Paul D Mitchell

Boston Children's Hospital, Boston, Massachusetts, United States

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Publications (40)278.44 Total impact

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    ABSTRACT: Recent data from mainly homogeneous European and African populations implicate a 140-bp region 5' to the transcriptional start site of LCT (the lactase gene) as a regulatory site for lactase persistence and nonpersistence. Because there are no studies of US nonhomogeneous populations, we performed genotype/phenotype analysis of the -13910 and -22018 LCT single nucleotide polymorphisms (SNPs) in New England children, mostly of European ancestry. Duodenal biopsies were processed for disaccharidase activities, RNA quantification by reverse transcription polymerase chain reaction (RT-PCR), allelic expression ratios by PCR, and genotyping and SNP analysis. Results were compared with clinical information. Lactase activity and mRNA levels, and sucrase-to-lactase ratios of enzyme activity and mRNA, showed robust correlations with genotype. None of the other LCT SNPs showed as strong a correlation with enzyme or mRNA levels as did -13910. Data were consistent, with the -13910 being the causal sequence variant instead of -22018. Four individuals heterozygous for -13910T/C had allelic expression patterns similar to individuals with -13910C/C genotypes; of these, 2 showed equal LCT expression from the 2 alleles and a novel variant (-13909C>A) associated with lactase persistence. The identification of -13910C/C genotype is likely to predict lactase nonpersistence, consistent with prior published studies. A -13910T/T genotype will frequently, but not perfectly, predict lactase persistence in this mixed European-ancestry population; a -13910T/C genotype will not predict the phenotype. A long, rare haplotype in 2 individuals with -13910T/C genotype but equal allele-specific expression contains a novel lactase persistence allele present at -13909.
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    ABSTRACT: Introduction: While parenteral nutrition (PN) has revolutionized the management of patients with intestinal failure (IF), central line-associated bloodstream infections (CLABSIs) remain a leading cause of mortality and morbidity in this population. The objective of this study is to characterize the presentation of CLABSIs in pediatric IF and to determine the time to positivity of blood cultures. Methods: A retrospective cohort study of children with IF who presented to our institution for evaluation of a possible CLABSI from January 1, 2012, to December 31, 2012, was performed. Results: Sixty patients with IF were identified. There were 33 cases of CLABSI in 16 patients, with a rate of 1.5 infections per 1000 catheter days. There were no significant differences in age, growth parameters, or catheter days between patients with or without CLABSI. Fever was documented in 85% of patients with CLABSI. These patients demonstrated an increased percentage of neutrophils and higher C-reactive protein levels compared with patients without CLABSI. The mean time to culture positivity was 13.2 hours, and 97% of cultures were positive within 24 hours. Conclusion: Our data suggest that most pediatric patients with IF who have CLABSI develop positive cultures within 24 hours, and the absence of fever and leukocytosis does not necessarily indicate the absence of infection. These findings may support clinical practice guidelines in favor of shorter hospital stay when CLABSI is suspected; however, a prospective analysis of CLABSI in this population is recommended to determine the safety and appropriate setting prior to any practice change. © 2015 American Society for Parenteral and Enteral Nutrition.
    Journal of Parenteral and Enteral Nutrition 01/2015; DOI:10.1177/0148607114567897 · 3.14 Impact Factor
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    ABSTRACT: Adult studies suggest antibodies to infliximab (ATI) correlate with loss of response in inflammatory bowel disease but pediatric data are limited. We conducted a cross-sectional study of trough infliximab levels and ATI in 134 pediatric and young adult patients receiving infliximab. At the time serum was obtained demographics, disease phenotype, duration of infliximab therapy, use of combination therapy (methotrexate or 6-mercaptopurine with infliximab), and surgery were recorded. Assays were performed on 134 subjects currently receiving infliximab (85 male; mean age, 17.3 ± 4.3 years; 114 Crohn's disease and 20 ulcerative colitis). Infliximab use ranged from 12 days to 12 years: median 2.0 (interquartile range (1.1-4.3) years. Twenty-seven of 134 (20%) patients had ATI ≥5 U/mL. Of patients with ATI ≥5 U/mL, 59% had infliximab levels <5 μg/mL, compared with 14% of patients with ATI <5 U/mL (P < 0.001). Ten (7%) patients (9 Crohn's disease, 1 ulcerative colitis) underwent bowel resections after beginning infliximab infusions. Sixty percent who underwent surgery had ATI ≥12 U/mL; in contrast, only 8% of patients who did not undergo surgery had ATI ≥12 U/mL (P = 0.01). At the time of serum sampling, 50 (37%) patients were receiving combination therapy, compared with 84 (63%) on infliximab alone. Combination therapy at the time of serum sampling did not correlate with either increase infliximab levels or lower ATI compared with infliximab monotherapy. However, prior immunomodulator use was associated with lower antibody levels (P = 0.007). ATI correlates with reduction in infliximab level and a higher risk of surgery in patients with inflammatory bowel disease.
