Cerebral oxygen consumption during asphyxia in fetal sheep.

Cerebral blood flow and cerebral arteriovenous oxygen content difference were measured in 17 fetal sheep, and cerebral oxygen uptake was calculated. The measurements were made under control conditions and after profound fetal asphyxia induced of uterine blood flow for up to 90 min. In 14 of the fetal sheep, sequential measurements were made to examine hemodynamic changes and cerebral oxygen consumption at comparable intervals up to 36 min of asphyxia. These fetuses initially had elevated blood pressure and lowered heart rate became hypoxemic, hypercarbic, and acidotic. There was an initial decrease in cerebral oxygen consumption. Sequential measurements, however, showed a relative stability in this decreased oxygenation during 4 to 36 min of asphyxia despite a progressive metabolic acidosis. The cerebral fractional oxygen extraction remained unchanged despite a mean pH of 6.98 at 36 min. The calculated cerebral oxygen uptake during asphyxia in all 17 sheep was grouped according to whether the ascending aortic oxygen content was greater or less than 1.0 mmol/l. In the first group with mean ascending aortic oxygen content of 1.3 mmol/l, blood flow to the brain was increased and cerebral oxygen consumption was 85% of control. In the second group with mean arterial blood oxygen content of 0.8 mmol/l, there was a narrowing of the arteriovenous oxygen content difference, but no further increase in cerebral blood flow. Cerebral oxygen consumption was only 48% of control in this more asphyxiated group. We conclude that the degree of hypoxemia in the second group represents a point where physiologic mechanisms cannot compensate, and may be associated with neuronal damage.

An indirect method of discovering primary traumatic experiences: two case examples.

Our primitive brain has the capacity to recall visual, auditory, olfactory, tactual, and postural memories. Consciously we all set limitations on our abilities to recall. The technique described here suggests that all of us can recall meaningful sensory experiences with the help of multiple subconscious reviews of an event. We are aware of moods unconsciously and can assign colors to these moods. The unconscious mind can localize the true site of pain even when the patient is consciously sure the pain is localized elsewhere. The methods of exploration are described, and possible values of the methods are pointed out.

Muscle cell potassium, RNA and hydration in pregnancy and pre-eclampsia.

Thirty four pregnant women from 26 to 38 weeks gestation and 24 pregnant women with pre-eclampsia gave samples of muscle (rectus abdominis) at caesarean section. Muscle samples were analysed for H2O, K+, Mg2+ and Na+. Cell extracellular H2O was partitioned by the use of the Cl- space. Also protein, nucleic acids and Zn2+ were determined. From 26 to 38 weeks gestation the concentration of K+ per litre of cell water ([Ki]) slowly declined. The slope was significant. Points for patients with pre-eclampsia fell below the line and analysis of covariance showed that the two populations were different (P less than 0.001). Patients A-J were regarded clinically as severe pre-eclamptics. Points for these patients, in general, fell between 1 and 2 SDs below the normal line. Since other cations per litre of muscle cell water did not change, questions are raised. is the cation gap filled by amino acids or does vascular spasm cause a leakage of K+ from muscle cells? Does hypotonicity eventually develop leading to water intoxication? The low oncotic pressure in pre-eclampsia (shown here), the negative free water clearance could all favour increased cell hydration (some evidence for this is presented here towards term). Assessment of available information concerning creatinine excretion during normal pregnancy and K40, K42 studies together with our own rodent studies leads us to believe that a significant increase in muscle mass occurs, but such may not be the case in pre-eclampsia since the reduction in RNA and Zn2+ concentrations in muscle would suggest excessive protein degradation.(ABSTRACT TRUNCATED AT 250 WORDS)

Malnutrition in aboriginal children at Yalata, South Australia.

