Thomas Aceto

Human Dicentric Y Chromosomes: Case Report and Review of the Literature

A phenotypic female with histological evidence of mixed gonadal dysgenesis, and 45,X/46,X,dic(Yq) mosaicism is described. A review of the literature yielded 15 additional cases of dicentric Y chromosomes. Among the cases, a wide range of variation in phenotype, external genitalia, histology, and chromosomal findings was observed. Factors possibly contributing to such variability are discussed and include: the exact site of breakage and exchange in the Y chromosome; the timing of dicentric formation (meiotic vs mitotic); the occurrence of non-disjunction; and the presence or absence of a Y chromosome in cells of the gonadal anlage during a critical ontogenic period.

Conjugated and Unconjugated Plasma Androgens in Normal Children

Extract: Methods developed in this laboratory permit measurement of the androgens, testosterone (T), dehydroepiandrosterone (D), and androstenedione (Δ) on a 10-ml sample of plasma. We have determined concentrations of the unconjugated androgens (T, Δ, D) as well as of the sulfates of dehydroepiandrosterone (DS) and androsterone (AS) in the plasma of 85 healthy children of both sexes from birth through the age of 20 years. Our results are shown and summarized, along with those of other investigators.Testosterone was elevated in both sexes in the newborn as compared with the 1-8-year-old group. In contrast, sulfated androgens, with one exception, were undetectable early in life. In males, there was a marked rise in all androgens, especially T, in the 9-18-year-old group. The increase in plasma androgens occurred before clinical manifestations of increased androgens became evident. In females, there was only a modest increase in plasma androgens in the 9-18-year-old group except in the case of A which did not change. The greatest increases were in D, DS and AS. This is the first report of unconjugated androgen concentrations in the adolescent female.Speculation: Measurement of the plasma androgens will aid in evaluation of children with sexual infantilism or sexual precocity. The prepubertal rise in plasma testosterone in males may be accompanied by a higher level of plasma protein binding than that which is found after puberty becomes evident.

Treatment of Young Cretins With Triiodothyronine

Abstract Ten cretins diagnosed before the age of 1 yr were treated initially with triiodothyronine. Close monitoring of the patients with special emphasis on their cardiac status showed rapid achievement of a euthyroid state without the development of any significant cardiac dysfunction. It is concluded that triiodothyronine is a safe drug in the initial treatment of cretins.

Effects of Human Growth Hormone (HGH) on 79 Hypopituitary Children

We have treated 58 idiopathic (IH) and 16 organic hypopituitary (OH) children for 12 months, using 5 treatment regiments, in order to determine optimum therapy with HGH and glucocorticoids. All patients had: growth hormone levels < 5 mμg/ml plasma during insulin induced hypoglycemia; bone ages of 12 years or less; sexual infantilism. In IH, height wa −4 SD or further below the mean. In OH, pretreatment growth rate was below 2.5 cm/year. Listed are 5 treatment regimens and growth rates during therapy.Conclusions: HGH stimulated linear growth of hypopituitary children to varying degrees; more effectively in younger smaller dwarfs, less effectively in the older larger or cortisone treated dwarfs. HGH from embalmed bodies is clinically useful. HGH, 10 U., was not more beneficial than 2 U. The craniopharyngiomas in the OH did not grow during short-term treatment with HGH.

SINGLE DAILY DOSE OF ANTITHYROID MEDICATION IN ADOLESCENTS WITH HYPERTHYROIDISM

Many adolescent patients with hyperthyroidism fail to take antithyroid medication several times daily and, consequently, remain hyperthyroid. Greer, (NEJM,272:888,65) and Barnes, (JCEM,35:250,72) have reported successful therapy of hyperthyroid adults using a large single daily dose (SDD) of propylthiouracil (PTU) or methimazole (M). We have studied 9 adolescents with hyperthyroidism, 7 initially treated with a SDD of PTU (300mg/m2/24hr) and 2 with a SDD of M(30mg/m2/24hr). Over a 3 month follow-up period, we have monitored several parameters: symptoms of patient; opinion of physician re: thyroid status; weight change; goiter size; WBC, and serum thyroxine(CPB). After 3 months, 5 patients were asymptomatic and 4 patients experienced minimal symptoms. The physician considered 2 patients euthyroid and 7 definitely improved but slightly hyperthyroid. Gain in weight, expressed as mean ±S.E. was 3.0 ± 1.3kg (range:−2.5 to 10.9); P<0.035. Goiter size decreased in 7, remained the same in 1, and increased in 1 patient. At no time did the WBC fall below 4,000/cc in any of the 9 patients. Initial thyroxine level was 21.6 ± 1.7ug%, (range 18.1 to 31.0). Decrease in thyroxine was 10.0 ± 2.2 (range 2.0 to 24.8). Although follow-up has been relatively short, these results suggest that a SDD of antithyroid medication is successful and safe in inducing a remission in adolescents with hyperthyroidism and would enhance compliance.

