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1.  PGC-1 Coactivator Activity Is Required for Murine Erythropoiesis 
Molecular and Cellular Biology  2014;34(11):1956-1965.
Peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1α (PGC-1α) and PGC-1β have been shown to be intimately involved in the transcriptional regulation of cellular energy metabolism as well as other biological processes, but both coactivator proteins are expressed in many other tissues and organs in which their function is, in essence, unexplored. Here, we found that both PGC-1 proteins are abundantly expressed in maturing erythroid cells. PGC-1α and PGC-1β compound null mutant (Pgc-1c) animals express less β-like globin mRNAs throughout development; consequently, neonatal Pgc-1c mice exhibit growth retardation and profound anemia. Flow cytometry shows that the number of mature erythrocytes is markedly reduced in neonatal Pgc-1c pups, indicating that erythropoiesis is severely compromised. Furthermore, hematoxylin and eosin staining revealed necrotic cell death and cell loss in Pgc-1c livers and spleen. Chromatin immunoprecipitation studies revealed that both PGC-1α and -1β, as well as two nuclear receptors, TR2 and TR4, coordinately bind to the various globin gene promoters. In addition, PGC-1α and -1β can interact with TR4 to potentiate transcriptional activation. These data provide new insights into our understanding of globin gene regulation and raise the interesting possibility that the PGC-1 coactivators can interact with TR4 to elicit differential stage-specific effects on globin gene transcription.
doi:10.1128/MCB.00247-14
PMCID: PMC4019057  PMID: 24662048
2.  Securing Information Technology in Healthcare 
IEEE security & privacy  2013;11(6):25-33.
Dartmouth College’s Institute for Security, Technology, and Society conducted three workshops on securing information technology in healthcare, attended by a diverse range of experts in the field. This article summarizes the three workshops.
doi:10.1109/MSP.2013.104
PMCID: PMC4219362  PMID: 25379030
3.  Concise Review: Guidance in Developing Commercializable Autologous/Patient-Specific Cell Therapy Manufacturing 
Stem Cells Translational Medicine  2013;2(11):871-883.
In this technical review, members of the International Society for Cell Therapy (ISCT) provide guidance in developing commercializable autologous and patient-specific manufacturing strategies from the perspective of process development. Guidance is provided to help small academic or biotech researchers determine what questions can be addressed at the bench level in order to make their cell therapy products more feasible for commercial-scale production.
Cell therapy is poised to play an enormous role in regenerative medicine. However, little guidance is being made available to academic and industrial entities in the start-up phase. In this technical review, members of the International Society for Cell Therapy provide guidance in developing commercializable autologous and patient-specific manufacturing strategies from the perspective of process development. Special emphasis is placed on providing guidance to small academic or biotech researchers as to what simple questions can be addressed or answered at the bench in order to make their cell therapy products more feasible for commercial-scale production. We discuss the processes that are required for scale-out at the manufacturing level, and how many questions can be addressed at the bench level. The goal of this review is to provide guidance in the form of topics that can be addressed early in the process of development to better the chances of the product being successful for future commercialization.
doi:10.5966/sctm.2013-0050
PMCID: PMC3808202  PMID: 24101671
Cellular therapy; Stem cells; Stem cell culture; Clinical translation
4.  Genetic determinants of haemolysis in sickle cell anaemia 
British journal of haematology  2013;161(2):270-278.