Comparative studies of body weight, height, intracellular water representing cell mass, and age, and plasma concentrations of albumin, vitamins, trace elements and iron stores in Aboriginal children aged 6 to 13.5 years, from two rural Aboriginal settlements and one rural Caucasian school (Hawker) provided evidence of significant deficits in one of the Aboriginal settlements (Yalata). Yalata Aboriginal children had lower body weights and heights for age and lower intracellular water values. Plasma albumin, zinc, iron, alpha-tocopherol, beta-carotene and retinol concentrations were lower relative to the normally grown Aboriginal children at Nepabunna. The latter children did not differ from rural Caucasian children for the parameters studied. The reasons for this poorer growth at Yalata may reside in poor nutrition, or repeated bowel infection in postnatal life leading to malabsorption, or both. Limited observational evidence suggests that Giardiasis has a high prevalence at Yalata, and it has been shown elsewhere that Giardiasis is capable of inducing malabsorption with resulting nutritional deficiencies.

Accumulation and clearance of morphine-3-beta-D-glucuronide in fetal lambs.

The time course and extent of morphine-3-beta-D-glucuronide (M3G) production from morphine (MOR) and the clearance of M3G from plasma was studied in the late gestation fetal lamb. MOR was infused at a constant rate into the fetal vena cava and plasma was sampled from the fetus and ewe. Amniotic fluid was also sampled in one animal. M3G was produced in the fetal lamb and accumulated extensively in fetal plasma and amniotic fluid. Seizure activity was observed in two fetal lambs with extremely high plasma concentrations of M3G and MOR. The molar ratio of M3G to MOR in fetal plasma was dependent upon the duration of infusion, reaching a plateau of 60 at about 3 days, but appeared to be independent of the infusion rate over the range studied, 3 to 30 mg hr-1. Maternal plasma MOR and M3G concentrations were substantially less than corresponding fetal plasma concentrations. Using the steady-state plasma concentration of M3G obtained from infusion of MOR and the clearance of M3G derived from single injection of M3G to fetal lambs, the fraction of MOR converted to M3G by the fetus was calculated to be 0.63. Although MOR is conjugated to glucuronic acid in the fetal lamb and excreted into the amniotic fluid it is not readily transferred across the epitheliochorial placenta to the ewe because of restricted permeability.

Effect of halothane on regional cerebral blood flow and cerebral metabolic oxygen consumption in the fetal lamb in utero.

The effects of halothane on maternal and fetal hemodynamics, distribution of fetal cardiac output, regional cerebral blood flow, and fetal cerebral oxygen consumption were studied in the ewe (N = 9) using radionuclide-labeled microspheres. An adjustable uterine artery occluder was used to produce a controlled state of fetal asphyxia. Measurements were taken during three periods of study: 1) control, 2) asphyxia, and 3) asphyxia plus 15 min of 1% maternal halothane. The fetal cardiovascular response to asphyxia was acidosis, hypoxia, hypertension, bradycardia, and preservation of vital organ blood flows. There was a significant drop in maternal blood pressure when halothane was administered but uterine blood flow was maintained, 308 ml X min-1 during asphyxia versus 275 ml X min-1 with halothane. Fetal blood pressure during asphyxia plus halothane (54 mmHg) was significantly lower than that during asphyxia alone (59 mmHg), while heart rate was significantly higher: 172 beats per minute (bpm) versus 125 bpm (P less than 0.05). Despite these changes, the administration of halothane during asphyxia did not produce a reduction in vital organ flows. Cerebral blood flow was maintained: 357 +/- 37 ml X 100 g-1 X min-1 during asphyxia alone and 344 +/- 26 ml X 100 g-1 X min-1 after halothane administration (P = NS, mean +/- SEM). Cerebral oxygen delivery also was maintained: 8.3 +/- 0.8 ml X 100 g-1 X min-1 during asphyxia alone versus 9.7 +/- 1.5 ml X 100 g-1 X min-1 after halothane, compared with 11.2 +/- 1.1 ml X 100 g-1 X min-1 during the control period.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of d-tubocurarine-induced histamine release by halothane.

