Biomedical subjects
Publications and source records attributed to T P Foley.
The seasonal and chronological distributions of birth dates of 820 patients with congenital hypothyroidism due to thyroid dysgenesis were analysed in eight areas in the world. The incidence had some seasonal variations in certain areas. These observations suggest that some environmental factors cause this disease.
The clinical, neuroradiologic, and endocrine features in 16 patients with septo-optic dysplasia are reviewed. All of the patients had clinical optic nerve hypoplasia with varying degrees of nystagmus and visual impairment. Only one-half of the patients had absence of the septum pellucidum. Fourteen children were growth hormone deficient, 9 were adrenocorticotrophic hormone deficient, 3 were thyroid-stimulating hormone deficient, and 4 had diabetes insipidus. In most instances, the diagnosis of septo-optic dysplasia can be established by physical examination and neuroradiologic findings, at which point a thorough evaluation of the hypothalamic-pituitary endocrine function is indicated because of the high incidence of hypopituitarism with this syndrome.
Spreading factor (SF) is a glycoprotein isolated from human plasma or serum that promotes attachment and spreading of a wide variety of mammalian cells in culture. Under appropriate conditions, this factor also affects cell proliferation and differentiation in vitro. An immunoassay employing a previously characterized monoclonal antibody to SF, with purified SF as a reference standard, was utilized to quantitate levels of SF in human plasma, serum, amniotic fluid, and urinary protein. Specific anti-SF monoclonal antibody-binding activities in individual samples of human serum were identical to specific anti-SF monoclonal antibody-binding activities in the plasma samples from which the sera were derived. Specific anti-SF monoclonal antibody-binding activity in plasma from adults, when compared with purified SF reference standards, represented an average of 4 micrograms of SF per mg plasma protein (range, 2.5 to 7 micrograms/mg). Specific anti-SF monoclonal antibody-binding activity in sera from fetal cord blood, infants, children, or adolescents was not significantly different from that of adults. Specific anti-SF monoclonal antibody-binding activities in amniotic fluid samples from pregnancies of 12 to 23 weeks' gestation were within the range observed in sera of adults. Anti-SF monoclonal antibody-binding activity in concentrated urinary protein, when compared with purified SF reference standards, represented a specific activity of 10.9 micrograms of SF per mg protein.
HLA antigens A and B were determined in a group of 41 patients with congenital hypothyroidism and 36 of their mothers. Twenty-nine patients had thyroid dysgenesis of whom 23 were functionally athyreotic, four had ectopic and two had hypoplastic thyroid glands. Twelve patients had thyroid dyshormonogenesis, seven of whom had iodide organification defect. A total of 48 antigens were typed in the A and B loci. The results were analyzed in comparison to 388 normal adult subjects from the general population. The only statistically significant difference was an increase in the frequency of HLA-Bw44(12) (48.8% vs 19.3%, P less than 0.02). The incidence of HLA-Bw44(12) was 44.2% in the mothers. There was a decreased frequency of HLA-B7 in the patients which was not significant.
Levels of multiplication-stimulating activity (MSA) in fetal rat serum are high (2-4 micrograms/ml), suggesting that MSA may have a role in fetal growth. We now demonstrate that fibroblasts derived from rat embryos (REFs) have specific MSA receptors and respond to MSA with increased DNA synthesis. Two types of insulin-like growth factor (IGF) receptors were demonstrated by competitive binding of radioiodinated MSA, IGF-I, and IGF-II and by chemical cross-linking of [125I]iodo-MSA and [125I]iodo-IGF-I to REFs. One type of receptor (mol wt, 260,000 under reducing conditions) did not interact with insulin, and another type of receptor (mol wt, 130,000, under reducing conditions) was recognized by insulin. Scatchard analysis of [125I]iodo-MSA binding data was consistent with one class of noninteracting binding sites. A biological response of MSA, increased DNA synthesis, was demonstrated with autoradiography in REFs. During a 16-hr incubation, DNA synthesis was stimulated by normal rat serum, and platelet-poor plasma plus platelet-derived growth factor (PDGF), but not by serum from hypophysectomized (hypox) rats or hypophysectomized (hypox) platelet-poor plasma plus PDGF. However, when MSA was added to hypox serum or to hypox platelet-poor plasma plus PDGF, DNA synthesis was stimulated to the level achieved by normal rat serum. By contrast, during a longer cell multiplication experiment, REFs grew equally well in normal or hypox rat serum, raising the possibility that REFs may produce a MSA-like factor.