Summary
Haemolytic anaemia is variable among patients with sickle cell anaemia and can be estimated by reticulocyte count, lactate dehydrogenase, aspartate aminotransferase and bilirubin levels. Using principal component analysis of these measurements we computed a haemolytic score that we used as a subphenotype in a genome-wide association study. We identified in one cohort and replicated in two additional cohorts the association of a single nucleotide polymorphism in NPRL3 (rs7203560; chr16p13·3) (P = 6·04 × 10−07). This association was validated by targeted genotyping in a fourth independent cohort. The HBA1/HBA2 regulatory elements, hypersensitive sites (HS)-33, HS-40 and HS-48 are located in introns of NPRL3. Rs7203560 was in perfect linkage disequilibrium (LD) with rs9926112 (r2 = 1) and in strong LD with rs7197554 (r2 = 0·75) and rs13336641 (r2 = 0·77); the latter is located between HS-33 and HS-40 sites and next to a CTCF binding site. The minor allele for rs7203560 was associated with the −∝3·7thalassaemia gene deletion. When adjusting for HbF and ∝ thalassaemia, the association of NPRL3 with the haemolytic score was significant (P = 0·00375) and remained significant when examining only cases without gene deletion∝ thalassaemia (P = 0·02463). Perhaps by independently down-regulating expression of the HBA1/HBA2 genes, variants of the HBA1/HBA2 gene regulatory loci, tagged by rs7203560, reduce haemolysis in sickle cell anaemia.
doi:10.1111/bjh.12245
PMCID: PMC4129543  PMID: 23406172
haemolysis; sickle cell anaemia; haemolytic anaemia; genetic analysis; thalassaemia
5.  Clinical correlates of acute pulmonary events in children and adolescents with sickle cell disease* 
Objectives
We aimed to identify risk factors for acute pulmonary events in children and adolescents in the Pulmonary Hypertension and the Hypoxic Response in SCD (PUSH) study.
Methods
Patients with hemoglobin SS (n=376) and other sickle cell genotypes (n=127) aged 3-20 years were studied at four centers in a cross-sectional manner. A sub-group (n=293) was followed for a median of 21 months (range 9-35).
Results
A patient-reported history of one or more acute pulmonary events, either acute chest syndrome (ACS) or pneumonia, was obtained in 195 hemoglobin SS patients (52%) and 51 patients with other genotypes (40%). By logistic regression, history of acute pulmonary events was independently associated with patient-reported history of asthma (p<0.0001), older age (p=0.001), >3 severe pain episodes in the preceding 12 months (p=0.002), higher tricuspid regurgitation velocity (TRV) (p=0.028), and higher white blood cell (WBC) count (p=0.043) among hemoglobin SS patients. History of acute pulmonary events was associated with >3 severe pain episodes (p=0.009) among patients with other genotypes. During follow-up, 43 patients (15%) had at least one new ACS episode including 11 without a baseline history of acute pulmonary events. History of acute pulmonary events (odds ratio 5.4; p<0.0001) and younger age (odds ratio 0.9; p=0.010) were independently associated with developing a new episode during follow-up.
Conclusions
Asthma history, frequent pain and higher values for TRV and WBC count were independently associated with history of acute pulmonary events in hemoglobin SS patients and frequent pain was associated in those with other genotypes. Measures to reduce pain episodes and control asthma may help to decrease the incidence of acute pulmonary events in SCD.
doi:10.1111/ejh.12118
PMCID: PMC3689858  PMID: 23560516
sickle cell disease; acute chest syndrome; vaso-occlusive crisis; asthma; pain
6.  Autoimmunity and the Gut 
Autoimmune Diseases  2014;2014:152428.
Autoimmune diseases have increased dramatically worldwide since World War II. This is coincidental with the increased production and use of chemicals both in industrial countries and agriculture, as well as the ease of travel from region to region and continent to continent, making the transfer of a pathogen or pathogens from one part of the world to another much easier than ever before. In this review, triggers of autoimmunity are examined, principally environmental. The number of possible environmental triggers is vast and includes chemicals, bacteria, viruses, and molds. Examples of these triggers are given and include the mechanism of action and method by which they bring about autoimmunity.
doi:10.1155/2014/152428
PMCID: PMC4036413  PMID: 24900918
7.  Gravitaxis in Spherical Janus Swimming Devices 
Langmuir  2013;29(46):14066-14073.
