Pontosubicular apoptosis ("necrosis") in human neonates with intrauterine growth retardation and placental infarction

In a previous study of 37 autopsied stillbirths with non-dysmorphic intrauterine growth retardation ( IUGR), 26 cases were associated with placental infarction, a morphologic marker of uteroplacental insufficiency. Nine of the 26 cases with both IUGR and placental infarction, where archival tissue was available, had grey matter ischaemic lesions that were subsequently identified as pontosubicular necrosis. This lesion is now regarded as a localized form of apoptosis. A further eight third trimester stillbirth cases with both IUGR and placental infarction were ascertained prospectively. Sixteen of these 17 cases showed pontosubicular apoptosis, identified morphologically and verified using activated caspase-3 and TUNEL. Five of the 17 cases showed apoptosis in the frontal or temporal cortex as well. In this current study, pontosubicular apoptosis was strongly associated with IUGR and placental infarction in third trimester stillborns, suggesting that uteroplacental insufficiency leading to chronic fetal hypoxaemia may cause cerebral apoptosis.

Hyposulfatemia, growth retardation, reduced fertility, and seizures in mice lacking a functional NaSi-1 gene

inorganic sulfate is required for numerous functions in mammalian physiology, and its circulating levels are proposed to be maintained by the Na+-SO42- cotransporter, (NaSi-1). To determine the role of NaSi-1 in sulfate homeostasis and the physiological consequences in its absence, we have generated a mouse lacking a functional NaSi-1 gene, Nas1. Serum sulfate concentration was reduced by >75% in Nas1(-/-) mice when compared with Nas1(+/+) mice. Nas1(-/-) mice exhibit increased urinary sulfate excretion, reduced renal and intestinal Na+-SO42- cotransport, and a general growth retardation. Nas1(-/-) mouse body weight was reduced by >20% when compared with Nas1(+/+) and Nas1(+/-) littermates at 2 weeks of age and remained so throughout adulthood. Nas1(-/-) females had a lowered fertility, with a 60% reduction in litter size. Spontaneous clonic seizures were observed in Nas1(-/-) mice from 8 months of age. These data demonstrate NaSi-1 is essential for maintaining sulfate homeostasis, and its expression is necessary for a wide range of physiological functions.

Fetal growth patterns in fetuses of women with pregestational diabetes mellitus

Objective To assess the effect of glucose control on the rate of growth of fetuses in women with pregestational diabetes mellitus (Types 1 and 2). Methods All pregestational diabetic women booked at Mater Mothers’ Hospital, Brisbane, Australia, between 1 January 1994 and 31 December 2002, were included. Pregnancies with congenital fetal anomalies, multiple pregnancies, and pregnancies terminated prior to 20 weeks’ gestation were excluded. Dating scans were performed before 14 weeks’ gestation and serial scans were performed at 18, 24, 28, 32 and 36 weeks. Fetal parameters, including biparietal diameter, femur length and abdominal circumference, were recorded. The daily growth rates for biparietal diameter, femur length, and fetal abdominal area were calculated and compared with those in a low-risk (non-diabetic) population. The growth rates in fetuses of women with satisfactory diabetic control (HbA1c

Expression of SHOX in human fetal and childhood growth plate

Abnormalities in the growth plate may lead to short stature and skeletal deformity including Leri Weil syndrome, which has been shown to result from deletions or mutations in the SHOX gene, a homeobox gene located at the pseudoautosomal region of the X and Y chromosome. We studied the expression of SHOX protein, by immunohistochemistry, in human fetal and childhood growth plates and mRNA by in situ hybridization in childhood normal and Leri Weil growth plate. SHOX protein was found in reserve, proliferative, and hypertrophic zones of fetal growth plate from 12 wk to term and childhood control and Leri Weil growth plates. The pattern of immunostaining in the proliferative zone of childhood growth plate was patchy, with more intense uniform immunostaining in the hypertrophic zone. In situ hybridization studies of childhood growth plate demonstrated SHOX mRNA expression throughout the growth plate. No difference in the pattern of SHOX protein or mRNA expression was seen between the control and Leri Weil growth plate. These findings suggest that SHOX plays a role in chondrocyte function in the growth plate.

