We found that human saliva contains both insulin-like growth factor I (IGF-I) and IGF-II but no significant binding proteins, and that salivary IGF-I levels correlated with plasma GH levels. Mixed saliva had globular proteins precipitated by freezing/thawing. After centrifugation the clear supernatant was used directly in the IGF-I RIA (Van Wyk and Underwood antibody) and in a human placental membrane RRA for IGF-II. The lower limits of detection for IGF-I and IGF-II were 0.7 ng/mL (micrograms/L) and 1.2 ng/mL (micrograms/L), respectively. Iodinated IGF added to saliva was not degraded, as assessed by trichloroacetic acid precipitability and placental membrane binding. In saliva from 14 normal subjects, IGF-I was measurable in all. IGF-II was detectable only in 8 of 14 subjects; the mean value in these 8 subjects was 2.6 +/- 0.6 (+/- SE) ng/mL (micrograms/L). The mol wt of salivary IGF was similar to that of free plasma IGF after acid or neutral pH gel chromatography. Human saliva contained no significant IGF-binding protein. Eluates from neutral gel chromatography of concentrated (20-fold) normal saliva did not inhibit IGF-II binding to placental membrane receptors. Eluted proteins from saliva samples subjected to prior acid gel chromatography failed to bind radiolabeled IGF after neutralization. Saliva samples assayed for binding protein using an amniotic fluid binding protein RIA had values at or below the lower limit of detection [less than 0.06 micrograms eq/mL (mgeq/L)]. Salivary IGF-I concentrations did not change with increasing salivary flow rates above normal, with time of day, or with storage at room temperature for up to 24 h before freezing. The mean IGF-I concentration in mixed saliva from 14 normal young adults (8 men) was 2.3 +/- 0.3 (+/- SE) ng/mL (micrograms/L), and their mean plasma IGF-I level was 315 +/- 27 ng/mL (micrograms/L). Mean salivary IGF-I was significantly lower in 15 patients with GH deficiency [1.3 +/- 0.2 ng/mL (micrograms/L); P less than 0.01] and 8-fold higher in 5 acromegalic patients [17.2 +/- 6.3 ng/mL (micrograms/L); P less 0.01]. Removal of their GH adenomas led to a fall in salivary IGF-I to 5.6 +/- 1.3 ng/mL (micrograms/L); P less than 0.05). In summary, saliva contains free IGFs but no significant quantities of specific binding proteins. Salivary IGF-I levels reflect the GH status of the donor.

Insulin-like growth factor-I (IGF-I) is a GH-dependent growth factor found in its highest concentrations in plasma. It is also measurable in saliva. The origins of salivary IGF-I concentrations were studied. Intracardial administration of Sprague-Dawley rats with 125I-labelled IGF-I and subsequent analysis of plasma and saliva samples by exclusion gel chromatography and SDS-PAGE, followed by autoradiography, demonstrated the apparent inability of IGF-I to cross from the plasma pool through to saliva. 125I-Labelled IGF-I was not chromatographed immediately before injection, resulting in administration of free iodide along with the iodinated peptide. This free iodide was demonstrable in saliva, indicating that movement of substances from plasma to saliva was measurable using the levels of 125I activity administered. Free iodide in saliva was not contributed to by 125I-labelled IGF-I degradation since 125I-labelled IGF-I was shown to be stable in saliva over 24 h. These data indicated that IGF-I in saliva is produced locally. Identification of a 4.7 kb IGF-I mRNA transcript in rat parotid salivary gland was consistent with IGF-I synthesis within that tissue.

The chronic administration of the long-acting LHRH agonist analog D-Ser(TBU)6-LHRH-EA10 (HOE 766, Buserelin) suppresses pituitary gonadotropin secretion. Since a similar analog was shown to be effective in the short term parenteral treatment of idiopathic precocious puberty in girls (10), we used Buserelin both intranasally and sc to treat patients of both sexes with idiopathic and secondary central precocious puberty to test its efficacy, safety, and potential for long term use. Six girls and two boys presented with advanced skeletal maturity, accelerated growth velocity, Tanner stage II-IV pubertal development, and pubertal levels of sex steroids and gonadotropins. Patients were treated for 6 months sc and up to 5 months intranasally. Optimal doses ranged from 10-20 micrograms/kg X day in girls and 30 micrograms/kg X day in boys, with marked individual variation. During sc therapy, there was significant suppression of growth velocity (P less than 0.001), serum gonadotropins (P less than 0.001), 17 beta-estradiol (P less than 0.005), and testosterone as well as clinical and behavioral improvement. The rate of bone maturation was reduced. All effects were reversed after discontinuation of therapy for 1 month in one girl. No reduction in efficacy was seen after changing four girls and one boy to intranasal therapy, but improved acceptability and compliance were reported by parents. Apart from withdrawal bleeding in one girl and transient acceleration of puberty in two patients during the initial phase of treatment, no serious unwanted effects occurred. Antibodies to native LHRH were not detected after 6 months of therapy. These results confirm the efficacy and safety of Buserelin by intranasal and sc routes in patients with sexual precocity and indicate a need for long term studies.

