The effect of maternal thyroidectomy prior to conception on foetal brain development in sheep

Merino ewes were surgically thyroidectomized, and mated 6 weeks later when their plasma thyroxine (T4) levels were negligible. Their foetuses were delivered by hysterotomy at 52, 71, 84, 98, 125, 140 days gestation or at term (150 days). Despite the very low levels of T4 in maternal plasma, the concentrations of T4 in foetal plasma were not significantly different after 71 days gestation from those of foetuses of sham-operated (control) ewes. Foetal brain and body weights, however, were reduced from 71 days compared to those of foetuses of sham-operated ewes. The foetal brain weights but not the body weights were restored to normal from 125 days to term. In addition to the weights, cell number (DNA) and cell size (protein:DNA ratio) appeared to be normal in the neonatal brain at parturition and this was confirmed by histological examination of the brains. Thus lack of maternal thyroid hormones in early pregnancy may cause a reduction in brain and body growth in the foetus which, in the case of the brain, appears to be restored to normal after the onset of foetal thyroid function.     

Secretion of lipoproteins from the liver of normal and Watanabe heritable hyperlipidemic rabbits.

We compared the rate of accumulation of lipoproteins in perfusates of isolated livers from normal New Zealand White rabbits and Watanabe heritable hyperlipidemic (WHHL) rabbits, in which a gene mutation has produced a virtually complete deficiency of low density lipoprotein (LDL) receptors. The rate of accumulation of apolipoprotein B-100 did not differ in perfusates of livers from normal and mutant animals and little or no apolipoprotein B-48 was detected. In both groups, virtually all apolipoprotein B accumulated in very low density lipoprotein (VLDL). Experiments in which [3H]lysine was added to the perfusates showed that the apolipoprotein B that accumulated in VLDL was newly synthesized by the liver whereas the small amount of apolipoprotein B found in lipoproteins of higher density appeared to be washed out of extravascular spaces during perfusion. Perfusate VLDL from both groups contained more triglycerides and less cholesteryl esters than their counterparts from blood plasma. As compared with perfusate VLDL from normal livers, those from livers of WHHL rabbits were enriched in cholesteryl esters. Experiments in which Triton WR-1339 was injected into the blood of intact rabbits confirmed the observations with perfused livers. Previous studies have shown that the extent to which VLDL is converted to LDL is increased several-fold in WHHL rabbits. Taken together with our present results, which fail to provide evidence for increased secretion of apolipoprotein B or de novo secretion of lipoproteins other than VLDL that contain apolipoprotein B, it can be concluded that overproduction of LDL in rabbits lacking LDL receptors is solely the result of altered metabolism of VLDL.     

The effects of growth hormone treatment of thyroid-deficient pregnant rats on maternal and fetal carbohydrate metabolism.

Maternal hypothyroidism in rats has been shown previously to result in alterations of maternal, placental, and fetal metabolism. Maternal treatment with 2 IU GH/day for three days prior to autopsy (on the 22nd day of pregnancy) corrected many of the observed alterations of carbohydrate metabolism in hypothyroidism. The maternal and fetal liver glycogen concentrations and the fetal serum glucose levels of the hypothyroid animals were elevated significantly by the GH treatment. In most cases, the utilization of a [1-14C]glucose tracer dose was returned to normal by GH treatment. These results suggest that the impairment of fetal metabolism occurring in maternal hypothyroidism may be due in part to insufficient maternal GH secretion. However, GH alone in the absence of sufficient thyroid hormones did not totally correct all of the observed fetal abnormalities.     

Glucose stimulation of insulin secretion from the isolated pancreas of foetal and newborn rats

Summary Pancreatic glands of 22-day-old rat foetuses or 0–12 day old rats were incubated in a Krebs-Ringer phosphate-buffered salt solution, and the insulin secretion measured at a lower (0.6 mg/ml) or a higher (3 mg/ml) glucose concentration in the medium. Stimulation of the insulin release by glucose could not be detected until the second postnatal day, when there was a marked increase in the amount of hormone secreted into the medium. Since the presence of insulin has been demonstrated in the B-cells of rat foetuses, the data suggest that in this species the cellular mechanism for insulin synthesis becomes manifest considerably earlier than that for glucose-regulated insulin release.This investigation was supported by grants from the Medical Faculty of Uppsala, the Swedish Medical Research Council (B69-12X-109-05A) and the U.S. Public Health Service (AM-12535).     