Birth weight and age at menopause in Australian female twin pairs: exploration of the fetal origin hypothesis

In a twin sample where duration of gestation can be controlled, a specific example of the fetal origins hypothesis concerning association between low birth weight and early age at menopause is explored. The hypothesis is based on the physiologically plausible path from intrauterine growth retardation and reduced numbers of primary follicles to an earlier menopause. The sample comprised 323 Australian female twin pairs where both co-twins had reached menopause naturally and reported on their weight at birth. Regression analysis showed no linear association between the two variables (P = 0.371, r(2) = 0.0009). Intra-pair differences in age at menopause were investigated in the context of relative birth weight of co-twins. In 265 pairs an intra-pair birth a eight difference was reported. In monozygotic (MZ) pairs (n = 168) this allowed for control of genetic effects as well as gestation duration. No significant differences dependent on birth weight relative to co-twin were found for age at natural menopause in either MZ or dizygotic (DZ) twin pairs, even in pairs whose birth weights differed markedly. There was some indication that twins with premature ovarian failure were heavier at birth than twins with normal or later menopausal age. We conclude that the hypothesis that lower birth weight is associated with earlier menopause is not supported by our data.

Collagen in the scarless fetal skin wound: Detection with Picrosirius-polarization

Our group has developed an ovine model of deep dermal, partial-thickness burn where the fetus heals scarlessly and the lamb heals with scar. The comparison of collagen structure between these two different mechanisms of healing may elucidate the process of scarless wound healing. Picrosirius staining followed by polarized light microscopy was used to visualize collagen fibers, with digital capture and analysis. Collagen deposition increased with fetal age and the fibers became thicker, changing from green (type III collagen) to yellow/red (type I collagen). The ratio of type III collagen to type I was high in the fetus (166), whereas the lamb had a much lower ratio (0.2). After burn, the ratios of type III to type I collagen did not differ from those in control skin for either fetus or lamb. The fetal tissue maintained normal tissue architecture after burn while the lamb tissue showed irregular collagen organization. In conclusion, the type or amount of collagen does not alter significantly after injury. Tissue architecture differed between fetal and lamb tissue, suggesting that scar development is related to collagen cross-linking or arrangement. This study indicates that healing in the scarless fetal wound is representative of the normal fetal growth pattern, rather than a response to burn injury.

Nephron number, hypertension, renal disease, and renal failure

Essential hypertension is one of the most common diseases in the Western world, affecting about 26.4% of the adult population, and it is increasing (1). Its causes are heterogeneous and include genetic and environmental factors (2), but several observations point to an important role of the kidney in its genesis (3). In addition to variations in tubular transport mechanisms that could, for example, affect salt handling, structural characteristics of the kidney might also contribute to hypertension. The burden of chronic kidney disease is also increasing worldwide, due to population growth, increasing longevity, and changing risk factors. Although single-cause models of disease are still widely promoted, multideterminant or multihit models that can accommodate multiple risk factors in an individual or in a population are probably more applicable (4,5). In such a framework, nephron endowment is one potential determinant of disease susceptibility. Some time ago, Brenner and colleagues (6,7) proposed that lower nephron numbers predispose both to essential hypertension and to renal disease. They also proposed that hypertension and progressive renal insufficiency might be initiated and accelerated by glomerular hypertrophy and intraglomerular hypertension that develops as nephron number is reduced (8). In this review, we summarize data from recent studies that shed more light on these hypotheses. The data supply a new twist to possible mechanisms of the Barker hypothesis, which proposes that intrauterine growth retardation predisposes to chronic disease in later life (9). The review describes how nephron number is estimated and its range and some determinants and morphologic correlates. It then considers possible causes of low nephron numbers. Finally, associations of hypertension and renal disease with reduced nephron numbers are considered, and some potential clinical implications are discussed.