In this work, we show that the asymmetrical distribution of mass at the surface of catalytic Janus swimmers results in the devices preferentially propelling themselves upward in a gravitational field. We demonstrate the existence of this gravitaxis phenomenon by observing the trajectories of fueled Janus swimmers, which generate thrust along a vector pointing away from their metallically coated half. We report that as the size of the spherical swimmer increases, the propulsive trajectories are no longer isotropic with respect to gravity, and they start to show a pronounced tendency to move in an upward direction. We suggest that this effect is due to the platinum caps asymmetric mass exerting an increasing influence on the azimuthal angle of the Janus sphere with size, biasing its orientation toward a configuration where the heavier propulsion generating surface faces down. This argument is supported by the good agreement we find between the experimentally observed azimuthal angle distribution for the Janus swimmers and predictions made by simple Boltzmann statistics. This gravitaxis phenomenon provides a mechanism to autonomously control and direct the motion of catalytic swimming devices and so enable a route to make autonomous transport devices and develop new separation, sensing, and controlled release applications.
doi:10.1021/la403450j
PMCID: PMC3901380  PMID: 24134682
8.  Brain injury and development in newborns with critical congenital heart disease 
Neurology  2013;81(3):241-248.
Objective:
To determine the relationship between radiologically identifiable brain injuries and delayed brain development as reflected by brain metabolic and microstructural integrity.
Methods:
Term newborns with congenital heart disease (CHD) (120 preoperatively and 104 postoperatively) were studied with MRI to determine brain injury severity (BIS), microstructure reflected by fractional anisotropy (FA) and average diffusivity (Dav), and metabolism reflected by N-acetylaspartate (NAA)/choline (Cho) and lactate/Cho. Brain development is characterized by increasing NAA/Cho and white matter FA, and by decreasing Dav and lactate/Cho.
Results:
Newly acquired brain injury was common (41% preoperative, 30% postoperative). Lower white matter FA (p = 0.005) and lower NAA/Cho (p = 0.01) were associated with increasing preoperative BIS. Higher neonatal illness severity scores (p = 0.03), lower preoperative oxygen saturation (p = 0.002), hypotension (p < 0.001), and septostomy (p = 0.002) were also predictive of higher preoperative BIS. Preoperative FA, Dav, and NAA/Cho did not predict new postoperative BIS. Increasing preoperative BIS predicted higher postoperative Dav (p = 0.002) and lactate/Cho (p = 0.008). Within the postoperative scan, new brain injuries were associated with lower white matter FA (p = 0.04). Postoperative BIS (new lesions) was associated with lower postoperative systolic (p = 0.03) and mean (p = 0.05) blood pressures.
Conclusions:
Brain injuries in newborns with CHD are strongly related to abnormalities of brain microstructural and metabolic brain development, especially preoperatively. Both newly acquired preoperative and postoperative brain injuries are related to potentially modifiable clinical risk factors.
doi:10.1212/WNL.0b013e31829bfdcf
PMCID: PMC3770166  PMID: 23771484
10.  Single ventricle anatomy predicts delayed microstructural brain development 
Pediatric research  2013;73(5):661-667.
Background
Term newborns with congenital heart disease (CHD) show delayed brain development as early as the third trimester, especially in single ventricle physiology (SVP). Mechanisms causing delayed brain development in CHD are uncertain, but may include impaired fetal brain blood flow. Our objective was to determine if cardiac anatomy associated with obstruction to antegrade flow in the ascending aorta is predictive of delayed brain development measured by diffusion tensor imaging (DTI) and magnetic resonance spectroscopic imaging (MRSI).
Methods
Echocardiograms (ECHO) from 36 term newborns with SVP were reviewed for presence of aortic atresia and the diameter of the ascending aorta. Quantitative MR imaging parameters measuring brain microstructural (fractional anisotropy (FA), average diffusivity (Dav)) or metabolic development (N-acetylaspartate (NAA), Lactate/choline (Lac/cho)) were recorded.
Results
Increasing NAA/cho and white matter FA, and decreasing Dav and lactate/cho characterize normal brain development. Consistent with the hypothesis that delayed brain development is related to impaired brain perfusion, smaller ascending aortic diameter and aortic atresia were associated with higher Dav and lower white matter FA. ECHO variables were not associated with brain metabolic measures.