To determine whether anesthetics modify mediator release, the authors measured the amount of histamine released by d-tubocurarine (dTC) in human foreskin preparations in the presence of high (2.0%) and low (0.5%) halothane concentrations and nitrous oxide (10%). Freshly excised human foreskins were divided into four matched pieces. Two matched pieces were aerated with oxygen, and the other two with an oxygen-anesthetic gas mixture. One chamber of each served as a control, while the other was stimulated with 3 X 10(-5) M d-tubocurarine for 30 min. Supernatant histamine concentrations were measured by automated fluorometry. Percent histamine release was determined by dividing the experimentally released histamine concentration by the total histamine released after the tissue was sonicated and boiled. Neither halothane nor N2O alone altered spontaneous histamine release. Histamine release by d-tubocurarine was significantly reduced by 2% halothane compared to d-tubocurarine alone (2.8% +/- 0.9 vs. 13.9% +/- 3.7, mean + SEM) (P less than 0.05) in the in vitro preparation. Histamine release was reduced in the preparations pretreated with 0.5% halothane group, but this was not statistically significant (P greater than 0.05) when compared to d-tubocurarine alone. N2O (10%) did not reduce d-tubocurarine-induced histamine release. The authors conclude that halothane, in clinically used concentrations, significantly impairs histamine release from human neonatal foreskin preparations.

The control of cell mass and replication. The DNA unit--a personal 20-year study.

The deoxyribonucleic acid (DNA) is constant per cell in diploid tissues and in polyploid tissues the DNA content and the cytoplasm increase commensurately. In muscle the DNA unit (protein/DNA) was described on the assumption that each nucleus has jurisdiction over a certain volume of cytoplasm. Such an approach allows a sensible interpretation of metabolic data. Since 66-70% of nuclei are within myofibres muscle represents a reasonably homogeneous tissue. A brief historical review is made concerning the use of DNA as a cell constant. The application of this knowledge to normal human somatic growth and to disease states is considered as well as reduced nutrition and overnutrition. The consequences of reduced nutrition as it related to brain growth are briefly mentioned as is our 7 year study on the fetal primate (Macaca mulatta). Attention is focussed on our work in the early 1960's concerning the role of insulin and growth hormone on the DNA unit. In the last decade this work culminated in the close study of the Little Mouse with isolated growth hormone deficiency--thus exposing the panhypopituitary model (the human pituitary dwarf, Snell Smith mouse or hypophysectomised rat) as non-optimal models. The findings indicate that growth hormone is indeed related to cell replication and insulin to cytoplasmic growth in the postnatal period but the role of other hormones is clearly important, augmenting or opposing these hormones. The concept of constant change of the DNA unit not only applies to major tissues such as muscle but to the study of kidney growth when the contralateral kidney is removed (renal compensatory growth). Species differences are noted in the pattern of cell growth in muscle, but emphasis is placed on cell replication rather than on cytoplasmic growth in the primate. Restriction of protein energy metabolism mainly affects cytoplasmic growth of muscle but restoration of growth to expected levels is the rule. Overnutrition and obesity relate to excessive growth of DNA units in number rather than size. Attention is drawn to factors other than calories, proteins and hormones that influence hormonal actions viz. trace metals such as zinc, chromium and vanadium. The cell mass of the body can readily be reached by relatively non-invasive methods and by monitoring the intracellular water. Muscle mass can be precisely measured by creatinine excretion. The cell mass of muscle constitutes 70% of the entire cell mass.(ABSTRACT TRUNCATED AT 400 WORDS)

Muscle cell growth and the distribution of water and electrolyte in human pregnancy.

Ten normal pregnant women had muscle composition analyses (rectus abdominis) carried out at 39-40 weeks of pregnancy. Water, chloride (Cl), chloride space (ECV), non-chloride space (ICW), potassium (K), sodium (Na), magnesium (Mg) and zinc (Zn) determinations were carried out. Analyses for DNA (cell number), protein: DNA ratio (cell size), RNA and collagen were also performed. Similar analyses were performed on uterine muscle and placentae before and after perfusion with Earle's solution. Data from pregnant patients were compared with similar estimations carried out on rectus abdominis samples from 13 non-pregnant subjects undergoing gynaecological procedures. Muscle tissue and predicted muscle mass (MM) (which constitutes 40% of body weight) demonstrated that the gain in body K was due to the products of conception, that ICW decreased per unit weight in muscle (8%), ECV increased (41%) without a radical change in muscle water content (2%). Overall a 6 l gain in ECV and a 2 l gain in ICW can be accounted for during pregnancy. The results of this study indicate that added hydration excluding the products of conception (placenta, infant, uterus) is mainly extracellular. Intracellular Na concentration decreases (50%) and it is speculated that the cation gap is made up by H+ in the presence of extracellular alkalosis. Muscle cells diminish in size but cell number per gram is constant. Zinc content (Zn/DNA) decreases. Previous experimental work suggests that MM increases by about 10% during pregnancy and this information has been included in considerations but it remains to be shown to what extent total muscle cell numbers increase and as to whether such increased muscle growth remains following pregnancy.

