PURPOSE: To examine the relationship between the objective premedical credentials and performances on Step 2 on the United States Medical Licensing Examination (USMLE) of 480 students in three classes at the Virginia Commonwealth University Medical College of Virginia School of Medicine. The purpose of the study was to seek those selection criteria that might best predict performance on an examination designed to assess problem-solving skills, the essence of clinical medicine. METHOD: Premedical data from two classes (1193, 1994) were analyzed, and a regression equation was used to calculate theoretical USMLE Step 2 scores for the students in the class of 1995, who had not yet taken this examination. The premedical variables were scores on the verbal and math section on the Scholastic Aptitude Test (SAT), scores on the six sections of the pre-1991 Medical College Admission Test (MCAT), grade-point average (GPA) in science courses required of premedical students, and undergraduate major. Once the class of 1995 had taken the USMLE Step 2, the equation was cross validated, and the theoretical and actual scores of the class of 1995 were correlated. RESULTS: The correlation between theoretical and actual scores was r = .443. In the analysis for the classes of 1993 and 1994, the single variables most highly predictive of USMLE Step 2 performance were scores on the verbal section of the SAT (r = .317) and the Skills Analysis: Reading section of the MCAT (r = .331). However, the MCAT scores were excluded from the final regression analysis because of the pre-1991 MCAT cannot be useful in predicting the performances of present medical school applicants. The resulting regression equation (using the SAT verbal section and premedical GPA) was able to account for 21.2% of the variance for the class of 1995. CONCLUSION: The use of the verbal section of the SAT as a predictive factor is unique. It is significant that this variable was strongly related to premedical GPA, suggesting that high verbal aptitude serves one well, even when coping with complex scientific concepts.

Aptitude↗

PubMed1994

Inborn errors of metabolism: a new purview of internal medicine.

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DNA↗

PubMed1994

On 'being led by the nose'. Rapid detection of inborn errors of metabolism.

We reviewed and emphasized the importance of olfaction for the diagnosis of inborn errors of metabolism. The "trained" nose has a remarkable sensitivity and specificity for discriminating odors that are associated with certain inborn errors of metabolism. These odors are often the first abnormality noticed on physical examination and should prompt the pediatrician to seek confirmatory laboratory studies.

Diagnosis, Differential↗

PubMed1994

Rapid and accurate random urinary porphyrin quantitation.

Urinary metabolite profiling, using randomly voided samples, has become accepted practice for such compounds as organic acids. To date, however, published methods for examining urinary porphyrin excretion have been based upon examination of 24-h urine collections. The inherent difficulties of obtaining an accurate collection, coupled with the intrinsic liabilities of porphyrins suggest that a method based upon random void analysis would be of great use. Thus, we have examined the porphyrin pattern of randomly excreted urine samples from normal adults of both genders, comparing our results with those obtained from analysis of 24-h collections. We have also evaluated the use of different alkalinizing agents. Finally, we have investigated the possibility that an underlying diurnal pattern of porphyrin excretion might influence the results obtained from random urine voids. The results indicate that NaOH retards spontaneous conversion of porphyrins within the first 24 h, thus optimizing recovery of uroporphyrin. Data from random voids mirror those obtained from 24-h collections and diurnal variations were not found to influence these results. Normal values are provided for random samples obtained from males and females. Thus, we conclude that random urine profiling is a rapid and accurate means of initial evaluation.

Adult↗

PubMed1993

Tissue distribution of succinylacetone in the rat in vivo: a possible basis for neurotoxicity in hereditary infantile tyrosinemia.