The production in culture of metalloproteinases and an inhibitor by joint tissues from normal rabbits,and from rabbits with a model arthritis

During the development of proliferative arthritis in the knee joints of rabbits, there was a large increase in the ability of articular cartilage explants to produce latent collagenase in culture. In parallel, the normally high levels of collagenase inhibitor produced by cartilage in culture fell, but active collagenase was never detectable. Characterisation of the collagenase and other proteinase activities produced by rabbit articular cartilage in culture showed that two activities could be separated by gel filtration, one with activities on gelatin and cartilage proteoglycan and the other degrading collage. Under the conditions employed in this paper no resolution of the gelatin and proteoglycan activities could be achieved. All the activities were in a latent form, activated by 4-aminophenylmercuric acetate (APMA), and inhibited by 1,10-phenanthroline or EDTA, but not by di-isopropylfluorophosphate (DFP), indicating that they are metalloproteinases. Characterization of the collagenase inhibitor showed a single peak of activity of apparent molecular weight of 28,000 on gel filtration. The inhibitor was sensitive to APMA and also inhibited other rabbit metalloproteinases, analogous to the system described for rabbit bone. The physiological significance of the synthesis by articular cartilage of proteinases that destroy connective tissue macromolecules and the presence of an enzyme-inhibitor control system is discussed.     

The production in culture of metalloproteinases and an inhibitor by joint tissues from normal rabbits,and from rabbits with a model arthritis

Summary During 5 days of culture, explants of normal rabbit synovium produced no active collagenase, negligible latent collagenase, but significant levels of free collagenase inhibitor. Synovium from joints exhibiting a proliferative arthritis produced greatly elevated levels of collagenase; the appearance of active enzyme in the medium during the second day of culture was associated with the disappearance of free inhibitor. Enzyme levels in the media correlated well with the arthritic status of joints, when explants were prepared up to 10 weeks after the induction of the model arthritis. Synovium from the contralateral joints of rabbits with unilaterally induced arthritis produced no active collagenase, but approximately one-third as much latent collagenase as found with arthritic joints. Enzymatic activities against gelatin and cartilage proteoglycan substrates were demonstrated in synovial culture media in addition to collagenolytic activity. Gel filtration showed that these activities were not due to a single enzyme, and further characterisation confirmed that the enzymes were metalloproteinases. The results are considered in the light of published data, and the involvement of metalloproteinases and their specific inhibitor in the development of arthritic lesions is discussed.     

Load sensitivity of relaxation in the foetal and newborn rabbit heart

Differences in the mechanism of cardiac relaxation and the influence of changes in the stimulation frequency were studied in foetal and newborn rabbit hearts. In the foetal rabbit heart which lacks a well developed sarcoplasmic reticulum, load sensitivity of relaxation was investigated and compared with that observed in the newborn. Load sensitivity was studied by measuring force and shortening length in twitches with increasing afterloads and also when load clamp steps were rapidly imposed during the twitch. Quantification of the load sensitivity was achieved by the measurement of the time to relaxation "tRi" which was linearly related to the relative developed force. The slope (S) of this linear relation quantifies the load sensitivity: the higher the slope, the more load sensitive is the relaxation. At a frequency of 24 beats X min-1, S was respectively 0.24 in the foetal heart and 0.36 in the newborn heart showing at both ages the existence of a load sensitivity and its significant increase at birth. No further increase in load sensitivity was observed from 1 day to 21 days after birth. Reducing the stimulation frequency from 24 to 10 beats X min-1 abolished the load sensitivity in foetal hearts (S = 0.05) while, in the newborn, a significant load sensitivity could still be observed (S = 0.25). Thus, in rabbit myocardium, the load sensitivity of cardiac relaxation depended upon the age and the stimulation frequency showing a perinatal development of the structures involved in the control of myocardial relaxation.     

The cytological composition of the foetal endocrine pancreas in normal and pathological conditions

Summary The islets of Langerhans of the neonatal pancreas are composed of B cells and non-B cells. The non-B cells are a heterogeneous group and the composition appears to vary according to the staining method used. Silver impregnation methods sometimes impregnate a small number of B cells. No complete identity exists between argyrophilic cells (Hellerström-Hellman modifications of the Davenport technique) and D cells. In babies from mothers with reduced carbohydrate tolerance the islets contain an increased proportion of B cells and Ag⁺ cells. Such an increase is not found in babies with erythroblastosis or alpha-thalassaemia. An active hypothalamohypophyseal system seems to be obligatory for complete maturation of the foetal islet tissue. In babies of diabetic mothers hyperplasia of the B cell appears only when a complete hypothalamo-hypophyseal system is present.

