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1. A precocious development of UDP-glucuronosyltransferase activity (EC 2.4.1.17) towards o-aminophenol is demonstrated in 15-17 day foetal rat liver in utero after dexamethasone administration to the mother. 2. This stimulation of liver transferase activity in utero is directly proportional to the dose of dexamethasone infected. 3. Precocious development of transferase activity in utero can also be effected with the natural glucocorticoid cortisol by multiple injections of large amounts of this hormone into the mother. 4. Transferase activity towards o-aminophenolin foetal lung, kidney and upper alimentary tract can also be precociously stimulated by dexamethasone in 17-day foetuses in utero. 5. Natural development of hepatic transferase activity between days 18 and 20 of gestation is retarded after foetal hypophysectomy by decapitation in utero. 6. Overall glucuronidation of o-aminophenol, as observed in foetal rat liver, is also precociously stimulated by dexamethasone. 7. From this and from evidence previously presented we suggest that glucocorticoids, which are known to increase in rat foetuses between days 17 and 20 of gestation, trigger the normal development in utero of hepatic transferase activity towards o-aminophenol which occurs at that time. We also suggest that these hormones are responsible for the rise in activity of the enzyme in foetal lung, kidney and upper alimentary tract which occurs during the same gestational period.
Our fetal surgical model was utilized to perform in utero fetal lamb thyroidectomy and autograft transplantation of thyroid tissue to fetal thigh at 82-93 days gestation. Successful in utero transplantation was possible in two of six experimental animals. In one twin pregnancy with an unoperated control lamb, observations were continued to age six months. The athyrotic lamb with a thigh autograft was larger at birth and had a transient weak sucking reflex and awkward gait. It then grew and developed normally with no stigmata of cretinism or delay in bone maturation. At age six months an increase in thyroid stimulating hormone (oTSH) was the single distinguishing observation in the twin with the transplant. Although oTSH levels were elevated to age six months, the pituitary continued to be responsive to thyrotropin releasing hormone (TRH) stimulation. These findings suggest that in utero transplantation of thyroid tissue is technically feasible and that the previously described development of in utero cretinism following fetal thyroidectomy can be prevented by a functioning autograft. This technique will be useful in attempting allograft transplantation in utero.
1. The administration of dexamethasone to foetal rats in utero does not result in the appearance of specific tyrosine aminotransferase activity even after 24 h. 2. When foetal hepatocytes are cultured in vitro from animals treated in utero with dexamethasone, significantly higher activities of specific tyrosine aminotransferase are found than in untreated controls. 3. Dexamethasone in vitro induces specific tyrosine aminotransferase in cells cultured from control animals and the effect is maximal at 10 nM in the culture medium. 4. Actinomycin D at 0.2 microgram/ml in the culture medium completely prevents the induction of activity in vitro. 5. In cultures established from animals treated with dexamethasone in utero, the increase in specific tyrosine aminotransferase activity over the control cultures is only marginally decreased in the presence of actinomycin D. 6. The results can be interpreted to mean that dexamethasone in utero stimulates the transcription of enzyme-specific mRNA, which is not rranslated until a translational block in the foetal liver is removed by the conditions of culture in vitro.
BACKGROUND: The Lung is the major focus of therapeutic approaches for the inherited disorder cystic fibrosis (CF) as without treatment lung disease is life-limiting. However, the initiating events that predispose the CF lung to cycles of infection, inflammation and resultant tissue damage are still unclear. Inflammation may occur in the CF lung prior to birth in human and several large animal models suggesting an in utero origin for the disease and encouraging further studies prior to birth. METHODS: Here we used the sheep model of CF (CFTR-/-) and age-matched wild-type (WT) sheep of the same breed to investigate the single cell transcriptomes of proximal and distal lung tissue at 80 days and 120 days of gestation and at term (147 days). Single cell RNA-seq was performed on tissues from 4 to 7 animals of each genotype (WT and CFTR-/-) at each time point. RESULTS: At term, FOXJ1-expressing ciliated cells are overrepresented in both lung regions from CFTR-/- lambs, while secretory epithelial and basal cells are underrepresented in proximal lung, as are T cells and monocytes in distal lung. The imbalance in ciliated and basal cells was confirmed by immunohistochemistry. At 120 days of gestation, lymphoid cells are slightly more abundant in proximal and distal lung from CFTR-/- animals compared to WT, consistent with the transient CF-associated inflammatory response in utero. At 80 days of gestation, T and B cells are underrepresented in both lung regions. CONCLUSIONS: The differences in epithelial cell abundance observed in the CFTR-/- lambs at term may reflect sequelae from the loss of CFTR on lung development and differentiation in utero. These findings provide novel insights into the cellular mechanisms of pathology and may be relevant to the design of new therapeutic approaches for CF lung disease.
