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ABSTRACT: Venous thromboembolism (VTE) and recurrent venous thromboembolism (rVTE) are rare, but significant problems in pediatrics. Current recommendations for anticoagulant therapy arise from adult literature, and there is little data on clinical outcomes following therapeutic low-molecular-weight heparin in children.
All patients <19 years of age that were diagnosed with a VTE or right atrial thrombus via standard imaging methods at St. Jude Children's Research Hospital were retrospectively identified from January 2004 through August 2008. Demographic characteristics, coexisting clinic conditions, description of anticoagulant therapy, and record of rVTE were chronicled following a comprehensive chart review. Descriptive statistics of clinical characteristics and anticoagulation are presented.
Venous thrombosis was identified in 149 children with 21% (31/149) developing a rVTE. Coexisting clinical conditions were identified in 93% of children at initial diagnosis with 48% (71/149) of patients having a coexisting malignancy. Seventy-seven percent (114/149) of children received anticoagulant therapy with UFH (10/114) or enoxaparin (104/114). Neither duration of enoxaparin therapy (>6, 3-6, <3 months) (P = 0.61), nor quality of therapy (≥75% of time on anticoagulation spent with an anti-FXa of 0.5-1.0 U/ml) (P = 1.0) were found to be protective against rVTE.
Anticoagulation with enoxaparin based on adult literature may be suboptimal in preventing rVTE in pediatric populations. Future prospective randomized controlled trials in pediatrics using clinical outcomes with anticoagulant therapy are urgently needed.
Pediatric Blood & Cancer 11/2011; 59(1):105-9. · 1.89 Impact Factor
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ABSTRACT: Hydroxyurea has been shown to be efficacious for the treatment of sickle cell anemia (SCA), primarily through the induction of fetal hemoglobin (HbF). However, the exact mechanisms by which hydroxyurea can induce HbF remain incompletely defined, although direct transcriptional effects and altered cell cycle kinetics have been proposed. In this study, we investigated potential epigenetic and alternative molecular mechanisms of hydroxyurea-mediated HbF induction by examining methylation patterns within the (G)γ-globin promoter and miRNA expression within primary CD71(+) erythrocytes of patients with SCA, both at baseline before beginning hydroxyurea therapy and after reaching maximum tolerated dose (MTD). Using both cross-sectional analysis and paired-sample analysis, we found that the highly methylated (G)γ-globin promoter was inversely correlated to baseline HbF levels, but only slightly altered by hydroxyurea treatment. Conversely, expression of several specific miRNAs was significantly increased after hydroxyurea treatment, and expression of miR-26b and miR-151-3p were both associated with HbF levels at MTD. The significant associations identified in these studies suggest that methylation may be important for regulation of baseline HbF, but not after hydroxyurea treatment, whereas changes in miRNA expression may be associated with hydroxyurea-mediated HbF induction. This study was registered at ClinicalTrials.gov (NCT00305175).
Blood 09/2011; 118(20):5664-70. · 9.90 Impact Factor
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ABSTRACT: Blood oxygenation level-dependent (BOLD) and cerebral blood flow (CBF)-based functional magnetic resonance imaging (fMRI) were used to measure primary visual cortex responses to photic stimulation in 23 children (12.4 ± 0.7 years old) with sickle cell anemia (SCA) and 21 clinical controls (11 ± 1.0 years old). The objectives were to investigate the effect of SCA on detection of brain activation with fMRI and to explore the relationship between fMRI responses and global cognitive function. The BOLD responses were diminished in children with SCA. Clinical indicators of disease severity were greatest in patients without detectable visual cortex activation, but blood hemoglobin concentration and resting CBF were not predictive of BOLD signal amplitude in the SCA patients. Unexpectedly, the BOLD signal amplitude was positively associated (r(s) ≥ 0.8, p ≤ 0.05) with Wechsler Abbreviated Scale of Intelligence scores, suggesting that fMRI may help clarify medical, hemodynamic, and neural factors that mediate adverse effects of SCA on neurocognitive function.
Brain Imaging and Behavior 09/2011; 5(4):295-306. · 1.66 Impact Factor
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ABSTRACT: Skeletal bone accretion occurs throughout childhood. The integrity of this process can influence future adult bone health and the risk of osteoporosis. Although surveillance of children who are at risk of poor bone accretion is important, the most appropriate method to monitor childhood bone health has not been established. Previous investigators have proposed using bone age (BA) rather than chronological age (CA) when interpreting bone mineral density (BMD) values in children.
To investigate the value of BA assessment for BMD measurement in a cohort of children at risk of poor accretion.
A cohort of 163 children with brain tumors who completed both a BMD assessment (quantitative computed tomography, QCT) and who had a BA within a 6-month interval were identified. The difference in BMD Z-scores determined by CA and BA was determined. The impact of salient clinical features was assessed.
No significant difference between CA and BA Z-scores was detected in the overall cohort (P = 0.056). However, the scores in 18 children (all boys between the ages of 11 years and 15 years) were statistically determined to be outliers from the values in the rest of the cohort.
Interpretation of BMD with BA measurement might be appropriate and affect treatment decisions in peripubertal males.
Pediatric Radiology 10/2008; 38(12):1285-92. · 1.67 Impact Factor
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Amanda R Burton,
Erica Vincent,
Paula Y Arnold,
Greig P Lennon, Matthew Smeltzer,
Chin-Shang Li,
Kathryn Haskins,
John Hutton,
Roland M Tisch,
Eli E Sercarz,
Pere Santamaria,
Creg J Workman,
Dario A A Vignali
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ABSTRACT: Type 1 diabetes is mediated by T-cell entry into pancreatic islets and destruction of insulin-producing beta-cells. The relative contribution of T-cells specific for different autoantigens is largely unknown because relatively few have been assessed in vivo.
We generated mice possessing a monoclonal population of T-cells expressing 1 of 17 T-cell receptors (TCR) specific for either known autoantigens (GAD65, insulinoma-associated protein 2 (IA2), IA2beta/phogrin, and insulin), unknown islet antigens, or control antigens on a NOD.scid background using retroviral-mediated stem cell gene transfer and 2A-linked multicistronic retroviral vectors (referred to herein as retrogenic [Rg] mice). The TCR Rg approach provides a mechanism by which T-cells with broad phenotypic differences can be directly compared.
Neither GAD- nor IA2-specific TCRs mediated T-cell islet infiltration or diabetes even though T-cells developed in these Rg mice and responded to their cognate epitope. IA2beta/phogrin and insulin-specific Rg T-cells produced variable levels of insulitis, with one TCR producing delayed diabetes. Three TCRs specific for unknown islet antigens produced a hierarchy of insulitogenic and diabetogenic potential (BDC-2.5 > NY4.1 > BDC-6.9), while a fourth (BDC-10.1) mediated dramatically accelerated disease, with all mice diabetic by day 33, well before full T-cell reconstitution (days 42-56). Remarkably, as few as 1,000 BDC-10.1 Rg T-cells caused rapid diabetes following adoptive transfer into NOD.scid mice. CONCLUSIONS; Our data show that relatively few autoantigen-specific TCRs can mediate islet infiltration and beta-cell destruction on their own and that autoreactivity does not necessarily imply pathogenicity.
Diabetes 06/2008; 57(5):1321-30. · 8.29 Impact Factor
