral tissues, leading to increased local cortisol action. In conclusion, alterations in peripheral HPAA activity in the guinea pig due to restricted fetal growth may contribute to their prenatally programmed development of impaired glucose tolerance as young adults, but the extent of that contribution may vary with age and gender.<br>Thesis (Ph.D.) -- University of Adelaide, School of Paediatrics and Reproductive Health, 2008

Many studies have shown that short sleep duration and/or poor sleep quality is associated with increasing rates of cardiovascular (CVD) mortality and morbidity. One hypothesized explanation for this association has been that sleep loss is a type of chronic stress that induces dysregulation of biological systems that ultimately increase the risk of CVD. One biological system that has been thought to link sleep loss and CVD is the hypothalamus-pituitary-adrenal (HPA) axis. A number of studies using small or convenience samples have addressed the effects of sleep deprivation on cortisol. Only a few studies have examined the association of habitual short sleep duration and/or poor sleep quality with changes in the diurnal cortisol in population based-samples; those studies vary in their methodology and in findings. Another biological system that has been thought to link sleep loss and CVD is the autonomic nervous system (ANS), through overactivation of the sympathetic nervous system (SNS) and/or probably a withdrawal of the parasympathetic nervous system. Experimental studies have shown an association between the sleep stages and markers of the sympathetic system. However, very few studies of habitual sleep duration/sleep quality and ANS markers have been conducted. Even fewer studies have examined the association of habitual sleep duration and/or sleep quality and ANS responses to a stress challenge in a population-based sample. The findings again have been inconsistent probably due to the use of different methodology and different samples. This dissertation used measures of salivary diurnal cortisol as well as cortisol responses to a stress challenge protocol to assess the relationship of habitual sleep duration and/or sleep quality with diurnal cortisol profile in natural conditions and in response to a stress challenge protocol in a laboratory setting. Diurnal cortisol was assessed from up to 16 samples of salivary cortisol for two days. Cortisol responses to a stress challenge were assessed from four salivary samples taken during the stress challenge that was performed in a different day than the diurnal cortisol collection. To examine the relationship of habitual sleep duration and/or sleep quality and markers of the ANS, this dissertation used continuous cardiovascular measures (heart rate and heart rate variability) and four salivary amylase samples obtained during the stress challenge. The stress challenge included mental stress and orthostatic stress. Sleep duration and sleep efficiency (an objective measure of sleep quality) were assessed from 7-day actigraphy and sleep diaries. Insomnia symptoms (a subjective measure of sleep quality) were also assessed using a questionnaire that included the Women’s Health Initiative Insomnia rating scale (WHIIRS). We used mixed models so as to account for the repeated measures of diurnal salivary cortisol levels as well as the responses (reactivity and recovery) to the stress challenge tests. Chapter 1 presents an introduction to this dissertation discussing the relationship between short sleep duration and/or poor sleep quality and CVD morbidity and mortality. Chapter 2 presents a systematic literature review of studies of the association between habitual sleep duration and/or sleep efficiency and markers of neuro-endocrine systems: HPA and ANS. These are plausible mechanisms that link short and/or poor sleep to CVD morbidity and mortality. Chapter 3 presents our analyses of the relationship between short sleep duration and/or poor sleep quality and features of the diurnal cortisol. We hypothesized that those participants whose slept < 6 hours per night or whose sleep efficiency was < 85% would have higher cortisol levels on awakening, flatter cortisol awakening responses (CAR), and higher evening cortisol levels than participants who slept longer or slept better. We found that short sleepers had higher evening cortisol than the longer sleepers and that this association persisted after the adjustment for several known confounders. In chapter 4, we examined how the same groups of participants responded in terms of hormones (cortisol and amylase) and cardiovascular indices (heart rate (HR) and HR variability (HRV)) to a stress challenge test. We hypothesized that those participants who slept for a shorter time or whose sleep was of poorer quality would have more exaggerated responses to and less recovery from a stress challenge test than participants who slept longer or slept better. We found that participants with insomnia had exaggerated high frequency-HRV (HF-HRV) orthostatic reactivity. In an extended analysis, we found that participants who slept less than 7 hours/night had exaggerated heart rate reactivity to a mental stress test compared to participants who slept 7 or more hours/night, but this association was attenuated after adjustment for naps. Paradoxically, we also found that participants who slept less than 7 hours had higher HF-HRV recovery from mental stress compared to longer sleepers (≥7 hours). Short sleep duration or low sleep efficiency was not associated with cortisol or amylase responses to the stress challenge protocol. These findings suggest that sustained high evening cortisol levels and cardiovascular responses to a stress challenge may be among the mechanisms linking short/poor sleep and CV disease.