Administration of prostaglandin synthetase inhibitors to pregnant does and dams in late gestation was followed by in utero contraction of the fetal ductus arteriosus when studied by the whole-body freezing method. In the rat this contraction was well established within 6 h and persisted up to 36 h following 15 mg/kg indomethacin p.o. No effect was observed in the 18 d rat fetus but fetuses at 20 d and 22 d of gestation responded significantly to indomethacin. Doses of indomethacin approaching clinical usage (2.5 mg/kg also caused a positive response in utero. The rat was found to be sensitive also to sodium salicylate and in the rabbit both indomethacin and sodium salicylate were effective. Exposure in utero to prostaglandin synthetase inhibitors with resulting contraction of the ductus may seriously disturb cardiac function in the fetus.
Polyvinyl catheters were placed into the right and left utero-ovarian veins and saphenous vein and artery of three control (C) and four estradiol valerate (EV) treated gilts on Day 9 after onset of estrus. The EV treated gilts received 5mg EV/day on Days 11 through 15 after onset of estrus. On Days 12 through 17 utero-ovarian vein blood samples were collected at 15 min intervals from 0700 to 1000 hr and 1900 to 2200 hr and single samples were taken at 1100 and 2300 hr. Peripheral blood samples (saphenous vein or artery) were taken at 0700, 1100, 1900 and 2300 hr from Day 12 until the control gilts returned to estrus or until Day 25 for EV treated gilts and used to measure plasma steroid hormone concentrations. Utero-ovarian vein prostaglandin F (gf) concentrations (ng/ml, n-1,177) were measured by RIA. Status (control vs EV treated gilts) by day interactions were detected (P=.10). Curvilinear day trends were detected for plasma PGF concentrations in control (P less than .01) but not EV treated gilts. PGF concentrations (X +/- S.D.) for control and EV treated gilts were 1.20 +/- 2.08 and .26 +/- .84 ng/ml, respectively. PGF peaks (concentrations greater than X + 2 S.D.) occurred with greater frequency in control gilts (X2 =4.87; P less than .05). The interestrus interval (X +/- S.E.) for control and treated gilts was 19.0 +/- .6 and 146.5 +/- 74.8 days, respectively. Data indicate tht t estradiol valerate may exert its luteotrophic effect by preventing PGF release from the uterus.
This is a report about fetal death in utero in a case of monozygote, monochrionic, monoamnionic twin pregnancy (46,xy) 15 weeks after amniocentesis. The public prosecutor was occupied with the case by the patient. The accusation run as follows: Stab wound with following death in utero of one twin and thereby damage of the second twin also with following death in utero. Directly after delivery the first diagnosis by aspect of the fetuses was: transfusion syndrome. The following endoradiography of the blood vessels of the umbilical chords and placenta confirmed the first diagnosis (anastomosis). Additionally both chords were entangled and knotted variously. It was concluded that the extremely smaller fetus died from malnutrition (transfusion syndrome) whereas the taller fetus died from acute asphyxia (knotted chords in monoamnionic twin pregnancy). The forensic investigation was, as aspected, without any pathological findings concerning sequelae of stab wounds but revealed the lack of one chordvessel of the smaller fetus and the typical histological findings of an aspiration lung of the taller fetus.
The gross anatomic changes and the vaginal epithelial changes in 687 women exposed in utero to diethylstibestrol are described, as well as the findings in 66 of these women who agreed to undergo hysterosalpingography. Of 537 women in the study group whose time of in utero exposure to stilbestrol was known. 33% demonstrated gross anatomic changes of the cervix, whereas 44% of them were found on colposcopic examination to have vaginal epithelial changes. These changes occurred in a significantly higher percentage of women exposed in utero before the 20th week of gestation. Among the women included in the study on the basis of a review of their prenatal history, gross anatomic changes of the cervix seemed to be more common in those under the age of 19 years than in those older than 19 when they first entered the study. Gross abnormalities in the uterus were noted in 44 of the 66 women studied by hysterosalpingography. These changes consisted primarily of marked aberrations in the size and shape of the uterine cavity.
