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Cortez D.,CHOC Childrens | Sharma N.,Cleveland Clinic | Devers C.,Indiana Wesleyan University | Devers E.,Indiana Wesleyan University | Schlegel T.T.,NASA
Journal of Electrocardiology | Year: 2014

Background The 12-lead ECG-derived spatial QRS-T angle has prognostic and diagnostic utility, but most ECG machines currently fail to report it. The primary goal was to determine if reasonably accurate methods exist for rapid visual estimations of the spatial peaks QRS-T angle from conventional 12-lead ECG tracings. Methods and Results Simultaneous 12-lead and Frank XYZ-lead recordings were obtained from a publicly available database for 100 post-myocardial infarction patients and 50 controls. ANOVA, Pearson's correlation coefficients and concordance plots were used to evaluate agreement for spatial peaks QRS-T angle results from the true Frank leads versus from several visually applied 12-to-Frank XYZ-lead transforms. The latter included Kors et al.'s regression and quasi-orthogonal, Bjerle and Arvedson's quasi-orthogonal, Dower's inverse, and Hyttinen et al.'s, Dawson et al.'s and Guillem et al.'s transforms. Spatial peaks QRS-T angles derived from the true Frank leads were not statistically significantly different from those derived from any visually applied transform. Of the visually applied transforms, the Kors' regression and Kors' quasi-orthogonal yielded the highest Pearson correlation coefficients against the gold-standard true Frank lead results [0.84 and 0.77, respectively, when individuals with bundle branch blocks were included (N = 150), and 0.88 and 0.80, respectively, when individuals with bundle branch blocks were excluded (N = 137)]. Bland-Altman 95% confidence intervals showed similar results, with the two Kors'-related methods also having the narrowest confidence intervals. Conclusions When visually applied, the Kors' regression-related and quasi-orthogonal transforms allow for reasonably precise spatial peaks QRS-T estimates and thus a potentially practical way to visually estimate spatial peaks QRS-T angles from conventional 12-lead ECGs. © 2014 Elsevier Inc. All rights reserved.

Wang R.Y.,CHOC Childrens | Bodamer O.A.,University of Miami | Watson M.S.,Medical College of Wisconsin | Wilcox W.R.,Cedars Sinai Medical Center | Wilcox W.R.,University of California at Los Angeles
Genetics in Medicine | Year: 2011

PURPOSE: To develop educational guidelines for the diagnostic confirmation and management of individuals identified by newborn screening, family-based testing after proband identification, or carrier testing in at-risk populations, and subsequent prenatal or postnatal testing of those who are presymptomatic for a lysosomal storage disease. METHODS: Review of English language literature and discussions in a consensus development panel comprised an international group of experts in the clinical and laboratory diagnosis, treatment and management, newborn screening, and genetic aspects of lysosomal storage diseases. RESULTS: Although clinical trial and longitudinal data were used when available, the evidence in the literature is limited and consequently the recommendations must be considered as expert opinion. Guidelines were developed for Fabry, Gaucher, and Niemann-Pick A/B diseases, glycogen storage type II (Pompe disease), globoid cell leukodystrophy (Krabbe disease), metachromatic leukodystrophy, and mucopolysaccharidoses types I, II, and VI. CONCLUSION: These guidelines serve as an educational resource for confirmatory testing and subsequent clinical management of presymptomatic indivduals suspected to have a lysosomal storage disease; they also help to define a research agenda for longitudinal studies such as the American College of Medical Genetics/National Institutes of Health Newborn Screening Translational Research Network. © 2011 Lippincott Williams & Wilkins.