Zinc content of red and white blood cells in aboriginal children.

Studies were carried out on erythrocyte, granulocyte and lymphocyte zinc content of aboriginal children at the La Grange settlement in the north-west area of the Kimberley. Forty-eight children, 34 boys and 14 girls between 6 and 13 years were studied. Only the boys were investigated for white blood cell (WBC) zinc. Twenty-five Caucasian children volunteered to give blood for control studies. Two approaches were made concerning zinc analyses, atomic absorption spectroscopy and proton induced x-ray emission. It was found that lymphocyte, granulocyte and erythrocyte zinc content were significantly reduced in aboriginal boys aged 6 to 13 years. Since the turnover of white blood cells is relatively fast, it follows that the zinc content of these cells may be a true index of current zinc status confirming previous observations.

Cell hydration in the normally grown, the premature and the low weight for gestational age infant.

Total body water (TBW), extracellular volume (ECV) and intracellular water (ICW) were measured in a cross-sectional study of 107 infants up to four weeks after birth. Three groups of infants were selected for study: (1) mature normally grown infants, (2) mature low weight for gestational age (LWGA) infants and (3) premature normally grown infants. In the normal mature infants there was no significant change in TBW during the first 6 days after birth but there was a small but significant (P less than 0.02) redistribution of extracellular water into the cells by the sixth postnatal day. This suggests that the normal weight loss in infants after birth is due to a relative starvation rather than cell dehydration. In the LWGA infants, TBW levels were higher than normal and ICW significantly increased. This index of cell mass further increased throughout the 14-day period studied (P less than 0.01) and was the highest of all groups studied. It is argued that the changes are due to cytoplasmic growth. Premature babies (mean weight approximately 2000 g and greater than 30 weeks gestation) had higher TBW values than their mature normally grown counterparts. Hyponatraemia was infrequent and no shift of water into cells was detected. All groups of infants revealed loss of ECV over the first two weeks and in premature infants the loss was commensurate with that of TBW.

Compensatory renal growth in the mouse. III. Growth hormone and insulin deficiency.

The effect of combined insulin and growth hormone (GH) deficiency on compensatory renal growth (CRG) was studied in the dwarf mouse, "Little," after insulin suppression with streptozotocin (SZ). Nucleic acid and protein estimations were used to assess changes in cellular hyperplasia and hypertrophy. Mice aged 30 days received SZ while controls received buffers solution alone. Left nephrectomy was performed at 35 days of age with removal of the renoprival kidney 15 days later. In mice with normal GH, renoprival kidney weight was unaffected by SZ, but the total DNA (estimate of cell number) was higher than normal in both sham-operated and renoprival kidneys suggesting that insulin suppression may cause greater cell replication during both normal growth and CRG. The ratio of protein to DNA (estimate of cell size) in the renoprival kidney was not suppressed by SZ as reported in muscle. In GH-deficient mice (lit/lit) given SZ, CRG was significantly diminished (P less than 0.001). Total DNA in the renoprival kidney was slightly greater than the sham-operated control (P less than 0.005) but the protein:DNA ratio (cell size) was unchanged. These results suggest that when both GH and insulin are suppressed, adaptive cellular growth is inhibited. The proposal that GH and insulin are the two primary hormones controlling cellular growth is consistent with these results.

Hydration in the first 24 h of postnatal life in normal infants born vaginally or by caesarean section.