The insulin-like growth factor, multiplication stimulating activity (MSA), and insulin were recently shown to stimulate proteoglycan synthesis in monolayer cultures of chondrocytes derived from the Swarm rat chondrosarcoma. Insulin produced significant stimulation at a concentration of less than 1 ng/ml, suggesting that insulin was acting through the insulin receptor rather than through a somatomedin receptor. In this paper we have shown that the insulin-like growth factors IGF-I and IGF-II also are potent stimulators of [35S]sulfate incorporation into macromolecules recovered from the medium and cell layer matrix of the chondrosarcoma chondrocytes. Proinsulin was 3% as potent as insulin in stimulating [35S]sulfate incorporation. We identified receptors for insulin and the insulin-like growth factors, MSA, IGF-I, and IGF-II. Insulin, at concentrations 1000 times the concentration required to produce the biologic response, did not compete for binding of 125I-MSA-II-1 or of 125I-IGF-II and only partially competed for 125I-IGF-I binding. Anti-insulin receptor IgG stimulated proteoglycan synthesis and competed for 125I-insulin binding. Fab fragment prepared from anti-insulin receptor IgG completely blocked the stimulation of [35S]sulfate incorporation into macromolecules by insulin while only partially inhibiting the biologic response to insulin-like growth factors, MSA, IGF-I, and IGF-II. Similarly, the anti-insulin receptor IgG only partially inhibited the binding of 125I-IGF-I and 125I-IGF-II while completely blocking the binding of 125I-insulin. We conclude that insulin stimulates proteoglycan synthesis in the chondrosarcoma chondrocytes by acting through the insulin receptor whereas the insulin-like growth factors probably act through their own receptors.
Maturation of the hypothalamic pituitary thyroid axis as reflected in cord serum thyroid hormone concentrations was assessed in premature and full term infants born between 26 and 43 weeks gestation. Measurements of thyroxine (T4), free T4 (FT4), thyrotropin (TSH) and thyroxine binding globulin (TBG) in cord sera were correlated with gestational age, sex and birthweight and compared to similar measurements in well two month old infants and adults. There were significant increases in T4, FT4, and TBG with increasing gestational age (GA) between 26 and 33-35 weeks (P less than 0.001). After 34 weeks, none of these parameters varied with GA. When the infants were separated on the basis of sex the linear regression curves describing the relationships between hormone and TBG concentrations and GA were not different from the curves in the total population. The mean FT4/TSH ratio increased significantly with age throughout gestation (P less than 0.01) and was significantly lower in cord blood samples than in blood samples from the 2-month-old infants or the adults. The results suggest that the set point for negative feedback control of TSH secretion at the pituitary level is changing between 26 weeks GA and 2 months of life. Thyroid gland sensitivity to TSH stimulation also appears to be increasing between 26 and 33 weeks GA.
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Nine children aged 7 2/12 to 17 9/12 years with central diabetes insipidus were subjected to water deprivation and water loading during treatment with 1-deamino-8-D-arginine vasopressin (DDVAP). Urine output remained unchanged despite the large differences in water intake. Serum osmolarity was not significantly affected by water deprivation. However, there was a marked decrease in serum osmolarity during water loading. This not accompanied by any symptoms of haemodilution. Thus patients apparently tolerate large variations in fluid intake during therapy with DDVAP.
An adrenal cortical tissue tumor developed in a patient with poorly controlled salt-losing congenital adrenal hyperplasia. A 16-year-old girl became progressively virilized from 13 to 16 years of age. Base line serum progesterone, 17-hydroxyprogesterone, and testosterone levels were high and there was a diurnal pattern of the hormones. Initially elevated urinary 17-ketosteroid and serum steroid levels were decreased by high dose dexamethasone therapy, and at laparotomy an adenoma was found in the cortex of the hyperplastic left adrenal gland. It is inferred that persistent adrenocorticotrophic hormone stimulation may result in neoplastic transformation of hyperplastic adrenal cortical tissue in patients with congenital adrenal hyperplasia.
Somatomedin activity was determined by the simultaneous incorporation of 35S-sulfate and 3H-methyl thymidine into costal cartilage from hypophysectomized rats in cord sera from term and preterm infants and infants with intrauterine growth retardation. Mean Sm activity by sulfate incorporation was 0.49 +/- 0.04, 0.35 +/- 0.05, and 0.09 +/- 0.03 units/ml (+/- SE) in the term, preterm, and IGR cord sera, respectively. The levels for each group were significantly different from each of the other groups. There was no significant difference between the mean Sm activity by thymidine incorporation in cord sera from term (0.92 +/- 0.09 units/ml) and preterm (0.87 +/- 0.08 units/ml) infants. These levels were significantly higher, however, than the Sm activity by sulfate incorporation for the respective groups, P less than 0.001 for both groups. The mean Sm activity by thymidine incorporation in cord sera for IGR infants was 0.36 +/- 0.13 units/ml, and significantly lower than the levels in cord sera of term and preterm infants (P less than 0.01). Inhibition of Sm activity by mixing cord serum and pooled adult serum was found in one of the two cord specimens tested from IGR infants. The low levels of Sm activity in cord sera from IGR infants may reflect altered intrauterine nutrition. The discrepancy in the thymidine and sulfate incorporation by the costal cartilage bioassay for term and preterm cord sera might result from Sm-like factors in human fetal serum with greater mitogenic or thymidine transport activity compared to the activity for proteoglycan synthesis in cartilage.
