Jean H. Dussault

The response to long-term overfeeding in identical twins.

We undertook this study to determine whether there are differences in the responses of different persons to long-term overfeeding and to assess the possibility that genotypes are involved in such differences. After a two-week base-line period, 12 pairs of young adult male monozygotic twins were overfed by 4.2 MJ (1000 kcal) per day, 6 days a week, for a total of 84 days during a 100-day period. The total excess amount each man consumed was 353 MJ (84,000 kcal). During overfeeding, individual changes in body composition and topography of fat deposition varied considerably. The mean weight gain was 8.1 kg, but the range was 4.3 to 13.3 kg. The similarity within each pair in the response to overfeeding was significant (P less than 0.05) with respect to body weight, percentage of fat, fat mass, and estimated subcutaneous fat, with about three times more variance among pairs than within pairs (r approximately 0.5). After adjustment for the gains in fat mass, the within-pair similarity was particularly evident with respect to the changes in regional fat distribution and amount of abdominal visceral fat (P less than 0.01), with about six times as much variance among pairs as within pairs (r approximately 0.7). We conclude that the most likely explanation for the intrapair similarity in the adaptation to long-term overfeeding and for the variations in weight gain and fat distribution among the pairs of twins is that genetic factors are involved. These may govern the tendency to store energy as either fat or lean tissue and the various determinants of the resting expenditure of energy.

Screening for congenital hypothyroidism: Results of screening one million North American infants

Pilot programs for screening of newborn infants for congenital hypothyroidism began in North America in 1972. To date, the five oldest programs (Quebec, Pittsburgh, Toronto, Oregon Regional, and New England Regional) have screened 1,046,362 infants. A total of 277 infants with congenital hypothyroidism have been detected and seven have been missed, resulting in a total of 284 affected infants in the screened population and an overall incidence of one in 3,684 live births. Of the affected infants, 246 were determined to have primary hypothyroidism, an incidence of one in 4,254 births. Ten infants with secondary-tertiary hypothyroidism were detected in Quebec, Oregon, and Toronto, an incidence of one in 68,200 births. Of all the infants with primary hypothyroidism who were adequately studied, 63% were determined to have aplastic or hypoplastic glands, 14% normal or enlarged glands, and 23% ectopic thyroid tissue. The estimated minimum incidence of infants with TBG deficiency is one in 8,913 births. Only 8 of the 277 detected infants were suspected clinically to have congenital hypothyroidism prior to the time of confirmation of the diagnosis at 4 to 8 weeks of age. The cost of screening varied from

Preliminary report on a mass screening program for neonatal hypothyroidism

0.70 to

Oligodendrocyte maturation and progenitor cell proliferation are independently regulated by thyroid hormone

1.60 per infant, depending on which costs were included in the estimate. Preliminary evidence from Quebec suggests that infants treated in the program have normal developmental testing scores at 18 months of age.

Plasma catecholamine concentrations in hyperthyroidism and hypothyroidism.

We have recently developed an immunoassay that can measure thyroxine rapidly and accurately in the eluate of 40 mul of dried blood spotted on filter paper at the fifth day of life. The method is completely automated and by using the samples received by the Central Laboratory of the Quebec Network for Genetic Medicine and their follow-up facilities, we are now screening every newborn in the province of Quebec for neonatal hypothyroidism. To date, from 47,000 measurements, three newborn infants with abnormally low TBG and seven hypothyroid infants have been detected. From these data we conclude that the frequency of congenital hypothyroidism is about one in 7,000 births and that our method is effective in detecting thyroid hormone abnormalities with an acceptable percentage of false positive measurements; no false negative results have occurred to our knowledge.

Free thyroid hormone concentrations during postnatal development in the rat.

The development of oligodendrocyte progenitor cells is regulated by epigenetic factors which control their proliferation and differentiation. When oligodendrocyte progenitor cells, purified on a Percoll centrifugation gradient from neonate rat brain, are cultured in serum‐free medium in the presence of platelet‐derived‐growth factor (PDGF), they divide and their differentiation is delayed. Triiodothyronine (T3) treatment of progenitor cells blocks their proliferation and induces their differentiation into oligodendrocytes. T3 also induces morphological differentiation of oligodendrocytes as indicated by the marked increase in the length of oligodendrocyte processes. To determine whether the effects of T3 on progenitor cell proliferation and oligodendrocyte maturation are causally related, or instead, are independent, we examined the influence of T3 on secondary cultures of postmitotic oligodendrocytes. We show that T3 increases morphological and functional maturation of postmitotic oligodendrocytes as indicated by a well developed network of branched processes and by the expression of myelin/oligodendrocyte glycoprotein (MOG) and glutamine synthetase (GS). T3 increases glutamine synthetase activity and its message level after a lag period of 24–48 h, and these levels increase through a posttranscriptional event. In contrast, no effect of T3 was observed on myelin basic protein (MBP) gene expression as determined by Northern blot analysis.