    Inflammatory Bowel Diseases 01/2015; DOI:10.1097/MIB.0000000000000284 · 5.12 Impact Factor
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    ABSTRACT: Pediatric intestinal failure (IF) patients require many surgical procedures over the course of their illness. The number and variety of surgical procedures, as well as patient characteristics associated with this burden of surgical procedures, remain largely unknown.Methods Data from a large, multicenter retrospective study of pediatric intestinal failure (PIFCON) were reviewed. Infants from 14 multidisciplinary IF programs were enrolled, with study entry defined as PN dependence for > 60 days.ResultsA total of 272 infants were followed for a median (IQR) of 33.5 (16.2, 51.5) months, during which time they underwent 4.0 (3.0, 6.0) abdominal surgical procedures. Intestinal resections were performed in 88/97 (92%) necrotizing enterocolitis patients versus 138/175 (80%) in non-NEC patients (P < 0.05). Patients who underwent ≥ 5 operations had more septic events, compared to those who underwent ≤ 2 operations (3 (1, 6) versus 1 (0, 3), respectively, P < 0.01). Patients treated at centers with transplantation capability had lower odds of undergoing > 2 abdominal operations [OR 0.37 (95% CI: 0.21, 0.65)] after multivariable adjustment.Conclusions Individual and center-specific characteristics may help determine surgical practices experienced by infants with IF. Further study may delineate additional details about the nature of these characteristics, with the goal of optimizing patient care and minimizing individual and overall healthcare burden.
    Journal of Pediatric Surgery 11/2014; 49(12). DOI:10.1016/j.jpedsurg.2014.09.026 · 1.31 Impact Factor
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    ABSTRACT: Context: Vitamin D promotes bone health and regulates the immune system, both important actions for pediatric patients with inflammatory bowel disease (IBD). The supplementation dose that would maintain optimal serum 25 hydroxy vitamin D concentration (25OHD ≥ 32 ng/mL), is unknown. Objective: Compare two supplementation regimens' efficacy and safety in maintaining optimal 25OHD in children with IBD. Design: Randomized, not blinded, controlled trial Setting: The trial was conducted in the Boston Children's Hospital Clinical and Translational Study Unit. Participants: 63 patients, ages 8 to 18 yrs with IBD and baseline 25OHD > 20 ng/mL were enrolled; 48 completed the study, 1 withdrew for adverse events. Intervention: Arm A received daily oral vitamin D2; 400 IU (N = 32). Arm B, received 1,000 IU in the summer /fall and 2,000 IU in the winter/spring (N = 31). Main outcome: Probability of maintaining 25OHD ≥ 32 ng/mL in all tri-monthly visits for 12 months. Results: 3 participants in arm A (9.4%) and 3 in arm B (9.7%) achieved the primary outcome (P = 0.97). The incidence of adverse events - all minor - did not differ. More participants in arm A developed C-reactive protein level ≥ 1 mg/dL (31% vs. 10%, P = 0.04), and interleukin-6 > 3 pg/mL (54% vs. 27%, P = 0.05). Conclusions: Daily oral vitamin D2 doses up to 2,000 IU were inadequate to maintain optimal 25OHD, but well-tolerated. The finding of lower incidence of elevated inflammatory markers and cytokines among participants receiving higher vitamin D2 doses merits further study.