Health and developmental outcome of children following prenatal diagnosis of confined placental mosaicism

Objective To determine the long-term health and development of a cohort of children in whom confined placental mosaicism (CPM) was diagnosed at prenatal diagnosis. Methods A retrospective cohort study was performed comparing 36 children in whom CPM had been diagnosed prenatally with 195 controls subjects in whom a normal karyotype had been detected prenatally. Data comprising birth information, health, health service utilisation, growth, development, behaviour, and the family were collected by a maternal questionnaire administered when the subjects were aged between 4 and 11 years. Results CPM cases did not differ from controls across a broad range of health measures and there were no major health problems or birth defects among the CPM group. No increase was detected in the incidence of intrauterine growth retardation (IUGR) among CPM cases; however, postnatal growth was reduced compared with controls (p = 0.047). Development and behaviour in CPM cases was similar to that of controls. Conclusions The prenatal diagnosis of CPM is not associated with an increased risk of birth defects or developmental problems, but may be associated with decreased growth. Copyright (C) 2006 John Wiley & Sons, Ltd.

Reduced nephron number and glomerulomegaly in Australian Aborigines: A group at high risk for renal disease and hypertension

Aborigines in remote areas of Australia have much higher rates of renal disease, as well as hypertension and cardiovascular disease, than non-Aboriginal Australians. We compared kidney findings in Aboriginal and non-Aboriginal people in one remote region. Glomerular number and mean glomerular volume were estimated with the disector/fractionator combination in the right kidney of 19 Aborigines and 24 non-Aboriginal people undergoing forensic autopsy for sudden or unexpected death in the Top End of the Northern Territory. Aborigines had 30% fewer glomeruli than non-Aborigines-202000 fewer glomeruli per kidney, or an estimated 404000 fewer per person (P=0.036). Their mean glomerular volume was 27% larger (P=0.016). Glomerular number was significantly correlated with adult height, inferring a relationship with birthweight, which, on average, is much lower in Aboriginal than non-Aboriginal people. Aboriginal people with a history of hypertension had 30% fewer glomeruli than those without-250000 fewer per kidney (P=0.03), or 500000 fewer per person, and their mean glomerular volume was about 25% larger. The lower nephron number in Aboriginal people is compatible with their susceptibility to renal failure. The additional nephron deficit associated with hypertension is compatible with other reports. Lower nephron numbers are probably due in part to reduced nephron endowment, which is related to a suboptimal intrauterine environment. Compensatory glomerular hypertrophy in people with fewer nephrons, while minimizing loss of total filtering surface area, might be exacerbating nephron loss. Optimization of fetal growth should ultimately reduce the florid epidemic of renal disease, hypertension, and cardiovascular disease.

Glomerular number and size in autopsy kidneys: The relationship to birth weight

Background. In the Southeast United States, African Americans have an estimated incidence of hypertension and end-stage renal disease (ESRD) that is five times greater than Caucasians. Higher rates of low birth weight (LBW) among African Americans is suggested to predispose African Americans to the higher risk, possibly by reducing the number of glomeruli that develop in the kidney. This study investigates the relationships between age, race, gender, total glomerular number (N-glom), mean glomerular volume (V-glom), body surface area (BSA), and birth weight. Methods. Stereologic estimates of N-glom and V-glom were obtained using the physical disector/fractionator combination for autopsy kidneys from 37 African Americans and 19 Caucasians. Results. N-glom was normally distributed and ranged from 227,327 to 1,825,380, an 8.0-fold difference. A direct linear relationship was observed between N-glom and birth weight (r=0.423, P=0.0012) with a regression coefficient that predicted an increase of 257,426 glomeruli per kilogram increase in birth weight (alpha=0.050:0.908). Among adults there was a 4.9-fold range in V-glom , and in adults, V-glom was strongly and inversely correlated with N-glom (r=-0.640, P=0.000002). Adult V-glom showed no significant correlation with BSA for males (r=-0.0150, P=0.936), although it did for females (r=0.606, P=0.022). No racial differences in average N-glom or V-glom were observed. Conclusion. Birth weight is a strong determinant of N-glom and thereby of glomerular size in the postnatal kidney. The findings support the hypothesis that LBW by impairing nephron development is a risk factor for hypertension and ESRD in adulthood.