A Model for the Circadian-Episodic Secretion of Cortisol

Cortisol measurements were made on plasma obtained every 30 min. for 25 hrs. In a model using a catenary system consisting of adrenals and a body compartment, a cosine function was assumed to reflect the circadian variation in adrenal synthesis of cortisol, a switch function to describe its episodic release and first order kinetics to describe plasma clearance. Data was subjected to computer non-linear regression analysis to obtain least square estimates of model parameters. A correlation coefficient of 0.94 was obtained. Results (mean ± 1 S.D.) on 7/8 normal children (5-17 yrs.) are as follows. Adrenal secretory rate (SR) was 312 ± 84 ug/hr/m2 (or 7.5 ± 2.0 mg/d/m2) with an amplitude of 255 ± 57 ug/hr/m2 giving a mean maximum and minimum SR of 567 and 57 ug/hr/m2, respectively. Adrenal was maximally on 22% of the day and slowly secreting 54%. The results indicate that troughs of plasma cortisol concentration are caused by diminished secretion rather than lack of secretion. Maximal secretion occurred at 7.9 ± 1.9 hrs.A.M. Plasma clearance of cortisol was 104 ± 24 l/d/m2 corresponding to a half-life of 58 ± 11 min. Apparent adrenal content of cortisol equivalents was 337 ± 199 ug/m2(4.5% SR). This method has great potential for assessing adrenocortical metabolism during stress or during glucocorticoid therapy.

1088 CLINICAL CORRELATIONS OF CSF ENDOTOXIN-LIKE ACTIVITY IN GRAM-NEGATIVE MENINGITIS

Detection of endotoxin-like activity (ELA) in cerebrospinal fluid (CSF) by limulus amebocyte lysate (LAL) gelation has been suggested to be a useful technique for diagnosis of gram-negative meningitis. We prospectively screened 1503 CSF specimens with a microassay utilizing 20 μl of CSF added to 20 μl of limulus reagent on an endotoxin-free slide. Specimens and controls were observed for gel formation after 60 minutes incubation at 37°C in a moisture chamber. Serial dilutions of CSF were used to quantitate ELA. The limit of sensitivity of the assay was 0.01 ng/ml. All ELA positive (+) specimens were subjected to confirmatory retesting, after which 49 (3.3%) were ELA (+). Comparison with the 38 available culture results revealed that 33 specimens (87%) were culture (+), that 3 of the 5 culture negative (-) specimens were from patients on therapy for gram-negative meningitis and a fourth was from a neonate. Overall specificity of the test was 99.6% with a (+) predictive value of 86.8%. There was one false (-) specimen giving an overall sensitivity of 97.4% but a (-) predictive value of 99.9%. ELA values > 150 ng/ml correlated with the occurrence of seizures (p<0.05), levels > 3000 ng/ml with peripheral leukopenia and hypoglycorrhachia (p<0.02), and levels > 5×104 ng/ml with death (p<0.005). We conclude that LAL micromethod gelation test is a sensitive, specific, simple screening test for gram-negative meningitis that exhibits prognostic value.