    Journal of Clinical Endocrinology &amp Metabolism 06/2014; 99(9):jc20134218. DOI:10.1210/jc.2013-4218 · 6.31 Impact Factor
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    ABSTRACT: IMPORTANCE The introduction of hepatoprotective strategies and multidisciplinary management has significantly improved the outcome of neonates with short bowel syndrome (SBS) who require parenteral nutrition (PN). OBJECTIVE To determine the probability of weaning from PN based on intestinal length in neonates with SBS amidst the new era of hepatoprotective strategies and multidisciplinary management. DESIGN, SETTING, AND PARTICIPANTS Retrospective medical record review at a single-center academic institution. Neonates with no more than 100 cm of small intestine at a corrected gestational age of no more than 30 days who were diagnosed with a surgical gastrointestinal disease and PN dependent for at least 2 weeks were included. Data were collected from January 1, 2004, through June 1, 2012. EXPOSURE Neonates with SBS requiring PN. MAIN OUTCOMES AND MEASURES The probability of wean from PN without reinitiation for at least 1 year, as determined by logistic regression. Predictors of wean were evaluated using exact conditional logistic regression. Predictors of time to wean were determined by Cox proportional hazards regression. RESULTS Sixty-three patients with a median (25th percentile, 75th percentile [interquartile range (IQR)]) gestational age of 31 (27, 35) weeks, birth weight of 1423 (895, 2445) g, small intestinal length of 41.0 (24.0, 65.0) cm, and predicted length of 29.0% (17.1%, 45.5%) underwent analysis. Fifty-one patients (81%) received a fish oil-based lipid emulsion (1 g/kg/d), 40 (63%) were weaned, 11 (17%) remained PN dependent, 4 (6%) underwent transplant, and 8 (13%) died while on PN. Excluding patients who underwent transplant or died, the median (IQR) small intestinal length was 55.0 (28.0, 75.0) cm in weaned and 26.0 (14.0, 41.0) cm in PN-dependent patients (P = .006), with 40 of 51 (78%) weaned by study end. The cumulative probability of wean for patients with at least 50 cm of small intestine was 88% after 12 and 96% after 24 months. Patients with less than 50 cm of small intestine had a cumulative probability of wean of 23% after 12, 38% after 24, and 71% after 57 months. Small intestinal length was found to be the primary predictor of wean. Notable predictors of time to wean included the amount of small intestine remaining (hazard ratio, 1.94 [95% CI, 1.45-2.58] per 20 cm of intestine; P < .001), entirety of care within our institution (3.27 [1.59-6.72]; P = .001), and intestinal lengthening procedure (0.19 [0.04-0.84]; P = .03). CONCLUSIONS AND RELEVANCE The majority of patients will wean from PN despite short intestinal length, likely as a result of new management strategies combined with a multidisciplinary team approach.
    05/2014; 149(7). DOI:10.1001/jamasurg.2013.4332
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    ABSTRACT: Little is known about the emergence of structural asymmetry of white matter tracts during early brain development. We examined whether and when asymmetry in diffusion parameters of limbic and association white matter pathways emerged in humans in 23 brains ranging from 15 gestational weeks (GW) up to 3 years of age (11 ex vivo and 12 in vivo cases) using high-angular resolution diffusion imaging tractography. Age-related development of laterality was not observed in a limbic connectional pathway (cingulum bundle or fornix). Among the studied cortico-cortical association pathways (inferior longitudinal fasciculus [ILF], inferior fronto-occipital fasciculus, and arcuate fasciculus), only the ILF showed development of age-related laterality emerging as early as the second trimester. Comparisons of ages older and younger than 40 GW revealed a leftward asymmetry in the cingulum bundle volume and a rightward asymmetry in apparent diffusion coefficient and leftward asymmetry in fractional anisotropy in the ILF in ages older than 40 GW. These results suggest that morphometric asymmetry in cortical areas precedes the emergence of white matter pathway asymmetry. Future correlative studies will investigate whether such asymmetry is anatomically/genetically driven or associated with functional stimulation.
    Cerebral Cortex 05/2014; DOI:10.1093/cercor/bhu084 · 8.31 Impact Factor
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    ABSTRACT: In this pilot study, we analyzed serum insulin-like growth factor 1 (IGF-1)- and IGF-binding protein-3-for-age z scores from 54 inflammatory bowel disease children with no, temporary, or permanent growth impairment. Although our findings did not reach statistical significance, patients with permanent linear growth impairment had lower IGF-1-for-age z scores (-1.76 [-2.25 to -0.43]) compared with those with no or temporary growth impairment (-0.84 [-1.49 to -0.3]) and -1.16 [-1.59 to -1.51], respectively). IGF-binding protein-3 levels were similar across the 3 groups. In the absence of significant inflammation and malnutrition, lower IGF-1-for-age z scores may help distinguish patients likely to have permanent growth impairment from those whose growth impairment is likely to be temporary.