Conclusions
These observations support the hypothesis that obstruction to fetal cerebral blood flow impairs brain microstructural development.
doi:10.1038/pr.2013.29
PMCID: PMC3631295  PMID: 23407116
11.  Partnered Research Experiences for Junior Faculty at Minority-Serving Institutions Enhance Professional Success 
CBE Life Sciences Education  2013;12(3):394-402.
This paper describes achievements of faculty in federal funding, publication, and other areas following their participation in the Visiting Professorship (VP) Program. Achievements of participants were compared to those of matched peers and showed marked improvement following their VP experiences.
Scientific workforce diversity is critical to ensuring the realization of our national research goals and minority-serving institutions play a vital role in preparing undergraduate students for science careers. This paper summarizes the outcomes of supporting career training and research practices by faculty from teaching-intensive, minority-serving institutions. Support of these faculty members is predicted to lead to: 1) increases in the numbers of refereed publications, 2) increases in federal grant funding, and 3) a positive impact on professional activities and curricular practices at their home institutions that support student training. The results presented show increased productivity is evident as early as 1 yr following completion of the program, with participants being more independently productive than their matched peers in key areas that serve as measures of academic success. These outcomes are consistent with the goals of the Visiting Professorship Program to enhance scientific practices impacting undergraduate student training. Furthermore, the outcomes demonstrate the benefits of training support for research activities at minority-serving institutions that can lead to increased engagement of students from diverse backgrounds. The practices and results presented demonstrate a successful generalizable approach for stimulating junior faculty development and can serve as a basis for long-term faculty career development strategies that support scientific workforce diversity.
doi:10.1187/cbe.13-02-0025
PMCID: PMC3763007  PMID: 24006388
12.  Development of fully defined xeno-free culture system for the preparation and propagation of cell therapy-compliant human adipose stem cells 
Introduction
Adipose tissue is an attractive and abundant source of multipotent stem cells. Human adipose stem cells (ASCs) have shown to have therapeutic relevancy in diverse clinical applications. Nevertheless, expansion of ASCs is often necessary before performing clinical studies. Standard in vitro cell-culture techniques use animal-derived reagents that should be avoided in clinical use because of safety issues. Therefore, xeno- and serum-free (XF/SF) reagents are highly desirable for enhancing the safety and quality of the transplanted ASCs.
Methods
In the current study, animal component-free isolation and cell-expansion protocols were developed for ASCs. StemPro MSC SFM XF medium with either CELLstart™ CTS™ coating or Coating Matrix Kit were tested for their ability to support XF/SF growth. Basic stem-cell characteristics such as immunophenotype (CD3, CD11a, CD14, CD19, CD34, CD45RO, CD54, CD73, CD80, CD86, CD90, CD105, HLA-DR), proliferation, and differentiation potential were assessed in XF/SF conditions and compared with human serum (HS) or traditionally used fetal bovine serum (FBS) cultures.
Results
ASCs cultured in XF/SF conditions had significantly higher proliferation rates compared with HS/FBS cultures. Characteristic immunophenotypes of ASCs were maintained in every condition; however, cells expanded in XF/SF conditions showed significantly lower expression of CD54 (intercellular adhesion molecule 1, ICAM-1) at low passage number. Further, multilineage differentiation potential of ASCs was maintained in every culture condition.
Conclusions
Our findings demonstrated that the novel XF/SF conditions maintained the basic stem cell features of ASCs and the animal-free workflow followed in this study has great potential in clinical cell therapies.
doi:10.1186/scrt175
PMCID: PMC3707027  PMID: 23497764
Adipose stem cells; Xeno-free; Serum-free; Human serum; Fetal bovine serum; Multipotentiality; Proliferation rate; Immunophenotype; Flow cytometry; Cell therapy
13.  Addressing the Challenge of Diversity in the Graduate Ranks: Good Practices Yield Good Outcomes 
CBE Life Sciences Education  2013;12(1):19-29.
This paper describes practices designed to improve graduate student training outcomes in the sciences. It describes work to increase student diversity in the graduate ranks and documents the success of trainees. The practices designed to achieve these outcomes are broadly applicable to all graduate training programs and students.