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Die cytologische Zusammensetzung des foetalen endokrinen Pankreas unter normalen und pathologischen Bedingungen

Zusammenfassung Die Langerhans'schen Inseln des neonatalen Pankreas bestehen aus B Zellen und nicht-B Zellen. Die nicht-B Zellen bilden eine heterogene Gruppe, deren Zusammensetzung je nach der gebrauchten Färbungsmethode ändert. Silberimprägnierungsmethoden imprägnieren eine kleine Zahl B Zellen. Es besteht keine vollständige Identität zwischen argyrophilen (nach Davenport-Hellerström-Hellman) Zellen und D Zelle. Bei den Neugeborenen von Müttern mit reduzierter Kohlenhydrattoleranz enthalten die Inseln eine größere Proportion B Zellen und Ag+ Zellen. Eine solche Zunahme fehlt bei Neugeborenen mit Erythroblastose oder Alpha Thalassämie. Ein aktives hypothalamo-hypophysäres System ist notwendig um eine vollständige Reifung des foetalen-Insel-Gewebes zu erreichen. Bei Neugeborenen diabetischer Mütter kommt Hyperplasie der B Zellen nur dann vor, wenn ein vollständiges Hypothalamo-hypophysäres System anwesend ist.

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La composition cytologique du pancréas endocrine foetal dans les conditions normales et pathologiques

Résumé Les îlots de Langerhans du pancréas néonatal sont composés de cellules B et de cellules non-B. Les cellules non-B forment un groupe hétérogène, dont la composition varie selon la technique de coloration. L'imprégnation argentique marque un petit nombre de cellules B. Il n'y a pas d'équivalence entre les cellules argyrophiles (modifications de Hellerström et Hellman de la technique de Davenport) et les cellules D. Il existe une augmentation du rapport cellules B et cellules argentaffines dans les îlots de Langerhans d'enfants dont la mère présente un métabolisme glucidique perturbé. Ce phénomène n'a pas pu être mis en évidence chez les enfants présentant de l'érythroblastose ou de l'alpha thalassémie. On peut admettre la nécessité d'un système hypothalamo-hypophysaire actif pour la maturation complète des îlots foétaux. On constate chez les enfants de mères diabétiques une hyperplasie des cellules B lorsqu'un système hypothalamo-hypophysaire complet est présent.

     

Inhibitors of fibrinolysis in diabetic children, mothers, and their newborn.

Late diabetic complications are often related to vascular changes and formation of thrombi in the altered vasculature. Contributing factors to thrombosis susceptibility of diabetic patients include changes in clotting factors, platelets, and inhibition of fibrinolysis. We have measured various fibrinolytic inhibitors in the blood of diabetic children, diabetic pregnant women and their offspring, and healthy controls. Inhibitors studied included 1) fast (immediate) antiplasmin, 2) slow (progressive) antiplasmin, 3) alpha-2-macroglobulin, and 4) alpha-1-antitrypsin. It appears from our study that high fast-antiplasmin levels, and low or missing slow-antiplasmin levels are characteristic of diabetic patients and of newborn of diabetic mothers. The reason for high fast-antiplasmin levels is not clear: Levels are not connected with the age of the patient or duration of diabetes, and are not elevated in response to a fibrinolytic process (fibrin decomposition products could not be shown to be present in the serum of diabetic children). Alpha-2-macroglobulin was significantly higher and alpha-1-antitrypsin significantly lower in diabetic women than in controls. In the other groups of patients studied differences in these inhibitors from the appropriate control groups were not statistically significant.     

QT prolongation in the newborn and maternal alcoholism

I discuss a newborn whose mother is addicted to alcohol. On the third day of life, the newborn was found to have ventricular tachycardia. After spontaneous termination of the abnormal rhythm, the duration of the corrected QT interval was 0.48 s. During the next days, the duration of the interval normalized, and has now remained stable for 5 years. I conclude that the so-called "alcohol withdrawal syndrome of the newborn" might cause postnatal prolongation of the QT interval.