Improving the accuracy of retrieved cardiac electrical conductivities.

Accurate values for the six cardiac conductivities of the bidomain model are crucial for meaningful electrophysiological simulations of cardiac tissue and are yet to be achieved. A two-stage optimisation process is used to retrieve the cardiac conductivities from cardiac potentials measured on a multi-electrode array-the first stage simultaneously fits all six conductivities, and the second stage fits a subset of the conductivities (intracellular conductivities), while holding the remainder of the conductivities (extracellular conductivities) constant. Previous studies have shown that the intracellular conductivities are retrieved to a lesser degree of accuracy than extracellular conductivities. This study tests the proposition that there exists a relationship between the extracellular and intracellular conductivities during the second stage of the optimisation that affects the accuracy of the retrieved intracellular conductivities. A measure to quantify this relationship is developed using polynomial chaos. The results show that a significant relationship does exist, and thus any errors in the extracellular conductivities are magnified in the retrieved intracellular conductivities. Thus, it is suggested that future protocols for retrieving conductivities incorporate the uncertainty in the extracellular conductivities.

Role of the cerebrovascular and metabolic responses in the delayed phases of injury after transient cerebral ischemia in fetal sheep.

BACKGROUND AND PURPOSE: Perinatal hypoxic-ischemic injuries can trigger a cascade of events leading to delayed deterioration and cell death several hours later. The objective of this study was to characterize the cerebral blood flow responses and the changes in extracellular glucose and lactate during the delayed phases of injury and to determine their relationships with the pathophysiological events after hypoxic-ischemic injury. METHODS: Two groups of near-term chronically instrumented fetal sheep were subjected to 30 minutes of cerebral hypoperfusion. In the first group, regional cerebral blood flow was measured over the next 24 hours with radiolabeled microspheres. In the second, cortical extracellular glucose and lactate were measured by microdialysis. Parietal electrocorticographic activity and cortical impedance were recorded continuously in both groups, and the extent of neuronal loss was determined histologically at 72 hours after injury. RESULTS: Cerebral blood flow was transiently impaired in the cortex during reperfusion, whereas during the delayed phase, there was a marked increase in cerebral blood flow. The severity of cortical neuronal loss was related to the degree of hypoperfusion in the immediate reperfusion period and inversely related to the magnitude of the delayed hyperperfusion. Cortical extracellular lactate was elevated after injury, and both glucose and lactate secondarily increased during the delayed phase of injury. CONCLUSIONS: The delayed phase is accompanied by a period of hyperperfusion that may protect marginally viable tissue.

Administration of growth hormone or IGF-I to pregnant rats on a reduced diet throughout pregnancy does not prevent fetal intrauterine growth retardation and elevated blood pressure in adult offspring.

Increasing evidence from human epidemiological studies suggests that poor growth before birth is associated with postnatal growth retardation and the development of cardiovascular disease in adulthood. We have shown previously that nutritional deprivation in the pregnant rat leads to intrauterine growth retardation (IUGR), postnatal growth failure, changes in the endocrine parameters of the somatotrophic axis, and to increased blood pressure in later life. In the present study, we investigated whether administration of insulin-like growth factor-I (IGF-I) or bovine growth hormone (GH) during pregnancy could prevent IUGR and/or alter long-term outcome. Dams from day 1 of pregnancy throughout gestation received a diet of ad libitum available food or a restricted dietary intake of 30% of ad libitum fed dams. From day 10 of gestation, dams were treated for 10 days with three times daily subcutaneous injections of saline (100 microl), IGF-I (2 micrograms/g body weight) or GH (2 micrograms/g body weight). Maternal weight gain was significantly increased (P<0.001) in ad libitum fed dams treated with GH, (98.9+/-4.73 g) compared with the IGF-I (80.5+/-2.17 g) and saline-treated (70.7+/-2.65 g) groups. There was a small increase in maternal weight gain (P<0.06) in 30% ad libitum fed dams following GH (16.3+/-2.47 g) and IGF-I (15.8+/-1.97 g) treatment compared with saline (9.2+/-1.96 g). Whole spleen, kidney and carcass weights were significantly (P<0.05) increased in ad libitum fed and 30% ad libitum fed dams with GH treatment. Circulating IGF-I was significantly increased (P<0.001) in ad libitum fed dams with both IGF-I (369.6+/-32.33 ng/ml) and GH (457.9+/-33.32 ng/ml) compared with saline treatment (211.7+/-14.02 ng/ml), and with GH (223.4+/-23.72 ng/ml) compared with saline treatment (112.0+/-7.33 ng/ml) in 30% ad libitum fed dams. Circulating GH binding protein (GHBP) levels were significantly reduced (P<0.05) in GH-treated (299.1+/-51.54 ng/ml) compared with saline-treated (503.9+/-62.43 ng/ml) ad libitum fed dams, but were not altered in 30% ad libitum fed dams. There was no significant effect of either IGF-I or GH treatment on fetal weight, placental weight, fetal organ weights or circulating IGF-I levels in both ad libitum fed and 30% ad libitum fed fetuses. Offspring of 30% ad libitum fed dams remained significantly growth retarded postnatally and showed elevated blood pressure in later life. The increased maternal weight gain following IGF-I or GH administration, without an effect on fetal and placental weights, suggests a modification in the mode of maternal nutrient repartitioning during mid to late pregnancy at the expense of the fetus.