    Journal of pediatric gastroenterology and nutrition 04/2014; 58(4):472-6. DOI:10.1097/MPG.0000000000000234 · 2.18 Impact Factor
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    ABSTRACT: To examine the agreement of multifrequency bioelectric impedance analysis (BIA) and anthropometry with reference methods for body composition assessment in children with intestinal failure (IF). We conducted a prospective pilot study in children 14 years of age or younger with IF resulting from either short bowel syndrome (SBS) or motility disorders. Bland Altman analysis was used to examine the agreement between BIA and deuterium dilution in measuring total body water (TBW) and lean body mass (LBM); and between BIA and dual X-ray absorptiometry (DXA) techniques in measuring LBM and FM. Fat mass (FM) and percent body fat (%BF) measurements by BIA and anthropometry, were also compared in relation to those measured by deuterium dilution. Fifteen children with IF, median (IQR) age 7.2 (5.0, 10.0) years, 10 (67%) male, were studied. BIA and deuterium dilution were in good agreement with a mean bias (limits of agreement) of 0.9 (-3.2, 5.0) for TBW (L) and 0.1 (-5.4 to 5.6) for LBM (kg) measurements. The mean bias (limits) for FM (kg) and %BF measurements were 0.4 (-3.8, 4.6) kg and 1.7 (-16.9, 20.3)% respectively. The limits of agreement were within 1 SD of the mean bias in 12/14 (86%) subjects for TBW and LBM, and in 11/14 (79%) for FM and %BF measurements. Mean bias (limits) for LBM (kg) and FM (kg) between BIA and DXA were 1.6 (-3.0 to 6.3) kg and -0.1 (-3.2 to 3.1) kg, respectively. Mean bias (limits) for FM (kg) and %BF between anthropometry and deuterium dilution were 0.2 (-4.2, 4.6) and -0.2 (-19.5 to 19.1), respectively. The limits of agreement were within 1 SD of the mean bias in 10/14 (71%) subjects. In children with intestinal failure, TBW and LBM measurements by multifrequency BIA method were in agreement with isotope dilution and DXA methods, with small mean bias and clinically acceptable limits of agreement. In comparison to deuterium dilution, BIA was comparable to anthropometry for FM and %BF assessments with small mean bias, but the limits of agreement were large. BIA is a reliable method for TBW and LBM assessments in population studies. However, its reliability in individual patients, especially for FM assessments, cannot be guaranteed.
    Journal of pediatric gastroenterology and nutrition 03/2014; 59(1). DOI:10.1097/MPG.0000000000000364 · 2.18 Impact Factor
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    ABSTRACT: To determine the natural history of cirrhosis from parenteral nutrition-associated liver disease (PNALD) after resolution of cholestasis with fish oil (FO) therapy. Historically, cirrhosis from PNALD resulted in end-stage liver disease, often requiring transplantation for survival. With FO therapy, most children now experience resolution of cholestasis and rarely progress to end-stage liver disease. However, outcomes for cirrhosis after resolution of cholestasis are unknown and patients continue to be considered for liver/multivisceral transplantation. Prospectively collected data were reviewed for children with cirrhosis because of PNALD who had resolution of cholestasis after treatment with FO from 2004 to 2012. Outcomes evaluated included need for liver/multivisceral transplantation, mortality, and the clinical progression of liver disease. Fifty-one patients with cirrhosis from PNALD were identified, with 76% demonstrating resolution of cholestasis after FO therapy. The mean direct bilirubin decreased from 6.4 ± 4 mg/dL to 0.2 ± 0.1 mg/dL (P < 0.001) 12 months after resolution of cholestasis, with a mean time to resolution of 74 days. None of the patients required transplantation or died from end-stage liver disease. Pediatric End-Stage Liver Disease scores decreased from 16 ± 4.6 to -1.2 ± 4.6, 12 months after resolution of cholestasis (P < 0.001). In children who remained PN-dependent, the Pediatric End-Stage Liver Disease score remained normal throughout the follow-up period. Cirrhosis from PNALD may be stable rather than progressive once cholestasis resolves with FO therapy. Furthermore, these patients may not require transplantation and show no clinical evidence of liver disease progression, even when persistently PN-dependent.
