Miodrag Dodic

Programming Effects of Short Prenatal Exposure to Dexamethasone in Sheep

Abstract—Recent studies have linked fetal exposure to a suboptimal intrauterine environment with adult hypertension. The aims of the present study were to see whether prenatal dexamethasone administered intravenously to the ewe between 26 to 28 days of gestation (1) resulted in high blood pressure in male and female offspring and whether hypertension in males was modulated by testosterone status, and (2) altered gene expression for angiotensinogen and angiotensin type 1 (AT1) receptors in the brain in late gestation and in the adult. Basal mean arterial pressure (MAP) at 2 years of age was significantly higher in wethers exposed to prenatal dexamethasone (group D; 106±5 mm Hg, n=9) compared with the control group (group S; 91±3 mm Hg, n=8;P <0.01). Infusion of testosterone for 3 weeks had no effect on MAP in either treatment group. At 130 days of gestation, dexamethasone administered between 26 to 28 days of gestation (group DF; n=8), resulted in an increased expression of angiotensinogen in hypothalamus (in arbitrary units: 2.5±0.3 versus 1.3±0.3 in the saline group [group SF], n=10;P <0.05). In addition, there was higher expression of the AT1 receptors in medulla oblongata in group DF (2.6±0.6 versus 1.1±0.2 in group SF;P <0.01). This effect of prenatal dexamethasone treatment was still evident in females at 7 years of age (group DA; n=5; 2.6±0.5 versus 1.1±0.2 in group SA; n=6, P <0.05). In conclusion, brief prenatal exposure of the pregnant ewe to dexamethasone leads to hypertension in adult animals of both sexes. Most interestingly, the mechanism leading to programming of hypertension might be linked with the brain angiotensin system.

Programming effects of short prenatal exposure to cortisol

Recent studies have linked fetal exposure to a suboptimal intrauterine environment with adult hypertension. The aims of this study were twofold: 1) to see whether cortisol treatment administered to the ewe for 2 days at 27 days of gestation (term ~150 days) resulted in high blood pressure in offspring; 2) to study the effect of the same treatment on gene expression in the brain at 130 days of gestation and in lambs at 2 months of age. Mean arterial pressure was significantly higher in the adult female and male offspring of sheep treated with cortisol than in the control group (females: 89±2 mmHg vs. 81±2; P<0.05 and males: 102±4 mmHg vs. 91±3; P<0.05). Prenatal cortisol treatment led to up‐regulation of angiotensinogen, AT1, MR, and GR mRNA in the hippocampus in fetuses at 130 days of gestation but not in the animals at 2 months of age. This is the first evidence that short prenatal exposure to cortisol programmed high blood pressure in the adult female and male offspring of sheep. Altered gene expression in the hippocampus could have a significant effect on the development of the hippocampus, and on postnatal behavior.—Dodic, M., Hantzis, V., Duncan, J., Rees, S., Koukoulas, I., Johnson, K., Wintour, E. M., Moritz, K. Programming effects of short prenatal exposure to cortisol. FASEB J. 16, 1017–1026 (2002)

Prenatal glucocorticoid exposure in the sheep alters renal development in utero: implications for adult renal function and blood pressure control

Treatment of the pregnant ewe with glucocorticoids early in pregnancy results in offspring with hypertension. This study examined whether glucocorticoids can reduce nephron formation or alter gene expression for sodium channels in the late gestation fetus. Sodium channel expression was also examined in 2-mo-old lambs, while arterial pressure and renal function was examined in adult female offspring before and during 6 wk of increased dietary salt intake. Pregnant ewes were treated with saline (SAL), dexamethasone (DEX; 0.48 mg/h) or cortisol (CORT; 5 mg/h) over days 26-28 of gestation (term = 150 days). At 140 days of gestation, glomerular number in CORT and DEX animals was 40 and 25% less, respectively, compared with SAL controls. Real-time PCR showed greater gene expression for the epithelial sodium channel (α-, β-, γ-subunits) and Na(+)-K(+)-ATPase (α-, β-, γ-subunits) in both the DEX and CORT group fetal kidneys compared with the SAL group with some of these changes persisting in 2-mo-old female offspring. In adulthood, sheep treated with dexamethasone or cortisol in utero had elevated arterial pressure and an apparent increase in single nephron glomerular filtration rate, but global renal hemodynamics and excretory function were normal and arterial pressure was not salt sensitive. Our findings show that the nephron-deficit in sheep exposed to glucocorticoids in utero is acquired before birth, so it is a potential cause, rather than a consequence, of their elevated arterial pressure in adulthood. Upregulation of sodium channels in these animals could provide a mechanistic link to sustained increases in arterial pressure in cortisol- and dexamethasone-exposed sheep, since it would be expected to promote salt and water retention during the postnatal period.

Haemodynamic characteristics of hypertension induced by prenatal cortisol exposure in sheep

1. Administration of glucocorticoids to ewes early in pregnancy results in offspring with hypertension in adulthood. The hypertension in female offspring exposed to dexamethasone is associated with increased cardiac output, but whether this is also true in cortisol‐exposed offspring is unknown.