In this paper, we examine the impact of implementing three systemic practices on the diversity and institutional culture in biomedical and public health PhD training at Brown University. We hypothesized that these practices, designed as part of the National Institutes of Health–funded Initiative to Maximize Student Development (IMSD) program in the Division of Biology and Medicine, would have a positive effect on underrepresented minority (URM) recruitment and retention and objective measures of student success. These practices include: 1) develop strategic partnerships with selected undergraduate institutions; 2) provide a personalized education program of student support and skill-based modules to supplement discipline-based course work; and 3) transform institutional culture by engaging faculty in supporting diversity-related goals and practices. Data comparing URM numbers and key academic milestones before and after implementation of IMSD practices support the initial hypothesis and effectiveness of these practices at Brown. Program components are broadly applicable as best practices for others seeking to improve URM recruitment and achievements of graduate students traditionally underrepresented in the sciences.
doi:10.1187/cbe.12-04-0054
PMCID: PMC3587852  PMID: 23463225
14.  Spatial Segregation within the Spawning Migration of North Eastern Atlantic Mackerel (Scomber scombrus) as Indicated by Juvenile Growth Patterns 
PLoS ONE  2013;8(2):e58114.
A comparison of growth data (fish length) with latitude shows that southern juvenile mackerel attain a greater length than those originating from further north before growth ceases during their first winter. A similar significant relationship was found between the growth in the first year (derived from the otolith inner winter ring) and latitude for adult mackerel spawning between 44°N (Bay of Biscay) and 54°N (west of Ireland). These observations are consistent with spatial segregation of the spawning migration; the further north that the fish were hatched, the further north they will tend to spawn. No such relationship was found in mackerel spawning at more northerly latitudes, possibly as a consequence of increased spatial mixing in a more energetic regime with stronger currents. This study provides previously lacking support for spawning segregation behaviour among North East Atlantic mackerel – an important step towards understanding the migratory behaviour of mackerel and hence the spatiotemporal distribution dynamics around spawning time.
doi:10.1371/journal.pone.0058114
PMCID: PMC3585244  PMID: 23469149
15.  Markers of severe vaso-occlusive painful episode frequency in children and adolescents with sickle cell anemia 
The Journal of Pediatrics  2011;160(2):286-290.
Objective
To identify factors associated with frequent severe vaso-occlusive pain crises in a contemporary pediatric cohort of sickle cell anemia (SCA)enrolled in a prospective study of pulmonary hypertension and the hypoxic response in sickle cell disease (SCD).
Study design
Clinical and laboratory characteristics of children with SCA who had ≥3 severe pain crises requiring health care in the preceding year were compared with subjects with <3 such episodes.
Results
Seventy-five children (20%) reported ≥3 severe pain episodes in the preceding year, and 232 (61%) had none. Frequent pain episodes were associated with older age (OR 1.2; 95% CI 1.1–1.3; P<0.0001), α-thalassemia trait (OR 3.5; 1.6–6.7; P=0.002), higher median hemoglobin (OR 1.7; 95% CI: 1.2–2.4; P<0.003) and lower lactate dehydrogenase (LDH) concentration (OR 1.82; 95% CI: 1.07–3.11; P = 0.027). Children with high pain frequency also had an increased iron burden (serum ferritin 480 vs. 198 μg/L; P=0.006) and higher median tricuspid regurgitation jet velocity (2.41 vs. 2.31 m/s; P=0.001). Neither hydroxy urea use nor fetal hemoglobin levels were significantly different according to severe pain history.
Conclusions
In our cohort of children with SCA increasing age was associated with higher frequency of severe pain episodes as were α-thalassemia, iron overload, higher hemoglobin and lower LDH concentration and higher tricuspid regurgitation velocity.
doi:10.1016/j.jpeds.2011.07.018
PMCID: PMC3258348  PMID: 21890147
Sickle cell anemia; vaso-occlusive crisis; pain
16.  P-Rex1 Cooperates with PDGFRβ to Drive Cellular Migration in 3D Microenvironments 
PLoS ONE  2013;8(1):e53982.