treatment of congenital dislocation of the knee. J Bone Joint Surg 1967;49-B:112-20. 4. Curtis BH, Fisher RL. Congenital hyperextension with anterior subluxation of the knee. J Bone Joint Surg 1969;51-A:255-69. 5. Laurence M. Genu recurvatum congenitum. J Bone Joint Surg 1967;49-B:121-34. 6. McFarlane AL. A report on four cases of congenital genu recurvatum occurring in one family. Br J Surg 1947;34:388-91. 7. Provenzano RW. Congenital dislocation of the knee. N Engl J Med 1947;236:360-2. 8. Chapple CC, Davidson DT. A study of the relationship between fetal position and certain congenital deformities. J Pediatr 1941; 18:483-93. 9. Browne D. Congenital deformities of mechanical origin. Arch Dis Child 1955;30:37-41. 10. Boorstein SW. Congenital backward dislocation of the knee. Am J Dis Child 1929;38:107-11. 11. Vaughn VC, McKay RJ, eds. Nelson's textbook of pediatrics. Philadelphia : WB Saunders, 1979. 12. Middleton DS. The pathology of congenital genu recurvatum. Br J Surg 1935;22:696-702. 13. Carlson DH, O'Connor J. Congenital dislocation of the knee. AJR 1976:127:465-8. 14. Rao BS, Rao BS, Rao AS. Congenital dislocation of the knee joint. Int Surg 1975;60:32-3. 15. Larsen LJ, Schottstaedt ER, Bost FC. Multiple congenital dislocations associated with characteristic facial abnormality. J Pediatr 1950;37:574-81. 16. Weiss SM, Brooks DB. A simplified method of splinting for congenital dislocation of the knee. Clin Orthop CONCURRENT USE of other medications maỹ~O NCURRENT USE of other medications mayhave an effect on oral anticoagulant therapy (Table 1). We wish to bring to the attention of pediatricians a major clinical problem resulting from simultaneous administration of warfarin sodium (~oumadin~') and L-thyroxine. Case ReportA 13-year-old girl presented at The Hospital for Sick Children, Toronto, with short stature and decreasing height velocity over the previous 5 years. She had undergone total repair of a tetralogy of Fallot at the age of 5 years and was then placed on digoxin and a combination of spironolactone and hydrochlorothiazide (Aldactazide~'). At the age of 1 years, prosthetic pu~monary and aortic valves were implanted. The preoperative coagulation results were as follows: prothrombin time (PT) 11.3 seconds (controls 10-12 seconds), partial thromboplastin time (PTT) 38.5 seconds (controls 25-40 seconds), and platelet count 174,000/Al. There was no family history of a bleeding diathesis. After surgery, the child required warfarin 7.5 mg daily to maintain the PT at 1.5 to 2.0 times baseline values. She continued to take digoxin and Aldactazide but did not receive antiplatelet medication, and the platelet counts remained normai postoperatively. On this current admission 2 years postoperatively, the child's height was 120 cm (<3rd percentile), weight was 36 kg (<10th percentile), and height increment over the preceding 12 months was 2.5 cm. Heart rate was 90/minute and blood pressure 90/60. She appeared hypothyroid with coarse features, dry skin, and dry hair. The relaxation phase of her ankle reflexes...

A double antibody RIA was developed for the measurement of the long-acting GnRH agonist D-Ser(TBU)6EA10GnRH (buserelin). The antibody, raised in rabbits against a buserelin-hemocyanin conjugate, reacted with the intact molecule and also molecular fragments containing the C6-9 tetrapeptide sequence and permitted the measurement of buserelin activity in serum and urine. Natural GnRH, LH, and FSH did not cross-react in this assay system. The assay was applied to samples obtained from children receiving buserelin for the management of central precocious puberty either by once daily injection of 30 micrograms/kg or by nasal spray (in; 200 micrograms every 8 h). Urine and serum samples, chromatographed on Sephadex G-25, contained immunoreactive material corresponding closely in molecular size to [125I]buserelin. In unextracted serum samples taken at intervals after sc therapy in 11 girls, the peak immunoreactive buserelin levels of 52.2 +/- 14.8 ng/ml (mean +/- SEM) occurred at 30 min. The half-time of elimination was 74.9 +/- 36.9 min. Approximately 30% of the dose was detected in urine collected for 3 h after injection. Similar data were obtained in 3 normal adults given 10 micrograms/kg buserelin, iv. By contrast, after the administration of 200 micrograms buserelin by metered nasal spray, the mean peak serum concentration in 10 girls was 100-fold less (0.65 +/- 0.14 ng/ml), although the halftime of elimination was almost identical. Only 0.73% of the nasal dose was excreted by 3 h. Calculated relative bioavailability data indicated maximal nasal absorption of 6%. However, absorption after nasal administration varied greatly, and in 2 children, serum and urinary concentrations of buserelin after supervised administration were negligible. We conclude that in buserelin therapy, in the dose used in this study, does not represent optimal treatment for the initial management of patients with precocious puberty. The success of in therapy in sustaining initial effects of buserelin given by sc administration presumably reflects changes in receptor sensitivity induced by sc treatment.

The histological distribution of insulin like growth factor 1 (IGF 1) receptors in the rat gut was studied.

The "empty sella" (ES), a common entity in adults, is so named because a cerebrospinal fluid-filled arachnoid hernia fills the pituitary fossa and compresses the pituitary gland, creating the illusion of an "empty" sella. We report our experience of ES in childhood. Our four cases represent associations with ES that have not been previously described in childhood: case 1 was associated with central precocious puberty; case 2 with secondary ES resulting from shrinkage of a prolactinoma during bromocriptine therapy; case 3 with pseudotumor cerebri; and case 4 with no significant pathology. Together, they account for approximately 1 percent of cases of radiographically enlarged sella tursica investigated here. This brings the number of cases of ES reported in children to 27. Review of these 27 cases reveals seven with local skull dysplasia and/or a familial inheritance. The remainder lacked clinical homogeneity or similarity to the common adult variety of ES. Children with ES did not exhibit the higher female preponderance reported in adults with ES. They showed a higher frequency of secondary cases (4/27), and of associated endocrine (10/15) and visual (8/17) abnormalities than is seen in adults with the "empty sella."

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