    Annals of surgery 12/2013; 261(1). DOI:10.1097/SLA.0000000000000445 · 7.19 Impact Factor
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    ABSTRACT: To determine, in a cohort of young children with intestinal failure (IF), if estimates of basal metabolic rate (BMR) by standard equations, approximate measured REE by indirect calorimetry (IC). IC was performed by dilutional canopy technique. REE measurements were compared to standard, age-based estimation equations (WHO) for BMR. Subjects were classified as hypermetabolic (REE > 110% BMR), hypometabolic (REE < 90% BMR), or normal (REE = 90-110% BMR). Twenty-eight IF patients (11 female, 17 male) had an underlying diagnosis of necrotizing enterocolitis (n = 10) or a congenital gastrointestinal defect (n = 18). Median age was 5.3 months. Median (IQR) REE was 46 (42, 58) kcal/kg/day. Median (IQR) total energy intake provided 209 (172, 257)% of REE, with parenteral nutrition providing 76% (23%) of total energy intake. REE was variable, with 39% (n = 11) of measurements hypermetabolic, 39% (n = 11) hypometabolic, and the remaining 21% (n = 6) normal. Although REE was well correlated with estimated BMR (r = 0.82, P < 0.0001), estimated BMR was not consistently an adequate predictor of REE. BMR over- or under-estimated REE by more than 10 kcal/kg/d in 15/28 (54%) patients. REE was not significantly correlated with severity of liver disease, nutritional status, total energy intake or gestational age. Energy expenditure is variable among children with IF and IFALD, with nearly 80% of our cohort exhibiting either hypo- or hypermetabolism. Standard estimation equations frequently do not correctly predict individual REE. Longitudinal studies of energy expenditure and body composition may be needed to guide provision of nutrition regimens.
    Journal of pediatric gastroenterology and nutrition 12/2013; DOI:10.1097/MPG.0000000000000288 · 2.18 Impact Factor
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    ABSTRACT: PURPOSE The purpose of this study was to identify predictors of longitudinal changes in diffusion properties of white matter tracts of projection, association and commissural fibers in patients diagnosed with Tuberous Sclerosis Complex. METHOD AND MATERIALS Structural and diffusion magnetic resonance imaging was carried out in 17 subjects diagnosed with Tuberous Sclerosis Complex (TSC) (mean age, 7.2 ± 4.4 years, range: 2 – 17.5 years) and with at least 2 scans (mean number of days between the 2 scans 419.4 days ± 105.4 days, range: 309 – 741 days). There were 10 males and 7 females; 5 of whom had autism spectrum disorder (ASD); and 10 of whom had seizure disorder. A coordinate-based tractography atlas was used to guide ROI placement to delineate the internal capsule/corona radiata, cingulum, and corpus callosum. These ROIs were then co-registered using FLIRT to each subject’s second scan. The outcomes were mean change in apparent diffusion coefficient (ADC) and the mean change in fractional anisotropy (FA). RESULTS Multiple linear regression analyses showed gender to be a significant predictor of mean change in ADC in TSC subjects in the left internal capsule, right and left cingulum, and corpus callosum, adjusting for initial ADC scan measures. Gender was only a significant predictor of mean change in FA in the corpus callosum. Adjusting for initial ADC or FA scan measures, seizure disorder also emerged as a significant predictor of mean change in ADC, but not for mean change in FA, in the left internal capsule. ASD did not emerge as a significant predictor in either the mean change in ADC or FA in the studied white matter tract pathways. CONCLUSION Gender and seizure disorder were independent predictors of mean change in ADC or FA in some white matter tract pathways in TSC subjects. White matter microstructural integrity was more affected in males than in females in the left internal capsule, right and left cingulum, and corpus callosum and more affected in TSC subjects with seizure disorder in the left internal capsule than in subjects without seizure disorder. CLINICAL RELEVANCE/APPLICATION Effects of new therapies for TSC are being evaluated by changes seen on neuroimaging. Thus, understanding how specific patient characteristics differentially affects neuroimaging in TSC is recommended.
    Radiological Society of North America 2013 Scientific Assembly and Annual Meeting; 12/2013
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    ABSTRACT: Objective. To assess the safety and efficacy of a fish oil-based intravenous fat emulsion (FIFE) in reducing the incidence of cholestasis in neonates compared with the traditional soybean oil-based intravenous fat emulsion (SIFE). Methods. A double-blind randomized controlled trial was conducted. Nineteen neonates were enrolled (10 SIFE; 9 FIFE). Nutrition assessments and laboratory studies were serially obtained for the duration of PN support or until 6 months' corrected gestational age. Neurodevelopmental outcomes were assessed at 6 and 24 months' corrected age. Results. There were no differences between groups in demographic characteristics, with an overall median age of 2 days, gestational age of 36 weeks, and birth weight of 2410 g. There were no differences between groups in baseline laboratory values other than alkaline phosphatase (lower in the FIFE group) or in the duration of parenteral nutrition (PN), amount of enteral intake, or the number of operative procedures. The incidence of cholestasis among enrolled patients was significantly lower than expected, resulting in early study termination and an inability to assess for differences in the incidence of cholestasis. The FIFE was associated with no increased risk of growth impairment, coagulopathy, infectious complications, hypertriglyceridemia, or adverse neurodevelopmental outcomes. No patient developed essential fatty acid deficiency. Conclusion. The FIFE at 1 g/kg/d was well tolerated in the neonates recruited for this study. Given the necessary early termination of this study, a follow-up trial with revised eligibility criteria is necessary to determine whether the provision of FIFE decreases the incidence of PN-cholestasis compared with the traditional SIFE.