Expression of the Rac-guanine nucleotide exchange factor (RacGEF), P-Rex1 is a key determinant of progression to metastasis in a number of human cancers. In accordance with this proposed role in cancer cell invasion and metastasis, we find that ectopic expression of P-Rex1 in an immortalised human fibroblast cell line is sufficient to drive multiple migratory and invasive phenotypes. The invasive phenotype is greatly enhanced by the presence of a gradient of serum or platelet-derived growth factor, and is dependent upon the expression of functional PDGF receptor β. Consistently, the invasiveness of WM852 melanoma cells, which endogenously express P-Rex1 and PDGFRβ, is opposed by siRNA of either of these proteins. Furthermore, the current model of P-Rex1 activation is advanced through demonstration of P-Rex1 and PDGFRβ as components of the same macromolecular complex. These data suggest that P-Rex1 has an influence on physiological migratory processes, such as invasion of cancer cells, both through effects upon classical Rac1-driven motility and a novel association with RTK signalling complexes.
doi:10.1371/journal.pone.0053982
PMCID: PMC3559689  PMID: 23382862
18.  Migration and Fisheries of North East Atlantic Mackerel (Scomber scombrus) in Autumn and Winter 
PLoS ONE  2012;7(12):e51541.
It has been suggested that observed spatial variation in mackerel fisheries, extending over several hundreds of kilometers, is reflective of climate-driven changes in mackerel migration patterns. Previous studies have been unable to clearly demonstrate this link. In this paper we demonstrate correlation between temperature and mackerel migration/distribution as proxied by mackerel catch data from both scientific bottom trawl surveys and commercial fisheries. We show that mackerel aggregate and migrate distances of up to 500 km along the continental shelf edge from mid-November to early March. The path of this migration coincides with the location of the relatively warm shelf edge current and, as a consequence of this affinity, mackerel are guided towards the main spawning area in the south. Using a simulated time series of temperature of the shelf edge current we show that variations in the timing of the migration are significantly correlated to temperature fluctuations within the current. The proposed proxies for mackerel distribution were found to be significantly correlated. However, the correlations were weak and only significant during periods without substantial legislative or technical developments. Substantial caution should therefore be exercised when using such data as proxies for mackerel distribution. Our results include a new temperature record for the shelf edge current obtained by embedding the available hydrographic observations within a statistical model needed to understand the migration through large parts of the life of adult mackerel and for the management of this major international fishery.
doi:10.1371/journal.pone.0051541
PMCID: PMC3519697  PMID: 23251570
19.  Toward a Clinical-Grade Expansion of Mesenchymal Stem Cells from Human Sources: A Microcarrier-Based Culture System Under Xeno-Free Conditions 
Tissue Engineering. Part C, Methods  2011;17(12):1201-1210.
The immunomodulatory properties of mesenchymal stem cells (MSCs) make them attractive therapeutic agents for a wide range of diseases. However, the highly demanding cell doses used in MSC clinical trials (up to millions of cells/kg patient) currently require labor intensive methods and incur high reagent costs. Moreover, the use of xenogenic (xeno) serum-containing media represents a risk of contamination and raises safety concerns. Bioreactor systems in combination with novel xeno-free medium formulations represent a viable alternative to reproducibly achieve a safe and reliable MSC doses relevant for cell therapy. The main goal of the present study was to develop a complete xeno-free microcarrier-based culture system for the efficient expansion of human MSC from two different sources, human bone marrow (BM), and adipose tissue. After 14 days of culture in spinner flasks, BM MSC reached a maximum cell density of (2.0±0.2)×105 cells·mL−1 (18±1-fold increase), whereas adipose tissue-derived stem cells expanded to (1.4±0.5)×105 cells·mL−1 (14±7-fold increase). After the expansion, MSC expressed the characteristic markers CD73, CD90, and CD105, whereas negative for CD80 and human leukocyte antigen (HLA)-DR. Expanded cells maintained the ability to differentiate robustly into osteoblast, adipocyte, and chondroblast lineages upon directed differentiation. These results demonstrated the feasibility of expanding human MSC in a scalable microcarrier-based stirred culture system under xeno-free conditions and represent an important step forward for the implementation of a Good Manufacturing Practices–compliant large-scale production system of MSC for cellular therapy.
doi:10.1089/ten.tec.2011.0255
PMCID: PMC3226421  PMID: 21895491
20.  Malignant Peritoneal Mesothelioma in a Pediatric Patient Mimicking Inflammatory Bowel Disease 
Digestive diseases and sciences  2004;49(3):434-437.
