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Paola Leone, David Shera,
Scott W J McPhee,
Jeremy S Francis,
Edwin H Kolodny,
Larissa T Bilaniuk,
Dah-Jyuu Wang,
Mitra Assadi,
Olga Goldfarb,
H Warren Goldman,
Andrew Freese,
Deborah Young,
Matthew J During,
R Jude Samulski,
Christopher G Janson
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ABSTRACT: Canavan disease is a hereditary leukodystrophy caused by mutations in the aspartoacylase gene (ASPA), leading to loss of enzyme activity and increased concentrations of the substrate N-acetyl-aspartate (NAA) in the brain. Accumulation of NAA results in spongiform degeneration of white matter and severe impairment of psychomotor development. The goal of this prospective cohort study was to assess long-term safety and preliminary efficacy measures after gene therapy with an adeno-associated viral vector carrying the ASPA gene (AAV2-ASPA). Using noninvasive magnetic resonance imaging and standardized clinical rating scales, we observed Canavan disease in 28 patients, with a subset of 13 patients being treated with AAV2-ASPA. Each patient received 9 × 10(11) vector genomes via intraparenchymal delivery at six brain infusion sites. Safety data collected over a minimum 5-year follow-up period showed a lack of long-term adverse events related to the AAV2 vector. Posttreatment effects were analyzed using a generalized linear mixed model, which showed changes in predefined surrogate markers of disease progression and clinical assessment subscores. AAV2-ASPA gene therapy resulted in a decrease in elevated NAA in the brain and slowed progression of brain atrophy, with some improvement in seizure frequency and with stabilization of overall clinical status.
Science translational medicine 12/2012; 4(165):165ra163. · 7.80 Impact Factor
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ABSTRACT: Obesity and cigarette smoking are two of the most frequent and preventable causes of disease and death in the United States; both are often established during youth. We hypothesized that obese, adolescent girls would be at higher risk for nicotine addiction in young adulthood, and that particular individual and social factors would mediate this association.
Students surveyed in the National Longitudinal Study of Adolescent Health (Add Health), a nationally representative school-based and in-home survey conducted in three waves, comprised the sample. More than 4,000 respondents were used for the multivariate linear and logistic regression analyses used to determine the association between obesity and level of nicotine addiction. Potential mediation effects of the association were also examined.
Obesity doubled the risk of the highest level of nicotine addiction after controlling for demographic factors, parent and friend smoking, and baseline smoking (OR, 2.12; 95% CI, 1.22-3.68). Family smoking was the strongest predictor of nicotine addiction (OR, 4.72; 95% CI, 2.89-7.72). Grade point average was a partial mediator of this relationship (OR, .48; 95% CI, .32-.74).
Obese, adolescent females are at increased risk for high-level nicotine addiction in young adulthood as compared with their nonobese peers. Grade point average partially mediates the association, and may represent a confluence of factors including increased absenteeism, social marginalization, biases, and lack of confidence in academic ability. Obese, adolescent females may require targeted interventions to address their risk of subsequent high-level nicotine addiction, especially if risk factors such as parental smoking and poor school performance are present.
Journal of Adolescent Health 11/2011; 49(5):511-7. · 3.33 Impact Factor
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ABSTRACT: To understand how normal variations in white matter relate to cognition, magnetization transfer imaging ratios (MTR) of a hypothesized neural network were associated with a test of visual selective attention (VST). Healthy adults (N = 16) without abnormal signal on brain scans viewed a version of DeSchepper and Treisman's test of VST (1996) with two levels of processing (novel shape matching with and without distractors, contingency feedback). A hypothesized neural network and component regions was significantly associated with accuracy and response times when distractors were present, with betas predicting 55% of variance in accuracy, and 59% of response times. MTR for anterior and posterior cingulate, prefrontal region, and thalami comprised a model predicting 55% of accuracy when distractors were present, and the anterior cingulate accounted for the majority of this effect. Prefrontal MTR predicted longer response times which was associated with increased accuracy. Distal neural areas involved in complex, processing-driven tasks (error processing, response selection, and variable response competition and processing load) may be dependent on white matter fibers to connect distal brain regions/nuclei of a macronetwork, including prefrontal executive functions.