Programming Hypertension—Animal Models

Hypertension can be programmed by experimental manipulation of the intrauterine environment. Studies to date suggest that, at least in some models, common pathways such as glucocorticoids or the renin-angiotensin system cause programming of arterial pressure. How mechanisms involved in controlling “normal” arterial pressure have been altered, remains a largely unanswered question, though the process may include the programming of the major organs and endocrine/neural systems involved in long-term blood pressure regulation. Clear evidence demonstrates a prominent role for the programming of the kidney in the development of hypertension. The major mechanisms examined to date include a reduced nephron endowment and alterations to the function of renal renin-angiotensin system. These studies do not preclude a role for other major cardiovascular organ systems (brain, vasculature, heart) in the programming of hypertension. Several studies have identified sex-specific differences in the programming of hypertension, which may relate to fetal sex-specific rates of placental gene expression and/or sex-specific timing of fetal development. Future studies should be directed towards examining the integrative control of blood pressure in prehypertensive animals to differentiate between the primary initiating programming events and events secondary to the development of hypertension. Understanding the mechanisms involved will be essential for devising preventative and/or treatment strategies.

How do interprofessional student teams interact in a primary care clinic? A qualitative analysis using activity theory

Practice based interprofessional education opportunities are proposed as a mechanism for health professionals to learn teamwork skills and gain an understanding of the roles of others. Primary care is an area of practice that offers a promising option for interprofessional student learning. In this study, we investigated what and how students from differing professions learn together. Our findings inform the design of future interprofessional education initiatives. Using activity theory, we conducted an ethnographic investigation of interprofessional education in primary care. During a 5xa0months period, we observed 14 clinic sessions involving mixed discipline student teams who interviewed people with chronic disease. Teams were comprised of senior medicine, nursing, occupational therapy, pharmacy and physiotherapy entry level students. Semi-structured interviews were also conducted with seven clinical educators. Data were analysed to ascertain the objectives, tools, rules and division of labour. Two integrated activity systems were identified: (1) student teams gathering information to determine patients’ health care needs and (2) patients either as health consumers or student educators. Unwritten rules regarding ‘shared contribution’, ‘patient as key information source’ and ‘time constraints’ were identified. Both the significance of software literacy on team leadership, and a pre-determined structure of enquiry, highlighted the importance of careful consideration of the tools used in interprofessional education, and the way they can influence practice. The systems of practice identified provide evidence of differing priorities and values, and multiple perspectives of how to manage health. The work reinforced the value of the patients’ voice in clinical and education processes.

Interprofessional student teams augmenting service provision in residential aged care.

The aim of this study was to determine the usefulness of student‐led interprofessional consultations within residential aged care in augmenting patient care and enhancing student education. Volunteer fourth and final year health‐care students conducted interprofessional consultations. In a mixed methods design, residents health‐care changes and perspectives were collected prospectively, and student and educator perceptions were measured by survey and interview. Sixteen aged care residents were consulted by interprofessional teams. Students identified two new health issues and proposed 17 recommendations for referrals and five changes to medication management. At six‐weeks follow‐up, two recommendations had been acted upon clinically, and two medication changes had been implemented. Reasons for the low uptake of recommendations were determined. Residents, students and educators reported high levels of satisfaction. Residential care facilities offer a useful interprofessional learning environment. Student consultations are positively regarded by patients, students and educators and may augment existing health services.

Exploring the value of interprofessional student-led clinics for chronic disease patients

nterprofessional student-led clinics have recently been established to extend educational capacity beyond traditional single-discipline placements in the acute sector and to facilitate the development of a collaborative approach to health care. Although student satisfaction with interprofessional education (IPE) is common, it is unclear whether IPE improves chronic disease management, a global priority of health care practice. This study explored the impact of interprofessional student-led clinics on chronic disease management in the primary care setting.

Perinatal Programming of Adult Metabolic Homeostasis

Poor fetal growth and associated neonatal catch-up growth are independent risk factors for metabolic disease in later life. Epidemiological studies in humans consistently show associations of small size at birth and later glucose intolerance and/or diabetes. A primary defect is thought to be insulin resistance, which is associated with both small size at birth and neonatal catch-up growth. The available evidence suggests that this resistance may result from a signalling defect downstream of the insulin receptor in peripheral tissues. Recent evidence also suggests that insulin secretion may be impaired in the individual who was small at birth. Most of the contemporary data in humans relates later outcomes to size at birth rather than to specific exposures. Experimental models that restrict fetal growth or produce variation in size at birth have therefore been used to explore these associations between small size at birth, neonatal catch-up growth and later metabolic disease. In this chapter we will review what has been learnt from human and experimental studies about the mechanistic basis for poor metabolic homeostasis following restricted fetal growth and neonatal catch-up growth, and comment on future directions in this area.