Malignant peritoneal mesothelioma is a rare malignancy of the serosal membranes that is difficult to diagnose and carries a poor prognosis. Progression of presenting symptoms is slow and nonspecific. Diffuse peritoneal seeding by the neoplasm can present silently so that physical abnormalities may not be detected until the disease is far advanced. Standard laboratory and radiographic studies can also be inconclusive. We report a case of an adolescent female whose clinical presentation and initial response to management were consistent with inflammatory bowel disease (IBD) but who was ultimately diagnosed with malignant peritoneal mesothelioma.
PMCID: PMC3508066  PMID: 15139493
malignant mesothelioma; peritoneum; inflammatory bowel disease; child
21.  Infection and White Matter Injury in Infants with Congenital Heart Disease 
Cardiology in the young  2011;21(5):562-571.
More than 60 percent of newborns with severe congenital heart disease develop perioperative brain injuries. Known risk factors include: preoperative hypoxemia, cardiopulmonary bypass characteristics, and postoperative hypotension. Infection is an established risk factor for white matter injury in premature newborns. In this study, we examined term infants with congenital heart disease requiring surgical repair to determine whether infection is associated with white matter injury. Acquired infection was specified by site (bloodstream, pneumonia, or surgical site infection) according to strict definitions. Infection was present in 23/127. Pre and post-operative imaging was evaluated for acquired injury by a pediatric neuroradiologist. Overall, there was no difference in newly acquired postoperative white matter injury in infants with infection (30 percent), compared to those without (31 percent). When stratified by anatomy, infants with transposition of the great arteries and bloodstream infection had an estimated doubling of risk of white matter injury that was not significant, whereas those with single ventricle anatomy had no apparent added risk. When considering only infants without stroke, the estimated association was higher, and became significant after adjusting for duration of inotrope therapy. In this study, nosocomial infection was not associated with white matter injury. Nonetheless, when controlling for risk factors, there was an association between bloodstream infection and white matter injury in selected sub-populations. Infection prevention may have the potential to mitigate long-term neurologic impairment as a consequence of white matter injury, which underscores the importance of attention to infection control for these patients.
doi:10.1017/S1047951111000473
PMCID: PMC3171591  PMID: 21554828
Heart defects, congenital; Sepsis; Magnetic resonance imaging; Leukomalacia, periventricular; Pneumonia, ventilator acquired
22.  P-Rex1 is required for efficient melanoblast migration and melanoma metastasis 
Nature Communications  2011;2:555.
Metastases are the major cause of death from melanoma, a skin cancer which has the fastest rising incidence of any malignancy in the Western world. Molecular pathways that drive melanoblast migration in development are believed to underpin the movement and ultimately the metastasis of melanoma. Here we show that mice lacking P-Rex1, a Rac-specific Rho GTPase guanine nucleotide exchange factor (GEF), have a melanoblast migration defect during development evidenced by a white belly. Moreover, these P-Rex1−/− mice are resistant to metastasis when crossed to a murine model of melanoma. Mechanistically, this is associated with P-Rex1 driving invasion in a Rac-dependent manner. P-Rex1 is elevated in the great majority of human melanoma cell lines as well as tumor tissue. We conclude that P-Rex1 plays an important role in melanoblast migration and cancer progression to metastasis in mice and humans.
doi:10.1038/ncomms1560
PMCID: PMC3400057  PMID: 22109529
23.  Acute lymphoblastic leukemia cells that survive combination chemotherapy in vivo remain sensitive to allogeneic immune effects 
Leukemia research  2010;35(6):800-807.