Brain Imaging and Behavior 07/2011; 5(4):262-73. · 1.66 Impact Factor
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Bradley S Marino,
Ryan S Tomlinson,
Gil Wernovsky,
Dennis Drotar,
Jane W Newburger,
Lynn Mahony,
Kathleen Mussatto,
Elizabeth Tong,
Mitchell Cohen,
Charlotte Andersen, David Shera,
Philip R Khoury,
Jo Wray,
J William Gaynor,
Mark A Helfaer,
Anne E Kazak,
Judy A Shea
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ABSTRACT: The purpose of this multicenter study was to confirm the validity and reliability of the Pediatric Cardiac Quality of Life Inventory (PCQLI).
Seven centers recruited pediatric patients (8-18 years of age) with heart disease (HD) and their parents to complete the PCQLI and generic health-related quality of life (Pediatric Quality of Life Inventory [PedsQL]) and non-quality of life (Self-Perception Profile for Children [SPPC]/Self-Perception Profile for Adolescents [SPPA] and Youth Self-Report [YSR]/Child Behavior Checklist [CBCL]) tools. PCQLI construct validity was assessed through correlations of PCQLI scores between patients and parents and with severity of congenital HD, medical care utilization, and PedsQL, SPPC/SPPA, and YSR/CBCL scores. PCQLI test-retest reliability was evaluated.
The study enrolled 1605 patient-parent pairs. Construct validity was substantiated by the association of lower PCQLI scores with Fontan palliation and increased numbers of cardiac operations, hospital admissions, and physician visits (P<.001); moderate to good correlations between patient and parent PCQLI scores (r=0.41-0.61; P<.001); and fair to good correlations between PCQLI total scores and PedsQL total (r=0.70-0.76), SPPC/SPPA global self-worth (r=0.43-0.46), YSR/CBCL total competency (r=0.28-0.37), and syndrome and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-oriented scale (r=-0.58 to -0.30; P<.001) scores. Test-retest reliability correlations were excellent (r=0.78-0.90; P<.001).
PCQLI scores are valid and reliable for children and adolescents with congenital and acquired HD and may be useful for future research and clinical management.
PEDIATRICS 09/2010; 126(3):498-508. · 4.47 Impact Factor
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ABSTRACT: In "true" parachute mitral valve, mitral valve chordae insert into one papillary muscle. In parachute-like asymmetric mitral valve, most or all chordal attachments are to one papillary muscle. This study compared morphologic features, associated lesions, and palliation strategies of the two parachute mitral valve and dominant papillary muscle types and examined interventions and midterm outcomes in patients with biventricular circulation.
Echocardiography and autopsy databases were reviewed to identify patients with "true" parachute mitral valve or parachute-like asymmetric mitral valve from January 1987 to January 2006. Predictors of palliation strategy in the entire cohort, mitral stenosis on initial echocardiogram, and mortality in the biventricular cohort were determined with logistic regression.
Eighty-six patients with "true" parachute mitral valve (n = 49) or parachute-like asymmetric mitral valve (n = 37) were identified. Chordal attachments to the posteromedial papillary muscle were more common (73%). The presence "true" parachute mitral valve (P = .008), hypoplastic left ventricle (P < .001), and two or more left-sided obstructive lesions (P = .002) predicted univentricular palliation. Among 49 patients maintaining biventricular circulation at follow-up, 8 died median follow-up 6.4 years (7 days-17.8 years). Multivariate analysis revealed that "true" parachute mitral valve was associated with mitral stenosis on initial echocardiogram (P = .03), and "true" parachute mitral valve (P = .04) and conotruncal anomalies (P = .0003) were associated with mortality. Progressive mitral stenosis was found in 11 patients; 2 underwent mitral valve interventions, and 1 died.
