Robert H. Perelman

Changes in food intake during menstrual cycles and pregnancy of normal and diabetic rhesus monkeys

SummaryFood intake of control and streptozotocin-diabetic rhesus monkeys was measured during menstrual cycles and pregnancy. Intake of control monkeys was lower at the time of ovulation than during other phases of the menstrual cycle. Intake of control monkeys was also low during most of pregnancy, but this was accompanied by normal fetal growth and net maternal weight gain. Diabetic monkeys ate more than controls in all conditions and their intake did not vary reliably according to reproductive status. It is suggested that (1) oestrogen normally inhibits food intake during menstrual cycles and pregnancy, (2) food energy is utilized more efficiently during pregnancy than during non-pregnant states, and (3) the influence of oestrogen on food intake is either attenuated by insulinopenia or is obscured by the hyperphagia typically exhibited by the diabetic monkeys.

Fetal lung development in male and female nonhuman primates.

Abstract: Indices of lung maturation were assessed in 58 rhesus fetuses at five gestational ages during the last trimester of nonhuman primate pregnancy to determine whether fetal sex influences lung maturation. In addition to analysis of whole lung phospholipids, glycogen, protein, DNA, and pressure-volume curves surfactant fraction phosphatidylcholine (PC) was quantitated following isolation by sucrose gradient centrifugation and a combination of predictors were assessed by all possible subsets regression to attain a composite “maturity index.” For the total population, there was a uniform progression in physical growth characteristics, lung destensibility and stability and phospholipids with advancing gestation. The quantitative change in surfactant fraction PC concentration for both sexes was considerably greater than that observed for whole lung PC between 135 days gestation and term. Further, the increase in surfactant PC occurred in association with improving lung destensibility and deflation stability prior to maximum changes in the whole lung PC or disaturated PC concentration. There were no statistically discernible differences in biochemical or physiological assessment between sexes at any gestational age. These data in nonhuman primates suggest that documented differences in survival from the respiratory distress syndrome between males and females do not result from a discordance in lung maturation as a function of time throughout the last trimester of gestation.

Complications of Pregnancy and Fetal Development

Although the outcome of pregnancy for women with diabetes meilitus has improved in recent years, the infant of the diabetic mother has an increased risk of major clinical problems, particularly in the early neonatal period. These include birth injury due to macrosomia, neonatal hypoglycemia, respiratory distress syndrome, and serious congenital anomalies. Because of the great difficulties encountered during attempts to investigate these problems in clinical research protocols, there is a continuing need to establish appropriate animal models of the diabetic pregnancy. Studies carried out over the past decade, primarily with chemically-induced diabetes have suggested techniques which might be useful. In general, the choice of the animal to be studied will depend on the hypotheses being addressed. For instance, small animals such as rabbits and rats made diabetic with streptozotocin have been successfully used for investigation of fetal lung development. Furthermore, the rat model has been helpful for evaluation of fetal anomalies associated with maldevelopment of the spine and central nervous system. Larger animals, such as the nonhuman primate, are more appropriate for studying placental function and amniotic fluid composition in diabetic pregnancies. The task group on pregnancy and fetal development recommends that animal models of diabetes meilitus be used for a more extensive hormonal and metabolic characterization of diabetic mothers during pregnancy, for investigation of placental physiology with respect to the transfer of substrates from mother to fetus, for systematic and comprehensive study of mechanisms controlling fetal lung development, and for delineation of the pathophysiology of neonatal hypoglycemia. it is further recommended that animal models of spontaneous diabetes such as the BB/W rat be used in future studies dealing with pregnancy and fetal development. Because females with spontaneous diabetes show reduced conception rates, there is a pressing need to enhance the fertility of these animals in order to intensify studies on fetal development.

A Continuum of Competency Assessment: The Potential for Reciprocal Use of the Accreditation Council for Graduate Medical Education Toolbox and the Components of the American Board of Pediatrics Maintenance-of-Certification Program

Reduction of unexplained variation in medical practice and health outcomes is of paramount importance, which indicates a need for a continuum of medical learning that begins in medical school and continues until the end of a professional career. That, in turn, indicates need for continuing assessment of professional competence. The American Board of Pediatrics, the American Academy of Pediatrics, and the Accreditation Council for Graduate Medical Education are working together to develop a common approach to documenting acquisition of competence during residency and maintenance of competence thereafter. A common approach will eliminate redundancy and make it possible to follow the evolution of professional competence over time.