He M.,University of Pennsylvania | Smith L.D.,Childrens Mercy Hospital | Chang R.,CHOC Childrens | Li X.,University of Pennsylvania | Vockley J.,University of Pittsburgh
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2014

Deficiency of sterol C4 methyl oxidase, encoded by the SC4MOL gene, has recently been described in four patients from three different families. All of the patients presented with microcephaly, congenital cataracts, and growth delay in infancy. The first patient has suffered since the age of six years from severe, diffuse, psoriasiform dermatitis, sparing only her palms. She is now 20 years old. The second patient is a 5 year old girl who has just started to develop dry skin and hair changes. The third and fourth patients are a pair of affected siblings with a severe skin condition since infancy. Quantitative sterol analysis of plasma and skin scales from all four patients showed marked elevation of 4α-methyl- and 4, 4′-dimethylsterols, consistent with a deficiency in the first step of sterol C4 demethylation in cholesterol biosynthesis. Mutations in the SC4MOL have been identified in all of the patients. SC4MOL deficiency is the first autosomal recessive disorder identified in the sterol demethylation complex. Cellular studies with patient-derived fibroblasts have shown a higher mitotic rate than control cells in cholesterol-depleted medium, with increased de novo cholesterol biosynthesis and accumulation of methylsterols. Immunologic analyses of granulocytes and B cells from patients and obligate carriers in the patients' families indicated dysregulation of immune-related receptors. Inhibition of sterol C4 methyl oxidase in human transformed lymphoblasts induced activation of the cell cycle. Additional studies also demonstrated diminished EGFR signaling and disrupted vesicular trafficking in cells from the affected patients. These findings suggest that methylsterols play an important role in epidermal biology by their influence on cell proliferation, intracellular signaling, vesicular trafficking and immune response. SC4MOL is situated within the psoriasis susceptibility locus PSORS9, and may be a genetic risk factor for common skin conditions. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias. © 2013 Elsevier B.V.

Leydiker K.B.,CHOC Childrens | Neidich J.A.,Quest Diagnostics Nichols Institute | Lorey F.,Genetic Disease Screening Program | Barr E.M.,CHOC Childrens | And 3 more authors.
Molecular Genetics and Metabolism | Year: 2011

Prior to the advent of expanded newborn screening, sudden and unexplained death was often the first and only symptom of medium-chain acyl-CoA dehydrogenase deficiency (MCADD). With the use of tandem mass spectrometry, infants can now be identified and treated before a life threatening metabolic decompensation occurs. Newborn screening has also been shown to detect previously undiagnosed maternal inborn errors of metabolism. We have now diagnosed two women with MCADD following the identification of low free carnitine in their newborns. While one of the women reported prior symptoms of fasting intolerance, neither had a history of metabolic decompensation or other symptoms consistent with a fatty acid oxidation disorder. These cases illustrate the importance of including urine organic acid analysis and an acylcarnitine profile as part of the confirmatory testing algorithm for mothers when low free carnitine is identified in their infants. © 2011.

Puckett R.L.,CHOC Childrens | Orsini J.J.,New York State Department of Health | Pastores G.M.,New York University | Wang R.Y.,CHOC Childrens | And 7 more authors.
Molecular Genetics and Metabolism | Year: 2012

Purpose: To present clinical, biochemical and molecular information on six new clinically diagnosed Krabbe disease patients and assess the sensitivity of retrospective galactocerebrosidase measurement in their newborn screening samples. Methods: Medical records were reviewed. Galactocerebrosidase activity was measured in leukocytes and, retrospectively, in the patients' newborn screening cards (stored for 1.4 to 13.5. years).. GALC gene mutation analysis was performed. Results: Five patients with Krabbe disease, one of whom also had hydrocephalus, became symptomatic during infancy. A sixth patient presented with seizures and developmental regression at age two and had a protracted disease course. Galactocerebrosidase activity in leukocytes ranged from 0.00 to 0.20. nmol/h/mg protein. Low galactocerebrosidase activity (range: 3.2% to 11.1% of the daily mean), consistent with Krabbe disease, was detected in each of the newborn screening samples.. GALC molecular analysis identified six previously unreported mutations and two novel sequence variants. Conclusion: Our cases highlight the clinical variability of Krabbe disease. Galactocerebrosidase activity in newborn dried blood spots is a highly sensitive test, even when samples have been stored for many years. The high frequency of private mutations in the. GALC gene may limit the use of genetic information for making treatment decisions in the newborn period. © 2011 Elsevier Inc.

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