Nearly two thirds of this parachute mitral valve cohort underwent biventricular palliation. Some progression of mitral stenosis occurred, although mitral valve intervention was rare. "True" parachute mitral valve was associated with mitral stenosis on initial echocardiogram. "True" parachute mitral valve and conotruncal anomalies were associated with mortality in the biventricular population.
The Journal of thoracic and cardiovascular surgery 02/2009; 137(2):385-393.e4. · 3.41 Impact Factor
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ABSTRACT: Gambling has increased in the past decade, with growing opportunities for initiation by adolescents. More limited data, however, are available regarding gambling in preadolescents. In the investigation reported here, gambling for money was the most common risk behavior in 10- to 12-year-olds. Gamblers were more likely to be white, have tried alcohol, have positive affect toward gambling, and have friends who gamble.
Journal of Adolescent Health 08/2008; 43(1):91-3. · 3.33 Impact Factor
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Bradley S Marino, David Shera,
Gil Wernovsky,
Ryan S Tomlinson,
Abigail Aguirre,
Maureen Gallagher,
Angela Lee,
Catherine J Cho,
Whitney Stern,
Lauren Davis,
Elizabeth Tong,
David Teitel,
Kathleen Mussatto,
Nancy Ghanayem,
Marie Gleason,
J William Gaynor,
Jo Wray,
Mark A Helfaer,
Judy A Shea
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ABSTRACT: Mortality after surgery for congenital heart disease (CHD) has decreased. Quality of life (QOL) assessment in survivors has become increasingly important. The purpose of this project was to create the Pediatric Cardiac Quality of Life Inventory (PCQLI).
Items were generated through nominal groups of patients, parents, and providers. The pilot PCQLI was completed by children (age 8-12), adolescents (age 13-18), and their parents at three cardiology clinics. Item reduction was performed through analysis of items, principal components, internal consistency (IC), and patterns of correlation.
A total of 655 patient-parent pairs completed the pilot PCQLI. Principal components identified included: impact of disease (ID); psychosocial impact (PI); and emotional environment (EE). After item reduction ID and PI had excellent IC (ID = 0.88-0.91; PI = 0.78-0.85) and correlated highly with each other (0.81-0.90) and with the total score (TS) (ID = 0.95-0.96; PI = 0.87-0.93). EE was not correlated with ID, PI, or TS and was removed from the final forms. Two-ventricle CHD patients had a higher TS than single-ventricle CHD patients across all forms (P < 0.001).
The PCQLI has patient and parent-proxy forms, has wide age range, and discriminates between CHD subgroups. The ID and PI subscales of the PCQLI have excellent IC and correlate well with each other and the TS.
Quality of Life Research 03/2008; 17(4):613-26. · 2.30 Impact Factor
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ABSTRACT: Neo-aortic insufficiency (neo-AI) has been noted following the Ross procedure. The purpose of this study was to evaluate the ability of intraoperative transesophageal echocardiography (TEE) to predict future neo-AI in pediatric patients undergoing the Ross from January 1995 to December 2003, who had an intraoperative TEE, and discharge and follow-up transthoracic (TTE) echocardiograms.
Retrospective case series.
All patients who underwent the Ross procedure at Children's Hospital of Philadephia between January 1995 and December 2003, and had an intraoperative TEE, discharge, and follow-up (>6 months) transthoracic echocardiogram (TTE) (by July 1, 2004) were included.
Grade of neo-AI was assessed on intraoperative TEE, discharge, and follow-up TTE echocardiogram reports.
Follow-up was available in 99/115 (86%) survivors. Median age at Ross was 9.3 years (4 days-34 years). No patient had more than mild neo-AI on intraoperative TEE. At discharge, 2 patients (2%) had moderate neo-AI. At most recent follow-up (median 4.2 years, 8 months-9.3 years), 21 patients (21%) had moderate or greater neo-AI; 9 underwent neo-aortic reintervention. The presence of any neo-AI on intraoperative TEE had 100% sensitivity and negative predictive value for diagnosing moderate or greater neo-AI at discharge. Patients who had mild neo-AI on TEE were more likely to have moderate or greater neo-AI at most recent follow-up than those patients with no neo-AI on TEE (9% vs. 30%, P = 0.01).