Neurologic dysfunction is a significant component of hereditary infantile tyrosinemia, an autosomal recessive disorder of man. The specific enzyme defect leads to endogenous production of the biochemical marker compound, succinylacetone (SA). Earlier study of the role which SA plays in generation of the renal Fanconi syndrome, also associated with this disorder, led to speculation that SA might also have neurotoxic effects. Thus, we have studied the distribution and impact on heme metabolism of SA in brain, liver and kidney from rats treated in vivo. Our results show far greater retention of SA in brain and kidney than in liver, by a ratio of approx. 3:1. Delta-aminolevulinate dehydratase (ALAD) was reduced to less than 10% of control activity in all three tissues after three daily injections; after a 7-day recovery, activity was regained at different rates in the three tissues. Total heme content of each tissue showed a steady decline beyond the treatment period, the most marked reduction being found in kidney. Porphyrin intermediates, heme oxygenase activity and cytochrome P-450 content evidenced varying responses to SA exposure which differed from tissue to tissue. Our results show that brain tissue sequesters SA and that heme biosynthesis in brain, as distinct from liver and kidney, is adversely affected. Such effects could result in impaired oxidative metabolism in brain, producing the CNS manifestations of tyrosinemia.

Animals↗

PubMed1993

Hyperammonemia: the silent killer.

Nitrogen, derived from breakdown of dietary amino acids as ammonia, is normally converted to urea and excreted. Impairment in the conversion process (called the urea cycle) can occur, either as a consequence of primary genetic defects or through secondary suppression of enzyme activity. Either process results in hyperammonemia, producing a clinical picture virtually indistinguishable from many other diseases of infancy. Moreover, there is no way to detect hyperammonemia except to measure the blood ammonia level. Thus, the capability to do so is a minimum standard of care in any hospital setting. Use of commonly obtained laboratory studies is discussed in the context of rapid, presumptive diagnosis of the causes of hyperammonemia.

Amino Acid Metabolism, Inborn Errors↗

PubMed1993

All children are special: the child with PKU.

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Child, Preschool↗

PubMed1992

delta-Aminolevulinic acid dehydratase: effects of succinylacetone in rat liver and kidney in an in vivo model of the renal Fanconi syndrome.

Succinylacetone (SA) is a known inhibitor of the heme biosynthetic pathway in liver. We have demonstrated previously the SA enhancement of delta-aminolevulinic acid dehydratase (ALAD) in renal tubules, while this enzyme is known to be impaired by SA in the liver. The present studies, based on in vivo treatment of animals with SA, show equivalent degree of inhibition of specific ALAD activity in liver and kidney. Both tissues evidenced an ability to restore enzyme activity with time, the recovery occurring much more slowly in kidney than in liver. The discrepant in vitro and in vivo effect of SA on renal ALAD may be due to differences between a direct inhibitor-enzyme interaction and inhibitor actions in the living cell, respectively. Persistent tissue levels of SA, consistent with demonstrated SA in plasma and urine, might account for continuing inhibition, with the greatest tissue accumulation in kidney where the substance must be cleared for excretion.

Animals↗

PubMed1992

Physiological basis for an animal model of the renal Fanconi syndrome: use of succinylacetone in the rat.

1. The biochemical basis for the human renal Fanconi syndrome, including glucosuria, phosphaturia and aminoaciduria, remains enigmatic. This is due, in part, to the lack of an appropriate animal model. Since there is an association between the human genetic disease hereditary tyrosinaemia, for which urinary excretion of the compound succinylacetone constitutes a biochemical marker, and a renal Fanconi syndrome, we have examined the relationship between succinylacetone and renal tubular function in the rat. 2. Intraperitoneal injection of succinylacetone for 3 consecutive days into adult male Sprague-Dawley rats resulted in succinylacetone plasma concentration of 3 mmol/l. This concentration was associated with glucosuria, aminoaciduria, polyuria, reduced renal phosphate reabsorption and normal creatinine clearance. In addition, urinary porphobilinogen and total porphyrin excretions were markedly reduced. In animals permitted to recover for 7 days after succinylacetone administration, these renal functional changes remitted partially or completely. Ultrastructural examination of the kidneys after the 3 days of treatment showed no fine structural changes. 3. We conclude that the physiological alterations produced in normal rat renal tubules by succinylacetone provide the basis for the study of the biochemical changes underlying the human renal Fanconi syndrome.

Amino Acids↗

PubMed1991

Renal heme metabolism in hereditary tyrosinemia: use of succinylacetone in rat renal tubules.

