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Investigating milk-derived extracellular vesicles as mediators of maternal stress and environmental intervention.

Parental communication signals are transmitted through nursing and critically shape neurodevelopmental trajectories. Mirroring some well characterized effects of gestational challenges in rodents, maternal immune activation (MIA) during the lactational period disrupts maternal physiology, decreases lipid content, and is associated with adverse neurobehavioral outcomes in offspring. This occurs without MIA significantly affecting maternal care. While gestational MIA models are responsive to environmental interventions, which beneficially alter maternal milk composition and associated offspring outcomes, the bioactive mediators in milk underlying resilience remain poorly understood. Milk-derived extracellular vesicles (MEVs) transport and deposit biologically active cargo, including microRNAs (miRNAs) that induce post-translational regulation of candidate mRNA in the nursing offspring's tissues and cells. Using a rat model, we show that lactational MIA alters MEV-miRNA cargo and the expression of hippocampal miRNAs in offspring. Several miRNAs in MEVs were also found in the hippocampus of matching offspring. Remarkably, the miRNA changes in MEVs and the neonatal hippocampus were rescued when dams were raised in an enriched environment, suggesting environmental enrichment protected from the effects of MIA. This was supported by the behavioral phenotype. RNA-seq of adult offspring hippocampus showed long-term transcriptional changes associated with the gene targets of early-life regulated miRNAs. Our results position MEV-miRNA as dynamic programming signals by which maternal experience is communicated to offspring, encoding both stress-induced and protective cues that influence development. This suggests that breastfeeding interventions can regulate the genetic cargo of the milk, programming the life of developing infants.

Journal Article

Rat alpha-fetoprotein: isolation, radioimmunoassay and fetal-maternal distribution during pregnancy.

A method is described for the isolation of mg quantities of two forms of rat alpha-fetoprotein (AFP) from amniotic fluid by preparative disc-gel column electrophoresis using a continuous elution system. AFP isolated by this method is suitable for use as an antigen, can be labelled for use in a radioimmunoassay and serves as a reference standard. The characteristics of a new antiserum to AFP are also described. The protocol for a radioimmunoassay is outlined which permits the measurement of AFP in several fetal-maternal physiological compartments throughout gestation. Levels of AFP in fetal liver and fetal plasma suggest that secretion of AFP from liver occurs soon after synthesis with minimal hepatic storage. The pattern for AFP in maternal serum parallels that observed in amniotic fluid and fluctuations in maternal serum levels of AFP appear to be buffered by AFP accumulation in amniotic fluid. Fetal clearance of AFP under normal conditions may be relatively constant from Days 11-20 of gestation since an amniotic fluid: maternal serum AFP ratio of 30:1 is maintained during this period.

Amniotic Fluid

Fetal morphology in mice exposed to halothane.

The teratogenic potential of subanesthetic and anesthetic exposure to halothane was studied in Swiss/ICR mice. Two treatment regimens were employed: daily exposure of males and females for nine weeks prior to conception and on days 1 through 17 of pregnancy; and exposure of females only on days 6 through 15 of pregnancy. Mice were exposed to subanesthetic concentrations of halothane for 0.025, 0.1, 0.4, and 1.2 MAC hours/day; anesthetic exposure was 4.0 MAC hours/day. Fetal morphologic development was normal at the two lowest exposures. Exposures of 0.4 MAC hours/day and more were associated with decreased fetal ossification. At the 1.2 MAC hour/day exposure, renal pelvic masturation was retarded and the incidence of skeletal variants was increased. The incidences of major malformations and minor anomalies were not increased following exposure to subanesthetic concentrations of halothane. Anesthetic exposure to 4.0 MAC hours/day was lethal to both dams and embryos, and resulted in major developmental malformations in surviving fetuses. These effects were probably due to altered maternal physiologic status. It is concluded that exposure of mice to subanesthetic concentrations of halothane does not result in important morphologic abnormalities in their offspring.

Abnormalities, Drug-Induced

Physiological correlates of maternal separation in surrogate-reared infants: a study in altered attachment bonds.

Three pigtail infant monkeys (Macaca nemestrina) were separated from their mothers shortly after birth and raised in social isolation on cloth surrogates. At about 24 weeks of age they were surgically implanted with multichannel biotelemetry systems. Following the collection of baseline behavioral and physiological data, the cloth surrogates were removed for 4 days, then returned. The behavioral and physiological (heart rate, body temperature, sleep patterns) reaction to separation from the surrogate was much less intense than is the case in group-living pigtail infants that are separated from their mothers, suggesting that the attachment bond to a cloth surrogate may be different than the bond to a living mother in a social group. Heart rate mean values and variability were similar in surrogate-reared and mother-reared infants, suggesting a degree of environmental independence in heart rate regulation.

Animals

Economic importance of breastfeeding.

While an increasing body of research has documented the importance of breastfeeding for infant health, very little research has been done on its economic implications. From an economic perspective, breast milk can in many respects be regarded like any other food commodity. For example, it could be stored in milk banks, and redistributed from areas of surplus to areas of scarcity. But breast milk is inique in that many of its benefits are associated more with its method of delivery than with its physical or nutritional properties per se. In this study based on field work in West Africa, the authors evaluate the economics of breast-feeding versus artificial feeding, but point out that the major impact of breastfeeding at national level is associated with its health-promoting and birth-spacing effects, neither of which are quantifiable at present.

Africa, Western

Observations on the adequacy of breast-feeding.

The faltering of growth which frequently occurs in babies at the age of about 3 months in developing countries is sometimes attributed to insufficient food or to increased exposure to infection. The adequacy of breast-milk as a sole source of food for the young infant is examined in relation to the calculated average requirements for protein and energy. It is concluded that breast milk will fail to cover the energy needs of many infants after about 3 months unless a regulatory mechanism permits infants with higher than average requirements to obtain larger amounts of milk.