Differential regulation of suppressor of cytokine signaling-3 in the liver and adipose tissue of the sheep fetus in late gestation

Differential regulation of suppressor of cytokine signaling-3 in the liver and adipose tissue of the sheep fetus in late gestation. Am J Physiol Regul Integr Comp Physiol 290: R1044 - R1051, 2006. First published November 10, 2005; doi: 10.1152/ajpregu. 00573.2005. - It is unknown whether the JAK/STAT/suppressor of cytokine signaling-3 (SOCS-3) intracellular signaling pathway plays a role in tissue growth and metabolism during fetal life. We investigated whether there is a differential profile of SOCS-3 expression in the liver and perirenal adipose tissue during the period of increased fetal growth in late gestation and the impact of fetal growth restriction on SOCS-3 expression in the fetal liver. We also determined whether basal SOCS-3 expression in the fetal liver and perirenal adipose tissue is regulated by endogenous fetal prolactin (PRL). SOCS-3 mRNA abundance was higher in the liver than in the pancreas, spleen, and kidney of the sheep fetus during late gestation. In the liver, SOCS-3 mRNA expression was increased (P < 0.05) between 125 (n < 4) and 145 days (n < 7) gestation and lower (P < 0.05) in growth-restricted compared with normally grown fetal sheep in late gestation. The relative expression of SOCS-3 mRNA in the fetal liver was directly related to the mean plasma PRL concentrations during a 48-h infusion of either a dopaminergic agonist, bromocriptine (n < 7), or saline (n < 5), such that SOCS-3 mRNA expression was lower when plasma PRL concentrations decreased below similar to 20 ng/ml [y = 0.99 - (2.47/x) + (4.96/x(2)); r(2) = 0.91, P < 0.0001, n < 12]. No relationship was shown between the abundance of phospho-STAT5 in the fetal liver and circulating PRL. SOCS-3 expression in perirenal adipose tissue decreased (P < 0001) between 90 - 91 (n < 6) and 140 - 145 days (n < 9) gestation and was not related to endogenous PRL concentrations. Thus SOCS-3 is differentially expressed and regulated in key fetal tissues and may play an important and tissue-specific role in the regulation of cellular proliferation and differentiation before birth.

Customised birthweight: Coefficients for an Australian population and validation of the model

Background: Published birthweight references in Australia do not fully take into account constitutional factors that influence birthweight and therefore may not provide an accurate reference to identify the infant with abnormal growth. Furthermore, studies in other regions that have derived adjusted (customised) birthweight references have applied untested assumptions in the statistical modelling. Aims: To validate the customised birthweight model and to produce a reference set of coefficients for estimating a customised birthweight that may be useful for maternity care in Australia and for future research. Methods: De-identified data were extracted from the clinical database for all births at the Mater Mother's Hospital, Brisbane, Australia, between January 1997 and June 2005. Births with missing data for the variables under study were excluded. In addition the following were excluded: multiple pregnancies, births less than 37 completed week's gestation, stillbirths, and major congenital abnormalities. Multivariate analysis was undertaken. A double cross-validation procedure was used to validate the model. Results: The study of 42 206 births demonstrated that, for statistical purposes, birthweight is normally distributed. Coefficients for the derivation of customised birthweight in an Australian population were developed and the statistical model is demonstrably robust. Conclusions: This study provides empirical data as to the robustness of the model to determine customised birthweight. Further research is required to define where normal physiology ends and pathology begins, and which segments of the population should be included in the construction of a customised birthweight standard.