Relationship between the Severity of Experimental Diabetes and Altered Lung Phospholipid Metabolism

Abstract Glucose intolerance was induced in rats by iv infusion of streptozotocin (STZ) in doses of 30, 40, 50, and 100 mg/kg. Serum glucose concentrations were elevated versus controls and weight gains were reduced in a dose-dependent fashion up to 50 mg/kg. Urine outputs and blood urea nitrogen (BUN) values were higher than control values in the animals treated with 40 and 50 mg/kg and serum albumin concentrations were decreased after infusion with 50 mg STZ/kg. Lung phosphatidylcholine (PC) concentrations and dry-to-wet weight ratios were unchanged by STZ treatment, while lung protein and disaturated phosphatidylcholine (DSPC) concentrations were depressed in the 50-mg/kg group. Animals surviving treatment with 100 mg/kg demonstrated increased fasting blood glucose levels, BUN values, and 48-hr urine outputs, and decreased lung protein levels. However, these alterations were less than those found in the 50-mg/kg animals. Pulmonary concentrations of PC, DSPC, and lung dry-to-wet weight ratios were unchanged. It was found advantageous to express the results relative to fasting blood glucose levels. This demonstrated that urine output and BUN values increased and weight gain decreased with rising glucose concentrations, but serum albumin decreased only in moderate and severe hyperglycemia. Fasting glucose concentrations greater than 400 mg/dl were associated with reduced lung DSPC and protein levels, while pulmonary PC and dry-to-wet weight ratios demonstrated no change with increasing hyperglycemia.

578 DISCORDANCE BETWEEN MALE|[sol]|FEMALE DEATHS DUE TO THE RESPIRATORY DISTRESS SYNDROME (RDS): IS IT REAL?

Despite a marked diminution in national and Wisconsin (WISC) neonatal mortality rates (NNMR), RDS has remained the leading cause of death in 9 of 11 years previously analyzed, accounting for 19.5% of fatalities. Male/female (M/F) ratios of 1.35 for NNMR and 1.6 for RDS deaths support the contention that there is a distinct male disadvantage to premature birth. To better elucidate this assertion, we examined all relevant birth-weight-linked mortality statistics for the State of Wise, from 1979 through 1982. 5.3% of the average 74,500 births/year in Wise. (M/F ratio = 1.05) occurred at <2.5 kg. The data below indicate that neonatal deaths secondary to RDS are consistently greater in males and that the discordance between males and females occurrs most predominantly between 1-1.5 kg birthwelght. These significant differences are independent of mode of delivery, maternal age, and associated diagnoses (i.e. asphyxia). This epidemiologic survey coupled with recent animal research suggests that delivery within a limited “window” during gestation Increases male susceptibility to fatal RDS.

420 DISRUPTED OVARIAN FUNCTION IN RHESUS MONKEYS WITH EX-PERIMENTALLY INDUCED INSULIN INSUFFICIENCY

We are utilizing a nonhuman primate model to elucidate the mechanisms of abnormal fetal lung development in pregnancies complicated by maternal hyperglycemia. Healthy adult female Macaca mulatta were made severely diabetic by infusion of the pancreatic B-cell toxin streptozotocin (STZ, 47.5 mg/kg). These animals have impaired reproductive function as evidenced by daily ratings of coloration of sexual skin and incidence of menstruation. Prior to receiving insulin therapy, diabetic animals (n=6) exhibited only 26% of the expected number of apparently ovulatory menstrual cycles (1 cycle/30 days, 321-408 days of observation/animal) compared to 89% for control animals (n=7, 114-304 days/animal; t= 5.17, p<.01). Diabetic animals receiving insulin therapy (n=6, 62-436 days/animal) also exhibited fewer than expected normal cycles compared to controls (51%, t=2.45, p<.05). Radioimmunoassay revealed serum concentrations of estradiol and progesterone in amenorrheal diabetic monkeys to be comparable to those seen in ovariectomized monkeys. Three of 4 control pregnancies were maintained into the third trimester, while 1 of 1 untreated diabetic and 2 of 4 treated diabetic pregnancies were maintained. Additional monkeys treated recently with a lower dose of STZ (30mg/kg) have exhibited milder glucose intolerance and less disruption of ovarian function. (Support: NIH HD11429 and RR00167 and JDF 79R263.)