Indiana University-Purdue University Indianapolis (IUPUI)<br>Prospective epidemiologic evidence indicates that both stressful life events (SLEs) and depression are associated with an increased risk of subclinical atherosclerosis and cardiovascular disease (CVD) events. Even though stressful life events (SLEs) and depression co-occur and may act together to influence cardiovascular disease (CVD) risk, these psychosocial factors have been mainly examined in isolation. For instance, depression may moderate the relationship between SLEs and CVD outcomes. I hypothesized that depressive symptoms would potentiate the deleterious effect of SLEs on subclinical atherosclerosis. This hypothesis is plausible, given that depressed adults exhibit exaggerated and prolonged sympathetic nervous system, hypothalamic-pituitary-adrenal (HPA) axis, and inflammatory responses to stress, which in turn could promote atherosclerosis. As compared to their nondepressed counterparts, depressed individuals may also be more likely to engage in maladaptive methods to cope with SLEs (e.g., increased tobacco use, alcohol use, and consumption of low-nutrient, energy dense foods), which could also promote atherosclerosis. I examined cross-sectional data from 274 to 279 (depending on the outcome measure) older, African American adults (mean age = 66 years, 67% female) with no evidence of clinical CVD or dementia who participated in the St. Louis African American Health-Heart study (2009–2011). Number of SLEs was assessed using the Life Events Calendar, a structured interview. From this interview, a continuous SLEs variable was computed (number of adult SLEs: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11+). Severity of depression symptoms was measured using the 17-item Hamilton Rating Scale for Depression (HAM-D). Two measures of subclinical atherosclerosis were obtained: carotid intima-media thickness (CIMT; assessed by ultrasonography) and coronary artery calcification (CAC; assessed by multi-detector computerized tomography). I conducted linear (CIMT) and logistic (CAC) regression models, first adjusted for demographics (age, sex, education) and then fully-adjusted (demographics; mean arterial pressure; low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C); hemoglobin A1c; BMI; tobacco use; diabetes diagnosis; and use of antihypertensitve, lipid lowering, antidiabetic, and antidepressant medications). No main effects of SLEs or HAM-D were found for CIMT or CAC. There were also no SLEs by HAM-D interactions for CIMT or CAC. Because the current results are largely inconsistent with prior literature and there is a paucity of studies utilizing African American samples, future research is needed to examine the independent and interactive associations of SLEs and depressive symptoms with measures of subclinical atherosclerosis. If the present results are replicated, it may suggest that SLEs, depressive symptoms, and their interactive effect are not cardiotoxic among African American adults.

Events around conception such as maternal undernutrition and twinning may have effects on offspring physiology and disease risk in adulthood. Periconceptional undernutrition alters offspring physiology and adult pathology without affecting birth size, while twinning affects birth size and physiology but with inconsistent effects on adult pathology. We investigated the effects of these two periconceptional events and their interaction on maternal cardiovascular adaptation to pregnancy and fetal growth, physiology and endocrinology in late gestation in sheep. Pre and/or postconception undernutrition resulted in increased uterine blood flow in late gestation, but no change in maternal blood volume. Preconception undernutrition alone resulted in a relatively large placenta with a small, slow-growing fetus in late gestation. In contrast, postconception undernutrition alone resulted in a fetus with rapid late-gestation growth that was maintained through a maternal fast. Fetuses of ewes undernourished throughout both periods were similar in growth rate and size to controls. Maternal fasting also demonstrated that plasma levels of C-type natriuretic peptide are acutely and independently regulated by nutrient supply in mother and fetus. Fetuses of ewes undernourished both pre- and postconception had increased glucose disposal following a glucose challenge. Hypothalamic-pituitary-adrenal axis tests in these fetuses showed decreased pituitary adrenocorticotropin hormone response to direct stimulation but increased adrenal response to decreased cortisol negative feedback. Twin fetuses grew more slowly in late gestation than singletons. Twins also had a smaller insulin response to arginine and a greater insulin response to glucose, but periconceptional undernutrition abolished this difference. Twins had suppressed baseline hypothalamic-pituitary-adrenal axis function and decreased adrenal sensitivity compared to singletons, but increased fetal pituitary adrenocorticotropin hormone response to direct stimulation and decreased cortisol negative feedback. These studies suggest that firstly, fetal size is a poor reflection of fetal growth trajectory, physiology and endocrinology. Secondly, pre- and postconception undernutrition affect late-gestation fetal growth in different ways, while undernutrition in both periods alters fetal endocrine status in late gestation. Thirdly, the biology of twin fetal development is fundamentally different from that of singletons, which may explain the inconsistency of the relationship between birth weight and adult disease risk in twins.<br>Auckland Medical Research Foundation, Health Research Council of New Zealand