Electrolyte abnormalities and stress dosing predict illness-related hospitalizations among infants and toddlers with congenital adrenal hyperplasia.

OBJECTIVE: Infants and toddlers with classical congenital adrenal hyperplasia (CAH) are at high risk for morbidity/mortality arising from life-threatening adrenal crisis. Management of acute illnesses in CAH requires an understanding of factors leading to emergency department (ED) visits and hospitalizations in the first few years of life. We, therefore, examined adrenal crisis at prehospital and ED stages of illness in young children with CAH as they related to medical outcomes. PATIENTS AND DESIGN: Retrospective cohort study of 39 children with CAH due to 21-hydroxylase deficiency (0-4 years of age) and 27 age-matched controls. MEASUREMENTS: ED visit, acute illness symptoms (fever, vomiting, diarrhoea) and other characteristics (hospitalizations, administration of stress-dose hydrocortisone, electrolyte abnormalities). RESULTS: CAH infants and toddlers had significantly higher rates of ED visits (0.50 [0.25-0.88] per person-year) than controls (0 [0-0] per person-year; p < .001). Moreover, CAH children under 6 months old had significantly higher rates of ED visits compared with older ages. Only 50% (51/102) of illness-related ED visits in CAH children were preceded by the administration of either oral (46/51) or intramuscular (11/51) stress dosing by parents. A total of 10.8% of ED visits resulted in hospital admission. Controlling for age and 17-hydroxyprogesterone at diagnosis, electrolyte abnormalities and administration of parenteral hydrocortisone in the ED significantly predicted hospital admission. Receiving a hydrocortisone injection before the ED was a significant predictor of having electrolyte abnormalities. CONCLUSIONS: Infants and toddlers with classical CAH are at high risk for acute illness and hospitalizations and often do not receive adequate stress dosing before the ED.

Carotid Intima-Media Thickness Is Associated with Increased Androgens in Adolescents and Young Adults with Classical Congenital Adrenal Hyperplasia.

BACKGROUND/AIMS: Youth with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency develop cardiovascular disease (CVD) risk factors of obesity and hypertension. Carotid intima-media thickness (CIMT), a marker of CVD risk, is increased in CAH young adults. We examined CIMT and its relationship with androgens and obesity in adolescents/young adults with CAH. METHODS: Twenty CAH subjects (age 16 ± 3.3 years, 50% female) and 20 matched controls were studied cross-sectionally. Eight additional obese patients with CAH were included in within-group comparisons. CIMT by high-resolution ultrasound, androgens, anthropometry, bone age (BA), and metabolic/inflammatory markers were assessed. RESULTS: Within the CAH group, CIMT correlated with 17-hydroxyprogesterone (r = 0.48, p < 0.05) and androstenedione (r = 0.46, p < 0.05), and was greater in obese subjects. CIMT was greater in CAH males than females, but similar among CAH females with advanced BA, CAH males with normal BA, and control males. There was no difference in CIMT between CAH and controls, although high-density lipoprotein was inversely correlated with CIMT in both groups. CONCLUSION: CIMT is associated with increased androgens in CAH adolescents and young adults, with loss of sex differences in CAH females with excess androgen exposure. Our findings highlight the importance of hormonal control for CVD prevention in CAH.

Distinguishing type 2 diabetes from type 1 diabetes in African American and Hispanic American pediatric patients.

OBJECTIVE: To test the hypothesis that clinical observations made at patient presentation can distinguish type 2 diabetes (T2D) from type 1 diabetes (T1D) in pediatric patients aged 2 to 18. SUBJECTS AND METHODS: Medical records of 227 African American and 112 Hispanic American pediatric patients diagnosed as T1D or T2D were examined to compare parameters in the two diseases. Age at presentation, BMI z-score, and gender were the variables used in logistic regression analysis to create models for T2D prediction. RESULTS: The regression-based model created from African American data had a sensitivity of 92% and a specificity of 89%; testing of a replication cohort showed 91% sensitivity and 93% specificity. A model based on the Hispanic American data showed 92% sensitivity and 90% specificity. Similarities between African American and Hispanic American patients include: (1) age at onset for both T1D and T2D decreased from the 1980s to the 2000s; (2) risk of T2D increased markedly with obesity. Racial/ethnic-specific observations included: (1) in African American patients, the proportion of females was significantly higher than that of males for T2D compared to T1D (p<0.0001); (2) in Hispanic Americans, the level of glycated hemoglobin (HbA1c) was significantly higher in T1D than in T2D (p<0.002) at presentation; (3) the strongest contributor to T2D risk was female gender in African Americans, while the strongest contributor to T2D risk was BMI z-score in Hispanic Americans. CONCLUSIONS: Distinction of T2D from T1D at patient presentation was possible with good sensitivity and specificity using only three easily-assessed variables: age, gender, and BMI z-score. In African American pediatric diabetes patients, gender was the strongest predictor of T2D, while in Hispanic patients, BMI z-score was the strongest predictor. This suggests that race/ethnic specific models may be useful to optimize distinction of T1D from T2D at presentation.

Structure-based inhibitor design of AccD5, an essential acyl-CoA carboxylase carboxyltransferase domain of Mycobacterium tuberculosis.

Mycolic acids and multimethyl-branched fatty acids are found uniquely in the cell envelope of pathogenic mycobacteria. These unusually long fatty acids are essential for the survival, virulence, and antibiotic resistance of Mycobacterium tuberculosis. Acyl-CoA carboxylases (ACCases) commit acyl-CoAs to the biosynthesis of these unique fatty acids. Unlike other organisms such as Escherichia coli or humans that have only one or two ACCases, M. tuberculosis contains six ACCase carboxyltransferase domains, AccD1-6, whose specific roles in the pathogen are not well defined. Previous studies indicate that AccD4, AccD5, and AccD6 are important for cell envelope lipid biosynthesis and that its disruption leads to pathogen death. We have determined the 2.9-Angstroms crystal structure of AccD5, whose sequence, structure, and active site are highly conserved with respect to the carboxyltransferase domain of the Streptomyces coelicolor propionyl-CoA carboxylase. Contrary to the previous proposal that AccD4-5 accept long-chain acyl-CoAs as their substrates, both crystal structure and kinetic assay indicate that AccD5 prefers propionyl-CoA as its substrate and produces methylmalonyl-CoA, the substrate for the biosyntheses of multimethyl-branched fatty acids such as mycocerosic, phthioceranic, hydroxyphthioceranic, mycosanoic, and mycolipenic acids. Extensive in silico screening of National Cancer Institute compounds and the University of California, Irvine, ChemDB database resulted in the identification of one inhibitor with a K(i) of 13.1 microM. Our results pave the way toward understanding the biological roles of key ACCases that commit acyl-CoAs to the biosynthesis of cell envelope fatty acids, in addition to providing a target for structure-based development of antituberculosis therapeutics.