Effects of maternal captopril treatment on growth, blood glucose and plasma insulin in the fetal spontaneously hypertensive rat.

In the spontaneously hypertensive rat (SHR) fetal growth and metabolism are abnormal. It has been speculated that maternal hypertension may be the cause of these abnormalities. Captopril treatment, which reduces maternal blood pressure, during pregnancy and lactation, is reported to have a beneficial effect postnatally, normalizing the blood pressure of offspring in the SHR. In the present study, the effects of maternal captopril treatment on fetal growth and plasma metabolites were investigated in the fetuses of two rat strains (SHR and Wistar-Kyoto (WKY)), in order to determine whether normalizing maternal blood pressure also normalized abnormalities in fetal growth and metabolism. On fetal Day 20, SHR fetuses were lighter and placentae were heavier than for the corresponding WKY. Captopril had no effect on fetal weight in the SHR, but decreased it in the WKY. There was no effect of captopril on placental weight. Fetal plasma insulin levels were higher in the SHR than in the WKY and were decreased by captopril treatment in both strains. Fetal blood glucose was elevated and fetal blood lactate was decreased in captopril-treated litters from both strains. Captopril had no effect on fetal plasma IGF-1 but fetal plasma IGF-2 levels were lower in the captopril-treated SHR than in the captopril-treated WKY. These findings suggest that maternal captopril treatment decreases insulin secretion in the fetal rat. High levels of fetal plasma insulin suggest that the SHR fetus is insulin resistant. Fetal insulin levels may contribute to the adverse consequences of gestational captopril treatment observed in many species. The differences in the effect of captopril on the two strains suggest that there are underlying endocrine differences in the SHR.

Fetal and placental glucose and amino acid uptake in the spontaneously hypertensive rat.

Until late in gestation, fetal spontaneously hypertensive rat (SHR) is growth retarded. Fetal growth rate increases after placental hypertrophy occurs between fetal days 18 and 20. The increase in placental mass may result in improved transfer of macro nutrients to the fetus and thus stimulate growth. In this study, fetal and placental uptake of the glucose analog 3-O-methyl glucose (3MG) and the amino acid analog amino-isobutyric acid (AIB) from the maternal circulation were compared in the SHR and Wistar-Kyoto (WKY) on days 16, 20 and 22 of gestation. Placental 3MG uptake (d/min/g tissue wet weight) was decreased in the SHR on days 20 and 22 but no differences were observed in fetal 3MG uptake. Increased placental mass in the SHR meant that total placental 3MG uptake was greater in the SHR. Placental uptake of AIB (d/min/g tissue wet weight) was much lower in the SHR (on days 16, 20 and 22) and the decrease was not compensated for by increased placental mass. Fetal uptake of AIB was decreased on days 20 and 22 (P<0.05). AIB uptake (d/min/g tissue wet weight) by the carcass and the internal organs (brain, heart, kidney, liver and lung) was also lower in the SHR. These findings indicate that although fetal growth in the SHR increases rapidly in late gestation following placental hypertrophy, it does so despite a pronounced deficit in amino acid uptake.

Glucocorticoid activity in the fetal spontaneously hypertensive rat.