Intraoperative TEE is an excellent screening tool for the presence of significant neo-AI at the time of hospital discharge. Neo-AI progresses over time after Ross procedure and is more likely to progress in those patients with neo-AI on intraoperative TEE. However, predictive validity decreases over time as neo-AI progresses.
Congenital Heart Disease 02/2008; 3(1):39-46. · 0.90 Impact Factor
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ABSTRACT: Animal studies have clearly demonstrated the effects of in utero cocaine exposure on neural ontogeny, especially in dopamine-rich areas of cerebral cortex; however, less is known about how in utero cocaine exposure affects longitudinal neurocognitive development of the human brain. We used continuous arterial spin-labeling perfusion functional MRI to measure the effect of in utero cocaine exposure on resting brain function by comparing resting cerebral blood flow of cocaine-exposed adolescents with non-cocaine-exposed control subjects.
Twenty-four cocaine-exposed adolescents and 25 matched non-cocaine-exposed control subjects underwent structural and perfusion functional MRI during resting states. Direct subtraction, voxel-wise general linear modeling, and region-of-interest analyses were performed on the cerebral blood flow images to compare the resting cerebral blood flow between the 2 groups.
Compared with control subjects, cocaine-exposed adolescents showed significantly reduced global cerebral blood flow. The decrease of cerebral blood flow in cocaine-exposed adolescents was observed mainly in posterior and inferior brain regions, including the occipital cortex and thalamus. After adjusting for global cerebral blood flow, however, a significant increase in relative cerebral blood flow in cocaine-exposed adolescents was found in anterior and superior brain regions, including the prefrontal, cingulate, insular, amygdala, and superior parietal cortex. Furthermore, the functional modulations by in utero cocaine exposure on all of these regions except amygdala cannot be accounted for by the variation in brain anatomy.
In utero cocaine exposure may reduce global cerebral blood flow, and this reduction may persist into adolescence. The relative increase of cerebral blood flow in anterior and superior brain regions in cocaine-exposed adolescent participants suggests that compensatory mechanisms for reduced global cerebral blood flow may develop during neural ontogeny. Arterial spin-labeling perfusion MRI may be a valuable tool for investigating the long-term effects of in utero drug exposure.
PEDIATRICS 12/2007; 120(5):e1245-54. · 4.47 Impact Factor
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Timothy M Crombleholme, David Shera,
Hanmin Lee,
Mark Johnson,
Mary D'Alton,
Flint Porter,
Jacquelyn Chyu,
Richard Silver,
Alfred Abuhamad,
George Saade, [......],
William J Polzin,
Julian N Robinson,
Jack Rychik,
Per L Sandberg,
Istvan Seri,
Erin Simon,
Lynn L Simpson,
Larisa Yedigarova,
R Douglas Wilson,
Bruce Young
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ABSTRACT: The objective of the study was to examine the effect of selective fetoscopic laser photocoagulation (SFLP) vs serial amnioreduction (AR) on perinatal mortality in severe twin-twin transfusion syndrome (TTTS).
This was a 5 year multicenter, prospective, randomized controlled trial. The primary outcome variable was 30 day postnatal survival of donors and recipients.