14,919 newborn infants were screened for congenital hypothyroidism within the last 5 years using a sensitive TSH method. 10 infants with congenital hypothyroidism were discovered thus presenting a frequency of 1:4500. Four of these infants showed abnormally high TSH levels and normal thyroxine levels. The determination of TSH in cord blood--or combined with the screening program for phenylketonuria--in eluate of dried filter paper specimens is the most sensitive test for primary hypothyroidism without false negative results and a low false positive recall rate of 0.16%. After initiation of therapy with thyroxine the TSH level falls unless therapy is delayed for longer. In the latter case TSH levels may remain elevated for several months despite therapy with thyroxine. We would suggest to start therapy with triiodothyronine for up to 14 days prior to initiation of the usual thyroxine therapy.
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 $0.70 to $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.
The Northwest Regional Screening Program to detect congenital hypothyroidism in infants born in Oregon, Montana, Alaska, and Idaho (combined birthrate of 69,000/ yr) was added to our ongoing screening program in 1975. The program utilizes dried blood filter paper specimens collected routinely in the first few days of life in all four states and again at about 6 weeks of age in Oregon only. The screening test consist of an initial thyroxine (T4) measurement; a thyroid-stimulating hormore (TSH) determination is performed on those specimens with T4 concentrations in the lowest 3% group. Serum samples obtained by venipuncture are requested for confirmation of the diagnosis. In the first two years of the program, 25 infants with primary hypothyroidism were detected amont 110,667 infants screened, a frequency of 1:4,430. Fourteen cases of thyroxine-binding globulin deficiency were also detected, a frequency of 1:7,900. Using the T4 followed by TSH testing approach, the frequency of request for repeat specimens was 0.4% in Oregon and 0.05% in the other states. The cost per specimen was $1.96. The majority of infants lacked clinical signs or symptoms of hypothyroidism; only one infant was clinically suspected of having hypothyroidism prior to detection. The most common neonatal symptoms were constipation, lethargy, and prolonged jaundice, while the most common physical signs were hypotonia, umbilical hernia, and large fontanels. Thyroid scans showed the most common etiology to be thyroid aplasia, followed by an ectopic gland, hypoplasia, and goiter. Serum T4 concentrations were lowest in those infants with aplasia, intermediate in infants with an ectopic gland or hypoplasia, and normal in the infant with the goiter. Neonatal hypothyroidism varies in degree and has several different causes; the capacity to secrete thyroid hormone, the duration before hypothyroidism becomes clinically manifest, and possibly the eventual prognosis for intellectual function depend on the nature of the underlying cause. While the mean age at treatment was 59 days, the goal of diagnosing congenital hypothyroidism and treating affected infants by 1 month of age seems realistic.
We measured concentrations of thyroxine, triiodothyronine, reverse triiodothyronine, thyroxine-binding globulin, and thyrotropin in pooled samples of cord sera from normal newborns. Sera collected in winter contain significantly (p less than 0.05) higher concentrations of the first tour--14.9, 13.4, 9k9, and 7.5%, respectively--than do sera collected in summer; thyrotropin concentrations are similar in samples collected during winter and summer (p greater than 0.05). With storage, the values for the thyronines and thyrotropin decreased progressively at rates between 0.9 and 5.3% per year; those for thyroxine-binding globulin did not change significantly.
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The effectiveness of therapy with carbamazepine and clofibrate (oral therapy), intramuscular pitressin-in-oil, and intranasal 1-deamino-8-D-arginine vasopressin has been compared in 15 children with partial or complete central diabetes insipidus. Mean daily urine volume without therapy was 5.4 l and dropped to 1.1 and 1.6 l/day while receiving pitressin and DDAVP, respectively. Oral agents decreased the daily urine volume to 2.2 l in patients with partial DI, with good symptomatic control except for some nocturia. These agents had no effect in patients with complete DI and did not alter pitressin requirements. Duration of pitressin action was 24 to 36 hours with a significant incidence of hyponatremia. The duration of DDAVP effect was 8 to 20 hours, varying in individual patients. Children with partial DI required smaller doses of DDAVP and the duration of action was longer than in those with complete DI. Control of serum electrolytes was excellent using two doses per day and nocturia was eliminated. All patients who had received pitressin had growth hormone antibodies, but continued to grow normally unless there was pre-existing growth hormone deficiency. These antibodies gradually disappeared after approximately one year of therapy with oral agents or DDAVP. DDAVP did not alter growth hormone, cortisol, or prolactin levels during sleep. DDAVP is the antidiuretic therapy of choice in children with either complete or partial DI; to date, no side effects have been demonstrated.