Fetal exposure to high concentrations of corticosteroids in the rat is associated with elevated blood pressure in postnatal life. In this study we have investigated indicators of corticosteroid activity in fetal spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) in order to determine whether fetal corticosteroid exposure is increased in the SHR. Placental 11beta-hydroxysteroid dehydrogenase (11beta-HSD) activity, which prevents maternal steroids from crossing the placenta, was not impaired in the SHR. Concentrations of amniotic fluid corticosterone were significantly decreased in the SHR compared with the WKY at fetal Day 20, but were not significantly different on fetal Days 16 or 22. This suggests that rather than increased exposure to corticosteroids in the SHR fetus corticosteroid exposure may be reduced. Expression of lung surfactant protein A (Sp-A), a gene induced in late gestation by corticosteroids, was decreased in the SHR. In addition, differences in amniotic fluid electrolyte concentrations were observed which may reflect delayed renal maturation in the fetal SHR. These data suggest that the SHR fetus is exposed to low concentrations of corticosteroids and that the late gestation rise in fetal corticosteroid may be delayed in the SHR.

Perinatal growth disturbance in the spontaneously hypertensive rat.

Disproportionate fetal and placental growth are associated with the development of hypertension in the rat and human. Here we report differences in fetal, neonatal, and placental growth, and in metabolism and endocrinology, between the spontaneously hypertensive rat (SHR), a genetic model for human essential hypertension, and the control Wistar-Kyoto (WKY) strain. Gestation in SHR (23 d) was longer than in WKY by 20 h. Body weights were lower in the SHR from fetal d 16 to 20 and on postnatal d 15. However, on fetal d 22 and postnatal d 1, there was no significant difference in body weight between SHR and WKY. SHR placentas were larger than those of WKY at d 20, and by term there was a difference of 30% (p < 0.01). Other indices of disproportionate growth were hypertrophy of the fetal heart and kidney and decreased ponderal index in the SHR neonate. Blood glucose in SHR fetuses was lower than in WKY fetuses (p < 0.05), whereas blood lactate was higher (p < 0.05) and fetal hematocrit was reduced (p < 0.001). These findings suggest undernutrition and placental insufficiency may occur in SHR fetuses. Plasma IGF-II was increased on the last day of gestation in both strains, whereas IGF-I was unaltered. Fetal liver IGFBP-2 mRNA and plasma IGFBP-2 levels were reduced in SHR on fetal d 20 and 22 (p < 0.01). Differences in growth and endocrine and metabolic parameters suggest abnormal perinatal physiology in the SHR, which may influence the later development of hypertension.

The spatial and temporal distribution of insulin-like growth factor-1 following experimental myocardial infarction in the rat.

Insulin-like growth factor-1 (IGF-1) is believed to be involved in the repair and adaptation that follow ischemic injury to the myocardium. The aim of this study was to elucidate the role of IGF-1 by defining the changes that occur in its distribution following regional myocardial infarction. The left anterior descending coronary artery was ligated in adult male Wistar rats, and hearts were examined microscopically from 6 hours to 20 days later. IGF-1 was identified histochemically using the avitin-biotin-peroxidase method with a polyclonal antibody to IGF-1 and was quantified by optical density measurements of standard fields in sections of hearts prepared in a single batch. Immunoreactivity was located in the cytoplasm of viable myocytes, vascular smooth-muscle cells, mast cells, leukocytes, endothelial cells, and fibroblasts. The zone of viable myocardium immediately adjacent to infarcts reacted significantly more intensely for IGF-1 than all other regions at all stages, with a maximum optical density (617% higher than sham-operated control myocardium, p < .001) 24 hours after coronary artery ligation. Immunoreactivity in myocardium tissue distant from the infarcts also increased during the first day (382% at 24 hours), but this increase was not statistically significant thereafter. These temporal and spatial changes in the distribution and amount of IGF-1 indicate that this finding is predominantly associated with a localized response to injury by the viable myocytes adjacent to infarcts.

Chronic maternal undernutrition in the rat leads to delayed postnatal growth and elevated blood pressure of offspring.

