Short stature as a screening test for endocrinopathy in slipped capital femoral epiphysis.

Slipped capital femoral epiphysis may be associated with hypothyroidism and other endocrinopathies. Routine screening for such abnormalities is unlikely to be cost-effective since the overall incidence of these disorders, in association with slipped capital femoral epiphysis, is low. The identification of a presenting characteristic which would predict the chance of an associated endocrinopathy would allow only selected children to be screened. Our aim was to determine if certain characteristics were useful as a screen for patients with an underlying endocrinopathy who presented with slipped capital femoral epiphysis. Between January 1988 and December 1996 we recorded gender, age, height, unilateral or bilateral involvement and an associated diagnosis of endocrinopathy for all patients who were treated for slipped capital femoral epiphysis. Of 166 such patients 13 (7.8%) had an endocrinopathy. Height was the only useful screening characteristic, although bilateral involvement was more likely in those with an endocrinopathy. Most (90.9%) of this latter group were below the tenth percentile for height compared with only 5.4% in those who did not have an endocrinopathy (p < 0.005). The sensitivity and negative predictive value of detecting an underlying endocrinopathy in a patient presenting with a slipped capital femoral epiphysis and short stature (tenth percentile or less) were 90.2% and 98.6%, respectively. Patients who are on or below the tenth percentile for height at the time of presentation should be screened for a possible endocrine abnormality using measurement of thyroid-stimulating hormone and free thyroxine as a preliminary screening test. These hormones are most likely to be abnormal in the presence of endocrine dysfunction.

Co-amplification and overexpression of CDK4, SAS and MDM2 occurs frequently in human parosteal osteosarcomas.

Amplification of genes in the 12q13-15 region occurs frequently in several malignancies including osteosarcoma. The products of these amplified genes are thought to provide cancer cells with a selective growth advantage; however, the specific gene(s) driving this amplicon is unknown. We have previously shown that the SAS gene is amplified in most parosteal osteosarcomas. In this study we analysed additional putative growth regulatory genes in this chromosomal region in 24 primary osteosarcoma specimens. CDK4 and SAS were coamplified in 6/6 parosteal tumors, and MDM2 was also amplified in 4/5 parosteal cases. In comparison, amplification occurred in only 2/16 classical intramedullary osteosarcomas and involved the SAS gene. Each amplified gene had a correspondingly elevated mRNA level. Four high grade intramedullary tumors had elevated mRNA expression of SAS, but did not exhibit gene amplification. Gene amplification/overexpression was not associated with metastatic disease and did not change markedly with tumor progression, as evidenced by analysis of sequential tumor specimens from eight patients. Three other genes in the 12q13-15 region (CDK2, WNT1 and WNT10b) were not amplified in any of the tumors. The different patterns of gene amplification and overexpression of CDK4, SAS and MDM2 in parosteal and intramedullary osteosarcomas may help explain the disparity in the biological behaviour of these two types of osteosarcoma.

SAS is amplified predominantly in surface osteosarcoma.

The development of several types of human tumors is related to amplification of genes that are involved in cell growth. The protein products of these genes give the cells a selective growth advantage. The q13-15 region of chromosome 12 is frequently altered in human sarcomas, and the SAS gene has been identified in an amplification unit mapping to this region. Gene amplification of SAS was analyzed to determine the frequency of genetic alteration of this gene in osteosarcoma. Using Southern blot analysis as well as quantitative polymerase chain reaction, SAS was found to be amplified in 10 (36%) of 28 osteosarcomas. Gene amplification was evaluated in subtypes of osteosarcoma. All seven surface osteosarcomas displayed amplified SAS. In contrast, SAS was amplified in only two (13%) of 15 intramedullary osteosarcomas. The finding that all surface osteosarcomas demonstrated SAS gene amplification suggests that this gene may play a role in the pathogenesis of osteosarcoma subtypes and that surface osteosarcoma may be genetically different from high-grade intramedullary osteosarcoma.

Phenytoin cumulation kinetics.

Four male subjects were given phenytoin orally in single or twice-daily doses. Subjects were on 2 or 3 different dosing rates from 260 to 600 mg phenytoin sodium daily. Predose blood samples were obtained almost daily. The resulting serum levels, measured by gas-liquid chromatography, ranged from 1 to 18 micrograms/ml. Serum phenytoin concentration-time data were fit to a 1-compartment open model with zero-order input and Michaelis-Menten elimination. The resulting computer-generated parameter estimates (Vmax, 5.28 to 8.41 mg/kg/day; Km, 0.83 to 4.18 mg/1; Vd, 0.74 to 0.97 1/kg) are in agreement with the ranges of values in the literature. The time course of phenytoin cumulation is compatible with the presence of a major elimination pathway exhibiting Michaelis-Menten kinetic behavior.

Dose-dependent pharmacokinetic behavior of lidocaine in the conscious dog.

The apparent steady state blood concentration of lidocaine in dogs depends on the animal's lidocaine treatment history. For example, an infusion of 50 microgram/Kg/min X 240 min followed immediately by an infusion of 125 microgram/Kg/min X 240 min yields steady state lidocaine levels which are consistent with a linear drug dispositional system. However, when the sequence of these infusions is reversed the apparent steady state level during the low infusion rate step is much greater than those predicted from the steady state level observed during the high infusion rate (assuming a linear dispositional model). These data suggest that high dose lidocaine infusion treatment alters the dog's ability to clear lidocaine during a subsequent low infusion rate treatment period.

Bupivacaine and other amide local anesthetics inhibit the hydrolysis of chloroprocaine by human serum.

The rate of hydrolysis of chloroprocaine by human serum was studied in the presence and absence of a number of aminde local anesthetics and their metabolites. Bupivacaine (2.4 microgram/ml) and etidocaine (2.3 microgram/ml) caused 38% and 21% inhibition respectively of the rate of chloroprocaine hydrolysis. Circulating concentrations of these drugs have been reported in this range by several investigators following epidural doses of 150 to 400 mg of either drug. Mepivacaine, lidocaine, and two lidocaine metabolites (glycine xylidide and monoethylglycine xylidide) were only inhibitory at levels much greater than those seen in blood following the usual local anesthetic doses of the parent compounds. Since serum is an important site of chloroprocaine metabolism in man, the probability of chloroprocaine intoxication may be increased when it is administered with local anesthetics such as bupivacaine and etidocaine.