There was no statistically significant difference in 30-day postnatal survival between SFLP or AR treatment for donors at 55% (11 of 20) vs 55% (11 of 20) (P = 1.0, odds ratio [OR] 1, 95% confidence interval [CI] 0.242 to 4.14) or recipients at 30% (6 of 20) vs 45% (9 of 20) (P = .51, OR 1.88, 95% CI 0.44 to 8.64). There was no difference in 30 day survival of 1 or both twins on a per-pregnancy basis between AR at 75% (15 of 20) and SFLP at 65% (13 of 20) (P = .73, OR 1.62, 95% CI 0.34 to 8.09). Overall survival (newborns divided by the number of fetuses treated) was not statistically significant for AR at 60% (24 of 40) vs SFLP 45% (18 of 40) (P = .18, OR 2.01, 95% CI 0.76 to 5.44). There was a statistically significant increase in fetal recipient mortality in the SFLP arm at 70% (14 of 20) vs the AR arm at 35% (7 of 20) (P = .25, OR 5.31, 95% CI 1.19 to 27.6). This was offset by increased recipient neonatal mortality of 30% (6 of 20) in the AR arm. Echocardiographic abnormality in recipient twin Cardiovascular Profile Score is the most significant predictor of recipient mortality (P = .055, OR 3.025/point) by logistic regression analysis.
The outcome of the trial did not conclusively determine whether AR or SFLP is a superior treatment modality. TTTS cardiomyopathy appears to be an important factor in recipient survival in TTTS.
American journal of obstetrics and gynecology 11/2007; 197(4):396.e1-9. · 3.28 Impact Factor
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ABSTRACT: A multivariate classification approach has been presented to examine the brain abnormalities, i.e., due to prenatal cocaine exposure, using both structural and functional brain images. First, a regional statistical feature extraction scheme was adopted to capture discriminative features from voxel-wise morphometric and functional representations of brain images, in order to reduce the dimensionality of the features used for classification, as well as to achieve the robustness to registration error and inter-subject variations. Then, this feature extraction method was used in conjunction with a hybrid feature selection method and a nonlinear support vector machine for the classification of brain abnormalities. This brain classification approach has been applied to detecting the brain abnormality associated with prenatal cocaine exposure in adolescents. A promising classification performance was achieved on a data set of 49 subjects (24 normal and 25 prenatally cocaine-exposed teenagers), with a leave-one-out cross-validation. Experimental results demonstrated the efficacy of our method, as well as the importance of incorporating both structural and functional images for brain classification. Moreover, spatial patterns of group difference derived from the constructed classifier were mostly consistent with the results of the conventional statistical analysis method. Therefore, the proposed approach provided not only a multivariate classification method for detecting brain abnormalities, but also an alternative way for group analysis of multimodality images.
NeuroImage 08/2007; 36(4):1189-99. · 5.89 Impact Factor
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ABSTRACT: The purpose of this study was to describe the relationship between neo-aortic root size, neo-aortic insufficiency (AI), and reintervention at mid-term follow-up.
Data on neo-aortic valve function and growth after the Ross procedure in children are limited.
A total of 74 of 119 Ross patients from January 1995 to December 2003 had > or =2 follow-up echocardiograms at our institution and were included. Neo-aortic dimensions were converted to z-scores and modeled over time. Kaplan-Meier analysis was used to assess freedom from neo-aortic outcomes, and predictors were identified through multivariate analysis.
Median age at Ross was 9 years (range 3 days to 34 years). Over 4.7 years (range 3 months to 9.3 years) follow-up, there was disproportionate enlargement of the neo-aortic root (z-score increase of 0.75/year [p < 0.0001]). Neo-AI progressed > or =1 grade in 36% of patients and > or =2 grades in 15%. Nine patients (12%) had neo-aortic reintervention at 2.0 years (range 1.1 to 9.5 years) after the Ross procedure owing to severe neo-AI (n = 7), neo-aortic root dilation (n = 1), and neo-aortic pseudoaneurysm (n = 1). At 6 years after the Ross procedure, freedom from neo-aortic reintervention was 88%. Freedom from neo-aortic root z-score >4 was only 3% and from moderate or greater neo-AI was 60%. Longer follow-up time was associated with neo-aortic root dilation (p < 0.0001). Prior ventricular septal defect (VSD) repair predicted neo-AI (p = 0.02) and reintervention (p = 0.03). Prior aortic valve replacement (p = 0.002) also predicted neo-AI. Neo-aortic root dilation was not associated with neo-AI or reintervention.