To determine the effects of chronic maternal undernutrition on postnatal somatic growth and blood pressure, pregnant dams were randomly assigned to one of two dietary treatment groups. A control group was fed ad libitum throughout pregnancy and a restricted group was fed 30% of ad libitum intake. From birth, feeding was ad libitum in both groups, and litter size was adjusted to eight pups per litter. Litter size was not significantly altered by the reduced maternal intake. Offspring of the restricted fed group were significantly smaller than offspring from the ad libitum fed group from birth until 12 wk of age, but by 30 wk had similar body weights. Blood pressure was measured by tail cuff plethysmography. Offspring from the restricted fed group were found to have significantly (p < 0.05) elevated systolic blood pressure (5-8 mm Hg) at 30, 48, and 56 wk of age. These data demonstrate that nutritional deprivation in the pregnant rat leads to changes in postnatal allometric growth patterns, to delayed catch-up growth, and to elevated blood pressure in adulthood. The data are consistent with the hypothesis that poor maternal nutrition in pregnancy may irreversibly alter programming of the development of cardiovascular homeostasis.

A model of intrauterine growth retardation caused by chronic maternal undernutrition in the rat: effects on the somatotrophic axis and postnatal growth.

While it is well established that severe maternal undernutrition during pregnancy causes intrauterine growth retardation (IUGR), there has been relatively little study of the endocrine consequences and postnatal development of growth-retarded offspring. We have developed a model in the rat of IUGR by nutritional restriction of the mother throughout gestation and have examined the effects of fetal growth retardation on the endocrine and metabolic status during the perinatal period. Timed matings were performed in Wistar rats and dams were randomly assigned to one of two dietary treatment groups. Food was available ad libitum throughout pregnancy to a control group (at libitum group) and a restricted group was fed 30% of the ad libitum intake (restricted fed group). After birth, food was available ad libitum in both groups and litter size was adjusted to eight pups per litter. Dams lost a significant amount of body weight throughout gestation due to undernutrition but were able to catch up to the ad libitum group by day 10 postnatally. Litter size was not affected by maternal undernutrition. Maternal plasma IGF-I levels were significantly reduced in the restricted fed group throughout gestation (P < 0.001) but were not different postnatally. Maternal plasma IGF-binding proteins (IGFBPs)-1, -2 and -3 were significantly (P < 0.05) increased in the restricted fed dams. The mean body weights of fetuses in late gestation from the restricted fed dams were significantly lower (P < 0.001) in comparison with fetuses from control dams. Placental weights were also significantly (P < 0.01) reduced in the restricted fed compared with control dams. Body weights were significantly lower in the offspring of restricted fed dams than control dams from birth (P < 0.01) until 90 days of age (P < 0.05). Nose-rump length was reduced in the fetuses of the restricted fed group at day 22 of gestation (P < 0.001) until weaning (P < 0.05). Plasma IGF-I levels were significantly reduced in the pups of restricted fed dams from day 22 of gestation (P < 0.01) until postnatal day 9 (P < 0.05) but were not significantly different at the later time-points. Plasma insulin levels were significantly reduced in the pups of restricted fed dams at birth (P < 0.05) but not at later time-points. Plasma IGFBP-1 and -2 levels were significantly increased in the offspring from restricted fed dams at day 22 of gestation, at birth and at day 9 postnatally (P < 0.05). 125I-Bovine GH specific binding to liver membranes was significantly lower (P < 0.05) in offspring from restricted fed dams at 21 days of age but not at 90 days of age. These data demonstrate that nutritional deprivation in the pregnant rat leads to IUGR and postnatal growth failure and to changes in allometric growth patterns and endocrine parameters of the somatotrophic axis postnatally.

Insulin-like growth factor-1 is a potent neuronal rescue agent after hypoxic-ischemic injury in fetal lambs.

This study was designed to determine the potential of IGF-1 as a neuronal rescue agent after cerebral ischemia. Unanesthetized late gestation fetal sheep were subjected to 30-min cerebral ischemia by inflation of carotid artery occluder cuffs. 2 h later either 0.1 microgram rhIGF-1, 1 microgram rhIGF-1, 10 micrograms rhIGF-1, or vehicle was infused into a lateral cerebral ventricle over 1 h. Histologic outcome was assessed 5 d later. Overall neuronal loss was reduced with 0.1 microgram (P < 0.05) and 1 microgram (P < 0.002) rhIGF-1, but treatment with 10 micrograms was not effective. With 1 microgram rhIGF-1 neuronal loss scores were significantly lower in brain regions examined including cortex, hippocampus, and striatum, whereas with 0.1 microgram rhIGF-1 the parietal cortex and thalamus were not improved and the improvement seen in other regions was less than with 1 microgram rhIGF-1. Treatment with 1 microgram rhIGF-1 also delayed the onset of seizures and reduced their incidence. Moreover, the secondary phase of cytotoxic edema was reduced and delayed in onset. We conclude that low dose rhIGF-1 therapy promotes neuronal rescue after cerebral hypoxic-ischemic injury in utero, but the effect is dose dependent. Importantly, rhIGF-1 is effective and nontoxic when administered 2 h after the hypoxic ischemic insult. This distinguishes IGF-1 from most other neuroprotective therapies and suggests clinical application may be possible.