1711 FETAL LUNG DEVELOPMENT IN THE SUBHUMAN PRIMATE(MACACCA MULATTA)

Previous studies in subhuman primates have encompassed the entire third trimester to profile general patterns of fetal lung development(FLD); however, this work has not expanded the data base at key gestational ages(GA) to elucidate precise developmental changes. Accordingly, we have performed comprehensive pulmonary physiologic and biochemical analyses in 17 nonbreathing rhesus fetuses delivered by C-section at 4 gestational ages(term=165 days). Lung data including phosphatidylcholine(PC) and phosphatidylglycerol(PG) are presented in the table below(per gram wet wt) as mean±S.E. values. Marked changes in phospholipids were noted at 155 days GA. Additionally, lung protein, wet weight, %V10 and selected fatty acids in PC increased with advancing GA. Although parallel increases occurred in lung PC, DSPC and PG, mature physiologic indices were obtained later in gestation. Furthermore, amniotic fluid analyses revealed no clear relationship between PG concentration and lung maturation.

1712 A PRIMATE MODEL FOR THE STUDY OF FETAL LUNG DEVELOPMENT IN THE GLUCOSE INTOLERANT PREGNANCY

A procedure which reliably produces an insulin dependent state of glucose intolerance in Macaca mulatta is described, along with normal glucose disappearance rates(K) in adult female macaques and biochemical and physiologic indices of fetal lung development(FLD) in 3 diabetic progeny(IDM) and 5 matched controls. After an initial observation period and an IV glucose tolerance test, female monkeys received 47.5mg/kg of freshly mixed streptozotocin by rapid central intravenous injection. Subsequently the mean glucose disappearance rate was markedly decreased from 5.63±1.36% per min to 1.30±0.52% per min(P<.001) and no insulin response could be demonstrated. Fasting plasma glucose values averaged 245mg/dl and glycosylated hemoglobin levels were markedly elevated(x=14.7%). Urine volume was increased from 236±99ml/day to 1261±264ml/day(P<.001)and urine glucose from 10±3mg/dl/day to 4237±608mg/dl/day(P<.001). Lung biochemical analyses including phosphatidylcholine(PC) and phosphatidylglycerol(PG) are represented below(per gram wet wt) for fetuses delivered by C-section at 145 days gestation(term =165±3days). PG was not demonstrable in any of the 7 amniotic fluid samples analyzed and other lung indices (ie %V10, Vmax,γmin) did not vary significantly from controls. Weights for IDM were strikingly abnormal at 629, 529 and 341 gms vs 390±19 gms for controls. Mean maternal/fetal plasma glucose values at birth were 203/147 mg/dl for diabetics and 45739 mg/dl for controls. In this pilot study, fetal animals with somatic features of IDM and altered FLD compared to controls were obtained. Therefore, this model provides an apt homologue for human diabetes.

1010 A TEN YEARS EXPERIENCE WITH REGIONALIZED NEONATAL CARE

The Wisc. Perinatal Care Program including 6 regional centers has been functioning for over 10 years. Regionalization has offered educational enhancement to community health providers and allowed high risk mothers and infants more uniform exposure to intensive care and therapeutic advances. To assess the programs efficacy, we evaluated state mortality rates and compared these to national statistics. While the Wisc. birth rate of LBW infants has remained constant (6-7%), the death rate for these neonates decreased 32.7% over the survey period. Reflecting increased center utilization, 57% of neonatal deaths occurred in tertiary centers in ′74, as opposed to only 20% in ′68. Over the 10 yrs, the death rate during the first 24 hrs has decreased by 43% and during the first week by 36.1%. The decremental trend for Wisc. general and disease specific meonatal death rates has consistently surpassed national norms. Deaths/1000 live births due to HMD/RDS have continued to fall despite persistent high national trends. Further, Wisc. was unique among states with > 50,000 births/yr in showing decreasing HMD/RDS death rates between ′68-′73. Maintenance of low, declining neonatal mortality rates and consistent reduction in deaths from major causalities with a marked shift in timing and place of death, establishes the positive influence of regionalized care.