Richard E. Hillman

Growth hormone-dependent growth failure

Growth failure may be associated with low serum somatomedin concentrations despite normal to increased concentrations of serum growth hormone. We have recognized five patients who responded to GH administration with an increase in serum Sm and an acceleration in skeletal growth, and have characterized the circulating GH in an homologous human GH radioreceptor assay employing the IM-9 lymphocyte as a source of human GH receptor. These five prepubertal children, who had a mean height 7.8 SD below the mean for age, had a mean RIA-GH of 34.2 +/- 3.5 ng/ml in response to stimulation, a basal Sm activity by hypophysectomized rat cartilage bioassay of less than 0.3 IU/ml, and a mean peak Sm of 0.9 +/- 0.1 IU/ml in response to 48 hours of GH therapy. During a one-year trial of GH therapy, four of these children significantly increased their growth velocity as compared to their growth rate before GH therapy. These children had a mean RIA-GH/RRA-GH ratio of 2.f. The fifth patient had a low RIA-GH/RRA-GH ratio and had no increase in growth rate. These studies suggest that growth in certain growth retarded children may be dependent on exogenous GH, even though they are not GH deficient by standard criteria.

Clinical pharmacology of hexachlorophene in newborn infants.

Bathing with soap containing hexachlorophene was instituted during two major staphylococcal epidemics in a Neonatal Intensive Care Unit. Infants who weighed less than 1,200 gm, those with a postconceptional age of less than 35 weeks, and those with large areas of abraded skin were at highest risk to achieve elevated blood HCP concentrations. T 1/2 of HCP ranged from 6.1 to 44.2 hours and appeared to follow first order kinetics. Time of peak blood concentrations of HCP following a bath ranged from 6 to 10 hours. One infant with liver disease achieved a concentration of HCP of 4,350 ng/ml after seven baths and developed clinical symptoms consistent with HCP toxicity.

Sanfilippo A syndrome in the fetus

A family is reported in which Sanfilippo A syndrome affected three siblings: the proband and twin premature infants. The feasibility of intrauterine diagnosis of mucopolysaccharidoses (MPS) Type IIIA, was demonstrated by the excessive accumulation of 35SO4‐ mucopolysaccharides in fibroblasts cultured from amniotic fluid obtained by amniocentesis. Cross‐correction studies and enzymatic analysis of cultured skin fibroblasts from the proband and the infants revealed the absence of the MPS IIIA correction factor, heparan sulfate sulfatase. However, when the premature infants expired shortly after birth, no central nervous system histopathology or ultrastructural abnormalities were found. From these observations it would appear that the third trimester fetus with MPS type IIIA has little CNS involvement.

Biotin-responsive propionic acidemia presenting as the rumination syndrome†

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Brain Tissue Levels in a Fatal Case of Neonatal Mepivacaine (Carbocaine) Poisoning.

A fatal case of mepivacaine poisoning in a newborn infant is reported. Regional brain tissue concentrations of mepivacaine were determined by a sensitive and specific gas chromatographic-mass spectrometric method. The brain tissue levels in this patient were higher than those previously reported, possibly due to alkalosis occurring several hours prior to the infants death.

Elevation of postmortem triiodothyronine in sudden infant death syndrome and in infants who died of other causes: A marker of previous health

We measured serum concentrations of thyroxine (T4), triiodothyronine (T3), reverse T3, free T4, thyroid-stimulating hormone, and cortisol in 62 victims of sudden infant death syndrome (SIDS) in 30 infants who died of known causes and in 15 living controls. The mean T3 value was elevated in 69% of those with SIDS. 37% of the others who died, and in no control infants. After excluding those who died of known cause who had abnormal thyroid function (abnormal postmortem concentrations of T4, free T4, or reverse T3), the T3 values were elevated in 63% of those remaining. When the data were analyzed on the basis of case histories and autopsy findings, those infants who were in good health and died suddenly of accidental causes had an elevation in mean T3 similar to that seen in SIDS victims; those who died under conditions known to alter thyroid metabolism did not. The T4, free T4, reverse T3, thyroid-stimulating hormone, and cortisol values were not useful in differentiating those with SIDS from the living controls, or those who were healthy at the time of death. We were unable to find any difference in T3 serum concentrations between the total group who had SIDS and those who had SIDS with minor infections, with petechiae on intrathoracic organs, with premature birth, or those who were resuscitated. Our data point out the importance of using appropriate controls when evaluating SIDS. The normal reverse T3 values in SIDS, as well as confirmation of the normal T4 and free T4 values, constitute evidence against chronic persistent alveolar hypoventilation or prolonged episodes of hypoxia immediately preceding death from SIDS.