At mid-term follow-up after the Ross procedure, neo-aortic root size increases significantly out of proportion to somatic growth, and neo-AI is progressive. Prior VSD repair and aortic valve replacement were associated with neo-AI and reintervention.
Journal of the American College of Cardiology 05/2007; 49(17):1806-12. · 14.16 Impact Factor
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ABSTRACT: This study assessed the type, time course, and risk factors for right and left ventricular outflow tract reinterventions after the Ross procedure in a population of infants, children, and young adults.
Patients who underwent the Ross procedure between January 1995 and June 2004 were included (n = 121 consecutive patients). Kaplan-Meier and hazard analyses of right and left ventricular outflow tract reinterventions were performed, and predictors of reintervention were identified through multivariate analysis.
The median age at the Ross procedure was 8.2 years (4 days to 34 years); 20% were aged less than 1 year. Half of the patients had isolated aortic valve disease; the other half had complex left-sided heart disease. Early mortality (<30 days) was 2.5% (n = 3). There were 2 late deaths (1.7%). Follow-up (median 6.5 years [2.5 months to 10.4 years]) was available for 96% of survivors (n = 111). Right ventricular outflow tract reintervention (n = 22 in 15 patients) was performed 2.0 years (2.0 weeks to 9.8 years) after the Ross procedure because of stenosis in 19 of 22 cases. Freedom from right ventricular outflow tract reintervention at 8 years was 81%. Smaller homograft size was the strongest predictor (P < .001) of right ventricular outflow tract reintervention. Left ventricular outflow tract reintervention (n = 15 in 15 patients) was performed 2.8 years (1.0 months to 11.6 years) after the Ross procedure because of severe neoaortic insufficiency in 10 of 15 patients. Freedom from left ventricular outflow tract reintervention at 8 years was 83%. Native pulmonary valve abnormalities (P < .01), original diagnosis of aortic insufficiency (P < .01), prior aortic valve replacement (P = .01), and prior ventricular septal defect repair (P = .04) predicted left ventricular outflow tract reintervention.
At midterm follow-up after the Ross procedure, interim mortality is rare. Neoaortic insufficiency and right ventricle to pulmonary artery conduit obstruction are common postoperative sequelae, requiring reintervention in one quarter of patients.
The Journal of thoracic and cardiovascular surgery 05/2007; 133(4):893-9. · 3.41 Impact Factor
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Christopher G Janson,
Edwin H Kolodny,
Bai-Jin Zeng,
Srinivasa Raghavan,
Gregory Pastores,
Paola Torres,
Mitra Assadi,
Scott McPhee,
Olga Goldfarb,
Beth Saslow,
Andrew Freese,
D J Wang,
Larissa Bilaniuk, David Shera,
Paola Leone
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ABSTRACT: We describe two sisters with a mild-onset variant of Canavan's disease who presented at age 50 and 19 months with developmental delay but without macrocephaly, hypotonia, spasticity, or seizures. Remarkably, both patients had age-appropriate head control, gross motor development, and muscle tone. There were very mild deficits in fine motor skills, coordination, and gait. Both sisters had a history of strabismus, but otherwise vision was normal. The older child showed evidence of mild cognitive and social impairment, whereas language and behavior were normal for age in the infant. Both patients were found to be compound heterozygotes for C914A (A305E) and G212A (R71H) mutations in ASPA. Like all other known ASPA mutations, this previously unknown G212A mutation appears to have low absolute enzyme activity. Nevertheless, it is associated in these patients with an extremely benign phenotype that is highly atypical of Canavan's disease. Biochemical and clinical data were evaluated using a generalized linear mixed model generated from 25 other subjects with Canavan's disease. There were statistically significant differences in brain chemistry and clinical evaluations, supporting a distinct variant of Canavan's disease. Future studies of ASPA enzyme structure and gene regulation in these subjects could lead to a better understanding of Canavan's pathophysiology and improvements in ASPA gene therapy.
