Thuan Nguyen

Arrested preoligodendrocyte maturation contributes to myelination failure in premature infants.

The major form of magnetic resonance imaging–defined white matter injury (WMI) comprises diffuse lesions where the burden of small necrotic foci (microscopic necrosis) is poorly defined. We hypothesized that myelination failure associated with diffuse WMI involves an aberrant injury response linked to arrested preoligodendrocyte (preOL) maturation in reactive astrocyte‐rich lesions.

Comparing problem-based learning with case-based learning: Effects of a major curricular shift at two institutions

Purpose Problem-based learning (PBL) is now used at many medical schools to promote lifelong learning, open inquiry, teamwork, and critical thinking. PBL has not been compared with other forms of discussion-based small-group learning. Case-based learning (CBL) uses a guided inquiry method and provides more structure during small-group sessions. In this study, we compared faculty and medical students’ perceptions of traditional PBL with CBL after a curricular shift at two institutions. Method Over periods of three years, the medical schools at the University of California, Los Angeles (UCLA) and the University of California, Davis (UCD) changed first-, second-, and third-year Doctoring courses from PBL to CBL formats. Ten months after the shift (2001 at UCLA and 2004 at UCD), students and faculty who had participated in both curricula completed a 24-item questionnaire about their PBL and CBL perceptions and the perceived advantages of each format Results A total of 286 students (86%–97%) and 31 faculty (92%–100%) completed questionnaires. CBL was preferred by students (255; 89%) and faculty (26; 84%) across schools and learner levels. The few students preferring PBL (11%) felt it encouraged self-directed learning (26%) and valued its greater opportunities for participation (32%). From logistic regression, students preferred CBL because of fewer unfocused tangents (59%, odds ration [OR] 4.10, P = .01), less busy-work (80%, OR 3.97, P = .01), and more opportunities for clinical skills application (52%, OR 25.6, P = .002). Conclusions Learners and faculty at two major academic medical centers overwhelmingly preferred CBL (guided inquiry) over PBL (open inquiry). Given the dense medical curriculum and need for efficient use of student and faculty time, CBL offers an alternative model to traditional PBL small-group teaching. This study could not assess which method produces better practicing physicians.

Histopathological correlates of magnetic resonance imaging–defined chronic perinatal white matter injury

Although magnetic resonance imaging (MRI) is the optimal imaging modality to define cerebral white‐matter injury (WMI) in preterm survivors, the histopathological features of MRI‐defined chronic lesions are poorly defined. We hypothesized that chronic WMI is related to a combination of delayed oligodendrocyte (OL) lineage cell death and arrested maturation of preoligodendrocytes (preOLs). We determined whether ex vivo MRI can distinguish distinct microglial and astroglial responses related to WMI progression and arrested preOL differentiation.

Human Neural Stem Cells Induce Functional Myelination in Mice with Severe Dysmyelination

Transplanted banked human neural stem cells produce functional myelin detected by MRI in juvenile mice with severe dysmyelination. Bringing Insulation Up to Code Faulty insulation around household wiring is an electric shock and fire hazard; likewise, defects in the insulation around nerve fibers—the myelin sheath—can have destructive effects. Because of myelin’s crucial roles in promoting the rapid transmission of nerve impulses and in axon integrity, mutations that affect myelin formation in the central nervous system cause severe neurological decline. Uchida et al. and Gupta et al. now investigate the use of neural stem cells—which can differentiate into myelin-producing oligodendrocytes—as a potential treatment for such disorders. Previous work showed that transplantation of human oligodendrocyte progenitors into newborn shiverer (Shi) mice, a hypomyelination model, could prolong survival. In the new work, Uchida et al. transplanted human neural stem cells, which had been expanded and banked, into the brains of newborn and juvenile Shi mice. Whereas the newborn mice were asymptomatic, the juvenile mice were already symptomatic and displayed advanced dysmyelination. These transplanted cells preferentially differentiated into oligodendrocytes that generated myelin, which ensheathed axons and improved nerve conduction in both categories of mice. In an open-label phase 1 study, Gupta et al. then tested the safety and efficacy of such cells in four young boys with a severe, fatal form of Pelizaeus-Merzbacher disease (PMD), a rare X-linked condition in which oligodendrocytes cannot myelinate axons. Human neural stem cells were transplanted directly into the brain; the procedure and transplantation were well tolerated. Magnetic resonance imaging techniques, performed before transplant and five times in the following year, were used to assess myelination. The imaging results were consistent with donor cell–derived myelination in the transplantation region in three of the four patients. These results support further study of potential clinical benefits of neural stem cell transplantation in PMD and other dysmyelination disorders. Shiverer-immunodeficient (Shi-id) mice demonstrate defective myelination in the central nervous system (CNS) and significant ataxia by 2 to 3 weeks of life. Expanded, banked human neural stem cells (HuCNS-SCs) were transplanted into three sites in the brains of neonatal or juvenile Shi-id mice, which were asymptomatic or showed advanced hypomyelination, respectively. In both groups of mice, HuCNS-SCs engrafted and underwent preferential differentiation into oligodendrocytes. These oligodendrocytes generated compact myelin with normalized nodal organization, ultrastructure, and axon conduction velocities. Myelination was equivalent in neonatal and juvenile mice by quantitative histopathology and high-field ex vivo magnetic resonance imaging, which, through fractional anisotropy, revealed CNS myelination 5 to 7 weeks after HuCNS-SC transplantation. Transplanted HuCNS-SCs generated functional myelin in the CNS, even in animals with severe symptomatic hypomyelination, suggesting that this strategy may be useful for treating dysmyelinating diseases.