The antibody response to SRBC and E. coli 0127 lipopolysaccharide were determined in offspring from mice exposed in utero to diethylstilbestrol. The antibody response to SRBC, a T-cell dependent antigen, was similar in control and exposed animals. In contrast, the LPS antibody response was suppressed in treated females and enhanced in treated males. These studies indicated that in utero exposure to DES alters the humoral immune system to T-independent antigens.
Epididymal cysts and/or hypoplastic testes have been found in 31.5 per cent of 308 men exposed to diethylstilbestrol in utero, compared to 7.8 per cent of 307 placebo-exposed controls. Analyses of the spermatozoa have revealed severe pathological changes (Eliasson score greater than 10) in 134 diethylstilbestrol-exposed men (18 per cent) and 87 placebo-exposed men (8 per cent). Further investigation of the 26 diethylstilbestrol-exposed men with testicular hypoplasia has revealed that 65 per cent had a history of cryptorchidism. Only 1 of the 6 placebo-exposed controls with testicular hypoplasia had a history of testicular maldescent. Although none of our Diekmann's lying-in study group has had carcinoma to date one must keep in mind the reported increased risk of testicular carcinoma in testes that are or were cryptorchid. A 25-year-old man who was not part of the study group was treated recently by us for a testicular carcinoma ( mixed anaplastic seminoma plus embryonal cell carcinoma) and he had a history of diethylstilbestrol exposure in utero and cryptorchidism.
A specific state of T- and B-cell tolerance to human gamma-globulin (HGG) was induced in utero by intravenous administration of the deaggregated antigen to pregnant BALB/cCr mice. Tolerance persisted in the offspring until the 12th-wk of age and then began to gradually disappear. Suppressor cells could only be found when responsiveness to HGG ultimately appeared in the in utero-treated animals but not when they were completely unresponsives. In contrast, HGG-specific suppressors found in animals made unresponsive to HGG as adults appear to be associated with either the establishment and/or maintenance of the unresponsive state. To the extent that these experiments are consistent with natural self-tolerance to a serum protein, we conclude that active suppression is not a prerequisite from maintenance of unresponsiveness to self.
Among 199 women from 12 to 30 years of age who had been exposed to DES in utero, the colposcopic evaluation of the vagina and cervix was considered normal for only 13.6%. The incidence of colposcopically detected lesions was not related to the trimester of DES exposure, the patient's age, use of oral contraceptives, or presenting symptoms. Areas of punctation, mosaic patterns, white epithelium, and keratosis were not considered areas of adenosis. Cervical bands, hoods, cock's combs, etc., were considered as part of the cervix. Under this definition adenosis of the vagina was diagnosed in only 14.1% of the patients. Eight (4.0%) women were found to have cervical intraepithelial neoplasia (CIN), Grade 3 lesions, and an additional 36 (14.1%) women were found to have CIN, Grade 1 lesions based on the light microscopy evaluation of directed biopsies. There were no cases of clear cell adenocarcinoma. It appears that women with in utero DES exposure may be at a higher risk of developing squamous neoplasia compared with non-DES-exposed women.
Breathing responses to increasing fetal arterial CO2 pressure (PaCO2) were measured in 15 mature fetal lambs in utero during hyperoxic CO2 rebreathing in the ewe. Fetal breathing was expressed as 1) respiratory drive (RD), i.e., the early slope of intratracheal pressure during inspiration, and 2) ventilation equivalent (VEq), i.e., the product of intratracheal pressure and frequency of breathing. RD and VEq increased linearly with increasing PaCO2. CO2 threshold beyond which apneic fetuses started breathing was higher than the extrapolated CO2 threshold in spontaneously breathing fetuses. Afferent sciatic nerve stimulation, which induced regular breathing in apneic fetuses, lowered their CO2 threshold but did not alter their sensitivity to CO2. Naloxone resulted in initiation of fetal breathing, decreased CO2 threshold, and increased sensitivity to CO2. These studies demonstrate that respiratory center responsivity can be quantified in the lamb fetus in utero, that nonspecific somatic stimulation lowers fetal breathing threshold to CO2, and that endogenous opioid peptides could participate in the physiological suppression of breathing in fetal life.