Repeated episodes of umbilical cord occlusion in fetal sheep lead to preferential damage to the striatum and sensitize the heart to further insults.

The effect of repeated episodes of asphyxia on the fetal cardiovascular system and CNS was examined. The umbilical cord was occluded for 5 min, four times, at 30-min intervals in 11 chronically instrumented fetal sheep (118-126 d). Fetal electrocorticogram (ECoG), cortical impedance, ECG, heart rate, and blood pressure were continuously recorded for 3 d, after which neuronal loss was determined histologically. Each occlusion resulted in fetal hypoxemia and bradycardia accompanied by increased T/QRS ratio. Progressively severe hypotension and lactic acidosis developed during successive occlusions. The ECoG was depressed and cortical impedance increased with each occlusion. During the final occlusion, blood pressure fell to 3.5 +/- 1 kPa and heart rate to 93 +/- 9 bpm, T/QRS ratio increased to 0.44 +/- 0.3, and lactate rose to 7.2 +/- 1.2 mM/L. Three animals died from cardiac fibrillation during recirculation after the third or fourth occlusion. After the asphyxial episodes, blood pressure and heart rate returned to normal, and the T wave was inverted for 310 +/- 155 min. Lactate returned to baseline within 24 h. The ECoG remained depressed for 90 +/- 35 min, and intermittent seizures developed at 3.3 +/- 1.4 h after the last occlusion. Neuronal loss was primarily found in the striatum. The extent of neuronal loss correlated with the degree of hypotension, increase in T/QRS ratio, duration of postasphyxial ECoG depression, and number of seizures. These results indicate that transient asphyxial episodes compromise the ability of the heart to tolerate additional insults and further suggest that neuronal loss is a consequence of cardiovascular compromise secondary to asphyxia.(ABSTRACT TRUNCATED AT 250 WORDS)

Nutrition and fetal growth.

Nutrient supply to the fetus is a key factor in the regulation of fetal growth. However, the direct supply of nutrients to provide building blocks for tissue growth is likely to be only a minor component of this regulation. The indirect effects of nutrition on fetal endocrine and metabolic status, and on the interaction between the fetus, placenta and mother all of which must be coordinated to allow fetal growth are also important. Maternal undernutrition may alter the growth of the fetus and its different component tissues in a way which cannot be explained solely on the basis of reduced substrate supply during the rapid growth phase of the tissues involved. Adaptation to altered substrate supply, during both undernutrition and refeeding, involves sequential changes in the metabolic and endocrine interactions between the fetus and the placenta. In addition, undernutrition has long-term consequences for the fetus. There is evidence for nutritional programming of fetal endocrine and cardiovascular systems before birth. Nutritional effects may also persist over more than one generation. The effects of nutrition on fetal growth are far more complex than simply those of substrate deprivation.

Fetal growth retardation and increased placental weight in the spontaneously hypertensive rat.

Epidemiological studies have linked low birth weight and increased placental weight with increased risk of hypertension in adult life. It has been proposed that the cardiovascular changes which lead to hypertension are initiated in utero by processes associated with intrauterine growth retardation. The alternative possibility, that hypertension may result from genetic influences which also determine fetal and placental size, has had less support because birth weight is not determined genetically in humans. However, in the spontaneously hypertensive rat (SHR) essential hypertension is known to be transmitted genetically. Fetal and placental weights were, therefore, measured at Day 20 gestation in SHRs and compared with those in the normotensive Wistar Kyoto (WKY) control strain. Fetal weight (1.93 +/- 0.04 g) was significantly (P < 0.001) reduced in SHRs compared with WKY fetuses (2.23 +/- 0.01 g) but placental weight was heavier (P < 0.001) in SHRs (0.347 +/- 0.005 g) than in WKY rats (0.300 +/- 0.006 g) although litter size was not different. As expected, maternal blood pressure recorded under 1% halothane anaesthesia was higher (126 +/- 2.7 mm Hg) in SHR than WKY rats (100 +/- 2.1 mm Hg; 1 mm Hg = 133 Pa). In addition the concentration of maternal blood glucose in SHR was significantly (P < 0.001) higher (4.8 +/- 0.32 mM v. 3.7 +/- 0.11 mM) and the concentration of plasma insulin was significantly (P < 0.05) lower in SHRs (18.8 +/- 3.0 ng mL-1) than in WKY dams (29.4 +/- 3.1 ng mL-1). Thus, the data support human population studies which show an association between adult hypertension and a reduced fetal:placental weight ratio at birth. However, because hypertension in the SHR is genetically determined, these data suggest that fetal growth retardation and increased placental weight may also be determined genetically.