Succinylacetone (SA), a metabolic end-product found in urine from individuals with hereditary tyrosinemia and associated renal Fanconi syndrome and a known inhibitor of hepatic 5-aminolevulinic acid dehydratase (ALAD), has been used to study heme metabolism in isolated rat renal tubules. Heme biosynthetic porphyrin precursors are increased selectively in the presence of 4 mmol/1 SA. Total porphyrin content of the tubules are increased approximately 2-fold, while both ferrochelatase and heme oxygenase activities remain unaffected by SA. Nonetheless, total heme content is reduced, as was incorporation of radioactive label from amino[14C]levulinic acid. Cytochrome P-450 content remained unaffected. Impairment of iron uptake and/or transport within the cell or enhancement of heme catabolism via a non-heme oxygenase-dependent pathway could explain the observations.

Amino Acid Metabolism, Inborn Errors↗

PubMed1991

Effects of age and biotin status on postnatal development of plasma biotinidase activity in rats.

Biotinidase activity was measured in plasmas of 1-, 7-, 14-, and 21-day-old rats from control dams and dams that had been fed a biotin-depleting diet from Day 15 of gestation. Biotinidase activity increased significantly in the plasma of rats from control and depleted mothers until Postnatal Day 14, after which there was a small but significant decline at Day 21. Differences between the mean activities of the two groups of pups on each sampling day were not significant and there were no significant differences in activity levels attributable to sex. Plasma albumin concentrations increased from birth until Day 21, and plasma biotinidase activity and albumin concentration were significantly correlated (r = +/- 0.43). We suggested that these two proteins may be controlled by a common mechanism in the early postnatal period, and that biotin deficiency does not affect the development of biotinidase activity. Because biotin-depleted neonatal pups show developmental changes in biotinidase activity similar to those of human newborns, and they can be produced reliably by depleting dams from Day 15 of gestation, they may be useful models for studying the developmental abnormalities associated with human biotinidase deficiency.

Age Factors↗

PubMed1991

Inborn errors of metabolism: the essentials of clinical diagnosis.

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Acidosis↗

PubMed1991

Succinylacetone effects on renal tubular phosphate metabolism: a model for experimental renal Fanconi syndrome.

Phosphaturia is a prominent component of the renal Fanconi syndrome associated with the autosomal recessive disease, hereditary tyrosinemia. Succinylacetone (SA), the metabolic by-product of the enzyme deficiency, can be shown to produce multiple adverse effects on rat renal epithelial cell function in vitro. With the use of this compound, we have examined its interaction with Pi handling by the renal tubule cell in order to form a basis for understanding the effects of endogenously generated SA in causing phosphaturia in the genetically affected kidney. In this report we have shown complete inhibition of sodium-dependent phosphate uptake by renal brush border membrane vesicles, decreased ATP production by the SA-exposed renal tubule, and reversible inhibition of State 3 oxidation of glutamate by isolated renal mitochondria. We conclude that the phosphaturia observed in hereditary tyrosinemia results from multiple metabolic effects of SA on the renal tubule which are additive and lead to intracellular Pi depletion and diminished ATP production.

Adenosine Triphosphate↗

PubMed1990

On rat renal aminolevulinate transport and metabolism in experimental Fanconi syndrome.

Hereditary tyrosinemia, an autosomal recessive disease of human infants, is characterized by severe liver disease, a renal Fanconi syndrome, and urinary excretion of large quantities of both aminolevulinate (ALA) and succinylacetone (SA). The latter is a metabolic end-product of tyrosine catabolism in affected individuals, produced by both liver and kidney, and is a potent inhibitor of aminolevulinate dehydratase (ALAD) in liver. This inhibition has been assumed to result in release of large amounts of aminolevulinate from liver into the circulation, with subsequent urinary excretion. In the present report we examine the effects of succinylacetone on rat renal cortical tubular handling of ALA and the relationship to tubular heme content, demonstrating a marked impairment of each. In contrast, maleic acid was found to have no effect on either renal ALAD or heme content. Thus, we conclude that renal handling of ALA in SA-treated rat renal cortex may indicate a contribution by the kidney to the increased net ALA excretion observed in hereditary tyrosinemia.

Amino Acid Metabolism, Inborn Errors↗