Annals of Neurology 03/2006; 59(2):428-31. · 11.09 Impact Factor
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ABSTRACT: Low-carbohydrate diets have become a popular alternative to standard diets for weight loss. Our aim was to compare the cost-effectiveness of these two diets.
The patient population included 129 severely obese subjects (BMI = 42.9) from a randomized trial; participants had a high prevalence of diabetes or metabolic syndrome. We compared within-trial costs, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (CER) for the two study groups. We imputed missing values for QALYs. The CER was bootstrapped to derive 95% confidence intervals and to define acceptability cut-offs. We took a societal perspective for our analysis.
Total costs during the one year of the trial were 6742 dollars +/- 6675 and 6249 dollars +/- 5100 for the low-carbohydrate and standard groups, respectively (p = 0.78). Participants experienced 0.64 +/- 0.02 and 0.61 +/- 0.02 QALYs during the one year of the study, respectively (p = 0.17 for difference). The point estimate of the incremental CER was -1225 dollars/QALY (i.e., the low-carbohydrate diet dominated the standard diet). However, in the bootstrap analysis, the wide spread of CERs caused the 95% confidence interval to be undefined. The probabilities that the low-carbohydrate diet was acceptable, using cut-offs of 50,000 dollars/QALY, 100,000 dollars/QALY, and 150,000 dollars/QALY, were 72.4% 78.6%, and 79.8%, respectively.
The low-carbohydrate diet was not more cost-effective for weight loss than the standard diet in the patient population studied. Larger studies are needed to better assess the cost-effectiveness of dietary therapies for weight loss.
Obesity research 11/2005; 13(10):1834-40. · 4.95 Impact Factor
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ABSTRACT: Current evidence suggests that the effects of lithium on metabolic and signaling pathways in the brain may vary depending on the specific clinical condition or disease model. For example, lithium increases levels of cerebral N-acetyl aspartate in patients with bipolar disorder but does not appear to affect N-acetyl aspartate levels in normal human subjects. Conversely, lithium significantly decreases whole-brain levels of N-acetyl aspartate in a rat genetic model of Canavan disease in which cerebral N-acetyl aspartate is chronically elevated. While N-acetyl aspartate is a commonly used surrogate marker for neuronal density and correlates with neuronal viability, grossly elevated whole-brain levels of N-acetyl aspartate in Canavan disease are associated with dysmyelination and mental retardation. This report describes the first clinical application of lithium in a human subject with Canavan disease. Spectroscopic and clinical changes were observed over the time period in which lithium was administered, which reversed during a 2-week wash-out period after withdrawal of lithium. This investigation reports decreased N-acetyl aspartate levels in the brain regions tested and magnetic resonance spectroscopic values that are more characteristic of normal development and myelination, suggesting that a larger, controlled trial of lithium may be warranted as supportive therapy for Canavan disease by decreasing abnormally elevated N-acetyl aspartate.
Pediatric Neurology 11/2005; 33(4):235-43. · 1.52 Impact Factor
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ABSTRACT: C31G (Savvy) has been developed as a topical vaginal microbicide with broad-spectrum antibacterial and antiviral properties. The objective of this study was to evaluate the distribution of a 1.0% concentration of (3.5 mL) C31G vaginal gel in the human pelvis using magnetic resonance imaging (MRI). Gel delivery with a standard applicator was primarily to the upper vagina and was well tolerated. Vaginal mucosal coverage at 18 min was excellent with 92% linear coverage and 75% surface contact coverage of the vagina. The upper vagina was almost completely covered and gel was also noted in the lower vagina. Coverage 6 h after application was substantially decreased, with 60% of maximal linear coverage and 41% surface contact. There was a very minimal coverage of the vaginal mucosa noted 24 h following insertion. Simulated intercourse resulted in relatively little change in overall distribution at all three time points. Repeat application of the gel may be necessary if intercourse has not occurred within the first few hours after initial insertion.