121 MANAGEMENT OF INFANTS WITH UNIVENTRICULAR HEART

With definitive repair for the univentricular heart now available, review of the management of infants with this defect is important. Twenty-eight infants were seen at less than ly and followed for 8m-17y (mean=73m). All had cardiac cath. Eight who died had autopsy; 18 had single left ventricle with an outlet chamber, and 10 had other types; 13 had pulmonary stenosis (PS) and 7 pulmonary atresia (PAtr.); 8 had no PS; 4 had coarctation; and 1 subaortic stenosis. Nine patients (pts.) with severe cyanosis had 13 systemic-pulmonary artery (SA-PA) shunts (8 Blalock-Taussig, 5 Ao-PA with Impra graft); the initial shunt was done at ld-6m, and the second at 3m-14y; there was no operative death, but 4 died later. Two pts. with PAtr. and 1 with coarctation died without surgery. Of 6 pts. with pulmonary hypertension (PH) and PA banding (PAB) at 2-20m, 4 survived, 2 died. Three pts. had no surgery and are doing well. Of the total group of 28 pts., 20 survived beyond ly of age. Ten pts. subsequently had more surgery (7 Glenn shunt, 2 Fontan, and 1 ventricular septation & Rastelli procedure) and 3 pts. died. The overall mortality was 39.3% (11/28); 8 of them had PS. The prognosis is better if pts. survive beyond infancy. Most surviving pts. had clinical improvement. Pts. with severe PS need SA-PA shunts, and pts. with PH need PAB at an early age. If palliative procedures are successful, the pt. could undergo Glenn procedure and Fontan procedures at an older age.

792 FACTOR VIII INHIBITOR RESPONSE TO CYCLOPHOSPHAMIDE (C)

Immunosuppressive therapy for Factor VIII inhibitors has been studied by different investigators with variable results. Over a 6 year period, 68 patients with Factor VIII inhibitors were randomized into 3 separate protocols:The high responder group showed 3 separate patterns: 1) reduction of inhibitor & prevention of anamnestic response as long as cyclo-phosphamide therapy was maintained; 2) disappearance of inhibitor & no recurrence when exposed to Factor VIII after cyclophos-phamide therapy termination; 3) persistence of inhibitor but in low responder range without anamnestic response to Factor VIII infusions after cyclophosphamide therapy termination. Controls developed an anamnestic inhibitor response each time they were exposed to Factor VIII. The low responder group showed 2 patterns: 1) disappearance of inhibitor without recurrence when exposed to Factor VIII; 2) persistence of inhibitor in low responder range. The low responders reacted the same during immunosuppression & after termination of the immunosuppression therapy. Controls showed the same results as the protocol group. It is evident from these results that immunosuppression was apparently unnecessary for the low responders but gave beneficial results with the high responders.

179 POST-OPERATIVE ASSESSMENT OF FONTAN OPERATION

From 1975 to 1980, 10 patients (pts.) age 2.5-24 years (y)(mean 13.6±6y) had modified Fontan operation for tricuspid atresia (7), univentricular heart (2), and transposed great vessels (1). Six had right atrial (RA) to pulmonary artery (PA) anastomosis (ANS), 4 with valved conduit and 2 direct ANS. Four had RA to right ventricular (RV) ANS, 1 with a non-valved conduit and 3 direct ANS. Eight pts. also had Glenn shunts. All 9 survivors are in normal sinus rhythm. Seven pts. had cardiac catheterization 2-60 months (m) post-operatively (post-op)(median 8m). RA mean pressures (p) were 3-19mmHg with RA ‘a’ waves of 10-25mmHg. Pts. with RA-PA ANS had narrow PA pulse p of 2-3mmHg, while pts. with RA-RV ANS had wider, biphasic PA pulse p due to RV contractions. No RA-PA p gradients were present. Aortic saturation was 79%±9 pre-operatively (pre-op) and 95%±3 post-op; left ventricular (LV) end diastolic p was 7.0±5.8mmHg pre-op and 6.7±1.9 post-op. RA regurgitation into hepatic veins and coronary sinus was more marked in pts. with RA-PA ANS. Post-op LV contractility was decreased in all (average LV ejection fraction 53.2%±12) except the youngest pt. While all pts. had improved exercise tolerance post-op, treadmill testing in 5 was impaired with average duration of 6.9 minutes, and maximal endurance index of 238±49 (normal 344±65). These data suggest that RA-RV ANS results in better forward flow and less regurgitation than RA-PA ANS. Exercise tolerance and oxygenation improved post-op but most pts. have clinical and angiographic evidence of decreased cardiac function.