Age Factors

Selective primary health care: an interim strategy for disease control in developing countries.

Priorities among the infectious diseases affecting the three billion people in the less developed world have been based on prevalence, morbidity, mortality and feasibility of control. With these priorities in mind a program of selective primary health care is compared with other approaches and suggested as the most cost-effective form of medical intervention in the least developed countries. A flexible program delivered by either fixed or mobile units might include measles and diphtheria-pertussis-tetanus vaccination, treatment for febrile malaria and oral rehydration for diarrhea in children, and tetanus toxoid and encouragement of breast feeding in mothers. Other interventions might be added on the basis of regional needs and new developments. For major diseases for which control measures are inadequate, research is an inexpensive approach on the basis of cost per infected person per year.

Animals

Fetal hypothyroidism and maternal thyroid status in severe endemic goiter.

The relationship between maternal thyroid function and newborn thyroid function was studied in a region of very severe endemic goiter (Ubangi, Republic of Zaïre). T4, T3, and TSH concentrations were measured in the sera of 56 mothers (at the time of delivery) and 60 newborns (in the cord). The results obtained in these groups (untreated) were compared with those obtained in two control groups, comprising 53 mothers whose iodine deficiency had been corrected by the injection of iodized oil and 68 neonates born to such mothers. The results show that the mean (+/- SEM) T4 serum concentration (micrograms per dl) was 11.5 +/- 0.7 in the untreated mothers compared with 15.7 +/- 0.7 in the treated mothers (P less than 0.001), and 9.4 +/- 0.8 in the untreated newborns compared with 12.4 +/- 0.5 in the newborns of treated mothers (P less than 0.01). The values observed for the mean T3 serum concentrations (nanograms per dl) in the same groups were 171 +/- 10 and 154 +/- 9 (mothers; P greater than 0.05) and 68 +/- 6 and 55 +/- 6 (newborns; P greater than 0.05); the mean TSH serum concentrations (microunits per ml) were 8.7 (7.6 - 9.9) and 5.4 (4.9 - 5.9; mothers; P less than 0.001) and 19.6 (16.6 - 23.2) and 6.4 (5.8 - 7.0; newborns; P less than 0.001). The proportion of untreated newborns, i.e. 40%, with individual TSH values deviating by more than 2 SDS above the mean of the treated newborns is much greater than the corresponding proportion, i.e. 15%, of untreated mothers in relation to the treated ones. In 6 out of 34 untreated newborns, definite biochemical signs of congenital hypothyroidism were observed. Correlation coefficients were calculated between the untreated subjects. A positive correlation coefficient of 0.80 (P less than 0.001) was observed between the serum T4 concentrations of the mothers and those of the newborns, and one of 0.61 (P less than 0.001) was observed between their respective serum TSH values. Significant inverse correlations were observed between maternal serum T4 and cord serum TSH (-0.79; P less than 0.001) and between cord T4 concentrations and maternal TSH concentrations (-0.57; P less than 0.01). No definite trend is observed between the variations of serum T3 on one hand, and those of serum T4 or serum TSH on the other hand. Out of 51 mothers in whom serum T4 was determined, 11 showed values below 8 micrograms /dl; the newborns of those mothers showed very low serum T4 values (5.5 +/- 1.6 micrograms/100 ml) and extremely high serum TSH levels [144 (98-210) microU/ml]. It is concluded that, contrary to the situation observed in physiological conditions, maternal thyroid function in regions of severe endemic goiter is a good indicator of newborn thyroid function. The reasons for this probably lie in the influence of environmental factors acting simultaneously on the mother and the fetus.

Congenital Hypothyroidism

Birth interval study in a culturally stable urban population.

Five hundred women were interviewed within 2 days of delivery to examine indigenous birth spacing among the urban and rural population of Ife township. The crude birth interval was between 30 and 40 months due mainly to cultural attitudes towards lactation and sexual abstinence. The women studied possessed considerable knowledge of Western contraceptive methods, but they rejected them. The possible cause of this rejection is examined and solutions to the problem are suggested.

Birth Rate

The midwife in Indonesia.

In Indonesia, where a large percentage of the population lives in rural areas, the traditional midwife or dukun is essential in the field of obstetrics. Means to further her knowledge and improve her skills so that the population at large may benefit are discussed.

Child

Detection, evaluation, and treatment of pituitary microadenomas in patients with galactorrhea and amenorrhea.

Over a period of two and a half years, 34 women with galactorrhea or amenorrhea, all with an abnormal sellar polytomogram, underwent transsphenoidal microsurgical exploration of the sella. Eighteen women and microadenomas (less than or equal to 1 cm. in diameter), seven had macroadenomas (greater than than 1 cm. in diameter), and five had unidentified lesions. Only one women had a normal pituitary gland. Three women had cryosurgery without biopsy. Preoperatively, hyperprolactinemia occurred in 24 of 25 women with adenomas and two of five with nonadenomatous lesions. There were no operative deaths. Significant morbidity occurred in only three patients, none of whom had microadenomas. Postoperatively, menses resumed in 16 of the 17 women with microadenomas and in two of the seven with macroadenomas who presented with amenorrhea. Galactorrhea disappeared in 15 of the 17 women with microadenomas and in four of the seven with macroadenomas who presented with galactorrhea. In five patients with unidentified lesions, a return of menses occurred in two of four with previous amenorrhea, and galactorrhea abated in two of three who presented with lactation. We conclude that sellar polytomography in women with hyperprolactinemia is a useful technique technique for the diagnosis of pituitary adenomas, a lesion which may occur more frequently than previously realized. In addition, transsphenoidal microresection of microadenomas is safe and effective.

Adenoma