Response of the fetal kidney to metabolic acidosis was studied in five fetal lambs, 115-125 days gestation, in order to evaluate the renal contribution to elimination of hydrogen ion during intra-uterine development. Experiments were conducted on healthy unanesthetized fetuses, intact in utero, with catheters implanted at hysterotomy into a fetal femoral artery and vein and into the bladder via the urachus, four or more days prior to the study. A metabolic acidosis was induced by infusion of isotonic lactic acid, 15 m mole/kg, intravenously over a period of 90 minutes. Serial arterial samples were taken and urine collected in fractions before, during and for three hours following the infusion, for measurements of pH, bicarbonate, lactate and electrolytes as well as urine output. During the infusion, urine pH fell from 6.65 to 6.25 and was 6.34 three hours later (Figs. 1 to 4, Tabs. III to IV). Lactic acid infusion caused a prompt increase in urine output from a mean rate of 0.12 to a maximum of 0.28 ml/kg/min at the end of the infusion, returning to control rates three hours later. Lactate excretion increased from 0.05 to a maximum of 4.6 mumole/kg/min at the end of infusion; titratable acid increased from 0.22 to a maximum of 4 muEq/kg/min; the rates of excretion of lactate and titratable acid were still higher than control at the end of three hours. Ammonia excretion increased from 0.21 to a maximum of 0.56 muEq/kg/min three hours after the end of infusion. The acid infusion caused a small but significant fall in excretion of bicarbonate. During the 90 minutes of infusion and over the following three hours, about 800 mumole lactate was excreted while net acid excretion over the same period was no more than half that amount. The diuresis was also accompanied by a net loss of sodium and chloride, the excretion of these ions increasing more than threefold following acid infusion; excretion of potassium decreased to one-third its rate prior to the infusion. During the 90 minutes of infusion, blood pH fell from 7.36 to 7.13, base deficit rose from 3.8 to 16.4 mEq/L and lactate rose from 2.2 to 14.8 mM/L; there was also a small but significant rise in both blood PCO2 and PO2 (Figs. 1 to 2, Tabs. I to II). During the following three hours of recovery, pH rose gradually to 7.29, base deficit and lactate fell to 7.4 mEq/L and 8.7 mM/L respectively. Since renal excretion of net acid and lactate was small, the decrease in blood base deficit and lactate levels during the recovery must therefore be mainly due to equilibration in various fetal compartments as well as placental transfer. These experiments indicate that, in the lamb fetus, intact in utero, the kidney although limited by immaturity of several mechanisms, is capable of responding to an acid load and thus can make a small contribution to fetal homeostasis. The increase in excretion of net acid is accompanied by loss of sodium and chloride in the urine.
The "utero-vaginal junction" that connects the uterus and vagina of duck oviduct differs histologically and histochemically from the adjacent zones. The region is characterised by low, somewhat longitudinally arranged mucosal folds, lined by tall columner cilliated cells with apical nuclei alternating with mucous secreting goblet cells containing basal nuclei. Within the propria of the mucosa there are numerous tubular glands--the sperm host glands--which are responsible for sperm storage after copulation. The goblet cells of the utero-vaginal junction contain an admixture of neutral, sulfated and nonsulfated acid mucopolysaccharides, while the sperm host glands are devoid of any mucopolysaccharide and secrete complex lipoidal materials and exhibit intense acid phosphatase activity. The functional significance of the secretory materials of the sperm host glands have been discussed in the light of sperm release mechanism.
The demonstration of fetal diseases and anomalies in utero can now be performed with a high degree of accuracy with modern ultrasonic equipment. This paper describes the more common and important fetal anomalies which can be demonstrated by ultrasound and indicates the importance of meticulous attention to technique and the significance of the acquistion of skill in real-time sonography by the physician-sonologist. The thoroughness of all obstetric sonographic examinations is emphasized to enable detection of unsuspected fetal anomalies. Specific methods to demonstrate these anomalies in the high-risk patient are also described. Several pitfalls in the diagnosis of fetal disease in utero are included which show the nonspecificity of some of the ultrasonic signs.
The per centum distribution of T and B lymphocytes was determined in 30 full term newborns showing adequate development for their gestational age and in 42 full term newborns showing in utero malnutrition. A significant decrease (p less than 0.001) of both lymphocytic subpopulations was found in the in utero malnutrition group. The possibility of a decreased efficiency of the immune response in this group of patients is discussed.