    Journal of Parenteral and Enteral Nutrition 06/2013; 38(6). DOI:10.1177/0148607113492549 · 3.14 Impact Factor
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    ABSTRACT: There is extensive evidence implicating the intestinal microbiota in inflammatory bowel disease [IBD], but no microbial agent has been identified as a sole causative agent. Bacteroidales are numerically dominant intestinal organisms that associate with the mucosal surface and have properties that both positively and negatively affect the host. To determine precise numbers and species of Bacteroidales adherent to the mucosal surface in IBD patients, we performed a comprehensive culture based analysis of intestinal biopsies from pediatric Crohn's disease [CD], ulcerative colitis [UC], and control subjects. We obtained biopsies from 94 patients and used multiplex PCR or 16S rDNA sequencing of Bacteroidales isolates for species identification. Eighteen different Bacteroidales species were identified in the study group, with up to ten different species per biopsy, a number higher than demonstrated using 16S rRNA gene sequencing methods. Species diversity was decreased in IBD compared to controls and with increasingly inflamed tissue. There were significant differences in predominant Bacteroidales species between biopsies from the three groups and from inflamed and uninflamed sites. Parabacteroides distasonis significantly decreased in inflamed tissue. All 373 Bacteroidales isolates collected in this study grew with mucin as the only utilizable carbon source suggesting this is a non-pathogenic feature of this bacterial order. Bacteroides fragilis isolates with the enterotoxin gene [bft], previously associated with flares of colitis, were not found more often at inflamed colonic sites or within IBD subjects. B. fragilis isolates with the ability to synthesize the immunomodulatory polysaccharide A [PSA], previously shown to be protective in murine models of colitis, were not detected more often from healthy versus inflamed tissue.
    PLoS ONE 06/2013; 8(6):e63686. DOI:10.1371/journal.pone.0063686 · 3.53 Impact Factor
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    ABSTRACT: OBJECTIVE: To evaluate and compare the ability of serum hyaluronic acid (HA) and human cartilage glycoprotein-39 (YKL-40) values, as well as transient elastography (TE) findings, to predict advanced hepatic fibrosis in a cohort from a single pediatric center. STUDY DESIGN: Subjects who underwent liver biopsy analysis within 12 months before enrollment were eligible for this prospective study. HA and YKL-40 measurements were obtained within 1 month of TE. A METAVIR score of F3 or F4 was considered to indicate advanced fibrosis. RESULTS: A total of 128 patients (51% males) aged 1.4 months to 27.6 years (22% aged <2 years) were enrolled. Thirty-one subjects had data on only HA and YKL-40 measurements, and 97 subjects had data on both blood tests and TE. For the prediction of advanced fibrosis, the area under the receiver operating characteristic curve (AUC) values were 0.83 for TE, 0.72 for HA, and 0.52 for YKL-40. The AUC of 0.83 for TE was statistically significantly greater than the AUCs for HA (P = .03) and YKL-40 (P < .0001). Optimal cutpoints for predicting F3-F4 fibrosis were 8.6 kPa for TE (P < .0001), 43 ng/mL for HA (P < .0001), and 26.2 ng/mL for YKL-40 (P = .85). The combination of TE and HA was not better than TE alone for predicting advanced fibrosis (P = .15). CONCLUSION: In this study, which evaluated TE, HA, and YKL-40 to predict liver fibrosis in children in the US, YKL-40 had no predictive value and TE was superior to HA, but the addition of HA did not improve the performance of TE. Our data suggest that TE and HA may be useful noninvasive tools for assessing liver fibrosis in children.
