Follow-up of newborns with low thyroxine and nonelevated thyroid-stimulating hormone-screening concentrations: results of the 20-year experience in the Northwest Regional Newborn Screening Program.

OBJECTIVES: To determine the type and frequency of thyroid disorders detected in infants with low thyroxine (T4) and nonelevated thyroid-stimulating hormone (TSH) screening test results in the Northwest Regional Newborn Screening Program (NWRNSP) over the 20-year period from May 1975 to May 1995 and to determine the effect of follow-up of these infants on the overall recall rate. STUDY DESIGN: The NWRNSP requests a serum specimen in infants with an absolute T4 level < 38.6 nmol/L (< 3 mg/dl) and in infants with two filter paper T4 concentrations less than the 3%, regardless of the TSH concentration. We conducted a retrospective analysis of infants who were followed up because of low T4 and nonelevated TSH concentrations on newborn screening. To determine the effect of follow-up of infants with low T4 levels, nonelevated TSH concentrations on the recall rate, we selected 1 year (1994) for review. Serum sample requests were evaluated to determine the reason for the request. RESULTS: Over this 20-year period, the NWRNSP detected 450 infants with primary hypothyroidism among 1,747,805 infants screened (1:3,884). Of these, 416 were detected on the basis of low T4 levels and nonelevated TSH screening test results, whereas an additional 34 infants with primary hypothyroidism and 29 infants with hypopituitary hypothyroidism were detected as a result of follow-up of low T4 levels and nonelevated TSH screening test results. This included 25 infants with delayed TSH rise (1:67,226), 9 infants with mild hypothyroidism (TSH levels < 25 mU/L) (1:194,212), 29 infants with hypopituitary hypothyroidism (1:60,269), and 434 infants with T4-binding globulin deficiency (1:4,027). Excluding those with T4-binding globulin deficiency, the false-positive rate was 43.5:1. This compares with an overall false-positive rate of 12:1 for our screening program. CONCLUSION: Follow-up of infants with low T4 and nonelevated TSH concentration on screening led to the detection of 63 additional infants with hypothyroidism, for an overall frequency of 1:27,743. We believe this yield justifies continued follow-up of infants with low T4 levels, nonelevated (TSH) screening test results in our program.

The mouse intraovarian insulin-like growth factor I system: departures from the rat paradigm.

Although the rat intraovarian insulin-like growth factor I (IGF-I) system is well documented, the increasing availability of null mouse mutants for components of the IGF system necessitates characterization of the mouse model as well. Therefore, we undertook to define the components of the mouse intraovarian IGF-I system and to examine its operational characteristics. The cellular pattern of ovarian gene expression was comparable in the immature rat and mouse for IGF-I and the type I IGF receptor. In both species, IGF-I messenger RNA (mRNA) is selectively expressed by granulosa cells in growing, healthy appearing follicles. Type I IGF receptor mRNA was also concentrated in granulosa cells, but was uniformly expressed in all follicles large and small, healthy and atretic appearing alike. Cellular patterns of IGF-binding protein (IGFBP) gene expression were similar in mouse and rat, except in the case of IGFBP-2. IGFBP-2 mRNA was localized to the mouse granulosa cell, in contrast to its concentration in the rat thecal-interstitial compartment. This difference in IGFBP expression pattern was also noted in cultured mouse and rat granulosa cells. Although immunoreactive IGFBP-4 (24 and 28 kDa) and IGFBP-5 (29 kDa) were shared by both species, the cultured mouse granulosa cell also featured immunoreactive IGFBP-2 (30 kDa). The mouse paradigm further differed from its rat counterpart in that a maximal dose of FSH, previously shown to suppress the elaboration of rat granulosa cell-derived IGFBPs, was without effect. The addition of IGF-I proved stimulatory to the accumulation of the 28- to 29-kDa IGFBPs, as previously reported for the rat. However, IGF-I proved inhibitory to the accumulation of the 24-kDa IGFBP (presumptive nonglycosylated IGFBP-4); no consistent effect was reported for the rat model. Functional comparisons of mouse and rat ovarian cell cultures revealed qualitatively comparable FSH-stimulated steroidogenesis, disposition of radiolabeled pregnenolone, IGF-I-amplified FSH action, and IGFBP-mediated antigonadotropic activity. These findings indicate that the mouse intrafollicular IGF-I system differs from the rat paradigm in both the makeup and regulation of granulosa cell-derived IGFBPs as well as in the intensity and character of the steroidogenic process. Studies employing the mouse model must take into account these important distinctions relative to the more established rat paradigm.

Direct administration of insulin-like growth factor to fetal rhesus monkeys (Macaca mulatta).

A potential treatment for the amelioration of fetal growth failure is insulin-like growth factor-I (IGF-I). To address concerns of safety and efficacy, IGF-I (80 microg/kg; GroPep Pty.) was administered i.p. to healthy rhesus monkey fetuses via ultrasound guidance every other day between gestational days (GD) 110-120 and 130-140 (third trimester; term = approximately GD 165 +/- 10; n = 6). Pregnancies were monitored sonographically, and fetal/maternal blood samples were collected for complete blood counts, immunophenotyping, and biochemical analyses. Blood samples, external measures of the fetus and newborn, and tissue and organ weights were collected at fetal necropsy (GD 150; n = 2) or at term delivery of neonates (GD 160; n = 4). The results of these investigations have shown no evidence of hypoglycemia in the fetus or dam during the course of treatment. Circulating concentrations of fetal, but not maternal, IGF-I increased with treatment (approximately 80 to approximately 1015 ng/ml), and there was no evidence of a change in serum IGF-II or an increase in IGF binding protein-3 compared with historical control values. Fetal lymphocytes and select red cell parameters increased, and a significant elevation in circulating B cells and CD4/CD8 ratios in fetal lymph nodes was shown. Although no changes were detected in body weights, increases in thymic, splenic, and kidney weights and small intestine lengths occurred. Thus, administration of IGF-I to the fetal monkey is safe and results in 1) transient increases in circulating IGF-I, 2) a significant effect on fetal hematopoietic and lymphoid tissues, and 3) an increase in select fetal organ weights and measures. These data suggest that IGF-I may represent a potential candidate for therapeutic treatment of growth-compromised human fetuses in utero.

Kawasaki syndrome in the United States 1976 to 1980.

Review of 523 confirmed cases of Kawasaki syndrome reported to the Centers for Disease Control (CDC), during the period from July 1976 through December 1980, disclosed a previously unrecognized seasonal variation, with a peak incidence between February and May. A significantly higher incidence in black children, compared with white children, was also noted. Earlier reports of a higher incidence in children younger than 5 years of age, males, and children of Asian ancestry were confirmed. Frequently reported complications included joint involvement (27%) and cardiac abnormalities (22%); 1.2% of patients died. Four outbreaks (mean duration, 3.8 months) were investigated by the CDC, but no evidence of person-to-person transmission or a point source of exposure was found. These data suggest that some cases may be caused by an exogenous agent or toxin that is most prevalent in the late winter and spring. In addition, host, environmental, or other cofactors are likely to be important determinants of susceptibility.