Prolactin and the expression of suppressor of cytokine signaling-3 in the sheep adrenal gland before birth

Prolactin and the expression of suppressor of cytokine signaling-3 in the sheep adrenal gland before birth. Am J Physiol Regul Integr Comp Physiol 291: R1399-R1405, 2006. First published June 29, 2006; doi: 10.1152/ajpregu.00252.2006.-The fetal pituitary-adrenal axis plays a key role in the fetal response to intrauterine stress and in the timing of parturition. The fetal sheep adrenal gland is relatively refractory to stimulation in midgestation (90-120 days) before the prepartum activation, which occurs around 135 days gestation (term = 147 +/- 3 days). The mechanisms underlying the switch from adrenal quiescence to activation are unclear. Therefore, we have investigated the expression of suppressor of cytokine signaling-3 (SOCS-3), a putative inhibitor of tissue growth in the fetal sheep adrenal between 50 and 145 days gestation and in the adrenal of the growth-restricted fetal sheep in late gestation. SOCS-3 is activated by a range of cytokines, including prolactin (PRL), and we have, therefore, determined whether PRL administered in vivo or in vitro stimulates SOCS-3 mRNA expression in the fetal adrenal in late gestation. There was a decrease (P < 0.005) in SOCS-3 expression in the fetal adrenal between 54 and 133 days and between 141 and 144 days gestation. Infusion of the dopaminergic agonist, bromocriptine, which suppressed fetal PRL concentrations but did not decrease adrenal SOCS-3 mRNA expression. PRL administration, however, significantly increased adrenal SOCS-3 mRNA expression (P < 0.05). Similarly, there was an increase (P < 0.05) in SOCS-3 mRNA expression in adrenocortical cells in vitro after exposure to PRL (50 ng/ml). Placental and fetal growth restriction had no effect on SOCS-3 expression in the adrenal during late gestation. In summary, the decrease in the expression of the inhibitor SOCS-3 after 133 days gestation may be permissive for a subsequent increase in fetal adrenal growth before birth. We conclude that factors other than PRL act to maintain adrenal SOCS-3 mRNA expression before 133 days gestation but that acute elevations of PRL can act to upregulate adrenal SOCS-3 expression in the sheep fetus during late gestation.

Hypertension, glomerular number, and birth weight in African Americans and white subjects in the southeastern United States

Low nephron number has been related to low birth weight and hypertension. In the southeastern United States, the estimated prevalence of chronic kidney disease due to hypertension is five times greater for African Americans than white subjects. This study investigates the relationships between total glomerular number (N-glom), blood pressure, and birth weight in southeastern African Americans and white subjects. Stereological estimates of N-glom were obtained using the physical disector/fractionator technique on autopsy kidneys from 62 African American and 60 white subjects 30-65 years of age. By medical history and recorded blood pressures, 41 African Americans, and 24 white subjects were identified as hypertensive and 21 African Americans and 36 white subjects as normotensive. Mean arterial blood pressure ( MAP) was obtained on 81 and birth weights on 63 subjects. For African Americans, relationships between MAP, N-glom, and birth weight were not significant. For white subjects, they were as follows: MAP and N-glom ( r = -0.4551, P = 0.0047); Nglom and birth weight ( r = 0.5730, P = 0.0022); MAP and birth weight ( r = -0.4228, P = 0.0377). For African Americans, average N-glom of 961 840 +/- 292 750 for normotensive and 867 358 +/- 341 958 for hypertensive patients were not significantly different ( P = 0.285). For white subjects, average N-glom of 923 377 +/- 256 391 for normotensive and 754 319 +/- 329 506 for hypertensive patients were significantly different ( P = 0.03). The data indicate that low nephron number and possibly low birth weight may play a role in the development of hypertension in white subjects but not African Americans.