Allogeneic hematopoietic stem cell transplantation is often performed for patients with acute lymphoblastic leukemia (ALL) whose disease has relapsed after chemotherapy treatment. However, graft versus leukemia (GVL) effects in ALL are generally weak and the mechanisms of this weakness are unknown. These studies tested the hypothesis that ALL cells that have survived conventional chemotherapy in vivo acquire relative resistance to the allogeneic GVL effect. C57BL/6 mice were injected with murine pre-B ALL lines driven by human mutations and then were treated with combination chemotherapy. ALL cells surviving therapy were analyzed in vitro and in vivo for acquisition of resistance to chemotherapy, radiation, cytolytic T cells, NK cells, LAK cells and cytokines. In vivo drug treatment did lead to leukemia population with more rapid proliferation and also decreased sensitivity to vincristine, doxorubicin and radiation. However, drug treatment did not produce ALL populations that were less sensitive to GVL effects in vitro or in vivo.
doi:10.1016/j.leukres.2010.10.018
PMCID: PMC3050996  PMID: 21074852
graft versus leukemia effect; allogeneic hematopoietic stem cell transplantation; acute lymphoblastic leukemia; chemotherapy; cancer immunology; graft versus host disease
24.  Evidence of B cell immune responses to acute lymphoblastic leukemia in murine allogeneic hematopoietic stem cell transplantation recipients treated with donor lymphocyte infusion and/or vaccination 
These experiments explored mechanisms of control of acute lymphoblastic leukemia following allogeneic hematopoietic stem cell transplantation using a murine model of MHC-matched, minor histocompatibility antigen mismatched transplantation. The central hypothesis examined was that addition of active vaccination against leukemia cells would substantially increase the effectiveness of allogeneic donor lymphocyte infusion against ALL present in the host after transplant. While vaccination did increase the magnitude of type I T cell responses against leukemia cells associated with donor lymphocyte infusion, it did not lead to substantial improvement in long term survival. Analysis of immunological mechanisms of leukemia progression demonstrated that the failure of vaccination was not due to antigen loss in leukemia cells. However, analysis of survival provided surprising findings that, in addition to very modest type I T cell responses, a B cell response that produced antibodies that bind leukemia cells was found in long term survivors. The risk of death from leukemia was significantly lower in recipients that had higher levels of such antibodies. These studies raise the hypothesis that stimulation of B cell responses after transplant may provide a novel way to enhance allogeneic graft versus leukemia effects associated with transplantation.
doi:10.1016/j.bbmt.2010.08.021
PMCID: PMC3029484  PMID: 20831897
25.  The Contegra conduit: Late outcomes in right ventricular outflow tract reconstruction 
Objectives:
To report the clinical outcomes (early death, late death, and rate of reintervention) and performance of the Contegra conduit as a right ventricle outflow tract implant and to determine the risk factors for early reintervention.
Methods:
Forty-nine Contegra conduits were implanted between January 2002 and June 2009. Data collection was retrospective. The mean age and follow-up duration of Contegra recipients was 3.5 ± 4.6 years and 4.2 ± 2.0 years, respectively.
Results:
There were three deaths (two early, one late), giving a survival rate of 93.9%. The rate of conduit-related reintervention was 19.6% and was most often due to distal conduit stenosis. Age at implantation of <3 months, receipt of a conduit of 12–16 mm diameter, and a diagnosis of truncus arteriosus were each significant contributors to the rate of reintervention.
Conclusion:
The Contegra is a cost-effective and readily available solution. However, there is a limited range of larger calibers, which means that the homograft conduit (>22 mm) remains the first choice of implant in older children. The rates of reintervention are significantly higher with a diagnosis of truncus arteriosus, age at implantation of <3 months, and implantation of conduits sized 12–16 mm.
doi:10.4103/0974-2069.93706
PMCID: PMC3327010  PMID: 22529597
Contegra; outcome; pulmonary; reintervention; risk factor

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