Circulating and utero-placental adaptations to chronic placental ischemia in the rat.

While utero-placental insufficiency is associated with adverse outcomes for both mother and fetus, many of the maternal-fetal adaptations during pregnancy in models of fetal compromise remain unclear. The purpose of this study was to determine if chronically reduced uterine perfusion pressure (RUPP) during days 14-19 of gestation alters feto-placental growth differentially from the cervical to ovarian ends of the uterus and generates metabolic adaptations such as increased blood lactate (BLa) concentrations and lactate transporter expression in the placenta. Fetal growth restriction was evident, placental efficiency (fetal weight/placental weight) decreased (4.7 ± 0.35 vs. 5.9 ± 0.30; P < 0.05) and fetal growth pattern within the uterus was altered in the RUPP compared to the normal pregnant (NP) rats. Blood lactate concentrations were increased (3.3 ± 0.3 vs. 2.1 ± 0.4 mmol/l; P < 0.05) in NP compared to virgin rats, and in RUPP compared to NP (5.0 ± 0.6 vs. 3.3 ± 0.3 mmol/l; P < 0.05). Lactate concentration was increased (10.0 ± 0.6 vs. 7.1 ± 0.8 mmol/l; P < 0.05) in the media from hypoxic compared to normoxic BeWo cells. No changes in expression of placental MCT1, 2, or 4 were observed between RUPP and NP rats. RUPP resulted in decreased plasma leptin (2.0 ± 0.3 vs. 3.1 ± 0.4; P < 0.05) but no change in IGF-1 compared to NP. The present data indicate chronic placental ischemia results in numerous endocrine and metabolic changes during late pregnancy in the rat and that the RUPP model has differential effects on fetal growth depending on uterine position.

Systemic hemodynamic and regional blood flow changes in response to chronic reductions in uterine perfusion pressure in pregnant rats.

Preeclampsia (PE) is associated with increased total peripheral resistance (TPR), reduced cardiac output (CO), and diminished uterine and placental blood flow. We have developed an animal model that employs chronic reductions in uterine perfusion pressure (RUPP) in pregnant rats to generate a "preeclamptic-like" state during late gestation that is characterized by hypertension, proteinuria, and endothelial dysfunction. Although this animal model has many characteristics of human PE, the systemic hemodynamic and regional changes in blood flow that occur in response to chronic RUPP remains unknown. Therefore, we hypothesized that RUPP would decrease uteroplacental blood flow and CO, and increase TPR. Mean arterial pressure (MAP), CO, cardiac index (CI), TPR, and regional blood flow to various tissues were measured using radiolabeled microspheres in the following two groups of conscious rats: normal pregnant rats (NP; n = 8) and RUPP rats (n = 8). MAP was increased (132 +/- 4 vs. 99 +/- 3 mmHg) in the RUPP rats compared with the NP dams. The hypertension in RUPP rats was associated with increased TPR (2.15 +/- 0.02 vs. 0.98 +/- 0.08 mmHg x ml(-1) x min(-1)) and decreased CI (246 +/- 20 vs. 348 +/- 19 ml x min(-1) x kg(-1), P < 0.002) when contrasted with NP dams. Furthermore, uterine (0.16 +/- 0.03 vs. 0.38 +/- 0.09 ml x min(-1) x g tissue(-1)) and placental blood flow (0.30 +/- 0.08 vs. 0.70 +/- 0.10 ml x min(-1) x g tissue(-1)) were decreased in RUPP compared with the NP dams. These data demonstrate that the RUPP model of pregnancy-induced hypertension has systemic hemodynamic and regional blood flow alterations that are strikingly similar to those observed in women with PE.

Maternal undernutrition during early to mid-gestation in the ewe results in altered growth, adiposity, and glucose tolerance in male offspring.