Neuronal damage in the developing brain following intrauterine asphyxia.

Perinatal asphyxia is thought to be a significant cause of still birth and neurological sequelae. Although several different patterns of neuronal injury are seen in the newborn, previously little was known about the precise cause and effect relationships. This brief review summarizes recent research which has identified how prenatal factors such as recurrent episodes of asphyxia, gestational age, growth retardation and cerebral temperature may influence the severity and regional distribution of neuronal loss.

Increased vulnerability to neuronal damage after umbilical cord occlusion in fetal sheep with advancing gestation.

OBJECTIVE: The purpose of this study was to compare systemic responses and neurologic consequences of umbilical cord occlusion in fetal sheep with advancing gestation. STUDY DESIGN: The umbilical cord was occluded for 10 minutes in nine midgestation (90 to 92 days) and 10 late-gestation (135 to 136 days) chronically instrumented fetuses. Systemic and cortical electrophysiologic effects were compared by analysis of variance. The extent of neuronal loss was determined 3 days later. RESULTS: During occlusion, hypotension (23 +/- 2 mm Hg) and cortical cytotoxic edema were more marked in older fetuses (p < 0.001). On reperfusion, the edema, rebound tachycardia, and hypertension resolved within 20 minutes. Recovery of electroencephalographic activity (3.1 +/- 0.8 hours) and lactate levels (> 2 hours) was slower in late-gestation fetuses (p < 0.05). Neuronal loss, which was observed only in the older group, was predominantly in the hippocampus and was associated with the severity of hypotension during umbilical occlusion but not with systemic lactate levels. CONCLUSION: Late-gestation fetal sheep are neurologically more susceptible to umbilical cord occlusion than are midgestation fetal sheep. Possibly the lesser ability of the older fetuses to maintain blood pressure and cerebral plasma membrane function during asphyxia contributes to the greater vulnerability in the gray matter.

Peripheral chemoreceptors respond to hypoxia in pontine-lesioned fetal lambs in utero.

Acute hypoxia inhibits, rather than stimulates, fetal breathing movements (FBM), but there has been controversy as to the activity and role of the peripheral arterial chemoreceptors in the regulation of breathing movements in the unanesthetized fetus in utero. However, after midcollicular brain stem transection or lateral pontine lesion, hypoxia causes FBM to become continuous and stimulated in rate and depth. To determine whether this stimulatory response involves peripheral chemoreceptors, we used a two-stage approach to examine the response to hypoxia after peripheral chemodenervation in lateral pontine-lesioned fetal lambs. The lateral pons was lesioned at 119-121 days, and the response to hypoxia was tested in the unanesthetized fetus 4 days afterward. Fourteen fetuses in which hypoxia stimulated FBM underwent either peripheral chemodenervation or sham denervation in a second operation. Hypoxia had no effect when the fetus was tested 4-5 days after peripheral chemodenervation, and the basal incidence of FBM was significantly lower. The stimulatory response was unchanged by sham denervation. We conclude that the peripheral chemoreceptors are active in fetal life and that they mediate the stimulation of FBM seen in response to hypoxia after removal of the lateral pontine inhibition. In addition, after pontine lesion there is evidence of tonic chemoreceptor-mediated influences on FBM, which are normally overriden in the intact fetus.

Improvement of doxorubicin induced cardiomyopathy in rats treated with insulin-like growth factor I.