Fence methods for mixed model selection

Many model search strategies involve trading off model fit with model complexity in a penalized goodness of fit measure. Asymptotic properties for these types of procedures in settings like linear regression and ARMA time series have been studied, but these do not naturally extend to nonstandard situations such as mixed effects models, where simple definition of the sample size is not meaningful. This paper introduces a new class of strategies, known as fence methods, for mixed model selection, which includes linear and generalized linear mixed models. The idea involves a procedure to isolate a subgroup of what are known as correct models (of which the optimal model is a member). This is accomplished by constructing a statistical fence, or barrier, to carefully eliminate incorrect models. Once the fence is constructed, the optimal model is selected from among those within the fence according to a criterion which can be made flexible. In addition, we propose two variations of the fence. The first is a stepwise procedure to handle situations of many predictors; the second is an adaptive approach for choosing a tuning constant. We give sufficient conditions for consistency of fence and its variations, a desirable property for a good model selection procedure. The methods are illustrated through simulation studies and real data analysis.

Development and Validation of the Fecal Incontinence and Constipation Quality of Life Measure in Children With Spina Bifida

PURPOSE Fecal incontinence and constipation in children with spina bifida are recognized to impact quality of life. Most disease specific quality of life instruments on fecal incontinence target adults and/or children without neuropathic bowel. We developed an instrument to evaluate bowel function and its impact on quality of life in children with spina bifida and their caregivers. MATERIALS AND METHODS A 51-item questionnaire termed the FIC QOL (Fecal Incontinence and Constipation Quality of Life) survey was developed from expert opinion, patient interviews, and modification of previously published adult and pediatric studies for nonneuropathic bowel dysfunction. The items are divided into 7 quality of life factor groupings, including bowel program, dietary management, symptoms, travel and socialization, family relationships, caregiver emotional impact and financial impact. The questionnaire was given to caregivers of children with and without spina bifida. Discriminant validity was evaluated by comparing the spina bifida and control groups. Test-retest reliability was evaluated by having 41 patients complete 2 surveys within 4 to 6 weeks. RESULTS Comparing questionnaires from 92 index patients and 52 controls showed a statistically significant difference for all 7 quality of life factor groupings. The FIC QOL instrument objectively demonstrated the negative impact of fecal incontinence and constipation on quality of life in these families. Comparing 82 questionnaires at 2 time points demonstrated the reliability of all FIC QOL questions. CONCLUSIONS The FIC QOL instrument provides a valid and reliable measure of the effect of fecal incontinence and constipation on the quality of life of caregivers and their children with spina bifida.

Defining Left Ventricular Apex-to-Base Twist Mechanics Computed From High-Resolution 3D Echocardiography: Validation Against Sonomicrometry