Contraception 06/2005; 71(5):357-61. · 2.72 Impact Factor
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ABSTRACT: A microbicide is designed to coat the vaginal epithelium and prevent transmission of HIV. Complete coverage is desired for optimal protection. In vivo factors affecting coverage have not yet been studied. This randomized crossover trial evaluates the effect of gel volume and patient activity upon vaginal epithelial coating. Gynol II gel was mixed with a magnetic resonance imaging (MRI) contrast agent. Ten women self-inserted, on separate visits, 3 or 5 mL of gel and underwent serial MRI scanning both before and after simulated intercourse. Gel spread was dependent upon time and volume. There was modest spread during the first hour and greater spread 6 h after insertion. Five milliliters of gel resulted in statistically significantly greater coverage immediately following insertion, within the first 30 min and at 6 h after insertion. Simulated intercourse greatly enhances gel spread. After simulated intercourse, the distribution of the gel at each volume was similar. Less leakage of gel was reported with the smaller volume.
Contraception 12/2004; 70(6):498-505. · 2.72 Impact Factor
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ABSTRACT: Neuropsychologic tests are widely used to predict the course of progressive neurologic diseases, and recent research has demonstrated the specificity of cognitive measures, even in relatively diffuse diseases. However, the cognitive effects of brain tumors of similar histology and location are known to be highly variable. The authors used the specificity of cognitive function principle to compare two models for the early detection of low-grade brain tumor recurrence prior to detection with clinically scheduled neuroimaging.
To test the feasibility of these prediction models, 34 patients with supratentorial, low-grade brain tumors prospectively were administered serial comprehensive neuropsychologic examinations; 11 patients developed recurrent tumors during the series and 23 patients did not. A general model based on tests sensitive to malignancy and white matter disease was compared with a tumor-specific model based on indices related to each patient's tumor locus. A Cox proportional hazards model was used to identify the predictor variables that significantly changed immediately prior to recurrence.
Only the tumor-specific model achieved statistical significance (P < 0.02). A tumor-specific index decline of 1 standard deviation indicated a 5-fold increase in the probability of tumor recurrence.
Although this method needs to be tested with more frequent and regular observations and with a larger sample, these results provide evidence of the feasibility of the subject-specific model as a predictor of recurrence. The evidence of the predictive value of a tumor-specific model is consistent with studies that identify only limited, brain structure-specific cognitive decline from broad neuropsychologic batteries.
Cancer 02/2003; 97(3):649-56. · 4.77 Impact Factor
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Christopher Janson,
Scott McPhee,
Larissa Bilaniuk,
John Haselgrove,
Mark Testaiuti,
Andrew Freese,
Dah-Jyuu Wang, David Shera,
Peter Hurh,
Joan Rupin,
Elizabeth Saslow,
Olga Goldfarb,
Michael Goldberg,
Ghassem Larijani,
William Sharrar,
Larisa Liouterman,
Angelique Camp,
Edwin Kolodny,
Jude Samulski,
Paola Leone
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ABSTRACT: This clinical protocol describes virus-based gene transfer for Canavan disease, a childhood leukodystrophy. Canavan disease, also known as Van Bogaert-Bertrand disease, is a monogeneic, autosomal recessive disease in which the gene coding for the enzyme aspartoacylase (ASPA) is defective. The lack of functional enzyme leads to an increase in the central nervous system of the substrate molecule, N-acetyl-aspartate (NAA), which impairs normal myelination and results in spongiform degeneration of the brain. No effective treatment currently exists; however, virus-based gene transfer has the potential to arrest or reverse the course of this otherwise fatal condition. This procedure involves neurosurgical administration of approximately 900 billion genomic particles (approximately 10 billion infectious particles) of recombinant adeno-associated virus (AAV) containing the aspartoacylase gene (ASPA) directly to affected regions of the brain in each of 21 patients with Canavan disease. Pre- and post-delivery assessments include a battery of noninvasive biochemical, radiological, and neurological tests. This gene transfer study represents the first clinical use of AAV in the human brain and the first instance of viral gene transfer for a neurodegenerative disease.
Human Gene Therapy 08/2002; 13(11):1391-412. · 4.22 Impact Factor