    The Journal of pediatrics 06/2013; 163(4). DOI:10.1016/j.jpeds.2013.04.044 · 4.02 Impact Factor
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    ABSTRACT: Weight loss and changes in growth are noted in children treated with interferon alpha (IFN-α). The aim of this study was to prospectively determine changes in weight, height, body mass index (BMI), and body composition during and after treatment of children with hepatitis C virus (HCV). Children treated with pegylated interferon alpha-2a (Peg-IFN-α2a) ± ribavirin in the Pediatric Study of Hepatitis C (PEDS-C) trial underwent anthropometric measurements, dual-energy X-ray absorptiometry scan, as well as dietary and activity assessments during and after treatment. One hundred and fourteen (55% male) children, with a mean age of 11 ± 3 years, were randomized, and 107 received treatment for at least 24 weeks. Subjects were divided into three groups according to duration of treatment: 24 (N = 14), 48 (N = 82), or 72 (N = 11) weeks. Decrements of up to 0.50 z score were observed for weight, height, and BMI while on therapy among all groups (P ≤ 0.01, compared to baseline). In the group treated for 48 weeks, 29 (33%) subjects had greater than 0.5-unit decrement in height-for-age z (HAZ) score. Though weight-for-age and BMI z scores returned to baseline after cessation of therapy, mean HAZ score was slower to rebound, still lower than baseline at 96 weeks post-therapy for the long-treatment duration group (P = 0.03) and lower than baseline in most children treated for 48 weeks. Percent body fat, fat-free mass z scores, and triceps skinfold z scores decreased with therapy. Dietary energy intake and levels of physical activity did not change during treatment. CONCLUSIONS: Peg-IFN-α2a was associated with significant changes in body weight, linear growth, BMI, and body composition in children. These effects were generally reversible with cessation of therapy, although HAZ scores had not returned to baseline after 2 years of observation in many. Longer term growth data are needed among children treated for chronic HCV.
    Hepatology 08/2012; 56(2):523-31. DOI:10.1002/hep.25690 · 11.19 Impact Factor
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    ABSTRACT: BACKGROUND: Adhesions represent a major problem after abdominal and pelvic procedures. The purpose of the present study was to determine the effect of sunitinib (Sutent, SU11248), a Food and Drug Administration-approved receptor tyrosine kinase inhibitor, on recurrent pelvic adhesion formation after pelvic adhesiolysis in a rabbit model. MATERIALS AND METHODS: A total of 20 New Zealand white rabbits underwent a uterine abrasion procedure, followed by an adhesiolysis procedure 4 weeks later. Before adhesiolysis, the rabbits were randomized to sunitinib at 10 mg/kg/d or placebo. These were administered as 1 dose preoperatively followed by 10 doses postoperatively. The rabbits were killed 30 d after the adhesiolysis procedure. At death, the adhesions were scored, and a total adhesion score (presented as the median and interquartile range [IQR]) was calculated according to the percentage of uterine involvement and the tenacity of the adhesions. RESULTS: All the rabbits survived the operative procedures without complications. The sunitinib-treated rabbits (n = 10) had a significantly lower uterine involvement score (median 2.0, IQR 1.0-3.0) than the placebo-treated rabbits (median 4.0, IQR 3.0-4.0; P = 0.02). The sunitinib-treated rabbits also had median tenacity score of 3.0 (IQR 3.0-4.0) compared with a median of 4.0 (IQR 4.0-4.0; P = 0.04) in the placebo-treated rabbits (n = 10). The median total score in the sunitinib-treated rabbits was 5.0 (IQR 4.0-6.25) compared with 8.0 (IQR 6.75, 8.0) in the placebo-treated rabbits (P = 0.01). CONCLUSIONS: Sunitinib treatment might be an efficacious strategy to reduce recurrent adhesion formation after pelvic procedures.
    Journal of Surgical Research 08/2012; 178(2). DOI:10.1016/j.jss.2012.07.038 · 2.12 Impact Factor
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    ABSTRACT: The aim of this study was to determine the incidence of cholestasis and the correlation between cholestasis and weight-for-age z scores in parenteral nutrition-dependent neonates with gastroschisis. A single-center retrospective review of 59 infants born with gastroschisis from January 2000 to June 2007 was conducted. Demographic and clinical data were collected and analyzed. Subjects were divided into cholestatic and noncholestatic groups. Statistical analyses included the Student t test, Wilcoxon rank sum test, Fisher exact test, and a general linear model. Fifty-nine neonates with gastroschisis were identified, and 16 (28%) of 58 patients developed cholestasis. Younger gestational age and cholestasis were found to be independently associated with weight-for-age z score in 30 of 58 patients with available long-term follow-up data. Parenteral nutrition-dependent neonates with gastroschisis remain at considerable risk for the development of cholestasis. Both gestational age and cholestasis were found to be independent risk factors, predisposing these neonates to poor postnatal growth.