OBJECTIVES To compute left ventricular (LV) twist from 3-dimensional (3D) echocardiography. BACKGROUND LV twist is a sensitive index of cardiac performance. Conventional 2-dimensional based methods of computing LV twist are cumbersome and subject to errors. METHODS We studied 10 adult open-chest pigs. The pre-load to the heart was altered by temporary controlled occlusion of the inferior vena cava, and myocardial ischemia was produced by ligating the left anterior descending coronary artery. Full-volume 3D loops were reconstructed by stitching of pyramidal volumes acquired from 7 consecutive heart beats with electrocardiography gating on a Philips IE33 system (Philips Medical Systems, Andover, Massachusetts) at baseline and other steady states. Polar coordinate data of the 3D images were entered into an envelope detection program implemented in MatLab (The MathWorks, Inc., Natick, Massachusetts), and speckle motion was tracked using nonrigid image registration with spline-based transformation parameterization. The 3D displacement field was obtained, and rotation at apical and basal planes was computed. LV twist was derived as the net difference of apical and basal rotation. Sonomicrometry data of cardiac motion were also acquired from crystals anchored to epicardium in apical and basal planes at all states. RESULTS The 3D dense tracking slightly overestimated the LV twist, but detected changes in LV twist at different states and showed good correlation (r = 0.89) when compared with sonomicrometry-derived twist at all steady states. In open chest pigs, peak cardiac twist was increased with reduction of pre-load from inferior vena cava occlusion from 6.25 degrees +/- 1.65 degrees to 9.45 degrees +/- 1.95 degrees . With myocardial ischemia from left anterior descending coronary artery ligation, twist was decreased to 4.90 degrees +/- 0.85 degrees (r = 0.8759). CONCLUSIONS Despite lower spatiotemporal resolution of 3D echocardiography, LV twist and torsion can be computed accurately.

Three-dimensional speckle-tracking imaging for left ventricular rotation measurement: an in vitro validation study.

Objective. Left ventricular (LV) twist is manifested in oppositely directed apical and basal rotation. We studied a new 3‐dimensional (3D) echocardiography program (wall motion tracking; Toshiba America Medical Systems, Inc, Tustin, CA) for left ventricular rotation. Methods. We used a rotation model with a variable‐speed motor to rotate hearts in a water bath. We studied 10 freshly harvested pig hearts, which were mounted on the rotary actuator of our twist phantom with the heart base rotating and the apex held fixed to avoid translational motion, at rotations of 0°, 15°, 20°, and 25°. Full‐volume 3D image loops were acquired on a Toshiba Aplio Artida ultrasound system at a maximized frame rate. Results. As the actual heart rotation increased, computed segmental and global rotation also increased accordingly, with the measured rotations of the basal and middle segments greater than that of the apex (both P < .001). Segmental and global rotation at all 3 levels correlated well with the actual rotation (base: r = 0.93; middle: r = 0.92; apex: r = 0.82; global: r = 0.95; all P < .001). Conclusions. The new 3D program tracked LV rotation accurately.

Renal Cortical Deterioration in Children With Spinal Dysraphism: Analysis of Risk Factors

Abstract Background/Objective: Because hydronephrosis and reflux are reversible, we believe cortical loss represents true renal deterioration in children with spinal dysraphism. Our goal was to better define risk factors for cortical loss. Methods: After institutional review board approval, we reviewed the medical records of 272 children with spinal dysraphism. The following factors were evaluated: age, sex, renal and bladder imaging, urodynamic parameters, medications, catheterization program, continence, infections, and surgical history. Renal cortical loss was defined by scarring or a differential function greater than 15% using a nuclear scan. Univariate and multivariate logistic regression models were fitted to test the associations of specific variables with cortical loss. Results: Renal cortical loss was found in 41% of children with high-grade reflux vs 2% of children without reflux. Univariate analysis showed only high-grade reflux and female sex to be independent risk factors. Controlling for age and sex, reflux and initiation of catheterization after 1 year of age are significant risk factors. High bladder pressure and hydronephrosis in the absence of reflux were not associated with cortical loss. Multivariate analysis showed that girls with reflux have a 55-fold increased risk of cortical loss. Conclusion: By limiting the definition of renal deterioration to cortical loss, we identified relevant risk factors: reflux, female sex, and delayed initiation of clean intermittent catheterization. We have also discounted other suspected risk factors: hydronephrosis and elevated bladder pressure. Rather than continuing our focus on hydronephrosis and urodynamics, we believe more research and management debate should be afforded to females with reflux.

Imatinib mesylate causes growth deceleration in pediatric patients with chronic myelogenous leukemia

Imatinib mesylate, a tyrosine kinase inhibitor, is used in the treatment of chronic myelogeneous leukemia (CML). Given its ease of administration and manageable side effects in adults, imatinib mesylate was introduced as therapy for pediatric CML. Recently published case reports describe growth deceleration in children treated with imatinib. This study details the growth phenotype of seven pediatric patients maintained in remission on imatnib mesylate over an extended period of time.