This study utilized maternal undernutrition from early to midgestation in the ewe to determine the impact(s) of intrauterine growth restriction on postpartum growth of male offspring and the potential mechanisms involved. Multiparous ewes were fed 50% (nutrient-restricted) or 100% (control-fed) of their nutrient requirements (NRC, 1985) between d 28 and 78 of gestation, and then all ewes were fed 100% of the NRC requirements from d 79 through lambing. Male lambs born to nutrient-restricted (n = 9) and control-fed (n = 9) ewes exhibited similar BW (5.8 vs. 6.0 +/- 0.3 kg) and crown-rump lengths (53.8 vs. 55.4 +/- 1.0 cm) at birth. At 63 and 250 d of postnatal age, wether lambs were subjected to a glucose tolerance test, in which a bolus of glucose was administered i.v. to evaluate changes in glucose and insulin concentrations. After i.v. glucose administration at 63 d of age, lambs from nutrient-restricted ewes exhibited a greater area under the curve for glucose (AUCg; 6,281 vs. 5,242 +/- 429; P < 0.05) and insulin (AUCi; 21.0 vs. 8.6 +/- 1.9; P < 0.001) than lambs from control-fed ewes. After glucose administration at 250 d of age, lambs from nutrient-restricted ewes had greater AUCg (7,147 vs. 5,823 +/- 361; P < 0.01) but a lower AUCi (6.4 vs. 10.2 +/- 1.9; P = 0.05) than lambs from control-fed ewes. Lambs from nutrient-restricted ewes were heavier (26.6 vs. 21.8 +/- 2.3 kg; P < 0.05) and had more backfat (0.30 vs. 0.21 +/- 0.03 cm, P < 0.05) by 4 mo of age than the lambs from control-fed ewes. At slaughter at 280 d of age, lambs from nutrient-restricted ewes remained heavier than lambs from control-fed ewes, had greater (P < 0.05) amounts of kidney and pelvic-area adipose tissue, and tended (P < 0.10) to have reduced LM and semitendinosus muscle weights as a percentage of HCW. These data demonstrate that a bout of maternal undernutrition during early to midgestation in sheep increased BW and fat deposition during adolescence and dysregulated glucose uptake in the absence of any change in birth weight.

Effect of 30 per cent maternal nutrient restriction from 0.16 to 0.5 gestation on fetal baboon kidney gene expression.

Previous studies in rodents and sheep show that maternal nutrient restriction during pregnancy alters fetal renal development. To date, no studies using fetal baboon RNA with human Affymetrix gene chips have been published. In the present study we have (1) evaluated the specificity of the Affymetrix human gene array 'Laboratory on a Chip' system for use with fetal baboon mRNA and (2) investigated the effects of moderate maternal global nutrient restriction (NR; 70% of ad libitum animals) from early (30 days gestation (dG)) to mid-gestation (90 dG; term = 184 dG) on the fetal baboon kidney. Morphometric and blood measurements were made on 12 non-pregnant baboons before they were bred. All baboons were fed ad libitum until 30 days pregnant, at which time six control baboons continued to feed ad libitum (control - C) while six received 70% of the C diet on a weight adjusted basis. Fetal kidneys were collected following caesarean section at 90 dG, with samples flash frozen and fixed for histological assessment. Fetal hip circumference was decreased in the NR group (68 +/- 2 versus 75 +/- 2 mm), while fetal body weight and all other measurements of fetal size were not different between C and NR at 90 dG. Maternal body weight was decreased in the NR group (12.16 +/- 0.34 versus 13.73 +/- 0.55 kg). Having established the specificity of the Affymetrix system for fetal baboon mRNA, gene expression profiling of fetal kidneys in the context of our maternal nutrient restriction protocol shows that NR resulted in a down-regulation of genes in pathways related to RNA, DNA and protein biosynthesis, metabolism and catabolism. In contrast, genes in cell signal transduction, communication and transport pathways were up-regulated in the NR group. These changes indicate that even a moderate level of maternal global NR impacts fetal renal gene pathways. Our histological assessment of renal structure indicates decreased tubule density within the cortex of NR kidneys compared with controls. The number of glomerular cross-sections per unit area were unaffected by NR, suggesting that tubule tortuosity and/or tubule length was decreased in the NR kidney. Taken together the changes indicate that NR results in accelerated fetal renal differentiation. The negative impact of poor maternal nutrition on the fetal kidney may therefore be in part due to shortening of critical phases of renal growth resulting in decreased functional capacity in later life. These findings may have important implications for postnatal renal function, thereby contributing to the observed increased predisposition to hypertension and renal disease in the offspring of nutrient restricted mothers.

Guided and unguided self-help for binge eating.

This study compared the relative short- and longer-term efficacy of therapist-guided and unguided use of a cognitive behavioral self-help manual for binge eating [Fairburn, C. G. (1995). Overcome binge eating. New York: The Guilford Press.] Forty women (82.5% with binge eating disorder) were randomized to one of the two treatment levels. Results indicate that both conditions represent viable means of treating binge eating. Overall, patients improved their eating behavior, eliminated any inappropriate compensatory behaviors, reduced their shape concern, weight concern, and other symptoms of eating-related psychopathology, and improved their general psychological functioning. The guided self-help condition was notably superior in reducing the occurrence of binge eating and its associated symptomatology, as well as lowering interpersonal sensitivity. A high degree of general psychopathology was a negative prognostic indicator. The implications for a stepped-care approach to treating binge eating are discussed.