A total of 65 infants, 48 born vaginally and 17 by segment caesarean section, were studied prior to labour for extracellular volume (ECV) (corrected bromide space) and total body water (TBW) (deuterium space) during the first 24 h of postnatal life. The infants were mature and growth retardation excluded. A 'heel stick' blood sample was taken for micro determination of Br and urine for 2H2O concentration. ECV varied from 343 +/- 27 ml/kg at 6 h to 358 +/- 21 ml/kg at 24 h and TBW was 75.5 +/- 3.4% of body weight. Contrary to current opinion, neither TBW nor cell hydration differed in infants born by caesarean section compared with those born vaginally. Such modern methodology to study infant body hydration and the critical assessment of growth and maturity demonstrates that hydration during the first 24 h of life is relatively stable and is not affected by the mode of delivery.

Ontogeny of the brain in a marsupial (Macropus eugenii) throughout pouch life. I. Brain growth.

Growth characteristics of the tammar wallaby brain have been determined from 143 animals at various stages of growth from birth to adulthood, with particular emphasis on the 250 days of pouch life. The macroscopic anatomy of the brain is also described for pouch young at days 3, 5, 88 and 190 days after birth, and for the adult. The transition from the rapid to mature growth phases of each brain structure occurs between days 120 and 180 after birth, and coincides with the appearance of previously described developmental characters or behaviour. The allometric relationships of brain and body growth described in this marsupial resemble those described for primates. Because of the accessibility of the pouch young during the critical period of brain differentiation, this marsupial may provide a useful laboratory model for the study of brain development.

Compensatory renal growth in the mouse. I. Allometric approach to the effect of age.

Allometry, defined as the relationship between the growth rates of organs to the weight of the whole body (38), was used to study the effect of age on the degree of compensatory renal growth (CRG) in the mouse. The normal growth of the kidneys relative to body weight (BW) was determined in animals between 5 to 50 days of age. In one group, nephrectomy and sham operations were performed at 5, 15, and 35 days of age. The remaining ("renoprival") kidney was removed 15 days postnephrectomy. In a second group, nephrectomy was performed on 5-day-old animals, the renoprival kidney being removed after 30 or 45 days. Regression equations were calculated by least-squares after logarithmic transformation and different groups were compared by analysis of covariance. The regression equation for the control kidney was kidney weight (KW) = 0.0093 BW0.86 (r = 0.96). The regression for renoprival kidneys in females was KW = 0.0142 BW0.83 (R = 0.96) after 15 days and, in comparison, was not significantly different from 30 to 45 days. The interval between control and renoprival regressions was equivalent to a difference of congruent to 43% KW. In male mice, the regression for renoprival kidneys after 15 days was KW = 0.0103 BM0.96 (r = 0.98) and was not significantly different from 30 to 45 days. This study suggests that in young mice the time required for complete CRG may be a maximum of 15 days and that the amount of CRG does not depend on the age at operation. After CRG, a new equilibrium is reached which is thereafter maintained up to a minimum of 50 days of age.

Compensatory renal growth in the mouse. II. The effect of growth hormone deficiency.

Allometry was used to study the effect of growth hormones (GH) deficiency on compensatory renal growth (CRG) in a dwarf mouse strain (Little). Nucleic acid and protein estimations were used to assess changes in cellular hyperplasia and hypertrophy. Nephrectomy was performed at 5, 15, or 35 days of age with removal of the renoprival kidney 15 days later. Controls underwent sham nephrectomies at 35 days of age. The allometric growth of the normal kidney in the homozygote dwarf (lit/lit) between 8 and 50 days of age was closely related to that of the normal heterozygote (lit/+). A regression line for the renoprival kidneys in lit/lit animals was parallel to that of the control right kidney (P less than 0.001). The interval between the regression lines was equivalent to a constant difference of approximately 40% between renoprival and control right kidneys and was similar to that found in the normal heterozygote (43%). Increases in DNA, RNA, and protein in control animals during CRG indicate that cell division and hypertrophy were occurring in similar proportions. In the GH-deficient mouse, the total amount of DNA in renoprival kidneys was 0.451 mg compared with 0.439 mg in controls (NS). This suggests that cell replication was suppressed. The protein:DNA ratio increased from 20.91 to 24.27 (P less than 0.001) and the RNA:DNA ratio increased from 0.732 to 0.912 (P less than 0.001), suggesting that cell size was markedly increased. These findings suggest that reduced amounts of GH may produce a dissociation between hyperplasia an hypertrophy, with CRG occurring predominantly by cellular hypertrophy.