Megavitamin responsive aminoacidopathies.

Several different vitamins, primarily members of the B complex, serve as coenzymes which activate apoenzymes to produce active holoenzymes. These cofactors participate in reactions in various ways. Even after a specific enzyme diagnosis is made in a patient, it is difficult, if not sometimes impossible, to determine if the patient will respond to a specific cofactor in vivo. The safety and ease of administering these compounds demand that therapeutic trials be undertaken. Doses (see Table 1) of several hundred to several thousand times the normal daily requirements must be given to the patient parenterally or by mouth. The studies in patients with B6-responsive disorders and with maple syrup urine disease would indicate that long term trials of these agents should be given even if there is no short term response. When efficacious, these compounds greatly simplify therapy for patients with inborn errors of amino acid metabolism.

Isoleucine transport by cultured human fibroblasts. II. Selection of a cell line with reduced isoleucine uptake

Isoleucine uptake was studied in fibroblasts cultured from a patient with a defect in isoleucine metabolism. These fibroblasts after successive passage in a medium low in isoleucine (nutrient Mixture F-12) had been shown previously to lack the sodium-dependent isoleucine uptake seen in normal cell lines. In the present report the cells were shown to undergo additional changes in isoleucine uptake when grown in a medium high in isoleucine (Eagles minimal essential medium). The fibroblasts were no longer able to concentrate isoleucine. The apparent Km values for isoleucine were not different from those of the parent F-12 cell line. However, the apparent V values were somewhat reduced and the apparent diffusion constant was over two times greater. The cells, like the parent cell line did not display sodium-dependent uptake and were ouabain insensitive.

STUDIES ON KETOTIC HYPERGLYCINEMIA-INHIBITORS OF SERINE HYDROXYMETHYL TRANSFERASE

Recently Hillman and Otto showed tiglic acid to inhibit glycine-serine interconversion in fibroblasts from a patient with β-ketothiolase deficiency and normal cells. In order to elucidate the mechanism of these phenomena, the effects of tiglyl CoA and related compounds on partially purified rabbit liver serine hydroxymethyltransferase (SHMT) were investigated. The rate of conversion of serine to glycine was measured as described by Schirch. Using SHMT 27. 7 units/ml, serine 16mM, and dl-L-tetrahydrofolate 0.32mM, the concentration of tiglyl CoA and % inhibition (N=5, Mean ±S. E. M.) of the enzyme activity were 2.5mM 15±1.5, 5.0mM 28±2.4, 7.5mM 40±2.8, 10mM 41±3.3. Isovaleryl CoA, n-valeryl CoA, crotonyl CoA and isobutyryl CoA also showed inhibitory effects, but at a lesser degree than tiglyl CoA. n-Butyryl CoA, propionyl CoA and CoA inhibited only slightly. Tiglate, isovalerate, n-valerate, crotonate, isobutyrate and β-methylcrotonate at a concentration of 30mM were incapable of inhibiting SHMT activity. Tiglyl CoA inhibition showed competitive kinetics with tetrahydrofolate, but not serine. The findings suggest that impaired glycine-serine metabolism in the ketotic hyperglycinemia syndrome may, at least in part, result from inhibition of SHMT by high intracellular concentration of Tiglyl CoA.

859 SERUM 24,25 DIHYDROXY VITAMIN D CONCENTRATIONS IN LACTATING AND NON-LACTATING POST PARTUM WOMEN

In aminal systems prolactin (HPL) increases 1,25 dihydroxy vitamin D (1,25(OH)2D) and decreases 24,25 dihydroxy vitamin D (24,25(OH)2D) synthesis. 24,25(OH)2D is low during pregnancy with normal serum PTH. During pregnancy, serum HPL and other hormones are increased, but during lactation only HPL remains elevated. We studied lactating mothers and non-lactating controls for 24,25(OH)2D, 250HD, PTH, HPL, calcium and magnesium at 6 weeks post partum. In nursing mother 24,25(OH)2D was significantly lower than normal or post partum controls. During lactation only there was an inverse correlation between HPL and 24,25(OH)2D (R=-.51) and PTH and 24,25(OH)2D (R=-.47). During lactation there was no correlation between 24,25(OH)2D and 250HD (R=.18). Thus, changes in vitamin D metabolism probably mediated by HPL and PTH may enable the lactating woman to maintain normal serum calcium and magnesium while providing for milk production.