    Journal of Pediatric Surgery 08/2012; 47(8):1529-36. DOI:10.1016/j.jpedsurg.2011.12.028 · 1.31 Impact Factor
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    ABSTRACT: BACKGROUND: One of the most common and severe complications of long-term parenteral nutrition (PN) is PN-associated cholestasis. The soybean oil-based lipid emulsion administered with PN has been associated with cholestasis, leading to an interest in lipid reduction strategies. The purpose of this study was to determine whether the provision of a soybean oil-based lipid emulsion at 1 g/kg/d compared with 2-3 g/kg/d is associated with a reduced incidence of cholestasis. METHODS: Retrospective review of neonates admitted between 2007 and 2011 with a gastrointestinal condition necessitating ≥21 days of PN support. Neonates were divided into 2 groups based on the intravenous lipid emulsion dose: 1-g group (1 g/kg/d) and 2- to 3-g group (2-3 g/kg/d). The primary outcome measure was the incidence of cholestasis. RESULTS: Sixty-one patients met inclusion criteria (n = 29, 1-g group; n = 32, 2- to 3-g group). The 2 groups did not differ in any baseline characteristics other than associated comorbidities that were more common in the 2- to 3-g group. The duration of PN, the number of operative procedures and bloodstream infections, and enteral nutrition (EN) were similar between groups. The incidence of cholestasis was not different between groups (51.7%, 1-g group; 43.8%, 2- to 3-g group; P = .61), and there was no difference between groups in the time to cholestasis (32.6 ± 24.1 days, 1-g group; 27.7 ± 10.6 days, 2- to 3-g group; P = .48). Overall, 44.8% of patients with cholestasis were transitioned to full EN, and 55.2% were transitioned to a fish oil-based lipid emulsion after which the direct bilirubin normalized in all patients. Conclusion: Lipid reduction to 1 g/kg/d does not prevent or delay the onset of cholestasis in neonates. (JPEN J Parenter Enteral Nutr. XXXX;xx:xx-xx).
    Journal of Parenteral and Enteral Nutrition 07/2012; 37(4). DOI:10.1177/0148607112453072 · 3.14 Impact Factor
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    ABSTRACT: To determine the effect of sunitinib (Sutent; SU11248; Pfizer), a US Food and Drug Administration-approved receptor tyrosine kinase inhibitor previously shown to reduce de novo pelvic adhesion formation, on reproductive function after surgical uterine abrasion in a rabbit model. Randomized placebo-controlled study. Large animal facility within an academic hospital. Thirty New Zealand White adult female rabbits (2.2-3.0 kg). Administration of 11 doses (one preoperative and 10 postoperative) of oral sunitinib (10 mg/kg/d) or placebo. Effect of short-term postoperative sunitinib administration on reproductive function after surgical uterine abrasion. All animals were impregnated and survived until designated euthanasia. Sunitinib-treated animals had a larger average litter size (7.7 ± 1.9 vs. 5.6 ± 2.7 kits) and offspring viability (7.1 ± 2.7 vs. 3.5 ± 3.2 kits) compared with placebo-treated animals. There was no difference in gestational length or aberration in the maintenance of fertility. There were no gross abnormalities, detectable birth defects, or growth disparity in offspring from sunitinib versus placebo-treated mothers. The adhesion burden identified at euthanasia after parturition was lower in sunitinib compared with placebo-treated animals (N = 10/group). Sunitinib ameliorated adhesion-induced reproductive aberrations after surgical uterine abrasion and may be an efficacious strategy to reduce postoperative pelvic adhesions.
    Fertility and sterility 06/2012; 98(2):496-502. DOI:10.1016/j.fertnstert.2012.05.020 · 4.30 Impact Factor

Publication Stats

504 Citations
278.44 Total Impact Points


  • 2011–2015
    • Boston Children's Hospital
      • • Department of Pharmacy
      • • Clinical Effectiveness Research Center
      • • Center for Inflammatory Bowel Disease
      Boston, Massachusetts, United States
    • Children's Hospital of Richmond
      Ричмонд, Virginia, United States
  • 2008
    • New England Research Institutes
      Watertown, Massachusetts, United States