OBJECTIVES: This study was designed to assess the effects of treatment with insulin-like growth factor-I (IGF-I) on cardiac function and structure in rats with an established cardiomyopathy. METHODS: Adult male Wistar rats were injected with doxorubicin (2 mg.kg-1 subcutaneously) weekly for 12 weeks and either rhIGF-I (0.8 mg.kg-1.day-1; n = 16, D-I group) or saline (n = 25, D-S group) subcutaneously via an osmotic pump from weeks 9 to 12. A non-doxorubicin injected control group was also studied. After 12 weeks survivors were anaesthetised and cardiac output determined with radiolabelled microspheres. At postmortem pleural effusion and ascitic volumes were measured and the heart was removed for histological examination by light and transmission electron microscopy. RESULTS: Doxorubicin treated animals showed less mean weight gain from week 2 than the untreated control group. Animals treated with IGF-I from week 9 showed a significant (p < 0.05) but non-sustained increase in weight. Survival to 12 weeks was 56% in the D-I group and 44% in the D-S group (p = 0.2). Evidence of cardiac failure was seen in the D-I and the D-S groups, but there was a tendency (p = 0.06) for less ascites in the D-I group (21 (SEM 8) ml) than in the D-S group (46 (10) ml). Cardiac output was significantly higher in the D-I than in the D-S group (132 (7.2) v 91.4 (6.4) ml.min-1, p < 0.01), as was stroke volume (0.323 (0.03) v 0.226 (0.02) ml, p < 0.01). There was focal cardiac damage in both D-I and D-S animals. Scattered groups of myocytes showed prominent vacuolation of the nuclear envelope, sarcoplasmic reticulum, and t tubular system, mild to severe mitochondrial swelling, and loss of orientation and definition of myofibrils. No clear morphological differences were evident between the two groups. CONCLUSIONS: Administration of IGF-I may improve the function of damaged myocardium, although the mechanisms are unclear. Further studies with earlier coadministration of IGF-I, quantitative histological analysis, and with other models of cardiac injury are indicated.

Transient umbilical cord occlusion causes hippocampal damage in the fetal sheep.

OBJECTIVE: The purpose of our study was to examine the neuronal outcome after a standardized period of umbilical cord occlusion. STUDY DESIGN: The umbilical cord was clamped for 10 minutes in nine experimental and four control chronically instrumented fetal sheep. Three days later the animals were killed for histologic interpretation. Systemic, electrophysiologic, and neurohistologic effects were compared by analysis of variance. RESULTS: Clamping of the cord resulted in transient severe asphyxia, hypotension (24 +/- 5 mm Hg, p < 0.01), bradycardia (72 +/- 14 beats/min, p < 0.001), depressed electroencephalographic activity (-17 +/- 2 dB, p < 0.001), and an increase in cortical impedance. The electroencephalographic activity was depressed for 5 +/- 2 hours in spite of rapid recovery of arterial oxygen content. Neuronal loss was found in the hippocampus. Neither epileptiform electroencephalographic activity nor infarction were observed. Three animals with poor blood gas levels died during the occlusion. CONCLUSION: An isolated and brief period of umbilical cord occlusion in utero can cause predominantly hippocampal damage without persistent functional changes in cortical activity and with rapid recovery of other potential indicators of fetal asphyxia.

Childhood depression and conduct disorder: I. Behavioral, affective, and cognitive aspects of family problem-solving interactions.

We assessed the family interactions of depressed, conduct-disordered, mixed depressed-conduct-disordered, and nonclinic children, ages 7-14 years, during a standardized family problem-solving discussion in the clinic. The child's and the mother's problem-solving proficiency, aversive behavior, and associated affective behavior (depressed and angry-hostile) were observed. The child and mother also rated each other's affect during the interaction for the dimensions sad, angry, critical, and happy on Likert-type scales. The child's and mother's cognitive constructions about the interaction were assessed using video-mediated recall. Although all clinic groups had lower levels of effective problem solving than did nonclinic children, their deficiencies were somewhat different. Mixed and depressed children displayed high levels of depressed affect and low levels of angry affect, whereas conduct-disordered children displayed both angry and depressed affect. In addition, conduct-disordered children had lower levels of positive problem solving and higher levels of aversive content than did non-conduct-disordered children. Depressed and conduct-disordered children had higher levels of self-referent negative cognitions than did mixed and comparison children, and depressed children also had higher other-referent negative cognitions than did all other groups. The study provides support for theories and treatment that stress the importance of family problem-solving and conflict resolution skills in child psychopathology.