Useful parameters to predict the eventual mental outcome of hypothyroid children

Using a modification of the fluorometric method of Anton and Sayre, we have measured the plasma epinephrine (E) and norepinephrine (NE) concentrations in patients with thyroid dysfunction. There was no significant difference in plasma E in hyperthyroid or hypothyroid subjects, the values being similar to those observed in normal subjects. There was a striking relationship between age and plasma NE in the euthyroid individuals (r = 0.685, p less than 0.001, n = 41). Observed plasma NE concentrations were similar in control subjects (21.05 +/- 1.6 ng/100 ml; mean +/- SEM) and hyperthyroid patients (22.33+/- 2.0 ng/100 ml). However, plasma NE was significantly increased in hypothyroidism (35.46 +/- 3.9 ng/100 ml; p less than 0.01) and remained statistically different when the age factor was excluded (31.31 +/- 2.67 ng/100 ml; p less than 0.025). There was no correlation between plasma NE and serum thyroxine (T4), free thyroxine (FT4), or triiodothyronine (T3), in any of the three groups studied. These data indicate that hyperthyroidism is accompanied by normal plasma NE concentrations and that hypothyroidism is associated with significantly increased plasma NE concentrations, possible in an attempt to compensate for the lack of thyroid hormones.

Preliminary results on the mental development of hypothyroid infants detected by the Quebec Screening Program

Summary: Sprague-Dawley rats were sacrificed by decapitation at 5, 7, 12, 14, 22, 26, 32, and 40 days of age. Adult animals (175 to 225 g) were also studied. Serum-free thyroxine (FT4) concentrations rose rapidly between 5 and 12 days to levels similar to adult concentrations, whereas the percentage of FT4 was relatively high between 5 and 12 days before declining to adult values by 14 days. Serum-free triiodothyronine (FT3) concentrations rose progressively to attain peak concentrations at 26 days and subsequently declined to adult levels by 40 days. The percentage FT3 rose in parallel with the FT3 concentrations to peak values at 22 to 26 days before declining to adult levels. FT4/thyroid-stimulating hormone (TSH) and FT3/TSH ratios increased progressively through 22 days of age in parallel with the FT3/FT4 ratio. These data indicate that free thyroid hormone concentrations follow essentially the same developmental profile as do total thyroid hormone concentrations. Progressive maturation of the negative feedback control mechanism for the pituitary-thyroid axis, as assessed by the FT4/TSH and FT3/TSH ratios, occurs through 14 days. However, the continued rise in FT3 concentrations, FT3/TSH, and FT3/FT4 ratios through 26 days suggests a further resetting of the setpoint of the pituitary-thyroid axis possibly related to the stress of weaning.Speculation: Maturation of the pituitary-thyroid axis in the rat is principally a postnatal phenomenon. Careful study of the developmental profile of this axis under physiologic and pathologic states may afford considerable insight into the ontogenesis of the pituitary-thyroid axis in the human fetus.

TSH measurements from blood spots on filter paper: A confirmatory screening test for neonatal hypothyroidism

ABSTRACT: The Quebec Network for Genetic Medicine has followed the development of some 100 hypothyroid children treated by 1 month of age and evaluated at 18 months, 3 and 5 yr and the Griffiths Mental Development Scales, then at 7 and 9 yr with the Wechsler Intelligence Scale for Children Revised. Results show that the children as a group reach scores within the normal range of the tests. However, a few patients have low scores at each evaluation. Previously, we showed a correlation between a low serum thyroxine concentration, or a relatively retarded bone maturation before treatment, and low mental scores. To better characterize the significance of this relationship we correlated these pretreatment factors and the Wechsler Intelligence Scale for Children Revised results of 43 subjects reaching the age of 7 yr. Again, the same correlation was observed. Calculating a predictive factor (low thyroxine, <2 μg/dl and retarded bone surface, <0.05 cm2) from data recorded before therapy initiation, 10 of 13 children were correctly predicted to have I.Q. values <90. The use of these parameters might permit early intervention, and allow specific guidance of the more affected subjects.

Regional distribution of nuclear T3 receptors in rat brain and evidence for preferential localization in neurons1

A prospective study of the mental development of hypothyroid infants detected by the Quebec Network for Genetic Medicine began in January, 1976. The mean age at initiation of thyroid hormone therapy was 27 days. Forty-five hypothyroid infants and 37 normal control subjects were assessed at age 12 months with the Griffiths mental development test; 77 and 41, respectively, were assessed at age 18 months, and 59 and 40, respectively, at 36 months. There were no statistically significant differences in the various test scores between the two populations at age 12 months, but at age 18 and 36 months the hypothyroid infants had lower scores in hearing-speech performance scales and practical reasoning (36 months) which also decreased their global quotient. The mean scores were still above 100 and only nine were below 85. Further assessment of the influence of early therapy on mental development at age 6 years is needed before definitive statements can be made about the long-term mental development in these subjects.